Chemoenzymatic synthesis of (E)-3,7-dimethyl-2-octene-1,8-diol isolated from the hairpencils of male Danaus chrysippus (African Monarch)

Article abstract of DOI:10.1016/S0960-894X(03)00352-4

The synthesis of (E)-3,7-dimethyl-2-octene-1,8-diol (1), which was isolated from the hairpencils of male Danaus chrysippus (African Monarch), was investigated. The key step of the sequence involves asymmetric desymmetrization of the 1,3-propanediol 7 with

Full text of DOI:10.1016/S0960-894X(03)00352-4

Bioorganic & Medicinal Chemistry Letters 13(2003) 1967–1969
Chemoenzymatic Synthesis of (E)-3,7-Dimethyl-2-octene-1,8-diol
Isolated from the Hairpencils of Male Danaus chrysippus
(African Monarch)
Kunihiko Takabe,* Nobuyuki Mase, Hiroya Hashimoto, Atsushi Tsuchiya,
Takashi Ohbayashi and Hidemi Yoda
Department of Molecular Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu 432-8561, Japan
Received 4 March 2003; revised 7 April 2003; accepted 7 April 2003
Abstract—The synthesis of (E)-3,7-dimethyl-2-octene-1,8-diol (1), which was isolated from the hairpencils of male Danaus chry-
sippus (African Monarch), was investigated. The key step of the sequence involves asymmetric desymmetrization of the 1,3-propa-
nediol 7 with lipase, in which high enantioselectivity was observed. Total synthesis afforded (S)-1 in 12 steps and 26% overall yield
from readily available geraniol.
# 2003Elsevier Science Ltd. All rights reserved.
(E)-3,7-Dimethyl-2-octene-1,8-diol (1) has been isolated
as a major component from the hairpencils of male
Danaus chrysippus (African Monarch), which is an Old
World member of the subfamily Danainae.1 Unfortu-
nately, since the amount of this diol 1 in one butterfly is
only 0.05 mg, its bioactivity has not been clarified.
However, structurally similar dicarboxylic acid (S)-2 is
known as a pheromone of the azuki bean weevil, Callo-
sobruchus chinensis,2,3a,7 therefore, the undiscovered
bioactivity of 1 is interesting. Successful syntheses of 1
in optically active forms were previously reported, in
which the classical approach based on commercially
available chiral building blocks was employed.3,4
Recently, biocatalysts have become one of the most
useful catalysts in asymmetric syntheses.5,6
2-(6-Benzyloxy-4-methyl-4-hexenyl)propane-1,3-diol (7)
as a substrate for asymmetric desymmetrization was
prepared as shown in Scheme 2. Benzylation and epox-
idation of geraniol (4) gave the epoxide 5 in 78% yield,
followed by oxidation, reduction and tosylation to
afford the tosylate 6 in 79% yield.8 Treatment of 6 with
the anion derived from diethyl malonate gave the die-
ster, finally, reduction with lithium aluminium hydride
(LAH) yielded the 1,3-propanediol 7.
Lipase-catalyzed asymmetric desymmetrization of the
diol 7 was carried out as follows:9 in a test tube the diol
7 (0.1 mmol) and vinyl acetate (0.15 mmol) were added.
To the vessel lipase (0.1 or 0.25 g per 1 g of 7) was
added. The vessel was stirred with a magnetic stirrer at
appropriate temperature. On completion of the reac-
tion, the residual mixture was filtered, washed with
Gramatica and Manitto reported that the (S)-1 was
synthesized via stereoselective hydrogenation of the
carbonyl activated double bond of achiral precursors by
baker’s yeast,7 though chemical yield was considerably
low. Now we report herein the synthesis of (S)-1 from
commercially available and quite inexpensive geraniol
(4), employing lipase-catalyzed asymmetric desymme-
trization of the 1,3-propanediol 3 as shown in Scheme 1.
*Corresponding author. Tel.: +81-53-478-1148; fax: +81-53-478-
1148; e-mail: tcktaka@ipc.shizuoka.ac.jp
Scheme 1. Synthetic plan of 1 from geraniol 4.
0960-894X/03/$ - see front matter # 2003Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00352-4

