http://hdl.handle.net/1721.1/7794 http://hdl.handle.net/1721.1/49752 Total synthesis and study of myrmicarin alkaloids Ondrus, Alison Evelynn, 1981- I. Enantioselective Total Synthesis of Tricyclic Myrmicarin Alkaloids An enantioselective gram-scale synthesis of a key dihydroindolizine intermediate for the preparation of myrmicarin alkaloids is described. Key transformations in this convergent approach include a stereospecific palladium-catalyzed N-vinylation of a pyrrole with a vinyl triflate, a copper-catalyzed enantioselective conjugate reduction of a P-pyrrolyl enoate, and a regioselective Friedel-Crafts reaction. The synthesis of optically active and isomerically pure samples of (4aR)-myrmicarins 215A, 215B, and 217 in addition to their respective C4a epimers is presented. II. Palladium Catalyzed Synthesis of N-Vinyl Pyrroles and Indoles A stereospecific palladium catalyzed N-vinylation of azaheterocycles with vinyl triflates is described. Cyclic and acyclic vinyl triflates along with non-nucleophilic azaheterocycles were found to be substrates for this palladium catalyzed synthesis of N-vinyl pyrrole and indole derivatives. III. Dimerization of (+)-Myrmicarin 215B. A Potential Biomimetic Approach to Complex Myrmicarin Alkaloids The acid promoted diastereoselective dimerization of myrmicarin 215B is described. The reactivity of these sensitive alkaloids, structural assignment, and a possible mechanism for the observed dimerization are discussed. These finding raise the intriguing possibility of the synthesis of the highly sensitive myrmicarin alkaloids based on a strategy involving the direct dimerization of functional tricyclic myrmicarin derivatives. IV. (cont.) Efficient and Stereoselective Dimerization of Pyrroloindolizine Derivatives Inspired by a Hypothesis for the Biosynthesis of Complex Myrmicarin Alkaloids Pyrroloindolizine derivatives participate in efficient and stereoselective homo- and heterodimerization reactions upon treatment with Bronsted or Lewis acids. The distinctive ability of pyrroloindolizines to act as azafulvenium ion precursors provides direct access to both heptacyclic and hexacyclic dimeric products. The inherent reactivity of these structures suggests a concise synthesis of complex myrmicarin alkaloids via dimerization of pyrroloindolizines, and may have implications for the biosynthesis of these intriguing alkaloids. V. Reversible Dimerization of (+)-Myrmicarin 215B Bronsted acid-promoted reversible dimerization of myrmicarin 215B leads to formation of a new heptacyclic product, isomyrmicarin 430B, that possesses a C1,C2-trans, C2,C3-trans substituted cyclopentane ring. Mechanistic studies illustrate that isomyrmicarin 430B arises by isomerization of isomyrmicarin 430A via fragmentation to tricyclic azafulvenium ions. Factors influencing the structure of heptacyclic isomyrmicarin products and potential relevance of this reversible vinyl pyrroloindolizine dimerization to the biosynthesis of complex myrmicarins are discussed. Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2009. Vita. Includes bibliographical references. http://hdl.handle.net/1721.1/49751 Nonadiabatic electron transfer in the condensed phase, via semiclassical and Langevin equation approach Song, XiaoGeng, Ph. D. Massachusetts Institute of Technology In this dissertation, we discuss two methods developed during my PhD study to simulate electron transfer systems. The first method, the semi-classical approximation, is derived from the stationary phase approximation to the path integral in the spin-coherent representation. The resulting equation of motion is a classical-like ordinary differential equation subject to a two-ended boundary condition. The boundary value problem is solved using the "near real trajectory" algorithm. This method is applied to three scattering problems to compute the transmission and reflection probabilities. The strength and weakness of this approach is investigated in details. The second approach is based on the generalized Langevin equation, in which the quantum transitions of electronic states are condensed into a linear regression equation. The memory kernel in the regression equation is computed using a second perturbation expansion. The perturbation is optimized to achieve the best convergence of the second order expansion. This procedure results in a tow-hop Langevin equation, the THLE. Results from a spin-boson system validate the THLE in a wide range of parameter regimes. Lastly, we tested the feasibility of using Monte Carlo sampling to compute the memory kernel from the spin-boson system and proposed a smoothing technique to reduce the number of sampling points. Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2009. Includes bibliographical references (leaves 127-137). http://hdl.handle.net/1721.1/49750 Spectroscopic investigation of photo-induced proton-coupled electron transfer and Dexter energy transfer in model systems Young, Elizabeth R. (Elizabeth Renee), 1980- Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2009. Vita. Includes bibliographical references. http://hdl.handle.net/1721.1/49749 Two versatile cofactors, flavin adenine dinucleotide and non-heme iron, involved in DNA repair and natural product halogenation Wong, Cintyu Cofactors assist enzymes with a variety of complex chemistries. Two versatile cofactors, flavin adenine dinucleotide (FAD) and non-heme iron, together with molecular oxygen as an oxidizing agent, perform a wide array of reactions. Hydroxylation in DNA repair is one example. AidB is an adaptive response protein that is up-regulated in the presence of alkylating agents. AidB contains FAD; however, the precise role of the FAD has been determined. AlkB, another adaptive response protein that is up-regulated in the presence of alkylating agents, is a member of the alpha-ketoglutarate (aKG) non-heme iron-dependent superfamily. It uses the cofactor non-heme iron, and the co-substrates molecular oxygen a: G, to remove alkylated adducts on DNA bases via hydroxylation. Two well characterized 1 homologues of AlkB, hABH2 and hABH3, also belong to the XKG/Fe(II)-dependent superfamily, but their substrate preference differ from that of AlkB. Furthermore, FAD and non-heme iron, again with molecular oxygen as an oxidizing agent, can perform halogenation chemistry. Flavin-dependent halogenasess perform halogenation reactions on aromatic substrates, while non-heme iron-dependent halogenases perform halogenations reactions on unactivated aliphatic substrates. I is a flavin-dependent halogenase that catalyzes the chlorination of free tryptophan to form 7-chlorotryptophan in the biosynthesis of rebeccamycin. CytC3 is an cxKG and non-heme iron-dependent halogenase that catalyzes the chlorination of L-2-aminobutyric acid bound to thiolation domain in the biosynthesis of yy-dichloroaminobutyrate. (cont.) Here, we obtained the crystal structures of flavoproten I and non-heme iron-dependent halogenase CytC3. The structural and biochemical v n AidB provides new insights into various possible functions of this still poorly understood protein. The crystal structure of CytC3 suggests two important criteria for creating an enzyme--bound Fe-Cl catalyst. Additionally, we established a new purification scheme for AlkB ts human homologues, which has yielded protein for biochemical studies aimed at ex i ; substrate specificity. Finally, we have also obtained a new crystal form for E. coli AlkB. Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2009. Vita. Includes bibliographical references.