WO2006026053A1 - Catalytics asymmetric activation of unactivated c-h bonds, and compounds related thereto - Google Patents

Abstract

One aspect of the present invention is directed in part to catalytic and stereoselective functionalization of unactivated C-H bonds of simple organic substrates. The compounds and methods provided herein allow one to control the stereochemistry in a C-H activation step, activate substrates containing α-hydrogens next to the directing group, and remove a directing group under mild conditions. One aspect of the present invention relates to a transition-metal-catalyzed method for selective and asymmetric oxidation of carbons located in a β- or Ϝ-position relative to an auxiliary. Another aspect of the invention relates to the enantiomerically-enriched substrates and the enantiomerically-enriched products formed via said method. In certain embodiments, oxazoline and oxazinone directing groups are used. In addition, the Boc protecting group has been identified as a directing group which does not necessitate removal.

Description

Atty Docket: BUG-Ol 1.25

CATALYTIC ASYMMETRIC ACTIVATION OF UNACTIVATED C-H BONDS, AND COMPOUNDS RELATED THERETO

Related Applications

This application claims the benefit of priority to United States Provisional Patent Application serial number 60/605,679, filed August 30, 2004; the contents of which are hereby incorporated by reference. Background of the Invention

The demand for enantiomerically pure compounds has grown rapidly in recent years. One important use for such chiral, non-racemic compounds is as intermediates for synthesis in the pharmaceutical industry. For instance, it has become increasingly clear that enantiomerically pure drugs have many advantages over racemic drug mixtures. These advantages include the fewer side effects and greater potency often associated with enantiomerically pure compounds.

Traditional methods of organic synthesis were often optimized for the production of racemic materials. The production of enantiomerically pure material has historically been achieved in one of two ways: use of enantiomerically pure starting materials derived from natural sources (the so-called "chiral pool"); and the resolution of racemic mixtures by classical techniques. Each of these methods has serious drawbacks, however. The chiral pool is limited to compounds found in nature, so only certain structures and configurations are readily available. Resolution of racemates, which requires the use of resolving agents, may be inconvenient and time-consuming.

One type of reaction that could be harnessed to produce chiral material is C-H activation. The field of alkane activation and functionalization has already taken a strong hold on chemists' imaginations because it poses hard challenges. The central problem is to develop ways to replace selected H substituents of alkanes by any of a variety of functional groups. Progress has been slow and in spite of substantial work on the problem there exists much room for improvement and innovation, especially in developing ways to control the enantioselectivity of these reactions. Recently, it has emerged that catalytic activation of sp³ and sp² C-H bonds in readily available and inexpensive starting materials provides an array of new transformations that are welcome additions to the tool box of synthesis and fine chemical industry. See Sezen, B.; Franz, R.; Sames, D. J. Am. Chem. Soc. 2002, 124, 13372; Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900; Dyker, G. Atty Docket: BUG-Ol 1.25

Angew. Chem. Int. Ed. Engl. 1999, 38, 1699; Chen, H.; Schlecht, S.; Semple, T. C; Hartwig, J. F. Science 2000, 257, 1995; Cho, J. Y.; Tse, M. K.; and Holmes, D.; Maleczka, R. E., Jr.; Smith, M. R., EI. Science 2002, 295, 305. In particular, selective activation of sp³ C-H bonds is a potentially attractive strategy for developing catalytic reactions of broader applications.

Cyclometallation promoted by agostic interaction or sigma-chelation was one of the earliest observations of C-H activation. See Bennett, M. A.; Milner, D. L. J. Am. Chem. Soc. 1969, 91, 6983; and Ibers, J. A.; Dicosimo, R.; Whitesides, G. M. Organometallics 1982, 1, 13. Because they are both very weak σ-bases and π-acids, alkanes are among the least effective species to act as ligands for transition metals. Like other X-H molecules {e.g., X = H, R₃Si, R₂B), alkanes can form σ-complexes with metal fragments that can π- back-bond. See R. H. Crabtree, Angew. Chem., Int. Ed. Engl. 1993, 32, 789. The requirements for alkanes to bind successfully seem to be the presence of a low-valent metal and the absence of competitive decomposition pathways. Enhanced metal to alkane π-back donation into C-H σ* orbitals, causing enhanced metal-alkane binding, parallels the pattern seen for molecular hydrogen complexes, where stable binding also becomes possible when the metal π-back-bonds into the H-H σ* orbital. See G. J. Kubas, Ace. Chem. Rev. 1988, 21, 120. For both CH₄ and H₂, when back donation becomes very strong the C-H or H-H bond is cleaved and the oxidative addition product is formed. Indeed, a continuum of situations can be found in different complexes in which the C-H or H-H bond is progressively elongated. For the H₂ case, these are denoted as 'stretched' dihydrogen complexes. See R. H. Crabtree, Angew. Chem., Int. Ed. Engl. 1993, 32, 789. This means that alkane binding in this way is more likely for low valent, 2nd and 3rd row organometallic compounds than for 1st row coordination compounds, because the former are usually much stronger π-bases.

The classic Shilov system (Figure 1) is perhaps the most important of all alkane oxidation methods. See A. E. Shilov and G. B Shul'pin, Chem. Rev. 1997, 97, 2879; A. E. Shilov, Activation of Saturated Hydrocarbons by Transition Metal Complexes, Riedel, Dordrecht, 1994; and A. E. Shilov and G. B. Shul'pin, Activation and Catalytic Reactions of Saturated Hydrocarbons in the Presence of Metal Complexes, Kluwer, Dordrecht, 2000. The proposed pathway involves the formation of direct metal-carbon bonds, hence the assignment to the organometallic class. Garnett and Hodges had shown that Pt(II) salts in Atty Docket: BUG-011.25 aqueous CH₃COOD are able to effect H/D exchange in arenes. Exchange was even found at all three positions along the n-propyl side chain OfPhCH₂CH₂CH₃, terminal exchange being preferred. See J. L. Garnett and R. J. Hodges, J. Am. Chem. Soc. 1967, 89, 4546; R. J. Hodges and J. L. Garnett, J. Phys. Chem. 1968, 72, 1673; and R. J. Hodges and J. L. Garnett, J. Catal. 1969, 13, S3. Soon afterwards, Shilov et al. found that these conditions also cause H/D exchange in alkanes. See N. F. Goldshleger, M. B. Tyabin, A. E. Shilov and A. A. Shteinman, Zh. Fiz. KMm. 1969, 43, 2X1 A. The system showed a number of remarkable features. First, the selectivity tended to favor exchange at terminal CH₃ groups rather than the preferential attack at tertiary or benzylic CH bonds, as seen for electrophiles and radicals. This implied a new mechanism was involved and gave hope for potential practical application, although rates were low. Second, multiple exchange was seen at the earliest stage of the reaction, even for CH₄. Incorporating platinum(IV) salts as primary oxidant allowed conversion of alkanes to alkyl chlorides or alcohols, albeit with modest rates and conversions. See V. V. Eskova, A. E. Shilov and A. A. Shteinman, Kinet. Katal. 1972, 13, 534. The selectivity for terminal functionalization was essentially the same as earlier seen for the H/D exchange so it was concluded that conversion of Pt(E) to Pt(IV) oxidized the same intermediates responsible for H/D exchange. The selectivity pattern argues against an electrophilic attack of Pt on a CH bond, as does the kinetic analysis that identifies [PtCl₂(solvent)₂] as the most active species in the series [PtCl,_;(solv)_4-n]^(2"'ⁱ⁾⁺, with the W = O and 4 species being essentially inactive. Cyclic alkanes were converted to arenes by the same system as a result of HX elimination from the functionalized cyclohexane intermediates and subsequent functionalization of the alkene intermediates. In an important step, Shilov showed that a methylplatmum(IV) intermediate, [MePtCl₅]^2", could be directly detected in the reaction mixture from methane, strongly suggesting that metal alkyls are intermediates. The problem with the Shilov system, from a practical point of view, is that Pt(IV) is not an economically viable stoichiometric oxidant. Efforts to replace the Pt(IV) were complicated by the fact that the alkane interacts only with the Pt(H) catalyst, also present, but most primary oxidants tend to convert reactive Pt(H) to catalytically inactive Pt(IV). Palladium has also been used as a catalyst in several related reactions. For example, the activation of ortAo-arene C-H bonds leading to cyclopalladation via pre-coordination of a nitrogen atom. See Ryabov, A. D. Synthesis 1985, 233. There also exist a handful of Atty Docket: BUG-Ol 1.25 examples of cyclopalladation of aliphatic C-H bonds to form stable dimeric complexes. See Balavoine, G.; Clinet, J. C. J. Organomet. Chem. 1990, 390, C84. Relatedly, the C-H activation of sp² C-H bonds of benzene and ort/zø-substituted arenes has progressed to achieve catalytic turnover in C-C bond forming reactions, but only at high temperatures (typically 110 - 160 ^"C). See Jia, C; Kitamura, T.; Fujiwara, Y. Ace. Chem. Res. 2001, 34, 633; and Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 9692.

However, in spite of great efforts, the catalytic and asymmetric functionalization of sp³ C-H bonds has not been reported in the literature, in sharp contrast to the widespread reactions catalyzed by oxygenases in biological systems. See Chandrasena, R. E. P.; Vatsis, K. P.; and Coon, M. J.; Hollenberg, P. F.; Newcomb, M. J. Am. Chem. Soc. 2004, 126, 115. Remarkably, an oxidation system that renders the cyclopalladation catalytic has been discovered. Specifically, the identification of this problem has guided us to design a removable σ-chelating group to facilitate C-H activation reactions with a broad scope. Summary of the Invention

This application is directed in part to catalytic and stereoselective functionalization of unactivated C-H bonds of simple substrates that are feed stocks for organic synthesis and the chemical industry. Herein is disclosed that a cyclic chiral directing group can be used to control the stereoselectivity of C-H activation reactions of a broad range of simple substrates under mild conditions. The compounds and methods provided herein allow one to control the stereochemistry in a C-H activation step, activate substrates containing α- hydrogens next to the directing group, and remove a directing group under mild conditions. One aspect of the present invention relates to a transition-metal-catalyzed method for selective and asymmetric oxidation of carbons located in a β- or γ-position relative to an auxiliary. Another aspect of the invention relates to the enantiomerically-enriched substrates and the enantiomerically-enriched products formed via said method. In certain embodiments oxazoline and oxazinone directing groups are used. In addition, the Boc protecting group has been identified as a directing group which does not necessitate removal. Importantly, the novel and practical redox chemistry methods described herein allow one to achieve catalytic turnovers, using inexpensive oxidants, under synthetically applicable conditions. Atty Docket: BUG-Ol 1.25

Brief Description of the Drawings

Figure 1 depicts a proposed mechanism for the Shilov reaction.

Figure 2 depicts a proposed catalytic cycle for certain methods of the instant invention wherein (a) represents electrophilic cleavage, (b) represents oxidative addition and (c) represents reductive elimination.

Figure 3 depicts examples of the asymmetric iodination of the present invention; reaction conditions: 10 mol % Pd(OAc)₂, 1 equiv. I₂, 0.9 equiv. PhI(OAc)₂, CH₂Cl₂, 24 °C; time (a): 30 h, (b): 96 h, (c): 13 h.

Figure 4 depicts a model rationalizing the role of steric repulsion in the observed regioselectivity.

Figure 5 depicts examples of chiral materials accessible via an asymmetric iodination of the present invention.

Figure 6 depicts examples of chiral materials accessible via an asymmetric acetoxylation of the present invention. Figure 7 depicts examples of (a) multiply substituted and polycyclic chiral auxiliaries, (b) nitrogen-containing acyclic chiral auxiliaries, and (c) phosphorus-containing chiral auxiliaries.

Figure 8 depicts a crystal structure of trinuclear Pd-alkyl complex 6b.

Figure 9 depicts a proposed catalytic cycle. Detailed Description of the Invention

Stereoselectivity in the C-H activation step is important for C-H activation reactions to be broadly useful in synthetic chemistry. It is well established that σ-chelation assisted C-H activation takes place through a cyclic transition state. See Gomez, M.; Granell, J.; Martinez, M. "Mechanism of Cyclopalladation Reactions in Acetic Acid: Not So Simple One-Pot Process" Eur. J. Chem. 2000, 217-224; and Dupont, J.; Consorti, C. S.; Spencer, J. "The Potential of Palladacycles: More Than Just Precatalysts" Chem. Rev. 2005, 105, 2527- 2572. Therefore, the use of a cyclic chiral directing group could be advantageous in controlling the stereochemistry via a steric repulsion model as shown below. Atty Docket: BUG-Ol 1.25

A (favored) B (disfavored)

Less repulsion is expected in A (above) when R₁ is larger than the Me group, thereby favoring one stereoisomer. This hypothesis led to the development of cyclic directing groups with the following properties: allows for facile formation of either a three coordinate or square planar structure with a metal center that is known to be reactive for C- H cleavage; is readily available as chiral analogs for diastereoselective C-H activation; and is easily removal or direct transformable to other useful functionality. Oxazolines, as shown in C below, are an example of a cyclic directing group which can be used, for example, for the activation of carboxylic acids.

The common problem of requiring a quaternary center adjacent to the chelating group in cyclometalation reactions severely limits the scope of many known σ-chelation assisted C-H activation reactions. It is generally believed that a quaternary center favors the assembly of the cyclic transition state for cyclometalation. It was hypothesized that the presence of an α-hydrogen next to the chelating group could interfering with the interaction between the metal and the target C-H bond. A number of strategies to tackle this problem are proposed herein. For example, one might use a silyl group as a masked proton (protiodesilylation) or hydroxyl (Tamao-Fleming oxidation), as shown below (D), to overcome this limitation.

D E F G Atty Docket: BUG-Ol 1.25

Herein it is diclosed that the tert-leucinol derived oxazolines display high stereoselectivity. Interestingly, although the substituent at the 5-position of bisoxazoline chiral ligands usually has little impact on enantioselectivity in Lewis acid catalysis, a proposed stereomodel derived from crystal structures of the Pd-alkyl complexes (not shown) indicates that the steric bulkiness at the 5-position is equally important to that at the 4-position. It is therefore proposed that inexpensive 4,5-di-substituted oxazolines E is a useful substrate. In certain embodiments, the replacement of the t-butyl group at the A- position by a polar group such as CH₂OTBS might also facilitate the hydrolytic removal at a lower temperature. Herein are disclosed new directing groups to address these two problems. For example, l,4-oxazin-2-one, as a directing group, was found to activate keto esters in the presence of α-hydrogens (F above). In addition, the removal of this directing group by treatment with 2 N HCl at 0 °C or 24 °C is a highly desirable practical advantage.

Another imminent challenge in this field, which is addressed herein, is the discovery of a broad range of directing groups to activate different types of feed stocks. Remarkably it was found that a Boc group may be used to direct activation of an α-methyl group leads, which leads to an efficient exploitation of a simple amine source via a novel amino methylation reaction (G). In addition, C-H activation directed by a commonly used protecting group (such as Boc) eliminates the need to remove the directing groups as the functionalized products can be used directly in synthesis, thereby demonstrating the great potential of this approach.

However, one of the major restrictions of σ-chelation directed C-H activation is that unactivated methylene groups are in general not reactive except when adjacent to heteroatoms. The unfavorable steric interactions between ligated ligands and branched alkyl groups in the cyclopalladation step is frequently invoked to explain the poor reactivity of methylene groups. However, it is postulated that the steric repulsion between the eclipsed alkyl groups in cyclopalladation of the methylene groups is also problematic (H, below). The magnitude of this repulsion is reduced when only hydrogens are attached to the β- carbon (I) or α-carbon (J). The compatibility of 1,4-oxazinone directing groups with the presence of α-hydrogens allowed the testing this hypothesis.

H (hindered) I (less hindered) J (less hindered)

Enantioselective C-H activation using a suitable non-chiral directing group has not been reported in the literature to date. As it is disclosed herein that chiral carboxylates can be readily incorporated into the trinuclear Pd-alkyl complexes by treating the Pd-alkyl complexes with chiral carboxylic anhydrides, this observation suggests testing how the bridging chiral carboxylates might affect the stereoselectivity of the C-H activation. This effort is directed towards achieving enantioselective C-H activation using non-chiral directing groups.

Development of new redox chemistry to close the catalytic cycle is a central task in catalytic functionalization of unactivated C-H bonds. Two approaches may be employed to close the catalytic cycle depending, on the redox system of an individual reaction (see Figure 9). First, the oxidization L (MIT) to M (MIV) via oxidative addition of an oxidant (O-O) in a similar fashion to that of Shilov system (pathway a). Example of oxidants include but are not limited to dihalogens (e.g., I₂), IOAc, and dichacogenides (e.g., peroxides). Second, reoxidation of MO to Mil after the functionali-zation step such as reductive elimination (pathway b). Various protocols to promote the oxidation of PdO to Pdπ under mild conditions are known. It is also demonstrated herein that inexpensive oxidants may be used to close the catalytic cycle under mild reaction conditions. For example, the combination of the cheap peroxide, MeC(=O)OOt-Bu, and Ac₂O can oxidize methyl groups under mild conditions (see discussion and exemplification herein).

A new procedure was also established to allow catalytic turnovers in the direct coupling of C-H bond with organometallic reagents (e.g., trialkyltin) to form C-C bonds. The crucial finding is to allow the C-H activation, reoxidation and transmetalation to occur sequentially in one pot without interfering each other. This was achieved by using a portion- wise introduction of the reagent (e.g., tin) and an appropriate combination of solvent (e.g., CH₂Cl₂) and oxidant (e.g.,. benzoquinone). The optimal interval of each addition of the reagent is critically determined by the time needed for the C-H activation and reoxidation steps. Definitions

For convenience, certain terms employed in the specification, examples, and appended claims are collected here.

The term "nucleophile" is recognized in the art, and as used herein means a chemical moiety having a reactive pair of electrons. Examples of nucleophiles include uncharged compounds such as water, amines, mercaptans and alcohols, and charged moieties such as alkoxides, thiolates, carbanions, and a variety of organic and inorganic anions. Illustrative anionic nucleophiles include simple anions such as hydroxide, azide, cyanide, thiocyanate, acetate, formate or chloroformate, and bisulfite. Organometallic reagents such as organocuprates, organozincs, organolithiums, Grignard reagents, enolates, acetylides, and the like may, under appropriate reaction conditions, be suitable nucleophiles.

Hydride may also be a suitable nucleophile when reduction of the substrate is desired.

The term "electrophile" is art-recognized and refers to chemical moieties which can accept a pair of electrons from a nucleophile as defined above. Electrophiles useful in the method of the present invention include cyclic compounds such as epoxides, aziridines, episulfides, cyclic sulfates, carbonates, lactones, lactams and the like. Non-cyclic electrophiles include sulfates, sulfonates (e.g., tosylates), chlorides, bromides, iodides, and the like

The terms "electrophilic atom", "electrophilic center" and "reactive center" as used herein refer to the atom of the substrate which is attacked by, and forms a new bond to, the nucleophile. In most (but not all) cases, this will also be the atom from which the leaving group departs.

The term "electron-withdrawing group" is recognized in the art and as used herein means a functionality which draws electrons to itself more than a hydrogen atom would at the same position. Exemplary electron-withdrawing groups include nitro, ketone, aldehyde, sulfonyl, trifluoromethyl, -CN, chloride, and the like. The term "electron-donating group", as used herein, means a functionality which draws electrons to itself less than a hydrogen atom would at the same position. Exemplary electron-donating groups include amino, methoxy, and the like. The terms "Lewis base" and "Lewis basic" are recognized in the art, and refer to a chemical moiety capable of donating a pair of electrons under certain reaction conditions.

Examples of Lewis basic moieties include uncharged compounds such as alcohols, thiols, olefins, and amines, and charged moieties such as alkoxides, thiolates, carbanions, and a variety of other organic anions.

The terms "Lewis acid" and "Lewis acidic" are art-recognized and refer to chemical moieties which can accept a pair of electrons from a Lewis base. The term "meso compound" is recognized in the art and means a chemical compound which has at least two chiral centers but is achiral due to an internal plane, or point, of symmetry.

The term "chiral" refers to molecules which have the property of non- superimposability on their mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner. A "prochiral molecule" is an achiral molecule which has the potential to be converted to a chiral molecule in a particular process.

The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space, hi particular, the term "enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another. The term "diastereomers", on the other hand, refers to the relationship between a pair of stereoisomers that comprise two or more asymmetric centers and are not mirror images of one another.

Furthermore, a "stereoselective process" is one which produces a particular stereoisomer of a reaction product in preference to other possible stereoisomers of that product. An "enantioselective process" is one which favors production of one of the two possible enantiomers of a reaction product. The subject method is said to produce a "stereoselectively-enriched" product (e.g., enantioselectively-enriched or diastereoselectively-enriched) when the yield of a particular stereoisomer of the product is greater by a statistically significant amount relative to the yield of that stereoisomer resulting from the same reaction run in the absence of a chiral catalyst. For example, an enantioselective reaction catalyzed by one of the subject chiral catalysts will yield an e.e. for a particular enantiomer that is larger than the e.e. of the reaction lacking the chiral catalyst. The term "regioisomers" refers to compounds which have the same molecular formula but differ in the connectivity of the atoms. Accordingly, a "regioselective process" is one which favors the production of a particular regioisomer over others, e.g., the reaction produces a statistically significant preponderance of a certain regioisomer. The term "reaction product" means a compound which results from the reaction of a nucleophile and a substrate. In general, the term "reaction product" will be used herein to refer to a stable, isolable compound, and not to unstable intermediates or transition states.

The term "substrate" is intended to mean a chemical compound which can react with a nucleophile, or with a ring-expansion reagent, according to the present invention, to yield at least one product having a stereogenic center.

The term "catalytic amount" is recognized in the art and means a substoichiometric amount relative to a reactant. As used herein, a catalytic amount means from 0.0001 to 90 mole percent relative to a reactant, more preferably from 0.001 to 50 mole percent, still more preferably from 0.01 to 10 mole percent, and even more preferably from 0.1 to 5 mole percent relative to a reactant.

As discussed more fully below, the reactions contemplated in the present invention include reactions which are enantioselective, diastereoselective, and/or regioselective. An enantioselective reaction is a reaction which converts an achiral reactant to a chiral product enriched in one enantiomer. Enantioselectivity is generally quantified as "enantiomeric excess" (ee) defined as follows:

% Enantiomeric Excess A (ee) = (% Enantiomer A) - (% Enantiomer B) where A and B are the enantiomers formed. Additional terms that are used in conjunction with enatioselectivity include "optical purity" or "optical activity". An enantioselective reaction yields a product with an e.e. greater than zero. Preferred enantioselective reactions yield a product with an e.e. greater than 20%, more preferably greater than 50%, even more preferably greater than 70%, and most preferably greater than 80%.

A diastereoselective reaction converts a chiral reactant (which may be racemic or enantiomerically pure) to a product enriched in one diastereomer. If the chiral reactant is racemic, in the presence of a chiral non-racemic reagent or catalyst, one reactant enantiomer may react more slowly than the other. This class of reaction is termed a kinetic resolution, wherein the reactant enantiomers are resolved by differential reaction rate to yield both enantiomerically-enriched product and enantiomerically-enriched unreacted substrate. Kinetic resolution is usually achieved by the use of sufficient reagent to react with only one reactant enantiomer (i.e., one-half mole of reagent per mole of racemic substrate).

Examples of catalytic reactions which have been used for kinetic resolution of racemic reactants include the Sharpless epoxidation and the Noyori hydrogenation. A regioselective reaction is a reaction which occurs preferentially at one reactive center rather than another non-identical reactive center. For example, a regioselective reaction of an unsymmetrically substituted epoxide substrate would involve preferential reaction at one of the two epoxide ring carbons. The term "non-racemic" with respect to the chiral catalyst, means a preparation of catalyst having greater than 50% of a given enantiomer, more preferably at least 75%. "Substantially non-racemic" refers to preparations of the catalyst which have greater than 90% ee for a given enantiomer of the catalyst, more preferably greater than 95% ee. The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups, hi preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀ for branched chain), and more preferably 20 of fewer. Likewise, preferred cycloalkyls have from 4-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.

Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple carbon-carbon bond, respectively.

The term "acyl" is art-recognized and refers to any group or radical of the form RCO- where R is any organic group. Representative acyl group include acetyl, benzoyl, and malonyl.

The term "acyloxy" is art-recognized and refers to a moiety that can be represented by the general formula:

wherein R'π represents a hydrogen, an alkyl, an aryl, an alkenyl, an alkynyl or -(CH₂)_m-R₈, where m is 1-30 and R₈ represents a group permitted by the rules of valence.. As used herein, the term "amino" means -NH₂; the term "nitro" means -NO₂; the term "halogen" designates -F, -Cl, -Br or -I; the term "thiol" means -SH; the term "hydroxyl" means -OH; the term "sulfonyl" means -SO₂-; and the term "organometallic" refers to a metallic atom (such as mercury, zinc, lead, magnesium or lithium) or a metalloid (such as silicon, arsenic or selenium) which is bonded directly to a carbon atom, such as a diphenylmethylsilyl group.

The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e.g. , a moiety that can be represented by the general formula:

R R

10 10

/ N or N R₁₀

R₉ R₉ wherein Rg, Rio and R'_1O each independently represent a group permitted by the rules of valence.

The term "acylamino" is art-recognized and refers to a moiety that can be represented by the general formula:

wherein R₉ is as defined above, and R'π represents a hydrogen, an alkyl, an alkenyl or -(CH₂)_m-R₈, where m and R₈ are as defined above.

The term "amido" is art-recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula:

wherein R₉, R₁₀ are as defined above. Preferred embodiments of the amide will not include imides which may be unstable.

The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In preferred embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH₂)_m-R₈, wherein m and R₈ are defined above. Representative alkylthio groups include methylthio, ethyl thio, and the like. The term "carbonyl" is art-recognized and includes such moieties as can be represented by the general formula:

wherein X is a bond or represents an oxygen or a sulfur, and R₁₁ represents a hydrogen, an alkyl, an alkenyl, -(CH₂)_m-R₈ or a pharmaceutically acceptable salt, R'π represents a hydrogen, an alkyl, an alkenyl or -(CH₂)_m-Rg, where m and R₈ are as defined above. Where X is an oxygen and R₁₁ or R'π is not hydrogen, the formula represents an "ester". Where X is an oxygen, and R₁₁ is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when Ri _\ is a hydrogen, the formula represents a "carboxylic acid". Where X is an oxygen, and R'π is hydrogen, the formula represents a "formate". In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiolcarbonyl" group. Where X is a sulfur and Rn or R'π is not hydrogen, the formula represents a "thiolester". Where X is a sulfur and R₁₁ is hydrogen, the formula represents a "thiolcarboxylic acid". Where X is a sulfur and R'π is hydrogen, the formula represents a "thiolformate". On the other hand, where X is a bond, and R₁₁ is not hydrogen, the above formula represents a "ketone" group. Where X is a bond, and R₁₁ is hydrogen, the above formula represents an "aldehyde" group. The terms "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O- alkenyl, -O-alkynyl, -O-(CH₂)_m-R₈, where m and R₈ are as defined above.

