An Efficient Enantioselective Synthesis of (+)-Disparlure

Article abstract of DOI:10.1021/jo9820871

Synthesis of (+)-disparlure, 1, the sex pheromone of gypsy moth (Lymantria dispar), commenced from cis-vinyl epoxide 4 which was prepared by our asymmetric chloroallylboration in 99% de and 94% ee. Hydroboration of 4 using dicyclohexylborane in THF, followed by sodium perborate oxidation gave a crystalline cis-3,4-epoxy alcohol 3 whose enantiomeric purity was enhanced by recrystallization. Conversion of 3 to (+)-disparlure was via alkylation of the tosylate. (+)-Disparlure was produced in four steps with an overall yield of 27% and ≥99.5% ee.

Full text of DOI:10.1021/jo9820871

J . Org. Chem. 1999, 64, 3719-3721
3719
An Efficien t En a n tioselective Syn th esis of (+)-Disp a r lu r e
Shaojing Hu, Seetharaman J ayaraman,*,† and Allan C. Oehlschlager*,‡
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6
Received October 16, 1998
Synthesis of (+)-disparlure, 1, the sex pheromone of gypsy moth (Lymantria dispar), commenced
from cis-vinyl epoxide 4 which was prepared by our asymmetric chloroallylboration in 99% de and
94% ee. Hydroboration of 4 using dicyclohexylborane in THF, followed by sodium perborate oxidation
gave a crystalline cis-3,4-epoxy alcohol 3 whose enantiomeric purity was enhanced by recrystalli-
zation. Conversion of 3 to (+)-disparlure was via alkylation of the tosylate. (+)-Disparlure was
produced in four steps with an overall yield of 27% and g99.5% ee.
Sch em e 1
In tr od u ction
(+)-Disparlure, 1, (+)-(7R,8S)-cis-7,8-epoxy-2-methyl-
octadecane, is the sex pheromone of female gypsy moth,
Lymantria dispar (L). The pheromone is required to be
nearly enantiopure to elicit attraction. Many syntheses
of (+)-1 using chiral natural products,1,2 asymmetric
induction (Sharpless asymmetric epoxidation3 and asym-
metric dihydroxylation4), and catalytic biotransformation5
have been reported.
In the present work we have applied our recently
developed chloroallylboration of aldehydes to the prepa-
ration of (+)-1. The envisioned strategy involved hy-
droboration of cis-vinyl epoxide 4 to give cis-3,4-epoxy
alcohol 3 which, upon tosylation followed by cuprate
alkylation, would yield (+)-1 (Scheme 1). We considered
it likely that 3 would be crystalline and that enantiomeric
purity could be enhanced at this stage. The current
synthesis is noteworthy because of the low number of
steps and high enantiomeric purity of (+)-1 produced.
Sch em e 2
A. P r ep a r a tion of cis-Vin yl Ep oxid e. We have
recently6 demonstrated that reaction of aldehydes with
(Z)-(γ-chloroallyl)diisopinocampheylborane, 5, furnish
syn-vinylchlorohydrins or cis-vinyl epoxides with high
stereoselectivity (g90% de, 90-99% ee). Cyclization of
syn-vinylchlorohydrins with potassium carbonate in
methanol also gives the corresponding cis-vinyl epoxides
(Scheme 2). Employment of this process, using com-
mercially available undecanyl aldehyde gave the desired
cis-vinyl epoxide 4 in 63% yield (99% de, 94% ee).
Intermediate 4 could be obtained directly from the above
reaction by oxidation workup or by base-induced cycliza-
tion of syn-R-chlorohydrin 6 (R′ ) C10H21) produced via
ethanolamine workup.
B. Hyd r obor a tion of cis-Vin yl Ep oxid e 4. Initial
reactions examined hydroboration of 4 with 9-BBN and
BH3‚SMe2, followed by oxidation with NaOH/H2O2. No
cis-3,4-epoxy alcohol 3 was isolated. Hydroboration of 4
with 9-BBN followed by oxidation with various oxidation
reagents (NaOAc/H2O2, NaBO3) did not yield expected 3
either. Polar product similar to that expected from
epoxide opening was detected. It is reported that reaction
of vinyl epoxide with 9-BBN or BH3‚SMe2 leads to
opening of the epoxide.7a According to the proposed
mechanism, the borons of 9-BBN and BH3‚SMe2 coordi-
nate with the epoxide oxygen lone pair electrons promot-
ing opening.
