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.     

Asymmetric synthesis of enantiomerically pure zingerols by lipase-catalyzed transesterification and efficient synthesis of their analogues

The achiral zingerone 1, readily available from ginger, can be easily transformed into chiral derivatives. Zingerol 2, a reduced product of zingerone 1 is expected to be an important new medicinal lead compound. We have achieved a concise synthesis of optically active zingerol (R)-2 and (S)-2 by the lipase-catalyzed stereoselective transesterification of racemic 2. Under the optimized conditions, a lipase from Alcaligenes sp. (Meito QLM) and vinyl acetate in i-Pr₂O or hexane at 35 °C within 1 h gave the alcohol (S)-2 and the acetate (R)-9 with high enantioselectivity without producing acetylated by-products. Since optically active (S)-2 and (R)-9 were obtained through lipase-catalyzed transesterification, other enantiomerically pure novel compounds could all be synthesized.     

Approaches to (R)- and (S)-1′-(1-aminoethyl)ferrocene-1-carboxylic acid derivatives

Lipase-catalyzed esterification of (±)-methyl 1′-(1-hydroxyethyl)ferrocene-1-carboxylate 4 afforded its (R)-acetate (−)-5 (ee = 99%) and (S)-(+)-4 (ee = 90%). Stereoretentive azidation/amination/acetylation of (R)-(−)-5 gave (R)-(+)-methyl 1′-(1-acetamidoethyl)ferrocene-1-carboxylate (R)-3 (ee = 98%). In a similar manner (S)-(+)-4 was converted into (S)-(−)-3 (ee = 84%). Both enantiomers of 3 were obtained in high chemical yields without a loss of enantiomeric purity. The title compounds can be coupled with natural amino acids and peptides on both C- and N-termini.     

Enzymatic reactions for the preparation of homocalycotomine enantiomers

Homocalycotomine enantiomers (R)-4 and (S)-4 were prepared by the Candida antarctica lipase B (CAL-B)-catalysed asymmetric O-acylation of N-Boc-protected 2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)ethanol (±)-1. The preliminary small-scale experiments were performed either in a continuous-flow system or as batch reactions, while the preparative-scale resolution was carried out in two steps with vinyl acetate as the acyl donor in the presence of Et₃N and Na₂SO₄ in toluene at 3 °C, as a batch reaction. Treatment of the resulting amino alcohol (S)-1 and amino ester (R)-3 (ee ?94%) with 18% HCl, and then with 5 M NaOH, furnished the desired (R)-4 and (S)-4 without a decrease in the enantiomeric excess (ee ?94%).     

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F 3 was achieved from the chiral bithiazole-type primary alcohols [(S)- and (R)-4-ethoxycarbonyl-2′-(1-hydroxymethylethyl)-2,4′-bithiazoles 8], which were obtained based on the enzymatic resolution of racemic alcohol 8 and its acetate 9. From a direct comparison by means of chiral HPLC between natural cystothiazole F 3 and synthetic compounds [(4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles 3], natural cystothiazole F 3 was found to be a 33:67 diastereomeric mixture [(4R,5S,6E,14S)-3:(4R,5S,6E,14R)-3 = 33:67].     

Enthalpic changes on mixing two couples of S- and R-enantiomers of benzyl-(1-phenyl-ethyl)-amine, 1-phenylethylamine, 1-phenyl-ethanol,butyric acid oxiranylmethyl ester, 4-methyl-[1,3]dioxolan-2-one, 2-chloro-methyloxirane and 3-hydroxyisobutyric acid methyl ester at T = 298.15 K

Enthalpies of mixing of (R)- and (S)-enantomers of liquid chiral compounds such as benzyl-(1-phenyl-ethyl)-amine (1), 1-phenylethylamine (2), 1-phenyl-ethanol (3), butyric acid oxiranylmethyl ester (4), 4-methyl-[1,3]dioxolan-2-one (5), 2-Chloromethyloxirane (6) and 3-hydroxyisobutyric acid methyl ester (7) have been measured over the whole range of mole fractions at 298.15 K, albeit very small values. Mixing of heterochiral liquids of R-1 + S-1, R-5 + S-5, and R-7 + S-7 realized enthalpic stabilization over the whole range of mole fractions, whereas that of R-2 + S-2, R-3 + S-3, R-4 + S-4, and R-6 + S-6 realized enthalpic destabilization over entire compositions. The extreme values of enthalpies of mixing and the intermolecular interaction obtained by the molecular mechanics calculations showed a linear correlation, except few the compounds measured.     

