WO2024084227A1 - Substituted bicyclic dienes - Google Patents

Abstract

The invention provides a chiral single stereoisomer diene of Formula (I) wherein R1, R2, and R3 are each substituent groups that are independently selected from H, halogen groups, alkyl groups (which may be linear or branched), alkenyl groups (which may be linear or branched, and may in particular be allyl or methallyl), aryl groups, alkaryl groups, heteroaryl groups, and substituted amino groups, ether groups, or carbonyl groups; wherein each substituent group R may be optionally substituted; and wherein R1, R2, and R3 are selected such that at least one of these groups includes a stereogenic element. These 1,6,7,8,9-substituted (5r,7ar)-4,5-dihydro-5,7a-ethenoindol-2(1H)-one ligands according to the present invention may be used as ligands for metals in enantioselective catalysis and transition metal complexes of these ligands may in particular be used as catalyst in the manufacture of active pharmaceutical ingredients.

Description

SUBSTITUTED BICYCLIC DIENES

Field of the Invention

The present invention relates to bicyclo[2.2.2]octadienes, and in particular to derivatives of 1,6,7,8,9-substituted (5r,7ar)-4,5-dihydro-5,7a-ethenoindol-2(lL7)-one cores (known as the ‘Himbert Diene’).

bicyclo[2.2.2]octa-2,5-diene (5r,7ar)-4,5-dihydro-5,7a-ethenoindol-2(1 H)-one

The dienes of the present invention are beneficial in that they can be easily isolated and are stereoisomerically pure derivatives of the ‘Himbert Diene’ and they are useful for enantioselective catalysis. In particular, these ligands have been shown to exhibit high performance in nine types of enantioselective Rh(I)-catalyzed 1,4-addition or 1,2-addition reactions.

Background to the Invention

Simple dienes are commonly used as ligands, to stabilise or change the reactivity of transition metal complexes. Some diene ligands and their metal complexes are widely available and are used as catalysts, e.g. in processes producing high value fine chemicals. For example, low-cost 1,5-cycloctadiene (COD, CAS number 111-78-4) and norbornadiene (nbd, CAS number 121-46-0) are often used in transition metal catalysts. However, neither of these dienes alone is able to induce enantioselective catalysis, i.e. the enriched formation of one of two enantiomerically related organic products in a catalytic reaction.

Ligands that are able to induce enantioselective catalysis have high value. This applies especially to the pharmaceutical sector, where it is desirable to be able to prepare enantiomerically enriched drug intermediates and enantiomerically pure active agents. It is therefore desirable to be able to provide chiral, single stereoisomer, bicyclic diene ligands that can induce enantioselective catalysis. Various chiral single stereoisomer substituted dienes are known in the art. These diene ligands are valuable ligands, allowing a wide range of enantioselective catalysis in the presence of transition metal salts.

For example, T. Hayashi, K. Ueyama, N. Tokunaga, K. Yoshida, J. Am. Chem. Soc. 2003, 125, 11508 describes a chiral single stereoisomer diene ligand of the following formula:

Since this disclosure in 2003, many alternative stereoisomerically pure chiral diene ligand architectures have been disclosed.

Y. Huang, T. Hayashi, Chem. Rev. 2022, 122, 18, 14346 describes many such ligands; the most effective of which have the following general class formulae:

where R is potentially any group and Y any viable heteroatom.

However, synthetic routes to the chiral diene ligands exemplified above are normally stepintensive.

Additionally, attaining the ligands as chiral single stereoisomers normally requires:

(i) the use of expensive chiral HPLC - as in: Y. Otomaru, N. Tokunaga, R. Shintani, T. Hayashi, Org. Lett. 2005, 7, 307; Y. Otomaru, A. Kina, R. Shintani, T. Hayashi, Tetrahedron: Asymmetry 2005, 16, 1673; T. Nishimura, Y. Ichikawa, T. Hayashi, N. Onishi, M. Shiotsuki, T. Masuda, Organometallics 2009, 28, 4890; and T. Nishimura, H. Kumamoto, M. Nagaosa, T. Hayashi, Chem. Commun. 2009, 5713; or

(ii) time consuming enzymatic kinetic resolutions - as in: X. Q. Feng, H. F. Du, Chin. J. Org. Chem. 2015, 35, 259; Z.-Q. Wang, C.-G. Feng, M.-H. Xu, G.-Q. Lin, J. Am. Chem. Soc. 2007, 129, 5336; Y. Luo, A. J. Carnell, Angew. Chem., Int. Ed. 2010, 49, 2750; and C. Shao, H.-J. Yu, N.-Y. Wu, C.-G. Feng, G.-Q. Lin, Org. Lett. 2010, 12, 3820; or

(iii) wasteful resolution of derived rhodium complexes with chiral auxiliaries (rather than the simpler dienes themselves) - as in: N. M. Ankudinov, D. A. Chusov, Y. V. Nelyubina, D. S. Perekalin, Angew. Chem., Int. Ed. 2021, 60, 18712; or

(iv) use of technically demanding catalytic asymmetric reactions to prepare them - as in: T. Hayashi, K. Ueyama, N. Tokunaga, K. Yoshida, J. Am. Chem. Soc. 2003,

125, 11508; and S. Abele, R. Inauen, D. Spielvogel, C. Moessner, J. Org. Chem. 2012, 77, 4765; or

(v) the use of chiral pool single stereoisomer starting materials that typically give unequal cost access to the enantiomeric (or pseudoenantiomeric) diene ligands - as in: C. Fischer, C. Defieber, T. Suzuki, E. M. Carreira, J. Am. Chem. Soc. 2004,

126, 1628; C. Defieber, J.-F. Paquin, S. Serna, E. M. Carreira, Org. Lett. 2004, 6, 3873; and K. Okamoto, T. Hayashi, V. H. Rawal, Org. Lett. 2008, 10, 4387.

G. Himbert and L. Henn in Angew. Chem., Int. Ed. Engl. 1982, 21, 620 were the first describe the single-step (cycloaddition) preparation of a non-chiral diene of the formula:

(5r,7ar)-1 -methyl-4,5-dihydro-5,7a-ethenoindol-2(1 H)-one

These dienes are known in the art as ‘Himbert Dienes’ .

Further disclosures of ‘Himbert Dienes’ are made in: a) G. Himbert, K. Diehl, G. Mass, J. Chem. Soc., Chem. Commun. 1984, 900; b) H. Lothar, H. Gerhard, D. Klaus, K. Menahem, Chem. Ber. 1986, 119, 1953-1963; c) K. Diehl, G. Himbert, Chem. Ber. 1986, 119, 2874- 2888; d) G. Himbert, K. Diehl, H.-J. Schlindwein, Chem. Ber. 1986, 119, 3227-3235; e) H.-J. Schlindwein, K. Diehl, G. Himbert, Chem. Ber. 1989, 122, 577-584; f) G. Himbert, D. Fink, J. Prakt. Chem. 1996, 338, 355-362; g) L. S. Trifonov, A. S. Orahovats, Helv. Chim. Acta 1986, 69, 1585-1587; h) L. S. Trifonov, A. S. Orahovats, Helv. Chim. Acta 1987, 70, 262-270; i) L. S. Trifonov, S. D. Simova, A. S. Orahovats, Tetrahedron Lett. 1987, 28, 3391-3392; j) J. K. Lam, Y. Schmidt, C. D. Vanderwal, Org. Lett. 2012, 14, 5566-5569; k) H. V. Pham, A. S. Karns, C. D. Vanderwal, K. N. Houk, J. Am. Chem. Soc. 2015, 137, 6956-6964; and 1) G. Cheng, X. He, L. Tian, J. Chen, C. Li, X. Jia, J. Li, J. Org.

Chem. 2015, 80, 11100-11107. These known dienes have the following general structures:

Aik = simple alkyl; Ar = aryl, mostly Ph However, none of these is isolated as a single stereoisomer, with defined absolute chirality. Instead, the chiral species above have only been prepared as inseparable mixtures of stereoisomers. This renders them unusable in enantioselective catalysis using a single stereoisomer. Chiral ‘Himbert Dienes’ that are highly enriched in one stereoisomer are limited to the structural formulae below. However, these are still not completely stereochemically pure single isomers.

5,7a-ethenobenzofuran-2-one core L. S. Trifonov and A. S. Orahovats in Helv. Chim. Acta 1989, 72, 59-64; and Y. Schmidt, J. K. Lam, H. V. Pham, K. N. Houk, C. D. Vanderwal in J. Am. Chem. Soc. 2013, 135, 7339-7348 used rare chiral allenes to partially control the stereochemistry at position 4. Q. Lin, S. Zheng, L. Chen, J. Wu, J. Li, P. Liu, S. Dong, X. Liu, Q. Peng, X. Feng, Angew. Chem., Int. Ed. 2022, 61, e202203650 achieved a similar outcome, but by use of a chiral catalyst. However, all three derivatives have limited potential for use in enantioselective catalysis, because there is no 7, 6, 8 or 9-substitution of the diene (C=C) bonds.

D. P. Hari, G. Pisella, M. D. Wodrich, A. V. Tsymbal, F. F. Tirani, R. Scopelliti and J. Waser in Angew. Chem., Int. Ed. 2021, 60, 5475-5481 disclose one example of a chiral single stereoisomer (a 5,7a-ethenobenzofuran-2-one derivative) with methyl substituents at the 7,9-positions. This can be used for asymmetric catalysis of the 1,4-addition of PhB(OH)2 to 2-cyclo-hexenone. However, the diene is not easily isolated into a single stereoisomer; separation of a racemic mixture by chiral HPLC is required and only gave access to a small quantity of the enantiopure chiral diene. There are, therefore, practical limitations to this approach.

A range of chiral diene ligands are also the subject of previous patent publications: a) US8586810B2; b) JP2015172024A; c) CN111217809B; d) CN101845056B; e) CN100482644C; f) CN105985364B; g) CN106040299B; h) US2013096348A1B; and i) WO2014126068A1.

However, none of these documents disclose the 1,6,7,8,9-substituted (5r,7ar)-4,5-dihydro- 5,7a-ethenoindol-2(lH)-one cores according to the present invention. In general, there remains a need for dienes that can be isolated as a pure single stereoisomer, with defined absolute chirality, such that a single stereoisomer of the diene can be used in enantioselective catalysis.

There remains a need for chiral diene ligands that are straightforward to access and that can be manufactured in a cost-effective manner. There remains a need for chiral diene ligands that can be synthesised on a multi -gram scale, or an even larger scale.

