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【结 构 式】 
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【分子编号】32464 【品名】benzyl (1S,3S,6S,7S,8R,9R)-7,9-dihydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-3-yl(methyl)carbamate 【CA登记号】 |
【 分 子 式 】C28H36N2O5 【 分 子 量 】480.60432 【元素组成】C 69.98% H 7.55% N 5.83% O 16.65% |
合成路线1
该中间体在本合成路线中的序号：(XV)The methylation of N-(tert-butoxycarbonyl)-L-tyrosine methyl ester (I) with methyl iodide and KOH gives the protected 4-O-methyl-L-tyrosine methyl ester (II), which is deprotected with TFA yielding (III). The Grundke oxidation of (III) affords the N-hydroxy derivative (IV), which is cyclocondensed with cyclohexane-1,4-dione monoethylene ketal (V) and ethyl acrylate (VI) in refluxing toluene to afford the spiroisoxazolidinone (VII). The reductive rearrangement of (VII) with H2 over Pd/C in acetic acid provides the spiropyrrolidinone (VIII), which is treated successively with tosyl chloride and with sodium azide to obtain the azido derivative (IX). The reduction of (IX) with H2 over Pd/C, protection of the resulting amine with Boc2O, and methylation of the resulting carbamate with NaH and methyl iodide affords the N-methylcarbamate (X). The reduction of the methoxycarbonyl group of (X) with LiBH4 in THF gives the carbinol (XI), which is oxidized with Dess-Martin periodinane to the aldehyde (XII). The rearrangement of (XII) by means of potassium tert-butoxide, followed by deprotection of the carbamate group yields the 7,10a-methanopyrrolo[1,2-a]azocin-8-one derivative (XIII), which is reduced at the carbonyl group with LiAlH4 in THF affords the 8(R)-hydroxy derivative (XIV). The protection of the amino group of (XIV) with benzyloxycarbonyl chloride and triethylamine yields the carbamate (XV).
| 【1】 Snider, B.B.; et al.; Total synthesis of (-)-FR901483. J Am Chem Soc 1999, 121, 34, 7778. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (I) | 19875 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate | 4326-36-7 | C15H21NO5 | 详情 | 详情 |
| (II) | 32453 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propanoate | C16H23NO5 | 详情 | 详情 | |
| (III) | 32454 | methyl (2S)-2-amino-3-(4-methoxyphenyl)propanoate | C11H15NO3 | 详情 | 详情 | |
| (IV) | 32455 | methyl (2S)-2-(hydroxyamino)-3-(4-methoxyphenyl)propanoate | C11H15NO4 | 详情 | 详情 | |
| (V) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
| (VI) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (VII) | 32456 | ethyl (3R)-1-[(1S)-2-methoxy-1-(4-methoxybenzyl)-2-oxoethyl]-2,9,12-trioxa-1-azadispiro[4.2.4.2]tetradecane-3-carboxylate | C24H33NO8 | 详情 | 详情 | |
| (VIII) | 32457 | methyl (2S)-2-[(11R)-11-hydroxy-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphenyl)propanoate | C22H29NO7 | 详情 | 详情 | |
| (IX) | 32458 | methyl (2S)-2-[(11S)-11-azido-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphenyl)propanoate | C22H28N4O6 | 详情 | 详情 | |
| (X) | 32459 | methyl (2S)-2-[(11S)-11-[(tert-butoxycarbonyl)(methyl)amino]-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphenyl)propanoate | C28H40N2O8 | 详情 | 详情 | |
| (XI) | 32460 | tert-butyl (3S)-1-[(1S)-2-hydroxy-1-(4-methoxybenzyl)ethyl]-2,8-dioxo-1-azaspiro[4.5]dec-3-yl(methyl)carbamate | C25H36N2O6 | 详情 | 详情 | |
| (XII) | 32461 | tert-butyl (3S)-1-[(1S)-1-formyl-2-(4-methoxyphenyl)ethyl]-2,8-dioxo-1-azaspiro[4.5]dec-3-yl(methyl)carbamate | C25H34N2O6 | 详情 | 详情 | |
| (XIII) | 32462 | (1S,3S,6S,7S,8S)-7-hydroxy-6-(4-methoxybenzyl)-3-(methylamino)-5-azatricyclo[6.3.1.0(1,5)]dodecan-9-one | C20H28N2O3 | 详情 | 详情 | |
| (XIV) | 32463 | (1S,3S,6S,7S,8R,9R)-6-(4-methoxybenzyl)-3-(methylamino)-5-azatricyclo[6.3.1.0(1,5)]dodecane-7,9-diol | C20H30N2O3 | 详情 | 详情 | |
| (XV) | 32464 | benzyl (1S,3S,6S,7S,8R,9R)-7,9-dihydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-3-yl(methyl)carbamate | C28H36N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)The sulfonation of the 8(R)-hydroxy group of (XV) with 4-nitrophenylsulfonyl chloride, Et3N and DMAP provides the sulfonate (XVI), which is treated with Tes-OTf and Et3N in dichloromethane to protect the 6-hydroxy group yielding the silyl ether (XVII). The reaction of (XVII) with Cs-OAc and 18-crown-6 in hot benzene gives the 8(S)-acetoxy derivative (XVIII) with inversion of the configuration at the C(8). The reaction of (XVIII) with K2CO3 in methanol gives the corresponding 8(S)-hydroxy compound (XIX), which is treated with diisopropylaminophosphinic acid dibenzyl ester (XX) and tetrazole, and oxidized with tert-butyl hydroperoxide yielding the dibenzyl phosphate ester (XXI). The desilylation of (XXI) with tetrabutylammonium fluoride (TBAF) in THF affords the benzyl protected intermediate (XXII), which is finally debenzylated with H2 over Pd/C in methanol.
| 【1】 Snider, B.B.; et al.; Total synthesis of (-)-FR901483. J Am Chem Soc 1999, 121, 34, 7778. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 | |
| (XV) | 32464 | benzyl (1S,3S,6S,7S,8R,9R)-7,9-dihydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-3-yl(methyl)carbamate | C28H36N2O5 | 详情 | 详情 | |
| (XVI) | 32465 | (1S,3S,6S,7S,8S,9R)-3-[[(benzyloxy)carbonyl](methyl)amino]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-9-yl 4-nitrobenzenesulfonate | C34H39N3O9S | 详情 | 详情 | |
| (XVII) | 32466 | (1S,3S,6S,7S,8S,9R)-3-[[(benzyloxy)carbonyl](methyl)amino]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-9-yl 4-nitrobenzenesulfonate | C40H53N3O9SSi | 详情 | 详情 | |
| (XVIII) | 32467 | (1S,3S,6S,7S,8R,9S)-3-[[(benzyloxy)carbonyl](methyl)amino]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-9-yl acetate | C36H52N2O6Si | 详情 | 详情 | |
| (XIX) | 32468 | benzyl (1S,3S,6S,7S,8R,9S)-9-hydroxy-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-3-yl(methyl)carbamate | C34H50N2O5Si | 详情 | 详情 | |
| (XX) | 32469 | Diisopropylamidophosphoric acid dibenzyl ester | C20H28NO3P | 详情 | 详情 | |
| (XXI) | 32470 | benzyl (1S,3S,6S,7S,8S,9S)-9-[[bis(benzyloxy)phosphoryl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-3-yl(methyl)carbamate | C48H63N2O8PSi | 详情 | 详情 | |
| (XXII) | 32471 | benzyl (1S,3S,6S,7S,8S,9S)-9-[[bis(benzyloxy)phosphoryl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-3-yl(methyl)carbamate | C42H49N2O8P | 详情 | 详情 |