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【结 构 式】 
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【分子编号】17368 【品名】(1R,2R,5R)-5-[(E)-2-bromo-1-propenyl]-2-[[tert-butyl(diphenyl)silyl]oxy]cyclohexyl methyl ether; ([(1R,2R,4R)-4-[(E)-2-bromo-1-propenyl]-2-methoxycyclohexyl]oxy)(tert-butyl)diphenylsilane 【CA登记号】 |
【 分 子 式 】C26H35BrO2Si 【 分 子 量 】487.5522 【元素组成】C 64.05% H 7.24% Br 16.39% O 6.56% Si 5.76% |
合成路线1
该中间体在本合成路线中的序号：(XXIII)Subsequent reduction of the ketonic group of (XV) with L-selectride in THF afforded the enantiomerically pure alcohol (XVI), which was treated with p-methoxybenzyl trichloroacetimide (XVII) and a catalytic amount of triphenylmethyl tetrafluoroborate to give the expected p-methoxybenzyl ether (XVIII). The desilylation of (XVIII) with tetrabutylammonium fluoride (TBAF) in THF gives the diol (XIX), which was selectively resilylated at the primary OH group yielding the se-condary alcohol (XX). The selective debenzylation of (XX) with H2 over W-2 RaNi in ethanol afforded the vicinal diol (XXI), which was submitted to cleavage with sodium per-iodate in THF to obtain the aldehyde (XXII). Finally, this compound is condensed with the vinyl bromide (XXIII) by means of butyllithium and magnesium bromide in THF to afford the desired C16-C34 fragment of FK-506, the key intermediate in the total synthesis described in Tetrahedron 1997, 53(39): 13257.
| 【1】 Liu, L.B.; Roper, T.D.; Ireland, R.E.; Total synthesis of FK-506. 1. Construction of the C16-C34 fragment. Tetrahedron 1997, 53, 39, 13221. |
| 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) | 17369 | (E,3S,4S)-4-[11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-4-yl]-1-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-2-methyl-1-penten-3-ol | C60H92O9Si2 | 详情 | 详情 | |
| (XV) | 17357 | 4-((1R,2S)-3-(benzyloxy)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methylpropyl)-11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undecan-9-one | C40H70O7Si2 | 详情 | 详情 | |
| (XVI) | 17363 | 4-((1R,2S)-3-(benzyloxy)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methylpropyl)-11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undecan-9-ol | C40H72O7Si2 | 详情 | 详情 | |
| (XVII) | 17358 | (2R)-3-methoxy-2-methylpropyl 4-methylbenzenesulfonate | C12H18O4S | 详情 | 详情 | |
| (XVIII) | 17359 | (4S)-5-methoxy-4-methyl-1-pentyne; methyl (2S)-2-methyl-4-pentynyl ether | C7H12O | 详情 | 详情 | |
| (XIX) | 17364 | (2S,4E)-5-[4-[(1S,2S)-3-(benzyloxy)-2-hydroxy-1-methylpropyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-2,4-dimethyl-4-penten-1-ol | C36H52O8 | 详情 | 详情 | |
| (XX) | 17365 | (2S,3S)-1-(benzyloxy)-3-[11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-4-yl]-2-butanol | C42H66O8Si | 详情 | 详情 | |
| (XXI) | 17366 | (2S,3S)-3-[11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-4-yl]-1,2-butanediol | C35H60O8Si | 详情 | 详情 | |
| (XXII) | 17367 | (2R)-2-[11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-4-yl]propanal | C34H56O7Si | 详情 | 详情 | |
| (XXIII) | 17368 | (1R,2R,5R)-5-[(E)-2-bromo-1-propenyl]-2-[[tert-butyl(diphenyl)silyl]oxy]cyclohexyl methyl ether; ([(1R,2R,4R)-4-[(E)-2-bromo-1-propenyl]-2-methoxycyclohexyl]oxy)(tert-butyl)diphenylsilane | C26H35BrO2Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The intermediate (IX) has been obtained as follows: The reduction of the spiroenone (I) with Li(s-Bu)3BH gives the corresponding alcohol that is protected with Tbdms-Cl and imidazole to yield the silyl ether (II). The oxidation of the vinyl group of (II) with OsO4, NaIO4 and NMO affords the carbaldehyde (III), which is condensed with the vinyl bromide (IV) by means of t-BuLi to provide the alcohol (V). The esterification of the alcohol (V) with the chiral piperidine-2-carboxylic acid (VI) by means of DCC and DMAP gives the ester (VII), which is selectively monodesilylated by means of TBAF to yield the alcohol (VIII). Finally this alcohol is oxidized by means of Dess Martin periodinane (DMP) to afford the target spiroenone (IX).
