Redox-triggered Reversible Switching between Dynamic and Quasi-static α-Helical Peptides.

We report the reversible transformation between a singly stapled dynamic α-helical peptide and a doubly stapled quasi-static one through redox-triggered dithiol/disulfide conversions of a stapling moiety. This process allows the rate of interconversion between the right-handed (P) and left-handed (M) α-helices to be altered by a factor of approximately 103 before and after the transformation. An as-obtained doubly stapled α-helical peptide, which is composed of an achiral peptide having an L-valine carboxylic acid residue at the C-terminus, a disulfide-based reversible staple, and a biphenyl-based fixed staple, adopts an (M)-rich form as a kinetically trapped state. The (M)-rich helix was subsequently transformed into the thermodynamically stable (P)-rich form in 1,1,2,2-tetrachloroethane with the half-life time (t1/2) of approximately 44 days at 25 ºC. Reduction of the doubly stapled peptide with tri-n-butylphosphine in tetrahydrofuran/water (10/1, v/v) produced the corresponding singly stapled dynamic α-helical peptide bearing two thiol groups at the side chains, which underwent solvent-induced reversible helicity inversion. The resulting dithiol of the singly stapled peptide could be reoxidized to form the original doubly stapled form using 4,4'-dithiodipyridine. Furthermore, the P/M interconversion of a doubly stapled peptide with two flexible hydrocarbon-based staples is considerably more rapid than that with more rigid staples.

Separation of enantiomers of chiral fullerene derivatives through enantioselective encapsulation within an adaptable helical cavity of syndiotactic poly(methyl methacrylate) with helicity memory.

Optically active left (M)- and right (P)-handed helical syndiotactic poly(methyl methacrylate)s (M- and P-st-PMMAs) with a helicity memory enantioselectively encapsulated the racemic C60 derivatives, such as 3,4-fulleroproline tert-butyl ester (rac-1) and tetraallylated C60 (rac-2), as well as the C60-bound racemic 310-helical peptides (rac-3) within their helical cavities to form peapod-like inclusion complexes and a unique "helix-in-helix" superstructure, respectively. The enantiomeric excess (ee) and separation factor (enantioselectivity) (α) of the analyte 1 (ee = 23%-25% and α = 2.35-2.50) encapsulated within the helical cavities of the M- and P-st-PMMAs were higher than those of the analytes 2 and 3 (ee = 4.3%-6.0% and α = 1.28-1.50). The optically pure (S)- and (R)-1 were found to more efficiently induce an excess one-handed helical conformation in the st-PMMA backbone than the optically pure (S)- and (R)-1-phenylethylamine, resulting in intense mirror-image vibrational circular dichroism (VCD) spectra in the PMMA IR regions. The excess one-handed helices induced in the st-PMMAs complexed with (S)- and (R)-1 were memorized after replacement with the achiral C60, and the complexes exhibited induced electric CDs in the achiral C60 chromophore regions.

Stapling strategy for slowing helicity interconversion of α-helical peptides and isolating chiral auxiliary-free one-handed forms.

In nature, α-helical peptides adopt right-handed conformations that are dictated by L-amino acids. Isolating one-handed α-helical peptides composed of only achiral components remains a significant challenge. Here, this goal is achieved by optical resolution of the corresponding racemic (quasi-)static α-helical peptide with double stapling, which effectively freezes the interconversion between the right-handed (P)- and left-handed (M)-α-helices. An as-obtained doubly stapled analogue having an unprotected L-valine residue at the C-terminus transforms from a kinetically trapped (M)-α-helix to a thermodynamically stable (P)-α-helix upon heating. In contrast, the corresponding singly stapled α-helical peptide undergoes an acid/base-triggered and solvent-induced reversible inversion of its preferred helicity within minutes. The interconversion rates of the singly and doubly stapled α-helical peptide foldamers are approximately 106 and 1012 times slower, respectively, than that of a non-stapled dynamic helical peptide. Therefore, the enantiopure doubly-stapled (quasi-)static α-helical peptide would retain its optical activity for several years at 25 °C.

Supramolecular Helical Assemblies of Dirhodium(II) Paddlewheels with 1,4-Diazabicyclo[2.2.2]octane: A Remarkable Substituent Effect on the Helical Sense Preference and Amplification of the Helical Handedness Excess of Metallo-Supramolecular Helical Polymers.

