Work

Bifunctional Catalysis of Aldol Reactions by Foldamer Dihydrazides: Assessment of Conformational Preorganization

Year: 2025

Type: article

Abstract: We previously reported that molecules containing two cyclic hydrazide units connected by a polymethylene linker could catalyze aldol condensations via a bifunctional mechanism. One hydrazide apparently provides nucleophilic activation, via enamine formation, while the other provides electrophilic activation, via iminium formation. Here, we ask whether catalytic efficacy can be enhanced by using a conformationally preorganized linker to connect the hydrazide units. In the new catalyst series, the linkers are α/β-peptides (oligomers containing α- and β-amino acid residues). The α/β-peptide scaffold features a 1:2 α:β backbone repeat and forms a helix with approximately three residues per turn. When α residues with hydrazide-containing side chains have an i, i +3 sequence relationship, helical folding induces alignment of the hydrazides. Incremental variation of side chain length allowed us to identify an optimal spacing between the hydrazide units, comprising 16 atoms. Catalytic efficacy, as judged by relative initial rates of an aldol condensation, was ∼3.5-fold greater for this α/β-peptide relative to the dihydrazide with a flexible 16-atom spacer from the previous series. Single-crystal X-ray crystallographic analyses of three α/β-peptide catalysts provide insight into modes of conformational flexibility available to these foldamers.

Source: Journal of the American Chemical Society

DOI: 10.1021/jacs.5c10914

Authors: Philip P. Lampkin, Kyana M. Sanders, Leah C. Garman, Ilia A. Guzei, Samuel H. Gellman

Institution: University of Wisconsin–Madison

Language: English

Topic: Chemical Synthesis and Analysis

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: hybrid

Estimated APC paid: $4,500

Funders: William F. Vilas Trust Estate, Division of Chemistry