Regioselective routes towards 14-hydroxyabietane diterpenes. A formal synthesis of immunosuppressant (-)-triptolide from (+)-abietic acid

Article abstract of DOI:10.1016/j.tet.2007.07.088

Two procedures to introduce an oxygenated function into the C-14 of abietane diterpenes with complete regioselectivity have been developed. Utilizing these, the synthesis of the antileishmanial quinone (-)-12-deoxyroyleanone (1) and a formal synthesis of antitumour and immunosuppressant (-)-triptonide (7) and (-)-triptolide (8) from (+)-abietic acid (13) have been carried out.

Full text of DOI:10.1016/j.tet.2007.07.088

Tetrahedron 63 (2007) 11204–11212
Regioselective routes towards 14-hydroxyabietane diterpenes.
A formal synthesis of immunosuppressant (L)-triptolide
from (D)-abietic acid
*
Enrique Alvarez-Manzaneda, Rachid Chahboun, Faouzia Bentaleb, Esteban Alvarez,
ꢀ
M. Angeles Escobar, Said Sad-Diki, Maria Jose Cano and Ibtissam Messouri
Departamento de Quꢀımica Orgaꢀnica, Facultad de Ciencias, Instituto de Biotecnologꢀıa,
Universidad de Granada, 18071 Granada, Spain
Received 24 May 2007; revised 12 July 2007; accepted 23 July 2007
Available online 31 July 2007
Abstract—Two procedures to introduce an oxygenated function into the C-14 of abietane diterpenes with complete regioselectivity have been
developed. Utilizing these, the synthesis of the antileishmanial quinone (ꢀ)-12-deoxyroyleanone (1) and a formal synthesis of antitumour and
immunosuppressant (ꢀ)-triptonide (7) and (ꢀ)-triptolide (8) from (+)-abietic acid (13) have been carried out.
Ó 2007 Published by Elsevier Ltd.
1. Introduction
O
O
Natural abietane phenols and quinones, as well as other var-
O
O
O
R
iously oxidized related compounds, constitute an interesting
group of diterpene metabolites, due to the significant bio-
logical activities exhibited by some of them such as (ꢀ)-
12-deoxyroyleanone (1), an antileishmanial agent,1 and
cryptoquinone (2) with antifungal and cytotoxic activities
against mouse lymphoid neoplasm (P388) cells.2 Other sig-
nificant compounds are the antifungal (ꢀ)-deoxybuddlejone
(3),3 and a group of A ring modified terpenoids such as (+)-
triptoquinone A (4), which is under study with respect to the
treatment of rheumatoid arthritis,4 the leukotriene D4 antag-
onists (+)-triptinine A (5) and B (6),5 and the lactones (ꢀ)-
triptonide (7) and (ꢀ)-triptolide (8), which exhibit a variety
of features, including antitumour,6 anti-inflammatory,7
immunosuppressive7b,8 and antifertile activities (Fig. 1).7b,9
HOOC
R
1 R, R: H
2 R, R: =O
3
4
O
O
R2
R1
OR
O
O
HOOC
O
5 R: Me
6 R: H
7 R1, R2: =O
8 R1: H; R2: OH
Figure 1. 12-Deoxyroyleanone (1) and other bioactive oxidized abietane
terpenoids.
Despite the interest in these metabolites, few syntheses have
been reported, and most of these have been total syntheses
involving Diels–Alder cycloaddition,10 Robinson annula-
tion,4 radical cyclizations11 and electrophilic cyclizations.12
A synthesis of lactones 7 and 8 from dehydroabietic acid has
been reported by van Tamelen,13 utilizing 14-hydroxydehy-
droabietic acid, prepared by electrophilic substitution,14 as
a key intermediate.
Subsequently, Matsushita et al. described the synthesis of
quinones 1 and 2 from dehydroabietic acid, utilizing an
electrophilic substitution strategy.17 Very recently, Yajima
et al. reported an asymmetric synthesis of quinones 1 and
2, utilizing a B-alkyl Suzuki–Miyaura coupling and subse-
quent electrophilic cyclization.18 These authors pay special
attention to the 13C NMR chemical shift of aromatic car-
bons, which they assign incorrectly, of the phenol precursor
of quinone 1. Yajima et al. criticize our previous results on
the basis of a small discrepancy with our spectroscopic
data for this intermediate and their inability to reproduce
our described oxidation of this phenol to quinone 1, utilizing
Fremy’s salt.
Our group recently communicated the first synthesis of
quinone 1 from abietic acid, utilizing a novel methodology
for introducing an oxygenated function into C-14.15,16
* Corresponding author. Tel./fax: +34 958 24 80 89; e-mail: eamr@ugr.es
0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.07.088

E. Alvarez-Manzaneda et al. / Tetrahedron 63 (2007) 11204–11212
11205
In this paper we report our studies on the synthesis towards
14-hydroxyabietic acid derivatives, including a very
efficient alternative route to that we had previously commu-
nicated, which reaffirms our first synthesis of (ꢀ)-12-deoxy-
royleanone (1), and a formal synthesis of (ꢀ)-triptonide
(7) and (ꢀ)-triptolide (8). Moreover, we aim to end the
controversy provoked by Yajima’s article and correct the
erroneous 13C NMR assignments made in the latter.
OH
OH (iii)
OH
OMe
(i)
COOH
COOR
14 R: H
11 R: Me
COOMe
12
13
(ii)
(iv)
(v)
OMe
OMe
OMe
+
2. Results and discussion
COOMe
9
COOMe
16
COOMe
15
During our research in the synthesis of bioactive compounds
starting from natural diterpenes, we focused on the synthesis
of this type of oxygenated terpenoids from thevery accessible
abietic acid (13). The key intermediate should be
14-hydroxydehydroabietic acid or related compounds such
as 9. The procedure based on the electrophilic substitution
in dehydroabietic acid derivatives, involving nitration of the
aromatic ring and the further transformation of the nitro into
the hydroxyl group, could raise some problems of regio-
and/or chemoselectivity. Thus, we planned an alternative
method to prepare methoxy ester 9 directly from acid 13, as
depicted in the retrosynthetic Scheme 1. Compound 9 is ob-
tained after aromatization of dienol ether resulting from the
dehydration of b-methoxy alcohol 12. Alternatively, ester 9
couldbepreparedfromthephenolsynthesizedbydehydration
and subsequent aromatization of hydroxy ketone 10, resulting
from the oxidation of 13,14-diol 11, which can be synthesized
by regioselective dihydroxylation of abietic acid (13).19
(vi)
Scheme 2. Synthesis of ester 9 from acid 13 via methoxyalcohol 12. Re-
agents, conditions and yields: (i) OsO4, Me3NO, pyridine, t-BuOH, reflux,
seven days; (ii) MeI, K2CO3, acetone, reflux, 24 h; (iii) NaH, THF, MeI,
rt, 2 h (96%); (iv) SOCl2, Et3N, CH2Cl2, ꢀ78 ꢁC, 20 min (74%); (v) Br2,
CCl4, CaCO3, reflux, 12 h (70%); (vi) H2, Pd–C, MeOH, 24 h (94%) or
Et3SiH, CF3COOH, CH2Cl2, ꢀ40 ꢁC, 16 h (93%).
The alternative sequence from acid 13 to key intermediate 9,
via hydroxy ketone 10, is depicted in Scheme 3. After ester-
ification of carboxylic acid 14, oxidation of the secondary
hydroxyl group was undertaken. The transformation of
diol 11 into ketone 10 was assayed under different oxidizing
conditions, as shown in Table 1.
OH
OH
OH
O
OH
(i)
(v)
O
OH
O
COOMe
17
O
OMe
COOMe
COOMe
R
(ii)
11
10
(iv)
R
(vi)
COOMe
9
COOMe
10
1 R, R: H
2 R, R: =O
16
O
O
15
17
11
20
O
(iii)
OH
OMe
OH
OR
1
O
R2
R1
14
9
10
COOMe
COOMe
19
COOMe
9
3
7
5
O
18
COOH
13
COOMe
O
19
18
7 R1, R2: =O
8 R1: H; R2: OH
11 R:H
Scheme 3. Synthesis of ester 9 via hydroxy ketone 10. Reagents, conditions
and yields: (i) PhSeSePh, t-BuOOH, CCl4, reflux, 2 h (92%); (ii) TsOH,
benzene, reflux, 36 h (78%); (iii) K2CO3, MeOH, reflux, three days
(70%); (iv) H2, Pd–C; MeOH, 24 h (96%); (v) TsOH, toluene, reflux,
10 h (91%); (vi) MeI, K2CO3, acetone, reflux, 15 h (91%).
