Applications of ring-closing metathesis reactions tot he total syntheses of (+)-anatoxin-a and 8-epi-xanthatin and progress toward the total synthesis of (+)-pinnamine
MetadataShow full item record
The application of ring-closing enyne metathesis (RCEYM) reactions to the preparation of biologically active natural products has been described. During the course of the studies toward the assembly of the potent nicotinic acetylcholine receptor agonists (+)-anatoxin-a and (+)-pinnamine, several new methods were developed to obtain suitable metathesis precursors. A method to prepare α-branched enones bearing a high degree of functional group diversity was accomplished from carboxylic acid precursors using a new titanium-mediated Peterson olefination sequence, and a new catalytic diastereoselective method for the preparation of cis-2,5-disubstituted pyrrolidines bearing unsaturated moieties was discovered. The application of these methods to the total synthesis of (+)-anatoxin-a constituting the first application of a RCM approach to the azabicyclo[4.2.1]nonane skeleton is described. Studies directed toward the total synthesis of the related alkaloid (+)-pinnamine are also discussed. In a related effort, the first total synthesis of the cytotoxic farnesyltransferase inhibitor 8-epi-xanthatin was achieved. The total synthesis featured a palladiumcatalyzed carbonylation-lactonization sequence to prepare an α-methylene lactone bearing enyne moieties. A subsequent domino RCEYM-cross metathesis between this enyne and methyl vinyl ketone produced the fully functionalized pseudoguaianolide skeleton and completed the total synthesis. Additionally, a new chiral Nenoyloxazolidininone bearing a dinaphthylmethyl group was prepared and utilized as a substrate to explore the addition reactions of aluminum acetylides to imides.