Enantioselective total syntheses of 13-acetyl-12-hydroxy-podocarpane-8,11,13-triene-7-one

Article abstract of DOI:10.1081/SCC-120002407

A enantioselective total synthetic route to (+)-13-acteyl-12-hydroxy-podocarpane-8,11,13-triene-7-one la and (-)-13-acetyl-12-hydroxy-podocarpane-8,11,13-triene-7-one 1b from (S)-(-)-α-cyclocitral 8a and (R)-(+)-α-cyclocitral 8b was developed.

Full text of DOI:10.1081/SCC-120002407

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ENANTIOSELECTIVE TOTAL SYNTHESES OF 13-
ACETYL- 12-HYDROXY-PODOCARPANE- 8,11,13-
TRIENE-7-ONE
Anpai Li a , Pingyan Bie a , Xiaoshui Peng a , Tongxing Wu a , Xinfu Pan b , Albert S. C.
Chan c & Teng-Kuei Yang d
a Department of Chemistry , National Laboratory of Applied Organic Chemistry , Lanzhou
University , Lanzhou Gansu, 730000, P. R. China
b Department of Chemistry , National Laboratory of Applied Organic Chemistry , Lanzhou
University , Lanzhou Gansu, 730000, P. R. China
c Union Laboratory of Asymmetry Synthesis and Department of Applied Biology and
Chemical Technology , The Hong Kong Polytechnic University , Hong Kong
d Department of Chemistry , National Chung-Hsing University , Taichung, Taiwan
Published online: 16 Aug 2006.
To cite this article: Anpai Li , Pingyan Bie , Xiaoshui Peng , Tongxing Wu , Xinfu Pan , Albert S. C. Chan & Teng-Kuei Yang
(2002) ENANTIOSELECTIVE TOTAL SYNTHESES OF 13-ACETYL- 12-HYDROXY-PODOCARPANE- 8,11,13-TRIENE-7-ONE, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:4, 605-610, DOI:
10.1081/SCC-120002407
To link to this article: http://dx.doi.org/10.1081/SCC-120002407
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SYNTHETIC COMMUNICATIONS, 32(4), 605–610 (2002)
ENANTIOSELECTIVE TOTAL
SYNTHESES OF 13-ACETYL-
12-HYDROXY-PODOCARPANE-
8,11,13-TRIENE-7-ONE
Anpai Li,1 Pingyan Bie,1 Xiaoshui Peng,1
Tongxing Wu,1 Xinfu Pan,1, Albert S. C. Chan,2
*
and Teng-Kuei Yang3
1Department of Chemistry, National Laboratory of
Applied Organic Chemistry, Lanzhou University,
Lanzhou Gansu 730000, P. R. China
2Union Laboratory of Asymmetry Synthesis and
Department of Applied Biology and Chemical
Technology, The Hong Kong Polytechnic
University, Hong Kong
3Department of Chemistry, National Chung-Hsing
University, Taichung, Taiwan
ABSTRACT
A enantioselective total synthetic route to (þ)-13-acteyl-12-
hydroxy-podocarpane-8,11,13-triene-7-one 1a and (À)-13-
acetyl-12-hydroxy-podocarpane-8,11,13-triene-7-one 1b from
(S)-(À)-a-cyclocitral 8a and (R)-(þ)-a-cyclocitral 8b was
developed.
*Corresponding author.
605
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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Many diterpenoids exhibit significant bioactivities, such as: anti-
bacterial,1,2 antidermatophytic,2,3 antioxidant,4 etc. Nimbosodione is a
diterpenoid isolated by Siddiqui and his co-workers from the stem bark of
Azadirachta and assigned the structure 1 based mostly on spectral evidence,5
but Sukumer et al. report the synthesis of the racemic dioxophenol 1 and the
spectral data of which differ considerably from those reported for
Nimbosodione.6 In order to study the relationship between the structure
and bioactivities, and to further clarify the structure of Nimbosodione,
it is desirable to develop a novel route to the trans isomer 4. This key
intermediate was obtained in low yield by King, but it is not stereospecific.7
In connection with our synthetic studies on a series of natural occurring
diterpenes,8,9 we report herein a high yield stereoselective synthetic
route to (þ)-13-acetyl-12-hydroxy-podocarpane-8,11,13-triene-7-one 1a and
(À)-13-acetyl-12-hydroxy-podocarpane-8,11,13-triene-7-one 1b.
As shown in Scheme 1, our synthetic strategy to build the ring struc-
ture is AC ! ABC. We used p-anisic acid as the C ring starting material,
(S)-(À)-a-cyclocitral 8a and (R)-(þ)-a-cyclocitral 8b which were prepared
from geranic acid according to reference10 as the A ring starting material.
Condensation of 8a with 7 (prepared from Anisic acid via four steps in
high yield) in the presence of n-BuLi/hexane afforded the desired stilbene
1
derivative 6 in 70% yield. The H-NMR of 6 reveals a trans double bond
(the vicinal coupling constant of vinyl protons is 15.8 Hz). Selective hydro-
genation of 6 over 5% Pd/C give the phenethyl derivative 5. In the intra-
cyclization step, in order to get all-trans figure, we found BF3ÁEt2O in
CH2Cl2 at room temperature is better condition, which give sole trans
(HPLC and 1H-NMR7) isomer 4 in 93% yield. The compound 4 was acety-
lated by acetyl chloride and anhydrous AlCl3 in CH2Cl2 in ice bath to give
compound 3 in 90% yield. When the reaction was carried out at room
temperature, demethylation took place to give 1a from 2 in 95% yield.
Oxidation of 3 by CrO3/HOAc/H2O give compound 2. Although our
spectrum data were not identical with Siddiqui’s,5 same with Sukumer’s.6

