hydrothermal liquefaction of municipal wastewater cultivated algae

670 Pages·2012·48.29 MB·English

by  Kyu Ok Jeon

Synthetic Approaches to Skeletally Diverse Sultams
Using Vinyl- and α-Halo Benzenesulfonamides
By
Kyu Ok Jeon
M.S., Kangwon National University, South Korea, 2004

Submitted to the Department of Chemistry and the Faculty of the Graduate School of
the University of Kansas in partial fulfillment of the requirements of the degree of
Doctor of Philosophy

________________________________
Paul R. Hanson, Chairperson

________________________________
Richard S. Givens

________________________________
Jeff Aubé

________________________________
Jon Tunge

________________________________
Minae Mure

July 24, 2012
Date Defended
The Dissertation Committee for Kyu Ok Jeon certifies that this is the approved
version of the following dissertation:

Synthetic Approaches to Skeletally Diverse Sultams
Using Vinyl- and α-Halo Benzenesulfonamides

________________________________
Paul R. Hanson, chair

________________________________
Richard S. Givens

________________________________
Jeff Aubé

________________________________
Jon Tunge

________________________________
Minae Mure

___________ July 24, 2012
Date Approved
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Abstract
Kyu Ok Jeon
Department of Chemistry
The University of Kansas
July 2012
The development of new chemical methods to generate novel and diverse
structures to probe chemical space is an important aspect of early phase drug
discovery. Diversity-Oriented Synthesis (DOS) is a powerful strategy that seeks to
generate chemical methods capable of delivering an array of molecular scaffolds with
structural and functional diversity. Ultimately, these methods can be adapted to
produce molecular libraries. It is the purpose of this thesis to highlight a series of
new chemical methods that deliver an array of drug-like sultam scaffolds to be
screened for broad biological activity in the molecular library program run by the
National Institutes of Health.
The first project described in chapter one of this dissertation includes the
synthesis of a collection of diverse bi- and tricyclic sultams in an overall DOS
approach utilizing a ring-opening metathesis / ring-closing metathesis / cross
metathesis (ROM–RCM–CM) cascade strategy. A variety of functionalized, tricyclic
sultams were generated as precursors derived from a diastereoselective IMDA
reaction in good yields and selectivity. The ROM–RCM–CM strategy to produce
skeletal and appendage-based diverse sultams is presented.
The second project is the generation of diverse sultams utilizing α,β-
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unsaturated γ- and δ-sultams. These 5- and 6-membered sultams were prepared and
applied to further diversifications using aza-Michael reactions, cycloadditions,
alkylation/benzylations and propargylation-[3+2]-cycloadditions. Utilizing the aza-
Michael reaction, we have developed an efficient protocol for the synthesis of a 141-
member library collection of isothiazolidine 1,1-dioxide derivatives.
The last project outlined in chapter four is the synthesis of novel 7- and 8-
membered tricyclic, biaryl sultams using an intramolecular Pd-catalyzed C-arylation
reaction. Namely, in the amino ester-derived sultams, remote 1,5- and 1,6-
asymmetric induction emanating from the external stereogenic center is operative,
whereby a favorable Cα–H/S=O syn pentane interaction, is the source of asymmetric
induction for a highly atropdiastereoselective thermodynamic equilibration process
yielding a low energy conformer of “like” configuration (S,S ).
a
In the course of X-ray crystallographic analysis, as well as detailed NMR
studies, we uncovered a number of notable and interesting structural features of the
7-membered amino ester-derived sultams in both solid and solution phases that
confirm a structure as a single conformer (>95:5) containing biaryl axial chirality of
“like” configuration (S,S ) with respect to the stereogenic center in the external side
a
chain. Moreover, variable temperature NMR analysis has indicated that the axis of
chirality at the biaryl bond has a relatively small interconversion barrier that allows
for this rapid thermodynamic equilibration of the “like” and “unlike”
atropdiastereomers. Detailed variable NMR analyses on a number of analogs, vide
infra, point to rotamer dynamics (about the N–C bond in the external side chain) and
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ring size of the corresponding benzothiazepine (n = 1)/benzothiazocine (n = 2) 1,1-
dioxides as governing factors in this notable thermodynamic equilibration of
atropdiastereomers. Current efforts are focused on the computational calculation for
the energy barrier between two atropdiastereomers interconversion, as well as the
further development of an “atropdiastereoselective” C-arylation process. In addition,
future studies will continue to probe the dynamic factors involved in the origins of
atropselectivity. Utilizing this methodology, we are also generating additional
libraries of diverse tricyclic, biaryl sultams for high throughput screening of
biological activity with our collaborators at the National Institutes of Health.

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To Mom and Dad, my sisters and brother
For all support and love
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Acknowledgements
I would like to thank my supervisor Prof. Paul Hanson for the opportunity to work on
several interesting projects as well as participating within the group. And I will never
forget that you make fun of my name even though that’s not true. I would also like to
thanks Paul again for securing the funding throughout the research; which made this
opportunity possible.

I would like to thank Prof. Lee, Chang Kiu and his wife, Prof. Han, In Sook in Korea.
I didn’t know anything about organic chemistry when I joined in your research group
in 1998 and I learned a lot from you not only as an organic chemist but also as a
human being. You always encourage me for everything until today. It was
impossible to finish this journey without your guidance.

I am forever indebted to my mom, dad, two sisters and brother for their unconditional
love and support throughout my life journey. I thank you all for everything.

