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【结 构 式】

【分子编号】62615

【品名】(3aR,9R,9aR,9bS)-2,2-dimethyloctahydro[1,3]dioxolo[4,5-a]indolizin-9-yl benzyl ether; (3aR,9R,9aR,9bS)-9-(benzyloxy)-2,2-dimethyloctahydro[1,3]dioxolo[4,5-a]indolizine

【CA登记号】

【 分 子 式 】C18H25NO3

【 分 子 量 】303.40144

【元素组成】C 71.26% H 8.31% N 4.62% O 15.82%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XXII)

The reduction of (R)-malic acid (I) with BH3/Me2S and NaBH4 gives 1,2(R),4-butane-triol (II), which is treated with benzaldehyde dimethylacetal (III) and Ts-OH to yield the 1,3-dioxane (IV). The oxidation of the hydroxymethyl group of (IV) by means of oxalyl chloride in DMSO/dichloromethane affords the carbaldehyde (V), which is submitted to a Wittig condensation with allyltriphenylphosphonium bromide (VI) and potassium tert-butoxide to provide the butadienyl derivative (VII). The reductive cleavage of the benzylidene acetal (VII) by means of DIBAL, followed by Z/E photoisomerization of the resulting diene gives (E)-3(R)-(benzyloxy)-4,6-heptadien-1-ol (VIII). The reaction of the OH group of (VIII) with TsCl and pyridine yields the corresponding tosylate (IX), which is treated with NaCN in DMSO to afford (E)-4(R)-(benzyloxy)-5 ,7-octadienonitrile (X). The hydrolysis of the CN group of (X) with NaOH in methanol/water provides the carboxylic acid (XI), which is esterified with diazomethane to afford the methyl ester (XII). The reaction of (XII) with hydroxylamine and KOH in methanol provides the hydroxamic acid (XIII), which is oxidized with tetrapropylammonium periodate in water to generate an acylnitroso intermediate (XIV), which undergoes a (4+2) cycloaddition to give the trans-1,2-oxazinolactam (XV) along with some cis isomer that is separated by chromatography. The reductive cleavage of the N-O bond of (XV) by means of sodium amalgam yields the allyl alcohol (XVI), which is silylated with Tbdps-Cl and imidazole affording the silyl ether (XVII). The catalytic dihydroxylation of the double bond of (XVII) by means of OsO4 and NMO provides the diol (XVIII) along with some diastereoisomer that is separated by chromatography. The protection of the OH groups of (XVIII) by reaction of 2,2-dimethoxypropane (XIX) and PPTS gives the acetonide (XX). The reduction of the lactone group of (XX) with LiAlH4 in THF proceeds with simultaneous desilylation yielding the piperidino-alcohol (XXI), which is cyclized by means of CBr4, PPh3 and TEA to provide the indolizidine derivative (XXII). The hydrogenolytic removal of the benzyl group of (XXII) with H2 over PdCl2 gives the alcohol (XXIII), which is finally submitted to hydrolysis of its acetonide group by means of 6N HCl in THF to afford the target swainsonine.

1 Thiam, M.; et al.; Malic acid as a chiral synthon: Synthesis of 1,2 and 1,3 optically active diols. Synth Commun 1992, 22, 1, 83.
2 Naruse, M.; et al.; New chiral route to (-)-swainsonine via an aqueous acylnitroso cycloaddition approach. J Org Chem 1994, 59, 6, 1358.
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) 11058 (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid 97-67-6 C4H6O5 详情 详情
(II) 30098 (2S)-1,2,4-butanetriol; (S)-1,2,4-butanetriol 42890-76-6 C4H10O3 详情 详情
(III) 27515 Methoxy(phenyl)methyl methyl ether; Dimethylacetal benzaldehyde; Benzaldehyde dimethylacetal 1125-88-8 C9H12O2 详情 详情
(IV) 62598 [(2R,4R)-2-phenyl-1,3-dioxan-4-yl]methanol C11H14O3 详情 详情
(V) 62599 (2R,4R)-2-phenyl-1,3-dioxane-4-carbaldehyde C11H12O3 详情 详情
(VI) 62600 allyl(triphenyl)phosphonium bromide C21H20BrP 详情 详情
(VII) 62601 (2R,4R)-4-[(1E)-1,3-butadienyl]-2-phenyl-1,3-dioxane C14H16O2 详情 详情
(VIII) 62602 (3R,4E)-3-(benzyloxy)-4,6-heptadien-1-ol C14H18O2 详情 详情
(IX) 62603 (3R,4E)-3-(benzyloxy)-4,6-heptadienyl 4-methylbenzenesulfonate C21H24O4S 详情 详情
(X) 62604 (4R,5E)-4-(benzyloxy)-5,7-octadienenitrile C15H17NO 详情 详情
(XI) 62605 (4R,5E)-4-(benzyloxy)-5,7-octadienoic acid C15H18O3 详情 详情
(XII) 62606 methyl (4R,5E)-4-(benzyloxy)-5,7-octadienoate C16H20O3 详情 详情
(XIII) 62607 (4R,5E)-4-(benzyloxy)-N-hydroxy-5,7-octadienamide C15H19NO3 详情 详情
(XIV) 62608 (4R,5E)-4-(benzyloxy)-N-oxo-5,7-octadienamide C15H17NO3 详情 详情
(XV) 62609 (4aS,5R)-5-(benzyloxy)-4a,5,6,7-tetrahydropyrido[1,2-b][1,2]oxazin-8(2H)-one C15H17NO3 详情 详情
(XVI) 62610 (5R,6S)-5-(benzyloxy)-6-[(Z)-3-hydroxy-1-propenyl]-2-piperidinone C15H19NO3 详情 详情
(XVII) 62611 (5R,6S)-5-(benzyloxy)-6-((Z)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-propenyl)-2-piperidinone C31H37NO3Si 详情 详情
(XVIII) 62612 (5R,6S)-5-(benzyloxy)-6-((1S,2R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1,2-dihydroxypropyl)-2-piperidinone C31H39NO5Si 详情 详情
(XIX) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(XX) 62613 (5R,6R)-5-(benzyloxy)-6-[(4S,5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-piperidinone C34H43NO5Si 详情 详情
(XXI) 62614 {(4R,5S)-5-[(2R,3R)-3-(benzyloxy)piperidinyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methanol C18H27NO4 详情 详情
(XXII) 62615 (3aR,9R,9aR,9bS)-2,2-dimethyloctahydro[1,3]dioxolo[4,5-a]indolizin-9-yl benzyl ether; (3aR,9R,9aR,9bS)-9-(benzyloxy)-2,2-dimethyloctahydro[1,3]dioxolo[4,5-a]indolizine C18H25NO3 详情 详情
(XXIII) 62616 (3aR,9R,9aR,9bS)-2,2-dimethyloctahydro[1,3]dioxolo[4,5-a]indolizin-9-ol C11H19NO3 详情 详情
Extended Information