A convenient strategy for the total synthesis of pisiferic acid type diterpenes

Article abstract of DOI:10.1081/SCC-200046500

A practical method for the total synthesis of pisiferic acid type diterpenoids is described. This involves Robinson annulation of the keto ester for the key intermediate.

Full text of DOI:10.1081/SCC-200046500

This article was downloaded by: [Harvard Library]
On: 05 October 2014, At: 09:04
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
A Convenient Strategy for the
Total Synthesis of Pisiferic Acid
Type Diterpenes
Hui Zhu a & Pengfei Tu a
a School of Pharmaceutical Sciences , Health Science
Center of Peking University , Beijing, 100083, China
Published online: 05 Aug 2006.
To cite this article: Hui Zhu & Pengfei Tu (2005) A Convenient Strategy for the
Total Synthesis of Pisiferic Acid Type Diterpenes, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:1,
71-78, DOI: 10.1081/SCC-200046500
To link to this article: http://dx.doi.org/10.1081/SCC-200046500
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,

and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 35: 71–78, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200046500
A Convenient Strategy for the Total
Synthesis of Pisiferic Acid Type Diterpenes
Hui Zhu and Pengfei Tu
School of Pharmaceutical Sciences, Health Science Center of Peking
University, Beijing, China
Abstract: A practical method for the total synthesis of pisiferic acid type diterpenoids
is described. This involves Robinson annulation of the keto ester for the key
intermediate.
Keywords: Diterpenoid, pisiferic acid, robinson annulation, total synthesis
INTRODUCTION
(þ)-Pisiferic acid 1 (Scheme 1) is a kind of C-aromatic tricyclic diterpene
acids, which was first isolated from the leaves and twigs of Chamacecpyparis
pisifers Endle in 1978.[1] Since then, the isolation of other structural related
compounds, such as (þ)-pisiferial 2,[2] (þ)-pisiferol 3,[3] (þ)-O-methyl
pisiferic acid 4,[2] (þ)-O-methyl pisiferate 5,[2] and (þ)-blephaein 6,[4] were
reported. These natural products have many important biological activities,
such as antimicrobial activity[5] and regulating mite growth activity.[6] This
triggered many interests for their synthesis.
Pisiferic acids are different from the other C-aromatic tricycle diterpe-
noids because they have a unique oxidized angular group instead of a
methyl angular group. In the case of a methyl angular group, the tricycle
framework can be established easily using cyclization catalyzed by Lewis
acids, and their total syntheses have been fully studied.[7] However, the
Received in Japan April 22, 2004
Address correspondence to Pengfei Tu, School of Pharmaceutical Sciences, Health
Science Center of Peking University, Beijing 100083, China. Fax: þ86 10 82802750;
E-mail: zhuhui360@sohu.com or pengfeitu@bjmu.edu.cn

72
H. Zhu and P. Tu
Scheme 1.
unique oxidized angular group of pisiferic acids makes their total synthesis
difficult. Mori et al. reported a route for the total synthesis of (+)-Pisiferol.
It started from a Wieland-Miescher ketone[8] and followed by mutisteps
construction of the aromatic C-ring. Similar approaches have also been
published.[9–11] Another strategy was reported by Mukherjee et al., where
aryl participated intramolecular cyclization of the diazomethyl ketone was
applied.[12,13] All the reported methods have some limitations, such as
tedious synthetic procedures, difficulty in practice, low overall yield, and
starting materials that are commercially unavailable.
We aimed to develop a new methodology for the synthesis of pisiferic
acids and their analogues, which would be feasible in practical and useful
for elucidating their structure and activity relationship. The method
involved the initial synthesis of a key intermediate. The catalytic hydrogen-
ation of the intermediate would generate the trans-stereochemistry at the
A/B ring junction[14] and can be applied for further synthesis. Here, we
reported a practical approach for the synthesis of the key intermediate
(Scheme 2, compound 13) using Robinson annulation.
RESULTS AND DISSCUSSION
The alkoxynaphthalene 8 (scheme 2) was prepared from the commercially
available 2,7-dihydroxynaphalene 7 in 97% yield.[15,16] The dihydro enol
ether 9 was synthesized by the selective Birch reduction of 8.[17] The selectiv-
ity in the reduction was due to a highly resonance stabilized benzene structure
of 9, which inhibited its further reduction. The reaction conditions have been
optimized, showing that 2.6 equivalent of metallic sodium produced a good
yield. Acid hydrolysis of 9 yielded the 2-tetralon 10 in 80% overall yield.

