DNA-Encoded Chemistry Technology (Dec-Tec) has proven to be a successful innovation for ligand discovery, allowing for the screening of greater than a billion drug-like molecules for activity against a given target. In Dec-Tec, each synthetic reaction is encoded using an oligonucleotide, which can be utilized to determine a hit using an affinity binding assay with a particular protein target. Protecting groups play a key role in synthesizing these compounds, providing a means of carrying out location-specific diversification of the scaffold. One of the main challenges of Dec-Tec is the need to maintain the integrity of the DNA during the diversification steps, and this places constraints on the reagents and conditions that can be utilized. For example, DNA solubility limits reactions to aqueous conditions and its stability prevents acidic and high temperature conditions. Unfortunately, there is little information on DNA-compatible protection and deprotection conditions for the most commonly used protecting groups in synthetic organic chemistry. We therefore investigated 6 commonly used protecting groups [t-butyl carbamate (Boc), 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), alloxycarbonyl (Alloc), o-nitrobenzylsulfonyl (Ns), 4,5-dimethoxy-2-nitrobenzyloxycarbonyl (Nvoc)], specifically evaluating DNA-compatible methods of deprotection in aqueous conditions, as well as their relative orthogonality. We are developing new conditions to utilize these protecting groups in Dec-Tec to build libraries containing hundreds of millions of regio- and stereochemically diverse molecules.

Protecting group strategies in the synthesis of DNA-encoded libraries

251st National Meeting (2016)

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