Chiral bicyclo [1.1. 1] pentane derivative and preparation method thereof

Abstract

The invention relates to the technical field of organic chemistry, and particularly discloses a chiral bicyclo [1.1. 1] pentane derivative and a preparation method thereof.According to the chiral bicyclo [1.1. 1] pentane derivative, bicyclic hydrocarbon rich in C (sp3) is used for replacing aromatic rings, chiral bicyclo [1.1. 1] pentane is replaced by biological isosteres, and the chiral bicyclo [1.1. 1] pentane is used for preparing the chiral bicyclo [1.1. 1] pentane derivative. The invention plays a crucial role in modern medicine function research. Bicyclo [1.1. 1] pentane derivatives are particularly concerned due to its unique three-dimensional stereochemical complexity, the present invention provides a method for synthesizing bicyclo [1.1. 1] pentane through nitrogen atom insertion and deletion strategies, which has good stereoselectivity and couples chiral bicyclo [1.1. 1] pentane with a plurality of drugs for altering the properties and efficacy of the drugs, in order to improve the therapeutic effect of the drugs. For example, pharmacokinetic properties and water solubility are altered.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemistry, and specifically discloses a chiral bicyclo[1.1.1]pentane derivative and a preparation method thereof. Background Art

[0002] Patent CN117700456A "Arylamine photocatalyst and preparation method thereof, defluorinated single-bridged cyclic propeller compound, preparation method and application thereof" uses bicyclo[1.1.1]pentane (BCP) to couple and modify multiple drugs to obtain a variety of different drug derivatives, and conducts physical and chemical property tests after electron isosteric substitution.

[0003]

[0004] Patent CN118894799A "A disubstituted bicyclo[1.1.1]pentane and its synthesis method" provides a method for obtaining an ibuprofen azonitrile derivative by modifying ibuprofen compounds, such as:

[0005]

[0006] Rich in sp 3 Carbon-substituted bicyclic hydrocarbons, such as bicyclo[1.1.1]pentane (BCP), have shown potential in drug design due to their bioisosteric substitution, structural stability, and stereochemical properties. They can significantly enhance drug stability and pharmacological properties, playing a crucial role in modern drug discovery. For example, "1,2-Difunctionalized bicyclo[1.1.1]pentanes: Long–sought-after mimetics for ortho / meta-substituted arenes" used bicyclo[1.1.1]pentane (BCP) to couple sonidegib, boscalid, meclizine, tolvaptan, phthalylsulfathiazole, lomitapide and telmisartan, and studied the HHEP (human hepatocyte stability), KS (kinetic solubility) and other properties of the coupled derivatives of each drug. The coupling showed that the construction of BCP-substituted derivatives can regulate the electronic structure and spatial configuration of biological molecules through changes in functional groups and structures, change the properties of drugs, and significantly affect their interactions with other molecules. Summary of the Invention

[0007] The first aspect of the present invention provides a chiral bicyclo[1.1.1]pentane derivative represented by formula BCP, or a deuterated product thereof,

[0008]

[0009] The R 5 Selected from hydrogen, ester, carboxyl, acyl, amino, sulfonyl, borate, thioalkyl, alkylhydroxy, alkyl ester aryl, alkyl acylaryl, acylaryl, acylamino, acylalkyl, alkyl, aryl;

[0010] The R 6 is selected from substituted or unsubstituted monocyclic aryl, hydrogen, ester group, alkyl, alkenyl, cycloalkyl, monocyclic heterocyclic group;

[0011] The R 7 is selected from substituted or unsubstituted monocyclic aromatic groups, substituted or unsubstituted fused aromatic groups, hydrogen, an ester group, and a monocyclic heterocyclic group;

[0012] The carbon atoms marked with * are independently R-configuration, S-configuration, or achiral carbon atoms.

[0013] In some specific embodiments of the first aspect, the R 5 Selected from -C(=O)OR d ,-C(=O)R e ,-NHR f , -SR g , -S(=O)2R ga Any one of the R d Selected from any one of alkyl and monocyclic aromatic groups, the R e Selected from alkyl, aryl, amino, said R f Selected from amino protecting groups, hydrogen, said R g Selected from alkyl, monocyclic aryl, said R ga is selected from monocyclic aromatic groups;

[0014] The R 6 Selected from The Ar is selected from a monocyclic aromatic group, a condensed aromatic group, a cycloalkyl group, a thienyl group, a furyl group, and the R h is selected from substituted or unsubstituted alkyl, hydrogen, amino, ester, nitro, alkoxy, cyano, halogen, wherein the hydrogen on the amino group is replaced by Substituted, said p is selected from any positive integer from 1 to 5, or said R 6 Selected from -C(=O)OR j , the R j Selected from linear or branched alkyl, or, said R 6 Selected from C1 to C6 straight chain alkyl or C2 to C6 branched chain alkenyl, said R 6Any hydrogen atom is replaced by a monocyclic aromatic group;

[0015] The R7 is selected from -C(=O)OR l , the R k Selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted monocyclic aromatic group, halogen, ester group, alkoxy group, Said p is selected from any positive integer from 1 to 5, or said R l Selected from

[0016] In some specific embodiments of the first aspect, the R d is selected from C1 to C4 straight or branched alkyl, benzyl, monocyclic aromatic group, said R e Selected from

[0017] The R g is selected from monocyclic aromatic groups, wherein R g Any hydrogen atom is replaced by a halogen atom;

[0018] The R h is selected from C1 to C4 alkyl, said R h Any hydrogen atom is replaced by a halogen atom;

[0019] The R j Selected from C1 to C4 straight or branched chain alkyl;

[0020] The R k Selected from C1 to C4 straight or branched chain alkyl, halogen, and hydrogen.

[0021] For more detailed technical solutions, please refer to the specific embodiments.

[0022] The term "cycloalkyl" refers to a saturated monocyclic ring group consisting only of carbon atoms, having a specified number of carbon atoms (e.g., 3 to 6 carbon atoms), wherein monocyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0023] The term "sulfanylalkyl" is exemplified by structures such as -SR xa , where R xa is an aryl group, a linear or branched alkyl group having 1 to 6 carbon atoms, R xa Any hydrogen on the substituted group may be optionally substituted with a halogen, exemplified by any of fluorine, chlorine, bromine and iodine, with a non-limiting exemplary being -S-PhBr.

[0024] The term "alkylhydroxyl" is exemplified by structures such as -R xb -OH, where R xb It can be any of cycloalkyl, aryl, linear or branched alkyl, a non-limiting example of which is -CH2OH.

[0025] The term "alkyl acyl aryl" is exemplified by structures such as -R xc C(=O)R xd , where R xc is selected from a linear or branched alkyl group of 1 to 6 carbon atoms, R xd is selected from monocyclic aromatic groups, a non-limiting example of which is -CH2C(=O)Ph.

[0026] The term "acylamino" is exemplified by structures such as -C(=O)NHR xe , where R xe It is selected from hydrogen, and a substituted or unsubstituted heterocyclic group, an exemplary but not limited heterocyclic group being piperidine.

[0027] The term "acylalkyl" is exemplified by structures such as -C(=O)R xf , where R xf A linear or branched alkyl group selected from 1 to 6 carbon atoms;

[0028] The term "ester group" is exemplified by structures such as -C(=O)OCR xg , where R xg Any one selected from a linear or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a monocyclic aromatic group or a condensed ring, non-limiting examples of which are -C(=O)OMe and -C(=O)OPh.

[0029] The term "alkyl ester group" is exemplified by the structure -R xh C(=O)OR xi , where R xh is a linear or branched alkyl group with 1 to 6 carbon atoms, R xi It is a linear or branched alkyl group of 1 to 6 carbon atoms, a monocyclic aromatic group or a condensed aromatic group.

[0030] The reagents used in the present invention were purchased from the open legal market and were not further purified.

[0031] Advantages of the present invention:

[0032] Chirality has a certain impact on drug efficacy. In view of the fact that the optical rotation of the structure is insufficiently considered in the synthesis route of the existing technology, the present invention proposes a class of novel BCP chiral bicyclo[1.1.1]pentane compounds. The hydrogen on the BCP is replaced by functional groups of various structures. This class of compounds has good optical rotation. The present invention synthesizes chiral BCP derivatives through nitrogen atom occupation during the synthesis process. The chirality is well maintained during the synthesis process, the yield is high, and the reaction conditions are mild. The chiral BCP can be conveniently embedded in the drug molecule to improve drug properties such as metabolic stability and water solubility. The method of the present invention can be applied to the modification of drug molecules, which can significantly improve the screening efficiency of drug molecules and obtain drug molecules with better properties. DETAILED DESCRIPTION

[0033] Example 1: Synthesis of Compound 1k

[0034]

[0035] Titanium tetrachloride (TiCl₄, 13.0 mmol, 1.5 equiv) was slowly added over 30 minutes to a solution of benzoyl chloride (26.1 mmol, 3.0 equiv), 1k-a (8.7 mmol, 1 equiv), and triethylamine (Et₃N, 52.2 mmol, 6.0 equiv) in dry acetonitrile (MeCN, 12 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 15 minutes. Water was then added, and the mixture was extracted with ethyl acetate (EtOAc, 3 x 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate (Na₂SO₄) and concentrated. The residue was purified by column chromatography to afford the product, 1k-b, as a colorless oil (78% yield).

[0036] 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 5.3 mmol, 1.0 equiv) was slowly added over 30 minutes to a solution of the benzoylated ester (1.0 equiv) and 4-acetamidobenzenesulfonyl azide (p-ABSA, 1.0 equiv) in dry acetonitrile (MeCN, 40 mL) at 0°C. The reaction was monitored for residual starting material. Additional 4-acetamidobenzenesulfonyl azide (0.5 equiv) and DBU (0.4 mL, 0.5 equiv) were added dropwise over 30 minutes. After stirring for an additional 30 minutes, the mixture was partitioned between water and ethyl acetate (EtOAc, 3 x 30 mL) and extracted. The combined organic layers were dried over anhydrous sodium sulfate (NaSO) and concentrated. The residue was purified by column chromatography to afford the product 1k-c as a yellow oil (77% yield).

[0037] Under argon, chloroform (CHCl₃, 8 mL) and Rh₂(Oct)₄ (0.1 mol%) were added to a dry 25 mL Schlenk reaction tube. Subsequently, the diazo compound 1k-c (1.0 mmol, 1.0 equivalent) dissolved in chloroform (2 mL) was added dropwise via syringe over 30 minutes at room temperature. After the addition was complete, the mixture was stirred for 15 minutes. TLC analysis confirmed complete reaction of the diazo compound to yield 1k.

[0038] Example 2: Addition of N-phenylimine to 1a

[0039] Under the catalysis of Cat.a to Cat.d, the addition reaction of N-phenylimine with BCB 1a produced a mixture of azetidines (N-Ph-a) and cyclobutenylmethylamines (N-Ph-b).

[0040]

[0041] 1a (0.05 mmol, 1.0 equivalent) and N-phenylimine (compound of formula 2-2, 0.1 mmol, 2.0 equivalent) were dissolved in 1 mL of toluene solvent (0.05 M), introduced into a dried 10 mL reaction bottle, cooled to 0°C, and a reaction system was obtained. A toluene solution (50 μL) containing the catalyst shown in Table 1 was added to the reaction system, and the concentration of the catalyst in the reaction system was adjusted to 5 mol%, and stirring was continued at the above temperature for 15 hours. After the reaction was completed, it was quenched with a saturated aqueous solution of sodium bicarbonate (NaHCO3) and extracted with ethyl acetate (EtOAc). Dimethyl terephthalate was added as an internal standard, and the solvent was removed by evaporation to obtain Entry 1 to 4 in Table 1. The yield was determined by the crude mixture. 1 The residue and analytical sample were combined and purified by preparative thin layer chromatography (TLC), and the ee value was determined by chiral high performance liquid chromatography (HPLC).

[0042] Table 1 Effect of different catalysts on yield and enantiomeric content

[0043]

[0044]

[0045] Example 3: Effect of different N-protecting groups R and catalyst types on activity and enantioselectivity

[0046]

[0047] 1a (0.05 mmol, 1.0 equivalent) and the various substituents of N-phenylimine (compound 2-1, 0.1 mmol, 2.0 equivalent) listed in Table 2 were dissolved in 1 mL of toluene (0.05 M) and poured into a dried 10 mL reaction flask. The flask was cooled to 0°C to obtain a reaction system. A toluene solution (50 μL) containing the catalyst listed in Table 2 was added to the reaction system to adjust the catalyst concentration to 5 mol%. Stirring was continued at the above temperature for 24 hours. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate (NaHCO₃) and extracted with ethyl acetate (EtOAc). Dimethyl terephthalate was added as an internal standard, and the solvent was removed by evaporation to obtain Table 2.

[0048] Table 2 Enantiomeric amounts of compound P under different R protecting groups and catalysts:

[0049] Cat.a Cat.b Cat.c Cat.e R=Bz N.D 37%e.e. 24%e.e. 9%e.e. R=Boc N.D 64%e.e. 39%e.e. 37%e.e.

