CN114478242B - Salen-Ti complex catalyst and method for catalyzing asymmetric hydrogen atom transfer reaction by using same - Google Patents
Salen-Ti complex catalyst and method for catalyzing asymmetric hydrogen atom transfer reaction by using same Download PDFInfo
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Abstract
The invention discloses a Salen-Ti complex catalyst and a method for catalyzing asymmetric hydrogen atom transfer reaction by using the same, belonging to the field of asymmetric catalysis of organic chemistry. The method comprises the following steps of reacting a substrate with a structure shown in a formula I with a hydrogen atom donor under the action of a Salen-Ti complex catalyst to obtain a product with a structure shown in a formula II; the Salen-Ti complex catalyst is used only in catalytic amount, and the obtained R configuration product has high enantioselectivity and high yield.
Description
Technical Field
The invention belongs to the field of asymmetric catalysis of organic chemistry, and particularly relates to a Salen-Ti complex catalyst and a method for catalyzing asymmetric hydrogen atom transfer reaction by using the same.
Background
The reduction of carbon-centered radicals is a fundamental reaction, usually accomplished by Hydrogen Atom Transfer (HAT). Although this promoiety is ubiquitous and can achieve a wide range of transitions from natural combustion to industrial organic synthesis to enzymatic oxidation in vivo, enantioselective hydrogen atom transfer is still rare. This can be attributed to the challenges posed by less stereochemical communication between the free radical intermediate and the less sterically hindered hydrogen atom in the early stereodetermined transition state. Some chiral hydrogen atom donors, where the chiral agent is used in a stoichiometric manner, as well as templates based on non-covalent interactions have proven effective for enantioselective control.
The use of catalytic amounts of chiral reagents for enantioselective control is clearly more attractive in terms of sustainability. To date, the implementation of such catalyzed asymmetric hydrogen atom transfers has relied on carefully designed polarity-reversing catalysis and emerging enzymatic catalysis. Although coordination control of chiral lewis acids has long been well developed in asymmetric catalysis and successfully applied to many Enantioselective radical mediated reactions inspired by the pioneering work of Sibi (j. Zimmerman, m.p. Sibi, energetic chemical reactions, top Curr chem.2006,263, 107-162), it has not been fully exploited in catalytic asymmetric hydrogen atom transfer. To the best of our knowledge, the chiral Lewis acids are usually used stoichiometrically, and very rarely are reacted in sub-stoichiometric amounts of 30% and 20%. Lower catalyst loadings generally reduce enantioselectivity and sometimes reduce reaction efficiency.
Previously reported schemes for high Lewis acid loadings may involve unrelated free radical generation and chiral control systems (endogenous H-atom transfer reactions: a new method for the synthesis of beta) 2 Amino acids, angew. Chem. Int. Ed.2004,43,1235-1238.Enantioselective hydrogen atom transfer reactions. In this form, the radical intermediate is generated by extrinsic radical initiation of the substrate, while chiral control is achieved by a chiral lewis acid. In view of the reactivity of the radical reaction, which generally shows a small difference between lewis acid activated and non-activated substrates, the radical intermediate is not controlled by chiral lewis acids and thus enantioselectivity cannot be induced. Thus, these non-coordinating radicals leave chiral control during asymmetric hydrogen atom transfer, thereby destroying the critical enantioselectivity.
Disclosure of Invention
1. Problems to be solved
Aiming at the problem that the relatively low catalyst loading capacity in the prior art can generally reduce the enantioselectivity, the invention provides a Salen-Ti complex catalyst and a method for catalyzing asymmetric hydrogen atom transfer reaction by using the Salen-Ti complex catalyst, wherein the reaction is carried out by using a catalytic amount to obtain high enantioselectivity without reducing the reaction efficiency.
2. Technical scheme
To address the above-mentioned problems, the present invention overcomes this inherent challenge by a bifunctional transition metal redox catalytic strategy to coordinate a related radical generation and chiral control system: (i) Reducing transition metal complex LxM n And a substrate to generate carbon radicals, and (ii) the resulting L M n+1 Subsequently, a key enantioselective HAT response is induced.
