Oxidative C-ring opening of abietane diterpenes with ammonium cerium(IV) nitrate

Article abstract of DOI:10.1055/s-2007-977418

The oxidation reaction of 11,12-di-O-methylcarnosol with ammonium cerium(IV) nitrate (CAN) gave an abietane diterpene with the C-ring opened and a diester function. The structure of this diester was established by spectroscopic analysis and by chemical means. The reaction of 11,12-di-O-dimethylgaldosol with CAN gave a similar result, yielding a δ-lactone which structure was established as 7-hydroxy-11,12-seco-8,13- abietadien-12,7:20,6β-dilacton-11-oic acid methyl ester by spectroscopic analysis and chemical means. These results could be useful to accede to other natural products like rosmic acid Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-977418

LETTER
1127
Oxidative C-Ring Opening of Abietane Diterpenes with Ammonium
Cerium(IV) Nitrate
Oxidative
o
C-Ring Ope
n
ing of Abi
q
etane
D
iter
p
u
Instituto Universitario de Bio-Orgánica ‘Antonio González’, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2,
38206 La Laguna, Tenerife, Canary Islands, Spain
Fax +34(922)318571; E-mail: landrest@ull.es
Received 16 November 2006
OH
OH
OH
Abstract: The oxidation reaction of 11,12-di-O-methylcarnosol
with ammonium cerium(IV) nitrate (CAN) gave an abietane diter-
pene with the C-ring opened and a diester function. The structure of
this diester was established by spectroscopic analysis and by chem-
ical means. The reaction of 11,12-di-O-dimethylgaldosol with CAN
gave a similar result, yielding a d-lactone which structure was estab-
lished as 7-hydroxy-11,12-seco-8,13-abietadien-12,7:20,6b-dilac-
ton-11-oic acid methyl ester by spectroscopic analysis and chemical
means. These results could be useful to accede to other natural
products like rosmic acid.
HO
H
HO
HO
O
O
HOOC
O
O
R1
R2
H
H
1
2
3 R1 = OH; R2 = H
5 R1 = OMe; R2 = H
6 R1 = OEt; R2 = H
7 R1 = R2 = O
O
O
Key words: oxidation, abietane diterpenes, ring opening, ammoni-
um cerium(IV) nitrate
O
8 R1 = H; R2 = OH
O
OH
H
The genus Salvia (Lamiaceae) consists of approximately
500 species found worldwide. Salvia species are used as
traditional medicines all around the world for the treat-
ment of a variety of diseases, including infectious condi-
tions. Studies of their chemical constituents have revealed
the presence of a large variety of diterpenoids with anti-
bacterial,1 antioxidant,2 antidiabetic,3 antitumor,4 leish-
manicidal,5 and antiplasmodial5 properties among others.
Unfortunately, most of these diterpenes are almost always
present in the plant in very low quantities. In previous
work6 we have reported the partial synthesis of rosmanol
(3), rosmaquinone (4), 7-methoxyrosmanol (5), 7-ethoxy-
rosmanol (6), galdosol (7) and epirosmanol (8) from the
abundant diterpene carnosol (1, Figure 1) as an efficient
alternative method to obtain these minority compounds.
4
Figure 1
opening of the aromatic ring and obtaining a diester deriv-
ative.
11,12-Di-O-carnosol (10) was obtained from carnosol (1),
an abundant natural product of the Salvia species, which
can also be obtained by oxidation6 of carnosic acid (2), an-
other abundant natural product, as indicated in Scheme 1.
Reaction of 11,12-di-O-carnosol (10) with CAN in aque-
ous acetonitrile gave the diester 11 with 90% of yield
(Scheme 1). The structure of 11 was established by its
physical and spectroscopic data as 11,12-seco-8,13-abi-
etadien-20,7b-lacton-11,12-dioic acid dimethyl ester,
In the course of our work on the partial synthesis of these
minority diterpenes and their derivatives with biological
interest, we have found that ammonium cerium(IV)
nitrate [Ce(NH4)2(NO3)6, CAN] in aqueous acetonitrile
oxidizes the o-dimethoxyphenyl group present in the
diterpene structure with the unexpected opening of the
C-ring.
OH
HO
COOMe
O
O
O
Pb(OAc)4
O
COOMe
benzene–MeOH (1:1)
Castagnoli et al.7 reported the oxidative demethylation re-
action of o-dimethoxybenzenes with bulky substituents to
the corresponding o-quinones and p-quinones (as second-
ary products) using ammonium cerium(IV) nitrate. When
we attempted to use this reaction with abietatriene diter-
penes to obtain the o-quinone and/or p-quinone deriva-
tives, we found a completely different result with the
H
H
11
1
CAN
MeCN–H2O (2:1)
MeI/K2CO3
acetone
OMe
MeO
OMe
MeO
O
MeOOC
O
+
H
H
SYNLETT 2007, No. 7, pp 1127–1129
Advanced online publication: 13.04.2007
2
4.
0
4.
2
0
0
7
9
10
DOI: 10.1055/s-2007-977418; Art ID: D34506ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

