Total Synthesis of Chaetoglobin A via Catalytic, Atroposelective Oxidative Phenol Coupling

Abstract

The first total synthesis of chaetoglobin A (1), which features a chiral axis between two identical highly oxygenated bicyclic cores, was successfully completed in 12 steps from 2,6-dimethoxytoluene. Vanadium-catalyzed oxidative phenol coupling, as a key step, enabled generation of the axial chirality.

Synthetic Applications of Oxidative Aromatic Coupling—From Biphenols to Nanographenes

“…N ‐Benzyl‐2‐hydroxycarbazoles also reacted under similar conditions to give the corresponding 1,1′‐coupled dimers enantioselectively. Kozlowski and co‐workers utilized the new catalyst in the total synthesis of chaetoglobin, where a key chiral biaryl intermediate was prepared by atroposelective oxidative dimerization of phenols catalyzed by 109 …”

“…N-Benzyl-2-hydroxycarbazoles also reacted under similar conditions to give the corresponding 1,1'-coupled dimers enantioselectively.K ozlowski and coworkers utilized the new catalyst in the total synthesis of chaetoglobin, where ak ey chiral biaryl intermediate was prepared by atroposelective oxidative dimerization of phenols catalyzed by 109. [98] Very recently,T akizawa, Sasai, and co-workers developed ad inuclear vanadium complex that mediated the oxidative homocoupling of various 5-arylresorcinols to furnish the corresponding biaryls with up to 98 % ee. [99]…”

Recent advances in the chemistry and biology of azaphilones

“…3 Recently, several synthetic strategies of signicance have been developed for these novel diversied azaphilones, which mainly focused on stereoselectivity, 29 complementary biocatalysts, 93 and the formation of angular lactone and chiral azaphilone dimers. 94 In general, cazisochromene and dioxinone have been employed as important intermediates and precursors, whilst AzaH and AfoD have been applied in synthesis as common biocatalysts. 93,95 The recently reported chemical synthetic study of azaphilones were summarized herein.…”

“…The rst total synthesis of chiral azaphilone dimer, chaetoglobin A (273), was nished in 12 steps by Kang and his co-workers in 2017. 94 The vanadium-catalyzed atroposelective oxidative phenol coupling was a key step to form stereoaxis of chiral azaphilone dimer. 94 Optimization of Sonogashira coupling between iodide 274 and alkyne 275 afforded oxidative phenol coupling precursor 276 in 98% yield.…”

“…94 The vanadium-catalyzed atroposelective oxidative phenol coupling was a key step to form stereoaxis of chiral azaphilone dimer. 94 Optimization of Sonogashira coupling between iodide 274 and alkyne 275 afforded oxidative phenol coupling precursor 276 in 98% yield. Catalytic 276 with chiral vanadyl catalyst 277 led to the formation of dimer 278, which underwent the Vilsmeier-Haack formylation to provide 279 in 86% yield.…”