The technical scheme adopted by the invention is as follows:
a method for catalyzing asymmetric hydrogen atom transfer reaction by a Salen-Ti complex catalyst comprises the following steps that a substrate with a structure shown in a formula I and a hydrogen atom donor generate asymmetric Hydrogen Atom Transfer (HAT) reaction under the action of the Salen-Ti complex catalyst to obtain a product with a structure shown in a formula II;
wherein:
R a selected from:
wherein R is c Is selected from-CH 3 ，-CH(CH 3 ) 2 ，-C(CH 3 ) 3 ，-OCH 3 ，-CF 3 ；
R b Is selected from-CH 3 ，-CH 2 CH 3 ，-CH 2 CH 2 CH 3 ，-CH(CH 3 ) 2 ，-CH 2 CH(CH 3 ) 2 ，
As shown in FIG. 1, this bifunctional catalysis was achieved in the Single Electron Transfer (SET) and Hydrogen Atom Transfer (HAT) processes we developed Salen-Ti catalysis. Specifically, the redox-active Salen-Ti complex initiates homolytic cleavage of the C — O bond by coordination with an epoxy substrate and subsequent one-electron transfer. The initial radical intermediate a then undergoes a key enantioselective hydrogen atom transfer process to provide a stereogenic carbon centre. Subsequent metal protonation of B with acid to liberate Salen-Ti IV While eliminating potential product inhibition issues, which are common challenges in lewis acid catalysis. By reduction of Salen-Ti IV To regenerate reducing Ti III Material to complete the catalytic cycle. Among these, homolytic radical ring opening of the substrate and subsequent enantioselective asymmetric hydrogen atom transfer of a constitute the key steps determining the catalytic efficiency and selectivity of the radical.
Thus, the bifunctional Salen-Ti redox strategy correlates free radical generation and chiral control, providing an important catalytic asymmetric hydrogen atom transfer reaction.
On the other hand, the Salen-Ti catalyzed asymmetric hydrogen atom transfer reaction has excellent enantiomer control and good functional group tolerance, and can synthesize a plurality of tertiary stereocenters with different structural characteristics. In view of the high synthesis value of the simple and easily available racemic glycidyl ester substrate and the chiral alpha-tertiary stereocenter-beta-hydroxy ester product, the method provides a promising alternative method for asymmetric aldol reaction.
Preferably, the Salen-Ti complex catalyst is selected from the group consisting of:
preferably, the Salen-Ti complex catalyst is:
preferably, the Salen-Ti (Salen-Ti) IV ) The complex catalyst is used in an amount of less than 30mol% of stoichiometric. Wherein 30mol% represents (the mole number of the added catalyst is 30% of that of the substrate with the structure of formula I).
Preferably, the hydrogen atom donor is selected from tBu 3 SnH or (TMS) 3 SiH。
Preferably, the asymmetric hydrogen atom transfer reaction comprises: a substrate of formula I, in Salen-Ti (Salen-Ti) IV ) Reacting the complex catalyst, a metal reducing agent and a demetallized protonized acid with a hydrogen atom donor in an aprotic solvent at low temperature to obtain a product with a structure shown in a formula II.
Preferably, the metallic reducing agent is selected from Zn or Mn; and/or
The demetallized protonated acid is selected from the group consisting of imidazole p-toluenesulfonate (IMTS), pyridine methanesulfonate, pyridine ethanesulfonate, pyridine p-toluenesulfonate, pyridine trifluoroacetate, pyridine tetrafluoroborate; and/or
The aprotic solvent is selected from ethyl acetate, toluene, tetrahydrofuran, 1, 4-dioxane, and ethylene glycol dimethyl ether.
Preferably, the low temperature is-20 ℃ to 0 ℃.
