Preparation of Novel meta- and para-Substituted N-Benzyl Protected Quinuclidine Esters and Their Resolution with Butyrylcholinesterase 英文参考文献.docVIP

Molecules 2012, 17, 786-795; doi:10.3390/moleculeOPEN ACCESS molecules ISSN 1420-3049 /journal/molecules Article Preparation of Novel meta- and para-Substituted N-Benzyl Protected Quinuclidine Esters and Their Resolution with Butyrylcholinesterase Ines Primo?i? *, Marijana Bolant, Alma Rami? and Sr?anka Tomi? Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102A, HR-10 000 Zagreb, Croatia * Author to whom correspondence should be addressed; E-Mail: ines.primozic@chem.pmf.hr. Received: 8 December 2011; in revised form: 5 January 2012 / Accepted: 11 January 2012 / Published: 16 January 2012 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 ) 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: