First enantiospecific synthesis of antileishmanial 12-deoxyroyleanone from abietic acid

Article abstract of DOI:10.1055/s-2004-835625

12-Deoxyroyleanone (1), an abietane diterpenoid with appreciable antileishmanial activity, has been efficiently synthesized from abietic acid (10; 11 steps for a 25% overall yield).

Full text of DOI:10.1055/s-2004-835625

LETTER
2701
First Enantiospecific Synthesis of Antileishmanial 12-Deoxyroyleanone from
Abietic Acid
E
nantiospecific
.
Synthesis of
J
A
ntileish
.
manial 12-D
A
eoxyroyleanone lvarez-Manzaneda Roldán,*a R. Chahboun,a F. Bentaleb,a E. Cabrera Torres,a E. Alvarez,a A. Haidour,a
J. M. Ramos López,a R. Alvarez-Manzaneda Roldán,b S. El Houssamea
a
Departamento de Química Orgánica, Facultad de Ciencias, Instituto de Biotecnología, Universidad de Granada, 18071 Granada, Spain
Fax +34(958)248089; E-mail: eamr@ugr.es
b
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Almería, 04120 Almería, Spain
Received 30 September 2004
been reported by van Tamelen;16 14-hydroxydehydro-
Abstract: 12-Deoxyroyleanone (1), an abietane diterpenoid with
abietic acid, the key intermediate in the synthetic se-
appreciable antileishmanial activity, has been efficiently synthe-
quence, being prepared by electrophilic substitution via
sized from abietic acid (10; 11 steps for a 25% overall yield).
the corresponding diazonium salt.17
Key words: enantiospecific synthesis, diterpenoids, antileishma-
nial activity
Following our research into the synthesis of natural bioac-
tive compounds based on homochiral synthons obtained
from natural sources,18 we are developing a route to this
type of compound starting from abietic acid (10).
In recent years, the isolation of a wide variety of abietane
diterpenes with various biological activities, e.g. antivi-
ral,1 antibiotic,1b,2 antimalarial,3 antioxidant,4 antitumor5
and antileishmanial,6 has been reported.
As noted above, our initial objective was to devise an ef-
ficient synthesis of the key 14-hydroxyabietic acid, or re-
lated compounds such as 6, from abietic acid (10). The
procedure previously reported involving nitration of the
aromatic ring and further transformation of the nitro group
into the hydroxyl group17 proved to be unsuitable because
of its length and low regioselectivity. Thus, we planned an
alternative method to prepare ester 6 directly from 10, as
depicted in the retrosynthetic Scheme 1. Compound 6 is
obtained after aromatization of the methyl 14-methoxy-
abietate (7), resulting from the dehydration of mono-
methylether 9, derived from the 13,14-diol 8, which can
be synthesized by regioselective dihydroxylation of
abietic acid (10).19
Noteworthy among these, because of their remarkable and
potent activities, is a number of variously oxidized com-
pounds bearing an oxygenated function on C-14. Repre-
sentative examples of the latter are 12-deoxyroyleanone
(1), an antileishmanial agent,6 and cryptoquinone (2),
which shows cytotoxic activity against mouse lymphoid
neoplasm (P388) cells.7 Other interesting related com-
pounds include tryptoquinone A (3), a promising agent
for treatment of rheumatoid arthritis,8 and triptonide (4)
and triptolide (5), which have potent antitumor,9 anti-
inflammatory,10 immunosuppressive10b,11 and antifertility
activities10b,12 (Figure 1).
Scheme 2 shows the complete sequence from 10 to 6.
Abietic acid (10) was efficiently converted into diol 11, by
means of a procedure improved from that reported in the
literature. After esterification of the carboxylic acid, the
secondary hydroxyl group was methylated, affording 9,
which underwent regioselective dehydration by treating
Despite the evident interest of these metabolites, few syn-
theses have been reported, most of them being total syn-
theses involving Diels–Alder cycloaddition,13 Robinson
annulation,8 electrophilic cyclizations14 and radical cy-
clizations.15 A synthesis of 5 from dehidroabietic acid has
O
O
O
O
R2
O
O
R1
O
R
O
HOOC
R
O
4 R1, R2: =O
5 R1: H; R2: OH
1 R, R: H
2 R, R: =O
3
Figure 1
SYNLETT 2004, No. 15, pp 2701–2704
0
7
.1
2
.2
0
0
4
Advanced online publication: 22.10.2004
DOI: 10.1055/s-2004-835625; Art ID: D27204ST
© Georg Thieme Verlag Stuttgart · New York

