The Versatility of Ether-Bridged Cycloadducts Towards the Synthesis of Complex Natural Products

183 Pages·2013·4.85 MB·English

by  Harold Deshaun Cooper

University of Connecticut
OpenCommons@UConn
Doctoral Dissertations University of Connecticut Graduate School
6-20-2013
The Versatility of Ether-Bridged Cycloadducts
Towards the Synthesis of Complex Natural
Products
Harold Deshaun Cooper
University of Connecticut - Storrs, [email protected]
Follow this and additional works at:https://opencommons.uconn.edu/dissertations
Recommended Citation
Cooper, Harold Deshaun, "The Versatility of Ether-Bridged Cycloadducts Towards the Synthesis of Complex Natural Products"
(2013).Doctoral Dissertations. 226.
https://opencommons.uconn.edu/dissertations/226
The Versatility of Ether-Bridged Cycloadducts Towards the Synthesis of Complex
Natural Products

Harold Deshaun Cooper, PhD
University of Connecticut, 2013

The presence of a heterocyclic moiety can be observed in many of today’s
bioactive natural products. One of the most commonly observed is furan, an aromatic
five-membered ring containing an oxygen atom. Furan is a simple compound, yet
versatile enough to be used as a synthetic synthon leading to complex structures such as
the antioxidant Phelligridin G and the antibacterial agent Platensimycin. In the former, it
is spiro-fused to the five-membered carbocycle of the 6-5-5 tricyclic domain while in the
latter it makes up the ether-bridged cycloadduct of the hydrophobic cage.
Conventionally, furan can undergo cycloadditions in the presence of reactive dienophiles
via the Diels-Alder reaction to form oxabicyclic synthons.
A strategy for the synthesis of the embedded spirocyclic core of phelligridin G
from a 2-phenylfuran system was developed. Finding a suitable dienophile compatible
with this biphenyl ring was a daunting task; however, we successfully obtained the
oxabicyclo[2.2.1]heptadiene intermediate upon surveying a plethora of available
dienophiles. Exposure of the strained ring system to the Grubbs’ 2nd generation
ruthenium-based catalyst facilitated a domino ring-opening metathesis/ring-closing
metathesis (ROM/RCM) to give a spiroannulated furan. Further evaluation showed the
highly reactive tetrachlorocyclopropene was a compatible dienophile leading to the
formation of spiro-fused pyran ring structures through a related metathesis approach.
Recently, we have developed a novel and expedient route towards the tetracyclic
caged domain of platensimycin using an oxabicyclo[3.2.1]octadiene building block.
Within our methodology a late-stage intermediate has been established from the [4+3]
cycloaddition of a substituted furan with tetrabromocyclopropene along with an
intramolecular γ–alkylation to form the seco-cage of this hydrophobic region. It has been
postulated that structural modifications could help improve its poor pharmacokinetic
profile while retaining potent bioactivity. Utilizing this furan-based route has led to the
synthesis of several novel analogues that will be evaluated for their antimicrobial activity
against methicillin-resistant Staphylococcus aureus (MRSA). We have assembled a
unique derivative in which the cyclohexanone moiety has been replaced with the more
constricted cyclopentanone ring. A second series of analogues synthesized have the C-
ring completely removed from the caged domain and manipulation of the ketone
functionality was evaluated.
The Versatility of Ether-Bridged Cycloadducts Towards the Synthesis
of Complex Natural Products

By
Harold Deshaun Cooper
B.S., Norfolk State University, 2004

A Dissertation
Submitted in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy
at the
University of Connecticut
2013
Copyright by
Harold Deshaun Cooper

2013
APPROVAL PAGE
Doctor of Philosophy Dissertation

The Versatility of Ether-Bridged Cycloadducts Towards the Synthesis of Complex
Natural Products

Presented by
Harold D. Cooper

Major Advisor __________________________________________________
Dennis L. Wright

Associate Advisor __________________________________________________
Amy Anderson

Associate Advisor __________________________________________________
Mark Peczuh

University of Connecticut
2013
Dedicated to my mother, and in memory of my grandmother, Margaret M. Cooper, and
my uncle, James P. Highter.

