Automated, Capsule-Based Suzuki-Miyaura Cross Couplings.

The development of an automated process for Suzuki-Miyaura cross couplings is described, in which the complete reaction, workup, and product isolation are effected automatically with no user involvement, aside from loading of the starting materials and reaction capsule. This practical and simple method was successfully demonstrated to provide the desired biaryl products using a range of aryl bromides and boronic acids and is also effective for the late-stage functionalization of aryl halides in bioactive molecules.

Non-invasive monitoring of microbiota and host metabolism using secondary electrospray ionization-mass spectrometry.

The metabolic "handshake" between the microbiota and its mammalian host is a complex, dynamic process with major influences on health. Dissecting the interaction between microbial species and metabolites found in host tissues has been a challenge due to the requirement for invasive sampling. Here, we demonstrate that secondary electrospray ionization-mass spectrometry (SESI-MS) can be used to non-invasively monitor metabolic activity of the intestinal microbiome of a live, awake mouse. By comparing the headspace metabolome of individual gut bacterial culture with the "volatilome" (metabolites released to the atmosphere) of gnotobiotic mice, we demonstrate that the volatilome is characteristic of the dominant colonizing bacteria. Combining SESI-MS with feeding heavy-isotope-labeled microbiota-accessible sugars reveals the presence of microbial cross-feeding within the animal intestine. The microbiota is, therefore, a major contributor to the volatilome of a living animal, and it is possible to capture inter-species interaction within the gut microbiota using volatilome monitoring.

A vending machine for drug-like molecules - automated synthesis of virtual screening hits.

As a result of high false positive rates in virtual screening campaigns, prospective hits must be synthesised for validation. When done manually, this is a time consuming and laborious process. Large "on-demand" virtual libraries (>7 × 1012 members), suitable for preparation using capsule-based automated synthesis and commercial building blocks, were evaluated to determine their structural novelty. One sub-library, constructed from iSnAP capsules, aldehydes and amines, contains unique scaffolds with drug-like physicochemical properties. Virtual screening hits from this iSnAP library were prepared in an automated fashion for evaluation against Aedes aegypti and Phytophthora infestans. In comparison to manual workflows, this approach provided a 10-fold improvement in user efficiency. A streamlined method of relative stereochemical assignment was also devised to augment the rapid synthesis. User efficiency was further improved to 100-fold by downscaling and parallelising capsule-based chemistry on 96-well plates equipped with filter bases. This work demonstrates that automated synthesis consoles can enable the rapid and reliable preparation of attractive virtual screening hits from large virtual libraries.

An integrated console for capsule-based, automated organic synthesis.

The current laboratory practices of organic synthesis are labor intensive, impose safety and environmental hazards, and hamper the implementation of artificial intelligence guided drug discovery. Using a combination of reagent design, hardware engineering, and a simple operating system we provide an instrument capable of executing complex organic reactions with prepacked capsules. The machine conducts coupling reactions and delivers the purified products with minimal user involvement. Two desirable reaction classes - the synthesis of saturated N-heterocycles and reductive amination - were implemented, along with multi-step sequences that provide drug-like organic molecules in a fully automated manner. We envision that this system will serve as a console for developers to provide synthetic methods as integrated, user-friendly packages for conducting organic synthesis in a safe and convenient fashion.

Cartridge-based Automated Synthesis - A New Tool for the Synthetic Chemist.

Despite recent advances in reaction methodologies, organic synthesis remains complex and challenging. Many of the fundamental processes in use have not changed in over 100 years, with a large proportion of the work being carried out manually, using lengthy procedures and difficult or hazardous reaction conditions. As such, organic synthesis still presents a bottle-neck in discovery research. Endeavours to automate synthesis in discovery, through robotic platforms, have so far not been widely successful because the highly complex nature of such machines, and the level of skill required for their operation, presents a barrier too great for most discov- ery chemists. Synple Chem has developed a safe, easy to use, efficiency-enhancing automated technology for the acceleration of discovery research. The automated flow-batch hybrid system utilises a range of innovative pre-packed reagent cartridges for different reaction classes, along with pre-programmed, highly optimised but editable reaction protocols. The combination of these three key elements, provides users with a convenient, easy to use, time-saving technology that makes the synthesis of molecules far simpler, faster and more efficient. The described technology offers all discovery chemists access to real synthesis automation without any of the barriers that have previously restricted its utility.

Catalytic Kinetic Resolution of Disubstituted Piperidines by Enantioselective Acylation: Synthetic Utility and Mechanistic Insights.

The catalytic kinetic resolution of cyclic amines with achiral N-heterocyclic carbenes and chiral hydroxamic acids has emerged as a promising method to obtain enantio-enriched amines with high selectivity factors. In this report, we describe the catalytic kinetic resolution of disubstituted piperdines with practical selectivity factors (s, up to 52) in which we uncovered an unexpected and pronounced conformational effect resulting in disparate reactivity and selectivity between the cis- and trans-substituted piperidine isomers. Detailed experimental and computational studies of the kinetic resolution of various disubstituted piperidines revealed a strong preference for the acylation of conformers in which the α-substituent occupies the axial position. This work provides further experimental and computational support for the concerted 7-member transition state model for acyl transfer reagents and expands the scope and functional group tolerance of the secondary amine kinetic resolution.

Reprogramming nonribosomal peptide synthetases for "clickable" amino acids.

Nonribosomal peptide synthetases (NRPSs) are multifunctional enzymes that produce a wide array of bioactive peptides. Here we show that a single tryptophan-to-serine mutation in phenylalanine-specific NRPS adenylation domains enables the efficient activation of non-natural aromatic amino acids functionalized with azide and alkyne groups. The resulting 10(5)-fold switch in substrate specificity was achieved without appreciable loss of catalytic efficiency. Moreover, the effective communication of the modified A domains with downstream modules in dipeptide synthetases permitted incorporation of O-propargyl-L-tyrosine into diketopiperazines both in vitro and in vivo, even in the presence of competing phenylalanine. Because azides and alkynes readily undergo bioorthogonal click reactions, reprogramming NRPSs to accept non-natural amino acids that contain these groups provides a potentially powerful means of isolating, labeling, and modifying biologically active peptides.

Stereoelectronic basis for the kinetic resolution of N-heterocycles with chiral acylating reagents.

The kinetic resolution of N-heterocycles with chiral acylating agents reveals a previously unrecognized stereoelectronic effect in amine acylation. Combined with a new achiral hydroxamate, this effect makes possible the resolution of various N-heterocycles by using easily prepared reagents. A transition-state model to rationalize the stereochemical outcome of this kinetic resolution is also proposed.

Enantioselective synthesis of dihydropyridinones via NHC-catalyzed aza-Claisen reaction.

N-Heterocyclic carbene catalyzed aza-Claisen annulations of enals or their α'-hydroxyenone surrogates with vinylogous amides afford dihydropyridinones. The reaction proceeds with a broad range of substrates, and no nitrogen protecting group is required.