Summary of the Invention

The present invention provides the chiral single stereoisomer ‘Himbert Dienes’ of Formula (I):

wherein: R¹, R², and R³ are general independent variables encompassing H, halogen, linear and branched alkyls, substituted amino, ether, aryl, heteroaryl or carbonyl units that are all optionally substituted as necessary; wherein: R¹, R², and R³ are selected such that chiral ‘Himbert Dienes’ result that are either single stereoisomers themselves; or that if mixtures of stereoisomers result they are separable without recourse to chiral HPLC, enzymatic resolution, or other resolution processes; and whereby: the typically inseparable stereoisomeric mixtures associated with chiral ‘Himbert Dienes’ are avoided.

Specifically, the first aspect of the present invention provides a chiral single stereoisomer diene of Formula (I):

wherein R¹, R², and R³ are each substituent groups that are independently selected from H, halogen groups, alkyl groups (which may be linear or branched), alkenyl groups (which may be linear or branched, and may in particular be allyl or methallyl), aryl groups, alkaryl groups, heteroaryl groups, and substituted amino groups, ether groups, or carbonyl groups.

Each substituent group R may optionally be substituted.

In the present invention, the product is provided as a single stereoisomer; this may be as a result of the diene being directly produced as a single stereoisomer in the manufacturing method, or it may be that a mixture of stereoisomers results, and these are then separated. Preferably, the stereoisomers are separable without recourse to chiral HPLC, enzymatic resolution, or other resolution processes. It is desired that the separation is achieved using crystallization or standard column chromatography.

The skilled reader will understand that in order for the diene to be chiral but readily separable, an additional stereogenic element is required, meaning that the diene is separable as a diastereomer. Thus it is desired that R¹, R², and R³ are selected such that at least one of these groups includes a stereogenic element. Accordingly, the product of Formula (I) is a chiral ‘Himbert Diene’. In one embodiment, only one of R¹, R², and R³ includes a stereogenic element.

In this regard, the skilled reader will appreciate that typically it is possible to obtain more than one stereoisomer of a diene of Formula (I). As used herein, the phrase "chiral single stereoisomer ‘Himbert Dienes implicitly implies an ability to both make Formula (I) as a single stereoisomer and/or to be able to separate the stereoisomers of Formula (I) completely into near stereoisomer forms (called pseudoenantiomers, as defined by S Ricko, J. A. Izzo and K. A. Jorgensen in Chem. Eur. J. 2020, 67, 15727).

The skilled reader will appreciate that a pair of diastereomeric products can be more readily separated than a pair of enantiomeric products, because diastereomers have distinct physical properties. This enables the use of conventional and straightforward techniques such as chromatography in the separation of diastereomers. Diastereomers are, of course, known in the art as compounds having the same molecular formula but which are non- superimposable non-mirror images of each other. This contrasts with enantiomers which are compounds having the same molecular formula and which are non-superimposable but are mirror images of each other.

The present invention incorporates a chiral auxiliary into the [4+2] cyclo-addition precursor to give diastereomeric cycloaddition products that have the potential to be readily separated. This is achieved by one of R¹, R², and R³ including a stereogenic element.

In one embodiment, the diene of the present invention has a 1,6,7,8,9-substituted (5r,7ar)- 4, 5 -dihydro-5, 7a-ethenoindol-2(127)-one core.

The diene of the invention can be isolated as a single (of defined absolute chirality) stereoisomer. In one embodiment, the diene of the invention is obtained as stereoisomers of Formula (I) and then separated completely into near stereoisomer forms.

In one embodiment, the diene of the invention is a chiral ‘Himbert Dienes’ that is provided as a completely stereochemically pure single isomer.

The diene of the present invention is able to induce enantioselective catalysis (enriched formation of one of two enantiomerically related organic products in a catalytic reaction).

In one embodiment, R¹ to R³ are each substituent groups that are independently selected from:

• hydrogen (H),

• halogen (F, Cl, Br, I),

• C1-C12 alkyl,

• allyl or methallyl,

• C5-12 aryl,

• C6-C22 alkaryl,

• C5-12 heteroaryl,

• substituted amino (NH(2-n)R^an, where n = 1 or 2),

• substituted ether (OR^a),

• substituted carbonyl derivatives [C(=O)NH(2-_n)R^an where n = 1 or 2; or C(=O)OR^a; or C(=O)R^a]; wherein each R^a group is independently selected from hydrogen, C1-C12 alkyl, allyl, methallyl, C5-12 aryl, C6-C22 alkaryl, C5-12 heteroaryl; and wherein each R group (R¹, R², R³, R^a) is optionally substituted.

In one embodiment, R¹ is a C1-C22 alkyl group and R² and R³ are selected from H, halogen, linear and branched alkyls, alkaryl, allyl, methallyl, aryl, heteroaryl, and substituted amino, ether, and carbonyl groups (as defined above), wherein each R group is optionally substituted.

In one embodiment, R¹ is a C1-C22 alkyl group and R² and R³ are selected from H, halogen, linear and branched alkyls, aryl, heteroaryl, and substituted amino, ether, and carbonyl groups (as defined above), wherein each R group is optionally substituted.

In one embodiment, R¹ is a C1-C22 alkyl group, R² is C(=O)NH-CHMe-Aryl of either (R) or (.S') absolute stereochemistry, and R³ is selected from H, halogen, linear and branched alkyls, aryl, heteroaryl, alkaryl, allyl, methallyl, and substituted amino, ether, and carbonyl groups (as defined above), wherein each R group is optionally substituted.

In one embodiment, R¹ is a C1-C22 alkyl group, R² is C(=O)NH-CHMe-Aryl of either (R) or (.S') absolute stereochemistry, and R³ is selected from H, halogen, linear and branched alkyls, aryl, heteroaryl, and substituted amino, ether, and carbonyl groups (as defined above), wherein each R group is optionally substituted.

In one embodiment, R¹ is a C1-C22 alkyl group, R² is C(=O)NH-CHMe-Aryl of either (R) or (.S') absolute stereochemistry, and R³ is halogen.

In one embodiment, R¹ is an alkyl group C1-C22, R² is C(=O)NH-CHMe-(l -naphthyl) of either (R) or (.S') absolute stereochemistry and R³ is Br.

In one embodiment, R¹ is -CHMe-Aryl of either (R) or (.S') absolute stereochemistry, and R² and R³ are independently selected from H, halogen, linear and branched alkyls, substituted amino, ether, aryl, heteroaryl and carbonyl groups, which are each optionally substituted. For example, R¹ may be -CHMe-(l -naphthyl) of either (R) or (.S') absolute stereochemistry. In one embodiment, R¹, R², and R³ are selected such that at least one of R² and R³ includes a stereogenic element. It is believed that connecting the chiral auxiliary through one of the alkenyl positions of the chiral diene framework, where the effect of its stereogenic center would be better expressed, may lead to greater differences in the physical properties of the final diastereomeric ligands, thus increasing the chances of separating them through crystallization or column chromatography.

In general, the chiral single stereoisomers of Formula (I) of the invention will be used as ligands for metals in enantioselective catalysis. Specifically, they can be used as direct replacements for current chiral diene ligands. They may provide improvements over said current hard-to-attain and expensive ligands.

The skilled reader will readily understand that diene ligands and their metal complexes are widely available and are used as catalysts, e.g. in processes producing high value fine chemicals. It is straightforward for the skilled reader to recognise that the claimed dienes can be used in catalysis in essentially the same manner as is conventionally known, e.g. with the ligands being provided in the form of transition metal complexes and with these metal complexes being used in catalysis, e.g. enantioselective catalysis, such as in the manufacture of fine chemicals, agrochemicals or pharmaceuticals.

Use of these ligands in the pharmaceutical sector is foreseen to be a major utilisation of this invention, due to the need to prepare single-enantiomer active pharmaceutical ingredients at scale, using chiral ligand-based catalysis.

The chiral dienes of Formula (I) can, in particular, be used as the ligands in enantioselective Rh(I)-catalyzed reactions.

Thus, in a second aspect of the invention, there is provided a metal complex in which one or more diene ligand according to the first aspect is bound to (coordinated with) a metal ion. The metal may be a transition metal, such as rhodium or copper or ruthenium or palladium.

In a third aspect, there is provided the use of the metal complex according to the second aspect as a catalyst, e.g. in enantioselective catalysis. In a fourth aspect, there is provided a method of preparing an enantiomerically pure compound, wherein the compound is prepared in the presence of a catalyst which is a metal complex according to the second aspect.

Detailed Description of the Invention

In the compound of Formula (I), R¹, R², and R³ are each substituent groups that are independently selected from H, halogen groups, alkyl groups (which may be linear or branched), alkenyl groups (which may be linear or branched, and may in particular be allyl or methallyl), aryl groups, alkaryl groups, heteroaryl groups, substituted amino groups, ether groups, or carbonyl groups. Each substituent group may be optionally substituted. R¹, R², and R³ are selected such that at least one of these groups includes a stereogenic element. In one embodiment, only one of R¹, R², and R³ includes a stereogenic element.

In one embodiment of the compound of Formula (I), R¹, R², and R³ are independently selected groups that are optionally substituted, wherein each of R¹, R², and R³ are independently selected from hydrogen, halogen (F, Cl, Br, I), C1-C12 alkyl, allyl, methallyl, C5-12 aryl, C6-C22 alkaryl, C5-12 heteroaryl, substituted amino (NH(2-n)R^an, n = 1 or 2), substituted ether (OR^a), or substituted carbonyl derivatives [C(=O)NH(2 n)R^an; or C(=O)OR^a; or C(=O)R^a]; wherein each R^a is selected from hydrogen, C1-C12 alkyl, allyl, methallyl, C5-12 aryl, C6-C22 alkaryl, and C5-12 heteroaryl.

The halogen group may be selected from F, Cl, Br, and I.

When the alkyl group has three or more carbon atoms, it may be straight chain or branched. In one embodiment, the alkyl group is C1-C12 alkyl.

When the alkenyl group has three or more carbon atoms, it may be straight chain or branched. In one embodiment, the alkenyl group is C2-C12 alkenyl. The alkenyl groups may in particular be allyl or methallyl.

Alkaryl refers to -alkylene-aryl groups, preferably having from 1 to 10 carbon atoms in the alkylene moiety and preferably having from 6 to 10 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, a-methylbenzyl, a-methyl naphthyl and the like. In one embodiment, the group is C6-C22 alkaryl. The aryl group is a carbocyclic group having aromatic character, examples of which include phenyl and naphthyl. The aryl group can, for example, be a five-membered or sixmembered monocyclic ring or may be a bicyclic structure formed from fused five- and sixmembered rings or formed from two fused six-membered rings, or formed from two fused five-membered rings. In one embodiment, the aryl group is a C5-12 aryl. The aryl group can, for example, have from 5 to 10 ring members.

