Biorenewable Chemicals in Organic Synthesis: Applications of Methyl Coumalate and Nitroquinones
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Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2019 Biorenewable chemicals in organic synthesis: Applications of methyl coumalate and nitroquinones Huangchao Yu Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Part of the Organic Chemistry Commons Recommended Citation Yu, Huangchao, "Biorenewable chemicals in organic synthesis: Applications of methyl coumalate and nitroquinones" (2019). Graduate Theses and Dissertations. 17624. https://lib.dr.iastate.edu/etd/17624 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Biorenewable chemicals in organic synthesis: Applications of methyl coumalate and nitroquinones by Huangchao Yu A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Chemistry Program of Study Committee: George A. Kraus, Major Professor Arthur Winter Gregory Phillips Wenyu Huang Levi Stanley The student author, whose presentation of the scholarship herein was approved by the program of study committee, is solely responsible for the content of this dissertation. The Graduate College will ensure this dissertation is globally accessible and will not permit alterations after a degree is conferred. Iowa State University Ames, Iowa 2019 Copyright © Huangchao Yu, 2019. All rights reserved. ii DEDICATION To Professor Kraus To my grandparents To my mother and fiancée Thank you for your love and support iii TABLE OF CONTENTS Page ABBREVIATIONS ........................................................................................................... iv ABSTRACT ........................................................................................................................ v CHAPTER 1. PYRONE CONTAINING COMPOUNDS IN ORGANIC SYNTHESIS ....................................................................................................................... 1 1.1. Chapter 1. Introduction ...................................................................................... 1 1.1.1. Natural Products Bearing a 2-Pyrone Motif ................................................... 1 1.1.2. Biorenewable Chemicals and Methyl Coumalate .......................................... 3 1.1.3. Polyethylene Terephthalate and Polyethylene Naphthalate ......................... 12 1.1.4. Indole Mediated Cycloaddition Chemistry .................................................. 16 1.1.5. Anthraquinones and Naphthoquinones ........................................................ 20 1.2. Result and Discussion ...................................................................................... 24 1.2.1. Diels-Alder Reaction of Pyrones and Enamines .......................................... 24 1.2.2. Diels-Alder Reaction of Pyrones and Indole Anions ................................... 33 1.2.3. Diels-Alder Reaction of Pyrones and Hydroxyquinones ............................. 35 1.3. Conclusion ....................................................................................................... 40 1.4. Experimental .................................................................................................... 42 1.5. References ....................................................................................................... 59 CHAPTER 2. SYNTHETIC APPLICATION OF NITROQUINONES .......................... 64 2.1. Chapter 2. Introduction .................................................................................... 64 2.1.1. Quinone Subunits in Natural Product ........................................................... 64 2.1.2. Current Synthesis of Nitroquinone Containing Compounds ........................ 68 2.1.3. Synthesis of Benzoquinone and its Reactions .............................................. 72 2.1.4. Previous Synthesis of Phenantroviridone and Lagumycin ........................... 77 2.2. Results and Discussion .................................................................................... 82 2.3. Conclusion ....................................................................................................... 93 2.4. Experimental .................................................................................................... 94 2.5. References ..................................................................................................... 116 CHAPTER 3. GENERAL CONCLUSION .................................................................... 