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

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.