Synthesis of trehazolin analogues containing modified aminocyclitol moieties

Abstract

In order to elucidate structure–activity relationships of the trehalase inhibitor trehazolin 1, three analogues: deoxytrehazolin D-2, and de(hydroxymethyl)trehazolin D-3 and its diastereoisomer L-3 were synthesized by coupling of the sugar isothiocyanate 18 with the newly prepared aminocyclopentanetetraols D-10, D-26 and L-26, followed by cyclisation to give the isourea, and deprotection. In addition, an attempt was made to synthesize the analogue 4, the aminocyclitol moiety being replaced with the 5a-carba sugar, validamine. A biological assay showed that enantiomers D-3 and L-3 are strong inhibitors of trehalase, and, interestingly, the latter isomer, having the unnatural-type structure, is ∼ 50 times more potent.