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【结 构 式】 
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【分子编号】61821 【品名】benzyl (4S)-4-({7-[5-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl}-2-(methoxymethoxy)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate 【CA登记号】 |
【 分 子 式 】C39H45N3O10 【 分 子 量 】715.80052 【元素组成】C 65.44% H 6.34% N 5.87% O 22.35% |
合成路线1
该中间体在本合成路线中的序号：(XII)The reaction of N-(benzyloxycarbonyl)-L-serine methyl ester (I) with 2-mercaptobenzothiazole (II) by means of DIAD and PPh3 in THF gives the thioether (III), which is reduced with NaBH4 and CaCl2 in THF to yield the alcohol (IV). The cyclization of (IV) with 2,2-dimethoxypropane (V) by means of TsOH in dichloromethane affords the oxazolidine (VI), which is oxidized at the thioether group by means of Mo7O24(NH4)6 and H2O2 in ethanol to provide the sulfone (VII). The condensation of (VII) with 7-iodoisatin (VIII) employing LiHMDS and DMPU in THF gives the adduct (IX), which is condensed with the boronic ester (X) -obtained by reaction of the tyrosine derivative (XI) with bis(pinacolato)diboron, KOH and Pd(dppf)Cl2 in hot DMSO- by means of K2CO3 and Pd(dppf)Cl2 in aqueous DME to yield the coupled product (XII). The hydrolysis of the ester group of (XII) with LiOH, followed by condensation with asparagine benzyl ester (XIII) by means of HOAT, EDC and NMM in dichloromethane affords the amide (XIV). This is oxidized at its exocyclic double bond by means of OsO4 and pyridine in THF/methanol to provide the diol (XV).
| 【1】 Albrecht, B.K.; Williams, R.M.; A concise formal total synthesis of TMC-95A/B proteasome inhibitors. Org Lett 2003, 5, 2, 197. |
| 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) | 51660 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoate | C12H15NO5 | 详情 | 详情 | |
| (II) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
| (III) | 61814 | methyl (2R)-3-(1,3-benzothiazol-2-ylsulfanyl)-2-{[(benzyloxy)carbonyl]amino}propanoate | C19H18N2O4S2 | 详情 | 详情 | |
| (IV) | 61815 | benzyl (1R)-2-(1,3-benzothiazol-2-ylsulfanyl)-1-(hydroxymethyl)ethylcarbamate | C18H18N2O3S2 | 详情 | 详情 | |
| (V) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VI) | 61816 | benzyl (4S)-4-[2-(1,3-benzothiazol-2-ylsulfanyl)ethyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C22H24N2O3S2 | 详情 | 详情 | |
| (VII) | 61817 | benzyl (4S)-4-[2-(1,3-benzothiazol-2-ylsulfonyl)ethyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C22H24N2O5S2 | 详情 | 详情 | |
| (VIII) | 61824 | 7-iodo-1H-indole-2,3-dione | C8H4INO2 | 详情 | 详情 | |
| (IX) | 61818 | benzyl (4S)-4-[(7-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C22H21IN2O4 | 详情 | 详情 | |
| (X) | 61820 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate | C23H36BNO8 | 详情 | 详情 | |
| (XI) | 61819 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-iodo-4-(methoxymethoxy)phenyl]propanoate | C17H24INO6 | 详情 | 详情 | |
| (XII) | 61821 | benzyl (4S)-4-({7-[5-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl}-2-(methoxymethoxy)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C39H45N3O10 | 详情 | 详情 | |
| (XIII) | 61825 | benzyl (2S)-2,4-diamino-4-oxobutanoate | C11H14N2O3 | 详情 | 详情 | |
| (XIV) | 61822 | benzyl (4S)-4-({7-[5-{(2S)-3-({(1S)-3-amino-1-[(benzyloxy)carbonyl]-3-oxopropyl}amino)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}-2-(methoxymethoxy)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C49H55N5O12 | 详情 | 详情 | |
| (XV) | 61823 | benzyl (4R)-4-[(R)-{(3S)-7-[5-{(2S)-3-({(1S)-3-amino-1-[(benzyloxy)carbonyl]-3-oxopropyl}amino)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}-2-(methoxymethoxy)phenyl]-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl}(hydroxy)methyl]-2,2-dimethyl-1,3-oxazoli | C49H57N5O14 | 详情 | 详情 |