Enantioselective reactions of alpha-lithiated allyl aryl sulfides using chiral bis(oxazoline)s

The reaction of alpha-lithio allyl aryl sulfides, generated by treatment with n-BuLi and chiral ligands at -78 degrees C, with ketones was examined. The alpha-addition products were formed in preference to the gamma-addition products. The enantioselectivity of the alpha-addition products varied depending on the chiral ligand, and bis(oxazoline)-(t)Bu showed the highest enantioselectivity. Chirality 16:86-89, 2004.     

Biomimetic asymmetric hydrogenation.

Enzymes and synthetic organometallic catalysts utilize different approaches for the creation of chiral centers in prochiral substrates. While chiral organometallic catalysts realize the transfer of chirality mainly by repulsive interactions, several enzymes use preferentially stereodiscriminating hydrogen bonding. To investigate if hydrogen bonding within the catalyst-substrate assembly can also have a benefit on the rhodium diphosphine-catalyzed asymmetric hydrogenation, some model metal complexes and substrates were investigated. As 'biomimetically acting' functionalities, hydroxy groups were incorporated in the chiral ligand. Three secondary interactions could be identified by different analytical methods which influence rate and enantioselectivity of the catalytic reaction: 1) HO/Rh-interactions, 2) HO/HO-interactions within the backbone of the ligand, and 3) hydrogen bonding between HO-groups of the ligand and functional groups of an appropriate substrate. Due to the effect of the additional hydroxy groups, enantioselectivities by up to 99% ee could be induced in the hydrogenation product even with water as solvent.     

Electronic effects on the regio- and enantioselectivity of the asymmetric aminohydroxylation of O-substituted 4-hydroxy-2-butenoates

Regio- and enantioselectivity in the asymmetric aminohydroxylation (AA) reaction of O-substituted 4-hydroxy-2-butenoates as well as the mechanism of the reaction were studied. When the electronic properties of the phenyl group in a substrate were altered by using different substituents, two conflicting trends were observed: The O-benzoyl substrates showed greater regio- and enantioselectivity when an electron-donating substituent was attached at the C-4 position of the phenyl group, while the O-benzyl substrates exhibited better regio- and enantioselectivity with an electron-withdrawing substituent at the C-4 position of the phenyl moiety. Thus, these results have disclosed hitherto unknown remarkable electronic effects in the AA reaction. Detailed analysis of possible electronic interactions in the chiral catalyst-substrate complex has revealed the importance of dipolar aromatic-aromatic interactions between the aromatic substituent of the substrate and the nitrogen heteroaromatic moiety of the chiral ligand for effective regiocontrol as well as enantioface selection in the AA reaction. A plausible model of the key intermediate in the AA reaction of O-substituted 4-hydroxy-2-butenoates is proposed.     

Preparation and enantioseparation characteristics of two chiral stationary phases based on mono(6(A)-azido-6(A)-deoxy)-perphenylcarbamoylated alpha- and gamma-cyclodextrin

Two chiral stationary phases, ph-alpha-CD and ph-gamma-CD, were prepared from mono(6(A)-azido-6(A)-deoxy)perphenylcarbamoylated alpha- and gamma-cyclodextrin immobilized onto silica gel via the Staudinger reaction. The chromatographic characteristics of these two chiral stationary phases were evaluated. The influence of different cyclodextrins (CDs) on the enantioselectivities was also investigated in this study. Compared to ph-gamma-CD, ph-alpha-CD exhibited quite good enantioselectivity toward the analytes with bulky molecular structures. It was found that the formation of inclusion complex might play a quite important role in the chiral recognition not only under reverse phases but also under normal phases.     

Axially dissymmetric N-thioacylated (S)-(-)-1,1'-binaphthyl-2,2'-diamine ligands for copper-catalyzed asymmetric Michael addition of diethylzinc to alpha,beta-unsaturated ketone

Axially chiral thioamide ligands L5, L6, L8, L11, and bis(thioamide) ligand L13 were prepared from the reaction of (S)-(-)-1,1'-binaphthyl-2,2'-diamine with acyl chlorides and phosphorus pentasulfide (P2S5). The catalytic asymmetric 1,4-addition of diethylzinc to alpha,beta-unsaturated ketones was examined using this novel chiral ligand system with 28-73% ee in moderate to good yields.     

Development of a nonchiral HPLC method with circular dichroism detection for chiral analysis of molybdenum-catalyzed enantioselective synthesis products

The combination of a circular dichroism detector and nonchiral liquid chromatography was used for the chiral analysis of unresolved enantiomers to determine the enantioselectivity of a molybdenum-catalyzed asymmetric allylic alkylation reaction. The CD/UV peak area ratio of the unresolved enantiomers was calculated and compared with that of a reference standard to determine the enantiomeric purity. The limit of quantitation (LOQ) is 20 ng for the chiral ligand and 1 microg for the branched chiral product. The viability of the system depends on the limit of quantitation of the CD response and the linearity range of the CD and UV response.     

