Enantioselective Cu(I)-catalyzed borylative cyclization of enone-tethered cyclohexadienones and mechanistic insights

Sandip B Jadhav,Kumar Vanka,Soumya Ranjan Dash,Sundaram Maurya,Rambabu Chegondi,Jagadeesh Babu Nanubolu

doi:10.1038/s41467-022-28288-7

Abstract

The catalytic asymmetric borylation of conjugated carbonyls followed by stereoselective intramolecular cascade cyclizations with in situ generated chiral enolates are extremely rare. Herein, we report the enantioselective Cu(I)-catalyzed β-borylation/Michael addition on prochiral enone-tethered 2,5-cyclohexadienones. This asymmetric desymmetrization strategy has a broad range of substrate scope to generate densely functionalized bicyclic enones bearing four contiguous stereocenters with excellent yield, enantioselectivity, and diastereoselectivity. One-pot borylation/cyclization/oxidation via the sequential addition of sodium perborate reagent affords the corresponding alcohols without affecting yield and enantioselectivity. The synthetic potential of this reaction is explored through gram-scale reactions and further chemoselective transformations on products. DFT calculations explain the requirement of the base in an equimolar ratio in the reaction, as it leads to the formation of a lithium-enolate complex to undergo C-C bond formation via a chair-like transition state, with a barrier that is 22.5 kcal/mol more favourable than that of the copper-enolate complex.

Highlights

The catalytic asymmetric borylation of conjugated carbonyls followed by stereoselective intramolecular cascade cyclizations with in situ generated chiral enolates are extremely rare
The major challenge of this reaction is the chemoselective 1,4-addition of nucleophilic boron on three different enone-functionalities within the starting substrate and diastereoselective C–C bond formation
When the base loading was increased (2 equiv), the required bicyclic product 2a was obtained exclusively in 78% yield. Several bases such as KtOBu, K2CO3, Cs2CO3, and LitOBu were subjected to borylative cyclization, and the yield of 2a was significantly improved, especially with LitOBu

Summary

A Si-face attack

Enone and subsequent intramolecular Si-face attack of chiral enolate on the cyclohexadienone ring via a six-membered chair-like transition state, as depicted in intermediate A, fixing the stereochemistry at the four new contiguous stereocenters. The major challenge of this reaction is the chemoselective 1,4-addition of nucleophilic boron on three different enone-functionalities within the starting substrate and diastereoselective C–C bond formation

Results and discussion

H O Me Ph

Methods