Synthesis of cyclopamine

Abstract

This disclosure relates to the field of organic synthesis technology and discloses a method for synthesizing cyclopamine. The method involves using compound 1 as a starting material, undergoing an addition reaction to obtain compound 2, followed by cyanation of compound 2 to obtain compound 3, a rearrangement reaction of compound 3 to obtain compound 4, catalytic hydrogenation of compound 4 to obtain compound 5, epoxide ring-opening reaction of compound 5 and elimination of the hydroxyl group to obtain compound 6, reduction reaction of compound 6 to obtain compound 7, condensation reaction of compound 7 with tert-butylsulfinamide to obtain compound 8, reductive coupling reaction of compound 8 with compound 9 to obtain compound 10, E-ring closure and desulfonylation reaction of compound 10, and further lactamation reaction to obtain compound 11, followed by reductive amide reaction of compound 11 to obtain the natural product cyclopamine. This synthetic method can shorten the reaction route and improve the reaction yield, thereby achieving efficient chemical synthesis of cyclopamine.

Description

Technical Field

[0001] This disclosure relates to the field of organic synthesis technology, and specifically to a method for synthesizing cyclic pharmacamine. Background Technology

[0002] Cyclopamine is an alkaloid of the genus Veratrum, first isolated in 1968 by American chemist Richard F. Keller and his colleagues from Veratrum californicum, a plant in the Liliaceae family in California, USA. Its structural formula is as follows:

[0003]

[0004] It can be seen that cyclopamine is a complex hexacyclic natural product with a molecular structure including: 1) a C-nor-D-homo steroid skeleton and a fully substituted tetrahydrofuran E ring connected by a spirocyclic structure; 2) a unique trans-6,5-EF ring; and 3) the middle D ring contains a tetrasubstituted olefin.

[0005] Beachy et al.'s research showed that cyclopamine is a potent inhibitor of the Hedgehog signaling pathway. By targeting the Smoothened (Smo) receptor and inhibiting the Hedgehog (Hh) signaling pathway, it exhibits anti-tumor activity. As the first discovered Smo inhibitor, cyclopamine has become a research hotspot in anticancer drug development in recent years since it was found to effectively block Hh pathway signal transduction and thus inhibit tumor growth. For example, patidegib (also known as saridegib, IPI-926, SGT-610), prepared semi-synthetically from cyclopamine, is undergoing a phase III clinical trial for the treatment of basal cell nevus syndrome.

[0006] Since cyclopamine is present in limited quantities in nature, chemical synthesis has become an effective strategy for preparing this compound.

[0007] Currently reported methods for synthesizing cyclic pharmacamine include:

[0008] 1) In 2009, Giannis's group used dehydroepiandrosterone as a starting material to construct a C-nor-D-homo steroid skeleton through biomimetic 1,2-skeletal rearrangement. Through 26 reaction steps, they achieved the semi-synthesis of cyclic pamine. The reaction route is as follows:

[0009]

[0010] 2) In 2023, Baran's group used (S)-Wieland-Miescherone as the starting material and completed the convergent enantioselective total synthesis of cyclic dopamine using key reactions such as halogenation, Tsuji-Trost cyclization, and late-stage ring closure metathesis (RCM) reaction. The longest linear step was 16 steps, and the total number of steps was 22. The reaction route is as follows:

[0011]

[0012] 3) In 2023, Gao's group achieved the total synthesis of veratridine using the key photoinduced excited-state Nazarov reaction, and then converted veratridine to cyclopamine through subsequent functional group transformations. The longest linear step was 23 steps, and the total number of steps was 31. The reaction route is as follows:

[0013]

[0014] However, although the above three synthetic strategies have solved the problem of artificially synthesizing cyclic pamine, they still have drawbacks such as lengthy steps (more than 22 steps in total) and low overall yield (less than 1%).

[0015] Therefore, in order to further solve the problem of cyclic pharmacamine sources, it is essential to develop more efficient and concise synthetic routes. Summary of the Invention

[0016] The purpose of this disclosure is to overcome the shortcomings of the prior art and provide a method for synthesizing cyclic pamine, so as to at least shorten the reaction route and increase the reaction yield, thereby achieving the effect of efficient chemical synthesis of cyclic pamine.

[0017] The purpose of this disclosure is achieved through the following technical solution:

[0018] On the one hand, a method for synthesizing cyclic pharmacamine is provided. The method includes the following steps:

[0019] S1.

[0020] Compound 1 is provided, and compound 1 is subjected to an addition reaction to obtain compound 2; wherein, R 1 Selected from acetyl or tert-butyldimethylsilyl;

[0021] S2. Compound 2 is subjected to a cyanidation reaction to obtain compound 3;

[0022] S3. Compound 3 was subjected to a rearrangement reaction under alkaline conditions to obtain compound 4;

[0023] S4. Compound 4 was subjected to a catalytic hydrogenation reaction to obtain compound 5;

[0024] S5. Compound 5 was subjected to an epoxy ring-opening reaction to obtain compound 6;

[0025] S6. Compound 6 was reduced to obtain compound 7;

[0026] S7.

[0027] tert-butylsulfinamide is provided, and compound 7 is subjected to a condensation reaction with tert-butylsulfinamide to obtain compound 8;

[0028] S8.

[0029] Compound 9 is provided, and compound 8 is subjected to a reductive coupling reaction with compound 9 to obtain compound 10;

[0030] S9.

[0031] Compound 10 was subjected to a desulfonation reaction under acidic conditions to form a fully substituted tetrahydrofuran spirocycle, and then subjected to a lactamation reaction under alkaline conditions to obtain compound 11.

[0032] S10.

[0033] Compound 11 was subjected to a reductive amide reaction to obtain the cyclic pamine.

[0034] In some embodiments, R 1 Selected from the acetyl group.

[0035] In some embodiments, S1, the addition reaction includes a metal reagent addition reaction.

[0036] It should be noted that the reaction principle of the metal reagent addition reaction includes: providing a metal reagent and causing the metal reagent to undergo an addition reaction with compound 1; the carbon-metal bond in the metal reagent has strong polarity, causing the carbon atom bonded to the metal to carry a partial negative charge and have strong nucleophilicity; when the metal reagent encounters the ketone carbonyl group of compound 1, the negatively charged carbon atom in the metal reagent will launch a nucleophilic attack on the positively charged carbon atom in the ketone carbonyl group of compound 1, thereby generating the corresponding alcohol addition product (i.e., compound 2).

[0037] It should be understood that the selection of the metal reagent can include a variety of options. Any metal reagent that can cause compound 1 to undergo the metal reagent addition reaction through the above reaction principle to obtain compound 2 is included within the protection scope of the metal reagent. Those skilled in the art can make selections according to actual needs, and this disclosure does not impose any restrictions on this.

[0038] In some embodiments, in S1, the metal reagent used in the metal reagent addition reaction includes at least one of acetylenyl magnesium bromide, trimethylsilylacetylenyl magnesium bromide, acetylenyl lithium, and trimethylsilylacetylenyl lithium.

[0039] It should be noted that the metal reagent addition reaction can be a Grignard addition reaction, and correspondingly, the metal reagent can be a Grignard reagent.

[0040] In some examples, the metallic reagent includes at least one of the acetylenyl magnesium bromide and the trimethylsilylacetylenyl magnesium bromide.

[0041] In this context, it should be understood that the metal reagent addition reaction is the Grignard addition reaction, and the metal reagent is the Grignard reagent.

