DOCSLIB.ORG

Chemical Investigations of the Alkaloids from the Plants of the Family Elaeocarpaceae

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Chemical Investigations of the Alkaloids from the Plants of the Family Elaeocarpaceae Chemical Investigations of the Alkaloids from the Plants of the Family Elaeocarpaceae Author Katavic, Peter L Published 2006 Thesis Type Thesis (PhD Doctorate) School School of Science DOI https://doi.org/10.25904/1912/3377 Copyright Statement The author owns the copyright in this thesis, unless stated otherwise. Downloaded from http://hdl.handle.net/10072/367380 Griffith Research Online https://research-repository.griffith.edu.au CHEMICAL INVESTIGATIONS OF THE ALKALOIDS FROM THE PLANTS OF THE FAMILY ELAEOCARPACEAE Peter L. Katavic, BSc (Hons) School of Science/Natural Product Discovery (NPD) Faculty of Science, Griffith University Submitted in fulfillment of the requirements of the degree of Doctor of Philosophy December, 2005 ii iii Abstract A phytochemical survey to detect alkaloids was performed on extracts of 339 discrete plants parts from a total of 77 species from five genera of Elaeocarpaceae, including 30 species from Queensland, 38 from PNG, and nine from China. An alkaloid detecting reagent, bismuth (III) tetraiodide (Dragendorff’s reagent) was used in a preliminary test for alkaloids, with positive ESIMS used to confirm the presence of alkaloids. A total of 35 extracts of various plant parts produced positive results with Dragendorff’s reagent. Positive ESIMS detected alkaloids in only 13 of these extracts. Bismuth (III) tetraiodide was demonstrated to produce false positive results with the new non-alkaloidal poly- oxygenated compounds 112 and 113, which were purified from the extract of Sloanea tieghemii. Two new alkaloid producing species, Elaeocarpus habbeniensis, and E. fuscoides were detected from the survey. These species were chemically investigated for the first time. Two other previously investigated species, E. grandis and Peripentadenia mearsii, were also studied. A total of 16 alkaloids, 11 of which are new, were purified from the extracts of these four species. The novel pyrrolidine alkaloids habbenine (114) and peripentonine (123), were isolated from the leaves of E. habbeniensis and Peripentadenia mearsii, respectively. Both of these compounds were purified as inseparable mixtures of diastereomers. The new pyrrolidine alkaloid mearsamine 1 (124), and the novel amino alkaloid mearsamine 2 (125), were also purified from the leaves of P. mearsii. The known pyrrolidine alkaloid peripentadenine (81), was purified from the bark of P. mearsii. Peripentonine (123) was reduced to peripentadenine (81) upon reaction with Pd/C. Four aromatic indolizidine alkaloids were isolated from the extract of the leaves of E. fuscoides. One new compound, elaeocarpenine (122), was isolated from this New Guinean plant. Three known Elaeocarpus alkaloids, isoelaeocarpicine (62), elaeocarpine (60) and isoelaeocarpine (61) were also purified from E. fuscoides. Elaeocarpenine (122) was demonstrated to produce the epimeric compounds elaeocarpine and isoelaeocarpine via reaction with ammonia. iv The chemical investigation of the Queensland plant E. grandis by two separate purification procedures was performed. An SCX/C18 isolation protocol was used to purify the new indolizidine alkaloids grandisine C (127), D (126), and E (128), in conjunction with the known tetracyclic indolizidine isoelaeocarpiline (63). The second purification of E. grandis was achieved with the use of ammonia in an acid/base partitioning protocol. Grandisine F (129) and G (130), and compounds 131a and b were purified by this procedure, as were 63, 126 and 127. Grandisine F and G were proposed to be ammonia adducts of grandisine D (126). Compound 131a and b were isolated as a mixture of diastereomers. The