Carboxylic esters, hydrolysis enantioselective reactions

The highly ordered cyclic TS of the D-A reaction permits design of diastereo-or enantioselective reactions. (See Section 2.4 of Part A to review the principles of diastereoselectivity and enantioselectivity.) One way to achieve this is to install a chiral auxiliary.80 The cycloaddition proceeds to give two diastereomeric products that can be separated and purified. Because of the lower temperature required and the greater stereoselectivity observed in Lewis acid-catalyzed reactions, the best diastereoselectivity is observed in catalyzed reactions. Several chiral auxiliaries that are capable of high levels of diastereoselectivity have been developed. Chiral esters and amides of acrylic acid are particularly useful because the auxiliary can be recovered by hydrolysis of the purified adduct to give the enantiomerically pure carboxylic acid. Early examples involved acryloyl esters of chiral alcohols, including lactates and mandelates. Esters of the lactone of 2,4-dihydroxy-3,3-dimethylbutanoic acid (pantolactone) have also proven useful. 

The asymmetric aUcoxycarbonylation of aUcenes is a reaction of particular interest, especially for vinylarenes, because it gives a two steps access (alkoxycarbonyla-tion, ester hydrolysis) to enantiomerically pure carboxylic acids from alkenes. For instance, a few arylpropionic acids such as (S j-Ibuprofen, (5)-Ketoprofen, and (5)-Naproxen, are popular non-steroidal anti-inflammatory agents [99]. Although good regio- and enantioselectivities have already been reported for asymmetric aUcoxycarbonylation, no systems, to the best of our knowledge, possesses both types of selectivities [100-104]. We tested ligands 7 in the asymmetric... 

Aziridine carboxylates are chiral intermediates for the synthesis of -lactams and amino acids [200]. The use of enantioselective ester hydrolysis in the synthesis of optically active A -unsubstituted and A-substituted aziridine carboxylate by Candida cylindraceae lipase has been demonstrated by Bucciareli et al. [199]. Racemic methyl aziridine-2-car-boxylate and 2,3-dicarboxylate 110 were used as substrates both for enzymatic hydrolysis and for the synthesis of AAchloro, iV-acyl and A-sulfonyl derivatives (Fig. 38). The reaction yield of 35-45% (theoretical maximum yield is 50%) and the e.e. s of 90-98% were obtained depending on substrate used in the reaction mixture. 

Ammonia lyases catalyze the enantioselective addition of ammonia to an activated double bond. A one-pot, three-step protocol was developed for the enantioselective synthesis of L-arylalanines 50 using phenylalanine ammonia lyase (PAL) in the key step (Scheme 2.20). After formation of the unsaturated esters 48 in situ via a Wittig reaction from the corresponding aldehydes, addition of porcine Ever esterase and basification of the reaction mixture resulted in hydrolysis to the carboxylic acids 49. Once this reaction had gone to completion, introduction of PAL and further addition of ammonia generated the amino acids 50 in good yield and excellent optical purity [22]. 

The third group of target molecules comprises chiral carboxylic acid and their derivatives esters, amides and nitriles. Enantiomerically pure esters are prepared in an analogous manner to the enantiomerically pure alcohols discussed earlier [i.e. by esterase- or lipase-catalyzed hydrolysis or (trans)esterification]. However, these reactions are not very interesting in the present context of cascade reactions. Amides can be produced by enantioselective ammoniolysis of esters or even the... 

Enantioselective acylation of amine and hydrolysis of amide are widely studied. These reactions are catalyzed by acylases, amidases and lipases. Some examples are shown in Figure 21.22 Aspartame, artificial sweetener, is synthesized by a protease, thermolysin (Figure 21(a)).22a In this reaction, the L-enantiomer of racemic phenylalanine methyl ester reacted specifically with the a-carboxyl group of N-protected L-aspartate. Both the separation of the enantiomers of the phenylalanine and the protection of the y-carboxyl group of the L-aspartate were unnecessary, which simplified the synthesis. 

While the conventional carboxylate protecting groups interfere with the course of the reaction, the enantioselective epoxidation on the oxazole 77b followed by photo-oxygenation and hydrolysis of triamide 78b affords the ester 79 in good yield with the desired stereochemistry [76b], Starting from alkoxyoxazoles, rearrangement to dioxetanes [75b] or dioxazoles [75] has been observed, and a simple and high-yield route for stable 377-1,2,4-dioxazoles 80 has been described (Sch. 46) [77]. 

Lipases are the most frequently used enzymes in organic chemistry, catalyzing the hydrolysis of carboxylic acid esters or the reverse reaction in organic solvents [3,5,34,70]. The first example of directed evolution of an enantioselective enzyme according to the principle outlined in Fig. 11.2 concerns the hydrolytic kinetic resolution of the chiral ester 9 catalyzed by the bacterial lipase from Pseudomonas aeruginosa [8], This enzyme is composed of 285 amino acids [32]. It is an active catalyst for the model reaction, but enantioselectivity is poor (ee 5 % in favor of the (S)-acid 10 at about 50 % conversion) (Fig. 11.10) [71]. The selectivity factor E, which reflects the relative rate of the reactions of the (S)- and (R)-substrates, is only 1.1. 

Enantioselective D-A reactions of chiral esters and amides of acrylic acid can be achieved using achiral Lewis acid such as TiCU. After the reaction, enantiomeric pure carboxylic acid can be recovered on hydrolysis. For example, the reaction of acrylic acid with cyclopentadiene using chiral a-hydroxy ethyl propionate 95a as chiral auxiliary in the presence of TiCU gives only one enantiomeric product in large excess (93 %) [82]. The chiral auxiliary 95a reacts with dienophile to produce a chiral ester 95, which participates in the reaction with cyclopentadiene. 

Organic aqueous two-phase solvent systems are also widely applied for other biotransformations, for example, in hydrolase-catalyzed processes [37,49]. A typical example is the enantioselective hydrolysis of a racemic, water-immisdble ester as a substrate. The reaction yields a water-soluble carboxylic acid (in depro-tonated form as a salt). Ionic liquids have also been used in biphasic systems, a topic that is discussed in detail in Chapter 3 in this book [50]. 

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