|
【结 构 式】 
|
【分子编号】37829 【品名】(2S)-2-hydroxy-3-methylbutyric acid 【CA登记号】 |
【 分 子 式 】C5H10O3 【 分 子 量 】118.1326 【元素组成】C 50.84% H 8.53% O 40.63% |
合成路线1
该中间体在本合成路线中的序号：(XIX)Protection of 2-hydroxyisovaleric acid (XIX) with tert-butyldimethylsilyl chloride and imidazole in DMF, followed by condensation with Meldrum's acid (XX) by use of diethyl phosphorocyanidate (DEPC) and Et3N in THF, furnishes derivative (XXI), which is then subjected to reaction with benzyl alcohol (XXII) in refluxing benzene to afford beta-keto ester (XXIII). Next, derivative (XXIII) is methylated with MeI and NaH and its benzyl group is removed by hydrogenation over Pd/C in THF to yield carboxylic acid (XXIV). Coupling between H-Pro-OBzl.HCl (XXV) and Boc-Leu-OH (XXVI) by means of DEPC and Et3N in DMF affords dipeptide (XXVII), which is then converted into fragment (XXVIII) by first condensation with carboxylic acid (XXIV) by means of DCC, HOBt and NMM in THF/DMF and treatment with tetrabutylammonium fluoride for TBDMS protecting group removal. Coupling of fragment (XXVIII) with fragment (XVIII) by means of DCC and DMAP in CH2Cl2 furnishes linear peptide (XXIX), which is hydrogenated over Pd/C in THF and then subjected to cyclization by means of BOPCl and Et3N in CH2Cl2 to give macrolide (XXX). Next, deprotection of (XXX) with TMSOTf affords intermediate (XXXI) (didemnin A).
| 【1】 Harris, B.D.; et al.; Synthetic studies of didemnins. II. Approaches to statine diastereomers. Tetrahedron Lett 1987, 28, 25, 2837. |
| 【2】 Hamada, Y.; Shioiri, T.; Anti-tumor active cyclic peptide derived from marine organism: Synthesis, conformation and bioactivity. Kagaku Zokan 1990, 118, 31. |
| 【3】 Hamada, Y.; et al.; Efficient total synthesis of didemnins A and B. J Am Chem Soc 1989, 111, 2, 669. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 50786 | (5S,8R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-5-(4-methoxybenzyl)-4,8-dimethyl-9-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-3,6,10-trioxo-1-phenyl-2,7-dioxa-4,11-diazapentadecan-15-oic acid | C44H70N4O10Si | 详情 | 详情 | |
| (XIX) | 37829 | (2S)-2-hydroxy-3-methylbutyric acid | C5H10O3 | 详情 | 详情 | |
| (XX) | 17938 | 8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | C18H20ClN3 | 详情 | 详情 | |
| (XXI) | 50789 | 5-((2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-3-methylbutylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione | C17H30O6Si | 详情 | 详情 | |
| (XXII) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
| (XXIII) | 50790 | benzyl (4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-3-oxohexanoate | C20H32O4Si | 详情 | 详情 | |
| (XXIV) | 50791 | (2S,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2,5-dimethyl-3-oxohexanoic acid | C14H28O4Si | 详情 | 详情 | |
| (XXV) | 20930 | benzyl (2S)-2-pyrrolidinecarboxylate | 16652-71-4 | C12H15NO2 | 详情 | 详情 |
| (XXVI) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (XXVII) | 50792 | benzyl (2S)-1-[(2S)-2-amino-4-methylpentanoyl]-2-pyrrolidinecarboxylate | C18H26N2O3 | 详情 | 详情 | |
