Preparation of Novel meta- and para-Substituted N-Benzyl Protected Quinuclidine Esters and Their Resolution with Butyrylcholinesterase

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 3.1.1.8) 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.

Design and evaluation of selective butyrylcholinesterase inhibitors based on Cinchona alkaloid scaffold

“…Twenty quaternary derivatives of cinchonidines (CD compounds) and their corresponding pseudo -enantiomers cinchonines (CN compounds) were synthesized following standard procedures for the Menshutkin reaction [ 25 – 28 ] starting from commercially available cinchonidine (CD) or cinchonine (CN) ( Fig 2 ; detailed in S1 File ). Compounds CD-(mBr), CD-(mMet), CD-(mCl), CD-(mNO 2 ) CN-(pMet), and CN-(mMet) were novel compounds.…”

“…The compounds were synthesized following standard procedures for the Menshutkin reaction [ 25 – 28 ] starting from commercially available cinchonidine or cinchonine (≥98.0%, Sigma-Aldrich, St. Louis, MO, USA). Cinchona alkaloid (1 mmol) and appropriate halide (1.05 mmol for para - or 1.2 mmol for meta -substituted benzyl bromide) in toluene were heated to reflux and end of reaction was detected with thin layer chromatography (CHCl 3 : MeOH = 9:1).…”

One-pot hydrogen production and cascade reaction of furfural to bioproducts over bimetallic Pd-Ni TUD-1 type mesoporous catalysts

“…The reduced palladium species likely triggered the FUR conversion. The use of acetic acid [97][98][99][100][101] or ammonium formate [102,103] as hydrogen sources instead of FAc, did not give bioPs. Tan et al [99] reported for a commercial palladium catalyst the effective H2 production from FAc, but not from acetic acid; conversely, a commercial nickel oxide catalyst converted acetic acid to H2, albeit at very high temperature (300 ºC).…”