A systematic study of chiral homoprolinols and their derivatives in the catalysis of enantioselective addition of diethylzinc to aldehydes

Homoprolinol analogs, a class of optically active γ‐amino alcohols, were examined systematically in the enantioselective addition reactions of diethylzinc to aldehydes. By comparison of the results catalyzed by these γ‐amino alcohols with those by the β‐amino alcohols based on pyrrolidine architecture reported in the literature references, we have observed that the γ‐amino alcohols are superior to the corresponding β‐amino alcohols when the nitrogen and the oxygen are unsubstituted. Among the homoprolinols we tested, 2b gave the best results (45–88% yields, 44–81% ee) in the addition reactions. To the best of our knowledge, 2b has been noticed as one of the most efficient γ‐amino alcohol catalysts based on pyrrolidine framework. Chirality, 2011. © 2011 Wiley‐Liss, Inc.     

Enantioseparation of chiral alcohols by complex formation and subsequent supercritical fluid extraction

The very first application of supercritical fluid extraction (SFE) on enantioseparation of alcohols is discussed. Resolution of three chiral alcohols (trans-2-chloro-cyclohexanol, trans-2-bromo-cyclohexanol, and trans-2-iodo-cyclohexanol) were performed by partial complexation with (-)-O,O'-dibenzoyl-(2R,3R)-tartaric acid monohydrate (DBTA). DBTA formed diastereomeric complexes with all S,S-enantiomers stable enough to extract the unreacted alcohols with supercritical carbon dioxide. Resolution efficiency increased with the size of halogen substituents, and by the proper selection of molar ratio, pure (-)-R,R-trans-2-iodo-cyclohexanol (ee > 99%, yield: 39%) or (+)-S,S-trans-2-iodo-cyclohexanol (ee = 98%, yield: 8%) were prepared in one process step. Achieved resolution efficiency values were much higher in all resolution procedures than in any other known enantioseparation of these racemic compounds. The developed method offers an environmentally friendly, efficient alternative of currently applied resolution processes, also on a preparative scale.     

Synthesis of new pryridyl alcohols and their use as catalysts in the asymmetric addition of diethylzinc to aldehydes.

Optically active new pyridyl alcohols 1-4, which can be easily synthesized by the reaction of (+)-camphor or (-)-menthone with lithiated pyridine derivatives, were applied as chiral ligands in the asymmetric addition of diethylzinc to aldehydes. Good yields with up to 94.0% enantiomeric excesses were observed in these reactions.     

Practical enantioresolution of alcohols with 2-methoxy-2-(1-naphthyl)propionic acid and determination of their absolute configurations by the (1)H NMR anisotropy method.

The enantioresolution of racemic alcohols as esters of 2-methoxy-2-(1-naphthyl)propionic acid (MalphaNP acid 1) and the determination of their absolute configurations on the basis of (1)H NMR anisotropy effect are described. The enantiopure MalphaNP acid (S)-(+)-1 was allowed to react with racemic 2-alkanols and 1-octyn-3-ol, yielding diastereomeric mixtures of esters, which were easily separated by HPLC on silica gel. To determine the absolute configurations of the first-eluted diastereomeric esters by the (1)H NMR anisotropy method, the general scheme was proposed. Separated esters were reduced with LiAlH(4) or hydrolyzed with KOH/EtOH to recover enantiopure alcohols.     

Enantioselective addition of diethylzinc to aldehydes catalyzed by optically active C2-symmetrical bis-beta-amino alcohols

The syntheses of new optically active C(2)-symmetrical bis-beta-amino alcohols 1-6 from (S)-2-(1-hydroxy-1,1-diphenylmethyl)-pyrrolidine are described. Especially attention is focused on bridges, which link the two beta-amino alcohol units. These new chiral ligands have been successfully applied in the catalytic enantioselective addition of diethylzinc to aldehydes to give sec-alcohols in good yields with up to 95% enantiomeric excess.     

