Development of a Diastereoselective Phosphorylation of a Complex Nucleoside via Dynamic Kinetic Resolution

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Chemical Synthesis

Background:

• Nucleoside monophosphate pro-drugs are crucial in antiviral and anticancer therapies.
• Achieving high diastereoselectivity in nucleoside phosphorylation is challenging but essential for therapeutic efficacy.
• Existing methods often yield mixtures of isomers, complicating purification and reducing effectiveness.

Purpose of the Study:

• To develop a novel, highly diastereoselective method for nucleoside phosphorylation.
• To synthesize a single isomer of a complex nucleoside monophosphate pro-drug.
• To optimize reaction conditions for high yield and diastereomeric purity.

Main Methods:

• Coupling of a stable phosphoramidic acid derivative to a nucleoside.
• Utilizing HATU (1-[Bis(dimethylamino)methylene]-1H-1,2-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) and quinine as mediators.
• Employing dynamic kinetic resolution of activated phosphonate ester diastereoisomers.
• Purification via single crystallization from anisole.

Main Results:

• The process yields a single isomer of the nucleoside monophosphate pro-drug with high chemical yield and diastereoselectivity.
• Optimized conditions resulted in an 89% in-process yield and a ∼7:1 diastereomeric ratio ([S,S(P)]:[S,R(P)]).
• Isolation by crystallization afforded the major isomer in 57% yield, >95% purity, and >50:1 diastereomeric ratio.

Conclusions:

• A robust and efficient diastereoselective nucleoside phosphorylation method has been established.
• The developed method enables the synthesis of enantiomerically pure nucleoside monophosphate pro-drugs.
• This approach holds significant potential for the streamlined production of complex pharmaceutical intermediates.