Exploration of Diverse Reactive Diad Geometries for Bifunctional Catalysis via Foldamer Backbone Variation

Abstract

What is the best spatial arrangement of a pair of reactive groups for bifunctional catalysis of a chemical transformation? The conformational versatility of proteins allows reactive group geometry to be explored and optimized via evolutionary selection, but it has been difficult for chemists to identify synthetic scaffolds that allow broad comparative evaluation among alternative reactive group geometries. Here we show that a family of helices, adopted predictably by oligomers composed partially or exclusively of β-amino acid residues, enables us to explore a range of orientations for a pair of pyrrolidine units that must work in tandem to catalyze a crossed aldol reaction. Thus, the crossed aldol reaction serves as an assay of reactive diad efficacy. We have chosen a test reaction free of stereochemical complexity in order to streamline our study of reactivity. The best geometry enhances the initial rate of product formation by two orders of magnitude. Our findings raise the possibility that rudimentary catalysts involving an isolated secondary structure might have facilitated the development of prebiotic reaction networks.

Conformational Preferences of Cyclopentane‐Based Oligo‐δ‐peptides in the Gas Phase and in Solution

“…Recently, the hybrid heptapeptide with a 1 : 2 α:β repeat of the Aib-ACPC-ACPC sequence displayed a distinct helical structure and its derivative bearing adjacent amine diads exhibited a good performance for catalysis of the crossed aldol condensation and the cyclodimerization of dialdehyde. [14] Hence, we tried to design a potential catalyst for organic reactions by introducing pyrrolidines into H 16/14 II and H 14 IV helical structures of Ac-(δAc 5 a) 6 -NHMe. Two cyclopentanes at the third and fifth residues of these helical structures of Ac-(δAc 5 a) 6 -NHMe, which are almost exactly one turn apart, were replaced by pyrrolidines to place amine diads adjacent in sequence.…”

“…[13] The hybrid heptapeptide with a 1 : 2 α : β repeat of the Aib-ACPC-ACPC sequence displayed a distinct helical structure (here ACPC stands for trans-2-aminocyclopentanecarboxylic acid) and its derivative bearing amine diads exhibited a good performance for catalysis of the crossed aldol condensation and the cyclodimerization of dialdehyde. [14] H 9 -helical pentamers of thiazolebased γ-amino acid residues modified by introducing a pyrrolidine and a carboxylic acid in the middle of the sequence efficiently catalyzed the stereoselective conjugate addition of cyclohexanone to β-trans-nitrostyrene. [15] δ-Amino acid residue has a unique backbone sequence resembling a dipeptide unit in α-peptides (Figure 1).…”

Increasing the Functional Group Diversity in Helical β-Peptoids: Achievement of Solvent- and pH-Dependent Folding

“…Such materials may find use as efficient catalysts as recently demonstrated by Gellman and coworkers. [78][79] The ability to conformationally respond to external stimuli may offer yet another level of sophistication in catalysts design. 80,81 Investigation of metal ion binding properties and potential effects on self-assembly is currently ongoing in our laboratories.…”

A catalytic protein–proteomimetic complex: using aromatic oligoamide foldamers as activators of RNase S

“…molecular recognition,15 control over reactivity,55 transduction of information 56. Catalytic foldamers57 have proven considerably more elusive; aldolase foldamers have been described which are more efficient than designed aldolases,58 but do not reach the activities of natural enzymes, whilst the addition of catalytic groups to foldamers results in stereoselective oxidations 59. In asking the question: “Can the astonishing 3D structures and functions of proteins be attained with building blocks other than α-amino acids?” we have taken a different approach in replacing parts of a functional protein; applied to an extremely efficient enzyme such as RNase S as we have done here places a high bar for success.…”