基于噁唑烷酮的不对称催化合成构建多官能化手性氨基酸类化合物

多官能化手性氨基酸及其衍生物是一类重要的手性药物以及合成手性药的关键中间体,如现在大量用于临床的左甲状腺素、赖诺普利、阿莫西林、缬沙坦、头孢氨苄以及青霉素等。进行多官能化手性氨基酸类化合物的不对称催化合成,可为新型化学药的设计与发现开辟新的视野。噁唑烷酮(Azlactone)被证明是合成四取代氨基酸衍生物的优秀底物。可通过不对称催化手段向其中引入需要的基团,再经多取代的噁唑烷酮直接开环得到一系列的目标化合物。本文主要综述了近年来基于恶唑烷酮的不对称催化反应构建四取代氨基酸类化合物的研究。     

Semipreparative enantioseparation of Tröger base derivatives by HPLC

We describe the enantioseparation of functionalized derivatives of the Tr?ger base by HPLC on commercially available chiral stationary phases. Cellulose-derived Chiralcel OJ and brush-type Whelk O1 are demonstrated to be complementary to each other in their scope. On the basis of the results obtained, the separation of selected compounds was successfully transferred onto semipreparative columns. We believe that the availability of enantiopure functionalized derivatives of the Tr?ger base will stimulate the further use of this interesting molecular scaffold in molecular recognition, asymmetric catalysis, and related areas of research and technology.     

Cheap and Long‐Life Reusable Polymer for Asymmetric Organozinc Catalysis Based on Camphor‐Derived Hydroxyamides

Polystyrene grafted with a chiral zinc‐complexing camphor‐derived N,N‐disubstituted hydroxyamide is proposed as a new type of functional polymer of high reusability for the development of sustainable organozinc‐catalyzed asymmetric reactions. The main goal of this new functional polymer is the ease of the hydroxyamide‐moiety preparation (cheap chiral ligand obtained straightforwardly from an enantiopure starting material coming from the chiral pool), as well as its chemical robustness when compared with other related zinc‐complexing functional groups. The latter allows the polymer to be active after multiple applications, without significant loss of its catalytic activity. This fact is exemplified by the design and preparation of a polymer functionalized with a bis(hydroxyamide) proved previously as active in the homogeneous enantioselective addition of diethylzinc to aldehydes. The result is a cheap functional polymer with a very high reusability (the enantioselectivity and chemical yield are maintained practically constant after 20 applications). Additionally, a methodology for the multicycle use of these functional polymers is presented. Chirality, 2012. © 2012 Wiley Periodicals, Inc.     

微生物酶转化合成手性药物的研究进展

通过微生物酶催化不对称合成反应或拆分外消旋体合成医药手性中间体具有独特的优势。结合作者自身近年来在该技术领域的实践对相关课题作了介绍,总结了微生物酶催化不对称反应和拆分反应得到手性药物的研究进展。     

Multifunctional chiral aminophosphines for enantiodivergent catalysis in a palladium-catalyzed allylic alkylation reaction

Trifunctional MAP-based chiral phosphines were tested as new ligands in a Pd-catalyzed asymmetric allylic alkylation, demonstrating fast and enantiodivergent catalysis. The palladium complexes of representative ligands by X-ray analysis revealed a novel mode of P,N-coordination of the ligand to the palladium center, which may contribute to switching the sense of the asymmetric induction via combined steric and tunable H-bonding interactions between the metal complex and the substrates.     

Dissipative structures and amplification of enantiomeric excess (an experimental point of view)

Various mathematical models have been proposed to account for the origin of chiral molecules in biological systems. Most of these models invoke non-linear phenomena, and are based on the general concept of dissipative structures. These theoretical models define the fundamental criteria which must be obeyed by the experimental systems that we have investigated. Our initial approach to this problem was an extensive search of the literature data in order to select a few systems or experimental situations which would satisfy the criteria defined by the theoretical models. For these reasons, we carried out a study of the possibility of stereospecific autocatalysis in the asymmetric polymerisation of benzofuran. Similarly, the formation of spatial dissipative structures by coupling of a transport process with an interfacial reaction was investigated as a simple experimental example of symmetry breaking.     

