An efficient synthesis of (+)-exo-brevicomin via chloroallylboration

Full text of DOI:10.1021/jo981604c

2
524
J . Org. Chem. 1999, 64, 2524-2526
Sch em e 1a
An Efficien t Syn th esis of
(
+)-exo-Br evicom in via Ch lor oa llylbor a tion
†
Shaojing Hu, Seetharaman J ayaraman, and
Allan C. Oehlschlager*
Department of Chemistry, Simon Fraser University,
Burnaby, British Columbia, Canada V5A 1S6
Received August 6, 1998
In tr od u ction
We have recently shown that (Z)-(γ-chloroallyl)diiso-
pinocampheylboranes 1a ,b (Scheme 1) are readily acces-
1
sible. The chloroallylboration of 1a or 1b with aldehydes
provides a highly diastereo- (g90% de) and enantio-
selective (90-99% ee) synthesis of chiral syn-vinylchlo-
rohydrins and cis-vinylepoxides.1 Our interest in chiral
pheromone synthesis prompted us to utilize this new
strategy for the synthesis of (+)-exo-brevicomin, (+)-2.
,2
(
+)-exo-Brevicomin 2 is a component of the attracting
pheromone system of several bark beetle species belong-
ing to genera Dendroctonus and Dryocoetes. Although a
number of syntheses of 2 have been reported, many are
3
4
not satisfactory in terms of process simplicity or enan-
tiomeric and diastereomeric purities of 2. Herein, we wish
to report an efficient synthesis of (+)-2 starting from cis-
vinylepoxide 7, which is obtained via chloroallylboration
in 97% ee, 99% de.
a
Key: (a) Et2O, -95 °C, LiN(c-Hex)2; (b) BF3‚OEt2, -95 °C; (c)
-
R′CHO, -95 °C; (d) HOCH2CH2NH2; (e) OH /H2O2.
Sch em e 2a
Resu lts a n d Discu ssion
The synthesis commenced with the preparation of
aldehyde 6 according to Scheme 2. Acid-catalyzed protec-
tion of 5-chloro-2-pentanone with 2,2-dimethyl-1,3-pro-
panediol gave 4 which was alkylated with the dianion of
propargyl alcohol. Lithium metal reduction afforded
5
allylic alcohol 5, which was transformed, without puri-
fication, to aldehyde 6.
Chloroallylboration was carried out with 1a and 6 at
-
95 °C for 4 h (Scheme 1, Scheme 3). The key intermedi-
a
+
ate, cis-vinylepoxide 7, was prepared in 64% yield with
excellent enantiomeric and diastereomeric purities (97%
ee, 99% de) by standard oxidation workup. Acid-induced
epoxide-carbonyl cyclization was the most common
strategy for the synthesis of brevicomins. Cyclization of
Key: (a) 2,2-dimethyl-1,3-propanediol, H ; (b) propargyl al-
cohol, LiNH2; (c) Li/NH3; (d) O3, then SMe2.
cis-vinylepoxide 7 in a methanol and water mixture (70:
0) with a catalytic amount of p-toluenesulfonic acid gave
8% of 8 that had enantiomeric and diastereomeric
3
6
*
Present address: ChemTica Internacional, Apdo. 159-2150, San
purities of 88% ee and 90% de, obtained through gas
chromatographic analysis performed on a Cyclodex B
fused-silica column. Since the starting material 7 had
higher enantiomeric and diastereomeric purities, acid-
mediated cyclization must be accompanied by some side
racemization. Catalytic hydrogenation of 8 furnished 83%
of (+)-2 with undiminished optical and diastereomeric
purities.
J ose, Costa Rica.
†
Present address: SynPhar Laboratories, Inc., 4290-91A Street,
Edmonton, AB, Canada T6E 5V2.
(
1) (a) Hu, S.; J ayaraman, S.; Oehlschlager, A. C. J . Org. Chem.
996, 61, 7513. (b) J ayaraman, S.; Hu, S.; Oehlschlager, A. C.
Tetrahedron Lett. 1995, 27, 4765-4768.
2) (a) For the importance of halohydrins in organic synthesis, see
1
(
the following: Bonini, C.; Righi, G. Synthesis 1994, 225. Also, see as
follows: Wright, A. D.; Konig, G. M.; de Nys, R.; Sticher, O. J . Nat.
