DOCSLIB.ORG

PDF (Thesis Document)

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
PDF (Thesis Document) A Multidisciplinary Investigation into the Design, Synthesis and Evaluation of a Novel Class of Anti-Glioblastoma Drug Fragments Christopher Sherer A thesis submitted in partial fulfilment for the requirements for the degree of Doctor of Philosophy at the University of Central Lancashire January 2017 STUDENT DECLARATION FORM Concurrent registration for two or more academic awards Either *I declare that while registered as a candidate for the research degree, I have not been a registered candidate or enrolled student for another award of the University or other academic or professional institution Or *I declare that while registered for the research degree, I was with the University’s specific permission, a *registered candidate/*enrolled student for the following award: _____________________________________________________________________________ Material submitted for another award Either *I declare that no material contained in the thesis has been used in any other submission for an academic award and is solely my own work Or *I declare that the following material contained in the thesis formed part of a submission for the award of _____________________________________________________________________________ * delete as appropriate Collaboration Where a candidate’s research programme is part of a collaborative project, the thesis must indicate in addition clearly the candidate’s individual contribution and the extent of the collaboration. Please state below: Signature of Candidate _________________________________________________________ Type of Award Doctor of Philosophy School School of Pharmacy and Biomedical Sciences 2 ABSTRACT Cancer is the second biggest global killer,[1,2] with cancers of the brain and central nervous system accounting for a disproportionately high number of deaths.[3] The most prolific cancer of the central nervous system is glioblastoma, for which prognosis is still very poor. In this project, analogues of two lead compounds with known activity against glioblastoma cell lines (compounds 4 and 5, Figure 1) were produced in order to develop structure-activity relationships and discover compounds with superior activities against glioblastoma. H HO OH N N H 4 H 5 4 5 Figure 1 - The structures of the lead compounds 4 and 5 Analogues of compound 4 were the result of a rigorous similarity search of the ZINC database,[4,5] as well as using chemical intuition to identify potential analogues. A scaffold-hopping approach was undertaken, through which two new compound classes were identified as potentially superior lead compounds for future work (Figure 2). OH HO N N H 168 214 Figure 2 - The structures of two analogues of compound 4 with different scaffolds and superior activity, compounds 168 and 214 Compound 4 is known to induce cell death through the induction of elevated levels of cellular reactive oxygen species (ROS),[6] which may be formed via the radical form of compound 4 and its analogues. The connection between the anticancer activity of 4 and its analogues with the propensity of these compounds to form radicals was also investigated. Enthalpic values relevant to radical formation (BDE, AIP, PDE, PA and ETE) were calculated using a density functional theory (DFT) approach. Although no strong correlation was found for the whole series of compounds, the data indicates that correlations may exist within certain structural classes. The anticancer activity of compound 5, a prodrug, was compared against 11 analogues of both the prodrug and active form of the compound (Scheme 1). It was found that compound 9 has superior activity to that of the prodrug 5. Substitutions at the N-position of 5 were also found 3 to have a significant effect on activity, with an N-tosyl analogue having significantly improved activity against glioblastoma cell lines and short term cultures. The results obtained suggest that future work on this series should therefore be based around compound 9, a subclass of indoles that have wide ranging anticancer activity, but have not yet been reported against glioblastoma. H N OH H N H 5 N H 9 Scheme 1 - The degradation of 5 into its suspected active form (9) In conclusion, analogues were discovered within this project which improved upon the anticancer activity of both compounds 4 and 5. For compound 4, two alternative scaffolds were identified as superior and novel lead compounds against glioblastoma, and there is some indication that there may be a correlation between radical formation and anticancer activity within specific structural classes of this functional class of compounds. For prodrug 5, substituents at the N-positon were found to have a significant effect on activity, and the activity of the active form (9) was found to be superior to the activity of the prodrug. 4 CONTENTS STUDENT DECLARATION FORM .................................................................................................... 2 ABSTRACT ...................................................................................................................................... 3 CONTENTS ..................................................................................................................................... 5 LISTS OF ILLUSTRATIVE MATERIALS ............................................................................................ 12 List of figures ........................................................................................................................... 