Graduate Thesis Or Dissertation

Studies toward the total synthesis of alkaloids : nagelamide A and D, agelastatin D, dragmacidin A-C, salacin and almazoles

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  • Studies toward the total syntheses of highly potent cytotoxic alkaloids including the bromopyrrole alkaloids and indole alkaloids were conducted and are described. Studies carried out in the course of this dissertation consist of five total syntheses of natural products that include bromopyrrole alkaloids nagelamide A, D and agelastatin D as well as indole-based alkaloids dragmacidin A-C, salacin and almazoles. The total synthesis of dimeric bromopyrroles, nagelamide A, was achieved in 8 steps from ornithine by using NCS oxidative dimerization of 2-aminoimidazole as a key step. The total synthesis of nagelamide D was accomplished in 6 steps using acidpromoted dimerization as a key feature. These methods provide a short and rapid entry into the syntheses of nagelamides without the use of protecting groups on nitrogen. In studies toward the synthesis of agelastatin D, the ABD-ring system was derived from a β–functionalization of linear imidazolone. The studies carried out in the course of this thesis have set in place a major ABD-ring core for the agelastatin D. Only the construction of the C-ring through a one-carbon bridge remains to be done. In the synthesis of bisindole alkaloids, a short synthetic strategy for dragmacidin A, B and C was accomplished by involving the dimerization of oxotryptamines to give bis(indolyl)pyrazines, which upon reduction and selective methylation with sodium cyanoborohydride in acetic acid or formic acid afforded the target piperazine natural products as the key steps. The application of the interrupted Pictet-Spengler cyclization involving halotryptamine spirocyclization with aldehydes having various functionalities has been investigated. The methodology appears to work well with aldehydes containing alcohol or ester groups but not with ketones or protected aldehydes. Furthermore, we have demonstrated the synthesis of salacin via halotryptamine spirocyclization. A short synthesis of almazole C and D are described. The key steps involve the peptide coupling and Gabriel-Robinson oxazole synthesis with chiral, nonracemic ketoamides. An integral aspect of the research involves the preparation of the key β–oxotryptophan synthon and demonstration of its utility. These investigations have lead to a revision of the structure of almazole D as 5-(3-indolyl)oxazole.
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