Total synthesis of topsentolide B2

Article abstract of DOI:10.1016/j.tetlet.2011.02.014

A stereoselective total synthesis of topsentolide B₂, a selective cytotoxic oxylipin against SK-OV-3 and SK-MEL-2 cancer cell lines has been achieved based on asymmetric dihydroxylation, Roush allylation, and ring closing metathesis (RCM) react

Full text of DOI:10.1016/j.tetlet.2011.02.014

Tetrahedron Letters 52 (2011) 1788–1790
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of topsentolide B2
⇑
Rodney A. Fernandes , Pullaiah Kattanguru
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective total synthesis of topsentolide B2, a selective cytotoxic oxylipin against SK-OV-3 and SK-
MEL-2 cancer cell lines has been achieved based on asymmetric dihydroxylation, Roush allylation, and
ring closing metathesis (RCM) reactions. The synthesis is completed in 11 steps and 2.1% overall yield.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 6 January 2011
Revised 31 January 2011
Accepted 2 February 2011
Available online 23 February 2011
Keywords:
Topsentolides
Stereoselective synthesis
Asymmetric dihydroxylation
Roush allylation
Ring closing metathesis (RCM)
Oxylipins constitute a growing family of oxygenated natural
products formed from fatty acids. Recently Jung and co-workers1
isolated seven new oxylipins called topsentolides (1–7, Fig. 1) from
the marine sponge Topsentia sp. The precedents halicholactone and
neohalicholactone with the same structural frame were isolated
from the marine sponge Halichondria okadai.2,3 These have been
the targets of considerable synthetic interest.4 The topsentolides
have been shown to be cytotoxic against SK-OV-3 and SK-MEL-2 hu-
man solid tumor cell lines.1 Watanabe’s group have disclosed the
first enantioselective synthesis of (8S,11S,12R)-topsentolide A1 and
its (8S,11R,12S) diastereomer and have established the absolute ste-
reochemistry of the natural isolate to be (8R,11R,12S).5 These results
have further supported the original prediction by Jung’s group about
the absolute stereochemistry at C-12 as (S) in topsentolides C1 and
C2. Topsentolide B2 (4) has three stereocenters, a nine-membered
lactone, vicinal diol functionality, and three isolated double bonds
of which two are cis and one trans. The relative stereochemistry of
the diol functionality is proposed to be threo by spectroscopic
analysis,1 however the absolute stereochemistry of the three stereo-
centers is yet to be ascertained. The synthesis of topsentolide B3 is
just reported.6 In continuation to our synthetic efforts on total
synthesis of natural products,7 we describe in the present work
the synthesis of (8S,11R,12R)-topsentolide B2.
tion of 11 and Wittig olefination would provide 9. Further extension
would involve asymmetric Roush allylation8 to set the C-8 stereo-
genic center and acylation to produce 8. The final step would be ring
closing metathesis (RCM) to give (8S,11R,12R)-4.
The synthesis commenced from 1,3-propane diol (12) to get the
intermediate 9 as shown in Scheme 2. 1,3-Propane diol (12) was
converted into olefin 10 following the literature procedure.9 Asym-
metric dihydroxylation of 10 using (DHQD)2-PHAL ligand afforded
the diol 14 in 86% yield and 95% ee.10 Sequential diol protection as
acetonide 15 (99%) and debenzylation gave the alcohol 16 in quan-
titative yield. Swern oxidation of alcohol 16 to the corresponding
aldehyde and low temperature Wittig olefination provided 17 in
good yield (68% over two steps). Further, DIBAL-H reduction of
the ester to the corresponding aldehyde and Horner–Wittig olefin-
ation delivered 9 in 72% yield over two steps.
O
O
18
17
1
9
8
12
11
X
5
Y
The retrosynthetic analysis of (8S,11R,12R)-topsentolide B2 (4) is
shown in Scheme 1. Our approach is based on asymmetric dihydr-
oxylation of 10 and subsequent step-wise addition of the side chains
based on Wittig and Horner–Wittig olefinations to deliver 9
(Scheme 1). Alternatively, regioselective asymmetric dihydroxyla-
Topsentolide A1 (1) : X,Y = 11,12-cis-epoxide
Topsentolide A2 (2) : X,Y = 11,12-cis-epoxide, 17,18-dihydro
3
Topsentolide B1 ( ) : X = Y = OH, (11,12-threo)
Topsentolide B2 (4) : X = Y = OH, (11,12-threo), 17,18-dihydro
Topsentolide B3 (5) : X = Y = OH, (11,12-erythro), 17,18-dihydro
β
Topsentolide C1 (6) : X = OH, Y = OMe
7
β
Topsentolide C2 ( ) : X = OH, Y = OMe, 17,18-dihydro
⇑
Corresponding author. Tel.: +91 22 25767174; fax: +91 22 25767152.
