Studies of Intramolecular Cyanoamidation with Alkenes and Application Toward the Total

215 Pages·2017·10.12 MB·English

Studies of Intramolecular Cyanoamidation with Alkenes
and Application Toward the Total Synthesis of Natural Products

A DISSERTATION SUBMITTED TO
THE FACULTY OF
THE UNIVERSITY OF MINNESOTA
BY

Sadie Catherine Otte

IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY

Advisor: Christopher J. Douglas

October 2017
© Sadie C. Otte 2017
ACKNOWLEDGEMENTS

I thank Chris for his guidance and for challenging me to reach my full potential. I can’t
imagine a more supportive or caring advisor.

I thank Letitia, Jodi, Wegs, and Sarah for their mentorship.

I thank the members of team cyanoamidation and team quebrachamine, especially Matt,
for collaboration, discussion, and encouragement.

I thank all members of the Douglas group, past and present, for providing a supportive and
engaging learning environment.

I thank WISE for teaching me that there is more to graduate school than research.

I thank the chemistry department members for their friendship, assistance, and community.

I thank my family and friends for keeping me (mostly) sane.

I thank Kellen for being a true partner through thick and thin.

i
DEDICATION

To my parents

ii
ABSTRACT

Chapter One. A brief discussion of the relevant background in intramolecular
cyanoamidation. Examples from successive methodology studies are given. The proposed
mechanism and published mechanistic experiments are presented, along with its
applications in the synthesis of complex molecules.

Chapter Two. A summary of the design, discovery, and optimization of the
diastereoselective intramolecular cyanoamidation reaction is presented. Significant
findings are discussed along with a preliminary substrate scope. A detailed description of
our attempts to cleave the chiral directing group is given.

Chapter Three. An overview of the Aspidosperma alkaloid family with an emphasis on
quebrachamine is presented. A discussion is given of the isolation, biological activity, and
previous total syntheses of quebrachamine. Strategies for the synthesis of the all–carbon
quaternary center and formation of the nine–membered ring are specified.

Chapter Four. A novel strategy for the total synthesis of quebrachamine via intramolecular
cyanoamidation is proposed. Three routes to the key cyanoformamide intermediate are
presented. Optimization of the intramolecular cyanoamidation is described along with
reproducibility studies. Progress toward the final ring closure between indole and nitrile
groups via one– and two–step methods is discussed, along with future work.
iii
Chapter Five. The application of a serendipitously discovered Bischler–Napieralski-type
reaction toward the total synthesis of eburnamonine is proposed. Optimization of the
reaction is discussed along with attempts to grow high-quality crystals of the product.
Subsequent efforts to hydrogenate the iminium ion product are presented.

iv
TABLE OF CONTENTS

Acknowledgements………………………………………………………………………...i
Dedication…………………………………………………………………………………ii
Abstract…………………………………………………………………………………...iii
Table of Contents………………………………………………………………………….v
List of Tables…………………………………………………………………………...…ix
List of Figures……………………………………………………………………….…….x
List of Schemes…………………………………………………………………...……...xii
List of Abbreviations……………………………………………………………………xvii

PART ONE

Development of a Diastereoselective Intramolecular

Cyanoamidation Reaction with Alkenes

Chapter One: An Overview of Intramolecular Cyanoamidation
1.1 Methodology studies………………………………………………………………2
1.2 Proposed mechanism………………………………………………………………6
1.2.1 Mechanistic studies………………………………………………………..7
1.2.2 Additive studies……………………………………………………..……..9
1.3 Applications of cyanoamidation reactions……………………………………….10

v
Chapter Two: Diastereoselective Intramolecular Cyanoamidation with Alkenes
2.1 Reaction discovery and optimization…………………………………………….14
2.2 Directing group removal…………………………………………………………17

PART TWO

Application of Intramolecular Cyanoamidation in Total Synthesis

Chapter Three: Quebrachamine and Related Compounds
3.1 The Aspidosperma alkaloid family……………………………………………….30
3.1.1 Isolation and biological relevance of quebrachamine…………………….31
3.1.2 Quebrachamine structure elucidation…………………………………….32
3.2 Total syntheses of quebrachamine………………………………………………..33
3.2.1 The Stork ketone…………………………………………………………34
3.2.2 Other general approaches………………………………………………...35
3.2.3 Strategies to form the quaternary center………………………………….38
3.2.4 Formation of the nine–membered ring…………………………………...41

Chapter Four: Progress Toward the Total Synthesis of Quebrachamine
4.1 Proposed novel strategy for the total synthesis…………………………………...46
4.2 Progress via proposed route 1…………………………………………………….47
4.2.1 Hydroalkylation of propargyl alcohol……………………………………49
4.2.2 Johnson–Claisen rearrangement………………………………………….51
vi
4.2.3 Carbodiimide coupling…………………………………………………...54
4.2.4 Amide reduction………………………………………………………….55
4.3 Progress via proposed route 2…………………………………………………….56
4.3.1 Iridium–catalyzed reaction……………………………………………….57
4.3.2 Palladium–catalyzed reaction…………………………………………….58
4.4 Progress via proposed route 3…………………………………………………….66
4.4.1 Betaine allylation and Claisen rearrangment/decarboxylation.………….67
4.4.2 Reductive amination……………………………………………………..67
4.4.3 Cyanoformamide synthesis………………………………………………73
4.5 Optimization of the cyanoamidation key step………………………………...…75
4.5.1 Proof of concept and early studies……………………………….………75
4.5.2 Reproducibility optimization…………………………………………….83
4.5.3 Re-optimization under improved conditions…………………………….85
4.6 Progress toward the final ring closure…………………………………………...90
4.6.1 Direct ring closure attempts……………………………………………...92
4.6.2 Selective reduction of the lactam………………………………………...96

Chapter Five: Progress Toward the Total Synthesis of Eburnamonine
5.1 Proposed route to Eburnamonine and Leucophylidine…………………………106
5.2 Iminium ion formation………………………………………………………….109
5.3 Iminium ion hydrogenation……………………………………………………..111
5.4 Conclusion……………………………………………………………………...112

vii
Bibliography…………………………………………………………………………...114

Appendix: Experimental and Characterization Data
General details…………………………………………………………………………..145
Instrument details……………………………………………………………………….145
i. 2-methylenebutanol……………………………………………………………..146
ii. N-(2-(1H-indol-3-yl)ethyl)-4-methylenehexanamide…………………………..151
iii. N-(2-(1H-indol-3-yl)ethyl)-4-methylenehexan-1-amine……………………….155
iv. 2-((vinylxoy)methyl)but-1-ene…………………………………………………159
v. 3-(2-methylenebutoxy)acrylic acid……………………………………………..161
vi. 4-methylenehexanal…………………………………………………………….163
vii. (2-(1H-indol-3-yl)ethyl)(4-methylpent-4-en-1-yl)carbamoyl cyanide…………166
viii. (2-(1H-indol-3-yl)ethyl)(4-methylenehexyl)carbamoyl cyanide……………….171
ix. 2-(1-(2-(1H-indol-3-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetonitrile….......176
x. 2-(1-(2-(1H-indol-3-yl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetonitrile………..180
xi. 1-(2-amino-2-oxoethyl)-1-ethyl-2,3,4,6,7,12-hexahydro-1H-indolo[2,3-
a]quinolizin-5-ium trifluoromethanesulfonate……………....………………….185
xii. N-(2-(1H-indol-3-yl)ethyl)-4-methylpent-4-en-1-amine……………………….191

viii