Chiral amide compound containing silicon group or germanium group as well as synthesis method and application of chiral amide compound

Abstract

The invention relates to the technical field of organic synthesis, and discloses a chiral amide compound containing a silicon group or a germanium group and a synthesis method and application thereof.The chiral amide compound containing the silicon group or the germanium group is prepared by taking alpha, beta-unsaturated amide and silane or germane as raw materials, taking a complex formed by chiral amine oxide and metal salt as a Lewis acid catalyst and taking a quinone compound as a photocatalyst through a one-step reaction. The chiral amide compound containing the silicon group or the germanium group is obtained through a reaction in an organic solvent under the illumination condition, high-yield and high-enantioselectivity synthesis is achieved, and the effects of being simple, efficient, environmentally friendly and good in substrate universality are achieved. In addition, the chiral amide compound can also be used for further synthesizing various chiral drug intermediates such as chiral tropine acid, chiral 3-(dimethyl phenyl silyl)-2-phenyl-1-propanol, chiral 2-phenyl-1-propanol and the like, so that the chiral amide compound is wide in applicability.

Description

Technical Field

[0001] The present disclosure relates to the technical field of organic synthesis, and for example, to a chiral amide compound containing a silicon group or a germanium group, and a synthesis method and application thereof. Background Art

[0002] 1. Synthesis of chiral silicon-containing compounds or chiral germanium-containing compounds

[0003] The synthesis of silicon-containing compounds is a challenging problem in organosilicon chemistry. With the rapid development of photocatalysis in recent years, methods for synthesizing various silicon-containing compounds using silicon free radicals have also developed rapidly. Reactions can be categorized by the initiation method of silicon free radicals as follows: peroxide initiation, homolytic cleavage of organosilicon compounds (Si-B, Si-Si, etc.), photocatalysis, and electrocatalysis. Currently, a wealth of methods for generating silicon free radicals and the various organosilicon compounds they can synthesize are known. However, most of these reactions are limited to the preparation of racemates, with only a few reports on the synthesis of chiral silicon-containing compounds using asymmetric catalysis.

[0004] In 2019, Liu Xinyuan et al. used Cu(I) to initiate peroxide (LPO) to generate alkyl radicals, which were then further extracted from silicon hydrides via hydrogen atom transfer to generate silicon radicals, ultimately achieving intramolecular asymmetric aminosilylation of olefins. (Sci. China. Chem., 2019, 62, 1529.)

[0005]

[0006] In 2022 and 2023, Ye Juntao and others used chiral thiols as hydrogen atom transfer reagents to achieve asymmetric silylation of exocyclic alkenes. (Nat. Commun., 2022, 13, 4453.)(Org. Chem. Front., 2023, 10, 1182.)

[0007]

[0008]

[0009] As can be seen, there are currently few reports on the synthesis of chiral organosilicon compounds via asymmetric reactions involving silicon radicals. In addition, there are currently no reports on the synthesis of chiral germanium compounds via germanium radicals.

[0010] 2. Synthesis of chiral tropic acid

[0011] Chiral tropic acid is the main backbone and synthetic intermediate for drug molecules such as atropine, tropicamide, scopolamine, anisodamine, and ipratropium bromide. Currently reported synthetic methods for chiral tropic acid fall into three main categories: chiral resolution, chiral induction, and asymmetric catalysis (primarily enzymatic). Chiral resolution and chiral induction are the most common methods, while non-enzymatic catalysis is less explored in the field of asymmetric catalysis.

[0012] In 1995, Mitsuhisa Yamano and Toshiaki Nagata used 2-phenylacrylic acid as a substrate and successfully obtained chiral tropic acid using a Pt / H2 catalytic strategy. (JP07278019A)

[0013]

[0014] In 2018, Lü Hui, Zhong Longhua, and others used silyl-substituted styrene as a substrate and, using CO / H₂ in the presence of transition metal Rh, obtained the chiral tropic acid precursor 2-phenyl-3-(dimethylbenzyl)silyl-1-propanal. They then oxidized the aldehyde group to a carboxyl group, which was then desilylated to a hydroxyl group, ultimately yielding chiral tropic acid. (Nat. Commun., 2018, 9, 2045.)

[0015]

[0016] Therefore, strategies for synthesizing chiral tropic acid primarily rely on chiral resolution, chiral induction, and enzymatic catalysis. However, chiral resolution offers only a 50% yield at best, resulting in poor atom economy. Chiral induction requires the pre-preparation of the chiral substrate, while enzymatic catalysis requires a buffer system. Currently, only a few reports have reported the derivation of chiral tropic acid via non-enzymatic asymmetric catalysis, but these have all employed precious metals or relatively harsh conditions.