Transformation of racemic ethyl 3-hydroxybutanoate into the (R)-enantiomer exploiting lipase catalysis and inversion of configuration

Racemic ethyl 3-hydroxybutanoate rac-1 was transformed into ethyl (R)-acetoxybutanoate (ee = 92%) with 85–90% chemical yields using enantioselective acylation with isopropenyl acetate in the presence of Candida antarctica lipase B (CAL-B, Novozym 435) under solvent-free conditions, followed by mesylation of the unreacted (S)-alcohol in the reaction mixture and inversion of configuration with cesium acetate in DMF in one pot. When the (R)-acetoxybutanoate was subjected to alcoholysis with ethanol and CAL-B, enantiopure (R)-1 (ee >99%) was produced.     

Advanced procedure for the enzymatic ring opening of unsaturated alicyclic β-lactams

Enantiopure β-amino acids 1a–4a and β-lactams 1b–4b were prepared simultaneously through the lipolase-catalysed enantioselective ring opening of unsaturated racemic β-lactams (±)-1-(±)-4. High enantioselectivities (E>200) were observed when the reactions were performed with 1 equiv of water in iPr₂O at 70 °C. The resolved (1R,2S)-amino acids (yield⩾45%) and (1S,5R)-, (1S,6R)- and (1S,8R)-lactams (yield⩾47%) could be easily separated. The ring opening of lactam enantiomers 1b–4b with 18% HCl afforded the corresponding β-amino acid hydrochlorides 1c·HCl–4c·HCl (ee >95%).     

Heterocycles 35. CaL-B mediated synthesis of enantiomerically pure (R)- and (S)-ethyl 3-(2-arylthiazol-4-yl)-3-hydroxypropanoates

Herein we present the lipase catalyzed synthesis of four new enantiomerically pure (R)- and (S)-ethyl 3-(2-arylthiazol-4-yl)-3-hydroxypropanoates and their butanoates by enzymatic enantioselective acylation of the racemic alcohols rac-1a–d and by ethanolysis of the corresponding racemic esters rac-2a–d mediated by lipase B from Candida antarctica (CaL-B) in organic solvents. In terms of stereoselectivity and activity, both procedures, the acylation and alcoholysis, are successful (50% conversion, E ≫ 200). The absolute configuration of the resolution products was determined by a detailed ¹H NMR study of the Mosher’s derivatives of (S)-1a.     

Continuous-flow enzymatic resolution strategy for the acylation of amino alcohols with a remote stereogenic centre: synthesis of calycotomine enantiomers

Both enantiomers of calycotomine (R)-5 and (S)-5 were prepared through the CAL-B-catalysed asymmetric O-acylation of N-Boc-protected (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol [(±)-3)]. The optimum conditions for the enzymatic resolution were determined under continuous-flow conditions, while the preparative-scale resolution of (±)-3 was performed as a batch reaction with high enantioselectivity (E >200). The resulting amino alcohol (S)-3 and amino ester (R)-4, obtained with high enantiomeric excess (ee = 99%), were transformed into the desired calycotomine (S)-5 and (R)-5 (ee = 99%). A systematic study was carried out in a continuous-flow system on the O-acylation of tetrahydroisoquinoline amino alcohol homologues (±)-1 to (±)-3 containing a remote stereogenic centre.     