Prod. 1993, 56, 394. (b) For the importance of chiral vinylepoxides,
see the following: Ley, S. V. Pure Appl. Chem. 1994, 66, 1415.
Hudlicky, T.; Reed, J . W. In Comprehensive Organic Synthesis;
Paquette, L. A., Ed.; Pergamon Press: Oxford, 1991; Vol. 5, pp 928-
Palladium-mediated vinylepoxide ring opening with
carbon dioxide has been shown to lead to diol with
retention of stereochemistry (cis hydroxylation equiva-
9
37.
3) (a) Wood, D. L.; Browne, L. E.; Ewing, B.; Lindahl, K.; Bedard,
W. D.; Tilden, P. E.; Mori, K.; Pitman, G. B.; Hughes, P. R. Science
976, 192, 896. (b) Vit e´ , J . P.; Billings, R. F.; Ware, C. W.; Mori, K.
Naturwissenschaften 1985, 72, 99.
4) (a) Mori, K. Tetrahedron 1989, 45, 3233. (b) Mori, K. In The Total
7
7a
(
lent). Following Trost’s strategy, palladium(0) cata-
lyzed epoxy ring opening of cis-vinylepoxide 7 was carried
1
(
(6) Hoffmann, R. W.; Kemper, B.; Metternich, R.; Lehmeier, T.
Liebigs Ann. Chem. 1985, 2246.
Synthesis of Natural Products; ApSimon, J ., Ed.; J ohn Wiley: New
York, 1992; Vol. 9.
(7) (a) Trost, B. M.; Angle, S. J . Am. Chem. Soc. 1985, 107, 6123-
6124. (b) Wershofen, S.; Scharf, H. D. Synthesis 1988, 854-858.
(5) Oehlschlager, A. C.; J ohnston, B. J . Org. Chem. 1987, 52, 940.
1
0.1021/jo981604c CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/05/1999

Notes
J . Org. Chem., Vol. 64, No. 7, 1999 2525
Sch em e 3a
Sch em e 4a
a
Key: (a) Pd(0), 40 Psi CO2. (b) 0.5 M NaOH in 50% aqueous
dioxane, 15 min. (c) 2 N HCl, 20 min. (d) H2/Pd-C.
a
-
Key: (a) 6, -95 °C, 4 h. (b) OH /H2O2. (c) p-TsOH, MeOH/H2.
combination of organic extracts, washing with ice-cold brine,
(
d) H2/Pd-C.
4
drying over anhydrous MgSO , and concentration in vacuo. H
1
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.
2
out in a CO atmosphere (40 psi) for 30 min (Scheme 4).
Concentration of the reaction mixture in vacuo and
column chromatography yielded 78% of cyclic carbonate
with excellent diastereoselectivity (g99.5%). Surpris-
2
,5,5-Tr im eth yl-2-(3-for m ylp r op yl)-1,3-d ioxa n e (6). 5 was
prepared according to the procedure described in ref 5. Ozone
was bubbled through a cold solution (-78 °C) of 5 (11.4 g, 100
mmol) in a 1:1 mixture of CH Cl /MeOH (250 mL) and 10 g of
9
ingly, the cyclic carbonate 9 possessed trans stereochem-
istry, that was assigned on the basis of its clear NMR
spectrum (see the Experimental Section). It can be
hypothesized that neighboring-group participation of 1,3-
dioxane in the epoxy ring opening may be the origin of
the unusual trans palladium-mediated opening of cis-
vinylepoxide.
Various strategies for the cyclization of 9 to form 8
were investigated. Treatment of 9 with dilute acid led to
the formation of an unidentified product with high
polarity. A two-step approach was more successful in
securing the desired product 8. The one-pot, two-step
reaction was carried out by the treatment of the cyclic
carbonate 9 with 0.5 M NaOH in dioxane for 15 min,
followed by dilution with excess 2 N HCl solution and
stirring for another 20 min. This process led to the
formation of 99% of 8 with excellent enantiomeric and
diastereomeric purities (97% ee, g99.5% de).
