Synthesis of (1S,3R,5R,7S)-sordidin, the main component of the aggregation pheromone of the banana weevil Cosmopolites sordidus

Article abstract of DOI:10.1055/s-0028-1087373

A synthesis of the banana weevil pheromone component (1S,3R,5R,7S)-sordidin starting from (S)-2-(2-ethyl-1,3-dioxolanyl) propan-1-ol and (R)-4-hydroxypentan-2-one is described. No epimerization was observed for the final, intramolecular, acid-catalyzed cy

Full text of DOI:10.1055/s-0028-1087373

100
LETTER
Synthesis of (1S,3R,5R,7S)-Sordidin, the Main Component of the Aggregation
Pheromone of the Banana Weevil Cosmopolites sordidus
S
ynthesis of (1
S
,3
R
a
,5
R
,7
S
)-So
m
r
didin illa Lundhaug,a Lars Skattebøl,*b Arne Jørgen Aasena
a
School of Pharmacy, University of Oslo, P.O. Box 1068, 0316 Oslo, Norway
Department of Chemistry, University of Oslo, P.O. Box 1033, 0315 Oslo, Norway
Fax +47(22)85507; E-mail: lars.skattebol@kjemi.uio.no
b
Received 27 August 2008
approach is illustrated retrosynthetically in Scheme 1, de-
picting the preparation of building blocks (R)-3 and (R)-4
as our primary objective. We intended to metalate the bro-
mide (R)-3 and react it with the ketone (R)-4, thereby cre-
ating the third stereogenic center of 2.
Abstract: A synthesis of the banana weevil pheromone component
(1S,3R,5R,7S)-sordidin starting from (S)-2-(2-ethyl-1,3-dioxola-
nyl)propan-1-ol and (R)-4-hydroxypentan-2-one is described. No
epimerization was observed for the final, intramolecular, acid-cata-
lyzed cyclization step using aqueous oxalic acid.
Key words: pheromone, enzymatic resolution, Grignard reaction,
diastereoselectivity
O
O
O
HO
OH
The banana, which is an important food crop in tropical
and subtropical areas of the world, is threatened by dis-
ease and predators.1 The banana weevil, Cosmopolites
sordidus (Germar), is a serious pest insect for this plant.
1a
2
O
O
+
Br
O
OTBDMS
(R)-4
The weevil elicits
a
male-produced aggregation
pheromone2 of which the main component, (+)-sordidin,
was proven to be (1S,3R,5R,7S)-1-ethyl-3,5,7-trimethyl-
2,8-dioxabicyclo[3.2.1]octane (1a).3–5
(R)-3
Scheme 1
With the purpose of finding satisfactory conditions for the
metalation of (R)-3 some metalation reactions were car-
ried out on the racemic compound. First we attempted a
bromine–lithium exchange reaction with t-BuLi in THF at
–78 °C, and the subsequent reaction with 4-methylpentan-
2-one (5) as a model substance gave the alcohol 6 in 42%
yield (Figure 2); replacing THF with other solvents
caused no improvement in the yield, and neither did the
use of Barbier conditions. The lithium derivative was also
formed from 3 and lithium metal in the presence of naph-
thalene as catalyst, and reaction with 5 furnished a mix-
ture of 6 (41%) and the dimer 7 (30%). We then turned to
the Grignard reagent derived from 3, prepared in THF as
solvent and 1,2-dibromoethane as entrainer,14 but reaction
with 5 gave a mixture of products containing the alcohol
6 (10%) and the dimer 7 (20%). Apparently, a more reac-
tive magnesium was needed and we resorted to Rieke
magnesium, prepared by reduction of magnesium dichlo-
ride immediately before use.15 In this case the Grignard
reaction afforded 6 in 52% yield together with a small
amount of the dimer (5%). Other products were formed as
well and it appeared that opening of the dioxolane ring
took place. The CeCl3-catalyzed Grignard reagents16 or
metalations involving zinc17 gave even lower yields of 6
besides other products. Hence, Rieke magnesium seemed
the best choice for the metalation of 3.
4
5
O
O
O
O
O
6
O
O
O
3
7
1a
1b
1c
1d
ratio:
44
4
1
4
Figure 1
Oehlschlager and co-workers6,7 conducted field studies
with synthetic compounds and showed the pheromone to
consist of a mixture of the diastereomers 1a–d in approx-
imately the ratio given in Figure 1. Additional syntheses
of sordidin or its stereoisomers have been published.8–11
Recently, two asymmetric syntheses of (+)-sordidin (1a)
have been reported12,13 The need for a more practical syn-
thesis of the pheromone enantiomers seemed apparent to
us at the time our project was initiated, and our goal was
a synthesis of the major component 1a, without having to
resort to preparative GC for isolation of the final product.
A synthesis of sordidin (1a) requires control of three ste-
reogenic centers in the open-chain precursor
(Scheme 1). Furthermore, the subsequent cyclization
should take place without epimerization at C-7 (see
Figure 1 for numbering), which has been a problem.5 Our
2
SYNLETT 2009, No. 1, pp 0100–0102
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087373; Art ID: D30508ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8
We then focused on the chiral bromide (R)-3, which was
prepared as outlined in Scheme 2. Protection of the carbo-
nyl group of the chiral oxazolidinone 818 was achieved

