Stereoselective total synthesis of (+)-mueggelone, a novel inhibitor of fish development

Article abstract of DOI:10.1016/j.tetlet.2008.02.022

An efficient stereoselective total synthesis of (+)-mueggelone, a novel inhibitor of fish development, is described. Highlights of the strategy include the utilization of Sharpless asymmetric epoxidation, Yamaguchi lactonization and an olefin cross-metathesis as the key steps.

Full text of DOI:10.1016/j.tetlet.2008.02.022

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2848–2850
Stereoselective total synthesis of (+)-mueggelone,
a novel inhibitor of fish development
J. S. Yadav *, R. Somaiah, K. Ravindar, L. Chandraiah
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 22 December 2007; revised 2 February 2008; accepted 6 February 2008
Available online 9 February 2008
Abstract
An efficient stereoselective total synthesis of (+)-mueggelone, a novel inhibitor of fish development, is described. Highlights of the
strategy include the utilization of Sharpless asymmetric epoxidation, Yamaguchi lactonization and an olefin cross-metathesis as the
key steps.
Ó 2008 Published by Elsevier Ltd.
(+)-Mueggelone (1) is a naturally occurring C18 lipid,
containing a ten-membered lactone unit, isolated from a
field-collected sample of Aphanizomenon flos-aquae in
1997.1 This cyanobacterium is well known as a producer
of several neurotoxins such as saxitoxin and neosaxitoxin.2
(+)-Mueggelone has been shown to have an inhibitory
effect on fish embryo larval development, and thought to
play an ecologically important role in the inhibition of
the development of herbivorous fish. In the presence of
(+)-mueggelone at a concentration of 10 lg/mL, Zebra fish
larva showed 45% mortality and the surving larvae showed
edema in the heart region and thrombosis. Considering its
selective biological profile, compound 1 has been identified
by many scientists world-wide as an attractive synthetic
target. Kithara et al. determined the absolute configuration
of mueggelone by synthesizing all the four possible stereo-
isomers. To the best of our knowledge, only one synthesis
of mueggelone has been reported in the literature to date.3
The novel structure and the scarcity of this natural
material has prompted us to investigate the total synthesis
of (+)-mueggelone. As part of our continuing interest in
the total synthesis of bioactive natural products,4 we herein
report a total synthesis of (+)-meuggelone. Retrosynthetic
analysis reveals that the target natural product mueggelone
1 can be obtained by cross olefin metathesis of the two key
fragments 2 and 3, which in turn are synthesized by the
sequential transformations of propargyl alcohol 4 and
1,9-dihydroxynonane 5, respectively (Scheme 1).
The synthesis of fragment 2 started with commercially
available propargyl alcohol 4 (Scheme 2), which upon
alkylation with ethylbromide gave 2-pentyne-1-ol 6.
Compound 6 was converted to its bromo derivative 7
and then coupled with propargyl alcohol to afford 1,4-
diyne (skipped diyne) 8 in 70% yield.5,6
Selective reduction of the propargylic triple bond of 8
using LiAlH4 gave the allylic alcohol 9 in 75% yield. Sharp-
less asymmetric epoxidation of allylic alcohol 9 yielded
epoxide 10, which was subjected to Lindlar hydrogenation
to give the cis-olefin 11.7 Swern oxidation followed by a
1C-Wittig homologation of 11 yielded key intermediate 2
in good yield.8
The synthesis of lactone component 3 started from the
commercially available 1,9-dihydroxynonane 5 (Scheme
3). Mono hydroxyl protection of
5 with p-meth-
oxybenzylbromide in the presence of NaH gave 12 in
90% yield. Oxidation under Swern conditions and subse-
quent Wittig olefination afforded a,b-unsaturated ester
13.9 Ester 13 was then reduced with DIBAL-H to give
allylic alcohol 14,10 which was converted to epoxyalcohol
15 under Sharpless conditions. The epoxy alcohol 15 was
*
Corresponding author. Tel.: +91 40 27193030; fax: +91 40 27160387.
E-mail address: yadavpub@iict.res.in (J. S. Yadav).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.02.022

