Stereoselective synthesis of the spirocyclic core of 13-desmethyl spirolide C using an aza-Claisen rearrangement and an -selective Diels-Alder cycloaddition.

13-Desmethyl spirolide C is a marine natural product of the cyclic imine class that demonstrates remarkable bioactivity against several biomarkers of Alzheimer's Disease, which renders its [7,6]-spirocyclic imine pharmacophore of significant synthetic interest. This work describes a facile and efficient synthesis of the [7,6]-spirocyclic core of 13-desmethyl spirolide C from inexpensive starting materials, featuring an aza-Claisen rearrangement to simultaneously set both stereocentres of the dimethyl moiety with complete atom economy, and a highly -selective Diels-Alder cycloaddition to construct the challenging contiguous tertiary and quaternary stereocentres of the spirocyclic core of 13-desmethyl spirolide C. A comprehensive study of the key Diels-Alder reaction was also performed to evaluate the stereoselectivity and reactivity of various functionalised dienes and protected lactam dienophiles, wherein the first successful -selective Diels-Alder cycloaddition to construct spirocyclic structures using a bromodiene and α--methylene dienophiles is reported.