120 iv ABBREVIATIONS Ac acetyl aq. aqueous CoA coenzyme A equiv. equivalent ESI electrospray ionization HRMS high-resolution mass spectrometry NBS N-Bromosuccinimide Nu nucleophile Pd/C palladium on carbon Ph phenyl PTSA para-toluenesulfonic acid QTOF quadrupole time of flight TBS tert-butyldimethlsilyl t-BuOH tert-butanol TfOH trifluoromethanesulfonic acid TLC thin-layer chromatography TMS trimethylsilyl v ABSTRACT Methyl coumalate is a bio-renewable material derived from malic acid. In the first chapter, we focused on the Diels-Alder reaction of methyl coumalate with a variety of dienophiles, including enamines, magnesium salts of indoles and hydroxyquinones. Some provided the bicyclic lactone intermediates, which could be further transformed into aromatic esters by acid/base catalyzed ring opening reactions. Others went through a Diels-Alder/retro Diels-Alder cascade and the carbon dioxide was extruded, affording the corresponding products. As a result, isophthalates, naphthalates and anthraquinone derivatives were successfully synthesized according to this strategy. The natural product Tomichaedin was also synthesized in over 40% yield. In the second chapter, we have developed a method to in situ generate nitroquinone, and a variety of nucleophiles were tested for the conjugate addition. Substituted nitroquinones can be synthesized in moderate yield via a 1,4-addition – tautomerization cascade. Nucleophiles including indoles, electron rich aromatics and heterocycles all showed good reactivity. Additionally, a divergent synthesis towards Lagumycin and Phenathroviridone skeleton was proposed. 1 CHAPTER 1. PYRONE CONTAINING COMPOUNDS IN ORGANIC SYNTHESIS 1.1. Chapter 1. Introduction 1.1.1. Natural Products Bearing a 2-Pyrone Motif Pyrones are a family of cyclic organic compounds containing an oxygen atom in a 6-membered ring system. The isomer with a lactone unit is known as 2-pyrone, while the oxygen atom at the 4-position is named as 4-pyrone (Figure 1.1). Both pyrones share the chemical properties of unsaturated alkene together with aromatic ring due to the unique unsaturated lactone structure1,2. Figure 1.1 Structure of pyrones Pyrone containing compounds are highly abundant in natural products. The biosynthetic pathway of pyrones was studied in recent years. The most accepted pathway is via the polyketide intermediates3. For example, the biosynthesis of 4-hydroxypyrones was revealed in Scheme 1.1. Starting with preformed long-chain fatty acyl-CoA thioesters, malonyl-CoA, as an extender unit, was added to the substrate twice, forming the triketide thioester intermediate. Cyclization via a Claisen-condensation mechanism followed by elimination of S-CoA afforded the 4-hydroxy pyrones. Other pathways for the generation of 2-pyrones were proposed, resulting in diverse structures of the ring or the side chain systems4a,4b. 2 Scheme 1.1 Biosynthetic pathway of 4-hydroxy-2-pyrones Some natural products with pyrone subunits showed excellent biological activities, as listed in Figure 1.2. Neurymenolide A, which was isolated from Fijian red macroalga, Neurymenia fraxinifolia, was found to have moderate cytotoxicity against cancer cell lines in vitro5. Moreover, Arisugacin A, was proved to show great potential in the treatment of Alzheimer’s disease6. Other structure also provided good properties for future uses in the drug industry for their anti-fungal, anti-HIV or anti-tumor properties7. Figure 1.2 Bioactive pyrone containing natural products 3 1.1.2. Biorenewable Chemicals and Methyl Coumalate Biorenewable chemicals are in general divided into two parts by their production methods (Scheme 1.2). One could be obtained via a chemical pathway, where the production of hydroxymethylfurfural (HMF) is representative. HMF can be chemically 8 produced from Jerusalem artichoke by FeCl2/H2O2 catalyzed dehydration process , or by 9 the treatment of grape biomass extract with CrCl3/HCl in ionic liquid . On the other hand, an alternative pathway is through a pure biocatalysis approach, where the production of methanol/ethanol by enzymatic catalysis from soybean is an example for demonstration 10. Other types of biodiesel can be manufactured from similar biocatalysis conversion, using different plants and enzymes as feedstock11. Scheme 1.2 Pathways of production for bioreneable chemicals Shanks and Dumesic developed the concept of combining chemical and biological catalysis for producing sustainable chemicals in 201411, as briefly described in Figure 1.3. Common sugars (C5 and C6 sugars) can be produced from biomass feedstock, and further selectively transformed into highly functionalized shorter carbon chain molecules (platform molecules) through fermentation by different bacteria in a biological