Chiral azabicyclo [2.1. 1] hexane derivative intermediate and preparation method thereof

Abstract

The invention relates to the technical field of organic chemistry, and particularly discloses a chiral azabicyclo [2.1. 1] hexane derivative intermediate and a preparation method thereof.The chiral azabicyclo [2.1. 1] hexane derivative (BCH) can be used for synthesizing a chiral bicyclo [1.1. 1] pentane (BCP) derivative, the yield and chiral conversion rate of the preparation method are high, and the method is suitable for industrial production. According to the method for synthesizing the bicyclo [1.1. 1] pentane through a nitrogen atom insertion and deletion strategy, the reaction path has good stereoselectivity, the chirality is maintained, and the synthesized chiral bicyclo [1.1. 1] pentane (BCP) derivative is a bicyclic hydrocarbon substituted aromatic ring rich in C (sp3), is called as bioisostere substitution, has wide application research in modern medicine function research, and has broad application prospects. In a plurality of literatures, the chiral bicyclo [1.1. 1] pentane (BCP) can be coupled with a plurality of drugs, and the drug effect, the pharmacokinetic property and the water solubility can be remarkably improved.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemistry, and specifically discloses a chiral azabicyclo[2.1.1]hexane derivative intermediate and a preparation method thereof. Background Art

[0002] With greater three-dimensional rigidity C(sp 3 )-based ring systems are gaining increasing attention as scaffolds and drug derivatives in medicinal chemistry. Incorporating these unique, more complex topological structures into drug molecules often improves the pharmaceutical properties of the final molecules, including solubility, lipophilicity, and metabolic stability. Azabicyclo[2.1.1]hexane derivatives have promising applications as alternative intermediates for synthesizing these spatially structured compounds, such as in the synthesis of bicyclo[1.1.1]pentanes for drug conjugation. However, existing synthetic processes encounter many challenges. As drug scaffolds, both yield and chirality preservation must be considered during the synthetic route. For example, the paper "Beyond Bioisosteres: Divergent Synthesis of Azabicyclohexanes and Cyclobutenyl Amines from Bicyclobutanes" suggests that obtaining more refined bicyclic structures, especially heterocyclic variants, remains difficult. There is a lack of synthetic methods that can achieve higher yields and better chirality preservation while being adaptable to a wider range of structural substrates. Another example is "1,2-Difunctionalized bicyclo[1.1.1]pentanes: Long–sought-after mimetics for The article "Ortho / meta-substituted arenes" proposes the coupling of tolvaptan, phthalylsulfathiazole, lomitapide, and telmisartan. Bicyclo[1.1.1]pentane coupling compounds of different chirality have different property data. How to maintain chirality in the synthetic route has research prospects. Summary of the Invention

[0003] In a first aspect, the present invention provides a chiral azabicyclo[2.1.1]hexane derivative as shown in formula BCH, or an isotope-labeled product thereof:

[0004]

[0005] The R 1 is selected from ester, acylaryl, hydrogen, and sulfonyl;

[0006] The R 2and R 3 Each is selected from alkyl, alkenyl, monocyclic aromatic, cycloalkyl, condensed aromatic, heterocyclic, cycloalkyl, and ester groups;

[0007] The R 4 is selected from an amino protecting group, hydrogen;

[0008] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

[0009] In some specific embodiments of the first aspect, the R 2 and R 3 Each monocyclic aromatic group, the monocyclic aromatic group structure is as follows: The R a is selected from hydrogen, C1 to C4 alkyl, halogen, alkoxy, nitro, cyano, ester, monocyclic aromatic, thienyl, furyl, wherein n is selected from any positive integer from 1 to 5, and R a Any hydrogen is replaced by a halogen,

[0010] or,

[0011] The R 2 and R 3 Each is selected from C3 to C6 cycloalkyl, any hydrogen on the cycloalkyl is replaced by an aryl group, and the carbon on the cycloalkyl is independently R-configuration, S-configuration or an achiral carbon atom.

[0012] In some specific embodiments of the first aspect, the R 2 Selected from alkyl, alkenyl, said R 2 Any hydrogen atom is replaced by an aryl group.

[0013] In some specific embodiments of the first aspect, the R 1 Selected from -C(=O)R b or -S(=O)2R c , the R b is selected from substituted or unsubstituted C1-C6 alkyl, monocyclic aryl, said R c is selected from substituted or unsubstituted monocyclic aromatic groups,

[0014] or,

[0015] The R 1 Selected from ester groups, the ester group structure is such as -C(=O)OR d , the R d Selected from C1-C6 alkyl, monocyclic aromatic group, condensed heterocyclic group.

[0016] In some specific embodiments of the first aspect, the R d is selected from fused heterocyclic groups, wherein R d Structure such as

[0017] For more detailed technical solutions, please refer to the specific embodiments.

[0018] In the present invention, BCB is as follows 1a to 1o:

[0019]

[0020] The imine compounds of the present invention are as follows: 2a to 2s

[0021]

[0022] The BCH compounds of the present invention are as follows: 3a~3z, 3aa~3ae

[0023]

[0024]

[0025] PIDA in the present invention is iodophenyl diacetic acid CAS: 3240-34-4;

[0026] The term "cycloalkyl" refers to a saturated monocyclic ring group consisting only of carbon atoms with a specified number of carbon atoms (e.g., C3 to C10), including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0027] The term "acylaryl" refers to a structure such as -C(=O)R x , where R x is a monocyclic aromatic group or a condensed-ring aromatic group, a non-limiting example of which is -C(=O)Ph.

[0028] The term "alkyl" refers to a group of formula C n H 2n+1 wherein n is a number greater than or equal to 1, and the alkyl group may be linear or branched. Non-limiting examples include methyl, ethyl, n-butyl, and tert-butyl.

[0029] The term "alkenyl" refers to an unsaturated hydrocarbon group, which may be linear or branched, containing one or more carbon-carbon double bonds. Suitable alkenyl groups contain 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and more preferably 2 to 3 carbon atoms. Non-limiting exemplary alkenyl groups include vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and isomers thereof, 2-hexenyl and isomers thereof, 2,4-pentadienyl, and the like.

[0030] The drugs used in the present invention are purchased from the open legal market and have not been further purified.

[0031] Advantages of the present invention:

[0032] The present invention provides an azabicyclo[2.1.1]hexane derivative intermediate and a preparation method. The method can obtain a chiral azabicyclo[2.1.1]hexane derivative with high selectivity through the catalytic action of (R)-11. The chirality of the compound can be well maintained during the synthesis route. As one of the candidate uses, a chiral azabicyclo[2.1.1]hexane derivative (BCH) can be used as an intermediate to efficiently synthesize a chiral bicyclo[1.1.1]pentane derivative (BCP) by deleting or adding nitrogen atoms. Through this route, a benzene ring bioisostere is ultimately obtained, which can be coupled with multiple drugs and used for drug modification to change the properties of the drug. DETAILED DESCRIPTION

[0033] The present invention will be further described in detail below with reference to specific embodiments. The described specific embodiments are merely intended to illustrate the present invention and are not intended to limit the present invention.

[0034] Example 1: Synthesis of Compound 1i

[0035]

[0036] To a solution of 1-bromo-3,5-dimethylbenzene (66 mmol, 2.2 equivalents) in dry THF (100 mL) was slowly added dropwise, under argon, at -78°C. The mixture was stirred at -78°C for 1 hour, after which 3-oxocyclobutane-1-carboxylic acid 1i-a (30 mmol, 1.0 equivalents) dissolved in dry THF (10 mL) was added all at once, and the temperature was slowly raised to 25°C. After stirring for 1 hour, the mixture was quenched with saturated NH4Cl solution. The organic layer was separated, and the aqueous phase was acidified with 1.0 M hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product 1i-b was used directly in the next step without purification. 1i-b was dissolved in toluene (80 mL), followed by the addition of concentrated hydrochloric acid (80 mL). The resulting mixture was stirred at room temperature for 12 hours. The organic phase was separated, washed with water and saturated brine, and concentrated under reduced pressure to obtain compound 1i-c. The crude product was used directly in the next reaction without purification.

[0037] 1i-c (20 mmol, 1.0 equiv) was dissolved in dichloromethane (CH2Cl2, 40 mL, 0.5 M) and magnetically stirred under argon. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 30 mmol, 1.5 equiv), methanol (30 mmol, 1.5 equiv), and 4-dimethylaminopyridine (DMAP, 4 mmol, 0.2 equiv) were added. The mixture was stirred for 3 hours. Dichloromethane (20 mL) was then added to the mixture, and the reaction was quenched with saturated aqueous ammonium chloride (NH4Cl). The reaction mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate (Na2SO4). The solvent was removed by rotary evaporation to yield 1i-d, which was a crude product without further purification.

