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Multicomponent Reactions in the
Synthesis of Novel Antibacterial Agents
HONORS THESIS IN CHEMISTRY

BROWN
SUBMITTED BY:

Daniel Greenwald
ADVISOR:

Prof. Jason Sello, Ph.D.
Brown University
Providence, Rhode Island
May 2012

© 2012 by Daniel Greenwald
This work is licensed under the Creative Commons AttributionNonCommercial-ShareAlike 3.0 Unported License. To view a copy of
this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

CONTENTS:

Acknowledgements ......................................................................................................................... iii
List of Schemes ................................................................................................................................ iv
List of Tables and Figures ............................................................................................................... v
Chapter 1 – Introduction.......................................................................................................... 1
The Problem of Antimicrobial Drug Resistance ............................................................. 1
The Ugi Four-Component Reaction ................................................................................. 2
References .............................................................................................................................. 6
Chapter 2 – Diversity-Oriented Synthesis of Efflux Pump Inhibitors in
Streptomyces coelicolor ....................................................................................... 7
Introduction ........................................................................................................................... 7
Synthesis and Testing of MC-02,595 (2) Analogs ....................................................... 11
Structure-Activity Studies of BU-005 Analogs .............................................................. 13
Confirmation of Efflux Pump Inhibition ........................................................................ 17
Summary and Future Directions ...................................................................................... 18
Experimental ........................................................................................................................ 19
References ............................................................................................................................ 20
Chapter 3 – Toward a Convergent Synthesis of the Dapdiamide Antibiotics ........ 21
Introduction ......................................................................................................................... 21
Generation of a Di-Protected Ugi Product .................................................................... 23
A One-Pot MCR Strategy for Dapdiamide Synthesis .................................................. 24
Use of t-Butyl Protected Amino Acid Isocyanides........................................................ 26
Fumaramate Formation through Phosphate-Mediated Deamination...................... 28

i

Summary and Future Directions ...................................................................................... 29
Experimental ........................................................................................................................ 30
References ............................................................................................................................ 35
Chapter 4 – Toward a Convergent Synthesis of the TAN-1057 Antibiotics ........... 36
Introduction ......................................................................................................................... 36
Retrosynthesis and Convertible Isocyanides ................................................................. 37
β-Homoarginine Synthesis: Arndt-Eistert Homologation .......................................... 38
β-Homoarginine Synthesis: Alternative Diazoketone Syntheses .............................. 39
Convertible Isocyanide Syntheses ................................................................................... 41
Summary and Future Directions ...................................................................................... 42
Experimental ........................................................................................................................ 44
References ............................................................................................................................ 48
Appendix A – List of Abbreviations ..................................................................................... 49
Appendix B – Representative Spectra................................................................................. 50
For Compounds in Ch. 2 ................................................................................................... 51
For Compounds in Ch. 3 ................................................................................................... 71
For Compounds in Ch. 4 ................................................................................................... 84

