Facile and simple synthesis of ring C aromatic diterpenes: Synthesis of (+)-13-hydroxypodocarpa-8,11,13-triene and (+)-7-deoxynimbidiol

Article abstract of DOI:10.1080/00397911.2010.492078

A convenient synthesis of the natural (+)-13-hydroxypodocarpa-8,11,13- triene 1 and (+)-7-deoxynimbidiol 2 from (+)-manool 4 has been achieved in good overall yield.

Full text of DOI:10.1080/00397911.2010.492078

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Facile and Simple Synthesis of Ring
C Aromatic Diterpenes: Synthesis of
(+)-13-Hydroxypodocarpa-8,11,13-triene
and (+)-7-Deoxynimbidiol
José E. Villamizar a , Carlos Gamez a , Antonio Alcalá a , Franklin
Salazar a , Eleonora Tropper a , Ana Angarita a & Nieves Canudas b
a Centro de Química, Instituto Venezolano de Investigaciones
Científicas (I.V.I.C.), Caracas, Venezuela
b Departamento de Química, Universidad Simón Bolívar, Caracas,
Venezuela
Version of record first published: 29 Apr 2011.
To cite this article: José E. Villamizar, Carlos Gamez, Antonio Alcalá, Franklin Salazar, Eleonora
Tropper, Ana Angarita & Nieves Canudas (2011): Facile and Simple Synthesis of Ring C Aromatic
Diterpenes: Synthesis of (+)-13-Hydroxypodocarpa-8,11,13-triene and (+)-7-Deoxynimbidiol, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:12, 1733-1741
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Synthetic Communications1, 41: 1733–1741, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.492078
FACILE AND SIMPLE SYNTHESIS OF RING C
AROMATIC DITERPENES: SYNTHESIS OF
(+)-13-HYDROXYPODOCARPA-8,11,13-TRIENE
AND (+)-7-DEOXYNIMBIDIOL
1
Jose E. Villamizar, Carlos Gamez, Antonio Alcala,
1
1
´
´
Franklin Salazar,1 Eleonora Tropper,1 Ana Angarita,1 and
Nieves Canudas2
1
´
Centro de Quımica, Instituto Venezolano de Investigaciones Cientıficas
(I.V.I.C.), Caracas, Venezuela
´
2
´
´
´
Departamento de Quımica, Universidad Simon Bolıvar, Caracas, Venezuela
GRAPHICAL ABSTRACT
Abstract A convenient synthesis of the natural (þ)-13-hydroxypodocarpa-8,11,13-triene 1
and (þ)-7-deoxynimbidiol 2 from (þ)-manool 4 has been achieved in good overall yield.
Keywords Abietane diterpenes; 7-deoxynimbidiol; nimbidiol; podocarpane diterpenes;
synthesis
INTRODUCTION
Abietane and biosynthetically related polycyclic diterpenes constitute a major
group of ring C aromatic diterpenes.[1] They have been reported to exhibit interesting
biological properties such as antibiotic, antivirus, antioxidant, antimalarial, and
cytotoxic activities.[2] Recently, some biologically active podocarpane phenols have
been isolated. In 2000, Kuo et al. isolated from the bark of Taiwania criptomeriodes
the podocarpane diterpene (þ)-13-hydroxypodocarpa-8,11,13-triene 1.[3] Recently,
Received January 28, 2010.
Address correspondence to Jose E. Villamizar, Centro de Quımica, Instituto Venezolano de
´
Investigaciones Cientıficas (I.V.I.C.), apartado 21827, Caracas 1020-A, Venezuela. E-mail: jvillami@
´
´
ivic.gob.ve
1733

