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Biosynthesis of Lignans. Part I . Biosynthesis of Arctiin

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Biosynthesis of Lignans. Part I . Biosynthesis of Arctiin Bd. 31 (1977) Η. 2 Biosynthesis of Lignans. Part I· 41 Biosynthesis of Lignans Part I. Biosynthesis of Arctiin (3) and Phillyrin (5) By Joachim Stöckigt and Martina Klischies Lehrstuhl für Pflanzenphysiologie, Ruhr-Universität Bochum, D-4630 Bochum, Germany Keywords Biosynthesis of Lignans. Part I. Biosynthesis of Arctiin (3) and Phillyrin (5) Lignans Arctiin Summary Phillyrin Lignans constitute a class of naturally occuring phenolic compounds, widely distributed in higher Biosynthesis plants. They are formally composed of two phenylpropanoid units, stercospecifically joined at the Synthesis /f-carbon atoms of their side chains. Their biosynthesis has as yet not been investigated. To sec, of Cg-Cg-precursors if these plant phenolics originate from simple phenylpropancs, various radioactively labelled, Dimerisation putative precursors were fed to Forsythia shoots. Chemically synthezised arylpropane derivatives, GC-MS such as Ή/1 'C-glucoferulic acid, -glucoferulic aldehyde, and -coniferin were incorporated into the Forsythia suspensa lignans arctiin (3) and phillyrin (5) while 3H-3,4-dimcthoxycinnamic acid was not incorporated. From these results it may be concluded that the hydroxylated compounds are direct precursors of these dimeric phenylpropanes and are incorporated through a dimerisation step without degrada­ tion of the Q-Q skeleton. Biosynthese von Lignanen. Teil I. Biosynthese von Arctiin (3) und Phillyrin (5) Schlüsselwörter Zusammenfassung (Sachgebiete) Lignane sind eine Klasse natürlich vorkommender phenolischer Verbindungen, die in höheren Lignane Pflanzen weit verbreitet sind. Sie bestehen formal aus zwei Phenylpropaneinheiten, die stereo• Arctiin spezifisch an den ß-C-Atomen verbunden sind. Ihre Biosynthese ist bisher nicht untersucht Phillyrin worden. Um zu prüfen, ob diese pflanzlichen Phenole aus einfachen Phenylpropanen aufgebaut Biosynthese werden, wurden verschiedene radioaktiv markierte präsumptive Vorstufen an Sproßspitzen von Synthese Forsythien gefüttert. Die chemisch synthetisierten Arylpropanderivate (^H/1 •C-Glucoferulasäure, 3 von Ce-Cj-Vorstufen -Glucoferulaaldehyd und -Coniferin) wurden mit Ausnahme von H-3,4-Dimethoxyzimtsäure in Dimerisierung die Lignane Arctiin (3) und Phillyrin (5) eingebaut. GC-MS Aus diesen Ergebnissen kann geschlossen werden, daß die hydroxylierten Verbindungen direkte Forsythia suspensa Vorstufen dieser dimeren Phenylpropane sind und ohne Veränderung des Ce-C3 Kohlenstoff- skeletts über einen Dimerisierungsschritt eingebaut werden. Introduction Lignans are a class of phenylpropanoids, which have a widespread occurrence in many different plant species and can be isolated from roots, leaves, bark, wood and resinous exudates. It is uncertain, whether they have an essential function in the plants in which they occur (Erdtman 1955). Apart from the group of scco-isotariciresinol (2) neolignans, investigated by Gottlieb (1972), more than one hundred of these natural products have now been found, their structures elucidated and syntheses developed (see Devon and Scott 1975). With the exception of some special types, such as sesamolin (Haslam and Haworth 1955) or the phrymarolins OH (Taniguchi 1972), lignans (Fig. 1) can be classified arctiin (3) lariciresinol (A) on the basis of carbon skeleton (1) into simple diols e. g. Raglucosyl secoisolariciresinol (2), lactones, e. g. arctiin (3), tetra- hydrofuran derivatives, e. g. lariciresinol (4), tetrahy- drofuranofurans, e. g. phillyrin (5), or tetrahydro- naphthalene compounds, e. g. conidendrin (6). At present, a number of theories exist on the bio• synthesis of these phenylpropanoids, including the phillyrin (5) proposed dimerisation of two phenylpropane units Rsglucosyl through coupling between the /8-carbon atoms of the Fig. i. Main types of lignans side chains (Erdtman 1955; Neish 1966), however direct experimental evidence is lacking. Thus, it is not known, whether simple arylpropanes, such as Results and Discussion cinnamic acids and their derivatives, are direct pre• The structures of arctiin (3) and phillyrin (5) suggest cursors of lignans. that ferulic acid and coniferyl alcohol might serve as In this paper, the first investigation of the biosyn• biosynthetic precursors of these compounds. thesis of the lignans, arctiin (3) and phillyrin (5) in To investigate the possible incorporation of these Forsythia is reported. compounds into (3) and (5), we used the glucose deri- 6 Holzforschung Bd. 31» Heft 2 Holzforschung 42 J. Stöckigt and Μ. Klischies vatives of ferulic add, coniferyl alcohol and coniferyl (11,15, 16 and 18) were found to be taken up rapidly aldehyde. In addition, 34-dimethoxycinnamic add through the cut ends of the stems. After a feeding time was also tested as a precursor. The glucose derivatives of 20 hours, the plant material was extracted and chro- were used to protect the phenolic groups of the cinna- matographed