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【结 构 式】

【分子编号】44493

【品名】(1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate

【CA登记号】

【 分 子 式 】C13H16INO2S

【 分 子 量 】377.24605

【元素组成】C 41.39% H 4.27% I 33.64% N 3.71% O 8.48% S 8.5%
与该中间体有关的原料药合成路线共 19 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19

合成路线1

该中间体在本合成路线中的序号：(XXVII)

Synthesis of the thiazole intermediate (XXVI): The Grignard reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XVII) with vinylmagnesium bromide (XVIII) in THF gives the racemic secondary alcohol (XIX), which is submitted to enzymatic optical resolution with Pseudomonas AK lipase and vinyl acetate to yield the desired (S)-secondary alcohol (XX) along with the (R)-acetate, which is easily separated by chromatography. The silylation of (XX) with Tbdms-Cl and imidazole in DMF affords the silyl ether (XXI). The selective hydroboration of the terminal double bond of (XXI) with dicyclohexylborane followed by oxidation with H2O2 provided the primary alcohol (XXII), which is oxidized with DMP in dichloromethane to give the corresponding aldehyde (XXIII). The reaction of (XXIII) with the iodomethyl phosphonium salt (XXIV) by means of NaHMDS in THF yields the cis-iodovinyl compound (XXV), which is desilylated with aqueous HF in acetonitrile, affording the corresponding alcohol (XXVI). Finally, this alcohol is treated with acetic anhydride, TEA and DMAP to provide the desired thiazole intermediate (XXVII).

参考文献 中间体
合成目标
【1】 Panek, J.S.; Zhu, B.; Total synthesis of apothilone A. Org Lett 2000, 2, 17, 2575.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVII) 44456 (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal C8H9NOS 详情 详情
(XVIII) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(XIX) 44488 (1E)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,4-pentadien-3-ol C10H13NOS 详情 详情
(XX) 44489 (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,4-pentadien-3-ol C10H13NOS 详情 详情
(XXI) 44490 tert-butyl(dimethyl)silyl (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-vinyl-2-propenyl ether; 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,4-pentadienyl)-2-methyl-1,3-thiazole C16H27NOSSi 详情 详情
(XXII) 40821 (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol C16H29NO2SSi 详情 详情
(XXIII) 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
(XXIV) 42718 (iodomethyl)(triphenyl)phosphonium iodide n/a C19H17I2P 详情 详情
(XXV) 44491 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether C17H28INOSSi 详情 详情
(XXVI) 44492 (1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol C11H14INOS 详情 详情
(XXVII) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情

合成路线2

该中间体在本合成路线中的序号：(XXVII)

Assembly of the target compound: The condensation of intermediates (XVI) and (XXVII) by means of 9-BBN, a Pd catalyst and Cs2CO3 in THF/DMF gives the adduct (XXVIII), which is selectively deprotected with HF/pyridine in THF, yielding the primary alcohol (XXIX). The oxidation of (XXIX) with DMP in dichloromethane affords the aldehyde (XXX), which is condensed with the silyl enol ether (XXXI) by means of TiCl4 in dichloromethane to provide the isopropyl carboxylate (XXXII). The desilylation of (XXXII) with TBAF in THF gives the dihydroxyester (XXXIII), which is selectively monosilylated with Tbdms-Cl and imidazole, yielding the hydroxyester (XXXIV). The oxidation of (XXXIV) with DMP in dichloromethane affords the ketoester (XXXV), which was submitted to a basic hydrolysis of its acetoxy and isopropyl ester groups with NaOH in refluxing methanol to furnish the hydroxyacid (XXXVI).

参考文献 中间体
合成目标
【1】 Panek, J.S.; Zhu, B.; Total synthesis of apothilone A. Org Lett 2000, 2, 17, 2575.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVI) 44487 (5R)-5-[(1R,2S,3S)-2-(benzyloxy)-1,3-dimethyl-5-hexenyl]-2,2,3,3,6,6,9,9,10,10-decamethyl-4,8-dioxa-3,9-disilaundecane; benzyl (1S,2S)-1-((1R,2R)-2,4-bis[[tert-butyl(dimethyl)silyl]oxy]-1,3,3-trimethylbutyl)-2-methyl-4-pentenyl ether C32H60O3Si2 详情 详情
(XXVII) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(XXVIII) 44494 (1S,3Z,8S,9S,10R,11R)-9-(benzyloxy)-11,13-bis[[tert-butyl(dimethyl)silyl]oxy]-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-tridecenyl acetate C45H77NO5SSi2 详情 详情
(XXIX) 44495 (1S,3Z,8S,9S,10R,11R)-9-(benzyloxy)-11-[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-tridecenyl acetate C39H63NO5SSi 详情 详情
(XXX) 44496 (1S,3Z,8S,9S,10R,11R)-9-(benzyloxy)-11-[[tert-butyl(dimethyl)silyl]oxy]-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-13-oxo-3-tridecenyl acetate C39H61NO5SSi 详情 详情
(XXXI) 44497 1-isopropoxyvinyl trimethylsilyl ether; [(1-isopropoxyvinyl)oxy](trimethyl)silane C8H18O2Si 详情 详情
(XXXII) 44498 isopropyl (3S,5R,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-7-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-12,16-heptadecadienoate C44H71NO7SSi 详情 详情
(XXXIII) 44499 isopropyl (3S,5R,6S,7S,8S,12Z,15S,16E)-15-(acetoxy)-7-(benzyloxy)-3,5-dihydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-12,16-heptadecadienoate C38H57NO7S 详情 详情
(XXXIV) 44500 isopropyl (3S,5R,6S,7S,8S,12Z,15S,16E)-15-(acetoxy)-7-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-12,16-heptadecadienoate C44H71NO7SSi 详情 详情
(XXXV) 44501 isopropyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-7-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate C44H69NO7SSi 详情 详情
(XXXVI) 44502 (3S,6R,7S,8S,12Z,15S,16E)-7-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H61NO6SSi 详情 详情