[0017] 3. Synthesis of chiral 3-(dimethylphenylsilyl)-2-phenyl-1-propanol

[0018] Currently, there is no relevant synthesis method for chiral 3-(dimethylphenylsilyl)-2-phenyl-1-propanol. Based on the Fleming-Tamao oxidation reaction, the silicon group can be regarded as a precursor of the hydroxyl group, and thus can serve as a chiral molecular equivalent of two identical hydroxyl substituents, making it a very promising synthetic intermediate.

[0019] 4. Synthesis of Chiral 2-Phenyl-1-Propanol

[0020] Numerous reports have been published on the synthesis of chiral 2-phenyl-1-propanol, including but not limited to asymmetric reduction of alkenes and chiral resolution. Given that this chiral molecule serves as a key backbone and intermediate for several pharmaceutical molecules, developing a novel asymmetric catalytic method for its synthesis is of particular interest.

[0021] In summary, there is an urgent need to explore a method for synthesizing chiral organic silicon-containing compounds or chiral organic germanium-containing compounds through an asymmetric reaction involving silicon radicals or germanium radicals, which can not only achieve high yield and high enantioselectivity, but also can be used for the construction of various chiral drug intermediates (for example, chiral tropic acid, chiral 3-(dimethylphenylsilyl)-2-phenyl-1-propanol, chiral 2-phenyl-1-propanol), thereby achieving the effects of simplicity, high efficiency, environmental friendliness and wide application. Summary of the Invention

[0022] The purpose of the present disclosure is to overcome the shortcomings of the prior art and provide a chiral amide compound containing a silicon or germanium group and its synthesis method and application, so as to at least enable it to not only achieve high yield and high enantioselectivity synthesis, but also achieve simplicity, high efficiency, environmental friendliness, good substrate universality and wide applicability.

[0023] The purpose of this disclosure is achieved through the following technical solutions:

[0024] In one aspect, a chiral amide compound containing a silicon group or a germanium group is provided. The chiral amide compound has a structure as shown in Formula III:

[0025]

[0026] wherein R1, R2 and R3 are each independently selected from any one of a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted phenyl group and a substituted or unsubstituted alkenyl group;

[0027] X is selected from any one of a carbon atom and an oxygen atom;

[0028] Y is selected from any one of a silicon atom and a germanium atom;

[0029] R4 is selected from any one of a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group and a substituted or unsubstituted alkyl group.

[0030] It should be understood that, when Y is a silicon atom, the chiral amide compound is a silicon-containing chiral amide compound; and when Y is a germanium atom, the chiral amide compound is a germanium-containing chiral amide compound.

[0031] In some examples, X is an oxygen atom.

[0032] It should be noted that, when X is an oxygen atom, the chiral amide compound is an α-unsaturated oxazolidinone chiral compound containing a silicon group or a germanium group.

[0033] In some examples, when at least one of R1, R2 and R3 is an unsubstituted alkyl group, the unsubstituted alkyl group is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and cyclohexyl.

[0034] In other examples, when at least one of R1, R2, and R3 is a substituted alkyl group, the substituted alkyl group is selected from any one of 1-chloropropyl and 1-chloromethyl.

[0035] In some further examples, when at least one of R1, R2 and R3 is a substituted phenyl group, the substituted phenyl group is selected from any one of 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl and 4-(dimethyl)silylphenyl.

[0036] In some examples, when R4 is a substituted phenyl group, the substituted phenyl group is obtained by independently replacing one or more hydrogen atoms in an unsubstituted phenyl group with any one of halogen, methyl, isobutyl and methoxy.

[0037] In some examples, when R4 is a substituted naphthyl group, the substituted naphthyl group is obtained by independently replacing one or more hydrogen atoms in an unsubstituted naphthyl group with a methoxy group.

[0038] It should be noted that the “unsubstituted phenyl group” mentioned in the present disclosure is a phenyl group; similarly, the “unsubstituted naphthyl group” mentioned in the present disclosure is a naphthyl group.

[0039] For example, when X is a carbon atom, R4 is a phenyl group, Y is a silicon atom, any two of R1, R2 and R3 are methyl groups, and the rest are phenyl groups.

[0040] As another example, when X is an oxygen atom, R4 is a phenyl group, and Y is a germanium atom, at least one of R1, R2, and R3 is a methyl group, and the rest are phenyl groups.

[0041] As another example, when X is an oxygen atom, R4 is a phenyl group, and Y is a germanium atom, R1, R2, and R3 are all n-butyl groups.

[0042] As another example, when X is an oxygen atom, R4 is a phenyl group, and Y is a silicon atom, any two of R1, R2, and R3 are methyl groups, and the rest are phenyl, cyclohexyl, ethyl, isopropyl, tert-butyl, 1-chloropropyl, 1-chloromethyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, or 4-(dimethyl)silylphenyl.

