In 2004, Uemura and co-workers identified the anti-osteoclastogenic marine natural product (+)-symbioimine (1), a secondary metabolite isolated from symbiotic dinoflagellates (Symbiodinium sp). Intrigued by the complex zwitterionic structure and the unusual biological activity, studies were initiated focusing on an efficient and general total synthesis of the symbioimine family using an intramolecular Diels-Alder (IMDA) approach. An initial route mimicking the proposed biosynthetic pathway through an unusual exoselective IMDA reaction resulted in a Lewis acid catalyzed cis-decalenone product, a more traditional endo outcome. This product was isolated as a single diastereomer and characterized as an O,N-hemiacetal by X-ray crystallography, providing a C-3,4 isomer of 1. Next, a novel approach using a doubly-activated, methacrylate-type dienophile was tested in the IMDA reaction, resulting in a cis-fused, C-9,12 isomer of 1. Finally, a modified approach using (Z,E,E)-decatrienone 3 was tested in the IMDA approach and successfully cyclized to give the desired stereochemistry and correct carbon-framework of related natural product (+)-neosymbioimine (2).