Total synthesis of cyclotryptamine and diketopiperazine alkaloids and biosynthetic pathway investigation of unsymmetrical diketopiperazine dimers

Thesis: Ph. D. in Organic Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2018.Cataloged from PDF version of thesis. Vita.Includes bibliographical references.I. Total Synthesis of (-)-Hodgkinsine, (-)-Calycosidine, (-)-Hodgkinsine B, (-)-Quadrigemine C and (-)-Psycholeine The enantioselective total synthesis of (-)-hodgkinsine, (-)-calycosidine, (-)-hodgkinsine B, (-)- quadrigemine C, and (-)-psycholeine through a diazene-directed assembly of cyclotryptamine fragments is described. Our synthetic strategy enables multiple and directed assembly of intact cyclotryptamine subunits for convergent synthesis of highly complex bis- and tris-diazene intermediates. Photoextrusion of dinitrogen from these intermediates enables completely stereoselective formation of all C3a-C3a' and C3a-C7' carbon-carbon bonds and all the associated quaternary stereogenic centers. The synthesis of these complex diazenes was made possible through a new methodology for synthesis of aryl-alkyl diazenes using electronically attenuated hydrazine-nucleophiles in a silver-promoted addition to C3a-bromocyclotryptamines. The application of Rh- and Ir-catalyzed C-H amination reactions in complex settings were used to gain rapid access to C3a- and C7-functionalized cyclotryptamine monomers, respectively, used for diazene synthesis. II. Total Synthesis of (-)-Naseseazine C and Identification of its Biosynthetic Pathway The biogenesis of unsymmetrical dimeric diketopiperazines is investigated, in collaboration with the Sherman group at the University of Michigan. Sequencing and mining the genome of Streptomyces sp. CB MQ-030, known to produce unsymmetrical diketopiperazine dimers, allowed the identification of NasB, a cytochrome P450 responsible for catalyzing late-stage oxidative dimerization of brevianamide F into (-)-naseseazine C. The relative and absolute stereochemical assignment was confirmed via its total synthesis using highly convergent late-stage fragment union of complex diketopiperazines.by Petra Lindovská.Ph. D. in Organic Chemistr