The total synthesis of spiro-prorocentrimine represents a daunting challenge in organic chemistry. Isolated from a laboratory-cultured benthic strain of the dinoflagellate Prorocentrum, spiro-prorocentrimine contains a unique aza-spirocyclic ring system flanked by a 23-membered macrocyclic ether and a 15-membered macrolactone. Spiro-prorocentrimine and related molecules (e.g., pinnatoxins, gymnodimines, and spirolides), dubbed """"""""fast acting toxins"""""""" are responsible for seafood intoxications, e.g. ciguatera, paralytic shellfish poisoning (PSP), and diarrhetic shellfish poisoning (DSP). The spiro-cyclic imine moiety that characterizes these molecules has been identified as the probable active pharmacophore. Moreover, this motif is reported to activate Ca ion channels, although the scarcity of natural supply has prevented additional biological evaluation. Based upon natures own design, a flexible and convergent synthesis of spiro-prorocentrimine is proposed. It is suspected that spiro-prorocentrimine and related molecules may be biosynthesized by an intramolecular Diels-Alder (IMDA) reaction between an iminium dienophile and diene. IMDA reactions of this kind are scarce in literature and no clear trends pertaining to transition state geometries are known. It is for this reason that a thorough investigation of substrate structure and solvent effects on diastereoselectivity is proposed in conjunction with the synthesis plan. In speculating on the biosynthesis, the order of the macrocyclization events is not clear. The synthesis described herein allows for each avenue to be investigated. The long-term objective of this research proposal is to make a significant contribution to science concerning imine IMDA reactions while supplying sufficient quantities of spiro-prorocentrimine for further biological evaluation for the improvement of public health. The development of strategies and techniques for the creation of complex molecules found in Nature is of fundamental importance. Spiro-prorocentimine and related compounds have been shown to exhibit potent biological properties, specifically with regard to Ca ion channel activation. This research provides an efficient convergent route toward these molecules with the ability to re-evaluate an under-developed area of chemistry, aiding in the teaching aspect of the endeavor.