reduction of grandisine D (126) with Pd/C yielded a mixture of isoelaeocarpine (61) and elaeocarpine (60), whereas the reduction of isoelaeocarpiline (63) produced isoelaeocarpine (61). All of the alkaloids isolated from the Elaeocarpaceae, except grandisine E (128) and 131a and b, were evaluated for binding affinity against the human δ opioid receptor. Every compound except mearsamine 2 (125) possessed a binding affinity of less than 100 μM. The most active compounds were grandisine F (129), D (126), C (127), elaeocarpenine (122), isoelaeocarpine (61), isoelaeocarpiline (63) and peripentadenine (81). The IC50 values for these compounds were 1.55, 1.65, 14.6, 2.74, 13.6, 9.86 and 11.4 μM, respectively. The SAR of the active compounds was compared. These observations indicated that the indolizidine alkaloids were more active than the pyrrolidine alkaloids, and a phenol or ketone at position C-12 of the indolizidine alkaloids produced better binding affinity. All of these alkaloids, except 129, were proposed to interact with two of the three binding domains of the δ opioid receptor. Grandisine F (129) was proposed to have a different mode of action than the other alkaloids in the series. Synthetic modifications to isoelaeocarpine (61) and peripentadenine (81) were investigated in an attempt to incorporate an extra aromatic group into these molecules. An extra aromatic group was proposed to provide increased binding affinity to the δ opioid receptor by interaction with the third binding domain of the receptor. Two different aromatic amines were successfully attached to peripentadenine (81) by a v reductive amination reaction using NaBH(OAc)3 and a titanium catalyst. The reductive amination of the ketone in isoelaecarpine (61) with various amines and NaBH(OAc)3 or NaBH4 proved unsuccessful. vi Declaration "This work has not previously been submitted for a degree or diploma in any university. To the best of my knowledge and belief, the thesis contains no material previously published or written by another person except where due reference is made in the thesis itself" _____________ _________ Name Date vii Acknowledgments First of all, I would like to thank my supervisors, A. R. Carroll and D. A. Venables, for their patience and guidance during this PhD experience. My skills as a scientist have definitely matured under the supervision of Tony and Debra, and for that I am most grateful. I am also most grateful for receiving financial assistance from the Australian Research Council for an Australian Postgraduate Award, and from AstraZeneca for an industry funded scholarship, which allowed me to pursue my research full-time. I wish to thank the following people for help with the project: Greg Pierens for advice and help with NMR experiments, Greg Fechner and Matthew Crampton for assistance with δ opioid screening, Paul Baron and Jennifer Mitchell for acquiring high resolution mass spectra, Leanne Towerzey and Carolyn Tranter for computer related issues, Justin Ripper for invaluable discussions on synthetic chemistry, and Marc Campitelli for advice on molecular modeling. I would like to extend thanks to my friends and colleagues Fredrik Lindahl, Rohan Davis, Declan McKeveney, Carla Rosell and Brendan Wilkinson for many scientific and non- scientific conversations. I could not have achieved what I have without the love and support of my mum, for being there and having faith in me. viii Table of Contents Abstract iii Declaration vi Acknowledgements vii Abbreviations xv List of Figures xvii List of Tables xxi List of Schemes xxii List of publications arising from this thesis xxiii CHAPTER 1 - INTRODUCTION 1 1.1 The Significance of Medicines, Toxins and Hallucinogens from Nature 1 1.2 Alkaloids 5 1.3 Natural Products and the Pharmaceutical Industry 13 1.4 The Family Elaeocarpaceae 23 1.4.1 Distribution 23 