The transition from prebiotic racemic chemistry towards homochiral biology represents one of the unsolved riddles about the origin of life. [1,2] Its elucidation requires the development of possible scenarios for the conversion of racemic monomers into long bio-like homochiral (isotactic) polymers. [3][4][5] The polymerization of a-amino acids in buffer solutions has been reported to yield small amounts of isotactic oligopeptides, in a process that departs from the Bernoulli random kinetics; however, the mechanism responsible for this deviation was not elucidated. [6] A way to override the disadvantage of the tendency to form polymeric chains composed from heterochiral repeat units in the polymerization of racemic monomers may require the emergence of supramolecular architectures as intermediates in nonlinear processes. [7][8][9] A commonly accepted hypothesis for the formation of long primeval peptides of homochiral sequence from racemic precursors suggests the involvement of either a helices, as proposed by Wald, [10] or enantiomorphous pleated b sheets, as suggested by Brack and Spach, [11] as templates. Their formation requires, however, oligopeptides composed from eight (or more) repeat units of the same handedness in the polymerization of racemates, a process that obeys binomial kinetics with a probability of 1 molecule out of 2 8 (256). [12][13][14][15] Although it has been demonstrated that both these architectures might exert asymmetric induction in the polymerization reactions of activated a-amino acids, [16] their role in the formation of long homochiral peptides from racemates has not been supported by laboratory experiments.By contrast, we anticipate on kinetic grounds that racemic b sheets composed of mixtures of isotactic oligopeptides, delineated by chiral rims, might be advantageous architectures, provided that they can operate as templates for the formation of long peptides. The formation of these b sheets should be much faster as it depends upon the concentration of both the R and the S isotactic chains, whereas that of the enantiopure pleated b sheets depends upon the concentration of only one of the enantiomers. Although racemic antiparallel (ap) b sheets had been proposed by Pauling and Corey [17] to be closely similar to the natural pleated ap b sheets, they have been overlooked as possible participants in chemobiogenesis.Here we show that racemic ap b sheets play a dominant role in the generation of libraries of isotactic oligopeptides comprising up to 25 repeat units of the same handedness in the polymerization reaction of racemic N-carboxyanhydrides of valine (ValNCA) or leucine (LeuNCA) in aqueous solution and in the presence of primary amines (Scheme 1).(R,S)-ValNCA and (R,S)-LeuNCA, enantioselectively tagged with deuterium (98 %), were polymerized in water with n-butylamine (25 mol %, pH 6-7.5) and analyzed by MALDI-TOF MS. The diastereomeric compositions of oligoVal and oligo-Leu in the product samples are shown in Figure 1 a and b. In these spectra, the peaks for the isotactic oligo...

The transition from prebiotic racemic chemistry towards homochiral biology represents one of the unsolved riddles about the origin of life. [1,2] Its elucidation requires the development of possible scenarios for the conversion of racemic monomers into long bio-like homochiral (isotactic) polymers. [3][4][5] The polymerization of a-amino acids in buffer solutions has been reported to yield small amounts of isotactic oligopeptides, in a process that departs from the Bernoulli random kinetics; however, the mechanism responsible for this deviation was not elucidated. [6] A way to override the disadvantage of the tendency to form polymeric chains composed from heterochiral repeat units in the polymerization of racemic monomers may require the emergence of supramolecular architectures as intermediates in nonlinear processes. [7][8][9] A commonly accepted hypothesis for the formation of long primeval peptides of homochiral sequence from racemic precursors suggests the involvement of either a helices, as proposed by Wald, [10] or enantiomorphous pleated b sheets, as suggested by Brack and Spach, [11] as templates. Their formation requires, however, oligopeptides composed from eight (or more) repeat units of the same handedness in the polymerization of racemates, a process that obeys binomial kinetics with a probability of 1 molecule out of 2 8 (256). [12][13][14][15] Although it has been demonstrated that both these architectures might exert asymmetric induction in the polymerization reactions of activated a-amino acids, [16] their role in the formation of long homochiral peptides from racemates has not been supported by laboratory experiments.By contrast, we anticipate on kinetic grounds that racemic b sheets composed of mixtures of isotactic oligopeptides, delineated by chiral rims, might be advantageous architectures, provided that they can operate as templates for the formation of long peptides. The formation of these b sheets should be much faster as it depends upon the concentration of both the R and the S isotactic chains, whereas that of the enantiopure pleated b sheets depends upon the concentration of only one of the enantiomers. Although racemic antiparallel (ap) b sheets had been proposed by Pauling and Corey [17] to be closely similar to the natural pleated ap b sheets, they have been overlooked as possible participants in chemobiogenesis.Here we show that racemic ap b sheets play a dominant role in the generation of libraries of isotactic oligopeptides comprising up to 25 repeat units of the same handedness in the polymerization reaction of racemic N-carboxyanhydrides of valine (ValNCA) or leucine (LeuNCA) in aqueous solution and in the presence of primary amines (Scheme 1).(R,S)-ValNCA and (R,S)-LeuNCA, enantioselectively tagged with deuterium (98 %), were polymerized in water with n-butylamine (25 mol %, pH 6-7.5) and analyzed by MALDI-TOF MS. The diastereomeric compositions of oligoVal and oligo-Leu in the product samples are shown in Figure 1 a and b. In these spectra, the peaks for the isotactic oligo...

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.