In general, when an aromatic ring system is present in R¹, R², or R³ (or R^a in amino, ether and carbonyl derivatives) this may be a monocyclic ring or may be a fused ring, e.g. resulting from the condensation of multiple benzene rings or resulting from the condensation of benzene and other rings. In one embodiment the fused ring is formed from two or three rings. In one embodiment it is formed from a fused five-membered ring plus six-membered ring, or from two fused six-membered rings, or from two fused fivemembered rings. Examples of fused rings include a pentalene ring, indene ring, naphthalene ring, anthracene ring, azulene ring, biphenylene ring, indacene ring, acenaphthylene ring, fluorene ring, phenalene ring, and a phenanthrene ring.

When a heterocyclic aromatic ring is present in R¹, R², R³ (or R^a in amino, ether and carbonyl derivatives), this includes at least one heteroatom in the ring, e.g. the aromatic ring system includes one or more S, N or O atom within the ring system. The skilled reader will appreciate that the heteroatom(s) replace one or more of the carbon atoms within the ring. In general in the heterocyclic aromatic ring there may suitably be up to four heteroatoms which replace a carbon in the ring, e.g. one, two or three heteroatoms which replace a carbon in the ring. Examples of heterocyclic rings include a pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, carbazole ring, indole ring, isoindole ring, indolizine ring, quinoline ring, isoquinoline ring and a purine ring.

As noted above, the group may also be substituted amino (NH(2-njR^an, n = 1 or 2), or substituted ether (OR^a). If substituted amino or substituted ether groups are used the R^a group may be selected from alkyl, allyl, methallyl, aryl, heteroaryl units; preferably each R^a is selected from hydrogen, C1-C12 alkyl, allyl, methallyl, C5-12 aryl, C6-C22 alkaryl, and C5-12 heteroaryl. For example, R^a may be independently selected from hydrogen, methyl, ethyl, w-propyl, allyl, Ph, a-CHMe-Aryl. As noted above, the group may also be a substituted carbonyl derivative [C(=O)NH(2-n)R^an; or C(=O)OR^a; or C(=O)R^a] . If substituted carbonyl derivatives are used the R^a group may be selected from alkyl, allyl, methallyl, aryl, or heteroaryl units; preferably each R^a is selected from hydrogen, C1-12 alkyl, allyl, methallyl, C5-12 aryl, C6-C22 alkaryl, and C5-12 heteroaryl. For example, R^a may be independently selected from hydrogen, methyl, ethyl, M-propyl, allyl, Ph, a-CHMe-Aryl.

In one embodiment, each of R¹, R², R³ (or R^a in amino, ether and carbonyl derivatives) may be independently selected from hydrogen, bromo, methyl, ethyl, w-propyl, Ph, a-CHMe- Aryl.

It may be that each substituent group (R¹, R², R³ or R^a) is independently substituted with an electron-donating group or an electron-accepting group.

Electron-donating groups can be any functional group capable of donating at least a portion of its electron density into the linear or ring fragment to which it is directly attached, such as by resonance or inductive effects. Exemplary electron-donating groups can be selected from, but are not limited to, one or more of the following groups: alkoxy, thioether, amide, amine, hydroxyl, thiol, acyloxy, aliphatic (e.g., alkyl, alkenyl, alkynyl), aryl, or combinations thereof.

Electron-accepting groups can be any functional group capable of accepting electron density from the linear or ring fragment to which it is directly attached, such as by inductive electron withdrawal. Exemplary electron-accepting groups can be selected from, but are not limited to, one or more of the following: aldehyde, ketone, ester, carboxylic acid, acyl, acyl halide, cyano, sulfonate, nitro, nitroso, quaternary amine, pyridinyl (or pyridinyl wherein the nitrogen atom is functionalized with an aliphatic or aryl group), alkyl halide, or combinations thereof.

In a preferred embodiment of the invention, the chiral single stereoisomer bicyclic diene ligands are selected from dienes of Formula (I-a) and (I-b):

wherein X is a halogen (e.g. F, Cl, Br, or I).

Formulae (I-a) and (I-b) are rendered pseudo-enantiomeric, and thus easily separable, by the presence of the (R)-NH-CHMe(l -naphthyl) unit in both (I-a) and (I-b). It will be recognised by the skilled reader that equivalent formulae to (I-a) and (I-b) can be attained through use of a (S)-NH-CHMe(l -naphthyl) unit as an equivalent presentation of this preferred embodiment. These dienes based on (S)-NH-CHMe(l -naphthyl) are disclosed and claimed.

In a preferred embodiment, therefore, R¹ is an alkyl group (w-propyl), R² is C(=O)NH- CHMe-(l -naphthyl) of either (R) or (.S') absolute stereochemistry and R³ is X where X is a halogen.

It will be recognised by the skilled reader that Formulae (I), (I-a) and (I-b) can be reached through a range of chemistries, including those given in the Examples.

An attraction of this embodiment is that (I-a) and (I-b) are readily separated by low-cost (achiral) chromatography into completely pure pseudo-enantiomeric chiral, single stereoisomer, bicyclic diene ligands. This is technologically simple and greatly facilitates a practical implementation in enantioselective catalysis applications.

Embodiments (I-a) and (I-b) are particularly favoured when X = Br.

In this case, the modification of either stereochemical isomer (I-a) or (I-b), by known processes, allows the preparation of wide-ranging derivatives of Formula (I-c) shown below:

It should be understood that the abbreviated Formula (I-c) captures and represents all of the separated stereochemical pseudo-enantiomeric species available through use of Formulae (I-a) and (I-b).

In one embodiment, R³ is Me, allyl, Ph, 1-naphthyl, 2-MeOC₆H₄, 3,5-Me2CeH₃, or 3,4- (MeO)2C₆H₃.

In a preferred embodiment, therefore, R¹ is an alkyl group (w-propyl), R² is C(=O)NH- CHMe-( 1-naphthyl) of either (R) or (.S') absolute stereochemistry, and R³ is selected from alkyl, allyl, alkaryl and aryl groups, which are each optionally substituted (e.g., Me, allyl, Ph, 1-naphthyl, 2-MeOC₆H₄, 3,5-Me₂C₆H₃, or 3,4-(MeO)₂C₆H₃).

Additional preferred embodiments of the invention are dienes selected from those represented by Formulae (I-d) and (I-e):

(I-d) (I-e)

In one embodiment, Aryl is phenyl or 1-naphthyl. In one embodiment, R³ is Br, Me, allyl, Ph, 1-naphthyl, 2-MeOC₆H₄, 3,5-Me₂C₆H₃, or 3,4-(MeO)₂C₆H₃.

It will be recognised by the skilled reader that equivalent formulae to (I-d) and (I-e) would be attained through use of a (S)-NH-CHMe(Aryl) unit as an equivalent presentation of this preferred embodiment. These dienes based on (S)-NH-CHMe(Aryl) are disclosed and claimed.

In a preferred embodiment, therefore, R¹ is an alkyl group (Me), R² is C(=O)NH-CHMe- Aryl of either (R) or (.S') absolute stereochemistry (e.g. where Aryl is phenyl or 1 -naphthyl), and R³ is selected from halogen, alkyl, allyl, alkaryl and aryl groups, which are each optionally substituted (e.g. Br, Me, allyl, Ph, 1-naphthyl, 2-MeOC₆H₄, 3,5-Me₂CeH₃, or 3,4-(MeO)₂C₆H₃).

Embodiments for Formulae (I-d) and (I-e) are desirable because, in addition to being separable by chromatographic methods, they are also separable by virtue of their different solubilities.

Additional preferred embodiments of

invention are dienes selected from those represented by Formulae (I-f) and (I-g):

In one embodiment, Aryl is phenyl or 1-naphthyl. In one embodiment, R² is H, Br, Me, allyl, Ph, or 1-naphthyl. In one embodiment, R³ is H, Br, Me, allyl, Ph, or 1-naphthyl.

In one preferred embodiment, the chiral single stereoisomer bicyclic diene is of Formula (I-f), which is completely separable from its pseudo enantiomeric isomer (I-g).

It will be recognised by the skilled reader that equivalent formulae to (I-f) and (I-g) would be attained through use of a (S)-CHMe(Aryl) unit as an equivalent presentation of this preferred embodiment. These dienes based on (S)-CHMe(Aryl) are disclosed and claimed.

In a preferred embodiment, therefore, R¹ is an alkaryl group (-CHMe(Aryl), e.g. where Aryl is phenyl or 1-naphthyl) of either (R) or (.S') absolute stereochemistry, R² is selected from H, halogen, alkyl, allyl, alkaryl and aryl groups, which are each optionally substituted, (e.g. H, Br, Me, allyl, Ph, or 1-naphthyl), and R³ is selected from H, halogen, alkyl, allyl, alkaryl and aryl groups, which are each optionally substituted (e.g. H, Br, Me, allyl, Ph, or 1-naphthyl). Compounds of Formulae (I-f) and (I-g) are, in preferred cases, separable into chiral single stereoisomer bicyclic dienes.

Alternatively, in symmetrical cases only a single stereoisomer is formed. For example if R² and R³ are both H and Aryl is 1 -naphthyl, then the diene is of Formula (I-h). naphthyl '"Me

(I-h) where use of (S)-l-(naphthalen-l-yl)ethan-l -amine leads to the enantiomer of (I-h) directly, without separation of any isomer.

The dienes of the present invention can be provided in the form of metal complexes. Thus, one or more diene of the invention is a ligand that is bound to (coordinated with) a metal ion, especially a transition metal ion. The metal may, for example, be rhodium or copper.

Specifically, the dienes of the invention can be used as improved direct replacements for current (hard to attain and expensive) chiral diene ligands.

The metal complex can be used in enantioselective catalysis. Use of the metal-ligand complexes in the pharmaceutical sector is foreseen to be the major utilisation of this invention, due to the need to prepare single enantiomer active pharmaceutical ingredients at scale using chiral ligand-based catalysis. However, the metal complexes are relevant for and useful in the catalysis of any chemical manufacture where enantioselectivity is important, e.g. agrochemicals and fine chemicals, as well as pharmaceuticals.

The disclosure includes, inter alia, the subject matter of the following clauses:

1. chiral single stereoisomer ‘Himbert Dienes’ of Formula (I):

wherein: R¹, R², and R³ are general independent variables encompassing H, halogen, linear and branched alkyls, substituted amino, ether, aryl, heteroaryl or carbonyl units that are all optionally substituted as necessary. wherein: R¹, R², and R³ are selected such that chiral ‘Himbert Dienes’ result that are either single stereoisomers themselves; or that if mixtures of stereoisomers result they are separable without recourse to chiral HPLC, enzymatic resolution, or other resolution processes.

2. A compound of clause 1 wherein R¹ is an alkyl group C1-C22 and R², and R³ are general independent variables encompassing H, halogen, linear and branched alkyls, substituted amino, ether, aryl, heteroaryl or carbonyl units that are all optionally substituted as necessary.

