DOCSLIB.ORG

Synthesis of Natural and Non-Natural Polycylic Alkaloids by Adam Thomas Hoye B.A., Grinnell College, 2004 Submitted to the Grad

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Synthesis of Natural and Non-Natural Polycylic Alkaloids by Adam Thomas Hoye B.A., Grinnell College, 2004 Submitted to the Grad Synthesis of Natural and Non-Natural Polycylic Alkaloids by Adam Thomas Hoye B.A., Grinnell College, 2004 Submitted to the Graduate Faculty of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2010 UNIVERSITY OF PITTSBURGH SCHOOL OF ARTS AND SCIENCES This thesis was presented by Adam Thomas Hoye It was defended on August 16th, 2010 and approved by Professor Dennis P. Curran, Department of Chemistry Professor Paul E. Floreancig, Department of Chemistry Professor Billy W. Day, Department of Pharmaceutical Sciences Dissertation Advisor: Professor Peter Wipf, Department of Chemistry ii Copyright © by Adam Thomas Hoye 2010 iii Synthesis of Natural and Non-Natural Polycylic Alkaloids Adam T. Hoye, PhD University of Pittsburgh, 2010 Part one of this dissertation describes the synthesis of novel polycyclic natural product- like compounds from dicyclopropylmethylamine starting materials. Using methodology previously developed in our group, products from the initial one-pot multicomponent reaction via the rearrangement of a bicyclo[1.1.0]butane intermediate were successfully transformed into polycyclic systems. These small, medium and large heterocycles mimic complex alkaloids found in nature, and were further elaborated to incorporate additional functionalities. Part two describes our investigation into the parvistemonine class of Stemona alkaloids. We developed a unified strategy to target several related Stemona natural products. A [3,3]- sigmatropic rearrangement was used to relay key stereochemical information across the characteristic pyrrolo[1,2-a]azepine core of these molecules and install contiguous stereocenters in a controlled fashion. This approach produced advanced intermediates towards the syntheses of parvistemonine and sessilifoliamides B and D, and culminated in the first enantioselective total syntheses of sessilifoliamide C and 8-epi-stemoamide. iv ACKNOWLEDGEMENTS First and foremost I would like to thank Professor Peter Wipf for his mentorship and instruction over the past 6 years. I have had the extreme fortune of being the beneficiary of Peter’s unyielding dedication to organic chemistry and to his students. I thank him for providing me with the physical and, more importantly, intellectual resources needed to conduct research at this level. Professor Wipf’s pursuit of success and excellence in science far surpasses that of anyone I have ever met, and to have those qualities in an advisor demands the best of each student. I thank Peter for continually pushing me to discover my potential. Above all else, I am truly grateful to Professor Wipf for providing me with a superb education in synthetic organic chemistry and for a bright beginning to my career. I express my sincere appreciation to Professors Paul Floreancig, Dennis Curran and Billy Day for their continued mentorship and instruction in both formal and informal settings. I thank them for their constructive suggestions regarding my research and their willingness to share their extensive knowledge with me as part of my thesis committee. I would like to thank the many students and postdocs of the Wipf Group and the University of Pittsburgh Chemistry Department who have made my time in graduate school so memorable. I sincerely appreciate the collegial and friendly atmosphere that was cultivated by the excellent minds I have had the great fortune of meeting, and I am proud to call you my peers and colleagues. v I thanks my parents of their priceless guidance and advice, and my brother and sister for their inspiration and encouragement. Finally, I would like to dedicate this thesis to my wife, Lauren M. Hoye, for without her unwavering support and devotion none of this would have been possible. Thank you. vi TABLE OF CONTENTS 1.0 SYNTHESIS OF NON-NATURAL POLYCYCLIC ALKALOIDS ....................... 1 1.1 INTRODUCTION ............................................................................................... 1 1.1.1 Preparation and Reactions of Alkenylzirconocenes .................................. 1 1.1.2 Synthesis of C-Cyclopropylalkylamines ...................................................... 9 1.1.3 Simmons-Smith Cyclopropanation and Applications ............................. 11 1.1.4 Synthesis of C, C-Dicyclopropylmethylamines ......................................... 15 1.1.5 Synthesis and Applications of Bicyclo[1.1.0]butanes ............................... 17 1.1.6 Synthesis of Azaspirocycles ........................................................................ 20 1.2 RESULTS AND DISCUSSION ........................................................................ 23 1.2.1 Initial Investigations ................................................................................... 23 1.2.2 Revised Approach to Polycyclic Structures .............................................. 27 1.2.3 Improvement of Cyclization Diastereoselectivity .................................... 29 1.2.4 RCM and Completion of the Polycylic Core ............................................ 31 1.2.5 Incorporation of Indole Moiety ................................................................. 35 1.3 CONCLUSION .................................................................................................. 41 2.0 STUDIES ON STEMONA ALKALOIDS: PARVISTEMOLINE, STEMOAMIDE AND SESSILIFOLIAMIDES .................................................................................................... 42 2.1 INTRODUCTION ............................................................................................. 