A furan route to (-)-exo-isobrevicomin

Article abstract of DOI:10.1016/S0957-4166(98)00117-7

A new enantiocontrolled synthesis of (-)-exo-isobrevicomin, isolated from male mountain pine beetles, Dendroctonus ponderosae, has been established starting from 5-ethyl-2-furfural by employing AD-mix-induced asymmetric induction and oxidative furan ring-

Full text of DOI:10.1016/S0957-4166(98)00117-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1451–1456
A furan route to (−)-exo-isobrevicomin
Takahiko Taniguchi, Miwako Takeuchi and Kunio Ogasawara∗
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 5 March 1998; accepted 18 March 1998
Abstract
A new enantiocontrolled synthesis of (−)-exo-isobrevicomin, isolated from male mountain pine beetles, Den-
droctonus ponderosae, has been established starting from 5-ethyl-2-furfural by employing AD-mix-induced asym-
metric induction and oxidative furan ring-expansion reaction as the key steps. © 1998 Published by Elsevier
Science Ltd. All rights reserved.
1. Introduction
(−)-exo-Isobrevicomin 1, (1S,5R,7S)-5-ethyl-7-methyl-6,8-dioxabicyclo[3.2.1]octane, was isolated
from male mountain pine beetles, Dendroctonus ponderosae in 1996 by Francke and co-workers1
and determined by the synthesis starting from (+)-tartaric acid.1 Later in 1997, Mori and co-workers
synthesized it in enantiomerically pure form through a sequence of steps involving the Sharpless asym-
metric dihydroxylation (AD reaction), which attained 75% ee with enantiomeric purification steps via
recrystallization.2,3 We wish to report here an alternative synthesis of (−)-exo-isobrevicomin 1 starting
from 5-ethyl-2-furfural 2 by employing the AD reaction4 and oxidative furan ring-expansion reaction5,6
as the key steps. Although the present synthesis employed the same AD reaction to induce asymmetry
as in Mori’s synthesis, the optical induction was raised to 97.5% ee probably due to the molecular
background of the substrate2 (Scheme 1).
Scheme 1.
∗
Corresponding author. Fax: +81-22-217-6845; e-mail: konol@mail.cc.tohoku.ac.jp
0957-4166/98/$19.00 © 1998 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00117-7

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T. Taniguchi et al. / Tetrahedron: Asymmetry 9 (1998) 1451–1456
2. Results and discussion
Horner–Emmons reaction of 5-ethyl-2-furfural 2 with ethyl diethylphosphonoacetate in the presence
of sodium hydride afforded the (E)-α,β-unsaturated ester 3 stereoselectively in 96% yield. Reduction of
3 with diisobutylaluminum hydride (DIBAL) followed by alkylation of the resulting allylic alcohol 4 with
benzyl bromide gave the allyl benzyl ether 5 in excellent overall yield. The ether 5 was then subjected
to the AD reaction6 using a commercially available AD-mix-α reagent7 under standard conditions in
the presence of methanesulfonamide4 to give the optically active 1,2-glycol 6 in 93% yield. As its
optical purity could not be determined at this stage, 6 was oxidized with m-chloroperbenzoic acid
(mCPBA) to initiate the ring-expansion to give the 3-pyranone 7 as a mixture of two epimers which,
without separation, was acid-cyclized to give the bicyclic enone 8 having a 6,8-dioxabicyclo[3.2.1]octane
framework in 64% overall yield as a single isomer. Enantiomeric excess of 8 was determined at this
stage as 97.5% ee by hplc using a chiral column (CHIRALCEL OJ). As no enantiomer purification was
involved during the transformation, it was assumed that the enantiomeric excess of 8 directly reflected the
chiral integrity of the 1,2-glycol 6. The high enantioselectivity was presumed to be due to the presence
of the furan ring, as simple trans-substituted olefins, as appeared in the Mori’s synthesis,2 did not exhibit
such high induction.4
Having determined the enantiomeric excess, 8 was hydrogenated on 10% palladized carbon in ethyl
acetate under hydrogen under atmospheric pressure to give the keto-alcohol 9, in excellent yield,
by concurrent hydrogenation and hydrogenolysis. To remove the hydroxy and the ketone oxygen
functionalities, 9 was sequentially tosylated and thioketalized to give the tosyl-dithiolane 11 via 10 in
a satisfactory overall yield. Treatment of 11 with lithium aluminum hydride (LAH) led to reductive
removal of the tosyloxy group to give 12 whose dithiolane group was then removed with Raney nickel8
to give (−)-exo-isobrevicomin 1. Overall yield of (−)-exo-isobrevicomin 1 from 5-ethyl-2-furfural 2 was
17% in 11 steps. Its enantiomeric excess estimated by comparison with Mori’s specific rotation value2
was 92.5% ee though a higher ee value could be expected based on the enantiomeric excess of the
intermediate 6 determined by hplc analysis (Scheme 2).
