Synthesis of 12-deoxyroyleanone, cryptoquinone, 11,14-dihydroxy-8,11,13- abietatrien-7-one, and related derivatives from dehydroabietic acid

Article abstract of DOI:10.1016/j.tetlet.2005.03.170

Naturally occurring abietane quinones and hydroquinone, namely, 12-deoxyroyleanone (1a), cryptoquinone (4a), and 11,14-dihydroxyabieta-8,11,13- trien-7-one (5a), together with the epimers of tryptoquinones D (2) and F (3), were first synthesized from dehydroabietic acid (6).

Full text of DOI:10.1016/j.tetlet.2005.03.170

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3629–3632
Synthesis of 12-deoxyroyleanone, cryptoquinone,
11,14-dihydroxy-8,11,13-abietatrien-7-one, and related
derivatives from dehydroabietic acid
Yoh-ichi Matsushita,* Yoshihisa Iwakiri, Satoru Yoshida,
Kazuhiro Sugamoto and Takanao Matsui
Faculty of Engineering, University of Miyazaki, Gakuen-Kibanadai, Miyazaki 889-2192, Japan
Received 3 March 2005; revised 18 March 2005; accepted 24 March 2005
Available online 8 April 2005
Abstract—Naturally occurring abietane quinones and hydroquinone, namely, 12-deoxyroyleanone (1a), cryptoquinone (4a), and
11,14-dihydroxyabieta-8,11,13-trien-7-one (5a), together with the epimers of tryptoquinones D (2) and F (3), were first synthesized
from dehydroabietic acid (6).
Ó 2005 Elsevier Ltd. All rights reserved.
12-Deoxyroyleanone (1a) was newly isolated from
O
H
O
H
O
H
Salvia cilicica, which exhibited potent inhibitory activity
against the amastigote forms of Leishmanial donovani
and L. major (Fig. 1).1 Tryptoquinones D (2) and F (3)
were isolated from the stems of Tripterygium wilfordii
var. regelii and had potent inhibitory activities against
the release of interleukin-1a and -1b for human cells.2
Cryptoquinone (4a) was isolated from the bark of Cryp-
tomeria japonica and showed antifungal activities
against Pyricularia orizae and Alternaria alternata and
cytotoxic activity against mouse lymphoid (P388) cells.3
11,14-Dihydroxy-8,11,13-abietatrien-7-one (5a) was
found from the heartwood of Chamaecyparis obtus.4 It
seems to be important to develop synthetic routes of
these new abietane quinones and related derivatives
for elucidation of the relationship between their struc-
tures and promising activities.
O
O
O
O
R
R
R
1a: R = Me
2: R = CH2OH
3: R = COOH
4a: R = Me
4b: R = COOMe
1b: R = COOMe
1c: R = CH2OH
1d: R = COOH
OH
12
HO
11
1
2
3
14
OH
4
7
O
6
H
H
H
COOH
HOOC
R
Although several syntheses of abietane quinones and
hydroquinones bearing an oxygen function at C-12
position, for example, royleanone, 7-oxoroyleanone,
cyptojaponol, and hyptol, have been reported from abi-
etic acid (6),5–8 few syntheses of abietane quinones hav-
ing no oxygen function at the C-12 position, namely,
8,12-abietadien-11,14-dione derivatives were reported.
6
5a: R = Me
5b: R = COOMe
7
Figure 1.
The 8,11,13-abietatriene derivatives bearing alkoxy or
hydroxy group(s) at the C-11 position or both C-11
and C-14 positions have been only accomplished by
reconstruction of the B-ring lactones, which were pre-
pared from 8,11,13-abietatrien-7-one derivatives by the
Baeyer–Villiger oxidation, via the Friedel–Craft acyla-
tion.9–12 Cambie et al. recently improved this synthetic
Keywords: Synthesis; Dehydroabietic acid; 12-Deoxyroyleanone; Cryp-
toquinone; 11,14-Dihydroxyabieta-8,11,13-trien-7-one.