[0043] As another example, when X is an oxygen atom, R4 is a phenyl group, and Y is a silicon atom, any two of R1, R2, and R3 are phenyl groups, and the rest are methyl groups, tert-butyl groups, or hydrogen atoms.

[0044] As another example, when X is an oxygen atom, R4 is a phenyl group, and Y is a silicon atom, any two of R1, R2, and R3 are ethyl groups, and the rest are methyl groups or hydrogen atoms.

[0045] As another example, when X is an oxygen atom, R4 is a phenyl group, and Y is a silicon atom, any two of R1, R2, and R3 are tert-butyl groups, and the rest are hydrogen atoms.

[0046] As another example, when X is an oxygen atom, R4 is a phenyl group, and Y is a silicon atom, one of R1, R2, and R3 is a methyl group, another is a phenyl group, and the rest are hydrogen atoms or vinyl groups.

[0047] As another example, when X is an oxygen atom, R4 is a phenyl group, and Y is a silicon atom, R1, R2, and R3 are all phenyl, ethyl, isopropyl, n-propyl, or n-butyl.

[0048] As another example, when X is an oxygen atom, Y is a silicon atom, any two of R1, R2 and R3 are methyl groups and the rest are phenyl groups, R4 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 1-naphthyl or 2-naphthyl.

[0049] In another aspect, a method for synthesizing the chiral amide compound described in any one of the above embodiments is provided. The method comprises the following steps:

[0050]

[0051] Compound I and compound II are used as raw materials, a complex formed by chiral amine oxide and metal salt is used as a Lewis acid catalyst, and a quinone compound is used as a photocatalyst. The chiral amide compound III is obtained by reacting the chiral amide compound III in an organic solvent under light conditions.

[0052] In the above embodiment, the complex formed by the chiral amine oxide and the metal salt is used as the Lewis acid catalyst, which can not only improve the reactivity of olefins, but also provide a suitable chiral cavity. On this basis, the quinone compound is excited to a triplet diradical under the light conditions, and as a hydrogen atom transfer reagent, it can generate silicon radicals by capturing hydrogen from silicon hydrogen to participate in subsequent reactions. In addition, the quinone compound can also participate in the chirality determination step, ultimately achieving a high yield and high enantioselectivity synthesis.

[0053] In some embodiments, the chiral amine oxide has a structure as shown in Formula IX or Formula X:

[0054]

[0055]

[0056] In the formula, R is selected from any one of substituted or unsubstituted alkyl and substituted or unsubstituted phenyl;

[0057] n is 0 or 1.

[0058] In some examples, when R is selected from an unsubstituted alkyl group, the unsubstituted alkyl group is selected from any one of n-propyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, and adamantyl.

[0059] Exemplarily, R is tert-butyl.

[0060] In other examples, when R is selected from a substituted alkyl group, the substituted alkyl group is selected from any one of benzyl, diphenylmethyl and triphenylmethyl.

[0061] In some further examples, when R is selected from a substituted phenyl group, the substituted phenyl group is obtained by independently replacing one or more hydrogen atoms in the unsubstituted phenyl group with any one of a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a tert-butyl group, an isobutyl group, an n-butyl group and an adamantyl group.

[0062] In some embodiments, the metal salt includes magnesium trifluoromethanesulfonate [Mg(OTf)2], aluminum trifluoromethanesulfonate [Al(OTf)3], scandium trifluoromethanesulfonate [Sc(OTf)3], nickel trifluoromethanesulfonate [Ni(OTf)2], copper trifluoromethanesulfonate [Cu(OTf)2], zinc trifluoromethanesulfonate [Zn(OTf)2], cobalt trifluoromethanesulfonate [Co(OTf)2], ferrous trifluoromethanesulfonate [Fe(OTf)2], lanthanum trifluoromethanesulfonate [La(OTf)3], yttrium trifluoromethanesulfonate [Y(OTf)3], vanadium acetylacetonate [V(acac)3], trifluoromethanesulfonate [V(OTf)3], vanadium ... At least one of hafnium trifluoromethanesulfonate [Hf(OTf)4], cerium trifluoromethanesulfonate [Ce(OTf)3], praseodymium trifluoromethanesulfonate [Pr(OTf)3], rubidium trifluoromethanesulfonate [Nd(OTf)3], gadolinium trifluoromethanesulfonate [Gd(OTf)3], dysprosium trifluoromethanesulfonate [Dy(OTf)3], holmium trifluoromethanesulfonate [Ho(OTf)3], erbium trifluoromethanesulfonate [Er(OTf)3], thulium trifluoromethanesulfonate [Tm(OTf)3], lutetium trifluoromethanesulfonate [Lu(OTf)3], zinc perchlorate hexahydrate [Zn(ClO4)2·6H2O] and zinc chloride [ZnCl2].

[0063] In some examples, the metal salt is zinc trifluoromethanesulfonate [Zn(OTf)2].