[0042] For example, the Grignard reagent includes the acetylenyl magnesium bromide.

[0043] In some examples, the molar ratio of compound 1 to the metal reagent is 1:2 to 10.

[0044] For example, the molar ratio of compound 1 to the Grignard reagent is 1:2 to 10.

[0045] In some embodiments, in S1, the solvent used in the metal reagent addition reaction includes at least one of tetrahydrofuran, toluene, dichloromethane, diethyl ether, methyl tert-butyl ether, and ethylene glycol dimethyl ether.

[0046] In some examples, in S1, the solvent used for the Grignard addition reaction includes at least one of tetrahydrofuran, toluene, dichloromethane, diethyl ether, methyl tert-butyl ether, and ethylene glycol dimethyl ether.

[0047] In some embodiments, in S1, the temperature of the metal reagent addition reaction is -78°C to 25°C.

[0048] In some examples, in S1, the temperature of the Grignard addition reaction is –78 to 25°C.

[0049] In some embodiments, in S1, the time for the metal reagent addition reaction is 2 to 24 hours.

[0050] In some examples, in S1, the Grignard addition reaction takes 2 to 24 hours.

[0051] It should be noted that the reaction principle of the cyanation reaction includes: providing a cyanating reagent, a catalyst, and a reducing agent; using the reducing agent to reduce the catalyst to generate a Ni(O) species, which then undergoes an oxidative addition reaction with water to generate a Ni(II) intermediate; an alkyne compound (i.e., compound 2) is inserted into the Ni(II) intermediate via nickel hydrotreating to form an alkenyl nickel complex; the alkenyl nickel complex undergoes a transmetallization reaction with the cyanating reagent, followed by reduction and elimination to generate the cyanation product (i.e., compound 3).

[0052] It should be understood that the selection of the cyaniding reagent can include a variety of reagents. Any cyaniding reagent that can cause the compound 2 to undergo the cyanidation reaction and obtain the compound 3 through the above reaction principle is included within the protection scope of the cyaniding reagent. Those skilled in the art can select according to actual needs, and this disclosure does not limit it.

[0053] In some embodiments, in S2, the cyaniding reagent used in the cyanidation reaction includes at least one of zinc cyanide and cuprous cyanide.

[0054] In some examples, the cyaniding agent includes zinc cyanide.

[0055] In some examples, the molar ratio of compound 2 to the cyaniding agent is 1:0.018 to 1.8.

[0056] Similarly, it should be understood that the selection of the catalyst can include a variety of catalysts. Any catalyst that can enable the compound 2 to undergo the cyanidation reaction to obtain the compound 3 through the above reaction principle is included within the protection scope of the catalyst. Those skilled in the art can select according to actual needs, and this disclosure does not limit it.

[0057] In some embodiments, in S2, the catalyst used in the cyanidation reaction includes at least one of nickel acetylacetonate and nickel iodide.

[0058] In some examples, the catalyst includes the nickel acetylacetone.

[0059] In some examples, the molar ratio of compound 2 to the catalyst is 1:0.015 to 1.5.

[0060] In some embodiments, in S2, the reducing agent used in the cyanidation reaction includes at least one of magnesium powder, manganese powder, and zinc powder.

[0061] In some examples, the molar ratio of compound 2 to the reducing agent is 1:0.12 to 6.

[0062] In some embodiments, in S2, the ligands used in the cyanation reaction include at least one of the following: a new copper reagent, 2,2'-bipyridine, and 4,4'-di-tert-butyl-2,2'-dipyridine.

[0063] In some examples, the ligand includes the novel copper reagent.

[0064] In some examples, the molar ratio of compound 2 to the ligand is 1:0.005 to 0.5.

[0065] In some embodiments, in S2, the solvent used in the cyanidation reaction includes at least one of acetonitrile, tetrahydrofuran, and water.

[0066] In some examples, the solvent includes the acetonitrile and the water.

[0067] For example, the volume ratio of acetonitrile to water is 1-10:1-5.

[0068] In some embodiments, in S2, the temperature of the cyanidation reaction is 0–80°C.

[0069] In some embodiments, the cyanidation reaction in S2 takes 2 to 48 hours.

[0070] In some embodiments, in S3, the activator used in the rearrangement reaction includes trifluoromethanesulfonic anhydride.

[0071] In some examples, the molar ratio of compound 3 to the activator is 1:1 to 9.

[0072] In some embodiments, in S3, the base used in the rearrangement reaction includes at least one of 4-dimethylaminopyridine, pyridine, 2-fluoropyridine, 2-bromopyridine, and 2-chloropyridine.

[0073] In some examples, the base includes at least one of 4-dimethylaminopyridine, 2-fluoropyridine, 2-bromopyridine, and 2-chloropyridine.

[0074] In some examples, the molar ratio of compound 3 to the base is 1:2.5 to 15.

[0075] In some embodiments, in S3, the solvent used in the rearrangement reaction includes at least one of dichloromethane, tetrahydrofuran, toluene, diethyl ether, ethylene glycol dimethyl ether, DMF, and methanol.

[0076] In some embodiments, in S3, the temperature of the rearrangement reaction is –78 to 25°C.

[0077] In some embodiments, in S3, the rearrangement reaction takes 0.5 to 6 hours.

[0078] In some embodiments, in S4, the catalyst used in the catalytic hydrogenation reaction includes at least one of triphenylphosphine rhodium chloride, palladium on carbon, Raney nickel, platinum dioxide, palladium hydroxide, and platinum on carbon.

[0079] In some examples, the catalyst includes at least one of triphenylphosphine rhodium chloride, palladium on carbon, Raney nickel, platinum dioxide, and platinum on carbon.

[0080] In some examples, the molar ratio of compound 4 to the catalyst is 1:0.01 to 10.

[0081] In some embodiments, in S4, the solvent used in the catalytic hydrogenation reaction includes at least one of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, methanol, ethyl acetate, acetone, MTBE, DMF, and NMP.

[0082] In some embodiments, in S4, the pressure of the catalytic hydrogenation reaction is 1 to 50 bar.

[0083] In some embodiments, in S4, the temperature of the catalytic hydrogenation reaction is 25–80°C.

[0084] In some embodiments, in S4, the catalytic hydrogenation reaction takes 2 to 24 hours.

[0085] It should be noted that the reaction principle of the epoxy ring-opening reaction includes: providing an epoxy-opening reagent, and reacting the compound 5 with the epoxy-opening reagent to undergo epoxy ring-opening to generate an active intermediate, which then undergoes elimination to generate a diene compound (i.e., the compound 6).

[0086] It should be understood that the selection of the epoxy-opening reagent can include a variety of reagents. Any epoxy-opening reagent that can cause compound 5 to undergo the epoxy ring-opening reaction to obtain compound 6 through the above reaction principle is included within the protection scope of the epoxy-opening reagent. Those skilled in the art can select according to actual needs, and this disclosure does not limit it.

[0087] In some embodiments, in S5, the epoxy ring-opening reagent used in the epoxy ring-opening reaction includes at least one of bis(dimethylamino)chlorate phosphoric acid / H2O, bis(diethylamino)phosphoryl chloride / H2O, and SmI2 / NiI2.

[0088] In some examples, the epoxy-opening reagent includes the bis(dimethylamino)chloric acid phosphorus / H2O.

[0089] In some examples, the molar ratio of compound 5 to the epoxy-opening reagent is 1:5 to 60.

[0090] In some embodiments, in S5, the solvent used in the epoxy ring-opening reaction includes at least one of dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, benzene, methanol, ethyl acetate, acetone, MTBE, diethyl ether, DMF, and NMP.

