Enantioselective Hydrogenation of a Methoxypyrone with Cinchona-Modified Palladium

Hydrogenation of 4-methoxy-6-methyl-2-pyrone 1 has been investigated over cinchona-modified Pd/TiO₂. The appropriate start-up procedure including a catalyst reduction—oxidation—reduction cycle and short pretreatment with the modifier in the absence of reactant can remarkably enhance the enantiomeric excess (ee) to the dihydropyrone 2. Another key parameter is the alkaloid/Pd_s molar ratio; the alkaloid concentration in the slurry or the alkaloid/reactant ratio is not crucial. Under the best conditions 94% ee and 95% chemoselectivity to 2 were achieved at 80% conversion of 1, in only 30 min reaction time under ambient conditions. The ee can be further increased by kinetic resolution of 2. In the second reaction step the diasteroselectivity to the cis-tetrahydropyrone 3 is about 99%.     

Asymmetric Aldol Reaction Catalyzed by New Recyclable Polystyrene-supported l-proline in the Presence of Water

Two l-proline-based linear polystyrene anchored catalysts (1a–b) have been efficiently synthesized. By using only 5 mol% of catalysts, the corresponding products of the aldol reaction were obtained in good yields (up to 91%) with excellent anti diastereoselectivity (up to 93:7) and enantioselectivity (up to 98% ee) in DMF in the presence of water. The yields of these reactions in the ketone/water mixture were lower than those in wet DMF (up to 84%). However, the stereoselectivity was comparable (up to 92:8 anti/syn ratio and 96% ee, respectively). In addition, catalysts 1a–b could be recovered by a simple precipitation and filtration process. They can also be re-used for at least five times without obvious loss of catalytic efficiency.     

Pyrrolidine-Based Chiral Quaternary Alkylammonium Ionic Liquids as Organocatalysts for Asymmetric Michael Additions

Abstract  

A series of chiral pyrrolidine-type quaternary alkylammonium ionic liquids were synthesized and served as efficient catalysts for asymmetric Michael additions of aldehydes and ketones to nitroolefins, and the corresponding adducts were obtained in excellent enantioselectivities (>99% ee) and diastereoselectivities (>99% dr) under solvent-free reaction conditions. Furthermore, the catalyst 7c could be recovered for next run of the reaction with similar yield and selectivity.     

Construction of Adjacent Quaternary and Tertiary Stereocenters by Conjugate Addition Using Polymer-Supported Cinchona Alkaloids as Catalysts

Abstract  

A series of polymer-bound cinchona alkaloids has been prepared. The resultant polymer-bound cinchona alkaloids have been used as the catalysts for the asymmetric Michael reaction of 1,3-dicarbonyl compounds and N-benzylmaleimide. The corresponding asymmetric Michael addition product, the first example of adjacent quaternary and tertiary stereocenters synthesized in the presence of a polymer-bound catalyst, has a selectivity of up to 86% ee. Besides, immobilized alkaloid V retains stereochemical reactivity even after being recycled for six times.     

Stereoselective synthesis of dominicalure 1 and 2: Components of aggregation pheromone from male lesser grain borerRhyzopertha dominica (F.)

Dominicalure 1 (9a) and dominicalure 2 (9b), were synthesized by esterification of ,-unsaturated acids4a and4b with (S)-(+)-2-pentanol (8). The key step was the asymmetric reduction of 3-penten-2-one (5) to give the chiral intermediate6, which, upon diimide reduction, DNB derivatization, recrystallization, and hydrolysis, yielded8 in 63% ee. Acids4a and4b were prepared in a simple and efficient three-step synthesis with an overall yield of 54% and 62%, respectively, in stereoisomerically pure form.     

Asymmetric Epoxidation of Chromenes Using Manganese(III) Complexes with Novel Chiral Salen-like Schiff Base Ligands

Abstract  

Three novel chiral salen-like schiff base ligands and their Mn(III) complexes containing different amino acid unit have been synthesized and characterized. Asymmetric epoxidation reactions show these complexes are effective catalysts for the chromenes with buffer NaOCl as terminal oxidant and pyridine N-oxide as co-catalyst in the presence of ionic liquid. Good-to -excellent enantioselectivity and acceptable yields can be obtained under optimum reaction conditions. Catalyst 4c gives the highest ee (95%) for 6-chloro-2,2-dimethylchromene among these catalytic performances. Furthermore, compared the enantioselectivity of catalyst 4c with the other two catalysts 4a and 4b, the positive experimental results suggest that the steric effect of the ligands plays an important role in the asymmetric catalysis.     

