Sets of aldolase antibodies with antipodal reactivities. Formal synthesis of epothilone E by large-scale antibody-catalyzed resolution of thiazole aldol

[formula: see text] Three monoclonal aldolase antibodies, generated against a beta-diketone hapten by reactive immunization, catalyzed rapid and highly enantioselective retro-aldol reactions of ent-8a-k, providing optically pure 8a-k by kinetic resolution. Compounds (+/-)-8a, (+/-)-8g, and (+/-)-8k have been resolved in multigram quantities using 0.003, 0.005, and 0.0004 mol% antibody catalysts, respectively. Resolved compounds 8a-k are useful synthons for the construction of epothilones A-E (2-6) and their analogues. Here, a formal synthesis of epothilone E, 6 has been achieved starting from compound 8g.     

Chromatographic separation of diastereoisomeric esters-II Mandelates and lactates of 2-methylbutanol-1, 3-methylbutanol-2, pentanol-2 and hexanol-2

The racemic alcohols, 2-methylbutanol-l, 3-methylbutanol-2, pentanol-2 and hexanol-2 have been esterified with optically active mandelic or lactic acid, and the resultant mixtures of diastereoisomeric esters separated chromatographically with an optically inactive sulphonated polystyrene resin as the stationary phase and water or dilute aqueous sodium sulphate as the mobile phase. Lactate esters were more easily separated than mandelate esters. The Chromatographic separation of 26 mmole of (+/-)-3-methyl-2-butyl(+)-lactate and subsequent hydrolysis of the fractions containing only the ester of the (+)-alcohol yielded 1-2 mmole of pure 3-methyl-2-butanol.     

A simple resolution procedure using the Staudinger reaction for the preparation of P-stereogenic phosphine oxides.

The resolution of a variety of (+/-)-P-stereogenic phosphines is achieved by exploiting the Staudinger reaction of a (+/-)-phosphine with enantiopure (1S,2R)-O-(tert-butyldimethylsilyl)isobornyl-10-sulfonyl azide. The resulting mixtures of diastereomeric phosphinimines are generally separable by fractional crystallization or flash chromatography. Subsequent acid-catalyzed hydrolysis provides the corresponding optically pure phosphine oxides in high yields.     

Direct resolution of (+/-)-ephedrine and atropine into their enantiomers by impregnated TLC

Direct resolution of (+/-)-ephedrine and atropine into their enantiomers was achieved by normal-phase thin layer chromatography on silica gel plates impregnated with optically pure L-tartaric acid and L-histidine, respectively, as chiral selectors. The mobile phases enabling successful resolution were different combinations of acetonitrile-methanol-water. The spots were detected with iodine vapours and the detection limits were 2 and 6 microg, respectively, in terms of the racemate. The effects of concentration of the impregnating reagent, temperature and pH on resolution have been studied.     

Resolution of (+/-)-ibuprofen using (-)-brucine as a chiral selector by thin layer chromatography

The enantiomeric resolution of (+/-)-ibuprofen into its enantiomers was achieved by TLC on silica gel plate using optically pure (-)-brucine as a chiral selector and acetonitrile-methanol (5:1, v/v) as the solvent system. Spots were located in an iodine chamber. The detection limit was 4.9 microg. The effect of concentration of the chiral selector, temperature and pH on resolution has been studied.     

Lipase-catalyzed kinetic resolution of cyclic trans-1,2-diols bearing a diester moiety: synthetic application to chiral seven-membered-ring alpha,alpha-disubstituted alpha-amino acid

Chiral cycloalkane-trans-1,2-diols (+/-)-3 and (+/-)-8 having a diester moiety have been prepared from dimethyl dialkenylmalonate using olefin metathesis by Grubbs catalyst, followed by epoxidation and acidic hydrolysis. Kinetic resolution of racemic cyclopentane-trans-1,2-diol (+/-)-3 by lipase-catalyzed transesterification afforded an optically active monoacetate (-)-5 of 95% ee in 46% yield and the recovered diol (-)-3 of 92% ee in 51% yield, and that of cycloheptane-trans-1,2-diol (+/-)-8 gave a monoacetate (+)-10 of 95% ee in 51% yield and the diol (-)-8 of >99% ee in 43% yield, respectively. The enantiomer selectivity of racemic cyclic trans-1,2-diols bearing a diester moiety by lipases (Amano PS and Amano AK) was opposite to that of the reported simple racemic cycloalkane-trans-1,2-diols. To explain the lipase-catalyzed enantiomer selectivity, computer modeling of lipase-substrate complexes was performed. Furthermore, the optically active diester (-)-8 could be efficiently converted into an optically active seven-membered-ring alpha,alpha-disubstituted amino acid (4R,5R)-(-)-15.     