ii

ACKNOWLEDGEMENTS

O

VER THE COURSE OF THE LAST FOUR YEARS,

PROFESSOR JASON SELLO has generously
extended his guidance and mentorship in ways that far exceeded anything I could have
expected as an incoming freshman. In addition guiding my academic development and
providing a supportive environment in which to learn and to grow, Professor Sello has dedicated
his scarce time and resources to providing as challenging and as enriching of an academic
experience as possible. Whether by taking the time to discuss experimental results or through
his discretionary funding of my first summer’s research, Professor Sello has done everything
possible to make my Brown experience exceptional. I would like to thank him for his time, for
his flexibility, and for his invaluable guidance.
I would also like to thank Dr. Babajide Okandeji, who trained me in the lab during my first
summer at Brown and with whom I conducted the research on efflux pump inhibitors. Jide
showed a willingness to help and to explain concepts which was matched only by his unfailing
humor in the lab. The second chapter of this thesis is based in large part on our published results
and the work in his thesis. Additionally, I would like to thank Bennett Ferris, a truly gifted
undergraduate scientist with whom I worked collaboratively during my third summer, and who
was as patient with my teaching as Jide was with my learning.
I could not have completed my work at Brown without the constant support of the whole
Sello Lab, whose members were always willing to take the time to teach and to provide
assistance. In particular Aaron Socha, Dan Carney, James Vecchione, Jennifer Reeve Davis,
Jesse Morin, Jessica Wroten, Kyle Totaro, and Nicholas Tan all directly supported the research
in this thesis at one time or another.
Other individuals without whom I could not have completed this work include Dr. Russ
Hopson, who managed the NMR equipment and provided assistance and training, and Dr. TunLi Shen, who both conducted mass spectrometry analysis and who trained undergraduates on
the use of his equipment. I am also indebted to Kerri Heffernan, whose leadership of the Royce
Fellowship program funded my second summer of research and allowed me to exchange ideas
with an exciting subset of the Brown community. I would like to thank all of the other members
of the Chemistry Department who made this research possible, including the members of the
Cane group, my professors, the UTRA committee, and those who offered materials and
expertise to my research at Brown.
Finally, I would like to thank my parents for funding my education and for supporting me in
all of my work, and I would like to thank all of my friends (especially Elise) who made my time
pursuing research rewarding and fun on so many levels.

iii

List of Schemes
Scheme 1.1:
Scheme 1.2:
Scheme 1.3:
Scheme 1.4:
Scheme 1.5:
Scheme 2.1:
Scheme 3.1:
Scheme 3.2:
Scheme 3.3:
Scheme 3.4:
Scheme 3.5:
Scheme 3.6:
Scheme 3.7:
Scheme 3.8:
Scheme 3.9:
Scheme 3.10:
Scheme 3.11:
Scheme 3.11:
Scheme 3.12:
Scheme 4.1:
Scheme 4.2:
Scheme 4.3:
Scheme 4.4:
Scheme 4.5:
Scheme 4.6:
Scheme 4.7:
Scheme 4.8:
Scheme 4.9:
Scheme 4.10:
Scheme 4.11:
Scheme 4.12:

The Ugi four-component reaction ......................................................................................................... 2
The proposed mechanism of the Ugi reaction .................................................................................... 2
The Ugi 4-CR in the targeted synthesis of nocardicin D ................................................................... 3
The Ugi 4-CR in the diversity-oriented synthesis of a library of putative
antimicrobial agents.................................................................................................................................. 4
Retrosynthetic analyses of synthetic targets in this thesis that feature the Ugi 4-CR................... 5
Retrosynthesis of 2 using the Ugi reaction ......................................................................................... 10
Retrosynthesis and orthogonal deprotection of the dapdiamides ................................................. 22
Retrosynthesis of dapdiamides C and C* ........................................................................................... 23
Synthesis of isocyano-leucine methyl ester ........................................................................................ 23
Orthogonal deprotection of 2 ............................................................................................................... 24
Retrosynthesis of dapdiamide C* using protected fumaramate ..................................................... 24
Synthesis of N-para-methoxybenyl fumaramic acid ......................................................................... 25
Attempted synthesis of a protected dapdiamide C* ......................................................................... 25
Synthesis of MA-protected fumaramic acid ....................................................................................... 26
Attempted synthesis of a protected dapdiamide C* ......................................................................... 26
Retrosynthesis of dapdiamide C* using isocyano L-leucine t-butyl ester (13) ........................... 27
Attempted syntheses of isocyano L-leucine t-butyl ester ................................................................. 27
Retrosynthesis of dapdiamide C* using asparagine .......................................................................... 28
Attempted synthesis of a dapdiamide C* proof-of-concept analog ............................................... 28
The last three steps of Yuan and Williams’ total synthesis of TAN-1057 A/B ............................ 37
Convertible isocyanides in the Ugi reaction ...................................................................................... 27
Retrosynthesis of 2 using an Ugi reaction .......................................................................................... 38
Attempted β-homoarginine syntheses ................................................................................................ 38
Mechanism of the Arndt-Eistert homologation ................................................................................ 38
Alternative attempted β-homoarginine synthesis ............................................................................. 39
Diazoketone synthesis reported by Bio et al....................................................................................... 40
Determination of a viable synthesis of tri-CBz-argininyl chloride ................................................. 40
Attempted synthesis of a hydrazidoyl chloride.................................................................................. 41
Synthesis and mechanism of cleavage of a convertible isocyanide ................................................ 41
Synthesis and side reactions in the production of an alternative convertible isocyanide .......... 42
Possible variations of TAN-1057 A/B ................................................................................................ 43

