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【结 构 式】 
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【分子编号】50358 【品名】(5S,6R)-6-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methyltetrahydro-2H-pyran-2-one 【CA登记号】 |
【 分 子 式 】C14H28O3Si 【 分 子 量 】272.46002 【元素组成】C 61.72% H 10.36% O 17.62% Si 10.31% |
合成路线1
该中间体在本合成路线中的序号：(XXXIX)The condensation of 3-(tert-butyldimethylsilyloxy)propanal (XXXIII) with the chiral borane (XXXIV) by means of H2O2 and NaHCO3 gives the chiral alcohol (XXXV), which is oxidized with OsO4 and NaIO4 to yield the aldehyde (XXXVI). The Wittig condensation of (XXXVI) with phosphorane (XVI) affords the heptenoic ester (XXXVII), which is reduced with H2 over Pd/C to provide the saturated hydroxy ester (XXXVIII). The cyclization of (XXXVIII) by means of PPTS in refluxing dichloromethane gives the lactone (XXXIX), which by reaction with Cp2TiMe2 yields the methylene derivative (I).
| 【1】 Guzzupe, A.N.; et al.; Total synthesis of the epidermal growth factor inhibitor (-)-reveromycin B. J Org Chem 2001, 66, 7, 2382. |
| 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) | 41537 | tert-butyl(dimethyl)[2-[(2R,3S)-3-methyl-6-methylenetetrahydro-2H-pyran-2-yl]ethoxy]silane; tert-butyl(dimethyl)silyl 2-[(2R,3S)-3-methyl-6-methylenetetrahydro-2H-pyran-2-yl]ethyl ether | C15H30O2Si | 详情 | 详情 | |
| (XVI) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (XXXIII) | 45546 | 3-[[tert-butyl(dimethyl)silyl]oxy]propanal | 570-24-1 | C9H20O2Si | 详情 | 详情 |
| (XXXIV) | 50353 | (E)-2-butenyl[bis[(1R,2R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C24H41B | 详情 | 详情 | |
| (XXXV) | 50354 | (3R,4S)-1-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-hexen-3-ol | C13H28O2Si | 详情 | 详情 | |
| (XXXVI) | 50355 | (2R,3R)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-2-methylpentanal | C12H26O3Si | 详情 | 详情 | |
| (XXXVII) | 50356 | methyl (E,4S,5R)-7-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4-methyl-2-heptenoate | C15H30O4Si | 详情 | 详情 | |
| (XXXVIII) | 50357 | methyl (4S,5R)-7-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4-methylheptanoate | C15H32O4Si | 详情 | 详情 | |
| (XXXIX) | 50358 | (5S,6R)-6-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methyltetrahydro-2H-pyran-2-one | C14H28O3Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Alkylation of ethyl 1-benzyloxycarbonyl-3-oxopyrrolidine-4-carboxylate (I) with iodomethane and K2CO3 produced the 4-methylpyrrolidine (II). The keto group of (III) was then protected as the corresponding ketal (IV) with 2,2-dimethyl-1,3-propanodiol (III). Replacement of the benzyloxycarbonyl protecting group of (IV) with a benzyl group (V) was accomplished by catalytic hydrogenolysis, followed by alkylation of the resulting pyrrolidine with benzyl chloride. The ester group of (V) was then reduced to the primary alcohol (VI) using LiAlH4. After conversion of alcohol (VI) to the corresponding mesylate, displacement with NaN3 provided the alkyl azide (VII). This was reduced to the primary amine (VIII) by catalytic hydrogenation over Raney-Ni. Resolution of the racemic amine (VIII) was carried out via acylation with N-tosyl-L-proline (IX), followed by chromatographic separation of the diastereomeric amides. Base-promoted hydrolysis of the chiral auxiliary from the desired diastereoisomer (X) provided the (R)-amine, which was further protected as the N-Boc derivative (XI). The N-benzyl group of (XI) was then removed by catalytic hydrogenolysis over Pd/C to yield the target pyrrrolidine (XII).
| 【1】 Yoon, S.J.; Chung, Y.H.; Lee, C.W.; Choi, D.R.; Lee, J.S.; Yang, W.Y.; Kim, N.D.; Jin, Y.H.; Song, W.J.; Kim, I.H.; Shin, J.H. (Dong-Wha Pharmaceuticals Industry Co. Ltd); Optically active quinoline carboxylic acid derivs. having 7-pyrrolidine substitutes causing optical activity and a process for preparing thereof. WO 0071541 . |
| 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) | 53053 | 1-benzyl 3-ethyl 4-oxo-1,3-pyrrolidinedicarboxylate | n/a | C15H17NO5 | 详情 | 详情 |
| (II) | 53054 | 1-benzyl 3-ethyl 3-methyl-4-oxo-1,3-pyrrolidinedicarboxylate | n/a | C16H19NO5 | 详情 | 详情 |
| (III) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (IV) | 53055 | 2-benzyl 4-ethyl 4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-2,4-dicarboxylate | n/a | C21H29NO6 | 详情 | 详情 |
| (V) | 53056 | ethyl 2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-4-carboxylate | n/a | C20H29NO4 | 详情 | 详情 |
| (VI) | 53057 | (2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl)methanol | n/a | C18H27NO3 | 详情 | 详情 |
| (VII) | 50358 | (5S,6R)-6-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methyltetrahydro-2H-pyran-2-one | C14H28O3Si | 详情 | 详情 | |
| (VIII) | 53059 | (2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl)methanamine; (2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl)methylamine | n/a | C18H28N2O2 | 详情 | 详情 |
| (IX) | 53060 | (2S)-1-[(4-methylphenyl)sulfonyl]-2-pyrrolidinecarboxylic acid | n/a | C12H15NO4S | 详情 | 详情 |
| (X) | 53061 | (2S)-N-{[(4R)-2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl]methyl}-1-[(4-methylphenyl)sulfonyl]-2-pyrrolidinecarboxamide | n/a | C30H41N3O5S | 详情 | 详情 |
| (XI) | 53062 | tert-butyl [(4R)-2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl]methylcarbamate | n/a | C23H36N2O4 | 详情 | 详情 |
| (XII) | 53063 | tert-butyl [(4S)-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl]methylcarbamate | n/a | C16H30N2O4 | 详情 | 详情 |