Kinetically controlled optical resolution of racemic norbornene aldehyde derivatives

A new method for obtaining optically pure 5-norbornene 2-endo-aldehyde derivatives was developed. The reaction of a diastereomeric mixture of the ene acetals 2 and 2', derived from racemic norbornene aldehydes (+/-)-1 and chiral nonracemic (S,S)-hydrobenzoin 7, with NBS (0.5-0.6 eq.) in the presence of H(2)O proceeded in a kinetically controlled manner to give the optically pure hydroxy aldehydes 3 along with the intact ene acetals 2'. Both compounds 3 and 2' were converted into the optically pure norbornene aldehydes 1 and ent-1, respectively. This method opens the way to produce various types of 5-norbornene 2-endo-aldehydes with 3-exo- or 3-endo-substituents in optically pure forms.     

Metabolism of deuterium-labeled jasmonic acid and OPC 8:0 in the potato plant (Solanum tuberosum L.)

The metabolism of deuterium-labeled (+/-)-jasmonicacid and 3-oxo-2-[(Z)pent-2'-enyl]-cyclopentan-1- octanoic acid in potato (Solanum tuberosum L.) was examined by using cultures of potato single-node stems. Deuterium-labeled (+/-)-jasmonic acid and 3-oxo-2-[(Z) pent-2'-enyl]cyclopentan-1-octanoic acid, which had been prepared from commercially available methyl (+/-)-jasmonate, were fed to the cultures, and the metabolites were extracted from the plants and analyzed by a liquid chromatography-selected ion monitoring system. The metabolism of deuterium-labeled (+/-)-jasmonic acid and 3-oxo-2-[(Z)-2'-pentenyl]cyclopentan-1-octanoic acid to 5' and 4'-O-glucopyranosyloxyjasmoic acids was strongly suggested.     

New efficient chiral derivatizing agent, alpha-cyano-alpha-fluoro(2-naphthyl)acetic acid (2-CFNA). application to the EE determination of (-)-3-acetoxy-2-fluoro-2-(hexadecyloxymethyl)propan-1-ol

The new chiral derivatizing agent (CDA), alpha-cyano-alpha-fluoro(2-naphthyl)-acetic acid (2-CFNA) 1 was prepared in optically pure form by chiral HPLC separation of racemic 2-CFNA methyl ester (2-CFNA Me ester) (+/-)-2. The ester was obtained by fluorination of methyl alpha-cyano(2-naphthyl)acetate with FClO3. 2-CFNA 1 has proven to be a significantly superior CDA for determination of enantiomeric excess (ee) of a primary alcohol when compared to alpha-methoxy-alpha-trifluoromethylphenylacetic acid (MTPA, Mosher's agent) and alpha-cyano-alpha-fluoro(p-tolyl)acetic acid (CFTA). The ee of (-)-3-acetoxy-2-fluoro-2-(hexadecyloxymethyl)propan-1-ol (-)-9, a fluorinated analog of anticancer active ether lipids, was determined using (+)-2-CFNA (+)-1.     

Synthesis of an affinity ligand ('UPHIT') for in vivo acylation of the kappa-opioid receptor

The isothiocyanate analog (1S,2S-trans-2-isothiocyanato-4,5-dichloro-N- methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide, 3a) of the highly selective kappa-opioid receptor agonist, U50,488, was prepared as a potential site-directed affinity ligand for acylation of kappa-opioid receptors in vivo. The isothiocyanate (3a) which we have designated UPHIT and its enantiomer (3b) were synthesized in 3 steps starting from optically pure (1S,2S)-(+)-trans-2-pyrrolidinyl-N-methyl-cyclohexylamine (4a) and its enantiomer (4b), respectively, thus defining their absolute stereochemistry. Binding in vitro of the 1S,2S enantiomer 3a to kappa receptors labelled by [3H]U69,593 was shown to occur with an IC50 value of 25.92 +/- 0.36 nM, whereas 827.42 +/- 5.88 and 115.10 +/- 1.23 nM were obtained for the IC50 value of the 1R,2R enantiomer (3b) and (+/-)-3 respectively. Intracerebroventricular (ICV) injection of 100 micrograms of (+/-)-3 into guinea-pig brain followed by analysis of remaining kappa-binding sites 24 h later revealed that (+/-)-3 depleted 98% of the kappa receptors that bind [3H]U69,593 and 40% of those that bind [3H]bremazocine. These preliminary data suggest exciting uses for these compounds in furthering our knowledge of the kappa-opioid receptor.     