Microbial hydroxylation of (+/-)- and (-)-(2Z,4E)-5-(1',2'-epoxy-2',6',6'-trimethylcyclohexyl)-3-methyl-2,4-pentadienoic acid into (+/-)- and (-)-xanthoxin acid by Cunninghamella echinulata

Microbial hydroxylation of (+/-)-(2Z,4E)-5-(1',2'-epoxy-2',6',6'-trimethylcyclohexyl)-3-methyl-2,4-pentadienoic acid (3a) with Cercospora cruenta, a fungus producing (+)-abscisic acid, gave a four-stereoisomeric mixture consisting of (+)- and (-)-xanthoxin acid (4a), and (+)- and (-)-epi-xanthoxin acid (5a) by an HPLC analysis with a chiral column. Screening of the microorganisms capable of oxidizing (+/-)-3a showed that Cunninghamella echinulata stereoselectively oxidized (+/-)-3a to xanthoxin acid (4a) with the some degree of enantioselectivity as (-)-3a to (-)-4a.     

Enantioselective Michael addition catalyzed by cinchona alkaloids.

Enantioselective Michael additions of cyclic beta-ketoesters to methyl vinyl ketone catalyzed by cinchona alkaloids were studied. The results revealed that the induced enantioselectivity was significantly influenced by both the structure of the catalyst and that of the substrate. Interesting differences in the effect of the structure of the alkaloid on the enantioselectivity of this reaction in the case of three beta-ketoesters were discovered. High enantioselectivities were obtained in the reaction of ethyl 2-oxocyclopentanecarboxylate and ethyl 2-oxocyclohexanecarboxylate (up to 83 and 80%, respectively) at a low cinchona:reactant ratio of 1:500. As the specific rotations of the product enantiomers were unknown, they were determined by optical rotation and chiral GC measurements and verified by NMR experiments.     

Synthetic and novel biocatalytic resolution studies on (+/-)-5/6/7-acetoxy-4-aryl-3,4-dihydrocoumarins

Eleven (+/-)-5/6/7-acetoxy-4-aryl-3,4-dihydrocoumarins have been synthesised in two steps starting from the coupling of cinnamic acid/substituted cinnamic acid with appropriate phenols, followed by acetylation in 50-83% overall yields. All hydroxy- and acetoxycoumarins were unambiguously identified on the basis of their spectral data. Candida antarctica lipase-catalysed deacetylation of these racemic acetoxydihydrocoumarins in dioxane occurred with moderate enantioselectivity. This is one of the rare examples of resolution using phenolic ester moiety as a remote handle for chiral recognition by a lipase.     

Synthesis of chiral vicinal diols and analysis of them by capillary zone electrophoresis

This paper describes an improved access to 1,4-bis (9-O-quininyl) phthalazine [(QN)(2)PHAL], a very useful chiral ligand for catalytic asymmetric dihydroxylation (AD), by using CaH(2) as acid-binding reagent in a high yield under mild conditions. The application of (QN)(2)PHAL to the AD reactions of eight olefins exhibited excellent enantioselectivity and activity with corresponding chiral vicinal diols. Furthermore, a capillary zone electrophoresis method was developed to separate the aforementioned chiral vicinal diols by using of neutral beta-cyclodextrin (beta-CD) as chiral selector and borate as running buffer. High resolution was achieved under the optimal conditions of beta-CD 2.2% (w/v), pH 10, 200 mM borate buffer at 15 kV, and 20 degrees C within 15 min. The relative standard deviations of the corrected peak areas and migration time were less than 3.9% and 1.3%, respectively. In addition, the developed method was successfully applied to the determination of the purity and the enantiomeric excesses value (%ee) of the AD reaction products.     

Asymmetric epoxidation of unfunctionalized alkenes catalyzed by sugar moiety-modified chiral salen-Mn(III) complexes

Several chiral Schiff-base ligands with sugar moieties at C-3 (3′) or C-5 (5′) of salicylaldehyde were synthesized from reaction of salicylaldehyde derivatives with diamine. These ligands coordinated with Mn(III) to afford the corresponding chiral salen-Mn(III) complexes characterized by FT-IR, MS, and elementary analysis. These complexes were used as catalysts for the asymmetric epoxidation of unfunctionalized alkenes. Only weak enantioselectivity is induced by the chiral sugar moieties at C-3 (3′) or C-5 (5′) in the case of absence of chirality in the diimine bridge moiety. It was also shown that the sugars at C-5 (5′) having the same rotation direction of polarized light as the diimine bridge in the catalyst could enhance the chiral induction in the asymmetric epoxidation, but the sugars with the opposite rotation direction would reduce the chiral induction.     