Synthesis of the (1S,2S)- and (1R,2S)-stereoisomers of the respective E- and Z-isomers of ethyl 4-[(2-hydroxycyclohexyl)methyl]phenoxy-3-methyl-2-butenoate using yeast whole cell bioreduction of the parent ketones

Saccharomyces cerevisiae, strain DBM 2115, was successfully employed in the reduction of the separated Z- and E-isomers of ethyl 4-[(2-oxocyclohexyl)methyl]phenoxy-3-methyl-2-butenoates 1 and 2, in order to prepare the (1S,2S)- and (1R,2S)-enantiomers of the corresponding ethyl 4-[(2-hydroxycyclohexyl)methyl]phenoxy-3-methyl-2-butenoates 3–6. The products were obtained with the required absolute configuration: (1S,2S)-3 (ee = 98%; yield 48%), (1R,2S)-4 (ee = >99%; yield 45%), (1S,2S)-5 (ee = 98.5%; yield 47%), and (1R,2S)-6 (ee = >99%; chemical yield 44%).     

Lipase-catalyzed kinetic and dynamic kinetic resolution of 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

A dynamic kinetic resolution method for the preparation of enantiopure 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (R)-2 was developed involving the CAL-B-catalyzed enantioselective hydrolysis of the corresponding ethyl ester (±)-1 in toluene/acetonitrile (4:1) containing 1 equiv of added water and 0.25 equiv of dipropylamine. This method allowed the preparation of (R)-2 (ee = 96%) with 80% isolated yield. The kinetic resolution of (±)-1 in diisopropyl ether at 3 °C afforded both enantiomers with ee ⩾92%.     

Kinetic resolution of 5-(hydroxymethyl)-3-phenyl-2-isoxazoline by using the ‘low-temperature method’ with porous ceramic-immobilized lipase

A significant enhancement of the enantioselectivity (E value = 249) in the lipase-catalyzed resolution of a primary alcohol, racemic 5-(hydroxymethyl)-3-phenyl-2-isoxazoline (±)-1, was obtained by using the ‘low-temperature method’ (−60 °C) with porous ceramic-immobilized lipase (Amano PS-C II) and vinyl acetate in acetone.     

Synthesis and crystal structure of (S)-pindolol

Racemic 3-(4-indolyloxy)-1,2-propanediol 2 has been effectively resolved into (S)- and (R)-enantiomers by a preferential crystallization procedure. Non-racemic (S)-2 was converted into (S)-4-(2,3-epoxypropoxy)-1H-indole (S)-4 via a Mitsunobu reaction and then into (S)-pindolol (S)-1. The crystalline (S)-1 was studied by single crystal X-ray diffraction. A large number of symmetry independent molecules (Z′ = 6) led to a weakening of the system of strong intermolecular hydrogen bonds, which combined with a loose packing (PI = 64.6%), may be the cause of the abnormally low melting point of (S)-1 as compared with rac-1.     

Reactions of a hydrido(hydrosilylene)tungsten complex with oxiranes

Reactivity of a hydrido(hydrosilylene)tungsten complex, Cp¹(CO)₂(H)WSi(H)[C(SiMe₃)₃] (1), toward oxiranes was investigated. Treatment of 1 with racemic mono-substituted oxiranes with a substituent R (R = Ph, vinyl, ^tBu, or ⁿBu) at room temperature produced dihydrido(vinyloxysilyl)tungsten complexes, (E)- and/or (Z)-Cp¹(CO)₂(H)₂W{Si(H)(OCHCHR)[C(SiMe₃)₃]} [(E/Z)-2: R = Ph, (E)-3: R = vinyl, (E)-4: R = ^tBu, (E/Z)-5: R = ⁿBu] in high yields via regioselective ring-opening of oxiranes. When the substituent R on oxirane was relatively large, (E)-isomers (2, 3, and 4) were obtained predominantly (87–97%), while the substituent was a relatively small ⁿBu group, an approximately 1:1 mixture of (E)- and (Z)-isomers [(E/Z)-5] was obtained. Reaction of 1 with 2,2-dimethyloxirane afforded the corresponding complex, Cp¹(CO)₂(H)₂W{Si(H)(OCHCMe₂)[C(SiMe₃)₃]} (6), quantitatively. A reaction mechanism is also discussed.     

