Synthesis method of cyclopamine

Abstract

The invention relates to the technical field of organic synthesis, and discloses a cyclopamine synthesis method, which comprises the following steps: carrying out an addition reaction on a compound 1 as a starting raw material to obtain a compound 2, carrying out a cyanation reaction on the compound 2 to obtain a compound 3, carrying out a rearrangement reaction on the compound 3 to obtain a compound 4, and carrying out a catalytic hydrogenation reaction on the compound 4 to obtain a compound 5. Carrying out an epoxy ring-opening reaction on the compound 5 and eliminating hydroxyl to obtain a compound 6; carrying out a reduction reaction on the compound 6 to obtain a compound 7; carrying out a condensation reaction on the compound 7 and tert-butylsulfinamide to obtain a compound 8; carrying out a reduction coupling reaction on the compound 8 and a compound 9 to obtain a compound 10; according to the synthetic method, cyclopamine is taken as a raw material, a lactamization reaction is further performed to obtain a compound 11, the compound 11 is subjected to an amide reduction reaction to obtain the natural product cyclopamine, and the synthetic method can shorten the reaction route and improve the reaction yield, so that efficient chemical synthesis of cyclopamine is realized.

Description

Technical Field

[0001] The present disclosure relates to the technical field of organic synthesis, and in particular to a method for synthesizing cyclopamine. Background Art

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

[0003]

[0004] It can be seen from this that cyclopamine is a 6 / 6 / 5 / 6 / 5 / 6 six-ring complex natural product, and its molecular structural characteristics include: 1) the C-nor-D-homo steroid skeleton and the fully substituted tetrahydrofuran E ring are connected in a spiro form; 2) a unique trans 6,5-EF ring; 3) the middle D ring contains a tetrasubstituted olefin.

[0005] Beachy et al. have shown through research that cyclopamine is a potent Hedgehog signaling pathway inhibitor, inhibiting the Hedgehog (Hh) signaling pathway by targeting the Smoothened (Smo) receptor and exhibiting anti-tumor effects. As the first Smo inhibitor discovered, cyclopamine has become a research hotspot in anticancer drug development in recent years since its discovery that it effectively blocks Hh pathway signal transduction, thereby inhibiting tumor growth. For example, patidegib (also known as saridegib, IPI-926, SGT-610), prepared through semi-synthesis using cyclopamine as a starting material, is currently undergoing a Phase III clinical trial for the treatment of basal cell nevus syndrome.

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

[0007] Currently, the reported synthesis methods of cyclopamine include:

[0008] 1) In 2009, Giannis' group used dehydroepiandrosterone as the starting material and constructed a C-nor-D-homo steroid skeleton through a biomimetic 1,2-skeleton rearrangement. After 26 steps of reaction, they achieved the semi-synthesis of cyclopamine. The reaction route is as follows:

[0009]

[0010] 2) In 2023, the Baran group completed a convergent enantioselective total synthesis of cyclopamine using (S)-Wieland-Miescher ketone as the starting material, utilizing key reactions such as halogenation, Tsuji-Trost cyclization, and late-stage ring-closing metathesis (RCM) reactions. The longest linear step was 16, and the total steps were 22. The reaction route is as follows:

[0011]

[0012] 3) In 2023, Gao's team used the key photoinduced excited-state Nazarov reaction to achieve the total synthesis of veratramine. Then, through subsequent functional group transformation, they achieved the conversion of veratramine to cyclopamine. The longest linear step was 23, and the total steps were 31. The reaction route is as follows:

[0013]

[0014] However, although the above three synthetic strategies have solved the problem of artificial synthesis of cyclopamine, they still have defects such as lengthy steps (more than 22 steps in total) and low total yield (less than 1%).

[0015] Therefore, in order to further solve the problem of the source of cyclopamine, it is necessary to develop a more efficient and simple synthetic route. Summary of the Invention

[0016] The purpose of the present disclosure is to overcome the deficiencies of the prior art and provide a method for synthesizing cyclopamine, so as to at least shorten the reaction route and improve the reaction yield, thereby achieving the effect of efficient chemical synthesis of cyclopamine.

