Enzymatic production of (3S,4R)-(−)-4-(4′-fluorophenyl)-6-oxo-piperidin-3-carboxylic acid using a commercial preparation from Candida antarctica A: the role of a contaminant esterase

The enantioselective hydrolysis of (3RS,4RS)-trans-4-(4′-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylate (±)-2 was effected using a commercial preparation of lipase from C. antarctica A (CAL-A). We found that the hydrolytic activity of the lipase (immobilized on a number of very different supports) with this substrate was negligible. However, a contaminant esterase with Mw of 52 KDa from this commercial preparation exhibited much higher activity with (±)-2. This enzyme was purified and immobilized on PEI-coated support and the resulting enzyme preparation was highly enantioselective in the hydrolysis of (±)-2 (E >100), hydrolyzing only the (3S,4R)-(−)-3, which is a useful intermediate for the synthesis of pharmaceutically important (−)-paroxetine. Optimization of the reaction system was performed using a racemic mixture with a substrate concentration of 50 mM. This enzyme preparation was used in three reaction cycles and maintained its catalytic properties.     

Synthesis of 1,1′-methylenedi[(1R,1′R,3R,3′R,5R,5′R)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] and derivatives: precursors of long-chain polyketides

Racemic 1,1′-methylene[(1RS,1′RS,3RS,3′RS,5RS,5′RS)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] ((±)-6) derived from 2,2′-methylenedifuran has been resolved kinetically with Candida cyclindracea lipase-catalysed transesterification giving 1,1′-methylenedi[(1R,1′R,3R,3′R,5R,5′R)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] (−)-6 (30% yield, 98% ee) and 1,1′-methylenedi[(1S,1′S,3S,3′S,5S,5′S)-8-oxabicyclo[3.2.1]oct-6-en-3-yl] diacetate (+)-8, (40% yield, 98% ee). These compounds have been converted into 1,1′-methylenedi[(4S,4′S,6S,6′S)- and (4R,4′R,6R,6′R)-cyclohept-1-en-4,6-diyl] derivatives.     

Structures of propionaldehyde, butyraldehyde, and pivalaldehyde complexes of the chiral rhenium fragment [(η-C5H5)Re(NO)(PPh3)]

The crystal structures of propionaldehyde complex (RS,SR)-(η⁵-C₅H₅)Re(NO)(PPh₃)(η²-O=CHCH₂CH₃)]⁺ PF₆⁻ (1b⁺ PF₆^s−; monoclinic, P2₁/c (No. 14), a = 10.166 (1) Å, b = 18.316(1) Å, c = 14.872(2) Å, β = 100.51(1)°, Z = 4) and butyraldehyde complex (RS,SR)-[(η⁵-C₅H₅)Re(NO)(PPh₃)(η²-O=CHCH₂CH₂CH₃)]⁺ PF₆⁻ (1c⁺PF₆⁻; monoclinic, P2₁/a (No. 14), a = 14.851(1) Å, b = 18.623(3) Å, c = 10.026(2) Å, β = 102.95(1)°, Z = 4) have been determined at 22°C and −125°C, respectively. These exhibit C O bond lengths (1.35(1), 1.338(5) Å) that are intermediate between those of propionaldehyde (1.209(4) Å) and 1-propanol (1.41 Å). Other geometric features are analyzed. Reaction of [(η⁵-C₅H₅)Re(NO)(PPh₃)(ClCH₂Cl)]⁺ BF₄⁻ and pivalaldehyde gives [(η⁵-C₅H₅)Re(NO)(PPh₃)(η²-O=CHC(CH₃)₃)]⁺BF₄⁻ (81%), the spectroscopic properties of which establish a π C O binding mode.     

Synthesis and configurational assignment of some novel bicyclic sulphamidites and sulphamidates

(S)-Prolinol and 2(RS)-piperidine-methanol each react with thionyl chloride to give a pair of diastereoisomeric bicyclic sulphamidites which differ only in their configuration at sulphur. By contrast 2(RS)-pyrrolidine-ethanol and 2(RS)-piperidine-ethanol each react with thionyl chloride to give single diastereoisomeric products. The configurations of these bicyclic sulphamidites, and the sulphamidates derived from them, have been determined.     