We report unique coordination-driven supramolecular helical assemblies of a series of dirhodium(II) tetracarboxylate paddlewheels bearing chiral phenyl- or methyl-substituted amide-bound m-terphenyl residues with triethylene glycol monomethyl ether (TEG) or n-dodecyl tails through a 1:1 complexation with 1,4-diazabicyclo[2.2.2]octane (DABCO). The chiral dirhodium complexes with DABCO in CHCl3/n-hexane (1:1) form one-handed helical coordination polymers with a controlled propeller chirality at the m-terphenyl groups, which are stabilized by intermolecular hydrogen-bonding networks between the adjacent amide groups at the periphery mainly via a cooperative nucleation-elongation mechanism as supported by circular dichroism (CD), vibrational CD, and variable-temperature (VT) absorption and CD analyses. The VT visible-absorption titrations revealed the temperature-dependent changes in the degree of polymerization. The columnar supramolecular helical structures were elucidated by X-ray diffraction and atomic force microscopy. The helix sense of the homopolymer carrying the bulky phenyl and n-dodecyl substituents is opposite those of other chiral homopolymers despite having the same absolute configuration at the pendants. A remarkably strong "sergeants and soldiers" (S&S) effect was observed in most of the chiral/achiral copolymers, while the copolymers of the bulky chiral phenyl-substituted dirhodium complexes with n-dodecyl chains displayed an "abnormal" S&S effect accompanied by an inversion of the helix sense, which could be switched to a "normal" S&S effect by changing the solvent composition. A nonracemic dirhodium complex of 20% enantiomeric excess bearing the less bulky chiral methyl substituents with n-dodecyl chains assembled with DABCO to form an almost one-handed helix (the "majority rule" (MR) effect), whereas the three other nonracemic copolymers showed a weak MR effect.

Encapsulation of Aromatic Guests in the Bisporphyrin Cavity of a Double-Stranded Spiroborate Helicate: Thermodynamic and Kinetic Studies and the Encapsulation Mechanism.

A double-stranded spiroborate helicate bearing a bisporphyrin unit in the middle forms an inclusion complex with electron-deficient aromatic guests that are sandwiched between the porphyrins. In the present study, we systematically investigated the effects of size, electron density, and substituents of a series of aromatic guests on inclusion complex formations within the bisporphyrin. The thermodynamic and kinetic behaviors during the guest-encapsulation process were also investigated in detail. The guest-encapsulation abilities in the helicate increased with the increasing core sizes of the electron-deficient aromatic guests and decreased with the increasing bulkiness and number of substituents of the guests. Among the naphthalenediimide derivatives, those with bulky N-substituents at both ends hardly formed an inclusion complex. Instead, they formed a [2]rotaxane-like inclusion complex through the water-mediated dynamic B-O bond cleavage/reformation of the spiroborate groups of the helicate, which enhanced the conformational flexibility of the helicate to enlarge the bisporphyrin cavity and form an inclusion complex. Based on the X-ray crystal structure of a unique pacman-like 1:1 inclusion complex between the helicate and an ammonium cation as well as the molecular dynamics simulation results, a plausible mechanism for the inclusion of a planar aromatic guest within the helicate is also proposed.

Water-Mediated Reversible Control of Three-State Double-Stranded Titanium(IV) Helicates.

A stimuli-responsible reversible structural transformation is of key importance in biological systems. We now report a unique water-mediated reversible transformation among three discrete double-stranded dinuclear titanium(IV) achiral meso- and chiral rac-helicates linked by a mono(µ-oxo) or a bis(µ-hydroxo) bridge between the titanium ions through hydration/dehydration or its combination with a water-mediated dynamic cleavage/re-formation of the titanium-phenoxide (Ti-OPh) bonds. The bis(µ-hydroxo) bridged titanium(IV) meso-helicate prepared from two tetraphenol strands with titanium(IV) oxide was readily dehydrated in CD3CN containing a small amount of water upon heating, accompanied by Ti-OPh bond cleavage/re-formation catalyzed by water, resulting in the formation of the mono(µ-oxo)-bridged rac-helicate, which reverted back to the original bis(µ-hydroxo)-bridged meso-helicate upon hydration in aqueous CD3CN. These reversible transformations between the meso- and rac-helicates were also promoted in the presence of a catalytic amount of an acid, which remarkably accelerated the reactions at lower temperature. Interestingly, in anhydrous CD3CN, the bis(µ-hydroxo)-bridged meso-helicate was further slowly converted to a different helicate, while its meso-helicate framework was maintained, namely the mono(µ-oxo)-bridged meso-helicate, through dehydration upon heating and its meso to meso transformation was significantly accelerated in the presence of cryptand[2.2.1], which contributes to removing Na+ ions coordinated to the helicate. Upon cooling, the backward meso to meso transformation took place via hydration. Hence, three different, discrete double-stranded chiral rac- and achiral meso-titanium(IV) helicates linked by a mono(µ-oxo) or a bis(µ-hydroxo) bridge were successfully generated in a controllable manner by a change in the water content of the reaction media.

