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

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.

Advances in Chemocatalytic Asymmetric Baeyer–Villiger Oxidations

“…Inspired by the above CPA‐catalyzed B‐V oxidation, together with their interest in developing peptide catalysts, Miller et al. recently described that phosphothreonine (pThr)‐embedded peptides could serve as chiral Brønsted acid catalysts for the asymmetric B‐V oxidations of cyclobutanones (Scheme ) . Compared with the BINOL‐derived chiral phosphoric acids (CPAs), the functional diversity of the peptidic scaffold could provide multiple hydrogen bonding interactions with the ketone substrates.…”

Enantioselective Desymmetrization of Cyclobutanones: A Speedway to Molecular Complexity

“…[34] Small peptides with an embedded phosphothreonine unit are also capable catalysts for asymmetric Baeyer-Villiger oxidations.Their mode of action is closely related to BINOLderived phosphoric acid 25,b ut offers multiple sides for contact with substrates through hydrogen bonding,t hus mimicking enzymatic processes.I n2 019, Miller and coworkers introduced oligopeptide 32 as ac ompetent catalyst for such an endeavor (Scheme 7). [35] Depending on the position of the carbamate within the phenyl ring, substrates 33 and 34 underwent Baeyer-Villiger oxidation with reversal of the absolute configuration. Thus, R-configured lactam 35 and S-configured lactam 36 were accessible in excellent yield and good enantioselectivity with the same catalyst 32.Onthe basis of structure-selectivity studies,t he authors propose hydrogen bonding between the acyl-protected amine and the polar carbamate group to be crucial for this reversal.…”

Enantioselektive Desymmetrisierung von Cyclobutanonen: Eine Schnellstraße zu molekularer Komplexität

“…Ihre Wirkungsweise ist eng mit jener der Phosphorsäure 25 verwandt, bietet aber mehrere Seiten für den Kontakt mit Substraten durch Wasserstoffbrücken, die enzymatische Prozesse nachahmen. 2019 führte Millers Gruppe das Oligopeptid 32 als kompetenten Katalysator für ein solches Unterfangen ein (Schema ) . Basierend auf der Position des Carbamats innerhalb des Phenylrings wurden die Substrate 33 und 34 oxidiert, wobei sich die absolute Konfiguration umkehrt.…”

“…2019 führte Millers Gruppe das Oligopeptid 32 als kompetenten Katalysator für ein solches Unterfangen ein (Schema 7). [35]…”