Synthesis and conformational analysis of a sulfonium-ion analogue of the glycosidase inhibitor castanospermine

The synthesis of a bridgehead sulfonium salt analogue (7) of the indolizidine alkaloid castanospermine has been achieved by a multistep procedure starting from 5-thio-D-glucopyranose pentaacetate. The compound was intended to test the theory that glycosidase inhibitory activity of the indolizidine alkaloids might be due to electrostatic stabilization of a positively charged species in the enzyme active site and that a sulfonium salt carrying a permanent positive charge might be advantageous. The structure of the bicylic sulfonium salt (7) [3(R), 4(S),S(R),6(S)-3,4,5-trihydroxy-cis-1-thioniabicyclo[4.3.0]nonane perchlorate] was confirmed by X-ray crystallography. Analysis of the H-1 NMR spectrum of compound 7 indicated that a similar conformation was adopted in solution. This conformational preference, with hydroxyl groups in the more sterically hindered axial orientations, has been attributed to the dominance of stabilizing electrostatic interactions between the oxygen atoms and the sulfonium center.