Chemo-enzymatic synthesis of (R)- and (S)-3,4-dichlorophenylbutanolide intermediate in the synthesis of sertraline

3,4-Dichlorophenacylchloride was reduced with whole cell biocatalysts to give the (R)- or (S)-chlorohydrine in high yields and good to high enantiomeric excess. Yields and enantiomeric purity of the (S)-enantiomer were increased to 95 and >98%, respectively, using growing cells from Geotrichum candidum (CBS 233.76) in the presence of hydrophobic adsorbing resins at 4 g/l. The latter compound was transformed into (R)-3,4-dichlorophenylbutanolide, intermediate in the synthesis of (+)-cis-1S,4S-sertraline.     

Enantioconvergent synthesis of (-)-(2R,5S)-1-allyl-2,5-dimethylpiperazine,an intermediate to delta-opioid receptor ligands

A convenient, high-yield enantioconvergent synthesis of (-)-1-allyl-(2S,5R)-dimethylpiperazine from trans-2,5-dimethylpiperazine has been developed. This compound is an important intermediate in the synthesis of delta-opioid receptor ligands. The process allows for the laboratory preparation of 100 g quantities of this enantiomerically pure diamine without chromatography. The key steps in the sequence were an efficient optical resolution using relatively inexpensive resolving agents, followed by interconversion of the unwanted (+)-enantiomer into the desired (-)-enantiomer.     

Validated chiral high-performance liquid chromatography method for a novel anti-methicillin-resistant Staphylococcus aureus fluoroquinolone WCK 771

A sensitive, simple, specific, precise, accurate and rugged method for the assay and determination of enantiomeric purity of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate (WCK 771) in bulk drug has been developed. The method is RP-HPLC using endcapped C-18 stationary phase and chiral mobile phase. Chirality to the mobile phase was imparted with addition of beta-cyclodextrin. The UV-vis detector was operated at 290 nm. The flow rate of mobile phase was 2 ml/min. The method offers excellent separation of two enantiomers with resolution more than 2 and tailing factor less than 1.5. The method was validated for the assay of WCK 771 and quantification of R-(+)-enantiomer impurity in bulk drug. The calibration curves showed excellent linearity over the concentration range of 0.05-0.15 mg/ml for WCK 771 and 0.5-7.5 microg/ml for R-(+)-enantiomer. The precision (RSD) of the assay was 0.23%. The limit of detection and limit of quantitation of the method for WCK 771 were 0.015 and 0.06 microg/ml, respectively. The limit of detection and limit of quantitation for R-(+)-enantiomer were 0.025 and 0.09 microg/ml, respectively. The average recovery of the R-(+)-enantiomer was 100.5%. Same method was applied for the assay and determination of enantiomeric purity of WCK 771 in the intravenous formulation.     

Enzyme-catalysed improved resolution of (RS)-4-cyano-4-(3,4-dimethoxyphenyl)-4-isopropyl-1-butanol

Resolutions of (RS)-4-cyano-4-(3,4-dimethoxyphenyl)-4-isopropyl-1-butanol 1 using various enzymes were performed. Among them, Pseudomonas fluorescens resolved it with moderate stereoselectivity (E=13) and reacted faster with the (S)-enantiomer. To optimize enzyme-catalysed reaction conditions for the resolution, the effect of solvents and additives was studied. In n-hexane:ethyl acetate (9:1), both reaction rate and selectivity were high. When pyridine, potassium carbonate and molecular sieves were used as additives, the enantiomeric excess of the (R)-enantiomer was 99, 99 and 98% at 52–60% conversion, respectively. However, in diisopropyl ether, the enantiomeric excess of unreacted alcohol (R)-1 was up to 99% at 70% conversion without additives.     

Synthesis of enantiomeric menthol derivatives for forming and probing chiral surfaces. X-ray crystal and molecular structures of (+)-(1S,2R,5S)-1-(2-tricyanovinyl-1H-pyrrol-1-yl-methoxy)-2-isopropyl-5-methylcyclohexane

Two enantiomeric pairs of menthol derivatives, the menthol ester with 10-undecynoic acid and the 2-tricyanovinyl-pyrrole derivative of the methoxy-menthol, have been synthesized and their pure enantiomers obtained. The X-ray crystal and molecular structure of the (+)-enantiomer of the latter compound is reported.     

