Short Scalable Route to Bis-morpholine Spiroacetals and Oxazepane Analogues: Useful 3D-Scaffolds for Compound Library...

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• sp³-rich molecular scaffolds with nitrogen heterocycles are crucial for drug discovery.
• Developing novel, conformationally defined scaffolds is essential for expanding chemical space.

Purpose of the Study:

• To report a four-step synthesis of a novel sp³-rich scaffold with two morpholine rings in a spiroacetal framework.
• To explore variations including 1,4-oxazepanes and different spiroacetal analogues.
• To generate a diverse compound library for drug discovery.

Main Methods:

• Synthesis initiated from epichlorohydrin and β-aminoalcohols to form a 2-chloromethyl-substituted morpholine intermediate.
• Base-mediated dehydrochlorination followed by a two-step construction of the second morpholine ring.
• Sequential functionalization of amine groups to create a compound library.

Main Results:

• A high-yielding, scalable synthesis of the sp³-rich spiroacetal scaffold was achieved.
• The methodology allows for the incorporation of 1,4-oxazepanes and generation of 6,7- and 7,7-spiroacetal analogues.
• A diverse library of compounds was synthesized, occupying a similar chemical space to approved drugs but with novel structures.

Conclusions:

• The developed synthetic route provides efficient access to novel sp³-rich scaffolds.
• The generated compound library offers potential for discovering drugs targeting novel biological targets.
• This work expands the accessible chemical space for drug discovery efforts.