Chapter 3 - Intermolecular oxidopyrylium [5 + 2] cycloaddition chemistry and its application toward the synthesis and study of highly oxygenated troponoids
Introduction
As a postdoctoral associate at Yale University interested in a career in academia, I was in search of ideas for projects that would allow me to develop organic reactions and synthetic strategies that would satisfy my interest in doing novel chemistry, while simultaneously opening up opportunities to pursue biology or medicine-related endeavors. I had been tangentially familiar with oxidopyrylium chemistry, in part due to some furan oxidation chemistry I had worked on during my PhD studies at Boston College in Marc Snapper's lab,1, 1(a), 1(b) as this had naturally exposed me to the Achmatowicz reaction2 and its revolutionary role enabling oxidopyrylium [5 + 2] cycloaddition reactions (Scheme 3.1A).3 At a certain point, the realization came to me that 3-hydroxy-4-pyrones (e.g., 4) were effectively tautomers of 4-hydroxy-substituted oxidopyrylium ylides (5, Scheme 3.1B). Sitting down with a pencil and paper, I started to sketch out some ideas of what could be done with the resultant cycloadducts, and one of the things that came to mind was that a ring opening through a retro-oxy-Michael on alkyne-derived cycloadducts would rapidly lead to a group of highly oxygenated troponoids called 7-hydroxytropolones (6 → 8, Scheme 3.1B). I turned to SciFinder with the goal of identifying impressive-looking natural products that had this chemotype, and I remember being a bit disappointed in both the scarcity and simplicity of 7-hydroxytropolone natural products (Scheme 3.1C). In fact, the most widely studied of the molecules was an extremely simple terpene called β-thujaplicinol (9) that had only a single isopropyl appendage.4
Synthetic organic chemistry is by its nature an exceptionally novel field of study. Think about how many times in a given day a prospective author is told that their manuscript does not meet the requisite novelty for publication when it likely possesses molecules that have never existed in the history of the universe. By extension, those of us in the field tend to set a high bar for what we personally consider novel, and while this is often based upon our own personal experiences and biases, it can often seem quite arbitrary to outside observers. It is thus worth noting that when I found out that 3-hydroxy-4-pyrones had been established as oxidopyrylium ylide sources since the late 1970s,5 and oxidopyrylium cycloaddition/ring-opening routes were already established for tropolone synthesis (see Section 2), I almost abandoned the idea due to a perceived lack of synthetic organic chemistry novelty. However, what kept me interested in the project was that β-thujaplicinol was among the most potent inhibitors of HIV reverse transcriptase ribonuclease H (HIV RT RNaseH) known.6, 6(a), 6(b) Having grown up in the 1980s and 1990s at the height of the AIDS epidemic, HIV has been ingrained into my subconscious as one of the most terrifying diseases known, and the thought of having a program that could help develop novel anti-HIV therapies was exceptionally appealing to me. Thus, it was the interest in pursuing medicinal chemistry studies, and not the novelty of the chemistry, that drove me to develop the idea further and ultimately include it in my job application packet.
After a year at Brooklyn College, a manuscript appeared in Journal of Medicinal Chemistry by a group of researchers led by Stuart Le Grice at the National Cancer Institute that focused on the synthesis and biological evaluation of derivatives of the α-hydroxytropolone natural product manicol (12).7 This manuscript emboldened me to pursue the oxidopyrylium approach to hydroxytropolones for a number of reasons. Firstly, while β-thujaplicinol and manicol had previously demonstrated potent activity against HIV RT RNaseH biochemically with submicromolar IC50 values—in fact among the most potent inhibitors of the enzyme known at the time—neither molecule showed any protective effects in cell-based assays (Scheme 3.2).6, 6(a) This is presumably due to the compounds' cytotoxicity prohibiting the higher concentrations needed to observe protective effects, which is exacerbated by the lengthy (1 week) assay time of HIV-associated antiviral assays. Many of the manicol derivatives synthesized in these studies had lower cytotoxicity and, as a result, showed some protective effects in cell-based assays (e.g., 13, 14, Scheme 3.2). The other aspect of the manuscript that struck me at the time was the realization that a team comprised of several highly established research groups found it worth their time to take and modify manicol because they were excited enough in the potential of the α-hydroxytropolone chemotype. Aside from the limited structural diversity afforded by this semisynthetic strategy, manicol is not a molecule you can readily order from standard commercial vendors, and very few people outside of the NCI would have even had access to it. It was isolated in 1977 from a rare Guyanan tree called Dulacia guianensi by French natural product chemist Judith Polonsky,8 who shared the material with Mathew Suffness at the NCI to carry out some antileukemia studies in mice. Following the studies, presumably the leftover material was sent to the NCI's natural product repository, and from there ended up in the lab's initial screen.6, 6(a) Fortunately, animal model studies require a lot of material, and thus, Polonsky's team must have sent a great deal of material to Suffness—John Beutler has told me that when he requested the material, they were able to get 4 g to carry out the manicol derivative studies. Thus, for Stuart, John, and their collaborators, getting the initial material simply required a request, but in John's words “getting further samples of plant material is what would likely be a huge headache.”