12 List of schemes ........................................................................................................................ 18 List of tables ............................................................................................................................ 22 List of equations ...................................................................................................................... 24 List of graphs ........................................................................................................................... 26 ACKNOWLEDGEMENTS ............................................................................................................... 27 ABBREVIATIONS, ACRONYMS AND INITIALISMS......................................................................... 28 CHAPTER 1 – INTRODUCTION ..................................................................................................... 33 1.1 Cancer ......................................................................................................................... 34 1.1.1 Glioblastoma ....................................................................................................... 35 1.1.2 The Blood-Brain Barrier ...................................................................................... 37 1.1.3 Chemoresistance ................................................................................................. 38 1.2 Reactive Oxygen Species ............................................................................................. 39 1.2.1 Using ROS to kill cancer cells ............................................................................... 40 1.2.2 Antioxidants ........................................................................................................ 41 1.3 The Lead Compounds .................................................................................................. 43 1.3.1 The Lead Compound 5 ........................................................................................ 44 5 1.3.2 The Lead Compound 4 ........................................................................................ 48 1.4 Project Structure ......................................................................................................... 50 CHAPTER 2 – PROJECT BACKGROUND ........................................................................................ 51 2.1 The Indole Privileged Structure................................................................................... 52 2.2 Indole Syntheses ......................................................................................................... 53 2.2.1 The Fischer Indole Synthesis ............................................................................... 54 2.2.2 Synthesis of Indoles From 2-Alkynyl Anilines ...................................................... 56 2.2.3 Larock Indole Synthesis ....................................................................................... 60 2.2.4 Reductive Cyclisations ......................................................................................... 61 2.2.5 The Bartoli Indole Synthesis ................................................................................ 65 2.2.6 Summary of Indole Syntheses ............................................................................. 66 2.3 Developing Analogues................................................................................................. 68 2.3.1 Chemical Space ................................................................................................... 69 CHAPTER 3 – INTRODUCTION TO QUANTUM CHEMICAL METHODS FOR ENERGETIC CALCULATIONS OF MOLECULAR SPECIES ................................................................................... 78 3.1 Introduction ................................................................................................................ 79 3.2 The Schrödinger Equation ........................................................................................... 79 3.3 The Born-Oppenheimer
Load more

Recommended publications
  • Indoles Indoles Are Very Commonly Encountered in Nature and Many
    Indoles Indoles are very commonly encountered in nature and many, many individual examples which have biological implcations. Below is a very small selection of examples. CO2H H HO MeO MeO CO H NH2 NH2 NHAc 2 N N N H H H N tryptophan seratonin melatonin (Essential amino acid) (neurotransmitter) (diurnal rhythym) O OH Cl indomethacin Et O N (rheumatoid arthritic) MeHN S N O NMe2 N vincristine H Et N MeO2C H (leukemia treatment) H H sumatriptin OAc MeO N (migraines) CO2Me CHO OH Although these compounds are simply benzo- fused pyrroles, they have their own set of ring synthesis reactions that are disctinct from pyrrole syntheses. A. Fischer Indole Synthesis Reviews: Gribble, G. W. J. Chem. Soc., Perkin trans 1 2000 , 1045; Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006 , 106 , 2875. The Fischer Indole Synthesis is the reaction of a hydrazine derivative of a ketone or aldehyde formed from an aryl hydrazine. It is a multistep process involving a sigmatropic rearrangement, much like the Cope or Claisen rearrangement. It can occur purely thermally, but is normally done at much lower temperature in the presence of a protic acid or Lewis acid. Polyphosphoric acid, 100 oC are often used conditions. 2 R2 R -H O acid or + R1 2 N R1 Lewis acid NH R1 2 N ∆ N H ∆∆ N H O R2 H Here is the mechanism: 2 R R2 2 2 R [3,3]- R R1 -H+ R1 H+ R1 sigmatropic R1 rearr. N+ + N H N N NH N H N H N + 2 H H H H -H+ H +H+ 2 2 R2 R R2 -H+ R 1 H +H+ R R1 R1 R1 + + + NH NH2 .
