Exploring Aldol Reactions on DNA and Applications to Produce Diverse Structures: An Example of Expanding Chemical Space of DNA‐Encoded Compounds by Diversity‐Oriented Synthesis

Abstract

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.

Design, Construction, and Screening of Diversified Pyrimidine-Focused DNA-Encoded Libraries

“…Figure illustrates two synthetic strategies for pyrimidine-based libraries. One strategy involves in situ cyclization between DNA-tagged α,β-unsaturated ketone and guanidine . However, the limited availability of guanidine BBs restricts their use in generating large-scale compound collections.…”

“…One strategy involves in situ cyclization between DNA-tagged α,β-unsaturated ketone and guanidine. 19 However, the limited availability of guanidine BBs restricts their use in generating large-scale compound collections. Another strategy involves substitution between the DNA-linked pyrimidine scaffold and nucleophilic BBs, which is more efficient and enables access to large-scale BBs.…”

DNA-Conjugated Cyclopropane Derivatives Constructed from Sulfonium Ylides with α,β-Unsaturated Ketones

“…There are three main approaches for traditional organic synthesis of cyclopropanes: (1) Simons-Smith cyclopropanation; (2) transition metal-catalyzed diazolidine decomposition; (3) Michael-initiated ring closure. , We notice that a wide source of halogenated alkanes can be used as starting materials in the third method, reacting with pyridines, sulfoxides, and thioethers to conveniently offer ylide precursors (Scheme b). Stable sulfoxonium ylides can be prepared by α-bromocarbonyl compounds with sulfide in the presence of bases (e.g., K 2 CO 3 or KOH). , These ylides can react smoothly with Michael receptors to obtain the corresponding cyclopropane derivatives. − DNA-compatible methods for constructing Micheal receptors have also been reported in several articles: Aldo reaction, − Claisen–Schmidt reaction, , Horner–Wadsworth–Emmons (HWE) reaction, and Wittig reaction …”

Vinyl azide as a synthon for DNA-compatible divergent transformations into N-heterocycles

“…[33][34][35][36][37][38][39][40] Diversity-oriented synthesis (DOS) represents a fast approach for generating distinct structures based on the uniform intermediate, which is in accordance with the DEL concept. [41][42][43] More structural diversity would undoubtedly increase the chemical space and broaden the structural complexity of the library. 44,45 Interestingly, considering that N-heterocycles (imidazole, isoquinoline, etc.)…”