ja028167a_si_002.pdf (2.07 MB)
Total Synthesis of (−)-Gambierol
journal contribution
posted on 2002-11-20, 00:00 authored by Haruhiko Fuwa, Noriko Kainuma, Kazuo Tachibana, Makoto SasakiThe 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(PPh3)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 SmI2-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(PPh3)4/CuCl/LiCl-promoted Stille conditions completed the total synthesis of (−)-gambierol
(1).
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SmI 2vinyl stannane 3marine polycyclic ether toxinH ringCareful choicedeprotection stageTotal SynthesisEFGH ring fragmentsoctacyclic polyether core 4C ringStereoselective hydroborationH ringsKey featuresconvergent unionEFGH ring fragment 6endocyclic enol ether 45synthesisreductive cyclization methodologytriene side chainhydroxy epoxide 7stereoselective constructionABC ring fragment 5
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