Total synthesis of gambierol

Article abstract of DOI:10.1021/ja028726d

The convergent total synthesis of gambierol (1) is described. The octacyclic ether framework of 1 was constructed via the intramolecular allylation of α-chloroacetoxy ether followed by ring-closing metathesis. A modified Stille coupling was successfully applied to the synthesis of the triene side chain. Copyright

Full text of DOI:10.1021/ja028726d

Published on Web 12/11/2002
Total Synthesis of Gambierol
Isao Kadota,† Hiroyoshi Takamura,‡ Kumi Sato,‡ Akio Ohno,‡ Kumiko Matsuda,‡ and
Yoshinori Yamamoto*,‡
Research Center for Sustainable Materials Engineering, Institute of Multidisciplinary Research for AdVanced
Materials, and Department of Chemistry, Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
Received September 27, 2002 ; E-mail: yoshi@yamamoto1.chem.tohoku.ac.jp
In recent years, there has been an explosion of interest in
biologically active natural products of marine origin.1 Because of
their structural novelty and toxicity, polycyclic ethers are particularly
attractive targets for synthetic chemists.2 Gambierol (1), a potent
neurotoxin isolated from the cultured cells of Gambierdiscus
toxicus, has 8 ether rings and 18 stereogenic centers.3 The compound
shows toxicity against mice (LD50 50 µg/kg), and the symptoms
resemble those caused by ciguatoxins, inferring the possibility that
it is also implicated in ciguatera poisoning.1 The unique structural
features have attracted the attention of synthetic chemists, and a
number of strategies have been investigated.4,5 In this paper, we
describe a new approach to the total synthesis of gambierol (1).
Figure 1 illustrates our retrosynthetic analysis of 1. Recently,
we developed a convergent method for the synthesis of polycyclic
ether frameworks via the intramolecular allylation of R-acetoxy
ethers and subsequent ring-closing metathesis.4i,l On the basis of
this methodology, the octacyclic ether framework of 1 was
retrosynthetically broken down into the ABC ring segment 3 and
the FGH fragment 4 via the diene 2.
Figure 1. Retrosynthetic analysis of gambierol (1).
as a single stereoisomer. TBS protection and subsequent selective
deprotection of the primary silyloxy group afforded 15 in 82%
overall yield.
We have already succeeded in the stereoselective synthesis of
the triene moiety via the Uenishi hydrogenolysis of dibromoalkene
followed by a modified Stille coupling in a model study.4c However,
the coupling reaction of Z-bromoalkenes was very slow. This
problem prompted us to develop an efficient method for the
construction of the triene side chain. After several unfruitful
attempts, we found that the reduction of diiodoalkenes with a Zn-
Cu couple gaVe reactiVe Z-iodoalkenes in a highly stereoselectiVe
manner.15 Thus, PCC oxidation of 15 followed by treatment of the
The initial task of the total synthesis was the construction of the
octacyclic framework. The carboxylic acid 3 and the alcohol 46
were connected by Yamaguchi conditions7 to give the ester 5 in
94% yield (Scheme 1). A series of reactions including desilylation
with TBAF, acid-catalyzed acetal formation with 6, and acetal
cleavage with TMSI/HMDS furnished the allylic stannane 7 in 77%
overall yield.8 The ester 7 was then subjected to the modified
Rychnovsky acetylation. Thus, partial reduction of 7 with DIBALH,
followed by treatment of the resulting aluminum hemiacetal with
(CH2ClCO)2O/pyridine/DMAP,9 gave the R-chloroacetoxy ether 8
as a 3:2 inseparable mixture of diastereoisomers in 88% yield.
Treatment of 8 with BF3‚OEt2 gave a 2:1 mixture of the desired
product 2 and its epimer 9 in 87% yield.10,11 The diene 2 obtained
was subjected to ring-closing metathesis using the second generation
Grubbs catalyst 1012 to give the octacyclic ether 11 in 88% yield.
We then focused on the modification of the H ring moiety.
Hydrolysis of the benzylidene acetal of 11 led to the corresponding
diol. Selective protection of the primary alcohol followed by TPAP
oxidation of the secondary alcohol gave the ketone 12 in 77%
overall yield. Hydrogenation of 12 followed by debenzylation gave
the saturated diol. The primary and secondary alcohols were
protected by Pv and TIPS groups, respectively, to afford 13 in 80%
overall yield. Treatment of 13 with LiHMDS/TMSCl/Et3N5 gave
the corresponding enol silyl ether, which was subjected to de-
16
resulting aldehyde with CI4 and PPh3 gave the diiodoalkene 16
in 92% overall yield. Stereoselective hydrogenolysis of 16 was
carried out by using a Zn-Cu couple and AcOH in THF-MeOH
to give the Z-iodoalkene 17 as a single stereoisomer, which was
then treated with DIBALH, furnishing 18 in quantitative yield.
Deprotection of the bis-silyl ether 18 with SiF4 proceeded smoothly
