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New Methods for the Synthesis of alpha-Amino Acid Derivatives From N-tert-Butanesulfinyl Imines AND The Synthesis and Application of Novel Amino Acid Based N-tert-Butanesulfinyl Amide Organocatalysts
Full text linkAbstractNew Methods for the Synthesis of alpha-Amino Acid Derivatives From N-tert-Butanesulfinyl IminesANDThe Synthesis and Application of Novel Amino Acid Based N-tert-Butanesulfinyl Amide OrganocatalystsbyMelissa Ann HerbageDoctor of Philosophy in ChemistryUniversity of California, BerkeleyProfessor Jonathan A. Ellman, ChairChapter 1. Methods for the synthesis of alpha-amino acid derivatives prepared from N-tert-butanesulfinyl imines are reviewed.Chapter 2. The rhodium-catalyzed addition of arylboronic acids to N-tert-butanesulfinyl imino esters is described. This chemistry is compatible with a variety of electronically and sterically diverse arylboronic acids providing the N-tert-butanesulfinyl protected alpha-arylglycine products in good yields and high diastereoselectivities. In addition, the utility of this method is demonstrated by subjecting the enantiomerically enriched N-tert-butanesulfinyl protected products to selective synthetic manipulations with little to no racemization. The synthesis of an N-tert-butanesulfinyl isatin imine and its use in the rhodium-catalyzed addition of arylboronic acids reaction is also described. Chapter 3. The copper-catalyzed addition of bis(pinacolato)diboron to N-tert-butanesulfinyl imines is described. This chemistry is amenable to a variety of alkyl and aryl N-tert-butanesulfinyl imines and provides rapid access to use of a number of chiral alpha-amino boronate esters, a biologically relevant scaffold that is difficult to access by other means. The utility of this methodology was demonstrated by the efficient synthesis of bortezomib (Velcade®), the first FDA approved proteasome inhibitor drug. The further functionalization of the alpha-amino boronate products is also described. This includes the homologation of the alpha-amino boronate ester products as well as the conversion of the boronate ester to the potassium trifluoroborate salt. The application of this methodology for the enantioselective synthesis of alpha-amino boronate esters is also addressed. Chapter 4. The synthesis of new N-tert-butanesulfinyl amide organocatalysts and their application to the intermolecular aldol reaction is described. A number of catalysts were prepared in one step from commercially available amino acid precursors and were tested for their activity in the intermolecular aldol reaction. However, preliminary results indicate that the primary amine catalysts are not competitive with other amino acid derived catalysts reported in the literature. Further optimization is necessary to fully evaluate the potential for this new class of catalysts
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Fragment Based Identification of Phosphatase Inhibitors
Full text linkPhosphatases are broadly introduced as an enzyme class with therapeutic implications in a variety of disease areas. A substrate-based fragment approach is used to identify novel phosphatase inhibitors of first Mycobacterium tuberculosis protein tyrosine phosphatase PtpA, for potential therapeutic implications in tuberculosis, then for striatal-enriched protein tyrosine phosphatase (STEP), which has therapeutic implications for Alzheimer's disease. Finally, benzopentathiepins and seleninic acids are investigated as redox-reversible inhibitors of STEP. Aditionally, a method for the asymmetric additions of Knochel-type benzyl zinc reagents to N-tert-butanesulfinyl aldimines is described
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Development and Applications of N-Sulfinyl Organocatalysts
Full text linkThe development of new catalysts for asymmetric organic transformations is a broad and important research goal in modern synthetic organic chemistry. The use of chiral ligands as a source of asymmetric induction in metal-catalyzed reactions has been a traditional focus of this field. One class of chiral ligands is those which incorporate enantiomerically pure sulfinamides. Chapter 1 provides an overview of this area of research. Also included are examples of sulfinamide-based ligands for reactions involving stoichiometric metals, as well as a few examples of sulfinamide-based organocatalysts that have been reported in the literature. The literature reviewed serves as an important foundation for the research described in Chapters 2 and 3. Asymmetric organocatalysis, the use of chiral small molecules as metal-free catalysts, has developed into an area of intense research in the past decade. One mode of substrate activation by organocatalysts is hydrogen bonding. The urea/thiourea scaffold is one of the most effective and well developed types of hydrogen bonding organocatalysts. The acidity (and corresponding