Control of peptide helix sense by temperature tuning of noncovalent chiral domino effect

We have investigated temperature effect on control of a peptide helix sense through the noncovalent chiral domino effect (NCDE: Inai, Y. et al., J. Am. Chem. Soc. 2003, 125, 8151-8162). Nonapeptide (1: Inai, Y.; Komori, H. Biomacromolecules 2004, 5, 1231-1240), which alone prefers a right-handed helix, maintained a screw-sense balance or a small imbalance at room temperature in the presence of Boc-d-amino acid. Cooling of the solution induced a left-handed helix more clearly. Conversely, heating from room temperature recovered the original right-handed sense. This helix-helix transition was essentially reversible in cooling-heating cycles. An increase in the Boc-d-amino acid concentration elevated temperature for switching CD signs based on the conformational transition. A similar thermal-driven inversion of helix sense was observed for 1 at other initial concentrations, suggesting that this behavior is insensitive to some peptide aggregation. NMR study provided direct evidence for the domino-type control of helix sense, in which Boc-Leu-OH is mainly located at the N-terminal segment. In addition, a left-handed helix induced by the d-isomer was shown to participate in equilibrium with a right-handed helix, whereas the right-handed helix was predominant in the presence of l-isomer. Consequently, we here have proposed a model for controlling a peptide helix sense (or its screw-sense bias) through temperature tuning of the external chiral interaction specific to the N-terminal sequence.     

Role reversal in a supramolecular assembly: a chiral cyanine dye controls the helicity of a peptide-nucleic acid duplex

A new dicarbocyanine dye bearing branched, chiral N-alkyl substituents was synthesized and its ability to form helical aggregates on peptide nucleic acid (PNA) double-helical templates was studied. The dye aggregates less effectively than an analogous dye bearing linear, achiral substituents, presumably due to steric problems with packing the branched substituents compared with the linear substituents. When the PNA duplex has a left-handed helicity, addition of the achiral dye leads to formation of a left-handed dye aggregate. However, when the chiral dye aggregates in the presence of this duplex, a right-handed structure is formed, suggesting that the dye alters the helicity of the underlying template. When a racemic PNA duplex (i.e., equal amounts of right- and left-handed helices) is used, no chirality is observed for the dye aggregate formed by the achiral dye but a right-handed helical aggregate is once again formed by the chiral dye. These results indicate that chirality is transferred from the dye to the PNA, as opposed to other examples of polymer-templated dye aggregation where chirality is transferred from the template to the dye.     

Mechanism for the noncovalent chiral domino effect: new paradigm for the chiral role of the N-terminal segment in a 3(10)-helix

Recently, novel chiral interactions on 3(10)-helical peptides, of which the helicity is controlled by external chiral stimulus operating on the N-terminus, were proposed as a "noncovalent chiral domino effect (NCDE)" (Inai, Y.; et al. J. Am. Chem. Soc. 2000, 122, 11731. Inai, Y.; et al. J. Am. Chem. Soc. 2002, 124, 2466). The present study clarifies the mechanism for generating the NCDE. For this purpose, achiral nonapeptide (1), H-beta-Ala-(Delta(Z)Phe-Aib)(4)-OMe [Delta(Z)Phe = (Z)-didehydrophenylalanine, Aib = alpha-aminoisobutyric acid], was synthesized. Peptide 1 alone adopts a 3(10)-helical conformation in chloroform. On the basis of the induced CD signals of peptide 1 with chiral additives, chiral acid enabling the predominant formation of a one-handed helix was shown to need at least both carboxyl and urethane groups; that is, Boc-l-amino acid (Boc = tert-butoxycarbonyl) strongly induces a right-handed helix. NMR studies (NH resonance variations, low-temperature measurement, and NOESY) were performed for a CDCl(3) solution of peptide 1 and chiral additive, supporting the view that the N-terminal H-beta-Ala-Delta(Z)Phe-Aib, including the two free amide NH's, captures effectively a Boc-amino acid molecule through three-point interactions. The H-beta-Ala's amino group binds to the carboxyl group to form a salt bridge, while the Aib(3) NH is hydrogen-bonded to either oxygen of the carboxylate group. Subsequently, the free Delta(Z)Phe(2) NH forms a hydrogen bond to the urethane carbonyl oxygen. A semiempirical molecular orbital computation explicitly demonstrated that the dynamic looping complexation is energetically permitted and that the N-terminal segment of a right-handed 3(10)-helix binds more favorably to a Boc-l-amino acid than to the corresponding d-species. In conclusion, the N-terminal segment of a 3(10)-helix, ubiquitous in natural proteins and peptides, possesses the potency of chiral recognition in the backbone itself, furthermore enabling the conversion of the terminally acquired chiral sign and power into a dynamic control of the original helicity and helical stability.     