A Convenient Strategy for Synthesis of Pisiferic Acid Type Diterpenes
73
Scheme 2. Reagents and Conditions: (a) 10% NaOH, Me2SO4; (b) Na, NH3(l);
(c) 3 N HCl, Acetone, rt, 3 h; (d) NaH, CO(OCH3)2, Benzene, reflux; (e) CH3ONa,
CH3OH, EVK; (f) t-BuOK, t-BuOH, CH3I, 50–608C.
In order to synthesize the tricyclic intermediate 13, it is critical to
introduce a carboxylic group at the angular position. Our initial attempt was
to carboxymethylate the 2-tetralone 10 using the classic enamine
method.[18] It started with conversion of 10 into the corresponding enamine
by the procedure of Stork with tetrahydropyrrole. A subsequent reaction of
the enamine with methyl chloroformate yielded only 15% keto ester 11. An
improved method has been explored later using a similar approach for the
high-yield carboxymethylation of 6-methyl-5- heptene-2-one.[19] The keto
ester 11 has been prepared in a quantitative yield by the reaction of 10 with
dimethyl carbonate and excess of sodium hydride in benzene. Worthy to
1
note, most of 11 was in its enolic form as determined by H NMR.
For the further construction of the A-cycle, 11 was reacted with ethyl
vinyl ketone (EVK) to yield the tricyclic nucleus 12 using Robinson annula-
tion.[20] Under the classic refluxing condition,[20] the reactants were too
complex to isolate 12. However, when the reaction was stirred overnight at
room temperature using sodium methoxy as the base, a high yield of 12
was been achieved directly, which did not need further base-catalyzed intra-
t
molecular aldol cyclization. The subsequent reaction of 12 with BuOK and
CH3I at 50–608C for 5 h gave the key intermediate 13 in 63% yield. Its
structure has been determined by various NMR spectrums.
In summary, a practical route for the total synthesis of pisiferic acid type
diterpenoids has been developed. It started with a commercially available
reagent and used Robinson annulation of the keto ester in one-step reaction
for its key intermediate. Works are continuing in our lab for the total

74
H. Zhu and P. Tu
synthesis and the asymmetric total synthesis of similar natural products and
their derivatives.
EXPERIMENTAL
All commercially obtained chemicals were used as received. Tetrahydrofuran
(THF) and Benzene were freshly distilled from sodium/benzophenone ketyl.
Methanol was dried over Magnesium. tBuOH was dried over sodium. tBuOK
was purchased from Aldrich Company. Melting points were uncorrected. IR
spectra were recorded on an Avatar Nicolet 360 system infrared spectropho-
1
tometer. H NMR and 13C NMR spectra were recorded on a Buker AC-
400 MHz spectrometer. Chemical shifts (d) were given in ppm relative to
TMS and coupling constants (J) were given in Hz. ESI mass spectra were
acquired using a Bruker Esquire-LC ion trap mass spectrometer in positive
ion mode. High-resolution ESI mass spectra were obtained on a Bruker
APEX II spectrometer in positive ion mode.
7-Methoxy-2-tetralone 10
To a solution of alkoxynaphthalene 8 (10 g, 5.3 mmol) in anhydrous ethanol
(50 mL), liquid ammonia (about 200 mL) was condensed. Metallic sodium
(3.1 g, 13.5 mmol) was added in small pieces. After the solution’s blue color
disappeared, excess ammonium chloride (10 g) was added in portions. The
reaction mixture was kept at room temperature until most of the ammonia
was evaporated. The residue was poured into water (100 mL), then acidified
to pH 5 with 3 N hydrochloric acid and extracted with ether (3 ꢀ 100 mL).
The combined organic extracts were washed with brine and then dried over
sodium sulfate and evaporated. The crude product 9 can be used without
further purification.
A solution of 9 in acetone (50 mL) and hydrochloric acid (3N, 10 mL) was
refluxed for 30 min under Argon. Acetone was evaporated off and the aqueous
phase was extracted with ether (3 ꢀ 50 mL). The combined organic extracts
were washed with brine, dried over sodium sulfate, filtered, and evaporated.
Purification by vacuum distillation gave 10 (8.2 g, 88.0% yield) as a
colorless solid.
IR: 3000, 2947, 1716, 1611, 1504, 1261, 1154, 1038, 813
1H NMR (CDCl3, 300 MHz): 7.14 (d, 1H, J ¼ 8.4 Hz), 6.76 (dd, 1H,
J ¼ 2.4 Hz, J ¼ 8.4 Hz), 6.67(d, 1H, J ¼ 2.4 Hz), 3.79(s, 3H), 3.55(s, 2H),
3.00(t, 2H, J ¼ 6.6 Hz), 2.54(t, 2H, J ¼ 6.6 Hz)
ESI-MS(þ): 199 (M þ Na)þ