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607
Thus the structure of Nimbosodione should not be the title compound
13-acteyl-12-hydroxy-podocarpane-8,11,13-triene-7-one 1.
Reagents and conditions: i) n-BuLi, n-hexane, r.t., 5 h (70%); ii) 5% Pd/C, ethanol
(95%); iii) BF3ÁEt2O, CH2Cl2, 12 h (93%); iv) acetyl chloride, anhydrous AlCl3,
À5ꢀC, 2 h, (90%); v) CrO3/HOAc/H2O, r.t., 0.5 h (90%) ; vi) anhydrous AlCl3,
CH2Cl2, r.t., 8 h (95%).
Scheme 1.
EXPERIMENTAL SECTION
1
The H-NMR and 13C-NMR data were recorded in CDCl3 solution
with Bruker Am-80 or Am-400 MHz spectrometers. The chemical shifts are
reported in ppm relative to TMS or CDCl3. Mass spectrum were reported
on a ZAB-Hs mass spectrometer (EI). Microanalyses were performed on
a MOD-1106 elemental analyser. Optical rotations were determined on a
JASCO J-20C polarimeter with a 0.2 dm tube. Chiral analysis was per-
formed on a Varian Dynamax SD-300 using Chiralcel column CDMPC
(150 Â 4.6 mmD) with hexane/isopropyl alcohol as eluent.
3-(4-Methoxystyryl)-2,4,4-trimethyl-1-cyclohexene 6
A solution of n-butyllithium in hexane (1.6 N, 5 mL) was added to
a suspension of 7 (4.8 g, 11.5 mmol) in dry hexane (30 mL), under an

