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【结 构 式】 
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【分子编号】43593 【品名】(E)-4-methyl-2-penten-1-ol 【CA登记号】 |
【 分 子 式 】C6H12O 【 分 子 量 】100.16068 【元素组成】C 71.95% H 12.08% O 15.97% |
合成路线1
该中间体在本合成路线中的序号：(XIII)Sharpless epoxidation of (XIII) with cumene hydroperoxide, diisopropyl L-tartrate ((+)-DIPT) and Ti(O-i-Pr)4 affords epoxide (-)-(XIV), which is then treated with benzyl isocyanate and NaH in refluxing THF to yield oxazolidinone (XV). Oxidation of (XV) by means of CrO3 in H2SO4 (Jones reagent) in acetone gives the corresponding carboxylic acid (XVI), which is converted into methyl ester (XVII) via diazomethane esterification in Et2O. Exposure of (XVII) to ethanolic KOH affords the trans-acid (XVIII), which is then converted into (2R,3S)-hydroxyleucine (XIX) by treatment with KOH and hydrogenolysis over Pd(OH)2 in MeOH. Esterification of (XIX) by means of MeOH and HCl (gas) provides (XX), which is treated with methyl benzimidate (Ph(MeO)C=NH) or methyl orthobenzoate (PhC(OMe)3) in the presence of catalytic p-TsOH to yield trans-oxazoline (XXI). Aldol condensation of (XXI) with formaldehyde and LHMDS via the Seebach protocol gives (XXII), which is converted into (XXIII) via Moffat oxidation with DCC and TFA in benzene/DMSO. Brown asymmetric allylboration of (XIII) in THF with (E)-crotyl(diisopinocampheyl)borane (XXIV) in Et2O affords a homoallylic alcohol mixture from which diastereomer (-)-(XXV) is obtained. Ozonolysis of (-)-(XXV) and reductive treatment with dimethylsulfide (DMS), followed by oxidation with NaClO2, NaH2PO4 and 2-methyl-2-butene, provides carboxylic acid (XXVI), which is then converted into (X) by means of Pd and HCOONH4 in refluxing HOAc followed by saponification with NaOH. Lactam ester derivative (X) reacts with N-acetyl-L-cysteine allyl ester (XXVII), BOPCl and Et3N in CH2Cl2 to furnish (XVIII), which is finally deallylated by means of Pd(PPh3)4, HCO2H and Et3N in THF.
| 【1】 Sunazuka, T.; et al.; Total synthesis of (+)-lactacystin, the first non-protein neurotrophic factor. J Am Chem Soc 1993, 115, 5302. |
| 【2】 Nagamitsu, T.; et al.; Total synthesis of (+)-lactacystin. J Am Chem Soc 1996, 118, 15, 3584. |
| 【3】 Corey, E.J.; Li, W.-D.Z.; Total synthesis and biological activity of lactacystin, omuralide and analogs. Chem Pharm Bull 1999, 47, 1, 1. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 43607 | (2S,3S,4R)-3-hydroxy-2-[(1S)-1-hydroxy-2-methylpropyl]-4-methyl-5-oxo-2-pyrrolidinecarboxylic acid | C10H17NO5 | 详情 | 详情 | |
| (XIII) | 43593 | (E)-4-methyl-2-penten-1-ol | C6H12O | 详情 | 详情 | |
| (XIV) | 43594 | [(2R,3S)-3-isopropyloxiranyl]methanol | C6H12O2 | 详情 | 详情 | |
| (XV) | 43595 | (4R,5S)-3-benzyl-4-(hydroxymethyl)-5-isopropyl-1,3-oxazolidin-2-one | C14H19NO3 | 详情 | 详情 | |
| (XVI) | 43596 | (4S,5S)-3-benzyl-5-isopropyl-2-oxo-1,3-oxazolidine-4-carboxylic acid | C14H17NO4 | 详情 | 详情 | |
| (XVII) | 43597 | methyl (4S,5S)-3-benzyl-5-isopropyl-2-oxo-1,3-oxazolidine-4-carboxylate | C15H19NO4 | 详情 | 详情 | |
