A general method for the synthesis of nonracemic trans-epoxides: Concise syntheses of trans-epoxide-containing insect sex pheromones

Article abstract of DOI:10.1021/ol702273n

A general method for the synthesis of chiral nonracemic frans-epoxides has been developed that provides rapid access to alkyl-, alkenyl-, alkynyl-, and phenyl-substituted frans-epoxides from aldehydes. This methodology has also been applied in concise and

Full text of DOI:10.1021/ol702273n

ORGANIC
LETTERS
2
007
Vol. 9, No. 24
083-5086
A General Method for the Synthesis of
Nonracemic trans-Epoxides: Concise
Syntheses of trans-Epoxide-Containing
Insect Sex Pheromones
5
Baldip Kang and Robert Britton*
Department of Chemistry, Simon Fraser UniVersity, 8888 UniVersity DriVe, Burnaby,
British Columbia, V5A 1S6, Canada
rbritton@sfu.ca
Received September 17, 2007
ABSTRACT
A general method for the synthesis of chiral nonracemic trans-epoxides has been developed that provides rapid access to alkyl-, alkenyl-,
alkynyl-, and phenyl-substituted trans-epoxides from aldehydes. This methodology has also been applied in concise and high-yielding syntheses
of both trans-epoxide containing insect sex pheromones.
6
Over the last half century the structure elucidation of insect
sex pheromones has provided a growing arsenal of chemicals
for crop protection. Whereas many methods for insect control
often involve the indiscriminate eradication of pestiferous
and beneficial insects alike, small quantities of insect sex
pheromones can selectively disrupt the reproduction of harm-
ful insects or lure these pests to traps, providing opportunities
epoxy pheromones with high levels of optical purity. The
asymmetric synthesis of vinyl epoxide-containing phero-
mones, however, remains a significant challenge. Thus, while
7
the asymmetric epoxidation of dienones, R,â,γ,δ-unsaturated
amides, esters, and carbinols have been reported, the
epoxidation of unfunctionalized dienes often suffer from
8
9
10
9
(
5) (a) Hentges, S. G.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
263. (b) Jacobsen, E. N.; Mark o´ , I.; Mungall, W. S.; Schr o¨ der, G.;
Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968. (c) Morikawa, K.;
Park, J.; Andersson, P. G.; Hashiyama, T.; Sharpless, K. B. J. Am. Chem.
Soc. 1993, 115, 8463.
(6) For examples see: (a) Keinan, E.; Sinha, S. C.; Sinha-Bagchi, A.;
Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B. Tetrahedron Lett. 1992, 33,
1
for ecologically sensible crop management. However, insect
4
2
chemoreception can be highly enantiodiscrimatory, and
oftentimes the development of an economically feasible
asymmetric pheromone synthesis represents a significant
challenge. In this regard, a number of developments in asym-
6
411. (b) Mori, K.; Sano, S.; Yokoyama, Y.; Bando, M.; Kido, M. Eur. J.
3
metric catalysis have had a profound impact. In particular,
Org. Chem. 1998, 1135. (c) Zhang, Z.-B.; Wang, Z.-M.; Wang, Y.-X.; Liu,
H.-Q.; Lei, G.-X.; Shi, M. J. Chem. Soc., Perkin Trans. 1 2000, 53.
(7) For examples see: (a) Allen, J. V.; Bergeron, S.; Griffiths, M. J.;
Mukherjee, S.; Roberts, S. M.; Williamson, N. M.; Wu, L. E. J. Chem.
Soc., Perkin Trans. 1 1998, 3171. (b) Nemoto, T.; Ohshima, T.; Yamaguchi,
K.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2725.
4
robust procedures for the asymmetric epoxidation and dihy-
5
droxylation of olefins has provided access to a variety of
(1) Jones, O. T. Pestic. Sci. 1998, 54, 293.
(
2) (a) Mori, K. Chirality 1998, 10, 578. (b) Mori, K. Chem. Commun.
(8) For examples see: (a) Kakei, H.; Nemoto, T.; Ohshima, T.; Shibasaki,
M. Angew. Chem., Int. Ed. 2004, 43, 317. (b) Kinoshita, T.; Okada, S.;
Park, S.-R.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2003,
42, 4680.
(9) For examples see: (a) Chang, S.; Lee, N. H.; Jacobsen, E. N. J. Org.
Chem. 1993, 58, 6939. (b) Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-
X.; Shi, Y. J. Org. Chem. 1998, 63, 2948. (c) Burke, C. P.; Shi, Y. Angew.