1.4.2 Previous Chemical Investigations of the Family Elaeocarpaceae 24 1.4.3 Previous Chemical Investigations of Species from the Genus Aristotelia 25 1.4.4 Previous Chemical Investigations of Species from the Genus Elaeocarpus 25 1.4.5 Previous Chemical Investigations of Species from the Genus Peripentadenia 37 1.4.6 The Value of Chemical Investigations of the Family Elaeocarpaceae 39 1.4.7 The Extraction Process used in the Isolation of Elaeocarpus and Peripentadenia Alkaloids 39 1.5 Pharmacological Activity of Indolizidine and Elaeocarpus Alkaloids 43 1.6 The Aims of the Chemical Investigation 47 ix 1.7 References 48 CHAPTER 2 – Phytochemical Evaluation of Plants from the Family Elaeocarpaceae for Alkaloids 55 2.1 Introduction 55 2.2 Procedure of the CSIRO Phytochemical Survey 59 2.3 Procedure and Results of the Phytochemical Survey of Plants from the Family Elaeocarpaceae 60 2.4 Investigation of Sloanea tieghemii 64 2.4.1 The Isolation of 112 and 113 64 2.4.2 Structure Elucidation of 112 65 2.4.3 Structure Elucidation of 113 72 2.4.4 Determination of the Absolute Stereochemistry of the Biphenyl Group in 112 and 113 76 2.5 The Application of Strong Cation Exchange to Alkaloid Isolation 78 2.6 Structure Elucidation Strategy 79 2.7 References 80 CHAPTER 3 – Isolation and Structure Elucidation of Habbenine, a Novel Pyrrolidine Alkaloid from Elaeocarpus habbeniensis 83 3.1 Introduction 83 3.2 The Isolation of Habbenine (114) from the Leaves of E. habbeniensis 83 3.3 Structure Elucidation of Habbenine (114) 85 x 3.4 The Proposed Biogenesis of Habbenine (114) and Chemotaxonomic Considerations 93 3.5 Habbenine as a Potential Inhibitor of Ion Channels 96 3.6 References 97 CHAPTER 4 – Isolation and Structure Elucidation of Indolizidine Alkaloids from Elaeocarpus fuscoides. 99 4.1 Introduction 99 4.2 The Isolation of Indolizidine Alkaloids from the Leaves of E. fuscoides 100 4.3 Structure Elucidation of Elaeocarpenine (122) 102 4.4 Structure Elucidation of Isoelaeocarpicine (63) 107 4.5 Structure Elucidation of Isoelaeocarpine (61) 112 4.6 Structure Elucidation of Elaeocarpine
Load more

Recommended publications
  • Ew Routes to Indolizidine Alkaloids: the Total Synthesis of (−)Grandisine B
    ew Routes to Indolizidine Alkaloids: The Total Synthesis of (−)-Grandisine B James David Cuthbertson Thesis submitted in partial fulfilment of the requirements for the Degree of Doctor of Philosophy The University of York Department of Chemistry September 2011 Abstract The plant family Elaeocarpaceae has been the source of a plethora of structurally related alkaloids isolated over the last 50 years. This Thesis describes our synthetic approaches to (−)-grandisine B I, a bioactive indolizidine alkaloid isolated from Elaocarpus grandis in 2005. An overview of alkaloids isolated from the family Elaeocarpaceae is provided and preliminary studies into the synthesis of grandisine B I are described (Chapters 1 and 2). Novel routes to bicyclic lactams II and isoquinuclidinone frameworks III have been developed using aqueous ammonia in a one-pot amination/cyclisation sequence (Chapters 3 and 4). The scope of the developed methodology was initially demonstrated with a concise synthesis of the alkaloid (−)-mearsine V. A biomimetic synthesis of (±)- grandisine B I, using the alkaloid grandisine D IV as a synthetic precursor, is then described in Chapter 5. The development of a formic acid mediated alkyne/acetal cyclisation for the synthesis of heterocyclic scaffolds is also reported. The scope and limitations of the methodology are discussed and applications of the methodology in the synthesis of (−)-grandisine B I and structurally related Elaeocarpus alkaloids are described (Chapter 6). I Contents Abstract ...........................................................................................................................