| 【1】 Gleason, J.L.; The total synthesis of FK-506 and its spiroketal analogs. Diss Abstr Int B - Sci Eng 1994, 54, 12, Part 1, 6206. |
| 【2】 Ireland, R.E.; et al.; A total synthesis of FK-506. J Org Chem 1996, 61, 20, 6856. |
| 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) | 57299 | (4S,6R)-2,2-dimethyl-4-[(1S)-1-methyl-2-propenyl]-1,3,7-trioxaspiro[5.5]undec-10-en-9-one | C14H20O4 | 详情 | 详情 | |
| (II) | 57300 | tert-butyl(dimethyl)silyl (4S,6R,9R)-2,2-dimethyl-4-[(1S)-1-methyl-2-propenyl]-1,3,7-trioxaspiro[5.5]undec-10-en-9-yl ether; tert-butyl({(4S,6R,9R)-2,2-dimethyl-4-[(1S)-1-methyl-2-propenyl]-1,3,7-trioxaspiro[5.5]undec-10-en-9-yl}oxy)dimethylsilane | C20H36O4Si | 详情 | 详情 | |
| (III) | 57301 | (2R)-2-((4S,6R,9R)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-10-en-4-yl)propanal | C19H34O5Si | 详情 | 详情 | |
| (IV) | 17368 | (1R,2R,5R)-5-[(E)-2-bromo-1-propenyl]-2-[[tert-butyl(diphenyl)silyl]oxy]cyclohexyl methyl ether; ([(1R,2R,4R)-4-[(E)-2-bromo-1-propenyl]-2-methoxycyclohexyl]oxy)(tert-butyl)diphenylsilane | C26H35BrO2Si | 详情 | 详情 | |
| (V) | 57302 | (E,3S,4S)-4-((4R,6R,9R)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-10-en-4-yl)-1-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-2-methyl-1-penten-3-ol | C45H70O7Si2 | 详情 | 详情 | |
| (VI) | 11487 | (2S)-1-(tert-Butoxycarbonyl)hexahydro-2-pyridinecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
| (VII) | 57303 | 1-(tert-butyl) 2-[(1S,2E)-1-[(1R)-1-((4R,6R,9R)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-10-en-4-yl)ethyl]-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-2-methyl-2-propenyl] (2S)-1,2-piperid | C56H87NO10Si2 | 详情 | 详情 | |
| (VIII) | 57304 | 1-(tert-butyl) 2-((1S,2E)-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-{(1R)-1-[(4R,6R,9R)-9-hydroxy-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-10-en-4-yl]ethyl}-2-methyl-2-propenyl) (2S)-1,2-piperidinedicarboxylate | C50H73NO10Si | 详情 | 详情 | |
| (IX) | 57305 | 1-(tert-butyl) 2-((1S,2E)-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-{(1R)-1-[(4R,6R)-2,2-dimethyl-9-oxo-1,3,7-trioxaspiro[5.5]undec-10-en-4-yl]ethyl}-2-methyl-2-propenyl) (2S)-1,2-piperidinedicarboxylate | C50H71NO10Si | 详情 | 详情 |