Supramolecular chiroptical switching of helical-sense preferences through the two-way intramolecular transmission of a single chiral source.

We demonstrate a chiroptical switching system with a simple molecule. The molecule contains a pair of chromophores of diphenylacetylene that are linked with a diyne bond and arranged to exert exciton coupling in helically folded forms with (M)- or (P)-helicity. A tertiary amide group is attached to each end of the looped molecule. The amide carbonyls were used to capture a ditopic hydrogen-bonding guest. A chiral auxiliary group on the amide nitrogen acted as a chiral handle to control the helical-sense preference of dynamic helical forms of the loop. The helical-sense preference is brought about by an intramolecular transmission of point chirality associated with the loop. The preferred sense was switched upon complexation with an achiral additive through the formation of hydrogen bonds. In both states, before and after complexation, the helical-sense preferences were controlled through two-way transmission of the single chiral source.

Assembly of an Axially Chiral Dynamic Redox System with a Perfluorobiphenyl Skeleton into Dumbbell- or Tripod-type Electron Donors.

The incorporation of F atoms endows a diethenylbiphenyl-based electron donor with configurational stability and SN Ar reactivity. The former enables the dynamic redox pair of (Rax)-1/(Rax ,R,R)-1(2+) to exhibit drastic UV/Vis and CD spectral changes upon electrolysis, whereas the latter makes it possible for (Rax)-1 to serve as a useful chiral synthon for the production of larger assemblies [(Rax ,Rax)-2 d,p,m and (Rax ,Rax ,Rax)-3] containing two or three dyrex units. These dyads and triad also exhibit a clean electrochiroptical response with isosbestic points owing to one-wave multi-electron transfer.

Bis(10-methylacridinium)s as a versatile platform for redox-active functionalized dyes and novel structures.

10-Methylacridinium is a stable aromatic cation exhibiting yellow-orange color and strong green fluorescence (FL), and can be used as a versatile building block in constructing a wide variety of novel π-electron systems. The dications with the two chromophores connected by a proper π spacer undergo reversible "dyrex" (dynamic redox) behavior, and C-C bond formation/cleavage is accompanied by their redox reactions. The prototype is biphenyl-2,2'-diylbis(10-methylacridinium), which exhibits electrochromic response with ON/OFF switching of FL during the reversible interconversion with the di(spiroacridan)-type electron donor. Slight structural alteration under the concept of "MFMS" (maximum function on the minimum skeleton) endowed the dyrex system with metal-binding or chiroptical properties, which could be modified by the redox reactions. Some of the di(spiroacridan) derivatives generated from bis(10-methylacridinium)s have extreme structural parameters, such as the greatest C-C bond length ever reported.

Dynamic Figure Eight Chirality: Multifarious Inversions of a Helical Preference Induced by Complexation.

We demonstrate two types of inversion of a helical preference upon the 1:1 complexation of a dynamic figure eight molecule with a guest molecule through the controlled transmission of point chirality. We designed a series of macrocycles that prefer a nonplanar conformation with figure eight chirality. These macrocycles are composed of a chirality-transferring unit (terephthalamide) and a structure-modifying unit (two o-phenylene rings spaced with a varying number of triple bonds). The former unit provides a binding site for capturing a guest molecule through the formation of hydrogen bonds. The attachment of chiral auxiliaries to the former unit induces a helical preference for a particular sense through the intramolecular transmission of point chirality. For relatively small-sized macrocycles, the preferred sense was reversed upon complexation with an achiral guest. Contrary preferences before and after complexation were both seen for chiral auxiliaries associated with a figure eight host through two-way intramolecular transmission of the single chiral source. Alternatively, the helical preference induced in relatively large-sized macrocycles was reversed only when a figure eight host formed a 1:1 complex with a particular enantiomeric guest through the supramolecular transmission of point chirality in the guest. This stereospecific inversion of a helical preference is rare.

New insights into the hexaphenylethane riddle: formation of an α,o-dimer.