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

[0018] In one aspect, a method for synthesizing cyclopamine is provided. The method comprises the following steps:

[0019] S1.

[0020] Providing compound 1, and subjecting compound 1 to an addition reaction to obtain compound 2; wherein, R 1 Selected from acetyl or tert-butyldimethylsilyl;

[0021] S2. subjecting the compound 2 to a cyanation reaction to obtain compound 3;

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

[0023] S4. subjecting the compound 4 to a catalytic hydrogenation reaction to obtain compound 5;

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

[0025] S6. subjecting the compound 6 to a reduction reaction to obtain compound 7;

[0026] S7.

[0027] Providing tert-butylsulfenamide, and subjecting the compound 7 to a condensation reaction with the tert-butylsulfenamide to obtain compound 8;

[0028] S8.

[0029] Providing compound 9, and subjecting compound 8 to a reductive coupling reaction with compound 9 to obtain compound 10;

[0030] S9.

[0031] Compound 10 is subjected to a desulfonylation reaction under acidic conditions to form a fully substituted tetrahydrofuran spiro ring, and then subjected to a lactamization reaction under alkaline conditions to obtain compound 11;

[0032] S10.

[0033] The compound 11 is subjected to a reductive amide reaction to obtain the cyclopamine.

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

[0035] In some embodiments, in S1, the addition reaction comprises 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 allowing the metal reagent to undergo an addition reaction with the compound 1; the carbon-metal bond in the metal reagent has a strong polarity, so that the carbon atom connected to the metal carries a partial negative charge and has a strong nucleophilicity; when the metal reagent meets the ketone carbonyl of the compound 1, the negatively charged carbon atom in the metal reagent will initiate a nucleophilic attack on the positively charged carbon atom in the ketone carbonyl of the compound 1, thereby generating the corresponding alcohol addition product (i.e., the compound 2).

[0037] In this regard, it should be understood that there are multiple options for the metal reagent. Any metal reagent that can cause the compound 1 to undergo the metal reagent addition reaction and obtain the compound 2 through the above reaction principle is included in the protection scope of the metal reagent. Those skilled in the art can make a selection according to actual needs, and this disclosure does not limit this.

[0038] In some embodiments, in S1, the metal reagent used in the metal reagent addition reaction includes at least one of ethynylmagnesium bromide, trimethylsilylacetylmagnesium bromide, ethynyllithium, and trimethylsilylacetyllithium.

[0039] In this regard, it should be noted that the metal reagent addition reaction may be a Grignard addition reaction, and correspondingly, the metal reagent may be a Grignard reagent.

[0040] In some examples, the metal reagent includes at least one of the ethynylmagnesium bromide and the trimethylsilylacetylmagnesium bromide.

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

[0042] Exemplarily, the Grignard reagent includes ethynylmagnesium bromide.

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

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

[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 in 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 metal reagent addition reaction time is 2 to 24 hours.

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

[0051] It should be noted that the reaction principle of the cyanation reaction includes: providing a cyanation reagent, a catalyst and a reducing agent; using the reducing agent to reduce the catalyst to generate a Ni(0) species, and oxidizing and adding the Ni(0) species with water to generate a Ni(II) intermediate; an alkyne compound (i.e., the compound 2) is inserted into the Ni(II) intermediate through hydrogen nickelation to form an alkenyl nickel complex; the alkenyl nickel complex undergoes a transmetalation reaction with the cyanation reagent and then undergoes reduction elimination to generate a cyanation product (i.e., the compound 3).

[0052] In this regard, it should be understood that there are multiple options for the cyanation reagent. Any cyanation reagent that can cause the compound 2 to undergo the cyanation reaction and obtain the compound 3 through the above-mentioned reaction principle is included in the protection scope of the cyanation reagent. Those skilled in the art can make a selection according to actual needs, and this disclosure does not limit this.

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

[0054] In some examples, the cyanation reagent includes zinc cyanide.

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

[0056] Similarly, it should be understood that there may be multiple options for the catalyst. Any catalyst that can cause the compound 2 to undergo the cyanation reaction and obtain the compound 3 through the above reaction principle is included in the protection scope of the catalyst. Those skilled in the art can make a selection according to actual needs, and this disclosure does not limit this.

