Asymmetric Synthesis of the Frog Alkaloid 205B and Progress toward the Total Synthesis of Lepadiformine and Isaindigotidione

The family of piperidine-containing alkaloids serves as a unique source of novel compounds in the continuous search for effective pharmacological agents to combat a variety of human diseases. Given their unparalleled structural diversity and interesting biological activities, these natural products became attractive targets for total synthesis. These studies were directed toward the preparation of three different alkaloids: lepadiformine, 205B and isaindigotidione.;The lepadiformine project was centered on the idea of implementing an asymmetric N-acylpyridinium salt reaction of 4-methoxy-5,6,7,8-tetrahydroquinoline with hexyl Grignard to install the first stereocenter. Multiple approaches were attempted to introduce the quaternary center of the molecule with the correct stereochemistry including addition of Grignard reagents, cuprates, allyl tin and silicon compounds to alpha,beta-unsaturated ketones and N-acyliminium ions. Despite the fact that all efforts resulted only in the synthesis of an epimeric molecule, significant progress was achieved in understanding the intrinsic reactivity of the studied system. In addition, several methods were developed to selectively install substituents in different positions of the perhydroquinoline with a full stereocontrol.;The investigation of a route toward the natural product 205B led to the development of an efficient total synthesis of this selective inhibitor of alpha7-nicotinic receptors, in 11 steps and 8% overall yield. The synthesis features an asymmetric N-acylpyridinium salt reaction, a Tsuji-Trost allylic amination, a novel stereoselective TFAA-mediated allylation, and a PhSeH-mediated Barton-McCombie deoxygenation.;The third project was concentrated on an approach to the synthesis of the natural product isaindigotidione, which possesses strong antiendotoxin activity. N-Acylpyridinium salt chemistry provided an easy access toward the first stereocenter and indolizidine fragment of the molecule. A Pd-catalyzed ketone arylation strategy and Suzuki coupling were investigated in detail in order to stereoselectively introduce the key trimethoxyphenyl substituent.