Titanium(IV) alkoxide ligand exchange with alpha-hydroxy acids: the enantioselective aldol addition

Ligand exchange of titanium(IV) alkoxides with alpha-hydroxy acids presents an unexpected and novel approach to enantioselective aldol additions of aldehydes and ketones. The aldol products were isolated in a high degree of syn-diastereoselectivity. High enantioselectivities were observed by using simple optically pure alpha-hydroxy acids in this novel aldol addition.     

Dynamic kinetic resolution via dual-function catalysis of modified cinchona alkaloids: asymmetric synthesis of alpha-hydroxy carboxylic acids

A highly enantioselective catalytic transformation of racemic alpha-hydroxy acids to optically active alpha-hydroxy acids is reported. A new procedure was developed for the condensation of racemic alpha-hydroxy acids with trichloromethyl chloroformate (diphosgene) at room temperature in the presence of activated charcoal to form 5-substituted-1,3-dioxolane-2,4-diones in 90-100% yield. An efficient dynamic kinetic resolution of 5-aryl dioxolanediones was realized via a modified cinchona alkaloid-catalyzed alcoholytic opening of the dioxolanedione ring, generating a variety of optically active alpha-hydroxy esters in 91-96% ee and 61-85% chemical yield. In this dynamic kinetic resolution, the modified cinchona alkaloid was found to serve dual catalytic roles, mediating both the rapid racemization of the 5-aryl dioxolanediones and the enantioselective alcoholytic ring opening of the 5-aryl dioxolanediones. Consequently, both enantiomers of the 5-aryl dioxolanediones were converted to highly enantiomerically enriched aromatic alpha-hydroxy esters in yields (61-85%), far exceeding the maximum of 50% for a normal kinetic resolution. This development not only represents an expansion of the scope of asymmetric acyl-transfer catalysis of synthetic catalysts but also provides a new approach for the development of efficient chemical dynamic kinetic resolutions promoted by a single catalyst. 5-Alkyl dioxolanediones were resolved by a conventional but highly enantioselective kinetic resolution to provide alpha-hydroxy acids and esters in high optical purity and good yields.     

Enantioselective conjugate addition of N,N-dialkylhydrazones to alpha-hydroxy enones

The activation of alpha-hydroxy enones by the Zn(OTf)2/tBuBOX catalyst enables the enantioselective conjugate addition of 1-methyleneaminopyrrolidine as a neutral d1 synthon. Experimental evidence supports a stereochemical model where a triflate ligand controls the geometry of the catalyst-substrate complex by means of a OH-OTf hydrogen bond. The synthesis of beta-cyano acids illustrates the potential of the methodology.     

Enantioselective total synthesis of erogorgiaene: applications of asymmetric Cu-catalyzed conjugate additions of alkylzincs to acyclic enones

The first enantioselective synthesis of erogorgiaene (1), an inhibitor of mycobacterium tuberculosis, is disclosed. The total synthesis highlights the utility of asymmetric conjugate additions (ACA) of alkylzincs to acyclic alpha,beta-unsaturated ketones catalyzed by peptidic phosphine ligands and (CuOTf)(2).C(6)H(6). Moreover, several critical attributes of this catalytic C-C bond-forming reaction are illustrated in the context of the total synthesis; these include the significance of various structural features of the amino acid-based chiral ligands and the chiral ligand's effectiveness in reactions involving achiral and chiral substrates. In addition, the total synthesis showcases some of the special properties of nonphosphine Ru complex 3 as a highly effective catalyst for olefin cross-metathesis.     

Application of the chiral acyl anion equivalent,trans-1,3-dithiane 1,3-dioxide,to an asymmetric synthesis of (R)-salbutamol

An enantioselective synthesis of (R)-salbutamol has been carried out using the chiral, C2 symmetric acyl anion equivalent, (1R,3R)-1,3-dithiane 1,3-dioxide, which undergoes addition to an aromatic aldehyde with very high stereocontrol at 0 degrees C. Pummerer reaction and work-up with lithium ethanethiolate generated the alpha-hydroxy thiolester in high yield and further transformations led to the target compound with high enantiomeric excess.     

Unexpected stereorecognition in nitrilase-catalyzed hydrolysis of beta-hydroxy nitriles

Biocatalytic enantioselective hydrolysis of beta-hydroxy nitriles to corresponding (S)-enriched beta-hydroxy carboxylic acids has been achieved for the first time by an isolated nitrilase bll6402 from Bradyrhizobium japonicum USDA110. This offers a new "green" approach to optically pure beta-hydroxy nitriles and beta-hydroxy carboxylic acids. The observed remote stereorecognition is surprising because this nitrilase shows no enantioselectivity for the hydrolysis of alpha-hydroxy nitriles such as mandelonitrile.     

Palladium-catalysed asymmetric arylation of tert-cyclobutanols via enantioselective C-C bond cleavage

Palladium-catalysed arylation of tert-cyclobutanols with aryl bromide involving enantioselective C-C bond cleavage affords chiral ketones with moderate to good enantioselectivity.     