[0050] Example 4: General Synthesis Method of BCH

[0051]

[0052] General Synthesis Method A (1.0 mmol scale): Dissolve BCB (1.0 mmol, 1.0 equiv) and an imine (2.0 mmol, 2.0 equiv) in 10 mL of tetrahydrofuran (THF) and 10 mL of chloroform (CHCl₃) in a dry 50 mL Schlenk reaction tube. Cool the reaction system to -30°C, then add a 200 μL THF solution containing (R)-C11 (3 mol%). Stirring is continued at -30°C until complete reaction (monitored by thin-layer chromatography (TLC), 24 hours). The reaction is quenched with saturated aqueous sodium bicarbonate (NaHCO₃) and extracted with ethyl acetate (EtOAc). The combined organic phases are dried over anhydrous sodium sulfate (Na₂SO₄), the solvent is concentrated under reduced pressure, and the product is purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (2% to 10%), to afford the desired product, BCH.

[0053] General Synthesis Method B (0.2 mmol scale): Dissolve BCB (0.2 mmol, 1.0 equiv) and an imine (0.4 mmol, 2.0 equiv) in 2 mL of tetrahydrofuran (THF) and 2 mL of chloroform (CHCl₃) in a dry 25 mL Schlenk reaction tube. Cool the reaction to -30°C and add a 50 μL THF solution containing (R)-C11 (5 mol%). Stirring is continued at -30°C until the reaction is complete (monitored by thin-layer chromatography (TLC), typically 24 hours). The reaction is quenched with saturated aqueous sodium bicarbonate (NaHCO₃) and extracted with ethyl acetate (EtOAc). The combined organic phases are dried over anhydrous sodium sulfate (Na₂SO₄), concentrated under reduced pressure, and purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (2% to 10%), to afford the desired product, BCH.

[0054] The BCB structure is as follows 1a~1o:

[0055]

[0056] The structures of imine compounds are as follows: 2a~2s

[0057]

[0058] The structures of BCH derivatives are as follows: 3a~3z, 3aa~3ae

[0059]

[0060] Example 5: Synthesis of 3a-3z, 3aa-3ae: BCB 1a, imine 2a, and General Method A were used to synthesize 3a (94% yield, 92% ee). BCB 1b, imine 2a, and General Method A were used to synthesize 3b (89% yield, 93% ee). BCB 1c, imine 2a, and General Method A were used to synthesize 3c (85% yield, 91% ee). BCB 1d, imine 2a, and General Method B were used to synthesize 3d (86% yield, 90% ee). BCB 1e, imine 2a, and General Method A were used to synthesize 3e (83% yield, 95% ee). BCB 1f, imine 2a, and General Method A were used to synthesize 3f (90% yield, 95% ee).

[0061] BCB (1 g) and imine compound (2a) were synthesized using General Method A (88% yield, 94% ee).

[0062] BCB was used as 1h, imine compound was used as 2a, and 3h was synthesized by general method B (73% yield, 95% ee).

[0063] BCB was used as 1i, imine compound was used as 2a, and 3i was synthesized by general method A (90% yield, 90% ee).

[0064] BCB was used as 1j, imine compound was used as 2a, and 3j was synthesized by General Method A (88% yield, 92% ee).

[0065] BCB was used as 1k, and imine compound 2a was used to synthesize 3k using General Method B (88% yield, 93% ee).

[0066] BCB was used as 1a, and imine compound 2b was used to synthesize 3l using General Method A (94% yield, 95% ee).

[0067] BCB was used as 1a, and imine compound 2c was used to synthesize 3m using General Method A (91% yield, 90% ee).

[0068] BCB was used as 1a, imine compound was used as 2d, and 3n was synthesized by General Method A (87% yield, 95% ee).

[0069] BCB was used as 1a, and the imine compound was used as 2e. 3o was synthesized using General Method A (87% yield, 93% ee).

[0070] BCB was used as 1a, and imine compound 2f was used to synthesize 3p using General Method A (89% yield, 94% ee).

[0071] BCB was used as 1a, imine compound was used as 2g, and 3q was synthesized by general method B (81% yield, 96% ee).

[0072] BCB was used as 1a, and the imine compound was used as 2h. 3r was synthesized using General Method A (91% yield, 95% ee).

[0073] BCB was used as 1a, imine compound was used as 2i, and 3s was synthesized by General Method A (92% yield, 95% ee).

[0074] BCB was used as 1a, imine compound was used as 2j, and 3t was synthesized by General Method A (88% yield, 96% ee).

[0075] BCB was used as 1a, and the imine compound was used as 2k. 3u was synthesized using General Method A (95% yield, 91% ee).

[0076] BCB was used as 1a, and imine compound 2l was used to synthesize 3v using General Method A (93% yield, 88% ee).

[0077] BCB was used as 1a, and the imine compound was used as 2m. 3w was synthesized using General Method B (86% yield, 90% ee).

[0078] BCB was used as 1a, and the imine compound was used as 2n. 3x was synthesized using General Method B (79% yield, 94% ee).

[0079] BCB was used as 1a, and imine compound 2o was used as 3y (93% yield, 92% ee) by General Method A.

[0080] BCB was used as 1a, and the imine compound was used as 2p. 3z was synthesized using General Method A (93% yield, 91% ee).

[0081] BCB was used as 1a, and the imine compound was used as 2q. 3aa was synthesized using General Method B (90% yield, 91% ee).

[0082] BCB was used as 1l, imine compound was used as 2a, and 3ab was synthesized by general method A (91% yield, 95% ee).

[0083] BCB was used as 1m, and the imine compound was used as 2a. 3ac was synthesized using General Method B (93% yield, 90% ee).

[0084] BCB was used as 1n, and imine compound 2a was used to synthesize 3ad using General Method A (95% yield, 96% ee).

[0085] BCB was used as 1o, imine compound was used as 2a, and 3ae was synthesized using General Method B (76% yield, 89% ee).

[0086] Example 7 General Synthesis of Compound BCP

[0087]

[0088] General Synthesis Method C: BCH (0.2 mmol, 1.0 equiv) and anhydrous dichloromethane (CH2Cl2, 8 mL) were added to a dry 25 mL Schlenk tube equipped with a Teflon-coated magnetic stirrer. Subsequently, TMSOTf (40 μL, 0.22 mmol, 1.1 equiv) was added at 0°C under argon. After stirring for 3 hours, the reaction was quenched with aqueous sodium bicarbonate (NaHCO3) and extracted with dichloromethane (CH2Cl2). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated to remove the solvent to yield the crude product, which was used directly in the next reaction without further purification.

[0089] The crude product was dissolved in CD3OD (0.15 M, 1.34 mL) at room temperature, followed by the addition of aqueous ammonia (NH3·H2O, 25% in water, 150 μL, 2.0 mmol, 10.0 equiv) and PIDA (193 mg, 0.60 mmol, 3.0 equiv). The reaction tube was sealed and quickly placed in an oil bath preheated to 40°C. After stirring at 40°C for 12 hours, the solvent was removed by evaporation and the product, BCP, was purified by flash column chromatography (petroleum ether / ethyl acetate = 20 / 1) to yield the product.

[0090] General Synthesis Method D: BCH (0.15 mmol, 1.0 equiv) and anhydrous dichloromethane (CH2Cl2, 6 mL) were added to a dry 25 mL Schlenk tube equipped with a Teflon-coated magnetic stirrer. Subsequently, TMSOTf (30 μL, 0.17 mmol, 1.1 equiv) was added at 0°C under argon. After stirring for 12 hours, the reaction was quenched with aqueous sodium bicarbonate (NaHCO3) and extracted with dichloromethane (CH2Cl2). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated to remove the solvent to yield the crude product, which was used directly in the next reaction without further purification.

[0091] (Note: For the synthesis of 5k, 5aa, and 5ae, the amount of TMSOTf was changed from 1.1 equivalents to 2.5 equivalents, and sodium bicarbonate was replaced by triethylamine (Et3N, 0.75 mmol, 5 equivalents)).

[0092] The crude product was dissolved in CD3OD (0.15 M, 1.0 mL) at room temperature, followed by the addition of aqueous ammonia (NH3·H2O, 25% in water, 112 μL, 1.5 mmol, 10.0 equiv) and PIDA (0.45 mmol, 3.0 equiv). The reaction tube was sealed and quickly placed in an oil bath preheated to 40°C. After stirring at 40°C for 12 hours, the solvent was removed by evaporation and the product, BCP, was purified by flash column chromatography (petroleum ether / ethyl acetate = 20 / 1) to yield the product.

[0093] The structures of BCP compounds are as follows: 5a~5z, 5aa~5ag

[0094]

[0095]

[0096] Example 8: Synthesis of compound 5a, BCH is 3a, 5a was synthesized using general method A (61% yield, 91% ee).

[0097] 1 H NMR (400MHz, CD2Cl2): δ7.35-7.18(m,8H),7.06-7.04(m,2H),3.98(d,J=6.7Hz,1H),3.74(s,3H),2.74 (dd,J=9.6,2.7Hz,1H),2.44(dd,J=9.6,1.7Hz,1H),2.35(dd,J=6.8,2.6Hz,1H),2.28(d,J=1.7Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ170.52,138.84,137.99,128.96,128.66,128.32,127.35 ,127.02,126.81,67.41,54.28,52.03,47.03,45.61,40.76.HRMS(ESI)m / z:[M+H] + calcd.for C 19 H 19 O2,279.1380;found,279.1374.

[0098] Example 9: Synthesis of compound 5b, BCH 3b, 5b was synthesized using General Method C (41% yield, 92% ee).

[0099] 1H NMR (400MHz, CD2Cl2): δ7.24-7.18(m,3H),7.16-7.13(m,2H),7.09-7.03(m,4H),3.94(d,J=6.7Hz,1H),3.74(s,3H),2. 71(dd,J=9.6,2.7Hz,1H),2.41(dd,J=9.6,1.7Hz,1H),2.34(s,3H),2.32(dd,J=6.7,2.6Hz,1H),2.25(d,J=1.6Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ170.57,138.12,137.13,135.80,129.32,128.96,128.28,12 6.90,126.76,67.33,54.31,52.00,47.03,45.44,40.73,21.26.HRMS(ESI)m / z:[M+H] + calcd.forC 20 H 21 O2,293.1536;found,293.1529.

[0100] Example 10: Synthesis of compound 5c, BCH is 3c, 5c was synthesized using General Method C (26% yield, 88% ee).

[0101] 1 H NMR (400MHz, CD2Cl2): δ7.37-7.34(m,2H),7.25-7.17(m,3H),7.15-7.11(m,2H),7.09-7.07(m,2H),3.96(d,J=6.7Hz,1H),3.73( s,3H),2.72(dd,J=9.6,2.7Hz,1H),2.40(dd,J=9.6,1.7Hz,1H),2.33(dd,J=6.7,2.7Hz,1H),2.25(d,J=1.7Hz,1H),1.31(s,9H); 13 C NMR (100MHz, CD2Cl2): δ170.56,150.39,138.15,135.82,129.03,128.30,126.78,12 6.69,125.60,67.27,52.00,47.16,45.39,40.82,34.80,31.48.HRMS(ESI)m / z:[M+H] + calcd.for C 23 H 27O2,335.2006;found,335.2000.

[0102] Example 11: Synthesis of compound 5d, BCH 3d, using General Method D, 5d (54% yield, 90% ee).

[0103] 1 H NMR (400MHz, CD2Cl2): δ7.23-7.12(m,5H),7.04-6.98(m,4H),3.93(d,J=6.7Hz,1H),3.73(s,3H),2.72 (dd,J=9.6,2.7Hz,1H),2.41(dd,J=9.6,1.7Hz,1H),2.32(dd,J=6.8,2.7Hz,1H),2.27(d,J=1.7Hz,1H); 19 F NMR (376MHz, CDCl3): δ-116.14; 13 C NMR (100 MHz, CD2Cl2): 13 C NMR(101MHz,Methylene Chloride-d2)δ170.38,162.45(d,J=244.7Hz),137.82,134.85(d,J=3.2Hz),128.95,128.80(d,J=8.1Hz ),128.39,126.91,115.50(d,J=21.6Hz),67.61,54.20,52.06,47.25,45.10,40.69.HRMS(ESI)m / z:[M+H] + calcd.for C 19 H 18 FO2,297.1285; found,297.1282.

[0104] Example 12: Synthesis of compound 5e, BCH is 3e, 5e was synthesized using General Method C (63% yield, 93% ee).

[0105] 1H NMR (400MHz, CD2Cl2): δ7.33-7.29(m,2H),7.25-7.20(m,3H),7.15-7.12(m,2H),7.05-7.02(m,2H),3.96(d,J=6.7Hz,1H) ,3.74(s,3H),2.73(dd,J=9.6,2.7Hz,1H),2.43(dd,J=9.6,1.7Hz,1H),2.34(dd,J=6.8,2.7Hz,1H),2.29(d,J=1.7Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ170.31,137.67,137.48,133.16,128.90,128.81,128 .59,128.39,126.93,67.59,52.08,47.13,45.09,40.72.HRMS(ESI)m / z:[M+H] + calcd.for C 19 H 18 ClO2,313.0990; found,313.0984.

[0106] Example 13: Synthesis of compound 5f, BCH is 3f, 5f was synthesized using General Method C (65% yield, 94% ee).

