Automated stopped-flow library synthesis for rapid optimisation and machine learning directed experimentation.

For the discovery of new candidate molecules in the pharmaceutical industry, library synthesis is a critical step, in which library size, diversity, and time to synthesise are fundamental. In this work we propose stopped-flow synthesis as an intermediate alternative to traditional batch and flow chemistry approaches, suited for small molecule pharmaceutical discovery. This method exploits the advantages of both techniques enabling automated experimentation with access to high pressures and temperatures; flexibility of reaction times, with minimal use of reagents (µmol scale per reaction). In this study, we integrate a stopped-flow reactor into a high-throughput continuous platform designed for the synthesis of combinatory libraries with at-line reaction analysis. This approach allowed ∼900 reactions to be conducted in an accelerated timeframe (192 hours). The stopped flow approach used ∼10% of the reactants and solvents compared to a fully continuous approach. This methodology demonstrates a significantly improved synthesis success rate of smaller libraries by simplifying the implementation of cross-reaction optimisation strategies. The experimental datasets were used to train a feed-forward neural network (FFNN) model providing a framework to guide further experiments, which showed good model predictability and success when tested against an external set with fewer experiments. As a result, this work demonstrates that combining experimental automation with machine learning strategies can deliver optimised analyses and enhanced predictions, enabling more efficient drug discovery investigations across the design, make, test and analysis (DMTA) cycle.

Synthesis and biological evaluation of truncated derivatives of abyssomicin C as antibacterial agents.

The synthesis and antibacterial activity of two new highly truncated derivatives of the natural product abyssomicin C are reported. This work outlines the limits of structural truncation of the natural product and consequently provides insights for further structure-activity relationship studies towards novel antibiotics targeting 4-amino-4-deoxychorismate (ADC) synthase. Specifically, it is demonstrated that the synthetically challenging bicyclic motif is essential for activity towards methicillin-resistant Staphylococcus aureus (MRSA).

Redox-Neutral Dual Functionalization of Electron-Deficient Alkenes.

Visible-light photoredox catalysis has been utilized in a new multicomponent reaction forming ß-functionalized δ-diketones under mild conditions in an operationally convenient manner. Single-electron reduction of in situ generated carboxylic acid derivatives forms acyl radicals that react further via 1,2-acylalkylation of olefins in an intermolecular, three-components cascade reaction, giving valuable synthetic entities from readily available starting materials. A diverse set of substrates has been used, demonstrating robust methodology with broad substrate scope.

Visible-Light-Mediated Photocatalytic Difunctionalization of Olefins by Radical Acylarylation and Tandem Acylation/Semipinacol Rearrangement.

A novel method for the mild photoredox-mediated tandem radical acylarylation and tandem acylation/semipinacol rearrangement has been developed. The synthesis of highly functionalized ketones bearing all-carbon α- or ß-quaternary centers has been achieved using easily available symmetric aromatic carboxylic anhydrides as the acyl radical source. The method allows for a straightforward introduction of the keto functionality and concomitant construction of molecular complexity in a single operation.

Acyl Radicals from Aromatic Carboxylic Acids by Means of Visible-Light Photoredox Catalysis.

Simple and abundant carboxylic acids have been used as acyl radical precursor by means of visible-light photoredox catalysis. By the transient generation of a reactive anhydride intermediate, this redox-neutral approach offers a mild and rapid entry to high-value heterocyclic compounds without the need of UV irradiation, high temperature, high CO pressure, tin reagents, or peroxides.

Enantioselective organocatalytic alkylation of aldehydes and enals driven by the direct photoexcitation of enamines.

Disclosed herein is a photo-organocatalytic enantioselective α- and γ-alkylation of aldehydes and enals, respectively, with bromomalonates. The chemistry uses a commercially available aminocatalyst and occurs under illumination by a fluorescent light bulb in the absence of any external photoredox catalyst. Mechanistic investigations reveal the previously hidden ability of transiently generated enamines to directly reach an electronically excited state upon light absorption while successively triggering the formation of reactive radical species from the organic halides. At the same time, the ground state chiral enamines provide effective stereochemical induction for the enantioselective alkylation process.

