Part A. Efficient and Stereoselective Synthesis of (+)-MK7607 and its C-1 Epimer via the Transposition of a Tertiary Allylic Alcohol; Part B. Synthesis and Evaluation of Novel Artificial Nucleic Acids as a New Class of Biomolecules

다국어 초록 (Multilingual Abstract)

Part A. Efficient and Stereoselective Synthesis of (+)-MK7607 and its C-1 Epimer via the Transposition of a Tertiary Allylic Alcohol

An efficient and stereoselective synthesis of (+)-MK7607 and its C-1 epimer has been accomplished from a readily obtainable common intermediate in high overall yields.
The synthetic methodologies mainly rely on the stereospecific 1,3-allylic transposition of the hindered tertiary alcohol group through a palladium-catalyzed allylic rearrangement as well as a PBr3-mediated allylic-transposed bromination. To our knowledge, only a few precedents exist for the cyclic systems, but the stereochemistry of the rearranged products was ambiguously determined. Based on our experimental data, that it could be a result of the SNi′ reaction mechanism of intermediate phosphate ester. The synthetic process was highly selective and efficiently provided synthetically useful intermediates particularly in the preparation of MK7607-containing analogues.


Part B. Synthesis and Evaluation of Novel Artificial Nucleic Acids as a New Class of Biomolecules

To further develop novel artificial nucleic acid analogues as potential therapeutics, triazole-containing cyclic dinucleotides were designed and synthesized. The construction of the (bis)triazole macrocycle was achieved via a copper(I)-catalyzed Huisgen reaction in both one-pot and stepwise procedures. The docking study revealed that the cyclic di-GG, the representative analogue, exhibits the same binding interactions in Vc2 RNA (class I c-di-GMP riboswitch aptamer) active-site cavities as the natural ligand bis-(3’,5’)-cyclic dimeric guanosine monophosphate (c-di-GMP). To investigate the supramolecular properties of the cyclic TNAs, self-assembly studies were performed. The initial results indicate the potential of cyclic TNAs in the development of supramolecular assemblies and bioinspired materials.
Further studies are currently in progress including a biological evaluation and a more detailed self-assembly study.

목차 (Table of Contents)

• Abstract
• Contents
• Part A.
• I. Introduction 1
• II. Results and Discussion 3
• III. Conclusion 11
• IV. Experimental 12
• V. References 25
• Part B.
• I. Introduction 29
• I.1. Nucleotide-Based Second Messengers 29
• I.2. Brief Overview of Cyclic-di-GMP 30
• I.2.1. Signaling and Biosynthesis 30
• I.2.2. Synthetic Studies and Modification of c-di-GMP 33
• I.2.3. Nonionic Analogues of c-di-GMP 34
• I.3. Clickable Nucleotide-Based Analogues 36
• I.3.1. Promising Backbone: 1,2,3-Triazole Unit 36
• I.3.2. Triazole-Containing Nucleic Acid Analogues 37
• I.3.3. Synthesis of Linear Triazole Nucleic Acids 38
• I.4. Objective of This Dissertation 40
• II. Results and Discussion 41
• II.1. Synthesis of Cyclic TNAs 41
• II.2. Docking Study 47
• II.3. Ongoing Research: Self-Assembly 49
• III. Conclusion 51
• IV. Experimental 53
• IV.1. General 53
• IV.2. Synthetic Methods and Characterization of Compounds 54
• IV.3. Molecular Docking Method 82
• V. References 83
• Appendix I 89
• Appendix II 105
• 국문초록 123