Lateral lithiation in terpenes: Synthesis of (+)-ferruginol and (+)-sugiol

Article abstract of DOI:10.1016/j.tet.2010.07.066

This paper describes the use of (-)-sclareol in the synthesis of the tricyclic diterpenes of abietane skeleton, such as (+)-ferruginol and (+)-sugiol, using as key step the lateral lithiation of a dinorditerpene derivative.

Full text of DOI:10.1016/j.tet.2010.07.066

Tetrahedron 66 (2010) 7773e7780
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Lateral lithiation in terpenes: synthesis of (þ)-ferruginol and (þ)-sugiol
*
I.S. Marcos , A. Beneitez, R.F. Moro, P. Basabe, D. Díez, J.G. Urones
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca. Plaza de los Caídos 1-5, 37008 Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 June 2010
Received in revised form 19 July 2010
Accepted 22 July 2010
Available online 30 July 2010
This paper describes the use of (ꢀ)-sclareol in the synthesis of the tricyclic diterpenes of abietane
skeleton, such as (þ)-ferruginol and (þ)-sugiol, using as key step the lateral lithiation of a dinorditerpene
derivative.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Diterpenes
Abietanes
(ꢀ)-Sclareol
Ferruginol
Sugiol
Lateral lithiation
1. Introduction
most common variation of known derivatives with aromatic ring C
and C-15 and/or C-16 functionality or not.
The diterpene tricyclic of abietane skeleton, are one of the
natural product groups widely distributed in nature some of which
display an interesting range of biological activities.1 A major part of
these compounds have ring C aromatic. In Figure 1, are shown the
Diterpene abietanes as (þ)-ferruginol 1 and (þ)-sugiol 2,
isolated from Podocarpus ferruginenus2 and Juniperus communis
L.,3 respectively, are widely distributed in nature.4 Recently it
has been found that (þ)-ferruginol has a potent activity as
OH
OH
15
13
20
16
A
C
B
1
14
9
10
5
8
COOH
OH
4
19
18
Abietane skeleton
E
D
F
Figure 1. Abietane skeleton structure types differently substituted on the side chain.
gastric protector in animals,5 while, (þ)-sugiol shows antiin-
flamatory,6 antitumoral,7 antioxidant and antimicrobiane prop-
erties.8 Other interesting abietanes are more functionalized as
incanone 3, that shows cytotoxic activity against human leuke-
mia cells9 or cyrtophyllone B 410 (Fig. 2).
* Corresponding author. Tel.: þ34 923 294474; fax: þ34 923 294574; e-mail
address: ismarcos@usal.es (I.S. Marcos).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.066

7774
I.S. Marcos et al. / Tetrahedron 66 (2010) 7773e7780
OH
OH
OH
OH
HO
HO
H
OH
OH
OH
O
O
O
H
H
H
(+)-ferruginol
(+)-sugiol
incanone
cyrtophyllone B
HO
OH
H
H
(-)-sclareol
5
Figure 2. Diterpenes with abietane and abeo-abietane skeletons, accesibles from (ꢀ)-sclareol through norditerpene 5.
Recently our group has synthesised the dinorpimarane 5 from
Br
(ꢀ)-sclareol, Figure 2, in three steps in good yield.11 In this paper it
is shown that 5, is an excellent starting material for the synthesis of
abietanes with different side chain. The methodology will be ap-
plied to the synthesis of the natural products (þ)-ferruginol 1 and
(þ)-sugiol 2 and analogues of incanone 3 and cyrtophyllone B, 4.
ii or iii
i
Br
H
H
5
H
6
7
2. Results and discussion
Scheme 2. (i) NBS, AIBN cat., CCl4, 70 ꢁC, 2 h, 62%; (ii) NBS, AIBN cat., TFH/H2O, h
n
(200 W), 10 min, 46%; (iii) NBS, AIBN cat., [bmim]PF6, 80 ꢁC, 2 h 30 min, 46%.
In Scheme 1, it is shown the retrosynthetic analysis for the
synthesis of (þ)-ferruginol 1, (þ)-sugiol 2 and analogues of inca-
none, 3 and cyrtophyllone B, 4 from (ꢀ)-sclareol using the dinor-
pimarane 5 as the key intermediate.
directing regioselectively the addition or substitution of aromatic
compounds differently substituted with different electrofiles.
Considering that the objective of this work is the synthesis of
(þ)-ferruginol 1, (þ)-sugiol 2, analogues of incanone 3 and of
cyrtophyllone B 4, that present and oxygenated function in C-12,
the carbamoyl was chosen group as the one for directing the lateral
lithiation. For this reason first of all will be synthesised compound
11 (Scheme 3). FriedeleCrafts acylation of 5 gave the acylderivative
8, that by BaeyereVilliger oxidation gave 9 in 80% yield for the two
steps. The hydrolysis of the last compound gave phenol 10, that by
treatment with N,N-diisopropilcarbamoyl chloride in presence NaH
(Scheme 3) gave the required 11 in good yield.
OH
HO
15
OH
R
H
H
H
R
(+)-ferruginol H2
1
5
sclareol
(+)-sugiol
2
O
O
OH
HO
OH
HO
OH
HO
OH
OH
i
ii
OH
O
H
O
H
H
H
H
5
8
cyrtophyllone B, 4
incanone, 3
(-)-sclareol
Scheme 1. Retrosynthetic analysis for access the abietane skeleton from (ꢀ)-sclareol.
iii
The transformation of 5 into abietane diterpenes requires
functionalization at C-15 or alkylation at this carbon. The direct
functionalization of C-15 of compound 5, first attempted under
radical conditions. However treatment of 5 with NBS and catalytic
AIBN in CCl4 at 70 ꢁC,12 gave 6 (72%), while reaction with NBS/AIBN
under irradiation with a lamp of 200 W in THF/H2O (Scheme 2),13
gave 7 (66%) and the reaction with NBS/AIBN in ionic solvent as
[bmim]PF6, led again to 7 with in lower yield 46 %.
N
Cb
OAc
OH
O
O
v
iv
H
H
H
9
10
11
As the direct functionalization did not gave the expected results, it
was decided the use of lateral lithiation for the activation of C-15.
ortho-Lithiation14 and lateral lithiation,15 are two excellent method-
ologies for the regioselective synthesis of natural products.16 Several
groups, such as methoxyls,17 N,N-alquilamides,18 N,N0-diarylureas,19
oxazolines,20 carbamates21 and toluensulfonamides22 are capable of
Scheme 3. (i) Ref. 11, 71%; (ii) AcCl, SnCl4 85 ꢁC, 45 min, 90%; (iii) UHP, TFAA, rt, 24 h,
91%; (iv) K2CO3, MeOH, H2O, 3%, rt, 30 min, 98%, (v) (1) NaH 60%, THF, 0 ꢁC/rt, 15 min;
(2) (i-Pr)2NCOCl, 2 h, rt, 92%.