    [Show full text]
  • Indolizidine Alkaloids Baran Group Meeting
    5/10/06 Richter Indolizidine Alkaloids Baran Group Meeting Me O O Background/Introduction: HO H H H HO Me 1. Isolated from a myriad of sources, including, but not limited to ants, N frogs, fungi, and trees. Me N HO H N N 2. A host of effects including, but not limited to, harvest failures, edemas, Me Me necrosis, and rashes. elaeokanine C 3. A host of activities including, but not limited to, phytotoxic, insecticidal, Me Me N antibacterial, and fungicidal. allopumiliotoxin 267A myrmicarin 215A 4. It is unclear what defines the limits of the family, however scores of rhazinilam H H natural products contain the core structure shown below. A sampling Me HO H is provided at the end of the handout. HO 5. The ring is numbered as shows below. N N OH Me Me N 8 1 Me 7 9 2 Me Me OH 6 N Me Me 4 myrmicarin 215B myrmicarin 217 5 3 allopumiliotoxin 339B Me Me OH OH H H Me OH H Syntheses Discussed (in order): H H OAc Me H OH OH N N HO O N Me N Me N H Me swainsonine N nuphar alkaloids Me H2N N indolizidine 223AB slaframine N indolizidine 209D indolizidine 223A serratinine Me tashiromine O Me Me HO H H HO H HO H OH H OH OH Me H Me N N N Me N N OH N H OH OH Me Me OH Me Me lentiginosine O pumiliotoxin 323A lepadiformine pumiliotoxin 307A pumiliotoxin 251D gephyrotoxin O OH OH O H H OH H Me H HO H H N H Me N H N N Me OH N HO H N Me H castanospermine H N H Me securinine gephyrotoxin indolizomycin O alkaloid 205B indolizidine 167B HO ipaldibine Me Me Me 5/10/06 Richter Indolizidine Alkaloids Baran Group Meeting Gallagher, Tetrahedron Lett.
    [Show full text]
  • Plant Toxins: Alkaloids and Their Toxicities
    GSC Biological and Pharmaceutical Sciences, 2019, 06(02), 021–029 Available online at GSC Online Press Directory GSC Biological and Pharmaceutical Sciences e-ISSN: 2581-3250, CODEN (USA): GBPSC2 Journal homepage: https://www.gsconlinepress.com/journals/gscbps (REVIEW ARTICLE) Plant toxins: alkaloids and their toxicities Kamarul Zaman Munirah Adibah and Mohamad Azzeme Azzreena * Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia. Publication history: Received on 09 January 2019; revised on 28 January 2019; accepted on 29 January 2019 Article DOI: https://doi.org/10.30574/gscbps.2019.6.2.0003 Abstract Since ancient civilization, plants have been utilized in many aspects of life, especially in medicinal purposes due to the presence of distinctive secondary metabolites like alkaloids, phenolics and terpenoids. Among them, alkaloids represent a large group of secondary metabolites that have basic properties and comprise nitrogen atom within the heterocyclic ring. Plant synthesizes alkaloids to maintain their survivability under unfavorable conditions. Over 3000 years, indigenous people have been used alkaloid-containing plant extracts to treat several ailments such as fever, snakebite and insanity. However, despite significant benefits to humans and pharmaceutical industries, some of the plant alkaloids are categorized as main plant toxins due to their enormous structural diversity and various modes of actions. Humans and animals can be exposed to
    [Show full text]
  • 1 Introduction
    1.1 Indolizidines as Natural Products 1 1 Introduction 1.1 Indolizidines as Natural Products Indolizidines are widely distributed in nature – in plants as well as in many animals. Their structures can be described either as derivatives of the aromatic bicyclic indolizine or as azabicyclo[4.3.0]- nonanes.1 1 8 5 9 7 6 7 4 2 8 N N 6 3 9 1 3 4 2 5 Indolizine Azabicyclo[4.3.0]nonane Fig. 1 The bicyclic core of indolizidine alkaloids The indolizidine alkaloids display a wide range of biological activities2 and have been the subject of numerous synthetic studies.3 The development of general methods for the synthesis of racemic and enantiopure indolizidines remains an area of active investigation. Most of the naturally occurring indolizidines have been isolated from species of the genus Dendrobates (poison-arrow frogs); Monomorium (ants), Dendrobium (orchids), Tylophora and the Leguminosae family (plants). The classification of the indolizidines according to their natural sources is difficult due to the structural diversity within these species. Nevertheless some characteristic structural motives are unique for the species and often linked to the high biological activities of the compounds. Among them the lipophilic pumiliotoxins and hydrophilic polyhydroxy indolizidines are the two most important classes of compounds. 1 In this work the azabicyclo[4.3.0]nonane nomenclature was used in order to maintain clarity and consistency when comparing different heterocyclic systems 2 For leading references to the biological activity of indolizidine Alkaloids, see: (a) Michael, J. P. Nat. Prod. Rep. 1997, 14, 21-41. (b) Takahata, H.; Momose, T.