Scheme 2. Reagents and conditions: (i) (EtO)2POCH2CO2Et, NaH, THF, 96%; (ii) DIBAL, CH2Cl2, 97%; (iii) BnBr, NaH,
THF:DMF (1:1), 97%; (iv) AD-mix-α, MeSO2NH2, tert-BuOH:H2O (1:1), 93%; (v) mCPBA, CH2Cl2; (vi) pTsOH, benzene,
63% from 6; (vii) H2, 10% Pd–C, AcOEt, 96%; (viii) pTsCl, Et3N, DMAP, CH2Cl2, 96%; (ix) (CH2SH)2, BF3·OEt2, CH2Cl2,
79%; (x) LAH, THF, 79%; (xi) Raney Ni, EtOH, 56%
In summary, a combination of AD reaction and oxidative furan-ring expansion reaction allowed
construction of (−)-exo-isobrevicomin in high enantiomeric excess and in satisfactory overall yield.

T. Taniguchi et al. / Tetrahedron: Asymmetry 9 (1998) 1451–1456
1453
3. Experimental
1
IR spectra were recorded on a JASCO-IR 700 spectrometer. H NMR spectra were recorded on a
Varian Gemini-2000 (300 MHz) spectrometer. Optical rotations were measured with a JASCO-DIP 370
digital polarimeter. Optical purities were determined on a Gilson Model-307 instrument equipped with a
chiral column.
3.1. Ethyl (E)-3-(5-ethylfurfuryl)prop-2-enoate 3
To a stirred suspension of NaH (60% oil dispersion, 820 mg, 20.5 mmol) in THF (40 ml) was added
ethyl diethylphosphonoacetate (4.74 ml, 23.9 mmol) and 27 (2.12 g, 17.1 mmol) in THF (20 ml) was
added at 0°C. After stirring for 10 min at the same temperature, the reaction was quenched by addition of
water and the mixture was extracted with Et2O. The extract was washed with brine, dried over MgSO4,
evaporated under reduced pressure, and chromatographed (SiO2, 45 g, elution with AcOEt:hexane=1:20
v/v) to give the unsaturated ester 3 (3.18 g, 96%) as a pale yellow oil. IR (film): ν=1706, 1637 cm−1
.
1H NMR (CDCl3): δ=7.37 (d, 1H, J=15.7 Hz), 6.51 (d, 1H, J=3.3 Hz), 6.24 (d, 1H, J=15.7 Hz), 6.08
(dt, 1H, J=3.3, 0.8 Hz), 4.23 (q, 2H, J=7.1 Hz), 2.68 (q, 2H, J=7.5 Hz), 1.32 (t, 3H, J=7.1 Hz), 1.26 (t,
3H, J=7.5 Hz). HRMS: calcd for C11H14O3: 194.0943. Found: 194.0939. Anal. calcd for C11H14O3: C
68.02, H 7.26. Found: C 67.84, H 7.34.
3.2. (E)-3-(5-Ethyl-2-furfuryl)prop-2-en-1-ol 4
To a stirred solution of 3 (3.08 g, 15.8 mmol) in CH2Cl2 (60 ml) was added dropwise DIBAL (1.5 M
in toluene: 26.4 ml, 39.6 mmol) at −78°C. After stirring for 5 h at the same temperature, the reaction
was quenched by addition of H2O (26.4 ml). After stirring for 1 h at room temperature, the mixture was
extracted with EtO2. The extract was washed with brine, dried over MgSO4, evaporated under reduced
pressure, and chromatographed (SiO2, 65 g, elution with AcOEt:hexane=1:3 v/v) to give 4 (2.33 g, 97%)
as a pale yellow oil. IR (film): ν=3342, 1659 cm−1. 1H NMR (CDCl3): δ=6.38 (d, 1H, J=15.9 Hz), 6.22
(dt, 1H, J=15.9, 5.8 Hz), 6.14 (d, 1H, J=3.2 Hz), 5.96 (dt, 1H, J=3.2, 0.5 Hz), 4.28 (t, 2H, J=5.8 Hz),
2.65 (q, 2H, J=7.7 Hz), 1.50 (br s, 1H), 1.24 (t, 3H, J=7.7 Hz). HRMS: calcd for C9H12O2: 152.0837.
