Rhodium(II)-Catalyzed Asymmetric Transformations and Their Applications in The Development of Novel CNS Drug Candidates Öffentlichkeit

Abstract

Synthetic methodologies using rhodium carbenoids derived from aryldiazoacetates holds
the promise of synthesizing new molecules, more cleanly and at higher purity and higher
stereoselectivity, than alternative substrates and methodologies. Amino alcohols have
applications throughout biology and medicine; however, their functionalization often
involves lengthily and inefficient synthetic methodologies. In the first part of this study it
was demonstrated that amino alcohols could be stereoselectively functionalized using
rhodium carbenoids derived from aryldiazoacetates. To characterize this process the
effect of the nature of the protecting group was quantified and a model of the mechanism
is proposed.
In the subsequent studies, cyclopropanation with rhodium carbenoids was used to
synthesize new biologically active molecules for treating Parkinson's disease and
neuropathic pain. Twelve analogs of antidepressant molecules, used in the treatment of
depression associated with PD, were synthesized. These analogs were tested for VMAT2
activity. While the molecules studied here did not show the desired biological activity,
the synthetic methodology has not been completely exhausted and future studies using
combinatorial approaches may yield more promising results.
In the final study, molecules that have high potency toward the neurotransmitter
transporters, SERT and NET, with a wide range of relative potencies for the two
transporters were generated by computational approaches. In total 30 molecules were
hypothesized. Out of those, 12 of the most promising candidates were synthesized and
tested in vitro.

Table of Contents

TABLE OF CONTENTS
Chapter 1. Introduction
1

1.1 Catalytic C-H Activation
2
1.2 Carbenes and Carbenoids
5
1.3 Catalysts for Carbenoid Transformations
9
1.4 Catalytic C-H Activation by Traditional Alkyldiazoacetate Derived Metal
Carbenoids
12
1.5 Catalytic C-H Activation by Donor/Acceptor Substituted Rhodium Carbenoids 14
1.6 Catalytic C-H Activation at Benzylic and Allylic Positions
19
1.7 Intermolecular C-H Activation Adjacent to Nitrogen
21
1.8 C-H Insertion Adjacent to Oxygen
25
1.9 Relative Rates of C-H Activation Adjacent to Oxygen
29
1.10 Relative Rates of C-H Insertion into Cyclic Amines
31
Chapter 2 Regioselective Intermolecular C-H Functionalization of Protected Amino
Alcohols
34
2.1 Background
34
2.2 Preparation of diazo compounds
35
2.3 Synthesis of amino alcohols
37
2.4 Synthesis of protected amino alcohols
38
2.5 Regioselective Catalytic Asymmetric C-H Functionalization of Protected Amino
Alcohols
45
2.6 Relative Rate Study
55

2.7 Conclusion
60
Chapter 3. Novel Class of Cyclopropylaminocarboxylic Acid for Parkinson's
Disease Treatment
61
3.1 Introduction of Parkinson's Disease
61
3.1.1 Oxidative Stress
62
3.1.2 Mitochondrial Defect
64
3.1.3 Abnormal Protein Aggregation (Lewy Body)
66
3.2 VMAT2 and PD
68
3.3 Current Treatment for PD
71
3.4 Drug Development for Treating PD
73
3.5 In Vitro Data from Dr. Gary Miller's Laboratory
80
3.6 Conclusion
87
Chapter 4. Combinatorial Approach to The Design and Synthesis of
Cyclopropylamines for Neuropathic Pain Treatment
88
4.1 Introduction
88
4.2 Major Mechanisms Involved in Neuropathic Pain
90
4.2.1 Peripheral Mechanisms
90
4.2.2 Central Mechanisms
90
4.3 Current Treatment of Neuropathic Pain
92
4.4 CNS drug development in the Davies group
94
4.5 Computational Modeling and Design of Novel Cyclopropylamine Drug Candidates
for Treating Neuropathic Pain
100
4.6 Synthesis of Novel Cyclopropylamine Drug Candidates
107

About this Dissertation

Rights statement

• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Stichwort	Parkinson's Disease Asymmetric C-H Functionalization CNS Amino Alcohol Neuropathic Pain
Committee Chair / Thesis Advisor	Davies, Huw, Emory University
Committee Members	Menger, Fred M, Emory University Liebeskind, Lanny S, Emory University

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