Late-Stage Diversification of Biologically Active Molecules via Chemoenzymatic C-H Functionalization.

Engineered variants of rebeccamycin halogenase were used to selectively halogenate a number of biologically active aromatic compounds. Subsequent Pd-catalyzed cross-coupling reactions on the crude extracts of these reactions were used to install aryl, amine, and ether substituents at the halogenation site. This simple, chemoenzymatic method enables non-directed functionalization of C-H bonds on a range of substrates to provide access to derivatives that would be challenging or inefficient to prepare by other means.

Synthesis and profiling of a diverse collection of azetidine-based scaffolds for the development of CNS-focused lead-like libraries.

The synthesis and diversification of a densely functionalized azetidine ring system to gain access to a wide variety of fused, bridged, and spirocyclic ring systems is described. The in vitro physicochemical and pharmacokinetic properties of representative library members are measured in order to evaluate the use of these scaffolds for the generation of lead-like molecules to be used in targeting the central nervous system. The solid-phase synthesis of a 1976-membered library of spirocyclic azetidines is also described.