The term "sulfonate" is art-recognized and includes a moiety that can be represented by the general formula:

in which R₄₁ is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

The term "sulfonylamino" is art-recognized and includes a moiety that can be represented by the general formula:

The term "sulfamoyl" is art-recognized and includes a moiety that can be represented by the general formula:

R O

N S

^R O .

The term "sulfonyl", as used herein, refers to a moiety that can be represented by the general formula:

in which R₄₄ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

The term "sulfoxido" as used herein, refers to a moiety that can be represented by the general formula:

in which R₄₄ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.

The term "sulfate", as used herein, means a sulfonyl group, as defined above, attached to two hydroxy or alkoxy groups. Thus, in a preferred embodiment, a sulfate has the structure:

in which R₄₀ and R₄₁ are independently absent, a hydrogen, an alkyl, or an aryl. Furthermore, R₄₀ and R_4I, taken together with the sulfonyl group and the oxygen atoms to which they are attached, may form a ring structure having from 5 to 10 members.

Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, alkenylamines, alkynylamines, alkenylamides, alkynylamides, alkenylimines, alkynylimines, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls, alkenoxyls, alkynoxyls, metalloalkenyls and metalloalkynyls.

The term "aryl" as used herein includes aromatic groups which may include from zero to four heteroatoms, for example, benzene, naphthalene, anthracene, phenanthrene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "heteroaryl". The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or -(CH₂)_m-R₈, -CF₃, -CN, or the like.

The terms "heterocycle" or "heterocyclic group" refer to 4 to 10-membered ring structures, more preferably 5 to 7 membered rings, which ring structures include one to four heteroatoms. Heterocyclic groups include pyrrolidine, oxolane, thiolane, imidazole, oxazole, piperidine, piperazine, morpholine. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or -(CH₂)_m-Rs, -CF₃, -CN, or the like. The terms "polycycle" or "polycyclic group" refer to two or more cyclic rings (e.g. , cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocycles) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or -(CH₂)_m-R8, -CF₃, -CN, or the like. The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur, phosphorus and selenium.

For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortAo-dimethylbenzene are synonymous. The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, j9-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms, represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.

The phrase "protecting group" as used herein means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2^nd ed.; Wiley: New York, 1991).

As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described hereinabove. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

As used herein, the term "covalent tether" refers to a tether of between 1 and 10 backbone atoms connected by covalent bonds; the backbone of said tether may also comprise π-bonds, provided that the configuration of said π-bonds are such that the described reaction is geometrically feasible, or that said π-bonds can adopt a configuration under the reaction conditions that renders the reaction geometrically feasible; said tether additionally may itself be either unsubstituted or bear any number of substituents of any type permitted by stability and the rules of valence. The rings formed by said covalent tethers include cyclopropane, cyclobutanes, cyclopentanes, cyclohexanes, cycloheptanes, and cyclooctanes, along with their unsaturated and heterocyclic analogues. Catalysts of the Invention

Transition metal complexes which are useful in the present invention may be determined by the skilled artisan according to several criteria. In general, a suitable transition metal complex will have one or more of the following properties: 1) It will be capable of reaction with the substrate at the desired site; 2) It will yield a useful product upon reaction with the substrate; 3) It will not react with the substrate at functionalities other than the desired site; 4) it will react with the substrate at least partly through a mechanism involving the chiral auxiliary; 5) It will not substantially undergo further undesired reaction after reacting with the substrate in the desired sense; 6) It will be able to be reoxidized by an oxidant so as to be catalytic. It will be understood that while undesirable side reactions may occur, the rates of such reactions can be rendered slow — through the selection of reactants and conditions -- in comparison with the rate of the desired reaction.

Transition metal complexes which satisfy the above criteria can be chosen for each substrate and may vary according to the substrate structure and desired product. Routine experimentation may be necessary to determine the preferred transition metal for a given transformation. In one embodiment of the present invention transition metal complexes with carbonyl containing ligands are utilized. In a preferred embodiment these ligands are selected from the group consisting of esters, amides, acetates, benzoates, oximies, phosphonates, phosphinates, phosphites and thioesters. In a preferred embodiment of the present invention, transition metal acetates are used. In a preferred embodiment of this invention, the transition metal acetates are palladium acetate, nickel acetate or platinum acetate. In another preferred embodiment, the metal acetate is palladium acetate. Oxidizer of the Invention

As explained below, in order to make the reaction catalytic in metal, an oxidizer is required in certain embodiments. Any compound capable of oxidizing a metal(II) species to the catalytically active metal(IV) species can be utilized, hi one embodiment, the oxidizer is selected from the group consisting of peroxides, hydroperoxides, hypervalent acyloxy iodides, transition metal acyloxy complexes and dihalogens. In certain embodiment, the oxidizer is selected from the group consisting of copper(I) acetate, copper(π) acetate, silver acetate, phenyl iodoacetate and iodine. In certain embodiments, the oxidizer is iodine.

Additional discussion of other oxidizers of the invention can be found in the following section entitled "Catalytic and Diastereoselective Oxidation of sp3 C-H Bonds Using Inexpensive Oxidants". In certain embodiments, the oxidizer is a peroxide or hydroperoxide of the following formula R-O-O-R' or R-O-O-H, wherein R and R' are, for example, alkyl, aryl or acyl. Examples of such peroxides and hydroperoxides are MeC(=0)tBu, PhC(=O)OOtBu, [PhC(=O)]₂O₂, [CH₃(CH₂)₁₀C(=O)]₂O₂, tBuOOtBu, and tBuOOH. Substrates with Chiral Auxiliaries

As discussed below, a wide variety of substrates are useful in the methods of the present invention. The choice of the chiral auxiliary will depend on factors such as which C-H bond one wishes to functionalize, and an appropriate substrate will be apparent to the skilled artisan. It will be understood that the substrate and auxiliary preferably will not contain any interfering functionalities. In certain embodiments, an appropriate substrate will contain a C-H bond in the beta or gamma position, relative to the chiral auxiliary. The catalyzed, stereoselective C-H bond functionalization will produce a chiral non-racemic product. Most of the substrates contemplated for use in the methods of the present invention contain a non-racemic chiral heterocycle which presents an asymmetric environment, allowing for regio- and stereospecific C-H bond functionalization via transition-metal catalysis. In general, auxiliaries intended by the present invention can be characterized by a number of features. For instance, substrates contemplated by the present invention includes chiral substituted 1,3-oxazole, 1,3-diazole, 1,3-thiazole, l,4-oxazin-2- one, l,4-azazin-2-one, l,4-thiozin-2-one or compounds derived thereof; chiral amines or amides; and chiral phosphites.

A chiral auxiliary of the present invention may be a 5-membered heterocyclic ring which possesses a 1,3 arrangement of heteroatoms. hi a preferred embodiment, the chiral auxiliary is selected from the group consisting of substituted 1 ,3-oxazolines and their amino- and thio-analogues {e.g., substituted 4,5-dihydro-l,3-diazoles and substituted 4,5- dihydro-l,3-thiazoles). It is envisioned that these chiral auxiliaries may be multiply substituted and/or polycyclic; see, e.g., those shown in Figure 7a. Azlactones, derived from natural and non-natural amino acids, may also be used as auxiliaries {e.g., Example 34). A chiral auxiliary of the present invention may be a 6-membered heterocyclic ring which possesses a 1,4 arrangement of heteroatoms. hi a preferred embodiment, the chiral auxiliary is selected from the group consisting of substituted l,4-oxazin-2-one and their amino- and thio-analogues.

A chiral auxiliary of the present invention need not be cyclic. In an embodiment, a chiral amine can be used to form an enamine, or, conversely, an amine can be condensed with a chiral ester, or the like, to form a chiral amide. Examples of both types of compounds are shown in Figure 7b. In one embodiment the chiral auxiliary is a Boc group. In yet another embodiment, as shown in Figure 7c, the chiral auxiliary may be a phosphite. Reaction Conditions The reactions of the present invention may be performed under a wide range of conditions, though it will be understood that the solvents and temperature ranges recited herein are not limitative and only correspond to a preferred mode of the process of the invention.

In general, it will be desirable that reactions are run using mild conditions which will not adversely effect the substrate, the catalyst, or the product. For example, the reaction temperature influences the speed of the reaction, as well as the stability of the reactants, products, and catalyst. The reactions will usually be run at temperatures in the range of -78 ⁰C to 100 ⁰C, more preferably in the range -20 ⁰C to 50 ⁰C and still more preferably in the range -20 ⁰C to 25 ⁰C. In general, the asymmetric synthesis reactions of the present invention are carried out in a liquid reaction medium. The reactions may be run without addition of solvent. Alternatively, the reactions may be run in an inert solvent, preferably one in which the reaction ingredients, including the catalyst, are substantially soluble. Suitable solvents include ethers such as diethyl ether, 1,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran and the like; halogenated solvents such as chloroform, dichloromethane, dichloroethane, chlorobenzene, and the like; aliphatic or aromatic hydrocarbon solvents such as benzene, toluene, hexane, pentane and the like; esters and ketones such as ethyl acetate, acetone, and 2-butanone; polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide and the like; or combinations of two or more solvents. Furthermore, in certain embodiments it may be advantageous to employ a solvent which is not inert to the substrate under the conditions employed, e.g., use of ethanol as a solvent when ethanol is the desired nucleophile. In embodiments where water or hydroxide are not preferred nucleophiles, the reactions can be conducted under anhydrous conditions. In certain embodiments, ethereal solvents are preferred. In embodiments where water or hydroxide are preferred nucleophiles, the reactions are run in solvent mixtures comprising an appropriate amount of water and/or hydroxide.

The invention also contemplates reaction in a biphasic mixture of solvents, in an emulsion or suspension, or reaction in a lipid vesicle or bilayer. In certain embodiments, it may be preferred to perform the catalyzed reactions in the solid phase.

In certain embodiments it is preferable to perform the reactions under an inert atmosphere of a gas such as nitrogen or argon. In many embodiments sealing of the reaction flask is critical to prevent the decomposition on the metal(IV) species. The asymmetric synthesis processes of the present invention can be conducted in continuous, semi-continuous or batch fashion and may involve a liquid recycle and/or gas recycle operation as desired. The processes of this invention are preferably conducted in batch fashion. Likewise, the manner or order of addition of the reaction ingredients, catalyst and solvent are also not critical and may be accomplished in any conventional fashion.

The reaction can be conducted in a single reaction zone or in a plurality of reaction zones, in series or in parallel or it may be conducted batchwise or continuously in an elongated tubular zone or series of such zones. The materials of construction employed should be inert to the starting materials during the reaction and the fabrication of the equipment should be able to withstand the reaction temperatures and pressures. Means to introduce and/or adjust the quantity of starting materials or ingredients introduced batchwise or continuously into the reaction zone during the course of the reaction can be conveniently utilized in the processes especially to maintain the desired molar ratio of the starting materials. The reaction steps may be effected by the incremental addition of one of the starting materials to the other. Also, the reaction steps can be combined by the joint addition of the starting materials to the optically active metal-ligand complex catalyst. When complete conversion is not desired or not obtainable, the starting materials can be separated from the product and then recycled back into the reaction zone.

The processes may be conducted in either glass lined, stainless steel or similar type reaction equipment. The reaction zone may be fitted with one or more internal and/or external heat exchanger(s) in order to control undue temperature fluctuations, or to prevent any possible "runaway" reaction temperatures. Furthermore, the catalyst can be immobilized or incorporated into a polymer or other insoluble matrix by, for example, covalently linking it to the polymer or solid support through one or more of its substituents. An immobilized catalyst may be easily recovered after the reaction, for instance, by filtration or centrifugation. Subsequent Transformations A product synthesized by a process of the present invention may be either an end- product or an intermediate in a synthesis scheme, hi cases where the product synthesized by a process of the present invention is an intermediate, the product may be subjected to one or more additional transformations to yield the desired end-product. The set of additional transformations contemplated comprises isomerizations, hydrolyses, oxidations, reductions, additions, eliminations, olefinations, functional group interconversions, transition metal- mediated reactions, transition metal-catalyzed reactions, bond-forming reactions, cleavage reactions, fragmentation reactions, thermal reactions, photochemical reactions, cycloadditions, sigmatropic rearrangements, electrocyclic reactions, chemoselective reactions, regioselective reactions, stereoselective reactions, diastereoselective reactions, enantioselective reactions, and kinetic resolutions. The invention expressly comprises use of a process of the present invention as a step - either initial, intermediate or final - in the synthesis of known or new pharmaceuticals, e.g., antivirals, antibiotics, and analgesics. Oxazoline Directed C-H Bond Cleavage at Room Temperature

Overview. One aspect of the invention relates to a cyclic directing group and a metal center that forms a reactive three coordinate or square planar complex. The cyclic directing group is used to control the stereochemistry of the C-H cleavage step. A wide range of simple substrates, such as carboxylic acids, nitriles, epoxides and ketones, maybe transformed into or attached to a cyclic chiral auxiliary, thereby installing a removable cyclic directing group for C-H activation. In certain embodiments said cyclic chiral auxiliary is a oxazoline. Methods for the installation and removal of oxazolines has been previously established. See Meyers, A. I. "Asymmetric Carbon-Carbon Bond Formation from Chiral Oxazolines" Ace. Chem. Res. 1978, 11, 375-381; and Rajaram, S.; Sigman, M. S. "Modular Synthesis of Amine-Functionalized Oxazolines" Org. Lett. 2002, 4, 3399- 3401. A single case of stoichiometric activation of a β -methyl group in an oxazoline, to form the five-member dimeric palladocycle, has been observed. See Balavoine, G.; Clinet, J. C. "Cyclopalladated 2-t-Butyl-4,4-Dimethyl-2-Oxazoline: Its Preparation and Use in the Functionalization of a Non- Activated Carbon-Hydrogen Bond" J. Organomet. Chem. 1990, 390, C84-C88. However, a catalytic process for the formation of these stable dimeric Pd complexes has not been reported in the literature to date. Murai further explored the oxazoline as a directing group to activate ortho-aryl C-H bond using a Ru(II) catalyst. However, it was concluded that a chiral oxazoline bearing a hydrogen α to the nitrogen was not suitable for C-H activation, due to a possible interference from this hydrogen. See Kakiuchi, F.; Sato, T.; Yamauchi, M.; Chatani, N.; Murai, S. "Ruthenium-Catalyzed

Coupling of Aromatic Carbon-Hydrogen bonds in Aromatic Imidates with Olefins" Chem. Lett. 1999, 19-20; and Ie, Y.; Chatani, N.; Ogo, T.; Marshall, D. R.; Fukuyama, T.; Kakiuchi, F.; Murai, S. "Direct Carbonylation at a C-H Bond in the Benzene Ring of 2- Phenyloxazolines Catalyzed by Ru₃(CO)₁₂. Scope, Limitations, and Mechanistic Aspects" J. Org. Chem. 2000, 65, 1475-1488.

Preliminary Reaction. Iodination of trimethylacetic acid was selected for an initial test due to its structural simplicity, as the nine sp³ C-H bonds from methyl groups are equivalent. It was found that oxazoline 6a derived from pivalic acid and (ιS)-tert-leucinol reacts with Pd(OAc)₂ at 24 ⁰C to give a trinuclear Pd-alkyl complex, via cleaving the β-C-H bond, as a single isomer 6b (by ¹H NMR). This single isomer was purified by washing with cold hexane to give 60% isolated yield. Crystal structure analysis determined that this complex possesses an αntz-geometry, with the top and bottom oxazoline units being anti to each other (Figure 8). It was found that Pd(OAc)₂/I₂ was an effective stoichiometric reagent for the iodination of a methyl in 6a. Stirring 6a (1 equiv) with Pd(OAc)₂ (1 equiv) and I₂ (1 equiv) in CH₂Cl₂ at 24 ⁰C for 24 h led exclusively to iodination of the methyl group, generating the mono-iodide in 80 % isolated yield. PdI₂ was isolated in nearly quantitative yield as a precipitate after the completion of the stoichiometric reaction (characterized by powder X-ray diffraction and elemental analysis). Since PdI₂ was shown to be not reactive. However different scavengers of iodide and donors of acetate to convert PdI₂ to Pd(OAc)₂ would close the catalytic cycle. Catalytic turnover was observed in the presence of metal acetates. In certain embodiments, AgOAc or PhI(OAc)₂ was used. Thus, substrate 6a was stirred with 1 equiv of I₂, 1 equiv of PhI(OAc)₂ and 10 mol% Pd(OAc)₂ in CH₂Cl₂ for 48 h to afford the iodination product 6c in 92% isolated yield (Table 2).

6c Monitoring the reaction by ¹H NMR revealed that PhI(OAc)₂ reacts with I₂ to give

PhI and an unidentified new species in the first 3 h. This new species is responsible for converting PdI₂ into Pd(OAc)₂. Indeed, a control experiment showed that only catalytic amount of I₂ is required for PhI(OAc)₂ to convert PdI₂ into Pd(OAc)₂. Interestingly, in the absence of I₂, the combination of PdZPhI(O AcVoxazoline performs acetoxylation reaction in a similar manner to that of Sanford's acetoxylation reaction. This new oxidant was also found to be effective in the activation of methyl amines. Both the acetoxylation reaciton and the activation of methyl amines is discussed in more depth below.

Based on our experimental data and previous studies on the stoichiometric oxidative addition of I₂ to Pd^π and Pt¹¹ species, a catalytic cycle is proposed (Figure 2). First, electrophilic cleavage of the C-H bond takes place to give the trinuclear bis-μ- acetatopalladium¹¹ complex. Next, I₂ reacts with this complex, presumably by oxidative addition and reductive elimination to form the iodinated product and PdI₂. A new oxidant generated from PhI(OAc)₂ and I₂ converts PdI₂ back to Pd(OAc)₂ to close the catalytic cycle.

Catalyst Recycling. A clear advantage of this catalytic system is the ease of recycling the palladium catalyst. As PhI(OAc)₂ is consumed towards the completion of the reaction, PdI₂ precipitates out from the solution. It can be recycled by simply centrifuging and decanting the supernatant and then reusing with additional I₂ and PhI(OAc)₂. Table 1 below shows recycling experiments using substrate 16a (reaction conditions: Pd(OAc)₂ (10 mol %), I₂ (1 equiv), PhI(OAc)₂, (1 equiv), CH₂Cl₂, 24 ⁰C, 13-20 h). Table 1. Recycling experiments using substrate 16a

Run 1 2 3 4 5

Yield (%) 98 97 93 88 84

Iodination of Alkenes. The highly selective activation of primary C-H bonds versus secondary C-H bonds was conclusively demonstrated by using substrate 7a and 8a. Interestingly, the oxazoline prepared from triethyl acetic acid did not react under the same conditions. This observation is consistent with the unfavorable steric interactions between ligated ligands and branched alkyl groups, thus indicating the involvement of a cyclometallation step instead of a radical pathway. For free-radical iodination of alkanes see Liguori, L.; Bjorsvik, H. R.; Bravo, A.; Fontana, F.; Minisci, F. Chem. Commun. 1997, 1501; Montoro, R.; Wirth, T. Organic Lett. 2003, 5, 4729. For superelectrophile initiated iodination of alkanes see Akhrem, L; Orlinkov, A.; Vitt, S.; Chistyakov, A. Tetrahedron Lett. 2002, 43, 1333. Cyclic substrates (9a-lla) were also examined, and consistently the primary C-H bonds are selectively iodinated in high yields. See Table 2. The striking rate- difference observed between substrates 12a and 13a provided further evidence of the remarkable selectivity of the methods of the invention. Table 2. Pd(OAc)₂ catalyzed mono-iodination of methyl groups

6a-8a 6b-8b 9a-lla 9b-llb entry substrate yield (%)

1 6a R₁ = CH₃₅ R₂ = CH₃ 92

2 7a R₁ = CH₃₅ R₂ = CH₂CH₃ 91^a

3 8a R₁ = CH₂CH₃₅ R₂ = CH₂CH₃ 88^b

4 9a n = l 90^b

5 10a n = 2 97^b

6 11a n = 3 81

Reaction conditions: Pd(OAc)₂, 10 mol%, I₂, 1 equiv, PhI(OAc)₂, 1 equiv, CH₂Cl₂, 24 C₅ 48 h. (a) 25 % de was observed by NMR and GC-MS. (b) PdI₂ precipitated out at 48 h, and 0.5 equiv OfPhI(OAc)₂ was added and kept stirring for another 48 h. The diastereoselectivity of iodination observed using substrate 7a was encouraging for asymmetric C-H activation considering the small difference in size between a methyl and an ethyl group. Iodination of the methyl group in substrate 14a exhibited improved stereoselectivity. Using the reaction conditions shown in Figure 3, the iodinated products were isolated as a mixture of the two diastereomers in 91 : 9 ratio (82% de; Figure 3). Employment of a bulkier oxazoline auxiliary, as described herein, will allow a wide range of open chain carboxylic acids to be iodinated and acetoxylated at the β-position

Iodination of Cyclopropyls. The well-documented amide-directed lithiations of cyclopropyls prompted us to test whether the newly developed catalytic system could functionalize the secondary cyclopropyl C-H bond in the presence of a methyl group. See Eaton, P. E.; Daniels, R. G.; Casucci, D.; Cunkle, G. T. J. Org. Chem. 1987, 52, 2100.

Cyclopropane substrate 15a was prepared and subjected to the same conditions. Indeed, the selectivity was reversed from primary to secondary C-H bonds completely (Figure 3). Of particular importance, exclusive iodination (and acetoxylation) of the cyclopropyl C-H bond was achieved with excellent control of the stereochemistry. Reaction of 15a gives 65 % isolated yield of the iodinated product 15b as a single isomer. The czs-geometry of 15b was established by NOE experiment. The enantiomer of 15b was also obtained using oxazoline substrate prepared m (i?)-tert-leucinol. Both 15b and its enantiomer were then hydrolyzed by refluxing in 4 M E^SO^dioxane for 8 h to give the corresponding carboxylic acids in > 99% ee as determined by HPLC analysis. Examination of models suggests that steric repulsion between the tert-butyl group complex 1 (Figure 2) positions the Pd in an asymmetric environment in which the agostic complex with one of the prochiral C-H bonds is preferred. The establishment of the absolute configuration of the newly created stereogenic center led us to propose the stereomodel shown in Figure 3. The iodinated product 15b was converted to the known compound (IS, 2»S)-methyl-l-methyl-2- phenylcyclopropane carboxylate to establish the absolute configuration. See Rubina, M.; Rubin, M.; Gevorgyan; V. J Am. Chem. Soc. 2003, 125, 7198.

Iodination of Arenes. The scope of this C-H activation reaction was further examined using arene-containing substrate 16a. It was found that the arene C-H bond was iodinated with high selectivity in the presence of a methyl group. The mono-iodinated product 16b was isolated in 98 % yield and 99 % de (Figure 3) as determined by NMR and GC-MS. Oxazoline 16b was also hydrolyzed to give the iodo acid in >99 % ee. Clearly, γ- functionalization of the arene (cyclopalladation assisted by a six-member ring chelation) occurred, in preference to β-C-H functionalization of the methyl group. See Hiraki, K.; Fuchita, Y.; Takechi, K. Inorg. Chem. 1986, 20, 4216. The observed reactivity is distinct from the well documented ørt/ϊø-metallations involving five-membered ring chelation. This reaction could prove synthetically useful in establishing absolute configuration of tertiary and quaternary carbon centers bearing two substituted aryl moieties, which is a well-known challenge in asymmetric catalysis. See BoIm, C; Kesselgruber, M.; Hermanns, N.; Hildebrand, J. P.; Raabe, G. Angew. Chem. Int. Ed. Engl. 2001, 40, 1488. Catalytic and Diastereoselective Oxidation of sp³ C-H Bonds Using Inexpensive Oxidants

In this section we disclose a Pd-catalyzed oxidation of unactivated methyl groups using the peroxyester MeCOOOt-Bu as the stoichiometric oxidant and Ac₂O as a crucial promoter (e.g., P to Q as shown below), hi addition results on diastereoselective oxidation of methyl groups using lauroyl or benzoyl peroxide as the stoichiometric oxidants are also described.

P Q

Characterization of a Oxazoline/Palladium Complex. The reaction of substrate 19 with 1.5 equiv of Pd(OAc)₂ in CH₂Cl₂ at 24 °C for 36 h afforded a mixture of anti- and syn- trinuclear complexes in 1 : 1 ratio. The molecular structure of the αntz-isomer 19a determined by X-ray diffraction (Figure 8), is related to a recently obtained ferrocene derivative, and confirms earlier proposals based on ¹H NMR analysis. Gin, R.; Chen, X.; Yu, J. Q. Angew. Chem. Int. Ed. 2005, 44, 2112-2115; and Moyano, A.; Rosol, M.; Moreno, R. M.; Lopez, C; and Maestro, M. A. Angew. Chem. Int. Ed. 2005, 44, 1865-

1869. The predominant formation of a dimeric complex by refluxing Pd(OAc)₂ and 2-tert- butyl-4,5-dihydro-4,4-dimethyloxazole in HOAc was previously reported. A mixture of syn and anti trinuclear Pd alkyl species in 2 : 3 ratio were also observed as minor products by ¹H NMR. Balavoine, G.; Clinet, J. C. J. Organomet. Chem. 1990, 390, C84.

19a

Acetoxylation. It was envisioned that the reaction of 19a with TBHP would oxidize the Pd-C bond to give Pd-OR complex 19b since TBHP/VO(acac)₂ is known to insert an oxygen atom into the Pd-C bond of dimeric Pd-aryl complexes (Scheme 2). Alsters, P. L.; Teunissen, H. T.; Boersma, J.; Spek, A. L.; Koten, G. V. Organometallics 1993, 12, 4691- 4696. It was found that reaction of 19a with 5 equiv of TBHP in CH₂Cl₂ at 24 ⁰C for 36 h, followed by reduction with NH₂NH₂, afforded the hydroxylated product 19c in 35 % isolated yield. It was further hypothesized that Ac₂O would acetylate the Pd-OR complex 19b and regenerate Pd(OAc)₂ thereby rendering this reaction catalytic. Following treatment of 19a with TBHP, the addition OfAc₂O was found to give the product in the form of acetate 19d and regenerate Pd(OAc)₂.

c, 35% yield

19d, 55% yield

Carrying out this reaction using only a catalytic amount OfPd(OAc)₂ established that peroxyester MeCOOOt-Bu generated from the reaction of TBHP with Ac₂O is an efficient oxidant for the oxidation of methyl groups. A combination OfPd(OAc)₂ (5 mol%) and MeCOOOt-Bu (2 equiv) in Ac₂O was able to acetoxylate 19 in 71% yield. A wide range of substrates are oxidized in good yields (Table 3 below). Polar functional groups such as ketals, imides, esters and chlorides are tolerated. Substrate 27 was used directly without protecting the hydroxyl group. The hydroxyl group was acetylated in the reaction. Since MeCOOOt-Bu is a cheap oxidant, this oxidation protocol is especially useful in the laboratory.

