A novel approach for introduction of C-1 oxygenated group on decalin skeleton: First asymmetric total synthesis of 1α,6α-dihydroxy- eudesm-3-ene

Article abstract of DOI:10.1016/j.tet.2004.05.056

This paper describes a novel approach for introduction of C-1 hydroxy on decalin ring system starting from (-)-carvone. Utilizing the substrate controlled Mukaiyama aldol reaction and alkaline cyclization as key steps, the C-1 oxygenated decalin eudesmane

Full text of DOI:10.1016/j.tet.2004.05.056

Tetrahedron 60 (2004) 6177–6182
A novel approach for introduction of C-1 oxygenated group on
decalin skeleton: first asymmetric total synthesis of
1a,6a-dihydroxy-eudesm-3-ene
*
Guojun Zheng, Jinchun Chen, Lijing Fang, Zhiyong Tang and Yulin Li
State Key Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry, Lanzhou University, Lanzhou 730000,
People’s Republic of China
Received 2 March 2004; revised 5 May 2004; accepted 13 May 2004
Available online 11 June 2004
Abstract—This paper describes a novel approach for introduction of C-1 hydroxy on decalin ring system starting from (2)-carvone.
Utilizing the substrate controlled Mukaiyama aldol reaction and alkaline cyclization as key steps, the C-1 oxygenated decalin eudesmane
skeleton 20 and its four isomers were synthesized efficiently. What’s more, X-ray structural analysis confirmed sufficiently that something
was wrong about the structure of natural product: 1b,6b-dihydroxy-7-epi-eudesm-3-ene as reported by the literature.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Although considerable efforts have been devoted to the total
synthesis of eudesmane and agarofuran sesquiterpenoids
over the past decades, introduction of C-1 oxygenated group
on decalin skeleton still represents a significant challenge
for synthetic chemist.1 To our knowledge, many C-1
oxygenated decalin of eudesmane and agarofuran ses-
quiterpenoids have been isolated in recent years,2 but there
Figure 1.
was few report on total synthesis of them. In connection
with our ongoing studies on the total synthesis of bioactive
sesquiterpenoids,3–5 we intended to explore a new strategy
for the introduction of an oxygenated functional group at the
C-1 position in the decalin ring system.
The total synthesis of compounds 10 and 20 is detailed in
Scheme 1. Compound 7 could be readily prepared from
commercially available (2)-carvone by catalytic hydrogen-
ation and refluxing with tert-butyldimethylsilyl chloride
(TBSCl) in N,N-dimethylformamide. After refluxing for 2
days, the silyl enol ether 7 was obtained in 90% yield and
the selectivity of thermodynamic and kinetic silyl enol
2. Result and discussion
ethers was up to 20:1 when the solvent was tripled the
amount of the literature procedure.7 However, for our
substrate, the literature procedure gave less than 10% yield
Compounds 1 and 2 (Fig. 1) were first isolated in 1997 from
the leaves of Pluchea dioscoridis, the structures were
confirmed to be 1b,6a-dihydroxy-7-epi-eudesm-3-ene and
of 7 and we found that high temperature (about 140 8C) was
it’s C-6 epimer.6 They both had an oxygenated group in C-1
essential for good yield. Mukaiyama aldol reaction8 of
position. Our first attempt was to synthesize the aimed
aldehyde 6 and 7 successfully introduced C-1 oxygenated
compounds 10 and 20 (the enantiomner of 1 and 2).
group to give 8 and 9 (2:1 in ratio) which were both key
Surprisingly, when we accomplished the aimed compounds
10 and 20, we found that the spectral data of two compounds
were inconsistent with the literature.
optical intermediates for the synthesis of natural occurring
compounds. The stereochemistry of methyl group was
determined as a by NOESY due to the steric bulk of the tert-
butyldimethylsilyl group. After the hydroxy of 8 was
Keywords: Asymmetric synthesis; C-1 oxygenated; Eudesmane; X-ray
protected with p-methoxybenzyl group and deprotection
structural analysis; Wrong structure.
of benzoyl group, the resulting compound was oxidized with
PCC to afford aldehyde keto 11.
*
Corresponding author. Tel.: þ86-931-8912595; fax: þ86-931-8912283;
e-mail address: liyl@lzu.edu.cn
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.056

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G. Zheng et al. / Tetrahedron 60 (2004) 6177–6182
Scheme 1. Reagents and conditions: (a) pd/C/H2, EtOH; then TBSCl/Et3N, DMF, reflux 2 days, 90%; (b) 6 (BzOCH2CH2CHO)/TiCl4, CH2Cl2, 60%;
(c) PMBOC(vNH)CCl3, p-TsOH, CH2Cl2, 85%; (d) 2% NaOH, MeOH, 96%; (e) PCC, Py, CH2Cl2, 80%; (f) 278 8C, EtMgBr, THF, 75%; PCC, Py, CH2Cl2,
90%; (g) 0.2% NaOMe/MeOH, 98%; MsCl, NEt3, 89%; (h) AcCl, Ac2O, DMAP, NaOAc,82%; (i) m-CPBA, CH2Cl2, 83%; (j) PMBOC(vNH)CCl3, p-TsOH,
CH2Cl2, 82%; (k) TsNHNH2/HOAc, NaBH4, 80%; (l) DDQ,CH2Cl2–H2O, 87%; (m) Dess–Martin reagent, CH2Cl2, 92%; (n) NaBH4/MeOH, 80–90%.
