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【结 构 式】 
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【分子编号】13484 【品名】Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide 【CA登记号】2065-66-9 |
【 分 子 式 】C19H18IP 【 分 子 量 】404.230152 【元素组成】C 56.46% H 4.49% I 31.39% P 7.66% |
合成路线1
该中间体在本合成路线中的序号：(VII)YM-796 can be obtained by two different ways: 1) The Wittig condensation of 1-methylpiperidin-4-one (I) with 2-(diethoxyphosphoryl)acetic acid ethyl ester (II) by means of NaH in dimethoxyethane gives 2-(1-methylpiperidin-4-ylidene) acetic acid ethyl ester (III), which is cyclized with ethyl lactate (IV) by means of NaH in DMSO yielding 2,8-dimethyl-3-oxo-1-oxa-8-azaspiro[4.5]decane-4-carboxylic acid ethyl ester (V). The decarboxylation of (V) with refluxing aqueous 1N HCl affords 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one (VI), which is submitted to a new Wittig condensation with methyltriphenylphosphonium iodide (or bromide) (VII) by means of NaH in DMSO to give racemic 2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane (VIII). Finally, this compound is submitted to optical resolution with L-tartaric acid or with di-p-toluoyl-D-tartaric acid. 2) The Wittig condensation of 4-oxopiperidine-1-carboxylic acid ethyl ester (IX) with phosphorane (VII) as before gives the corresponding methylene derivative (X), which is submitted to alkoxybromination with N-bromosuccinimide (NBS) and (S)-3-butyn-2-ol (XI) yielding (S)-4-(bromomethyl)-4-(1-methyl-2-propynyloxy)piperidine-1-carboxylic acid ethyl ester (XII). The radical cyclization of (XII) with NaBH4 catalyzed by bis(dimethylglyoximato)(pyridine)cobalt(III) chloride [chlorocobaloxime(III)] affords (S)-2-methyl-3-methylene-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid ethyl ester (XIII), which is finally reduced with sodium bis(2-methoxyethoxy)aluminum hydride (vitride) in toluene and treated with fumaric acid to obtain the sesquifumarate salt.
| 【1】 Ngo, J.; Martel, A.M.; Castaner, J.; YM-796. Drugs Fut 1997, 22, 2, 144. |
| 【2】 Tsukamoto, S.; Kondo, Y.; Igarashi, S.; An efficient synthesis of (S)-(-)-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane by cobaloxime(I)-mediated radical cyclization. Heterocycles 1995, 41, 8, 1771-1778. |
| 【3】 Tsukamoto, S.; Fujii, M.; Yasunaga, T.; Matsuda, K.; Wanibuchi, F.; Hidaka, K.; Furuya, T.; Tamura, T.; Synthesis and structure-activity studies of a series of 1-oxa-8-azaspiro[4.5]decanes as M1 muscarinic agonists. Chem Pharm Bull 1995, 43, 5, 842-852. |
| 【4】 Tsukamoto, S.-I.; Nagaoka, H.; Usuda, S.; Harada, M.; Tamura, T. (Yamanouchi Pharmaceutical Co., Ltd.); Heterocyclic spiro cpds. and their preparation. AU 8823449; EP 0311313; JP 1990036183; US 4996210 . |
| 【5】 Tsukamoto, S.; Kohinata, T.; Fujii, M.; Tomisawa, S. (Yamanouchi Pharmaceutical Co., Ltd.); (-)-(S)-2,8-Dimethyl-3-methylene-1-oxa-8-azaspiro[4,5]decane L-tartrate. EP 0590150; JP 1993508699; WO 9220683 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10919 | 1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one | 1445-73-4 | C6H11NO | 详情 | 详情 |
| (II) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (III) | 13480 | ethyl 2-(1-methyl-4-piperidinylidene)acetate | C10H17NO2 | 详情 | 详情 | |
| (IV) | 13481 | ethyl lactate; ethyl 2-hydroxypropanoate | 97-64-3 | C5H10O3 | 详情 | 详情 |
| (V) | 13482 | ethyl 2,8-dimethyl-3-oxo-1-oxa-8-azaspiro[4.5]decane-4-carboxylate | C13H21NO4 | 详情 | 详情 | |
| (VI) | 13483 | 2,8-Dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one | C10H17NO2 | 详情 | 详情 | |
