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【结 构 式】 
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【分子编号】50334 【品名】(2S)-2-[((2S,3R)-3-[[(3R,4S)-3-hydroxy-4-(methylamino)-5-phenylpentanoyl]oxy]-2-methyldecanoyl)oxy]-3-methylbutyric acid 【CA登记号】 |
【 分 子 式 】C28H45NO7 【 分 子 量 】507.66784 【元素组成】C 66.25% H 8.93% N 2.76% O 22.06% |
合成路线1
该中间体在本合成路线中的序号：(XIII)The condensation of the choral oxazolidinone (I) with octanal (II) by means of Bu2B-OTf and TEA in dichloromethane gives the chiral alcohol (III), which is protected with DHP and PPTS, yielding the tetrahydropyranyl ether (IV). The cleavage of the chiral adjuvant of (IV) by means of LiOH and H2O2 affords the carboxylic acid (V), which is esterified with (2S)-hydroxy-3-methylbutyric acid benzyl ester (VI) by means of trichlorobenzoyl chloride and TEA to provide the adduct (VII). Elimination of the tetrahydropyranyl protecting group of (VII) by means of Ts-OH gives the hydroxyester (VIII), which is condensed with the chiral amino acid (IX) by means of trichlorobenzoyl chloride as before to yield the triester compound (X). Elimination of the Mom protecting group of (X) by means of Tms-Cl and tetrabutylammonium bromide affords the hydroxy compound (XI), which is hydrogenated with H2 over Pd(OH)2 to provide the carboxylic acid (XII). Elimination of the Boc protecting group of (XII) by means of TFA gives the amino acid (XII), which is finally submitted to a macrocyclization by means of DPPA and DIEA in DMF to yield the target hapalosin.
| 【1】 Hermann, C.; et al.; Total synthesis of hapalosin and two ring expanded analogs. Tetrahedron 2000, 56, 43, 8461. |
| 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) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (II) | 25714 | octanal | 124-13-0 | C8H16O | 详情 | 详情 |
| (III) | 25715 | (4S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methyldecanoyl]-1,3-oxazolidin-2-one | C21H31NO4 | 详情 | 详情 | |
| (IV) | 50327 | Cyanoethane; Ethyl cyanide; Propionitrile | 107-12-0 | C26H39NO5 | 详情 | 详情 |
| (V) | 50328 | (2S,3R)-2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)decanoic acid | C16H30O4 | 详情 | 详情 | |
| (VI) | 25720 | benzyl (2S)-2-hydroxy-3-methylbutanoate | C12H16O3 | 详情 | 详情 | |
| (VII) | 50329 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)decanoate | C28H44O6 | 详情 | 详情 | |
| (VIII) | 25722 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-3-hydroxy-2-methyldecanoate | C23H36O5 | 详情 | 详情 | |
| (IX) | 50330 | (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-(methoxymethoxy)-5-phenylpentanoic acid | C19H29NO6 | 详情 | 详情 | |
| (X) | 50331 | benzyl (6S,7R,11R,12S,15S)-6-benzyl-11-heptyl-15-isopropyl-7-(methoxymethoxy)-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oate | C42H63NO10 | 详情 | 详情 | |
| (XI) | 50332 | benzyl (6S,7R,11S,12S,15S)-6-benzyl-11-heptyl-7-hydroxy-15-isopropyl-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oate | C40H59NO9 | 详情 | 详情 | |
| (XII) | 50333 | (6S,7R,11R,12S,15S)-6-benzyl-11-heptyl-7-hydroxy-15-isopropyl-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oic acid | C33H53NO9 | 详情 | 详情 | |
| (XIII) | 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：(XVII)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 |