Spectroscopy for model heterogeneous asymmetric catalysis

Heterogeneous catalysis has vastly benefited from investigations performed on model systems under well‐controlled conditions. The application of most of the techniques utilized for such studies is not feasible for asymmetric reactions as enantiomers possess identical physical and chemical properties unless while interacting with polarized light and other chiral entities. A thorough investigation of a heterogeneous asymmetric catalytic process should include probing the catalyst prior to, during, and after the reaction as well as the analysis of reaction products to evaluate the achieved enantiomeric excess. I present recent studies that demonstrate the strength of chiroptical spectroscopic methods to tackle the challenges in investigating model heterogeneous asymmetric catalysis covering all the abovementioned aspects.     

On the role of chiral catalysts in the alkenyl zirconocene/zinc addition to aldehydes: a study of ligand loading and asymmetric amplification

Unusual nonlinear asymmetric amplification and chiral ligand loading effects were discovered for the use of catalytic quantities of chiral aminoalcohols in the in situ hydrozirconation-transmetalation-aldehyde addition processes. While the stereochemically most efficient aminothiol ligands demonstrated mechanistically conventional reaction parameters in excellent agreement with Kagan's ML(2) system, the asymmetric induction in the presence of a chiral aminoalcohol was found to vary greatly with loading and %ee of the ligand. Aminothiols remain the ligands of choice for the highly enantioselective formation of allylic alcohols and provide experimentally more predictable reaction variables. However, new, optimized conditions lead to a synthetically useful product %ee using the readily available and scalable aminoalcohol 2a.     

Strategic use of preparative chiral chromatography for the synthesis of a preclinical pharmaceutical candidate

The modern use of preparative chromatography in pharmaceutical development is illustrated by the case of a recent preclinical candidate from these laboratories. The synthesis of the candidate employed a coupling of two enantiopure intermediates, each of which could be resolved using preparative chiral chromatography. SFC screening was employed to identify the enantioselective stationary phases, and semipreparative SFC methods derived from this screening were used to produce gram amounts of enantiopure intermediate for initial studies. However, initial larger scale resolution required the translation of the SFC methods to HPLC conditions. Preparative chiral HPLC on a 30-cm i.d. column was then used to produce enantiopure intermediates which were coupled to give 170 g of the preclinical candidate. Subsequent preparation of the candidate at larger scale for later-stage clinical evaluation employed an improved synthesis in which one component was constructed by asymmetric synthesis. Resolution of the other component, now a more advanced intermediate, was carried out using newly obtained large-scale SFC equipment. Some discussion is presented on the varying strategies whereby preparative chiral chromatography can be used to support either short-term or long-term synthetic goals in preclinical pharmaceutical development.     

Polyamino acids as synthetic enzymes: mechanism, applications and relevance to prebiotic catalysis

Polyamino acids, such as polyleucine, behave as synthetic enzymes in the asymmetric epoxidation of chalcone and other electron-deficient alkenes (the Julià-Colonna reaction). The influences of reaction conditions, of the molecular structure of the catalysts and of the scaling-up of the process on the enantioselectivity of the reaction have been determined. The kinetics and mechanism have been investigated using a soluble PEG-polyleucine conjugate, which behaves in a similar way to an enzyme, showing saturation kinetics for both chalcone and HOO-. Enantioselective catalysis is achieved with peptides with as few as five residues and scalemic catalysts show high chiral amplification. Here, we discuss the relevance of these-enzyme like catalysts to prebiotic processes, such as the role of small peptides in the formation of optically active cyanohydrins.     

Design, classification, and strategies of synthesis of modular bidentate ligands based on aryl[2.2]paracyclophane backbone

The aryl[2.2]paracyclophane backbone, which is a "hybrid" of a configurationally rigid [2.2]paracyclophanyl unit and a biphenyl unit, is proposed as a new source for the chiral ligands. Classification of such ligands in accordance with mutual arrangement of the functional substituents and their nature is also introduced. Key strategic approaches to the synthesis of regioisomeric biphenols and hydroxyaldehydes, including Suzuki cross-coupling reaction, lithiation/electrophilic quench, and chiral resolution, are elaborated. Examples of their further modification and application of several O,O- and N,O-ligands as chiral inductors in asymmetric catalysis are described.     

