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【结 构 式】 
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【分子编号】42375 【品名】2-bromo-1-propene；2-bromopropene;Isopropenyl bromide;a-Methylvinyl bromide 【CA登记号】557-93-7 |
【 分 子 式 】C3H5Br 【 分 子 量 】120.9767 【元素组成】C 29.79% H 4.17% Br 66.05% |
合成路线1
该中间体在本合成路线中的序号：(VII)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)Synthesis of intermediate (XIV): The condensation of epoxide (VIII) with isopropenyl bromide (IX) by means of n-BuLi and CuCN gives the alcohol (X), which is treated with 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (Boc-ON) and n-BuLi in toluene to yield the cyclic carbonate (XI). The epoxidation of (XI) with HOAc in THF affords the epoxide (XII), which is selectively monoprotected with ethyl vinyl ether to provide the secondary alcohol (XIII). Finally this compound is silylated with TBDMSCl and imidazole to furnish the desired intermediate (XIV).
| 【1】 Guo, J.; et al.; Total synthesis of altohyrtin A (spongistatin 1): Part 1. Angew Chem. Int Ed Engl 1998, 37, 1-2, 187. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 18762 | 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 | |
| (VIII) | 42374 | tert-butyl(dimethyl)[(2R)oxiranylmethoxy]silane; tert-butyl(dimethyl)silyl (2R)oxiranylmethyl ether | C9H20O2Si | 详情 | 详情 | |
| (IX) | 42375 | 2-bromo-1-propene；2-bromopropene;Isopropenyl bromide;a-Methylvinyl bromide | 557-93-7 | C3H5Br | 详情 | 详情 |
| (X) | 42376 | (2R)-1-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-4-penten-2-ol | C12H26O2Si | 详情 | 详情 | |
| (XI) | 42377 | (4S,6R)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-(iodomethyl)-4-methyl-1,3-dioxan-2-one | C13H25IO4Si | 详情 | 详情 | |
| (XII) | 42378 | (2R)-3-[(2S)-2-methyloxiranyl]-1,2-propanediol | C6H12O3 | 详情 | 详情 | |
| (XIII) | 42379 | (2R)-1-(2-ethoxyethoxy)-3-[(2S)-2-methyloxiranyl]-2-propanol | C10H20O4 | 详情 | 详情 | |
| (XIV) | 42380 | tert-butyl(dimethyl)silyl (1R)-2-(2-ethoxyethoxy)-1-[[(2S)-2-methyloxiranyl]methyl]ethyl ether; (5R)-2,2,3,3-tetramethyl-5-[[(2S)-2-methyloxiranyl]methyl]-4,7,10-trioxa-3-siladodecane | C16H34O4Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)The intermediate phenyl sulfone (XXIII) has been obtained as follows. The reaction of tetrahydropyranyl glycidol (I) with isopropenyl bromide (X) by means of CuCN in THF gives the secondary alcohol (XI), which is treated with allyl bromide (XII) and KH in THF to yield the allyl ether (XIII). A ring closing metathesis reaction with (XIII) catalyzed by a Ru catalyst yields the protected dihydropyran derivative (XIV), which is treated with CSA in methanol to afford the carbinol (XV). The oxidation of (XV) with (COCl)2 and DMSO in dichloromethane provides the carbaldehyde (XVI), which is treated with CBr4 and PPh3 in dichloromethane to give the dibromovinyl derivative (XVII). The condensation of (XVII) with the intermediate aldehyde (VI) by means of BuLi in THF yields the propargyl alcohol derivative (XVIII), which is oxidized with DMP to the corresponding acetylenic ketone (XIX). Alternatively, acetylenic ketone (XIX) can also be obtained by condensation of dibromovinyl derivative (XVII) with the intermediate Weinreb amide (IX) by means of BuLi in THF. The enantioselective reduction of ketone (XIX) with L-Selectride in THF affords the chiral propargyl alcohol (XX), which is reduced with Red-Al and treated with TFA to provide the trans-allylic alcohol (XXI). The reaction of the diol (XXI) with Pmp-CH(OEt)2 and CSA gives the acetal (XXII), which is finally reduced with DIBAL in dichloromethane to yield the intermediate Pmb-protected phenyl sulfone (XXIII).
