Tài liệu Polyphenols trong thực vật (vegetable tannins) gallic acid metabolism

View Article Online / Journal Homepage / Table of Contents for this issue Plant Polyphenols (Vegetable Tannins*) : Gallic Acid Metabolism E. Haslama and Y. Caib aDepartmentof Chemistry, University of Sheffield, Sheffield S3 7HF ’Department of Pharmacognosy, The School of Pharmacy, University of L ondon, Brunswick Square, London, W C I N IAX (b) Molecular weights. Natural polyphenols encompass a substantial molecular weight range from 500 to 3-4000. Suggestions that polyphenolic metabolites occur which retain the ability to act as tannins but possess molecular weights up to 20000 must be doubtful in view of the solubility proviso. (c) Structure andpolyphenolic character. Polyphenols, per 1000 relative molecular mass, possess some 12-1 6 phenolic groups and five to seven aromatic rings. (d) Intermolecular complexation. Besides giving the usual phenolic reactions they have the ability to precipitate some alkaloids, gelatin, and other proteins from ~ o l u t i o n .These ~ complexation reactions are not only of intrinsic scientific interest as studies in molecular recognition and possible biological function, but also they have important and wideranging practical applications - in the manufacture of fashion leathers, in foodstuffs and beverages, in herbal medicine, and in chemical defence and pigmentation in plants. (e) Structural characteristics. Plant polyphenols are based upon two broad structural themes :(i) Galloyl and hexahydroxydiphenoyl esters and their derivatives. These metabolites are almost invariably found as multiple esters with D-glucose2,4-11and a great many can be envisaged as being derived from the key biosynthetic intermediate p- 1,2,3,4,6-pentagalloyl-~-glucose.Derivatives of hexahydroxydiphenic acid are assumed to be formed by oxidative coupling of vicinal galloyl ester groups in a galloyl Dglucose ester. Gallic acid is most frequently encountered in plants in ester form. These may be classified into several broad categories : (1) Simple esters. (2) Depside metabolites (syn-gallotannins). (3) Hexahydroxydiphenoyl and dehydrohexahydroxydiphenoyl esters (syn-ellagitannins) based upon : (a) 4C1con- Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 1 Introduction 1.1 1.2 2 2.1 2.2 2.2.1 2.2.2 2.2.3 2.2.4 2.2.5 2.2.6 3 4 Properties and Classification Isolation and Structure Elucidation Biosynthesis Secondary Metabolism Biosynthesis of Gallic Acid and its Esters Depside Metabolites Hexahydroxydiphenoyl? Esters and Related Metabolites Oxidative Metabolism - Pathway (b) Oxidative Metabolism - Pathway (c) Oxidative Metabolism - Pathway (d) ‘Open-chain ’ Derivatives of D-Glucose Comments and Conclusions Epilogue References 1 Introduction Emil Fischer, at the turn of the century, made some characteristically brilliant and perceptive contributions to the study of the constitution of the gallotannins from Chinese and Aleppo (Turkish) galls.’ His work, and that of Paul Karrer and Karl Freudenberg, stimulated a great deal of interest amongst chemists. These initial enthusiasms waned however as the great complexity of many plant extracts (often natural, but frequently induced by the many and varied post mortem processes required to derive them) was realized. By the 1950s the topic had become one of the dark impenetrable areas of Organic Chemistry. Its renaissance coincided with the advent of new methods of analysis and separation in the 1950s and the 1960s. Today the composition of many plant extracts can usually be adequately defined in terms of their polyphenolic (tannin) and simple phenolic constituents. There is thus, for the first time, a firm base from which to embark upon studies of the biological properties of plant polyphenols and in particular their complexation reactiom2 If there are exceptions to this generalization then these relate to the polyphenolic metabolites obtained from the wood and bark of trees. Here post mortem events multiply the complexities of normal metabolism. As a result the nature and total composition of many of these commercially important polyphenolic extracts remain uncertain. OH OH Galloyl ester I 1.1 Properties and Classification It is now possible to describe in broad terms the nature of plant polyphenols. They are secondary metabolites widely distributed in various sectors of the higher plant kingdom. They are distinguished by the following general features. (a) Water solubility. Although when pure some plant polyphenols may be only sparingly soluble in water, in the natural state polyphenol-polypheno1 interactions usually ensure some minimal solubility in aqueous media. -2H OH * Vegetable Tannins - because of its imprecision the authora has, over the past 25 years, sought to use this terminology as little as possible. However, like original sin, it declines to disappear; hence its use in the title of this review. t Hexahydroxydiphenoyl is used throughout this review as a convenient trivial radical. name for the 6,6’-dicarbonyl-2,2’,3,3’,4,4’-hexahydroxybiphenyl OH Hexahydroxydiphenoyl ester 41 Article Online NATURAL PRODUCTView REPORTS, 1994 42 H” 0 H’ HO OH y y o H OH 6 = 6.97 Flavan-3-01olgomer unit 6 = 7.08 ’ * Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 6,= 6.92 formation of D-glucose; (b) ‘C, conformation of D-glucose ; (c) ‘ open-chain ’ derivatives of D-glUC0Se. (4) ‘ Dimers ’ and ‘higher oligomers ’ formed by oxidative coupling of ‘monomers’, principally those of class (3) above. (ii) Condensed proan thocyanidins. The fundamental structural unit in this group is the phenolic flavan-3-01 (‘catechin’) nucleus. Condensed proanthocyanidins exist as oligomers (soluble), containing two to five or six ‘catechin’ units, and polymers (insoluble). The flavan-3-01 units are linked principally through the 4 and the 8 positions.2 In most plant tissues the polymers are of greatest quantitative significance but there is also usually found a range of soluble molecular species - monomers, dimers, trimers, etc. Oligomeric condensed proanthocyanidins have been held to be most commonly responsible for (Bate-Smith et the many distinctive properties of plants typically attributed to ‘condensed tannins ’. On the basis of solubility differences Sir Robert and Lady Robinson14-l5 subdivided the leucoanthocyanins (condensed proanthocyanidins) into three classes : (1) those that are insoluble in water and the usual organic solvents or give only colloidal solutions. (2) those readily soluble in water but not readily extracted therefrom by means of ethyl acetate. (3) those capable of extraction from aqueous solution by ethyl acetate. In so far as the total complement of condensed proanthocyanidins (procyanidins and prodelphinidins) found in plant tissues is concerned the soluble oligomeric forms (monomers, dimers, trimers ...) are, in metabolic terms, but the ‘tip of the iceberg’. According to the Robinsons’ classification they represent category (3) above. For the generality of plants it is quite clear that condensed proanthocyanidins, which fall within the two other categories (1 and 2), invariably strongly predominate over the more freely soluble forms. They are, metaphorically speaking, the base of the ‘metabolic iceberg ’. Indeed in the tissues of some plants such as ferns, and fruit such as the persimmon (Diospyros kaki), there is an overwhelming preponderance of these forms. They are also of frequent occurrence in plant gums and exudates. ~ 1 . ~ ~ 9 ~ ~ ) 1.2 Isolation and Structure Elucidation Real and substantial progress in the chemistry of the proanthocyanidins began to be made in the 1960s following the pioneering work of Weinges and his collaborators in Heidelberg. 