Debenzylative Cycloetherification as a Synthetic Tool in the Diastereoselective Synthesis of 3,6-Disubstituted Hexahydro-2-furo[3,2-]pyrroles, PDE1 Enzyme Inhibitors with an Antiproliferative Effect on Melanoma Cells.

Two series of novel chiral hexahydro-2-furo[3,2-]pyrroles, 4-(7,8-dimethoxyquinazolin-4-yl) series A and 4-(6,7- dimethoxyquinazolin-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 -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 values in the high nanomolar/low micromolar concentration range, and showed antiproliferative activity on A375 melanoma cells.

Michael addition of carbonyl compounds to nitroolefins under the catalysis of new pyrrolidine-based bifunctional organocatalysts.

Novel bifunctional pyrrolidine-based organocatalysts for the asymmetric Michael addition of carbonyl compounds to nitroolefins have been synthesised from homoallylamines, which are easily obtained from (R)-glyceraldehyde as a chiral precursor. Under optimal reaction conditions, these bifunctional organocatalysts showed a high catalytic efficiency (almost quantitative yield in most cases) and stereoselectivity in the Michael addition reactions of a variety of aldehydes (up to 98 : 2 dr and 97% ee) and ketones (up to 98 : 2 dr and 99% ee) to nitroolefins.

Diastereoselective Construction of the 6-Oxa-2-azabicyclo[3.2.1]octane Scaffold from Chiral α-Hydroxyaldehyde Derivatives by the Aza-Prins Reaction.

(R)-2,3-Di-O-benzylglyceraldehyde and N-tosyl homoallylamine undergo aza-Prins cyclization to afford (1R,5S,7S)-7-[(benzyloxy)methyl]-2-tosyl-6-oxa-2-azabicyclo[3.2.1]octane in a highly diastereoselective manner through an unexpected intramolecular nucleophilic attack.

Synthesis of new pyrrolidine-based organocatalysts and study of their use in the asymmetric Michael addition of aldehydes to nitroolefins.

New pyrrolidine-based organocatalysts with a bulky substituent at C2 were synthesized from chiral imines derived from ()-glyceraldehyde acetonide by diastereoselective allylation followed by a sequential hydrozirconation/iodination reaction. The new compounds were found to be effective organocatalysts for the Michael addition of aldehydes to nitroolefins and enantioselectivities up to 85% ee were achieved.