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【结 构 式】

【分子编号】26244

【品名】tert-butyl (6R,7S,8S)-4,4,6,8-tetramethyl-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-10-undecenoate

【CA登记号】

【 分 子 式 】C22H33Cl3O7

【 分 子 量 】515.85792

【元素组成】C 51.22% H 6.45% Cl 20.62% O 21.71%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(VI)

Treatment of diketoester (I) with trimethylsilyl diazomethane and diisopropyl ethylamine produced enol ether (II). This was condensed with (S)-2-methyl-4-pentenal (III) in the presence of LDA at -120 C to afford the aldol condensation product (IV) as the major isomer. Protection of the 7-hydroxyl group of (IV) with trichloroethoxycarbonyl chloride gave carbonate (V). Enol ether of (V) was then hydrolyzed with p-TsOH in acetone to provide diketoester (VI). Hydroboration of the terminal olefin of (VI) with 9-borabicyclo[3.3.1]nonane gave organoborane (VII). Then, Suzuki coupling of (VII) with vinyl iodide (VIII), followed by acid hydrolysis of the silyl protecting group, provided the thiazolyl heptadecadienoate (IX). Asymmetric hydrogenation of 3-keto group of (IX) in the presence of the modified Noyori's catalyst [RuCl2(R)-BINAP)]2[Et3N] furnished the desired 3-(S) alcohol (X).

1 Harris, C.R.; et al.; New chemical synthesis of the promising cancer chemotherapeutic agent 12,13-desoxyepothilone B: Discovery of a surprising long-range effect on the diastereoselectivity of an aldol condensation. J Am Chem Soc 1999, 121, 30, 7050.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
13664 1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate 17341-93-4 C3H2Cl4O2 详情 详情
(I) 26239 tert-butyl 4,4-dimethyl-3,5-dioxoheptanoate C13H22O4 详情 详情
(II) 26240 tert-butyl (Z)-3-methoxy-4,4-dimethyl-5-oxo-2-heptenoate C14H24O4 详情 详情
(III) 26241 (2S)-2-methyl-4-pentenal C6H10O 详情 详情
(IV) 26242 tert-butyl (2Z,6R,7S,8S)-7-hydroxy-3-methoxy-4,4,6,8-tetramethyl-5-oxo-2,10-undecadienoate C20H34O5 详情 详情
(V) 26243 tert-butyl (2Z,6R,7S,8S)-3-methoxy-4,4,6,8-tetramethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-2,10-undecadienoate C23H35Cl3O7 详情 详情
(VI) 26244 tert-butyl (6R,7S,8S)-4,4,6,8-tetramethyl-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-10-undecenoate C22H33Cl3O7 详情 详情
(VII) 26245 tert-butyl (6R,7S,8S)-11-(9-borabicyclo[3.3.1]non-9-yl)-4,4,6,8-tetramethyl-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]undecanoate C30H48BCl3O7 详情 详情
(VIII) 26246 tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-heptadienyl)-2-methyl-1,3-thiazole C18H30INOSSi 详情 详情
(IX) 26247 tert-butyl (6R,7S,8S,12Z,15S,16E)-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-12,16-heptadecadienoate C34H50Cl3NO8S 详情 详情
(X) 26248 tert-butyl (3S,6R,7S,8S,12Z,15S,16E)-3,15-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-12,16-heptadecadienoate C34H52Cl3NO8S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XVII)

The treatment of diketoester (XII) with trimethylsilyl diazomethane and DIEA gives enol ether (XIII), which is condensed with 2(S)-methyl-4-pentenal (XIV) by means of LDA to yield the aldol condensation product (XV) as the major isomer. The protection of the OH group of (XV) with Troc-Cl and pyridine affords the trichloroethyl carbonate (XVI), whose enol ether group is hydrolyzed with TsOH in acetone to provide the diketoester (XVII). The condensation of (XVII) with iodovinyl intermediate (XI) by means of BBN, (dppf)2PdCl2, AsPh3 and Cs2CO3 in THF/DMF/water gives adduct (XVIII), which is desilylated by means of HCl in methanol to yield the secondary alcohol (XIX). The asymmetric hydrogenation of (XIX) with H2 over a chiral Ru catalyst in acidic methanol affords the secondary diol (XX), which is silylated with Tes-OTf and lutidine to provide the bis-silyl ether (XXI). The selective desilylation of (XXI) with simultaneous hydrolysis of its tert-butyl ester by means of HCl in methanol gives the hydroxyacid (XXII) suitable for cyclization.

1 Zhang, X.-G.; Chappell, M.D.; Lee, C.B.; Kuduk, S.D.; Danishefsky, S.J.; Chou, T.-C.; Wang, Z.-G.; Stachel, S.J.; Total synthesis and antitumor activity of 12,13-dexoxyepothilone F: An unexpected solvolysis problem at C15, mediated by remote substitution at C21. J Org Chem 2000, 65, 20, 6525.
2 Harris, C.R.; et al.; New chemical synthesis of the promising cancer chemotherapeutic agent 12,13-desoxyepothilone B: Discovery of a surprising long-range effect on the diastereoselectivity of an aldol condensation. J Am Chem Soc 1999, 121, 30, 7050.
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) 49358 [4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-heptadienyl)-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate C21H31Cl3INO4SSi 详情 详情
(XII) 26239 tert-butyl 4,4-dimethyl-3,5-dioxoheptanoate C13H22O4 详情 详情
(XIII) 26240 tert-butyl (Z)-3-methoxy-4,4-dimethyl-5-oxo-2-heptenoate C14H24O4 详情 详情
(XIV) 26241 (2S)-2-methyl-4-pentenal C6H10O 详情 详情
(XV) 26242 tert-butyl (2Z,6R,7S,8S)-7-hydroxy-3-methoxy-4,4,6,8-tetramethyl-5-oxo-2,10-undecadienoate C20H34O5 详情 详情
(XVI) 26243 tert-butyl (2Z,6R,7S,8S)-3-methoxy-4,4,6,8-tetramethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-2,10-undecadienoate C23H35Cl3O7 详情 详情
(XVII) 26244 tert-butyl (6R,7S,8S)-4,4,6,8-tetramethyl-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-10-undecenoate C22H33Cl3O7 详情 详情
(XVIII) 49359 tert-butyl (6R,7S,8S,12Z,15S,16E)-15-[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-17-[2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazol-4-yl]-12,16-heptadecadienoate C43H65Cl6NO11SSi 详情 详情
(XIX) 49360 tert-butyl (6R,7S,8S,12Z,15S,16E)-15-hydroxy-4,4,6,8,12,16-hexamethyl-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-17-[2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazol-4-yl]-12,16-heptadecadienoate C37H51Cl6NO11S 详情 详情
(XX) 49361 tert-butyl (3S,6R,7S,8S,12Z,15S,16E)-3,15-dihydroxy-4,4,6,8,12,16-hexamethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-17-[2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazol-4-yl]-12,16-heptadecadienoate C37H53Cl6NO11S 详情 详情
(XXI) 49362 tert-butyl (3S,6R,7S,8S,12Z,15S,16E)-4,4,6,8,12,16-hexamethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-17-[2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazol-4-yl]-3,15-bis[(triethylsilyl)oxy]-12,16-heptadecadienoate C49H81Cl6NO11SSi2 详情 详情
(XXII) 49363 (3S,6R,7S,8S,12Z,15S,16E)-15-hydroxy-4,4,6,8,12,16-hexamethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-17-[2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazol-4-yl]-3-[(triethylsilyl)oxy]-12,16-heptadecadienoic acid C39H59Cl6NO11SSi 详情 详情
Extended Information