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【结 构 式】 
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【分子编号】32435 【品名】(2S,3R,4S,5S,6R,9S,11S)-2-[(2S,3S)-7-bromo-2-hydroxy-3-methyl-6-heptynyl]-9-ethyl-4-hydroxy-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one 【CA登记号】 |
【 分 子 式 】C22H36BrNO4 【 分 子 量 】458.43618 【元素组成】C 57.64% H 7.92% Br 17.43% N 3.06% O 13.96% |
合成路线1
该中间体在本合成路线中的序号：(XXIII)The hydrogenation of the double bond of (XVIII) with H2 and Lindlar catalyst affords the corresponding saturated aldehyde (XIX), which is condensed with the diazophosphonate (XX) giving the acetylenic derivative (XXI). The bromination of (XXI) with N-bromosuccinimide (NBS) and AgNO3 yields the bromoacetylenic compound (XXII), which is desilylated with HF and TBAF affording the dihydroxy derivative (XXIII). The resilylation of (XXIII) with CF3CO-N(Me)-Tms gives the bis(trimethylsilyl) derivative (XXIV), which is finally converted into the desired intermediate, the stannane (XXV) by reaction with tributyltin hydride, PPh3 and Pd dibenzylideneacetone complex.
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of sanglifehrin A. Angew Chem. Int Ed Engl 1999, 38, 16, 2447. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 21859 | 2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)acetamide | C6H12F3NOSi | 详情 | 详情 | ||
| (XVIII) | 32430 | (E,4S,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2S,3S,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-8-oxo-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undec-2-yl]-4-methyl-2-hexenal | C33H63NO5Si2 | 详情 | 详情 | |
| (XIX) | 32431 | (4S,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2S,3S,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-8-oxo-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undec-2-yl]-4-methylhexanal | C33H65NO5Si2 | 详情 | 详情 | |
| (XX) | 32432 | 1-Diazo-2-oxopropylphosphonic acid dimethyl ester | C5H9N2O4P | 详情 | 详情 | |
| (XXI) | 32433 | (2S,3S,4S,5S,6R,9S,11S)-2-((2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-6-heptynyl)-9-ethyl-3,5,11-trimethyl-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undecan-8-one | C34H65NO4Si2 | 详情 | 详情 | |
| (XXII) | 32434 | (2S,3S,4S,5S,6R,9S,11S)-2-((2S,3S)-7-bromo-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-6-heptynyl)-9-ethyl-3,5,11-trimethyl-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undecan-8-one | C34H64BrNO4Si2 | 详情 | 详情 | |
| (XXIII) | 32435 | (2S,3R,4S,5S,6R,9S,11S)-2-[(2S,3S)-7-bromo-2-hydroxy-3-methyl-6-heptynyl]-9-ethyl-4-hydroxy-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one | C22H36BrNO4 | 详情 | 详情 | |
| (XXIV) | 32436 | (2S,3R,4S,5S,6R,9S,11S)-2-[(2S,3S)-7-bromo-3-methyl-2-[(trimethylsilyl)methyl]-6-heptynyl]-9-ethyl-3,5,11-trimethyl-4-[(trimethylsilyl)methyl]-1-oxa-7-azaspiro[5.5]undecan-8-one | C30H56BrNO2Si2 | 详情 | 详情 | |
| (XXV) | 32437 | (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-2-[(2S,3S,6E)-3-methyl-7-(tributylstannyl)-2-[(trimethylsilyl)methyl]-6-heptenyl]-4-[(trimethylsilyl)methyl]-1-oxa-7-azaspiro[5.5]undecan-8-one | C42H85NO2Si2Sn | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXX)The regiocontrolled condensation of (spirolactam (XVII) with the chiral borane (+)(Z)-crotyl-diisopinocampheylborane (XX) in THF gives the diol (XXI), which is silylated with TBDMS-OTf and lutidine in dichloromethane yielding the bis(silyloxy) compound (XXII). The ozonolysis of the terminal double bond of (XXII) with O3 in dichloromethane affords the aldehyde (XXIII), which is condensed with the silyl aldimine (XXIV) by means of LDA in THF giving the unsaturated aldehyde (XXV). Hydrogenation of the double bond of (XXV) yields aldehyde (XXVI), which is condensed with the diazo phosphonate (XXVII) by means of K2CO3 in methanol providing the terminal acetylenic compound (XXVIII). The reaction of (XXVIII) with TBAF in THF gives the desilylated acetylenic compound (XXIX), which is brominated with NBS and AgNO3 in acetone yielding the omega-bromoacetylenic compound (XXX). Finally, this compound is treated with tributyltin hydride, Pd2(dba)3 and PPh3 in chloroform to afford the desired tributyl stannane intermediate (I).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of the novel immunosuppressant Sanglifehrin A. J Am Chem Soc 2000, 122, 16, 3830. |
| 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) | 35874 | (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S,6E)-2-hydroxy-3-methyl-7-(tributylstannyl)-6-heptenyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one | C34H65NO4Sn | 详情 | 详情 | |