16, l 7 As techniques and strategies for the separation and isolation of plant proanthocyanidins developed then so did work on their structure, chemistry, and biosynthesis. These researches have been regularly reviewed,2-18-20 particularly since 1975; the most recent by Porter21in 1988. This last article gives a detailed and comprehensive summary of flavans and proanthocyanidins : nomenclature ; a comprehensive register of plant sources and botanical distribution ; biosynthesis ; biomimetic synthesis ; chemistry ; and conformational characteristics. Other reviews which have recently been published deal with chemical transformations and conformational features of this group.22-24Although such statements are inevitably dangerous ones to make in science, it is difficult not to conclude that this area has now become a scientifically mature one. The most spectacular recent advances in the chemistry and biochemistry of plant polyphenols have undoubtedly been =G I HO \*. OH 6‘= 6.94 ‘6 = 7.02 Figure 1 Proton chemical shift values for the galloyl ester protons (*) of p- 1,2,3,4,6-pentagalloyl-~-glucose (D,O at 60 “C) made2q4-11in the field defined by the first structural group - the galloyl and hexahydroxydiphenoyl esters and their derivatives -the most dramatic feature of which has been the increase, by several orders of magnitude, of the number of known compounds in this class, now well over 700. Much of this work has emerged from two schools in Japan; those of Okuda in Okayama and Nishioka in Fukuoka. Substantial progress has been made possible by the application of new techniques of isolation and analysis,’ i.e. MPLC and HPLC using Sephadex gels, Toyo pearl (TSK HW-40), Diaion HP-20, Mitsubishi MCI gel CHP-20P, reverse phase C-8 and C-18 supports, centrifugal, partition, and droplet counter current chromatography, etc. High resolution NMR spectroscopy has provided a mine of structural information, and tables of diagnostic ‘H and 13C chemical shift and coupling constant data have been published.2v4.8q 25-29 Extensive use has been made of the nuclear Overhauser effect but particular note should be made of the use of IH--13C long range 2D NMR spectra which provide specific information concerning the orientation and location of different phenolic acyl groups, such as galloyl, hexahydroxydiphenoyl, valoneoyl, dehydrodigalloyl, sanguisorboyl, euphorbinoyl, trilloyl, chebuloyl, elaeocarpinusinoyl, on the polyol (usually D-glucose) core of the polyphenolic e ~ t e r . ~ ’This ~ - ‘ ~technique is based on the ability to establish connectivity between the aroyl proton(s) of an acyl group (*) and the proton(s) at the position of acylation on the polyol (usually D-glucose) core (m). This connectivity is established via the three bond couplings of the two groups of proton(s) to the ester carbonyl carbon atom (@, JCH 5 Hz). The method has been fully described30 and permits, for example, each of the five two-proton singlets associated with each of the five galloyl ester groups of /?- 1,2,3,4,6-pentagalloylD-glucose to be defined, Figure 1. This type of information is also of crucial importance for studies of the complexation of polyphenolic esters with other 32, e.g. caffeine, cyclodextrins, anthocyanins, peptides, and small proteins. - 2 Biosynthesis 2.1 Secondary Metabolism The distinctive features of gallic acid metabolism in higher plants bear all the hallmarks of secondary metabolism. 33-36 Thus three prominent characteristics are : (a) Structural diversity. At least 750 metabolites of gallic acid, which fall within the remit of the description polyphenol given above, have now been described. Despite their number, the structures of the overwhelming majority of these metabolites may be envisaged as being derived by chemical ‘embellishment and embroidery ’ of one key intermediate : /?- 1,2,3,4,6-penta-Ogalloyl-D-glucopyranose.2 , 4, lo,11, 36 In this sense they bear a very close analogy to other groups of secondary metabolites, such as the various classes of terpenes and alkaloids, where derivation from a common precursor is postulated. (b) Accumulation and storage. Gallic acid containing NATURAL PRODUCT REPORTS, 1994-E. View Article Online 43 HASLAM AND Y. CAI OH OH OH R = H, (-)-Epigallocatechin R = G, (-)-Epigallocatechin-3-Ogallate R = H, (-)-Epicatechin R = G, (-)-Epicatechin6-Ogallate 0 galloyl group, G = *m Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 OH Shikimate Pathway Phosphoenolpyrwate + 13-Erythrose-4-phosphate I 1 tico, 0f i O H OH M1 ?, 3-Dehydroshikimate t I t M2 f ~1,2,3,4,6-Pentagalloyl-~-glucose, M OH Gallic acid, G-OH L-Phenylalanine Figure 2 Secondary metabolism - gallic acid: an idealized picture; M,, M,, M,, efc. - secondary metabolites derived from the key secondary intermediate, /3- 1,2,3,4,6-pentagalloyl-~-glucose, M metabolites often accumulate in substantial quantities in plant tissues. The apotheosis of this characteristic is the storage (up to 70% of the dry weight) of complex polyphenols of the gallotannin class in Chinese galls (Rhus semialata). Similarly the vegetative tissues of the green tea flush (Camellia sinensis) may contain up to 25-30 YOof phenolic flavan-3-ols, prominent amongst which are ( - )-epigallocatechin and ( - )-epicatechin and their 3-gallate (c) Taxonomic distribution. Gallic acid containing metabolites are not universally distributed in higher plants. They occur within clearly defined taxonomic limits in both woody and herbaceous dicotyledons. l 3 Ellagitannins are widely distributed in the lower Hamamelidae, Dilleniidae, and Rosidae (the HDR complex) and have been used as prominent chemotaxonomic markers. It has been suggested that the low degree of diversification in gallate-dominated taxa may be a result of the electron scavenging properties of these metabolites which, in turn, inhibit oxidation, the most important reaction in the biosynthesis of secondary metabolite^.^^ One extant theory34,36 suggests that secondary metabolism provides organisms with a means of adjustment to changing circumstances. The synthesis of enzymes designed to execute the processes of secondary metabolism thus permits the network of enzymes operative in primary/intermediary metabolism to continue to function until such time as conditions are propitious for renewed metabolic activity and growth. Within this framework Bu'Lock and formulated a sequence of events which they envisaged would lead to the expression of secondary metabolism : a termination of balanced growth, leading to a sudden accumulation of intermediates in a primary metabolic pathway, leading to the induced synthesis of secondary metabolites. , In their idealized picture they suggested that a key secondary metabolite (P) was first formed and then transformed by secondary metabolic reactions to a diverse array of secondary metabolites, P,, P,, P,, ..., P,. These reactions would not have a high substrate specificity and their interplay in related organisms would result in the production of characteristic overlapping patterns of secondary metabolites. The