[0091] In some embodiments, in S5, the temperature of the epoxy ring-opening reaction is 25–120°C.

[0092] In some embodiments, in S5, the time for the epoxy ring-opening reaction is 1 to 24 hours.

[0093] In some embodiments, in S6, the reducing agent used in the reduction reaction includes at least one of diisobutylaluminum hydride, lithium aluminum hydride, red aluminum, sodium borohydride / aluminum trichloride, and Li(EtO)3AlH.

[0094] In some examples, the molar ratio of compound 6 to the reducing agent is 1:1 to 8.

[0095] In some embodiments, in S6, the solvent used in the reduction reaction includes at least one of dichloromethane, dichloroethane, tetrahydrofuran, toluene, benzene, ethyl acetate, MTBE, diethyl ether, and NMP.

[0096] In some embodiments, in S6, the temperature of the reduction reaction is –78 to 0°C.

[0097] In some embodiments, in S6, the reduction reaction takes 0.5 to 8 hours.

[0098] In some embodiments, in S7, the molar ratio of compound 7 to tert-butylsulfinamide is 1:0.5 to 6.

[0099] In some embodiments, in S7, the catalyst used in the condensation reaction includes at least one of tetraethyl titanate, tetraisopropyl titanate, potassium hydrogen sulfate, copper sulfate, magnesium sulfate, and PPTS.

[0100] In some examples, the molar ratio of compound 7 to the catalyst is 1:2 to 8.

[0101] In some embodiments, in S7, the solvent used in the condensation reaction includes at least one of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, benzene, ethyl acetate, acetone, MTBE, diethyl ether, 2-methyltetrahydrofuran, acetonitrile, and NMP.

[0102] In some examples, the solvent includes at least one of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, benzene, ethyl acetate, acetone, MTBE, diethyl ether, 2-methyltetrahydrofuran, and NMP.

[0103] In some embodiments, in S7, the temperature of the condensation reaction is 0–80°C.

[0104] In some embodiments, in S7, the condensation reaction takes 1 to 24 hours.

[0105] In some embodiments, in S8, the molar ratio of compound 8 to compound 9 is 1:0.5 to 6.

[0106] In some embodiments, in S8, the promoter used for the reductive coupling reaction includes samarium diiodide.

[0107] In some examples, the molar ratio of compound 8 to the promoter is 1:1 to 8.

[0108] In some embodiments, in S8, the activator used in the reductive coupling reaction includes at least one of tert-butanol, ethanol, and isopropanol.

[0109] In some examples, the activator includes the tert-butanol.

[0110] In some examples, the molar ratio of compound 8 to the activator is 1:1 to 8.

[0111] In some embodiments, in S8, the solvent used in the reductive coupling reaction includes at least one of dichloromethane, tetrahydrofuran, toluene, diethyl ether, 2-methyltetrahydrofuran, and NMP.

[0112] In some embodiments, in S8, the temperature of the reductive coupling reaction is -78 to -25°C.

[0113] In some embodiments, in S8, the reductive coupling reaction takes 0.5 to 18 hours.

[0114] In some embodiments, in S9, the acid used in the desulfonation reaction includes at least one of hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid, methanesulfonic acid, camphorsulfonic acid, and p-toluenesulfonic acid.

[0115] In some examples, the molar ratio of compound 10 to the acid is 1:2 to 20.

[0116] In some embodiments, in S9, the solvent used for the desulfonylation reaction includes at least one of methanol, ethanol, isopropanol, tert-butanol, acetonitrile, water, diethyl ether, dioxane, acetone, tetrahydrofuran, and ethyl acetate.

[0117] In some embodiments, in S9, the temperature of the desulfonylation reaction is –20 to 50°C.

[0118] In some embodiments, in S9, the desulfonylation reaction takes 0.5 to 6 hours.

[0119] In some embodiments, in S9, the base used in the lactamation reaction includes at least one of potassium carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium tert-butoxide, and sodium methoxide.

[0120] In some examples, the molar ratio of compound 10 to the base is 1:5 to 30.

[0121] In some embodiments, in S9, the solvent used for the lactamation reaction includes at least one of methanol, ethanol, isopropanol, tert-butanol, acetonitrile, water, diethyl ether, dioxane, acetone, tetrahydrofuran, and ethyl acetate.

[0122] In some embodiments, in S9, the temperature of the lactamation reaction is –20 to 50°C.

[0123] In some embodiments, in S9, the time for the lactamation reaction is 0.5 to 6 hours.

[0124] In some embodiments, in S10, the reducing agent used in the reducing amide reaction includes at least one of lithium aluminum hydride, red aluminum, diisobutylaluminum hydride, and sodium borohydride / aluminum trichloride.

[0125] In some examples, the molar ratio of compound 11 to the reducing agent is 1:1 to 10.

[0126] In some embodiments, in S10, the solvent used in the reducing amide reaction includes at least one of tetrahydrofuran, toluene, benzene, 2-methyltetrahydrofuran, diethyl ether, and ethylene glycol dimethyl ether.

[0127] In some embodiments, in S10, the temperature of the reducing amide reaction is –20 to 100°C.

[0128] In some embodiments, in S10, the time for the reducing amide reaction is 0.5 to 8 hours.

[0129] It is worth noting that the reaction principle of the synthetic method of cyclopamine provided in this disclosure includes: starting with compound 1 (i.e., a ketone compound) as a starting material, an addition reaction is carried out to obtain compound 2; compound 2 undergoes a cyanation reaction to obtain compound 3; compound 3 undergoes a rearrangement reaction under alkaline conditions to obtain compound 4; compound 4 undergoes a catalytic hydrogenation reaction to obtain compound 5; compound 5 undergoes an epoxy ring-opening reaction and eliminates the hydroxyl group to obtain compound 6 (i.e., a diene compound); compound 6 undergoes a reduction reaction to obtain compound 7; compound 7 undergoes a condensation reaction with tert-butylsulfinamide to obtain compound 8; compound 8 undergoes a reductive coupling reaction with compound 9 to obtain compound 10; compound 10 undergoes an E-ring closure and desulfonation reaction under acidic conditions, and further undergoes a lactamation reaction under alkaline conditions to obtain compound 11; compound 11 undergoes a reductive amide reaction to obtain the natural product cyclopamine.

[0130] The beneficial effects of this disclosure are:

[0131] The method for synthesizing cyclic pamine disclosed herein has a total of only 10 reaction steps and an overall yield of 5.3% to 11.6%, which can shorten the reaction route and improve the reaction yield, thereby achieving efficient chemical synthesis of cyclic pamine. Detailed Implementation

[0132] The technical solutions in some embodiments of this disclosure will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this disclosure, and not all embodiments. Based on the embodiments provided in this disclosure, all other embodiments obtained by those skilled in the art are within the scope of protection of this disclosure.

[0133] In describing some embodiments, the expression "A and / or B" may be used. It is readily understood that "A and / or B" includes the following three combinations: A only, B only, and a combination of A and B.

[0134] In describing some embodiments, the expressions "at least one of A, B and C" and "at least one of A, B or C" may be used, both of which have the same meaning and include the following combinations of A, B and C: only A, only B, only C, a combination of A and B, a combination of A and C, a combination of B and C, and a combination of A, B and C.

[0135] In describing some embodiments, the term "A / B" is used to indicate the type of reagent, meaning that the reagent is essentially a system containing both component A and component B. For example, for a reducing agent, "sodium borohydride / aluminum trichloride" is essentially a reducing system containing both sodium borohydride and aluminum trichloride.