12 R:Me
Scheme 1. Retrosynthetic analysis of 12-deoxyroyleanone (1) and other
related terpenoids from abietic acid (13).
Scheme 2 shows the synthesis of ester 9 from acid 13 via the
b-methoxy alcohol 12. Abietic acid (13) was efficiently con-
verted into diol 14, utilizing a modification of the method re-
ported in the literature.19 Compound 12, which is obtained
after methylation of dihydroxy ester 11, underwent regiose-
lective dehydration by treating with SOCl2 and Et3N to give
the dienol ether 15. This compound was then transformed
into the corresponding dehydroabietic acid derivative by
treating with Br2 in CCl4 under reflux. It should be noted
that the desired compound 9 resulted when 1 equiv of Br2
was utilized; however, the use of Br2 in excess afforded
a mixture of ester 9 and the D6 derivative 16, which can eas-
ily be converted into 9 after hydrogenation or by treating
with Et3SiH and CF3COOH.
Diol 11 remained unaltered after treatment with MnO2 at
room temperature; however, keto aldehyde 20 was obtained
in good yield when the mixture was refluxed for 16 h. Small
quantities of this compound, together with aromatic esters
21 and 22 resulted when Jones reagent was utilized. Diol
11 was recovered unaltered after treatment with IBX in
DMSO at room temperature; nevertheless, keto aldehyde
2020 resulted when the reaction was carried out in THF under
reflux.21 Treatment with PCC in CH2Cl2 gave the desired hy-
droxy ketone 10, together with the keto aldehyde 20. Utiliza-
tion of Swern reagent gave compounds 10 and 18 in low
yields. Oxidation with DDQ and TsOH in benzene gave sim-
ilar results. Treatment with PDC and t-BuOOH in benzene
gave only hydroxy ketone 10, but in low yield. A successful

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E. Alvarez-Manzaneda et al. / Tetrahedron 63 (2007) 11204–11212
Table 1. Reaction of diol 11 under different oxidizing conditions
OMe
OMe
OMe
OMe
(i)
(ii)
O
CHO
CHO
24
R
R
CH2OH
23
COOMe
9
COOMe
20
COOMe
(iii)
(iv)
(v)
21 R, R: H
22 R, R: =O
O
Entry Conditions
Product(s) (%)
OR1
O
(vii)
1
MnO2, benzene, rt, 24 h
MnO2, benzene, reflux, 16 h
Jones reagent, acetone, rt, 20 h
IBX, DMSO, rt, 16 h
No reaction
20 (75)
20 (5), 21 (20), 22 (11)
No reaction
20 (72)
R
R
CH2R
27 R: OMs
28 R: I
2
3
4
5
(vi)
(ix)
1 R: Me
25 R, R1: Me
29 R: COOMe
(viii)
26 R: Me, R1: H
IBX, THF, reflux, 48 h
˚
17 R: COOMe, R1: H
PCC, CH2Cl2, 4 A molecular
20 (37), 10 (30)
sieves, 0 ꢁC, 30 min
(COCl)2, DMSO, Et3N, CH2Cl2, rt, 24 h 10 (15), 18 (5)
6
7
8
9
Scheme 4. Synthesis of 12-deoxyroyleanone (1) from ester 9. Reagents, con-
ditions and yields: (i) LiAlH4, THF, rt, 3 h (95%); (ii) PCC, CH2Cl2, rt, 1 h
(70%); (iii) N2H4, KOH, ethyleneglycol–ethyleneglycol dimethylether
(3:2), 180 ꢁC, three days (70%); (iv) MsCl, Et3N, CH2Cl2, 0 ꢁC–rt, 4 h
(93%); (v) LiAlH4, THF, reflux, 24 h (95%); (vi) NaI, HMPA, reflux, three
days (90%); (vii) Zn, NaI, HMPA, 110 ꢁC, three days (75%) for 27, or
LiAlH4, THF, reflux, 24 h (96%) for 28; (viii) BBr3, CH2Cl2, ꢀ10 ꢁC,
30 min(95%);(ix)Fremy’ssalt, MeOH–H2O, rt(91%for26and83%for17).
DDQ, TsOH, benzene, rt, 48 h
PDC, t-BuOOH, benzene, rt, 3 h
PhSeSePh, t-BuOOH, CCl4, reflux, 2 h 10 (92)
10 (18), 18 (12)
10 (36)
oxidation of diol 11 was attained after reaction with PhSe-
SePh and t-BuOOH in CCl4 under reflux:22 the desired com-
pound 10 was obtained in 92% yield (entry 9). This ketone
was converted into enone 18 by refluxing with TsOH in ben-
zene; this compound could be a suitable intermediate for
synthesizing compounds such as deoxybuddlejone (3).
Treatment of enone 18 with K2CO3 in MeOH under reflux
led to phenol 19,23 which was then hydrogenated to give
phenol 17. This compound was directly obtained in high
yield when the enone 10 was refluxed with TsOH in toluene.
Finally, this phenol was transformed into the desired me-
thoxy ester 9. Compound 17, which has also been synthe-
sized by Matsushita et al.,17 had the same spectroscopic
properties as those reported by these authors.
reported by Matsushita et al.,17 and emphasize a small dis-
crepancy with our previously reported data.15 However,
Yajima et al. make a wrong assignment, which they also
attribute unfoundedly to Matsushita et al. The signal at
123.24 ppm, assigned to C-8 by Yajima et al. is due to a me-
thine carbon, as the DEPT experiment revealed, and there-
fore it would be attributed to C-12. On the other hand, the
signal at 120.62 ppm, which they assigned to C-12, and
which as the DEPT indicated is a quaternary carbon, would
be attributed to C-8. Then, a tentative assignation for the aro-
matic ring carbons, in accordance with the chemical shift
pattern observed in similar structures, is d 116.5 (C-11),
120.7 (C-8), 123.3 (C-12), 130.1 (C-13), 149.1 (C-9),
150.3 (C-14). This assignation agrees with that of Yajima
et al., but interchanging the assignations for C-8 and C-12.
Ester 9, which as indicated is a suitable precursor of bioac-
tive metabolites such as 1,2 and 4–8, was then transformed
into 12-deoxyroyleanone (1) (Scheme 4). First, the methyl
ester was converted into methyl group. Treatment of 9
with LiAlH4 gave alcohol 23, which was oxidized to alde-
hyde 24 and this transformed into compound 25 under the
Wolff–Kishner conditions. Alternative transformations of
23 into 25, via mesyl derivative 27, were investigated. The
treatment of 27 with LiAlH4 regenerated alcohol 23; never-
theless, compound 25 was obtained after treating mesylate
27 with Zn and NaI.24 It should be noted that the yield of
this reaction depends upon the quantity of mesylate; a
more suitable procedure applicable to large amounts of com-
pound 27 involves its conversion into iodide 28, by treating
with NaI in HMPA under reflux, and further reduction with
LiAlH4. Deprotection of methyl ether with BBr3 led to
phenol 26.
Finally, phenol 26 was transformed into 12-deoxyroylea-
none (1) by treating with potassium nitrosodisulfonate. It
should be noted that Yajima et al. indicate that they also as-
sayed this oxidation unsuccessfully. However, we insist on
the total reproducibility of this reaction. In fact, before syn-
thesizing compound 1, we assayed this oxidation over the
less elaborated phenol 17, which under the same reaction
conditions afforded quinone 29, which had also been pre-
pared by Matsushita et al.;17 our spectroscopic data and
those reported by these authors were identical.
As we initially postulated, ester 9 is a suitable precursor of the
A ring functionalized bioactive compounds 4–8. Thus, alde-
hyde 24 was efficiently transformed into alkene 31, utilizing
novel procedures developed by our group (Scheme 5). The
treatment of compound 24 with MCPBA gave in good yield
formate 30,25 which was converted with complete regiose-
lectivity into the trisubstituted alkene 31 by treating with I2
and PPh3.26 Compound 31 has previously been transformed
into (ꢀ)-triptonide (7) and (ꢀ)-triptolide (8),13 and therefore
the sequence reported herein involves a formal synthesis of
these bioactive compounds from (+)-abietic acid (13).
