Microbial reduction of 2-(6-m-methoxyphenyl-3-oxohexyl)-2,4-dimethylcyclopenta-1,3-dione with Schizosaccharomyces pombe (NRRL Y-164)

A mixture of cis- and trans-2-(6-m-methoxyphenyl-3-oxohexyl)-2,4-dimethylcyclopenta-1,3-dione (±)-10 was synthesized and incubated with Schizosaccharomyces pombe (NRRL Y-164) to give (+)-11, (+)-12, (−)-13, and (−)-14 in 19, 13, 22, and 16% yields, respectively. Chromic acid oxidation of these microbiologically reduced products gave (−)-10a, (+)-10b, (+)-10a, and (−)-10b, respectively.     

A practical synthesis of (R)-3-chlorostyrene oxide starting from 3-chloroethylbenzene

A novel and practical synthesis of (R)-3-chlorostyrene oxide (−)-1 was achieved starting from commercially available 3-chloroethylbenzene 3. Enantiopure (−)-3-chlorostyrene bromohydrin (−)-5 was obtained by the treatment of racemic (±)-5 with lipase QL in the presence of acylating reagents. 3-Chloro-α,β-dibromoethylbenzene 4, a precursor of (±)-5, was synthesized via the expeditious bromination of 3 which was developed by these authors.     

Efficient preparation of (1′R)-(−)-1-(2′-hydroxy-1′-phenylethyl)piperidin-2-one: synthesis of (2′S,3R)-(+)-stenusine

An efficient oxidation of (2′R)-(−)-2′-phenyl-2′-(piperidin-1-yl)ethanol 2 with bromine to generate the corresponding piperidin-2-one 3 in 96% is described. In addition, starting from 3, (2′S,3R)-(+)-stenusine 8 was synthesized in 70% overall yield. The X-ray analysis of piperidine 6·HCl is also reported.     

Synthesis of (S)-(−)- and (R)-(+)-O-methylbharatamine using a diastereoselective Pomeranz–Fritsch–Bobbitt methodology

Laterally lithiated (S)-(−)- and (R)-(+)-o-toluamides 6 with a chiral auxiliary derived from (S)- and (R)-phenylalaninol, respectively, were used as the building blocks and chirality inductors in the asymmetric modification of the Pomeranz–Fritsch–Bobbitt synthesis of isoquinoline alkaloids. Their addition to imine 2 proceeded with partial cyclization, giving isoquinolones (+)-7 and (−)-7 along with acyclic products, (−)-8 and (+)-8, respectively. LAH-reduction of (+)-7 and (−)-7, followed by cyclization, afforded both enantiomers of the alkaloid, (S)-(−)- and (R)-(+)-O-methylbharatamine 5, in 32% and 40% overall yield and with 88% and 73% ees, respectively.     

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.     

First stereoselective synthesis of (4aS,5R)-4,4a,5,6,7,8-hexahydro-4a,5-dimethyl-2(3H)-naphthalenone

The synthesis of enantiomerically pure (4aS,5R)-hexahydro-4a,5-dimethyl-2(3H)-naphthalenone (−)-1 is described for the first time. The synthesis starts from (R)-3-methylcyclohexanone and involves the preparation of Piers enol lactone 6 in its enantiopure form as the key intermediate. Treatment of (+)-6 with methyl lithium followed by an intramolecular aldol reaction gives the bicyclic enone (−)-1.     

Racemization of (S)-(+)-10,11-dimethoxyaporphine and (S)-(+)-aporphine: efficient preparations of (R)-(−)-apomorphine and (R)-(−)-aporphine via a recycle process of resolution

Efficient preparations of (R)-(−)-apomorphine (R)-1 and (R)-(−)-aporphine (R)-2 based on a recycle process of resolution are described. In this recycle process of resolution, (RS)-(±)-10,11-dimethoxyaporphine 3 as the precursor of 1, and (RS)-(±)-aporphine 2 were successfully resolved into both enantiomers with (+)-dibenzoyltartaric acid (DBTA). The desired (R)-3 and (R)-2 were obtained and then, respectively, transformed to compound (R)-1, the hydrochloride salt of (R)-1, diacetate compound 4 and the hydrochloride salt of (R)-2; while the undesired (S)-3 and (S)-2 were racemized to obtain a racemate, which was suitable for further resolution. A method for the racemization of the undesired (S)-3 and (S)-2 was extensively studied, in order to obtain high-yielding racemization conditions. A plausible mechanism for the racemization of (S)-3 and (S)-2 was also proposed.     

