Total Synthesis of (+)‐Cochlearol B by an Approach Based on a Catellani Reaction and Visible‐Light‐Enabled [2+2] Cycloaddition**

Abstract

A 14-step synthesis of (+)-cochlearol B is reported. This renoprotective meroterpenoid features a unique core structure containing a densely substituted cyclobutane ring with three stereocenters. Our strategy employed an organocatalytic Kabbe condensation in route to the key chromenyl triflate. A subsequent Catellani reaction incorporated the remaining carbon atoms featured in the skeleton of cochlearol B. An ensuing visible-light-mediated [2+2] photocycloaddition closed the cyclobutane and formed the central bicyclo-[3.2.0]heptane core. Notably, careful design and tuning of the Catellani and photocycloaddition reactions proved crucial in overcoming undesired reactivity, including cyclopropanation reactions and [4+2] cycloadditions.

Structural diversity, hypothetical biosynthesis, chemical synthesis, and biological activity ofGanodermameroterpenoids

“…Schindler′s group employed an organocatalytic Kabbe condensation in route to the key chromenyl triflate. 105 A pyrrolidine-catalyzed condensation between phenol 237 and sulcatone formed the chromanone 238 . Subsequent treatment with Comins′ reagent provided triflate (+)- 239 in 86% yield.…”

Visible Light‐Mediated Cyclopropanation: Recent Progress

“…And the energy transfer catalytic cycloaddition/cyclopropanation methodology has also been applied to the total synthesis of natural products such as (+)-Cochlearol B. [75]…”

“…Finally, 164 formed both the cyclopropane ring and the C−Cl bond through transition state 165 , which was followed by deprotonation to the final product 161 . And the energy transfer catalytic cycloaddition/cyclopropanation methodology has also been applied to the total synthesis of natural products such as (+)‐Cochlearol B [75] …”

Synthetic Strategies Towards the Meroterpenoids Cochlearols A and B from Ganoderma cochlear

“…Similarly to Sugita’s strategy towards cochlearol B ( 2 ), Schindler and co-workers planned on a key [2+2]-cycloaddition strategy to build up the natural product’s cyclobutane core structure albeit relying on a distinct cycloaddition precursor (Scheme 10 ). 18 Specifically, the authors envisaged installing the enal moiety characteristic for cochlearol B ( 2 ) via an oxidative sequence relying on terminal alkene 49 , which could be accessible via a visible-light-enabled intramolecular [2+2] photocycloaddition utilizing an iridium photocatalyst from chromene 50 . Ring C could be introduced utilizing a strategy based on a Catellani reaction to achieve concomitant dialkylation of the chromene core.…”