The diketo 12, obtained by the highly selective reaction of
EtMgBr and aldehyde keto 11 at 278 8C and subsequent
PCC oxidation, was cyclized and dehydrated under
condition of 0.2% CH3ONa/CH3OH and MsCl/NEt3
respectively.9 We have tried many other conditions, such
as 10% KOH/MeOH10 refluxing, NaOMe/MeOH11 reflux-
ing and TsOH/benzene refluxing, but none of them turned
out to be ideal. That is, under such conditions, either the
yield is rather low or the product is unwanted (obtaining
compound 21, Fig. 2). Refluxing enone 13 in AcCl and
Ac2O (2:1 in ratio) with the addition of sodium acetate
(2 equiv.) to prevent eliminating of C-1 oxygenated group
afforded 14.12 Oxidation of 14 with 3-chloroperoxybenzoic
acid and subsequent deacetylation under acidity condition
gave the alcohol 15. The reaction went on in a highly
stereoselective way to give 100% (S)-alcohol, which could
be deduced from the coupling constants (J6,7¼2.4 Hz), and
also proved by the X-ray structure analysis. The protection
of alcohol 15 with p-methoxybenzyl group afforded 16. The
reaction of 16 with TsNHNH2 in acetic acid for 10 h
followed by addition of NaBH4 generated compounds 17
and 18,13 which couldn’t be separated by silica gel
chromatography. Deprotection of p-methoxybenzyl group
with DDQ in CH2Cl2–H2O (18:1)14 afforded 20 and 3 (1:4 in
ratio), which could be easily separated. Oxidation of diol 20
with Dess–Martin reagent and subsequent reduction with
NaBH4 gave diol 10. Similarly, we got diol 4 and 5 (6:1 in
ratio) from 3.
Unfortunately, the spectral data of 10 and 20 were
inconsistent with those of 1 and 2 in literature. Based on
the inevitability of the reaction (from 16 to 17 and 18), only
one chiral carbon (C-5) was introduced and two compounds
were generated. Obviously, they must be epimers of C-5, 17
was trans-fused-ring and 18 was cis-fused-ring. However, it
was difficult to determine which one was the trans-fused-
1
ring from the spectral data of H NMR and 13C NMR. For
this reason, a single crystal X-ray structural analysis of the
compound 3 (relatively more in amount) was performed to
confirm the absolute configuration (Fig. 3). Thus, the
configuration of 20 was determined as the just right
compound we anticipated. The configurations of com-
pounds 10, 4 and 5 could be elucidated according to the
stereoselectivity of the reaction and the spectral data of the
compounds. However, none of the five isomers was
consistent with the two compounds in literature.
What’s wrong with the compounds 1 and 2? In literature, the
configuration of compound 1 was determined by the
coupling constants (J5,6¼9.5 Hz, J6,7¼5 Hz), which were
in agreement with an (axial–axial and axial–equatorial)
pattern for these protons. So the configuration was assigned
as 5a,6a,7b (H). The conclusion seemed plausible. Those
configurations were also proved by the NOE 1D. It couldn’t
Figure 2.

G. Zheng et al. / Tetrahedron 60 (2004) 6177–6182
6179
CDCl3) d 23.7, 23.4, 16.4, 18.4, 19.9, 20.2, 25.9, 26.7,
30.7, 32.4, 34.3, 41.9, 111.4, 143.0.
4.1.2. 2b-(3-Benzyloxy-1a(b)-hydroxy-propyl)-5b-iso-
propyl-2a-methyl-cyclohexanone 8 (9). A mixture of
aldehyde 6 (900 mg, 5 mmol) and silyl enol ether 7
(1.33 g, 5 mmol) in 5 mL CH2Cl2 was added dropwise to
TiCl4 (0.5 mL, 5 mmol) in 20 mL dry CH2Cl2 under argon
at 278 8C. The mixture was allowed to warm up to 240 8C,
stirred for 2 h and quenched with aqueous sodium carbonate
at 240 8C then to room temperature. The mixture was
extracted with ether and washed successively with saturated
aqueous NaHCO3 and brine, dried over MgSO4. After
chromatographic purification, 332 mg of 9 (yellow oil) and
670 mg of pure 8 (white crystal, mp 84–86 8C) were
obtained, yielding 60%. Compound 8 [a]2D5¼þ218 (c 1.4,
CHCl3); 1H NMR (400 MHz, CDCl3) d 0.82 (d, 3H,
J¼4.1 Hz, Me), 0.83 (d, 3H, J¼4.1 Hz, Me), 1.05 (s, 3H,
Me), 1.34–1.49 (m, 2H), 1.62–1.74 (m, 4H), 2.14–2.19 (m,
1H), 2.24–2.28 (m, 1H), 2.39–2.44 (dd, 1H, J¼4.4, 14 Hz),
2.55 (d, 1H, J¼5.8 Hz), 4.15–4.19 (m, 1H, CHOH), 4.40–
4.45 (m, 1H, OCH2), 4.56–4.62 (m, 1H, OCH2), 7.43 (t, 2H,
J¼7.9 Hz, Ar), 7.55–7.57 (t, 1H, J¼7.6 Hz, Ar), 8.01–8.03
(d, 2H, J¼8.4 Hz, Ar); 13C NMR (100 MHz, CDCl3) d 17.5,
19.5, 19.6, 23.5, 30.8, 31.2, 32.9, 42.9, 45.2, 53.1, 62.3,
68.9, 128.4, 129.5, 130.1, 133.1, 166.9, 216.0; MS m/z (%):
314 (M2H2O, 0.6), 192 (5), 154 (50), 122 (14), 111 (10),
105 (100), 77 (41), 69 (17), 55 (20), 41 (21); IR (film, cm21)
nmax¼3476, 2959, 2931, 1718, 1689, 1272, 1121, 1099,
1070, 974, 710. Compound 9 [a]2D5¼þ558 (c 1.2, CHCl3);
1H NMR (300 MHz, CDCl3) d 0.82 (d, 3H, J¼5.1 Hz, Me),
0.84 (d, 3H, J¼5.1 Hz, Me), 1.06 (s, 3H, Me), 1.46–1.49
(m, 2H), 1.58–1.70 (m, 4H), 1.86–1.89 (m, 2H), 2.40–2.43
(m, 2H), 4.20 (dd, 1H, J¼8.1, 1 Hz, CHOH), 4.49–4.60 (m,
2H, BzOCH2), 7.42–7.45 (m, 2H, Ar), 7.55–7.58 (m, 1H,
Ar), 8.01–8.06 (m, 2H, Ar); 13C NMR (75 MHz, CDCl3) d
16.3, 19.5, 23.7, 25.6, 30.2, 31.5, 34.9, 42.0, 45.2, 52.2,
62.3, 70.6, 128.3, 129.6, 133.0, 166.7, 216.2.
