sp³ -Rich Heterocycle Synthesis on DNA: Application to DNA-Encoded Library Production.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• DNA-encoded libraries (DELs) offer a powerful platform for synthesizing and screening vast compound collections.
• Current DEL synthesis methods often favor sp2-rich and peptidomimetic structures due to DNA compatibility constraints.
• This limits the chemical diversity accessible through DEL technology.

Purpose of the Study:

• To develop novel synthetic chemistry compatible with DNA-encoded libraries.
• To expand the accessible chemical space within DELs beyond traditional peptidomimetics.
• To generate sp3-rich, mono- and bicyclic heterocycles using DNA-templated synthesis.

Main Methods:

• Ketochlorohydrin aldol products were utilized as starting materials.
• A reductive amination and cyclization strategy was employed for compound synthesis on DNA.
• The synthesized compounds were characterized for their structural features.

Main Results:

• Successfully synthesized sp3-rich mono- and bicyclic heterocycles directly on DNA.
• The developed method overcomes limitations of existing DEL chemistries.
• The resulting hydroxypyrrolidines represent a novel class of compounds for DEL applications.

Conclusions:

• This study demonstrates a new method for generating diverse sp3-rich heterocycles within DNA-encoded libraries.
• The findings significantly broaden the scope of chemical structures accessible through DEL technology.
• The novel compounds generated target a distinct and pharmaceutically relevant chemical space, enhancing drug discovery efforts.