Strategies and Tactics for the Synthesis of Polycyclic Alkaloids Adel

331 Pages·2012·11.94 MB·English

by  Adel Elsohly

Strategies and Tactics for the Synthesis of Polycyclic Alkaloids

Adel M. ElSohly

Submitted in partial fulfillment of the
requirements for the degree of
Doctor of Philosophy
In the Graduate School of Arts and Sciences

COLUMBIA UNIVERSITY

2012
© 2012
Adel M. ElSohly
All rights reserved
ABSTRACT

Strategies and Tactics for the Synthesis of Polycyclic Alkaloids

Adel M. ElSohly

Chapter 1. The Myrmicarin Alkaloids: Isolation, Characterization, and Previous
Synthetic Approaches
The myrmicarin family of oligomeric natural products comprises one of the most
ornate collections of polycyclic alkaloids known. The structural characterization of their
unique scaffolds was accomplished through elegant spectroscopic studies. Furthermore,
the synthesis of these alkaloids has attracted the attention of the synthetic community,
with several syntheses of the monomeric myrmicarins completed. Significant effort has
been put forth toward the synthesis of the higher order structures, though no successful
approach has been reported to date. These isolation and characterization studies as well as
synthetic approaches toward the family are reviewed.

Chapter 2. The Evolution of Efficient, Enantioselective Total Syntheses of
Monomeric Myrmicarin Alkaloids
In order to provide a family-level solution to the myrmicarin alkaloids, we
adopted a strategy-level approach to their synthesis. Utilizing concepts from
retrosynthetic analysis and diversity oriented synthesis, an enantioselective and highly
streamlined synthesis of the monomeric myrmicarin alkaloids as well as potential
dimerization precursors was established from a common intermediate with late stage
diversification.
Chapter 3. Dimerization Studies Toward the Synthesis of Myrmicarin 430A
An alternative strategy for the synthesis of myrmicarin 430A is presented using a
dienamine precursor. This approach allows for the stereoselective synthesis of the all
trans stereotriad of the central cyclopentane moiety of myrmicarin 430A. Mechanistic
aspects concerning the final bond closure are presented in light of quantum chemical
calculations.

Chapter 4. An Introduction to the Securinega Alkaloids and NHC Catalysis
The Securinega alkaloids comprise a large family of tetracyclic alkaloids, many
of which contain a conjugated butenolide moiety. While many distinct synthetic
approaches have appeared for the synthesis of members of this family, only a relatively
small number of approaches are applied to the synthesis of the butenolide portion of these
natural products. The various synthetic endeavors to accessing this structural motif are
presented.
NHC catalysis is a growing field of research for its ability to promote unusual
chemical transformations. As this field of research is of relevance to our latter studies, a
brief overview of modern NHC catalysis is presented.

Chapter 5. Development of an NHC-Catalyzed Cascade Reaction to Access the Core
Architecture of the Securinega Alkaloids
In targeting the family of Securinega alkaloids, a retrosynthesis was devised that
proposes a novel intramolecular cyclization approach of an ynal and ketone to deliver the
bridging butenolide moiety of these natural products. The development of this reaction
and its application toward the synthesis of various Securinega alkaloids is presented.
TABLE OF CONTENTS
General Introduction....................................................................................................1

Chapter 1. The Myrmicarin Alkaloids: Isolation, Characterization, and Previous
Synthetic Approaches
1.1 Isolation and Structural Elucidation of the Myrmicarin Alkaloids............4
1.2 Previous Total Syntheses of the Monomeric Myrmicarins........................7
1.3 Movassaghi’s Efforts Toward Myrmicarin 430A....................................19
1.4 Our General Strategy to Target the Entire Family of Myrmicarin
Alkaloids...............................................................................................28
1.5 References.............................................................................................31

Chapter 2. The Evolution of Efficient, Enantioselective Total Syntheses of
Monomeric Myrmicarin Alkaloids
2.1 First Generation Total Synthesis of Myrmicarin 217..............................33
2.2 Second Generation Synthesis of Myrmicarin 217...................................37
2.3 Enantioselective Total Synthesis of Myrmicarins 215A and 215B..........42
2.4 Conclusions and Remarks......................................................................51
2.5 References.............................................................................................54
2.6 Experimental Section.............................................................................56

Chapter 3. Dimerization Studies Toward the Synthesis of Myrmicarin 430A
3.1 Initial Efforts to Effect a Direct, Biomimetic Dimerization...................121
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3.2 A Controlled, Stepwise Dimerization Approach...................................122
3.3 Total Synthesis of Isomyrmicarin 430C...............................................130
3.4 Computational Studies.........................................................................137
3.5 References...........................................................................................145
3.6 Experimental Section...........................................................................146

Chapter 4. An Introduction to the Securinega Alkaloids and NHC Catalysis
4.1 A Brief Overview of the Securinega Alkaloids.....................................183
4.2 Total Syntheses of Various Securinega Alkaloids................................189
4.3 A Brief Introduction to NHC Catalysis.................................................207