Convenient method for determining the absolute configuration of chiral alcohols with racemic 1H NMR anisotropy reagent,M(alpha)NP acid: use of HPLC-CD detector

A convenient method for determining the absolute configuration of chiral secondary alcohols using the racemic NMR anisotropy reagent, (+/-)-2-methoxy-2-(1-naphthyl)propionic acid [(+/-)-M(alpha)NP acid], and an HPLC-CD detector was developed. The method was successfully applied to some chiral alcohols derived from (-)-alpha-santonin.     

Controlled Release of Volatile Secondary and Tertiary Alcohols by Neighboring Group Participation: Stepwise Cyclization and Re‐Opening of 2,2′‐Bis(carbamoyl)dibenzoates at Neutral pH

Bioactive, volatile, secondary and tertiary fragrance alcohols are efficiently released by intramolecular neighboring‐group‐assisted hydrolysis of 2,2′‐bis(carbamoyl)dibenzoates at neutral pH. The stepwise cyclization of 2,2′‐[(methylimino)bis(propane‐3,1‐diylcarbamoyl)]dibenzoates is followed by the re‐opening of the intermediately formed diphthalimide and proceeds in an overall four‐step consecutive reaction sequence. Kinetic rate constants for all four reaction steps could be determined pairwise by reversed‐phase HPLC. At neutral pH, secondary alcohols were released by one order of magnitude faster than the tertiary alcohols, and the rate constants for the re‐opening of the diphthalimides were found to be in the same order of magnitude as the release of the tertiary alcohols. Dynamic headspace analysis on a dry cotton surface finally confirmed the efficient release of tertiary alcohols under mild reaction conditions generally encountered for applications in functional perfumery.     

The genome-wide screening of yeast deletion mutants to identify the genes required for tolerance to ethanol and other alcohols

A set of homozygous diploid deletion mutants of the yeast Saccharomyces cerevisiae was screened for the genes required for tolerance to aliphatic alcohols. The screen identified 137, 122 and 48 deletion mutants sensitive to ethanol, 1-propanol and 1-pentanol, respectively. A number of the genes required for ethanol tolerance were those also required for tolerance to other alcohols. Numerous mutants with defective genes encoding for vacuolar H+ -ATPase (V-ATPase) were cosensitive to these alcohols. A global screening approach of yeast deletion library mutants was useful in elucidating the mechanisms of alcohol tolerance based on different lipophilicities.     

Alcohol Dehydrogenase Activities of Wine Yeasts in Relation to Higher Alcohol Formation

Alcohol dehydrogenase activities were examined in cell-free extracts of 10 representative wine yeast strains having various productivities of higher alcohols (fusel oil). The amount of fusel alcohols (n-propanol, isobutanol, active pentanol, and isopentanol) produced by the different yeasts and the specific alcohol dehydrogenase activities with the corresponding alcohols as substrates were found to be significantly related. No such relationship was found for ethanol. The amounts of higher alcohols formed during vinification could be predicted from the specific activities of the alcohol dehydrogenases with high accuracy. The results suggest a close relationship between the control of the activities of alcohol dehydrogenase and the formation of fusel oil alcohols. Also, new procedures for the prediction of higher alcohol formation during alcoholic beverage fermentation are suggested.     

Insect blood-brain barrier: an electrophysiological investigation of its permeability to the aliphatic alcohols.

The anaesthetic effects of the aliphatic alcohols were used to measure their concentration at the neuronal surfaces of the cockroach central nervous system. The results were in most cases fairly closely described by first-order kinetics. The exchange half-times of the lower alcohols were only a few seconds, being little affected by the removal of the nerve sheath. The half-times for the higher alcohols were somewhat longer, and were more significantly reduced by desheathing; these observations were interpreted in terms of a reservoir effect resulting from their higher liposolubility. It was shown that the ionic diffusion barrier in intact nerve cords remained undamaged in the presence of the alcohols.     

