Desyl and Phenacyl as Versatile, Photocatalytically Cleavable Protecting Groups: A Classic Approach in a Different (Visible) Light

Abstract

A highly efficient, catalytic strategy for the deprotection of classical phenacyl (Pac) as well as desyl (Dsy) protection groups has been developed using visible light photoredox catalysis. The deliberate use of a neutral two-phase acetonitrile/water mixture with K 3 PO 4 applying catalytic amounts of [Ru(bpy) 3 ](PF 6 ) 2 in combination with ascorbic acid is the key to this truly catalytic deprotection of Pac- and Dsy-protected carboxylic acids. Our mild yet robust protocol allows for fast and selective liberation of the free carboxylic acids in very good to quantitative yields, while only low catalyst loadings (1 mol %) are required. Both Pac and Dsy, easily introduced from commercially available precursors, can be applied for the direct protection of carboxylic acids and amino acids, offering orthogonality to a great variety of other common protecting groups. We further demonstrate the general applicability and versatility of these formerly underrated protecting groups in combination with our catalytic cleavage conditions, as underscored by the gained high functional group tolerance. Moreover, this method could successfully be adapted to the requirements of solid-phase synthesis. As a proof of principle for an efficient visible light, photocatalytic linker cleavage, a Boc-protected tripeptide was split off from commercially available brominated Wang resin.