2
2
3
NaHCO . The reaction was monitored by the appearance of a
characteristic blue color. Then, excess ozone was removed by a
stream of nitrogen. This was followed by the addition of dimethyl
sulfide (50 mL) and, finally, stirring overnight. The reaction
mixture was concentrated in vacuo to one-third of the volume,
2
diluted with water (200 mL), and then extracted with Et O (3
× 100 mL). The combined Et O extract was dried over anhyd
2
2 4 2
Na SO . Column chromatography (7:3 hexane/Et O) yielded 8.4
1
3
1
g (84%) of 6 as a colorless liquid. C NMR and H NMR spectral
data are in agreement with reported values.9
Ch lor oa llylbor a tion of Ald eh yd e 6 Usin g d Ip c
4R,5S)-2,5,5-Tr im eth yl-2-(cis-4,5-ep oxy-6-h ep ten yl)-1,3-d i-
oxa n e (7). To a stirred and cooled (-95 °C) mixture of dIpc
BOMe (11.5 mmol) and allyl chloride (15 mmol) in anhyd ether
(50 mL) was added a solution of LiN(c-Hex) (15 mmol) in THF
25 mL). After being stirred for 1 h, BF ‚OEt (30 mmol) was
2
BOMe.
(
2
-
2
(
3
2
added, followed by aldehyde 6 (11.5 mmol). The reaction was
continued at -95 °C for 4 h. All 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 supernatant
was transferred to another predried flask through a 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.
Palladium catalyzed hydrogenation of 8 gave 86% of
+)-2 with undiminished enantiomeric and diastereo-
meric purities.
(
In summary, cis-vinylepoxide 7, which is readily
prepared via chloroallylboration, undergoes acid-induced
cyclization to furnish exo-brevicomin (+)-2 in 88% ee and
Oxid a tion of Bor on In ter m ed ia tes. The residue obtained
was dissolved in THF (20 mL) with stirring and cooled to 0 °C.
Then, 3 M NaOH (12 mL) and 30% H O2 (12 mL) were
2
9
0% de. Under palladium-mediated epoxy ring opening
sequentially added. The reaction mixture was allowed to warm
to room temperature (14 h). Standard workup followed by flash
chromatography yielded a colorless liquid, 7 (1.48 g, 66% yield);
with carbon dioxide, 7 leads to the formation of cyclic
carbonate 9 via an abnormal trans opening. The latter
is converted to (+)-2 with excellent enantiomeric and
diastereomeric purities.
2
3
13
[
9
R]
D
+8.34 (c ) 2.11, Et
2
O); C NMR (CDCl ) δ 132.6, 120.3,
3
1
8.7, 70.4, 58.7, 57.1, 38.1, 29.9, 27.9, 22.8, 22.4, 20.2, 20.0; H
NMR (CDCl ) δ 5.72 (ddd, J ) 17.2, 10.4, 7.2 Hz, 1H), 5.47 (ddd,
3
J ) 17.2, 1, 1 Hz, 1H), 5.34 (ddd, J ) 10.4, 1, 1 Hz, 1H), 3.56 (d,
J ) 11.6 Hz, 2H), 3.42 (d, J ) 11.6 Hz, 2H), 3.40 (dd, J ) 4.8,
Exp er im en ta l Section
7
.2 Hz, 1H), 3.08 (m, 1H), 1.52-1.73 (m, 6H), 1.36 (s, 3H), 1.03
+
Gen er a l Ch em ica l P r oced u r es. THF and diethyl ether
(s, 3H), 0.88 (s, 3H); CIMS m/z (isobutane, rel intensity) 241 (M
were distilled from sodium benzophenoneketyl. Dicyclohexyl-
24 3
+ 1, 23), 223 (18), 155 (100), 137 (97). Anal. Calcd for C14H O :
amine [(c-Hex)
Allyl chloride was freshly distilled over P
dIpc BOMe was purchased from Aldrich and used without
2
NH] was freshly distilled from CaH
2
prior to use.
C, 69.96; H, 10.07. Found: C, 70.01; H, 10.01.
2
O
5
prior to use. The
(+)-(1R,7R)-exo-5-Meth yl-7-vin yl-6,8-d ioxa bicyclo[3.2.1]-
octa n e (8). A mixture of 7 (240 mg, 1 mmol), 5 mL of MeOH/
2
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
H
2
O (70:30), and p-TsOH (20 mg, 0.1 mmol) was stirred
overnight at room temperature. The mixture was then diluted
with Et O (20 mL) and washed with saturated NaHCO solution.
The organic layer was dried over anhyd Na SO and concen-
2
3
2
4
8
reagents. Unless otherwise stated, standard workup refers to
trated in vacuo. Purification by column chromatography over
silica gel gave 8 (96 mg, 68% yield, 90% de, 88% ee) as a volatile
(
8) Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M.