Photocatalytic decarboxylative reduction of carboxylic acids and its application in asymmetric synthesis.

The decarboxylative reduction of naturally abundant carboxylic acids such as α-amino acids and α-hydroxy acids has been achieved via visible-light photoredox catalysis. By using an organocatalytic photoredox system, this method offers a mild and rapid entry to a variety of high-value compounds including medicinally relevant scaffolds. Regioselective decarboxylation is achieved when differently substituted dicarboxylic acids are employed. The application of this method to the synthesis of enantioenriched 1-aryl-2,2,2-trifluoroethyl chiral amines starting from natural α-amino acids further testifies to the utility of the developed photocatalytic decarboxylative reduction protocol.

Synthesis of 9-amino(9-deoxy)epi cinchona alkaloids, general chiral organocatalysts for the stereoselective functionalization of carbonyl compounds.

We describe two procedures for the synthesis of primary amines derived from 9-amino(9-deoxy)epi cinchona alkaloids, valuable catalysts used in the asymmetric functionalization of carbonyl compounds. The first approach allows the one-pot 5-g-scale syntheses of four cinchona-based analogs (1, 3, 5 and 7) from the alkaloids quinine (QN), quinidine (QD), dihydroquinine (DHQN) and dihydroquinidine (DHQD), respectively, performed by means of a Mitsunobu reaction to introduce an azide group, followed by reduction and hydrolysis. Demethylation of 1, 3, 5 and 7 with BBr(3) provided direct access to the bifunctional aminocatalysts 2, 4, 6 and 8. A second approach, more convenient for scale-up (tested to a 20-g scale), is also provided. In this second procedure, the azides, formed from the O-mesylated derivatives of QN and QD, are selectively reduced with LiAlH(4) to afford catalysts 1 and 3, whereas hydrogenation (Pd/C) provides 5 and 7. Demethylation of 1, 3, 5 and 7 using an alkylthiolate affords 2, 4, 6 and 8 in a process in which the less-expensive QN and QD are the only starting materials used.

Direct catalytic enantioselective vinylogous aldol reaction of α-branched enals with isatins.

The direct vinylogous aldol reaction of α-substituted α,ß-unsaturated aldehydes with isatins is described. The chemistry provides easy access to valuable 3-substituted 3-hydroxyoxindole derivatives with high stereocontrol and perfect γ-site selectivity. Preliminary mechanistic studies suggest that, depending on the nature of the α-branched enal substituents, two divergent reaction mechanisms can be operating, leading to different products and stereochemical outcomes.

Diastereodivergent asymmetric sulfa-Michael additions of α-branched enones using a single chiral organic catalyst.

A significant limitation of modern asymmetric catalysis is that, when applied to processes that generate chiral molecules with multiple stereogenic centers in a single step, researchers cannot selectively access the full matrix of all possible stereoisomeric products. Mirror image products can be discretely provided by the enantiomeric pair of a chiral catalyst. But modulating the enforced sense of diastereoselectivity using a single catalyst is a largely unmet challenge. We document here the possibility of switching the catalytic functions of a chiral organic small molecule (a quinuclidine derivative with a pendant primary amine) by applying an external chemical stimulus, in order to induce diastereodivergent pathways. The strategy can fully control the stereochemistry of the asymmetric conjugate addition of alkyl thiols to α-substituted α,ß-unsaturated ketones, a class of carbonyls that has never before succumbed to a catalytic approach. The judicious choice of acidic additives and reaction media switches the sense of the catalyst's diastereoselection, thereby affording either the syn or anti product with high enantioselectivity.

Multiple approaches to enantiopure spirocyclic benzofuranones using organocatalytic cascade reactions.

Three distinct aminocatalytic cascade reactions leading to enantiomerically pure spirocyclic benzofuranones have been devised, highlighting the ability of organocascade to generate high degrees of stereochemical and architectural complexity in a single chemical transformation.