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LI ET AL.
atmosphere of Ar and stirred at room temperature for 1 h. Then a solution of
8a (1 g, 7 mmol) in dry hexane (15 mL) was added over 10 min. The solution
was stirred for 4 h to complete the reaction then, poured into diluted
HCl, the mixture was extracted with ether, the combined organic
layer was washed with brine, dried with Na2SO4. The crude product
was purified by column chromatography to give the desired compound
6 (1.2 g, 70%). ([a]2D5-302 (c 0.25, CHCl3), e.e. 90% by HLPC), H-NMR
1
(80 MHz, CDCl3) d ppm 0.94 and 1.00 (s, each 3H), 1.63 (bs, 3H), 3.83
(s, 3H), 5.50 (brs, 1H), 6.00 (dd, J ¼ 9.4, 15.8 Hz, 1H), 6.40 (d, J ¼ 15 Hz,
1H), 6.88 (d, J ¼ 8.9 Hz, 2H), 7.34 (d, J ¼ 8.9 Hz, 2H). MS (EI): 256,
200, 185, 121 and 91. (Found: C, 84.56; H, 9.40. C18H24O requires C,
84.32; H, 9.44%).
3-(4-Methoxyphenylethyl)-2,4,4-trimethyl-1-cyclohexene 5
A suspension of 6 (1.0 g) and 5% Pd/C (0.3 g) in anhydrous ethanol
(20 mL) was stirred at room temperature in an atmosphere of hydrogen.
The reaction was monitored by TLC, when the reaction completed, the
mixture was filtered. The filtrate was evaporated in vacuo to yield the desired
compound 5 (0.95 g, 95%) as colorless oil. ([a]2D5-132 (c 0.08, CHCl3),
1
e.e. 92%). H-NMR (80 MHz, CDCl3) d ppm 0.91 and 1.00 (s, each 3H),
1.70 (bs, 3H), 3.80 (s, 3H), 5.34 (brs, 1H), 6.84 (d, J ¼ 8.6 Hz, 2H), 7.13
(d, J ¼ 8.6 Hz, 2H). MS (EI): 258, 243, 121, (Found: C, 83.55; H, 10.10.
C18H26O requires C, 83.67; H, 10.14%).
12-Methoxyl-podocarpane-8,11,13-triene 4
To a solution of 5 (0.8 g, 3.1 mmol) in CH2Cl2 (30 mL) was added
BF3ÁEt2O (1.8 mL) dropwise. The mixture was stood overnight. Then
50 mL of ether was added and the solution was neutralized with saturated
NaHCO3. The mixture was extracted with ether and the combined organic
layer was washed successively with saturated NaHCO3 and brine, then dried
with Na2SO4. Purification by column chromatography gave the all trans
compound 4 (0.75 g, 93%). ([a]D25-32 (c 0.10, CHCl3), e.e. 90%), H-NMR
1
(400 MHz, CDCl3) d ppm 0.99 (s, 6H), 1.24 (s, 3H), 1.32–2.37 (m, 11H), 3.82
(s, 3H), 6.70 (dd, J ¼ 8.0, 2.0 Hz, 1H), 6.85 (d, J ¼ 2.0 Hz, 1H), 6.93
(d, J ¼ 8.0 Hz, 1H). MS (EI): 258, 243, 187, 161, 121. (Found: C, 83.57;
H, 10.09. C18H26O requires C, 83.67; H, 10.14%).