With compound 11 in hand, several conditions for the lateral
lithiation were tested. (Scheme 4). Compound 11 was treated with

I.S. Marcos et al. / Tetrahedron 66 (2010) 7773e7780
OCb OCb
7775
OCb
OCb
OH
O
i
iii
H
H
H
H
14
11
16
vi
12
ii
v
viii
iv
17
15
OCb
OCb
OCb
OCb
16
CO2Et
OR
OH
H
H
H
H
R
13
19
15
17 Ac
vii
18
H
ix
OR1
OH
OH
OH
HO
H
HO
H
OH
OH
OH
x
R2
R1 R2
O
O
H
H
incanone, 3
(+)-ferruginol, 1
cyrtophyllone B, 4
20 Ac H2
xi
21 Ac
O
O
xii
(+)-sugiol,
2
H
Scheme 4. (i) (1) 10 equiv sec-BuLi, ꢀ78 ꢁC, 10 min; (2) 10 equiv MeI, ꢀ78 ꢁC/rt 20 min, 94%; (ii) (1) 10 equiv sec-BuLi, ꢀ78 ꢁC, 10 min; (2) 10 equiv CH3CHO, ꢀ78 ꢁC/rt 20 min,
87%; (iii) (1) 32 equiv sec-BuLi, ꢀ78 ꢁC, 10 min; (2) 5 equiv HCHO, ꢀ78 ꢁC/rt 20 min, 68%. (iv) (1) 10 equiv sec-BuLi, ꢀ78 ꢁC, 10 min; (2) 10 equiv ClCO2Et, ꢀ78 ꢁC/rt,74%; (v) TPAP/
NMO, DCM, rt, 10 min, 99%; (vi) m-CPBA, DCM, rt, 16 h, 74%; (vii) K2CO3, MeOH, rt, 45 min, 97%; (viii) (1) 10 equiv sec-BuLi, ꢀ78 ꢁC, 10 min; (2) 10 equiv MeI, ꢀ78 ꢁC/rt, 20 min,
82%; (ix) LiAlH4, Et2O, reflux 16 h, 93%; (x) Ac2O, py, 6 h, rt, 98%; (xi) Na2CrO4, NaOAc, AcOH/Ac2O, 65 ꢁC, 45 min, 77%; (xii) K2CO3, MeOH, rt, 96%.
a big excess of sec-BuLi (10 equiv) at ꢀ78 ꢁC and the lithiated species
were made to react with different electrophiles as MeI, acetaldehyde
and formaldehyde, obtaining compounds 12,13 and 14, in good yield,
not being found the products of ortho-lithiation (Scheme 4). Com-
pounds 12 and 14 are norpimaranes and the side chain of 13, corre-
spond to a 17(15/16)-abeo-abietane, partial structure C in Figure 1,
as the natural product incanone 3.9
In order to prove the interest of compounds 12 and 13, they
have been transformed into more complex abietanes. Reaction of
12 with sec-BuLi and ethyl chloroformiate gave ester 15, a very
interesting intermediate for the synthesis of cyrtophyllone B type
abietanes and other compounds of partial structure as B and F in
Figure 1.
284e286 ꢁC, were coincident with the ones of the natural
(þ)-sugiol 2, [
a
]
25 þ12.3 (c 0.1, CHCl3) and mp 282e285 ꢁC.9
D
3. Conclusions
It has been shown, that lateral lithiation reaction is a direct an
easy way to accede to the tricyclic diterpenes with abietane (i.e.,
cyrtophyllone B) and abeo-abietane (i.e., incanone) skeletons. This
methodology has been applied in the synthesis of the natural
compounds (þ)-ferruginol 1 and (þ)-sugiol 2 from (ꢀ)-sclareol
with 37% and 27% overall yields, respectively.
4. Experimental
4.1. General
Oxidation of 13 with TPAP/NMO in DCM afforded ketone 16,
Scheme 4. BaeyereVilliger oxidation of 16, gave 17 that treated with
K2CO3/MeOH led to the hydroxyderivative 18. This compound can
be used for the synthesis of abietanes differently substituted at C-
15, of type D and E, Figure 1.
Unless otherwise stated, all chemicals were purchased as the
highest purity commercially available and were used without fur-
ther purification. IR spectra were recorded on a BOMEM 100 FT-IR
or an AVATAR 370 FT-IR Thermo Nicolet spectrophotometers. 1H
and 13C NMR spectra were performed in CDCl3 and referenced to
2.1. Synthesis of (D)-ferruginol 1 and (D)-sugiol 2
To put in value the lateral lithiation, we decided to synthesis two
abietanes, such as (þ)-ferruginol 1 and (þ)-sugiol 2 from 12,
Scheme 4. Reaction of 12 with an excess of sec-BuLi followed by the
the residual peak of CHCl3 at
13C, respectively, using Varian 200 VX and Bruker DRX 400 in-
struments. Chemical shifts are reported in parts per million and
d 7.26 ppm and d
77.0 ppm, for 1H and
d
addition of MeI, abietane 19 was obtained in good yield, Scheme 4.
coupling constants (J) are given in hertz. MS were performed at
a VG-TS 250 spectrometer at 70 eV ionising voltage. Mass spectra
are presented as m/z (% rel int.). HRMS were recorded on a VG
Platform (Fisons) spectrometer using chemical ionisation (ammo-
nia as gas) or Fast Atom Bombardment (FAB) technique. For some of
the samples, QSTAR XL spectrometer was employed for electro-
spray ionisation (ESI). Optical rotations were determined on a Per-
kineElmer 241 polarimeter in 1 dm cells. Diethyl ether and THF
20
Reduction of 19 with LAH in refluxing ether for 16 h, gave 1, [a]
D
þ42.9 (c 0.2, CHCl3), which physical properties were coincident
with the ones of natural (þ)-ferruginol, [
a
]
25 þ55.7 (c 0.5, CHCl3).23
D
Acetylation of 1 with Ac2O in the usual conditions gave the
acetyl derivative 20, which by oxidation with Na2CrO4 led to ketone
21 (Scheme 4). Hydrolysis of 21 with K2CO3/MeOH gave 2 whose
20
spectroscopical properties, [
a]
þ15.3 (c 0.3, CHCl3) and mp
D

7776
I.S. Marcos et al. / Tetrahedron 66 (2010) 7773e7780
were distilled from sodium, and dichloromethane was distilled
from calcium hydride under argon atmosphere.
atmosphere. The reaction mixture was heated at 70 ꢁC for 1 h. Then,
the reactionwas cooled to room temperature and ice was added. The
reaction mixture was extracted with ether. The organic phase was
washed with aqueous 6% NaHCO3 and H2O, dried over Na2SO4, fil-
tered and the solvent evaporated to afford 8 (48 mg, 90%).
4.2. Reaction of 5 with NBS/AIBN to yield 6
To a solution of 5 (50 mg, 0.20 mmol) in CCl4 (0.8 mL), NBS
(35 mg, 0.20 mmol) and AIBN (2 mg) were added. The mixture was
heated at 70 ꢁC for 2 h and after that, diluted with Et2O, washed
with H2O and brine, the organic phase was dried over Na2SO4, fil-
tered and the solvent was evaporated under reduced pressure.
After column chromatography on silica gel compounds 5 (15 mg,
30%) and 6 (39 mg, 62%) were obtained.
20
4.5.1. 12-Acetyl-15,16-dinor-pymara-8,11,13-triene (8). Rf 0.65; [a]
D
þ13.3 (c 2.8, CHCl3); IR nmax (film): 2925, 1707, 1679, 1458, 1375,
1262, 1212, 1162, 1039, 893 cmꢀ1; 1H NMR (200 MHz, CDCl3)
d
: 7.63
(1H, s, H-11), 6.91 (1H, s, H-14), 2.86e2.81 (2H, m, H-7), 2.56 (3H, s,
MeCOe), 2.46 (3H, s, Me-17), 2.34e1.12 (9H, m), 1.19 (3H, s, Me-20),
0.96 (3H, s, Me-18), 0.94 (3H, s, Me-19); 13C NMR (50 MHz, CDCl3)
d:
201.7 (MeCOe), 147.9 (C-9), 140.1 (C-8), 135.5 (C-12), 135.2 (C-13),
132.8 (C-14), 126.4 (C-11), 50.6 (C-5), 41.8 (C-3), 39.0 (C-1), 37.7 (C-
10), 33.7 (C-4), 33.5 (C-18), 30.5 (C-7), 29.6 (MeCOe), 25.2 (C-20),
21.8 (C-19), 21.5 (C-17), 19.4 (C-2), 19.0 (C-6); EIHRMS: calcd for
C20H28ONa (MþNaþ): 307.2038, found: 307.2035.