E-mail address: rfernand@chem.iitb.ac.in (R.A. Fernandes).
Figure 1. The structures of topsentolides (1–7).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.014

R. A. Fernandes, P. Kattanguru / Tetrahedron Letters 52 (2011) 1788–1790
1789
ii
O
O
i
HO
HO
O
Roush
allylation
OH
OTBDMS
19
18
O
RCM
C5H11
O
EtO2C
iii
C5H11
HO
O
EtO
OTBDMS
O
OH
O
OTBDMS
OH
11
8
4
OH
O
20
O
OEt
O
O
iv
vi
O
v
Horner-Wittig
C5H11
EtO
O
OBn
OTBDMS
asymmetric
dihydroxylation
EtO
EtO
OTBDMS
10
O
22
OH
OR
OTBDMS
21
O
Wittig
OEt
O
EtO
9
O
vii
O
O
OH
C5H11
11
EtO
O
O
Scheme 1. Retrosynthetic analysis of topsentolide B2 (4).
23
9
Scheme 3. Aletrnative synthesis of intermediate 9. Reagents and conditions: (i)
NaH (1.0 equiv), TBDMSCl (1.0 equiv), THF, 0 °C to rt, 2 h, 80%; (ii) (a) PCC
(2.0 equiv), NaOAc (2.0 equiv), CH2Cl2, 0 °C to rt, 3 h; (b) ethylpropiolate (1.2 equiv),
LiHMDS (1.4 equiv), THF, ꢁ78 °C, 1.5 h, 65% (over two steps); (iii) Ph3P (1.2 equiv),
C6H6, rt, 5 h, 75%; (iv) K3Fe(CN)6 (3.0 equiv), K2CO3 (3.0 equiv), MeSO2NH2
(1.0 equiv), (DHQD)2PHAL (1.0 mol %), K2OsO4ꢂ2H2O (0.4 mol %), t-BuOH–H2O
(1:1), 0 °C, 24 h, 81%; (v) 2,2-DMP (2.0 equiv), p-TsOH (catalytic), acetone, rt, 12 h,
80%; (vi) TBAF (1.5 equiv), THF, 0 °C to rt, 3 h, 82%; (vii) (a) (COCl)2 (1.5 equiv),
DMSO (3.0 equiv), CH2Cl2, ꢁ78 °C, 10 min, alcohol 23, 45 min, Et3N (4.0 equiv),
CH2Cl2, ꢁ78 °C, 30 min, rt, 1 h; (b) hexyltriphenylphosphonium bromide
(1.5 equiv), n-BuLi (1.8 equiv), THF, 0 °C, 15 min, then ꢁ80 °C, aldehyde (from
alcohol 23), 2 h, rt, 2 h, 65% (over two steps).
Alternatively, intermediate 9 was synthesized as shown in
Scheme 3. 1,4-Butane diol (18) was mono-protected to give 19 in
80% yield. Subsequent oxidation of the alcohol to the aldehyde
and ethyl propiolate addition afforded the alkynoate 20 (65% over
two steps). The allene-type rearrangement11 of 20 with PPh3 gave
the diene 1112a in 75% yield. The regioselective asymmetric dihydr-
oxylation of 11 gave 21 in 81% yield and 96% ee.12b,13 Acetonide
protection of diol to 22 (80%) and the subsequent removal of
TBDMS group delivered the alcohol 23 in 82% yield. Further, Swern
oxidation to the aldehyde and Wittig olefination provided the
intermediate compound 914 in 65% yield over two steps.