    [Show full text]
  • Synthesis and Chemistry of Indole
    Synthesis and Chemistry of Indole 1. Introduction: ➢ Indole is a benzo[b]pyrrole formed by the fusion of benzene ring to the 2,3 positions of pyrrole nucleus. ➢ The word “Indole” is derived from the word India, as the heterocycle was first isolated from a blue dye “Indigo” produced in India during sixteenth century. ➢ In 1886, Adolf Baeyer isolated Indole by the pyrolysis of oxindole with Zn dust. Oxindole was originally obtained by the reduction of isatin, which in turn was isolated by the oxidation of Indigo. ➢ Commercially indole is produced from coal tar ➢ Indole is the most widely distributed heterocyle ➢ Indole nucleus is an integral part of thousands of naturally occurring alkaloids, drugs and other compounds. By Dr. Divya Kushwaha 2. Synthesis of Indole 2.1. Fischer Indole Synthesis: ➢ This reaction was discovered in 1983 by Emil Fischer and so far remained the most extensively used method of preparation of indoles. ➢ The synthesis involves cyclization of arylhydrazones under heating conditions in presence of protic acid or lewis acids such as ZnCl2, PCl3, FeCl3, TsOH, HCl, H2SO4, PPA etc. ➢ The starting material arylhydrazoles can be obtained from aldehydes, ketones, keto acids, keto esters and diketones etc. ➢ Reaction produces 2,3-disubtituted products. Unsymmetrical ketones can give a mixture of indoles. 2.2 Madelung Synthesis: ➢ Base catalyzed cyclization of 2-(acylamino)-toluenes under very harsh conditions (typically sodium amide or potassium t-butoxide at 250-300oC). ➢ Limited to the synthesis of simple indoles such as 2-methyl indoles without having any sensitive groups. By Dr. Divya Kushwaha Mechanism: ➢ A modern variant of madelung reaction is performed under milder conditions by the use of alkyllithiums as bases.
    [Show full text]
  • The Synthesis of Tryptophan Derivatives, 2
    Graduate Theses, Dissertations, and Problem Reports 2009 The synthesis of tryptophan derivatives, 2- and/or 3-substituted indoles, progress toward dilemmaones A-C, and synthetic studies towards fistulosin via palladium-catalyzed reductive N- heteroannulation Christopher Andrew Dacko West Virginia University Follow this and additional works at: https://researchrepository.wvu.edu/etd Recommended Citation Dacko, Christopher Andrew, "The synthesis of tryptophan derivatives, 2- and/or 3-substituted indoles, progress toward dilemmaones A-C, and synthetic studies towards fistulosin via palladium-catalyzed reductive N-heteroannulation" (2009). Graduate Theses, Dissertations, and Problem Reports. 4454. https://researchrepository.wvu.edu/etd/4454 This Dissertation is protected by copyright and/or related rights. It has been brought to you by the The Research Repository @ WVU with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you must obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in WVU Graduate Theses, Dissertations, and Problem Reports collection by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. The Synthesis of Tryptophan Derivatives, 2- and/or 3- Substituted Indoles, Progress Toward Dilemmaones A-C, and Synthetic Studies Towards Fistulosin via Palladium-Catalyzed Reductive N-Heteroannulation Christopher Andrew Dacko Dissertation submitted to the Eberly College of Arts and Sciences at West Virginia University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry Björn C.