3. A compound of clause 1 wherein R¹ is an alkyl group C1-C22, R² is NH-CHMe-Aryl of either (R) or (.S') absolute stereochemistry and R³ is a general independent variable encompassing H, halogen, linear and branched alkyls, substituted amino, ether, aryl, heteroaryl or carbonyl units that are all optionally substituted as necessary.

4. A compound of clause 1 wherein R¹ is an alkyl group C1-C22, R² is NH-CHMe-(l- naphthyl) of either (R) or (.S') absolute stereochemistry and R³ is Br.

5. A compound of clause 1 wherein R¹ is -CHMe-Aryl of either (R) or (.S') absolute stereochemistry and R², and R³ are general independent variables encompassing H, halogen, linear and branched alkyls, substituted amino, ether, aryl, heteroaryl or carbonyl units that are all optionally substituted as necessary.

Brief Description of the Drawings

Figure 1 shows reaction schemes summarizing the pairs of diastereomeric diene ligands 7a, b to 15a,b that have been prepared and which all fall within the scope of Formula (I). Examples

The invention will be further illustrated by the following non-limiting examples.

Example 1

An oven-dried round bottom flask was charged with but-3-ynoic acid (8.93 g, 106.3 mmol) and CH₂CI₂ (80 mb) under argon. The solution was cooled to 0-5 °C, oxalyl chloride (8.75 mb, 102 mmol) and DMF (0.2 mb) were added, and the mixture was stirred at room temperature for 2.5 h. The resulting acid chloride solution was transferred via syringe [using CH₂CI₂ (2x 15 mL) to rinse] to a cooled (0-5 °C) biphasic mixture of amide 3 (34.96 g, 85.0 mmol) in CH₂CI₂ (80 mL) and saturated aqueous NaHCCL solution (80 mL), and reaction mixture was then stirred at room temperature for 30 min. The organic layer was separated, dried (Na2SC>4), and concentrated in vacuo to leave the corresponding alkyne as an off-white foam.

An oven-dried round bottom flask was charged with the crude material from the previous reaction, K2CO3 (5.87 g, 42.5 mmol), and toluene (800 mL), and the mixture was heated at 130 °C for 15 h. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved CHCL (400 mL) and the solution was washed with H2O (100 mL) and brine (100 mL), dried (Na2SC>4), filtered, and concentrated in vacuo. Purification of the residue by column chromatography (20% EtOAc/petrol to EtOAc) gave diene (I-a) (13.38 g, 33%) as a pale yellow solid and diene (I-b) (13.46 g, 33%) as a pale-yellow solid.

(5S)-9-Bromo-N-[(R)-l-(naphthalen-l-yl)ethyl]-2-oxo-l-propyl-l,2, 4,5-tetrahydro-5, 7a- ethenoindole-7-carboxamide (I-a) X = Br.

R_f = 0.58 (EtOAc); m.p. 186-188 °C (EtOAc/cyclohexane); [a]^⁵ +60.0 (c 1.02, CHC1₃); IR 3275, 3047, 2967, 1672 (C=O), 1649 (C=O), 1586, 1525, 1342, 779, 730 cm ¹; ’ H NMR (400 MHz, CDCI3) 5 8.06 (1H, d, J = 8.3 Hz, ArH), 7.86 (1H, d, J = 8.0 Hz, ArH), 7.81 (1H, d, J= 1A Hz, ArH), 7.58-7.43 (4H, m, ArH), 6.89 (1H, d, J= 6.5 Hz, =CHCH), 6.31 (1H, d, J = 2.2 Hz, =CHC), 6.05-5.93 (1H, m, NHCH), 5.87 (1H, br s, NH), 5.83 (1H, s, CHC=O), 4.04-3.97 (1H, m, CH₂CH), 3.17-3.05 (1H, m, NCH₂), 2.90-2.78 (1H, m, NCH₂), 2.56 (1H, d, J= 16.7 Hz, =CCH₂), 2.35 (1H, d, J= 16.7 Hz, =CCH₂), 1.66 (3H, d, J = 6.7 Hz, CHCH₃), 1.64-1.55 (1H, m, CH₂CH₃), 1.50-1.33 (1H, m, CH₂CH₃), 0.61 (3H, t, J = 7.4 Hz, CH₂CH₃); ¹³C NMR (101 MHz, CDC1₃) 5 173.3 (C), 162.7 (C), 158.0 (C),

138.8 (C), 137.5 (CH), 137.4 (C), 134.0 (C), 131.2 (C), 129.5 (CH), 129.0 (CH), 128.8 (CH), 126.9 (CH), 126.1 (CH), 125.5 (CH), 124.3 (C), 123.3 (CH), 122.9 (CH), 116.6 (CH), 76.8 (C), 48.2 (CH), 45.2 (CH₂), 44.5 (CH), 29.6 (CH₂), 21.6 (CH₂), 20.3 (CH₃), 11.4 (CH₃); HRMS (ESI) Exact mass calculated for [C₂₆H₂₆BrN₂O₂]⁺ [M+H]⁺: 477.1172, found 477.1166.

(5R)-9-Bromo-N-[(R)-l-(naphthalen-l-yl)ethyll-2-oxo-l-propyl-l ,2, 4,5-tetrahydro-5, 7a- ethenoindole-7-carboxamide (I-b) X = Br.

R_f = 0.39 (EtOAc); m.p. 185-187 °C (EtOAc/cyclohexane); [a]^⁵ D48.0 (c 1.02, CHC1₃); IR 3276, 3046, 2969, 1672 (C=O), 1648 (C=O), 1585, 1524, 1359, 779, 731 cm ¹; ’H NMR (400 MHz, CDC1₃) 5 8.10 (1H, d, J = 8.3 Hz, ArH), 7.86 (1H, dd, J = 7.8, 1.7 Hz, ArH), 7.79 (1H, dd, J = 6.7, 2.7 Hz, ArH), 7.57-7.47 (2H, m, ArH), 7.47-7.39 (2H, m, ArH), 6.75 (1H, d, J = 6.5 Hz, =CHCH), 6.37 (1H, d, J = 2.2 Hz, =CHC), 6.00-5.90 (1H, m, NHCH), 5.84 (1H, s, CHC=O), 5.81 (1H, d, J = 8.7 Hz, NH), 4.01 (1H, dd, J = 6.4, 2.7 Hz, CH₂CH), 3.84 (1H, ddd, J = 14.2, 11.0, 5.6 Hz, NCH₂), 3.24 (1H, ddd, J = 14.2, 10.8, 5.2 Hz, NCH₂), 2.55 (1H, d, J= 16.7 Hz, =CCH₂), 2.33 (1H, d, J= 16.7 Hz, =CCH₂), 1.96- 1.78 (1H, m, CH₂CH₃), 1.72-1.59 (1H, m, CH₂CH₃), 1.66 (3H, d, J = 6.7 Hz, CHCH₃), 0.93 (3H, t, J = 7.4 Hz, CH₂CH₃); ¹³C NMR (101 MHz, CDC1₃) 5 173.4 (C), 163.3 (C),

157.7 (C), 139.5 (C), 137.8 (C), 135.9 (CH), 134.1 (C), 131.1 (C), 129.6 (CH), 129.0 (CH),

128.7 (CH), 126.8 (CH), 126.1 (CH), 125.4 (CH), 124.1 (C), 123.3 (CH), 122.8 (CH), 116.7 (CH), 77.0 (C), 48.2 (CH), 45.4 (CH₂), 44.7 (CH), 29.7 (CH₂), 22.2 (CH₂), 20.8 (CH₃),

11.8 (CH₃); HRMS (ESI) Exact mass calculated for [C₂₆H₂₆BrN₂O₂]⁺ [M+H]⁺: 477.1172, found 477.1173.

Example 2

Exemplary preparation of diene starting materials.

Precursor: 4-Bromo-2-(propylamino)benzoic acid (2).

A solution of 4-bromo-2-fluorobenzonitrile (7, 20.0 g, 100 mmol), w-propylamine (24.6 mb, 300 mmol), and A'.A'-diisopropylcthylaminc (17.0 mb, 100 mmol) in EtOH (20 mb) was heated at 90 °C for 6 h. The reaction was cooled at room temperature and transferred to a separating funnel. H2O (50 mb) was added and the mixture was extracted with Et2O (3 x 100 mL). The combined organic layers were dried (Na2SC>4) and concentrated in vacuo. The crude material was dissolved in MeOELEEO (1 : 1, 200 mL) and NaOH (20.0 g, 5.0 equivalents) was added. The mixture was heated at 100 °C for 24 h, cooled to room temperature, transferred to a beaker, and dissolved in H2O (1 L). The solution was then slowly acidified to -pH 4 with concentrated aqueous HC1. The resulting precipitate was collected by filtration, and dried in an oven to afford intermediate acid 2 (25.6 g, 99% over two steps from 1) as a white powder that was used without further purification. m.p. 170-172 °C (Et₂O/petrol); IR 3359 (OH), 2955, 2861, 1663 (C=O), 1567, 1504, 1241, 1153, 893, 756 cm⁴; ’ H NMR (400 MHz, DMSO-D₆) 5 12.82 (1H, br s, OH), 7.94 (1H, s, NH), 7.68 (1H, d, J = 8.5 Hz, ArH), 6.86 (1H, d, J = 1.9 Hz, ArH), 6.68 (1H, dd, J = 8.5, 1.9 Hz, ArH), 3.12 (2H, t, J = 7.0 Hz, NCH₂), 1.59 (2H, sext, J = 7.2 Hz, CH₂CH₃), 0.94 (3H, t, J = 7.4 Hz, CH₃); ¹³C NMR (101 MHz, DMSO-D₆) 5 169.6 (C), 151.7 (C), 133.5 (CH), 128.7 (C), 116.8 (CH), 113.4 (CH), 109.0 (C), 43.7 (CH₂), 21.7 (CH₂), 11.4 (CH₃); HRMS (ESI) Exact mass calculated for [Ci₀HnBrNO₂] [M-H]- : 255.9979, found 255.9979.

Intermediate amine: (R)-4-Bromo-N- [ 1 -(naphthalen- 1-yl) ethyl] -2-(propylamino) benzamide (3)

A solution of the acid 2 (25.8 g, 100 mmol) and thionyl chloride (21.8 mL, 300 mmol) in toluene (200 mL) was heated at 70 °C for 3 h, cooled to room temperature and the solvent and volatile residues were removed under reduced pressure. The resulting crude acid chloride was dissolved in CH₂CI₂ (100 mL) and the solution was slowly added to a solution of (R)-l -(naphthalen- l-yl)ethan-l -amine (4, 15.41 g, 90.0 mmol), Et₃N (41.8 mL, 300 mmol) in CH₂CI₂ (150 mL) at 0-5 °C. The mixture was stirred at room temperature for 1 h and the transferred to a separating funnel. The mixture was washed with H2O (100 mL) followed by brine (100 mL). The organic layer was dried (Na₃SO4) and concentrated in vacuo. The residue was dissolved in the minimum amount of CH₂CI₂ before petrol was added to induce precipitation. More petrol was added until no more precipitation was observed. The precipitate was collected by filtration and dried to leave intermediate amide 3 (34.99 g, 95%) as a colourless solid.