Figure 3. Molecular structure of 3 (CCDC 220322).
be denied that the result of NOE 1D was a very important
factor to determine the configuration of the compound, but it
could not be the sole evidence.
3. Conclusion
In summary, a novel approach for introduction of C-1
oxygenated group on decalin skeleton was exemplified in
synthesis of 1a,6a-dihydroxy-eudesm-3-ene and its four
isomers. The strategy is of great potential for the divergent
synthesis of complex polyhydroxylated eudesmane and
agarofuran sesquiterpenoids. The application of the estab-
lished method to the further synthesis of a number of C-1
oxygenated natural products is under active investigation.
4. Experimental
4.1. General
IR spectra were recorded on a Nicolet NEXUS 670 FT-IR
spectrometer. 1H NMR and 13C NMR spectra were recorded
on Bruker AM-400 or Varian Mercury Plus-300 spec-
trometer in CDCl3 using TMS as an internal reference, and J
values were given in Hertz. Mass spectra were determined
on a HP5988A spectrometer by direct inlet at 70 eV. Optical
rotation measurements were carried out on a Perkin–Elmer
141 polarimeter. Flash chromatography was performed on
silica gel, with petroleum ether (PE) and diethyl ether (Et)
mixtures as eluent.
4.1.3. 2b-[3-Benzyloxy-1a-(4-methoxy-benzyloxy)-
propyl]-5b-isopropyl-2a-methyl-cyclohexanone
(10).
p-TsOH (25 mg) was added to alcohol 8 (1.66 g, 5 mmol)
in 5 mL dry CH2Cl2 under argon. The mixture was cooled to
0 8C, then 2, 2, 2-trichloro-acetimidic acid 4-methoxy-
benzyl ester (1.7 g, 6 mmol) in 2 mL dry CH2Cl2 was added,
the mixture was allowed to warm up to room temperature
and stirred for 24 h. The crude was directly chromato-
graphed on silica gel to afford a colorless oil 10 (1.92 g,
1
85%). [a]2D5¼þ16.58 (c 3.6, CHCl3); H NMR (300 MHz,
CDCl3) d 0.74 (d, 3H, J¼3.6 Hz, Me), 0.76 (d, 3H,
J¼3.9 Hz, Me), 0.96 (s, 3H, Me), 1.25–1.27 (m, 1H),
1.41–1.60 (m, 4H), 1.75–1.80 (m, 2H), 2.06–2.10 (m, 2H),
2.22–2.28 (m, 2H), 3.68 (s, 3H, OMe), 4.04 (d, 1H,
J¼9.6 Hz, CHOCH2), 4.28–4.32 (m, 2H, OCH2), 4.52 (s,
2H, OCH2Ar), 6.75 (d, 2H, J¼8.4 Hz, Ar), 7.17 (d, 2H,
J¼8.4 Hz, Ar), 7.35 (t, 2H, J¼7.5 Hz, Ar), 7.49 (t, 1H,
J¼7.5 Hz, Ar), 7.94 (d, 2H, J¼8.7 Hz, Ar); 13C NMR
(75 MHz, CDCl3) d 17.5, 19.2, 19.4, 23.9, 30.7, 32.3, 34.6,
43.3, 45.6, 53.9, 55.1, 62.0, 74.7, 75.7, 113.7, 128.4, 130.0,
130.1, 133.0, 159.2, 166.2, 214.9; MS m/z (%): 452 (Mþ, 0.8),
316 (10), 194 (17), 179 (7), 151 (9), 137 (10), 121 (100), 77
(17), 41 (7); IR (film, cm21) nmax¼2958, 2871, 1718, 1611,
1513, 1456, 1273, 1250, 1176, 1112, 1074, 1033, 823.