biosynthesis of the myriad of gallic acid derivatives in plants may be most readily comprehended within the compass of this hypothetical sequence of events, Figure 2. Article Online NATURAL PRODUCT View REPORTS, 1994 44 HO OH OH Gallic acid G-OH HHO O q1 A OH UDP Uridine diphosphate glucose (UDP-glucose) HHO O a , OH 0-1-0Galloyl-D-glucose (P-o-Glucogallin) Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 \ I P- 1,2,3,4,6-Pentagalloyl-D-glucose P-1,2,3,6-Tetragalloyl-D-glucose Figure 3 Biosynthesis of p- 1,2,3,4,6-pentagalloyl-~-glucose; P-D-glucogallin as galloyl group donor enzyme from young oak leaves (EC 2.3.1 .90) catalyses the 2.2 Biosynthesis of Gallic Acid and its Esters formation of P- 1,6-digalloyl-~-glucosefrom two molecules of Gallic acid is unique amongst the various naturally occurring P-glucogallin. The sequence continues in an analogous fashion, hydroxybenzoic acids'l, 40 both in respect to its relative ubiquity with P-glucogallin as prime galloyl donor, via P- 1,2,6-trigalloylin the plant kingdom and of the quantitative significance of its D-glucose and P- 1,2,3,6-tetragalloyl-~-ghcose,to give finally Pmetabolism in many plants. Although some evidence exists to I ,2,3,4,6-pentagalloyl-~-glucose, Figure 3. One of the most show that gallic acid may arise by oxidative degradation of striking features of this biosynthetic pathway is that the ~-phenylalanine,~l the weight of experimental data favours sequence of esterification steps with gallic acid, 1-OH, then the view that it is nevertheless formed primarily via the 6-OH, 2-OH, 3-OH, 4-OH, exactly parallels the sequence in the Figure 2. In this dehydrogenation of 3-dehydro~hikimate,~~-~~ chemically mediated esterification of the hydroxyl groups of Dcontext, and that of Bu'lock and Powell's general h y p o t h e s i ~ , ~ ~ glucopyranose. 53 observations made with genetically engineered strains of This ~-D-glUCOgallindependent pathway is however by no Escherichia ~ o l i46~ are ~ . significant. These demonstrate that means exclusive. Studies with enzyme extracts of sumach (Rhus under conditions of an artificially induced high carbon flux typhina) have shown that, in addition to P-D-glucogallin, P- 1,6through the Shikimate pathway the organism responds by the digalloyl-D-glucose, p- 1,2,6-trigalloyl-~-ghcose,and P- 1,2,3,6production of enzymes which act solely and specifically to tetragalloyl-D-glucose may also act, although with progressively remove excessive concentrations of the intermediate 3decreasing efficiency, as galloyl group donors (from the 1dehydroshikimate as they arise (in this instance as position of the galloyl-ester), Figure 4.Thus two molecules of protocatechuate and the P-ketoadipate pathway). P- 1,6-digalloyl-~-glucosedisproportionate, Figure 4 (i), to give P-Glucogallin (p-1-0-galloyl-D-glucose), first isolated from p- 1,2,6-trigalloyl-~-glucose and 6-O-galloyl-~-glucose; simiChinese rhubarb (Rheum oficinale) in 1903,47is, following the larly P- 1,6-digalloyl-~-glucose may substitute for P-Dextensive studies of G ~ o s s , ~considered ~ - ~ ~ to be the key glucogallin as galloyl group donor in the conversion of p- 1,2,6intermediate in the biosynthesis of esters of gallic acid. Work trigalloyl-D-glucose to P- 1,2,3,6-tetragalloyl-D-glucose, Figure with cell-free extracts from oak leaves, and subsequently with 4 (ii). Although alternative explanations are possible these the partially purified glucosyl transferase, verified that observations may have some bearing upon the observation P-glucogallin is generated by the reaction of gallic acid with (vide infra, Section 2.2.6) that many polygalloyl (and UDP-glucose. Thereafter P-glucogallin undergoes a series of hexahydroxydiphenoyl) esters of D-glucose are frequently found further galloyl transfer reactions to yield ultimately P- 1,2,3,4,6in plant extracts in a form in which the anomeric hydroxyl pentagalloyl-D-glucose. It is very interesting to note that group is unacylated. P-glucogallin acts as the principal galloyl-group donor in these Strong circumstantial evidence now exists to support the reactions. Thus in the first of these reactions a partially purified proposition2-4 , lo.11*36 that the metabolite p- 1,2,3,4,6-penta- View Article Online 45 HASLAM AND Y. CAI NATURAL PRODUCT REPORTS, 1994-E. p-1,6-DigalloyCD-glucose , HHO (i) o ';i;* HHOO g OG G o G OG OH p-1,6-Digalloyl-O-glucose p-1,2,6-Trigalloyl-~-glucose t, HHOO k O H OH Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 6-Gallo yl-D-glucose HHO O a a OH p-1,6-Digalloyl-o-glucose I p-1,2,6-Trigalloyl-D-glucose ;, i p-1,2,3,6-Tetragalloyl-D-glucose FOG HoHO *OH OH 6-Galloyl-D-glucose Figure 4 Biosynthesis of galloyl esters of D-glucose: p- 1,6-digalloyl-~-glucoseas galloyl group donor Pathway (d): Oxidative coupling; ring opened -open chain derivatives Pathway (b): Oxadative coupling; Dehydrogenation,4-6and 2-3; Oligomerizationby G O coupling GGO o*m OG ~-1,2,3,4,6-Pentagalloy~-D-glucose ~Glucopyranose-~C~ conformation / J' 4 ococ p-1,2,3,4,6-Pentagalloyl-D-glucose D-Glucopyranose-'C4 conformation Pathway (a): Additional galloyl groups esterified as mdepsides to the performedgalloyl glucose I J -1% Pathway (c): Oxadative coupling; Dehydrogenation, 3-6, 1-6 and 2-4; Dehydmhexahydmydiphenoylesters Figure 5 Biogenesis of the gallotannins and ellagitannins ; the metabolic embellishment of ~-1,2,3,4,6-pentagalloy1-~-glucose, principal pathways galloyl-D-glucose, Figure 3, then plays a pivotal role, Figure 2, in the formation of the vast majority of gallotannins and ellagitannins which occur in many plants. Its biosynthetic position is analogous to those of norlaudanosoline and strictosidine in the formation of the benzylis~quinoline~~ and the terpene-ind~le~~ alkaloids respectively. Four distinctive and principal pathways, (a), (b), (c), and (d), are then presumed to lead from /?-1,2,3,4,6-pentagalloyl-~-glucose to give, by appropriate chemical embellishment, the various classes of metabolites, Figure 5. Article Online NATURAL PRODUCT View REPORTS, 1994 46 n 0 lusitanica) yield a gallotannin in which additional galloyl groups are linked as m-depsides to a mixture of p-1,2,3,4,6pentagalloyl-D-glucose and p- 1,2,3,6-tetragalloyl-~-gluC O S ~ . Likewise ~ ~ , ~ * the fruit pods of Caesalpinia spinosa give and a gallotannin based on a trigalloyl-quinic acid similar polygalloyl esters have been isolated from Castanopsis cuspidata and Acer saccharinum, respectively, which are based upon shikimic acid59and 1,5-anhydro-~-glucitol. Hofmann and GrossG1have very recently described enzymic studies with extracts of Rhus typhina which begin to chart the biosynthetic pathway from ~-1,2,3,4,6-pentagalloyl-~-glucose to the gallotannins in sumach (mixtures of hexa-, hepta-, and octagalloyl-D-glucose derivatives). Detailed ‘H and 13C NMR analysis of the hexagalloyl-D-glucose fraction showed it to contain at least three hexagalloyl esters in which additional galloyl ester groups were linked as m-depsides to the galloyl ester groups attached to C-2, (2-3, and C-4 of the Dglucopyranose ring. 27v G= HO HO 6H =G-G O Y 0 ‘ 0 QOH Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 OH Chinese gallotannin,tannic acid OH @OH -2H ~ C02Me ___) OH HO HO ;68v ;653 OH OH Methyl gallate OH 2.2.2 Hexahydroxydiphenoyl Esters and Related Metabolites In the thirty year period from 1950 to 1980 the Heidelberg school of Otto Schmidt and Walter Mayer made distinguished and seminal contributions to the study of naturally occurring hexahydroxydiphenoyl e s t e r ~ . ~They ~ - ~ lisolated and identified key metabolites such as corilagin 70-72 pedunculagin ;75 chebulinic and chebulagic acids 71, 73 dehydrodigallic, valoneic, and brevifolin carboxylic acids ;66, 6 7 , 7 8 trilloic acid ;87 t e r ~ h e b i nand ~ ~ the dehydrohexahydroxydiphenoyl esters brevilagin 1 and 2 77 vescalin, castalin, vescalagin, and castalagin ;*O, 8 3 * 8 5 ,8 8 . 