The subsequent reaction steps involving the construction of the
nine-membered lactone ring from the intermediate 9 are shown in
Scheme 4. The DIBAL-H reduction of ester group in 9 to the corre-
OEt
i
O
HO
C5H11
C5H11
O
O
O
O
9
24
i
ii
HO
OH
HO
OBn
O
iii
ii
12
13
O
OH
O
O
C5H11
O
iii
v
iv
EtO
OBn
OH
EtO
OBn
OBn
O
8
OH
10
14
O
O
O
O
iv
O
O
O
O
vi
O
EtO
HO
EtO
EtO
O
OH
O
O
25
4
16
15
Scheme 4. Synthesis of topsentolide B2 (4). Reagents and conditions: (i) (a) DIBAL-
OEt
O
H (1.0 equiv), CH2Cl2, ꢁ78 °C, 45 min; (b) (R,R)-diisopropyl tartrate allylboronate
O
0
O
O
(2.0 equiv), toluene, MS 4 ÅA, ꢁ78 °C, 1 h, 72% (over two steps); (ii) 5-hexenoic acid
(2.0 equiv), DCC (2.0 equiv), DMAP (catalytic), CH2Cl2, 0 °C to rt, 12 h, 90%; (iii)
Grubbs-I catalyst (20 mol %), Ti(Oi-pr)4 (20 mol %), CH2Cl2, reflux, 12 h, 52%; (iv)
TFA, CH2Cl2, 0 °C, 2 h, 92%.
vii
C5H11
C5H11
O
O
17
9
Scheme 2. Synthesis of intermediate 9. Reagents and conditions: (i) NaH
(1.1 equiv), BnBr (1.0 equiv), TBAI (catalytic), THF, 0 °C to rt, 12 h, 90%; (ii) (a)
(COCl)2 (1.5 equiv), DMSO (3.0 equiv), CH2Cl2, ꢁ78 °C, 10 min, alcohol 13, 45 min,
Et3N (4.0 equiv), ꢁ78 °C, 30 min, to rt, 1 h; (b) (EtO)2POCH2CO2Et (1.2 equiv), NaH
(1.3 equiv), THF, 0 °C to rt, 3 h, 80% (over two steps); (iii) K3Fe(CN)6 (3.0 equiv),
K2CO3 (3.0 equiv), MeSO2NH2 (1.0 equiv), (DHQD)2PHAL (1.0 mol %), K2OsO4ꢂ2H2O
(0.4 mol %), t-BuOH–H2O (1:1), 0 °C, 24 h, 86%; (iv) 2,2-DMP (2.0 equiv), p-TsOH
(catalytic), acetone, rt, 12 h, 99%; (v) H2, Pd/C, EtOH, rt, 30 h, quant.; (vi) (a) (COCl)2
(1.5 equiv), DMSO (3.0 equiv), CH2Cl2, ꢁ78 °C, 10 min, alcohol 16, 45 min, Et3N
(4.0 equiv), ꢁ78 °C, 30 min, to rt, 1 h; (b) hexyltriphenylphosphonium bromide
(1.5 equiv), THF, n-BuLi (1.8 equiv), 0 °C, 15 min, then ꢁ80 °C, aldehyde (from
alcohol 16), 2 h, rt, 2 h, 68% (over two steps); (vii) (a) DIBAL-H (1.0 equiv), CH2Cl2,
ꢁ78 °C, 45 min; (b) (EtO)2POCH2CO2Et (1.2 equiv), NaH (1.3 equiv), THF, 0 °C to rt,
2 h, 72% (over two steps).
sponding aldehyde and subsequent asymmetric Roush allylation8
efficiently placed the allyl group and fixed the C-8 stereochemistry
providing 24 in 72% yield over two steps. Acylation of 24 with 5-
hexenoic acid provided the bis-terminal olefin compound 815 in
90% yield. Further the RCM reaction using Grubbs-II catalyst pro-
vided the nine-membered lactone in lower yields.16 After several
trials the reaction settled with the use of Grubbs-I catalyst
(20 mol %) and Ti(OiPr)4 (20 mol %)17 providing the lactone 25 in
52% yield. Removal of acetonide group afforded (8S,11R,12R)-tops-
entolide B2 (4)18 in 92% yield, ½a 2D5
ꢀ
+8.9 (c 0.27, MeOH), lit.1 ½a D23
ꢀ
+9.8
(c 0.27, MeOH).

1790
R. A. Fernandes, P. Kattanguru / Tetrahedron Letters 52 (2011) 1788–1790
9. Compound 10 was prepared following literature procedure, see: Davis, F. A.; Qi,
In summary, the first total synthesis of (8S,11R,12R)-topsento-
H.; Sundarababu, G. Tetrahedron 2000, 56, 5303–5310.
10. Asymmetric dihydroxylation of 10 was similar to the synthesis of ent-10 as
reported in Badalassi, F.; Nguyun, H. K.; Crotti, P.; Reymond, J.-L. Helv. Chim.
Acta 2002, 85, 3090–3098.
lide B2 has been accomplished in 11 steps and 2.1% overall yield.