Amplification of chirality of the majority-rules type in helical supramolecular polymers: the impact of the presence of achiral monomers

We present a theoretical treatment describing the conformational state of helical supramolecular polymers that consist of three types of monomer: right-handed and left-handed chiral monomers and achiral ones. We find that chirality amplification of the majority-rules type, that is, a disproportionately large shift in the helix screw sense due to a small enantiomeric excess, can occur in these polymers. The strength of the chirality amplification depends on the free-energy penalty of a helix reversal along the self-assembled chain and on that of a mismatch between the conformation of a bond and the preferred conformation of the preceding monomer. It turns out that the impact of achiral monomers also depends on these two parameters. For high values of these free energies, the net helicity does not change much from the situation where no achiral material is present. However, if the free-energy penalties are not both large, the impact of the achiral monomers on the conformational state of the aggregates can be quite substantial.     

Control of helix sense in protein-mimicking backbone by the noncovalent chiral effect

We have reviewed our previous work regarding induction or control of a peptide helix sense through chiral stimulus to the peptide chain terminus. An optically inactive 3(10)-helix designed mainly with unusual alpha-amino acid residues was commonly employed. Such an N-terminal-free peptide generates a preferred helix sense by chiral acid molecule. A helix sense pre-directed in chiral sequence is also influenced or controlled by the chiral sign of such external molecule. Here free amide groups in the 3(10)-helical N-terminus participate in the formation of a multipoint coordinated complex. The terminal asymmetry produces the noncovalent chiral domino effect (NCDE) to influence the whole helix sense. The NCDE-mediated control of helicity provides the underlying chiral nature of protein-mimicking helical backbones: notably, chiral recognition at the terminus and modulation of helical propensity through chiral stimulus. The above items from our previous reports have been outlined and reviewed together with their significance in biopolymer science and chiral chemistry.     

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.     

Chiral induction in quinoline-derived oligoamide foldamers: assignment of helical handedness and role of steric effects

Chiral groups attached to the end of quinoline-derived oligoamide foldamers give rise to chiral helical induction in solution. Using various chiral groups, diastereomeric excesses ranging from 9% to 83% could be measured by NMR and circular dichroism. Despite these relatively weak values and the fact that diastereomeric helices coexist and interconvert in solution, the right-handed or left-handed helical sense favored by the terminal chiral group could be determined unambiguously using X-ray crystallography. Assignment of chiral induction was performed in an original way using the strong tendency of racemates to cocrystallize, and taking advantage of slow helix inversion rates, which allowed one to establish that the stereomers observed in the crystals do correspond to the major stereomers in solution. The sense of chiral helical induction was rationalized on the basis of sterics. Upon assigning an Rs or Ss chirality to the stereogenic center using a nomenclature where the four substituents are ranked according to decreasing sizes, it is observed that Rs chirality always favors left-handed helicity and Ss chirality favors right-handed helicity (P). X-ray structures shed some light on the role of sterics in the mechanism of chiral induction. The preferred conformation at the stereocenter is apparently one where the bulkiest group should preferentially point away from the helix, the second largest group should be aligned with the helix backbone, and the smallest should point to the helix.     

