Amplification of the enantiomeric excess of a compound in kinetic resolution by a racemic reagent

The possibility of amplifying the small ee of a enantioimpure substance using a racemic reagent in kinetic resolution is discussed. A kinetic treatment of this problem along with some experimental proofs of the concept is presented. Simulation on kinetic resolution of small ee substrate by a racemic reagent showed an important enantioenrichment in the substrate ee, sometimes reaching close to absolute ee. Experiments of kinetic resolution of an amine of a small ee by a racemic acylating reagent gave a substantial amplification in ee of the amine. The possible transformation of an undetectable low ee in substrate to a detectable higher ee by using a suitable racemic reagent is also briefly discussed with help of calculations. The usefulness of asymmetric amplification by a racemic reagent is considered in the context of the biomolecular homochirality on earth.     

A simple chiral shift reagent for measurement of enantiomeric excesses of phosphine oxides

(R)-(?)-N-(3,5-dinitrobenzoyl)-α-phenylethylamine is a chiral shift reagent which allows ee measurements of various phosphine oxides. Good results were obtained for monophosphine oxides with asymmetric phosphorus centers as well as with an asymmetric carbon in α position of phosphorus. The reagent is also able to differentiate the two enantiomers of racemic DIOP dioxide.     

Amplification of chirality as a pathway to biological homochirality

Amplification of enantiomeric enrichment is a key feature for the chemical evolution of biological homochirality from the origin of chirality. The aggregations of the enantiomers by diastereomeric interactions enable the modification of their enantiomeric excess during some chemical processes. Fluorine-containing chiral compounds possess large amplification effect via distillation, sublimation and achiral chromatography by self-disproportionation. Asymmetric amplifications in enantioselective catalysis occur by the differential formation and reactivity between homochiral and heterochiral aggregate in solution.We described the amplification of ee in asymmetric autocatalysis of 5-pyrimidyl alkanol in the reaction between diisopropylzinc and pyrimidine-5-carbaldehdye. During the reactions extremely low ee (ca. 0.00005% ee) can be amplified to achieve more than 99.5% ee. Since the proposed origins of chirality such as CPL, quartz, chiral organic crystals of achiral compounds and statistical fluctuation of ee can initiate the asymmetric autocatalysis with amplification of ee, the proposed origin of chirality can be linked with enantiopure organic compound in conjunction with amplification of ee by asymmetric autocatalysis. In addition, we described that the carbon isotopically chiral compound triggers the asymmetric autocatalysis of 5-pyrimiodyl alkanol to afford the enantioenriched product with the absolute configuration correlated with that of carbon isotope chirality, that is, isotope chirality including hydrogen isotopes can control the enantioselectivity of asymmetric addition of alkyl metal reagent to aldehyde.     

Pd-catalyzed asymmetric allylic alkylation. A short route to the cyclopentyl core of viridenomycin

A palladium-catalyzed asymmetric allylic alkylation effects a dynamic kinetic asymmetric transformation of racemic isoprene monoepoxide and a surrogate for Nazarov's reagent in which a quaternary center is created with exellent ee. The resultant adduct allows easy access to a substrate for ring-closing metathesis to form a cyclopentenone and sets the stage for an 11-step synthesis of the cyclopentyl core of the antibiotic antitumor agent viridenomycin. [reaction: see text]     

Transitioning enantioselective indicator displacement assays for alpha-amino acids to protocols amenable to high-throughput screening

Enantioselective indicator displacement assays (eIDAs) for alpha-amino acids were conducted in a 96-well plate format to demonstrate the viability of the technique for the high-throughput screening (HTS) of enantiomeric excess (ee) values. Chiral receptors [Cu(II)(1)](2+) and [Cu(II)(2)](2+) with the indicator chrome azurol S were implemented for the eIDAs. Enantiomeric excess calibration curves were made using both receptors and then used to analyze true test samples. These results were compared to those previously obtained with a conventional UV-vis spectrophotometer, and they showed little to no loss of accuracy, while the speed of analysis was increased. A sample of valine of unknown ee was synthesized through an asymmetric reaction to produce a realistic reaction sample, which was analyzed using receptor [Cu(II)(1)](2+). The experimentally determined ee using our eIDA was compared to that obtained by chiral HPLC and (1)H NMR chiral shift reagent analysis. This gave errors of 4.7% and 12.0%, respectively. In addition to the use of ee calibration curves, an artificial neural network (ANN) was used to determine the % L-amino acid of the test samples and of the sample of valine of unknown ee from the asymmetric reaction. This method obtained errors of 5.9% and 2.2% compared to chiral HPLC and (1)H NMR chiral shift reagent analysis, respectively. The technique using calibration curves for the determination of ee on a 96-well plate allows one to determine 96 ee values in under a minute, enabling its use for HTS of asymmetric reactions with acceptable accuracy.     

