Journal article

Asymmetric syntheses of new polyhydroxylated quinolizidines: Cross-aldol reactions of 7-oxabicyclo[2.2.1]heptan-2-one and 3a,4a,7a,7b-tetrahydro[1,3]dioxolo[4,5]furo[2,3-d]isoxazole-3-carbaldehy de derivatives

The cross-aldolization of (-)-(1S,4R,5R,6R)-6-endo-chloro-5-exo-(phenylseleno)-7-oxabicyclo[2.2.1] heptan-2-one ((-)-25) and of(+)-(3aR,4aR,7aR,7bS)- ((+)-26) and(-)-(3aS,4aS,7aS,7bR)-3a,4a,7a,7b-tetrahydro-6,6-dimethyl[1,3]dioxolo [4,5]furo[2,3-d]isoxazole-3-carbaldehyde ((-)-26) was studied for the lithium enolate of (-)-25 and for its trimethylsilyl ether (-)-31 under Mukaiyama's conditions (Scheme 2). Protocols were found for highly diastereoselective condensation giving the four possible aldols (+)-27 ('anti'), (+)-28 ('syn). 29 ('anti'). and (-)-30 ('syn') resulting from the exclusive exo-face reaction of the bicyclic lithium enolate of (-)-25 and bicyclic silyl ether (-)-31. Steric factors can explain the selectivities observed. Aldols (+)-27 (+)-28, 29, and (-)-30 were converted stereoselectively to (+)-1,4-anhydro-3-((S)-[(tert-butyl)dimethylsilyl-oxy][(3aR,4aR,7aR.7bS) -3a,4a,7a.7b-tetrahydro-6,6-dimethyl[1,3]dioxolo[4,5]-furo[2,3-d]isoxazo l-3-yl]methyl}-3-deoxy-2,6-di-O-(methoxymethyl)-alpha-D-galactopyranose ((+)-62), its epimer at the exocyclic position (+)-70, (-)-1,4-anhydro-3-((S)-[(tert-butyl)dimethylsilyloxy][(3aS,4aS,7aS,7bR)- 3a,4a,7a,7b-tetrahydro-6,6-dimethyl[1,3]-dioxolo[4,5]furo[2,3-d]isoxazol -3-yl]methyl}-3-deoxy-2,6-di-O-(methoxymethyl)-alpha-D-galactopyranose ((-)-77), and its epimer at the exocyclic position (+)-84, respectively (Schemes 3 and 5). Compounds (+)-62, (-)-77 and (+)-84 were transformed to (1R,2R,3S,7R,8S,9S,9aS)-1,3,4,6,7,8,9,9a-octahydro-8-[(1R,2R)-1,2,3-trih ydroxypropyl]-2H-quinolizine-1,2,3,7,9-pentol (21), its (1S,2S,3R,7R,8S,9S,9aR) stereoisomer (-)-22, and to its (1S,2S,3R,7R,8S,9R,9aR) stereoisomer (+)-23, respectively (Schemes 6 and 7). The polyhydroxylated quinolizidines (-)-22 and (+)-23 adopt 'trans-azadecalin' structures with chair/chair conformations in which H-C(9a) occupies an axial position anti-periplanar to the amine lone electron pair. Quinolizidines tl, (-)-22. and (+)-23 were tested for their inhibitory activities toward 25 commercially available glycohydrolases. Compound 21 is a weak inhibitor of beta-galactosidase from jack bean, of amyloglucosidase from Aspergillus niger, and of beta-glucosidase from Caldocellum saccharolyticum. Stereoisomers (-)-22 and (+)-23 are weak but more selective inhibitors of beta-galactosidase from jack bean.


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