    [Show full text]
  • Indole & Pyrrole Synthesis: Cliffsnotes (Richter, 2004)
    9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting Disclaimer: Indole: This lecture will only cover methodology for the construction of the indole and pyrrole ring systems, rather than functionalionalization of pre-existing heterocycles, Nature: which would be the topic of another series of lectures. – The most abundant heterocycle in nature – Found in tryptophan, indole-3-acetic acid (plant growth hormone), Partial List of Transforms Discussed: serotonin (neurotransmitter), natural products, drugs – Isolated industrially from coal tar 1. Batcho-Leimgruber Indole Synthesis – Biosynthesis of tryptophan 2. Reissert Indole Synthesis CO H 3. Hegedus Indole Synthesis 15 2 3 serine 4. Fukuyama Indole Synthesis glucose Steps NH Steps N 5. Sugasawa Indole Synthesis 2 H 6. Bischler Indole Synthesis anthranilate 7. Gassman Indole Synthesis tryptophan 8. Fischer Indole Synthesis 9. Japp-Klingemann Indole Synthesis Reactivity: 10. Buchwald Indole Synthesis C–4 C–3 11. Bucherer Carbazole Synthesis C–5 C–2 12. Japp-Maitland Carbazole Synthesis C–6 N 13. Larock Indole Synthesis C–7 H 14. Bartoli Indole Synthesis 15. Castro Indole Synthesis – Isoelectronic with naphthalene (slightly lower stabilization energy) 16. Hemetsberger Indole Synthesis – Indole has a higher stabilization energy than benzene 17. Mori-Ban Indole Synthesis – Very weakly basic: pKa of protonated indole: –2.4 18. Graebe-Ullmann Carbazole Synthesis – Protonation occurs at C–3 preferentially 19. Madelung Indole Synthesis – Easily oxidized (atmospheric oxygen) – very electron rich 20. Nenitzescu Indole Synthesis – Less prone to oxidation of EWG's on the ring – less electron rich 21. Piloty Pyrrole Synthesis – Electrophilic attack occurs at C–3 (site of most electron density) 13 22.
    [Show full text]
  • Studies Toward the Total Synthesis of (+)-Pyrenolide D Honors Research
    Studies toward the Total Synthesis of (+)-Pyrenolide D Honors Research Thesis Presented in partial fulfillment of the requirements for graduation with honors research distinction in Chemistry in the undergraduate colleges of The Ohio State University by Adam Doane The Ohio State University 24 May 2012 Project Advisor: Dr. Christopher Callam, Department of Chemistry i Abstract Spiro lactones have had an extensive impact in both medicinal and organismal biology. Since their discovery, various methods for preparing spiro lactones have been studied and investigated. One of these spiro lactones, pyrenolide D, which is one of the four metabolites, A- D, was isolated from Pyrenophora teres by Nukina and Hirota in 1992 and shows cytotoxicity towards HL-60 cells at IC50 4 µg/ mL. The structural determination, via spectroscopic methods, reported that unlike pyrenolides A-C, pyrenolide D contained a rare, highly oxygenated tricyclic spiro-γ-lactone structure and did not contain the macrocyclic lactone seen in the other pyrenolides. The purpose of this project is the determination of a cost effective and efficient synthesis of pyrenolide D from the naturally occurring sugar, D-xylose. Herein we report studies towards the total synthesis of pyrenolide D. i Acknowledgments I would like to thank my research advisor, Dr. Christopher Callam for his constant help, encouragement, and inspiration throughout the past 3 years. He has sacrificed an immeasurable number of hours answering questions and providing support for the duration of this project. I would also like to thank The Ohio State University Department of Chemistry for financial support as well as Chemical Abstracts Service, the William Marshall MacNevin Memorial foundation, and Mr.
