No abstract

A rhodium(I)-catalyzed allenic Alder ene reaction to prepare cross-conjugated trienes has been discovered. The scope and limitations are currently being investigated, and the results obtained to date are reported on. This method shows enticing functional group compatibility by tolerating terminal and internal alkynes, hydroxyl, sulfonamide, ether, and diester groups. Progress has been made to increase the stereoselectivity of the olefinic side chain via an unprecendented iridium(I) catalyzed Alder-ene reaction.

[reaction: see text] Treatment of alkynyl allenes with [Rh(CO)(2)Cl](2) results in a formal [2 + 2 + 1] cycloaddition reaction. This reaction occurs with complete regioselectivity for a variety of substrates affording only 4-alkylidene cyclopentenones in good yields. Moreover, seven-membered rings have been prepared in high yields.

Abstract-Botulinum neurotoxin serotype A (BoNTA) is one of the most toxic substances known. Currently, there is no antidote to BoNTA. Small molecules identified from high-throughput screening reportedly inhibit the endopeptidase-the zinc-bound, catalytic domain of BoNTA-at a drug concentration of 20 lM. However, optimization of these inhibitors is hampered by challenges including the computational evaluation of the ability of a zinc ligand to compete for coordination with nearby residues in the active site of BoNTA. No improved inhibitor of the endopeptidase has been reported. This article reports the development of a serotype-selective, small-molecule inhibitor of BoNTA with a K i of 12 lM. This inhibitor was designed to coordinate the zinc ion embedded in the active site of the enzyme for affinity and to interact with a species-specific residue in the active site for selectivity. It is the most potent small-molecule inhibitor of BoNTA reported to date. The results suggest that multiple molecular dynamics simulations using the cationic dummy atom approach are useful to structure-based design of zinc protease inhibitors.