Controllable growth of one-dimensional chiral nanostructures from an achiral molecule

One achiral molecule of thioxanthone-anthracene (TX-A) is able to self-assemble into chiral nanowires by tuning the solvent with different polarity. Left- and right-handed nanowires with helix structure can be produced from chloroform and acetic ester solution of TX-A respectively. The SEM and TEM images confirm the formation of the helical nanowires. The results indicate that the solvent polarity has great influence in controlling of the self-assembly of organic molecules. The growth process demonstrates a promising pathway to investigate the self-assembling from achiral organic molecules to chiral aggregations.     

Solvent polarity driven helicity inversion and circularly polarized luminescence in chiral aggregation induced emission fluorophores

Development of functional materials capable of exhibiting chirality tunable circularly polarized luminescence (CPL) is currently in high demand for potential technological applications. Herein we demonstrate the formation of both left- and right-handed fluorescent helical superstructures from each enantiomer of a chiral tetraphenylethylene derivative through judicious choice of the solution processing conditions. Interestingly, both the aggregation induced emission active enantiomers exhibit handedness inversion of their supramolecular helical assemblies just by varying the solution polarity without any change in their molecular chirality. The resulting helical supramolecular aggregates from each enantiomer are capable of emitting circularly polarized light, thus enabling both right- and left-handed CPL from a single chiral material. The left- and right-handed supramolecular helical aggregates in the dried films have been characterized using spectroscopy, scanning electron microscopy, and transmission electron microscopy techniques. These new chiral aggregation induced emission compounds could find applications in devices where CPL of opposite handedness is required from the same material and would facilitate our understanding of the formation of helical assemblies with switchable supramolecular chirality.

The formation of both left- and right-handed helical superstructures with circularly polarized luminescence has been achieved in a chiral tetraphenylethylene derivative just by varying the solution polarity without any change in molecular chirality.     

Supramolecular chirogenesis in zinc porphyrins: mechanism, role of guest structure, and application for the absolute configuration determination.

The achiral syn folded (face-to-face conformation) host molecule of the ethane-bridged bis(zinc porphyrin) transforms into the corresponding chiral extended anti bis-ligated species in the presence of enantiopure amine guests. The mechanism of the supramolecular chirogenesis is based upon the screw formation in bis(zinc porphyrin), arising from steric interactions between the largest substituent at the ligand's asymmetric carbon and peripheral alkyl groups of the neighboring porphyrin ring pointing toward the covalent bridge. The screw direction is determined by the guest's (amines) absolute configuration resulting in a positive chirality induced by (S)-enantiomers due to formation of the right-handed screw, and a negative chirality produced by the left-handed screw of (R)-enantiomers. The screw magnitude is strongly dependent upon the structure of the chiral guests. The amines with bulkier substituents result in stronger CD signals and larger (1)H NMR resonance splittings of enantiotopic protons. This system possesses a high degree of chiroptical activity, which allows the differentiation of one of the smallest homologous elements of organic chemistry, that is, the methyl and ethyl groups attached to the asymmetric carbon, and additionally, which senses a remote chiral center at a position beta to the amine binding group.     

A Single-Enantiomer Emitter Enabled Superstructural Helix Inversion for Upconverting and Downshifting Luminescence with Bidirectional Circular Polarization

The helical twisting tendency of liquid crystals (LCs) is generally governed by the inherent configuration of the chiral emitter. Here, we introduce the multistage inversion of supramolecular chirality as well as circularly polarized luminescence (CPL) by manipulating the ratio of single enantiomeric emitters (R-PCP) to LC monomers (5CB). Increasing the content of R-PCP from 1 wt % to 3 wt % inverted the helix of LCs from left-handed to right-handed, accompanying a CPL sign changed from positive to negative. The biaxiality of chiral emitters, as well as the steric effect of chiral-chiral and chiral-achiral interaction, were identified as the reasons for helical sense inversion. Due to the strong helical twisting power, 4 wt % R-PCP drove the photonic band gap (PBG) of chiral LCs to match up with their emission range, leading to an inversion of the CPL again with a high dissymmetry factor (≈1.2). Directly adjusting the PBG using chiral emitters is seldom achieved in cholesteric LCs. On this basis, an achiral sensitizer PtTPBP was assembled into the helical superstructure. The generation of triplet-triplet annihilation-induced upconverted CPL from R-PCP and the downshifting CPL from PtTPBP with opposite rotation was achieved in a single chiral LC system by tuning the position of the PBG.     