Synthesis of (-)-methyl shikimate via enzymatic resolution of (1S*, 4R*, 5R*)-4-hydroxy-6-oxabicyclo[3.2.1]oct-2-en-7-one.

The synthesis of methyl (-)-shikimate [(-)-2] was achieved via lipase-catalyzed optical resolution of (1S*, 4R*, 5R*)-4-hydroxy-6-oxabicyclo[3.2.1]oct-2-en-7-one (3). Transesterification of (+/-)-3 and vinyl acetate with lipase MY and subsequent hydrolysis gave optically pure (-)-3. This compound was converted to (-)-2 in two steps.     

First synthesis of the two enantiomers of alpha-methyldiphenylalanine [(alphaMe)Dip] by HPLC resolution.

A strategy for the preparation of enantiomerically pure (R)- and (S)-alpha-methyldiphenylalanine, constrained phenylalanine analogs, is described. A racemic precursor was prepared in high yield from easily available starting products and subjected to HPLC resolution on a noncommercial chiral stationary phase. More than 600 mg of each enantiomer was isolated in optically pure form by using a 150 x 20 mm ID column containing mixed 10-undecenoate/3,5-dimethylphenylcarbamate of cellulose covalently bonded to allylsilica gel and a mixture of n-hexane/2-propanol/acetone as the mobile phase.     

Potent, easily synthesized huperzine A-tacrine hybrid acetylcholinesterase inhibitors.

Hybrid acetylcholinesterase inhibitors composed of a key fragment of huperzine A and an intact tacrine unit were prepared. The syntheses are quite direct, proceeding in a maximum of 4 linear steps from commercially available starting materials. The optimum hybrid inhibitor (+/-)-9g is 13-fold more potent than (-)-huperzine A, and 25-fold more potent than tacrine.     

The first preparation of enantiopure 1-methyl-7-oxabicyclo[2.2.1]heptan-2-one, a versatile chiral building block for terpenoids

Methods for the resolution of (+/-)-1-methyl-7-oxabicyclo[2.2.1]heptan-2-one 1, a versatile chiral building block for terpenoids, have been investigated. While no efficient result was obtained with kinetic resolution methods, both enantiomers of 1 were prepared optically pure for the first time via esterification of the reductive products of 1 with (+)-mandelic acid and oxidation of the saponified products of diastereomer esters, in an overall yield of 70%. The absolute configurations of (-)-1 and (+)-1 were determined as (1S,4R)-(-)-1 and (1R,4S)-(+)-1 by the CD exciton chirality method and confirmed by Moshers (1)H-NMR method.     

Identification of putative calcium channels in skeletal muscle microsomes

Saturable binding sites for the labelled calcium antagonist (+/-)[3H]nimodipine were found in guinea-pig hind limb skeletal muscle homogenates. Binding sites were enriched in a microsomal pellet by differential centrifugation of the homogenate. [3H]Nimodipine binding (Kd = 1.5 +/- 0.03 nM, Bmax = 2.1 +/- 0.25 pmol/protein, at 37 degrees C) copurified (6-fold) in this fraction with [3H]ouabain binding (6.6-fold) and 125I-alpha-bungarotoxin binding (5-fold). d-cis-Diltiazem (but not 1-cis-diltiazem) stimulated (+/-) [3H]nimodipine binding (ED50 1 microM) by increasing the Bmax. Binding sites discriminated between the optical enantiomers of 1.4-dihydropyridine calcium antagonists and the optically pure enantiomers of D-600. The data confirm, with biochemical techniques, the presence of 1,4-dihydropyridine and (+/-) D-600 inhibitable calcium channels in skeletal muscle, previously found with electrophysiological techniques.     

Chiral discrimination promoted by (1S,2S)-1-phenyl-2-amino-1,3-propanediol derivatives in the asymmetric Reformatsky reaction

Some 3-t-butyldimethylsilyloxy derivatives, synthesized from the cheap commercially available (1S,2S)-2-amino-1-phenyl-1,3-propanediol [(1S,2S)- 1 ], have been successfully employed as new chiral ligands in the asymmetric Reformatsky reaction on aldehydic substrates. The influence both of the substrate and of the ligand on the stereochemical pathway has been investigated by varying the structure of the carbonyl substrate and of the optically active aminodiols. © 1995 Wiley-Liss, Inc.     