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

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

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

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

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

[0062] In some embodiments, in S2, the ligand used in the cyanation reaction includes at least one of neocopper reagent, 2,2'-bipyridine, and 4,4'-di-tert-butyl-2,2'-bipyridine.

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

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

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

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

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

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

[0069] In some embodiments, in S2, the cyanation reaction time is 2 to 48 hours.

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

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

[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 the compound 3 to the base is 1:2.5-15.

[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 time is 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 carbon, Raney nickel, platinum dioxide, palladium hydroxide, and platinum 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 the compound 4 to the catalyst is 1:0.01-10.

[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 time is 2 to 24 hours.

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

[0086] In this regard, it should be understood that there are multiple options for the epoxy ring-opening reagent. Any epoxy ring-opening reagent that can cause the compound 5 to undergo the epoxy ring-opening reaction and obtain the compound 6 through the above reaction principle is included in the protection scope of the epoxy ring-opening reagent. Those skilled in the art can make a selection according to actual needs, and this disclosure does not limit this.

[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)phosphorus oxychloride / H2O, bis(diethylamino)phosphorus oxychloride / H2O, and SmI2 / NiI2.

[0088] In some examples, the epoxy-opening reagent includes bis(dimethylamino)phosphonium chloride / H 2 O.

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

[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, 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 epoxy ring-opening reaction lasts for 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 tetrahydride, red aluminum, sodium borohydride / aluminum trichloride, and Li(EtO)3AlH.

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

[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 time is 0.5 to 8 hours.

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

[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 the compound 7 to the catalyst is 1:2-8.

[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 time is 1 to 24 hours.

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

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

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

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

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

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

[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 time is 0.5 to 18 hours.

[0114] In some embodiments, in S9, the acid used in the desulfonylation 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 the compound 10 to the acid is 1:2-20.

[0116] In some embodiments, in S9, the solvent used in 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 time is 0.5 to 6 hours.

[0119] In some embodiments, in S9, the base used in the lactamization 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 the compound 10 to the base is 1:5 to 30.

[0121] In some embodiments, in S9, the solvent used in the lactamization 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 lactamization reaction is -20 to 50°C.

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

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

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

[0126] In some embodiments, in S10, the solvent used in the amide reduction 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 amide reduction reaction is -20 to 100°C.

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

[0129] It is worth noting that the reaction principle of a synthetic method of cyclopamine provided in the present disclosure includes: using compound 1 (i.e., a ketone compound) as a starting material for an addition reaction 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-butylsulfenamide to obtain compound 8, compound 8 and compound 9 undergo a reductive coupling reaction to obtain compound 10, compound 10 undergoes an E-ring closure and desulfonylation reaction under acidic conditions, and further undergoes a lactamization reaction under alkaline conditions to obtain compound 11, and compound 11 undergoes a reductive amide reaction to obtain the natural product cyclopamine.

[0130] The beneficial effects of the present disclosure are:

[0131] The present invention discloses a method for synthesizing cyclopamine, wherein the total reaction route comprises only 10 steps and the total yield is 5.3% to 11.6%. This method can shorten the reaction route and improve the reaction yield, thereby realizing efficient chemical synthesis of cyclopamine. DETAILED DESCRIPTION

[0132] The following is a clear and complete description of the technical solutions in some embodiments of the present disclosure. Obviously, the embodiments described are only some of the embodiments of the present disclosure, not all of them. Based on the embodiments provided by the present disclosure, all other embodiments obtained by ordinary technicians in this field are within the scope of protection of the present disclosure.

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

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

[0135] When describing some embodiments, the expression "A / B" is used to describe the type of reagent, which means that the reagent is essentially a system containing both component A and component B. For example, with respect to the reducing agent, "sodium borohydride / aluminum chloride" is essentially a reducing system containing both sodium borohydride and aluminum chloride.

