Aerobic oxidation of 8,11,13-abietatrienes catalyzed by N-hydroxyphthalimide combined with 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) and its application to synthesis of naturally occurring diterpenes

Article abstract of DOI:10.1016/j.tetlet.2010.05.090

Methyl 8,11,13-abietatriene-18-oate (1b) and 7-oxo-8,11,13-abietatrienes 10 and 15 were converted into 15-hydroperoxy-7-oxo-8,11,13-abietatrienes 13 and 16 by aerobic oxidation catalyzed by N-hydroxyphthalimide (NHPI) combined with 2,2′-azobis(4-methoxy-2

Full text of DOI:10.1016/j.tetlet.2010.05.090

Tetrahedron Letters 51 (2010) 3931–3934
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Tetrahedron Letters
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Aerobic oxidation of 8,11,13-abietatrienes catalyzed by N-hydroxyphthalimide
combined with 2,20-azobis(4-methoxy-2,4-dimethylvaleronitrile) and its
application to synthesis of naturally occurring diterpenes
*
Yoh-ichi Matsushita , Kazuhiro Sugamoto, Yoshihisa Iwakiri, Satoru Yoshida, Takehito Chaen,
Takanao Matsui
Faculty of Engineering, University of Miyazaki, Gakuen-Kibanadai, Miyazaki 889-2192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Methyl 8,11,13-abietatriene-18-oate (1b) and 7-oxo-8,11,13-abietatrienes 10 and 15 were converted into
15-hydroperoxy-7-oxo-8,11,13-abietatrienes 13 and 16 by aerobic oxidation catalyzed by N-hydroxyph-
thalimide (NHPI) combined with 2,20-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70) at room tem-
perature, and several abietane and podocarpane terpenes were synthesized from 13 and 16.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 19 April 2010
Revised 18 May 2010
Accepted 21 May 2010
Available online 26 May 2010
The oxidized derivatives1 of 8,11,13-abietatrien-18-oic acid (1a)
and 8,11,13-abietatriene (2) such as 15-hydroxy-7-oxo compounds
3a1c,d and 41b and 7,14-dihydroxy compounds 5a1a,c,e and 6a1d
have been isolated from the extracts of plants or from microorgan-
ism metabolites of 1a and some of them have demonstrated prom-
ising antimicrobial and tumor-inhibitory properties (Fig. 1).1c,f,g
Isolation and identification of 3a, 5a, and 6a were carried out after
converting into methyl esters 3b, 5b, and 6b. Podocarpane phenols
7a2a and 82b have been isolated, respectively, from Pinus massoni-
ana and Taiwania cryptomerioides, and the antibacterial activity of
8 was reported.2c 13-Hydroxy-7-oxo compound 9 was also known
as a potential antiviral agent.3
Since 1a is readily and abundantly available from dispropor-
tionated rosin, 1a has been utilized as a starting compound for nat-
urally occurring abietane and podocarpane terpenes. A method for
the preparation of 3a and 9 from 1a was already reported.4 Oxida-
tion of 1a with chromic trioxide in acetic anhydride and acetic acid
followed by hydrolysis with aqueous potassium hydroxide gave 3a
(26% from 1a), and the corresponding methyl ester 3b was oxi-
dized with t-butyl hydroperoxide in acetic acid containing H2SO4
to afford 9 (19% from 1a). However, the yields of 3a and 9 were
low in this method, and the use of noxious chromic trioxide for oxi-
dation should be avoided if possible.
benzoyl peroxide at 90 °C to give the reaction mixture containing
hydroperoxide 13 (hydroperoxide content 40–50%); 13 was not
isolated from the mixture.6 The crude mixture was treated with
acetic acid containing 1% HClO4 to afford 9 in 30–35% yield. This
method seems unsatisfactory for the preparation of 9, because
noxious chromic trioxide was used for oxidation of 1b and the
yield of 9 was low (ca. 15% from 1b). A more efficient catalyst than
benzoyl peroxide is necessary for the oxidation of 10.
Novel aerobic oxidation of arylalkanes by N-hydroxyphthali-
mide (NHPI) as a catalyst at 100 °C was first reported by Ishii
et al.7,8 and the oxidation under milder conditions has been
achieved by NHPI and co-catalyst systems such as NHPI and
cobalt(II) acetate at room temperature,9 NHPI and azobis(isobuty-
ronitrile) (AIBN) at 75 °C,10 and NHPI and 2,20-azobis(4-methoxy-
2,4-dimethylvaleronitrile) (V-70) at 30 °C.11 It is expected that
the aerobic oxidation at around room temperature by the NHPI-
cobalt(II) system or the NHPI-V-70 system can be applied to the
conversion of abietatrienes 1b, 2, 10, and 15 into the corresponding
hydroperoxides 13 and 16, which are important intermediates for
the synthesis of naturally occurring diterpenes 3–6 and trinordit-
erpenes 7–9. We report herein the optimal reaction conditions
for the NHPI-catalyzed aerobic oxidation of 8,11,13-abietatrienes
and its application to the synthesis of naturally occurring abietane
and podocarpane terpenes.
The aerobic oxidation of methyl 8,11,13-abietatrien-18-oate
(1b) in the presence of benzoyl peroxide was reported to give 7-
oxo compound 10 (25%) and 7-hydroperoxide 11 (29%) along with
a small amount of 15-hydroperoxide 12.5 15-hydroperoxy-7-oxo
compound 13 was not found on oxidation. On the other hand,
the 7-oxo compound 10, prepared from 1b by chromic oxidation
in 52% yield, was oxidized under O2 in the presence of 2.5 mol %
The reaction of 1b, prepared from 1a by the treatment with
CH2N2 in quantitative yield, under oxygen (1 atm) in acetonitrile
in the presence of 0.1 equiv of NHPI and 0.04 equiv of cobalt(II)
acetate was first examined (Table 1). When the reaction was per-
formed at 30 °C for 48 h, 10, 13, 3b, and 14 were obtained in 6%,
24%, 44%, and 14% yields, respectively (entry 1). The reaction at
50 °C chiefly afforded 3b and 14 (entry 2). Although the production
of 3b and 14 was predicted because redox decomposition of the
hydroperoxide with cobalt ion was already reported to give alcohol
* Corresponding author. Tel.: +81 985 58 7389; fax: +81 985 58 7323.
E-mail address: matusita@cc.miyazaki-u.ac.jp (Y. Matsushita).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.090

