Novel chiral copper complexes of N,P-ferrocenyl ligands with central and planar chirality as efficient catalyst for asymmetric addition of diethylzinc to imines

A new type of chiral copper complexes of N,P-ferrocenyl ligands with central and planar chirality as efficient catalyst was applied to the enantioselective addition of diethylzinc to N-diphenylphosphinoylimines. The (R)- and (S)-enantiomers of the addition reaction were obtained for this transformation. In the presence of 6 mol % of bidentate ligand 1 and 12 mol % of Cu(OTf)₂, the asymmetric addition process affords N-diphenylphosphinoylamides in up to 97% ee and 95% yields.     

Chiral para-alkyl phenyl ethers of glycerol: synthesis and testing of chirality driven crystallization,liquid crystal,and gelating properties

A series of enantiopure and racemic p-alkylphenyl glycerol ethers 1a–k were synthesized. A new, sensitive, and pictorial method of comparison of the IR spectra of solid enantiopure and racemic samples was developed to obtain preliminary information on the crystallization types of these compounds. In order to detect the subtle differences in the organization of the chiral solid phase, a new easily implemented approach, based on a chromatographic measuring of the relative abundance of the enantiomers in a single solution in equilibrium with a solid sample of arbitrary (0 < ee < 1) composition, is reported. One new conglomerate compound (Alk = n-Pr) and one borderline case (Alk = n-Bu) are disclosed. Higher members of the series of 1 (starting with an n-Bu derivative) are turned into liquid crystals upon melting; no significant differences between racemic and non-racemic samples were found. Only enantiopure methyl-, n-butyl, n-pentyl, n-hexyl, and n-heptyl substituted 1 were able to form supramolecular gels in hydrocarbon solvents; all racemic ethers 1 did not show such ability.     

Asymmetric addition of diethylzinc to aldehydes catalyzed by a camphor-derived β-amino alcohol

The asymmetric addition of diethylzinc to aromatic and aliphatic aldehydes, including linear aliphatic ones, catalyzed by 2 mol % of β-amino alcohol (1S, 2R)-7,7-dimethyl-1-morpholin-4-yl-bicyclo[2.2.1]heptan-2-ol 10 gave the corresponding secondary alcohols in high yields and with up to 94% ee at ambient temperature after 15 min.     

Synthesis of chiral C/N-functionalized morpholine alcohols: study of their catalytic ability as ligand in asymmetric diethylzinc addition to aldehyde

A broad variety of chiral C/N-functionalized morpholine alcohols sharing a common structural motif in the 3-(hydroxymethyl)morpholine 6 were prepared from enantiomerically pure serine for the purpose of studying their catalytic ligand properties. The asymmetric addition of diethylzinc to benzaldehyde in the presence of 10 mol % of chiral C/N-functionalized morpholine alcohols gave 1-phenyl-1-propanol in 59–81% yield with 10–30% ee. The addition of 10 mol % of n-butyl lithium to the reaction mixture resulted in a significant enhancement of the stereoselectivity in the case of ligands bearing the two geminal phenyl substituents on the backbone. In the presence of n-butyl lithium and using (S)-3-(hydroxydiphenylmethyl)morpholine (S)-19 as the chiral promoter, (S)-1-phenyl-1-propanol was obtained in 81% yield with 76% ee. The geminal diphenyl-class of morpholine ligands was examined for the diethylzinc addition to four different aldehydes in the presence of n-butyl lithium. (S)-N-Benzyl-3-(hydroxydiphenylmethyl)morpholine (S)-27 was found to be most enantioselective in the case of 4-methoxybenzaldehyde to give (R)-alcohol in 87% yield with 80% ee. Catalysts (S)-19 and its N-methyl derivative (S)-26 gave alcohols with an (S)-absolute configuration while the N-benzylated derivative (S)-27 gave the opposite enantiomeric products. The tentative transition state models to account for the observed product stereoselectivity with morpholine ligands holding the geminal diphenyl group on the β-amino alcohol segment are proposed.     

trans-(2R,3R)-2,3-Diphenylcyclopropane-1,1-dimethanol: a pivotal diol for the synthesis of novel C2-symmetric ligands for asymmetric transition metal catalysis

Various chiral ligands bearing phosphorus or nitrogen donor atoms were obtained in a straightforward manner starting from trans-(2R,3R)-diphenylcyclopropane-1,1-dimethanol as a key structure. These chiral ligands were tested and compared in palladium(0)-catalyzed asymmetric allylic alkylation reactions (up to 71% ee) and rhodium(I)-catalyzed asymmetric hydrogenations (up to 88% ee). Moreover, in the asymmetric allylic alkylation, we observed excellent activity with a diphosphinite ligand (TOF = 600 mol 17 × [mol Pd × h)^?1].     

