Unreacted Alcohol Research Articles

High-efficiency and minimum-waste continuous kinetic resolution of racemic alcohols by using lipase in supercritical carbon dioxide.

A novel continuous-flow scCO(2) process for kinetic resolution of racemic alcohols can be performed with an immobilized lipase to lead to a quantitative mixture of the corresponding optically active acetates with up to 99% ee and unreacted alcohols with up to 99% ee, in which the productivity of the optically active compounds was improved by over 400 times compared to the corresponding batch reaction using scCO(2).

Synthesis of (+)-goniothalamin and its enantiomer by combination of lipase catalyzed resolution and alkene metathesis

(+)-Goniothalamin has been synthesized by lipase catalyzed resolution of (1 E)-1-phenylhexa-1,5-dien-3-ol using vinyl acrylate as acyl donor followed by ring closing metathesis of the formed (1 R)-1-[( E)-2-phenylvinyl]but-3-enyl acrylate. The unreacted alcohol from the resolution, (1 E,3 S)-1-phenylhexa-1,5-dien-3-ol, was esterified non-enzymatically, and used for synthesis of (−)-goniothalamin.

1-Alkylthio-3-aryloxypropan-2-ols: synthesis and enantiomer separation by lipase-catalyzed transesterification

The optically active ( R)- and ( S)-1-alkylthio-3-aryloxypropan-2-ols were prepared in the reaction of the appropriate arylglycidyl ethers and alkyl thiols followed by lipase-catalyzed transesterification. The effect of aryl and alkyl substituents, the enzyme preparation as well as the reaction conditions have been compared in terms of enantiomeric excess of the obtained acetate and the unreacted alcohol.

Multi-functional trickle bed reactor for butylacetate synthesis

Esterification—the reaction of acetic acid and butanol in a trickle bed reactor, packed with a strong acid ion-exchange resin, operating with partial evaporation of reaction mixture into inert gas (nitrogen) stream—was investigated in this study. The experiments were carried out under atmospheric pressure. Reaction temperature was maintained in the interval from 70 to 120 °C, i.e. above the boiling point of the azeotropic mixture containing part of unreacted alcohol and both reaction products, i.e. ester and water. Partial evaporation of the reaction mixture into the inert gas (nitrogen) stream passing through the catalyst bed and consequent separation of reaction products into vapour and liquid phases shifted the chemical equilibrium of the reaction. The paper propose two different techniques for increasing the performance of trickle bed reactor for mentioned esterification: simultaneous reaction and evaporation and periodic modulation of the feed rate.

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.

Enantiopure building blocks for chiral drugs from racemic mixtures of secondary alcohols by combination of lipase catalysis and Mitsunobu esterification.

The racemic alcohols 3-chloro-1-(2-thienyl)-1-propanol, 3-chloro-1-phenylpropanol, and 1-chloro-3-(3,4-difluorophenoxy)-2-propanol were converted into a mixture of one enantiomer as butanoate and the other as alcohol by lipase catalysis. Subsequent Mitsunobu esterification without separation proceeded with inversion of the unreacted alcohols to give high yield and ee of the three enantiopure butanoates. The butanoates of opposite configuration were produced in a similar manner, but starting with lipase-catalyzed hydrolysis of the racemic butanoates.

Regioselective acetylation of 4- t-butylcyclohexanol in presence of β-cyclodextrin and its derivatives

Regioselective acetylation of 4- t-butylcyclohexanol (I) in the presence of β-CD, DMβ-CD, HPβ-CD and β-CD-polymer was carried out with 10–20 times excess acetic anhydride. At 1:10 ratio I and acetic anhydride, the control showed good amount of conversion (99.0%) to 4- t-butylcyclohexyl acetate (II) with a trans/ cis ratio of 3.48 with very little unreacted alcohols present ( trans/ cis ratio 2.5). With increase in concentration of β-CD, although the ester yield was less than the control, the trans/ cis ratio increased steadily from 3.46 for 1:0.1 (yield 57.7%) to 5.49 for 1:1 eq.(yield 74.4%) of I to β-CD. However, the trans ester yield was comparable to the control (76.9%) in the presence of 1 eq. of β-CD. The results indicated selectivity in esterification between the trans and cis alcohols due to inclusion inside β-CD cavity.