4.2.1. 7-Bromo-16,17-dinor-pymara-8,11,13-triene (6). Rf 0.12 (n-
Hex/EtOAc 9/1); [
a
]
20 þ7.6 (c 0.6, CHCl3); IR nmax (film): 2928, 1402,
D
1378, 1203, 997, 818, 767 cmꢀ1
;
1H NMR (200 MHz, CDCl3)
d: 7.22
(2H, d, J¼2.2 Hz, H-11), 7.17 (2H, d, J¼2.2 Hz, H-12), 7.13 (2H, s, H-14),
4.95e4.90 (1H, m, H-7), 4.75 (1H, t, J¼1.8 Hz, H-7), 2.33 (6H, s, Me-
15), 2.31e1.05 (18H, m,), 1.63 (6H, s, Me-20), 1.26 (6H, s, Me-18), 1.08
4.6. BaeyereVilliger oxidation of 8 to yield 9
(6H, s, Me-19); 13C NMR (50 MHz, CDCl3)
d: 145.8 (C-9), 136.1 (C-13),
132.2 (C-8), 131.3 (C-14), 130.3 (C-12), 126.3 (C-11), 75.8 (C-7), 50.7
(C-5), 47.7 (C-6), 43.8 (C-1), 43.5 (C-3), 39.1 (C-10), 34.7 (C-4), 33.5 (C-
18), 25.7 (C-20), 22.8 (C-19), 21.0 (C-15),19.7 (C-2); EIHRMS: calcd for
C18H25BrNa (MþNaþ): 343.1036, found: 343.1040.
To a solution of 8 (105 mg, 0.37 mmol) in dichloromethane
(4.0 mL), UHP (122 mg, 1.3 mmol) was added at 0 ꢁC, then TFAA
(0.21 mL, 1.48 mmol) was added under argon atmosphere. The re-
action was allowed at room temperature for 1 h 30 min. After the
work-up with Na2SO3 the reaction was left at room temperature for
20 min. The organic phase was washed with aqueous 6% NaHCO3, 6%
K2CO3, 10% Na2SO3, H2O and brine, dried over anhydrous Na2SO4,
filtered and evaporated the solvent, 9 (100 mg, 91%) was obtained.
4.3. Reaction of 5 with NBS/hn to yield 7
To a solution of 5 (20 mg, 0.08 mmol) in H2O (0.5 mL) and THF
(0.1 mL), NBS (34 mg, 0.2 mmol) and AIBN (1 mg) were added at
room temperature. The reaction was allowed to stir for 10 min
under 200 W lamp. After this time, the mixture was diluted with
Et2O and the organic phase washed with H2O and brine, dried over
Na2SO4, filtered and the solvent was evaporated. By column chro-
matography over silica gel in n-Hex/EtOAc (9/1), compounds 5
(9 mg, 45%) and 7 (12 mg, 46%) were separated.
4.6.1. 12-Acetoxy-15,16-dinor-pymara-8,11,13-triene (9). Rf 0.56;
20
[a
]
þ44.2 (c 0.74, CHCl3); IR nmax (film): 2926, 1761, 1700, 1498,
D
1458, 1367, 1206, 1171, 1024, 915, 665 cmꢀ1
;
1H NMR (200 MHz,
CDCl3) : 6.89 (1H, s, H-14), 6.85 (1H, s, H-11), 2.86e2.80 (2H, m, H-
d
7), 2.30 (3H, s, MeCOOe), 2.09 (3H, s, Me-17), 2.34e1.22 (9H, m),
1.17 (3H, s, Me-20), 0.94 (3H, s, Me-18), 0.91 (3H, s, Me-19); 13C NMR
(50 MHz, CDCl3) d: 169.9 (MeCOOe), 149.4 (C-9), 147.5 (C-12), 133.3
4.3.1. 12-Bromo-16,17-dinor-pymara-8,11,13-triene (7). Rf 0.59 (n-
(C-13), 131.6 (C-14), 126.8 (C-8), 117.7 (C-11), 50.3 (C-5), 41.8 (C-3),
39.0 (C-1), 37.8 (C-10), 33.6 (C-4), 33.5 (C-18), 29.9 (C-7), 25.1 (C-
20), 21.8 (C-19), 21.1 (MeCOOe), 19.4 (C-2), 19.2 (C-6), 15.9 (C-17);
EIHRMS: calcd for C20H28O2 (MþNaþ): 323.1987, found: 323.1986.
Hex); [
a
]
20 þ51.4 (c 0.8, CHCl3); IR nmax (film): 2925, 2865,1472,1388,
D
1314, 1211, 1145, 1083, 974, 874 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d:
7.38 (1H, s, H-11), 6.90 (1H, s, H-14), 2.85 (1H, dd, J¼10.7 and 4.0 Hz,
HA-7), 2.76 (1H, dd, J¼10.7 and 4.0 Hz, HB-7), 2.30 (3H, s, Me-15),
2.20e2.19 (1H, m, H-1), 1.80e1.74 (4H, m, H-2 and H-6), 1.50e1.49
(m, 1H, H-3), 1.29e1.27 (1H, m, H-1), 1.28e1.26 (1H, m, H-5),
1.21e1.19 (1H, m, H-3), 1.16 (3H, s, Me-20), 0.94 (3H, s, Me-18), 0.92
4.7. Reaction of 9 with K2CO3 to yield 10
To a solution of 9 (21 mg, 0.07 mmol) in MeOH (1 mL), K2CO3
(50 mg, 0.36 mmol) was added and stirred at room temperature for
30 min. Then, water was added and extracted with ether. The organic
phase was washed with H2O and brine. After dried over Na2SO4, fil-
tered and evaporated the solvent 10 (18 mg, 98%) was obtained.
(3H, s, Me-19); 13C NMR (100 MHz, CDCl3)
d: 149.8 (C-9), 134.4 (C-8),
131.2 (C-14), 128.2 (C-11), 123.1 (C-12), 121.9 (C-13), 50.1 (C-5), 41.5
(C-3), 38.8 (C-1), 37.6 (C-10), 33.4 (C-4), 33.2 (C-18), 29.7 (C-7), 24.8
(C-20), 22.2 (C-19), 21.5 (C-15), 19.1 (C-2), 18.8 (C-6); EIHRMS: calcd
for C18H25BrNa (MþNaþ): 343.1042, found: 343.1045.
4.7.1. 15,16-Dinor-pymara-8,11,13-trien-12-ol (10). Rf 0.58; mp
20
4.4. Reaction of 5 with NBS/[bmim]PF6 to yield 7
241 ꢁC; [
a]
þ39.3 (c 1.4, CHCl3); IR nmax (film): 3397, 2925, 2865,
D
1717, 1684, 1507, 1458, 1375, 1265, 1193, 1135, 1013, 889, 665 cmꢀ1
;
In a 5 mL round-bottom flask containing compound 5 (20 mg,
0.08 mmol), [bmim]PF6 (0.01 mL), NBS (16 mg, 0.09 mmol) and
AIBN (1 mg) were added at room temperature. The reaction mix-
ture was heated at 80 ꢁC for 2 h 30 min, after that, the mixture was
diluted with Et2O and the organic phase washed with H2O and
brine, dried over Na2SO4, filtered and the solvent evaporated. By
column chromatography on silica gel compound 7 (11 mg, 45%) was
separated.
1H NMR (200 MHz, CDCl3)
d
: 6.80 (1H, s, H-14), 6.68 (1H, s, H-11),
4.62 (1H, br s, eOH), 2.82e2.77 (2H, m, H-7),1.84e1.22 (9H, m), 2.18
(3H, s, Me-17), 1.17 (3H, s, Me-20), 0.94 (3H, s, Me-18), 0.92 (3H, s,
Me-19); 13C NMR (50 MHz, CDCl3)
d: 152.0 (C-9), 149.5 (C-12), 131.5
(C-14), 127.5 (C-13), 121.1 (C-8), 110.9 (C-11), 50.7 (C-5), 41.9 (C-3),
39.1 (C-1), 37.8 (C-10), 33.7 (C-4), 33.6 (C-18), 29.8 (C-7), 25.0 (C-
20), 21.9 (C-19), 19.6 (C-2), 19.4 (C-6), 15.5 (C-17); EIHRMS: calcd for
C18H26O (MþNaþ): 281.1882, found: 281.1880.
