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2.9 On-DNA Functional-Group Transformations

DOI: 10.1055/sos-SD-241-00134

Simmons, N.; Chheda, P.; Schuman, D.Science of Synthesis: DNA Encoded Librariesearly view.

General Introduction

Although the implementation of DNA-encoded library (DEL) technologies through the DEL design, production, screening, and data-analysis phases may vary greatly between organizations, in general, the strategy for accessing diverse DEL chemical matter centers around a few approaches. These include the diversity inherent in coupling large building-block sets with multiple cycles of chemistry, which may also bring chemotypes that cannot be formed through on-DNA chemistries; the use of designed multifunctional core sets with subsequent decoration by building blocks; or the crafting of bespoke chemistries to access specific chemotypes, albeit often at the expense of reagent availability and scope.[‌1‌‌3‌] Within these approaches, the predominant technique is to rely on functional groups already installed within the reactants for product formation. This is attractive, as it simplifies build complexity and improves DEL product purity by limiting the accumulation of on-DNA-generated side products that are often impractical or impossible to remove and which can complicate later DEL resynthesis campaigns.[‌4‌,‌5‌] However, the incorporation of additional on-DNA functional-group transformations, broadly defined here as an alteration of an on-DNA functional group without incorporation of a new diversity element, can also be an avenue to enhance overall DEL chemical matter diversity. The application of on-DNA functional-group transformations includes: the use of protecting groups to ensure regioselectivity, orthogonality, or better coupling efficiency; the in situ preparation of commercially rare or unstable intermediates for multistep protocols; the extension of valuable in-stock cores or building blocks to new DEL synthetic pathways through functional-group interconversion; the installation of a desired functional group within the final molecule as part of the planned diversity or as a formal encoding of an expected byproduct; and, in some cases, additionally as a handle that modulates other reactivity within the planned DEL synthetic sequence.

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References


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