Racemic alcohol ester

One approach called enzymatic resolution, involves treating a racemic mixture with an enzyme that catalyzes the reaction of only one of the enantiomers Some of the most commonly used ones are lipases and esterases enzymes that catalyze the hydrol ysis of esters In a typical procedure one enantiomer of the acetate ester of a racemic alcohol undergoes hydrolysis and the other is left unchanged when hydrolyzed m the presence of an esterase from hog liver... 

The TSIL used in this study has an ester moiety in its structure, which enables it to react in enzyme-catalyzed transesterification reaction. In the first part of the cycle, one of the enantiomers of the racemic alcohol is preferentially transformed into an ester of the IL-coupled acid. The other, unreacted enantiomer of the alcohol is then extracted, while the newly formed IL ester is treated with an excess of ethanol in the presence of the same enzyme. This process is accompanied by the regeneration of TSIL in the active form. The main advantage of the presented... 

A combination of an enzymatic kinetic resolution and an intramolecular Diels-Alder has recently been described by Kita and coworkers [23]. In the first step of this domino process, the racemic alcohols ( )-8-55 are esterified in the presence of a Candida antarctica lipase (CALB) by using the functionalized alkenyl ester 8-56 to give (R)-8-57, which in the subsequent Diels-Alder reaction led to 8-58 in high enantioselectivity of 95 and 91 % ee, respectively and 81 % yield (Scheme 8.15). In-... 

Marr and coworkers have used the combination of the iridium W-heterocyclic carbene complex 100 (0.1 mol%) with the lipase Novozyme 435 to convert racemic alcohols 101 into enantiomerically enriched esters 102 with excellent yield and enantioselectivities (Scheme 25) [85]. Peris and coworkers have used complex 25... 

A racemic alcohol may be converted into a racemic acid by reaction with one molar equivalent of phthalic anhydride the product is a half ester of a dicarboxylic acid (see Section 7.9.1). This can now be subjected to the resolution process for acids and, in due course, the alcohols can be regenerated by hydrolysis of the ester. 

Although in recent years transesterification processes of racemic alcohols have received major attention, enzymatic acylation of amines for synthetic purposes is also being employed as a conventional tool for the synthesis of chiral amines and amides [31], using CALB as the biocatalyst in the majority of these reactions [31a]. The main difference between enzymatic acylation of alcohols and amines is the use of the corresponding acyl donor, because activated esters which are of utility... 

The initial medicinal chemistry route to the azabicyclo[3.3.0]octane-3-carboxylic acid produced the azabicyclo system in a diastereoselective but racemic manner, and required a classical resolution to achieve enantioenriched material (Teetz et al., 1984a, b 1988). Reaction of (R)-methyl 2-acetamido-3-chloropropanoate (43) and 1-cyclopentenylpyrrolidine (44) in DMF followed by an aqueous acidic work-up provided racemic keto ester 45 in 84% yield (Scheme 10.11). Cyclization of 45 in refluxing aqueous hydrochloric acid provided the bicyclic imine, which was immediately reduced under acidic hydrogenation conditions. The desired cis-endo product 46 was obtained upon recrystaUization. The acid was protected as the benzyl ester using thionyl chloride and benzyl alcohol, providing subunit 47 as the racemate. Resolution of 47 was accomplished by crystallization with benzyloxy-carbonyl-L-phenylalanine or L-dibenzoyl-tartaric acid. 

Kinetic resolution technology has also been applied to the duloxetine problem (Scheme 14.13). In this case, chloroketone 41 was converted to racemic alcohol 43 using sodium borohydride. The racemate was then treated with vinyl butanoate in hexanes, in the presence of catalytic immobilized Candida antarctica Lipase B (CALB). The reaction was stopped after reaching 50% conversion, leading to the isolation of the desired (5)-chloroalcohoI 43a, as well as the (Zf)-ester 45 in good yields and excellent enantiomeric excesses. Chloroalcohol 43a was converted to duloxetine (3) via the... 

The best known of the muscarinic blocking drugs are the belladonna alkaloids, atropine (Atropine) and scopolamine (Scopolamine). They are tertiary amines that contain an ester linkage. Atropine is a racemic mixture of DL-hyoscyamine, of which only the levorotatory isomer is pharmacologically active. Atropine and scopolamine are parent compounds for several semisynthetic derivatives, and some synthetic compounds with little structural similarity to the belladonna alkaloids are also in use. All of the antimuscarinic compounds are amino alcohol esters with a tertiary amine or quaternary ammonium group. 

Kinetic resolutions by means of the selective formation or hydrolysis of an ester group in enzyme-catalyzed reactions proved to be a successful strategy in the enantioseparation of 1,3-oxazine derivatives. Hydrolysis of the racemic laurate ester 275 in the presence of lipase QL resulted in formation of the enantiomerically pure alcohol derivative 276 besides the (23, 3R)-enantiomer of the unreacted ester 275 (Equation 25) <1996TA1241 >. The porcine pancreatic lipase-catalyzed acylation of 3-(tu-hydroxyalkyl)-4-substituted-3,4-dihydro-2/7-l,3-oxazines with vinyl acetate in tetrahydrofuran (THF) took place in an enantioselective fashion, despite the considerable distance of the acylated hydroxy group and the asymmetric center of the molecule <2001PAC167, 2003IJB1958>. 

Figure 2.10 Hydrolysis of a racemic secondary ester or transesterification of the corresponding secondary alcohol with CALB as catalyst both yield the same enantiomer as product. The product of hydrolysis is the (R)-alcohol while the product of transesterification is the (R)-ester. The R,S-notation in this case is done on the assumption that Rj has higher priority than R2. This is not necessarily in the same order as large , small in model considerations.