42 vii 2.1.1 Introduction to Stemona Alkaloids ............................................................ 42 2.1.2 Approaches to Stemona Alkaloids ............................................................. 43 2.1.3 Stemona Alkaloid Synthesis in the Wipf Group ....................................... 52 2.1.3.1 Total Synthesis of Stenine .................................................................. 52 2.1.3.2 Total Synthesis of Tuberostemonine ................................................. 56 2.1.3.3 Hypothetical Biosynthetic Relationship of the Tuberosteminone Family .............................................................................................................. 60 2.1.3.4 Hydroindoline Fragmentation Approach to Tuberostemonone .... 62 2.1.3.5 Hydroindoline Fragmentation Approach to Parvistemonine ......... 64 2.2 RESULTS AND DISCUSSION ........................................................................ 67 2.2.1 Retrosynthetic Analysis of Parvistemoline ............................................... 67 2.2.2 Model System Study ................................................................................... 69 2.2.3 Synthesis of the 5,7-Pyrrolo[1,2-a]azepine Core ...................................... 73 2.2.4 Second-Generation Route to the Pyrroloazepine Core ........................... 76 2.2.5 [3,3]-Sigmatropic Rearrangement Strategy ............................................. 82 2.2.6 Eschenmoser-Claisen Rearrangement and Synthesis of epi-Stemoamide . ....................................................................................................................... 84 2.2.7 Sessilifoliamides and Hypothetical Biosynthetic Relationship to Parvistemoline ............................................................................................................ 87 2.2.8 Ireland-Claisen Rearrangement and Application to Sessilifoliamides and Parvistemoline ............................................................................................................ 95 2.2.9 Future Directions ...................................................................................... 105 2.3 CONCLUSION ................................................................................................ 107 viii 3.0 EXPERIMENTAL ................................................................................................... 109 3.1 GENERAL ........................................................................................................ 109 3.2 EXPERIMENTAL PROCEDURES .............................................................. 110 APPENDIX A ............................................................................................................................ 188 APPENDIX B ............................................................................................................................ 213 REFERENCES .......................................................................................................................... 230 ix LIST OF TABLES Table 1-1. Reagent screening for the a. reductive amination and b. cyclodehydration/reduction approaches. .................................................................................................................................... 31 Table 2-1. Conditions screened for the Johnson-Claisen rearrangement in Scheme 3-39. .......... 89 Table 2-2. Screening various orthoesters in the Johnson-Claisen rearrangement of 2-238 shown in Scheme 2-41. ............................................................................................................................ 91 Table 2-3. 1H NMR comparison of synthetic and natural 2-227. ............................................... 103 Table 2-4. 13C NMR comparison of synthetic and natural 2-227. .............................................. 104 x LIST OF FIGURES Figure 1-1. Total syntheses using Zr→Zn aldehyde additions to assemble allylic alcohol intermediates. .................................................................................................................................
Load more

Recommended publications
  • Download Answer
    Question #72514, Chemistry / Organic Chemistry Explain the electrocyclic and sigmatropic reaction in detail. Answer: In organic chemistry, an electrocyclic reaction is a type of pericyclic rearrangement where the net result is one pi bond being converted into one sigma bond or vice versa. The Diels-Alder reaction is a common example. The especially interesting thing about this reaction is its stereochemistry. When performing an electrocyclic reaction, it is often desirable to predict the cis/trans geometry of the reaction's product. The first step in this process is to determine whether a reaction proceeds through conrotation or disrotation. Reactions can be either photochemical or thermal and their mexanisms are different. Mechanism of thermal reactions: Correlation diagrams, which connect the molecular orbitals of the reactant to those of the product having the same symmetry, can then be constructed for the two processes. Mechanism of photochemical reactions: If the ring opening of 3,4-dimethylcyclobutene were carried out under photochemical conditions the resulting electrocyclization would be occur via a disrotatory mode instead of a conrotatory mode as can be seen by the correlation diagram for the allowed excited state ring opening reaction. A sigmatropic reaction in organic chemistry is a pericyclic reaction wherein the net result is one σ-bond is changed to another σ-bond in an uncatalyzed intramolecular process. The most well-known of the sigmatropic rearrangements are the [3,3] Cope rearrangement, Claisen rearrangement, Carroll rearrangement [3,3] sigmatropic shifts are well studied sigmatropic rearrangements. The Woodward– Hoffman rules predict that these six electron reactions would proceed suprafacially, via a Huckel topology transition state.
