Substituent effects in the transannular cyclizations of germacranes. Synthesis of 6-epi-costunolide and five natural steiractinolides

Azarken, Redouan; Guerra, Francisco M.; Moreno‐Dorado, F. Javier; Jorge, Zacarías D.; Massanet, Guillermo M.

doi:10.1016/j.tet.2008.09.017

Cited by 29 publications

(35 citation statements)

References 29 publications

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“…The confirmation of either of these Fig. 4 The proposed formation of eudesmanolides and guaianolides from costunolide in Chicory (De Kraker et al 1998 hypotheses would explain the biogenetic origin of guaianolides Azarken et al 2008).…”

Section: Biosynthesis Of Sesquiterpene Lactonesmentioning

confidence: 86%

“…This is of particular interest with regards to the similarities and differences between Apiaceae and Asteraceae. Numerous sesquiterpene lactones have been isolated from both families (Ghisalberti 1994;Holub and Budesinsky 1986;Fraga 2006), but the guaianolides exhibit a peculiar difference between the two Azarken et al 2008). In Apiaceae, the conformation of all guaianolides identified so far is different from that of guaianolides that have been identified in Asteraceae (Fig.…”

Section: Biosynthesis Of Sesquiterpene Lactonesmentioning

confidence: 96%

“…Holub and Budesinsky (1986) proposed that these features arise through different enzymatic activity in the two families that cyclizes the trans,trans-farnesyl diphosphate in different conformations. Azarken et al (2008) recently presented an alternative route based on the observation that (E,E)-germacradienes adopt several conformations of which UU, UD, DU and DD are the most stable ones. U (up) and D (down) refers to the orientation of the C-14 and C-15 methyl groups.…”

Section: Biosynthesis Of Sesquiterpene Lactonesmentioning

confidence: 99%

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Guaianolides in apiaceae: perspectives on pharmacology and biosynthesis

et al. 2009

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The guaianolide group of sesquiterpene lactones contains a large number of compounds with biological activity. One of these guaianolides, thapsigargin from the genus Thapsia (Apiaceae), has been a subject of particular interest in recent years because of its ability to induce apoptosis, as the active part of a pro-drug, has produced promising results for the targeted treatment of prostate cancer. In this review, recent advances in understanding the biosynthetic pathway of sesquiterpenes in plants is described with a special emphasis on guaianolides, and a hypothetical pathway for the biosynthesis of thapsigargin is presented. Eighty-seven guaianolides from Apiaceae are presented. These compounds provide clues to possible enzymatic mechanisms generating the guaianolides in Apiaceae. Some of these 87 compounds have proven or might prove interesting with regards to their biological activity.

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Section: Biosynthesis Of Sesquiterpene Lactonesmentioning

confidence: 86%

Section: Biosynthesis Of Sesquiterpene Lactonesmentioning

confidence: 96%

Section: Biosynthesis Of Sesquiterpene Lactonesmentioning

confidence: 99%

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Guaianolides in apiaceae: perspectives on pharmacology and biosynthesis

et al. 2009

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“…[89] They then applied Coreys MnO 2 /cyanide procedure to efficiently generate the substituted a-methylene-g-butyrolactone (e. preparation of 6-epicostunolide (136), Massanet and coworkers demonstrated that cyanide is not always required for such oxidative lactonizations (Scheme 26). [90] …”

Section: Methodsmentioning

confidence: 99%

The Renaissance of α‐Methylene‐γ‐butyrolactones: New Synthetic Approaches

Kitson¹,

Millemaggi²,

Taylor³

2009

Angew Chem Int Ed

412

249

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The amount of research activity concerning alpha-methylene-gamma-butyrolactones and alpha-alkylidene-gamma-butyrolactones has increased dramatically in recent years. This Review summarizes the structural types, biological activities, and biosynthesis of these compounds, concentrating on publications from the past 10 years. Traditional approaches to alpha-methylene-gamma-butyrolactones and alpha-alkylidene-gamma-butyrolactones are then reviewed together with novel approaches, including those from our own research group, reported more recently.

