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【结 构 式】 
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【分子编号】39393 【品名】(4S)-4-benzyl-3-(2-chloroacetyl)-1,3-oxazolidin-2-one 【CA登记号】 |
【 分 子 式 】C12H12ClNO3 【 分 子 量 】253.68492 【元素组成】C 56.82% H 4.77% Cl 13.98% N 5.52% O 18.92% |
合成路线1
该中间体在本合成路线中的序号：(I)The resolution of racemic 3,3alpha-beta,4,5,6,6alpha-beta-hexahydro-4beta-nitromethyl-5alpha-carboxy-2H-cyclopenta[b]furan-2-one (I), with R(+)-alpha-methyl-p-nitrobenzylamine gives optical active 3,3aR,4,5,6,6aS-hexahydro-4R-nitromethyl-5R-carboxy-2H-cyclopenta[b]furan-2-one (I), which is reduced with borane-methyl sulfide complex in ethyl acetate yielding the corresponding hydroxymethyl compound (II). The reaction of (II) with I2 and triphenylphosphine in HMPT affords the iodomethyl derivative (III), which is finally reduced with sodium cyanoborohydride in the same solvent to give 3,3aR,4,5,6,6aS-hexahydro-4S-nitromethyl-5R-methyl-2H-cyclopenta[b]furan-2-one (IV). The treatment of (IV) with sodium methoxide in methanol and with H2SO4-methanol yields the 4S-dimethoxymethyl derivative (V), which is hydrolyzed with trifluoro acetic acid in water-CHCl3 to afford the corresponding 4S-formyl compound (VI). The Wittig reaction of (VI) with dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate (VII) in 1,2-dimethoxyethane affords 3,3aR,4,5,6,6aS-hexahydro-4R-(4,4-dimethyl-3-oxo-1-trans-octenyl)-5R-methyl-2H-cyclopenta[b]furan-2-one (VIII), which is reduced with NaBH4 in methanol to yield the corresponding 3S-hydroxy compound (IX). The protection of the hydroxy group of (IX) with dihydropyran/p-toluenesulfonic acid in CH2Cl2 affords the 3S-tetrahydropyranyloxy compound (X), which is reduced again with diisobutyl aluminum hydride in toluene to afford 3,3aR,4,5,6,6-hexahydro-4R-(4,4-dimethyl-3R-tetrahydropyranyloxy-1-trans-octenyl)-5R-methyl-2H-cyclopenta[b]furan-2-ol (XI).
| 【1】 Holland, G.W.; et al.; US 4112225 . |
| 【2】 Hillier, K.; Blancafort, P.; Serradell, M.N.; Castaner, J.; RO-21-6937/000. Drugs Fut 1981, 6, 1, 42. |
| 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) | 39393 | (4S)-4-benzyl-3-(2-chloroacetyl)-1,3-oxazolidin-2-one | C12H12ClNO3 | 详情 | 详情 | |
| (II) | 37394 | (3aR,4S,5R,6aS)-5-(hydroxymethyl)-4-(nitromethyl)hexahydro-2H-cyclopenta[b]furan-2-one | C9H13NO5 | 详情 | 详情 | |
| (III) | 37395 | (3aR,4R,5R,6aS)-5-(iodomethyl)-4-(nitromethyl)hexahydro-2H-cyclopenta[b]furan-2-one | C9H12INO4 | 详情 | 详情 | |
| (IV) | 37396 | (3aR,4S,5R,6aS)-5-methyl-4-(nitromethyl)hexahydro-2H-cyclopenta[b]furan-2-one | C9H13NO4 | 详情 | 详情 | |
