Stereoselective Synthesis of the IDO Inhibitor Navoximod

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Biocatalysis

Background:

• Indoleamine 2,3-dioxygenase (IDO) is a key target in cancer immunotherapy.
• Navoximod is a potent IDO inhibitor with therapeutic potential.
• Efficient and stereoselective synthesis of complex drug molecules is crucial.

Purpose of the Study:

• To develop a highly efficient asymmetric synthesis of the IDO inhibitor navoximod.
• To stereoselectively install multiple stereocenters from a racemic intermediate.
• To achieve high yield and enantiomeric purity of navoximod.

Main Methods:

• Asymmetric synthesis utilizing crystallization-induced dynamic resolution.
• Biocatalytic ketoreduction using a ketoreductase enzyme.
• Substrate-controlled hydride reduction with LiAlH(O*t*-Bu)₃.
• 10-step synthesis starting from 2-fluorobenzaldehyde.

Main Results:

• Successful stereoselective installation of two relative and two absolute stereocenters.
• Navoximod synthesized in 10 steps with 23% overall yield.
• Achieved 99.7% enantiomeric excess (ee) and high purity of the final product.

Conclusions:

• The described synthetic strategy is highly efficient for producing navoximod.
• The combination of dynamic resolution and selective reductions provides a robust method for stereocenter installation.
• This approach enables the scalable and high-purity synthesis of a promising IDO inhibitor.