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【结 构 式】 
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【分子编号】37805 【品名】methyl (4R,5S)-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate 【CA登记号】 |
【 分 子 式 】C14H17NO3 【 分 子 量 】247.29392 【元素组成】C 68% H 6.93% N 5.66% O 19.41% |
合成路线1
该中间体在本合成路线中的序号：(VII)The oxidation of protected hydroxymethyl lactone (I) with DCC/DMSO gives the aldehyde (II), which is condensed with phosphorane (III) to yield the pentenone (IV). The reduction of (IV) with NaBH4 in methanol affords the pentenol (Va-b), which is further reduced with DIBAL to provide the lactol (VIa-d). The condensation of (VIa-d) with phosphorane (VII) by means of KOtBu gives the trihydroxyheptenoic acid (VIIIa-b), which is esterified with isopropyl iodide (A) and DBU, yielding the isopropyl ester (IXa-b). Finally, this compound is selectively oxidized with DDQ to afford the target compound.
| 【1】 Stjernschantz, J.; Resul, B.; Phenyl substituted prostaglandin analogs for glaucoma treatment. Drugs Fut 1992, 17, 8, 691. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXa) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (Va) | 43181 | (3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-5-phenyl-1-pentenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C31H30O5 | 详情 | 详情 | |
| (Vb) | 43182 | (3aR,4R,5R,6aS)-4-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C31H30O5 | 详情 | 详情 | |
| (VIa) | 43183 | (2R,3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-5-phenyl-1-pentenyl]hexahydro-2H-cyclopenta[b]furan-2,5-diol | C18H24O4 | 详情 | 详情 | |
| (VIb) | 43184 | (2S,3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-5-phenyl-1-pentenyl]hexahydro-2H-cyclopenta[b]furan-2,5-diol | C18H24O4 | 详情 | 详情 | |
| (VIc) | 43185 | (2R,3aR,4R,5R,6aS)-4-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]hexahydro-2H-cyclopenta[b]furan-2,5-diol | C18H24O4 | 详情 | 详情 | |
| (VId) | 43186 | (2S,3aR,4R,5R,6aS)-4-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]hexahydro-2H-cyclopenta[b]furan-2,5-diol | C18H24O4 | 详情 | 详情 | |
| (VIIIa) | 43187 | (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-heptenoic acid | C23H32O5 | 详情 | 详情 | |
| (VIIIb) | 43188 | (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-heptenoic acid | 38344-08-0 | C23H32O5 | 详情 | 详情 |
| (IXb) | 43189 | isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-heptenoate | C26H38O5 | 详情 | 详情 | |
| (I) | 43178 | (3aR,4S,5R,6aS)-4-(hydroxymethyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | 31752-99-5 | C21H20O5 | 详情 | 详情 |
| (II) | 32042 | (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C21H18O5 | 详情 | 详情 | |
| (III) | 43179 | 4-phenyl-1-(triphenylphosphoranylidene)-2-butanone | C28H25OP | 详情 | 详情 | |
| (IV) | 43180 | (3aR,4R,5R,6aS)-2-oxo-4-[(E)-3-oxo-5-phenyl-1-pentenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C31H28O5 | 详情 | 详情 | |
| (VII) | 37805 | methyl (4R,5S)-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate | C14H17NO3 | 详情 | 详情 | |
| (X) | 43190 | isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-heptenoate | C26H38O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVIII)On the other hand, Wittig condensation of isobutyraldehyde (X) with methyl (triphenylphosphoranylidene)acetate (XI) afforded (E)-4-methylpent-2-enoic acid methyl ester (XII). Sharpless catalytic asymmetric dihydroxylation of (XII) gave diol (XIII). Condensation of diol (XIII) with trimethyl orthobenzoate in the presence of BF3.Et2O, followed by treatment of the crude cyclic orthoester with acetyl bromide produced bromo ester (XIV). The required alpha-amino group was then introduced by nucleophilic displacement of the bromide of (XIV) with NaN3 in DMSO, followed by catalytic hydrogenation of the resulting azide (XV). The intermediate amino ester (XVI) was then rearranged to hydroxy amide (XVII) upon refluxing in EtOAc. Cyclization of (XVII) to the required trans oxazoline (XVIII) was then achieved by treatment with p-toluenesulfonic acid in boiling toluene.
