R-(-)-3-Quinuclidinol and S-(+)-3-Quinuclidinol
The two enantiomers of 3-quinuclidinol are frequently also known by other names, such as 3-hydroxyquinuclidine, 3-HQD and 1-Azabicyclo[2.2.2]octan-3-ol.
The quinuclidinol nucleus appears as a common pharmacophore in many ligands of muscarinic receptors (mAChR), of which there are five subtypes named M1-5
. These are G protein-coupled acetylcholine receptors found in the plasma membranes of certain neurons and other cells, and are involved in diverse physiological functions such as smooth muscle contraction, exocrine and endocrine secretion, and nerve-to-nerve transmision. Radiolabelled derivatives of 3-quinuclidinyl benzilate (1
), a non subtype-selective muscarinic receptor antagonist, are used in receptor binding assays and research into the roles of the individual receptors.
Quinuclidinol derived molecules with subtype selectivity amongst the five muscarinic receptors are of significant interest to the pharmaceutical industry. For example, Talsaclidine (M1
agonist), has been clinically evaluated as a cognition enhancer,1,2
and revatropate (M3
antagonist) has been investigated for the treatment of asthma.3
Carbamoyl derivatives of 3-quinuclidinol such as 2
(Scheme 1) are known to inhibit the enzyme acetylcholinesterase, which is responsible for the degradation of the neurotransmitter acetylcholine.4,5
)-enantiomer of 2
and racemic 3
have been shown to be protective against organophosphate poisoning in guinea pigs and mice respectively.
In organic synthesis (R)- or (S)-3-quinuclidinol, or the racemate, is used as a catalytic base in the Baylis-Hillman reaction.6,7
The Baylis-Hillman reaction (also known as the Morita-Baylis-Hillman or MBH reaction) entails the coupling of a carbon electrophile such as an aldehyde and activated alkene, as shown in Scheme 2. Less commonly α-keto esters, fluorinated ketones and aldimine derivatives are utilised as electrophiles, and the scope of active alkenes extends to acrylic esters, acrylonitrile, vinyl sulfones and vinyl ketones amongst others.
In an aza-variant of the Baylis-Hillman reaction, 3-quinuclidinol has been used to efficiently catalyse the coupling of methyl acrylate with N-
(benzylidene)polyfluoroanilines, as illustrated in Scheme 3. A recent communication from Shang and co-workers reports the co-catalysis of the Baylis-Hillman reaction between aromatic aldehydes and activated alkenes with 3-quinuclidinol and Sc(OTf)3
. This new modification addresses the slow reaction rate which is a major drawback of the reaction.8
1. Leusch, A.; Troger, W.; Greischel, A.; Roth, W. Xenobiotica 2000
2. Walland, A.; Burkard, S.; Hammer, R.; Trijger, W. Life Sci. 1997
3. Ticehurst, M. D.; Basford, P. A.; Dallman, C. I.; Lukas, T. M.; Marshall, P. V.; Nichols, G.; Smith, D. Int. J. Pharm
4. Sterling, G. H.; Doukas, P. H.; Jackson, C.; Caccese, R.; O’Neill, K. J.; O’Neill, J. J. Biochem. Pharmacol
5. Reiner, E.; Skrinjaric-Spoljar, M.; Dunaj, S.; Simeon-Rudolf, V.; Primozic, I.; Tomic, S. Chem. Biol. Interact
6. Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996
7. Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988
8. Shang, Y.; Wang, D.; Wu, J. Synth. Commun