Table 3. Pd(OAc)₂-catalyzed oxidation of methyl groups by MeCOOOt-Bu

Entry Substrate Product Yield% Entry Substrate Product Yield%

Reaction conditions: Entries 1-5, Pd(OAc)₂ (5 mol %), Ac₂O, MeCOOOt-Bu (2 equiv), 65 °C, 48 h. Entries 6-9, Pd(OAc)₂ (10 mol %). The presence of air or pure O₂ increases the conversion. Oxa = 4,4-dimethyl-2-oxazoline.

Next, it was attempted to extend this protocol to diastereoselective oxidation using a chiral oxazoline. However it was found that MeCOOOt-Bu is not compatible with a chiral oxazoline containing a hydrogen α to the nitrogen, as this hydrogen is readily oxidized and eventually leaing to the oxazole. However, this side reaction can be prevented by using inexpensive benzoyl or lauroyl peroxide as the oxidants (Table 4). Moderate diastereoselectivity (12-82% de) was also observed with substrates containing prochiral methyl groups. Table 4. Pd(OAc)2 catalyzed diastereoselective oxidation of methyl groups by lauroyl peroxides

Reaction conditions: Pd(OAc)₂ (5 mol %), Ac₂O, lauroyl peroxide (2 equiv), 50 ⁰C, 48 h. Oxa = 4-tert-butyl-oxazorine-2-.

As reported previously, a mixture of HO Ac/ Ac₂O has been used as the reaction media for Pd(IT) catalyzed C-H activation reactions. Desai, L. V.; Hull, K. L.; Sanford, M. S. J Am. Chem. Soc. 2004, 126, 9542-9543; Kao, L. C; Hutson, A. C; Sen, A. J. Am. Chem. Soc. 1991, 113, 700-701; Ingrosso, G.; Midollini, N. J. MoI. Catal. A-Chem. 2003, 204-205, 425-431; and jia, C; Lu, W.; Kitamura, T. Fujiwara, Y. Org. Lett. 1999, 1, 2097- 2100. However, the role OfAc₂O remains obscure in C-H bond oxidation reactions. The isolation of the complex 19a allowed us to investigate the influence OfAc₂O on the C-H cleavage and oxidative addition steps independently. For extensive investigations into the oxidative addition of the benzoyl peroxide to Pd¹¹ complexes of pincer ligands, see: (a) Canty, A. J.; Denney, M.; Koten, G.; Skelton, B. W.; White, A. H. Organometallics 2004, 23, 5432-5439. (b) For the first charaterization of a organopalladium™ complex, PdIMe₃(bρy), see, Byers, P. K.; Canty, A. J.; Skelton, B. W.; White, A. H. J. Chem. Soc, Chem. Commun. 1986, 1722-1724. The formation of 19a in CH₂Cl₂ was monitored by ¹H NMR in the absence and presence of various amount OfAc₂O (see exemplification). The results showed that the rate was not affected by Ac₂O. The oxidative addition step, however, was shown to require Ac₂O since no reaction of 19a with MeCOOOt-Bu was observed in CH₂Cl₂ at 50 °C. Other Anhydrides. The use of other anhydrides such as propionic and isobutyric anhydrides consistently affords the corresponding carboxylates. This further suggests that the acetate ligand at the apical positions of the octahedral Pd^w complex 19f is also rapidly exchanging with anhydrides to give 19g prior to reductive elimination.

_R _ _{B 730/ / p} °

Oxidants. The use of lauroyl peroxide or benzoyl peroxide as the oxidant has led to the identification a second role for Ac₂O. The reaction of 19a with both peroxides proceeds to give the acetoxylated products in the absence OfAc₂O. However, the presence OfAc₂O is essential for the catalytic turnover. Rate measurement by GC using 20% Pd(OAc)₂ shows that the reaction in the first 10% conversion is not influenced by the addition of Ac₂O, but does not proceed further after 15% conversion in the absence OfAc₂O. This result suggests that Ac₂O is crucial for the regeneration of the reactive Pd(OAc)₂ as shown above. Diastereoselective iodination of cyclopropyl groups

The overwhelming importance of cyclopropane containing compounds due to their diversified biological activity has led to the discovery and advance of cyclopropane forming reactions. Doyle, M. P.; Forbes, D. "Recent Advances in Asymmetric Catalytic Metal Carbene Transformations" Chem. Rev. 1998, 98, 911-935; and Gnad, F.; Reiser, O. "Synthesis and Applications of β-Aminocarboxylic Acids Containing a Cyclopropane Ring" Chem. Rev. 2003, 103, 1603-1623. The iodination reaction described above has been shown to be applicable to cyclopropane functionalization, giving 99% de in the iodination of the certain cyclopropanes. However, in certain embodiments the presence of an α- hydrogen inhibits the reaction and hence limits the synthetic utility.

However, protection of the α-proton by a silyl group would solve this problem since PhMe₂Si- group can be removed with retention of the stereochemistry using a recently developed protocol. Heitz, C. L.; Lambert, W. T.; Mertz, E.; Shotwell, J. B.; Tinsley, J. M.; Va, P.; Roush, W. R. "Efficient Protiodesilylation of Unactivated C(sρ³)-SiMe₂Ph Bonds Using Tetrabutylammonium Fluoride" Org. Lett. 2005, ASAP. The presence of a bulky silyl group might also enhance the reactivity by assisting the assembly of the cyclopalladation transition state. α-Silyl-cyclopropane carboxylic acid 74 can be readily prepared following a literature method. Arney, B. E. Jr.; Wilcox, K.; Campbell, E.; Gutierrez, M. O. "A Preparatively Viable in situ Synthesis of Methyl l-Cyclopropenecarboxylate" J. Org. Chem. 1993, 58, 6126-6128. The expected iodination product 74c can be further elaborated by Suzuki cross-couplings with boronic acids. Charette, A. B.; Giroux, A. "Palladium- Catalyzed Suzuki-Type Cross -Couplings of Iodocyclopropanes with Boronic Acids: Synthesis of trans- 1,2-Dicyclopropyl Alkenes" J. Org. Chem. 1996, 61, 8718-8719. Recently, 74c was demonstrated to react with a wide range of electrophiles such as aldehydes, trialkyltin chlorides and allylic bromides to afford highly valuable building blocks for cyclopropane natural product synthesis. Vu, V. A.; Marek, L; Polborn, K.; Knochel, P. "Preparation of New Functionalized Cyclopropylmagnesium Reagents" Angew. Chem. Int. Ed. 2002, 41, 351-352.

Suzuki c ^ R = aryl, vinyl coupling ✓ R COOMe

1.TBAF, DMSO/THF ^Λ^H / ^74d

2.2 N HCΪ "Y ^''coOMe ^'^s

3.CH₂N₂

74c /-PrMgCI ^ A/^H R = aryl, vinyl, allyl electrophiles ^ ^''cooMe ^SnMe3- ^phS. ^CN

74e Diastereoselective iodination sp³ C-H bonds using l,4-oxazin-2-one directing groups

One of the major problems encountered in the oxazoline assisted C-H activation of sp³ C-H bonds is the requirement of a quaternary carbon center at the α-position of the oxazoline, thus limiting the substrate scope. Another challenging issue associated with using a directing group is the ease of removal under mild conditions. To address these problems, l,4-oxazin-2-one as a cyclic directing group was developed to activate keto esters stereoselectively.

Substrate 75a was prepared from the corresponding commercial keto ester and 2- amino-2-methyl-l-propanol using a literature procedure (Harwood, L. M.; Vines, K. J.; Drew, M. G. B. "Synthesis of Homochiral α-Substituted Alanine Derivatives by Diastereocontrolled Alkylation of (5R)-5-Phenyl-3-Methyl-3,4-Dehydromorpholinones" Syn. Lett. 1996, 1051-1053). The hydrolysis of 75a in a 1:1 mixture of 2 N HCl/dioxane readily occurs to give the corresponding keto acid at 24 °C. To investigate the reactivity of this new directing group, both acetoxylation and iodination reactions were attempted. The previously reported acetoxylation protocol (Sanford's conditions) using Ac₂O/HOAc as the solvent at 100 °C affords 30% yield. Carrying out the reaction using Ac₂O as the only solvent at a lower temperature (70 °C) gives 60% yield. The inventive iodination protocol gives less than 10% yield of the iodinated product and the iodination of the α-hydrogen was observed as the side reaction, hi certain embodiments, oxazinones can be prepared from various commercial amino alcohols.

75a 75b

e

76a 76b

To test the functional group tolerance and demonstrate the synthetic utility, the activation of the enantiomerically pure substrate 77a would prepare densely functionalized synthons 77c and 77d (see below). Keto ester 77 is readily accessible via a straightforward procedure starting from the inexpensive poly-[(i?)-3-hydroxybutyric] acid (largely available from cane industry; Rodrigues, J. A. R.; Moran, P. J. S.; Milagre, C. D. F.; Ursini, C. V. "Diastereo- and Enantioselective Syntheis of a Conagenin Skeletal Amide Moiety" Tetrahedron Lett. 2004, 45, 3579-3582.) The iodinated product 77b can be converted to a synthetically useful α-hydroxy γ-butyrolactone 77d (Pansare, S. V.; Shinkre, B. A.; Bhattacharyya, A. "Enantioselective Synthesis of α-Hydroxy γ-butyrolactones from an Ephedine-derived Morpholine-dione" Tetrahedron 2002, 55, 8985-8991).

77c 77d

It is also proposed to test diastereoselective iodination of substrates 78a - 81a (see below). Commercially available amino alcohols may be used. In one embodiment (S)- valinol may be used. 4,5-cis-disubstituted oxazolines, may also be used.

78a 79a 80a 81a

82a 82b 82c

Since a chiral center at the α-position of keto acids is prone to racemization under basic or acidic conditions, the conditions for removing the directing groups will be optimized to avoid racemization, for example, hydrolysis at O °C. An alternative route is to use oxazinones made from (/?)-phenyl-glycmol such as 82a. This directing group can be removed by hydrogenolysis to afford novel chiral α-amino acids (see above). The amino acid 82c can be readily transformed to more complex α-amino acids by Suzuki coupling.

The kinetic resolution of the oxazoline substrate 83 a has previously been tested, and 50% de of the iodinated product 83b at 38% conversion was obtained (see below). Using the optimized iodination conditions, substrates 84a - 87a may be used to establish the scope. Since the products produced from the pro-chiral substrates are limited to α,α- dimethyl compounds, the kinetic resolution approach substantially expands the diversity of the substrate scope.

83a 83bconversion% = 38 de% = 50

New directing groups may also be extended to an α-hydrogen containing cyclopropane substrate 88a (see below). This approach expands the scope of the stereoselective functionalization of cyclopropanes.

88a 88b 88c reductive _u Λ H Suzuki coupling a ammiinnaattiinonn ^ ^H^ . V ■. or Grinard reaction ^ c _ay_mc_il_no_opr _ao_cp_ja_dn _be_u c _jido _jn_nt_gai _bn_|i_on_cg_ks

' / COOH for novel peptide synthesis

88d

Diiodination of gem-dimethyl groups leads to efficient constructions of cyclopropane rings

The iodination of the chiral 4-tert-butyl-oxazolines gives mono-iodinated products in high selectivity (see above). The iodination of the non-chiral 4,4-dimethyl-oxazoline 38a proceeds at a slower rate. It was found that mild heating (50-60 °C) leads to di-iodination or tri-iodination of oxazoline 38a depending on the amount of the oxidant used (see below). The obtained diiodides are shown to be efficient precursors for the construction of cyclopropane rings using a reported procedure (Bailey, W. F.; Gagnier, R. P.; Patricia J. J. "Reactions of tert-Butyllithium with ά,ω-Dihaloalkanes. Evidence for Single-Electron- Transfer-Mediated Metal-Halogen Interchange Involving Alkyl Radical-Halide Ion Adducts" J Org. Chem. 1984, 49, 2098-2107). This protocol provides a novel route to prepare cyclopropane compounds from simple starting material such as pivalic acid. Notably, α-cyclopropyl-modified β-alanines such as 96b, when fused into peptides, exhibit important biological activities (Doyle, M. P.; Forbes, D. "Recent Advances in Asymmetric Catalytic Metal Carbene Transformations" Chem. Rev. 1998, 98, 911-935).

Me oxazoline

.. J-_v. formation , Me MTe -COOH equiv h

96a, 91% 96b To prepare cyclopropane α-amino acid 97c, 2-aminoisobutyric acid was initially protected using N-phthalimide. It was found that reaction was slow and mainly monoiodide was obtained. Since the protection of the hydroxyl as an OTBS was successful in both iodination and acetoxylation, it is proposed to use a widely used silylating reagent to protect the amino group (Sofia, M. J.; Chakravarty, P. K.; Katzenellenbogen, J. A. "Synthesis of Five- Membered Halo Enol Lactone Analogous of α- Amino Acids: Potential Protease Suicide

Substrates" J. Org. Chem. 1983, 48, 3318-3325). Other substrates are envisioned to be used to prepare functionalized cyclopropane compounds.

gOTTIBib e

It was recently found that the presence of an oxygen or nitrogen atom at the α-position promotes the hydrolysis of the oxazoline ring. Following the cyclization reaction, the removal of the directing group is expected to take place at room temperature in the presence of 2 N HCl. Despite the remarkable progress of cyclopropane ring forming reactions, this reaction demonstrates the potential of C-H activation to develop new transformations using inexpensive starting materials such as pivalic acid and glycine derivatives (Doyle, M. P.; Forbes, D. "Recent Advances in Asymmetric Catalytic Metal Carbene Transformations" Chem. Rev. 1998, 98, 911-935; and Gnad, F.; Reiser, O. "Synthesis and Applications of β- Aminocarboxylic Acids Containing a Cyclopropane Ring" Chem. Rev. 2003, 103, 1603- 1623).

These compound also may be further reacted with chiral catalysts to produce chiral centers. For example, chiral organometallic reagents (e.g., those used for Suzuki or Stille couplings) used sequentially would enable the formation of chiral quaternary centers. Diastereoselective Acetoxylation, Etherifϊcation and Lactonization of C-H Bonds

Diastereoselective acetoxylation. initial efforts to achieve a palladium mediated C- H bond hydroxylation reaction have led to the discovery of a novel protocol to carboxylate α-methyl groups of oxazolines. The use of different carboxylic anhyrides affords various carboxylated products (see above). This reaction employs inexpensive oxidants such as MeCOOOt-Bu or lauroyl peroxide as the stoichiometric oxidants. Considering the excellent functional group tolerance (halides, esters, ethers, ketals and hydroxyls) and the low cost of the oxidants, this reaction should find broad applications in syntheses to make oxygenated compounds.

The removal of the oxazoline directing group in the acetoxylated products is easier than the iodinated products. Treatment of the acetoxylated product with 2 N HCl/dioxane at 24⁰C affords the corresponding amide in 90% yield. Further reduction of the amide using DIBAL under various conditions will be tested. As described in herein, the use of cyclic directing groups containing a polar attendant on the ring will further increase both the solubility in the aqueous phase and reactivity of the chiral auxiliary towards the nucleophile H₂O. hi one embodiment the chiral auxiliary is a chiral 4,5-disubstituted oxazoline.

Diastereoselective etherification. t-Butyl, benzyl, and TMS protected ethers as masked alcohols are highly valuable for multi-step syntheses. Preliminary studies of the palladium catalyzed acetoxylation reaction may lead one to assume the formation of a Pd^ intermediate on the reaction pathway (see below). Based on this hypothesis, the anionic ligands at the apical positions of the intermediates should vary when different oxidants oxidatively add to the Pd^π-alkyl complex 104 (see below). It was found, however, that the acetoxylated products were consistently formed with various oxidants. This result suggests that, prior to the reductive elimination, the anionic ligands are rapidly substituted by the acetate from the solvent Ac₂O. oxidants: MeCOOOf-Bu (PhCO)₂O₂ [CH₃(CH₂)₁₀CO]₂O₂ PhCOOOf-Bu

h

hi order to obtain the t-Butyl ether product, it is necessary to prevent the anionic exchange process and accelerate the reductive elimination of the t-butoxyl group from 104a or 104d. It was found that the use of PhCOOOt-Bu at 70 °C led to the formation of the t- butyl ether 19k as the major product. This finding has provided a new way to convert methyl groups into ethers.

It is further proposed the preparation of ether products protected by benzyl type protecting groups such as 191, which can be readily removed by hydrogenolysis. Thus, a new oxidant PhCOOOCMe₂Ph was prepared in 87% yield by stirring cumene hydroperoxide and benzoyl chloride in the presence OfEt₃N. This oxidant will be used to oxidize various substrates described herein.

Diastereoselective lactonization. The rapid degenerate acetate exchange between the Pd^π-alkyl complex 6b and

suggested attempting a novel lactonization reaction. By installing an anhydride group in substrate 105, it is hoped that the intramolecular exchanging process in 105a will lead to the formation of 105b. The subsequent oxidative addition and reductive elimination would then give the desired lactone 105d. Substrate 105 may be prepared from the corresponding monoester. Diastereoselective lactonization to prepare chiral lactones is also envisaged.

105d 105c 105b Metal-Catalyzed Coupling of C-H Bonds with Organometallic Reagents

Palladium catalyzed cross-coupling reaction is a powerful tool in organic synthesis. The remarkable progress of coupling the sp³ alkyl halides with organometallic species has expanded the scope substantially and provided new insights into the cross-coupling reaction. Encouraged by the facile oxazoline directed C-H cleavage process, we propose to explore the palladium-catalyzed coupling of C-H bonds with organometallic reagents.

It is shown herein that an oxazoline group is capable of directing C-H activation via 5-, 6-, 7- and 8- member ring chelation in the iodination reaction. This feature is highly valuable for expanding the substrate scope. Most importantly, one can envisioned the possibility of using a cyclic chiral directing group to achieve diastereoselective C-C bond forming reactions when prochiral C-H bonds are activated.

Surprisingly, the catalytic system to couple C-H bonds with sp³ organotin reagents has not been developed to date despite its great potential in synthesis. Palladium catalyzed Stille coupling of halides with organotin reagents is one of the most commonly used tools in synthesis. However, two major problems need to be addressed in the application of the inventive process to Stille-type reactions: first, Pd(OAc)₂ decomposes the organotin reagents rapidly to form homocoupling side products; second, conditions for reoxidizing the Pd⁰ are not compatible with either the C-H activation step or the transmetalation step. Due to the facile C-H cleavage assisted by the oxazoline directing group, it is envisioned that the first problem can be overcome by adding the tin reagents batch-wise after the completion of C-H cleavage in each cycle to avoid the contact with Pd(OAc)₂. The batch- wise addition can be performed by an automated syringe pump. The optimal interval of the batch- wise addition is determined by the time required for the C-H activation and reoxidation.

DMF and HOAc are the most efficient solvent for the reoxidation of Pd⁰. Unfortunately, DMF inhibits the C-H cleavage and HOAc decomposes the tin reagents. Extensive screening using substrate 112 (shown below) established that the combination of Cu(OAc)₂/ benzoquinone/CH₂Cl2 allows the reoxidation of Pd⁰ and C-H cleavage to occur simultaneously at a rapid rate.

112 112a, 79%

Table 5. Palladium-catalyzed coupling of aryl C-H bonds with sp³ organotin reagents Entry Substrate Methylation product Yield% Entry Product Yield%

Reaction Conditions: Pd(OAc)₂ (10 mol%), organotin reagents (0.75 equiv), Cu(OAc)₂ (1 equiv), benzoquinone (1 equiv), CH₂Cl₂, 100 °C, 50 h. Oxa₂ = 4,4-dimethyl-2- oxazoline.

The ratio of Cu(OAc)₂/benzoquinone was found to be critical. 5-10 mol% of benzoquinone is commonly used in C-H activation reaction, however, we found that Cu(OAc)₂ suppresses C-H activation completely in the presence of 10 mol% of benzoquinone. We hypothesized that the formation of a previously reported cyclic trinuclear mixed metal acetate [Cu₂Pd(OAc)J₆ could render Pd(OAc)₂ unreactive. The use of 1 equiv of benzoquinone to keep Pd(OAc)₂ reactive is critical. In one embodiment, optimized conditions use 10 mol% Pd(OAc)₂, 1 equiv Of Cu(OAc)₂ and benzoquinone. 0.75 Equiv of the tin reagent is added in 10 batches at every 5 h. The substrates prepared for the iodination project were tested and the results are listed in table 5 (above).

Et₄Sn was tested as the coupling partner to investigate whether β-hydride elimination could be a problem; good yields are consistently obtained (Table 5). We believe, with further optimization of the reaction conditions, Pd(OAc)₂ loading can be further reduced. An additional advantage of this coupling reaction is that moisture and air does not affect the reaction.

106 106b, 79%

106c 106d, 34% 106e, 38%

With these newly developed conditions, pyridine directed C-H activation was tested. The coupling of 106 with Me₄Sn proceeds smoothly to give the methylated product 106b in 79% isolated yield (see above). This protocol was also extended to substrate 106c successfully, which demonstrates an additional advantage as the some of the coupling protocols described above are restricted to substrates containing a heteroatom in π- conjugation with the aryl rings. It is further proposed to couple sp³ C-H bonds with organotin reagents. Encouraging results were obtained by stirring oxazoline substrates with stoichiometric amount of Pd(OAc)₂ at 24 °C for 24 h, followed by the addition of 0.8 equiv of tin reagents (Scheme 59a). Interestingly, oxygen from the air was incorporated into product 6f when tetraallyltin is used.

72% (Me₄Sn) 95% (Ph₄Sn) starting products using material : 6a various tin reagents : 6c 6d

91 % [(CH₂=CH)₄Sn] 65% [(CH₂=CHCH₂)₄Sn]

6e 6f Using the catalytic protocol described above, C-H coupling of 6a with Me₄Sn affords only 20-30 % yield. However, by increasing the interval time of adding the tin reagents to 12 h, the yield was raised to 46%. Interestingly, the observed aggregation of Pd⁰ seems to prevent the reoxidation. Therefore it is proposed to run the reaction under microwave irradiation. Automated microwave technology is a very useful tool for high-throughput reaction optimization. The enhancing effect in C-H activation process has recently been reported (Tan, K. L.; Vasudevan, A.; Bergman, R. G.; Ellman, J. A.; Souers, A. J. "Microwave- Assisted C-H Bond Activation: A Rapid Entry into Functionalized Heterocycles" Org. Lett. 2003, 5, 2131-2134). The shortening of the interval time needed for the C-H activation and reoxidation steps by microwave irradiation could also reduce the Pd loading for the coupling reactions using this protocol.

Numerous cyclopropane containing drugs and natural products suggested the investigation of direct coupling of cyclopropyl C-H bonds with organotin reagents (Wurz, R. P.; Charette, A. B. "An Expedient and Practical Method for the Synthesis of a Diverse Series of Cyclopropane α- Amino Acids and Amines" J Org. Chem. 2004, 69, 1262-1269). Exceedingly high diastereoselectivity was observed in the iodination of cyclopropane substrate 35a. It is also observed that the presence of α-hydrogen inhibits C-H cleavage. It is proposed to install PhMe₂Si group as a masked proton or hydroxyl group if needed. It is expected that the bulky silica group at the α-position would accelerate the reaction as steric hindrance is known to facilitate the cyclonietalation process. It is envisaged that stereoselective alkylation or arylation of the cyclopropyl C-H bond to create two chiral centers will provide a short route to various chiral cyclopropane synthons for a wide range of natural products. hi addition, diiodides prepared by the nonchiral oxazoline directed C-H activation described herein can be coupled to organometallic species enantioselectively to give accesses to a wide range of valuable building blocks containing full-carbon quaternary centers (e.g., Gregory Fu recently reported enantioselective coupling using a monobromide; J. Am. Chem. Soc. 2005, 127, 4594).

Further Development of Highly Efficient Directing Groups

Functionalization of Simple Amines. Pyridine directed activation of α-hydrogen adjacent to a nitrogen atom to form C-C bond has been previously achieved with specially designed substrate 139 (Chatani, N.; Asaumi, T.; Yorimitsu, S.; Bceda, T.; Kakiuchi, F.; Murai, S. "Ru₃(CO)₁₂-Catalyzed Coupling Reaction of sp³ C-H Bonds Ajacent to a

Nitrogen Atom in Alkylaniines with Alkenes" J. Am. Chem. Soc. 2001,723, 10935-10941). Recently, pyridine directed acetoxylation of α-hydrogen was also observed with a single substrate 140 (Desai, L. V.; Hull, K. L.; Sanford, M. S. "Palladium-Catalyzed Oxygenation of Unactivated sp³ C-H Bonds" J. Am. Chem. Soc. 2004, 126, 9542-9543; and Dick, A. R.; Hull, K. L.; Sanford, M. S. "A Highly Selective Catalytic Method for the Oxidative Functionalization of C-H Bonds." J. Am. Chem. Soc. 2004, 126, 2300-2301). Progress towards activating cyclic amines without using directing groups has been reported using substrate 141 (Sezen, B.; Sames, D. "Selective and Catalytic Arylation of N- Phenylpyrrolidine: sp³ C-H Bond Functionalization in the Absence of a Directing Group" J Am. Chem. Soc. 2005,127, 5284-5285; and Yi, C. S.; Yun, S. Y. "hitermolecular Coupling Reaction of Cyclic Amines and Alkenes Catalyzed by a Ruthenium-Hydride Complex (PCy₃)₂(CO)RuHCl Organometallics 2004, 23, 5392-5395). Despite these advances, a practical catalytic method to functionalize simple amines, such as methyl amines, under mild conditions has not yet been reported.

139 139a, 50%

140 140a, 70%

141 141a, 40%

Inspired by the amide directed stoichiometric and catalytic palladation reactions of aryl C-H bonds, it was decided to employ the synthetically useful Boc protecting group to direct the activation of sp³ C-H bonds of simple amines. The newly developed iodination protocol is used to screen for reactivity and reaction conditions. It was found that the iodination protocol is an efficient catalytic system for oxidizing the α-methyl group in simple amines to give products 142b and 143a-145a in good yields. The compatibility of this catalytic reaction with the N,O-dimethylhydroxylamine is very useful since the subsequent Zn/HOAc reduction at a later stage would provide the Boc protected primary amines. In addition, methoxylamine groups are frequently encountered structural motifs in alkaloid natural products, such as xestamines.