| (VII) | 13484 | Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide | 2065-66-9 | C19H18IP | 详情 | 详情 |
| (VIII) | 13485 | 2,8-Dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane | C11H19NO | 详情 | 详情 | |
| (IX) | 13486 | Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone | 29976-53-2 | C8H13NO3 | 详情 | 详情 |
| (X) | 13487 | ethyl 4-methylene-1-piperidinecarboxylate | C9H15NO2 | 详情 | 详情 | |
| (XI) | 13488 | (2S)-3-Butyn-2-ol; (S)-(-)-3-Butyn-2-ol | 2914-69-4 | C4H6O | 详情 | 详情 |
| (XII) | 13489 | ethyl 4-(bromomethyl)-4-[[(1S)-1-methyl-2-propynyl]oxy]-1-piperidinecarboxylate | C13H20BrNO3 | 详情 | 详情 | |
| (XIII) | 13490 | ethyl (2S)-2-methyl-3-methylene-1-oxa-8-azaspiro[4.5]decane-8-carboxylate | C13H21NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)The condensation of (XI) with phosphonate (XII) by means of NaH in THF furnishes the unsaturated ester (XIII). The reduction of the double bond of (XIII) with H2 over Rh/Al2O3, followed by reduction of the ester group with DIBAL and oxidation of the resulting alcohol with DMP, gives rise to the aldehyde (XIV). The Wittig condensation of (XIV) with phosphonium salt (XV) by means of BuLi in THF yields the terminal olefin (XVI), which is selectively desilylated with Ts-OH to afford the primary alcohol (XVII). Finally, this compound is oxidized to the target carboxylic acid intermediate (XVIII) with DMP and NaClO2 in dichloromethane/THF.
| 【1】 Sinha, S.C.; Barbas, C.F. III; Lerner, R.A.; The antibody catalysis route to the total synthesis of epothilones. Proc Natl Acad Sci USA 1998, 95, 25, 14603. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 45549 | (3S,4S,5R,8S)-4,8,10-tris[[tert-butyl(dimethyl)silyl]oxy]-3,5,7,7-tetramethyl-6-oxodecanal | C32H68O5Si3 | 详情 | 详情 | |
| (XII) | 35909 | ethyl 3-(diethoxyphosphoryl)propanoate | 3699-67-0 | C9H19O5P | 详情 | 详情 |
| (XIII) | 45550 | ethyl (E,5S,6S,7R,10S)-6,10,12-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7,9,9-tetramethyl-8-oxo-2-dodecenoate | 2463-77-6 | C36H74O6Si3 | 详情 | 详情 |
| (XIV) | 45551 | (5S,6S,7R,10S)-6,10,12-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7,9,9-tetramethyl-8-oxododecanal | 94-59-7 | C34H72O5Si3 | 详情 | 详情 |
| (XV) | 13484 | Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide | 2065-66-9 | C19H18IP | 详情 | 详情 |
| (XVI) | 44436 | (5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one | C35H74O4Si3 | 详情 | 详情 | |
| (XVII) | 44437 | (5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one | C29H60O4Si2 | 详情 | 详情 | |
| (XVIII) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XV)The aldol condensation of 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XIX) with acetone (XX) catalyzed by antibody 38C2 gives the chiral aldol (XXI), which is protected with Tbdms-Cl and imidazole, yielding the silyl ether (XXII). The reaction of (XXII) with Tbdms-OTf, followed by oxidation with MCPBA and reduction with NaBH4, affords the vicinal diol (XXIII), which is cleaved with Pb(OAc)4 to provide the aldehyde (XXIV). The Wittig condensation of (XXIV) with phosphonium salt (XV) gives olefinic silyl ether (XXV), which is desilylated with TBAF in THF to yield the homoallylic alcohol (XXVI). The esterification of alcohol (XXVI) with the previously described carboxylic acid (XVIII) by means of EDC in dichloromethane affords the ester (XXVII), which is submitted to a ring-closing metathesis by means of Grubb's catalyst to provide the macrolactone (XXVIII). The desilylation of (XXVIII) with HF and pyridine furnishes the precursor (XXIX), which is finally epoxidated with trifluoroacetone and oxone to give the target epothilone A.
