Parallel kinetic resolution of racemic aldehydes by use of asymmetric Horner-Wadsworth-Emmons reactions

[reaction: see text] A racemic aldehyde can undergo parallel kinetic resolution (PKR) by simultaneous reaction with two different chiral phosphonates, differing either in the structure of the chiral auxiliary or in the structure of the phosphoryl group (i.e., one (E)- and one (Z)-selective reagent). This strategy allows conversion of a racemic aldehyde to two different, synthetically useful chiral products with essentially doubled material throughput and similar or improved selectivities as compared to conventional kinetic resolution.     

Solvent-dependent dynamic kinetic asymmetric transformation/kinetic resolution in molybdenum-catalyzed asymmetric allylic alkylations

Catalytic asymmetric alkylation reactions of branched racemic carbonates 1a and 1b with sodium dimethyl malonate, promoted by molybdenum and ligand 5, proceed by a kinetic resolution in toluene, THF, tetrahydropyran, i-PrOAc, 1,2-dichloroethane, and MeCN with k(rel) of 7-16. In THF, MeCN, tetrahydropyran, and i-PrOAc using the (S,S)-5 ligand, the fast reacting (S)-carbonate enantiomer provides the branched product with high ee (97-99.5%) and branched/linear selectivity, but the ee erodes as the reaction of the slow-reacting (R)-enantiomer takes place. This implies that the rate of equilibration of the oxidative addition complexes in these solvents is competitive with the subsequent malonate displacement step. In toluene and dichloroethane, the ee and branched/linear ratios diminish during the reaction of the slow-reacting (R)-isomer, but not nearly as much as in the other solvents. This is most likely due to either an increase in the rate of equilibration of the oxidative addition complexes relative to the malonate displacement step, or vice versa. Because of the minimal stereochemical memory effect in toluene and 1,2-dichloroethane, the reactions in these solvents can be carried to completion (dynamic kinetic asymmetric transformation) and still provide product with excellent ee (>95%). The anion of dimethyl methylmalonate also reacts via a kinetic resolution, although the ee's, rates, and k(rel) values differ from those of the reactions with dimethyl malonate.     

Lipase-catalyzed kinetic resolution of aryltrimethylsilyl chiral alcohols

Lipase-catalyzed kinetic resolution of aryltrimethylsilyl chiral alcohols through a transesterification reaction was studied. The optimal conditions found for the kinetic resolution of m- and p-aryltrimethylsilyl chiral alcohols, led to excellent results, high conversions (c = 50%), high enantiomeric ratios (E > 200) and enantiomeric excesses for the remaining (S)-alcohol and (R)-acetylated product (>99%). However, kinetic resolution of o-aryltrimethylsilyl chiral alcohols did not occur under the same conditions applied to the other isomers.     

Complementary kinetic and thermodynamic resolution of a chiral biaryl axis

The condensation of 2′-formylbiphenyl-2-carboxylic acid 4 with (S)-valinol proceeds under kinetic control to give a major product, (4bR,7S,aS)-6,7-dihydro-7-isopropyldibenz[c,e]oxazolo[3,2-a]azepin-9(4bH)-one 6a (84%), in which the biaryl axis has the (S)-configuration. Heating 6a at 140°C with a catalytic amount of acid gives rise to an equilibrium dominated by the diastereoisomeric (4bS,7S)-lactam 6b (6a:6b ratio 27:73), in which the biaryl unit has the (R)-configuration. The structures of both lactams were established by X-ray crystallography; no other diastereoisomers were obtained.     

Synthesis of a [2.2]paracyclophane based planar chiral palladacycle by a highly selective kinetic resolution/C-H activation reaction

Kinetic resolution of racemic 4-N,N-dimethylaminomethyl[2.2]paracyclophane with 50% sodium tetrachloropalladate and (R)-N-acetylphenylalanine under basic conditions resulted in the formation of a (S(p))-planar chiral palladacycle (35%, >99% ee). Similarly use of 100 mol% sodium tetrachloropalladate resulted in higher levels of conversion and recovery of (S(p))-4-N,N-dimethylaminomethyl[2.2]paracyclophane (41%, >97% ee).     

