Determination of absolute configuration of C14-C23 fragment in symbiodinolide

Article abstract of DOI:10.1016/j.tetlet.2009.07.014

The degradation product C14-C23 2 was obtained using ethenolysis with the 2nd-generation Hoveyda-Grubbs catalyst from 62-membered lactone in symbiodinolide (1). The absolute configurations of three chiral centers in fragment 2 were assigned as 17R, 18R, a

Full text of DOI:10.1016/j.tetlet.2009.07.014

Tetrahedron Letters 50 (2009) 5280–5282
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Tetrahedron Letters
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Determination of absolute configuration of C14ÀC23 fragment
in symbiodinolide
Chunguang Han a, Yoshi Yamano a, Masaki Kita b, Hiroyoshi Takamura a, Daisuke Uemura a,c,
*
a Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8602, Japan
b Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8571, Japan
c Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, 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:
The degradation product C14ÀC23 2 was obtained using ethenolysis with the 2nd-generation Hoveyda-
Grubbs catalyst from 62-membered lactone in symbiodinolide (1). The absolute configurations of three
chiral centers in fragment 2 were assigned as 17R, 18R, and 21R by a combination of J-based configuration
analysis and the Mosher–Riguera method.
Received 18 May 2009
Revised 24 June 2009
Accepted 6 July 2009
Available online 9 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Ethenolysis
2nd-generation Hoveyda-Grubbs catalyst
Absolute configuration
J-based configuration analysis
Symbiodinolide (1), a unique super-carbon-chain compound
(SCC)1 with a molecular weight of 2860, was isolated from the Okin-
awan symbiotic dinoflagellate Symbiodinium sp. (Fig. 1). Recently, its
isolation, structure elucidation, and the partial stereochemistries
were reported.2 In our continuing investigation on the stereochem-
ical assignment of symbiodinolide (1), the absolute configurations of
three chiral centers (C17, C18, and C21) in degradation product 2
were assigned by a combination of J-based configuration analysis
(JBCA),3 ROESY correlations, and the Mosher–Riguera method.4
In the course of the further stereochemical analysis of symbio-
dinolide (1), the relative configurations between the vicinal stereo-
thro configuration B-3 was finally assigned on the basis of the
crucial ROESY correlations for C18-Me/H15 (Fig. 2). The relative
configurations of vicinal centers C17 and C18 were concluded as
shown in Figure 3.
However, the stereochemical assignment of the other stereo-
centers in the 62-membered polyunsaturated lactone of 1 could
not be completed by spectral analysis due to that the signals are
largely overlapping. Thereby, the chemical degradation reaction
was essential for symbiodinolide (1). Ethenolysis5 (cross-metathe-
sis with ethene) is an attractive alternative to ozonolysis and per-
iodate oxidation of alkenes because of its wide functional group
tolerance, comparatively mild reaction conditions and the de-
graded products without redundant modification. Here, we carried
out an effective ethenolysis with the commercially available 2nd-
generation Hoveyda-Grubbs (Hoveyda-Grubbs II) catalyst6 under
ordinary ethene pressure (balloon) at room temperature as
described before.7 As a result, an acetal C14ÀC23 2 and two other
terminal olefin degradation products (in small amounts, respec-
tively) were successfully obtained from the 62-membered polyun-
saturated lactone (Scheme 1). The structure of C14ÀC23 fragment
2 was confirmed by the analysis of 1H NMR, COSY correlations, and
HR MS.8
centers C17 and C18 were determined by J-based configuration
1
analysis. Two- and three-bond 13CÀ H coupling constants (2,3JC,H
)
3
of symbiodinolide were measured in CD3OD. The small JC19/H17
values (1.1 Hz) indicated that C19 is gauche to H17, and the gem-
1
inal 13CÀ H coupling constants (2JC,H) also provide conformational
information (when an oxygen functionality on a carbon atom is
2
gauche to its geminal proton, JC,H becomes large, and when it is
2
anti, the value becomes small), so the large JC17/H18 values
(5.5 Hz) identified that 17ÀOH is gauche to H18. Thereby, three
possible conformers A-3 (threo), B-1, and B-3 (erythro) can be iden-
tified in Figure 2.
The ROESY correlations for C18-Me/H17 in symbiodinolide indi-
cated gauche relations for C18-Me and H17 in two conformers A-3
and B-3. Because of anti-relations for C18-Me and H15 in A-3, ery-
The absolute configurations at two chiral centers (C17 and C21)
of 1,5-diol 2 could be determined using the Mosher–Riguera meth-
od. A trace diol 2 (ꢀ 0.1 mg) was dissolved in 2% DMAP solution in
CH2Cl2, and then added Et3N, and (R)-(À)- or (S)-(+)-MTPACl. The
mixture was stirred at room temperature for 21 h. After the
addition of N,N-dimethyl-1,3-propanediamine, the solvent was
* Corresponding author. Tel./fax: +81 45 566 1842.
E-mail address: uemura@bio.keio.ac.jp (D. Uemura).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.014