联二萘酚类磷酸吡哆醛模拟酶的合成与应用研究进展

模拟酶化合物的合成与应用研究具有重要的理论和实际意义。近年来研究的一些联二萘酚类磷酸吡哆醛模拟酶具有氨基酸构型转换的功能,并可用于手性氨基醇的对映选择性识别。本文简要介绍了该类化合物的合成方法,综述了近年来联二萘酚类磷酸吡哆醛模拟酶在手性氨基酸构型转换、手性氨基醇对映选择性识别以及萃取拆分等方面的应用。     

A New Strategy for the Synthesis of alpha-Difluoromethyl-Substituted alpha-Hydroxy and alpha-Amino Acids

A new method for the preparation of alpha-chlorodifluoromethyl-, alpha-bromodifluoromethyl-, and alpha-difluoromethyl-substituted alpha-hydroxy and alpha-amino acid esters 11, 19-21 is described. The key step of the synthesis is the regioselective alkylation of ketones 5, 7-9 and imines 16-18 with C-nucleophiles. The ketones 7-9 are readily available from 3,3,3-trifluorolactate 1 by a five-step procedure. Subsequent removal of the protecting groups from 19-21 provides the corresponding free amino acids 25, 26, 28.     

Kinetic resolution of racemic carboxylic acids by an L-histidine-derived sulfonamide-induced enantioselective esterification reaction

The direct and catalytic kinetic resolution of racemic carboxylic acids bearing a Br?nsted base such as O-protected alpha-hydroxy carboxylic acids and N-protected alpha-amino acids has been accomplished through an L-histidine-derived sulfonamide-induced enantioselective esterification reaction with tert-butyl alcohol for the first time. Highly asymmetric induction [S( k fast/ k slow) = up to 56] has been achieved under the equilibrium between a chiral catalyst and two diastereomeric acylammonium salts through an intramolecular hydrogen-bonding interaction.     

Enantioselective synthesis of 2-substituted cyclobutanones

[formula: see text] An enantioselective synthesis of 2-substituted cyclobutanones has been achieved by sequential application of the titanium-mediated cyclopropanation of alpha-hydroxy esters and the pinacol-type rearrangement of the resulting alpha-hydroxycyclopropylcarbinols.     

Bifunctional transition metal-based molecular catalysts for asymmetric syntheses

The discovery and development of conceptually new chiral bifunctional transition metal-based catalysts for asymmetric reactions is described. The chiral bifunctional Ru catalyst was originally developed for asymmetric transfer hydrogenation of ketones and imines and is now successfully applicable to enantioselective C-C bond formation reaction with a wide scope and high practicability. The deprotonation of 1,3-dicarbonyl compounds with the chiral amido Ru complexes leading to the amine Ru complexes bearing C- or O-bonded enolates, followed by further reactions with electrophlies gives C-C bond formation products. The present bifunctional Ru catalyst offers a great opportunity to open up new fundamentals for stereoselective molecular transformation including enantioselective C-H and C-C as well as C-O, C-N bond formation.     

Asymmetric reduction of representative ketones with a bis-chiral oxazaborolidine system

In recent years, many optically active β-amino alcohols, mostly derived from naturally occurring α-amino acids, have been incorporated into the asymmetric synthesis as chiral auxiliaries or ligands.1 An effective asymmetric catalysts, the oxazaborolidine-borane reagents, which were originally pioneered by Itsuno and Corey,2 were generally prepared from chiral β-amino alcohols by the reaction with boric acid or formed in situ in the presence of borane. These reagents provide excellent enanti…     

Palladium-catalyzed asymmetric arylation,vinylation, and allenylation of tert-cyclobutanols via enantioselective C-C bond cleavage

A novel enantioselective C-C bond cleavage has been achieved using palladium catalysts and chiral N,P-bidentate ligands in the asymmetric arylation, vinylation, and allenylation of tert-cyclobutanols. In these reactions, the enantioselective beta-carbon elimination of Pd(II) alcoholate formed in situ is the key step. Treatment of tert-cyclobutanols with arylating reagents in toluene in the presence of Pd(OAc)(2), a chiral ferrocene-containing N,P-bidentate ligand, and Cs(2)CO(3) affords optically active gamma-arylated ketones in excellent yields with high enantioselectivity (up to 95% ee). When vinylating reagents are used in place of arylating ones, the asymmetric vinylation also proceeds to afford optically active gamma-vinylated ketones in high yields with good to high enantioselectivity. When propargylic acetates are used, which are known to generate (sigma-allenyl)palladium complexes with Pd(0) species, asymmetric allenylation occurs to afford optically active gamma-allenylated ketones in moderate to good yields with moderate to high enantioselectivity.     

Catalytic asymmetric reductive coupling of alkynes and aldehydes: enantioselective synthesis of allylic alcohols and alpha-hydroxy ketones

A highly enantioselective method for catalytic reductive coupling of alkynes and aldehydes is described. Allylic alcohols are afforded with complete E/Z selectivity, generally >95:5 regioselectivity, and in up to 96% ee. In conjunction with ozonolysis, this process is complementary to existing methods of enantioselective alpha-hydroxy ketone synthesis.     