合成路线3

该中间体在本合成路线中的序号：(XXXIV)

Synthesis of the thiazole intermediate (XXXIV): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with lithium trimethylsilylacetylide (A) in THF provides the adduct (XXVII), which is esterified with methyl chloroformate (XXVIII), furnishing the carbonate (XXIX). The reduction of (XXIX) by means of Pd(OAc)2, Bu3P and ammonium formate gives the protected acetylenic compound (XXX). The selective reduction of the triple bond of (XXX) by means of Ti(OiPr)4 and iPr-MgBr in ethyl ether yields the cis-silylated vinyl compound (XXXI), which is iodinated with I2 in dichloromethane to afford the cis-iodovinyl compound (XXXII). The desilylation of (XXXII) with HF and pyridine in THF gives the secondary alcohol (XXXIII), which is finally acetylated with Ac2O, TEA and DMAP in CH2Cl2 to yield the target thiazole intermediate (XXXIV).

参考文献 中间体
合成目标
【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 16299 Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium 54655-07-1 C5H9LiSi 详情 详情
(XXII) 44456 (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal C8H9NOS 详情 详情
(XXIII) 44520 (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile C9H10N2OS 详情 详情
(XXIV) 44521 ethyl (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate C11H15NO3S 详情 详情
(XXV) 44522 ethyl (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate C17H29NO3SSi 详情 详情
(XXVI) 44523 (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal C15H25NO2SSi 详情 详情
(XXVII) 44524 (4R,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1-(trimethylsilyl)-5-hexen-1-yn-3-ol C20H35NO2SSi2 详情 详情
(XXVIII) 16993 methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate 79-22-1 C2H3ClO2 详情 详情
(XXIX) 44525 (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-1-[2-(trimethylsilyl)ethynyl]-3-butenyl methyl carbonate C22H37NO4SSi2 详情 详情
(XXX) 44526 4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether C20H35NOSSi2 详情 详情
(XXXI) 44527 tert-butyl(dimethyl)silyl (1S,3Z)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butenyl ether; 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1,5-hexadienyl]-2-methyl-1,3-thiazole C20H37NOSSi2 详情 详情
(XXXII) 44491 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether C17H28INOSSi 详情 详情
(XXXIII) 44492 (1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol C11H14INOS 详情 详情
(XXXIV) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XXXIV)

Assembly of the target compound: The condensation of intermediates (XXI) and (XXXIV) by means of 9-BBN, a PdCl2 catalyst and K3PO4 in hot DMF/water gives the adduct (XXXV), which is hydrolyzed with NaOH in methanol/water to yield the hydroxyacid (XXXVI). The macrolactonization of (XXXVI) by the Yamaguchi procedure using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF affords the macrolactone (XXXVII), which is desilylated with HF and pyridine in THF, furnishing the dihydroxylactone (XXXVIII). Finally, this compound is epoxidated by means of dimethyldioxirane (XXXIX) in dichloromethane.

参考文献 中间体
合成目标
【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXI) 44519 phenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate C33H58O5Si2 详情 详情
(XXXIV) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(XXXV) 44528 phenyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate C46H75NO7SSi2 详情 详情
(XXXVI) 44473 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C38H69NO6SSi2 详情 详情
(XXXVII) 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
(XXXVIII) 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
(XXXIX) 31501 3,3-dimethyl-1,2-dioxirane C3H6O2 详情 详情

合成路线5

该中间体在本合成路线中的序号：(IX)

Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) catalyzed by (S)(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to give the desired thiazole intermediate (IX).

参考文献 中间体
合成目标
【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073.
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) 44455 2-methyl-1,3-thiazole-4-carbaldehyde C5H5NOS 详情 详情
(II) 39940 2-(triphenylphosphoranylidene)propanal C21H19OP 详情 详情
(III) 44456 (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal C8H9NOS 详情 详情
(IV) 40599 Allyltributyltin; Tributyl-2-propenylstannane 24850-33-7 C15H32Sn 详情 详情
(V) 43171 (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol C11H15NOS 详情 详情
(VI) 44530 (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H17NO2S 详情 详情
(VII) 44531 (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate C12H15NO3S 详情 详情
(VIII) 44532 (iodomethylene)(triphenyl)phosphorane C19H16IP 详情 详情
(IX) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 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 cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provide the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane, furnishing the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of KOtBu in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of TsOH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).

