Science of Synthesis

Granados, A.; Molander, G. A., Science of Synthesis: DNA-Encoded Libraries, (2024) 1, 274.

The first photoredox catalysis strategy applied as part of a DEL process furnished 1,4 adducts from on-DNA acrylamides and N-(tert-butoxycarbonyl) α-amino acids (‌Table 1‌).[‌20‌] The C(sp3)—C(sp3) bond formed in such transformations is of particular interest in drug development.[‌21‌] The reaction requires the use of [Ir{dF(CF3)ppy}2(bipy)]PF6 as a photocatalyst, the desired N-Boc-protected amino acid ‌4‌ as a radical precursor, and a potassium phosphate dibasic buffer, under irradiation with blue LEDs. Following photoexcitation of the iridium(III) species in the ground state, the resulting (IrIII)* species is reduced by the amino acid, giving rise to an α-amino radical and the reduced iridium(II) species. Subsequently, the α-amino radical adds to the on-DNA acrylamide though a Giese-type addition,[‌22‌] where the generated radical closes the photocatalytic cycle by single-electron reduction and subsequent protonation. The scope of this transformation encompasses primary (e.g., ‌Table 1‌, entry 1), secondary (e.g., entry 2), and tertiary (e.g., entry 3) N-Boc-protected amino acids. Moreover, benzyloxycarbonyl (Cbz) protected radical precursors and heterocyclic derivatives (e.g., entry 4) also proved to be suitable for this reaction, as are thioethers, which are normally quite easily oxidized to the sulfoxide. In addition, on-DNA α-substituted acrylamides (e.g., entry 5), vinyl benzamides, and styrenes (e.g., entry 6) were used as radical acceptors.[‌20‌]

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Meeeeeeeeeee Meeeeeeee

Me-MMM 8-[(eeee-Meeeeeeeeeeeee)eeeee]eeeeeeeeeee (‌Meeee 8‌, Meeee 8); Meeeeee Meeeeeeee:[‌88‌]

M eeee ee Mee-Mee-MM (8.8 ee, 88 µeee, 8888 eeeee) ee MMMM (88 µM), eee eeeeeeeeeeeee [Me{eM(MM8)eee}8(eeee)]MM8 (88 µe, 88 eeee) ee MMMM (8 µM), eee M8MMM8 (8.8 ee, 88 µeee) ee M8M (88 µM) eeee eeeee ee e eeee ee eee MMM-eeeeee eeeeeeeeee eeeeeee eeeeeeee (8.8 ee, 88 eeee) ee M8M (88 µM). Mee eeeee eeee eee eeee eeeeee eee eeeeeeee ee eeeeeeee eeee M8 eee 8 eee. Mee eeeeeee eee eeeeeeeeee eeee eeee eeeee eee 8 e ee ee (eeeeeee eee eeeeeeee eee e eee). Meeeeeeeeeee, 8 M ee MeMe (88 µM) eee eeeee, eeeeeeee ee eee eeeeeeee ee eeee MeMM (8 eM). Mee eeeeeee eee eeee ee −88 °M eee 88 eee eee eeee eeeeeeeeeee ee 88 888 eee eee 8 eee. Mee eeeeeeeeeee eee eeeeeeeee, eee eee MMM eeeeee eee eeeeeeeeeee ee M8M (88 µM). Me eeeeeee (8 µM) eee eeeee, eeeeeee eeee M8M (888 µM), eee eeeeeeee eee MMMM. Mee eeeeeeee eeeeeee eee eeeeee ee 88% eeeee. Mee MMM eeeeeeee eeee ee eeee eeeee eeeeeeeee eee eeee-eeeeeeeeeeeee eeeeeeeeee eeeee eee eee 8′-eeeeeeee eeeeeeeeeee. Mee eeeeeeeeee eeeeeeee eee ee eeeeeee: 8′-MMMMMM-eeeeee-MMMMMMMM-8′.

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