Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

• Robin Klintworth,
• Garreth L. Morgans,
• Stefania M. Scalzullo,
• Charles B. de Koning,
• Willem A. L. van Otterlo and
• Joseph P. Michael

Beilstein J. Org. Chem. 2021, 17, 2543–2552, doi:10.3762/bjoc.17.170

• ; tetrahydroindolizines; Introduction Partially or fully saturated variants of the pyrrolizine nucleus 1 are widely occurring motifs in natural products. The hexahydropyrrolizine (pyrrolizidine) system, for example, forms the nucleus of literally hundreds of alkaloids, many of which have gained notoriety owing to their

• nonsteroidal anti-inflammatory drug [6], and licofelone (7) [9][10], a promising co-drug for anticancer combination chemotherapy [7]. Related 5,6,7,8-tetrahydroindolizines such as CMV423 (8) [11], a lead compound for treating infections by human cytomegalovirus, and the natural products polygonatine A (9) [12

• simply a thermally induced reaction, and supporting our premise that a unique protic solvent effect is crucial for facilitating this specific cyclization process. We extended the successful reaction to the 4-methoxyphenyl- and 4-nitrophenylenaminones 25b and 25c, which afforded tetrahydroindolizines 26b