参考文献 中间体
合成目标
【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073.
【2】 Bertinato, P.; Danishefsky, S.J.; Su, D.-S.; Kamenecka, T.; Meng, D.F.; Sorensen, E.J.; Savin, K.A.; Chou, T.-C.; Balog, A. (Sloan-Kettering Institute); Synthesis of epothilones, intermediates thereto, analogues and uses thereof. JP 2001507716; US 6242469; WO 9901124 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIIIa) 44545 tert-butyl(dimethyl)silyl (1S,2S,3E)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether; (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2E)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane C40H58O3S2Si2 详情 详情
(XXIIIa) 44546 (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2Z)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S,3Z)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether C40H58O3S2Si2 详情 详情
(IX) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(X) 44533 (2S)-3-(benzyloxy)-2-methylpropanal C11H14O2 详情 详情
(XI) 44534 (Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl trimethylsilyl ether; ([(Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl]oxy)(trimethyl)silane C10H20O2Si 详情 详情
(XII) 44535 (2S,3R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-2,3-dihydro-4H-pyran-4-one C17H22O3 详情 详情
(XIII) 44536 (2S,3S,4R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-3,4-dihydro-2H-pyran-4-ol C17H24O3 详情 详情
(XIV) 44537 (1R,3S,4S,5R,6R)-3-[(1S)-2-(benzyloxy)-1-methylethyl]-4,6-dimethyl-2-oxabicyclo[4.1.0]heptan-5-ol C18H26O3 详情 详情
(XV) 44538 (3R,4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-3-(iodomethyl)-2-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol C19H29IO4 详情 详情
(XVI) 44539 (4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-ol C19H30O4 详情 详情
(XVII) 44540 benzyl (2S)-2-[(2S,3R,4R)-6-methoxy-3,5,5-trimethyl-4-[(triphenylsilyl)oxy]tetrahydro-2H-pyran-2-yl]propyl ether; ([(4R,5R,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-yl]oxy)(triphenyl)silane C37H44O4Si 详情 详情
(XVIII) 44541 (2S,3S,4R,5R)-1-(benzyloxy)-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-3-heptanol C39H48O3S2Si 详情 详情
(XIX) 44542 (3R,4R,5S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; benzyl (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptyl ether C45H62O3S2Si2 详情 详情
(XX) 44543 (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-1-heptanol C38H56O3S2Si2 详情 详情
(XXI) 44544 (2R,3R,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptanal C38H54O3S2Si2 详情 详情
(XXII) 39163 (methoxymethyl)(triphenyl)phosphonium chloride 4009-98-7 C20H20ClOP 详情 详情
(XXIV) 44547 (3S,4S,5R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-7-(1,3-dithian-2-yl)-3,5,7-trimethyl-6-[(triphenylsilyl)oxy]octanal C39H56O3S2Si2 详情 详情
(XXV) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XXVI) 44548 (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether C40H58O2S2Si2 详情 详情
(XXVII) 44549 tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane C39H58O4Si2 详情 详情
(XXVIII) 44550 (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate C52H75NO6SSi2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(IX)

Alternatively, the hydrolysis of the intermediate dimethylacetal (XXVII) with TsOH in dioxane/water gives the aldehyde (XXXVII), which is condensed with tert-butyl acetate (XXXVIII) by means of LDA in THF, yielding the hydroxyester (XXXIX). The desilylation of (XXXIX) with HF/pyridine in THF affords the trihydroxy compound (XL), which is selectively resilylated with Tbdms-OTf and lutidine, providing the bis-silylated compound (XLI). The oxidation of the free OH group of (XLI) with DMP in dichloromethane gives the ketonic compound (XLII), which is treated with Tbdms-OTf and lutidine in dichloromethane to furnish the silyl ester (XLIII). The condensation of (XLIII) with the thiazole intermediate (IX) as before gives the adduct (XLIV), which is hydrolyzed by means of K2CO3 in methanol/water, yielding the hydroxyacid (XLV). The intramolecular lactonization of (XLV) by means of 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in toluene affords the previously reported macrolactone (XXXV), which is desilylated with HF/pyridine to (XXXVI) and finally epoxidated with DMDO in dichloromethane.

参考文献 中间体
合成目标
【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(XXVII) 44549 tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane C39H58O4Si2 详情 详情
(XXXV) 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
(XXXVI) 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
(XXXVII) 44557 (3R,4R,5S,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,2,4,6-tetramethyl-3-[(triphenylsilyl)oxy]-8-nonenal C37H52O3Si2 详情 详情
(XXXVIII) 15397 tert-butyl acetate 540-88-5 C6H12O2 详情 详情
(XXXIX) 44558 tert-butyl (3S,5R,6R,7S,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-4,4,6,8-tetramethyl-5-[(triphenylsilyl)oxy]-10-undecenoate C43H64O5Si2 详情 详情
(XL) 44559 tert-butyl (3S,5R,6R,7S,8S)-3,5,7-trihydroxy-4,4,6,8-tetramethyl-10-undecenoate C19H36O5 详情 详情
(XLI) 44560 tert-butyl (3S,5R,6S,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4,4,6,8-tetramethyl-10-undecenoate C31H64O5Si2 详情 详情
(XLII) 44561 tert-butyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate C31H62O5Si2 详情 详情
(XLIII) 44562 tert-butyl(dimethyl)silyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate C33H68O5Si3 详情 详情
(XLIV) 44563 tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate C46H85NO7SSi3 详情 详情
(XLV) 44473 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C38H69NO6SSi2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(IX)

The reaction of (R)-glycidol (XLVI) with dihydropyran (DHP) and PPTS in dichloromethane gives the protected glycidol (XLVII), which is treated with the lithium acetylide (XLVIII) and BF3/Et2O in THF to yield the acetylenic alcohol (IL). The protection of the OH group of (IL) with Mem-Cl and DIEA in hot dichloroethane affords compound (L), which is treated with PPTS in methanol to provide the primary alcohol (LI). The oxidation of (LI) with oxalyl chloride in DMSO/dichloromethane gives the corresponding aldehyde (LII), which is treated with Me-MgBr in ethyl ether to yield the secondary alcohol (LIII). The oxidation of (LIII) with TPAP and NMO in dichloromethane affords the methyl ketone (LIV), which is condensed with the phosphine oxide (LV) by means of BuLi in THF, providing the adduct (LVI). The reaction of (LVI) with N-iodosuccinimide (NIS) and Cy2BH in ethyl ether gives the iodovinyl compound (LVII), which is treated with acetic anhydride, yielding the intermediate (IX).

