The synthesis of 5- and 6-substituted quinuclidine-3-carboxylic esters: intermediates for novel muscarinic ligands

Abstract

Quinuclidine-3-carboxylic esters bearing 5-hydroxy, 5-methyl and 6-methyl substituents are of interest as precursors to novel muscarinic ligands. All diastereoisomers of these disubstituted quinuclidines have been prepared, in each case using an appropriately substituted quinuclidin-3-one as the key intermediate. The keto ester 5a was obtained stereoselectively, either by intramolecular alkylation of a bromoacetylpiperidine, or by Dieckmann cyclisation of the differentially protected piperidine 18. 5-Methylquinuclidin-3-one was formed as a single isomer 24b by Dieckmann cyclisation. Piperidine-2,4-diester 33, in contrast, yielded a mixture of 2,5-disubstituted quinuclidine isomers 34 on cyclisation. Elaboration of the quinuclidinones gave the required esters, in several cases with high stereoselectivity. The stereochemical outcome of the Dieckmann cyclisation has been rationalised on the basis of molecular mechanics calculations.