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【结 构 式】 
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【分子编号】62616 【品名】(3aR,9R,9aR,9bS)-2,2-dimethyloctahydro[1,3]dioxolo[4,5-a]indolizin-9-ol 【CA登记号】 |
【 分 子 式 】C11H19NO3 【 分 子 量 】213.2768 【元素组成】C 61.95% H 8.98% N 6.57% O 22.51% |
合成路线1
该中间体在本合成路线中的序号：(XXIII)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 |
合成路线2
该中间体在本合成路线中的序号：(XIV)The reaction of benzyl alpha-D-mannopyranoside (I) with Tbdms-Cl and imidazole gives the silyl ether (II), which is treated with 2,2-dimethoxypropane (III) and CSA in dichloromethane to yield the acetonide (IV). The oxidation of the free OH group of (IV) with PCC in dichloromethane affords the ketone (V), which is reduced with NaBH4 to provide benzyl 6-O-(tert-butyldimethylsilyl)-2,3-O-isopropylidene-alpha-D-talopyranoside (VI) with inverted configuration at C4. The reaction of (VI) with Tf2O and pyridine gives the triflate (VII), which is treated with NaN3 in DMF to yield the 4-azido derivative (VIII) with a new inversion of configuration at C4. The reaction of (VIII) with TBAF, followed by oxidation with PCC afforded the carbaldehyde (IX), which is condensed with the phosphorane (X) to provide the unsaturated azidoaldehyde (XI). The treatment of (XI) with H2 over Pd/C in methanol produces the reduction of the double bond, the reduction of the azide group to amine, and subsequent reductive cyclization of the resulting aminoaldehyde to give the perhydropyranopyridine derivative (XII). Further reductive debenzylation of (XII) with H2 over Pd/C in AcOH produces the formation of a lactol in equilibrium with the open chain aminoaldehyde (XIII), which undergoes a reductive amination to form the acetonide of swainsonine (XIV). Finally, this acetonide is decomposed by reaction with TFA to afford the target swainsonine.
| 【1】 Bashyal, B.P.; et al.; Synthesis of the alpha-mannosidase inhibitors swainsonine [(1S,2R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizine and 1,4-dideoxy-1,4-imino-D-mannitol from mannose. Tetrahedron 1987, 43, 13, 3083. |
| 【2】 Fleet, G.W.J.; et al.; Enantiospecific synthesis of swainsonine (1S,2R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizine, from D-mannose. Tetrahedron Lett 1984, 25, 17, 1853. |
| 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) | 62617 | (2S,3S,4S,5S,6R)-2-(benzyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol | C13H18O6 | 详情 | 详情 | |
| (II) | 62618 | (2S,3S,4S,5S,6R)-2-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)tetrahydro-2H-pyran-3,4,5-triol | C29H36O6Si | 详情 | 详情 | |
| (III) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (IV) | 62619 | (3aS,4S,6R,7R,7aS)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol | C32H40O6Si | 详情 | 详情 | |
| (V) | 62620 | (3aS,4S,6R,7aR)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyldihydro-4H-[1,3]dioxolo[4,5-c]pyran-7(6H)-one | C32H38O6Si | 详情 | 详情 | |
| (VI) | 62621 | (3aS,4S,6R,7S,7aS)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol | C32H40O6Si | 详情 | 详情 | |
| (VII) | 62622 | (3aS,4S,6R,7S,7aR)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl trifluoromethanesulfonate | C33H39F3O8SSi | 详情 | 详情 | |
| (VIII) | 62623 | [(3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]methyl tert-butyl(diphenyl)silyl ether; {[(3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]methoxy}(tert-butyl)diphenylsilane | C32H39N3O5Si | 详情 | 详情 | |
| (IX) | 62624 | (3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-carbaldehyde | C16H19N3O5 | 详情 | 详情 | |
| (X) | 55468 | 2-(triphenylphosphoranylidene)acetaldehyde | C20H17OP | 详情 | 详情 | |
| (XI) | 62625 | (E)-3-[(3aS,4S,6R,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]-2-propenal | C18H21N3O5 | 详情 | 详情 | |
| (XII) | 62626 | (3aS,4S,5aR,9aR,9bS)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridin-4-yl benzyl ether; (3aS,4S,5aR,9aR,9bS)-4-(benzyloxy)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridine | C18H25NO4 | 详情 | 详情 | |
| (XIII) | 62627 | (4S,5S)-5-[(2R,3R)-3-hydroxypiperidinyl]-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | C11H19NO4 | 详情 | 详情 | |
| (XIV) | 62616 | (3aR,9R,9aR,9bS)-2,2-dimethyloctahydro[1,3]dioxolo[4,5-a]indolizin-9-ol | C11H19NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXVIII)The reaction of (XXIV) with Ms-Cl and TEA in dichloromethane gives the mesylate (XXV), which is cyclized by means of K2CO3 in hot dioxane to yield the perhydroindolizinone (XXVI). The reductive debenzylation of (XXVI) with H2 over Pd/C in ethanol affords the hydroxy-perhydroindolizinone (XXVII), which is finally reduced with BH3/Me2S in THF to provide the target swainsonine acetonide (XXVIII) intermediate.
| 【1】 Honda, T.; et al.; Enantioselective synthesis of indolizidine alkaloids: Formal synthesis of (-)-swainsonine and of (+)-pumiliotoxin 251D. J Chem Soc - Perkins Trans I 1994, 15, 2091. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIV) | 62648 | (5R,6R)-5-(benzyloxy)-6-[(4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-piperidinone | C18H25NO5 | 详情 | 详情 | |
| (XXV) | 62649 | {(4R,5S)-5-[(2R,3R)-3-(benzyloxy)-6-oxopiperidinyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methyl methanesulfonate | C19H27NO7S | 详情 | 详情 | |
| (XXVI) | 62650 | (3aR,9R,9aR,9bS)-9-(benzyloxy)-2,2-dimethylhexahydro[1,3]dioxolo[4,5-a]indolizin-6(4H)-one | C18H23NO4 | 详情 | 详情 | |
| (XXVII) | 62651 | (3aR,9R,9aR,9bS)-9-hydroxy-2,2-dimethylhexahydro[1,3]dioxolo[4,5-a]indolizin-6(4H)-one | C11H17NO4 | 详情 | 详情 | |
| (XXVIII) | 62616 | (3aR,9R,9aR,9bS)-2,2-dimethyloctahydro[1,3]dioxolo[4,5-a]indolizin-9-ol | C11H19NO3 | 详情 | 详情 |