Stereoselective synthesis of (-)-6,7-dehydroferruginyl methyl ether

Article abstract of DOI:10.1016/S0957-4166(00)00007-0

A stereoselective synthetic route to (-)-6,7-dehydroferruginyl methyl ether was developed from (S)-(-)-α-cyclocitral. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00007-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 781–787
Stereoselective synthesis of (−)-6,7-dehydroferruginyl
methyl ether
Yonghong Gan,a Anpai Li,a Xinfu Pan,a,∗ Albert S. C. Chan b and Teng-Kuei Yang c
aDepartment of Chemistry, National Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000,
People’s Republic of China
bUnion Laboratory of Asymmetry Synthesis and Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Kowloon, Hong Kong
cDepartment of Chemistry, National Chung-Hsing University, Taichang, Taiwan
Received 10 November 1999; accepted 14 December 1999
Abstract
A stereoselective synthetic route to (−)-6,7-dehydroferruginyl methyl ether was developed from (S)-(−)-α-
cyclocitral. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Most diterpenoids exhibit significant bioactivities, such as antibacterial,1,2 antidermatophytic,2,3
antioxidant,4 etc. (−)-6,7-Dehydroferruginol 2, a diterpenoid with the abietane skeleton, was separated
from Juniperus communis lin, wood by Bredenberg.5 Barton et al.6 concluded that the A/B ring junction
in the diterpenoids is trans and this was confirmed by King et al.7 The synthetic route followed by
King et al. is not stereospecific and the key intermediate 1 was obtained in low yield by a laborious
process. In order to study further the relationship between the structure and bioactivities, it is desirable to
develop a stereoselective synthetic route whereby the trans-isomer could be obtained predominantly.
In connection with our synthetic studies on the naturally occurring diterpenes,8,9 and based on our
knowledge, no stereoselective synthetic work has been reported on the title compound. Here, we report a
highly stereoselective synthetic route to (−)-6,7-dehydroferruginyl methyl ether 3.
∗
Corresponding author. E-mail: panxf@lzu.edu.cn
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00007-0
tetasy 3230

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2. Results and discussion
As shown in Schemes 1 and 2, our synthetic strategy is AC→ABC. Compared with Matsumoto’s
work,10 we used readily available p-anisic acid as the C ring starting material. (S)-(−)-α-Cyclocitral 9
([α]25D −708, c 0.03, CHCl3; lit.11 [α]25D −743, c 0.05, CHCl3), which was prepared from geranic acid
via five steps, was used as the A ring starting material (Scheme 1).
Scheme 1. Reagents and conditions: (i) 85% H3PO4, toluene; (ii) K2CO3/MeI; (iii) LiAlH4; (iv) PCC, CH2Cl2
As shown in Scheme 2, condensation of 9 with 10 in the presence of n-BuLi/hexane afforded the
desired stryene derivative 11 in 60% yield. The 1H NMR of 11 reveals a trans disubstituted double bond
(the vicinal coupling constant of vinyl protons is J=15 Hz). Selective hydrogenation of 11 over 10% Pd/C
gave the phenethyl derivative 12. In order to get a better yield and stereoselectivity in the intracyclization
step, several conditions had been tested; we found BF3·Et2O in CH2Cl2 to be the best condition, which
1
gives the trans-isomer 1 in over 90% yield (d.e. >95%, determined by H NMR). Compound 1 was
acetylated by acetyl chloride and anhydrous AlCl3 in CH2Cl2 to give the compound 13 in 90% yield.
Compound 13 was then reacted with CH3Li to give the alcohol 14 in high yield. Alcohol 14 was
dehydrated with p-TosOH/benzene to give the styrene derivative 15, then hydrogenation of 15 afforded
(+)-ferruginyl methyl ether 16, quantitatively. Oxidation of 16 by CrO3/HOAc gave (+)-sugiyl methyl
ether 17 in 85% yield. After reduction and dehydration, the title compound, (−)-6,7-dehydroferruginyl
methyl ether 3, was successfully obtained. To determine the stereochemistry of 3, we introduced the
stereogenic center from (S)-(−)-α-cyclocitral. According to the literature,12 when the A/B ring is a cis
junction, the δ value of the C4-α-methyl group will appear at about 0.4 ppm, if the A/B ring is a trans
1
junction, the δ value of the C4-α-methyl group will appear at about 0.9–1.0 ppm. From the H NMR
of 3, we did not find any signal at 0.4 ppm, so the trans-isomer was obtained in high stereoselectivity
(d.e. >95% determined by NMR). Based on the above analysis, the compound 3 was assigned as (−)-
6,7-dehydroferruginyl methyl ether.
