FU Berlin Digitale Dissertation
Alexander Sudau : Synthesis and Reactions of Planar Chiral Azoninones - Total Syntheses of Pumiliotoxins Synthese und Reaktionen planar chiraler Azoninone - Totalsynthesen von Azoninonen
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Abstract In this work the synthesis of planar chiral azoninones and their conversion into biologically active compounds was studied. Azoninones (cyclic unsaturated nine-membered lactams) are of considerable interest because of their unusual conformational properties and their applicability to generate optically active indolizidines. The term planar chirality characterises a form of chirality originating from a stereogenic plane, e.g. a planar arrangement of at least four centres (atoms) with a fifth centre placed outside of this original plane. An (E) olefin, incorporated in a ring, fulfills the requirements of a planar-chiral subunit. Since unsaturated optically active, planar chiral, eight-membered rings are known to be stable, many nine- and ten-membered rings suffer from a fast racemisation due to the facile flipping of the double bond with respect to the ring. In contrast, the azoninones described in this work were found to maintain the planar chiral information at room temperature. Directly after their formation by the zwitterionic aza-Claisen rearrangement of vinyl pyrrolidines, all azoninones were pS- configured. This arrangement was found to possess an outstanding stability. Heating to about 60 °C allowed to convert the pS-azoninones into thermodynamically more stable pR-azoninones. This planar chiral isomerisation required an activation energy of ~25 kcal, as determined by calculations and kinetic measurements. Such controllable epimerisation is of a high synthetic value because the labile planar chiral information can be selectively converted into new stereogenic centres by transannular ring-contractions and cycloaddition reactions. Numerous indolizidines and azonanones (saturated nine-membered lactams) have been prepared with high regio- and stereoselectivities. The mild reaction conditions required for these reactions allowed a directed conversion of planar chirality into central chirality, and furthermore the synthesis of D- and L-proline derived indolizidinones from the same ex-chiral pool precursor. The applicability of this new concept has been demonstrated by the completion of a new total synthesis of (+)-pumiliotoxin 251D and congeners. These compounds are highly physiologically active and not available from natural sources in sufficient amounts. Key reactions conducting this synthesis are: (i) the generation of the hydroxyindolizidinone core by the transannular ring-opening of epoxy-azonanones, (ii) the conversion of a bicyclic amide into an amido phosphonate and (iii) the stereoselective introduction of the (Z)-alkylidene side chain via a Horner-Wittig reaction of the amido phosphonate and a chiral aldehyde. Finally, the correct structure of the (+) Pumiliotoxin 251D was undoubtedly proven via X-ray analysis of the hydrochloride.

Table of Contents Download the whole PhDthesis as a zip-tar file or as zip-File For download in PDF format click the chapter title   TITLE   TABLE OF CONTENTS   1 INTRODUCTION 1 1.1 Indolizidines as Natural Products 1 1.2 Azoninones as Key Intermediates in Natural Product Synthesis 13 1.3 Objectives 20 2 RESULTS AND DISCUSSION 22 2.1 Syntheses of Azoninones - Unsaturated Nine-Membered Ring Lactams 22 2.2 The Planar Chirality of Azoninones 36 2.3 Transannular Reactions of Optically Active Azoninones 58 2.4 Cycloaddition Reactions of Optically Active Azoninones 67 2.5 Synthesis of Hydroxy Indolizidinones by Ring Opening Reactions of Epoxy Azonanones 76 2.6 Total Syntheses of Pumiliotoxins (Part I) - Preparation of the Bicyclic Core 83 2.7 Total Syntheses of Pumiliotoxins (Part II) - Synthesis of the Side Chain subunit 86 2.8 Total Syntheses of Pumiliotoxins (Part III) - Aldol approach 88 2.9 Total Syntheses of Pumiliotoxins (Part IV) - Horner Approach 95 2.10 Summary and Outlook 108 3 EXPERIMENTAL PART 112 3.1 Materials and Methods 112 3.2 Syntheses of Vinyl pyrrolidines 114 3.3 Preparation of Acid Fluorides 125 3.4 Aza-Claisen Rearrangements 127 3.5 Transannular Ring Contractions 144 3.6 Preparation of Hydroxy Indolizidinones by Substitution Reactions 178 3.7 Cycloaddition Reactions 182 3.8 Synthesis of Hydroxy Indolizidinones by Ring Opening Reactions of Epoxy Azonanones 213 3.9 Total Syntheses of Pumiliotoxins (Part I) - Preparation of the Bicyclic Core 225 3.10 Total Syntheses of Pumiliotoxins ( Part II) - Preparation of the Side Chain 234 3.11 Total Syntheses of Pumiliotoxins (Part III) - Aldol approach 242 3.12 Total Syntheses of Pumiliotoxins (Part IV) - Horner Approach 248 4 APPENDIX 272 4.1 X-ray Data 272 4.2 List of Compounds 283

More Information:
Online available:	http://www.diss.fu-berlin.de/2002/89/indexe.html
Language of PhDThesis:	english
Keywords:	azoninones, planar chirality, pumiliotoxins, aza-Claisen rearrangement
DNB-Sachgruppe:	30 Chemie
Date of disputation:	17-May-2002
PhDThesis from:	Fachbereich Biologie, Chemie, Pharmazie, Freie Universität Berlin
First Referee:	Prof. Dr. Udo Nubbemeyer
Second Referee:	Prof. Dr. Arnulf Dieter Schlüter
Contact (Author):	alexander.sudau@gmx.de
Contact (Advisor):	udonubb@chemie.fu-berlin.de
Date created:	24-May-2002
Date available:	29-May-2002

 

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