Acid Promoted Cinnamyl Ion Mobility within Peptide Derived Macrocycles

Abstract

We are developing methods that restrict the conformational mobility of peptides and related heteropolymers while simultaneously altering their properties. Our experiments occur as processes wherein a conserved, lipophilic reagent is activated in stages to form composite products with unprotected polyamides in parallel. For each starting oligomer, the goal is to create not one, but rather a collection of products. The intent is for those materials to retain molecular recognition elements of the biopolymer, yet display that functionality as part of stable, cyclic structures having defined shapes and enhanced membrane solubility/permeability. Here we describe reagent 2 and its two-step integration into peptides to afford macrocyclic ethers (e.g., 4 when starting with W-W-Y). When those materials are treated with protic acid in anhydrous solvent, the cinnamyl unit migrates from the oxygen of tyrosine to distribute throughout the structure, forming new products via carbon/carbon bonding. These changes occur concomitantly with acid-promoted rearrangements/cyclizations of the dienyne appendage to generate mixtures containing unique macrocycles such as 15. Similar amalgamations of 2 with more diverse peptides is a means to begin accessing complex peptidomimetics systematically. From a library of screening fractions generated in this way, we have identified a small molecule that selectively promotes hippocampal neurogenesis in the adult mouse brain.

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

“…1B) is reminiscent of a lignan monomer. It is a simplified, achiral form of a structure we described previously (51). The intent was to study large ring-forming reactions involving palladium π-allyl intermediates generated from the cinnamyl carbonate in this molecule.…”

“…We observed that decomposition of a cinnamyl carbonate within the template could capture pendant tyrosine residues to form cyclic ethers (51,54). This result followed from catalysis pioneered by Tsuji and Trost.…”

“…Degrado and coworkers (46), Boger and Myers (47), and others have shown the utility of such template-constrained cyclic peptides (48,49), and how polarity and geometry of the template can influence the shape and function of the peptide domain (50). Our laboratory has also explored templates for forming macrocyclic peptides (51)(52)(53). In this work, templates were designed as multiply reactive inserts.…”

Large ring-forming alkylations provide facile access to composite macrocycles

“…It also opens the possibility for multi-step sequences wherein the template modifies the oligomer more substantially and in increments. 18 …”

What went wrong?

“…Two uses of n-butyl lithium were noted, one in a very recent (2008) publication. 7,8 No uses of the much more air-reactive t-butyl lithium were found. It would be enlightening to know just how much experience the Harran research program has in working with extremely pyrophoric chemicals.…”