Stereocontrolled synthesis of the C79-C96 fragment of symbiodinolide

Article abstract of DOI:10.1016/j.tetlet.2008.05.078

The stereoselective synthesis of the C79-C96 fragment of symbiodinolide is described in which the spiroacetalization and Kotsuki coupling are the key steps.

Full text of DOI:10.1016/j.tetlet.2008.05.078

Tetrahedron Letters 49 (2008) 4626–4629
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Tetrahedron Letters
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Stereocontrolled synthesis of the C79–C96 fragment of symbiodinolide
b
a
b
a,
b,
Hiroyoshi Takamura a, , Junki Ando , Takashi Abe , Takeshi Murata , Isao Kadota , Daisuke Uemura
*
*
a Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushimanaka, Okayama 700-8530, Japan
b Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective synthesis of the C79–C96 fragment of symbiodinolide is described in which the
spiroacetalization and Kotsuki coupling are the key steps.
Received 3 April 2008
Revised 13 May 2008
Accepted 16 May 2008
Available online 22 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Symbiodinolide
Polyol macrolide
Spiroacetal
Kotsuki coupling
Marine organisms produce various secondary metabolites that
exhibit remarkable biological activities and chemical structures.1
In particular, huge polyol and polyether compounds, such as paly-
toxins, brevetoxins, halichondrins, and maitotoxin are some of the
most attractive molecules in natural products chemistry.2 In our
continuing search for these types of compounds,3 we reported
the isolation of symbiodinolide (1) from the symbiotic marine
dinoflagellate Symbiodinium sp. in 2007 (Fig. 1).4,5
Symbiodinolide (1), a novel polyol macrolide with a molecular
weight of 2859 mu, exhibits a voltage-dependant N-type Ca2+
channel-opening activity at 7 nM and COX-1 inhibitory effect at
2 nM. The planar structure and partial stereochemistries of 1 were
elucidated by spectroscopic analysis and chemical degradations.4
Herein, as a part of our structural study and synthetic study on 1,
we describe the enantio- and stereocontrolled synthesis of the
C79–C96 fragment of 1 by using the spiroacetalization and Kotsuki
coupling as key steps.
Scheme 1 shows the retrosynthetic analysis of the C79–C96
fragment 2. The carbon framework of 2 would be constructed via
the coupling of alkynyllithium reagent derived from 3, and triflate
4 under Kotsuki conditions.6 The spiroacetal 4 would be synthe-
sized through the stereoselective spiroacetalization of the dihydr-
oxyketone 5, which can be broken down into the alkyne 6 (C79–
C85) and the epoxide 7 (C86–C92).
Synthesis of the alkyne 13 (C79–C85) is shown in Scheme 2.
Treatment of the aldehyde 87 with the lithium acetylide, prepared
from trimethylsilyl acetylene and n-BuLi, afforded the correspond-
ing propargylic alcohol. Subsequent TPAP oxidation8 provided the
a
,b-ynone 9. Asymmetric reduction of 9 was performed by using
chiral Ru(II) catalyst 10 and i-PrOH as the hydrogen donor9 to give
the optically pure propargylic alcohol 11 in 98%. The TMS group
was removed with K2CO3 in MeOH to give the alkyne 12, and then
the hydroxy group was protected with TBSOTf/2,6-lutidine to af-
ford the silyl ether 13.
Next, we investigated the stereoselective construction of the
spiroacetal moiety (Scheme 3). The ester 1410 was converted to
the iodide 15 through the two-step sequence; DIBALH reduction
and iodination. Treatment of 15 with allyltributylstannane and
AIBN gave the alkene 16 in 82% yield.11 Treatment of 16 with
mCPBA provided the epoxide 17 as a diastereomixture. The epox-
ide 17 reacted with the acetylide, prepared from 13 and n-BuLi,
to give the coupling product 18 in 75% yield.12 Hydrogenation of
18 followed by TPAP oxidation8 afforded the ketone 19. Deprotec-
tion of TBS groups and subsequent spiroacetalization were per-
formed by using catalytic CSA in MeOH to result in the formation
of the spiroacetal 20 as the sole product.13
With the spiroacetal 20 in hand, remaining task was the ster-
eoselective construction of the C93–C96 side chain (Scheme 4).
The alcohol 20 was converted to the triflate 21 by the standard
procedure in 89% yield. Coupling of 21 with the acetylide, de-
rived from the alkyne 2214 and n-BuLi, under the Kotsuki condi-
tions gave the desired product 23 in 83% yield.6 The TBDPS
group was removed with TBAF, and the resulting alcohol was
protected with TIPSCl/imidazole to give 24. The alkyne 24 was
* Corresponding authors. Tel.: +81 86 251 7839; fax: +81 86 251 7836.
E-mail address: takamura@cc.okayama-u.ac.jp (H. Takamura).
Present address. Faculty of Science and Technology, Keio University, 3-14-1
Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.078