R_f = 0.44 (10% EtOAc/petrol); m.p. 134-136 °C (EtOAc/petrol); [a]^⁵ +52.0 (c 1.00, CHCI3); IR 3370, 3303, 2957, 1621 (C=O), 1566, 1504, 1263, 1235, 1152, 768 cm ¹; ’ H NMR (400 MHz, CDCI3) 5 8.12 (1H, dd, J = 7.9, 1.7 Hz, ArH), 7.92-7.85 (1H, m, ArH), 7.82 (1H, d, J = 8.1 Hz, ArH), 7.69 (1H, br s, ArNH), 7.59-7.41 (4H, m, ArH), 7.05 (1H, d, J = 8.3 Hz, ArH), 6.79 (1H, d, J = 1.9 Hz, ArH), 6.57 (1H, dd, J = 8.4, 1.9 Hz, ArH), 6.24 (1H, d, J = 7.8 Hz, CHNH), 6.07-5.97 (1H, m, NHCH), 3.08 (2H, t, J = 7.0 Hz, NCH₂), 1.74 (3H, d, J = 6.8 Hz, CHCH₃), 1.68 (2H, sext, J = 7.3 Hz, CH2CH₃), 1.02 (3H, t, J = 7.4 Hz, CH2CH₃); ¹³C NMR (101 MHz, CDCI3) 5 168.3 (C), 151.0 (C), 138.3 (C), 134.2 (C), 131.2 (C), 129.0 (CH), 128.64 (CH), 128.61 (CH), 127.7 (C), 126.8 (CH), 126.0 (CH), 125.4 (CH), 123.4 (CH), 122.7 (CH), 117.2 (CH), 114.4 (CH), 113.6 (C), 45.1 (CH), 45.0 (CH₂), 22.4 (CH₂), 21.0 (CH₃), 11.9 (CH₃); HRMS (ESI) Exact mass calculated for [C₂₂H₂₄BrN₂O]⁺ [M+H]⁺: 411.1067, found 411. 1064.

Example 3

Exemplary chiral single stereoisomer diversification to Formula (I) with R¹ = n-Pr, R² = (R)-C(=O)NHCHMe(l-naphthyl), R³ = Ph.

(5S)-N-[(R)-l-(Naphthalen-l-yl)ethyl]-2-oxo-9-phenyl-l-propyl-l,2, 4,5-tetrahydro-5, 7 a- ethenoindole-7-carhoxamide (I-c) R³ = Ph.

A solution of alkenyl bromide I-a (477 mg, 1.00 mmol), phenylboronic acid (244 mg, 2.00 mmol), K2CO3 (276 mg, 2.00 mmol), and Pd(dppf)C12 (18.3 mg, 0.025 mmol) in toluene (5 mb) was heated at 110 °C for 8 h. The reaction was cooled to room temperature, H2O (15 mL) was added, and the mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were dried (Na2SC>4), filtered, and concentrated in vacuo. Purification of the residue by column chromatography (20% EtOAc/petrol to EtOAc) gave I-c R³ = Ph (441 mg, 93%) as a pale-yellow solid.

R_f = 0.53 (EtOAc); m.p. 136-138 °C (EtOAc/cyclohexane); [a]^⁵ -44.0 (c 0.99, CHC1₃); IR 3270, 3050, 2965, 1646 (C=O), 1594, 1511, 1342, 1248, 777, 750 cm ¹; 'H NMR (400 MHz, CDCL) 5 8.12 (1H, d, J = 8.4 Hz, ArH), 7.87 (1H, dd, J = 8.0, 1.5 Hz, ArH), 7.83 (1H, dd, J = 7.8, 1.7 Hz, ArH), 7.59-7.45 (4H, m, ArH), 7.38-7.25 (5H, m, ArH), 7.08 (1H, d, J = 6.5 Hz, =CHCH), 6.33 (1H, d, J = 2.0 Hz, =CHC), 6.10-5.98 (1H, m, NHCH), 5.89 (1H, d, J= 8.6 Hz, NH), 5.84 (1H, s, CHC=O), 4.49-4.41 (1H, m, CH₂CH), 3.06 (1H, ddd, J = 14.1, 11.5, 5.2 Hz, NCH₂), 2.86 (1H, ddd, J = 14.1, 11.3, 5.1 Hz, NCH₂), 2.46 (2H, s, =CCH₂), 1.73-1.62 (1H, m, CH2CH₃), 1.67 (3H, d, J = 6.7 Hz, CHCH₃), 1.55-1.38 (1H, m, CH2CH₃), 0.58 (3H, t, J = 7.3 Hz, CH2CH₃); ¹³C NMR (101 MHz, CDCL) 5 173.8 (C), 163.0 (C), 159.9 (C), 146.3 (C), 139.4 (C and CH), 137.6 (C), 135.9 (C), 134.0 (C),

131.3 (C), 129.0 (CH), 128.9 (2 x CH), 128.8 (CH), 128.5 (CH), 126.9 (CH), 126.1 (CH), 125.5 (CH), 125.2 (2 x CH), 124.3 (CH), 123.5 (CH), 123.0 (CH), 116.0 (CH), 76.1 (C),

45.3 (CH₂), 44.3 (CH), 41.3 (CH), 30.0 (CH₂), 21.7 (CH₂), 20.4 (CH₃), 11.5 (CH₃); HRMS (ESI) Exact mass calculated for [C3₂H₃iN₂O₂]⁺ [M+H]⁺: 475.2380, found 475.2383.

Example 4

Exemplary chiral single stereoisomer diversification to Formula (I) with R¹ = n-Pr, R² = (R)-C(=O)NHCHMe(l-naphthyl), I-c R³ = Me.

(5S)-9-Methyl-N-[(R)-l-(naphthalen-l-yl)ethyl]-2-oxo-l-propyl-l,2, 4,5-tetrahydro-5, 7 a- ethenoindole-7-carhoxamide (I-c) R³ = Me.

To a solution of alkenyl bromide I-a X = Br (477 mg, 1.00 mmol), Pd2(dba)3 (27.5 mg, 0.03 mmol) and Xphos (28.6 mg, 0.06 mmol) in THF (5.0 mb) was added a solution of DABAL-Mes (512 mg, 2.00 mmol) in THF (3 mL). The mixture was heated at 85 °C for 4 h, cooled to room temperature and quenched carefully with 1 M aqueous HC1 solution (10 mL). The mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were dried (Na2SC>4), filtered, and concentrated in vacuo. Purification of the residue by column chromatography (20% EtOAc/petrol to EtOAc) gave diene I-c R³ = Me (347 mg, 84%) as off-white solid.

R_f = 0.41 (EtOAc); m.p. 140-142 °C;

+48.0 (c 1.00, CHCI3); IR 3255, 3044, 2964, 1654 (C=O), 1596, 1524, 1444, 1342, 799, 777 cm ¹; ’ H NMR (400 MHz, CDCI3) 5 8.11 (1H, d, J = 8.4 Hz, ArH), 7.86 (1H, d, J = 9.5 Hz, ArH), 7.82 (1H, dd, J = 7.2, 2.2 Hz, ArH), 7.58-7.44 (4H, m, ArH), 7.01 (1H, d, J = 6.4 Hz, =CHCH), 6.09-5.97 (1H, m, NHCH), 5.81 (1H, d, J = 8.7 Hz, NH), 5.77 (2H, s, =CHC and CHC=O), 3.76-3.68 (1H, m, CH₂CH), 2.88 (1H, ddd, J = 14.0, 11.5, 5.3 Hz, NCH₂), 2.71 (1H, ddd, J = 14.1, 11.4, 5.1 Hz, NCH₂), 2.35 (1H, d, J = 16.0, =CCH₂), 2.29 (1H, d, J = 16.0, =CCH₂), 1.83 (3H, d, J = 1.6 Hz, =CCH₃), 1.64 (3H, d, J = 6.7 Hz, CHCH₃), 1.62-1.51 (1H, m, CH2CH₃), 1.42-1.25 (1H, m, CH2CH₃), 0.48 (3H, t, J = 7.4 Hz, CH2CH₃); ¹³C NMR (101 MHz, CDCI3) 5 174.0 (C), 163.1 (C), 161.1 (C), 144.3 (C), 139.7 (CH), 138.9 (C), 137.7 (C), 134.0 (C), 131.4 (C), 129.0 (CH), 128.7 (CH), 126.9 (CH), 126.1 (CH), 125.6 (CH), 123.5 (CH), 123.2 (CH), 123.0 (CH), 115.2 (CH), 75.7 (C), 45.2 (CH₂), 44.2 (CH), 44.0 (CH), 29.5 (CH₂), 21.4 (CH₂), 20.4 (CH₃), 19.5 (CH₃), 11.3 (CH₃); HRMS (ESI) Exact mass calculated for [C₂₇H₂₉N₂O₂]⁺ [M+H]⁺: 413.2224, found 413.2224.

Example 5

Exemplary chiral single stereoisomer Formula I with R¹ = Me, R² = (R)- C(=O)NHCHMe(l-naphthyl), R³ = Hr. Separation by precipitation.

Aryl = 1 -naphthyl

(5S)-9-Bromo-l-methyl-N-[(R)-l-(naphthalen-l-yl)ethyl]-2-oxo-l,2, 4,5-tetrahydro-5, 7 a- ethenoindole-7-carboxamide (I-d) R¹ = Me, R³ = Br.

An oven-dried round bottom flask was charged with but-3-ynoic acid (2.52 g, 30.0 mmol) and CH₂CI₂ (30 mb) under argon. The solution was cooled to 0-5 °C, oxalyl chloride (2.47 mb, 28.7 mmol) and DMF (10 drops) were added, and the mixture was stirred at room temperature for 2.5 h. The resulting acid chloride solution was transferred via syringe [using CH₂CI₂ (10 mb) to rinse] to a cooled (0-5 °C) biphasic mixture of intermediate amide (9.58 g, 25.0 mmol) in CH₂CI₂ (50 mb) and saturated aqueous NaHCCh solution (50 mL), and the reaction mixture was then stirred at room temperature for 30 min. The organic layer was separated, dried (Na2SC>4), and concentrated in vacuo to leave the intermediate alkyne as an off-white foam (11.7 g) as a l : l mixture of atropisomers that was used without further purification.

An oven-dried reaction tube was charged with the crude material from the previous reaction, K2CO3 (1.73 g, 12.5 mmol), and toluene (250 mL), and the mixture was heated at 130 °C for 15 h. The reaction was cooled to room temperature and concentrated in vacuo. The crude material was filtered through a short silica gel column (5% MeOH/CH₂Cl₂) to give 7.89 g (70%) of diene (1: 1 mixture of I-d and I-e; R¹ = Me, R³ = Br) as brownish solid.