4.1.1. tert-Butyl-(5b-isopropyl-2-methyl-cyclohex-1-
enyloxy)-dimethyl-silane (7). A mixture of (2)-carvone
(9 g) and 10% Pd/C (900 mg) in EtOH 20 mL was stirred
under hydrogen for 30 h and the mixture was filtered
through a celite gel, which without further purification, was
taken in dry DMF (250 mL) and treated with NEt3 (24 mL,
3 equiv.) and TBSCl (13.1 g, 1.5 equiv.). The resulting
mixture was refluxed for 2 days before it was extracted with
petroleum ether and dried over MgSO4. After chromato-
graphic purification, the silyl enol ether 7 (14.4 g) was
obtained, yielding 90%. 1H NMR (300 MHz, CDCl3) d 0.11
(s, 6H), 0.87–1.00 (m, 15H, C(CH3)3 and CH(CH3)2),
1.02–1.19 (m, 2H), 1.32–1.50(m, 2H), 1.57 (s, 3H, CH3),
1.65–1.75 (m, 2H), 1.76–2.00 (m, 2H); 13C NMR (75 MHz,

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G. Zheng et al. / Tetrahedron 60 (2004) 6177–6182
4.1.4. 3-(4b-Isopropyl-1a-methyl-2-oxo-cyclohexyl)-3a-
(4-methoxy-benzyloxy)-propionaldehyde (11). To
to warm up to room temperature and stirred for 2 h. The
solution was evaporated to dryness in vacuum and the
residue was diluted with ether, washed with 5% HCl,
sodium hydrogencarbonate, brine, and dried over MgSO4.
Evaporation of the solvent in vacuum gave the crude
product, which without further purification, was taken in
CH2Cl2 (5 mL) and treated with NEt3 (1.8 mL) and MsCl
(1.2 mL). The resulting mixture was stirred for 8 h at room
temperature and diluted with ether, washed with 5% HCl,
saturated aqueous NaHCO3 and brine, dried over MgSO4.
Purification by flash chromatography gave white crystal 13
(415 mg, 87%, mp 116–118 8C). [a]2D5¼þ118 (c 1.6,
CHCl3); 1H NMR (300 MHz, CDCl3) d 0.77 (d, 3H,
J¼6.4 Hz, Me), 0.85 (d, 3H, J¼6.4 Hz, Me), 1.18 (s, 3H,
Me), 1.26–1.29 (m, 1H), 1.37–1.38 (m, 1H), 1.41–1.46 (m,
2H), 1.60–1.64 (m, 1H), 1.70 (s, 3H, Me), 1.71–1.74
(m, 1H), 2.16–2.21 (m, 1H), 2.39–2.46 (m, 1H), 2.68–2.75
(m, 2H), 3.45 (dd, 1H, J¼4.8, 12.8 Hz, CHOCH2), 3.73 (s,
3H, OMe), 4.31 (d, 1H, J¼11.6 Hz, OCH2Ar), 4.45 (d, 1H,
J¼11.6 Hz, OCH2Ar), 6.81 (d, 2H, J¼11.2 Hz, Ar), 7.19 (d,
2H, J¼11.2 Hz, Ar); 13C NMR (75 MHz, CDCl3) d 11.2,
18.2, 20.3, 21.6, 23.4, 28.6, 30.2, 32.5, 39.2, 41.7, 41.8,
55.2, 71.0, 79.8, 113.7, 129.1, 129.8, 130.5, 159.1, 162.8,
197.4; MS m/z (‰): 356 (Mþ, 0.5), 235 (32), 220 (15), 192
(12), 163 (4), 135 (26), 121(1000), 110 (19), 91 (47), 77(57),
43 (55); IR (film, cm21) nmax¼2966, 2889, 1658, 1608,
1512, 1459, 1348, 1309, 1246, 1072, 822.
a
solution of ketone 10 (1.8 g, 4 mmol) in 5 mL MeOH was
added 2% NaOH/MeOH (20 mL) at 0 8C and stirred for 3 h.
Then MeOH was evaporated under a reduced pressure,
diluted with ether, washed with water, brine, and dried over
MgSO4. Evaporation of the solvent in vacuum gave the
crude product, which without further purification, was taken
in CH2Cl2 (20 mL) and treated with PCC (1.7 g, 8 mmol),
pyridine (0.64 mL, 8 mmol) and SiO2 (2.4 g). The resulting
suspension mixture was stirred over night at room
temperature and diluted with ether. The mixture was filtered
through a silica gel. The solvent was removed and the
residue was purified by chromatography to furnish yellow
1
oil (1.06 g, 77%). [a]2D5¼þ1008 (c 1.1, CHCl3); H NMR
(300 MHz, CDCl3) d 0.78 (d, 6H, J¼6.3 Hz, Me), 0.93 (s,
3H, Me), 1.17–1.31 (m, 2H), 1.40–1.52 (m, 2H), 2.01–2.09
(m, 1H), 2.20–2.27 (m, 2H), 2.27–2.39 (m, 1H), 2.59–2.68
(m, 1H), 3.73 (s, 3H, OMe), 4.33 (d, 1H, J¼11.1 Hz,
OCH2Ar), 4.40 (dd, 1H, J¼3.6, 7.2 Hz, CHOCH2), 4.49 (d,
1H, J¼10.8 Hz, OCH2Ar), 6.81 (d, 2H, J¼14.7 Hz, Ar),
7.18 (d, 2H, J¼14.7 Hz, Ar), 9.73 (s, 1H, CHO); 13C NMR
(75 MHz, CDCl3) d 17.6, 19.4, 19.6, 23.8, 32.3, 34.3, 43. 6,
45.5, 45.9, 53.5, 55.3, 72.5, 72.8, 113.8, 129.7, 130.0, 159.3,
200.7, 215.1; MS m/z (%): 346 (Mþ, 0.4), 210 (2), 173 (14),
167 (11), 137 (24), 121 (100), 55 (13), 41 (23); IR (film,
cm21) nmax¼2957, 2871, 1722, 1702, 1612, 1514, 1462,
1249, 1176, 1081, 1034, 823.