† Present address: SynPhar Laboratories, Inc., Edmonton, AB,
Canada T6E 5V2.
‡ Present address: ChemTica International, Apdo. 159-2159, San
J ose, Costa Rica.
(1) (a) Mori, K. J . The Total Synthesis of Natural Products; Apsimon,
J ., Ed.; J ohn Wiley & Sons: New York, 1992; Vol. 9.
(2) (a) Masaki, Y.; Serizawa, Y.; Nagata, K.; Oda, H.; Nagashima,
H.; Kaji, K. Tetrahedron Lett. 1986, 27, 231. (b) J igajinni, V. B.;
Wightman, R. H. Carbohydr. Res. 1986, 147, 145.
(3) (a) Mori, K.; Ebata, T. Tetrahedron 1986, 42, 3471. (b) Lin, G.-
D.; J iang, Y.-Y.; Zhou, W.-S. Acta Chem. Sin. 1985, 257.
(4) Sinha-Bagchi, A.; Sinha, S. C.; Keinan, E. Tetrahedron: Asym-
metry 1995, 6, 2889.
(5) Tsuboi, S.; Yamafuji, N.; Utaka, M. Tetrahedron: Asymmetry
1997, 8, 375.
(6) (a) Hu, S.; J ayaraman, S.; Oehlschlager, A. C. J . Org. Chem.
1996, 61, 7513. (b) J ayaraman, S.; Hu, S.; Oehlschlager, A. C.
Tetrahedron Lett. 1995, 27, 4765.
(7) (a) Zaidlewicz, M.; Uzarewicz, A.; Sarnowski, R. Synthesis 1979,
62. (b) For a related hydroboration, see: Brown, H. C.; Vara Prasad,
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10.1021/jo9820871 CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/28/1999

3720 J . Org. Chem., Vol. 64, No. 10, 1999
Hu et al.
Sch em e 3
Exp er im en ta l Section
Gen er a l Ch em ica l P r oced u r es. THF and diethyl ether
were distilled from sodium-benzophenone ketyl. Dicyclohexyl-
amine [(c-Hex)2NH] was freshly distilled from CaH2 prior to
use. Allyl chloride was freshly distilled over P2O5 prior to use.
Undecanyl aldehyde was distilled prior to use. The lIpc2BOMe
and 9-BBN were purchased from Aldrich and used without
purification. Moisture- and air-sensitive reactions were con-
ducted under argon in vacuum-dried glassware. A nitrogen
glovebag was used to weigh moisture-sensitive compounds.
Syringes and cannulas were used to transfer air-sensitive
reagents.13 Unless otherwise stated, standard workup refers
the combination of organic extracts, washing with ice-cold
brine, drying over anhydrous MgSO4, and concentration in
vacuo. 1H NMR and 13C NMR spectra were recorded at 400
and 100 MHz, respectively. GC analyses were conducted using
a 30-m × 0.25-mm i.d. fused silica column coated with DB-1
with FID detection.
cis-(3R,4R)-3,4-Ep oxy-1-tetr a d ecen e, 4. To a stirred and
l
cooled (-95 °C) mixture of Ipc2BOMe (11.5 mmol) and allyl
chloride (15 mmol) in anhydrous ether (50 mL) was added a
solution of LiN(c-Hex)2 (15 mmol) in THF (25 mL). After
stirring for 1 h, BF3‚OEt2 (30 mmol) and undecanyl aldehyde
(11.5 mmol) were added sequentially. The reaction was
continued at -95 °C for 4 h. Solvents were removed in vacuo
at room temperature, and the residue was triturated with
n-pentane (40 mL) and allowed to settle (12 h). The superna-
tant was transferred to another predried flask by cannula. The
residue was further treated with pentane (2 × 30 mL), and
the pentane extracts were combined. Removal of pentane in
vacuo furnished a semisolid.
Since the boron of dicyclohexylborane is more sterically
encumbered, it would not be expected to coordinate as
strongly with the epoxide oxygen lone pair electrons.