91 punicalin and punicalagin ;** castavaloninic acid valolaginic acid and isovalolaginic acid.82In addition, as the work progressed they continued to proVide62-64,6 9 , 7 9 , 9 2 an intellectually satisfying biogenetic rationale for the derivation of this group of naturally occurring polyphenolic esters (syn. ellagitannins). This pioneering work has securely underpinned all subsequent developments in this field, particularly the explosive increase in knowledge of the past fifteen years which has resulted in the identification of at least 500 discrete compounds in this class. The following discussion does not attempt to be totally comprehensive, but classifies the major groups of metabolites within a structural and biogenetic framework. Whilst there is, as yet, no formal experimental proof it is generally assumed, following the hypo thesis enunciated by Schmidt and M a ~ e r , ~92’ . that naturally occurring hexahydroxydiphenoyl esters and their derivatives are derived by oxidative coupling of galloyl esters (with the formation of new C-C and C-0 bonds) and oxidative and hydrolytic aromatic ring fission. Support for the initial step in the putative biogenetic scheme has been obtained by oxidation of methyl gallate (potassium iodate,28 peroxidaseg3) to give dimethyl hexahydroxydiphenoate. In the context of any consideration of the range and chemical structure of metabolites now identified in plant extracts (vide infra), it is important to note the lability of dimethyl hexahydroxydiphenoate in aqueous media. Thus the biphenyl ester is readily transformed to the highly insoluble bis-lactone ellagic acid on standing in water. This transformation is undoubtedly facilitated by the proximal juxtaposition of the phenolic and ester groups on separate aromatic nuclei and by free rotation about the biphenyl linkage. Strong circumstantial evidence now also exists to suggest that the vast majority of metabolites are derived biosynthetically, cf. Figure 5, (with subsequent possible modifications in vivo by facile hydrolytic reactions), by oxidative transformations of the key precursor /3- 1,2,3,4,6-pentagalloylD-glucose, following a scheme first put forward in 1982,4 Figure 6 . In the ellagitannin metabolites now described, numerous intramolecular ‘ C-C ’ linked ester groups have been located in the ‘monomers ’ and similarly various intermolecular ‘ C-0 ’ linking ester groups have been defined in the formation of the Dimethylhexahydroxydiphenoate ;76v 1 -2MeOH OH HO OH Ellagic acid 2.2.1 Depside Metabolites The ability to metabolize depside derivatives of gallic acid [Figure 5, pathway (a)] may be used as a guide to interrelationships in particular plant families55 and there is, on present evidence, a close association of this form of metabolism with the Rhoideae tribe in the Anacardiaceae. Many of the products of this form of metabolism were often grouped together in the earlier literature under the generic term ‘gallotannin’. The most common and familiar example is Chinese gallotannin, or tannic acid, (galls, Rhus semialata), which possesses the overall composition of a hepta- to octagalloyl-P-D-glucose and in which, on average, two to three additional galloyl groups are esterified in depside form to a preexisting p- 1,2,3,4,6-pentagalloyl-~-glucosecore. A novel method of a n a l y s i ~ based ~ ~ , ~on ~ the use of HPLC and 13C NMR reveals the full heterogeneity of the typical Chinese gallotannin extract. This ranges from /3-pentagalloyl-D-glucose itself to compounds with up to five or six additional galloyl residues linked as m-depsides to this core. The proportion of each type determines the final overall composition of the gallotannin extract. Using 13C NMR the position of the additional depside residues has been determined to be predominantly to the galloyl groups at C-2 or C-3, C-4 and C-6. This polygalloyl-D-glucose is the most widely encountered ester of this type found in plants,2~4~27 but others have also been described. The galls of various oaks (Quercus infectoria, Q. NATURAL PRODUCT REPORTS, 1994-E. View Article Online 47 HASLAM AND Y. CAI p-1,2,3,4,6-PentagalloyI-D-glucose I intramolecular +I GC coupling hexahydroxydiphenoyl and dehydrohexahydroxydiphenoyl esters ('monomers') 1 intermolecular GO coupling [hexahydroxydiphenoyl and dehydrohexahydroxydiphenoyl esters], ('oligomers', n = 2,3,4) Figure 6 Overall patterns of oxidative metabolism of p- 1,2,3,4,6-pentagalloyl-D-glucose in higher plants to yield ellagitannins4 Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 OH I 0 HO co I HO HO HO HO HO OH ' I (R)-Hexahydroxydiphenoyl Figure 7 (S)-Hexahydroxydiphenoyl OH OH Flavogallonyl Gallagyl Ho&v Principal derivatives of hexahydroxydiphenic acid formed by intramolecular C-C oxidative coupling / 0 ' OH -OH OH 3H HO 0 Chebuloyl I 0 Dehydrochebuloyl ?H 0 Dehydohexahydroxydiphenoyl \c+ 0 OH -0c OH L-Ascorbic acid OH \ ? b 0 Brevifolyl Trilloyl Figure 9 Ester derivatives of hexahydroxydiphenic acid in which one aromatic ring has undergone hydrolytic cleavage Elaeocarpusinoyl Figure 8 The dehydrohexahydroxydiphenoyl ester group and its derivatives oligomeric' structures. The principal members of these two classes of ester group are shown in Figures 7 to 10. In the intramolecular formation of a hexahydroxydiphenoyl ester group the generation of a large-membered ring containing two cis ( 2 )double bonds reduces conformational flexibility 4 and gives the molecule much greater rigidity. Where the bridging occurs 1,6, 3,6, o r 2,4, the D-glucopyranose residue is forced to adopt a thermodynamically unfavourable C, conformation. One specific chirality is imposed upon the hexahydroxydiphenoyl group as it is formed and this chirality is determined by the need of the new ester group to bridge particular positions in the polyol (usually D-glucose) portion of the molecule. The absolute configuration of the twisted biphenyl system in corilagin has been deterrnined9,sg5as (R)by relation NPR 11 Article Online NATURAL PRODUCTView REPORTS, 1994 48 O ' co HO I H HO O OH W OH '/ OH HO occo 0 - OH I I oc I OH (S)-Sanguisotboyl oc I / \ oc co I I (S)-Valoneoyl OH OH - oc co I I I I OH - (R)-Valoneoyl \ / I I OH @ - DehydrodigalloyI Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 OH W OH OOH H I HO$O@ I L HOC (R)-Macaranoyl (R)-Tergalloyl -OH HO OH (R )-EuphorbinoyI Figure 10 Principal ester groups formed by intermolecular C-0 oxidative coupling of galloyl and hexahydroxydiphenoyl esters -2H ___) bb-Galloyl ester HO OH OH HO Hexahydroxydiphenoylester OH MeOOMe OMe OH - Me0 Me0 OMe OMe M e O Me02C w O M e COfle Dimethyl(R)-(+)-hexamethoxydiphenoate Corilagin, G = galloyl - \-I Ho Me Me Schizandrin 95 Figure 11 Determination of the absolute configuration of ( + )-hexahydroxydiphenic acid in the metabolite corilaging4* NATURAL PRODUCT REPORTS, 1994-E. Gemin D p-1,2,3,4,6-Pentagalloyl-D-glucose PterocatyaninC Tellimagrandin 2 (Eugeniin) Strictinin Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 View Article Online 49 HASLAM AND Y. CAI Sanguin H-4 Tellimagrandin 1 __..