Enantiomers 1a Research Articles

Gelozymes in organic synthesis. Part IV: Resolution of glycidate esters with crude Mung bean ( Phaseolus radiatus) epoxide hydrolase immobilized in gelatin matrix

A crude extract of Mung bean meal ( Phaseolus radiatus) possessing epoxide hydrolase activity immobilized in gelatin gel (gelozyme) is employed in the stereoselective epoxide ring opening of glycidate esters. Thus, ethyl trans-(±)-3-phenyl glycidate 1a and methyl trans-(±)-3-(4-methoxyphenyl) glycidate 1b gave (2 S,3 R)-glycidate esters (ee >99% and 45% yield) with gelatin immobilized enzyme in diisopropyl ether. The corresponding (2 R,3 S)-enantiomer of 1a was hydrolyzed by an epoxide hydrolase to predominantly give the anti-product, ethyl (2 R,3 R)-2,3-dihydroxy-3-phenylpropanoate, with a diastereomeric excess of 78% and ee 94% (40%). A small amount (5%) of racemic syn-product was also obtained as a result of the spontaneous hydrolysis. In the case of 1b, the hydrolysis product was racemic due to high reactivity of the glycidate toward water.

Determination of rabeprazole enantiomers and their metabolites by high-performance liquid chromatography with solid-phase extraction

Here, we describe the development of a rapid, simple and sensitive high-performance liquid chromatography (HPLC) method for the simultaneous quantitative determination of rabeprazole enantiomers ( 1a, b) and their metabolites, rabeprazole-thioether ( 2) and rabeprazole sulfone ( 3), in human plasma. Analytes and the internal standard (omeprazole-thioether) were separated using a mobile phase of 0.5 M NaClO 4–acetonitrile (6:4, v/v) over a Chiral CD-Ph column. Analysis required only 100 μl of plasma and involved solid-phase extraction with an Oasis HLB cartridge, which gave high recovery (>91.8%) with good selectivity for all analytes. The lower limit of quantification was 5 ng/ml for analytes 1a, 1b and 3 and 10 ng/ml for 2. Linearity of this assay was determined to lie between 5 and 1000 ng/ml for 1a, 1b and 3 and 10 and 1000 ng/ml for 2 ( r 2 > 0.982 of the regression line). Inter- and intra-day coefficients of variation were less than 7.8% and accuracies were within 8.4% over the linear range for all analytes. Our results indicate that this method is applicable to the simultaneous monitoring of plasma levels of rabeprazole enantiomers and associated metabolites in human plasma.

Synthesis and Structure Assignment of 2-(4-Methoxybenzyl)cyclohexyl β-D-Glucopyranoside Enantiomers

Glucosylation of the cis- and trans-isomers of 2-(4-methoxybenzyl)cyclohexan-1-ol (1a/1b, 2a/2b, 1a or 2a) was performed to prepare the corresponding alkyl β-D-glucopyranosides, mainly to get analytical data of pure enantiomers of the glucosides (3a-6b), required for subsequent investigations of related compounds with biological activity. One of the employed modifications of the Koenigs-Knorr synthesis resulted in achieving 85-95% yields of pure β-anomers 3a/3b, 4a/4b, 3a or 4a of protected intermediates, with several promoters and toluene as solvent, yielding finally the deprotected products 5a/5b, 6a/6b, 5a or 6a as pure β-anomers. To obtain enantiomerically pure β-anomers of the target structure (3a, 4a, 5a and 6a) for unambiguous structure assignment, an enzymic reduction of 2-(4-methoxybenzyl)cyclohexan-1-one by Saccharomyces cerevisiae whole cells was performed to get (1S,2S)- and (1S,2R)-enantiomers (1a and 2a) of 2-(4-methoxybenzyl)cyclohexan-1-ol. The opposite enantiomers of alkyl β-D-glucopyranosides (5b and 6b) were obtained by separation of the diastereoisomeric mixtures 5a/5b and 6a/6b by chiral HPLC. All stereoisomers of the products (3a-6b) were subjected to a detailed 1H NMR and 13C NMR analysis.

