An eight-step synthesis of epicolactone reveals its biosynthetic origin

Abstract

Epicolactone is a recently isolated fungal metabolite that is highly complex for its size, and yet racemic. With its array of quaternary stereocentres, high degree of functionalization and intricate polycyclic structure, it poses a considerable challenge to synthesis, a challenge that can be met by understanding its biosynthetic origin. If drawn in a certain way, epicolactone reveals a pattern that resembles purpurogallin, the archetype of ubiquitous natural colourants formed via oxidative dimerization. Based on this insight, we designed a biomimetic synthesis of epicolactone that proceeds in only eight steps from vanillyl alcohol. We have isolated a key intermediate that supports our biosynthetic hypothesis and anticipate that an isomer of epicolactone stemming from our synthetic efforts could also be found as a natural product.

Total Synthesis of Asperchalasines A, D, E, and H

“…Thes tructure of 22 was determined by X-ray crystallographic analysis.Both cycloadducts were subjected to deallylation [20] (Pd/C,HCO 2 NH 4 )tofurnish 24 and asperchalasine H( 4). [21] Then we entered the final stage of the synthesis.I nspired by Zhangsb iosynthetic hypothesis [7a] and Tr aunerse legant biomimetic synthesis of epicolactone, [18,22] we propose that 1 is formed through ar eaction cascade initiated with oxidation of the electron-rich aromatic ring in 24,followed by an intermolecular Michael addition of the resulting quinone to 6,a nd intramolecular aldol cyclization. Tr eatment of 24 with potassium ferricyanide led to facile oxidation of the electron-rich aromatic ring to yield the corresponding o-quinone,which was unstable and trapped by another molecule of 6 in the presence of sodium bicarbonate to furnish the formal the [5+ +2] adduct asperchalasine A(1)in 49 %y ield.…”

Total Synthesis of Epicolactone

“…Upon treatment of 22 with 2.1 equiv of SmI 2 in THF at À78 8 8Ca nd subsequent acidic workup,c lean formation of enone 24 was observed in high yield. [4] In conclusion, we have developed ar obust route for the synthesis of the structurally complex and highly oxygenated natural product epicolactone.A nu nusual [2+ +2] photocycloaddition between two electronically similar olefins was employed for the formation of the quaternary centers of the sterically encumbered molecule.Aretroaldol-aldol sequence dictated by functional group relationships was employed to synthesize the central cyclopentane embedded in the molecule.Inthe endphase,anunprecedented acid-catalyzed aldol addition of ad ioxene and an intramolecular carbonyl methenylation were developed en route to epicolactone. [21] With all carbon atoms of epicolactone now installed in 24,t he endphase of the synthesis consisted in transforming the dioxene and enone moieties in 24 to the bis-a-hydroxyenone motif of epicolactone.Selective nucleophilic oxidation of the enone was accomplished with TBHP and DBU.S trictly anhydrous conditions and aslight excess of base were crucial to avoid oxidation of the dioxene.Due to the high instability of the epoxide of enone 24,direct subjection of the reaction to HCl in BuOH at 110 8 8Cled to chloroethyl ether 25.W ith the correct bis-a-oxyenone moieties now in place,f ormation of the iodoethyl ether 26 (NaI, butanone) and reductive cleavage thereof with zinc in HOAc/EtOH gave synthetic epicolactone.T he synthetic material exhibited spectral data identical to those reported in its previous isolations [1,2] and total synthesis.…”

“…[3] Among these,acomplex and highly oxygenated caged pentacyclic structure,e picolactone (1), was first isolated in 2012. [1] Inspired by the accompanied isolation of speculated biosynthetic precursors from Epicoccum caftbo, [2] elegant biomimetic total syntheses of epicolactone [4] and its related analog dibefurin [5] were reported by Tr auner and co-workers.E picolactonesh igh density of electrophilic and nucleophilic functional groups make it af ormidable task for total synthesis.M oreover,g iven its quasisymmetric nature,asynthesis of this molecule necessitates the development of chemo-and regioselective transformations on ah ighly hindered molecular scaffold. Herein, we report at otal synthesis of epicolactone which addresses these challenges and provides ac omplementary entry into this structurally intriguing natural product.…”

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

“…can be easily employed for identifying such relationships, in addition to the capable human mind which is adept at pattern recognition. 32 Corey’s landmark 1979 synthesis of picrotoxinin ( 23 ) from carvone, 33 and the Hoffman La Roche synthesis of artemisinin ( 24 ) from isopulegol, 34 exemplify level 1 syntheses. It should be noted however, that this classification has no bearing on the actual tools, tactics, and exact starting terpene employed.…”