Found: 152.0806.
3.3. (E)-1-Benzyloxy-3-(5-ethyl-2-furfuryl)prop-2-ene 5
To a stirred solution of 4 (1.17 g, 7.70 mmol) in a mixture of DMF and THF (1:1 v/v, 30 ml) was added
NaH (60% oil dispersion, 400 mg, 10.0 mmol) at 0°C. After stirring for 10 min at the same temperature,
to the mixture was added benzyl bromide (1.28 ml, 10.8 mmol) at the same temperature and the stirring
was continued for 10 h at room temperature. The reaction was quenched by addition of water and the
organic layer was separated. The organic layer was washed with brine, dried over MgSO4, evaporated
under reduced pressure and chromatographed (SiO2, 25 g, elution with AcOEt:hexane=1:200 v/v) to give
5 (1.81 g, 97%) as a pale yellow oil. 1H NMR (CDCl3): δ=7.38–7.28 (m, 5H), 6.39 (dt, 1H, J=15.7, 1.4
Hz), 6.18 (dt, 1H, J=15.7, 6.0 Hz), 6.13 (d, 1H, J=3.0 Hz), 5.96 (dt, 1H, J=3.0, 1.1 Hz), 4.56 (s, 2H),
4.15 (dd, 2H, J=6.0, 1.4 Hz), 2.64 (q, 2H, J=7.5 Hz), 1.23 (t, 3H, J=7.5 Hz). HRMS: calcd for C16H18O2:
242.1307. Found: 242.1312.

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T. Taniguchi et al. / Tetrahedron: Asymmetry 9 (1998) 1451–1456
3.4. (1R,2S)-3-Benzyloxy-1-(5-ethyl-2-furfuryl)-1,2-dihydroxypropane 6
To a stirred solution of 5 (1.81 g, 7.48 mmol) and MeSO2NH2 (712 mg, 7.48 mmol) in aqueous
tert-BuOH (50%, 50 ml) was added AD-mix-α (10.4 g) at 0°C and the mixture was stirred for 61 h at
the same temperature. The reaction was quenched by addition of Na2SO3 (2.83 g, 22.5 mmol) and the
mixture, after 10 min at room temperature, was separated. The organic layer was washed successively
with 10% KOH and brine, dried over MgSO4, evaporated under reduced pressure, and chromatographed
(SiO2, 40 g, elution with AcOEt:hexane=1:3 v/v) to give (1R,2R)-6 (1.92 g, 93%) as a pale yellow oil:
30
[α]D −17.73 (c 1.23, CHCl3). IR (film): ν=3416 cm−1. 1H NMR (CDCl3): δ=7.38–7.30 (m, 5H), 6.21
(d, 1H, J=3.2 Hz), 5.92 (dt, 1H, J=3.2, 1.1 Hz), 4.69 (d, 1H, J=5.8 Hz), 4.54 (d, 2H, J=5.8 Hz), 4.09 (td,
1H, J=5.8, 3.7 Hz), 3.58 (dd, 1H, J=9.9, 3.7 Hz), 3.49 (dd, 1H, J=9.9, 5.8 Hz), 2.89 (br s, 1H), 2.78 (br
s, 1H), 2.62 (q, 2H, J=7.5 Hz), 1.21 (t, 3H, J=7.5 Hz). HRMS: calcd for C16H20O4: 276.1361. Found:
276.1363. Anal. calcd for C16H20O4: C 69.55, H 7.29. Found: C 69.36, H 7.30.
3.5. (1R,5R,7S)-7-Benzyloxymethyl-5-ethyl-6,8-dioxabicyclo[3.2.1]-oct-3-en-2-one 8
To a stirred solution of 6 (965 mg, 3.49 mmol) in CH2Cl2 (30 ml) was added mCPBA (70%, 948
mg, 3.84 mmol) at 0°C and the mixture was stirred at 0°C for 10 min and at room temperature for 3
h. The mixture was filtered through a Celite pad and evaporated to give a residue containing 7 which
was dissolved in benzene (30 ml) and refluxed with p-toluenesulfonic acid (6.65 mg, 0.03 mmol) with
removal of water using a Dean–Stark apparatus. The mixture was washed with 5% aqueous NaHCO3,
brine, dried over MgSO4, evaporated under reduced pressure, and chromatographed (SiO2, 20 g, elution
with Et2O:hexane=1:5 v/v) to give 8 (613 mg, 64%) as a pale yellow oil: [α]D31 +158.64 (c 1.26, CHCl3).