An enantiopure galactose oxidase model: synthesis of chiral amino alcohols through oxidative kinetic resolution catalyzed by a chiral copper complex

An enantiopure galactose oxidase (GO) enzyme model has been synthesized from readily available (R)-BINAM and Cu(OTf)₂, and the enantiopure GO model has been effectively used in situ as an efficient chiral catalyst for the synthesis of chiral amino alcohols through oxidative kinetic resolution (OKR), where molecular oxygen is used as the sole oxidant. Under the proposed catalytic conditions, both ortho- and para-substituted amino alcohols were resolved with good to excellent enantiomeric excesses through oxidative kinetic resolution.     

Rhodium-catalyzed asymmetric hydrogenation through dynamic kinetic resolution: asymmetric synthesis of anti-β-hydroxy-α-amino acid esters

Rhodium-catalyzed asymmetric hydrogenation of α-amino-β-keto ester hydrochlorides through dynamic kinetic resolution is described. The hydrogenation proceeds with the catalyst derived from a Rh complex and a chiral ferrocenylphosphine under hydrogen in the presence of sodium acetate in acetic acid to afford anti-β-hydroxy-α-amino acid esters with 58–83% ee in a diastereomeric ratio of 92:8–97:3.     

A highly efficient kinetic resolution of Morita-Baylis-Hillman adducts achieved by N-Ar axially chiral Pd-complexes catalyzed asymmetric allylation

Palladium complexes with an axially chiral N-Ar framework have been developed. These complexes showed high stereoselectivities in asymmetric allylic arylation to achieve the kinetic resolution of Morita-Baylis-Hillman adducts, affording up to 99% ee of (E)-allylation products and 92% ee of recovered Morita-Baylis-Hillman adducts.     

Palladium-catalyzed asymmetric allylic substitution using planar chiral hydrazone ligands

Palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate (3) with a dimethyl malonate–BSA–LiOAc system has been successfully carried out in the presence of planar chiral phosphine-hydrazone ligands such as 2a in good yields with good enantioselectivities (up to 96% ee).     

Unusual temperature dependence of enantioselectivity in asymmetric reductions by chiral NADH models

[reaction: see text] Unusual stereoselectivity changes, i.e., enhancement and inversion of enantioselectivity with increasing temperature, were observed in the asymmetric reduction of methyl benzoylformate with chiral 1,4-dihydropyridines possessing amino acid residues as ligating chiral auxiliaries. The differential activation parameters, DeltaDeltaH(S-R) and DeltaDeltaS(S-R), obtained from the Eyring plots demonstrate that the entropy term controls the enantiodifferentiating step, accounting for the observed unique temperature dependencies.     

Partial resolution through chiral synthesis using a racemic mixture

A racemic mixture of a compound bearing a reactive prochiral center can partially react with a chiral reagent ; diastereomeric products are formed and the starting material is kinetically resolved. The relationships between the relative amounts and the enantiomeric excesses of reaction products and recovered starting material are discussed. Applications are given for asymmetric hydrogenation of racemic AcΔPheAlaOMe catalyzed by a rhodiumdiop complex.     

A highly selective ferrocene-based planar chiral PIP (Fc-PIP) acyl transfer catalyst for the kinetic resolution of alcohols

Novel planar chiral ferrocene nucleophilic catalysts (Fc-PIP) containing both central and planar chiral elements were designed and synthesized for catalytic enantioselective acyl transfer of secondary alcohols. A remarkably efficient catalyst with high selectivity factors (up to S = 1892) was identified. Comparing the combination of central and planar chirality revealed a strong requirement for the "matched" chiral elements, indicating that the stereogenic center of the imidazole rings should present itself on the same face as the ferrocenyl fragment; otherwise, the catalyst is completely inactive. An exclusively stacked transition state that accounts for the high selectivity of the kinetic resolution of secondary alcohols is proposed. Notably, this newly designed catalyst family is suitable for the catalytic kinetic resolution of bulky arylalkyl carbinols, producing esters with extremely high ee (>99%).     

Nonenzymatic kinetic resolution of racemic β-hydroxyalkanephosphonates with a chiral copper catalyst

Kinetic resolution of β-hydroxyalkanephosphonates was efficiently performed by 2-fluorobenzoylation in the presence of copper(II) triflate and (R,R)-Ph-BOX as a catalyst with good s value of up to 21.     

