Asymmetric reactions based on activation and structure control of molecule--asymmetric reaction of lithiated nucleophiles

The methodology we developed relies on an external chiral coordinating reagent that forms a deaggregated chelate complex with organolithium reagents. Under the positive control of a chiral dimethyl ether of stilbenediol 4, an asymmetric conjugate addition reaction of organolithium reagents with unsaturated imines and esters proceeded successfully to yield the corresponding addition products with reasonably high stereoselectivity. The sense of stereochemistry is predictable based on a coordination model. The methodology has been extended to a catalytic asymmetric 1,2-addition reaction of organolithium reagents with imines. An enantiotopic group differentiating the opening of cyclohexene oxide with organolithium was also mediated by a chiral ligand. The asymmetric Horner-Wadsworth-Emmons reaction of phosphonates and Peterson reaction of alpha-silylester with 4-substituted cyclohexanone were another successful extension of the methodology. A three-component reagent of lithium ester enolate, lithium amide, and chiral diether reacts with imines to afford beta-lactam with reasonably high enantioselectivity. Tridentate aminoether ligands were also shown to affect the catalytic asymmetric addition of lithium ester enoaltes to imines, giving beta-lactams with high enantioselectivity. Asymmetric conjugate addition of lithium amide to enoates was mediated by a chiral diether ligand to give the beta-aminoester with high yield and enatioselectivity. The methodology has been successfully applied to an asymmetric synthesis of biologically potent compounds. Dihydrexidine, a promising anti-Parkinsonism candidate, and salsolidine, a representative isoquinoline alkaloid, have been synthesized using asymmetric addition reactions of organolithium reagents as the key steps.     

Development of highly stereoselective reactions using lone pairs of oxygen atoms

Highly stereoselective reactions have been developed using lone pairs of oxygen atoms, in other words, the nucleophilic ability of oxygen atoms. They consist of five types of reactions: 1) asymmetric synthesis using acetals, 2) organic reactions via Beckmann fragmentation intermediates, 3) organic reactions via dication equivalents, 4) rearrangement of 2,3-epoxy-1-alcohol derivatives, and 5) organic reactions using orthoesters. In this review, asymmetric syntheses using acetals are described in detail. They are divided into four categories: 1) diastereoselective 1,2-addition(alkylation, reduction) to the alpha-keto acetals and their derivatives, 2) asymmetric carbon-carbon bond formation by a combination of Beckmann fragmentation and asymmetric synthesis using C2-symmetric chiral acetals, 3) asymmetric synthesis via chiral oxonium ions prepared by intramolecular haloetherification of chiral ene acetals having C2-symmetric hydrobenzoin, and 4) asymmetric desymmetrization of meso-1,2-, meso-1,3-, and meso-1,4-diols via chiral oxonium ions prepared by intramolecular haloetherification of chiral ene acetals derived from optically pure norbornen aldehyde derivatives, and their applications to asymmetric syntheses of biologically active natural products.     

Scalable enantioselective processes for chiral pharmaceutical intermediates

The importance and practicality of asymmetric synthesis to obtain enantiomerically pure drug substances has been fully recognized by process chemists of the pharmaceutical industry. Catalytic enantioselective processes would be particularly advantageous, compared to processes requiring stoichiometric amounts of chiral initiators, and would also be of interest from an environmental perspective. Since the commercialization of the Monsanto process for the manufacturing of L-DOPA in the early 1970s, catalytic asymmetric reactions have often been utilized in the commercial production of active pharmaceutical ingredients. This review will focus on recent advances in the development of scalable enantioselective processes for chiral pharmaceutical intermediates.     

Development and applications of new reactions for construction of basic structures of natural products]

This review deals with the development of efficient methods to construct the basic structure of natural products and the versatile methods to control the stereochemistry, and these methods were applied to the synthesis of natural compounds. The photochemical spirodienone formation reaction was applied to the synthesis of proaporphine alkaloids. The alternative spirodienone formation reactions by the metal-catalyzed degradation reaction of phenolic alpha-diazoketones were applied to many natural spirocyclic compounds, such as chamigrane type sesquiterpenes, spirovetivane type phytoalexins, marine natural products, and so on. Lewis acid mediated spirocyclization reaction of cyclohexene bis-acetal derivative was developed, and this reaction was applied to the synthesis of aphidicolane and stemodane diterpenes. The regioselective cleavage reaction of the cyclopropane ring of tricyclooctanone derivatives was used for the syntheses of diquinane and triquinane compounds. A chiral pool synthesis of several aromadendrane sesquiterpenes was achieved via common tricyclic enone intermediates. The synthesis of macrocarpals, coupling products of aromadendrane skeleton and isopentylphloroglucinol dialdehyde, was also accomplished for the first time using an arene Cr(CO)3 complex as a chiral benzyl cation equivalent. The Fe(diene)(CO)3 complexes were used for the highly stereoselective asymmetric synthesis of several natural products, such as insect pheromones and alkaloid, as a versatile mobile chiral auxiliary.     

