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【结 构 式】

【分子编号】45554

【品名】(4S,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-5-hexene-1,2-diol

【CA登记号】

【 分 子 式 】C17H31NO3SSi

【 分 子 量 】357.58958

【元素组成】C 57.1% H 8.74% N 3.92% O 13.42% S 8.97% Si 7.85%
与该中间体有关的原料药合成路线共 2 条
合成路线1合成路线2

合成路线1

该中间体在本合成路线中的序号：(XXIII)

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.

参考文献 中间体
合成目标
【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2

该中间体在本合成路线中的序号：(XXIII)

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.

参考文献 中间体
合成目标
【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
Extended Information