Efforts toward the total synthesis of (±)-toxicodenane A utilizing an oxidopyrylium-based [5+2] cycloaddition of a silicon-tethered BOC-pyranone

Grabowski, Jacob P.; Ferrence, Gregory M.; Mitchell, T. Andrew

doi:10.1016/j.tetlet.2020.152324

Cited by 6 publications

(5 citation statements)

References 39 publications

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“…As part of our research program directed toward [5+2] cycloadditions [ 78 , 79 , 80 , 81 , 82 , 83 , 84 ] we explored mechanistic pathways of acetoxypyranone-derived oxidopyrylium species en route to [5+2] cycloadditions [ 81 ] that led to the discovery of polycyclic ether-benzopyran 4 ( Scheme 1 ). Commercially available aldehyde 2 was treated with 2-furyllithium to provide the desired alcohol (not shown) in quantitative yield.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Polycyclic Ether-Benzopyrans and In Vitro Inhibitory Activity against Leishmania tarentolae

et al. 2020

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Construction of a focused library of polycyclic ether-benzopyrans was undertaken in order to discover new therapeutic compounds that affect Leishmania growth and infectivity. This is especially of interest since there are few drug therapies for leishmaniasis that do not have serious drawbacks such high cost, side effects, and emerging drug resistance. The construction of these polycyclic ether-benzopyrans utilized an acetoxypyranone-alkene [5+2] cycloaddition and the Suzuki-Miyaura cross-coupling. The multi-gram quantity of the requisite aryl bromide was obtained followed by effective Pd-catalyzed coupling with boronic acid derivatives. Compounds were tested in vitro using the parasitic protozoan, Leishmania tarentolae. Effects of concentration, time, and exposure to light were evaluated. In addition, the effects on secreted acid phosphatase activity and nitric oxide production were investigated, since both have been implicated in parasite infectivity. The data presented herein are indicative of disruption of the Leishmania tarentolae and thus provide impetus for the development and testing of a more extensive library.

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Section: Resultsmentioning

confidence: 99%

Synthesis of Polycyclic Ether-Benzopyrans and In Vitro Inhibitory Activity against Leishmania tarentolae

et al. 2020

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“…Our synthesis relied on the desymmetric enantioselective reduction of diketone 9 , the hydroxy group-directed diastereoselective allylation of 10 , and the transacetalation and Prins cyclization cascade reaction of 11 . In addition to these successful total syntheses, in a 2020 report Mitchell and co-workers reported an intramolecular [5 + 2] cycloaddition of pyranone derivative 13 toward the construction of the tricyclic core 14 of (±)-toxicodenane A ( 1 ) (Scheme C). Despite these important advances, the development of an efficient route enabling diverse synthesis of other relevant natural products and structural analogues remains highly desired for an extensive evaluation of the correlation between structure and biological activity.…”

Section: Introductionmentioning

confidence: 99%

Synthetic Studies on the Synthesis of Toxicodenane A and 8,11-epi-Toxicodenane A

Qin

Han

2022

J. Org. Chem.

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The diverse synthesis of oxatricyclotridecanes and oxatricyclododecanes, which are the core structures of toxicodenane A and its skeletal analogues, via a unified manner is presented. The stereochemistry at the bridgehead position of the oxa-bridged bicycle could be efficiently controlled through a diastereoselective anti- and syn-Grignard allylation reaction by appropriately tuning the reaction conditions such as the solvent, the counterion of the Grignard reagent, the substrate, or a combination of these. The ring size could be precisely elaborated via a Lewis acid-mediated intramolecular transacetalation and Prins cyclization cascade reaction by varying the steric hindrance of olefin moiety. Namely, substrates bearing a terminally unsubstituted olefinic functionality afforded oxatricyclotridecanes with an overwhelming preference, while those bearing a dimethyl-substituted olefinic group produced exclusively oxatricyclododecanes. The wide utility and generality of the above key transformations are highlighted by the applications in the unified synthesis of (±)-toxicodenance A, (+)-toxicodenane A, (+)-8,11-epi-toxicodenane A, and other oxatricyclic cores with different stereochemistries and ring sizes.

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“…Many of these cycloadditions, such as the widely used Diels–Alder and azide–alkyne Huisgen cycloadditions, are often highly (if not completely) atom economical as well, which can greatly simplify reactions and further empower their usage. Intermolecular oxidopyrylium [5 + 2] cycloadditions, most commonly performed by the elimination of acetoxypyranose ( 1 ) in the presence of dipolarophiles (Scheme A), also have a proven value in the synthetic chemistry community . These methods, however, lead to potentially reaction-compromising conjugate acids or residual base in the reaction mixtures.…”

Section: Introductionmentioning

confidence: 99%

Investigations into a Stoichiometrically Equivalent Intermolecular Oxidopyrylium [5 + 2] Cycloaddition Reaction Leveraging 3-Hydroxy-4-pyrone-Based Oxidopyrylium Dimers

2021

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Oxidopyrylium [5 + 2] cycloaddition reactions are powerful strategies for constructing complex bicyclic architectures. However, intermolecular cycloadditions of oxidopyrylium ylides are limited due to competing dimerization processes; consequently, high equivalents of dipolarophiles are often used to help intercept the ylide prior to dimerization. Recent studies by our lab have revealed that oxidopyrylium dimers derived from 3-hydroxy-4-pyrones are capable of reverting back to ylides in situ and as a result can be used as clean oxidopyrylium ylide sources. The following manuscript investigates intermolecular cycloaddition reactions between 3-hydroxy-4-pyronederived oxidopyrylium dimers and stoichiometrically equivalent ratios of alkyne dipolarophiles under thermal conditions. With certain reactive alkynes, pure cycloadducts can be obtained following a simple evaporation of the solvent, which is a benefit of the completely atom-economical reaction conditions. However, when less reactive alkynes are used the yields suffer due to a competing dimer rearrangement. Finally, when reactive-yet-volatile alkynes are used, such as methyl propiolate, competing 2:1 ylide/alkyne cycloadducts are observed. Intriguingly, these complex cycloadducts, which can be obtained in good yields from the pure cycloadducts, form with high regio-and stereoselectivities; however, both the regio-and stereoselectivities differ remarkably based on the source of the oxidopyrylium ylide.

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Efforts toward the total synthesis of (±)-toxicodenane A utilizing an oxidopyrylium-based [5+2] cycloaddition of a silicon-tethered BOC-pyranone

Cited by 6 publications

References 39 publications

Synthesis of Polycyclic Ether-Benzopyrans and In Vitro Inhibitory Activity against Leishmania tarentolae

Synthesis of Polycyclic Ether-Benzopyrans and In Vitro Inhibitory Activity against Leishmania tarentolae

Synthetic Studies on the Synthesis of Toxicodenane A and 8,11-epi-Toxicodenane A

Investigations into a Stoichiometrically Equivalent Intermolecular Oxidopyrylium [5 + 2] Cycloaddition Reaction Leveraging 3-Hydroxy-4-pyrone-Based Oxidopyrylium Dimers

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