First total synthesis of mueggelone

Article abstract of DOI:10.1016/S0040-4039(00)01285-5

All the four possible stereoisomers of mueggelone, an inhibitor of fish development, were efficiently synthesized in a stereoselective manner starting from D-arabinose, and the absolute configuration was determined to be 9R,12S, 13S. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01285-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8897–8901
First total synthesis of mueggelone
Ken Ishigami, Hajime Motoyoshi and Takeshi Kitahara*
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences,
The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
Received 27 June 2000; revised 21 July 2000; accepted 24 July 2000
Abstract
All the four possible stereoisomers of mueggelone, an inhibitor of fish development, were efficiently
synthesized in a stereoselective manner starting from -arabinose, and the absolute configuration was
D
determined to be 9R,12S,13S. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; reduction; lactonisation; epoxides.
Mueggelone (1), which has a 10-membered lactone and epoxide, was isolated1 from a
bloom-foaming strain of Aphanizomenon flos-aquae in 1997 (Scheme 1). With mueggelone at a
concentration of 10 mg/mL, zebra fish larvae showed 45% mortality and the surviving larvae
showed edema in the heart region and thrombosis. This compound is thought to play an
ecologically important role in inhibition of the development of herbivorous fish. The stereo-
chemistry of epoxide was proposed to be trans by spectroscopic analysis; however, the relative,
as well as the absolute configuration of the three stereocenters remained unknown. Therefore,
we undertook the synthesis of all the four possible stereoisomers of mueggelone (1, ent-1, 2,
ent-2) to determine the absolute configuration and to provide samples for further biological
Scheme 1.
* Corresponding author. Fax: +81-3-5841-8019; e-mail: atkita@mail.ecc.u-tokyo.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01285-5

8898
assay. Our synthetic strategy is illustrated in Scheme 1. We decided to utilize the key
intermediate A, which could be transformed into any of the four stereoisomers via asymmetric
reduction of ketone, macrolactonization and, finally, epoxide formation. Compound A was
constructed by the Horner–Wadsworth–Emmons (HWE) reaction of the side chain part B with
the lactone part C. Aldehyde B and phosphonate C was derived from commercially available
compounds,
D
-arabinose and azelaic acid dimethyl ester, respectively.
-Arabinose was converted into
The synthesis of the side chain part is outlined in Scheme 2.
D
alcohol 3 according to the known procedure.2 Protection of the hydroxyl group, followed by
dethioacetalization with mercury salt gave an aldehyde, which was submitted to the Wittig
reaction to afford Z-olefin 4. The best ratio (E/Z=1:10) was provided by using NaHMDS as
a base, and the isomers were easily separated by silica gel column chromatography. The Z-olefin
4 was transformed into the corresponding primary alcohol in four steps, which was then mildly
oxidized3 to give the desired aldehyde 6.
Scheme 2.
Phosphonate 7 (prepared from azelaic acid dimethyl ester, dimethyl methylphosphonate,
n-BuLi, THF, −78°C, 22%) was subjected to the HWE reaction with the aldehyde 6 (Scheme 3).
Under the condition using n-BuLi as a base, the E/Z ratio was 96:4; however, partial
epimerization (25%) of the TBSO group was observed. On the other hand, the procedure
employing DBU-LiCl4 resulted in very little epimerization (1–2%) with excellent E/Z selectivity
(E/Z=>99:1). In the next step, we tried several conditions for the asymmetric reduction of
enone 8, and the best selectivity was obtained with the CBS-reagent5 and borane–THF complex.
The resultant two isomers and other undesired isomers (10Z isomer, TBSO epimer) were cleanly
separated by preparative HPLC and the stereochemistry of each isomer was confirmed by the
modified Mosher’s method (Table 1).6 The difference in chemical shifts ensured the stereochem-
Scheme 3.

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Table 1
14C NMR (300 MHz, CDCl3) data for (S)- and (R)-MTPA ester of the (9S) derivative
Position
1H Chemical shift (l)
lS–lR
(S)-MTPA
(R)-MTPA
2
8
10
11
12
13
2.28
1.63
5.68
5.94
4.14
3.32
2.29
1.64
5.60
5.83
4.12
3.30
−0.01
−0.01
0.08
0.11
0.02
0.02
istry. Hydrolysis with LiOH furnished pure hydroxycarboxylic acid 9a/b, respectively. Lac-
tonization of 9a was successfully achieved by Yamaguchi’s method7 to provide 10a in satisfac-
tory yield (Scheme 4), together with a small amount of a dimeric lactone (5–10%). On the other
hand, the Corey–Mukaiyama method8 was found to give only several unassignable compounds.
Removal of the PMB group with DDQ proceeded without complication. In the following
epoxide formation stage, we thought that the stereochemistry of the epoxide could be controlled
by the direction of elimination. Initially, we decided to synthesize the (12R,13R) isomer such
as 2. Mesylation of alcohol 11a, followed by treatment with TBAF provided the
Scheme 4.