In conclusion, we developed a route to (−)-6,7-dehydroferruginyl methyl ether via 15 steps with high
overall yield and stereoselectivity.

Y. Gan et al. / Tetrahedron: Asymmetry 11 (2000) 781–787
783
Scheme 2. Reagents and conditions: (i) n-BuLi, n-hexane (60%); (ii) 10% Pd/C, ethanol (98%); (iii) BF3·Et2O, CH2Cl2
(85%); (iv) acetyl choride, anhydrous AlCl3 (90%); (v) CH3Li ( 95%); (vi) p-Tos, benzene (90%); (vii) 5% Pd/C (95%);
(viii) CrO3/HOAc (85%); (ix) NaBH4/ethanol (95%); (x) p-Tos, benzene (90%)
3. Experimental
3.1. General
1
The H NMR and 13C NMR data were recorded in CDCl3 solution with Bruker AM-80 or AM-400
MHz spectrometers. The chemical shifts are reported in ppm relative to TMS or CDCl3. Optical rotations
were determined on a JASCO J-20C polarimeter with a 0.2 dm tube. Mass spectra were recorded on a
ZAB-HS mass spectrometer (EI). Microanalyses were performed on a MOD-1106 elemental analyser.
Chiral analysis was performed on a Varian Dynamax SD-300 using Chiralcel column CDMPC (150×4.6
mm D) with hexane/isopropyl alcohol as eluant. Column chromatographs were generally performed on
silica gel (200–300 mesh) eluting with petroleum ether:EtOAc (100:1→20:1 v/v) and TLC inspections
on silica gel GF254 plates with petroleum ether:EtOAc (20:1 v/v) if not noted specifically below.
3.2. (±)-α-Cyclogeranic acid 5
At 100°C, 85% H3PO4 (0.01 mmol) was added to geranic acid 4 (16 g, 0.1 mmol) in toluene (30 ml).
The reaction mixture was stirred for 2 h at this temperature, then reaction was quenched with saturated
NaHCO3, extracted with ethyl ether, the combined organic layer was washed with brine and then dried
with Na2SO4. After evaporation of the solvent under reduced pressure, the precipitate was recrystallized

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1
from n-hexane to give the pure compound 5 (14 g, 90%). H NMR (80 MHz) δ 0.90 (s, 3H), 0.96 (s,
3H), 1.60 (s, 3H), 1.8–2.5 (m, 5H), 5.6 (brs, 1H), 11.0 (s, 1H). MS (EI): 168, 153, 81 and 77. (Found: C,
71.29; H, 9.50. C10H16O2 requires: C, 71.39; H, 9.59%).
3.3. (S)-(−)-Cyclogeranic acid 6
Compound (±)-5 (16.0 g) in ether (50 mL) was added to (−)-α-methylbenzylamine (9.0 g). The
precipitate was recrystallized from n-hexane to give the (−)-salt. M.p. 110°C (needle). The solution of the
(−)-salt in methanol was acidified with 5% HCl and extracted with ether. The combined organic layer was
washed with brine, then dried with Na2SO4. Evaporation of the solvent under reduced pressure, followed
25
by recrystallization from n-hexane gave the pure compound 6. M.p. 101–102°C (as large prisms) ([α]D
−300 (c 0.5, ethanol), lit.11 ([α]D −319 ethanol); e.e. >90% compared with Charles et al.11). Other
25
spectra data were the same as those of 5.
3.4. (S)-Methyl-α-cyclogeranate 7
To (S)-(−)-cyclogeranic acid (5.0 g, 30 mmol) in acetone (30 mL) was added anhydrous K2CO3 (5.0
g, 36 mmol) and 3 mL MeI (6.0 g, 36 mmol), and the mixture was stirred at room temperature for 3 h.