A new chiral sulfonamide ligand based on tartaric acid: synthesis and application in the enantioselective addition of diethylzinc to aldehydes and ketones

A new sulfonamide ligand based on l-tartaric acid was synthesized and was employed as a chiral ligand in the enantioselective addition of diethylzinc to aldehydes, giving rise to the best enantiomeric excess up to 83% with 5 mol % of catalyst loading. Moreover, the addition of diethylzinc to ketones can also be achieved with good to excellent enantioselectivities by employing 7 mol % of the catalyst under mild conditions.     

New chemical and chemo-enzymatic routes for the synthesis of (RS)- and (S)-enciprazine

The chemo-enzymatic synthesis of racemic and enantiopure (RS)- and (S)-enciprazine 1, a non-benzodiazepine anxiolytic drug, is described herein. The synthesis started from 1-(2-methoxyphenyl) piperazine 3, which was treated with 2-(chloromethyl) oxirane (RS)-4 using lithium bromide to afford a racemic alcohol, 1-chloro-3-(4-(2-methoxyphenyl) piperazin-1-yl) propan-2-ol (RS)-6 in 85% yield. Intermediate (S)-6 was synthesized from racemic alcohol (RS)-6 using Candida rugosa lipase (CRL) with vinyl acetate as the acyl donor. Various reaction parameters such as temperature, time, substrate, enzyme concentration, and the effect of the reaction medium on the conversion and enantiomeric excess for the transesterification of (RS)-6 by CRL were optimized. It was observed that 10 mM of (RS)-6, 50 mg/mL of CRL in 4.0 mL of toluene with vinyl acetate (5.4 mmol) as acyl donor at 30 °C gave good conversion (C = 49.4%) and enantiomeric excess (ee_P = 98.4% and ee_S = 96%) after 9 h of reaction. Compound (S)-6 is a key intermediate for the synthesis of enantiopure (S)-1. The (RS)- and (S)-enciprazine drug 1 was synthesized by treating (RS)- and (S)-6 with 3,4,5-trimethoxyphenol 5 using MeCN as a solvent and K₂CO₃ as a base.     

Catalytic asymmetric hydrosilylation of acetophenone with new chiral thiourea ligands containing the (S)-α-phenylethyl group

New chiral thioureas 1–8 containing 1,2-ethylendiamine or trans-1,2-diaminocyclohexane as the carbon skeleton, and containing an (S)-α-phenylethyl group have been prepared (79–98% yield). Thioureas 1–8 were used as ligands for the zinc-based catalyzed asymmetric hydrosilylation of acetophenone with polymethylhydrosiloxane (PMHS). The best result was achieved with monothiourea 1 (up to 75% ee), in toluene and a catalyst load of 5 mol %.     

New β-amino thiols as efficient catalysts for highly enantioselective alkenylzinc addition to aldehydes

A series of new optically active β-amino thiols and thiolacetates prepared from the simple natural amino acid, (S)-(−)-valine, were found to be effective catalysts for the enantioselective addition of alkenylzinc to aldehydes and thereby providing an efficient route for chiral (E)-allylic alcohols with ees of up to >99% in the presence of 7a (1 mol %).     

Candida antarctica lipase B-catalyzed ring opening of 4-arylalkyl-substituted β-lactams

The Lipolase-catalyzed ring opening of racemic 4-benzyl- 3 and 4-phenylethyl-2-azetidinone 4 was performed with 0.5 equiv of H₂O in diisopropyl ether at 45 °C. The resulting (S)-β-amino acid 5 or 6 (ee ⩾ 87%) and (R)-β-lactam 7 or 8 (ee >99%) enantiomers could easily be separated. The ring opening of enantiomeric β-lactams with 18% aqueous HCl afforded the corresponding enantiopure β-amino acid hydrochlorides 9 and 10 (ee >99%).     

Chiral 1,4-morpholin-2,5-dione derivatives as α-glucosidase inhibitors: Part 2

A series of chiral 1,4-morpholin-2,5-dione derivatives were synthesized starting from chiral synthons 1 and 2, diastereomeric monolactim ethers derived from l-valine. The compounds investigated, were inactive toward β-glucosidase, α-mannosidase and α-galactosidase but behave as noncompetitive inhibitors against the α-glucosidase (from Saccharomices cervisiae) with some showing a good inhibition ability (0.05 < K_i < 0.18 mM).     

