Thesis: Ph. D. in Organic Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2017. / Vita. Scanning issues: Page 114 contains text that has been cropped/deleted from the right-side page margin. Appendix B section contains several graph pages with faint/illegible images. Cataloged from PDF version of thesis. / Includes bibliographical references. / I. Direct Observation of Intermediates Involved in the Interruption of the Bischler- Napieralski Reaction. The first mechanistic investigation of electrophilic amide activation of [alpha], [alpha]-disubstituted tertiary lactams and the direct observation of key intermediates by in situ FTIR, 1H, 13C, and 19F NMR in our interrupted Bischler-Napieralski based synthetic strategy to the aspidosperma alkaloids is described. Importantly, when considering base additives during electrophilic amide activation, more hindered c-quaternary tertiary lactams require the use of non-nucleophilic pyridine additives in order to avoid deactivation via a competing desulfonylation reaction. The isolation and full characterization of a tetracyclic iminium trifluoromethanesulfonate provided additional correlation between in situ characterization of sensitive intermediates and isolable compounds involved in this synthetic transformation. II. Total Synthesis of (+)-Fendleridine, (+)-Acetylaspidoalbidine, and (+)-Limaspermidine. An Tf2O-mediated electrophilic amide activation of a readily available C21-oxygenated lactam, followed by transannular cyclization and in situ trapping of a transiently formed C19-iminium ion, expediently provides access to the hexacyclic C19-hemiaminal ether alkaloids (+)- fendleridine, (+)-acetylaspidoalbidine, and (+)-limaspermidine. A highly effective enzymatic resolution of a non-[beta]-branched primary alcohol (E=22) allowed rapid preparation of both enantiomeric forms of a C21-oxygenated precursor for synthesis of these aspidosperma alkaloids. III. Development of an Ortho-Acetoxylation of Indoline Amides and its Application to the Total Synthesis of (+)-Haplocidine and (+)-Haplocine. The first total syntheses of (+)-haplocidine and its NI-amide congener (+)-haplocine is described. The concise synthesis of these alkaloids required the development of a late-stage and highly selective C-H oxidation of complex aspidosperma alkaloid derivatives. A versatile, amide directed ortho-acetoxylation of indoline amides enabled the implementation of a unified strategy for late-stage diversification of hexacyclic C19-hemiaminal ether structures via oxidation of the corresponding pentacyclic C19-iminium ions. / by Kolby Lyn White. / Ph. D. in Organic Chemistry

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2005. / Vita. / Includes bibliographical references. / Chapter 1: The capability of Mo(N[t-BulAr)₃ to act as a powerful one, two, and three electron reductant have been previously demonstrated. In this work, we show that Mo(NIt-BulAr)₃ forms a metastable adduct with the moderate [pi] acid PhCN; coordination of PhCN activates the nitrile carbon towards reaction with a variety of one-electron reagents such as dichalcogenides, nitric oxide, hydrogen atom donors, cobaltocene, and elemental phosphorus. Evidence is presented for the existence of an inner-sphere electron transfer mechanism for these reactions. Chapter 2: With the facile cleavage of N₂ by Mo(Njt-Bu]Ar)₃ already established, a Mo(NIt-Bu]Ar)₃-mediated process for the incorporation of N₂ into organic molecules is an exciting prospect; its realization depends critically on the development of methods for cleavage of the Mo-N bond formed in the early stages of the process. In this chapter, we demonstrate that appropriately-substituted Mo(IV) ketiminates (synthesized using the methods of Chapter 1) undergo [beta]-elimination to cleave the Mo-N bond and liberate PhCN. We present the kinetics of the reaction, substituent effects, and-in three cases - activation parameters. Chapter 3: Deprotonation of the titanium formate complex (ArIt-BuJN)₃TiOC(O)H with LiN(i-Pr)₂ resulted in the release of free CO and the formation of a titanium(IV) oxoanion complex, isolated as its lithium salt. Chapter 4: Previous work from these labs has shown that the unique combination of well-defined composition, steric bulk, and strong reducing ability embodied in Ti(N[t- Bu]Ar)₃ lends itself particularly well to mechanistic studies of the classical Pinacol coupling. / (cont.) As shown in Chapter 1, a similar relationship can be drawn between Mo(NIt- BulAr)₃ and reductive nitrile coupling. In this chapter we draw on this mechanistic understanding to develop three new classes of reductive cross-couplings: nitrile is coupled with pyridine to form dihydropyridines, with benzophenone to form substituted 1,4-cyclohexadienes, and with carbon dioxide to form a-iminocarboxylates. / by Arjun Mendiratta. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1995. / Includes bibliographical references (leaves 129-136). / by Pamela Michael Jeffrey England. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1987. / Includes bibliographies. / by Susannah Marie Hagadorn. