New extensions of the intramolecular Schmidt reaction: Methods development and dendrobatid alkaloid total synthesis

The research presented herein describes the utilization of the intramolecular Schmidt reaction in the synthesis of natural and unnatural products. Initial studies focused on the intramolecular reactions of benzylic azides tethered to ketones via carbon chains of varying lengths. It was discovered that the length of the chain between the reacting ketone and benzyl azide dictated what product was obtained from the reaction. The shorter carbon tether substrates were found to react via an intramolecular Schmidt reaction to deliver ring-expanded bicyclic lactams. Lengthening the tether shifted the reaction pathway to an intramolecular azido-Mannich reaction en route to keto amine products.; Also described is the use of the intramolecular Schmidt reaction in the asymmetric total synthesis of the dendrobatid alkaloid 251F. Preliminary studies on a model system were applied towards developing the chemistry necessary to accomplish the natural product synthesis. Key steps of the 251F synthesis involved an asymmetric Diels-Alder reaction, a tandem ring-opening/ring-closing metathesis, a one-pot conjugate addition/aldol reaction, and a key intramolecular Schmidt reaction.; Finally, experiments are presented describing how proper manipulation of keto azide substrates can allow the intramolecular Schmidt reaction to deliver bridged or twisted lactams. The strained lactams thus synthesized display chemistry unlike that of unstrained amides. Novel ring cleavage reactions of the twisted lactams, using conditions under which most amide bonds do not react, are presented.