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【结 构 式】 
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【分子编号】43649 【品名】bromo(isopropenyl)magnesium；isopropenyl magnesium bromide；1-Methylvinylmagnesiumbromide;1-Propen-2-ylmagnesium bromide;a-Methylvinylmagnesium bromide 【CA登记号】13291-18-4 |
【 分 子 式 】C3H5BrMg 【 分 子 量 】145.2817 【元素组成】C 24.8% H 3.47% Br 55% Mg 16.73% |
合成路线1
该中间体在本合成路线中的序号：(VII)The reduction of the protected (S)-ethyl lactate (I) with DIBAL in dichloromethane gives the aldehyde (II), which by a Grignard condensation with allylmagnesium bromide (III) in ethyl ether yields the homoallylic alcohol (IV). The reaction of (IV) with Tbdms-Cl and imidazole in DMF affords the silyl ether (V), which is ozonolyzed with O3 in dichloromethane/methanol to provide the aldehyde (VI), which, by a new Grignard condensation with isopropenylmagnesium bromide (VII) in THF, gives the allyl alcohol derivative (VIII). Compound (VIII) is treated with triethyl orthoacetate (refluxing xylene) in a Johnson Claisen rearrangement to yield the (E)-unsaturated ester (IX), which is debenzylated by treatment with DDQ to afford the secondary alcohol (X). The oxidation of (X) with oxalyl chloride provides the ketoester (XI), which is oxidized with AD-mix beta in tert-butanol/water to furnish the diol (XII) as an inseparable mixture of isomers. This mixture, by a Wittig condensation with the phosphonium salt (XIII) and KHMDS in THF, gives a mixture of the hydroxylactones (XIV) and (XV) that are separated by chromatography. Compound (XIV) is mesylated with MsCl and TEA and treated with K2CO3 in methanol to give the desired epoxyester (XVI). The diastereomer (XV) with wrong configuration is recovered by a double inversion: Compound (XV) is mesylated and the resulting derivative is then epoxidated with K2CO3 in methanol to yield the epoxide (XVII), which is treated with K2CO3 in methanol/water to afford the hydroxylactone (XIV) with the adequate configuration.
| 【1】 Martin, H.J.; et al.; How stable are epoxides? A novel synthesis of epothilone B. Angew Chem. Int Ed Engl 2000, 39, 3, 581. |
| 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) | 49259 | ethyl (2S)-2-[(4-methoxybenzyl)oxy]propanoate | C13H18O4 | 详情 | 详情 | |
| (II) | 49260 | (2S)-2-[(4-methoxybenzyl)oxy]propanal | C11H14O3 | 详情 | 详情 | |
| (III) | 10386 | Allyl(bromo)magnesium | 1730-25-2 | C3H5BrMg | 详情 | 详情 |
| (IV) | 49261 | (2S,3S)-2-[(4-methoxybenzyl)oxy]-5-hexen-3-ol | C14H20O3 | 详情 | 详情 | |
| (V) | 49262 | tert-butyl[((1S)-1-[(1S)-1-[(4-methoxybenzyl)oxy]ethyl]-3-butenyl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl (1S)-1-[(1S)-1-[(4-methoxybenzyl)oxy]ethyl]-3-butenyl ether | C20H34O3Si | 详情 | 详情 | |
| (VI) | 49263 | (3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4-methoxybenzyl)oxy]pentanal | C19H32O4Si | 详情 | 详情 | |
| (VII) | 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 |
| (VIII) | 49264 | (5S,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(4-methoxybenzyl)oxy]-2-methyl-1-hepten-3-ol | C22H38O4Si | 详情 | 详情 | |
| (IX) | 49265 | ethyl (E,7S,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-8-[(4-methoxybenzyl)oxy]-4-methyl-4-nonenoate | C26H44O5Si | 详情 | 详情 | |
| (X) | 49266 | ethyl (E,7S,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-4-methyl-4-nonenoate | C18H36O4Si | 详情 | 详情 | |
| (XI) | 49267 | ethyl (E,7S)-7-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-8-oxo-4-nonenoate | C18H34O4Si | 详情 | 详情 | |
| (XII) | 49268 | ethyl (7S)-7-[[tert-butyl(dimethyl)silyl]oxy]-4,5-dihydroxy-4-methyl-8-oxononanoate | C18H36O6Si | 详情 | 详情 | |
| (XIII) | 40820 | tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride | C17H33ClNPS | 详情 | 详情 | |
| (XIV) | 49269 | (5R)-5-[(1R,3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl]-5-methyldihydro-2(3H)-furanone | C21H35NO4SSi | 详情 | 详情 | |
| (XV) | 49270 | (5S)-5-[(1S,3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl]-5-methyldihydro-2(3H)-furanone | C21H35NO4SSi | 详情 | 详情 | |