| (XXVIII) | 50793 | benzyl (2S)-1-((2S)-2-[[(2S,4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoyl]amino]-4-methylpentanoyl)-2-pyrrolidinecarboxylate | C26H38N2O6 | 详情 | 详情 | |
| (XXIX) | 50794 | benzyl (2S)-1-[(2S,5S,7S,11S,12R,15S,16R,19S)-11-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-7-isopropyl-19-(4-methoxybenzyl)-5,16,20-trimethyl-15-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-4,6,9,14,18,21-hexaoxo-23-phenyl-8,17,22-trioxa-3,13,20-triazatricos-1-anoyl]-2-pyrrolidinecarboxylate | C70H106N6O15Si | 详情 | 详情 | |
| (XXX) | 50795 | (2R)-N-[(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-[[tert-butyl(dimethyl)silyl]oxy]-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-yl]-4-methyl-2-(methylamino)pentanamide | C55H92N6O12Si | 详情 | 详情 | |
| (XXXI) | 50796 | (2R)-N-[(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-yl]-4-methyl-2-(methylamino)pentanamide | C49H78N6O12 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XC)Diazotization of (S)-valine (LXXXIX) gave rise to the alpha-hydroxyacid (XC), which was reduced to diol (XCI) using LiAlH4. Tosylation of the primary hydroxyl of (XCI), followed by cyclization of the resulting tosylate (XCII) under basic conditions, furnished epoxide (XCIII). Condensation of epoxide (XCIII) with the lithium anion derived from sulfone (LXXXVIII) gave adduct (XCIV). Reductive elimination of the phenylsulfonyl group and then acidic rearrangement of the cyclopropane ring provided the dihydroxy steroid (XCV). After protection of (XCV) as the diacetate (XCVI), allylic oxidation with CrO3 in the presence of dimethylpyrazole yielded enone (XCVII).
| 【1】 Moriarty, R.M.; et al.; Stereoselective synthesis of squalamine dessulfate. Tetrahedron Lett 1995, 36, 29, 5139. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (LXXXVII) | 53768 | (2S)-2-[(1aR,3aR,3bS,5aS,6R,8aS,8bS,10R,10aR)-10-methoxy-3a,5a-dimethylhexadecahydrocyclopenta[a]cyclopropa[2,3]cyclopenta[1,2-f]naphthalen-6-yl]propyl phenyl sulfone; {(2S)-2-[(1aR,3aR,3bS,5aS,6R,8aS,8bS,10R,10aR)-10-methoxy-3a,5a-dimethylhexadecahydrocyclopenta[a]cyclopropa[2,3]cyclopenta[1,2-f]naphthalen-6-yl]propyl}(dioxo)phenyl-lambda~6~-sulfane | n/a | C29H42O3S | 详情 | 详情 |
| (LXXXIX) | 37828 | L-2-Amino-3-methylbutyric acid; L-2-Aminoisovaleric acid; 2-Aminoisovaleric acid; L-2-Amino-3-methylbutyric acid; L-alpha-Aminoisovaleric acid; L-valine; (S)-(+)-Valine; (S)-alpha-Aminoisovaleric acid | 72-18-4 | C5H11NO2 | 详情 | 详情 |
| (XC) | 37829 | (2S)-2-hydroxy-3-methylbutyric acid | C5H10O3 | 详情 | 详情 | |
| (XCI) | 53769 | (2S)-3-methyl-1,2-butanediol | n/a | C5H12O2 | 详情 | 详情 |
| (XCII) | 53770 | (2S)-2-hydroxy-3-methylbutyl 4-methylbenzenesulfonate | n/a | C12H18O4S | 详情 | 详情 |
| (XCIII) | 53771 | (2S)-2-isopropyloxirane | 123731-68-0 | C5H10O | 详情 | 详情 |
| (XCIV) | 53772 | (3R,6S)-6-[(1aR,3aR,3bS,5aS,6R,8aS,8bS,10R,10aR)-10-methoxy-3a,5a-dimethylhexadecahydrocyclopenta[a]cyclopropa[2,3]cyclopenta[1,2-f]naphthalen-6-yl]-2-methyl-5-(phenylsulfonyl)-3-heptanol | n/a | C34H52O4S | 详情 | 详情 |