IR (film): ν=1700 cm−1. 1H NMR (CDCl3): δ=7.36–7.29 (m, 5H), 7.00 (d, 1H, J=9.8 Hz), 6.06 (dd, 1H,
J=9.8, 1.5 Hz), 4.59 (s, 2H), 4.55 (t, 1H, J=1.1 Hz), 4.00 (ddd, 1H, J=6.6, 5.9, 1.1 Hz), 3.62 (dd, 1H,
J=9.9, 5.9 Hz), 3.50 (dd, 1H, J=9.9, 6.6 Hz), 1.97 (qd, 2H, J=7.5, 1.5 Hz), 1.04 (t, 3H, J=7.5 Hz). 13
C
NMR (75 MHz) CDCl3: δ=194.8, 150.6, 128.6, 127.9, 127.8, 126.6, 105.9, 82.5, 74.1, 73.4, 70.1, 27.8,
6.7. HRMS: Calcd for C16H18O4: 274.1205. Found: 274.1181. Anal. calcd for C16H18O4: C 70.06, H
6.61. Found: C 69.94, H 6.58. Optical purity was determined to be 97.5% ee by HPLC using a chiral
column (CHIRALCEL OJ, elution with PriOH:hexane=2:98 v/v).
3.6. (1R,5R,7S)-5-Ethyl-7-hydroxymethyl-6,8-dioxabicyclo[3.2.1]octan-2-one 9
A solution of 8 (957 mg, 3.49 mmol) in AcOEt (20 ml) was hydrogenated in the presence of 10% Pd–C
(10 mg) under an atmospheric pressure of hydrogen at room temperature for 24 h. After removal of the
catalyst by filtration, the filtrate was evaporated under reduced pressure and chromatographed (SiO2, 20
26
g, elution with AcOEt:hexane=1:2 v/v) to give 9 (624 mg, 96%) as a pale yellow oil: [α]D −40.29 (c
1.06, CHCl3). IR (film): ν=3442, 1730 cm−1. 1H NMR (CDCl3): δ=4.31 (s, 1H), 4.16 (t, 1H, J=6.2 Hz),
3.62 (d, 2H, J=6.2 Hz), 2.55–2.48 (m, 2H), 2.35 (br s, 1H), 2.21–2.03 (m, 2H), 1.88 (qd, 2H, J=7.5, 2.3
Hz), 1.03 (t, 3H, J=7.5 Hz). HRMS: calcd for C9H14O4: 186.0892. Found: 186.0889.
3.7. (1R,5R,7S)-5-Ethyl-7-[p-toluenesulfonyloxymethyl]-6,8-dioxabicyclo[3.2.1]octan-2-one 10
To a stirred solution of 9 (664 mg, 3.53 mmol) in CH2Cl2 (10 ml) was added Et3N (984 µl, 7.06 mmol),
4-(N,N-dimethylamino)pyridine (DMAP) (43 mg, 0.35 mmol), and p-toluenesulfonyl chloride (1.01 g,
5.29 mmol) at room temperature and the mixture was stirred for 6 h at the same temperature. The mixture

T. Taniguchi et al. / Tetrahedron: Asymmetry 9 (1998) 1451–1456
1455
was washed with brine, dried over MgSO4, evaporated under reduced pressure, and chromatographed
28
(SiO2, 15 g, elution with Et2O:hexane=1:3 v/v) to give 10 (1.15 g, 96%) as a pale yellow oil: [α]D
−27.65 (c 0.88, CHCl3). IR (film): ν=1733, 1366, 1177 cm−1. 1H NMR (CDCl3): δ=7.80 (d, 2H, J=8.5
Hz), 7.37 (d, 2H, J=8.5 Hz), 4.25 (s, 1H), 4.21 (dd, 1H, J=7.2, 5.7 Hz), 3.99 (dd, 1H, J=10.0, 5.7 Hz),
3.90 (dd, 1H, J=10.0, 7.2 Hz), 2.50–2.45 (m, 5H), 2.11–2.01 (m, 2H), 1.79 (qd, 2H, J=7.5, 3.8 Hz), 0.92
(t, 3H, J=7.5 Hz). HRMS: calcd for C16H20O6S: 340.0980. Found: 340.1000.