2.00 g of the above diene was stirred vigorously in 50 mL of 15% CHCL/EtOAc for 5 minutes and the precipitate was filtered to isolate 0.91 g (45%) of only I-d R¹ = Me, R³ = Br as white powder. The evaporation of filtrate leaves 1.02 g (51%) of 1 :7 mixture of diene I-d and I-e (R¹ = Me, R³ = Br) as brown residue.

R_f = 0.41 (EtOAc); m.p. 222-224 °C;

+44.0 (c 1.00, CHCI3); IR 3207, 2970, 1673 (C=O), 1650 (C=O), 1620, 1589, 1399, 1362, 986, 806, 783 cm⁴; ’ H NMR (500 MHz, CDCI3) 5 8.04 (1H, d, J = 8.0 Hz, ArH), 7.87 (1H, dd, J = 8.2, 1.5 Hz, ArH), 7.84-7.79 (1H, m, ArH), 7.57-7.53 (1H, m, ArH), 7.52-7.46 (3H, m, ArH), 6.98 (1H, d, J = 6.6 Hz, =CHCH), 6.25 (1H, d, J= 22 Hz, =CHC), 6.02 (1H, br d, J= 8.5 Hz, NH), 5.99-5.93 (1H, m, NHCH), 5.89-5.85 (1H, m, CHC=O), 4.10-4.03 (1H, m, CH₂CH), 2.74 (3H, s, NCH₃), 2.60 (1H, dt, J = 16.8, 2.3 Hz, =CCH₂), 2.37 (1H, dt, J = 16.8, 2.3 Hz, =CCH₂), 1.66 (3H, d, J = 6.5 Hz, CHCH₃); ¹³C NMR (126 MHz, CDCI3) 5 173.7 (C), 162.4 (C), 158.7 (C), 138.4 (C), 137.7 (CH), 137.5 (C), 134.0 (C), 131.1 (C), 129.0 (CH), 128.8 (CH), 128.3 (CH), 127.0 (CH), 126.1 (CH), 125.5 (CH), 124.7 (C), 123.3 (CH), 122.9 (CH), 116.2 (CH), 76.4 (C), 48.5 (CH), 44.7 (CH), 29.6 (CH₂), 28.0 (CH₃), 20.5 (CH₃); HRMS (ESI) Exact mass calculated for [C24H₂2BrN₂O2]⁺ [M+H]⁺: 449.0859, found 449.0856.

Example 6

Exemplary chiral single stereoisomer Formula I with R¹ = Me, R² = (R)- C(=O)NHCHMe(l-naphthyl), R³ = Cl. Separation by precipitation (I-d) R1 = Me, R² = (R)-C(=O)NHCHMe(l-naphthyl), R³ = Cl.

Aryl = 1 -naphthyl (5S)-9-Chloro-l-methyl-N-[(R)-l-(naphthalen-l-yl)ethyl]-2-oxo-l,2, 4,5-tetrahydro-5, 7a- ethenoindole-7 -carboxamide (I-d) R¹ = Me, R² = (R)-C(=O)NHCHMe(l-naphthyl), R³ = CL

An oven-dried round bottom flask was charged with but-3-ynoic acid (1.64 g, 19.5 mmol) and CH₂CI₂ (20 mb) under argon. The solution was cooled to 0-5 °C, oxalyl chloride (1.54 mL, 18.0 mmol) and DMF (5 drops) were added, and the mixture was stirred at room temperature for 2.5 h. The resulting acid chloride solution was transferred via syringe [using CH₂CI₂ (5 mL) to rinse] to a cooled (0-5 °C) biphasic mixture of intermediate amide (5.08 g, 15.0 mmol) in CH₂CI₂ (15 mL) and saturated aqueous NaHCCL solution (30 mL), and the reaction mixture was then stirred at room temperature for 30 min. The organic layer was separated, dried (Na2SC>4), and concentrated in vacuo to leave intermediate alkyne as an off-white foam (6.97 g) as a 1 : 1 mixture of atropisomers that was used without further purification.

An oven-dried reaction tube was charged with the crude material from the previous reaction, K2CO3 (1.04 g, 7.50 mmol), and toluene (150 mL), and the mixture was heated at 130 °C for 15 h. The reaction was cooled to room temperature and concentrated in vacuo. The crude material was filtered through a short silica gel column (5% MeOH/CLLCL) to give 4.48 g (74%) of diene (1 : 1 mixture of I-d and I-e, R¹ = Me, R³ = Br) as a brownish solid.

2.00 g of the above diene was stirred vigorously in 50 mL of 15% CHCL/EtOAc for 5 minutes and the precipitate was filtered to isolate 0.88 g (44%) of only I-d R¹ = Me, R³ = Br as white powder. The evaporation of filtrate left 1.08 g (54%) of 1 :7 mixture of diene I-d and I-e (R¹ = Me, R³ = Br) as a brown residue.

R_f = 0.39 (EtOAc); m.p. 239-240 °C; +48.0 (c 1.01, CHCI3); IR 3211, 3035, 1681 (C=O), 1651 (C=O), 1622, 1537, 985, 955, 828, 807 cm’¹; ’ H NMR (500 MHz, CDCI3) 5 8.04 (1H, d, J = 8.5 Hz, ArH), 7.87 (1H, d, J = 8.0 Hz, ArH), 7.83-7.80 (1H, m, ArH), 7.55 (1H, t, J= 1A Hz, ArH), 7.52-7.42 (3H, m, ArH), 6.99 (1H, d, J = 6.6 Hz, =CHCH), 6.07-6.00 (2H, m, =CHC and NH), 6.00-5.93 (1H, m, NHCH), 5.88 (1H, s, CHC=O), 4.00-3.91 (1H, m, CH₂CH), 2.73 (3H, s, NCH₃), 2.61 (1H, d, J = 16.8 Hz, =CCH₂), 2.40 (1H, d, J = 16.7 Hz, =CCH₂), 1.66 (3H, d, J = 6.6 Hz, CHCH₃); ¹³C NMR (126 MHz, CDC1₃) 5 173.6 (C), 162.4 (C), 159.1 (C), 138.8 (C), 137.6 (C), 137.5 [2xC (CH and C)], 134.0 (C), 131.1 (C), 129.0 (CH), 128.8 (CH), 126.9 (CH), 126.1 (CH), 125.5 (CH), 123.8 (CH), 123.2 (CH), 122.8 (CH), 116.2 (CH), 75.6 (C), 46.7 (CH), 44.7 (CH), 29.6 (CH₂), 27.9 (CH₃), 20.5 (CH₃); HRMS (ESI) Exact mass calculated for [Cz^ClNzChf [M+H]⁺: 405.1364, found 405.1359.

Example 7

(5R, 7 aS)-7 -Phenyl- 1 - [(S)- 1 -phenylethyl] -4, 5-dihydro-5 , 7a-ethenoindol-2( lH)-one (I-e)

R¹ = (R)-NCHMePh, R² = Ph, R³ = H.

An oven-dried round bottom flask was charged with but-3-ynoic acid (605 mg, 7.20 mmol) and CH₂CI₂ (7 mb) under argon. The solution was cooled to 0-5 °C, oxalyl chloride (0.51 mb, 6.00 mmol) and DMF (3 drops) were added, and the mixture was stirred at room temperature for 2.5 h. The resulting acid chloride solution was transferred via syringe [using CH₂CI₂ (3 mL) to rinse] to a cooled (0-5 °C) biphasic mixture of intermediate amine (1.09 g, 4.00 mmol) in CH₂CI₂ (10 mL) and saturated aqueous NaHCO₃ solution (20 mL), and the reaction mixture was then stirred at room temperature for 30 min. The organic layer was separated, dried (Na2SC>4), and concentrated in vacuo. Purification of the residue by column chromatography (petrol to 30% EtOAc/petrol) gave intermediate alkyne as an off-white solid (610 mg, 45%).

An oven-dried reaction tube was charged with the above alkyne (509 mg, 1.5 mmol), K2CO3 (104 mg, 0.75 mmol), and toluene (15 mL), and the mixture was heated at 145 °C for 15 h. The reaction was cooled to room temperature and concentrated in vacuo. Purification of the residue by column chromatography (petrol to 50% EtOAc/petrol) gave diene I-e (212 mg, 42%) as a white solid and diene I-d (208, 41%) as an off white solid.

R_f = 0.46 (40% EtOAc/cyclohexane); m.p. 164-166 °C; [a]^⁵ -28.0 (c 1.02, CHCh); IR 3064, 3024, 2920, 1666 (C=O), 1489, 1364, 1342, 1319, 734, 697 cm⁴; ’ H NMR (400 MHz, CDCh) 5 7.41-7.36 (2H, m, ArH), 7.36-7.29 (3H, m, ArH), 7.29-7.23 (2H, m, ArH), 7.23-7.17 (1H, m, ArH), 7.12-7.04 (2H, m, ArH), 6.37 (1H, dd, J = 7.5, 6.1 Hz, =CH), 6.28 (1H, d, J = 6.2 Hz, =CH), 5.95 (1H, dd, J = 7.5, 1.6 Hz, =CH), 5.89 (1H, s, =CH), 4.18 (1H, q, J = 7.2 Hz, NCH), 4.06-3.98 (1H, m, CH₂CH), 2.46 (1H, dt, J = 16.6, 2.3 Hz, =CCH₂), 2.33 (1H, dt, J = 16.5, 2.2 Hz, =CCH₂), 1.43 (3H, d, J = 7.2 Hz, CH₃); ¹³C NMR (101 MHz, CDCh) 5 175.0 (C), 160.9 (C), 144.6 (C), 143.8 (C), 137.3 (C), 134.3 (CH), 132.1 (CH), 130.8 (CH), 128.5 (2xCH), 128.2 (2xCH), 127.7 (2xCH), 127.5 (CH), 126.9 (CH), 126.8 (2xCH), 116.6 (CH), 79.6 (C), 58.0 (CH), 38.5 (CH), 31.0 (CH₂), 20.8 (CH₃); HRMS (ESI) Exact mass calculated for [C₂₄H₂₂NO]⁺ [M+H]⁺: 340.1696, found 340.1699. (5S,7aR)-7-Phenyl-l-[(S)-l -phenylethyl] -4,5 -dihydro-5, 7a-ethenoindol-2(lH)-one (I-d) R² = Ph, R³ = H.