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Table 2
13C NMR (75.5 MHz, CDCl3) data for natural mueggelone, 1/ent-1, and 2/ent-2
Carbon
Natural
1/ent-1
2/ent-2
Carbon
Natural
1/ent-1
2/ent-2
1
2
3
4
5
6
7
8
9
173.5
35.1
29.9
27.1
24.2
23.7
23.4
20.7
74.9
173.4
35.0
29.8
27.0
24.1
23.6
23.3
20.7
74.8
173.4
35.1
29.9
27.0
24.2
23.6
23.4
20.7
75.1
10
11
12
13
14
15
16
17
18
132.8
128.6
57.4
59.9
29.6
122.3
135.0
20.7
132.7
128.5
57.4
59.9
29.5
122.2
134.9
20.7
132.8
129.1
57.3
59.9
29.5
122.2
134.9
20.7
14.2
14.2
14.2
desired epoxylactone 2 in good yield. Next, we tried to obtain the (12S,13S) isomer in a similar
manner. So, allylic mesylate 13a was prepared from 10a; however, it readily decomposed under
the conditions of PMB deprotection. Therefore, we had to change the PMB group for another
protecting group. Masking the hydroxyl group of 11a with TBDPSCl was followed by selective
removal of the TBS group with HF/acetonitrile to give the corresponding alcohol 12a. It was
mesylated and then treated with TBAF without purification to furnish 1. Also, ent-1 and ent-2
were synthesized in the same way from 9b.
With the four stereoisomers in hand, we carefully analyzed the NMR spectra and specific
1
rotations. As for the H NMR, there was little difference between 1/ent-1 and 2/ent-2 to
distinguish them. However, in the 13C NMR spectra (Table 2), an obvious difference was
observed at the C-11 position (natural: 128.6 ppm, 1/ent-1: 128.5 ppm, 2/ent-2: 129.1 ppm),
which suggested 1/ent-1 should be the reasonable natural isomer. In addition, the value of
specific rotation (natural: +28.3, synthetic 1: +28.7, synthetic ent-1: −28.2) showed that 1 must
be the natural product, i.e. mueggelone has the absolute configuration10 of 9R,12S,13S. At first
we referred this to the absolute configuration of malyngic acid,9 analogous to 1; nevertheless, the
stereochemistry at C-9 was found to be the opposite.
In conclusion, we have completed the first synthesis of mueggelone (and its stereoisomers), in
2.1% overall yield from
D
-arabinose, and determined the absolute configuration of mueggelone
to be 9R,12S,13S. Work is under way to refine every step of the synthesis, and to submit these
isomers to further biological assay. Results will be reported in a full account.
Acknowledgements
The authors sincerely thank Professor Gabriele M. Ko¨nig, University of Bonn, for a kind gift
of the spectral charts of natural mueggelone.
References
1. Papendorf, O.; Ko¨nig, G. M.; Wright, A. D.; Chorus, I.; Oberemm, A. J. Nat. Prod. 1997, 60, 1298–1300.
2. Wong, M. Y. H.; Gray, G. R. J. Am. Chem. Soc. 1978, 100, 3548–3553.

8901
3. (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287. (b) Ireland, R. E.; Liu, L. J. Org. Chem.
1993, 58, 2899.
4. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron
Lett. 1984, 25, 2183–2186.
5. (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551–5553. (b) Corey, E. J.; Helal, C.
J. Angew. Chem. Int. Ed. 1998, 37, 1986–2012.
6. (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.;
Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092–4096.
7. (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
(b) Mulzer, J.; Mareski, P. A.; Buschmann, J.; Luger, P. Synthesis 1992, 215–228.
8. (a) Corey E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614–5616. (b) Gerlach, H.; Thalmann, A. Helv.
Chim. Acta 1974, 57, 2661–2663.
9. Malyngic acid is analogous to mueggelone, see: Cardellina II, J. H.; Moore, R. E. Tetrahedron 1980, 36, 993–996.
1
10. Spectral data of synthetic 1. IR (film): w 2930, 1730, 1470, 1240 cm−1; H NMR (300 MHz, CDCl3): l (ppm) 0.98
(3H, t, J=7.5 Hz, H-18), 1.05–1.80 (11H, m, Ha-3, H-4, H-5, H-6, H-7, H-8), 1.95–2.15 (3H, m, Hb-3, H-17),
2.20 (1H, m, Ha-2), 2.37 (2H, m, H-14), 2.53 (1H, ddd, J=2.7, 6.2, 15.2 Hz, Hb-2), 2.88 (1H, dt, J=2.2, 5.2 Hz,
H-13), 3.16 (1H, dm, J=7.5 Hz, H-12), 5.25–5.60 (4H, m, H-9, H-11, H-15, H-16), 5.95 (1H, dd, J=5.1, 15.6 Hz,
H-10); 13C NMR (75.5 MHz, CDCl3): l (ppm) 14.2, 20.7, 20.7, 23.3, 23.6, 24.1, 27.0, 29.5, 29.8, 35.0, 57.4, 59.9,
74.8, 122.2, 128.5, 132.7, 134.9, 173.4.
.