[0136] Example 1

[0137]

[0138] Compound 1 (20.0 g, 57.8 mmol) was dissolved in dry tetrahydrofuran (300 mL) under argon protection. Ethynylmagnesium bromide (0.5 M in THF, 576 mL, 289 mmol) was slowly added to the reaction solution at –78 °C. The reaction solution was stirred at –78 °C for 30 min, then moved to 0 °C and stirred for 12 h. The reaction was quenched by adding saturated ammonium chloride aqueous solution (800 mL). The mixture was extracted with ethyl acetate (3 × 500 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1–1:1) to give compound 2 (18.1 g, yield 84%, white solid).

[0139] TLC (petroleum ether / ethyl acetate, 1:1 v / v): R f =0.50.

[0140] 1 H NMR (400MHz, CDCl3): δ5.36–5.34(m,1H),4.60–4.52(m,1H),4.14(dd,J=11.2,4.8Hz,1H),2.92(s,1H),2.61(s,1H),2.41–2.19( m,4H),2.03–1.95(m,5H),1.89–1.79(m,2H),1.77–1.68(m,2H),1.62–1.33(m,6H),1.16–1.04(m,2H),1.02(s,3H),0.89(s,3H).

[0141] 13 C NMR (100MHz, CDCl3): δ170.6,139.5,122.1,86.9,79.7,74.5,74.2,73.7,50.5,4 9.4,49.0,38.5,37.9,36.9,36.6,31.5,31.0,29.8,27.6,22.9,21.4,19.2,7.2.

[0142] IR(neat):ν max =3425,3303,2948,1724,1438,1365,1248,1025,803,751cm -1 .

[0143] HRMS(ESI):m / z calcd.for C 23 H 33 O4[M+H] +373.2373, found 373.2374.

[0144] Example 2

[0145]

[0146] Under argon protection, trimethylsilylacetylene (135 μL, 0.96 mmol) was dissolved in tetrahydrofuran (4.8 mL), and n-butyllithium (2.5 M in THF, 392 μL, 0.98 mmol) was slowly added at -78 °C. After stirring for 2 hours, a solution of ketone 1a (100 mg, 0.239 mmol) in THF (0.5 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at 25 °C for 12 h, then quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1–1:1) to give compound 2a (75 mg, 71% yield, white solid).

[0147] TLC (petroleum ether / ethyl acetate, 2:1 v / v):R f =0.41.

[0148] 1 H NMR(400MHz, CDCl3) δ5.33–5.28(m,1H),4.15(dd,J=12.0,4.0Hz,1H),3.5 1–3.41(m,1H),2.61(s,1H),2.60(s,1H),2.34–2.14(m,3H),2.06–1.95(m ,2H),1.90(s,1H),1.83–1.77(m,1H),1.76–1.69(m,3H),1.59–1.39(m,6H ),1.13–1.04(m,2H),1.03(s,3H),0.91(s,3H),0.88(s,9H),0.05(s,6H).

[0149] 13 C NMR (100MHz, CDCl3) δ141.5,120.8,87.1,80.0,74.9,74.3,72.6,50.7,49.6,49.3,42. 8,38.6,37.5,36.8,32.1,31.7,31.2,30.1,26.0(×3),23.1,19.5,18.3,7.4,–4.4(×2).

[0150] IR(neat)ν max:3499,3414,3275,2928,1471,1254,1138,1022,835,612cm -1 .

[0151] HRMS(ESI):m / z calcd.for C 27 H 45 O3Si[M+H] + 445.3132, found 445.3134.

[0152] Example 3

[0153]

[0154] Under argon protection, Ni(acac)₂ (1.24 g, 4.84 mmol), new copper reagent (1.21 g, 5.81 mmol), zinc cyanide (4.55 g, 38.7 mmol), and manganese powder (1.33 g, 24.2 mmol) were dissolved in degassed acetonitrile (193 mL). The reaction mixture was reacted at 25 °C for 20 min, and then compound 2 (18.0 g, 48.4 mmol) and degassed water (39 mL) were added. The reaction mixture was heated to 50 °C and stirred for 16 h. Water (200 mL) and MTBE (100 mL) were added to the reaction mixture. After filtration through diatomaceous earth, the mixture was extracted with MTBE (3 × 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-2:1) to give compound 3 (17.6 g, 91% yield, white solid).

[0155] TLC (petroleum ether / ethyl acetate, 1:1 v / v): R f =0.43.

[0156] 1 H NMR (400MHz, CDCl3): δ6.15(s,1H),5.93(s,1H),5.40–5.27(m,1H),4.65–4.42(m,1H),3.62(dd,J=11.2,5.2Hz,1H),2.60(s,2H),2.35–2.22(m, 2H),2.09–1.93(m,6H),1.87–1.77(m,2H),1.75–1.65(m,2H),1.61–1.41 (m,5H),1.33–1.21(m,1H),1.14–1.03(m,2H),1.02(s,3H),0.99(s,3H).

[0157] 13C NMR (100MHz, CDCl3): δ170.5,139.4,131.6,129.5,121.9,118.6,85.5,73.6,73.3,51 .2,48.7,48.4,37.8,36.8,36.5,35.9,31.4,31.0,29.9,27.5,23.5,21.3,19.1,9.0.

[0158] IR(neat):ν max =3455,2947,1719,1375,1365,1250,1066,1027,955,746,666cm -1 .

[0159] HRMS(ESI):m / z calcd.for C 24 H 34 NO4[M+H] + 400.2482, found 400.2485.

[0160] Example 4

[0161]

[0162] Under argon protection, Ni(acac)₂ (1.4 mg, 0.0054 mmol), L₁ (1.7 mg, 0.0065 mmol), zinc cyanide (5.0 mg, 0.043 mmol), and manganese powder (1.5 mg, 0.027 mmol) were dissolved in degassed acetonitrile (0.5 mL). The reaction mixture was reacted at 25 °C for 20 min, and then compound 2 (20 mg, 0.054 mmol) and degassed water (0.1 mL) were added. The reaction mixture was heated to 50 °C and stirred for 16 h. Water (0.2 mL) and MTBE (0.1 mL) were added to the reaction mixture. After filtration through diatomaceous earth, the mixture was extracted with MTBE (3 × 0.3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-2:1) to give compound 3 (15.4 mg, yield 72%, white solid).

[0163] TLC, 1 H NMR, 13 C NMR, IR, and HRMS are the same as described in Example 3.

[0164] Example 5

[0165]

[0166] Compound 3 (6.00 g, 15.0 mmol) was dissolved in dry dichloromethane (750 mL) under argon protection. 2-chloropyridine (10.6 mL, 113 mmol) was added to the reaction solution at –78 °C, and the mixture was stirred for 10 min. Trifluoromethanesulfonic anhydride (7.6 mL, 45.0 mmol) was then slowly added dropwise, and the reaction was continued at –78 °C for 2 h. TLC monitoring showed complete disappearance of the starting material. The reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (3 × 400 mL), and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40:1–3:1) to give compound 4 (3.90 g, yield 68%, white bubbly substance).

[0167] TLC (petroleum ether / ethyl acetate, 5:1 v / v):R f =0.50.

