An Improved Synthesis of 2,7-Dihydroxytropone (3-Hydroxytropolone)

Takeshita, Hitoshi; Mori, Akira; Kusaba, Tomoyuki

doi:10.1055/s-1986-31713

Cited by 22 publications

(18 citation statements)

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“…[34] 136°C). Despite the deficiency in melting point, the 13 C NMR spectrum was consistent with the data reported for 29a, apart from negligible differences due to the different solvent (CD 3 OD) [35] . [18] 132.5Ϫ133.5°C).…”

Section: 1]oct-6-en-3-one (16d)supporting

confidence: 81%

A Novel Synthesis of 2‐Alkoxy‐3‐hydroxytropones and 2,7‐Dihydroxytropones from Dialkoxy‐8‐oxabicyclo[3.2.1]oct‐6‐en‐3‐ones

2004

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Trichloro‐substituted 8‐oxabicyclo[3.2.1]oct‐6‐en‐3‐ones 6 and 7 are solvolysed by methanolic sodium methoxide to form the bicyclo[3.2.1] α,α‐dimethoxy ketones 13 and 14, with preservation of one chloro substituent. In the case of 6a, prolonged reaction time with an excess of methanolic sodium methoxide provides a trimethoxy‐substituted oxanorbornene aldehyde 19 through ring contraction. Treatment of the mixture of 13 and 14 with zinc and aqueous acetic acid affords dechlorinated α‐oxo acetals 15 and 16. Starting with the [4+3] cycloadducts derived from 2‐methylfuran and tetrachloroacetones (6b and 7b), the same procedure, but with use of ethanol or trifluoroethanol, results in the corresponding ethoxy‐ and trifluoroethoxy acetals. These compounds can be converted into the oxabicyclic compounds 15, which undergo cleavage of the ether bridge on heating with KOH in methanol, thus providing 2‐alkoxy‐3‐hydroxytropones 20, which can be dealkylated to give the 2,7‐dihydroxytropones (7‐hydroxytropolones) 29. The lithium enolate generated from the α‐oxo acetal 15a can be exo‐alkylated with methyl iodide. Michael addition with 2‐nitro‐1‐butene followed by a Nef reaction furnishes the bicyclic dioxo acetal 5. Treatment of 5 with basic methanol results in an epoxyazulenone derivative 26, and a hydroxytropone 20f, which is in equilibrium with the cyclic hemiacetal form 28. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

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Section: 1]oct-6-en-3-one (16d)supporting

confidence: 81%

A Novel Synthesis of 2‐Alkoxy‐3‐hydroxytropones and 2,7‐Dihydroxytropones from Dialkoxy‐8‐oxabicyclo[3.2.1]oct‐6‐en‐3‐ones

2004

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“…Compound 46 was acquired from the National Cancer Institute (NCI) Developmental Therapeutics Program. ␣-Hydroxytropolone (compound 172) was synthesized in 3 steps from tropolone based on procedures described previously by Takeshita et al (48). Compounds 95 to 104 were synthesized from manicol as previously described (39) and exceeded 95% purity, as determined by liquid chromatography-mass spectrometry (LCMS).…”

Section: Methodsmentioning

confidence: 99%

Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses

Ireland

Tavis

D’Erasmo

et al. 2016

Antimicrob Agents Chemother

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cHerpes simplex virus 1 (HSV-1) and HSV-2 remain major human pathogens despite the development of anti-HSV therapeutics as some of the first antiviral drugs. Current therapies are incompletely effective and frequently drive the evolution of drug-resistant mutants. We recently determined that certain natural troponoid compounds such as ␤-thujaplicinol readily suppress HSV-1 and HSV-2 replication. Here, we screened 26 synthetic ␣-hydroxytropolones with the goals of determining a preliminary structure-activity relationship for the ␣-hydroxytropolone pharmacophore and providing a starting point for future optimization studies. Twenty-five compounds inhibited HSV-1 and HSV-2 replication at 50 M, and 10 compounds inhibited HSV-1 and HSV-2 at 5 M, with similar inhibition patterns and potencies against both viruses being observed. The two most powerful inhibitors shared a common biphenyl side chain, were capable of inhibiting HSV-1 and HSV-2 with a 50% effective concentration (EC 50 ) of 81 to 210 nM, and also strongly inhibited acyclovir-resistant mutants. Moderate to low cytotoxicity was observed for all compounds (50% cytotoxic concentration [CC 50 ] of 50 to >100 M). Therapeutic indexes ranged from >170 to >1,200. These data indicate that troponoids and specifically ␣-hydroxytropolones are a promising lead scaffold for development as anti-HSV drugs provided that toxicity can be further minimized. Troponoid drugs are envisioned to be employed alone or in combination with existing nucleos(t)ide analogs to suppress HSV replication far enough to prevent viral shedding and to limit the development of or treat nucleos(t)ide analog-resistant mutants.

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“…This method, used commonly by Nozoe in his early work on the chemistry of tropolones, 38 can be a rather efficient way to make the parent αHT. 39 Most common methods for this involve halogenation of the tropone or tropolone followed by hydrolysis. This can be done directly or through intermediate acetolysis, such as the use of an acetic anhydride/ trifluoroacetic acid/ acetic acid mixture.…”

Section: Synthetic Access To α-Hydroxytropolonesmentioning

confidence: 99%

The biology and synthesis of α-hydroxytropolones

et al. 2014

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α-Hydroxytropolones are a subclass of the troponoid family of natural products that are of high interest due to their broad biological activity and potential as treatment options for several diseases. Despite this promise, there have been scarce synthetic chemistry-driven optimization studies on the molecules. The following review highlights key developments in the biological studies conducted on α-hydroxytropolones to date, including the few synthetic chemistry-driven optimization studies. In addition, we provide an overview of the methods currently available to access these molecules. This review is intended to serve as a resource for those interested in biological activity of α-hydroxytropolones, and inspire the development of new synthetic methods and strategies that could aid in this pursuit.

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An Improved Synthesis of 2,7-Dihydroxytropone (3-Hydroxytropolone)

Cited by 22 publications

References 0 publications

A Novel Synthesis of 2‐Alkoxy‐3‐hydroxytropones and 2,7‐Dihydroxytropones from Dialkoxy‐8‐oxabicyclo[3.2.1]oct‐6‐en‐3‐ones

A Novel Synthesis of 2‐Alkoxy‐3‐hydroxytropones and 2,7‐Dihydroxytropones from Dialkoxy‐8‐oxabicyclo[3.2.1]oct‐6‐en‐3‐ones

Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses

The biology and synthesis of α-hydroxytropolones

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