    [Show full text]
  • Introduction (Pdf)
    Dictionary of Natural Products on CD-ROM This introduction screen gives access to (a) a general introduction to the scope and content of DNP on CD-ROM, followed by (b) an extensive review of the different types of natural product and the way in which they are organised and categorised in DNP. You may access the section of your choice by clicking on the appropriate line below, or you may scroll through the text forwards or backwards from any point. Introduction to the DNP database page 3 Data presentation and organisation 3 Derivatives and variants 3 Chemical names and synonyms 4 CAS Registry Numbers 6 Diagrams 7 Stereochemical conventions 7 Molecular formula and molecular weight 8 Source 9 Importance/use 9 Type of Compound 9 Physical Data 9 Hazard and toxicity information 10 Bibliographic References 11 Journal abbreviations 12 Entry under review 12 Description of Natural Product Structures 13 Aliphatic natural products 15 Semiochemicals 15 Lipids 22 Polyketides 29 Carbohydrates 35 Oxygen heterocycles 44 Simple aromatic natural products 45 Benzofuranoids 48 Benzopyranoids 49 1 Flavonoids page 51 Tannins 60 Lignans 64 Polycyclic aromatic natural products 68 Terpenoids 72 Monoterpenoids 73 Sesquiterpenoids 77 Diterpenoids 101 Sesterterpenoids 118 Triterpenoids 121 Tetraterpenoids 131 Miscellaneous terpenoids 133 Meroterpenoids 133 Steroids 135 The sterols 140 Aminoacids and peptides 148 Aminoacids 148 Peptides 150 β-Lactams 151 Glycopeptides 153 Alkaloids 154 Alkaloids derived from ornithine 154 Alkaloids derived from lysine 156 Alkaloids
    [Show full text]
  • Vinylogous Sulfonamides in the Total Synthesis of Indolizidine Alkaloids from Amphibians and Ants
    VINYLOGOUS SULFONAMIDES IN THE TOTAL SYNTHESIS OF INDOLIZIDINE ALKALOIDS FROM AMPHIBIANS AND ANTS Susan Winks A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg in fulfilment of the requirements for the Degree of Doctor of Philosophy. January 2010 i Declaration I declare that the work presented in this thesis was carried out exclusively by me under the supervision of Professor J. P. Michael and Professor C. B. de Koning. It is being submitted for the degree of Doctor of Philosophy at the University of the Witwatersrand, Johannesburg. It has not been submitted before for any degree or examination in any other university. ______________________ 15th day of January 2010. ii Abstract This thesis describes the application of vinylogous sulfonamides in a generalised synthetic protocol for the synthesis of indolizidine alkaloids, viz. monomorine I, 5-epi-monomorine I and the key precursor to indolizidine 209D. Chapter one puts the work into perspective with a review of the different classes of amphibian alkaloids, with specific emphasis on previous syntheses of indolizidine 209D and monomorine I. This is followed by a brief overview of previous synthetic strategies employed for alkaloid synthesis in the Wits laboratories and an introduction to vinylogous sulfonamides. Chapter 2 concludes with our aims and proposed strategies for the project. The attempted total synthesis of (−)-indolizidine 209D is described in Chapter 3. The initial three steps to prepare t-butyl (3R)-3-{benzyl[(1R)-1- phenylethyl]amino}nonanoate (274) proceeded well, but the fourth step, deprotecting the nitrogen, gave inconsistent results and hindered the completion of the synthesis.
