Synthesis of diterpenoid rosmic acid derivatives

Article abstract of DOI:10.3184/174751913X13618945224197

The partial synthesis of derivatives of the antimicrobial diterpenoid rosmic acid from the abundant diterpenoid carnosol is described. The key step involved the cleavage of ring C of rosmanol with lead tetraacetate or 7-O-methylrosmanol with mCPBA. Three

Full text of DOI:10.3184/174751913X13618945224197

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 193
APRIL, 193–196
Synthesis of diterpenoid rosmic acid derivatives
Joaquín G. Marreroa*, Lucía San Andrésb and Javier G. Luisb
aInstituto Politécnico Nacional, Unidad Profesional Interdisciplinaria de Ingeniería Campus Guanajuato, Av. Mineral de Valenciana No. 200
Col. Fracc. Industrial Puerto Interior, C.P. 36275 Silao de la Victoria, Guanajuato, México
bInstituto Universitario de Bio-Orgánica “Antonio González”, Departamento de Química Orgánica, Universidad de La Laguna, Avda.
Astrofísico Francisco Sánchez, 2, 38206 La Laguna, Tenerife, Canary Islands, Spain
The partial synthesis of derivatives of the antimicrobial diterpenoid rosmic acid from the abundant diterpenoid car-
nosol is described. The key step involved the cleavage of ring C of rosmanol with lead tetraacetate or 7-O-methylros-
manol with mCPBA. Three analogues of rosmic acid, 11,12-seco-8,13-abietadien-12,7:20,6β-dilacton-11-oic acid
methyl ester, 7α-O-methyl-11,12-seco-11,12-epoxy-11,12-dioxo-8,13-abietadien-20,6β-olide, its dimethyl ester, and
the known methylgaldosol and rosmaquinone were obtained.
Keywords: rosmic acid derivatives, rosmanol, oxidative ring opening
The genus Salvia (Lamiaceae) consists of approximately 500
species that are found worldwide. Sage (Salvia species) has
been used as a herb with beneficial healing properties for
millennia. Salvia species are used as traditional medicines
all around the world for the treatment of a variety of diseases.
Studies of their chemical constituents have revealed the pres-
ence of a large variety of diterpenoids with antibacterial,1–4
antioxidant,5 antidiabetic,6,7 antitumor,8,9 leishmanicidal and
antiplasmodial properties10 among others. Unfortunately, most
of these diterpenes almost always are present in the plant in
very low quantities. To address this problem, we have devel-
oped the partial synthesis of some of these compounds from
the abundant diterpene carnosol11 1 (Fig. 1) as an efficient
alternative method to obtain these minor constituents.
Rosmic acid 2 (Fig. 1) is a natural product isolated from
leaves of Rosmarinus officinalis with antimicrobial activity
against Streptomyces scabies, the plant pathogen that causes
common scab on potatoes.12 The isolation of this natural com-
pound was very tedious, and yields were very poor (0.014%
from fresh leaves of rosemary). These facts led us to propose
possible routes for the semisynthesis of several new deriva-
tives of rosmic acid. For this purpose, we applied our previous
work in the C-aromatic ring opening oxidation reaction in
abietatriene diterpenes.13,14
In a first approach to obtain these diterpenes with a hydroxyl
group on C-7, we considered that rosmanol 3 (Fig. 1), obtained
previously from carnosol 1,11 might serve as a suitable
precursor for this purpose.
Results and discussion
When rosmanol 3 was oxidised with lead tetraacetate follow-
ing the methodology described previously,15 we obtained a
mixture of two products which were separated using a silica
gel column chromatography. These products were identified
as the dilactone 5 and the previously reported 11,12-di-O-
methyl-galdosol 62,16 in 52.2% and 41.7% yield respectively
(Scheme 1).