Racemization and the origin of optically active organic compounds in living organisms

The organic compounds synthesized in prebiotic experiments are racemic mixtures. A number of proposals have been offered to explain how asymmetric organic compounds formed on the Earth before life arose, with the influence of chiral weak nuclear interactions being the most frequent proposal. This and other proposed asymmetric syntheses give only slight enantiomeric excess and any slight excess will be degraded by racemization. This applies particularly to amino acids where half-lives of 10(5)-10(6) years are to be expected at temperatures characteristic of the Earth's surface. Since the generation of chiral molecules could not have been a significant process under geological conditions, the origins of this asymmetry must have occurred at the time of the origin of life or shortly thereafter. It is possible that the compounds in the first living organisms were prochiral rather than chiral; this is unlikely for amino acids, but it is possible for the monomers of RNA-like molecules.     

Terrestrial and extraterrestrial sources of molecular homochirality

The unique chirality of biomolecules is reviewed, and the prebiotic requirement for the absolute chiral homogeneity of such molecules prior to their capability of self-replication is emphasized. Biotic and abiotic theories embracing both chance and determinate mechanisms which have been proposed for the origin of terrestrial chiral molecules are briefly summarized and evaluated, as are abiotic mechanisms for the subsequent amplification of the small enantiomeric excesses (e.e.s) in the chiral molecules which might be formed by such processes. While amplification mechanisms are readily validated experimentally and are potentially viable on the primitive Earth, it is concluded that all terrestrial mechanisms proposed for the origin of chirality have one or more limitations which make them either intrinsically invalid or highly improbable in the chaotic and turbulent environment of the prebiotic Earth. To circumvent these difficulties we have proposed an extraterrestrial scenario for the production of terrestrial chirality in which circularly polarized synchrotron radiation from the neutron star remnant of a supernova interacts with the organic mantles on interstellar grains, producing chiral molecules by the partial asymmetric photolysis of racemic constituent in the mantles, after which the interstellar grains with their enantiomerically enriched mantles are transported to Earth either by direct accretion or through cometary impact. At this point one of the known terrestrial e.e. enrichment mechanisms could promote the small extraterrestrially produced e.e.s. into the state of chiral homogeneity required for self-replicating biomolecules.     

Synthesis of the optical isomers of a new anticholinergic drug, penehyclidine hydrochloride (8018)

A practical diastereoselective synthetic method for 8018 enantiopure isomers is described. The intramolecular asymmetric epoxidation of mono-sulfonate 4 was applied for the execution of the synthesis of the key chiral building block for the first time. The isomers were obtained with 70-76% yields in 99-100% ee.     

Analysis of the mechanism of asymmetric amplification by chiral auxiliary trans-1,2-diaminocyclohexane bistriflamide

Asymmetric amplification is a phenomenon in which the enantiomeric excess (ee) of a product is higher than that of a chiral auxiliary for a catalyst. We analyzed the mechanism of asymmetric amplification observed in the addition of diethylzinc (Et(2)Zn) to benzaldehyde (PhCHO) to synthesize 1-phenyl-1-propanol in the presence of trans-1,2-diaminocyclohexane bistriflamide (DCBF) and titanium tetraisopropoxide (TIOP). In a manner similar to the reaction in which 1-piperidino-3,3-dimethyl-2-butanol is a chiral auxiliary for the catalyst, when asymmetric amplification was observed, the ee of the product varied as the reaction progressed. The mechanisms of variation in ee in the two reactions, however, were different. No asymmetric amplification was observed when TIOP and PhCHO were added to a mixture of DCBF and Et(2)Zn, while the ee of the product was always higher than that of DCBF when PhCHO and Et(2)Zn were added to a mixture of DCBF and TIOP. In the latter case, the product ee decreased as the reaction progressed. The results indicate that DCBF forms inactive heterochiral complex causing an increase in the ee of DCBF in the solution, which is the chiral auxiliary for the catalyst. But the complex is not very stable and gradually dissociates due to the reaction with Et(2)Zn. As a result, the asymmetric amplification decreases as the reaction progresses.     