[0064] In some embodiments, the quinone compound includes at least one of 9,10-anthraquinone, phenanthrenequinone, 2-chloro-9,10-anthraquinone, and 2-carboxyl-9,10-anthraquinone.

[0065] In some examples, the quinone compound is 9,10-anthraquinone.

[0066] In some embodiments, the molar ratio of the compound I to the compound II is 1:1 to 1:9, for example, 1:3.

[0067] In some embodiments, the molar ratio of the compound I to the chiral amine oxide is 1:0.05 to 1:0.2, for example, 1:0.1.

[0068] In some embodiments, the molar ratio of the chiral amine oxide to the metal salt is 0.8:1 to 1.5:1, for example, 1:1.1.

[0069] In some embodiments, the molar ratio of the compound I to the quinone compound is 1:0.05 to 1:0.2, for example, 1:0.1.

[0070] In some embodiments, the organic solvent includes at least one of ethyl acetate, acetonitrile, tetrahydrofuran, 1,2-dichloroethane, and N,N-dimethylformamide, such as acetonitrile.

[0071] In some embodiments, the molar concentration of the compound I in the organic solvent is 0.5 to 2 mmol / mL, for example 0.5 mmol / mL.

[0072] In some embodiments, the wavelength of the illumination condition is 365-440 nm.

[0073] In some examples, the wavelength of the illumination condition is 380-440 nm, for example, 420 nm.

[0074] In the above embodiment, limiting the wavelength of the illumination condition can avoid the problems of overly harsh reaction conditions and poor reaction effects, thereby enabling the illumination reaction to proceed better.

[0075] In some embodiments, the intensity of the lighting condition is 0.5-20W, for example, 5W.

[0076] In some embodiments, the reaction temperature is -30 to 20°C, for example -30°C.

[0077] In some embodiments, the reaction time is 24 to 72 hours, for example, 30 hours.

[0078] In another aspect, there is provided a use of the chiral amide compound described in any one of the above embodiments or the method described in any one of the above embodiments in the synthesis of a chiral drug intermediate.

[0079] In some embodiments, the chiral drug intermediate comprises at least one of chiral tropic acid, chiral 3-(dimethylphenylsilyl)-2-phenyl-1-propanol, and chiral 2-phenyl-1-propanol.

[0080] The beneficial effects of the present disclosure are:

[0081] 1. The present invention provides a method for synthesizing a chiral amide compound containing a silicon or germanium group, which utilizes a complex formed by a chiral amine oxide and a metal salt and a quinone compound to catalyze the photocatalytic asymmetric radical addition reaction of α,β-unsaturated amide with silane or germane under light conditions, thereby achieving a high yield and high enantioselectivity synthesis and good substrate universality.

[0082] 2. The present disclosure provides a method for synthesizing a chiral amide compound containing a silicon or germanium group. The obtained product is easy to separate from the catalyst and raw materials, and the reaction system is simple and clean, which complies with green chemistry and atom economy.

[0083] 3. The chiral amide compound containing silicon or germanium provided in the present disclosure can be further used to construct a variety of chiral drug intermediates and has a wide range of applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0084] To more clearly illustrate the technical solutions of the present disclosure, the following briefly introduces the drawings required for use in some embodiments of the present disclosure. Obviously, the drawings described below are only drawings of some embodiments of the present disclosure, and those skilled in the art can also derive other drawings based on these drawings. In addition, the drawings described below can be regarded as schematic diagrams and are not intended to limit the actual process of the methods involved in the embodiments of the present disclosure.

[0085] Figure 1 This is the NMR spectrum of the silicon-containing chiral amide compound prepared in Example 1;

[0086] Figure 2 This is the NMR spectrum of the chiral tropic acid prepared in Example 3;

[0087] Figure 3 This is the NMR spectrum of chiral 3-(dimethylphenylsilyl)-2-phenyl-1-propanol prepared in Example 4;

[0088] Figure 4 This is the NMR spectrum of chiral 2-phenyl-1-propanol prepared in Example 5;

[0089] Figure 5 This is the NMR spectrum of the germanium-containing chiral amide compound prepared in Example 6;

[0090] Figure 6 This is the NMR spectrum of the silicon-containing chiral amide compound prepared in Example 8;

[0091] Figure 7 This is the NMR spectrum of the silicon-containing chiral amide compound prepared in Example 9. DETAILED DESCRIPTION

[0092] The following is a clear and complete description of the technical solutions in some embodiments of the present disclosure. Obviously, the embodiments described are only some of the embodiments of the present disclosure, not all of them. Based on the embodiments provided by the present disclosure, all other embodiments obtained by ordinary technicians in this field are within the scope of protection of the present disclosure.

[0093] When describing some embodiments, the expression "A and / or B" may be used. It is easy to understand that "A and / or B" includes the following three combinations: only A, only B, and a combination of A and B.