| 【1】 Sinha, S.C.; Barbas, C.F. III; Lerner, R.A.; The antibody catalysis route to the total synthesis of epothilones. Proc Natl Acad Sci USA 1998, 95, 25, 14603. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 13484 | Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide | 2065-66-9 | C19H18IP | 详情 | 详情 |
| (XVIII) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 | |
| (XIX) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XX) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (XXI) | 45552 | (4S,5E)-4-hydroxy-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-5-hexen-2-one | C11H15NO2S | 详情 | 详情 | |
| (XXII) | 45553 | (4S,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-5-hexen-2-one | 2815-95-4 | C17H29NO2SSi | 详情 | 详情 |
| (XXIII) | 45554 | (4S,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-5-hexene-1,2-diol | C17H31NO3SSi | 详情 | 详情 | |
| (XXIV) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (XXV) | 44444 | 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether | C17H29NOSSi | 详情 | 详情 | |
| (XXVI) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XXVII) | 44445 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate | C40H71NO5SSi2 | 详情 | 详情 | |
| (XXVIII) | 44446 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C38H67NO5SSi2 | 详情 | 详情 | |
| (XXIX) | 44447 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C26H39NO5S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXXIIII)The selective deprotection of (XXX) with CSA in dichloromethane gives the primary alcohol (XXXI), which is oxidized with DMP in dichloromethane to yield the aldehyde (XXXII). The condensation of (XXXII) with methyltriphenylphosphonium iodide (XXXIII) by means of BuLi in hexane/THF, followed by treatment with HCl in ethanol, affords the diunsaturated vicinal diol (XXXIV), which is selectively silylated to provide the vicinal diol (XXXV). The monosulfonation of (XXXV) with Ms-Cl and TEA furnishes the mesylate (XXXVI), which is cyclized to the epoxide (XXXVII) by means of K2CO3 in methanol. The oxidation of the terminal double bond of (XXXVII) with OsO4 and NaIO4 gives the aldehyde (XXXVIII), which is condensed with the intermediate ketone (XVIII) by means of LDA in THF to provide the adduct (XXXIX).
| 【1】 Mulzer, J.; et al.; A novel highly stereoselective total synthesis of epothilone B and of its (12R,13R) acetonide. Tetrahedron Lett 2000, 41, 40, 7635. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIIII) | 13484 | Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide | 2065-66-9 | C19H18IP | 详情 | 详情 |
| (XVIII) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XXX) | 46184 | tert-butyl(dimethyl)silyl (2S)-5-[(4R,5R)-5-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl]-2-methylpentyl ether; 4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-methyl-1-butenyl]-2-methyl-1,3-thiazole | C33H63NO4SSi2 | 详情 | 详情 | |
| (XXXI) | 46186 | (2S)-5-[(4R,5R)-5-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl]-2-methyl-1-pentanol | C27H49NO4SSi | 详情 | 详情 | |
| (XXXII) | 46187 | (2S)-5-[(4R,5R)-5-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl]-2-methylpentanal | C27H47NO4SSi | 详情 | 详情 | |
| (XXXIV) | 46188 | (1E,3S,5R,6R,10S)-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-1,11-dodecadiene-3,5,6-triol | C19H31NO3S | 详情 | 详情 | |
| (XXXV) | 46189 | (1E,3S,5R,6R,10S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-1,11-dodecadiene-5,6-diol | C25H45NO3SSi | 详情 | 详情 | |
