Chapter 6 - Tetrapetalones ruminations, trials and tribulations

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Abstract

The tetrapetalones were pursued for well over a decade by numerous research groups. Herein, we detail our motivations and findings, which we imagine are very different from the many others who tackled this extremely challenging problem. In this chapter, we explain how our many failures caused us to revise our strategy eight times. Although we failed to reach the genuine natural product, we hope the reader will conclude that we nevertheless developed several valuable methods and that we gained important strategic insights from our trials and tribulations. At the very least, we can emphatically state that we developed a great appreciation of the wonderful ways in which our chemistry community is interconnected, and the great benefit we all enjoy from one another's achievements.

Section snippets

Ruminations

The process of digestion of complex plant proteins by mammals known as ruminants is a protracted and labored activity.1 It begins when hardy plant proteins are first masticated and swallowed so as to enter the rumen, a foregut found in grass feeding herbivores. Here the resilient proteins are partially broken down by fermentation, regurgitated back into the mouth as fermenta ingesta (otherwise known as cud), rechewed, and reswallowed. This ruminating process is repeated several times before the

First impressions

The four members (A–D) of the tetrapetalone family of natural products were isolated from the soil bacteria Streptomyces sp. USF-4727 (1–4, Fig. 6.1) in 2002 by Toshikazu Komoda and coworkers.2 These molecules were found to inhibit soybean lipoxygenase (SBL) at levels comparable with other potent SBL inhibitors, such as kojic acid and nordihydroguaiaretic acid, whereas C3 O-methylated derivatives of the tetrapetalones A–D, compounds such as 5, were found to be inactive. SBL activity is the

Recollections of tetramic and tetronic acids past

When I first saw the tetrapetalone structures in Komoda's 2004 article with the revised placement of the nitrogen atom within the overall structure, the newly claimed tetramic acid motif caught my attention. As a graduate student working in the Schlessinger group in the 1990s, I had investigated tetronic acids and their derivatives, including the reactivity of the vinylogous urethanes 6 (Scheme 6.1). Once deprotonated, the enolate species participated in both aldol and alkylation reactions and,

Porco's [4 + 3] proposition

Then, in the fall of 2005, only 2 years after their isolation, and a year after the structural revision, John Porco described the conversion of the nitro aromatic 10 to the hydroquinone 11 and the incredible oxidative (4 + 3) cyclization, leading to the rapid assembly of the tetracycle 15 via intermediacy of compounds 12–14 (Scheme 6.2). This amazing transformation provided an elegant and ingenious solution to processing all the seemingly incompatible functional groups; the tetramic acid was

Nails on hand

After the commotion caused by Porco's amendment subsided in 2006, and with our tenure secured, we earnestly began testing methods for fabricating the tetrapetalone skeleton. There is a well-known maxim erroneously attributed to Mark Twain. It advocates, “if your only tool is a hammer, then every problem looks like a nail.” Thus, our thoughts were shaped by the recent synthetic tool we had developed at UCSB as well as my own past experiences with tetramic acid derivatives at the University of

Second swing for the fence

For our subsequent NIH submission, we revised our strategy to include the construction of the entire family of tetrapetalones (Scheme 6.6). Dearomatization would be postponed until a very late stage, and we imagined reaching the cyclohexadienone precursor 28 by glycosylation of the secondary alcohol 30 with compound 29. In this manner, we could avoid many of the anticipated reactivity issues surrounding the fragile and reactive cyclohexadienone core by saving its revelation until the very end

A scrubbed launch

Soon after our final 2010 NIH resubmission, our second tetrapetalone strategy went off the rails, yet again. John Ward, who was steward of our new approach, was finding it difficult to procure a viable indene-1,3(2H)-dione from which to implement our o-QM chemistry. Construction of the desired indanone precursor toward 33 (Scheme 6.7) had proven tedious, due to facile enolization and elimination of the C9 hydroxyl residue. Moreover, addition of a vinyl Grignard to the o-QM precursor 34, a more

Sarpong's reckoning

In late 2010, with our project utterly stalled, Sarpong reported the first advanced strategy for the tetrapetalones (Scheme 6.8).14 It deployed the aryl dieneone 37 in a Nazarov cyclization to produce the cyclopentenone 38. This material was then converted into the azide 39, thereby establishing the elusive C–N bond. However, conversion of this material to the ketone 40 had required considerable gymnastics to coax a pyrrole intermediate through a series of oxidations into the desired tetramic

A failure to divinylate

Tetramic acid motifs are found in natural products with many important biological activities.18 Normally, an acyl residue is found at C3, as in the tirandimycins. Many synthetic methods for building these systems exist. The corresponding C3-hydrido examples are known, but scarce, and fewer synthetic methods exist for their fabrication. Remarkably, tetramic acid natural products bearing C3–Me motifs were entirely unknown until 2002, when palau'imide (76) was isolated.19 Soon thereafter, the

Revenge of the interconverting dienes

Dr. Jackson, whose 2-year stint was soon ending, immediately seized upon Bai's result (Scheme 6.16). Jackson used slightly modified conditions and deployed n-butyllithium as the base with compound 80 to construct the α-brominated amide 81. The samarium-mediated cyclization worked well and afforded upon methylation of the oxygen atom the desired tetramic acid derivative 82. While Jackson was unable to install two vinyl substituents on this material, he successfully demonstrated that sequential