参考文献 中间体
合成目标
【1】 Bertinato, P.; Danishefsky, S.J.; Su, D.-S.; Kamenecka, T.; Meng, D.F.; Sorensen, E.J.; Savin, K.A.; Chou, T.-C.; Balog, A. (Sloan-Kettering Institute); Synthesis of epothilones, intermediates thereto, analogues and uses thereof. JP 2001507716; US 6242469; WO 9901124 .
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) 46994 (2S)-1-(tetrahydro-2H-pyran-2-yloxy)-5-(trimethylsilyl)-4-pentyn-2-ol C13H24O3Si 详情 详情
(IX) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(XLVI) 16260 (R)-(+)-Glycidol; (2R)-Oxiranemethanol; (2R)oxiranylmethanol 57044-25-4 C3H6O2 详情 详情
(XLVII) 46993 (2S)oxiranylmethyl tetrahydro-2H-pyran-2-yl ether; 2-[(2S)oxiranylmethoxy]tetrahydro-2H-pyran C8H14O3 详情 详情
(XLVIII) 16299 Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium 54655-07-1 C5H9LiSi 详情 详情
(L) 46995 (2S)-2-(methoxymethoxy)-5-(trimethylsilyl)-4-pentynyl tetrahydro-2H-pyran-2-yl ether; [(4S)-4-(methoxymethoxy)-5-(tetrahydro-2H-pyran-2-yloxy)-1-pentynyl](trimethyl)silane C15H28O4Si 详情 详情
(LI) 46996 (2S)-2-(methoxymethoxy)-5-(trimethylsilyl)-4-pentyn-1-ol C10H20O3Si 详情 详情
(LII) 46997 (2S)-2-(methoxymethoxy)-5-(trimethylsilyl)-4-pentynal C10H18O3Si 详情 详情
(LIII) 46998 (3S)-3-(methoxymethoxy)-6-(trimethylsilyl)-5-hexyn-2-ol C11H22O3Si 详情 详情
(LIV) 46999 (3S)-3-(methoxymethoxy)-6-(trimethylsilyl)-5-hexyn-2-one C11H20O3Si 详情 详情
(LV) 47000 (2-methyl-1,3-thiazol-4-yl)methyl(diphenyl)phosphine oxide; 4-[(diphenylphosphoryl)methyl]-2-methyl-1,3-thiazole C17H16NOPS 详情 详情
(LVI) 47001 4-[(E,3S)-3-(methoxymethoxy)-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; methoxymethyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether C16H25NO2SSi 详情 详情
(LVII) 47002 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl methoxymethyl ether; 4-[(1E,3S,5Z)-6-iodo-3-(methoxymethoxy)-2-methyl-1,5-hexadienyl]-2-methyl-1,3-thiazole C13H18INO2S 详情 详情

合成路线9

该中间体在本合成路线中的序号：(XII)

The omega iodoalkyl thiazole intermediate (XII) is obtained as follows: The cyclization of 2-hydroxypropionaldehyde dimethyl acetal (I) with acetaldehyde (II) by means of warm Dowex (H+) and catalyzed by 2-deoxyribose-5-phosphate aldolase (DERA) gives the chiral tetrahydrofuran derivative (III), which is acylated with Ac-Cl and pyridine to yield the acetoxy compound (IV). The reaction of (IV) with BF3/Et2O, propane-1,3-dithiol (V) and TiCl4 affords the protected dithiane (VI), which is oxidized with oxalyl chloride in DMSO to provide the ketone (VII). The Wittig condensation of (VII) with phosphine oxide (VIII) by means of BuLi in THF provides the protected alkyl thiazole (IX), which is treated with HgClO4 to cleave the dithiane ring and yield carbaldehyde (X). Finally, this aldehyde is coupled with iodomethylenephosphorane (XI) by means of NaHMDS in THF/HMPA to afford the target omega iodoalkyl thiazole intermediate (XII).

参考文献 中间体
合成目标
【1】 Wong, C.-H.; Liu, J.; Aldolase-catalyzed asymmetric synthesis of novel pyranose synthons as a new entry to heterocycles and epothilones. Angew Chem. Int Ed 2002, 41, 8, 1404.
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) 54261 1,1-dimethoxy-2-propanol 42919-42-6 C5H12O3 详情 详情
(II) 11974 Acetaldehyde 75-07-0 C2H4O 详情 详情
(III) 54262 (4S,5R)-5-methyltetrahydro-2,4-furandiol C5H10O3 详情 详情
(IV) 54263 (2R,3S)-5-hydroxy-2-methyltetrahydro-3-furanyl acetate n/a C7H12O4 详情 详情
(V) 29729 1,3-propanedithiol; 3-sulfanylpropylhydrosulfide 109-80-8 C3H8S2 详情 详情
(VI) 54264 (1S,2R)-1-(1,3-dithian-2-ylmethyl)-2-hydroxypropyl acetate n/a C10H18O3S2 详情 详情
(VII) 54265 (1S)-1-(1,3-dithian-2-ylmethyl)-2-oxopropyl acetate C10H16O3S2 详情 详情
(VIII) 47000 (2-methyl-1,3-thiazol-4-yl)methyl(diphenyl)phosphine oxide; 4-[(diphenylphosphoryl)methyl]-2-methyl-1,3-thiazole C17H16NOPS 详情 详情
(IX) 54266 (1S,2E)-1-(1,3-dithian-2-ylmethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl acetate C15H21NO2S3 详情 详情
(X) 44531 (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate C12H15NO3S 详情 详情
(XI) 44532 (iodomethylene)(triphenyl)phosphorane C19H16IP 详情 详情
(XII) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XII)