| (XVIII) | 43598 | (4R,5S)-3-benzyl-5-isopropyl-2-oxo-1,3-oxazolidine-4-carboxylic acid | C14H17NO4 | 详情 | 详情 | |
| (XIX) | 43599 | (2R,3S)-2-amino-3-hydroxy-4-methylpentanoic acid | C6H13NO3 | 详情 | 详情 | |
| (XX) | 43600 | methyl (2R,3S)-2-amino-3-hydroxy-4-methylpentanoate | C7H15NO3 | 详情 | 详情 | |
| (XXI) | 43601 | (4S,5S)-5-isopropyl-4-methyl-2-phenyl-4,5-dihydro-1,3-oxazole | C13H17NO | 详情 | 详情 | |
| (XXII) | 43602 | methyl (4S,5S)-4-(hydroxymethyl)-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate | C15H19NO4 | 详情 | 详情 | |
| (XXIII) | 43603 | methyl (4R,5S)-4-formyl-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate | C15H17NO4 | 详情 | 详情 | |
| (XXIV) | 43604 | (E)-2-butenyl[bis[(1S,2R,3S,5S)-1,2,5,6,6-pentamethylbicyclo[3.1.1]hept-3-yl]]borane | C28H49B | 详情 | 详情 | |
| (XXV) | 43605 | methyl (4S,5S)-4-[(1S,2S)-1-hydroxy-2-methyl-3-butenyl]-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate | C19H25NO4 | 详情 | 详情 | |
| (XXVI) | 43606 | (2R,3S)-3-hydroxy-3-[(4S,5S)-5-isopropyl-4-(methoxycarbonyl)-2-phenyl-4,5-dihydro-1,3-oxazol-4-yl]-2-methylpropionic acid | C18H23NO6 | 详情 | 详情 | |
| (XXVII) | 43608 | allyl (2R)-2-(acetamido)-3-sulfanylpropanoate | C8H13NO3S | 详情 | 详情 | |
| (XXVIII) | 43609 | allyl (2R)-2-(acetamido)-3-[([(2S,3S,4R)-3-hydroxy-2-[(1S)-1-hydroxy-2-methylpropyl]-4-methyl-5-oxopyrrolidinyl]carbonyl)sulfanyl]propanoate | C18H28N2O7S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The condensation of isobutyraldehyde (I) with triethyl phosphonoacetate (II) by means of NaH in THF gives 4-methyl-2-pentenoic acid ethyl ester (III), which is reduced with DIBAL in THF to yield the allyl alcohol (IV). The Sharpless asymmetric epoxidation of (IV) by means of Ti(O-iPr)4, (+)-diethyl tartrate ((+)-DET) and tBu-OOH in toluene affords the epoxy alcohol (V), which is treated with trichloroacetonitrile and DBU to provide the acetimidate (VI). The cyclization of (VI) by means of triethyl aluminum chloride in dichloromethane gives the oxazoline (VII), which is silylated with Tbdms-OTf and TEA in dichloromethane to afford the silyl ether (VIII). The cleavage of the oxazoline ring of (VIII) by means of HCl in THF yields the chiral amino alcohol (IX), which is protected with Tbdms-OTf as before to afford the silylated amine (X). The monoalkylation of (X) with 1,3-dibromo-2-methylpropene (XI) and Cs-OH in DMF provides the secondary amine (XII). The cyclization of (XII) by means of KHMDS in toluene/ethyl ether gives the non isolated intermediate (XIII) that rearranges to the pyrroline (XIV). The reaction of (XIV) with TPAP and NMO in acetonitrile yields the cyclic imine (XV), which is oxidized with NaClO2 to the 1-chloropyrrolin-2-one (XVI). The dechlorination of (XVI) by means of NaBH4 affords the pyrrolinone (XVII), which is selectively monodesilylated with TBAF in THF to provide the primary alcohol (XVIII). The cyclization of (XVIII) with benzaldehyde dimethylacetal and Ts-OH in refluxing toluene gives the bicyclic pyrrolo oxazole (XIX), which is finally deprotected by means of TBAF in THF to yield the target bicyclic intermediate (XX) (see scheme no. 23327701c intermediate (XXXII)).
