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Formation of Lignans (-)-Secoisolariclresinol and (-)-Matairesinol with Forsythia Intermedia Cell-Free Extracts*

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Formation of Lignans (-)-Secoisolariclresinol and (-)-Matairesinol with Forsythia Intermedia Cell-Free Extracts* NASA-CR-20_I¥1 ! , : THE JOURNAL OF _IOLO(_ICAI. CIIEMISTRY ! Vok 266, No. 16, Issue of June 5, pp, 10210 10217, 1991 ( 1991 by The Amer can Society for Biochemlslry and .Mo ecu ar B gy Inc, Printed in U. S A. J Formation of Lignans (-)-Secoisolariclresinol and (-)-Matairesinol with Forsythia intermedia Cell-free Extracts* (Received for publication, December 10, 1990) Toshiaki Umezawa$, Laurence B. Davin§, and Norman G. Lewis§ From the Commonwealth Center f.r Wo,d Science and l)epartment o/Biochemistry, Virginia Polytechnic Institute and State l,rnit,er,sitv Blacksburg, Virginia 2,I061-0323 In vivo labeling experiments of Forsythia interme- secoisolariciresinol 1), 1,2-dibenzylbutyrolactones (e.g. ma- dia plant tissue with [8-_4C]- and [9,9-"H.,,OC"H:dcon- tairesinol 2, arctigenin 3, arctiin 4), furofurans (e.g. pinore- iferyl alcohols revealed that the lignans, (-)-secoiso- sinol 5, epipinoresinol 6), 1-phenylnaphthalenes and tetralins lariciresinol and (-)-matairesinol, were derived from (e.g. podophyllotoxin 7) (see Fig. 1). two coniferyl alcohol molecules; no evidence for the Like the closely related polymeric lignins, lignans have been formation of the corresponding (+)-enantiomers was isolated from all parts of plant material (roots, leaves, stems, found. Administration of (-+)-[Ar-:_H]secoisolariciresi - bark, etc.) but are mainly located in woody tissue, particularly nols to excised shoots of F. intermedia resulted in a heartwood (6-9). Currently, we have no knowledge regarding significant conversion into (-)-matairesinol; again, the the actual site of lignan formation (biosynthesis) and the (+)-antipode was not detected. Experiments using cell- free extracts of F. intermedia confirmed and extended subcellular location where they are initially deposited or these findings. In the presence of NAD(P)H and H_O.,, stored. It is often assumed that lignans are deposited first in the cell-free extracts catalyzed the formation of (-)- the vacuole and are then ultimately secreted into the cell wall secoisolariciresinol, with either [8-_C]- or [9,9- following vacuole collapse. This has never been rigorously 2H.,,OC_H:dconiferyl alcohols as substrates. The (+)- proven. enantiomer was not formed. Finally, when either (-)- In terms of their biosynthetic pathways and structures, [Ar-:_H] or (+)-[Ar-ZH]secoisolariciresinols were used lignans and lignins are products of the shikimate/chorismate as substrates, in the presence of NAD(P), only (-)- and and phenylpropanoid pathways, and both are structurally not (+)-matairesinol formation occurred. The other related. Many substructures in lignins contain the structural antipode, (+)-secoisolariciresinol, did not serve as a elements of isolated lignans. substrate for the formation of either (+)- or (-)-matai- Lignans and lignins, however, apparently differ in one resinol. Thus, in F. intermedia, the formation of the fundamentally important aspect, namely optical activity. For lignan, (-)-seeoisolariciresinol, occurs under strict the most part, dimeric lignans (e.g. secoisolariciresinol 1, stereochemical control, in a reaction or reactions re- pinoresinol 5, matairesinol 2, and podophyllotoxin 7) are quiring NAD(P)H and H.,O., as cofactors. This stereo- optically active (1, 2), whereas isolated lignins are not. It is selectivity is retained in the subsequent conversion into perhaps significant that higher oligomeric forms of lignans (-)-matairesinol, since (+)-secoisolariciresinol is not a (trimers, tetramers, etc.) typically have only very small [a]x) substrate. These are the first two enzymes to be discov- values (5). Indeed, the exact point of demarcation between ered in lignan formation. oligomeric lignans and lignins is not well defined. The optical rotation of a particular lignan can vary with plant source; e.g. l_brsythia su.spensa (10, 11) contains (+)- Lignans are a structurally diverse class of aromatic phen- pinoresinol 5a, whereas Xanthoxylum ailanthoides (12) has ylpropanoid compounds widely distributed in gymnosperms the (-)-enantiomer 5b. No satisfactory explanation has been (e.g. softwoods) and angiosperms (e.g. hardwoods). By 1978, proffered to account for this stereochemical control leading lignans had been found in 46 families, 87 genera, and 146 to optical activity, other than that the reaction is somehow species (1, 2); many more have since been isolated, and the enzymatically mediated. Such control is not possible via in- structures of several hundred are now known. tercession of a (vpical peroxidase/H_O_-catalyzed reaction, a Lignans are most frequently encountered as "dimers" elab- reaction often implicated in lignin