The protecting-group free selective 3'-functionalization of nucleosides

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Chemical Biology

Background:

• Nucleoside functionalization is crucial for developing therapeutic agents.
• Existing methods often require protection/deprotection steps or enzymatic approaches, limiting efficiency.
• Selective modification at the 3 position of nucleosides presents synthetic challenges.

Purpose of the Study:

• To describe direct and chemoselective 3 -phosphoramidation, phosphorylation, and acylation of nucleosides.
• To elucidate the mechanism behind a novel 3 -phosphorylamidation reaction.
• To develop a predictive computational model for 3 -functionalization.

Main Methods:

• Utilized 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) for novel 3 -phosphorylamidation.
• Employed Nuclear Magnetic Resonance (NMR) spectroscopy to study reaction mechanisms.
• Applied computational studies (e.g., DFT) to understand selectivity and build predictive models.

Main Results:

• Achieved direct and chemoselective 3 -phosphoramidation, phosphorylation, and acylation of various nucleosides.
• Discovered a novel 3 -phosphorylamidation of therapeutic nucleoside analogues using DBU.
• Developed a predictive computational model accurately assessing 3 -functionalization potential for diverse nucleosides and mimetics.

Conclusions:

• The developed computational model streamlines the synthesis of functionalized nucleosides.
• This approach bypasses the need for protection/deprotection or enzymatic methods.
• Demonstrated broad synthetic utility for nucleoside analogues and electrophiles, enabling access to previously challenging targets.