Chiral linear polymers bonded alternatively with salen and 1,4-dialkoxybenzene: synthesis and application for Ti-catalyzed asymmetric TMSCN addition to aldehydes

The synthesis of chiral linear polymers 1a–b having salen and 1,4-dioctyloxybenzene as alternate segments has been accomplished. The GPC analysis showed the molecular weights corresponding to ca. 15 (M_w = 10,999, M_n = 9165 and PDI = 1.20) repeating units for 1a and ca. 8 (M_w = 8547, M_n = 7883 and PDI = 1.08) repeating units for 1b. Polymers 1a–b have been studied with Ti(OⁱPr)₄ as a recyclable catalyst for the asymmetric addition of TMSCN to aldehydes while the selectivity of the polymer catalyst is identical to that of the monomer. The reactions are efficient affording the cyanohydrins with up to 88% ee. The selectivity of the polymer based catalyst 9a is found to be the same to that of the monomer 10a. The reaction provides the advantages of simplified product isolation and easy recovery and recyclability of polymer catalyst 9a without any loss of activity or selectivity.     

Asymmetric synthesis of the chiral synthon ethyl (S)-4-chloro-3-hydroxybutanoate using Lactobacillus kefir

Lactobacillus kefir was used as the whole cell biocatalyst for the asymmetric reduction of ethyl 4-chloro acetoacetate 1 to the chiral synthon ethyl (S)-4-chloro-3-hydroxybutanoate 2. Ketoester 1 was obtained as micro-droplets, without the use of an organic solvent as substrate reservoir. 2 (1.2 M) was produced using 2-propanol as co-substrate with a final yield of 97% within 14 h. A high space-time yield and a high specific product capacity of 85.7 mmol/L h and of 24 mmol/g_DCW were measured. The enantiomeric excess of the (S)-alcohol 2 was 99.5%.     

Synthesis of chiral ligands containing the N-(S)-α-phenylethyl group and their evaluation as activators in the enantioselective addition of Et2Zn to benzaldehyde

The synthesis of chiral ligands 4–18 derived from N-[(S)-α-phenylethyl]-trans-β-aminocyclohexanols (S,S,S)-1a and (R,R,S)-2 is described. Addition of diethylzinc to benzaldehyde catalyzed by ligands 4–18 (6 mol %) proceeds in fair to good yield (45–86%), and low to good enantioselectivities (1–76% ee). Highest enantioselectivities were induced by ligands (S,S,S)-4 and (S,S,S,S,R,R)-18 (76% and 68% ee, respectively). The configuration of the major enantiomer of carbinol 3 is (R) in both cases.     

Preparation of various enantiomerically pure (benzotriazol-1-yl)- and (benzotriazol-2-yl)-alkan-2-ols

(S)-(−)-(Benzotriazol-1-yl)- and (S)-(−)-(benzotriazol-2-yl)-alkan-2-ols 7a–9a, 7b–9b and their (R)-(+)-acetates 10a–12a and 10b–12b were prepared in high enantiomeric excess via lipase from Pseudomonas fluorescens (Amano AK) catalyzed enantioselective acetylation of racemic alcohols 4a–6a and 4b–6b with vinyl acetate in tert-butyl methyl ether or toluene at 23 °C. The enantioselectivity of this transformation was dependent on the length of the alkyl chain with E-values ranging from 30 to 57. Several benzotriazole substituted ketones 1a–3a and 1b–3b were synthesized from 1H-benzotriazole and corresponding haloketones. These compounds were stereoselectively reduced with Baker’s yeast in water or in organic solvent containing 5% v/v of water at 30 °C to give the (S)-(−)-alcohol. Better stereoselectivity was observed in the kinetic resolution of racemic alcohols 4a–6a and 4b–6b (ee = 69–92% at 44–52% conversion) compared to reduction of corresponding prochiral ketones 1a–3a and 1b–3b with Baker’s yeast (ee = 40–67% at 39–89% conversion). Enhanced enantioselectivities were observed at lower temperatures.     