Absolute Conformation and Configuration of (2S, 3S)-3-Acetoxy-5-(dimethylaminoethyl)-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one Chloride (Dilthiazem Hydrochloride)

Resolution of racemic cis-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl) propionic acid ( 2 ) via the cinchonidine salt 3 , and brucine salt 4 , isolation of the calcium salts (+)- and (?)- 5 , as well as their cyclization to enantiomeric 1,5-benzothiazepines (+)- and (?)- 1 , are described. X-Ray single-crystal analysis reveals (2S, 3S) absolute configuration of (+)- 1 on the basis of tentative comparison of CD data with those for the 1,4-benzodiazepine derivative (+)- 8 of known absolute configuration.     

1,5-Benzoxathiepin derivatives. III. Optical resolution of methyl (+/-)-cis-3-hydroxy-4-[3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydro- 2H-1,5-benzoxathiepin-4-carboxylate hydrochloride ((+/-)-CV-5197) with selective 5-hydroxytryptamine2(5-HT2)-antagonistic activity

The selective 5-HT2-receptor antagonist, methyl (+/-)-cis-3-hydroxy-4-[3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydro-2H- 1,5-benzoxathiepin-4-carboxylate hydrochloride ((+/-)-CV-5197) was resolved in high optical purity using (R)-(-)- and (S)-(+)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphates ((R)-(-)- and (S)-(+)-BNP). The absolute configuration of (+)-CV-5197 was determined to be 3S,4R by X-ray crystallographic analysis. In the binding assay, it was demonstrated that (+)-CV-5197 was a more active isomer (IC50 = 23 nM +/- 6.3) for 5-HT2 receptor binding than the (-)-enantiomer (IC50 = 1600 nM +/- 82). (+)-CV-5197 completely inhibited the 5-HT-induced contraction of the isolated pig coronary artery at a concentration of 3 x 10(-7) M, whereas (-)-CV-5197 showed little antagonistic activity, even at 3 x 10(-4) M. Thus, the agreement between the results of the binding assays and the biological activities for the 3S,4R enantiomer of CV-5197 suggests that its physiological activity is probably exerted through 5-HT2-receptor antagonism.     

Enantioselective total synthesis of (-)-triptolide, (-)-triptonide, (+)-triptophenolide, and (+)-triptoquinonide

The first enantioselective total synthesis of (-)-triptolide (1), (-)-triptonide (2), (+)-triptophenolide (3), and (+)-triptoquinonide (4) was completed. The key step involves lanthanide triflate-catalyzed oxidative radical cyclization of (+)-8-phenylmenthyl ester 30 mediated by Mn(OAc)3, providing intermediate 31 with good chemical yield (77%) and excellent diastereoselectivity (dr 38:1). (+)-Triptophenolide methyl ether (5) was then prepared in > 99% enantiomeric excess (> 99% ee), and readily converted to natural products 1-4. In addition, transition state models were proposed to explain the opposite chiral induction observed in the oxidative radical cyclization reactions of chiral beta-keto esters 17 (without an alpha-substituent) and 17a (with an alpha-chloro substituent).     

Studies of Diastereoselectivity in Diels-Alder Reactions of Enantiopure (SS)-2-(p-Tolylsulfinyl)-1,4-naphthoquinone and Chiral Racemic Acyclic Dienes

Enantiopure sulfinylnaphthoquinone (+)-5 reacted with racemic acyclic dienes 1a-f bearing a stereogenic allylic center, through a tandem cycloaddition/pyrolytic sulfoxide elimination, to afford optically enriched compounds 8a-f and 9a-f with good like/unlike selectivities (ca. 75:25) and good enantiomeric excesses (68-82%), arising from the partial kinetic resolution of the racemic dienes. The opposite diastereoselection (8g-i: 9g-i, up to 5:95) was observed in reactions with dienes 1g-i, having an additional methyl group at C-3, the enantiomeric purities being moderate (14-25%). Steric effects and torsional interactions in the corresponding approaches account for the observed diastereoselectivities.     

