手性尼莫地平绝对构型的确定和关联

概述了手性1, 4-二氢吡啶类（1, 4-DHPs）钙拮抗剂的立体化学结构及其药效与绝对构型的关系,以及尼莫地平（nimodipine）的多晶型现象。采用单晶X射线衍射与固体和溶液圆二色（ECD）光谱直接关联的方法,对自发拆分获得的一对尼莫地平外消旋聚集体进行了绝对构型确定,首次获得了手性1, 4-DHPs类化合物的固体和溶液ECD光谱图。本方法对确认有机小分子的绝对构型,以及关联系列手性1, 4-DHP衍生物的绝对构型具有重要参考价值,同时提供了有别于常规非手性方法鉴别优势手性药物晶型的有效手段。     

Chiral liquid chromatography contribution to the determination of the absolute configuration of enantiomers

The review covers examples in which chiral HPLC, as a source of pure enantiomers, has been combined with classical methods (X-ray, vibrational circular dichroism (VCD), enzymatic resolutions, nuclear magnetic resonance (NMR) techniques, optical rotation, circular dichroism (CD)) for the on- or off-line determination of absolute configuration of enantiomers. Furthermore, it is outlined that chiral HPLC, which associates enantioseparation process and classical purification process, opens new perspectives in the classical determination of absolute configuration by chemical correlation or chemical interconversion methods. The review also contains a discussion about the various approaches to predict the absolute configuration from the retention behavior of the enantiomers on chiral stationary phases (CSPs). Some examples illustrate the advantages and limitations of molecular modeling methods and the use of chiral recognition models. The assumptions underlying some of these methods are critically analyzed and some possible emerging new strategies are outlined.     

Chiral Induction and Remote Chiral Communication in Quinoline Oligoamide Foldamers for Determination of Enantiomeric Excess and Absolute Configuration of Chiral Amines and Their Derivatives

Two pentameric foldamers, Q5 and Q5C-S , containing a C−F bond were synthesized based on quinoline oligamide foldamers for the measurement of enantiomeric excess and for the determination of absolute configuration of chiral amines, diamines, amino alcohols, and α-amino acid esters. Chiral induction of Q5 was triggered in situ when the chiral analytes reacted with the C−F bond in Q5 by a N-nucleophilic substitution reaction, leading to a linear correlation between the CD amplitude at the region of quinoline chromophores and the ee values of the chiral analytes, which can be used for the ee determination of chiral analytes. Furthermore, the CD intensity of Q5C-S containing a chiral motif at its C-terminus enhances via remote, favorable chiral communication when the chiral induction was triggered in situ by chiral analytes at the N-terminus matches the original helicity of Q5C-S , but decreases via remote, conflicted chiral communication when the chiral induction is triggered in situ by chiral molecules at the N-terminus mismatches the original one. The system can thus be used for determination of the absolute configuration of chiral analytes, given that the chirality of the chiral motif at the C-terminus of Q5C-S is known.     

Chiral Cooperativity: The Effect of Distant Chiral Centers in Ferrocenylamine Ligands upon Enantioselectivity in the Gold(I)-Catalyzed Aldol Reaction

Long-range chiral cooperativity in enantiomerically pure ferrocenylamine ligands containing both planar and multiple centers of chirality (multiple stereogenic C-atoms) was demonstrated in the Au^I-catalyzed reaction of aldehydes and isocyanoesters. Synthetic methodology was developed for the synthesis of ferrocenylamine ligands with two and three chiral centers of known absolute configuration in the C-side chain in addition to the planar chirality of the molecule. The diastereo- and enantioselectivity of the Au^I-catalyzed formation of the trans- and cis-dihydrooxazoles 5 and 6 , respectively, from benzaldehyde ( 1 ) and methyl isocyanoacetate ( 2 ) depend upon the sequence of chirality (absolute configuration of the chiral centers) in the side chain of the ferrocenylamine ligands. Particularly significant effects were observed upon the enantioselectivity for the minor cis-dihydrooxazole 6 , for which, in certain cases, resulted in a change in the enantiomeric dihydrooxazole 6 produced in excess with a change in the absolute configuration of a distant chiral center. Significant effects upon diastereo- and enantioselectivity were observed when chiral ferrocenylamine ligands containing free OH groups were utilized. Using ligands containing a free OH group gave 6 with an absolute configuration opposite to that produced by the corresponding ester and carbamate derivatives. The possible mechanisms for the transmission of chiral information in the proposed stereoselective transition state (TS) was discussed, including both the formation of a stereogenic N-atom and steric effects based upon Newman's rule of six.     

