Studies on the synthesis of Schisandraceae natural products: Exploring a cyclopropylcarbinol ring expansion strategy

Article abstract of DOI:10.1002/ejoc.200700336

Acid mediated cyclopropylcarbinol ring expansion has been shown to be a viable method for the construction of the AB ring framework of lancifodilactone F and related terpenoids of the Schisandraceae family of natural products. We found that this rearrangement proceeds with good stereochemical control based on inversion of the C10 cyclopropyl center. Our studies indicate that the cis-decalin motif of 31 could be used as a key synthetic precursor of certain Schisandraceae metabolites. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700336

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700336
Studies on the Synthesis of Schisandraceae Natural Products: Exploring a
Cyclopropylcarbinol Ring Expansion Strategy
Derek Fischer[a] and Emmanuel A. Theodorakis*[a]
Keywords: Synthesis design / Cyclopropanation / Synthetic methods / Baeyer–Villiger oxidation / Ring expansion
Acid mediated cyclopropylcarbinol ring expansion has been
shown to be a viable method for the construction of the AB
ring framework of lancifodilactone F and related terpenoids
of the Schisandraceae family of natural products. We found
that this rearrangement proceeds with good stereochemical
control based on inversion of the C10 cyclopropyl center. Our
studies indicate that the cis-decalin motif of 31 could be used
as a key synthetic precursor of certain Schisandraceae me-
tabolites.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Fruits and extracts from the Schisandraceae family of
plants have been used in traditional Chinese medicine for
their immunostimulant and tissue-constricting properties.[1]
Efforts to investigate the bioactive constituents of these
plants led to the identification of a large family of terpe-
noids that includes schizandronic acid (1),[2] kadsuphilac-
tone B (2),[3] nigranoic acid (3),[4] lanciphodilactone F (4)[5]
and micrandilactones A (5)[6] and C (6)[7] (Figure 1). Most
of these natural products possess beneficial antihepatitis,
antitumor and antiviral activities. For instance, nigranoic
acid (3) showed activity on several anti-HIV reverse tran-
scriptase and polymerase assays,[4] while kadsuphilactone B
(2) was active against hepatitis B virus infection in vitro
(IC50 = 6 mg/mL).[3] The recently isolated micrandilac-
tone C (6) displayed potent activity against HIV-1 replica-
tion (EC50 = 7.71 mg/mL) with minimal cytotoxicity.[7]
The combination of promising pharmacological profile
and novel chemical architecture of Schisandraceae natural
products has attracted the interest of the synthetic com-
munity.[8] From a biosynthetic point of view, these com-
pounds are presumed to arise from a common cycloartane
skeleton, integral to the structure of schizandronic acid (1),
that upon a sequence of plant-specific oxidations, ring ex-
pansions and rearrangements could lead to more densely
functionalized terpenoids, with exquisite motifs such as the
micrandilactones.[9] The opening stages of this biosynthetic
Figure 1. Representative structures of natural products of the Schis-
andraceae family of plants.
proposal could involve conversion of schizandronic acid to Lactone hydrolysis and opening of the cyclopropane ring
natural products 2, 3 and 4.[10] Inspired by this concept, we would then lead to structure 10 which represents the AB
envisioned that oxidation of 7, reminiscent of the AB motif ring system of lancifodilactone F. We report here a study on
of schizandronic acid, would form lactone 8 (Scheme 1). the feasibility of this conversion using simplified scaffolds.
At the onset of this investigation we targeted compound
[a] Department of Chemistry and Biochemistry, University of Cali-
20, in which the cyclopropane is embedded in a trans-fused
fornia,
decalin motif. The synthesis of 20 is highlighted in
Scheme 2, and departed from commercially available 1,4-
cyclohexanedione (11). Protection of 11 with ethylene glycol
produced 90% of the C8 monoketal (schizandronic acid
San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA
Fax: +1-858-822-0386
E-mail: etheodor@ucsd.edu
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 4193–4196
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4193

D. Fischer, E. A. Theodorakis
SHORT COMMUNICATION
Scheme 1. Proposed biosynthetic pathway for the conversion of
schizandronic acid to other related natural products.