Helix-Sense-Selective Encapsulation of Helical Poly(lactic acid)s within a Helical Cavity of Syndiotactic Poly(methyl methacrylate) with Helicity Memory.

We report a highly enantio- and helix-sense-selective encapsulation of helical poly(lactic acid)s (PLAs) through a unique "helix-in-helix" superstructure formation within the helical cavity of syndiotactic poly(methyl methacrylate) (st-PMMA) with a one-handed helicity memory, which enables the separation of the enantiomeric helices of the left (M)- and right (P)-handed-PLAs. The M- and P-helical PLAs with different molar masses and a narrow molar mass distribution were prepared by the ring-opening living polymerization of the optically pure l- and d-lactides, respectively, followed by end-capping of the terminal residues of the PLAs with a 4-halobenzoate and then a C60 unit, giving the C60-free and C60-bound M- and P-PLAs. The C60-free and C60-bound M- and P-PLAs formed crystalline inclusion complexes with achiral st-PMMA accompanied by a preferred-handed helix induction in the st-PMMA backbone, thereby producing helix-in-helix superstructures with the same-handedness to each other. The induced helical st-PMMAs were retained after replacement with the achiral C60, indicating the memory of the induced helicity of the st-PMMAs. Both the C60-free and C60-bound helical PLAs were enantio- and helix-sense selectively encapsulated into the helical hollow space of the optically active M- and P-st-PMMAs with the helicity memory prepared using chiral amines. The M- and P-PLAs are preferentially encapsulated within the M- and P-st-PMMA helical cavity with the same-handedness to each other, respectively, independent of the terminal units. The C60-bound PLAs were more efficiently and enantioselectively trapped in the st-PMMA compared to the C60-free PLAs. The enantioselectivities were highly dependent on the molar mass of the C60-bound and C60-free PLAs and significantly increased as the molar mass of the PLAs increased.

Remote-controlled regio- and diastereodifferentiating photodimerization of a dynamic helical peptide-bound 2-substituted anthracene.

Photodimerization of a novel 2-substituted anthracene linked to a right-handed 310-helical nonapeptide induced by long-range chiral information transfer from the remote chiral l-Val residue through a chiral domino effect proceeded in a highly regio- and diastereo-differentiating manner to produce the chiral head-to-head anti-photodimer in 90% relative yield with up to 97% diastereomeric excess.

Enantiodifferentiating Photodimerization of a 2,6-Disubstituted Anthracene Assisted by Supramolecular Double-Helix Formation with Chiral Amines.

A novel 2,6-anthrylene-linked bis(m-terphenylcarboxylic acid) strand (1) self-associates into a racemic double-helix. In the presence of chiral mono- and diamines, either a right- or left-handed double-helix was predominantly induced by chiral amines sandwiched between the carboxylic acid strands with accompanying stacking of the two prochiral anthracene linker units in an enantiotopic face-selective way, as revealed by circular dichroism and NMR spectral analyses. The photoirradiation of the optically active double helices complexed with chiral amines proceeded in a diastereo- (anti or syn) and enantiodifferentiating way to afford the chiral anti-photodimer with up to 98 % enantiomeric excess when (R)-phenylethylamine was used as a chiral double-helix inducer. The resulting optically active anti-photodimer can recognize the chirality of amines and diastereoselectively complex with chiral amines.

Complementary double-stranded helical oligomers bearing achiral bifunctional groups that catalyze asymmetric aldol reaction.

Two novel chiral dimer and trimer strands composed of m-terphenyl groups linked through p-diethynylbenzene units with the chiral amidine group and achiral piperazine group introduced at the terminus or center of the strands, respectively, and its complementary achiral carboxylic acid dimer and trimer were synthesized. The complementary chiral/achiral strands form an excess-handed double-helical structure as supported by intense split-type Cotton effects in the absorption regions of the conjugated backbones biased by the chiral amidinium-carboxylate salt bridges. The double-helical trimer was found to catalyze the direct aldol reaction of cyclohexanone with 4-nitrobenzaldehyde and produce the products with a moderate enantioselectivity despite the fact that the catalytically active bifunctional piperazine/carboxylic acid pair introduced in the middle is achiral, indicating the key role of the one-handed double-helical framework for supramolecular bifunctional organocatalysis.