Synthesis and Structure Assignment of 2-(4-Methoxybenzyl)cyclohexyl β-D-Galactopyranoside Stereoisomers

Several promoters were used in the Koenigs-Knorr synthesis of the title alkyl β-D-galactopyranosides, both in their diastereoisomeric forms (5a/5b and 6a/6b), resulting from the synthesis performed with the respective racemic cis and trans isomers of 2-(4-methoxybenzyl)cyclohexan-1-ol, and in their enantiomerically pure forms 5a and 6a, starting only from the (1S,2S)- and (1S,2R)-enantiomers of 2-(4-methoxybenzyl)cyclohexan-1-ol. The aim of the study was to find convenient modification(s) of the Koenigs-Knorr synthesis of alkyl β-D-galactopyranosides from more hindered and more complex 2-substituted cycloalkanols. Separation of the diastereoisomeric compounds using HPLC on a chiral Nucleodex-β-OH column was used to obtain small quantities of all possibly existing enantiomerically pure products for unambiguous structure assignment by NMR analysis. The (1S,2S)- and (1S,2R)- enantiomers of 2-(4-methoxybenzyl)cyclohexan-1-ol (1a and 2a) were prepared by a reduction of 2-(4-methoxybenzyl)cyclohexan-1-one with Saccharomyces cerevisiae in enantiomeric purities: ee = 98.5% ((1S,2S)-enantiomer (1a)), and ee ≥ 99% ((1S,2R)-enantiomer (2a)).

Optically Active Seleninic Acid: Isolation, Absolute Configuration, Stability, and Chiral Crystallization

Abstract Each optical isomer of methaneseleninic acid (1a) was isolated as chiral crystals by recrystallization from methanol/toluene. The absolute configuration of one of the enantiomers was determined by X-ray crystallographic analysis, and the relationship between the absolute configuration and the circular dichroism spectra of 1a was clarified. The optically active seleninic acid (R)-1a was stable toward racemization in the solid state, although it racemized very rapidly in solution. Each enantiomer of 1a was obtained in bulk by chiral crystallization in the presence of a seed crystal or chiral solvents. The absolute configuration of optically active methanesulfinic acid (4) was also assigned by comparing its circular dichroism spectra with those of 1a.

(Cyclohexylmethylphenylphosphine)[(1-η1:6−8-η3)-octa- 2,6-diene-1,8-diyl]palladium(II) as a Model for Key Intermediates in Enantioselective Reactions of 1,3-Butadiene Catalyzed by Palladium(0)

(Cyclohexylmethylphenylphosphine)[(1-η1:6−8-η3)-octa-2,6-diene-1,8-diyl]palladium(II) (1) was synthesized from bis(η3-propenyl)palladium(II) and 1,3-butadiene in the presence of racemic cyclohexylmethylphenylphosphine (2) and exists in the form of two diastereomeric pairs of enantiomers 1a,b. The diastereomers have been fully characterized by NMR spectroscopic methods, with special focus on their stereochemistry. The molecular structure of 1b was determined by X-ray crystallography and confirmed the results of the NMR investigation: in both diastereomers the C8H12 chains exhibit the same rigid topology and thus represent an inherent chiral element in these intermediates originating from butadiene coupling. This is an essential prerequisite for subsequent enantioselective transformations of complexes of type 1.