*
Corresponding author. Tel.: +81 985 58 7389; fax: +81 985 58
7323; e-mail: matusita@cc.miyazaki-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.170

3630
Y. Matsushita et al. / Tetrahedron Letters 46 (2005) 3629–3632
route and synthesized the quinones 2 and 3 from podo-
carpic acid (7) in 12 steps via the Fries rearrangement of
the intermediary lactone.13 However, these synthetic
methods require longer steps due to the re-construction
of the B-ring. Therefore, we investigated a new synthetic
route of the 8,12-abietadien-11,14-dione derivatives
from 14-hydroxy-8,11,13-abietatriene derivatives in
expectation of reduction in synthetic steps. We herein re-
port a first synthesis of the quinones 1a and 4a, the
hydroquinone 5a, and related derivatives 1b–d, 4b, and
5b from 6.
NO2
NH2
10
6
a
b
c
NO2
NO2
H
H
R
R
11a: R = Me (Y: 50%)
11b: R = COOMe (Y:61%)
12a: R = Me (Y: 99%)
12b: R = COOMe (Y:99%)
Treatment of 6 with thionyl chloride gave acid chloride,
which was allowed to react with N,O-dimethylhydroxyl-
amine hydrochloride in the presence of Et3N in refluxing
THF to afford crude amide 8 (Scheme 1). Reduction of 8
with LiAlH4 in ether at ꢀ10 °C gave crude aldehyde 9,
which was reduced under the Wolff–Kishner reduction
conditions to produce 8,11,13-abietatriene (10) in 68%
yield from 6. Although the preparation of 9 has been
generally achieved via reduction of 6 with LAH fol-
lowed by oxidation with CrO3 in pyridine,14 the present
procedure has the advantage of permitting no use of
noxious CrO3 in large-scale preparation.
f
e
d
NH2
NO2
H
R
H
R
13a: R = Me (Y:71%)
14a: R = Me (Y: 99%)
13b: R = COOMe (Y:76%)
14b: R = COOMe (Y:99%)
g
h
OCOCF3
OH
1a (Y:73%)
1b (Y:73%)
H
H
Many efforts have been made toward nitration of
8,11,13-abietatriene derivatives.15–22 Mononitration of
10 was known to occur under mild conditions but re-
sulted in formation of a mixture of 12-nitro and 14-nitro
compounds in ratio of 3:1–1:1.15–17
R
R
16a (Y:79%, 2 steps)
16b (Y:85%, 2 steps)
15a: R = Me
15b: R = COOMe
Scheme 2. Reagents and conditions: (a) 65% HNO3 (25 equiv), 95%
H2SO4 (47 equiv), 0 °C then rt, 0.5 h; (b) 65% HNO3 (17 equiv), 95%
H2SO4 (32 equiv), 0 °C then rt, 0.5 h; excess CH2N2, Et2O, rt; (c)
HCOONH4 (8.5 equiv for 11a and 3.5 equiv for 11b), 10% Pd–C
(1.0 wt equiv), CH2Cl2–MeOH, rt, 6.5 h for 11a and 0.5 h for 11b,
under N2; (d) i-amylONO (2.0 equiv), dioxane, reflux, 1.5 h; (e)
HCOONH4 (18 equiv), 10% Pd–C (1.0 wt equiv), CH2Cl2–MeOH, rt,
10 h for 13a and 6 h for 13b, under N2; (f) i-amylONO (1.8 equiv for
14a and 1.2 equiv for 14b), CF3COOH, 0 °C, 10 min then rt, 2 h for
14a and 1 h for 14b; (g) 2 M K2CO3 (1.2 equiv), MeOH, rt, 1.5 h; (h)
30% H2O2 (4.0 equiv for 16a and 6.0 equiv for 16b), RuCl3Æ3H2O
(0.1 equiv), AcOH, 10–15 °C then rt, 2 h for 16a and rt, 5 h for 16b.
14-Hydroxy-8,11,13-abietatriene derivatives have been
synthesized via nitration of 8,11,13-abietatrien-7-one
derivatives at the C-14 position.19–23 However, the nitra-
tion of the abietatrienones has a demerit of producing a
mixture of 14-nitro and 13-nitro compounds in ratio of
ca. 1:1.19,20,22 Therefore, a synthetic route of 1a,b via
selective removal of 14-nitro substituent from 12,14-di-
nitro compounds was newly developed (Scheme 2).