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“…The stereochemistry o f ( + )-1 was unambiguously established from the X-ray crystallographic analysis [11] of acetate 6, revealing the cis-relationship between the 6-OH group and isopropylidene group in the 7-position. Hydroboration followed by oxidative work up of acetate 6 furnished the desired diol product, which was immediately oxidized (without further purification) with TEMPO and PhI(OAc) 2 to 11,13-dihydro-epi-parthenolide [12] (7) as a mixture of diastereomers. Converting 1 to acetate 6 is necessary for the hydroboration step, since a <40% conversion was observed otherwise.…”

Section: Nih Public Accessmentioning

confidence: 99%

Scalable, Enantioselective Synthesis of Germacrenes and Related Sesquiterpenes Inspired by Terpene Cyclase Phase Logic

et al. 2012

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Our laboratory has a longstanding interest in harvesting new chemical knowledge by learning from terpene biosynthesis. The straightforward construction of carbocyclic terpene backbones such as epoxy-germacrenol (1, Scheme 1A) in a low oxidation state (cyclase phase) followed by regio-, chemo-, and stereoselective oxidative modifications (oxidase phase) allow Nature to access a wide variety of related family members in a divergent manner. [1] Earlier this year, we reported our initial forays into the redox-economic synthesis of terpenes that resemble 1 by oligomerization of unfunctionalized isoprene (Scheme 1B, path a). [2] These studies ultimately led us to a new approach that utilizes the more advanced, yet readily available, C 15 building block farnesol (2, Scheme 1A) as a starting point. In this communication, a short, efficient, scalable, and enantioselective synthesis of 1 is described. Furthermore, we demonstrate how the key intermediate 1 can be processed not only to germacrane-type natural products by chemo-and stereoselective oxidations, but also to a variety of polycyclic sesquiterpene frameworks (like selinanes, guaianes, or elemenes) by acid-mediated transannular cyclization reactions.For the goal of establishing a scalable, divergent, and broadly applicable entry to a variety of related sesquiterpene families, the germacrenes were identified as strategic key intermediates due to the following reasons: 1) germacrenes constitute a large class of cyclic terpenes, many of which have been shown to exhibit promising bioactivities and, in addition, are of growing importance in the perfumery industry; 2) germacrenes are known to be a biosynthetic linchpin en route to various related terpene congeners; and 3) most importantly, many studies have demonstrated that germacrenes can be transformed into mono-, di-, and tricyclic sesquiterpene subclasses (e.g., the elemenes, cadinanes, eudesmanes, guaianes, and bourbonanes) with the "Achilles heel" of these approaches being the accessibility of germacrene precursors in quantity. [3] Despite the industrial interest in terpene natural products, most of the naturally occurring germacrenes and their congeners are not easily available in bulk quantities due to a variety of challenges associated with their synthesis and/or isolation: germacrenes featuring a * pbaran@scripps.edu. † These authors contributed equally to the paper.Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Although the total synthesis of sesquiterpenes has been an area of intense research efforts for decades, [4] there is still no reliable synthetic pathway to rapidly forge the ten-membered germacrene carbocycle. The most effective synthetic approaches published to date (Scheme 1B) suffer from serious drawbacks such as low overall yield, poor step economy, and/or are impractical to perform on scale In addition, these syntheses either yield racemic products or start from chiral-pool starting materials. Whereas Nature's cyclase enzymes c...

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Substituent effects in the transannular cyclizations of germacranes. Synthesis of 6-epi-costunolide and five natural steiractinolides

Cited by 29 publications

References 29 publications

Guaianolides in apiaceae: perspectives on pharmacology and biosynthesis

Guaianolides in apiaceae: perspectives on pharmacology and biosynthesis

The Renaissance of α‐Methylene‐γ‐butyrolactones: New Synthetic Approaches

Scalable, Enantioselective Synthesis of Germacrenes and Related Sesquiterpenes Inspired by Terpene Cyclase Phase Logic

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