Abstract
Eight chiral esters of quinuclidin-3-ol and butyric, acetic, pivalic and benzoic acid were synthe- sized as well as their racemic and chiral, quaternary N-benzyl derivatives. All racemic and chiral quater- nary compounds were studied as substrates and/or inhibitors of horse serum butyrylcholinesterase (BChE). The best substrate for the enzyme was (R)-N-benzyl butyrate. The rates of hydrolysis decreased in order (R)-butyrate >> (R)-acetate (7-fold slower) > (R)-pivalate (8-fold slower) > (R)-benzoate (9-fold slower reaction), while (S)-N-benzyl esters were much poorer substrates (320 (butyrate) - 4360-fold slow- er (pivalate) than the appropriate (R)-enantiomer). For all (S)-N-benzyl esters excluding (S)-N-benzyl ace- tate inhibition constants were determined (Ka = 3.3−60 μmol dm −3 ). The hydrolysis of racemic mixtures of N-benzyl esters proceeded 1.4 (for acetate) − 5.1 (for benzoate) times slower than that of pure (R)- enantiomers of the corresponding concentrations due to the inhibition with (S)-enantiomers. Change of the acyl moiety of the substrate effected both activity and stereoselectivity of the BChE.(doi: 10.5562/cca1829)
Highlights
Azabicyclo[2.2.2]octan-3-ol, its derivatives and other quinuclidine compounds display a broad range of biological activities and pharmaceutical industries have large interest to explore them.[1]
Since the racemates are regarded with suspicion as pharmaceuticals, the issue of quinuclidin-3-ol resolution has been addressed by using a number of chemical[5−7] and biocatalytic[8,9] methods
Chiral (R)- and (S)-quinuclidin-3-ols were obtained by the resolution of racemic quinuclidin-3-yl acetates with L- and D-tartaric acid.[5]
Summary
Azabicyclo[2.2.2]octan-3-ol, its derivatives and other quinuclidine compounds display a broad range of biological activities and pharmaceutical industries have large interest to explore them.[1]. It was possible to use BChE for the resolution of racemic nonquaternized quinuclidin-3-yl butyrate[8] and for the hydrolysis of (R)- and (S)-quinuclidin3-yl benzoates,[14−16] stereoselectivity of hydrolyses being in favour of the (R)-enantiomer. In this paper the synthesis of quaternary, N-benzyl derivatives of racemic, (R)- and (S)-quinuclidin-3-yl butyrate, acetate, pivalate and benzoate are reported, Figure 1.
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