H. Takamura et al. / Tetrahedron Letters 49 (2008) 4626–4629
4627
Figure 1. Structure of symbiodinolide (1).
Scheme 1. Retrosynthetic analysis of 2. P = protecting group.
subjected to the Birch reduction conditions to afford the trans-al-
kene 25, in which the benzyl protecting group was removed.15
Benzyl protection of 25 followed by removal of the TIPS group
gave the alcohol 26. Sharpless AD16 and subsequent selective
protection of the primary hydroxy group with TIPSCl resulted
in the formation of the desired C79–C96 fragment 2717,18 as a
single stereoisomer.
Table 1 shows the 1H NMR data of symbiodinolide (1)4 and syn-
thetic C79–C96 fragment 27. The chemical shifts for both com-
pounds are in excellent accordance. Thus, it can be said that the
proposed relative stereochemistries in C83–C95 moiety were
validated.
In conclusion, we have synthesized the C79–C96 fragment of 1
through the stereoselective spiroacetalization and Kotsuki cou-
pling as key steps. Further synthetic study and structural study
on 1 are underway in our laboratory.
Scheme 2. Reagents and conditions: (a) trimethylsilyl acetylene, n-BuLi, THF, ꢀ7-
8 °C; then 8, ꢀ78 °C, 92%; (b) TPAP, NMO, MS4A, CH2Cl2, rt, 72%; (c) 10, i-PrOH, rt,
98%, >99% ee; (d) K2CO3, MeOH, rt, 97%; (e) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, quant.

4628
H. Takamura et al. / Tetrahedron Letters 49 (2008) 4626–4629
Scheme 3. Reagents and conditions: (a) DIBALH, hexane, ꢀ78 °C, 77%; (b) I2, PPh3, imidazole, Et2O–CH3CN (3:1), reflux, 76%; (c) allyltributylstannane, AIBN, benzene, reflux,
82%; (d) mCPBA, CH2Cl2, 0 °C, 83%; (e) 13 (2.0 equiv), n-BuLi (2.2 equiv), THF, ꢀ78 °C; then BF3ꢁOEt2 (1.5 equiv), 17 (1.0 equiv), ꢀ78 °C, 75%; (f) H2, Pd-C, Et3N, EtOAc, rt, 95%;
(g) TPAP, NMO, MS4A, CH2Cl2, rt, 96%; (h) CSA, MeOH, rt, 96%.
Scheme 4. Reagents and conditions: (a) Tf2O, 2,6-lutidine, CH2Cl2, ꢀ78 °C, 89%; (b) 22 (2.5 equiv), n-BuLi (2.5 equiv), THF, ꢀ78 °C to 0 °C; then 21 (1.0 equiv), DMPU, ꢀ10 °C,
83%; (c) TBAF, THF, rt, 98%; (d) TIPSCl, imidazole, DMAP, DMF, rt, quant.; (e) Li, liq. NH3, t-BuOH, THF, ꢀ78 °C, 95%; (f) BnBr, NaH, TBAI, THF, 40 °C; (g) TBAF, THF, rt, 78% (two
steps); (h) AD-mix-b, CH3SO2NH2, t-BuOH–H2O (1:1), 0 °C to rt; (i) TIPSCl, imidazole, DMAP, CH2Cl2, rt, 51% (two steps), dr = >99:1.
Table 1
References and notes
Selected 1H NMR chemical shifts of symbiodinolide and synthetic fragment 27 in
CD3OD
1. (a) Uemura, D. In Bioorganic Marine Chemistry; Scheuer, P. J., Ed.; Springer:
Berlin Heidelberg, 1991; Vol. 4, pp 1–31; (b) Shimizu, Y. Chem. Rev. 1993, 93,
1685; (c) Uemura, D. Chem. Rec. 2006, 6, 235.
Position
Symbiodinolide
27
D
da
2. (a) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897; (b) Murata, M.;
Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293 and references cited therein.
3. For recent results, see: (a) Washida, K.; Koyama, T.; Yamada, K.; Kita, M.;
Uemura, D. Tetrahedron Lett. 2006, 47, 2521; (b) Kita, M.; Roy, M. C.; Siwu, E. R.
O.; Noma, I.; Takiguchi, T.; Itoh, M.; Yamada, K.; Koyama, T.; Iwashita, T.;
Uemura, D. Tetrahedron Lett. 2007, 48, 3423; (c) Kita, M.; Roy, M. C.; Siwu, E. R.
O.; Noma, I.; Takiguchi, T.; Yamada, K.; Koyama, T.; Iwashita, T.; Wakamiya, A.;
Uemura, D. Tetrahedron Lett. 2007, 48, 3429.
83
91
93
94
95
C95-Me
3.75
3.95
4.05
3.12
2.06
1.03
3.72
3.90
3.96
3.27
1.88
0.98
+0.03
+0.05
+0.09
ꢀ0.15
+0.18
+0.05
a
D
d = dsymbiodinolide ꢀ d27 in ppm.
4. Kita, M.; Ohishi, N.; Konishi, K.; Kondo, M.; Koyama, T.; Kitamura, M.; Yamada,
K.; Uemura, D. Tetrahedron 2007, 63, 6241.
5. Symbiodinolide (1) is a structural congener of zooxanthellatoxins. For the
structural elucidation of zooxanthellatoxins, see: (a) Nakamura, H.; Asari, T.;
Murai, A.; Kondo, T.; Yoshida, K.; Ohizumi, Y. J. Org. Chem. 1993, 58, 313; (b)
Asari, T.; Nakamura, H.; Murai, A.; Kan, Y. Tetrahedron Lett. 1993, 34, 4059; (c)
Nakamura, H.; Asari, T.; Murai, A.; Kan, Y.; Kondo, T.; Yoshida, K.; Ohizumi, Y. J.
Am. Chem. Soc. 1995, 117, 550; (d) Nakamura, H.; Asari, T.; Fujimaki, K.;
Maruyama, K.; Murai, A.; Ohizumi, Y.; Kan, Y. Tetrahedron Lett. 1995, 36, 7255;
(e) Nakamura, H.; Fujimaki, K.; Murai, A. Tetrahedron Lett. 1996, 37, 3153; (f)
Acknowledgment
This research was partially supported by Grant-in-Aid for Scien-
tific Research (19710184 and 16GS0206) from MEXT, Japan.

