Total synthesis of (-)-gambierol.
The first total synthesis of (-)-gambierol (1), a marine polycyclic ether toxin, has been achieved. Key features of the successful synthesis include (1) a convergent union of the ABC and EFGH ring fragments (5 and 6, respectively) via our developed B-alkyl Suzuki-Miyaura cross-coupling strategy leading to the octacyclic polyether core 4 and (2) a late-stage introduction of the sensitive triene side chain by use of Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille coupling. The ABC ring fragment 5 was synthesized in a linear manner (B --> AB --> ABC), wherein the A ring was formed by intramolecular hetero-Michael reaction and the C ring was constructed via 6-endo cyclization of hydroxy epoxide 7. An improved synthetic entry to the EFGH ring fragment 6 is also described, in which SmI(2)-induced reductive cyclization methodology was applied to the stereoselective construction of the F and H rings, leading to 6 with remarkable overall efficiency. Stereoselective hydroboration of 5 and subsequent Suzuki-Miyaura coupling with 6 provided endocyclic enol ether 45 in high yield, which was then converted to octacyclic polyether core 4. Careful choice of the global deprotection stage was a key element for the successful total synthesis. Functionalization of the H ring and global desilylation gave (Z)-vinyl bromide 2. Finally, cross-coupling of 2 with (Z)-vinyl stannane 3 under Corey's Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille conditions completed the total synthesis of (-)-gambierol (1).
Fuwa
Haruhiko
H
Department of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Kainuma
Noriko
N
Tachibana
Kazuo
K
Sasaki
Makoto
M
D002922:Ciguatoxins; D004988:Ethers, Cyclic / Q000138:chemical synthesis*; D008387:Marine Toxins / Q000138:chemical synthesis*; D019906:Nuclear Magnetic Resonance, Biomolecular; D011083:Polycyclic Compounds / Q000138:chemical synthesis*; D013237:Stereoisomerism; D035964:Oxocins
D002922:Ciguatoxins; D004988:Ethers, Cyclic; D008387:Marine Toxins; D011083:Polycyclic Compounds; C435770:gambierol; D035964:Oxocins