| (XVII) | 32424 | 2-[(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl]acetaldehyde | C16H27NO4 | 详情 | 详情 | |
| (XXI) | 35879 | (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S)-2-hydroxy-3-methyl-4-pentenyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one | C20H35NO4 | 详情 | 详情 | |
| (XXII) | 35880 | (2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-((2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-pentenyl)-9-ethyl-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one | C32H63NO4Si2 | 详情 | 详情 | |
| (XXIII) | 35881 | (2R,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-((2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-9-ethyl-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl)-2-methylbutanal | C31H61NO5Si2 | 详情 | 详情 | |
| (XXV) | 35882 | (E,4S,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-((2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-9-ethyl-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl)-4-methyl-2-hexenal | C33H63NO5Si2 | 详情 | 详情 | |
| (XXVI) | 35883 | (4S,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-((2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-9-ethyl-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl)-4-methylhexanal | C33H65NO5Si2 | 详情 | 详情 | |
| (XXVII) | 35884 | diethyl 1-diazo-2-oxopropylphosphonate | C7H13N2O4P | 详情 | 详情 | |
| (XXVIII) | 35885 | (2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-((2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-6-heptynyl)-9-ethyl-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one | C34H65NO4Si2 | 详情 | 详情 | |
| (XXIX) | 35886 | (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S)-2-hydroxy-3-methyl-6-heptynyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one | C22H37NO4 | 详情 | 详情 | |
| (XXX) | 32435 | (2S,3R,4S,5S,6R,9S,11S)-2-[(2S,3S)-7-bromo-2-hydroxy-3-methyl-6-heptynyl]-9-ethyl-4-hydroxy-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one | C22H36BrNO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(LII)The elimination of the Pmb protecting group of (L) by means of DDQ in dichloromethane affords compound (LI), which is brominated with NBS and AgNO3 in acetone to provide the bromoacetylene derivative (LII). The reaction of (LII) with tributyltin hydride, Pd2(dba)3 and PPh3 leads to the vinylstannane (LIII), which is condensed with the chiral tetracyclic macrolactone intermediate (XXXVI) by means of PdCl2(CH3CN)2 in DMF to give the cyclic precursor (LIV). Finally, this compound is submitted to an acidic hydrolysis by means of TsOH and BO3H3 in THF to provide the target Sanglifehrin A
| 【1】 Duan, M.S.; Paquette, L.A.; Enantioselective total synthesis of the cyclophilin-binding immunosuppressive agent sanglifehrin A. Angew Chem. Int Ed 2001, 40, 19, 3632. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXVI) | 32450 | (4R,7S,10S,16S,19S,25S,26R,27R)-10-(3-hydroxybenzyl)-19-[(E)-2-iodo-1-methylethenyl]-7-isopropyl-1,26-dimethyl-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1(12,16).0(4,27)]triaconta-21,23-diene-5,8,11,17-tetrone; (4R,7S,10S,16S,19S,25S,26R,27R)-10-(3-hydroxybenzyl)-19-[(E)-2-iodo-1-methylethenyl]-7-isopropyl-1,26-dimethyl-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1(12,16).0(4,27)]triaconta-21,23-diene-5,8,11,17-tetrone | C38H51IN4O8 | 详情 | 详情 | |
| (L) | 60143 | (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-2-[(2S,3S)-2-hydroxy-3-methyl-6-heptynyl]-4-[(4-methoxybenzyl)oxy]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one | C30H45NO5 | 详情 | 详情 | |
| (LI) | 35886 | (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S)-2-hydroxy-3-methyl-6-heptynyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one | C22H37NO4 | 详情 | 详情 | |
| (LII) | 32435 | (2S,3R,4S,5S,6R,9S,11S)-2-[(2S,3S)-7-bromo-2-hydroxy-3-methyl-6-heptynyl]-9-ethyl-4-hydroxy-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one | C22H36BrNO4 | 详情 | 详情 | |
| (LIII) | 35874 | (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S,6E)-2-hydroxy-3-methyl-7-(tributylstannyl)-6-heptenyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one | C34H65NO4Sn | 详情 | 详情 | |
| (LIV) | 32452 | (4R,7S,10S,16S,19S,25S,26R,27R)-19-{(1E,3E,7S,8S)-9-[(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl]-8-hydroxy-1,7-dimethyl-1,3-nonadienyl}-10-(3-hydroxybenzyl)-7-isopropyl-1,26-dimethyl-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1~12,16~.0~4,27~]triaconta-21,23-diene-5,8,11,17-tetrone | C60H89N5O12 | 详情 | 详情 |