Synthesis and structural determination of the C33-C42 fragment of symbiodinolide

Article abstract of DOI:10.1016/j.tetlet.2008.11.056

Symbiodinolide (1) is a polyol macrolide with a molecular weight of 2859 mu. As one of the degradation reactions, cross-metathesis of 2, which is a methyl ester of 1, with ethylene was performed to give the C33-C42 degraded fragment 4. The absolute config

Full text of DOI:10.1016/j.tetlet.2008.11.056

Tetrahedron Letters 50 (2009) 863–866
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and structural determination of the C33–C42
fragment of symbiodinolide
a
b
b
Hiroyoshi Takamura a, , Yuichiro Kadonaga , Yoshi Yamano , Chunguang Han ,
*
Yoko Aoyama b, Isao Kadota a, , Daisuke Uemura
b,c
*
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
c Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Symbiodinolide (1) is a polyol macrolide with a molecular weight of 2859 mu. As one of the degradation
reactions, cross-metathesis of 2, which is a methyl ester of 1, with ethylene was performed to give the
C33–C42 degraded fragment 4. The absolute configuration of 4 was estimated to be (36S,40S) by Mosher
method. Stereoselective synthesis of 4 was achieved in 14 steps from L-aspartic acid. Synthetic bis-(S)-
and (R)-MTPA esters exhibited the spectroscopic data identical with those of bis-(S)- and (R)-MTPA esters
Received 20 October 2008
Revised 14 November 2008
Accepted 17 November 2008
Available online 20 November 2008
derived from the degraded fragment 4. Thus, the absolute stereochemistry of 4 was elucidated to be
(36S,40S).
Keywords:
Polyol macrolide
Symbiodinolide
Ó 2009 Published by Elsevier Ltd.
Absolute configuration
Cross-metathesis degradation
Chemical synthesis
Symbiodinolide (1), isolated from the marine dinoflagellate
Symbiodinium sp. in 2007, is a polyol macrolide with a molecular
weight of 2859 mu which exhibits a voltage-dependant N-type
Ca2+ channel-opening activity at 7 nM and COX-1 inhibitory effect
at 2 nM.1,2 The planar structure and partial stereochemistry of 1
were elucidated by spectroscopic analysis1 and chemical synthe-
sis.3 Herein, we describe the structural elucidation and stereocon-
trolled synthesis of the C33–C42 fragment 4, a degraded product
obtained from 1, as a part of structural analysis and synthetic study
of 1 (Fig. 1).
Olefin cross-metathesis is utilized as one of the efficient degra-
dation methods of natural products.1,4 In order to obtain the de-
graded product of 1, we carried out cross-metathesis with
ethylene. Thus, treatment of 1 with Et3N in MeOH provided the
methyl ester 2, which was then subjected to cross-metathesis with
ethylene using Hoveyda-Grubbs 2nd generation catalyst 35 to give
the C33–C42 fragment 4 as one of the degraded products (Scheme
1).6 The planar structure of 4 was confirmed by the analyses of 2D
sponding bis-(S)- and (R)-MTPA esters derived from 4 by the stan-
dard procedures (MTPACl/Et3N/DMAP).9 The signs at the C33, C34,
and C35 positions showed negative, and those of the C41 and C42
positions exhibited positive. Therefore, we assigned the absolute
configuration of 4 to be (36S,40S) as shown in Figure 2.
We next examined the stereocontrolled synthesis of (36S,40S)-
diol 4 to confirm the assigned absolute structure (Scheme 2). The
synthesis started from L-aspartic acid which was converted to
(R)-epoxide 5 by the known procedure.10 The epoxide 5 was re-
acted with lithium acetylide, prepared from ethyl propiolate and
n-BuLi, to give homopropargylic alcohol 6 in 96% yield.11,12 The
alcohol 6 was protected with TBSOTf/2,6-lutidine to yield the bis-
TBS ether 7. Conjugate addition of the thiolate anion, derived from
thiophenol and NaOMe, provided (Z)-
Thioether 8 was reacted with MeMgBr and CuI to give (E)-
a
,b-unsaturated ester 8.
,b-
a
unsaturated ester 9 with complete retention of the olefinic config-
uration.13 The observed NOE between H-37 and H-39 clearly indi-
cates the (E)-configuration of 9. Reduction of the ester 9 with
NMR spectra and HR-ESIMS [m/z 205.1206,
D
+0.2 mmu for
DIBALH followed by Parikh–Doering oxidation14 gave
a,b-unsatu-
(M+Na)+].
rated aldehyde 10. The aldehyde 10 was subjected to asymmetric
allylation developed by Keck et al.15 to give homoallylic alcohol
11 in 41% yield (91% based on recovered starting material) with
82% diastereomeric excess (de).16 Protection of the alcohol 11 with
TBDPSCl/imidazole followed by selective deprotection of the TBS
moiety provided alcohol 12. Treatment of 12 with o-nitrophenyl
The absolute stereochemistry of 4 was determined by Mosher
method.7,8 Figure 2 shows the selected
D
dS–R values of the corre-
* Corresponding authors. Tel.: +81 86 251 7839; fax: +81 86 251 7836 (H.T.).
E-mail address: takamura@cc.okayama-u.ac.jp (H. Takamura).
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.11.056