Even though the structure of this phenol is quite evident,
given that a simple inspection of the 1H NMR spectrum re-
veals two doublets (J¼8.2 Hz) at 6.85 and 7.01 ppm, charac-
teristic of the H-11 and H-12 ortho protons, Yajima et al.18
pay special attention to the 13C NMR signals for the aromatic
carbons of this compound. In their article, these authors an-
nounce a good agreement between the aromatic 13C NMR
chemical shifts for the phenol they synthesized and those

E. Alvarez-Manzaneda et al. / Tetrahedron 63 (2007) 11204–11212
11207
atmosphere. After stirring for 5 min at room temperature,
a 2% aqueous solution of OsO4 (14 mL) was added and
the reaction mixture was further stirred under an atmosphere
of argon at reflux for seven days. NaHSO3 (10 mL) was
added and the solvent was evaporated, then AcOEt
(100 mL) was added and the mixture was washed with 5%
HCl (2ꢂ20 mL), water (3ꢂ20 mL) and brine. The organic
phase was dried over Na2SO4 and concentrated to give
a crude product, which was chromatographed on silica gel
(H–E, 3:7) to give pure 14 (6.5 g, 58%) as a colourless solid.
Mp 156–157 ꢁC [lit.:19a 154–155 ꢁC]; [a]2D5 ꢀ3.75 (c 0.8,
CHCl3); IR (KBr) n 3441, 2924, 1693, 1462, 1262, 1023,
OMe
OMe
OMe
(i)
(ii)
OCHO
30
CHO
24
31
Ref. 13
O
O
R2
R1
O
O
O
1
801 cmꢀ1; H NMR (300 MHz, CDCl3) d: 0.83 (3H, s),
7 R1, R2: =O
8 R1: H; R2: OH
0.87 (3H, d, J¼6.9 Hz), 0.93 (3H, d, J¼6.9 Hz), 1.32 (3H,
s), 1.43 (1H, dd, J¼11.6, 2.9 Hz), 1.91 (1H, m), 2.17 (1H,
h, J¼6.9 Hz), 3.68 (3H, s, COOMe), 4.02 (1H, br s), 5.88
(1H, d, J¼4.4 Hz); 13C NMR (75 MHz, CDCl3) d: 36.8
(C-1), 19.2 (C-2), 39.1 (C-3), 46.2 (C-4), 51.2 (C-5), 26.5
(C-6), 119.9 (C-7), 137.8 (C-8), 44.5 (C-9), 35.2 (C-10),
19.2 (C-11), 24.9 (C-12), 76.4 (C-13), 73.1 (C-14), 33.12
(C-15), 17.8 (C-16), 18.0 (C-17), 183.9 (C-18), 15.1 (C-
19), 19.2 (C-20); HRMS (FAB) m/z calcd for C20H32O4Na,
359.2198; found, 359.2202.
Scheme 5. Synthesis of alkene 31, precursor of bioactive compounds 7 and
8, from aldehyde 24. Reagents, conditions and yields: (i) MCPBA,
NaHCO3, CH2Cl2, reflux, 3 h (93%); (ii) I2, PPh3, CH2Cl2, rt, 12 h (91%).
3. Conclusion
In summary, two efficient procedures to prepare 14-hydroxy-
abietic acid and related compounds, from abietic acid (13)
are reported. Utilizing these, the synthesis of the antileish-
manial 12-deoxyroyleanone (1) and a formal synthesis of
antitumour and immunosuppressant (ꢀ)-triptonide (7) and
(ꢀ)-triptolide (8) from this diterpenic acid are described.
4.1.2. Methyl 13b,14b-dihydroxyabieta-7-en-18-oate
(11).
4.1.2.1. Synthesis of diol 11 from 14. K2CO3 (5.7 g,
41.97 mmol) was added to a solution of 14 (5.59 g,
16.79 mmol) in acetone (75 mL) and the reaction mixture
was kept stirring at room temperature for 15 min. Then,
iodomethane (3.1 mL, 51 mmol) was added and the reaction
mixture was stirred at reflux for 24 h. The solvent was evap-
orated and the crude reaction mixture was poured into ether–
water (60:10 mL) and it was extracted with ether (2ꢂ
30 mL). The organic phase was washed with brine, dried
over Na2SO4 and the solvent evaporated to give 11 (5 g,
94%) as a colourless solid. Mp 107–107.1 ꢁC; [a]D25 ꢀ0.57
4. Experimental
4.1. General
Dichloromethane (DCM) was dried over calcium hydride,
while toluene, tetrahydrofuran (THF) and benzene were
dried over sodium-benzophenone. Methanol was distilled
from magnesium at 760 Torr. Dimethylformamide (DMF)
1
(c 0.7, CHCl3). The MS, IR, H and 13C NMR data agreed
with the literature data.27
˚
and ethanol were dried over 4 A molecular sieves. Chroma-
tography separations were carried out by conventional
column on silica gel 60 (230–400 mesh) using hexane–
MeOt-Bu (H–E) mixtures of increasing polarity. Infrared
(IR) spectra were obtained using Perkin Elmer Spectrum
Models 782 and 983G spectrophotometers with samples
between sodium chloride plates or as potassium bromide
pellets. Data are presented as the frequency of absorption
(cmꢀ1). Proton and carbon-13 nuclear magnetic resonance
(1H NMR and 13C NMR) spectra were recorded on Varian
300 and 400 spectrometers, chemical shifts are expressed
in parts per million (d scale) downfield from tetramethylsi-
lane. Data are presented as follows: chemical shift, multiplic-
ity (s¼singlet, br s¼broad singlet, d¼doublet, br d¼broad
doublet, t¼triplet, m¼multiplet), J¼coupling constant in
hertz (Hz). The signals of the 13C NMR were assigned utiliz-
ing DEPT experiments and on the basis of literature data.
HRMS were obtained on a trisector WG AutoSpecQ spec-
trometer. FAB spectra acquisition was performed with
a 10,000 resolution and a relative error of 5 ppm.
4.1.2.2. Synthesis of diol 11 from 13. To a solution of
abietic acid (13) (5.00 g, 16.55 mmol) in t-BuOH (25 mL)
were added trimethylamine-N-oxide dihydrate (2.21 g,
19.9 mmol) and pyridine (0.1 mL) under argon atmosphere.
After stirring for 5 min at room temperature, a 2% aqueous
solution of OsO4 (7 mL) was added and the reaction mixture
was further stirred under an atmosphere of argon at reflux for
seven days. Following the same workup described for 14,
5.54 g of the crude product was obtained. This was dissolved
in acetone (75 mL) and K2CO3 (5.4 g, 39.76 mmol) was
added; after stirring for 10 min at room temperature, iodo-
methane was added (3.5 mL, 57.59 mmol) and the reaction
mixture was stirred at reflux for 24 h. Following the same
workup described above, a crude product (5.3 g) was
obtained. The chromatography of this crude on silica gel
(H–E, 7:3) gave pure 11 (5.2 g, 90%) as a colourless oil.
4.1.3. Methyl 13b-hydroxy-14b-methoxyabieta-7-en-18-
oate (12). NaH (60% dispersion in mineral oil) (170 mg,
4.26 mmol) was carefully added to a cold (0 ꢁC) solution
of 11 (0.5 mg, 1.43 mmol) in dry THF (10 mL) under argon
atmosphere and the mixture was stirred at this temperature
for 5 min. MeI (0.6 mL) was added and the resulting reaction
4.1.1. 13b,14b-Dihydroxyabieta-7-en-18-oic acid (14). To
a solution of abietic acid (13) (10.01 g, 33.11 mmol) in
t-BuOH (50 mL) were added trimethylamine-N-oxide dihy-
drate (4.42 g, 39.8 mmol) and pyridine (0.3 mL) under argon

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E. Alvarez-Manzaneda et al. / Tetrahedron 63 (2007) 11204–11212
mixture was stirred at room temperature for 2 h, at which
time TLC showed the disappearance of starting material.
The reaction mixture was poured into ice-water and it was
extracted with ether (2ꢂ20 mL). The organic phase was
washed with brine, dried over Na2SO4 and the solvent evap-
orated to give a crude product, which was purified by column
chromatography on silica gel (H–E, 85:15) affording pure 12
(0.51 g, 96%) as a colourless oil. [a]2D5 +5.13 (c 0.91, CHCl3);
diluted with ether (50 mL) and washed with satd aq NaHCO3
(2ꢂ10 mL), water (2ꢂ10 mL) and brine (2ꢂ10 mL). The
organic phase was dried over Na2SO4 and the solvent evap-
orated to give 9 (819 mg, 93%).
4.1.7. Oxidation of diol 11.
4.1.7.1. Treatment of 11 with MnO2. To a stirred solu-
tion of 11 (100 mg, 0.285 mmol) in dry benzene (10 mL)
was added MnO2 (0.49 g, 5.71 mmol). After stirring at reflux
for 48 h, TLC showed no 11, then the reaction was worked
up by the addition of ether (10 mL), and the resulting mix-
ture was filtered through a silica gel pad and washed with
ether (10 mL). The solvent was evaporated to yield 20
(74 mg, 75%) as a colourless oil.
