Brimble, MargaretLi, FredaMa, Chao2025-04-012025-04-012024-07-31https://hdl.handle.net/2292/71725Dinoflagellate-produced marine toxins, a class of cyclic imines, form the core of various pharmaceutically relevant natural products featuring a spirocyclic imine motif. These toxins are classified into three subgroups based on their imine ring sizes: 5,6-spirocyclic imines (e.g., portimine A (7a)), 6,6-spirocyclic imines (e.g., kabirimine (6)), and 7,6-spirocyclic imines (e.g., pinnatoxin G (2g)). The spirocyclic imine moiety is the key pharmacophore driving their diverse bioactivities, and synthesising this moiety is crucial for structure-activity relationship studies and the eventual total synthesis of these natural products. This study provides a convergent exo-selective Diels-Alder approach to access various spirolactams bearing the desired anti relative stereochemistry present in the cyclic imine marine toxins. It was revealed that the reactivity and diastereoselectivity of the Diels-Alder cycloadditions were significantly influenced by the protecting groups incorporated on the dienophile/diene (P and R), the ring size of the α-exo-methylene lactam dienophiles (n = 0-2), the side chain length of the substituent on dienes (m = 1-3), and the types of dienes (X). The 6,6-spirocyclic core 428 of kabirimine (6) was prepared from the Diels-Alder cycloaddition between α-exo-methylene lactam 139h and silyloxydiene 410d followed by the regioselective vinyl group installation. Alternatively, a tandem Diels-Alder/Stille coupling reaction sequence was employed, requiring the use of bromodiene 91g to effect a Diels-Alder cycloaddition with α-exo-methylene lactam 139g. The use of chiral methyl α-exo-methylene lactams 139h and 139g in Diels-Alder cycloadditions proceeded with a complete diastereocontrol to afford (6S,7R)-spirolactams 352a and 342a as the only isomer albeit bearing the opposite stereochemistry to kabirimine (6). This study established a robust platform for constructing the spirocyclic core of portimine A (7a) and kabirimine (6), paving the way for stereoselective synthesis of the more functionalised spirocyclic core of other cyclic imine natural products (e.g. pinnatoxin G (2g)).Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated.https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htmSpiroimineDiels-AlderThesisCopyright: The author