Erik Westman

Ribonucleoside H-Phosphonates. Pyridine vs Quinoline - Influence on Condensation Rate

Abstract Condensation of 5′-O-monomethoxytrity1-2′-O-t-butyldimethylsilyl- uridine 3′-H-phosphonate (triethylammonium salt) (1) with 2′,3′-0- dibenzoyluridine (2) using pivaloyl chloride (PV-C1)1, 2-chloro-5,5- dimethyl-l,3,2-dioxaphosphorinane 2-oxide (NPCP)2 and bis(2-oxo-3- oxazolidiny1)phosphinic chloride (OXPI2 as condensing agents, has been investigated. Pyridine or quinoline3 was used as a base and nucleophilic catalyst in the following solvent systems: neat pyridine or quinoline, pyridine (or quinoline)/acetonitrile (4:1, v/v,), pyridine (or quinoline)/acetonitrile (1 :1, v/v,), and pyridine (or quinoline)/acetonitrile (1:4, v/v,). Stoicheiometric amounts of 1 and 2 (concentration 25 pM) and 3 equiv. of the appropriate condensing reagent were used in all reactions.

Evaluation of the Use of the t-Butyldimethylsilyl Group for 2′-Protection in RNA-Synthesis Via the H-Phosphonate Approach

Abstract Two model compounds. 1 and 2. have been studied to test the stability of the tbutyldimethylsilyl group towards anhydrous acid, aqueous ammonia and tetrabutylammonlum fluoride In THF. Results of relevance to cleavage and migration of phosphodiesters during deprotection of synthetic RNA will be presented.

Synthesis of the Methyl, 1-Octyl, and D-Trifluoro-Acetamidophentlethyl α-Glycosides of 3,6-Di-O-(α-D-Galactopyranosyl)-D-Glucopyranose and an Acyclic Analogue Thereof

Abstract The title trisaccharides were synthesized from a common trisaccharide thioglycoside derivative, which was, in turn, prepared from monosaccharide thioglycoside precursors. An acyclic analogue, methyl 3-O-(α-D-galacto-pyranosyl)-6-O-[(2′-hydroxyethyl)oxymethyl]-α-D-glucopyranoside, which carries a 2′-hydroxyethyloxymethyl group in place of the 6-O-galactosyl residue, was also synthesized.

RNA-Synthesis Using the H-Phosphonate Approach and an Improved Protecting Group Strategy

Abstract An improved version of the H-phosphonate approach to RNA-synthesis is presented and the studies that led to alterations in the protecting group strategy are discussed.

The H-Phosphonate Method for Constructing Phosphodiester Linkages. A Progress Report

Abstract Ongoing research into the potential of the H-phosphonate method for synthesising oligonucleotides is discussed. Examples include the synthesis of an artificial Haemophilus influenzae antigen and also efforts to extend the method into the automated solid support synthesis of long RNA oligomers.

Recent Studies in Nucleoside Phosphonate Chemistry

Abstract New activation pathways have been found for H-phosphonate monoesters subjected to a reaction with alkyl chlorophosphates or sterically hindered aromatic acyl chlorides. Studies on synthesis of nucleoside methylphosphnate diesters using a new condensing system are also discussed.

Reactions of Nucleoside Hydrogenphosphonates with Diphenyl Chlorophosphate and Sterically Hindered Aromatic Acyl Chlorides

Abstract The final product of the reaction of H-phosphonate monoesters with diphenylchlorophosphate was found to be the corresponding dichlorophosphite. Stericalty hindered aromatic acyl chlorides react with H-phosphonate diesters affording C-phosphonate derivatives.

o-Chlorobenzoyl Protected Nucleoside Succinates for Functionalization of the Solid Support Used in Oligoribonucleotide Synthesis

Abstract In the final stages of automated oligonucleotide synthesis the oligomer has to be cleaved from the solid support. This is usually carried out using ammonolysis since the 3′-end of the oligomer is most commonly attached to the support via a succinate ester linkage. The t-butyldimethylsilyl (TBDMS) group is currently the most widely used 2′-hydroxyl in RNA-synthesis and is used together with phosphoroamidites1 as well as with H-phosphonates2. The nucleoside directly attached to the support, often carries the same TBDMS-protection on the secondary hydroxyl next to the succinate linker. The use of more labile acyl groups for N-protection in RNA-synthesis was suggested in reports where partial loss of the TBDMS groups during ammonolysis was detected3,4. This has since been introduced5,6 and is now general practice. However, one can question if all oligomer will be released from the support under the milder ammonolytic conditions used to remove these more labile N-protecting groups.