[0038] 1i-d (20 mmol, 1.0 equiv) was added to a 250 mL reaction flask and dissolved in 100 mL of tetrahydrofuran (THF) under argon. Potassium hexamethyldisilazane (KHMDS, 24 mmol, 1.2 equiv) was added dropwise at 0°C and stirred for 30 minutes, then at room temperature for another hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (NH4Cl). The organic layer was extracted with ethyl acetate (EtOAc), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated under vacuum. The crude product was purified by silica gel column chromatography to yield 1i as a colorless solid.

[0039] Example 2: Synthesis of Compound 1k

[0040]

[0041] Titanium tetrachloride (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 (52.2 mmol, 6.0 equiv) in dry acetonitrile (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 (3 x 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to afford the product 1k-b as a colorless oil (yield 78%).

[0042] 1H NMR (400MHz, CDCl3) δ7.86-7.80(m,2H),7.52-7.44(m,1H),7.34(dd,J=8.4,7.2Hz,2H),7.08(dd,J=5.1,1.2Hz,1H),6.95(dd,J=3.7 ,1.2Hz,1H),6.88(dd,J=5.1,3.6Hz,1H),5.29(s,1H),4.91(d,J=1.3Hz,1H),4.60(t,J=7.2Hz,1H),3.56(s,3H),3.20-3.05(m,2H). 13 C NMR (100MHz, CDCl3): δ194.47,169.67,143.86,137.99,136.07,133.56,128.65,1 28.56,127.41,124.70,123.74,113.50,52.56,52.49,34.63.HRMS(ESI)m / z:[M+H] + calcd.forC 17 H 17 O3S,301.0893;found,301.0892

[0043] At 0°C, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.8 mL, 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 (40 mL). The reaction was monitored for residual starting material. Additional 4-acetamidobenzenesulfonyl azide (640 mg, 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 (3 x 30 mL) and extracted. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to afford product 1k-c as a yellow oil (yield 77%).

[0044] 1 H NMR (500MHz, CDCl3): δ7.20 (dd, J=5.1, 1.2Hz, 1H), 7.09 (dd, J=3.7, 1.2Hz, 1H), 6.98 (dd, J=5.1,3.6Hz,1H),5.51(s,1H),5.04(t,J=1.2Hz,1H),3.78(s,3H),3.48(d,J=1.2Hz,2H). 13C NMR(125MHz, CDCl3): δ167.26,143.01,136.43,127.54,124.94,124.26,113.13,55.12,51.99,29.30.HRMS(ESI)m / z:[M+H] + calcd.forC 10 H 11 N2O2S,223.0536; found,223.0534

[0045] Under argon, chloroform (CHCl₃, 8 mL) and Rh₂(Oct)₄ (0.42 mg, 0.1 mol%) were added to a dry 25 mL Schlenk reaction tube. Subsequently, the diazo compound 1k-c (1.0 mmol, 1.0 equiv) dissolved in chloroform (2 mL) was added dropwise via syringe over 30 minutes at room temperature. After the addition, the mixture was stirred for an additional 15 minutes. TLC analysis confirmed complete reaction of the diazo compound to yield 1k.

[0046] 1k NMR data: 1 H NMR (400MHz, CDCl3): δ7.13 (dd, J = 5.0, 1.4Hz, 1H), 7.00-6.90 (m, 2H), 3.54 (s, 4H), 2.89 (s, 1H), 1.74 (d, J = 1.3Hz, 2H). 13 C NMR(100MHz, CDCl3): δ169.51,137.22,127.47,125.14,124.19,51.88,38.11,30.49,23.44.HRMS(ESI)m / z:[M+H] + calcd.forC 10 H 11 O2S,195.0474; found,195.0473.

[0047] Example 3: Addition of N-phenylimine to 1a

[0048] Under the catalysis of chiral Brønsted acid, the addition reaction of N-phenylimine with BCB1a produced a mixture of azetidinyl (N-Ph-a) and cyclobutenylmethylamine (N-Ph-b).

[0049]

[0050] 1a (0.05mmol, 1.0 equivalent) and N-phenylimine (compound of formula 2-2, 0.1mmol, 2.0 equivalent) were dissolved in 1mL toluene solvent (0.05M), introduced into a dried 10mL reaction bottle, cooled to 0°C, and a reaction system was obtained. A toluene solution (50μL) 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 5mol%. Stirring was continued at the above temperature for 15 hours. After the reaction was completed, it was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. 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).

[0051] Table 1 Effect of different catalysts on yield and enantiomeric content

[0052] Entry Cat. YieldofN-Ph-a E.e.ofN-Ph-a YieldofN-Ph-b E.e.ofN-Ph-b 1 Cat.a 6％ N.D 9％ N.D 2 Cat.b 48％ 38％ 40％ 55％,dr>20:1 3 Cat.c 34％ 28％ 30％ 36％,dr>20:1 4 Cat.d 53％ 51％ 39％ 54％,dr>20:1

[0053] Example 4: Effect of different N-protecting groups R and catalyst types on activity and enantioselectivity

[0054]

[0055] 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 catalysts 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 mixture 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.

[0056] Table 2 Enantiomeric amounts of compound P under different R protecting groups and catalysts:

[0057]

[0058]

[0059] Example 5: Effect of different types of catalysts

[0060]

[0061] 1a (0.05 mmol, 1.0 equivalent) and 2a (0.1 mmol, 2.0 equivalent) were dissolved in 1 mL of toluene solvent (0.05 M), introduced into a dried 10 mL screw bottle, and cooled to 0°C to obtain a reaction system. A toluene solution (50 μL) containing the catalyst shown in Table 3 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 or 24 hours. After the reaction was completed, it was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. Dimethyl terephthalate was added as an internal standard, and the solvent was removed by evaporation to obtain Entry 1 to 11 in Table 3. 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).

[0062] Table 3

[0063] Entry Cat. Yieldof3a E.e.of3a Yieldof3-bp-1 Resultof3-bp-2 1 (R)-C2 37％ -37％ 16％ 10％,1:1dr 2 (R)-C3 48％ -79％ 19％ N.D 3 (R)-C4 59％ -83％ 11％ N.D 4 (R)-C5 73％ -80％ 4％ N.D 5 (R)-C6 49％ -80％ 10％ N.D 6 (S)-C7 5％ -63％ 21％ 38％,4.4:1dr 7 (S)-C8 5％ -68％ N.D N.D 8 (S)-C9 16％ -93％ 21％ 28％,1.5:1dr 9 (S)-C10 15％ -80％ 33％ N.D 10 (R)-C11 37％ 96％ 4％ 33％,1.6:1dr

[0064] Example 6: Synthesis reaction condition screening

[0065]

[0066] 1a (0.05 mmol, 1.0 equivalent) and 2a (0.1 mmol, 2.0 equivalent) were dissolved in 1 mL of the solvent (0.05 M) shown in Table 4, introduced into a dried 10 mL reaction bottle, and cooled to the temperature shown in Table 4 to obtain a reaction system. A mixture of catalyst (R)-C11 and the solvent shown in Table 4 (50 μL) was added to the reaction system, and the concentration of catalyst (R)-C11 in the reaction system was adjusted to 5 mol%, and stirring was continued at the above temperature for 15 hours or 24 hours. After the reaction was completed, it was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. Dimethyl terephthalate was added as an internal standard, and the solvent was removed by evaporation to obtain Entry 1 to 20 in Table 4. 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).

[0067] Table 4. Evaluation of other reaction parameters

[0068]

[0069] Of which: 20 a The reaction and isolation yields of 1a using 3 mol% (R)-C11 catalyst at a 1 mmol scale are shown;

[0070] In entries 16 to 19, 1a is 0.02M, 0.04M, 0.06M, and 0.08M respectively.

[0071] Comparative Example 1:

[0072]

[0073] Any one of 1aa, 1ab, 1ac, 1ad, 1ae, 1af (0.05 mmol, 1.0 equivalent) and 2a (0.1 mmol, 2.0 equivalent) was dissolved in 1 mL of the solvent (0.05 M) shown in Table 5, introduced into a dried 10 mL reaction bottle, and cooled to the temperature shown in Table 5 to obtain a reaction system. A mixture of the catalyst and the solvent (50 μL) shown in Table 5 was added to the reaction system, and the catalyst concentration in the reaction system was adjusted to 5 mol%. Stirring was continued at the above temperature for 24 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 10 in Table 5. The yield was calculated 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).