Preparation of a chiral synthon for an HBV inhibitor: enzymatic asymmetric hydrolysis of (1α,2β,3α)-2-(benzyloxymethyl)cyclopent-4-ene-1,3-diol diacetate and enzymatic asymmetric acetylation of (1α,2β,3α)-2-(benzyloxymethyl)cyclopent-4-ene-1,3-diol

Enantioselective asymmetric hydrolysis of (1α,2β,3α)-2-(benzyloxymethyl)-cyclopent-4-ene-1,3-diol diacetate 1 to the corresponding (+)-monoacetate 2 was carried out using lipase PS-30 from Pseudomonas cepacia or pancreatin. A reaction yield of 85 M % with an enantiomeric excess (ee) of 98% was obtained. Using pancreatin, a reaction yield of 75 M % with an ee of 98.5% was obtained. Asymmetric acetylation of (1α,2β,3α)-2-(benzyloxymethyl)-cyclopent-4-ene-1,3-diol 3 to the corresponding (−)-monoacetate 4 was carried out using lipase PS-30 with isopropenyl acetate as the acylating agent. A reaction yield of 80 M % with an ee of 98% was obtained for (−)-monoacetate 4.     

Synthetic studies toward the preparation of (4R,5R)-(−)-3-[(benzyloxy)methyl]-4,5-O-isopropylidene-cyclopenten-2-one: an important synthetic intermediate for carbanucleosides

The carbocyclic compound (4R,5R)-(−)-3-[(benzyloxy)methyl]-4,5-O-isopropylidene-2-cyclopentenone 1 is an important synthetic intermediate to access a variety of carbanucleosides. Herein, synthetic studies that lead to this valuable compound employing inexpensive d-ribose as the chiral source are presented.     

A convenient access to chiral and racemic (Z)-1-bromo-3-benzoxy-1-butene

The conversion of propargylic trimethylsilyl ether 3 into (Z)-1-bromo-3-benzoxy-1-butène 1 was achieved by hydroboration with pinacolborane followed by successive treatment with bromine and DBU. The key step of the chiral synthesis involves the asymmetric reduction of the α,β-unsaturated ketone 7 with (−)-diisopinocampheylchloroborane [(−)-Ipc₂BCl].     

Chemoenzymatic synthesis of (S)-2-cyanopiperidine,a key intermediate in the route to (S)-pipecolic acid and 2-substituted piperidine alkaloids

The preparation of (S)-2-cyanopiperidine 4 provides a new access to 2-substituted piperidines. This synthesis is based on an enantioselective (R)-oxynitrilase-catalyzed reaction for the preparation of (R)-(+)-6-bromo-2-hydroxyhexanenitrile 1 and the subsequent cyclization of this compound to yield the piperidine ring. The utilization of 4 as the starting material for the synthesis of (S)-2-aminomethylpiperidine 6, (R)-(−)-coniine 10 and (S)-(−)-pipecolic acid 13 is also described.     

Collagen cross-links: a convenient synthesis of tert-butyl-(2S)-2-[(tert-butoxycarbonyl)amino]-4-(2-oxiranyl)butanoate

An efficient synthesis of tert-butyl-(2S)-2-[(tert-butoxycarbonyl)amino]-4-(2-oxiranyl) butanoate (5), the key intermediate for preparation of collagen cross-links (+)-pyridinoline (Pyd, 1) and (+)-deoxypyridinoline (Dpd, 2) was described from (4S)-5-(tert-butoxy)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid (6) in six steps. Also, an improved synthesis of iodide (2S)-(−)-4b was presented.     

Asymmetrization of all-cis-3,5-dihydroxy-1-(methoxycarbonyl)cyclohexane and of the 4-methyl and 4-ethyl substituted homologues

Enantiomerically pure mono acylated derivatives of cis,cis-3,5-dihydroxy-1-(methoxycarbonyl)cyclohexane 1, all-cis-3,5-dihydroxy-4-methyl-1-(methoxycarbonyl)cyclohexane 2 and all-cis-3,5-dihydroxy-4-ethyl-1-(methoxycarbonyl)cyclohexane 3 were obtained upon lipase catalyzed asymmetrization. PPL-catalyzed transesterification of 1 with vinyl acetate led in high yield to the (S)-monoacetate (+)-13. With substrates 2 and 3 this process was slower and gave the (R)-monoacetates (−)-14 and (−)-15; the best results were obtained with SAM II lipase. On the other hand, enantiotoposelective hydrolysis of their diacetates and especially dibutyrates gave useful results only for the 4-substituted substrates and produced the (S)-monoesters.     

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.     