| 【1】 Green, M.P.; et al.; An enantioselective formal synthesis of the proteasome inhibitor (+)-lactacystin. Tetrahedron Lett 2002, 43, 37, 6609. |
| 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) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (II) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (III) | 57196 | ethyl (E)-4-methyl-2-pentenoate | C8H14O2 | 详情 | 详情 | |
| (IV) | 43593 | (E)-4-methyl-2-penten-1-ol | C6H12O | 详情 | 详情 | |
| (V) | 57181 | [(2S,3S)-3-isopropyloxiranyl]methanol | C6H12O2 | 详情 | 详情 | |
| (VI) | 57182 | [(2S,3S)-3-isopropyloxiranyl]methyl 2,2,2-trichloroethanimidoate | C8H12Cl3NO2 | 详情 | 详情 | |
| (VII) | 57183 | (1S)-2-methyl-1-[(4R)-2-(trichloromethyl)-4,5-dihydro-1,3-oxazol-4-yl]-1-propanol | C8H12Cl3NO2 | 详情 | 详情 | |
| (VIII) | 57184 | (4R)-4-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-2-(trichloromethyl)-4,5-dihydro-1,3-oxazole; tert-butyl(dimethyl)silyl (1S)-2-methyl-1-[(4R)-2-(trichloromethyl)-4,5-dihydro-1,3-oxazol-4-yl]propyl ether | C14H26Cl3NO2Si | 详情 | 详情 | |
| (IX) | 57185 | (2R,3S)-2-amino-3-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-1-pentanol | C12H29NO2Si | 详情 | 详情 | |
| (X) | 57186 | (5S,6R)-5-isopropyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-amine; (1R,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylbutylamine | C18H43NO2Si2 | 详情 | 详情 | |
| (XI) | 57187 | (E)-1,3-dibromo-2-methyl-1-propene | C4H6Br2 | 详情 | 详情 | |
| (XII) | 57188 | N-[(E)-3-bromo-2-methyl-2-propenyl]-N-[(1R,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylbutyl]amine; (5S,6R)-N-[(E)-3-bromo-2-methyl-2-propenyl]-5-isopropyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-amine | C22H48BrNO2Si2 | 详情 | 详情 | |
| (XIII) | 57189 | (5S,6S)-N-[(Z)-3-bromo-2-methyl-2-propenyl]-5-isopropyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-amine; N-[(Z)-3-bromo-2-methyl-2-propenyl]-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylbutyl]amine | C22H48BrNO2Si2 | 详情 | 详情 | |
| (XIV) | 57190 | (2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-4-methyl-2,5-dihydro-1H-pyrrole; tert-butyl(dimethyl)silyl (1S)-1-[(2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methyl-2,5-dihydro-1H-pyrrol-2-yl]-2-methylpropyl ether | C22H47NO2Si2 | 详情 | 详情 | |
| (XV) | 57191 | tert-butyl(dimethyl)silyl (1S)-1-[(2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methyl-2H-pyrrol-2-yl]-2-methylpropyl ether; (2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-4-methyl-2H-pyrrole | C22H45NO2Si2 | 详情 | 详情 | |
| (XVI) | 57192 | (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-1-chloro-3-methyl-1,5-dihydro-2H-pyrrol-2-one | C22H44ClNO3Si2 | 详情 | 详情 | |
| (XVII) | 57193 | (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-3-methyl-1,5-dihydro-2H-pyrrol-2-one | C22H45NO3Si2 | 详情 | 详情 | |
| (XVIII) | 57194 | (5R)-5-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-5-(hydroxymethyl)-3-methyl-1,5-dihydro-2H-pyrrol-2-one | C16H31NO3Si | 详情 | 详情 | |
| (XIX) | 57195 | (3S,7aS)-7a-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-6-methyl-3-phenyl-1,7a-dihydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | C23H35NO3Si | 详情 | 详情 | |
| (XX) | 43612 | (3S,7aR)-7a-[(1S)-1-hydroxy-2-methylpropyl]-6-methyl-3-phenyl-1,7a-dihydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | C17H21NO3 | 详情 | 详情 |