Mechanistic possibilities in prebiotic thiophosphate chemistry

Two types of reactivities of thiophosphates have been demonstrated: one being nucleophilic displacement by the P-S moiety of nucleoside phosphorothioates and the other, phosphorylation via P-S cleavage as the driving force. We have designed a system where both displacement on carbon and P-S cleavage are possible. Adenosine derivatives have been synthesized with 5′-deoxy-5′-chloro and 5′-O-tosyl substitutions as leaving groups utilizing the 3′-O-phosphorothioate as the biphilic center. The main products of cyclization were 5′-O-tosyl and 5′-chloroadenosine 2′:3′-cyclic phosphate. Formation of 3′:5′-S-phosphorothioate was slow even using an excellent leaving group. This is possibly due to hydrogen bonding between the 2′-OH and the neighboring P-O.− KOH hydrolysis of the cyclic phosphorothioate yielded 2′(3′) phosphorothioates in a 1:1 ratio. The 2′ and 3′ isomers were separated and used to study the relative rates of cyclization. The cyclization via P-S cleavage of 2′(3′)-O-phosphorothioates showed that the 2′ isomer was more reactive. This is the first report of superior reactivity of the 3′-OH of a ribonucleoside.