Science of Synthesis

Wang, X.; Lu, X., Science of Synthesis: DNA-Encoded Libraries, (2024) 1, 215.

General Introduction

The C—H activation approach is a powerful strategy for synthesizing valuable building blocks and complex drug candidates via the direct formation of C—C and C—X bonds by regioselectively activating innate C—H bonds (‌Scheme 1‌).[‌1‌–‌7‌] Compared to the traditional cross-coupling transformations, C—H activation reactions circumvent the extra protocols to build up latent functional handles (halides/borates/trifluoromethanesulfonates), thus making C—H activation a more cost-effective and eco-friendly strategy. Another advantage of C—H activation approaches is that they apply innate C—H bonds as native reaction handles, preserving other functional groups for further chemistries, enabling many building blocks that were previously considered to be monofunctional to act as bifunctional building blocks. However, there are several challenges to be overcome in the development of DNA-compatible C—H functionalization reactions including the high energy required to activate the inert C—H bonds, the need to tolerate water, and the need to preserve the integrity of oligonucleotides. In concerted efforts, medicinal chemists have developed a variety of innovative on-DNA C—H activation approaches, which directly expand the encoded chemical diversification and increase hit enrichment in DNA-encoded libraries (DELs). In this chapter, we summarize the significant advances achieved in DNA-compatible C—H functionalization, including transition-metal-mediated reactions (Section ‌2.5.1.1‌), photocatalyst-mediated reactions (Section ‌2.5.1.2‌), and biocatalyst-mediated reactions (Section ‌2.5.1.3‌), showcasing the detailed experimental protocols and substrate scopes.

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References