numbering) after recycling the concomitantly formed dike-
tal.[11] Alkylation of the C5 enolate with methyl cyanofor-
mate, followed by Robinson annulation of the resulting β-
oxo ester 12 with methyl vinyl ketone, furnished enone 13
(39% combined yield). Treatment of 13 with potassium tert-
butoxide produced the vinylogous enolate that upon di-
methylation at C4 formed 14 (60% yield). Reduction of 14
with lithium aluminium hydride provided diol 15 in good
yield. Conversion of 15 to the corresponding C8 ethyl ketal,
followed by hydrogenation of the C5–C6 double bond from
the more accessible α-face gave rise to 16 (78% combined
yield). After acetylation of the C3 hydroxy group, com-
pound 16 was converted to hemiacetal 17 (70% combined
yield). Mesylation of 17 produced compound 18 (70% yield
after recycling of the secondary mesylate) that, upon treat-
ment with potassium tert-butoxide, provided the cyclopro-
pyl ring of 19 (87% yield).[12] The structure of 19 was un-
ambiguously confirmed by a single-crystal X-ray diffraction
analysis.[13] Deprotection of the C3 acetoxy group and oxi-
dation of the resulting alcohol gave rise to the desired
ketone 20. Much to our delight, under standard Baeyer–
Villiger conditions compound 20 was oxidized selectively
across the C3–C4 bond in excellent yield (95%). Reduction
of the C8 carbonyl group then produced 21 as a single ste-
reoisomer (85% yield). The stereochemistry of the resulting
cyclopropylcarbinol was tentatively assigned by comparison
Scheme 2. Reagents and conditions: (a) ethylene glycol (1.3 equiv.),
pTsOH (0.09 equiv.), benzene, 100 °C, 1.5 h, 35% (90% after re-
cycling); (b) LDA (1.2 equiv.), methyl cyanoformate (1.2 equiv.),
HMPA (1.0 equiv.), THF, 0 °C, 1 h, 65%; (c) Et3N (0.35 equiv.),
MVK (1.8 equiv.), MeOH, 25 °C, 40 h, then pyrrolidine
(0.2 equiv.), AcOH (0.2 equiv.), benzene, 100 °C, 2 h, 60 %; (d)
tBuOK (2.1 equiv.), MeI (6.0 equiv.), tBuOH, 40 °C, 3 h, 60%; (e)
LAH (1.4 equiv.), THF, 0 to 25 °C, 12 h, 73%; (f) pTsOH
(0.1 equiv.), EtOH, 100 °C, 20 min, 84%; (g) 10% Pd/C (0.1 equiv.),
H2 (1 atm), EtOH, 25 °C, 12 h, 93%; (h) Ac2O (3.0 equiv.), pyridine
(10 equiv.), CH2Cl2, 25 °C, 48 h, 85%; (i) pTsOH (0.2 equiv.), wet
acetone, 25 °C, 45 min, 82%; (j) iPr2NEt (1.2 equiv.), MsCl
(1.1 equiv.), CH2Cl2, 25 °C, 10 h, 40% (70% after recycling); (k)
tBuOK (1.2 equiv.), benzene, 25 °C, 1.5 h, 87%; (l) K2CO3
(1.1 equiv.), wet MeOH, 25 °C, 12 h, 90%; (m) DMP (1.3 equiv.),
CH2Cl2, 25 °C, 1.5 h, 97%; (n) mCPBA (1.5 equiv.), NaHCO3
(2.0 equiv.), CH2Cl2, 0 °C, 6 h, 95%; (o) NaBH4 (0.5 equiv.), THF,
0 °C, 4 h, 85 %. pTsOH: p-toluenesulfonic acid monohydrate, LDA:
lithium diisopropylamide, HMPA: hexamethylphosphoramide,
THF: tetrahydrofuran, MVK: methyl vinyl ketone, LAH: lithium
aluminum hydride, MsCl: methanesulfonyl chloride, DMP: Dess–
Martin periodinane.
