Mechanistic possibilities in prebiotic thiophosphate chemistry

Area of Science:

• Organic Chemistry
• Nucleoside Chemistry
• Biochemistry

Background:

• Thiophosphates exhibit dual reactivity: nucleophilic displacement and phosphorylation via P-S cleavage.
• Nucleoside phosphorothioates are key intermediates in various biochemical processes.

Purpose of the Study:

• To design and synthesize adenosine derivatives with a biphilic 3'-O-phosphorothioate center.
• To investigate the cyclization reactions and P-S cleavage mechanisms of these derivatives.
• To compare the reactivity of different isomers in cyclization reactions.

Main Methods:

• Synthesis of adenosine derivatives with 5'-deoxy-5'-chloro and 5'-O-tosyl leaving groups.
• Investigation of cyclization reactions forming 2':3'-cyclic phosphates and 3':5'-S-phosphorothioates.
• Hydrolysis of cyclic phosphorothioates and separation of 2'(3') phosphorothioate isomers.
• Kinetic studies to determine relative cyclization rates.

Main Results:

• Adenosine derivatives were successfully synthesized, acting as biphilic centers for cyclization.
• The primary cyclization products were 5'-O-tosyl and 5'-chloroadenosine 2':3'-cyclic phosphate.
• Formation of 3':5'-S-phosphorothioate was slow, potentially due to hydrogen bonding.
• KOH hydrolysis yielded 2'(3') phosphorothioates in a 1:1 ratio.
• The 2' isomer of 2'(3')-O-phosphorothioates exhibited higher reactivity in cyclization via P-S cleavage.

Conclusions:

• A novel system demonstrating dual thiophosphate reactivity in adenosine derivatives was developed.
• The study identified factors influencing cyclization pathways and reaction rates.
• The 2'-hydroxyl group of ribonucleosides was found to be more reactive in P-S cleavage-driven cyclization, a novel finding.