4.1.7. 1a-(4-Methoxy-benzyloxy)-10-epi-eudesm-3-
aceyloxy-3 (4), 5 (6)-dien (14). To a solution of enone 13
(350 mg, 0.98 mmol) in Ac2O (1 mL) was added NaOAc
(500 mg), DMAP (10 mg) and AcCl (2 mL) and stirred at
0 8C for 2 min. The resulting mixture was heated to reflux
and stirred for 20 min. The reaction was then cooled to 0 8C
and diluted with ether before NEt3 (10 mL) and water
(2 mL) was added. The resulting mixture was stirred for a
further 0.5 h prior to extraction with ether. The organic
phase was washed with water, 5% HCl, saturated aqueous
NaHCO3 and brine, dried over MgSO4. Evaporation of the
solvent followed by flash column chromatography on silica
gel afforded compound 14 (320 mg, 82%). [a]2D5¼þ1418 (c
4.1.5. 5b-Isopropyl-2b-[1a-(4-methoxy-benzyloxy)-3-
oxo-pentyl]-2a-methyl-cyclohexanone (12). To a solution
of aldehyde 11 (1.2 g, 3.46 mmol) in dry THF (5 mL) under
argon atmosphere was added dropwise EtMgBr (8 mL,
4 mmol) at 278 8C. The mixture was stirred at 278 8C for
30 min and quenched with aqueous ammonium chloride.
The resulting mixture was extracted with ether and washed
successively with sodium hydrogencarbonate and brine, and
dried over MgSO4. The solvent was removed in vacuum to
give the crude product, which without further purification,
was taken in CH2Cl2 (20 mL) and treated with PCC (1.48 g,
7 mmol), pyridine (0.5 mL, 7 mmol) and SiO2 (2.22 g). The
resulting suspension mixture was stirred for 2 days at room
temperature and diluted with ether. The mixture was filtered
through a silica gel. The solvent was removed and the
residue was purified by chromatography to furnish yellow
oil 12 (880 mg, 68%). [a]2D5¼þ628 (c 1.9, CHCl3); 1H NMR
(300 MHz, CDCl3) d 0.78 (d, 6H, J¼1.8 Hz, Me), 0.92 (s,
3H, Me), 0.96 (t, 3H, J¼7.2 Hz, Me), 1.14–1.21 (m, 2H),
1.43–1.50 (m, 4H), 2.09–2.13 (m, 1H), 2.18–2.34 (m, 2H),
2.30 (q, 2H, J¼7.5Hz, CH2), 2.55–2.63 (m, 1H), 3.73 (s,
3H, OMe), 4.33 (d, 1H, J¼11.1 Hz, OCH2Ar), 4.45 (m, 2H,
OCH2Ar and CHOCH2), 6.81 (d, 2H, J¼8.7 Hz, Ar), 7.18
(d, 2H, J¼8.7 Hz, Ar); 13C NMR (75 MHz, CDCl3) d 7.6,
17.1, 19.4, 19.5, 23.8, 32.5, 35.0, 36.9, 43.6, 44.0, 46.0,
53.7, 55.2, 72.8, 73.3, 113.7, 129.5, 131.9, 159.2, 210.0,
215.3; MS m/z (%): 374 (Mþ, 0.3), 238 (10), 202 (12), 167
(36), 121 (100), 57 (13); IR (film, cm21) nmax¼2958, 2938,
2872, 1702, 1603, 1513, 1460, 1250, 1161, 1035, 830.
1
1.3, CHCl3); H NMR (300 MHz, CDCl3) d 0.88 (d, 3H,
J¼5.1 Hz, Me), 0.92 (d, 3H, J¼5.1 Hz, Me), 0.98 (s, 3H,
Me), 1.29–1.36 (m, 1H), 1.54–1.63 (m, 2H), 1.65 (s, 3H,
Me), 1.78–1.83 (m, 1H), 1.91–1.95 (m, 1H), 2.05–2.08 (m,
1H), 2.19 (s, 3H, Me), 2.38–2.42 (m, 1H), 2.52–2.58 (m,
1H), 3.35–3.38 (m, 1H, CHOCH2), 3.80 (s, 3H, OMe), 4.38
(d, 1H, J¼8.7 Hz, OCH2Ar), 4.55 (d, 1H, J¼8.7 Hz,
OCH2Ar), 5.70 (d, 1H, J¼3.6 Hz, CHv), 6.86 (d, 2H,
J¼6.3 Hz, Ar), 7.25 (d, 2H, J¼6.3 Hz, Ar); 13C NMR
(75 MHz, CDCl3) d 11.4, 17.5, 20.3, 20.7, 20.8, 31.1, 31.4,
32.9, 37.9, 40.7, 55.3, 71.0, 80.8, 113.7, 113.8, 120.5, 126.7,
129.0, 131.1, 139.5, 141.0, 159.0, 169.0; MS m/z (‰): 398
(Mþ, 2.6), 356 (11), 313 (46), 235 (20), 193 (29), 175 (39),
161 (11), 135 (73), 121 (1000), 107 (24), 91 (44), 77 (56), 43
(145); IR (film, cm21) nmax¼2954, 2870, 1752, 1513, 1366,
1246, 1212, 1173, 1096, 1035, 822.