Microbiological resolution of chiral arylethyl carbinols by Nocardia corallina

Whole cells of Nocardia corallina B-276 oxidized enantioselectively racemates of arylethyl carbinols, at 0.5 mM, to give ketones in yields from 4 to 97% (w/w) and the unreacted alcohols showing enantiomeric excess ranging from 5 to > 99%. The configuration of the resulting alcohol is (R).

Identification of Alcohol Dehydration Sites on an Oxide Surface by Scanning Tunneling Microscopy

High-speed scanning tunneling microscopy (STM), temperature-programmed desorption (TPD), Auger electron spectroscopy and low-energy electron diffraction (LEED) were used to characterize the (001) surface of monoclinic γ-WO3, and to determine the structure and reactivity of active sites on this surface. Cleavage along the WO3(001) plane followed by heating in O2 to remove carbonaceous impurities and subsequent reduction above 775 K in ∼10-5 Torr of O2 resulted in a c(2 × 2) reconstruction that is visible in LEED and atomic resolution STM images. The catalytic activity of the c(2 × 2) surface was probed through exposure to a series of alcohols. No difference in the sticking coefficient for 1-propanol, 2-propanol and 2-methyl-2-propanol (tert-butyl alcohol) was detectable. As the surface temperature was increased during TPD, desorption of unreacted alcohol and water was seen at temperatures less than 600 K, independent of the alcohol. The water desorption is attributed to deprotonation of the adsorbed alcohols to form alkoxides; at this stage STM images show terraces covered with adsorbates with no preference for the adsorbates to occupy step or other defect sites. At higher temperatures the alkoxide all desorbs as alkenes: no dehydrogenation products were observed, indicating that the c(2 × 2) surface displays only dehydration activity under these conditions. The alkene desorption peak temperature decreases from primary to tertiary alcohol (1-propanol → tert-butyl alcohol), indicating that desorption is limited by the rate of C−O bond scission of the adsorbed alkoxide. STM images are presented in which the alkoxide intermediates are resolved simultaneously with atomic resolution of the WO3(001)-c(2 × 2) substrate. These demonstrate that the sites for oxidative dehydration of the alcohol molecules are the exposed 5-fold coordinated W6+ ions. Further, it is demonstrated that the alkoxide can be removed from the surface with the STM tip to reveal the structure of the underlying adsorption sites.

Enantioselective oxidation of diaryl carbinols by Nocardia corallina B-276

Whole cells of Nocardia corallina B-276 oxidized diaryl carbinols enantioselectively to give ketones in moderate yields, and some of the unreacted alcohols showed high ee's. This asymmetric oxidation is a simple and efficient method for preparing meta- and para-monosubstituted optically active diaryl carbinols from the racemates. The para-substituted chiral alcohols have an R configuration.

Enzyme-catalysed improved resolution of ( RS)-4-cyano-4-(3,4-dimethoxyphenyl)-4-isopropyl-1-butanol

Resolutions of ( RS)-4-cyano-4-(3,4-dimethoxyphenyl)-4-isopropyl-1-butanol 1 using various enzymes were performed. Among them, Pseudomonas fluorescens resolved it with moderate stereoselectivity ( E=13) and reacted faster with the ( S)-enantiomer. To optimize enzyme-catalysed reaction conditions for the resolution, the effect of solvents and additives was studied. In n-hexane:ethyl acetate (9:1), both reaction rate and selectivity were high. When pyridine, potassium carbonate and molecular sieves were used as additives, the enantiomeric excess of the ( R)-enantiomer was 99, 99 and 98% at 52–60% conversion, respectively. However, in diisopropyl ether, the enantiomeric excess of unreacted alcohol ( R)- 1 was up to 99% at 70% conversion without additives.

Catalytic Asymmetric Acylation of Racemic Secondary Alcohols with Benzoyl Chloride in the Presence of a Chiral Diamine

Abstract Nonenzymatic kinetic resolution of racemic secondary alcohols is an efficient synthetic method to obtain optically active compounds in organic chemistry. Catalytic asymmetric acylation of racemic secondary alcohols has been successfully performed with achiral benzoyl chloride in the presence of only 0.3 mol% of chiral diamine (3) derived from (S)-proline, combined with 0.5 equivalent of triethylamine. This asymmetric acylation of various racemic cyclic secondary alcohols, 5, 6, or 8 membered cycloalkanols (1a–1c), hydroxyesters (1d and 1e), and bromohydrins (1f and 1g) gave the corresponding optically active benzoates (84–97% ee) and unreacted alcohols (79–95% ee). Racemic acyclic secondary alcohols (1h–1j) were also acylated in moderate enantioselectivity.