三唑农药的手性拆分及对映体的转化

利用Chiralcel OJ-H和Chiralcel OD-H手性柱对烯唑醇、三唑酮和三唑醇的手性拆分进行了研究,进一步测定了烯唑醇和三唑酮对映体的旋光性质,据此确定了两种农药对映体的绝对构型,在此基础上结合三唑酮转化为三唑醇的还原实验确定了三唑醇4个对映异构体的绝对构型。考察了几种三唑农药在有机溶剂和缓冲溶液中的手性稳定性,其中三唑酮在甲醇、乙醇和水中存在明显的对映体转化行为,而烯唑醇和三唑醇则是手性稳定的,升高温度及碱性环境会加快三唑酮的对映体转化。     

Vibrational Circular Dichroism Spectroscopy of Chiral Molecular Crystals: Insights from Theory

Chirality is a curious phenomenon that appears in various forms. While the concept of molecular (RS-)chirality is ubiquitous in chemistry, there are also more intricate forms of structural chirality. One of them is the enantiomorphism of crystals, especially molecular crystals, that describes the lack of mirror symmetry in the unit cell. Its relation to molecular chirality is not obvious, but still an open question, which can be addressed with chiroptical tools. Vibrational circular dichroism (VCD) denotes chiral infrared (IR) spectroscopy that is susceptible to both, the molecular as well as the intermolecular space by means of vibrational transitions. When carried out in the solid state, VCD delivers a very rich set of non-local contributions that are determined by crystal packing and collective motion. Since its discovery in the 1970s, VCD has become the method of choice for the determination of absolute configurations, but its applicability reaches beyond towards the study of different crystal forms and polymorphism. This brief review summarises the theoretical concepts of crystal chirality and how computations of solid-state VCD can shed light into the intimate connection of chiral structure and vibrational optical activity.     

Neutral Chiral Tetrakis-Iodo-Triazole Halogen-Bond Donor for Chiral Recognition and Enantioselective Catalysis

Halogen bonding represents a powerful tool in the field of noncovalent interactions. However, applications in enantioselective recognition and catalysis remain almost nonexistent, due in part to the distinct features of halogen bonds, including long covalent and noncovalent bond distances and high directionality. Herein, this work presents a novel chiral tetrakis-iodo-triazole structure as a neutral halogen bond donor for both chiral anion-recognition and enantioinduction in ion-pair organocatalysis. NMR-titration studies revealed significant differences in anion affinity between the halogen bonding receptor and its hydrogen bonding parent. Selective recognition of chiral dicarboxylates and asymmetric induction in a benchmark organocatalytic reaction were demonstrated using the halogen bond donor. Inversions in the absolute sense of chiral recognition, enantioselectivity, and chiroptical properties relative to the related hydrogen donor were observed. Computational modeling suggested that these effects were the result of distinct anion-binding modes for the halogen- versus hydrogen-bond donors.     

Chiral 1,2-subnaphthalocyanines

Following the first suggestion of inherent molecular chirality in asymmetrically substituted subphthalocyanines by Torres and co-workers in 2000, elucidation of the relationship between structure and chirality has become an important issue. However, separation of the enantiomers has been prevented by the low solubility of the molecules synthesized to date, and it has not been possible to link the CD signs and intensities to their absolute structures. Recently, we observed that 1,2-subnaphthalocyanines possess two diastereomers with respect to the arrangement of the naphthalene moieties and that these novel chiral molecules exhibit moderate solubility in common organic solvents. This has enabled us to separate all of the diastereomers and enantiomers. The two diastereomers have been completely characterized by NMR spectroscopy and X-ray diffraction analysis. The absorption and magnetic circular dichroism spectra, together with theoretical calculation, reveal a small variation in the frontier molecular orbitals of the 1,2-subnaphthalocyanines compared with conventional subphthalocyanines, except for destabilization of the HOMO-3, which results in a characteristic absorption in the Soret band region. The chirality of 1,2-subnaphthalcyanines, including the CD signs and intensities, is discussed in detail for the first time with enantiomerically pure molecules whose absolute structures have been elucidated by single-crystal X-ray diffraction analysis.     