Synthesis and structural characterization of enantiopure (2R,5R)-(+)-2,5-dimethylthiolane

Enantiopure (2R,5R)-(+)-2,5-dimethylthiolane was synthesized by cyclization with sodium sulfide of the dimesylate of (2S,5S)-(+)-2,5-hexanediol, which was obtained by baker's yeast (Saccharomyces cerevisiae) reduction of acetonyl acetone in high enantiomeric purity. The structure of the diol and absolute stereochemistry of the sulfone derived from the title molecule were determined by X-ray crystal structure analysis.     

Conversion of (-)-3-dehydroshikimic acid into derivatives of the (+)-enantiomer

(-)-3-DHS (1), a compound available in large quantity through "engineering" of the shikimic acid pathway, has been converted over eight steps into the methyl ester, ent-2, of the (+)-enantiomer. Methyl (+)-shikimate (15) and its C-3 epimer (ent-5) have also been prepared by related means.     

Synthesis of (s)-(-)-Benzyl-2-tert-butoxycarbonyl amino-4-iodobutyrate

The proteinogenic (-amino acids constitute an important section of the "chiral pool", being inexpensive in the L-form (but available if necessary as the D enantiomers), structurally varied and chemically versatile1, they are useful starting materials for chiral reagents, auxiliaries and ligands2. Any high-yielding transformation of an (-amino acids which proceeds without racemization is thus of potential importance, especially if it generates another reactive center and may be applied to the s…     

Lipase catalyzed acylation of primary alcohols with remotely located stereogenic centres: the resolution of (±)-4,4-dimethyl-3-phenyl-1-pentanol

Enantioselective acylation of some (±)-3-alkyl-3-phenyl-1-propanols was performed with enzymes as catalysts. Moderate enantiomeric ratios (E), ranging up to E = 11.6, were obtained. In the resolution, some of the lipases selectively acylated the (+)-enantiomer while others acylated the (−)-enantiomer of the γ-substituted primary alcohols 1–4. Thus, it is possible to obtain both enantiomers of the alcohols as remaining substrate with high enantiomeric purity. The resolution of (±)-4,4-dimethyl-3-phenyl-1-pentanol 4 was extensively studied and screening experiments were conducted to select suitable lipase(s), reaction medium, acyl donor and appropriate temperature combinations to increase the enantiomeric ratio. Chirazyme^® L-6/chloroform/vinyl propionate/38 °C and Chirazyme^® L-7/di-iso-propyl ether/vinyl propionate/0 °C were chosen to obtain both enantiomers, (R)-(+)-4 and (S)-(−)-4, respectively, via sequential resolutions in excellent enantiomeric excess (>98%) and in 25% and 22% yield, respectively.     

Synthesis and pharmacological effects of optically active 2-[4-(4-benzhydryl-1-piperazinyl)phenyl]-ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate hydrochloride

Optically active 2-[4-(4-benzhydryl-1-piperazinyl)phenyl]ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate [(S)-(+)-1 and (R)-(-)-1] hydrochlorides were synthesized with high optical purities from (R)-(-)- and (S)-(+)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)- 3-pyridinecarboxylic acids [(R)-(-)-6 and (S)-(+)-6], which are available from (+/-)-6 by optical resolution using quinidine and cinchonidine, respectively. From pharmacological investigations of (S)-(+)-1 and (R)-(-)-1 such as the antihypertensive effect on spontaneously hypertensive rats and inhibition of [3H]nimodipine binding to rat cardiac membrane homogenate, the active form of 1 was defined to be the (4S)-(+)-enantiomer of 1.     

A New Convenient Method for the Resolution of 1, 1''''-Binaphthalene-2, 2''''-diol Via a Phosphite Using (-)-Menthol as Resolving Agent

Optically active 1,1-binaphthalene-2, 2-diol has become a quite important chiral source in different fields of chirotechnology, especially in asymmetric synthesis1. Its synthesis and resolution has been extensively studied and various resolution methods have been reported2. Among the reported resolution methods, the following three, namely, via the formation of phosphoric acid derivatives3, boric acid derivatives4 and inclusion complexes5, are the most important. OHOH+_( )-1(-)-(S)-1(+)-(R)…     

