Hydrogen-bonded rotamers of 2′,4′,6′-trihydroxy-3′-formyldihydrochalcone, an intermediate in the synthesis of a dihydrochalcone from Leptospermum recurvum
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Introduction
As an extension of our studies on the bioactive components of the New Zealand manuka, Leptospermum scoparium,1., 2. we have screened Leptospermum species for a range of biological activities. This study revealed that the ethanol extract of the foliage of Leptospermum recurvum Hook. f. (family Myrtaceae) possessed antiviral activity. This plant, endemic to Mt Kinabalu in the States of Sabah, Malaysia has been reported to contain the polyphenols, cyanidin, quercetin, ellagic acid, delphinidin and myricetin,3 but we could find no reports on medicinal properties. However, L. recurvum is almost identical (apart from leaf size) to L. flavescens3 which has been used traditionally in Malaysia to stimulate appetite and relieve stomach disorders and menstrual discomfort.4
In this paper we describe the isolation of flavonoid components of L. recurvum foliage, including the dihydrochalcone (1). Synthesis of 1 was subsequently achieved via the formyl derivative (2). NMR studies of 2 produced spectra with some broad peaks and some notable absences of signals. Searching the literature likewise revealed incomplete sets of NMR data. We here detail studies of the solution chemistry of 2, by low temperature NMR and by molecular mechanics and ab initio studies, that elucidate the conformational exchange responsible for these anomalies.
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Results and discussion
The dried foliage of L. recurvum was extracted with ethanol and, after repeated column chromatography and preparative TLC on silica gel, yielded 2′,4′,6′-trihydroxy-3′-methyldihydrochalcone 15 and an inseparable mixture of 2,5-dihydroxy-6-methyl-7-methoxyflavanone (3) and its isomer 2,5-dihydroxy-8-methyl-7-methoxyflavanone (4).6 Further components proved difficult to separate from the major component, the mixture of hydroxyflavanones 3 and 4. This mixture was dehydrated to convert 3 and 4 to
Conclusions
Although dihydrochalcone 7, flavanones 3, 4 and 8 and flavone 5 have all been reported from natural sources, this is the first report of dihydrochalcone 1 as a natural product. These flavonoids are unusual in that they have C-methylated A-rings and non-oxygenated B-rings. Synthesis of 1 has confirmed the cytotoxicity observed for the natural sample.
The complex NMR spectra of formyl dihydrochalcone 2 have been demonstrated to arise from conformational exchange between hydrogen-bonded rotamers.
General
UV and IR spectra were recorded on a Jasco 7800 UV–Vis spectrometer and a Perkin–Elmer 1600 FTIR instrument respectively. Melting points were determined on a hot bench Leica AG melting point apparatus first calibrated with standard samples of known melting points. NMR spectra were recorded on a Varian INOVA-500 spectrometer operating at 500 MHz for 1H and 125 MHz for 13C NMR spectra were recorded on ca. 0.075 M solutions in d6-acetone (referenced to solvent, δ 2.05 for 1H and δ 29.9 for 13C) or
Acknowledgements
Thanks to W. Harris and J. W. van Klink for plant material, M. Thomas and W. Redmond for assistance with NMR experiments, B. Clark for MS analysis; G. Ellis for biological assays, and M. Dick for microanalysis. This research was supported in part by the New Zealand Foundation for Research, Science and Technology and by the New Zealand Official Development Assistance (NZODA), Ministry of Foreign Affairs and Trade (PhD scholarship).
