Concise Synthesis of a Pateamine A Analogue with In Vivo Anticancer Activity Based on an Iron‐Catalyzed Pyrone Ring Opening/Cross‐Coupling

Abstract

The marine macrolide pateamine A and its non-natural sibling DMDA-Pat A are potent translation inhibitors targeting the eukaryotic initiation factor 4A (eIF4A), an enzyme with RNA helicase activity. Although essential for every living cell, this protein target seems “drugable” since DMDA-Pat A has previously been shown to exhibit remarkable in vivo activity against two different melanoma mouse models. The novel entry into this promising compound presented herein is shorter and significantly more productive than the literature route. Key to success was the masking of the signature Z,E-configured dienoate subunit of DMDA-Pat A in the form of a 2-pyrone ring, which was best crafted by a gold-catalyzed cyclization. While the robustness of the heterocycle facilitated the entire assembly stage, the highly isomerization-prone seco-Z,E-dienoic acid could be unlocked in due time for macrolactonization by an unconventional iron-catalyzed ring opening/cross coupling. Moreover, the crystal structure analysis of an advanced intermediate gave first insights into the conformation of the macrodilactone framework of the pateamine family, which is thought to be critical for eliciting the desired biological response

Polyunsaturated C‐Glycosidic 4‐Hydroxy‐2‐pyrone Derivatives: Total Synthesis Shows that Putative Orevactaene Is Likely Identical with Epipyrone A

“…[19,20] This gratifying result adds another entry to the growing list of exigent pyrone derivatives prepared by this method. [19][20][21] Selective oxidation of the primary hydroxy group in 15 followed by aT akai olefination [22] furnished product 16 as af irst fully functional building block en route to 1.…”

“…Compound 14 was then cyclized with the help of gold complex 19 as a p-acidic catalyst [18] to the desired 2-pyrone 15 according to ap rocedure previously developed by our group. [19][20][21] Selective oxidation of the primary hydroxy group in 15 followed by aT akai olefination [22] furnished product 16 as af irst fully functional building block en route to 1. [19][20][21] Selective oxidation of the primary hydroxy group in 15 followed by aT akai olefination [22] furnished product 16 as af irst fully functional building block en route to 1.…”

Gold Catalysis for Heterocyclic Chemistry: A Representative Case Study on Pyrone Natural Products

“…Then ew gold-catalyzed pyrone formation played an entirely different role in ar ecent synthesis of DMDApateamine A(73). [75] This compound is anon-natural variant of the marine macrolide pateamine A, [76,77] which retains the potency, selectivity,and mode of action of the parent natural product. Both compounds show promising differential anticancer activity in vivo; [78] moreover,p ateamine Aw as iden-tified as apossible lead in the quest for medication for the often deadly muscle-wasting syndrome ("cachexia") which affects many cancer-a nd immune-compromised patients.…”

Gold‐Katalyse für die Heterocyclenchemie: eine repräsentative Fallstudie zu Naturstoffen der Pyron‐Reihe

“…Im Zug der Synthese von DMDA‐Pateamin A ( 73 ) kam der Gold‐katalysierten Pyronbildung eine gänzlich andere Rolle zu . Dieses nichtnatürliche Derivat des marinen Naturstoffs Pateamin A kommt der Stammverbindung an Aktivität, Selektivität und Wirkungsweise praktisch gleich.…”