| (XVI) | 49271 | methyl 3-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]propanoate | C22H37NO4SSi | 详情 | 详情 | |
| (XVII) | 49272 | methyl 3-[(2S,3R)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]propanoate | C22H37NO4SSi | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(LXIII)Alternatively, intermediate omuralide (XI) can also be obtained by following this synthetic sequence: Methylsulfanyl derivative (LVII) is transformed into chiral mono ester (LVIII) by enantioselective hydrolysis with porcine liver esterase (PLE) followed by recrystallization of the quinine salt. Treatment of (LVIII) with oxalyl chloride in DMF, followed by coupling in dichloromethane with N-p-methoxybenzylglycinate (PMB-NHCH2COOMe) (B) and Et3N and subsequent Dieckmann cyclization with LDA in THF, affords keto lactam (LIX). Stereoselective alpha-hydroxymethylation of (LIX) by means of formalin and DBU in THF, followed by stereospecific reduction with NaBH(OAc)3 in AcOH, gives dihydroxy lactam (LX), which is then converted into TBDMS ether (LXI) by the following sequence: i) esterification of primary hydroxyl group by pivaloyl chloride (PivCl) in pyridine; ii) silylation of the secondary hydroxyl group by means of TBSOTf and 2,6-lutidine; and iii) cleavage of the pivalate ester by treatment with NaOMe in MeOH. Desulfurization of (LXI) with Ni Raney followed by Dess-Martin periodinane oxidation furnishes aldehyde (LXII), which then reacts with Grignard reagent (LXIII) and TMSCl to yield the addition product (LXIV). Hydrogenation of (LXIV) over Pd/C followed by desilylation with TFA/H2O produces (LXV), which is hydrolyzed by means of LiOH in THF/H2O and treated with BOP-Cl and Et3N, affording beta-lactone (LXVI). Finally, cleavage of the N-p-methoxybenzyl protecting group of (LXVI) with Ceric ammonium nitrate in acetonitrile/H2O yields omuralide (XI).
| 【1】 Corey, E.J.; et al.; An efficient and concise enantioselective total synthesis of lactacystin. Angew Chem. Int Ed Engl 1998, 37, 12, 1676. |
| 【2】 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 |
|---|---|---|---|---|---|---|
| (B) | 43643 | methyl 2-[(4-methoxybenzyl)amino]acetate | C11H15NO3 | 详情 | 详情 | |
| (LIXa) | 43644 | methyl (2S,4R)-1-(4-methoxybenzyl)-4-methyl-4-(methylsulfanyl)-3,5-dioxo-2-pyrrolidinecarboxylate | C16H19NO5S | 详情 | 详情 | |
| (LIXb) | 43645 | methyl (2R,4R)-1-(4-methoxybenzyl)-4-methyl-4-(methylsulfanyl)-3,5-dioxo-2-pyrrolidinecarboxylate | C16H19NO5S | 详情 | 详情 | |
| (XI) | 43591 | (1R,4R,5S)-1-[(1S)-1-hydroxy-2-methylpropyl]-4-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione | C10H15NO4 | 详情 | 详情 | |
| (LVII) | 43641 | dimethyl 2-methyl-2-(methylsulfanyl)malonate | C7H12O4S | 详情 | 详情 | |
| (LVIII) | 43642 | (2S)-3-methoxy-2-methyl-2-(methylsulfanyl)-3-oxopropionic acid | C6H10O4S | 详情 | 详情 | |
| (LX) | 43646 | methyl (2R,3R,4R)-3-hydroxy-2-(hydroxymethyl)-1-(4-methoxybenzyl)-4-methyl-4-(methylsulfanyl)-5-oxo-2-pyrrolidinecarboxylate | C17H23NO6S | 详情 | 详情 | |
| (LXI) | 43647 | methyl (2R,3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(hydroxymethyl)-1-(4-methoxybenzyl)-4-methyl-4-(methylsulfanyl)-5-oxo-2-pyrrolidinecarboxylate | C23H37NO6SSi | 详情 | 详情 | |
| (LXII) | 43648 | methyl (2S,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-formyl-1-(4-methoxybenzyl)-4-methyl-5-oxo-2-pyrrolidinecarboxylate | C22H33NO6Si | 详情 | 详情 | |
| (LXIII) | 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 |
| (LXIV) | 43650 | methyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[(1S)-1-hydroxy-2-methyl-2-propenyl]-1-(4-methoxybenzyl)-4-methyl-5-oxo-2-pyrrolidinecarboxylate | C25H39NO6Si | 详情 | 详情 | |
| (LXV) | 43651 | methyl (2R,3S,4R)-3-hydroxy-2-[(1S)-1-hydroxy-2-methylpropyl]-1-(4-methoxybenzyl)-4-methyl-5-oxo-2-pyrrolidinecarboxylate | C19H27NO6 | 详情 | 详情 | |
| (LXVI) | 43652 | (1R,4R,5S)-1-[(1S)-1-hydroxy-2-methylpropyl]-2-(4-methoxybenzyl)-4-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione | C18H23NO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXVIII)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 |