Organic Synthesis via Boranes; Wiley-Interscience: New York, 1975.
(9) Wuts, P. G. M.; Bigelow, S. S. Synth. Commun. 1981, 779.

2
526 J . Org. Chem., Vol. 64, No. 7, 1999
Notes
liquid (GC purity g99%): [R]23
+60.4 (c ) 2.10, Et
2
O); 13C NMR
10.4 Hz, 1H), 4.65 (t, J ) 7.2 Hz, 1H), 4.31 (dt, J ) 7.2, 4.4 Hz,
1H), 3.58 (d, J ) 11.4 Hz, 2H), 3.37 (d, J ) 11.4 Hz, 2H), 1.54-
1.77 (m, 6H), 1.36 (s, 3H), 1.05 (s, 3H), 0.88 (s, 3H); CIMS m/z
(isobutane, rel intensity) 285 (M + 1, 100), 199 (100). Anal.
24 5
Calcd for C15H O : C, 63.36; H, 8.51. Found: C, 63.47; H, 8.61.
D
1
and H NMR spectral data are in agreement with reported
6
values.
+
(
+)-(1R,7R)-exo-Br evicom in (2). Hydrogenation of 8 (924
mg, 6 mmol) was carried out with 67 mg of Pd/C catalyst (10%
on carbon) in ethyl acetate. After being stirred for 2 h, the
catalyst was removed by filtration. The filtrate was concentrated
in vacuo and purified by chromatography followed by distillation
to give 2 as a volatile liquid (770 mg, 83% yield, 88% ee, 90%
(
+)-(1R,7R)-exo-5-Meth yl-7-vin yl-6,8-d ioxa bicyclo[3.2.1]-
octa n e (8). A mixture of 9 (85 mg, 0.3 mmol) in 1 mL of 0.5 M
NaOH (50% aqueous dioxane) was stirred for 15 min at room
temperature. The solution was diluted with 2 N HCl (5 mL) and
2
3
4a
23
de): [R]
2
D
+60.8 (c ) 2.31, Et
2
O) (lit. [R]
D
+69.7, c ) 3.60,
stirred for another 20 min. Extraction with Et
concentration, and chromatography yielded 8 (46 mg, g99%
yield) with 97% ee and g99.5% de as a volatile liquid (GC purity
2
O (3 × 20 mL),
Et
O).
4
-(4R,5S)-[3-(2,5,5-Tr im et h yl-1,3-d ioxa n -2-yl)p r op yl]-5-
vin yl-1,3-d ioxola n -2-on e (9). To a stirred solution of Pd(OAc)
5.6 mg, 0.025 mmol) in 1 mL of THF was added triisopropyl
phosphite (20 µL, 0.175 mmol), and stirring was continued for
2
23
13
1
g99%): [R]
spectral data are in agreement with reported values.
+)-(1R,7R)-exo-Br evicom in (2). Hydrogenation of 8 was
effected following the same procedure described earlier. (+)-2
D
+87.2 (c ) 2.09, Et
2
O); C NMR and H NMR
(
6
(
1
0 min. BuLi (2.5 M in hexane; 20 µL, 0.05 mmol) was added
and the mixture stirred for another 30 min. The catalyst solution
2
3
was obtained in 86% yield (97% ee, g99.5% de): [R]
D
+67.9 (c
was poured into a solution of 7 (120 mg, 0.5 mmol) in 2 mL of
THF in an autoclave. The mixture was stirred at 5 bar CO at
2
O) (lit.4a [R]
23
)
1.41, Et
2
D
2
+69.7, c ) 3.60, Et O).
room temperature. After 30 min, the reaction mixture was
concentrated in vacuo and then chromatographed to give 9 as a
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.
2
3
13
light yellow liquid: [R]
D
+18.48 (c ) 2.33, Et
2
O); C NMR
(
CDCl ) δ 132.2, 121.31, 98.5, 82.5, 81.9, 70.4, 38.9, 33.1, 29.9,
3
1
2
1
2.8, 22.3, 19.3, 18.7, 15.2; H NMR (CDCl
3
) δ 5.86 (ddd, J )
7.1, 10.4, 7.2 Hz, 1H), 5.47 (d, J ) 17.2 Hz, 1H), 5.34 (d, J )
J O981604C