A simple biomimetic synthesis of dl-chamaejasmine, a unique 3,3′-biflavanone

Article abstract of DOI:10.1021/ol047718u

(Chemical Equation Presented) The first chemical synthesis of dl-chamaejasmine (1), a structurally unique 3,3′-biflavanone natural product, was achieved as shown above, by a two-step sequence starting from trimethyl ether derivatives of 3-iodonaringenin (cis + trans) involving (i) metallic lanthanum-mediated reductive dimerization in refluxing THF and (ii) global demethylation with BBr₃ in CH₂Cl₂. This synthesis represents a generally applicable biomimetic (reductive) radical dimerization approach to the 3,3′-biflavonoids.

Full text of DOI:10.1021/ol047718u

ORGANIC
LETTERS
2005
Vol. 7, No. 2
271-274
A Simple Biomimetic Synthesis of
dl-Chamaejasmine, a Unique
3,3′-Biflavanone
Wei-Dong Z. Li* and Bao-Chun Ma
State Key Laboratory of Applied Organic Chemistry, Lanzhou UniVersity,
Lanzhou 730000, China
liwd@lzu.edu.cn; isoc@lzu.edu.cn
Received November 7, 2004
ABSTRACT
The first chemical synthesis of dl-chamaejasmine (1), a structurally unique 3,3
by a two-step sequence starting from trimethyl ether derivatives of 3-iodonaringenin (cis
reductive dimerization in refluxing THF and (ii) global demethylation with BBr3 in CH2Cl2. This synthesis represents a generally applicable
biomimetic (reductive) radical dimerization approach to the 3,3 -biflavonoids.
′
-biflavanone natural product, was achieved as shown above,
+
trans) involving (i) metallic lanthanum-mediated
′
Flavonoids are a diverse group of plant natural products that
play important roles in plant growth, development, and self-
defense,1 and their wide ranges of physiological activities
have been well recognized.1 Chamaejasmine (1), a structur-
ally unique biflavanone possessing a rare 3/3′ C-C linkage
(Figure 1), was first discovered2 by Huang and Zhang in
1979 from a medicinal plant Stellera chamaejasmae L.
(known as Langdu in traditional herbal medicine in China)
and identified as a C2-symmetric racemate dimer of narin-
genin (3) at C-3. Many naturally occurring 3,3′-biflavanones
have thereafter been isolated3-10 from Langdu and other
plants, including isochamaejasmine (2),3a,b the meso isomer
(1) For reviews, see: (a) Geiger, H.; Quinn, C. In The FlaVonoids:
AdVances in Research; Harborne, J. B., Mabry, T. J., Eds.; Chapman &
Hall: London, 1982; Chapter 9, pp 505-534. (b) Plant Flavonoids in
Biology and Medicine I: Biochemical, Pharmacological and Structure-
Activity Relationships. Progress in Clinical and Biological Research; Cody,
V., Middleton, E., Jr., Harborne, J. B., Eds.; Alan R. Liss, Inc.: New York,
1986; Vol. 213. (c) Plant Flavonoids in Biology and Medicine II:
Biochemical, Cellular, and Medicinal Properties. Progress in Clinical and
Biological Research; Cody, V., Middleton, E., Jr., Harborne, J. B., Beretz,
A., Eds.; Alan R. Liss, Inc.: New York, 1988; Vol. 280.
(2) Huang, W.-K.; Zhang, Z.-J. Kexue Tongbao 1979, 24, 24; Chem.
Abstr. 1979, 90, 135086m. The partial racemate of 1 was isolated later; cf.
ref 3b.
(3) For leading references, see: (a) Niwa, M.; Chen, X.-F.; Liu, G.-Q.;
Tatematsu, H.; Hirata, Y. Chem. Lett. 1984, 1587. (b) Niwa, M.; Otsuji,
S.; Tatematsu, H.; Liu, G.-Q.; Chen, X.-F.; Hirata, Y. Chem. Pharm. Bull.
1986, 34, 3249. (c) Drewes, S. E.; Hudson, N. A.; Bates, R. B.; Linz, G. S.
J. Chem. Soc., Perkin Trans. 1 1987, 2809. (d) Castro, O.; Valverde, V.
Phytochemistry 1985, 24, 367. (e) Nyandat, E.; Hassanali, A.; De Vicente,
Y.; Multari, G.; Galeffi, C. Phytochemistry 1990, 29, 2361. (f) Baba, K.;
Taniguchi, M.; Kozawa, M. Phytochemistry 1994, 37, 879. (g) Jiang, Z.-
H.; Tanaka, T.; Sakamoto, T.; Kouno, I.; Duan, J.-O.; Zhou, R.-H. Chem.
