The formal synthesis of clavicipitic acid based on a biosynthetic proposal
Abstract
The formal synthesis of clavicipitic acid is reported. The synthetic strategy is based on the biosynthetic hypothesis of Floss which involves the azepino ring ring closure of 10-hydroxy($\gamma$,$\gamma$-dimethylallyl)tryptophan. This ring enclosure involves an intramolecular, nucleophilic attack of an amine on a protein-activated hydroxyl group. The starting material for the synthesis is indole-4-carboxaldehyde. An alternate proposal for the synthesis involving a proton-driven rearrangement of a 10-membered macrocyclic amine to the azepino was not able to be realized owing to the inaccessibility of the requisite substrate necessary for implementation of this strategy. Alternate approaches for the synthesis of this substrate are considered and preliminary synthetic work is presented. The most efficient route to the azepino system employs a proton-catalyzed ring closure and produces the simple dehydration product methyl-4-(3-methyl-1,3-butadien-1-yl)-3-(2-amino-2-carbomethoxy-3-indolyl)propionate in addition to the desired amination product. Attempts at an intramolecular Mitsunobu coupling were unsuccessful. The two dehydration products were demonstrated to be interconvertible upon acidic catalysis. Implications of the diene by-product to the biosynthesis of the Ergot alkaloids are considered. A comprehensive review of clavicipitic acid including its isolation, structure elucidation, biosynthesis, and synthesis is presented.
Degree
Ph.D.
Advisors
Nichols, Purdue University.
Subject Area
Organic chemistry
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