| (V) | 37397 | (3aR,4S,5R,6aS)-4-(dimethoxymethyl)-5-methylhexahydro-2H-cyclopenta[b]furan-2-one | C11H18O4 | 详情 | 详情 | |
| (VI) | 37398 | (3aR,4S,5R,6aS)-5-methyl-2-oxohexahydro-2H-cyclopenta[b]furan-4-carbaldehyde | C9H12O3 | 详情 | 详情 | |
| (VII) | 37399 | dimethyl 3,3-dimethyl-2-oxoheptylphosphonate | C11H23O4P | 详情 | 详情 | |
| (VIII) | 37400 | (3aR,4R,5R,6aS)-4-[(E)-4,4-dimethyl-3-oxo-1-octenyl]-5-methylhexahydro-2H-cyclopenta[b]furan-2-one | C18H28O3 | 详情 | 详情 | |
| (IX) | 37401 | (3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-4,4-dimethyl-1-octenyl]-5-methylhexahydro-2H-cyclopenta[b]furan-2-one | C18H30O3 | 详情 | 详情 | |
| (X) | 37402 | (3aR,4R,5R,6aS)-4-[(E,3R)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-methylhexahydro-2H-cyclopenta[b]furan-2-one | C24H40O4 | 详情 | 详情 | |
| (XI) | 37403 | (3aR,4R,5R,6aS)-4-[(E,3R)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-methylhexahydro-2H-cyclopenta[b]furan-2-ol | C24H42O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)C1-C9 Fragment: The condensation of 2,2-dimethyl-4,4-diphenyl-3-butenal (I) with the chiral oxazolidinone (II) by means of dibutylboron triflate gives the chiral ketol (III), which is dechlorinated with Zn and AcOH in THF yielding the beta-hydroxyimide (IV). The reduction of (IV) with LiBH4 in methanol/THF affords the chiral diol (V), which is treated with 4-methoxybenzaldehyde dimethyl acetal and PPTS in dichloromethane to give the cyclic ketal (VI). The regioselective reduction of (VI) with DIBAL in dichloromethane yields the monoprotected diol (VII), which is oxidized to aldehyde (VIII) with oxalyl chloride in DMSO. The condensation of (VIII) with the bis(trimethylsilyl)dienol ether (IX) by means of TiCl2(i-PrO)2 in toluene affords the ketoester (X), which by stereoselective reduction with (AcO)3BHNMe4 in acetonitrile/acetic acid gives the dihydroxyester (XI) with high stereoselectivity. The lactonization of (XI) by means of PPTS in refluxing benzene yields the hydroxylactone (XII), which is silylated with TBDMS-OTf and 2,6-lutidine in dichloromethane affording the silylated lactone (XIII). Opening of the lactone ring with aniline and Me3Al in dichloromethane gives the monoprotected dihydroxyamide (XIV), which is ozonolyzed with O3 in CH2Cl2/MeOH yielding the cyclic lactol (XV). Acetylation of (XV) with acetic anhydride and pyridine affords the acetate (XVI), which by reaction with TMS-SPh, ZnI2 and tetrabutylammonium iodide is converted regioselectively into the phenylsulfanyl derivative (XVII). Finally, this compound is oxidized with m-chloroperbenzoic acid (MCPBA) in EtOAc to provide the desired C1-C9 subunit fragment (XVIII).