This manuscript on manicol derivatives helped convince me that, while there had been methods available to synthesize functionalized 7-hydroxytropolones,9, 9(a), 9(b) a new de novo synthetic strategy for α-hydroxytropolones was needed and would likely be embraced by the biomedical community. This has proven to be accurate, and we have been able to establish several gratifying collaborations with various leaders in the biomedical community,10(d), 10(e), 10(f), 10(g), 10(h), 10(i), 10, 10(a), 10(b), 10(c) including the Le Grice and Beutler labs. What I did not anticipate at the time, however, was just how much we would discover and learn about oxidopyrylium [5 + 2] cycloaddition chemistry and tropolones more generally, and how satisfying and intellectually enriching the synthetic chemistry studies themselves would be. The following is a personal account that will attempt to summarize these advances and their significances, separated for clarity into advancements in oxidopyrylium chemistry (Section 3) as well as troponoid synthesis (Section 4). An additional goal is to personalize these advances and put into perspective the efforts and accomplishments of the students and collaborators that helped drive the published work resulting from this program to date. I would be remiss, however, to not start with an overview oxidopyrylium approaches to troponoids from other labs.
Section snippets
Katritzky's oxidopyridinium approach to tropolones
A reasonable place to start a discussion on the history of oxidopyrylium cycloaddition approaches to troponoids would be the work of Alan Katritzky and Yoshito Takeuchi in 1971,11 in which they described a closely related oxidopyridinium [5 + 2] cycloaddition approach to troponoids. This authors describe a Hoffman elimination-type ring-opening processes on a series of oxidopyridinium cycloadducts (e.g., Scheme 3.3A), which provides access to α-aminotropones (e.g., 18) as well as tropolones (e.g.,
Background
While the overwhelming starting material for accessing and using oxidopyrylium ylides in cycloadditions are furans (via acetoxypyranose, Scheme 3.1A),3 3-hydroxy-4-pyrones are perhaps the second most popular method historically,28 a status they undoubtedly have held over the past 30 years. The first mention of 3-hydroxy-4-pyrone-based oxidopyrylium cycloaddition came in 1977 from Volkmann and coworkers at Pfizer,29 who proposed the cycloaddition between oxidopyrylium ylide 77 and 16 as part of
Establishment of acid-mediated ring-opening conditions
Initial studies on oxabicyclo ring openings had focused on DMAD-derived bicycle 91, which in retrospect was a curious place to start, as the intermediate carbocation-like character generated upon ring opening would likely be destabilized. I would love to tell you that we chose to begin with this substrate because it represented a challenge, but in reality, we began here because it was the only alkyne-derived cycloadduct described in Wender and Mascareñas’ seminal publication,33 and as a result
Conclusion
Both oxidopyrylium cycloaddition chemistry and troponoids are well known throughout the synthetic organic chemistry community and, as a result, are perhaps viewed as highly mature areas of study. Indeed, my initial reaction to developing an oxidopyrylium cycloaddition route to 7-hydroxytropolones was motivated entirely on the medicinal chemistry applications that I believed would result. However, over the past decade, our work on a 3-hydroxy-4-pyrone-based oxidopyrylium [5 + 2] cycloaddition
Acknowledgments
I am grateful for financial support over the years from Brooklyn College, the National Institutes of Health, PSC-CUNY, and the Alfred P. Sloan Foundation. In particular, I would like to thank the NIH Support of Competitive Research (SCORE) program, which is devoted to funding faculty at colleges and universities that graduate a high percentage of students under-represented in the biomedical sciences. The highly generous funding of three grant applications (SC2GM099596, SC1GM111158) has been
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Carbocycloaddition strategies for troponoid synthesis
2023, TetrahedronCitation Excerpt :These cyclopropenone derivatives are highly versatile, and can react with electron rich, poor, and neutral dienes (Scheme 24A). Similar to the case with cyclopropenone, with appropriate leaving groups, these cycloadducts can rearrange to troponoids through norcaradiene intermediates (i.e., 170) [61]. In one instance, this intermediate was accessed through base-assisted elimination of an appended methyl ether (Scheme 24A), and in the other instance the cycloaddition with electron-withdrawing substituted α-pyrones facilitated decarboxylation (Scheme 24B).