[0136] Example 1

[0137]

[0138] Under argon, compound 1 (20.0 g, 57.8 mmol) was dissolved in dry tetrahydrofuran (300 mL). Ethynylmagnesium bromide (0.5 M in THF, 576 mL, 289 mmol) was slowly added to the reaction mixture at –78°C. The reaction mixture was stirred at –78°C for 30 minutes and then moved to 0°C and stirred for 12 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride (800 mL). The mixture was extracted with ethyl acetate (3 × 500 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 to 1:1) to obtain compound 2 (18.1 g, 84% yield, as a 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, trimethylsilyl acetylene (135 μL, 0.96 mmol) was dissolved in tetrahydrofuran (4.8 mL), and n-butyl lithium (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) dissolved in THF (0.5 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at 25°C for 12 hours, 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 obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-1:1) to obtain 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, Ni(acac)2 (1.24 g, 4.84 mmol), neocuproine (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 allowed to react at 25°C for 20 min, followed by the addition of compound 2 (18.0 g, 48.4 mmol) and degassed water (39 mL). The reaction mixture was heated to 50°C and stirred for 16 h. Water (200 mL) and MTBE (100 mL) were then added to the reaction mixture. The mixture was filtered through celite and extracted with MTBE (3 × 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-2:1) to afford compound 3 (17.6 g, 91% yield, as a 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, 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 allowed to react at 25°C for 20 minutes before the addition of compound 2 (20 mg, 0.054 mmol) and degassed water (0.1 mL). The reaction mixture was heated to 50°C and stirred for 16 hours. Water (0.2 mL) and MTBE (0.1 mL) were added to the reaction mixture, which was filtered through celite and extracted with MTBE (3 × 0.3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-2:1) to afford compound 3 (15.4 mg, 72% yield, as a white solid).

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

[0164] Example 5

[0165]

[0166] Under argon, compound 3 (6.00 g, 15.0 mmol) was dissolved in dry dichloromethane (750 mL). 2-Chloropyridine (10.6 mL, 113 mmol) was added to the reaction mixture at –78°C. After stirring for 10 minutes, trifluoromethanesulfonic anhydride (7.6 mL, 45.0 mmol) was slowly added dropwise. The reaction was maintained at –78°C for 2 hours. TLC confirmed the complete disappearance of the starting material. The reaction was quenched with saturated sodium bicarbonate solution and the mixture was extracted with dichloromethane (3 × 400 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 / ethyl acetate = 40:1 to 3:1) to obtain compound 4 (3.90 g, 68% yield, as a white foam).

[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] Under argon, compound 3 (50 mg, 0.125 mmol) was dissolved in dry dichloromethane (6.2 mL). 2-Bromopyridine (89 μL, 0.94 mmol) was added to the reaction mixture at –78°C. After stirring for 10 minutes, trifluoromethanesulfonic anhydride (63 μL, 0.375 mmol) was slowly added dropwise. The reaction was maintained at –78°C for 2 hours. TLC confirmed the complete disappearance of the starting material. The reaction was quenched with saturated sodium bicarbonate solution and the mixture was extracted with dichloromethane (3 × 10 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 / ethyl acetate = 40:1 to 3:1) to obtain compound 4 (25 mg, 52% yield, as a white foam).

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

[0176] Example 7

[0177]

[0178] Under argon, compound 3 (50 mg, 0.125 mmol) was dissolved in dry dichloromethane (6.2 mL). 2-Fluoropyridine (81 μL, 0.94 mmol) was added to the reaction mixture at –78°C. After stirring for 10 minutes, trifluoromethanesulfonic anhydride (63 μL, 0.375 mmol) was slowly added dropwise. The reaction was maintained at –78°C for 2 hours. TLC confirmed the complete disappearance of the starting material. The reaction was quenched with saturated sodium bicarbonate solution and the mixture was extracted with dichloromethane (3 × 10 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 / ethyl acetate = 40:1 to 3:1) to obtain compound 4 (19 mg, 39% yield, as a white foam).

[0179] TLC, 1 H NMR, 13 C NMR, IR, and HRMS were 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 tris(triphenylphosphine)rhodium 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 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 obtain compound 5 (6.60 g, 82% yield, white solid) and compound 5a (201 mg, 2.5% yield, 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 mixture was placed under H2 (1 atm), stirred at 25°C for 10 h, and then 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 obtain compound 5 (66 mg, 33% yield, white solid) and compound 5a (70 mg, 35% yield, white solid).

