Directed C–H Bond Oxidation of (+)-Pleuromutilin

Ma, Xiaoshen; Kučera, Roman; Goethe, Olivia; Murphy, Stephen K.; Herzon, Seth B.

doi:10.1021/acs.joc.8b00462

Cited by 26 publications

(27 citation statements)

References 42 publications

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“…Several semisynthetic derivatives of P are used to treat Gram-positive pathogens in humans (retapamulin) and in veterinary medicine (tiamulin, valnemulin), 18 and recently epi-mutilin derivatives have been developed as antibiotics with activity against some Gram-negative bacteria. 19–22 Investigation of the antibacterial activity of P and its derivatives has inspired several total synthesis efforts 20,21,23–25 that, combined with previous work on structure elucidation 26,27 and structure–activity relationship studies, 18,28,29 provide a wealth of synthetic information about the chemical reactivity of the pleuromutilin ring system. Structural transformations of the P ring system identified through these efforts afford several good starting points for novel diversification reactions.…”

Section: Resultsmentioning

confidence: 99%

Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis

et al. 2019

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The chemical diversification of natural products provides a robust and general method for creation of stereochemically rich and structurally diverse small molecules. The resulting compounds have physicochemical traits different from those in most screening collections, and as such are an excellent source for biological discovery. Herein, we subject the diterpene natural product pleuromutilin to reaction sequences focused on creating ring system diversity in few synthetic steps. This effort resulted in a collection of compounds with previously unreported ring systems, providing a novel set of structurally diverse and highly complex compounds suitable for screening in a variety of different settings. Biological evaluation identified the novel compound ferroptocide, a small molecule that rapidly and robustly induces ferroptotic death of cancer cells. Target identification efforts and CRISPR knockout studies reveal that ferroptocide is an inhibitor of thioredoxin, a key component of the antioxidant system in the cell. Ferroptocide positively modulates the immune system in a murine model of breast cancer and will be a useful tool to study the utility of pro-ferroptotic agents for treatment of cancer.

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Section: Resultsmentioning

confidence: 99%

Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis

et al. 2019

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“…The Herzon group also employed our MHAT-hydrogenation conditions during their studies on the late-stage oxidation of (+)-pleurumutilin. 18…”

Section: Thermodynamic Chemoselective Hydrogenation (First Generation)mentioning

confidence: 99%

The High Chemofidelity of Metal-Catalyzed Hydrogen Atom Transfer

et al. 2018

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CONSPECTUS. Implementation of any chemical reaction in a structurally complex setting (King, S. M., J. Org. Chem., 2014, 79, 8937) confronts structurally-defined barriers: steric environment, functional group reactivity, product instability, and through-bond electronics. But there are also practical barriers. Late stage reactions conducted on small quantities of material are run inevitably at lower than optimal concentrations. Access to late stage material limits extensive optimization. Impurities from past reactions can interfere, especially with catalytic reactions. Therefore, chemical reactions that can be relied upon at the front lines of a complex synthesis campaign emerge from the crucible of total synthesis as robust, dependable, and widely applied. Trost conceptualized ‘chemoselectivity’ as a reagent’s selective reaction of one functional group or reactive site in preference to others (Trost, B. M., Science, 1983, 219, 245). Chemoselectivity and functional group tolerance can be evaluated quickly using robustness screens (Collins, K. D., Nat. Chem., 2013, 5, 597). A reaction may also be characterized by its ‘chemofidelity’, its reliable reaction with a functional group in any molecular context. For example, ketone reduction by an electride (dissolving metal conditions) exhibits high chemofidelity, but low chemoselectivity: it usually works, but many other functional groups are reduced at similar rates. Conversely, alkene coordination chemistry effected by π Lewis acids can exhibit high chemoselectivity (Trost, B. M., Science, 1983, 219, 245), but low chemofidelity: it can be highly selective for alkenes, but sensitive to substitution patterns (Larionov, E., Chem Comm., 2014, 50, 9816). In contrast, alkenes undergo reliable, robust, and diverse hydrogen atom transfer reactions from metal hydrides to generate carbon-centered radicals. Although there are many potential applications of this chemistry, its functional group tolerance, high rates, and ease of execution have led to its rapid deployment in complex synthesis campaigns. Its success derives from high chemofidelity; its dependable reactivity in many molecular environments and with many alkene substitution patterns. Metal hydride H-atom transfer (MHAT) reactions convert diverse, simple building blocks to more stereochemically and functionally dense products (Crossley, S. W. M., Chem. Rev., 2016, 116, 8912). When hydrogen is returned to the metal, MHAT can be considered the radical equivalent of Brønsted acid catalysis—itself a broad reactivity paradigm. This Account summarizes our group’s contributions to method development, reagent discovery, and mechanistic interrogation. Our earliest contribution to this area—a stepwise hydrogenation with high chemoselectivity and high chemofidelity—has found application to many problems. More recently, we reported the first examples of a dual-catalytic cross-couplings that rely on the merger of MHAT cycles and nickel catalysis. With time, we anticipate MHAT will become a staple of chemical synthesis.

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“…3a) commenced with epoxidation of (S)-carvone, followed by Ti(III)-mediated reductive cyclization of the epoxy-carvone to give cyclobutanol 20 in excellent yield as a 1.5:1 mixture of epimers at C7. 27 A Brønsted acid-mediated semipinacol rearrangement 28 of 20, carried out using a modification of the conditions from our previous report, 14 yielded 8-hydroxycamphor, which was then oxidized to the corresponding aldehyde (21). Selective Wittig olefination of aldehyde 21, using the phosphonium ylide derived from 22, 29 furnished skipped-diene 16, which contains all the carbon atoms of longiborneol and its structurally related congeners.…”

Section: Resultsmentioning

confidence: 99%

“…In recent years, the use of such reactions to introduce myriad oxygenation patterns on complex molecules has been of intense interest to synthetic chemists. 19,20,21,22 Determining the positional selectivities of these methods on intricate hydrocarbon frameworks is pivotal to their further development and application. Therefore, we saw the implementation of a divergent synthesis of many longiborneol congeners as a valuable contribution to this effort.…”

mentioning

confidence: 99%

Total Synthesis of Nine Longiborneol Sesquiterpenoids Using a Functionalized Camphor Strategy

Lusi¹,

Sennari²,

Sarpong

2021

Preprint

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<p>Natural product total synthesis inspires strategy development in chemical synthesis. In the 1960s, Corey and coworkers demonstrated a visionary preparation of the terpenoid longifolene, using “strategic bond analysis” to craft a synthesis route. This approach proposes that efficient synthesis routes to bridged, polycyclic, structures should be formulated to introduce the bulk of the target’s topological complexity at a late stage. In subsequent decades, similar strategies have proved general for the syntheses of a wide variety of bridged, polycyclic molecules. Here, we demonstrate that an orthogonal strategy, which utilizes a topologically complex bicyclo[2.2.1] starting material accessed through a scaffold rearrangement of (<i>S</i>)-carvone, leads to a remarkably short synthesis of the longifolene-related terpenoid longiborneol. We also employ a variety of late-stage C–H functionalization tactics in divergent syntheses of many longiborneol congeners. Our strategy should prove effective for the preparation of other topologically complex natural products that contain the bicyclo[2.2.1] framework.</p>

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Directed C–H Bond Oxidation of (+)-Pleuromutilin

Cited by 26 publications

References 42 publications

Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis

Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis

The High Chemofidelity of Metal-Catalyzed Hydrogen Atom Transfer

Total Synthesis of Nine Longiborneol Sesquiterpenoids Using a Functionalized Camphor Strategy

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