Total Synthesis of Epothilone B

Valluri, Muralikrishna; Hindupur, Rama Mohan; Panicker, Bijoy; Labadié, Guillermo R.; Jung, Jae‐Chul; Avery, Mitchell A.

doi:10.1021/ol016173q

Cited by 48 publications

(12 citation statements)

References 22 publications

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“…As a result, there were no advanced synthetic intermediates available to us to fund an efficient synthesis of labeled epothilone D. This meant that a de novo total synthesis had to be considered. There are numerous reports of total syntheses of epothilone D and epothilone analogs in the literature . These literature reports offer ample opportunities to incorporate stable isotope labels into epothilone D. One report in particular describes a stable isotope‐labeled synthesis of a fluorinated analog of epothilone D .…”

Section: Resultsmentioning

confidence: 99%

Synthesis of stable isotope‐labeled epothilone D using a degradation–reconstruction approach

Burrell

Turley

Bonacorsi

2015

Labelled Comp Radiopharmac

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The stabilization of microtubules using epothilones represents a novel mechanism of action to treat Alzheimer's disease. Epothilone D is one such microtubule-stabilizing drug that has been investigated by Bristol-Myers Squibb. An important step in the development process was the synthesis of a stable isotope-labeled analog for use in bioanalytical assays to accurately quantify the concentration of the drug in biological samples. A novel synthetic route to stable isotope-labeled epothilone D is described. The synthetic route was based on a strategy to degrade epothilone B and then use that key intermediate to reconstruct stable isotope-labeled epothilone D. Epothilone B was treated with potassium osmate and sodium periodate. The thiazole moiety in epothilone B was efficiently cleaved to give (1S,3S,7S,10R,11S,12S,16R)-3-acetyl-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione. The epoxide in the macrocyclic ring of that intermediate was cleanly removed by treatment with tungsten hexachloride and n-butyllithium to give the corresponding olefin (4S,7R,8S,9S,16S,Z)-16-acetyl-4,8-dihydroxy-5,5,7,9,13-pentamethyloxacyclohexadec-13-ene-2,6-dione. Bis(triethylsilyl) protection produced (4S,7R,8S,9S,16S,Z)-16-acetyl-5,5,7,9,13-pentamethyl-4,8-bis(triethylsilyloxy)-oxacyclohexadec-13-ene-2,6-dione. This intermediate was coupled to a stable isotope-labeled thiazole using a Wittig reaction as the key step to provide (13)C5, (15)N-labeled epothilone D. In summary, the synthesis was completed in nine total steps, only six of which involved isotopically labeled reagents. A total of 168 mg of (13)C5, (15)N-labeled epothilone D was prepared in an 8% overall yield from (13)C2, (15)N-labeled thioacetamide and (13)C3-labeled ethyl bromopyruvate.

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Section: Resultsmentioning

confidence: 99%

Synthesis of stable isotope‐labeled epothilone D using a degradation–reconstruction approach

Burrell

Turley

Bonacorsi

2015

Labelled Comp Radiopharmac

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“…Epothilony vzbudily velký zájem nejen mezi biology a lékaři, ale také mezi chemiky. Bylo navrženo několik syntetických přístupů k jejich přípravě a dnes jsou všechny epothilony dostupné synteticky (Bertinato et al, 1996;Nicolaou et al, 1997;Valluri et al, 2001;Zhu a Panek, 2000), stejně jako mnohé jejich deriváty (Nicolaou et al, 1998).…”

Section: Chemie Epothilonůunclassified

Epothilones - new anti-cancer medicines

Patočka¹,

Hon²

2007

Kontakt

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Jihočeská univerzita v Českých Budějovicích, Zdravotně sociální fakulta, katedra radiologie a toxikologie SummaryEpothilones are a new group of cytotoxic molecules, originally identified as metabolites produced by the myxobacterium Sorangium cellulosum. Clinical success of paclitaxel and docetaxel stimulated the research of further substances with the same mechanism of effects and resulted in discovering three new types of natural substances of non-taxane type: Epothilones A and B from a soil bacterium, discodermolide from a sponge and eleutherobines and sarcodictyines from corals. All the three groups of substances stabilize microtubules and competitively inhibit the bond of paclitaxel to polymers of tubulin, which suggests that their binding sites are the same. Epothilones are natural substances stabilizing microtubules with strong in vivo and in vitro anti-cancer activity. Thus, epothilones were considered as potential chemotherapeutic drugs due to their intervention into the cytoskeleton. Recent studies in cancer cell lines and in humans with cancer diseases indicate their higher efficacy compared with taxanes. The mechanism of their effects is similar to that of taxanes, but their chemical structure is simpler and their solubility in water is higher. In addition, epothilones may be prepared in large amounts by the fermentation of bacteria and they also exert activities against cell lines and tumours, which are resistant to many other drugs. Due to their high activity and to clinical requirements for the treatment of cancer, epothilones are targets of many studies. The purpose of the present article is to familiarize Czech readers with problems of epothilones.

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“…[32][33][34][35] Our overall retrosynthetic approach to this class of molecules is shown in Scheme 1. [33] We envisioned using a convergent, two-step sequence involving a double-diastereoselective aldol condensation between the aldehyde 5 and the keto acid 6, followed by Yamaguchi macrolactonization to form the target epothilone framework.…”

Section: Recent Total Syntheses Of the Epothilonesmentioning

confidence: 99%

Recent Developments in the Syntheses of the Epothilones and Related Analogues

2006

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The macrocyclic class of antitumor compounds known as the epothilones has generated considerable interest since its discovery in 1993. Numerous total syntheses of this class of molecules have been published and countless structural analogues have been developed and tested for their abilities to promote tubulin polymerization. Several of these compounds are presently in clinical trials.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

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Total Synthesis of Epothilone B

Cited by 48 publications

References 22 publications

Synthesis of stable isotope‐labeled epothilone D using a degradation–reconstruction approach

Synthesis of stable isotope‐labeled epothilone D using a degradation–reconstruction approach

Epothilones - new anti-cancer medicines

Recent Developments in the Syntheses of the Epothilones and Related Analogues

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