--Casuariitin Potentillin OH Pedunculagin HO G= G-G = 0 HO (S)-Hexahydroxydphenyl Galloyl Figure 12 Principal ‘ monomeric’ hexahydroxydiphenoyl esters formed by oxidative coupling of vicinal galloyl ester groups in conformation ; pathway (b) pentagalloyl-wglucose ; Table 1 Principal naturally occurring ‘monomeric ’ ( S ) hexahydroxydiphenoyl esters ; 4C, D-glucopyranose. Structures - positions of esterification to the D-glucose core Trivial name Galloyl Hexahydroxydiphenoyl Ref. Tellimagrandin I1 (Eugeniin) Tellimagrandin I Casuarictin Potentillin Pedunculagin Gemin D Strictinin Heterophyllin A Sanguin H-1 Sanguin H-4 Nobotanin D Roxbin B Pterocaryanin B Pterocaryanin C p- 1,2,3 4,6 97,99 233 496 2,3 :4,6 2,3 :4,6 2.3 :4.6 97 28, lol 28, 102, 103 75, 104 105, 106 107 108 111 109, 110 112, 113 114 115 116 P-1 a-1 - I 3 P-1 a-1,3 a1,6 a-1 P-176 - 4 B- 1,4,6 + )-catechin derivatives Stenophynin A Stenophynin B I8-8-C-( - 6 2,3 :4,6 2,3 117 117 to the lignan schizandrin, Figure 11, and the chirality of other hexahydroxydiphenoyl esters may be determined by measurements of circular dichroism (CD) and comparison with corilagin. The C D spectra of hexahydroxydiphenoyl esters are characterized by a distinctive couplet centred at 200-210 nm with a positive or negative maximum at 228-238 nm. The AE values are approximately incremental for the number of hexahydroxydiphenoyl ester groups in the 94, 95 It is of interest to note that the same conclusions regarding the chirality of the hexahydroxydiphenoyl ester groups bound to - B- 1,2,3,4,6- the D-glucopyranose core may be deduced from theoretical considerations.4 , 28 These arguments also strongly suggest that the absolute configuration of the hexahydroxydiphenoyl esters is determined largely, if not solely, by the inbuilt stereochemistry of the sugar molecule. The principal mode of transformation (Figure 5, pathway (a)) is by oxidative C-C coupling of galloyl ester groups (4-6 and 2-3) in the thermodynamically most stable confollowed by formation of p- 1,2,3,4,6-pentagalloyl-~-glucose oxidative oligomerization (C-0, coupling). Two further modes of elaboration are also both oxidative in character. Pathway (c) (Figure 5) occurs via oxidative C-C coupling of galloyl ester groups (3-6, 1-6, and 2-4) in the thermodynamically least stable ‘C4 conformation of p- 1,2,3,4,6-pentagalloyI-~-glucose followed again by oxidative oligomerization (C-0, coupling). Metabolites in this class are also often characterized by the presence of the dehydrohexahydroxydiphenoyl ester group and derivatives, e.g. chebulinic and chebulagic 71 in which one aromatic nucleus of this functionality has undergone hydrolytic ring fission. Finally, in pathway (d) the oxidative transposition of p- 1,2,3,4,6-pentagalloyl-~-glucose takes place by ring opening and the formation of unique open-chain derivatives of D-glucose. 2.2.3 Oxidative Metabolism - Pathway ( b ) This represents the most commonly encountered biogenetic route to the ellagitannins. A series of metabolites (‘monomers ’) is first formed by C-C oxidative coupling of vicinal galloyl ester in its groups 4,6 and 2,3 in p- 1,2,3,4,6-pentagalloyl-~-glucose thermodynamically preferred 4C, conformation. Some details of this pattern of metabolism were hinted at in earlier work by Schmidt and M a ~ e r 7, 5~* 78~Hillis . and Siekel,96and Wilkins and B ~ h m . Plants ~’ whose phenolic metabolism places them within this category furnish, as principal metabolites, one or more of the (S)-hexahydroxydiphenoyl esters shown in Figure 12, Table 1. Interesting exceptions to this generalization are 4-2 Article Online NATURAL PRODUCTView REPORTS, 1994 50 Table 2 Principal naturally occurring ‘ dimeric ’ galloyl/(S)hexahydroxydiphenoyl esters ; 4C, D-glucopyranose; dehydrodigalloyl ester C-0 linking group. Structures positions of esterification of dehydrodigallic acid to the Dglucose cores a* Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 b* Monomer-I1 (b*) Casuarictin (1) Casuarictin (1) p- 1,2,3-TrigalloylD-glucose (1) Tellimagrandin 2 (1) Rugosin A Potentillin (1) Sanguin H-4 (1) Potentillin (1) 2-0-Galloyl-4,6-(S)hexahydroxydiphenoylD-glucose (2) Trivial name Monomer-I (a*) Gemin A Gemin B Gemin C Potentillin (1) Sanguin H-4 (1) Potentillin (1) Coriariin A Coriariin C Agrimoniin Laevigatin B Laevigatin C Laevigatin D Tellimagrandin 2 (1) Tellimagrandin 2 (1) Potentillin (1) Potentillin ( I ) Sanguin H-4 (1) Potentillin (1) Ref. 109, 118 109, 118 109, 1 18 119 119 120 120 120 120 Positions of esterification of the linking dehydrodigallic acid group are indicated as ‘a*’ and ‘b*’ and by the figures in parentheses. provided by cercidins A and B and cuspinin, all of which contain a 2,3-(R)-hexahydroxydiphenoyl ester group.98 It is then presumed that, as a second phase by oxidative intermolecular C-0 coupling, dimeric, trimeric, and tetrameric structures are subsequently formed, Figure 6 , Table 2. The isolation and structure determination of two ‘ dimers ’ formed by C-0 oxidative coupling of intermediates such as are shown in Figure 12 were first reported in 1982.28,120 Since that time more than seventy five ‘oligomers’ have been described. These are broadly divisible into several sub-types dependent on the mode of C-0 coupling between a phenolic hydroxyl group in one ‘monomer’ and an aromatic ring carbon in another ‘monomer’. The three principal modes of C-0 coupling, Figure 10, are those between two galloyl groups (to give a dehydrodigalloyl linking group), Table 2, and between one galloyl group and an (S)-hexahydroxydiphenoyl ester group to yield either a valoneoyl or the positionally isomeric sanguisorboyl linking ester group. Present evidence suggests that the (S)-valoneoyl linking ester group is the one most commonly formed, Table 3. For some time the most frequently encountered situation was that in which the linkage involved a galloyl ester group at the anomeric centre of at least one of the ‘monomers ’. Linkage through galloyl ester groups at other positions on the glucose ring have, however, now been noted in several instances, Table 3. Typical examples - gemin A, sanguin H-6, calamanin B, cornusiin C, and calamanin C [G = galloyl, G-G = (S)-hexahydroxydiphenoyl] - are shown in Figures 13 and 14. ‘Dimers’ with macro-ring structures formed by C-0 oxidative coupling between two galloyl ester groups and an (S)-hexahydroxydiphenoyl ester group have been reported, Sanguin H-6; (S)-sanguisorbic acid linking group Gernin A; dehydrodigallic acid linking group -- potentillin dehydrodigalloyl group 0 tellimagrandin 2 *.