Revision of absolute configuration of enantiomeric (methylenecyclopropyl)carbinols obtained from (R)-(-)- and (S)-(+)-epichlorohydrin and methylenetriphenylphosphorane. Implications for reaction mechanism and improved synthesis of antiviral methylenecyclopropane analogues of nucleosides

Absolute configurations of enantiomeric methylenecyclopropanecarbinols obtained by reaction of (R)- and (S)-epichlorohydrin 5 with methylenetriphenylphosphorane or resolution of the corresponding oxaphospholane 6 via a salt with L-(+)-tartaric acid and subsequent Wittig transformation with formaldehyde were revised. The (-)-oxaphospholane 6 has the S,S and (-)-(methylenecyclopropyl)carbinol (4) the R configuration. The configurations of (+)-6 and (+)-4 are then R,R and S, respectively. These assignments are in accord with an initial attack of phosphorane at the oxirane ring of epichlorohydrin. An improved preparation of key enantiomeric intermediates (R)-1a and (S)-1a, important for synthesis of antiviral purine methylenecyclopropane analogues of nucleosides, is also described.     

Annulated pyranosides—V : An wenantiospecific route to (+) and (-) chrysanthemum dicarboxylic acids

-Methyl 2,3-anhydro-4,6-O-benzylidene-α-D-allopyranoside undergoes the Wadsworth- Emmons cyclopropanation with phosphonopropionate to give a cyclopropyl carboxylate which is processed to give the gem-dimethylcyclopropano pyranoside. The glycosylic acetal of this substance is readily hydrolyzed by boiling water, and the resulting cis-cyclopropane carboxaldehyde may be epimerized quantitatively to the trans-analog by treatment with sodium methoxide. These aldehydes are now converted into the (+)- and (-)-chrysanthemum dicarboxylic acids, respectively, by the same sequence of reactions involving (a) olefination with methyl 2-(triphenylphosphoranylidene)propionate, (b) hydro- lysis of the benzylidine ring and cleavage of the resulting triol with sodium metaperiodate, and (c) oxidation of the resulting aldehyde with silver I oxide. In the case of the (+)-enantiomer the last reaction is proceeded by epimerization. The overall yields from the D-allopyranoside are respectively 27%, in 10 steps for the (+)-enantiomer, and 24%, in 10 steps for the (-)-enantiomer, from the known epoxide 7.     

Crystallization-induced chiral inversion as the key step for synthesis of (S)-2-acetylthio-3-phenylpropanoic acid from l-phenylalanine

[reaction: see text] A novel crystallization-induced chiral inversion of (S)-2-bromo-3-phenylpropanoic acid to its (R)-enantiomer with excellent enantiomeric excess (96-99%) is achieved. Optically pure (S)-2-acetylthio-3-phenylpropanoic acid can be prepared in good yield from inexpensive and commercially available l-phenylalanine via diazotization/bromination, chiral inversion, and thioacetate substitution reactions.     

The first enantioselective synthesis of (S)-5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine: a key intermediate for the preparation of SIB-1508Y

The first enantioselective synthesis of (S)-5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine is described via intramolecular hydroboration–cycloalkylation of an azido-olefin intermediate. The chiral homoallylic alcohol was efficiently synthesized by enantioselective reduction of the corresponding ketone using (+)-diisopinocamphenylchloroborane as the key reaction. The total synthesis of (S)-SIB-1508Y was achieved with an enantiomeric excess (e.e.) of 94% in ten steps and in 18% overall yield from the commercially available 5-bromo-3-pyridinecarboxylic acid.     

A general enantioselective approach to jasmonoid fragrances: synthesis of (+)-(1R,2S)-methyl dihydrojasmonate and (+)-(1R,2S)-magnolione

Methyl dihydrojasmonate 1 and magnolione 3 are of both academic and industrial interest. In this paper, we describe a flexible, high-yielding route to diastereomerically pure (+)-cis-(1R,2S)-methyl dihydrojasmonate 1 and the first synthesis of (+)-cis-(1R,2S)-magnolione 3, both with enantiomeric excesses up to 93%. The two syntheses diverged from the same advanced intermediate 5, readily available from the enantioenriched hydroxymethyl delta-lactone (-)-(3aS,4S,6aR)-6. The olfactory properties of (1R,2S)-1 and (1R,2S)-3 are reported.