Synthesis of Methoxy and Hydroxy Analogues of 1,2,3,4,4a,9a-Hexahydro-4a-fluorenamine: Rigid Phencyclidine Analogues as Probes of Phencyclidine Binding Site Topography

(+)-1,2,3,4,4a,9a-Hexahydro-4a-fluorenamine (HFA) was found to be a potent and selective ligand for the phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA) receptor. This conformationally rigid PCP analogue has provided information about the binding conformation of PCP and the topography of its binding site. To further probe the topography of the PCP binding site, methods were developed for the synthesis of six oxygenated analogues of HFA that serve as probes of the putative hydrogen bonding interaction between the ligands and this binding site. This chemistry involves the Diels-Alder reaction of an appropriately substituted methyl indene-3-carboxylate with butadiene. Synthetic routes to all possible monomethoxylated derivatives of indene-3-carboxylate were thus devised and are detailed herein. An alternative method was developed to generate the homoenolate equivalent of 1-indanone, and a fert-butyl ester was demonstrated to act as a masked acid equivalent in the Friedel-Crafts acylation reaction.