Two new conformationally restricted piperidinone PNA adenine monomers 12 an
d 13 have been synthesised using a stereoselective synthesis strategy analo
gous to a previously published strategy for pyrrolidinone analogues. In con
trast to the pyrrolidinone case, epimerisation occurred during the final hy
drolysis step. However, the diastereomeric mixture could be separated by RP
-HPLC to give small amounts of pure 12 and 13. These were built into a PNA
dodecamer (once in a central position), and the thermal stability (T-m) of
the modified oligomers hybridised to complementary DNA, RNA and PNA were me
asured. PNA modified with either 12 or 13 resulted in a decrease of the T-m
compared to unmodified PNA and to pyrrolidinone modified PNA. Thus, any pr
eorganisation for duplex formation of PNA with a six-membered piperidinone
ring seems to be inferior to preorganisation with a five-membered ring in t
he pyrrolidinone PNA analogues studied earlier.