The Suzuki coupling of the unsaturated ketoester (XXIX) with the omega iodoalkyl thiazole intermediate (XII) by means of PdCl2(dppf)2, AsPh3, Cs2CO3 and 9-BBN gives the heptadienoic ester (XXX), which is treated with MeONa, Tms-OTf and NaOH to yield the hydroxyacid (XXXI). The macrocyclization of (XXXI) under Yamaguchi conditions affords the macrolactone (XXXII), which is treated with DDQ (cleavage of the Pmb group) to provide the still silylated compound (XXXIII). The treatment of (XXXIII) with HF and pyridine (cleavage of the Tbdms group) gives the free macrolactone (XXXIV), which is finally epoxidated by means of DMDO to furnish the target epothilone A.

参考文献 中间体
合成目标
【1】 Wong, C.-H.; Liu, J.; Aldolase-catalyzed asymmetric synthesis of novel pyranose synthons as a new entry to heterocycles and epothilones. Angew Chem. Int Ed 2002, 41, 8, 1404.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(XXIX) 54281 tert-butyl (3S,6R,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate n/a C33H56O6Si 详情 详情
(XXX) 54282 tert-butyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate n/a C46H73NO8SSi 详情 详情
(XXXI) 54283 (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-15-hydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid n/a C40H63NO7SSi 详情 详情
(XXXII) 54284 (4S,7R,8S,9S,16S)-4-{[tert-butyl(dimethyl)silyl]oxy}-8-[(4-methoxybenzyl)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 n/a C40H61NO6SSi 详情 详情
(XXXIII) 43176 (4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C32H53NO5SSi 详情 详情
(XXXIV) 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11

该中间体在本合成路线中的序号：(XXVII)

Synthesis of the thiazole intermediate (XXVI): The Grignard reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XVII) with vinylmagnesium bromide (XVIII) in THF gives the racemic secondary alcohol (XIX), which is submitted to enzymatic optical resolution with Pseudomonas AK lipase and vinyl acetate to yield the desired (S)-secondary alcohol (XX) along with the (R)-acetate, which is easily separated by chromatography. The silylation of (XX) with Tbdms-Cl and imidazole in DMF affords the silyl ether (XXI). The selective hydroboration of the terminal double bond of (XXI) with dichlohexylborane followed by oxidation with H2O2 provides the primary alcohol (XXII), which is oxidized with DMP in dichloromethane to give the corresponding aldehyde (XXIII). The reaction of (XXIII) with the iodomethyl phosphonium salt (XXIV) by means of NaHMDS in THF yields the cis-iodovinyl compound (XXV), which is desilylated with aqueous HF in acetonitrile affording the corresponding alcohol (XXVI). Finally, this alcohol is treated with acetic anhydride, TEA and DMAP to provide the desired thiazole intermediate (XXVII).

参考文献 中间体
合成目标
【1】 Panek, J.S.; Zhu, B.; Total synthesis of apothilone A. Org Lett 2000, 2, 17, 2575.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVII) 44456 (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal C8H9NOS 详情 详情
(XVIII) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(XIX) 44488 (1E)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,4-pentadien-3-ol C10H13NOS 详情 详情
(XX) 44489 (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,4-pentadien-3-ol C10H13NOS 详情 详情
(XXI) 44490 tert-butyl(dimethyl)silyl (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-vinyl-2-propenyl ether; 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,4-pentadienyl)-2-methyl-1,3-thiazole C16H27NOSSi 详情 详情
(XXII) 40821 (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol C16H29NO2SSi 详情 详情
(XXIII) 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
(XXIV) 42718 (iodomethyl)(triphenyl)phosphonium iodide n/a C19H17I2P 详情 详情
(XXV) 44491 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether C17H28INOSSi 详情 详情
(XXVI) 44492 (1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol C11H14INOS 详情 详情
(XXVII) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情

合成路线12

该中间体在本合成路线中的序号：(XXVII)

Assembly of the target compound: The condensation of intermediates (XVI) and (XXVII) by means of 9-BBN, a Pd catalyst and Cs2CO3 in THF/DMF gives the adduct (XXVIII), which is selectively deprotected with HF/pyridine in THF, yielding the primary alcohol (XXIX). The oxidation of (XXIX) with DMP in dichloromethane affords the aldehyde (XXX), which is condensed with the silyl enol ether (XXXI) by means of TiCl4 in dichloromethane to provide the isopropyl carboxylate (XXXII). The desilylation of (XXXII) with TBAF in THF gives the dihydroxyester (XXXIII), which is selectively monosilylated with Tbdms-Cl and imidazole, yielding the hydroxyester (XXXIV). The oxidation of (XXXIV) with DMP in dichloromethane affords the ketoester (XXXV), which was submitted to a basic hydrolysis of its acetoxy and isopropyl ester groups with NaOH in refluxing methanol to furnish the hydroxyacid (XXXVI).

