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【结 构 式】 
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【分子编号】37830 【品名】allyl (2S)-2-hydroxy-3-methylbutanoate 【CA登记号】 |
【 分 子 式 】C8H14O3 【 分 子 量 】158.19736 【元素组成】C 60.74% H 8.92% O 30.34% |
合成路线1
该中间体在本合成路线中的序号：(XV)The condensation of the chiral oxazolidinone (VIII) with octanal (IX) by means of Bu2B-OTf and TEA in dichloromethane gives the chiral adduct (X), which is treated with benzyl alcohol and BuLi to yield the benzyl ester (XI). The esterification of the OH group of (XI) with the intermediate carboxylic acid (VIII) by means of DCC and DMAP in dichloromethane affords the corresponding ester (XII), whose benzyl ester is hydrogenolyzed with H2 over Pd(OH)2 in ethanol to provide the carboxylic acid (XIII). The esterification of (XIII) with the chiral hydroxyester (XIV) by means of DCC and DMAP as before gives the expected triester (XV), which is treated first with Pd(PPh3)4 and then with TFA (elimination of the allyl, Boc and Tbdms protecting groups) to yield the open-chain precursor (XVI). Finally, this compound is submitted to macrocyclization by means of DPPA and DIEA to afford the target macrocyclic compound.
| 【1】 Ohmori, K.; et al.; Synthetic study on hapalosin, a cyclic depsipeptide possessing multidrug resistance reversing activities. Tetrahedron Lett 1996, 37, 20, 3467. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 50338 | (4S,5R)-4-methyl-5-phenyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (IX) | 25714 | octanal | 124-13-0 | C8H16O | 详情 | 详情 |
| (X) | 50339 | (4S,5R)-3-[(2S,3R)-3-hydroxy-2-methyldecanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C21H31NO4 | 详情 | 详情 | |
| (XI) | 50340 | benzyl (2S,3R)-3-hydroxy-2-methyldecanoate | C18H28O3 | 详情 | 详情 | |
| (XII) | 50337 | (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-phenylpentanoic acid | C23H39NO5Si | 详情 | 详情 | |
| (XIII) | 50341 | benzyl (2S,3R)-3-[((3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-phenylpentanoyl)oxy]-2-methyldecanoate | C41H65NO7Si | 详情 | 详情 | |
| (XIV) | 50342 | (2S,3R)-3-[((3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-phenylpentanoyl)oxy]-2-methyldecanoic acid | C34H59NO7Si | 详情 | 详情 | |
| (XV) | 37830 | allyl (2S)-2-hydroxy-3-methylbutanoate | C8H14O3 | 详情 | 详情 | |
| (XVI) | 50343 | allyl (6S,7R,11R,12S,15S)-6-benzyl-7-[[tert-butyl(dimethyl)silyl]oxy]-11-heptyl-15-isopropyl-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oate | C42H71NO9Si | 详情 | 详情 | |
| (XVII) | 50334 | (2S)-2-[((2S,3R)-3-[[(3R,4S)-3-hydroxy-4-(methylamino)-5-phenylpentanoyl]oxy]-2-methyldecanoyl)oxy]-3-methylbutyric acid | C28H45NO7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)(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3
该中间体在本合成路线中的序号：(XII)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 |