The high resolution mass spectrum of 5 corresponded to
C21H26O6 for the molecular ion at m/z [M]+ at 374.1747, and
indicates nine degrees of unsaturation. The IR spectrum exhib-
ited characteristic bands for a γ-lactone (1792 cm−1) and δ-
1
lactone (1726 cm−1). In the H NMR spectrum, the presence
of an isopropyl group attached to the double bond of 5 was
revealed by a set of two doublets [δH 1.16 (d, J = 7.0 Hz,
Me-17), δH 1.11 (d, J = 7.0 Hz, Me-16)] and a septet proton
signal at δH 2.94 (sept, J = 7.0 Hz, Me-15). In addition, three
methyl singlets at δH 3.86 (–COOCH3), 0.90 (Me-19) and
1.03 (Me-18) were assigned to one methoxyl group of an ester
function and two methyls attached to a quaternary carbon. Two
doublets of one-proton each at δH 4.65 and 4.73 were ascribed
to the oxygenated methines H-6 and H-7 respectively, and a
Fig. 1 Structure of carnosol, rosmic acid and rosmanol
derivatives.
* Correspondent. E-mail: jgonzalezm@ipn.mx
Scheme 1 Oxidation of rosmanol with lead tetraacetate.

194 JOURNAL OF CHEMICAL RESEARCH 2013
one proton singlet at δH 6.98 to the vinylic proton H-14. Analy-
doublets [δH 1.12 (J = 7.0 Hz, Me-16) and 1.19 (J = 7.0 Hz,
H-17)] and a septet proton at δH 2.94 (J = 7.0 Hz, H-15).
In addition, three methyl singlets at δH 3.45 (–OCH3), 0.85
(Me-19) and 1.01 (Me-18), were assigned to one methoxyl
group and two methyls attached to a quaternary carbon. Two
doublets of one-proton each at δH 3.87 (J = 2.9 Hz) and 4.60
(J = 2.9 Hz), were assigned to the oxygenated methine H-6
and H-7 respectively, and a one proton singlet at δH 6.22 to the
vinylic proton H-14. All the above data were in accordance
with the structure of 7α-O-methoxy-11,12-seco-11,12-epoxy-
11,12-dioxo-8,13-abietadien-20,6β-olide (8).
In an effort to improve the yield of anhydride, we tried the
oxidation reaction with m-CPBA directly from 7α-O-methyl-
rosmanol 4. The 1H NMR spectrum of the product was identi-
cal with that reported above for the anhydride 8. Finally, the
yield of the reaction in one step (39.2%) was higher that
the synthetic sequence in two steps (overall yield 31.9%)
(Scheme 2).
1
sis of the H–1H-COSY spectrum revealed that the methine
proton at δH 4.65 (H-6) was coupled to the methine protons at
δH 4.73 (H-7). Since a coupling of 3.3 Hz was observed
between H-6 and H-7, it was concluded that the methine proton
at H-7 was in the β-position.11 The δ-lactone was further con-
firmed by a long-range coupling between H-7 and the carbonyl
at δC 178.7 (C-12) in the HMBC spectrum. The 13C NMR
spectrum of 5 revealed the presence of 21 carbon atoms. The
multiplicity of the carbon atoms was established by analysis of
the DEPT-90 and DEPT-135 experimental data and revealed
the presence of five methines including three carbons linked
to an oxygen function (δC 53.5, 73.5 74.0), three methylene,
and five methyl carbons of which one of the methyl groups
(δC 52.4) was linked to an oxygen function, and finally eight
quaternary carbons, including three carbonyl carbons (δC
163.0, 164.6 and 172.5). Four of the carbon signals were in the
double bond region [δC 131.1 (s), 132.4 (d), 138.1 (s) and 141.4
(s)] suggesting the presence of a diene system in the structure
of 5. Analysis of all of the above data, led to the structure for 5
as 11,12-seco-8,13-abietadien-12,7:20,6β-dilacton-11-oic acid
methyl ester. This novel product has been named rosmanolide.