Application of kinetic resolution using HCS as chiral auxiliary: novel synthesis of beta-blockers (S)-betaxolol and (S)-metoprolol

Optically pure (S)-betaxolol and (S)-metoprolol were prepared with an extremely facile and practical method using kinetic resolution of beta-amino alcohols employing HCS as chiral auxiliary. High enantiomeric purity (ee > 99%) was achieved and the synthetic strategy is amenable to industrial scale-up.     

Oxidation of secondary alcohols to methyl ketones by yeasts.

Cell suspensions of yeasts, Candida utilis ATCC 26387, Hansenula polymorpha ATCC 26012, Pichia sp. NRRL-Y-11328, Torulopsis sp. strain A1, and Kloeckera sp. strain A2, grown on various C-1 compounds (methanol, methylamine, methylformate), ethanol, and propylamine catalyzed the oxidation of secondary alcohols to the corresponding methyl ketones. Thus, isopropanol, 2-butanol, 2-pentanol, and 2-hexanol were converted to acetone, 2-butanone, 2-pentanone, and 2-hexanone, respectively. Cell-free extracts derived from methanol-grown yeasts catalyzed an oxidized nicotinamide adenine dinucleotide-dependent oxidation of secondary alcohols to the corresponding methyl ketones, Primary alcohols were not oxidized. The effect of various environmental factors on the production of methyl ketones from secondary alcohols by methanol-grown Pichia sp. was investigated.     

Oxidation of secondary alcohols to methyl ketones by yeasts.

Cell suspensions of yeasts, Candida utilis ATCC 26387, Hansenula polymorpha ATCC 26012, Pichia sp. NRRL-Y-11328, Torulopsis sp. strain A1, and Kloeckera sp. strain A2, grown on various C-1 compounds (methanol, methylamine, methylformate), ethanol, and propylamine catalyzed the oxidation of secondary alcohols to the corresponding methyl ketones. Thus, isopropanol, 2-butanol, 2-pentanol, and 2-hexanol were converted to acetone, 2-butanone, 2-pentanone, and 2-hexanone, respectively. Cell-free extracts derived from methanol-grown yeasts catalyzed an oxidized nicotinamide adenine dinucleotide-dependent oxidation of secondary alcohols to the corresponding methyl ketones, Primary alcohols were not oxidized. The effect of various environmental factors on the production of methyl ketones from secondary alcohols by methanol-grown Pichia sp. was investigated.     

Synthesis of enantiopure phthalides including 3-butylphthalide, a fragrance component of celery oil, and determination of their absolute configurations

Enantiopure phthalides 2 and 5-8 were synthesized via enantioresolution of the corresponding alcohols with a chiral auxiliary of camphorsultam dichlorophthalic acid, (1S,2R,4R)-(-)-CSDP acid 3, followed by solvolysis with KOH in MeOH and the catalytic oxidation of chiral glycols with iridium complex 28. The absolute configurations of phthalides 2 and 5-8 were determined by applying the (1)H-NMR anisotropy method of MalphaNP acid (4), 2-methoxy-2-(1-naphthyl)propionic acid, to the chiral synthetic precursory alcohols. In the case of 3-phenylphthalide (R)-(-)-7, the absolute configuration determined by the (1)H-NMR anisotropy method using MalphaNP acid 4 agreed with that by the X-ray crystallographic method. By applying these methods, 3-butylphthalide (S)-(-)-2, a fragrance component of essential oil of celery, has been synthesized in an enantiopure form, and its absolute configuration was unambiguously determined.     

Effects of a series of alcohols on the binding of a fluorescent dye to erythrocyte membranes.

1. The effects of a series of aliphatic alcohols (methanol to octanol) on membrane proteins of erythrocytes were studied by monitoring the flueorescence of a dye (1-anilino-8-naphthalenesulfonic acid (ANS)) that adsorbs to erythrocyte ghost membranes. Low concentrations of all the alcohols reduced the ANS fluorescence of the membrane-ANS suspensions; lent to those which protect against hypotonic hemolysis on intact erythrocytes; higher concentrations markedly increased the fluorescence. Ethanol and methanol decreased ANS fluorescence at all concentrations. 2. Lytic concentrations of saponin did not increase ANS fluorescence and did not modify the membrane action of the alcohols. 3. None of these effects were observed in liposomes prepared from lipid extracts of the erythrocyte membrane. 4. Since the apparent dissociation constant for the ANS-membrane interaction was unchanged in the presence of the alcohols, it was assumed that the fluorescence changes anesthetic concentration of the alcohols alter the conformation of membrane proteins, as indicated by the decreased number of ANS binding sites.     