Asymmetric total synthesis of highly symmetric squalene-derived cytotoxic polyethers

The efficient total synthesis of the cytotoxic meso polyether teurilene (1), rarely occurring in nature, was achieved through the effective combination of the concept of two-directional synthesis and rhenium(VII) chemistry. In the key rhenium(VII)-promoted syn oxidative cyclization reaction of the two-directional substrate 16, trans-syn diastereoselectivity (steric control) has been observed in contrast to our early observation of cis-syn diastereoselectivities (chelation control) for bishomoallylic tertiary alcohols 24-27 possessing the neighboring tetrahydrofuran (THF) ring. This synthesis in only 10 steps from commercially available methyl tiglate is significantly shorter than the previous one requiring 25 steps. The total syntheses of four possible C(s) symmetric (3 and 47-49) and one C2 symmetric (4) compounds for biogenetically squalene-derived pentaTHF polyether, glabrescol, was also achieved in relatively few steps by taking advantage of its intrinsic symmetry and one- and two-directional modes of double THF ring formations with vanadium catalyst, tert-butyl hydroperoxide (TBHP), and trifluoroacetic acid (TFA). Thus, the meso structure 3 originally proposed by Jacobs et al. has been revised to the optically pure C2 symmetric structure 4 through its enantioselective total synthesis.     

Synthesis and biological testing of Acyl-CoA-ketoprofen conjugates as selective irreversible inhibitors of COX-2

Ketoprofenoyl-CoA thioester 3 was synthesized by coupling ketoprofen to coenzyme A using the mixed anhydride method. Diastereoisomeric compounds 3a and 3b corresponding to the enantiomers of ketoprofen, were obtained in optically pure form by preparative HPLC. A non-acylating analogue, rac-3-(3-benzoylphenyl)-2-oxo-butanoyl-CoA (7) was also prepared. The biological evaluation suggested that 3a and 3b are reversible inhibitors of COX-1 and irreversible inhibitors of COX-2. Compound 7 appears to be a poor but selective inhibitor of COX-1.     

Bacterial metabolism of alpha-pinene: pathway from alpha-pinene oxide to acyclic metabolites in Nocardia sp. strain P18.3.

Over 20 gram-positive bacteria were isolated by elective culture with (+/-)-alpha-pinene as the sole carbon source. One of these strains, Nocardia sp. strain P18.3, was selected for detailed study. alpha-Pinene-grown cells oxidized, without lag, alpha-pinene, alpha-pinene oxide (epoxide), and the cis and trans isomers of 2-methyl-5-isopropylhexa-2,5-dienal. No other tested terpene was oxidized at a significant rate. alpha-Pinene was not metabolized by cell extracts in the presence or absence of NADH or NADPH. Cell extracts catalyzed a rapid decyclization of alpha-pinene oxide, in the absence of added cofactors, with the formation of cis-2-methyl-5-isopropylhexa-2,5-dienal. Further oxidation of the aldehyde to the corresponding acid occurred in the presence of NAD. Both activities were induced by growth with alpha-pinene. A rapid, nonenzymic transformation of the cis aldehyde into the trans isomer occurred in glycine buffer. The trans isomer was also a substrate for the NAD-linked aldehyde dehydrogenase. The distribution of the alpha-pinene oxide lyase in alpha-pinene-utilizing Pseudomonas spp. was also investigated and was compatible with the two alternative ring-cleavage sequences that have been proposed on the basis of accumulated metabolites.     

Large-scale preparation of (+)-disparlure,the gypsy moth pheromone,by a practical chemico-enzymatic procedure

The Sharpless asymmetric epoxidation of 8-methyl-2-nonen-1-ol performed on a large scale (over 5 moles) at room temperature gave (2S, 3R)-2, 3-epoxy-8-methyl-1-nonanol with 52%ee. The produced epoxy alcohol of low optical purity was subjected to lipase-catalyzed enatioselective acylation in order to increase the optical purity up to 85%ee. Recrystalyzation of the corresponding 3, 5-dinitrobenzoate gave optically pure epoxy alcohol. (+)-Disparlure, the gypsy moth pheromone, was synthesized in two steps from the thus obtained optically pure epoxy alcohol.     