IR (film) n 3519, 2944, 1726, 1460, 1371, 1242, 1146 cmꢀ1
;
HRMS (FAB) m/z calcd for C22H36O4Na, 387.2511; found,
387.2507. The 1H and 13C NMR data agreed with the litera-
ture data.15
4.1.4. Methyl 14-methoxyabieta-7,13-dien-18-oate (15).
SOCl2 (1 mL, 13.7 mmol) was added slowly to a solution
of 12 (1.7 mg, 4.67 mmol) and triethylamine (5 mL) in dry
CH2Cl2 (50 mL) at ꢀ78 ꢁC. The reaction mixture was stirred
at this temperature under argon atmosphere for 20 min, at
which time TLC showed no starting material. The reaction
mixture was quenched with satd aq NaHCO3 (6 mL) and
the cooling bath was removed. The mixture was poured
into ether–water (60:20 mL) and it was extracted with ether
(2ꢂ30 mL). The organic phase was washed with 2 N HCl
(3ꢂ20 mL), brine (3ꢂ20 mL), dried over Na2SO4 and the
solvent evaporated to give a crude product, which was puri-
fied byflash chromatography on silica gel (H–E, 95:5) afford-
ing pure 15 (1.2 g, 74%) as a colourless oil. [a]2D5 ꢀ11.0 (c
Methyl 13,14-dioxo-13-secoabieta-7,13-dien-18-oate (20).
IR (film) n 3500, 2951, 1714, 1652, 1631, 1462, 1386,
1246, 1187 cmꢀ1; 1H NMR (300 MHz, CDCl3) d: 0.78 (3H,
s), 1.03 (3H, d, J¼6.9 Hz), 1.05 (3H, d, J¼6.9 Hz), 1.21
(3H, s), 2.21 (1H, m), 2.40 (1H, m), 2.57 (1H, h,
J¼6.9 Hz), 3.05 (1H, m), 3.6 (3H, s, COOMe), 6.7 (1H, q,
J¼2.7 Hz, H-7), 9.3 (1H, s, H-CHO); 13C NMR (75 MHz,
CDCl3) d: 42.4 (C-1), 20.7 (C-2), 37.7 (C-3), 46.9 (C-4),
49.9 (C-5), 26.7 (C-6), 152.2 (C-7), 144.2 (C-8), 44.1 (C-9),
36.3 (C-10), 18.3 (C-11), 37.0 (C-12), 215.2 (C-13), 194.7
(C-14), 40.6 (C-15), 17.4 (C-16), 17.6 (C-17), 178.4 (C-18),
14.1 (C-19), 18.2 (C-20), 52.0 (C-COOMe); HRMS (FAB)
m/z calcd for C21H32O4Na, 371.2198; found, 371.2191.
0.85, CHCl3); IR (film) n 2836, 1726, 1624, 1385, 738 cmꢀ1
;
HRMS (FAB) m/z calcd for C22H34O3Na, 369.2405; found,
369.2412. The 1H and 13C NMR data agreed with the litera-
ture data.15
4.1.7.2. Treatment of 11 with Jones reagent. To a stirred
solution of 11 (0.32 g, 0.91 mmol) in acetone (15 mL) was
added at 0 ꢁC Jones reagent28 (0.5 mL) and the reaction
mixture was stirred for 30 min, at which time TLC showed
no 11. Then the solvent was evaporated and the crude prod-
uct was diluted with ether (30 mL), washed with water
(6ꢂ10 mL), brine, dried over anhyd Na2SO4 and concen-
trated to give a crude product, which was chromatographed
on silica gel (H–E, 9:1) to give 20 (15 mg, 5%), 21 (58 g,
20%) and 22 (32 mg, 11%).
4.1.5. Methyl 14-methoxyabieta-6,8,11,13-tetraen-18-
oate (16). A solution of bromine (0.18 mL, 3.51 mmol) in
CCl4 (15 mL) was added to a suspension of 15 (0.96 g,
2.90 mmol) and CaCO3 (0.79 g, 7.89 mmol) in CCl4
(20 mL), and the reaction mixture was stirred at reflux for
12 h, at which time TLC showed no 15. Then the precipitated
solid was filtered, the filtrate was washed with ether (10 mL)
and the solvent was evaporated to give a crude product, which
was purified by flash chromatography to give pure 16 (0.69 g,
70%) as a colourless oil. [a]2D5 +22.2 (c 1.0, CHCl3); IR (film)
n 2947, 1726, 1447, 1245, 816 cmꢀ1; HRMS (FAB) m/z calcd
Methyl 7-oxoabieta-8,11,13-trien-18-oate (22). IR (film) n
1
2952, 1726, 1682, 1460, 1249 cmꢀ1; H NMR (300 MHz,
CDCl3) d: 1.11 (3H, s), 1.16 (3H, d, J¼6.9 Hz), 1.18 (3H,
d, J¼6.9 Hz), 1.27 (3H, s), 2.65 (1H, dd, J¼6.9, 3.5 Hz),
2.85 (1H, h), 3.56 (3H, s, COOMe), 7.21 (1H, d, J¼
8.2 Hz), 7.34 (1H, dd, J¼8.2, 2.1 Hz), 7.79 (1H, d, J¼
2.1 Hz); 13C NMR (75 MHz, CDCl3) d: 16.4 (CH3), 18.2
(CH2), 23.8 (CH3), 23.9 (CH3), 24.0 (CH), 33.5 (CH3),
36.6 (CH2), 37.2 (CH2), 37.4 (C), 37.9 (CH2), 43.8 (CH),
52.2 (CH3), 123.5 (CH), 125.1 (CH), 132.6 (CH), 146.9
(C), 153.0 (C), 177.8 (C), 198.6 (C); HRMS (FAB) m/z calcd
for C21H28O3Na, 351.1936; found, 351.1928.
for C22H30O3Na, 395.2092; found, 365.2094. The 1H and 13
NMR data agreed with the literature data.15
C
4.1.6. Methyl 14-methoxyabieta-8,11,13-trien-18-oate
(9).
4.1.6.1. Treatment of 16 with H2/Pd–C. To a solution of
16 (0.50 g, 1.46 mmol) in methanol (30 mL), 10% Pd–C
(100 mg) was added and the reaction mixture was stirred at
room temperature under hydrogen atmosphere for 24 h. Fil-
tration and concentration gave 9 (472 mg, 94%) as a colour-
less solid. Mp 97 ꢁC; [a]D25 +38.2 (c 0.71, CHCl3); IR (KBr)
n 2956, 1726, 1620, 1448, 1246, 817 cmꢀ1; HRMS (FAB)
m/z calcd for C22H32O3Na, 367.2249; found, 367.2254. The
1H and 13C NMR data agreed with the literature data.15
4.1.7.3. Treatment of 11 with IBX in DMSO. IBX
(0.3 g, 1.07 mmol) was added to a solution of diol 11
(0.20 g, 0.57 mmol) in DMSO (6 mL) and the reaction mix-
ture was stirred at room temperature for 16 h. Then the reac-
tion mixture was diluted with ether (20 mL), washed with
satd aq Na2CO3 (2ꢂ6 mL), dried over Na2SO4 and the sol-
vent evaporated to give the unaltered 11 (194 mg).
4.1.6.2. Treatment of 16 with Et3SiH/CF3COOH. To
a solution of 16 (0.87 g, 2.56 mmol) in dichloromethane
(20 mL), triethylsilane (0.6 mL) and trifluoroacetic acid
(0.4 mL) were successively added at ꢀ40 ꢁC, and the result-
ing mixture was stirred for 16 h. Then, the mixture was
4.1.7.4. Treatment of 11 with IBX in THF. IBX (0.3 g,
1.07 mmol) was added to a solution of diol 11 (0.20 g,

E. Alvarez-Manzaneda et al. / Tetrahedron 63 (2007) 11204–11212
11209
0.57 mmol) in dry THF (10 mL) and the reaction mixture
was stirred at reflux for 48 h. Then the solvent was evapo-
rated and the residue was extracted with ether (2ꢂ15 mL),
the organic phase was washed with satd aq Na2CO3
(2ꢂ10 mL), dried over Na2SO4 and the solvent evaporated
to give a crude product, which was purified by flash chroma-
tography on silica gel (H–E, 7:3), affording 20 (143 mg,
72%) as a colourless oil.
Methyl 13b-hydroxy-14-oxoabieta-7-en-18-oate (10). [a]D25
+16.85 (c 0.94, CHCl3); IR (film) n 3500, 2951, 1714,
1652, 1631, 1462, 1386, 1246, 1187 cmꢀ1; HRMS (FAB)
m/z calcd for C21H32O4Na, 371.2198; found, 371.2192.