Nitration of 10 with 64% HNO3–95% H2SO4 gave dini-
tro compound 11a, and nitration of 6 under the same
conditions as used for 10 followed by treatment with
CH2N2 gave dinitro ester 11b.21,25 Thus obtained com-
pounds 11a,b were reduced selectively with HCOONH4
in the presence of Pd/C as a catalyst,26,27 to afford 12-
amino-14-nitro compounds 12a,b. Among several meth-
ods for deamination by diazotization–reduction,28–33 the
treatment of 12a,b with i-amyl nitrite in refluxing diox-
ane33 afforded 14-nitro compounds 13a,b in the best
yields, which were reduced with HCOONH4–Pd/C to
14-amino compounds 14a,b. Arenediazonium salts pre-
pared from arylamines have been usually decomposed
with hot protic solvents such as water, alcohols, and ace-
tic acid.22–24,34–38 In this work, it was found that in situ
diazotization–decomposition of 14a,b in trifluoroacetic
acid (TFA) successfully proceeded at room temperature
to afford crude 14-trifluoroacetoxy compounds 15a,b in
high yields. Without further purification, the crude 15a,b
were converted into 14-hydroxy compounds 16a,b. The
H
R1
6: R= COOH
a
8: R= CON(Me)OMe
39
b
oxidation of 16a,b with 30% H2O2 catalyzed by RuCl3
9: R= CHO
gave the abietane quinones 1a and 1b: their respective
yields from 10 and 6 were 20% and 28% yields in seven
steps. Physical and spectral data of synthetic 1a
were consistent with those reported for natural 1a:
c
10: R= Me
Scheme 1. Reagents and conditions: (a) SOCl2 (3.0 equiv), cat. DMF,
toluene, 90 °C, 3 h, then NH2OHÆHCl (1.5 equiv), Et3N (4.0 equiv),
THF, reflux, 2 d; (b) LiAlH4 (1.2 equiv), ꢀ10 °C, 20 min; (c)
N2H4ÆH2O (6.0 equiv), KOH (5.0 equiv), HO(CH2)2O(CH2)2OH,
210 °C, 2 h (Y: 68% from 6); (d) excess CH2N2, MeOH–Et2O (Y: 93%).
20
20
D
mp 83.8–84.8 °C, ½aꢁ ꢀ65.3 (c 0.407, MeOH); lit.1 ½aꢁ
D
ꢀ60.0 (c 0.05, MeOH), and no description of the melting
point of natural 1a.

Y. Matsushita et al. / Tetrahedron Letters 46 (2005) 3629–3632
3631
For synthesis of 4a,b, attempts of direct oxidation of
1a,b by oxidants such as pyridinium chlorochromate
(PCC), CrO3–Ac2O–AcOH, and MnO2 failed with
recovered 1a,b and/or complex reaction mixture. Syn-
thesis of 4a,b was achieved via conversion of 1a,b into
hydroquinones 17a,b by NaBH4 reduction as shown in
Scheme 3. After acetylation of 17a,b, 11,14-diacetoxy
compounds 18a,b were oxidized by the combined use
of CrO3 and acetic anhydride in acetic acid and benzene
gave 7-oxo compounds 19a,b, which were hydrolyzed by
concd HCl in MeOH to afford the hydroquinones 5a,b.
Spectral data of 5a were completely coincided with
those reported for synthetic 5a, though its melting
point was high and specific rotation value was some-
b or c
a
OAc
14b
Y: 87%
H
COOMe
20
d
OH
1c (Y: 57% from 20)
1d (Y: 51% from 20)
H
R
what large compared with those reported: mp 225.1–
+75.4 (c 0.371, CHCl3); lit.4 mp
25
D
21: R = CH2OH
22: R = COOH
226.3 °C, ½aꢁ
24
178–179 °C, ½aꢁ +65.8 (c 0.37, CHCl3). The hydroqui-
D
nones 5a,b were oxidized with MnO2, to afford the qui-
nones 4a,b. Physical and spectral data of synthetic 4a
were consistent with those reported for natural 4a: mp
Scheme 4. Reagents and conditions: (a) i-amylONO (1.2 equiv),
AcOH, 5–10 °C, 10 min then rt, 1.5 h; (b) LiAlH4 (8.0 equiv), Et2O,
0 °C then rt, 4 h, under N2 (to afford 21); (c) excess 5 M NaOH, EtOH,
reflux, 12 h, under N2 (to afford 22); (d) 30% H2O2 (4.0 equiv),
RuCl3Æ3H2O (0.1 equiv), AcOH, 5–15 °C, 10 min then rt, 2 h.
