Stereochemical assignment of topsentolide C2 by stereodivergent synthesis of its four diastereomers

Article abstract of DOI:10.1016/j.tetlet.2013.10.032

Four diastereomers of topsentolide C₂, a cytotoxic 9-membered lactone isolated from the marine sponge Topsentia sp., were synthesized stereodivergently from a common chiral seco acid by the combined use of the Yamaguchi and Mitsunobu lactonizations. Comparison of the NMR spectra of the four diastereomers with those of an authentic sample of topsentolide C₂ led to the stereochemical determination of topsentolide C₂ as 8R, 11S and 12S.

Full text of DOI:10.1016/j.tetlet.2013.10.032

Tetrahedron Letters 54 (2013) 6878–6881
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Tetrahedron Letters
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Stereochemical assignment of topsentolide C2 by stereodivergent
synthesis of its four diastereomers
⇑
Ryo Towada, Yusuke Kurashina, Shigefumi Kuwahara
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Four diastereomers of topsentolide C2, a cytotoxic nine-membered lactone isolated from the marine
sponge Topsentia sp., were synthesized stereodivergently from a common chiral seco acid by the com-
bined use of the Yamaguchi and Mitsunobu lactonizations. Comparison of the NMR spectra of the four
diastereomers with those of an authentic sample of topsentolide C2 led to the stereochemical determina-
tion of topsentolide C2 as 8R, 11S, and 12S.
Received 4 September 2013
Revised 1 October 2013
Accepted 7 October 2013
Available online 14 October 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Topsentolide
Oxylipin
Cytotoxic
Total synthesis
Lactonization
OMe
12
Topsentolide C2 is a cytotoxic oxylipin isolated, together with
six other congeners (topsentolides A1, A2, B1, B2, B3, and C1), by Jung
and co-workers from the marine sponge Topsentia sp.1,2 The struc-
ture of topsentolide C2 was proposed as A (Fig. 1) on the basis of
extensive spectroscopic analyses including the modified Mosher
method to determine its 12S stereochemistry, coupled with the
assumption that it would share the same S configuration at the
C8 stereocenter as structurally related natural fatty acid lactones
(halicholactone and neohalicholactone),3 although the stereo-
chemistry at the C11 position was left unassigned because of the
paucity of the isolated material. The naturally rare nine-membered
lactone unit embedded in common in the topsentolides and their
significant cytotoxicity against five human solid tumor cell lines
11
O
O
8
S
O
O
S
OH
A
O
R
S
R
B
Figure 1. Structure of topsentolide C2 (A) proposed by Jung et al. and the absolute
stereochemistry of topsentolide A1; (B) determined by Watanabe et al.
(ED50 = 2.0–17.5 lg/mL) have attracted considerable attention
Mosher method, its stereochemistry should be represented by
one of the four structures, 1, 8-epi-1, 11-epi-1, and 8,11-bis-epi-1
(Fig. 2). The synthesis of the four diastereomers and comparison
of their NMR data (or other physicochemical properties) with those
of topsentolide C2 would, therefore, give a decisive answer con-
cerning the stereochemistry of topsentolide C2. From a viewpoint
of accessibility, however, we chose to synthesize 8,12-bis-epi-1
and 12-epi-1 together with 1 and 8-epi-1, since 8,12-bis-epi-1
and 12-epi-1 are enantiomeric to 11-epi-1 and 8,11-bis-epi-1,
respectively, and therefore should provide the same NMR informa-
tion as the latter two isomers. As part of our ongoing efforts toward
the total synthesis of oxylipins8 as well as to unequivocally eluci-
date the stereochemistry of topsentolide C2, we conducted a ste-
reodivergent synthesis of 1, 8-epi-1, 8,12-bis-epi-1, and 12-epi-1.
