Stereo- and Regiochemistries of the Oxidations of 2-Methoxy-5-tert-butyl-1,3,2-dioxaphosphorinanes and the Cyclic Methyl 3',5'-Phosphite of Thymidine by H2O/I2 and O2/AIBN to P-Chiral Phosphates. (17)O NMR Assignment of Phosphorus Configuration to the Diastereomeric Thymidine Cyclic ...

Article abstract of DOI:10.1021/ja00193a034

The stereo- and regiochemistries of oxidation of six-membered ring trialkyl phosphites under nonaqueous conditions with O2, initiated thermally or photochemically by azobis(isobutyronitrile) (AIBN), and with the well-known reagent H2O/I2 have been investigated.Yields of product phosphates are high, and both reactions occur regio- and stereospecifically with retention of configuration at phosphorus as shown for the diastereomeric 2-methoxy-5-tert-butyl-1,3,2-dioxaphosphorinanes and cyclic methyl 3',5'-phosphite triesters derived from thymidine.Mechanistic rationalesare proposed for both processes.These oxidations are useful for the facile introduction of (17)O or (18)O label into the phosphoryl oxygen of the product cyclic phosphate.Demethylation of the cyclic thymidine methyl 3',5'-monophosphate so-labeled yields the individual cyclic 3',5'-monophosphate diastereomers with (18)O or (17)O specifically axial or equatorial.The O2/AIBN oxidation can be proposed as a nonaqueous method for the oxidation of dinucleoside phosphite triesters and perhaps in the synthesis of oligonucleotides by the phosphite intermediate route as well. (17)O NMR is shown to be a convenient method to assign the absolute configuration at phosphorus to the individual oxygen-labeled diastereomers of the cyclic thymidine methyl 3',5'-monophosphate triester on the basis of their P=(17)O resonances, which are well-separated at 54.2 MHz (Δδ = 9.5, 515 Hz) and relatively narrow in CD3CN at 80 deg C.One-bond oxygen phosphorus couplings are well-resolved as well.Application of the (17)O results in the determination of the configurations of P-chiral thymidine 3'- and 5'-monophosphate diesters is proposed.