1734
J. E. VILLAMIZAR ET AL.
Xiong et al. isolated from the stalks of Celastrus hypoleucus the podocarpane
diterpene (þ)-7-deoxynimbidiol 2, which has good antitumor activity[4] (Scheme 1).
To date, a number of synthetic investigations of these biologically active podo-
carpane diterpenes employing podocarpic acid, labdane diterpenes, or via polyene
cyclization have been reported.[5] However, they generally require long reaction
sequences, and furthermore, almost all of them produce the racemic form of the
natural substance.
(þ)-Manool 4 is a readily available natural diterpene with established absolute
stereochemistry. (þ)-Manool 4 has been used as a starting material for the efficient
syntheses of drimane-type sesquiterpenes,[6] podocarpane-type terpenes,[7] and
labdane-type diterpenes.[8] In these studies, two cleavage reactions (oxidative and
photochemical) were used sequentially to transform (þ)-manool 4 to the unstable
exocyclic diene in 52% overall yield. In 2003, Zambrano et al. reported the synthesis
of ring C aromatic diterpene derivative from (þ)-manool 4 via unstable intermedi-
ates and its synthetic application to the formal synthesis of (þ)-nimbidiol 3.[9]
Recently, Alvarez-Manzaneda et al. reported the synthesis of (þ)-7-deoxynimbidiol
2 from (ꢀ)-sclareol in 10 steps.[10]
As a part of our research program toward the synthesis of bioactive diterpene
compounds starting from natural diterpenes, we were interested in developing a
new route to ring C aromatic diterpenes, useful as a medicinal compound in which
antimicrobial properties and antioxidant activity are expected. This article presents
Scheme 1.

RING C AROMATIC DITERPENES
1735
a further extension of our work to the synthesis of podocarpane diterpene (þ)-
13-hydroxypodocarpa-8,11,13-triene 1 and (þ)-deoxynimbidiol 2 from (þ)-manool 4.
RESULTS AND DISCUSSION
Recently, Alvarez-Manzaneda Roldan et al. reported a new route to com-
pound 1 in seven steps via b-enone 7 from (þ)-sclareol.[11] The key step involves
the intramolecular aldol condensation of a trinorlabdane 1,5-diketone, aromatiza-
tion of the resulting b-enone, and benzylic oxidation. Previously, Nakano et al.[12]
reported the synthesis of b-enone 7 from (þ)-manool 4 in three steps. In an attempt
to increase the yield of the b-enone 7, (þ)-manool 4 was oxidized with anhydrous
KMnO4 in the presence of phase-transfer catalyst (CH3)C6H5NþClꢀ to obtain
ketone 5 in 90% yield.[13] Ozonolysis of ketone 5 afforded diketone 6. Intramolecular
aldol condensation utilizing a diluted solution of H2SO4 afford the desired com-
pound 7 in 80% yield.[14] To synthesize compound 1, we first tried aromatization
of b-enone 7 with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and SeO2. How-
ever, these methods failed to give compound 1. Aromatization of ring C was finally
achieved with a CuBr2=LiBr system,[15] yielding the desired compound 1 in 83% yield
along with only small amounts of compound 8 (Scheme 2). The spectroscopic data
were identical with the natural phenol, except the reported optical rotation value was
observed ([a]D þ 51, c 1.0, CHCl3, lit.[3] [a]D þ 16.7, c 0.43, CHCl3). Probably, the
difference between the optical rotation values can be due to the fact that the com-
pound 1, isolated by Kuo et al.,[3] was not pure and thus exhibits different values.
Compound 2 was synthesized via the 12-hydroxy-enone 10, which was
obtained from b-enone 7. Oxidation of compound 7 with manganese(III) acetate
Scheme 2. (i) O3, CH2Cl2, ꢀ78 ꢁC, 1 h; Zn, AcOH; (ii) H2SO4, MeOH, reflux; and (iii) CuBr2, LiBr,
CH3CN, rt, 10 min.