H. Takamura et al. / Tetrahedron Letters 49 (2008) 4626–4629
4629
Nakamura, H.; Sato, K.; Murai, A. Tetrahedron Lett. 1996, 37, 7267; (g)
Nakamura, H.; Takahashi, M.; Murai, A. Tetrahedron: Asymmetry 1998, 9,
2571; (h) Nakamura, H.; Maruyama, K.; Fujimaki, K.; Murai, A. Tetrahedron Lett.
2000, 41, 1927.
14. Trost, B. M.; Papillon, J. P. N.; Nussbaumer, T. J. Am. Chem. Soc. 2005, 127, 17921.
15. The structural confirmation of 25 was performed by observation of the
coupling constant (Ja,b = 15.2 Hz).
16. For a review of the Sharpless AD reaction, see: Kolb, H. C.; VanNieuwenhze, M.
S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
6. Kotsuki, H.; Kadota, I.; Ochi, M. Tetrahedron Lett. 1990, 31, 4609.
7. Chandrasekhar, S.; Vijeender, K.; Chandrashekar, G.; Raji Reddy, Ch.
Tetrahedron: Asymmetry 2007, 18, 2473.
8. For a review of TPAP oxidation, see: Ley, S. V.; Norman, J.; Griffith, W. P.;
Marsden, S. P. Synthesis 1994, 639.
9. Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119,
8738.
10. Yakura, T.; Ueki, A.; Kitamura, T.; Tanaka, K.; Nameki, M.; Ikeda, M. Tetrahedron
1999, 55, 7461.
17. The diol 27 was transformed to the mono-MTPA esters at C93 with MTPACl,
Et3N, and DMAP in CH2Cl2 at room temperature. The absolute stereochemistry
at C93 was confirmed to be R by Mosher method. The stereochemistry of C94
was determined to be R based on the reaction mechanism of the Sharpless AD
reaction.
18. Compound 27: Rf = 0.20 (hexane/EtOAc, 4:1); ½a D25
ꢂ
+18.1 (c 0.09, CHCl3); IR
(neat) 3465, 2938 cmꢀ1 1H NMR (400 MHz, CD3OD) d 7.31–7.24 (m, 5H), 4.48
;
(s, 2H), 3.96 (dt, J = 9.8, 2.7 Hz, 1H), 3.92–3.87 (m, 2H), 3.75–3.68 (m, 2H), 3.49
(t, J = 6.1 Hz, 2H), 3.27 (dd, J = 9.8, 2.7 Hz, 1H), 1.94–1.81 (m, 3H), 1.68–1.05 (m,
41H), 0.98 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CD3OD) d 140.0, 129.5, 128.9,
128.7, 97.2, 79.0, 74.0, 71.7, 70.5, 69.5, 67.3, 42.3, 40.1, 37.7, 36.9, 33.2, 32.8,
31.2, 23.8, 20.5, 20.2, 18.8, 18.8, 15.2, 13.4; HRMS (ESI TOF MS), calcd for
11. Hanessian, S.; Marcotte, S.; Machaalani, R.; Huang, G.; Pierron, J.; Loiseleur, O.
Tetrahedron 2006, 62, 5201.
12. Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
13. The spiroacetal 20 is thermodynamically the most stable due to the double
anomeric effect. The stereochemistry of 20 was determined by NOE
experiments as shown below. For the reviews of spiroacetals, see: (a) Perron,
F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617; (b) Aho, J. E.; Pihko, P. M.; Rissa, T. K.
Chem. Rev. 2005, 105, 4406.
C
35H62O6SiNa (M+Na)+: 629.4213, found: 629.4220.
83
O
NOE
H
H
91
OH
O
20