    [Show full text]
  • At the University of Edinburgh
    This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Functionalisable Cyclopolymers by Ring-Closing Metathesis Mohammed Alkattan BSc, MSc Drug Chemistry A thesis submitted at the University of Edinburgh and the University of Glasgow for the Degree of Doctor of Philosophy 2019 Abstract Post‐polymerisation modification of polymers is extremely beneficial in terms of designing brand new synthetic pathways toward functional complex polymers. While many chemical groups could provide a platform for chemical functionalisation, arguably one of the most versatile groups is the olefin functionality. This could be significant as the olefins do not readily interfere with common polymerisation techniques such as ring-opening polymerisation (ROP) but can be transformed into a broad range of functional groups. Ring-Closing Metathesis (RCM) is a powerful method for the preparation of cyclic compounds by the formation of new carbon- carbon double bonds.
    [Show full text]
  • R. B. Woodward Precipitation of Barium in the Copper-Tin Group Of
    HETEROCYCLES, Vol. 7, No. 1. 1977 R. B. Woodward Precipitation of barium in the copper-tin group of qualitative analysis. W.J.Hal1 and RBW, -Ind. Eng. Chem., Anal. Ed., 6, 478 (1934). A new pressure regulator for vacuum distillation. R.L.Emerson and RBW, g.,2, 347 (1937). The Staling of coffee. II. S.C.Prescott, R.L.Emerson, RBW, and R. Heggie, Food Re- --search, 2, 165 (1937). Pyrolysis of organomagnesium compounds. I. A new agent for the reduction of bemophenone. D.B.Clapp, and RBW, 1. ---Am. Chem. Soc., -60, 1019 (1938). The direct introduction of the angular methyl group. RBW, Ibid., 62, 1208 (1940). Experiments on the synthesis of oestrone. I. 2-(8-phenylethy1)-furans as components in the diene synthesis. RBW, Ibid., 62, 1478 (1940). The formation of Reissert's compounds in non-aqueous media. RBW, Ibid., 62, 1626 (1940). A new optically active reagent for carbonyl compounds. The resolution of -dl-camphor. RBW, T. P. Kohman, and G. C. Harris, Ibid., 63, lu) (1941). The isolation and properties of 1, 1-dineopentylethylene, a component of triisobutylene. P.D.Bartlett, G.L. Fraser, and RBW, x.,3, 495 (1941). Structure and absorption spectra of a,p-unsaturated ketones. RBW, Ibid., 3, 1123 (1941). 5 Structure and absorption spectra. II. 3-Acetoxy-A -(6)-~cholestene-7-carboxylicacid. RBW, and A.F.Clifiord, -Ibid., -63, 2727 (1941). The structure of cantharidine and the synthesis of desoxycantharidine. RLW, and R.B. Loftfield, Ibid., 3, 3167 (1941). -t-Butyllithium. P.D.Bardett, C .G.Swain, and RBW, --Ibid., 63, 3229 (1941).
    [Show full text]
  • Robert Burns Woodward 1917–1979
    NATIONAL ACADEMY OF SCIENCES ROBERT BURNS WOODWARD 1917–1979 A Biographical Memoir by ELKAN BLOUT Any opinions expressed in this memoir are those of the author and do not necessarily reflect the views of the National Academy of Sciences. Biographical Memoirs, VOLUME 80 PUBLISHED 2001 BY THE NATIONAL ACADEMY PRESS WASHINGTON, D.C. ROBERT BURNS WOODWARD April 10, 1917–July 8, 1979 BY ELKAN BLOUT OBERT BURNS WOODWARD was the preeminent organic chemist Rof the twentieth century. This opinion is shared by his colleagues, students, and by other distinguished chemists. Bob Woodward was born in Boston, Massachusetts, and was an only child. His father died when Bob was less than two years old, and his mother had to work hard to support her son. His early education was in the Quincy, Massachusetts, public schools. During this period he was allowed to skip three years, thus enabling him to finish grammar and high schools in nine years. In 1933 at the age of 16, Bob Woodward enrolled in the Massachusetts Institute of Technology to study chemistry, although he also had interests at that time in mathematics, literature, and architecture. His unusual talents were soon apparent to the MIT faculty, and his needs for individual study and intensive effort were met and encouraged. Bob did not disappoint his MIT teachers. He received his B.S. degree in 1936 and completed his doctorate in the spring of 1937, at which time he was only 20 years of age. Immediately following his graduation Bob taught summer school at the University of Illinois, but then returned to Harvard’s Department of Chemistry to start a productive period with an assistantship under Professor E.