Stereosensitive formation and interconversion of sulfur-bridged cobalt(III)–mercury(II) polynuclear complexes with d- and/or l-penicillaminates

The reaction of trans( N)-[Co( d-pen) 2] − (pen = penicillaminate) with HgCl 2 or HgBr 2 in the molar ratios of 1:1 gave the sulfur-bridged heterodinuclear complex, [HgX(OH 2){Co( d-pen) 2}] (X = Cl ( 1a) or Br ( 1b)). A similar reaction in the ratio of 2:1 produced the trinuclear complex, [Hg{Co( d-pen) 2} 2] ( 1c). The enantiomers of 1a and 1c, [HgCl(OH 2){Co( l-pen) 2}] ( 1a′) and [Hg{Co( l-pen) 2} 2] ( 1c′), were also obtained by using trans( N)-[Co( l-pen) 2] − instead of trans( N)-[Co( d-pen) 2] −. Further, the reaction of cis · cis · cis-[Co( d-pen)( l-pen)] − with HgCl 2 in the molar ratio of 1:1 resulted in the formation of [HgCl(OH 2){Co( d-pen)( l-pen)}] ( 2a). During the formations of the above six complexes, 1a, 1b, 1c, 1a′, 1c′, and 2a, the octahedral Co(III) units retain their configurations. On the other hand, the reaction of cis · cis · cis-[Co( d-pen)( l-pen)] − with HgCl 2 in the molar ratio of 2:1 gave not [Hg{Co( d-pen)( l-pen} 2] but [Hg{Co( d-pen) 2}{Co( l-pen) 2}] ( 2c), accompanied by the ligand-exchange on the terminal Co(III) units. The X-ray crystal structural analyses show that the central Hg(II) atom in 1c takes a considerably distorted tetrahedral geometry, whereas that in 2c is of an ideal tetrahedron. The interconversion between the complexes is also examined. The electronic absorption, CD, and NMR spectral behavior of the complexes is discussed in relation to the crystal structures of 1c and 2c.

Synthesis of enantiopure 1,4-ethyl- and 1,4-ethylene-bridged cispentacin by lipase-catalyzed enantioselective ring opening of β-lactams

1,4-Ethyl- and 1,4-ethylene-bridged cispentacin enantiomers 1a , 1c and 2a , 2c were prepared through the lipase-catalyzed enantioselective ring opening of racemic exo-3-azatricyclo[4.2.1.0 2.5]nonan-4-one, (±)− 1 , and exo-3-azatricyclo[4.2.1.0 2.5]non-7-en-4-one, (±)− 2 . High enantioselectivity ( E>200) was observed when the Lipolase-catalyzed reactions were performed with 1 equiv of H 2O in diisopropyl ether at 70 °C. The resolved β-amino acids 1a and 2a (yield 46%) and β-lactams 1b and 2b (yield ⩾40%) could be easily separated. The ring opening of lactam enantiomers with 18% HCl afforded the corresponding β-amino acid hydrochloride enantiomers (ee ⩾ 98%).

Biotransformation of alpha-isomethylionone to 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)propan-2-one.

The main biodegradation product of (+/-)-alpha-isomethylionone (2) with standard activated sludge was characterized as (+/-)-1-(2,6,6-trimethyl-2-cyclohexen-1-yl)propan-2-one (1) by its analysis and synthesis. Both enantiomers (1a and 1b) of 1 were synthesized by starting from (R)- and (S)-2,4,4-trimethyl-2-cyclohexen-1-ol (3a and 3b), respectively.

An improved synthesis of ethyl cis-5-iodo- trans-2-methylcyclohexanecarboxylate, a potent attractant for the Mediterranean fruit fly

Both racemic ethyl 5-iodo-2-methylcyclohexanecarboxylate ( 1 ), known as Mediterranean fruit fly attractant ceralure B 1, and its (−)-(1 R,2 R,5 R) enantiomer 1a were conveniently synthesized from commercially available racemic trans-6-methyl-3-cyclohexenecarboxylic acid 2 or its (1 R,6 R) enantiomer 2a . Key steps included an asymmetric Diels–Alder reaction using a sultam auxiliary and cyclization of the unwanted trans-5-iodo- trans-2-methylcyclohexanecarboxylic acid ( 8 ) to the intermediate lactone 7 (or 8a to 7a ). The new method may circumvent chromatographic separations and seems amenable to scale-up.