143a, 65% 144a,40% 145a, 77% Subjecting 142 to Crabtree's or Sanford's acetoxylation conditions led to full recovery of 142. Control experiments showed that no reaction occurred in the absence of the iodine. Quantitative isolation of the PdI₂ after the completion of the reaction indicated the involvement of the iodination pathway as described herein. The identification of the new oxidant generated by the reaction of I₂ and PhI(OAc)₂ is critical for further understanding of this reaction.

The exclusive selectivity for the activation of the methyl versus methylene groups is consistent with a carbonyl directed C-H activation pathway. The synthetic utility of the α- acetoxylated prolines has been previously demonstrated by a variety of transformations in total synthesis (Moeller, K. D. "Synthetic Applications of Anodic Electrochemistry"

Tetrahedron 2000, 56, 9527-9554; Barrett, A. G. M. "Electrochemical Oxidation of Proline Derivatives: Total Sytheses of Bulgecinine and Bulgecin C" J. Org. Chem. 1991, 56, 2787- 2800; Oba, M.; Koguchi, S.; Nishiyama, K. "Asymmetric Synthesis of 3,4- Dihydroxyglutamic Acids via Enantioselective Reduction of Cyclic meso-lmide" Tetrahedron 2004, 60, 8089-8092; and Hanessian, S.; Tremblay, M.; Petersen, J. F. W. "The N-Acyloxyiminium Ion Aza-Prins Route to Octahydroindoles: Total Synhtesis and Structural Confirmation of the Antithrombotic Marine Natural Product Oscillarin" J. Am. Chem. Soc. 2004, 126, 6064-6071).

The acetoxylated amines are versatile synthons for further elaborations. Treating 145a with trimethylallylsilane affords protected homoallylic amine 145b in 90% yield. Valuable nitrogen containing building blocks ranging from elongated amines (145b-d) to the α-amino acid derivative 145e can be easily accessed. The MeO groups in 145b-e can be removed by treating with Zn/HOAc to give the protected primary amine. A novel combination of C-H activation and metathesis to prepare cyclic amine 145i from simple dimethylamine 145f is also proposed. Double bond containing and cyclic amines are important building blocks that are broadly used in alkaloid syntheses.

Bo

1. SnBr₄ 1. BF₃-Et₂O H Me₃SiCN CH₂CI₂ BocN, ,R

145a + ^R\₌ toluene BocN. ,CN

145a

2. Zn/HOAc 145d B I r ^™" 2. Zn/HOAc _145e

„ _R ' \ ^B0

^BθcNvVπ

145f 145g 145h 145i

Encouraged by the initial findings, it is proposed to functionalize the methyl amine

146 to afford protected primary amine 146a. It is also proposed to couple α-C-H bonds with organotin reagents to prepare elongated amines 146b. Previous work has shown that an N-H bond is compatible with the Pd(OAc)₂ catalyzed activation of aryl C-H bonds (Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. "Oxidative C-H Activation/C-C Bond Forming Reactions: Synthetic Scope and Mechanistic Insights" J. Am. Chem. Soc. 2005, 127, 7330- 7331; Dagulis, O.; Zaitsev, V. G. "Anilide ortho- Arylation by Using C-H Activation Methodology" Angew. Chem. Int. Ed. 2005, 44, 4046-4048).

146 146a 146 146b

It is further proposed to activate methylene groups adjacent to the nitrogen atoms. Activation of protected L-proline 147 will be tested initially to establish the conditions. L- proline 147b has been used to synthesize natural products from the indolizidine alkaloid family (Moeller, K. D. "Synthetic Applications of Anodic Electrochemistry" Tetrahedron 2000, 56, 9527-9554; Barrett, A. G. M. "Electrochemical Oxidation of Proline Derivatives: Total Sytheses of Bulgecinine and Bulgecin C" J. Org. Chem. 1991, 56, 2787-2800; Oba, M.; Koguchi, S.; Nishiyama, K. "Asymmetric Synthesis of 3,4-Dihydroxyglutamic Acids via Enantioselective Reduction of Cyclic røesø-Imide" Tetrahedron 2004, 60, 8089-8092; and Hanessian, S.; Tremblay, M.; Petersen, J. F. W. "The N-Acyloxyiminium Ion Aza-Prins Route to Octahydroindoles: Total Synhtesis and Structural Confirmation of the Antithrombotic Marine Natural Product Oscillarin" J. Am. Chem. Soc. 2004, 126, 6064- 6071). CXc_O2Me -^l- ^P-^h'-⁽⁰-^A?⁾A. AcO-^-CO₂Me -f-t-L-. ^, CO₂Me ¹^ ² Pd(OAc)₂ 7 BF₃-Et₂O *t f-Boc t-Boc t-Boc

147 147a 147b key intermediate for indolizidine family

Further Development of Catalytic Enantioselective C-H Activation Reactions

One of the most significant goals in the field of σ-chelation directed C-H activation is to achieve stereoselective C-H activation using nonchiral directing groups. The combination of a nonchiral σ-chelating group and a catalytic amount of external chiral ligand is a powerful approach in asymmetric catalysis. For example, the presence of a σ- chelating group is often required for obtaining high ee in asymmetric hydrogenation (Lei, A.; Wu, S.; He, M.; Zhang, X. "Hihgly Enantioselective Asymmetirc Hydrogenation of α- Phthalimide Ketone: An Efficient Entry to Eantiomerically Pure Amino Alcohols" J. Am. Chem. Soc. 2004, 126, 1626-1627). One aspect of the invention is directed at identifying a chiral ligand to achieve enantioselective C-H functionarization using nonchiral oxazoline substrate 148.

functionalization

It was also decided to explore a different approach. It had been observed that the μ- carboxylate in the Pd-alklyl complex 6b exchanges rapidly with external carboxylate anhydrides. The observed reactivity provides a convenient method to incorporate a chiral carboxylate into Pd-alkyl complexes.

The chiral complexes can be readily prepared by stirring oxazoline substrate 148 with 1 equiv. OfPd(OAc)₂ and 10 equiv of chiral carboxylic anhydrides in CH₂Cl₂. Removal of the solvents affords crystalline chiral trinuclear Pd-alkyl complex 148c in 50- 70% yields (The structures of 148c are similar to 6b). Since the chiral carboxylate bridge may not remain intact during the oxidation reaction, initial use chiral PhI(OOCR*) as the oxidant might maintain the μ-bridge chiral. Chiral PhI(OOCR*) can be readily prepared by refluxing PhI(OAc)₂ with chiral carboxylic acids in benzene (Stang, P. J.; Boehshar, M.; Wingert, H.; Kitamura, T. "Acetylenic Esters. Preparation and Characterization of Alkynyl Carboxylates via Polyvalent Iodonium Species" J. Am. Chem. Soc. 1988, 110, 3272-3278). Alternatively, a chiral carboxylate that will bind strongly to the Pd center would maintain the chiral environment.

X = R*COO or I

Compounds of the Invention

One aspect of the present invention relates to a compound represented by formula I:

I wherein

R¹ and R² each independently are selected from the group consisting of hydrogen, alkyl, haloalkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, -OR, and -NR₂; R is independently selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, and heteroaryl;

R¹ and R² may be connected by a covalent tether, said covalent tether comprising 3, 4, 5, or 6 backbone atoms;

B is selected from the group consisting of -CI(R⁷)₂, - CBr(R⁷)₂, - CC1(R⁷)₂, -CHO, -C(R⁷)₂OC(O)R⁷, and C(R⁷)₃;

R is independently selected from the group consisting of hydrogen, halogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, and heteroaryl; A is selected from the group consisting of

any two instances of R⁸ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl;

X is selected from the group consisting of O, S, and NR⁹;

R⁹ is independently selected from the group consisting of hydrogen,' alkyl, alkenyl, alkynyl, and aryl;

R³, R⁴, R⁵, R⁶ each independently are selected from the group consisting of hydrogen, alkyl, aryl, alkenyl, and alkynyl;

R³ and R⁴ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; R⁵ and R⁶ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

R⁴ and R⁶ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

R³ and R⁵ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; and the stereochemical configuration at any stereocenter of a compound represented by I is R, S, or a mixture of these configurations.

In certain embodiments, the compounds of the present invention are represented by formula I, wherein R¹ and R² each independently are selected from the group consisting of hydrogen, alkyl, heteroalkyl, -OR, and -NR₂. In certain embodiments, the compounds of the present invention are represented by formula I, wherein R¹ and R² each independently are selected from the group consisting of hydrogen and alkyl. hi certain embodiments, the compounds of the present invention are represented by formula I, wherein B is selected from the group consisting of -CH₂I, -CH₂OC(O)R⁷ and - CH₃. hi certain embodiments, the compounds of the present invention are represented by formula I, wherein B is selected from the group consisting of -CH₂I, and -CH₂OC(O)R⁷; and R⁷ is alkyl or aryl. In certain embodiments, the compounds of the present invention are represented by

formula I, wherein A is selected from the group consisting of R⁶ ,

R⁶ R^{5 R} and -C(O)OR⁸; and X is O or S.

In certain embodiments, the compounds of the present invention are represented by

formula I, wherein A is selected from the group consisting of

R⁶ and -C(O)OH; X is O; R³, R⁴ and R⁵ are hydrogen; and R⁶ is alkyl or aryl.

In certain embodiments, the compounds of the present invention are represented by

formula I, wherein A is selected from the group consisting of R X⁶ R?⁵ R⁴ and -C(O)OH;

X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are hydrogen, alkyl or aryl.

In certain embodiments, the compounds of the present invention are represented by

butyl. In certain embodiments, the compounds of the present invention are represented by

formula I, wherein A is selected from the group consisting

and -C(O)OH;

X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl.

In certain embodiments, the compounds of the present invention are represented by formula I, wherein R¹ and R² each independently are selected from the group consisting of hydrogen, alkyl, heteroalkyl, -OR, and -NR₂; and B is selected from the group consisting of -CH₂I, -CH₂OC(O)R⁷ and -CH₃.

In certain embodiments, the compounds of the present invention are represented by formula I, wherein B is selected from the group consisting Of -CH₂I, -CH₂OC(O)R⁷ and -

CH₃; and A is selected from the group consisting of R⁶ , -

C(O)OH; X is O; R³, R⁴ and R⁵ are hydrogen; and R⁶ is alkyl or aryl. hi certain embodiments, the compounds of the present invention are represented by formula I, wherein R¹ and R² each independently are selected from the group consisting of hydrogen, alkyl, heteroalkyl, -OR, and -NR₂; and A is selected from the group consisting of

-C(O)OH; X is O; R³, R⁴ and R⁵ are hydrogen; and R⁶ is alkyl or aryl. In certain embodiments, the compounds of the present invention are represented by formula I, wherein R¹ and R² each independently are selected from the group consisting of hydrogen, alkyl, heteroalkyl, -OR, and -NR₂; and A is selected from the group consisting of

and -C(O)OH; X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are hydrogen, alkyl or aryl.

In certain embodiments, the compounds of the present invention are represented by formula I, wherein R¹ and R² each independently are selected from the group consisting of hydrogen and alkyl; and B is selected from the group consisting Of -CH₂I, -CH₂OC(O)R⁷; and R⁷ is alkyl or aryl.

In certain embodiments, the compounds of the present invention are represented by formula I, wherein B is selected from the group consisting Of-CH₂I, -CH₂OC(O)R⁷; R⁷ is

alkyl or aryl; and A is

X is O; R³, R⁴ and R⁵ are hydrogen; and R⁶ is tert- butyl.

In certain embodiments, the compounds of the present invention are represented by formula I, wherein R¹ and R² each independently are selected from the group consisting of

hydrogen and alkyl; and A is

R⁴ and R⁵ are hydrogen; and R⁶ is tert-butyl.

In certain embodiments, the compounds of the present invention are represented by formula I, wherein R¹ and R² each independently are selected from the group consisting of hydrogen and alkyl; B is selected from the group consisting Of -CH₂I, -CH₂OC(O)R⁷; R⁷ is

alkyl or aryl; and A is

O; R₃, R₄ and R₅ are hydrogen; and R₆ is tert- butyl.

In certain embodiments, the compounds of the present invention are represented by formula I, wherein B is selected from the group consisting Of -CH₂I, -CH₂OC(O)R⁷; R⁷ is

O

alkyl or aryl; and A is R⁶ R⁵ ; X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl. In certain embodiments, the compounds of the present invention are represented by formula I, wherein R¹ and R² each independently are selected from the group consisting of hydrogen and alkyl; and A is

X is O; R and R are

R T) 5 a _rtwnd J R τ> 6 are methyl.

In certain embodiments, the compounds of the present invention are represented by formula I, wherein R¹ and R² each independently are selected from the group consisting of hydrogen and alkyl; B is selected from the group consisting of -CH₂I, -CH₂OC(O)R⁷; R⁷ is

alkyl or aryl; and A is

X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl.

In certain embodiments, the compounds of the present invention are represented by formula I, wherein the compound has an ee of greater than or equal to 50%. In certain embodiments, the compounds of the present invention are represented by formula I, wherein the compound has an ee of greater than or equal to 70%. hi certain embodiments, the compounds of the present invention are represented by formula I, wherein the compound has an ee of greater than or equal to 80%. hi certain embodiments, the compounds of the present invention are represented by formula I, wherein the compound has an ee of greater than or equal to 90%. hi certain embodiments, the compounds of the present invention are represented by formula I, wherein the compound has an ee of greater than or equal to 95%.

Another aspect of the present invention relates to a compound represented by formula II:

II wherein

R and R each independently are selected from the group consisting of hydrogen, alkyl, haloalkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, -OR₃ and -NR₂; R is independently selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, and heteroaryl; R¹ and R² may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

B is selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl -OR⁷, and -N(R⁷)₂; R⁷ is independently selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, and heteroaryl;

R¹ and B may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

C is selected from the group consisting of -I, -Br, -Cl, -OC(O)R⁸, -OR⁸, alkenyl, alkynyl, and aryl;

R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl;

A is selected from the group consisting of R⁶ ,

R⁹ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl; any two instances of R⁹ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; X is selected from the group consisting of O, S, and NR¹⁰;

R¹⁰ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl;

R³, R⁴, R⁵, R⁶ each independently are selected from the group consisting of hydrogen, alkyl, aryl, alkenyl, and alkynyl; R R³³ a anndd R R⁴⁴ m maayy b bee c coonnnneecctteedd b byy a a c ccovalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; R⁵ and R⁶ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

R⁴ and R⁶ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; R³ and R⁵ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; and the stereochemical configuration at any stereocenter of a compound represented by II is R, S, or a mixture of these configurations. hi certain embodiments, the compounds of the present invention are represented by formula II, wherein B is selected from the group consisting of hydrogen, alkyl, -OR⁷, and -N(R⁷)₂.

In certain embodiments, the compounds of the present invention are represented by formula II, wherein B is selected from the group consisting of hydrogen and alkyl.

In certain embodiments, the compounds of the present invention are represented by formula II, wherein C is selected from the group consisting of -I, -OC(O)R⁸, alkenyl, alkynyl, and aryl.

In certain embodiments, the compounds of the present invention are represented by formula II, wherein C is selected from the group consisting of -I and -OC(O)CH₃. hi certain embodiments, the compounds of the present invention are represented by

formula II, wherein A is selected from the group consisting of

R⁶

and -C(O)OR⁹; and X is selected from the group consisting of O and S. Li certain embodiments, the compounds of the present invention are represented by

formula II, wherein A is selected from the group

X is O; R³, R⁴ and R⁵ are hydrogen; and R⁶ is tert-butyl. In certain embodiments, the compounds of the present invention are represented by

formula II, wherein A is selected from the group consisting of R⁶ R⁵ and -C(O)OH; X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl. hi certain embodiments, the compounds of the present invention are represented by formula II, wherein B is selected from the group consisting of hydrogen, alkyl, -OR⁷, and -N(R⁷)₂; and C is selected from the group consisting of -I, -OC(O)R⁸, alkenyl, alkynyl, and aryl. hi certain embodiments, the compounds of the present invention are represented by formula II, wherein C is selected from the group consisting of -I, -OC(O)R , alkenyl,

alkynyl, and aryl; A is selected from the group consisting of R⁶ , R⁶ R⁵ , and -C(O)OR⁹; and X is selected from the group consisting of O and S. hi certain embodiments, the compounds of the present invention are represented by

formula II, wherein A is selected from the group consisting

and -C(O)OR⁹; X is selected from the group consisting of O and S; and B is selected from the group consisting of hydrogen, alkyl, -OR⁷, and -N(R⁷)₂.

In certain embodiments, the compounds of the present invention are represented by

formula II, wherein A is selected from the group consisting

and -C(O)OR⁹; X is selected from the group consisting of O and S; B is selected from the group consisting of hydrogen, alkyl, -OR , and -N(R )₂; and C is selected from the group consisting of -I, -OC(O)R⁸, alkenyl, alkynyl, and aryl.

In certain embodiments, the compounds of the present invention are represented by formula II, wherein B is selected from the group consisting of hydrogen and alkyl; and C is selected from the group consisting of -I and -OC(O)CH₃.

In certain embodiments, the compounds of the present invention are represented by formula II, wherein C is selected from the group consisting of -I and -OC(O)CH₃; A is

selected from the group consisting of

and -C(O)OH; X is O; R³, R⁴ and R⁵ are hydrogen; and R⁶ is tert-butyl. In certain embodiments, the compounds of the present invention are represented by formula II, wherein C is selected from the group consisting of -I and -OC(O)CH₃; A is

selected from the group consisting of R⁶ R⁵ and -C(O)OH; X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl.

In certain embodiments, the compounds of the present invention are represented by

formula II, wherein A is selected from the group consisting of R⁶ and -C(O)OH;

X is O; R³, R⁴ and R⁵ are hydrogen; R⁶ is tert-butyl; and B is selected from the group consisting of hydrogen and alkyl. hi certain embodiments, the compounds of the present invention are represented by formula II, wherein C is selected from the group consisting of -I and -OC(O)CH₃; A is

selected from the group

and -C(O)OH; X is O; R³ and R⁴ are hydrogen; R⁵ and R⁶ are methyl; and B is selected from the group consisting of hydrogen and alkyl. In certain embodiments, the compounds of the present invention are represented by

formula II, wherein A is selected from the group

X is O; R³, R⁴ and R⁵ are hydrogen; R⁶ is tert-butyl; B is selected from the group consisting of hydrogen and alkyl; and C is selected from the group consisting of -I and -OC(O)CH₃. In certain embodiments, the compounds of the present invention are represented by formula II, wherein C is selected from the group consisting of -I and -OC(O)CH₃; A is

selected from the group consisting of R⁶ R⁵ and -C(O)OH; X is O; R³ and R⁴ are hydrogen; R⁵ and R⁶ are methyl; B is selected from the group consisting of hydrogen and alkyl; and C is selected from the group consisting of -I and -OC(O)CH₃. In certain embodiments, the compounds of the present invention are represented by formula II, wherein the compound has an ee of greater than or equal to 50%.

In certain embodiments, the compounds of the present invention are represented by formula II, wherein the compound has an ee of greater than or equal to 70%.

In certain embodiments, the compounds of the present invention are represented by formula II, wherein the compound has an ee of greater than or equal to 80%. hi certain embodiments, the compounds of the present invention are represented by formula II, wherein the compound has an ee of greater than or equal to 90%. hi certain embodiments, the compounds of the present invention are represented by formula II, wherein the compound has an ee of greater than or equal to 95%. Another aspect of the present invention relates to a compound represented by formula III:

R¹ is selected from the group consisting of hydrogen, alkyl, haloalkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, -OR, and -NR₂;

R² each independently are selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, hydroxyl, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, fluoroalkyl and cyano.

R is independently selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, and heteroaryl;

R¹ and R² may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; any two instances of R² may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5,or 6 backbone atoms;

B is selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl -OR⁷, and -N(R⁷)₂; R⁷ is independently selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, and heteroaryl;

R¹ and B may be connected by a covalent tether;

C is selected from the group consisting of -I, -Br, -Cl, -OC(O)R⁸, -OR⁸, alkenyl, alkynyl, and aryl; R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl;

A is selected from the group

R⁹ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl; any two instances of R⁹ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

X is selected from the group consisting of O, S, and NR¹⁰;

R¹⁰ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl;

R³, R⁴, R⁵, R⁶ each independently are selected from the group consisting of hydrogen, alkyl, aryl, alkenyl, and alkynyl;

R³ and R⁴ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; R⁵ and R⁶ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

R⁴ and R⁶ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

R³ and R⁵ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; and the stereochemical configuration at any stereocenter of a compound represented by III is R, S, or a mixture of these configurations.

In certain embodiments, the compounds of the present invention are represented by formula III, wherein R¹ is selected from the group consisting of hydrogen, alkyl, -OR, and - NR₂; and B is selected from the group consisting of hydrogen, alkyl, -OR, and -NR₂.

In certain embodiments, the compounds of the present invention are represented by formula III, wherein R¹ is selected from the group consisting of hydrogen and alkyl; and B is selected from the group consisting of hydrogen and alkyl.

In certain embodiments, the compounds of the present invention are represented by formula III, wherein C is selected from the group consisting of -I and -OC(O)R⁸.

In certain embodiments, the compounds of the present invention are represented by formula III, wherein C is selected from the group consisting of -I and -OC(O)CH₃. In certain embodiments, the compounds of the present invention are represented by

formula III, wherein A is selected from the group consisting of R⁶ ,

R⁶ R⁵ _* , and -C(O)OR⁹; and X is selected from the group consisting of O and S. In certain embodiments, the compounds of the present invention are represented by

formula III, wherein A is selected from the group

, and -

C(O)OH; X is O; R³, R⁴ and R⁵ are hydrogen; and R⁶ is tert-butyl.

In certain embodiments, the compounds of the present invention are represented by

formula III, wherein A is selected from the group

, and - C(O)OH; X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl. hi certain embodiments, the compounds of the present invention are represented by formula III, wherein R¹ is selected from the group consisting of hydrogen, alkyl, -OR, and - NR₂; B is selected from the group consisting of hydrogen, alkyl, -OR, and -NR₂; and C is selected from the group consisting of -I and -OC(O)R . hi certain embodiments, the compounds of the present invention are represented by formula III, wherein C is selected from the group consisting of -I and -OC(O)R⁸; A is

selected from the group consisting and -C(O)OR⁹; and X is selected from the group consisting of O and S. hi certain embodiments, the compounds of the present invention are represented by

formula III, wherein A is selected from the group consisting of

,

-C(O)OR⁹; X is selected from the group consisting of O and S; R¹ is selected from the group consisting of hydrogen, alkyl, -OR, and -NR₂; and B is selected from the group consisting of hydrogen, alkyl, -OR, and -NR₂.

In certain embodiments, the compounds of the present invention are represented by

formula III, wherein A is selected from the group consisting of R⁶ ,

and -C(O)OR⁹; X is selected from the group consisting of O and S; R¹ is selected from the group consisting of hydrogen, alkyl, -OR, and -NR₂; B is selected from the group consisting of hydrogen, alkyl, -OR, and -NR₂; and C is selected from the group consisting of -I and -OC(O)R⁸. In certain embodiments, the compounds of the present invention are represented by formula III, wherein R¹ is selected from the group consisting of hydrogen and alkyl; B is selected from the group consisting of hydrogen and alkyl; and C is selected from the group consisting of -I and -OC(O)CH₃. hi certain embodiments, the compounds of the present invention are represented by formula III, wherein C is selected from the group consisting of -I and -OC(O)CH₃; A is

selected from the

X is O; R³, R⁴ and R⁵ are hydrogen; and R⁶ is tert-butyl.

In certain embodiments, the compounds of the present invention are represented by formula III, wherein C is selected from the group consisting of -I and -OC(O)CH₃; A is

selected from the group

and -C(O)OH; X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl. In certain embodiments, the compounds of the present invention are represented by

formula III, wherein A is selected from the group consisting of

and -

C(O)OH; X is O; R³, R⁴ and R⁵ are hydrogen; R⁶ is tert-butyl; and R¹ is selected from the group consisting of hydrogen and alkyl; and B is selected from the group consisting of hydrogen and alkyl.

In certain embodiments, the compounds of the present invention are represented by

formula III, wherein A is selected from the group

and - C(O)OH; X is O; R³ and R⁴ are hydrogen; R⁵ and R⁶ are methyl; and R¹ is selected from the group consisting of hydrogen and alkyl; and B is selected from the group consisting of hydrogen and alkyl.

In certain embodiments, the compounds of the present invention are represented by

formula III, wherein A is selected from the group consisting of R⁶ and -

C(O)OH; X is O; R³, R⁴ and R⁵ are hydrogen; R⁶ is tert-butyl; and R¹ is selected from the group consisting of hydrogen and alkyl; B is selected from the group consisting of hydrogen and alkyl; and C is selected from the group consisting of -I and -OC(O)CH₃.

In certain embodiments, the compounds of the present invention are represented by

formula III, wherein A is selected from the group

and - C(O)OH; X is O; R³ and R⁴ are hydrogen; R⁵ and R⁶ are methyl; and R¹ is selected from the group consisting of hydrogen and alkyl; B is selected from the group consisting of hydrogen and alkyl; and C is selected from the group consisting of -I and -OC(O)CH₃.

In certain embodiments, the compounds of the present invention are represented by formula III, wherein the compound has an ee of greater than or equal to 50%.

In certain embodiments, the compounds of the present invention are represented by formula III, wherein the compound has an ee of greater than or equal to 70%. In certain embodiments, the compounds of the present invention are represented by formula III, wherein the compound has an ee of greater than or equal to 80%. hi certain embodiments, the compounds of the present invention are represented by formula III, wherein the compound has an ee of greater than or equal to 90%. In certain embodiments, the compounds of the present invention are represented by formula III, wherein the compound has an ee of greater than or equal to 95%. Methods of the Invention

In one aspect of the present invention there is provided a process for stereoselectively producing compounds with at least one stereogenic center from prochiral starting materials. An advantage of this invention is that enantiomerically enriched products can be synthesized from prochiral reactants. hi general, the invention features the functionalization of an unactivated C-H bond which comprises the appending of a chiral auxiliary of particular characteristics to a compound to form a substrate, combining said substrate with a reoxidizing source of particular characteristics, as well as at least a catalytic amount of a transition metal complex of particular characteristics, as discussed below. This combination is maintained under conditions appropriate for the catalyst to catalyze auxiliary-directed stereoselective C-H bond functionalization of the substrate by transition-metal-catalyzed hydride abstraction. This reaction can be applied to enantioselective processes as well as diasteroselective processes. It can also be applied to regioselective reactions.