| (XXXVI) | 46190 | (1R,2R,6S)-1-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-hydroxy-2,6-dimethyl-7-octenyl methanesulfonate | C26H47NO5S2Si | 详情 | 详情 | |
| (XXXVII) | 46191 | tert-butyl(dimethyl)silyl (1S,2E)-2-methyl-1-([(2S,3R)-3-methyl-3-[(4S)-4-methyl-5-hexenyl]oxiranyl]methyl)-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-4-[(2S,3R)-3-methyl-3-[(4S)-4-methyl-5-hexenyl]oxiranyl]-1-butenyl)-2-methyl-1,3-thiazole | C25H43NO2SSi | 详情 | 详情 | |
| (XXXVIII) | 46192 | (2S)-5-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-2-methylpentanal | C24H41NO3SSi | 详情 | 详情 | |
| (XXXIX) | 46193 | (4S,7R,8S,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-12-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-8-hydroxy-5,5,7,9-tetramethyl-1-dodecen-6-one | C40H73NO5SSi2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VII)The condensation of aldehyde (I) with boronate (II) in toluene gives the chiral alcohol (III), which is treated with Tbdms-OTf and TEA to yield the silyl ether (IV). The hydroxylation of the terminal double bond of (IV) by means of 9-BBN in refluxing THF affords the primary alcohol (V), which is oxidized by means of the Swern oxidant to provide the aldehyde (VI). The homologation of (VI) with methyltriphenylphosphonium iodide (VII) and NaHMDS gives the unsaturated compound (VIII), which is deprotected at the ketonide group by means of TFA in dichloromethane to afford the diol (IX). The dehydration of (IX) by means of tosylimidazole (X) and NaH in THF provides the epoxide (XI), which is condensed with the Grignard reagent (XIII) (obtained by reaction of the tributyltin derivative (XII) with MgBr2) to give the secondary alcohol (XIV). The reaction of 2-allyl-6-methoxybenzamide (XV) with I2 in THF/water gives the lactone (XVI), which is treated with Zn and AcOH to yield 2-allyl-6-methoxybenzoic acid (XVII). The esterification of acid (XVII) with alcohol (XIV) by means of DEAD and PPH3 affords the corresponding ester (XVIII), which is submitted to a ring closing metathesis reaction by means of a Ru catalyst to provide the macrolactone (XIX). The cleavage of the Pmb protecting group of (XIX) by means of DDQ gives the primary alcohol (XX), which is oxidized to the aldehyde (XXI) by means of DMP oxidant.
| 【1】 Smith, A.B.; Zheng, J.Y.; Total synthesis of (-)-salicylihalamide A and related congeners. Tetrahedron 2002, 58, 33, 6455. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 61703 | 2-[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]acetaldehyde | C9H16O3 | 详情 | 详情 | |
| (II) | 61704 | diisopropyl (4S,5S)-2-[(E)-2-butenyl]-1,3,2-dioxaborolane-4,5-dicarboxylate | C14H23BO6 | 详情 | 详情 | |
| (III) | 61705 | (2R,3S)-1-[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]-3-methyl-4-penten-2-ol | C13H24O3 | 详情 | 详情 | |
| (IV) | 61706 | tert-butyl(dimethyl)silyl (1R,2S)-1-{[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]methyl}-2-methyl-3-butenyl ether; tert-butyl[((1R,2S)-1-{[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]methyl}-2-methyl-3-butenyl)oxy]dimethylsilane | C19H38O3Si | 详情 | 详情 | |
| (V) | 61707 | (3S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]-3-methyl-1-pentanol | C19H40O4Si | 详情 | 详情 | |
| (VI) | 61708 | (3S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]-3-methylpentanal | C19H38O4Si | 详情 | 详情 | |
| (VII) | 13484 | Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide | 2065-66-9 | C19H18IP | 详情 | 详情 |