4.1.8. 1a-(4-Methoxy-benzyloxy)-10-epi-eudesm-4 (5)-
en-6a-hydroxy-3-one (15). To a solution of 14 (520 mg,
1.3 mmol) in CH2Cl2 (15 mL) was added m-CPBA
(387 mg, 70%, 1.56 mmol) and stirred for 24 h at room
temperature. Then saturated aqueous Na2S2O3 (5 mL) was
4.1.6. 1a-(4-Methoxy-benzyloxy)-10-epi-eudesm-4 (5)-
en-3-one (13). To a solution of diketone 12 (500 mg,
1.34 mmol) in dry MeOH 10 mL was added NaOMe
(20 mg) under argon at 0 8C. Then the mixture was allowed

G. Zheng et al. / Tetrahedron 60 (2004) 6177–6182
6181
added and stirred for 5 min before extraction. The combined
organic layers were washed successively with saturated
aqueous NaHCO3 and brine, dried over MgSO4, and
concentrated to give an oil. Flash column chromatography
on silica gel yielded alcohol 15 (400 mg, 83%). [a]2D5¼þ538
(c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3) d 0.88 (d, 3H,
J¼6.4 Hz, Me), 0.96 (d, 3H, J¼6.4 Hz, Me), 1.24–1.38 (m,
2H), 1.39 (s, 3H, Me), 1.41–1.48 (m, 2H), 1.51–1.58 (m,
1H), 1.85 (s, 3H, Me), 1.98–2.04 (m, 1H), 2.56 (dd, 1H,
J¼12.8, 16.8 Hz), 2.82 (dd, 1H, J¼4.8, 16.8 Hz), 3.50 (dd,
1H, J¼4.8, 12.8 Hz, CHOCH2), 3.81 (s, 3H, OMe), 4.39 (d,
1H, J¼11.2 Hz, OCH2Ar), 4.57 (d, 1H, J¼11.2 Hz,
OCH2Ar), 4.96 (d, 1H, J¼2.4 Hz, CHOH), 6.88 (d, 2H,
J¼8.8 Hz, Ar), 7.26 (d, 2H, J¼8.8 Hz, Ar); 13C NMR
(75 MHz, CDCl3) d 10.7, 18.0, 20.3, 20.6, 21.7, 27.0, 31.4,
39.5, 40.7, 48.2, 55.3, 69.5, 71.0, 80.0, 113.7, 129.1, 130.4,
133.2, 159.2, 159.5, 198.5; MS m/z (‰): 372 (Mþ, 0.4), 354
(0.2), 251 (3), 234 (26), 191 (37), 165 (34), 121 (1000),
and brine, dried over MgSO4. Evaporation of the solvent
followed by flash column chromatography on silica gel
afforded colorless oil 20 (10 mg, 17.4%) and white crystal 3
(40 mg, 70%, mp 140–142 8C). Compound 20 [a]D26¼2288
1
(c 0.4, CHCl3); H NMR (400 MHz, CDCl3) d 0.95 (d,
J¼4 Hz, 3H, Me), 0.96 (d, J¼4 Hz, 3H, Me), 1.05 (s, 3H,
Me), 1.17–1.24 (m, 1H), 1.31–1.34 (m, 1H), 1.57–1.66 (m,
4H), 1.80 (s, 3H, Me), 1.94–2.00 (m, 1H), 2.02 (s, br, 1H),
2.26–2.30 (m, 1H), 3.51 (dd, J¼10.2, 6.4 Hz, 1H, CHOH),
4.25 (s, br, 1H, CHOH), 5.42 (s, br, 1H, CHv); 13C NMR
(100 MHz, CDCl3) d 18.0, 20.3, 20.3, 21.4, 21.7, 26.9, 30.1,
32.3, 37.3, 45.0, 48.0, 69.5, 76.7, 122.1, 133.6; MS m/z 238
(Mþ, 0.5%), 220 (7), 205 (5), 202 (5), 177 (6), 159 (15), 135
(11), 123 (22), 107 (72), 93 (36), 83 (85), 69 (51), 43 (100);
IR (film, cm21) nmax¼3272.3, 2951.7, 2887.9, 1456.1,
1427.3, 1367.5, 1289.2, 1048.5, 1028.0, 989.0, 828.3, 804.2.
Compound 3 [a]2D6¼þ318 (c 1.2, CHCl3); 1H NMR
(400 MHz, CDCl3) d 0.81 (d, J¼6.4 Hz, 3H, Me), 0.85 (s,
3H, Me), 0.94 (d, J¼6.4 Hz, 3H, Me), 1.09–1.12 (m, 1H),
1.26–1.27 (m, 1H), 1.30–1.37 (m, 1H), 1.46–1.47 (m, 1H),
1.63–1.65(d, J¼14 Hz, 1H), 1.89 (s, 3H, Me), 1.90–1.95
(m, 1H), 2.03–2.06 (m, 1H), 2.07–2.17 (m, 1H), 2.49–2.53
(m, 1H), 3.46 (d, J¼9 Hz, 1H, CHOH), 4.02 (t, J¼8 Hz, 1H,
CHOH), 5.34 (s, br, 1H, CHv); 13C NMR (100 MHz,
CDCl3) d 16.0, 18.0, 20.2, 21.0, 25.9, 26.3, 33.3, 33.9, 38.9,
51.1, 57.3, 65.9, 75.9, 120.4, 137.0; MS m/z 238 (Mþ, 1%),
220 (7), 205 (6), 202 (3), 177 (7), 159 (10), 123 (31), 107
(92), 93 (33), 83 (15), 69 (30), 43 (100).