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13-Acetyl-12-methoxyl-podocarpane-8,11,13-triene 3
609
At À10ꢀC, to a solution of 4 (0.65 g, 2.5 mmol) in CH2Cl2 (30 mL),
anhydrous AlCl3 (400 mg) was added portionwise, then acetyl chloride
(0.2 mL) was added dropwise to keep reaction temperature below À5ꢀC.
After stirring for 2 h at room temperature, the mixture was poured to ice–
water, extracted with CH2Cl2. The combined organic layer was successfully
washed with saturated NaHCO3 and brine, then dried with Na2SO4. After
column chromatography purification, the compound 3 was obtained
as yellowish oil (0.65 g, 90%). 1H-NMR (400 MHz, CDCl3) d ppm 0.91
(s, 3H), 0.95 (s, 3H), 1.21 (s, 3H), 1.32–2.37 (m, 11H), 2.58 (s, 3H), 3.87
(s, 3H), 6.83 (s, 1H), 7.44 (s, 1H). MS (EI): 300, 285, 256, 203, 163, 91.
(Found: C, 79.73; H, 9.15. C20H28O2 requires C, 79.96; H, 9.39%).
13-Acetyl-12-methoxyl-podocarpane-8,11,13-triene-7-one 2
A solution of 3 (0.6 g, 2 mmol) in acetic acid (10 mL) was added CrO3
(2.5 mmol) in acetic acid (10 mL and water 0.2 mL) at room temperature, the
mixture was stirred for 0.5 h, then water was added to quench the reaction.
After extraction with ether, the combined organic layer was washed with
saturated NaHCO3 and brine. Purification by column chromatography gave
the compound 2 (0.58 g, 90%) as a white pellet crystals m.p. 190–192ꢀC.
([a]2D5 þ 54 (c 0.05, CHCL3), e.e. 90%, HLPC), 1H-NMR (400 MHz, CDCl3)
d ppm 0.95 and 1.01 (s, each 3H), 1.27 (s, 3H), 1.27 (d, 3H), 1.29–2.57 (m,
7H), 2.58 (s, 3H), 2.60–2.74 (m, 2H), 3.98 (s, 3H), 6.89 (s, 1H), 8.38 (s, 1H).
13C-NMR (100 MHz, CDCl3) d ppm 18.76, 21.36, 23.12, 31.33, 32.51, 33.28,
36.87, 37.83, 38.78, 41.17, 49.10, 55.78, 106.02, 124.30, 126.79, 130.78,
162.00, 162.50, 197.37, 198.51. MS (EI): 314, 299, 217, 111, 85, 69, 43.
(Found: C, 76.41; H, 8.29. C20H26O3 requires C, 76.39; H, 8.33%).
(Q)-13-Acetyl-12-hydroxy-podocarpane-8,11,13-triene-7-one 1a
Under Ar, to a solution of 2 (315 mg, 1 mmol) in CH2Cl2 (15 mL),
anhydrous AlCl3 (400 mg) was added portionwise at À10ꢀC, 10 min
later, keep reaction at room temperature. After stirring overnight, the
mixture was poured into ice–water, extracted with CH2Cl2. The combined
organic layer was successfully washed with saturated NaHCO3 and brine,
then dried with Na2SO4. After column chromatography purification,
the compound 1a was obtained as white pellet (280 mg, 95%). m.p.
234–235ꢀC. ([a]D25 þ 36 (c 0.05, CHCl3), e.e. 90%, HLPC) 1H-NMR

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(400 MHz, CDCl3) d ppm 0.90 (s, 3H), 0.95 (s, 3H), 1.18 (s, 3H), 1.23–2.26
(m, 7H), 2.63 (s, 3H), 2.55–2.66 (m, 2H), 6.89 (s, 1H), 8.43 (s, 1H), 12.55 (s,
1H). 13C-NMR (100 MHz, CDCl3) d ppm 18.56, 21.26, 22.76, 26.43, 32.58,
33.24, 35.69, 37.40, 38.53, 41.32, 48.45, 112.78, 117.64, 123.10, 131.35,
164.24, 166.19, 197.04, 204.41. MS (EI): 300, 285, 217, 203, 189, 177, 91,
69, 43. (Found: C, 76.01; H, 8.02. C19H24O3 requires C, 75.96; H, 8.05%).
(R)-13-Acetyl-12-hydroxy-podocarpane-8,11,13-triene-7-one 1b
Prepared by above method from compound 8b ([a]2D5-34 (c 0.05,
CHCl3), e.e. 90%).
ACKNOWLEDGMENTS
Support from the National Natural Science Foundation of China is
gratefully acknowledged (grant No. 29372050).
REFERENCES
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3. Luo, H.W.; Chen, S.X.; Lee, J.N.; Synder, J.K. Phytochemistry 1988,
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4. Houlihan, C.M.; Ho, C.T.; Chang, S.S. J. Am. Oil. Chem. Soc. 1985,
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5. Ara, I.; Siddiqui, B.S. J. Nat. Prod. 1990, 53, 816.
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Received in Japan November 13, 2000

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