Pharm. Bull. 2002, 50, 137.
Figure 1. Structures of chamaejasmine (1) and its meso-isomer 2.
10.1021/ol047718u CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/22/2004

of 1, other stereoisomers of 1, and corresponding (ethereal
or glycoside) derivatives, as well as other isomeric derivatives
(i.e., diphysin4 and chamaechromone5). 3,3′-Biflavonoids
have been shown to exhibit a wide range of pharmacological
activities, such as antiviral (HIV),6 antibacterial,7 and anti-
inflammatory,8 and potential antitumor activities.9 Moreover,
Yamada and Omura et al. have recently shown10 that ethereal
derivatives of 1 are potent antimalarials in vitro (IC50 ≈ 0.55
µg/mL) against the chloroquinine-resistant strain of Plas-
modium falciparum.
Scheme 1. Biomimetic Strategy to 3,3′-Biflavanones
The intriguing structures of these highly oxygenated plant
polyphenol substances have emerged as attractive synthetic
targets.11-14 Despite considerable synthetic efforts in the past
two decades, including oxidatiVe dimerization11 of naringenin
(3) or analogous flavanone derivatives, various reductiVe
(chemical, photochemical, or electrochemical) dimerizations12
of apigenin (4) or analogous flavone derivatives, hydrogena-
tion13 of 3,3′-biflavone derivatives, and other attempts,14
chemical synthesis of 1 is still an unanswered challenge to
date.15 Herein we report the first synthesis of dl-1 by a simple
biomimetic approach, which would be generally applicable
to the synthesis of 3,3′-biflavanones.
proposed to tautomerize to ii, then dimerize at C-3, and
subsequently cyclize to give 3,3′-biflavanones. Inspired by
these biogenetic investigations,17 we envisioned a biomimetic
synthetic strategy (pathway b) in which a cyclic radical
species iv derived from flavanone derivative iii is anticipated
to undergo a biomimetic dimerization, leading to 3,3′-
biflavanone in a direct fashion.
In view of the previous difficulties in generating the C-3
radical species from the corresponding flavanone derivatives
by oxidation methods,11 we decided to explore an alternative
reductive approach from readily accessible 3-halogenated
flavanone derivatives.18 Our initial attempts to reductively
dimerize 3-iodoflavanone 5 with n-Bu3SnH or (n-Bu3Sn)2
as mediators led to the predominate formation of corre-
sponding flavanone and small yields of chalcone and flavone
derivatives. After a survey of some metallic single electron
Botta and co-workers have recently realized16 a direct
biotransformation of chalcone substrates to the corresponding
3,3′-biflavanone products as a mixture of racemate and meso
isomers, by the action of a purified plant peroxidase. The
biosynthetic pathway was thus set forth (Scheme 1, pathway
a) in which an initial phenolic radical intermediate i was
(12) (a) Kirrstetter, R. G. H.; Vagt, U. Chem. Ber. 1981, 114, 630. (b)
Li, Y.-L.; Zhang, F.-J.; Wang, Q. Chinese J. Chem. 1992, 10, 359; Chem.
Abstr. 1993, 119, 95266. (c) Lu, K.-K.; Tan, Z.; Li, Y.-L.; Wang, X. Chinese
Chem. Lett. 1995, 6, 143; Chem. Abstr. 1995, 122, 290497. (d) Chen, A.-
H.; Cheng, C.-Y.; Chen, C. W. J. Chinese Chem. Soc. (Taipei) 2002, 49,
1105. (e) Yokoe, I.; Taguchi, M.; Shirataki, Y.; Komatsu, M. J. Chem.
Soc., Chem. Commun. 1979, 333. (f) Chen, C.-F.; Zhu, Y.; Liu, Y.-C.; Xu,
J.-X. Tetrahedron Lett. 1995, 36, 2835. (g) Chen, A.-H.; Kuo, W.-B.; Chen,
C.-W. J. Chinese Chem. Soc. (Taipei) 2003, 50, 123.
(4) Stermitz, F. R.; Mead, E. W.; Foderaro, T. A.; Castro, O. Phytochem-
istry 1993, 34, 287.
