Synthesis of Azabicyclo[2.1.1]hexane Aryl Amides as Potential Agonists for α7 Nicotinic Acetylcholine Receptors
Gunawardana, Vageesha W. Liyana
MetadataShow full item record
Nicotinic acetylcholine receptors (nAChRs) are a target for drug discovery due to their importance in cognitive functions. Notably, numerous azabicyclo compounds have been identified as agonists for the α7 subtype of the nAChRs and are potential therapies for cognitive deficit of Schizophrenia. We propose azabicylo[2.1.1]hexane, a novel azabicyclo aryl amide as a possible agonist for the α7 nAChR. Azomethine ylide cycloaddition with nitro alkenes offers access to the azabicyclo scaffold. Its primary amine allows for further transformation to various aryl amides. The focus of this study was to develop a synthetic route for the nitro alkene with a protected alcohol substituent that is required for the cycloaddition step. Two different synthetic routes were attempted using glyoxylic acid and allyl alcohol as starting materials. (E)-Ethyl-3-nitroacrylate was synthesized from glyoxylic acid via Henry reaction followed by esterification via the acid chloride intermediate and the elimination of the secondary alcohol using methane sulfonyl chloride. However, the attempted reduction of (E)-Ethyl-3-nitroacrylate using lithium aluminum hydride (LAH) and sodium borohydride did not yield the required primary alcohol. Alternatively, the nitration of the protected allyl alcohol using silver nitrite and TEMPO was attempted. Although the protection of the alcohol using tert-butyl silyl chloride was successful, nitration did not proceed as desired.