| 【1】 Lautens, M.; Prunet, J.A.; Carreira, E.M.; Carter, P.H.; Charette, A.B.; Evans, D.A.; Total synthesis of bryostatin 2. J Am Chem Soc 1999, 121, 33, 7540. |
| 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) | 39392 | 2,2-dimethyl-4,4-diphenyl-3-butenal | C18H18O | 详情 | 详情 | |
| (II) | 39393 | (4S)-4-benzyl-3-(2-chloroacetyl)-1,3-oxazolidin-2-one | C12H12ClNO3 | 详情 | 详情 | |
| (III) | 39394 | (4S)-4-benzyl-3-[(2S,3R)-2-chloro-3-hydroxy-4,4-dimethyl-6,6-diphenyl-5-hexenoyl]-1,3-oxazolidin-2-one | C30H30ClNO4 | 详情 | 详情 | |
| (IV) | 39395 | (4S)-4-benzyl-3-[(3S)-3-hydroxy-4,4-dimethyl-6,6-diphenyl-5-hexenoyl]-1,3-oxazolidin-2-one | C30H31NO4 | 详情 | 详情 | |
| (V) | 39396 | (3S)-4,4-dimethyl-6,6-diphenyl-5-hexene-1,3-diol | C20H24O2 | 详情 | 详情 | |
| (VI) | 39397 | 4-[(4S)-4-(1,1-dimethyl-3,3-diphenyl-2-propenyl)-1,3-dioxan-2-yl]phenyl methyl ether; (4S)-4-(1,1-dimethyl-3,3-diphenyl-2-propenyl)-2-(4-methoxyphenyl)-1,3-dioxane | C28H30O3 | 详情 | 详情 | |
| (VII) | 39398 | (3S)-3-[(4-methoxybenzyl)oxy]-4,4-dimethyl-6,6-diphenyl-5-hexen-1-ol | C28H32O3 | 详情 | 详情 | |
| (VIII) | 39399 | (3S)-3-[(4-methoxybenzyl)oxy]-4,4-dimethyl-6,6-diphenyl-5-hexenal | C28H30O3 | 详情 | 详情 | |
| (IX) | 39400 | (1Z)-1,3-bis[(trimethylsilyl)oxy]-1,3-butadienyl methyl ether; (Z)-4-methoxy-2,2,8,8-tetramethyl-6-methylene-3,7-dioxa-2,8-disila-4-nonene | C11H24O3Si2 | 详情 | 详情 | |
| (X) | 39401 | methyl (5S,7S)-5-hydroxy-7-[(4-methoxybenzyl)oxy]-8,8-dimethyl-3-oxo-10,10-diphenyl-9-decenoate | C33H38O6 | 详情 | 详情 | |
| (XI) | 39402 | methyl (3R,5R,7S)-3,5-dihydroxy-7-[(4-methoxybenzyl)oxy]-8,8-dimethyl-10,10-diphenyl-9-decenoate | C33H40O6 | 详情 | 详情 | |
| (XII) | 39403 | (4R,6R)-4-hydroxy-6-[(2S)-2-[(4-methoxybenzyl)oxy]-3,3-dimethyl-5,5-diphenyl-4-pentenyl]tetrahydro-2H-pyran-2-one | C32H36O5 | 详情 | 详情 | |
| (XIII) | 39404 | (4R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2S)-2-[(4-methoxybenzyl)oxy]-3,3-dimethyl-5,5-diphenyl-4-pentenyl]tetrahydro-2H-pyran-2-one | C38H50O5Si | 详情 | 详情 | |
| (XIV) | 39405 | (3R,5S,7S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-7-[(4-methoxybenzyl)oxy]-8,8-dimethyl-N,10,10-triphenyl-9-decenamide | C44H57NO5Si | 详情 | 详情 | |
| (XV) | 39406 | (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(2S,4S)-6-hydroxy-4-[(4-methoxybenzyl)oxy]-5,5-dimethyltetrahydro-2H-pyran-2-yl]-N-phenylbutanamide | C31H47NO6Si | 详情 | 详情 | |
| (XVI) | 39407 | (4S,6S)-6-((2R)-4-anilino-2-[[tert-butyl(dimethyl)silyl]oxy]-4-oxobutyl)-4-[(4-methoxybenzyl)oxy]-3,3-dimethyltetrahydro-2H-pyran-2-yl acetate | C33H49NO7Si | 详情 | 详情 | |
| (XVII) | 39408 | (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(2S,4S,6R)-4-[(4-methoxybenzyl)oxy]-5,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]-N-phenylbutanamide | C37H51NO5SSi | 详情 | 详情 | |
| (XVIII) | 63864 | (3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[(2S,4S,6R)-4-[(4-methoxybenzyl)oxy]-5,5-dimethyl-6-(phenylsulfonyl)tetrahydro-2H-pyran-2-yl]-N-phenylbutanamide | C37H51NO7SSi | 详情 | 详情 |