1736
J. E. VILLAMIZAR ET AL.
Scheme 3. (i) Mn(OAc)3, AcOH, benzene, reflux; (ii) K2CO3, MeOH, rt; (iii) CuBr2, LiBr, rt, 30 min; and
(iv) Ref. 5 [5g, 9, 10].
afforded acetate 9 in 80% yield.[16] To synthesize compound 2, we first tried aroma-
tization of acetate 9 with a CuBr2=LiBr system,[15] but unfortunately this method
gave the phenol 8. Deprotection of the acetate group of compound 9 with K2CO3
and aromatization of ring C of 12-hydroxy-enone 10 with CuBr2=LiBr system[15]
in CH3CN afforded the (þ)-deoxynimbidiol 2 in 61% yield, whose physical and spec-
troscopic data were identical to those reported.[4] The three-step conversions of 2 to
(þ)-nimbidiol 3 has been previously reported.[5g,9,10]
In summary, this work provides a short synthesis of natural ring C aromatic
diterpenes from (þ)-manool 4 (Scheme 3). The key intermediate for such preparation
is b-enone 7, which was easily prepared from (þ)-manool 4. Utilizing this, the synth-
eses of (þ)-13-hydroxypodocarpa-8,11,13-triene 1 and (þ)-7-deoxynimbidiol 2 have
been accomplished (54% and 32% overall yields from (þ)-manool 4). (þ)-Nimbidiol
3 has also been prepared (14% overall yield from (þ)-manool 4).
EXPERIMENTAL
Melting points were measured with a Kofler hot-stage apparatus and are
uncorrected. NMR spectra were recorded with Bruker Avance-300 and Avance-500
spectrometers. Infrared (IR) spectra were recorded using a Nicolet Magna 560
Fourier transform (FT)–IR spectrometer. High-resolution mass spectra (HRMS)
were obtained on a Jeol JMS-AX505WA mass spectrometer. Optical rotations were
obtained for CHCl3 solutions on a Perkin-Elmer 341 polarimeter, and their concen-
trations are expressed in g=100 mL. Manool resin was purchased from Westchem

RING C AROMATIC DITERPENES
1737
24
Industries, Ltd., and purified to obtain (þ)-manool, ½aꢂD þ 28 (c 1.5, CHCl3). Tetra-
hydrofuran (THF) and benzene were freshly distilled from Na-benzophenone before
use. CH2Cl2 was distilled from CaH2 under argon. All other solvents and reagents
were obtained from commercial suppliers and used without further purification.
Merck silica gel (70–230 mesh ASTM) was used for column chromatography.
Thin-layer chromatography (TLC) was performed on Analtech silica gel 60 G254
,
and the spots were observed either by exposure to iodine or by ultraviolet (UV) light.
All organic extracts were dried over MgSO4 and evaporated under reduced pressure
below 60 ꢁC.
14,15-Bisnorlabd-8(20)-ene-13-one (5)
KMnO4 (0.51 g, 3.22 mmol) and (CH3)3C6H5NþClꢀ (0.56 g, 3.25 mmol) were
added to a solution of manool 4 (1.04 g, 3.58 mmol) in CHCl3 (15 mL) and stirred
for 24 h at 10 ꢁC. The reaction mixture was filtered through silica gel, and the filtrate
was evaporated. The resulting crude product was chromatographed over silica gel,
and elution with 4% ether in hexane afforded ketone 5 (0.85 g, 90%) as a colorless
oil. The spectroscopic properties were similar to those reported in the literature.[1]
15,16,17-Trinorlabdane-8,13-dione (6)
A flow of ozone was applied to a solution of 5 (0.2 g, 0.76 mmol) in CH2Cl2
(5 mL) at 0 ꢁC until the solution became blue in color. The reaction mixture was
immediately degassed with N2 for 15 min, followed by dropwise addition of Zn
(200 mg) in AcOH (2 mL). The solution was allowed to warm to room temperature,
and stirring was continued for 2 h. The reaction mixture was filtered to remove the
Zn, after which 1.0 M NaHCO3 was added over 15 min and extracted with CHCl3.
The resulting crude product was chromatographed over silica gel, and elution with
5% ether in hexane afforded diketone 6 (0.180 g, 90%) as a colorless oil. The spectro-
scopic properties were similar to those reported in the literature.[11,12]
Podocarp-8(14)-en-13-one (6)
H2SO4 (0.6 mL) was added dropwise to a solution of diketone 6 (76 mg,
0.28 mmol) in methanol (5 mL) at room temperature. The solution was refluxed
for 2 h, diluted with water, and extracted with ether. The organic extract was dried
and evaporated, and the product was chromatographed over silica gel. Evaporation
of the hexane=ether (4%) elute afforded b-enone 7 (57 mg, 81%) as white crystals
(hexane): mp 90–91 ꢁC; IR (KBr) nmax 1674, 1617; HRMS m=z 246.1822 (Mþ,
C17H26O requires 246.1830); EIMS m=z 247 (45), 246 (14), 213 (6), 175 (5), 161
1
(7), 137 (60), 123 (60), 110 (100), 81 (62); H NMR (CDCl3, 300 MHz) d 0.76,
0.83, 0.88 (3H each, s, CH3), 2.04 (1H, m, H-9), 2.25 (1H, m, Ha-12), 2.52 (1H,
ddd, J ¼ 15.4, 4.71, 1.7 Hz, Hb-12), 5.82 (1H, dd, J ¼ 2.08, 1.88 Hz, H-14); 13C
NMR (CDCl3, 75.45 MHz) d 15.23, 18.68, 20.45, 21.89, 22.00, 33.32, 33.57, 35.58,
36.74, 38.90, 39.25, 41.71, 51.58, 53.85, 125.80, 165.64, and 199.76.

