Synthesis of diterpene alkaloids

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Iowa State University Capstones, Theses and
Retrospective Theses and Dissertations
Dissertations
1996
Synthesis of diterpene alkaloids
Tiberiu Mircea Siclovan
Iowa State University
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Siclovan, Tiberiu Mircea, "Synthesis of diterpene alkaloids " (1996).Retrospective Theses and Dissertations. 11488.
https://lib.dr.iastate.edu/rtd/11488
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Synthesis of diterpene alkaloids
by
Tiberiu Mircea Siclovan
A dissertation submitted to the graduate faculty
in partial fulfillment of the requirements for the degree of
DOCTOR OF PHILOSOPHY
Department: Chemistry
Major: Organic Chemistry
Major Professor: Dr. George A. Kraus
Iowa State University
Ames, Iowa
1996
Copyri^ © TiberiuMircea Sictovan, 1996. AD ri^its reserved.
UMI Ntimber: 9635354
Copyright 1996 by
Siclovan, Tiberiu Mircea
All rights reserved.
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ii
Graduate College
Iowa State University
This is to certify that the doctoral dissertation of
Tiberiu Mircea Siclovan
has met the dissertation requirements of Iowa State University
Signature was redacted for privacy.
Committee Member
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Committee Member
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ommittee Member
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Jommittee Member
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iajor Professor
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For the Major Department
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For the Graduate College
iii
Dedication
To all those who understood my desire to pursue a career in the demanding field of
synthetic organic chemistry and, paying the price of personal sacrifices, supported me
throughout this endeavor. To my parents, spouse and friends.
IV
TABLE OF CONTENTS
GENERAL INTRODUCTION 1
PART L A STUDY ON THE GENERATION AND TRAPPING OF
ADAMANTYL ANIONS 2
INTRODUCTION 3
BRIDGEHEAD INTERMEDIATES IN ORGANIC SYNTHESIS
A REPRODUCIBLE SYNTHESIS OF ADAMA>n" AJ4E-C0NTAINING COMPOUNDS 4
APPLICATIONS TOWARDS THE SYNTHESIS OF BIOLOGICALLY ACTIVE
COMPOUNDS CONTAINING THE ADAMANTANE UNIT 9
EXPERIMENTAL 12
FART n. SYNTHESIS OF DITERPENE ALKALOIDS 14
LITERATURE SURVEY 15
Conjugate addition of Co(III)-generated radicals to a, P-unsaturated ketones 15
Particularities of nucleophilic additions to bicyclo[3.3.1]nonan-9-one
and structurally related systems 17
Pharmacologicai properties of 3- aza-bicyclo[3.3.1 ]nonane derivatives 21
STUDIES DIRECTED TOWARDS THE SYNTHESIS OF DITERPENE ALKALOIDS 23
Introduction; Pharmacology 23
Historical 24
RESULTS AND DISCUSSION 33
Retrosynthetic analysis 33
Synthetic studies based on nucleophilic additions as key steps 35
Synthetic studies based on bridgehead intermediates 46
Studies on the generation and trapping of highly fiinctionalized bridgehead anions 46
Methods for bridgehead radical formation. Preparation of an
intermediate for the synthesis of gibberellins 48
V
Studies directed towards the synthesis of atisine and spiramine alkaloids 51
Studies directed towards the synthesis of aconitine alkaloids 73
EXPERIMENTAL 83
GENERAL SUMMARY / CONCLUSION 92
APPENDIX I. NUMBERING SYSTEM AND STRUCTURES OF
SOME DITERPENE ALKALOIDS 93
APPENDIX n. X-RAY STRUCTURE OF COMPOUND 71 97
REFERENCES 98
ACKNOWLEDGEMENTS 106
1
GENERAL INTRODUCTION
There are little chances of being wrong when stating that organic synthesis is the heart
of modem organic chemistry. Nowadays, it certainly is one of the most dynamic areas of
interest in chemistry. Synthetic orgsnic chemistry is a key mstrument in answering questions
such as the origins of life and those of the Universe known so far, the nature of the
interactions within ourselves, as well as with our surroundings, and ultimately whether we
may become a galactic civilization or succomb to our own mistakes. The impact that
synthesis has on our everyday lives is unparalleled, leaving practically no aspect unmarked.
Medicine, modem agriculture, computers, aircraft and space technology, to name just a few
areas, benefit and require an "mcreasingly unportant synthetic effort.
Natural product synthesis offers an excellent trainmg, as well as rewarding results.
Indeed, the synthesis of such complex targets requirest hat the scientist be familiar with a
variety of functional transformation procedures and their mechanistic aspects, and be able to
use them creatively and efiBciently in a field which is still perceived as a complex hybrid
between science and art, in spite of all the streamlining and computational involvement it
benefited fi'om in the past decade.
The interest that diterpene alkaloids received lately has prompted us to attempt an
efficient entry into this class of natural products. Some of our most relevant results are
described in this work.
The first part of this dissertation addresses some of the work done using adamantane
as a model for developing new methods of generating bridgehead reactive species. The
second part details relevant approaches towards the synthesis of complex natural products in
connection with the methodology previously described. The numbering of the compounds,
schemes and references used are independent in each section.