Asymmetric total synthesis of the indole alkaloid cyclopiazonic acid and first structure–activity data

Beyer, W.R. Christian; Woithe, Katharina; Lüke, Bettina; Schindler, Michael; Antonicek, Horst; Scherkenbeck, Jürgen

doi:10.1016/j.tet.2011.03.002

Cited by 26 publications

(11 citation statements)

References 30 publications

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“…Although the structure of CPA has been known since 1968, only three racemic syntheses have been published to date (Haskins and Knight, 2005;Kozikowski et al, 1984;Muratake and Natsume, 1985) and very little is known on the related structure-activity relationships. Beyer et al (2010Beyer et al ( , 2011 reported the first structure-activity data of several CPA derivatives and stereoisomers as well as the first asymmetric total synthesis of CPA by a modification of the Knight synthesis, currently the most efficient route to produce CPA.…”

Section: Cyclopiazonic Acid Chemistrymentioning

confidence: 99%

Cyclopiazonic acid: 50th anniversary of its discovery

Ostrý¹,

Toman

Grosse

et al. 2018

WMJ

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In 1968, the mycotoxin cyclopiazonic acid (CPA) was first discovered and characterised as a chemical substance. Within the following five decades, much has been learned from the results of CPA research. CPA is produced by several Penicillium species (P. griseofulvum, P. camemberti, P. commune, P. dipodomyicola) and Aspergillus species (A. flavus, A. oryzae and A. tamarii). It is widespread on naturally contaminated agricultural raw materials. CPA has been reported to occur in food commodities (e.g. oilseeds, nuts, cereals, dried figs, milk, cheese and meat products) and to possess toxicological significance. CPA is also frequently detected in peanuts and maize; the presence of CPA and aflatoxins in maize and peanuts contaminated with A. flavus suggests that synergism may occur. CPA is toxic to several animal species, such as rats, pigs, guinea pigs, poultry and dogs. After ingesting CPA-contaminated feeds, test animals display severe gastrointestinal upsets and neurological disorders. Organs affected include the liver, kidney, heart, and digestive tract, which show degenerative changes and necrosis. Biologically, CPA is a specific inhibitor of sarco(endo)plasmic reticulum Ca2+-ATPase. Data from toxicological evaluation of aflatoxins and CPA in broiler chickens demonstrate that both aflatoxins and CPA alone and the aflatoxin-CPA combination can adversely affect broiler health. The effects of aflatoxins and CPA combination were additive in most cases.

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Section: Cyclopiazonic Acid Chemistrymentioning

confidence: 99%

Cyclopiazonic acid: 50th anniversary of its discovery

Ostrý¹,

Toman

Grosse

et al. 2018

WMJ

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“…Both aliphatic and aromatic amines worked well; however, yields dropped when aminothiazole, ethanolamine, or acetohydrazide where used. For the library reported here, three different acyl ketene precursors ( p -methoxyphenyl, 13 cyclopropyl, 14 and methyl) as well as three different chlorooximes ( o -pyridinyl, 15 o -trifluoromethylphenyl, 16 and carboethoxy 17 ) were used. We also demonstrate that these substituted acyl ketenes and chlorooximes tolerate the 2•3CR reaction conditions.…”

Section: Resultsmentioning

confidence: 99%

Expedient Synthesis of a 72-Membered Isoxazolino-β-ketoamide Library by a 2·3-Component Reaction

et al. 2012

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An efficient 2•3-component reaction (2•3CR; a 2-component reaction followed, in one pot, by a 3-component reaction) is presented for the synthesis of isoxazolino-β-ketoamides. This 2•3CR proceeds by (i) a Meldrum's acid-generated acyl ketene, which is trapped by an amine to form a β-ketoamide intermediate in a 2CR followed, in one pot, by (ii) a Mannich reaction followed by elimination of dimethyl amine•HCl to generate an α,β-unsaturated β-ketoamide dipolarophile that reacts in a nitrile oxide 1,3-dipolar cycloaddition reaction. This one-pot 2•3CR process delivers the targeted isoxazolino-β-ketoamide product. A total of 72 compounds are presented, all of which have been submitted to the NIH Molecular Libraries Small Molecule Repository for high-throughput biological screening.

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“…Scherkenbeck [28] achieved the first asymmetric synthesis of α‐cyclcopiazonic acid 1 elaborating upon Knight's cationic cascade approach (Scheme 9). The authors prepared the key carbocation precursor 22 starting from indolyl acrylamide 31 , for which they have previously devised an asymmetric route [29] .…”

Section: Synthesis Of α‐Cyclopiazonic Acidmentioning

confidence: 99%

“…The second coupling partner, sulfonium salts 40 a – b , [28] were prepared from β‐ketoester 47 (Scheme 11). First, alcohol 48 was prepared in two steps by the known protocol [34] .…”

Section: Synthesis Of α‐Cyclopiazonic Acidmentioning

confidence: 99%

α‐Cyclopiazonic Acid from Synthesis Perspective

et al. 2020

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First reported in 1968, α‐cyclopiazonic acid is an ergot alkaloid that remained a synthetic challenge for the long time. The key problem lied with the diastereocontrol of three adjoining stereocentres at the core of the molecule. The early syntheses relied on stepwise approaches and classical reactions, such as intramolecular Michael addition and Dieckmann condensation. Later, advances in methodology allowed for concurrent construction of the stereochemical triad in one step, and expedient construction of the rest of the molecule. This review will cover the history of α‐cyclopiazonic acid highlighting important discoveries that came out of the synthetic efforts, in particular the use of sulfur ylides.

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Asymmetric total synthesis of the indole alkaloid cyclopiazonic acid and first structure–activity data

Cited by 26 publications

References 30 publications

Cyclopiazonic acid: 50th anniversary of its discovery

Cyclopiazonic acid: 50th anniversary of its discovery

Expedient Synthesis of a 72-Membered Isoxazolino-β-ketoamide Library by a 2·3-Component Reaction

α‐Cyclopiazonic Acid from Synthesis Perspective

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