Synthesis of Substituted Mandelic Acid Derivatives via Enantioselective Hydrogenation: Homogeneous versus Heterogeneous Catalysis

An extensive screening of both homogeneous and heterogeneous catalysts was carried out for the enantioselective hydrogenation of p‐chlorophenylglyoxylic acid derivatives. For p‐chlorophenylglyoxylic amides only homogeneous Rh‐diphosphine complexes gave satisfactory results, ees up to 87% were observed for the cy‐oxo‐pronop ligand. For methyl p‐chlorophenylglyoxylate both a homogeneous as well as a heterogeneous catalyst performed with ees >90%. A Pt catalyst modified with cinchona derivatives achieved 93% ee for the (R)‐ and 87% ee for the (S)‐methyl p‐chloromandelate. A Ru‐MeObiphep catalyst also reached 93% ee with TONs up to 4000 and TOFs up to 210 h⁻¹. For all catalytic systems the effects of the metal, the nature of the chiral auxiliary and the solvent as well as of the reaction conditions were investigated. The homogeneous process was scaled up to the kg scale and the enantiomeric purity of the product was enhanced to >99% ee by two recrystallizations of the free p‐chlorophenylmandelic acid.     

Highly Enantioselective Production of (R)-Halohydrins with Whole Cells of Rhodotorula rubra KCh 82 Culture

Biotransformation of ten α-haloacetophenones in the growing culture of the strain Rhodotorula rubra KCh 82 has been carried out. Nine of the substrates underwent an effective enantioselective reduction to the respective (R)-alcohols according to Prelog’s rule, with the exception of 2-chloro-1,2-diphenylethan-1-one that was not transformed by this strain. The expected reduction proceeded without dehalogenation, leading to the respective (R)-halohydrins in high yields. The use of this biocatalyst yielded (R)-2-bromo-1-phenyl-ethan-1-ol (enantiomeric excess (ee) = 97%) and its derivatives: 4''-Bromo- (ee = 99%); 4''-Chloro- (ee > 99%); 4''-Methoxy- (ee = 96%); 3''-Methoxy- (ee = 93%); 2''-Methoxy- (ee = 98%). There were also obtained and characterized 2,4''-dichloro-, 2,2'',4''-trichloro- and 2-chloro-4''-fluoro-phenyetan-1-ol with >99% of enantiomeric excesses.     

(Salen)chromium Complex Mediated Asymmetric Ring Opening of meso‐ and Racemic Epoxides with Different Fluoride Sources

The asymmetric ring opening of five meso‐ and three racemic epoxides with different fluorinating reagents in the presence of stoichiometric or slightly sub‐stoichiometric amounts of Jacobsen's enantiopure (salen)chromium chloride complex A gave the corresponding optically active vicinal fluorohydrins. Silver fluoride was used as one of the fluoride sources either in the presence of Bu₄N⁺H₂F₃⁻ in diethyl ether or in acetonitrile. The latter reactions starting from cyclohexene oxide ( 1 ) showed maximum 72% ee in the formed fluorohydrin 2 isolated in 90% yield. From other meso‐epoxides such as cyclopentene oxide and cycloheptene oxide the corresponding fluorohydrins were isolated in 80% and 82% yield with 65% and 62% ee, respectively. In case of ring opening under similar conditions of the racemic styrene oxide or phenyl glycidyl ether 83% and 75% of the fluorohydrins with fluorine in the primary position were isolated with 74% ee and 65% ee, respectively. Tetrahydronaphthalene oxide yielded a 2:1 mixture of trans‐ (23% ee) and cis‐2‐fluoro‐3,4‐benzocyclohexenol (2% ee) suggesting competing S_N2 and S_N1 type ring openings. Other epoxides such as cyclooctene oxide, cis‐stilbene oxide and α‐methylstyrene oxide did not react or gave the fluorohydrins with very small enantiomeric excess.     

Chiral Synthesis via Organoboranes 23. Enantioselective Ring Opening of meso-Epoxides with B-Halodiisopinocampheylboranes. The First General Synthesis of Optically Active 1,2-Halohydrins

