Atropisomerism is a dynamic type of axial chirality that is ubiquitous in medicinal chemistry. There are several examples of stable atropisomeric US FDA-approved drugs and experimental compounds, and in each case the atropisomers of these compounds possess drastically different biological activities. Rapidly interconverting atropisomerism is even more prevalent, and while such compounds are typically considered achiral, they bind their protein targets in an atroposelective fashion, with the nonrelevant atropisomer contributing little to the desired activities. It has been recently demonstrated that various properties of an interconverting atropisomer can be modulated through the synthesis of atropisomer stable and pure analogs. Herein we discuss examples of atropisomerism in drug discovery as well as challenges and opportunities moving forward.
Diarylamines and related scaffolds are among the most common chemotypes in modern drug discovery. While they can potentially possess two chiral axes, there are no studies on their enantioselective synthesis, as these axes typically possess lower stereochemical stabilities. Herein, we report a chiral phosphoric acid catalyzed atroposelective electrophilic halogenation of N-aryl quinoids, a class of compounds that are analogous to diarylamines. This chemistry yields a large range of stereochemically stable Naryl quinoids in excellent yields and atroposelectivity. This work represents the first example of the atroposelective synthesis of a diarylamine-like scaffold and will serve as a gateway to fundamental and applied studies on the scarcely studied chirality of these ubiquitous chiral scaffolds.A tropisomerism, or axial chirality, is ubiquitous throughout modern drug discovery 1−4 and natural products chemistry. 5,6 While most chemists recognize atropisomeric axes pertaining to biaryls, 7 benzamides, 8 and anilides, 9 axial chirality in diarylamines and related scaffolds such as N-aryl quinoids are largely overlooked. Nonetheless, these structural motifs are among the most common potentially atropisomeric chemotypes in medicinal chemistry, with the FDA-approved drugs binimetinib and bosutinib representing examples of diarylamines that exist as rapidly interconverting atropisomers, and a VEGFR inhibitor from Wyeth representing a potentially atropisomeric N-aryl quinoid (Scheme 1A). 10−12 Indeed, a cursory search in the PDB will reveal thousands of cocrystal
Diarylamines possess two potentially atropisomeric C−N axes; however, there are few examples of atropisomerically stable diarylamines in the literature, as the contiguous axes can allow for low energy racemization pathways via concerted bond rotations. Herein, we describe highly atropisomerically stable diarylamines that possess barriers to racemization of 30−36 kcal/ mol, corresponding to half-lives to racemization on the decade to century time scale at room temperature. Investigation of the factors that led to the high stereochemical stability suggests that increased conjugation of the aniline lone pair of electrons into a more electron-deficient aryl ring, coupled with intramolecular hydrogenbonding, locked the corresponding axis into a defined planar conformation, disfavoring the lower energy racemization pathways.
Catalysts that contain a thiourea tethered to a carboxylic acid were found to affect the sulfenylation of indoles and other N-heterocycles on the hour time scale at room temperature. The mild nature of these conditions allowed for the incorporation of diverse functionalities into more complex heterocycles.
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