(5) (a) Jin, C.; Michetich, R. G.; Daneshtalab, M. Phytochemistry 1999,
50, 505. (b) Feng, B.-M.; Pei, Y.-H.; Hua, H.-M. Chinese Chem. Lett. 2002,
13, 738. (c) Tang, S.; Bremner, P.; Kortenkamp, A.; Schlage, C.; Gray, A.
I.; Gibbons, S.; Heinrich, M. Planta Med. 2003, 69, 247.
(6) Ikegawa, T.; Ikegawa, A. JP Patent 08311056; Chem. Abstr. 1997,
126, 122450.
(7) Castro, O.; Lopez, J.; Vergara, A. J. Nat. Prod. 1986, 49, 680.
(8) Zeng, Y.-Q.; Recio, M. C.; Manez, S.; Giner, R. M.; Cerda-Nicolas,
M.; Rios, J.-L. Planta Med. 2003, 69, 893.
(13) (a) Zhu, J.-P.; Wang, Q.; Li, Y.-L. J. Chem. Soc., Chem. Commun.
1988, 1549. (b) Wang, Q.; Zhu, J.-P.; Li, Y.-L. Chinese Sci. Bull. 1990,
35, 744; Chem. Abstr. 1991, 114, 6071. Further studies were unfruitful due
to the reproducibility of these results (personal communications with Y.-L.
Li).
(9) Fujiki, H.; Horiuchi, T.; Yamashita, K.; Hakii, H.; Suganuma, M.;
Nishino, H.; Iwashima, A.; Hirata, Y.; Sugimura, T. Prog. Clin. Biol. Res.
(Plant FlaVonoids Bio. Med.) 1986, 213, 429.
(14) (a) Khan, M. S. Y.; Khan, M. H.; Javed, K. Indian J. Chem. 1990,
29B, 1101. (b) Lin, G.-Q.; Hong, R. J. Org. Chem. 2001, 66, 2877.
(15) Although a few earlier reports (cf.: refs 11b,c, 13b, and ref 10 of
ref 11a) had described the preparation of some 3,3′-biflavanone derivatives,
there are no conceivable spectroscopic evidences to support these claims.
(16) (a) Botta, B.; Ricciardi, P.; Vitali, A.; Vinciguerra, V.; Garcia, C.;
Delle-Monache, G. Heterocycles 1999, 50, 757. (b) Vitali, A.; Botta, B.;
Delle-Monache, G.; Zappitelli, S.; Ricciardi, P.; Melino, S.; Petruzzelli,
R.; Giardina, B. Biochem. J. 1998, 331, 513. (c) Botta, B.; Vinciguerra,
V.; De Rosa, M. C.; Scurria, R.; Carbonetti, A.; Ferrari, F.; Delle-Monache,
G.; Misiti, D. Heterocycles 1989, 29, 2175.
(10) Nunome, S.; Ishiyama, A.; Kobayashi, M.; Otoguro, K.; Kiyohara,
H.; Yamada, H.; Omura, S. Planta Med. 2004, 70, 76.
(11) For various attempts, see: (a) Molyneux, R. J.; Waiss, A. C., Jr.;
Haddon, W. F. Tetrahedron 1970, 26, 1409. (b) Berge, D. D.; Kale, A. V.;
Sharma, T. C. Chem. Ind. (London) 1980, 787. (c) Shivhare, A.; Kale, A.
V.; Berge, D. D. Acta Chim. Hungar. 1985, 120, 107. (d) Li, L.-Z.; Rui,
Y.-J. Beijing Daxue Xuebao (Nat. Sci. Ed.) 1990, 26, 421; Chem. Abstr.
1991, 114, 185079. For relevant studies on the synthesis of brackenin, a
3,3′-bisdihydrochalcone, see: (e) Li, Y.-L.; Zhu, J.-P.; Zhang, F.-J.; Wang,
Q. Chem. J. Chinese UniV. (Chinese Ed.) 1989, 10, 653; Chem. Abstr. 1990,
112, 197752. (f) Drewes, S. E.; Hogan, C. J.; Kaye, P. T.; Roos, G. H. J.
Chem. Soc., Perkin Trans. 1 1989, 1585. Although oxidative homocoupling
of ketone enolates (for example, cf.: Frazier, R. H.; Jr.; Harlow, R. L. J.
Org. Chem. 1980, 45, 5408 and refs therein) is well-known, this method
cannot be applied to 3,3′-biflavanone synthesis, due apparently to the
inherent lability of flavanone under strong basic or acidic conditions.
(17) Cf. also: Pelter, A.; Bradshaw, J.; Warren, R. F. Phytochemistry
1971, 10, 835.
