Studies of indole reactivity: Dimerization, reduction, and oxidation

Tryptophan plays an essential role in the structure and function of a variety of biologically important proteins. In addition, tryptophan is the core upon which a vast array of alkaloid natural products are constructed. The diverse chemistry of the indole ring enables tryptophan to participate in such a wide range of functions. This dissertation will detail a series of studies of the chemical behavior of the indole ring in three parts.; The dimerization of tryptophan produces a mixture of two diastereomers, previously reported to be the cis and trans indolines. Because this result contradicts the pattern of reactivity observed for other 3-alkyl indoles, we have undertaken a reinvestigation of the stereochemistry of tryptophan dimers. Through the elimination of the alpha-amino acid stereocenters, we have demonstrated that both indolines possess the same relative stereochemistry. In addition, we have provided spectroscopic evidence they are trans isomers based on correlation with a synthetic model system. This result implies that the intermolecular dimerization of all skatole derivatives in trifluoroacetic acid is stereoselective resulting in the formation of trans 2-(2'-indolyl)-3-alkylindolines.; A general two-step procedure for the reduction of indoles to the corresponding 4,5,6,7-tetrahydroindoles has been developed. A regioselective Birch reduction followed by catalytic hydrogenation is employed to accomplish this transformation. Yields for the sensitive pyrrole products are typically between 40 and 50%. This method provides access to pyrroles suitable for metal coordination and to complex chiral pyrroles that cannot be readily prepared by other methods. These new pyrrolyl ligands are utilized in the synthesis of two types of neutral eta 5-tetramethylpyrrolyl (NC4Me4) ruthenium complexes. Ru(eta5-NC4Me4)2 is prepared form (Ph3P)3RuCl2 and lithium tetramethyl-pyrrolide in refluxing THF. A chiral diazaruthenocene with C2 symmetry is prepared from 2,3-dimethyl-4,5,6,7-tetrahydroindole. Attempts to prepare diazaruthenocenes from [Ru(eta4-C8H 12)Cl2]n led to deprotonation of the COD ligand to form a complex Ru(1-3:5,6-eta5-C8H11)(eta 5-NC4Me4) isoelectronic with Ru(eta 5-NC4Me4)2.; Oxidation of tryptophol derivatives generates a 3-hydroxyfuranoindoline which represents the core of the natural products madindoline A and madindoline B. Madindoline A and madindoline B are selective inhibitors of inteleukin-6 mediated cell growth. An efficient racemic synthesis of madindoline A was been developed starting with 2,5-dibromo-3,6-dimethylquinone. A Moore azidoquinone rearrangement was utilized to construct the cyclopentene-1,3,-dione sidechain of the madindolines. The successful completion of this synthesis has lead to the initiation of a biological study of these natural products.