Reconfigurable Flow Platform for Automated Reagent Screening and Autonomous Optimization for Bioinspired Lignans Synthesis.

Naturally occurring benzoxanthenones, which belong to the vast family of lignans, are promising biologically relevant targets. They are biosynthetically produced by the oxidative dimerization of 2-propenyl phenols. In this manuscript, we disclose a powerful automated flow-based strategy for identifying and optimizing a cobalt-catalyzed oxidizing system for the bioinspired dimerization of 2-propenyl phenols. We designed a reconfigurable flow reactor associating online monitoring and process control instrumentation. Our machine was first configured as an automated screening platform to evaluate a matrix of 4 catalysts (plus the blank) and 5 oxidants (plus the blank) at two different temperatures, resulting in an array of 50 reactions. The automated screening was conducted on micromole scale at a rate of one fully characterized reaction every 26 min. After having identified the most promising cobalt-catalyzed oxidizing system, the automated screening platform was straightforwardly reconfigured to an autonomous self-optimizing flow reactor by implementation of an optimization algorithm in the closed-loop system. The optimization campaign allowed the determination of very effective experimental conditions in a limited number of experiments, which allowed us to prepare the natural products carpanone and polemannone B as well as synthetic analogues.

An Autonomous Self-Optimizing Flow Reactor for the Synthesis of Natural Product Carpanone.

A modular autonomous flow reactor combining monitoring technologies with a feedback algorithm is presented for the synthesis of the natural product carpanone. The autonomous self-optimizing system, controlled via MATLAB, was designed as a flexible platform enabling an adaptation of the experimental setup to the specificity of the chemical transformation to be optimized. The reaction monitoring uses either online high pressure liquid chromatography (HPLC) or in-line benchtop nuclear magnetic resonance (NMR) spectroscopy. The custom-made optimization algorithm derived from the Nelder-Mead and golden section search methods performs constrained optimizations of black-box functions in a multidimensional search domain, thereby assuming no a priori knowledge of the chemical reactions. This autonomous self-optimizing system allowed fast and efficient optimizations of the chemical steps leading to carpanone. This contribution is the first example of a multistep synthesis where all discrete steps were optimized with an autonomous flow reactor.

Zeolite-Based Organic Synthesis (ZeoBOS) of Acortatarin A: First Total Synthesis Based on Native and Metal-Doped Zeolite-Catalyzed Steps.

Similarly to polymer-supported assisted synthesis (PSAS), organic synthesis could be envisaged being performed by using zeolites, native or metal-doped, as heterogeneous catalysts. To illustrate this unprecedented Zeolite-Based Organic Synthesis (ZeoBOS), the total synthesis of acortatarin A was achieved through a novel strategy and using five out of eleven synthetic steps catalyzed by H- or metal-doped zeolites as catalysts. Notably, the formation of an yne-pyrrole intermediate with a copper-doped zeolite and the spiroketalization of an alkyne diol with a silver-doped zeolite have been developed as key steps of the synthesis.

Synthesis of a new class of iminosugars based on constrained azaspirocyclic scaffolds by way of catalytic C-H amination.

The synthesis of the first examples of a new class of iminosugars based on constrained spirocyclic scaffolds has been achieved via Rh-catalyzed C(sp(3))-H amination. In this process, the needed electronic control in securing high regioselectivity from substrates with a high density of activated C-H bonds was achieved by using a combination of activating and electron-withdrawing groups.