Organometal-catalyzed asymmetric synthesis stereocontrolled by organosulfur functionality

Our recent studies on asymmetric synthesis with the assistance of organometal catalysts stereocontrolled by organosulfur functionality involved in reaction substrates or ligands are reviewed. The studies focused on asymmetric synthesis via chiral pi-allylmetal complexes derived from (S)-proline allyl ester, olefinic cyclopropanes, chiral 2-alkynyl sulfinates, and chiral new ligands, and also focused on asymmetric cycloaddition reactions with chiral sulfoxides and sulfinates, such as intramolecular ene, metallo-type ene, and hetero Diels-Alder reactions. Participation of organosulfur functionality in organometal-catalyzed asymmetric reactions was unveiled on the basis of the stereochemical outcomes obtained.     

C2-对称面手性RuPHOX-Ru催化的不对称氢化反应及其在手性药物合成中的应用

相比于中心手性和轴手性的配体,具有面手性(主要是基于二茂铁)的配体受到的关注较少,基于二茂钌骨架的面手性配体更是鲜有报道。二茂铁与二茂钌的2个环戊二烯负离子环之间的距离分别是0.332 nm和0.368 nm,即二茂钌的2个环戊二烯负离子环之间的距离要比相应的二茂铁的长约10%,这使得以二茂钌为骨架的面手性配体在电子效应与立体效应方面与以二茂铁为骨架的有所差异。本课题组开发的基于二茂钌的C2-对称双膦-(口恶)唑啉配体RuPHOX在许多反应,特别是钌催化的不对称氢化反应中,显示出了优异的化学稳定性和催化性能。其与金属络合后具有双金属反应中心,在提高反应活性的同时,形成更大的空间位阻,合成的RuPHOX的钌络合物RuPHOX-Ru可直接用于含C=O或C=C键底物的不对称氢化反应中。本文简要综述了RuPHOX-Ru催化的含C=O、C=C以及同时含C=O和C=C双键等底物的不对称氢化反应,以及其在手性药物合成中的应用。     

Efficient chiral control based on five-membered heterocyclic and related systems

The synthetic potential of some simple five-membered heterocycles, including 2-oxazolone, 1,3-dihydro-2-imidazolone and 2-thiazolone as building blocks for chiral polyfunctional compounds as well as chiral heterocyclic auxiliaries for asymmetric synthesis is reviewed. The stereodefined introduction of easily replaceable groups to the 4,5-olefinic moiety of the 2-oxazolone ring to give versatile chiral synthons, followed by stereospecific and stepwise substitution, provides a working and versatile strategy for achieving a chiral synthesis, which leads to the preparation of a wide variety of 2-amino alcohols of biological interest. Sterically constrained chiral 2-oxazolidinones and the derived conformationally rigid amino alcohols, which are derived from cycloaddition reactions of the 2-oxazolone to cyclic dienes such as 9,10-dimethylanthracene and hexamethylcyclopentadiene, represent excellent chiral auxiliaries and chiral ligands which are of general use in asymmetric synthesis. The strategy developed using 2-oxazolone can also be used in the cases of the structurally similar 1,3-dihydro-2-imidazolone and 2-thiazolone derivatives.     

Functionalized S-thio-di- and S-oligosaccharide precursors as templates for novel SLex/a mimetic antimetastatic agents

