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

Abstract

AbstractCondensation 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 (TPS‐Cl), phosphonium 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, O6‐protection of guanines could become necessary with this reagent, since upon extended reaction time traces of O6‐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.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)