Analytical Chiral Separation of the Stereoisomers of a Novel Carbonic Anhydrase Inhibitor and Its Deethylated Metabolite,and the Assignment of Absolute Configuration of the Human Metabolite and Chiral Degradation Products

Several approaches to the separation of four stereoisomers, 1–4, of a novel, topically active, carbonic anhydrase inhibitor, 1, with two chiral centers in the molecule and four isomers, 5–8, of its chiral metabolite, 5, were evaluated. These methods include nonchiral derivatization followed by separation on chiral stationary phases (CSPs) and chiral derivatization and separation on nonchiral columns and on CSPs. Baseline separation of stereoisomers 1–4 was achieved in less than 15 min after chiral derivatization with (S)-(+)-l-(l-naphthyl)ethyl isocyanate (NEIC) and chiral chromatography on a (R)-N-(3,5-dinitrobenzoyl)phenyl glycine (DNBPG) column under normal phase (NP) conditions. Similarly, isomers 5-8 were baseline separated in less than 20 min after derivatization with NEIC and chromatography on nonchiral (nitrophenyl) and chiral [(S)-(3,5-dinitrobenzoyl)leucine; DNBL] columns in series under the same NP chromatographic conditions. Only partial separation of the diastereomeric derivatives was observed on a variety of nonchiral columns. In addition, all other direct and indirect chiral separation approaches gave only partial separation of at least two stereoisomers within the group of 1–4 or 5–8. The details of chiral separations using various methods and separation () and capacity factors (k) of the derivatized isomers 1–8 on a series of chiral and nonchiral columns are presented. Using these methods, the absolute configuration of the human metabolite of 1 was established as S ₁ S ₂ (5), and the heat (HD) and light (LD) degradation products of 1 as R ₁ S ₂ (3) and S₁ S ₂ (5), respectively.     

The synthesis of justicidinoside B and its atropisomer

The first synthesis of justicidinoside B and its atropisomer was reported and their absolute configurations were determined by the CD exciton chirality method. The structures were confirmed by ¹H NMR, ¹³C NMR, and HRMS.     

Oppositely Synchronized Lamellar Bending in Poly(l‐lactic acid) Versus Poly(d‐lactic acid) Blended with Poly(1,4‐butylene adipate)

Lamellar bending habits, as influenced by molecular‐chain chirality, in packing into dendritic spherulites with specific optical patterns are discussed using two model polymers of opposite chirality that are blended with a common polymer as examples: i) poly(l ‐lactic acid)/poly(butylene adipate) (PLLA/PBA) and ii) poly(d ‐lactic acid)/PBA (PDLA/PBA) blends. The bending habits in the spherulites of PLLA or PDLA blended with PBA are dictated by the chirality, specifically the counterclockwise and clockwise directions for the PLLA/PBA (50:50) and PDLA/PBA (50:50) blends, respectively. Straight lamellae in spiral lozenge crystals are packed with crystal aggregates of PLLA on top of the flat‐on lamellae plates acting as a basal plane during crystallization at T_c; spiral lozenge‐crystal frameworks are surrounded by needle‐like crystals resembling PBA crystals.

     

Hierarchical self-assembly of a striped gyroid formed by threaded chiral mesoscale networks