Foldamer‐Mediated Remote Stereocontrol: >1,60 Asymmetric Induction

An N‐terminal L ‐α‐methylvaline dimer induces complete conformational control over the screw sense of an otherwise achiral helical peptide foldamer formed from the achiral quaternary amino acids Aib and Ac₆c. The persistent right‐handed screw‐sense preference of the helix enables remote reactive sites to fall under the influence of the terminal chiral residues, and permits diastereoselective reactions such as alkene hydrogenation or iminium ion addition to take place with 1,16‐, 1,31‐, 1,46‐ and even 1,61‐asymmetric induction. Stereochemical information may be communicated in this way over distances of up to 4 nm.     

Synthesis of complementary double-stranded helical oligomers through chiral and achiral amidinium-carboxylate salt bridges and chiral amplification in their double-helix formation

A series of complementary molecular strands from 2-mer to 5-mer that are composed of m-terphenyl units bearing chiral/achiral amidine or achiral carboxyl groups linked via Pt(II) acetylide complexes were synthesized by sequential stepwise reactions, and their chiroptical properties on the double-helix formation were investigated by circular dichroism (CD) and (1)H NMR spectroscopies. In CHCl(3), the "all-chiral" amidine strands consisting of (R)- or (S)-amidine units formed preferred-handed double helices with the complementary achiral carboxylic acid strands through the amidinium-carboxylate salt bridges, resulting in characteristic induced CDs in the Pt(II) acetylide complex regions, indicating that the chiral substituents on the amidine units biased a helical sense preference. The Cotton effect patterns and intensities were highly dependent on the molecular lengths. The complementary double-helix formation was also explored using the chiral/achiral amidine strands with different sequences in which a chiral amidine unit was introduced at the center (center-chiral) or a terminus (edge-chiral) of the amidine strands. The effect of the sequences of the chiral and achiral amidine units on the amplification of chirality (the "sergeants and soldiers" effect) in the double-helix formation was investigated by comparing the CD intensities with those of the corresponding all-chiral amidine double helices with the same molecular lengths. Variable-temperature CD experiments of the all-chiral and chiral/achiral amidine duplexes demonstrated that the Pt(II)-linked complementary duplexes are dynamic and their chiroptical properties including the chirality transfer from the chiral amidine unit to the achiral amidine ones are significantly affected by the molecular lengths, sequences, and temperatures. On the basis of the above results together with molecular dynamics simulation results, key structural features of the Pt(II)-linked oligomer duplexes and the effect of the chiral/achiral amidine sequences on the amplification of chirality are discussed.     

Chirality control in optically active polysilane aggregates

A novel strategy for controlling the higher order chirality of aggregates prepared from enantiopure polysilanes is experimentally probed and discussed. Structurally similar poly[n-alkyl(aryl)]silanes were synthesized in which one side chain comprised the chiral (S)-2-methylbutyl group and the other an achiral m- or p-alkyl-substituted phenyl ring. In solution the polymers adopt helical conformations with the same induced preferential screw sense chirality, as evidenced by circular dichroism (CD) spectroscopy. Aggregates, however, formed by addition of a nonsolvent to a polymer solution, show oppositely signed CD spectra. Consistent results were obtained for another series of poly[p-n-alkyl(aryl)]silanes where alkyl is butyl, propyl, and ethyl. The sense of the aggregate higher order chirality is dependent on the chemical composition and environment and is coarse-tunable by adjusting the length of the achiral side chain and fine-tunable by adjusting the good/poor solvent ratio. The origin of these effects is discussed with reference to a simple model.     