Scheme 1 outlines our synthetic plan for the targeted four dia-
stereomers. We envisaged that 1 and 8-epi-1 would be obtainable
from organic chemists, and five synthetic studies on topsentolides
have been reported so far.4–7 Among them, the one disclosed by
Watanabe and co-workers led to the determination of the stereo-
chemistry of topsentolide A1 to be 8R, 11R, and 12S (structure B
in Fig. 1) through comparison of the 1H NMR spectra and specific
rotations of two stereoisomers of B with those of natural topsento-
lide A1.4 This Letter made us suspect that the genuine stereochem-
istry at the C8 position of topsentolide C2 might also be R, instead
of S as originally proposed by Jung and co-workers on the basis of
analogy with halicholactone and neohalicholactone.1,3
Since the absolute configuration at the C12 position of topsen-
tolide C2 was unambiguously determined to be S by the modified
⇑
Corresponding author. Tel./fax: +81 22 717 8783.
E-mail address: skuwahar@biochem.tohoku.ac.jp (S. Kuwahara).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.032

R. Towada et al. / Tetrahedron Letters 54 (2013) 6878–6881
6879
OMe
OMe
c
d
X
O
O
O
O
O
O
R
R
O
O
R
O
O
Et
CO2Me
Et
Et
OH
OH
Et
6
5a: X = OH
5b: X = I
5c: X = PPh3įI
a
b
1
8-epi-1
[(8S,11S,12S)-A]
[(8R,11S,12S)-A]
CHO
OTBS
g
OR1
OMe
O
OMe
O
OR2
R
CO2Me
CO2Me
OH
OH
3
7a: R1 = R2 = H
e
f
7b: R1 = R2 = TBS
7c: R1 = H, R2 = TBS
11-epi-1
8,11-bis-epi-1
[(8S,11R,12S)-A]
[(8R,11R,12S)-A]
Scheme 2. Preparation of 3. Reagents and conditions: (a) I2, Ph3P, Imid, CH2Cl2, 0 °C,
8 h; (b) Ph3P, MeCN, rt, 14 h, 82% from 5a; (c) NaHMDS, methyl 5-oxopentanoate,
THF, ꢁ78 °C to rt, 12 h, 70%; (d) TsOHꢀH2O, MeOH, reflux, 14 h, 96%; (e) TBSCl, Imid,
DMF, 0 °C, 2 h, 98%; (f) HFꢀPy, THF/Py, 0 °C to rt, 7 h, 75%; (g) (COCl)2, DMSO, Et3N,
CH2Cl2, ꢁ78 to ꢁ30 °C, 3 h, 94%.
R = (Z)-2-octenyl
OMe
OMe
O
O
O
R
O
R
OH
OH
The other coupling partner 4 in the Horner–Wadsworth–
Emmons reaction was obtained from known iodide 98b,11 by a
four-step sequence shown in Scheme 3. The Evans asymmetric
alkylation of 88b,12 with 9 gave 10 as an 15:1 mixture of diastereo-
mers, from which pure 10 was isolated in 62% yield by SiO2 column
chromatography. Hydrolytic removal of the chiral auxiliary in 10
and subsequent Weinreb amide formation from the resulting
carboxylic acid 11a afforded 11b, which was then treated with
dimethyl lithiomethylphosphonate to furnish 4.
8,12-bis-epi-1
[(8R,11S,12R)-A]
12-epi-1
[(8S,11S,12R)-A]
Figure 2. Stereoisomers of topsentolide C2.
OMe
OMe
O
O
O
R
O
R
OH
OH
With the two building blocks, 3 and 4, in hand, we proceeded to
the final stage of our stereodivergent synthesis of the four diaste-
reomers of topsentolide C2 (Scheme 4). The E-selective Horner–
1
2
12-epi-1
Wadsworth–Emmons reaction between
3 and 4 under the
R = (Z)-2-octenyl
Yamaguchi
Roush–Masamune conditions gave 12 in 86% yield;13 none of the
corresponding Z isomer could be detected by NMR analysis. Reduc-
tion of 12 under Luche’s conditions proceeded highly diastereose-
lectively,8b furnishing Felkin–Ahn product 13a in 85% isolated
yield. O-Methylation of the alcohol 13a followed by removal of
the TBS group of the resulting methyl ether 13b gave ester 13c,
which was then saponified with aqueous LiOH to afford seco acid
2. The Yamaguchi lactonization of 2 followed by deprotection of
the PMB group took place uneventfully, giving nine-membered lac-
tone 1 in 90% yield for the two steps. Subjection of the alcohol 1 to
the Mitsunobu inversion conditions using p-nitrobenzoic acid as a
nucleophile gave a p-nitrobenzoate intermediate, albeit in a mod-
est yield of 34% probably due to the elimination of H2O to generate
undesired tetraene lactones, as judged by 1H NMR analysis. Meth-
anolysis of the benzoate intermediate furnished 12-epi-1 in 63%
yield along with the starting benzoate recovered in 34% yield.
