Synthesis of small molecule therapeutics and ligands utilizing rhodium carbenoid chemistry Public
Park, Hyunmin (Summer 2018)
Published
Abstract
The primary objective of this thesis was to utilize the reactions of donor/acceptor substituted rhodium carbenoids for the synthesis of small molecule therapeutics and ligands. The first section of this thesis was to explore novel multi-functional antidepressants with HDAC and monoamine reuptake inhibitors (hydroxamic acid/ 2-aminobenzamide chelator) as potential therapeutic agents for the treatment of depression by utilizing the enantioselective cyclopropanation, reductive amination and amide coupling reaction. Moreover, several effective biological tests were performed and demonstrated that hydroxamic acid analogue with enantioenriched cyclopropane HM3a-R has great antidepressant effects in animal models. The second project was the development of new phosphoric acid ligands as organocatalysts for C-H insertion. In this project, the new phosphoric acid ligands were synthesized for organocatalysis for C-H insertion. As a result, C-H insertion with the phosphoric acid catalyst 12b has the most effective enatioselectivity of desired C-H insertion products. However, N-H insertion via the photochemistry reaction by using blue LED has no effect on increasing enantioselectivity. The third section was to develop diverse enantioenriched cyclopropyl amine derivatives for inhibition of EBOV by utilizing the enantioselective cyclopropanation and reductive amination. Furthermore, biological studies (infectivity and cell viability activity) suggested that (R,S) enantiomer was much better effect than (S,R) enantiomer, as well as secondary amine compounds had a greater effect than tertiary amine compounds. Especially, HDE-49 is the best for inhibiting EBOV infection with having a significant effect on the cell viability. In summary, one organocatalysts project for C-H insertion and two different medicinal chemistry projects could be initiated by using enabling technology unique to Davies’ group. The multidimensional, multidisciplinary rational approach and collaborative efforts led to the discovery of specific phosphoric acid organocatalysts as well as novel scaffolds for various targets, which might have a greater potential and broader impact in medication development for antidepressant, and ebola virus inhibitors.
Table of Contents
CHAPTER 1: RATIONAL DESIGN OF NOVEL AND MULTI-FUNCTIONAL ANTIDEPRESSANTS: HISTONE DEACETYLASE (HDAC) AND
MONOAMINE REUPTAKE INHIBITORS………………………………………….1
1.1. INTRODUCTION …………………………………………………………………...1
1.1.1. Histone Deacetylases (HDACs) and Histone Deacetylases Inhibitors (HDACIs)………………………………………………………………….……1
1.1.2. Monoamine Reuptake Inhibitors………………………………………….……..6
1.1.3. Design of Novel Antidepressants with HDAC and Monoamine Reuptake Inhibitors……………………………………………………………………….12
1.2. RESULTS AND DISCUSSION………………………………...……………………14
1.2.1. Chemistry………………………………………………………………………...14
1.2.1.1. Synthesis of Dichloro Aryl Diazoacetate……………………………………….15
1.2.1.2. Synthesis of (E)-buta-1,3-dienylbenzene……………………………………….15
1.2.1.3. Synthesis of Enantiomers of Arylcyclopropylaldehyde Compounds………… 16
1.2.1.4. Synthesis of Multi-functional Antidepressants with 2-Aminobenzamide……….17
1.2.1.4.1. INEFFICIENT Reaction of Antidepressant with 2-Aminobenzamide……...17
1.2.1.4.1.1. Synthesis of Primary Amine Intermediate with 2-Aminobenzamide..….…17
1.2.1.4.1.2. Synthesis of Secondary Amine Intermediate with O-Protection of TMS….18
1.2.1.4.2. EFFICIENT Reaction of Antidepressant with 2-Aminobenzamide…..….….19
1.2.1.4.2.1. Synthesis of Methylamine Intermediate with Benzyl Ester………………...19