B-Halodiisopinocampheylboranes, Ipc₂BX, where X is Cl, Br, or I, cleave cyclohexene oxide at low temperatures to give the 1,2-halohydrins, in 22, 84, and 91% enantiomeric excess (ee), respectively. 1,2-Epoxycyclohex-4-ene is converted to the bromohydrin and iodohydrin in 84 and 91% ee. cis-2,3-Epoxybutane, cis-3,4-epoxyhexane, and cyclopentene oxide were also studied with all three halides. In general, optical induction increases in the order I > Br > Cl for any given epoxide. Thus cis-2,3-epoxybutane furnishes the corresponding chlorohydrin in 35% ee, the bromohydrin in 69% ee, and the iodohydrin in 78% ee. In certain cases recrystallization provides essentially optically pure material, e.g., (1R, 2R)-2-bromocyclohexanol, (1R, 2R)-2-iodocyclohexanol and (1R, 2R)-2-iodocyclohex-4-en-1-ol. In all cases examined ^dIpc₂BX (derived from (+)-α-pinene) provide (1R, 2R) halohydrins, in which the enantiotopic S C—O bond is cleaved. Ring cleavage occurs in an anti-periplanar manner, consistent with an S_N2 type reaction pathway. Modified B-chloromonoisopinocampheylboranes, IpcBCl(OR), cleave cyclohexene oxide at a slower rate but furnish the chlorohydrin in up to 35% ee (R = Bnz). This study is not only a novel application of chiral haloboranes, but constitutes the first general synthesis of symmetrical optically active 1,2-halohydrins.     

Vanadium‐Catalyzed Enantioselective Sulfoxidation and Concomitant,Highly Efficient Kinetic Resolution Provide High Enantioselectivity and Acceptable Yields of Sulfoxides

Simple, inexpensive, preformed vanadium‐Schiff base complexes were facilely prepared and used in enantioselective sulfoxidation. Both the amount of aqueous H₂O₂ and reaction time greatly influenced the ee values and yields of chiral sulfoxides. High enantioselectivities (up to 99% ee) and reasonable yields (>40%) for various chiral sulfoxides were achieved by combining enantioselective sulfoxidation and appropriate concomitant kinetic resolution.     

Enzymes in Organic Chemistry, 11:[1] Hydrolase‐Catalyzed Resolution of α‐ and β‐Hydroxyphosphonates and Synthesis of Chiral,Non‐Racemic β‐Aminophosphonic Acids

The enantioselective acylation of racemic diisopropyl α‐ and β‐hydroxyphosphonates by hydrolases in t‐butyl methyl ether with isopropenyl acetate as acyl donor is limited by the narrow substrate specificity of the enzymes. High enantiomeric excesses (up to 99%) were obtained for the acetates of (S)‐diisopropyl 1‐hydroxy‐(2‐thienyl)methyl‐, 1‐hydroxyethyl‐ and 1‐hydroxyhexylphosphonate and (R)‐diisopropyl 2‐hydroxypropylphosphonate. The hydrolysis of a variety of β‐chloroacetoxyphosphonates by the lipase from Candida cylindracea and protease subtilisin in a biphasic system gives (S)‐β‐hydroxyphosphonates (ee 51–92%) enantioselectively. (S)‐2‐Phenyl‐2‐hydroxyethyl‐ and (S)‐3‐methyl‐2‐hydroxybutylphosphonates (ee 96% and 99%, respectively) were transformed into (R)‐2‐aminophosphonic acids of the same ee.     

Experimental and modeling studies on the enantio-separation of 3,5-dinitrobenzoyl-(R),(S)-leucine by continuous liquid–liquid extraction in a cascade of centrifugal contactor separators

The continuous enantioselective liquid–liquid extraction of aqueous 3,5-dinitrobenzoyl-(R),(S)-leucine (A_R,S) using O-(1-t-butylcarbamoyl)-11-octadecylsulfinyl-10,11-dihydro-quinine (C, a cinchona alkaloid) as extractant in 1,2-dichloroethane (DCE) was studied experimentally in a countercurrently operated pilot scale cascade of six centrifugal contactor separators (CCS) at 294 K. The extractant was efficiently recovered by back-extraction in a single CCS allowing the cascade to be run continuously for 10 h. The steady-state ee of A_R (ee_R) in the raffinate was 42% at a 99% yield, the A_S was obtained with high purity (98% ee_S) and a yield of 55% in the back-extraction raffinate. In total 2.23 g of A_S was obtained at steady-state operation from 8.11 g racemate feed. Deterioration of the ee in time was not observed, demonstrating the robustness of the chemistry. The experiments were modeled using an equilibrium stage approach. The correlation between model and experiment was satisfactory. The model was applied to optimize the production of both enantiomers in >97% ee. At zero reflux, 12 stages are required for 99% ee for both enantiomers. Application of a reflux allows a 25% reduction of the total liquid flow through the system by reduction of the wash feed as well as a reduction in the number of stages from 12 to 11. With a configuration of 12 CINC-V02’s operating at an aqueous feed flow of 360 mL/min, the model predicts that 17.7 kg racemate per week may be separated into both enantiomers with 99% ee using only 60 g of extractant.     

