Part One. Synthesis of optically active tryptophan derivatives with potential activity as indoleamine 2,3-dioxygenase inhibitors: An approach via asymmetric catalytic hydrogenation. Part Two. Design, synthesis and pharmacology of selective ligands for alp

Part I. An efficient and concise synthesis of optically active ring-A substituted tryptophan derivatives (see 198, for example) was achieved via a rhodium-catalyzed asymmetric hydrogenation of the related dehydroamino acids (see 197 ). The related dehydrotryptophan derivatives (see 197) were obtained by condensation of the Boc-protected 3-indole aldehyde 203 with an N-acyl-2-(dialkyloxy-phosphinyl)-glycine ester 204 via a Wittig reaction. The required aldehyde was prepared from the Vilsmier Hacck formylation and protection of the resulting ring-A substituted indole 202. The indole nucleus was prepared via a Castro indole synthesis or a metal alkoxide-mediated cyclization of the functionalized alkyne 206. A Sonogashira or Heck coupling was employed for preparation of the alkynes from different substituted ortho-iodoanilines (see 205), prior to the Castro process. The (R,R)/(S,S)-Et-DuPhOS-Rh catalyst was initially employed in the asymmetric hydrogenation. A chiral rhodium-phosphine catalyst, which was generated in situ by adding the commercially available phosphinoferrocenylaminophosphine ligand (BoPhoz) to a rhodium cyclooctadiene salt, was eventually chosen for this process. The enantioselectivity was confirmed by chiral HPLC. A wide range of substituted tryptophans can be prepared using this approach in optically active form (D or L) from different iodoanilines or commercial halides for screening as potential indoleamine 2,3-dioxygenase (IDO) inhibitors. A series of mono-substituted tryptophan analogs with groups at the 4, 5, 6 and 7-positions as well as disubstituted analogs (5- and 6-positions) of the indole nucleus were obtained from this approach. An alternative approach via the previously developed Larock palladium catalyzed heteroannulation between a Schollkopf substituted alkyne and an orthoaniline was also executed in this study. The enantiomers, which resulted from both approaches, were obtained in 93%–99.5%ee.;Part II. A series of active β-carbolines have been synthesized and evaluated in search of selective ligands for α 1-containing GABAA/benzodiazepine receptor subtypes. The efficient synthesis of chiral esters of β-carboline-3-carboxylate was carried out via a CDI-mediated process and the related synthesis of 3-, 6-disubstituted β-carbolines was completed via a Sonogashira or Stille coupling process. Analysis of the binding data indicated the above β-carbolines exhibited potent binding affinity at the α 1 subtype. In fact, 6-substituted acetylenyl βCCt (WYS8) is the most potent (in vitro) α1 selective ligand, reported to date. The bivalent ligands of βCCt (WYS2 and WYS6) were also designed and prepared via a palladium-catalyzed homocoupling process to provide an entry into many bivalent ligands, as well as different substituted β-carboline analogs. They were used to complete an SAR in search of α1 subtype selective antagonists. Results from this work illustrate that large substituents at positions –6 and –7 of β-carbolines actually project into the extracellular domain (L Di region) of the GABAA/BzR α1 subtype. In collaboration with Dr. June, the effects of βCCt and 3-βC were examined in Alcohol-Preferring (P) rats and High Alcohol Drinking (HAD) 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 the GABAA/.BzR α1 subtype. 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.;Part III. The first stereospecific total synthesis of (+)-polyneuridine aldehyde 17, 16-epivellosimine 19, (+)-polyneuridine 22 and macusine A 23 has been accomplished from commercially available D-(+)-tryptophan methyl ester. D-(+)-Tryptophan has served here both as the chiral auxiliary and the starting material for the synthesis of the common intermediate, (+)-vellosimine 27. This alkaloid was available in enantiospecific fashion in seven reaction vessels in 27% overall yield from D-(+)-tryptophan methyl ester 28 via a combination of the asymmetric Pictet-Spengler reaction, Dieckmann cyclization, and a stereocontrolled intramolecular enolate-driven palladium-mediated cross-coupling reaction. An enantiospecific total synthesis of (+)-polyneuridine aldehyde 17, which was proposed as an important biogenetic intermediate in the biosynthesis of quebrachidine 6, was then accomplished in an overall yield of 14.1% in 13 reaction vessels from D-(+)-tryptophan ethyl ester 28. Aldehyde 27 was protected as the Na-Boc aldehyde 63, and then converted into the prochiral C (16)-quaternary diol 64 via the practical Tollens' reaction and deprotection. The DDQ-mediated oxidative cyclization and TFA/Et3SiH reductive cleavage served as protection/deprotection step to provide a versatile entry into the three alkaloids, polyneuridine aldehyde 17, polyneuridine 22 and macusine A 23 from quarternary diol 26. The chemospecific and regiospecific oxidations of the 16-hydroxymethyl group contained in the axial position in contrast to the equatorial hydroxymethyl group was achieved with the Corey-Kim reagent to provide the desired aldehydes, polyneuridine aldehyde 17 and 16-epi-vellosimine 19 with absolute diastereoselectivity.