Preparation of C4'-modified nucleoside analogs

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Nucleoside Chemistry

Background:

• C4 -modified nucleoside analogs are crucial for infectious disease treatments and oligonucleotide therapeutics.
• Existing semi-synthetic methods are lengthy and limit chemical space exploration.
• A need exists for efficient, scalable synthesis of diverse C4 -modified nucleosides.

Purpose of the Study:

• To develop a de novo synthetic strategy for pilot- and process-scale preparation of C4 -modified nucleoside analogs.
• To enable rapid exploration of chemical space for novel nucleoside analog development.
• To provide a versatile protocol for synthesizing both L- and D-nucleoside analogs with various modifications.

Main Methods:

• Enantioselective proline-catalyzed aldol reaction between 2,2-dimethoxyacetaldehyde and a dioxanone.
• 1,2-addition to install C4 -modification, followed by intramolecular trans-acetalization for ribose core formation.
• Peracetylation and Vorbrüggen glycosylation to complete the synthesis of nucleoside analogs.

Main Results:

• Successful pilot-scale (250 mg) and process-scale (85 g) preparation of 4 '-methyl-ribothymidine (4 ',5-dimethyluridine).
• Demonstrated interchangeability of 10 C4 ' modifications and 20 nucleobases.
• Achieved good yields and excellent enantiopurity for the synthesized analogs.

Conclusions:

• The developed de novo strategy offers an efficient and scalable route to C4 '-modified nucleoside analogs.
• This method significantly expands the accessible chemical space for nucleoside analog discovery.
• The protocol is adaptable for producing diverse L- and D-nucleoside analogs for therapeutic applications.