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2020, Phytochemistry LettersCitation Excerpt :Cytotoxic and antibacterial activities of the isolated compounds, which were obtained in sufficient quantity, were evaluated. The acetone extract (44.6 g) of the dried leaves of E. jambos was subjected to chromatographic purification to yield four new compounds, eugejambones A–D (1–4), along with seventeen known compounds, 5-hydroxy-6-methyl-7-methoxyflavanone (5) (Mustafa et al., 2003), flavokawain B (6) (Jhoo et al., 2006), 2′-hydroxy-4′,6′-dimethoxy-3′-methylchalcone (7) (Amor et al., 2007), 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (8) (Salem and Werbovetz, 2005), lupeol (9) (Reynolds et al., 1986), betuline (10) (Tijjani et al., 2012), cryptostrobin (11) (Seligmann and Wagner, 1981), betulinic acid (12) (Sharma et al., 2010), stercurensin (13) (Mustafa et al., 2005), 2,4-dihydroxy-6-methyl-3-methoxychalcone (14) (Mustafa et al., 2005), trans-cinnamic acid (15) (Gao et al., 2012), (2S)-7-hydroxy-5-methoxy-6,8-dimethylflavanone (5-O-methyl-4′-desmethoxymatteucinol, 16) (Resurreccion-Magno et al., 2005), (2S)-5-hydroxy-7-methoxy-8-methylflavanone (17) (Massaro et al., 2014), (2R)-5-hydroxy-6-methyl-7-methoxyflavanone (18) (Mustafa et al., 2003), 5-hydroxymethylfurfural (19) (Chen et al., 2014), protocatechuic acid (20) (Lee et al., 2011) and 1,7-diphenyl-1,6-heptadiene-3,5-dione (21) (Dai et al., 2009) (Fig. 1). The structures of all isolated compounds were elucidated using NMR spectroscopy, especially 1D and 2D NMR techniques.
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2020, PhytochemistryCitation Excerpt :The remaining proton and carbon signals were comparable to those of 4 except the absence of signals for the p-hydroxyphenyl group at C-7 in 4. Instead, the spectra of 5 showed five aromatic protons at δ 7.15–7.08 (H-2–6) and six aromatic carbons at δ 143.3 (C-1), 129.5 (4C, C-2/6 and C-3/5), and 127.0 (C-4) attributable to a phenyl group, suggesting the presence of a 4-dehydroxylated phloretin moiety (Mustafa et al., 2003). Thus, compound 5 was identified as 4-dehydroxyphloretin 3′-C-[(2-O-trans-p-coumaroyl)-β-d-fucopyranosyl]-6′-O-β-d-fucopyranosyl-(1→2)-α-l-arabifuranoside.
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2016, Journal of Functional FoodsCitation Excerpt :Therefore, the structure of 1 was established as 6-methyl-(2R,3S)-alpinone. The known compounds were identified as 6-methyltectochrysin (2) (Mustafa, Kjaergaard, Perry, & Weavers, 2003), 6-methylapigenin (3) (Tofighi et al., 2014), (S)-isosakuranetin (4) (Fletcher et al., 2011; Vasconcelos, Silva, & Cavaleiro, 1998), (-)-naringenin (5) (Fletcher et al., 2011; Prescott, Stamford, Wheeler, & Firmin, 2002), (R)-isosakuranetin (6) (Fletcher et al., 2011; Vasconcelos et al., 1998), (S)-homoeriodictyol (7) (Fletcher et al., 2011; Liu, Ho, Cassady, Cook, & Baird, 1992), ergosterol peroxide (8) (Krzyczkowski et al., 2009), (3β,22E,24S)-3-hydroxy-ergosta-5,22-dien-7-one (9) (Notaro, Piccialli, & Sica, 1992), 7-ketocampesterol (10) (Gao, Yue, Ji, Cheng, & Zhang, 2013), coprostanol (11) (Giner et al., 2002), betulinic acid (12) (Siddiqui, Hafeez, Begum, & Siddiqui, 1988), ursolic acid (13) (Seebacher, Simic, Weis, Saf, & Kunert, 2003), 2α-hydroxyursolic acid (14) (Taniguchia et al., 2002), (+)-23-hydroxyursolic acid (15) (Tapondjou et al., 2003), oleanolic acid (16) (Seebacher et al., 2003), and maslinic acid (17) (Taniguchia et al., 2002) by comparing the spectroscopic data with previously reported values as well as by measurement of the specific rotation. The other known fatty acids were identified as 8-monooxoelaidic acid methyl ester (19) (Dang et al., 2008) and palmitic acid (20) (Couperus, Clague, & Van Dongen, 1978) by comparing the spectroscopic data with previously reported values and ESI-MS.