Study Towards Asymmetric Synthesis of 3-epi-Eupomatilone-6
Sariya Yodwaree1,*, Manat Pohmakotr1, Chutima Kuhakarn1, Patoomratana Tuchinda1,
Vichai Reutrakul1, Darunee Soorukram1,#
1
Organic Chemistry Program, Department of Chemistry, Faculty of Science, Mahidol
University, Rama VI Road, Bangkok 10400, Thailand
*e-mail: y.sariya@hotmail.com, #e-mail: darunee.soo@mahidol.ac.th
Abstract
Eupomatilones, such as eupomatilone-3 and eupomatilone-6, are structurally novel
lignan natural products. Their unusual biaryl skeleton was proposed to derive from an
unprecedented rearrangement. Asymmetric synthesis towards 3-epi-eupomatilone-6 was
investigated in this study.
Keywords: eupomatilone, lignan, conjugate addition
Introduction
Lignans produced by oxidative dimerization of two phenylpropane (C6-C3) units, are
a large group of natural products. Many lignans exhibit important pharmacological activities,
such as antioxidant, antitumor, anti-inflammatory, antifungal, and antiviral activity.1
Eupomatilonesisolated from theAustralian shrub Eupomatia bennettii are unusual subclass of
lignans. All members of the eupomatilones,such as eupomatilone-3, eupomatilone-6, and 3epi-eupomatilone-6possess the C4-C5 cis-stereochemistry in the γ-butyrolactone ring2 (Aring)(Figure 1).
Figure 1
As proposed by Carroll and Taylor in 1991,3 the spirocyclohexadienone skeleton of
eupodienone precursor 1 underwent hemiketal formation to provide intermediate 2, which
fragmented to eupomatilone-4(3)(Scheme 1).
Scheme 1 Proposed mechanism by Carroll and Taylor
As part of our ongoing research in asymmetric synthesis of bioactive lignan natural
products, we are interested in developing asymmetric approach to synthesis eupomatilones.
Methodology
The 1H- and 13C-NMR spectra were recorded on a Bruker Advance-400 (400 MHz)
and a Bruker Advance-500 (500 MHz) spectrometer.
Our synthetic strategy to synthesize 3-epi-eupomatilone-6 was depicted in Scheme 2.
The key synthetic strategies involve the transformation of 4 to 6 and 6 to 7, respectively.
Oxidative cleavage of compound 4 followed by the addition of aryl lithium 5 provided
alcohol product 6 after desilylation. From compound 6, oxidative lactonization was carried
out to give the -butyrolactone 7.
Scheme 2
Preparation of (2S,3R)-1-(4-(benzyloxy)-3,5-dimethoxyphenyl)-2,3-dimethylbutane1,4-diol64 : A solution of 2,3-dimethylpentene 4 (1.0 mmol) and N-methylmorpholine-Noxide(3.0 mmol)in CH2Cl2 (40 mL) was treated with 5 mol% of OsO4 (solution in t-butanol,
0.54 mL, 0.05 mmol) and water (0.54 mL) at room temperature for 10 h. After that, NaIO4
was added to the reaction mixture and it was stirred at room temperature for 30 min. Then the
resulting mixture was quenched by Na2S2O3 solution (10 mL) and extracted with CH2Cl2 (3 x
10 mL). The combined organic phase was washed with brine (10mL) and dried over anh.
Na2SO4. After removal of solvent in vacuo, the crude product was treated with ArLi (5) in
THF at −78 oC for 2 h. The reaction mixture was quenched by NH4Cl solution (10 mL) and
extracted with EtOAc (3x10 mL). The combined organic phase was washed with brine (10
mL) and dried over anh. Na2SO4. The crude product was purified by column chromatography
(SiO2). After purification, the product (0.5mmol) was treated TBAF solution (0.5 mL, 1 M in
THF, 0.5 mmol) and stirred at 25 oC for 2 h. Then the resulting mixture was extracted with
EtOAc (3 x 10 mL) and combined organic phase, which was washed with brine (10 mL) and
dried over anh. Na2SO4.
Results and Discussion
Compound 4, which was used in our study, was prepared in 92% yield from the
corresponding alcohol.5 Oxidative cleavage of 4 by using OsO4 NMO and NaIO4 gave an
aldehyde which was proved to be unstable. It was therefore treated with ArLi 5 at −78 oC for
2 h to provide the corresponding adduct 8 in 70% yield as a mixture of diastereomers, which
could be separated by means of chromatography. Next, pure isomer 8a,was treated with
TBAF to provide the corresponding diol which was subjected to oxidative lactonization to
give -butyrolactone 7a in 80% yield.6 -Butyrolactone 7a will be used as a precursor for the
synthesis of 3-epi-eupomatilone-6 (9).7
Scheme 3 Synthesis of 3-epi-eupomatilone-6 (9)
Conclusion
In conclusion, asymmetric synthesis leading to 3-epi-eupomatilone-6 (9) was
investigated. -Butyrolactone 7a, which was the key intermediate, was synthesized in good
yield starting from compound 4. The transformation of 7a to 3-epi-eupomatilone-6 (9) is
currently under investigation.
References
1.
2.
3.
4.
5.
6.
7.
Rye E C, Barker D. Asymmetric synthesis of (+)-galbelgin, (−)-kadangustin J, (−)-cyclogalgravin and
(−)-pycnanthulignenes A and B, three structurally distinct lignan classes, using a common chiral
precursor. J. Org. Chem. 2011; 76:6636-6648.
Hong S, McIntosh C M. An approach to the synthesis of the eupomatilones. Org. Lett. 2002; 4:19-21.
Coleman R S, Gurrala S R. Total synthesis of eupomatilones 4 and 6: structurally rearranged and
atroppisomerically fluxional lignan natural products. Org. Lett. 2004; 6:4025-4028.
Stadler D, Bach T. Concise stereoselective synthesis of (−)-podophyllotoxin by an intermolecular
Iron(III)-catalyzed friedel–crafts alkylation. Angew. Chem. Int. Ed. 2008; 47: 7557-7559.
Hoffmann W R, Menzel K, Harms K. Synthesis and conformational analysis of bis(1,3-dioxan-5yl)ethane derivatives. Eur. J. Org. Chem. 2002; 2603-2612.
Hansen T M, Florence G J, Lugo-Mas P, Chen J, Abrams J N, Forsyth C J. Highly chemoselective
oxidation of 1,5-diols to δ-lactones with TEMPO/BAIB. Tetrahedron Lett. 2003; 44:57-59.
Johnson B J, BercotA E, Williams M C, Rovis T. A concise synthesis of eupomatilones 4, 6, and 7 by
rhodium-catalyzed enantioselective desymmetrization of cyclic mesoanhydrides with organozinc
reagents generated in situ.Angew. Chem. Int. Ed. 2007; 46:4514-4518.
Acknowledgements: Financial support from the Thailand Research Fund (to D.S.,
MRG5580046), the Office of the Higher Education Commission and Mahidol University
under the National Research Universities Initiative, Mahidol University, and the Center of
Excellence for Innovation in Chemistry (PERCH-CIC) are gratefully acknowledged.