Flexible Synthesis of Planar Chiral Azoninones and Optically Active Indolizidinones

The flexible synthesis of defined substituted optically active indolizidinones starting from chiral pool (S)-proline and trans 4-hydroxy-(S)-proline is described. Several defined 2-vinylpyrrolidines were generated in short sequences. The aza-Claisen rearrangement using chloro and phenylketene equivalents delivered nine-membered-ring lactams with up to three stereogenic centres and pS-arranged E olefins. Depending on the substitution pattern, certain azoninones had a flexible conformation and showed pS/pR double-bond flipping. Treatment of the unsaturated lactams with the soft electrophile iodine induced diastereoselective transannular ring contractions. Here, the planar chiral arrangement of the azoninone double bond predetermined the bridgehead configuration of the product indolizidinones. Thus, the (S)-proline starting materials could be used to gain access to either one of the two antipodal series of indolizidinone products. The indolizidinone scaffolds should serve as versatile key intermediates in the synthesis of natural products and pharmaceutically important molecules.