A new hope

With Dr. Jackson's departure in late 2012, Mr. Bai was now firmly in the driver's seat of the tetrapetalone project, and he was very anxious to advance it further. About the same time, Jennifer Howell, who coincidently had interviewed at UCSB for admission to our department, published her PhD thesis on the tetrapetalones from her work in the Wood group at Colorado State.24 While the retrosynthesis captured in her thesis (Scheme 6.17) was entirely different from Wood's eventual success, it was

Return to nitroaromatics

We poured over the available synthetic materials published on the tetrapetalones, pondered our few successes and many failures, and devised our fifth strategy (Scheme 6.18). We decided that Porco's original notion of using a nitroaromatic was the best manner in which to access the essential C–N aryl bond. Starting from the nitroaromatic 92, Bai proposed to deploy some rather unusual Suzuki and Molander chemistry to access the carboxylic acid 93. This acid would then be subjected to a

A robust strategy

Bai imagined accessing the aldehyde 115 from the ester 107 (Scheme 6.21) and then carrying out an intramolecular aldol condensation to access the seven-membered ring found in the tricyclic compound 114. At the time, Bai was training a starting first-year student, Johnathan David, in the nuances of intermolecular aldol chemistry of tetramic acid derivatives.30 The intramolecular reaction affording the seven-membered ring seemed well-worth exploring, though I had reservations about its success.

Seven carbons for brother Tom

Bai jumped headfirst into this new sixth strategy (Scheme 6.22). With the Heck adduct 107 on hand from the prior approach, he successfully reduced the ester to produce the allylic alcohol 118. Oxidation of this material provided the desired aldehyde 120. Later, Bai found that the aldehyde could be produced more efficiently by treatment of 118 with Crabtree's catalyst under hydrogen, via the intermediary iridium complex 119. Bai then shortened the route even further, demonstrating that the

The quaternary conundrum

We were now faced with the proposition of the long-range ε-deprotonation of the alpha–beta, gamma–delta unsaturated racemic tetramic acid derivative 122 to form an achiral enolate or ketene acetal of the oxygenated pyrrole 123 (Scheme 6.23). Much to our chagrin, strong bases, such as n-BuLi, failed to deprotonate the tricycle 122 and provide an enolate that could be deuterated. On the other hand, a Lewis acid (TMSOTf) and a mild base (Et3N), again, provided the desired triene 123 as its

Applying vinyl siding

To obtain the desired ethylenated adduct 127, we first attempted direct removal of the nitro functionality by radical reduction of compound 124d. While this reduction failed, we subsequently found that the xanthate ester 124c underwent the expected radical erasure using nBu3SnH/AIBN to afford the terminal olefin 127 on multigram scale and in nearly quantitative yields (Scheme 6.23). However, better overall yields were obtained by a two-step process, whereby adduct 124d was first formed from

Five-membered death punch

With the OTBDPS-protected phenol 133e, application of AlCl3 at elevated temperatures was observed to cause a rearrangement in nearly quantitative yield to the tetracyclic compound 136. Bai theorized that the initial acylium ion 137 had formed. However, it had been attacked by the internal Cdouble bondC bond of the seven-membered ring resulting in cation 138. This species then underwent an aryl migration to afford the cation 139, whereupon proton elimination provided the cyclopentenone 136. Next, he

A friend in need

“A Friend in Need”.37

A bit latter in January 2014, Alison Frontier called to see if we might be close to finishing and to discuss dearomatization conditions. Such personal contact may seem strange to organic chemists today, where rivals have been known to decline or sit on a competitor's manuscripts under their review to ensure their own work publishes first. However, in years past, reaching out to a competitor before publication was a common courtesy. I recall Dick Schlessinger communicating

Frontier's aglycone

Professor Alison Frontier first revealed her syntheses of the tetrapetalone aglycon at the Heterocyclic Gordon conference in the summer 2014. As I understand it, she graciously acknowledged our assistance in choosing Doyle's dearomatization conditions. Frontier's published synthesis, which appeared a few months later, was quite impressive (Scheme 6.29).41 I recall Alison once sharing a personal sentiment from Danishefsky who stated, “I provide the staring materials, a key transformation, and a

Desperate measures

At the time I had shared the dearomatization conditions, I felt that Bai and I were mired in an inescapable morass. However, to his credit, his stubbornness, and his persistence, he was already working on a strategy to circumvent the impenetrable barricade that lay before us (Scheme 6.30). His daring strategy, our eighth revision, did not engender much hope, at least for me. Bai proposed to reduce the many acids and esters (133a–f)—which he had on hand and had obtained from the acetates 131ab

Wood’s synthesis

In 2017, Professor John Wood reported the first total synthesis of tetrapetalones A and C (1, 3) (Scheme 6.31).43 The strategy was quite imaginative, and it was vastly different from approaches shared previously in his students' thesis. Wood began with the nitroaromatic 155 and in short order reduced it to the corresponding aniline, constructed a masked tetramic acid, and closed the seven-membered ring by a Dieckman cyclization to arrive at the tricyclic compound 156. The masterful move in this

Life of Bai

The tetrapetalone natural products have proven to be an amazing conglomerate of carbon, hydrogen, and oxygen atoms surrounding a single atom of nitrogen, forged together in a truly unique tetracyclic array, with a sugar dangling off to one side. Having caught so much attention from the chemical community, one might expect a molecule this complex to cure cancer or some other challenging human malady; sadly, it does not. Rather, it has proven to be a useful testbed for the development of numerous

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