1
with the H NMR spectra of related structures.[14]
With cyclopropylcarbinol 21 in hand, we studied the
conditions for the cyclopropane ring expansion reaction
(Scheme 3). Treatment of 21 with BF3·Et2O under anhy-
drous conditions produced only 20% of 22 in conjuction
with several unidentified products.[15] Aqueous acids pro-
duced better results favoring the formation of compound
23. The best results were obtained upon treatment of 21
with 7% aqueous HClO4 in acetonitrile at room tempera-
The above studies demonstrate that the lactonization/cy-
ture, and gave rise to alcohol 23 (75% yield) along with the clopropyl ring expansion process occurs with inversion of
dehydrated compound 22 (20% yield).[16] The structure of stereochemistry at the C10 center. These results are in
23 was confirmed through X-ray crystallography.[13] These agreement with literature data reporting stereoselective sol-
conditions were also successfully applied to compound 24 volytic cyclopropyl ring expansions in similar sub-
that afforded spirolactone 25 in 60% yield. However, it strates.[16,17] It should be noted that the chemical origins
should be noted that similar attempts to open the cyclopro- of the observed selectivity have not been unambiquously
pyl ring of the Baeyer–Villiger adduct of 20 were unsuccess- defined, although intimate ion pair,[18] non-classical ions
ful.
and neighboring group or anchimeric effects have been pro-
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Eur. J. Org. Chem. 2007, 4193–4196

Studies on the Synthesis of Schisandraceae Natural Products
SHORT COMMUNICATION
Scheme 3. Reagents and conditions: (a) 7% HClO4 (1.0 equiv.),
acetonitrile, H2O, 25 °C, 1.5 h, 75% of 23 and 20% of 22; (b)
TBSCl (2.0 equiv.), imidazole (3.0 equiv.), DMAP (0.2 equiv.),
DMF, 25 °C, 14 h, 92%; (c) LiHMDS (2.5 equiv.), PhSeBr
(2.0 equiv.), THF, –78 °C, 1.5 h, 48%; (d) NaIO4 (2.0 equiv.), THF/
H2O (1:1), 0 °C, 2 h, 65%; (e) HClO4 (1.0 equiv.), acetone, H2O,
25 °C, 2.0 h, 60%. LiHMDS: lithium bis(trimethylsilyl)amide,
TBSCl: tert-butyldimethylsilyl chloride, DMAP: 4-(dimethylamino)-
pyridine, DMF N,N-dimethylformamide.
posed in certain cases.[16,17] Nonetheless, the relative stereo-
chemistry of 22, 23, and 25 did not match that found in the
structures of lancifodilactone and micrandilactones.
Scheme 4. Reagents and conditions: (a) [Ir(Cod)Py(PCy3)]PF6
(0.04 equiv.), H2 (1 atm), CH2Cl2, 25 °C, 5 h, 77%; (b) pTsOH
(0.05 equiv.), EtOH, 40 °C, 30 m, 92%; (c) AcCl (1.5 equiv.),
DMAP (0.07 equiv.), pyridine/CH2Cl2 (1:1), 25 °C, 1.5 h, 90%; (d)
pTsOH (0.15 equiv.), acetone, 40 °C, 2 h, 85%; (e) iPr2NEt
(1.3 equiv.), MsCl (1.3 equiv.), CH2Cl2, 0 °C, 5 min, 30% (60% af-
ter recycling); (f) tBuOK (1.5 equiv.), benzene, 25 °C, 4 h, 95%; (g)
K2CO3 (1.2 equiv.), NaOMe (0.05 equiv.), MeOH, 25 °C, 24 h,
82%; (h) DMP (1.3 equiv.), CH2Cl2, 25 °C, 30 min, 95%; (i)
mCPBA (1.5 equiv.), NaHCO3 (4.1 equiv.), CH2Cl2, 0Ǟ25 °C, 8 h,
98%; (j) Bu4NBH4 (5.0 equiv.), CH2Cl2, 0Ǟ25 °C, 8 h, 82 %; (k)
HClO4 (1.0 equiv.), acetone, H2O, 25 °C, 1.5 h, 55%.