More preferably, the asymmetric hydrogen atom transfer reaction comprises: a substrate of formula I is reacted with tBu in the presence of a Salen-Ti complex catalyst C1, zn, IMTS in ethyl acetate at-20 deg.C 3 SnH reaction to obtain the product in the structure as shown; the structural formula of the Salen-Ti complex catalyst C1 is as follows:
the invention also provides a Salen-Ti complex catalyst for catalyzing asymmetric hydrogen atom transfer reaction, which is selected from the following structures:
3. advantageous effects
Compared with the prior art, the invention has the beneficial effects that: the substrate with the structure of the formula I reacts with a hydrogen atom donor under the action of a Salen-Ti complex catalyst to obtain a product with the structure of the formula II, wherein the Salen-Ti complex catalyst is used only in a catalytic amount, and the obtained product with the R configuration has high enantioselectivity and does not reduce the yield.
Drawings
FIG. 1 shows the reaction mechanism of the present invention (M: metal; L: chiral ligand; SET: single electron transfer; HAT: hydrogen atom transfer;
FIG. 2 is a plot of Charton value versus the enantiomeric ratio of the product for a hydrogen atom donor tin hydride substituent.
Detailed Description
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs; as used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are conventional products which are not indicated by manufacturers and are commercially available.
As used herein, the term "about" is used to provide the flexibility and inaccuracy associated with a given term, measure or value. The degree of flexibility for a particular variable can be readily determined by one skilled in the art.
Concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a numerical range of about 1 to about 4.5 should be interpreted to include not only the explicitly recited limit values of 1 to about 4.5, but also include individual numbers (such as 2, 3, 4) and sub-ranges (such as 1 to 3, 2 to 4, etc.). The same principle applies to ranges reciting only one numerical value, such as "less than about 4.5," which should be construed to include all of the aforementioned values and ranges. Moreover, such an interpretation should apply regardless of the breadth of the range or feature being described.
All reactions involving air or moisture sensitive compounds were performed under argon using standard Schlenk and double row tube techniques. The solvent used was purified by distillation over the indicated drying agent and transferred under argon: etOAc (CaH) 2 ) Toluene (Na), THF (Na), CH 2 Cl 2 (CaH 2 ). All reactions were monitored by Thin Layer Chromatography (TLC) on Merck silica gel 60F254 plates, using UV detection (if applicable), and ammonium molybdate tetrahydrate (25 g/L) and Ce (SO) 4 ) 2 ·4H 2 H in a solution of O (10 g/L) at 10% 2 SO 4 Aqueous solution or KMnO 4 In the stain, and then heated. The product is purified by flash column chromatography on merck silica gel 60 or merck alumina 90.
The instrument comprises the following steps: 1 h NMR and 13 c NMR spectra were measured on a Bruker AMX 300MHz or Bruker 400MHz, 500MHz spectrometer. 1 H NMR chemical shifts are given in ppm and are in terms of the solvent peak (CHCl) of the deuterated reagent 3 (7.26 ppm), d 6-benzene (7.16 ppm)). 13 C NMR solvent Peak (CDCl) 3 (77.0ppm)、C 6 D 6 (128.0 ppm)) are reported in ppm units. The IR spectra were measured as pure films on an ATR-IR-Spectrometer Nicolet TM 380 instrument. High resolution mass spectrometry data were obtained on a MAT 95XL instrument from semer airlines. Chiral analysis was performed using shimadzu HPLC instrument.
Abbreviations used: DCM-dichloromethane, DMF-N, N-dimethylformamide, etOAc-ethyl acetate, tol-toluene, THF-tetrahydrofuran, IMTS-imidazole p-toluenesulfonate, DCC-dicyclohexylcarbodiimide, (Boc) 2 Di-tert-butyl O-carbonate, DMAP-4-dimethylaminopyridine, DMPO-5, 5-dimethyl-1-pyrroline oxide, mCPBA-m-chloroperoxybenzoic acid, L-DET-L-diethyl tartrate, np-alpha-Naphthyl, RT-RT, TLC-thin layer chromatography;
ee value-R configuration product enantioselectivity excess value; r. -diastereomer ratio;
if not specifically stated, the yield refers to the column chromatography separation yield of the product; the nuclear magnetic yield is obtained by quantitative calculation of a nuclear magnetic spectrogram of a reaction crude product by taking 1,3, 5-trimethoxybenzene as an internal standard.