The usual ether work-up gave the compound 7 as a colorless oil (5.0 g, 90%). 1H NMR δ 0.90 (s, 3H),
0.96 (s, 3H), 1.60 (s, 3H), 1.8–2.5 (m, 5H), 3.1 (s, 3H), 5.6 (brs, 1H). MS (EI): 168, 153, 81 and 77.
(Found: C, 71.29; H, 9.50. C10H16O2 requires: C, 71.39; H, 9.59%). This compound was used for the
next step without further identification.
3.5. (S)-2,6,6-Trimethyl-1-cyclohexenemethanol 8
At −10°C, to a suspension of LiAH4 (600 mg, 16 mmol) in anhydrous ethyl ether (30 mL), compound
7 (4.5 g, 25 mmol) in anhydrous ether (10 mL) was added dropwise. The mixture was stirred at this
temperature for 1 h. Then the reaction was quenched with ice-water, extracted with ether, and the
combined organic layer washed with brine and dried with Na2SO4. Evaporation of the solvent under
reduced pressure gave the alcohol 8 (4.5 g, 90%), which was used for the next step immediately without
further identification.
3.6. (S)-(−)-Cyclocitral 9
The alcohol 8 (4.0 g, 23 mmol) was dissolved in anhydrous CH2Cl2 (30 mL) containing 0.3 g 4 Å
m.s. and anhydrous NaOAc (1.5 g). PCC (5.0 g, 26 mmol) in 30 mL anhydrous CH2Cl2 was added to the
above solution portionwise at −10°C. The solution was stirred at this temperature for 1 h, then the salt
was removed by passing through a short column of Al2O3. Purification by column chromatography gave
25
25
the pure compound 9 (3.0 g, 75%) ([α]D −708 (c 0.03, CHCl3), lit.11 ([α]D −743 (c 0.05, CHCl3);
e.e. >90% by HPLC, lit.11); 1H NMR δ 0.92 (s, 3H), 0.98 (s, 3H), 1.60 (s, 3H), 1.8–2.5 (m, 5H), 5.7 (brs,
1H), 9.2 (s, 1H). MS (EI): 152, 123, 137, 81 and 77.
3.7. 3-(4-Methoxystyryl)-2,4,4-trimethyl-1-cyclohexene 11
A solution of n-butyllithium in hexane (1.6 N, 4 mL) was added to a suspension of (4-
methoxybenzyl)triphenylphosphonium chloride (3.2 g, 7.55 mmol) in dry hexane (20 mL), under

Y. Gan et al. / Tetrahedron: Asymmetry 11 (2000) 781–787
785
an atmosphere of Ar, and stirred at room temperature for 1 h. Then a solution of 9 (700 mg, 4.6 mmol)
in dry hexane (10 mL) was added over 10 min. The solution was stirred for 4 h to complete the reaction.
Then the mixture was poured into diluted HCl, extracted with ether, and the combined organic layer was
washed with brine and dried with Na2SO4. The crude product was purified by column chromatography
25
to give the desired compound 11 (700 mg, 60%) ([α]D −302 (c 0.25, CHCl3); e.e. >90% by HPLC10);
1H NMR (80 MHz) δ 0.94 and 1.00 (s, each 3H), 1.63 (bs, 3H), 3.83 (s, 3H), 5.50 (brs, 1H), 6.00 (1H,
dd, J=8, 15 Hz), 6.40 (1H, d, J=15 Hz), 6.88 (2H, d, J=8.9 Hz), 7.34 (2H, d, J=8.9 Hz). MS (EI): 256,
200, 185, 121 and 91. (Found: C, 89.40; H, 9.40. C18H24O requires: C, 84.32; H, 9.44%).
3.8. 3-(4-Methoxyphenylethyl)-2,4,4-trimethyl-1-cyclohexene 12
A suspension of 11 (500 mg) and 10% Pd/C (250 mg) in anhydrous ethanol (10 mL) was stirred at room
temperature in an atmosphere of hydrogen. The reaction was monitored by TLC; when the reaction was
completed, the mixture was filtered. The filtrate was evaporated in vacuo to yield the desired compound
25
12 (480 mg, 95%) as a colorless oil ([α]D −132 (c 0.08, CHCl3); e.e. >92%10); 1H NMR δ 0.91 and
1.00 (s, each 3H), 1.70 (bs, 3H), 3.80 (s, 3H), 5.34 (brs, 1H), 6.84 (2H, d, J=8.6 Hz), 7.13 (2H, d, J=8.6
Hz). MS (EI): 258, 243, 121. (Found: C, 83.55; H, 10.10. C18H26O requires: C, 83.67; H, 10.14%).