Highly efficient asymmetric reduction of arylpropionic aldehydes by horse liver alcohol dehydrogenase through dynamic kinetic resolution

The enantioselective synthesis of (2S)-2-phenylpropanol and (2S)-2-(4-iso-butylphenyl)propanol ((S)-Ibuprofenol) has been achieved by means of Horse Liver Alcohol Dehydrogenase (HLADH) in buffered aqueous solution or buffered organic solvent mixtures; under the reaction conditions, a dynamic kinetic resolution (DKR) process was realized with good reaction yields and enantiomeric ratios.     

Practical stereoselective synthesis of beta-branched alpha-amino acids through efficient kinetic resolution in the phase-transfer-catalyzed asymmetric alkylations

Phase-transfer-catalyzed alkylation of glycinate Schiff base with racemic secondary alkyl halides proceeded with excellent levels of syn- and enantioselectivities under the influence of chiral quaternary ammonium bromide 1d and 18-crown-6. The alkylation product can be selectively converted to the corresponding anti isomer, allowing the preparation of all the stereoisomers of beta-alkyl-alpha-amino acid derivatives, an extremely valuable chiral building block.     

Synthesis of chiral 1-ferrocenylaldols and 1-ferrocenyl-1,3-diols via asymmetric reductions

The asymmetric transfer hydrogenation promoted by the (R,R)-(Ts-DPEN)–Ru complex of some 1-ferrocenyl-1,3-diketones was investigated and in all the cases only the carbonyl group distant to the metallocene moiety was reduced with variable selectivity depending on the C-3 substituent. The CBS-catalyzed reduction of 1-ferrocenyl-β-hydroxy-1-ketones, previously protected as acetates, was also found effective, giving both the corresponding syn- and anti-1,3-diols in satisfactory enantiomeric purity.     

Dynamic kinetic resolution in the stereoselective synthesis of 4,5-diaryl cyclic sulfamidates by using chiral rhodium-catalyzed asymmetric transfer hydrogenation

The dynamic kinetic resolution of 4,5-diaryl cyclic sulfamidate imines was achieved via asymmetric transfer hydrogenation using a HCO(2)H/Et(3)N mixture as the hydrogen source and chiral Rh catalysts (R,R)- or (S,S)-RhCl(TsDPEN)Cp* affording the corresponding cyclic sulfamidates in good yields with up to >20 : 1 dr and up to >99% ee.     

Dynamic kinetic resolution catalyzed by Ir axially chiral phosphine catalyst: asymmetric synthesis of anti aromatic beta-hydroxy-alpha-amino acid esters

The anti selective hydrogenation of alpha-amino-beta-keto esters via dynamic kinetic resolution was achieved for the first time by using the iridium-MeOBIPHEP catalyst in asymmetric synthesis of anti aromatic beta-hydroxy-alpha-amino acid esters with excellent diastereo- and enantioslectivities. Acetic acid as a solvent and sodium acetate as an additive affected dramatically the yield and the enantioselectivity, respectively. The product anti aromatic beta-hydroxy-alpha-amino acid esters are useful for synthesis of pharmaceuticals and natural products.     

Enzymatic kinetic resolution and chemoenzymatic dynamic kinetic resolution of delta-hydroxy esters. An efficient route to chiral delta-lactones

A successful kinetic resolution of a racemic mixture of delta-hydroxy esters 1 was obtained via lipase-catalyzed transesterification (E value up to 360). The combination of the enzymatic kinetic resolution with a ruthenium-catalyzed alcohol racemization led to an efficient dynamic kinetic resolution (ee up to 99% and conversion up to 92%). The synthetic utility of this procedure was illustrated by the practical syntheses of delta-lactones (R)-6-methyl- and (R)-6-ethyl-tetrahydropyran-2-one and (S)-5-(tert-butyldimethylsiloxy)heptanal. The former are important building blocks in the synthesis of natural products and biologically active compounds, and the latter is a key intermediate in the synthesis of widely used commercial insecticide Spinosyn A.     

Catalytic asymmetric reductive amination of aldehydes via dynamic kinetic resolution

A novel organocatalytic asymmetric reductive amination of aldehydes has been developed. Treating racemic alpha-branched aldehydes with p-anisidine and a Hantzsch ester in the presence of our previously developed phosphoric acid catalyst, TRIP, gave beta-branched secondary amines in excellent yields and enantioselectivities via an efficient dynamic kinetic resolution. The process is applicable to several different aromatic aldehydes and amines but gives slightly reduced enantiomeric ratios with aliphatic aldehydes.