[0074] Table 5

[0075] Entry BCB Cat. Solvent Temp.(℃) Yieldof3 E.e.of3 1 1aa (R)-C11 <![CDATA[CHCl3 / THF(1:1)]]> -30℃ N.D N.D 2 1ab (R)-C11 <![CDATA[CHCl3 / THF(1:1)]]> -30℃ N.D N.D 3 1ac (R)-C11 <![CDATA[CHCl3 / THF(1:1)]]> -30℃ N.D N.D 4 1aa (R)-C5 THF 0℃ N.D N.D 5 1ab (R)-C5 THF 0℃ N.D N.D 6 1ac (R)-C5 THF 0℃ N.D N.D 4 1ad (R)-C11 <![CDATA[CHCl3 / THF(1:1)]]> -30℃ N.D N.D 5 1af (R)-C11 <![CDATA[CHCl3 / THF(1:1)]]> -30℃ N.D N.D 7 1ad (R)-C5 THF -30℃ N.D N.D 8 1af (R)-C5 THF -30℃ N.D N.D 9 1ae (R)-C11 <![CDATA[CHCl3 / THF(1:1)]]> -30℃ N.D N.D 10 1ae (R)-C5 THF r.t. N.D N.D

[0076] Example 7: General Synthesis Method of BCH

[0077]

[0078] General Synthesis Method A (1.0 mmol scale): Dissolve BCB (1.0 mmol, 1.0 equivalent) and an imine compound (Formula 2, 2.0 mmol, 2.0 equivalent) 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 the reaction is complete (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 yield the desired product, BCH.

[0079] General Synthesis Method B (0.2 mmol scale): Dissolve BCB (0.2 mmol, 1.0 equiv) and an imine compound (Formula 2, 0.4 mol, 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 system to -30°C and add a THF solution (50 μL) 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 yield the desired product, BCH.

[0080] Example 8: Synthesis of 3a, BCB is 1a, imine compound is 2a, and 3a was synthesized using General Method A (94% yield, 92% ee).

[0081] The NMR data of compound 3a are: 1 H NMR (400MHz, CDCl3): δ7.45 (d, J = 7.2Hz, 2H), 7.37-7.33 (m, 6H), 7.31-7.25 (m, 2H), 5.32 (s, 1H),3.69(s,3H),2.62(d,J=6.1Hz,1H),2.52-2.45(m,2H),2.12-1.83(m,1H),1.04(s,9H); 13 C NMR (100MHz, CDCl3): δ170.48,156.86,139.00,138.80,128.15,127.98,127.46,127.29,12 6.76,126.30,79.68,70.54,66.78,52.04,51.74,47.95,42.99,27.76.HRMS(ESI)m / z:[M+H] +

[0082] calcd.forC 24 H 28 NO4,394.2013; found,394.2009.

[0083] Example 9: Synthesis of 3b, BCB as 1b, imine compound as 2a, 3b was synthesized using General Method A (89% yield, 93% ee)

[0084] The NMR data of compound 3b are:1 H NMR (400MHz, CDCl3): δ7.44(d,J=7.3Hz,2H),7.37-7.33(m,2H),7.29-7.24(m,3H),7.17(d,J=7.8Hz,2H),5 .30(s,1H),3.69(s,3H),2.59-2.58(m,1H),2.48-2.46(m,2H),2.36(s,3H),1.97-1.91(m,1H),1.06(s,9H); 13 C NMR (100MHz, CDCl3): δ170.56,156.69,139.10,136.94,135.73,128.66,128.12,127.42,126.7 8,126.25,79.63,70.41,66.78,52.03,51.73,48.12,42.85,27.81,21.22.HRMS(ESI)m / z:[M+H] + calcd.forC 25 H 30 NO4,408.2169; found,408.2166.

[0085] Example 10: Synthesis of 3c, BCB is 1c, imine compound is 2a, and 3c was synthesized using General Method A (85% yield, 91% ee).

[0086] The NMR data of compound 3c are: 1 H NMR (400MHz, CDCl3): δ7.46-7.43(m,2H),7.39-7.33(m,4H),7.29-7.25(m,3H),5.33(s,1H),3.6 9(s,3H),2.59(d,J=6.1Hz,1H),2.52-2.44(m,2H),2.03-1.94(m,1H),1.33(s,9H),1.02(s,9H); 13 C NMR (100MHz, CDCl3): δ170.57,156.93,150.24,139.00,135.79,128.16,127.44,126.75,126.08,1 24.83,79.54,70.52,66.65,52.01,51.71,48.06,42.82,34.50,31.34,27.73.HRMS(ESI)m / z:[M+H] + calcd.forC 28 H 36NO4,450.2639; found,450.2635.

[0087] Example 11: Synthesis of 3d, BCB is 1d, imine compound is 2a, and 3d was synthesized using General Method B (86% yield, 90% ee).

[0088] The NMR data of compound 3d are: 1 H NMR (400MHz, CDCl3): δ7.45-7.42(m,2H),7.37-7.26(m,5H),7.06(t,J=8.8Hz,2H),5.31(s,1H),3. 69(s,3H),2.59(dd,J=4.6,1.7Hz,1H),2.47(dd,J=4.9,2.0Hz,2H),1.99-1.93(m,1H),1.08(s,9H); 19 F NMR(376MHz, CDCl3):-114.88; 13 C NMR (100 MHz, CDCl3): 13 C NMR(101MHz, CDCl3) δ170.33,162.08(d,J=245.9Hz),156.70,138.85,134.64(d,J=3.2Hz),128.17,127.98(d,J=8.1Hz ),127.51,126.73,114.93(d,J=21.6Hz),79.89,69.88,66.76,51.96,51.79,48.09,42.91,27.83.HRMS(ESI)m / z:[M+H] + calcd.forC 24 H 27 FNO4,412.1919; found,412.1913.

[0089] Example 12: Synthesis of 3e, BCB is 1e, imine compound is 2a, and 3e is synthesized by general method A (83% yield, 95% ee).

[0090] The NMR data of compound 3e are: 1 H NMR (400MHz, CDCl3): δ7.45-7.42(m,2H),7.37-7.26(m,7H),5.31(s,1H),3.70 (s,3H),2.62-2.56(m,1H),2.49-2.43(m,2H),1.98-1.92(m,1H),1.08(s,9H); 13CNMR (100MHz, CDCl3): δ170.28,156.74,138.81,137.35,133.12,128.23,128.20,127.72,12 7.55,126.74,80.08,69.85,66.81,52.04,51.82,47.95,43.05,27.82.HRMS(ESI)m / z:[M+H] + calcd.forC 24 H 27 ClNO4,428.1623; found,428.1620.

[0091] Example 13: Synthesis of 3f, BCB is 1f, imine compound is 2a, synthesized by general method A, 3f (90% yield, 95% ee).

[0092] The NMR data of compound 3f are: 1 H NMR (400MHz, CDCl3): δ7.50(d,J=8.6Hz,2H),7.43(d,J=7.2Hz,2H),7.35(t,J=7.4Hz,2H),7.29(d,J=7.2Hz,1H),7. 24(d,J=8.3Hz,2H),5.31(s,1H),3.70(s,3H),2.62-2.56(m,1H),2.49-2.43(m,2H),1.99-1.92(m,1H),1.08(s,9H); 13 C NMR (100MHz, CDCl3): δ170.24,156.73,138.76,137.84,131.15,128.18,128.05,127.54,12 6.72,121.19,80.09,69.87,66.79,52.03,51.82,47.88,43.00,27.80.HRMS(ESI)m / z:[M+H] + calcd.forC 24 H 27 BrNO4,472.1118; found,472.1113.

[0093] Example 14: Synthesis of 3g, BCB is 1g, imine compound is 2a, and 3g is synthesized using general method A (88% yield, 94% ee).

[0094] The NMR data of compound 3g are: 1H NMR (400MHz, CDCl3): δ7.61 (dd, J=8.5, 1.5Hz, 4H), 7.50-7.42 (m, 6H), 7.40-7.34 (m, 3H), 7.32-7.27 (m, 1H),5.36(s,1H),3.72(s,3H),2.66(d,J=6.1Hz,1H),2.57-2.49(m,2H),2.04-2.01(m,1H),1.08(s,9H); 13 C NMR (100MHz, CDCl3): δ170.47,156.89,140.96,140.31,138.97,137.87,128.75,128.19,127.50,12 7.25,127.08,126.79,79.88,70.37,66.80,52.11,51.78,48.06,43.07,27.80.HRMS(ESI)m / z:[M+H] + calcd.forC 30 H 32 NO4,470.2326; found,470.2322.

[0095] Example 15: Synthesis of 3h, BCB is 1h, imine compound is 2a, and 3h was synthesized using General Method B (73% yield, 95% ee).