[0168] 1 H NMR (400MHz, CDCl3): δ6.08(s,1H),5.96(s,1H),5.37–5.35(m,1H),4.62–4.54(m,1H),2.39–2.33(m,1H),2.30–2.08(m,4H),2.01(s ,3H),1.92–1.79(m,3H),1.78–1.71(m,1H),1.70–1.59(m,3H),1.54–1.42(m,1H),1.42–1.27(m,3H),1.27–1.16(m,5H),0.98(s,3H).

[0169] 13 C NMR (100MHz, CDCl3): δ170.4,140.4,131.4,123.1,122.6,116.9,73.8,66.0,65.8,53 .1,44.3,41.1,40.2,38.1,37.5,36.8,32.0,28.0,27.4,27.2,24.6,21.3,18.6,18.4.

[0170] IR(neat):ν max :3020,2941,2225,1729,1377,1363,1244,1033,750,665cm -1 .

[0171] HRMS(ESI):m / z calcd.for C 24 H 32 NO3[M+H] + 382.2377, found 382.2380.

[0172] Example 6

[0173]

[0174] Compound 3 (50 mg, 0.125 mmol) was dissolved in 6.2 mL of dry dichloromethane under argon protection. 2-Bromopyridine (89 μL, 0.94 mmol) was added to the reaction solution at –78 °C, and the mixture was stirred for 10 min. Trifluoromethanesulfonic anhydride (63 μL, 0.375 mmol) was then slowly added dropwise, and the reaction was continued at –78 °C for 2 h. TLC monitoring showed complete disappearance of the starting material. The reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (3 × 10 mL), and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40:1–3:1) to give compound 4 (25 mg, yield 52%, white bubbly substance).

[0175] TLC, 1 H NMR, 13 C NMR, IR, and HRMS are the same as described in Example 5.

[0176] Example 7

[0177]

[0178] Compound 3 (50 mg, 0.125 mmol) was dissolved in 6.2 mL of dry dichloromethane under argon protection. 2-Fluoropyridine (81 μL, 0.94 mmol) was added to the reaction solution at –78 °C, and the mixture was stirred for 10 min. Trifluoromethanesulfonic anhydride (63 μL, 0.375 mmol) was then slowly added dropwise, and the reaction was continued at –78 °C for 2 h. TLC monitoring showed complete disappearance of the starting material. The reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (3 × 10 mL), and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40:1–3:1) to give compound 4 (19 mg, yield 39%, white bubbly substance).

[0179] TLC, 1 H NMR, 13 C NMR, IR, and HRMS are the same as described in Example 5.

[0180] Example 8

[0181]

[0182] Compound 4 (8.00 g, 21.0 mmol) was dissolved in dry 1,2-dichloroethane (175 mL), and rhodium tris(triphenylphosphine)chloride (1.94 g, 2.10 mmol) was added. The reaction mixture was placed under H2 (30 atm) and stirred at 50 °C for 10 h, then directly concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-2:1) to give compound 5 (6.60 g, yield 82%, white solid) and compound 5a (201 mg, yield 2.5%, white solid).

[0183] Compound 5

[0184] TLC (petroleum ether / ethyl acetate, 3:1 v / v):R f =0.45.

[0185] 1 H NMR (400MHz, CDCl3): δ5.40–5.33(m,1H),4.65–4.53(m,1H),2.81(d,J=7.6Hz,1H) ,2.40–2.33(m,1H),2.32–2.22(m,1H),2.22–2.18(m,1H),2.18–2.14(m,1H),2.14– 2.08(m,1H),2.03(s,3H),1.91–1.75(m,4H),1.72–1.60(m,3H),1.45–1.42(m,1H), 1.42–1.40(m,1H),1.39–1.35(m,4H),1.33(s,3H),1.27–1.13(m,3H),0.99(s,3H).

[0186] 13 C NMR (100MHz, CDCl3): δ170.5,140.4,123.1,120.5,73.9,64.9,64.7,53.2,43.9,41. 8,40.8,38.1,37.5,36.8,32.1,31.1,27.9,27.4,24.4,23.6,21.4,18.7,18.5,14.8.

[0187] IR(neat):ν max :3017,2940,2858,2240,1990,1730,1648,1448,1373,1245,1032,756cm -1 .

[0188] HRMS(ESI):m / z calcd.for C 24 H 34 NO3[M+H]+ 384.2533, found 384.2535.

[0189] Compound 5a

[0190] TLC (petroleum ether / ethyl acetate, 3:1 v / v):R f =0.61.

[0191] 1 H NMR (400MHz, CDCl3): δ5.46–5.28(m,1H),4.68–4.52(m,1H),2.78(q,J=7.2Hz,1H), 2.42–2.32(m,1H),2.32–2.26(m,1H),2.26–2.20(m,1H),2.20–2.13(m,1H),2.02(s, 3H),2.01–1.94(m,1H),1.94–1.82(m,3H),1.82–1.75(m,1H),1.74–1.60(m,3H),1. 53–1.45(m,1H),1.42(d,J=7.2Hz,3H),1.40(s,3H),1.38–1.16(m,5H),0.98(s,3H).

[0192] 13 C NMR (100MHz, CDCl3): δ170.5,140.5,123.2,120.3,73.9,65.4,64.9,53.2,43.9,41. 6,40.4,38.1,37.5,36.8,32.1,28.1,27.8,27.5,24.5,22.7,21.4,19.1,18.5,13.4.

[0193] IR(neat):ν max :3023,2941,2242,1728,1452,1371,1244,1030,905,810,752cm -1 .

[0194] HRMS(ESI):m / z calcd.for C 24 H 34 NO3[M+H] + 384.2533, found 384.2537.

[0195] Example 9

[0196]

[0197] Compound 4 (200 mg, 0.525 mmol) was dissolved in ethyl acetate (4 mL), and palladium on carbon (20 mg) was added. The reaction solution was placed under H2 (1 atm) and stirred at 25 °C for 10 h, then directly concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-2:1) to give compound 5 (66 mg, yield 33%, white solid) and compound 5a (70 mg, yield 35%, white solid).

[0198] TLC, 1 H NMR, 13 C NMR, IR, and HRMS are the same as described in Example 8.

[0199] Example 10

[0200]

[0201] Compound 4 (200 mg, 0.525 mmol) was dissolved in ethyl acetate (4 mL), and Pd(OH)₂ (20 mg) was added. The reaction solution was placed under H₂ (1 atm) and stirred at 25 °C for 10 h, then directly concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-2:1) to give compound 5 (80 mg, yield 40%, white solid) and compound 5a (62 mg, yield 31%, white solid).

[0202] TLC, 1 H NMR, 13 C NMR, IR, and HRMS are the same as described in Example 8.

[0203] Example 11

[0204]

[0205] Under argon protection, compound 5 (4.50 g, 11.7 mmol) was dissolved in a mixed solution of toluene and bis(dimethylamino)phosphoric acid (1:1, 90 mL). Water (4.5 mL) was added at 25 °C, and the reaction solution was stirred at 70 °C for 10 h. The reaction solution was then diluted with water (90 mL) and extracted with diethyl ether (3 × 80 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane = 3:1-1:4) to give compound 6 (2.79 g, yield 65%, white solid).

[0206] TLC (petroleum ether / dichloromethane, 2:1 v / v):R f =0.43.

[0207] 1H NMR (400MHz, CDCl3): δ5.69(s,1H),5.49–5.42(m,1H),4.67–4.58(m,1H),3.83(d,J=7.2Hz,1H),2.44–2.37(m,2H),2.31–2.23(m,2H),2.21–2.13 (m,3H),2.12–2.05(m,1H),2.04(s,3H),1.94–1.88(m,2H),1.84(s,3H), 1.78–1.59(m,3H),1.40(d,J=7.2Hz,3H),1.34–1.26(m,2H),1.00(s,3H).