Optically active titanium complexes containing a tridentate linked amido-cyclopentadienyl ligand

Optically active titanium complexes Tieta5:eta1-C5R4SiMe2NC6H10 (OCH2Ph)-2Cl2 (R = H, Me), containing a cyclopentadienyl ligand linked to the chiral trans-2-benzyloxycyclohexylamido group, were synthesized and characterized in both enantiomerically pure forms. A single crystal X-ray structure analysis of (-)-(R, R)-Tieta5:eta1-C5H4SiMe2NC6H10(OCH2Ph)-2Cl2 shows a structure in which the benzyloxy group in the amido sidechain is not interacting with the titanium center. Upon activation with n-butyllithium, these complexes hydrogenate acetophenone N-benzylimine with low enantioselectivity.     

Enantioselective epoxidation of non-functionalized alkenes using carbohydrate based salen-Mn(III) complexes

Three new salen ligands with carbohydrate moieties were prepared from a salicylaldehyde derivative obtained by reaction of 1,2:5,6-di-O-isopropylidene-alpha-D-glucofuranose with 3-tert-butyl-5-(chloro-methyl)-2-hydroxybenzaldehyde. These ligands were coordinated with Mn(III) to give three chiral salen-Mn(III) complexes. The complexes were characterized and employed in the asymmetric epoxidation of unfunctionalized alkenes. Catalytic results showed that although there are no chiral groups on the diimine bridge, these complexes had some enantioselectivity, which indicates the carbohydrate moiety has an asymmetric inducing effect in the epoxidation reaction.     

Modification of chiral dimethyl tartrate through transesterification: Immobilization on POSS and enantioselectivity reversal in sharpless asymmetric epoxidation

Modification of dimethyl tartrate has been investigated through transesterification with aminoalcohols to provide reactive functionalities for the covalent bonding of chiral tartrate to polyhedral oligomeric silsesquioxanes. The transesterification of dimethyl tartrate has been widely studied using different catalytic systems and reaction conditions. Through the proper selection of both the catalytic system and the reaction conditions, it is possible to achieve monosubstituted or bis‐substituted tartrate derivatives as sole products. All the intermediate chiral tartrate‐derived ligands were successfully used in the homogeneous enantioselective epoxidation of allylic alcohols providing moderate enantiomeric excess over the products. Attached amine groups have been used to support the modified tartrate ligands on to a haloaryl‐functionalized silsesquioxane moiety. This final chiral tartrate ligand displays reverse enantioselectivity in the asymmetric epoxidation of allylic alcohols with regard to the starting dimethyl tartrate ligand, both molecules having the same chiral sign. However, the POSS‐containing ligand can be easily recovered in almost quantitative yield and reused in asymmetric epoxidation reactions. In addition, recovered silsesquioxane‐pendant ligand, though displaying decreasing catalytic activity in recycling epoxidation tests, showed very stable enantioselective behavior. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Cooperativity of chirality in homogeneous catalysis: The gold(I)-catalyzed aldol reaction and the vanadium(IV)-catalyzed hetero Diels–Alder cycloaddition

The notion of internal (or intramolecular) cooperativity of chirality is reviewed on the basis of various examples of diastereoisomeric ferrocenylphosphine ligands used in the gold(I)-catalyzed aldol reaction. It was found that the stereochemical outcome of this reaction strongly depends on the specific combination of the absolute configuration of the different stereogenic centers present in the ligand. Thus, individual chirotopic segments in these ligand molecules can act either in a cooperative or noncooperative manner in determining both diastereo-and enantioselectivity. Furthermore, several examples of application of the strategy of double stereodifferentiation (external, or intermolecular cooperativity of chirality) in the gold(I)-catalyzed aldol reaction and the vanadium(IV)-catalyzed hetero Diels–Alder condensation are presented. Based on our work it is apparent that, whether the diastereoselectivity of these two reactions is controlled by the catalyst or by a chiral substrate, cannot be predicted and very much depends on the nature of every individual reactant. Thus, it was found that in both reactions the chiral aldehyde substrate usually has a strong impact on the diastereoselectivity, leading to interesting patterns of double asymmetric induction. On the other hand, chiral isocyanoacetate and chiral-activated dienes, respectively, showed little or no effect on the stereochemical outcome of the reactions.     

