Part One. Efficient asymmetric synthesis of ring-A substituted tryptophans, synthesis of 6-methoxy-(D)-tryptophan required for the total synthesis of ring-A oxygenated indole alkaloids. Part Two. Syntheses of selective ligands for GABA(A)/benzodiazepin

Part I. A novel and concise synthesis of optically active tryptophan derivatives was developed via palladium-catalyzed heteroannulation reactions of substituted ortho-iodoanilines with an internal alkyne substituted with a protected amino acid moiety. The required internal alkyne was prepared in greater than 96% de via alkylation of the Schöllkopf chiral auxiliary employing diphenylphosphate as the leaving group. The Schöllkopf chiral auxiliary was chosen here for the preparation of L-tryptophans would be available from D-valine while the D-isomers required for natural product synthesis would originate from the inexpensive L-valine on 300 gram scale. Applications of the palladium-catalyzed heteroannulation reaction were extended to the first asymmetric synthesis of L-benzo[f]tryptophan as well as L-isotryptophan. More importantly, the optically pure 6-methoxy-(D)-tryptophan was prepared by this protocol on large scale (>150g). This permits entry into many ring-A oxygenated indole alkaloids when employed in the asymmetric Pictet-Spengler reaction. In addition, a formal total synthesis of tryprostatin A was accomplished in high overall yield employing this new method.; Part II. A series of novel imidazobenzodiazepines and βCCt analogs were synthesized in search of subtype selective ligands for GABA_A/benzodiazepine receptor subtypes. An efficient route to the synthesis of chiral esters of β-carbolines and imidazobenzodiazepines was developed via a CDI-mediated process. Analysis of the binding data indicates that the 8-methoxy-4,5-azetidinyl-imidazobenzodiazepine 3-t-butyl ester (CM-D45) exhibited potent binding affinity (with K_i values less than 1 nM) and selectivity at DI subtypes. In fact, it is the most potent (in vitro) diazepam insensitive ligand reported, to date. In addition, the synthesis of βCCt the most α1 subtype selective ligand, was dramatically improved. βCCt is at least 20 times more selective for the α1 subtype compared to the well know BZD antagonist flumazenil, and 3.5 times more selective than zolpidem. In collaboration with Dr. June, the effects of βCCt were examined in alcohol-preferring (P) rats. Analysis of the experimental data suggests that βCCt is a reliable and selective antagonist of EtOH-motivated responding under several schedules of EtOH presentation. It is suggested that the attenuation of EtOH-motivated responding effected by this agent is mediated at least, in part, via α1β3γ2 receptors. This may have significance in regard to mediation of dopamine levels in the nucleus accumbens via GABAergic projections from the ventral pallidum, a system extremely important in the reinforcing effects of drugs of abuse.