A Metal-free Multicomponent Strategy for Amidine Synthesis

Amidines are a ubiquitous class of bioactive compounds found in a wide variety of natural products; thus, efficient strate-gies for their preparation are in great demand. Specifically, their common structural core decorated with three substitu-ents, set amidines as perfect candidates for multicomponent synthesis. Herein, we present a highly modular metal-free multicomponent strategy for the synthesis of sulfonyl amidines. This work was focused on selecting readily accessible reagents to facilitate the in situ formation of enamines by the addition of amines to ketones. These components were coupled with azides to provide a broad reaction scope with respect to all three coupling partners. Aromatic and aliphatic amines and ketones were tolerated under our reaction conditions. Likewise, the presence of a methyl group on the ke-tone was critical to reactivity, which was leveraged for the design of a highly regioselective reaction with aliphatic ke-tones. A biologically active compound was successfully synthesized in one step, demonstrating the practical utility of our methodology. Finally, the postulated mechanism was investigated and supported both experimentally and by means of a multivariate statistical model

Engineering a Photoenzyme to Use Red Light

Photoenzymatic catalysis is an emerging platform for asymmetric synthesis. In most of these reactions, the protein templates a charge transfer complex between the cofactor and substrate, which absorbs in the blue region of the electromagnetic spectrum. Here, we report the engineering of a photoenzymatic ‘ene’-reductase to utilize red light (620 nm) for a radical cyclization reaction. Mechanistic studies indicate that red light ac-tivity is achieved by introducing a broadly absorbing shoulder off the previously identified cyan absorption feature. Molecular dynamics simulations, docking, and excited-state calculations suggest that red light absorption is a → * transition from flavin to the substrate, while the cyan feature is the red-shift of the flavin → * transition, which occurs upon substrate binding. Differences in the excitation event help to disfavor alkylation of the flavin cofactor, a pathway for catalyst decomposition observed with cyan light but not red