The formation of the dilactone 5 can be explained by the
oxidative C-ring opening13 and subsequent lactonisation with
the C-7 hydroxyl group.
To confirm the structure of anhydride 8, the compound was
methylated immediately with methyl iodide in the presence of
dry potassium carbonate, to yield the corresponding diester 9
(Scheme 3).
The molecular formula of diester 9 was shown to be C23H32O7
from the [M]+ ion peak at m/z 420.2148 in HR-ES-MS, imply-
ing the presence of eight degrees of unsaturation. The IR spec-
trum exhibited characteristic bands for a γ-lactone (1788 cm−1)
and α,β-unsaturated esters (1731 cm−1). A significant ion at m/z
= 377.4116 (C20H25O7) was due to the loss of isopropyl group
(C3H7) from the parent molecular ion at m/z = 420.2148. The
presence of an isopropyl group attached to the double bond
At this point, we decided to change our starting material,
to avoid the lactonisation reaction. We considered that 7α-O-
methylrosmanol 4, obtained previously from carnosol 1,11
might serve as a suitable precursor for this purpose.
Due to the low yield of the C-ring cleaved product obtained
using lead tetraacetate as oxidant, we decided to change the
oxidant agent to m-CPBA.13
1
of 9 was confirmed in the H NMR spectrum by a set of
two doublets signals at δH 1.06 (J = 7.0 Hz, Me-16) and 1.08
(J = 7.0 Hz, Me-17), and a septet methine at δH 2.76 (J =
7.0 Hz, H-15). The NMR spectrum also displayed signals
attributed to a geminal dimethyl group at 0.87 (s, Me-19) and
0.94 (s, Me-18), and one vinylic methine proton at δH 6.40 (s,
H-14). In addition, signals from three methoxy groups were
As we previously reported,11 treatment of carnosol 1 with
sodium methoxide in methanol afforded 7α-O-methylrosmanol
4 (Scheme 2), which was oxidised with freshly prepared Ag2O
in diethyl ether, to obtain the natural product, rosmaquinone
B 7.17,18
1
When we treated rosmaquinone B 7 with solid sodium
hydrogencarbonate and m-chloroperbenzoic acid in dichloro-
methane at room temperature13 we obtained an unstable
product, that was identified on the basis of its 1H NMR as the
anhydride 8 (Scheme 2).
observed in the H NMR spectrum at δH 3.51, 3.64 and 3.67,
while signals at 3.84 (1H, d, J = 3.0 Hz, H-6) and 4.53 (1H, d,
J = 3.0 Hz, H-7) were assigned to two methine protons attached
1
to carbons bearing oxygen. Analysis of the H–1H-COSY
spectrum revealed that the methine proton at δH 3.84 (H-6) was
coupled to the methine protons at δH 4.53 (H-7). Furthermore,
the HMBC experiment revealed cross-peaks from the vinylic
In the 1H NMR spectrum, the presence of an isopropyl group
attached to a double bond of 8 was revealed by a set of two
Scheme 2 Synthesis of anhydride (8).

JOURNAL OF CHEMICAL RESEARCH 2013 195
pressure and chloroform (10 mL) was added to the residue. The pre-
cipitate of lead(II) acetate was filtered off and the filtrate was washed
with water (10 mL × 2), dried over Na2SO4, and evaporated under
reduced pressure. The crude product was chromatographed on silica
gel using dichlomethane as the eluent to give rosmanolide 5 (9.6 mg,
52.2%) and 11,12-di-O-methylgaldosol 6 (8.6 mg, 41.7%).