| 【1】 Soucy, F.; et al.; A novel and efficient synthesis of a highly active analogue clasto-lactacystin beta-lactone. J Am Chem Soc 1999, 121, 43, 9967. |
| 【2】 Plamondon, L.; Soucy, F.; Behnke, M.; Roush, W.; Synthesis of clasto-lactacystin beta-lactone and analogs thereof. WO 9909006 . |
| 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) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (XI) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (XII) | 37799 | methyl (E)-4-methyl-2-pentenoate | C7H12O2 | 详情 | 详情 | |
| (XIII) | 37800 | methyl (2S,3R)-2,3-dihydroxy-4-methylpentanoate | C7H14O4 | 详情 | 详情 | |
| (XIV) | 37801 | (1S,2S)-2-bromo-1-isopropyl-3-methoxy-3-oxopropyl benzoate | C14H17BrO4 | 详情 | 详情 | |
| (XV) | 37802 | (1S,2R)-2-azido-1-isopropyl-3-methoxy-3-oxopropyl benzoate | C14H17N3O4 | 详情 | 详情 | |
| (XVI) | 37803 | (1S,2R)-2-amino-1-isopropyl-3-methoxy-3-oxopropyl benzoate | C14H19NO4 | 详情 | 详情 | |
| (XVII) | 37804 | methyl (2R,3S)-2-(benzoylamino)-3-hydroxy-4-methylpentanoate | C14H19NO4 | 详情 | 详情 | |
| (XVIII) | 37805 | methyl (4R,5S)-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate | C14H17NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVIII)Treatment of the lithium enolate of oxazoline ester (XVIII) with dimethylaluminum chloride, followed by aldol condensation with aldehyde (IX) at -80 C diastereoselectively led to adduct (XIX). Hydrogenolysis of the oxazoline (XIX) with concomitant cyclization of the intermediate aminodiol produced lactam (XX). The methyl ester group of (XX) was then hydrolyzed with NaOH to give hydroxyacid (XXI). This was finally cyclized to the title lactone employing either TBTU or isopropenyl chloroformate in the presence of Et3N.
| 【1】 Soucy, F.; et al.; A novel and efficient synthesis of a highly active analogue clasto-lactacystin beta-lactone. J Am Chem Soc 1999, 121, 43, 9967. |
| 【2】 Plamondon, L.; Adams, J.; Elliot, P. (ProScript, Inc.); Proteasome inhibitors, ubiquitin pathway inhibitors or agents that interfere with the activation of NF-kappaB via the ubiquitin proteasome pathway to treat inflammatory and autoimmune diseases. WO 9915183 . |
| 【3】 Plamondon, L.; Soucy, F.; Behnke, M.; Roush, W.; Synthesis of clasto-lactacystin beta-lactone and analogs thereof. WO 9909006 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 37798 | (2R)-N,N-diethyl-2-formylpentanamide | C10H19NO2 | 详情 | 详情 | |
| (XVIII) | 37805 | methyl (4R,5S)-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate | C14H17NO3 | 详情 | 详情 | |
| (XIX) | 37806 | methyl (4S,5S)-4-[(1S,2R)-2-[(diethylamino)carbonyl]-1-hydroxypentyl]-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate | C24H36N2O5 | 详情 | 详情 | |
| (XX) | 37807 | methyl (2R,3S,4R)-3-hydroxy-2-[(1R)-1-hydroxy-2-methylpropyl]-5-oxo-4-propyl-2-pyrrolidinecarboxylate | C13H23NO5 | 详情 | 详情 | |
| (XXI) | 37808 | (2R,3S,4R)-3-hydroxy-2-[(1R)-1-hydroxy-2-methylpropyl]-5-oxo-4-propyl-2-pyrrolidinecarboxylic acid | C12H21NO5 | 详情 | 详情 |