2702
E. J. Alvarez-Manzaneda Roldán et al.
LETTER
O
O
R
OMe
OMe
R
COOMe
COOMe
1 R, R: H
2 R, R: =O
6
7
O
OH
OR
O
R2
R1
O
O
COOH
COOMe
O
4 R1, R2: =O
5 R1: H; R2: OH
8 R: H
9 R: Me
10
Scheme 1
OH
OH
OH
OMe
i
iii
COOR
COOR
COOH
11 R: H
R: Me
9
10
ii
8
iv
OMe
vi
OMe
OMe
v
COOMe
COOMe
COOMe
6
7
12
Scheme 2 (i) ac. OsO4 0.2%, Me3NO, pyridine, t-BuOH, Ar, reflux, 7 d; (ii) MeI, K2CO3, acetone, reflux, 24 h (90% from 10); (iii) NaH,
THF, MeI, 0 °C, 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,
r.t., 3 h (96%).
with thionyl chloride and triethylamine. The resulting investigated. When 16 was treated with lithium aluminum
methoxydiene 7 was then transformed into the dehydro- hydride, 13 was regenerated; nevertheless, 15 was ob-
abietic acid derivative 12 by treatment with bromine in tained by treating 16 with zinc and sodium iodide.20
carbon tetrachloride under reflux. Hydrogenation of 12 Deprotection of methylether with boron tribromide lead to
under conventional conditions gave methyl 14-methoxy- phenol 17,21 which was finally converted into 1 after treat-
dehydroabietate (6).
ment with potassium nitrosodisulfonate.
Ester 6 is a suitable precursor of bioactive metabolites In summary, a short and efficient procedure to prepare key
such as 1–5, and so we synthesized 12-deoxyroyleanone intermediate 6 from abietic acid (10) has been developed.
(1) starting from 6 (Scheme 3). First, the methoxycarbon- The antileishmanial 12-deoxyroyleanone (1) was synthe-
yl was transformed into the methyl group. Treatment of 6 sized starting from compound 6.
with lithium aluminum hydride gave alcohol 13, which
was oxidized to aldehyde 14 and this converted into 15
under the Wolff–Kishner conditions. An alternative trans-
Acknowledgment
Financial support was received from Ministerio de Ciencia y
Tecnologia (Project PPQ 2002-03308).
formation of 13 into 15, via the mesyl derivative 16, was
Synlett 2004, No. 15, 2701–2704 © Thieme Stuttgart · New York

LETTER
Enantiospecific Synthesis of Antileishmanial 12-Deoxyroyleanone
2703
OMe
OMe
OMe
i
ii
CHO
14
CH2OH
COOMe
13
6
iii
iv
v
O
OMe
OR
O
vi
CH2OMs
16
15 R: Me
17 R: H
1
vii
viii
Scheme 3 (i) LiAlH4, THF, r.t., 3 h (95%); (ii) PCC, CH2Cl2, r.t., 1 h (70%); (iii) NH2NH2, KOH, ethyleneglycol–ethyleneglycol dimethyl-
ether 3:2, 180 °C, 3 d (70%); (iv) MsCl, Et3N, CH2Cl2, 0 °C to r.t., 4 h (93%); (v) LiAlH4, THF, reflux, 24 h (95%); (vi) Zn, NaI, HMPA,
110 °C, 3 d (75%); (vii) BBr3, CH2Cl2, –10 °C, 30 min (95%); (viii) (KSO3)2NO, MeOH, r.t., 4 h (91%).
Z.-Z. Int. J. Immunopharmacol. 1992, 14, 963. (c) Qiu, D.-
M.; Zhao, G.-H.; Aoki, Y.; Shi, L.-F.; Uyei, A.; Nazarina, S.;
References
Ng, J. C.-H.; Kao, P. N. J. Biol. Chem. 1999, 274, 13443.
(12) Zhen, Q.-S.; Ye, X.; Wei, Z.-J. Contraception 1995, 51, 121.
(1) (a) Tada, M.; Chiba, K.; Okuno, K.; Ohnishi, E.; Yoshii, T.
Phytochemistry 1994, 35, 539. (b) Batista, O.; Simoes, M.
F.; Duarte, A.; Valdivia, M. L.; De La Torre, M. C.;
Rodriguez, B. Phytochemistry 1995, 38, 167.
(13) Engler, T. A.; Sampath, U.; Naganathan, S.; Van der Velde,
D.; Takusagawa, F. J. Org. Chem. 1989, 54, 5712.