This observation led us to consider inverting the stereo-
chemistry at the C5 center. In principle this would require
hydrogenation of 15 from the top face. To this end, diol
15 was treated under a variety of hydrogenation conditions
designed to take advantage of the directing effect of the C11
hydroxy group. Best results were obtained with Crabtree’s
catalyst,[19] which provided 26 in 77% yield (Scheme 4).
Compound 26 was then converted to hemiacetal 29 accord-
ing to the reaction sequence described previously. A single-
crystal X-ray diffraction analysis of 29 confirmed the cis
stereochemistry of the decalin ring.[13] Conversion of 29 to
cyclopropyl ketone 31 was accomplished by a sequence of
four steps that included: mesylation of the C11 hydroxy
group, formation of the C9–C11 bond with tBuOK, and
deprotection/oxidation of the C3 hydroxy group (45% com-
bined yield). Baeyer–Villiger oxidation of 31, followed by
selective reduction of the C8 carbonyl group, formed cy-
clopropyl carbinol 32 as a 1:1 mixture of stereoisomers at
the C8 center. Treatment of 32 with HClO4 then produced
compound 33 along with small amounts of the dehydration
product. Compound 33 was found to have the desired (lan-
cifodilactone) stereochemistry at the C5 and C10 centers.
In conclusion, inspired by the proposed biosynthesis of
the Schisandraceae metabolites, we studied a novel acid-me-
diated cyclopropylcarbinol ring-expansion reaction as the
key rearrangement for the construction of the AB-ring sys-
tem of lancifodilactone F and related terpenoids. We found
that this rearrangement proceeds with good stereochemical
control defined by inversion of configuration at the C10
cyclopropyl center. In turn, this illustrates that the desired
stereochemistry at the C5 and C10 centers of the lancifodi-
lactone F framework can be installed departing from deca-
lin 31 in which the C5 hydrogen atom and the C10 cy-
clopropyl ring are cis to each other. Our observations en-
hance the synthetic potential of carbocationic rearrange-
ments in stereocontrolled syntheses. In addition, our studies
pave the way for a potentially biomimetic synthesis of se-
lected Schisandraceae natural products.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data for com-
pounds 19–23, 25 and 31–33 and 1H and 13C NMR spectra of
compounds 15, 16, 18–25, 27, 28, and 30–33.
Acknowledgments
Financial support from the Cancer Research Coordinating Com-
mittee (6-446228-37607) is gratefully acknowledged. We also thank
Dr. L. N. Zakharov and Professor A. L. Rheingold (UCSD, X-ray
Facility) for the reported crystallographic studies and Dr. Y. Su
(UCSD Mass Spectrometry Facility) for mass analysis.
[1] a) Compilation of Chinese Herb Medicine, People’s Publishing
House, Beijing, 1975, vol. 1, p. 581; b) Pharmacopoeia of the
People’s Republic of China, People’s Health Press, Bejing, 1977,
vol. 1, p. 396–397; c) Jiangsu College of New Medicine, Dictio-
nary of Chinese Traditional Medicine, Shanghai Science and
Technology Press, Shanghai, 1986, p. 1859–1860.
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D. Fischer, E. A. Theodorakis
SHORT COMMUNICATION
[2] K. Takahashi, M. Takani, Chem. Pharm. Bull. 1975, 23, 538–
542.
[3] Y.-C. Shen, Y.-C. Lin, M. Y. Chiang, S. F. Yeh, Y.-B. Cheng,
C.-C. Liao, Org. Lett. 2005, 7, 3307–3310.
[11] J.-M. Kamenka, P. Geneste, A. El Harfi, Bull. Soc. Chim. Fr.
1983, 3-4 (pt. 2), 87–88.
[12] Y. Tsuda, K. Yoshimoto, T. Yamashita, M. Kaneda, Chem.
Pharm. Bull. 1981, 29, 3238–3248.
[4] a) H.-D. Sun, S.-X. Qui, L.-Z. Lin, Z.-Y. Wang, Z.-W. Lin, T.
Pengsuparp, J. M. Pezzuto, H. H. S. Fong, G. A. Cordell, N. R.
Farnsworth, J. Nat. Prod. 1996, 59, 525–527; b) R.-T. Li, Q.-
B. Han, A.-H. Zhao, H.-D. Sun, Chem. Pharm. Bull. 2003, 51,
1174–1176.