4.5. Reaction of 5 with AcCl/SnCl4 to yield 8
4.8. Reaction of 8 with N,N-diisopropyl carbamoyl chloride to
yield 11
To a stirred solution of 5 (47 mg, 0.19 mmol) and acetyl chloride
(0.05 mL, 0.76 mmol) in dichloromethane (2.0 mL) at 0 ꢁC, a solution
1 M of SnCl4 in heptane (0.3 mL, 0.3 mmol) was added under argon
In a 25 mL round-bottom flask equipped with magnetic stirring,
NaH 60% in mineral oil (48 mg, 2.0 mmol) was washed with THF

I.S. Marcos et al. / Tetrahedron 66 (2010) 7773e7780
7777
(3ꢂ2 mL), then, a solution of compound 8 (50 mg, 0.19 mmol) in
THF (0.7 mL) was added at 0 ꢁC under argon atmosphere via can-
nula. The reaction was stirred for 15 min at 0 ꢁC. Then, a solution of
N,N-diispropil carbamoyl chloride (33 mg, 0.20 mmol) in THF
(0.8 mL) was added and the mixture was left to stir for 2 h. After
this time, the reaction was quenched with EtOAc saturated in water.
The crude was extract with EtOAc, and washed with HCl 2 M, H2O
and brine. After that, the crude mixture was dried over Na2SO4,
filtered and the solvent evaporated. After column chromatography
on silica gel compound 9 (67 mg, 92%) was separated.
the organic layer was washed with H2O and brine. The crude
was dried over Na2SO4, filtered and solvent evaporated to give
a crude oil, which was chromatographed on silica to afford
compound 13 (22 mg, 87%).
4.10.1. 12-N,N-diisopropylcarbamoyloxy-17(15/16)-abeo-abieta-
20
8,11,13-trien-16-ol (13). Rf 0.15 (n-Hex/EtOAc 8/2); [
a
]
þ35.8 (c
D
0.9, CHCl3); IR nmax (film): 3420 (broad), 2928, 1696, 1436, 1375,
1318, 1257, 1135, 1049, 902, 740 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
:
6.92 (2H, s, H-14), 6.86 (2H, s, H-11), 4.05e3.98 (6H, m, H-16 and
-OCON(CHMe2)2), 2.87 (2H, dd, J¼18.0 and 7.2 Hz, HA-7), 2.83 (2H,
ddd, J¼18.0, 10.8 and 7.2 Hz, HB-7), 2.68 and 2.65 (1H, dd each,
J¼14.0 and 3.2 Hz, HA-15), 2.52 and 2.49 (1H, dd each, J¼14.0 and
7.2 Hz, HB-15), 2.21e2.18 (6H, m, H-1 and H-5),1.48e1.46 (2H, m, H-
3), 1.39e1.33 (24H, m, eOCON(CHMe2)2), 1.27e1.24 (4H, m, H-2),
1.26e1.23 (4H, m, H-6), 1.24 (3H, d each, J¼6.8 Hz, Me-17), 1.18 (6H,
s, Me-20), 1.14e1.12 (2H, m, H-3), 0.94 (6H, s, Me-18), 0.92 (6H, s,
4.8.1. 16,17-Dinor-pymara-8,11,13-trien-12-ol N,N-diisopropilcarba-
mate (11). Rf 0.51 (n-Hex/EtOAc 9/1); [
a
]
20 þ38.0 (c 0.8, CHCl3); IR
D
nmax (film): 2929, 1713, 1460, 1433, 1314, 1271, 1202, 1136, 1028,
796 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d: 6.87 (1H, s, H-14), 6.86 (1H,
s, H-11), 4.16e3.96 (2H, m, eOCON(CHMe2)2), 2.85 (1H, dd, J¼12.5
and 4.9 Hz, HA-7), 2.78 (1H, dd, J¼8.7 and 4.9 Hz, HB-7), 2.21e2.09
(2H, m, H-6), 2.11 (3H, s, Me-15), 1.88e1.22 (7H, m), 1.32e1.29 (12H,
m, eOCON(CHMe2)2), 1.18 (3H, s, Me-20), 0.94 (3H, s, Me-18), 0.92
Me-19); 13C NMR (100 MHz, CDCl3)
d: 154.5 (eOCON(CHMe2)2),
149.9 (C-9), 147.8 (C-12), 132.5 (C-8), 131.3 (C-14), 127.9 (C-13), 118.5
(C-11), 67.9 (C-16), 50.1 (C-5), 46.7/46.2 (eOCON(CHMe2)2), 41.6 (C-
3), 39.8 (C-15), 38.7 (C-1), 37.6 (C-10), 33.4 (C-4), 33.2 (C-18), 29.6
(C-7), 24.7 (C-20), 23.4 (C-17), 21.6 (eOCON(CHMe2)2), 20.5 (C-19),
19.1 (C-2), 18.9 (C-6); EIHRMS: calcd for C27H43NO3Na (MþNaþ):
452.3131, found: 452.3129.
(3H, s, Me-19); 13C NMR (100 MHz, CDCl3)
d: 158.4 (eOCON(CH
(Me)2)2), 148.9 (C-9), 147.9 (C-12), 132.0 (C-8), 131.1 (C-14), 127.2 (C-
13), 117.8 (C-11), 50.2 (C-5), 46.6 (eOCON(CH(Me)2)2), 41.7 (C-3),
38.8 (C-1), 37.5 (C-10), 33.4 (C-4), 33.2 (C-18), 29.7 (C-7), 24.7 (C-
20), 21.2 (C-19), 21.5 (eOCON(CH(Me)2)2), 19.2 (C-2), 19.0 (C-6), 16.0
(C-15); EIHRMS: calcd for C25H40NO2 (MþHþ): 386.3070, found:
386.3069.
4.11. Reaction of 11 with sec-BuLi/CH2O to yield 14
4.9. Reaction of 11 with sec-BuLi/MeI to yield 12
To asolution ofcompound 9 (20 mg, 0.05 mmol) inTHF (0.2 mL)at
ꢀ78 ꢁC under argon atmosphere, a solution of sec-BuLi 1.4 M in THF
(0.62 mL) was added and the reaction stirred for 10 min. Then, CH2O
To a solution of compound 11 (10 mg, 0.03 mmol) in THF
(0.3 mL) at ꢀ78 ꢁC under argon atmosphere, a solution of sec-BuLi
1.4 M in THF (0.34 mL) was added dropwise and the reaction
mixture was stirred for 10 min. Then, MeI (0.02 mL, 0.3 mmol) was
added slowly and the mixture was left to stir for another 30 min.
After this time, the reaction was allowed to reach room tempera-
ture and then, NH4Cl was added dropwise carefully. The mixture
was extracted with Et2O and the combined extracts were washed
with H2O and brine, dried over Na2SO4 and the solvent evaporated.
After column chromatography over silica gel compound 12 (10 mg,
94%) was separated.
(10 mL, 37 wt % aqueous solution) was added and the reaction was left
with stirring for another 30 min. After this time, the reaction was
allowed to warm to room temperature and then NH4Cl was added.
ThemixturewasextractedwithEt2O and washedwith H2O and brine,
dried over Na2SO4 and the solvent evaporated. By column chroma-
tography on silica gel compound 14 (15 mg, 68%) was separated.