Chiral N,N-disubstituted trifluoro-3-amino-2-propanols are potent inhibitors of cholesteryl ester transfer protein.

A novel series of substituted N-benzyl-N-phenyl-trifluoro-3-amino-2-propanols are described that reversibly inhibit cholesteryl ester transfer protein (CETP). Starting with screening lead 22, various structural features were explored with respect to inhibition of the CETP-mediated transfer of [(3)H]cholesterol from high-density cholesterol donor particles to low-density cholesterol acceptor particles. The free hydroxyl group of the propanol was required for high potency, since acylation or alkylation reduced activity. High inhibitory potency was also associated with 3-ether moieties in the aniline ring, and the highest potencies were exhibited by 3-phenoxyaniline analogues. Activity was substantially reduced by oxidation or substitution in the methylene of the benzylic group, implying that the benzyl ring orientation was important for activity. In the benzylic group, substitution at the 3-position was preferred over either the 2- or the 4-positions. Highest potencies were observed with inhibitors in which the 3-benzylic substituent had the potential to adopt an out of plane orientation with respect to the phenyl ring. The best 3-benzylic substituents were OCF(2)CF(2)H (42, IC(50) 0.14 microM in buffer, 5.6 microM in human serum), cyclopentyl (39), 3-iso-propoxy (27), SCF(3) (67), and C(CF(3))(2)OH (36). Separation of 42 into its enantiomers unexpectedly showed that the minor R(+) enantiomer 1a was 40-fold more potent (IC(50) 0.02 microM in buffer, 0.6 microM in human serum) than the major S(-) enantiomer 1b, demonstrating that the R-chirality at the propanol 2-position is key to high potency in this series. The R(+) enantiomer 1a represents the first reported acyclic CETP inhibitor with submicromolar potency in plasma. A chiral synthesis of 1a is reported.

Oxidative Addition of Allylammonium BPh4- to Nickel(0): Synthesis, Crystal Structure, Fluxional Behavior, and Catalytic Activity of Chiral [(η3-allyl)(NH3)(PCy3)Ni]BPh4

The synthesis, crystal structure, fluxional behavior, and reactivity of [(η3-C3H5)Ni(PCy3)(NH3)]BPh4 (1) are described. Complex 1 was obtained by oxidative addition of allylammonium tetraphenylborate, (CH2CHCH2NH3)BPh4, to Ni(0) [(Cy3P)2Ni(η2-CO2) or (Cy3P)2NiNNNi(PCy3)2], under mild conditions, through selective activation of the N−C-allyl bond. Complex 1 is a unique example of an allyl−Ni cationic complex with three different ligands and donor atoms. It has been fully characterized both in the solid state and in solution. The X-ray study shows that the cation [(η3-C3H5)Ni(PCy3)(NH3)]+ (1+) is chiral as a result of the two possible orientations of the allyl group and the different ancillary ligands bound to the (η3-C3H5)Ni+ moiety. In the solid state, cation 1+ exists as a racemic mixture of the two enantiomers 1a+ and 1b+. In solution, complex 1+ is involved in a slow fluxional process that causes the left-to-right exchange of syn and anti protons of the allyl group and leads to the interconversion of t...

(R)-(-)- and (S)-(+)-Synadenol: synthesis, absolute configuration, and enantioselectivity of antiviral effect.