A process of this invention can provide optically active products with very high stereoselective {e.g., enantioselectivity or diasteroselectivity) or regioselectivity. hi preferred embodiments of the subject C-H bond functionalization, products with enantiomeric excess of greater than about 50%, greater than about 70%, greater than about 90% and most preferably greater than about 95% can be obtained. The processes of this invention can also be carried out under reaction conditions suitable for commercial use, and typically proceed at reaction rates suitable for large scale operations.

As is clear from the following discussion, the chiral products produced by an asymmetric synthesis process of this invention can undergo further reaction(s) to afford desired derivative thereof. Such permissible derivatization reactions can be carried out in accordance with conventional procedures known in the art. For example, potential derivatization reactions include hydroylsis, transition-metal-catalyzed carbon-carbon bond- forming reactions, and the like. This invention expressly contemplates the preparation of end-products and synthetic intermediates which are useful for the preparation or development or both of cardiovascular drugs, non-steroidal anti-inflammatory drugs, central nervous system agents, and antihistaminics.

One aspect of the present invention relates to a method of catalytically oxidizing a compound, comprising the step of combining said compound with a transition metal, a ligand, and an oxidant, to form a chiral non-racemic product, wherein said compound is selected from the group represented by compounds of formula IV and V:

IV V wherein

R¹ is selected from the group consisting of hydrogen, alkyl, haloalkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, -OR, and -NR₂;

R each independently are selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, -OR, and -NR₂; R is independently selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, and heteroaryl;

R¹ and R² may be connected by a covalent tether, said covalent tether comprising 2, 3, 4, 5, 6 or 7 backbone atoms; the two instances of R may be connected by a covalent tether, said covalent tether comprising 2, 3, 4, 5, 6 or 7 backbone atoms;

X is selected from the group consisting of O, S, and NR⁹;

R⁹ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl;

R³, R⁴, R⁵, R⁶ each independently are selected from the group consisting of hydrogen, alkyl, aryl, alkenyl, and alkynyl;

R³ and R⁴ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

R³ and R⁴ and the carbon to which they are bound may be C(=O); R⁵ and R⁶ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; R⁴ and R⁶ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

R³ and R⁵ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; and the stereochemical configuration at any stereocenter of a compound represented by

IV or V is R, S, or a mixture of these configurations.

In certain embodiments, the present invention relates to the aforementioned method, wherein said transition metal is selected from the group consisting of palladium, platinum, or nickel. hi certain embodiments, the present invention relates to the aforementioned method, wherein said transition metal is palladium. hi certain embodiments, the present invention relates to the aforementioned method, wherein said ligand is acyloxy. hi certain embodiments, the present invention relates to the aforementioned method, wherein said ligand is acetate. hi certain embodiments, the present invention relates to the aforementioned method, wherein said oxidant is MeC(=O)tBu, PhC(=O)OOtBu, [PhC(=O)]₂O₂, [CH₃(CH₂)₁₀C(=O)]₂O₂, tBuOOtBu, and tBuOOH, copper(I) acetate, copper(IT) acetate, silver acetate, phenyl iodoacetate or iodine. hi certain embodiments, the present invention relates to the aforementioned method, wherein said oxidant is [PhC(^:=O)]₂O₂, [CH₃(CH₂)₁₀C(^:=O)]₂O_2> phenyl iodoacetate or iodine. hi certain embodiments, the present invention relates to the aforementioned method, wherein said transition metal is selected from the group consisting of palladium, platinum, and nickel; said ligand is acyloxy; and said oxidant is MeC(=O)tBu, PhC(=O)OOtBu, [PhC(=O)]₂O₂, [CH₃(CH₂)₁₀C(=O)]₂O₂, tBuOOtBu, and tBuOOH, copper(I) acetate, copper(II) acetate, silver acetate, phenyl iodoacetate or iodine. hi certain embodiments, the present invention relates to the aforementioned method, wherein said transition metal is palladium; said ligand is acetate; and said oxidant is [PhC(=O)]₂O₂, [CH₃(CH₂)₁₀C(=O)]₂O₂, phenyl iodoacetate or iodine.

In certain embodiments, the present invention relates to any of the aforementioned methods, wherein X is O. In certain embodiments, the present invention relates to any of the aforementioned methods, wherein X is O; and R¹ is alkyl.

In certain embodiments, the present invention relates to any of the aforementioned methods, wherein X is O; and R¹ is methyl. In certain embodiments, the present invention relates to any of the aforementioned methods, wherein X is O; R² is alkyl; and the two instances of R² are connected by a covalent tether of 2 atoms.

In certain embodiments, the present invention relates to any of the aforementioned methods, wherein X is O; and R¹ is aryl. In certain embodiments, the present invention relates to any of the aforementioned methods, wherein X is O; and R¹ is phenyl. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein the chiral non-racemic product has an enantiomeric excess greater than about 50%. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein the chiral non-racemic product has an enantiomeric excess greater than about 70%. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein the chiral non-racemic product has an enantiomeric excess greater than about 80%. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein the chiral non-racemic product has an enantiomeric excess greater than about 90%.

In certain embodiments, the present invention relates to any of the aforementioned methods, wherein the chiral non-racemic product has an enantiomeric excess greater than about 95%.

In certain embodiments, the present invention relates to any of the aforementioned methods, wherein the reaction is preformed in a sealed flask. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula IV.

In certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula IV; X is O; and R³, R⁴, and R⁵ are hydrogen. In certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula IV; X is O; R³, R⁴, and R⁵ are hydrogen; and R⁶ is alkyl. ha certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula IV; X is O; R³, R⁴, and R⁵ are hydrogen; and R⁶ is t-butyl. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula IV; X is O; R¹ is alkyl; and R³, R⁴, and R⁵ are hydrogen. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula IV; X is O; R¹ is alkyl; R³, R⁴, and R⁵ are hydrogen; and R⁶ is alkyl. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula IV; X is O; R¹ is alkyl; R³, R⁴, and R⁵ are hydrogen; and R⁶ is t-butyl. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula IV; X is O; R¹ is methyl; and R³, R⁴, and R⁵ are hydrogen. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula IV; X is O; R¹ is methyl; R³, R⁴, and R⁵ are hydrogen; and R⁶ is alkyl. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula IV; X is O; R¹ is methyl; R³, R⁴, and R⁵ are hydrogen; and R⁶ is t-butyl. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula IV; X is O; R² is alkyl; the two instances of R² are connected by a covalent tether of 2 atoms; and R³, R⁴, and R⁵ are hydrogen. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula IV; X is O; R² is alkyl; the two instances of R² are connected by a covalent tether of 2 atoms; R³, R⁴, and R⁵ are hydrogen; and R⁶ is t-butyl. In certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula IV; X is O; R¹ is aryl; and R³, R⁴, and R⁵ are hydrogen.

Ih certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula IV; X is O; R¹ is aryl; R³, R⁴, and R⁵ are hydrogen; and R⁶ is alkyl.

In certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula IV; X is O; R¹ is aryl; R³, R⁴, and R⁵ are hydrogen; and R⁶ is t-butyl. In certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula V.

In certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula V; X is O; and R³ and R⁵ are hydrogen. In certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula V; X is O; R³ and R⁴ are hydrogen.

In certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula V; X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula V; X is O; R¹ is alkyl; R³ and R⁵ are hydrogen.

In certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula V; X is O; R¹ is methyl; and R³ and R⁴ are hydrogen.

In certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula V; X is O; R¹ is methyl; R³ and R⁵ are hydrogen. In certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula V; X is O; R¹ is methyl; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl. In certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula V; X is O; R² is alkyl; the two instances of R² are connected by a covalent tether of 2 atoms; and R³ and R⁵ are hydrogen. In certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula V; X is O; R is

O ¹X A alkyl; the two instances of R are connected by a covalent tether of 2 atoms; R and R are hydrogen.

In certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula V; X is O; R² is alkyl; the two instances of R² are connected by a covalent tether of 2 atoms; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl.

In certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula V; X is O; R¹ is aryl; and R³ and R⁵ are hydrogen. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula V; X is O; R¹ is aryl; R³ and R⁴ are hydrogen. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein said compound is represented by compounds of formula V; X is O; R¹ is aryl; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl.

Another aspect of the present invention relates to a method of catalytically oxidizing a compound, comprising the step of combining said compound with a transition metal, a ligand, and an oxidant, to form a chiral non-racemic product, wherein said compound is represented by formula VI:

VI wherein,

R¹ is selected from the group consisting of hydrogen, alkyl, haloalkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, -OR, and -NR₂; R² each independently are selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, -OR, and -NR₂;

R is independently selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, and heteroaryl; R¹ and R² may be connected by a covalent tether, said covalent tether comprising 2,

3, 4, 5, 6 or 7 backbone atoms; the two instances of R² may be connected by a covalent tether, said covalent tether comprising 2, 3, 4, 5, 6 or 7 backbone atoms;

R³ each independently are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl; the two instances of R³ may be connected by a covalent tether, said covalent tether comprising 2, 3, 4, 5, 6 or 7 backbone atoms; the stereochemical configuration at any stereocenter of a compound represented by VI is R, S, or a mixture of these configurations. hi certain embodiments, the present invention relates to the aforementioned method, wherein R¹, R², and R³ are restricted as previously presented. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein the reaction is preformed in a sealed flask.

Yet another aspect of the present invention relates to a method of catalytically oxidizing a compound, comprising the step of combining said compound with a transition metal, a ligand, and an oxidant, to form a chiral non-racemic product, wherein said compound is represented by formula VII:

VII wherein,

R¹ is selected from the group consisting of hydrogen, alkyl, haloalkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, -OR, and -NR₂;

R² each independently are selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, -OR, and -NR₂; R is independently selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, and heteroaryl;

R¹ and R² may be connected by a covalent tether, said covalent tether comprising 2, 3, 4, 5, 6 or 7 backbone atoms; the two instances of R may be connected by a covalent tether, said covalent tether comprising 2, 3, 4, 5, 6 or 7 backbone atoms;

R³ each independently are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl; the two instances of R³ may be connected by a covalent tether, said covalent tether comprising 2, 3, 4, 5, 6 or 7 backbone atoms; the stereochemical configuration at any stereocenter of a compound represented by VII is R, S, or a mixture of these configurations.

In certain embodiments, the present invention relates to the aforementioned method, wherein R¹, R², and R³ are restricted as previously presented. In certain embodiments, the present invention relates to any of the aforementioned methods, wherein the reaction is preformed in a sealed flask.

Yet another aspect of the present invention relates to a method of catalytically oxidizing a compound, comprising the step of combining said compound with a transition metal, a ligand, and an oxidant, to form a chiral non-racemic product, wherein said compound is represented by formula VIII:

VIII wherein,

R¹ is selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, -OR, and -NR₂;

R² each independently are selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, -OR, and -NR₂;

R³ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl; R⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl;

R is independently selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, and heteroaryl;

1 ¹J R and R may be connected by a covalent tether, said covalent tether comprising 2,

3, 4, 5, 6 or 7 backbone atoms;

R³ and R⁸ may be connected by a covalent tether, said covalent tether comprising 2, 3, 4, 5, 6 or 7 backbone atoms; the two instances of R² may be connected by a covalent tether, said covalent tether comprising 2, 3, 4, 5, 6 or 7 backbone atoms; the stereochemical configuration at any stereocenter of a compound represented by VII is R, S, or a mixture of these configurations. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein X is O. In certain embodiments, the present invention relates to any of the aforementioned methods, wherein X is O; and R is hydrogen. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein X is O; R is hydrogen; and R is alkyl. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein X is O; R³ is hydrogen; and R⁸ is t-butyl.

In certain embodiments, the present invention relates to the aforementioned method, wherein R¹, R², R³ and R⁸ are restricted as previously presented. hi certain embodiments, the present invention relates to any of the aforementioned methods, wherein the reaction is preformed in a sealed flask.

Exemplification

The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention. Example 1

Carboxylic acids for oxazolines 8a, 9a and 11a were prepared by methylation of 2- ethylbutyric acid, cyclopentanecarboxylic acid and cycloheptanecarboxylic acid, respectively. See Shinkai, H.; Maeda, K.; Yamasaki, T.; Okamoto, H.; Uchida, I. J. Med. Chem. 2000, 43, 3566. In case of 12a and 13a, a mixture of cis- and trans-A-tert- butylcyclohexanecarboxylic acids was first methylated and the cis- and trans-products were separated by silica gel column chromatography (diethyl ether :hexane/l : 10). For substrate 14a and 14c, the carboxylic acid was prepared by alkylation of methyl trimethylsilyl dimethylketene acetal and subsequent hydrolysis. See Reetz, M. T.; Schwellnus, K. Tetrahedron Lett. 1978, 17 1455; and Chang, F. C; Wood, N. F. Tetrahedron Lett. 1964, 2969. Example 2

Preparation of oxazoline substrates: Carboxylic acids were converted to their acid chlorides using either oxalyl chloride (6a, 7a, 9a-13a, 15a, 15d, 17a) or thionyl chloride (8a, 14a, 14c, 16a, 16d). See Broady, S. D.; Rexhausen, J. E.; Thomas, E. J. J. Chem. Soc, Perkin Trans. 1, 1999, 1083. The acid chlorides were then reacted with (iS)-tert-leucinol or (i?)-tert-leucinol to form amides which were subsequently cyclized to oxazolines using triphenylphosphine. See Kawasaki, K.; Katsuki, T. Tetrahedron, 1997, 53, 6337; and Zhang, X.; Lin, W.; Gong, L.; Mi, A.; Cui, X.; Jiang, Y.; Choi, M. C. K.; Chan, A. S. C. Tetrahedron Lett. 2000, 43, 1535.

12a, trans 13a, cis 14a, (S)

14c, (R) 15a, (S) i5d, (R)

16a, (S) Ud, (R) 17a

Example 3

General procedure for Examples 4-24. The reaction was carried out under atmospheric air. Methylene chloride was used as received without distillation. Oxazoline (1 mmol) was placed in a 20 mL scintillation vial and dissolved in methylene chloride. Palladium acetate (22.4 mg, 0.1 mmol), iodobenzene diacetate (322 mg, 1 mmol) and iodine (253.8 mg, 1 mmol) were added to the solution. The vial was tightly sealed with a polypropylene lined cap and the resulting violet solution was stirred at room temperature until black palladium iodide precipitated out. The solvent was removed in a rotary evaporator. The product was purified by silica gel column chromatography eluting first with hexane to remove iodine and iodobenzene, and then with ethylacetate:hexane (1 :20). Example 4

61>

(S)-4-tør£J5utyl-4,5-dihydro-2-(l-iodo-2-methylpropan-2-yl)oxazole (6b): Palladium iodide precipitated out at 48 h and 6b was obtained as an orange-red oil (284 mg, 92% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 0.89 (s, 9H), 1.35 (s, 6H), 3.36 (d, J= 9.8 Hz, IH), 3.41 (d, J= 9.8 Hz, IH), 3.84 (dd, J= 9.8, 7.3 Hz, IH), 4.08 (t, J=7.3 Hz, IH), 4.14-4.18 (m, IH); ¹³C NMR (100 MHz, CDCl₃) δ 18.26, 26.21, 26.46, 30.66, 34.12, 37.81, 69.19, 75.97, 169.72; IR (neat) v 2957, 1664, 1477, 1364, 1152 cm⁴; HRMS (EI) Calcd for C₁₁H₂₀INO (M⁺) 309.0590, found 309.0586. Example 5

(S)-4-te^-Butyl-4,5-dihydro-2-(l-iodo-2-methylbutan-2-yl)oxazole (7b), mixture of diastereomers: Palladium iodide precipitated out at 48 h and 7b was obtained as an orange-red oil (294 mg, 91% yield) after purification by column chromatography. 7b was a mixture of diastereomers with 25% de as measured by ¹H NMR. The diastereomers were not further separated. ¹H NMR (400 MHz, CDCl₃) δ 0.85-0.92 (m, 3H), 0.89 (s, 9H x 0.63), 0.90 (s, 9H x 0.37), 1.28 (s, 3H), 1.59-1.79 (m, 2H), 3.34 (d, J= 9.1 Hz, IH x 0.63), 3.36 (d, J= 9.1 Hz, IH x 0.37), 3.43 (d, J= 9.1 Hz, IH x 0.37), 3.48 (d, J= 9.1 Hz, IH x 0.63), 3.83-3.88 (m, IH)₅ 4.02-4.07 (m, IH), 4.16 (dd, J= 9.8, 8.5 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ 9.41, 9.47, 17.12, 17.15, 23.85, 24.13, 26.25, 26.38, 31.57, 33.96, 34.02, 41.06, 41.10, 68.93, 76.05, 76.15, 168.64, IR (neat) v 2960, 1660, 1478, 1364, 1150 cm^"1; HRMS (EI) Calcd for C₁₂H₂₃INO (MH⁺) 324.0824, found 324.0827. Example 6

(S)-4-ter^Butyl-4,5-dihydro-2-(3-(iodomethyl)pentan-3-yl)oxazole (8b):

Palladium iodide precipitated out at 48 h and 0.5 equiv OfPhI(OAc)₂ was added and kept stirring for another 48 h. 8b was obtained as an orange-red oil (296 mg, 88% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 0.79 (t, J= 7.3 Hz, 6H), 0.89 (s, 9H), 1.6-1.73 (m, 4H), 3.86 (dd, J= 8.5, 7.9 Hz, IH), 4.00 (t, J= 7.9 Hz, IH), 4.15 (dd, J= 9.2, 8.5 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ 8.68, 13.99, 26.41, 29.11, 29.17, 33.85, 44.03, 68.66, 76.26, 167.18; IR (neat) v 2966, 1657, 1478, 1362, 1112 cm^"1; GC-MS (M⁺) 337. Example 7

(S)-4-tert-Butyl-4,5-dihydro-2-(l-(iodomethyl)cyclopentyl)oxazole (9b):

Palladium iodide precipitated out at 48 h and 0.5 equiv OfPhI(OAc)₂ was added and kept stirring for another 48 h. 9b was obtained as an orange-red oil (301 mg, 90% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 0.90 (s, 9H), 1.65- 1.78 (m, 6H), 2.15-2.19 (m, IH), 2.24-2.29 (m, IH), 3.37 (d, J= 9.8 Hz, IH), 3.51 (d, J= 9.8 Hz, IH), 3.85 (dd, J= 9.8, 7.3 Hz, IH), 4.09 (t, J= 7.3 Hz, IH), 4.18 (dd, J= 9.8, 8.5 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ 16.58, 25.61, 25.81, 26.28, 34.22, 37.67, 49.52, 69.27, 75.96, 169.92; IR (neat) v 2955, 1665, 1477, 1358, 1148 cm^"1; HRMS (EI) Calcd for C₁₃H₂₂INO (M⁺) 335.0746, found 335.0754. Example 8

101)

(S)-4-tert-Butyl-4,5-dihydro-2-(l-(iodomethyl)cycIohexyl)oxazole (1 Ob) :

Palladium iodide precipitated out at 48 h and 0.5 equiv OfPhI(OAc)₂ was added and kept stirring for another 48 h. 10b was obtained as an orange-red oil (338 mg, 97% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 0.92 (s, 9H), 1.28- 1.68 (m, 8H), 1.04-2.07 (m, IH), 2.11-2.15 (m, IH)₅ 3.31 (d, J= 9.8 Hz, IH), 3.41 (d, J= 9.8 Hz, IH), 3.89 (dd, J= 10.4, 7.9 Hz, IH), 4.04 (t, J= 7.9 Hz, IH), 4.15 (dd, J= 10.4, 8.5 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ 17.93, 22.75, 23.23, 26.00, 26.49, 26.60, 34.07, 34.79, 34.91, 41.48, 68.64, 76.26, 168.57; IR (neat) v 2947, 1666, 1477, 1363, 1137 cm^"1; HRMS (EI) Calcd for C₁₄H₂₃INO (M-H)⁺ 348.0824, found 348.0810. Example 9

lib

(S)-4-tert-Butyl-4,5-dihydro-2-(l-(iodomethyl)cycloheptyl)oxazole (llb):

Palladium iodide precipitated out at 48 h and lib was obtained as an orange-red oil (294 mg, 81% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 0.90 (s, 9H), 1.43-1.69 (m, 10H), 2.11 (dd, J= 14.6, 8.5 Hz, IH), 2.21-2.26 (m, IH), 3.31 (d, J= 9.8 Hz, IH), 3.40 (d, J= 9.8 Hz, IH), 3.86 (d, J= 10.4, 7.3 Hz, IH), 4.06 (t, J= 7.9 Hz, IH), 4.16 (d, J= 10.4, 8.5 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ 18.06, 23.60, 23.83, 26.09, 26.36, 30.61, 30.63, 30.69, 34.13, 36.62, 36.68, 44.80, 68.92, 75.98, 170.09; IR (neat) v 2928, 1664, 1477, 1364, 1150 cm^"1; HRMS (EI) Calcd for C₁₅H₂₇INO (MH⁺) 364.1137, found 364.1139. Example 10

12b

^rans-(S)-4-te^-Butyl-2-(4-te^-butyl-l-(iodomethyl)cyclohexyl)-4,5- dihydrooxazole (12b): Palladium iodide precipitated out at 48 h and 12b was obtained as an orange-red oil (397 mg, 98% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 0.85 (s, 9H), 0.90 (s, 9H), 0.96-1.13 (m, 3H), 1.60-1.65 (m, 2H), 1.76-1.87 (m, 2H), 2.04-2.12 (m, 2H), 3.53 (s, 2H), 3.84 (dd, J= 10.4, 7.9 Hz, IH), 4.04-4.17 (m, 2H), ; ¹³C NMR (100 MHz, CDCl₃) δ 12.56, 22.07, 22.25, 26.25, 27.67, 27.74, 32.62, 33.51, 34.00, 34.06, 40.53, 47.86, 68.85, 75.70, 170.96; IR (neat) v 2948, 1667, 1478, 1364, 1155 cm^'1; HRMS (EI) Calcd for C₁₈H₃₃INO (MH⁺) 406.1607, found 406.1621. Example 11

13b c/s-(S)-4-terf-ButyI-2-(4-tørtf~butyl-l -(iodomethyl) cy cIohexyl)-4, 5- dihydrooxazole (13b): Palladium iodide precipitated out at 48 h and 13b was obtained as a white solid (130 mg, 32% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 0.83 (s, 9H), 0.92 (s, 9H), 1.05-1.68 (m, 7H), 2.19-2.24 (m, IH), 2.33- 2.38 (m, IH), 3.16 (d, J= 9.8 Hz, IH), 3.36 (d, J= 9.8 Hz, IH), 3.90 (dd, J= 10.4, 7.9 Hz, IH), 4.03 (t, J= 7.9 Hz, IH), 4.15 (dd, J= 10.4, 8.5 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ 20.03, 24.24, 24.96, 26.50, 27.84, 27.94, 32.65, 34.00, 35.49, 36.04, 41.62, 48.11, 68.54, 76.48, 167.59; IR (neat) v 2948, 1664, 1475, 1360, 1153 cm^"1; HRMS (EI) Calcd for C₁₈H₃₃INO (MH⁺) 406.1607, found 406.1606. Example 12

14b

(S)-4-tert-Butyl-4,5-dihydro-2-(2-(iodomethyl)-3,3-dimethylbutan-2-yl)oxazole (14b), mixture of diastereomers: Palladium iodide precipitated out at 30 h and 14b was obtained as an orange-red oil (291 mg, 83.0% yield) after purification by column chromatography. 14b was a mixture of diastereomers with 82% de as measured by GC-MS; 60°C (3 min) to 28O⁰C (30 min), oven ramp rate: 10°C/min, helium flow rate: 1 mL/min, t_r (major) = 17.5 min, t_r (minor) = 17.4 min. The diastereomers were not further separated. ¹H NMR (400 MHz, CDCl₃) δ 0.93 (s, 9H), 1.03 (s, 9H), 1.34 (s, 2H), 3.26 (d, J= 9.2 Hz, IH x 0.1), 3.27 (d, J= 9.2 Hz, IH x 0.9), 3.87-3.92 (m, 2H), 4.01-4.20 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 16.99, 22.00, 26.63, 27.23, 34.11, 36.61, 47.16, 68.56, 76.12, 169.02; IR (neat) v 2957, 1656, 1478, 1366, 1147 cm^"1; HRMS (EI) Calcd for C₁₄H₂₇INO (MH⁺) 352.1137, found 352.1124. Example 13

(R)-4-te^-Butyl-4,5-dihydro-2-(2-(iodomethyl)-3,3-dimethylbutan-2-yl)oxazole

(14d), mixture of diastereomers: Oxazoline 14c (0.1 mmol) was placed in a 20 niL scintillation vial and dissolved in methylene chloride. Palladium acetate (2.2 mg, 0.01 mmol), iodobenzene diacetate (32.2 mg, 0.1 mmol) and iodine (25.4 mg, 0.1 mmol) were added to the solution. The vial was tightly sealed with a polypropylene lined cap and the resulting violet solution was stirred at room temperature. Palladium iodide precipitated out at 30 h. The solvent was removed in a rotary evaporator. The product was purified by silica gel column chromatography eluting first with hexane to remove iodine and iodobenzene, and then with ethylacetate:hexane /1:20. 14d was obtained as an orange-red oil (28.1 mg, 80% yield). 14d was a mixture of diastereomers with 81% de as measured by GC-MS; 60°C (3 min) to 28O⁰C (30 min), oven ramp rate: 10°C/min, helium flow rate: 1 rnL/min, t_r (major) = 17.5 min, t_r (minor) = 17.4 min. The diastereomers were not further separated. ¹H NMR (400 MHz, CDCl₃) δ 0.93 (s, 9H), 1.02 (s, 6H), 1.34 (d, J= 1.2 Hz, 3H), 3.26 (d, J= 9.2 Hz, IH x 0.1), 3.27 (d, J= 9.2 Hz, IH x 0.9), 3.87-3.91 (m, 2H), 4.00-4.19 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 17.03, 22.03, 26.66, 27.29, 34.12, 36.63, 47.16, 68.56, 76.24, 168.92; HRMS (EI) Calcd for C₁₄H₂₇INO (MH⁺) 352.1137, found 352.1131. Example 14