[0094] When describing some embodiments, the expressions "at least one of A, B and C" and "at least one of A, B or C" may be used, both of which have the same meaning and include the following combinations of A, B and C: only A, only B, only C, the combination of A and B, the combination of A and C, the combination of B and C, and the combination of A, B and C.

[0095] Example 1 Different metal salts (metal) are respectively reacted with chiral amine oxide L3-Pr t The complex formed by Bu catalyzes the photocatalytic asymmetric radical addition reaction of α,β-unsaturated amide (compound I) and dimethylphenylsilane (compound II), and the reaction formula is as follows:

[0096]

[0097] Metal salts (0.011 mmol) [Mg(OTf)2, Al(OTf)3, Sc(OTf)3, Ni(OTf)2, Cu(OTf)2, Zn(OTf)2, Co(OTf)2, Fe(OTf)2, ZnCl2, Zn(ClO4)2·6H2O], chiral amine oxide L3-Pr tBu (0.01 mmol), 9,10-anthraquinone (0.01 mml), α,β-unsaturated amide (0.1 mmol), stirring bar, nitrogen replacement, ultra-dry acetonitrile (2.0 mL) was added, activated at 35 ° C for 30 minutes, dimethylphenylsilane (0.3 mmol) was added, the temperature was lowered to 0 ° C, and the reaction was carried out under the conditions of wavelength of 400 nm and power of 5 W for 24 hours. The product was separated and purified by petroleum ether / ethyl acetate column chromatography to obtain the product silicon-containing α-unsaturated oxazolidinone chiral compound (Compound III). The enantiomeric excess of the product was determined by high performance liquid chromatography (Daicel chiralcel IG, V 正己烷 :V 异丙醇 =95:5, flow rate 1.0 mL / min).

[0098] The results are shown in the following table:

[0099]

[0100]

[0101] Among them, Zn(OTf)2 and L3-Pr t The NMR spectrum of the silicon-containing α-unsaturated oxazolidinone chiral compound (Compound III) obtained by the photocatalytic asymmetric radical addition reaction of α,β-unsaturated amide and silane formed by the complex catalyzed by Bu (i.e., the reaction corresponding to No. 6) is shown as follows Figure 1 shown.

[0102] It should be noted that, in this embodiment, two methyl groups and one phenyl group are connected to the silicon atom in compound III.

[0103] Example 2 Chiral amine oxides (ligands) of different structures, respectively, and metal salt zinc trifluoromethanesulfonate [Zn(OTf)2] formed complexes to catalyze the photocatalytic asymmetric radical addition reaction of α,β-unsaturated amide (Compound I) and dimethylphenylsilane (Compound II), the reaction formula of which is as follows:

[0104]

[0105] Zinc trifluoromethanesulfonate (0.011 mmol), chiral amine oxide (0.01 mmol), 9,10-anthraquinone (0.01 mmol), α,β-unsaturated amide (0.1 mmol) and a stirring bar were added to a dry reaction flask, nitrogen was replaced, ultra-dry acetonitrile (2.0 mL) was added, and the mixture was activated at 35°C for 30 minutes. Dimethylphenylsilane (0.3 mmol) was added, and the temperature was lowered to 0°C. The mixture was reacted under illumination at a wavelength of 400 nm and a power of 5 W for 24 hours. The product, a silicon-containing α-unsaturated oxazolidinone chiral compound (Compound III), was separated and purified by petroleum ether / ethyl acetate column chromatography. The enantiomeric excess of the product was determined by high performance liquid chromatography (Daicelchiralcel IG, V 正己烷 :V 异丙醇 =95:5, flow rate: 1.0 mL / min).

[0106] The results are shown in the following table:

[0107]

[0108]

[0109] It should be noted that, in this embodiment, two methyl groups and one phenyl group are connected to the silicon atom in compound III.

[0110] Example 3 Synthesis of chiral tropic acid, its reaction formula is as follows:

[0111]

[0112] Compound III (0.1 mmol) and Yb(OTf) 3 (5 mol%) were added to an oven-dried reaction tube, 3.0 mL of MeOH was added as a reaction solvent, and the mixture was reacted at 35° C. overnight. The mixture was filtered through silica gel to obtain compound IV.

[0113] The above compound IV was dissolved in 1.0 mL DCM, and then HBF4·Et2O (2.5 equiv) was added to the reaction tube at 0°C and stirring was continued for 1 hour; after completion, the solvent DCM was dried using a rotary evaporator; KF (2.0 equiv) and KHCO3 (10.0 equiv) were added to the reaction tube, and 0.5 mL MeOH and 0.5 mL THF were used as reaction solvents; stirring was continued at 0°C for 15 minutes; then H2O2 (13.0 equiv, 30% in H2O) was added to the reaction mixture at 0°C and stirring was continued for about 10 minutes; the temperature was slowly raised to room temperature and the reaction was allowed to react overnight; after completion of the reaction, the reaction was quenched with Na2S2O3 and extracted with DCM; the combined organic phases were dried over anhydrous Na2SO4 and filtered, and the solvent was dried using a rotary evaporator to obtain compound V.