Synthesis of (R)-(-)- and (S)-(+)-synadenol (1a and 2a, 95-96% ee) is described. Racemic synadenol (1a + 2a) was deaminated with adenosine deaminase to give (R)-(-)-synadenol (1a) and (S)-(+)-hypoxanthine derivative 5. Acetylation of the latter compound gave acetate 6. Reaction with N, N-dimethylchloromethyleneammonium chloride led to 6-chloropurine derivative 7. Ammonolysis furnished (S)-(+)-synadenol (2a). Absolute configuration of 1a was established by two methods: (i) synthesis from (R)-methylenecyclopropanecarboxylic acid (8) and (ii) X-ray diffraction of a single crystal of (-)-synadenol hydrochloride. Racemic methylenecyclopropanecarboxylic acid (10) was resolved by a modification of the described procedure. The R-enantiomer 8 was converted to ethyl ester 13 which was brominated to give vicinal dibromides 14. Reduction with diisobutylaluminum hydride then furnished alcohol 15 which was acetylated to the corresponding acetate 16. Alkylation-elimination procedure of adenine with 16 yielded acetates 17 and 18. Deprotection with ammonia afforded a mixture of Z- and E-isomers 1a and 19 of the R-configuration. Comparison with products 1a and 2a by chiral HPLC established the R-configuration of (-)-synadenol (1a). These results were confirmed by X-ray diffraction of a single crystal of (-)-synadenol hydrochloride. The latter forms a pseudosymmetric dimer with adenine-adenine base pairing in the lattice with the nucleobase in an anti-like conformation. Enantiomers 1a and 2a exhibit varied enantioselectivity toward different viruses. Both enantiomers are equipotent against human cytomegalovirus (HCMV) and varicella zoster virus (VZV). The S-enantiomer 2a is somewhat more effective than R-enantiomer 1a in herpes simplex virus 1 and 2 (HSV-1 and HSV-2) assays. By contrast, enantioselectivity of antiviral effect is reversed in Epstein-Barr virus (EBV) and human immunodeficiency virus type 1 (HIV-1) assays where the R-enantiomer 1a is preferred. In these assays, the S-enantiomer 2a is less effective (EBV) or devoid of activity (HIV-1).

Resolution of the [6,6′-μ-(CH 3) 2P-(1,7-(C 2B 9H 10) 2)-2-Co] bridged cobaltacarborane to enantiomers pure by chiral HPLC, circular dichroism spectra and absolute configurations by X-ray diffraction

Racemic [6,6′-μ-(CH 3) 2P-(1,7-(C 2B 9H 10) 2)-2-Co] zwitterion 1R was resolved into enantiomers 1A and 1B by chiral HPLC, and, for the first time for a chiral metallacarborane, absolute configurations of both enantiomers were determined by X-ray diffraction. HPLC results, circular dichroism spectra and crystallographic data [orthorhombic, space group P2 12 12, Z=8; 1A: a=11.5180(5) Å, b=12.4741(6) Å, c=13.8335(8) Å, V=1987.6(2) Å 3, 1B: a=11.5177(3) Å, b=12.4700 Å, c=13.8326(6) Å, V=1986.7(1) Å 3] are presented. Nomenclature and correlation of the CD curves with those reported earlier for closely related analogs, are discussed, along with general implications for chiral HPLC resolutions on a β-cyclodextrin column.

Synthesis of (2 S,5 S)-5-fluoromethylornithine; a potent inhibitor of ornithine aminotransferase

Only one of the four enantiomers of 5-fluoromethylornithine 1 was an irreversible inhibitor of ornithine aminotransferase. The active enantiomer 1a was synthesized from diaminoadipic acid 2 with a chemical diastereomeric separation and an enantiomeric resolution by hydrolysis of a phenylacetamide with benzylpenicillinase.

Determination of the Configuration of Wine Lactone

AbstractThe intense sweet and coconut‐like smelling odorant 1, named ‘wine lactone’, was isolated from different wine varieties. The chemical structure of this compound, which has not yet been detected in wine or a food, was identified by high‐resolution mass spectrometry (HR‐MS) as 3a,4,5,7a‐tetrahydro‐3,6‐dimethylbenzofuran‐2(3H)‐one. For the evaluation of the configuration of wine lactone, stereochemically controlled syntheses were developed. All eight isomers were characterized by NMR, MS, IR, and CD measurements. The configuration of ‘wine lactone’ was in agreement with synthesized (3S,3aS,7aR)‐enantiomer (1a) on the basis of enantioselective GC. For this isomer, the lowest odor threshold (0.02 pg/1 air) was detected.