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 2848–2850
2849
O
O
O
O
+
O
O
2
3
Mueggelone-1
OH
7
HO
OH
4
5
Scheme 1.
a
b
c
OH
OH
Br
OH
8
7
4
6
f
d
e
O
OH
OH
9
10
O
O
g, h
OH
11
2
Scheme 2. Reagents and conditions: (a) nBuLi, HMPA, ethyl bromide, THF, ꢀ30 °C, 18 h, 70%; (b) PBr3, Et2O, 0–25 °C, 1 h, 80%; (c) Propargyl alcohol
i
˚
CuI, Na2CO3, TBAI, DMF, rt, 10 h, 70%; (d) LiAlH4, Et2O, reflux, 1 h, 75%; (e) (+)-DET, Ti( PrO)4, TBHP, CH2Cl2, 4 A MS, ꢀ20 °C, 90%; (f) Lindlars
t
catalyst, benzene, 1 h, 90%; (g) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C, 1 h, 80%; (h) PPh3CH3I, BuOK, THF, 0–25 °C, 2 h, 70%.
O
a
d
b, c
7
PMBO
HO
OH
7
OH
PMBO
7
OEt
5
12
13
O
O
e
f
7
PMBO
g
OH
PMBO
7
PMBO
7
OH
I
14
15
16
OH
OTBS
OTBS
7
h
i
PMBO
7
7
PMBO
HO
17
18
19
O
O
OTBS
O
OH
7
j, k
l
O
m
7
HO
HO
20
21
3
Scheme 3. Reagents and conditions: (a) p-CH3OC6H4CH2Br, NaH, dry DMF, 0–25 °C, 1 h, 90%; (b) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 to ꢀ60 °C,
i
˚
2 h, 90%; (c) Ph3P@CHCO2Et, benzene, 25 °C, 10 h, 80%; (d) DIBAL-H, CH2Cl2, 0–25 °C, 2 h, 95%; (e) (ꢀ)-DET, Ti( PrO)4, TBHP, CH2Cl2, 4 A MS,
ꢀ20 °C, 90%; (f) Ph3P, imidazole, I2, 0–25 °C, 1 h, 90%; (g) Zn, CH3OH, reflux, 1 h, 95%; (h) TBS-Cl, imidazole, CH2Cl2, rt, 80%; (i) DDQ, CH2Cl2–H2O
t
(9:1), 0–25 °C, 2 h, 85%; (j) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 to ꢀ60 °C, 2 h, 90%; (k) NaClO2, NaH2PO4ꢁ2H2O, BuOH: 2-methyl,2-butene (3:1),
0–25 °C, 1 h, 85%; (l) HF, CH3CN, 60%; (m) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, then DMAP, toluene, reflux, 12 h, 65%.
converted to the corresponding epoxy iodide 16 in 90%
yield and subjected to a reductive ring opening reaction
in the presence of zinc and methanol to yield secondary
allylic alcohol 17.11 Protection of alcohol 17 as TBS ether
18 using TBSCl and imidazole followed by the deprotec-
tion of the PMB group with DDQ resulted in primary alco-
hol 19. This hydroxyl functional group was oxidized to an
aldehyde and then to acid 20, sequentially.12 The TBS-pro-
tected carboxylic acid 20 was converted to the hydroxy acid
21 by treatment with HF–CH3CN and then converted to