strength of the hydrogen bonding interaction) of the hydrogen bond donor is an important consideration for the development of efficient catalysts. Chapter 2 details the development of organocatalysts that incorporate an N-sulfinyl urea as a hydrogen bond donor. In these catalysts, the sulfinyl substituent serves both to acidify the urea N-H bond and to act as a source of asymmetric induction by virtue of the sulfur-based chirality that is presented proximal to the hydrogen bond donor. The application of these catalysts to two different nucleophilic addition reactions is described. Organocatalysts that incorporate a nucleophilic amine have also been developed extensively in recent years. One of the earliest reported examples of this type of catalysis was the use of proline as a catalyst for the enantioselective intermolecular aldol reaction via a nucleophilic enamine intermediate. While the amine may be considered the primary catalytic site, the carboxylic acid has also been implicated in the catalytic cycle, and is proposed to provide a key hydrogen bonding interaction in the enantiodetermining step of the reaction. Chapter 3 describes the development of an N-sulfinyl proline amide as a novel and superior catalyst for the aldol reaction, again demonstrating the utility a sulfinyl N-H as a chiral hydrogen bond donor
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Fragment-Based Identification of Phosphatase Inhibitors
Full text linkAbstractFragment-Based Identification of Phosphatase InhibitorsbyKatherine Anne RawlsDoctor of Philosophy in ChemistryUniversity of California, BerkeleyProfessor Jonathan A. Ellman, ChairChapter 1. A new fragment-based method for the identification of phosphatase inhibitors, Substrate Activity Screening, is described. Application of the method to Mycobacterium tuberculosis protein tyrosine phosphatase PtpB resulted in the identification of novel, nonpeptidic substrate scaffolds that were optimized by rapid analog synthesis and evaluation. These substrate scaffolds were then converted to low molecular weight inhibitors for PtpB by incorporation of a variety of established phosphate mimetics, resulting in nanomolar affinity inhibitors that were highly selective for PtpB over mycobacterial and human phosphatases.Chapter 2. The design and synthesis of new inhibitor analogs based on the scaffold identified in Chapter 1 is described. The synthesis of more challenging inhibitor scaffolds was achieved, resulting in a panel of low molecular weight, nanomolar to micromolar affinity inhibitors for the Mycobacterium tuberculosis protein tyrosine phosphatase PtpB. These compounds represent chemical tools for further dissection of the biochemical role of PtpB in tuberculosis infection.Chapter 3. Application of the method described in Chapter 1 to Mycobacterium tuberculosis protein tyrosine phosphatase PtpA is described. Inhibitors incorporating a well established phosphate mimetic were explored, resulting in compounds with low micromolar affinity for PtpA. Modeling studies provided a rationale for the observed structure-activity relationships and guided further compound optimization. The most potent compound was additionally shown to be selective for PtpA over a variety of human enzymes as well as the other Mycobacterium tuberculosis phosphatase PtpB. This inhibitor represents a chemical tool that can be used in conjunction with the inhibitors described in Chapters 1-2 to further probe the role of PtpA and PtpB in tuberculosis infection, and to examine potential synergistic effects.Chapter 4. The application of inhibitors developed in Chapters 1-3 to the pathogenic target Staphylococcus aureus, the causative agent of Staph infection, is described. Several of the inhibitors described in Chapter 1 were found to have activity versus Staphylococcus aureus bacteria, prompting further probing of structure-activity relationships. The synthesis of new analogs was realized by developing a new synthetic strategy to allow for rapid analog synthesis and evaluation. The cellular target is postulated to be Staphylococcus aureus protein tyrosine phosphatases SaPtpA and SaPtpB, newly discovered enzymes which may play a role in pathogenesis. Compounds were evaluated directly in cell assays, and the mechanism of action of these compounds, which show activity in Staphylococcus aureus strains that are resistant to traditional beta-lactam antibiotics, is under investigation
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Design of Cruzain Inhibitors for the Treatment of Chagas Disease AND Development and Application of Methods for the Asymmetric Synthesis of α-Branched Amines
