Justin A. M. Lummiss

The synthesis of complex organic molecules requires several stages, from ideation to execution, that require time and effort investment from expert chemists. Here, we report a step toward a paradigm of chemical synthesis that relieves chemists from routine tasks, combining artificial intelligence-driven synthesis planning and a robotically controlled experimental platform. Synthetic routes are proposed through generalization of millions of published chemical reactions and validated in silico to maximize their likelihood of success. Additional implementation details are determined by expert chemists and recorded in reusable recipe files, which are executed by a modular continuous-flow platform that is automatically reconfigured by a robotic arm to set up the required unit operations and carry out the reaction. This strategy for computer-augmented chemical synthesis is demonstrated for 15 drug or drug-like substances.

The recent uptake of molecular metathesis catalysts in specialty-chemicals and pharmaceutical manufacturing is reviewed.

As society faces a future of dwindling petrochemical supplies at increasing cost, much attention has been focused on methods to degrade biomass into renewable commodity-chemical building blocks. Reported here is a powerful complementary approach that amplifies the complexity of molecular structures present in plant materials. Essential-oil phenylpropenoids are transformed via acrylate cross-metathesis into potent antioxidants that are widely used in perfumery and cosmetics, and in treating disorders associated with oxidative damage.

A long-standing question in olefin metathesis centers on whether the “release–return” (boomerang) mechanism contributes to the productivity of Hoveyda-class catalysts. According to this mechanism, a molecule of o-isopropoxystyrene (A) is liberated during catalyst initiation, but recaptures the active catalyst following metathesis. The relevance of this pathway for the second-generation Hoveyda catalyst HII was assessed in metathesis of 1,1- and 1,2-disubstituted olefins. Crossover studies with 13C-labeled A*, as well as competition experiments involving ring-closing or cross metathesis (RCM, CM) in the presence of A (equimolar with HII) indicated rapid reuptake of styrenyl ether. The crossover studies indicated highly efficient catalyst initiation, with the entire catalyst charge being activated before metathesis was complete. In a comparative study involving CM of anethole with methyl acrylate, sustained activity was shown for HII, whereas the second-generation Grubbs catalyst GII was rapidly deactivated. These data demonstrate that the release–return mechanism is indeed operative for HII in these demanding metathesis reactions, and that facile shuttling from a protected recapture cycle into the productive metathesis cycle contributes to the superior performance of HII relative to GII.

. Similarly inhibited initiation is predicted for other metal-NHC catalysts in which a π-acceptor ligand L must be dissociated to permit substrate binding. Conversely, enhanced reactivity can be expected where such L ligands are pure σ-donors. These effects are expected to be particularly dramatic where the NHC ligand has minimal π-acceptor capacity (as in the unsaturated Arduengo carbenes), and in geometries that maximize NHC-M-L orbital interactions.