Stereo- and Regiochemical Transannular Cyclization of a Common Hexahydro‑1H‑azonine to Afford Three Different Indolizidinone Dipeptide Mimetics

Sets of azabicyclo­[X.Y.0]­alkanone amino acids have been effectively used to identify active conformers in peptide-based drug discovery, but they usually require multiple routes to synthesize. Employing a common method from the same nine-membered unsaturated lactam precursor, we developed conditions for stereo- and regiochemical transannular cyclizations to synthesize three different indolizidin-2- and 9-one amino acid (I2aa and I9aa) analogues. For example, (3S,5R,6R,9S)- and (3S,5S,6S,9S)-I2aa diastereomers were prepared from hexahydro-1H-azonines by using iodine in THF and in MeCN with DIB as an additive. The regioselectivity of the transannular cyclization was influenced by amine protection to favor the synthesis of the I9aa isomer. Moreover, side chains were added onto the I2aa and I9aa ring systems by way of olefin intermediates that underwent Pd-catalyzed C–H bond activation and allylic oxidation.