hrvatski

Resolucija racemičnih N-kvaternih derivata kinuklidin-3-il-izobutirata butirilkolinesterazom

Many esters of optically active quinuclidin-3-ol have been tested and recognized as pharamacological agents. Previous work also showed that butyryl cholinesterase (BChE ; 3.1.1.8.) catalyzed the hydrolysis of N-benzyl protected quinuclidinium esters in a stereoselective manner. In order to study the influence of substrate structure on kinetic resolution, racemic, (R)- and (S)-esters of quinuclidin-3-ol and isobutyric acid were synthesized as well as their racemic and chiral, quaternary N-benzyl and N-p-bromobenzyl derivatives. Racemic quinuclidin-3-yl acetate was synthesized in the first step by esterification of quinuclidin-3-ol with acetic anhydride. Resolution of the racemate with L- and D-tartaric acid, enantiomerically pure acetates were obtained. Chiral (R)- and (S)-quinuclidin-3-ols were prepared by hydrolysis of (R)- and (S)-acetates, respectively. N-Benzyl and N-p-bromobenzyl derivatives were synthesized in the next step by quaternization of appropriate chiral or racemic esters with benzyl bromide and p-bromobenzyl bromide. The rates of hydrolysis were monitored (HPLC) at 30°C in 0.1 M phosphate buffer, pH 7.4. Kinetic studies revealed that (R)-enatiomers of the tested esters are much better substrates than (S)-enantiomers. Introduction of the bromine atom in the para position of the phenyl ring resulted in a remarkable improvement of hydrolysis enantioselectivity.

butirilkolinesteraza; esteri kinuklidin-3-ola

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