1968
K. Takabe et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1967–1969
Table 1. Lipase-catalyzed asymmetric desymmetrization of the 1,3-propanediol 7a
Entry
Lipaseb
Solvent
Temp (ꢀC)
Time (h)
8 Yield (%)
9 Yield (%)
eec (%)
7 yield (%)
1
2
3PL
4
5
6
7
8
9
10
AK
AY
i-Pr2O
i-Pr2O
i-Pr2O
i-Pr2O
i-Pr2O
i-Pr2O
i-Pr2O
—
hexane
THF
acetone
1,4-dioxane
25
25
25
25
25
25
0
0
0
0
0
42
48
3
2
3
41
56
0
50
3
3
5
6
9
5
8
6
7
58
12
CHIRAZYME, L2
7
87
82
77
75
57
53
2
64
63
2
3
1
PS-D
PSA
PSA
PSA
PSA
PSA
PSA
PSA
6
73
12
52
75
14
117
2323 75
48
2
1381
21
25
35
6
834
69
18
12
78
87
11
12
13PSA
34
37
90
88
89
2
0
0
2203
1,4-dioxane:THF=5:1
0
75
aThe diol 7 (0.1 mmol) and vinyl acetate (0.15 mmol) were used.
b0.1 g for entries 1–6 and 0.25 g for entries 7–13of lipase per 1 g of 7 were used, respectively.
cDetermined by HPLC analysis (Chiralcel OD, hexane/isopropanol=97:3, 0.8 mL/min, Rt of (R)-isomer: 60.4 min, Rt of (S)-isomer:83.6 min).
higher enantioselectivity than
a nonpolar solvent
(entries 8–12). Finally, a mixed solvent in a 1,4-dioxane/
THF of 5/1 resulted in the best enantioselectivity (90%
ee, R configuration) and good chemical yield (75%)
(entry 13).
The desired diol 1 was synthesized from chiral mono-
acetate (R)-9 in 3steps as shown in Scheme 3. Mesyla-
tion followed by reduction with LAH of the chiral
monoacetate (R)-9 (90% ee) gave the alcohol (S)-10 in
82% yield with slightly decreasing enantiomeric excess
(81% ee11). Deprotection of the benzyl group by Birch
reduction afforded the desired diol (S)-1 ([a]1D5=À7.18ꢀ
(c 0.31, CHCl3))12 in 88% yield.
Scheme 2. Synthesis of the 1,3-propanediol 7.
ether, and analyzed with HPLC. The results are shown
in Table 1. Enantioselectivities were highly affected by
the nature of lipases. Lipase AK (Pseudomonas fluores-
cence), AY (Candida rugosa) and PL (Alcaligenes sp.)
gave the monoacetate 9 with low enantioselectivities
(entries 1–3). CHIRAZYME1, L-2 (insoluble polymer-
supported lipase from Candida antarctica, Type B)
showed higher reactivity and chemoselectivity except
enantioselectivity (entry 4). Lipase PS-D (Celite-sup-
ported lipase from Pseudomonas cepacia) and PSA
(Pseudomonas cepacia) improved the enantioselectivity,
and the monoacetate 9 was obtained in 81% yield with
77% ee (entries 5–6). Lower reaction temperature
increased enantioselectivity up to 83% ee (entry 7).
Solvents mainly influenced reactivity and enantio-
selectivity,10 in which a polar solvent such as 1,4-diox-
ane, acetone and tetrahydrofuran (THF) afforded
In conclusion, lipase-catalyzed asymmetric desymme-
trization of the 1,3-propanediol 7 is a valid approach to
total synthesis of naturally occurring diol 1. Total
synthesis afforded (S)-1 in 12 steps and 26% overall
yield from readily available geraniol. We hope that this
simple synthesis of (S)-1 will be helpful for solving uni-
dentified bioactive properties in the future.
Acknowledgements
Thanks to Amano Pharmaceutical Co., Ltd., Meito
Sangyo Co., Ltd. And Roche Diagnostic Gmbh for a
generous gift of some enzymes.
References and Notes
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39, 3289.
Scheme 3. Transformations of the monoacetate (R)-9 to the desired
chiral diol (S)-1.

K. Takabe et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1967–1969
1969
4. (a) Racemic form: Dhokte, U. P.; Rao, A. S. Synth. Com-
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9. We also examined the enantioselective hydrolysis of the
diacetate 8 in a buffer solution; however, moderate yield (13–
78%) and enantioselectivities (22–76% ee) were observed.
10. (a) The correlation between enantioselectivity and such phys-
icochemical characteristics of the solvent as dielectric constant
and hydrophobicity is less clear, and various explanations have
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11. The ee was determined by HPLC analysis (Chiralcel OD,
hexane/isopropanol=100:1, 0.8 mL/min, Rt of (R)-isomer:
67.5 min, Rt of (S)-isomer:83.3 min).
12. A value of optical rotation in literature: (S)-1 (>97% ee):
[a]2D5=À9.1ꢀ (c 4.6, CHCl3),7 (R)-1 (85% ee): [a]2D0=+6.9ꢀ (c
3.9, CHCl3).3a