Quantified chirality, molecular similarity, and helical twisting power in lyotropic chiral nematic guest/host systems

Lyotropic liquid crystals can exhibit phase chirality. The mechanism behind the transfer of chirality between a chiral dopant and a liquid crystalline host phase is still under discussion. Our own recent results and proposals are the following. Lyotropic phase chirality can exist even at very low concentrations of chiral dopants, with less than 1 chiral dopant per 50 micelles. There is evidence for an intramicellar double twist which could be due to the induction of chiral conformations in the achiral surfactant chains. The chirality of arbitrary molecules can be quantified by means of the 'Hausdorff distance'. Increasing chirality of a dopant does not necessarily imply increasing helical twisting power, and molecular similarity between chiral guest and achiral host is essential for effective chirality transfer.     

Helix-sense-selective polymerization of phenylacetylene having two hydroxy groups using a chiral catalytic system

We have found a simple and novel synthetic method for obtaining a chiral polymer from an achiral monomer by using a chiral catalytic system. The chirality of the polymer was caused only by a one-handed helical backbone, and the polymer had no other chiral structures in the side groups. In addition, the helical conformation was stable in solution by itself. This is the first example of helix-sense-selective polymerization of a substituted acetylene. The stability of the helicity was found to be caused by intramolecular hydrogen bonds.     

Spontaneous resolution of chiral polyoxometalate-based compounds consisting of 3D chiral inorganic skeletons assembled from different helical units

Four enantiomerically pure 3D chiral POM-based compounds, [Ni(2)(bbi)(2)(H(2)O)(4)V(4)O(12)]2 H(2)O (1 a and 1 b) and [Co(bbi)(H(2)O)V(2)O(6)] (2 a and 2 b) (bbi=1,1'-(1,4-butanediyl)bisimidazole) based on the achiral ligand, different vanadate chains, and different metal centers have been synthesized by hydrothermal methods. Single-crystal X-ray diffraction analyses revealed that 1 a and 1 b, and 2 a and 2 b, respectively, are enantiomers. In 1 a and 1 b two kinds of vanadate chains with different screw axes link Ni cations to generate 3D chiral inorganic skeletons, which are connected by the achiral bbi ligands to form complicated 3D 3,4-connected chiral self-penetrating frameworks with (7(2)8)(7(2)8(2)9(2))(7(3)8(2)10) topology. They represent the first examples of chiral self-penetrating frameworks known for polyoxometalate (POM) systems. Contrary to 1 a and 1 b, in 2 a and 2 b the vanadate chains link Co(II) cations to generate 3D chiral inorganic skeletons, which are assembled from two kinds of heterometallic helical units of opposite chirality along the c axes. The chiral inorganic skeletons are connected by bbi to form 3D 3,4-connected chiral POM-based frameworks with (6(2)8)(2)(6(2)8(2)10(2)) topology. It is believed that the asymmetrical coordination modes of the metal cations in 1 a-2 b generate the initial chiral centers, and that the formation of the various helical units and the hydrogen bond interactions are responsible for preservation of the chirality and spontaneous resolution when the chirality is extended into the homochiral 3D-networks. This is the first known report of chiral POM-based compounds consisting of 3D chiral inorganic skeletons being obtained by spontaneous resolution upon crystallization in the absence of any chiral source, which may provide a rational strategy for synthesis of chiral POM-based compounds by using achiral ligands and POM helical units.     