15b

(S)-4-tert-Butyl-4,5-dihydro-2-(2-iodo-l-methyIcyclopropyl)oxazole (15b): The reaction was stopped at 96 h and no palladium iodide precipitated out. 15b was obtained as an orange-red oil (200 mg, 65% yield) after purification by column chromatography. 15b was obtained in 99% de as measured by GC-MS; 60°C (3 min) to 28O⁰C (30 min), oven ramp rate: 10°C/min, helium flow rate: 1 mL/min, t_r (major) = 22.3 min, t_r (minor) = 22.7 min. ¹H NMR (400 MHz, CDCl₃) δ 0.93 (s, 9H), 1.28 (dd, J= 8.4, 6.5 Hz, IH), 1.45 (s, 3H), 1.62 (t, J= 6.1 Hz, IH), 2.53 (dd, J= 7.9, 5.5 Hz, IH), 3.91 (dd, J= 9.8, 8.5 Hz, IH), 4.08 (t, J= 8.5, IH), 4.23 (dd, J= 9.8, 8.5 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ -6.32, 21.32, 21.81, 23.00, 26.43, 33.67, 68.98, 76.16, 167.28; IR (neat) v 2959, 1664, 1478, 1364, 1141 cm^"1; HRMS (EI) Calcd for C₁₁H₁₈INO (M⁺) 307.0433, found 307.0434. The cis- geometry of iodide to oxazoline ring was confirmed by ID NOESY experiment. Example 15

15c

Methyl l-iodo-l-methylcyclopropanecarboxylate (15c): 15b (0.037 g, 0.12 mmol) was dissolved in dioxane:4N H₂SO₄ (1:1 v/v, 4 niL) and refluxed for 18 h. The solution was extracted with chloroform (3 x 2 mL), washed with water (3 x 1 mL) and dried over magnesium sulfate. The solvent was removed in a rotary evaporator to give crude carboxylic acid. The crude acid was then esterified¹ to 15c (0.022 g, 76% yield), ee was determined by HPLC using isopropanol:hexane/0.5:99.5, flow rate: 1 mL/min, t_r(major) = 7.8 min, t_r(minor) = 8.8 min, 99% ee. [α]_D ²⁵ = -3.8 (c 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 1.27 (dd, J= 7.9, 6.1 Hz, IH), 1.4 (s, 3H), 1.64 (t, J= 6.7 Hz, IH), 2.60 (dd, J= 7.9, 6.1 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ -6.82, 20.08, 24.04, 52.54, 62.38; IR (neat) v 2947, 1731, 1456, 1329, 1158 cm^'1; GC-MS (M⁺) 240. Example 16

15e (R)-4-ter^-Butyl-4,5-dihydro-2-(2-iodo-l-methylcycIopropyl)oxazoIe (15e):

Oxazoline 15d (0.1 mmol) was placed in a 20 mL scintillation vial and dissolved in methylene chloride. Palladium acetate (2.2 mg, 0.01 mmol), iodobenzene diacetate (32.2 mg, 0.1 mmol) and iodine (25.4 mg, 0.1 mmol) were added to the solution. The vial was tightly sealed with a polypropylene lined cap and the resulting violet solution was stirred at room temperature. The reaction was stopped at 96 h and no palladium iodide precipitated out. The solvent was removed in a rotary evaporator. The product was purified by silica gel column chromatography eluting first with hexane to remove iodine and iodobenzene, and then with ethylacetate:hexane /1:20. 15e was obtained as an orange-red oil (18.4 mg, 60% yield). 15e was obtained in 99% de as measured by GC-MS; 60°C (3 min) to 280°C (30 min), oven ramp rate: 10°C/min, helium flow rate: 1 mL/min, t_r (major) = 22.3 min, t_r

(minor) = 22.7 min. ¹H NMR (400 MHz, CDCl₃) δ 0.93 (s, 9H), 1.27 (dd, J= 8.4, 6.5 Hz, IH), 1.42 (s, 3H), 1.62 (t, J= 6.1 Hz₅ IH), 2.53 (dd, J= 7.9, 5.5 Hz, IH), 3.91 (dd, J= 9.8, 8.5 Hz, IH), 4.08 (t, J= 8.5, IH), 4.23 (dd, J= 9.8, 8.5 Hz, 1H);¹³C NMR (100 MHz, CDCl₃) δ -6.34, 21.31, 21.82, 26.43, 33.68, 68.99, 76.15, 167.29; GC-MS (M⁺) 307. Example 17

ISf

Methyl l-iodo-l-methylcyclopropanecarboxylate (15f): 15e was converted to 15f as described for 15c. ee was determined by HPLC using isopropanol:hexane/0.5:99.5, flow rate: 1 mL/min, t_r(major) = 8.8 min, t_r(minor) = 7.8 min, 99% ee. [α]_D ²⁵ = +3.0 (c 0.1,

CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 1.27 (dd, J= 7.9, 6.1 Hz, IH), 1.4 (s, 3H), 1.64 (t, J = 6.7 Hz, IH), 2.60 (dd, J= 7.9, 6.1 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ -6.82, 20.08, 24.04, 52.54, 62.38; GC-MS (M⁺) 240. Example 18

(S) -4-tert- Butyl -4,5- dihydro-2- (1- (2- iodophenyl) -1-phenylethyl) oxazole

(16b): Palladium iodide precipitated out at 13 h. 16b was obtained as a reddish brown oil (424 mg, 98% yield) after purification by column chromatography. 16b was obtained as the only detectable isomer by GC-MS; 60°C (3 min) to 280°C (30 min), oven ramp rate: 10°C/min, helium flow rate: 1 mL/min, t_r = 24.5 min. ¹H NMR (400 MHz, CDCl₃) δ 0.69 (s, 9H), 2.16 (s, 3H), 3.94 (dd, J= 10.4, 7.3 Hz, IH), 6.87 (t, J= 7.9 Hz, IH), 6.93 (dd, J= 7.9, 1.2 Hz, IH), 7.20 (t, J= 7.9 Hz, IH), 7.26-7.33 (m, 3H), 7.49 (d, J= 7.3 Hz, 2H), 7.93 (d, J= 7.9 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ 25.79, 26.05, 34.62, 53.36, 69.28, 75.68, 97.69, 127.31, 128.10, 128.27, 128.47, 128.90, 130.66, 142.86, 143.33, 147.31, 169.69; IR (neat) v 2953, 1654, 1462, 1366,1229 cm^"1; HRMS (EI) Calcd for C₂₁H₂₅INO (MH⁺) 434.0981, found 434.0991. Example 19

16c

Methyl 2-(2-iodophenyl)-2-phenylpropanoate (16c): 16b (0.06 g, 0.14 mmol) was refluxed in methanol:2N H₂SO₄ (1:1 v/v, 4 mL) at 8O⁰C for 15 h. The reaction mixture was diluted with water (2 mL) and extracted in CHCl₃ (3 ^χ 2 mL). The combined organic fraction was washed with water (3 x 1 mL), dried over magnesium sulfate and concentrated in a rotary evaporator to a crude light yellow oil. Triethylamine (0.014 g, 0.14 mmol), di- tert-butyl dicarbonate (0.061 g, 0.28 mmol) and 4-(dimethylamino)pyridine (0.017 g, 0.14 mmol) were added to the crude oil in CH₂Cl₂ (1 mL). The solution was stirred for 12 h at room temperature under nitrogen atmosphere. Solvent was removed in a rotary evaporator and the intermediate product was partially purified by rapid silica gel column chromatography (diethyl ether :hexane/l :5) to yield a white solid. The solid was then refluxed in methanol :5N KOH (1:1 v/v, 2 mL) for 15 h. The reaction mixture was acidified with 2N HCl (5 mL) and then extracted in CHCl₃ (3 x 2 mL). The combined organic fraction was washed with water (3 x 1 mL), dried over magnesium sulfate and concentrated in a rotary evaporator to yield a white crude product. The carboxylic acid was obtained as a white solid by silica gel column chromatography (diethyl ether:hexane/l :5) (0.030 g, 60% yield). [α]_D ²⁵ = +13.4 (c 0.27, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 2.08 (s, 3H), 6.89- 6.92 (m, 2H), 7.21 (t, J= 7.9 Hz, IH), 7.28-7.37 (m, 3H), 7.53 (d, J= 7.3 Hz, 2H), 7.94 (d, J= 8.5 Hz, IH); GC-MS (M⁺) 352. The carboxylic acid was esterified⁷ to 16c. ee was determined by HPLC using isoproρanol:hexane/5:95, t_r = 11.9 min, >99% ee. ¹H NMR (400 MHz, CDCl₃) δ 2.07 (s, 3H), 3.75 (s, 3H), 6.86-6.94 (m, 2H), 7.21 (t, J= 7.9 Hz, IH), 7.30- 7.39 (m, 3H), 7.53 (d, J= 7.3 Hz, 2H), 7.93 (d, J= 8.5 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ 25.59, 53.15, 59.24, 99.29, 127.79, 128.18, 128.66, 128.68, 128.90, 130.29, 141.89, 142.39, 147.57, 174.93; GC-MS (M⁺) 366. Example 20

16e

(R)-4-tert-Butyl -4,5-dihydro-2-(l-(2- iodophenyl)-l-phenylethyl) oxazole (16e):

Oxazoline 16d (30.7 mg, 0.1 mmol) was placed in a 20 niL scintillation vial and dissolved in methylene chloride. Palladium acetate (2.2 mg, 0.01 mmol), iodobenzene diacetate (32.2 mg, 0.1 mmol) and iodine (25.4 mg, 0.1 mmol) were added to the solution. The vial was tightly sealed with a polypropylene lined cap and the resulting violet solution was stirred at room temperature. Palladium iodide precipitated out at 13 h. The solvent was removed in a rotary evaporator. The product was purified by silica gel column chromatography eluting first with hexane to remove iodine and iodobenzene, and then with ethylacetate:hexane /1:20. 16e was obtained as a reddish brown oil (416 mg, 96% yield). 16e was obtained as the only detectable isomer by GC-MS; 6O⁰C (3 min) to 280⁰C (30 min), oven ramp rate: 10°C/min, helium flow rate: 1 mL/min, t_r = 24.5 min. ¹H NMR (400 MHz, CDCl₃) δ 0.70 (s, 9H), 2.16 (s, 3H), 3.94 (dd, J= 10.4, 7.3 Hz, IH), 6.87 (t, J= 7.9 Hz, IH), 6.92 (dd, J= 7.9, 1.2 Hz, IH), 7.19 (t, J= 7.9 Hz, IH), 7.25-7.32 (m, 3H), 7.50 (d, J= 7.3 Hz, 2H), 7.94 (d, J= 7.9 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ 25.80, 26.05, 34.62, 53.36, 69.27, 75.68, 97.68, 127.31, 128.11, 128.27, 128.47, 128.89, 130.66, 142.85, 143.33, 147.31, 169.69; GC-MS (M⁺) 366. Example 21

Uf

Methyl 2-(2-iodophenyl)-2-phenylpropanoate (16f): 16e was hydrolyzed to carboxylic acid as described for 16c. [α]_D ²⁵ = +13.0 (c 0.23, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 2.07 (s, 3H), 6.83-6.95 (m, 2H), 7.22 (t, J= 7.9 Hz, IH), 7.28-7.37 (m, 3H), 7.53 (d, J= 7.3 Hz, 2H), 7.94 (d, J= 8.5 Hz, IH); GC-MS (M⁺) 352. The carboxylic acid was esterified to 16f. ee was determined by HPLC using isopropanol:hexane/5:95, t_r = 15.8 min, >99% ee. See Liotta, F. J., Jr.; Duyne, G. V.; Carpenter, B. K. Organ ometallics, 1987, 6, 1010. ¹H NMR (400 MHz, CDCl₃) δ 2.06 (s, 3H), 3.74 (s, 3H), 6.85-6.93 (m, 2H), 7.19 (t, J= 7.9 Hz, IH), 7.30-7.38 (m, 3H), 7.52 (d, J= 7.3 Hz, 2H), 7.94 (d, J- 8.5 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ 25.58, 53.14, 59.23, 99.28, 127.78, 128.17, 128.65, 128.67, 128.89, 130.29, 141.88, 142.38, 147.57, 174.92; GC-MS (M⁺) 366. Example 22

17b

Crystal structure of Pd(Oxazoline)2X2 complex (17b): Oxazoline 17a (0.06 g,

0.26 mmol) was stirred with Pd(OOCF₃)₂ (0.043 g, 0.13 mmol) in n-heptane (2 niL) under nitrogen atmosphere at room temperature for 12 h. CH₂Cl₂ (2 mL) was added to the reaction mixture, filtered through Celite and concentrated in a rotary evaporator to a yield light yellow complex (0.09 g, 90% yield) which on recrystallization from diethyl etheπn- heptane/1 :1 gave a brown cubic crystal 17b. ¹H NMR (400 MHz, CDCl₃) δ 1.23 (s, 9H), 3.71 (t, J= 8.5 Hz, IH), 4.22-4.26 (m, 2H), 4.83 (s, br, 2H), 7.27-7.32 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 26.21, 34.21, 36.86, 70.83, 74.03, 127.90, 129.11, 129.60, 133.28, 174.20; IR (neat) v 2952, 1697, 1631, 1394,1183 cm^"1. Example 23 General procedure for acetoxylation: The reaction was carried out under atmospheric air. Methylene chloride was used as received without distillation. Oxazoline (1 mmol) was placed in a 20 mL scintillation vial and dissolved in methylene chloride. Palladium acetate (22.4 mg, 0.1 mmol), iodobenzene diacetate (483 mg, 1.5 mmol) and triphenylphosphine (131 mg, 0.5 mmol) were added to the solution. The vial was tightly sealed with a polypropylene lined cap and the solution was stirred at room temperature for 24-60 h. The solvent was removed in a rotary evaporator and the product was purified by silica gel column chromatography (ethylacetate:hexane /1:10).

Example 24

18

2-(4-ter^Butyl-4,5-dihydrooxazol-2-yl)-2-ethylbutyl acetate (18): Used method of Example 23. Reaction was stopped at 60 h and the title compound was obtained as a colorless oil (204 mg, 76% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 0.80-0.85 (m, 6H), 0.88 (s, 9H), 1.58-1.68 (m, 4H), 2.03 (s, 3H), 3.84 (dd, J= 9.8, 7.9 Hz, IH), 4.00 (t, J= 7.9 Hz, IH), 4.10 (dd, J= 9.8, 8.5 Hz, IH), 4.16 (d, J = 11.3 Hz, IH), 4.22 (d, J= 11.3 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ 8.50, 8.58, 21.25, 25.92, 26.21, 33.91, 44.32, 65.00, 68.28, 76.00, 168.48, 171.25. Example 25

General Information for Examples 26-33. Solvents were obtained from Acros and used directly without further purification. The reactions were carried out under atmospheric air. Methylene chloride and anhydrides were used as received without further distillation. Analytical thin layer chromatography was performed on 0.25 mm silica gel 60- F₂₅₄. Visualization was carried out with UV light and Vogel's permanganate. ¹H and ¹³C NMR spectra were recorded on a Varian instrument (400 MHz and 100 MHz, respectively) and internally referenced to SiMe₄ signal. Exact mass spectra for new compounds were recorded on a VG 7070 high resolution mass spectrometer. Analytical GC-MS was performed on a Hewlett-Packard Gl 800C instrument connected to an electron ionization detector using a MS-5 GC column (30 x 0.25 mm). Infrared spectra were recorded on a

Perkin Elmer FT-IR Spectrometer. Data Collection for crystal structure of complex 19a was carried out at room temperature on an Enraf-Nonius CAD-4 Turbo diffractometer equipped with MoKa radiation. Peroxyesters and peroxides were obtained from Aldrich. Carboxylic acids were purchased from Aldrich and Acros and were used as received. Pd(OAc)₂ was procured from Acros. Carboxylic acids for oxazolines 20 and 23 were prepared by methylation (Shinkai, H.; Maeda, K.; Yamasaki, T.; Okamoto, H.; Uchida, I. J. Med. Chem. 2000, 43, 3566-3572) of cyclopentanecarboxylic acid and 2-ethylbutyric acid, respectively. In the carboxylic acid for substrates 25 and 30, the amino group was protected as N- phthalimide (Al-Hassan, S. S.; Cameron, R. J.; Curran, A. W. C; Lyall, W. J. S.; Nicholson, S. H.; Robinson, D. R.; Stuart, A.; Suckling, C. J.; Stirling, L; Wood, H. C. S. J. Chem. Soc, Perkin Trans. 1, 1985, 1645-1659) by heating a mixture of 2-aminoisobutyric acid and phthalic anhydride at 180 ⁰C. For substrates 26 and 31, methyl ester of 2, 2- dimethylglutaric acid was prepared by selectively methylating the less hindered carboxylic group, first converting it into acid chloride with oxalyl chloride and then reacting the acid chloride with methanol. For substrate 33, the carboxylic acid was prepared by alkylation of methyl trimethylsilyl dimethylketene acetal (Reetz, M. T.; Schwellnus, K. Tetrahedron Lett. 1978, 17 1455-1458) and subsequent hydrolysis (Chang, F. C; Wood, N. F. Tetrahedron Lett. 1964, 2969-2973). Example 26

Preparation of oxazolines. Carboxylic acids were converted to their acid chlorides using either oxalyl chloride (Shinkai, H.; Maeda, K.; Yamasaki, T.; Okamoto, H.; Uchida, I. J. Med. Chem. 2000, 43, 3566-3572; oxazolines 19, 20, 22, 24, 26, 28, 29 and 31) or thionyl chloride (Al-Hassan, S. S.; Cameron, R. J.; Curran, A. W. C; Lyall, W. J. S.; Nicholson, S. H.; Robinson, D. R.; Stuart, A.; Suckling, C. J.; Stirling, L; Wood, H. C. S. J. Chem. Soc, Perkin Trans. 1, 1985, 1645-1659; oxazolines 23, 25, 30 and 33). The acid chlorides were then reacted with 2-amino-2-methyl-l-propanol or ((S)-tert-leucinol to form amides (Zhang, X.; Lin, W.; Gong, L.; Mi, A.; Cui, X.; Jiang, Y.; Choi, M. C. K.; Chan, A. S. C. Tetrahedron Lett. 2002, 43, 1535-1537) which were subsequently cyclized to oxazolines using triphenylphosphine (Kawasaki, K.; Katsuki, T. Tetrahedron, 1997, 53, 6337-6350). Oxazoline 27 was prepared from oxazoline 26 by reducing the ester group with LiAlH₄. Oxazoline 32 was prepared by heating 2-hydroxyisobutyric acid with (iS)-tert-leucmol under reflux and protecting the free hydroxyl group with a TBS group using tert- buryldimethylsilyl trifluoromethanesulfonate (TBSOTf).

25 26 27

28 29

30

MeOOC

31 32 33

Example 27

Stoichiometric hydroxylation with terf-butyl hydroperoxide. Complex 19a (94.4 mg, 0.1 mmol) (vide infra) was placed in a 20 mL scintillation vial and dissolved in CH₂Cl₂ (2 niL). tert-Butyl hydroperoxide (90% solution in water) (54 μL, 0.5 mmol) was added to the solution. The vial was tightly capped and the resulting solution was stirred at 24 °C for 36 h. The reaction mixture was then reduced with excess hydrazine monohydrate at 24 °C for 1 h and the solvent removed in a rotary evaporator. The product was purified by silica gel column chromatography using ethylacetate:hexane /1 :5. (l-(4,5-Dihydro-4,4-dimethyloxazol-2-yl)cyclohexyI)methanol (19c): 19c was obtained as a colorless oil (74 mg, 35% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 1.25 (s, 6H), 1.42-1.57 (m, 7H), 1.83-1.88 (m, 3H), 3.44 (s, br, IH), 3.58 (s, br, 2H), 3.88 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 22.23, 26.12, 28.74, 30.87, 42.35, 67.07, 67.63, 78.81, 170.43; GC-MS (MH⁺) 212. Example 28

Catalytic carboxylation with tert-bntyl peroxyacetate using various carboxylic anhydrides. Oxazoline 19 (97.5 mg, 0.5 mmol) was placed in a 40 niL pressure tube and dissolved in anhydride (5 mL). Palladium acetate (5.6 mg, 0.025 mmol) and tert-butyl peroxyacetate (75 wt. % in aliphatic hydrocarbons) (199 μL, 1 mmol) were added to the solution and the solution was flushed with oxygen. The tube was tightly capped and the resulting solution was heated at 65°C for 60 h. The reaction mixture was cooled to room temperature and then the carboxylic anhydride was hydrolyzed at 24 ⁰C with saturated aqueous sodium bicarbonate for 1 h (entries 1-2) or 2N potassium hydroxide (entries 3-5) for 5 h. The crude product was extracted with methylene chloride (3 x 5 mL), dried over sodium sulfate and the solvent was removed in a rotary evaporator. The product was purified by silica gel column chromatography eluting with ethylacetate:hexane /1:10.

19d (l-(4,5-Dihydro-4,4-dimethyloxazol-2-yl)cyclohexyl)methyI acetate (19d): 19d was obtained as a colorless oil (90 mg, 71% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 1.27 (s, 6H), 1.22-1.57 (m, 8H), 2.03 (s, 3H), 2.05 (d, br, J= 14 Hz, 2H), 3.88 (s, 2H), 4.08 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 21.14, 22.68, 26.13, 28.56, 31.64, 41.62, 67.53, 70.08, 78.97, 167.31, 171.21; IR (neat) v 2933, 2858, 1745, 1659, 1453, 1365, 1232 cm^"1; HRMS (EI) Calcd for C₁₄H₂₃NO₃ (M⁺) 253.1678, found 253.1684.

19g (l-(4,5-Dihydro-4,4-dimethyIoxazol-2-yl)cycIohexyl)methyl propionate (19g):

19g was obtained as a colorless oil (98 mg, 73% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 1.12 (t, J= 7.3 Hz, 3H), 1.26 (s, 6H), 1.22- 1.35 (m, 3H), 1.41-1.48 (m, 2H), 1.57-1.60 (m, 3H), 2.05 (d, br, J= 14 Hz, 2H), 2.31 (q, J= 7.3 Hz, 2H), 3.87 (s, 2H), 4.08 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 9.44, 22.66, 26.18, 27.86, 28.57, 41.61, 67.52, 69.94, 78.95, 167.34, 174.46; IR (neat) v 2937, 2860, 1743, 1659, 1463, 1364, 1178 cm^"1; HRMS (EI) Calcd for C₁₅H₂₅NO₃ (M⁺) 267.1834, found

267.1838.

19h

(l-(4,5-Dihydro-4,4-dimethyloxazoI-2-yl)cyclohexyl)methyl isobutyrate (19h): 19h was obtained as a colorless oil (69 mg, 49% yield) after purification by column chromatography.¹H NMR (400 MHz, CDCl₃) δ 1.15 (d, J= 7.3 Hz, 6H), 1.27 (s, 6H), 1.25- 1.59 (m, 8H), 2.04 (d, br, J= 13.4 Hz, 2H), 2.53 (sp, J= 7.3 Hz, IH), 3.87 (s, 2H), 4.07 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 19.32, 22.66, 26.22, 28.65, 31.69, 34.44, 41.59, 67.55, 69.99, 78.98, 167.50, 177.07; JR (neat) v 2934, 1738, 1658, 1466, 1196, 1157 cm^"1; GC-MS (MH⁺) 282. Example 29

19 19d 191

(9%) (65%)

Catalytic oxidation with tert-butyl peroxybenzoate. Oxazoline 19 (97.5 mg, 0.5 mmol) was placed in a 40 mL pressure tube and dissolved in anhydride (5 mL). Palladium acetate (5.6 mg, 0.025 mmol) and tert-butyl peroxybenzoate (187 μL, 1 mmol) were added to the solution and the solution flushed with oxygen. The tube was tightly capped and the resulting solution was heated at 65⁰C for 60 h. The reaction mixture was cooled to room temperature and then the acetic anhydride hydrolyzed with saturated aqueous sodium bicarbonate at 24 °C for 1 h. The crude product was extracted with methylene chloride (3 x 5 mL), dried over sodium sulfate and the solvent removed in a rotary evaporator. The product was purified by silica gel column chromatography eluting with ethylacetate:hexane /1:20.

2-(l-ter^-ButoxymethyI)cycIohexyl)-4,5-dihydro-4,4-dimethyloxazoIe (19I): 191 was obtained as a colorless oil (87 mg, 65% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 1.11 (s, 9H), 1.27 (s, 6H), 1.21-1.56 (m, 8H), 1.99 (d, br, J= 12.8 Hz, 2H), 3.26 (s, 2H), 3.85 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 23.08, 26.48, 27.76, 28.75, 31.94, 42.29, 67.33, 69.16, 72.50, 78.75, 168.87; IR (neat) v 2972, 2857, 1759, 1661, 1452, 1363, 1197 cm⁴; HRMS (EI) Calcd for C₁₆H₂₉NO₂ (M⁺) 267.2198, found 267.2192. Example 30

h

¹ R₂ -/ Me 20-27 20a-27a

Catalytic acetoxylation with tert-butyl peroxyacetate. Oxazoline (0.5 mmol) was placed in a 40 mL pressure tube and dissolved in acetic anhydride (5 mL). Palladium acetate (0.025-0.05 mmol) and tert-butyl peroxyacetate (75 wt. % in aliphatic hydrocarbons) (199 μL, 1 mmol) were added to the solution and the solution was flushed with oxygen. The tube was tightly capped and the resulting solution was heated at 48-65 ⁰C for 48-72 h. The reaction mixture was cooled to room temperature and then the acetic anhydride was hydrolyzed with saturated aqueous sodium bicarbonate at 24 °C for 1 h. The crude product was extracted with methylene chloride (3 x 5 mL), dried over sodium sulfate and the solvent was removed in a rotary evaporator. The product was purified by silica gel column chromatography eluting with ethylacetate:hexane /1:10.

20a (l-(4,5-Dihydro-4,4-dimethyloxazol-2-yl)cycIopentyl)methyl acetate (20a): The reaction was carried out using 5 mol% Pd(OAc)₂. The reaction mixture was heated at 65 ⁰C for 60 h and then subjected to the standard workup procedure as described. 20a was obtained as a colorless oil (74 mg, 62% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 1.25 (s, 6H), 1.63-1.70 (m, 6H), 2.04 (s, 3H), 2.04-2.07 (m, 2H), 3.89 (s, 2H), 4.14 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 21.22, 25.34, 28.48, 33.88, 48.15, 67.28, 68.56, 79.46, 169.07, 171.41; IR (neat) v 2963, 1746, 1660, 1463, 1365, 1237 cm^"1 ; HRMS (EI) Calcd for C₁₃H₂₂NO₃ (MH⁺) 240.1600, found 240.1597.

