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Preparation of Novel meta- and para-Substituted N-Benzyl Protected Quinuclidine Esters and Their Resolution with Butyrylcholinesterase
Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102A, HR-10 000 Zagreb, Croatia
* Author to whom correspondence should be addressed.
Received: 8 December 2011; in revised form: 5 January 2012 / Accepted: 11 January 2012 / Published: 16 January 2012
(This article belongs to the Special Issue ECSOC-15
Abstract: Since the optically active quinuclidin-3-ol is an important intermediate in the preparation of physiologically or pharmacologically active compounds, a new biocatalytic method for the production of chiral quinuclidin-3-ols was examined. Butyrylcholinesterase (BChE; EC 22.214.171.124) was chosen as a biocatalyst in a preparative kinetic resolution of enantiomers. A series of racemic, (R)- and (S)-esters of quinuclidin-3-ol and acetic, benzoic, phthalic and isonicotinic acids were synthesized, as well as their racemic quaternary N-benzyl, meta- and para-N-bromo and N-methylbenzyl derivatives. After the resolution, all N-benzyl protected groups were successfully removed by catalytic transfer hydrogenation with ammonium formate (10% Pd-C). Hydrolyses studies with BChE confirmed that (R)-enantiomers of the prepared esters are much better substrates for the enzyme than (S)-enantiomers. Introduction of bromine atom or methyl group in the meta or para position of the benzyl moiety resulted in a considerable improvement of the stereoselectivity compared to the non-substituted compounds. Optically pure quinuclidin-3-ols were prepared in high yields and enantiopurity by the usage of various N-benzyl protected groups and BChE as a biocatalyst.
Keywords: quinuclidin-3-ol; esters, resolution; butyrylcholinesterase; N-benzyl protected groups
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Primožič, I.; Bolant, M.; Ramić, A.; Tomić, S. Preparation of Novel meta- and para-Substituted N-Benzyl Protected Quinuclidine Esters and Their Resolution with Butyrylcholinesterase. Molecules 2012, 17, 786-795.
Primožič I, Bolant M, Ramić A, Tomić S. Preparation of Novel meta- and para-Substituted N-Benzyl Protected Quinuclidine Esters and Their Resolution with Butyrylcholinesterase. Molecules. 2012; 17(1):786-795.
Primožič, Ines; Bolant, Marijana; Ramić, Alma; Tomić, Srđanka. 2012. "Preparation of Novel meta- and para-Substituted N-Benzyl Protected Quinuclidine Esters and Their Resolution with Butyrylcholinesterase." Molecules 17, no. 1: 786-795.