乙烯基二联苯单体的螺旋选择性自由基聚合

为了深入理解乙烯基二联苯单体自由基聚合过程中的手性传递,进行了手性单体(+)-2-[(S)-异丁氧羰基-5-(4′-己氧基苯基)苯乙烯、非手性单体2-丁氧羰基-5-(4′-己氧基苯基)苯乙烯的均聚反应及它们二者的共聚反应,探讨了聚合温度和溶剂性质对手性单体均聚物旋光活性、手性单体含量对共聚物旋光活性以及聚合反应溶剂的超分子手性对共聚物旋光活性的影响.研究发现,降低聚合温度、采用液晶性反应介质有利于得到旋光度大的聚合物;少量手性单体的引入即可诱导共聚物形成某一方向占优的螺旋构象,比旋光度随手性单体的含量增加呈线性增长;在胆甾相液晶中制备的非手性单体聚合物不具有光学活性.这些结果表明,该类乙烯基二联苯聚合物具有动态螺旋构象,其光学活性主要依赖于主链的立构规整度和侧基不对称原子的手性.     

Probing the role of the C-H...O hydrogen bond stabilized polypeptide chain reversal at the C-terminus of designed peptide helices. Structural characterization of three decapeptides

The structural characterization in crystals of three designed decapeptides containing a double d-segment at the C-terminus is described. The crystal structures of the peptides Boc-Leu-Aib-Val-Xxx-Leu-Aib-Val-(D)Ala-(D)Leu-Aib-OMe, (Xxx = Gly 2, (D)Ala 3, Aib 4) have been determined and compared with those reported earlier for peptide 1 (Xxx = Ala) and the all l analogue Boc-Leu-Aib-Val-Ala-Leu-Aib-Val-Ala-Leu-Aib-OMe, which yielded a perfect right-handed alpha-helical structure. Peptides 1 and 2 reveal a right-handed helical segment spanning residues 1 to 7, ending in a Schellman motif with (D)Ala(8) functioning as the terminating residue. Polypeptide chain reversal occurs at residue 9, a novel feature that appears to be the consequence of a C-H.O hydrogen bond between residue 4 C(alpha)H and residue 9 CO groups. The structures of peptides 3 and 4, which lack the pro R hydrogen at the C(alpha) atom of residue 4, are dramatically different. Peptide 3 adopts a right-handed helical conformation over the 1 to 7 segment. Residues 8 and 9 adopt alpha(L) conformations forming a C-terminus type I' beta-turn, corresponding to an incipient left-handed twist of the polypeptide chain. In peptide 4, helix termination occurs at Aib(6), with residues 6 to 9 forming a left-handed helix, resulting in a structure that accommodates direct fusion of two helical segments of opposite twist. Peptides 3 and 4 provide examples of chiral residues occurring in the less favored sense of helical twist; (D)Ala(4) in peptide 3 adopts an alpha(R) conformation, while (L)Val(7) in 4 adopts an alpha(L) conformation. The structural comparison of the decapeptides reported here provides evidence for the role of specific C-H.O hydrogen bonds in stabilizing chain reversals at helix termini, which may be relevant in aligning contiguous helical and strand segments in polypeptide structures.     

Fabrication of chiral Langmuir-Schaefer films of achiral amphiphilic Schiff base derivatives through an interfacial organization

Supramolecular chirality in the Langmuir-Schaefer (LS) films of two achiral amphiphilic Schiff bases, 2-(2'-benzimidazolyliminomethyl)-4-octadecyloxyphenol (BSC18) and 2-(2'-benzthiazolyliminomethyl)-4-octadecyloxyphenol (TSC18), was investigated. Both of these amphiphiles could form LS films from the water surface or coordinate with Ag(I) in the subphase to form Ag(I)-coordinated LS films. Although both of these amphiphiles were achiral, TSC18 formed a chiral LS film from the water surface, while BSC18 formed a chiral Ag(I)-coordinated LS film from the aqueous AgNO3 subphase. The supramolecular chirality in these LS films was suggested to be due to a cooperative stereoregular pi-pi stacking of the functional groups together with the long alkyl chains in a helical sense. The relationship between the chirality of the LS films and the molecular structures of TSC18 and BSC18 as well as their H-bond or coordination behaviors was discussed. The Schiff base films showed a reversible color change upon exposure to HCl and NH3 gas alternatively; however, the supramolecular chirality was irreversible during these processes.