No abstract

Ni-catalyzed reductive macrocyclizations of ynals are reported. Disubstituted alkynes afford either endocyclic or exocyclic allylic alcohols depending on the ligand. Phosphine ligands favor the formation of endocyclic olefins, whereas N-heterocyclic carbene ligands favor the formation of exocyclic olefins. Terminal alkynes provide 1,2-disubstituted olefins with N-heterocyclic carbene ligands.

The total synthesis of aigialomycin D was carried out using a nickel-catalyzed ynal macrocyclization as a key step. This key step allowed macrocycle assembly and formation of a disubstituted alkene and a secondary hydroxyl stereocenter in a single step, although the stereocenter was formed unselectively. An interesting side reaction involving five-membered-ring synthesis by an aldehyde/styrene cyclization was observed when macrocyclization of an alkynyl silane was attempted. A mechanistic basis for this surprising process is provided.

We report herein the discovery of isoxazole amides as potent and selective SET and MYND Domain-Containing Protein 3 (SMYD3) inhibitors. Elucidation of the structure–activity relationship of the high-throughput screening (HTS) lead compound 1 provided potent and selective SMYD3 inhibitors. The SAR optimization, cocrystal structures of small molecules with SMYD3, and mode of inhibition (MOI) characterization of compounds are described. The synthesis and biological and pharmacokinetic profiles of compounds are also presented.