Kinetically guided radical-based synthesis of C(sp ³ )−C(sp ³ ) linkages on DNA

Abstract

DNA-encoded libraries (DEL)-based discovery platforms have recently been widely adopted in the pharmaceutical industry, mainly due to their powerful diversity and incredible number of molecules. In the two decades since their disclosure, great strides have been made to expand the toolbox of reaction modes that are compatible with the idiosyncratic aqueous, dilute, and DNA-sensitive parameters of this system. However, construction of highly important C(sp)-C(sp) linkages on DNA through cross-coupling remains unexplored. In this article, we describe a systematic approach to translating standard organic reactions to a DEL setting through the tactical combination of kinetic analysis and empirical screening with information captured from data mining. To exemplify this model, implementation of the Giese addition to forge high value C-C bonds on DNA was studied, which represents a radical-based synthesis in DEL.

Employing Photoredox Catalysis for DNA‐Encoded Chemistry: Decarboxylative Alkylation of α‐Amino Acids

“…Expectedly, the decarboxylative alkylation did not proceed in the absence of photocatalyst or light (entries 5 and 6). It is worth mentioning that Baran and co‐workers have recently also achieved on‐DNA Giese coupling by using redox‐active N ‐hydroxyphthalimide esters, which can generate radicals via zinc‐mediated reduction . Likewise, they observed good DNA‐compatibility (based on preliminary mass spectrometric analysis).…”

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

“…In particular,t he chemistry that is necessary for aD EL-DNA-compatible chemistry-is different from that of typical organic reactions. In ar ecent paper by Baran and co-workers,t he following features of DNA-compatible synthesis wereoutlined: [110] 1) limitations imposed by DNA solubility require concentrations of reactionc omponents that are severalo rders of magnitude lower (0.001 m vs. about 0.1 m;a nd water content)o ft he solvents employed (ppm vs. > 20 vol %) for conventional synthetic techniques; 2) DEL-based transformations should proceed with at least 40 %y ield;p urification between synthetic steps is not an option because millions of the library members are present in the mixture; 3) the atom-economy principle is not applicable because the libraryi su suallyp repared from less than 100 mmol DNA and can be used many times for discovery purposes only; 4) the reaction conditions should not damage the functionalgroup-rich DNA-based barcode;h ence, the pH values shouldn ot exceed 4-14, the temperature should must be kept below 90 8C, and strong oxidants or reactiver adicals shouldb eavoided.…”

“…[111] New DNA-compatible chemistry is being developed, for example, olefin metathesis, [112] nitro group reduction with subsequentb enzimidazole synthesis, [113] and the first examples of radicalc hemistry in the presence of DNA wered escribed. [110] 3.3. Biology-oriented synthesis (BIOS)…”

A Chemical Biology View of Bioactive Small Molecules and a Binder‐Based Approach to Connect Biology to Precision Medicines

“…Nevertheless, impressive gains have recently been reported, and it seems likely that synthetic chemists will master this new challenge. [27] As a lab that is coming to this field later than many others, we have already achieved several of our goals, including synthesizing DNA bar-coded compounds related to those shown in Figure 5.…”