Selective Metal-Site-Guided Arylation of Proteins.

We describe palladium-mediated S-arylation that exploits natural metal-binding motifs to ensure high site selectivity for a proximal reactive residue. This allows the chemical identification not only of proteins that bind metals but also the environment of the metal-binding site itself through proteomic analysis of arylation sites. The transformation is easy to perform under standard conditions, does not require the isolation of a reactive Ar-Pd complex, is broad in scope, and is applicable in cell lysates as well as to covalent inhibition/modulation of metal-dependent enzymatic activity.

Total Synthesis, Stereochemical Revision, and Biological Reassessment of Mandelalide A: Chemical Mimicry of Intrafamily Relationships.

Mandelalide A and three congeners had recently been isolated as the supposedly highly cytotoxic principles of an ascidian collected off the South African coastline. Since these compounds are hardly available from the natural source, a concise synthesis route was developed, targeting structure 1 as the purported representation of mandelalide A. The sequence involves an iridium-catalyzed two-directional Krische allylation and a cobalt-catalyzed carbonylative epoxide opening as entry points for the preparation of the major building blocks.

Synthesis, molecular editing, and biological assessment of the potent cytotoxin leiodermatolide.

It was by way of total synthesis that the issues concerning the stereostructure of leiodermatolide (1) have recently been solved; with the target now being unambiguously defined, the mission of synthesis changes as to secure a meaningful supply of this exceedingly scarce natural product derived from a deep-sea sponge. To this end, a scalable route of 19 steps (longest linear sequence) has been developed, which features a catalytic asymmetric propargylation of a highly enolizable β-keto-lactone, a ring closing alkyne metathesis and a modified Stille coupling as the key transformations. Deliberate digression from this robust blueprint brought a first set of analogues into reach, which allowed the lead qualities of 1 to be assessed.

Catalysis-based total synthesis of putative mandelalide A.

A concise synthesis of the putative structure assigned to the highly cytotoxic marine macrolide mandelalide A (1) is disclosed. Specifically, an iridium-catalyzed two-directional Krische allylation and a cobalt-catalyzed carbonylative epoxide opening served as convenient entry points for the preparation of the major building blocks. The final stages feature the first implementation of terminal-acetylene metathesis into natural product synthesis, which is remarkable as this class of substrates was beyond reach until very recently; key to success was the use of the highly selective molybdenum alkylidyne complex 42 as the catalyst.

Investigating N-methoxy-N'-aryl ureas in oxidative C-H olefination reactions: an unexpected oxidation behaviour.

Herein, we report a urea derived directing group for mild and highly selective oxidative C-H bond olefination. Subsequent intramolecular Michael addition affords dihydroquinazolinones in good yields. The N-O bond of the urea substrate exhibits superior oxidative behaviour compared to a variety of other external oxidants.