Synthesis of (2S,7S)-dibutyroxynonane, the sex pheromone of the orange wheat blossom midge, Sitodiplosis mosellana (Géhin) (Diptera: Cecidomyiidae), by diastereoselective silicon-tethered ring-closing metathesis

Article abstract of DOI:10.1016/j.tetlet.2007.06.124

The sex pheromone of Sitodiplosis mosellana, (2S,7S)-dibutyroxynonane, has been synthesised using a mixed di-t-butylsilaketal prepared from (S)-5-hexen-2-ol and prochiral 1,4-pentadiene-3-ol. Ring-closing metathesis occurs diastereoselectively and after t

Full text of DOI:10.1016/j.tetlet.2007.06.124

Tetrahedron Letters 48 (2007) 5991–5994
Synthesis of (2S,7S)-dibutyroxynonane, the sex pheromone
of the orange wheat blossom midge, Sitodiplosis mosellana
´
(Gehin) (Diptera: Cecidomyiidae), by diastereoselective
silicon-tethered ring-closing metathesis
Antony M. Hooper, Samuel Dufour, Sophie Willaert, Sophie Pouvreau and
John A. Pickett*
Biological Chemistry Department, Rothamsted Research, Harpenden, Herts AL5 2JQ, UK
Received 20 April 2007; revised 12 June 2007; accepted 20 June 2007
Available online 24 June 2007
Abstract—The sex pheromone of Sitodiplosis mosellana, (2S,7S)-dibutyroxynonane, has been synthesised using a mixed di-t-butyl-
silaketal prepared from (S)-5-hexen-2-ol and prochiral 1,4-pentadiene-3-ol. Ring-closing metathesis occurs diastereoselectively and
after the removal of the silyl group and the reduction of the double bonds, generates (2S,7S)-nonanediol with a diastereoisomeric
excess of 94% as measured by gas chromatographic analysis of the diacetylated product.
ꢀ 2007 Published by Elsevier Ltd.
The orange wheat blossom midge, Sitodiplosis mosellana
ing to coincide with the presence of emerging adult S.
mosellana, so optimising pesticide treatment.5 Although
the pheromone traps only catch males, the data provide
the time of peak emergence, midge abundance through
the season and predict the level of larval damaged grain
through the laying of eggs by females. Traps with lures
containing a mixture of stereoisomers of 2,7-dibutyroxy-
nonane in our study,5 and in other published work,4
were effective at catching male insects. However, the
greatest biological activity shown in both studies was
found with the (2S,7S)-1 isomer, the same isomer as
the natural pheromone. We previously reported the
preparation of (2S,7S)-1 by a biotechnological ap-
proach, resolving racemic 2,7-nonanediol with a lipase
from Pseudomonas cepacia. This approach utilised the
racemic diol and a minimum loss of 75% in the resolu-
tion step to remove undesired stereoisomers makes this
route very inefficient.5 Other workers have described
the synthesis of (2S,7S)-1 using chiral pool (S)-propyl-
ene oxide to produce the 2S stereocentre and enantio-
selective hydrolytic kinetic resolution of a racemic
terminal epoxide with Jacobsen’s catalyst to generate
(7S)-configuration of the stereocentre at C7, but only
achieved a moderate de of 77%.4 The distance of five
carbon atoms between the two stereocentres makes it
difficult for one stereocentre to direct the creation of
the second with high stereoselectivity. However, the
´
(Gehin) (Diptera: Cecidomyiidae), is a serious pest in all
parts of the world where wheat is grown. Adult insects
emerge from the soil during a short period in spring
and, after mating, females lay eggs producing larvae that
feed on the developing kernels causing damage, a de-
crease in grain quality and facilitating secondary fungal
attack.1,2 S. mosellana within a region has a patchy dis-
tribution, is difficult to detect and infestations can vary
enormously from year to year depending on climatic
conditions around the time of adult emergence in the
spring.3 Measures to protect crops from the orange
wheat blossom midge therefore employ prophylactic
spraying of insecticides throughout the time of possible
emergence and so are wasteful economically and detri-
mental to the environment. The sex pheromone of S.
mosellana has been identified as (2S,7S)-dibutyroxynon-
ane4 ((2S,7S)-1) and a mixture of (2,7)-dibutyroxynon-
ane isomers is now used in trap monitoring of
emerging adults to allow the timing of insecticide spray-
Keywords: Sitodiplosis mosellana; Orange wheat blossom midge; Sex
pheromone; Ring-closing metathesis; Silicon-tethered; Diastereo-
selective.
*
Corresponding author. Tel.: +44 1582 763133; fax: +44 1582
762595; e-mail: john.pickett@bbsrc.ac.uk
0040-4039/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.06.124