A Convenient Strategy for Synthesis of Pisiferic Acid Type Diterpenes
Methyl 7-Methoxy-2-oxotertralin-1-carboxylate 11
75
NaH (50%) (2.6g, 54mmol) was washed with dry petroleum ether three times
(20 mL ꢀ 3). After the petroleum ether was decanted, dry benzene (50 mL)
and dimethyl carbonate (3.2mL, 38mmol) were added. The mixture was
heated to reflux. A solution of 7-Methoxy-2-tetralone 10 (3.33 g, 18.9mmol) in
dry benzene (20 mL) was added slowly during 1 h under Argon. The reaction
mixture was refluxed for another 2 h and then stirred overnight at room temp-
erature. Acetic acid (10 mL) was added carefully to destroy excess NaH. Then
the mixture was poured into ice water (100mL). The product was extracted
with ethyl acetate (3 ꢀ 100 mL). The combined extracts were washed with
water, brine, and dried over sodium sulfate. After the solvent was removed
under reduced pressure, purification by vacuum column chromatography on
silica gel (eluant: petroleum ether/ethyl acetate 20: 1) gave the 11 (4.40 g) in
almost quantitative yield as colorless oil, which solidified in the refrigerator.
IR: 2951, 1640, 1605, 1489, 1447, 1319, 1234, 873
1H NMR (CDCl3, 400 MHz): 13.39 (s, 1H), 7.29 (d, 1H, J ¼ 2.6 Hz), 7.00
(d, 1H, J ¼ 8.2 Hz), 6.59 (dd, 1H, J ¼ 2.6 Hz, J ¼ 8.2 Hz), 3.89 (s, 3H),
3.78 (s, 3H), 2.72 (t, 2H, J ¼ 7.5 Hz), 2.50 (t, 2H, J ¼ 7.5 Hz).
13C NMR (CDCl3): 178.9, 172.3, 158.1, 132.3, 127.5, 125.4, 112.8, 109.1,
99.7, 55.2, 51.6, 29.9, 26.7.
ESI-MS(þ): 257 (M þ Na)þ
6-Methoxy-1-methyl-2-oxo-3,4,9,10-tetrahydro-2H-phenanthrene-
4a-carboxylic acid methyl ester 12
To a stirred solution of keto ester 11 (1.807g, 7.72mmol) in dry methanol
(20mL), 30% (wt %) sodium methoxide in methanol (432mg, 8.00mmol) was
added slowly under Argon atmosphere at 08C. The obtained solution was
stirred for another 30min. The solution turned purple. Ethyl vinyl ketone
(EVK) (672mg, 8.00mmol) was added to the solution in one portion. The
solution was stirred overnight at room temperature. The mixture was acidified
to pH 4 with hydrochloric acid (1N). Most of the methanol was evaporated
under vacuum, and ether (100mL) was added. The ether was washed with 5%
NaCO3, water, brine, and dried over sodium sulfate. After removal of the
solvent under reduce pressure, purification by vacuum column chromatography
on silica (eluant: petroleum ether/ethyl acetate 8 : 1) gave the product 12 (1.12 g)
in 75.5% yield (based on recovered keto ester 650 mg) as colorless crystalline.
m.p.: 97–988C
IR: 3005, 2950, 1718, 1664, 1610, 1236, 1163, 865