The 1H and 13C NMR data agreed with the literature data.15
4.1.7.9. Treatment of 11 with PhSeSePh/t-BuOOH. Di-
phenyl diselenide (0.60 g, 1.92 mmol) and 6 M t-BuOOH in
decane (0.65 mL, 3.9 mmol) were added to a stirred solution
of 11 (0.50 g, 1.43 mmol) in dry CCl4 (20 mL) and the mix-
ture was kept stirring at reflux under argon atmosphere for
2 h, at which time TLC showed no remaining starting mate-
rial. Then, the solvent was evaporated and the residue was
purified by flash chromatography on silica gel (H–E, 7:3)
affording 10 (457 mg, 92%) as a colourless oil.
4.1.7.5. Treatment of 11 with PCC. Pyridinium chloro-
chromate (PCC) (1.28 g, 5.49 mmol) and molecular sieves
˚
3 A (3.75 g) were added to a stirred solution of 11 (0.50 g,
1.43 mmol) in dry CH2Cl2 (20 mL) and the mixture was
kept stirring at room temperature under argon atmosphere
for 30 min, at which time TLC showed no remaining starting
material. Then, the reaction was worked up by the addition
of CH2Cl2 (10 mL) and the resulting mixture was filtered
through a silica gel pad and washed with a mixture of
ether–CH2Cl2 (20:30 mL). The solvent was evaporated to
yield a crude product, which was chromatographed on silica
gel (H–E, 7:3) to yield 10 (150 mg, 30%) and 20 (184 mg,
37%).
4.1.8. Methyl 7-oxoabieta-7,12-dien-18-oate (18). Hy-
droxy ketone 10 (0.30 g, 0.862 mmol) and p-toluenesulfonic
acid (140 mg, 0.736 mmol) in dry benzene (15 mL) were
heated at reflux for 36 h, at which time TLC showed the dis-
appearance of starting material. Then the solvent was evap-
orated to give a crude product, which was purified by flash
chromatography on silica gel (H–E, 7:3) affording 18
(0.22 g, 78%) as a colourless oil. [a]2D5 ꢀ0.66 (c 0.91,
CHCl3); IR (film) n 2870, 1724, 1667, 1612, 1460, 1424,
1385, 1302, 1005, 911, 827, 756 cmꢀ1; 1H NMR (500 MHz,
CDCl3) d: 0.86 (3H, s), 0.97 (3H, d, J¼6.9 Hz), 1.03 (3H, d,
J¼6.9 Hz), 1.24 (3H, s), 2.90 (1H, h, J¼6.9 Hz), 3.63 (3H, s,
COOMe), 6.69 (1H, d, J¼8.3 Hz), 7.00 (1H, q, J¼2.9 Hz);
13C NMR (125 MHz, CDCl3) d: 36.9 (C-1), 18.2 (C-2),
38.1 (C-3), 46.1 (C-4), 43.6 (C-5), 26.0 (C-6), 135.7 (C-7),
135.0 (C-8), 49.6 (C-9), 37.0 (C-10), 23.1 (C-11), 140.6
(C-12), 145.7 (C-13), 186.3 (C-14), 26.7 (C-15), 22.3 (C-
16), 23.1 (C-17), 178.5 (C-18), 14.9 (C-19), 16.9 (C-20),
52.0 (C-COOMe); HRMS (FAB) m/z calcd for
C21H30O3Na, 353.2092; found, 353.2091.
4.1.7.6. Swern oxidation of 11. To a stirred solution of
(COCl)2 (1.79 mL, 20.57 mmol) in dry dichloromethane
(17 mL) was added DMSO (2.5 mL) at ꢀ78 ꢁC, the reaction
mixture was stirred for 2 min and the cooling bath was re-
moved for 5 min. Then a solution of 11 (3.0 g, 8.57 mmol)
in dichloromethane (35 mL) was added at ꢀ78 ꢁC and the
reaction mixture was stirred at this temperature for an addi-
tional 15 min. Then, triethylamine (5 mL) was added and the
cooling bath was removed. After stirring for 15 min, the re-
action mixture was diluted with ether (80 mL) and washed
with 2 N HCl (3ꢂ20 mL), water and brine. The organic
phase was dried over Na2SO4 and concentrated to give
a crude product (2.9 g), which was purified by column chro-
matography on silica gel (H–E, 3:2), to give 10 (447 mg,
15%) and 18 (142 mg, 5%).
4.1.9. Methyl 7-hydroxyabieta-8,11,13-trien-18-oate (17).
Ketone 10 (0.2 mg, 0.575 mmol) and p-toluenesulfonic acid
(0.1 mg, 0.526 mmol) in dry toluene (10 mL) were heated at
reflux for 10 h. Then the solvent was evaporated to give
a crude product, which was purified by flash chromato-
graphy on silica gel (H–E, 85:15) affording 17 (172 mg,
91%) as a colourless oil. [a]2D5 +7.7 (c 1.0, CHCl3) [lit.:17
4.1.7.7. Treatment of 11 with DDQ. 2,3-Dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ; 113 mg, 0.49 mmol)
and p-toluenesulfonic acid (15 mg, 0.079 mmol) were added
to a stirred solution of 14 (95 mg, 0.271 mmol) in dry
benzene (6 mL) and the reaction mixture was stirred at
room temperature for 48 h, at which time TLC showed no
14. Then it was diluted with ether (25 mL), washed with
water, satd aq NaHCO3 and brine to give a crude product,
which was purified by column chromatography on silica
gel (H–E, 9:1), to give 10 (17 mg, 18%) and 18 (11 mg,
12%).
1
+51.7 (c 0.5, CHCl3)]. The MS, IR, H and 13C NMR data
agreed with the literature data.17
4.1.10. Methyl 14-hydroxyabieta-6,8,11,13-tetraen-18-
oate (19). K2CO3 (0.39 g, 2.85 mmol) was added to a solu-
tion of 18 (92 mg, 0.28 mmol) in MeOH (6 mL), and the
reaction mixture was kept stirring at reflux for three days,
at which time TLC showed the disappearance of compound
18. The reaction was quenched with 2 N HCl (1 mL). The
mixture was poured into ether–water (20:5 mL) and it was
extracted with ether (2ꢂ15 mL). The organic phase was
washed with brine, dried over Na2SO4 and the solvent evap-
orated to give 19 (70 mg, 70%) as a colourless oil. IR (film)
n 3583, 2948, 2923, 2869, 1724, 1627, 1566, 1433, 1386,
1123, 1002, 762 cmꢀ1; 1H NMR (300 MHz, CDCl3) d: 1.05
(3H, s), 1.21 (3H, d, J¼6.9 Hz), 1.24 (3H, d, J¼6.9 Hz), 1.38
(3H, s), 2.16 (1H, m), 2.86 (1H, t, J¼3.0 Hz), 3.10 (1H, h,
J¼6.9 Hz), 3.65 (3H, s, COOMe), 5.77 (1H, dd, J¼9.8,
2.9 Hz), 6.73 (1H, d, J¼8.3 Hz), 6.77 (1H, dd, J¼9.8,
4.1.7.8. Treatment of 11 with PDC. Pyridinium dichro-
mate (PDC; 13.9 g, 36.25 mmol) and 6 M t-BuOOH in
decane (7.32 mL, 43.92 mmol) were added to a stirred solu-
tion of 11 (3.14 g, 8.97 mmol) and Celite (10.78 g) in dry
benzene (114 mL). The reaction mixture was stirred at
room temperature under argon atmosphere for 3 h 15 min,
at which time TLC showed no 11. The resulting mixture
was filtered through a silica gel pad and washed with a 1:1
mixture of hexane–ether (50 mL) and the solvent was evap-
orated to give a crude product (3.5 g). The chromatography
of this crude on silica gel (H–E, 7:3) gave 10 (1.13 g, 36%)
as a colourless oil.

11210
E. Alvarez-Manzaneda et al. / Tetrahedron 63 (2007) 11204–11212
3.1 Hz), 7.03 (1H, d, J¼8.1 Hz); 13C NMR (75 MHz,
CDCl3) d: 35.5 (C-1), 18.4 (C-2), 35.6 (C-3), 46.3 (C-4),
46.2 (C-5), 129.6 (C-6), 125.2 (C-7), 119.8 (C-8), 146.6
(C-9), 37.6 (C-10), 114.2 (C-11), 121.0 (C-12), 131.8 (C-
13), 148.4 (C-14), 26.9 (C-15), 22.5 (C-16), 22.8 (C-17),
17.9 (C-19), 20.5 (C-20), 52.0 (C-COOMe); HRMS (FAB)
m/z calcd for C21H28O3Na, 351.1936; found, 351.1929.
