Singh and Guiry
JOCNote
SCHEME 1
and therefore of interest.12 Our approach involved the ring-
opening of epoxide 20, formed in 99.5% ee and 85% yield
employing the Sharpless asymmetric epoxidation protocol,7
by the Grignard reagent derived from 2-(2-bromoethyl)-2-
methyl-1,3-dioxolane, Scheme 2. Takano’s synthesis of exo-
brevicomin in 29% overall yield and 78.5% ee required 6
steps and also started with the same epoxide 20.12e Our ring-
opening of epoxide 20 in the presence of CuI (10 mol %) at -
78 °C afforded syn-diol 21 in 80% yield. The diol 21 was
treated with ZrCl4 (10 mol %) in methanol under microwave
irradiation to give an 86% yield of (1R,5S,7S)-5-methyl-7-
vinyl-6,8-dioxabicyclo[3.2.1]octane (22) via the formation of
(S)-1-((2R,6S)-6-methoxy-6-methyltetrahydro-2H-pyran-2-
yl)prop-2-en-1-ol (23), which was also recovered in 12%
yield. Acetal 23 could be quantitatively transformed into
the required compound 22 upon treatment with ZrCl4 in
MeOH under microwave irradiation. Hydrogenation of 22
in the presence of a catalytic amount of 5% Pd/C (5 wt %) at
10 bar of pressure in an autoclave gave (þ)-endo-brevicomin
(18) in 95% yield and ee 98.5%. The configuration of (þ)-
TABLE 1. Optimization of Microwave-Assisted Deprotection and
Cyclization of 1,3-Dioxane (1) Catalyzed by ZrCl4
a
catalyst loading
(mol %)
time
isolated
epimeric
entry
temp (°C) (min) yieldb (%) ratio of (2:3)c
1
2
3
4
5
6
10
10
10
10
5
80
60
50
40
50
50
3
3
3
80
87
87
75:25
73:27
73:27
73:27 (71:29)
75:25
73:27
3 (2 h)d 84 (86)
3
3
87
76
2
aZrCl4 (5 mol %) and diol (0.5 mmol) were dissolved
in 200 μL of methanol and irradiated under MW at 150 W.
bIsolated yield of both epimers after purification by column
chromatography. cEpimeric ratio was determined by 1H
NMR spectroscopy as well as by GC. dThe results in
parentheses refer to reactions carried out thermally at 40 °C.
1
endo-brevicomin was confirmed by comparing the H, 13C
NMR, and optical rotation14 with literature data.12 We have
also synthesized (-)-endo-brevicomin 18 in 99.3% ee using
the same synthetic sequence, this time starting with the
enantiomer of epoxide 20.
acids such as CAN, Cu(OTf)2, SnCl2, Ti(OiPr)4, FeCl3, and
InCl3 did not catalyze the required transformation.
We extended our study to investigate the microwave-
assisted deprotection of 1,3-dioxalane and intramolecular
cyclization of (3R,4S)-diols (4-8)7 to give the corresponding
6-methoxytetrahydropyrans 9-17 in good to very high
yields (Table 2). 6- and 7-methyl-substituted diols (4 and 5)
gave 84% and 76% yields of the corresponding acetals under
microwave irradiation (entries 1 and 2). The best dr (80:20)
was observed with diol 7 (entry 4) and this methodology was
also found to be applicable for the synthesis of phenyl-
substituted tetrahydropyran 16, 17 (entry 5).
We were keen to expand this methodology by applying it
in total synthesis and believed that it could be used in an
asymmetric synthesis of endo- and exo-brevicomin 18 and 19.
The exo- and endo-isomers of brevicomin are constituents of
volatiles from several species of bark beetles and have been
shown to be necessary for their communication. (þ)-exo-
Brevicomin (19) is the aggregation pheromone of the western
pine beetle, Dendroctonus brevicomis.11 (þ)-endo-Brevico-
min enhances the response of southern pine beetles,
Dendroctonus frontalis, to the female-produced pheromone
frontalin, and (-)-endo-brevicomin significantly reduces this
response.11e
We have also investigated the synthesis of (þ)-exo-brevi-
comin 19, employing our ZrCl4-catalyzed methodology,
Scheme 3. The epoxide 20 was converted to the p-nitro-
benzoate 24 by using Mitsunobu reaction conditions in 80%
yield. The nitrobenzoate ester 24 was hydrolyzed with
K2CO3 to afford (2R,3R)-(þ) epoxide 25 in 75% yield.13
(þ)-exo-Brevicomin 19 was subsequently synthesized in
99.0% ee with 65% overall yield from epoxide 25 by using
the same synthetic sequence as outlined in Scheme 2. The
enantiomeric purity was determined by using a chiral β-Dex
GC column and the absolute configuration was determined
by comparing the optical rotation14 with literature data.12
In summary, we have developed a microwave-assisted
ZrCl4-catalyzed synthesis of 6-methoxy-substituted tetrahy-
dropyrans in good to very high yields. We have also used this
(12) For the syntheses of optically pure brevicomin, see: (a) Mori, K.