Chiral photochemistry within zeolites

Chiral induction of chemical reactions continues to be one of the main concerns of chemists. While basic rules of chiral induction of thermal reactions have been reasonably established, the same is not true of photochemical reactions. Short excited state lifetime and low activation energies for reactions in the excited state(s) leave very little room for manipulating the diastereomeric transition states. Yet impressive chiral induction of photochemical reactions in the solid state has been achieved. On the other hand, chiral induction of photoreactions of organic molecules in solution continues to be inefficient at ambient conditions. We are exploring the possibility of employing zeolites as a media for achieving chiral induction during photoreactions. The motivating force for such an attempt is the fact that chiral chemistry in the solid state is not completely general due to the fact that not all molecules crystallize. To achieve chiral induction one needs a chiral perturber. Zeolites are not chiral and therefore the perturber is added to the medium. Thus the medium for a photoreaction is a chirally modified zeolite. Of the several reactions investigated, results on photoelectrocylization of tropolone alkyl ethers are discussed at length. The confined space offered by the zeolite supercage forces a reactant and the chiral inductor to interact intimately to yield enantiomerically enriched product. Due to the transitory nature of the reaction cavity in solution such close interactions are less likely in isotropic solvent media. The examples discussed herein show negligible chiral induction in solution, whereas in a zeolite one obtains induction as high as 90%.     

Chiral crystallization of helical polymers

Crystallization of achiral or racemic helical polymers in chiral crystals is quite frequent and while in some cases it may relate to the thermodynamic stability of the chiral polymorph, in others it must be associated with kinetic factors. Analysis of the available literature data suggests that in the second instance a key role must be played by the nucleation step, i.e. specifically by the formation of precrystalline entities. Furthermore a survey of the chiral crystal structures for helical polymers evidences that they are frequently characterized by a quasi-hexagonal packing. The hexagonality index H, defined as the ratio of the largest to the smallest distance between the axis of the reference helix and its six nearest neighbors, appears to be a reliable indicator of the presence of helices of a single handedness or, respectively, of both in a given crystal structure. A detailed analysis of the general energetic and entropic factors favouring chiral crystallization of helical polymers is carried out. It is shown that a hexagonal or pseudo-hexagonal arrangement (i.e. the six-fold coordination) in either the crystalline or in a precrystalline state, promotes chiral crystallization and is in its own turn favoured by clustering of isochiral helices.     

Chiral silylation reagents for the determination of absolute configuration by NMR spectroscopy

We have investigated the use of chiral silylating reagents as analytical probes for determining the absolute stereochemistry of natural products by NMR spectroscopy. These reagents are prepared in high chemical yield in one step and can be used to derivatize chiral allylic alcohols which are incompatible with ester-based methodologies. Microscale ( approximately 400 nmol) derivatization conditions have been defined. The resulting siloxane diastereomers are readily distinguished by their (1)H NMR spectra.     

Enantioselective Light Harvesting with Perylenediimide Guests on Self‐Assembled Chiral Naphthalenediimide Nanofibers

Self‐assembling molecular systems often display amplified chirality compared to the monomeric state, which makes the molecular recognition more sensitive to chiral analytes. Herein, we report the almost absolute enantioselective recognition of a chiral perylenediimide (PDI) molecule by chiral supramolecular nanofibers of a bichromophoric naphthalenediimide (NDI) derivative. The chiral recognition was evaluated through the Förster resonance energy transfer (FRET) from the NDI‐based host nanofibers to the guest PDI molecules. The excitation energy was successfully transferred to the guest molecule through efficient energy migration along the host nanofiber, thus demonstrating the light‐harvesting capability of these hybrid systems. Furthermore, circularly polarized luminescence (CPL) was enantioselectively sensitized by the guest molecule as the wavelength band and sign of the CPL signal were switched in response to the chiral guest molecule.     

Chiral attachment of styrene mediated by surface dimers on Ge100

We have investigated the chiral adsorption configurations of styrene on Ge(100) using scanning tunneling microscopy at 300 K. The chemisorbed styrene on a single Ge dimer reduces the symmetry of the molecule, which produces a chiral center, and leads to the (S) or (R) chiral on-top configuration. We have found that the dimeric adsorption of styrene induced by the Ge surface dimer structure forms the enantiomeric and diastereomeric paired end-bridge configurations. We determine the absolute chirality of adsorbed styrene on Ge(100) and demonstrate a novel method for the achiral molecule to produce dimeric enantiomers and diastereomers attached to the semiconductor surface.     

Chiral Overpass Induction in Dynamic Helical Polymers Bearing Pendant Groups with Two Chiral Centers

The dynamic behavior of helical polymers bearing pendant groups with two chiral centers was studied. Controlled conformational changes at the chiral units placed either closer to or further away from the main chain promote different helical structures. Although the first residue is usually responsible for determining a specific helicity (P or M), we now found that the second chiral center is also able to induce a preferred helical sense when it is located closer in space to the main chain, thereby cancelling the order from the first chiral moiety. This result was achieved through proper coordination with a metal cation. As proof of concept, poly(phenylacetylene)s (PPAs) that bear one and two chiral amino acid units of different sizes and configuration combinations (l /d ‐alanine and l /d ‐phenylalanine) as pendants were evaluated. In total, ten polymers were studied. This constitutes the first report of axial control from a remote stereocenter in polymers bearing complex chiral pendants.     

