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【结 构 式】 
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【分子编号】26248 【品名】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 【CA登记号】 |
【 分 子 式 】C34H52Cl3NO8S 【 分 子 量 】741.21292 【元素组成】C 55.1% H 7.07% Cl 14.35% N 1.89% O 17.27% S 4.33% |
合成路线1
该中间体在本合成路线中的序号：(X)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：(X)Further treatment of (X) with Et3SiOTf and 2,6-lutidine protected both 3- and 15-hydroxyl groups as the triethylsilyl ethers and cleaved the tert-butyl ester to yield carboxylic acid (XI). The bis(triethylsilyl)-protected diol (XI) was selectively hydrolyzed to the required 15-hydroxy acid (XII) upon treatment with cold 0.12 M HCl in MeOH. Macrolactonization of (XII) was then performed by means of 2,4,6-trichlorobenzoyl chloride, Et3N and DMAP yielding (XIII). Removal of the trichloroethoxycarbonyl protecting group from the resulting lactone (XIII) employing SmI2 and a catalytic amount of NiI2 in THF at -78 C yielded (XIV). Finally, desilylation of (XIV) with HF-pyridine afforded the target compound.
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XI) | 26249 | (3S,6R,7S,8S,12Z,15S,16E)-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-3,15-bis[(triethylsilyl)oxy]-12,16-heptadecadienoic acid | C42H72Cl3NO8SSi2 | 详情 | 详情 | |
| (XII) | 26250 | (3S,6R,7S,8S,12Z,15S,16E)-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-3-[(triethylsilyl)oxy]-12,16-heptadecadienoic acid | C36H58Cl3NO8SSi | 详情 | 详情 | |
| (XIII) | 26251 | (4S,7R,8S,9S,16S)-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-2,6-dioxo-4-[(triethylsilyl)oxy]oxa-13-cyclohexadecen-8-yl 2,2,2-trichloroethyl carbonate | C36H56Cl3NO7SSi | 详情 | 详情 | |
| (XIV) | 26252 | (4S,7R,8S,9S,16S)-8-hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-[(triethylsilyl)oxy]oxa-13-cyclohexadecene-2,6-dione | C33H55NO5SSi | 详情 | 详情 |