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【结 构 式】 
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【分子编号】43591 【品名】(1R,4R,5S)-1-[(1S)-1-hydroxy-2-methylpropyl]-4-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione 【CA登记号】 |
【 分 子 式 】C10H15NO4 【 分 子 量 】213.23344 【元素组成】C 56.33% H 7.09% N 6.57% O 30.01% |
合成路线1
该中间体在本合成路线中的序号：(XI)Treatment of cis-oxazolidine derivative (I) with isobutyraldehyde (II), LDA and LiBr in THF yields aldol product (III), which is then converted into (IV) by first aminal cleavage by means of MeOH and TfOH, followed by silylation with Tbdms-Cl and imidazole in DMF. Reaction of (IV) with formaldehyde and TsOH in benzene gives oxazolidine system (V), which is then first reduced with LiBH4 in THF/MeOH and then oxidized by means of DMSO, oxalyl chloride and Et3N in CH2Cl2 to provide aldehyde (VI). Mukaiyama aldol coupling of (VI) and (VII) in CH2Cl2 with MgI2 as catalyst, followed by treatment with K2CO3 in MeOH, yields aldol product (VIII), which is then converted into hydroxy lactam (IX) by the sequence: i) N-benzyl cleavage by hydrogenolysis over Pd/C in EtOH in the presence of DIEA; ii) ring closure by heating in MeOH; and iii) desilylation by treatment with HF in acetonitrile. Conversion of alcohol (IX) into dihydroxy acid (X) is achieved by a first oxidation with DMSO, oxalyl chloride and Et3N in CH2Cl2, followed by reaction with NaClO2, NaH2PO4 in t-BuOH and 2-Me-butene and final N/O methylene bridge removal with 1,3-propanedithiol (A) catalyzed by HCl and TFA. Compound (X) undergoes beta-lactonization to omuralide (XI) by means of BOPCl and Et3N in CH2Cl2 and finally (XI) is coupled to N-acetyl-L-cysteine (XII) in CH2Cl2 in the presence of Et3N.
| 【1】 Corey, E.J.; Li, W.-D.Z.; Total synthesis and biological activity of lactacystin, omuralide and analogs. Chem Pharm Bull 1999, 47, 1, 1. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 29729 | 1,3-propanedithiol; 3-sulfanylpropylhydrosulfide | 109-80-8 | C3H8S2 | 详情 | 详情 |
| (I) | 43582 | methyl (2R,4S)-3-benzyl-2-(tert-butyl)-1,3-oxazolidine-4-carboxylate | C16H23NO3 | 详情 | 详情 | |
| (II) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (III) | 43583 | methyl (2R,4R)-3-benzyl-2-(tert-butyl)-4-(1-hydroxy-2-methylpropyl)-1,3-oxazolidine-4-carboxylate | C20H31NO4 | 详情 | 详情 | |
| (IV) | 43584 | methyl (2R,3S)-2-(benzylamino)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-hydroxy-4-methylpentanoate | C21H37NO4Si | 详情 | 详情 | |
| (V) | 43585 | methyl (4R,5S)-3-benzyl-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-isopropyl-1,3-oxazolidine-4-carboxylate | C22H37NO4Si | 详情 | 详情 | |
| (VI) | 43586 | (4R,5S)-3-benzyl-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-isopropyl-1,3-oxazolidine-4-carbaldehyde | C21H35NO3Si | 详情 | 详情 | |
| (VII) | 43587 | (E)-1-methoxy-1-propenyl trimethylsilyl ether; [[(E)-1-methoxy-1-propenyl]oxy](trimethyl)silane | 34880-70-1 | C7H16O2Si | 详情 | 详情 |
| (VIII) | 43588 | methyl (2R,3S)-3-[(4S,5S)-3-benzyl-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-isopropyl-1,3-oxazolidin-4-yl]-3-hydroxy-2-methylpropanoate | C25H43NO5Si | 详情 | 详情 | |
| (IX) | 43589 | (1S,6R,7S,7aS)-7-hydroxy-7a-(hydroxymethyl)-1-isopropyl-6-methyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | C11H19NO4 | 详情 | 详情 | |
| (X) | 43590 | (2R,3S,4R)-3-hydroxy-2-[(1S)-1-hydroxy-2-methylpropyl]-4-methyl-5-oxo-2-pyrrolidinecarboxylic acid | C10H17NO5 | 详情 | 详情 | |
| (XI) | 43591 | (1R,4R,5S)-1-[(1S)-1-hydroxy-2-methylpropyl]-4-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione | C10H15NO4 | 详情 | 详情 | |
| (XII) | 43592 | (2R)-2-(acetamido)-3-sulfanylpropionic acid | C5H9NO3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Alternatively, intermediate omuralide (XI) can also be obtained by following this synthetic sequence: Methylsulfanyl derivative (LVII) is transformed into chiral mono ester (LVIII) by enantioselective hydrolysis with porcine liver esterase (PLE) followed by recrystallization of the quinine salt. Treatment of (LVIII) with oxalyl chloride in DMF, followed by coupling in dichloromethane with N-p-methoxybenzylglycinate (PMB-NHCH2COOMe) (B) and Et3N and subsequent Dieckmann cyclization with LDA in THF, affords keto lactam (LIX). Stereoselective alpha-hydroxymethylation of (LIX) by means of formalin and DBU in THF, followed by stereospecific reduction with NaBH(OAc)3 in AcOH, gives dihydroxy lactam (LX), which is then converted into TBDMS ether (LXI) by the following sequence: i) esterification of primary hydroxyl group by pivaloyl chloride (PivCl) in pyridine; ii) silylation of the secondary hydroxyl group by means of TBSOTf and 2,6-lutidine; and iii) cleavage of the pivalate ester by treatment with NaOMe in MeOH. Desulfurization of (LXI) with Ni Raney followed by Dess-Martin periodinane oxidation furnishes aldehyde (LXII), which then reacts with Grignard reagent (LXIII) and TMSCl to yield the addition product (LXIV). Hydrogenation of (LXIV) over Pd/C followed by desilylation with TFA/H2O produces (LXV), which is hydrolyzed by means of LiOH in THF/H2O and treated with BOP-Cl and Et3N, affording beta-lactone (LXVI). Finally, cleavage of the N-p-methoxybenzyl protecting group of (LXVI) with Ceric ammonium nitrate in acetonitrile/H2O yields omuralide (XI).