| (XCV) | 53773 | (3S,8S,9S,10R,13R,14S,17R)-17-[(1R,4R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol | n/a | C27H46O2 | 详情 | 详情 |
| (XCVI) | 53774 | (3S,8S,9S,10R,13R,14S,17R)-17-[(1R,4R)-4-(acetyloxy)-1,5-dimethylhexyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | n/a | C31H50O4 | 详情 | 详情 |
| (XCVII) | 53775 | (3S,8S,9S,10R,13R,14S,17R)-17-[(1R,4R)-4-(acetyloxy)-1,5-dimethylhexyl]-10,13-dimethyl-7-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C31H48O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(LV)Similarly, (S)-2-hydroxy-3-methylbutyric acid (LV) was protected as the silyl ether (LVI) and then condensed with benzyl acetate, via activation with CDI, to afford keto ester (LVII). Subsequent methylation of (LVII) using iodomethane and NaH provided (XVI) as a diastereomeric mixture. The unstable keto acid (XVII), obtained in situ by catalytic hydrogenolysis of (XVI), was then coupled to the dipeptide ester (XV) to afford, after desilylation, the hydroxy keto amide (XIX). Esterification of alcohol (XIX) with the isostatine derivative (XI) as in Scheme 3, followed by acidic cleavage of the O-silyl and N-Boc protecting groups led to depsipeptide (XXI)
| 【1】 Edge, A. (Diacrin, Inc.); Method for improving graft acceptance in a recipient by administration of a cytokine profile altering agent. WO 0051630 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 50802 | (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-methylheptanoic acid | C19H39NO5Si | 详情 | 详情 | |
| (XV) | 50792 | benzyl (2S)-1-[(2S)-2-amino-4-methylpentanoyl]-2-pyrrolidinecarboxylate | C18H26N2O3 | 详情 | 详情 | |
| (XVI) | 62563 | benzyl (4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,5-dimethyl-3-oxohexanoate | C21H34O4Si | 详情 | 详情 | |
| (XVII) | 50791 | (2S,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2,5-dimethyl-3-oxohexanoic acid | C14H28O4Si | 详情 | 详情 | |
| (XIX) | 62564 | benzyl (2S)-1-((2S)-2-{[(4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoyl]amino}-4-methylpentanoyl)-2-pyrrolidinecarboxylate | C26H38N2O6 | 详情 | 详情 | |
| (XXI) | 62536 | benzyl (2S)-1-{(2S)-2-[((4S)-4-{[(3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoyl]oxy}-2,5-dimethyl-3-oxohexanoyl)amino]-4-methylpentanoyl}-2-pyrrolidinecarboxylate | C34H53N3O8 | 详情 | 详情 | |
| (LV) | 37829 | (2S)-2-hydroxy-3-methylbutyric acid | C5H10O3 | 详情 | 详情 | |
| (LVI) | 52726 | (2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3-methylbutanoic acid | C11H24O3Si | 详情 | 详情 | |
| (LVII) | 50790 | benzyl (4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-3-oxohexanoate | C20H32O4Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)(S)-2-Hydroxyisovaleric acid (IX) was obtained from L-valine (VIII) by diazotization in the presence of sulfuric acid. After protection as the allyl ester (X), coupling with isostatine derivative (VII) using DCC and DMAP afforded (XI). Then, removal of the allyl group of (XI) by means of Pd(PPh3)4 gave acid (XIII), which was activated as the pentafluorophenyl ester (XIII).