[0107] 1 H NMR (400MHz, CD2Cl2): δ7.48-7.44(m,2H),7.24-7.19(m,3H),7.09-7.02(m,4H),3.96(d,J=6.7Hz,1H),3.74(s, 3H),2.73(dd,J=9.6,2.7Hz,1H),2.43(dd,J=9.6,1.7Hz,1H),2.33(dd,J=6.8,2.7Hz,1H),2.29(d,J=1.7Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ170.29,137.95,137.64,131.76,128.93,128.89,128.40 ,126.93,121.29,67.55,54.07,52.08,47.09,45.14,40.72.HRMS(ESI)m / z:[M+H] + calcd.for C 19 H 18 BrO2,357.0485; found,357.0475.

[0108] Example 14: Synthesis of compound 5g, BCH 3g, using the general method C synthesis 5g (45% yield, 91% ee).

[0109] 1 H NMR (400MHz, CD2Cl2): δ7.62-7.57(m,4H),7.46-7.43(m,2H),7.37-7.33(m,1H),7.29-7.20(m,5H),7.11-7.08(m,2H),4.02(d,J=6 .7Hz,1H),3.75(s,3H),2.77(dd,J=9.6,2.7Hz,1H),2.47(dd,J=9.5,1.6Hz,1H),2.38(dd,J=6.7,2.7Hz,1H),2.32(d,J=1.6Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ170.48,141.06,140.15,137.97,137.95,129.18,128.99,128.36,127.69 ,127.54,127.33,127.30,126.85,67.51,54.34,52.05,47.15,45.44,40.84.HRMS(ESI)m / z:[M+H] + calcd.for C 25 H 23 O2,355.1693;found,355.1684.

[0110] Example 15: Synthesis of compound 5h, BCH is 3h, 5h was synthesized using general method D (39% yield, 92% ee)

[0111] 1 H NMR (400MHz, CDCl3): δ7.22-7.12(m,6H),7.05-7.01(m,3H),4.23(d,J=6.8Hz,1H),3.77(s,3H),2.81(dd,J= 9.7,2.7Hz,1H),2.65(dd,J=9.6,1.8Hz,1H),2.47(dd,J=6.8,2.7Hz,1H),2.40(s,3H),2.32(d,J=1.7Hz,1H). 13C NMR (100MHz, CDCl3): δ170.29,137.85,136.86,135.89,130.74,128.43,128.25,128.03,127 .43,126.45,125.95,66.46,53.54,51.77,47.83,46.16,41.57,20.56.HRMS(ESI)m / z:[M+H] + calcd.for C 20 H 21 O2,293.1536;found,293.1534.

[0112] Example 16: Synthesis of compound 5i, BCH 3i, 5i was synthesized using General Method C (49% yield, 88% ee).

[0113] 1 H NMR (400MHz, CD2Cl2): δ7.24-7.18(m,3H),7.08-7.05(m,2H),6.91(s,1H),6.82(s,2H),3.95(d,J=6.7Hz,1H),3.74(s,3H) ,2.68(dd,J=9.6,2.7Hz,1H),2.39(dd,J=9.6,1.6Hz,1H),2.32(dd,J=6.7,2.7Hz,1H),2.29(s,6H),2.23(d,J=1.6Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ170.58,138.67,138.28,138.18,129.00,128.97,128.28,12 6.77,124.72,67.13,54.55,52.00,46.89,45.49,40.76,21.36.HRMS(ESI)m / z:[M+H] + calcd.forC 21 H 23 O2,307.1693;found,307.1686.

[0114] Example 17: Synthesis of compound 5j, BCH 3j, 5j was synthesized using General Method C (40% yield, 90% ee).

[0115] 1H NMR (400MHz, CD2Cl2): δ7.86-7.79(m,3H),7.62(d,J=1.7Hz,1H),7.50-7.45(m,2H),7.38(dd,J=8.4,1.7Hz,1H),7.22-7.15(m,3H),7.07-7.05(m,2 H),4.08(d,J=6.7Hz,1H),3.77(s,3H),2.83(dd,J=9.6,2.6Hz,1H),2.54(dd,J=9.6,1.7Hz,1H),2.45(dd,J=6.8,2.6Hz,1H),2.36(d,J=1.6Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ170.51,137.99,136.40,133.66,132.89,128.96,128.37,128.34,128.05,128.01 ,126.83,126.62,126.18,125.82,125.04,67.47,54.40,52.07,47.06,45.82,40.91.HRMS(ESI)m / z:[M+H] + calcd.for C 23 H 21 O2,329.1536;found,329.1529.

[0116] Example 18: Synthesis of compound 5k, BCH 3k, 5k was synthesized using General Method D (41% yield, 93% ee).

[0117] 1 H NMR (400MHz, CD2Cl2): δ7.27-7.19(m,4H),7.15-7.12(m,2H),6.95(dd,J=5.0,3.4Hz,1H),6.81(dd,J=3.5,1.2Hz,1 H),3.93(d,J=6.8Hz,1H),3.72(s,3H),2.77(dd,J=9.6,2.6Hz,1H),2.42(dd,J=9.6,1.7Hz,1H),2.38-2.36(m,2H); 13 C NMR (100MHz, CD2Cl2): δ170.10,142.33,137.57,128.95,128.42,127.46,127.01 ,125.61,125.22,68.80,55.43,52.09,49.26,41.96,41.48.HRMS(ESI)m / z:[M+H] +calcd.for C 17 H 17 O2S,285.0944; found,285.0939.

[0118] Example 19: Synthesis of compound 5l, BCH was 3l, 5l was synthesized using the general method C (54% yield, 90% ee).

[0119] 1 H NMR (400MHz, CD2Cl2): δ7.35-7.24(m,3H),7.20-7.18(m,2H),7.03(d,J=7.9Hz,2H),6.93(d,J=8.0Hz,2H),3.93(d,J=6.7Hz,1H),3. 73(s,3H),2.73(dd,J=9.6,2.6Hz,1H),2.41(dd,J=9.6,1.7Hz,1H),2.33(dd,J=6.8,2.6Hz,1H),2.28(s,3H),2.27(d,J=2.8Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ170.56,138.93,136.49,134.82,128.98,128.82,128.63,12 7.30,127.01,67.24,54.26,52.00,47.00,45.54,40.72,21.14.HRMS(ESI)m / z:[M+H] + calcd.for C 20 H 21 O2,293.1536;found,293.1527.

[0120] Example 20: Synthesis of compound 5m, BCH 3m, 5m (57% yield, 90% ee) was synthesized using the general method C.

[0121] 1 H NMR (400MHz, CDCl3): δ7.35-7.30(m,2H),7.28-7.19(m,5H),7.01-6.99(m,2H),3.97(d,J=6.7Hz,1H),3.76(s,3H),2. 79(dd,J=9.6,2.6Hz,1H),2.42(dd,J=9.5,1.7Hz,1H),2.36(dd,J=6.8,2.6Hz,1H),2.29(d,J=1.7Hz,1H),1.27(s,9H). 13C NMR (100MHz, CDCl3): δ170.45,149.19,138.55,134.42,128.28,128.25,126.94,126.68 ,124.89,66.68,54.14,51.73,46.85,45.17,40.41,34.38,31.31.HRMS(ESI)m / z:[M+H] + calcd.forC 23 H 27 O2,335.2006;found,335.2003.

[0122] Example 21: Synthesis of compound 5n, BCH is 3n, 5n was synthesized using General Method C (56% yield, 0% ee).

[0123] 1 H NMR (400MHz, CD2Cl2): δ7.35-7.24(m,3H),7.20-7.17(m,2H),6.99-6.95(m,2H),6.76-6.74(m,2H),3.92(d,J=6.7Hz,1H),3.74( s,3H),3.73(s,3H),2.73(dd,J=9.5,2.6Hz,1H),2.41(dd,J=9.6,1.7Hz,1H),2.33(dd,J=6.7,2.6Hz,1H),2.27(d,J=1.7Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ170.57,158.66,138.93,129.99,128.64,127.30,127.00 ,113.71,66.89,55.49,54.21,52.00,47.03,45.51,40.74.HRMS(ESI)m / z:[M+H] + calcd.forC 20 H 21 O3,309.1485;found,309.1479.

[0124] Example 22: Synthesis of compound 5o, BCH is 3o, 5o was synthesized using General Method C (66% yield, 92% ee).

[0125] 1H NMR (400MHz, CD2Cl2): δ7.89-7.86(m,2H),7.36-7.26(m,3H),7.20-7.14(m,4H),4.00(d,J=6.7Hz,1H),3.86(s,3H),3. 76(s,3H),2.72(dd,J=9.6,2.8Hz,1H),2.48(dd,J=9.6,1.8Hz,1H),2.37(dd,J=6.8,2.8Hz,1H),2.32(d,J=1.7Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ170.27,167.15,143.29,138.38,129.45,129.10,128.88,128.75 ,127.56,127.02,67.36,54.14,52.27,52.12,47.29,45.96,40.90.HRMS(ESI)m / z:[M+H] + calcd.for C 21 H 21 O4,337.1434;found,337.1425.

[0126] Example 23: Synthesis of compound 5p, BCH is 3p, 5p was synthesized using General Method C (49% yield, 93% ee).

[0127] 1 H NMR (400MHz, CD2Cl2): δ7.53-7.50(m,2H),7.36-7.27(m,3H),7.21-7.16(m,4H),3.97(d,J=6.7Hz,1H),3.75(s, 3H),2.66(dd,J=9.7,2.9Hz,1H),2.47(dd,J=9.7,1.8Hz,1H),2.38(dd,J=6.8,2.9Hz,1H),2.32(d,J=1.8Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ170.09,143.51,138.03,132.13,129.83,128.83,127.69,126 .96,119.23,110.73,67.00,54.16,52.19,47.35,46.02,40.92.HRMS(ESI)m / z:[M+H] + calcd.for C 20 H 18 NO2,304.1332; found,304.1324.

[0128] Example 24: Synthesis of compound 5q, BCH was 3q, 5q was synthesized using General Method D (48% yield, 94% ee).

[0129] 1 H NMR (400MHz, CD2Cl2): δ8.07-8.04(m,2H),7.37-7.28(m,3H),7.27-7.24(m,2H),7.19-7.17(m,2H),4.00(d,J=6.7Hz,1H) ,3.76(s,3H),2.67(dd,J=9.7,3.0Hz,1H),2.50(dd,J=9.7,1.9Hz,1H),2.40(dd,J=6.7,2.9Hz,1H),2.34(d,J=1.8Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ170.04,147.06,145.73,137.90,129.99,128.87,127 .76,126.98,123.44,66.90,52.23,47.47,46.19,41.02.HRMS(ESI)m / z:[M+H] + calcd.for C 19 H 18 NO4,324.1230; found,324.1227.

[0130] Example 25: Synthesis of compound 5r, BCH 3r, 5r was synthesized using General Method C (60% yield, 94% ee).

[0131] 1 H NMR (400MHz, CDCl3): δ7.35-7.25(m,3H),7.18-7.15(m,2H),7.04-7.00(m,2H),6.93-6.88(m,2H),3.93(d,J=6.7Hz,1H), 3.76(s,3H),2.72(dd,J=9.6,2.7Hz,1H),2.44(dd,J=9.6,1.8Hz,1H),2.36(dd,J=6.8,2.7Hz,1H),2.31(d,J=1.7Hz,1H).; 19 F NMR (376MHz, CDCl3): δ-116.09; 13C NMR (100MHz, CDCl3): δ170.23, 161.56 (d, J = 244.9Hz), 138.02, 133.12 (d, J = 3.3Hz), 130.08 (d, J = 7.8Hz), 12 8.37,127.11,126.58,114.84(d,J=21.2Hz),66.26,53.80,51.82,46.83,45.20,40.38.HRMS(ESI)m / z:[M+H] + calcd.forC 19 H 18 FO2,297.1285; found,297.1278.

[0132] Example 26: Synthesis of compound 5s, BCH 3s, 5s was synthesized using General Method C (64% yield, 98% ee).

[0133] 1 H NMR (400MHz, CD2Cl2): δ7.37-7.26(m,5H),7.19-7.17(m,2H),6.98-6.95(m,2H),3.91(d,J=6.7Hz,1H),3.74(s, 3H),2.70(dd,J=9.6,2.8Hz,1H),2.44(dd,J=9.6,1.8Hz,1H),2.36(dd,J=6.8,2.8Hz,1H),2.30(d,J=1.7Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ170.29,138.42,137.08,131.39,130.84,128.74,127.51 ,126.99,120.76,66.75,54.14,52.10,47.18,45.65,40.74.HRMS(ESI)m / z:[M+H] + calcd.for C 19 H 18 BrO2,357.0485; found,357.0475.

[0134] Example 27: Synthesis of compound 5t, BCH 3t, 5t was synthesized using General Method C (63% yield, 93% ee).

[0135] 1H NMR (400MHz, CDCl3): δ7.55-7.53(m,2H),7.45(d,J=8.3Hz,2H),7.40(t,J=7.6Hz,2H),7.36-7.27(m,4H),7.23-7.20(m,2H),7.14(d,J=8.1Hz,2H ), 4.02(d,J=6.7Hz,1H),3.78(s,3H),2.83(dd,J=9.6,2.7Hz,1H),2.47(dd,J=9.5,1.7Hz,1H),2.39(dd,J=6.8,2.7Hz,1H),2.33(d,J=1.7Hz,1H). 13 C NMR (100MHz, CDCl3): δ170.37,140.88,139.32,138.30,136.52,129.04,128.70,128.34,127.12, 127.06,126.97,126.71,126.68,66.87,53.94,51.81,46.99,45.35,40.48.HRMS(ESI)m / z:[M+H] + calcd.forC 25 H 23 O2355.1693; found, 355.1689.