I would like to thanks all past and present members of the Hanson group for the
constant support, friendship and entertainment. I would like to thank Dr. Rayabarapu,
Dr. Chegondi, Dr. Zang, and Dr. Maity for your help for my research project. I am
truly indebted to Jana Markley for proofreading this thesis. I will promise that you
can ask me whenever you want to visit Korea. In addition, I would also like to thank
Dr. Justin Douglas for his constant support for spectra analysis and experiments
throughout. Without him my project would not have proceeded as smoothly.

To my committee: Dr. Givens, Dr. Aubé, Dr. Tunge, and Dr. Mure, I really appreciate
for your time to discuss about my research projects. I have learned a lot from each
one of you. I feel blessed to have had such wonderful professors here at KU.
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Synthetic Approaches to Skeletally Diverse Sultams
Using Vinyl- and α-Halo Benzenesulfonamides

Contents Page #

Title Page i
Acceptance Page ii
Abstract iii
Dedications vi
Acknowledgements vii
Table of Contents viii
Abbreviations xii
Chapter 1: Introduction: Biologically Active Sultams 1
1.1 Introduction 2
1.1.1 Properties of Sulfonamides 2
1.1.2 Sultam Bioactivities 6
1.2 Sultam-Containing Drugs 8
1.3 Bioactive Compounds Containing 5-Membered Sultam Moiety 11
1.3.1 Naphthoisothiazole 1,1-Dioxide Derivatives 11
1.3.2 1,2-Benzisothiazol-3-one 1,1-Dioxide
(Saccharin) Derivatives 13
1.3.3 Benzo[d]isothiazole 1,1-Dioxide Derivatives 19
1.3.4 Isothiazole 1,1-Dioxide Derivatives 20
1.3.5 2,3-Dihydroisothiazole 1,1-Dioxide Derivatives 21
1.4 Bioactive Compounds Containing 6-Membered Sultam Moiety 22
1.4.1 1,2-Thiazinane 1,1-Dioxide Derivatives 22
1.4.2 Benzodithiazine 1,1-Dioxide Derivatives 23
1.4.3 Benzothiazine 1,1-Dioxide Derivatives 28
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Contents (continued) Page #

1.4.4 Benzothiadiazine 1,1-Dioxide Derivatives 30
1.4.5 4-Hydroxy-2H-benzo[e][1,2]thiazine
1,1-Dioxide Derivatives 41
1.4.6 Benzothiadiazine-hydroxyquinolin-2(1H)-one
Derivatives 43
1.5 Bioactive Compounds Containing 7-Membered Sultam Moiety 46
1.5.1 Benzothiazepine 1,1-Dioxide Derivatives 46
1.5.2 Benzothiadiazepine 1,1-Dioxide Derivatives 48
1.5.3 Thiadiazepinoindole 2,2-Dioxide Derivatives 50
1.6 Conclusions 51
References for Chapter 1 53
Chapter 2: Metathesis Cascade Strategies (ROM–RCM–CM):
A Diversity-Oriented Approach to Skelletally Diverse Sultams 71
2.1 Introduction 72
2.1.1 Metathesis Reaction in Diversity-Oriented Synthesis 72
2.2 Results and Discussion 76
2.2.1 Intramolecular Diels-Alder Reaction 76
2.2.2 ROM–RCM–CM Strategy to a Tetrahydro-2H-3a,6-
epoxybenzo[d]isothiazole 1,1-Dioxide Sultams 78
2.2.3 ROM–RCM–CM Strategy to a Hexahydro-4a,7-
epoxybenzo[e][1,2]thiazine 1,1-Dioxide Sultams 85
2.2.4 ROM–RCM–CM Strategy to a Functionalized Tetrahydro-
2H-3a,6-epoxybenzo[d]isothiazole 1,1-Dioxide Sultams 87
2.3 Conclusions 90
References for Chapter 2 91
Chapter 3: Vinyl Sulfonamide in Diversity-Oriented Synthesis:
Utilizing 5- and 6-Membered Sultam Synthons for Library Production 97
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Contents (continued) Page #

3.1 Introduction 98
3.1.1 Aza-Michael Reaction 98
3.2 Results and Discussion 100
3.2.1 Diversifications of 2,3-Dihydroisothiazole
1,1-Dioxide Sultams 100
3.2.2 Diversification of 3,4-Dihydro-2H-1,2-thiazine
1,1-Dioxide Sultams 108
3.2.3 141-Member Library Production 110
3.3 Conclusions 116
References for Chapter 3 118
Chapter 4: Intramolecular C-Arylation to Tricyclic, Biaryl Sultams: Long-range
Asymmetric Induction in an Atropdiastereoselective, Thermodynamic
Equilibration Process 121
4.1 Introduction 122
4.1.1 Biaryl and Axially Chiral Compounds and Atropselectivity 122
4.2 Result and Discussion 127
4.2.1 Synthesis of 7-Membered Tricyclic, Biaryl Sultams
Derived from tert-Butylamine 127
4.2.2 Synthesis of 7-Membered Tricyclic, Biaryl Sultams
Derived from Chiral, Non-racemic Amino Esters 129
4.2.3 Synthesis of 8-Membered Tricyclic, Biaryl Sultams
Derived from Chiral, Non-racemic Amino Esters 131
4.2.4 Further Synthetic Applications of C-Arylation 135
4.2.5 X-ray and NMR Stuides Tricyclic,
Biaryl Sultam Compounds 140
4.2.5.1 X-ray Structures 140
4.2.5.2 NMR Studies 141
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