76
H. Zhu and P. Tu
1H NMR (CDCl3, 400 MHz): 7.03 (d, 1H, J ¼ 8.3 Hz, H-14), 6.97 (d, 1H,
J ¼ 2.6 Hz, H-11), 6.73 (dd, 1H, J ¼ 2.6, J ¼ 8.33 Hz, H-13), 3.75 (s, 3H,
H-OCH3), 3.60 (s, 3H, H-CO2CH3), 2.90 (d ꢀ q, 1H), 2.70–2.84(m,4H),
2.56(m, 2H), 2.09(dt, 1H),1.82(s, 3H).
13C NMR (CDCl3): 197.2, 172.2, 158.5, 155.0, 138.4, 131.4, 129.4, 129.0,
112.6, 112.1, 55.2, 52.7, 51.2, 34.8, 33.8, 29.3, 27.8, 11.1.
ESI-MS(þ): 323 (M þ Na)þ.
HR ESI-MS(þ): 301.1428[M þ H]þ(calculated 301.1434)
6-Methoxy-1,1-dimethyl-2-oxo-1,3,4,9-tetrahydro-2H-
phenanthrene-4a-carboxylic acid methyl ester 13
Compound 12 (260mg, 0.87mmol) was added to a solution of tBuOK (100mg,
0.9 mmol) in tBuOH (10 mL) at 50–608C. The mixture was stirred for another
30min. Then, methyl iodide (128mg, 0.9 mmol) in dry THF (5mL) was added
slowly. The mixture was stirred for another 3 h. After being cooled to room
temperature, the mixture was acidified to pH 4 with 1 N hydrochloric acid.
The mixture was diluted with ether (100mL). The ether layer was washed
with 5% NaCO3, water, brine, and dried over sodium sulfate. After removal
of the solvent under reduced pressure, purification by vacuum column chrom-
atography on silica (eluant: petroleum ether/ethyl acetate 8 : 1) gave the
product 13 (167mg, 61% yield) yield as colorless crystalline.
m.p.: 112–1148C
IR: 2946, 1715, 1606, 1504, 1453, 1227, 826
1H NMR (CDCl3): 7.08 (d, 1H, J ¼ 8.38 Hz), 6.92(d, 1H, J ¼ 2.46 Hz),
6.80(dd, 1H, J ¼ 2.51 Hz, J ¼ 8.39 Hz), 6.12(dd, 1H, J ¼ 3.01 Hz,
J ¼ 4.72 Hz), 3.79(s, 3H, OCH3), 3.58(s, 3H, CO2CH3), 3.49(dd, 1H,
J ¼ 2.26 Hz, J ¼ 22.6 Hz), 3.46(d, 1H, J ¼ 4.8 Hz), 3.12(m, 1H),
3.02(m, 1H), 2.47(m,1H), 1.98(m, 1H), 1.35(s, 3H), 1.26(s, 3H);
13C NMR (CDCl3): 213.0, 174.5, 158.2, 139.6, 137.7, 129.0, 124.8, 122.5,
113.4, 111.0, 55.2, 52.4, 51.1, 49.1, 35.4, 34.1, 29.6, 27.4, 24.7.
ESI-MS(þ): 317 (M þ Na)þ.
HR ESI-MS(þ): 337.1415[M þ Na]þ(calculated 337.1410)
ACKNOWLEDGMENT
Financial support from the National Science Foundation of China (NSFC No.
39600183) is gratefully acknowledged.