[0208] 13 C NMR (100MHz, CDCl3): δ170.5,146.0,140.5,130.3,127.0,123.4,123.3,121.5,73.9,5 9.7,47.9,45.2,38.0,37.7,37.1,29.7,28.5,27.5,27.5,26.8,21.4,19.1,17.2,13.7.

[0209] IR(neat):ν max :3020,2925,2236,1731,1655,1444,1371,1244,1088,1033,964,766cm -1 .

[0210] HRMS(ESI):m / z calcd.for C 24 H 32 NO2[M+H] + 366.2428, found 366.2426.

[0211] Example 12

[0212]

[0213] Under argon protection, samarium diiodide (0.1 M in THF, 4.2 mL, 0.42 mmol) was added to a solution of compound 5 (20 mg, 0.052 mmol) and nickel diiodide (6.5 mg, 0.021 mmol) in tetrahydrofuran (0.8 mL). The reaction mixture was stirred at 50 °C for 10 h, quenched with saturated sodium thiosulfate solution, and extracted with ethyl acetate (3 × 12 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane = 3:1-1:4) to give compound 6 (9.7 mg, yield 51%, white solid).

[0214] TLC, 1 H NMR, 13 C NMR, IR, and HRMS are the same as described in Example 11.

[0215] Example 13

[0216]

[0217] Under argon protection, compound 6 (6.00 g, 16.4 mmol) was dissolved in dry toluene (328 mL), and DIBAL-H (1.0 M in THF, 65.7 mL, 65.7 mmol) was slowly added dropwise at –78 °C. After the addition was complete, the reaction was carried out at –78 °C for 4 h. The reaction was quenched by adding dropwise 20% aqueous acetic acid solution (164 mL), followed by the addition of ethyl acetate (300 mL) and water (600 mL). The mixture was stirred at 25 °C until distinct layers were formed. The aqueous phase was extracted with ethyl acetate (3 × 300 mL), and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1-2:1, v / v) to give compound 7 (4.45 g, yield 83%, white bubbly substance).

[0218] TLC (petroleum ether / ethyl acetate, 2:1 v / v):R f =0.47.

[0219] 1 H NMR (400MHz, CDCl3): δ9.56(s,1H),5.66(s,1H),5.45–5.38(m,1H),3.62–3.48(m,2H),2.41–2.34(m,1H),2.24–2.10(m,5H),2.05–1.99( m,1H),1.99–1.91(m,2H),1.91–1.83(m,5H),1.67–1.62(m,1H),1.62–1.56(m,2H),1.30–1.21(m,2H),1.19(d,J=6.8Hz,3H),0.99(s,3H).

[0220] 13 C NMR (100MHz, CDCl3): δ201.2,146.5,141.6,131.5,128.3,122.5,122.3,71.9,59 .7,50.4,48.1,45.3,41.8,38.3,37.0,31.3,29.8,27.8,27.7,19.2,14.0,11.2.

[0221] IR(neat):νmax :3364,2925,2833,2716,1721,1450,1378,1282,1216,1051,818,757cm -1 .

[0222] HRMS(ESI):m / z calcd.for C 22 H 31 O2[M+H] + 327.2319, found 327.2321.

[0223] Example 14

[0224]

[0225] Potassium hydrogen sulfate (7.01 g, 51.5 mmol), (R)-tert-butylsulfinamide (2.34 g, 19.3 mmol), and compound 7 (4.20 g, 12.9 mmol) were weighed into a dry reaction flask, and the mixture was purged with argon three times. After dissolving in dry toluene (250 mL), the reaction mixture was stirred at 25 °C for 10 h. The reaction was quenched with a saturated ammonium chloride aqueous solution (300 mL), and the aqueous phase was extracted with ethyl acetate (3 × 200 mL). The organic phases were combined, washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1-1:1, v / v) to give compound 8 (4.48 g, yield 81%, pale yellow solid).

[0226] TLC (petroleum ether / ethyl acetate, 2:1 v / v):R f =0.45.

[0227] 1 H NMR (400MHz, CDCl3): δ7.93 (d, J=4.0Hz, 1H), 5.61 (s, 1H), 5.46–5.38 (m, 1H), 3.89–3.80(m,1H),3.59–3.49(m,1H),2.41–2.32(m,1H),2.22–2.11(m,5H),2 .09–1.94(m,3H),1.93–1.87(m,2H),1.86(s,3H),1.70–1.65(m,1H),1.65–1. 57(m,2H),1.27(d,J=6.8Hz,3H),1.24–1.20(m,2H),1.18(s,9H),0.98(s,3H).

[0228] 13C NMR (100MHz, CDCl3): δ169.8,146.7,141.7,133.7,126.9,122.5,121.8,71.9,59.7,56.8 ,48.1,45.3,42.7,41.9,38.3,37.0,31.4,29.8,27.8,26.5,22.4(×3),19.1,14.1,13.7.

[0229] IR(neat):ν max :3402,2972,2924,1735,1612,1453,1365,1282,1214,1055,815,751cm -1 .

[0230] HRMS(ESI):m / z calcd.for C 26 H 40 NO2S[M+H] + 430.2774, found 430.2777.

[0231] Example 15

[0232]

[0233] Anhydrous copper sulfate (98 mg, 0.613 mmol), (R)-tert-butylsulfinamide (27.8 mg, 0.23 mmol), pyridine 4-methylbenzenesulfonate (3.8 mg, 0.0153 mmol), and compound 7 (50 mg, 0.153 mmol) were weighed into a dry reaction flask, and the mixture was purged with argon three times. After dissolving the compound in dry dichloromethane (3 mL), the reaction mixture was stirred at 25 °C for 10 h. The reaction was quenched with saturated ammonium chloride aqueous solution (5 mL), and the aqueous phase was extracted with dichloromethane (3 × 5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1-1:1, v / v) to give compound 8 (53 mg, 80% yield, pale yellow solid).

[0234] TLC, 1 H NMR, 13 C NMR, IR, and HRMS are the same as described in Example 14.

[0235] Example 16

[0236]

[0237] Compound 7 (50 mg, 0.153 mmol) and (R)-(+)-tert-butylsulfinamide (27.8 mg, 0.23 mmol) were dissolved in a mixed solvent (3 mL, CH3CN:THF = 4:1). Ti(OEt)4 (128 μL, 0.613 mmol) was slowly added dropwise at 0 °C, and the reaction was carried out at 50 °C for 10 h. The reaction was quenched with saturated NaCl aqueous solution at 0 °C. The mixture was extracted with ethyl acetate (3 × 10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1-2:1, v / v) to give product 8 (27 mg, yield 41%, white solid) and compound 7 (22 mg, yield 32%, white vesicle).

[0238] TLC, 1 H NMR, 13 C NMR, IR, and HRMS are the same as described in Example 14.

[0239] Example 17

[0240]

[0241] Under argon protection, compound 8 (4.20 g, 9.79 mmol), compound 9 (3.82 g, 29.4 mmol), and tert-butanol (3.75 mL, 39.2 mmol) were dissolved in dry tetrahydrofuran (200 mL). The mixture was added dropwise to samarium diiodide solution (0.1 M in THF, 392 mL, 39.2 mmol) at –78 °C and stirred overnight at –78 °C. The reaction was quenched with saturated sodium thiosulfate aqueous solution (500 mL) and water (500 mL). The aqueous phase was extracted with dichloromethane (3 × 300 mL). The combined organic phases were washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:1–20:1, v / v) to give compound 10 (3.84 g, 70% yield, white solid).