| 【1】 Liang, B.; et al.; The first total synthesis of (-)-tamadarin A. Org Lett 1999, 1, 8, 1319. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 | |
| (VII) | 37827 | (3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoic acid | C25H43NO5Si | 详情 | 详情 | |
| (VIII) | 37828 | L-2-Amino-3-methylbutyric acid; L-2-Aminoisovaleric acid; 2-Aminoisovaleric acid; L-2-Amino-3-methylbutyric acid; L-alpha-Aminoisovaleric acid; L-valine; (S)-(+)-Valine; (S)-alpha-Aminoisovaleric acid | 72-18-4 | C5H11NO2 | 详情 | 详情 |
| (IX) | 37829 | (2S)-2-hydroxy-3-methylbutyric acid | C5H10O3 | 详情 | 详情 | |
| (X) | 37830 | allyl (2S)-2-hydroxy-3-methylbutanoate | C8H14O3 | 详情 | 详情 | |
| (XI) | 37831 | (1S)-1-[(allyloxy)carbonyl]-2-methylpropyl (3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoate | C33H55NO7Si | 详情 | 详情 | |
| (XII) | 37832 | (2S)-2-([(3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoyl]oxy)-3-methylbutyric acid | C30H51NO7Si | 详情 | 详情 | |
| (XIII) | 37833 | (1S)-2-methyl-1-[(2,3,4,5,6-pentafluorophenoxy)carbonyl]propyl (3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoate | C36H50F5NO7Si | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(X)The synthesis of the carboxylic acid intermediate (VIII) has been performed as follows: The reaction of D-valine (I) with benzyl chloroformate and NaHCO3 gives the protected valine (II), which is esterified with pentafluorophenol and EDAC to yield the activated ester (III). The condensation of (III) with the lithium enolate of methyl acetate (IV) affords the beta ketoester (V), which is stereoselectively reduced with KBH4 and crystallized to afford the desired enantiomeric beta hydroxyester (VI). The silylation of (VI) with Tips-OTf and lutidine provides the silyl ether (VII), which is hydrolyzed with NaOH to give the desired carboxylic acid intermediate (VIII). The synthesis of the activated ester intermediate (XV) has been performed as follows: The reaction of L-valine (IX) with NaNO2 and H2SO4 gives the hydroxyacid (X), which is esterified with allyl bromide (XI) and K2CO3 to yield the allyl ester (XII). The condensation of (XII) with the intermediate (VIII) by means of EDAC and DMAP affords the adduct (XIII), which is treated with Pd(PPh3)4 to provide the carboxylic acid (XIV). Finally, this compound is esterified with C6F5-OTf to give the activated ester intermediate (XV).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 21056 | (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid | 640-68-6 | C5H11NO2 | 详情 | 详情 |
| (II) | 49332 | (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 | |
| (III) | 49323 | 2,3,4,5,6-pentafluorophenyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate | C19H16F5NO4 | 详情 | 详情 | |
| (IV) | 49324 | C3H5LiO2 | 详情 | 详情 | ||
| (V) | 49325 | methyl (4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-oxohexanoate | C16H21NO5 | 详情 | 详情 | |
| (VI) | 49326 | methyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxy-5-methylhexanoate | C16H23NO5 | 详情 | 详情 | |
| (VII) | 49327 | methyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoate | C25H43NO5Si | 详情 | 详情 | |
| (VIII) | 49328 | (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoic acid | C24H41NO5Si | 详情 | 详情 | |
| (IX) | 37828 | L-2-Amino-3-methylbutyric acid; L-2-Aminoisovaleric acid; 2-Aminoisovaleric acid; L-2-Amino-3-methylbutyric acid; L-alpha-Aminoisovaleric acid; L-valine; (S)-(+)-Valine; (S)-alpha-Aminoisovaleric acid | 72-18-4 | C5H11NO2 | 详情 | 详情 |
| (X) | 37829 | (2S)-2-hydroxy-3-methylbutyric acid | C5H10O3 | 详情 | 详情 | |
| (XI) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XII) | 37830 | allyl (2S)-2-hydroxy-3-methylbutanoate | C8H14O3 | 详情 | 详情 | |
| (XIII) | 49329 | (1S)-1-[(allyloxy)carbonyl]-2-methylpropyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoate | C32H53NO7Si | 详情 | 详情 | |
| (XIV) | 49330 | (2S)-2-([(3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoyl]oxy)-3-methylbutyric acid | C29H49NO7Si | 详情 | 详情 | |
| (XV) | 49331 | (1S)-2-methyl-1-[(2,3,4,5,6-pentafluorophenoxy)carbonyl]propyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoate | C35H48F5NO7Si | 详情 | 详情 |