Benzyl 2-cyano-3,3-dimethyl-1-pyrrolidinecarboxylate, a versatile intermediate for the synthesis of 3,3-dimethylproline derivatives

The synthesis of racemic nitrile (+/-)-9 was accomplished in four steps and 58% overall yield from the known pyrrolidinone 5. Nitrile (+/-)-9 was resolved via preparative chiral HPLC to afford optically pure nitriles (+)-9 and (-)-9, from which 3,3-dimethylprolines (+)-1 and (-)-1 and 3,3-dimethylprolinamides (+)-2 and (-)-2 could be accessed in nearly quantitative yield, without loss of optical purity. The absolute configurations of the resolved prolines and prolinamides were determined by correlation with an intermediate of known absolute stereochemistry.     

Ligand self-recognition in the stereoselective assembly of [2 + 2] metallomacrocycles from racemic chiral bisbipyridyl molecular clefts and zinc(II)

The synthesis of racemic and optically pure ligand L, in which two 6,6'-disubstituted bipyridines are connected by methyleneoxy linkers to the molecular cleft dibenzobicyclo[b,f][3.3.1]nona-5a,6a-diene-6,12-dione, is reported. In the presence of 2 equivalents of zinc(ii) trifluoromethansulfonate (+/-)- undergoes slow reversible coordination over 24 h to form a pair of enantiomeric [2 + 2] metallomacrocycles, [Zn2(+)L2](OTf)(4) and [Zn2(-)L2](OTf)(4) respectively, that contain either two (+)-L ligands or two (-)-L ligands. This assignment was confirmed by independent studies with either (+)-L or (-)-L which formed the same complexes but at a significantly faster rate (3 h), and circular dichroism spectra of [Zn2(+)L2](OTf)(4) and [Zn2(-)L2](OTf)(4) which gave signals of the same intensity with the opposite sign. Treatment of (+/-)-L or optically pure L with copper(I) showed rapid formation of a mixture of oligomers as well as the [2 + 2] metallomacrocycle. The complex Zn2L2(OTf)(4) exhibits slow exchange between two species on the NMR time scale at room temperature. The results are consistent with the formation of a library of metal complexes in which the zinc(ii) binds initially to the most accessible bipyridyl binding sites in (+/-)-. Equilibration over several hours results in self-recognition of enantiomeric ligands to form a pair of enantiomeric metallomacrocycles, which have been tentatively assigned as having the helical configuration. Slow exchange is attributed to the preference for both metal centres to adopt 6-coordinate geometries involving the linker oxygens, but are limited to exchanging 5-coordinate complexes due to the shape of the cleft and the short linker.     

Asymmetric synthesis of 4-deoxyverrucarol via two types of ring expansion reactions

Asymmetric synthesis of a trichothecane analogue, 4-deoxyverrucarol (2), was carried out through two types of ring expansion reactions. First, synthesis of the racemate of 2 was investigated. Thus, 1-[1-(tert-butyldimethylsiloxy)-ethyl]-1-methoxycarbonyl-2-hexen-4-on e (10), prepared by Diels-Alder reaction, was converted into the cyclopropylidene 15. The cyclobutanone (+/-)-18 was obtained from 15 via dihydroxylation, followed by successive treatments with SO(2)Cl(2) in the presence of imidazole and Florisil. After transformation of (+/-)-18 into the vinylcyclobutanol (+/-)-19, the second ring expansion reaction was performed with Pd(OAc)(2) to provide the cyclopentanone (+/-)-20. The product was converted into the racemate of 4-deoxyverrucarol (2) through the cyclohexenone (+/-)-22, but the diastereoselectivity during the introduction of the double bond was unsatisfactory. The selectivity was improved in the case of the asymmetric synthesis. The optically active cyclobutanone (+)-18 was prepared via AD reaction of 15 with 73% ee. After the transformation of (+)-18 into the cyclohexanone (-)-30 through the palladium-mediated ring expansion reaction, (-)-30 was subjected to the diastereoselective deprotonation reaction using the chiral amide. The key synthetic intermediate (-)-25 of 4-deoxyverrucarol (2) was synthesized in an optically pure form by taking advantage of a kind of kinetic resolution that occurred during the deprotonation step.     

