Enantioselective Total Syntheses of Manginoids A and C and Guignardones A and C

Abstract

An enantioselective synthetic approach for preparing manginoids and guignardones, two types of biogenetically related meroterpenoids, is reported. This bioinspired and divergent synthesis employs an oxidative 1,3-dicarbonyl radical-initiated cyclization and cyclodehydration of the common precursor to forge the central ring of the manginoids and guignardones, respectively, at a late stage. Key synthetic steps include silica-gel-promoted semipinacol rearrangement to form the 6-oxabicyclo[3.2.1]octane skeleton and the Suzuki-Miyaura reaction of vinyl bromide to achieve fragment coupling. This synthesis protocol enables the asymmetric syntheses of four fungal meroterpenoids from commercially available materials. Figure 1. Representative structures of manginoids and guignardones.

Scalable Birch reduction with lithium and ethylenediamine in tetrahydrofuran

“…Benzyl alcohol was reduced to diene 33 in 26% yield under our conditions without losing the benzylic hydroxy group. This diene was previously prepared in two steps ( 39 ).…”

Ruthenium‐Catalyzed Remote Difunctionalization of Nonactivated Alkenes for Double meta‐C(sp2)−H/C‐6(sp3)−H Functionalization

“…With the optimized reaction conditions in hand, the viable substrate scope of the ruthenium-catalyzed two fold distal functionalization was examined with differently substituted heteroarenes 1 (Scheme 2, top row). A range of 2arylpyridines 1 a-1 h bearing electron-withdrawing or the electron-donating groups were well tolerated, resulting in corresponding products (5)(6)(7)(8)(9)(10)(11) in good to excellent yields. Notably, substrates with other heteroarenes, including pyrazole, pyrimidine, oxazoline and purine, worked efficiently under otherwise identical conditions (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

“…While 1,2-difunctionalization of alkenes has been well explored, alkene 1,n-difunctionalization (n > 2) is signifi-cantly more challenging and has gained considerable attention. For instance, the radical fluoroalkylation of alkenes and subsequent intramolecular 1,n-migration [6] has been documented by Zhu, [7] Studer, [8] Liu [9] among others [10] to furnish a variety of fluoroalkylated ketones (Scheme 1b, 1). In addition, the merger of radical addition onto alkenes, hydrogen atom transfer (HAT) and remote CÀ H functionalization allowed for site-selective remote olefin difunctionalizations to assemble structurally diverse scaffolds (Scheme 1b, 2).…”

Combining the best of both worlds: radical-based divergent total synthesis

“…(Lou 2021) [47]: Magninoids and guignardones are two classes of biogenetically related meroterpenoids, bearing a highly substituted cyclopentane moiety and a 6-oxabicyclo[3.2.1]octane fragment [48,49]. These classes exhibit diverse biological properties, such as potent inhibition of 11-βhydroxysteroid dehydrogenase type I and inhibition of Candida albicans [48].…”