Chemoenzymatic synthesis of both enantiomers of cispentacin

Based on the lipase-catalysed kinetic resolution of the silyloxyalcohol (1RS,2SR)-5 by transesterification with vinyl acetate in the presence of lipase from Pseudomonas cepacia a synthesis of both enantiomers of the β-amino acid cispentacin (1R,2S)-1 and (1S,2R)-1 using simple functional group interconversions is described.     

Molecular self-assembling of chiral and racemic butan-2-ol in carbon tetrachloride solutions

The self-association of (R)-, (S)- and (RS)-butan-2-ol in their carbon tetrachloride solutions was studied through the mid-infrared (mid-IR) and near-infrared (NIR) spectroscopic observations. The mid-IR and NIR spectra for each chiral butan-2-ol were compared with those for the racemic (RS)-butan-2-ol. Although it has been reported that the hydrogen bonding among the chiral butan-2-ol molecules was stronger than that among the racemic ones, any distinguishable differences between the chiral and the racemic butan-2-ol in CCl₄ solution or even in their pure liquid state were not observed both in their mid-IR and NIR spectra. A superior analytical method, assuming a successive association process for the alcohol molecules, was applied to the analysis of the sharp band at 3630 cm⁻¹ (the OH-stretching vibration mode attributed to free OH-monomer) for the (R)-, (S)- or (RS)-butan-2-ol in CCl₄. The mean association number N for each alcohol increased with increasing in concentration until 0.12 mol dm⁻³ and then becomes constant (about four). On the other hand, Zanker's plotting method, assuming an equilibrium between monomers and only one kind of polymer species, was also applied to the analysis of the above spectroscopic results; the association number n evaluated from the Zanker's method fairly agreed with the N value in the concentration region of 0.12–0.60 mol dm⁻³.     

Stereoselective hydration of (RS)-phenylglycine nitrile by new whole cell biocatalysts

Five new bacterial isolates with stereoselective nitrile hydratase activity against (RS)-2-phenylpropionitrile and (RS)-phenylglycine nitrile were investigated. The permeabilized whole cell isolates selectively hydrate the (S)-enantiomer of phenylglycine nitrile with E values of 1.2–5.4. One isolate, which was identified as Pantoea endophytica, produced pure (S)-phenylglycine (>99% ee) as a result of hydrolysis of (S)-phenylglycine amide by an (S)-specific amidase. Surprisingly, in the hydrolysis of (RS)-phenylglycine nitrile, it was found that the (R)-amide was accumulated in excess (21% ee) despite the nitrile hydratase produced by Pantoea endophytica was (S)-selective. The synthesis of pure (R)-phenylglycine (>99% ee) was achieved in time course studies using another Pantoea sp. with (R)-selective amidase. In the case of Nocardioides sp. the intermediate product, (S)-phenylglycine amide, could be produced (52% ee) without its subsequent hydrolysis into the acid due to the apparent absence of any amidase activity.     

Enantiomeric synthesis of the key synthon of the oviposition-deterring pheromone of Rhagoletis cerasi L

A convenient and enantioselective synthesis of ethyl (8RS, 15R)-8-acetoxy-15-hydroxyhexadecanoate15 via a chemoenzymatic approach has been described. The salient features of the synthesis were operational simplicity, use of easily accessible materials, and excellent enantiocontrol via lipase catalyzed acetylation of 2-alkanol.     

Enzymatic resolution of (RS)-β-hydroxy selenides in organic media

Kinetic resolutions of a number of β-hydroxy selenides promoted by enzymes were performed using PPL (free Porcine pancreatic lipase), PSL (Amano PS—free Pseudomonas sp. lipase) and CALB (NOVOZYM 435^®—immobilized Candida Antarctica lipase type B) with (RS)-1-phenylselanyl-propan-2-ol. CALB gave the best results and provided both (R)- and (S)-enantiomers in high enantiomeric purity. A comparative study of the effect of temperature, solvent, enzyme immobilization and the structure of the substrates on the resolution is presented.     