4.11.1. 12-N,N-Diisopropylcarbamoyloxy-17-nor-pymara-8,11,13-
20
trien-16-ol (14). Rf 0.35 (n-Hex/EtOAc 7/3); [
a]
þ28.7 (c 0.5,
D
CHCl3); IR nmax (film): 3411 (broad), 2927, 1712, 1438, 1375, 1316,
1253, 1134, 1044, 900 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d: 6.93 (1H,
4.9.1. 17-Nor-pymara-8,11,13-trien-12-ol N,N-diisopropylcarbamate
s, H-14), 6.86 (1H, s, H-11), 4.07e4.01 (2H, m, eOCON(CHMe2)2),
3.82 (2H, t, J¼6.0 Hz, H-16), 2.88 (1H, dd, J¼7.8 and 4.6 Hz, HA-7),
2.81 (1H, dd, J¼7.8 and 4.6 Hz, HB-7), 2.73 (2H, t, J¼6.0 Hz, H-15),
2.22e2.20 (2H, m, H-1 and H-5), 1.49e1.48 (1H, m, H-1), 1.48e1.46
(1H, m, H-3), 1.42e1.38 (12H, m, eOCON(CHMe2)2), 1.33e1.30 (4H,
m, H-2 and H-6), 1.23e1.22 (1H, m, H-3), 1.18 (3H, s, Me-20), 0.94
20
(12). Rf 0.48 (n-Hex/EtOAc 9/1); [
a]
þ41.1 (c 0.5, CHCl3); IR nmax
D
(film): 2964, 2928, 2870, 1716, 1460, 1432, 1375, 1313, 1258, 1214,
1135, 1044, 804 cmꢀ1; 1H NMR (200 MHz, CDCl3)
d
: 6.88 (1H, s, H-
14), 6.87 (1H, s, H-11), 4.11e3.99 (2H, m, eOCON(CHMe2)2),
2.89e2.82 (2H, m, H-7), 2.49 (2H, c, J¼7.5 Hz, H-15), 2.21e1.22 (9H,
m), 1.31e1.26 (12H, m, eOCON(CHMe2)2), 1.19 (3H, s, Me-20), 1.17
(3H, t, J¼7.5 Hz, Me-16), 0.93 (3H, s, Me-18), 0.91 (3H, s, Me-19); 13C
(3H, s, Me-19), 0.92 (3H, s, Me-18); 13C NMR (100 MHz, CDCl3)
d:
154.7 (eOCON(CHMe2)2), 149.9 (C-9), 147.9 (C-12), 132.6 (C-8),
130.9 (C-14), 128.0 (C-13), 118.4 (C-11), 62.7 (C-16), 50.0 (C-5), 46.8/
46.1 (eOCON(CHMe2)2), 41.6 (C-3), 38.9 (C-1), 37.6 (C-10), 33.7 (C-
4), 33.4 (C-18), 33.2 (C-15), 29.6 (C-7), 24.7 (C-20), 21.8 (eOCON
(CHMe2)2), 20.5 (C-19), 19.1 (C-2), 18.9 (C-6); EIHRMS: calcd for
C26H41NO3Na (MþNaþ): 438.2964, found: 438.2958.
NMR (50 MHz, CDCl3) d: 154.2 (eOCON(CHMe2)2), 149.0 (C-9), 147.6
(C-12), 133.1 (C-13), 132.4 (C-8), 129.6 (C-14), 118.4 (C-11), 50.4 (C-
5), 46.6/46.0 (eOCON(CHMe2)2), 41.9 (C-3), 39.0 (C-1), 37.8 (C-10),
33.7 (C-18), 33.5 (C-4), 30.0 (C-7), 25.0 (C-20), 23.1 (C-15), 21.8
(eOCON(CHMe2)2), 20.8 (C-19), 19.4 (C-6), 19.3 (C-2), 14.5 (C-16);
EIHRMS: calcd for C26H41NO2Na (MþNaþ): 422.3028, found:
422.3026.
4.12. Reaction of 12 with EtCO2Cl /sec-BuLi to yield 15
4.10. Reaction of 11 with sec-BuLi/CH3CHO to yield 13
To a solution of 12 (38 mg, 0.1 mmol) in THF (0.6 mL) at ꢀ78 ꢁC
under argon atmosphere, a solution of sec-BuLi 1.4 M in THF
(0.6 mL) was added dropwise. The mixture was stirred for 10 min.
To a solution of compound 9 (20 mg, 0.06 mmol) in THF
(0.2 mL) at ꢀ78 ꢁC under argon atmosphere, a solution of sec-
BuLi 1.4 M in THF (0.42 mL) was added dropwise carefully. Then,
CH3CHO (0.03 mL, 0.6 mmol) was added and the reaction was
stirred for 30 min. After this time, the mixture was allowed to
reach room temperature and NH4Cl was added slowly to quench
the reaction. The reaction mixture was extracted with Et2O and
After this time, ethyl chloroformate (57 mL, 0.6 mmol) was added,
and the mixture was left to stir for 30 min. Then, EtOAc saturated in
water was added slowly to quench the reaction. The mixture was
extracted with EtOAc and washed with H2O and brine. After dried
over Na2SO4 and filtered, the solvent was evaporated, to give

7778
I.S. Marcos et al. / Tetrahedron 66 (2010) 7773e7780
a crude oil, which was chromatographed on silica gel to afford
compound 15 (35 mg, 74%).
148.0 (C-9), 132.8 (C-13), 131.1 (C-14), 125.2 (C-8), 119.0 (C-11), 62.3
(C-15), 50.2 (C-5), 47.3/46.5 (eOCON(CHMe2)2), 41.8 (C-3), 38.9 (C-
1), 38.1 (C-10), 33.7 (C-18), 33.5 (C-4), 29.9 (C-7), 24.9 (C-20), 21.8
(eOCOMe), 21.3 (eOCON(CHMe2)2), 20.7 (C-19), 19.4 (C-6), 19.1 (C-
2); EIHRMS: calcd for C27H41NO4Na (MþNaþ): 466.2904, found:
466.2905.
4.12.1. Ethyl 12-N,N-diisopropylcarbamoyloxy-abieta-8,11,13-trien-
16-oate (15). Rf 0.74 (n-Hex/EtOAc 8/2); [
a
]
20 þ5.9 (c 1.0, CHCl3); IR
D
nmax (film): 2964, 2874, 1744, 1712, 1462, 1370, 1257, 1155 cmꢀ1; 1H
NMR (200 MHz, CDCl3) d: 6.87 (2H, s, H-14), 6.77 (2H, s, H-11),
4.35e4.08 (4H, m, eOCON(CHMe2)2), 4.18 (4H, c, J¼7.3 Hz,
eCO2CH2CH3), 2.88e2.78 (4H, m, H-7), 2.68 and 2.49 (1H, c each,
J¼7.2 Hz, H-15), 2.21e1.24 (18H, m), 1.33e1.29 (24H, m, eOCON
(CHMe2)2), 1.28 (6H d, J¼7.2 Hz, Me-17), 1.05 and 1.02 (3H, s each,
Me-20), 0.93 (6H, s, Me-18), 0.91 (6H, s, Me-19), 0.86 and 0.85 (3H, t
4.15. Hydrolysis of 17 with K2CO3/MeOH to yield 18
To a solution of 17 (70 mg, 0.12 mmol) in MeOH (0.8 mL), K2CO3
(88 mg, 0.64 mmol) was added at room temperature and the re-
action was left to stir for 45 min. After this time, the mixture was
diluted in Et2O and washed with H2O and brine. The organic phase
was dried over Na2SO4, filtered and the solvent evaporated to afford
18 (48 mg, 97%).
each, J¼7.3 Hz, eCO2CH2CH3); 13C NMR (50 MHz, CDCl3)
d: 175.3 (C-
16), 153.7 (eOCON(CHMe2)2), 147.1 (C-12), 140.0 (C-9), 132.6 (C-13),
132.5 (C-8), 129.9 (C-14), 118.6 (C-11), 61.3 (eCO2CH2CH3), 43.9 (C-
5), 41.9 (C-3), 41.4/41.0 (eOCON(CHMe2)2), 40.5 (C-15), 39.0 (C-10),
38.9 (C-1), 33.6 (C-4), 33.5 (C-18), 27.7 (C-7), 21.8 (C-20), 19.4 (C-6),
18.3 (C-2), 17.7 (C-19), 14.6/14.5 (eOCON(CHMe2)2), 14.3
(eCO2CH2CH3), 11.9 (C-17); EIHRMS: calcd for C29H45NO4Na
(MþNaþ): 494.3245, found: 494.3247.
