A Double Allylation Strategy for Gram‐Scale Guaianolide Production: Total Synthesis of (+)‐Mikanokryptin

Abstract

With over 5000 members isolated to date, sesquiterpene lactones represent a prolific source of medicinal agents with several derivatives in human clinical trials. The guaianolides, a major subset of this group, have been intensely investigated from both medicinal and chemical synthesis perspectives for decades. To date, the myriad stereochemical permutations presented by this enormous family have precluded the synthesis of many unique members. Herein we report the first total synthesis of the trans-fused 8,12-guaianolide (+)-mikanokryptin in 10 steps from (+)-carvone.Notably this represents the first gram-scale total synthesis of any guaianolide natural product. Graphical AbstractKeywords total synthesis; terpene; allylation; natural product; guaianolide Sesquiterpene lactones from the Asteraceae family of plants represent one of the largest and most biologically significant classes of plant secondary metabolites. [1] Their presence in both traditional herbal medicine regimes as well as modern human medicine have been extensively documented. [1][2] In particular, α-methylene-γ-lactone-containing members have strong documented anticancer, [3] anti-inflammatory, [4] anthelmintic, [5] and anti-migraine activity. [6] Multiple members have also been shown to inhibit aspects of the NF-κB Correspondence to: Thomas J. Maimone. Current address of Prof. Dr. Silong Xu: Department of Chemistry, School of Science, Xi'an Jiaotong University, Xi'an, 710049, P. R. China.Supporting information for this article is given via a link at the end of the document. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript signaling pathway, [7] a central mediator of the human immune response whose deregulation is noted in inflammatory and autoimmune diseases as well as various human cancers. [8] The 5,7-fused bicyclic family of guaianolides is perhaps the flagship subset of sesquiterpene lactone natural products and two major, isomeric sub-types, the 6,12-guaianolides and 8,12-guaianolides, have been isolated ( Figure 1A). Despite extensive studies on the chemical synthesis of 6,12-guaianolides, [9] 8,12-guaianolides have received relatively limited attention from the synthetic community. [10] Mikanokryptin (1), isolated in 1975 by Herz and co-workers, belongs to the continually growing family of trans-fused 8,12-guaianolides which are largely unexplored and present stereochemistry patterns not easily addressed by current strategies ( Figure 1A). [11] In developing a synthetic route to this family, we viewed a double allylation disconnection as potentially being capable of constructing the guaianolide ring system (see 2) from two simple, hypothetical fragments (see 3 and 4, Figure 1B). Of significant concern to us was the paucity of examples of 7-membered ring formation via metal-mediated intramolecular Barbier-type allylation relevant to this synthetic problem. [12,13] Herein we disclose the realization of this plan resulting in a simple total synthesis of 1 capable of forming multi-gram ...

Parthenolide Covalently Targets and Inhibits Focal Adhesion Kinase in Breast Cancer Cells

“…Antibodies were obtained from Cell Signaling Technologies unless otherwise noted. Mikanokryptin was synthesized as previously described (Hu et al, 2017). Synthesis and characterization of cysteine-reactive covalent ligands screened against FAK1 were either described previously or described in Supporting Methods (Bateman et al, 2017;Grossman et al, 2017;Roberts et al, 2017b).…”

“…Consistent with these results, parthenolide, costunolide, and dehydrocostus lactone, but not a-santonin, exhibited FAK1 cysteine reactivity as shown by competitive IA-rhodamine labeling of FAK1 (Figure 3B). Moreover, the more highly oxidized guaianolide sesquiterpene mikanokryptin (Hu et al, 2017), which also possesses differing stereochemistry relative to dehydrocostus lactone, also showed FAK1 cysteine reactivity and impaired 231MFP breast cancer cell proliferation and survival (Figures 3C-3E). Taken together, these findings indicate some flexibility in targeting this druggable hotspot with sesquiterpene natural products harboring reactive a-methylene-g-butyrolactone homo-Michael acceptors.…”

Parthenolide Covalently Targets and Inhibits Focal Adhesion Kinase in Breast Cancer Cells

“…3B). Moreover, the more highly oxidized guaianolide sesquiterpene mikanokryptin (Hu et al, 2017), which also possesses differing stereochemistry relative to dehydrocostus lactone, also showed FAK1 cysteine reactivity and impaired 231MFP breast cancer cell proliferation and survival ( Fig. 3C-E).…”

“…Antibodies were obtained from Cell Signaling Technologies unless otherwise noted. Mikanokryptin was synthesized as previously described (Hu et al, 2017). Synthesis and characterization of cysteine-reactive covalent ligands screened against FAK1 were either described previously or described in Supporting Methods Grossman et al, 2017;Roberts et al, 2017b).…”

Uncovering the pharmacological response of novel sesquiterpene derivatives that differentially alter gene expression and modulate the cell cycle in cancer cells

“…Notably, the total synthesis of sesquiterpenes and SLs has led to intense research efforts for decades; however, only a few unified synthetic protocols have been published to analyze the diverse carbocyclic complexity presented by the sesquiterpenoid family (20,21,40,41). Furthermore, despite extensive studies on the chemical synthesis and biology of 6,12-SLs, the isomeric 8,12-SLs, comprising almost half of the natural substances, have received relatively limited attention in the pharmacological field, restricting the identification of the pharmacological potential of this family of compounds (42). Thus, efforts to improve our understanding of the molecular mechanisms underlying the effects of SLs in cancer cells are urgently required to ensure the clinical exploitation and application of these compounds as potential anticancer therapeutic agents.…”