“The fear of the LORD is the beginning of knowledge, But fools despise wisdom and
instruction.”
Proverbs 1:7 NKJV
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Acknowledgements
I would like to thank God for giving me the patience, strength, and faith to accomplish
my greatest challenge yet. I am a witness that “I can do all things through Christ that strengthens
me.” It has taken a lot of prayer to make it through this long journey; however, this is just the
beginning. To the professor responsible for exposing me to research, my undergraduate advisor,
Dr. Suely Black I owe you so much for keeping me at NSU and pushing me as a Chemistry
major!
I would like to thank my advisor Dr. Dennis Wright for his guidance throughout my
graduate career. With his help I have transitioned from an inexperienced first-year graduate
student to a well-trained scientist. He has exposed me to a new world of scientific research by
contributing his knowledge, experience, and enthusiasm. He has given me a better understanding
of the role organic chemistry plays in developing new drugs. When things were not going well in
the lab Dr. Wright would inspire me by discussing new potential routes towards our desired
target. I want him to know I really appreciate all his help, and because of great advisors like him
working towards my Ph.D. was a little less stressful. In addition, I would like to show my
appreciation to Dr. Amy Anderson. She was key player in my professional development. I also
want to thank Dr. Mark Peczuh for being so enthusiastic about chemistry; it rubbed off on me a
lot. I appreciate Drs. Amy Howell and James Henkel for recruiting me to UConn and their
encouragement during my time here; Dr. Kyle Hadden for his time and advice. I thank them all
for serving on my committee. Dr. Dan Eustace became my mentor and helped my career
development. Dr. Martha Morton deserves special thanks for her help with NMR spectroscopy.
I am truly grateful for my colleagues, past and present lab members Drs. David Bolstad,
Paul Sabila, Teather Sundstrom, E. Zack Oblak, Kishore Viswanathan, Santosh Keshipeddy, and
Jennifer Berlein; Eric Scocchera, Michael VanHeyst, Narendran G-Dayanandan, Eric Falcone,
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and Chris Merguerian . You guys have made stressful days in the lab more tolerable. Our
scientific dialogue over the years in the lab has been beneficial to my professional growth as a
chemist. I could not ask for a better group of scientist to work with. Additionally, I will miss our
trips to the Dairy Barn, Teds, Utsav, the Union, and Jack Rabbits.
I would like to thank my entire family for all their support throughout my life. They have
been a major source of inspiration. My mommy Diane especially since she had to raise me as a
single parent until I graduated high school; she has taught me to never give up and always do my
best no matter how difficult the task. Ultimately she is the reason for my ambition, confidence,
and cheerful personality, and my stepfather Eddie who came in my life years later, but just at the
right time. I love you both very much! Of course my aunts and uncles, who always told me to
pray about the situation; my cousins Tiffany, Micah, Adrienne, and Charra who constantly
remind me that I must finish because I will be the first doctor in the family; my 2nd cousins Isaiah,
Josiah, Jalen, Alex and Amani who will follow in my footsteps. My love Dr. Jasmine Robinson
thanks for the encouragement, devotion, and support you have expressed during this long journey
babes. My friends both Kevins, Bluye, Adrian, Jason, Evan, Tarae, Charles, and Tanya, who have
been there to listen to me vent. Ms. Jackie, the Ellis & the Robinson families who all became my
parents while living in Connecticut.
Drs. Danielle Watt, Ranyelle Reid, Robin Walker, Cheryl Bell, Randy Jackson, D.P., the
“Docs”, GSCA, and my fraternity brothers of Iota Phi Theta must know how much I appreciate
your continued support and assistance in smoothing out the nonchemistry problems that arose
over the years. Finally, I thank the University of Connecticut for the numerous fellowships and
for giving me the opportunity to play an integral role in enhancing its excellent research program.

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TABLE OF CONTENTS
ABSTRACT……………………………………………………………………………
ACKNOWLEDGEMENTS……………………………………………………………v
CHAPTER
1 INTRODUCTION……………………………………………………………..1
Exploitation of Heterocyclic Chemistry: Studies on Furan Synthons
Oxabicyclic Ethers…………..………………………………………………….2
Furan Diels-Alder Reactions………..………………………………….2
Diels-Alder Cycloaddition [4+2]……………………………………….3
Higher-Order Cycloaddition [4+3].…………………………………….4
Techniques towards Spiroannulations…………………………………………..6
Routes to Oxaspiro Compounds………………………………………………..14
Application of Electrooxidative Cyclizations (EOC)…………………..14
Olefin Metathesis Reactions……………………………………………16
Palladium-Catalyzed Reactions towards Spiro-fused Furans………….17
Robinson Annelation toward Spiro-fused Pyrans………………………19
Natural Products and Targets………………………………………………...20
Antioxidants in Drug Discovery.………………………………………..21
Phelligridin G……………………………………………………22
Antibacterial Drug Development..………………………………………24
Platensimycin: Background……………………………………..25
Survey of Structural Analogues………..………………………..26
Summary and Conclusions………………………………………38
Notes and References……………………………………………………39
2 RESULTS/DISCUSSION……………………………………………………….42
Spirocyclic Core of Phelligridin G……...……………………………………….42
Anodic Oxidation of Silyl Enol ethers…..……………………………....43
Cyclic Voltammetry Studies……...……………………………………...47
Domino Ring-Opening/Ring-Closing Metathesis (ROM/RCM)……...…50
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