Pharmacological discrimination between enantiomeric germanes by muscarinic receptors: a study on germanium/silicon bioisosterism

The (hydroxymethyl)diorgano(2-piperidinoethyl)germanes rac-Ph( c-Hex)Ge(CH 2OH)CH 2CH 2NR 2 ( rac- 1a), Ph 2Ge(CH 2OH)CH 2-CH 2NR 2 ( 3a) and ( c-Hex) 2Ge(CH 2OH)CH 2CH 2NR 2 ( 5a) (NR 2 = piperidino) were synthesized starting from Cl 3GeCH 2Cl. The ( R)- and ( S)-enantiomer of 1a were obtained by resolution of rac- 1a using the antipodes of O,O′-di- p-toluoyltartaric acid as resolving agents (resolution by fractional crystallization of diastereomeric salts). The enantiomeric purities of the resolved antipodes of 1a were shown to be at least 98 ( 1H NMR) and 97% ee ( 13C NMR) respectively (NMR studies using a chiral shift reagent). Reaction of rac- 1a, ( R)- 1a, ( S)- 1a, 3a and 5a with methyl iodide gave the corresponding methiodides rac- 2a, ( R)- 2a, ( S)- 2a, 4a and 6a ( 1a → 2a, 3a → 4a, 5a → 6a). The absolute configuration of ( R)- 2a was determined by single-crystal X-ray diffraction. On the basis of the experimentally established absolute configuration of ( R)- 2a, the absolute configurations of all the other aforementioned optically active germanium compounds were assigned by chemical and optical correlations. The enantiomerically pure germanium compounds ( R)- 1a, ( S)- 1a, ( R)- 2a and ( S)- 2a and their achiral derivatives 3a–6a were studied for their affinities for muscarinic M1, M2, M3 and M4 receptors by functional pharmacological experiments (M1, rabbit vas deferens; M2, guinea-pig atria; M3, guinea-pig ileum) and radioligand binding experiments (M1, human NB-OK 1 cells; M2, rat heart, M3, rat pancreas; M4, rat striatum). The receptor affinities obtained in these studies were compared with those of the related silicon analogues, the (hydroxymethyl)diorgano(2-piperidinoethyl)silanes ( R)- and ( S)-Ph( c-Hex)Si(CH 2OH)CH 2CH 2NR 2[( R)- 1b and ( S)- 1b], Ph 2Si(CH 2OH)CH 2CH 2NR 2 ( 3b) and ( c-Hex) 2Si(CH 2OH)CH 2CH 2NR 2 ( 5b) (NR 2 = piperidino) and their corresponding methiodides ( R)- 2b, ( S)- 2b, 4b and 6b ( a → b: Ge → Si: studies on Ge Si bioisosterism). According to these studies, all the germanes and the related silicon analogues behaved as simple competitive antagonists at muscarinic M1–M4 receptors. The p K i values obtained in binding studies at M1–M3 receptors were similar to the corresponding functional affinities (p A 2 values). The receptor affinities of the respective Ge Si analogues were found to be very similar, indicating a strongly pronounced Ge Si bioisosterism. The ( R)-enantiomers (eutomers) of the Ge Si pairs 1 a 1 b and 2 a 2 b exhibited higher affinities (up to 26-fold) for M1–M4 receptors than their corresponding ( S)-antipodes (distomers), the stereoselectivity ratios being higher at M1, M3 and M4 than at M2 receptors. In most cases, the diphenyl ( 3 a 3 b and 4 a 4 b ) and dicyclohexyl ( 5 a 5 b and 6 a 6 b ) compounds displayed lower affinities to M1–M4 receptors than the related ( R)-enantiomers of 1 a 1 b and 2 a 2 b , and the sums of the respective affinity differences were very similar to the experimentally established stereoselectivity ratios [ (R) (S) ]. Thus, the stereoselective interaction of the enantiomers of 1 a 1 b and 2 a 2 b with muscarinic receptors is best explained in terms of opposite and weaker binding of the phenyl and cyclohexyl ring of the ( S)-antipodes. The highest receptor selectivity was observed for compound ( R)- 1b at M1 M2 receptors (25-fold in binding studies).

