Esterase lactam hydrolysis

The double Henry reaction was examined by Luzzio and Fitch for the synthesis of a key intermediate 21 of perhydrohistrionicotoxin (22) [3]. Reaction of nitroalkane 15 and glutaraldehyde 16 using TMG (3) in dry tetrahydrofiiran (THF) proceeded via a double nitroaldol reaction to give meso-17 in 80-87% yield. After conversion of the diol to meso lactamdiacetate 19, esterase mediated hydrolysis gave optically active 20 in 87% yield with 93% ee (Scheme 7.2). This hydroxyacetate was successfully led to the Kishi lactam (21) [4], a key intermediate for 22. 

Pivaloyloxymethyl (Pom) esters are useful as prodrugs of penicillin and other 0-lactam antibiotics owing to their easy hydrolysis in vivo by ubiquitous non-specific esterases. Mascaretti and co-workers showed that Pom esters can also by cleaved under mild conditions with 2 equivalents of bis(tri-/i-butyltin)oxide as shown in Scheme 6.32. The intermediate tributylstannyl esters are readily hydrolysed on treatment with water to release the carboxylic acid. Functional groups such as aldehydes, thioacetals, amides, vinyl bromides, and nitro compounds are compatible.22... 

We end this section with two examples of the effects amines may have on esterase activity. The aggressive nitrogen nucleophile can obviously interfere with ester formation or hydrolysis. In designing a synthesis based on these enzymes we must find a symmetrical intermediate that might be desymmetrised. In the synthesis of the simple P-lactam 48, simple disconnections led to the symmetrical amino-diester 50, with the nitrogen atom protected. 

The serine beta-lactamases work in a mechanism similar to serine proteases and esterases, where the Ser center performs a ring opening electrophilic attack on the beta-lactam ring. Water then enters the site and enables the hydrolysis of the enzyme drug intermediate. The inactive penicillin is released and the enzyme is ready to attack another ring. This group of beta-lactamases is by far the more clinically important form of drug inactivation. 

In contrast to y- and 8-lactams, highly strained p-lactams are more easily susceptible to enzymatic hydrolysis and thus can be (slowly) hydrolyzed by carboxyl ester hydrolyses, such as esterases [162] and lipases [163] (Scheme 2.20). 

Early pharmacokinetic studies with epothilones in rodents pointed to a distinct vulnerability of the ester bond in the macrocycle to hydrolysis by (rodent) plasma esterases. Although esterase activity in rodent plasma is known to be substantially higher than in humans, these early findings also raised concerns about the metabolic stability of natural, macrolactone-based epothilones in humans. In response to these concerns the group at BMS conceived the metabolically more stable lactam analog of Epo B (53) as an alternative for future therapeutic applications. This work has resulted in an efficient process for the preparation of the Epo B lactam, a compound that was developed into a clinical anticancer drug and is marketed under the trade name Ixempra (ixabepilone, 53, Figure 3.11). 

Recently, two enantioselective syntheses of (—)-alloyohimbane (82) have been reported. The synthetic route utilized by Riva s group featured an enzymatic hydrolysis as the key step (Scheme 3.8S) (135). Prochiral diester 489 was hydrolyzed with pig liver esterase to provide the hydroxyester (—)-490 in good yield and with a high enantiomeric excess. One carbon homologation of (—)-490 followed by subsequent lactonization generated the bi-cyclic lactone (—)-491. Condensation of (—)-491 with tryptamine afforded tetracyclic lactam (—)-81, an intermediate in Isobe s synthesis of (—)-alloyohimbane ((—)-82). 

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