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【结 构 式】 
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【分子编号】43612 【品名】(3S,7aR)-7a-[(1S)-1-hydroxy-2-methylpropyl]-6-methyl-3-phenyl-1,7a-dihydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one 【CA登记号】 |
【 分 子 式 】C17H21NO3 【 分 子 量 】287.35868 【元素组成】C 71.06% H 7.37% N 4.87% O 16.7% |
合成路线1
该中间体在本合成路线中的序号：(XXXII)Methylation of bicyclic oxazolidine (XXIX) by means of LDA and MeI, followed by selenenylation with PhSeBr/LDA in THF and ozonolysis in CH2Cl2, affords unsaturated derivative (XXX). Treatment of (XXX) with Tbdms-OTf and 2,6-lutidine in CH2Cl2 yields silyloxypyrrole (XXXI), which is converted into (XXXII) by an aldol reaction with (II) in the presence of SnCl4 in Et2O. Acetylation of (XXXII) by means of Ac2O, pyridine followed by dihydroxylation with OsO4 and N-methylmorpholine N-oxide allows formation of diol (XXXIII), whose tertiary hydroxyl group is removed by means of N,N'-thiocarbonyldiimidazole, followed by reduction with Bu3SnH and catalytic AIBN in toluene to provide derivative (XXXIV). Treatment of (XXXIV) with NaOH in MeOH followed by hydrogenolysis over Pd/C in HCl yields derivative (XXXV), which is converted into (XXXVI) by protection of primary alcohol by means of Et3SiCl and acetylation of secondary alcohol by treatment with Ac2O in pyridine. Regeneration of primary alcohol by treatment of (XXXVI) with HF in CH3CN furnishes (XXXVII), which is then oxidized by means of Jones reagent to yield (XXXVIII). Finally, saponification of diacetate acid (XXXVIII) with NaOH gives lactam (X).
| 【1】 Uno, H.; et al.; Stereocontrolled Mukaiyama-type aldol reaction of siloxypyrroles derived from (S)-glutamic acid. Synlett 1997, 390. |
| 【2】 Uno, H.; et al.; Total synthesis of (+)-lactacystin from (R)-glutamate. J Am Chem Soc 1994, 116, 5, 2139. |
| 【3】 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 |
|---|---|---|---|---|---|---|
| (XXXIVa) | 43614 | (1S)-1-[(3S,6S,7S)-7-hydroxy-6-methyl-5-oxo-3-phenyldihydro-1H-pyrrolo[1,2-c][1,3]oxazol-7(5H)-yl]-2-methylpropyl acetate | C19H25NO5 | 详情 | 详情 | |
| (XXXIVb) | 43615 | (1S)-1-[(3S,6R,7S)-7-hydroxy-6-methyl-5-oxo-3-phenyldihydro-1H-pyrrolo[1,2-c][1,3]oxazol-7(5H)-yl]-2-methylpropyl acetate | C19H25NO5 | 详情 | 详情 | |
| (II) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 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 | |
| (XXIX) | 43653 | (3S,7aR)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | C12H13NO2 | 详情 | 详情 | |
| (XXX) | 43610 | (3S,7aR)-6-methyl-3-phenyl-1,7a-dihydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | C13H13NO2 | 详情 | 详情 | |
| (XXXI) | 43611 | (3S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-3-phenyl-1H-pyrrolo[1,2-c][1,3]oxazole; tert-butyl(dimethyl)silyl (3S)-6-methyl-3-phenyl-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl ether | C19H27NO2Si | 详情 | 详情 | |
| (XXXII) | 43612 | (3S,7aR)-7a-[(1S)-1-hydroxy-2-methylpropyl]-6-methyl-3-phenyl-1,7a-dihydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | C17H21NO3 | 详情 | 详情 | |
| (XXXIII) | 43613 | (1S)-1-[(3S,6R,7R)-6,7-dihydroxy-6-methyl-5-oxo-3-phenyldihydro-1H-pyrrolo[1,2-c][1,3]oxazol-7(5H)-yl]-2-methylpropyl acetate | C19H25NO6 | 详情 | 详情 | |
| (XXXV) | 43616 | (1S)-1-[(2S,3S,4R)-3-hydroxy-2-(hydroxymethyl)-4-methyl-5-oxopyrrolidinyl]-2-methylpropyl acetate | C12H21NO5 | 详情 | 详情 | |
| (XXXVI) | 43617 | (1S)-1-((2R,3S,4R)-3-(acetoxy)-4-methyl-5-oxo-2-[[(triethylsilyl)oxy]methyl]pyrrolidinyl)-2-methylpropyl acetate | C20H37NO6Si | 详情 | 详情 | |
| (XXXVII) | 43618 | (1S)-1-[(2R,3S,4R)-3-(acetoxy)-2-(hydroxymethyl)-4-methyl-5-oxopyrrolidinyl]-2-methylpropyl acetate | C14H23NO6 | 详情 | 详情 | |
| (XXXVIII) | 43619 | (2R,3S,4R)-3-(acetoxy)-2-[(1S)-1-(acetoxy)-2-methylpropyl]-4-methyl-5-oxo-2-pyrrolidinecarboxylic acid | C14H21NO7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XX)The condensation of isobutyraldehyde (I) with triethyl phosphonoacetate (II) by means of NaH in THF gives 4-methyl-2-pentenoic acid ethyl ester (III), which is reduced with DIBAL in THF to yield the allyl alcohol (IV). The Sharpless asymmetric epoxidation of (IV) by means of Ti(O-iPr)4, (+)-diethyl tartrate ((+)-DET) and tBu-OOH in toluene affords the epoxy alcohol (V), which is treated with trichloroacetonitrile and DBU to provide the acetimidate (VI). The cyclization of (VI) by means of triethyl aluminum chloride in dichloromethane gives the oxazoline (VII), which is silylated with Tbdms-OTf and TEA in dichloromethane to afford the silyl ether (VIII). The cleavage of the oxazoline ring of (VIII) by means of HCl in THF yields the chiral amino alcohol (IX), which is protected with Tbdms-OTf as before to afford the silylated amine (X). The monoalkylation of (X) with 1,3-dibromo-2-methylpropene (XI) and Cs-OH in DMF provides the secondary amine (XII). The cyclization of (XII) by means of KHMDS in toluene/ethyl ether gives the non isolated intermediate (XIII) that rearranges to the pyrroline (XIV). The reaction of (XIV) with TPAP and NMO in acetonitrile yields the cyclic imine (XV), which is oxidized with NaClO2 to the 1-chloropyrrolin-2-one (XVI). The dechlorination of (XVI) by means of NaBH4 affords the pyrrolinone (XVII), which is selectively monodesilylated with TBAF in THF to provide the primary alcohol (XVIII). The cyclization of (XVIII) with benzaldehyde dimethylacetal and Ts-OH in refluxing toluene gives the bicyclic pyrrolo oxazole (XIX), which is finally deprotected by means of TBAF in THF to yield the target bicyclic intermediate (XX) (see scheme no. 23327701c intermediate (XXXII)).