NMR (300 MHz, CDCl3) d: 1.15 (3H, s), 1.18 (6H, d,
J¼6.9 Hz), 1.21 (3H, s), 1.31–1.90 (8H, m), 2.31 (1H, br
d, J¼12.7 Hz), 2.73 (1H, ddd, J¼17.6, 11.3, 6.2 Hz), 2.96
(1H, dd, J¼17.6, 6.2 Hz), 3.27 (1H, h, J¼6.9 Hz), 3.69
(3H, s), 7.01 (1H, d, J¼8.1 Hz), 7.06 (1H, d, J¼8.1 Hz);
13C NMR (75 MHz, CDCl3) d: 14.1 (CH3), 17.8 (CH2),
20.9 (CH2), 23.9 (CH3), 24.0 (CH3), 24.3 (CH2), 25.2
(CH), 26.1 (CH), 32.0 (CH2), 36.5 (C), 38.0 (CH2), 42.5
(CH), 49.8 (C), 60.5 (CH), 120.2 (CH), 123.9 (CH), 128.3
(C), 138.4 (C), 147.9 (C), 155.0 (C), 206.2 (C); HRMS
(FAB) m/z calcd for C21H30O2Na, 337.2143; found,
337.2138.
4.1.11. Treatment of 19 with H2/Pd–C. To a solution of 19
(0.5 g, 1.52 mmol) in methanol (30 mL), 10% Pd–C
(100 mg) was added and the reaction mixture was stirred
at room temperature under hydrogen atmosphere for 24 h.
Filtration and concentration gave 17 (0.48 g, 96%) as a
colourless oil.
4.1.15. 14-Methoxyabieta-8,11,13-triene (25). Hydrazine
hydrate (0.5 mL) and KOH (0.20 g) were added to a solution
of aldehyde 24 (0.40 g, 1.27 mmol) in ethyleneglycol–
ethylenglycol dimethylether (3:2, 15 mL) and the reaction
mixture was heated at 180 ꢁC for three days, at which time
TLC showed no 24. The reaction mixture was allowed to
cool to room temperature and was diluted with water
(5 mL) and extracted with ether (2ꢂ20 mL). The combined
organic phases were washed with water and brine, dried over
Na2SO4 and the solvent evaporated to give a crude product,
which was purified by column chromatography on silica gel
(H–E, 95:5), affording 25 (267 mg, 70%) as a colourless
syrup. [a]2D5 +15.1 (c 1.0, CHCl3); IR (film) n 2963, 2945,
4.1.12. Methylation of 17. K2CO3 (0.60 g, 4.35 mmol) was
added to a solution of 17 (575 mg, 1.74 mmol) in acetone
(15 mL) and the reaction mixture was kept stirring at room
temperature for 15 min. Then iodomethane (0.54 mL,
8.71 mmol) was added and the reaction mixture was stirred
at reflux for 15 h. The solvent was evaporated and the crude
reaction mixture was poured into ether–water (30:10 mL)
and it was extracted with ether (2ꢂ10 mL). The organic
phase was washed with brine, dried over Na2SO4 and the sol-
vent evaporated to give 9 (545 mg, 91%) as a colourless oil.
4.1.13. 14-Methoxyabieta-8,11,13-trien-18-ol (23).
LiAlH4 (0.5 g, 13.16 mmol) was added to a stirred solution
of 9 (1.0 g, 3.01 mmol) in dry THF (10 mL) cooled to
0 ꢁC, and the reaction mixture was kept stirring at room tem-
perature under argon atmosphere for 3 h, at which time TLC
showed the disappearance of starting material. Then, 2 N
HCl (0.5 mL) was added slowly at 0 ꢁC and the mixture
was extracted with ether (2ꢂ25 mL). The organic phase
was washed with brine, dried over Na2SO4 and the solvent
evaporated to give 23 (0.9 g, 95%) as a colourless solid.
Mp 102 ꢁC; [a]D25 +5.7 (c 0.04, CHCl3); IR (KBr) n 3401,
1605, 1452, 1378, 1050, 1018, 980 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d: 0.93 (3H, s), 0.96 (3H, s), 1.18 (3H,
s), 1.21 (3H, d, J¼6.8 Hz), 1.20 (3H, d, J¼6.8 Hz), 1.32
(1H, dd, J¼12.5, 2.1 Hz), 1.39 (1H, ddd, J¼13.1, 13.1,
3.6 Hz), 1.48 (1H, br d, J¼13.1 Hz), 1.55–1.85 (8H, m),
1.93 (1H, dd, J¼13.2, 7.8 Hz), 2.26 (1H, br d, J¼12.7 Hz),
2.73 (ddd, J¼17.7, 11.4, 7.7 Hz), 3.01 (1H, dd, J¼17.6,
7.7 Hz), 3.28 (1H, h, J¼6.9 Hz), 3.72 (3H, s), 7.02 (1H, d,
J¼8.4 Hz), 7.05 (1H, d, J¼8.4 Hz); 13C NMR (100 MHz,
CDCl3) d: 18.7 (CH2), 19.4 (CH2), 21.7 (CH3), 23.4
(CH3), 24.0 (CH3), 25.0 (CH3), 29.5 (CH2), 26.1 (CH),
33.4 (CH3), 33.4 (C), 37.8 (C), 39.0 (CH2), 41.7 (CH2),
50.2 (CH), 60.5 (CH3), 120.4 (CH), 123.7 (CH), 128.7 (C),
137.8 (C), 149.4 (C), 154.0 (C); HRMS (FAB) m/z calcd
for C21H32ONa, 323.2351; found, 323.2347.
1
1484, 1410, 1329, 1263, 1212, 1031, 817 cmꢀ1; H NMR
(300 MHz, CDCl3) d: 0.88 (3H, s), 1.18 (3H, d, J¼
6.9 Hz), 1.20 (3H, d, J¼6.9 Hz), 1.22–1.95 (8H, m), 2.25
(1H, br d, J¼12.7 Hz), 2.74 (1H, ddd, J¼17.6, 11.3,
6.2 Hz), 2.98 (1H, dd, J¼17.6, 6.2 Hz), 3.23 (1H, d, J¼
10.8 Hz), 3.27 (1H, h, J¼6.9 Hz), 3.48 (1H, d, J¼10.8 Hz),
3.70 (3H, s), 7.01 (1H, d, J¼8.1 Hz), 7.04 (1H, d, J¼8.1 Hz);
13C NMR (75 MHz, CDCl3) d: 17.4 (CH3), 18.4 (CH2), 18.7
(CH2), 23.9 (CH3), 24.0 (CH3), 24.6 (CH2), 25.3 (CH3), 26.1
(CH), 35.0 (CH2), 37.6 (C), 37.9 (C), 38.6 (CH2), 43.6 (CH),
60.5 (CH3), 72.2 (CH2), 120.3 (CH), 123.6 (CH), 128.6 (C),
137.9 (C), 149.1 (C), 154.8 (C); HRMS (FAB) m/z calcd for
C21H32O2Na, 339.2300; found, 339.2304.
