Heterocyclic glucocorticoid receptor modulators with a 2,2-dimethyl-3-phenyl-N-(thiazol or thiadiazol-2-yl)propanamide core

Xiao, Hai-Yun; Wu, Dauh‐Rurng; Sheppeck, James E.; Habte, Sium; Cunningham, Mark D.; Somerville, John; Barrish, Joel C.; Nadler, Steven G.; Dhar, T. G. Murali

doi:10.1016/j.bmcl.2013.08.049

Cited by 7 publications

(1 citation statement)

References 17 publications

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“…In addition to demonstrating the utility of FDHs for enantioselective catalysis, desymmetrization of methylenedianilines via halogenation provides a handle for subsequent Pd-catalyzed transformations . We envisioned that a Larock-type cyclization would be particularly useful for generating enantioenriched 5-substituted indoles, which have been explored as monoamine uptake inhibitors and glucocorticoid receptor modulators. , This sequence would leave an aniline substituent on the resulting product (Ar in Scheme ) that could be further functionalized via diazotization. In practice, heating enantioenriched 1a with 4-octyne in the presence of a Pd catalyst led to formation of the desired indole with no loss of enantiopurity (Scheme ).…”

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confidence: 99%

Enantioselective Desymmetrization of Methylenedianilines via Enzyme-Catalyzed Remote Halogenation

Payne

Butkovich

et al. 2018

J. Am. Chem. Soc.

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Extensive effort has been devoted to engineering flavin-dependent halogenases (FDHs) with improved stability, expanded substrate scope, and altered regioselectivity. Here we show that variants of rebeccamycin halogenase (RebH) catalyze enantioselective desymmetrization of methylenedianilines via halogenation of these substrates distal to their pro-stereogenic center. Structure-guided engineering was used to increase the conversion and selectivity of these reactions, and the synthetic utility of the halogenated products was shown via conversion of to a chiral α-substituted indole. These results constitute the first reported examples of asymmetric catalysis by FDHs.

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confidence: 99%