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.

Iron‐Catalyzed C−O Bond Activation: Opportunity for Sustainable Catalysis

“…The authors demonstrated the utility of this method in the total synthesis of pateamine A analogue, ap otent anticancer agent,t og ive the key (Z/E)-dienoic acid fragment (75 %y ield, diastereomericr atio > 18:1; not shown). [35] In 2016, as ingle example of Hiyama cross-couplingo fa ryl carbamate catalyzed by FeCl 2 (10 mol %) in the presenceo f PCy 3 ,C uF 2 ,t etrabutylammonium bromide (TBAB), Zn, and TMSCl (TMS = trimethylsilyl) at 120 8Cw as reported by Shi and co-workers( Scheme 13). [36] Although the reaction proceeded in lower yield than the same transformation by using aN i 0 -based catalytic system (54 vs.9 1% yield), this example demonstrates the viability of SiÀFe transmetalation.…”

“…Iron-catalyzed cross-coupling of enol carbamates with alkyl Grignard reagents by Frantz et al [32] Scheme12. [35] In 2016, as ingle example of Hiyama cross-couplingo fa ryl carbamate catalyzed by FeCl 2 (10 mol %) in the presenceo f PCy 3 ,C uF 2 ,t etrabutylammonium bromide (TBAB), Zn, and TMSCl (TMS = trimethylsilyl) at 120 8Cw as reported by Shi and co-workers( Scheme 13). The authors demonstrated the utility of this method in the total synthesis of pateamine A analogue, ap otent anticancer agent,t og ive the key (Z/E)-dienoic acid fragment (75 %y ield, diastereomericr atio > 18:1; not shown).…”

Towards Synthesis of Simplified Analogues of Pateamine A

“…The coupling constants of the alkenes of compound 440 were consistent with the reported characterisation data of the macrocyclic compound 154 in Fürstner's synthesis of DMDA PatA (vide supra, Section 1.4.2.2). 128 Subsequent desilylation of compound 440 with buffered TBAF provided primary alcohol 441 in good yield.…”

“…As aldehyde 363 prepared from the alcohol 441 is structurally similar to aldehyde 155, an intermediate in Fürstner's synthesis of DMDA PatA (refer to Section 1.4.2.2), 128 it is presumed to be rather sensitive and prone to epimerisation on storage. We then decided to stockpile the alcohol 441 and not to perform the oxidation reaction until the side chain fragment was ready for coupling with it.…”

“…If silyl ether 485 is proven to have the desired E,E,E-configuration, macrocyclic alcohol 441 will be oxidised to provide the aldehyde 363. As Fürstner and Zhuo reported that the oxidation under optimised Parikh-Doering conditions provided the macrocyclic aldehyde 155 in reproducibly good yield (vide supra, Section 1.4.2.2), 128 the oxidation step will initially utilise their conditions.…”