Homochiral oligopeptides generated by induced "mirror symmetry breaking" lattice-controlled polymerizations in racemic crystals of phenylalanine N-carboxyanhydride

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.     

Twisted perylene stereodimers reveal chiral molecular assembly codes

Unique perylene diastereomeric linear and cyclic dimers were synthesized from twisted perylene monomers, revealing that pi-stacking stereoisomerism imparted specific intermolecular self-assembly and intramolecular folding. Only the homochiral twisted tetrachloroperylene monomers cyclized via a cooperative reaction, forming the homochiral diastereomers. The heterochiral tetrachloroperylene monomers proceeded through a stepwise reaction and yielded a linear heterochiral dimer, which equilibrated with the linear homochiral dimers. The linear homochiral dimers cyclized to produce the same cyclic homochiral diastereomers. These results demonstrated that homochiral and heterochiral self-assemblies were two distinct molecular codes, directing two specific chemical pathways. The homochiral cyclic dimers remain isomerically pure at -20 degrees C but can be interconverted to the heterochiral cyclic dimer meso compound at room temperature. The diastereomers were readily separated by HPLC. While driven by solvophobic forces, foldable linear dimers synthesized from the same twisted monomers using phosphoramidite chemistry folded into homodimer and heterodimer, confirming the inherent molecular codes, which were dictated by the perylene chirality, ultimately gauged the weak pi-stack forces, and directed self-assembly and folding.     

Chiral recognition in cyclic alpha-hydroxy carbonyl compounds: a theoretical study

A theoretical study (DFT and MP2) of the self-association of homochiral (RR or SS) and heterochiral (RS or SR) dimers of three series of cyclic alpha-hydroxy-carbonyl derivatives has been carried out. The solvation effect on the parent derivative dimers has been explored, showing nonsignificant changes in the configurations preferred but altering in some cases the homo/heterochiral preference of the dimers. The results in the gas phase of the systems with different substituents show a preference for the heterochiral dimers. The energetic results have been analyzed with the NBO and AIM methodologies. Optical rotatory power calculations of the monomers and homochiral dimers show large variations of this parameter depending on the substituents and the complexation.     

Homo- and heterochiral alkylzinc fencholates: linear or nonlinear effects in dialkylzinc additions to benzaldehyde

Scalemic mixtures of chiral anisyl fenchols with different ortho-substituents (X) in the anisyl moieties [X = H (1), Me (2), SiMe3 (3) and tBu (4)] are employed as pre-catalysts in enantioselective additions of diethylzinc to benzaldehyde. While a remarkable asymmetric depletion is apparent for X = H and Me, a linear relationship between the enantiomeric purity of the chiral source and the product 1-phenylpropanol is observed for X = SiMe3 and tBu. X-ray single crystal analyses show that racemic methylzinc fencholates obtained from 1 (X = H) and 2 (X = Me) yield homochiral dimeric complexes, while for 3 (X = SiMe3) and 4 (X = tBu) the heterochiral dimeric alkylzinc structures are formed. The enantiopure fenchols 1-4 all yield homochiral dimeric methylzinc complexes. Computed relative energies of homo- and heterochiral fencholate dimers with X = H and Me reveal an intrinsic preference for the formation of the homochiral dimers, consistent with the observed negative NLE. In contrast, similar stabilities are computed for homo- and heterochiral complexes of ligands 3 (X = SiMe3) and 4 (X = tBu), in agreement with the absence of a nonlinear effect for bulky ortho-subsituents.     

Self‐Discriminating Termination of Chiral Supramolecular Polymerization: Tuning the Length of Nanofibers

Directing the supramolecular polymerization towards a preferred type of organization is extremely important in the design of functional soft materials. Proposed herein is a simple methodology to tune the length and optical chirality of supramolecular polymers formed from a chiral bichromophoric binaphthalene by the control of enantiomeric excess (ee). The enantiopure compound gave thin fibers longer than a few microns, while the racemic mixture favored the formation of nanoparticles. The thermodynamic study unveils that the heterochiral assembly gets preference over the homochiral assembly. The stronger heterochiral binding over homochiral one terminated the elongation of fibrous assembly, thus leading to a control over the length of fibers in the nonracemic mixtures. The supramolecular polymerization driven by π–π interactions highlights the effect of the geometry of a twisted π‐core on this self‐sorting assembly.     

