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A wide range of unsaturated aryl-, alkenyl-, alkynylcopper compounds can be selectively homologated by a methylene unit using (iodomethy1)zinc iodide or bis(iodomethy1)zinc. These reactions allow the generation of mixed allylic zinc-copper compounds which can be efficiently trapped with carbonyl compounds. An application to a general preparation of functionalized a-methylene-y-butyrolactones is described. The homologation of alkynylcoppers with (iodomethy1)zinc iodide allows a one-pot preparation of propargylic copper reagents which in the presence of a carbonyl compound provide various homopropargylic alcohols in excellent yields. In the absence of an electrophile, a clean quadruple methylene homologation of alkynylcoppers occurs to furnish dienic copper reagents. The homologation of other types of copper reagents is also possible, and carbanions at the a-position to amines as well as homoenolates of aldehydes or ketones can also be prepared by this method.

A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046.