Convergent synthesis of the F-K ring segment of brevetoxin B

Article abstract of DOI:10.1016/j.tetlet.2003.09.003

A convergent synthesis of the F-K ring segment of brevetoxin B has been achieved via the intramolecular allylation of an α-chloroacetoxy ether and subsequent ring-closing metathesis.

Full text of DOI:10.1016/j.tetlet.2003.09.003

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7929–7932
Convergent synthesis of the F–K ring segment of brevetoxin B
Isao Kadota,a,* Naoko Nishina,b Hiroki Nishii,b Shigetoshi Kikuchib and Yoshinori Yamamotob,*
aResearch Center for Sustainable Materials Engineering, Institute of Multidisciplinary Research for Advanced Materials,
Tohoku University, Sendai 980-8578, Japan
bDepartment of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 31 July 2003; revised 20 August 2003; accepted 1 September 2003
Abstract—A convergent synthesis of the F–K ring segment of brevetoxin B has been achieved via the intramolecular allylation of
an a-chloroacetoxy ether and subsequent ring-closing metathesis.
© 2003 Elsevier Ltd. All rights reserved.
Brevetoxin B (1), a potent neurotoxin was isolated from
the red tide organism Gymnodinium breve Davis in 1981
as the first example of a marine polycyclic ether.1 The
unique structural features and biological activity of this
molecule have attracted the attention of synthetic
chemists.2 In 1995, the first total synthesis of 1 was
achieved by Nicolaou and co-workers using a hydroxy
dithioacetal cyclization for the key segment connection
constructing the H ring moiety.3 Nakata, et al. reported
the second total synthesis based on the same segment
coupling strategy in 2002.4 Recently, we developed an
efficient method for the convergent synthesis of poly-
cyclic ethers via the intramolecular allylation of an
a-acetoxy ether and subsequent ring-closing metathe-
sis.5 In this paper, we wish to report a new approach to
the convergent synthesis of the F–K ring segment of 1
based on our own methodology.
Barbier type allylation using allyl bromide and Zn
powder in the presence of satd NH4Cl to give a 2:1
mixture of the desired homoallylic alcohol 7 and its
stereoisomer 8 in 93% combined yield.6,7 Ozonolysis of
Scheme 1 shows the synthesis of the FG ring segment.
The known olefin 22d was converted to the alcohol 3 via
TBS protection and hydroboration in 86% yield. Swern
oxidation of 3 followed by Wittig reaction gave 4 in
87% yield. Treatment of the silyl ether 4 with TBAF
gave the FG ring segment 5 in 90% yield.
The synthesis of the JK ring segment is illustrated in
Scheme 2. Ozonolysis of the known olefin 62d afforded
the corresponding aldehyde, which was subjected to the
Scheme 1. Reagents and conditions: (a) (i) TBSOTf, 2,6-
lutidine, CH2Cl2, rt, 97%; (ii) 9-BBN, THF, rt, then 3N
NaOH, 30% H2O2, 0°C, 89%; (b) (i) (COCl)2, DMSO,
CH2Cl2, −78°C, then Et3N, −78°C to rt; (ii) Ph3P+CH3Br−,
NaHMDS, THF, 0°C, 87% (two steps); (c) TBAF, THF, rt,
90%.
Keywords: brevetoxin B; polycyclic ethers; convergent synthesis.
* Corresponding authors. Tel.: +81-22-217-6581; fax: +81-22-217-
6784; e-mail: ikadota@mail.cc.tohoku.ac.jp; yoshi@yamamoto1.
chem.tohoku.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.003