Chem., Int. Ed. 2006, 45, 4475.
1
997, 1153. (c) Mori, K. Acc. Chem. Res. 2000, 33, 102.
3) (a) Mori, K. Top. Curr. Chem. 2004, 239, 1. (b) Mori, K.; Tashiro,
T. Curr. Org. Synth. 2004, 1, 11.
4) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
b) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am. Chem.
(
(
(
Soc. 1990, 112, 2801. (c) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.;
Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224. (d) Xia, Q.-H.; Ge, H.-Q.;
Ye, C.-P.; Liu, Z.-M.; Su, K.-X. Chem. ReV. 2005, 105, 1603. (e) Zhang,
W.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 287.
(10) Katsuki, T.; Martin, V. S. Organic Reactions; Paquette, L. A., Ed.;
John Wiley & Sons, Inc.: New York, 1996; Vol. 48, pp 1-285.
1
0.1021/ol702273n CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/02/2007

poor regio- and enantiocontrol.11 Alternative routes to
optically active vinyl epoxides include dihydroxylation of
dienes and subsequent transformation of the vicinol diol to
a cis- or trans-epoxide,12 chloroallylboration of aldehydes
to afford vinyl chlorohydrins followed by base-induced
cyclization,13 and reaction of chiral sulfur ylides with R,â-
unsaturated aldehydes. As a complement to these proce-
dures, we report here a general method for the asymmetric
synthesis of trans-vinyl epoxides and the application of this
methodology to the synthesis of both trans-epoxide-contain-
ing insect sex pheromones.
istry of both of these compounds, the total number of
synthetic transformations required (9 and 10-13, respec-
tively) may well limit their practical application. In order to
support the field-testing of compound 1, we sought to
develop a concise and general method for the synthesis of
trans-vinyl epoxides that would also afford access to
posticlure (2). With this in mind, it was anticipated that both
1 and 2 could be constructed following a straightforward
sequence of events that involves the diastereoselective
addition of a diynyl anion (e.g., 4) to an R-chloro aldehyde
(e.g., 5) followed by Lindlar reduction and epoxide formation
(Scheme 1). Surprisingly, while the enantioselective synthesis
14
Recently, the first examples of trans-epoxide-containing
insect sex pheromones were reported from the pine looper
1
5
moth Bupalus piniarius and the tussock moth Orgyia
1
6
postica. Throughout Europe, the pine looper moth has
become a serious threat to the Scots pine (Pinus sylVestris),
while in Japan the tussock moth is a major concern for litchi
and mango producers.16 Interestingly, the females of these
moths rely on unusual trans-epoxide containing sex phero-
mones to attract males. As detailed in Figure 1, the sex
Scheme 1. General Synthetic Strategy for Construction of the
Dienyl Epoxide Subunit Found in Both 1 and 2
of R-chloro aldehydes was reported independently by Jør-
1
8
19
gensen and MacMillan close to 3 years ago, to the best
of our knowledge, the results presented here represent the
first application of this straightforward and seemingly general
strategy to the enantioselective synthesis of trans-epoxides.
The asymmetric R-chlorination of pentanal and undecanal
is summarized in Table 1. In our hands, the R-chlorination
of pentanal with the perchlorinated quinone 13 and imida-
2
0
zolidinone catalyst 14 afforded the R-chloro aldehyde 10
in good yield but only moderate enantiomeric excess. In fact,
entry 2 represents our most favorable result following this
protocol, and typically the enantiomeric excess of 10 varied
from 10 to 40%, indicating that racemization occurred during
the reaction or subsequent purification. Fortunately, by
employing N-chlorosuccinimide (NCS) and the diphenylpyr-
rolidine catalyst 17, 10 was obtained in good yield and
optical purity (entry 3). The enantioselectivity of this process
was further improved through the use of commercially
available (L)-prolinamide (16), affording (2R)-2-chloropen-
tanal in 85% enantiomeric excess (entry 4). Following this
procedure, the asymmetric R-chlorination of undecanal
provided 12 in good yield and enantiomeric excess (entry
Figure 1. Insect sex pheromones isolated from female Bupalus
piniarius (1) and Orgyia postica (2) moths and their common
(3Z,6Z,1S,2S)-1,2-epoxyhepta-3,6-diene subunit 3.
pheromones isolated from B. piniarius and O. postica share
remarkable structural similarities in that both 1 and 2 contain
the (3Z,6Z,1S,2S)-1,2-epoxyhepta-3,6-diene subunit 3. Based
on the potential importance of these pheromones for crop
2
1
protection, syntheses of 115 and 2
16a,17
have been reported.