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A. M. Hooper et al. / Tetrahedron Letters 48 (2007) 5991–5994
recent popularity of metathesis reactions,6 in particular
ring-closing metathesis (RCM)7,8 and silicon-tethered
ring-closing metathesis,9–12 has revealed that long-range
asymmetric induction of 1,4-, 1,5- and 1,6-stereocentres
is possible. We hypothesised that this methodology
could be applied to our particular challenge, the synthe-
sis of (2S,7S)-1, by 1–6 induction to generate the (7S)-
configuration.
Table 1. Diastereoselectivity of RCM on silaketals
Diacetylated
product
RCM substrate
(Si group)
Diastereomeric
excess (%)
(2SR,7SR)-4
(2SR,7SR)-4
(2SR,7SR)-4
(2S,7S)-4
2a (phenyl)
2b (i-propyl)
2c (t-butyl)
89
91
95
94
(S)-2c (t-butyl)
O
O
NMR and GC analysis revealed that 2a and 2b were
contaminated with the symmetric silaketals which were
difficult to remove chromatographically. Also, in the
case of 2b, a fivefold excess of reagent was required to
reduce the amount of symmetric product making the
synthesis inefficient. We anticipated that using a pendant
silyl group with greater steric bulk than the isopropyl or
phenyl group would increase the diastereoselectivity and
might also allow preparation of the desired mixed silak-
etal without using excess silylating reagent. Indeed, a
chemoselective synthesis of the desired silaketal could
be achieved by treating di-t-butyl bis(trifluoromethane-
sulfonate) with pyridine and adding 5-hexen-2-ol drop-
wise at ꢀ78 ꢁC, then adding 1,4-pentadien-3-ol after
warming the mixture to room temperature. When 2c
was subjected to RCM, the crude mixture contained
only 4% of the symmetric silaketal by GC analysis.
Deprotection of 2c was problematic as there was no
reaction with TBAF, HF, HF/pyridine or BF3ÆEt2O,
O
O
(2S,7S)-1
The substrates for RCM examination, silaketals 2a and
2b, were prepared from their respective dichlorosilane,
racemic 5-hexen-2-ol and prochiral 1,4-pentadien-3-ol
(Scheme 1) and purified only by filtration through a neu-
tral alumina plug in petroleum ether. After RCM, the
crude product was analysed by 1H NMR, which re-
vealed a dioxasilacycle with the internal double bond
being exclusively cis (J = 11.4 Hz). This crude product
was reduced with H2 and subsequently desilylated with
TBAF to yield diol 3. Finally, the respective nonanediols
were diacetylated for analysis by enantioselective gas
chromatography. Diacetates 4 were prepared for analy-
sis, as the dibutyrates were not separable using the b-
cyclodextrin column available,13 and the stereochemis-
try was defined by GC co-elution with samples prepared
by resolution using a P. cepacia lipase.5,14 The desired
stereoisomer, (2SR,7SR)-4, was generated in 89% de
from 2a and 91% de from 2b (Table 1). However,
˚
but was solved by adding 4 A molecular sieves to an ex-
cess of TBAF and refluxing overnight. Reduction with
H2/PtO2 and diacetylation yielded (2SR,7SR)-4 with
95% de by GC. With the diastereoselectivity of RCM
on 2c giving excellent results, commercially available15
(S)-5-hexen-2-ol was used to synthesise a single enantio-
mer of di-t-butylsilaketal (S)-2c (Scheme 2) which was
converted to the sex pheromone (2S,7S)-116 in an overall
R
O
R
O
R
O
R
Si
Si
(i)
(iii)-(iv)
R
R
(ii)
OR
O
Si
Cl
Cl
OR
R = H; 3
R = COCH3; 4
R = Ph; 2a
R = -Pr; 2b
(v)
i
Scheme 1. Synthesis of (2SR,7SR)-4. Reagents and conditions (2a): (i) lithium 5-hexen-2-oxide, ꢀ78 ꢁC, THF, dichlorodiphenylsilane (1 equiv),
warm to rt, imidazole, 1,4-pentadien-3-ol, 71%; (2b): (i) lithium 5-hexen-2-oxide, ꢀ78 ꢁC, THF, diisopropyldichlorosilane (5 equiv), warm to rt, high
vacuum, imidazole, 1,4-pentadien-3-ol, 86%; (ii) Grubbs’ 1st generation catalyst (bis(tricyclohexylphosphine)benzylidene ruthenium(IV) chloride),
CH2Cl2, 40 ꢁC; R = Ph, 57%; R = i-Pr, 94%; (iii) H2, 10% Pd/C, MeOH; (iv) 3 equiv TBAF, 3: R = Ph, 57% over two steps; R = i-Pr, 80% over two
steps; (v) CH3COCl, pyridine, DMAP, quant.
O
O
(ii)
(i)
(iii)-(vi)
Si
Si
Si
O
O
TfO OTf
O
O
O
O
(2S,7S)-1
2c
Scheme 2. Synthesis of (2S,7S)-1. Reagents and conditions: (i) 0 ꢁC, THF, pyridine, DMAP, cool to ꢀ78ꢁC, (S)-5-hexen-2-ol, warm to rt, 1,4-
pentadien-3-ol; (ii) Grubbs’ catalyst (bis(tricyclohexylphosphine)benzylidene ruthenium(IV) chloride), CH2Cl2, 40 ꢁC, 70% over two steps; (iii)
˚
10 equiv TBAF, 4 A mol sieves, reflux 18 h, 78%; (iv) H2, PtO2, MeOH, 83%, (v) butyric anhydride, pyridine, DMAP, 85%.