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Scheme 2. Reagents and conditions: (a) (i) O3, MeOH, −78°C, then Me2S; (ii) allyl bromide, Zn powder, satd NH4Cl, THF, 0°C,
93% (two steps, 7:8=2:1); (b) (i) O3, CH2Cl2, −78°C, then PPh3; (ii) Ac2O, pyridine, DMAP, CH2Cl2, reflux, 97% (two steps); (c)
allyltrimethylsilane, BF3·OEt2, CH3CN, 0°C, 65%; (d) (i) NaOMe, MeOH, rt, 98%; (ii) BnBr, KH, THF, rt, 100%; (e) 9-BBN,
THF, rt, then 30% H2O2, 3N NaOH, 0°C, 96%; (f) (i) BnBr, KH, THF, rt; (ii) CSA, MeOH, rt, 95% (two steps); (g) (i) TsCl,
Et3N, CH2Cl2, reflux, 89%; (ii) NaCN, DMSO, 50°C, 100%; (iii) TBSOTf, 2,6-lutidine, CH2Cl2, 0°C, 100%.
7 followed by acetylation of the resulting hemiacetal
gave 9 in 97% yield. Treatment of 9 with allyltrimethyl-
silane and BF3·OEt2 gave 10 as the sole product in 65%
yield. Removal of the acetyl group followed by benzyl
protection of the resulting alcohol afforded 11 in quan-
titative yield. Hydroboration of 11 gave the alcohol 12
in 96% yield. Benzyl protection followed by hydrolysis
of the benzylidene acetal provided the diol 13 in 95%
yield. Selective tosylation of the primary alcohol, treat-
ment with sodium cyanide, and TBS protection of the
remaining secondary alcohol gave the JK ring segment
14 in 89% yield.
chloroacetic anhydride gave the cyclization precursor
21 in quantitative yield.10,11 Intramolecular allylation of
21 was carried out using BF3·OEt2 to afford 22 as a
single stereoisomer in 75% yield. Finally, the diene 22
was subjected to ring-closing metathesis using the sec-
ond generation Grubbs catalyst 2312 to furnish the F–K
ring framework 24 in 91% yield. The trans relationship
between Ha and Hb was confirmed by the large cou-
pling constant, JHa-Hb=8.5 Hz.
In conclusion, we have achieved the convergent synthe-
sis of the F–K ring segment of brevetoxin B (1) via the
intramolecular allylation of a-chloroacetoxy ether 21
and subsequent ring-closing metathesis. Further studies
toward the total synthesis of 1 are now in progress in
our laboratories.
Scheme 3 describes the coupling of the FG and JK ring
segments. DIBAL-H reduction of 14 followed by oxida-
tion of the resulting aldehyde with NaClO2 gave the
carboxylic acid 15, which was subjected to the
Yamaguchi esterification8 with the alcohol 5 to give the
ester 16 in 55% yield. Desilylation of the TBS group of
16 with TBAF, acid catalyzed reaction of 17 with 18
gave the mixed acetal 19. Subsequent acetal cleavage
with TMSI/HMDS furnished the allylic stannane 20 in
73% yield.9 Modified Rychnovsky acetylation including
the partial reduction of 20 with DIBAL-H followed by
trapping of the resulting aluminum hemiacetal with
Acknowledgements
This work was financially supported by the Naito
Foundation and the Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.

