The synthesis of 2-cyclohexylideneperhydro-4,7-methanoindenes. Non-steroidal analogues of steroidal GABAA receptor modulators

Abstract

Racemic (3aα,4β,7β,7aα)-2-cyclohexylideneperhydro-4,7-methanoindene derivatives (±)-3 and (±)-4 were synthesised as analogues of steroidal GABA_A receptor modulators 1 and 2 respectively. The lithium dianion generated from epimeric 2,3,3a,4,7,7a-hexahydro-4,7-methano-1H-indene-2-carboxylic acids, 8 and 9, reacted with a commercially available cyclohexanone to generate β-hydroxy carboxylic acids. Cyclodehydration to β-lactones followed by the thermal elimination of carbon dioxide gave a suitably functionalised 2-cyclohexylidenehexahydro-4,7-methano-1H-indene derivative 18. Regio- and stereospecific hydrocyanation of the bicyclo[2.2.1]hept-2-ene moiety of 18 was achieved via hydroboration affording a racemic nitrile, 19. This underwent further transformations to give (±)-3 and (±)-4 and their hydroxy group epimers (±)-5 and (±)-6 respectively. X-Ray structure data was obtained for (±)-3. The effects of compounds (±)-3–(±)-6 on the binding of the GABA_A receptor agonist [³H]muscimol to rat synaptic membranes were measured. Compound (±)-4 was a weak positive modulator while the others were inactive.