The invention is further described with reference to specific examples.
Examples
1. General Synthesis procedure for Salen-Ti Complex catalysts
(1) Synthesis of Salen ligands
The salicylaldehyde derivative (2.0 eq), (R, R) -1, 2-cyclohexanediamine (1.0 eq), and ethanol were added to a round-bottom flask, and the mixture was stirred at reflux for 4 hours, and then cooled to room temperature. After filtration and vacuum drying, a yellow solid is obtained, which is washed with ethanol or methanol.
(2) Synthesis of Salen-Ti complex catalyst
To a dry Schlenk flask, salen ligand (5.0 mmol,1.0 eq) and freshly distilled THF were added in N 2 The resulting yellow solution was then cooled to-78 ℃. Then TiCl is reacted at the same temperature 4 Solution (1.0M toluene solution, 1.0eq, dropwise added to the above solution, the resulting red suspension was warmed to room temperature, heated under reflux for 3 hours, the reaction was cooled to room temperature, and the dark red solid was filtered off and washed with diethyl ether or n-hexane to give a Salen-Ti complex catalyst (Salen-Ti complex catalyst) IV )。
2. Substrate synthesis
(1) General Synthesis procedure for epoxypropionate substrates
In the formula II, R a Is phenyl, R b For methyl as an example: to a THF solution of methacrylic acid (1.0 eq) was added phenol (1.0 eq), (Boc) at room temperature 2 O(1.0eq)、Mg(OH) 2 (0.02 eq), liOH (0.08 eq). The mixture was stirred at reflux for 6 hours and then cooled to room temperature. The mixture was extracted with ethyl acetate and then with Na 2 SO 4 And (5) drying. After removal of the solvent under reduced pressure, the crude methacrylate product was used in the next step without further purification.
To a solution of the methacrylate (1.0 eq) obtained above in DCM was added mCPBA (85 wt%,2.0 eq). The mixture was stirred at reflux for 48 hours and then cooled to 0 ℃. The precipitated 3-chlorobenzoic acid was removed by vacuum filtration. The resulting reaction mixture was washed with saturated sodium thiosulfate and extracted with DCM. After removal of the solvent under reduced pressure, the crude product was purified by flash column chromatography on silica gel.
(2) Synthesis of 2-methyloxirane-2-carboxylic acid- (1) -naphthol ester
According to the step in the step (1), R a Is alpha-naphthyl, R b Is methyl; wherein methacrylic acid (860mg, 10mmol, 1.0eq), 1-naphthol (1.44g, 10mmol, 1.0eq), (Boc) 2 O(2.18g,10mmol,1.0eq),Mg(OH) 2 (12mg, 0.2mmol, 0.02eq), liOH (19mg, 0.8mmol, 0.08eq), mCPBA (4.06g, 20mmol,85wt%,2.0 eq), to give 2-methyloxirane-2-carboxylic acid- (1) -naphtholate (1.46g, 64% overall yield) as a white solid. Mp is 81.1-82.1 deg.C; IR v max (neat)/cm -1 :1751,1441,1386,1126,798； 1 H NMR(400MHz,CDCl 3 )δ7.86(dt,J＝8.9,6.0Hz,2H),7.74(d,J＝8.3Hz,1H),7.57–7.48(m,2H),7.45(t,J＝7.9Hz,1H),7.26(q,J＝6.8Hz,1H),3.45(d,J＝5.9Hz,1H),2.97(d,J＝5.9Hz,1H),1.80(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ169.5,146.2,134.7,128.1,126.7,126.6,126.5,126.4,125.4,120.9,117.8,54.1,53.4,17.7；HRMS(ESI)m/z C 14 H 13 O 3 [M+H] + Calculated 229.0859, found 229.0858.
(3) Synthesis of other substrates
When other substrates are synthesized, corresponding raw materials are adopted, and the synthesis steps are basically the same as those in the step (2).