The Mitsunobu lactonization of 2, on the other hand, afforded
8-epi-1 in 56% yield, after removal of the PMB group. Finally,
CHO
OTBS
lactonization
OMe
R
CO2Me
3
+
OH PMBO
O
O
CO2H
(MeO)2P
R
PMBO
4
Mitsunobu
lactonization
OMe
OMe
O
O
O
R
O
R
OH
OH
8-epi-1
8,12-bis-epi-1
Scheme 1. Retrosynthetic analysis of 1, 8-epi-1, 12-epi-1, and 8,12-bis-epi-1.
by the Yamaguchi and Mitsunobu lactonization, respectively, from
common seco acid 2. Subjection of 1 and 8-epi-1 to the Mitsunobu
inversion reaction would then provide 12-epi-1 and 8,12-bis-epi-1,
respectively. The common hydroxy acid intermediate 2 should
readily be prepared from aldehyde 3 and phosphonate 4 via the
Horner–Wadsworth–Emmons olefination.
The preparation of the aldehyde intermediate 3 began with the
conversion of known protected alcohol 5a9 into the corresponding
phosphonium ion 5c via iodide 5b in 82% yield for the two steps
(Scheme 2). The Wittig reaction of 5c with methyl 5-oxopentano-
ate afforded Z-olefin 6; the corresponding E isomer was not de-
tected by NMR analysis. Deprotection of the acetal group of 6
followed by bis-TBS protection of the resulting diol 7a gave 7b,
the treatment of which with HFꢀPy in THFꢀPy effected selective
unmasking of the primary hydroxy group,10 furnishing 7c. Finally,
exposure of 7c to the Swern oxidation conditions afforded 3.
O
I
O
O
O
a
O
N
+
O
N
OPMB
O
OPMB
Bn
Bn
8
9
10
O
O
b
d
(MeO)2P
X
OPMB
11a: X = OH
11b: X = NMe(OMe)
PMBO
4
c
Scheme 3. Preparation of 4. Reagents and conditions: (a) NaHMDS, THF, ꢁ78 °C,
19 h, 62%; (b) LiOOH, THF/H2O, 0 °C to rt, 3 h; (c) NHMe(OMe)ꢀHCl, DCC, DMAP,
CH2Cl2, 0 °C to rt, 4 h, 80% from 10; (d) MePO(OMe)2, n-BuLi, THF, ꢁ78 °C, 6 h, 87%.

6880
R. Towada et al. / Tetrahedron Letters 54 (2013) 6878–6881
O
topsentolide C2 was more similar to that of 8-epi-1 rather than 1
(see Supplementary data). As a whole, we led to the conclusion
that the absolute stereochemistry of topsentolide C2 should be
represented by structure 8-epi-1.15,16
In conclusion, four diastereomers of topsentolide C2 (1, 8-epi-1,
12-epi-1, and 8,12-bis-epi-1) were synthesized stereodivergently
from the common chiral seco acid 2 by the combined use of the
Yamaguchi and Mitsunobu lactonizations. Comparison of the
NMR spectra of the four diastereomers with those of topsentolide
C2 indicated that the absolute stereochemistry of topsentolide C2
should be represented by structure 8-epi-1 [(8R,11S,12S)-isomer].
a
b
3 + 4
OTBS
12
OPMB
CO2Me
OR1
OR3
OPMB
CO2R2
13a: R1 = H, R2 = Me, R3 = TBS
13b: R1 = R2 = Me, R3 = TBS
13c: R1 = R2 = Me, R3 = H
e
c
d
OMe
Acknowledgements
OH
OPMB
CO2H
2
f, g
We are grateful to Professor Jung (Pusan National University)
for providing a copy of the 1H NMR spectrum of topsentolide C2.
