A synthesis strategy yielding skeletally diverse small molecules combinatorially

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• Diversity-oriented synthesis (DOS) faces challenges in efficiently generating molecules with varied molecular skeletons.
• Current methods often lack the combinatorial capacity to produce a wide array of distinct molecular architectures.

Purpose of the Study:

• To develop and demonstrate a novel synthesis strategy for efficient generation of molecular skeletal diversity.
• To leverage pre-encoded information in substrates, analogous to protein folding, for combinatorial synthesis.

Main Methods:

• Developed a synthesis strategy using common reaction conditions to transform substrates with distinct 'sigma-elements' (appendages encoding skeletal information).
• Employed a fully encoded, split-pool synthesis approach.
• Generated approximately 1260 unique compounds.

Main Results:

• Successfully transformed similar substrates into products with distinct molecular skeletons under uniform reaction conditions.
• Demonstrated efficient generation of skeletal diversity through combinatorial pre-encoding of information.
• Achieved a synthesis yielding diverse building block, stereochemical, and skeletal elements.

Conclusions:

• The developed strategy efficiently generates molecular skeletal diversity in DOS.
• The approach, inspired by protein folding, offers a powerful method for combinatorial synthesis.
• This method enables the creation of large libraries of structurally distinct small molecules.