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Atropisomerism in Diarylamines: Structural Requirements and Mechanisms of Conformational Interconversion.

ABSTRACT: In common with other hindered structures containing two aromatic rings linked by a short tether, diarylamines may exhibit atropisomerism (chirality due to restricted rotation). Previous examples have principally been tertiary amines, especially those with cyclic scaffolds. Little is known of the structural requirement for atropisomerism in structurally simpler secondary and acyclic diarylamines. In this paper we describe a systematic study of a series of acyclic secondary diarylamines, and we quantify the degree of steric hindrance in the ortho positions that is required for atropisomerism to result. Through a detailed experimental and computational analysis, the role of each ortho-substituent on the mechanism and rate of conformational interconversion is rationalised. We also present a simple predictive model for the design of configurationally stable secondary diarylamines.

SUBMITTER: Costil R

PROVIDER: S-EPMC7589358 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Atropisomerism in Diarylamines: Structural Requirements and Mechanisms of Conformational Interconversion.

Costil Romain R Sterling Alistair J AJ Duarte Fernanda F Clayden Jonathan J

Angewandte Chemie (International ed. in English) 20200820 42

In common with other hindered structures containing two aromatic rings linked by a short tether, diarylamines may exhibit atropisomerism (chirality due to restricted rotation). Previous examples have principally been tertiary amines, especially those with cyclic scaffolds. Little is known of the structural requirement for atropisomerism in structurally simpler secondary and acyclic diarylamines. In this paper we describe a systematic study of a series of acyclic secondary diarylamines, and we qu ...[more]

PMID: 32633101

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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.

Dataset Information

Atropisomerism in Diarylamines: Structural Requirements and Mechanisms of Conformational Interconversion.

Publications

Atropisomerism in Diarylamines: Structural Requirements and Mechanisms of Conformational Interconversion.

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