Adhesive interactions between molecules expressed on vascular endothelium and circulating tumor cells are key early events in cancer metastasis. Best characterized to date is the selectin family of cell adhesion molecules, which can bind to and stabilize blood-borne cells on organ vasculature, facilitating the cell-cell and cell-substratum interactions leading to tumor seeding and proliferation. Major ligands of E-selectin, the selectin family member expressed on vascular endothelial cells, include sialylated, fucosylated glycans such as Sialyl Lewis type carbohydrate complexes (SLe(x) and SLe(a)). These carbohydrate antigens are ubiquitously expressed on tumor cells with high metastatic potential, including colon and pancreatic carcinomas, and have been found to selectively and avidly bind E-selectin. Compounds that prevent E-selectin-SLe(x/a)binding represent an attractive tool in the prevention of cancer dissemination. Review of preclinical in vitro and in vivo studies suggest that SLe(x/a) 'mimetics' may serve as a potent class of anti-metastatic compounds. These agents are designed to outcompete SLe(x/a) antigens expressed on tumor cell surfaces to prevent initial vascular adhesion. Critical in generating exogenous oligosaccharides as SLe(x/a) mimetics is the stereoselective joining of specific mono- and di- saccharides that express functional groups integral in E-selectin-SLe(x/a) binding. Employing sulfur linkages to couple saccharide units enhances the biological stability of these complex carbohydrates. The synthesis of novel S-thiodisaccharides and C-disaccharides as SLe(x/a) precursors using the chiral sugars levoglucosenone, isomeric isolevoglucosenone and their functionalized analogs is described. The highly stereoselective functionalization of both enones at the C-4, C-3 and C-2 positions by the set of Michael addition reactions of reactive 1-thiosugars is reviewed. These functionalized S-thio di- and S-oligosaccharide precursors have direct application for use as templates in the synthesis of novel SLe(x/a)mimetics.     

Stereoselective heterocycle synthesis through oxidative carbon-hydrogen bond activation

Heterocycles are ubiquitous structures in both drugs and natural products, and efficient methods for their construction are being pursued constantly. Carbon-hydrogen bond activation offers numerous advantages for the synthesis of heterocycles with respect to minimizing the length of synthetic routes and reducing waste. As interest in chiral medicinal leads increases, stereoselective methods for heterocycle synthesis must be developed. The use of carbon-hydrogen bond activation reactions for stereoselective heterocycle synthesis has produced a range of creative transformations that provide a wide array of structural motifs, selected examples of which are described in this review.     

Enantioselective organocatalysis

Enantioselective organocatalysis has emerged as a powerful synthetic paradigm that is complementary to metal-catalysed transformations and has accelerated the development of new methods to make diverse chiral molecules. The operational simplicity, ready availability of catalysts and low toxicity associated with organocatalysis makes it an attractive method to synthesise complex structures. Here, we discuss the impact of enamine, iminium, nucleophilic and Br?nsted acid catalysts in organic synthesis, and highlight key strategic methods to assemble useful molecules with high enantiomeric purity.     

Synthesis and properties of optically active organoantimony compounds

The chemistry of chiral ligands for transition metal-catalyzed asymmetric reactions is an interesting research field in synthetic chemistry and has recently been the focus of much attention. Although a number of chiral ligands containing phosphorus (P) and arsenic (As) have been widely studied and are well documented, asymmetric reactions with optically active organoantimony compounds have not been reported so far. We are interested in the synthesis and utilization of optically active organoantimony compounds for asymmetric synthesis. We present here the synthesis and resolution of Sb-chiral and C2-symmetric compounds containing antimony as well as their physical and chemical properties. Resolution of (+/-)-1-phenyl-2-trimetylsilylstibindole (1), Sb (R/S)-(aryl) [2-(S)-(1-dimethylaminoethyl) phenyl] (p-tolyl) stibane (9), and (+/-)-2,2'-bis(diarylstibano)-1,1'-binaphthyl (13) can be achieved by the separation of a mixture of the diastereomeric antimony-palladium complexes. The optically pure Sb-chiral stibanes (1, 9) isolated here were optically stable, and no racemization on the chiral antimony center was observed even when they were heated under a neutral or a basic condition. Single-crystal X-ray analysis of Sb-chiral triarylstibane 9b-B revealed the presence of an intramolecular interaction between the antimony and nitrogen atoms. The optically active BINASb (13) can be used as powerful chiral ligand for the palladium-catalyzed asymmetric allylic alkylation of racemic 1,3-diphenyl-2-propen-1-yl acetate with dimethyl malonate. We also report the synthesis, molecular structure, and fluxional behavior of the (R)-(-)-7-p-tolyl-dinaphtho [2, 1-b; 1',2'-d] stibole (21c) which is the first isolated example of optically active C2-symmetric group 15 dinaphthoheteroles.     