** potentillin 0 Calarnanin B; (S)-valoneic acid linking group OH tellirnagrandin 2 potentillin HO (S)-valoneoyl group OH Figure 13 ‘ Dimeric ’ ellagitannins : different modes of C-0 oxidative coupling (----) groups, [G-G = (S)-hexahydroxydiphenoyl, G = galloyl] to give dehydrodigalloyl, sanguisorbyl, and valoneoyl ester View Article Online 51 NATURAL PRODUCT REPORTS, 1 9 9 6 E . HASLAM AND Y. CAI ~ ~ ~~ Table 3 Principal naturally occurring ‘dimeric ’ galloyl/(S)-hexahydroxydiphenoyl esters ; 4C, D-glucopyranose ; (S)-valoneoyl ester C-0 linking group. Structures - positions of esterification of (S)-valoneic acid to the D-glucose cores OH Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 OH Trivial name Monomer-I (a*) Monomer-I1 (b*, c*) Ref. Rugosin D Rugosin E Rugosin F Cornusiin A Cornusiin D Cornusiin E Camptothin A Camptothin B Roxbin A Coriariin D Coriariin E Nobotanin A Tellimagrandin-2 (6,4) Tellimagrandin- 1 (6,4) Casuarictin (6,4) Tellimagrandin- 1 (4,6) Tellimagrandin- I (4,6) Tellimagrandin-2 (4,6) Gemin D (4,6) Tellimagrandin- 1 (4,6) Tellimagrandin- 1 (6,4) Tellimagrandin- 1 (6,4) Gemin D (6,4) Casuarictin (6,4) 119, 121-123 119, 121-123 119, 121-123 124-125 124-125 124125 126 126 127 119 119 112, 113 Casuarictin (4,6) Casuarictin (6,4) Casuarictin (3,2) Casuarictin (3,2) Pedunculagin (6,4) 112, 113 112, 113 128 130 112, 113 Isorugosin D Phillyraeoidin B Phillyraeoidin C Phillyraeoidin D Tellimagrandin-2 (1) Tellimagrandin-2 (1) Tellimagrandin-2 (1) Tellimagrandin- 1 (2) Tellimagrandin-2 (2) Tellimagrandin-2 (2) Tellimagrandin- 1 (2) Tellimagrandin- 1 (2) Casuarictin (1) Rugosin A (1) Tellimagrandin-2 (1) 4,6-Digalloyl-2,3-hexahydroxydiphenoyl-~glucose (4) Pterocaryanin C (4) Pterocaryanin C (4) p- 1,4,6-Trigalloyl-~-glucose(4) Rugosin A 4,6-Digalloyl-2,3-(S)-hexahydroxydiphenoyl-~glucose (4) Tellimagrandin-2 (1) p- 1,2,3,4,6-pentagalloyl-~-glucose (4) /3-1,2,3,4,6-pentagalloyl-~-glucose (4) p- 1,2,3,4,6-pentagalloyl-~-glucose (4) 129 130 130 130 Phillyraeoidin E 2,3,4,6-Tetragalloyl-~-glucose (4) Woodfordin A Woodfordin B p- 1,2,3,6-Tetragalloyl-~-glucose(2) Tellimagrandin- 1 (2) Eusupinin A Calamanin B Camelliin A Tellimagradin-2 (1) Tellimagrandin-2 (1) Tellimagrandin- 1 (2) Tellimagrandin-2 (4,6) Tellimagrandin-2 (6,4) Tellimagrandin- 1 (6,4) p- 1-Galloyl-4,6-(S)-hexahydroxydiphenoyl-~glucose (4,6) p- 1 -Galloyl-4,6-(S)-hexahydroxydiphenoyl-~glucose (4,6) Tellimagrandin-2 (6,4) a- 1,2,3-Trigalloy1-4,6-(S)hexahydroxydiphenoyl-D-glucose (6,4) Rugosin A (6,4) Potentillin (6,4) Pedunculagin (6,4) Nobotanin B Nobotanin F Nobotanin G Nobotanin H Medinillin B 130 131, 132 131, 132 133 134 135 Positions of esterification of the linking (S)-valoneic acid group are indicated as ‘a*’, ‘b*’ and c* and by the figures in parentheses. Table 4 Principal naturally occurring ‘macrocyclic ’ galloyl/(S)-hexahydroxydiphenoyl esters ; 4C, Dglucopyranose ; (S)-valoneoyl ester C-O linking groups Trivial name ‘ Monomer’ composition Ref. Camelliin B Tellimagrandin 1 Tellimagrandin 2 2 x Tellimagrandin 1 3 x Tellimagrandin 1 Rugosin A + Casuarictin Tellimagrandin 1 +a-1,2,3Trigalloyl-4,6-(S)hexahydroxydiphenoylD-glucose 2 x Tellimagrandin 1 + a1,2,3-Trigalloyl-4,6-(S)hexahydroxydiphenoylD-glucose 135 Oenothein B Oenothein A Nobatannin I Woodfordin C (Woodfructicosin) Woodfordin D + 139 140 141 131, 132 Table 5 Principal naturally occurring higher ‘ oligomeric’ galloyl/(S)-hexahydroxydiphenoyl esters ; 4C, Dglucopyranose ; (S)-valoneoyl ester C-O linking groups Trivial name ‘ Monomer ’ composition Ref. Rugosin G Cornusiin C Cornusiin F Calamanin C Trapanin B Trapanin A Prostatin B 3 x Tellimagrandin 2 3 x Tellimagrandin 1 2 x Tellimagrandin 1 + Gemin D 2 x Tellimagrandin 2 + Potentillin 4 x Tellimagrandin 1 3 x Tellimagrandin 1 2 x Tellimagrandin 2 + Tellimagrandin 1 4,6-Digalloyl-2,3-(S)hexahydroxydiphenoy1-Dglucose + Casuarictin + Pterocaryanin C Pterocaryanin C + Casuarictin + Pterocaryanin C 119, 121-123 124,125 125 134 136 136 137 Nobotanin C 140 Nobotanin E 138 138 View Article Online NATURAL PRODUCT REPORTS, 1994 52 Catamanin C-2x(S)-valoneoyl linking groups Cornusiin C-2x(S)-valoneoyllinking groups G (S)-valoneoyl group OH tellimagrandin 1 HO ' , , Go tellimagrandin 2 OH OH (S)-valoneoyl group HO OH OH OH 0 teliirnagrandin 2 \ --. Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 --..- (S)-valoneoyl HO OH tellimagkndin 1 G = galloyl; G-G = (S)-hexahydroxydiphenoyl Figure 14 'Trimeric' ellagitannins, formed by C-0 oxidative (----) coupling to give (S)-valoneoyl linking ester groups J5 HO Ho OH H&H iH'"-y : \ --1 co, '9 0 \ / OH Hovco OH Ho OH 0-co HO OH HO OH Cornusiin A Oenothein B Figure 15 Suggested pathway of biogenesis of oenothein B by intermolecular C-0 coupling of two molecules of tellimagrandin 1 ; G = galloyl NATURAL PRODUCT REPORTS, 1994-E. View Article Online 53 HASLAM AND Y. CAI OH 'OG OH Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 Rugosin A PhillyraeoidinA Stenophynin B Stenophynin A Table 6 Principal naturally occurring 'monomeric ' (R)hexahydroxydiphenoyl esters. Structures - positions of esterification to the D-glucose core Trivial name Hexahydroxydiphenoyl groups Galloyl groups Ref. 'C,D-glycopyranose Corilagin Punicafolin Tercatain p- 1 p- 1,2,4 p- 1,4 p- 132 p- 1-m-digalloyl Nupharin B a-1,2,4 Cercidinin A Cercidinin B p- 1,4,6 4,6 376 3,6 3,6 396 3,6 396 4C1D-glucopyranose 273 273 68, 70, 71, 150 151, 152 149,151 116, 153 116, 153 154 155 155 Table 4, as have higher oligomers (seven 'trimers' and two ' tetramers') based on the same C-0 oxidative oligomerization processes, Table 5. Typical examples of macrocyclic polyphenolic esters are those of camelliin B, oenotheins A and B, and woodfordins C and D. The biogenesis of oenethein A is presumed to be typical and to follow a pathway such as that shown in Figure 15. In addition to the various oligomeric (S)-hexahydroxydiphenoyl and galloyl esters which have been described (Tables 1-S), 'monomeric ' esters have been isolated from plants containing principally the (S)-valoneoyl or dehydrodigalloyl ester groups either in a lactonized form or in a state in which one of the carboxyl groups is free. Typical examples of such metabolites are rugosins A, B, and C,142*143 praecoxins A, C, and D,lg2* 144* 145 cornusiin B,146,147 phillyraeoidin A,130 isorugosin B,12, coriariins B and F,'19 isocoriariin F,12, calamanin A,134schimawalin A,146oenothein C,lg6l g 7 medinillin A,128tirucallin A,147, prostatins A and C,lg7. "* sanguin H-2,11' and m a ~ a r a n i n . ' The ~ ~ important question of whether these are true natural products or Table 7 Principal naturally occurring ' monomeric ' ( S ) hexahydroxydiphenoyl esters ; 'C,D-glycopyranose. Structures - positions of esterification to the D-glucose core Trivial name Macarangdnin Davidiin Helioscopinin B Nupharin A Gallo yl groups /3-1,2,4 2,394 3 01- 1,2,4 Hexahydroxydipheno yl groups 336 p- 1,6 p- 1,6 376 Ref. 152 29,156 I57 154 derivatives which are formed by mild hydrolysis in either the plant cell or during extraction is addressed later in this review (vide infra, Section 2.2.6). Finally stenophynins A and B117 represent an interesting structural variation upon the polyphenolic esters outlined above with the linking by a C-C bond at the anomeric centre of the ,C, D-glucopyranose ring of a ( + )-catechin residue. 