While these efforts have confirmed the absolute stereochem-
(
11) Olofsson, B.; Somfai, P. Aziridines and Epoxides in Organic
Synthesis; Yudin, A. K., Ed.; Wiley-VCH Verlag GmbH & Co.: Weinheim,
2
006; Chapter 9, pp 315.
5
).
(12) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515.
13) Hu, S.; Jayaraman, S.; Oehlschlager, A. C. J. Org. Chem. 1996,
(
6
1, 7513.
14) (a) Aggarwal, V. K.; Alonso, E.; Bae, I.; Hynd, G.; Lydon, K. M.;
(18) Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen,
K. A. J. Am. Chem. Soc. 2004, 126, 4790.
(
Palmer, M. J.; Patel, M.; Porcelloni, M.; Richardson, J.; Stenson, R. A.;
Studley, J. R.; Vasse, J.-L.; Winn, C. L. J. Am. Chem. Soc. 2003, 125,
(19) Brochu, M. P.; Brown, S. P.; Macmillan, D. W. C. J. Am. Chem.
Soc. 2004, 126, 4108.
1
0926. (b) Aggarwal, V. K.; Bae, I.; Lee, H.-Y.; Richardson, J.; Williams,
D. T. Angew. Chem., Int. Ed. 2003, 42, 3274.
15) Francke, W.; Gries, G.; Gries, R.; H a¨ uâler, D.; M o¨ ller, K.; Plass,
E. German Patent DE 19814330A1, March 31, 1998.
16) (a) Wakamura, S.; Arakaki, N.; Yamamoto, M.; Hiradate, S.; Yasui,
(20) The imidazolidinone catalyst 14 ([R]D ) -63.0 (c 2.0, CHCl3))
was prepared as described in: Jen, W. S.; Wiener, J. J. M.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2000, 122, 9874. The observed specific rotation
of our synthetic material was consistent with the reported value ([R]D )
-63.2 (c 2.0, CHCl3)).
(21) The (2S,5S)-Diphenylpyrrolidine catalyst 17 ([R]D ) -103.8 (c 1.0,
CHCl3)) was prepared as described in: Chong, J. M.; Clarke, I. S.; Koch,
I.; Olbach, P. C.; Taylor, N. J. Tetrahedron: Asymmetry 1995, 6, 409. The
observed specific rotation of our synthetic material is consistent with that
reported for ent-17 ([R]D ) 104.5 (c 1.0, CHCl3)).
(
(
H.; Yasuda, T.; Ando, T. Tetrahedron Lett. 2001, 42, 687. (b) Wakamura,
S.; Arakaki, N.; Yamamoto, M.; Hiradate, S.; Yasui, H.; Kinjo, K.; Yasuda,
T.; Yamazawa, H.; Ando, T. Biosci. Biotechnol. Biochem. 2005, 69, 957.
(17) (a) Fernandes, R. A.; Kumar, P. Tetrahedron 2002, 58, 6685. (b)
Muto, S.; Mori, K. Eur. J. Org. Chem. 2001, 4635.
5084
Org. Lett., Vol. 9, No. 24, 2007

stereochemical outcome of the 1,2-addition reaction (10 f
8a-f) could be confirmed by application of Murata’s
method for J-based analysis, the trans-configuration of the
1
Table 1. Asymmetric R-Chlorination of Pentanal and
Undecanal
27
epoxides 19a-e was confidently assigned by analysis of
2
8
NOE spectra and/or scalar coupling constants.
Table 2. Synthesis of trans-Epoxides
cat. chlorinating
product
%
entry aldehyde (mol %)
reagent
conditionsa (% yield) ee
b
b
b
b
c
1
2
3
4
5
9
9
15 (10)
14 (5)
17 (10)
16 (10)
16 (10)
NCS
13
NCS
NCS
NCS
A
B
A
A
A
10 (>97)
2
10 (80) 58
10 (>97) 77
10 (>97) 85
12 (91) 89
9
9
11
a
A: CH2Cl2, 0 °C (1 h) to rt (3 h); B: acetone, -30 °C, (6 h). b ee
determined by chiral GC analysis (see SI) of the corresponding chloro-
hydrin generated by NaBH4 reduction. ee determined by conversion to
c
posticlure (2) and comparison of the specific rotation of 2 with literature
values.
With the optically active R-chloro aldehyde 10 in hand,
we next turned our attention to the diastereoselective addition
a
Ratio of diastereomers determined by analysis of 1H NMR spectra
22,23
b
of organometallic reagents to this substance.