3. Experimental conditions for catalyzing hydrogen atom transfer reaction by Salen-Ti complex catalyst
(1) General conditions for Salen-Ti complex catalyst to catalyze hydrogen atom transfer reaction
To a hot dried Schlenk tube was added the demetallized protonated acid (3.0 eq), the metal reducing agent (4.0 eq), the Salen-Ti complex catalyst (less than 0.3eq, and may range, for example, from 0.025 to 0.1 eq), and the freshly distilled aprotic solvent (1.0 mL), followed by stirring the mixture at low temperature (e.g., any temperature from-20 ℃ to 0 ℃) for 2 hours under an inert gas such as argon atmosphere. Then hydrogen atom donor reagent (2.5 eq) was added followed by glycidyl ester substrate (0.2mmol, 1.0 eq). Stirring the mixture at the aforementioned low temperature (e.g., -20 deg.C-0 deg.C) for several hours (e.g., 72 hours), adding saturated NaHCO 3 Quench with aqueous solution, dilute with solvent, wash with brine and MgSO 4 And (5) drying. After removal of the solvent under reduced pressure, the crude product was purified by flash column chromatography on silica gel.
(2) Example of Salen-Ti Complex catalyst C1 catalyzing Hydrogen atom transfer reaction
To a hot dried Schlenk tube were added imidazole p-toluenesulfonate (144mg, 0.6mmol, 3.0eq), zn (52mg, 0.8mmol, 4.0eq), salen-Ti complex catalyst Cl (24mg, 0.02mmol, 0.1eq), and freshly distilled EtOAc (1.0 mL), followed by stirring the mixture at-20 ℃ for 2 hours under an argon atmosphere. Then tBu was added 3 SnH (146mg, 0.5mmol, 2.5eq), followed by the addition of the substrate of formula I (0.2mmol, 1.0eq). The mixture is at-20Stirred at temperature for 72 hours and saturated NaHCO is used 3 Quench with EtOAc, wash with brine and MgSO 4 And (5) drying. After removal of the solvent under reduced pressure, the crude product was purified by flash column chromatography on silica gel.
4. Influencing factor for catalyzing asymmetric hydrogen atom transfer reaction by adopting Salen-Ti complex catalyst
(1) Screening of Salen-Ti complex catalyst in asymmetric hydrogen atom transfer reaction
In this example, the epoxy carboxylic acid naphthol ester (R) is substituted with a methyl group a Is alpha-naphthyl, R b The asymmetric hydrogen atom transfer reaction of the compound 1) for methyl was used to study the catalytic effect of the Salen-Ti complex catalyst. Methyl substituent at C2 position (R) b ) Of particular interest, since it is not only expected to provide biologically relevant common structures in macrolide and polyether antibiotics, but, due to its low steric hindrance, it also represents a key challenge in stereoselective asymmetric hydrogen atom transfer reaction processes. The invention obtains a reaction system with high yield and high stereoselectivity through multiple optimization, and the reaction system comprises methyl epoxy naphthol carboxylate as a substrate, salen-Ti C1 as a catalyst, and zinc powder for generating active Ti through single electron reduction III With tBu 3 SnH as hydrogen atom donor, imidazole p-toluenesulfonate (IMTS) as demetallized protonated acid, in ethyl acetate at-20 ℃ to form α -methyl- β -hydroxy ester (R) in satisfactory isolated yield (87%) and enantioselectivity (92% ee) a Is alpha-naphthyl, R b For methyl, compound 2), see [ tris (2)](wherein the substrate (0.2 mmol), salen-Ti complex catalyst C1 (10 mol%), tBu 3 SnH (2.5 equiv), zn (4.0 equiv), IMTS (3.0 equiv), etOAc (1.0 mL), reacted at-20 ℃ for 72 hours.
