Belmar Dissertation Dec 2012

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Dissertation submitted in partial fulfillment of PhD in chemistry. Covers the syntheses of the alkaloids, communesin F and isophellibiline.

Transcript of Belmar Dissertation Dec 2012

  • The Pennsylvania State University

    The Graduate School

    Eberly College of Science

    TOTAL SYNTHESES OF ()-ISOPHELLIBILINE AND ()-COMMUNESIN F, AND DESIGN, SYNTHESIS AND PHARMACOLOGICAL EVALUATION

    OF DIHYDRO--ERYTHROIDINE (DHE) ANALOGS

    A Dissertation in

    Chemistry

    by

    Johannes Belmar

    2012 Johannes Belmar

    Submitted in Partial Fulfillment of the Requirements

    for the Degree of

    Doctor of Philosophy

    December 2012

  • The dissertation of Johannes Belmar was reviewed and approved* by the following:

    Raymond L. Funk Professor of Chemistry Dissertation Advisor Chair of Committee

    Kenneth S. Feldman Professor of Chemistry

    Scott T. Phillips Assistant Professor of Chemistry

    Robert Rioux Friedrich G. Helfferich Assistant Professor of Chemical Engineering

    Barbara J. Garrison Shapiro Professor of Chemistry Head of the Chemistry Department

    *Signatures are on file in the Graduate School

  • iii

    ABSTRACT

    The intramolecular cycloaddition reactions of 2-amidoacroleins are

    discussed in Part I. Application of this methodology in natural product synthesis

    resulted in the first total synthesis of a member of the nonaromatic

    homoerythrinan class of natural products, ()-isophellibiline. The synthesis was

    completed in 16 linear steps from 2,2-dimethyl-1,3-dioxan-5-one in an overall

    yield of 2.3%. In addition, the design, synthesis and pharmacological evaluation

    of analogs of the nicotinic acetylcholine receptor (nAChR) antagonist dihydro--

    erythroidine (DHE) are described.

    In Part II efforts towards the total synthesis of the marine natural product

    ()-communesin F are discussed. First, we describe the reactions of aza-ortho-

    xylylenes generated via the Lewis acid catalyzed retrocycloaddition reaction of

    3,1-benzoxazin-2-ones. Although, the total synthesis of communesin F was not

    realized through application of this methodology, it resulted in the preparation

    of an advanced intermediate towards communesin F.

    Next, we explore the DielsAlder cycloaddition reactions of indol-2-one

    and detail the successfully applied this methodology in a concise total synthesis

    of ()-communesin F. The synthesis was completed in 15 linear steps from 4-

    bromotryptophol in an overall yield of 6.7%.

  • iv

    TABLE OF CONTENTS

    LIST OF SCHEMES ................................................................................................... vi LIST OF FIGURES ..................................................................................................... x LIST OF TABLES ....................................................................................................... xi ACKNOWLEDGEMENTS ....................................................................................... xii Part I: Total Synthesis of ()-Isophellibiline and Design, Synthesis and

    Pharmacological Evaluation of Dihydro--Erythroidine (DHE) Analogs ................................................................................................................ 1 Chapter 1. Introduction and Background ...................................................... 2

    1.1. The Erythrina alkaloids ...................................................................... 2 1.2. Pharmacology of the Erythrina alkaloids ........................................ 2 1.3. Biosynthesis of the Erythrina alkaloids ............................................ 5 1.4. Previous synthetic efforts towards the Erythrina alkaloids ........... 8

    1.4.1. Padwas strategy for the synthesis of erythrinan and homoerythrinan alkaloids ........................................................... 9

    1.4.2. Tus strategy for the synthesis of erythrinan and homoerythrinan alkaloids ........................................................... 10

    1.4.3. Tsudas syntheses of erythrinan and homoerythrinan alkaloids via a unified synthetic strategy ................................. 11

