New routes to clavine-type ergot alkaloids. Part 2: Synthesis of the last, so far not yet synthesized member of the clavine alkaloid family, (±)-cycloclavine

Incze, Mária; Dörnyei, Gábor; Moldvai, István; Temesvári-Major, Eszter; Egyed, Orsolya; Szántay, Csaba

doi:10.1016/j.tet.2008.01.101

Cited by 38 publications

(32 citation statements)

References 10 publications

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“…A number of cyclopropanation reactions are known in the literature [28] such as the Simmon-Smith reaction [29,30] and its variants, e.g. that involving triisobutylaluminium [52] or diazomethane in the presence of a catalyst [32].…”

Section: Methodsmentioning

confidence: 99%

“…recently [28], the Simmons-Smith reaction [29,30], reaction with dimethyloxosulfonium methylide [31], and cyclopropanation with diazomethane [32] in the presence of a catalyst are frequently used.…”

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confidence: 99%

“…Secondly, a reaction between 1 and diazomethane -generated from Nmethyl-N-nitrosourea in dichloromethane solution in the presence of palladium(II) acetate [32] at 0 o C -resulted in a new derivative of galanthamine (Scheme 1). Cyclopropanation has not taken place but from the reaction mixture we could isolate a cycloheptatriene derivative (4) in 8% yield.…”

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confidence: 99%

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Cyclopropanation of Some Alkaloids

Keglevich

Hazai

Kalaus

et al. 2015

Period. Polytech. Chem. Eng.

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Section: Methodsmentioning

confidence: 99%

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Cyclopropanation of Some Alkaloids

Keglevich

Hazai

Kalaus

et al. 2015

Period. Polytech. Chem. Eng.

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“…[5,6,7,[8][9] However, no enantioselective total synthesis of cycloclavine has been accomplished. In order to meet this objective and establish a concise route to either enantiomer as well as analogs of the natural product, we fundamentally revised our previous 14-steps/1.2% yield approach to racemic product and developed a streamlined asymmetric total synthesis of the unnatural enantiomer (−)-cycloclavine, (−)-(1) (Figure 2).…”

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confidence: 99%

“…The degree of enantioinduction depended on the nature of the ester, with the sterically hindered t-butyl diazopropanoate providing the best er at low temperatures (entries 2 and 3). However, MCPs bearing an activated ester facilitated direct aminolysis and were therefore strategically more appealing (entries [4][5][6]. While the succinimide and pentachlorophenyl diazopropanoates provided only moderate enantioinduction (entries 4 and 5), the pentafluorophenyl diazopropanoate provided the desired cyclopropane in high yield with a good er of 87:13 that could be further upgraded to an excellent er by crystallization (vide infra).…”

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Eight‐Step Enantioselective Total Synthesis of (−)‐Cycloclavine

McCabe

Wipf

2016

Angewandte Chemie

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The first enantioselective total synthesis of (−)-cycloclavine has been accomplished in 8 steps and 7.1% overall yield. Key features include the first catalytic asymmetric cyclopropanation of allene, mediated by dirhodium catalyst Rh 2 (S-TBPTTL) 4 , and the enone 1,2-addition of a new TEMPOcarbamate methyl carbanion. An intramolecular strain-promoted Diels-Alder methylenecyclopropane (IMDAMC) reaction provided a pivotal tricyclic enone intermediate in >99% ee after crystallization. The synthesis of (−)-1 was completed by a late stage intramolecular Diels-Alder furan (IMDAF) cycloaddition to install the indole. Graphical Abstract KeywordsClavine alkaloids; allene; enantioselective; cyclopropanation; sequential cycloadditions Cycloclavine (1) was originally isolated from the seeds of the African morning glory shrub Ipomoea hildebrandtii and later from Aspergillus japonicus, a species of filamentous fungus. [1,2] In preliminary biological evaluations, it demonstrated promising insecticidal and anti-parasitic activity. [3] Cycloclavine belongs to the clavine subset of ergot alkaloids, a prominent group of natural products that share a fused indole core (Figure 1). Members of this family have long served as an inspiration for the design of therapeutic agents and agrochemicals due to their potent and diverse biological activities. [4] In recent years, major advances in elucidating the biogenetic origin of ergot alkaloids have been made. [4] A unique Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript structural feature of cycloclavine is a pyrrolidine-fused cyclopropane in place of the piperidine that is typical for other clavine and lysergic acid alkaloids.While its biological properties remain largely unexplored, cycloclavine's unusual pentacyclic scaffold has attracted the interest of synthetic chemists. Particularly, the assembly of three consecutive stereogenic carbons at C(5), C(8) and C(10), two of them allcarbon quaternary stereocenters, requires robust synthetic methodologies and high stereochemical control.To date, three total syntheses and three formal syntheses of racemic cycloclavine have been reported, including a prior total synthesis accomplished by our group. [5,6,7,[8][9] However, no enantioselective total synthesis of cycloclavine has been accomplished. In order to meet this objective and establish a concise route to either enantiomer as well as analogs of the natural product, we fundamentally revised our previous 14-steps/1.2% yield approach to racemic product and developed a streamlined asymmetric total synthesis of the unnatural enantiomer (−)-cycloclavine, (−)-(1) (Figure 2). Our main goals were: (a) to introduce the enone moiety in 2 directly from the ketone product of the methylenecyclopropane (MCP)-Diels-Alder reaction; (b) to develop an asymmetric cyclopropanation of unsubstituted allene 5 to install the quaternary stereocenter that directs the formation of the two neighboring stereogenic carbons in (−)-1; and (c) to generate the amide linkage in 3 by direct amino...

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Gespannte Moleküle in der Naturstoffsynthese

Wilson

Taylor

2013

Angewandte Chemie

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Gespannte Moleküle sind von außerordentlichem Interesse in der Chemie, und ihre hochenergetischen Bindungen dienen als “Treibstoff” für komplexe Synthesen. Entwicklungen auf diesem Gebiet führten in jüngster Zeit zur vermehrten Nutzung gespannter Alkene als Intermediate in der Naturstoffsynthese. Dieser Kurzaufsatz präsentiert diese neuen Fortschritte zusammen mit Entwicklungen im Hinblick auf das Verständnis der einzigartigen Reaktivität gespannter Alkene.

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New routes to clavine-type ergot alkaloids. Part 2: Synthesis of the last, so far not yet synthesized member of the clavine alkaloid family, (±)-cycloclavine

Cited by 38 publications

References 10 publications

Cyclopropanation of Some Alkaloids

Cyclopropanation of Some Alkaloids

Eight‐Step Enantioselective Total Synthesis of (−)‐Cycloclavine

Gespannte Moleküle in der Naturstoffsynthese

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