A Formal Total Synthesis of Epothilone A: Enantioselective Preparation of the C1−C6 and C7−C12 Fragments1

Our continued interest in the anticancer agent paclitaxel is driven by the desire to understand the structural features and spatial arrangement necessary for tubulin binding2 and stabilization of microtubule dynamics.3 The recently reported class of natural products, epothilone, now provides us with compounds structurally distinct from taxol and taxol analogues but with similar biological activity. In addition, epothilones have much greater activity against multi-drug resistant cell lines.4 After independently determining the relative stereochemistry of epothilone A we reported our synthetic approach, Figure 1, which includes a late-stage macrocyclic olefin metathesis.5 Our initial publication presented an enantioselective preparation of thiazole fragment C and the successful application of a ring-closing olefin metathesis reaction to an epothilone model system. Concurrently, three other synthetic groups reported similar approaches to epothilone A all of which have culminated in total synthesis.6-10 Herein we report the details of our independent, enantioselective preparation of the ketone fragment B and aldehyde A. Ketone B has been prepared from a sequence which is highlighted by a samarium-mediated Reformatsky reaction11 originally developed by Molander, Scheme 1. The sequence begins with racemic alcohol 2 readily prepared in one step from propionaldehyde and 3-methyl-2-butenylmagnesium chloride. Enzymatic resolution in methyl tert-butyl ether using Altus Biologics12 Chiro-CLECPC(which is reusable without significant loss of activity) provided an efficient route to gram quantities of (R)-2 after purification and deacylation. The enantioselectivity of the resolution at 47% conversion was determined to be >20:1 by Mosher ester methodology13 and chiral capillary gas chromatography (see Experimental Section for details). The enantiomeric excess was found to be dependent upon percent conversion (97% ee at 15% conversion and 92% ee at 48% conversion). The unreacted alcohol 2 can be easily recycled by a two-step oxidationreduction sequence. Acylation of the secondary hydroxyl occurred readily with bromoacetyl bromide in the presence of N,N-dimethylaniline to provide ester 3 in excellent yield. Ozonolytic cleavage of the terminal olefin yielded the necessary Reformatsky precursor which under exposure to freshly prepared SmI2 provided the lactone 4 in quantitative yield with >20:1 diastereose-

Stereoselective acetylation of racemic 7-[ N, N′-bis-(benzyloxycarbonyl)- N-(guanidinoheptanoyl)]-α-hydroxyglycine

Chiral intermediate (−)-7-[ N, N′-Bis(benzyloxycarbonyl)- N-(guanidinoheptanoyl)]-α-acetoxyglycine 2 was prepared for the total synthesis of a (−)-15 deoxyspergualin, an antitumor antibiotic and immunosuppressive agent. The stereoselective acetylation of racemic 7-[ N, N′-Bis(benzyloxycarbonyl)- N-(guanidinoheptanoyl)]-α-hydroxyglycine 1 was carried out in methyl ethyl ketone (MEK) using lipase from Pseudomonas sp. (lipase AK). Vinyl acetate was used as an acylating agent. A reaction yield of 48% (theoretical max 50%) and an optical purity of 98% were obtained for S-(−)-acetate 2. The unreacted alcohol (+)- 1 was obtained in 41% yield and 98.5% optical purity.

Properties of Polyoxyethylene/Polyoxypropylene-Type Nonionic Surfactant with Narrow Adduct Distribution.

Alcohol-ethyleneoxide (EO) /propyleneoxide (PO) adducts, synthesized by the block polymerization of higher alcohol, EO and PO using a composite metal oxide catalyst (NREPs), show quicker foaming-off than similar EO/PO adducts (BREPs) prepared using an alkaline catalyst. This rapid foaming-off appears to result from decrease in hydrophobic content, such as unreacted alcohol owing to narrow EO/PO adduct distribution, or increased molecular area at the air/water interface caused by terminal PO adduct structures of NREPs. With a branched alcohol, the foaming-off is even more rapid. NREPs are thus excellent nonionic surfactants with better biodegradability than BREPs.

Convenient practical resolution of racemic alkyl-aryl alcohols via enzymatic acylation with succinic anhydride in organic solvents

Enantiomerically pure alkyl-aryl secondary alcohols were conveniently obtained on a kilogram scale from their racemic mixtures by enzymatic acylation with succinic anhydride in organic solvents. A major advantage of this acylation method is the ease of separating the ester from the unreacted alcohol. This is achieved by extracting the organic solution with aqueous NaHCO 3 after the enzymatic reaction is completed.