4.15.1. 12-N,N-Diisopropylcarbamoyloxy-16,17-dinor-pymara-
20
8,11,13-trien-15-ol (18). Rf 0.31 (n-Hex/EtOAc 8/2); [
a]
þ35.9 (c
D
1.9, CHCl3); IR nmax (film): 3447 (broad), 2929, 1695, 1435, 1370,
1314, 1150, 1136, 1044, 903, 733 cmꢀ1; 1H NMR (200 MHz, CDCl3)
d
:
7.13 (1H, s, H-14), 6.89 (1H, s, H-11), 4.42 (2H, s, H-15), 4.18e3.98
(2H, m, eOCON(CHMe2)2), 3.15 (1H, s, eOH), 2.96e2.86 (2H, m, H-
7), 2.22e1.18 (9H, m), 1.36 (6H, d, J¼3.8 Hz, eOCON(CHMe2)2), 1.27
(6H, d, J¼3.8 Hz, eOCON(CHMe2)2), 1.18 (3H, s, Me-20), 0.94 (3H, s,
4.13. Oxidation of 13 with TPAP/NMO to yield 16
To a solution of compound 13 (10 mg, 0.02 mmol) in DCM
(0.4 mL), NMO (8.0 mg, 0.06 mmol) and TPAP (1 mg) were added at
room temperature, and the mixture was stirred for 10 min. After
this time, the crude was filtered through a column packed with
CeliteÒ and washed with EtOAc and Et2O. Then, the solvent was
evaporated to afford compound 16 (9 mg, 99%).
Me-18), 0.92 (3H, s, Me-19); 13C NMR (50 MHz, CDCl3)
d: 155.5
(eOCON(CHMe2)2), 151.8 (C-12), 147.4 (C-9), 133.5 (C-13), 131.5 (C-
14), 130.4 (C-8), 118.0 (C-11), 60.7 (C-15), 50.2 (C-5), 47.3/46.5
(eOCON(CHMe2)2), 41.8 (C-3), 39.0 (C-1), 38.0 (C-10), 33.7 (C-18),
33.5 (C-4), 29.9 (C-7), 25.0 (C-20), 21.7 (eOCON(CHMe2)2), 20.7 (C-
19), 19.4 (C-6), 19.1 (C-2); EIHRMS: calcd for C25H39NO3Na
(MþNaþ): 424.2828, found: 424.2826.
4.13.1. 12-N,N-Diisopropylcarbamoyloxy-17(15/16)-abeo-abieta-
20
8,11,13-trien-16-one (16). Rf 0.42 (n-Hex/EtOAc 8/2); [
a
]
þ38.0 (c
D
0.7, CHCl3); IR nmax (film): 2927, 1716, 1432, 1315, 1253, 1135, 1043,
4.16. Reaction of 12 with sec-BuLi/MeI to yield 19
900, 757 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
: 6.91 (1H, s, H-14), 6.87
(1H, s, H-11), 4.02e3.98 (2H, m, eOCON(CHMe2)2), 3.52 (2H, s, H-
15), 2.88e2.81 (2H, m, H-7), 2.24e1.21 (9H, m), 2.10 (3H, s, Me-17),
1.30 (6H, d, J¼2.4 Hz, eOCON(CHMe2)2), 1.26 (6H, d, J¼2.4 Hz,
eOCON(CHMe2)2), 1.23 (3H, s, Me-20), 0.94 (3H, s, Me-18), 0.92 (3H,
To a solution of compound 12 (24 mg, 0.06 mmol) in THF
(0.2 mL), a solution of sec-BuLi 1.4 M in THF (0.43 mL) was added
dropwise at ꢀ78 ꢁC, and after that, the mixture was left to stir for
10 min. Subsequent, MeI (0.04 mL, 0.60 mmol) was added and left
stirring for 30 additional minutes. After this time, the reaction was
allowed to reach room temperature and NH4Cl was added slowly.
The mixture was then extracted with Et2O and washed with H2O
and brine. The crude mixture was dried over Na2SO4, filtered and
the solvent was evaporated. By column chromatography on silica
gel compound 19 (20 mg, 82%) was separated.
s, Me-19); 13C NMR (100 MHz, CDCl3)
d: 206.4 (C-16),153.3 (eOCON
(CHMe2)2), 150.5 (C-9), 147.7 (C-12), 132.6 (C-13), 131.3 (C-14), 124.2
(C-8), 118.5 (C-11), 50.0 (C-5), 46.6/46.3 (eOCON(CHMe2)2), 45.6 (C-
15), 41.6 (C-3), 38.6 (C-1), 37.7 (C-10), 33.4 (C-4), 33.0 (C-18), 30.0
(C-17), 29.6 (C-7), 24.7 (C-20), 21.6 (eOCON(CHMe2)2), 20.4 (C-19),
19.1 (C-2), 18.9 (C-6); EIHRMS: calcd for C27H41NO3Na (MþNaþ):
450.2984, found: 450.2986.
4.16.1. Abieta-8,11,13-trien-12-ol N,N-diisopropylcarbamate (19). Rf
4.14. BaeyereVilliger’s reaction of 16 with m-CPBA to yield 17
0.40 (n-Hex); [
a
]
D
20 þ33.8 (c 2.23, CHCl3); IR nmax (film): 2964, 2870,
1716, 1460, 1431, 1375, 1312, 1248, 1153, 1044, 899, 758 cmꢀ1
;
1H
To a solution of compound 16 (20 mg, 0.05 mmol) in DCM
(1 mL), m-CPBA (26 mg, 0.15 mmol) was added at 0 ꢁC. The reaction
was stirred at room temperature for 16 h. After this time, Na2SO3
was added carefully at 0 ꢁC and the mixture was left with stirring
for another 20 min. Then the reaction mixture was extracted with
Et2O and washed successively with aqueous 10% Na2SO3, 6%
NaHCO3, H2O and brine, dried (Na2SO4), filtered and the solvent
evaporated to yield compound 17 (15 mg, 74%).
NMR (200 MHz, CDCl3) d: 6.92 (1H, s, H-14), 6.84 (1H, s, H-11),
4.18e4.01 (2H, m, eOCON(CHMe2)2), 2.99 (1H, sep, J¼6.5 Hz, H-15),
2.98e2.81 (2H, m, H-7), 2.24e1.22 (9H, m), 1.35e1.26 (12H, m,
eOCON(CHMe2)2), 1.21 (3H, d, J¼6.5 Hz, Me-16), 1.17 (3H, d,
J¼6.5 Hz, Me-17), 1.19 (3H, s, Me-20), 0.94 (3H, s, Me-19), 0.92 (3H,
s, Me-18); 13C NMR (50 MHz, CDCl3)
d: 154.2 (eOCON(CHMe2)2),
148.7 (C-9), 146.9 (C-12), 137.4 (C-13), 132.3 (C-8), 126.7 (C-14),
118.5 (C-11), 50.3 (C-5), 46.6/46.4 (eOCON(CHMe2))2, 41.9 (C-3),
39.0 (C-1), 37.8 (C-10), 33.7 (C-4), 33.5 (C-18), 30.2 (C-7), 27.2 (C-
15), 23.4 (C-20), 23.1 (C-19), 21.8 (eOCON(CHMe2)2), 20.8 (C-16),
20.1 (C-17), 19.4 (C-2), 19.3 (C-6); EIHRMS: calcd for C27H43NO2Na
(MþNaþ): 436.3178, found: 436.3174.
