First total synthesis of (±)-puyanin and (±)-4′-O-methylbonannione

Article abstract of DOI:10.1016/j.cclet.2010.06.037

A facile approach for the first total synthesis of two naturally occurring geranylated flavonoids, (±)-puyanin 1 and (±)-4′-O-methylbonannione 2 has been obtained with total yield 27% and 21%, respectively. The key steps were regioselective cyclization of geranylated trihydroxychalcone and regioselective geranylation of 2,4,6-trihydroxyacetophenone.

Full text of DOI:10.1016/j.cclet.2010.06.037

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Chinese Chemical Letters 21 (2010) 1267–1269
www.elsevier.com/locate/cclet
First total synthesis of (ꢀ)-puyanin and (ꢀ)-40-O-methylbonannione
*
Jin Hui Yang , Yu Heng Zhang, Hong Jun Li, Shi Zhi Jiang, Yun Feng Li
Key Laboratory of Energy Sources and Chemical Engineering of Ningxia, Ningxia University, Yinchuan 750021, China
Received 16 April 2010
Abstract
A facile approach for the first total synthesis of two naturally occurring geranylated flavonoids, (ꢀ)-puyanin 1 and (ꢀ)-40-O-
methylbonannione 2 has been obtained with total yield 27% and 21%, respectively. The key steps were regioselective cyclization of
geranylated trihydroxychalcone and regioselective geranylation of 2,4,6-trihydroxyacetophenone.
# 2010 Jin Hui Yang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Puyanin; 40-O-methylbonannione; Flavanone; Geranylated flavonoids; Total synthesis
Natural flavanones exist widely in the plant kingdom and exhibit many important biological and pharmacological
activities such as antibacterial [1,2], antifungal [3], antitumor [4] and hypotensive [5]. Prenylated flavanones are a
unique class of flavonoids characterized by the presence of a prenylated side chain (i.e., prenyl, geranyl) in the
flavonoid skeleton [6,7] and the flavanones having prenyl or geranyl groups showed greater activity than the normal
flavanones [8].
In continuation of our ongoing program on the studies of flavanoids [9,10], we report herein a facile synthetic
approach (Scheme 1) for the synthesis of both C-8 and C-6 geranylated flavanoids puyanin 1 and 40-O-
methylbonannione 2 isolated from the leaf extracts of Glycosmis collected in Thailand and Malaysia [11] (Fig. 1). The
Glycosmis plants are widely distribute in tropical and subtropical regions, some of which species were used as
indigenous medicines. 40-O-Methylbonannione 2 had also been isolated from the fruits of Schizolaena hystrix
(Sarcolaenaceae) and possessed against the A2780 human ovarian cancer cell line and displayed weak cytotoxicity, its
IC50 values is 17 mg/mL [12]. As far as we know, the total synthesis of (ꢀ)-puyanin 1 and (ꢀ)-40-O-methylbonannione
2 has not been reported yet. The research on the total synthesis of (ꢀ)-1 and (ꢀ)-2 does not only have theoretical
importance, but also have the potential medical prospect.
4,6-Bis[(methoxy)methoxy]-2-hydroxy-3-(10-geranyl)acetophenone 5, which is readily prepared from 2,4,6-
trihydroxyacetophenone by the geranylation according to Huang’s report [13] and selective bismethoxy-methylation,
was condensed with p-methoxybenzaldehyde to afford chalcone 6 in 75% yield. Cyclization of chalcone 6 by
treatment with NaOAc in EtOH was followed by demethoxymethylation to give the title (ꢀ)-puyanin 1 (mp 158–
162 8C) in 64% yield. The (ꢀ)-40-O-methylbonannione 2 was synthesized as isomeric mixture in yield 51% from
chalcone 6 by a two–step sequence: (1) demethoxymethylation (MeOH, 3 mol/L HCl, 65%); (2) cyclization (EtOH,
* Corresponding author.
E-mail address: yang_jh@nxu.edu.cn (J.H. Yang).
1001-8417/$ – see front matter # 2010 Jin Hui Yang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.06.037