Resolution of racemic 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid with enantiopure (S)-phenylalanine N-benzylamide via diastereomeric salt formation

The resolution of racemic 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid 1, a potent chiral synthon with high pharmacological activity, was investigated with a variety of basic chiral resolving agents via diastereomeric salt formation. The findings in the optimization of resolution conditions aiming at an industrial-scale production revealed that (S)-phenylalanine benzylamide (S)-10 and 2-propanol containing ca. 4 mol % of water to (RS)-1 were the best conditions for obtaining enantiopure less-soluble diastereomeric salt, (S)-1/(S)-10/0.5H₂O (81%, 98% de, E 79%). X-ray crystallographic analysis of the salt clearly revealed that water molecules play a key role in crystallizing the enantiopure salt crystals, while stabilizing the crystal structure via three types of hydrogen-bond network associated with water molecules in addition to usual acid–base hydrogen bond.     

Washing effects on the anchoring energy and surface order parameter on rubbed polymer surfaces containing the trifluoromethyl moiety

The washing effects on liquid crystal (LC) alignment capability in a NLC, 4-n-pentyl-4'-cyanobiphenyl (5CB), on a rubbed polyimide (PI) surface containing the trifluoromethyl moiety were studied. The extrapolation length d_e of 5CB on the rubbed PI surface decreases with the rubbing strength RS. Also, the large extrapolation length d_e of 5CB for washing with IPA was measured at RS=114 mm. The polar anchoring energy of 5CB on the rubbed PI surface was decreased by the washing process; it increased with the rubbing strength RS on the PI surface. The surface order parameter S_S of 5CB for all the washing processes is smaller than for the non-washing process. Consequently, the polar anchoring energy and surface order parameter S_s in 5CB are largely attributed to washing effects.     

Optically active transition metal compounds : LXXXI. Crystal structure of (+)546-[C5H5Mo(CO)2LL]PF (LL = 2-benzoylpyridine-(R)-1-phenylethylimine)

Racemic [C₅H₅Mo(CO)₂LL]PF₆, (2) with LL = 2-benzoylpyridine-1-phenylethylimine, undergoes spontaneous resolution upon crystallization from acetone/CH₂Cl₂/ethanol. The absolute configuration of the (+)₅₄₆-isomer was shown to be (R) at the Mo atom and (R) at the asymmetric carbon atom. Comparison of 2 with [C₅H₅Mo(CO)₂LL]PF₆ (1) (LL = 2-carbaldehydepyridine-1-phenylethylimine) reveals distinct changes caused by the differences resulting from the presence of the phenyl group in 2 and the change from the (RR)- to the (RS)-configuration.     

Convenient diastereospecific synthesis of a rociverine precursor and its resolution by lipase-catalyzed transesterification

(±)-1-Cyclohexyl-c-2-hydroxymethyl-r-1-cyclohexanol 3, a precursor of the antimuscarinic drug Rociverine 1, was obtained diastereospecifically in very high yield, from the Grignard reaction between C₆H₁₁MgCl and an appropriately protected 2-(hydroxymethyl)cyclohexanone. The preparation of enantiomerically enriched cis diol (+)-(1R,2S)-3 and the corresponding 2-acetoxymethyl derivative (+)-(1S,2R)-12 was achieved by lipase PPL-catalyzed transesterification of racemic diol (±)-3.     

The structure of 2,4-dibromomenthone

A three-dimensional X-ray diffraction study has shown that the product obtained by bromination of - or -menthone is 2,4-dibromomenthone [2(a), 6(e)-dibromo-2(e)-isopropyl-5(e)methyl cyclohexanone]. The two Br atoms are trans, and the isopropyl and methyl groups are also trans. There are four molecules in the unit cell, which has symmetry P2₁2₁2₁ and dimensions a = 13·58, b = 13·81 and c = 6·25 Å. One intermolecular Br … Br contact of 3·52 ± 0·01 Å occurs, a distance which is about 0·4 Å shorter than the van der Waals distance.     