Chiral recognition in self-complexes of tetrahydroimidazo[4,5-d]imidazole derivatives: from dimers to heptamers

The chiral discrimination in the self-association of chiral 1,3a,4,6a-tetrahydroimidazo[4,5-d]imidazoles has been studied using density functional theory methods. Clusters from dimers to heptamers have been considered. The heterochiral dimers (RR:SS or SS:RR) are more stable than the homochiral ones (RR:RR or SS:SS) with energy differences up to 17.5 kJ/mol. Besides, in larger clusters the presence of two adjacent homochiral molecules impose an energetic penalty when compared to alternated chiral systems (RR:SS:RR:SS...). The differences in interaction energy within the dimers of the different derivatives have been analyzed based on the atomic energy partition carried out within the atoms in molecules framework. The mechanism of proton transfer in the homo- and heterochiral dimers shows large transition-state barriers except in those cases in which a third additional molecule is involved in the transfer. The optical rotatory power of several clusters of the parent compound have been calculated and rationalized based on the number of homochiral interactions and the number of monomers of each enantiomer within the complexes.     

Mass spectrometric and quantum-chemical study on the structure, stability, and chirality of protonated serine dimers

Stability and structure of homo- and heterochiral protonated serine (Ser) dimers were investigated by a combination of mass spectrometry and ab initio quantum chemical calculations. This established that the energy difference between the most stable homo- and heterochiral forms is very small: tandem mass spectrometry with Cooks' kinetic method yielded a negligible difference in Gibbs free energy (0.2+/-0.2 kJ mol(-1)). The various isomeric forms of (Ser)2 H+ and their energetics were determined by extensive electronic-structure calculations, which yielded homo- and heterochiral forms of the isomers with distinctly different relative energies. The most stable homochiral isomer is stabilized by two hydrogen bonds and is far more stable than any other homochiral isomer. The most stable heterochiral isomer has completely different features, and it is characterized by a salt-bridge structure. This clearly shows that salt-bridge structures do exist in the gas phase even in comparatively small molecules and in the absence of particularly basic or acidic functional groups.     

Enantiomeric β-sheet peptides from Aβ form homochiral pleated β-sheets rather than heterochiral rippled β-sheets

In 1953, Pauling and Corey postulated “rippled” β-sheets, composed of a mixture of d- and l-peptide strands, as a hypothetical alternative to the now well-established structures of “pleated” β-sheets, which they proposed as a component of all-l-proteins. Growing interest in rippled β-sheets over the past decade has led to the development of mixtures of d- and l-peptides for biomedical applications, and a theory has emerged that mixtures of enantiomeric β-sheet peptides prefer to co-assemble in a heterochiral fashion to form rippled β-sheets. Intrigued by conflicting reports that enantiomeric β-sheet peptides prefer to self-assemble in a homochiral fashion to form pleated β-sheets, we set out address this controversy using two β-sheet peptides derived from Aβ_17–23 and Aβ_30–36, peptides 1a and 1b. Each of these peptides self-assembles to form tetramers comprising sandwiches of β-sheet dimers in aqueous solution. Through solution-phase NMR spectroscopy, we characterize the different species formed when peptides 1a and 1b are mixed with their respective d-enantiomers, peptides ent-1a and ent-1b. ¹H NMR, DOSY, and ¹H,¹⁵N-HSQC experiments reveal that mixing peptides 1a and ent-1a results in the predominant formation of homochiral tetramers, with a smaller fraction of a new heterochiral tetramer, and mixing peptides 1b and ent-1b does not result in any detectable heterochiral assembly. ¹⁵N-edited NOESY reveals that the heterochiral tetramer formed by peptides 1a and ent-1a is composed of two homochiral dimers. Collectively, these NMR studies of Aβ-derived peptides provide compelling evidence that enantiomeric β-sheet peptides prefer to self-assemble in a homochiral fashion in aqueous solution.

In aqueous solution, mixtures of l- and d- macrocyclic β-sheet peptides derived from Aβ self-assemble to form homochiral pleated β-sheets but do not co-assemble to form heterochiral rippled β-sheets.     

