NEW PROLINE DERIVED CHIRAL BUILDING-BLOCKS FOR NUCLEOSIDE METHYLPHOSPHONATE SYNTHESIS

P-Prolyl-nucleoside-P-methyl-phosphanamidites P-chiral building blocks for nucleoside methylphosphonate synthesis were prepared by two different methods. First starting from dichloromethylphosphine 1 prochiral bis-proline-methylphosphines 3a-e were obtained. Their reaction with tritylthymidine in presence of an acid like tetrazole or better 2,6-di-tert. -butyl4-methylpyridinium-tetrafluoroborate furnished the amidites 5a-e. The absolute configuration of the phosphorus center could be determined by single crystal X-ray diffraction. Based on this determination configuration of the amidites 5a-e and 10a-e could be assigned by NMR spectroscopy. Alternatively starting from dichloromethylphosphine reaction with dimethoxytritylthymidine followed by addition of the proline derivative 2a-i in the presence of triethylamine yielded the Phosphorus-chiral amidites 10a-i with a de up to 81%.