[0136] Example 28: Synthesis of compound 5u, BCH is 3u, 5u was synthesized using General Method C (60% yield, 90% ee).

[0137] 1 H NMR (400MHz, CDCl3): δ7.34-7.24(m,3H),7.19-7.17(m,2H),7.10(t,J=7. 6Hz,1H),7.00(d,J=7.5Hz,1H),6.88(s,1H),6.83(d,J=7.7Hz,1H),3.95(d ,J=6.7Hz,1H),3.76(s,3H),2.78(dd,J=9.6,2.6Hz,1H),2.43(dd,J=9.5,1 .7Hz,1H),2.35(dd,J=6.8,2.6Hz,1H),2.29(d,J=1.6Hz,1H),2.24(s,3H); 13C NMR (100MHz, CDCl3): δ170.42,138.36,137.48,137.34,129.29,128.24,127.85,127.19,126 .96,126.66,125.60,67.10,53.79,51.75,46.83,45.20,40.35,21.43.HRMS(ESI)m / z:[M+H] + calcd.for C 20 H 21 O2,293.1536;found,293.1527.

[0138] Example 29: Synthesis of compound 5v, BCH 3v, 5v was synthesized using General Method C (56% yield, 88% ee).

[0139] 1 H NMR (400MHz, CDCl3): δ7.35-7.30(m,2H),7.28-7.24(m,1H),7.21-7.18(m,2H),7. 12(t,J=7.9Hz,1H),6.74(dd,J=8.3,2.6Hz,1H),6.65(d,J=7.6Hz,1H),6.62-6.61 (m,1H),3.96(d,J=6.8Hz,1H),3.77(s,3H),3.64(s,3H),2.78(dd,J=9.6,2.7Hz,1 H),2.44(dd,J=9.6,1.7Hz,1H),2.35(dd,J=6.8,2.7Hz,1H),2.30(d,J=1.7Hz,1H). 13 C NMR (100MHz, CDCl3): δ170.35,159.20,139.06,138.30,128.97,128.29,127.04,126.69,120 .86,114.00,112.24,67.08,54.92,53.76,51.78,46.91,45.30,40.47.HRMS(ESI)m / z:[M+H] + calcd.for C 20 H 21 O3,309.1485;found,309.1483.

[0140] Example 30: Synthesis of compound 5w, BCH 3w, 5w (47% yield, 90% ee) was synthesized using General Method D.

[0141] 1H NMR (400MHz, CD2Cl2): δ7.51-7.48(m,1H),7.38-7.28(m,6H),7.17-7.15(m,2H),3.93(d,J=6.7Hz,1H),3.74(s, 3H),2.65(dd,J=9.7,3.0Hz,1H),2.45(dd,J=9.7,1.9Hz,1H),2.38(dd,J=6.7,2.9Hz,1H),2.31(d,J=1.8Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ170.06,139.50,138.00,133.64,132.59,130.69,129.18,128.88,127 .75,126.93,119.19,112.50,66.34,54.21,52.20,47.35,45.85,40.85.HRMS(ESI)m / z:[M+H] + calcd.for C 20 H 18 NO2,304.1332; found,304.1327.

[0142] Example 31: Synthesis of compound 5x, BCH 3x, using the general method D to synthesize 5x (54% yield, 94% ee).

[0143] 1 H NMR (400MHz, CDCl3): δ7.29-7.23(m,3H),7.15-7.05(m,6H),4.00(d,J=6.4Hz,1H),3.72(s,3H),3.05(dd,J= 9.6, 2.8Hz, 1H), 2.50 (dd, J=9.6, 1.7Hz, 1H), 2.29 (dd, J=6.5, 2.8Hz, 1H), 2.26 (d, J=1.7Hz, 1H), 1.84 (s, 3H). 13 C NMR (100MHz, CDCl3): δ170.47,138.62,138.48,134.72,130.34,128.90,128.28,127.00,126 .67,126.44,125.22,68.53,52.00,51.78,46.58,45.38,40.15,19.01.HRMS(ESI)m / z:[M+H] + calcd.for C 20 H 21 O2,293.1536;found,293.1534.

[0144] Example 32: Synthesis of compound 5y, BCH is 3y, 5y was synthesized using General Method C (68% yield, 91% ee).

[0145] 1 H NMR (400MHz, CD2Cl2): δ7.80-7.76(m,1H),7.70-7.68(m,2H),7.55(s,1H),7 .45-7.41(m,2H),7.37-7.27(m,3H),7.24-7.22(m,2H),7.16(dd,J=8.5,1.8 Hz,1H),4.12(d,J=6.7Hz,1H),3.78(s,3H),2.85(dd,J=9.6,2.7Hz,1H),2.5 1(dd,J=9.6,1.7Hz,1H),2.39(dd,J=6.7,2.7Hz,1H),2.34(d,J=1.7Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ170.56,138.80,135.58,133.44,132.53,128.69,128.05,127.85,127.77 ,127.43,127.08,126.28,125.97,67.78,54.15,52.09,47.30,45.83,40.89.HRMS(ESI)m / z:[M+H] + calcd.forC 23 H 21 O2,329.1536;found,329.1531.

[0146] Example 33: Synthesis of compound 5z, BCH is 3z, 5z was synthesized using General Method C (41% yield, 80% ee).

[0147] 1 H NMR (400MHz, CD2Cl2): δ7.34-7.30(m,3H),7.28-7.24(m,1H),7.21-7.19(m,3H),6.19(d,J=1.9Hz,1H),3.72(s,3H),3. 69(d,J=6.8Hz,1H),2.81(dt,J=9.5,1.8Hz,1H),2.39(dt,J=9.5,1.5Hz,1H),2.34(dd,J=6.7,2.4Hz,1H),2.31(s,1H); 13C NMR (100MHz, CD2Cl2): δ170.24,142.66,140.85,138.67,128.64,127.42,126.85 ,121.31,111.65,59.85,54.41,51.98,48.10,45.20,40.47.HRMS(ESI)m / z:[M+H] + calcd.forC 17 H 17 O3,269.1172;found,269.1168.

[0148] Example 34: Synthesis of compound 5aa, BCH is 3aa, 5aa was synthesized using General Method D (67% yield, 60% ee).

[0149] 1 H NMR (400MHz, CD2Cl2): δ7.35-7.22(m,5H),7.14(dd,J=5.0,1.2Hz,1H),6.89(dd,J=5.1,3.5Hz,1H),6.78(dt,J=3.5,1.2Hz,1H),4.04(dd,J =6.6,1.1Hz,1H),3.73(s,3H),2.88(dd,J=9.6,2.7Hz,1H),2.43(dd,J=9.7,1.9Hz,1H),2.39(dd,J=6.6,2.7Hz,1H),2.32(d,J=1.9Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ169.89,140.44,138.16,128.68,127.61,127.13,126.76 ,126.54,124.66,63.01,54.64,52.05,47.70,46.47,41.64.HRMS(ESI)m / z:[M+H] + calcd.for C 17 H 17 O2S,285.0944; found,285.0940.

[0150] Example 35: Synthesis of compound 5ab, BCH is 3ab, 5ab was synthesized using General Method C (61% yield, 93% ee).

[0151] 1H NMR (400MHz, CD2Cl2): δ7.42-7.26(m,8H),7.23-7.17(m,5H),7.04-7.02(m,2H),5.22(s,2H),4.02(d,J=6.7Hz, 1H),2.77(dd,J=9.6,2.7Hz,1H),2.48(dd,J=9.6,1.7Hz,1H),2.39(dd,J=6.8,2.7Hz,1H),2.32(d,J=1.7Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ169.86,138.85,137.93,136.51,129.00,128.91,128.68,128.59,128 .29,127.37,127.04,126.81,67.50,66.67,54.38,47.03,45.62,40.89.HRMS(ESI)m / z:[M+H] + calcd.for C 25 H 23 O2,355.1693;found,355.1684.

[0152] Example 36: Synthesis of compound 5ac, BCH is 3ac, 5ac was synthesized using General Method D (46% yield, 89% ee).

[0153] 1 H NMR (400MHz, CD2Cl2): δ7.33-7.29(m,2H),7.27-7.24(m,1H),7.23-7.16(m,5H),7.07-7.05(m,2H),3.91(d,J=6.7Hz,1H) ,2.65(dd,J=9.6,2.6Hz,1H),2.37(dd,J=9.6,1.6Hz,1H),2.27(dd,J=6.8,2.7Hz,1H),2.21(d,J=1.6Hz,1H),1.48(s,9H); 13 C NMR (100MHz, CD2Cl2): δ169.56,139.18,138.39,129.06,128.65,128.24,127.26,12 7.07,126.70,81.08,67.30,54.20,46.75,45.10,41.73,28.24.HRMS(ESI)m / z:[M+H] + calcd.forC 22 H 25O2,321.1849;found,321.1841.

[0154] Example 37: Synthesis of compound 5ad, BCH is 3ad, 5ad was synthesized using General Method C (48% yield, 95% ee).

[0155] 1 H NMR (400MHz, CD2Cl2): δ8.09-8.06(m,2H),7.62-7.58(m,1H),7.52-7.48(m,2H),7.40-7.36(m,2H),7.33-7.27(m,3H),7.17-7.15(m,3H),6.97- 6.94(m,2H),4.36(d,J=6.8Hz,1H),2.92(dd,J=9.6,2.9Hz,1H),2.77(dd,J=9.6,1.8Hz,1H),2.57(dd,J=6.8,2.8Hz,1H),2.50(d,J=1.8Hz,1H); 13 C NMR (100MHz, CD2Cl2): δ197.73,139.00,138.08,137.31,133.39,129.20,129.00,128.99,128 .73,128.34,127.43,127.09,126.87,69.68,56.76,47.64,47.19,46.14.HRMS(ESI)m / z:[M+H] + calcd.for C 24 H 21 O,325.1587;found,325.1580.

[0156] Example 38: Synthesis of compound 5ae, BCH is 3ae, 5ae was synthesized using General Method D (18% yield, 88% ee).

[0157] 1H NMR (400MHz, CDCl3): δ7.90-7.88(m,2H),7.65-7.61(m,1H),7.53(dd,J=8.4,7 .0Hz,2H),7.32-7.30(m,2H),7.27-7.22(m,3H),6.97(d,J=8.7Hz,2H),6.81(d, J=8.7Hz,2H),3.90(d,J=6.7Hz,1H),3.77(s,3H),2.98(dd,J=9.5,2.6Hz,1H), 2.34(dd,J=6.8,2.5Hz,1H), 2.25(dd,J=9.4,1.8Hz,1H), 2.09(d,J=1.8Hz,1H). 13 C NMR (100MHz, CDCl3): δ159.04,137.46,134.87,133.63,129.23,129.08,128.61,128.47,128. 01,127.72,126.92,113.88,68.00,55.23,54.37,53.01,47.34,44.39.HRMS(ESI)m / z:[M+Na] + calcd.for C 24 H 22 O3SNa,413.1182; found,413.1175.

[0158] Example 39: Synthesis of Compound 3s

[0159]

[0160] 1a (5.4 mmol, 1.0 equiv) and 2i (8.8 mmol, 1.63 equiv) were dissolved in 54 mL of THF and 54 mL of CHCl₃ in a 250 mL dry flask. The reaction mixture was cooled to -30°C, and then a 1 mL THF solution containing (R)-C11 (3 mol%) was added dropwise. The reaction was stirred at -30°C until 1a was fully reacted (approximately 12 hours). The reaction was quenched by the addition of saturated aqueous NaHCO₃, followed by extraction with ethyl acetate (EtOAc). The combined organic phases were dried over Na₂SO₄, concentrated under reduced pressure, and purified by silica gel column chromatography using ethyl acetate / petroleum ether (2% to 10%) as the eluent to afford product 3s (92% yield, 95% ee). Recrystallization from CHCl₂ / petroleum ether afforded product 3s in 83% yield with >99% ee.

[0161] Example 40: Synthesis of Compound 5s

[0162]

[0163] 3s (2.4 mmol, 1.0 eq) and dry CH2Cl2 (96 mL) were added to a dry 100 mL Schlenk tube equipped with a Teflon-coated magnetic stirrer. Subsequently, TMSOTf (587 mg, 1.1 eq) was added at 0°C and stirred under argon for 3 hours. After completion, the reaction was quenched with saturated NaHCO3 solution and extracted with CH2Cl2. The combined organic phases were washed with brine, dried (Na2SO4), and concentrated. The crude product was used directly in the next step without further purification. The reaction was carried out at room temperature. The crude product was dissolved in CD3OD (0.15 M, 16 mL), followed by the addition of NH3·H2O (25% aqueous solution, 1.8 mL, 24 mmol, 10.0 eq) and PIDA (2.32 g, 3.0 eq), and stirred at 40°C for 12 hours. After the reaction, the solvent was evaporated and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give the product 5s (57% yield, 98% ee).

