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Benzylic C-H isocyanation/amine coupling sequence enabling high-throughput synthesis of pharmaceutically relevant ureas.

ABSTRACT: C(sp³)-H functionalization methods provide an ideal synthetic platform for medicinal chemistry; however, such methods are often constrained by practical limitations. The present study outlines a C(sp³)-H isocyanation protocol that enables the synthesis of diverse, pharmaceutically relevant benzylic ureas in high-throughput format. The operationally simple C-H isocyanation method shows high site selectivity and good functional group tolerance, and uses commercially available catalyst components and reagents [CuOAc, 2,2'-bis(oxazoline) ligand, (trimethylsilyl)isocyanate, and N-fluorobenzenesulfonimide]. The isocyanate products may be used without isolation or purification in a subsequent coupling step with primary and secondary amines to afford hundreds of diverse ureas. These results provide a template for implementation of C-H functionalization/cross-coupling in drug discovery.

SUBMITTER: Suh SE

PROVIDER: S-EPMC8336431 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Atropisomerism is a conformational chirality that occurs when there is hindered rotation about a σ-bond. While atropisomerism is exemplified by biaryls, it is observed in many other pharmaceutically relevant scaffolds including heterobiaryls, benzamides, diarylamines, and anilides. As bond rotation leads to racemization, atropisomers span the gamut of stereochemical stability. LaPlante has classified atropisomers based on their half-life of racemization at 37 °C: class 1 (t1/2 < 60 s), class 2 (60 s < t1/2 < 4.5 years), and class 3 (t1/2 > 4.5 years). In general, class-3 atropisomers are considered to be suitable for drug development. There are currently four FDA-approved drugs that exist as stable atropisomers, and many others are in clinical trials or have recently appeared in the drug discovery literature. Class-1 atropisomers are more prevalent, with ∼30% of recent FDA-approved small molecules possessing at least one class-1 axis. While class-1 atropisomers do not possess the requisite stereochemical stability to meet the classical definition of atropisomerism, they often bind a given target in a specific set of chiral conformations.Over the past decade, our laboratory has embarked on a research program aimed at leveraging atropisomerism as a design feature to improve the target selectivity of promiscuous lead compounds. Our studies initially focused on introducing class-3 atropisomerism into promiscuous kinase inhibitors, resulting in a proof of principle in which the different atropisomers of a compound can have different selectivity profiles with potentially improved target selectivity. This inspired a careful analysis of the binding conformations of diverse ligands bound to different target proteins, resulting in the realization that the sampled dihedral conformations about a prospective atropisomeric axis played a key role in target binding and that preorganizing the prospective atropisomeric axis into a desired target's preferred conformational range can lead to large gains in target selectivity.As atropisomerism is becoming more prevalent in modern drug discovery, there is an increasing need for strategies for atropisomerically pure samples of pharmaceutical compounds. This has led us and other groups to develop catalytic atroposelective methodologies toward pharmaceutically privileged scaffolds. Our laboratory has contributed examples of atroposelective methodologies toward heterobiaryl systems while also exploring the chirality of less-studied atropisomers such as diarylamines and related scaffolds.This Account will detail recent encounters with atropisomerism in medicinal chemistry and how atropisomerism has transitioned from a "lurking menace" into a leverageable design strategy in order to modulate various properties of biologically active small molecules. This Account will also discuss recent advances in atroposelective synthesis, with a focus on methodologies toward pharmaceutically privileged scaffolds. We predict that a better understanding of the effects of conformational restriction about a prospective atropisomeric axis on target binding will empower chemists to rapidly "program" the selectivity of a lead molecule toward a desired target.

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Benzylic C-H isocyanation/amine coupling sequence enabling high-throughput synthesis of pharmaceutically relevant ureas.

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