Numerical simulations reveal a family of hierarchical and chiral multicontinuous network structures self-assembled from a melt blend of Y-shaped ABC and ABD three-miktoarm star terpolymers, constrained to have equal-sized A/B and C/D chains, respectively. The C and D majority domains within these patterns form a pair of chiral enantiomeric gyroid labyrinths (srs nets) over a broad range of compositions. The minority A and B components together define a hyperbolic film whose midsurface follows the gyroid minimal surface. A second level of assembly is found within the film, with the minority components also forming labyrinthine domains whose geometry and topology changes systematically as a function of composition. These smaller labyrinths are well described by a family of patterns that tile the hyperbolic plane by regular degree-three trees mapped onto the gyroid. The labyrinths within the gyroid film are densely packed and contain either graphitic hcb nets (chicken wire) or srs nets, forming convoluted intergrowths of multiple nets. Furthermore, each net is ideally a single chiral enantiomer, induced by the gyroid architecture. However, the numerical simulations result in defect-ridden achiral patterns, containing domains of either hand, due to the achiral terpolymeric starting molecules. These mesostructures are among the most topologically complex morphologies identified to date and represent an example of hierarchical ordering within a hyperbolic pattern, a unique mode of soft-matter self-assembly.Liquid crystals formed by molecular self-assembly provide fascinating examples of complicated space partitions in soft-material science. Relatively complex examples are the bicontinuous mesostructures found ubiquitously in both natural and synthetic soft matter, including lipid–water systems and block copolymer melts, namely the double diamond (symmetry ), the primitive , and, particularly, the gyroid mesophases. The structure of these mesophases can be described by a molecular membrane folded onto one of the three simplest triply periodic minimal surfaces (TPMS), namely the D, P, and G(yroid) surfaces, named by Schoen in the 1960s (1). From a 3D perspective, these structures are characterized by the nets describing the pair of mutually threaded labyrinths carved out of space by the convoluted hyperbolic architecture of the TPMS. For the gyroid, this is a racemic mixture of two chiral srs nets, one left- and the other right-handed [the three-letter nomenclature follows the Reticular Chemistry Structure Resource naming convention for 3D nets (2)]. This leads to an overall achiral structure when the two nets are chemically identical, which is the case in most experimentally identified gyroid liquid-crystal structures. One such structure recently reported is a gyroid assembly found in an ABC three-miktoarm star terpolymer melt (3). In this structure, the majority C component constitutes the two labyrinth nets while the A and B minority components together form the dividing membrane. Because of the connectivity of the star molecular architecture and because all components microphase separate, the A and B components segregate on the dividing hyperbolic interface. This structure is an experimental indication of a unique mode of self-assembly, namely “hierarchical assembly of a hyperbolic pattern.” Complementing this finding and further motivating our work reported here, a recent simulation study by one of us (J.J.K.K.) explored self-assembly of blends of equal amounts of two distinct three-miktoarm stars, namely ABC and ABD three-miktoarm star terpolymers (Fig. 1). Both molecules were assigned equal molecular weights, and the proportions of the equal volume C (green) and D (yellow) chains relative to the equal A (red) and B (blue) chains were varied (4). Despite these severe compositional constraints, a number of unique four-colored mesophases were revealed. The most striking feature of the predicted phase behavior in this system was the presence of interesting patterns whose general features are reminiscent of the gyroid, albeit far more complex in both geometric and topological aspects. In the system reported here, two ordering regimes form. At the larger length scale, ordering induces a gyroid-like membrane, which is itself also spontaneously ordered at a smaller length scale, giving unique microdomain patterning due to the membrane confinement to a hyperbolic curved interface. Each of these patterns contain distinct numbers and types of interwoven 2D and 3D A and B domains forming nets of equal hand, immersed within the hyperbolic interface between an enantiomeric pair of C and D srs nets. These structures are spectacularly convoluted in 3D space and correspond to special members of a sequence of chiral cubic patterns that emerge by local striping of the gyroid membrane. We demonstrate how this is performed systematically by mapping a particular family of tilings in the hyperbolic plane onto the gyroid in 3D euclidean space. Careful analysis of the morphologies formed in the simulations, described below, reveals the presence of up to three distinct chiral cubic mesophases within this striped gyroid region of the phase diagram. We explore the geometric and topological variety of these self-assemblies in detail and discuss how they emerge as a response to a hierarchy of frustrations imposed by the three-arm star molecular architecture, acting in both two and three dimensions.Open in a separate windowFig. 1.(A) Model ABC and ABD three-miktoarm star terpolymer molecules. All molecules contain equal-sized A (red) and B (blue) arms, and longer C (green) and D (yellow) arms, also of equal size. The parameter x (equal to in this image), corresponds to the number ratio of C to A beads. (B) C and D domain geometry, a pair of intertwined srs nets. (C–G) Single-unit cell snapshots illustrating the curved striped pattern formed by the minority components A and B for varying x. (C) x = 2, (D) x = 3.33, (E) x = 3.67, (F) x = 5, and (G) x = 6. Note the threefold branching of the stripes for all values of x.     