    [Show full text]
  • Fischer Indole Synthesis Applied to the Total Synthesis of Natural Products Cite This: RSC Adv.,2017,7,52852 Majid M
    RSC Advances REVIEW View Article Online View Journal | View Issue Fischer indole synthesis applied to the total synthesis of natural products Cite this: RSC Adv.,2017,7,52852 Majid M. Heravi, * Sahar Rohani, Vahideh Zadsirjan* and Nazli Zahedi One of the oldest and most useful reactions in organic chemistry is the Fischer indole synthesis (FIS). It is known to have a wide variety of applications including the synthesis of indole rings, often present as the Received 27th September 2017 framework in the total synthesis of natural products, particularly those found in the realm of alkaloids, Accepted 3rd November 2017 which comprise a ring system known as an indole alkaloid. In this review, we are trying to emphasize the DOI: 10.1039/c7ra10716a applications of FIS as an old reaction, which is currently applied to the total synthesis of biologically rsc.li/rsc-advances active natural products and some other complex targets. 1. Introduction prescribed drugs or medications.1 Remarkably, the name indole is a combination of the words indigo and oleum because Creative Commons Attribution 3.0 Unported Licence. Nowadays, there has been increasing attention on the total initially, indole was prepared and identied from the reaction synthesis of bioactive natural products and their synthetic of the indigo dye with oleum.2 As a matter of fact, one of the analogues in the arena of organic chemistry. Novel synthetic most plentiful heterocyclic systems found in nature is indole. It approaches and strategies are available that permit formation is a vital functional nucleus in the structures of different dyes, of novel complex molecules or already structurally known fragrances, pharmaceuticals and agricultural chemicals.3,4 naturally occurring compounds which can be used as Indole ring moieties became important structural components in diverse natural pharmaceutical agents, hence their synthesis and functionalization is a key eld in heterocyclic chemistry, Department of Chemistry, School of Science, Alzahra University, Vanak, Tehran, Iran.
    [Show full text]
  • Fischer Indole Synthesis in Low Melting Mixtures
    ORGANIC LETTERS 2012 Fischer Indole Synthesis in Low Melting Vol. 14, No. 17 Mixtures 4568–4571 Sangram Gore,†,‡ Sundarababu Baskaran,*,† and Burkhard Konig*€ ,‡ Department of Chemistry, Indian Institute of Technology-Madras, Chennai 600036, India and Institut fur€ Organische Chemie, Universitat€ Regensburg, D-93040, Regensburg, Germany [email protected]; [email protected] Received July 23, 2012 ABSTRACT Functionalized indoles are synthezised under mild conditions in a tartaric acidÀdimethylurea melt. The melt serves as the solvent and as the catalyst. Under these reaction conditions, sensitive functional groups such as N-Boc, N-Cbz, or azides are stable, and indolenines are obtained regioselectively in excellent yields. The practical use of the method is demonstrated in the synthesis of the hormone melatonin. Organic transformations are typically carried out in transformations.9 The melt consists of nontoxic and non- solution phase,1 but as most organic solvents are toxic, volatile compounds readily available from natural re- flammable and may lead to environmental hazards2 on- sources. The melt mixtures are environmentally friendly, going efforts aim to replace hazardous solvents by non- as they are easily biodegradable. Since the polarity of toxic and environmentally friendly reaction media.3 Some these melts is high, reactions involving a polar transition of the “green” solvents, which are finding their way into state are usually favored in this medium.10 We have applied chemical processes are water,4 polyethylene
    [Show full text]
  • Continuous Flow Synthesis of Heterocycles: a Recent Update on the Flow Synthesis of Indoles
    molecules Review Continuous Flow Synthesis of Heterocycles: A Recent Update on the Flow Synthesis of Indoles Marco Colella, Leonardo Degennaro * and Renzo Luisi * Flow Chemistry and Microreactor Technology FLAME-Lab, Department of Pharmacy—Drug Sciences, University of Bari “A. Moro” Via E. Orabona 4, 70125 Bari, Italy; [email protected] * Correspondence: [email protected] (L.D.); [email protected] (R.L.) Academic Editor: Derek J. McPhee Received: 16 June 2020; Accepted: 10 July 2020; Published: 16 July 2020 Abstract: Indole derivatives are among the most useful and interesting heterocycles employed in drug discovery and medicinal chemistry. In addition, flow chemistry and flow technology are changing the synthetic paradigm in the field of modern synthesis. In this review, the role of flow technology in the preparation of indole derivatives is showcased. Selected examples have been described with the aim to provide readers with an overview on the tactics and technologies used for targeting indole scaffolds. Keywords: flow chemistry; indoles; organic synthesis 1. Introduction Among heterocycles, the indole ring is one of the most ubiquitous in nature as well as in man-made products, such as pharmaceuticals, agrochemicals, dyes, and materials [1,2]. In particular, the indole core appears as a substructure of various biologically active compounds, including the neurotransmitter serotonin; the regulatory hormone melatonin; and various medicines, such as antihypertensive, anti-inflammatory, antimigraine, anti-tumor, and many others (Scheme1)[ 3]. In addition, indole is a privileged scaffold in drug discovery programs targeting new antivirals. Examples of marketed indole-containing antiviral drugs include Arbidol and Delavirdine. Arbidol is used for the treatment and prophylactic prevention of influenza A and B virus and SARS.