[0164] Example 41: Synthesis of Compound 7

[0165]

[0166] To a stirred solution of 5s (0.12 mmol, 1.0 equiv) in dry dichloromethane (CH2Cl2, 1.2 mL) was added DIBAL-H (1.0 M in hexane, 0.24 mmol, 2.0 equiv) dropwise at -78°C under argon. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated sodium potassium tartrate solution, and the resulting slurry was stirred vigorously until the two phases became clear. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated by evaporation. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to afford alcohol 7 as a white solid (95% yield, 97% ee).

[0167] 1 H NMR (400MHz, CDCl3): δ7.34-7.30(m,4H),7.27-7.19(m,3H),6.95(d,J=8.2Hz,2H),3.81(s,2H) ),3.62(d,J=6.7Hz,1H),2.40(dd,J=9.8,2.6Hz,1H),2.10-2.06(m,2H),1.97(d,J=1.7Hz,1H); 13C NMR (100MHz, CDCl3): δ139.16,137.58,131.06,130.65,128.33,126.71,126 .43,120.02,62.56,61.54,51.80,45.30,44.71,42.59.HRMS(APCI)m / z:[MH] - calcd.for C 18 H 16 BrO,327.0390; found,327.0393.

[0168] Example 42: Synthesis of Compound 8

[0169]

[0170] A stirring bar, 5S (2.0 mmol, 1.0 eq), and LiOH (2.0 eq) were added to a 10 mL round-bottom flask. The solid was dissolved in a THF / water mixture (20 mL, 1 / 1 volume ratio) and stirred overnight at room temperature. The mixture was then concentrated under reduced pressure. The resulting residue was dissolved in water, acidified to pH 4-6 with HCl (1.0 M), and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford product 8 (93% yield) as a white solid.

[0171] 1 H NMR (400MHz, CDCl3): δ7.38-7.27(m,5H),7.19-7.16(m,2H),6.99(d,J=8.3Hz,2H),3.95(d,J=6.7Hz,1H),2 .77(dd,J=9.6,2.8Hz,1H),2.50(dd,J=9.6,1.8Hz,1H),2.41(dd,J=6.7,2.8Hz,1H),2.38(d,J=1.7Hz,1H); 13 C NMR (100MHz, CDCl3): δ175.88,137.60,136.04,131.17,130.35,128.44,127 .29,126.58,120.69,66.42,53.90,46.88,45.28,40.30.HRMS(ESI)m / z:[MH] - calcd.for C 18 H 14 BrO2,341.0183; found,341.0178.

[0172] Example 43: Synthesis of Compound 9

[0173]

[0174] 8 (0.12 mmol, 1.0 equiv) was dissolved in dry toluene (1.2 mL), and triethylamine (34 μL, 0.24 mmol, 2.0 equiv) and DPPA (0.144 mmol, 1.2 equiv) were added. The reaction mixture was stirred at 100°C for 5 hours. After cooling to room temperature, the mixture was concentrated by evaporation. The crude isocyanate was dissolved in dichloromethane (CH2Cl2, 2 mL), and t-BuOH (1.0 mmol, 8.0 equiv) and TMSCl (26 mg, 0.24 mmol, 2.0 equiv) were added. The reaction mixture was stirred at room temperature for 12 hours, quenched with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4, the solvent was removed by evaporation, and the residue was purified by preparative thin-layer chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to afford the product 9 as a colorless oil (70% yield, 59% ee).

[0175] 1 H NMR (500MHz, CD3CN): δ7.39-7.37(m,2H),7.35-7.31(m,2H),7.27-7.22(m,3H),6.97-

[0176] 6.96(m,2H),6.05(brs,1H),3.92(brs,1H),2.55(dd,J=9.7,2.4Hz,1H),2.47(d ,J=9.6Hz,1H),2.30(dd,J=6.6,2.4Hz,1H),2.10(d,J=1.3Hz,1H),1.43(s,9H); 13 C NMR (125MHz, CD3CN): δ155.86,139.06,138.59,131.80,131.44,129.31,127.67,127.61,120.51,79.68,65.92,56.50,49.06,48.46,43.53,

[0177] 28.52.HRMS(APCI)m / z:[MH] - calcd.for C 22 H 23 BrNO2,412.0918; found,412.0914.

[0178] Example 44: Synthesis of Compound 10

[0179]

[0180] 8 (1.2 mmol, 1.0 eq), N-hydroxyphthalimide (1.44 mmol, 1.2 eq), and DMAP (15 mg, 0.1 eq) were dissolved in 25 mL of CH2Cl2 and placed in a dry 100 mL reaction flask. Dicyclohexylcarbodiimide (1.44 mmol, 1.2 eq) was added, and the mixture was stirred at room temperature overnight. The mixture was filtered through celite. The filtrate was concentrated by rotary evaporation. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford product 10 as a white solid (80% yield, 99% ee).

[0181] 1 H NMR (400MHz, CDCl3): δ7.94-7.89(m,2H),7.84-7.79(m,2H),7.42-7.30(m,5H),

[0182] 7.22-7.20(m,2H),7.09-7.07(m,2H),4.15(d,J=6.7Hz,1H),2.89(dd,J=9.5,2.9Hz, 1H), 2.69 (dd, J=9.6, 1.9Hz, 1H), 2.58 (dd, J=6.8, 2.8Hz, 1H), 2.57 (d, J=2.0Hz, 1H); 13 C NMR (100MHz, CDCl3): δ165.15,161.84,137.25,135.30,134.82,131.34,130.34,128.95,128. 56,127.53,126.59,124.03,121.05,67.65,54.31,47.62,46.37,38.11.HRMS(APCI)m / z:[M+H] + calcd.for C 26 H 19 BrNO4,488.0492; found,488.0481.

[0183] Example 45: Synthesis of Compound 11

[0184]

[0185] 10 (0.1 mmol, 1.0 eq) and TBAI (3.7 mg, 0.01 mmol, 0.1 eq) were added to a 10 mL Schlenk tube and a stirring bar was added. The tube was then evacuated and filled with argon (this process was repeated three times). Enol silyl ether (0.5 mmol, 5.0 eq) and anhydrous DMA (1.2 mL) were added. The reaction tube was sealed and then irradiated with a blue LED (8 W, 425-430 nm) at room temperature for 24 hours. Subsequently, water (2.0 eq) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NaCl solution and extracted with ethyl acetate. The organic phases were combined and dried over Na2SO4. The solvent was removed by evaporation and the residue was purified by preparative TLC (eluent: petroleum ether / ethyl acetate).

[0186] =30 / 1), affording product 11 (37% yield, 99% ee) as a colorless oil.

[0187] 1 H NMR (400MHz, CDCl3): δ7.96-7.92(m,2H),7.60-7.55(m,1H),7.47(t,J=7.7 Hz,2H),7.36-7.33(m,2H),7.31-7.28(m,2H),7.25-7.15(m,3H),7.00-6.9 7(m,2H),3.72(d,J=6.6Hz,1H),3.36(d,J=15.2Hz,1H),3.22(d,J=15.2Hz, 1H),2.51(dd,J=9.8,2.7Hz,1H),2.14-2.10(m,2H),2.00(d,J=1.9Hz,1H); 13 C NMR (100MHz, CDCl3): δ198.45,139.01,137.54,137.19,133.23,131.11,130.68,128.69,128.64,128 .31,128.28,126.62,126.42,120.06,64.18,54.43,47.41,45.95,39.21,38.83.HRMS(ESI)m / z:[M+H] + calcd.forC 25 H 22 BrO,417.0849; found,417.0838.

[0188] Example 46: Synthesis of Compound 12

[0189]

[0190] A Schlenk tube equipped with a stirrer was evacuated and filled with argon (repeated three times). 10 (0.1 mmol, 1.0 equiv) and Hantzsch ester (CAS: 1149-23-1, 0.15 mmol, 1.5 equiv) were then added to the tube. Anhydrous DMA (1.2 mL) was added using a syringe under argon. The reaction mixture was stirred under irradiation with a blue LED (8 W, 455-460 nm) and maintained at room temperature with a cooling fan for 12 hours. The reaction mixture was quenched with saturated NaCl solution and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4. The solvent was removed by evaporation, and the residue was purified by preparative thin-layer chromatography (eluent: petroleum ether / ethyl acetate = 40 / 1) to afford product 12 (60% yield, 68% ee) as a colorless oil.

[0191] 1 H NMR (400MHz, CDCl3): δ7.36-7.29(m,4H),7.27-7.22(m,1H),7.16-7.13(m,2H),6.90-6.88(m,2H),3.58( d,J=6.8Hz,1H),2.90(s,1H),2.43(dd,J=9.8,2.7Hz,1H),2.19(dd,J=9.8,1.9Hz,1H),2.09-2.07(m,2H); 13 C NMR (100MHz, CDCl3): δ139.80,138.71,130.90,130.32,128.18,126.59,126.47,119.87,65.15,50.19,50.08,46.64,29.66.HRMS(APCI)m / z:[M+H] + calcd.for C 17 H 16 Br,299.0430;found,299.0427.

[0192] Example 47: Synthesis of Compound 13

[0193]

[0194] 10 (1.0 equiv) and bis(catechol)diboron (36 mg, 0.15 mmol, 1.5 equiv) were added to a Schlenk tube. The tube was evacuated and filled with argon (this process was repeated three times), and anhydrous DMA (1.0 mL) was added. The reaction tube was sealed, and the reaction was irradiated with a blue LED (8 W, 455-460 nm) at room temperature. After 16 hours, pinacol (48 mg, 4.0 equiv) and triethylamine (0.4 mL) were added, and the mixture was stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution (3 mL) and extracted with ethyl acetate. The combined organic phases were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) over 10 minutes to obtain product 13 (83% yield, 98% ee) as a colorless oil.

[0195] 1 H NMR (400MHz, CDCl3): δ7.34-7.28(m,4H),7.26-7.21(m,1H),7.15-7.12(m,2H),6.99(d,J=8.3Hz,2H),3.71(d,J=6.7Hz,1H) ,2.55(dd,J=9.8,2.9Hz,1H),2.26(dd,J=9.7,1.9Hz,1H),2.17(dd,J=6.8,2.9Hz,1H),2.13(d,J=1.9Hz,1H),1.30(s,12H); 13 C NMR (100MHz, CDCl3): δ140.23,138.86,130.78,130.55,128.17,126.60,126.26 ,119.80,83.69,66.36,52.09,50.35,46.84,24.82,24.77.HRMS(ESI)m / z:[M+H] + calcd.forC 23 H 27 BBrO2,425.1282; found,425.1267.

[0196] Example 48: Synthesis of Compound 14

[0197]

[0198] 10 (0.1 mmol, 1.0 equiv), 4-bromothiophenol (23 mg, 0.12 mmol, 1.2 equiv), and Cs2CO3 (0.15 mmol, 1.5 equiv) were added to a clear Schlenk tube equipped with a stirrer. The tube was evacuated and filled with argon (this process was repeated three times), and anhydrous DMF (1.5 ml) was added to the solids. The reaction tube was sealed and then irradiated with a blue LED (8 W, 455-460 nm) at room temperature for 12 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined and dried over Na2SO4. The solvent was removed by evaporation, and the residue was purified by preparative TLC (eluent: petroleum ether / ethyl acetate = 30 / 1) to afford product 14 (56% yield, 99% ee) as a slightly yellow oil.

[0199] 1 H NMR (400MHz, CDCl3): δ7.45-7.43(m,2H),7.38-7.33(m,4H),7.31-7.22(m,3H),7.11-7.07(m,4 H),3.58(d,J=6.6Hz,1H),2.65(dd,J=9.6,2.6Hz,1H),2.22-2.20(m,2H),2.14(d,J=1.8Hz,1H); 13 C NMR (100MHz, CDCl3): δ137.55,136.33,135.43,132.19,132.12,131.08,130.47,128.40, 127.03,126.46,122.33,120.61,66.15,56.21,49.50,46.40,44.69.HRMS(APCI)m / z:[MH] - calcd.for C 23 H 17 Br2S,482.9423; found,482.9414.

[0200] Example 49: Synthesis of Compound 15

[0201]

[0202] Redox-active ester 10 (0.07 mmol, 1.4 equiv), Hantzsch ester (CAS: 1149-23-1, 17.7 mg, 0.07 mmol, 1.4 equiv), and benzyl acrylate (0.05 mmol, 1.0 equiv) were added to a clear Schlenk tube equipped with a stirrer. Anhydrous DMA (0.5 mL) was added using a sealed syringe under argon. The tube was evacuated and then filled with argon (this process was repeated three times). The reaction tube was sealed and then irradiated with a blue LED (8 W, 450-460 nm) at room temperature for 12 hours. The reaction was quenched with saturated NaCl solution and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4. The solvent was removed by evaporation, and the residue was purified by preparative TLC (eluent: petroleum ether / ethyl acetate = 20 / 1) to afford product 15 (40% yield, 99% ee) as a colorless oil.