[0242] TLC (dichloromethane / methanol, 20:1 v / v): R f =0.43.

[0243] 11H NMR (400 MHz, CDCl3): δ 5.61 (s, 1H), 5.45–5.36 (m, 1H), 3.91–3.83 (m, 1H), 3.69 (s, 3H), 3.59–3.51 (m, 1H), 3.48 (s, 1H), 3.43–3.36 (m, 1H), 3.01–2.91 (m, 1H), 2.91–2.81 (m, 1H), 2.41–2.32 (m, 2H), 2.24–2.07 (m, 6H), 2.06–2.01 (m, 1H), 1.99–1.92 (m, 1H), 1.92–1.85 (m, 3H), 1.84 (s, 3H), 1.71–1.66 (m, 2H), 1.65–1.59 (m, 2H), 1.59–1.53 (m, 1H), 1.37–1.31 (m, 1H), 1.23 (d, J = 7.2 Hz, 3H), 1.12 (s, 9H), 1.09 (d, J = 6.4 Hz, 3H), 0.93 (s, 3H).

[0244] 13 13C NMR (100 MHz, CDCl3): δ 177.3, 146.6, 141.5, 137.0, 127.3, 122.7, 122.1, 71.9, 71.1, 59.8, 59.5, 55.7, 51.7, 47.9, 45.5, 41.9, 38.3, 37.0, 36.3, 36.2, 35.1, 31.3, 29.7, 27.8, 24.8, 22.6 (×3), 18.8, 18.4, 16.1, 13.8.

[0245] IR (neat): ν max : 3380, 3255, 3015, 2837, 1994, 1726, 1663, 1455, 1287, 1215, 1026, 744 cm -1 .

[0246] HRMS (ESI): m / z calcd. for C 32 1H 52 NO5S [M + H] + 562.3561, found 562.3563.

[0247] Example 18

[0248]

[0249] Under argon protection, compound 10 (3.00 g, 5.34 mmol) was dissolved in acetone (110 mL), and hydrochloric acid methanol solution (4.0 M, 13.4 mL, 53.5 mmol) was added dropwise at 0 °C. After the addition was complete, the temperature was raised to 25 °C and the reaction was allowed to proceed for 2 h. After the reaction was complete as monitored by LC-MS, the reaction solution was cooled to 0 °C, and potassium hydroxide aqueous solution (1.3 M, 62 mL, 80.1 mmol) was added. After the addition was complete, the temperature was raised to 25 °C and the reaction was allowed to proceed for 4 h. The reaction was quenched with saturated ammonium chloride aqueous solution at 0 °C, extracted with dichloromethane (3 × 100 mL), and the organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane (containing 0.5% ammonia) / methanol = 80:1-10:1, v / v) to obtain compound 11 (1.64 g, yield 72%, white solid).

[0250] TLC (dichloromethane / methanol, 20:1 v / v): R f =0.40.

[0251] 1 H NMR (400MHz, CDCl3): δ5.88(s,1H),5.41–5.32(m,1H),3.68–3.59(m,1H),3.59–3.47(m,2H),2.56–2 .42(m,2H),2.42–2.33(m,2H),2.30–2.14(m,4H),1.95(dd,J=14.8,3.2Hz,1H),1.87–1.80(m,2H),1 .77–1.66(m,3H),1.66–1.63(m,3H),1.62(s,1H),1.58–1.49(m,3H),1.46–1.37(m,1H),1.33(d,J=7 .2Hz,3H),1.31–1.30(m,1H),1.27(d,J=5.2Hz,1H),1.19(dd,J=13.2,3.6Hz,1H),1.00–0.87(m,6H).

[0252] 13 C NMR (100MHz, CDCl3): δ175.8,144.0,141.6,125.5,121.8,87.6,73.1,71.8,60.9,52.0,49.2, 41.8,41.6,39.8,38.1,36.5,35.1,34.4,31.8,31.3,31.0,29.0,24.5,18.7,18.3,13.2,10.5.

[0253] IR(neat):ν max:3390,3289,3075,2928,1748,1655,1459,1389,1273,1044,810,751cm -1 .

[0254] HRMS(ESI):m / z calcd.for C 27 H 40 NO3[M+H] + 426.3003, found 426.3006.

[0255] Example 19

[0256]

[0257] Under argon protection, compound 11 (1.60 g, 3.76 mmol) was dissolved in dry tetrahydrofuran (75 mL), and LiAlH4 (2.5 M in THF, 7.5 mL, 18.8 mmol) was added at 0 °C. After the addition was complete, the temperature was raised to 75 °C and the reaction was allowed to proceed for 4 h. After the reaction was cooled to room temperature, the reaction was quenched with saturated sodium potassium tartrate and potassium carbonate aqueous solutions. The aqueous phase was extracted with dichloromethane (5 × 100 mL), and the organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane (containing 0.5% ammonia) / methanol = 80:1-10:1, v / v) to give cyclopamine (1.40 g, 90% yield, white solid).

[0258] TLC (dichloromethane / methanol, 10:1 v / v): R f =0.45.

[0259] 1H NMR(400MHz,CD2Cl2):δ5.37(dt,J=4.8,2.0Hz,1H),3.47(td,J=11.2,4.4Hz,1H),3.15(dd,J=10.4,4.0Hz,1H),3.00(dd,J=12.8,4.4Hz,1H),2.59(d,J=9.2Hz,1H),2.43–2.36(m,1H),2.36–2.30(m,1H),2.28–2.20(m,3H),2.20–2.04(m,3H),1.84(dt,J=13.6,4.0,2.4Hz,1H),1.81–1.75(m,2H),1.75–1.65(m,3H),1.61(s,3H),1.57–1.55(m,1H),1.54–1.52(m,1H),1.49–1.46(m,1H),1.44–1.36(m,1H),1.32–1.25(m,1H),1.25–1.16(m,2H),1.09(d,J=11.2Hz,1H),0.96(s,3H),0.91(d,J=6.8Hz,3H),0.88(d,J=7.6Hz,3H).

[0260] 13 C NMR(100MHz,CD2Cl2):δ142.6,142.3,127.4,122.0,85.4,75.9,72.1,66.9,55.2,52.5,49.5,42.3(×2),40.3,39.5,38.6,36.9,32.3,32.0,31.9,31.5,29.2,25.1,19.1,18.8,13.2,10.8.

[0261] IR(neat):ν max :3344,2926,1457,1377,1259,1208,1117,1040,984,923,808,749cm -1 .

[0262] HRMS(ESI):m / z calcd.for C 23 H 33 O4[M+H] + 412.3210,found 412.3211.

[0263] The above description is merely a preferred embodiment of this disclosure. It should be understood that this disclosure is not limited to the forms disclosed herein and should not be construed as excluding other embodiments. It can be used in various other combinations, modifications, and environments, and can be altered within the scope of the concept described herein through the above teachings or techniques or knowledge in related fields. Any modifications and variations made by those skilled in the art that do not depart from the spirit and scope of this disclosure should be within the protection scope of the appended claims.