[0114] Compound V (0.2 mmol) was hydrolyzed with LiOH·H2O (5.0 equiv) using 2.0 mL each of H2O and THF as the reaction solvent. After about 2 hours, the reaction was complete as monitored by TLC. Ethyl acetate and water were added for extraction and the aqueous phase was collected. The aqueous phase was acidified with dilute hydrochloric acid and then extracted again with ethyl acetate, and the organic phase was collected. The combined organic phases were dried over anhydrous Na2SO4 and filtered, and the product (R-) tropic acid was obtained by rotary evaporation. The NMR spectrum is shown in FIG. Figure 2 As shown, the enantiomeric excess of the product was determined by high performance liquid chromatography (Daicel chiralcel IC, V 正己烷 :V 异丙醇 =70:30, flow rate: 1.0 mL / min).

[0115] It should be noted that, in this embodiment, two methyl groups and one phenyl group are connected to the silicon atom in compound III.

[0116] Example 4 Synthesis of chiral 3-(dimethylphenylsilyl)-2-phenyl-1-propanol, the reaction formula is as follows:

[0117]

[0118] Compound III (0.1 mmol) and Yb(OTf) 3 (5 mol%) were added to an oven-dried reaction tube; 3.0 mL of MeOH was added as the reaction solvent, and the mixture was reacted at 35° C. overnight; the mixture was filtered through silica gel to obtain compound IV.

[0119] The above compound IV was added to a reaction tube, nitrogen was replaced, and 1.0 mL of THF was added as a reaction solvent; LiAlH4 (2.5 equiv) was then added, and the reaction was allowed to proceed at 35°C overnight; after the reaction, the reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous Na2SO4 and filtered, and purified by petroleum ether / ethyl acetate column chromatography to obtain the product chiral 3-(dimethylphenylsilyl)-2-phenyl-1-propanol (Compound VI), the NMR spectrum of which is shown in FIG. Figure 3 As shown, the enantiomeric excess of the product was determined by high performance liquid chromatography (Daicel chiralcel AD-H, V 正己烷 :V 异丙醇 =95:5, flow rate: 1.0 mL / min).

[0120] It should be noted that, in this embodiment, two methyl groups and one phenyl group are connected to the silicon atom in compound III.

[0121] Example 5 Synthesis of chiral 2-phenyl-1-propanol, the reaction formula is as follows:

[0122]

[0123] Compound V was prepared according to the method described in Example 3. Compound V (0.16 mmol) was added to a reaction tube, and TsCl (2.0 equiv) and pyridine (2.2 equiv) were added. Subsequently, 0.5 mL of DCM was added as the reaction solvent, and the mixture was reacted at -10°C for 36 hours. After completion of the reaction, compound VII was purified by petroleum ether / ethyl acetate column chromatography.

[0124] The above compound VII was added to a reaction tube, nitrogen was replaced, and 1.0 mL of THF was added as the reaction solvent; LiAlH4 (2.5 equiv) was then added and the reaction was allowed to proceed at 35°C overnight; after the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous Na2SO4 and filtered, and filtered through silica gel to obtain the product chiral 2-phenyl-1-propanol (compound VIII), the NMR spectrum of which is shown in FIG. Figure 4 As shown, the enantiomeric excess of the product was determined by high performance liquid chromatography (Daicel chiralcel AY-H, V 正己烷 :V 异丙醇 =97:3, flow rate: 1.0 mL / min).

[0125] It should be noted that, in this embodiment, two methyl groups and one phenyl group are connected to the silicon atom in compound III.

[0126] Example 6 Metal salt zinc trifluoromethanesulfonate [Zn(OTf)2] and chiral amine oxide L3-Pr t The complex formed by Bu catalyzes the photocatalytic asymmetric radical addition reaction of α,β-unsaturated amide (compound I) and dimethylphenylgermane (compound II), and the reaction formula is as follows:

[0127]

[0128] Zinc trifluoromethanesulfonate (0.011 mmol), chiral amine oxide (0.01 mmol), 9,10-anthraquinone (0.01 mmol), α,β-unsaturated amide (0.1 mmol) and a stirring bar were added to a dry reaction flask, nitrogen was replaced, ultra-dry acetonitrile (2.0 mL) was added, and the mixture was activated at 35°C for 30 minutes. Dimethylphenylgermane (0.3 mmol) was added, the temperature was lowered to -30°C, and the reaction was carried out under light conditions of a wavelength of 420 nm and a power of 5 W for 30 hours. The product was separated and purified by petroleum ether / ethyl acetate column chromatography to obtain a germanium-containing α-unsaturated oxazolidinone chiral compound (Compound III). The NMR spectrum is shown as follows: Figure 5 As shown, the enantiomeric excess of the product was determined by high performance liquid chromatography (Daicel chiralcel IG, V 正己烷 :V 异丙醇=95:5, flow rate: 1.0 mL / min).