(14) 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) Yang, D.; Ye, X.-Y.; Xu, M. J. Org. Chem. 2000, 65, 2208.
(16) van Tamelen, E. E.; Demers, J. P.; Taylor, E. G.; Koller, K.
J. Am. Chem. Soc. 1980, 102, 5424.
(2) (a) Dellar, J. E.; Cole, M. D.; Waterman, P. G.
Phytochemistry 1996, 41, 735. (b) Ululuben, A.; Sonmez,
U.; Topcu, G.; Bozok-Johansson, C. Phytochemistry 1996,
42, 145. (c) Ululuben, A.; Topcu, G.; Eris, C.; Sonmez, U.;
Kartal, M.; Kurucu, S.; Bozok-Johansson, C.
Phytochemistry 1994, 36, 971. (d) Moujir, L.; Gutierrez-
Navarro, A. M.; San Andrés, L.; Luis, J. G. Phytochemistry
1993, 34, 1493.
(17) Tahara, A.; Akita, H. Chem. Pharm. Bull. 1975, 23, 1976.
(18) (a) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Romera, J. L.;
Chahboun, R. Synlett 2003, 2313. (b) Armstrong, V.;
Barrero, A. F.; Alvarez-Manzaneda, E. J.; Cortés, M.;
Sepúlveda, B. J. Nat. Prod. 2003, 66, 1382. (c) Barrero, A.
F.; Alvarez-Manzaneda, E. J.; Alvarez-Manzaneda, R.;
Chahboun, R.; Meneses, R.; Cuerva, J. M.; Aparicio, M.;
Romera, J. L. Org. Lett. 2001, 5, 647. (d) Barrero, A. F.;
Alvarez-Manzaneda, E. J.; Chahboun, R.; González Díaz, C.
Synlett 2000, 1561. (e) Barrero, A. F.; Alvarez-Manzaneda,
E. J.; Chahboun, R.; Cuerva, J. M.; Segovia, A. Synlett 2000,
1269. (f) Barrero, A. F.; Cortés, M.; Alvarez-Manzaneda, E.
J.; Cabrera, E.; Chahboun, R.; Lara, M.; Rivas, A. R. J. Nat.
Prod. 1999, 1488. (g) Barrero, A. F.; Alvarez-Manzaneda,
E.; Chahboun, R.; Cortés, M.; Armstrong, V. Tetrahedron
1999, 55, 15181. (h) Barrero, A. F.; Alvarez-Manzaneda, E.;
Herrador, M. M.; Chahboun, R.; Galera, P. Bioorg. Med.
Chem. Lett. 1999, 2325. (i) Barrero, A. F.; Alvarez-
Manzaneda, E.; Chahboun, R. Tetrahedron 1998, 54, 5635.
(j) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Herrador, M.
M.; Valdivia, M. V.; Chahboun, R. Tetrahedron Lett. 1998,
39, 2425. (k) Barrero, A. F.; Alvarez-Manzaneda, E.;
Chahboun, R. Tetrahedron Lett. 1997, 38, 8101.
(3) Achenbach, H.; Walbel, R.; Nkunya, M. H. H.; Weenen, H.
Phytochemistry 1992, 31, 3781.
(4) Nakatani, N.; Iwatani, R. Agric. Biol. Chem. 1984, 48, 2081.
(5) (a) Kupchan, S. M.; Karim, A.; Marcks, C. J. Org. Chem.
1969, 34, 3912. (b) Kupchan, S. M.; Karim, A.; Marcks, C.
J. Am. Chem. Soc. 1968, 90, 5923. (c) Gao, J.; Han, G.
Phytochemistry 1997, 44, 759.
(6) Tan, N.; Kaloga, M.; Radtke, O. A.; Kiderlen, A. F.; Oksuz,
S.; Ululuben, A.; Kolodziej, H. Phytochemistry 2002, 61,
881.
(7) Kofujita, H.; Ota, M.; Taakahashi, K.; Kawai, Y.; Hayashi,
Y. Phytochemistry 2002, 61, 895.
(8) Shishido, K.; Got, K.; Miyoshi, S.; Takaishi, Y.; Shibuya, M.
J. Org. Chem. 1994, 59, 406.
(9) (a) Kupchan, S. M.; Schubert, R. M. Science 1974, 185,
791. (b) Lee, K. Y.; Chang, W.-T.; Qiu, D.-M.; Kao, P. N.;
Rosen, G. D. J. Biol. Chem. 1999, 274, 13451.
