Ligand-promoted Enantioselective C-H Activation Reactions

Scripps Research Institute, The, La Jolla CA

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Abstract

Project Summary By harnessing abundant prochiral C(sp3)–H bonds as entry points for the stereoselective installation of complex functionality, enantioselective C(sp3)–H functionalization represents a potentially transformative strategy in synthesis. Although enantioselective transition metal-catalyzed C(sp3)–H activation reactions have been reported, many require bespoke directing groups – a serious synthetic limitation. The use of functional groups native to common organic substrates (amides, acids, alcohols, ethers, amines, and esters) to recruit the catalyst for C–H metalation is ideal, but many native functionalities are either weakly coordinating or have otherwise undesirable binding capabilities with the catalyst. This proposal addresses these challenges through two distinct design strategies, which aim to enable both reactivity and enantioselectivity for native functionality-directed C(sp3)–H activation reactions. In particular, our research strategy aims to achieve the enantioselective C–H activation of carboxylic acid, amide, alcohol, ester, aldehyde, ketone, and amine-containing substrates with diverse reacting partners through (A) the design of chiral bidentate L,X-type scaffolds bearing N-acetyl (NHAc) or pyridone motifs to accelerate C–H cleavage, and (B) the design of chiral transient directing groups (TDGs). The advances from this proposal can fundamentally impact both how chiral molecules are constructed and diversified in pharmaceutical and synthesis contexts. Moreover, these new catalytic platforms will be immediately applied in a pharmaceutical context through industrial (with BMS), and academic collaborations (with Prof. Benjamin Cravatt), where the synthesis of novel chiral β-lactones and lactams through enantioselective C–H activation will expedite the discovery of novel enzyme inhibitors in an anticancer context.