    [Show full text]
  • Applied Sciences
    applied sciences Article βArticle-Nitroacrylates: New Key Precursors of β-Nitroacrylates: New Key Precursors of Indole-2- Indole-2-Carboxylates via Fischer Indole Synthesis Carboxylates via Fischer Indole Synthesis Serena Gabrielli, Deepak Panmand, Roberto Ballini and Alessandro Palmieri * Serena Gabrielli, Deepak Panmand, Roberto Ballini and Alessandro Palmieri * Green Chemistry Group, Chemistry Division, School of Science and Technology, University of Camerino, Via Green Chemistry Group, Chemistry Division, School of Science and Technology, University of Camerino, Via S. Agostino n. 1, 62032 Camerino (MC), Italy; [email protected] (S.G.); [email protected] (D.P.); S. Agostino n. 1, 62032 Camerino (MC), Italy; [email protected] (S.G.); [email protected] [email protected] (R.B.) (D.P.); [email protected] (R.B.) * Correspondence: [email protected]; Tel.: +39-0737-402-262 * Correspondence: [email protected]; Tel.: +39-0737-402-262 Received: 5 November 2019 2019;; Accepted: 23 November 2019 2019;; Published: date 28 November 2019 Abstract: Indole 2-carboxylates2-carboxylates are very important scaffold scaffoldss that are widely investigated for their activities andand areare used used as as key key intermediates intermediate ofs of biologically biologically active active molecules. molecules Herein,. Herein, we reportwe report a new a procedurenew procedure for the for preparation the preparation of this of class this class of derivatives, of derivatives, via Fischer via Fis indolecher indole synthesis, synthesis, starting starting from βfrom-nitroacrylates β-nitroacrylates and arylhydrazines.and arylhydrazine Thes. The protocol protocol permits permits the the production production of of the the title title targetstargets in satisfactory overall yields,yields, avoids any wasteful aqueous work-up,work-up, and has with evident advantages from a sustainabilitysustainability point of view.