| 【1】 Green, M.P.; et al.; An enantioselective formal synthesis of the proteasome inhibitor (+)-lactacystin. Tetrahedron Lett 2002, 43, 37, 6609. |
| 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) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (II) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (III) | 57196 | ethyl (E)-4-methyl-2-pentenoate | C8H14O2 | 详情 | 详情 | |
| (IV) | 43593 | (E)-4-methyl-2-penten-1-ol | C6H12O | 详情 | 详情 | |
| (V) | 57181 | [(2S,3S)-3-isopropyloxiranyl]methanol | C6H12O2 | 详情 | 详情 | |
| (VI) | 57182 | [(2S,3S)-3-isopropyloxiranyl]methyl 2,2,2-trichloroethanimidoate | C8H12Cl3NO2 | 详情 | 详情 | |
| (VII) | 57183 | (1S)-2-methyl-1-[(4R)-2-(trichloromethyl)-4,5-dihydro-1,3-oxazol-4-yl]-1-propanol | C8H12Cl3NO2 | 详情 | 详情 | |
| (VIII) | 57184 | (4R)-4-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-2-(trichloromethyl)-4,5-dihydro-1,3-oxazole; tert-butyl(dimethyl)silyl (1S)-2-methyl-1-[(4R)-2-(trichloromethyl)-4,5-dihydro-1,3-oxazol-4-yl]propyl ether | C14H26Cl3NO2Si | 详情 | 详情 | |
| (IX) | 57185 | (2R,3S)-2-amino-3-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-1-pentanol | C12H29NO2Si | 详情 | 详情 | |
| (X) | 57186 | (5S,6R)-5-isopropyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-amine; (1R,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylbutylamine | C18H43NO2Si2 | 详情 | 详情 | |
| (XI) | 57187 | (E)-1,3-dibromo-2-methyl-1-propene | C4H6Br2 | 详情 | 详情 | |
| (XII) | 57188 | N-[(E)-3-bromo-2-methyl-2-propenyl]-N-[(1R,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylbutyl]amine; (5S,6R)-N-[(E)-3-bromo-2-methyl-2-propenyl]-5-isopropyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-amine | C22H48BrNO2Si2 | 详情 | 详情 | |
| (XIII) | 57189 | (5S,6S)-N-[(Z)-3-bromo-2-methyl-2-propenyl]-5-isopropyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-amine; N-[(Z)-3-bromo-2-methyl-2-propenyl]-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylbutyl]amine | C22H48BrNO2Si2 | 详情 | 详情 | |
| (XIV) | 57190 | (2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-4-methyl-2,5-dihydro-1H-pyrrole; tert-butyl(dimethyl)silyl (1S)-1-[(2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methyl-2,5-dihydro-1H-pyrrol-2-yl]-2-methylpropyl ether | C22H47NO2Si2 | 详情 | 详情 | |
| (XV) | 57191 | tert-butyl(dimethyl)silyl (1S)-1-[(2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methyl-2H-pyrrol-2-yl]-2-methylpropyl ether; (2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-4-methyl-2H-pyrrole | C22H45NO2Si2 | 详情 | 详情 | |
| (XVI) | 57192 | (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-1-chloro-3-methyl-1,5-dihydro-2H-pyrrol-2-one | C22H44ClNO3Si2 | 详情 | 详情 | |
| (XVII) | 57193 | (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-3-methyl-1,5-dihydro-2H-pyrrol-2-one | C22H45NO3Si2 | 详情 | 详情 | |
| (XVIII) | 57194 | (5R)-5-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-5-(hydroxymethyl)-3-methyl-1,5-dihydro-2H-pyrrol-2-one | C16H31NO3Si | 详情 | 详情 | |
| (XIX) | 57195 | (3S,7aS)-7a-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-6-methyl-3-phenyl-1,7a-dihydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | C23H35NO3Si | 详情 | 详情 | |
| (XX) | 43612 | (3S,7aR)-7a-[(1S)-1-hydroxy-2-methylpropyl]-6-methyl-3-phenyl-1,7a-dihydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | C17H21NO3 | 详情 | 详情 |