Synthesis and characterization of novel chiral dimers exhibiting highly frustrated liquid crystal phases

Two novel series of optically active dimers comprising cholesterol and biphenyl-4-yl 4-(n-alkoxy)benzoate cores interlinked though either an odd-parity/even-parity spacer have been prepared and characterized. They stabilize an extremely complex, frustrated liquid crystalline state viz., the twist grain boundary (TGB) phase with chiral smectic C structure, denoted as TGBC^∗ phase, over a wide (50–110 °C) temperature range. Notably, the dimers with an odd-parity spacer show an additional frustrated liquid crystal phase namely, the blue phase (BP). The presence of such frustrated phases suggests that the synthesized dimers are characterized by high enantiomeric excess and strong molecular chirality. Thus, 12 new optically active, nonsymmetric dimers reported herein constitute new examples of rarely found strongly chiral, optically pure dimers showing frustrated liquid crystal phase over an adequately wide thermal range.     

Liquid crystalline behavior of comb–branch copolymers of di-[6-(4-methoxy-4′-biphenyloxy)hexyl]-2-methylene butane-1,4-dioate with two non-mesogenic chiral monomers

A mesogenic monomer di-[6-(4-methoxy-4′-biphenyloxy) hexyl]-2-methylene butane-1,4-dioate, has been copolymerized with non-mesogen monomers, one racemic and one optically pure, with a view to examining the potential for using these to induce chiral liquid crystal line phases in the copolymer. This proved to be ineffective, with the copolymer exhibiting only smectic A or smectic B phases. Transition temperature–copolymer composition diagrams have been constructed for both copolymer series and their features have been contrasted. Monomer reactivity ratios have been derived for both copolymer systems.     

Syntheses and Peculiar Behavior in Solutions of Optically Active Telluronium Salts

A diastereomeric (epimeric) mixture of ethylmethylphenyltelluronium (1S)-(+)-camphor-10-sulfonate (dia.-1) was optically resolved by fractional recrystallization into the diastereomerically pure isomers (R)(Te)-1 and (S)(Te)-1. The absolute configurations of the isomers were determined by the X-ray crystallographic analysis of (R)(Te)-1. Enantiomerically pure (R)-ethylmethylphenyltelluronium perchlorate, tetrafluoroborate, p-chlorobenzenesulfonate, bornane-10-sulfonate, tetraphenylborate, and picrylsulfonate (R)-2-7 were isolated, respectively, by anion-exchange reactions of diastereomerically pure (R)(Te)-1. The optically active telluronium salts were found to show peculiar optical properties on their specific rotations and circular dichroism spectra in solutions compared with those of the corresponding sulfonium and selenonium salts. On the basis of NMR studies, the behavior on the optical properties of the optically active telluronium salts was found to be caused by a strong solvation in polar solvents.     

Chirality-induced phase transitions in some liquid crystalline binary mixtures

Novel binary mixtures have been prepared between an optically active antiferroelectric liquid crystal, (S)-4-(1-methylheptyloxycarbonyl)phenyl 4'-octyloxy-biphenyl-4-carboxylate, and an optically active twin liquid crystal, (R)-3-methyladipic acid bis[4-(5-octyl-2-(pyrimidinyl)phenyl] ester, and the liquid crystalline properties investigated. The stability of each liquid crystal phase was found to decrease by mixing these two liquid crystalline materials. Furthermore, a phase diagram between these compounds showed a clear discontinuity in phase sequences. These results indicate that the liquid crystal phases are different in nature between these materials. The mixture consisting of the antiferroelectric material (40 per cent) and the twin material (60 per cent) shows an unusual liquid crystal phase, where the texture is similar to that reported for the twist grain boundary (TGB) phase. Related binary mixtures have been prepared between optically active or racemic materials, where the chirality of the system is expected to be altered systematically. The TGB phase was found to be induced only in the mixture between the optically active materials. Two kinds of effect on the appearance of the TGB phase, i.e. a strong helical structure induced by the optically active twin liquid crystal and a decrease of the smectic layer strength achieved by mixing between two types of liquid crystalline materials, are discussed.     