    [Show full text]
  • Novel Biodegradable Protonic Ionic Liquid for the Fischer Indole Synthesis Reaction
    Rowan University Rowan Digital Works Faculty Scholarship for the College of Science & Mathematics College of Science & Mathematics 3-9-2016 Novel biodegradable protonic ionic liquid for the Fischer indole synthesis reaction William C. Neuhaus Ian J. Bakanas Joseph R. Lizza Charles T. Boon Jr. Gustavo Moura-Letts Rowan University, [email protected] Follow this and additional works at: https://rdw.rowan.edu/csm_facpub Part of the Organic Chemistry Commons Recommended Citation Neuhaus, W. C., Bakanas, I. J., Lizza, J. R., Boon, C. T., & Moura-Letts, G. (2016). Novel biodegradable protonic ionic liquid for the fischer indole synthesis eaction.r Green Chemistry Letters and Reviews, 9(1), 39-43. This Article is brought to you for free and open access by the College of Science & Mathematics at Rowan Digital Works. It has been accepted for inclusion in Faculty Scholarship for the College of Science & Mathematics by an authorized administrator of Rowan Digital Works. Green Chemistry Letters and Reviews ISSN: 1751-8253 (Print) 1751-7192 (Online) Journal homepage: http://www.tandfonline.com/loi/tgcl20 Novel biodegradable protonic ionic liquid for the Fischer indole synthesis reaction William C. Neuhaus, Ian J. Bakanas, Joseph R. Lizza, Charles T. Boon , Jr. & Gustavo Moura-Letts To cite this article: William C. Neuhaus, Ian J. Bakanas, Joseph R. Lizza, Charles T. Boon , Jr. & Gustavo Moura-Letts (2016) Novel biodegradable protonic ionic liquid for the Fischer indole synthesis reaction, Green Chemistry Letters and Reviews, 9:1, 39-43, DOI: 10.1080/17518253.2016.1149231 To link to this article: http://dx.doi.org/10.1080/17518253.2016.1149231 © 2016 The Author(s).
    [Show full text]
  • Synthesis and Functionalization of Indole Skeleton Compounds Via Nitrosoarene-Alkyne Cycloadditions
    UNIVERSITÀ DEGLI STUDI DELL’INSUBRIA Dipartimento di Scienza e Alta Tecnologia Dottorato di Ricerca in Scienze Chimiche – XXVI ciclo SYNTHESIS AND FUNCTIONALIZATION OF INDOLE SKELETON COMPOUNDS VIA NITROSOARENE-ALKYNE CYCLOADDITIONS Supervisor : Dr. Andrea PENONI Co-supervisor : Prof. Giovanni PALMISANO Ph.D. dissertation by GABRIELLA IERONIMO Index GENERAL INTRODUCTION ..................................................................................................................... 7 1 INDOLES ...................................................................................................................................... 9 2 REFERENCES ........................................................................................................................... 12 CHAPTER 1 – INDOLE SYNTHESES..................................................................................................... 15 1 INTRODUCTION .............................................................................................................................. 17 1.1 Disconnection “a” .................................................................................................................... 17 1.1.1 Fischer Indole Synthesis ............................................................................................................. 18 1.1.2 Bailey-Liebeskind Indole Synthesis ............................................................................................. 21 1.1.3 Bischler-Möhlau Indole Synthesis ...............................................................................................
    [Show full text]
  • Chapter 2 – Orthogonal Synthesis of Indolines and Isoquinolines Via Aryne Annulation 38
    Chapter 2 – Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation 38 CHAPTER 2 Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation 2.1 INTRODUCTION The challenge of incorporating nitrogen into organic molecules has confronted researchers since the emergence of organic synthesis as an independent field of study.1 As synthetic chemistry has advanced, the target structures for synthesis have grown increasingly complex, requiring constant evolution in the methods available to make them. Consequently, there has been a sustained focus on the synthesis of nitrogen- containing benzannulated heterocycles that spans more than 120 years.2 The justification for this persistent synthetic effort is due to the prevalence of these heterocycle motifs in molecules that have interesting structures3 or unique biological activity.4 In the chapter that follows, the efforts to construct two such benzannulated moieties—indoles and isoquinolines—will be discussed in the context of both historical and contemporary reports devoted to the synthesis of these exceptionally valuable molecules.5 This survey of indole and isoquinoline syntheses will focus on well-cited techniques used to make Chapter 2 – Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation 39 these heterocycles, and consider their impact from a strategic perspecitive. Methods that incorporate the base structural motif into a larger, polycyclic system have been omitted. 2.2 A SURVEY OF INDOLE AND ISOQUINOLINE SYNTHETIC METHODS 2.2.1 Indole Synthesis 2.2.1.1 Indole Background As organic synthesis began to coalesce as an established scientific field during the late 19th century, the rational design of methodical approaches to specific structures was superseded in importance by efforts to understand basic chemical reactivity.
    [Show full text]