A Concise and Divergent Approach to Hydroxylated Piperidine Alkaloids and Azasugar Lactams

Abstract

The vinylogous Mannich reaction (VMR) between 2-(tert-butyldimethylsilyloxy)furan (TBSOF) and (R-S)-t-BS-imine 12a and the application of the VMR adduct butenolide 13a as a versatile chiral building block for the synthesis of hydroxylated piperidine alkaloids and azasugars were investigated. Firstly, both the anti diastereoselectivity and the chemical yield of the asymmetric VMR between TBSOF and (R-S)-t-BS-imine 12a were improved by the use of Sm(OTf)(3)/H2O (1.5 equiv.) as the promoter. Similar diastereoselectivities were also obtained with Yb(OTf)(3)/H2O, Cu(OTf)(2)/H2O, Zn(OTf)(2)/H2O, or the Bronsted acids TfOH or MsOH as the promotors. Secondly, an efficient four-step procedure for the elaboration of butenolide 13a into piperidine alkaloid (-)-deoxoprosophylline (2) was established. Thirdly, by taking advantage of the olefin functionality in the butenolide 13a, polyhydroxylated delta-lactams 23 and 21, which are ready precursors of azasugars L-deoxyallonojirimycin (ent-7) and L-3-epi-fagomine (ent-6), were obtained in two and three steps, respectively, via dihydroxylated lactone 17. The easily available synthetic intermediate 17 can also serve as a key intermediate for the synthesis of the glycosyl nucleoside amino acid cores of polyoxins and nikkomycins.