A Biomimetic Approach to Okilactomycin and Chrolactomycin and the Hexadehydro-Diels–Alder (HDDA) Reaction

A Biomimetic Approach to Okilactomycin and Chrolactomycin and The Hexadehydro-Diels–Alder (HDDA) Reaction A DISSERTATION SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL OF THE UNIVERSITY OF MINNESOTA BY Dawen Niu IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY Thomas R. Hoye December 2013 © Dawen Niu 2013 Acknowledgements So many things could have happened differently in the past 27 years and if any of them had, my career would have taken totally different pathways. I am so glad to be where I am today and need to acknowledge many people that made me here. First of all, I thank my parents. Born in remote villages, neither of them was able to receive good school education. They have been making very little money for what they do. To pay my (and my sister’s) tuition, they chose to work extremely hard. While I was in college, my father worked ca. 12 hours a day and >300 days a year even though he was suffering severe back pain. They tried all they could to make ends meet and yet never complained. But they started to complain after I left for US and stopped asking for tuition. They complain because they aren’t sure if I could get used to the American lifestyle and because they fear my feet will be dragged in US. “Mother worries when son travels a thousand miles.” This recent five years passed really fast to me, but it must have been the longest five years to them. I understand all these better after being a parent myself. What they have done to me is so much that no way could I pay them back. Second, I have to thank my advisor, Dr. Thomas Hoye. My PhD life wouldn’t have been nearly as joyful and smooth without Tom’s help. Each and every of the past and present group members I know of enjoyed working him, and I am not an exception. Most people in synthetic community know Tom is a great scientist: he is very knowledgable, intelligent, insightful, and scientifically rigorous; in addition, he makes fantastic presentations and is a superb writer. But less people know how much dedicated Tom is to things that apparently don’t/won’t get him much fame. For example: he spends tremendous amount of time on creating/grading problem sets for the students; he spends more of his time on the supporting information than on the manuscript of a paper; he never hesitates to offer help to students that are outside of our group to discuss synthesis- related problems that they have encountered in their research. As the manager of our lab, he treats everyone in the group with utmost patience, respect, and most importantly, fairness. He always puts students’s future as his first priority. It has been absolutely wonderful to work with a scholar like Tom. What I have learned from Tom is far beyond i chemistry, and he sets me a role model to emulate as one day I become a professor myself. I would also like to thank my labmates. Dr. Aaron Burns oriented me into the group. He is very enthusiastic about organic chemistry and has so comprehensive understanding of recent and old literatures. Dr. Enver Izgu is so tenacious a chemist, and never gives up his projects. It was inspiring to see him finally completing his natural product synthesis a couple of days before his final defense. Dr. Patrick Willoughly, my classmate, is an extremely industrious lab member. I went to subgroup meeting with him, and the long list of reactions he accomplished every week embarrassed me very often. Because of their positive influence, I became a much better chemist than I could have been otherwise. I also need to thank Dr. Susan Brown, Dr. Mathew Jansma, Brian Woods, Andrew Michel, Sean Ross, Junhua Chen, and Tao Wang for their incredible tolerance of the mess I have created in the lab. In the end, I thank my wife, Xia Zhang, for she has been supporting me unconditionally, even when it means she needs to compromise her own career future to do so; for she has been and will always be by my side sharing with me our ups and downs. ii Dedication This dissertation is dedicated to my family—my spiritual support. iii Abstract I O O O O O R O O O O post-PKS non-enzymatic OH O OH HOOC IMDA 1 , (+)-Okilactomycin, R = Me 3, (–)-Okilactomycin D 2, (–)-Chrolactomycin, R = OMe 4 II HDDA El-Nu El or π-donor Nu 5 6 7 7' 8 We hypothesized that spirotetronate (+)-okilactomycin (1) and (–)-chrolactomycin (2) are biogenetically derived from a common intermediate, (–)-okilactomycin D (3), which in turn arises via an intramolecular Diels-Alder (IMDA) reaction from the linear precursor 4. Guided by this hypothesis, we have achieved an efficient synthesis of okilactomycin D by a route featuring a substrate-controlled, diastereoselective intramolecular Diels–Alder (IMDA) reaction of an analogue of polyene 4. The assigned absolute configuration of (−)-3 was confirmed. Conversion of (−)-3 toward 1 and 2 has also been explored. ortho-Benzyne (1,2-didehydrobenzene, 7 or 7’) is one of the oldest, most interesting, most useful and most well-studied of all reactive intermediates in chemistry. The multifaceted and efficient reactions of benzynes with suitable trapping reagents (7→8) have long been employed in the service of synthetic chemistry to give products that are iv used as pharmaceuticals, agrochemicals, dyes, polymers, and other fine chemicals. An accidental observation made in this laboratory led us to establish an unorthodox yet general aryne-generating strategy—the hexadehydro-Diels–Alder (HDDA) reaction. This enabling transformation, which produces the highly reactive benzyne intermediate from the thermal [4+2] cycloisomerization of a 1,3-diyne (like 6) with a ‘diynophile’ (like 5) in the absence of any metals or reagents, has allowed us to uncover some unprecedented aryne reactivities. v Table of Contents Acknowledgements i Dedication iii Abstract iv Table of Contents vi List of Tables viii List of Figures ix List of Schemes x List of Abbreviations xvii A Biomimetic Approach to (+)-Okilactomycin and (-)-Chrolactomycin Chapter 1. Introduction to the okilactomycins (1001-1018) 2 1.1 Historical background of okilactomycins 2 1.2 Previous studies directed to the total synthesis of okilactomycins 5 1.3 Biosynthetic hypothesis/synthetic plan of okilactomycins 8 Chapter 2. Intramolecular Diels–Alder (IMDA) Reaction in Natural Product Syntheses (2001-2063) 10 2.1 Diels–Alder reaction in biosynthesis of natural products 10 2.2 IMDA in chemical synthesis of spirotetronates 19 Chapter 3. Total Synthesis of (–)-Okilactomycin D (3001-3038) 25 3.1 First generation synthesis of IMDA substrate 25 3.2 Second generation synthesis of IMDA substrate 32 3.3 Endgame of (–)-okilactomycin D synthesis 36 3.4 On the diastereoselectivity of the biomimetic IMDA reaction in okilactomycin D synthesis 40 Chapter 4. Progress toward the Total Synthesis of Okilactomycins (4001-4021) 45 4.1. Attempted strategies to convert okilactomycin D to okilactomycin 45 4.2. Future directions 49 vi The Hexadehydro-Diels–Alder (HDDA) Reaction Chapter 5. Introduction to o-Benzyne (5001-5069) 53 5.1 Historical background of o-benzyne 53 5.2 A brief review of o-benzyne trapping methods 59 5.3 A brief review of o-benzyne generating methods 74 Chapter 6. The HDDA Reaction: Its Discovery and Initial Explorations on Its Scope (6001-6028) 77 6.1 Discovery of HDDA reaction 77 6.2 Initial explorations on the substrate scope of HDDA reaction 81 6.3 Initial explorations on the intermolecular trapping reactions of HDDA-born arynes 85 6.4 Thermodynamics of HDDA reaction 89 Chapter 7. Some Additional Reactions of Benzynes Generated by HDDA Reactions (7001-7113) 92 7.1 A HDDA approach to generate substituted indoline and carbazoles 92 7.2 The ene reaction between phenols and HDDA-born benzynes 100 7.3 Dichlorination of arynes 104 7.4 The aromatic ene reaction 109 7.5 Double hydrogen transfer between saturated alkanes and benzynes 124 Chapter 8. A Protocol to Investigate Kinetics of Benzyne-Trapping Reactions (8001-8028) 136 8.1 Mathematical background 136 8.2 Kinetics of aryne trapping by alcohols 139 Experimental Section 145 Notes 322 Bibliography 324 vii List of Tables Table 3.1 | Summary of reactivity profiles of 3002, 3026, and 3027 36 viii List of Figures Figure 1.1 | Structures of (+)-okilactomycin and (-)-chrolactomycin 2 Figure 2.1 | Examples of natural products for which biosynthetic IMDA reactions have been proposed 10 Figure 5.1 | Structures of benzynes 53 Figure 5.2 | Summary of physical properties of o-benzyne 58 Figure 5.3 | Conventional methods of generating arynes 74 Figure 7.1 | Some selected examples of natural products and functional materials that contain indole, indoline, or carbazole units 92 ix List of Schemes Scheme 1.1 | Smith’s total synthesis of (-)-okilactomycin 5 Scheme 1.2 | Scheidt’s total synthesis of (-)-okilactomycin 6 Scheme 1.3 | Biosynthetic hypothesis of okilactomycins 8 Scheme 2.1 | Enzymatic IMDA reactions in the biosynthesis of solanapyrones 12 Scheme 2.2 | Lovastatin nonaketide synthase (LNKS) as a Diels–Alderase 14 Scheme 2.3 | Macrophomate synthase (MPS) as a Diels–Alderase 15 Scheme 2.4 | A propose catalyzing mechanism of riboflavin synthase 16 Scheme 2.5 | Spn F enhances the transannular [4+2] cycloaddition rate of 2039 by 500- fold 17 Scheme 2.6 | A) IMDA reaction in the total synthesis of chlorothricolide; B) A hypothetical IMDA reaction of a less oxygenated analogue 2046 20 Scheme 2.7 | Uenishi’s Total synthesis of (–)-ircinianin and (+)-wistarin 21 Scheme 2.8 | Total of abyssomicin C by Sorensen, Snider, and Couladouros groups 22 Scheme 2.9 | Takeda’s model study directed to the total synthesis of okilactomycin 23 Scheme 2.10 | Takeda’s model study vs.

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