We also thank Assistant Professor Hitosugi (Tohoku University)
for his help in the measurement of NMR spectra. This work was
supported, in part, by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Culture, Sports, Science and Technology
of Japan (No. 24658105).
OMe
O
O
j, k
OMe
O
OH
O
O
O
1
OH
h, i
OMe
8-epi-1
Supplementary data
O
l, m
OH
12-epi-1
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
10.032. These data include MOL files and InChiKeys of the most
important compounds described in this article.
OMe
O
OH
8,12-bis-epi-1
References and notes
Scheme 4. Synthesis of four diastereomers of topsentolide C2: Reagents and
conditions: (a) Et3N, LiBr, THF, rt, 23 h, 86%; (b) NaBH4, CeCl3ꢀ7H2O, MeOH, ꢁ78 °C,
1 h, 85%; (c) NaHMDS, MeI, THF, ꢁ78 °C to rt, 24 h, 83%; (d) TBAF, THF, 0 °C, 6 h,
98%; (e) LiOHꢀH2O, THF/H2O, rt to 40 °C, 12 h, quant; (f) Cl3C6H2COCl, i-Pr2NEt, THF,
0 °C to rt, then DMAP, toluene, 90 °C, 15 h, 90%; (g) DDQ, THF/H2O, 0 °C to rt, 2 h,
quant; (h) DEAD, Ph3P, p-(NO2)C6H4CO2H, toluene, 0 °C to rt, 4 h, 34%; (i) K2CO3,
MeOH, 0 °C, 7 h, 63% (95% brsm); (j) DEAD, Ph3P, toluene, 0 °C to rt, 24 h, 56%; (k)
DDQ, THF/H2O, 0 °C to rt, 2 h, quant; (l) DEAD, Ph3P, p-(NO2)C6H4COCl, toluene, 0 °C
to rt, 5 h, 50%; (m) K2CO3, MeOH, 0 °C, 8 h, 61% (96% brsm).
1. Luo, X.; Li, F.; Hong, J.; Lee, C.-O.; Sim, C. J.; Im, K. S.; Jung, J. H. J. Nat. Prod. 2006,
69, 567–571.
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Prog. Lipid Res. 2009, 48, 148–170; (b) Böttcher, C.; Pollmann, S. FEBS J. 2009,
276, 4693–4704; (c) Brodhun, F.; Feussner, I. FEBS J. 2011, 278, 1047–1063.
3. (a) Niwa, H.; Wakamatsu, K.; Yamada, K. Tetrahedron Lett. 1989, 30, 4543–
4546; (b) Kigoshi, H.; Niwa, H.; Yamada, K.; Stout, T. J.; Clardy, J. Tetrahedron
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1997, 62, 6638–6657.
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2764.
5. Sreedhar, E.; Venkanna, A.; Chandramouli, N.; Babu, K. S.; Rao, J. M. Eur. J. Org.
Chem. 2011, 1078–1083.
6. (a) Fernandes, R. A.; Kattanguru, P. Tetrahedron Lett. 2011, 52, 1788–1790; (b)
Fernandes, R. A.; Kattanguru, P. Tetrahedron: Asymmetry 2011, 22, 1930–1935.
7. Wetzel, I.; Krauss, J.; Bracher, F. Lett. Org. Chem. 2012, 9, 169–174.
8. (a) Miura, A.; Kuwahara, S. Tetrahedron 2009, 65, 3364–3368; (b) Kurashina, Y.;
Miura, A.; Enomoto, M.; Kuwahara, S. Tetrahedron 2011, 67, 1649–1653; (c)
Kurashina, Y.; Kuwahara, S. Biosci. Biotechnol. Biochem. 2012, 76, 605–607.
9. (a) Honjo, E.; Kutsumura, N.; Ishikawa, Y.; Nishiyama, S. Tetrahedron 2008, 64,
9495–9506; (b) Jackson, S. K.; Karadeolian, A.; Driega, A. B.; Kerr, M. A. J. Am.
