Neuronal nicotinic acetylcholine receptors are members of the ligand-gated ion channel receptor superfamily and may play important roles in modulating neurotransmission, cognition, sensory gating, and anxiety. Because of its distribution and abundance in the CNS, the alpha 7 nicotinic receptor is a strong candidate to be involved in some of these functions. In this paper we describe the synthesis and in vitro profile of AR-R17779, (-)-spiro[1-azabicyclo[2.2. 2]octane-3,5'-oxazolidin-2'-one] (4a), a potent full agonist at the rat alpha 7 nicotinic receptor, which is highly selective for the rat alpha 7 nicotinic receptor over the alpha 4 beta 2 subtype. Preliminary SAR of AR-R17779 presented here indicate that there is little scope for modification of this rigid molecule as even minor changes result in significant loss of the alpha 7 nicotinic receptor affinity.
When hydroboration of 1-octene is carried out in the presence of catalytic amounts of rhodium trichloride followed by the usual oxidation (hydrogen peroxide in aqueous alkali), only minor proportions of 1-octanol (2.4%) are formed accompanied by very significant amounts of 2- (17.4%), 3- (36.9%), and 4-octanol (43.3%). These product compositions are obtained in good overall yield when the borane-THF complex is slowly added to a stirred solution of 1-octene in THF solvent containing the rhodium trichloride. Isomerization of 1-octene to 2-, 3-, and 4-octene in the presence of rhodium trichloride alone is far too slow to account for the foregoing results. The mechanism likely involves multiple and reversible addition/elimination of a Rh-activated B-H species across the double bonds.
A direct, short chiral synthesis of the selective alpha7 nicotinic receptor agonist (-)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one] (AR-R17779) is presented. The key step utilized attack of the dianion of the (R)-HYTRA ester [(R)-(+)-2-hydroxy-1,2,2-triphenylethyl acetate] on quinuclidin-3-one, followed by a selective precipitation of the diasteriomeric tertiary alcohol that led to (S)-(-)-AR-R17779 in two additional steps.
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