Self-discrimination of enantiomers in hydrogen-bonded dimers

The homochiral and heterochiral hydrogen-bonded (HB) dimers of a set of small model molecules (alpha-amino alcohols) have been studied by means of ab initio methods. The gas-phase calculations have been carried out with the hybrid HF/DFT B3LYP method and the 6-311++G** basis set. The electron density of the complexes has been analyzed using the atoms in molecules (AIM) methodology, which allows characterization of the HB interactions and additional intermolecular contacts. To take into account the water solvation effect, the polarized continuum model (PCM) method has been used to evaluate the Delta G(solv). The gas-phase results show that the heterochiral dimers are the most stable ones for each case studied, while in solution for several cases, the relative stability is reversed and the homochiral dimers become more stable. The AIM analysis shows the typical bond critical points characteristic of the HB and additional bond critical points denoting, in this case, destabilization of intermolecular interaction as CF(3)...F(3)C and CH(3)...H(3)C contacts.     

Simulated adsorption properties and synthesis prospects of homochiral porous solids based on their heterochiral analogs

Molecular simulations of chiral molecules in porous heterochiral materials were performed to investigate fundamental adsorption properties and possibilities for production of homochiral porous solids. Zeolite BEA polymorph A and zeotype UCSB-7K each provide separated pores of opposite chirality. Single enantiomer and racemic mixture adsorption results are presented and indicate that significant equilibrium enantiomeric excesses of 40-70% in UCSB-7K and 10% in BEA can be achieved. Larger, better-fitting molecules display higher enantiomeric excesses. For dimethylallene, which moves on molecular dynamics time scales in UCSB-7K, self-diffusivities vary by almost an order of magnitude between the two opposite-handed UCSB-7K pores for a given enantiomer. The predicted properties indicate that equilibrium and nonequilibrium strategies using related homochiral materials for separations may be successful. To this end, a discussion of strategies for selectively blocking pores of one chirality on the basis of enantiomer segregation is provided.     

Self-organization of lactates in the gas phase

Chiral recognition and subsequent selective self-organisation into hydrogen-bonded n-mers is observed in supersonic methyl lactate expansions. The nu(OH) and nu(C=O)-vibrations are investigated by ragout-jet FTIR-spectroscopy and lead to the assignment of homo- and heterochiral clusters of at least three different cluster sizes. Whereas homo- and heterochiral dimers are formed in similar amounts in the racemic mixture, prominent absorptions due to different homochiral and heterochiral lactate trimers and tetramers indicate highly specific chiral self-recognition beyond molecular pairs. Chemical modification of the ester-group (methyl-, ethyl- and isopropyl-lactate) and argon admixture to the helium expansion contribute importantly to an understanding of the cluster spectra and topology.     

Interstrand side chain--side chain interactions in a designed beta-hairpin: significance of both lateral and diagonal pairings

The contributions of interstrand side chain-side chain contacts to beta-sheet stability have been examined with an autonomously folding beta-hairpin model system. RYVEV(D)PGOKILQ-NH2 ((D)P = D-proline, O = ornithine) has previously been shown to adopt a beta-hairpin conformation in aqueous solution, with a two-residue loop at D-Pro-Gly. In the present study, side chains that display interstrand NOEs (Tyr-2, Lys-9, and Leu-11) are mutated to alanine or serine, and the conformational impact of the mutations is assessed. In the beta-hairpin conformation Tyr-2 and Leu-11 are directly across from one another (non-hydrogen bonded pair). This "lateral" juxtaposition of two hydrophobic side chains appears to contribute to beta-hairpin conformational stability, which is consistent with results from other beta-sheet model studies and with statistical analyses of interstrand residue contacts in protein crystal structures. Interaction between the side chains of Tyr-2 and Lys-9 also stabilizes the beta-hairpin conformation. Tyr-2/Lys-9 is a "diagonal" interstrand juxtaposition because these residues are not directly across from one another in terms of the hydrogen bonding registry between the strands. This diagonal interaction arises from the right-handed twist that is commonly observed among beta-sheets. Evidence of diagonal side chain-side chain contacts has been observed in other autonomously folding beta-sheet model systems, but we are not aware of other efforts to determine whether a diagonal interaction contributes to beta-sheet stability.     

