Enantioselective Synthesis of γ‑Phenyl-γ-amino Vinyl Phosphonates and Sulfones and Their Application to the Synthesis of Novel Highly Potent Antimalarials

Racemic
and enantioselective syntheses of γ-phenyl-γ-amino
vinyl phosphonates and sulfones have been achieved using Horner–Wadsworth–Emmons
olefination of trityl protected α-phenyl-α-amino aldehydes
with tetraethyl methylenediphosphonate and diethyl ((phenylsulfonyl)­methyl)­phosphonate,
respectively, without any racemization. The present strategy has also
been successfully applied to the synthesis of peptidyl vinyl phosphonate
and peptidyl vinyl sulfone derivatives as potential cysteine protease
inhibitors of Chagas disease, K11002, with 100% de. The developed
synthetic protocol was further utilized to synthesize hybrid molecules
consisting of artemisinin as an inhibitor of major cysteine protease
falcipain-2 present in the food vacuole of the malarial parasite.
The synthesized artemisinin–dipeptidyl vinyl sulfone hybrid
compounds showed effective in vitro inhibition of
falcipain-2 and potent parasiticidal efficacies against Plasmodium falciparum in nanomolar ranges. Overall,
the developed synthetic protocol could be effectively utilized to
design cysteine protease inhibitors not only as novel antimalarial
compounds but also to be involved in other life-threatening diseases.