Bicyclic N-hydroxyurea inhibitors of 5-lipoxygenase: pharmacodynamic, pharmacokinetic, and in vitro metabolic studies characterizing N-hydroxy-N-(2,3-dihydro-6-(phenylmethoxy)-3-benzofuranyl)urea.

A series of N-hydroxyurea derivatives have been prepared and examined as inhibitors of 5-lipoxygenase. Oral activity was established by examining the inhibition of LTB4 biosynthesis in an ex vivo assay in the mouse. The pharmacodynamic performance in the mouse of selected compounds was assessed using an ex vivo LTB4 assay and an adoptive peritoneal anaphylaxis assay at extended pretreat times. Compounds with an extended duration of action were re-examined as the individual enantiomers in the ex vivo assay, and the (S) enantiomer of N-hydroxy-N-[2,3-dihydro-6-(phenylmethoxy)-3-benzofuranyl]urea, (+)-1a (SB 202235), was selected as the compound with the best overall profile. Higher plasma concentrations and longer plasma half-lives were found for (+)-1a relative to its enantiomer in the mouse, monkey, and dog. In vitro metabolic studies in mouse liver microsomes established enantiospecific glucuronidation as a likely mechanism for the observed differences between the enantiomers of 1a. Enantioselective glucuronidation favoring (-)-1a was also found in human liver microsomes.

Synthesis of (r)‐ and (s)‐1‐formyl‐6,7,8,9‐tetrahydro‐ N,N‐(dipropyl)‐3H‐benz[e]indol‐8‐amines: Potent and orally active 5‐ht1a receptor agonists

AbstractAn efficient synthesis of the potent and orally active 5‐HT1A agonists, (R)‐(+)‐ and (S)‐(‐)‐1‐formyl‐6,7,8,9‐tetrahydro‐N,N‐dipropyl‐3H‐benz[e]indol‐8‐amines 1a and 1b, is described. This synthesis was accomplished in twelve steps from commercially available 1,5,6,7‐tetrahydro‐4H‐indol‐4‐one (5). The key step involved a regio‐controlled Friedel‐Crafts acylation of 1‐(p‐toluenesulfonyl)indol‐4‐acetyl chloride with ethylene to yield a versatile synthon, 3‐(p‐toluenesulfonyl)‐6,7,8,9‐tetrahydro‐3H‐benz[e]indol‐8‐one (10). Subsequent coupling of this ketone with chiral α‐methylbenzylamine under reductive amination conditions yielded a mixture of diastereomers. These diastereomers were efficiently separated by either chromatography or fractional recrystallization of the derived hydrochloride salts. Debenzylation of the pure diastereomers was followed by alkylation and formylation to yield (R)‐(+)‐ and (S)‐(‐)‐enantiomers 1a and 1b with >99% purity.

Absolute configuration and biological activity of mequitamium iodide enantiomers

The enantiomers of 1-methyl-3-(10H-phenothiazine-10-ylmethyl)-1-azoniabicyclo[2 ,2,2]octane iodide (1) were prepared by chiral chromatographic resolution of the precursor mequitazine (2). The (+)-(S)-enantiomer 1b is 10-fold more potent than (-)-(R)-enantiomer 1a as a histamine antagonist, while the two enantiomers show the same antimuscarinic activity in vitro. The absolute configuration of the more active dextrorotatory isomer has been determined by X-ray analysis. Conformational analysis and molecular modeling suggest that the (+)-(S)-enantiomer can adopt a conformation similar to that attributed to the receptor binding conformers of classical antihistamines.