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.
Florence Pojer, Kelvin Ka Ching Lau, Oliver Hantschel, Grégory La Sala
Rosario Scopelliti, Kay Severin, Jérôme Waser, Farzaneh Fadaei Tirani, Abdusalom Suleymanov, Zhaowen Dong, Bastian Antoine Rodolphe Claude Muriel, Eliott Hugo Joran Le Du