Fluorescent molecular spring that visualizes the extension and contraction motions of a double-stranded helicate bearing terminal pyrene units triggered by release and binding of alkali metal ions.

A novel double-stranded spiroborate helicate bearing terminal pyrene residues exhibited reversible fluorescence color changes (green and blue colors) due to the unique unidirectional springlike motions of the helicate triggered by catch and release of alkali metal ions.

Water-mediated deracemization of a bisporphyrin helicate assisted by diastereoselective encapsulation of chiral guests.

Deracemization is a powerful method by which a racemic mixture can be transformed into an excess of one enantiomer with the aid of chiral auxiliaries, but has been applied only to small chiral molecular systems. Here we report a deracemization of a racemic double-stranded spiroborate helicate containing a bisporphyrin unit upon encapsulation of chiral aromatic guests between the bisporphyrin. The chiral guest-included helicate is kinetically stable, existing as a mixture of right- and left-handed double helices, which eventually undergo an inversion of the helicity triggered by water resulting from the water-mediated reversible diastereoselective B-O bond cleavage/reformation of the spiroborate groups, thus producing an optically-active helicate with a high enantioselectivity. Quantum chemical calculations suggest that the stereospecific CH-π interactions between the porphyrin hydrogen atoms of the helicate and an aromatic pendant group of the chiral guest play a key role in the enhancement of the helical handedness of the helicate.

Spiroborate-Based Double-Stranded Helicates: Meso-to- Racemo Isomerization and Ion-Triggered Springlike Motion of the Racemo-Helicate.

A one-handed double-stranded spiroborate helicate exhibits a unique reversible extension-contraction motion coupled with a twisting motion in one direction triggered by binding and release of a Na+ ion while retaining its handedness. Here we report that an extended meso-helicate was also produced together with the racemo-helicate, and the meso-helicate was readily converted to the racemo-helicate assisted by a Na+ ion as a template in the presence of water. The thermodynamic analyses of the ion-triggered springlike motion of the racemo-helicate using a series of monovalent cations with different sizes revealed that the association constants of the extended racemo-helicate decreased in the following order: Li+ > Na+ > NH4+ > Ag+ ≥ K+ > Cs+ > Rb+, which roughly agrees with the reverse order of their ionic radii except for the NH4+ ion due to the more elongated contracted helicates when complexed with larger cations as supported by the crystal and DFT calculated structures. The one-handed contracted helicates showed characteristic CD spectra depending on the cation species due to the differences in their contracted helical structures, and its absolute handedness of the spiroborate helicate was determined by X-ray crystallography. The kinetic studies of the springlike motions of the racemo-helicate showed that the exchange rate between the extended and contracted helicates tend to increase in the following order: Li+ < Na+ < K+ ≤ NH4+ < Rb+ < Cs+ < Ag+ as anticipated from the association constants, being in good agreement with the order of the cation sizes except for Ag+.

Tug-of-War in a Dynamic Helical Peptide: Solvent-Induced Helix-Helix Transition of a Lactam-Bridged Peptide Composed of Point- and Axial Chiralities Remote from Each Other.

The dynamic axial chirality of oligopeptide-bound 2,2'-bipyridine (bpy) residues can be remote-controlled and diastereoselectively locked. A right-handed (P)-310 -helix is first induced in the dynamic helical oligopeptide by an l-valine (l-Val) far from the bpy moiety and the induced axial bpy chirality is diastereoselectively dioxidized. The resulting l-Val-containing linear oligopeptides at the 3,3'-positions retain their (P)-310 -helices independent of the axial chirality (aR or aS) of the N-terminal N,N'-dioxide-bpy unit, while a lactam-bridged dynamic helical oligopeptide exhibits a unique solvent-induced helix-helix transition as a result of competitive helix-inducing biases between the l-Val and (aR) or (aS)-N,N'-dioxide-bpy residues remote from each other along the entire oligopeptide chain in a tug-of-war like manner.

Allosteric regulation of metal-binding sites inside an optically-active helical foldamer and its tubular assemblies.

