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【结 构 式】 
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【分子编号】43028 【品名】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 【CA登记号】 |
【 分 子 式 】C14H25NO4 【 分 子 量 】271.35684 【元素组成】C 61.97% H 9.29% N 5.16% O 23.58% |
合成路线1
该中间体在本合成路线中的序号：(IX)Coupling of threonine benzyl ester (I) to Fmoc-Ile-OH (A) with HBTU, HOBt and DIEA in dichloromethane followed by protection of the hydroxyl group with TBDPS-Cl and imidazole in THF affords protected dipeptide (II). Removal of the Fmoc group of (II) with piperidine/DMF followed by coupling of Fmoc-N-Me-Ile-OH (B) with HBTU, HOBt and DIEA gives fully protected tripeptide (III), which is treated with piperidine/DMF for Fmoc removal and acetylated by means of Ac2O, DIEA in dichloromethane to furnish (IV). Debenzylation of (IV) by hydrogenolysis over Pd/C provides intermediate (V). Addition of 2-bromopropene (VII) and t-BuLi to the Boc-leucine Weinreb amide (VI) in Et2O yields alpha',beta'-unsaturated ketone (VIII), which is oxidized by treatment with H2O2 and DIEA in H2O/benzonitrile/MeOH to afford a mixture of epoxides from which (IX) is separated by column chromatography. Boc deprotection and coupling of peptide (V) with intermediate (IX) by means of TFA, HATU, HOAt, DIEA in dichloromethane, furnishes TBDPS-protected derivative (X), which is finally deprotected by treatment with TBAF in THF.
| 【1】 Sin, N.; et al.; Total synthesis of the potent proteasome inhibitor epoxomicin: A useful tool for understanding proteasome biology. Bioorg Med Chem Lett 1999, 9, 15, 2283. |
| 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) | 64559 | (2S,3S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-methylpentanoic acid | C21H23NO4 | 详情 | 详情 | |
| (B) | 64679 | (2S,3S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-3-methylpentanoic acid | C22H25NO4 | 详情 | 详情 | |
| (I) | 43023 | benzyl (2S,3R)-2-amino-3-hydroxybutanoate | C11H15NO3 | 详情 | 详情 | |
| (II) | 43022 | benzyl (2S,3R)-3-[[tert-butyl(diphenyl)silyl]oxy]-2-[((2S,3S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylpentanoyl)amino]butanoate | C48H54N2O6Si | 详情 | 详情 | |
| (III) | 43024 | benzyl (5S,8S,11S)-11-((1R)-1-[[tert-butyl(diphenyl)silyl]oxy]ethyl)-1-(9H-fluoren-9-yl)-4-methyl-5,8-bis[(1S)-1-methylpropyl]-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oate | C55H67N3O7Si | 详情 | 详情 | |
| (IV) | 43025 | benzyl (2S,3R)-2-[[(2S,3S)-2-([(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino)-3-methylpentanoyl]amino]-3-[[tert-butyl(diphenyl)silyl]oxy]butanoate | C42H59N3O6Si | 详情 | 详情 | |
| (V) | 43026 | (2S,3R)-2-[[(2S,3S)-2-([(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino)-3-methylpentanoyl]amino]-3-[[tert-butyl(diphenyl)silyl]oxy]butyric acid | C35H53N3O6Si | 详情 | 详情 | |
| (VI) | 40395 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (VII) | 42375 | 2-bromo-1-propene；2-bromopropene;Isopropenyl bromide;a-Methylvinyl bromide | 557-93-7 | C3H5Br | 详情 | 详情 |
| (VIII) | 43027 | tert-butyl (1S)-1-isobutyl-3-methyl-2-oxo-3-butenylcarbamate | C14H25NO3 | 详情 | 详情 | |
| (IX) | 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 | |
| (X) | 43029 | (2S,3S)-2-[acetyl(methyl)amino]-N-((1S,2S)-1-[[((1S,2R)-2-[[tert-butyl(diphenyl)silyl]oxy]-1-[[((1R)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl)amino]carbonyl]propyl)amino]carbonyl]-2-methylbutyl)-3-methylpentanamide | C44H68N4O7Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)Alternatively, a solid phase procedure can be followed: Fmoc-Thr(O-TBDMS)-OH (XI) is anchored on 2-chlorotrityl chloride resin by means of DIEA in CH2Cl2 to yield (XII), which then follows a standard solid-phase peptide synthesis (SPPS) protocol to be converted into (XIII). Peptide (XIV) is obtained by treatment of resin (XIII) with HOAc, trifluoroethanol/dichloromethane and is then coupled with intermediate (IX) to afford (XV) in the conditions described above. Finally, the TBDMS group is removed by means of TBAF in THF.
