A Concise Total Synthesis of (−)‐Berkelic Acid

Abstract

Reported here is a concise total synthesis of (À)berkelic acid in eight linear steps. This synthesis features a Catellani reaction/oxa-Michael cascade for the construction of the isochroman scaffold, a one-pot deprotection/spiroacetalization operation for the formation of the tetracyclic core structure, and a late-stage Ni-catalyzed reductive coupling for the introduction of the lateral chain. Notably, four stereocenters are established from a single existing chiral center with excellent stereocontrol during the deprotection/spiroacetalization process. Stereocontrol of the intriguing deprotection/ spiroacetalization process is supported by DFT calculations.

Sterically controlled isodesmic late-stage C–H iodination of arenes

“…Substrates 1y-aa highlight the steric control of our catalyst system as only the sterically favored yet electronically disfavored position is iodinated. 26 A stronger electronic bias towards the sterically disfavored positions reduces the activity of our system. Nevertheless, an arene bearing a deactivating keto group ( 1ab ) could be iodinated.…”

Transition‐Metal Catalyzed C−H Alkylation Using Epoxides as Alkylating Reagents

“…At almost the same time, Zhou and co-workers also accomplished a concise total synthesis of (À )-berkelic acid [38] (Scheme 22). After a slight modification of their previously developed reaction conditions, [33] the key isochroman intermediate 47 e was obtained as a 1.2 : 1 diastereomeric mixture in a combined yield of 67 % from a simple aryl iodide 43 c, (R)-2pentyl epoxide 2 e and racemic enone 45 b.…”

Nickel-catalyzed cross-electrophile coupling: applications in natural product synthesis

“…In 2021, the Zhou group reported an eight-step total synthesis of (-)-berkelic acid from commercially available starting materials (Scheme 12). 64 The concise route involves three key transformations: a Catellani reaction/oxa-Michael cascade to construct the isochroman scaffold, a one-pot deprotection/ spiroacetalization to forge the tetracyclic core, and a late-stage nickel-catalyzed reductive cross-coupling for lateral chain introduction. A three-component Catellani reaction using substrates 71, 72, and 73 under the conditions of 15 mol% Pd (OAc) 2 , 36 mol% XPhos, and 1 equiv.…”