C. Han et al. / Tetrahedron Letters 50 (2009) 5280–5282
OH OH OH
5281
O
O
23
14
OH
HO
HO
OH
OH
OH
OH
OSO3Na
OH
HO
OH OH
1
O
O
61
OH OH
OH OH
OH
HO
HO
OH
OH
OH
O
O
O
OH OH OH
OH
OH
OH
OH
HO
H
O
HO
104
OH
O
NH OH
OH
OH
1'
O
25'
OH
HO
OH OH
OH
OH
1
Figure 1. Structure of symbiodinolide (1) with the absolute configurations (17R, 18R, and 21R) in fragment 2 determined in the present study.
15
17
16
18
19
2,3
Figure 2.
C18 of 1.
J
values were used to assign the relative configurations of C17 and
C,H
18Me
20
evaporated in vacuo. The residue was purified through a silica gel
column, and then HPLC [Develosil ODS-HG-5 (Ø 10 Â 250 mm),
Nomura Chemical, flow rate 4 ml/min, 80–100% aq MeCN,
40 min, linear gradient] to afford a trace amount of bis-(S)- and
(R)-MTPA esters 2s9 and 2r10 of 2, respectively. The 1H NMR data
for two bis-MTPA derivatives are assigned by the analysis of COSY
Figure 3. ROESY correlations (black) between C18-Me/H17 and H15 in 3D model.
correlations.
D
d values (
D
d = dS À dR) obtained from the 1H NMR
C21 possessed R- and R-configurations, respectively. Therefore, the
absolute configurations of C14ÀC23 2 were assigned as 17R, 18R,
and 21R.
In conclusion, an erythro configuration was assigned between
the vicinal centers C17 and C18 in 62-membered lactone of
data of 2s and 2r showed positive signs for H21 (+0.03), H22
(+0.05), H23 (+0.12), and H24 (+0.09), and negative signs for H17
(À0.06), H16 (À0.11), H15 (À0.08), and H14 (À0.03) shown in
Figure 4. These results were consistent with the syn-1,5-diols noted
by Riguera for acyclic systems (Fig. 5).4,5b Thus, suggesting C17 and
MesN NMes
Cl
Ru
Cl
O
OH
OH
Hoveyda-
23
Grubbs II
(5 equiv.)
14
MeO
Symbiodinolide (1)
MeOH/DCM (3/1), 24 h, RT
CH2=CH2
OMe
fragment C14−C23 2, and
two other fragments
Scheme 1. C14ÀC23 fragment 2 obtained by olefin cross-metathesis with ethene.