Full text linkChapter 1. The development of inhibitors of cruzain, the major cysteine protease of the Trypanosoma cruzi parasite that causes Chagas disease, has been demonstrated to be a promising drug discovery avenue for the treatment of this neglected disease. The development of a new class of potent nonpeptidic inhibitors of cruzain is described. Application of the substrate activity screening method to cruzain resulted in the identification of a nonpeptidic substrate. Guided by a molecular replacement model, substrate cleavage efficiency was further improved by introducing additional binding interactions. The optimized substrates were then converted to inhibitors by the introduction of cysteine protease mechanism-based pharmacophores. This led to the development of a new class of nonpeptidic 2,3,5,6-tetrafluorophenoxymethyl ketone inhibitors that exhibit potent inhibitory activity against cruzain. It was also established that this class of compounds completely eradicates the T. cruzi parasite from mammalian cell culture and substantially ameliorates symptoms of acute Chagas disease in a mouse model with no apparent toxicity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the potential to fulfill the urgent need for improved Chagas disease chemotherapy. Chapter 2. A high-resolution crystal structure confirmed the mode of inhibition and revealed key binding interactions of the novel nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor class identified in Chapter 1. Subsequent structure-guided optimization then resulted in inhibitor analogs with improvements in potency despite minimal or no additions in molecular weight. Evaluation of these second-generation tetrafluorophenoxymethyl ketone cruzain inhibitors in cell culture is also described. Chapter 3. The rhodium(I)-catalyzed addition of alkenylboron reagents to imines is described. The diastereoselective addition of alkenyl trifluoroborates and MIDA boronates to both aromatic and aliphatic N-tert-butanesulfinyl aldimines provides α-branched allylic amines in good yields and with very high selectivity. The chemistry is demonstrated to be compatible with a variety of electronically and sterically diverse N-sulfinyl imines and alkenyl boron reagents. This new methodology enables the general and efficient asymmetric synthesis of the important class of α-branched allylic amines from readily available and stable starting materials. Also included is a preliminary investigation into the enantioselective addition of alkenylboron reagents to activated imines. Chapter 4. A one-pot preparation of N-tert-butanesulfinylamine diastereomer mixtures that proceeds in excellent yields for a diverse set of N-sulfinyl imine addition products is described. The method is operationally simple, and extractive isolation provides analytically pure mixtures of diastereomers as standards for stereoselectivity determinations. This method enabled the rapid and accurate determination of diastereomeric purity of the N-sulfinylamines prepared in Chapters 3 and 5. Chapter 5. The concise total synthesis of (–)-aurantioclavine has been achieved by taking advantage of strategies for the asymmetric alkenylation of N-tert-butanesulfinyl imines. The enantiomerically pure natural product was prepared both by using the Rh-catalyzed addition of a MIDA boronate developed in Chapter 3 and by employing a Grignard reagent addition sequence. Exploration of (–)-aurantioclavine's role as an intermediate en route to the complex polyclic alkaloids of the communesin family is also described
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Enantio- and Diastereoselective Additions to Nitroalkenes via N-Sulfinyl Urea Organocatalysis
Full text linkAbstractEnantio- and Diastereoselective Additions to Nitroalkenes via N-Sulfinyl Urea OrganocatalysisbyKyle Lawrence KimmelDoctor of Philosophy in ChemistryUniversity of California, BerkeleyProfessor Robert G. Bergman, Chair Chapter 1. An introduction to my work with sulfinyl ureas as a new class of hydrogen-bonding catalysts is presented. The conception of this type of catalysis is discussed, and highlights in the sulfinyl urea-catalyzed additions of thioacetic acid and Meldrum's acid are presented. Chapter 2. The sulfinyl urea-catalyzed enantioselective addition of thioacetic acid to a broad range of &beta- and cyclic &alpha,&beta-disubstituted nitroalkenes is described. This method is shown to be useful for accessing pharmaceutically relevant 1,2-aminothiol products. Chapter 3. The enantio- and diastereoselective addition of cyclohexyl Meldrum's acid to &beta- and &alpha,&beta-disubstituted nitroalkenes is presented. This method is demonstrated to be a viable route to &gamma-amino acid derivatives with multiple stereocenters. Chapter 4. The conjugate addition-enantioselective protonation of Meldrum's acid with terminal nitroalkenes is described. This process utilizes a sulfinyl urea catalyst that is chiral solely at the sulfinyl group. Rapid conversion of the addition products to pharmaceutically relevant &alpha,&gamma-disubstituted &gamma-lactams is demonstrated
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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