Development and application of new strategies for synthesis of complex diketopiperazine alkaloids

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. Quantitative Modeling of Bis(pyridine)silver (I) Permanganate Oxidation of Hydantoin Derivatives: Guidelines for Predicting the Site of Oxidation in Complex Substrates The bis(pyridine)silver(I) permanganate promoted hydroxylation of diketopiperazines has served as a pivotal transformation in the synthesis of complex epipolythiodiketopiperazine alkaloids. This late-stage C-H oxidation chemistry is strategically critical to access N-acyl iminium ion intermediates necessary for nucleophilic thiolation of advanced diketopiperazines en route to potent epipolythiodiketopiperazine anticancer compounds. In this study, we develop an informative mathematical model using hydantoin derivatives as a training set of substrates by relating the relative rates of oxidation to various calculated molecular descriptors. The model prioritizes Hammett values and percent buried volume as key contributing factors in the hydantoin series while correctly predicting the experimentally observed oxidation sites in various complex diketopiperazine case studies. Thus, a method is presented by which to use simplified training molecules and resulting correlations to explain and predict reaction behavior for more complex substrates. II. Total Synthesis of (+)-Asperazine A and (+)-Pestalazine B The highly convergent total synthesis of dimeric diketopiperazine alkaloids (+)-asperazine A and (+)-pestalazine B is described. A critical aspect of our expedient route was the development of a directed regio- and diastereoselective C3-N 1' coupling of complex tetracyclic diketopiperazine components. This late-stage heterodimerization reaction was made possible by design of tetracyclic diketopiperazines that allow C3-carbocation coupling of the electrophilic component to the Ni' locus of the nucleophilic fragment. The application of this new coupling reaction to the first total synthesis of (+)-asperazine A led to our revision of the sign and magnitude of the optical rotation for the reported structure. III. Concise Total Synthesis of (-)-Lasiodiplines E and F and (+)-Desmethyl Lasiodipline E The concise, biogenetically inspired total synthesis of (-)-lasiodiplines E and F and (+)- desmethyl lasiodipline E was achieved. The unique structural architechture of (-)- lasiodipline F, a previously unknown architecture in diketopiperazine natural products, required an advanced biosynthetic analysis and the acyclic thiolated diketopiperazines provided the opportunity to develop new methods for stereoselective thiolation. The use of a tetracyclic cyclotryptophan core to control sulfidation stereochemistry before revealing the acyclic core proved to be highly efficient and enabling. This total synthesis allowed for the revision of the stereochemistry of the C15 methyl sulfide of (-)-lasiodipline E to the cis stereoisomer.by Brandon M. Nelson.Ph. D. in Organic Chemistr