Functionalization of DNA-Tagged Alkenes Enabled by Visible-Light-Induced C–H Activation of N-Aryl Tertiary Amines

Abstract

A highly efficient approach to C­(sp3)–C­(sp3) bond construction via on-DNA photoredox catalysis between on-DNA alkenes and N-aryl tertiary amines was developed. The methodology demonstrated 55%–95% conversions without obvious DNA damage, as seen by qPCR tests. Furthermore, various functional groups, such as carboxylic acids, aldehydes, and aryl halides, that can be used to create library diversities were shown to be tolerant of the C–H activation conditions.

On the design of lead-like DNA-encoded chemical libraries

“…Recent advances in synthetic methodology suggest that this situation will improve further in the near future. [78][79][80][81][82][83][84] In addition to the need for chemistry compatible with DNA, an additional constraint for an ideal reaction for DEL construction is the ability to incorporate a monomer class that is populated with a large number of diverse, readily available compounds. Further diversity could be introduced using synthetic schemes that do not rely on a single scaffold.…”

Photoredox Deaminative Alkylation in DNA-Encoded Library Synthesis

“…In 2021, the Lu group and our team almost simultaneously developed a highly efficient on-DNA procedure for C−H functionalization that is mediated by photoredox catalysis (Scheme 1b). 10,11 With these results, we subsequently set a goal to further expand the scope of radical precursors that can afford C-centered radicals upon activation and be applied to a DEL synthesis. Having a vast number of such commercially available radical precursors would be instrumental in constructing DELs with high degrees of diversity.…”

“…In Rovis' work, 2,4,6-trimethoxybenzaldehyde was demonstrated to be the optimal electron-rich aldehyde for activation of primary amines to generate C-centered radicals under photoredox conditions. 10,11 Hence, we followed Rovis' procedure to obtain 99% pure imine radical precursor 2a by heating adamantylamine and 2,4,6-trimethoxybenzaldehyde in a Dean−Stark apparatus. 10,11 Subsequently, under our optimized reaction conditions (employing Ir[dF(CF 3 )ppy] 2 (bpy)PF 6 as a photocatalyst and K 3 PO 4 as an additive), DNA-conjugated acrylamide 1a (see full structures of DNA in the Supporting Information) reacted with imine 2a to afford the desired product 3a in 74% yield (Table 1, entry 2).…”

“…Three control experiments were designed and carried out to understand the reactivity of reactants and further confirm structures of products (Scheme 5). 11 First, acrylamide 1a was treated with adamantanamine 2a-1 under the reaction conditions without preactivation with 2,4,6-trimethoxybenzaldehyde. No desired product was observed (Scheme 5a), thus suggesting that the imine intermediate was, in fact, the key radical precursor necessary for this conversion.…”

“…The work featured iridium-based photoredox catalyst-mediated decarboxylation of α-amino acids in an aqueous environment, whereby the generated radicals were reacted with various DNA-tagged radical acceptors to afford on-DNA amine intermediates (Scheme a). In 2021, the Lu group and our team almost simultaneously developed a highly efficient on-DNA procedure for C–H functionalization that is mediated by photoredox catalysis (Scheme b). , With these results, we subsequently set a goal to further expand the scope of radical precursors that can afford C-centered radicals upon activation and be applied to a DEL synthesis. Having a vast number of such commercially available radical precursors would be instrumental in constructing DELs with high degrees of diversity.…”