[0203] 1 H NMR (400MHz, CDCl3): δ7.38-7.29(m,9H),7.25-7.21(m,1H),7.16-7.14(m,2H),6.91(d,J=8.2Hz,1H),5.12(s,2H),3.45(d,J=6.7Hz,1H),2.4 4(td,J=7.5,1.8Hz,2H),2.34(dd,J=9.8,2.7Hz,1H),2.06-2.01(m,2H),1.98(dd,J=6.8,2.7Hz,1H),1.92(dd,J=9.8,1.8Hz,1H),1.88(s,1H). 13 C NMR (100MHz, CDCl3): δ173.16,139.21,137.77,135.82,131.02,130.55,128.58,128.33,128.30,128.27 ,126.58,126.45,119.95,66.39,63.43,52.64,45.85,44.83,41.88,31.27,25.11.HRMS(ESI)m / z:[M+H] + calcd.for C 27 H 26 BrO2,461.1111; found,461.1106.

[0204] Example 50: Synthesis of Compound 3af

[0205]

[0206] 1a (1.0 mmol, 1.0 equiv) and 2r (2.0 mmol, 2.0 equiv) were dissolved in 10 mL of THF and 10 mL of CHCl₃ and added to a dried 50 mL Schlenk tube. After cooling to -30°C, a THF solution containing (R)-C11 (3 mol%) (200 μL) was added. Stir at -30°C until 1a was completely consumed (monitored by TLC, approximately 12 hours). The reaction was quenched by adding saturated NaHCO₃ solution and extracted with ethyl acetate. The extract was dried over Na₂SO₄, concentrated under reduced pressure, and purified by silica gel column chromatography to afford product 3af as a white solid (85% yield, 94% ee).

[0207] 1 H NMR (400MHz, CDCl3): δ7.45-7.42(m,2H),7.36-7.22(m,8H),6.81(dd,J=15.9,1.2Hz,1H),6.35(dd,J=15.7,6.5Hz,1H),4.76(d,J=6.5Hz,1 H),3.72(s,3H),2.59(d,J=7.0Hz,1H),2.50(dd,J=10.0,7.6Hz,1H),2.30(dd,J=9.9,7.0Hz,1H),2.11(dd,J=7.6,1.3Hz,1H),1.12(s,9H); 13 C NMR (100MHz, CDCl3): δ170.32,157.08,138.81,136.77,133.78,128.40,127.92,127.58,127.19,12 6.64,126.49,126.15,79.63,70.61,65.78,51.93,50.85,46.65,44.80,27.86.HRMS(ESI)m / z:[M+H] + calcd.for C 26 H 30 NO4,420.2169; found,420.2163.

[0208] Example 51: Synthesis of Compound 16

[0209]

[0210] A 50 mL round-bottom flask was charged with olefin 3af (126 mg, 0.3 mmol), 10% Pd / C (10.0 mg), and ethyl acetate (8.0 mL). The flask was evacuated and then filled with hydrogen (via balloon). The mixture was stirred at room temperature for 3 hours and then filtered through a Celite filter cake, which was washed with ethyl acetate. The filtrate was concentrated and purified by silica gel flash column chromatography to afford pure product 16 as a white solid (95% yield, 93% ee).

[0211]

[0212] 16 (0.15 mmol, 1.0 eq) and dry CH2Cl2 (6.0 mL) were added to a pre-dried 25 mL Schlenk tube equipped with a Teflon-coated magnetic stir bar. Subsequently, Et3N (0.75 mmol, 5.0 eq) and TMSOTf (83 mg, 0.375 mmol, 2.5 eq) were added at 0°C under argon. After stirring for 12 hours, the reaction was quenched with saturated NaHCO3 solution and extracted with CH2Cl2. The organic phases were combined, washed with brine, dried over Na2SO4, and concentrated to yield the crude product, which was used directly in the next reaction without further purification.

[0213] The crude product was dissolved in CD3OD (0.15 M, 1.0 mL) at room temperature, and NH3·H2O (25% aq., 115 μL, 1.5 mmol, 10.0 equiv) and PIDA (145 mg, 0.45 mmol, 3.0 equiv) were added. The reaction mixture was then stirred at 40°C for 12 hours. After completion of the reaction, the solvent was evaporated, and the residue was purified by preparative TLC (petroleum ether / ethyl acetate = 20 / 1) to afford product 17 as a colorless oil (52% yield, 79% ee).

[0214] 1 H NMR (400MHz, CD2Cl2): δ7.31-7.27(m,2H),7.25-7.20(m,3H),7.17-7.09(m,5H),3.67(s,3H),2.88(dd,J=10.1,2.8Hz,1H),2.67(dt,J =7.5,6.1Hz,1H),2.61-2.46(m,2H),2.24-2.16(m,3H),2.06(dddd,J=13.6,10.2,7.4,6.0Hz,1H),1.89(ddt,J=14.0,10.4,6.0Hz,1H); 13C NMR (100MHz, CD2Cl2): δ170.69,142.81,139.21,128.68,128.63,128.60,127.19,12 6.74,126.08,66.20,51.79,46.94,45.12,40.34,34.59,27.62.HRMS(ESI)m / z:[M+H] + calcd.for C 21 H 23 O2,307.1693;found,307.1687.

[0215] Example 52: Synthesis of Compound 18

[0216]

[0217] 3af (0.5 mmol, 1.0 eq) was dissolved in a mixture of CCl4 (2.5 mL), acetonitrile (2.5 mL), and water (5.0 mL) and stirred at room temperature. RuCl3 (0.05 eq) and NaIO4 (5.0 mmol, 10.0 eq) were added, and the reaction mixture was stirred vigorously at room temperature for 12 hours. 4M HCl (5 mL) was added and the mixture was extracted with ethyl acetate, washed with dilute aqueous Na2S2O3 solution and brine, and dried over Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was used directly in the next reaction without further purification.

[0218] The crude product was dissolved in CH2Cl2 / MeOH (4.5 mL / 0.5 mL), and TMSCH2N2 (1.5 mL, 2 M in hexane) was added at 0°C. The reaction was stirred for 10 minutes. After removal of the solvent, purification by preparative TLC (petroleum ether / ethyl acetate = 4 / 1) afforded the desired product 18 as a colorless oil (59% yield over two steps, 93% ee).

[0219]

[0220] 18 (0.1 mmol, 1.0 eq) and dry CH2Cl2 (4 mL) were added to a dry 25 mL Schlenk tube equipped with a Teflon-coated magnetic stir bar. Subsequently, Et3N (70 μL, 0.5 mmol, 5.0 eq) and TMSOTf (56 mg, 0.25 mmol, 2.5 eq) were added at 0°C and stirred under a positive argon atmosphere for 12 hours. The reaction was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated. The crude product was used directly in the next reaction without further purification.

[0221] The crude product was dissolved in CD3OD (0.1 M, 1.0 mL) at room temperature. NH3·H2O (25% aqueous solution, 80 μL, 1.0 mmol, 10.0 equiv) and PIDA (96 mg, 0.3 mmol, 3.0 equiv) were then added, and the mixture was stirred at 40°C for 5 hours. After removal of the solvent, the product was purified by preparative TLC (petroleum ether / ethyl acetate = 8 / 1) to afford product 19 as a colorless oil (69% yield, 85% ee).

[0222] 1 H NMR (400MHz, CDCl3): δ7.35-7.25(m,5H),3.75(s,3H),3.68(s,3H),3.37(d,J=7.0Hz,1H),3.07(dd ,J=9.8,2.9Hz,1H),2.36(dd,J=7.0,2.9Hz,1H),2.28(dd,J=9.8,1.9Hz,1H),2.22(d,J=1.9Hz,1H); 13 C NMR (100MHz, CDCl3): δ169.86,168.97,137.05,128.29,127.46,126.52,63.94,52.90,51.97,51.67,48.71,46.30,40.23.HRMS(ESI)m / z:[M+H] + calcd.for C 15 H 17 O4,261.1121;found,261.1121.

[0223] Example 53: Synthesis of Compound 20

[0224]

[0225] 5f (0.1 mmol, 1.0 equiv), ethinyl progesterone (0.15 mmol, 1.5 equiv), Pd(PPh3)2Cl2 (10 mol%), and CuI (20 mol%) were added to a dry 10 mL Schlenk tube. The tube was evacuated and filled with argon (repeated three times). Subsequently, anhydrous Et3N (0.8 mL) and THF (0.8 mL) were added under argon. The tube was sealed, and the reaction mixture was heated to 75°C. After 18 hours, TLC analysis showed near-complete consumption of 5f. The reaction mixture was filtered through a short silica gel column, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (eluent: CH2Cl2 / MeOH = 35 / 1) to afford product 20 as a colorless oil (55% yield).

[0226] 1 H NMR (400MHz, CD2Cl2): δ7.36 (d, J = 8.1Hz, 2H), 7.21-7.16 (m, 3H), 7.13-7.10 (m, 2H), 7. 01-6.99(m,2H),5.66(d,J=1.7Hz,1H),3.94(d,J=6.7Hz,1H),3.72(s,3H),2.71(dd,J=9 .6,2.7Hz,1H),2.42-2.23(m,9H),2.08-2.00(m,2H),1.86-1.82(m,1H),1.76-1.62(m, 5H),1.59-1.52(m,2H),1.46-1.34(m,2H),1.18(s,3H),1.07-0.94(m,2H),0.91(s,3H). 13 C NMR (100MHz, CD2Cl2): δ199.46,199.44,171.60,171.58,170.36,139.03,137.71,1 31.87,128.88,128.36,127.10,126.91,124.01,121.98,93.58,85.83,80.35,67.6 2,54.16,53.93,52.08,50.62,47.55,47.05,45.46,40.78,39.42,39.01,36.64,36 .09,34.33,33.22,33.13,31.97,23.51,21.17,17.63,13.03.HRMS(ESI)m / z:[M+H] + calcd.for C 40 H 45 O4,589.3312;found,589.3296.

[0227] Example 54: Synthesis of Compound 21

[0228]

[0229] 5s (17.9 mg, 0.05 mmol, 1.0 eq), apixaban (27.6 mg, 0.06 mmol, 1.2 eq), Pd2(dba)3 (2.5 mg, 5 mol%), Cs2CO3 (22.7 mg, 0.07 mmol, 1.4 eq), and xantphos (2.9 mg, 0.1 eq) were added to a dry 10 mL Schlenk tube. The tube was evacuated and filled with argon three times. Anhydrous 1,4-dioxane (0.5 mL) was added to the solids and the mixture was operated under an argon atmosphere.

[0230] The reaction was then heated to 100°C. After 12 hours, the mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation. The residue was purified by preparative thin-layer chromatography (CH2Cl2 / MeOH = 30 / 1) to afford the product (95% yield) as a white solid.

[0231] HRMS(ESI)m / z:[M+H] + calcd.for C 44 H 42 N5O6,736.3130; found,736.3111.

[0232] Example 55: Synthesis of Compound 5ag

[0233]

[0234] 1k (971 mg, 5.0 mmol, 1.0 eq) and 2s (2.19 g, 1.6 eq) were added to a dry 250 mL round-bottom flask and dissolved in THF (50 mL) and CHCl₃ (50 mL). The solution was cooled to -30°C, and a THF solution (400 μL) containing (R)-C11 (143 mg, 3 mol%) was added. The reaction was stirred at -30°C for 12 hours. After completion, the reaction was quenched with saturated aqueous NaHCO₃ and extracted with EtOAc. The extract was dried over Na₂SO₄, concentrated under vacuum, and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to afford product 3ag as a white solid (82% yield, 95% ee).

[0235]

[0236] To a 250 mL round-bottom flask, oven-dried and equipped with a Teflon-coated magnetic stir bar, was added 3ag (1.64 g, 3.5 mmol, 1.0 equiv) and anhydrous CH2Cl2 (105 mL). Et3N (2.43 mL, 5.0 equiv) and TMSOTf (1.9 mL, 10.5 mmol, 3.0 equiv) were added sequentially at 0°C under a positive pressure of argon. After stirring for 5 hours, the reaction was quenched with aqueous NaHCO3 and subsequently extracted with CH2Cl2. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to yield the crude product, which was used directly in the next reaction without further purification.

[0237] Under normal atmospheric conditions, the crude product was dissolved in MeOH (0.15 M, 23.5 mL). NH3·H2O (25% aqueous solution, 2.6 mL, 35 mmol, 10.0 equiv) and PIDA (3.38 g, 10.5 mmol, 3.0 equiv) were subsequently added. After stirring at 40°C for 3 hours, NH3·H2O (10.0 equiv) and PIDA (3.0 equiv) were added again, and stirring was continued for 2 hours. The solvent was removed by evaporation, and water was added, followed by extraction with EtOAc. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation. Purification by silica gel column chromatography (eluent: CH2Cl2 / MeOH = 30 / 1) afforded the product 5ag (38% yield, 90% ee) as a colorless oil.

[0238] 1 H NMR (400MHz, CDCl3): δ7.52(d,J=8.1Hz,2H),7.30-7.27(m,2H),7.24(dd,J=5.1,1.2Hz,1H),6.97(dd,J=5.1,3.4Hz,1H),6.81(dd, J=3.4,1.2Hz,1H),3.96(d,J=6.8Hz,1H),3.77(s,3H),2.76(dd,J=9.5,2.8Hz,1H),2.48(dd,J=9.6,1.8Hz,1H),2.44-2.42(m,2H); 19 F NMR (376MHz, CDCl3): δ-62.51; 13 C NMR (100MHz, CDCl3): δ169.61, 141.19, 141.07, 128.93 (q, J = 32.3Hz), 128.91, 127.17, 125.38, 125.11, 12 4.98(q,J=3.9Hz),124.21(q,J=272.0Hz),67.87,55.05,51.92,49.13,41.80,41.17.HRMS(ESI)m / z:[M+H] + calcd.for C 18 H 16 F3O2S,353.0818; found,353.0810.