5282
C. Han et al. / Tetrahedron Letters 50 (2009) 5280–5282
OR
OR
Acknowledgments
-0.06
-0.08
+0.12
-0.03
-0.02
MeO
This work was supported in part by a Grant-in-Aid for Creative
-0.06
+0.03
-0.07
+0.05
-0.11
+0.09
Scientific Research (16GS0206) from JSPS, and G-COE program in
chemistry at Nagoya University from the Ministry of Education,
Science, Sports and Culture, Japan.
OMe
Me +0.02
2s, R = (S)-MTPA
2r, R = (R)-MTPA
References and notes
Figure 4.
DdS–R values for the bis-MTPA derivatives of 2.
1. (a) Uemura, D.. In Bioorganic Marine Chemistry; Scheuer, P. J., Ed.; Springer:
Berlin, Heidelberg, 1991; Vol. 4, p 1; (b) Uemura, D. Chem. Rec. 2006, 6, 235; (c)
Uemura, D.; Kita, M.; Arimoto, H.; Kitamura, M. Pure Appl. Chem. 2009, 81, 1093.
2. Kita, M.; Ohishi, N.; Konishi, K.; Kondo, M.; Koyama, T.; Kitamura, M.; Yamada,
K.; Uemura, D. Tetrahedron 2007, 63, 6241.
3. Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.; Tachibana, K. J. Org.
Chem. 1999, 64, 866.
OMTPA
OMTPA
OMTPA
OMTPA
ˇ
4. Freire, F.; Manuel, J.; Quiná, E.; Riguera, R. J. Org. Chem. 2005, 70, 3778.
+
−
−
+
?
?
?
5. (a) Grubbs, R. H. Tetrahedron 2004, 60, 7117; (b) Williams, P. G.; Miller, E. D.;
Asolkar, R. N.; Jensen, P. R.; Fenical, W. J. Org. Chem. 2007, 72, 5025; (c) Mol, J.
C.; Buffon, R. J. Braz. Chem. Soc. 1998, 9, 1.
R2
−
R2
+
R1
+
R1
−
?
?
?
6. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 8168.
OMTPA
OMTPA
OMTPA
OMTPA
7. Han, C.; Uemura, D. Tetrahedron Lett. 2008, 49, 6988.
8. C14ÀC23 fragment 2: 1H NMR (800 MHz, CDCL3) d 5.86 (dd, J = 6.4, 15.8 Hz, 1H,
H16), 5.80 (m, 1H, H23), 5.68 (dd, J = 4.6, 15.8 Hz, 1H, H15), 5.61 (m, 2H, H19
and H20), 5.14 (m, 2H, C23CH2), 4.81 (d, J = 4.6 Hz, 1H, H14), 4.18 (m, 1H, H21),
3.96 (m, 1H, H17), 3.33 and 3.32 (s, 6H, C14-OMe  2), 2.34 and 2.31 (m, 3H,
H18 and H22a,b), 1.03 (d, J = 6.9 Hz, 1H, C18-Me); HR ESI-TOF-MS m/z
279.1579 (M+Na)+, calcd for C14H24O4Na: 279.1572.
−
−
−
−
+
+
+
+
R2
R1
?
R2
R1
−
+
?
?
?
Figure 5. Preditive
D
dS–R (+ or À) patterns for the bis-MTPA esters of acyclic
9. C14ÀC23 fragment bis-(S)-MTPA ester (2s): 1H NMR (800 MHz, CDCl3) d 7.50
(m, 4H, Ph), 7.39 (m, 6H, Ph), 5.70 (m, 1H, H23), 5.68 (dd, J = 5.5, 15.8 Hz, 1H,
H16), 5.64 (dd, J = 4.1, 15.8 Hz, 1H, H15), 5.63 (dd, J = 7.8, 15.2 Hz, 1H, H19),
5.46 (m, 2H, H20 and H21), 5.34 (t, J = 5.5 Hz, 1H, H17), 5.10 (m, 2H, C23CH2),
4.74 (d, J = 4.1 Hz, 1H, H14), 3.50 and 3.53 (s, 6H, C14-OMe  2), 2.54 (m, 1H,
H18), 2.39 and 2.43 (m, 2H, H22a,b), 0.97 (d, J = 6.9 Hz, 3H, C18-Me); HR ESI-
TOF-MS m/z 711.2262 (M+Na)+, calcd for C34H38F6O8Na: 711.2369.
10. C14ÀC23 fragment bis-(R)-MTPA ester (2r): 1H NMR (800 MHz, CDCl3) d 7.49
(m, 4H, Ph), 7.38 (m, 6H, Ph), 5.79 (dd, J = 5.5, 15.6 Hz, 1H, H16), 5.72 (dd,
J = 4.2, 15.6 Hz, 1H, H15), 5.70 (dd, J = 7.8, 15.6 Hz, 1H, H19), 5.59 (m, 1H, H23),
5.53 (dd, J = 7.4, 15.6 Hz, 1H, H20), 5.44 (m, 1H, H21), 5.40 (t, J = 5.5 Hz, 1H,
H17), 5.01 (m, 2H, C23CH2), 4.77 (d, J = 4.2 Hz, 1H, H14), 3.50 and 3.53 (s, 6H,
C14-OMe  2), 2.56 (m, 1H, H18), 2.33 and 2.37 (m, 2H, H22a,b), 0.95 (d,
J = 7.4 Hz, 3H, C18-Me); HR ESI-TOF-MS m/z 711.2341 (M+Na)+, calcd for
C34H38F6O8Na: 711.2369.
1,5-diols.
symbiodinolide (1) on the basis of J-based configuration analysis
and ROESY correlations. Using ethenolysis with Hoveyda-Grubbs
II catalyst, a degradation product C14ÀC23 2 was obtained from
1, and the absolute configurations of three chiral centers in 2 were
assigned as 17R, 18R, and 21R by the Mosher–Riguera method.
Further chemical degradation studies in order to obtain the new
fragments and a complete assignment of the absolute stereochem-
istry of symbiodinolide are currently underway.