Screening of a series of chiral Salen-Ti complex catalysts C1-C10 (the reaction conditions are the same as C1) shows that Katsuki type ligands (C1, C7-C10, especially C1, C8-C10) show remarkably superior stereoselectivity compared with common Salen-Ti complexes (C2, C3). The binaphthediamine-derived Salen-Ti complex (C4) yields a nearly racemic product. The two enantiomers of the diamine are condensed with the same salicylaldehyde to give two classes of Salen ligands, respectively, to give poor and good results (C7 vs C5; C8 vs C6), probably due to the selectivity resulting from the matching and mismatching of the structures. 3, 5-dimethylphenyl substitution on binaphthyl units (C1) is more suitable than larger 3, 5-di-tert-butylphenyl (C9) or smaller phenyl (C8). Dinaphthylethylenediamine complex C10 showed essentially the same selectivity as C8, indicating that the polarizability of the aromatic rings had little effect on the enantiomeric differentiation.
(2) R in the substrate structure in asymmetric hydrogen atom transfer reaction a Influence of (2)
Using Salen-Ti C1 as catalyst, and adopting zinc powder to produce active Ti by single electron reduction III With tBu 3 SnH as a hydrogen atom transfer donor and IMTS as a demetallized protonated acid, in ethyl acetate at-20 ℃ to form an alpha-methyl-beta-hydroxy ester, according to the specific experimental procedures [ tris (1) ]](substrate (0.2 mmol), C1 (10 mol%), tBu 3 SnH (2.5 equiv), zn (4.0 equiv), IMTS (3.0 equiv), etOAc (1.0 mL), -20 deg.C (wherein the reaction temperature of the glycidyl ester derived from tyrosine and estrone is-10 deg.C), 72 hours. IMTS: imidazole p-toluenesulfonate). When R in the substrate of formula I b Is methyl, R a The yields and ee values correspond to the following groups:
preliminary screening of the ester groups in this example shows that phenyl ester provides a higher enantioselectivity than benzyl alcohol ester. The restricted vertical conformation of phenyl esters may minimize the degree of freedom of the key intermediate complex a in fig. 1 and thus impose greater discrimination on the prochiral radical orientation. Wherein the ee value and the yield of the alpha-naphthol ester are highest.
Each with different spacesPhenyl esters of both meso and electronic character are well suited to high efficiencies and consistent stereoselectivity (spatial difference R) c = Me, iPr, tBu, the electrical difference being R c ＝OMe,CF 3 ). The similar enantioselectivities possessed by the different substituents proved a strong enantiomeric distinction. Whereas tyrosine and estrone derived glycidyl esters give the expected product with a moderate diastereomer ratio.
(3) R in the substrate structure in asymmetric hydrogen atom transfer reaction b Influence of (2)
In step [ three (1)]Under the conditions (specific conditions: substrate (0.2 mmol), C1 (10 mol%), tBu 3 SnH (2.5 equiv), zn (4.0 equiv), IMTS (3.0 equiv), etOAc (1.0 mL), reacted for 72 hours; wherein the reaction temperature is as follows: 5,7:0 ℃;6,8, 10-18: -10 ℃;2-4,9: -20 ℃) using alkyl substituents R having different steric hindrance b Chiral carbon substrate glycidyl ester (R) a Alpha-naphthyl) as a substrate, all showed good enantioselectivity (2 to 9). At-20 ℃ the selectivity for the isopropyl substituent was very good (93% ee), but the yield was slightly lower (56%), and the starting material remained largely, indicating that the substrate containing the bulky substituent was close to Salen-Ti III The catalyst process is somewhat slow. Simply raising the temperature to 0 ℃ facilitates this approach and provides good reactivity (5,82% yield) and better enantioselectivity (85% ee). Product 9 is readily crystallized and characterized by X-ray crystallography to determine the absolute configuration as R.
The functional group tolerance of this reaction is high (10 to 18). A plurality of radicals, including R b Are benzyl ethers, nitriles, amides, imides and carbamates, all exhibiting high yields and enantioselectivities. Especially, substrates having functional groups unstable under acidic conditions, such as ketal (11) and silyl ether (12), perform well in the asymmetric HAT reaction of the present invention. It is noted that menthol and proline derived glycidyl esters are also possibleThe substrates of the rows, forming products combined with multiple stereocenters, have higher diastereoselectivities (17 and 18).