    [Show full text]
  • Curriculum Vitae
    CURRICULUM VITAE Prof. Stephen Geoffrey Pyne PERSONAL DETAILS Date of birth/ birthplace 27th April 1954; Melbourne, Australia Nationality Australian Address Department of Chemistry University of Wollongong Wollongong, NSW, 2522 Australia Telephone (02) 42213511 Facsimile (02) 42214287 e-mail [email protected] ACADEMIC QUALIFICATIONS B.Sc. (Hons), University of Adelaide, 1975, Top first class honours, (Organic Chemistry) Ph.D., Australian National University, 1979 (with Prof. L. N. Mander) AWARDS AND MEMBERSHIPS Awards C.S.R. Chemistry Prize for Honours Chemistry 1975 Australian Commonwealth Postgraduate Scholarship, 1976-1979. La Trobe University Research Fellowship 1983-1985 Deutsche Forschungsgemeinshaft Fellowship, 1988 Elected to Fellow of the Royal Australian Chemical Institute (FRACI), 1991 Von Humboldt Fellowship, 1992 Young Researcher of the Year Award for 1992 (offered by the Australian Research Council and the von Humboldt Foundation) Rhone Poulenc Fellow under the Bede Morris Fellowship Scheme, 1994 ARC Senior Fellowship 1994-1998 Tasmanian Alkaloid Lectureship of the University of Tasmania, 2003. Vice Chancellor’s Award for Research Partnerships 2009. Curriculum vitae Professor Stephen Geoffrey Pyne Page 1 of 26 Memberships Associate of the Royal Australian Chemical Institute 1984-1990. Fellow of the Royal Australian Chemical Institute 1991- Editorial Board Membership Member, Editorial Advisory Board of Sulfur Letters 1997-99. Member, Editorial Advisory Board of Sulfur Reports 1997-99. Managing Editor of Sulfur Letters 1999-2002 Managing Editor of SulfurReports 1999-2002 Associate Editor of Mini Reviews in Organic Chemistry 2002-current Member, Editorial Advisory Board of Current Organic Synthesis 2002-current Managing Editor of Asian Coordinating Group for ChemistryChem. Res. Commun.1996-2004. Member, Editorial Advisory Board of Asian Coordinating Group for Chemistry (ACGC) Chem.
    [Show full text]
  • Synthetic Study of Indolizidine Alkaloids with Structural Diversity: Indolizidine 167B, Indolizidine 209D, Tabertingine
    SYNTHETIC STUDY OF INDOLIZIDINE ALKALOIDS WITH STRUCTURAL DIVERSITY: INDOLIZIDINE 167B, INDOLIZIDINE 209D, TABERTINGINE, TASHIROMINE AND SPIROINDOLIZIDINE -OXINDOLE By MR. Kittisak THAMMAPICHAI A Thesis Submitted in Partial Fulfillment of the Requirements for Master of Science (CHEMISTRY) Department of CHEMISTRY Graduate School, Silpakorn University Academic Year 2020 Copyright of Graduate School, Silpakorn University การศึกษาการสังเคราะห์อินโดลิซิดีนอัลคาลอยด์ที่มีความหลากหลายทางโครงสร้าง Indolizidine 167B และ Indolizidine 209D Tabertinggine Tashiromine และ Spiroindolizidine-oxindole โดย นายกิตติศักดิ์ ธรรมาภิชัย วิทยานิพนธ์นี้เป็นส่วนหนึ่งของการศึกษาตามหลักสูตรวิทยาศาสตรมหาบัณฑิต สาขาวิชาเคมี แผน ก แบบ ก 2 ปริญญามหาบัณฑิต ภาควิชาเคมี บัณฑิตวิทยาลัย มหาวิทยาลัยศิลปากร ปีการศึกษา 2563 ลิขสิทธิ์ของบัณฑิตวิทยาลัย มหาวิทยาลัยศิลปากร SYNTHETIC STUDY OF INDOLIZIDINE ALKALOIDS WITH STRUCTURAL DIVERSITY: INDOLIZIDINE 167B, INDOLIZIDINE 209D, TABERTINGINE, TASHIROMINE AND SPIROINDOLIZIDINE-OXINDOLE By MR. Kittisak THAMMAPICHAI A Thesis Submitted in Partial Fulfillment of the Requirements for Master of Science (CHEMISTRY) Department of CHEMISTRY Graduate School, Silpakorn University Academic Year 2020 Copyright of Graduate School, Silpakorn University 4 Title Synthetic Study of Indolizidine Alkaloids with Structural Diversity: Indolizidine 167B, Indolizidine 209D, Tabertingine, Tashiromine and Spiroindolizidine-Oxindole By Kittisak THAMMAPICHAI Field of (CHEMISTRY) Study Advisor Assistant Professor Punlop Kuntiyong , Ph.D. Graduate School Silpakorn
    [Show full text]
