Dual Electrocatalytic Enantioselective C-O Bond Formation via Benzylic C-H Functionalization

NIH RePORTER · NIH · F32 · $65,610 · view on reporter.nih.gov ↗

Abstract

Project Summary Benzylic ethers are prominent motifs in pharmaceuticals and biologically active molecules. Previous methods for enantioselective synthesis of these motifs have relied on asymmetric reduction of a carbonyl compound with a hydride or carbon nucleophile, requiring pre- functionalized starting materials and therefore additional chemical steps. Ideally, C–O bond formation would occur through direct C–H/O–H cross-coupling, while avoiding solvent quantities of the alcohol coupling partner and tolerating a broad range of both coupling partners. Although C–H oxygenation methods have recently been developed, an enantioselective variant remains elusive. In this research strategy, we propose directly accessing optically active benzylic ethers using readily available alkyl arenes and alcohol coupling partners through dual electrocatalysis. This strategy will enable us to effectively merge hydrogen-atom transfer (HAT) mediated by phthalimide N-oxyl (PINO) radicals with copper-promoted radical alkoxylation, two established radical processes. Replacing a conventional chemical oxidation with electrochemistry will not only improve sustainability and scalability of the proposed transformation but will also address the key overoxidation problem associated with enantioselective Cu-mediated C–O bond formation. If successful, this reaction would provide the first example of enantioselective benzylic ether synthesis via C–H functionalization. This project has three specific aims: 1) investigating organic mediators such as N-hydroxyphthalimide (NHPI) for generating benzylic radicals under mild electrochemical oxidation conditions; 2) identifying conditions and chiral ligands for enantioselective C–O bond formation by Cu-catalyzed radical trapping; 3) accessing sterically hindered dialkyl ethers from racemic substrates in an enantioconvergent manner.

Key facts

NIH application ID
10235455
Project number
1F32GM142264-01
Recipient
CORNELL UNIVERSITY
Principal Investigator
Minsoo Ju
Activity code
F32
Funding institute
NIH
Fiscal year
2021
Award amount
$65,610
Award type
1
Project period
2021-04-01 → 2024-03-31