Computational study of ground-state chiral induction in small peptides: comparison of the relative stability of selected amino acid dimers and oligomers in homochiral and heterochiral combinations

The relative stabilities of homochiral and heterochiral forms of selected dipeptides, AA, AS, AC, AV, AF, AD, AK, tripeptides, AAA, AVA, and an acetylpentapeptide, AcGLSFA, have been calculated using thermodynamic integration protocols and the GROMOS 53A6 force field. Integration pathways have been designed that produce minimal disturbance to the system, including the use of soft atoms, low-energy intermediates, and chiral inversion of the smaller amino acid in the peptide. Comparison of the results obtained by thermodynamic integration between the diastereomeric forms (in explicit water, at 300 K) and from exhaustive global minimum-energy searches for the individual dipeptides (implicit water, epsilon = 78, 0 K) suggests that entropic contributions to the relative stability of the chiral forms are important. This conclusion is supported by the results of explicit calculation of the effect of temperature on the relative stability of alanylvalylalanine diastereomers. The Gibbs free energy calculations predict that at ambient temperature and pressure homochiral dipeptides with small side chains or polar groups in the vicinity of the peptide backbone, AA, AS, and AD, are more stable than their heterochiral counterparts by fractions of a kJ/mol. For bigger side chains, AC, AV, AF, and AK, the heterochiral diastereomers appear to be more stable. Predicted relative stabilities are in line with observations reported in the literature for AE and YY. Excellent agreement is found for the calculated and experimentally determined relative stabilities of the diastereomers of the dipeptide AA and of all-L AcGLSFA and its diastereomer containing D-serine in the central position. Addition of counterions to the solvent box has no significant effects on charged and neutral forms. From the present findings it would appear unlikely that the intrinsic stability difference between homo- and heterochiral dipeptides has been a driving force in a primordial selection process leading to the incorporation of amino acids with a single enantiomeric configuration in natural proteins.     

Determination of the Dimerization Equilibrium Constants of Omeprazole and Pirkle's Alcohol through Optical‐Rotation Measurements

A new procedure to measure the equilibrium constants for the dimerization (homochiral and heterochiral) reactions of enantiomers in solution was applied to two different compounds, namely omeprazole and Pirkle's alcohol, both in CHCl₃. This procedure is based on the measurement of the optical rotation of the solution as a function of its composition, which exhibits a nonlinear dependence on the enantiomer enrichment. Such nonlinearity depends on the extent of dimerization, and it is a strong effect in the case of omeprazole, whose equilibrium constants are 14.0±3.5 l/mol and 25.2±4.0 l/mol for the formation of homochiral and of heterochiral dimers, respectively. Pirkle's alcohol exhibits a weaker effect that allows only to estimate the order of magnitude of these constants, i.e., ca. 0.10 and 0.34 l/mol, respectively.     

On the Role of Chirality in Guiding the Self‐Assembly of Peptides

Homochirality in peptides is crucial in sustaining “like–like” intermolecular interactions that allow the formation of assemblies and aggregates and is ultimately responsible for the resulting material properties. With the help of a series of stereoisomers of the tripeptide F–F–L, we demonstrate the critical role that peptide stereochemistry plays in the self‐assembly of peptides, guided by molecular recognition, and for self‐sorting. Homochiral self‐assemblies are thermally and mechanically more robust compared to heterochiral self‐assemblies. Morphological studies of the multicomponent peptide systems showed that aggregates formed from homochiral peptides possessed a uniform nano‐fibrous structure, whereas heterochiral systems resulted in self‐sorted systems with a heterogeneous morphology. In essence, homochiral peptides form the stronger aggregates, which may be one of reasons why homochirality is preferred in living systems.     

Chiral discrimination of a gemini-type surfactant with rigid spacer at the air-water interface

Spontaneous separation of chiral phases was observed in the monolayers of a racemate of gemini-type twin-tailed, twin-chiral amphiphiles, (2R,3R)-(+)-bis(decyloxy)succinic acid and (2S,3S)-(-)-bis(decyloxy)succinic acid. The pressure-area isotherms of the interfacial monolayers formed at the liquid-air interface, and the 2D lattice structures studied through surface probe measurements revealed that the racemate exhibits a homochiral discrimination of the enantiomers in two dimensions. An enantiomeric excess (e,e) of 20% was sufficient to break the chiral symmetry at the air-water interface for a homochiral interaction. Langmuir monolayers on ZnCl2 and CaCl2 subphases manifested chiral discrimination with Zn2+ evidencing homochiral interaction with a chelate-type complex, whereas Ca2+ resulted in a heterochiral interaction forming an ionic-type complex. For the chiral asymmetric units, oblique and rectangular unit cells of the racemic monolayer had exclusive requirements of homo- and heterochiral recognitions for Zn2+ and Ca2+ ions, respectively. Monolayers transferred from the condensed phase at 25 mN/m onto hydrophilic Si(100) and quartz substrates revealed the formation of bilayers through transfer-induced monolayer buckling. The emergence of homochiral discrimination was explained using the effective-pair-potential (EPP) approach.     