A Convenient Strategy for Synthesis of Pisiferic Acid Type Diterpenes
REFERENCES
77
1. Fukui, H.; Koshimizu; Egawa, H.
A new diterpene with antimicrobial
activity from Chamaecyparis pisifera Endle. Agric. Biol. Chem. 1978, 42 (7),
1419–1423.
2. Yatagai, M.; Takashashi, T. New diterpenes from Chamaecyparis pisifera. Phyto-
chemistry 1980, 19 (6), 1149–1151.
3. Yatagai, M.; Takahashi, T. Diterpenes of the ferruginol type from Chamaecyparis
pisifera. Phytochemistry 1979, 18 (1), 176–176.
4. Ulubelen, A.; Oksuz, S.; Topcu, G.; Goren, A. C.; Voelter, W. Antibacterial diter-
penes from the roots of Salvia blepharochlaena. J. Nat. Prod. 2001, 64 (4),
549–551.
5. Kobayashi, K.; Nishino, C. Biological-activities of pisiferic acid and o-methyl
pisiferic acid. Agric. Biol. Chem. 1986, 50 (9), 2405–2407.
6. Ahn, J. W.; Wada, K.; Marumo, S.; Tanaka, H.; Osaka, Y. A mite growth-regulator
from chamaecyparis-pisifera which inhibits hatching and larval feeding of the
2-spotted spider-mite, tetranychus-urticae. Agric. Biol. Chem. 1984, 48 (8),
2167–2169.
7. Banik, B. K.; Ghosh, S.; Ghatak, U. R. Influence of methoxy-aromatic and methyl-
aromatic substituents on stereochemistry of the products in the acid-catalyzed
cyclization of 2-(2-arylethyl)-1,3,3-trimethylcyclohexanols—stereocontrolled
total synthesis of (+)-nimbidiol and (þ)-nimbio. Tetrahedron 1988, 44 (22),
6947–6955.
8. Tamai, Y.; Hagiwara, H.; Uda, H. A total synthesis of (þ)-pisiferol. J. Chem. Soc.
Perkin Trans 1 1986 (7), 1311–1315.
9. Mori, K.; Mori, H. Diterpenoid total synthesis. 24. Synthesis of both the enantio-
mers of O-methyl pisiferic acid, a mite growth-regulator isolated from chamaecy-
paris-Pisifera endl.. Tetrahedron 1986, 42 (20), 5531–5538.
10. Banerjee, A. K. A formal total synthesis of (+)-carnosic acid dimethyl ether.
J. Chem. Res.(S) 1992 (1), 50–50.
11. Banerjee, A. K.; Hurtado, H.; Laya, M.; Acevedo, J. C.; Alvarez, J. Total
synthesis of (+)-pisiferic acid. J. Chem. Soc. Perkin Trans 1 1988 (4),
931–938.
12. Das, S.; Saha, A. K.; Mukherjee, D. A new application of aryl participated cycli-
zation involving diazomethyl ketone—stereocontrolled synthesis of angularly
ester substituted trans-octahydrophenanthrene ring-system related to diterpenes.
Tetrahedron Lett. 1995, 36 (13), 2315–2316.
13. Pal, S. K.; Mukherjee, D. A stereocontrolled total synthesis of methyl (+)-O-
methylpisiferate. Tetrahedron Lett. 1998, 39 (32), 5831–5832.
14. Matsumoto, T.; Endo, Y.; Okimoto, M. Bull. Total synthesis of (+)-pisiferic acid,
methyl (+)-pisiferate, and (+)-pisiferol. Chem. Soc. Jpn. 1982, 55 (5),
1599–1604.
15. Jones, J. B.; Dodds, D. R. Enzymes in organic-synthesis 37. Preparation and
characterization of potential decalindione substrates of horse liver alcohol-
dehydrogenase. Can. J. Chem. 1987, 65 (10), 2397–2404.
16. Vyas, G. N.; Shan, N. N. Org. Synth. Coll. 1963, 4, 837–839.
17. Sdassi, H.; Revial, G.; Pfau, M.; Dangelo, J. Enantioselective approach to morphi-
nans. Tetrahedron Lett. 1990, 31 (6), 875–878.

78
H. Zhu and P. Tu
18. Stork, G.; Terrel, R.; Szmuszkowicz, J. A new synthesis of 2-alkyl and 2-acyl
ketones. J. Am. Chem. Soc. 1954, 76 (7), 2029–2030.
19. Xiao, Q.; Cui, Y. X.; Tu, P. F. A concise approach to the synthesis of carnosic acid
type diterpenes. Chin. Chem. Lett. 2001, 12 (3), 197–198.
20. Gawley, R. E. The Robinson annelation and related reactions. Synthesis 1976 (12),
777–794.