2850
J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 2848–2850
O
O
O
a
O
O
O
+
2
Mueggelone-1
3
(E/Z 100:0)
MesN
Cl
NMes
Ph
+
Ru
O
O
Cl
PCy3
2nd generation
Grubbs catalyst
(
)
2
22
Scheme 4. Reagents and conditions: (a) 2nd generation Grubbs catalyst, CH2Cl2, 25 °C, 2 h, 40%.
5. Cossy, J.; Aclinou, P. Tetrahedron Lett. 1990, 52, 7615–7618.
6. Han, L.; Razdan, R. J. Tetrahedron Lett. 1998, 39, 771–774.
7. Corey, E. J.; Gato, G.; Marfat, A. J. Am. Chem. Soc. 1980, 102, 6607–
6608.
8. Corey, E. J.; Marfat, A.; Laguzza, B. C. Tetrahedron Lett. 1981, 22,
3339–3342.
9. Kumar, P.; Naidu, S. J. Org. Chem. 2005, 70, 4207–4210.
10. Cossy, J.; Reymond, S. Eur. J. Org. Chem. 2006, 4800–4804.
11. (a) Marshall, J. A.; Johns, B. A. J. Org. Chem. 2000, 65, 1501–1510.
The product 17 was also obtained from 15 in single step with
titanocene in 85% yield. See: (b) Yadav, J. S.; Shekharam, T.; Gadgil,
V. R. J. Chem. Soc., Chem. Commun. 1990, 843–844.
12. Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37,
2091–2096.
the key fragment 3 (10 membered lactone) using the
Yamaguchi macrolactonization procedure.13
The final reaction was the olefin cross-metathesis
between precursors 2 and 3. Accordingly, the treatment
of epoxy olefin 2 with 3 in the presence of Grubbs 2nd gen-
eration catalyst14 in methylene chloride afforded the target
compound (+)-mueggelone 1 in 40% yield with complete E
selectivity, as determined by 1H NMR spectroscopy. In this
reaction, homodimer 22 was also obtained as a side prod-
uct as confirmed by mass spectroscopy. The spectral data
and optical rotation of compound 1 was found to be iden-
tical with that reported.15
In conclusion, an efficient total synthesis of (+)-muegge-
lone 1 has been achieved in a stereo-controlled manner
using Sharpless asymmetric epoxidation, Yamaguchi
lactonization, and olefin cross-metathesis as key steps
(Scheme 4).
13. Inanaga, J.; Hirata, K.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc.
Jpn. 1979, 52, 1989–1993.
14. McDonald, F. E.; Wei, X. Org. Lett. 2002, 4, 593–595.
20
15. Spectral data of selected compounds. Compound 10: colorless oil; ½aꢂD
ꢀ11.30 (c 2.5, CHCl3); 1H NMR (300 MHz, CDCl3): d 3.97–3.85 (m,
1H), 3.69–3.55 (m, 1H), 3.13–3.02 (m, 2H), 2.65–2.52 (m, 1H), 2.47–
2.36 (m, 1H), 2.22–2.09 (m, 2H), 1.13 (t, 3H, J = 7.55 Hz); 13C NMR
(75 MHz, CDCl3): d 84.4, 73.4, 61.4, 58.2, 53.7, 21.8, 14.1, 12.5;
HRMS. Calcd for C8H12O2Na: 163.0734. found: 163.0734. Compound
Acknowledgment
20
15: colorless oil; ½aꢂD +8.80 (c 2.5, CHCl3); 1H NMR (300 MHz,
CDCl3): d 7.19 (d, 2H, J = 8.36 Hz), 6.82 (d, 2H, J = 9.06 Hz), 4.39
(s, 2H), 3.89–3.80 (m, 1H), 3.79 (s, 3H), 3.64–3.53 (m, 1H), 3.38 (t,
2H, J = 6.78 Hz), 2.93–2.82 (m, 2H), 1.69–1.49 (m, 4H), 1.39–1.22 (m,
10H); 13C NMR (75 MHz, CDCl3): d 129.1, 113.8, 72.4, 70.3, 61.8,
58.3, 56.0, 55.2, 31.4, 29.7, 29.3, 29.2, 26.1, 25.8; HRMS: calcd for
C19H30O4Na: 345.2041, found: 345.2036. Compound 1: colorless oil;
K.R. and R.S. thank the CSIR for the award of
fellowships.
References and notes
25
28
½aꢂD +29.0 (c 0.7, CHCl3); {lit. ½aꢂD +28.7 (c 0.63, CHCl3)}3; IR
1. Papendrof, O.; Koning, G. M.; Wright, A. D.; Chorus, I.; Oberemn,
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(film); mmax 2931, 1730, 1465, 1236, 1068, 971 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d 5.94 (dd, 1H, J = 15.6, 5.1 Hz), 5.54 (m, 1H),
5.46 (ddd, 1H, J = 15.6, 7.8, 1.4 Hz), 5.42–5.30 (m, 2H), 3.15 (dd, 1H,
J = 7.80, 2.20 Hz), 2.87 (dt, 1H, J = 5.3, 2.20 Hz), 2.52 (ddd, 1H,
J = 15.5, 6.2, 3.0 Hz), 2.36 (m, 2H), 2.20 (ddd, 1H, J = 15.5, 11.8,
2. Sawyer, P.; Gentile, J. H.; Sasner, J. J. Can. J. Microbial. 1968, 14,
1199–1204.
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41, 8897–8901; (b) Motoyoshi, H.; Ishigami, K.; Kithara, T.
Tetrahedron 2001, 57, 3899–3908.
2.6 Hz), 2.15–1.95 (m, 4H), 1.8–1.0 (m, 10H), 0.97 (t, 3H, J = 7.5); 13
C
NMR (75 MHz, CDCl3): d 172.9, 134.0, 132.7, 128.6, 121.5, 74.7,
59.0, 57.2, 35.0, 29.8, 29.5, 27.2, 24.3, 23.7, 23.5, 20.7, 20.7, 14.0;
EIMS: 293 [M+H]+.
4. For recent publications see: (a) Yadav, J. S.; Chetia, L. Org. Lett.
2007, 9, 4587–4589; (b) Yadav, J. S.; Pratap, T. V.; Rajender, V. J.
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