Upon reduction of a 1H-cyclobuta[de]naphthalene-4,5-diylbis(diarylmethylium) species, a new CC bond is formed between the Cα and Cortho atoms of the two chromophores, which presents an unprecedented coupling pattern for the dimerization of two trityl units. By attaching an annulated cyclobutane ring at the opposite peri position of the naphthalene core, the distance between the Cα  carbon atoms was elongated beyond the limit of σ-bond formation through "scissor effects". The suppression of Cα Cα bond formation, which would lead to hexaphenylethane-type compounds, is key to the first successful isolation of the α,o-adducts. The 5-diarylmethylene-6-triarylmethyl-1,3-cyclohexadiene unit in the α,o-adducts is stable, and isomerization of the cyclohexadiene unit into an aromatic system was not observed. The newly formed Cα Cortho bond was cleaved upon two-electron oxidation to regenerate the dicationic dye.

A foldable cyclic oligomer: chiroptical modulation through molecular folding upon complexation and a change in temperature.

A foldable cyclic oligomer 1 consisting of three terephthalamide units spaced with a 3-fold o-phenylene unit presented a dynamic pair of enantiomeric forms through molecular folding, to which the external chirality on a ditopic guest [(S,S)-2 or (R,R)-2] was supramolecularly transferred to prefer a particular sense of dynamic helicity [(M,M)-/(P,P)-1 and (M,M,P)-/(P,P,M)-1]. In the macrocycle, the terephthalamide units acted as exotopic binding sites to fold into helical forms upon complexation. The internal chirality associated with a host [(R,R,R,R,R,R)-1b] had no preference in a helical sense in the absence of a guest. Instead, the internal chirality was responsible for the signal modulation that it was cooperatively or competitively transferred in response to the external chirality on a guest (S,S)-2 or (R,R)-2. During the diastereomeric complexation, a particular sense of dynamic helicity was favored due to cooperative transmission of chirality when the helical preference was matched between the host and guest. Alternatively, the host complexed with an antipodal guest underwent a drastic change in conformation upon a change in temperature.

Chiroptical molecular propellers based on hexakis(phenylethynyl)benzene through the complexation-induced intramolecular transmission of local point chirality.

We designed hexakis(phenylethynyl)benzene derivatives with a tertiary amide group on each blade to achieve a helically biased propeller arrangement through the complexation-induced intramolecular transmission of point chirality. A hydrogen-bonding ditopic guest was captured at two amide groups, and thus could pair two neighboring blades to form a supramolecular cyclic structure, in which an auxiliary chiral group associated with a blade acted as a chiral handle to control the helical bias, while the chiral auxiliary did not exert any helical influence on the dynamic helicity in the absence of a guest due to the high flexibility of each blade.

Total synthesis of pectenotoxin-2.

Pectenotoxin-2 (PTX2) is a shellfish toxin and has a non-anomeric spiroacetal, which is not stabilized by an anomeric effect. The selective construction of the non-anomeric spiroacetal has been a major problem in the synthesis of PTX2. Described herein is the stereoselective total synthesis of PTX2 via the isomerization of anomeric spiroacetal pectenotoxin-2b (PTX2b). The synthesis of PTX2b was achieved by a simple process including sulfone-mediated assembly of spirocyclic and bicyclic acetals and subsequent macrocyclization by ring-closing olefin metathesis. Finally, the selective construction of PTX2 was accomplished by the early termination of a dynamic transition process to equilibrium in the acid-catalyzed isomerization of anomeric PTX2b. [6,6]-Spiroacetal pectenotoxin-2c (PTX2c) was also synthesized from PTX2b. The cytotoxicity assay of the synthetic compounds against HepG2 and Caco2 cancer cells showed a potency of the order: PTX2≫PTX2b>PTX2c.

Hydrindacene-based acetylenic macrocycles with horizontally and vertically ordered functionality arrays.

The macrocyclization of 2,6-diethynyl hydrindacenes (1) with functional groups at mutually perpendicular positions results in the formation of novel macrocycles which, as a result of the hindered rotation of the hydrindacene units, possess directionally persistent peripheral functionalities. The two hydrindacene units in the dimer macrocycle (2) have been shown to interact electronically through their respective butadiyne moieties, whereas the trimer macrocycle (3) demonstrates a moderate degree of geometrical flexibility as a result of the five-membered hydrindacene rings. In addition, these trimer macrocycles contain a central cavity suitably sized for the inclusion of various solvent molecules. These new macrocycles can be further modified by introducing π-conjugated side groups, such as styryl and thienyl groups, as well as by attaching a variety of peripheral ester groups.