    [Show full text]
  • UC Berkeley UC Berkeley Electronic Theses and Dissertations
    UC Berkeley UC Berkeley Electronic Theses and Dissertations Title Synthetic Strategies toward Aconitine-type and Hetisine-type Diterpenoid Alkaloids Permalink https://escholarship.org/uc/item/2ws9p3b7 Author Pflueger, Jason Jon Publication Date 2016 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California Synthetic Strategies toward Aconitine-type and Hetisine-type Diterpenoid Alkaloids By Jason Jon Pflueger A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Chemistry in the Graduate Division of the University of California, Berkeley Committee in Charge: Professor Richmond Sarpong, Chair Professor Thomas Maimone Professor Leonard Bjeldanes Fall 2016 Abstract Synthetic Strategies toward Aconitine-type and Hetisine-type Diterpenoid Alkaloids by Jason Jon Pflueger Doctor of Philosophy in Chemistry University of California, Berkeley Professor Richmond Sarpong, Chair Diterpenoid alkaloid natural products, isolated from plants in the Aconitum, Delphinium, Consolida, and Spiraea genera, possess complex, caged, highly oxygenated skeletons and display potent biological activities through interactions with voltage-gated ion channels. Several of these alkaloids are currently used clinically for the treatment of arrhythmia, while others act as incredibly potent neurotoxins. Until recently, there were very few successful total syntheses of any diterpenoid alkaloid natural products, a testament to the structural complexity of these
    [Show full text]
  • Literature Seminar#1
    Literature Seminar (B4 part) January 17, 2012 Seiko KITAHARA (B4) Total synthesis of Laulimalide OH H O O 15 23 20 17 O O OH 1 H H O 3 5 9 1: Laulimalide (fijianolide B) Contents 1. Introduction 2. Previous Total Synthesis 2-1. Retrosynthetic Analysis 3. Trost's Total Synthesis -toward the atom economy- 3-1. What is "synthetic efficiency" ?? 3-2. Retrosynthetic Analysis 3-3. Total Synthesis Marine Sponge, 3-4. Asymmetric Direct Aldol Reaction Cacospongia mycofijiensis via a Dinuclear Zn Catalyst 3-5. Rh-Catalyzed Cycloisomerization 3-6. Ru-Catalyzed Alkene-Alkyne Coupling Barry M. Trost 1. Introduction OH OH H O H O 15 O OH 20 O 23 17 17 15 20 O O OH 1 H H On exposure to acid O O O 5 9 3 (within two hours) H H O 1: Laulimalide : intrinsically unstable isolaulimalide (fijianolide B) (fijianolide A) <Isolation> -From various marine sponges such as hyattela sp., Cacospongia mycofijiensis, f asciospongia rimosa a marine sponge in the genus Dactylospongia a nudibranch, Chromodoris lochi with its tetrahydrofuran containing isomer isolaulimalide <Structure> -Determined NMR analysis and X-ray crystallographic analysis Corley, D. G et al. J. Org. Chem. 1988, 53, 3644. Quinoa, E et al. J. Org. Chem. 1988, 53, 3642. -20-membered macrolide <Biological activity> -like Taxol (paclitaxel), induces microtubule polymerization and stabilization -unlike Taxol (paclitaxel), retains activity in multidrug resistant cell lines -binds to a different site than other known microtubule stabilzers suggesting new opportunities forchemotherapy ?? <Total synthesis> -Hot topic for over a decade (more than 10 reports !) due to its significant clinical potential its strict natural supply unique and complex molecular architecture Ghosh, A.
    [Show full text]
  • Information to Users
    INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. University Microfilms International A Bell & Howell Information C om pany 300 North Z eeb Road. Ann Arbor. Ml 48106-1346 USA 313/761-4700 800 521-0600 Order Number 9120692 Part 1. Synthesis of fiuorinated catecholamine derivatives as potential adrenergic stimulants and thromboxane A 2 antagonists. Part 2.
