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. 2017 Nov 3;82(21):11326-11336.
doi: 10.1021/acs.joc.7b02339.

Desymmetrization of Diarylmethylamido Bis(phenols) through Peptide-Catalyzed Bromination: Enantiodivergence as a Consequence of a 2 amu Alteration at an Achiral Residue within the Catalyst

Anna E Hurtley  1 , Elizabeth A Stone  1 , Anthony J Metrano  1 , Scott J Miller  1
Affiliations

Desymmetrization of Diarylmethylamido Bis(phenols) through Peptide-Catalyzed Bromination: Enantiodivergence as a Consequence of a 2 amu Alteration at an Achiral Residue within the Catalyst

Anna E Hurtley et al. J Org Chem. .

Abstract

Diarylmethylamido bis(phenols) have been subjected to peptide-catalyzed, enantioselective bromination reactions. Desymmetrization of compounds in this class has been achieved such that enantioenriched products may be isolated with up to 97:3 er. Mechanistically, the observed enantioselectivity was shown to be primarily a function of differential functionalization of enantiotopic arenes, although additional studies unveiled a contribution from secondary kinetic resolution of the product (to afford the symmetrical dibromide) under the reaction conditions. Variants of the tetrapeptide catalyst were also evaluated and revealed a striking observation-enantiodivergent catalysis is observed upon changing the achiral amino acid residue in the catalyst (at the i+2 position) from an aminocyclopropane carboxamide residue (97:3 er) to an aminoisobutyramide residue (33:67 er) under a common set of conditions. An expanded set of catalysts was also evaluated, enabling structure/selectivity correlations to be considered in a mechanistic light.

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Conflict of interest statement

Notes

The authors declare no competing financial interests. Crystallographic data are deposited with the Cambridge Crystallographic Data Center under the accession number CCDC 1573490 (1), 1570899 (2a), 1510509 (4), CCDC 1510523 (7).

Figures

Figure 1
Figure 1
Targeted remote desymmetrization of diarylmethylamido bis(phenols) to access drug-like, chiral molecules.
Figure 2
Figure 2
X-ray crystal structures of enantiodivergent catalysts 4 and 7 and their overlay.
Figure 3
Figure 3
Identification of a linear correlation between enantioselectiv-ity and τ(i+2) in the bromination of 1. Product ratios were determined by 1H NMR analysis of the crude reaction mixture with respect to an internal standard prior to methylation. Enantiomeric excess was measured post O-methylation (2b). The average ee values are uncorrected for the extent of conversion and the associated secondary kinetic resolution (Eq 2). Additional details are provided in the Supporting Information.
Figure 4
Figure 4
(a) Classical π-facial selectivity determinants for enantiomeric control. (b) Substrate rotation could lead to opposite enantiomers of the monobrominated products. (c) Possible reactive orientations of catalyst and substrate with subtle changes in the non-covalent interactions that may lead to enantiodivergence: (i) Catalyst 4 in type II′ β-hairpin conformation. (ii) Catalyst 7 in type II′ β-hairpin conformation. (iii) Catalyst 4 in type I′ pre-helical β-turn conformation. (iv) Catalyst 7 in type I′ pre-helical β-turn conformation.
Scheme 1
Scheme 1
See this image and copyright information in PMC

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