[(Scheme_1)TD$FIG]
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J.H. Yang et al. / Chinese Chemical Letters 21 (2010) 1267–1269
Scheme 1. (a) Geranyl bromine, anhydrous K2CO3, acetone, reflux, 78%; (b) anhydrous K2CO3, acetone, MOMCl, reflux, 72%; (c) p-
methoxybenzaldehyde, KOH, H2O-EtOH (v/v = 2:3), under nitrogen, 0–20 8C, 75%; (d) EtOH, NaOAc, reflux, 80%, 78%; (e) MeOH, 3 mol/
L HCl, reflux, 80%, 65%.
NaOAc and H2O, 78%). Cyclization of chalcone 8 resulted to a mixture of (ꢀ)-1 and (ꢀ)-2 in a ratio 5:1. It is
interesting to note that the 1H and 13C data of the isomeric pair (ꢀ)-1 and (ꢀ)-2 were almost same. Because cyclization
of 6 was followed by demethoxymethylation to give single (ꢀ)-puyanin 1, so we can tell (ꢀ)-2 from (ꢀ)-1 by
comparation 1H NMR of two compounds. The synthetic C-8 geranylated flavanone (ꢀ)-puyanin 1 and C-6 geranylated
flavanone (ꢀ)-40-O-methylbonannione 2 have identical spectral data [14] with those of natural product [10,11].
Cyclization of chalcone 8 resulted to a mixture of 2 and 1 in a ratio 5:1. The remarkable regioselectivity for the
cyclization of the geranylated polyhydroxy chalcone 8 may result from the presence of the geranyl group, as a large
nonpolar group which would lead to a greater tendency for the formation of intramolecular hydrogen bonding of C-20
phenoxy over C-60 phenoxy with the carbonyl group.
In summary, the present synthetic method provides a selective and facile route for the synthesis of C-6 and C-8
prenylated natural flavanoids, by which two geranylated natural flavanoids (ꢀ)-puyanin 1 and (ꢀ)-40-O-
methylbonannione 2 were first synthesized.
[(Fig._1)TD$FIG]
Fig. 1. The structure of puyanin and 40-O-methylbonannione.

J.H. Yang et al. / Chinese Chemical Letters 21 (2010) 1267–1269
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Acknowledgments
This work was financially supported by the National Natural Science Foundation (Nos. 20562010, 20962016),
Ningxia Natural Science Foundation, Program for New Century Excellent Talents in University (No. NCET-09-0860)
and the National Basic Research Program 973 of China (No. 2010CB534916).
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[14] Spectral data of (ꢀ)-puyanin 1: yellow amorphous solid, mp 158–162 8C, IR (KBr, cmꢁ1) n: 3232, 2929, 1635, 1585, 1515, 1436, 1375, 1296,
1253, 1174, 1074, 1031; 1H NMR (400 MHz, CDCl3): d 1.59, 1.66, 1.71 (s, 9H, 3 ꢂ CH3), 2.01–2.09 (m, 4H, CH2), 2.80 (dd, 1H, J = 3.0,
17.0 Hz, H3b, 3.06 (dd, 1H, J = 13.0, 17.2 Hz, H3a, 3.32 (d, 2H, J = 7.2 Hz, 100-2H), 3.84 (s, 3H, OCH3), 5.03 (m, 1H, CH), 5.21 (t, 1H,
J = 6.8 Hz, CH), 5.36 (dd, 1H, J = 3.2, 13.0 Hz, 2-CH), 6.02 (s, 1H, 6-H), 6.25 (s, 1H, 7-OH), 6.95 (d, 2H, J = 8.8 Hz, 30-H, 50-H), 7.38 (d,
2H, J = 8.4 Hz, 2H, 20-H, 60-H), 12.02 (s, 1H, 5-OH); EIMS m/z [M]+: 422 (12), 299 (100), 219 (33), 205 (13), 177 (6), 165 (77), 134 (16), 91
(11), 69 (14), 55 (5). Spectral data of (ꢀ)-40-O-methylbonannione 2: pale yellow solid, mp 140–145 8C, IR (KBr, cmꢁ1) n: 3406, 3120, 2921,
2850, 1627, 1585, 1517, 1460, 1379, 1296, 1253, 1172, 1089; 1H NMR (400 MHz, CDCl3): d 1.59, 1.69, 1.80 (s, 9H, 3 ꢂ CH3), 2.04–2.11 (m,
4H, CH2), 2.78 (dd, 1H, J = 3.2, 17.2 Hz, H3b), 3.09 (dd, 1H, J = 13.0, 17.2 Hz, H3a), 3.37 (d, 2H, J = 6.8 Hz, 100-2H), 3.83 (s, 3H, OCH3), 5.03
(m, 1H, CH), 5.25 (t, 1H, J = 7.2 Hz, CH), 5.34 (dd, 1H, J = 3.2, 13.0 Hz, 2-CH), 5.98 (s, 1H, 8-H), 6.33 (s, 1H, 7-OH), 6.94 (d, 2H,
J = 8.4 Hz, 30-H, 50-H), 7.38 (d, 2H, J = 8.4 Hz, 20-H, 60-H), 12.40 (s, 1H, 5-OH); EIMS m/z [M]+: 422 (31), 337 (15), 299 (100), 219 (73), 203
(13), 177 (11), 165 (70), 134 (27), 121 (27), 91 (34), 79 (12), 69 (40), 55 (24).