    [Show full text]
  • I the Tandem Chain Extension-Acylation Reaction II Synthesis of Papyracillic Acid A
    University of New Hampshire University of New Hampshire Scholars' Repository Doctoral Dissertations Student Scholarship Fall 2013 I The tandem chain extension-acylation reaction II Synthesis of papyracillic acid A: Application of the tandem homologation- acylation reaction III Synthesis of tetrahydrofuran-based peptidomimetics Carley Meredith Spencer Follow this and additional works at: https://scholars.unh.edu/dissertation Recommended Citation Spencer, Carley Meredith, "I The tandem chain extension-acylation reaction II Synthesis of papyracillic acid A: Application of the tandem homologation-acylation reaction III Synthesis of tetrahydrofuran-based peptidomimetics" (2013). Doctoral Dissertations. 749. https://scholars.unh.edu/dissertation/749 This Dissertation is brought to you for free and open access by the Student Scholarship at University of New Hampshire Scholars' Repository. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of University of New Hampshire Scholars' Repository. For more information, please contact [email protected]. I. THE TANDEM CHAIN EXTEN SION - AC YL ATION REACTION II. SYNTHESIS OF PAPYRACILLIC ACID A: APPLICATION OF THE TANDEM HOMOLOGATION-ACYLATION REACTION III. SYNTHESIS OF TETRAHYDROFURAN-BASED PEPTIDOMIMETICS BY Carley Meredith Spencer B.A., Connecticut College, 2008 DISSERTATION Submitted to the University of New Hampshire in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Chemistry September 2013 UMI Number: 3575989 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion.
    [Show full text]
  • Synthesis of Aza-Heterocyclic Monoamidines As Potential DNA Minor Groove Binders, Anti-Trypanosomals, and Boron Neutron Capture Therapy Agents
    Georgia State University ScholarWorks @ Georgia State University Chemistry Dissertations Department of Chemistry Fall 12-17-2014 Synthesis of Aza-Heterocyclic Monoamidines as Potential DNA Minor Groove Binders, Anti-Trypanosomals, and Boron Neutron Capture Therapy Agents Julius Green Follow this and additional works at: https://scholarworks.gsu.edu/chemistry_diss Recommended Citation Green, Julius, "Synthesis of Aza-Heterocyclic Monoamidines as Potential DNA Minor Groove Binders, Anti- Trypanosomals, and Boron Neutron Capture Therapy Agents." Dissertation, Georgia State University, 2014. https://scholarworks.gsu.edu/chemistry_diss/101 This Dissertation is brought to you for free and open access by the Department of Chemistry at ScholarWorks @ Georgia State University. It has been accepted for inclusion in Chemistry Dissertations by an authorized administrator of ScholarWorks @ Georgia State University. For more information, please contact [email protected]. SYNTHESIS OF AZA-HETEROCYCLIC MONOAMIDINES AS POTENTIAL DNA MINOR GROOVE BINDERS, ANTI-TRYPANOSOMALS, AND BORON NEUTRON CAPTURE THERAPY AGENTS by JULIUS GREEN I Under the Direction of David W. Boykin ABSTRACT A series of combilexin-like monoamidines has been synthesized by linking an intercala- tive unit with the DNA minor groove binder DB 818 via “Click chemistry.” DB 818 is a dicationic minor groove binder that has shown strong binding affinity to AT sequences. The aim was to synthesize novel classes of DNA minor groove binders that are combilexin-like – minor groove binder / intercalator hybrid – as potential unique DNA binding agents and therapeutics against African Sleeping Sickness. Additionally, a series of novel benzo[d]1,3,2-diazaboroles DAPI derivatives were also synthesized and investigated. These boron compounds have the po- tential to be strong DNA minor groove binders because of their lower pK a and act as potential chromophores for Boron Neutron Capture Therapy.