Axially dissymmetric (R)-(+)-5,5',6,6',7,7',8,8' octahydro-[1,1']binaphthyldiimine chiral salen type-ligands for copper-catalyzed asymmetric aziridination

Axially dissymmetric chiral diimine ligand 2 was prepared from the reaction of (R)-(+)-5,5',6,6',7,7',8,8'-octahydro-[1,1']binaphthyl-2,2'-diamine 1 with 2,6-dichlorobenzaldehyde. The catalytic asymmetric aziridination of alkenes was examined using this novel chiral ligand. Excellent enantioselective aziridination of cinnamates was achieved using C(2)-symmetric chiral ligand 2.     

New bulky chiral Lewis acid catalyst: 3,3'-di(2-mesitylethynyl)binaphthol-titanium(IV) complex

A new chiral Lewis acid catalyst 9 was prepared in situ from a 1:2 molar mixture of (R)-3,3'-di(2-mesitylethynyl)binaphthol (6) and titanium(IV) isopropoxide at ambient temperature. The 3- and 3'-substituents on 6 were effective for preventing undesired aggregation between Ti(IV) complexes and increasing the enantioselectivity (up to 82% ee) in the Diels-Alder reaction of methacrolein with cyclopentadiene.     

Chiral ligand optimization in the asymmetric zirconium-zinc transmetalation aldehyde addition reaction

The in situ hydrozirconation-transmetalation-aldehyde addition process is a convenient method for the generation of allylic alcohols. Ongoing research has focused on enhancing the enantioselectivity and substrate scope of this process. A chiral beta-amino thiol scaffold was evaluated in the addition reaction. Amino thiols tend to provide the highest ee's, in part due to the higher affinity of sulfur for zinc over zirconium. A class of valine-based thiol ligands was identified to be effective for the formation of enantiomerically enriched allylic alcohols in terms of low ligand loading and high % ee.     

Effects of solvent, water activity and temperature on lipase and hydroxynitrile lyase enantioselectivity

The influence of the reaction conditions on the enantioselectivity of reactions catalysed by lipases or hydroxynitrile lyases (HNLs) in organic solvents was investigated. The lipases catalysed kinetic resolution of chiral secondary alcohols or chiral carboxylic acids and the HNLs catalysed asymmetric addition of hydrogen cyanide to aldehydes.

The temperature effects on enantioselectivity were studied in detail. From measurements of the enantiomeric ratio (E) at different temperatures the activation parameters ΔΔH^# and ΔΔS^# were determined. In the lipase-catalysed reactions the enthalpic and entropic effects on E always counteracted, while in a few of the HNL-catalysed reactions, ΔΔH^# and ΔΔS^# had opposite signs and therefore the effects cooperated to give high E values (−RTlnE = ΔΔG^# = ΔΔH^# − TΔΔS^#). In all the HNL-catalysed reactions and most of the lipase-catalysed ones, the enantioselectivity increased with decreasing reaction temperature. However, in one of the lipase-catalysed reactions, the enantioselectivity decreased with decreasing temperature. The theoretical background of these observations was discussed.

In the HNL-catalysed reactions, the enantioselectivity increased with increasing water content up to water saturation, while in the lipase-catalysed reactions the opposite trend was found in one case and in the others no significant effect was observed. Solvent mixtures of diisopropylether and hexane were used to obtain solvents with different log P values. The log P value of the solvent did not influence the enantioselectivity in the HNL-catalysed reactions, while the enantioselectivity increased with increasing log P value in two of the lipase-catalysed reactions. The reaction temperature was shown to be a very useful way to influence enzyme selectivity and the effects obtained could be rationalised. The influence of the reaction medium (solvent and water activity) is much more difficult to rationalise and predict.     

Immobilization conditions of ketoreductase on enantioselective reduction in a gas-solid bioreactor

The immobilization conditions of commercial ketoreductase for continuous enantioselective reduction in the gas-phase reaction were investigated with respect to the immobilization efficiency (residual activity and protein loading) and the gas-phase reaction efficiency (initial reaction rate, half-life, and enantioselectivity). For the analyses, ketoreductase was first immobilized by physical deposition on glass supports and the reduction of 2-butanone to (S)-2-butanol with the concomitant regeneration of NADH by 2-propanol was used as a model reaction. The optimal conditions of enzyme immobilization were obtained using an absolute pressure of 100 hPa for drying, a pH between 6.5 and 7.0, and a buffer concentration of 50 mM. The buffer concentration in particular had a strong effect on both the enzyme activity and enantioselectivity. Under optimal immobilization conditions, the thermostability of ketoreductase in the gas-phase system was enhanced compared to the aqueous-phase system, while the enantioselectivity was successfully maintained at a level identical to that of the native enzyme. These results indicate that the gas-phase reaction has a great potential for industrial production of chiral compounds, but requires careful optimization of immobilization conditions for the reaction to progress effectively.