I. Kadota et al. / Tetrahedron Letters 44 (2003) 7929–7932
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Scheme 3. Reagents and conditions: (a) (i) DIBAL-H, CH2Cl2, −78°C, (ii) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/THF/
H2O, rt; (b) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, rt, then 5, DMAP, toluene, rt, 55% (three steps); (c) TBAF, THF, rt,
96%; (d) 18, CSA, CH2Cl2, rt, 95%; (e) TMSI, HMDS, CH2Cl2, 0°C, 83%; (f) DIBAL-H, CH2Cl2, −78°C, then (CH2ClCO)2O,
pyridine, DMAP, −78°C, 100%; (g) BF3·OEt2, CH3CN–CH2Cl2 (20:1), −45 to 0°C, 75%; (h) 23, CH2Cl2, rt, 91%.
References
Rutjes, F. P. J. T.; Theodorakis, E. A.; Tiebes, J.; Sato, M.;
Untersteller, E. J. Am. Chem. Soc. 1995, 117, 1173–1174;
(c) Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E.; Nugiel,
D. A.; Abe, Y.; Bal Reddy, K.; Defrees, S. A.; Reddy, D.
R.; Awartani, R. A.; Conley, S. R.; Rutjes, F. P. J. T.;
Theodorakis, E. A. J. Am. Chem. Soc. 1995, 117, 10227–
10238; (d) Nicolaou, K. C.; Theodorakis, E. A.; Rutjes, F.
P. J. T.; Sato, M.; Tiebes, J.; Xiao, X.-Y.; Hwang, C.-K.;
Duggan, M. E.; Yang, Z.; Couladouros, E. A.; Sato, F.;
Shin, J.; He, H.-M.; Bleckman, T. J. Am. Chem. Soc. 1995,
117, 10239–10251; (e) Nicolaou, K. C.; Rutjes, F. P. J. T.;
Theodorakis, E. A.; Tiebes, J.; Sato, M.; Untersteller, E.
J. Am. Chem. Soc. 1995, 117, 10252–10263.
1. Lin, Y.-Y.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy,
J.; Golik, J.; James, J. C.; Nakanishi, K. J. Am. Chem. Soc.
1981, 103, 6773–6775.
2. For the synthetic studies of brevetoxin B, see: (a) Nicolaou,
K. C.; Duggan, M. E.; Hwang, C.-K. J. Am. Chem. Soc.
1989, 111, 6666–6675; (b) Nicolaou, K. C.; Duggan, M. E.;
Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 6676–6682; (c)
Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E. J. Am.
Chem. Soc. 1989, 111, 6682–6690; (d) Nicolaou, K. C.;
Nugiel, D. A.; Couladouros, E.; Hwang, C.-K. Tetra-
hedron 1990, 46, 4517–4552; (e) Matsuo, G.; Matsukura,
H.; Hori, N.; Nakata, T. Tetrahedron Lett. 2000, 41,
7673–7676; (f) Matsuo, G.; Hori, N.; Matsukura, H.;
Nakata, T. Tetrahedron Lett. 2000, 41, 7677–7680; (g)
Matsukura, H.; Hori, N.; Matsuo, G.; Nakata, T. Tetra-
hedron Lett. 2000, 41, 7681–7684.
4. Matsuo, G.; Kawamura, K.; Hori, N.; Matsukura, H.;
Nakata, T. Tennen Yuki Kagobutsu Toronkai Koen
Yoshishu 2002, 163–168.
5. Kadota, I.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am.
Chem. Soc. 2002, 124, 3562–3566.
3. (a) Nicolaou, K. C.; Theodorakis, E. A.; Rutjes, F. P. J.
T.; Tiebes, J.; Sato, M.; Untersteller, E.; Xiao, X.-Y. J. Am.
Chem. Soc. 1995, 117, 1171–1172; (b) Nicolaou, K. C.;
6. Pe´trier, C.; Luche, J.-L. J. Org. Chem. 1985, 50, 910–912.
7. The Grignard reaction of the hydroxy aldehyde gave poor
results.

7932
I. Kadota et al. / Tetrahedron Letters 44 (2003) 7929–7932
11. For the original conditions, see: (a) Dahanukar, V. H.;
8. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;
Rychnovsky, S. D. J. Org. Chem. 1996, 61, 8317–8320;
(b) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem.
2000, 65, 191–198; (c) Kopecky, D. J.; Rychnovsky, S. D.
Org. Synth. 2003, 80, 177–183.
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–
1993.
9. Kadota, I.; Sakaihara, T.; Yamamoto, Y. Tetrahedron
Lett. 1996, 37, 3195–3198.
12. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org.
10. Kadota, I.; Takamura, H.; Sato, K.; Ohno, A.; Matsuda,
Lett. 1999, 1, 953–956.
K.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 46–47.