Radical‐Cation Cascade to Aryltetralin Cyclic Ether Lignans Under Visible‐Light Photoredox Catalysis

Abstract

The development of concise, sustainable, and cost‐effective synthesis of aryltetralin lignans, bearing either a fused lactone or cyclic ether, is of significant medicinal importance. Reported is that in the presence of Fukuzumi's acridinium salt under blue LED irradiation, functionalized dicinnamyl ether derivatives are converted into aryltetralin cyclic ether lignans with concurrent generation of three stereocenters in good to high yields with up to 20:1 diastereoselectivity. Oxidation of an alkene to the radical cation is key to the success of this formal Diels–Alder reaction of electronically mismatched diene and dienophile. Applying this methodology, six natural products, aglacin B, aglacin C, sulabiroin A, sulabiroin B, gaultherin C, and isoshonanin, are synthesized in only two to three steps from readily available biomass‐derived monolignols. A revised structure is proposed for gaultherin C.

Taming the radical cation intermediate enabled one-step access to structurally diverse lignans

“…3c). Treatment of the known tricyclic compound 18a whose relative stereochemistry has been determined by X-ray crystallographic analysis 36 under standard conditions with an excess of MeOH (8.0 equiv) afforded the same products 20a as a mixture of two diastereomers 38 . The reaction proceeded much slower presumably due to the sluggish oxidation of the benzylic carbon of compound 18a, but the diastereoselectivity of this reaction (dr = 4.5:1) was higher than the one-pot process from 17a and MeOH.…”

“…Most of the aryltetralin cyclic ether lignans bear multiple alkoxyl or hydroxyl substituents on the aromatic rings with a trans-fused B/C ring system. We have previously shown that the stereochemical outcome of the formal [4 + 2] cycloaddition of dicinnamyl ether derivatives under photoredox catalytic conditions depends on the number of hydroxyl/alkoxyl groups on the aromatic rings 36 . The reaction of di(p-methoxy)cinnamyl ether 17a afforded the tricyclic lignan with a cis-fused B/C ring 18, while those derived from polymethoxylated cinnamic alcohols provided the trans-fused B/C ring system 19 (cf Fig.…”

“…Instead of incorporating an oxidant into the reaction mixture, we suspected that adding an efficient hydrogen atom donor might quench the radical intermediate leading to C-7 mono-functionalized dibenzyl tetrahydrofuran 24, another sub-class of lignans. While conceptually simple, it is not obvious to accomplish this transformation since the formation of 24 would have to outcompete with that of aryltetralin cyclic ethers 18/19 whose formation involved a very similar reaction sequence 36 . Gratefully, we found that the presence of MeOH changed completely the reaction outcome.…”

“…Inspired by the pioneering work of Yoon [27][28][29] and Nicewicz 30,31 on the visible-light photoredox-catalyzed [2 + 2] and [4 + 2] cycloadditions of styrene derivatives, we recently reported an acridinium salt (Fukuzumi's salt, 16) [32][33][34][35] catalyzed intramolecular formal [4 + 2] cycloaddition of functionalized dicinnamyl ethers 17 to aryltetralin cyclic ethers 18 or 19 under blue LED irradiation (Fig. 2b, path a) 36 . We hypothesized that the reaction is initiated by single electron transfer (SET) of the substrate 17 to 16 leading to radical cation A.…”

Pharmaceutically relevant (hetero)cyclic compounds and natural products from lignin-derived monomers: Present and perspectives

“…The aryltetralin cyclic ether lignans ( Xiang et al., 2020 ), namely, isoshonanin and gaultherin C have been synthesized by Zhu and co-workers from monolignols in three steps in the presence of Fukuzumi's acridinium salt under blue LED irradiation ( Scheme 1 C). The obtained members of this family of natural products display analgetic and anti-inflammatory properties.…”