As part of our program on biochirogenesis of homochiral peptides from racemic precursors, we report the feasibility of obtaining peptides with homochiral sequences composed of up to 25 residues of the same handedness in the polymerization of racemic valine or leucine N-carboxyanhydrides in aqueous solutions, as initiated by amines. The composition of the oligopeptides was determined by MALDI-TOF mass spectrometry, and the sequences of some of the heterochiral diastereoisomers were studied by MALDI-TOF MS/MS performed on samples in which the S enantiomers of the monomer were tagged with deuterium atoms. The process comprises several steps: 1) a Markov mechanism of asymmetric induction in the early stages of the polymerization yields libraries of racemic oligopeptides enriched with isotactic diastereoisomers, together with oligopeptide sequences containing enantiomeric blocks of homochiral residues; 2) the short peptides self-assemble into racemic colloidal architectures that serve as regio-enantioselective templates in the ensuing process of chain elongation; 3) homochiral residues of the amino acids located at the periphery of these colloidal aggregates exert efficient enantioselection, which results in the formation of long isotactic oligopeptides. The final diastereoisomeric distribution of the peptides depends upon the composition of the templates, which is determined by the concentration of the initiator. The racemic mixtures of isotactic peptides can be desymmetrized by using enantiopure methyl esters of alpha-amino acids as initiators.

Dedicated to Professor Duilio Arigoni on the occasion of his 75th birthday Racemic S-ethyl thioesters of N e -stearoyllysine ( S-ethyl (R,S)-2-amino-6-(stearoylamino)hexanethioate) and S-ethyl thioesters of g-stearyl glutamic acid ( stearyl (R,S)-4-amino-5-(ethylsulfanyl)-5-oxopentanoate) self-assemble as separated two-dimensional crystalline monolayers within an achiral phospholipid environment of racemic 1,2-dipalmitoylglycerol (DPG) and 1,2-dipalmitoylglycero-3-phosphoethanolamine (DPPE), as demonstrated by grazing-incidence X-ray-diffraction (GIXD) measurements performed on the surface of H 2 O. Lattice-controlled polycondensation within these crystallites with deuterium-enantiolabeled monomers was initiated by injecting aqueous solutions of Ag or I 2 /KI beneath the monolayers, which yielded mixtures of diastereoisomeric oligopeptides containing up to six to eight repeating units, as analyzed by MALDI-TOF mass spectrometry. Analysis of the diastereoisomeric distribution showed an enhanced relative abundance of the oligopeptides with homochiral sequences containing three or more repeating units. Within the DPPE monolayers, the nucleophilic amino group of the phospholipid operates as an initiator of polymerization at the periphery of the monomer two-dimensional crystallites. Enhanced relative abundance of enantiomerically enriched homochiral oligopeptides was obtained by the polycondensation of nonracemic monomers. This enhancement indicated a phase separation into racemic and enantiomorphous monomer crystallites within the phospholipid environment, although this separation could not be observed directly by GIXD. A possible role that might have been played by crystalline assemblies for the abiotic generation and amplification of oligopeptides with homochiral sequences is discussed.Introduction. ± One of the central enigmata in the abiotic origin of life is related to the question of how homochiral biopolymers have been formed under prebiotic conditions. An accepted scenario for early formation of biopolymers from abiotic atomic or molecular ingredients is based on the assumption that primitive polymers might have been formed on surfaces then concentrated and sequestered within primeval membrane-like films that were subsequently converted into proto-cells to form primitive vesicle-like architectures capable of engulfing the polymers for further self-replication [1 ± 3]. This scenario invokes an essential role played by early membrane-like materials in the form of primitive proto-cells. It does not, however, consider the formation of homochiral polymers from racemates or from nonracemic mixtures of activated racemic monomers of low enantiomeric imbalance within these membrane-like environments.

Dedicated to Professor Duilio Arigoni on the occasion of his 75th birthday A grazing-incidence X-ray-diffraction (GIXD) study of the self-assembly, on water, of nonracemic gstearyl glutamic acid (pure or as a mixture with racemic or (S)-1,2-dipalmitoyl-glycero-3-phosphoethanolamine (DPPE)) demonstrated a phase separation of the a-amino acid amphiphile into racemic and enantiomorphous two-dimensional crystallites within the phospholipid domains. The packing arrangements of the two a-amino acid crystalline phases were identical to those found in the absence of DPPE and have been determined, at almost atomic resolution, by X-ray structure-factor calculations. By contrast, racemic and nonracemic N estearoyllysine spontaneously segregated into two-dimensional enantiomorphous domains within the DPPE environment that induced a change in the tilt direction of the hydrocarbon chains of the a-amino acid molecules. Phase separation of nonracemic amphiphiles, originating from preferred lateral homochiral or heterochiral intermolecular interactions, is in agreement with the formation of enantiomerically pure or enriched homochiral oligopeptides in overrepresented amounts in the polycondensation of activated nonracemic amphiphilic aamino acids on plain water or within phospholipid monolayers.Introduction. ± As a part of our studies on the formation of homochiral oligopeptides from nonracemic activated a-amino acid monomers, we have proposed a general mechanism for the amplification of chirality that encompasses a phase separation of the nonracemic monomers into two-dimensional (2D) crystallites, either on H 2 O or within a membrane-like environment of a phospholipid monolayer, followed by a lattice-controlled polymerization. In the preceding article of this journal issue [1], we demonstrated that polycondensation of nonracemic S-ethyl thioesters of both lysine and glutamic acid amphiphiles gives rise to homochiral oligopeptides, when embedded within a phospholipid monolayer, as determined by MALDI-TOF MS of deuteriumenantiolabeled monomers. Grazing-incidence X-ray-diffraction (GIXD) studies of the films composed of an equimolar mixture of racemic phospholipids with racemic thioesters clearly showed a phase separation between 2D crystalline domains of phospholipid and those of the thioesters, very similar to those observed for the pure components. However, it was not possible for these systems to demonstrate, by direct GIXD measurement, the occurrence of a phase separation of the nonracemic thioesters into a mixture of racemic and enantiomorphous domains. This was due to either similar X-ray diffraction patterns or an induced line-epitaxial crystallization of the enantiomorphous crystalline phase alongside the racemic crystallites, as discussed elsewhere [2].

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N(epsilon)-stearoyl-lysine-ethyl-ester (C18-OE-Lys) operates as an efficient desymmetrizing agent for the generation of homochiral oligopeptides via a reaction catalyzed by silver ions in two-dimensional (2D) quasi-racemic crystallites of the corresponding thio-ester (C18-TE-Lys) self-assembled on water.