参考文献 中间体
合成目标
【1】 Panek, J.S.; Zhu, B.; Total synthesis of apothilone A. Org Lett 2000, 2, 17, 2575.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVI) 44487 (5R)-5-[(1R,2S,3S)-2-(benzyloxy)-1,3-dimethyl-5-hexenyl]-2,2,3,3,6,6,9,9,10,10-decamethyl-4,8-dioxa-3,9-disilaundecane; benzyl (1S,2S)-1-((1R,2R)-2,4-bis[[tert-butyl(dimethyl)silyl]oxy]-1,3,3-trimethylbutyl)-2-methyl-4-pentenyl ether C32H60O3Si2 详情 详情
(XXVII) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(XXVIII) 44494 (1S,3Z,8S,9S,10R,11R)-9-(benzyloxy)-11,13-bis[[tert-butyl(dimethyl)silyl]oxy]-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-tridecenyl acetate C45H77NO5SSi2 详情 详情
(XXIX) 44495 (1S,3Z,8S,9S,10R,11R)-9-(benzyloxy)-11-[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-tridecenyl acetate C39H63NO5SSi 详情 详情
(XXX) 44496 (1S,3Z,8S,9S,10R,11R)-9-(benzyloxy)-11-[[tert-butyl(dimethyl)silyl]oxy]-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-13-oxo-3-tridecenyl acetate C39H61NO5SSi 详情 详情
(XXXI) 44497 1-isopropoxyvinyl trimethylsilyl ether; [(1-isopropoxyvinyl)oxy](trimethyl)silane C8H18O2Si 详情 详情
(XXXII) 44498 isopropyl (3S,5R,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-7-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-12,16-heptadecadienoate C44H71NO7SSi 详情 详情
(XXXIII) 44499 isopropyl (3S,5R,6S,7S,8S,12Z,15S,16E)-15-(acetoxy)-7-(benzyloxy)-3,5-dihydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-12,16-heptadecadienoate C38H57NO7S 详情 详情
(XXXIV) 44500 isopropyl (3S,5R,6S,7S,8S,12Z,15S,16E)-15-(acetoxy)-7-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-12,16-heptadecadienoate C44H71NO7SSi 详情 详情
(XXXV) 44501 isopropyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-7-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate C44H69NO7SSi 详情 详情
(XXXVI) 44502 (3S,6R,7S,8S,12Z,15S,16E)-7-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H61NO6SSi 详情 详情

合成路线13

该中间体在本合成路线中的序号：(XXXIV)

Synthesis of the thiazole intermediate (XXXIV): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with lithium trimethylsilylacetylide (A) in THF provides the adduct (XXVII), which is esterified with methyl chloroformate (XXVIII), furnishing the carbonate (XXIX). The reduction of (XXIX) by means of Pd(OAc)2, Bu3P and ammonium formate gives the protected acetylenic compound (XXX). The selective reduction of the triple bond of (XXX) by means of Ti(OiPr)4 and iPr-MgBr in ethyl ether yields the cis-silylated vinyl compound (XXXI), which is iodinated with I2 in dichloromethane to afford the cis-iodovinyl compound (XXXII). The desilylation of (XXXII) with FH and pyridine in THF gives the secondary alcohol (XXXIII), which is finally acetylated with Ac2O, TEA and DMAP in dichloromethane to yield the target thiazole intermediate (XXXIV).

参考文献 中间体
合成目标
【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 16299 Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium 54655-07-1 C5H9LiSi 详情 详情
(XXII) 44456 (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal C8H9NOS 详情 详情
(XXIII) 44520 (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile C9H10N2OS 详情 详情
(XXIV) 44521 ethyl (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate C11H15NO3S 详情 详情
(XXV) 44522 ethyl (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate C17H29NO3SSi 详情 详情
(XXVI) 44523 (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal C15H25NO2SSi 详情 详情
(XXVII) 44524 (4R,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1-(trimethylsilyl)-5-hexen-1-yn-3-ol C20H35NO2SSi2 详情 详情
(XXVIII) 16993 methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate 79-22-1 C2H3ClO2 详情 详情
(XXIX) 44525 (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-1-[2-(trimethylsilyl)ethynyl]-3-butenyl methyl carbonate C22H37NO4SSi2 详情 详情
(XXX) 44526 4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether C20H35NOSSi2 详情 详情
(XXXI) 44527 tert-butyl(dimethyl)silyl (1S,3Z)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butenyl ether; 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1,5-hexadienyl]-2-methyl-1,3-thiazole C20H37NOSSi2 详情 详情
(XXXII) 44491 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether C17H28INOSSi 详情 详情
(XXXIII) 44492 (1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol C11H14INOS 详情 详情
(XXXIV) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情

合成路线14

该中间体在本合成路线中的序号：(XXXIV)

Assembly of the target compound: The condensation of intermediates (XXI) and (XXXIV) by means of 9-BBN, a PdCl2 catalyst and K3PO4 in hot DMF/water gives the adduct (XXXV), which is hydrolyzed with NaOH in methanol/water to yield the hydroxyacid (XXXVI). The macrolactonization of (XXXVI) by the Yamaguchi procedure using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF affords the macrolactone (XXXVII), which is finally desilylated with HF and pyridine in THF to provide the target epothilone C.