Palladium-catalyzed enantioselective 1,3-rearrangement of racemic allylic sulfinates: asymmetric synthesis of allylic sulfones and kinetic resolution of an allylic sulfinate

Described is an asymmetric synthesis of cyclic and acyclic allylic S-aryl and S-alkyl sulfones through a highly selective palladium(0)-catalyzed 1,3-rearrangement of racemic allylic sulfinates. Treatment of racemic cyclic and acyclic allylic S-tolyl- and S-tert-butylsulfinates with Pd(2)(dba)(3).CHCl(3) as precatalyst and N,N'-(1R,2R)-1,2-cyclohexanediylbis[2-(diphenylphosphino)benzamide] as ligand for the palladium atom afforded the corresponding isomeric allylic S-tolyl and S-tert-butyl sulfones of 93-99% ee in 82-96% yield. The rearrangement of the allylic sulfinates most likely proceeds in an intermolecular fashion via formation of a cationic pi-allylpalladium complex and the sulfinate ion. The racemic allylic sulfinates were obtained from the corresponding racemic alcohols and racemic tolylsulfinyl chloride and racemic tert-butylsulfinyl chloride, respectively, in high yields. Rearrangement of the racemic tert-butylsulfinic acid 2-cyclooct-1-enyl ester with Pd(2)(dba)(3).CHCl(3) and the bisphosphane was accompanied by a highly selective kinetic resolution of the substrate and gave at 50% conversion the (R)-configured sulfinate as mixture of the S(S) and R(S) diastereomers of 92% ee and 85% ee and the (S)-configured 3-tert-butylsulfonyl cyclooctene sulfone 15a with 98% ee in almost quantitative yields.     

Asymmetric allylic oxidation of bridged-bicyclic alkenes using a copper-catalysed symmetrising-desymmetrising Kharasch-Sosnovsky reaction

Enantioselective symmetrising-desymmetrising allylic oxidation of racemic bridged bicyclic alkenes using an asymmetric copper-catalysed Kharasch-Sosnovsky reaction has been explored. Good yields and reasonable levels of induction (up to 70% ee) have been obtained using carbocyclic systems as substrates.     

Asymmetric hydrogenolysis of racemic tertiary alcohols, 3-substituted 3-hydroxyisoindolin-1-ones

Asymmetric hydrogenolysis of racemic tertiary alcohols, 3-substituted 3-hydroxyisoindolin-1-ones, was developed using chiral phosphoric acid as catalyst and a Hantzsch ester as the hydrogen source with up to 95% ee. The reaction process of this asymmetric transfer hydrogenation may occur directly through the acyliminium ion intermediate.     

Enantioselective synthesis of optically active secondary amines via asymmetric reduction

The enantioselective synthesis of optically active secondary amines via the asymmetric reduction of N-substituted ketimines with various chiral hydride reagents, such as Itsuno's reagent (1), Corey's reagent (2), K glucoride (3), Sharpless' reagent (4), and Mosher's reagent (5) has been investigated. Among the hydride reagents examined, 1 gave the best results in terms of asymmetric induction. Thus, the reduction of N-phenylimine derivatives of aromatic ketones with 1 provided the corresponding amines in 96–98% yields with high optical induction, such as 73 % ee for acetophenone N-phenylimine (6a), 87 % ee for propiophenone N-phenylimine (6b), 88 % ee for bulyrophenone N-phenylimine (6c), and 71 % ee for isobutyrophenone N-phenylimine (6d). In the case of N-alkyl ketimine derivatives, the reduction afforded somewhat lower optical inductions as compared to those of N-phenyl derivatives, giving 46 % ee for acetophenone N-benzylimine (6f), 52 % ee for acetophnone N-ⁿ-heptylimine (6g) and 43 % ee for acetophenone N-cyclohexylimine (6h). However, the substitution of a bulky alkyl group on nitrogen of the ketimines increases remarkably the optical induction of product amine, such as 80 % ee for acetophenone N-tert-butylimine (6e). The reduction of N-substituted aliphatic ketimines gave very low optical inductions (7.4 – 24 % ee). The catalytic effects of oxazaborolidines (1a and 2a) in the reduction of ketimines with 1 and 2 were also examined.     