(18) 3-Iodoflavanone derivatives are superior substrates comparing to
the corresponding 3-bromo analogues. 3-Halogenated flavanone derivatives
are selectively synthesized by either SeO2-I2 in refluxing CH3CN, NIS in
refluxing CCl4, or CuBr2 in refluxing ethyl acetate-chloroform (3:2, v/v)
as a chromatographically separable mixture of cis and trans isomers in a
ratio of ca. ∼4-5:1; see the Supporting Information for details.
272
Org. Lett., Vol. 7, No. 2, 2005

reductants, we found that a racemate dimeric product 6 (mp
199-201 °C) was produced in a small yield (3∼5%) from
3-iodoflavanone 5 (mixture of cis and trans isomers), by the
action of metallic indium in refluxing DMF,19 along with
the corresponding flavone (20%), chalcone (25%), and
flavanone (5%) in the product mixture (Scheme 2). The
identity of 3,3′-biflavanone dl-6 was fully confirmed spec-
troscopically.
the C-I bond and subsequent radical dimerization may have
taken place during the collisional activation.20
Encouraged by these initial results, we next examined
metallic lanthanoids as reducing agents in view of their recent
use21 in reductive homocoupling of alkyl halides. Among
available lanthanoid metals we screened,22 lanthanum turned
out to be the most effective reductant for the reductive
dimerization of 3-iodoflavanone derivatives in refluxing
THF. Thus, racemate dimers 6, 10, and 11 were obtained in
an average isolated yield of 15-20% from the corresponding
3-iodoflavanones 5, 7, and 8 respectively, after preparative
TLC purification (Scheme 3). Other major isolable products
Scheme 2. Reductive Dimerization of 5 Mediated by In
Scheme 3. Biomimetic Synthesis of dl-Chamaejasmine (1)
Interestingly, a dehalogenated dimeric product, likely to
be 3,3′-biflavanone 6, was distinctly observed (Figure 2, m/z
447.1596) in the FT-ICR (SIMS) HR mass spectrometry
analysis of iodide 5, which implies a ready homolysis of
include the corresponding flavanone (5%), chalcone (25%),
and flavone (15%) derivatives, which are recyclable to the
starting 3-iodoflavanone derivatives in principle. Remarkably,
all dimerization products were obtained solely as racemates23
regardless of the stereochemistry (cis or trans) of the starting
3-iodoflavanone derivatives employed.
The reductive dimerization of 3-iodonaringenin trimethyl
ether 9 proceeded smoothly under the above conditions (La,
THF, refluxing) to give dl-chamaejasmine hexamethyl ether
12 (from petroleum ether-EtOAc, mp 185-187 °C)24 in
10% isolated yield.25 Global demethylation of dl-12 was
achieved by exposure to excess BBr3 (10 equiv) in CH2Cl2
(-78 °C to rt, 24 h) to give fully demethylated dl-1 (from
acetone, mp 293-295 °C)26 in 70% isolated yield. The
synthetic dl-1 was identical in every respect (TLC mobility,
(19) Cf.: Ranu, B. C.; Dutta, P.; Sarkar, A. Tetrahedron Lett. 1998, 39,
9557. Slow reductive dehalogenation occurred at lower reaction temperature.
For a recent review on the use of indium in organic synthesis, see: Podlech,
J.; Maier, T. C. Synlett 2003, 633.
(20) This phenomenon cannot be observed by other ionization methods
(i.e., EI, ESI, or FAB). Substituted 3-iodoflavanone derivatives 7-9 behave
similarly; see Table 2 of the Supporting Information (file 1).
(21) Nishino, T.; Watanabe, T.; Okada, M.; Nishiyama, Y.; Sonoda, N.
J. Org. Chem. 2002, 67, 966.
(22) Use of other metals, i.e., Ce, Nd, Sm, Yb, Lu, etc., gave mainly or
exclusively a product mixture of the corresponding chalcone and flavone.
(23) Mesomeric dimers were not detectable by 1H NMR analysis of the
crude reaction products. As one reviewer pointed out, we cannot rule out
the possibility that the meso dimer undergoes a rapid homo cleavage at
C-3/C-3′. We are currently working on the asymmetric synthesis of chiral
naringenin derivatives (i.e., 9) and hope to test this possibility in our
subsequent work.
Figure 2. HRMS (SIMS) spectra of 5 (above) and 6 recorded on
a Bruker Daltonics APEX II 47e FT-ICR mass spectrometer.