The synthesis features asymmetric dihydroxylation, Wittig and
Horner–Wittig olefinations, Roush allylation and RCM as the key
steps. Further application of this strategy to the synthesis of other
members of topsentolide family is in progress in our laboratory.
11. Guo, C.; Lu, X. J. Chem. Soc., Chem. Commun. 1993, 394–395.
12. Compound 11 was prepared following a similar literature procedure, see: (a)
Reddy, C. R.; Dharmapuri, G.; Rao, N. N. Org. Lett. 2009, 11, 5730–5733; (b)
Asymmetric dihydroxylation of 11 was similar to the synthesis of ent-11 as
reported in the above reference.
Acknowledgments
13. For similar regio- and stereoselective asymmetric dihydroxylation of distant
olefinic bond of a a,b,c,d-unsaturated esters see: (a) Zhang, Y.; O’Doherty, G. A.
The authors are indebted to IRCC, IIT Bombay and DST New Del-
hi for financial support. P.K. is grateful to CSIR New Delhi for senior
research fellowship.
Tetrahedron 2005, 61, 6337–6351; (b) Hunter, T. J.; O’Doherty, G. A. Org. Lett.
2001, 3, 1049–1052; (c) Berker, H.; Soler, M. A.; Sharpless, K. B. Tetrahedron
1995, 51, 1345–1376; (d) Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem.
Soc. 1992, 114, 7570–7571.
14. Data for compound 9: colorless oil, ½a D25
ꢀ
= +26.6 (c 0.5, CHCl3). IR (CHCl3)
= 2927, 2857, 1726, 1662, 1464, 1371, 1303, 1219, 1164, 1113, 1035, 978,
References and notes
m
857, 756 cmꢁ1
.
1H NMR (400 MHz, CDCl3/TMS): d = 6.86 (dd, J = 15.6, 5.5 Hz,
1H), 6.11 (dd, J = 15.6, 1.2 Hz, 1H), 5.52ꢁ5.58 (m, 1H), 5.37ꢁ5.43 (m, 1H),
4.19ꢁ4.23 (m, 3H), 3.80 (dt, J = 8.2, 6.0 Hz, 1H), 2.37ꢁ2.43 (m, 2H), 2.0ꢁ2.06
(m, 2H), 1.44 (s, 3H), 1.41 (s, 3H), 1.24ꢁ1.37 (m, 6H), 1.29 (t, J = 6.7 Hz, 3H),
0.88 (t, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3): d = 166.0, 144.1, 133.3,
123.2, 122.5, 109.4, 80.1, 79.7, 60.5, 31.4, 29.7, 29.1, 27.4, 27.1, 26.6, 22.5, 14.1,
14.0. HRMS (ESI+) calcd for [C18H30O4+H]+: 311.2222, found: 311.2225.
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.
2. Niwa, H.; Wakamatsu, K.; Yamada, K. Tetrahedron Lett. 1989, 30, 4543–4546.
3. Kigoshi, H.; Niwa, H.; Yamada, K.; Stout, T. J.; Clardy, J. Tetrahedron Lett. 1991,
32, 2427–2428.
4. (a) Zhu, C.-Y.; Cao, X.-Y.; Zhu, B.-H.; Deng, C.; Sun, X.-L.; Wang, B.-Q.; Shen, Q.;
Tang, Y. Chem. Eur. J. 2009, 15, 11465–11468; (b) Mohapatra, D. K.; Durugkar, K.
A. Arkivoc 2004, 1, 146–155; (c) Takahashi, T.; Watanabe, H.; Kitahara, T.
Heterocycles 2002, 58, 99–104; (d) Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.;
Tanaka, T.; Ibuka, T.; Ohishi, H.; Takemoto, Y. J. Org. Chem. 2001, 66, 81–88; (e)
Takemoto, Y.; Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.; Tanaka, T.; Ibuka, T.
Tetrahedron Lett. 2000, 41, 3653–3656; (f) Mohapatra, D. K.; Datta, A. J. Org.
Chem. 1998, 63, 642–646; (g) Critcher, D. J.; Connolly, S.; Wills, M. J. Org. Chem.
1997, 62, 6638–6657; (h) Critcher, D. J.; Connolly, S.; Wills, M. Tetrahedron Lett.
1995, 36, 3763–3766; (i) Critcher, D. J.; Connolly, S.; Mohan, M. F.; Wills, M. J.
Chem. Soc. Chem. Commun. 1995, 2, 139–140.
15. Data for compound 8: colorless oil,
½ ꢀ = +4.9 (c 1.0, CHCl3). IR (CHCl3)
a 2D5
m
= 3018, 2930, 2853, 1738, 1620, 1375, 1219, 1104, 1019, 967, 918, 767 cmꢁ1
.