参考文献 中间体
合成目标
【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXI) 44519 phenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate C33H58O5Si2 详情 详情
(XXXIV) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(XXXV) 44528 phenyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate C46H75NO7SSi2 详情 详情
(XXXVI) 44473 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C38H69NO6SSi2 详情 详情
(XXXVII) 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

合成路线15

该中间体在本合成路线中的序号：(IX)

Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) catalyzed by (S)(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to give the desired thiazole intermediate (IX).

参考文献 中间体
合成目标
【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073.
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) 44455 2-methyl-1,3-thiazole-4-carbaldehyde C5H5NOS 详情 详情
(II) 39940 2-(triphenylphosphoranylidene)propanal C21H19OP 详情 详情
(III) 44456 (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal C8H9NOS 详情 详情
(IV) 40599 Allyltributyltin; Tributyl-2-propenylstannane 24850-33-7 C15H32Sn 详情 详情
(V) 43171 (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol C11H15NOS 详情 详情
(VI) 44530 (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H17NO2S 详情 详情
(VII) 44531 (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate C12H15NO3S 详情 详情
(VIII) 44532 (iodomethylene)(triphenyl)phosphorane C19H16IP 详情 详情
(IX) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情

合成路线16

该中间体在本合成路线中的序号：(IX)

The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provides the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane, furnishing the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of tBu-OK in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of Ts-OH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).

参考文献 中间体
合成目标
【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIIIa) 44545 tert-butyl(dimethyl)silyl (1S,2S,3E)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether; (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2E)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane C40H58O3S2Si2 详情 详情
(XXIIIb) 44546 (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2Z)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S,3Z)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether C40H58O3S2Si2 详情 详情
(IX) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(X) 44533 (2S)-3-(benzyloxy)-2-methylpropanal C11H14O2 详情 详情
(XI) 44534 (Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl trimethylsilyl ether; ([(Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl]oxy)(trimethyl)silane C10H20O2Si 详情 详情
(XII) 44535 (2S,3R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-2,3-dihydro-4H-pyran-4-one C17H22O3 详情 详情
(XIII) 44536 (2S,3S,4R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-3,4-dihydro-2H-pyran-4-ol C17H24O3 详情 详情
(XIV) 44537 (1R,3S,4S,5R,6R)-3-[(1S)-2-(benzyloxy)-1-methylethyl]-4,6-dimethyl-2-oxabicyclo[4.1.0]heptan-5-ol C18H26O3 详情 详情
(XV) 44538 (3R,4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-3-(iodomethyl)-2-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol C19H29IO4 详情 详情
(XVI) 44539 (4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-ol C19H30O4 详情 详情
(XVII) 44540 benzyl (2S)-2-[(2S,3R,4R)-6-methoxy-3,5,5-trimethyl-4-[(triphenylsilyl)oxy]tetrahydro-2H-pyran-2-yl]propyl ether; ([(4R,5R,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-yl]oxy)(triphenyl)silane C37H44O4Si 详情 详情
(XVIII) 44541 (2S,3S,4R,5R)-1-(benzyloxy)-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-3-heptanol C39H48O3S2Si 详情 详情
(XIX) 44542 (3R,4R,5S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; benzyl (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptyl ether C45H62O3S2Si2 详情 详情
(XX) 44543 (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-1-heptanol C38H56O3S2Si2 详情 详情
(XXI) 44544 (2R,3R,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptanal C38H54O3S2Si2 详情 详情
(XXII) 39163 (methoxymethyl)(triphenyl)phosphonium chloride 4009-98-7 C20H20ClOP 详情 详情
(XXIV) 44547 (3S,4S,5R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-7-(1,3-dithian-2-yl)-3,5,7-trimethyl-6-[(triphenylsilyl)oxy]octanal C39H56O3S2Si2 详情 详情
(XXV) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XXVI) 44548 (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether C40H58O2S2Si2 详情 详情
(XXVII) 44549 tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane C39H58O4Si2 详情 详情
(XXVIII) 44550 (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate C52H75NO6SSi2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(IX)

Alternatively, the hydrolysis of the intermediate dimethylacetal (XXVII) with Ts-OH in dioxane/water gives the aldehyde (XXXVI), which is condensed with tert-butyl acetate (XXXVII) by means of LDA in THF, yielding the hydroxyester (XXXVIII). The desilylation of (XXXVIII) with HF/pyridine in THF affords the trihydroxy compound (XXXIX), which is selectively resilylated with Tbdms-OTf and lutidine, providing the bis-silylated compound (XL). The oxidation of the free OH group of (XL) with DMP in dichloromethane gives the ketonic compound (XLI), which is treated with Tbdms-OTf and lutidine in dichloromethane to furnish the silyl ester (XLII). The condensation of (XLII) with the thiazole intermediate (IX) as before gives the adduct (XLIII), which is hydrolyzed by means of K2CO3 in methanol/water, yielding the hydroxyacid (XLIV). The intramolecular lactonization of (XLIV) by means of 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in toluene affords the already reported macrolactone (XXXV), which is finally desilylated with HF/pyridine to give the target epothilone C.

