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

Abstract

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 (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)

Evaluation of molecularly imprinted polymers using 2′,3′,5′-tri-O-acyluridines as templates for pyrimidine nucleoside recognition

“…Azo-bis-dimethylvaleronitrile (ABDV) (DuPont, Netherlands) and 2′,3′,5′-tri-O-acetyl-uridine (2) (Carbosynth, Compton, UK) were used as received. The templates 2′,3′,5′-tri-O-propionyl uridine (3) and 2′,3′,5′-tri-Obutyryl uridine (4) were prepared from uridine and the appropriate acid anhydride using a literature method [25]. The functional monomer, 2,6-bis-acrylamidopyridine (5), was prepared as reported previously [26].…”

Phosphonomethyl Oligonucleotides as Backbone-Modified Artificial Genetic Polymers

“…). 3 To a solution of thymidine (10.0 g, 41.3 mmol) in dry pyridine (100 mL) was added pivaloyl chloride (5.6 mL, 45.4 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred overnight.…”

Insights into a surprising reaction: The microwave-assisted direct esterification of phosphinic acids

“…6 The addition of an acid to an unsaturated species may be carried out in the presence of catalysts. 7 An additional possibility for the synthesis of phosphinates involves the use of coupling reagents, such as carbodiimides, [8][9][10] uronium, 11 and phosphonium derivatives. 11 The esterification of phosphinic acids is also possible by special methods applying orthoacetates, 12 chloroformates, 13 orthosilicates [14][15][16] and trialkyl phosphites.…”