Concise Synthesis of (±)‐Myrioneurinol Enabled by Sequential [2+2] Cycloaddition/Retro‐Mannich Fragmentation/Mannich Reaction

Abstract

A concise total synthesis of (�)-myrioneurinol has been achieved in 14 steps. An efficient AgSbF 6 /t-BuCl-catalyzed intramolecular [2+2] cycloaddition reaction of the alkynone-tethered enamine was developed to prepare the highly strained cyclobutene. It was used in combination with a subsequent retro-Mannich fragmentation/Mannich reaction to efficiently construct the tricyclic core of myrioneurinol.

Symmetry-Driven Total Synthesis of Myrioneurinol

“…As noted above, this target was prepared in racemic form by the Weinreb group in 2014 utilizing a strategy built around two key Michael reactions (a spirocyclization and malonate nitrosoalkene addition) and a late-stage intramolecular Sakurai reaction to provide (±)- 2 in 27 steps (Figure B) . As we were finalizing our manuscript, Ma and co-workers reported a more step economical route to (±)- 2 via an intramolecular [2 + 2] cycloaddition/retro-Mannich/Mannich approach in 14 steps from (6-iodohex-1-ynyl)­trimethylsilane. , Herein, we report a distinct total synthesis of myrioneurinol enabled by the recognition of hidden symmetry within its complex framework, leveraging this strategy to provide the first asymmetric entry to this target.…”