Aza-Claisen rearrangement: Synthesis of 5'-branched 5'-aminothymidines

The syntheses of both diastereoisomers of 5'-ethyl-substituted thymidine dimers; the (5'R)- and (5'S)-configurated 33a and 33b, respectively, in which the natural phosphodiester linkage is replaced by an amide group (C(3')-CH2CONH-CH(5')(Et)), are described. Their fully protected derivatives 35a and 35b, respectively, are suitable for incorporation into antisense oligonucleotides. Unexpectedly, an attempted Pd-II-catalysed aza-Claisen rearrangement of trichloroacetimidate 7 provided the diastereoisomerically pure cyclopropane derivative 17, whose structure was confirmed by X-ray analysis.