Enantioselective Synthesis of a γ-Secretase Modulator via Vinylogous Dynamic Kinetic Resolution

Area of Science:

• Organic Synthesis
• Medicinal Chemistry
• Catalysis

Background:

• Alzheimer's disease poses a significant global health challenge.
• γ-secretase modulators are a promising therapeutic strategy.
• Efficient synthesis of drug candidates is crucial for development.

Purpose of the Study:

• To develop efficient asymmetric synthesis routes for γ-secretase modulator BMS-932481.
• To establish challenging stereocenters with high selectivity.
• To explore novel catalytic transformations for complex molecule synthesis.

Main Methods:

• Enantioselective hydrogenation of a trisubstituted alkene.
• Vinylogous dynamic kinetic resolution (VDKR) of a ketone.
• Density Functional Theory (DFT) computations for pathway design.

Main Results:

• Successful development of two distinct asymmetric routes to BMS-932481.
• Achieved high enantioselectivity in the hydrogenation of a complex alkene substrate.
• Demonstrated the first vinylogous dynamic kinetic resolution for non-contiguous stereocenters.

Conclusions:

• The developed routes offer efficient and selective access to BMS-932481.
• The novel VDKR strategy expands the toolkit for asymmetric synthesis.
• Computational chemistry played a key role in designing the innovative VDKR pathway.