Ultrasonic Agitation Accelerates cis-Glycosylation with Heterogeneous Promoters

Ultrasonic agitation increases the yield of glycosylations with donors such as 3,4,6-tri-O-acetyl-2-azido-2-deoxy-α-D-galactopyranosyl chloride using the heterogeneous promoters silver zeolite, cadmium zeolite or a mixture of silver perchlorate and silver carbonate on celite. The stereospecificity of the glycosylation depends on the nature of the alcohol to be glycosylated, the nature of the solid support and the solvent. Glycosylation catalyzed by silver zeolite in toluene solutions of the donor 3,4,6-tri-O-acetyl-2-deoxy-2-phtalimido-β-D-glucopyranosyl bromide, that usually produce trans-β-glycosides, yield cis-glycosides with unreactive alcohols. In these unreactive alcohols, e.g. methyl 2-O-benzoyl-4,6-O-benzilidene-β-D-galactopyranoside and benzyl 3,4,6-tri-O-benzyl-α-D-mannopyranoside, the hydroxyls to be glycosylated are hydrogen-bonded to a cis vicinal oxygen. This feature was evident in their AM1 minimized conformations and was indicated by the solution J(OH,CH) 1H NMR coupling constants.

Synthesis of Ethylene Oxide Adducts of s-Alcohols

Using the s-alcohols having a carbon range C12C14 prepared from available technical paraffins (C12C14), a technically effective synthetic method for obtaining highly purified s-alkyltri (oxyethylene) ethers using a BF3 catalyst was developed.To prepare s-alkyl tri (oxyethylene) ethers, about 1.5 mol of EO were added to the alcohol and as a result, unreacted alcohols were recovered by distillation. The recovered alcohols were recycled after purification by a newly developed ketone elimination method, in which esterification for the first portion of recovered alcohols with boric acid was carried out followed by separation of carbonyl compounds present in the alcohols by distillation.s-Alkyl tri (oxyethylene) ethers were continuously obtained with consistently excellent quality, containing no unreacted alcohols.The bad odor of s-ethylene oxide adducts of s-alkohol was thus shown to be due to the accumulation of carbonyl compounds such as ketone or diketone.In this study, a mechanism for the formation of by-product of PEG is also discussed.

Silver Trifluoromethanesulfonate(Triflate) Activation of Trichloroacetimidates in Glycosylation Reactions

Abstract Chemical syntheses of biologically active oligosaccharides, glycolipids and glycopeptides requires efficient stereospecific glycosylation reactions.2 One of the most effective glycosylation methods involves activation of anomeric imidates, particularly mchloroacetimidates, by Lewis acids such as boron trifluoride etherate (BF3·OEt2), mmethylsilyl mfluoromethanesulfonate (TMSOTF)3 and mfluoromethanesulfonic anhydride.4 In a recent example from this laboratory, BF3·OEt2, has been used to promote the glycosylation of methyl 2,3,6-tri-O-benzoyl-B-D-galactopyranoside (I)5 with 2-deoxy-2-phthalimido-3,4,6-tri-O-acetyl-B-D-galactopyranosyl mchloroacetimidate (I): see Scheme 1. The expected β1-4-linked disaccharide III was obtained in 40% yield. The yield was so low since both the α-anomer and a 1-3-linked disaccharide were formed as by products, the latter in particularly large quantities (cf. Ref.7). The 1-3 disaccharide could be formed from a product of acid-catalyzed 3,4-migration of the benzoyl group which is not surprising, considering the cis relationship of the 3,4-hydroxyl groups in galactose.8 In fact, when the glycosylation reaction was quenched before all unreacted alcohol was consumed, the chromatographic fraction corresponding to the starting alcohol II contained at least three different tribenzoates (as shown by NMR analysis).9 Other promoters, ZnBr2 10 and TMSOTF, led to lower yields and more complicated mixtures than BF3·OEt2.

Chiral Thiazolidine-2-Thione Derived Iminium Salts as Reagents for Kinetic Resolution

Abstract There are currently few simple reagent systems available which can effect efficient kinetic resolution of racemic compounds. We report here a series of chiral bicyclic iminium salts, which can resolve racemic secondary alcohols to give both the unreacted alcohol and the sulphide resulting from reaction in moderate enantiomeric excess.