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【结 构 式】 
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【分子编号】37840 【品名】(2R)-2-[([(2S)-1-[(2S)-2-hydroxypropanoyl]pyrrolidinyl]carbonyl)(methyl)amino]-4-methylpentanoic acid 【CA登记号】 |
【 分 子 式 】C15H26N2O5 【 分 子 量 】314.38192 【元素组成】C 57.31% H 8.34% N 8.91% O 25.45% |
合成路线1
该中间体在本合成路线中的序号：(XXXVIII)Protection of ethyl lactate (XXX) with tert-butyldimethylsilyl chloride in DMF in the presence of imidazole provides derivative (XXXI), which is then converted into dipeptide (XXXII) by first hydrolysis with LiOH in THF/H2O followed by coupling with L-proline methyl ester (X) by means of DCC, HOBt and NMM. Next, hydrolysis of the methyl ester of (XXXII) with LiOH in THF/H2O yields carboxylic acid (XXXIII). Esterification of Z-D-N-Me-Leu (XXXIV) with 2-(trimethylsilyl)ethanol (XXXV) by means of EDCI, DMAP and Et3N in DMF furnishes leucine derivative (XXXVI), whose Z protecting group is removed by hydrogenation over Pd/C in MeOH/AcOEt to afford secondary amine (XXXVII). Coupling of carboxylic acid (XXXIII) with amine (XXXVII) is then performed by means of BOPCl, Et3N. Treatment with tetrabutylammonium fluoride in DMF allows protecting group removal to provide carboxylic acid derivative (XXXVIII), which is then attached to macrocycle (XXIX) by means of BOP and NMM in CH2Cl2 to furnish the target didemnin.
| 【1】 Li, W.-R.; et al.; Total synthesis and structural investigations of didemnins A, B, and C. J Am Chem Soc 1990, 112, 21, 7659. |
| 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) | 29552 | methyl (2S)-2-pyrrolidinecarboxylate | 2133-40-6 | C6H11NO2 | 详情 | 详情 |
| (XXIX) | 50769 | ethyl (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoate | C11H24O3Si | 详情 | 详情 | |
| (XXX) | 16659 | ethyl (2S)-2-hydroxypropanoate; (S)-ethyl lactate | 687-47-8 | C5H10O3 | 详情 | 详情 |
| (XXXI) | 50769 | ethyl (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoate | C11H24O3Si | 详情 | 详情 | |
| (XXXII) | 50770 | methyl (2S)-1-((2S)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoyl)-2-pyrrolidinecarboxylate | C15H29NO4Si | 详情 | 详情 | |
| (XXXIII) | 50771 | (2S)-1-((2S)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoyl)-2-pyrrolidinecarboxylic acid | C14H27NO4Si | 详情 | 详情 | |
| (XXXIV) | 50772 | (2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoic acid | C15H21NO4 | 详情 | 详情 | |
| (XXXV) | 20323 | 2-(trimethylsilyl)-1-ethanol | 2916-68-9 | C5H14OSi | 详情 | 详情 |
| (XXXVI) | 50773 | 2-(trimethylsilyl)ethyl (2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoate | C20H33NO4Si | 详情 | 详情 | |
| (XXXVII) | 50774 | 2-(trimethylsilyl)ethyl (2R)-4-methyl-2-(methylamino)pentanoate | C12H27NO2Si | 详情 | 详情 | |
| (XXXVIII) | 37840 | (2R)-2-[([(2S)-1-[(2S)-2-hydroxypropanoyl]pyrrolidinyl]carbonyl)(methyl)amino]-4-methylpentanoic acid | C15H26N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XX)Treatment of (XVIII) with HCl in EtOAc cleaved both Boc and triisopropylsilyl protecting groups to yield (XIX). This was finally coupled with the preformed side chain (XX) using BOP to afford the title compound.
| 【1】 Liang, B.; et al.; The first total synthesis of (-)-tamadarin A. Org Lett 1999, 1, 8, 1319. |
合成路线3
该中间体在本合成路线中的序号：(XXIII)The two remaining protecting groups of (XXI) are simultaneously removed by treatment with HCl in ethyl acetate to give the free cyclopeptide (XXII). Finally, this compound is condensed with (S)-lactoyl-S-prolyl-S-(N-methyl)leucine (XXIII) by means of DEPBT and DIEA to yield the target cyclopeptide (-)-tamandarin B.
| 【1】 Liang, B.; et al.; Total syntheses and biological investigations of tamandarins A and B and tamandarin A analogs. J Am Chem Soc 2001, 123, 19, 4469. |
| 【2】 Joullie, M.M.; et al.; Total synthesis of (-)-tamandarin B. Tetrahedron Lett 2000, 41, 49, 9373. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 49337 | (3S,6R,7S,10R,11S,15S,18S,23aS)-7-amino-11-hydroxy-18-isobutyl-10,15-diisopropyl-3-(4-methoxybenzyl)-2,6-dimethyltetradecahydro-15H-pyrrolo[1,2-g][1,13,4,7,10,17]dioxatetraazacyclohenicosine-1,4,8,13,16,19-hexone | C38H59N5O10 | 详情 | 详情 | |
| (XXI) | 49336 | tert-butyl (3S,6R,7S,10R,11S,15S,18S,23aS)-18-isobutyl-10,15-diisopropyl-3-(4-methoxybenzyl)-2,6-dimethyl-1,4,8,13,16,19-hexaoxo-11-[(triisopropylsilyl)oxy]icosahydro-15H-pyrrolo[1,2-g][1,13,4,7,10,17]dioxatetraazacyclohenicosin-7-ylcarbamate | C52H87N5O12Si | 详情 | 详情 | |
| (XXIII) | 37840 | (2R)-2-[([(2S)-1-[(2S)-2-hydroxypropanoyl]pyrrolidinyl]carbonyl)(methyl)amino]-4-methylpentanoic acid | C15H26N2O5 | 详情 | 详情 |