The development of addition reactions wherein the product is the simple sum of the reactants plus anything else (only needed catalytically) constitutes an important goal for enhanced synthetic efficiency. The C−H bond of terminal alkynes (the donor alkynes) can be added to either terminal alkynes (self-coupling) or activated internal alkynes (cross-coupling) (the acceptor alkynes) in the presence of a catalytic amount of palladium acetate and an electron rich sterically encumbered ligand, tris(2,6-dimethoxyphenyl)phosphine. The activated internal alkynes for cross-coupling (the acceptor alkyne) include alkynes bearing an ester, sulfone, and ketone. Self-coupling is completely overwhelmed by cross-coupling, even at 1:1 ratios of donor and acceptor alkynes. The reaction exhibits extraordinary chemoselectivity with free carboxaldehydes, alcohols, ketones (saturated and conjugated), esters (saturated and conjugated), sulfones (saturated and conjugated), malonates, and silyl ethers all proving to be compatible. A 1:2 donor/acceptor alkyne adduct can also be optimized. Ethyl propiolate fails as an acceptor but its C-silylated analogue serves with the proper choice of silyl substituent. The products of the latter serve as useful precursors to β-keto esters. An iterative sequence is readily performed and led to a novel conformationally rigid retinoid analogue. The mechanism of this mild method for construction of conjugated enynes, versatile building blocks, is discussed.

Activity-based probes (ABPs) that specifically target subsets of related enzymatic proteins are finding increasing use in proteomics research. One of the main applications for these reagents is affinity isolation of probe-labeled targets. However, the use of cheap and efficient biotin affinity tags on ABPs can be problematic due to difficulty in release of captured proteins. Here we describe the evaluation of activity-based probes carrying a chemically cleavable linker that allows selective release of probelabeled proteins under mild elution conditions that are compatible with mass spectrometric analysis. Specifically, we compare results from standard on-bead digestion of probe-labeled targets after affinity purification with the results obtained using chemoselective cleavage. Results are presented for multiple APBs that target both serine and cysteine proteases. These results highlight significant improvements in the quality of data obtained by using the cleavable linker system.

Acetoxy Meldrum’s acid can serve as a versatile acyl anion equivalent in the Pd-catalyzed asymmetric allylic alkylation. The reaction of this nucleophile with various meso and racemic electrophiles afforded alkylated products in high yields and enantiopurities. These enantioenriched products are versatile intermediates that can be further functionalized using nitrogen– and oxygen–centered nucleophiles, affording versatile scaffolds for the synthesis of nucleoside analogues. These scaffolds were used to complete formal syntheses of the anti-HIV drugs carbovir, abacavir, and the antibiotic aristeromycin.

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