Org. Lett., Vol. 7, No. 2, 2005
273

IR, MS, and NMR spectroscopic properties) via direct
comparison with an authentic sample of chamaejasmine
racemate isolated by Huang and Zhang. A partially de-
methylated tetramethyl ether dl-13 (trihydrate from petroleum
ether-acetone, mp 118-120 °C) was obtained when the
above demethylation reaction was quenched in 1 h, and its
stereostructure was verified by a single-crystal X-ray dif-
fraction analysis (Figure 3).27
Figure 4. Possible transition assembly of radical dimerization.
In summary, a simple and general approach based on a
biomimetic (reductive) radical dimerization strategy30 was
developed for the stereoselective synthesis of 3,3′-bi-
flavanones, by which the first chemical synthesis of dl-
chamaejasmine (1) was achieved. This method would
facilitate further evaluation of 3,3′-biflavanones as potential
chemotherapeutical agents or a novel type of C2-symmetric
ligand31 in asymmetric catalysis. Further investigations along
these lines are underway in our laboratory.23
Figure 3. X-ray crystal structure of 13.
Acknowledgment. This paper is dedicated in memory
of the late Wen-Kui Huang, the discoverer of chamaejasmine.
We are grateful to Dr. Xin-Ping Yang for mass spectrometry
and Mr. Li-Xiang Cai for X-ray crystallographic analysis
assistance, respectively. We thank the National Natural
Science Foundation of China (Distinguished Youth Fund
29925204 and Group Fund 20021001) for financial support.
The Cheung Kong Scholars program is gratefully acknowl-
edged.
The conformation revealed28 by the unique C2-symmetric
X-ray crystal structure of dl-13 may suggest a preferable
transition conformational alignment (Figure 4) for this highly
stereoselective radical homocoupling process, in which a
π-π stacking interaction (see arrows) might be responsible
for directing the predominate Re-Re (or Si-Si) facial-
selective radical dimerization.29
Supporting Information Available: Detailed experi-
mental procedures, spectral data and spectrum of compounds
1 and 5-13. X-ray crystallographic data of compound 13.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(24) A melting point of 117-119 °C (from n-hexane) was recorded for
a partial racemate of hexamethyl ether derivative of (2S,3R)-chamaejasmine
(enantiomeric ratio of ca. 2:1) by Galeffi et al. (ref 3e).
(25) It is evident that 5-methoxylated 3-iodoflavanone derivatives gave
a relatively lower yield of dimerization products, due probably to the
formation of a more delocalized metal-chelated radical species, while
metallic indium could not induce the desired C-3 radical dimerization of
5-methoxylated 3-iodoflavanone derivatives, led to the formation of the
corresponding dehydrohalogenatated and demethylated flavone products
instead (eq 1):
OL047718U
(29) For a recent oxidatiVe radical dimerization strategy in natural product
synthesis, see: Nicolaou, K. C.; Gray, D. L. F. J. Am. Chem. Soc. 2004,
126, 607; Angew. Chem., Int. Ed. 2001, 40, 761. In contrast, plant
peroxidase-catalyzed biotransformation of chalcone derivatives gave the
corresponding 3,3′-biflavanones as a mixture of racemate and meso isomers
(cf.: ref 16), and reductiVe dimerization of flavone derivatives produced a
mixture of racemic and meso isomers of 2,2′-biflavanones (cf. ref 12).
(30) For other representative examples of this biomimetic radical
dimerization strategy in natural product synthesis, see: (a) Scott, A. I.;
McCapra, F.; Hall, E. S. J. Am. Chem. Soc. 1964, 86, 302. (b) Hendrickson,
J. B.; Goschke, R.; Rees, R. Tetrahedron 1964, 20, 565. (c) Barton, D. H.
R.; Deflorin, A. M.; Edwards, O. E. J. Chem. Soc. 1956, 530.
(26) A melting point of 309 °C (uncorrected, recrystallized from ethanol)
for racemate chamaejasmine was recorded by Huang and Zhang (ref 2).
(27) See the Supporting Information for detailed X-ray crystallographic
data.
(28) Cf.: Jiang, R.-W.; Ye, W.-C.; Woo, K.-Y.; Du, J.; Che, C.-T.; But,
P. P.-H.; Mak, T. C. W. J. Mol. Struct. 2002, 642, 77.
(31) An asymmetric synthesis of 3,3′-biflavanones based on this approach
can be envisioned starting from optically pure flavanones.
274
Org. Lett., Vol. 7, No. 2, 2005