Preparation,molecular structures,and characteristic properties of (E)-1-(2-furyl)- and (E)-1-(2-thienyl)-2-(3-guaiazulenyl)ethylenes and (E)-1-(3-furyl)- and (E)-1-(3-thienyl)-2-(3-guaiazulenyl)ethylenes

Wittig reactions of 2-furaldehyde (20) [and thiophene-2-carbaldehyde (21)] with (3-guaiazulenylmethyl)triphenylphosphonium bromide (19) in ethanol containing NaOEt at 25 °C for 24 h under argon give (E)-1-(2-furyl)-2-(3-guaiazulenyl)ethylene (22E) and (E)-1-(2-thienyl)-2-(3-guaiazulenyl)ethylene (23E) in 53 and 36% yields. Similarly, Wittig reactions of 3-furaldehyde (29) [and thiophene-3-carbaldehyde (30)] with 19 under the same reaction conditions as for 20 and 21 afford (E)-1-(3-furyl)-2-(3-guaiazulenyl)ethylene (31E) and (E)-1-(3-thienyl)-2-(3-guaiazulenyl)ethylene (32E) in 32 and 46% yields. Molecular structures and characteristic properties as well as preparation of the title E (i.e., one of the geometrical isomers) forms, with a view to comparative study, are reported. Moreover, reactions of those conjugated π-electron systems with TCNE (=tetracyanoethylene) in benzene [and in DMF (=N,N-dimethylformamide)] at 25 °C for 24 h under argon yield unique products, possessing interesting molecular structures, respectively, whose characteristic properties and crystal structures are documented, also.     

Kinetic resolution of 1,2-dihydroxy-3-ferrocenylpropane by sequential lipase-catalysed esterification

One-pot sequential esterification of 1,2-dihydroxy-3-ferrocenylpropane 1, catalysed by lipase from Pseudomonas cepacia, allowed kinetic resolution of the racemate, affording (−)-(R)-1-acetoxy-2-hydroxy-3-ferrocenyl-propane (−)-2, and (+)-(S)-1,2-diacetoxy-3-ferrocenylpropane (+)-3, in high chemical yield and enantiomeric excess.     

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.     

Diastereoselective synthesis of enantiopure 5-[2-(alkoxyalkyl)-1-(hydroperoxypropyl)]-3-alkoxycarbonyl-2-alkyl furans

The diastereoselective approach to enantiomerically pure furyl hydroperoxides of general type 1 has been accomplished starting from (S)-(−)-ethyl lactate. In the first part of the synthesis the alkylating reagents 7a,b were efficiently produced to be used in the second part for a 4-step known methodology to obtain furyl hydroperoxides. The most relevant transformation of the synthesis is the first reported diastereoselective iodoenoletherification of 2-acetyl-4-heptenoate esters 8a,b possessing a φ-chiral center. Furthermore, the final radical oxidation performed on (E)-5-alkylidene-4,5-dihydrofurans 11a,b led to formation of hydroperoxides (S,S)-12a,b in a diastereocontrolled manner due to 1,2-asymmetric induction.     

2-Methoxy-2-(1-naphthyl)propionic acid,a powerful chiral auxiliary for enantioresolution of alcohols and determination of their absolute configurations by the 1H NMR anisotropy method

Racemic 2-methoxy-2-(1-naphthyl)propionic acid (1, MαNP acid) was enantioresolved as its esters derived from various chiral alcohols. For example, a diastereomeric mixture of esters prepared from (±)-1 and (1R,3R,4S)-(−)-menthol was easily separated by HPLC on silica gel yielding esters (−)-2a and (−)-2b, the separation factor α=1.83 being unusually large. The ¹H NMR chemical shift differences, Δδ=δ(R)–δ(S), between diastereomers 2a and 2b, are much larger than those of conventional chiral auxiliaries, e.g. Mosher’s MTPA and Trost’s MPA acids. This acid 1 is therefore very powerful for determining the absolute configuration of chiral alcohols by the ¹H NMR anisotropy method. Solvolysis of the separated esters yielded enantiopure acids (S)-(+)-1 and (R)-(−)-1, which are useful for enantioresolution of racemic alcohols.     

Synthesis of (−)-(5R,6S)-6-acetoxyhexadecan-5-olide by l-proline-catalyzed asymmetric aldol reactions

The natural mosquito attractant pheromone, (−)-(5R,6S)-6-acetoxyhexadecan-5-olide 1, was synthesized from readily available aldehyde 3 and cyclopentanone 4 using l-proline catalyzed asymmetric aldol reactions as the key step.