Investigation on Condensing Agents for Phosphinate Ester Formation with Nucleoside 5′-Hydroxyl Functions

Condensation of a uridine 3'-deoxy-3'-C-methylenephosphinate with thymidine and guanosine derivatives to form methylenephosphinate esters was investigated. A number of different condensing agents were compared, and these include pivaloyl chloride, triisopropylbenzenesulfonyl chloride (TPSCl), phosphoniurn and uronium derivatives, numerous chlorophosphates and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (OXP). The phosphonium derivatives gave slow condensations or oxidative side reactions (hydroxybenzotriazole derivatives) during preactivation of the methylenephosphinate. Pivaloyl chloride gave long coupling times, and competing 5'-O-pivaloylation was detected. TPS-Cl gave rapid condensation but also rapid oxidation of the product. Most chlorophosphates gave competing 5'-O-phosphorylation of the nucleoside component, as well as base phosphorylation. However, 2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane (DMOCP) gave a rather efficient formation of dinucleoside methylenephosphinates at a decent rate. However, O-6-protection of guanines could become necessary with this reagent, since upon extended reaction time traces of O-6-phosphorylation were detected even with a low concentration (60 mm) of DMOCP (2 equiv. to phosphinate). Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (OXP) can, unlike DMOCP, be used in nearly equimolar amounts to phosphinate. Under such conditions OXP gives virtually quantitative condensation at a rate comparable to that of 2 equiv. of DMOCP and with no side reactions detected. We could also not detect any decomposition of OXP-preactivated phosphinate. Nucleophilic catalysts, more powerful than pyridine (N-methylimidazole, iodide and 4-methoxypyridine), accelerated the reactions with OXP, but preactivation in the absence of the 5'-OH component led to decomposition of the activated phosphinate. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008).