| 【1】 Ghosh, A.K.; Wang, Y.; Kim, J.T.; Total synthesis of microtubule-stabilizing agent (-)-laulimalide. J Org Chem 2001, 66, 26, 8973. |
| 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) | 63105 | 2-[(2R)oxiranyloxy]tetrahydro-2H-pyran; (2R)oxiranyl tetrahydro-2H-pyran-2-yl ether | C7H12O3 | 详情 | 详情 | |
| (VI) | 63109 | (2S)-2-[(4-methoxybenzyl)oxy]-4-(phenylsulfonyl)butanal | C18H20O5S | 详情 | 详情 | |
| (IX) | 63111 | (2S)-N-methoxy-2-[(4-methoxybenzyl)oxy]-N-methyl-4-(phenylsulfonyl)butanamide | C20H25NO6S | 详情 | 详情 | |
| (X) | 42375 | 2-bromo-1-propene；2-bromopropene;Isopropenyl bromide;a-Methylvinyl bromide | 557-93-7 | C3H5Br | 详情 | 详情 |
| (XI) | 63112 | (2S)-4-methyl-1-(tetrahydro-2H-pyran-2-yloxy)-4-penten-2-ol | C11H20O3 | 详情 | 详情 | |
| (XII) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XIII) | 63113 | allyl (1S)-3-methyl-1-[(tetrahydro-2H-pyran-2-yloxy)methyl]-3-butenyl ether; 2-{[(2S)-2-(allyloxy)-4-methyl-4-pentenyl]oxy}tetrahydro-2H-pyran | C14H24O3 | 详情 | 详情 | |
| (XIV) | 63114 | 2-{[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]methoxy}tetrahydro-2H-pyran; [(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]methyl tetrahydro-2H-pyran-2-yl ether | C12H20O3 | 详情 | 详情 | |
| (XV) | 61173 | [(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]methanol | C7H12O2 | 详情 | 详情 | |
| (XVI) | 61148 | (2S)-4-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde | C7H10O2 | 详情 | 详情 | |
| (XVII) | 63115 | (2S)-2-(2,2-dibromovinyl)-4-methyl-3,6-dihydro-2H-pyran | C8H10Br2O | 详情 | 详情 | |
| (XVIII) | 63116 | (4S)-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-6-(phenylsulfonyl)-1-hexyn-3-ol | C26H30O6S | 详情 | 详情 | |
| (XIX) | 63117 | (4S)-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-6-(phenylsulfonyl)-1-hexyn-3-one | C26H28O6S | 详情 | 详情 | |
| (XX) | 63118 | (3S,4S)-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-6-(phenylsulfonyl)-1-hexyn-3-ol | C26H30O6S | 详情 | 详情 | |
| (XXI) | 63119 | (E,3S,4S)-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-6-(phenylsulfonyl)-1-hexene-3,4-diol | C18H24O5S | 详情 | 详情 | |
| (XXII) | 63120 | 2-((4S,5S)-2-(4-methoxyphenyl)-5-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-1,3-dioxolan-4-yl)ethyl phenyl sulfone; (2S)-2-((E)-2-{(4S,5S)-2-(4-methoxyphenyl)-5-[2-(phenylsulfonyl)ethyl]-1,3-dioxolan-4-yl}ethenyl)-4-methyl-3,6-dihydro-2H-pyran | C26H30O6S | 详情 | 详情 | |
| (XXIII) | 63121 | (3S,4S,5E)-4-[(4-methoxybenzyl)oxy]-6-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1-(phenylsulfonyl)-5-hexen-3-ol | C26H32O6S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXIX)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 |