Claims

1. A method of synthesizing cyclopamine, characterized by, Includes the following steps: S1. Providing compound 1, subjecting the compound 1 to Grignard addition reaction to obtain compound 2; wherein R 1 is selected from acetyl; S2. Compound 2 is subjected to a cyanidation reaction to obtain compound 3; S3. Compound 3 was subjected to a rearrangement reaction under alkaline conditions to obtain compound 4; S4. Compound 4 was subjected to a catalytic hydrogenation reaction to obtain compound 5; S5. Compound 5 was subjected to an epoxy ring-opening reaction to obtain compound 6; S6. Compound 6 was reduced to obtain compound 7; S7. tert-butylsulfonamide is provided, and compound 7 is subjected to a condensation reaction with tert-butylsulfonamide to obtain compound 8; S8. Compound 9 is provided, and compound 8 is subjected to a reductive coupling reaction with compound 9 to obtain compound 10; S9. Compound 10 was subjected to a desulfonation reaction under acidic conditions to form a fully substituted tetrahydrofuran spirocycle, and then subjected to a lactamation reaction under alkaline conditions to obtain compound 11. S10. Compound 11 was subjected to a reductive amide reaction to obtain the cyclic pamine.

2. The method of synthesis of claim 1, wherein, In S1, the metal reagent used in the Grignard addition reaction is acetylenyl magnesium bromide; And / or, in S1, the solvent used in the Grignard addition reaction is at least one of tetrahydrofuran, toluene, dichloromethane, diethyl ether, methyl tert-butyl ether, and ethylene glycol dimethyl ether; And / or, in S1, the temperature of the Grignard addition reaction is –78°C to 25°C; And / or, in S1, the Grignard addition reaction takes 2 to 24 hours.

3. The method of synthesis of claim 1, wherein, In S2, the cyaniding reagent used in the cyanidation reaction is zinc cyanide; And / or, in S2, the catalyst used in the cyanation reaction is nickel acetylacetonate; And / or, in S2, the reducing agent used in the cyanidation reaction is at least one of magnesium powder, manganese powder, and zinc powder; And / or, in S2, the solvent used in the cyanidation reaction is acetonitrile and water; And / or, in S2, the temperature of the cyanidation reaction is 0~80℃; And / or, in S2, the cyanidation reaction takes 2 to 48 hours.

4. The method of synthesis of claim 1, wherein, In S3, the activator used in the rearrangement reaction is trifluoromethanesulfonic anhydride; And / or, in S3, the base used in the rearrangement reaction is at least one of 4-dimethylaminopyridine, 2-fluoropyridine, 2-bromopyridine, and 2-chloropyridine; And / or, in S3, the solvent used in the rearrangement reaction is at least one of dichloromethane, tetrahydrofuran, toluene, diethyl ether, ethylene glycol dimethyl ether, DMF, and methanol; And / or, in S3, the temperature of the rearrangement reaction is –78~25°C; And / or, in S3, the rearrangement reaction takes 0.5 to 6 hours.

5. The method of synthesis of claim 1, wherein, In S4, the catalyst used in the catalytic hydrogenation reaction is at least one of triphenylphosphine rhodium chloride, palladium on carbon, Raney nickel, platinum dioxide, and platinum on carbon. And / or, in S4, the solvent used in the catalytic hydrogenation reaction is at least one of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, methanol, ethyl acetate, acetone, MTBE, DMF, and NMP. And / or, in S4, the pressure of the catalytic hydrogenation reaction is 1~50 bar; And / or, in S4, the temperature of the catalytic hydrogenation reaction is 25~80°C; And / or, in S4, the catalytic hydrogenation reaction takes 2 to 24 hours.

6. The method of synthesis of claim 1, wherein, In S5, the epoxy ring-opening reagent used in the epoxy ring-opening reaction is bis(dimethylamino)chloric acid phosphorus / H2O; And / or, in S5, the solvent used in the epoxy ring-opening reaction is at least one of dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, benzene, methanol, ethyl acetate, acetone, MTBE, diethyl ether, DMF and NMP. And / or, in S5, the temperature of the epoxy ring-opening reaction is 25~120℃; And / or, in S5, the time for the epoxy ring-opening reaction is 1~24h.

7. The method of synthesis of claim 1, wherein, In S6, the reducing agent used in the reduction reaction is at least one of diisobutylaluminum hydride, lithium aluminum hydride, red aluminum, sodium borohydride / aluminum trichloride, and Li(EtO)3AlH; And / or, in S6, the solvent used in the reduction reaction is at least one of dichloromethane, dichloroethane, tetrahydrofuran, toluene, benzene, ethyl acetate, MTBE, diethyl ether, and NMP; And / or, in S6, the temperature of the reduction reaction is –78~0℃; And / or, in S6, the reduction reaction takes 0.5 to 8 hours.

8. The method of synthesis of claim 1, wherein, In S7, the molar ratio of compound 7 to tert-butylsulfinamide is 1:0.5~6; And / or, in S7, the catalyst used in the condensation reaction is at least one of tetraethyl titanate, tetraisopropyl titanate, potassium hydrogen sulfate, copper sulfate, magnesium sulfate, and PPTS. And / or, in S7, the solvent used in the condensation reaction is at least one of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, benzene, ethyl acetate, acetone, MTBE, diethyl ether, 2-methyltetrahydrofuran, and NMP. And / or, in S7, the temperature of the condensation reaction is 0~80°C; And / or, in S7, the condensation reaction takes 1 to 24 hours.

9. The method of synthesis of claim 1, wherein, In S8, the molar ratio of compound 8 to compound 9 is 1:0.5~6; And / or, in S8, the promoter used for the reductive coupling reaction is samarium diiodide; And / or, in S8, the activator used in the reductive coupling reaction is tert-butanol; And / or, in S8, the solvent used in the reductive coupling reaction is at least one of dichloromethane, tetrahydrofuran, toluene, diethyl ether, 2-methyltetrahydrofuran, and NMP; And / or, in S8, the temperature of the reductive coupling reaction is –78 to –25°C; And / or, in S8, the reductive coupling reaction takes 0.5 to 18 hours.

10. The synthesis method according to claim 1, characterized in that, In S9, the acid used in the desulfonation reaction is at least one of hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid, methanesulfonic acid, camphorsulfonic acid, and p-toluenesulfonic acid; And / or, in S9, the solvent used for the desulfonylation reaction is at least one of methanol, ethanol, isopropanol, tert-butanol, acetonitrile, water, diethyl ether, dioxane, acetone, tetrahydrofuran, and ethyl acetate. And / or, in S9, the temperature of the desulfonylation reaction is –20~50°C; And / or, in S9, the desulfonylation reaction takes 0.5 to 6 hours; And / or, in S9, the base used in the lactamation reaction is at least one of potassium carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium tert-butoxide, and sodium methoxide. And / or, in S9, the solvent used in the lactamation reaction is at least one of methanol, ethanol, isopropanol, tert-butanol, acetonitrile, water, diethyl ether, dioxane, acetone, tetrahydrofuran, and ethyl acetate. And / or, in S9, the temperature of the lactamation reaction is –20~50°C; And / or, in S9, the lactamation reaction takes 0.5 to 6 hours.

11. The method of synthesis of claim 1, wherein, In S10, the reducing agent used in the reducing amide reaction is at least one of lithium aluminum hydride, red aluminum, diisobutylaluminum hydride, and sodium borohydride / aluminum trichloride. And / or, in S10, the solvent used in the reducing amide reaction is at least one of tetrahydrofuran, toluene, benzene, 2-methyltetrahydrofuran, diethyl ether, and ethylene glycol dimethyl ether; And / or, in S10, the temperature of the reducing amide reaction is –20~100°C; And / or, in S10, the time for the reducing amide reaction is 0.5~8h.

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