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H. Takamura et al. / Tetrahedron Letters 50 (2009) 863–866
Figure 1. Structure of symbiodinolide (1).
Scheme 1. Cross-metathesis degradation with ethylene.
Figure 2. Chemical shift differences (DdS–R) of bis-MTPA esters derived from 4.
R = MTPA. MTPA = a-methoxy-a-(trifluoromethyl)phenylacetyl.
selenocyanate/n-Bu3P/pyridine followed by oxidative workup
afforded alkene 13.17 Removal of the silyl protecting groups with
TBAF provided the diol 4. The 1H NMR spectrum of the synthetic
4 was identical with that of the degraded product 4 obtained from
1.18
Furthermore, to confirm the absolute stereochemistries at C36
and C40 positions of the degraded product 4, we prepared the
bis-(S)- and (R)-MTPA esters from the synthetic 4, and
compared the spectroscopic data of the synthetic MTPA esters with
those of the MTPA esters derived from natural 1. As shown in
Figure 3, the spectra of the synthetic bis-MTPA esters are identical
with those of the bis-MTPA esters derived from the degraded
product 4 (a to b, c to d), respectively. Therefore, we concluded
that the absolute configuration of the C33–C42 fragment was
(36S,40S).
Scheme 2. Reagents and conditions: (a) ethyl propiolate, n-BuLi, THF, ꢀ78 °C, then
BF3ꢁOEt2, 5, ꢀ78 °C to 0 °C, 96%; (b) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 78%; (c) PhSH,
NaOMe, MeOH, rt; (d) MeMgBr, CuI, THF, ꢀ78 °C to rt; (e) DIBALH, CH2Cl2, ꢀ78 °C,
77% (3 steps); (f) SO3ꢁpyr, Et3N, DMSO, CH2Cl2, 0 °C, 94%; (g) allyltributylstannane,
Ti(Oi-Pr)4, (S)-BINOL, CF3SO3H, MS4A, CH2Cl2, ꢀ78 °C to ꢀ20 °C, 41% (91% based on
recovered starting material), 82% de; (h) TBDPSCl, imidazole, CH2Cl2, rt, 95%; (i) CSA,
CH2Cl2–MeOH (2:1), 0 °C, 56%; (j) o-NO2PhSeCN, n-Bu3P, pyridine, THF, rt, then H2O2,
rt; (k) TBAF, THF, 40 °C, 65% (2 steps). BINOL = 1,10-bi-2,20-naphthol, CSA =
camphorsulfonic acid, DIBALH = diisobutylaluminum hydride, DMAP = 4-dimethyl-
aminopyridine, DMSO = dimethyl sulfoxide, TBAF = tetrabutylammonium fluoride.

