Chemistry of [3 + 3] Hetero-Annulations

A Bio-Inspired Strategy for Natural Product Synthesis

We have developed a formal [3 + 3] cycloaddition reaction that can construct complex dihydropyranyl and dihydropyridinyl heterocycles from simple alpha,beta-unsaturated iminiums and 1,3-dicarbonyl equivalents such as vinylogous amides or other. This reaction proceeds through a tandem process consisting of a Knoevenagel condensation followed by a 6pi-electron electrocyclic ring-closure of the 1-oxa- or 1-azatriene intermediates. The net result of this step-wise or formal cycloaddition reaction is the formation of two sigma-bonds along with a new stereocenter adjacent to the heteroatom. The new stereocenter can be controlled using chiral vinylogous amide, and an intramolecular variant of this reaction has also been recently developed. This process has allowed us to achieve numerous total syntheses of complex natural products such as arisugacin A, simulenoline, huajiaosimuline, tangutorine, hongoquercin A, perhydrohistrionicotoxin, cylindricines, lepadiformine, the entire lepadin family, the aza-phenylene family, rhododaurichromanic acids, and most recently, phomactin A. We are currently applying this strategy toward syntheses of a series of other natural products shown below.

 A. An Oxa-[3 + 3] Annulation Approach to Natural Products

area-i- Hsung Lab

B. Aza-[3 + 3] Annulation: A Unified Strategy for Total Syntheses of Alkaloids

area-ii- Hsung Lab