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2007. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Vita. / Includes bibliographical references. / E. coli biotin ligase (BirA) catalyzes the site-specific ligation of biotin to the lysine within its 15-amino acid peptide substrate (AP). We harnessed the high peptide substrate specificity of BirA to develop a general methodology for site-specific protein labeling with biophysical probes. We synthesized an isosteric ketone analog of biotin and discovered that BirA also ligates it to the AP with similar kinetics while retaining the high peptide specificity of the native reaction. Because ketones are absent from native cell surfaces, recombinant AP-fused cell surface proteins can be tagged with the ketone analog, and then specifically conjugated to hydrazide- or hydroxylamine-functionalized molecules. We demonstrated this two-step protein labeling methodology on purified protein, in the context of mammalian cell lysate, and on epidermal growth factor receptor expressed on the surface of live HeLa cells. Both fluorescein and a benzophenone photoaffinity probe were incorporated, with total labeling times as short as 20 minutes. To develop new protein labeling methodology, we synthesized azide analogs of biotin, but found that BirA did not accept them as substrates. Our efforts to rationally design mutations in the active site to accommodate these analogs met with little success. We thus investigated in vitro compartmentalization as a platform for re-engineering the substrate specificity of BirA through in vitro evolution. / (cont.) Selections did not enrich for BirA mutants that could catalyze ligation of the azide analog to the AP, but instead highlighted the technical difficulties of our in vitro compartmentalization strategy. We used phage display to engineer a new and orthogonal biotin ligase-acceptor peptide pair for site-specific protein labeling. Yeast biotin ligase (yBL) does not biotinylate the AP, but we discovered a new 15-amino acid substrate for yBL, which we call the yeast acceptor peptide (yAP). The yAP is not biotinylated by BirA, and thus we were able to specifically label AP and yAP fusion proteins co-expressed in the same cell with differently colored quantum dots. We fused the yAP to a variety of recombinant proteins and demonstrated biotinylation by yBL at the N-terminus, C-terminus, and within a flexible internal region. yBL is also very sequence-specific, as endogenous proteins on the surface of yeast and HeLa cells are not biotinylated. This new methodology expands the scope of biotin ligase labeling to two-color imaging and yeastbased applications. / by Irwin Chen. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2006. / Vita. / Includes bibliographical references (p. 247-254). / The reaction matrix of multichannel quantum defect theory, K, gives a complete picture of the electronic structure and the electron - nuclear dynamics for a molecule. The reaction matrix can be used to examine both bound states and free electron scattering properties of molecular systems, which are characterized by a Rydberg/scattering electron incident on an ionic-core. An ab initio computation of the reaction matrix for fixed molecular geometries is a substantive but important theoretical effort. In this thesis, a generalized quantum defect method is presented for determining the reaction matrix in a form which minimizes its energy dependence. This reaction matrix method is applied to the Rydberg electronic structure of Calcium monofluoride. The spectroscopic quantum defects for the ... states of CaF are computed using an effective one-electron calculation. Good agreement with the experimental values is obtained. The E-symmetry eigenquantum defects obtained from the CaF reaction matrix are found to have an energy dependence characteristic of a resonance. The analysis shows that the main features of the energy-dependent structure in the eigenphases are a consequence of a broad shape resonance in the 2E+ Rydberg series. / (cont.) This short-lived resonance is spread over the entire 2E+ Rydberg series and extends well into the ionization continuum. The effect of the shape resonance is manifested as a global "scarring" of the Rydberg spectrum, which is distinct from the more familiar local level-perturbations. This effect has been unnoticed in previous analyses. The quantum chemical foundation of the quantum defect method is established by a many-electron generalization of the reaction matrix calculation. Test results that validate the many-electron theory are presented for the quantum defects of the lsagnpo, E+ Rydberg series of the hydrogen molecule. It is possible that the reaction matrix calculations on CaF and H2 can pave the way for a novel type of quantum chemistry that aims to calculate the electronic structure over the entire bound-state region, as opposed to the current methods that focus on state by state calculations. / by Serhan Altunata. / Ph.D.