1.2.1.4.2.2. Synthesis of Secondary Amine Intermediate……………..…………...…...20
1.2.1.4.2.3. Synthesis of Novel Antidepressant with 2-Aminobenzamide……………...21
1.2.1.5. Synthesis of Multi-functional Antidepressant with Hydroxamic Acid……...…...22 1.2.2. Biological Activity………………………………………………………………...24
1.2.2.1. In Vitro Data for HDACI Activity……………………………..………………24
1.2.2.2. In Vivo Data for Anti-inflammation Activity………………………..………….25
1.2.2.3. In Vivo Data for Antidepressant Activity (Tail Suspension Test)…..…………...27
1.2.2.4. In Vivo Data for Antidepressant Activity (Forced Swim Test)…………………28
1.3. CONCLUSIONS……………………………………………………………………..31
1.4. EXPERIMENTAL SECTION……………………………………………………….32
1.5. REFERENCES………………………………………………………………………52
CHAPTER 2: DEVELOPMENT OF NEW PHOSPHORIC ACID LIGANDS AS ORGANOCATALYSTS FOR C-H INSERTION..…………59
2.1. INTRODUCTION ………………………………………………………………….59
2.1.1. C-H Insertion and Phosphoric Acid Ligands for Organocatalysis for Enantioselective C-H Insertion…………………………………………..………………………….59
2.1.2. Design of New Phosphoric Acid Ligands for Organocatalysis for C-H Insertion …61
2.2. RESULTS AND DISCUSSION……………………………………………………...65
2.2.1. Chemistry………………………………………………………………………….65
2.2.1.1. Synthesis of Diazophosphate (9)…………………..………………..…………..65
2.2.1.2. Synthesis of Diverse Enantioselective Cyclopropyl Phosphonate Intermediates…………………………66
2.2.1.3. Synthesis of Diverse Phosphoric Acids with Cyclopropane……………...……...68
2.2.1.4. Synthesis and Optimization of C-H Insertion with Methyl Indole, Diazoacetate and Organocatalyst (12a) in High Yield and Enantioselectivity……………...…..69
2.2.1.5. Synthesis of C-H Insertion with Methyl Indole, Diazoacetate with Br or Cl, and Organocatalyst (12a)……………………72
2.2.1.6. Synthesis of C-H Insertion with Dimethyl Indole, Diazoacetate, and Organocatalyst (12a)………74
2.2.1.7. Synthesis of C-H Insertion with Diverse Organocatalysts (12 series)……… 76
2.2.1.8. Photochemistry of Aryldiazoacetates…………………………………………...80
2.2.1.8.1. Synthesis of 4-Bromophenyl Ethyl Diazoacetate………………………… 81
2.2.1.8.2. Synthesis of N-H Insertion with Diverse Organocatalysts via Photochemistry………………………81
2.3. CONCLUSIONS…………………………………………………………………..…83
2.4. EXPERIMENTAL SECTION…………………………………………………..…...85
2.5. REFERENCES……………………………………………………………………..114
CHAPTER 3: DEVELOPMENT OF DIVERSE ENANTIOSELECTIVE CYCLOPROPYL AMINE DERIVATIVES FOR INHIBITION OF EBOV ... 119
3.1. INTRODUCTION ……………………………………………………………… 119
3.1.1. Ebola Virus (EBOV)…………………………………………………………….119
3.1.2. Overview of Current Approaches of EBOV Vaccines and Therapeutics…………122
3.1.3. Design of Diverse Enantioselective Cyclopropanes for Inhibition of EBOV……..126
3.2. RESULTS AND DISCUSSION ………………….………………………………...130
3.2.1. Chemistry………………………………………………………………………..130
3.2.1.1. Synthesis of Methanesulfonyl Azide…………………………………………...130
3.2.1.2. Synthesis of N-Sulfonyl-1,2,3-triazole Derivatives……………………………..131
3.2.1.3. Enantioselective Synthesis of Cyclopropyl Aldehyde Intermediates…….……...132
3.2.1.4. Enantioselective Synthesis of Various Cyclopropylamines…………………….133 3.2.2. Biological Analysis……………………………………………………………….136
3.2.2.1. Preliminary test of Cyclopropane Scaffolds against EBOV……………………136
3.2.2.2. In Vitro Test of (S,R) or (R,S) Cyclopropane Enantiomers with Secondary or Tertiary Amine Derivatives for EBOV Infection Activity and Cell Viability…...140
3.2.2.3. In Vitro Test of (R,S) Cyclopropane Enantiomers with Secondary Amine Derivatives for EBOV Infection Activity and Cell Viability……142
3.3. CONCLUSIONS……………………………………………………………………144
3.4. EXPERIMENTAL SECTION……………………………………………………...145
3.5. REFERENCES…………………………………………………………………… 198
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