A helical foldamer possessing conformationally switchable metal-binding linkers underwent supramolecular polymerization to form a helical nanofiber. A reversible helix-to-helix transition of the helical nanofiber took place upon cooperative binding and release of Ag(i) ions via a metal-coordination-driven W-to-U-shape conformational change of the linkers in a positive allosteric manner.

Chiral Template-Directed Regio-, Diastereo-, and Enantioselective Photodimerization of an Anthracene Derivative Assisted by Complementary Amidinium-Carboxylate Salt Bridge Formation.

A series of optically active amidine dimers composed of m-terphenyl backbones joined by a variety of linkers, such as achiral and chiral p-phenylene and chiral amide linkers, were synthesized and used as templates for the regio- (head-to-tail (HT) or head-to-head (HH)), diastereo- (anti or syn), and enantioselective [4 + 4] photocyclodimerization of an achiral m-terphenyl-based carboxylic acid monomer bearing a prochiral 2-substituted anthracene at one end (1) through complementary amidinium-carboxylate salt bridges. The amidine dimers linked by p-phenylene linkages almost exclusively afforded the chiral syn-HT and anti-HH dimers at 25 °C, while those joined by amide linkers produced all four dimers. The p-phenylene-linked templates tended to enhance the syn-HT-photodimer formation at high temperatures with no significant changes in the product enantiomeric excess (ee), while the anti-HH-photodimer formation remarkably increased with the decreasing temperature accompanied by a significant enhancement of the product ee up to -86% at -50 °C. Temperature-dependent inversion of the chirality of the anti-HH dimer was observed when the chiral phenylene-linked amidine dimer was used and the product ee was changed from 22% at 50 °C to -86% at -50 °C. A similar enhancement of the enantioselectivity of the anti-HH dimer was also observed for the chiral amide-linked template, producing the anti-HH dimer with up to -88% ee at -50 °C. The observed difference in the regio-, diastereo-, and enantioselectivities due to the difference in the linker structures of the amidine dimers during the template-directed photodimerization of 1 was discussed on the basis of a reversible conformational change in the amidine dimers complexed with 1.

Double-Stranded Helical Oligomers Covalently Bridged by Rotary Cyclic Boronate Esters.

Novel double helices covalently bridged by cyclic boronate esters were synthesized from complementary dimers with an m-terphenyl backbone joined by a chiral or achiral phenylene linker bearing diethyl boronates and diols, respectively. The X-ray crystallographic analysis and variable-temperature NMR and circular dichroism measurements, along with theoretical calculations, revealed that the double helices function as a "molecular rotor" in which the cyclic boronate ester units rotate, yielding two stable rotamers at low temperatures. Moreover, our data indicates that the covalently bonded double helices can undergo a unique helix-inversion simultaneously with a rotational motion of the boronate esters.

Chirality Control and Its Memory at Microphase-Separated Interface of Self-Assembled Chiral Block Copolymers for Nanostructured Chiral Materials.

Here, we show the induced chirality of an achiral chromophoric dye as a joint of polylactide-containing chiral block copolymers (BCPs*) driven by self-assembly, giving the achiral dyes preferentially arranged in a one-handed helical array at the microphase-separated interface. This helical arrangement of the achiral dyes can be "memorized" after hydrolysis of the polylactides in the BCPs* and serves as a chiral template for further chirality induction of different achiral dyes, probably through attractive aromatic π-π interactions at the interface, producing nanostructured chiral materials with tunable circular dichroism signals at desired wavelengths.

"Helix-in-Helix" Superstructure Formation through Encapsulation of Fullerene-Bound Helical Peptides within a Helical Poly(methyl methacrylate) Cavity.

A one-handed 310 -helical hexapeptide is efficiently encapsulated within the helical cavity of st-PMMA when a fullerene (C60 ) derivative is introduced at the C-terminal end of the peptide. The encapsulation is accompanied by induction of a preferred-handed helical conformation in the st-PMMA backbone with the same-handedness as that of the hexapeptide to form a crystalline st-PMMA/peptide-C60 inclusion complex with a unique optically active helix-in-helix structure. Although the st-PMMA is unable to encapsulate the 310 -helical peptide without the terminal C60 unit, the helical hollow space of the st-PMMA is almost filled by the C60 -bound peptides. This result suggests that the C60 moiety can serve as a versatile molecular carrier of specific molecules and polymers in the helical cavity of the st-PMMA for the formation of an inclusion complex, thus producing unique supramolecular soft materials that cannot be prepared by other methods.