  • The Synthesis of Indolizidine and Quinolizidine Derivatives Using the Electron-Rich Dearomatization Agent, {Wtp(NO)(Pme3)}
    The Synthesis of Indolizidine and Quinolizidine Derivatives using the Electron-rich Dearomatization Agent, {WTp(NO)(PMe3)} Benjamin Kaufman Liebov Brooklyn, New York B.S. Chemistry, Muhlenberg College, 2011 B.A. English, Muhlenberg College, 2011 A Dissertation Presented to the Graduate Faculty of the University of Virginia in Candidacy for the Degree of Doctor of Philosophy Department of Chemistry, University of Virginia, November 2016 Abstract Chapter 1 introduces the reader to aromaticity and the activation of aromatic molecules through coordination to electron deficient and electron-rich metal fragments. Coordination of aromatics to electron-deficient metals in an η6 fashion activates them towards nucleophilic additions. Conversely, coordination to an electron-rich metal fragment through η2 (dihapto) coordination renders aromatic molecules dearomatized and makes them susceptible to electrophilic addition. Chapter 2 gives an overview of alkaloid chemistry and the syntheses of several alkaloid analogs using electron-rich dearomatization techniques. Through dihapto- coordination, several inexpensive aromatics can be chemically transformed to alkaloid analogs. The chapter ends with the introduction of the synthetic challenges of converting pyrroles and pyridines to indolizidines and quinolizidines, respectively. Chapter 3 focuses on the reactivity of pyrrole and its activation through electron- rich dearomatization. Upon coordination of 2-methylpyrrole to a tungsten(0) dearomatization agent followed by protonation, a dihapto-coordinated 2H-2- methylpyrrolium complex is isolated. After a Michael addition of MVK or EVK to the 2- methylpyrrolium complex, an intramolecular cyclization takes place to form an indolizidinium core. Chapter 4 explores the formation and reactivity of a coordinated indolizidinium complex. The indolizidinium core has an α,β-unsaturated iminium where the alkene portion can be dihydroxylated or hydrogenated.
    [Show full text]
  • Review on Chemistry of Natural and Synthetic Indolizines with Their Chemical and Pharmacological Properties Sandeep C, Katharigatta N
    REVIEW ARTICLE Review on Chemistry of Natural and Synthetic Indolizines with their Chemical and Pharmacological Properties Sandeep C, Katharigatta N. Venugopala1,2, Mohammed A. Khedr1,3, Mahesh Attimarad1, Basavaraj Padmashali4,5, Rashmi S. Kulkarni6, Rashmi Venugopala7, Bharti Odhav2 Laboratory of Self-Assembled Biomaterials (Chemistry Core), Institute for Stem Cell Biology and Regenerative Medicine, NCBS, TIFR, GKVK Campus, Bellary Road, Bengaluru, Karnataka, India, 1Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Kingdom of Saudi Arabia, 2Department of Biotechnology and Food Technology, Durban University of Technology, Durban, South Africa, 3Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Ein Helwan, Cairo, Egypt, 4Department of Chemistry, Sahyadri Science College (Autonomous), Shimoga, Karnataka, India, 5Department of Studies and Research in Chemistry, School of Basic Sciences, Rani Channamma University, Belagavi, Karnataka, India, 6Department of Chemistry, Jain University, Bengaluru, Karnataka, India, 7Department of Public Health Medicine, University of KwaZulu-Natal, Howard College Campus, Durban, South Africa ABSTRACT Correspondence: Access this article online This review emphasizes chemistry of synthetic indolizine analogs including Dr. Katharigatta N. Venugopala, Website: www.jbclinpharm.org chemical reactions in addition to natural indolizidine alkaloids and their physical Department of Pharmaceutical Sciences, and pharmacological properties.