Bacterial rheotaxis

The motility of organisms is often directed in response to environmental stimuli. Rheotaxis is the directed movement resulting from fluid velocity gradients, long studied in fish, aquatic invertebrates, and spermatozoa. Using carefully controlled microfluidic flows, we show that rheotaxis also occurs in bacteria. Excellent quantitative agreement between experiments with Bacillus subtilis and a mathematical model reveals that bacterial rheotaxis is a purely physical phenomenon, in contrast to fish rheotaxis but in the same way as sperm rheotaxis. This previously unrecognized bacterial taxis results from a subtle interplay between velocity gradients and the helical shape of flagella, which together generate a torque that alters a bacterium's swimming direction. Because this torque is independent of the presence of a nearby surface, bacterial rheotaxis is not limited to the immediate neighborhood of liquid-solid interfaces, but also takes place in the bulk fluid. We predict that rheotaxis occurs in a wide range of bacterial habitats, from the natural environment to the human body, and can interfere with chemotaxis, suggesting that the fitness benefit conferred by bacterial motility may be sharply reduced in some hydrodynamic conditions.     

二氢菲类化合物赫尔西酚的手性异构体研究

目的研究中华石仙桃(Pholidota chinensis Lindl)全草中分离得到的二氢菲类化合物赫尔西酚(hircinol)的立体结构并进行手性异构体的分离。方法采用多种柱色谱法进行分离纯化,并根据比旋光度和圆二色谱数据进行构型确定。利用手性色谱柱对分离得到的赫尔西酚进行手性异构体的拆分。结果与结论得到赫尔西酚A、赫尔西酚B两种手性异构体,两种异构体比例为78.9∶22.1,两种异构体的比旋光度分别为+25.4°和-25.4°。本文首次报道赫尔西酚是具有旋光性的对映体,经圆二色谱(CD)测定和解析证明赫尔西酚A为S构型、赫尔西酚B为R构型。     

Twisted molecular wires polarize spin currents at room temperature

A critical spintronics challenge is to develop molecular wires that render efficiently spin-polarized currents. Interplanar torsional twisting, driven by chiral binucleating ligands in highly conjugated molecular wires, gives rise to large near-infrared rotational strengths. The large scalar product of the electric and magnetic dipole transition moments (μ→ij⋅m→ij), which are evident in the low-energy absorptive manifolds of these wires, makes possible enhanced chirality-induced spin selectivity–derived spin polarization. Magnetic-conductive atomic force microscopy experiments and spin-Hall devices demonstrate that these designs point the way to achieve high spin selectivity and large-magnitude spin currents in chiral materials.