Synthesis, resolution, and applications of 1,16-dihydroxytetraphenylene as a novel building block in molecular recognition and assembly

This paper concerns the synthesis of 1,16-dihydroxytetraphenylene (DHTP) (2) by employing a novel NBS bromination route. (+/-)-DHTP 2 was successfully resolved into its optical antipodes and converted to (+/-)-1,16-bis(diphenylphosphino)tetraphenylene (BPTP) (26), whose platinum complex BPTP-PtCl(2) (27) was also obtained. As a hydrogen bond donor, racemic and optically active DHTP 2 was allowed to assemble with 4,4'-bipyridine to form single crystals of good quality. X-ray Diffraction studies of these crystals revealed that the crystallographic packing of the hydrogen bonded complex between (+/-)-2 and 4,4'-bipyridine was different from the one formed from (S)-2 and 4,4'-bipyridine. It was found that an infinite zigzag chain with alternate chirality was formed in the assembly of (+/-)-2 and 4,4'-bipyridine, while (S)-2 and 4,4'-bipyridine failed to show the same assembly pattern. The reason (+/-)-2 formed an alternate and zigzag chain with 4,4'-bipyridine was most likely due to the inherent stability of this supramolecular assembly. The chiral recognition between 2 and optically active BINAP under the direction of platinum(II) has also been examined. (1)H and (31)P NMR spectroscopic studies demonstrated that there was an obvious discrimination of 2 between the enantiomers of BINAP-PtCO(3).     

Energy-Minimized Structures and Calculated and Experimental Isomer distributions in the hexaamine-cobalt(III) system [Co(L)2]3+ with the chiral facially-coordinating triamine (l = butane-1,2,4-triamine)

Butane- 1,2,4-triamine (trab) is the smallest tridentate aliphatic unsubstituted chiral triamine. With optically pure trab, there are three, with racemic trab five isomers of [Co(trab)₂]³⁺, One of the five isomers is centrosymmetrical, the others are chiral. For one of the isomers, there are four possible conformations (all combinations of chair and skew boat conformations for the chelate six ring of each ligand), for the others there exist only three independent conformers. All sixteen independent structures have been calculated by strain-energy minimization. The calculated isomer distribution, based on total strain energies corrected with statistical entropy contributions (21%:16%:16%:4%:43%, and 40%:30%:30%, for racemic and optically pure trab, respectively) are in excellent agreement with the experimental data based on HPLC and ¹³C-NMR analyses of equilibrium solutions of the hexaamine-Co(III) compounds prepared by oxygenation of aqueous solutions in presence of activated charcoal. The results are also briefly discussed in relation to possible stereoselectivity upon complexation of optically pure trab and a racemic chiral ligand to a transition-metal center.     

First Resolution of a Free Fluorophosphine Chiral at Phosphorus. Resolution and Reactions of Free and Coordinated (+/-)-Fluorophenylisopropylphosphine