21a 2-(4,5-Dihydro-4,4-dimethyloxazol-2-yl)-2-methylpropyl acetate (21a): The reaction was carried out using 5 mol% Pd(OAc)₂. The reaction mixture was heated at 65 °C for 60 h and then subjected to the standard workup procedure as described. 21a was obtained as a colorless oil (74 mg, 69% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 1.22 (s, 6H), 1.25 (s, 6H), 2.04 (s, 3H), 3.88 (s, 2H), 4.08 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 21.15, 23.14, 28.55, 37.27, 67.33, 70.42, 79.34, 169.07, 171.18; IR (neat) v 2974, 1746, 1662, 1463, 1376, 1245 cm^"1; HRMS (EI) Calcd for C₁₁H₂₀NO₃ (MH⁺) 214.1443, found 214.1449.

22a 2-(4,5-Dihydro-4,4-dimethyloxazol-2-yl)-2-methyIbutyl acetate (22a): The reaction was carried out using 5 mol% Pd(OAc)₂. The reaction mixture was heated at 65 °C for 60 h and then subjected to the standard workup procedure as described. 22a and 22b were obtained as colorless oils (22a, 53 mg, 47% yield; 22b, 60 mg, 42% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 0.86 (t, J= 7.3 Hz, 3H), 1.20 (s, 3H), 1.26 (s, 6H), 1.42-1.53 (m, IH), 1.65-1.74 (m, IH), 2.04 (s, 3H), 3.88 (s, 2H), 4.07 (d, J= 11 Hz, IH), 4.16 (d, J= 11 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ 8.66, 20.02, 21.16, 28.68, 28.70, 28.79, 41:00, 67.42, 69.25, 79.18, 168.03, 171.21; IR (neat) v 2771, 2935, 1747, 1660, 1463, 1365, 1236 cm^"1; HRMS (EI) Calcd for C₁₂H₂₂NO₃ (MH⁺)

228.1600, found 228.1598.

22b 2-(4,5-Dihydro-4,4-dimethyloxazol-2-yl)-3-acetoxy-2-ethylpropyl acetate (22b):

¹H NMR (400 MHz, CDCl₃) δ 0.86 (t, J= 7.3 Hz, 3H), 1.25 (s, 6H), 1.61 (q, J= 7.3 Hz, 2H), 2.04 (s, 3H), 3.88 (s, 2H), 4.22 (d, J= 11 Hz, IH), 4.30 (d, J= 11 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ 8.18, 21.12, 23.70, 28.64, 44.50, 63.38, 67.71, 78.86, 164.40, 170.89; IR (neat) v 2971, 1748, 1663, 1464, 1367, 1230 cm^"1; HRMS (EI) Calcd for C₁₄H₂₄NO₅

(MH⁺) 286.1654, found 286.1664.

23a 2-(4,5-Dihydro-4,4-dimethyloxazol-2-yl)-2-ethylbutyl acetate (23a): The reaction was carried out using 5 mol% Pd(OAc)₂. The reaction mixture was heated at 65 °C for 60 h and then subjected to the standard workup procedure as described. 23a was obtained as a colorless oil (109 mg, 90% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 0.82 (t, J= 7.9 Hz, 3H), 1.26 (s, 6H), 1.61 (q, J= 7.3 Hz, 2H), 2.04 (s, 3H), 3.87 (s, 2H), 4.19 s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 8.35, 21.20, 25.64, 28.80,

44.18, 64.50, 67.46, 78.86, 167.35, 171.53. GC-MS (MH⁺) 242.

24a 2-(4,5-Dihydro-4,4-dimethyloxazoI-2-yl)-3-chloro-2-methyIpropyl acetate (24a) : The reaction was carried out using 10 mol% Pd(OAc)₂. The reaction mixture was heated at 65 ⁰C for 60 h and then subjected to the standard workup procedure as described. 24a was obtained as a colorless oil (84 mg, 68% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 1.25 (s, 3H), 1.26 (s, 3H), 1.29 (s, 3H), 2.05 (s, 3H), 3.71 (d, J= 11 Hz, IH), 3.78 (d, J= 11 Hz, IHO, 3.90 (s, 2H), 4.19 (d, J= 11 Hz, IH), 4.32 (d, J= 11 Hz, IH); ¹³C NMR (IOO MHZ, CDCl₃) δ 19.22, 21.08, 28.49, 42.34, 48.01, 65.87, 67.74, 79.29, 165.67, 170.76; IR (neat) v 2971, 2896, 1749, 1665, 1465, 1375, 1234 cm^"1; HRMS

(EI) Calcd for C₁₁H₁₉ClNO₃ (MH⁺) 248.1053, found 248.1057.

2-(4,5-Dihydro-4,4-dimethyIoxazol-2-yI)-2-(l,3-dioxoisoindoIin-2-yl)propyl acetate (25a): The reaction was carried out using 10 mol% Pd(OAc)₂. The reaction mixture was heated at 65 ⁰C for 72 h and then subjected to the standard workup procedure as described. 25a was obtained as a colorless oil (86 mg, 50% yield) after purification by column chromatography. ¹HNMR (400 MHz, CDCl₃) δ 1.30 (s, 3H), 1.33 (s, 3H), 1.92 (s, 3H), 2.00 (s, 3H), 3.93 (d, J= 7.9 Hz, IH), 3.96 (d, J= 7.9 Hz, IH), 4.69 (d, J= 11 Hz, IH), 4.93 (s, J= 11 Hz, IH), 7.69-7.12 (m, 2H), 7.77-7.81 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 21.09, 21.47, 28.13, 28.14, 59.00, 66.04, 67.92, 79.74, 123.49, 132.03, 134.42, 164.44, 168.50, 170.80; IR (neat) v 2973, 2896, 1781, 1715, 1670, 1612, 1467, 1372, 1231 cm^"1; HRMS (EI) Calcd for C₁₈H₂₀N₂O₅ (M⁺) 344.1372, found 344.1364.

26a 2-(4,5-Dihydro-4,4-dimethyIoxazol-2-yl)-4-carbomethoxy-2-methylbutyl acetate (26a): The reaction was carried out using 10 mol% Pd(OAc)₂. The reaction mixture was heated at 65 ⁰C for 60 h and then subjected to the standard workup procedure as described. 26a was obtained as a colorless oil (100 mg, 70% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 1.22 (s, 3H), 1.25 (s, 6H), 1.78-1.85 (m, 2H), 2.04 (s, 3H), 2.29-2.35 (m, 2H), 3.66 (s, 3H), 3.88 (s, 2H), 4.09 (d, J= 11 Hz, IH), 4.14 (d, J= 11 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ 20.44, 21.13, 28.66, 29.44, 30.79, 40.11, 52.05, 67.54, 68.97, 79.26, 167.19, 171.06, 173.97; IR (neat) v 2969, 1743, 1660, 1438, 1376, 1236 cm^"1; HRMS (EI) Calcd for C₁₄H₂₄NO₅ (MH⁺) 286.1654, found 286.1658.

27a 2-(4,5-Dihydro-4,4-dimethyloxazol-2-yl)- 5-acetoxy-2-methylpentyl acetate

(27a): Oxazoline 27 (99.7 mg, 0.5 mmol) was dissolved in Ac₂O (5 mL) in a 40 mL pressure tube and heated at 50 °C. After 1 h, the reaction mixture was cooled to room temperature and Pd(OAc)₂ (11.2 mg, 0.05 mmol) and tert-butyl peroxyacetate (75 wt. % in aliphatic hydrocarbons) (199 μL, 1 mmol) were added to it. Heating was continued at 50 °C for 48 h and then subjected to the standard workup procedure as described. 27a was obtained as a colorless oil (75 mg, 50% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 1.23 (s, 3H), 1.25 (s, 6H), 1.47-1.72 (m, 4H), 2.04 (s, 3H), 2.05 (s, 3H), 3.89 (s, 2H), 4.03 (tJ= 6.7 Hz, 2H), 4.08 (d, J= 11 Hz, IH), 4.16 (d, J= 11 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ 20.51, 21.15, 21.33, 23.70, 28.66, 32.20, 40.39, 64.82, 67.51, 69.09, 79.26, 167.75, 171.12, 171.47; IR (neat) v 2968, 1743, 1660, 1466, 1367, 1240 cm^"1; HRMS (EI) Calcd for C₁₅H₂₆NO₅ (MH⁺) 300.1811, found 300.1813. Example 31

28-33 28a-33a

Diastereoselective acetoxylation using lauroyl peroxide. Oxazoline (0.5 mmol) was placed in a 40 mL pressure tube and dissolved in acetic anhydride (5 mL). Palladium acetate (5.6 mg, 0.025 mmol) and lauroyl peroxide (199.3 mg, 0.5 mmol) were added to the solution and the solution was flushed with oxygen. The tube was tightly capped and the resulting solution was heated at 5O⁰C. After 24 h, the reaction mixture was cooled to room temperature and one equivalent of lauroyl peroxide (199.3 mg, 0.5 mmol) was added to it. Heating was continued at 50 °C for another 24 h. The reaction mixture was cooled to room temperature and then the acetic anhydride was hydrolyzed with saturated aqueous sodium bicarbonate at 24 ⁰C for 1 h. The crude product was extracted with methylene chloride (3 x 5 mL), dried over sodium sulfate and the solvent removed in a rotary evaporator. The product was purified by silica gel column chromatography eluting with ethylacetate:hexane /1:10.

28a

2-((S)-4-te^-Butyl-4,5-dihydrooxazol-2-yl)-2-methylbutyI acetate (28a), mixture of diastereomers: 28a and 28b were obtained as light yellow oils (28a, 86 mg, 67% yield; 28b, 36 mg, 23% yield) after purification by column chromatography. 28a was a mixture of diastereomers with 18% de as measured by ¹H NMR and GC-MS; 50 ⁰C (50 min) to 280 °C (550 min), oven ramp rate: 0.5 °C/min, helium flow rate: 1 mL/min, t_r (major) = 162.1 min, t_r (minor) = 162.7 min. The diastereomers were not further separated. ¹H NMR (400 MHz, CDCl₃) δ 0.85-0.89 (m, 2H), 0.87 (s, 9H * 0.59), 0.88 (s, 9H x 0.41), 1.20 (s, 3H x 0.59), 1.22 (s, 3H x 0.41), 1.45-1.73 (m, 3H), 2.03 (s, 3H x 0.41), 2.04 (s, 3H x 0.59), 3.83 (dd, J = 11, 7.3 Hz, IH), 4.02-4.22 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 8.83, 8.86, 20.34, 20.45, 21.21, 21.25, 26.07, 26.10, 28.76, 29.04, 34.01, 41.00, 41.09, 68.65, 68.71, 69.05, 69.36, 75.91, 169.31, 169.45, 171.31; IR (neat) v 2965, 1747, 1665, 1478, 1365, 1241 cm^"1;

HRMS (Cl) Calcd for C₁₄H₂₆NO₃ (MH⁺) 256.1913, found 256.1916.

28b 2-((S)-4-te/"^-Butyl-4,5-dihydrooxazol-2-yI)-3-acetoxy-2-ethylpropyl acetate

(28b): ¹H NMR (400 MHz, CDCl₃) δ 0.86 (s, 12H), 1.59 (q, J= 7.3 Hz, 2H), 2.01 (s, 3H), 2.03 (s, 3H), 3.85 (dd, J= 10.4, 7.9 Hz, IH), 7.3 (t, J= 7.3 Hz, IH), 4.11 (dd, J= 10.4, 8.5 Hz, IH),4.22(s,2H),4.24(d,J=11Hz, IH),4.33(d,J-11Hz, IH); ¹³CNMR(100 MHz,CDCl₃)δ8.34,21.13,21.18,23.98,26.03,33.89,44.56,63.30,63.84,68.46,75.90,

165.76, 170.99, 171.02;IR(neat)v2959, 1748, 1667, 1466, 1367, 1240cm^'1.

29a 2-((S)-4-ter^Butyl-4,5-dihydrooxazol-2-yI)-3-chIoro-2-methylpropyl acetate

(29a), mixture of diastereomers: 29a was obtained as a light yellow oil (91 mg, 66% yield) after purification by column chromatography. 29a was a mixture of diastereomers with 38% de as measured by ¹H NMR and GC-MS; 50 °C (4 min) to 280 °C (30 min), oven ramp rate: 10 °C/min, helium flow rate: 1 mL/min, t_r (major) = 17.6 min, t_r (minor) = 17.7 min. The diastereomers were not further separated. ¹H NMR (400 MHz, CDCl₃) δ 0.87 (s, 9H), 1.29 (s, 3H x 0.31), 1.30 (s, 3H x 0.69), 2.03 (s, 3H x 0.31), 2.05 (s, 3H x 0.69), 3.72 (d, J= 11 Hz, IH x 0.69), 3.74 (d, J= 11 Hz, IH x 0.31), 3.79 (U₉ J= U Hz, IH x 0.69), 3.83 (dd, J= 11, 6.7 Hz, IH), 4.05 (dd, J= 8.5, 7.3 Hz, IH x 0.31), 4.06 (dd, , J= 8.5, 7.3 Hz, IH x 0.69), 4.14 (dd, J= 10.4, 8.5 Hz, IH), 4.21 (d, J= 11 Hz, IH x 0.69), 4.24 (d, J= 11 Hz, IH x 0.31), 4.28 (d, J- 11 Hz, IH x 0.31), 4.35 (d, J= 11 Hz, IH x 0.69); ¹³C NMR (100 MHz, CDCl₃) δ 19.53, 19.67, 21.14, 25.98, 26.02, 34.01, 42.27, 42.45, 47.83, 47.95, 65.85, 66.04, 68.96, 75.99, 166.93, 170.79, 170.84; IR (neat) v 2958, 2906, 1748, 1668, 1479, 1468, 1365, 1237 cm^"1; HRMS (CI) Calcd for C₁₃H₂₃ClNO₃ (MH⁺) 276.1366, found 276.1362.

30a

2-((S)-4-te^-Butyl-4,5-dihydrooxazoI-2-yl)-2-(l,3-dioxoisoindolin-2-yl)propyl acetate (30a), mixture of diastereomers: 30a was obtained as a light yellow oil (71 mg, 38% yield) after purification by column chromatography. 30a was a mixture of diastereomers with 12% de as measured by ¹H NMR. The diastereomers were not further separated. ¹H NMR (400 MHz, CDCl₃) δ 0.90 (s, 9H x 0.56), 0.93 (s, 9H x 0.44), 1.99 (s, 3H), 2.00 (s, 3H x 0.44), 2.01 (s, 3H x 0.56), 3.89-3.97 (m, IH), 4.02-4.10 (m, IH), 4.15- 4.25 (m, IH), 4.63 (d, J= 11.6 Hz, IH x 0.44), 4.72 (d, J= 11.6 Hz, IH x 0.56), 4.89 (d, J = 11.6 Hz, IH x 0.56), 4.96 (d, J- 11.6 Hz, IH x 0.44); ¹³C NMR (100 MHz, CDCl₃) δ 15.62, 21.13, 21.70, 21.81, 26.17, 26.38, 33.99, 34.16, 59.24, 59.27, 66.21, 66.43, 66.52, 69.33, 69.53, 76.06, 76.40, 123.49, 132.06, 134.40, 165.69, 165.74, 168.50, 168.63, 170.86, 170.95; IR (neat) v 2956, 2871, 1783, 1719, 1674, 1613, 1468, 1368, 1326, 1230 ran ¹;

HRMS (EI) Calcd for C₂₀H₂₅N₂O₅ (MH⁺) 373.1763, found 373.1757.

31a

2-((S)-4-tør£-Butyl-4,5-dihydrooxazol-2-yI)-4-carbomethoxy-2-methylbutyl acetate (31a), mixture of diastereomers: 31a was obtained as a light yellow oil (115 mg, 73% yield) after purification by column chromatography. 31a was a mixture of diastereomers with 24% de as measured by ¹H NMR. The diastereomers were not further separated. ¹H NMR (400 MHz, CDCl₃) δ 8.70 (s, 9H), 1.22 (s, 3H x 0.62), 1.23 (s, 3H x 0.38), 1.79-2.02 (m, 2H), 2.03 (s, 3H x 0.38), 2.04 (s, 3H x 0.62), 3.66 (s, 3H), 3.82 (dd, J= 9.8, 7.3 Hz, IH), 4.00-4.05 (m, IH), 4.08-4.14 (m, IH), 4.11 (d, J= 11 Hz, IH), 4.17 (d, J= 11 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ 20.71, 21.01, 21.17, 21.19, 26.05, 26.07, 29.63, 29.68, 30.83, 31.10, 33.97, 40.16, 40.25, 52.02, 68.77, 68.85, 69.20, 75.95, 168.48, 168.53, 171.11, 174.08, 174.12; IR (neat) v 2955, 2907, 1744, 1665, 1478, 1438, 1365, 1239 cm-¹;

HRMS (CI) Calcd for C₁₆H₂₈NO₅ (MH⁺) 314.1967, found 314.1968.

32a 2-((S)-4-te^-Butyl-4,5-dihydrooxazoI-2-yl)-2-(terr-butyldimethylsilyIoxy)propyl acetate (32a), mixture of diastereomers: 32a was obtained as a light yellow oil (77 mg, 43% yield) after purification by column chromatography. 32a was a mixture of diastereomers with 62% de as measured by ¹H NMR and GC-MS; 50 °C (50 min) to 280 °C (550 min), oven ramp rate: 0.5 °C/min, helium flow rate: 1 mL/min, t_r (major) = 223.9 min, t_r (minor) = 222.8 min. The diastereomers were not further separated. ¹H NMR (400 MHz, CDCl₃) δ 0.07 (s, 3H), 0.09 (s, 3H), 0.86 (s, 9H), 0.88 (s, 9H), 1.47 (s, 3H x 0.19), 1.51 (s, 3H x 0.81), 2.04 (s, 3H x 0.81), 2.05 (s, 3H x 0.19), 3.86 (dd, J= 8.4, 7.6 Hz, IH), 4.08 (t, J = 8.0 Hz, IH), 4.14-4.18 (m, 3H), 4.28 (d, J= 11 Hz, IH x 0.19); ¹³C NMR (100 MHz, CDCl₃) δ -3.15, -2.60, 18.40, 21.04, 24.37, 25.80, 25.83, 25.93, 25.99, 68.93, 69.84, 72.47, 75.99, 167.51, 170.73; IR (neat) v 3426, 2957, 1749, 1668, 1474, 1369, 1250 cm^"1; GC-MS (MH⁺) 358. 50% starting material was recovered.

2-((S)-4-te^-Butyl-4,5-dihydrooxazol-2-yl)-2,3,3-trimethylbutyl acetate (33a), mixture of diastereomers: 33a was obtained as a light yellow oil (70 mg, 49% yield) after purification by column chromatography. 33a was a mixture of diastereomers with 82% de as measured by ¹H NMR and GC-MS; 50 ⁰C (50 min) to 280 °C (550 min), oven ramp rate: 0.5 °C/min, helium flow rate: 1 rnL/min, t_r (major) = 191.0 min, t_r (minor) = 192.2 min. The major diastereomer was isolated in 35% yield. ¹H NMR (400 MHz, CDCl₃) δ 0.88 (s, 9H), 0.98 (s, 9H), 1.21 (s, 3H), 2.01 (s, 3H), 3.81 (m, IH), 4.00-4.13 (m, 3H), 4.52 (d, J= 10.4 Hz, IH); ¹³C NMR (100 MHz, CDCl₃) δ 16.58, 20.98, 25.91, 26.57, 33.72, 35.16, 45.92, 67.95, 67.93, 75.55, 168.59, 171.11; IR (neat) v 2958, 1743, 1655, 1479, 1385, 1243 cm^"1; HRMS (CI) Calcd for C₁₆H₃₀NO₃ (MH⁺) 284.2226, found 284.2230. 47% starting material was recovered.

34 CH₂CI₂, 24 ⁰C 34a 34b

(major) (minor)

Effect Of Ac₂O on acetoxylation reaction: Stock solutions of oxazoline 34 (223 mg/mL), Pd(OAc)₂ (44.8 mg/mL), lauroyl peroxide (199.3 mg/mL) and Ac₂O (102 mg/mL) were prepared in CH₂Cl₂. Oxazoline 34 (100 μL, 0.1 mmol), lauroyl peroxide (400 μL, 0.2 mmol), Ac₂O (200 μL, 2 mmol) and CH₂Cl₂ (200 μL) were placed in a 20 mL scintillation vial. Pd(OAc)₂ (100 μL, 0.02 mmol) was added to it (final volume: 1 mL) and the reaction mixture was stirred at 24 °C. A parallel reaction was also carried out in absence of acetic anhydride. Reactions were performed in triplicates and aliquots of the reaction mixture were taken at 2, 4, 8, 16, 22 and 26 hours for GC-MS analysis. Percentage yields of the products (acetate as a major and laurate as a minor product) were determined relative to the starting oxazoline 34 and the values in the table represent the average of three reactions (Table 2 below).

Table 2. Percentage of product formation

Reaction Time Combined Product Yield, %

00 with Ac₂O without Ac₂O

2 2.9 4.4

4 4.6 6.2

8 8.1 9.2

16 20.7 14.2

22 34.4 14.3

26 46.3 15.1

Effect of oxygen on acetoxylation reaction: Stock solutions of oxazoline 34 (223 mg/niL), Pd(OAc)₂ (22.4 mg/niL) and lauroyl peroxide (199.3 mg/mL) were prepared in CH₂Cl₂. Oxazoline 34 (100 μL, 0.1 mmol), lauroyl peroxide (200 μL, 0.1 mmol) and Pd(OAc)₂ (50 μL, 0.005 mmol)) were placed in a 20 niL pressure tube. CH₂Cl₂ was removed by fridge-thaw process. Ac₂O (1 mL) was added to the reaction mixture and oxygen was removed by fridge-thaw process under argon (3 cycles of vacuum/ Ar). The reaction was heated at 50 °C. A parallel reaction was also carried out under oxygen. Reactions were performed in triplicates and aliquots of the reaction mixture were taken at 1, 2, 4 and 8 hours for GC-MS analysis. Percentage yields of the products (acetate as a major and laurate as a minor product) were determined relative to the starting oxazoline 34 and the values in the table represent the average of three reactions (Table 3 below).

Table 3. Product Formation in the Presence and Absence of Oxygen Reaction Time Combined Product Yield, %

(h) under Argon under Oxygen

_

O O

1 9.8 8.3

2 19.4 15.2 4 27.3 26.1 8 28.1 46.5

Example 33

Mechanistic studies using trinuclear palladium complex

Formation of trinuclear bis-//-acetato palladium complex (19a). Oxazoline 19 (195 mg, 1 mmol) was stirred with palladium acetate (336 mg, 1.5 mmol) in CH₂Cl₂ (10 ml) at 24 °C for 36 h. The solvent was removed in a rotary evaporator to give a brown residue. The residue was repeatedly washed with diethyl ether, centrifuged and dried under high vacuum to yield a greenish yellow complex 19a (755 mg, 80% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.18 (s, 3H x 0.67), 1.21 (s, 3H x 0.33), 1.46 (s, 3H x 0.67), 1.47 (s, 3H x 0.33), 1.46-1.83 (m, 8H), 1.72 (s, 3H x 0.33), 1.78 (s, 3H x 0.67), 1.79 (s, 3H x 0.67), 1.83 (s, 3H x 0.33), 2.01 (d, br, J= 9.8 Hz, 2H), 2.16 (d, J= 8.5 Hz, IH x 0.33), 2.20 (d, J= 7.9 Hz, IH x 0.67), 2.74 (d, J= 8.5 Hz, IH x 0.33), 2.79 (d, J= 7.9 Hz, IH x 0.67), 4.11 (dd, J = 12.2, 8.5 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 21.23, 21.92, 21.94, 22.17, 23.29, 23.39, 23.65, 23.78, 25.99, 27.47, 27.50, 27.55, 33.69, 33.75, 34.43, 44.55, 65.62, 65.66, 80.04, 181.81, 182.02, 183.35, 183.58. Crystallization of 19a. Complex 19a (47.2 mg) was dissolved in CH₂Cl₂ (2 niL) and diluted with hexane (2 niL). The solution was filtered through a Cameo 3N syringe filter (0.45 μ, 3 mm) (Osmonics Inc.) in a glass sample vial. The complex was crystallized as brown prisms in 16 days at 24 °C.

19a 19a-d₁₂

Exchange of bridge acetate of complex Ia with Ac₂O-^₆- Complex 19a (47.2 mg, 0.05 mmol) was mixed with Ac₂O-J₆ (1 mL) in a 20 mL scintillation vial. The vial was capped and the mixture was stirred at 24 °C. After 36 h, the mixture was centrifuged and acetic anhydride was removed. The complex was repeatedly washed with excess of diethyl ether, centrifuged and the ether removed. After drying under high vacuum for 1 h, the complex 19a-d₁₂ was obtained as a brown powder (38.3 mg, 80% yield). ¹H NMR of the complex showed the disappearance of peaks at δ 1.72, 1.78, 1.79 and 1.83 ppm corresponding to the bridge acetates of syn- and anti-isomers of the complex 19a.

; 34c

Effect of acetic anhydride on C-H cleavage. Stock solutions of oxazoline 34 (223 mg/mL), Ac₂O (408 mg/mL) and Pd(OAc)₂ (44.8 mg/mL) were prepared in CD₂Cl₂. Oxazoline 34 (100 μL, 0.1 mmol) and CD₂Cl₂ (400 μL) were placed in an NMR tube. Pd(OAc)₂ (500 μL, 0.1 mmol) was added to it (final volume: 1 mL), the NMR tube was tightly screw-capped and the reaction mixture stirred at 24 ⁰C. Parallel reactions were carried out in presence of 5 equivalents (125 μL, 0.5 mmol) and 10 equivalents (250 μL, 1 mmol) of acetic anhydride keeping the final reaction volume at 1 mL with CD₂Cl₂. Reactions were carried out in triplicates. Formation of the complex 34c was followed by ¹H NMR at 1, 2, 4 and 6 hours. Percentage of the complex formation was determined by measuring the ratio of t-butyl peak of the complex 34c at δ 1.04 ppm and t-butyl peak of oxazoline 34 at δ 0.89 ppm. Rate of complex formation in presence of acetic anhydride was found to be the same as the rate of complex formation in absence of acetic anhydride (3.7 mmole L^"1 h^"1).

Complex 34c: ¹H NMR (400 MHz, CDCl₃) δ 1.04 (s, 9H), 1.38-1.68 (m, 8H), 1.75 (s, 3H), 1.79 (s, 3H), 2.11 (d, br, 2H), 2.23 (d, J = 7.9 Hz, IH), 2.91 (d, J = 7.9 Hz, IH), 3.50 (dd, J= 9.2, 3.1 Hz, IH), 4.21 (t, J= 9.2 Hz, IH), 4.41 (dd, J= 9.2, 3.1 Hz, IH).