[0129] It should be noted that, in this embodiment, the germanium atom in compound III is connected to two methyl groups and one phenyl group.

[0130] Example 7 Metal salt zinc trifluoromethanesulfonate [Zn(OTf)2] and chiral amine oxide L3-Pr t The complex formed by Bu catalyzes the photocatalytic asymmetric radical addition reaction of α,β-unsaturated amide (compound I) and methyldiphenylgermane (compound II), and the reaction formula is as follows:

[0131]

[0132] Zinc trifluoromethanesulfonate (0.011 mmol), chiral amine oxide (0.01 mmol), 9,10-anthraquinone (0.01 mmol), α,β-unsaturated amide (0.1 mmol), and a stirring bar were added to a dry reaction flask. The nitrogen atmosphere was replaced, and ultra-dry acetonitrile (2.0 mL) was added. The mixture was activated at 35°C for 30 minutes, and methyldiphenylgermane (0.3 mmol) was added. The temperature was lowered to -30°C, and the reaction was carried out under illumination at a wavelength of 420 nm and a power of 5 W for 30 hours. The product was separated and purified by petroleum ether / ethyl acetate column chromatography to obtain a chiral α-unsaturated oxazolidinone compound containing a germanium group (Compound III). The enantiomeric excess of the product was determined by high performance liquid chromatography (Daicel chiralcel IG, V 正己烷 :V 异丙醇 =95:5, flow rate: 1.0 mL / min).

[0133] It should be noted that, in this embodiment, the germanium atom in compound III is connected to one methyl group and two phenyl groups.

[0134] Example 8 Metal salt zinc trifluoromethanesulfonate [Zn(OTf)2] and chiral amine oxide L3-Pr t The complex formed by Bu catalyzes the photocatalytic asymmetric radical addition reaction of α,β-unsaturated amide (compound I) and dimethylphenylsilane (compound II), and the reaction formula is as follows:

[0135]

[0136] Zinc trifluoromethanesulfonate (0.011 mmol), chiral amine oxide (0.01 mmol), 9,10-anthraquinone (0.01 mmol), α,β-unsaturated amide (0.1 mmol) and a stirring bar were added to a dry reaction bottle, nitrogen was replaced, ultra-dry acetonitrile (2.0 mL) was added, and the mixture was activated at 35°C for 30 minutes. Dimethylphenylsilane (0.3 mmol) was added, the temperature was lowered to -30°C, and the reaction was carried out under light conditions of a wavelength of 420 nm and a power of 5 W for 30 hours. The product was separated and purified by petroleum ether / ethyl acetate column chromatography to obtain a silicon-containing α-unsaturated oxazolidinone chiral compound (Compound III). The NMR spectrum is shown as follows: Figure 6 As shown, the enantiomeric excess of the product was determined by high performance liquid chromatography (Daicel chiralcel IC, V 正己烷 :V 异丙醇 =95:5, flow rate: 1.0 mL / min).

[0137] It should be noted that, in this embodiment, two methyl groups and one phenyl group are connected to the silicon atom in compound III.

[0138] Example 9 Metal salt zinc trifluoromethanesulfonate [Zn(OTf)2] and chiral amine oxide L3-Pr t The complex formed by Bu catalyzes the photocatalytic asymmetric radical addition reaction of α,β-unsaturated amide (compound I) and dimethylphenylsilane (compound II), and the reaction formula is as follows:

[0139]

[0140] Zinc trifluoromethanesulfonate (0.011 mmol), chiral amine oxide (0.01 mmol), 9,10-anthraquinone (0.01 mmol), α,β-unsaturated amide (0.1 mmol) and a stirrer were added to a dry reaction flask. The nitrogen was replaced, and ultra-dry acetonitrile (2.0 mL) was added. The mixture was activated at 35°C for 30 minutes, and dimethylphenylsilane (0.3 mmol) was added. The temperature was lowered to -30°C, and the reaction was carried out under light conditions of a wavelength of 420 nm and a power of 5 W for 30 hours. The product, a silicon-containing chiral amide compound (Compound III), was separated and purified by petroleum ether / ethyl acetate column chromatography. The NMR spectrum is shown as follows: Figure 7 As shown, the enantiomeric excess of the product was determined by high performance liquid chromatography (Daicel chiralcel IG, V 正己烷 :V 异丙醇 =95:5, flow rate: 1.0 mL / min).