Chapter 5. Development of an NHC-Catalyzed Cascade Reaction to Access the Core
Architecture of the Securinega Alkaloids
5.1 Retrosynthetic Analysis of Secu’amamine A........................................217
5.2 Initial Studies to Access the [3.3.1] Bicyclic Framework of
Secu’amamine A..................................................................................219
5.3 Adaptation to a [3.2.1] Bicyclic Framework.........................................222
5.4 Examination of Substrate Scope and Reaction Optimization................225
5.5 Application of the NHC Cascade Toward the Total Synthesis of
Norsecurinine, Allonorsecurinine, and Secu’amamine A......................233
5.6 Conclusions.........................................................................................240
5.7 References...........................................................................................235
5.8 Experimental Section...........................................................................242
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ACKNOWLEDGEMENTS
I have the insurmountable task of thanking all of the people who have made this
Ph. D. possible, and what follows is my best attempt at doing so.

Prof. Scott Snyder for being a mentor and putting up with my crazy ideas for the past 5
years. You are also thanked for giving me creative freedom to explore chemistry.
The Snyder Group past and present members who have made this research group a joy
to work in and for inspiring me to always push myself.

Dr. Ferenc Kontes is thanked for being the best collaborator I have ever worked with.
Having you as a research partner and hood-mate enriched my Ph. D. experience in ways I
cannot express. You are an invaluable mentor and a sincere friend.
Dr. Yunqing Lin is thanked for all of her moral support and for taking us to Dim Sum.
Dr. Daniel Wespe is thanked for being a great friend and a wonderful colleague. Egypt
was a blast!
Alexandria Brucks and Nathan Wright are thanked for making this corner the coolest
corner in the lab. Nate is specifically thanked for putting up with me as a hood mate for a
year.
Wes and Aaron Sattler are thanked first and foremost for always being great friends and
for being willing to discuss random chemistry with me. You are also thanked for X-ray
chrystallographic expertise.
Profs. Jim Leighton and Tristan Lambert are thanked for serving on my committee
and for discussions and suggestions about chemistry.

Dr. John Decatur and Dr. Yasuhiro Itagaki are thanked for immense support in
providing expertise in spectroscopic analysis.

Carlos, Socky, Daisy, Dani, and Alix are thanked for all of their administrative
assistance. I was once told I am an administrative nightmare, so I thank you all for your
patience and helpfulness!
Robert and Chris for being really helpful whenever a chemical got lost in shipment.
Bill and Jay are thanked for making sure our labs were always up and running.

The National Science Foundation is thanked for a pre-doctoral fellowship.
The Paul and Daisy Soros Fellowship is thanked for funding and for being an overall
awesome program.
Roche is thanked for an invitation to the Excellence in Chemistry Symposium.

My family for all of their love and support throughout my life. Your confidence in me is
humbling, and I cannot express my gratitude enough.
My wife, Donia Elsherbeni cannot be thanked enough for everything she has put up
with over the past 5 years. Your constant love and support have made this Ph.D. not only
possible but enjoyable.
My daughter, Iris is thanked for being my shining reminder that there’s more to life than
research. Your smile instantly makes me forget bad days in lab.
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1

General Introduction
2
The molecular scaffolds isolated from natural sources covers an expansive range
of chemical space, often times exhibiting carbon skeletons that are completely
unprecedented or that would appear too strained to exist. The challenges associated with
the synthesis of these complex frameworks has pushed synthetic organic chemistry to its
limits, requiring the development of new reactions, reagents, and strategies to provide
solutions to access the desired targets. Furthermore, the tools developed during these
endeavors have found broad-reaching application in various fields of study, such as
materials science, chemical biology, and medicinal chemistry. With this background in
mind, the work disclosed in this dissertation aims to address two major challenges in the
synthesis of complex natural product motifs: new strategies and reactions to rapidly build
molecular complexity. Specifically, the science disclosed in this dissertation encompasses
two major projects that each focused on the synthesis of polycyclic alkaloids.
First, Chapters 1–3 address the development of a unique strategy to access the
polycyclic frameworks of the myrmicarin family of alkaloids. Central to these studies is
the development of an efficient strategy to access dimerization precursors that exhibit
unprecedented reactivity to access key stereochemical features of myrmicarin 430A, a
molecule containing a central cyclopentane core that is asymmetrically substituted on
every carbon. Indeed, general methods for accessing these types of frameworks are
completely absent in the literature. The second project, detailed in Chapters 4 and 5, is
concerned with the development of a new reaction to access the strained, polycyclic
framework of the Securinega alkaloids. Specifically, this new reaction provides the first
example of a nucleophilic homoenolate derived from an ynal substrate, greatly expanding
the scope of N-heterocyclic carbene mediated transformations.