Table 4. Complex Formation in Presence and Absence of Acetic Anhydride

Reaction Time Combined Product Yield, %

(h) without Ac₂O Ac₂O (5 mol%) Ac₂O (10 mol%)

1 3.1 3.3 3.6 2 6.4 6.7 6.9 4 13.7 14.4 14.7 6 23.1 22.8 23.2

34c

Reaction of lauroyl peroxide with the trinuclear Pd complex in presence and absence of acetic anhydride: Stock solutions of complex 34c (65.6 mg/mL), lauroyl peroxide (262.7 mg/mL) and Ac₂O (336.6 mg/mL) were prepared in CH₂Cl₂. Complex 34c (500 μL, 0.033 mmol), Ac₂O (100 μL, 0.33 mmol) and lauroyl peroxide (250 μL, 0.165 mmol) were placed in a 20 niL scintillation vial (final volume: 1 niL) and tightly capped. The reaction mixture was stirred at 24 ⁰C. A parallel reaction was also carried out in absence OfAc₂O. Reactions were performed in triplicates and aliquots of the reaction mixture were taken at 1, 2, 3, 6, 9 and 12 minutes and the unreacted complex 34c was quenched with I₂ (I₂ instantly reacts with the trinuclear complex 34c giving iodinated product). Percentage yields of the products (acetate as a major and laurate as a minor product) were determined relative to the iodinated product by GC-MS. The values in the table below represent the average of three reactions (Table 5).

Table 5. Product Formation in Presence and Absence of Acetic Anhydride

Reaction Time Combined Product Yield, %

(min) with Ac₂O without Ac₂O

0 0 0

2 17.1 13.3

8 23.2 20.0

16 28.4 23.1

26 34.3 29.6

Example 34

Azlactone-assisted acetoxylation and iodination

Procedure 1: Azlatone (1 mmol) was placed in a 20 mL pressure tube and dissolved in a CH2CI2 (5 mL). Palladium acetate (22.4 mg, 0.1 mmol) and iodobenzene diacetate (322 mg, 1 mmol) were added to the solution to give a mixture of suspension. The tube was tightly sealed and the resulting solution was stirred at 80^° C for 24 h. The solvent was removed in a rotary evaporator. The product was purified by silica gel column chromatography eluting first with hexane to remove iodobenzene and then with ethylacetate:hexane /1:10.

Procedure 2: Azlatone (1 mmol) was placed in a 20 mL pressure tube and dissolved in a CH2CI2 (5 mL). Palladium acetate (22.4 mg, 0.1 mmol), I₂ (253.8 mg, 1 mmol) and iodobenzene diacetate (322 mg, 1 mmol) were added to the solution to give a mixture of suspension. The tube was tightly sealed and the resulting solution was stirred at 80^°C for 24 h. The solvent was removed in a rotary evaporator. The product was purified by silica gel column chromatography eluting first with hexane to remove iodobenzene and then with ethylacetate:hexane /1:10.

2-(4,5-dihydro-4,4-dimethyl-5-oxooxazoI-2-yl)-2-methylpropyl acetate. The reaction mixture was stirred at 80^° C for 24 h and the acetoxylated product was obtained as a light yellow oil (195.3 mg, 81% yield) after purification by column chromatography. ¹H NMR (400 MHz, CDCb) δ 1.29 (s, 6H), 1.41 (s, 6H), 2.03 (s, 3H), 4.13 (s, 2H); '³C NMR (100 MHz, CDCb) δ 24.64, 22.01, 65.64, 69.22, 70.37, 166.79, 170.87, 181.43. Incorporation by Reference All of the U.S. patents and U.S. published patent applications cited herein are hereby incorporated by reference. Equivalents

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims

Claims

We claim:

1. A compound represented by formula I :

R¹

_R ^κ ₂Λ B'"^A

I wherein

R¹ and R² each independently are selected from the group consisting of hydrogen, alkyl, haloalkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, -OR, and -NR₂;

R is independently selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, and heteroaryl; R¹ and R² may be connected by a covalent tether, said covalent tether comprising 3,

4, 5, or 6 backbone atoms;

B is selected from the group consisting of -CI(R⁷)₂, - CBr(R⁷)₂, - CC1(R⁷)₂, -CHO,

-C(R⁷)₂OC(O)R⁷, and C(R⁷)₃;

R⁷ is independently selected from the group consisting of hydrogen, halogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, and heteroaryl;

A is selected from the group consisting of R⁶ ,

-C(O)OR⁸, -CH₂OR⁸, -CHO, R⁸

any two instances of R maybe connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl;

X is selected from the group consisting of O, S, and NR⁹;

R⁹ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl; R³, R⁴, R⁵, R⁶ each independently are selected from the group consisting of hydrogen, alkyl, aryl, alkenyl, and alkynyl;

R³ and R⁴ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; R⁵ and R⁶ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

R⁴ and R⁶ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

R³ and R⁵ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; and the stereochemical configuration at any stereocenter of a compound represented by I is R, S, or a mixture of these configurations. 2. The compound of claim 1 , wherein R¹ and R² each independently are selected from the group consisting of hydrogen, alkyl, heteroalkyl, -OR, and -NR₂. 3. The compound of claim 1, wherein R¹ and R² each independently are selected from the group consisting of hydrogen and alkyl.

4. The compound of claim 1, wherein B is selected from the group consisting Of -CH₂I, -CH₂OC(O)R⁷, and -CH₃.

5. The compound of claim 1, wherein B is selected from the group consisting Of -CH₂I and -CH₂OC(O)R⁷; and R⁷ is alkyl or aryl.

6. The compound of claim 1, wherein A is selected from the group consisting of

and -C(O)OR⁸; and X is O or S. 7. The compound of claim 1, wherein A is selected from the group consisting of

and -C(O)OH; X is O; R³, R⁴ and R⁵ are hydrogen; and R⁶ is alkyl or aryl. 8. The compound of claim 1, wherein A is selected from the group consisting of

and -C(O)OH; X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are hydrogen, alkyl or aryl.

9. The compound of claim 1 , wherein A is

R⁶ ; X is O; R , R and R are hydrogen; and R⁶ is tert-butyl.

10. The compound of claim 1, wherein A is selected from the group consisting of

and -C(O)OH; X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl.

11. The compound of claim 1 ,wherein R¹ and R² each independently are selected from the group consisting of hydrogen, alkyl, heteroalkyl, -OR, and -NR₂; and B is selected from the group consisting Of -CH₂I, -CH₂OC(O)R⁷, and -CH₃.

12. The compound of claim 1, wherein B is selected from the group consisting Of -CH₂I,

-CH₂OC(O)R⁷ and -CH₃; and A is selected from the group consisting of

and -C(O)OH; X is O; R³, R⁴ and R⁵ are hydrogen; and R⁶ is alkyl or aryl.

13. The compound of claim 1, wherein R¹ and R² each independently are selected from the group consisting of hydrogen, alkyl, heteroalkyl, -OR, and -NR₂; and A is

selected from the group consisting of R⁶ and -C(O)OH; X is O; R³, R⁴ and R⁵ are hydrogen; and R⁶ is alkyl or aryl. 14. The compound of claim 1, wherein R¹ and R² each independently are selected from the group consisting of hydrogen, alkyl, heteroalkyl, -OR, and -NR₂; A is selected from the group

and -C(O)OH; X is O; R 3 and j τ R>4 are hydrogen; and R⁵ and R⁶ are hydrogen, alkyl or aryl.

15. The compound of claim 1, wherein R and R each independently are selected from the group consisting of hydrogen and alkyl; B is selected from the group consisting of -CH₂I, -CH₂OC(O)R⁷; and R⁷ is alkyl or aryl.

16. The compound of claim 1, wherein B is selected from the group consisting of -CH₂I,

-CH₂OC(O)R⁷; R⁷ is alkyl or aryl; A is

are hydrogen; and R⁶ is tert-butyl.

17. The compound of claim 1, wherein R¹ and R² each independently are selected from

the group consisting of hydrogen and alkyl; A is

R³, R⁴ and

R⁵ are hydrogen; and R⁶ is tert-butyl.

18. The compound of claim 1, wherein R¹ and R² each independently are selected from the group consisting of hydrogen and alkyl; B is selected from the group consisting

Of -CH₂I and -CH₂OC(O)R⁷; R⁷ is alkyl or aryl; A is X iS Oj R₃₅ R₄ and R₅ are hydrogen; and R₆ is tert-butyl.

19. The compound of claim 1, wherein B is selected from the group consisting Of -CH₂I

and -CH₂OC(O)R⁷; R⁷ is alkyl or aryl; A is

X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl. 20. The compound of claim 1, wherein R¹ and R² each independently are selected from

the group consisting of hydrogen and alkyl; A is

R⁶ R⁵ ; X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl.

21. The compound of claim 1, wherein R¹ and R² each independently are selected from the group consisting of hydrogen and alkyl; B is selected from the group consisting

of -CH₂I, -CH₂OC(O)R⁷; R⁷ is alkyl or aryl; A is

R⁶ R⁵ ; X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl.

22. The compound of claim 1, wherein the compound has an ee of greater than or equal to 80%. 23. The compound of claim 1, wherein the compound has an ee of greater than or equal to 90%.

24. The compound of claim 1, wherein the compound has an ee of greater than or equal to 95%.

25. A compound represented by formula II:

II wherein

R¹ and R² each independently are selected from the group consisting of hydrogen, alkyl, haloalkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, -OR, and -NR₂; R¹ and R² may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

R is independently selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, and heteroaryl;

B is selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl -OR⁷, and -N(R⁷)₂; R⁷ is independently selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, and heteroaryl;

R¹ and B may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

C is selected from the group consisting of -I, -Br, -Cl, -OC(O)R⁸, -OR⁸, alkenyl, alkynyl, and aryl;

R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl;

A is selected from the group consisting of

R⁹ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl; any two instances of R⁹ maybe connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

X is selected from the group consisting of O, S, and NR¹⁰;

R¹⁰ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl;

R³, R⁴, R⁵, R⁶ each independently are selected from the group consisting of hydrogen, alkyl, aryl, alkenyl, and alkynyl;

R³ and R⁴ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

R⁵ and R⁶ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; R⁴ and R⁶ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; R³ and R⁵ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; and the stereochemical configuration at any stereocenter of a compound represented by II is R, S, or a mixture of these configurations. 26. The compound of claim 25, wherein B is selected from the group consisting of hydrogen, alkyl, -OR⁷, and -N(R⁷)₂.

27. The compound of claim 25, wherein B is selected from the group consisting of hydrogen and alkyl.

28. The compound of claim 25, wherein C is selected from the group consisting of -I, -OC(O)R⁸, alkenyl, alkynyl, and aryl.

29. The compound of claim 25, wherein C is selected from the group consisting of -I and -OC(O)CH₃.

30. The compound of claim 25, wherein A is selected from the group consisting of

and -C(O)OR⁹; and X is selected from the group consisting of O and S .

31. The compound of claim 25, wherein A is selected from the group consisting of

-C(O)OH; X is O; R³, R⁴ and R⁵ are hydrogen; and R⁶ is tert- butyl.

32. The compound of claim 25, wherein A is selected from the group consisting of

and -C(O)OH; X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl.

33. The compound of claim 25, wherein B is selected from the group consisting of hydrogen, alkyl, -OR⁷, and -N(R⁷)₂; and C is selected from the group consisting of - I, -OC(O)R⁸, alkenyl, alkynyl, and aryl. 34. The compound of claim 25, wherein C is selected from the group consisting of -I, -OC(O)R , alkenyl, alkynyl, and aryl; A is selected from the group consisting of

and X is selected from the group consisting of O and S.

35. The compound of claim 25, wherein A is selected from the group consisting of

and -C(O)OR⁹; X is selected from the group consisting of O and S; and B is selected from the group consisting of hydrogen, alkyl, -OR⁷, and -N(R⁷)₂.

36. The compound of claim 25, wherein A is selected from the group consisting of

X is selected from the group consisting of O and S; B is selected from the group consisting of hydrogen, alkyl, OR⁷, and -N(R⁷)₂; and C is selected from the group consisting of -I, -OC(O)R⁸, alkenyl, alkynyl, and aryl.

37. The compound of claim 25, wherein B is selected from the group consisting of hydrogen and alkyl; and C is selected from the group consisting of -I and -OC(O)CH₃. 38. The compound of claim 25, wherein C is selected from the group consisting of -I

and -OC(O)CH₃; A is selected from the group consisting

C(O)OH; X is O; R³, R⁴ and R⁵ are hydrogen; and R⁶ is tert-butyl. 39. The compound of claim 25, wherein C is selected from the group consisting of -I

and -OC(O)CH₃; A is selected from the group consisting

and - C(O)OH; X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl. 40. The compound of claim 25, wherein A is selected from the group consisting of

X is O; R³, R⁴ and R⁵ are hydrogen; R⁶ is tert-butyl; and B is selected from the group consisting of hydrogen and alkyl.

41. The compound of claim 25, wherein C is selected from the group consisting of -I

and -OC(O)CH₃; A is selected from the group consisting of R⁶ R⁵ and -

C(O)OH; X is O; R³ and R⁴ are hydrogen; R⁵ and R⁶ are methyl; and B is selected from the group consisting of hydrogen and alkyl.

42. The compound of claim 25, wherein A is selected from the group consisting of

-C(O)OH; X is O; R³, R⁴ and R⁵ are hydrogen; R⁶ is tert-butyl; B is selected from the group consisting of hydrogen and alkyl; and C is selected from the group consisting of -I and -OC(O)CH₃.

43. The compound of claim 25, wherein C is selected from the group consisting of -I

and -OC(O)CH₃; A is selected from the group consisting

and - C(O)OH; X is O; R³ and R⁴ are hydrogen; R⁵ and R⁵ are methyl; B is selected from the group consisting of hydrogen and alkyl; and C is selected from the group consisting of -I and -OC(O)CH₃.

44. The compound of claim 25, wherein the compound has an ee of greater than or equal to 80%.

45. The compound of claim 25, wherein the compound has an ee of greater than or equal to 90%.

46. The compound of claim 25, wherein the compound has an ee of greater than or equal to 95%. compound represented by formula III:

wherein

R¹ is selected from the group consisting of hydrogen, alkyl, haloalkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, -OR, and -NR₂;

R² each independently are selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, hydroxyl, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, fluoroalkyl and cyano.

R is independently selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, and heteroaryl;

R¹ and R² may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; any two instances of R² may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5,or 6 backbone atoms;

B is selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl -OR⁷, and -N(R⁷)₂;

R⁷ is independently selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, and heteroaryl;

R¹ and B may be connected by a covalent tether; said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5,or 6 backbone atoms;

C is selected from the group consisting of -I, -Br, -Cl, -OC(O)R⁸, -OR⁸, alkenyl, alkynyl, and aryl;

R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl; A is selected from the group

-C(O)OR⁹, -CH₂OR⁹, -CHO, R⁹

R⁹ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl; any two instances of R⁹ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

X is selected from the group consisting of O, S, and NR¹⁰;

R¹⁰ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl;

R³, R⁴, R⁵, R⁶ each independently are selected from the group consisting of hydrogen, alkyl, aryl, alkenyl, and alkynyl;

R³ and R⁴ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; R⁵ and R⁶ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

R⁴ and R⁶ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms;

R³ and R⁵ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; and the stereochemical configuration at any stereocenter of a compound represented by

III is R, S, or a mixture of these configurations. 48. The compound of claim 47, wherein R¹ is selected from the group consisting of hydrogen, alkyl, -OR, and -NR₂; and B is selected from the group consisting of hydrogen, alkyl, -OR, and -NR₂. 49. The compound of claim 47, wherein R¹ is selected from the group consisting of hydrogen and alkyl; and B is selected from the group consisting of hydrogen and alkyl.

50. The compound of claim 47, wherein C is selected from the group consisting of -I and -OC(O)R⁸.

51. The compound of claim 47, wherein C is selected from the group consisting of -I and -OC(O)CH₃.

52. The compound of claim 47, wherein A is selected from the group consisting of

and X is selected from the group consisting of O and S .

53. The compound of claim 47, wherein A is selected from the group consisting of

, and -C(O)OH; X is O; R³, R⁴ and R⁵ are hydrogen; and R⁶ is tert- butyl.

54. The compound of claim 47, wherein A is selected from the group consisting of

and -C(O)OH; X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl.

55. The compound of claim 47, wherein R¹ is selected from the group consisting of hydrogen, alkyl, -OR, and -NR₂; B is selected from the group consisting of hydrogen, alkyl, -OR, and -NR₂; and C is selected from the group consisting of -I and -OC(O)R⁸.

56. The compound of claim 47, wherein C is selected from the group consisting of -I

and -OC(O)R⁸; A is selected from the group consisting

and -C(O)OR⁹; and X is selected from the group consisting of O and S.

57. The compound of claim 47, wherein A is selected from the group consisting of

is selected from the group consisting of O and S; R¹ is selected from the group consisting of hydrogen, alkyl, -OR, and - NR₂; and B is selected from the group consisting of hydrogen, alkyl, -OR, and -NR₂.

58. The compound of claim 47, wherein A is selected from the group consisting of

and -C(O)OR ; X is selected from the group consisting of O and S; R¹ is selected from the group consisting of hydrogen, alkyl, - OR, and -NR₂; B is selected from the group consisting of hydrogen, alkyl, -OR, and

-NR₂; and C is selected from the group consisting of -I and -OC(O)R⁸. In certain embodiments, the compounds of the present invention are represented by formula III, wherein R¹ is selected from the group consisting of hydrogen and alkyl; B is selected from the group consisting of hydrogen and alkyl; and C is selected from the group consisting of -I and -OC(O)CH₃.

59. The compound of claim 47, wherein C is selected from the group consisting of -I

and -OC(O)CH₃; A is selected from the group consisting of R⁶ and -

C(O)OH; X is O; R³, R⁴ and R⁵ are hydrogen; and R⁶ is tert-butyl.

60. The compound of claim 47, wherein C is selected from the group consisting of -I

and -OC(O)CH₃; A is selected from the group

and -

C(O)OH; X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl. 61. The compound of claim 47, wherein A is selected from the group consisting of

and -C(O)OH; X is O; R³, R⁴ and R⁵ are hydrogen; R⁶ is tert-butyl; and R¹ is selected from the group consisting of hydrogen and alkyl; and B is selected from the group consisting of hydrogen and alkyl. 62. The compound of claim 47, wherein A is selected from the group consisting of

and -C(O)OH; X is O; R³ and R⁴ are hydrogen; R⁵ and R⁶ are methyl; R¹ is selected from the group consisting of hydrogen and alkyl; and B is selected from the group consisting of hydrogen and alkyl.

63. The compound of claim 47, wherein A is selected from the group consisting of

R⁴ and R⁵ are hydrogen; R⁶ is tert-butyl; R¹ is selected from the group consisting of hydrogen and alkyl; B is selected from the group consisting of hydrogen and alkyl; and C is selected from the group consisting of -I and -OC(O)CH₃.

64. The compound of claim 47, wherein A is selected from the group consisting of

and -C(O)OH; X is O; R³ and R⁴ are hydrogen; R⁵ and R⁶ are methyl;

R¹ is selected from the group consisting of hydrogen and alkyl; B is selected from the group consisting of hydrogen and alkyl; and C is selected from the group consisting of -I and -OC(O)CH₃.

65. The compound of claim 47, wherein the compound has an ee of greater than or equal to 80%.

66. The compound of claim 47, wherein the compound has an ee of greater than or equal to 90%.

67. The compound of claim 47, wherein the compound has an ee of greater than or equal to 95%. 68. A method of catalytically oxidizing a compound, comprising the step of combining said compound with a transition metal, a ligand, and an oxidant, to form a chiral non-racemic product, wherein said compound is selected from the group represented by compounds of formula IV and V:

IV V wherein

R¹ is selected from the group consisting of hydrogen, alkyl, haloalkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, -OR, and -NR₂; R² each independently are selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, -OR, and -NR₂;

R is independently selected from the group consisting of hydrogen, alkyl, acyl, aryl, cycloalkyl, heteroalkyl, and heteroaryl;

R¹ and R² may be connected by a covalent tether, said covalent tether comprising 2, 3, 4, 5, 6 or 7 backbone atoms; the two instances of R² may be connected by a covalent tether, said covalent tether comprising 2, 3, 4, 5, 6 or 7 backbone atoms;

X is selected from the group consisting of O, S, and NR⁹;

R⁹ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl;

R³, R⁴, R⁵, R⁶ each independently are selected from the group consisting of hydrogen, alkyl, aryl, alkenyl, and alkynyl;

R³ and R⁴ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; R³ and R⁴ and the carbon to which they are bound may be C(=O);

R⁵ and R⁶ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; R⁴ and R⁶ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; R³ and R⁵ may be connected by a covalent tether, said covalent tether consisting of one or more substituents and 1, 2, 3, 4, 5, or 6 backbone atoms; and the stereochemical configuration at any stereocenter of a compound represented by IV or V is R, S, or a mixture of these configurations. 69. The method of claim 68, wherein said transition metal is selected from the group consisting of palladium, platinum, or nickel.

70. The method of claim 68, wherein said transition metal is palladium.

71. The method of claim 68, wherein said ligand is acyloxy.

72. The method of claim 68, wherein said ligand is acetate. 73. The method of claim 68, wherein said oxidant is MeC(=O)tBu, PhC(=O)OOtBu,

[PhC(=O)]₂O₂, [CH₃(CH₂)ioC(=0)]₂0₂, tBuOOtBu, and tBuOOH, copper(I) acetate, copper(IT) acetate, silver acetate, phenyl iodoacetate or iodine.

74. The method of claim 68, wherein said oxidant is [PhC(=O)]₂O₂, [CH₃(CH₂)_!oC(=0)]₂θ_2, phenyl iodoacetate or iodine. 75. The method of claim 68, wherein said transition metal is selected from the group consisting of palladium, platinum, and nickel; said ligand is acyloxy; and said oxidant is MeC(=O)tBu, PhC(=O)OOtBu, [PhC(=O)]₂O₂, [CH₃(CH₂)₁₀C(=O)]₂O₂, tBuOOtBu, and tBuOOH, copper(I) acetate, copper(II) acetate, silver acetate, phenyl iodoacetate or iodine. 76. The method of claim 68, wherein said transition metal is palladium; said ligand is acetate; and said oxidant is [PhC(=O)]₂O₂, [CH₃(CH₂)₁₀C(=O)]₂O₂, phenyl iodoacetate or iodine.

77. The method of claim 68, wherein X is O.

78. The method of claim 68, wherein X is O; and R¹ is alkyl. 79. The method of claim 68, wherein X is O; and R¹ is methyl.

80. The method of claim 68, wherein X is O; R² is alkyl; and the two instances of R² are connected by a covalent tether of 2 atoms.

81. The method of claim 68, wherein X is O; and R¹ is aryl.

82. The method of claim 68, wherein X is O; and R¹ is phenyl. 83. The method of claim 68, wherein the chiral non-racemic product has an enantiomeric excess greater than about 80%.

84. The method of claim 68, wherein the chiral non-racemic product has an enantiomeric excess greater than about 90%. 85. The method of claim 68, wherein the chiral non-racemic product has an enantiomeric excess greater than about 95%.

86. The method of claim 68, wherein the reaction is preformed in a sealed flask.

87. The method of claim 68, wherein said compound is represented by compounds of formula IV.

88. The method of claim 87, wherein X is O; and R³, R⁴, and R⁵ are hydrogen.

89. The method of claim 87, wherein X is O; R³, R⁴, and R⁵ are hydrogen; and R⁶ is alkyl.

90. The method of claim 87, wherein X is O; R³, R⁴, and R⁵ are hydrogen; and R⁶ is t-butyl.

91. The method of claim 87, wherein X is O; R¹ is alkyl; and R³, R⁴, and R⁵ are hydrogen.

92. The method of claim 87, wherein X is O; R¹ is alkyl; R³, R⁴, and R⁵ are hydrogen; and R⁶ is alkyl. 93. The method of claim 87, wherein X is O; R¹ is alkyl; R³, R⁴, and R⁵ are hydrogen; and R⁶ is t-butyl.

94. The method of claim 87, wherein X is O; R¹ is methyl; and R³, R⁴, and R⁵ are hydrogen.

95. The method of claim 87, wherein X is O; R¹ is methyl; R³, R⁴, and R⁵ are hydrogen; and R⁶ is alkyl.

96. The method of claim 87, wherein X is O; R¹ is methyl; R³, R⁴, and R⁵ are hydrogen; and R⁶ is t-butyl.

97. The method of claim 87, wherein X is 0; R² is alkyl; the two instances of R² are connected by a covalent tether of 2 atoms; and R³, R⁴, and R⁵ are hydrogen. 98. The method of claim 87, wherein X is O; R² is alkyl; the two instances of R² are connected by a covalent tether of 2 atoms; R³, R⁴, and R⁵ are hydrogen; and R⁶ is t-butyl.

99. The method of claim 87, wherein X is O; R¹ is aryl; and R³, R⁴, and R⁵ are hydrogen.

100. The method of claim 87, wherein X is O; R¹ is aryl; R³, R⁴, and R⁵ are hydrogen; and R⁶ is alkyl.

101. The method of claim 87, wherein X is O; R¹ is aryl; R³, R⁴, and R⁵ are hydrogen; and R⁶ is t-butyl. 102. The method of claim 68, wherein said compound is represented by compounds of formula V.

103. The method of claim 102, wherein X is O; and R³ and R⁵ are hydrogen.

104. The method of claim 102, wherein X is O; R³ and R⁴ are hydrogen. 105. The method of claim 102, wherein X is O; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl.

106. The method of claim 102, wherein X is O; R¹ is alkyl; R³ and R⁵ are hydrogen.

107. The method of claim 102, wherein X is O; R¹ is methyl; and R³ and R⁴ are hydrogen.

108. The method of claim 102, wherein X is O; R¹ is methyl; R³ and R⁵ are hydrogen. 109. The method of claim 102, wherein X is O; R¹ is methyl; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl.

110. The method of claim 102, wherein X is O; R² is alkyl; the two instances of R² are connected by a covalent tether of 2 atoms; and R³ and R⁵ are hydrogen.

111. The method of claim 102, wherein X is O; R² is alkyl; the two instances of R² are connected by a covalent tether of 2 atoms; R³ and R⁴ are hydrogen.

112. The method of claim 102, wherein X is O; R² is alkyl; the two instances of R² are connected by a covalent tether of 2 atoms; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl.

113. The method of claim 102, wherein X is O; R¹ is aryl; and R³ and R⁵ are hydrogen. 114. The method of claim 102, wherein X is O; R¹ is aryl; R³ and R⁴ are hydrogen.

115. The method of claim 102, wherein X is O; R¹ is aryl; R³ and R⁴ are hydrogen; and R⁵ and R⁶ are methyl.