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Catalytic Atroposelective Synthesis of N-Aryl Quinoid Compounds.

ABSTRACT: 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 N-aryl 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.

SUBMITTER: Vaidya SD

PROVIDER: S-EPMC7239344 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Catalytic Atroposelective Synthesis of <i>N</i>-Aryl Quinoid Compounds.

Vaidya Sagar D SD Toenjes Sean T ST Yamamoto Nobuyuki N Maddox Sean M SM Gustafson Jeffrey L JL

Journal of the American Chemical Society 20200128 5

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 <i>N</i>-aryl quinoids, a class of compounds that are analogous to diarylamines. This chemistry yields a large range of stereoc ...[more]

PMID: 31944689

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Project description:Enantioenriched diaryl-, aryl heteroaryl-, and diheteroarylmethanols exhibit important biological and medicinal properties. One-pot catalytic asymmetric syntheses of these compounds beginning from readily available aryl bromides are introduced. Thus, lithium-bromide exchange with commercially available aryl bromides and n-BuLi was followed by salt metathesis with ZnCl(2) to generate ArZnCl. A second equivalent of n-BuLi was added to form the mixed organozinc, ArZnBu. In the presence of enantioenriched amino alcohol-based catalysts, ArZnBu adds to aldehydes to afford essentially racemic diarylmethanols. The low enantioselectivities were attributed to a LiCl-promoted background reaction. To inhibit this background reaction, the chelating diamine TEEDA (tetraethylethylene diamine) was introduced prior to aldehyde addition. Under these conditions, enantioenriched diarylmethanols were obtained with >90% ee. Arylations of enals generated allylic alcohols with 81-90% ee. This procedure was unsuccessful, however, when applied to heteroaryl bromides, which was attributed to decomposition of the heteroaryl lithium under the salt metathesis conditions. To avoid this problem, the metathesis was conducted with EtZnCl, which enabled the salt metathesis to proceed at low temperatures. The resulting EtZn(Ar(Hetero)) intermediates (Ar(Hetero) = 2- and 3-thiophenyl, 2-benzothiophenyl, 3-furyl, and 5-indolyl) were successfully added to aldehydes and heteroaryl aldehydes with enantioselectivities between 81-99%. These are the first examples of catalytic and highly enantioselective syntheses of diheteroarylmethanols. In a similar fashion, ferrocenyl bromide was used to generate FcZnEt and the ferrocenyl group added to benzaldehyde and heteroaromatic aldehydes to form ferrocene-based ligand precursors in 86-95% yield with 96-98% ee. It was also found that the arylation and heteroarylation of enals could be followed by diastereoselective epoxidations to provide epoxy alcohols with high enantio- and diastereoselectivities in a one-pot procedure.

Dataset Information

Catalytic Atroposelective Synthesis of N-Aryl Quinoid Compounds.

Publications

Catalytic Atroposelective Synthesis of <i>N</i>-Aryl Quinoid Compounds.

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