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.

A DNA-encoded chemical library (DECL) is built with combinatorial chemistry, which works by bringing chemical fragments together to generate diverse structures. However, chemical diversity of DNA-encoded chemical libraries is often limited by DNA compatible synthetic reactions. This report shows a conceptual strategy to expand chemical space of DNA-encoded chemical libraries by incorporation of diversity-oriented synthesis in DECL synthesis. We developed Aldol reactions on DNA in a combinatorial way. After obtaining DNA-tagged α, βunsaturated ketones which represent important chemical intermediates, many distinct structures with skeletal diversities are achieved by diversity-oriented synthesis.

Herein, we report a method that enables the synthesis of carbohydrate−DNA conjugates by radical addition. Key to the success is the use of readily available, bench-stable, and unprotected glycosyl sulfinates as precursors to glycosyl radicals. The redox neutral reaction proceeds under mild and simple conditions and tolerates a broad substrate scope. A small library of carbohydrate−DNA conjugates was prepared. D NA-encoded library (DEL) has emerged as a powerful tool for hit identification in academia and pharmaceutical industry. 1 A DEL is a collection of compounds, each of which is linked to a unique DNA sequence. The DNA serves as an identifier for the compound, which allows for the highthroughput screening of large numbers of compounds to identify those binding to a particular target. On the basis of such affinity selection, millions to billions of DNA-encoded molecules can be conveniently screened against biological targets all at once, in a single experiment. Compared with traditional screening strategies, the DEL technology shows advantages in terms of cost, speed, and scale. 2 Shown in Scheme 1a are some representative lead compounds found by DEL technology. 3 To construct structurally diverse and pharmaceutically relevant DELs, the development of DNA-compatible reactions is in high demand. 4 However, the required DNA tag, which is not soluble in most organic solvents and is easily degraded or modified, places stringent requirements on the mildness of a potential synthetic method to be used. 5 In addition, since DNA tags are in highly dilute solution, to modify DNA tags requires a reaction to be efficient even at low concentrations. Methods that fulfill the above requirements are rare.Carbohydrates are extremely valuable organic molecules in nature and are involved in various crucial life-sustaining processes, including immune response, fertilization, and cell− cell interactions. 6 They represent a privileged class of compounds in drug discovery, with over one hundred carbohydrate-based small molecules already marketed to treat various diseases. 7 Considering the structural diversity and biological activity of carbohydrates, to incorporate sugar