Therefore, ring opening should be a slower process.7b
Hydroboration using HB(c-Hex)2 followed by addition of
NaOH/H2O2 also failed to produce 3. The failure of
hydroboration of 4 in the foregoing reactions could be
because of complications during the oxidation due to the
sensitivity of the epoxide to strong base.8 Thus, we
reexamined hydroboration of 4 using dicyclohexylborane
in several solvents and determined that the reaction
proceeded well in THF but was much slower in Et2O,
pentane, or toluene. Oxidation with various reagents
gave 3. Surprisingly, NaOAc/H2O2, which is useful for
organoboranes with base-sensitive functional groups did
not give a good result. Sodium perborate9 is the reagent
of choice providing 3 in 67% yield (Scheme 3).10
Oxid a tion of Bor on In ter m ed ia te. The residue obtained
from chloroallylboration reaction was dissolved in THF (20 mL)
with stirring and cooled to 0 °C. Then, 3 M NaOH (12 mL)
and 30% H2O2 (12 mL) were sequentially added. The reaction
mixture was allowed to warm to room temperature (14 h).
Standard workup followed by flash chromatography yielded a
colorless liquid 4 (1.32 g, 63% yield). [R]23 +21.09 (c ) 8.81,
D
CH2Cl2); 13C NMR (CDCl3, ppm) 132.78, 120.13, 58.79, 57.17,
31.90, 29.58, 29.53, 29.42, 29.30, 27.75, 26.29, 22.66, 14.04.
1H NMR (CDCl3, ppm) 5.69 (ddd, J ) 17.2, 10.4, 7.2 Hz, 1H),
5.46 (ddd, J ) 17.2, 1, 1 Hz, 1H), 5.34 (ddd, J ) 10.2, 1, 1 Hz,
1H), 3.39 (dd, J ) 7.2, 4.3 Hz, 1H), 3.06 (m, 1H), 1.58-1.26
(m, 18H), 0.87 (t, J ) 6.8 Hz, 3H); CIMS m/z (isobutane, rel
intensity) 211 (M+ + 1, 18), 169 (100). Anal. Calcd for
Two recrystallizations from 1% ether in hexane solu-
tion yielded 3 (mp: 38.5-39.5 °C) in enantiopure form.11
C. Syn th esis of (+)-Disp a r lu r e. Tosylation of cis-3,4-
epoxy alcohol 3 with tosyl chloride in pyridine for 2 days
gave a low yield of 2 (50% yield). However, reaction of 3
with tosyl chloride and powdered potassium hydroxide
in ethyl ether gave a good yield of 2 (86%). Cuprate-
mediated alkylation of 2 furnished with (+)-1 in 76%
yield (Scheme 3). Enantiomeric purity of (+)-1 was
determined to be g99.5% by Oliver’s method.12
C
14H26O: C, 79.94; H, 12.46. Found: C, 79.80; H, 12.55.
Enantiomeric purity was determined to be 94% by 1HNMR
analysis using chiral shift reagent Eu(hfc)3.
cis-(3R,4R)-3,4-E p oxyt et r a d eca n -1-ol, 3. Dicyclohexyl-
borane is prepared from freshly distilled cyclohexene and BH3‚
SMe2. Further purification by sublimation is performed. A
solution of epoxide 4 (420 mg, 2 mmol) in THF (1 mL) was
added to 2 mmol of dicyclohexylborane-THF solution (2 mL)
via syringe while stirring. Stirring was continued for 4 h at
room temperature. The reaction was quenched by addition of
910 mg of NaBO3‚H2O and 0.5 mL of H2O. The mixture was
stirred overnight, and then 4 g of anhydrous K2CO3 was added.
After 2 h, the mixture was diluted with 15 mL of anhydrous
Et2O. Solid was removed by filtration and washed with Et2O.
Concentration of the filtrate in vacuo, followed by flash
chromatography using hexane:Et2O, 7:3, as eluant yielded 291
mg of 3 (67% yield), mp 33-37.5 °C. Two cycles of recrystal-
Con clu sion s
cis-Vinyl epoxide 4 (94% ee) was generated by chloro-
allylboration of undecanaldehyde using (Z)-γ-chloroal-
lylborane, 5. Subsequent hydroboration using dicyclo-
hexylborane in THF followed by sodium perborate
oxidation gave cis-epoxy alcohol 3 which was converted
to (+)-1 in overall yield of 27% and g99.5% ee.
lization from 1% Et2O in hexane gave mp 37.7-38.5 °C. [R]23
D
-8.34 (c ) 6.32, Et2O); 13C NMR (CDCl3, ppm) 60.81, 56.68,
54.94, 31.88, 30.68, 29.66, 29.56, 29.53, 29.49, 29.28, 27.96,
(8) Matteson, D. S. Stereodirected Synthesis with Organoboranes;
Springer-Verlag: New York, 1995.
(9) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J . Org. Chem.
1989, 54, 5930.