Enantioresolution of fluorinated diphenylmethanols and determination of their absolute configurations by X-Ray crystallographic and 1H NMR anisotropy methods

Various fluorinated diphenylmethanols were enantioresolved by the methods of chiral camphorsultam-dichlorophthalic acid (CSDP acid) and/or 2-methoxy-2-(1-naphthyl)propionic acid (MalphaNP acid) yielding enantiopure alcohols. Their absolute configurations were unambiguously determined by X-ray crystallography of CSDP esters and/or by the (1)H NMR anisotropy method of MalphaNP esters for the first time.     

A series of new C2-symmetric amino alcohols with multicoordination groups: promising catalysts for synthesis of both enantiomers in the borane-mediated reduction of prochiral ketones

A series of new C(2)-symmetric amino alcohols with multicoordination groups have been synthesized and successfully applied as catalysts in the borane asymmetric reduction of prochiral ketones in refluxing toluene, providing the corresponding secondary alcohols with up to 90% ee. An unusual temperature-dependent reversal of stereochemistry was also observed.     

Enantioresolution and absolute configurations of chiral meta-substituted diphenylmethanols as determined by X-ray crystallographic and 1H NMR anisotropy methods

meta-Substituted diphenylmethanols were enantioresolved by the method of chiral phthalic acid yielding enantiopure alcohols. Their absolute configurations were unambiguously determined by X-ray crystallography of chiral phthalate esters and/or by the (1)H NMR anisotropy method using 2-methoxy-2-(1-naphthyl)propionic acid.     

Ester synthesis from trimethylammonium alcohols in dry organic media catalyzed by immobilized Candida antarctica lipase B

Twenty-one different organic solvents were assayed as possible reaction media for the synthesis of butyryl esters from trimethylammonium alcohols in dry conditions catalyzed by immobilized Candida antarctica lipase B. The reactions were carried out following a transesterification kinetic approach, using choline and L-carnitine as primary and secondary trimethylammonium alcohols, respectively, and vinyl butyrate as acyl donor. The synthetic activity of the enzyme was strictly dependent on the water content, the position of the hydroxyl group in the trimethylammonium molecule, and the Log P parameter of the assayed solvent. Anhydrous conditions and a high excess of vinyl butyrate over L-carnitine were necessary to synthesize butyryl-L-carnitine. The synthetic reaction rates of butyryl choline were practically 100-fold those of butyryl-L-carnitine with all the assayed solvents. In both cases, the synthetic activity of the enzyme was dependent on the hydrophobicity of the solvent, with the optimal reaction media showing a Log P parameter of between -0.5 and 0.5. In all cases, 2-methyl-2-propanol and 2-methyl-2-butanol were shown to be the best solvents for both their high synthetic activity and negligible loss of enzyme activity after 6 days.     

Radiation-induced binding of methanol, ethanol and 1-butanol to haemoglobin

Aqueous solutions of haemoglobin were irradiated under N2 and under N2O in the presence of methanol, ethanol and 1-butanol, which were partly 14C-labelled. The amount of bound alcohol was measured after gel filtration on Sephadex G-100 and with sodium dodecyl sulphate on Sepharose 6B-CL. All alcohols became covalently linked to haemoglobin. After radiolysis under N2 the G values for the three different alcohols were very similar, but under N2O the yield of cross-linking of haemoglobin with 1-butanol is twice that of methanol or ethanol. The high degree of modification by butanol results in extensive dissociation to dimers. Possible mechanisms yielding covalent cross-links between alcohols and haemoglobin are discussed. The high G value for cross-linking with butanol suggests that butanol radicals can add very efficiently to double bonds.