25
107.3–108.2 °C, ½aꢁ ꢀ661.1 (c 0.338, CHCl3); lit.3 mp
D
25
D
105–106 °C, ½aꢁ ꢀ680 (c 0.1, CHCl3).
The diazotization–decomposition of amino compound
14b using acetic acid instead of TFA under the similar
conditions described above gave 14-acetoxy compound
20 in high yield (Scheme 4). Reduction of 20 with
LiAlH4 afforded 14,18-diol 21 and hydrolysis of 20 with
excess of 5 M NaOH followed by neutralization gave 14-
hydroxy acid 22. The epimers 1c and 1d of tryptoqui-
nones D (2) and F (3) were synthesized from 21 and
22, respectively, by the RuCl3-catalyzed oxidation with
H2O2: Their respective yields from 6 were 23% and
20% in seven steps.
In conclusion, a first and short-steps synthesis of 12-
deoxyryleanone (1a), cryptoquinone (4a), and 11,14-
dihydroxy-8,11,13-abietatrien-7-one (5a) together with
related derivatives has been achieved from dehydroabi-
etic acid (6). Antimicrobial activities of these quinones
and related derivatives is currently evaluated in our
laboratory.
AcO
HO
b
a
OAc
OH
1a,b
Supplementary data
H
R
H
R
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.03.170.
2 steps
18a: R = Me (Y: 73%)
18b: R = COOMe (Y: 84%)
17a: R = Me
17b: R = COOMe
References and notes
AcO
1. Tan, N.; Kaloga, M.; Radtke, O. A.; Kiderlen, A. F.;
¨
Oksuz, S.; Ulubelen, A.; Kolodziej, H. Phytochemistry
c
d
OAc
5a: R = Me (Y: 81%)
5b: R = COOMe (Y: 91%)
¨
2002, 61, 881–884.
O
H
2. Shishido, K.; Nakano, K.; Wariishi, N.; Tateishi, H.;
Omodani, T.; Shibuya, M.; Goto, K.; Ono, Y.; Takaishi,
Y. Phytochemistry 1994, 35, 731–737.
R
19a: R = Me (Y: 70%)
3. Kofujita, H.; Ota, M.; Takahashi, K.; Kawai, Y.;
Hayashi, Y. Phytochemistry 2002, 61, 895–898.
4. Kuo, Y.-H.; Chen, C.-H.; Huang, S.-L. J. Nat. Prod. 1998,
61, 829–831.
5. Matsumoto, T.; Harada, S. Chem. Lett. 1976, 1311–1314.
6. Matsumoto, T.; Ohsuga, Y.; Harada, S.; Fukui, K. Bull.
Chem. Soc. Jpn. 1977, 50, 266–272.
7. Ohtsuka, Y.; Tahara, A. Chem. Pharm. Bull. 1978, 26,
2007–2013.
8. Matsumoto, T.; Terao, H.; Wada, M.; Imai, S. Bull.
Chem. Soc. Jpn. 1991, 64, 2762–2765.
19b: R = COOMe (Y: 73%)
e
4a (Y: 92%)
4b (Y: 95%)
Scheme 3. Reagents and conditions: (a) NaBH4 (8.0 equiv), MeOH,
0 °C, 10 min then rt 1 h, under N2; (b) Ac2O (8.0 equiv), DMAP
(0.2 equiv), 0 °C then rt, 22 h for 17a and 18 h for 17b, under N2; (c)
CrO3 (3.0 equiv), AcOH, 10–15 °C then rt, 5 h for 18a; CrO3
(5.0 equiv), Ac2O (13 equiv), AcOH–benzene, 0 °C, 10 min then rt,
0.5 h for 18b; (d) concd HCl, MeOH, reflux, 4 h, under N2; (e) MnO2,
(1.2 wt equiv), CH2Cl2, rt 1 h.