Asymmetric Synthesis of Indoline from Achiral Phthalimide Involving Crystallization-Induced Deracemization

Asymmetric synthesis was performed by combining the photochemical reaction of an achiral substrate followed by crystallization-induced deracemization. The results indicated that a fused indoline produced by photochemical intramolecular δ-hydrogen abstraction and cyclization of N-(5-chloro-2-methylphenyl)phthalimide crystallized as a racemic conglomerate. Since this substrate has an aminal skeleton, racemization involving a ring-opening and ring-closing equilibrium process occurred under suitable conditions. Efficient racemization was observed in acetone containing a catalytic base, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Crystallization-induced dynamic deracemization by Viedma ripening from racemic indoline was performed with an excellent enantioselectivity of 99 % ee. Furthermore, one-pot asymmetric synthesis of the indoline was achieved by the photochemical reaction of achiral phthalimide followed by continuous attrition-enhanced deracemization converging to 99 % ee of enantiomeric crystals. This is the first example of asymmetric expression and amplification by photochemical hydrogen abstraction and crystallization-induced dynamic deracemization.     

Direct catalytic synthesis of enantiopure 5-substituted oxazolidinones from racemic terminal epoxides

A venerable scaffold for asymmetric synthesis and drug development, chiral 5-substituted oxazolidinones are obtained in almost enantiomerically pure form (up to 99.9% ee) starting from racemic terminal epoxides. The salient features of this process include the very simple and convenient experimental protocol and the employment of a readily accessible catalyst and inexpensive, easily handled starting materials. An enantioconvergent approach for the total conversion of racemic epoxide into a single stereoisomeric oxazolidinone is also described.     

Enantioselective synthesis of near enantiopure compound by asymmetric autocatalysis triggered by asymmetric photolysis with circularly polarized light

Right- and left-handed circularly polarized light (CPL) has been proposed as one of the origins of homochirality of biomolecules. However, the enantiomeric excess induced by CPL has been only very low (<2% ee). We found the unprecedented example of asymmetric autocatalysis triggered directly by a chiral physical factor, that is, right- and left-handed CPL, leading to a near enantiopure compound. Asymmetric photolysis of racemic pyrimidyl alkanol by r-CPL irradiation followed by asymmetric autocatalysis affords (R)-pyrimidyl alkanol with >99.5% ee. On the other hand, irradiation with l-CPL affords (S)-pyrimidyl alkanol with >99.5% ee. Thus, chiral physical power, such as CPL, in conjunction with asymmetric autocatalysis, provides a highly enantioenriched compound.     

The first asymmetric esterification of free carboxylic acids with racemic alcohols using benzoic anhydrides and tetramisole derivatives: an application to the kinetic resolution of secondary benzylic alcohols

A variety of optically active carboxylic esters are produced by the kinetic resolution of racemic secondary benzylic alcohols using free carboxylic acids with benzoic anhydride and tetramisole derivatives. 4-Methoxybenzoic anhydride (PMBA) is the best reagent to use in producing the corresponding esters in high ee when the reaction is catalyzed by (+)-benzotetramisole (BTM); by contrast, when non-substituted benzoic anhydride is used as a coupling reagent, the resulting optically active alcohols are obtained with high selectivities. This protocol directly produces chiral carboxylic esters from free carboxylic acids and racemic secondary alcohols by utilizing the trans-acylation process to generate mixed anhydrides from acid components and benzoic anhydride derivatives under the influence of chiral catalysts.     

