Base-catalyzed, acylation alcohols

It is remarkable that better enantioselectivities are achieved when CALB-catalyzed acylations of the alcohol are carried out in organic solvent rather than in water. Excellent enantioselectivities are obtained when the process is carried out with vinyl esters [22]. However, in some cases the use of vinyl or alkyl esters as acyl donors has the drawback of the separation of the ester (product) and the alcohol (substrate). A practical strategy to avoid this problem is the use of cyclic anhydrides [23]. In this case an acid is obtained as product, which can be readily separated from the unreacted alcohol by a simple aqueous base-organic solvent liquid-liquid extraction. This methodology has been successfully used for the synthesis of (-)-paroxetine as indicated in Scheme 10.11 [24]. 

The most important reactions of alkyl substituents a and y to the ring heteroatom are those which proceed via base-catalyzed deprotonation. Treatment of 2- and 4-alkyl heterocycles with strong bases such as sodamide and liquid ammonia, alkyllithiums, LDA, etc., results in an essentially quantitative deprotonation and formation of the corresponding carbanions. These then react normally with a wide range of electrophiles such as alkyl halides and tosylates, acyl halides, carbon dioxide, aldehydes, ketones, formal-dehyde/dimethylamine, etc., to give the expected condensation products. Typical examples of these transformations are shown in Scheme 17. Deprotonation of alkyl groups by the use of either aqueous or alcoholic bases can also be readily demonstrated by NMR spectroscopy, and while the amount of deprotonation under these conditions is normally very small, under the appropriate conditions condensations with electrophiles proceed normally (Scheme 18). 

There are many reactions in which pyridines are used as bases. However in a large number of reactions only pyridine itself is reactive. a-Substituted pyridines behave differently, e.g. in the catalysis of acylation reactions with acyl chlorides or anhydrides [45]. The sterical hinderance of the a-substituents decelerates reactions in which a pyridine reacts as a nucleophile. A reaction which can be base-catalyzed by a-substituted pyridines is the addition of alcohols to hetero-cumulenes such as ketenes and isocyanates. Therefore this reaction was investigated as a model reaction for base catalysis by concave pyridines. 

In 1887, Claisen and Lowman reported that the condensation of 2 mol of an ester, such as ethyl acetate, in the presence of base gave the p-keto ester, ethyl acetoacetate (ethyl 3-oxobutanoate equation 1). The intramolecular equivalent was recognized by Dieckmann in 1894. He found that heating an adipic acid ester with sodium and a trace of alcohol led to cyclization, with the formation of a cyclopentanone (equation 2). The reaction was, at an early stage, extended to the acylation of ketones. Claisen himself reported the base-catalyzed reaction of acetophenone and ethyl benzoate to give dibenzoylmethane in 1887. This reaction, too, has an intramolecular parallel. The acylation of ketones with esters and other acid derivatives is sometimes called a Claisen condensation, although this usage is criticized by some writers and avoided by others. A widely used example of ketone acylation is the synthesis of a-formyl (hydroxymethylene) ketones (equation 3). Intramolecular variants of this reaction include the classical synthesis of dimedone (Scheme 1). 

Based on their work on supercritical CO2 (see also Scheme 23), Reetz and Leitner introduced a technologically new and interesting continuous flow process for enzymatic reactions [65]. The group designed a protocol for enzymatic reactions, namely the lipase-catalyzed acylation (CAL B) of octan-1 -ol by vinyl acetate in ionic liquids (l-butyl-3-methylimidazolium bis(trifluo-romethanesulfonimide) [BMIM] [BTA]) using supercritical CO2 as the mobile phase (Scheme 25). The alcohol is pumped through the biphasic system and the products are obtained in solvent-free form in a cold trap. The enzyme/ionic liquid mixture can be recycled in batchwise or continuous flow operations. 

The synthesis of etoxazoie is shown in Scheme 26.2.3 [19, 26]. Starting from 2-ethoxy-4- butyl acetophenone standard procedures lead to an oxime intermediate, which is reduced to the corresponding amino alcohol. Acylation of this amino alcohol with 2,6-difluorobenzoyl chloride and subsequent base-catalyzed cydization after activation of the hydroxy group leads to etoxazoie (4). An alternative route starts with the amino acid ester, which is first acylated using 2,6-difluorobenzoyl chloride and then reduced with sodium borohydride to the same final intermediate. 

Fig. 5 Base-catalyzed addition of alcohols to diphenylketene. Formation of a complex 17 between a concave pyridine and an alcohol activates the OH group and facilitates the formation of the ester 18. When the concave pyridine Fh is used, the carbohydrate 19 can be acylated exclusively in 2-position to give 20.

Dynamic resolution of various sec-alcohols was achieved by coupling a Candida antarctica lipase-catalyzed acyl transfer to in-situ racemization based on a second-generation transition metal complex (Scheme 3.17) [237]. In accordance with the Kazlauskas rule (Scheme 2.49) (/ )-acetate esters were obtained in excellent optical purity and chemical yields were far beyond the 50% limit set for classical kinetic resolution. This strategy is highly flexible and is also applicable to mixtures of functional scc-alcohols [238-241] and rac- and mcso-diols [242, 243]. In order to access products of opposite configuration, the protease subtilisin, which shows opposite enantiopreference to that of lipases (Fig. 2.12), was employed in a dynamic transition-metal-protease combo-catalysis [244, 245]. 

---