Trehazolin (1) is a unique natural pseudodisaccharide possessing strong trehalase-specific inhibitory activity. To determine its argued correct stereochemistry, the syntheses of trehazolin (1), its components, the aglycon moiety, trehalamine (4) and its aminocyclitol hexaacetate (6), were accomplished from d-glucose using intramolecular [3+2] cycloaddition as the key step. In order to investigate the structure-activity relationships with regard to the stereochemistry of the aminocyclitol moiety and that of the anomeric position of trehazolin (1), trehalostatin (2) (trehazolin C-5 epimer), trehazolin β-anomer (32) and, trehazolin C-6 epimer (33) were all synthesized. In particular, with respect to the synthesis of trehazolin C-6 epimer (33), a tandem aldol-Wittig type reaction was developed as the key step to synthesize the highly functionalized 5-membered cyclitol. Moreover, on the basis of the outcome of these synthetic studies, a number of trehazolin-related compounds (49-52), modified at the terminal amino group of trehalamine (4), were synthesized to be evaluated as candidates directed to anti-NIDDM (non-insulin-dependent diabetes mellitus) drugs. Copyright (C) 1999 Elsevier Science Ltd.
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