Herein we present the design, synthesis, and evaluation of a structurally novel library of 20 peptidyl 3-aryl vinyl sulfones as inhibitors of cathepsins L and B. The building blocks, described here for the first time, were synthesized in a highly efficient and enantioselective manner, starting from 3-aryl-substituted allyl alcohols. The corresponding vinyl sulfones were prepared by a new approach, based on a combination of solid-phase peptide synthesis using the Fmoc/tBu strategy, followed by solution-phase coupling to the corresponding (R)-3-amino-3-aryl vinyl sulfones as trifluoroacetate salts. The inhibitory activity of the resulting compounds against cathepsins L and B was evaluated, and the compound exhibiting the best activity was selected for enzymatic characterization. Finally, docking studies were performed in order to identify key structural features of the aryl substituent.

A set of diversely substituted N-Boc-gamma-amino vinyl sulfones has been prepared by a four-step procedure from readily available, highly enantiopure anti-N-Boc-3-amino-1,2-alkanediols. This new route, which does not depend on the accessibility of alpha-amino acids as starting materials, is noteworthy for its efficiency, for its generality, and for the fact that both enantiomers of a given gamma-amino vinyl sulfone can be obtained with equal ease.

Sulfones Sulfones Q 0600Enantiodivergent, Catalytic Asymmetric Synthesis of γ-Amino Vinyl Sulfones.-A short and efficient four-step synthesis of γ-amino vinyl sulfones (VI) is presented, starting from readily available, highly enantiopure anti-3-aminoalkane-1,2-diols (I).The method involves Mitsunobu cyclization of the diols (I), followed by regio-and stereoselective epoxide ring opening with various thiols or thiolates. Oxidation of the obtained sulfides (IV) to sulfones (V) is smoothly achieved with MCPBA. Dehydration to furnish the vinyl sulfone moiety proceeds by elimination of an in situ generated mesylate. This method, however, is not suitable for γ-aryl-γ-amino sulfones (Va) and (Vb) due to concomitant formation of regioisomers, but a copper-catalyzed reaction with morpho-CDI is successful. -(PICO, A.; MOYANO*, A.; PERICAS, M. A.; J. Org.

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An efficient enantioselective route to N-propargyl-γ-amino vinyl sulfones has been developed, and their Pauson-Khand cyclization has been investigated. The stereoselectivity of the reaction depends both on the structure of the substrate and on the nature of the metal-carbonyl promoter.