3.8. (1R,5R,7S)-5-Ethyl-2-(1,3-dithiolane)-7-[p-toluenesulfonyloxymethyl]-6,8-dioxabicyclo[3.2.1]-
octane 11
To a stirred solution of 10 (1.15 g, 3.39 mmol) in CH2Cl2 (25 ml) was added ethane dithiol (313
µl, 3.73 mmol) followed by BF3·OEt2 (543 µl, 4.41 mmol) at 0°C. After stirring for 3 h at the
same temperature, the mixture was treated with H2O (3 ml) and extracted with Et2O. The extract
was washed with 0.5 N NaOH and brine, dried over MgSO4, evaporated under reduced pressure, and
chromatographed (SiO2, 25 g, elution with Et2O:hexane=1:5 v/v) to give 11 (1.11 g, 79%) as a colorless
30
1
oil: [α]D +0.48 (c 1.10, CHCl3). IR (film): ν=1363, 1176 cm−1. H NMR (CDCl3): δ=7.82 (dt, 2H,
J=8.5, 1.9 Hz), 7.35 (dd, 2H, J=8.5, 0.7 Hz), 4.24 (t, 1H, J=6.5 Hz), 4.12 (d, 1H, J=1.9 Hz), 3.91 (d, 2H,
J=6.5 Hz), 3.36–3.17 (m, 4H), 2.45 (s, 3H), 2.25 (ddd, 1H, J=14.1, 11.9, 6.0 Hz), 2.07 (ddt, 1H, J=14.1,
5.1, 1.9 Hz), 1.86–1.69 (m, 2H), 1.64 (qd, 2H, J=7.6, 2.3 Hz), 0.81 (t, 3H, J=7.6 Hz). HRMS: calcd
for C18H24O5S3: 416.0786. Found: 416.0775. Anal. calcd for C18H24O5S3: C 51.90, H 5.81. Found: C
52.04, H 5.72.
3.9. (1R,5R,7S)-5-Ethyl-7-methyl-2-(1,3-dithiolane)-6,8-dioxabicyclo[3.2.1]octane 12
A solution of 11 (172 mg, 0.41 mmol) and LiAlH4 (78.4 mg, 2.07 mmol) in THF (5 ml) was refluxed
for 8 h. After cooling, the reaction was quenched by addition of water (1 ml) and the mixture was filtered
through a Celite pad. The filtrate was evaporated under reduced pressure and chromatographed (SiO2, 5
g, elution with Et2O:hexane=1:30 v/v) to give 12 (80 mg, 79%) as a colorless oil: [α]D29 +11.39 (c 1.62,
CHCl3). 1H NMR (CDCl3): δ=4.26 (q, 1H, J=6.3 Hz), 3.98 (d, 1H, J=1.9 Hz), 3.37–3.19 (m, 4H), 2.36
(ddd, 1H, J=14.0, 12.0, 5.8 Hz), 2.08 (ddt, 1H, J=14.0, 5.2, 1.9 Hz), 1.88–1.64 (m, 4H), 1.24 (d, 3H,
J=6.3 Hz), 0.96 (t, 3H, J=7.6 Hz). HRMS: calcd for C11H18O2S2: 246.0748. Found: 246.0734.
3.10. (−)-exo-Isobrevicomin[(1S,5R,7S)-5-ethyl-7-methyl-6,8-dioxabicyclo[3.2.1]octane] 1
A solution of 12 (62 mg, 0.005 mmol) in EtOH (2 ml) was refluxed with Raney Ni (W-2) (50 mg) for
21 h. After cooling, the mixture was filtered through a Celite pad, evaporated under reduced pressure, and
chromatographed (SiO2, 5 g, elution with Et2O:pentane=1:20 v/v) to give 1 (22 mg, 56%) as a colorless
28
24
22
oil: [α]D −55.9 (c 1.00, CHCl3) [lit.: [α]D −54.3 (c 1.34, CHCl3);1 [α]D −60.4 (c 1.16, CHCl3)2].
1H NMR (CDCl3): δ=4.21 (q, 1H, J=6.3 Hz), 4.05 (br s, 1H), 1.98–1.43 (m, 6H), 1.18 (d, 3H, J=6.3 Hz),
0.96 (t, 3H, J=7.4 Hz). The spectral data including H NMR were identical with those reported.1,2
1
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