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Y. Matsushita et al. / Tetrahedron Letters 51 (2010) 3931–3934
Table 2
Aerobic oxidation of 1b and 10 catalyzed by NHPI combined with 2,20-azobis(4-
methoxy-2,4-dimethylvaleronitrile) (V-70)
Entry Substrate NHPI
(equiv)
V-70
(equiv)
Isolated yield (%)
Recov.
(%)
10 11 12 13
1
2
3
4
1b
1b
10
10
0.1
0.02
0.20
0.02
0.20
10 31 17
4
24
0
1.0
0.1
1.0
16
—
8
—
—
10 41
—
—
23 74
90 Trace
—
Scheme 1.
the presence of NHPI (0.1 equiv) and V-70 (0.02 equiv) under O2
(1 atm) in acetonitrile for 48 h afforded 7-hydroperoxy and 7-oxo
compounds 10 and 11 (41%), 15-hydroperoxide 12 (17%), and 15-
hydroperoxy-7-oxo compound 13 (4%) (entry 1). Increasing NHPI
and V-70 afforded 13 in 41% yield (entry 2). On the other hand,
the oxidation of 7-oxo compound 10 predominantly gave 13, and
its yield was 90% when using 1.0 equiv of NHPI and 0.2 equiv of
V-70 (entries 3 and 4).13 When 10 obtained in 16% yield from the
reactions shown in entry 2 is oxidized under the same conditions
as described in entry 4, the total yield of 13 can reach up to 55%
through twice oxidation processes.
Figure 1. Abietane and podocarpane derivatives.
Table 1
Aerobic oxidation of 1b catalyzed by NHPI combined with cobalt(II) acetate
Thus, oxidations of 1b by the catalytic systems of both NHPI-co-
balt(II) acetate (0.1 equiv and 0.04 equiv) and NHPI-V-70
(1.0 equiv and 0.2 equiv) gave the 15-hydroperoxy-7-oxo com-
pound 13 in moderate yields, however, the oxidations of 1b always
accompanied minor products such as 10, 11, and 12. The selective
conversion of 10 into 13 by the NHPI-V-70-catalyzed oxidation is
probably used as it is advantageous for the synthesis of naturally
occurring diterpenes, if 10 is selectively prepared from 1b by other
methods. Chromic oxidation of 8,11,13-abietatrienes 1b and 2 with
chromic trioxide in aqueous acetic acid has been usually used for
preparation of the corresponding 7-oxo compounds 10 and 15 in
52% and 67% yields, respectively.6,14 In order to avoid chromic oxi-
dation process, we first examined a new method for the oxidation
of 1b and 2.15 Murahashi and et al. have reported that a catalytic
oxidation system with t-BuOOH in the presence of RuCl2(PPh3)2
in benzene was suitable for the synthesis of aryl ketones from aryl-
alkanes.16 We applied this oxidation system to 1b and 2 and opti-
mized the reaction conditions. When 5% Ru/C in ethyl acetate was
used in place of RuCl2(PPh3)2 in benzene on oxidation with t-
BuOOH, 1b and 2 were oxidized to 10 and 15 in best yields of
70% and 78% as shown in Scheme 1. Details of optimization on
the oxidation will be reported elsewhere.
Entry
Temp (°C)
Time (h)
Isolated yield (%)
Recov. (%)
10
13
3b
14
1
2
3
4
30
50
30
23
48
48
24
48
6
0
40
41
24
0
38
34
44
55
13
7
14
20
Trace
Trace
0
0
0
0
and ketone,9 it is noteworthy that the hydroperoxide 13 was ob-
tained under the conditions using NHPI and cobalt(II) acetate. To
our knowledge this is the first isolation of the hydroperoxide on
the oxidation of arylalkanes by the NHPI and cobalt(II) system
When the reaction was carried out at 30 °C for 24 h or 23 °C for
48 h, 10 and 13 were the major products (entries 3 and 4).12 Oxi-
dation at a low temperature appreciably prevents the redox
decomposition of the hydroperoxide 13 (entry 4). The 15-hydro-
peroxide 12 was not isolated in all cases. It seems likely that the
production of 12 occurs first, followed by a more rapid conversion
into 13 under the present oxidation conditions. One of the short-
comings of this reaction is that chromatographic separation of
the hydroperoxide 13 and the alcohol 3b is somewhat difficult.
The aerobic oxidation of 1b and 10 catalyzed by NHPI combined
with V-70 was investigated next (Table 2). The oxidation of 1b in
Scheme 2 summarizes the synthesis of the oxidized abietane
terpenes from 10 and 15. The aerobic oxidation of 10 and 15 cata-
lyzed by NHPI and V-70 afforded 15-hydroperoxides 13 and 16 in