Furostanol saponins with inhibitory action against COX-2 production from Tupistra chinensis rhizomes

Two furostanol saponins were obtained from the n-butanol fraction of methanol extract from Tupistra chinensis rhizomes,a folk medicine of Shennongjia Forest District of Hubei Province.Their structures were determined as (25S)-26-O-(β-D-glucopyranosyl)- furost-1β,3β,22α,26-tetrol-3-O-β-D-glucopyranosyl-(1→4)-β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside (1) and (25R)- 26-O-(β-D-glucopyranosyl)-furost-1β,3β22α,26-tetrol 3-O-β-D-glucopyranosyl-(1→4)-β-D-glucopyranosyl-(1→2)-β-D-glu- copyranoside (2),on basis of chemical and spectroscopic evidences.1 and 2 displayed marked inhibitory action towards COX-2 production in macrophages of the rat abdomen induced by LPS at 20μg/mL.     

Solid state properties of 1,2-epoxy-3-(2-methoxyphenyloxy)-propane—valuable intermediate in non-racemic drug synthesis

Racemic 1,2-epoxy-3-(2-methoxyphenyloxy)-propane 1 undergoes spontaneous resolution upon crystallization. This fact is confirmed by coincidence of the IR spectra of racemic and scalemic crystalline samples of 1, by thermal analysis (single eutectic V-shape binary melting phase diagram), and X-ray analysis (space group P2₁2₁2₁, Z = 4). Racemic 1 could be resolved into (S)-(+)- and (R)-(−)-1 by a preferential crystallization procedure.     

A new strategy for the synthesis of hydroxylated pyrrolizidinic alkaloids by highly stereoselective indium-mediated allylation of pyrrolidinic aldehydes

Indium-mediated allylation of N-Cbz-l-prolinal 3, under Grignard conditions, was carried out with high yield and stereoselectivity (de = 90%) to afford intermediate (2S,1′R)-N-benzyloxycarbonyl-2-(1′-hydroxybut-3′-en-1′-yl)pyrrolidine 4, which was transformed in two steps into (1R,3R,7aS)-1-hydroxy-3-hydroxymethylpyrrolizidine 9. Commercial Cbz-l-proline was a source of functionalization and chirality.     

Synthesis of rigid and C2-symmetric 18-crown-6 type macrocycles bearing diamide–diester groups: enantiomeric recognition for α-(1-naphthyl)ethylammonium perchlorate salts

A series of rigid and chiral C₂-symmetric 18-crown-6 type macrocycles (S,S)-4, (S,S)-5, (S,S)-6 and (R,R)-2 bearing diamide–ester groups were synthesized. The binding properties of these macrocycles were examined for α-(1-naphthyl)ethylammonium perchlorates salts by an ¹H NMR titration method. Taking into account the host employed, important differences were observed in the K_a values of (R)- and (S)-enantiomers of guests for macrocycles (S,S)-4 and (S,S)-6, K_S/K_R = 3.6, and K_S/K_R = 0.1 (K_R/K_S = 10.3) ΔΔG = 3.19 and ΔΔG = ?5.77 kJ mol^?1, respectively. The results indicated excellent enantioselectivity of macrocyclic (S,S)-6 towards the enantiomers of α-(1-naphthyl)ethylammonium perchlorate salts.     

Diastereoselective and enantioselective alkaline-hydrolysis of 2-aryl-1-cyclohexyl acetate: a CAL-B catalyzed deacylation/acylation tandem process

Candida antarctica lipase proved to be a particularly efficient lipase for the resolution of racemic 2-arylcyclohexyl acetate in hydrolysis reaction with Na₂CO₃ in an organic medium. The (1R,2S)-trans-2-arylcyclohexanols 2a–2d were obtained with high ee values (up to >99%) and the selectivity reached E > 200. The influence of the enol ester and the solvent on (±)-trans-2-arylcyclohexanol in the CAL-B catalyzed acylation was also studied and compared with the deacylation. The CAL-B exhibits a better affinity for the alkaline hydrolysis reaction compared with acylation with the enol esters in the same organic solvents. The best conditions were applied to resolve a stereoisomeric mixture cis/trans-2-phenyl-1-cyclohexanol and its corresponding acetate by acylation and deacylation. The obtained results show a highly enantio- and diastereoselectivity of the CAL-B during the acylation and the deacylation in favor of the trans-(R)-enantiomer product. The resolution of a mixture of cis/trans-2-arylcyclohexanols was an easy, convenient approach to provide only one stereoisomer of a mixture of four with high enantiomeric excess.