7,7,8,8-Tetraaryl-o-quinodimethane stabilized by dibenzo annulation: a helical π-electron system that exhibits electrochromic and unique chiroptical properties.

When two benzene rings are fused to a tetraaryl-o-quinodimethane skeleton, sterically hindered helical molecules 1 acquire a high thermodynamic stability. Because the tetraarylbutadiene subunit contains electron-donating alkoxy groups, 1 undergo reversible two-electron oxidation to 2(2+), which can be isolated as deeply colored stable salts. Intramolecular transfer of the point chirality (e.g., sec-butyl) on the aryl groups to helicity induces a diastereomeric preference in dications 2 b(2+) and 2 c(2+), which represents an efficient method for enhancing circular-dichroism signals. Thus, those redox pairs can serve as new electrochiroptical response systems. X-ray analysis of dication 2(2+) revealed π-π stacking interaction of the diarylmethylium moieties, which is also present in solution. The stacking geometry is the key contributor to the chirosolvatochromic response.

Effects of axle-core, macrocycle, and side-station structures on the threading and hydrolysis processes of imine-bridged rotaxanes.

Imine-bridged rotaxanes are a new type of rotaxane in which the axle and macrocyclic ring are connected by imine bonds. We have previously reported that in imine-bridged rotaxane 5, the shuttling motion of the macrocycle could be controlled by changing the temperature. In this study, we investigated how the axle and macrocycle structures affect the construction of the imine-bridged rotaxane as well as the dynamic equilibrium between imine-bridged rotaxane 5 and [2]rotaxane 7 by using various combinations of axles (1 A,B), macrocycles (2 a-e), and side-stations (XYL and TEG). In the threading process, the flexibility of the macrocycle and the substituent groups at the para position of the aniline moieties affect the preparation of the threaded imines. The size of the imine-bridging station and the macrocyclic tether affects the hydrolysis of the imine bonds under acidic conditions.

Total synthesis of thelephantin O, vialinin A/terrestrin A, and terrestrins B-D.

The first total synthesis of natural, unsymmetrical 2',3'-diacyloxy-p-terphenyls, thelephantin O (1) and terrestrins C and D (2 and 3, respectively), was achieved via a practical route which was also applicable to the synthesis of the symmetrical diesters vialinin A/terrestrin A (4) and terrestrin B (5). Compounds 1-5 exhibited cytotoxicity against cancer cells (HepG2 and Caco2) with IC(50) values of 13.6-26.7 µmol/L.

4-(2,5-Dimethyl-1H-pyrrol-1-yl)-N-(2,5-dioxopyrrolidin-1-yl) benzamide improves monoclonal antibody production in a Chinese hamster ovary cell culture.

There is a continuous demand to improve monoclonal antibody production for medication supply and medical cost reduction. For over 20 years, recombinant Chinese hamster ovary cells have been used as a host in monoclonal antibody production due to robustness, high productivity and ability to produce proteins with ideal glycans. Chemical compounds, such as dimethyl sulfoxide, lithium chloride, and butyric acid, have been shown to improve monoclonal antibody production in mammalian cell cultures. In this study, we aimed to discover new chemical compounds that can improve cell-specific antibody production in recombinant Chinese hamster ovary cells. Out of the 23,227 chemicals screened in this study, 4-(2,5-dimethyl-1H-pyrrol-1-yl)-N-(2,5-dioxopyrrolidin-1-yl) benzamide was found to increase monoclonal antibody production. The compound suppressed cell growth and increased both cell-specific glucose uptake rate and the amount of intracellular adenosine triphosphate during monoclonal antibody production. In addition, the compound also suppressed the galactosylation on a monoclonal antibody, which is a critical quality attribute of therapeutic monoclonal antibodies. Therefore, the compound might also be used to control the level of the galactosylation for the N-linked glycans. Further, the structure-activity relationship study revealed that 2,5-dimethylpyrrole was the most effective partial structure of 4-(2,5-dimethyl-1H-pyrrol-1-yl)-N-(2,5-dioxopyrrolidin-1-yl) benzamide on monoclonal antibody production. Further structural optimization of 2,5-dimethylpyrrole derivatives could lead to improved production and quality control of monoclonal antibodies.