107(20), 91 (33), 77 (43), 43 (84); IR (film, cm21
)
nmax¼3438, 2954, 2872, 1662, 1612, 1513, 1461, 1248,
1175, 1081, 1036, 1005, 820.
4.1.9. 1a,6a-Di-(4-methoxy-benzyloxy)-10-epi-eudesm-4
(5)-en-3-one (16). To a mixture of alcohol 15 (400 mg,
1.08 mmol) and p-TsOH (8 mg) in dry CH2Cl2 (5 mL) was
added dropwise 2,2,2-trichloro-acetimidic acid 4-methoxy-
benzyl ester (456 mg, 1.61 mmol) in CH2Cl2 (2 mL) under
argon at 0 8C. The mixture was allowed to warm up to room
temperature and stirred for 24 h. The crude was directly
chromatographyed on silica gel and afforded colorless oil 16
(434 mg, 82%). [a]D25¼þ218 (c 1.2, CHCl3); 1H NMR
(400 MHz, CDCl3) d 0.84 (d, 3H, J¼6.8 Hz, Me), 0.88 (d,
3H, J¼6.8 Hz, Me), 1.17–1.31 (m, 2H), 1.38 (s, 3H, Me),
1.50–1.55 (m, 1H), 1.61–1.71 (m, 1H), 1.72 (s, 3H, Me),
1.79–1.95 (m, 2H), 2.60 (dd, 1H, J¼16.8, 12.8 Hz), 2.83
(dd, 1H, J¼4.8, 12.8 Hz), 3.53 (dd, 1H, J¼4.8, 12.8 Hz,
CHOCH2), 3.80 (s, 6H, OMe), 4.25 (d, 1H, J¼7.2 Hz,
OCH2Ar), 4.38–4.41 (m, 2H, OCH2Ar and CHOCH2),
4.43–4.59 (m, 2H, OCH2Ar), 6.86–6.89 (m, 4H, Ar), 7.24–
7.27 (m, 4H, Ar); 13C NMR (100 MHz, CDCl3) d 11.4, 19.1,
19.8, 20.2, 21.6, 27.4, 31.3, 39.3, 41.4, 47.7, 55.2, 69.5,
71.1, 76.0, 79.1, 113.7, 128.8, 129.1, 130.4, 130.6, 134.4,
157.8, 159.0, 159.1, 198.5; MS m/z (‰): 492 (Mþ, 1), 463
(1), 371 (1.6), 235 (10), 191 (10), 177 (2), 121 (1000), 91
(22), 77 (35), 43 (16); IR (film, cm21) nmax¼2952, 2870,
1669, 1612, 1513, 1461, 1248, 1174, 1080, 1038, 821.
4.1.11. 1a,6b-Dihydroxy-5b-H-10-epi-eudesm-3 (4)-ene
(10). To a solution of 20 (5 mg) in CH2Cl2 (2 mL) was added
Dess–Martin regent (10 mg) at 0 8C and stirred for 8 h
before it was quenched by saturated aqueous Na2S2O3
(1 mL) at 0 8C. After stirring for a further 15 min, the
reaction mixture was extraction with ether. The organic
phase was washed with water, saturated aqueous NaHCO3,
brine, and dried over MgSO4. Evaporation of the solvent in
vacuum gave the crude product, which without further
purification, was taken in CH3OH (2 mL) and treated with
NaBH4 (10 mg). The resulting mixture was stirred for 1 h at
room temperature and diluted with ether, washed with 5%
HCl, saturated aqueous NaHCO3 and brine, dried over
MgSO4. Purification by flash chromatography gave color-
0
1
less oil 1 (4 mg, 80%). [a]2D6¼2218 (c 0.3, CHCl3); H
NMR (400 MHz, CDCl3) d 0.82 (s, 3H, Me), 0.95 (d,
J¼6.8 Hz, 3H, Me), 0.97(d, J¼6.4 Hz, 3H, Me), 1.26–1.30
(m, 1H), 1.42–1.43 (m, 1H), 1.45–1.55 (m, 2H), 1.64–1.69
(m, 2H), 1.71 (s, 3H, Me), 1.93–1.95 (m, 1H), 2.02–2.03
(m, 1H), 2.12–2.13 (m, 1H), 2.40–2.44 (m, 1H), 3.98 (s, br,
1H, CHOH), 4.44 (t, J¼8.6 Hz, 1H, CHOH), 5.57 (s, br, 1H,
CHv); MS m/z 238 (Mþ, 1.8%), 220 (57), 205 (45), 202
(5), 177 (25), 159 (17), 135 (13), 123 (47), 107 (66), 93 (25),
84 (100), 69 (21), 43 (47); IR (film, cm21) nmax¼3368,
2957, 2928, 2851, 1456, 1372, 1275, 1154, 1072, 1049,
1025, 835.