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2009. / Vita. / Includes bibliographical references (leaves 23-24). / A series of monomeric copper complexes that allow for the tuning of the emission properties is reported. Luminescence lifetimes up to 150 [mu]s are observed in benzene solution at ambient temperature, which are comparable to the lifetimes of the longest-lived previously reported copper luminophores. These complexes also exhibit quantum yields up to 0 = 0.70 at 298 K. The results of time-dependent density functional theory (TDDFT) calculations indicate emission from a triplet state in all cases. The calculations also successfully correlate the energy of the transition from this triplet state to the energy of the observed emission. Such luminescence from a first-row metal is highly unusual, especially when considering the phosphine-based ligand framework used. / by Seth F. Mickenberg. / S.M.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1995. / Vita. / Includes bibliographical references. / by Paweł Czubarow. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2005. / Vita. / Includes bibliographical references. / Modular peptide-based fluorescent chemosensors utilizing the chelation-sensitive fluorophore 8-hydroxy-5-(N,N-dimethylsulfonamido)-2-methylquinoline are powerful tools for sensing Zn²⁺ and for sensing protein kinase activity. This signaling component is prepared as the protected amino acid derivative Fmoc-Sox-OH, and integrated into peptide sequences. Selective and tunable chemosensors for Zn²⁺ can afford qualitative and quantitative information about the presence, distribution and concentration of this biologically-important metal ion. Nineteen synthetic peptides incorporating Sox exhibit a range of affinities for Zn²⁺ through variation of the type and number of Zn²⁺ ligands, ligand arrangement and the [beta]-turn sequence that acts as a preorganization element between the ligands. The binding stoichiometry and fluorescence response to pH changes and various relevant competing metal ions was carefully characterized. Eleven of these sequences form only 1:1 complexes with Zn²⁺ and their affinities range from 10 nM to nearly 1 [mu]M. When used in concert, the relative intensities of different chemosensor readouts can provide Zn²⁺ concentration information in a valuable range. This modular scaffold is useful for ratiometric sensing when an additional fluorophore is incorporated in the peptide sequence. New methods to quantify protein kinase activities are critical for understanding biological regulatory pathways. Fluorescent chemosensors of protein kinase activity utilizing Sox and physiological Mg²⁺ concentrations report phosphorylation with dramatic fluorescence changes in a continuous, high-throughput sensing format. / (cont.) The chemosensor comprises a small sensing module, containing Sox and a [beta]-turn sequence, appended to an optimized peptide substrate for the target kinase. The Mg²⁺ -binding affinity of the product phosphopeptide is much greater than the substrate peptide, which results in a large fluorescence increase upon phosphorylation. Notably, the reactivity of substrates is not affected by introduction of the sensing module on either side of the serine, threonine or tyrosine to be phosphorylated. Further, a homogeneous kinase assay utilizing these probes was developed that was reproducible, linear and highly preferential for monitoring changes in cellular activity of the target kinase in unfractionated cell lysates. These kinase chemosensors are powerful tools for studying the activity of recombinant kinases in vitro and endogenous kinases ex vivo. / by Melissa Dawn Shults. / Ph.D.

Thesis: S.M., Massachusetts Institute of Technology, Department of Chemistry, 2016. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 57-59). / In this thesis, possibility of using anionic metal complexes to limit crossover of active species in redox flow batteries was explored. A series of first row transition metal trimetaphosphate complexes as bis(triphenylphosphine)iminium (PPN) salts have been prepared. Their electrochemical properties have been studied to evaluate them for redox flow battery applications. [PPN]₃[Fe(P₃Og)₂] and [PPN]₂[VO(P₃O₉)(acac)] were identified as a suitable couple for a dual-active-species redox flow battery with an open cell potential of 1.5 V. [PPN]₃[V(P₃Og)₂] can be oxidized and reduced within the stability window of acetonitrile and it is therefor a promising candidate for single-active-species redox flow battery applications. The difference in redox potentials between the V(III)/V(IV) and V(II)/V(III) couples is 2.7 V which is the highest peak to peak separation reported in the literature to date. / by Laura Avena. / S.M.