Total synthesis of macquarimicins using an intramolecular Diels-Alder approach inspired by a biosynthetic pathway.
A total synthesis of the macquarimicins A-C (1-3), 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.
Munakata
Ryosuke
R
Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.
Katakai
Hironori
H
Ueki
Tatsuo
T
Kurosaka
Jun
J
Takao
Ken-Ichi
K
Tadano
Kin-Ichi
K
D032701:Biomimetics; D003500:Cyclization; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D013237:Stereoisomerism
D018942:Macrolides; C094822:macquarimicin A; C094823:macquarimicin B; C094824:macquarimicin C