Rf = 0.37 (40% EtOAc/cyclohexane); m.p. 149-151 °C; [a]^⁵ +120.0 (c 0.50, CHCh); IR 3023, 1666 (C=O), 1389, 1364, 1020, 758, 716, 696, 574, 557 cm⁴; ’ H NMR (400 MHz, CDCh) 5 7.23-7.12 (8H, m, ArH), 7.00-6.95 (2H, m, ArH), 6.49 (1H, dd, J = 7.5, 6.1 Hz, =CH), 6.35 (1H, dd, J = 7.6, 1.7 Hz, =CH), 6.32 (1H, d, J = 6.3 Hz, =CH), 5.94 (1H, t, J = 1.7 Hz, =CH), 5.06 (1H, q, J = 7.4 Hz, NCH), 4.11-4.06 (1H, m, CH₂CH), 2.48 (1H, dt, J = 16.5, 2.3 Hz, =CCH₂), 2.38 (1H, dt, J = 16.4, 2.1 Hz, =CCH₂), 1.23 (3H, d, J= 7.4 Hz, CH₃); ¹³C NMR (101 MHz, CDCh) 5 175.0 (C), 162.5 (C), 144.2 (C), 143.9 (C), 138.4 (C), 133.8 (CH), 132.4 (CH), 131.2 (CH), 128.43 (2xCH), 128.41 (2xCH), 127.4 (CH), 127.0 (2xCH), 126.7 (3 xCH), 115.9 (CH), 78.0 (C), 54.0 (CH), 38.6 (CH), 31.0 (CH₂), 19.9 (CH₃); HRMS (ESI) Exact mass calculated for [C₂₄H₂₂NO]⁺ [M+H]⁺: 340.1696, found 340.1697.

Example 8

(5R, 7aR)-l-[(R)-l-(Naphthalen-2-yl)ethyl]-4,5-djhydro-5, 7a-ethenoindol-2( lH)-one (I-f) with R¹ = (R)-NCHMe(l -naphthyl), R² = H, R³ = H.

An oven-dried round bottom flask was charged with but-3-ynoic acid (453 mg, 5.40 mmol) and CH₂CI₂ (6 mb) under argon. The solution was cooled to 0-5 °C, oxalyl chloride (0.38 mL, 4.50 mmol) and DMF (3 drops) were added, and the mixture was stirred at room temperature for 2.5 h. The resulting acid chloride solution was transferred via syringe [using CH₂CI₂ (3 mL) to rinse] to a cooled (0-5 °C) biphasic mixture of intermediate amine (742 mg, 3.00 mmol) in CH₂CI₂ (6 mL) and saturated aqueous NaHCCL solution (10 mL), and the reaction mixture was then stirred at room temperature for 30 min. The organic layer was separated, dried (Na2SC>4), and concentrated in vacuo. Purification of the residue by column chromatography (cyclohexane to 20% EtOAc/cyclohexane) gave intermediate alkyne as an off-white solid (799 mg, 85%).

An oven-dried reaction tube was charged with the above alkyne (313 mg, 1.00 mmol), K2CO3 (30 mg, 0.22 mmol), and toluene (10 mL), and the mixture was heated at 145 °C for 15 h. The reaction was cooled to room temperature and concentrated in vacuo. Purification of the residue by column chromatography (cyclohexane to 40% EtOAc/cyclohexane) gave diene I-d R¹ = (R)-NCHMe(l -naphthyl), R² = H, R³ = H (223 mg, 71%) as an off-white solid.

R_f = 0.49 (40% EtOAc/cyclohexane);

-28.0 (c 1.00, CHCI3); m.p. 157D 159 °C; IR 2929, 1658, 1453, 1433, 1262, 1239, 827, 804, 691, 539 cm ¹; ’ H NMR (400 MHz, CDCI3) 5 8.24 (1H, d, J = 8.5 Hz, ArH), 7.86 (1H, dd, J = 8.2, 1.5 Hz, ArH), 7.81 (1H, d, J = 8.2 Hz, ArH), 7.68 (1H, d, J = 7.2 Hz, ArH), 7.60-7.53 (1H, m, ArH), 7.53-7.47 (1H, m, ArH), 7.46-7.40 (1H, m, ArH), 6.53 (1H, q, J = 7.2 Hz, NCH), 6.49 (1H, d, J = 7.8 Hz, =CH), 6.33 (1H, dd, J = 7.5, 6.1 Hz, =CH), 5.86-5.78 (2H, m, =CH), 4.55 (1H, dd, J = 7.5, 1.5 Hz, =CH), 3.89-3.76 (1H, m, CH₂CH), 2.15 (1H, dt, J = 16.5, 2.2 Hz, =CCH₂), 2.06 (1H, dt, J = 16.7, 2.2 Hz, =CCH₂), 1.97 (3H, d, J = 7.1 Hz, CH₃); ¹³C NMR (101 MHz, CDCI3) 5 173.4 (C), 160.9 (C), 135.9 (C), 133.7 (C), 133.5 (CH), 132.2 (C), 131.9 (CH), 131.2 (CH), 131.1 (CH), 128.89 (CH), 128.86 (CH), 127.2 (CH), 126.1 (CH), 125.3 (CH), 124.7 (CH), 123.7 (CH), 114.9 (CH), 75.2 (C), 46.8 (CH), 38.5 (CH), 30.2 (CH₂), 19.4 (CH₃); HRMS (ESI) Exact mass calculated for [C₂2H₂₀NO]⁺ [M+H]⁺: 314.1539, found: 314.1539.

Example 9

(5S,7aS)-N-[(S)-l-(naphthalen-l-yl)ethyl]-2-oxo-l-propyl-9-(quinolin-8-yl)-l,2,4,5-tetrahydro-

5, 7a-eth en oindole- 7-carboxamide

A solution of alkenyl bromide (477.4 mg, 1.00 mmol), 8-quinoline boronic acid (346.0 mg, 2.00 mmol), Pd(dppf)C12 (18.3 mg, 0.025 mmol), and K2CO3 (276.4 mg, 2.00 mmol) in toluene (5.0 mb) was heated at 110 °C for 8 h. The reaction was cooled to room temperature, H2O (15 mb) was added, and the mixture was extracted with EtOAc (3 x 15 mb). The combined organic layers were dried (Na2SC>4), filtered, and concentrated in vacuo. Purification of the residue by column chromatography (90% EtOAc/cyclohexane) gave the product as a light brown solid (378.5 mg, 72%).

Example 10

Reaction of ligands to form coordination complexes with metals. a) Rhodium complex

Reaction of diene 8a (I-c R³ = Me) with [Rh(C2H4)2Cl]2 in CH₂CI₂ at room temperature for 3 h produced the dimeric Rh(I)-diene complex [Rh(8a)Cl]2 in 80% yield. In a similar manner, [Rh(8b)Cl]2 was prepared in 82% yield. b) Copper complex

A solution of CuCl (10.9 mg, 0.1 1 mmol) and chiral Himbert diene (52.5 mg, 0.1 mmol) in CH₂CI₂ was stirred at 40 °C for 3 h. The precipitate was filtered and washed with cold EtOAc to give the target Cu complex as a yellow solid (42.9 mg, 78.3%). Slow diffusion of cyclohexane into a solution of the Cu complex in chloroform gave crystals that were suitable for X-ray crystallography. This material was found to be a coordination polymer, in which the coordination sphere of copper is completed by coordination to the carbonyl group of the lactam of another molecule of the diene. There is also one chloroform molecule included as a solvent of recrystallisation.

Example 11

Testing efficacy of dienes in enantioselective catalysis using the Rh(I)-catalyzed addition of PhB(OH)₂ to 2-cyclohexenone (16)

A mixture of 16, PhB(0H)2 (2.0 equiv), [Rh(C2H4)2Cl]2 (1.5 mol%), Himbert Diene (3.5 mol%), and KOH (0.5 equiv) was heated in a 10: 1 mixture of 1,4-dioxane and H2O at 30 °C for 5 h.

The Himbert Dienes as tested are shown in Figure 1.

The results are shown in Table 1.

Table 1. Evaluation of Himbert dienes in the enantioselective Rh(I)-catalyzed addition of PhB(OH)2 to 2-cyclohexenone.^[al

6 12a >99 >99 (R) 15 12b 96 >99 (S)

7 13a 98 99 (R) 16 13b 94 >99 (S)

8 14a 97 99 (R) 17 14b >99 >99 (S)

9 15a 54 93 (R) 18 15b 54 98 (S) [a] Reactions were conducted with 0.30 mmol of 15 in 1,4-dioxane (1 mL) and H₂O (0.1 mL).

[b] Yield of isolated 16.

[c] Determined HPLC analysis on a chiral stationary phase.

In almost all cases (entries 2-8 and 11-17), the product 17 was obtained in excellent yields and high enantioselectivities (>97% ee). Only the reactions using the alkenyl bromides 7a and 7b (entries 1 and 10) and phenyl-ester-substituted dienes 15a and 15b (entries 9 and 18) gave somewhat inferior (but still satisfactory) results. Comparison of the results using ligands 7a-15a (entries 1-9) with their diastereomeric counterparts 7b-15b (entries 10-18) showed that there was only a marginal mismatch of the individual stereochemical elements within the ligands in favor of 7b-15b, which gave slightly higher enantioselectivities. In other words, the ligands according to the invention can be used to effectively control the stereochemistry of the product in the catalysed reaction.

Example 12 Enantioselective Rh(I)-catalyzed nucleophilic additions of organoboron reagents

A number of reactions were carried out involving nucleophilic additions of organoboron reagents, to assess the effectiveness of metal complexes of the diene ligands in catalysis of the reaction.

%ene yjeid (%) es (%)

PhB(OHh (2.3 equiv)

Highest so reosMed ptw&xadv: 8a OS 98 (S)

OSH (ref 25f} 8b 07 07 (/?)

Good results were obtained using ligands 8a and 8b, but the allyl-substituted ligands 9a and 9b were superior, giving 19 in higher yields and 95% and 97% ee, respectively. These enantioselectivities are higher than those reported previously for all other processes catalyzed by either Rh(I) or Pd(II).

With dienes 8a and 8b, good results were also observed in enantioselective 1,4-additions of arylboronic acids to unsaturated amide 20 using Sc(OTf)3 as an additive, nitroalkene 22, and 2-alkenylquinoxaline 24 which gave the corresponding products 21, 23, and 25 in reasonable to good yields and high enantioselectivities (93->99% ee).

In the case of alkenylquinoxazoline 24, the 1-naphthyl-substituted Himbert dienes Ila and 11b gave comparable results to dienes 8a and 8b. Comparison of these results with the highest enantioselectivities reported previously for products 19 (90% ee), 21 (99% ee), 23 (99% ee), and products similar to 25 (90-97% ee) demonstrates the new chiral Himbert dienes are competitive with existing best-in-class chiral ligands for asymmetric Rh(I)- catalyzed 1,4-arylations.

Example 13

Enantioselective Rh(I) catalyzed 1,2-additions to imines.