to afford the corresponding triol.17 Finally, the iodoalkene obtained
was subjected to the modified Stille coupling with 19 to give
gambierol (1) in 72% yield.18 The synthetic gambierol exhibited
physical and spectroscopic data identical to those reported previ-
ously.3,5
In conclusion, the convergent total synthesis of gambierol has
been achieved using the intramolecular allylation of R-chloroacetoxy
ether and subsequent ring-closing metathesis. The longest linear
sequence leading to 1 was 66 steps with 1.2% overall yield, and
the total number of steps was 102, while the synthesis by Sasaki
and Tachibana gave an overall yield of 0.57% by 71 steps, with a
total of 107 steps.5 The present synthesis demonstrated that this
methodology is efficient and practical for constructing polycyclic
ether frameworks. Application of the present strategy to the
synthesis of other marine natural products is in progress.
13
hydrosilylation with Pd(OAc)2 to afford the enone 14 in 92%
overall yield. Stereoselective introduction of the methyl group was
carried out using MeMgI in toluene14 to give the tertiary alcohol
† Institute of Multidisciplinary Research for Advanced Materials.
‡ Graduate School of Science.
9
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J. AM. CHEM. SOC. 2003, 125, 46-47
10.1021/ja028726d CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1 a
a (a) 2,4,6-Trichlorobenzoyl chloride, Et3N, THF, 40 °C, then 4, DMAP, toluene, 40 °C, 94%; (b) TBAF, THF, room temperature, 99%; (c) 6, CSA,
CH2Cl2, room temperature; (d) HMDS, TMSI, CH2Cl2, 0 °C, 78% (two steps); (e) DIBALH, CH2Cl2, -78 °C, then (CH2ClCO)2O, DMAP, pyridine, -78
°C to room temperature, 88%; (f) BF3‚OEt2, MS4A, CH3CN, -40 to 0 °C, 87% (2:9 ) 2:1); (g) 10, CH2Cl2, room temperature, 88%; (h) CSA, CH2Cl2-
MeOH, 30 °C; (i) TBSCl, imidazole, CH2Cl2, 0 °C, 80% (two steps); (j) TPAP, NMO, MS4A, CH2Cl2, room temperature, 96%; (k) H2, Pd-C, EtOAc, room
temperature; (l) H2, Pd(OH)2-C, EtOAc, room temperature; (m) PvCl, DMAP, CH2Cl2, room temperature; (n) TIPSOTf, 2,6-lutidine, DMF, 65 °C, 80%
(four steps); (o) LiHMDS, TMSCl, Et3N, THF, -78 °C; (p) Pd(OAc)2, CH3CN, 92% (two steps); (q) MeMgI, toluene, -78 °C; (r) TBSOTf, 2,6-lutidine,
CH2Cl2, room temperature; (s) CSA, CH2Cl2-MeOH, 0 °C, 82% (three steps); (t) PCC, MS4A, CH2Cl2, room temperature; (u) CI4, PPh3, CH2Cl2, 0 °C,
92% (two steps); (v) Zn-Cu, AcOH, THF-MeOH, 0 °C; (w) DIBALH, CH2Cl2, -78 °C, 100% (two steps); (x) SiF4, CH2Cl2-CH3CN, 0 °C; (y) 19,
Pd2dba3‚CHCl3, P(furyl)3, CuI, DMSO, 40 °C, 72% (two steps).
(5) During our study, very recently the Sasaki and Tachibana group reported
Acknowledgment. We thank Professor T. Yasumoto (Tohoku
the first total synthesis of 1. (a) Fuwa, H.; Sasaki, M.; Satake, M.;
University) for providing the 1H NMR spectrum of 1, and Professor
Tachibana, K. Org. Lett. 2002, 4, 2981-2984. (b) Fuwa, H.; Kainuma,
N.; Tachibana, K.; Sasaki, M. J. Am. Chem. Soc., in press.
(6) For the preparation of 3 and 4, see Supporting Information.
(7) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989-1993.
M. Hirama (Tohoku University) for supporting the measurement
of MALDI TOF mass spectra. This work was financially supported
by the Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan.
(8) Kadota, I.; Sakaihara, T.; Yamamoto, Y. Tetrahedron Lett. 1996, 37,
3195-3198.
(9) Acetic anhydride was used in the original procedure, see: (a) Dahanukar,
V. H.; Rychnovsky, S. D. J. Org. Chem. 1996, 61, 8317-8320. (b)
Rychnovsky, S. D.; Hu, Y.; Ellsworth, B. Tetrahedron Lett. 1998, 39,
7271-7274. (c) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000,
65, 191-198. (d) Rychnovsky, S. D.; Thomas, C. R. Org. Lett. 2000, 2,
1217-1219. (e) Jaber, J. J.; Mitsui, K.; Rychnovsky, S. D. J. Org. Chem.
2001, 66, 4679-4686.
Supporting Information Available: Schemes for the preparation
of compounds 3 and 4. Experimental procedures and characterization
data for all new compounds reported in Scheme 1. Copies of 1H NMR
spectra for selected compounds (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(10) The reaction of the corresponding R-acetoxy ether gave the undesired
isomer 9, predominantly. Perhaps, the poor leaving ability of acetyl group,
in comparison with chloroacetoxy group, would force the reaction course
to proceed through the SN2 pathway. The D ring of the desired isomer 2,
in which all of the substituents take an equatorial position, is more
thermally stable than that of 9. The details of the mechanism are under
investigation. We appreciate a referee who pointed out the above problems,
and we also thank Professor T. Oishi (Osaka University) and Professor
M. Inoue (Tohoku University) for suggesting the use of the chloroacetyl
group.
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