Rosmanolide (5): Colourless syrup; UV (EtOH) λmax (log ε) nm 280
(3.92); IR (NaCl) νmax cm−1 2958, 1792, 1726, 1594, 1460, 1373, 1282,
1093; 1H NMR (300 MHz, CDCl3): 0.90 (3H, s, Me-19), 1.03 (3H, s,
Me-18), 1.11 (3H, d, J = 7.0 Hz, Me-16), 1.16 (3H, d, J = 7.0 Hz,
Me-17), 1.97 (1H, s, H-5), 2.55 (1H, bd, J = 13.4 Hz, H-1β), 2.94 (1H,
hept, J = 7.0 Hz, H-15), 3.86 (3H, s, –OCH3), 4.65 (1H, d, J = 1.9 Hz,
H-6), 4.73 (1H, d, J = 1.9 Hz, H-7), 6.98 (1H, s, H-14); 13C NMR
(75 MHz, CDCl3) δC 18.1 (t, C-2), 21.0 (q, C-18), 21.9 (q, C-16), 22.0
(q, C-17), 25.2 (t, C-1), 29.0 (d, C-15), 31.4 (q, C-19), 31.5 (s, C-4),
38.0 (t, C-3), 44.6 (s, C-10), 52.4 (q, –OCH3), 53.5 (d, C-5), 73.5 (d,
C-6), 74.0 (d, C-7), 131.1 (s, C-9), 132.4 (d, C-14), 138.1 (s, C-8),
141.4 (s, C-13), 163.0 (s, C-11), 164.6 (s, C-12), 172.5 (s, C-20);
EIMS m/z (%): 374 [M]+ (12), 343 (28), 330 (100), 315 (89), 283 (48),
271 (56), 243 (89), 201 (85); HR-EI-MS m/z [M]+ 374.1747 calcd for
C21H2606, found 374.1729. =
11,12-Di-O-methyl-galdosol (6): Colourless syrup; UV (EtOH)
λmax (log ε) nm 237 (4.46), 297 (3.82); IR (NaCl) νmax cm−1 2962, 2873,
1784, 1704, 1589, 1459, 1313, 1225, 1047, 964; 1H NMR (300 MHz,
CDCl3): 0.98 (3H, s, Me-19), 1.03 (3H, s, Me-18), 1.20 (6H, d, J =
7.0 Hz, Me-16 and Me-17), 2.42 (1H, s, H-5), 3.27 (2H, overlapping
signals, H-1β and H-15), 3.80 (3H, s, –OCH3), 3.89 (3H, s, -OCH3),
4.71 (1H, s, H-6), 7.78 (1H, s, H-14); 13C NMR (75 MHz, CDCl3):
18.9 (t, C-2), 22.0 (q, C-18), 22.8 (q, C-16), 23.1 (q, C-17), 27.0 (d,
C-15), 27.6 (t, C-1), 31.6 (q, C-19), 32.5 (s, C-4), 37.9 (t, C-3), 49.7
(s, C-10), 60.5 (q, –OCH3), 60.7 (d, C-5), 61.0 (q, –OCH3), 80.7 (d,
C-6), 122.9 (d, C-14), 125.6 (s, C-9), 136.1 (s, C-8), 144.1 (s, C-13),
151.6 (s, C-11), 157.4 (s, C-12), 176.6 (s, C-20), 189.8 (s, C-7); EIMS
m/z (%): 404 [M]+ (12), 372 (100), 313 (96), 285 (17), 258 (73), 243
(75), 165 (4), 129 (5), 55 (9).
Scheme 3 Synthesis of diester (9).
proton H-14 to C-7 (δC 78.6), C-9 (δC 135.3), C-12 (δC 167.1)
and C-15 (δC 31.3) suggesting that the isopropyl group was
attached to C-13 of the diene system. Its position was proven
by HMBC correlations between H-15 and C-12, C-13, C-14,
C-16 and C-17.