Chem. Soc. 2008, 130, 4196–4201.
application of the two-step protocol, employed for the conversion
of 1 into 12-epi-1, to 8-epi-1 provided 8,12-bis-epi-1.14
With the four diastereomers in hand, we compared their spec-
tral data with those of an authentic sample of topsentolide C2 to
elucidate its stereochemistry. Although the 13C NMR spectral data
of the four diastereomers were very similar to one another, slight
differences were observed, especially in the chemical shift differ-
ence between the C-8 and C-12 carbons: dC-12–dC-8 = 0.8 and
1.0 ppm for
1 and 8-epi-1 (11,12-syn isomers), respectively,
10. Ruiz, P.; Murga, J.; Carda, M.; Marco, J. A. J. Org. Chem. 2005, 70, 713–716.
11. Singh, J.; Kaur, J.; Nayyar, S.; Bhandari, M.; Kad, G. L. J. Indian Chem., Sect B: Org.
Chem. Incl. Med. Chem. 2001, 40B, 386–390.
12. Askin, D.; Reamer, R. A.; Joe, D.; Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1989,
30, 6121–6124.
0.5 ppm for both 12-epi-1 and 8,12-bis-epi-1 (11,12-anti isomers),
and 0.9 ppm for topsentolide C2 (see Supplementary data). More-
over, the 1H NMR spectra of 12-epi-1 and 8,12-bis-epi-1 (11,12-anti
isomers) were clearly different from that of topsentolide C2; the
signals for the 11-H and 12-H of the 11,12-anti isomers were
observed as two separate sets of peaks [d 3.54 (1H, dd, J = 7.6,
4.3 Hz) and 3.63 (1H, dt, J = 7.6, 4.8 Hz) for 12-epi-1, and d 3.54
(1H, dd, J = 7.6, 4.5 Hz) and 3.62 (1H, dt, J = 7.6, 4.8 Hz) for 8,
12-bis-epi-1], while those of the 11,12-syn isomers as well as tops-
entolide C2 appeared as overlapping peaks at d 3.47–3.55 (2H, m).
From these results, coupled with the 12S configuration assigned by
the modified Mosher method, we could conclusively determine the
stereochemistry at the side chain moiety of topsentolide C2 as 11S
and 12S. The difference between the two 11,12-syn isomers in 1H
NMR was, on the other hand, quite subtle, but close inspection of
the spectra of 1, 8-epi-1, and authentic topsentolide C2 indicated
some noticeable differences in the shape of peaks in the region
of d 2.3–2.5 ppm, and the peak appearance in that region of
13. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush,
W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183–2186.
14. Physical and spectral data 1: ½a D28
ꢂ
ꢁ95.8 (c 0.570, MeOH); 1H NMR (400 MHz,
CD3OD) d 0.90 (3H, t, J = 6.9 Hz), 1.25–1.40 (6H, m), 1.70–1.82 (1H, m), 2.00–
2.24 (7H, m), 2.30–2.58 (4H, m), 3.29 (3H, s), 3.47–3.55 (2H, m), 5.25–5.31 (1H,
m), 5.42–5.53 (4H, m), 5.69 (1H, ddd, J = 15.6, 7.7, 1.2 Hz), 5.87 (1H, dd, J = 15.6,
5.7 Hz); 13C NMR (100 MHz, CD3OD) d 14.4, 23.6, 26.3, 27.6, 28.4, 30.4, 31.8,
32.7, 34.4, 35.6, 57.0, 74.0, 74.8, 85.7, 125.6, 126.6, 130.3, 132.7, 134.0, 136.2,