[0096] The NMR data of compound 3h are: 1 H NMR (600MHz, DMSO-d6, 80℃): δ7.41-7.35(m,4H),7.32-7.29(m,1H),7.20-7.14(m,4H),5.20(s,1H),3.66(s,3H),2.7 1(d,J=6.9Hz,1H),2.61-2.57(m,1H),2.51(s,3H),2.47(dd,J=10.0,7.0Hz,1H),1.93(d,J=7.8Hz,1H),0.97(s,9H); 13 C NMR (150MHz, DMSO-d6, 80℃): δ169.34,155.29,138.80,136.11,129.56,127.52,127.28,126.83,126.72 ,126.07,124.72,78.12,70.94,66.38,50.88,50.70,48.20,40.25,26.97,19.05.HRMS(ESI)m / z:[M+Na] + calcd.for C 25 H29 NO4Na,430.1989; found,430.1988.

[0097] Example 16: Synthesis of 3i, BCB as 1i, imine compound as 2a, 3i was synthesized using General Method A (90% yield, 90% ee).

[0098] The NMR data of compound 3i are: 1 H NMR (400MHz, CDCl3): δ7.47-7.44(m,2H),7.36(t,J=7.6Hz,2H),7.29-7.25(m,1H),6.95(s,2H),6.92(s,1H),5 .30(s,1H),3.69(s,3H),2.58(d,J=6.1Hz,1H),2.49-2.42(m,2H),2.34(s,6H),1.95-1.93(m,1H),1.05(s,9H); 13 C NMR (100MHz, CDCl3): δ170.58,156.85,139.09,138.60,137.32,128.91,128.13,127.42,126.7 9,124.11,79.51,70.55,66.78,52.00,51.72,48.05,42.91,27.79,21.27.HRMS(ESI)m / z:[M+H] + calcd.forC 26 H 32 NO4,422.2326; found,422.2322.

[0099] Example 17: Synthesis of 3j, BCB as 1j, imine compound as 2a, 3j was synthesized using General Method A (88% yield, 92% ee).

[0100] The NMR data of compound 3j are: 1 H NMR (400MHz, CDCl3): δ7.87-7.84(m,3H),7.72(d,J=1.7Hz,1H),7.59(dd,J=8.5,1.7Hz,1H),7.53-7.45(m,4H),7.39(t,J=7. 6Hz,2H),7.33-7.29(m,1H),5.39(s,1H),3.72(s,3H),2.79-2.73(m,1H),2.62-2.56(m,2H),2.06-2.00(m,1H),0.96(s,9H); 13C NMR (100MHz, CDCl3): δ170.47,156.84,138.99,136.39,133.09,132.69,128.19,127.73,127.69,127.60,127.51,12 6.82,126.11,125.82,124.70,124.62,79.82,70.74,66.83,52.12,51.79,47.99,43.22,27.70.HRMS(ESI)m / z:[M+H] + calcd.forC 28 H 30 NO4,444.2169; found,444.2164.

[0101] Example 18: Synthesis of 3k. BCB was 1k, and the imine compound was 2a. 3k was synthesized using General Method B (88% yield, 93% ee).

[0102] The NMR data of compound 3k are: 1 H NMR (400MHz, CDCl3): δ7.43-7.41(m,2H),7.36-7.32(m,2H),7.30-7.25(m,2H),6.97-6.94(m,2H),5.30 (s,1H),3.68(s,3H),2.64(d,J=6.6Hz,1H),2.55-2.44(m,2H),2.07(dd,J=7.6,1.3Hz,1H),1.13(s,9H); 13 C NMR (100MHz, CDCl3): δ170.08,156.53,141.75,138.61,128.12,127.47,126.74,126.12,12 4.99,124.96,79.85,66.76,66.58,52.47,51.75,49.59,43.93,27.78.HRMS(ESI)m / z:[M+H] + calcd.forC 22 H 26 NO4S,400.1577; found,400.1573.

[0103] Example 19: Synthesis of 3l, BCB as 1a, imine compound as 2b, 3l was synthesized using General Method A (94% yield, 95% ee).

[0104] The NMR data of compound 31 are: 1H NMR (400MHz, CDCl3): δ7.39-7.33(m,6H),7.31-7.27(m,1H),7.16(d,J=7.9Hz,2H),5.30(s,1H),3.70( s,3H),2.61(d,J=6.1Hz,1H),2.53-2.44(m,2H),2.34(s,3H),1.97(dd,J=7.1,1.3Hz,1H),1.05(s,9H); 13 C NMR (100MHz, CDCl3): δ170.56,156.88,138.89,136.99,135.99,128.88,127.96,127.25,126.6 5,126.31,79.61,70.49,66.63,52.00,51.73,47.89,43.03,27.77,21.08.HRMS(ESI)m / z:[M+H] + calcd.forC 25 H 30 NO4,408.2169; found,408.2163.

[0105] Example 20: Synthesis of 3m, BCB 1a, imine compound 2c, 3m was synthesized using General Method A (91% yield, 90% ee).

[0106] The NMR data of compound 3m are: 1 H NMR (400MHz, CDCl3): δ7.38-7.33(m,8H),7.30-7.27(m,1H),5.31(d,J=1.3Hz,1H),3.72(s,3H), 2.61(d,J=6.4Hz,1H),2.52-2.43(m,2H),1.98(dd,J=7.4,1.3Hz,1H),1.31(s,9H),1.03(s,9H). 13 C NMR (100MHz, CDCl3): δ170.63,157.11,150.08,139.07,135.86,127.99,127.23,126.42,126.30,1 25.12,79.66,70.58,66.55,51.99,51.77,47.91,43.23,34.43,31.37,27.77.HRMS(ESI)m / z:[M+H] + calcd.forC 28 H 36 NO4,450.2639; found,450.2631.

[0107] Example 21: Synthesis of 3n. BCB is 1a, and the imine compound is 2d. 3n was synthesized using General Method A (87% yield, 95% ee).

[0108] The NMR data of compound 3n are: 1 H NMR (400MHz, CDCl3): δ7.40-7.35(m,6H),7.32-7.29(m,1H),6.92-6.89(m,2H),5.29(s,1H),3.80(s, 3H), 3.70 (s, 3H), 2.62 (d, J = 6.1Hz, 1H), 2.52-2.44 (m, 2H), 1.98 (dd, J = 7.1, 1.4Hz, 1H), 1.05 (s, 9H). 13 C NMR (100MHz, CDCl3): δ170.49,158.87,156.87,138.82,131.11,127.91,127.82,127.19,126.2 2,113.54,79.56,70.44,66.31,55.12,51.95,51.69,47.78,42.94,27.71.HRMS(ESI)m / z:[M+H] + calcd.forC 25 H 30 NO5,424.2118; found,424.2112.

[0109] Example 22: Synthesis of 3o: BCB 1a and imine 2e were synthesized using General Method A (87% yield, 93% ee).

[0110] The NMR data of compound 3o are: 1 H NMR (400MHz, CDCl3): δ8.04(d,J=8.5Hz,2H),7.54(d,J=8.3Hz,2H),7.40-7.27(m,5H),5.35(s,1H),3.91 (s,3H),3.69(s,3H),2.64(d,J=6.6Hz,1H),2.52-2.42(m,2H),2.00(dd,J=7.6,1.3Hz,1H),1.04(s,9H); 13C NMR (100MHz, CDCl3): δ170.10,166.85,156.63,144.25,138.34,129.47,129.34,127.98,127.39,12 6.85,126.24,79.92,70.62,66.52,52.04,51.98,51.81,48.02,42.88,27.68.HRMS(ESI)m / z:[M+H] + calcd.forC 26 H 30 NO6,452.2068; found,452.2063.

[0111] Example 23: Synthesis of 3p, BCB 1a, imine 2f, 3p was synthesized using General Method A (89% yield, 94% ee).

[0112] The NMR data of compound 3p are: 1 H NMR (400MHz, CDCl3): δ7.67(d,J=8.3Hz,2H),7.60(d,J=8.2Hz,2H),7.40-7.28(m,5H),5.33(s,1H),3.71(s,3H),2.67 (d,J=7.0Hz,1H),2.49(dd,J=10.0,7.0Hz,1H),2.38(dd,J=10.0,8.1Hz,1H),2.03(dd,J=8.1,1.2Hz,1H),1.03(s,9H); 13 C NMR (100MHz, CDCl3): δ169.88,156.70,144.54,138.13,132.04,128.07,127.78,127.54,126.22 ,118.77,111.43,80.25,70.83,66.27,52.05,51.98,48.13,42.93,27.67.HRMS(ESI)m / z:[M+H] + calcd.forC 25 H 27 N2O4,419.1965; found,419.1957.