The 13C NMR spectrum of 9 revealed the presence of 23
carbon atoms. The multiplicity of the carbon atoms was deter-
mined by analysis of the DEPT-90 and DEPT-135 experimen-
tal data and revealed the presence of five methines including
three carbons linked to an oxygen function (δC 50.3, 73.8 and
78.6), three methylenes, and seven methyl carbons of which
three of the methyl groups (δC 51.6, 52.1 and 59.7) were linked
to an oxygen function, and finally eight quaternary carbons,
including three carbonyl carbons (δC 166.1, 167.1, 176.4). Four
of the carbon signals were in the double bond region [δC 129.9
(d), 135.3 (s), 136.9 (s) and 143.1 (s)] suggesting the presence
of diene in the structure of 9. Analysis of all of the above data,
led to the structure for 9 as 7α-O-methyl-11,12-seco-8,13-
abietadien-20,6β-lacton-11,12-dioic acid dimethyl ester.
Consequently, we confirmed the structure of anhydride 8.
Reaction of rosmaquinone B (7) with m-CPBA
Conclusion
Solid NaHCO3 (104.0 mg, 1.24 mmol, 13.3 eq) and m-CPBA (50.1 g,
0.29 mmol, 3.12 equiv.) were added to a solution of rosmaquinone B
(7) (33.3 mg, 0.093 mmol) in dry dichloromethane (15 mL) at room
temperature under nitrogen atmosphere. The reaction mixture was
stirred at room temperature for 24 h and then filtered through Celite.
The filtrate was evaporated under reduced pressure, and the crude
product was chromatographed on Sephadex LH-20 using acetone as
the eluent to give 7α-O-methyl-11,12-seco-11,12-epoxy-11,12-dioxo-
8,13-abietadien-20,6β-olide 8 (6.7 mg, 37.9%).
7α-O-Methyl-11,12-seco-11,12-epoxy-11,12-dioxo-8,13-abietadien-
20,6β-olide (8): Colourless syrup. 1H NMR (300 MHz, CDCl3): 0.85
(3H, s, Me-19), 1.01 (3H, s, Me-18), 1.12 (3H, d, J = 7.0 Hz, Me-16),
1.19 (3H, d, J = 7.0 Hz, Me-17), 1.98 (1H, s, H-5), 2.62 (1H, bd,
J = 13.2 Hz, H-1β), 2.94 (1H, hept, J = 7.0 Hz, H-15), 3.45 (3H, s,
–OCH3), 3.87 (1H, d, J = 2.9 Hz, H-6), 4.60 (1H, d, J = 2.9 Hz, H-7),
6.22 (1H, s, H-14).
In conclusion, an efficient method to obtain new derivatives of
rosmic acid (2) through the oxidation of the aromatic ring C in
abietatriene diterpenes is presented. The oxidation was carried
out with lead tetraacetate and m-CPBA. We obtained the best
results with lead tetraacetate. In the case of the oxidation with
m-CPBA, we tried two strategies: 1. The 7α-O-methylrosma-
nol (4) was first oxidised to rosmaquinone B (7), which
was then treated with m-CPBA; 2. We tried directly oxidise
7α-O-methylrosmanol. In this case, the yield of the one-step
reaction (39.2%) was higher that the synthetic sequence in two
steps (overall yield 31.9%). In this process we have obtained
three new C-ring opened abietane diterpenes by partial synthe-
sis from rosmanol (3) and 7α-O-methylrosmanol (4), which
were both obtained from carnosol (1).
Methylation of 7α-O-methyl-11,12-seco-11,12-epoxy-11,12-dioxo-
8,13-abietadien-20,6β-olide (8): The freshly prepared anhydride (8)
(23.3 mg, 0.0622 mmol) was dissolved in a mixture of acetone–water
(5 ml, 9:1) and cooled to 0 °C under a nitrogen atmosphere. Then solid
potassium carbonate (178.5 mg, 1.29 mmol, 20.7 equiv.) and methyl
iodide (0.25 mL, 4.02 mmol, 64.6 eq) were added. After 12 h, 10 mL
of water was added and the reaction mixture was extracted withAcOEt
(3x10 mL). The organic layers were washed with 15 mL of brine and
dried over anhydrous Na2SO4. The solvent was evaporated on under
reduced pressure, and the crude extract was purified by preparative
TLC using n-hexane/ethyl acetate (7:3) as eluent to give compound 9
(21.2 mg, 81.1%).