Spectroscopic,Structural, and Computational Characterization of Three Bispidinone Derivatives,as Ligands for Enantioselective Metal Catalyzed Reactions

Three chiral derivatives of the alkaloid sparteine (bispidines), characterized by the 3,7‐diazabicyclo[3.3.1]nonane moiety, were designed as efficient ligands in a number of enantioselective reactions due to their metal coordination properties. A full evaluation of the 3D properties of the compounds was carried out, as the geometrical features of the bicyclic framework are strictly related to the efficiency of the ligands in the asymmetric catalysis. The selected molecules have different molecular complexity for investigating the effects of different chiral groups on the bicycle conformation. We report here a thorough analysis of their molecular arrangement, by NMR spectroscopy, single crystal X‐ray crystallography, and computational techniques, which put in evidence their conformational preferences and the parameters needed for the design of more efficient ligands in asymmetric synthetic routes. The results confirmed the high molecular flexibility of the compounds, and indicated how to achieve a control of the chair–chair/boat–chair conformational ratio, by adjusting the relative size of the substituents on the piperidine nitrogens. Chirality 28:332–339, 2016. © 2016 Wiley Periodicals, Inc.     

Asymmetric Autocatalysis Induced by Chiral Crystals of Achiral Tetraphenylethylenes

The achiral hydrocarbon tetraphenylethylene crystallizes in enantiomorphous forms (chiral space group: P2₁) to afford right- and left-handed hemihedral crystals, which can be recognized by solid-state circular dichroism spectroscopic analysis. Chiral organic crystals of tetraphenylethylene mediated enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde to give, in conjunction with asymmetric autocatalysis with amplification of chirality, almost enantiomerically pure (S)- and (R)-5-pyrimidyl alkanols whose absolute configurations were controlled efficiently by the crystalline chirality of the tetraphenylethylene substrate. Tetrakis(p-chlorophenyl)ethylene and tetrakis(p-bromophenyl)ethylene also show chirality in the crystalline state, which can also act as a chiral substrate and induce enantioselectivity of diisopropylzinc addition to pyrimidine-5-carbaldehyde in asymmetric autocatalysis to give enantiomerically enriched 5-pyrimidyl alkanols with the absolute configuration correlated with that of the chiral crystals. Highly enantioselective synthesis has been achieved using chiral crystals composed of achiral hydrocarbons, tetraphenylethylenes, as chiral inducers. This chemical system enables significant amplification of the amount of chirality using spontaneously formed chiral crystals of achiral organic compounds as the seed for the chirality of asymmetric autocatalysis.     

Zirconium-mediated asymmetric baeyer-villiger oxidation

Combinations of axially chiral C2-symmetric diols were used as ligands in zirconium-mediated Baeyer-Villiger reactions. The in situ preformed Zr-diol species proved effective in the asymmetric oxidation of bicyclic and monosubstituted cyclobutanones when a hydroperoxide was employed as oxidant. Asymmetric induction could be preserved upon replacement of one out of two enantiopure BINOL ligands by conformationally flexible 2,2'-biphenol.     

Synthesis of highly potent second-generation taxoids through effective kinetic resolution coupling of racemic beta-lactams with baccatins

A series of highly potent second-generation taxoids bearing a 2-methylprop-1-enyl or a 2-methylpropyl group at C-3' with modifications at the C-2, C-10, and C-14 positions was synthesized through the coupling of racemic cis-beta-lactams with properly protected/modified baccatin and 14-OH-baccatin. A high level of kinetic resolution was observed for all cases examined. The observed highly efficient enantiomer differentiation is ascribed to the markedly different chiral environment between the (+)- and (-)-beta-lactams in their approach to the chiral framework of the enantiopure lithium alkoxide of a baccatin in the ring-opening coupling process. It was also observed that substantially higher selectivity was achieved when 14-OH-baccatin-1,14-carbonate was used. Analysis of the transition state models revealed that the repulsive interactions between the 3-TIPS group of a (-)-beta-lactam with 1, 14-carbonate group of the baccatin substantially increases the asymmetric bias in the kinetic resolution process, favoring the reaction of a (+)-beta-lactam, which leads to the observed excellent selectivity.     

Regioselective enzymatic acylation of multi-hydroxyl compounds in organic synthesis

With current developments in enzyme-catalyzed reactions and techniques available for rational redesign of natural biocatalysts, the enzymatic biosynthesis can become one of the most valuable synthetic methods. Enzymatic regioselective catalysis in organic media has played a key role in pursuing asymmetric synthesis for active chiral compounds. Here, we shortly describe some historical issues of the rapidly growing area, enzymatic catalysis in synthetic organic chemistry and then review researches that have been carried out in the regioselective enzymatic catalysis for the past two decades. An application of this technology to the modification of some potential target drug compound will be also presented.