Mechanistic study of the Soai autocatalytic reaction informed by kinetic analysis

Detailed kinetic studies of the Soai reaction affirm the basic mechanistic picture previously developed in kinetic, spectroscopic and molecular modelling studies, and also suggest that refinements to the proposed elementary reaction steps must be considered. The alkanol reaction product is driven strongly and without bias towards the formation of homochiral and heterochiral dimers. The reaction is catalyzed by only the homochiral dimers. Consideration of the kinetic profiles from reactions carried out with different initial dialkylzinc concentrations support a proposal for a tetrameric transition state, but further experimental work is required to delineate the nature of this species. The power of reaction calorimetry as a kinetic tool for discerning subtle effects of the shape of the kinetic profile is highlighted. The importance of combining kinetic evidence with spectroscopic and other characterization tools is emphasized.     

Induction of a heterochiral helix through the covalent chiral domino effect originating in the "Schellman motif"

We report unique phenomena where the transition from a homochiral helix to a heterochiral helix occurs by increasing the chain length of the l-sequence. Peptides composed of the l-Leu sequences with different lengths and the achiral nona-sequence at the C-terminal side were used here. Conformation of their peptides in solution was investigated mainly by using CD analysis in various solvents, or additionally by IR and NMR. When the l-sequence has a sufficient length, a left-handed helicity was induced in the achiral sequence. Notably, the polymeric l-sequence produced a heterochiral helix that switches the helix sense around the boundary of the chiral/achiral sequence. Energy calculation demonstrated that a stable heterochiral helix favors a bending form, while a homochiral helix takes a relatively straight form. Such a bending form was suggested to be advantageous to solvent effects. The "Schellman motif" has been recognized as a local heterochiral structure in protein helices. We propose a nucleation model of a heterochiral helix through the covalent chiral domino effect derived from the Schellman motif. The present findings not only offer us novel design of a heterochiral helix but also support an elementary model for the origins of homochiral-heterochiral structures from primitive chiral/achiral sequences.     

Pairing of propellers: dimerization of octahedral ruthenium(II) and osmium(II) complexes of eilatin via pi-pi stacking featuring heterochiral recognition

Five octahedral eilatin complexes of the type [M(L-L)(2)(eilatin)](2+) (M = Ru, Os; L-L = bipyridyl-type ligands) were synthesized, and their dimerization via pi-pi stacking was studied by crystallography and (1)H NMR techniques. The X-ray structures of these racemic complexes were solved and revealed that the eilatin complexes are organized as discrete dimers in which the eilatin residues of each complex are stacked in centrosymmetric packing. Chemical shift dependence on concentration in the (1)H NMR spectra support fast dimer-monomer equilibrium, and the structures of the dimers in acetonitrile solution are proposed to be analogous to their solid-state structures. Dimerization constants in acetonitrile were measured for the five racemic eilatin complexes that exhibit different structural parameters, as well as for the two enantiomeric forms of one of these complexes. They were found to be independent of the metal (Ru vs Os), strongly dependent on the steric effects introduced by the L-L ligands (2,2'-bipyridine, 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, and 2,2'-biquinoline), and dependent on the optical purity of the complexes. A clear preference for heterochiral over homochiral dimer formation was demonstrated. This is the first report of chiral recognition in solution, exhibited by simple chemical systems held solely by pi-stacking interactions.     

Mechanism of the Asymmetric Autocatalytic Soai Reaction Studied by Density Functional Theory

The mechanism of the Soai reaction has been thoroughly investigated at the M05‐2X/6‐31G(d) level of theory, by considering ten energetically distinct paths. The study indicates the fully enantioselective catalytic cycle of the homochiral dimers to be the dominant mechanism. Two other catalytic cycles are shown to both be important for correct understanding of the Soai reaction. These are the catalytic cycle of the heterochiral dimer and the non‐enantioselective catalytic cycle of the homochiral dimers. The former has been proved to be not really competitive with the principal cycle, as required for the Soai reaction to manifest chiral amplification, whereas the latter, which is only slightly competitive with the principal one, nicely explains the experimental enantioselectivity observed in the reaction of 2‐methylpyrimidine‐5‐carbaldehyde. The study has also evidenced the inadequacy of the B3LYP functional for mechanistic investigations of the Soai reaction.