synthesis (13). orated from two "phenylpropanoid" monomers (1, 2), al- Surprisingly, the biosynthesis of lignans has been a ne- though higher oligomers have been isolated {3-5). Typically, glected area, even for medicinally important compounds such "dimeric" lignans (1, 2) are grouped according to structural as podophyllotoxin 7, a chemical precursor for the drugs type. Among the most common groups are diarylbutanes (e.g. etoposide and teniposide in cancer chemotherapy (14, 15). .... Indeed, not a single enzymatic step in the initial coupling of * This work was supported by NASA Granl NAGW-1277 and U. monomers, or any of the subsequent modifications (oxida- S. Department of Agriculture Grant 88 33521 4082. The costs of publication of this article were defrayed in part by the payment of tions, ring closures, etc.), has ever been reported. This is all page charges. This article must therefore be hereby marked "adver- the more surprising because of the close chemical relationship tisement" in accordance with 18 U.S.C. Section 1734 solely to indicate between lignans and lignins. this fact. In spite of substantive efforts (16, 17), unambiguous proof This paper is dedicated to the memory of Professor K. V. Sarkanen. of the exact chemical nature of the phenylpropanoid mono- :_Present address: Research Section of l,ignin Chemistry, Wood mers undergoing coupling to afford the lignan dimer skeleton Research Inst., Kyoto University, l!ji, Kyoto 611, Japan. § To whom correspondence should be addressed. [)resent address: had not been obtained. From our standpoint, two possibilities Inst. of Biological Chemistry, Washington State University, Pullman, were under consideration: the lignans, matairesinol 2, arcti- WA 99164-6340. Tel.: 509-335-2682; Fax: 509-335-7643. genin 3, arctiin 4, and podophyllotoxin 7, could be formed 10210 Formation o[ (-)-Secoisolariciresinol and (-)-Matairesinol 10211 = OH HO HO./_"_,/'OCH 3 °" . co H OH n_c°_ "OCH 3 OCH 3 OC H 3 OH OH 5a: (+)-plnoresinol 510: (-)-plnoresinol la: (+)-secolsolariciresinol 110: (-)-secoisolariciresinol OH OCH 3 H_o_'2' 7';., i_ °" __- :_ o H 5 3 HO _jco 3 OH OH OCH3 OCH3 OCH3 6: eplplnoraslnol 7: podophyllotoxln 2a: (+)-matalreslnol 2b: (-)-matalreslnol H 3: arctigenin, R1 = CH3, R2 = H _: arctlln, R1 = CH3, R2 = glc 7_s B_: coniferyl alcohol, R_ CH2OH, R2 H 68/_._-_,2 ¢J: slnapyl alcohol, R1 = CH2OH, R2 = OCH3 _F" OCH3 10: ferullc acid, R1 = COOH, R2 = H OR t R S 3 OCH3 --11: slnaplc acid, R1 = COOH, R2 = OCH3 OH FIG. 1. Representative lignans, monolignols, and hydroxycinnamic acids. via coupling of a monolignol (e.g. coniferyl 8 or sinapyl 9 istry. For a molecule such as matairesinol 2, its formation alcohol) and a hydroxycinnamic acid (e.g. ferulic 10 or sinapic could occur either by coupling of one molecule of coniferyl 11 acid). Alternatively, their formation could arise via direct alcohol 8 and one molecule of ferulic acid 10 followed by coupling of either two monolignols or two hydroxycinnamic spontaneous lactone formation or via direct coupling of two acids, with subsequent transformations occurring post-cou- coniferyl alcohol moieties to afford secoisolariciresinol 1 with pling. For example, secoisolariciresinol 1, pinoresinol 5, and subsequent dehydrogenation to give matairesinol 2. Alterna- epipinoresinol 6 could arise via direct coupling of the two tively, ferulic acid 10 or coniferaldehyde could serve as im- mediate precursors. monolignol molecules, coniferyl alcohol 8. Based on structural considerations, we rationalized that the It must be emphasized that this uncertainty, as regards initial coupling product was either secoisolariciresinol 1 or identity of the phenylpropanoid monomer(s) undergoing cou- matairesinol 2, and both lignans were obtained in racemic pling, was a key issue, since none of the possibilities described (+)-form by total synthesis. (+)-Matairesinols 2a/2b were above could be ruled out. Herein, we describe the direct formed using the method of Brown and Daugan (21) with the coupling of two coniferyl alcohol 8 moieties affording only following exception: reduction of methyl 2-carboxymethyl-3- (-)-secoisolariciresinol lb, which is then stereoselectively (4-hydroxy-3-methoxyphenyl)propionate was carried out in converted into (-)-matairesinol 2b. These conversions have 38.7% yield using a reducing agent, made in situ from n- been demonstrated using cell-free preparations from F. inter- butyllithium and diisobutyllithium aluminium hydride, rather media. than Ca(BH4)_, which, in our hands, consistently gave low yielding reactions. (+)-Secoisolariciresinols la/lb were ob- EXPERIMENTAL PROCEDURES 1 tained by LiAIH4 reduction of (+)-matairesinols 2a/2b. Each racemic lignan was resolved into its separate enantiomeric RESULTS AND DISCUSSION forms following passage through a Chiralcel OD column (Figs. 2A and 3A ). (-)-Secoisolariciresinol lb was synthesized from The first goal of our
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