3,4-difunctionalized piperidines are privileged structures found in numerous pharmaceuticals and biologically active natural products such as the antidepressant paroxetine and the antihistamine levocabastine. Such drugs are notably enantioenriched, but the research field around the enantioselective synthesis of disubstituted piperidines has been underexplored. This study demonstrates that a variety of enantioenriched 3,4-difunctionalized piperidines can be easily accessed by an enantioselective Tsuji-Trost coupling followed by a Cope rearrangement. To form the Cope rearrangement products, Tsuji-Trost couplings were performed with piperidinone-derived nucleophiles and allylic electrophiles with a chiral ligand-palladium complex. Upon heating, the 1,5-dienes were observed to undergo diastereoselective Cope rearrangement. These studies show that this method can be performed enantio- and diastereoselectively and that it is applicable with a variety of electrophiles that include aliphatic, aromatic, and heteroaromatic allylic electrophiles. The studies of different (hetero)cycloalkyl nucleophiles are also ongoing. The Cope rearrangement products were derivatized by reduction and oxidative amidation demonstrating the importance of such substrates and presenting the type of products that can be access through this methodology. As such these products are of high value and will provide insights into stereoselective strategies related to the synthesis of 3,4-difunctionalized piperidines.

3,4-disubstituted piperidines synthesis <i>via</i> enantioselective Tsuji-Trost coupling and cope rearrangement

ACS Spring 2022

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3,4-disubstituted piperidines synthesis via enantioselective Tsuji-Trost coupling and cope rearrangement