(4) Influence of hydrogen atom donors in asymmetric Hydrogen atom transfer reactions
In step [ three (1)]Conditions, wherein the specific experimental conditions: substrate (R) a (= alpha-naphthyl), R b Me,0.2 mmol), C1 (10 mol%), hydrogen atom donor (2.5 equiv), zn (4.0 equiv), IMTS (3.0 equiv), etOAc (1.0 mL), -20 ℃ for 72 hours.
The hydrogen atom donor apparently plays an important role in influencing stereoselectivity. With tBu 3 Compounds less sterically hindered than SnH (Ph) 3 SnH，27％ee；nBu 3 SnH，53％ee；iPr 3 SnH, 69%) ee) showed poor results. A strong linear free energy dependence was observed between the product enantiomeric ratio and Charton value (v) of the tin hydrogen substituent (fig. 2), indicating that the effect of the H atom donor is primarily steric hindrance in nature. The rather large positive ψ value (1.65) indicates that asymmetric hydrogen atom transfer is highly sensitive to the nature of the hydrogen atom donor substituent, larger hydrogen atom donors being able to significantly enhance ee. (TMS) 3 SiH provided a slightly lower but still good selectivity (85% ee), while 1, 4-cyclohexadiene showed a poor reactivity (33% yield) and selectivity (32% ee).
(5) Influence of reaction temperature in asymmetric Hydrogen atom transfer reaction
In step [ three (1)]Under conditions, wherein the specific experimental conditions: substrate (R) a = alpha-naphthyl, R b ＝Me，0.2mmol)，C1(10mol％)，tBu 3 SnH (2.5 equiv), zn (4.0 equiv), IMTS (3.0 equiv), etOAc (1.0 mL), reaction at-20 ℃ to 0 ℃ for 72 hours.
As in table 1, decreasing the temperature leads to an increase in enantioselectivity, demonstrating that the usual enthalpy controls the process of steric differentiation, in good agreement with the observed steric effect of tin-hydrogen.
TABLE 1 Effect of temperature on product
(6) Effect of solvents on asymmetric Hydrogen atom transfer
The concrete steps are shown in [ three (1)]And the specific experimental conditions are as follows: substrate (R) a = α -naphthyl), R b ＝Me，0.2mmol)，C8(10mol％)，nBu 3 SnH (2.5 equiv), zn (4.0 equiv), IMTS (3.0 equiv). Respectively reacting in ethyl acetate, toluene, 1, 4-dioxane, tetrahydrofuran and glycol dimethyl ether solvent at room temperature for 72h.
As in table 2, the results show that: preferred solvents for this reaction are ethyl acetate and toluene.
TABLE 2 influence of the solvent on the asymmetric Hydrogen atom transfer
(7) Effect of counter ions on asymmetric Hydrogen atom transfer reactions
The concrete steps are shown in [ three (1)]Wherein the experimental conditions substrate (R) a (= alpha-naphthyl), R b ＝Me，0.2mmol)，C8(10mol％)，nBu 3 SnH (2.5 equiv), zn (4.0 equiv), py. HX (3.0 equiv), etOAc (1.0 mL). Respectively reacting with different Py. HX (wherein X is CH) 3 SO 3 - 、EtSO 3 - 、TsO - 、CF 3 COO - 、BF 4 - 、PF 6 - ) As demetallized protonated acid, reaction was carried out at room temperature for 72h.
TABLE 3 Effect of counterions on asymmetric Hydrogen atom transfer reactions
As table 3, the results show that: preferred counterions for this reaction are p-toluenesulfonate, ethanesulfonate and methanesulfonate.
