Homochiral Oligopeptides via a Lattice‐Controlled Polymerisation in Racemic Crystals of Valine N‐Carboxyanhydride Suspended in Aqueous Solutions

Abstract

As part of our program on the biochirogenesis of homochiral peptides, we report the formation of racemic parallel (p) beta sheets composed of alternating R and S chains of up to 14-15 repeat units of the same handedness through the polymerisation of (R,S)-valine N-carboxyanhydride (NCA) crystals suspended in aqueous solutions of a primary amine as the initiator. The occurrence of such a lattice-controlled reaction accompanied by a reduction in volume implies the operation of a mechanism that differs from that of the common solid-state polymerisation in vinyl systems. The topotacticity of the reaction is explained through the operation of a multistep nonlinear process comprising lattice control coupled with an asymmetric induction in the formation of homochiral short peptides followed by their self-assembly into racemic p beta sheets, which operate as efficient templates in the ensuing process of enantioselective chain elongation at the polymer/crystal interface. The composition of the diastereoisomeric libraries of oligopeptides was determined by MALDI-TOF and MALDI-TOF-TOF MS analyses of the products obtained from monomers enantioselectively labelled with deuterium. The structure of the p beta sheets could be determined by initiating the polymerisation reaction with water-soluble esters of enantiopure alpha-amino acids or short peptides. The same reaction performed with the monomer crystals suspended in hexane yielded a complex mixture of diastereoisomeric oligopeptides, thus highlighting the indispensable role played by water in controlling the stereoselectivity of the reaction. By contrast, polymerisation of (R,S)-leucine NCA crystals, with a different packing arrangement that presumably does not endorse the formation of periodic peptide templates, yielded, both in aqueous and hexane suspensions, libraries of peptides dominated by heterochiral diastereoisomers.

Racemic β‐Sheets as Templates for the Generation of Homochiral (Isotactic) Peptides from Aqueous Solutions of (RS)‐Valine or ‐Leucine N‐Carboxy‐ anhydrides: Relevance to Biochirogenesis

“…Another reported example is a solubility study showing that the mixing of equal amounts of water-soluble polylysine of opposite handedness results in the precipitation of the racemate. [22,23] The formation of rippled ap b-sheets and rippled p bsheets has been reported in the polymerization of racemic crystals of (RS)-Phe-NCA [11,12,24] and (RS)-Val-NCA, [13] re-spectively, suspended in an organic solvent or water containing the initiator. On the other hand, NMR spectroscopy studies of short racemic oligopeptides forming b-sheet-like architectures in chloroform have shown that the interactions between residues residing in neighboring chains of the same handedness are more stable than those of opposite handedness by 0.6-0.8 kcal per residue.…”

“…The racemic mixtures of isotactic peptides can be desymmetrized by using enantio-In our approach, we have followed a working hypothesis that comprises several steps: the formation of libraries of short oligomers composed from blocks of homochiral sequence, followed by the self-assembly of the oligomers through hydrogen bonding into aggregates that operate as regio-enantiospecific templates and control the ensuing process of chain elongation. [11][12][13][14][15] Such a scenario has common features with the process of crystallization, which comprises the steps of crystal nucleation and stereospecific growth.…”

Prebiotic Peptides: Molecular Hubs in the Origin of Life

“…N -Carboxy anhydrides (NCAs), 2-thiono-5-oxazolidones, and 5­(4 H )-oxazolones are important intermediates in the context of plausibly prebiotic amino acid polymerization reactions (Chart ). These cyclic compounds are among the simplest known activated amino acid derivatives, and their polymerization has been studied considerably over the past 60 years both in aqueous solutions and in organic solvents. ,− High degrees of polymerization, with a degree of preference for generating homochiral products, − are possible for NCAs and 2-thiono-5-oxazolidones since their structure, which simultaneously activates the carboxylate toward nucleophilic attack and engages the free amine, circumvents the common side reaction of DKP formation. Furthermore, reactions of NCA with nucleophiles other than amino acids have been shown to yield a variety of aminoacyl derivatives that may have been prebiotically important, including aminoacyl phosphates, , aminoacyl adenylates, , aminoacyl nucleoside esters, aminoacyl fatty acids, aminoacyl thioacids, and aminoacyl thioesters (Scheme ).…”

“Absolute” Asymmetric Polymerization within Crystalline Architectures: Relevance to the Origin of Homochirality

“…Indeed, when the enantioselectively tagged crystals were suspended in aqueous solutions containing either n-butylamine or enantiopure Val-OMe or Leu-OMe, they yielded, as the insoluble fraction, a mixture of peptides enriched with the isotactic chains [76]. The crystal structure of (RS)-Leu NCA (Figure 8.15) differs from that of PheNCA and ValNCA.…”