[0113] Example 24: Synthesis of 3q, BCB 1a, imine compound 2g, using General Method B to synthesize 3q (81% yield, 96% ee).

[0114] The NMR data of compound 3q are: 1H NMR (400MHz, CDCl3): δ8.23(d,J=8.8Hz,2H),7.67(d,J=8.7Hz,2H),7.40-7.29(m,5H),5.38(s,1H),3.71(s,3H),2.69 (d,J=7.0Hz,1H),2.51(dd,J=10.0,7.1Hz,1H),2.40(dd,J=10.1,8.1Hz,1H),2.06(dd,J=8.0,1.2Hz,1H),1.04(s,9H); 13 C NMR (100MHz, CDCl3): δ169.80,156.66,147.38,146.52,138.03,128.06,127.91,127.55,12 6.21,123.41,80.29,70.88,66.11,52.09,51.99,48.15,42.92,27.65.HRMS(ESI)m / z:[M+H] + calcd.forC 24 H 27 N2O6,439.1864; found,439.1859.

[0115] Example 25: Synthesis of 3r. BCB was 1a, and the imine compound was 2h. 3r was synthesized using General Method A (91% yield, 95% ee).

[0116] The NMR data of compound 3r are: 1 H NMR (400MHz, CDCl3): δ7.47-7.43(m,2H),7.40-7.33(m,4H),7.32-7.28(m,1H),7.08-7.04(m,2H) ,5.30(s,1H),3.68(s,3H),2.64-2.63(m,1H),2.50-2.43(m,2H),2.01-1.99(m,1H),1.05(s,9H); 19 F NMR (376MHz, CDCl3): δ-115.42; 13 CNMR (100MHz, CDCl3): δ170.30,163.42,160.98,156.85,138.59,134.79,134.76,128.43,128.35,127.98,12 7.33,126.23,115.13,114.92,79.82,70.60,66.15,51.99,51.79,47.89,42.88,27.70.HRMS(ESI)m / z:[M+H]+ calcd.for C 24 H 27 FNO4,412.1919; found,412.1914.

[0117] Example 26: Synthesis of 3s, BCB 1a, imine 2i, 3s was synthesized using General Method A (92% yield, 95% ee).

[0118] The NMR data of compound 3s are: 1 H NMR (400MHz, CDCl3): δ7.51-7.48(m,2H),7.40-7.34(m,6H),7.32-7.28(m,1H),5.28(s,1H),3.70(s ,3H),2.64(d,J=6.5Hz,1H),2.45(qd,J=10.0,7.0Hz,2H),2.01(dd,J=7.4,1.3Hz,1H),1.05(s,9H); 13 C NMR (100MHz, CDCl3): δ170.14,156.74,138.44,138.10,131.25,128.56,127.97,127.35,12 6.21,121.44,79.88,70.61,66.15,51.86,51.82,47.94,42.86,27.69.HRMS(ESI)m / z:[M+H] + calcd.forC 24 H 27 BrNO4,472.1118; found,472.1111.

[0119] Example 27: Synthesis of 3t, BCB 1a, imine compound 2j, 3t was synthesized using General Method A (88% yield, 96% ee).

[0120] The NMR data of compound 3t are: 1 H NMR (400MHz, CDCl3): δ7.60-7.57(m,4H),7.53(d,J=8.4Hz,2H),7.45-7.43(m,2H),7.41-7.27(m,6H),5.37(s,1H),3.71(s,3H) ), 2.64 (d, J = 6.3Hz, 1H), 2.54 (dd, J = 10.0, 7.4Hz, 1H), 2.49 (dd, J = 10.0, 6.4Hz, 1H), 2.01 (dd, J = 7.4, 1.4Hz, 1H), 1.05 (s, 9H); 13C NMR (100MHz, CDCl3): δ170.43,156.92,140.92,140.32,138.77,138.06,128.66,127.97,127.28,127.21,12 7.11,127.04,126.95,126.29,79.74,70.60,66.55,52.03,51.78,47.96,43.07,27.74.HRMS(ESI)m / z:[M+H] + calcd.forC 30 H 32 NO4,470.2326; found,470.2322.

[0121] Example 28: Synthesis of 3u. BCB is 1a, and the imine compound is 2k. 3u was synthesized using General Method A (95% yield, 91% ee).

[0122] The NMR data of compound 3u are: 1 H NMR (400MHz, CDCl3): δ7.39-7.34(m,4H),7.32-7.26(m,1H),7.24-7.23(m,3H),7.09-7.07(m,1H),5.29(s,1H) ,3.69(s,3H),2.60(d,J=6.2Hz,1H),2.53-2.43(m,2H),2.36(s,3H),1.96(dd,J=7.2,1.3Hz,1H),1.04(s,9H); 13 C NMR (100MHz, CDCl3): δ170.52,156.89,138.86,138.83,137.57,128.23,128.02,127.94,127.37,127.2 4,126.29,123.81,79.62,70.48,66.78,51.99,51.67,47.90,42.94,27.74,21.59.HRMS(ESI)m / z:[M+H] + calcd.forC 25 H 30 NO4,408.2169; found,408.2166.

[0123] Example 29: Synthesis of 3v, BCB as 1a, imine compound as 2l, 3v was synthesized using General Method A (93% yield, 88% ee).

[0124] The NMR data of compound 3v are: 1H NMR (400MHz, CDCl3): δ7.38-7.35(m,4H),7.31-7.25(m,2H),7.04-7.02(m,2H),6.84-6.81(m,1H),5.30(s,1H),3.81(s,3H),3.71( s,3H),2.61(d,J=6.2Hz,1H),2.50(dd,J=10.0,7.2Hz,1H),2.46(dd,J=10.0,6.2Hz,1H),1.98(dd,J=7.2,1.3Hz,1H),1.04(s,9H); 13 C NMR (100MHz, CDCl3): δ170.51,159.50,156.94,140.70,138.80,129.21,127.99,127.30,126.31,119.1 7,112.94,112.57,79.75,70.56,66.67,55.14,52.04,51.79,48.01,43.10,27.78.HRMS(ESI)m / z:[M+H] + calcd.forC 25 H 30 NO5,424.2118; found,424.2111.

[0125] Example 30: Synthesis of 3w, BCB 1a, imine compound 2m, 3w was synthesized using General Method B (86% yield, 90% ee).

[0126] The NMR data of compound 3w are: 1 H NMR (400MHz, CDCl3): δ7.81(t,J=1.8Hz,1H),7.71(d,J=7.9,1H),7.60(dt,J=7.7,1.4Hz,1H),7.48(t,J=7.8Hz,1H),7.41-7.29(m,5H),5.32(s ,1H),3.72(s,3H),2.67(d,J=7.0Hz,1H),2.48(dd,J=10.0,7.0Hz,1H),2.37(dd,J=10.0,8.1Hz,1H),2.04(dd,J=8.1,1.3Hz,1H),1.03(s,9H); 13C NMR (100MHz, CDCl3): δ169.88,156.82,140.76,138.14,131.55,131.29,130.64,129.03,128.08,127.53 ,126.23,118.97,112.40,80.30,70.90,65.92,52.00,51.98,48.03,42.91,27.68.HRMS(ESI)m / z:[M+Na] + calcd.forC 25 H 26 N2O4Na,441.1785; found,441.1779.

[0127] Example 31: Synthesis of 3x, BCB as 1a, imine compound as 2n, 3x was synthesized using General Method B (79% yield, 94% ee).

[0128] The NMR data of compound 3x are: 1 H NMR (400MHz, CDCl3): δ7.65(dd,J=7.7,1.5Hz,1H),7.40-7.35(m,4H),7.32-7.23(m,2H),7.21-7.13(m,2H),5.47(s,1H),3.60(s,3H), 2.83(dd,J=10.0,8.0Hz,1H),2.63(d,J=7.2Hz,1H),2.50(dd,J=9.9,7.2Hz,1H),2.34(s,3H),1.91(dd,J=8.0,1.2Hz,1H),1.01(s,9H); 13 C NMR (100MHz, CDCl3): δ171.04,156.47,138.63,136.85,135.86,130.35,127.99,127.37,127 .34,127.10,126.47,125.65,79.54,69.73,63.96,51.75,51.50,47.50,43.32,27.74,19.00.

[0129] HRMS(ESI)m / z:[M+H] + calcd.forC 25 H 30 NO4,408.2169; found,408.2166.

[0130] Example 32: Synthesis of 3y: BCB 1a, imine 2o, and 3y were synthesized using General Method A (93% yield, 92% ee).