    [Show full text]
  • Pericyclic Reactions Notes
    - 1 - PERICYCLIC REACTIONS NOTES Pericyclic reactions cannot be treated adequately by “curly-arrow” formalisms and a knowledge of molecular orbital theory is crucial to their understanding. They are reactions in which “all first order changes in bonding relationships takes place in concert on a closed curve” (Woodward & Hoffmann). More simply, the term “pericyclic” covers all concerted reactions involving a cyclic flow of electrons through a single transition state. Pericyclic reactions can be predicted and controlled to a great degree, which makes them very useful in synthesis. There are broadly four classes of pericyclic reaction: Sigmatropic – These are unimolecular isomerisations, and involve the movement of a σ-bond from one position to another. An illustration would be the first step of the Claisen Rearrangement: Note the nomenclature of this reaction, being described as a [i,j] shift. For example, this following is a [1,7] shift: Electrocyclic – These are unimolecular. They are characterised by ring opening or closing with a σ- bond forming at one end. Ring closing is more common, since this is formation of a σ-bond at the expense of a π-bond, but ring strain can lead to opening. Two examples are: Cycloaddition – This is the largest class of pericyclic reaction. It is characterised by two fragments coming together to form two new σ-bonds in a ring. Some examples are Diels-Alder and Ozonolysis reactions, which are described below. Chelotropic reactions are a specific type of cycloaddition, where the two bonds are made or broken at the same atom. The classic example of this is carbene addition to a double bond.
    [Show full text]
  • Arynes in Synthesis; New Reaction and Precursor Development
    ARYNES IN SYNTHESIS; NEW REACTION AND PRECURSOR DEVELOPMENT A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Engineering and Physical Sciences 2014 By Donald McAusland School of Chemistry 2 Contents Abstract 11 Declaration 12 Copyright 13 Acknowledgements 14 1 Introduction 15 1.1 Generationofbenzyne ............................ 17 1.2 Reactionsofbenzyne............................. 19 1.2.1 Pericyclicreactions. 19 1.2.2 Nucleophilicadditiontoarynes . 21 1.2.3 Transition-metal-catalysed reactions . 26 1.3 Selectivitywithsubstitutedarynes . ..... 28 1.4 (Trimethylsilyl)phenyl triflates and related aryne precursors . 32 1.4.1 ortho-Lithiation ........................... 33 1.4.2 [4+2]Cycloaddition . 34 1.4.3 Oxidative para-triflation of acetanilides . 34 1.4.4 Commerciallyavailableprecursors . 35 1.4.5 Precursors for the synthesis of polyaromatic structures...... 35 1.4.6 Other functionalised Kobayashi precursors . ..... 37 1.4.7 Relatedaryneprecursors. 39 1.5 Arynesinsynthesis.............................. 41 1.5.1 Indolesyntheses ........................... 42 2 The Benzyne Fischer Indole Reaction 46 2.1 Introduction.................................. 46 2.1.1 Buchwaldmodification. 47 Contents 3 2.1.2 The arylation of hydrazones with benzyne . 52 2.2 Application of aryne electrophiles to the Fischer indole synthesis . 52 2.2.1 Aryne reactions of other hydrazones . 55 2.2.2 BenzyneFischerindolescope . 58 2.2.3 Substitutedarynes . 60 2.2.4 Miscellaneoustosylhydrazones. 66 2.3 Conclusions .................................. 67 3 Synthesis and Applications of New Aryne Precursors 68 3.1 Introduction.................................. 68 3.1.1 Palladium cross-coupling chemistry . 68 3.1.2 TheSuzukireaction ......................... 69 3.1.3 Organoboronreagents . 71 3.1.4 Chemoselectivity in Suzuki couplings . 74 3.2 Aims.....................................
    [Show full text]
  • Use of Isotopes for Studying Reaction Mechanisms 1
    SERIES I ARTICLE Use of Isotopes for Studying Reaction Mechanisms 1. Isotopes as Markers Uday Maitra and J Chandrasekhar Isotopes can be used as markers to keep track of positions of atoms during a chemical transformation. This strategy Uday Maitra and of determining reaction mechanisms is illustrated in the J Chandrasekhar are members of the Organic article with several examples. Chemistry faculty in Indian Institute of Introduction Science at Bangalore. When a reaction is carried out, the primary effort goes towards the identification of the product(s) of the reaction. A more time consuming endeavour, however, is the elucidation of the reaction mechanism. The study of reaction mechanisms is intellectually challenging, and at the same time provides opportunities to excercise greater control over the reaction. For example, a detailed knowledge of the intermediate formed in a reaction would help us optimize reaction conditions to effect higher yields, minimize reaction times, etc. The transformation of a reactant A to product B can in principle take place via a number of pathways. To find experimental evidence for one of these pathways detailed physical studies are needed. The techniques normally used for studying reaction mechanisms include kinetic analysis, trapping of a reactive intermediate, etc. One of the most powerful techniques is the use of isotopes as labels in a reaction. An atom in the reactant is selectively replaced by one of its isotopes. The reaction is carried out as usual, and the location (and/or distribution) of the isotopic label in the product(s) is determined (see Box 1). The probable mechanism can then be inferred.
    [Show full text]