Y. Matsushita et al. / Tetrahedron Letters 51 (2010) 3931–3934
3933
Scheme 2.
high yields, which were converted into alcohols 3b and 4 by reduc-
tion with trimethyl phosphite. Hydrolysis of 3b afforded the
desired acid 3a. On the other hand, the keto alcohol 3b was re-
duced with sodium borohydride in methanol to give 7b,15-dihy-
droxy compound 5b. The reaction of 5b with p-nitrobenzoic acid
15-acetylperoxy-7-oxo compounds 18 and 19 in good yields,
which readily underwent rearrangement in acetic acid at 100 °C
to afford 13-hydroxy-7-oxopodocarpatriene derivatives 9 and 20
in high yields. Reduction of 9 and 20 with triethylsilane in trifluo-
roacetic acid gave 7b and 8. Hydrolysis of 7b gave the desired acid
7a.
using the Mitsunobu method17 afforded 7
a-p-nitrobenzoyloxy
compound 17. Methanolysis of 17 with refluxing methanol in the
presence of the anion exchange resin Amberlite IRA 400 yielded
methyl 7a,15-dihydroxy compound 6b in 20% yield from 1a.
Although 6b has been reported to be isolated from the microorgan-
ism metabolites of 1a,1e its chemical conversion into 6b was first
reported in the present work.
Scheme 3 shows the synthesis of the naturally occurring podo-
carpane terpenes. The aerobic oxidation of 10 and 15 catalyzed by
NHPI and V-70 followed by acetylation with acetic anhydride gave
In conclusion, the aerobic oxidation of abietatrienes 1b, 10, and
15 catalyzed by NHPI and V-70 gave 15-hydroperoxy-7-oxo-
8,11,13-abietatriene derivatives 13 and 16. Naturally occurring
abietane diterpenes 3a, 4, 5b, and 6b were synthesized from 13
and 16 as key intermediates. Furthermore, a facile synthesis of
13-hydroxy-8,11,13-podocarpatrienes 7a, 8, and 9 was accom-
plished via the present hydroperoxygenation of 10 and 15 followed
by acetylation and rearrangement reaction.
References and notes
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1226; (f) Kinouchi, Y.; Ohtsu, H.; Tokuda, H.; Nishino, H.; Matsunaga, S.;
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7903; (b) Kuo, Y.-H.; Chang, C.-I.; Lee, C.-K. Chem. Pharm. Bull. 2000, 48, 597; (c)
Evans, G. B.; Furneaux, R. H.; Gravestock, M. B.; Lynch, G. P.; Scott, G. K. Bioorg.
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3. Mauldin, S. C.; Munroe, J. E. (Eli Lilly and Company) U.S. Patent 96-16902.
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723.
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Commun. 2008, 3417.
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12. General procedure: To an acetonitrile (10 ml) solution of 1b (314 mg, 1 mmol)
and NHPI (16.3 mg, 0.1 mmol) in a 50-ml kjeldahl flask equipped with three-
Scheme 3.