Not supris-
obtained on the crude chlorohydrins 18a-f. Isolated yield from 10.
c
d
ingly,22 the addition of Grignard reagents derived from
Isolated as a 17:1 mixture of trans:cis epoxide isomers. Isolated as a
1
4:1 mixture of trans:cis epoxide isomers. e Isolated as a 8:1 mixture of
1
-heptyne to 10 in Et O afforded the chlorohydrin 18a in
2
trans:cis epoxide isomers.
good yield but moderate diastereomeric excess (dr ) 4:1).
While a brief survey of solvents (THF, hexane) failed to
significantly improve upon this result, we were pleased to
find that the alkynyl lithium24 reagent, derived from the
The application of this methodology to the synthesis of
the two trans-epoxide-containing insect sex pheromones is
detailed in Scheme 2. The diynes 23 and 24 are readily
available from 1-undecyne (21) and 1-heptyne (22), respec-
tively, following deprotonation and alkylation with propargyl
mesylate. As both compounds 23 and 24 proved to be
unstable even when stored in solution in the freezer (-22
°C), both were prepared fresh and/or purified immediately
prior to their subsequent use. Unfortunately, following our
standard procedure (see Table 2), addition of the lithium
anion derived from 23 to a THF solution of the R-chloro
aldehyde 10 provided a complex mixture of products, from
which the desired chlorohydrin 25 was isolated by flash
chromatography in very low yield (<10%). However, after
considerable experimentation it was found that treatment of
2
addition of n-BuLi to 1-heptyne in Et O, reacted with
compound 10 to afford the chlorohydrin 18a as a 9:1 mixture
of anti:syn diastereomers. This ratio was further improved
to 20:1 when the reaction was carried out in THF. Conversion
of the crude chlorohydrin 18a into the corresponding trans-
epoxide 19a (KOH, EtOH) proceeded in good overall yield.
Following this general procedure, it was demonstrated that
a variety of trans-epoxides could be synthesized from (2R)-
2
9
2
-chloropentanal. Thus, this route provides rapid access to
25
alkynyl-, trans-alkenyl-, cis-alkenyl-, phenyl-, and alkyl-
substituted trans-epoxides.26 While in certain instances the
(22) For examples of the diastereoselective addition of organometallic
reagents to R-chloro aldehydes see: (a) Cornforth, J. W.; Cornforth, R. H.;
Mathew, K. K. J. Chem. Soc. 1959, 112. (b) Bernard, D.; Doutheau, A.;
Gore, J.; Moulinoux, J.; Quemener, V.; Chantepie, J.; Quash, G. Tetrahedron
(26) The ee of the epoxides 19a and 19c-e was determined to be 85%
by chiral GC analysis and/or conversion to known compounds and
comparison of [R]D values with those in the literature (see Supporting
Information), indicating that there is no erosion of optical purity during the
1,2-addition reactions (10 f 18a-f).
1
1
4
989, 45, 1429. (c) Brinkmann, H.; Hoffmann, R. W. Chem. Ber. 1990,
23, 2395. (d) Frenking, G.; K o¨ hler, K. F.; Reetz, M. T. Tetrahedron 1991,
7, 9005. (e) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191. (f)
Concell o´ n, J. M.; Rodr ´ı guez-Solla, H.; Simal, C.; G o´ mez, C. Synlett 2007,
7
5.
(
(27) Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.; Tachibana,
K. J. Org. Chem. 1999, 64, 866.
23) For a theoretical investigation of nucleophilic addition to an R-chloro
aldehyde see: Cee, V. J.; Cramer, C. J.; Evans, D. A. J. Am. Chem. Soc.
006, 128, 2920 and references therein.
24) For the diastereoselective addition of optically pure lithio-vinyl
1
(28) The overlapping H4/H5 resonances at δ 2.66 ppm in the H NMR
2
spectrum of 19f precluded nOe analysis; however, their chemical shift is
consistent with those reported for the H4/H5 resonances in trans-(4S,5S)-
4,5-epoxynonane (δ 2.61-2.70 ppm) and differ significantly from those
reported for cis-(4S,5R)-4,5-epoxynonane (δ 2.87-2.96 ppm) in: Besse,
P.; Sokoltchik, T.; Veschambre, H. Tetrahedron: Asymmetry 1998, 9, 4441.
(29) Gries, G.; Slessor, K. N.; Gries, G.; Khaskin, G.; Wimalaratne, P.
