Synthesis of (3R,6R)- and (3S,6R)-piperidinone PNA

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Abstract
Two new conformationally restricted piperidinone PNA adenine monomers 12 and 13 have been synthesised using a stereoselective synthesis strategy analogous to a previously published strategy for pyrrolidinone analogues. In contrast to the pyrrolidinone case, epimerisation occurred during the final hydrolysis 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 (Tm) of the modified oligomers hybridised to complementary DNA, RNA and PNA were measured. PNA modified with either 12 or 13 resulted in a decrease of the Tm compared to unmodified PNA and to pyrrolidinone modified PNA. Thus, any preorganisation for duplex formation of PNA with a six-membered piperidinone ring seems to be inferior to preorganisation with a five-membered ring in the pyrrolidinone PNA analogues studied earlier.