2.2.4 Oxidative Metabolism - Pathway ( c ) According to present evidence a rather smaller group of plants adopts an alternative metabolic variation in which oxidative coupling of adjacent galloyl ester groups occurs ' one-three ' to form both (R)-and (S)-hexahydroxydiphenoyl esters, (and their derivatives) in a D-glycopyranose precursor which itself adopts the less favourable lC4, or an intermediate skew-boat, conformation. An additional significant feature of this form of metabolism is that one or more of the hexahydroxydiphenoyl ester groups may be further dehydrogenated to give derivatives of the dehydrohexahydroxydiphenoyl ester group, Figure 8. Phenolic metabolites of this class have been discerned in members of the plant families Cercidiphyllaceae, Ericaceae, Onagraceae, Combretaceae, Nyssaceae, Aceraceae, Punicaceae, Simaroubaceae, and G e ~ a n i a c e a e .Some ~~ of the principal 'monomeric' esters of this class are listed in Tables 6 to 9. View Article Online NATURAL PRODUCT REPORTS, 1994 54 Table 8 Principal naturally occurring ' monomeric ' dehydrohexahydroxydiphenoyl esters. Structures - positions of esterification to the D-glucose core. I @ OH OH 0 0 OH OH C, D-Glucopyranose Trivial name Hexahydroxydipheno y 1 Dehydrohexahydroxydiphenoyl Ref. Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 ' C , D-glucopyranose Terchebin Geraniin Deh ydrogeraniin Furosin Furosinin Carpinusin Helioscopinin A Tanarinin Granatin A Granatin B Supinanin Euphorscopin Mallotusonic acid Macaranin C (R)-2,4* (R)-2,4* (R)-2,4* : 3,6* (R)-2,4* (R)-2,4* : 3,6* (R)-2,4* (S)-2*,4 (R)-3*,6 (S)-2*,4 (S)-2* ,4 (S)-2*,4 p- 1934s 1 (R)-2,4* (R)-2,4* Isoterchebin Brevilagin 1 Brevilagin 2 (R)-4* ,6 p- 1,3:4,6 p-1,3 74, 116, 152, 157 29, 137, 147, 156 158 159 160 159 I57 157 152 29, 161 29, 161 123 123 116 149 ,C1D-glucopyranose 158 76 77 Table 9 Principal naturally occurring 'monomeric ' elaeocarpusinoyl esters ; 'C, D-glucopyranose ; positions of esterification to the D-glucose core. 0- I 0 OH Elaeocarpusinoyl Trivial name Galloyl Elaeocarpusinoyl Hexahydroxydiphenoyl Ref. Elaeocarpusin Helioscopin A Helioscopin B Mallonin Mallojaponin P-1 3 p- 1,3,6 2,4* 2,4* 2,4* 2,4* 2,4* (R1-336 p- 1964s) 116, 162, 163 157 157 116 116 P-1 P-1 For its routine metabolic processes Nature appears to prefer the conformationally most stable sugars, and amongst the D-aldohexoses glucose, mannose, and galactose are widely distributed ; those with less favourable steric interactions occur rarely. It is a point of some curiosity, therefore, that, in this particular form of oxidative metabolism of galloyl esters of Dglucose, the transformations apparently occur with the galloyl D-glucopyranose derivative in an energetically unfavourable chair ('C,) or related skew-boat conformation. The difference in free energy between the ' C , and the ,C1 forms of Dglucopyranose has been calculated as + 5.95 kcal mol-' (24.8 kJ mol-l) and this difference may, in part, explain why oxidative coupling of galloyl ester groups via the ,C1conformation of the D-glucopyranose precursor (pathway (b), above) is much more widely encountered in the plant kingdom than the alternative (pathway (c)) which is presumed to proceed via a chair (lC,) or related skew-boat conformation. A key - 3,6-(R)-valoneoyl metabolite in this particular sub-class is the beautifully yellow, crystalline compound geraniin, first isolated from Geranium and Euphorbia species by Okuda et al.137,147*15s7'5a and by the Sheffield group from Acer and Cercidiphyllum species.29In this, as in other derivatives of the dehydrohexahydroxydiphenoyl ester group, the dehydroester is found as an internal hemiacetal. On dissolution in aqueous media equilibration occurs with other internal hemiacetal forms, Figure 8. Other significant 'monomeric' species found in this mode of metabolism include corilagin, davidiin, elaeocarpusin, tanarinin, and helioscopin A, e.g. Figure 16, Tables 6-9. The elaeocarpusinoyl ester group presents an interesting structural variation on the theme of the dehydrohexahydroxydiphenoyl ester, Table 9. A significant number of metabolites have now been recorded which contain this unusual functionality and there is prima facie evidence to suggest that its biosynthetic origin is probably a result of the interaction of a View Article Online 55 NATURAL PRODUCT REPORTS, 1994-E. HASLAM AND Y. CAI HO OH OH \ OH HO 0 4 wo HO \ OH Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 HO OH Geraniin 0 Elaeocarpusin Carpinusin HO Davidiin Figure 16 Monomeric' metabolites of OH OH H O W Corilagin How p- 1,2,3,4,6-pentagalloyl-~-glucose - oxidative conversions of the 'C,form, pathway OH O \ / H (c) OH *G o qc-0 HO 1 OH HO OH NupharinC (Dehydrodigalloyl) HO Euphorbin C (Euphorbinoyl) hexahydroxydiphenoyl ester group with L-dehydroascor162 during the generation of a dehydrohexahydroxybate,116* diphenoyl ester, Figure 8. More recently, 'dimeric ' species involving these various types of hexahydroxydiphenoyl ester and dehydrohexahydroxydiphenoyl ester metabolites have been described. These natural products are all based upon the typical C-O coupling patterns noted earlier for hexahydroxydiphenoyl esters formed via pathway (b) of oxidative metabolism. Compounds in which the linking ester group is dehydrodigalloyl (nupharins C , D, and E,164and jolkianinlZ3), (R)-valoneoyl ( e ~ p h o r e l i n euphor,~~~ euphorbin F,148tirucallin B,148 exbins A and B,148*165,166 coecarianin, 167 and eumaculin A133), and euphorbinoyl (excoecarinins A and B,167euphorbins C166and have been described, as has a 'trimeric' species nupharin F.164 Perhaps because of their ready crystalline nature, two View Article Online NATURAL PRODUCT REPORTS, 1994 56 Table 10 Principal naturally occurring phenolic esters derived from hexahydroxydiphenic acid, in which one aromatic ring has been modified? by ring cleavage (chebulic) or contraction (brevifolin); esterification to a 'C,D-glucopyranose core (* ; Figure 17). Trivial name Gallo yl Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 Chebulinic acid Chebulagic acid Repandusinic acid A Repandusinic acid B Repandusinin Mallorepandusic acid Heterophyllin E Macaranin A Ho2c*o" ?' I 'Ring-opened' ester? Other ester groups Ref. 2,4*-Chebulo yl 2,4*-Chebuloyl 4-Deh ydrochebuo yl 4-Deh ydrochebuo yl 4-Brevifol yl 2,4*-Chebulo yl 3-Brevifolyl 2,4*-Chebuloyl - 1, 4, 5, 65, 69, 169-171 71, 73, 169-171 172, 173 172, 173 172, 173 149 174 I49 3,6-Hexahydroxydiphenoyl (R) 3,6-Hexahydroxydiphenoyl (R) 3,6-Valoneoyl (R) 3,6-Valoneoyl (R) 3,6-Tergalloyl 4,6-Hexahydroxydiphenoyl ( S ) 3,6-Macaranoyl Hexahydroxydiphenoylester Dehydrohexahydroxydiphenoylester I \ O H O H OH HO OH 0 0 Brevifolin cahoxylic acid (bound form) Chebulic acid (bound form) Go&; 4 -'*OH %cl HOZC HO 0 Chebulinic acid, G = galloyl Figure 17 Putative biogenetic pathways to 'ring-opened ' hexahydroxydiphenoyl esters, chebulic and brevifolin carboxylic acids; structure of chebulinic acid metabolites dominated much of the early chemistry of the ellagitannins : chebulinic acid', 4 , 5 *65,69*169 and the closely related chebulagic a ~ i d .These ~ ~ .compounds ~ ~ are now seen to belong to a relatively small group of metabolites of the hexahydroxydiphenoyl ester class in which one of the aromatic rings has apparently undergone hydrolytic cleavage to generate one or more additional carboxylate groups, Table 10. The significance of this presumed biogenetic process was first highlighted by Schmidt and MayeP9 and Haworth et u I . , ' ~ ~ Figure 17. Valolaginic acid, valolinic acid, isovalolaginic acid, and isovalolinic acid are all metabolites based upon the unique ' open-chain ' D-glucose structure (pathway (d), vide infra). They are formulated as derivatives of trilloic acid which are presumed to be formed analogously by hydrolytic ring fission of one aromatic ring of a nonahydroxytriphenoyl ester. 8 2 9 8 7 * 9 0 2.2.5 Oxidative Metabolism - Pathway ( d ) . 