A. M. Hooper et al. / Tetrahedron Letters 48 (2007) 5991–5994
5993
choice, use of pheromone traps and treatment thresholds.
HGCA Project Report No. 363, 2005.
(2S,7R)-4 (2R,7S)-4
2. Barnes, H. F. In Gall Midges of Economic importance.
Volume VII. Cereal Crops; Crosby Lockwood & Son Ltd:
London, 1956; pp 57–82.
3. Oakley, J. N.; Cumbleton, P. C.; Corbett, S. J.; Saunders,
P.; Green, D. I.; Young, J. E. B.; Rodgers, R. Crop Prot.
1998, 17, 145–149.
(2S,7S)-4
(2R,7R)-4
4. Gries, R.; Gries, G.; Khaskin, G.; King, S.; Olfert, O.;
Kaminski, L-A.; Lamb, R.; Bennett, R. Naturwissenschaf-
ten 2000, 87, 450–454.
5. Bruce, T. J. A.; Hooper, A. M.; Ireland, L.; Jones, O. T.;
Martin, J. L.; Smart, L. E.; Oakley, J.; Wadhams, L. J.
Pest Manag. Sci. 2007, 63, 49–56.
6. Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003,
42, 1901–1923.
7. Lee, C. W.; Grubbs, R. H. J. Org. Chem. 2001, 66, 7155–
7158.
8. Delgado, M.; Martin, J. D. J. Org. Chem. 1999, 64, 4798–
4816.
9. Evans, P. A.; Cui, J.; Buffone, G. P. Angew. Chem., Int.
Ed. 2003, 42, 1734–1737.
10. Hoye, T.; Promo, M. A. Tetrahedron Lett. 1999, 40, 1429–
1432.
11. Postema, M. D.; Piper, J. L. Tetrahedron Lett. 2002, 43,
7095–7099.
12. Boiteau, J.-G.; Van de Weghe, P.; Eustache, J. Tetra-
hedron Lett. 2001, 42, 239–242.
(2S,7S)-4
13. Enantioselective GC was performed using a b-cyclodextrin
GC column, 30 m · 0.32 mm id · 25 lm film thickness,
40–180 ꢁC at 3 ꢁC minꢀ1 with cold on-column injection.
Samples were compared with standards of the four
possible isomers prepared biotechnologically with a Pseu-
domonas cepaciae lipase.3 Standard GC analysis was
performed using an HP-1 column, 50 m · 0.32 mm
id · 0.52 lm film thickness, 40–150 ꢁC at 5 ꢁC minꢀ1 and
(2S,7R)-4
(2R,7S)-4
(2R,7R)-4
150–250 ꢁC at 10 ꢁC minꢀ1
.
14. Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.;
Cuccia, L. A. J. Org. Chem. 1991, 56, 2656–2665.
15. Sigma–Aldrich.
36
Figure 1. Enantioselective gas chromatograms of a mixture of the four
isomers of 2,7-diacetoxynonane (4) (above) and (below) the diacet-
oxynonane mixture produced after silicon-tethered RCM of silaketal
(S)-2c.
16. Methodology for the synthesis of (2S,7S)-1.
Pyridine (0.34 ml, 4.2 mmol) and a small spatula of
DMAP were added to a solution of di-t-butylsilyl bis(tri-
fluoromethanesulfonate) (0.65 ml, 2.0 mmol) in dry THF
(10 ml) in a flame-dried flask at room temperature. The
solution was cooled to ꢀ78 ꢁC and a solution of (S)-5-
hexen-2-ol (0.24 ml, 2 mmol) in dry THF (5 ml) at ꢀ78 ꢁC
was added dropwise via a cannula. The reaction was
warmed to room temperature over 5 h and a solution of
1,4-pentadien-3-ol (0.19 ml, 2 mmol) in dry THF (1 ml)
was added dropwise. The mixture was stirred overnight,
concentrated in vacuo and filtered through a pad of
neutral alumina to yield 540 mg of crude (S)-2c. To a
solution of the crude product (300 mg, 0.93 mmol) in dry
CH2Cl2 (40 ml) was added a solution of Grubbs’ catalyst
yield of 22% in 99% ee and 94% de (Fig. 1). Thus, this
cheaper and more direct route to the natural pheromone
isomer, with high chemical and isomeric purity confer-
ring a high biological activity, provides the potential
basis for a commercial pheromone lure production.
Acknowledgement
(bis(tricyclohexylphosphine)benzylidene
ruthenium(IV)
chloride) (40 mg, 5 mol%) in CH2Cl2 (10 ml) via a
cannula. All apparatus was flame-dried under N2. The
mixture was heated to reflux for 1 h, cooled, concentrated
in vacuo and filtered through a pad of neutral alumina to
yield the product (230 mg, 70% over two steps). Without
further purification, the product (220 mg, 0.75 mmol) was
dissolved in dry THF (20 ml), treated with TBAF
J. Galman, UCL, is thanked for the optical rotation
data. Rothamsted Research receives grant-aided sup-
port from the Biotechnology and Biological Sciences
Research Council (BBSRC).
˚
(7.5 mmol, 1 M, 7.5 ml), microwave-dried 4 A molecular
References and notes
sieves (8 g) and refluxed overnight. The mixture was
filtered through Celite and purified by flash column
chromatography (Et2O) to yield (2S,7S)-1,4-nonadien-
2,7-diol (90 mg, 78%). Dienediol (45 mg, 0.29 mmol) was
dissolved in anhydrous MeOH (5 ml) and treated with a
1. Oakley, J. N.; Talbot, G.; Dyer, C.; Self, M. M.; Freer, J.
B. S.; Angus, W. J.; Barret, J. M.; Feuerhelm, G.; Snape,
J.; Sayers, L.; Bruce, T. J. A.; Smart, L. E.; Wadhams, L.
J. Integrated control of wheat blossom midge: variety