[0198] TLC, 1 H NMR, 13 C NMR, IR, and HRMS were the same as those 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 mixture was placed under H2 (1 atm), stirred at 25°C for 10 h, and then 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 obtain compound 5 (80 mg, 40% yield, white solid) and compound 5a (62 mg, 31% yield, white solid).

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

[0203] Example 11

[0204]

[0205] Under argon, compound 5 (4.50 g, 11.7 mmol) was dissolved in a mixture of toluene and bis(dimethylamino)phosphonium chloride (1:1, 90 mL). Water (4.5 mL) was added at 25°C. The reaction solution was stirred at 70°C for 10 h, diluted with water (90 mL), and extracted with diethyl ether (3 x 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 obtain compound 6 (2.79 g, 65% yield, as a 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, samarium diiodide (0.1M in THF, 4.2mL, 0.42mmol) was added to a solution of compound 5 (20mg, 0.052mmol) and nickel diiodide (6.5mg, 0.021mmol) in tetrahydrofuran (0.8mL). The reaction solution was stirred at 50°C for 10h, quenched with saturated sodium thiosulfate solution, and extracted with ethyl acetate (3×12mL). 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 obtain compound 6 (9.7mg, 51% yield, as a white solid).

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

[0215] Example 13

[0216]

[0217] Under argon, compound 6 (6.00 g, 16.4 mmol) was dissolved in dry toluene (328 mL). DIBAL-H (1.0 M in THF, 65.7 mL, 65.7 mmol) was slowly added dropwise at –78°C. The reaction was allowed to react at –78°C for 4 h. The reaction was quenched by the dropwise addition of 20% aqueous acetic acid (164 mL). Ethyl acetate (300 mL) and water (600 mL) were added. The mixture was stirred at 25°C until distinct layers separated. The aqueous phase was extracted with ethyl acetate (3 × 300 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 / ethyl acetate = 8:1-2:1, v / v) to afford compound 7 (4.45 g, 83% yield, as a white foam).

[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 bisulfate (7.01 g, 51.5 mmol), (R)-tert-butylsulfenamide (2.34 g, 19.3 mmol), and compound 7 (4.20 g, 12.9 mmol) were weighed into a dry reaction flask and the argon atmosphere was purged three times. Dry toluene (250 mL) was added to dissolve the mixture, and the reaction mixture was stirred at 25°C for 10 h. The reaction was quenched with saturated aqueous ammonium chloride (300 mL), and the aqueous phase was extracted with ethyl acetate (3 × 200 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 (petroleum ether / ethyl acetate = 8:1 to 1:1, v / v) to obtain compound 8 (4.48 g, 81% yield, as a light 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-butylsulfenamide (27.8 mg, 0.23 mmol), 4-methylbenzenesulfonate pyridinium (3.8 mg, 0.0153 mmol), and compound 7 (50 mg, 0.153 mmol) were weighed into a dry reaction flask and the argon atmosphere was purged three times. Dry dichloromethane (3 mL) was added to dissolve the mixture, and the reaction mixture was stirred at 25°C for 10 h. The reaction was quenched with saturated aqueous ammonium chloride (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 the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1 to 1:1, v / v) to obtain compound 8 (53 mg, 80% yield, as a light yellow solid).

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

[0235] Example 16

[0236]

[0237] Compound 7 (50 mg, 0.153 mmol) and (R)-(+)-tert-butylsulfenamide (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 allowed to react at 50°C for 10 h. The reaction was quenched with saturated aqueous NaCl 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 obtain product 8 (27 mg, 41% yield, white solid) and compound 7 (22 mg, 32% yield, white foam).

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

[0239] Example 17

[0240]

[0241] Under argon, 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 a 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 aqueous sodium thiosulfate (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 obtain compound 10 (3.84 g, 70% yield, as a 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 H 52 NO5S [M + H] + 562.3561, found 562.3563.