Chiral discrimination of cryptochiral saturated quaternary and tertiary hydrocarbons by asymmetric autocatalysis

Chiral discrimination of saturated hydrocarbons has been very difficult to establish, or has not been possible at all. The first chiral discrimination of cryptochiral 5-ethyl-5-propylundecane 1, that is, (n-butyl)ethyl(n-hexyl)(n-propyl)methane, a chiral saturated quaternary hydrocarbon, which is known to exhibit practically no detectable value of optical rotation between 280 and 580 nm, has been accomplished by asymmetric autocatalysis of pyrimidyl alkanol. The absolute configuration of 1 has been determined. In the presence of (R)- or (S)-1, the reaction between pyrimidine-5-carbaldehyde and diisopropylzinc affords (S)- and (R)-pyrimidyl alkanol with 91-97% ee, respectively. Thus, asymmetric autocatalysis serves as a powerful tool for the chiral discrimination of saturated hydrocarbons.     

万古霉素手性固定相的制备与对映体分离研究

采用双官能团试剂4,4′-二苯基甲烷二异氰酸酯在无水二甲基甲酰胺(DMF)中直接与大环糖肽类抗生素万古霉素及γ-氨丙基硅胶键合,得到环状抗生素手性固定相(CSP)并用于高效液相色谱手性分析。实验结果证实,合成的万古霉素CSP在正相和反相条件下均有一定的拆分能力,其中在反相条件下拆分了17种对映体,显示出其较为广泛的拆分范围,且磷酸缓冲体系略优于三乙胺-乙酸缓冲体系;对一些物质,如D,L-丹酰化氨基酸的拆分有一定的规律,能给出绝对构型信息。所制备的CSP在相体系转化时不发生老化和变性,显示了一定的稳定性。对该CSP的拆分机理进行分析所得到的结果与Armstrong等的分析结果基本一致。     

Chiral conformations induced by cyclodextrin

Studies of chiroptical properties need separation or at least enrichment of enantiomers. The separation is difficult with chiral conformers of molecules with very low barriers of internal rotation. However, in association with cyclodextrin, these labile molecules can exhibit a strong Cotton effect in solution: one chiral conformer is favoured by complexation. The cyclodextrins have the advantage to yield inclusion complex in solution as well as crystalline clathrates. Therefore, the absolute configuration of the guest can be obtained by determining the structure of the cyclodextrin. In this work, the first CD spectrum of 4-helicene is recorded and crystal structures of several clathrates of labile molecules are studied.     

杯芳烃手性识别在核磁中的检测

杯芳烃是一类重要的主体化合物,在主-客体识别分析中有着广泛的用途.手性杯芳烃因其良好的手性识别、对映体分离和不对称催化等特点,成为杯芳烃化学中最令人瞩目的研究热点之一.在手性识别的研究中,核磁因其检测方便、直观、效果显著等优点,成为检测手性化合物的对映体ee值和绝对构型中最为广泛的方法.综述了近年来以杯芳烃为分子骨架的手性受体的合成及其在核磁中的手性识别,最后对手性杯芳烃的发展前景作了展望.     

Chiral trialkanolamine-based hemicryptophanes: synthesis and oxovanadium complex

[reaction: see text] A novel class of chiral hemicryptophane hosts has been synthesized in diastereoisomerically pure form, namely, M-(R,R,R)-1a/P-(S,S,S)-1a and M-(S,S,S)-1b/P-(R,R,R)-1b. The C3-symmetrical precursor 9 was prepared, using either (R)- or (S)-glycidyl nosylate, repectively, as the chiral pool reactant and subsequently cyclized (trimerized) in the presence of Sc(OTf)3. The four stereoisomers were fully characterized and displayed two pairs of mirror-image CD spectra, which were used to determine their absolute configuration. The formation of the oxovanadium(V) complex of hemicryptophane 1a is also reported.     

振动圆二色谱: 一种确定手性分子绝对构型的新方法

手性分子绝对构型的确定是一个极其重要且长期存在的问题. 振动圆二色谱是在红外波长区域测定分子圆二色性的一种新方法, 极大地扩展了圆二色谱的应用范围. 振动圆二色谱法通过构象搜索、量子化学计算等手段准确预测手性分子的振动圆二色谱图, 进而与实测谱图进行比较确定其绝对构型. 该方法已经得到了越来越广泛的应用, 必将成为一种有效测定手性分子绝对构型的常规方法.