1738
J. E. VILLAMIZAR ET AL.
(þ)-13-Hydroxypodocarpa-8,11,13-triene (1)
The b-enone 7 (50 mg, 0.20 mmol) in dry CH3CN (2 mL) were added to CuBr2
(94.71 mg, 0.40 mmol) and LiBr (17.6 mg, 0.20 mmol), and the reaction mixture was
stirred for 10 min at room temperature. The reaction mixture was diluted with
AcOEt, washed with brine, dried, and evaporated, and the product was chromato-
graphed over silica gel. Elution with 3% ethyl acetate in hexane yielded only small
amounts of compound 8. Elution with 5% ethyl acetate in hexane afforded com-
pound 1 (41 mg, 83%) as white crystals (hexane): mp 125–127 ꢁC; ([a]D þ 51, c 1.0,
CHCl3) lit.[3] [a]D þ 16.7, c 0.43, CHCl3); IR (KBr) nmax 3264, 3052, 2995, 1585,
1238; HRMS m=z 244.1822 (Mþ, C17H24O requires 244.1830); EIMS m=z 244
1
(14), 229 (M-CH3, 100), 201 (7), 159 (34), 147 (54), 133 (52), 91 (11); H NMR
(CDCl3, 300 MHz) d 0.89, 0.92, 1.13 (3H each, s, CH3), 4.51 (1H, bs, OH), 6.48
(1H, d, J ¼ 2.6 Hz), 6.58 (1H, dd, J ¼ 8.5 2.6 Hz), 7.09 (1H, d, J ¼ 8.5 Hz); 13C
NMR (CDCl3, 75.45 MHz) d 18.95, 19.31, 21.57, 24.94, 30.44, 33.30, 33.38, 37.27,
39.09, 41.69, 50.55, 112.84, 114.83, 125.65, 136.89, 142.91, and 152.77.
Podocarp-8(14)-en-13-one-12a-yl Acetate (9)
Manganese(III) acetate (1.75 g, 6.52 mmol) in acetic acid (5 mL) was added to a
solution of the b-enone 7 0.541 g (2.2 mmol) in dry benzene (5 mL). The resulting sus-
pension was heated to 80 ꢁC for 48 h. The reaction mixture was filtered through silica
gel and eluted with AcOEt, and the filtrate was washed with HCl 2 M solution, satu-
rated 10% NaHCO3 solution, and brine, which were evaporated under reduced
pressure. The product was chromatographed over silica gel. Elution with 5% AcOEt
in hexane afforded acetate 9 (0.520 g, 78%) as a white crystals (hexane): mp
117–119 ꢁC; [a]D ꢀ 56 (c 1.0, CHCl3); IR (KBr) nmax 2923, 1740, 1685, 1618; HRMS
m=z 327.3712 ([M þ Na]þ C18H29O3Na requires 327.4260); 1H NMR (CDCl3,
300 MHz) d 0.82, 0.88, 0.95 (3H each, s, CH3), 2.08 (3H, s, COCH3), 2.49 (1H,
dd, J ¼ 11.49 1.86 Hz), 5.35 (1H, J ¼ 11.10 5.49 Hz), 5.85 (1H, s, H-14); 13C NMR
(CDCl3, 75.45 MHz) d 15.85, 18.87, 20.89, 21.73, 23.41, 26.63, 33.44, 33.68, 36.58,
39.53, 41.33, 41.78, 50.40, 54.52, 71.29, 123.20, 166.14, 170.15, and 193.63.
13-Hydroxypodocarpa-6,8,11,13-tetraene (8)
CuBr2 (71.36 mg, 0.32 mmol) and LiBr (14 mg, 0.16 mmol) were added to a sol-
ution of the acetate 9 (50 mg, 0.16 mmol) in dry CH3CN (3 mL) and stirred for
30 min at room temperature. The reaction mixture was diluted with AcOEt washed
with brine, dried, evaporated under reduced pressure, and chromatographed over sil-
ica gel. Elution with 4% ethyl acetate in hexane afforded compound 8 (23 mg, 58%)
as an oil; IR (KBr) nmax 3264, 3052, 2995, 1585, 1238; HRMS m=z 242.1670 (Mþ,
1
C17H22O requires 242.3540); H NMR (CDCl3, 300 MHz) d 0.96, 1.02, 1.03 (3H
each, s, CH3), 2.10 (1H, bs), 2.15 (1H, m), 4.94 (1H, bs, OH), 6.02 (1H, dd,
J ¼ 9.63 2.67 Hz), 6.45 (1H, dd, J ¼ 9.63 2.67 Hz), 6.53 (1H, d, J ¼ 2.7 Hz), 6.54
(1H, dd, J ¼ 8.31 2.7 Hz), 7.02 (1H, d, J ¼ 8.31 Hz); 13C NMR (CDCl3,
75.45 MHz) d 18.94, 20.47, 22.47, 32.56, 32.73, 36.12, 37.42, 40.97, 51.33, 113.01,
113.78, 123.08, 127.23, 131.31, 134.21, 141.10, and 153.27.