4.1.10. 1a,6a-Dihydroxy-5b(a)-H210-epi-eudesm-3 (4)-
ene 20 (3). To a solution of 16 (150 mg, 0.3 mmol) in acetic
acid (1.5 mL) was added TsNHNH2 (57 mg, 0.45 mmol)
and stirred for 10 h at room temperature. Then NaBH4
(342 mg, 9 mmol) was added in batches during 0.5 h. The
resulting mixture was diluted with ether and washed
successively with 5% HCl, saturated aqueous NaHCO3
and brine, dried over MgSO4, and concentrated to give an
oil. Flash column chromatography on silica gel afforded
compound 17 and 18 (117 mg, 80%), which without further
purification, was taken in 5 mL CH2Cl2·H2O (18:1), and
treated with DDQ (82 mg, 0.36 mmol) at 0 8C and stirred for
3 h before it was quenched by saturated aqueous NaHCO3
(1 mL) at 0 8C. After stirring for a further 15 min, the
reaction mixture was extraction with ether. The organic
phase was washed with water, saturated aqueous NaHCO3
4.1.12. 1a(b),6b-Dihydroxy-5a-H-10-epi-eudesm-3 (4)-
ene 4 (5). To a solution of 3 (30 mg) in CH2Cl2 (4 mL) was
added Dess–Martin regent (60 mg) at 0 8C and stirred for
14 h before it was quenched by saturated aqueous Na2S2O3
(2 mL) at 0 8C. After stirring for a further 15 min, the
reaction mixture was extraction with ether. The organic
phase was washed with water, saturated aqueous NaHCO3

6182
G. Zheng et al. / Tetrahedron 60 (2004) 6177–6182
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4755–4764. (c) Heathcock, C. H.; Ratcliffe, R. J. Am. Chem.
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and brine, dried over MgSO4. Evaporation of the solvent in
vacuum gave the crude product, which without further
purification, was taken in CH3OH (4 mL) and treated with
NaBH4 (50 mg). The resulting mixture was stirred for 1 h at
room temperature and diluted with ether, washed with 5%
HCl, saturated aqueous NaHCO3 and brine, dried over
MgSO4. Purification by flash chromatography gave white
crystal 4 (18 mg, 60%, mp 174–176 8C) and gave colorless
oil 5 (3 mg, 10%). Compound 4 [a]2D6¼þ88 (c 0.7, CHCl3);
1H NMR (400 MHz, CDCl3) d 0.87 (s, 3H, Me), 0.90 (d,
J¼6.4 Hz, 3H, Me), 0.94 (d, J¼6.8 Hz, 3H, Me), 1.29–1.37
(m, 2H), 1.56–1.58 (m, 2H), 1.59–1.71(m, 2H), 1.77 (s, 3H,
Me), 1.84–1.90 (m, 1H), 2.03–2.08 (m, 1H), 2.37–2.44 (m,
1H), 3.41 (d, J¼4.2 Hz, 1H, CHOH), 4.12 (s, br, 1H,
CHOH), 5.47 (s, br, 1H, CHv); MS m/z 238 (Mþ, 0.7%),
220 (29), 205 (6), 202 (5), 177 (6), 159 (23), 135 (7), 123
(20), 107 (100), 93 (24), 81 (20), 69 (24), 43 (81); IR (film,
cm21) nmax¼3360, 2955, 2916, 2854, 1447, 1372, 1301,
1148, 1062, 854, 788. Compound 5 [a]2D6¼þ188 (c 0.3,
4. Zhou, G.; Gao, X. L.; Li, W. D.; Li, Y. L. Tetrahedron Lett.
2001, 42, 3101–3103.
1
CHCl3); H NMR (400 MHz, CDCl3) d 0.81 (s, 3H, Me),
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7. House, H. O.; Czuba, L. J.; Gall, M.; Olmstead, H. D. J. Org.
Chem. 1969, 34, 2324–2336.
0.95 (d, J¼6.8 Hz, 3H, Me), 0.97 (d, J¼6.8 Hz, 3H, Me),
1.19–1.23 (m, 2H), 1.31–1.61 (m, 2H), 1.63–1.69 (m, 1H),
1.71 (s, 3H, Me), 1.75 (s, br, 1H), 1.87–1.94 (m, 1H), 2.07–
2.18 (m, 1H), 2.44–2.50 (m, 1H), 3.98 (s, br, 1H, CHOH),
4.44 (s, br, 1H, CHOH), 5.56 (s, br, 1H, CHv); MS m/z 238
(Mþ, 1.3%), 220 (74), 205 (63), 202 (1.6), 177 (32), 159
(21), 136 (26), 123 (50), 107 (85), 93 (34), 84 (59), 69 (28),
43 (100); IR (film, cm21) nmax¼3351, 2929, 1444, 1372,
1231, 1150, 1069, 1046, 1024, 829.
8. (a) Mukayaima, T.; Banno, K.; Narasaka, K. J. Am. Chem.
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1999, 55, 8609. (c) Moritz, V.; Vogel, P. Tetrahedron Lett.
1992, 33, 5243–5244.
9. Mcmurry, J. E.; Dushin, R. G. J. Am. Chem. Soc. 1990, 112,
6942–6949.
10. Francisco, A. M.; Jose Maria, A.; Jose Maria, G. M.;
Francisco, R. L.; Isidro, G. C.; Guillermo, M. M.; Frank,
R. F. Tetrahedron 2000, 56, 3409–3414.
Acknowledgements
11. Xiong, Z. M.; Yang, J.; Li, Y. L.; Liao, R. A.; Li, Z. M. Chin.
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We are grateful for the financial supports from NNSFC
(Grant No. 20272021).
12. Zhou, G.; Xiong, Z. M.; Chen, Y. G.; Li, Y. L. J. Chem. Res.
(S) 1998, 650–651.
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References and notes
14. Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu,
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1. (a) Wharton, P. S.; Sundin, C. E.; Johnson, D. W.; Kluender,
H. C. J. Org. Chem. 1972, 37, 34–38. (b) Minnaard, A. J.;