Development of asymmetric synthesis of optically active compounds including fluoroorganic molecules

The synthesis of chiral fluorinated molecules is important in the biological and medicinal chemistry fields in view of the influence of fluorine's unique properties on biological activity. In recent years, we have studied asymmetric synthesis focussing on such optically active compounds. This review describes 1) diastereoselective trifluoromethylation of chiral N-acyloxazolidinones, 2) catalytic enantioselective aldol reactions of fluorine-substituted ketene silyl acetals, and 3) catalytic enantioselective allylation of aldehydes mediated by chiral Lewis bases. The trifluoromethylation of lithium enolates of N-acyloxazolidinones with iodotrifluoromethane is mediated by triethylborane to give the corresponding trifluoromethylated products with up to 86% diastereomeric excess. The stereoselective reaction is considered to proceed through the attack of the trifluoromethyl radical on the less hindered face of the lithium imide. Difluoroketene and bromofluoroketene trimethylsilyl ethyl acetals react with various aldehydes in the presence of chiral Lewis acids to afford the corresponding desired aldols with up to 99% enantiomeric excess (ee). It is noteworthy that the aldol reactions of the fluorine-substituted acetals at -78 degrees C and at higher temperatures (-45 or -20 degrees C) provide the (+)- and (-)-aldols, respectively, with excellent-to-good enantioselectivity. Chiral phosphoramides newly prepared from (S)-proline were found to catalyze the allylation and crotylation of aromatic aldehydes with allylic trichlorosilanes in good enantioselective yields (up to 90% ee). (S,S)-Bis(alpha-methylbenzyl)formamide developed as an efficient catalyst for the allylation and crotylation of aliphatic aldehydes mediates the enantioselective addition with the assistance of hexamethylphosphoramide (HMPA) to afford the corresponding homoallylic alcohols in up to 98% ee.     

Carbon-carbon bond formation based on alkenylphosphonates]

We have been engaged in the development of asymmetric conjugate addition reactions of lithium thiolates, organolithiums and organocopper reagents under the control of external chiral ligands and we have also developed an efficient asymmetric Horner-Wadsworth-Emmons (HWE) reaction using an external chiral Ligand. We attempted to synthesize axial chiral allenes by combination of these conjugate addition reaction and HWE reaction. In the course of this study, we found that Michael-aldol reaction of alkenylphosphonates 1 using LDA and aldehydes results in the direct formation of alpha,beta-unsaturated hydroxyphosphonate 4, which was efficiently converted to allene by treatment with KH or KH-18-crown-6. Furthermore, allenes were synthesized by sequential double HWE reaction in one-flask manner starting from methylenebisphosphonate 8. The key to success is a metal exchange of intermediate lithium alkoxide 4-Li to potassium alkoxide 4-K by the addition of t-BuOK. As our continuous study of carbon-carbon bond formation based on alkenylphosphonates, a cyclization reaction of bisalkenylphosphonate 6 was developed. Although the treatment of 6 with organolithium reagents afforded a mixture of addition-cyclization product 9 and deprotonation-cyclization product 10, the treatment of 6 with LDA gave 10 selectively. These cyclization methods were applied to the synthesis of efficient chiral phosphine ligands.     

Separation processes for organic molecules using SCF Technologies

Supercritical fluids have been applied for many years for the separation of solutes from solids or solute mixtures in both exploratory and industrial applications. In the pharmaceutical industry the generation of pure solid states without impurities is important as the presence of impurities can result in a change in chemical properties or lead to physical instability. The literature on the separation and purification of solutes from solid matrices and solute mixtures using supercritical fluids, with the main emphasis on pharmaceutically important molecules, is reviewed in this article. Also discussed is the application of supercritical fluids in the control of process impurities such as chemical intermediates and residual solvent and in polymorphic control and chiral resolution. As the generation of organic molecules of pharmaceutical interest with high purity is important in pharmaceuticals this review additionally provides a brief overview of highly selective chemical reactions in supercritical fluids.     

Enantioseparation of gantofiban precursors on chiral stationary phases of the poly-(N-acryloyl amino acid derivative)-type.

A separation strategy for the preparative enantioseparation of intermediates of the synthesis route towards the new antithrombotic drug Gantofiban is outlined. The selectivities of six different intermediates on a series of chiral stationary phases of the poly-[N-(meth-)acryloyl amino acid derivative]-type are determined. The separations are optimized with respect to high enantioselectivities and good solubilities in the mobile phase. For three optimized combinations of chiral stationary and mobile phases the separation parameters for a simulated moving bed-systems are determined.     