[0247] Example 18

[0248]

[0249] Under argon, compound 10 (3.00 g, 5.34 mmol) was dissolved in acetone (110 mL). Hydrochloric acid in methanol (4.0 M, 13.4 mL, 53.5 mmol) was added dropwise at 0°C. After addition, the temperature was raised to 25°C and allowed to react for 2 h. After complete reaction, as monitored by LC-MS, the reaction mixture was cooled to 0°C and potassium hydroxide (1.3 M, 62 mL, 80.1 mmol) was added. After addition, the temperature was raised to 25°C and allowed to react for 4 h. The reaction was quenched with saturated ammonium chloride at 0°C and extracted with dichloromethane (3 × 100 mL). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield 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 yield compound 11 (1.64 g, 72% yield, as a 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, compound 11 (1.60 g, 3.76 mmol) was dissolved in dry tetrahydrofuran (75 mL). LiAlH₄ (2.5 M in THF, 7.5 mL, 18.8 mmol) was added at 0°C. After addition, the temperature was raised to 75°C and the reaction mixture was allowed to react for 4 h. After cooling to room temperature, the reaction was quenched with saturated aqueous potassium sodium tartrate and aqueous potassium carbonate. The aqueous phase was extracted with dichloromethane (5 × 100 mL), and the combined organic phases were 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% aqueous ammonia) / methanol = 80:1-10:1, v / v) to afford cyclopamine (1.40 g, 90% yield, as a 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 foregoing description is merely a preferred embodiment of the present disclosure. It should be understood that the present disclosure is not limited to the form disclosed herein and should not be construed as excluding other embodiments. Rather, the present disclosure is applicable to various other combinations, modifications, and environments and can be modified within the scope of the concepts described herein through the above teachings or techniques or knowledge in the relevant fields. Modifications and variations made by those skilled in the art that do not depart from the spirit and scope of the present disclosure are intended to be protected by the claims appended hereto.

Claims

1. A method for synthesizing cyclopamine, characterized in that: The following steps are involved: S1. Providing compound 1, and subjecting compound 1 to an addition reaction to obtain compound 2; wherein, R 1 Selected from acetyl or tert-butyldimethylsilyl; S2. subjecting the compound 2 to a cyanation reaction to obtain compound 3; S3. The compound 3 is subjected to a rearrangement reaction under alkaline conditions to obtain compound 4; S4. subjecting the compound 4 to a catalytic hydrogenation reaction to obtain compound 5; S5. The compound 5 is subjected to an epoxy ring-opening reaction to obtain compound 6; S6. subjecting the compound 6 to a reduction reaction to obtain compound 7; S7. Providing tert-butylsulfenamide, and subjecting the compound 7 to a condensation reaction with the tert-butylsulfenamide to obtain compound 8; S8. Providing compound 9, and subjecting compound 8 to a reductive coupling reaction with compound 9 to obtain compound 10; S9. Compound 10 is subjected to a desulfonylation reaction under acidic conditions to form a fully substituted tetrahydrofuran spiro ring, and then subjected to a lactamization reaction under alkaline conditions to obtain compound 11; S10. The compound 11 is subjected to a reductive amide reaction to obtain the cyclopamine.

2. The synthesis method according to claim 1, wherein R 1 is selected from the acetyl group.

3. The synthesis method according to claim 1, wherein In S1, the addition reaction includes a metal reagent addition reaction.

4. The synthesis method according to claim 3, characterized in that In S1, the metal reagent used in the metal reagent addition reaction includes at least one of acetylenic magnesium bromide, trimethylsilyl acetylenic magnesium bromide, acetylenic lithium and trimethylsilyl acetylenic lithium; And / or, 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; and / or, in S1, the temperature of the metal reagent addition reaction is -78°C to 25°C; And / or, in S1, the metal reagent addition reaction time is 2 to 24 hours.

5. The synthesis method according to claim 1, characterized in that In S2, the cyanation reagent used in the cyanation reaction includes at least one of zinc cyanide and cuprous cyanide; And / or, in S2, the catalyst used in the cyanation reaction includes at least one of nickel acetylacetonate and nickel iodide; and / or, in S2, the reducing agent used in the cyanation reaction comprises at least one of magnesium powder, manganese powder and zinc powder; and / or, in S2, the ligand used in the cyanation reaction comprises at least one of neocopper reagent, 2,2'-bipyridine and 4,4'-di-tert-butyl-2,2'-bipyridine; and / or, in S2, the solvent used in the cyanation reaction comprises at least one of acetonitrile, tetrahydrofuran and water; and / or, in S2, the temperature of the cyanation reaction is 0 to 80° C.; And / or, in S2, the cyanation reaction time is 2 to 48 hours.