4.14.1. 15-Acetoxy-16,17-dinor-pymara-8,11,13-trien-12-ol N,N-diiso-
propylcarbamate (17). Rf 0.43 (n-Hex/EtOAc 8/2); [
a
]
20 þ35.0 (c 2.1,
D
CHCl3); IR nmax (film): 2965, 1742, 1716, 1432, 1376, 1314, 1226, 1043,
900, 732 cmꢀ1; 1H NMR (200 MHz, CDCl3)
d: 7.05 (1H, s, H-14), 6.96
(1H, s, H-11), 4.98 (2H, s, H-15), 4.14e3.88 (2H, m, eOCON
(CHMe2)2), 2.91e2.82 (2H, m, H-7), 2.21e1.18 (9H, m), 2.05 (3H, s,
eOCOMe), 1.34e1.26 (12H, m, eOCON(CHMe2)2), 1.18 (3H, s, Me-
20), 0.94 (3H, s, Me-18), 0.92 (3H, s, Me-19); 13C NMR (50 MHz,
4.17. Reduction of 19 with LiAlH4 to yield 1
To a solution of compound 19 (22 mg, 0.05 mmol) in Et2O
(0.4 mL), LAH (19 mg, 0.5 mmol) was added at 0 ꢁC. Subsequent, the
mixture was heated to boil during 16 h. After this time, the reaction
CDCl3) d: 171.1 (eOCOMe), 153.9 (eOCON(CHMe2)2), 152.1 (C-12),

I.S. Marcos et al. / Tetrahedron 66 (2010) 7773e7780
7779
was allowed to reach room temperature and then, EtOAc saturated
in water was added dropwise carefully. The mixture was extracted
with EtOAc, washed with H2O and brine, dried over Na2SO4, filtered
and the solvent was evaporated to afford compound 1 (14 mg, 93%).
(C-10), 36.4 (C-6), 33.5 (C-4), 32.7 (C-18), 27.5 (C-15), 23.1 (C-20),
23.0 (C-19), 22.9 (eOCOMe), 21.5 (C-16), 21.2 (C-17), 19.0 (C-2);
EIHRMS: calcd for C22H30O3Na (MþNaþ): 365.2091, found:
365.2088.
4.17.1. Abieta-8,11,13-trien-12-ol (1). Rf 0.34 (n-Hex); [
a
]
20 þ42.9 (c
D
4.20. Hydrolysis of 21 with K2CO3/MeOH to yield 2
0.2, CHCl3); IR nmax (film): 3388 (broad), 2925, 2866, 1508, 1460,
1417, 1375, 1002, 892, 733 cmꢀ1; 1H NMR (200 MHz, CDCl3)
d: 6.83
To a solution of compound 21 (10 mg, 0.03 mmol) in MeOH
(3 mL), K2CO3 (41 mg, 0.3 mmol) was added and the mixture left to
stir at room temperature for 45 min. After this time, the mixture
was diluted in Et2O, washed with H2O and brine, dried over Na2SO4,
filtered and the solvent was evaporated affording compound 2
(9 mg, 96%).
(1H, s, H-14), 6.63 (1H, s, H-11), 4.48 (1H, s, eOH), 3.16 (1H, sep,
J¼6.5 Hz, H-15), 2.84e2.79 (2H, m, H-7), 2.21e1.22 (9H, m), 1.24
(3H, d, J¼6.5 Hz, Me-16), 1.21 (3H, d, J¼6.5 Hz, Me-17), 1.17 (3H, s,
Me-20), 0.93 (3H, s, Me-19), 0.91 (3H, s, Me-18); 13C NMR (50 MHz,
CDCl3) d: 150.4 (C-12),148.4 (C-9),131.1 (C-13),127.0 (C-8),126.3 (C-
14), 110.7 (C-11), 50.1 (C-5), 41.4 (C-3), 38.6 (C-1), 37.2 (C-10), 33.1
(C-4), 33.0 (C-18), 29.5 (C-7), 26.5 (C-15), 24.5 (C-20), 22.5 (C-19),
22.3 (C-16), 21.3 (C-17), 19.0 (C-2), 18.9 (C-6); EIHRMS: calcd for
C20H30ONa (MþNaþ): 309.2195, found: 309.2190.
4.20.1. 12-Hidroxy-abieta-8,11,13-trien-7-one (2). Rf 0.22 (n-Hex/
20
EtOAc 9/1); mp 282e284 ꢁC; [
a
]
þ15.3 (c 0.3, CHCl3); IR nmax
D
(film): 3247 (broad), 2926, 2854, 1725, 1598, 1461, 1265, 1124,
864 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
: 7.91 (1H, s, H-14), 6.69 (1H,
4.18. Reaction of 1 with Ac2O/Py to yield 20
s, H-11), 5.54 (1H, s, eOH), 3.18 (1H, sep, J¼6.2 Hz, H-15), 2.66 (1H,
dd, J¼18.4 and 4.4 Hz, HA-6), 2.60 (1H, dd, J¼18.4 and 14.0 Hz, HB-
6), 1.83 (1H, dd, J¼14.0 and 4.4 Hz, H-5), 1.84e1.22 (6H, m), 1.27 (3H,
d, J¼6.2 Hz, Me-16), 1.24 (3H, d, J¼6.2 Hz, Me-17), 1.22 (3H, s, Me-
20), 0.98 (3H, s, Me-19), 0.92 (3H, s, Me-18); 13C NMR (100 MHz,
To a solution of compound 1 (15 mg, 0.05 mmol) in Ac2O
(0.2 mL), pyridine (0.2 mL) was added at room temperature and the
mixture was left to stir for 6 h. After this time, ice was added and
extracted with EtOAc and washed with NaHCO3 6%, H2O and brine,
dried over Na2SO4, filtered and the solvent was evaporated to afford
compound 20 (17 mg, 98%).
CDCl3) d: 197.6 (C-7), 158.1 (C-12), 156.4 (C-9), 132.5 (C-13), 126.5
(C-14), 124.6 (C-8), 109.9 (C-11), 49.4 (C-5), 41.3 (C-3), 37.8 (C-1),
36.0 (C-10), 35.0 (C-6), 33.6 (C-4), 33.2 (C-18), 26.7 (C-15), 23.2 (C-
20), 22.7 (C-19), 22.4 (C-16), 21.3 (C-17), 18.8 (C-2); EIHRMS: calcd
for C20H28O2Na (MþNaþ): 323.1987, found: 323.1988.
4.18.1. Abieta-8,11,13-trien-12-ol acetate (20). Rf 0.67 (n-Hex/EtOAc
20
9/1); [
a]
þ31.0 (c 1.2, CHCl3); IR nmax (film): 2926, 2868, 1760,
D
1460, 1368, 1206, 1016, 914 cmꢀ1; 1H NMR (200 MHz, CDCl3)
d: 6.94
Acknowledgements
(1H, s, H-14), 6.82 (1H, s, H-11), 2.93e2.82 (3H, m, H-7 and H-15),
2.30 (3H, s, eOCOMe), 2.50e1.24 (9H, m), 1.20 (3H, d, J¼6.2 Hz, Me-
16), 1.16 (3H, d, J¼6.2 Hz, Me-17), 1.17 (3H, s, Me-20), 0.94 (3H, s,
The authors gratefully acknowledge the help of A. Lithgow
(NMR) and C. Raposo (MS) of Universidad de Salamanca and
MICINN CTQ2009-11557BQU, Junta de Castilla and León (GR-178,
SA063A07) for financial support. A.B.M. is grateful to the Uni-
versidad de Salamanca for a fellowship.
Me-19), 0.92 (3H, s, Me-18); 13C NMR (50 MHz, CDCl3)
d: 170.2
(eOCOMe), 149.0 (C-9), 146.3 (C-12), 136.8 (C-13), 133.4 (C-8), 127.1
(C-14), 118.2 (C-11), 50.2 (C-5), 41.9 (C-3), 39.0 (C-1), 37.8 (C-10),
33.6 (C-4), 33.5 (C-18), 30.2 (C-7), 27.4 (C-15), 25.0 (C-20), 23.3 (C-
19), 23.2 (eOCOMe), 21.8 (C-16), 21.2 (C-17), 19.4 (C-2), 19.2 (C-6);
EIHRMS: calcd for C22H32O2Na (MþNaþ): 351.2302, found:
351.2308.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.07.066.
4.19. Oxidation of 20 with Na2CrO4 to yield 21
References and notes
To a solution of compound 20 (12 mg, 0.04 mmol) in benzene
(2 mL), AcOH (0.3 mL), Ac2O (0.3 mL), NaOAc (10 mg, 0.12 mmol)
and Na2CrO4 (19 mg, 0.12 mmol) were added at room temperature.