iv

List of Tables and Figures
Figure 1.1: The decline in antibiotic discovery ............................................................................................................ 1
Figure 2.1: Mechanisms of antibiotic resistance in bacteria ...................................................................................... 7
Figure 2.2: Families of multi-drug resistance pumps found in Gram-positive and Gram-negative
bacteria ............................................................................................................................................................ 8
Figure 2.3: Illustration of efflux pump inhibitors causing the accumulation of antibiotics in a
bacterial cell .................................................................................................................................................... 8
Figure 2.4: Efflux pump inhibitors discovered by MPEX Pharmaceuticals ............................................................ 9
Figure 2.5: A colony of S. coelicolor............................................................................................................................... 10
Table 2.1: Analogs of 2 .................................................................................................................................................. 12
Figure 2.6: Variations of the first amino acid.............................................................................................................. 13
Figure 2.7: Variations of the moiety connecting amino acids 1 and 2 ................................................................... 14
Figure 2.8: Variations of the second amino acid ........................................................................................................ 15
Figure 2.9: Variations of the C-cap............................................................................................................................... 16
Table 2.2: BU-005 activity in S. coelicolor variants ................................................................................................... 17
Figure 3.1: The dapdiamides ......................................................................................................................................... 21
Table 3.1: Ugi reactions for the generation of 16-19 .............................................................................................. 28
Figure 3.2: Potential modifications of the dapdiamide core structure .................................................................. 29
Figure 4.1: TAN-1057 A-D ........................................................................................................................................... 36
Figure 4.2: Possible products of the reaction of 4 with cyanuric chloride ............................................................ 41

v

CHAPTER 1
Introduction
The Problem of Antimicrobial Drug Resistance
The resistance of pathogens to antimicrobial agents is poised to become one of the most formidable
challenges in modern medicine. While the phenomenon of antimicrobial drug resistance is not new—the first
drug-resistant infections emerged shortly after the mass-production of penicillin [1]—over the last few decades
the emergence of drug-resistant diseases has begun to outpace the development of new strategies to combat them.
This deficit in the discovery of novel antimicrobial agents has been growing even as lethal diseases such as
extensively drug-resistant tuberculosis (XDR-TB) and multiple-resistant Staphylococcus aureus (MRSA) have
proliferated first in hospitals, then in the community at large. Already the American Medical Association
estimates that there are over 18,000 deaths in the U.S. per year from MRSA alone [2].

Total number of new antibacterial drugs

18

Figure 1.1: The decline in antibiotic discovery [3]

16
14
12
10
8
6
4
2
0
1983-1987 1988-1992 1993-1997 1998-2002 2003-2007

To combat the continual emergence of antimicrobial drug resistance among pathogenic microorganisms,
scientists have been actively pursuing three different strategies. First, research can be directed at developing or
discovering antibacterial agents with novel structures and mechanisms of action. These drugs are often highly
effective if successfully brought to market, however the costs and financial risks associated with their development
are quite high. Alternatively scientists can optimize the efficacy of existing drugs or drug candidates by creating
and testing novel analogs of these compounds. Finally, scientists can develop compounds which mitigate the
mechanisms of resistance, restoring the effective use of older drugs that were once considered obsolete.
The latter two options motivated the research presented in this thesis. The goal of each of the three projects
presented in this thesis was to develop a novel, diversity-oriented chemical synthesis of an existing antimicrobial
agent that would enable the efficient introduction of subtle variations into the compounds’ molecular structures.
Testing these new, varied compounds in vitro would allow us to elucidate the relationships between molecular
structure and the compounds’ efficacies. Systematically establishing these so-called “structure-activity
relationships” (or “SAR’s”) would then enable us to produce novel molecules with optimized activity against
drug-resistant pathogens.

1


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