[0131] The NMR data of compound 3y are: 1 H NMR (400MHz, CDCl3): δ7.99(s,1H),7.93-7.85(m,3H),7.60(dt,J=8.6,2.2Hz,1H),7.54-7.41(m,6H),7.35(ddt,J=7.5,6.2,1 .8Hz,1H),5.54(s,1H),3.71(s,3H),2.70(dd,J=6.3,2.1Hz,1H),2.67-2.55(m,2H),2.04(dt,J=7.4,1.5Hz,1H),1.09(s,9H); 13 C NMR (100MHz, CDCl3): δ170.46,156.91,138.71,136.60,133.18,132.92,128.04,127.97,127.76,127.52,127.30,12 6.29,125.88,125.76,125.68,124.91,79.74,70.58,66.93,52.08,51.74,47.98,42.99,27.73.HRMS(ESI)m / z:[M+H] + calcd.forC 28 H 30 NO4,444.2169; found,444.2167.

[0132] Example 33: Synthesis of 3z, BCB as 1a, imine compound as 2p, 3z was synthesized using General Method A (93% yield, 91% ee).

[0133] The NMR data of compound 3z are: 1 H NMR (400MHz, CDCl3): δ7.49(dt,J=1.7,1.0Hz,1H),7.37(t,J=1.7Hz,1H),7.36-7.26(m,5H),6.43(dd,J=1.9,0.9Hz,1H),5.18(s,1H),3 .74(s,3H),2.61(d,J=6.8Hz,1H),2.44(dd,J=10.0,7.6Hz,1H),2.35(dd,J=10.1,6.8Hz,1H),2.11(dd,J=7.5,1.4Hz,1H),1.07(s,9H); 13C NMR (100MHz, CDCl3): δ170.29,157.19,142.74,140.46,138.78,127.92,127.20,126.10,12 4.53,109.74,79.73,70.84,60.22,51.86,50.93,47.08,44.57,27.74.HRMS(ESI)m / z:[M+H] + calcd.for C 22 H 26 NO5,384.1805; found,384.1799.

[0134] Example 34: Synthesis of 3aa. BCB is 1a, and the imine compound is 2q. 3aa was synthesized using General Method B (90% yield, 91% ee).

[0135] The NMR data of compound 3aa are: 1 H NMR (400MHz, CDCl3): δ7.37-7.25(m,5H),7.22(dd,J=5.0,1.3Hz,1H),7.07(dt,J=3.6,1.1Hz,1H),6.99(dd,J=5.1,3.6Hz ,1H),5.50(s,1H),3.74(s,3H),2.66-2.59(m,2H),2.40(dd,J=9.9,6.9Hz,1H),2.13(dd,J=7.9,1.4Hz,1H),1.07(s,9H); 13 C NMR (100MHz, CDCl3): δ169.97,157.03,143.23,138.59,127.95,127.27,126.77,126.15,12 4.82,124.43,79.99,70.95,63.26,52.08,51.89,47.56,44.43,27.72.HRMS(ESI)m / z:[M+H] + calcd.forC 22 H 26 NO4S,400.1577; found,400.1573.

[0136] Example 35: Synthesis of 3ab. BCB was 1l, and the imine compound was 2a. 3ab was synthesized using General Method A (91% yield, 95% ee).

[0137] The NMR data of compound 3ab are: 1H NMR (400MHz, CDCl3): δ7.38-7.33(m,9H),7.30-7.23(m,6H),5.32(s,1H),5.20(d,J=12.2Hz,1H), 5.09(d,J=12.2Hz,1H),2.63(d,J=6.1Hz,1H),2.54-2.46(m,2H),2.00-1.98(m,1H),1.03(s,9H); 13 C NMR (100MHz, CDCl3): δ169.86,156.87,138.86,138.80,135.33,128.55,128.42,128.36,128.15,127.98,12 7.41,127.29,126.83,126.32,79.70,70.51,66.75,66.51,52.12,48.01,43.01,27.76.HRMS(ESI)m / z:[M+H] + calcd.forC 30 H 32 NO4,470.2326; found,470.2321.

[0138] Example 36: Synthesis of 3ac, BCB as 1m, imine compound as 2a, 3ac was synthesized using General Method B (93% yield, 90% ee).

[0139] The NMR data of compound 3ac are: 1 H NMR (400MHz, CDCl3): δ7.53-7.50(m,2H),7.37-7.33(m,6H),7.29-7.25(m,2H),5.28(s,1H),2.56(d ,J=6.3Hz,1H),2.44(qd,J=10.0,6.8Hz,2H),1.92(dd,J=7.3,1.3Hz,1H),1.43(s,9H),1.03(s,9H); 13 C NMR (100MHz, CDCl3): δ169.31,156.96,139.19,139.05,127.97,127.91,127.37,127.15,126.9 9,126.30,81.33,79.54,70.13,66.64,52.88,47.92,42.93,27.97,27.74.HRMS(ESI)m / z:[M+H] + calcd.forC 27 H 34NO4,436.2482; found,436.2478.

[0140] Example 37: Synthesis of 3ad. BCB was 1n, and the imine compound was 2a. 3ad was synthesized using General Method A (95% yield, 96% ee).

[0141] The NMR data of compound 3ad are: 1 H NMR (400MHz, CDCl3): δ7.77-7.74(m,2H),7.56-7.52(m,1H),7.43-7.35(m,6H),7.31- 7.19(m,6H),5.60(s,1H),2.82-2.72(m,3H),2.04(dd,J=7.6,1.3Hz,1H),1.06(s,9H); 13 C NMR (100MHz, CDCl3): δ198.33,156.87,138.80,138.52,136.22,133.19,128.65,128.53,128.14,127.97 ,127.47,127.26,126.45,126.34,79.78,70.14,68.37,58.07,49.31,44.46,27.74.HRMS(ESI)m / z:[M+H] + calcd.forC 29 H 30 NO3,440.2220; found,440.2217.

[0142] Example 38: Synthesis of 3ae. BCB was 1o, and the imine compound was 2a. 3ae was synthesized using General Method B (76% yield, 89% ee).

[0143] The NMR data of compound 3ae are: 1 H NMR (400MHz, CDCl3): δ7.56-7.48(m,5H),7.36-7.32(m,2H),7.28-7.26(m,3H),7.23(d,J=8.6Hz,2H),6.89(d,J=8.8Hz,2H),5.35(s, 1H),3.80(s,3H),2.76(dd,J=9.9,7.6Hz,1H),2.67(d,J=7.0Hz,1H),2.56(dd,J=9.8,7.0Hz,1H),2.10(d,J=6.8Hz,1H),1.01(s,9H); 13C NMR (100MHz, CDCl3): δ159.19,155.61,137.30,136.99,133.50,129.52,128.71,128.60,128.33,128.11 ,127.95,127.48,113.55,80.00,68.75,66.45,65.34,55.25,47.39,43.56,27.77.HRMS(ESI)m / z:[M+Na] + calcd.forC 29 H 31 NO5SNa,528.1815; found,528.1812.

[0144] Example 39: Removal of N-Boc protecting group

[0145]

[0146] 3s (3.6 mmol, 1.0 equiv) and anhydrous dichloromethane (CH2Cl2, 144 mL) were added to a 250 mL oven-dried round-bottom flask equipped with a Teflon-coated magnetic stirrer. Subsequently, trimethylsilyl trifluoromethanesulfonate (TMSOTf, 4.0 mmol, 1.1 equiv) was added at 0°C, and the reaction was carried out under argon. After stirring for 3 hours, the reaction was quenched with saturated 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. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford 4s (93% yield, 99% ee) as a white solid.

[0147] 1 H NMR (400MHz, CDCl3): δ7.48-7.37(m,8H),7.34-7.30(m,1H),4.84(s,1H),3.69(s,3H),2.5 7(d,J=6.7Hz,1H),2.37-2.33(m,3H),2.13(dd,J=10.0,7.5Hz,1H),2.03(d,J=7.5Hz,1H); 13 C NMR (100MHz, CDCl3): δ171.65,140.33,139.10,131.14,129.34,128.43,127.75, 126.19,121.21,67.75,62.39,54.45,51.89,51.67,40.10.HRMS(ESI)m / z:[M+H] + calcd.forC19 H 19 BrNO2,372.0594; found,372.0585.

[0148] Example 40: Synthesis of Compound 6

[0149]

[0150] 4s (0.1 mmol, 1.0 equiv), HTIB (98 mg, 0.25 mmol, 2.5 equiv), and ammonium carbamate (0.8 mmol, 8.0 equiv) were dissolved in 2,2,2-trifluoroethanol (1 mL), stirred at room temperature, and reacted at 80°C for 2 hours. After the reaction, the reaction was cooled to room temperature and the cap of the reaction vial was slowly opened. After removing the solvent under reduced pressure, the residue was purified by preparative thin-layer chromatography (TLC) to yield product 6 as a pair of trans isomers (6-a: 43%; 6-b: 30%).

