Annika Kers

Studies on aryl H-phosphonates. 3. Mechanistic investigations related to the disproportionation of diphenyl H-phosphonate under anhydrous basic conditions

Abstract Diphenyl H-phosphonate undergoes under anhydrous reaction conditions a base-promoted disproportionation to triphenyl phosphite and phenyl H-phosphonate. On the basis of 31P NMR data the most likely mechanism for this transformation was proposed. In order to substantiate these findings and to get a deeper insight into the chemistry of aryl H-phosphonate esters, we carried out also some studies on activation of phenyl and diphenyl H-phosphonates with various condensing agents. We found that aryl vs alkyl esters of phosphonic acid often follow different reaction pathways during the activation, and this can most likely be traced back to higher electrophilicity of the phosphorus centre and to higher reactivity of the P-H bonds in aryl H-phosphonate derivatives.

A NEW TYPE OF NUCLEOTIDE ANALOGUE WITH 4-PYRIDYLPHOSPHONATE INTERNUCLEOTIDE LINKAGE

Abstract Suitably protected dithymidine H-phosphonates were quantitatively converted into the corresponding dinucleoside 4-pyridylphosphonates by treatment with 1,8-diazabicylo[5.4.0]undec-7-ene (DBU) in the presence of trityl chloride in pyridine. The reaction was found to be stereospecific and proceeded, most likely, with retention of configuration at the phosphorus centre.

Nucleoside Phosphonates. Development of Synthetic Methods and Reagents

Abstract In this paper a short account of our recent research concerning development of new synthetic methods and new reagents for the preparation of DNA and RNA fragments and their analogues is given. #Dedicated to Professor Yoshihisa Mizuno on the occasion of his 75th birthday. ¶Present address: Astra Production Chemicals, S-151 85 Sodertalje, Sweden.

2-Pyridylphosphonates: a new type of modification for nucleotide analogues

Suitably protected dithymidine H-phosphonates afforded the corresponding dinucleoside 2-pyridylphosphonates upon treatment with N-methoxypyridinium tosylate in acetonitrile in the presence of 1,8-diazabicylo[5.4.0]undec-7-ene (DBU). The reaction was rapid (ca. 5 min), practically quantitative and proceeded stereospecifically, most likely with retention of configuration at the phosphorus centre.

Aryl H-phosphonates. 7. Studies on the formation of phosphorus-carbon bond in the reaction of trityl and benzyl halides with dialkyl and diphenyl H-phosphonates

Abstract The reactions of H-phosphonate diesters with trityl and benzyl halides were investigated using 31P NMR spectroscopy. It was found that extensive oxidation, which usually accompanies the formation of trityl- or p-nitrobenzylphosphonates from the corresponding alkyl bromides in the Michaelis-Becker reaction, can be considerably suppressed or completely eliminated by reacting p-nitrobenzyl or trityl bromides with diphenyl H-phosphonate in acetonitrile in the presence of DBU.

Aryl Hphosphonates. 8. Simple and efficient method forv the preparation of nucleoside Hphosphonothioate monoesters

Abstract An efficient method for the preparation of nucleoside 3′-Hphosphonothioate monoesters was developed. It consists of phosphonylation of suitably protected nucleosides with diphenyl H-phosphonate to produce nucleoside phenyl H-phosphonates, followed by their sulfhydrolysis with hydrogen sulfide.

Preparation of nucleoside 5′-deoxy-5′-methylenephosphonates as building blocks for the synthesis of methylenephosphonate analogues

Efficient synthesis of suitably protected 2′-deoxycytidine, 2′-deoxyadenosine, and 2′-deoxyguanosine derivatives bearing the 5′-methylenephosphonate moiety with the 4-methoxy-1-oxido-2-picolyl function as an intramolecular nucleophile catalytic group is described.

The reaction of diphenyl and dialkyl phosphorochloridates with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Formation of phosphonate diesters via N→C phosphorus migration

Diphenyl and neopentylene phosphorochloridates react with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile to form amidine adducts 3 or 10. These undergo further conversion into the corresponding alkene aminals, followed by probable N→C phosphorus migration to produce stable 6-substituted phosphinoyl derivatives of DBU, 6 or 12, respectively. Diethyl phosphorohalidates (chloride and bromide) also form amidine adduct 13 with DBU, but this does not undergo N→C phosphorus migration.

Studies on the reaction of trityl derivatives withH-phosphonate diesters: Their relevance to the synthesis of 4-pyridylphosphonates

Transesterification of diphenyl H-phosphonate with tritanol in pyridine afforded equimolar amounts of phenyl H-phosphonate monoester and diphenyl 4-pyridylphosphonate as the only phosphorus-containing species. Using 31P NMR spectroscopy a plausible reaction pathway for the observed transformation was proposed and some of the postulated intermediates were identified. These studies also enabled us to develop an efficient protocol for the formation of diphenyl and diethyl 4-pyridylphosphonates from the corresponding H-phosphonate diesters under mild reaction conditions.

Solid Phase Synthesis of 5′-Methylenephosphonate DNA

Abstract A new approach to the solid phase synthesis of 5′-methylenephosphonate DNA is described. It makes use of intramolecular catalysis which ensures rapid and high-yielding condensations and thus provides a convenient entry to ionic, achiral analogs of thymidylic acids up to 20 nucleotides in length.