LETTER
Synthesis of (1S,3R,5R,7S)-Sordidin
101
gave an almost theoretical yield of the alcohol (S)-13 and
the acetate (R)-14. The latter was quantitatively hydro-
lyzed to (R)-13, and both enantiomers were protected with
tert-butyldimethylchlorosilane furnishing (S)- and (R)-15,
respectively. Selective deprotection with Hg(ClO4)2 buff-
O
O
O
O
Br
O
OH
5
6
3
23
ered by CaCO3 gave after 5–10 minutes reaction time
the ketones (S)- and (R)-4 with better than 98% ee.20 Thus,
both enantiomers of 4 were available from 2,4-pentanedi-
one in 60% overall yield. This simple route was, however,
hampered by the slow rate of the enzymatic resolution.
O
O
O
O
7
Using Rieke magnesium (R)-3 was converted to the
Grignard reagent and the reaction with (R)-4 gave a 2:1
mixture of the diastereomeric alcohols 16a and 16b in
50% yield; however, when two equivalents of the Grig-
nard reagent were used the yield was actually improved to
69% based on (R)-4 (Scheme 4). The poor diastereoselec-
tivity was disappointing, but study of models did not indi-
cate any significant selectivity for the addition reaction.
Compounds 16a and 16b could not be separated by flash
chromatography, but deprotection with TBAF furnished
the corresponding diols, which were easily separated by
chromatography, yielding 17a in 42% overall yield.
Figure 2
with ethylene glycol under rather harsh conditions yield-
ing the dioxolane 9 in 93% yield without detectable race-
mization. Reduction of 9 with LiBH4 in the presence of
one equivalent of water19 furnished the alcohol (S)-10 in
90% yield. Finally, the alcohol was converted in 96%
yield to the bromide (R)-3 with better than 98% ee.20 The
overall yield of the bromide from 8 was 80%.
O
O
O
O
O
O
O
i
O
N
O
N
O
O
O
O
i
(R)-3 + (R)-4
HO
HO
OR
OR
8
9
16a R = TBDMS
17a R = H
16b R = TBDMS
17b R = H
ii
O
O
ii
iii, iv
(R)-3
OH
Scheme 4 Reagents and conditions: i) Mg (Rieke), THF, 0 °C to
r.t., 69%; ii) TBAF, THF, r.t., 42% overall of 17a.
(S)-10
Scheme 2 Reagents and conditions: i) ethylene glycol, 20 mol%
TsOH, PhH, reflux, 48 h, 93%; ii) LiBH4, THF, r.t., 90%; iii) TsCl,
pyridine; iv) NaBr, NaHCO3, DMF, 60 °C; 96% overall from (S)-10.
For the final step in the synthesis, the acid-catalyzed cy-
clization of the diols, epimerization at C-7 was a major
concern. Treatment of a CH2Cl2 solution of 17a with
TsOH (10 mol%) at room temperature caused rapid cy-
clization with epimerization at C-7 furnishing sordidin 1a
and 1b in a 1:1 ratio. In addition a substantial amount of
the tetrahydrofuran 185 was formed. Several other proton
and Lewis acids were tried and cyclization took place, but
most of them caused epimerization at C-7 as well. A
breakthrough was attained when oxalic acid was used as
catalyst. The free acid gave no reaction even in excess, but
The second building block, (R)-4, was obtained by enzy-
matic resolution of the racemic dithiolane 11, prepared by
NaBH4 reduction of the dithiolane 1221 (Scheme 3). We
had previously shown that this method resolved similar
dithiolanes in high yields and optical purity.22 Treatment
of 11 with vinyl acetate in the presence of the commercial-
ly available B-lipase from Candida antarctica (CALB)
OAc
OTBDMS
v
S
S
iii, iv
S
S
(R)-4
(R)-14
(R)-15
O
OH
i
ii
S
S
S
S
12
11
iv
v
OTBDMS
OH
(S)-4
S
S
S
S
(S)-13
(S)-15
Scheme 3 Reagents and conditions: i) NaBH4, 90%; ii) vinyl acetate, CALB, r.t., two weeks, 50%; iii) K2CO3, MeOH–H2O (4:1), reflux,
100%; iv) t-BuMe2SiCl, imidazole, DMF, r.t.; v) Hg(ClO4)2, CaCO3, THF–H2O, 90%.
Synlett 2009, No. 1, 100–102 © Thieme Stuttgart · New York