3934
Y. Matsushita et al. / Tetrahedron Letters 51 (2010) 3931–3934
1130 cmꢁ1 1H NMR (CDCl3) d 1.27 (3H, s, H-20), 1.35 (3H, s, H-19), 1.59 and
way stopcock was added cobalt(II) acetate tetrahydrate (10.0 mg, 0.04 mmol).
.
The atmosphere in the flask was replaced with oxygen by bubbling for 5 min,
and then an oxygen balloon was attached to the flask through the three-way
stopcock. The reaction mixture was stirred at 23, 30, or 50 °C for 48 or 24 h. The
solvent was removed under reduced pressure to afford the crude product,
which was purified by flash column chromatography on silica gel with
hexane–ethyl acetate (4:1 and then 2:1) to give the corresponding products.
13. Typical procedure: An acetonitrile (15 ml) solution of 10 (329 mg, 1 mmol) and
NHPI (163 mg, 1.0 mmol) in a 50-ml kjeldahl flask equipped with three-way
stopcock was added V-70 (62 mg, 0.2 mmol). The atmosphere in the flask was
replaced with oxygen by bubbling for 5 min, and then an oxygen balloon was
attached to the flask through the three-way stopcock. The reaction mixture
was stirred at 30 °C for 48 h. The solvent was removed under reduced pressure
to afford the residual solid. The residue was dissolved in hexane–ethyl acetate
(1:1) and insoluble NHPI was filtered off and washed with hexane–ethyl
acetate (1:1). After the filtrate has been evaporated under reduced pressure,
the crude product was purified by flash column chromatography on silica gel
with hexane–ethyl acetate (4:1 and then 2:1) to give 13 (324 mg) in 90% yield:
1.60 (each 3H, s, H-16 and H-17), 1.60–1.64 (5H, m, H-1a, H-2, H-3), 2.33–2.45
(2H, m, H-1b, H-6), 2.68–2.83 (2H, m, H-5, H-6), 3.66 (3H, s, COOCH3), 7.39 (1H,
d, J = 8.4 Hz, H-11), 7.53 (1H, dd, J = 8.4 Hz, 2.4 Hz, H-12), 7.74 (1H, s, OOH),
8.04 ppm (1H, d, J = 2.4 Hz, H-14). 13C NMR (CDCl3) d 16.31 (C-19), 18.05 (C-2),
23.55 (C-20), 25.91 and 26.11 (C-16 and C-17), 36.47 (C-3), 36.96 (C-1), 37.34
(C-10), 37.71 (C-6), 43.58 (C-5), 46.60 (C-4), 52.17 (C–OCH3), 83.38 (C-15),
123.73 (C-14), 124.30 (C-11), 130.60 (C-8), 131.40 (C-12), 143.35 (C-13),
154.30 (C-9), 177.78 (C-18), 198.58 (C-7); Anal. Calcd for C21H28O5: C, 69.98; H,
7.83. Found: C, 70.20; H, 8.02.
14. Ohsawa, T.; Mizuno, H.; Takizawa, T.; Itoh, M.; Saito, S.; Tahara, A. Chem. Pharm.
Bull. 1976, 24, 705.
15. A method for preparation of 2 from 1a: Matsushita, Y.; Iwakiri, Y.; Yoshida, S.;
Sugamoto, K.; Matsui, T. Tetrahedron Lett. 2005, 46, 3692.
16. (a) Murahashi, S.-I.; Oda, Y.; Naota, T.; Kuwabara, T. Tetrahedron Lett. 1993, 34,
1299; (b) Murahashi, S.-I.; Komiya, N.; Oda, Y.; Kuwabara, T.; Naota, T. J. Org.
Chem. 2000, 65, 9186.
17. (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380; (b) Kurihara,
T.; Nakajima, Y.; Mitsunobu, O. Tetrahedron Lett. 1976, 2455; (c) Dodge, J. A.;
Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994, 59, 234.
mp 128.8–130.0 °C (hexane–diethyl ether).
½ ꢀ +9.38 (CHCl3, c 0.95). IR
a 2D0
(CHCl3) 3570, 3400, 3025, 2980, 2900, 1740, 1695, 1620, 1470, 1270, and
m