1128
J. González Marrero et al.
LETTER
which was previously reported by us,8 and was confirmed
by chemical means. Thus, reaction of carnosol (1) with
lead tetraacetate in benzene–MeOH yielded a product
with the same structure as 11 (Scheme 1).
Recently Flowers et al.9 described a possible and reason-
able mechanism for the oxidation reactions with CAN.
We can explain the formation of diester 11 applying the
mechanism proposed by Flowers et al. In which after ox-
idation of the aromatic ring by Ce(IV) and internal ligand
transfer of nitrate, leads to cyclic intermediate 11a which
by rearrangement with loss of nitroso ion gave the diester
11 (Scheme 2).
OH
OMe
HO
H
MeO
O
O
MeI/K2CO3
acetone
O
O
OH
OH
H
12
3
PCC, CH2Cl2
r.t.
OMe
11
16
MeO
20 COOMe
O
14
9
O
15
13
12
1
17
CAN
8
O
5
7
O
4
MeCN–H2O
NO3
MeO
OMe
OMe
O
O
6
O
H
18
OH
MeO
H
19
O
O
14
13
Ce(IV)
O
O
Scheme 3
H
H
10
O
N
O
Me
NO3
OMe
OMe
O
O
O
O
O
O
N
MeO
O
MeO
MeO
N
OMe
OMe
O
O
O
O
MeO
MeO
Ce(IV)
O
O
O
O
O
Ce(IV)
O
O
O
O
H
O
H
H
13
H
H
O
Ce(IV)
Me
O
O
N
O
Me
O
O
O
OMe
N
N
O
O
O
Me
O
MeO
O
O
O
O
MeO
O
COOMe
O
O
O
NO
O
O
COOMe
O
H
H
H
H
11a
11
–NO
Scheme 2
COOMe
O
COOMe
O
O
When we repeated the reaction with 11,12-di-O-methyl-
galdosol (13) generated from rosmanol (3) we obtained a
compound of which physical and spectroscopic data10
were in accordance with the lactone structure of 7-
hydroxy-11,12-seco-8,13-abietadien-12,7:20,6b-dilacton-
11-oic acid methyl ester for 14 (Scheme 3).
OMe
O
COOMe
OH
O
O
OH
H
H
14a
– MeOH
H2O
COOMe
O
The formation of lactone 14 could be explained by the
process shown in Scheme 4. First an oxidative C-ring
opening occurs in the presence of H2O to give the gem-
diol 14a, which then attacks the ester group closest to the
C-7 position, resulting finally in the d-lactone 14.
O
O
O
H
OH
14
We think that these results could be useful for accessing
other natural products like rosmic acid11 isolated from
leaves of Rosmarinus officinalis with antimicrobial activ-
ity against Streptomyces scabies (the plant pathogen that
causes common scab on potatoes).
Scheme 4
Synlett 2007, No. 7, 1127–1129 © Thieme Stuttgart · New York

LETTER
Oxidative C-Ring Opening of Abietane Diterpenes
1129
(10) 7-Hydroxy-11,12-seco-8,13-abietadien-12,7:20,6b-
Acknowledgment
dilacton-11-oic Acid Methyl Ester (14)
We thank the CYTED Project IV.11 for financial support and J. G.
Marrero is thankful to the CajaCanarias for a fellowship.
To a solution of 11,12-di-O-methylgaldosol (13, 19.5 mg,
0.0524 mmol) in MeCN (2 mL), was added a solution of
CAN (163.2 mg, 0.298 mmol) in H2O (1 mL). The reaction
mixture was stirred at r.t. for 72 h and then H2O (10 mL) was
added, extracted with EtOAc (3 × 5 mL), washed with brine
(2 × 5mL), dried over anhyd Na2SO4, and filtered. The sol-
vent was eliminated under reduced pressure, and the crude
product was purified by preparative TLC using n-hexane–
EtOAc (6:4) as eluent to obtain 7-hydroxy-11,12-seco-8,13-
abietadien-12,7:20,6b-dilacton-11-oic acid methyl ester (14,
9.2 mg, 44.8%). 1H NMR (300 MHz, CDCl3): d = 0.91 (3 H,
s, Me-19), 1.04 (3 H, s, Me-18), 1.12 (3 H, d, J = 7.0 Hz, Me-
16), 1.13 (3 H, d, J = 7.0 Hz, Me-17), 2.42 (1 H, br d, J = 9.8
Hz, H-1b), 2.61 (1 H, s, H-5), 2.92 (1 H, hept, J = 7.0 Hz, H-
15), 3.89 (3 H, s, OCH3), 4.79 (1 H, s, H-6), 5.15 (1 H, br s,
OH), 6.91 (1 H, s, H-14). 13C NMR (75 MHz, CDCl3): d =
17.7 (t, C-2), 21.1 (q, C-16), 21.1 (q, C-17), 21.3 (q, C-18),
23.8 (t, C-1), 28.7 (d, C-15), 30.9 (s, C-4), 31.1 (q, C-19),
37.6 (t, C-3), 46.5 (s, C-10), 52.3 (q, OCH3), 53.2 (d, C-5),
77.2 (d, C-6), 96.7 (s, C-7), 129.1 (d, C-14), 130.0 (s, C-8),
139.8 (s, C-9), 140.0 (s, C-13), 164.6 (s, C-12), 165.1 (s, C-
11), 174.5 (s, C-20). MS (EI): m/z (%) = 390 (16) [M]+, 345
(4), 313 (100), 303 (27), 281 (33), 272 (32), 259 (55), 231
(20), 217 (24), 197 (61), 181 (13), 166 (19), 137 (18), 69
(54). HRMS (EI): m/z calcd for C21H26O7: 390.1679; found:
390.1678.
References and Notes
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Synlett 2007, No. 7, 1127–1129 © Thieme Stuttgart · New York

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