Conclusion
The invention realizes the catalysis of asymmetric hydrogen atom transfer reaction by a well-designed bifunctional Salen-Ti complex redox strategy. With Salen-Ti III Initiating free radical formation to obtain Salen-Ti IV Affecting enantioselectivity, the continuous oxidation state change function allows the catalyst loading to be reduced to 2.5mol% without loss of enantioselectivity, compared to classical stereoselectivity control strategies using stoichiometric amounts of lewis acids to ensure no reduction. Extensive screening of the invention reveals a highly selective system comprising a Salen ligand of the Katsuki type as a deep chiral environment, tert-butyltin hydride as a hydrogen atom donor with a large Charton value, and naphthyl ester as a conformationally constrained modifier to minimize the freedom of transition states. It exerts excellent enantiomeric control by enhancing the weak stereochemical exchange inherent in the early enantiomeric decision transition states of hydrogen atom transfer reactions in a rational manner. The reaction converts readily available racemic glycidyl ester into alpha-tertiary stereocenter beta-hydroxy ester in a chiral convergence manner, providing a promising alternative to asymmetric aldol reactions.
The above description is illustrative of the present invention and its embodiments, and is not to be construed as limiting, and the embodiments shown in the examples are only one embodiment of the present invention, and the actual embodiments are not limited thereto. Therefore, if a person skilled in the art should appreciate that they can design embodiments and examples similar to the above-mentioned technical solutions without departing from the spirit of the present invention, and they should fall into the protection scope of the present invention.
Claims (6)
1. A method for catalyzing asymmetric hydrogen atom transfer reaction by a Salen-Ti complex catalyst is characterized in that a substrate with a structure shown in a formula I and a hydrogen atom donor perform asymmetric hydrogen atom transfer reaction at low temperature in an aprotic solvent in the presence of the Salen-Ti complex catalyst, a metal reducing agent and an acid for removing metal protonation to obtain a product with a structure shown in a formula II;
the compound has a structure shown in a formula I,
the compound of the formula II is shown in the specification,
wherein: r a Selected from:
wherein R is c Is selected from-CH 3 ，-CH(CH 3 ) 2 ，-C(CH 3 ) 3 ，-OCH 3 ，-CF 3 ；
R b Is selected from-CH 3 ，-CH 2 CH 3 ，-CH 2 CH 2 CH 3 ，-CH(CH 3 ) 2 ，-CH 2 CH(CH 3 ) 2 ，
The Salen-Ti complex catalyst is selected from the group consisting of:
C1,
C8,
C9，
C10;
the hydrogen atom donor is selected fromtBu 3 SnH or (TMS) 3 SiH；
The metal reducing agent is selected from Zn or Mn;
the demetallized protonated acid is selected from imidazole p-toluenesulfonate IMTS, pyridine methanesulfonate, pyridine ethanesulfonate, pyridine p-toluenesulfonate, pyridine trifluoroacetate, pyridine tetrafluoroborate;
the aprotic solvent is selected from ethyl acetate, toluene, tetrahydrofuran, 1, 4-dioxane, and ethylene glycol dimethyl ether.
2. The method of catalyzing asymmetric hydrogen atom transfer reactions with the Salen-Ti complex catalyst according to claim 1, wherein said Salen-Ti complex catalyst is:
C1。
3. the method of catalyzing asymmetric hydrogen atom transfer reactions using the Salen-Ti complex catalyst according to claim 1, wherein the Salen-Ti complex catalyst is used in an amount of less than 30mol% of the stoichiometric amount.
4. The method of catalyzing an asymmetric hydrogen atom transfer reaction with the Salen-Ti complex catalyst of claim 1, wherein the low temperature is in the range of-20 ℃ to 0 ℃.
5. The method of catalyzing an asymmetric hydrogen atom transfer reaction with the Salen-Ti complex catalyst according to claim 1, wherein the asymmetric hydrogen atom transfer reaction comprises: a substrate of formula I is reacted with tBu in ethyl acetate at-20 ℃ in the presence of a Salen-Ti complex catalyst C1, zn and IMTS 3 SnH reaction to obtain the product in the structure as shown; the structural formula of the Salen-Ti complex catalyst C1 is as follows:
C1。
6. a Salen-Ti complex catalyst for catalyzing asymmetric hydrogen atom transfer reactions, said catalyst selected from the group consisting of the following structures:
C1，
C8,
C9,
C10。
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