RING C AROMATIC DITERPENES
1739
Podocarp-8(14)-en-12a-hydroxy-13-one (10)
Acetate 9 (121 mg, 0.40 mmol) was treated with K2CO3 (50 mg, 0.43 mmol)
in MeOH (3 mL) and stirred at room temperature for 1 h. The solution was then
acidified with hydrochloric acid, diluted with water, and extracted with AcOEt.
The organic extracted was dried, evaporated under reduced pressure, and chromato-
graphed over silica gel. Elution with 10% AcOEt in hexane afforded compound 10
(101 mg, 97%) as a colorless oil. The spectroscopic properties were similar to those
reported in the literature.[12]
(þ)-Deoxynimbidiol (2)
The 12-hydroxy-enone 10 (40 mg, 0.15 mmol) in dry CH3CN (2 mL) were
added to CuBr2 (66 mg, 0.29 mmol) and LiBr (13 mg, 0.15 mmol), and the reaction
mixture was stirred for 10 min at room temperature. The reaction mixture was
diluted with water and extracted with AcOEt. The organic extract was washed with
brine, evaporated, and chromatographed over silica gel. Elution with ethyl acetate in
hexane (1:1) afforded compound 2 (24 mg, 61%) as crystal (hexane): mp 88–90 ꢁC;
[a]D þ 38 (c 1.0, MeOH), lit.[4] [a]D þ 49.44 (c 0.1, MeOH); IR (KBr) nmax 3360,
1
1609, 1520; HRMS m=z 283.1669 ([M þ Na]þ C17H24O2Na requires 283.1670); H
NMR (CDCl3, 300 MHz) d 0.88, 0.91, 1.12 (3H each, s, CH3), 1.45 (1H, bd,
J ¼ 13.8 Hz), 2.12 (1H, bd, J ¼ 12 Hz), 2.74 (1H, m), 2.80 (1H, m), 4.99 (2H, bs,
OH), 6.50 (1H, s), 6.74 (1H, s); 13C NMR (CDCl3, 75.45 MHz) d 19.32, 19.50,
21.81, 25.10, 30.01, 33.52, 33.60, 37.64, 39.35, 41.88, 50.82, 111.72, 115.43, 128.33,
141.28, 141.58, and 143.59.
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