Facile macrocyclizations to beta-turn mimics with diverse structural, physical, and conformational properties

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Chemical Synthesis

Background:

• Macrocyclic beta-turn mimics are crucial scaffolds in drug discovery.
• Developing efficient solid-phase synthesis methods is key for generating diverse compound libraries.

Purpose of the Study:

• To explore the utility of on-resin S(N)Ar reactions for synthesizing macrocyclic beta-turn mimics.
• To introduce alkyne and aryne functionalities into these mimics using solid-phase reactions.
• To investigate the conformational preferences of the synthesized mimics.

Main Methods:

• On-resin S(N)Ar reactions utilizing iodinated aromatic electrophiles.
• Solid-phase Sonogashira and Suzuki reactions for functional group introduction.
• NMR spectroscopy, circular dichroism, and computational simulations for conformational analysis.

Main Results:

• Efficient preparation of macrocyclic beta-turn mimics (1a-n) via S(N)Ar.
• Successful introduction of alkyne (compound 2) and aryne (compound 3) moieties.
• Conformational analysis revealed type-I-like beta-turns as preferred conformations.
• Aryl substituent interactions influenced the conformational orientation in compound 3.

Conclusions:

• Iodinated electrophiles enhance efficiency in solid-phase S(N)Ar reactions for macrocycle synthesis.
• Solid-phase strategies enable the creation of diverse beta-turn mimics with varied functionalities.
• This approach expands molecular and conformational diversity in compound libraries for potential therapeutic applications.