    [Show full text]
  • Quinolizidine Alkaloid Biosynthesis: Recent Advances and Future Prospects
    PERSPECTIVE ARTICLE published: 26 October 2012 doi: 10.3389/fpls.2012.00239 Quinolizidine alkaloid biosynthesis: recent advances and future prospects Somnuk Bunsupa1, MamiYamazaki1 and Kazuki Saito1,2* 1 Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan 2 RIKEN Plant Science Center, Yokohama, Japan Edited by: Lys-derived alkaloids, including piperidine, quinolizidine, indolizidine, and lycopodium alka- Gustavo Bonaventure, Max Planck loids, are widely distributed throughout the plant kingdom. Several of these alkaloids have Institute for Chemical Ecology, Germany beneficial properties for humans and have been used in medicine. However, the molecular mechanisms underlying the biosynthesis of these alkaloids are not well understood. In the Reviewed by: Masami Y. Hirai, RIKEN Plant Science present article, we discuss recent advances in our understanding of Lys-derived alkaloids, Center, Japan especially the biochemistry, molecular biology, and biotechnology of quinolizidine alkaloid Taketo Okada, Tokushima Bunri (QA) biosynthesis. We have also highlighted Lys decarboxylase (LDC), the enzyme that University, Japan Kalina Bermudez Torres, Instituto catalyzes the first committed step of QA biosynthesis and answers a longstanding ques- Politécnico Nacional, Mexico tion about the molecular entity of LDC activity in plants. Further prospects using current *Correspondence: advanced technologies, such as next-generation sequencing, in medicinal plants have also Kazuki Saito, Graduate School of been discussed. Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Keywords: Lupinus, lysine decarboxylase, lysine-derived alkaloids, o-tigloyltransferase, quinolizidine alkaloids Chiba 260-8675, Japan. e-mail: [email protected] INTRODUCTION (−)-huperzine A is used in the treatment of Alzheimer’s disease Plant secondary metabolites play multiple roles in the interac- (Decker et al., 1992; Bai et al., 2000; Dwoskin et al., 2000; Dwoskin tion between plants and their environment (Dixon, 2001).
    [Show full text]
  • Farming New Resources for Plant Alkaloid Production
    Opportunities in metabolic engineering to facilitate scalable alkaloid production The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Leonard, Effendi et al. “Opportunities in metabolic engineering to facilitate scalable alkaloid production.” Nature Chemical Biology 5.5 (2009): 292-300. As Published http://dx.doi.org/10.1038/nchembio.160 Publisher Nature Publishing Group Version Author's final manuscript Citable link http://hdl.handle.net/1721.1/68707 Terms of Use Creative Commons Attribution-Noncommercial-Share Alike 3.0 Detailed Terms http://creativecommons.org/licenses/by-nc-sa/3.0/ Opportunities in metabolic engineering to enable scalable alkaloid production Effendi Leonard§1 Weerawat Runguphan§2 Sarah O’Connor2 Kristala Jones Prather*1 1Department of Chemical Engineering, 2Department of Chemistry Massachusetts Institute of Technology Cambridge, MA, 02139 Submitted for publication in: Nature Chemical Biology * Corresponding author: Department of Chemical Engineering 77 Massachusetts Avenue Room 66-458 Cambridge, MA 02139 Phone: 617.253.1950 Fax: 617.258.5042 Email: [email protected] § These authors contributed equally to this publication. 1 1 Abstract 2 3 Numerous drugs and drug precursors in the current pharmacopoeia 4 originate from plant sources. The limited yield of bioactive compounds in 5 plant tissues, however, presents a significant challenge for large-scale 6 drug development reliant on whole plant extracts. Because of their 7 sophisticated molecular architecture, efficient chemical syntheses for 8 many plant-derived drugs are also seldom available. Metabolic engineering 9 has facilitated the development of plant cell and tissue systems for the 10 overproduction of high-value plant pharmaceuticals that can be 11 conveniently scaled-up in a controlled environment.
    [Show full text]