7α-O-Methyl-11,12-seco-8,13-abietadien-20,6β-lacton-11,12-dioic
acid dimethyl ester (9): Colourless syrup. UV (EtOH) λmax (log ε) nm
248 (3.56); IR (NaCl) νmax cm−1 2925, 2854, 1788, 1731, 1461, 1374,
1307, 1220, 1176, 1087, 1003, 960; 1H NMR (300 MHz, CDCl3): 0.87
(3H, s, Me-19), 0.94 (3H, s, Me-18), 1.06 (3H, d, J = 7.0 Hz, Me-16),
1.08 (3H, d, J = 7.0 Hz, Me-17), 2.05 (1H, s, H-5), 2.76 (1H, hept,
J = 7.0 Hz, H-15), 3.51 (3H, s, –OCH3), 3.64 (3H, s, –OCH3), 3.67
(3H, s, –OCH3), 3.84 (1H, d, J = 3.0 Hz, H-6), 4.53 (1H, d, J = 3.0 Hz,
H-7), 6.40 (1H, s, H-14). 13C NMR (75 MHz, CDCl3): 18.1 (t, C-2),
21.4 (q, C-18), 21.6 (q, C-16), 21.8 (q, C-17), 21.9 (q, C-19), 24.4 (t,
Experimental
IR spectrum (film on NaCl pellets) were obtained in the 400–
4000 cm−1 range using a Bruker IFS 28/55 (FTIR) spectrometer. The
NMR spectra were recorded on Bruker Avance 300 MHz and Bruker
Avance 400 MHz spectrometers in CDCl3. Chemical shifts are given
in ppm with TMS as the internal standard. Low-resolution mass
spectra were run on a VG Micromass ZAB-2F and high-resolution
mass spectra on a VG Micromass ZAB-2F at 70 eV. The solvents used
for purification were distilled prior to use. Merck silica gel (0.063–
0.2 mm) was used for column chromatography. Analytical thin-layer
chromatography (TLC) and preparative TLC were carried out on pre-
coated Schleicher and Schüll plates. Compounds were detected either
under UV light (at 254 nm) or by spraying with a mixture of acetic
acid:water:sulfuric acid, 80:16:4.
Reaction of rosmanol (3) with lead tetraacetate
A solution of rosmanol (3) (17 mg, 0.0491 mmol) in benzene:metha-
nol (2 mL, 1:1) was added to a solution of lead tetraacetate (72.3 mg,
0.163 mmol, 3.32 eq) in 4 mL of a mixture of Benzene/MeOH (1:1) at
0 ºC under nitrogen atmosphere. After stirring the reaction mixture for
48 h at room temperature, the solvent was distilled off under reduced

196 JOURNAL OF CHEMICAL RESEARCH 2013
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C-1), 30.9 (s, C-4), 31.3 (d, C-15), 38.3 (t, C-3), 44.2 (s, C-10), 50.3
(d, C-5), 51.6 (q, –OCH3), 52.1 (q, –OCH3), 59.7 (q, –OCH3), 73.8 (d,
C-6), 78.6 (d, C-7), 129.9 (d, C-14), 135.3 (s, C-9), 136.9 (s, C-8),
143.1 (s, C-13), 166.1 (s, C-11), 167.1 (s, C-12), 176.4 (s, C-20);
EI-MS m/z (%): 420 [M]+ (13), 377 (17), 361 (100), 269 (5), 139 (4),
69 (6), 57 (8); HR-EI-MS m/z [M]+ 420.2148 calcd for C23H32O7,
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5
6
7
8
9
This work was economically supported by SIP–IPN under
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Received 5 January 2013; accepted 25 January 2013
Paper 1301706 doi: 10.3184/174751913X13618945224197
Published online: 19 April 2013
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