Dynamic molecular propeller: supramolecular chirality sensing by enhanced chiroptical response through the transmission of point chirality to mobile helicity.

The secondary terephthalamide host 1a-H attached to four aryl blades was prepared from tetrabromide 2a by Suzuki-Miyaura coupling and undergoes a conformational change from a nonpropeller anti-form to a propeller-shaped syn-form upon complexation with ditopic guests such as p-xylylenediammonium derivatives (R,R)/(S,S)-3 (chirality generation). Through transmission of the point chiralities attached on the nitrogens in the chiral guests to the mobile helicity in 1a-H, the propeller-shaped host in the complex is biased to prefer a particular handedness (chirality biasing). While chiral guests with simple point chiralities such as (R,R)/(S,S)-3 exhibit only very weak CD activity, complexation with the dynamic propeller host 1a-H results in much stronger chiroptical signals (chiroptical enhancement). The chirality generation-chirality biasing protocol was successfully applied to a neurotransmitter, (-)-phenylephrine 4, acting as a chiral ditopic guest. When the chiral auxiliaries are attached to the host as in (R,R)-1b-H, complexation with (S,S)-3 causes CD enhancement but not with (R,R)-3, due to chiral recognition.

Intramolecular methylacridan-methylacridinium complexes with a phenanthrene-4,5-diyl or related skeleton: geometry-property relationships in isolable C-H bridged carbocations.

Bridging the gap: Snapshots of 1,6-H-shift precursors indicate that a narrower C-HC(+) separation (D in the ORTEP diagram) in the title complexes induces faster degenerate rearrangement of 1(+). A contact distance of less than 2.7 A is necessary to realize the organic three-center two-electron bond of [C-H-C](+), as indicated by extrapolation of the X-ray data.The isolation and low-temperature X-ray analyses of a series of intramolecular methylacridan-methylacridinium complexes have been achieved. The two chromophores are in close proximity due to an arylene spacer, such as a phenanthrene-4,5-diyl or biphenyl-2,2'-diyl unit. These bridged carbocations prefer the C-H localized structure both in solution and in the solid state. The bridging hydrogen atom undergoes a facile intramolecular hydride shift from one carbon atom to another in solution, and the energy barrier is linearly correlated with the intramolecular CC(+) distance in the solid-state geometry, as determined by single-crystal X-ray analyses. By extrapolation from the data, the delocalized three-center bond of [C-H-C](+) would be formed when the CC(+) distance is less than 2.7 A.

Multi-input/multi-output molecular response system based on the dynamic redox behavior of 3,3,4,4-tetraaryldihydro[5]helicene derivatives: reversible formation/destruction of chiral fluorophore and modulation of chiroptical properties by solvent polarity.

3,3,4,4-Tetaaryldihydro[5]helicenes (1) and 1,1'-binaphthyl-2,2'-diylbis(diarylcarbenium)s (2(2+)) can be reversibly interconverted upon electron transfer, which is accompanied by a vivid color change (electrochromism) as well as by the formation/cleavage of a C-C bond ("dynamic redox behavior"). Because only the neutral donor 1 exhibits strong fluorescence, electrochemical input can further modify the fluorescent properties of the pair. Due to the configurational stability of the helicity in 1 and axial chirality in 2(2+), the redox reaction of optically pure material proceeds stereospecifically, which induces a chiroptical change such as circular dichroism (CD) as an additional output. The CD spectra of dications 2(2+) exhibit solvent dependency (chiro-solvatochromism), which is accompanied by solvatochromic behavior based on the pi-pi interaction of the two cationic chromophores as well as coordinative interaction of the Lewis basic solvent to the Lewis acidic triarylcarbenium moieties. Thus, the present system is endowed with multi-input functionality for modifying multiple output signals.