(10) (a) Zheng, Y.-L.; Lin, J.-F.; Lin, C.-C.; Xu, Y. Acta Pharm.
Sin. 1994, 15, 540. (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.
(l) Barrero, A. F.; Alvarez-Manzaneda, E.; Chahboun, R.
Tetrahedron Lett. 1997, 38, 2325. (m) Barrero, A. F.;
Alvarez-Manzaneda, E.; Altarejos, J.; Salido, S.; Ramos, J.
M.; Simmonds, M. S. J.; Blaney, W. M. Tetrahedron 1995,
51, 7435. (n) Barrero, A. F.; Alvarez-Manzaneda, E. J.;
(11) (a) Gu, W.-Z.; Chen, R.; Brandwein, S.; McAlpine, J.;
Burres, N. Int. J. Immunopharmacol. 1995, 17, 351.
(b) Yang, S.-X.; Gao, H.-L.; Xie, S.-S.; Zhang, W.-R.; Long,
Synlett 2004, No. 15, 2701–2704 © Thieme Stuttgart · New York

2704
E. J. Alvarez-Manzaneda Roldán et al.
LETTER
Altarejos, J.; Salido, S.; Ramos, J. M. Tetrahedron Lett.
1994, 35, 2945. (o) Barrero, A. F.; Sánchez, J. F.; Alvarez-
Manzaneda, E.; Altarejos, J.; Muñoz, M.; Haïdour, A.
Tetrahedron 1994, 50, 6653.
35.3 (C), 37.1 (CH2), 39.3 (CH2), 44.9 (CH), 46.5 (C), 51.3
(CH), 51.9 (CH3), 60.2 (CH3), 76.3 (C), 83.5 (C), 120.0
(CH), 134.8 (C), 179.3 (C).
Compound 12: 1H NMR (300 MHz, CDCl3): d = 1.04 (3 H,
s), 1.19 (6 H, d, J = 6.9 Hz), 1.38 (3 H, s), 1.60–1.85 (4 H,
m), 2.14 (2 H, m), 2.88 (1 H, dd, J = 3.1, 2.8 Hz), 3.28 (1 H,
h, J = 6.9 Hz), 3.63 (3 H, s), 3.70 (3 H, s), 5.76 (1 H, dd,
J = 9.8, 2.8 Hz), 6.78 (1 H, dd, J = 9.8, 3.1 Hz), 6.90 (1 H, d,
J = 8.1 Hz), 7.08 (1 H, d, J = 8.1 Hz). 13C NMR (75 MHz,
CDCl3): d = 17.9 (CH3), 18.5 (CH2), 20.7 (CH3), 23.9 (CH3),
24.0 (CH3), 26.2 (CH), 35.6 (CH2), 35.7 (CH2), 37.5 (C),
44.7 (C), 46.4 (CH), 52.0 (CH3), 62.3 (CH3), 117.8 (CH),
122.6 (CH), 125.7 (CH), 125.7 (C), 129.8 (CH), 139.0 (C),
146.9 (C), 153.4 (C), 178.5 (C).
(19) Okawara, H.; Nakai, H.; Ohno, M. Tetrahedron Lett. 1982,
23, 1087.
(20) Lee, H.-J.; Ravn, M. M.; Coates, R. M. Tetrahedron 2001,
57, 6155.
(21) All new compounds were fully characterized
spectroscopically and had satisfactory HRMS data. Selected
data: Compound 6: 1H NMR (300 MHz, CDCl3): d = 1.23
(6 H, d, J = 6.9 Hz), 1.23 (3 H, s), 1.40–1.60 (m, 2 H), 1.60–
1.95 (m, 5 H), 2.24 (1 H, dd, J = 12.5, 2.0 Hz), 2.30 (1 H, br
d, J = 12.7 Hz), 2.79 (1 H, ddd, J = 17.6, 11.3, 6.2 Hz), 2.99
(1 H, dd, J = 17.6, 6.2 Hz), 3.34 (1 H, h, J = 6.9 Hz), 3.67 (3
H, s), 3.73 (3 H, s), 7.02 (1 H, d, J = 8.1 Hz), 7.10 (1 H, d,
J = 8.1 Hz). 13C NMR (75 MHz, CDCl3): d = 16.5 (CH3),
18.6 (CH2), 21.3 (CH2), 23.8 (CH3), 23.9 (CH3), 24.5 (CH3),
25.1 (CH3), 26.0 (CH), 36.6 (CH3), 37.1 (C), 38.1 (CH2),
44.6 (CH), 47.6 (C), 51.9 CH3), 60.4 (CH3), 120.2 (CH),
123.8 (CH), 128.4 (C), 138.0 (C), 148.5 (C), 154.8 (C),
179.0 (C).