参考文献 中间体
合成目标
【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(XXVII) 44549 tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane C39H58O4Si2 详情 详情
(XXXV) 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
(XXXVII) 44557 (3R,4R,5S,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,2,4,6-tetramethyl-3-[(triphenylsilyl)oxy]-8-nonenal C37H52O3Si2 详情 详情
(XXXVIII) 15397 tert-butyl acetate 540-88-5 C6H12O2 详情 详情
(XXXIX) 44558 tert-butyl (3S,5R,6R,7S,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-4,4,6,8-tetramethyl-5-[(triphenylsilyl)oxy]-10-undecenoate C43H64O5Si2 详情 详情
(XL) 44559 tert-butyl (3S,5R,6R,7S,8S)-3,5,7-trihydroxy-4,4,6,8-tetramethyl-10-undecenoate C19H36O5 详情 详情
(XLI) 44560 tert-butyl (3S,5R,6S,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4,4,6,8-tetramethyl-10-undecenoate C31H64O5Si2 详情 详情
(XLII) 44561 tert-butyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate C31H62O5Si2 详情 详情
(XLIII) 44562 tert-butyl(dimethyl)silyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate C33H68O5Si3 详情 详情
(XLIV) 44563 tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate C46H85NO7SSi3 详情 详情
(XLV) 44473 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C38H69NO6SSi2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(XII)

The omega iodoalkyl thiazole intermediate (XII) is obtained as follows: The cyclization of 2-hydroxypropionaldehyde dimethyl acetal (I) with acetaldehyde (II) by means of warm Dowex (H+) and catalyzed by 2-deoxyribose-5-phosphate aldolase (DERA) gives the chiral tetrahydrofuran derivative (III), which is acylated with Ac-Cl and pyridine to yield the acetoxy compound (IV). The reaction of (IV) with BF3/Et2O, propane-1,3-dithiol (V) and TiCl4 affords the protected dithiane (VI), which is oxidized with oxalyl chloride in DMSO to provide the ketone (VII). The Wittig condensation of (VII) with phosphine oxide (VIII) by means of BuLi in THF provides the protected alkyl thiazole (IX), which is treated with HgClO4 to cleave the dithiane ring and yield carbaldehyde (X). Finally, this aldehyde is coupled with iodomethylenephosphorane (XI) by means of NaHMDS in THF/HMPA to afford the target omega iodoalkyl thiazole intermediate (XII).

参考文献 中间体
合成目标
【1】 Wong, C.-H.; Liu, J.; Aldolase-catalyzed asymmetric synthesis of novel pyranose synthons as a new entry to heterocycles and epothilones. Angew Chem. Int Ed 2002, 41, 8, 1404.
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) 54261 1,1-dimethoxy-2-propanol 42919-42-6 C5H12O3 详情 详情
(II) 11974 Acetaldehyde 75-07-0 C2H4O 详情 详情
(III) 54262 (4S,5R)-5-methyltetrahydro-2,4-furandiol C5H10O3 详情 详情
(IV) 54263 (2R,3S)-5-hydroxy-2-methyltetrahydro-3-furanyl acetate n/a C7H12O4 详情 详情
(V) 29729 1,3-propanedithiol; 3-sulfanylpropylhydrosulfide 109-80-8 C3H8S2 详情 详情
(VI) 54264 (1S,2R)-1-(1,3-dithian-2-ylmethyl)-2-hydroxypropyl acetate n/a C10H18O3S2 详情 详情
(VII) 54265 (1S)-1-(1,3-dithian-2-ylmethyl)-2-oxopropyl acetate C10H16O3S2 详情 详情
(VIII) 47000 (2-methyl-1,3-thiazol-4-yl)methyl(diphenyl)phosphine oxide; 4-[(diphenylphosphoryl)methyl]-2-methyl-1,3-thiazole C17H16NOPS 详情 详情
(IX) 54266 (1S,2E)-1-(1,3-dithian-2-ylmethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl acetate C15H21NO2S3 详情 详情
(X) 44531 (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate C12H15NO3S 详情 详情
(XI) 44532 (iodomethylene)(triphenyl)phosphorane C19H16IP 详情 详情
(XII) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情

合成路线19

该中间体在本合成路线中的序号：(XII)

The Suzuki coupling of the unsaturated ketoester (XXIX) with the omega iodoalkyl thiazole intermediate (XII) by means of PdCl2(dppf)2, AsPh3, Cs2CO3 and 9-BBN gives the heptadienoic ester (XXX), which is treated with MeONa, Tms-OTf and NaOH to yield the hydroxyacid (XXXI). The macrocyclization of (XXXI) under Yamaguchi conditions affords the macrolactone (XXXII), which is treated with DDQ (cleavage of the Pmb group) to provide the still silylated compound (XXXIII). Finally, the treatment of (XXXIII) with HF and pyridine (cleavage of the Tbdms group) gives the the target epothilone C.

参考文献 中间体
合成目标
【1】 Wong, C.-H.; Liu, J.; Aldolase-catalyzed asymmetric synthesis of novel pyranose synthons as a new entry to heterocycles and epothilones. Angew Chem. Int Ed 2002, 41, 8, 1404.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(XXIX) 54281 tert-butyl (3S,6R,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate n/a C33H56O6Si 详情 详情
(XXX) 54282 tert-butyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate n/a C46H73NO8SSi 详情 详情
(XXXI) 54283 (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-15-hydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid n/a C40H63NO7SSi 详情 详情
(XXXII) 54284 (4S,7R,8S,9S,16S)-4-{[tert-butyl(dimethyl)silyl]oxy}-8-[(4-methoxybenzyl)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 n/a C40H61NO6SSi 详情 详情
(XXXIII) 43176 (4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C32H53NO5SSi 详情 详情
Extended Information