[0239] Example 56: Synthesis of Compound 22

[0240]

[0241] 5ag (245 mg, 0.7 mmol, 1.0 equivalent) was dissolved in a mixture of CCl₄ (7 mL) and acetonitrile (7 mL). NaIO₄ (7.0 mmol, 10.0 equivalents in 10 mL of H₂O) and RuCl₃ (0.035 mmol, 0.05 equivalents in 1.4 mL of H₂O) were then added, and the reaction mixture was stirred vigorously at room temperature for 2 hours. After adding 1 M HCl and mixing thoroughly, the reaction product was extracted with CHCl₂. The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated by rotary evaporation. The crude product was used directly in the next reaction without further purification.

[0242] The resulting acid was dissolved in 25 mL of CH2Cl2 along with N-hydroxyphthalimide (0.77 mmol, 1.1 equivalents) and DMAP (8.5 mg, 0.07 mmol, 0.1 equivalents). N,N'-dicyclohexylcarbodiimide (0.77 mmol, 1.1 equivalents) was then added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through a celite pad and the filtrate was concentrated by rotary evaporation. The residue was purified by column chromatography (petroleum ether / ethyl acetate)

[0243] =10 / 1) to obtain the target product 22 (56% yield, 90% ee).

[0244] 1 H NMR (400MHz, CDCl3): δ7.92-7.88(m,2H),7.82-7.78(m,2H),7.64(d,J=8.2Hz,2H),7.56(d,J=8.8Hz,2H),4.2 6(d,J=6.7Hz,1H),3.78(s,3H),2.84(dd,J=10.1,3.2Hz,1H),2.68-2.64(m,2H),2.60(dd,J=6.8,3.2Hz,1H). 19 F NMR (376 MHz, CDCl3): δ-62.60. 13 CNMR (100MHz, CDCl3): δ168.30, 164.20, 161.64, 139.19 (d, J = 1.5Hz), 134.90, 129.63 (q, J = 32.6Hz), 128.92, 128.82, 125.41(q,J=3.7Hz),124.09(q,J=272.1Hz),124.06,67.77,53.02,52.21,48.77,41.98,38.90.HRMS(ESI)m / z:[M+Na] + calcd.for C 23H 16 F3NO6Na,482.0822; found,482.0807.

[0245] Example 57: Synthesis of Compound 23

[0246]

[0247] Redox-active ester 22 (0.4 mmol, 1.0 equivalent) and Hantzsch ester (CAS: 1149-23-1, 152 mg, 0.6 mmol, 1.5 equivalent) were placed in a clear Schlenk reaction tube equipped with a stirrer. The tube was evacuated and filled with argon (repeated three times). Under argon protection, anhydrous DMA (4.8 mL) was added to the solid via syringe. The reaction mixture was stirred under illumination with a blue LED (6 W, 455-460 nm) while maintaining room temperature with a cooling fan. The reaction was allowed to proceed for 3 hours.

[0248] After the reaction, the product was quenched with saturated NaCl solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous NaSO and the solvent removed by rotary evaporation. The residue was purified by preparative thin-layer chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to afford the desired product 23 (yield 69%) as a colorless oil.

[0249] 1 H NMR (400MHz, CDCl3): δ7.57(d,J=8.0Hz,2H),7.37(d,J=7.7Hz,2H),3.75(d,J=6.8Hz,1H),3. 72(s,3H),2.81(s,1H),2.36(dd,J=9.6,3.0Hz,1H),2.19(d,J=2.0Hz,1H),2.19-2.13(m,2H). 19 F NMR (376 MHz, CDCl3): δ-62.46. 13 C NMR (100MHz, CDCl3): δ169.37, 142.65, 128.82, 128.77 (q, J = 32.3Hz), 125.01 (q, J = 3.8Hz ),124.28(d,J=271.8Hz),64.58,51.70,49.81,47.80,45.68,31.02.HRMS(ESI)m / z:[M+H] + calcd.forC 14 H 14 F3O2,271.0940; found,271.0934.

[0250] Example 58: Synthesis of Compound 25

[0251]

[0252] A 10 mL round-bottom flask equipped with a stirrer was charged with 23 (0.274 mmol, 1.0 equivalent) and LiOH (0.55 mmol, 2.0 equivalent). The solid was dissolved in a THF / water mixture (6.0 mL, 1:1 volume ratio) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in water, adjusted to a pH of 4-6 with HCl (1.0 M), and then extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, concentrated under reduced pressure, and used directly in the next reaction without further purification.

[0253] The crude product was dissolved, and 4-amino-1-Boc-piperidine (0.34 mmol, 1.2 equivalents), HATU (129 mg, 0.34 mmol, 1.2 equivalents), and dry DMF (4.0 mL) were added sequentially. DIPEA (146 μL, 0.84 mmol, 3.0 equivalents) was then added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over Na₂SO₄, filtered, and concentrated by rotary evaporation. The residue was purified by column chromatography to afford compound 25 as a white solid (93% yield, 90% ee).

[0254] 1 H NMR (400MHz, CDCl3): δ7.55(d,J=8.0Hz,2H),7.34(d,J=8.7Hz,2H),5.29(d,J =8.2Hz,1H),4.08-3.88(m,3H),3.72(d,J=6.8Hz,1H),2.86-2.79(m,3H),2.2 6(dd,J=9.6,2.6Hz,1H),2.15(dd,J=9.6,2.0Hz,1H),2.08(d,J=2.0Hz,1H),2 .01(dd,J=6.8,2.7Hz,1H),1.90-1.85(m,2H),1.43(s,9H),1.31-1.19(m,2H). 19 F NMR (376 MHz, CDCl3): δ-62.43. 13C NMR (100MHz, CDCl3): δ168.30, 154.73, 142.75, 128.94 (d, J = 32.4Hz), 128.89, 125.14 (q, J = 3.8Hz), 124.31 ( d, J=271.9Hz),79.80,64.49,49.15,47.67,46.73,46.70,42.76,32.15,29.93,28.47.HRMS(ESI)m / z:[M+Na] + calcd.for C 23 H 29 F3N2O3Na,461.2022; found,461.2009.

[0255] Example 59: Synthesis of Compound 27

[0256]

[0257] TFA (1.5 mL) was added dropwise to a stirred solution of compound 25 (0.25 mmol) in DCM (8 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed by evaporation to afford the crude ammonium salt, which was used directly in the next reaction.

[0258] The crude ammonium salt was dissolved in MeCN (4 mL), and 9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide (compound 26, 0.275 mmol, 1.1 equiv) and Et3N (175 μL, 1.25 mmol, 5.0 equiv) were added. The mixture was heated to 50°C and stirred at this temperature for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to provide compound 27 as a white solid (85% yield, 90% ee).

[0259] 1H NMR (600MHz, CDCl3): δ7.76(d,J=7.6Hz,2H),7.51(t,J=6.8Hz,4H),7.45(t,J=7.5Hz,2H),7.37(t,J=7.5Hz,2H) ,7.31(d,J=7.9Hz,2H),6.09(d,J=8.4Hz,1H),5.36(t,J=6.5Hz,1H),3.96(tdt,J=12.2,8.5,4.3Hz,1H),3.72-3. 65(m,3H),3.28(d,J=11.9Hz,2H),2.81(s,1H),2.59-2.56(m,2H),2.51-2.47(m,2H),2.42-2.39(m,2H),2.25(dd ,J=9.7,2.9Hz,1H),2.14-2.01(m,5H),1.97-1.91(m,2H),1.61(td,J=11.7,10.0,5.8Hz,2H),0.77-0.71(m,2H). 19 F NMR (565MHz, CDCl3): δ-65.00,-75.38. 13 C NMR (150MHz, CDCl3): δ173.09,168.71,144.63,142.68,140.88,128.83,128.76,12 8.71(d,J=35.1Hz),128.30,124.97(q,J=3.7Hz),124.19(q,J=271.9Hz),124.17,1 23.74(q,J=278.8Hz),120.55,64.29,62.02,56.98,51.85,49.25,47.36,46.67,44 .32,40.68(q,J=34.5Hz),35.52,29.95,29.07,24.11,21.26.HRMS(ESI)m / z:[M+H] + calcd.for C 38 H 40 F6N3O2,684.3019; found,684.3007.

[0260] Example 60: Observation of 1,3-radical migration

[0261]

[0262] 3af (0.4 mmol, 1.0 equiv) and anhydrous CH2Cl2 (16.0 mL) were added to a dry 25 mL Schlenk reaction tube equipped with a Teflon magnetic stirrer. TMSOTf (98 mg, 0.44 mmol, 1.1 equiv) was added at 0°C under a positive argon atmosphere. After stirring for 3 hours, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated to yield the crude product, which was used in the next step without further purification.

[0263] The crude product was dissolved in CD3OD (0.15 M, 2.67 mL) at room temperature and pressure. NH3·H2O (25% aqueous solution, 0.3 mL, 4.0 mmol, 10.0 equiv) and PIDA (386 mg, 1.20 mmol, 3.0 equiv) were added sequentially. The reaction was stirred at 40°C for 12 hours. After evaporation of the solvent, the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 20 / 1) to afford products 31 (19% yield) and 32 (10% yield).

[0264] NMR data of compound 31: 1 H NMR (400MHz, CDCl3): δ7.38-7.35(m,2H),7.31-7.27(m,4H),7.25-7.18(m,4H),6.64-6.55(m,2H),3.70(s,3H),3 .44(ddd,J=6.9,5.6,1.6Hz,1H), 3.04(dd,J=10.1,2.9Hz,1H), 2.36(dd,J=6.6,2.9Hz,1H), 2.29(d,J=8.7Hz,2H). 13 C NMR (100MHz, CDCl3): δ169.91,138.38,137.15,134.66,128.48,128.27,127.45,127.02, 126.37,126.28,124.17,67.99,52.91,51.73,47.94,46.19,41.22.HRMS(ESI)m / z:[M+H] + calcd.for C 21 H 21 O2,305.1536;found,305.1529.

[0265] NMR data of compound 32: 1H NMR (400MHz, CDCl3): δ7.18-7.05(m,6H),6.85(dd,J=8.9,2.3Hz,1H),6.73-6.71(m,2H),6.68-6.65(m,2H),5.91(dd,J=8.9,2. 8Hz,1H),3.86(t,J=2.5Hz,1H),3.74(s,3H),2.71(dd,J=7.8,0.9Hz,1H),2.49(ddd,J=7.7,5.2,2.1Hz,1H),2.41-2.36(m,2H). 13 C NMR (100MHz, CDCl3): δ174.07,146.72,140.18,136.34,129.45,128.52,127.77,127.32, 126.44,125.91,125.58,55.01,51.96,47.91,46.83,43.53,36.19.HRMS(ESI)m / z:[M+H] + calcd.for C 21 H 21 O2,305.1536;found,305.1531

[0266] Example 61: Synthesis of Compound 34

[0267]

[0268] At room temperature, 33 (0.2 mmol, 1.0 equiv) was dissolved in CD3OD (0.15 M, 1.34 mL). Ammonia (NH3·H2O, 25% aqueous solution, 150 μL, 2.0 mmol, 10.0 equiv) and PIDA (193 mg, 0.60 mmol, 3.0 equiv) were then added. The mixture was stirred at 40°C for 12 h.

[0269] After the reaction was completed, the solvent was removed by evaporation, and the residue was purified by silica gel column chromatography and preparative thin layer chromatography (developing solvent: petroleum ether / ethyl acetate = 20 / 1) to obtain the target product 34 as a colorless oil (40% yield, 85% ee).

[0270] 1H NMR (400MHz, CDCl3): δ7.28-7.16(m,7H),7.13-7.09(m,1H),6.90-6.88(m,2H),3.74(s,3H),2.96(dd,J=9.7,2.7Hz,1H),2.28-2.19(m,3H),2.1 4(dd,J=9.6,1.8Hz,1H), 1.68(dt,J=8.7,5.0Hz,1H), 1.39(tdd,J=8.3,5.6,4.5Hz,1H), 1.09(dt,J=8.6,5.2Hz,1H), 0.93(dt,J=8.6,5.3Hz,1H). 13 C NMR (100MHz, CDCl3): δ170.33,142.60,138.52,128.20,128.17,126.87,126.51,125.82,12 5.40,70.18,52.62,51.64,48.11,45.79,40.76,22.12,19.68,14.21.HRMS(ESI)m / z:[M+H] + calcd.for C 22 H 23 O2,319.1693;found,319.1691.