3.9. 12-Methoxy-podocarpane-8,11,13-triene 1 (intramolecular cyclization of 12)
To a solution of 12 (300 mg, 1.2 mmol) in CH2Cl2 (15 mL) was added BF3·Et2O (0.6 mL) dropwise.
The mixture was left to stand overnight. Then 30 mL of ether was added and the solution was
neutralized with saturated NaHCO3. The mixture was extracted with ether and the combined organic
layer was washed successively with saturated NaHCO3 and brine, then dried with Na2SO4. Column
chromatography purification gave the pure trans compound 1 (260 mg, 85%) (no cis compound was
1
25
1
1
detected by H NMR) ([α]D −32 (c 0.10, CHCl3); d.e. >95% determined by H NMR); H NMR δ
0.99 (s, 6H), 1.24 (s, 3H), 1.32–2.37 (m, 11H), 3.82 (s, 3H), 6.70 (1H, dd, J=8.0, 2.0 Hz), 6.85 (1H, d,
J=2.0 Hz), 6.93 (1H, d, J=8.0 Hz). MS (EI): 258, 243, 187, 161, 121, 91. (Found: C, 83.57; H, 10.09.
C18H26O requires: C, 83.67; H, 10.14%).
3.10. 13-Acetyl-12-methoxy-podocarpane-8,11,13-triene 13
At −10°C, to a solution of 1 (300 mg, 1.2 mmol) in CH2CL2 (15 mL), anhydrous AlCl3 (350 mg) was
added portionwise, then acetyl chloride (0.2 mL) was added dropwise to keep the reaction temperature
below −5°C. After stirring overnight, the mixture was poured into ice-water and extracted with CH2Cl2.
The combined organic layer was successively washed with saturated NaHCO3 and brine, then dried with
Na2SO4. After column chromatography purification, the compound 13 was obtained as a yellowish oil
(310 mg, 95%; d.e. >95% determined by 1H NMR); 1H NMR δ 0.91 (s, 3H), 0.95 (s, 3H), 1.21 (s, 3H),
1.32–2.37 (m, 11H), 2.58 (s, 3H), 3.87 (s, 3H), 6.83 (s, 1H), 7.44 (s, 1H). MS (EI): 300, 285, 256, 203,
163, 91. (Found: C, 79.73; H, 9.15. C20H28O2 requires: C, 79.96; H, 9.39%).
3.11. Alcohol 14
To a solution of 13 (300 mg, 1.1 mmol) in anhydrous THF (5 mL), CH3Li (1.3 N, 1.5 mL) was
added at 0°C and the solution stirred for 4 h, then poured into ice-water and extracted with ether. The
combined organic layer was washed with brine and dried with Na2SO4. The solvent was removed under

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reduced pressure to give the alcohol 14 (310 mg, 95%), which was used for the next step without further
identification.
3.12. 13-(10-Methenylethyl)-12-methoxy-podocarpane-8,11,13-triene 15
To a solution of 14 (500 mg, 1.6 mmol) in benzene was added cat. p-TosOH, and the solution
was refluxed for 0.5 h. After cooling, saturated NaHCO3 was added to the solution and the mixture
was extracted with ether. The combined organic layer was washed with brine and dried with Na2SO4.
25
Purification by column chromatography gave the styrene derivative 15 (450 mg, 90%) ([α]D +52 (c
0.04, CHCl3); d.e. >95% determined by 1H NMR); 1H NMR δ 0.92 (s, 3H), 0.94 (s, 3H), 1.21 (s, 3H),
1.71 (s, 3H), 1.32–2.37 (m, 11H), 3.8 (s, 3H), 5.05 (s, 1H), 5.10 (s, 1H), 6.75 (s, 1H), 6.85 (s, 1H). MS
(EI): 298, 285, 163, 91. (Found: C, 79.73; H, 9.15. C18H26O5 requires: C, 79.96; H, 9.39%).
