Reaction Discovery Using Neopentylene-Tethered Coupling Partners

Within the past few decades, metal-catalysis has emerged as a key facet in synthetic organic chemistry, perpetuating a continuous need for the development of methods within this sect of chemistry. In tandem, cycloisomerization reactions of tethered enynes have garnered considerable interest as emphasis on annulation strategies to access polycyclic systems becomes necessary for the generation of important bioactive structures. Driven by both methodological and total synthesis applications, metal-catalyzed cycloisomerizations remain at the forefront of interest for effective atom-economic reactions. We have identified a strategic gap in the methodology of 1,6-enyne cycloisomerizations bearing heteroatom, methylene, and malonate tethers. Herein will be described a method for the [4 + 2] formal Diels-Alder cycloisomerization of neopentylene-tethered dienynes, closing the gap previously mentioned and highlighting a valuable reactivity profile of this new tether. Also demonstrated is significant progress in the Diels-Alder cyclization of electron-deficient dienynes, for which the literature has shown to be relatively unexplored, presumably due to the apparent poor reactivity of these substrates. Further investigation into isolation of the [4 + 2] Diels-Alder products as well as elaboration on the previously published fragmentation/olefination methodology is included in this manuscript. Using these effective annulation strategies developed in our lab, we have sought to gain access to sesquiterpene natural products of particular interest bearing the gem-dimethylcyclopentane, an extension of the indane core. These methods have been employed in a six-step total synthesis of Alcyopterosin A and in the efforts toward the synthesis of Fomajorin D.