Towards practical biocatalytic Baeyer-Villiger reactions: applying a thermostable enzyme in the gram-scale synthesis of optically-active lactones in a two-liquid-phase system

Baeyer-Villiger monooxygenases (BVMOs) are extremely promising catalysts useful for enantioselective oxidation reactions of ketones, but organic chemists have not used them widely due to several reasons. These include instability of the enzymes in the case of in vitro and even in vivo systems, reactant/product inhibition, problems with upscaling and the necessity of using specialized equipment. The present study shows that the thermally stable phenylacetone monooxygenase (PAMO) and recently engineered mutants can be used as a practical catalysts for enantioselective Baeyer-Villiger oxidations of several ketones on a preparative scale under in vitro conditions. For this purpose several parameters such as buffer composition, the nature of the solvent system and the co-factor regeneration system were optimized. Overall a fairly versatile and efficient catalytic system for enantioselective laboratory scale BV-oxidations of ketones was developed, which can easily be applied even by those organic chemists who are not well versed in the use of enzymes.     

Catalytic asymmetric cyanosilylation of ketones with chiral Lewis base

The development of broadly applicable and practical catalytic approaches for the enantioselective creation of quaternary stereocenters remains a highly desirable yet challenging goal. In this Communication, we describe a highly enantioselective cyanosilylation of acetal ketones (alpha,alpha-dialkoxy ketones) catalyzed by modified cinchona alkaloids. This reaction is the first highly enantioselective cyanosilylation of ketones catalyzed by an organic chiral Lewis base and is found to be highly efficient with acetal ketones bearing a broad range of alkyl, aryl, alkenyl, and alkynyl substituents. This new catalytic asymmetric reaction, coupled with the versatility of the acetal functionality, provides a broadly useful synthetic method for chiral building blocks bearing quaternary stereocenters. Acetal ketones, readily accessible but previously unexplored in asymmetric synthesis, demonstrate unusual reactivity and selectivity toward the nucleophilic cyanosilylation, thereby suggesting that they may be interesting substrates for other catalytic enantioselective reactions.     

Catalytic concepts for the enantioselective synthesis of alpha-amino and alpha-hydroxy phosphonates

The enantioselective synthesis of alpha-amino- and alpha-hydroxy phosphonates by catalytic processes has attracted considerable interest in the last few years, not least because of the pharmaceutical interest in such compounds. This article contains a compilation of the asymmetric synthesis methods developed to date. The described synthetic routes are based on different catalytic concepts, namely, hydrogenation, reductions, dihydroxylation, aminohydroxylation, and hydrophosphonylation.     

过渡金属催化的有机硼试剂对醛酮的不对称加成研究进展

手性芳基醇是一类重要的合成砌块,广泛存在于许多生物活性分子以及天然产物中,因此,高效高选择性地构建该类化合物是有机化学家们一直关注的研究热点.金属试剂对羰基化合物的不对称加成是构建手性芳基醇的一个简单高效的方法,其中,有机硼试剂由于其方便易得、稳定、低毒、官能团耐受性好等优点而被广泛用于醛、酮的不对称加成反应中.本文综述了过去二十年来过渡金属催化的有机硼试剂对醛、酮的不对称加成反应研究进展,并介绍了一些方法在生物活性手性分子合成中的应用.     

Enantioselective synthesis of chiral sulfones by Rh-catalyzed asymmetric addition of boronic acids to alpha,beta-unsaturated 2-pyridyl sulfones

A general and efficient method for the rhodium-catalyzed enantioselective catalytic conjugate addition of organoboronic acids to alpha,beta-unsaturated sulfones is described. The success of the process relies on the use of alpha,beta-unsaturated 2-pyridyl sulfones as key metal-coordinating substrates; typical sulfones such as vinyl phenyl sulfones are inert under the reaction conditions. Among a variety of chiral ligands, Chiraphos provided the best asymmetric induction. This rhodium [Rh(acac)(C2H4)2]/Chiraphos catalyst system has a broad scope, being applicable to the addition of both aryl and alkenyl boronic acids to cis and trans alpha,beta-unsaturated 2-pyridyl sulfones. In most cases, especially in the addition of aryl boronic acids, the reactions take place cleanly and with high enantioselectivity, affording chiral beta-substituted 2-pyridyl sulfones in good yields and enantioselectivities (70-92% ee). The sense and magnitude of this enantioselectivity have been studied by DFT theoretical calculations of the aryl-rhodium insertion step. These calculations strongly support the formation of a five-membered pyridyl-rhodium chelated species as the most stable complex after the insertion into the C=C bond. These highly enantioenriched chiral sulfones are very appealing building blocks in enantioselective synthesis. For instance, the straightforward elimination of the 2-pyridylsulfonyl group by either Julia-Kociensky olefination or alkylation/desulfonylation sequences provides a variety of functionalized chiral compounds, such as allylic substituted alkenes or beta-substituted ketones and esters.