Total Synthesis of (±)-Cycloclavine and (±)-5-<i>epi</i>-Cycloclavine

Petronijević, Filip; Wipf, Peter

doi:10.1021/ja2026882

Cited by 135 publications

(54 citation statements)

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“…A catalytic amount of TBAF in acetic acid was slowly added to 9 in dry THF at 0°C, and the key intermediate 10 was obtained after stirring. 23 Condensation of 10 with various sugar donors (14)(15)(16)(17)(18)(19)(20), as described for the preparation of 3, generated 11 and 11a-11f, which were subjected to hydrogenation with H 2 over Pd/C. Finally debenzoylation and deacetylation with a catalytic amount of NaOMe in DCM-MeOH furnished the target compound albiziabioside A (1) and its analogues 12a-12f.…”

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confidence: 99%

Synthesis and evaluation of the anticancer activity of albiziabioside A and its analogues as apoptosis inducers against human melanoma cells

et al. 2014

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We have efficiently synthesized albiziabioside A (1) together with its six disaccharide analogues through a linear synthesis, and evaluated their cytotoxicity against six different skin cancer cells. All of the analogues showed weak cytotoxicity, with the exception of compound 1, which exhibited strong cytotoxicity against A375 cells. Albiziabioside A can induce cell cycle arrest in both the S and G2/M phases. Moreover, albiziabioside A can induce A375 cell apoptosis via mitochondrial pathways involving a caspase cascade. These results provide for the first time a basic mechanism for the anticancer activity of 1.

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Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of the anticancer activity of albiziabioside A and its analogues as apoptosis inducers against human melanoma cells

et al. 2014

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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).…”

Section: Author Manuscriptmentioning

confidence: 99%

“…A conventional approach would have required ester conversion into a more reactive acid chloride or anhydride for N-acylation of the vinylogous amide. The successful implementation of this two-step approach to 3 would represent a major improvement compared to our previous [6] synthesis, which required seven steps to access an analogous intermediate.We first explored an experimental validation of the key cyclopropanation. Allene (5) represents an ideal, atom-economical precursor to MCPs.…”

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confidence: 98%

“…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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confidence: 99%

“…In prior work, this transformation required two steps and the use of stoichiometric transition metal. [6] Enone 2 was obtained as a crystalline solid and provided 2 in >99% ee after recrystallization.…”

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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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