1H NMR (400 MHz, CDCl3/TMS): d = 5.62ꢁ5.82 (m, 4H), 5.47ꢁ5.52 (m, 1H),
5.32ꢁ5.42 (m, 2H), 5.03ꢁ5.10 (m, 3H), 4.98 (dt, J = 10.7, 1.2 Hz, 1H), 4.03 (t,
J = 7.6 Hz, 1H), 3.70 (dt, J = 8.3, 5.8 Hz, 1H), 2.29ꢁ2.40 (m, 6H), 2.05ꢁ2.10 (m,
2H), 1.98ꢁ2.04 (m, 2H), 1.63ꢁ1.73 (m, 2H), 1.41 (s, 3H), 1.40 (s, 3H), 1.25ꢁ1.37
(m, 6H), 0.88 (t, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3): d = 172.6, 137.6,
133.0, 132.7, 132.0, 129.7, 123.8, 118.1, 115.4, 108.7, 81.0, 80.3, 72.3, 38.9, 33.7,
33.0, 31.5, 29.4, 29.2, 27.4, 27.1, 26.9, 24.0, 22.5, 14.0. HRMS (ESI+) calcd for
[C25H40O4+Na]+: 427.2824, found: 427.2831.
16. For a similar low yielding RCM reaction in the synthesis of helicholactone using
Grubbs-II catalyst see Ref. 4a.
17. For a similar use of Grubbs-I and Ti(OiPr)4 (in the synthesis of halicholactone)
see Refs. 4a and 4d.
5. Kobayashi, M.; Ishigami, K.; Wtanabe, H. Tetrahedron Lett. 2010, 51, 2762–2764.
6. Sreedhar, E.; Venkanna, A.; Chandramouli, N.; Babu, K. S.; Rao, J. M. Eur. J. Org.
Chem. 2011, 1078–1083.
7. (a) Fernandes, R. A.; Mulay, S. V. J. Org. Chem. 2010, 75, 7029–7032; (b)
Fernandes, R. A.; Mulay, S. V. Synlett 2010, 2667–2671; (c) Fernandes, R. A.;
Chavan, V. P. Eur. J. Org. Chem. 2010, 4306–4311; (d) Fernandes, R. A.; Ingle, A.
B. Synlett 2010, 158–160; (e) Fernandes, R. A.; Ingle, A. B.; Chavan, V. P.
Tetrahedran: Asymmetry 2009, 20, 2835–2844; (f) Fernandes, R. A.; Chowdhury,
A. K. J. Org. Chem. 2009, 74, 8826–8829.
8. For asymmetric Roush allylation see: (a) Roush, W. R.; Walts, A. E.; Hoong, L. K.
J. Am. Chem. Soc. 1985, 107, 8186–8190; (b) Roush, W. R.; Palkowitz, A. D. J. Am.
Chem. Soc. 1987, 109, 953–955; (c) Roush, W. R.; Hoong, L. K.; Palmer, M. A. J.;
Park, J. C. J. Org. Chem. 1990, 55, 4109–4117.
18. Data for topsentolide B2 (4): colorless oil, ½a D25
ꢀ
= +8.9 (c 0.27, MeOH), lit.1 a 2D3
½ ꢀ
+9.8 (c 0.27, MeOH). IR (CHCl3)
m = 3400, 2918, 2850, 1712, 1660, 1455, 1217,
1117, 973, 758 cmꢁ1
.
1H NMR (500 MHz, CD3OD): d = 5.62ꢁ5.85 (m, 2H),
5.32ꢁ5.56 (m, 4H), 5.06ꢁ5.25 (m, 1H), 3.97 (br, J = 2.5 Hz, 1H), 3.42ꢁ3.47 (m,
1H), 2.25ꢁ2.51 (m, 6H), 2.01ꢁ2.31 (m, 4H), 1.63ꢁ1.73 (m, 2H), 1.31ꢁ1.45 (m,
6H), 0.91 (t, J = 6.5 Hz, 3H). 13C NMR (100 MHz, CD3OD): d = 174.7, 136.6, 132.3,
131.5 (2C), 127.1, 126.9, 75.0, 74.4, 71.5, 34.8, 32.8, 31.7, 30.8, 30.4, 28.5, 26.6,
26.2, 23.6, 13.5. HRMS (ESI+) calcd for [C20H32O4+Na]+: 359.2356, found:
359.2350.