ja048320w_si_004.pdf (5.29 MB)

Total Synthesis of Macquarimicins Using an Intramolecular Diels−Alder Approach Inspired by a Biosynthetic Pathway

Download (5.29 MB)
journal contribution
posted on 15.09.2004, 00:00 by Ryosuke Munakata, Hironori Katakai, Tatsuo Ueki, Jun Kurosaka, Ken-ichi Takao, Kin-ichi Tadano
A total synthesis of the macquarimicins A−C (13), 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 (E,Z,E)-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 (+)-1 in 27 linear steps with 4.3% and 9.9% overall yields from readily available ethyl (2E,4S)-4,5-(isopropylidene)dioxy-2-pentenoate (22) and (R)-epichlorohydrin (30), respectively. Furthermore, efficient syntheses of 2, 3, and the 9-epi-cochleamycins A (57) and B (58) were accomplished. Additionally, the present work established the absolute stereochemistry of macquarimicins and revised the C(2)−C(3) geometry of 1.