Synthesis of the racemate and both enantiomers of massoilactone

A simple and efficient synthesis of (+/-)-massoilactone (1) as a key substance for the butter and milk flavor was accomplished from n-hexanal in only a few steps. Application of its racemic synthesis enabled natural (R)-(-)- and unnatural (S)-(+)-massoilactone (1a, 1b) to be synthesized by starting from commercially available (R)-(+)-1,2-epoxyheptane (5).     

Occurrence of Taurine-Pyruvate Aminotransferase in Bacterial Extract

Natural ( + )-(1R,2S,3S)-methyl cucurbate (1b) and the ( – )-δ-lactone of 3-epi-cucurbic acid (16) were synthesized from (+)-(1R,6S,7R)-bicyclo [4.3.0] non-3-en-7-ol (5). Asymmetric hydrolysis of the acetate (8) of ( ± )-5 with pancreatin gave optically pure the ( + )-(7R)-alcohol (5) and (–)-(7S)-acetate (8). An ozonolysis product of ( + )-5 was transformed to ( – )-16 and ( + )-(3S)-1b with inversion of the (7R)-hydroxyl group. Similarly, unnatural (–)-1b and (+)-16 were prepared from optically pure ( — )-5. The growth inhibitory activities of these synthesized chiral compounds toward lettuce seedlings were examined.     

Enzymatic synthesis of chloro-L-tryptophans

4-Chloro-L-tryptophan (1a), 5-chloro-L-tryptophan (1b), 6-chloro-L-tryptophan (1c and 7-chloro-L-tryptophan (1d) were prepared from 4-, 5-, 6- and 7-chloroindoles (2a-d) by reaction with L-serine using tryptophan synthase. The chlorotryptophans were optically pure ( > 99% e.e).     

Preparation of optically active 2-aminobutanoic acid via optical resolution by replacing crystallization

An attempt was made to use a simple procedure to obtain (R)- and (S)-2-aminobutanoic acids [(R)- and (S)-1] which are non-proteinogenic alpha-amino acids and are useful as chiral reagents in asymmetric syntheses. Compound (RS)-1 p-toluenesulfonate [(RS)-2], which is known to exist as a conglomerate, was optically resolved by replacing crystallization with (R)- and (S)-methionine p-toluenesulfonate [(R)- and (S)-3] as optically active co-solutes. When (S)-3 was employed as the co-solute, (R)-2 was preferentially crystallized from a supersaturated solution of (RS)-2 in 1-propanol, as was (S)-2 in the presence of (R)-3. (R)- and (S)-2 recrystallized from 1-propanol were treated with triethylamine in methanol to give (R)- and (S)-1 in optically pure forms.     

Protective group-free syntheses of (±)-frontalin, (±)-endo-brevicomin, (±)-exo-brevicomin, and (±)-3,4-dehydro-exo-brevicomin: racemic pheromones with a 6,8-dioxabicyclo[3.2.1]octane ring

Protective group-free syntheses of four racemic pheromones with a 6,8-dioxabicyclo[3.2.1]octane ring were achieved in five or six steps from commercially available (±)-3-butyn-2-ol (6) and 2-alkenyl halides or 2-alken-1-ol by employing Lewis acid-catalyzed acetalization of δ, ε-epoxy ketones as the key reaction. (±)-Frontalin (1) was prepared in a 25% overall yield in five steps from methallyl chloride (5a), (±)-endo-brevicomin (2) was prepared in a 23% overall yield in five steps from (E)-2-pentenyl bromide (5b), and (±)-exo-brevicomin (3) and (±)-3,4-dehydro-exo-brevicomin (4) were both prepared in a 4% overall yield in six steps based on (Z)-2-penten-1-ol (12).     

A novel enantioselective synthesis of (S)-(-)- and (R)-(+)-nornicotine via alkylation of a chiral 2-hydroxy-3-pinanone ketimine template

An asymmetric synthesis of the optically pure isomers of the minor tobacco alkaloid and CNS nicotine metabolite, nornicotine, has been achieved with moderately high optical purity. The synthetic pathway involves alkylation of a chiral ketimine, prepared from either 1R,2R,5R-(+)- or 1S,2S,5S-(-)-2-hydroxy-3-pinanone and 3-(aminomethyl)pyridine with 3-bromopropan-1-ol. After cleavage of the respective C-alkylated ketimines with NH2OH.HCl, and treatment of the resulting amino alcohols with HBr, followed by base-catalyzed intramolecular ring closure, (S)-(-)-nornicotine and (R)-(+)-nornicotine were obtained with ee values of 91% and 81%, respectively.