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. 2023 Aug 30;13(18):12134-12141.
doi: 10.1021/acscatal.3c03422. eCollection 2023 Sep 15.

Dynamic Kinetic Resolution of Indole-Based Sulfenylated Heterobiaryls by Rhodium-Catalyzed Atroposelective Reductive Aldol Reaction

Carlos Rodríguez-Franco  1 , Abel Ros  1 , Pedro Merino  2 , Rosario Fernández  3 , José M Lassaletta  1 , Valentín Hornillos  3   1
Affiliations

Dynamic Kinetic Resolution of Indole-Based Sulfenylated Heterobiaryls by Rhodium-Catalyzed Atroposelective Reductive Aldol Reaction

Carlos Rodríguez-Franco et al. ACS Catal. .

Abstract

A highly enantio- and diastereoselective dynamic kinetic resolution (DKR) of configurationally labile 3-aryl indole-2-carbaldehydes is described. The DKR proceeds via a Rh-catalyzed intermolecular asymmetric reductive aldol reaction with acrylate esters, with simultaneous generation of three stereogenic elements. The strategy relies on the labilization of the stereogenic axis that takes place thanks to a transient Lewis acid-base interaction (LABI) between the formyl group and a thioether moiety strategically located at the ortho' position. The atropisomeric indole products present a high degree of functionalization and can be further converted to a series of axially chiral derivatives, thereby expanding their potential application in drug discovery and asymmetric catalysis.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Selected 3-aryl indole frameworks.
Scheme 1
Scheme 1. Atropisomerization via Lewis Acid/Base Interactions
Figure 2
Figure 2
(A) Transition structures for the racemization of 3-aryl indole A and biaryl B. (B) NCI analysis. Thin, delocalized green surfaces indicate van der Waals interactions. Small, lenticular, and bluish surfaces indicate strong interactions. Steric clashes are shown as red isosurfaces.
Scheme 2
Scheme 2. Reaction Scope
Reactions performed at 0.1 mmol scale in 0.3 mL of toluene. Compounds 1a–w (1 equiv), tert-butyl acrylate (1.5 equiv). Isolated yields after chromatography. HPLC on chiral stationary phases determined the ee values. Reaction performed at 1.2 mmol scale.
Scheme 3
Scheme 3. Representative Transformations from 2m
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References

    1. Bringmann G.; Gulder T.; Gulder T. A. M.; Breuning M. Atroposelective Total Synthesis of Axially Chiral Biaryl Natural Products. Chem. Rev. 2011, 111, 563–639. 10.1021/cr100155e. - DOI - PubMed
    1. Toenjes S. T.; Gustafson J. L. Atropisomerism in Medicinal Chemistry: Challenges and Opportunities. Future Med. Chem. 2018, 10, 409–422. 10.4155/fmc-2017-0152. - DOI - PMC - PubMed
    2. Clayden J.; Moran W. J.; Edwards P. J.; LaPlante S. R. The Challenge of Atropisomerism in Drug Discovery. Angew. Chem., Int. Ed. 2009, 48, 6398–6401. 10.1002/anie.200901719. - DOI - PubMed
    3. Smyth J. E.; Butler N. M.; Keller P. A. A Twist of Nature-The Significance of Atropisomers in Biological Systems. Nat. Prod. Rep. 2015, 32, 1562–1583. 10.1039/C4NP00121D. - DOI - PubMed
    1. Dotsevi G.; Sogah Y.; Cram D. J. Total Chromatographic Optical Resolution of α-Amino Acid and Ester Salts through Chiral Recognition by a Host Covalently Bound to Polystyrene Resin. J. Am. Chem. Soc. 1976, 98, 3038–3041. 10.1021/ja00426a073. - DOI - PubMed
    2. Takaishi K.; Yasui M.; Ema T. Binaphthyl-Bipyridyl Cyclic Dyads as a Chiroptical Switch. J. Am. Chem. Soc. 2018, 140, 5334–5338. 10.1021/jacs.8b01860. - DOI - PubMed
    3. Li Q.; Green L.; Venkataraman N.; Shiyanovskaya I.; Khan A.; Urbas A.; Doane J. W. Reversible Photoswitchable Axially Chiral Dopants with High Helical Twisting Power. J. Am. Chem. Soc. 2007, 129, 12908–12909. 10.1021/ja0747573. - DOI - PubMed
    1. Privileged Chiral Ligands and Catalysts; Zhou Q.-L., Ed.; Wiley-VCH: Weinheim, Germany, 2011.
    2. Li Y.-M.; Kwong F.-Y.; Yu W.-Y.; Chan A. S.C. Recent Advances in Developing New Axially Chiral Phosphine Ligands for Asymmetric Catalysis. Coord. Chem. Rev. 2007, 251, 2119.10.1016/j.ccr.2007.07.020. - DOI
    3. Chen Y.; Yekta S.; Yudin A. K. Modified BINOL Ligands in Asymmetric Catalysis. Chem. Rev. 2003, 103, 3155.10.1021/cr020025b. - DOI - PubMed
    1. Parmar D.; Sugiono E.; Raja S.; Rueping M. Complete Field Guide to Asymmetric BINOL-Phosphate Derived Brønsted Acid and Metal Catalysis: History and Classification by Mode of Activation; Brønsted Acidity, Hydrogen Bonding, Ion Pairing, and Metal Phosphates. Chem. Rev. 2014, 114, 9047.10.1021/cr5001496. - DOI - PubMed
    2. Min C.; Seidel D. Asymmetric Brønsted Acid Catalysis with Chiral Carboxylic Acids. Chem. Soc. Rev. 2017, 46, 5889.10.1039/C6CS00239K. - DOI - PubMed