Studies on Total Synthesis of the Cytotoxic Marine Alkaloid Agelastatin A

Anderson, Glen T.; Chase, Charles E.; Koh, Yung Hyo; Stien, Didier; Weinreb, Steven M.; Shang, Maoyu

doi:10.1021/jo981785i

Cited by 47 publications

(21 citation statements)

References 16 publications

(13 reference statements)

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“…Formal total synthesis of (−)‐agelastatin A : With tricycle 19 in hand, we turned to examine the feasibility of transforming this advanced intermediate to the natural (−)‐enantiomer of agelastatin A. Inspired by the work of Weinreb,10, 40 pyrrolopiperazinone 19 was subjected to allylic amination conditions 41. As shown in Equation (6) (Table 6), several modifications were attempted in order to improve the yield for this Kresze reaction,41b but the original thermal conditions gave the best results (43–47 % yield).…”

Section: Resultsmentioning

confidence: 99%

A Stereodivergent Strategy to Both Product Enantiomers from the Same Enantiomer of a Stereoinducing Catalyst: Agelastatin A

Trost

Dong

2009

Chemistry A European J

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In this article, we report a full account of our recent development of pyrroles and N-alkoxyamides as new classes of nucleophiles for palladium-catalyzed AAA reactions, along with application of these methodologies in the total synthesis of agelastatin A, a marine natural product with exceptional anti-cancer activity and other biological properties. Our method allows for access to either regioisomer of the pyrrolopiperazinones (6 and 19) with high efficiency and enantioselectivity. Note that isomer 19 was obtained via a cascade reaction through a double allylic alkylation pathway. From regioisomer 6, the total synthesis of (+)-agelastatin A was completed in a very short fashion (four steps from 6), during the course of which we developed a new copper catalyst for aziridination and an In (OTf) 3 -DMSO system to oxidatively open an Ntosyl aziridine. Starting with the other pyrrolopiperazinone 19, a five-step sequence has been developed to furnish a formal total synthesis of (−)-agelastatin A. A unique feature of our syntheses is the use of two rather different strategies for the total syntheses of both enantiomers of agelastatin A using the same enantiomer of a chiral palladium catalyst.

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Section: Resultsmentioning

confidence: 99%

A Stereodivergent Strategy to Both Product Enantiomers from the Same Enantiomer of a Stereoinducing Catalyst: Agelastatin A

Trost

Dong

2009

Chemistry A European J

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“…In 1999, Weinreb completed the first total synthesis of agelastatin A ( 1 ) employing a key N -sulfinyl dienophile hetero-Diels–Alder reaction 15,16. Feldman reported the first enantioselective syntheses of (–)-Agelastatin A ( 1 ) and (–)-Agelastatin B ( 2 ) using an alkylidenecarbene C−H insertion reaction 17,18.…”

Section: Introductionmentioning

confidence: 99%

Total synthesis of all (−)-agelastatin alkaloids

2010

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The pyrrole-imidazole family of marine alkaloids, derived from linear clathrodin-like precursors, constitutes a diverse array of structurally complex natural products. The bioactive agelastatins are members of this family that possess a tetracyclic molecular framework incorporating C4–C8 and C7–N12 bond connectivities. We provide a hypothesis for the formation of the unique agelastatin architecture that maximally exploits the intrinsic chemistry of plausible biosynthetic precursors. We report the concise enantioselective total syntheses of all known agelastatin alkaloids including the first total syntheses of agelastatins C, D, E, and F. Our gram-scale chemical synthesis of agelastatin A was inspired by our hypothesis for the biogenesis of the cyclopentane C-ring and required the development of new transformations including an imidazolone-forming annulation reaction and a carbohydroxylative trapping of imidazolones.

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“…An alternative strategy to form the final B ring from bicyclic intermediate 24 , would be a transient base‐induced opening of the cyclic urea (D ring) to a cyclopentenone followed by an aza‐Michael addition and reformation of the cyclic urea. Interestingly, several previous syntheses of agelastatin A that required late‐stage B‐ring closure involved an enone intermediate, thus bolstering this idea further 6a. h, i, k, o, q The Tse protecting group on one of the urea nitrogen atoms was removed to enable greater conformational mobility and thus facilitate D‐ring cleavage.…”

Section: Methodsmentioning

confidence: 98%

Bioinspired Total Synthesis of Agelastatin A

Reyes

Romo

2012

Angewandte Chemie

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Über C und B zu A: Zwei Cyclisierungen eines Keramadin‐Analogons mit potenzieller Relevanz für die Biosynthese führen zu Agelastatin A (siehe Schema): Die diastereoselektive 5‐exo‐trig‐Cyclisierung oder Nazarov‐Cyclisierung einer roten N‐Acyliminium‐Zwischenstufe baut die drei benachbarten Stereozentren des Cyclopentanrings C auf, und über eine durch Kieselgel vermittelte Cyclisierung des Nagelamid‐J‐Analogons gelangt man dann zu Agelastatin A.

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Studies on Total Synthesis of the Cytotoxic Marine Alkaloid Agelastatin A

Cited by 47 publications

References 16 publications

A Stereodivergent Strategy to Both Product Enantiomers from the Same Enantiomer of a Stereoinducing Catalyst: Agelastatin A

A Stereodivergent Strategy to Both Product Enantiomers from the Same Enantiomer of a Stereoinducing Catalyst: Agelastatin A

Total synthesis of all (−)-agelastatin alkaloids

Bioinspired Total Synthesis of Agelastatin A

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