on TLC plates. Fig. 4 shows the distri• myl compounds against oxidation and also to facilitate bution of radioactivity among metabolic products better solubility and effident uptake into the plant derived from glucoferulic acid (11) after chromato• material. graphy on Silicagel. As can be seen, a good incorpora• tion into (27,8% of the radioactivity which could be extracted with methanol) arctiin (3) and phyllirin (5) Synthesis of precursors was obtained. Feeding experiments with glucoferulic Since the glucoside derivatives of these dnnamyl aldehyde (15) and coniferin (16) gave similar distribu• compounds were not commerdally available, each was tions of radioactivity. After purification of both lignans synthesized and doubly labelled with dther 14C, and to constant specific activity (for unequivocally identifi• 3H (see experimental for synthesis details). In these cation of arctiin (3) and phillyrin (4), see Table 2 and syntheses, the benzaldehyde (9) is the key compound GC-MS analysis in the experimental section) by for preparation of the dnnamyl derivatives, since each chromatography and separation on acetylated polya- is ultimately derived from this intermediate (Fig. 2, 3). mide the specific incorporation of the precursors The Knoevenagd reaction with malonic add and (9) (11,15,16) into the lignans (see Table 1) changed from yielded acetylated glucoferulic add (10) almost quanti­ 1,9 to 0.7% for arctiin (3) and 1.4 to 0.4% for phillyrin tatively. The acid was de-acetylated to glucoferulic (5). Highest incorporation was achieved with glucofe• acid (11) according to published methods (Fuchs rulic acid, but merely on the basis of the incorporation 1955). *n this earlier study, however, it was reported data it cannot be determined at which oxidation level the that upon reduction of the acid chloride (12) with most effective incorporation into lignans occurs. Also sodium trimethoxyborohydride at —8o° C, only alde­ there is a likehood that the precursors might be differ• hyde was produced. However, by varying the tempe­ entially translocated and metabolized, e. g. into rature we were able to effect both aldehyde and alcohol production and at —18* C equimolar yields were lignin, since 53% of the radioactivity could not be obtained. Therefore, the temperature is critical for extracted from the plant material. reduction reaction. AcBrGtu CH2N2/HTq f^j 3 ^ ^OH V^0CH2 H KAc-p-D-Glu O-TAc-ß-D-Glu Ö 9 fco2H C02H Nx^H/Py/PIp. NaOCH^ V 3 3 0CH2 H ^v^0CH2 H Arctiin (3) O-TAc-ß-D-Glu Ο-β-0-Gtu PhiUyria(5) 10 11 Fig. 4. Purification of plant-MeOH extracts Fig. 2. Synthesis of 3H/14C-/?-D-gIucoferulic acid. (Precursor: Glucoferulic add-3!!/1^) (· - 0~"C, A - y-»C) Recent studies in Forsythia and other higher plants have shown the presence of an enzyme system capable of the sequential reduction of ferulic add to coniferyl SOC'a. (f^| NaBHtOCH^ + alcohol via the aldehyde (Mans ell et al. 1972,1974; 3 3 :H2 H Y^OCH23H "γ^Η^Η Y^OCH2 H Gross etal. 1973). Since reduction involves three differ• ent dnnamyl compounds it is possible that our substrates -TAc-ß-O-Glu O-TAe-ß-D-Glu O-TAc-ß-D-Glu O-TAc-ß-D-Glu 10 12 13 Η were first de-glucosylated by an endogenous /?-gluco- sidase then reduced to the aldehyde or alcohol just prior to incorporation into the lignans. NaOOfr Feeding experiments with doubly labelled precursors indicated no significant change in the 3H/14C ratios O-ß-D-Glu O-ß-D-Glu (Table 1). These results show unequivocally that the 15 16 precursors are incorporated without degradation of the carbon skeleton and indicate the direct dimerization Fig. 3. Synthesis of »H/i4C-^D-glucoferuHc aldehyde and of the two arylpropane units to the corresponding -coniferyl alcohol. (· ß-uC, A = y-uC) lignans. Feeding experiments Since 34-dimethoxydnnamic acid was not incorpo• rated in lignans (Table 1) and can not be reduced by Young Forsythia shoots which already contain the enzymes involved in lignin biosynthesis (Gross and lignans, arctiin (3) and phillyrin (5), in their leaves Zenk 1974, Gross et al. 1975) it seems that the dimeri• (Thieme and Winkler 1968) were used for feeding zation of the precursors occurs after the reduction to experiments. From aqueous solutions all precursors the appropriate aldehyde or alcohol. Moreover, there Bd. 31 (1977) Η. 2 Biosynthesis of Lignans. Part I 43 Table 1 Incorporation of *H and 3H/llC labelled ferulic acid derivatives into the lignans aictiin (3) and phillyrin (5) Amount Arctiin (3) Phillyrin (5) 3 incorp. incorp. Precursor taken up H: *'C aH: "C 3H: l!C (//mole) absol. spec. absoi. spec. Co) (,,o) C/o) Co) Glucoferulic acid O^'Cj-OCH^H) . 2.43 10.65 5 r 3.66 1.9 10.37 ' ι 0.68 T.40 ιο.π : 1 (-OCHj'H) 2.74 6.27 5.1 x.81 347 3 (y-^CO^H; -OCH2 H) 9.90 :r 9.98 ί ι 9.98 : ι Glucoferulic aldehyde . 4 3 GM C;-OCH2 H) . 0.41 12.80: ι 1.37 1.2 π.63 : ι 0.20 0.40 11.27 : r Coniferin u (ß- C; -OCH2*H) . 1.41 12.90: χ 0.74 O.7 11.48 : χ 0.x 6 0.40 12.25 : ι SA-Dtmethoxycinnamic acid (4-0-CH2*H) 0.50 0 0 0 0 are some indications, from feeding experiments with acid, the add (10) crystallized.
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