175.6; HRMS (FAB) m/z calcd for
C
21H34O4Na ([M+Na]+) 373.2355, found
373.2351. 12-epi-1: ½a D28
ꢂ
ꢁ55 (c 0.47, MeOH); 1H NMR (400 MHz, CD3OD) d
0.90 (3H, t, J = 6.9 Hz), 1.25–1.40 (6H, m), 1.70–1.82 (1H, m), 2.01–2.24 (7H, m),
2.25–2.41 (2H, m), 2.42–2.58 (2H, m), 3.28 (3H, s), 3.54 (1H, dd, J = 7.6, 4.3 Hz),
3.63 (1H, dt, J = 7.6, 4.8 Hz), 5.26–5.32 (1H, m), 5.40–5.53 (4H, m), 5.74 (1H, dd,
J = 15.7, 7.6 Hz), 5.85 (1H, dd, J = 15.7, 5.4 Hz); 13C NMR (100 MHz, CD3OD) d
14.4, 23.6, 26.3, 27.6, 28.5, 30.5, 31.8, 32.7, 34.4, 35.6, 56.9, 74.0, 74.5, 85.8,
125.6, 126.6, 129.7, 132.8, 134.4, 136.2, 175.7; HRMS (FAB) m/z calcd for
C
21H34O4Na ([M+Na]+) 373.2355, found 373.2359. 8-epi-1: ½a 2D8
ꢂ
+86.8 (c 1.33,
MeOH); 1H NMR (400 MHz, CD3OD) d 0.90 (3H, t, J = 6.9 Hz), 1.25–1.40 (6H, m),
1.70–1.82 (1H, m), 2.00–2.24 (7H, m), 2.30–2.58 (4H, m), 3.29 (3H, s), 3.47–

R. Towada et al. / Tetrahedron Letters 54 (2013) 6878–6881
6881
3.55 (2H, m), 5.24–5.30 (1H, m), 5.42–5.53 (4H, m), 5.70 (1H, ddd, J = 15.8, 7.4,
1.0 Hz), 5.87 (1H, dd, J = 15.8, 5.5 Hz); 13C NMR (100 MHz, CD3OD) d 14.4, 23.6,
26.3, 27.6, 28.4, 30.4, 31.8, 32.7, 34.4, 35.5, 57.0, 73.9, 74.9, 85.7, 125.6, 126.6,
15. Topsentolide C2 was suspected by Jung et al. to be an artifact derived from
topsentolide A2 (17,18-dhihydro-B, see Fig. 1) during its extraction with MeOH
(see Ref. 1), and the absolute stereochemistry of topsentolide A1 (B) was
determined as dipicted in Figure 1 through synthetic studies by Watanabe
et al. (see Ref. 4). Therefore, it would be natural to consider that topsentolide C2
was formed by epoxide ring opening of topsentolide A2 by MeOH at the allylic
C11 position with inversion of configuration.
130.1, 132.7, 134.0, 136.2, 175.7; HRMS (FAB) m/z calcd for
C
21H34O4Na
([M+Na]+) 373.2355, found 373.2354. 8,12-bis-epi-1:
½ ꢂ
a 2D8
+66.2 (c 0.520,
MeOH); 1H NMR (400 MHz, CD3OD) d 0.90 (3H, t, J = 6.8 Hz), 1.25–1.40 (6H, m),
1.70–1.82 (1H, m), 2.01–2.24 (7H, m), 2.25–2.41 (2H, m), 2.42–2.58 (2H, m),
3.29 (3H, s), 3.54 (1H, dd, J = 7.6, 4.5 Hz), 3.62 (1H, dt, J = 7.6, 4.8 Hz), 5.25–5.31
(1H, m), 5.40–5.53 (4H, m), 5.73 (1H, dd, J = 15.8, 7.7 Hz), 5.85 (1H, dd, J = 15.8,
5.6 Hz); 13C NMR (100 MHz, CD3OD) d 14.4, 23.6, 26.3, 27.6, 28.5, 30.4, 31.8,
32.7, 34.4, 35.6, 56.9, 74.0, 74.5, 85.9, 125.6, 126.6, 129.7, 132.8, 134.4, 136.2,
16. Unfortunately, the specific rotation values of 8-epi-1 ½a D29
ꢂ
+86.8 (c 1.33, MeOH)
and 1 {½a 2D8
ꢁ95.8 (c 0.570, MeOH) were both far different from that reported
ꢂ
for topsentolide C2 {½a D23
ꢂ
+14.5 (c 0.27, MeOH)}. Remeasurement of the specific
rotation of authentic topsentolide C2 is needed to solve the discrepancy.
175.7; HRMS (FAB) m/z calcd for
C
21H34O4Na ([M+Na]+) 373.2355, found
373.2353.