| (VIII) | 61709 | tert-butyl(dimethyl)silyl (1R,2S)-1-{[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]methyl}-2-methyl-4-pentenyl ether; tert-butyl[((1R,2S)-1-{[(4S)-2,2-diethyl-1,3-dioxolan-4-yl]methyl}-2-methyl-4-pentenyl)oxy]dimethylsilane | C20H40O3Si | 详情 | 详情 | |
| (IX) | 61710 | (2S,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-7-octene-1,2-diol | C15H32O3Si | 详情 | 详情 | |
| (X) | 47846 | 1-[(4-methylphenyl)sulfonyl]-1H-imidazole | 2232-08-8 | C10H10N2O2S | 详情 | 详情 |
| (XI) | 61711 | tert-butyl(dimethyl)({(1R,2S)-2-methyl-1-[(2S)oxiranylmethyl]-4-pentenyl}oxy)silane; tert-butyl(dimethyl)silyl (1R,2S)-2-methyl-1-[(2S)oxiranylmethyl]-4-pentenyl ether | C15H30O2Si | 详情 | 详情 | |
| (XII) | 61712 | tributyl{(E)-3-[(4-methoxybenzyl)oxy]-1-propenyl}stannane; 4-methoxybenzyl (E)-3-(tributylstannyl)-2-propenyl ether | C23H40O2Sn | 详情 | 详情 | |
| (XIII) | 61713 | bromo{(E)-3-[(4-methoxybenzyl)oxy]-1-propenyl}magnesium | C11H13BrMgO2 | 详情 | 详情 | |
| (XIV) | 61716 | (2E,5R,7R,8S)-7-{[tert-butyl(dimethyl)silyl]oxy}-1-[(4-methoxybenzyl)oxy]-8-methyl-2,10-undecadien-5-ol | C26H44O4Si | 详情 | 详情 | |
| (XV) | 61714 | 2-allyl-6-methoxy-N,N-dipropylbenzamide | C17H25NO2 | 详情 | 详情 | |
| (XVI) | 61715 | 3-(iodomethyl)-8-methoxy-3,4-dihydro-1H-isochromen-1-one | C11H11IO3 | 详情 | 详情 | |
| (XVII) | 47491 | 2-allyl-6-methoxybenzoic acid | C11H12O3 | 详情 | 详情 | |
| (XVIII) | 61717 | (1S,3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-{(E)-4-[(4-methoxybenzyl)oxy]-2-butenyl}-4-methyl-6-heptenyl 2-allyl-6-methoxybenzoate | C37H54O6Si | 详情 | 详情 | |
| (XIX) | 61718 | (3S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-14-methoxy-3-{(E)-4-[(4-methoxybenzyl)oxy]-2-butenyl}-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one | C35H50O6Si | 详情 | 详情 | |
| (XX) | 61719 | (3S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-3-[(E)-4-hydroxy-2-butenyl]-14-methoxy-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one | C27H42O5Si | 详情 | 详情 | |
| (XXI) | 61720 | (E)-4-((3S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-14-methoxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenal | C27H40O5Si | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IX)The condensation of 3-[2-(hydroxymethyl)thiazol-4-yl]-2-methylpropenal (I) with acetone (II) gives the racemic aldol derivative (III), which is submitted to a enantioselective retroaldol reaction catalyzed by antibodies 84G3, 85H6 or 93F3, yielding the chiral aldol (IV) with 99% ee purity. The protection of the OH groups of (IV) with TbdmsCl and imidazole affords the bis silyl ether (V), which is oxidized with Tms-OTf, trifluoroacetone and oxone to provide the hydroxyketone (VI). The reduction of (VI) with NaBH4 in methanol gives the vicinal diol (VII), which is cleaved with Pb(OAc)4 to yield the aldehyde (VIII). The Wittig reaction of (VIII) with methyltriphenylphosphonium iodide (IX) and BuLi in THF affords the olefin (X), which is desilylated with TBAF in THF and selectively monosilylated at the primary alcohol with Tbdms-Cl and DIEA to give the secondary alcohol (XI). The esterification of (XI) with the known carboxylic acid (XII) (see later) by means of EDC in dichloromethane yields the ester (XIII), which is submitted to a ring-closing metathesis catalyzed by the Grubb's catalyst in dichloromethane to afford the protected macrolactone (XIV). The desilylation of (XIV) with HF and pyridine in THF gives the precursor (XV), which is finally epoxidated with H2O2 and KHCO3 in methanol to yield the target epothilone E.