5994
A. M. Hooper et al. / Tetrahedron Letters 48 (2007) 5991–5994
spatula tip of PtO2 and stirred under H2 for 10 min. The
1.54–1.38 (6H, m, 3-, 6-,8-H2), 1.25 (4H, m, 4-,5-H2), 1.14
(3H, d, J = 6.3 Hz, 1-H3), 0.90 (3H, t, J = 7.4 Hz, Butyl-
CH3), 0.89 (3H, t, J = 7.4 Hz, Butyl-CH3), 0.82 (3H, t,
J = 7.4 Hz, 9-H3); dC (CDCl3, 125 MHz) 173.4, 173.2,
74.9, 70.4, 36.5, 36.5, 35.8, 33.4, 26.9, 25.2, 25.1, 19.9, 18.5,
18.4, 13.6, 13.5, 9.5. EIMS at 70 eV; m/z 213 (1,
M+ꢀC4H7O2), 212 (1, M+ꢀC4H8O2), 183 (3), 168 (4),
154 (6), 141 (5), 125 (9, M+ꢀ2(C4H7O2)-H), 124 (10,
M+ꢀ2(C4H8O2)), 113 (14), 95 (14), 89 (13), 83 (10), 82
(19), 71 (100), 69 (18), 55 (10), 43 (32). HRMS calcd for
C17H32O4 (M+): 300.2301, found: 300.2319.
product was filtered to yield the nonanediol (22 mg, 48%).
Acylations were performed with acyl anhydride/pyridine/
DMAP as previously described2 to yield either diacetate
for enantioselective GC analysis or dibutyrate (2S,7S)-1
(85%), 99% ee, 94% de. Analytical data of (2S,7S)-
20
dibutyroxynonane. ½aꢁD ꢀ6.7 (c 0.6, CHCl3). dH (CDCl3,
500 MHz) 4.84 (1H, sex, J = 6.5 Hz, 2-H), 4.76 (1H, qn,
J = 6.5 Hz, 7-H), 2.22 (2H, t, J = 7.4 Hz, CH2CO), 2.20
(2H, t, J = 7.4 Hz, CH2CO), 1.61 (2H, sep, J = 7.4 Hz,
CH2CH2CO), 1.60 (2H, sep, J = 7.4 Hz, CH2CH2CO),