6. The synthesis method according to claim 1, characterized in that In S3, the activating agent used in the rearrangement reaction includes trifluoromethanesulfonic anhydride; and / or, in S3, the base used in the rearrangement reaction comprises at least one of 4-dimethylaminopyridine, pyridine, 2-fluoropyridine, 2-bromopyridine and 2-chloropyridine; and / or, in S3, the solvent used in the rearrangement reaction comprises 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 to 25°C; And / or, in S3, the rearrangement reaction time is 0.5 to 6 hours.

7. The synthesis method according to claim 1, characterized in that In S4, the catalyst used in the catalytic hydrogenation reaction includes at least one of triphenylphosphine rhodium chloride, palladium carbon, Raney nickel, platinum dioxide, palladium hydroxide and platinum carbon; And / or, 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; and / or, in S4, the pressure of the catalytic hydrogenation reaction is 1 to 50 bar; And / or, in S4, the temperature of the catalytic hydrogenation reaction is 25 to 80°C; And / or, in S4, the catalytic hydrogenation reaction time is 2 to 24 hours.

8. The synthesis method according to claim 1, characterized in that In S5, the epoxy ring-opening reaction uses an epoxy ring-opening reagent comprising at least one of bis(dimethylamino)phosphorus oxychloride / H2O, bis(diethylamino)phosphorus oxychloride / H2O, and SmI2 / NiI2; And / or, 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, ether, DMF and NMP; and / or, in S5, the temperature of the epoxy ring-opening reaction is 25 to 120° C.; And / or, in S5, the time of the epoxy ring-opening reaction is 1 to 24 hours.

9. The synthesis method according to claim 1, characterized in that In S6, the reducing agent used in the reduction reaction includes at least one of diisobutylaluminum hydride, lithium aluminum tetrahydride, red aluminum, sodium borohydride / aluminum trichloride and Li(EtO)3AlH; And / or, 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; And / or, in S6, the temperature of the reduction reaction is -78 to 0°C; And / or, in S6, the reduction reaction time is 0.5 to 8 hours.

10. The synthesis method according to claim 1, characterized in that In S7, the molar ratio of the compound 7 to the tert-butylsulfenamide is 1:0.5-6; And / or, 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; And / or, 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; and / or, in S7, the temperature of the condensation reaction is 0 to 80° C.; And / or, in S7, the condensation reaction time is 1 to 24 hours.

11. The synthesis method according to claim 1, characterized in that In S8, the molar ratio of the compound 8 to the compound 9 is 1:0.5-6; and / or, in S8, the promoter used in the reductive coupling reaction includes samarium diiodide; And / or, in S8, the activating agent used in the reductive coupling reaction includes at least one of tert-butyl alcohol, ethanol and isopropanol; And / or, in S8, the solvent used in the reductive coupling reaction includes 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 reduction coupling reaction time is 0.5 to 18 hours.

12. The synthesis method according to claim 1, characterized in that In S9, the acid used in the desulfonylation reaction includes 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 in the desulfonylation reaction comprises 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 to 50°C; and / or, in S9, the desulfonylation reaction time is 0.5 to 6 hours; and / or, in S9, the base used in the lactamization reaction includes 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 lactamization reaction comprises 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 lactamization reaction is -20 to 50°C; And / or, in S9, the lactamization reaction time is 0.5 to 6 hours.

13. The synthesis method according to claim 1, characterized in that In S10, the reducing agent used in the amide reduction reaction includes at least one of lithium aluminum tetrahydride, red aluminum, diisobutylaluminum hydride, and sodium borohydride / aluminum trichloride; And / or, in S10, the solvent used in the amide reduction reaction includes at least one of tetrahydrofuran, toluene, benzene, 2-methyltetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether; and / or, in S10, the temperature of the amide reduction reaction is -20 to 100° C.; And / or, in S10, the time of the amide reduction reaction is 0.5 to 8 hours.

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