Total Synthesis of Macquarimicins Using an Intramolecular Diels−Alder Approach Inspired by a Biosynthetic Pathway MunakataRyosuke KatakaiHironori UekiTatsuo KurosakaJun TakaoKen-ichi TadanoKin-ichi 2004 A total synthesis of the macquarimicins A−C (<b>1</b><b>−</b><b>3</b>), novel natural products with intriguing tetra- or pentacyclic frameworks, has been achieved. The synthesis features an extensive investigation of the biosynthesis-based intramolecular Diels−Alder (IMDA) reactions of (<i>E</i>,<i>Z</i>,<i>E</i>)-1,6,8-nonatrienes. Considering possible biosynthetic sequences, four types of substrates were synthesized, and their IMDA reactions were examined. From one of the four substrates, the total synthesis was achieved via a transannular Diels−Alder reaction, which led to the stereoselective construction of the unique molecular framework. The convergent and efficient synthetic pathway afforded (+)-<b>1</b> in 27 linear steps with 4.3% and 9.9% overall yields from readily available ethyl (2<i>E</i>,4<i>S</i>)-4,5-(isopropylidene)dioxy-2-pentenoate (<b>22</b>) and (<i>R</i>)-epichlorohydrin (<b>30</b>), respectively. Furthermore, efficient syntheses of <b>2</b>, <b>3</b>, and the 9-<i>epi</i>-cochleamycins A (<b>57</b>) and B (<b>58</b>) were accomplished. Additionally, the present work established the absolute stereochemistry of macquarimicins and revised the C(2)−C(3) geometry of <b>1</b>.