[0271] Example 62: Synthesis of Compound A:

[0272]

[0273] 3ah (2.0 mmol, 1.0 equiv) and LiOH (4.0 mmol, 2.0 equiv) were placed in a 10 mL round-bottom flask equipped with a stirrer. A THF / water mixture (20 mL, 1 / 1 volume ratio) was added for dissolution and stirred at room temperature for 5 hours. The mixture was then concentrated under reduced pressure, and the resulting residue was dissolved in water, adjusted to a pH of 4-6 with 1.0 M HCl, and extracted with ethyl acetate. The organic phase was dried over anhydrous NaSO and concentrated under vacuum. The resulting product was used directly in the next reaction without further purification.

[0274] The obtained acid (2.0 mmol, 1.0 equiv), N-hydroxyphthalimide (2.4 mmol, 1.2 equiv), and DMAP (24 mg, 0.2 mmol, 0.1 equiv) were dissolved in CHCl (40 mL) and the solution was placed in a dry 100 mL Schlenk tube. N,N'-dicyclohexylcarbodiimide (2.4 mmol, 1.2 equiv) was added and stirred at room temperature overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated by rotary evaporation. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain the desired product A as a white solid (88% yield, 91% ee).

[0275]

[0276] Compound A (1.0 mmol, 1.0 equiv) and Hantzsch ester (CAS: 1149-23-1, 380 mg, 1.5 mmol, 1.5 equiv) were added to a clear Schlenk tube equipped with a stirrer. The tube was evacuated and then filled with argon three times. Under argon, anhydrous DMA (8.0 mL) was added to the solids using a sealed syringe. The reaction mixture was stirred for 4 hours under irradiation with a blue LED (6 W, 455-460 nm) while maintaining room temperature with a cooling fan. The reaction was then quenched with saturated NaCl solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, the solvent removed by evaporation, and the residue purified by preparative thin-layer chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to afford the desired product B as a colorless oil (58% yield, 91% ee).

[0277] 1 H NMR (400MHz, CDCl3): δ7.45-7.43(m,2H),7.32(t,J=7.6Hz,2H),7.25-7.19(m,3H),7.1 3(d,J=7.9Hz,2H),6.73(dd,J=15.9,1.2Hz,1H),6.40(dd,J=15.8,6.3Hz,1H),4.53(dd ,J=6.3,1.4Hz,1H),2.74(td,J=3.1,1.3Hz,1H),2.34-2.30(m,4H),2.24(dd,J=10.3,7 .5Hz,1H),1.91(dd,J=10.2,7.2Hz,1H),1.81(ddd,J=7.5,3.2,1.2Hz,1H),1.14(s,9H). 13C NMR (100MHz, CDCl3): δ157.54,137.17,137.06,136.37,131.89,129.66,128.47,127.37,12 6.48,126.23,79.06,74.00,65.14,43.54,42.50,39.30,28.02,21.18.HRMS(ESI)m / z:[M+H] + calcd.for C 25 H 30 NO2,376.2271; found,376.2252.

[0278] Example 63: Synthesis of Compound 35

[0279]

[0280] Compound B (0.45 mmol) was dissolved in CHCl (15.0 mL) and stirred at -78°C while an O stream was introduced via pipette for 15 minutes. Residual O was removed by nitrogen purging for 5 minutes. Dimethyl sulfide (2 drops) was added and stirred at 0°C for 1 hour. The reaction was then quenched with saturated NaCl solution, extracted with CHCl, and the organic layers were combined and dried over NaSO. The solvent was removed under reduced pressure. The resulting crude aldehyde was dissolved in tetrahydrofuran (9.0 mL) and tert-butanol (9.0 mL), followed by the addition of 2-methyl-2-butene (0.76 mL, 7.2 mmol, 16.0 equiv) and the reaction was allowed to react at room temperature. Subsequently, NaClO (80%, 303 mg, 2.7 mmol, 6.0 equiv) and NaHPO (2.7 mmol, 6.0 equiv) in H2O (3.0 mL) were added dropwise. After stirring for 5 hours, the reaction was concentrated. The residue was dissolved in EtOAc and acidified to pH ≈ 3 with 1 M HCl. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and used in the next step without further purification. The acidic product was dissolved in CH2Cl2 / MeOH (4.5 mL / 0.5 mL), and TMSCH2N2 (2 M in hexane, 0.75 mL, 1.5 mmol, 3.3 equiv) was added at 0°C. The reaction was stirred for 10 minutes. After evaporation of the solvent, the product was purified by preparative thin-layer chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to afford the desired product 35 as a colorless oil (84% yield over three steps).

[0281] 1H NMR (400MHz, CDCl3): δ7.19(d,J=8.1Hz,2H),7.12(d,J=8.3Hz,2H),4.43(d,J=1.2Hz,1H),3.78(s,3H),2.95(td,J=3.0,1.4Hz,1H),2.40 (dd,J=10.4,7.6Hz,1H),2.32(s,3H),2.27(dd,J=7.3,3.1Hz,1H),1.96(dd,J=10.4,7.3Hz,1H),1.85(dd,J=7.6,3.0Hz,1H),1.10(s,9H). 13 C NMR (100MHz, CDCl3): δ171.88,155.51,136.72,135.41,128.32,126.48,79.30 ,74.02,63.20,51.93,44.09,42.43,38.50,27.78,21.07.HRMS(ESI)m / z:[M+H] + calcd.for C 19 H 25 NO4Na,354.1676; found,354.1671.

[0282] Example 64: Synthesis of Compound 36

[0283]

[0284] Compound 35 (0.38 mmol, 1.0 equiv) and anhydrous CH2Cl2 (10 mL) were added to a dry 25 mL Schlenk tube with a Teflon-coated magnetic stir bar. Subsequently, Et3N (260 μL, 1.9 mmol, 5.0 equiv) and TMSOTf (210 μL, 1.14 mmol, 3.0 equiv) were added and the reaction was allowed to proceed at 0°C under a positive pressure of argon. After stirring for 5 hours, the reaction was quenched with saturated NaHCO3 solution and extracted with CH2Cl2. The combined organic layers were washed with brine, dried, and then concentrated with Na2SO4 to afford the crude product without further purification. The crude product was dissolved in CD3OD (0.15 M, 2.5 mL), and NH3·H2O (25% aqueous solution, 285 μL, 3.8 mmol, 10.0 equiv) and PIDA (366 mg, 1.14 mmol, 3.0 equiv) were added at room temperature. The mixture was stirred at 40°C for 5 hours. After evaporation of the solvent, the residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 20 / 1) to give product 36 (8% yield, 61% ee), the Z isomer (2% yield), and the E isomer (10% yield) of 37.

[0285] NMR data of compound 36: 1 H NMR (600MHz, CDCl3): δ7.17(d,J=8.5Hz,2H),7.12(d,J=7.7Hz,2H),3.66(d,J=1.5Hz,3H),3.10(d,J=7.1Hz,1H),2.86(d,J=1.4H z,1H),2.78(dd,J=10.0,2.8Hz,1H),2.33(s,3H),2.08(dd,J=7.2,2.8Hz,1H),2.00(dt,J=9.8,1.8Hz,1H),1.94(d,J=2.2Hz,1H). 13 C NMR (150MHz, CDCl3): δ171.76,136.49,135.98,128.77,126.32,63.29,51.28,50.74,49.95,48.22,30.49,21.12.HRMS(ESI)m / z:[M+H] + calcd.for C 14 H 17 O2,217.1223;found,217.1224.

[0286] NMR data of compound 37Z: 1 H NMR (400MHz, CDCl3): δ7.33(d,J=8.2Hz,2H),7.14(d,J=8.0Hz,2H),6.25(dt,J=11.5,7.1Hz,1H),5.83(dt,J =11.5,2.0Hz,1H),5.37(s,1H),5.07(d,J=1.4Hz,1H),3.89(dt,J=7.1,1.7Hz,2H),3.74(s,3H),2.34(s,3H). 13 C NMR (150MHz, CDCl3): δ166.79,148.03,145.52,137.48,137.36,129.05,125.94,119.94,112.68,51.15,34.79,21.08.HRMS(ESI)m / z:[M+H] + calcd.for C 14 H 17 O2,217.1223;found,217.1223.

[0287] NMR data of compound 37E: 1H NMR (600MHz, CDCl3): δ7.30(d,J=8.1Hz,2H),7.14(d,J=7.8Hz,2H),7.05(dt,J=15.6,6.7Hz,1H),5.89( dt,J=15.6,1.7Hz,1H),5.44(s,1H),5.06(s,1H),3.70(s,3H),3.37(dt,J=6.6,1.5Hz,2H),2.34(s,3H). 13 C NMR (150MHz, CDCl3): δ166.87,146.71,144.06,137.58,137.07,129.10,125.71,122.41,113.66,51.43,37.85,21.06.HRMS(ESI)m / z:[M+H] + calcd.for C 14 H 17 O2,217.1223;found,217.1223.

[0288] The above description is only a preferred embodiment of the present application and is not intended to limit the scope of protection of the present application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application are included in the scope of protection of the present application.

Claims

1. A chiral bicyclo[1.1.1]pentane derivative of formula BCP, or a deuterated derivative thereof, The R 5 Selected from hydrogen, ester, carboxyl, acyl, amino, sulfonyl, borate, thioalkyl, alkylhydroxy, alkylester, alkylacylaryl, acylaryl, acylamino, acylalkyl, alkyl, aryl; The R 6 is selected from monocyclic aryl, hydrogen, ester, alkyl, alkenyl, cycloalkyl, monocyclic heterocyclic; The R 7 is selected from monocyclic aromatic groups, condensed aromatic groups, hydrogen, ester groups, and monocyclic heterocyclic groups; The carbon atoms marked with * are independently R-configuration, S-configuration, or achiral carbon atoms.

2. The chiral bicyclo[1.1.1]pentane derivative according to claim 1, characterized in that The R 5 Selected from -C(=O)OR d ,-C(=O)R e ,-NHR f , -SR g , -S(=O)2R ga Any one of the R d Selected from alkyl, monocyclic aryl, said R e Selected from alkyl, aryl, amino, the R f Selected from amino protecting groups, hydrogen, said R g Selected from alkyl, monocyclic aryl, said R ga is selected from monocyclic aromatic groups; The R 6 Selected from The Ar is selected from a monocyclic aromatic group, a condensed aromatic group, a cycloalkyl group, a thienyl group, a furyl group, and the R h is selected from substituted or unsubstituted alkyl, hydrogen, amino, ester, nitro, alkoxy, cyano, halogen, wherein the hydrogen on the amino group is replaced by Substituted, said p is selected from any positive integer from 1 to 5, or said R 6 Selected from -C(=O)OR j , the R j Selected from linear or branched alkyl, or, said R 6 Selected from C1 to C6 straight chain alkyl or C2 to C6 branched chain alkenyl, said R 6 Any hydrogen atom is replaced by a monocyclic aromatic group; The R7 is selected from -C(=O)OR l , the R k Selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted monocyclic aromatic group, halogen, ester group, alkoxy group, The q is selected from any positive integer from 1 to 5, the R l Selected from 3. The chiral bicyclo[1.1.1]pentane derivative according to claim 2, characterized in that The R d is selected from C1 to C4 straight or branched alkyl, benzyl, monocyclic aromatic group, said R e Selected from The R g is selected from monocyclic aromatic groups, wherein R g Any hydrogen atom is replaced by a halogen atom; The R h is selected from C1 to C4 alkyl, said R h Any hydrogen atom is replaced by a halogen atom; The R j Selected from C1 to C4 straight or branched chain alkyl; The R k Selected from C1 to C4 straight or branched chain alkyl, halogen, and hydrogen.

4. A chiral bicyclo[1.1.1]pentane derivative, specifically:

5. A method for synthesizing a chiral bicyclo[1.1.1]pentane derivative, comprising: The compound of formula BCH is mixed with an organic solvent, the temperature is controlled, TMSOTf is added, the organic phase is separated, the organic phase is dissolved in alcohol, a base and PIDA are added to obtain a compound of formula BCP; The R 1 、R 2 、R 3 、R 4 As defined in any one of claims 1 to 5; The carbon atoms marked with * are independently R-configuration, S-configuration, or achiral carbon atoms.

6. A synthesis of compound 22, comprising: S1: Dissolve 5ag in an organic solvent, then add NaIO4, RuCl3, acid, and extract the organic phase. S2: The organic phase, NHPI and DMAP were dissolved in an organic solvent, and then DCC was added to react to obtain compound 22.

7. A synthesis of compound 23, comprising: Compound 22 and Hantzsch ester were mixed, and DMA was added under the protection of inert gas to obtain a mixture. The mixture was irradiated with 55-460 nm light and the temperature was controlled to react to obtain compound 23.

8. A synthesis of compound 25, comprising: Compound 23 and LiOH were mixed, and the solid was dissolved in a mixed solution of a first organic solvent and water for reaction. After concentration, 4-amino-1-Boc-piperidine, HATU and a second organic solvent were added, followed by DIPEA to react and obtain compound 25.

9. Synthesis of Compound 27, TFA and compound 25 are dissolved in an organic solution, reacted, and concentrated to obtain a salt. The salt is dissolved in an organic solvent, and compound 26 and a base are added to react under temperature control to obtain compound 27.

10. Synthesis of Compound 20, 5f, ethinyl progesterone, Pd(PPh3)2Cl2 and CuI were mixed, and a base and an organic solvent were added under an inert atmosphere. The reaction was carried out under temperature control to obtain compound 20.

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