| 【1】 Sinha, S.C.; et al.; Sets of aldolase antibodies with antipodal reactivities. Formal synthesis of epothilone E by large-scale antibody-catalyzed resolution of thiazole aldol. Org Lett 1999, 1, 10, 1623. |
| 【2】 Nicolaou, K.C.; et al.; Total synthesis of epothilone E and analogs with modified side chains through the Stille coupling reaction. Angew Chem. Int Ed Engl 1998, 37, 1-2, 84. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 45949 | (E)-3-[2-(hydroxymethyl)-1,3-thiazol-4-yl]-2-methyl-2-propenal | C8H9NO2S | 详情 | 详情 | |
| (II) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (III) | 45950 | (E)-4-hydroxy-6-[2-(hydroxymethyl)-1,3-thiazol-4-yl]-5-methyl-5-hexen-2-one | C11H15NO3S | 详情 | 详情 | |
| (IV) | 45951 | (4S,5E)-4-hydroxy-6-[2-(hydroxymethyl)-1,3-thiazol-4-yl]-5-methyl-5-hexen-2-one | C11H15NO3S | 详情 | 详情 | |
| (V) | 45952 | (4S,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3-thiazol-4-yl]-5-methyl-5-hexen-2-one | C23H43NO3SSi2 | 详情 | 详情 | |
| (VI) | 45953 | (4S,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3-thiazol-4-yl]-1-hydroxy-5-methyl-5-hexen-2-one | C23H43NO4SSi2 | 详情 | 详情 | |
| (VII) | 45954 | (4S,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3-thiazol-4-yl]-5-methyl-5-hexene-1,2-diol | C23H45NO4SSi2 | 详情 | 详情 | |
| (VIII) | 45955 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-[2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3-thiazol-4-yl]-4-methyl-4-pentenal | C22H41NO3SSi2 | 详情 | 详情 | |
| (IX) | 13484 | Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide | 2065-66-9 | C19H18IP | 详情 | 详情 |
| (X) | 45956 | 2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-1,3-thiazole; tert-butyl(dimethyl)silyl [4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-1,3-thiazol-2-yl]methyl ether | C23H43NO2SSi2 | 详情 | 详情 | |
| (XI) | 45957 | (1E,3S)-1-[2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3-thiazol-4-yl]-2-methyl-1,5-hexadien-3-ol | C17H29NO2SSi | 详情 | 详情 | |
| (XII) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 | |
| (XIII) | 45958 | (1S)-1-[(E)-2-[2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3-thiazol-4-yl]-1-methylethenyl]-3-butenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate | C46H85NO6SSi3 | 详情 | 详情 | |
| (XIV) | 45959 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-16-[(E)-2-[2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3-thiazol-4-yl]-1-methylethenyl]-5,5,7,9-tetramethyloxa-13-cyclohexadecene-2,6-dione | C44H81NO6SSi3 | 详情 | 详情 | |
| (XV) | 37960 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-16-[(E)-2-[2-(hydroxymethyl)-1,3-thiazol-4-yl]-1-methylethenyl]-5,5,7,9-tetramethyloxa-13-cyclohexadecene-2,6-dione | C26H39NO6S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(LII)The condensation of (XLVIII) with phosphonate (XLIX) by means of NaH in THF furnishes the unsaturated ester (L). The reduction of the double bond of (L) with H2 over Rh/Al2O3, followed by reduction of the ester group with DIBAL and oxidation of the resulting alcohol with DMP, gives rise to the aldehyde (LI). The Wittig condensation of (LI) with phosphonium salt (LII) by means of BuLi in THF yields the terminal olefin (LIII), which is selectively desilylated with TsOH to afford the primary alcohol (LIV). Finally, this compound is oxidized to the target carboxylic acid intermediate (XII) with DMP and NaClO2 in dichloromethane/THF.
| 【1】 Sinha, S.C.; Barbas, C.F. III; Lerner, R.A.; The antibody catalysis route to the total synthesis of epothilones. Proc Natl Acad Sci USA 1998, 95, 25, 14603. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IL) | 35909 | ethyl 3-(diethoxyphosphoryl)propanoate | 3699-67-0 | C9H19O5P | 详情 | 详情 |
| (XII) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 | |
| (XLVIII) | 45549 | (3S,4S,5R,8S)-4,8,10-tris[[tert-butyl(dimethyl)silyl]oxy]-3,5,7,7-tetramethyl-6-oxodecanal | C32H68O5Si3 | 详情 | 详情 | |
| (L) | 45550 | ethyl (E,5S,6S,7R,10S)-6,10,12-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7,9,9-tetramethyl-8-oxo-2-dodecenoate | 2463-77-6 | C36H74O6Si3 | 详情 | 详情 |
| (LI) | 45551 | (5S,6S,7R,10S)-6,10,12-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7,9,9-tetramethyl-8-oxododecanal | 94-59-7 | C34H72O5Si3 | 详情 | 详情 |
| (LII) | 13484 | Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide | 2065-66-9 | C19H18IP | 详情 | 详情 |
| (LIII) | 44436 | (5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one | C35H74O4Si3 | 详情 | 详情 | |
| (LIV) | 44437 | (5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one | C29H60O4Si2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XV)The condensation of (XI) with phosphonate (XII) by means of NaH in THF furnishes the unsaturated ester (XIII). The reduction of the double bond of (XIII) with H2 over Rh/Al2O3, followed by reduction of the ester group with DIBAL and oxidation of the resulting alcohol with DMP, gives rise to the aldehyde (XIV). The Wittig condensation of (XIV) with phosphonium salt (XV) by means of BuLi in THF yields the terminal olefin (XVI), which is selectively desilylated with Ts-OH to afford the primary alcohol (XVII). Finally, this compound is oxidized to the target carboxylic acid intermediate (XVIII) with DMP and NaClO2 in dichloromethane/THF.