[0151] NMR data of 6-a: 1 H NMR (400MHz, CDCl3): δ7.74-7.72(m,2H),7.50-7.46(m,2H),7.44-7.36(m,3H),7.20 -7.18(m,2H),4.92(s,1H),4.54-4.42(m,2H),3.84-3.58(m,5H),3.40-3.24(m,2H). 19 F NMR (376MHz, CDCl3): δ-73.70; 13 C NMR (100MHz, CDCl3): δ173.67,171.11,135.13,133.78,131.96,130.71,129.09,128.45,127.46,123.6 3(q,J=279.1Hz),123.20,83.15,67.02,66.37(q,J=34.6Hz),59.46,52.52,38.85.HRMS(ESI)m / z:[M+H] + calcd.forC 21 H 20 BrF3NO3,470.0573; found,470.0561.

[0152] NMR data of 6-b: 1H NMR (400MHz, CDCl3): δ7.63-7.61(m,2H),7.42-7.34(m,5H),7.19-7.16(m,2H),5.00(s, 1H),4.26-4.14(m,2H),3.80-3.70(m,4H),3.65-3.55(m,2H),3.36(d,J=17.8Hz,1H).19F NMR (376MHz, CDCl3): δ-73.91; 13 C NMR (100MHz, CDCl3): δ173.89,172.15,134.08,133.47,131.87,130.72,129.16,128.39,127.33,123.6 0(q,J=279.0Hz),123.25,84.04,66.32(q,J=34.6Hz),65.61,59.09,52.66,39.52.HRMS(ESI)m / z:[M+H] + calcd.forC 21 H 20 BrF3NO3,470.0573; found,470.0565.

[0153] Example 41 General Synthesis of Compound BCP

[0154]

[0155] 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.

[0156] 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.

[0157] Example 42: Synthesis of Compound 5f

[0158]

[0159] BCH is 3f, using General Method C, 5f (65% yield, 94% ee).

[0160] 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.forC 19 H 18 BrO2,357.0485; found,357.0475.

[0161] Example 43: Synthesis of Compound 3s

[0162]

[0163] 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 a 1 mL THF solution containing (R)-C11 (160 mg, 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 (83% yield, 99% ee).

[0164] Example 44: Synthesis of Compound 5s

[0165]

[0166] 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).

[0167] Example 45: Synthesis of Compound 3af

[0168]

[0169] 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).

[0170] 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.

[0171] Example 46: Synthesis of Compound 16

[0172]

[0173] A 50 mL round-bottom flask was charged with olefin 3af (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).

[0174] 1 H NMR (400MHz, CDCl3): δ7.34-7.27(m,5H),7.26-7.16(m,5H),4.17(t,J=6.1Hz,1H),3.74(s,3H),2.89(ddd,J=13.7,12.0,5.4Hz,1H), 2.73(td,J=13.0,5.1Hz,1H),2.52(d,J=6.9Hz,1H),2.41(dd,J=10.0,7.8Hz,1H),2.26-2.17(m,2H),2.10-1.96(m,2H),1.11(s,9H); 13 C NMR (100MHz, CDCl3): δ171.26,157.87,142.36,139.29,128.34,128.32,127.91,127.03,126.06,12 5.76,79.56,70.51,64.84,51.92,50.46,46.98,45.17,35.79,33.68,27.88.HRMS(ESI)m / z:[M+Na] + calcd.forC 26 H 31 NO4Na,444.2145; found,444.2134.

[0175] Example 47: Synthesis of Compound 18

[0176]

[0177] 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 resulting crude product was used directly in the next reaction without further purification.

[0178] 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).

[0179] 1 H NMR (400MHz, CDCl3): δ7.35-7.27(m,5H),4.62(s,1H),3.80(s,3H),3.75(s,3H),2.88(dd,J=10.1, 7.6Hz,1H),2.52(d,J=7.2Hz,1H),2.32(dd,J=10.1,7.2Hz,1H),2.16(d,J=7.6Hz,1H),1.09(s,9H); 13 C NMR (100MHz, CDCl3): δ170.82,169.48,155.21,137.35,127.93,127.64,126.62,80 .12,70.78,63.65,52.34,52.19,50.69,47.53,44.57,27.79.HRMS(ESI)m / z:[M+Na] + calcd.forC 20 H 25 NO6Na,398.1574; found,398.1563.

[0180] Example 48: Synthesis of Compound 20

[0181]

[0182] 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 reaction 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).

[0183] 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.forC 40 H 45 O4,589.3312;found,589.3296.

[0184] Example 49: Synthesis of Compound 21

[0185]

[0186] 5S (0.05 mmol, 1.0 eq), apixaban (0.06 mmol, 1.2 eq), Pd2(dba)3 (2.5 mg, 5 mol%), Cs2CO3 (0.07 mmol, 1.4 eq), and xantphos (2.9 mg, 0.1 eq) were placed in 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.

[0187] 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 product 21 (95% yield) as a white solid.

[0188] HRMS(ESI)m / z:[M+H] + calcd.forC 44 H 42 N5O6,736.3130; found,736.3111.

[0189] Example 50: Synthesis of Compound 27

[0190]

[0191] 1k (5.0 mmol, 1.0 eq) and 2s (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 the product 3ag as a white solid (82% yield, 95% ee).

[0192] 1H NMR (400MHz, CDCl3): δ7.63(d,J=8.3Hz,2H),7.57(d,J=8.3Hz,2H),7.32-7.30(m,1H),6.98-6.96(m,2H),5.34(s,1H),3.71(s ,3H),2.69(d,J=6.9Hz,1H),2.55(dd,J=9.9,7.0Hz,1H),2.40(dd,J=9.9,8.0Hz,1H),2.12(dd,J=8.0,1.3Hz,1H),1.14(s,9H); 19 F NMR (376MHz, CDCl3): δ-62.49; 13 C NMR (100MHz, CDCl3): δ169.74, 156.56, 142.82 (d, J = 1.5Hz), 141.38, 129.82 (q, J = 32.4Hz), 127.34, 126.24, 125.20 (q, J = 3.8 Hz),125.18,125.12,124.15(q,J=272.0Hz),80.32,66.91,66.34,52.53,51.94,49.75,44.02,27.78.HRMS(ESI)m / z:[M+Na] + calcd.forC 23 H 24 F3NO4SNa,490.1270; found,490.1266.

[0193]

[0194] To a 250 mL round-bottom flask, oven-dried and equipped with a Teflon-coated magnetic stir bar, was added 3ag (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 argon pressure. 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 step without further purification.

[0195] 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.

[0196]

[0197] 5ag (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, dissolved in 10 mL of H₂O) and RuCl₃ (0.035 mmol, 0.05 equivalents, dissolved in 1.4 mL of H₂O) were then added, and the reaction mixture was vigorously stirred 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.

[0198] 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)

[0199] =10 / 1) to obtain the target product 22 (56% yield, 90% ee).

[0200]

[0201] 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, 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.

[0202] 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.

[0203]

[0204] 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 NaSO, concentrated under reduced pressure, and used directly in the next reaction without further purification.

[0205] 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).

[0206]

[0207] 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.

[0208] 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).

[0209] 1 H 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. 13C 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.forC 38 H 40 F6N3O2,684.3019; found,684.3007.

[0210] Example 51: Effect of (R)-C11 Purity on Product Enantiomeric Amount

[0211]

[0212] Using General Method B, a mixture of catalyst enantiomers was added, wherein (R)-C11 accounted for 1% of the enantiomer mixture as shown in Table 8, and the enantiomeric value of each product 3a was measured.

[0213] Table 8

[0214] E.eofCat.(%) 0 10 20 30 40 50 60 70 80 90 100 E.eofproduct.(%) 3.4 13.7 21.5 29.7 39.0 48.8 57.3 66.7 76.0 85.1 95.0

[0215] Example 52: Free Radical Clock Experiment

[0216]

[0217] Diethylzinc (1.0 M in n-hexane, 2 mL, 2.0 mmol, 5.0 equiv) was added to dry dichloromethane (2 mL) at 0°C. A dichloromethane solution (1 mL) of trifluoroacetic acid (153 μL, 2.0 mmol, 5.0 equiv) was slowly added dropwise to the reaction mixture to form an opaque solution, which was then stirred at 0°C for 20 minutes.