| 【1】 Sin, N.; et al.; Total synthesis of the potent proteasome inhibitor epoxomicin: A useful tool for understanding proteasome biology. Bioorg Med Chem Lett 1999, 9, 15, 2283. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI),(XII) | 43030 | (2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]butyric acid | C25H33NO5Si | 详情 | 详情 | |
| (XIII),(XIV) | 43031 | (2S,3R)-2-[[(2S,3S)-2-([(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino)-3-methylpentanoyl]amino]-3-[[tert-butyl(dimethyl)silyl]oxy]butyric acid | C25H49N3O6Si | 详情 | 详情 | |
| (IX) | 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 | |
| (XV) | 43032 | (2S,3S)-2-[acetyl(methyl)amino]-N-((1S,2S)-1-[[((1S,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-[[((1R)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl)amino]carbonyl]propyl)amino]carbonyl]-2-methylbutyl)-3-methylpentanamide | C34H64N4O7Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXVI)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 |
合成路线4
该中间体在本合成路线中的序号：(XXVI)Condensation of N-Boc-leucine (X) with N,O-dimethylhydroxylamine hydrochloride by means of i-BuOCOCl, NMM and Et3N in CH2Cl2 gives N-Boc-L-leucine Weinreb amide (XXVII) , which is then coupled with isopropenyl magnesium bromide (XXVIII) in THF (1) or 2-bromopropene (XXIX) in the presence of BuLi in Et2O at –78 °C to yield the heptenone derivative (XXX) . Reduction of heptenone (XXX) with NaBH4 and CeCl3·7H2O in MeOH results in a diastereomeric mixture of allylic alcohols (XXXIa) and (XXXIb), which is then epoxidized by treatment with mCPBA in CH2Cl2 to afford a mixture of oxiranes (XXXIIa) and (XXXIIb). Finally, this mixture is oxidized with Dess Martin periodinane in acetonitrile, followed by chromatographic separation . Compound (XXVI) can also be prepared by epoxidation of heptenone derivative (XXX) with H2O2 in the presence of PhCN and DIEA in MeOH or NaOCl in pyridine or Ca(OCl)2 in NMP , followed by separation by means of column chromatography .
| 【2】 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. |
| 【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. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIa) | 69411 | tert-butyl ((3S,4R)-3-hydroxy-2,6-dimethylhept-1-en-4-yl)carbamate | C14H27NO3 | 详情 | 详情 | |
| (XXXIb) | 69412 | tert-butyl ((3R,4R)-3-hydroxy-2,6-dimethylhept-1-en-4-yl)carbamate | C14H27NO3 | 详情 | 详情 | |
| (XXXIIa) | 69413 | tert-butyl ((1R,2S)-1-hydroxy-4-methyl-1-(2-methyloxiran-2-yl)pentan-2-yl)carbamate | C14H27NO4 | 详情 | 详情 | |
| (XXXIIb) | 69414 | tert-butyl ((1S,2S)-1-hydroxy-4-methyl-1-(2-methyloxiran-2-yl)pentan-2-yl)carbamate | C14H27NO4 | 详情 | 详情 | |
| (X) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 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 | |
| (XXVII) | 40395 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (XXVIII) | 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 |
| (XXIX) | 42375 | 2-bromo-1-propene；2-bromopropene;Isopropenyl bromide;a-Methylvinyl bromide | 557-93-7 | C3H5Br | 详情 | 详情 |
| (XXX) | 43027 | tert-butyl (1S)-1-isobutyl-3-methyl-2-oxo-3-butenylcarbamate | C14H25NO3 | 详情 | 详情 |