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ACS Catal. 2019 Jan 4;9(1):242-252. doi: 10.1021/acscatal.8b04132. Epub 2018 Nov 20.

Phosphothreonine (pThr)-Based Multifunctional Peptide Catalysis for Asymmetric Baeyer-Villiger Oxidations of Cyclobutanones.

Author information

1
Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 06520-8107, United States.

Abstract

Biologically inspired phosphothreonine (pThr)-embedded peptides that function as chiral Brønsted acid catalysts for enantioselective Baeyer-Villiger oxidations (BV) of cyclobutanones with aqueous H2O2 are reported herein. Complementary to traditional BINOL-derived chiral phosphoric acids (CPAs), the functional diversity of the peptidic scaffold provides the opportunity for multiple points of contact with substrates via hydrogen bonding, and the ease of peptide synthesis facilitates rapid diversification of the catalyst structure, such that numerous unique peptide-based CPA catalysts have been prepared. Utilizing a hypothesis-driven design, we identified a pThr-based catalyst that contains an N-acylated diaminopropionic acid (Dap) residue, which achieves high enantioselectivity with catalyst loadings as low as 0.5 mol%. The power of peptide-based multi-site binding is further exemplified through reversal in the absolute stereochemical outcome upon repositioning of the substrate-directing group (ortho- to meta). Modifications to the i+3 residue (LDap to LPhe) lead to an observed enantiodivergence without inversion of any stereogenic center on the peptide catalyst, due to noncovalent interactions. Structure-selectivity and 1H-1H-ROESY studies revealed that the proposed hydrogen bonding interactions are essential for high levels of enantioinduction. The ability for the phosphopeptides to operate as multifunctional oxidation catalysts expands the scope of pThr catalysts and provides a framework for the future selective diversification of more complex substrates, including natural products.

KEYWORDS:

Baeyer–Villiger; asymmetric catalysis; chiral phosphoric acid; peptides; phosphothreonine

PMID:
31007966
PMCID:
PMC6467539
[Available on 2020-01-04]
DOI:
10.1021/acscatal.8b04132

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