Compound 15: 1H NMR (400 MHz, CDCl3): d = 0.93 (3 H,
s), 0.96 (3 H, s), 1.18 (3 H, s), 1.21 (3 H, d, J = 6.8 Hz), 1.20
(3 H, d, J = 6.8 Hz), 1.32 (1 H, dd, J = 12.5, 2.1 Hz), 1.39 (1
H, dt, J = 13.1, 3.6 Hz), 1.48 (1 H, br d, J = 13.1 Hz), 1.55–
1.85 (8 H, m), 1.93 (1 H, dd, J = 13.2, 7.8 Hz), 2.26 (1 H, br
d, J = 12.7 Hz), 2.73 (1 H, ddd, J = 17.7, 11.4, 7.7 Hz), 3.01
(1 H, dd, J = 17.6, 7.7 Hz), 3.28 (1 H, h, J = 6.9 Hz), 3.72 (3
H, s), 7.02 (1 H, d, J = 8.4 Hz), 7.05 (1 H, d, J = 8.4 Hz). 13
C
Compound 7: 1H NMR (300 MHz, CDCl3): d = 0.82 (3 H,
s), 0.95 (3 H, d, J = 6.9 Hz), 0.98 (3 H, d, J = 6.9 Hz), 1.14
(1 H, dd, J = 12.5, 4.9 Hz), 1.26 (3 H, s), 1.40–2.20 (13 H,
m), 3.11 (1 H, h, J = 6.9 Hz), 3.52 (3 H, s), 3.64 (3 H, s), 5.74
(1 H, br s). 13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 17.0
(CH3), 18.2 (CH2), 20.5 (CH3), 20.7 (CH3), 22.4 (CH2), 22.7
(CH2), 25.5 (CH2), 26.8 (CH), 34.8 (C), 37.0 (CH2), 38.5
(CH2), 44.8 (CH), 46.6 (C), 51.5 (CH), 51.9 (CH3), 60.5
(CH3), 117.1 (CH), 130.5 (C), 130.7 (C), 147.8 (C), 179.1
(C).
NMR (100 MHz, CDCl3): d = 18.7 (CH2), 19.4 (CH2), 21.7
(CH3), 24.0 (CH3), 23.4 (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).
Compound 17: 1H NMR (300 MHz, CDCl3): d = 0.92 (3 H,
s), 0.95 (3 H, s), 1.18 (3 H, s), 1.24 (6 H, d, J = 6.8 Hz), 1.95
(1 H, m), 2.26 (1 H, br d, J = 12.7 Hz), 2.60 (1 H, ddd,
J = 16.5, 11.5, 6.2 Hz), 2.80 (1 H, dd, J = 16.5, 6.2 Hz), 3.14
(1 H, h, J = 6.8 Hz), 4.50 (1 H, s), 6.85 (1 H, d, J = 8.2 Hz),
7.01 (1 H, d, J = 8.2 Hz). 13C NMR (75 MHz, CDCl3): d =
18.5 (CH2), 19.4 (CH2), 21.7 (CH3), 22.6 (CH3), 22.9 (CH3),
24.4 (CH3), 24.9 (CH3), 26.9 (CH), 33.4 (CH3), 33.4 (C),
38.8 (C), 39.0 (CH2), 41.7 (CH2), 49.8 (CH), 116.5 (CH),
123.3 (CH), 130.9 (C), 130.9 (C), 149.1 (C), 150.3 (C).
Compound 9: 1H NMR (300 MHz, CDCl3): d = 0.83 (3 H,
s), 0.85 (3 H, d, J = 6.9 Hz), 0.89 (3 H, d, J = 6.9 Hz), 1.22
(3 H, s), 2.05 (1 H, h, J = 6.9 Hz), 3.42 (3 H, s), 3.44 (1 H, br
s), 3.60 (3 H, s), 5.66 (1 H, br s). 13C NMR (75 MHz,
CDCl3): d = 15.6 (CH3), 16.5 (CH3), 17.5 (CH3), 18.0 (CH2),
18.2 (CH3), 19.5 (CH2), 25.0 (CH2), 26.6 (CH2), 33.4 (CH),
Synlett 2004, No. 15, 2701–2704 © Thieme Stuttgart · New York