A green route to enantioenriched (S)-arylalkyl carbinols by deracemization via combined lipase alkaline-hydrolysis/Mitsunobu esterification

Herein we report results of the chemoenzymatic deracemization of a range of secondary benzylic acetates 1a–9a via a sequence of hydrolysis with CAL-B lipase in non-conventional media, combined with esterification of the recovered alcohol according to the Mitsunobu protocol following an enzymatic kinetic resolution (KR). The KR of racemic acetates 1a–9a via an enzymatic hydrolysis, with CAL-B lipase and Na₂CO₃, in non-aqueous media was optimized and gave high selectivities (E ? 200) at good conversions (C >49%) for all of the substrates studied. This method competes well with the traditional one performed in a phosphate buffer solution. The deracemization using Mitsunobu inversion gave the (S)-acetates in moderate to excellent enantiomeric excess 75% < ee < 99%, in acceptable isolated yields 70% < yield < 89%, and with some variations according to the acetate structure.     

Enantioselective construction of all-carbon quaternary spirocenters through a Pd-catalyzed asymmetric intramolecular ipso-Friedel–Crafts allylic alkylation of phenols

A novel catalytic asymmetric synthetic method for making spirocyclohexadienones with an all-carbon quaternary spirocenter was developed based on the Pd-catalyzed intramolecular ipso-Friedel–Crafts allylic alkylation of phenols. When 5 mol % of the Pd catalyst and 12 mol % of (?)-9-NapBN (?)-3e were used, the spirocyclic adduct was obtained with up to 93% ee, albeit with low chemical yield. On the other hand, when using 6 mol% of the Trost ligand (R,R)-3k, the spirocyclic adducts were obtained in good yields with up to 89% ee (diastereoselectivity = 9.2:1).     

Enantioselective 1,4-conjugate addition of diethylzinc to (E)-alkenyl aryl ketones catalysed by Cu/DiPPAM complex

We report here the use of the DiPPAM-L1 ligand for copper-catalysed asymmetric conjugate addition (ACA) of diethylzinc to various (E)-alkenyl aryl ketones where the aryl ring is either a phenyl group substituted by nitro, chloro or methoxy groups or not substituted, or a naphthyl group. When the conjugate addition was performed in the greener AcOEt solvent with 1 or 2 mol % of Cu(OTf)₂/DiPPAM complex, moderate to good yields (45–83%) and high enantioselectivities (up to 98%) were reached.     

Thermal properties of some small peptides (N-acetyl-amino acid-N′-methylamides) with non-polar side groups

Temperatures and molar enthalpies of fusion of a series of uncharged small peptides, namely the methylamides of N-acetyl substituted glycine, α-amino-butyric acid, alanine, valine, norvaline, leucine, isoleucine, norleucine, and proline, were measured by differential scanning calorimetry (d.s.c.), and molar entropies of fusion were derived. Both l- and dl-compunds were taken into account for the chiral molecules. No solid-to-solid transitions were detected from room temperature to fusion except for N-acetyl-N′-methyl alaninamide. Comparisons were made with the values for the N-acetyl amides of the corresponding amino acids previously reported. Both l enantiomers and dl racemates of α-aminobutyric acid, alanine, valine and isoleucine methylamides displayed temperatures of fusion sharply increasing as a function of molar mass, whereas much lower values, in countertendency with their molar mass increase, were found for proline and leucine methylamides. The racemic dl crystals showed temperatures of fusion of about 40 °C lower than those of the corresponding pure l enantiomers, except for proline and leucine derivatives. The enthalpies and entropies of fusion also varied as a function of molar mass following a similar trend with that of temperatures of fusion, except for alanine derivatives which showed lower values than expected. The values of ideal solubility of solids at T = 298.15 K were estimated based on their temperatures and molar entropies of fusion. Results were discussed with reference to the packing patterns based on hydrogen bonding and hydrophobic interactions.     

Preparation of isoxazolidinyl nucleoside enantiomers by lipase-catalysed kinetic resolution

An efficient biocatalytic procedure to obtain chiral N,O-nucleoside derivatives consisting of a lipase-catalysed resolution of the corresponding racemates in organic solvent has been developed. Enantioselective esterification of thymine and cytosine derivatives, (±)-9a and (±)-9b, has been investigated by comparing the efficiency of different lipases and acyl donors. Since esterification of (±)-9a and (±)-9b, occurred with low enantioselectivity (E ? 14) in the presence of the lipases considered, for preparative purposes we resorted, with success, to a double sequential kinetic resolution, using Lipozyme IM as the best catalyst. This approach enables us to obtain all the enantiomers with ee ? 95%. The absolute configuration of the new chiral N-acetyl cytosine derivative 9b was established by circular dichroism spectroscopy.