Enabling Deoxygenative C(sp2)-C(sp3) Cross-Coupling for Parallel Medicinal Chemistry.

Herein we report the development of an automated deoxygenative C(sp2)-C(sp3) coupling of aryl bromide with alcohols to enable parallel medicinal chemistry. Alcohols are among the most diverse and abundant building blocks, but their usage as alkyl precursors has been limited. Although metallaphotoredox deoxygenative coupling is becoming a promising strategy to form C(sp2)-C(sp3) bond, the reaction setup limits its widespread application in library synthesis. To achieve high throughput and consistency, an automated workflow involving solid-dosing and liquid-handling robots has been developed. We have successfully demonstrated this high-throughput protocol is robust and consistent across three automation platforms. Furthermore, guided by cheminformatic analysis, we examined alcohols with comprehensive chemical space coverage and established a meaningful scope for medicinal chemistry applications. By accessing the rich diversity of alcohols, this automated protocol has the potential to substantially increase the impact of C(sp2)-C(sp3) cross-coupling in drug discovery.

Accelerated Synthesis of Bicyclo[1.1.1]pentylamines: A High-Throughput Approach.

Strained bicyclic substructures such as bicyclo[1.1.1]pentylamines (BCPAs) are increasingly targeted in medicinal chemistry as arylamine bioisosteres. Here, we leverage high-throughput automated synthesis to rapidly develop library-amenable reaction conditions and maximize design space to expand access to BCPAs. This new protocol relies on a copper-mediated C-N coupling approach and uses accessible and bench-stable iodo-BCP building blocks. Its applicability has been exemplified by incorporating BCPs in drug-like compounds, providing straightforward access to a library of valuable aniline-like isosteres.

End-to-End Automated Synthesis of C(sp3)-Enriched Drug-like Molecules via Negishi Coupling and Novel, Automated Liquid-Liquid Extraction.

Herein, we report an end-to-end process including synthesis, work-up, purification, and post-purification with minimal human intervention using Negishi coupling as a key transformation to increase Fsp3 in bioactive molecules. The main advantages of this protocol are twofold. First, the automated sequential generation of organozinc reagents from readily available alkyl halides offers a large diversity of alkyl groups to functionalize (hetero)aryl halide scaffolds via Pd-catalyzed Negishi coupling in continuous flow. Second, a fully automated liquid-liquid extraction has been developed and successfully applied for unattended operations. The workflow was completed with mass-triggered preparative high-performance liquid chromatography HPLC, providing an efficient production line of compounds with enriched sp3 character and better drug-like properties. The modular nature allows a smooth adaptation to a wide variety of synthetic methods and protocols and makes it applicable to any medchem laboratory.

Activation Mechanism of Nickel(0) N-Heterocyclic Carbene Catalysts Stabilized by Fumarate Ligands.

Nickel(0) catalysts of N-heterocyclic carbenes (NHCs) that are stabilized by electron-deficient alkenes possess desirable properties of air tolerance and ease of handling while also retaining high catalytic activities. Since catalyst stability often comes at the expense of catalytic activity, we have undertaken a detailed study of the activation mechanism of an IMes-nickel(0) catalyst stabilized by di(o-tolyl) fumarate that converts the stable precatalyst form into a catalytically active species. Computational evaluation provided evidence against a simple ligand exchange as the activation mechanism for this catalyst, and a stoichiometric activation process that covalently modifies the stabilizing ligand was identified. A detailed computational picture for the activation process was developed, with predictive insights that elucidate an unexpected catalyst activation pathway that operates when ligand exchange is thermodynamically unfavorable.

Recent Advances in Enantioselective Pd-Catalyzed Allylic Substitution: From Design to Applications.

This Review compiles the evolution, mechanistic understanding, and more recent advances in enantioselective Pd-catalyzed allylic substitution and decarboxylative and oxidative allylic substitutions. For each reaction, the catalytic data, as well as examples of their application to the synthesis of more complex molecules, are collected. Sections in which we discuss key mechanistic aspects for high selectivity and a comparison with other metals (with advantages and disadvantages) are also included. For Pd-catalyzed asymmetric allylic substitution, the catalytic data are grouped according to the type of nucleophile employed. Because of the prominent position of the use of stabilized carbon nucleophiles and heteronucleophiles, many chiral ligands have been developed. To better compare the results, they are presented grouped by ligand types. Pd-catalyzed asymmetric decarboxylative reactions are mainly promoted by PHOX or Trost ligands, which justifies organizing this section in chronological order. For asymmetric oxidative allylic substitution the results are grouped according to the type of nucleophile used.

Synthesis, reactivity, X-ray characterization and docking studies of N7/N9-(2-pyrimidyl)-adenine derivatives.

The reaction of adenine with 2-chloropyrimidine yields as a major product the unexpected N7-(2-pyrimidyl)-adenine (1) and as a minor one N9-(2-pyrimidyl)-adenine (2). Both compounds have been characterized by X-ray diffraction analysis. Moreover, we report the formation of a 1:1 co-crystal (3) composed by compound (1) and adenine that was formed serendipitously during the synthesis of (1). Unexpectedly, the treatment of (1) with Brönsted acids like HCl or HNO3 causes the opening of the imidazole ring of the N7-substituted adenine, yielding N5-(pyrimidin-2-yl)pyrimidine-4,5,6-triamine (4-7) which we have X-ray characterized in its neutral, (4), monoprotonated [nitrate salt (6)] and diprotonated forms [hydrochloride salt (5) and, also, a tetrachlorozincate salt (7)]. Finally, we have used compound (5) as ligand to synthesize and X-ray characterize its complexes with Ir(III) and Ag(I) (compounds (8) and (9), respectively), where the latter is a 2D coordination polymer and the former is a discrete mononuclear complex. We have studied the supramolecular assemblies formed in the solid state by using density functional theory (DFT) calculations. Finally, DNA-docking studies of several compounds have been carried out in order to analyze their ability to interact with the DNA.

Nickel-Catalyzed Reductive [2+2] Cycloaddition of Alkynes.

The nickel-catalyzed synthesis of tetrasubstituted cyclobutenes from alkynes is reported. This transformation is uniquely promoted by the use of a primary aminophosphine, an unusual ligand in nickel catalysis. Mechanistic insights for this new transformation are provided, and postreaction modifications of the cyclobutene products to stereodefined cyclic and acyclic compounds are reported, including the synthesis of epi-truxillic acid.

Development of C2-Symmetric Chiral Bifunctional Triamines: Synthesis and Application in Asymmetric Organocatalysis.

The synthesis and application of a newly designed C2-symmetric chiral bifunctional triamine family ( C2-CBT) is reported. These enantiopure chiral triamine scaffolds can be accessed in multigram amounts from simple amino acids while avoiding chromatographic purification. As a proof of principle, C2-CBT has been studied in the aldol reaction of cyclic ketones with isatins, with the target tertiary alcohols being formed in a highly efficient manner. Catalyst recovery by simple extraction techniques and subsequent reuse has been performed.

Stable, Well-Defined Nickel(0) Catalysts for Catalytic C-C and C-N Bond Formation.

The synthesis and catalytic activity of several classes of NHC-Ni(0) pre-catalysts stabilized by electron-withdrawing alkenes are described. Variations in the structure of fumarate and acrylate ligands modulate the reactivity and stability of the NHC-Ni(0) pre-catalysts and lead to practical and versatile catalysts for a variety of transformations. The catalytic activity and efficiency of representative members of this class of catalysts have been evaluated in reductive couplings of aldehydes and alkynes and in N-arylations of aryl chlorides.