The stereoselective synthesis of D-fagomine, D-3-epi-fagomine, and D-3-epi-fagomine analogs starting from readily available D-glyceraldehyde acetonide has been achieved. The synthesis involves diastereoselective anti-vinylation of its homoallylimine, ring-closing metathesis, and stereoselective epoxidation followed by regioselective ring-opening or stereoselective dihydroxylation. The lack of a strong activity as glycosidase inhibitors of these compounds could be advantageous for their therapeutic use as chaperones.
Two series of novel chiral hexahydro-2H-furo [3,2b]pyrroles, 4-(7,8-dimethoxyquinazolin-4-yl) series A and 4-(6,7dimethoxyquinazolin-4-yl) series B, were synthesized in enantiomerically pure form and evaluated for their inhibitory effects on phosphodiesterase 1 (PDE1) and phosphodiesterase 4 (PDE4) as well as for their inhibitory activity on cell proliferation in A375 melanoma and 3T3 fibroblast cells in vitro. Key steps of synthesis were (i) diastereoselective nucleophilic addition of vinylmagnesium bromide to N-allylimine derived from conveniently protected D-glyceraldehyde, (ii) ring-closing metathesis, (iii) debenzylative cycloetherification, and (iv) aromatic nucleophilic substitution. Some of the obtained compounds were proven to be active as inhibitors of PDE1 isoforms, with IC 50 values in the high nanomolar/low micromolar concentration range, and showed antiproliferative activity on A375 melanoma cells.
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