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Catalytic enantioselective Minisci-type addition to heteroarenes

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Science  27 Apr 2018:
Vol. 360, Issue 6387, pp. 419-422
DOI: 10.1126/science.aar6376
  • Fig. 1 Strategies to access enantioenriched α-heterocyclic amines.

    (A) Typical current approaches. (B) The method reported herein. Ms, methanesulfonyl; Ac, acetyl; tBu, tert-butyl.

  • Fig. 2 Reaction development.

    (A) Hypothesis for enabling enantioselective Minisci-type addition. (B) Initial reaction evaluation on 4-methylquinoline, structures of the catalysts used in this study, and x-ray structure of 3a. dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)-pyridinyl; dtbpy = 4,4′-bis(tert-butyl)bipyridine; Ph, phenyl; Et, ethyl; iPr, isopropyl.

  • Fig. 3 Exploration of substrate scope.

    All yields are isolated yields; enantiomeric excesses were determined by HPLC. Absolute stereochemistries of products were assigned by analogy to 3a. (A) Evaluation of scope of redox-active ester (RAE) component. (B) Scope of quinoline component. (C) Scope of compatible pyridines. (D) Application to enantioselective late-stage functionalization of pharmaceuticals. Boc, tert-butyloxycarbonyl; Me, methyl. *O-Acetyl group was cleaved upon purification. †2 mol % photocatalyst and 10 mol % chiral Brønsted acid were used.

  • Fig. 4 Preliminary experiments to probe mechanism.

    (A) Outcome of reaction of a proline-derived RAE that bears no hydrogen bond donors. (B) Competition experiment to determine kinetic isotope effect.

Supplementary Materials

  • Catalytic enantioselective Minisci-type addition to heteroarenes

    Rupert S. J. Proctor, Holly J. Davis, Robert J. Phipps

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

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    • Materials and Methods
    • Figs. S1 to S5
    • Tables S1 to S10
    • HPLC Traces
    • NMR Spectra
    • References

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