The trivalent fluorophosphine (+/-)-PFPh(i-Pr), (+/-)-1, has been prepared by halogen exchange of the corresponding chlorophosphine with sodium fluoride in hot sulfolane. The neat fluorophosphine rapidly decomposes by equilibrium redox disproportionation into PF(3)Ph(i-Pr) and (R,R)/(R,S)-Ph(i-Pr)PPPh(i-Pr), but in benzene, (+/-)-1 has considerable thermodynamic stability. The resolution of (+/-)-1 was achieved by a fractional crystallization of the diastereomers (R,R(P))- and (R,S(P))-chloro[1-[1-(dimethylamino)ethyl]-2-naphthalenyl-C,N](fluorophenylisopropylphosphine)palladium(II), (R,R(P))- and (R,S(P))-5, whereby the less soluble (R,R(P)) diastereomer selectively crystallized in 64% yield in a typical second-order asymmetric transformation. Optically pure (S)-(-)-1, -210 (c 0.59, C(6)H(6)), was liberated from (R,R(P))-5 with (R,S)-1,2-phenylenebis(methylphenylphosphine). The optically active phosphine in benzene racemizes over 6 h without significant redox disproportionation. The methoxyphosphine (+/-)-P(OMe)Ph(i-Pr), (+/-)-9, was also resolved by the method of metal complexation. Thus, fractional crystallization of (R,R(P))- and (R,S(P))-chloro[1-[1-(dimethylamino)ethyl]-2-naphthalenyl-C,N](methoxyphenylisopropylphosphine)palladium(II), (R,R(P))- and (R,S(P))-8, followed by liberation of the respective optically active methoxyphosphines from the separated diastereomers with 1,2-bis(diphenylphosphino)ethane, gave (R)-(+)- and (S)-(-)-9 of 92% and 96% ee, respectively. The barrier to unimolecular inversion for (+/-)-9 was determined to be >82.9 +/- 0.5 kJ mol(-)(1) by variable temperature (1)H NMR spectroscopy. The substitution of fluoride in (R,R(P))-5 by methoxide proceeds with predominant inversion of the configuration at phosphorus to give (R,R(P))- and (R,S(P))-8 with (R,S(P))/(R,R(P)) = (1)/(5). The crystal structures of (R,R(P))-5 and (R,R(P))-8 have been determined: (R,R(P))-5 (C(23)H(28)ClFNPPd) crystallizes in the orthorhombic space group P2(1)2(1)2(1) with a = 9.967(2) ?, b = 10.998(4) ?, c = 21.324(3) ?, Z = 4, and R = 0.031; (R,R(P))-8 (C(24)H(31)ClNOPPd) crystallizes in the space group P2(1)2(1)2(1) with a = 10.444(3) ?, b = 12.146(3) ?, c = 19.047(2) ?, Z = 4, and R = 0.026.     

A PLS-based extractive spectrophotometric method for simultaneous determination of carbamazepine and carbamazepine-10,11-epoxide in plasma and comparison with HPLC

Carbamazepine (CBZ) undergoes enzyme biotransformation through epoxidation with the formation of its metabolite, carbamazepine-10,11-epoxide (CBZE). A simple chemometrics-assisted spectrophotometric method has been proposed for simultaneous determination of CBZ and CBZE in plasma. A liquid extraction procedure was operated to separate the analytes from plasma, and the UV absorbance spectra of the resultant solutions were subjected to partial least squares (PLS) regression. The optimum number of PLS latent variables was selected according to the PRESS values of leave-one-out cross-validation. A HPLC method was also employed for comparison. The respective mean recoveries for analysis of CBZ and CBZE in synthetic mixtures were 102.57 (+/-0.25)% and 103.00 (+/-0.09)% for PLS and 99.40 (+/-0.15)% and 102.20 (+/-0.02)%. The concentrations of CBZ and CBZE were also determined in five patients using the PLS and HPLC methods. The results showed that the data obtained by PLS were comparable with those obtained by HPLC method.     

The Mutual Resoluton of Dl-ephedrine and N-Benzyloxycarbonyl-Dl-Amino Acids

D(-)-Ephedrine was prepared by resolving the racemate through its N-benzyloxycarbonyl-L-phenylalanine salt in ether solution. The L(+)-ephedrine in mother liquid was recovered and precipitated exclusivly with N -benzyloxycarbonyl-L-alanine in ethyl acetate. The amino acid derivatives were recovered from the salts by acid decomposition and the optically pure ephedrine was also recovered, which was again useful for the resolution of racemic amino acid derivatives synthesized chemically. Other amino acid derivatves are also tested for the mutual resolution. Mutual resolution was also effected by dissolving DL-ephedrine and N -benzyloxycarbonyl-DL-alanine in ethyl acetate to obtain the optically pure D(-)-ephedrine and N -benzyloxycarbonyl-D-alanine.     

2H NMR spectroscopy of liquid crystals: structure and orientational order of a chiral smectogen in its A,C* and J* phases

²H NMR spectroscopy is employed to investigate the orientational order, molecular structure and phase transitions of the chiral smectic liquid crystal 1-methylheptyl 4'-(4-n-decyloxybenzoyloxy)biphenyl-4-carboxylate (10B1M7), showing smectic A, C* and J phases, as well as several sub-smectic C* phases. Two optically pure, differently deuteriated isotopomers have been purposely synthesized and studied.     

Syntheses of (-)-pelletierine and (-)-homopipecolic acid

Enantiomeric syntheses of (-)-homopipecolic acid and (-)-pelletierine have been achieved by chiral resolution of tropanol followed by Baeyer-Villiger oxidation. The methodology provides a practical route for the synthesis of optically pure piperidines.