4.1.16. 14-Methoxy-18-mesyloxyabieta-8,11,13-triene
(27). Mesyl chloride (0.7 mL) was added to a solution of
23 (0.40 g, 1.26 mmol) and triethylamine (1 mL) in di-
chloromethane (15 mL) at 0 ꢁC and the reaction mixture
was stirred at room temperature for 4 h, at which time
TLC showed no 23. The reaction mixture was quenched
with water (1 mL) and it was diluted with ether (40 mL)
and washed with 2 M aq HCl, water and brine. The organic
phase was dried over anhyd Na2SO4 and concentrated under
vacuum to yield 27 (461 mg, 93%) as a colourless oil. [a]D25
+13.5 (c 1.06, CHCl3); IR (film) n 1495, 1355, 1175,
4.1.14. 14-Methoxyabieta-8,11,13-trien-18-al (24). Pyridi-
nium chlorochromate (PCC) (0.50 g, 2.32 mmol) was added
to a stirred solution of 22 (0.50 g, 1.58 mmol) in dry CH2Cl2
(25 mL) and the mixture was kept stirring at room tempera-
ture under argon atmosphere for 1 h, at which time TLC
showed no remaining starting material. Then, the reaction
was worked up by the addition of CH2Cl2 (20 mL) and the
resulting mixture was filtered through a silica gel pad and
washed with a mixture of ether–CH2Cl2 (15:30 mL). The
solvent was evaporated to yield 23 (0.35 g, 70%), as a colour-
less oil. [a]2D5 +7.13 (c 1.1, CHCl3); IR (film) n 1725, 1449,
1
1028, 956, 847, 755 cmꢀ1; H NMR (300 MHz, CDCl3) d:
0.95 (3H, s), 1.16 (3H, s), 1.18 (3H, d, J¼6.9 Hz), 1.21
(6H, d, J¼6.9 Hz), 1.45–1.90 (8H, m), 2.26 (1H, br d, J¼
12.7 Hz), 2.70 (1H, ddd, J¼16.5, 11.5, 6.2 Hz), 2.96 (3H,
s), 3.00 (1H, dd, J¼16.5, 6.2 Hz), 3.27 (1H, h, J¼6.9 Hz),
3.69 (3H, s), 3.79 (1H, d, J¼9.4 Hz), 4.05 (1H, d, J¼
9.4 Hz), 6.99 (1H, d, J¼8.1 Hz), 7.01 (1H, d, J¼8.1 Hz);
13C NMR (75 MHz, CDCl3) d: 17.1 (CH3), 18.4 (CH2),
18.5 (CH2), 23.9 (CH3), 24.0 (CH3), 24.4 (CH2), 25.3 (CH3),
26.1 (CH), 35.1 (CH2), 37.2 (CH3), 37.2 (C), 37.6 (C), 38.2
1
1410, 1330, 1219, 1152, 1029, 872, 818, 757 cmꢀ1; H

E. Alvarez-Manzaneda et al. / Tetrahedron 63 (2007) 11204–11212
11211
(CH2), 43.4 (CH), 60.5 (CH3), 77.1 (CH2), 120.3 (CH),
123.8 (CH), 128.3 (C), 138.1 (C), 148.4 (C), 154.8 (C);
HRMS (FAB) m/z calcd for C22H34O4SNa, 417.2075; found,
417.2081.
2.26 (1H, dt, J¼12.7, 3.2 Hz), 2.59 (1H, ddd, J¼16.5,
11.3, 6.8 Hz), 2.78 (1H, dd, J¼16.5, 6.3 Hz), 3.12 (1H, h,
J¼6.8 Hz), 4.61 (1H, s), 6.84 (1H, d, J¼8.2 Hz), 7.00 (1H,
d, J¼8.2 Hz); 13C NMR (75 MHz, CDCl3) d: 18.3 (CH2),
19.3 (CH2), 21.7 (CH3), 22.6 (CH3), 22.8 (CH3), 22.9
(CH3), 24.4 (CH3), 24.9 (CH3), 27.1 (CH), 33.4 (CH3),
33.4 (C), 38.8 (C), 39.0 (CH2), 41.7 (CH2), 49.8 (CH),
116.5 (CH), 120.7 (C), 123.3 (CH), 130.1 (C), 149.1 (C),
150.3 (C); HRMS (FAB) m/z calcd for C20H30ONa,
309.2194; found, 309.2187.
4.1.17. Treatment of 27 with NaI/Zn. NaI (160 mg,
0.81 mmol) and zinc (105 mg, 1.59 mmol) were added to
a solution of 27 (120 mg, 0.30 mmol) in HMPA (5 mL)
and the reaction mixture was stirred at 110 ꢁC for three
days, at which time TLC showed no 27. The reaction mix-
ture was quenched with water (2 mL), diluted with ether
(30 mL) and washed with water (6ꢂ10 mL) and brine. The
organic phase was dried over anhyd Na2SO4 and concen-
trated under vacuum to yield 25 (68 mg, 75%).
4.1.21. Oxidation of 17 with (KSO3)2NO. Potassium nitro-
sodisulfonate (0.60 g, 2.23 mmol) was added to a stirred so-
lution of 17 (200 mg, 0.606 mmol) in methanol (60 mL) and
water (6 mL). After stirring for 10 h, TLC showed no start-
ing material. Then, the solvent was evaporated and the crude
product was extracted with ether (2ꢂ20 mL). The combined
organic phases were washed with brine, dried over Na2SO4
and concentrated to give a crude product, which was purified
by flash chromatography on silica gel (H–E, 3:2) to give 29
4.1.18. 14-Methoxy-18-iodoabieta-8,11,13-triene (28).
NaI (560 mg, 2.83 mmol) was added to a solution of 27
(420 mg, 1.06 mmol) in HMPA (8 mL) and the reaction mix-
ture was stirred at reflux for three days, at which time TLC
showed no 27. The reaction mixture was quenched with
water (2 mL), diluted with ether (30 mL) and washed with
water (6ꢂ10 mL) and brine. The organic phase was dried
over Na2SO4 and concentrated under vacuum to yield 28
(407 mg, 90%) as a yellow oil. [a]2D5 ꢀ7.6 (c 1.1, CHCl3);
1
(173 mg, 83%) as a yellow oil. The MS, IR, H and 13C
NMR data agreed with the literature data.17
4.1.22. Oxidation of 26 with (KSO3)2NO. Potassium nitro-
sodisulfonate (0.80 g, 2.98 mmol) was added to a stirred so-
lution of 26 (150 mg, 0.524 mmol) in methanol (50 mL) and
water (5 mL). After stirring for 4 h, TLC showed no starting
material. Following the same workup described for 17,
143 mg (91%) of 12-deoxyroyleanone (1) was obtained as
a yellow oil.
IR (film) n 1456, 1381, 1260, 1212, 1030, 979, 819 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d: 1.10 (3H, s), 1.20 (3H, s),
1.21 (3H, d, J¼6.9 Hz), 1.21 (3H, d, J¼6.9 Hz), 1.30–1.82
(7H, m), 2.24 (1H, ddd, J¼12.8, 12.8, 3.1 Hz), 2.79 (1H,
ddd, J¼17.7, 11.0, 7.5 Hz), 3.01 (1H, ddd, J¼17.7, 6.2,
1.4 Hz), 3.25 (1H, d, J¼10.0 Hz), 3.29 (1H, h, J¼6.9 Hz),
3.38 (1H, d, J¼10.0 Hz), 3.72 (3H, s), 7.02 (1H, d,
J¼8.4 Hz), 7.06 (1H, d, J¼8.4 Hz); 13C NMR (125 MHz,
CDCl3) d: 18.5 (CH2), 18.8 (CH3), 19.2 (CH2), 24.1
(CH3), 24.1 (CH3), 24.8 (CH2), 24.9 (CH3), 26.3 (CH),
38.3 (CH2), 35.9 (C), 38.1 (C), 38.7 (CH2), 47.2 (CH),
60.7 (CH3), 120.7 (CH), 124.0 (CH), 128.7 (C), 138.2 (C),
148.9 (C), 155.0 (C).
4.1.23. 4-Formyloxy-14-methoxy-18-norabieta-8,11,13-
triene (30). To a stirred solution of 24 (1.0 g, 3.18 mmol)
and NaHCO3 (0.6 g) in CH2Cl2 (50 mL), m-chloroperben-
zoic acid (MCPBA) (1.1 g, 4.78 mmol) was added at room
temperature. After stirring at reflux for 3 h, TLC indicated
that no starting aldehyde 24 remained. The reaction mixture
was quenched with 10% aq Na2SO3 (5 mL) and the mixture
was stirred for an additional 45 min. Then, it was poured into
ether–water (80:20 mL), and the organic phase washed with
satd aq NaHCO3 (8ꢂ20 mL), brine and dried over Na2SO4.
After evaporating the solvent in vacuo, 30 (0.98 g, 93%) was
obtained as a colourless oil. [a]2D5 +13.2 (c 0.52, CHCl3); IR
(film) n 1719, 1567, 1584, 1385, 1330, 1198, 1102, 1029,
4.1.19. Treatment of 28 with LiAlH4. LiAlH4 (0.3 g,
7.9 mmol) was added to a stirred solution of 28 (0.75 g,
1.76 mmol) in dry THF (15 mL) cooled to 0 ꢁC, and the re-
action mixture was kept stirring under argon atmosphere at
reflux for 24 h, at which time TLC showed the disappearance
of starting material. Then, 2 N HCl (0.5 mL) was added
slowly and the mixture was extracted with ether
(3ꢂ20 mL). The organic phase was washed with brine, dried
over Na2SO4 and the solvent evaporated to give 25 (507 mg,
96%) as a colourless oil.
