Reaction at the Ester Site

L-( + )-Lactic acid (1), the naturally occurring form, is commercially available from a large number of suppliers, and is inexpensive. At this writing, the price of 1 kg is less than 60. Although 1 may be esterified with an alkyl iodide in the presence of CsF [1], carrying out this process is unnecessary since many lactic acid esters are commercially available, and some are even less expensive then the parent acid. For example, 500 g of ethyl ( S)-( — )-lactate (2) can be purchased for less than 14. 

Analogous to amino acids, a-hydroxy acids form cyclic anhydrides when treated with phosgene. However, a much more efficient reagent for this transformation with lactic acid is trichloromethyl chloroformate. By this method, L-lactic acid O-carboxyanhydride (3) is prepared as a crystalline solid in 46% yield [2]. Although 3 has found application in polymer chemistry, its use in asymmetric synthesis has been limited. Reaction of 3 with 4-bromo-benzaldehyde methylthio(thiocarbonyl)hydrazone in the presence of TFA gives a mixture of 4 (25%) and 5 (56%), which is separable by column chromatography [3]. 

Simple amides of lactic acid (6) are readily prepared by reaction of methyl lactate 

Further reactions of dimethylamide 6c lead to interesting chiral molecules. 0-Methylation with dimethylsulfate followed by LiAlH4 reduction of the amide carbonyl furnishes —)-2-methoxy-A,ALdimethylpropylamine (8) in high yield [6]. 

Alkylation of 6c with a MEM group is accomplished with MEM-Cl in the presence of diisopropylamine. The resulting protected lactamide 9, when treated with butylmagnesium bromide, gives the O-protected a-hydroxyketone (10) in good yield with an enantiomeric excess 99% [5]. 

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Entries 8 to 15 are examples of intramolecular reactions. Entry 8 involves two unactivated double bonds and was carried out at a temperature of 280°C. The product was a mixture of epimers at the ester site but the methyl group and cyclohexenyl double bond are cis, which indicates that the reaction occurred entirely through an endo TS. 

An attractive alternative is to study intramolecular reactions. These are generally faster than the corresponding intermolecular processes, and are frequently so much faster that it is possible to observe those types of reaction involved in enzyme catalysis. Thus groups like carboxyl and imidazole are involved at the active sites of many enzymes hydrolysing aliphatic esters and amides. Bimolecular reactions in water between acetic acid or imidazole and substrates such as ethyl acetate and simple amides are frequently too slow to... 

Oxocarboxylic acid esters (78JA4225 85TH1) offer two distinct electrophilic sites to amine (II), the nucleophile. Selective nucleophilic attack at the ester function of (I) may be accomplished by selecting the reaction temperature. 

Figure 7.5 Examples of the reactions to enhance or form the electrophilic centres of suicide inhibitors and their subsequent reaction with a nucleophile at the active site of the enzyme. The general structures used for the enzyme-inhibitor complexes are to illustrate the reactions the enzyme ester groups may or may not be present in the final complex...

Phosphonate ester 30 can also be considered as a mimic of the transition state for subsequent esterolysis and aminolysis of the 8-lactone. In fact, the antibody that promotes ring formation was shown to catalyze the stereoselective reaction between 29 and 1,4-phenylenediaminc.39 The kinetic mechanism of the bimolecular process involves random equilibrium binding of lactone and amine, and the observed turnover rate could be approximated from the measured difference between the binding of reactants and the TSA. Again, entropic factors are presumed largely responsible for the observed rate acceleration, with minimal contributions derived from specific catalytic groups at the active site. 

The detailed mechanism by which AChE and BChE hydrolyze ACh has been the subject of much research, especially since the crystal structure of the Torpedo califomica AChE was elucidated by Sussman et al. in 1991 [12]. (Reviews of these enzymes and their interactions can be found in Refs. [5,13]). This mechanism will be described here only briefly, as an introduction to the reaction of the enzyme with carbamates. The active site of AChE is located at the bottom of a 20 A-deep gorge, where acetylcholine fits in by attachment of the quaternary ammonium group to the so-called anionic site (mainly through cation interaction with the n electrons of Trp84), and by dipole interactions between the ester group and Ser200 at the esteratic site . 

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