102
K. Lundhaug et al.
LETTER
(2) Budenberg, W. J.; Ndiege, I. O.; Karago, F. W. J. Chem.
treatment of a pentane solution of 17a with an excess of a
saturated aqueous solution of oxalic acid at room temper-
ature caused rapid conversion to (+)-sordidin (1a)24 with-
out any detectable epimerization; the yield by this two-
phase reaction was 75% (Scheme 5). The compound was
unchanged after several weeks at 4 °C, but epimerization
at C-7 was detected after storage at room temperature for
only a few days. On the other hand, when treating the diol
17b under the same conditions cyclization occurred with
epimerization furnishing a 2:1 mixture of the diastereo-
mers 1e and 1f in 92% yield; the compounds were charac-
terized by comparison of the spectral data with those of
the racemates.6
Ecol. 1993, 19, 1905.
(3) Beauhaire, J.; Ducrot, P.-H.; Malosse, C.; Rochat, D.;
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L.; Alpizar, D.; Falles, M. Naturwissenschaften 1996, 83,
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L. M.; Alpizar, D.; Falles, M.; Budenberg, W. J.; Ahuya, P.
J. Chem. Ecol. 1997, 23, 1145.
(8) Ducrot, P.-H. Synth.Commun. 1996, 26, 3923.
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O
O
(10) Wardrop, D. J.; Forslund, R. E. Tetrahedron Lett. 2002, 43,
i
O
O
17a
737.
(11) Wardrop, D. J.; Forslund, R. E.; Landrie, C. L.; Velter, A.-I.;
Wink, D.; Surve, B. Tetrahedron: Asymmetry 2003, 14, 929.
(12) Yadav, J. S.; Reddy, K. B.; Prasad, A. R.; Rehman, H. U.
Tetrahedron 2007, 64, 2063.
(13) Enders, D.; Breuer, I.; Nühring, A. Eur. J. Org. Chem. 2005,
2677.
1b
1a
O
O
O
O
18
i
O
O
+
17b
(14) Ponaras, A. A. Tetrahedron Lett. 1976, 3105.
(15) Rieke, R. D.; Li, P. T.-J.; Burns, T. P.; Uhm, S. T. J. Org.
Chem. 1981, 46, 4323.
1e
1f
(16) Imamoto, T.; Takiyama, N.; Nakamura, K. Tetrahedron
Lett. 1985, 26, 4763.
Scheme 5 Reagents and conditions: i) sat. aq oxalic acid, pentane,
r.t.
(17) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117.
(18) Evans, D. A.; Ennis, M. D.; Le, T. J. Am. Chem. Soc. 1984,
106, 1154.
(19) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.;
Miyashiro, J. M.; Rowell, B. W.; Yu, S. S. Synth. Commun.
1990, 20, 307.
(20) The ee was determined by GC using a CP Chirasil-DEX CB
(25 m × 0.25 mm, 0.25 mm film thickness) fused silica
capillary column at isothermic temperatures.
(21) (a) Barros, M. T.; Geraldes, C. F. G. C.; Maycock, C. D.;
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Manske, R.; Gosselck, J. Chem. Ber. 1980, 113, 800.
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L.; Sundby, E. Acta Chem. Scand. 1999, 53, 360.
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(24) Spectroscopic Data for 1a
In conclusion, the synthesis of (+)-sordidin was achieved
in an overall yield that compares well with results from
earlier syntheses. Saturated aqueous oxalic acid was a su-
perior catalyst for the cyclization of the diol 17a, yielding
pure 1a without having to resort to preparative GC for iso-
lation.
Acknowledgment
We thank the Research Council of Norway for a grant to K. L.
References and Notes
1H NMR (300 MHz, CDCl3): d = 0.96 (d, J = 7.0 Hz, 3 H),
0.96 (t, J = 7.5 Hz, 3 H), 1.14 (d, J = 6.1 Hz, 3 H), 1.28 (s,
3 H), 1.18–1.35 (m, 3 H), 1.65 (m, 2 H), 2.13 (dd, J = 8.4,
12.4 Hz, 1 H), 2.31 (m, 1 H), 3.93 (m, 1 H). 13C NMR (75
MHz, CDCl3): d = 8.0, 19.9, 21.9, 26.5, 27.4, 40.1, 44.1,
44.9, 64.5, 78.7, 108.6.
(1) Gold, C. S.; Pinese, B.; Pena, J. E. In Tropical Fruit Pests
and Pollinators: Biology, Economic Importance, Natural
Enemies and Control; Pena, J. E.; Sharp, J.; Wysoki, M.,
Eds.; Cabi Publishing: University of Florida USA, 2002, 13–
56.
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