94%ee (rof, 308} Sb 78 31 (S)

4-methylphenylboronic acid reacted with 7V-tosylimine 26 to give 27 in high enantioselectivities using dienes 8a, 8b, 10a, or 10b.

Nucleophilic additions of a potassium alkenyltrifluoroborate and potassium allyltrifluoroborate to cyclic imine 28b, respectively, were also successful when using dienes 8a and 8b, to give products 29 and 30 in 89-97% ee.

Comparison of these results with the highest enantioselectivities reported previously for product 27 (99% ee), a product similar to 29 (chloride instead of bromide; 97% ee), and product 30 (94% ee) indicates the new ligands are competitive with existing best-in-class chiral dienes for asymmetric Rh(I)-catalyzed 1,2-additions of organoboron reagents. Example 14

Catalytic enantioselective allenylation of imines using a trimethylsilyl-substituted propargylboron reagent.

2.0 mol% of chiral rhodium complexes [Rh(8a)Cl]2 or [Rh(8b)Cl]2 catalyzed the addition of propargyl boronate 31 to a variety of cyclic imines 28 in the presence of KOH (0.05 equiv) and MeOH (2.5 equiv) in l,4-dioxane/H2O (60: 1) at 60 °C for 6 h.

Benzoxathiazine-2,2-dioxides with a range of substituents (including bromo, chloro, methyl, dioxole, or methoxy) at various positions reacted successfully to give allenylation products32a-32g in 37-82% yield and 92-97% ee.

[Rh(8b)Cl]2 also catalyzed the addition of 31 to cyclic ketimines such as a 1,2,5- thiadiazolidine- 1 , 1 -dioxide and a benzoisothiazole 1, 1- ee), the propargylation product 33a was also isolated in 19% yield but interestingly, with a much lower enantiomeric excess (16% ee).

The allenylation of 28a with 31 was also conducted using (S,S)-Ph-bod*, a commercially available (but expensive) chiral diene that has been shown to be highly effective in a range of enantioselective Rh(I)-catalyzed reactions, including 1,2-additions to imines. This reaction gave (R)-32a in 43% yield and 84% ee, with an allenylation to propargylation ratio of 2.8: 1, which shows that chiral Himbert dienes 8a and 8b provide better results than (S,S)-Ph-bod* in this transformation.

(R)-32a 78 %.95%ee R 32b 81%.86%e (R)32s 75%.93% ae 32s :33a ~ 4:1 32i>:33b^ 6.2:1 32c:33c « 3.6'1

[a] Reactions were conducted with 0.25 mmol of 28. The stated yields are of isolated allenylation products 32. The ratios of 32 to 33 were determined by

NMR analysis of the unpurified reaction mixtures. Except for 33a, propargylation products 33 were not isolated. The absolute configuration of 33a was not determined. Enantiomeric excesses were determined by HPLC analysis on a chiral stationary phase.

[b] Conducted with 0.15 mmol of 28a. Conclusion

It has been shown that chiral Himbert dienes of Formula (I) are easily prepared by the intramolecular [4+2] cycloaddition of an allenecarboxamide and these dienes are excellent chiral ligands for a range of enantioselective Rh(I)-catalyzed reactions, including hitherto undescribed allenylations of cyclic imines.

Although many different types of chiral diene ligands have been reported previously, some of which exhibit high catalytic activity and enantioselectivities across several types of reactions, there are several features of these new chiral Himbert dienes that make them advantageous:

(i) their synthesis can be conducted straightforwardly on multigram scales without recourse to more specialized techniques such as enzymatic resolution, preparative chiral HPLC, or the use of catalytic asymmetric reactions;

(ii) both pseudo enantiomeric series of the ligands can be readily accessed, which is not always the case for known chiral dienes that are prepared from chiral pool starting materials; and

(iii) the synthesis proceeds through intermediates that can be modified at the final stage by cross-coupling to give diverse chiral dienes for fine-tuning of catalytic performance, which may be important for particularly challenging transformations.

The extent to which all three features are manifested in these new chiral Himbert dienes of Formula (I) makes them particularly attractive for use in asymmetric catalysis.

Claims

1. A chiral single stereoisomer diene of Formula (I):

wherein R¹, R², and R³ are each substituent groups that are independently selected from H, halogen groups, alkyl groups (which may be linear or branched), alkenyl groups (which may be linear or branched, and may in particular be allyl or methallyl), aryl groups, alkaryl groups, heteroaryl groups, and substituted amino groups, ether groups, or carbonyl groups; wherein each substituent group may optionally be substituted; and wherein R¹, R², and R³ are selected such that at least one of these groups includes a stereogenic element.

2. The diene of claim 1, wherein R¹ to R³ are each substituent groups that are independently selected from:

• hydrogen (H),

• halogen (F, Cl, Br, I),

• C1-C12 alkyl,

• allyl or methallyl,

• C5-12 aryl,

• C6-C22 alkaryl,

• C5-12 heteroaryl,

• substituted amino (NH(2-n)R^an, where n = 1 or 2),

• substituted ether (OR^a),

• substituted carbonyl derivatives [C(=O)NH(2-_n)R^an where n = 1 or 2; or C(=O)OR^a; or C(=O)R^a]; wherein each R^a group is independently selected from hydrogen, C1-C12 alkyl, allyl, methallyl, C5-12 aryl, C6-C22 alkaryl, C5-12 heteroaryl; and wherein each R group (R¹ to R³ and R^a) may optionally be substituted.

3. The diene of claim 1 or claim 2, wherein R¹ is a C1-C22 alkyl group and R² and R³ are selected from H, halogen, linear and branched alkyls, aryl, heteroaryl, alkaryl, allyl, methallyl, and substituted amino, ether and carbonyl groups, and where each R group is optionally substituted.

4. The diene of claim 3, wherein R¹ is a C1-C22 alkyl group and R² and R³ are selected from H, halogen, linear and branched alkyls, aryl, heteroaryl, and substituted amino, ether and carbonyl groups, and where each R group is optionally substituted.

5. The diene of any one of the preceding claims, wherein R¹ is a C1-C22 alkyl group, R² is C(=O)NH-CHMe-Aryl of either (R) or (.S') absolute stereochemistry, and R³ is selected from H, halogen, linear and branched alkyls, aryl, heteroaryl, alkaryl, allyl, methallyl, and substituted amino, ether, and carbonyl groups, and where each R group is optionally substituted.

6. The diene of claim 5, wherein R¹ is a C1-C22 alkyl group, R² is C(=O)NH-CHMe- Aryl of either (R) or (.S') absolute stereochemistry, and R³ is selected from H, halogen, linear and branched alkyls, aryl, heteroaryl, and substituted amino, ether, and carbonyl groups, and where each R group is optionally substituted.

7. The diene of any one of the preceding claims, wherein R¹ is a C1-C22 alkyl group, R² is C(=O)NH-CHMe-Aryl of either (R) or (.S') absolute stereochemistry, and R³ is halogen.

8. The diene of claim 7, wherein R¹ is a C1-C22 alkyl group, R² is C(=O)NH-CHMe- (1 -naphthyl) of either (R) or (.S') absolute stereochemistry and R³ is Br.

9. The diene of claim 1 or claim 2, wherein R¹ is -CHMe-Aryl of either (R) or (.S') absolute stereochemistry, and R² and R³ are independently selected from H, halogen, linear and branched alkyls, substituted amino, ether, aryl, heteroaryl, alkaryl, allyl, methallyl, and carbonyl groups, and where each R group is optionally substituted.

10. The diene of claim 9, wherein R¹ is -CHMe-Aryl of either (R) or (.S') absolute stereochemistry, and R² and R³ are independently selected from H, halogen, linear and branched alkyls, substituted amino, ether, aryl, heteroaryl and carbonyl groups, and where each R group is optionally substituted.

11. The diene of claim 9 or claim 10, wherein R¹ is -CHMe-(l -naphthyl) of either (R) or (.S') absolute stereochemistry.

12. The diene of any one of the preceding claims, wherein only one of R¹, R², and R³ includes a stereogenic element.

13. The diene of any one of the preceding claims, wherein R¹, R², and R³ are selected such that at least one of R² and R³ includes a stereogenic element.

14. The diene of claim 1 or claim 2, wherein R¹ is an alkyl group (e.g. w-propyl), R² is C(=O)NH-CHMe-(l -naphthyl) of either (R) or (.S') absolute stereochemistry and R³ is a halogen.

15. The diene of claim 1 or claim 2, wherein R¹ is an alkyl group (e.g. where R¹ is n- propyl), R² is C(=O)NH-CHMe-(l -naphthyl) of either (R) or (.S') absolute stereochemistry, and R³ is selected from alkyl, allyl, alkaryl and aryl groups which are each optionally substituted (e.g. where R³ is Me, allyl, Ph, 1-naphthyl, 2-MeOCeH4, 3,5-Me2CeH₃, or 3,4- (MeO)2C₆H₃).

16. The diene of claim 1 or claim 2, wherein R¹ is an alkyl group (e.g. where R¹ is Me), R² is C(=O)NH-CHMe-Aryl of either (R) or (.S') absolute stereochemistry (e.g. where Aryl is phenyl or 1-naphthyl), and R³ is selected from halogen, alkyl, allyl, alkaryl and aryl groups which are each optionally substituted (e.g. where R³ is Br, Me, allyl, Ph, 1-naphthyl, 2-MeOC₆H₄, 3,5-Me₂C₆H₃, or 3,4-(MeO)₂C₆H₃).

17. The diene of claim 1 or claim 2, wherein R¹ is an alkaryl group (e.g. where R¹ is -CHMe(Aryl), such as where Aryl is phenyl or 1-naphthyl) of either (R) or (.S') absolute stereochemistry, R² is selected from H, halogen, alkyl, allyl, alkaryl and aryl groups which are each optionally substituted, (e.g. where R² is H, Br, Me, allyl, Ph, or 1-naphthyl), and R³ is selected from H, halogen, alkyl, allyl, alkaryl and aryl groups which are each optionally substituted (e.g. where R³ is H, Br, Me, allyl, Ph, or 1-naphthyl).

18. The diene of claim 1 or claim 2, wherein the diene is:

- of Formula (I-a) or (I-b)

wherein X is a halogen (e.g. F, Cl, Br, or I);

- of Formula (I-c)

- of Formulae (I-d) or (I-e):

- of Formulae (I-f) and (I-g):

(I-f) (I-g)

19. A metal complex in which one or more diene ligand as defined in any one of claims 1-18 is bound to a metal ion.

20. The metal complex of claim 19, wherein the metal is a transition metal.

21. The use of the metal complex according to claim 19 or claim 20 as a catalyst, e.g. in enantioselective catalysis.

22. A method of preparing an enantiomerically pure compound, wherein the compound is prepared in the presence of a catalyst which is a metal complex according to claim 19 or claim 20.