3.13. (+)-Ferruginyl methyl ether 16
A suspension of 15 (300 mg) and 5% Pd/C (150 mg) in ethanol (10 mL) was stirred at room
temperature in an atmosphere of hydrogen. The reaction was monitored by TLC, and when the reaction
was completed, the mixture was filtered. The filtrate was evaporated in vacuo to yield the desired
25
compound 16 as a colorless heavy oil (280 mg, 95%) ([α]D +45 (c 0.07, CH2Cl2); d.e. >95%
1
1
determined by H NMR); H NMR δ 0.83 and 0.85 (s, each 3H), 1.14 (d, 6H, J=7.5 Hz), 1.17 (s,
3H), 1.10–3.00 (m, 11H), 3.25 (sept, 1H, J=7.5 Hz), 3.70 (s, 3H), 6.75 (s, 1H), 6.69 (s, 1H). MS (EI):
300, 176, 163, 133, 69. (Found: C, 83.75; H, 10.52. C21H32O requires: C, 83.94; H, 10.73%).
3.14. (+)-Sugiyl methyl ether 17
To a solution of 16 (300 mg, 1 mmol) in acetic acid (5 mL) was added CrO3 (1 mmol) in acetic acid
(5 mL) at room temperature, and the mixture was stirred for 0.5 h, then water was added to quench the
reaction. After extraction with ether, the combined organic layer was washed with saturated NaHCO3
and brine. Column chromatography purification gave the compound 17 (280 mg, 90%) as white needle
25
25
crystals. M.p. 130–132°C ([α]D +27 (c 0.9, MeOH), lit.13 ([α]D +32 (c 0.1, MeOH); d.e. >95%);
1H NMR δ 0.93 and 1.00 (s, each 3H), 1.23 (d, 3H, J=7.0 Hz), 1.27 (d, 3H, J=7.0 Hz), 1.28 (s, 3H),
1.29–2.71 (m, 9H), 3.25 (sept, 1H, J=7.0 Hz), 3.88 (s, 3H), 6.75 (s, 1H), 7.89 (s, 1H). MS (EI): 300, 285,
189, 163, 69. (Found: C, 80.10; H, 9.52. C21H30O2 requires: C, 80.21; H, 9.62%) .
3.15. Alcohol 18
To a solution of 17 (200 mg, 0.67 mmol) in methanol (10 mL) was added NaBH4 (30 mg), and the
reaction mixture was stirred for 1 h. Then water was added, the mixture was extracted with ether, and
the combined organic layer was washed with brine and then dried with Na2SO4. Evaporation of the
solvent gave the alcohol 18 (200 mg, 95%). The compound 18 was used for the next step without further
identification.
3.16. (−)-6,7-Dehydroferruginyl methyl ether 3
To a solution of 18 (100 mg, 0.4 mmol) in benzene was added cat. p-Tos, and the solution was refluxed
for 0.5 h. After completion of the reaction, ether (100 mL) was added and the organic layer was washed

Y. Gan et al. / Tetrahedron: Asymmetry 11 (2000) 781–787
787
with saturated NaHCO3 and brine, and dried with Na2SO4. The crude product was purified by column
25
chromatography to give the (−)-6,7-dehydroferruginyl methyl ether 3 (480 mg, 90%) ([α]D −45 (c
0.05, CHCl3); d.e. >90% determined by 1H NMR); 1H NMR δ 1.02 (s, 3H), 1.09 (s, 3H), 1.10 (s, 3H),
1.24 (d, 3H, J=7.0 Hz), 1.30 (d, 3H, J=7.0 Hz), 1.32–2.24 (m, 7H), 3.31 (sept, 1H, J=7.0 Hz), 3.88
(s, 3H), 5.93 (dd, 1H, J=3.0, 9.5 Hz), 6.55 (dd, 1H, J=9.5 Hz), 6.75 (s, 1H), 6.96 (s, 1H). 13C NMR δ
19.0, 20.1, 22.5, 22.9, 26.4, 32.6, 32.8, 36.1, 37.9, 41.1, 51.1, 55.5, 104.7, 124.3, 125.8, 127.4, 133.8,
146.9, 156.4. MS (EI): 298, 283, 216, 173. (Found: C, 84.45; H, 10.05. C21H30O requires: C, 84.51; H,
10.13%).
Acknowledgements
Support from the National Natural Science Foundation of China is gratefully acknowledged.
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