Spintronics offers exciting possibilities in applications that include information storage and magnetic sensing with reduced power consumption (1). Molecular organic semiconductors offer tremendous potential for electron spin transmission, as well as controlling spin decoherence and relaxation times (2). These opportunities derive in part from the fact that light-atom–based organic compositions have intrinsically weaker spin–orbit coupling (SOC) and hyperfine interactions than conventional inorganic semiconductors; such properties have enabled advances that include spin-polarized organic light-emitting diodes (3), organic spin valves (4), and spin-photovoltaic cells (5).While organic molecules have small SOCs, the recently discovered chirality-induced spin selectivity (CISS) effect provides a new approach to control spins in molecules (6). Numerous experiments show that chiral molecules act as spin filters in electron transport. The same is true when an electric field is applied across a chiral molecule and induces charge reorganization. Because spin polarization accompanies charge polarization in chiral molecules (7), the CISS effect provides a potential solution to resolve the technological hurdles associated with injecting spin-polarized electrons from inorganic ferromagnets into organic molecules or vice versa; commonly, in such devices, the Schottky barrier limits spin injection efficiency and drives spin depolarization (8). Importantly, in this regard, the CISS effect has been used to generate spin polarizations approaching 100% under ambient conditions, even in the absence of a magnetic field (9). Because the CISS effect enables ambient temperature control of the electron spin through applied electrical and electromagnetic fields, it bears keen relevance to quantum information science, as it provides a potential pathway to generate coherent spin states (entangled electron pairs or spin qubits).Spin-selective transmission made possible by the CISS effect has been demonstrated for chiral tunneling barriers fabricated from chiral molecules [e.g., oligopeptides (10, 11), l/d-cysteine (12), and oligonucleotides (13)], chiral nanoparticles [e.g., CdSe quantum dots (14) and chiral helicoidal three-dimensional metal organic frameworks (9)], and other materials (15, 16). Chiral organic structures that possess substantial charge mobilities and suppress spin dephasing offer the potential to realize materials that have dramatically enhanced CISS functionality. In this regard, we demonstrated recently that low-resistance molecular wires, with a mix of tunneling, hopping, and resonant transport mechanisms (17, 18), uniquely propagate spin-polarized currents (19). These exemplary compositions exploit conjugated zinc porphyrin wires (PZn_n), which manifest long spin-relaxation times (20), support highly delocalized hole and electron polaron states (21, 22), and feature extraordinarily low charge transport resistances (17, 18). In contrast to pioneering studies that have induced chirality in conjugated oligomers via H-bonding interactions (23), we demonstrate here that chiral twisted molecular wires can be engineered with conjugated PZn_n oligomers through coordination of chiral binucleating ligands; this strategy integrates both spin-polarizing and spin-propagating functionality in a single conductive organic framework, controls the handedness of the polarized spin, and thus regulates spin currents via the CISS mechanism.     

(+)-4-(2-甲基丁基)-4′-氰基联苯的合成

以(+)-对甲苯磺酸-2-甲基丁酯与联苯基溴化镁反应,在催化剂作用下实现手性戊基与联苯偶联,再经碘化和氰化,合成了(+)-4-(2-甲基丁基)-4′-氰基联苯(CB-15)。总收率为15%(以左旋戊醇计算)。同时,就手性戊基与联笨偶联的机理等问题作了讨论。     

Enantioselectivity in environmental safety of current chiral insecticides

Chiral pesticides currently constitute about 25% of all pesticides used, and this ratio is increasing as more complex structures are introduced. Chirality occurs widely in synthetic pyrethroids and organophosphates, which are the mainstay of modern insecticides. Despite the great public concerns associated with the use of insecticides, the environmental significance of chirality in currently used insecticides is poorly understood. In this study, we resolved enantiomers of a number of synthetic pyrethroid and organophosphate insecticides on chiral selective columns and evaluated the occurrence of enantioselectivity in aquatic toxicity and biodegradation. Dramatic differences between enantiomers were observed in their acute toxicity to the freshwater invertebrates Ceriodaphnia dubia and Daphnia magna, suggesting that the aquatic toxicity is primarily attributable to a specific enantiomer in the racemate. In field sediments, the (-)enantiomer of cis-bifenthrin or cis-permethrin was preferentially degraded, resulting in relative enrichment of the (+)enantiomer. Enantioselective degradation was also observed during incubation of sediments under laboratory conditions. Enantioselectivity in these processes is expected to result in ecotoxicological effects that cannot be predicted from our existing knowledge and must be considered in future risk assessment and regulatory decisions.     

他汀类药物中间体的生物催化合成研究进展

他汀类药物是一类重要的降血脂药物,(3R,5S)-二羟基酯是他汀类药物发挥作用的关键结构,也是合成该类药物过程中的重要中间体,因其结构中具有两个手性碳原子,故含有(3R,5S)-二羟基酯结构中间体的制备在某种程度上已成为他汀类药物制备的限速步骤。该文对他汀类药物的类型、作用机制、化学结构和合成路线进行概述。着重对近几年采用生物催化方式制备具有 (3R,5S)-二羟基酯结构中间体的方法进行简述。