[0141] It should be noted that, in this embodiment, two methyl groups and one phenyl group are connected to the silicon atom in compound III.

[0142] The foregoing description is merely a preferred embodiment of the present disclosure. It should be understood that the present disclosure is not limited to the form disclosed herein and should not be construed as excluding other embodiments. Rather, the present disclosure is applicable to various other combinations, modifications, and environments and can be modified within the scope of the concepts described herein through the above teachings or techniques or knowledge in the relevant fields. Modifications and variations made by those skilled in the art that do not depart from the spirit and scope of the present disclosure are intended to be protected by the claims appended hereto.

Claims

1. A chiral amide compound containing a silicon group or a germanium group, characterized in that: The chiral amide compound has a structure as shown in Formula III: wherein R1, R2 and R3 are each independently selected from any one of a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted phenyl group and a substituted or unsubstituted alkenyl group; X is selected from any one of a carbon atom and an oxygen atom; Y is selected from any one of a silicon atom and a germanium atom; R4 is selected from any one of a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group and a substituted or unsubstituted alkyl group.

2. The method for synthesizing the chiral amide compound according to claim 1, characterized in that: The following steps are involved: Compound I and compound II are used as raw materials, a complex formed by chiral amine oxide and metal salt is used as a Lewis acid catalyst, and a quinone compound is used as a photocatalyst. The chiral amide compound III is obtained by reacting the chiral amide compound III in an organic solvent under light conditions.

3. The method according to claim 2, characterized in that The chiral amine oxide has a structure as shown in Formula IX or Formula X: In the formula, R is selected from any one of substituted or unsubstituted alkyl and substituted or unsubstituted phenyl; n is 0 or 1.

4. The method according to claim 2, characterized in that The metal salts include magnesium trifluoromethanesulfonate [Mg(OTf)2], aluminum trifluoromethanesulfonate [Al(OTf)3], scandium trifluoromethanesulfonate [Sc(OTf)3], nickel trifluoromethanesulfonate [Ni(OTf)2], copper trifluoromethanesulfonate [Cu(OTf)2], zinc trifluoromethanesulfonate [Zn(OTf)2], cobalt trifluoromethanesulfonate [Co(OTf)2], ferrous trifluoromethanesulfonate [Fe(OTf)2], lanthanum trifluoromethanesulfonate [La(OTf)3], yttrium trifluoromethanesulfonate [Y(OTf)3], vanadium acetylacetonate [V(acac)3], hafnium trifluoromethanesulfonate [H f(OTf)4], cerium trifluoromethanesulfonate [Ce(OTf)3], praseodymium trifluoromethanesulfonate [Pr(OTf)3], rubidium trifluoromethanesulfonate [Nd(OTf)3], gadolinium trifluoromethanesulfonate [Gd(OTf)3], dysprosium trifluoromethanesulfonate [Dy(OTf)3], holmium trifluoromethanesulfonate [Ho(OTf)3], erbium trifluoromethanesulfonate [Er(OTf)3], thulium trifluoromethanesulfonate [Tm(OTf)3], lutetium trifluoromethanesulfonate [Lu(OTf)3], zinc perchlorate hexahydrate [Zn(ClO4)2·6H2O] and zinc chloride [ZnCl2], at least one of.

5. The method according to claim 2, characterized in that The quinone compound includes at least one of 9,10-anthraquinone, phenanthrenequinone, 2-chloro-9,10-anthraquinone and 2-carboxyl-9,10-anthraquinone.

6. The method according to claim 2, characterized in that The molar ratio of the compound I to the compound II is 1:1 to 1:9; and / or, the molar ratio of the compound I to the chiral amine oxide is 1:0.05 to 1:0.2; and / or, the molar ratio of the chiral amine oxide to the metal salt is 0.8:1 to 1.5:1; And / or, the molar ratio of the compound I to the quinone compound is 1:0.05 to 1:0.

2.

7. The method according to claim 2, characterized in that The organic solvent comprises at least one of ethyl acetate, acetonitrile, tetrahydrofuran, 1,2-dichloroethane and N,N-dimethylformamide; And / or, the molar concentration of the compound I in the organic solvent is 0.5 to 2 mmol / mL.

8. The method according to claim 2, characterized in that The wavelength of the illumination condition is 365-440 nm; and / or, the intensity of the illumination condition is 0.5 to 20W; And / or, the reaction temperature is -30 to 20°C; And / or, the reaction time is 24 to 72 hours.

9. Use of the chiral amide compound according to claim 1 or the method according to any one of claims 2 to 8 in the synthesis of chiral drug intermediates.

10. The use according to claim 9, characterized in that The chiral drug intermediate includes at least one of chiral tropic acid, chiral 3-(dimethylphenylsilyl)-2-phenyl-1-propanol and chiral 2-phenyl-1-propanol.

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