Tetrahedron 1974, 30, 4223-4227. (b) Bernardi, R.; Fugani, C.; Grasselli, P.
Tetrahedron Lett. 1981, 22, 4021–4024. (c) Mori, K.; Seu, Y.-B. Tetrahedron
1985, 41, 3429–3431. (d) Larcheveque, M.; Lalande, J. J. Chem. Soc., Chem.
Commun. 1985, 83–84. (e) Hatakeyama, S.; Sakurai, K.; Takano, S. J. Chem.
Soc., Chem. Commun. 1985, 1759–1761. (f) Yusufoglu, A.; Antones, S.; Scharf,
H.-D. J. Org. Chem. 1986, 51, 3485–3487. (g) Seu, Y.-B.; Mori, K. Agric. Biol.
Chem. 1986, 50, 2923–2924. (h) Oehlschlager, A. C.; Johnston, B. D. J. Org.
Chem. 1987, 52, 940–943. (i) Matsumoto, K.; Suzuki, N.; Ohta, H. Tetrahedron
Lett. 1990, 31, 7163–7166. (j) Padwa, A.; Fryxell, G. E.; Zhi, L. J. Am. Chem.
Soc. 1990, 112, 3100–3109. (k) Vettel, S.; Diefenbach, L. A.; Haderlein, G.;
Hammerschmidt, S.; Kuhling, K.; Mofid, M.-R.; Zimmermann, T.; Knochel, P.
Tetrahedron: Asymmetry 1997, 8, 779–800. (l) Burke, S. D.; Muller, N.;
Beaudry, C. M. Org. Lett. 1999, 1, 1827–1829. (m) Hu, S.; Jayaraman, S.;
Oehlschlager, A. C. J. Org. Chem. 1999, 64, 2524–2526. (n) Gallos, J. K.;
Kyradjoglou, L. C.; Koftis, T. V. Heterocycles 2001, 55, 781–784. (o) Mayer, S.
F.; Mang, H.; Steinreiber, A.; Saf, R.; Faber, K. Can. J. Chem. 2002, 80, 362–369.
(p) Kumar, D. N.; Rao, B. V. Tetrahedron Lett. 2004, 45, 2227–2229. (q) Prasad,
K. R.; Angarasan, P. Tetrahedron: Asymmetry 2005, 16, 3951–3953.
Numerous asymmetric syntheses of endo- and exo-brevi-
comin (18 and 19) have been reported but the development
of a short synthetic route with overall good yield was lacking
(13) Albert, B. J.; Sivaramakrishnan, A.; Naka, T.; Czaicki, N. L.; Koide,
(11) (a) Silverstein, R. M.; Brownlee, R. G.; Bellas, T. E.; Wood, D. L.;
Browne, L. E. Science 1968, 159, 889–891. (b) Bedard, W. D.; Tilden, P. E.;
Wood, D. L.; Silverstein, R. M.; Brownlee, R. G.; Rodin, J. O. Science 1969,
164, 1284–1285. (c) Kinzer, G. W.; Fentiman, A. F., Jr.; Page, T. E., Jr.; Foltz,
K. J. Am. Chem. Soc. 2007, 129, 2648–2659.
(14) Optical rotation for (þ)-endo-brevicomin [R]20D þ77.9 (c 1.2, Et2O,
98.5% ee) [lit.12c [R]20D þ78.8 (c 0.5, Et2O), lit.12e [R]26D þ74.6 (c 1.06, Et2O)],
lit.12f [R]21D þ79.5 (c 1.18, Et2O)], (-)-endo-brevicomin [R]20D -76.6 (c 1.5,
Et2O, 99.3% ee), [lit.12c [R]20D -75.9 (c 0.717, Et2O), lit.12b [R]20D -76.7 (c
ꢁ
R. L.; Vite, J. P.; Pitman, G. B. Nature 1969, 221, 477–478. (d) 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 1976, 192, 896–898. (e) Vite, J. P.; Ware,
C. W.; Billings, R. F.; Mori, K. Naturwissenschaften 1985, 72, 99–100.
2.0, Et2O), lit.12f [R]22D -78.9 (c 0.99, Et2O)]. and (þ)-exo-brevicomin [R]20
D
þ 76.3 (c 1.35, ether, 99.0% ee), [lit.12a [R]20 þ 84.2 (c 2.2, Et2O), lit.12m
D
[R]20D þ 67.9 (c 1.41, Et2O), lit.12d [R]20D þ 64.8 (c 1.25, CHCl3)].
J. Org. Chem. Vol. 74, No. 15, 2009 5759