A novel organocatalyst for direct asymmetric Michael additions of cyclohexanone to nitroolefins

A novel catalyst combining pyrrolidinyl and cyclohexanediamine was designed and synthesized. Only 5 mol% of catalyst loading was required for enantioselective Michael additions of cyclohexanone and nitroolefins affording desired γ-nitroketones with > 99% yield, up to 91% ee and up to > 99/1 dr under mild conditions. The enantioselectivity of the product could be further improved to > 99% ee after a single recrystallization in petroleum ether/ethyl acetate.     

Catalytic Asymmetric Total Synthesis of the Muscarinic Receptor Antagonist (R)‐Tolterodine

A convenient and high yielding method for the preparation of (R)‐tolterodine, utilizing a catalytic asymmetric Me‐CBS reduction was developed. Highly enantioenriched ( R)‐6‐methyl‐4‐phenyl‐3,4‐dihydrochromen‐2‐one (94% ee) was recrystallized to yield practically enantiopure material (ee >99%) and converted to (R)‐tolterodine in a four‐step procedure. The configuration of the crucial stereocenter was preserved during the synthesis and the obtained product was identified by chiral HPLC to be the (R)‐tolterodine enantiomer.     

A Practical NMR‐Based High‐Throughput Assay for Screening Enantioselective Catalysts and Biocatalysts

Two NMR‐based approaches for high‐throughput screening of enantioselective catalysts and biocatalysts are described. One version makes use of pseudo‐enantiomers or pseudo‐meso‐compounds based on ¹³C‐labeling. A throughput of at least 1400 ee determinations per day is possible by using an appropriate flow‐through cell and an autosampler. The other approach is based on traditional diastereomer formation using a chiral reagent or complexing agent. The ee values are accurate to within ±2% and ±5% of the true values.     

Enantioselective phase transfer alkylation using orthopalladated complex in chiral ionic liquid

The optically active orthopalladated phenanthrylamine phase transfer catalyst has been produced and explored for asymmetric glycine alkylation. The catalyst (10 mol%) in toluene/chloroform with 50% aqueous KOH (25 °C) promoted benzylation of benzophenone imine tert-butyl glycine. The product was obtained in 85% yield and 15% enantiomeric excess (ee). Addition of the chiral ionic liquid N,N-dimethyl ephedrinium bis(trifluoromethansulfon)imidate enhanced reactivity and selectivity for PTC glycine alkylation. It appears that the chiral ionic liquid has a cooperative effect to boost the ee content of an asymmetric reaction.     

Improvement in the enantioselective hydrogenation of methyl pyruvate over platinum clusters by addition of rare earth cations

The modification of some rare earth metal cations to polymer-stabilized Pt colloidal clusters leads to significant increase in both the ee and the activity in the homogeneous enantioselective hydrogenation of methyl pyruvate to (R)-(+)-methyl lactate. Compared to ee (72.5%) in the absence of rare earth cations, the highest ee (88.0%) in ethanol solvent is obtained by adding a suitable amount of Yb³+ into the Pt colloidal cluster catalyst. The modification effect of rare earth cations is also effective in other alcohol and water solvents.     

Poly(ethylene glycol)‐Supported Chiral Imidazolidin‐4‐one: An Efficient Organic Catalyst for the Enantioselective Diels–Alder Cycloaddition

A tyrosine‐derived imidazolidin‐4‐one was immobilized on a modified poly(ethylene glycol) and converted in situ into a soluble polymer‐supported catalyst for the enantioselective Diels–Alder cycloaddition of acrolein to 1,3‐cyclohexadiene (up to 92% ee) and 2,3‐dimethyl‐1,3‐butadiene (73% ee). Catalyst recycling (up to four cycles) was accompanied by some loss of the chemical efficiency and marginal erosion of the enantioselectivity.     

(R)-(+)-palasonin,a cantharidin-related plant toxin,also occurs in insect hemolymph and tissues

Gas chromatographic and mass spectroscopic analyses of extracts of cantharidin-containing meloid, clerid, and staphylinid beetles revealed the presence of minor to significant amounts of palasonin, previously only known from seeds and fruits of the Indian shrub Butea frondosa (Leguminaceae). Unlike (S)-(–)-palasonin (>99% ee) from B. frondosa, the insects produce palasonin of low ee with the (R)-(+)-enantiomer (0–50% ee) prevailing. The ee of palasonin from individual specimens of predatory insects (Trichodes apiarius), which acquire their chemical protection from cantharidin-producing insects, may vary considerably. The absolute configuration of (S)-(–)-palasonin, previously deduced from indirect chemical and spectroscopic methods, was confirmed by X-ray crystal structure analysis of a cyclic imide derived from (S)-(–)-palasonin and (S)-(–)-1-(4-nitrophenyl)-ethylamine.