D. C.; Gray, T. G.; Grant, G. G.; Tracey, A. S.; Hulme, M. J. Chem. Ecol.
1997, 23, 19.
(
sulfoxides to a racemic R-chloro aldehyde see: Marino, J. P.; Anna, L. J.;
Fern a´ ndez de la Pradilla, R.; Martinez, M. V.; Montero, C.; Viso, A. J.
Org. Chem. 2000, 65, 6462.
(
25) As a prelude to the synthesis of 1 it was also demonstrated that the
alkynyl epoxide 19a could be converted to the cis-alkenyl epoxide 19d
Lindlar’s catalyst, quinoline, H2, EtOH) in excellent yield (94%).
(
Org. Lett., Vol. 9, No. 24, 2007
5085

pheromone displayed identical chromatographic properties
(
chiral GC) to an authentic sample of this substance.31
In summary, exploiting recent advances in the asymmetric
Scheme 2. Total Synthesis of trans-Epoxide-Containing Insect
Sex Pheromones (-)-1 and (-)-2
1
8,19
R-chlorination of aldehydes,
we have developed an
efficient and general method for the construction of alkynyl,
phenyl, alkyl, and alkenyl trans-epoxides that complements
existing methodologies for their syntheses. In addition, we
have applied this methodology to the synthesis of the trans-
epoxide-containing insect sex pheromones (-)-1 and
(
(
-)-2. Notably, the overall yields for (-)-1 (80%) and
-)-2 (76%) from pentanal and undecanal, respectively,
and the total number of synthetic steps required compare
well with the existing literature syntheses of these sub-
1
5,16a,17
stances.
Moreover, the entire sequence of reactions
required to access compounds (-)-1 or (-)-2 is often carried
out in less than 1 day, further highlighting the efficiency of
this process, which has now provided sufficient amounts of
(
-)-1 to initiate a population monitoring study of B.
32
piniarius. We are currently exploring the utility of variously
substituted chlorohydrins as chiral builiding blocks for
complex molecule synthesis, and the results of these efforts
will be reported in due course.
the diyne 23 with n-BuLi at -78 °C in THF followed after
60 s by the addition of 10 and, after a further 5 min at -78
°
C, aqueous workup afforded the desired chlorohydrin 25
in reproducibly excellent yield (>80%). The optimization
of this reaction was critical, as all synthetic intermediates
involved in the syntheses of 1 or 2 decompose on storage in
the freezer (<12 h), and consequently the subsequent Lindlar
reduction and epoxidation reactions were necessarily carried
out in direct succession. Deviation from this optimized
reaction protocol led to the production of numerous byprod-
ucts that both compromised the overall yield of the processes
and complicated the final purification of the pheromones.
With this in mind, the crude chlorohydrins 25 or 26 were
treated directly with Lindlar’s catalyst and a stoichiometric
Acknowledgment. We thank NSERC and Merck Frosst
Canada for support. B.K. was supported in part by a SFU
Graduate Fellowship. We thank Regine Gries (SFU) for
carrying out chiral GC analysis, Dr. Andrew Lewis (SFU)
for assistance with NMR spectroscopy, and Tristen Gilchrest
for carrying out some preliminary experiments.
Supporting Information Available: Detailed experi-
mental procedures and characterization data for each com-
pound. This material is available free of charge via the
Internet at http://pubs.acs.org.
3
0
amount of quinoline and hydrogenated at 0 °C. The
OL702273N
1
progress of these reactions were monitored by H NMR
(
30) Use of less than one equivalent of quinoline led to partial
spectroscopy, and upon complete reduction of both alkyne
functions KOH was directly added to effect the epoxida-
tion reaction, providing the sex pheromones from B. piniarius
and O. postica in excellent overall yields. The spectral data
9,10
6,7
hydrogenation of the ∆ alkene function in 25 or the ∆ alkene function
in 26. Lindlar reduction of 25 or 26 at room temperature led to the
production of unidentified byproducts.
(31) We thank Professor Gerhard Gries for kindly providing an authentic
sample of (-)-1 and Regine Gries for carrying out the comparative GC
analysis with our synthetic material.
1
13
(
H NMR, C NMR, MS, IR, [R]
D
) derived from these
(32) Field-studies will be carried out by the Forest Research Institute in
substances were in complete agreement with that reported
Eberswalde, Germany. The results of these studies will be published in
due course.
1
5,16
in the literature,
and the synthetic B. piniarius sex
5086
Org. Lett., Vol. 9, No. 24, 2007