In certain cases, especially for neutral substrates, the formation of covalent p,n-pairs, instead of salts, may be necessary to achieve optical resolution by crystallization. Suitable derivatives are esters of camphanic acid (1) or chrysanthemic acid (2) with racemic alcohols, or esters of menthol (3) and 1-phenylethanol (5) with racemic acids, or hydrazones of menthylhydrazine (4) with racemic aldehydes and ketones. 

The Pd-catalyzed allylic alkylation of sulfinate ions, thiols, and thiocarboxylate ions with racemic cyclic and acyclic allylic esters in the presence of bisphosphane BPA generally provides for an efficient asymmetric synthesis of allylic sulfones, sulfides, and thioesters. The Pd-catalyzed rearrangements of allylic sulfinates and allylic O-thiocarbamates, both of which proceed very efficiently in the presence of BPA, are attractive alternative ways to the asymmetric synthesis of allylic sulfones and allyUc thioesters also starting from the corresponding racemic alcohols. 

Esters are widespread in fruits and especially those with a relatively low molecular weight usually impart a characteristic fruity note to many foods, e.g. fermented beverages [49]. From the industrial viewpoint, esterases and lipases play an important role in synthetic chemistry, especially for stereoselective ester formations and kinetic resolutions of racemic alcohols [78]. These enzymes are very often easily available as cheap bulk reagents and usually remain active in organic reaction media. Therefore they are the preferred biocatalysts for the production of natural flavour esters, e.g. from short-chain aliphatic and terpenyl alcohols [7, 8], but also to provide enantiopure novel flavour and fragrance compounds for analytical and sensory evaluation purposes [12]. Enantioselectivity is an impor-... 

Problem 16.42 Acid-catalyzed hydrolysis with H2 "0 of an ester of an optically active 3° alcohol, RCOOC R R"R", yields the partially racemic alcohol containing O, R R R C "OH. Similar hydrolyses of esters of 2° chiral alcohols, RCOOC HR R", produce no change in the optical activity of the alcohol, and "O is found in RC OjH. Explain these observations. ... 

Thus it is very easy to acetylate a racemic alcohol and treat the racemic mixture of acetates with a lipase. One enantiomer is hydrolyzed to the alcohol and the other remains as die ester. These are separated chromatographically and each component is obtained widi high optical purity. This technique is becoming more important and could be die most general technique for resolution in the future. 

The acid esters of 1,2-dicarboxylic acids are conveniently prepared by heating the corresponding cyclic anhydride with one molar proportion of the alcohol (see the preparation of alkyl hydrogen phthalates from phthalic anhydride and their use in the resolution of racemic alcohols, Section 5.19). 

The Pasteur method can also be applied to the resolution of neutral racemates, if these can be first converted into an acidic or basic derivative from which eventually a mixture of crystalline diastereoisomeric salts may be prepared by appropriate neutralisation. Thus, a racemic alcohol (e.g. ( )-octan-2-ol, Expt 5.220) may be converted into the corresponding racemic hydrogen phthalate ester by heating with phthalic anhydride, and the ester is then resolved by the Pasteur procedure using an optically active base. The resulting optically active hydrogen phthalate ester is then carefully hydrolysed with aqueous sodium hydroxide to regenerate one of the optically active forms of the alcohol. 

Phthalic anhydrides readily form hydrogen phthalate esters on reaction with alcohols the derivatives from 3-nitrophthalic anhydride are usually nicely crystalline compounds and are hence suitable for purposes of characterisation. Hydrogen phthalate esters are also useful in appropriate instances for the resolution of racemic alcohols (Section 5.19). 

This chapter covers the kinetic resolution of racemic alcohols by formation of esters and the kinetic resolution of racemic amines by formation of amides [1]. The desymmetrization of meso diols is discussed in Section 13.3. The acyl donors employed are usually either acid chlorides or acid anhydrides. In principle, acylation reactions of this type are equally suitable for resolving or desymmetrizing the acyl donor (e.g. a meso-anhydride or a prochiral ketene). Transformations of the latter type are discussed in Section 13.1, Desymmetrization and Kinetic Resolution of Cyclic Anhydrides, and Section 13.2, Additions to Prochiral Ketenes. 

Key words optical resolution, diastereoisomeric complexes, 0,0 -dibenzoyltartaric acid, hydroxycarboxylic acid esters, hydroxycarboxylic acids, chiral phosphine oxides, racemic alcohols. 

Actually, coordination complexes of different metal salts of DBTA with hydroxycarboxylic acid esters, hydroxycarboxylic acids and alcohols as well as host-guest complexes of DBTA with chiral phosphine oxides and racemic alcohols can be prepared and used for separation of optical isomers. In the next subchapters theoretical and practical aspects of these recent resolution processes are summarised. 

Combination of the coordinating ability of metal ions for hydroxy group containing compounds with the before mentioned exceptional behaviours of DBTA in chiral recognation processes gave us a new possibility for direct resolution of a-alkoxycarboxylic acids, a-hydroxycarboxylic acid esters and series of racemic alcohols... 

Amphoteric compounds such as amino acids can be resolved as acid or amine forms after deriving corresponding esters or N-acyl compounds. Racemic alcohols and amines are also resolved by use of optically active isocyanates, where the alcohols and amines are derived the corresponding diastereomeric urethanes or ureas. 

Acid anhydrides have been also used due to the irreversibities of the reaction and the advantage in downprocessing.6 For example, the esterification of a racemic alcohol with succinic anhydride gives (S)-alcohol and (R)-ester (Figure 6(d)). The latter has an acid moiety so can be separated easily from the former due to the solubility difference in weakly basic water. 

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