Structural and spectral studies of N-2-(pyridyl)-, N-2-(3-, 4-, 5-, and 6-picolyl)- and N-2-(4,6-lutidyl)-N′-2-thiomethoxyphenylthioureas

Structures of the following compounds have been obtained: N-(2-pyridyl)-N′-2-thiomethoxyphenylthiourea, PyTu2SMe, monoclinic, P2₁/c, a=11.905(3), b=4.7660(8), c=23,532(6) Å, β=95.993(8)°, V=1327.9(5) ų and Z=4; N-2-(3-picolyl)-N′-2-thiomethoxyphenyl-thiourea, 3PicTu2SeMe, monoclinic, C2/c, a=22.870(5), b=7.564(1), c=16.941(4) Å, β=98.300(6)°, V=2899.9(9) ų and Z=8; N-2-(4-picolyl)-N′-2-thiomethoxyphenylthiourea, 4PicTu2SMe, monoclinic P2₁/a, a=9.44(5), b=18.18(7), c=8.376(12) Å, β=91.62(5)°, V=1437(1) ų and Z=4; N-2-(5-picolyl)-N′-2-thiomethoxyphenylthiourea, 5PicTu2SMe, monoclinic, C2/c, a=21.807(2), b=7.5940(9), c=17.500(2) Å, β=93.267(6)°, V=2893.3(5) ų and Z=8; N-2-(6-picolyl)-N′-2-thiomethoxyphenylthiourea, 6PicTu2SMe, monoclinic, P2₁/c, a=8.499(4), b=7.819(2), c=22.291(8) Å, β=90.73(3)°, V=1481.2(9) ų and Z=4 and N-2-(4,6-lutidyl)-N′-2-thiomethoxyphenyl-thiourea, 4,6LutTu2SMe, monoclinic, P2₁/c, a=11.621(1), b=9.324(1), c=14.604(1) Å, β=96.378(4)°, V=1572.4(2) ų and Z=4. Comparisons with other N-2-pyridyl-N′-arylthioureas having substituents in the 2-position of the aryl ring are included.     

Synthesis of new chiral amino ether derivatives: synthetic application of meso aziridinium ions prepared from β-amino alcohols

Methods of synthesis of new chiral amino ether derivatives through the opening of aziridinium ions, prepared in situ using trans-(±)-2-(1-N,N-dialkylamino)cyclohexyl mesylate with (R)-(+)-1,1′-bi-2-naphthol, are described. The (R,R,R)-diastereomer was obtained as the major product and isolated as an enantiopure salt, and characterized by single crystal X-ray analysis. The C₂-chiral (R,R,R,R,R)-diamino ether was obtained as the major product by opening of the aziridinium ion, prepared using trans-(±)-2-(1-pyrrolidino)cyclohexyl mesylate and (R)-(+)-1,1′-bi-2-naphthol in the presence of aq NaOH. This was also characterized by single crystal X-ray analysis.     

The position of electrophilic substitution of 2-methyl-2H-cyclopenta[d]pyridazine and the crystal structures of two substitution products

2-Methyl-2H-cyclopenta[d]pyridazine reacts with trifluoracetic anhydride to give the 5- and 7-trifluoroacetyl products in about a 1:3 ratio. A series of HMO calculations have been made for similar ten π-electron heterocycles in an attempt to predict the positions in the 5-membered rings which would be most reactive to electrophilic substitution. The predictions based on the relative π-electron stabilities of the possible cationic intermediates are in accord with the available experimental data. If the atoms in the 6-ring are numbered 1-6 with the π-excessive heteroatom at the 1-position, then the most reactive site to electrophilic substitution in the 5-ring will be the atom which is linked to either the 1-, 3- or 5-positions. The structures of the major and minor trifluoroacetyl isomers of 2-methyl-2H-cyclopenta[d]pyridazine have been determined by X-ray crystallographic analyses, and the HMO predictions agree with the finding that C(7) is the most reactive position. 2-Methyl-5-trifluoroacetyl-2H-cyclopenta[d]pyridazine crystallizes in the monoclinic space group P2₁/m, cell constants a = 8·109, b = 6·713, c = 8·768 Å, β = 91·88°, with two molecules per unit cell. All of the atoms have been located and refined by full-matrix least-squares and the final residual is 0·056. The bond lengths appear to be influenced by a contribution of a pyridazinium form to the resonance hybrid. 2-Methyl-5-bromo-7-trifluoroacetyl-2H-cyclopenta[d]pyridazine crystallizes in the orthorhombic space group Pnam, cell constants a = 12·920, b = 12·513, c = 6·752 Å, with four molecules per unit cell. Although the quality of the diffraction data was severely limited by rapid decomposition of the specimen in the X-ray beam, the gross features of the structure were revealed. The residual following isotropic refinement was 0·19.     

