Enantiospecific stereospecific total synthesis of the oxindole alkaloid (+)-alstonisine and stereocontrolled total synthesis of (-)-11-methoxy-17-epivincamajine as well as studies directed toward the total synthesis of N(b)-demethylalstophylline oxindole

The first enantiospecific stereospecific total synthesis of alstonisine has been accomplished in an overall yield of 12% (from D-tryptophan methyl ester) in 17 reaction vessels. D-(+)-Tryptophan has served here both as the chiral auxiliary and the starting material. The stereospecific conversion of D-(+)-tryptophan methyl ester 144 into the key template (-)- Na H, Nb-benzyl tetracyclic ketone 9 via the asymmetric Pictet-Spengler reaction (600 gram scale) and Dieckmann cyclization on multi-hundred gram scale was reduced to only two reaction vessels. In the course of this work, a method that would provide entry into either spirocyclic oxindole, diastereomeric at C(7), has been developed. The diastereospecific osmylation process permitted the conversion of the 2,3-indole double bond of 177 into the oxindole moiety of 195 in 81% yield. Mechanistic studies of the stereoselective osmylation of the 2,3-indole double of indole alkaloids has been carried out. Compelling evidence for the intramolecular delivery of OsO4 via Nb-complexation was obtained with the hydrochloride salt of ketone 193 in the osmylation process. A practical method for the removal of the Nb-benzyl protecting group in the hindered azabicyclo[3.2.1]nonane system has been developed. The structure of alstonisine was determined by NOE spectroscopic experiments and was confirmed by single crystal X-ray analysis. This confirmed the configuration of the spirocenter at C(7) in alstonisine was the same as in the structure proposed earlier by Le Quesne on biogenetic grounds. The original structure of alstonisine reported by Nordman (X-ray crystallography) in 1963 was the enantiomer of natural alstonisine.;A stereocontrolled total synthesis of (-)-11-methoxy-17-epivincamajine 247, which comprises the southern unit of the bisindole alkaloid (-)-11-methoxy-10-(11 '-vincorinyl)-17-epivincamajine 246, was accomplished in an overall yield of 8.4% in 14 reaction vessels from N a-methyl-6-methoxy-D-(-)-tryptophan ethyl ester. The 6-methoxy tryptophan ethyl ester 213 has been synthesized on 300 gram scale via a palladium catalyzed heteroannulation process. The regiospecific synthesis of the template, 11-methoxy tetracyclic ketone 217, was executed enantiospecifically via the asymmetric Pictet-Spengler reaction in 46% overall yield (from iodoaniline 209). The synthesis of 16-epi- Na methylgardneral 222 and 16-epi- Na-methylgardnerine 223 has been accomplished in high yield and in stereospecific fashion via the enolate-driven, palladium-catalyzed cross coupling reaction. (Abstract shortened by UMI.).