[0218] Next, a solution of diiodomethane (CH2I2, 162 μL, 2.0 mmol, 5.0 equiv) in dichloromethane (1 mL) was slowly added dropwise to the mixture. Once a clear solution formed, stirring was continued at 0°C for 20 minutes. Then, a solution of 3af (0.4 mmol, 1.0 equiv) in dichloromethane (1.0 mL) was slowly added dropwise to the reaction system. The reaction system was allowed to warm to room temperature and stirred for 12 hours.

[0219] After completion of the reaction, the reaction was quenched with 0.1 M HCl, and the product was extracted with dichloromethane (3 × 10 mL). The organic layer was washed sequentially with saturated aqueous sodium bicarbonate and saturated brine, then dried over anhydrous Na2SO4, filtered, and concentrated by evaporation. The product was purified by silica gel column chromatography to afford target compound 33 as a white solid (74% yield, cis-trans ratio > 20:1).

[0220] 1 H NMR (400MHz, CDCl3): δ7.39-7.31(m,4H),7.29-7.21(m,3H),7.15-7.11(m,1H),7.04-

[0221] 7.02(m,2H),3.78(s,3H),3.19(d,J=9.2Hz,1H),2.99(brs,1H),2.35(d,J=6.6Hz,1H),2.27-2 .19(m,3H),2.03(ddd,J=8.5,5.9,4.4Hz,1H),1.21-1.14(m,1H),1.01(tt,J=8.3,5.2Hz,2H). 13 C NMR (100MHz, CDCl3): δ171.70,142.19,138.36,128.40,128.33,127.84,126.20,125.68,12 5.65,67.89,66.75,52.99,51.71,49.46,41.61,25.30,21.02,14.23.HRMS(ESI)m / z:[M+H] + calcd.forC 22 H 24 NO2,334.1802; found,334.1798.

[0222] Example 53: Monitoring of Ring-Opening Diene By-Products

[0223]

[0224] In a dry 250 mL round-bottom flask, 1b (4.0 mmol, 1.0 equiv) and 2r (6.0 mmol, 1.5 equiv) were dissolved in a mixture of THF (40 mL) and CHCl₃ (40 mL). The reaction system was cooled to -30°C, and a THF solution (500 μL) containing catalyst (R)-C11 (115 mg, 3 mol%) was added. The mixture was stirred at -30°C until 1b was completely consumed (monitored by thin-layer chromatography). After completion of the reaction, the reaction was quenched with saturated NaHCO₃ solution and extracted with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄, concentrated by rotary evaporation, and purified by silica gel column chromatography to afford compound 3ah as a white solid (85% yield, 91% ee).

[0225] 1 H NMR (400MHz, CDCl3): δ7.44-7.42(m,2H),7.33-7.29(m,2H),7.25-7.13(m,5H ),6.79(d,J=15.7Hz,1H),6.34(dd,J=15.8,6.5Hz,1H),4.74(dt,J=6.5,1.3H z,1H),3.72(s,3H),2.56(d,J=7.0Hz,1H),2.48(dd,J=9.9,7.7Hz,1H),2.34( s,3H),2.29(dd,J=10.0,7.0Hz,1H),2.08(dd,J=7.6,1.3Hz,1H),1.15(s,9H). 13 C NMR (100MHz, CDCl3): δ170.39,156.95,136.83,136.81,135.77,133.76,128.60,128.41,127.57,126.63 ,126.59,126.10,79.59,70.50,65.80,51.90,50.85,46.80,44.70,27.93,21.18.HRMS(ESI)m / z:[M+Na] + calcd.forC 27 H 31 NO4Na,456.2145; found,412.456.2127.

[0226] Example 54: Synthesis of Compound A:

[0227]

[0228] 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.

[0229] 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 (494 mg, 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).

[0230] 1 H NMR(400MHz, CDCl3):7.80-7.88(m,2H),7.69-7.67(m,2H),7.44(d,J=7.0Hz,2H), 7.25(t,J=7.6Hz,2H),7.18-7.08(m,5H),6.86(d,J=15.8Hz,1H),6.44(dd,J=15.8 ,5.7Hz,1H),4.90(d,J=5.6Hz,1H),2.80(d,J=7.1Hz,1H),2.56(dd,J=9.8,7.7Hz, 1H), 2.44(dd,J=9.9,7.1Hz,1H),2.27(s,3H),2.20(d,J=7.6Hz,1H),1.10(s,9H). 13 C NMR (100MHz, CDCl3): δ166.17,161.56,156.88,137.09,136.74,135.14,134.75,134.31,128.86,128.71, 128.42,127.63,126.82,126.06,125.51,123.97,79.98,71.15,65.76,48.65,47.20,45.00,27.93,21.19.

[0231] HRMS(ESI)m / z:[M+H] + calcd.forC 34 H 33 N2O6,565.2333; found,565.2304.

[0232] Example 55: Synthesis of Compound B

[0233]

[0234] Redox-active ester A (1.0 mmol, 1.0 equiv) and Hantzsch ester (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 protection, 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 was removed by evaporation, and the residue was purified by preparative thin-layer chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to afford the desired product 23 as a colorless oil (58% yield, 91% ee).

[0235] 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.forC 25 H 30 NO2,376.2271; found,376.2252.

[0236] Example 56: Synthesis of Compound 35

[0237]

[0238] 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 (324 mg, 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 1M HCl. The organic layer was separated and the aqueous phase was extracted with EtOAc. The organic layers were combined, 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) was added at 0°C.

[0239] 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).

[0240] 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.

[0241] HRMS(ESI)m / z:[M+H] + calcd.forC 19 H 25 NO4Na,354.1676; found,354.1671.

[0242] 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 azabicyclo[2.1.1]hexane derivative of formula BCH, or an isotope-labeled product thereof: The R 1 is selected from ester, acylaryl, hydrogen, and sulfonyl; The R 2 and R 3 Each is selected from an alkyl group, an alkenyl group, a monocyclic aromatic group, a cycloalkyl group, a condensed aromatic group, a heterocyclic group, and an ester group; The R 4 is selected from an amino protecting group, hydrogen; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

2. The chiral azabicyclo[2.1.1]hexane derivative according to claim 1, characterized in that The R 2 and R 3 Each monocyclic aromatic group, the monocyclic aromatic group structure is as follows: The R a is selected from hydrogen, C1 to C4 alkyl, halogen, alkoxy, nitro, cyano, ester, monocyclic aromatic, thienyl, furyl, wherein n is selected from any positive integer from 1 to 5, and R a Any hydrogen is replaced by a halogen, or, The R 2 and R 3 Each is selected from C3 to C6 cycloalkyl, any hydrogen on the cycloalkyl is replaced by an aryl group, and the carbon on the cycloalkyl is independently R-configuration, S-configuration or an achiral carbon atom.

3. The chiral azabicyclo[2.1.1]hexane derivative according to claim 1, characterized in that The R 2 Selected from alkyl, alkenyl, said R 2 Any hydrogen atom is replaced by an aryl group.

4. The chiral azabicyclo[2.1.1]hexane derivative according to any one of claims 1 to 3, characterized in that The R 1 Selected from -C(=O)R b or -S(=O)2R c , the R b is selected from substituted or unsubstituted C1-C6 alkyl, monocyclic aryl, said R c is selected from substituted or unsubstituted monocyclic aromatic groups, or, The R 1 Selected from ester groups, the ester group structure is such as -C(=O)OR d , the R d Selected from C1-C6 alkyl, monocyclic aromatic group, condensed heterocyclic group.

5. The chiral azabicyclo[2.1.1]hexane derivative according to claim 4, characterized in that The R d is selected from fused heterocyclic groups, wherein R d Structure such as 6. A chiral azabicyclo[2.1.1]hexane derivative, as follows:

7. A chiral azabicyclo[ 2.1.1] A method for synthesizing a hexane derivative, comprising: Dissolving the compound of formula 1 and the compound of formula 2 in an organic solvent to obtain a reaction system, controlling the temperature, and adding a catalyst to obtain a compound of formula 3; The catalyst structure is selected from: The R 1 、R 2 、R 3 、R 4 As defined in any one of claims 1 to 5; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

8. A method for synthesizing a compound of formula 33, comprising: Diethyl zinc is mixed with an organic solvent to obtain a mixture, trifluoroacetic acid and diiodomethane are added in sequence, and the temperature is controlled to obtain a reaction system. 3af is added to the reaction system to obtain a compound of formula 33.

9. A method for synthesizing a compound of formula 6, comprising: Compound 4s, HTIB, and ammonium carbamate are dissolved in an organic solvent and reacted under controlled temperature to obtain the product compound 6.

10. A method for synthesizing the compound of formula 18, comprising: 3af was put into a mixture of organic solvent and water, and RuCl3 and NaIO4 were added. The organic phase was extracted and TMSCH2N2 was added to obtain compound 18.

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