9. Matsumoto, T.; Imai, S.; Aizawa, M.; Kitagawa, H.;
Fukui, K. Chem. Lett. 1972, 581–586.

3632
Y. Matsushita et al. / Tetrahedron Letters 46 (2005) 3629–3632
10. Ohtsuka, Y.; Tahara, A. Chem. Pharm. Bull. 1973, 21,
643–652.
11. Ohtsuka, Y.; Tahara, A. Chem. Pharm. Bull. 1973, 21,
653–658.
12. Pelletier, S. W.; Ohtsuka, Y. Tetrahedron 1977, 33, 1021–
1027.
13. Cambie, R. C.; Mitchell, L. H.; Rutledge, P. S. Aust. J.
Chem. 1998, 51, 931–940.
25. Gigante, B.; Esteves, M. A.; Curto, M. J. M.; Ascenso, J.;
Prabhakar, S.; Lobo, A. M. Synth. Commun. 1998, 28,
639–652.
26. Ram, S.; Ehrenkaufer, E. Tetrahedron Lett. 1984, 25,
3415–3418.
27. Ram, S.; Ehrenkaufer, E. Synthesis 1988, 93–94.
28. Henry, R. A.; Finnegan, W. G. J. Am. Chem. Soc. 1954,
76, 290–292.
14. Tahara, A.; Shimagaki, M.; Ohara, S.; Tanaka, T.;
Nakata, T. Chem. Pharm. Bull. 1975, 23, 2329–2338.
15. Campbell, W. P.; Morgana, M. J. Am. Chem. Soc. 1941,
63, 1838–1843.
16. Ochiai, E.; Ohta, M. Yakugaku Zasshi 1954, 74, 203–
207.
17. Levinson, A. S. J. Org. Chem. 1971, 36, 3062–3064.
18. Ohtsuka, Y.; Akita, H.; Tahara, A. Chem. Lett. 1973, 229–
232.
29. Kornblum, N. Org. Synth. 1955, Coll. Vol. 3, 295–299.
30. Rutherford, K. G.; Redmond, W. A. J. Org. Chem. 1963,
28, 568–571.
31. McDonald, R. N.; Richmond, J. M. J. Chem. Soc., Chem.
Commun. 1973, 605–606.
32. Cadogan, J. I. G.; Molina, G. A. J. Chem. Soc., Perkin
Trans. 1 1973, 541–542.
33. Doyle, M.; Dellaria, J. F., Jr.; Siegfried, B.; Bishop, S. W.
J. Org. Chem. 1977, 42, 3494–3498.
19. Tahara, A.; Akita, H.; Ohtsuka, Y. Chem. Pharm. Bull.
1974, 22, 1547–1554.
34. Smith, L. E.; Haller, H. L. J. Am. Chem. Soc. 1939, 61,
143–144.
20. Tahara, A.; Akita, H.; Ohtsuka, Y. Chem. Pharm. Bull.
1974, 22, 1555–1559.
35. Lambooy, J. P. J. Am. Chem. Soc. 1950, 72, 5327–
5328.
21. Tahara, A.; Shimagaki, M.; Itoh, M.; Harigaya, Y.; Onda,
M. Chem. Pharm. Bull. 1975, 23, 3189–3202.
22. Akita, H.; Oishi, T. Chem. Pharm. Bull. 1981, 29, 1567–
1579.
36. Hunt, R. R.; Rickard, R. L. J. Chem. Soc. (C) 1966, 344–
345.
37. Norcross, B. E.; Becker, D.; Cukier, R. I.; Schultz, R. M.
J. Org. Chem. 1967, 32, 220–223.
23. Tahara, A.; Akita, H. Chem. Pharm. Bull. 1975, 23, 1976–
1983.
24. Tahara, A.; Akita, H. Chem. Pharm. Bull. 1975, 23, 1984–
1988.
38. Canning, P. S. J.; McCrudden, K.; Maskill, H.; Sexton, B.
J. Chem. Soc., Perkin Trans. 2 1999, 2735–2740.
39. Ito, S.; Aihara, K.; Matsumoto, M. Tetrahedron Lett.
1983, 24, 5249–5252.