    1.5. Studies towards the erythrinan and homoerythrinan alkaloids in the Funk laboratory: A 2-Amidoacrolein Cycloaddition Route ..................................................................................................... 12 1.5.1. 2-Amidoacroleins ...................................................................... 12 1.5.2. Previous synthetic effort directed toward the Erythrina

    alkaloids in the Funk laboratory ................................................ 15 Chapter 2. Total Synthesis of ()-Isophellibiline ........................................... 18

    2.1. Retrosynthetic analysis of isophellibiline ........................................ 18 2.2. Total synthesis of ()-isophellibiline ................................................. 19 2.3. Concluding remarks ............................................................................ 26

    Chapter 3. Preparation of Dihydro--Erythroidine (DHE) Analogs ........ 27 3.1. Background and significance ............................................................. 27

    3.1.1. Nicotinic acetylcholine receptors (nAChRs) ......................... 27 3.1.2. Pharmacophore models for nAChR ligands ......................... 29 3.1.3. Dihydro--erythroidine (DHE) ............................................. 32

    3.2. Synthesis of DHE analogs ................................................................ 39 3.3. Results and discussion ........................................................................ 42

    Chapter 4. Experimental ................................................................................... 44 4.1. Materials and Methods ....................................................................... 44

  • v

    4.2. Preparative Procedures ....................................................................... 45 Spectra of Isophellibiline (Authentic and Synthetic) .................................... 72 References ........................................................................................................... 77

    Part II: Total Synthesis of ()-Communesin F ....................................................... 81 Chapter 5. Introduction and Background ...................................................... 82

    5.1. Isolation and structural characterization of the communesins and perophoramidine ......................................................................... 82

    5.2. Pharmacology of the communesins and perophoramidine .......... 84 5.3. Biosynthesis of the communesins and perophoramidine ............. 84 5.4. Previous synthetic approaches to the communesins ...................... 88

    5.4.1. Stoltzs approach to the communesin ring system ............... 88 5.4.2. Adlingtons approach to the communesin ring system ....... 89 5.4.3. Qins total synthesis of ()-communesin F ............................ 90 5.4.4. Weinrebs total synthesis of ()-communesin F .................... 92 5.4.5. Mas total synthesis of (-)-communesin F .............................. 93 5.4.6. Mas total synthesis of communesins A and B ...................... 94

    Chapter 6. Studies Towards the Communesins in the Funk Laboratory: An Aza-ortho-xylylene Route .............................................. 97 6.1. Introduction .......................................................................................... 97 6.2. Previous synthesis efforts directed towards the communesins

    in the Funk laboratory ........................................................................ 100 Chapter 7. An Approach to the Synthesis of Communesin F: An Aza-

    ortho-xylylene Route ................................................................................... 103 7.1. Retrosynthetic analysis of communesin F ........................................ 103 7.2. Synthesis of an advanced intermediate towards the synthesis

    of communesin F ................................................................................. 104 7.3. Concluding remarks ............................................................................ 110

    Chapter 8. Studies Towards the Communesins in the Funk Laboratory: An Indol-2-one Route ........................................................... 111 8.1. Introduction .......................................................................................... 111 8.2. Prior work in the Funk laboratory .................................................... 113

    Chapter 9. Total Synthesis of ()-Communesin F via a Cycloaddition with Indol-2-one ......................................................................................... 118 9.1. Retrosynthetic analysis of communesin F ........................................ 118 9.2. Total synthesis of ()-communesin F ................................................ 119 9.3. Concluding remarks ............................................................................ 135

    Chapter 10. Experimental ................................................................................. 137 10.1. Materials and Methods ..................................................................... 137 10.2. Preparative Procedures ..................................................................... 138

    Spectra of 1-Deoxocommunesin F and Communesin F ............................. 171 References ........................................................................................................... 176

  • vi

    LIST OF SCHEMES

    Scheme 1.3.1. Bartons proposed biosynthesis of the Erythrina alkaloids ........ 6 Scheme 1.3.2. Zenks proposed biosynthesis of the Erythrina alkaloids ........... 7 Scheme 1.4.1. Synthetic strategies for the construction of the erythtinan

    and homo