1
861, 820, 755 cmꢀ1; H NMR (500 MHz, CDCl3) d: 1.20
(3H, s), 1.21 (3H, d, J¼6.9 Hz), 1.22 (3H, d, J¼6.9 Hz),
1.59 (3H, s), 1.98 (1H, dd, J¼12.3, 1.8 Hz), 2.12 (1H, dd,
J¼12.9, 7.6 Hz), 2.24 (1H, d, J¼12.5 Hz), 2.64 (1H, m),
2.75 (1H, ddd, J¼17.6, 12.9, 7.6 Hz), 3.06 (1H, dd,
J¼17.6, 5.5 Hz), 3.14 (1H, h, J¼6.9 Hz), 3.72 (3H, s),
7.02 (1H, d, J¼8.2 Hz), 7.07 (1H, d, J¼8.2 Hz), 8.08 (1H,
s); 13C NMR (125 MHz, CDCl3) d: 16.9 (CH2), 18.9
(CH3), 19.0 (CH2), 22.9 (CH3), 23.7 (CH3), 25.1 (CH),
36.6 (CH2), 36.9 (CH2), 37.6 (C), 48.4 (CH), 59.4 (OCH3),
119.5 (CH), 122.9 (CH), 127.4 (C), 137.3 (C), 146.6 (C),
153.9 (C), 159.5 (C); HRMS (FAB) m/z calcd for
C21H30O3Na, 353.2093; found, 353.2100.
4.1.20. Abieta-8,11,13-trien-14-ol (26). BBr3 (0.25 mL,
2.6 mmol) was added to a solution of 25 (250 mg,
0.83 mmol) in dichloromethane (15 mL) at ꢀ10 ꢁC and
the reaction mixture was stirred for 30 min, at which time
TLC showed no 25. The reaction mixture was poured into
ice-water and it was diluted with ether (30 mL) and washed
with water (5ꢂ10 mL) and brine. The organic phase was
dried over Na2SO4 and concentrated under vacuum to yield
26 (225 mg, 95%) as a yellow oil. [a]2D5 +15.1 (c 1.0, CHCl3)
[lit.:17 +52.9 (c 0.5, CHCl3); lit.:18 +27.9 (c 0.96, CHCl3)].
IR (film) n 3500, 1569, 1491, 1420, 1381, 1216, 1177,
4.1.24. 14-Methoxy-18-norabieta-3,8,11,13-tetraene
(31).13 Iodine (1.0 g, 3.94 mmol) was added to a solution
of Ph3P (1 g, 3.8 mmol) in CH2Cl2 (10 mL) and the mixture
was stirred at room temperature for 5 min. A solution of 30
(1 g, 3.03 mmol) in CH2Cl2 (10 mL) was then added and the
1
1103, 995, 809 cmꢀ1; H NMR (300 MHz, CDCl3) d: 0.88
(3H, s), 1.17 (3H, s), 1.19 (3H, s), 1.22 (3H, d, J¼6.8 Hz),
1.23 (3H, d, J¼6.8 Hz), 1.41 (1H, dd, J¼12.3, 1.8 Hz),

11212
E. Alvarez-Manzaneda et al. / Tetrahedron 63 (2007) 11204–11212
7. (a) Zheng, Y.-L.; Lin, J.-F.; Lin, C.-C.; Xu, Y. Acta Pharmacol.
Sin. 1994, 15, 540–543; (b) Zheng, J.-R.; Gu, K.-X.; Xu, L. F.;
Gao, J.-W.; Yu, Y.-H.; Tang, M.-Y. Acta Acad. Med. Sin. 1991,
13, 391–395.
reaction mixture was stirred at room temperature for 12 h, at
which time TLC showed no 30. The reaction mixture was
quenched with 5% aq NaHSO3 (3 mL) and the mixture
was stirred for an additional 15 min. Then, it was diluted
with ether (30 mL) and the organic phase was washed suc-
cessively with satd aq NaHCO3 (2ꢂ10 mL), brine, dried
over anhyd Na2SO4 and concentrated under vacuum. The
crude product was purified by flash chromatography (H–E,
9:1) to give 31 (783 mg, 91%) as a colourless oil. [a]D25
+38.4 (c 0.7, CHCl3); IR (film) n 1647, 1561, 1447, 1329,
8. (a) Gu, W.-Z.; Chen, R.; Brandwein, S.; McAlpine, J.; Burres,
N. Int. J. Immunopharmacol. 1995, 17, 351–356; (b) Yang,
S.-X.; Gao, H.-L.; Xie, S.-S.; Zhang, W.-R.; Long, Z.-Z. Int.
J. Immunopharmacol. 1992, 14, 963–969; (c) Qiu, D.-M.;
Zhao, G.-H.; Aoki, Y.; Shi, L.-F.; Uyei, A.; Nazarina, S.; Ng,
J. C.-H.; Kao, P. N. J. Biol. Chem. 1999, 274, 13443–13449.
9. Zhen, Q.-S.;Ye, X.; Wei, Z.-J. Contraception 1995, 51, 121–129.
10. Engler, T. A.; Sampath, U.; Naganathan, S.; Vander Velde, D.;
Takusagawa, F. J. Org. Chem. 1989, 54, 5712–5727.
11. Yang, D.; Ye, X.-Y.; Xu, M. J. Org. Chem. 2000, 65, 2208–
2217.
12. Tada, M.; Nishiiri, S.; Zhixiang, Y.; Imai, Y.; Tajima, S.;
Okazaki, N.; Kitano, Y.; Chiba, K. J. Chem. Soc., Perkin
Trans. 1 2000, 2657–2659.
13. Garver, L. C.; van Tamelen, E. E. J. Am. Chem. Soc. 1982, 104,
867–869.
1260, 1203, 1032, 820, 757 cmꢀ1 1H NMR (500 MHz,
;
CDCl3) d: 1.21 (3H, d, J¼6.9 Hz), 1.22 (3H, d, J¼6.9 Hz),
1.26 (3H, s), 150–1.60 (2H, m), 1.76 (3H, s), 1.87 (1H, br
d, J¼10.7 Hz), 2.06 (1H, m), 2.61 (1H, ddd, J¼16.8, 10.4,
5.0 Hz), 2.89 (1H, dd, J¼16.8, 4.7 Hz), 3.30 (1H, h,
J¼6.9 Hz), 3.71 (3H, s), 5.42 (1H, br s), 7.06 (1H, d,
J¼6.8 Hz), 7.08 (1H, d, J¼6.8 Hz); 13C NMR (125 MHz,
CDCl3) d: 22.6 (CH3), 23.3 (CH2), 23.9 (CH2), 24.1
(CH3), 24.1 (CH3), 26.4 (CH), 27.4 (CH3), 33.8 (CH2),
36.6 (C), 46.8 (CH), 60.7 (OCH3), 121.6 (CH), 123.2
(CH), 123.9 (CH), 130.1 (C), 135.5 (C), 137.8 (C), 145.1
(C), 154.5 (C); HRMS (FAB) m/z calcd for C20H28ONa,
307.2038; found, 307.2042.
14. Tahara, A.; Akita, H. Chem. Pharm. Bull. 1975, 23, 1976–1983.
15. Alvarez-Manzaneda, E. J.; Chahboun, R.; Bentaleb, F.;
ꢀ
Cabrera Torres, E.; Alvarez, E.; Haidour, A.; Ramos Lopez,
J. M.; Alvarez-Manzaneda, R.; El Houssame, S. Synlett 2004,
2701–2704.
16. The present authors regret making some errors in Ref. 15. The
13C NMR chemical shifts for the aromatic carbons in com-
pound 17 should be d 116.5 (CH), 120.7 (C), 123.3 (CH),
130.1 (C), 149.1 (C), 150.3 (C). Compounds 8, 9 and 11 are
13b,14b-disubstituted derivatives.
Acknowledgements
The authors thank the Spanish Ministry of Science and Tech-
nology (Project CTQ 2006-12697) and the ‘Junta de Anda-
lucia’ (PAI group FQM-348) for their financial support.
17. Matsushita, Y.; Iwakiri, Y.; Yoshida, S.; Sugamoto, K.; Matsui,
T. Tetrahedron Lett. 2005, 46, 3629–3632.
18. Yajima, A.; Yamaguchi, A.; Saitou, F.; Nukada, T.; Yabuta, G.
Tetrahedron 2007, 63, 1080–1084.
19. (a) Cross, B. E.; Myers, P. L. J. Chem. Soc. C 1969, 711–713;
(b) Okawara, H.; Nakai, H.; Ohno, M. Tetrahedron Lett. 1982,
23, 1087–1090.
Supplementary data
Copies of H NMR, 13C NMR and DEPT spectra for com-
1
pounds 1, 9, 10, 12, 15–19, 23–28, 30 and 31 are included
as supplementary data. Supplementary data associated
with this article can be found in the online version, at
doi:10.1016/j.tet.2007.07.088.
€
20. Haslinger, E.; Hufner, A. Monatsh. Chem. 1995, 126, 1109–
1123.
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References and notes
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