H. Takamura et al. / Tetrahedron Letters 50 (2009) 863–866
865
Figure 3. 800 MHz 1H NMR spectra of bis-MTPA esters in CDCl3: (a) bis-(S)-MTPA ester derived from natural 1, (b) synthetic bis-(S)-MTPA ester, (c) bis-(R)-MTPA ester
derived from natural 1, (d) synthetic bis-(R)-MTPA ester.
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)
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.
In conclusion, we obtained the C33–C42 fragment 4 by cross-
metathesis degradation of 2 with ethylene. The absolute stereo-
chemistry of 4 was estimated by Mosher method. The proposed
structure including absolute configuration was unambiguously
confirmed by the enantio- and stereocontrolled synthesis of 4 in
14 steps from L-aspartic acid. Further structural and synthetic stud-
ies on 1 are underway in our laboratories.
3. Takamura, H.; Ando, J.; Abe, T.; Murata, T.; Kadota, I.; Uemura, D. Tetrahedron
Lett. 2008, 49, 4626.
4. For some examples of the degradation of natural products by cross-metathesis,
see: (a) Ratnayake, A. S.; Hemscheidt, T. Org. Lett. 2002, 4, 4667; (b) Niggemann,
J.; Bedorf, N.; Flörke, U.; Steinmetz, H.; Gerth, K.; Reichenbach, H.; Höfle, G. Eur.
J. Org. Chem. 2005, 5013; (c) Williams, P. G.; Miller, E. D.; Asolkar, R. N.; Jensen,
P. R.; Fenical, W. J. Org. Chem. 2007, 72, 5025.
5. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 8168.
6. Structural determination of other degraded products obtained by cross-
metathesis will be reported in the near future.
Acknowledgments
We thank Okayama Foundation for Science and Technology and
The Naito Foundation for their financial supports. This research
was partially supported by Grant-in-Aid for Scientific Research
from MEXT, Japan.
7. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092.
References and notes
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9. Bis-(S)-MTPA ester: 1H NMR (800 MHz, CDCl3) d 7.50 (m, 4H, Ph), 7.39 (m, 6H,
Ph), 5.76 (ddd, J = 17.0, 10.6, 7.3 Hz, 1H, H41), 5.68 (dt, J = 8.7, 6.4 Hz, 1H, H36),
5.58 (m, 1H, H34), 5.56 (m, 1H, H40), 5.33 (d, J = 17.0 Hz, 1H, H42a), 5.24 (d,
J = 10.6 Hz, 1H, H42b), 5.23 (m, 1H, H37), 5.01 (dt, J = 17.0, 1.4 Hz, 1H, H33a),
5.00 (m, 1H, H33b), 3.53 (s, 3H, OCH3), 3.52 (s, 3H, OCH3), 2.45 (dd, J = 13.3,
6.0 Hz, 1H, H39a), 2.36 (m, 1H, H35a), 2.31 (dd, J = 13.3, 7.8 Hz, 1H, H39b), 2.26
2. Symbiodinolide (1) is a structural congener of zooxanthellatoxins which are
polyol macrolides isolated from the dinoflagellate Symbiodinium sp. 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)
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866
H. Takamura et al. / Tetrahedron Letters 50 (2009) 863–866
(m, 1H, H35b), 1.71 (d, J = 1.4 Hz, 3H, C38-CH3). Bis-(R)-MTPA ester: 1H NMR
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16. Absolute stereochemistry of the resulting chiral center in the allylation of 10
was determined by Mosher method.
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18. The diol possessing (36R,40S) absolute stereochemistry was synthesized from
the aldehyde 10. The 1H NMR spectrum of (36R,40S)-diol was different from
that of the degraded product 4. Details will be discussed in the full account.
(800 MHz, CDCl3) d 7.48 (m, 4H, Ph), 7.39 (m, 6H, Ph), 5.70 (m, 1H, H36), 5.69
(m, 1H, H34), 5.64 (m, 1H, H41), 5.53 (m, 1H, H40), 5.22 (d, J = 17.0 Hz, 1H,
H42a), 5.17 (d, J = 10.1 Hz, 1H, H42b), 5.17 (m, 1H, H37), 5.10 (d, J = 17.5 Hz, 1H,
H33a), 5.09 (d, J = 10.6 Hz, 1H, H33b), 3.52 (s, 3H, OCH3), 3.51 (s, 3H, OCH3),
2.48 (dd, J = 14.7, 6.4 Hz, 1H, H39a), 2.45 (dd, J = 14.7, 6.9 Hz, 1H, H35a), 2.34
(m, 1H, H35b), 2.34 (m, 1H, H39b), 1.77 (d, J = 1.4 Hz, 3H, C38-CH3).
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12. Absolute stereochemistry of 6 was confirmed by Mosher method.