| 【1】 Corey, E.J.; et al.; An efficient and concise enantioselective total synthesis of lactacystin. Angew Chem. Int Ed Engl 1998, 37, 12, 1676. |
| 【2】 Corey, E.J.; Li, W.-D.Z.; Total synthesis and biological activity of lactacystin, omuralide and analogs. Chem Pharm Bull 1999, 47, 1, 1. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 43643 | methyl 2-[(4-methoxybenzyl)amino]acetate | C11H15NO3 | 详情 | 详情 | |
| (LIXa) | 43644 | methyl (2S,4R)-1-(4-methoxybenzyl)-4-methyl-4-(methylsulfanyl)-3,5-dioxo-2-pyrrolidinecarboxylate | C16H19NO5S | 详情 | 详情 | |
| (LIXb) | 43645 | methyl (2R,4R)-1-(4-methoxybenzyl)-4-methyl-4-(methylsulfanyl)-3,5-dioxo-2-pyrrolidinecarboxylate | C16H19NO5S | 详情 | 详情 | |
| (XI) | 43591 | (1R,4R,5S)-1-[(1S)-1-hydroxy-2-methylpropyl]-4-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione | C10H15NO4 | 详情 | 详情 | |
| (LVII) | 43641 | dimethyl 2-methyl-2-(methylsulfanyl)malonate | C7H12O4S | 详情 | 详情 | |
| (LVIII) | 43642 | (2S)-3-methoxy-2-methyl-2-(methylsulfanyl)-3-oxopropionic acid | C6H10O4S | 详情 | 详情 | |
| (LX) | 43646 | methyl (2R,3R,4R)-3-hydroxy-2-(hydroxymethyl)-1-(4-methoxybenzyl)-4-methyl-4-(methylsulfanyl)-5-oxo-2-pyrrolidinecarboxylate | C17H23NO6S | 详情 | 详情 | |
| (LXI) | 43647 | methyl (2R,3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(hydroxymethyl)-1-(4-methoxybenzyl)-4-methyl-4-(methylsulfanyl)-5-oxo-2-pyrrolidinecarboxylate | C23H37NO6SSi | 详情 | 详情 | |
| (LXII) | 43648 | methyl (2S,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-formyl-1-(4-methoxybenzyl)-4-methyl-5-oxo-2-pyrrolidinecarboxylate | C22H33NO6Si | 详情 | 详情 | |
| (LXIII) | 43649 | bromo(isopropenyl)magnesium；isopropenyl magnesium bromide；1-Methylvinylmagnesiumbromide;1-Propen-2-ylmagnesium bromide;a-Methylvinylmagnesium bromide | 13291-18-4 | C3H5BrMg | 详情 | 详情 |
| (LXIV) | 43650 | methyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[(1S)-1-hydroxy-2-methyl-2-propenyl]-1-(4-methoxybenzyl)-4-methyl-5-oxo-2-pyrrolidinecarboxylate | C25H39NO6Si | 详情 | 详情 | |
| (LXV) | 43651 | methyl (2R,3S,4R)-3-hydroxy-2-[(1S)-1-hydroxy-2-methylpropyl]-1-(4-methoxybenzyl)-4-methyl-5-oxo-2-pyrrolidinecarboxylate | C19H27NO6 | 详情 | 详情 | |
| (LXVI) | 43652 | (1R,4R,5S)-1-[(1S)-1-hydroxy-2-methylpropyl]-2-(4-methoxybenzyl)-4-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione | C18H23NO5 | 详情 | 详情 |