'Open-chain ' Derivatives of &Glucose An intriguing and distinctive group of polyphenolic compounds derived from gallic acid are esters formed with the open-chain form of D-glucose; such esters are probably unique in natural product chemistry. Vescalin, vescalagin, castalin, and castalagin are compounds which typify this group and whose structures testify to this uniqueness. They were first isolated from oak and chestnut species and their structures determined by Mayer and his colleague^.^^-^^^^^* 88, 91 They characterize this very distinctive pattern of gallic acid metabolism, which occurs in particular members of the plant families Casuarinaceae, Fagaceae, Juglandaceae, Myrtaceae, and Stachyuraceae. lo'*'04 The ability to bring about both 4,6 and 2,3 oxidative coupling of vicinal galloyl ester groups in p- 1,2,3,4,6-pentagalloyl-~- View Article Online 57 NATURAL PRODUCT REPORTS, 1994-E. HASLAM A N D Y. CAI HO OH Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 AH lsovalolinic acid Valolaginic acid HO HO OH co a - 0 H HO OH OH Potentillin OH O HO W OH OH O H OH Pedunculagin L A HO’ OH C-1, p -OH, Stachyurin C-1, a-OH, Casuarinin OH C-1, p -OH, Vescalagin C- 1, a-OH, Castahgin OH C-1 , p -OH, Vescalin C-1, a-OH, Castalin Figure 18 Oxidative metabolism of /3- 1,2,3,4,6-pentagalloyl-D-glucose,pathway (d) : suggested biogenetic relationships in ‘open-chain ’ polyphenolic esters glucose [pathway (b), vide supra] is retained in these plant families, and the metabolites pedunculagin, casuarictin, and potentillin (Figure 12) generally co-occur with these open-chain ester derivatives of D-glucose. Whilst it is possible that these unique open-chain esters are formed from pedunculagin, by opening of the D-glucopyranose ring at the hemiacetal anomeric centre, formation of a C-glycosidic link to the hexahydroxydiphenoyl group bridging the 2,3 positions, and finally galloylation at C-5, a plausible biogenetic route to their formation can also be elaborated, via redox reactions, directly from the a-glucoside potentillin by ring opening and concommitant galloyl group transfer from C-1 to C-5. In this context it is interesting to note that all of the recorded ‘ openchain ’ derivatives of D-glucose contain a hexahydroxydiphenoyl ester group bridging C-2 and C-3 of the sugar. The formal biogenetic relationship of the principal metabolites in this class are shown in Figure 18 and Tables 11 to 17. Perhaps the most significant discoveries amongst this class of Article Online NATURAL PRODUCTView REPORTS, 1994 58 Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 Table 11 Naturally occurring ‘open-chair ’ polyphenolic esters related to vescalagin OH Trivial name Vescalagin Acutissimin A Acutissimin B Eugenigrandin A Vescalagin carboxylic acid Grandinin Mongolicin A Mongolicin B Mongolicanin Ref. 80, 91, 183 177 R H ydroxyl (+)-Catechin; position C-8 (+)-Catechin; position C-6 (+)-Gallocatechin ; position C-8 Carboxyl C, alcohol, from L-ascorbate Taxifolin-3-P-~-glucoside ; position C-8 Taxifolin-3-/3-~-glucoside; position C-6 Procyanidin B-3 ; position 8’ Table 12 Naturally occurring ‘ open-chain ’ polyphenolic esters related to castalagin 177 185 181 185 180 180 181 Table 13 Naturally occurring ‘ open-chain ’ polyphenolic esters related to casuariin OH HO OH Trivial name Castalagin 1-0-Galloyl castalagin Castovaloninic acid R‘ H galloyl H OH R2 H H Gallic acid, position C-2 Ref. 80, 88, 183 184 81 compound are the ~tenophyllanins,”~ ac~tissimins,~” camelliatannins, 178 g u a v i n ~ , mongolicins, ~’~ 180 mongolicanin, 180 mongo1inin,lS1 and mongo1icainslS2 derived from a range of botanical sources including the bark of Castanea and Quercus Trivial name Casuariin Casuarinin Flosin B R1 Hydroxyl Hydroxyl Hydroxyl R2 H Galloyl Valoneoyl dilactone Ref. 101, 104 101, 104 188 species. All these compounds possess structures in which a flavan-3-01 unit is linked through a carbonsarbon bond to the anomeric centre of an ‘open-chain ’ hexahydroxydiphenoyl or related polyphenolic ester. They are thus phenolic metabolites NATURAL PRODUCT REPORTS, 1994-E. View Article Online 59 HASLAM AND Y . CAI Table 14 Naturally occurring ‘open-chain ’ polyphenolic esters related to stachyurin Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 HO OH Trivial name R’ R2 Ref. Stachyurin 5-Desgalloylstachurin Stenophyllanin A Stenophyllanin B Stenophyllanin C Camelliatannin A Camelliatannin B Pterocarinin A 5-Desgalloylpterocarinin A Pterocarinin B Lagerstromin H ydroxyl H ydroxyl (+)-Catechin; position C-8 ( + )-Catechin ; position C-6 (+)-Catechin; position C-8 (-)-Epicatechin ; position C-8 (-)-Epicatechin; position C-6 C, polyalcohol from L-ascorbate C, polyalcohol from L-ascorbate C, polyalcohol, origins unknown H ydroxyl Galloyl H Gallo yl Galloyl H H H Gallo yl H 101, 104 101, 104, 105, 186 176 176 176 178 178 187 187 187 186 H Valoneoyl dilactone ~~ Table 15 Miscellaneous ‘ open-chain ’ derivatives of hexahydroxydiphenic acid ~ Table 17 Naturally occurring polyphenolic esters. ‘ Dimeric ’ structures in which at least one ‘monomeric’ component is derived from an ‘open-chain ’ polyphenolic ester metabolite ‘ Monomeric’ components Direct C-C link between ‘monomers’ Alienanin A Pedunculagin + stachyurin Alienanin B Casuarinin stachyurin Castamollinin 2 x Vescalagin/castalagin Anogeissusin A 2 x Vescalagin/castalagin, ( + )-catechin Anogeissusin B 2 x Vescalagin/castalagin, ( + )-gallocatechin Trivial name + OH Trivial name R’ R2 Other esters Ref. Punicacortein A Punicacortein B Punicacortein C Punicacortein D Epipunicacortein A H H H OH OH OH OH OH H H 5-Galloyl 6-Galloyl 4,6-(S,S)-gallagyl 4,6-(S,S)-gallagyl 190 190 190 190 189 - Heterophyllin B Heterophyllin C Reginin A Reginin B Reginin C Reginin D (S)-valoneoyl linking ester group Tellimagrandin 2 +casuarinin Casuarinin + casuarictin Casuarinin + pedunculagin Stachyurin + pedunculagin Pterocarinin A + pedunculagin Casuarinin + pedunculagin Ref. 189 189 183 185 185 174 174 186 186 188 188 Table 16 Miscellaneous ‘open-chain ’ derivatives of nonahydroxytriphenic acid OH Trivial name R’ R2 Ref. Vescalin Acutissimin C Castalin OH (+)-Catechin, position C-8 H H H OH 85 183 88 which embrace the structural and chemical features associated with both the hydrolysable and condensed groups of tannins. A typical example of this class of metabolite is acutissimin A (derived presumably from vescalagin/castalagin and ( + )catechin). The alcoholic hydroxyl group at C-1 of metabolites such as castalin, castalagin, vescalin, and vescalagin is benzylic and therefore, in principle, subject to possible displacement and the formation of a resonance stabilized carbocation at C-1. This provides a chemical rationale for a possible biogenetic pathway to metabolites such as the stenophyllanins, acutissimins, camelliatannins, guavins, mongolicins, mongolicanin, and mongolicains. It is presumed that such metabolites may be derived by interaction of the transient C- 1 carbocation species, in a metabolite such as vescalagin, with the electron rich A-ring View Article Online NATURAL PRODUCT REPORTS, 1994 60 Downloaded by University of Sussex on 21 December 2012 Published on 01 January 1994 on http://pubs.rsc.org | doi:10.1039/NP9941100041 OH Hoqo Vescalagin/Castalagin HO OH (+)-Catechin t 6H Acutksimin A Figure 19 Suggested pathway of biogenesis from castalagin/vescalagin of acutissimin A OH OH OH Anogeissinin Alienanin B