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【结 构 式】 
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【分子编号】69408 【品名】benzyl ((1S,2S)-1-hydroxy-4-methyl-1-((R)-2-methyloxiran-2-yl)pentan-2-yl)carbamate 【CA登记号】 |
【 分 子 式 】C17H25NO4 【 分 子 量 】307.38984 【元素组成】 C 66.43% H 8.2% N 4.56% O 20.82% |
合成路线1
该中间体在本合成路线中的序号：(XXIVa)The epoxide building blocks (VIII) and (IX) are prepared starting from N-Cbz-4(S)-amino-2,6-dimethyl-1-hepten-3-one (XXII). Reduction of ketone (XXII) with NaBH4 in the presence of CeCl3·7H2O in MeOH gives a diastereomeric mixture of allylic alcohols (XXIIIa) and (XXIIIb), which by epoxidation with mCPBA in CH2Cl2 or VO(acac)2 and t-BuOOH also in CH2Cl2 yields a mixture of oxiranes (XXIVa) and (XXIVb). Oxidation of the mixture of alcohols (XXIVa) and (XXIVb) by means of NMO and TPAP in CH2Cl2 or Dess Martin periodinane in DMSO or by Swern oxidation (treatment with DMSO and [COCl]2 in CH2Cl2, followed by Et3N in CH2Cl2), and then chromatographic separation of the diastereomers affords N-Cbz-2(S)-amino-4-methyl-1-[2(R)-methyloxiran-2-yl]pentan-1-one (XXV) , which is then deprotected by transfer hydrogenation with HCOOH and Pd/C or by catalytic hydrogenation over Pd/C in the presence of TFA, providing the corresponding formic acid salt (IX) and TFA salt (VIII) . Alternatively, deprotection of the epoxy amino acid (XXVI) by means of TFA also gives the TFA salt (VIII) .
| 【1】 Phiasivongsa, P., Sehl, L.C., Fuller, W.D., Laidig, G.J. (Proteolix, Inc.). Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides. WO 2009045497. |
| 【2】 Laidig, G.J., Radel, P.A., Smyth, M.S. (Proteolix, Inc.). Synthesis of amino acid keto-epoxides. EP 1756079, JP 2007538081, US 2005256324, WO 2005111009. |
| 【3】 Sin, N., Kim, K.B., Elofsson, M., Meng, L., Auth, H., Kwok, B.H.B., Crews, C.M. Total synthesis of the potent proteasome inhibitor epoximicin: A useful tool for understanding proteosome biology. Bioorg Med Chem Lett 1999, 9(15): 2283-8. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIIIa) | 69406 | benzyl ((3S,4S)-3-hydroxy-2,6-dimethylhept-1-en-4-yl)carbamate | C17H25NO3 | 详情 | 详情 | |
| (XXIIIb) | 69407 | benzyl ((3R,4S)-3-hydroxy-2,6-dimethylhept-1-en-4-yl)carbamate | C17H25NO3 | 详情 | 详情 | |
| (XXIVa) | 69408 | benzyl ((1S,2S)-1-hydroxy-4-methyl-1-((R)-2-methyloxiran-2-yl)pentan-2-yl)carbamate | C17H25NO4 | 详情 | 详情 | |
| (XXIVb) | 69409 | benzyl ((1R,2S)-1-hydroxy-4-methyl-1-((R)-2-methyloxiran-2-yl)pentan-2-yl)carbamate | C17H25NO4 | 详情 | 详情 | |
| (VIII) | 69396 | 2(S)-amino-4-methyl-1-[2(R)-methyloxiran-2-yl]pentan-1-one trifluoroacetate salt | C9H17NO2.C2HF3O2 | 详情 | 详情 | |
| (IX) | 69397 | (S)-2-amino-4-methyl-1-((R)-2-methyloxiran-2-yl)pentan-1-one formate | C9H17NO2.CH2O2 | 详情 | 详情 | |
| (XXII) | 69405 | (R)-benzyl (2,6-dimethyl-3-oxohept-1-en-4-yl)carbamate | C17H23NO3 | 详情 | 详情 | |
| (XXV) | 69410 | benzyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate；N-Cbz-2(S)-amino-4-methyl-1-[2(R)-methyloxiran-2-yl]pentan-1-one | C17H23NO4 | 详情 | 详情 | |
| (XXVI) | 43028 | tert-butyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate；tert-butyl (1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butylcarbamate | C14H25NO4 | 详情 | 详情 |