ortho-Quinone Methides (o-QMs) are highly reactive chemical motifs harnessed by nature for a variety of purposes. Their applications in organic synthesis had been very limited until the low-temperature controllable generation of o-QMs developed by our group. To accelerate the synthetic renaissance for this venerable species, we expanded the application of the o-QM Diels-Alder (o-QMDA) reaction in the total synthesis of pterocarpan family and paecilospirone.

Pterocarpans constitute the second largest family of plant-derived isoflavanoids. Their structural diversity, which results from a variety of oxygen and carbon substituents projecting off their central tetracyclic benzopyran-benzofuran core, gives the pterocarpan family a broad range of differing pharmacological activities. In this project, three pterocarpans: (-)-medicarpin, (-)-sophoracarpan A, and (+/-)-kushecarpin A were synthesized for the first time in 9, 10, and 11 steps, respectively. Key features include the o-QMDA reaction to construct the chroman core and p-QM cyclization to furnish the furan ring. A unified synthetic route for most pterocarpans was developed that is amenable to enantioselectivity. The stereochemistry of sophoracarpan A and B were reassigned based on nOe experiments and crystal structure.

Paecilospirone, isolated in 2000 from a marine fungus Paecilomyces sp., was the first reported spiro[chroman-2,1'(3' H)-isobenzofuran] natural product. This potential mitotic inhibitor was first synthesized in 2011 by Brimble and coworkers in 19 steps. To access this challenging target more efficiently, our strategy using o-QMDA reaction has constructed the carbon skeleton of paecilospirone in 6 steps. Despite the inability to install the final benzylic alcohol, we were able to advance the material to provide access to des-hydroxy paecilospirone in a rapid fashion.