Molecular Wires with Controllable π-Delocalization Incorporating Redox-Triggered π-Conjugated Switching Units.

A perfluorobiphenyl-2,2'-diyl dication and its corresponding dihydrophenanthrene-type electron donor are interconvertible upon two-electron transfer. Redox-triggered C-C bond-formation/cleavage caused a drastic change in the torsion angle of the biphenyl unit. Thus, π-delocalization ON/OFF switching was observed as a change in the UV absorption upon electrolysis of the linearly extended analogue with two phenylethynyl groups. A further extended π-system with a molecular length of ca. 3.5 nm, which has two switching units, was synthesized. Spectroelectrograms as well as voltammetric analyses showed that the two units act nearly simultaneously because of the very small inter-unit electrostatic repulsion in the tetracationic state. Thus, the present pair is a promising candidate as a switching unit for "molecular wires" with controllable π-delocalization, in which a higher ON/OFF ratio of delocalization could be realized by incorporating multiple switching units.

Entropy- and hydrolytic-driven positional switching of macrocycle between imine- and hydrogen-bonding stations in rotaxane-based molecular shuttles.

The construction and switching properties of a novel class of molecular shuttles 1 with imine-bonding stations for macrocyclic diamine parts are reported. Studies on dithioacetalized [2]rotaxane 4 with two hydrogen-bonding stations and a masked imine-bonding station showed that protonation of a macrocycle increases the shuttling barrier due to hydrogen-bond formation between NH 3 (+) groups and the TEG-stations. Hydrolysis of the imine-bonds of the imine-bridged molecular shuttles 1b, c with TEG-stations could exclusively give the [2]rotaxane 2b, c.2H (2+), with the macrocycle hydrogen-bonded with the TEG-station. In contrast, 1a without TEG-stations gave an equilibrated mixture of 1a, monoimine 3a.H (+), and 2a.2H (2+) under similar acidic hydrolytic conditions. The equilibrium between 1b, c and 2b, c.2H (2+) to control the position of the macrocycle could be successfully switched to either side by applying acidic hydrolytic or dehydrating conditions. Furthermore, the equilibrium was largely biased to [2]rotaxane 2b, c.2H (2+) under acidic hydrolytic conditions and could be reversed in favor of bis-imine 1b, c just by heating. This is a successful example of a molecular shuttle exhibiting entropy-driven translational isomerism with remarkable positional discrimination. An examination of thermodynamic parameters showed that imine-bond hydrolyses and the formation of hydrogen bonds between the macrocycle and the station are thermodynamically matched processes, because both processes are enthalpically favored and accompanied by a loss of entropy. The combination of imine-bonding and hydrogen-bonding station in a rotaxane system is the key to realizing the clear entropy-driven positional switching of the macrocycle observed.

Designed molecular propellers based on tetraarylterephthalamide and their chiroptical properties induced by biased helicity through transmission of point chirality.

The syn-atropisomers of the title bis(tertiary amide)s were designed as six-bladed molecular propellers based on the "directing effects" of amide dipoles; the helicity of the propeller is biased to prefer one handedness upon the attachment of point chirality to the amide nitrogens to attain stronger circular-dichroism activity than for the non-propeller-shaped anti-isomers.

Enhanced circular dichroism at elevated temperatures through complexation-induced transformation of a three-layer cyclophane with dualistic dynamic helicity.

When two planes stacked one above the other are twisted, they provide a dynamic pair of helical conformations with (M)- or (P)-helicity. We designed a three-layer cyclophane that consists of two such dynamic pairs: the top and middle planes, and the middle and bottom planes. Hence, several global conformations could be created for the overall molecule, e.g., double-helical forms with a pair with the same helicity [(M,M) or (P,P)], and a meso-like form with a pair with a different helicity (M,P). These conformations dynamically interconvert to each other in solution. Chiroptical properties were given by the helical-sense preference of the double-helical forms, which was brought about through complexation with a chiral hydrogen-bonding guest. In terms of the conformational energy in a complexed state, when a desirable relationship between double-helical and meso-like forms was attained, complexation-induced circular dichroism was enhanced at elevated temperatures and decreased at lowered temperatures.