Stereoselective synthesis of (1R,2S)-2-amino-1,3-diols from (R)-cyanohydrins

Vinyl substituted (1R,2S)-amino alcohols 5 were obtained by addition of vinyl magnesium bromide to the corresponding cyanohydrin O-trimethylsilyl ethers (R)-2. The O- and N-protected vinyl amino alcohols 6 were ozonized at −78°C in methanol yielding (1R,2S)-2-amino-1,3-diols7 in high enantiomeric and diastereomeric excesses. For purification, compounds 7 in some cases were acetylated to give the derivatives (1R,2S)-8. Racemic 6a was converted by oxidative ozonolysis at −78°C in methanolic NaOH solution to the corresponding methyl N-acetyl-β-hydroxy propanoate 9a. The configuration of (1R,2S)-8a was confirmed by x-ray crystallographic analysis.     

Ab initio studies of the conformations of ethynyl formate, cyano formate and related ethynyl and cyano compounds

The optimized geometries, relative free energies and related thermodynamic properties, harmonic frequencies, and dipole moments have been calculated at the HF and MP2 levels for ethynyl formate (1a), ethynyl acetate (1b), cyano formate, HCO₂CN (1c), cyano acetate (1d), S-ethynyl thioformate (2a), S-ethynyl thioacetate (2b), S-cyano thioformate (2c), S-cyano thioacetate (2d), N-ethynylformamide (3a), N-ethynylacetamide (3b), N-cyanoformamide (3c), and N-cyanoacetamide (3d) with the gaussian 98 program. For ethynyl formate, the calculation for 25 °C at the MP2/6-311++G(df,pd) level predicts that the Z isomer is more stable by 1.23 kcal/mol. For S-ethynyl thioformate, calculations at the MP2/6-311++G(2d,2p) level predict that the E isomer is favored by 0.71 kcal/mol at 25 °C. The E isomers of N-ethynylformamide and N-ethynylacetamide were found at all levels to be more stable than the Z isomers at 25 °C. For cyano formate and cyano acetate, calculations at the MP2/6-311++G(df,pd) level predict that the Z isomers are more stable at 25 °C by 1.50 and 2.72 kcal/mol, respectively. At this level and temperature, the Z isomers of 2c, 2d, 3c, and 3d are predicted to have free energies of 0.46, −0.07, 1.22, and 2.28 kcal/mol, respectively, relative to the E conformations. Z to E free-energy barriers at 25 °C of 8.63, 10.64, 17.63, 7.39, and 14.03 kcal/mol were calculated for 1a, 2a, 3a, 1c, and 3c at the HF/6-311G(d,p) level, and at the HF/6-311+G(d,p) level, the free-energy barrier for 2c was 7.08 kcal/mol.     

Convenient resolution of (±)-piperidine-2-carboxylic acid ((±)-pipecolic acid) by separation of palladium(II) diastereomers containing orthometallated (S)-(−)-1-[1-(dimethylamino)ethyl]naphthalene

(±)-Piperidine-2-carboxylic acid ((±)-pipecolic acid) has been resolved by the fractional crystallisation of diastereomeric palladium(II) complexes containing orthometallated (S)-(−)-1-[1-dimethylamino)ethyl]naphthalene. The enantiomers of the acid were liberated from the individual configurationally homogeneous diastereomers of the complex in high yield with []_D ± 26.0 (c 1.00, H₂O). The crystal and molecular structures of both diastereomers of the complex have been determined.