1
26.46, 22.63, 14.01. H NMR (CDCl3, ppm) 3.86 (m, 2H), 3.09
(dt, J ) 8.0, 4.4 Hz, 1H), 2.93 (td, J ) 5.6, 4.4 Hz, 1H), 1.92-
1.26 (m, 21H), 0.87 (t, J ) 6.8 Hz, 3H). IR (film) 3308, 2917,
2850, 1417, 1068, 1047, 843 cm-1. CIMS m/z (isobutane, rel
intensity) 229 (M+ + 1, 100), 211 [(M+ - 18) + 1, 95]. Anal.
Calcd for C14H28O2: C, 73.63; H, 12.36. Found: C, 73.80; H,
(10) For
a preliminary account of hydroboration of some vinyl
epoxides, see: Hu, S.; J ayaraman, S.; Oehlschlager, A. C. Tetrahedron
Lett. 1998, 39, 8059.
(11) As the enantiomeric purity of (+)-1 is g99.5% based on the
method of Oliver (see ref 12), it is reasonable to assume 3 possessing
enantiomeric purity of g99.5%.
(13) Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M.
(12) Oliver, J . E.; Waters, R. M. J . Chem. Ecol. 1995, 21, 199.
Organic Synthesis via Boranes; Wiley-Interscience: New York, 1975.

Efficient Enantioselective Synthesis of (+)-Disparlure
J . Org. Chem., Vol. 64, No. 10, 1999 3721
12.45. Alternatively, 3 can be synthesized from hydroboration
of protected syn-chlorohydrin 6 (R′ ) C10H21) by a one-pot
three-step process.10
stirred slurry of cuprous iodide (385 mg, 2 mmol) in Et2O (15
mL) at -40 °C. After stirring for 30 min, the flask was warmed
to 0 °C for 5 min and then cooled to -78 °C, and a solution of
tosylate 2 (382 mg, 1 mmol) in Et2O (5 mL) was added
dropwise. After 30 min stirring, the reaction was allowed to
warm to room temperature. The reaction was quenched with
saturated aqueous ammonium chloride at 0 °C. The organic
extract was separated, and the aqueous layer was extracted
with Et2O (3 × 15 mL). The combined organic extract was
washed with brine (2 × 15 mL) and then dried over Na2SO4.
Column chromatography over silica gel (hexane:Et2O, 100:1)
cis-(3R,4R)-3,4-Ep oxytetr a d eca n yl tosyla te, 2. A solu-
tion of 3 (228 mg, 1 mmol) in anhydrous ether (2 mL) was
cooled to -5 °C. p-Toluenesulfonyl chloride (190 mg, 1 mmol)
was added, followed by the addition of powdered KOH in small
portions over 15 min. After 4 h, the reaction was quenched
with ice-water (10 mL). The aqueous layer was extracted with
ether (3 × 10 mL). The combined ether extract was dried over
anhydrous Na2SO4. Solvent removal followed by column chro-
matography yielded 2 (328 mg, 86% yield). [R]23 +9.16 (c )
D
gave 1 (204 mg, 76% yield). [R]23D +0.61 (c ) 5.06, CCl4), (lit.3a
2.62, Et2O); 13C NMR (CDCl3, ppm) 129.85, 127.90, 67.71,
56.90, 53.24, 31.88, 29.53, 29.48, 29.43, 29.26, 27.91, 27.75,
1
[R]23 +0.6, c ) 5.6, CCl4). H NMR and 13C NMR spectra of 1
D
are identical to those reported.3a
1
26.41, 22.62, 21.58, 14.04. H NMR (CDCl3, ppm) 7.80 (d, J )
16 Hz, 2H), 7.36 (d, J ) 16 Hz, 2H), 4.19 (m, 2H), 2.92 (m,
1H), 2.93 (m, 1H), 2.44 (s, 3H), 1.98 (m, 1H), 1.76 (m, 1H),
1.43-1.26 (m, 18H), 0.89 (t, J ) 6.8 Hz, 3H). Anal. Calcd for
Ack n ow led gm en t. We thank the National Sciences
and Engineering Research Council, Canada, for finan-
cial support through a research grant to A.C.O.
C
21H34O4S: C, 65.93; H, 8.96. Found: C, 66.07; H, 8.89.
(+)-(7R,8S)-cis-7,8-Ep oxy-2-m eth ylocta d eca n e, 1. Iso-
pentyllithium in hexane (5.44 mL, 4 mmol) was added to a
J O9820871