[5] W.-L. Xiao, R.-T. Li, S.-H. Li, X.-L. Li, H.-D. Sun, Y.-T.
Zheng, R.-R. Wang, Y. Lu, C. Wang, Q.-T. Zheng, Org. Lett.
2005, 7, 1263–1266.
[13] CCDC-643516 (19), -643517 (23), and -643492 (29) contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/
data_request/cif.
[14] a) D. M. Hodgson, Y. K. Chung, J.-M. Paris, J. Am. Chem.
Soc. 2004, 126, 8664–8665; b) S. E. Denmark, J. P. Edwards, J.
Org. Chem. 1991, 56, 6974–6981; c) E. Erzen, J. Cerkovnik, B.
ˇ
[6] R.-T. Li, Q.-S. Zhao, S.-H. Li, Q.-B. Han, H.-D. Sun, Y. Lu,
L.-L. Zhang, Q.-T. Zheng, Org. Lett. 2003, 5, 1023–1026.
[7] R.-T. Li, Q.-B. Han, Y.-T. Zheng, R.-R. Wang, L.-M. Yang, Y.
Lu, S.-Q. Sang, Q.-T. Zheng, Q.-S. Zhoa, H.-D. Sun, Chem.
Commun. 2005, 2936–2938.
[8] a) Y.-D. Zhang, Y.-F. Tang, T.-P. Luo, J. Shen, J.-H. Chen, Z.
Yang, Org. Lett. 2006, 8, 107–110; b) Y. Tang, Y. Zhang, M.
Dai, T. Luo, L. Deng, J. Chen, Z. Yang, Org. Lett. 2005, 7,
885–888; c) K. S. Krishnan, M. Smitha, E. Suresh, K. V. Rad-
hakrishnan, Tetrahedron 2006, 62, 12345–12350.
[9] R.-T. Li, W.-L. Xiao, Y.-H. Shen, Q.-S. Zhao, H.-D. Sun,
Chem. Eur. J. 2005, 11, 2989–2996; see also corrigendum for
above paper: R.-T. Li, W.-L. Xiao, Y.-H. Shen, Q.-S. Zhao, H.-
D. Sun, Chem. Eur. J. 2005, 11, 6763–6765.
[10] a) A. Rahman, H. Nasir, E. Asif, S. S. Ali, Z. Iqbal, M. I.
Choudhary, J. Clardy, Tetrahedron 1992, 48, 3577–3584; b) Y.
Shen, Y. Lin, M. Chiang, S. Yeh, Y. Cheng, C. Liao, Org. Lett.
2005, 7, 3307–3310.
Plesnicˇar, J. Org. Chem. 2003, 68, 9129–9131; d) G. A. Mo-
lander, L. S. Harring, J. Org. Chem. 1989, 54, 3525–3532; e) J.-
P. Barnier, V. Morisson, I. Volle, L. Blanco, Tetrahedron: Asym-
metry 1999, 10, 1107–1117.
[15] E. J. Corey, B.-C. Hong, J. Am. Chem. Soc. 1994, 116, 3149–
3150.
[16] J. A. Marshall, R. H. Ellison, J. Org. Chem. 1975, 40, 2070–
2073; J. A. Marshall, R. H. Ellison, J. Am. Chem. Soc. 1976,
98, 4312–4313.
[17] L. G. Mueller, R. G. Lawton, J. Org. Chem. 1979, 44, 4741–
4742; M. L. de Faria, R. de A. Magalhaes, F. C. Silva, L. G.
de O. Matias, M. A. Ceschi, U. Brocksom, J. Brocksom, Tetra-
hedron: Asymmetry 2000, 11, 4093–4103.
[18] C. J. Collins, Chem. Soc. Rev. 1975, 4, 251–262.
[19] G. Stork, D. E. Kahne, J. Am. Chem. Soc. 1983, 105, 1072–
1073; R. Crabtree, Acc. Chem. Res. 1979, 12, 331–337.
Received: April 17, 2007
Published Online: May 31, 2007
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Eur. J. Org. Chem. 2007, 4193–4196