Late-stage oxidative C(sp³)-H methylation

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Catalysis

Background:

• The 'magic methyl effect' significantly boosts the potency of biologically active molecules by adding methyl groups, particularly adjacent to heteroatoms.
• Existing methylation methods have limitations in scope and applicability to complex molecular structures, hindering drug development.

Purpose of the Study:

• To develop a regioselective and chemoselective oxidative C(sp3)-H methylation method for late-stage functionalization of drug scaffolds and natural products.
• To enable efficient and targeted methylation of complex molecules, facilitating the exploration of the 'magic methyl effect'.

Main Methods:

• A novel approach combining site-selective C-H hydroxylation with mild, functional-group-tolerant methylation using a manganese catalyst (Mn(CF3PDP)).
• Utilized fluorine or Lewis acid-assisted formation of reactive intermediates for methylation with an organoaluminium reagent.
• Applied the method to 41 diverse substrates, including medicinally important cores, drugs, and natural products.

Main Results:

• Achieved site-selective late-stage C(sp3)-H methylation on 18 pharmacologically relevant molecules, including drugs like tedizolid and natural products.
• Demonstrated successful synthesis of two 'magic methyl' drug candidates via late-stage methylation.
• Showcased remote methylation on an abiraterone analogue, highlighting the method's versatility.

Conclusions:

• The developed method offers a powerful tool for late-stage C(sp3)-H methylation, compatible with complex drug scaffolds and natural products.
• This technique significantly reduces synthetic efforts, accelerating the discovery and development of novel therapeutics and chemical probes.
• Expands the application of the 'magic methyl effect' in medicinal chemistry research.