The mixture was heated to boil during 45 min. After this time, the
reaction was allowed to reach room temperature and then, MeOH
(0.5 mL) was added, and the mixture was stirred for 15 additional
minutes. The reaction was extracted with Et2O and washed with
NaHCO3 6%, K2CO3 6%, H2O and brine. Then, the mixture was dried
over Na2SO4, filtered and the solvent was evaporated. After column
chromatography on silica gel compound 21 (10 mg, 77%) was
separated.
1. Hanson, J. R. Nat. Prod. Rep. 2009, 26e1156 and reviews of the series.
2. Keimatsu, S.; Ishiguro, T.; Fukui, G. J. Pharm. Soc., Jpn. 1937, 57, 92.
3. Bredenberg, J. B.-S.; Gripenberg, J. Acta Chem. Scand. 1954, 1728.
€
4. Ulubelen, A.; Topcu, G.; Erix, C.; Sonmez, U.; Kartal, M.; Kurucu, S.; Bozok-
Johansson, C. Phytochemistry 1994, 36, 971.
5. (a) Espinoza, M.; Santos, S. L.; Theoduloz, C.; Schmeda-Hirschmann, G.;
Rodríguez, J. A. Planta Med. 2008, 74, 802; (b) Areche, C.; Schmeda-Hirschmann,
G.; Theoduloz, C.; Rodriguez, J. A. J. Pharm. Pharmacol. 2009, 61, 1689.
6. Chao, K.-P.; Hua, K.-F.; Hsu, H.-Y.; Su, Y.-C.; Chang, S.-T. Planta Med. 2005, 71,
300.
7. (a) Iwamoto, M.; Minami, T.; Tokuda, H.; Ohtsu, H.; Tanaka, R. Planta Med. 2003,
69, 69; (b) Tu, W.-C.; Wang, S.-Y.; Chien, S.-C.; Lin, F.-M.; Chen, L.-R.; Chiu, C.-Y.;
Hsiao, P.-W. Planta Med. 2007, 73, 1407.
8. (a) Pereda-Miranda, R.; Hernández, L.; López, R. Planta Med. 1992, 58, 223; (b)
Haraguchi, H.; Ishikawa, H.; Kubo, I. Planta Med. 1997, 63, 213; (c) Politi, M.;
Braca, A.; de Tommasi, N.; Morelli, I.; Manunta, A.; Battinelli, L.; Mazzanti, G.
Planta Med. 2003, 69, 468.
4.19.1. 12-Acetoxy-abieta-8,11,13-trien-7-one (21). Rf 0.55 (n-Hex/
20
EtOAc 9/1); [
a]
þ22.4 (c 0.3, CHCl3); IR nmax (film): 2962, 2930,
D
1766, 1683, 1610, 1368, 1199, 1166, 1014, 910 cmꢀ1
;
1H NMR
9. Gao, J.; Han, G. Phytochemistry 1997, 44, 759.
(200 MHz, CDCl3) : 7.99 (1H, s, H-14), 6.98 (1H, s, H-11), 2.98 (1H,
d
10. (a) Tian, X.; Min, Z.; Xie, N.; Lei, Y.; Tian, Z.; Zheng, Q.; Xu, R.; Tanaka, T.; Iinuma,
M.; Mizuno, M. Chem. Pharm. Bull. 1993, 41, 1415; (b) Costa-Lotufo, L. V.; Silveira,
E. R.; Barros, M. C. P.; Lima, M. A. S.; Amaral de Moraes, M. E.; Odorico de
Moraes, M.; Pessoa, C. Planta Med. 2004, 70, 180.
sep, J¼6.5 Hz, H-15), 2.73 (1H, dd, J¼18.4 and 4.4 Hz, HA-6), 2.63
(dd, 1H, J¼18.4 and 12.0 Hz, HB-6), 2.35 (3H, s, eOCOMe), 1.90 (1H,
dd, J¼12.0 and 4.4 Hz, H-5), 1.89e1.4 (6H, m), 1.24 (3H, d, J¼6.5 Hz,
Me-16), 1.21 (3H, d, J¼6.5 Hz, Me-17), 1.18 (3H, s, Me-20), 0.99 (3H,
11. Marcos, I. S.; Beneitez, A.; Castañeda, L.; Moro, R. F.; Basabe, P.; Diez, D.; Urones,
J. Synlett 2007, 1589.
€
s, Me-19), 0.93 (3H, s, Me-18); 13C NMR (50 MHz, CDCl3)
d: 199.0 (C-
12. (a) Offermann, W.; Vogtle, F. Synthesis 1977, 272; (b) Hauser, F. M.; Rhee, R. P.;
Prasanna, S.; Weinreb, S. M.; Dodd, J. H. Synthesis 1980, 72.
7), 170.0 (eOCOMe), 155.4 (C-9),152.9 (C-12), 138.6 (C-13),129.3 (C-
8), 126.7 (C-14), 118.1 (C-11), 49.4 (C-5), 41.5 (C-3), 38.2 (C-1), 38.1
13. (a) Chiappe, C.; Leandri, E.; Pieraccini, D. Chem. Commun. 2004, 2536; (b)
ꢀ
Podgorsek, A.; Stavber, S.; Zupan, M.; Iskra, J. Tetrahedron Lett. 2006, 47, 1097.

7780
I.S. Marcos et al. / Tetrahedron 66 (2010) 7773e7780
14. (a) Clayden, J.; Pink, J. H.; Westlund, N.; Wilson, F. X. Tetrahedron Lett. 1998, 39,
8377; (b) Chauder, B.; Green, L.; Snieckus, V. Pure Appl. Chem. 1999, 71, 1521 and
references cited therein; (c) Clayden, J.; Turner, H.; Pickworth, M.; Adler, T. Org.
Lett. 2005, 7, 3147.
Chem. Res. 1986, 19, 356; (d) Clayden, J.; Pink, J. H. Tetrahedron Lett. 1997, 38,
2561.
19. Clayden, J.; Turner, H.; Helliwell, M.; Moir, E. J. Org. Chem. 2008, 73, 4415.
20. (a) Chenard, B. L. J. Org. Chem. 1983, 48, 2610; (b) Pansegrau, P. D.; Rieker, W. F.;
Meyers, A. I. J. Am. Chem. Soc. 1988, 110, 7178; (c) Chadwick, S. T.; Ramirez, A.;
Gupta, L.; Collum, D. B. J. Am. Chem. Soc. 2007, 129, 2259.
21. Clayden, J.; Farnaby, W.; Grainger, D. M.; Hennecke, U.; Mancinelli, M.; Tetlow,
D. J.; Hillier, I. H.; Vincent, M. A. J. Am. Chem. Soc. 2009, 131, 3410.
22. (a) Watanabe, H.; Hauser, C. R. J. Org. Chem. 1968, 33, 4278; (b) Watanabe, H.;
Mao, C.-L.; Barnish, I. T.; Hauser, C. R. J. Org. Chem. 1969, 34, 919.
23. Tada, M.; Nishiiri, S.; Zhixiang, Y.; Imai, Y.; Tajima, S.; Okazaki, N.; Kitano, Y.;
Chiba, K. J. Chem. Soc., Perkin Trans. 1 2000, 2657.
15. (a) Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 1.
16. Uchida, K.; Fukuda, T.; Iwao, M. Tetrahedron 2007, 63, 7178.
17. (a) Winkle, M. R.; Ronald, R. C. J. Org. Chem. 1982, 47, 2101; (b) Braun, M.; Ringer,
E. Tetrahedron Lett. 1983, 24, 1233; (c) Bates, R. B.; Siahaan, T. J. J. Org. Chem.
1986, 51, 1432; (d) Bates, R. B.; Siahaan, T. J.; Suvannachut, K. J. Org. Chem. 1990,
55, 1328.
18. (a) Fuhrer, W.; Gschwend, H. W. J. Org. Chem. 1979, 44, 1133; (b) Houlihan, W. J.;
Parrino, V. A.; Uike, Y. J. Org. Chem. 1981, 46, 4511; (c) Beak, P.; Meyers, A. I. Acc.