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The optimization of multistep chemical syntheses is critical for the rapid development of new pharmaceuticals. However, concatenating individually optimized reactions can lead to inefficient multistep syntheses, owing to chemical interdependencies between the steps. Herein, we develop an automated continuous flow platform for the simultaneous optimization of telescoped reactions. Our approach is applied to a Heck cyclization-deprotection reaction sequence, used in the synthesis of a precursor for 1-methyltetrahydroisoquinoline C5 functionalization. A simple method for multipoint sampling with a single online HPLC instrument was designed, enabling accurate quantification of each reaction, and an in-depth understanding of the reaction pathways. Notably, integration of Bayesian optimization techniques identified an 81 % overall yield in just 14 h, and revealed a favorable competing pathway for formation of the desired product.

The consideration of discrete variables (e.g. catalyst, ligand, solvent) in experimental self-optimisation approaches remains a significant challenge. Herein we report the application of a new mixed variable multi-objective optimisation (MVMOO) algorithm for the self-optimisation of chemical reactions. Coupling of the MVMOO algorithm with an automated continuous flow platform enabled identification of the trade-off curves for different performance criteria by optimizing the continuous and discrete variables concurrently. This approach utilizes a Bayesian methodology to provide high optimisation efficiency, enhances process understanding by considering key interactions between the mixed variables, and requires no prior knowledge of the reaction. Nucleophilic aromatic substitution (SNAr) and palladium catalyzed Sonogashira reactions were investigated, where the effect of solvent and ligand selection on the regioselectivity and process efficiency were determined respectively whilst simultaneously determining the optimum continuous parameters in each case.

Herein is described the full scope of a desulfinylative cross-coupling of aryl sulfinates with aryl bromides. Optimized conditions were established and a bidentate phosphine ligand was found to be the key in obtaining good cross-coupling yields. Preliminary efforts to elucidate the reaction mechanism suggest that a Pd(0)-catalyzed mechanism is operative.

Optimized conditions are developed to provide the synthesis of biphenyls by Pd(0)-catalyzed coupling.

A short and efficient synthesis of an advanced intermediate (1) in the Clive route to halichlorine has been achieved in 12 steps and 13.2% yield by a combined two-directional synthesis/tandem reaction strategy.

Total syntheses of alkaloid cis-223B and xenovenine are reported in 3 and 4 steps respectively using a two-directional synthesis/triple reductive amination strategy, and their neurotoxic properties assessed.