Innovative Cyclic Nucleotides - Nucleoside 2',3'-Seven-Membered Cyclic Diphosphonate Derivatives. Theoretical...

Area of Science:

• Organic Chemistry
• Nucleoside Chemistry
• Synthetic Chemistry

Background:

• Seven-membered cyclic nucleotides remain largely unexplored.
• Natural cyclic nucleotides typically feature 5- and 6-membered rings.
• Lack of synthetic methods for 7-membered cyclic nucleosides.

Purpose of the Study:

• To report the first synthesis of 7-membered cyclic nucleosides.
• To develop a novel, efficient synthetic route for 2',3'-cyclic nucleosides (tetrathio)diphosphonate (2',3'-cNTDPs).

Main Methods:

• A one-step, regioselective, and protection-free reaction.
• Utilized methylene-bis(1,3,2-dithia-phospholane-2-sulfide) (DTPS) with various nucleobases (U, A, C, I, G).
• Employed Density Functional Theory (DFT) calculations to confirm reaction feasibility and regioselectivity.

Main Results:

• Instantaneous and quantitative synthesis of 2',3'-cNTDPs achieved even at -35 °C.
• Demonstrated high regioselectivity and efficiency attributed to strain release in DTPS and thiirane elimination.
• Synthesized 2',3'-cNTDPs from uracil, adenine, cytosine, inosine, and guanine.

Conclusions:

• Established the first synthetic pathway to 7-membered cyclic nucleosides (2',3'-cNTDPs).
• The synthesized 2',3'-cNTDPs display enhanced hydrolytic stability.
• These novel compounds exhibit increased structural rigidity in solution compared to free nucleosides.