Amino(hydroxymethyl)cyclopentanetriols, an Emerging Class of Potent Glycosidase Inhibitors-Part I: Synthesis and Evaluation of β-D-Pyranoside Analogues in the manno, gluco, galacto, and GlcNAc Series

In order to rationalize the strong inhibition of α‐D‐mannosidases by mannostatin A (1), a series of 1‐amino‐5‐hydroxymethyl‐2,3,4‐cyclopentanetriols 2 were prepared as analogues of this lead compound and of the natural glycopyranoside substrates. High inhibitory activities, with Ki values below 1 μM, were found in all stereochemical series studied (D‐gluco, D‐manno, D‐galacto, and D‐GlcNAc configuration). Based on the promising results for the parent compounds 2, the β‐D‐galacto‐configured series was chosen for optimization by varying the substitution at the nitrogen atom of the amino group. Highly potent N‐benzyl‐substituted derivatives with Ki values down to 0.0007 μM were obtained such as the bromo compound 3.