Homochiral Oligopeptides Generated by Induced “Mirror Symmetry Breaking” Lattice‐Controlled Polymerizations in Racemic Crystals of Phenylalanine N‐Carboxyanhydride

Abstract

The formation of diastereoisomeric libraries of oligopeptides through the heterogeneous polymerization of racemic crystals of phenylalanine N-carboxyanhydride (PheNCA) is reported. The diastereoisomeric compositions of the oligopeptides formed on polymerization of (R,S) crystals incorporating the deuterium-tagged S enantiomer were determined by MALDI-TOF mass spectrometry. The racemic mixtures of the oligopeptides longer than pentamers are represented primarily by diastereoisomers of homochiral sequence and with peptides containing only one heterochiral repeating unit. A mechanism comprising the following three sequential steps to account for this unusual observation is proposed: 1) formation of dimers and trimers at a partially damaged liquid/solid interface, 2) chain propagation that takes place within the bulk of the crystal through a lattice-controlled "zipper-like" mechanism between homochiral molecules arranged in a head-to-tail motif to yield crystalline antiparallel beta-sheets of alternating oligopeptide chains of homochiral sequence of opposite handedness, and 3) enantiomeric cross-inhibition that results in chain termination. Induced desymmetrization of the racemic mixtures of the formed peptides was achieved by the polymerization of the mixed quasi-racemic crystals of (R)-PheNCA, ((S)-PheNCA), and (S)-ThieNCA (3-(2-thienyl)-alanine N-carboxyanhydride) of various compositions. These experiments resulted in the formation of nonracemic libraries of oligopeptides composed of homochiral chains of (R)-Phe and copolymers of randomly distributed (S)-Phe and (S)-Thie sequences. From these findings, we propose a stochastic model for the generation of libraries of nonracemic mixtures of oligopeptides from the polymerization of host (R,S)-PheNCA with racemic mixtures of other guest NCA amino acids dissolved in limited quantities in the crystal.

Polypeptides and 100 Years of Chemistry of α‐Amino Acid N‐Carboxyanhydrides

“…Recent results from Lahav and co-workers [349,350] fit in with the afore-mentioned studies. When the S-ethyl esters of N e -stearoyl-d,l-Lys or g-stearyl-d,l-Glu were polymerized in the 2D lattices formed at the air-water interface, preferential formation of homochiral blocks was detected.…”

“…Predominantly homochiral oligopeptides were also formed when the polymerization of crystalline d,l-Phe-NCA was performed in the solid state. [350] 11. Various Aspects A few publications in the field of NCA chemistry that do not fit into one of the Sections presented above are summarized at the end of this Review article.…”

Polypeptide und 100 Jahre Chemie der α‐Aminosäure‐N‐carboxyanhydride

“…Neue Ergebnisse von Lahav und Mitarbeitern [349,350] passen gut zu den oben erwähnten Untersuchungen. Wenn die S-Ethylester von N e -Stearyl-d,l-Lys oder g-Stearyl-d,lGlu in einem Film an der Luft-Wasser-Grenzfläche "polykondensiert" wurden, entstanden überwiegend homochirale Blöcke.…”

“…Überwiegend homochirale Blöcke wurden auch dann erhalten, wenn die Polymerisation von kristallinem d,l-Phe NCA in festem Zustand durchgeführt wurde. [350] 11. Verschiedene Aspekte Einige wenige Veröffentlichungen auf dem Gebiet der NCA-Chemie, die nicht in einen der vorstehenden Abschnitte passen, sollen nun am Ende dieses Aufsatzes zusammengefasst werden.…”

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

“…This disadvantage might be overcome if the short polymers of homochiral sequence (isotactic) would self-assemble into ordered architectures that could exert steric control on the ensuing process of chain elongation occurring at the polymer/crystal interface. [15][16][17] The operation of such interplay requires an understanding of the role played by the structure of the monomer crystal at the early stages of the reaction, its role in dictating the self-assembly of the formed peptides into supramolecular architectures, such as a helices or b sheets, and the ultimate role played by the latter as stereospecific or enantioselective templates in the ensuing stages of polymer propagation. Here, we provide support for this hypothesis for the solidstate polymerisation of racemic crystals of valine N-carboxyanhydride (ValNCA, Scheme 1) and leucine N-carboxyanhydride (LeuNCA) suspended in hexane or water solutions of a primary-amine initiator.…”