Total Synthesis of Pyrolaside B: Phenol Trimerization through Sequenced Oxidative C−C and C−O Coupling

Abstract

A facile method to oxidatively trimerize phenols using a catalytic aerobic copper system is described. The mechanism of this transformation was probed, yielding insight that enabled cross‐coupling trimerizations. With this method, the natural product pyrolaside B was synthesized for the first time. The key strategy used for this novel synthesis is the facile one‐step construction of a spiroketal trimer intermediate, which can be selectively reduced to give the natural product framework without recourse to stepwise Ullmann‐ and Suzuki‐type couplings. As a result, pyrolaside B can be obtained expeditiously in five steps and 16 % overall yield. Three other analogues were synthesized, thus highlighting the utility of the method, which provides new accessibility to this area of chemical space. A novel xanthene was also synthesized through controlled Lewis acid promoted rearrangement of a spiroketal trimer.

Catalytic Oxidative Coupling of Phenols and Related Compounds

“…We have discovered that a copper catalytic system with oxygen can provide a high yielding ordered assembly of 2,4-substituted phenols in a manner similar to that found in pyrolaside B and related trimeric phenol natural products (Scheme 23). 58 Investigation of the mechanism revealed how such an ordered assembly can occur and why other reaction manifolds (e.g., C−O polymerization) are not dominant (Scheme 24). 58 The first product observed in this process is a dimeric adduct from C−C bond formation.…”

“…58 Investigation of the mechanism revealed how such an ordered assembly can occur and why other reaction manifolds (e.g., C−O polymerization) are not dominant (Scheme 24). 58 The first product observed in this process is a dimeric adduct from C−C bond formation. Notably, the oxidation potential of this C−C dimer is lower than that of the monomer.…”

Stereoselective O-Glycosylation of Glycals with Arylboronic Acids Using Air as the Oxygen Source

“…For example, vancomycin, a glycopeptide antibiotic, was considered the last resort for the treatment of serious infections of Gram-positive bacteria . Aromatic O -glycosides of pharmaceutical interest also include the antitumor lead compound phyllanthusmin C, antibiotics pyrolaside B, and orally active antibiotic drug novobiocin . Manifold chemical approaches for synthesizing O -glycosides have been developed successfully in the last few decades, typically requiring anhydrous and inert atmosphere-protected reaction conditions .…”

Biaryl bond formation through biocatalytic oxidative cross-coupling reactions

“…21,[32][33][34] Numerous metal catalysts and metal-free oxidants have been reported for the dimerization and cross-coupling of phenolic substrates; however, the application of these methods is commonly restricted to electron-rich phenols or those bearing only mildly electron-withdrawing groups such as halides. [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] When general reactivity can be achieved, controlling the selectivity of the oxidative coupling reaction presents several additional layers of difficulty with the need to exert control over chemo-, site-, and atroposelectivity to form sterically hindered biaryl bonds (Figure 1c). Extensive investigation over the last two decades has provided insight into the selectivity outcomes of phenolic oxidative cross-couplings, leading to the development of computational tools and predictive models based on mechanistic investigation of select catalysts and the electronics of each phenol to better understand the chemoselectivity outcomes of these reactions .…”