General asymmetric hydrogenation of alpha-branched aromatic ketones catalyzed by TolBINAP/DMAPEN-ruthenium(II) complex

[reaction: see text] A catalyst system consisting of RuCl2[(S)-tolbinap][(R)-dmapen] and t-C4H9OK in 2-propanol effects asymmetric hydrogenation of arylglyoxal dialkylacetals to give the alpha-hydroxy acetals in up to 98% ee. Hydrogenation of racemic alpha-amidopropiophenones under dynamic kinetic resolution predominantly gives the syn alcohols in up to 99% ee and >98% de, while the reaction of racemic bezoin methyl ether gives the anti alcohols in excellent stereoselectivity.     

Enantioselective Lewis acid-catalyzed Mukaiyama-Michael reactions of acyclic enones. Catalysis by allo-threonine-derived oxazaborolidinones

allo-Threonine-derived O-aroyl-B-phenyl-N-tosyl-1,3,2-oxazaborolidin-5-ones 1g,n catalyze the asymmetric Mukaiyama-Michael reaction of acyclic enones with a trimethylsilyl ketene S,O-acetal in high enantioselectivity. A range of alkenyl methyl ketones is successfully employed as Michael acceptors affording ee values of 85-90% by using 10 mol % of the catalyst. The use of 2,6-diisopropylphenol and tert-butyl methyl ether as additives is found to be essential to achieve high enantioselectivity in these reactions. The effects of the additives are discussed in terms of the retardation of an Si(+)-catalyzed racemic pathway, which seriously deteriorates the enantioselectivity of asymmetric Mukaiyama-Michael reactions. A working model for asymmetric induction is proposed based on correlation between catalyst structures and enantioselectivities.     

Lipase-catalyzed domino kinetic resolution of alpha-hydroxynitrones/intramolecular 1,3-dipolar cycloaddition: a concise asymmetric total synthesis of (-)-rosmarinecine

The title domino reactions were developed to directly provide tetrahydrofuro[3,4-c]isoxazole derivatives (5 and 9) in > or =90% ee from racemic alpha-hydroxynitrones (2 and 6), which were used in the concise asymmetric total synthesis of (-)-rosmarinecine .     

Organocatalyzed regio- and enantioselective allylic trifluoromethylation of Morita-Baylis-Hillman adducts using Ruppert-Prakash reagent

The organocatalyzed regioselective allylic trifluoromethylation of Morita-Baylis-Hillman adducts using Ruppert-Prakash reagent was achieved in high to excellent yields via a successive S(N)2'/S(N)2' mode for the first time. The reaction was extended to the asymmetric allylic trifluoromethylation by the use of a bis-cinchona alkaloid catalyst with high enantioselectivities up to 94% ee.     

Synthesis of a new insoluble polymer-supported chiral alcohol auxiliary and its first application to nucleophilic addition to ketenes

The preparation of a new optically active alcohol with a carboxylic function that allowed its attachment to an amine-functionalized insoluble polymer is described. Its first use as a polymer supported chiral auxiliary is demonstrated by asymmetric transformation of two racemic aryl propionic acids via ketene formation (95-96% ee).     

Chiral ruthenium-SDPs/diamine complexes-catalyzed enantioselective hydrogenation of α-alkyl arylacetones via dynamic kinetic resolution

The asymmetric hydrogenation of the conformationally flexible racemic α-substituted acyclic dialkyl ketones via dynamic kinetic resolution (DKR) has been developed by using Ru-SDPs/diamine catalysts. Chiral alcohols were produced in high yields with good to excellent enantioselectivities (85%–97% ee) and diastereoselectivities (up to 97:3). This hydrogenation reaction provided a new approach to the synthesis of the key intermediate of J-104118.     

Stereoselective Lewis acid-catalyzed alpha-acylvinyl additions

Silyloxyallenes derived from alpha-hydroxypropargylsilanes undergo efficient addition to aldehydes with catalytic amounts of Lewis acids. The allenes are accessed from the corresponding propargylsilanes in a base-catalyzed 1,2-Brook rearrangement/SE2' process. Enantioenriched propargylsilanes are synthesized by a new zinc-promoted addition of alkynes to acylsilanes in up to 74% ee. This work demonstrates that conversion to the silyloxyallenes occurs with minimal erosion in optical activity. The use of a chiral chromium(III) Lewis acid effects the catalytic asymmetric addition of racemic silyloxyallenes to aromatic aldehydes in up to 92% ee. The overall reaction is broad in scope and accommodates a wide variety of aromatic and aliphatic substituents on both the propargylsilane and aldehyde.