Synthesis of a biologically active isomer of kotalanol, a naturally occurring glucosidase inhibitor

The syntheses of an isomer of kotalanol, a naturally occurring glucosidase inhibitor, and of kotalanol itself are described. The target compounds were synthesized by nucleophilic attack of PMB-protected 1,4-anhydro-4-thio-D-arabinitol at the least hindered carbon atom of two 1,3-cyclic sulfates, which were synthesized from D-mannose. Methoxymethyl ether and isopropylidene were chosen as protecting groups. The latter group was critical to ensure the facile deprotection of the coupled products in a one-step sequence to yield kotalanol and its isomer. The stereoisomer of kotalanol, with the opposite stereochemistry at the C-6' stereogenic centre, inhibited the N-terminal catalytic domain of intestinal human maltase glucoamylase (ntMGAM) with a K-i value of 0.20 +/- 0.02 mu M; this compares to a K-i value for kotalanol of 0.19 +/- 0.03 mu M. The results indicate that the configuration at C-6' is inconsequential for inhibitory activity against this enzyme. (C) 2010 Elsevier Ltd. All rights reserved.