手性叔丁基亚磺酰胺的制备方法及其在药物合成中的应用

手性叔丁基亚磺酰胺是近年来发展起来的一种新型医药中间体,也是合成手性胺类药物及其中间体的关键手性源,其相关研究受到研究人员的广泛关注。综述手性叔丁基亚磺酰胺的制备方法以及该化合物在药物合成领域中的应用情况。     

Development of new methods in asymmetric reactions and their applications

Several novel methods using chiral reagents and biocatalysts for asymmetric reactions are described. Among those reactions, asymmetric reduction via a novel tandem Michael addition/Meerwein-Ponndorf-Verley reduction of acyclic alpha,beta-unsaturated ketones using a chiral mercapto alcohol, asymmetric synthesis of allene-1,3-dicarboxylate via crystallization induced asymmetric transformation, and improved asymmetric nitroolefination of lactones and lactames at alpha-carbon using new chiral reagents were developed. In the reactions using biocatalysts, asymmetric dealkoxycarbonylation of bicyclic beta-keto diesters having sigma-symmetry with lipase or esterase to give optically active beta-keto esters, the asymmetric reduction of bicyclic 1,3-diketones having sigma-symmetry with Baker's yeast to give optically active keto alcohols, and the asymmetric aldol reaction of glycine with threonine aldolase were also developed. The above mentioned products were effectively utilized as chiral building blocks for the asymmetric synthesis of natural products and drugs.     

Redox enzymes used in chiral syntheses coupled to coenzyme regeneration

Due to their ability to perform reactions in a stereo- and regiospecific manner, while functioning under mild conditions of temperature and pH, enzymes are increasingly used for chiral synthesis in the pharmaceutical industry, in medicinal chemistry, agriculture, cosmetic and food industry. The oxidoreductases as catalysts require a coenzyme (cofactor) which functions as an electron carrier. If used in stoichiometric amounts the cost of coenzymes makes synthetic applications of redox enzymes prohibitively expensive for industrial applications. The present review updates previous discussions about the objectives of cofactor regeneration as a requirement for the applicability of enzymatic redox reactions, and about the strategies customarily used to this end. Different types of chiral syntheses coupled successfully to coenzyme regeneration (amino acid synthesis, lactone synthesis, synthetic reactions involving alcohols, hydroxy acid and steroid synthesis, deracemization) are then discussed. New catalysts, cross-linked enzyme crystals, prepared from redox enzyme are presented in a small paragraph together with some of their applications. Special attention is given to whole cells used in this type of synthesis and their advantages and disadvantages are presented in one paragraph. Finally, different reactors, within which were conducted chiral syntheses catalyzed by oxireductases and coupled to cofactor regeneration, are briefly discussed.     

Boehringer Ingleheim's selective glucocorticoid receptor agonist development candidate: evaluation of WO2010141331, WO2010141332 and WO2010141333

Three applications from Boehringer Ingelheim all relate to the preparation of non-steroidal glucocorticoid receptor agonists useful in the treatment of inflammatory respiratory diseases. The first two applications claim chiral processes for the preparation of these compounds or intermediates useful therein. These provide two alternative routes, respectively, using achiral and chiral reagents. The third application relates to the preparation of a crystalline salt of the preferred compound on a multi-kilogram scale in micronised form.     

Spectroscopic methods for determining enantiomeric purity and absolute configuration in chiral pharmaceutical molecules

Analytical support, such as methods development, along with identification and characterization of intermediates and impurities, are critical in the development of a chemical process. The preparation of a drug substance requires the development of analytical methods for monitoring reactions and identifying impurities. Methods development for a chiral drug molecule is more difficult as the method must be capable of monitoring the overall reaction as well as possible racemization of starting materials and products. Chiral methods are often required to monitor the reaction steps of a synthesis, however, the development of enantiomeric purity methods are time-consuming and expensive. The use of chiroptical detectors, such as circular dichroism (CD), optical rotation (OR) and vibrational circular dichroism (VCD), can help to reduce or eliminate the need to develop chiral monitoring methods and also to predict absolute configuration. Recently, VCD has shown remarkable success with the latter and currently holds the most promise as a general, direct method that can be used as an alternative to X-ray crystallography. Each of the mentioned techniques can help analytical chemists to reduce the time associated with traditional enantiomeric purity methods development and to determine absolute configuration. This review will discuss the scope and limitations of these techniques for the rapid and routine determination of both enantiomeric excess and absolute configuration.