| 【1】 Sinha, S.C.; Barbas, C.F. III; Lerner, R.A.; The antibody catalysis route to the total synthesis of epothilones. Proc Natl Acad Sci USA 1998, 95, 25, 14603. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 45549 | (3S,4S,5R,8S)-4,8,10-tris[[tert-butyl(dimethyl)silyl]oxy]-3,5,7,7-tetramethyl-6-oxodecanal | C32H68O5Si3 | 详情 | 详情 | |
| (XII) | 35909 | ethyl 3-(diethoxyphosphoryl)propanoate | 3699-67-0 | C9H19O5P | 详情 | 详情 |
| (XIII) | 45550 | ethyl (E,5S,6S,7R,10S)-6,10,12-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7,9,9-tetramethyl-8-oxo-2-dodecenoate | 2463-77-6 | C36H74O6Si3 | 详情 | 详情 |
| (XIV) | 45551 | (5S,6S,7R,10S)-6,10,12-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7,9,9-tetramethyl-8-oxododecanal | 94-59-7 | C34H72O5Si3 | 详情 | 详情 |
| (XV) | 13484 | Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide | 2065-66-9 | C19H18IP | 详情 | 详情 |
| (XVI) | 44436 | (5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one | C35H74O4Si3 | 详情 | 详情 | |
| (XVII) | 44437 | (5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one | C29H60O4Si2 | 详情 | 详情 | |
| (XVIII) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XV)The aldol condensation of 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XIX) with acetone (XX) catalyzed by antibody 38C2 gives the chiral aldol (XXI), which is protected with Tbdms-Cl and imidazole, yielding the silyl ether (XXII). The reaction of (XXII) with Tbdms-OTf, followed by oxidation with MCPBA and reduction with NaBH4, affords the vicinal diol (XXIII), which is cleaved with Pb(OAc)4 to provide the aldehyde (XXIV). The Wittig condensation of (XXIV) with phosphonium salt (XV) gives olefinic silyl ether (XXV), which is desilylated with TBAF in THF to yield the homoallylic alcohol (XXVI). The esterification of alcohol (XXVI) with the already described carboxylic acid (XVIII) by means of EDC in dichloromethane affords the ester (XXVII), which is submitted to a ring-closing metathesis by means of Grubb's catalyst to provide the macrolactone (XXVIII). Finally, the desilylation of (XXVIII) with HF and pyridine furnishes the target epothilone C.
| 【1】 Sinha, S.C.; Barbas, C.F. III; Lerner, R.A.; The antibody catalysis route to the total synthesis of epothilones. Proc Natl Acad Sci USA 1998, 95, 25, 14603. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 13484 | Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide | 2065-66-9 | C19H18IP | 详情 | 详情 |
| (XVIII) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 | |
| (XIX) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XX) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (XXI) | 45552 | (4S,5E)-4-hydroxy-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-5-hexen-2-one | C11H15NO2S | 详情 | 详情 | |
| (XXII) | 45553 | (4S,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-5-hexen-2-one | 2815-95-4 | C17H29NO2SSi | 详情 | 详情 |
| (XXIII) | 45554 | (4S,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-5-hexene-1,2-diol | C17H31NO3SSi | 详情 | 详情 | |
| (XXIV) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (XXV) | 44444 | 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether | C17H29NOSSi | 详情 | 详情 | |
| (XXVI) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XXVII) | 44445 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate | C40H71NO5SSi2 | 详情 | 详情 | |
| (XXVIII) | 44446 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C38H67NO5SSi2 | 详情 | 详情 |