DNA-encoded libraries (DEL) have emerged as rich sources of small molecules interacting with targets of interest. However, the limited arsenal of DNA-compatible reactions required for library generation naturally translates into an overrepresentation of sp2-rich architectures and peptidomimetics. For the synthesis of complementary libraries, chemical transformations that enable access to more complex, sp3-rich entities are therefore highly desirable. Despite the successful history of strain-promoted cycloaddition reactions in the field of chemical biology (i.e. in the presence of water and biopolymers), there has been no report on the use of this concept in DEL synthesis. Strained allenes for example, usually generated under anhydrous conditions, are known to exhibit various reactivity modes when allowed to react with activated olefins ([2+2]), 1,3-dipoles ([3+2]) or dienes ([4+2]), and the resulting sp3-rich products exhibit high structural diversity. We document the successful in-situ generation and trapping of DNA-conjugated strained allenes in the presence of various coupling partners. The significance of our findings for future libraries is demonstrated by two-step diversification of DNA-linked substrates involving strain-promoted cycloadditions and N-capping reactions. Due to the mild conditions and general applicability, the process is thought to be an attractive addition to existing on-DNA bond forming reactions.

Strain-promoted cycloadditions for DNA-encoded library synthesis

2019 Fall National Meeting

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