Phytochemwy, Vol 28, No 4, Pp 967-998, 1989 Prlnted I” Great Bntaln

0031&9422/89 $3OC+OOO 0 1989 Pergamon Press plc

Key

REVIEW ARTICLE NUMBER 43

XANTHONES FROM GUTTIFERAE

GRAHAM J. BENNETT and HIOK-HUANG LEE

Department of Chemistry, National Umverslty of Singapore, 10 Kent Ridge Crescent, Smgapore 0511

(Recerued m reused form 1 November 1988)

Word Index-Guttlferae, xanthones; benzophenones, chemotaxonomy; blosynthesls.

Abstract-Since the last review m 1980, over eighty new xanthones have been isolated from the Guttiferae. These are listed with reference to structure elucidation and synthesis. The distribution of xanthones is exammed m relation to the taxonomic divisions of the Guttiferae Xanthone biosynthesis is discussed m the light of new biosynthetic results and the various pharmacological properties of xanthones are summarized

INTRODUCTION

As the quest for new natural products continues, it becomes increasingly clear that xanthones are very re- stricted in occurrence. The malority of natural xanthones have been found in Just two families of higher plants- Guttiferae and Gentianaceae [l] Simple, oxygenated xanthones occur in both famihes and are generally more highly oxygenated in the Gentianaceae. Prenylated xan- thones are widely distributed m the Guttiferae but not known in the Gentianaceae, and whereas O-glycosylxan- thones are common in the Gentianaceae [2], only two have been reported from the Guttiferae

Xanthones occur sporadically throughout the remam- der of the plant kingdom. The Moraceae contain several Guttiferae-type prenylated xanthones and the Polygala- cae, simple hydroxy- and alkoxyxanthones [l]. C-Glu- cosylxanthones have been found m certain ferns, and in over one hundred species of higher plants [3], and fungi produce xanthones with substitution patterns character- istic of then acetate derivation [4].

Several earher reviews have summarized the literature on xanthones [S-lo], with emphasis on biosynthesis [7,8], synthesis [6,9] or phylogeny [lo]. In the last review in 1980, Sultanbawa listed 95 xanthones from the Gutttferae [l]. Smce then there has been a steady stream of reports in which more than 80 new xanthones have been characterized and many known xanthones re-iso- lated from ca 60 species of Guttiferae.

The aim of this review is to summarize the recent work on xanthones from the Guttiferae as a supplement to the 1980 review. The combined data will then be studied from a chemotaxonomic pomt of view to determine if any patterns of xanthone distribution exist within the family, and the imphcations of new biosynthetrc results will be discussed. Structure elucidation, synthesis, and pharma- cology will also be covered.

DISTRIBUTION

The family Guttiferae numbers over 1000 species, mainly confined to the tropics-the major exception being the genus Hyperrcum, which occurs widely in

temperate regions. According to Engler’s Syllabus [ 1 l] the family comprises six subfamilies (Table 1). The sub- family Hypericoideae has been treated by some taxon- omists (notably Hutchinson [12]) as a separate family, but the recent surge of interest m the chemistry of this group has led to the isolation of several prenylated xanthones, supporting its mclusion m the Guttiferae. The only related family m which xanthones have been found is the Bonnetiaceae, which, m keeping with Thorn’s recent classification [13], is included in the Kielmeyeroideae subfamily in Table 1.

Xanthones or the related benzophenones have been found in all the major and several minor genera of the Guttiferae. The approximate number of species [14], and the number that have been found to contam xanthones 1s given for each genus (Table 1). It appears from the number of chemically investigated species (for three of the larger genera), that a large proportion of the species contains xanthones. A species-xanthone index is mcluded as an appendix

Simple oxygenated xanthones

The symmetrical nature of the xanthone nucleus, coup- led with its mixed biogenetic origin m higher plants, necessitates that the carbons be numbered according to a biosynthetic convention. Carbons 14 are assigned to the acetate-derived ring A, (often characterized by 1,3-di- oxygenation) and carbons 5-8 to the shikimate-derived ring B (e.g. 1,3,7,8_tetrahydroxy rather than 1,2,6,8). All higher plant xanthones appear to have S- and/or 7- oxygenation [S] and with this assumption, only xan- thones with 2,5(or 4,7)-oxygenation have alternative names. In cases where only ring B ts oxygenated the lowest numbers are used except in the biosynthetic discussion [e.g. 2- rather than 7-hydroxyxanthone (l)].

Structural assignments are based mainly on ‘H NMR and UV spectroscopy. Shifts of rmg or side-chain protons due to acetylatton or alkylation of adjacent hydroxyls and changes in the UV spectrum on addition of the usual shift reagents, are especially useful m determining substi- tution patterns. Confirmation of assignment may be

967

968 G J BENNETT and H-H LEE

Table 1 The family Guttlferae

SUB-FAMILY TRIBE GENUS NO. OF SPECIES*

Clusioideae

Moronoboideae

Lorostemonoideae

Hypericoideae

Clusleae

Garclnieae

Cratoxyleae

Hypericeae

VI smleae

Kielmeyeroideae Kielmeyereae Kielmeyera

Wahurea

Caralpeae CaraCpa

Haploclathra

(Bonnetiaceae) Bonnetia

Archytaea

20/9( 10)

8/l

20/4

413

18/l

2/l

Calophylloideae Calophylleae CalophylLum

!Jesua(inc.Kayea)

Wammea(inc.

Ochrocarpus)

110/21(32)

4015

50/5

CLusLa 14514

Touomi ta 60/6

AllanbLackLa 8/l

GarcLnia 400/29(38)

PentaphaLangium 7/l

Rheedia 45/4

Horonobea

Pentadesma

PLatonia

Symphonia

7/l

4/l

l-211

20/l

Lorostemon 3/2

CratoryLum 6/2

Hypericum 400/18

Harungana l/l

Psorospermum 40/l

Vismia 35/3

*Approx no. ofspecIes [14]/no ofspecIes m which xanthones and closely rdaled compounds have

been found Numbers m parentheses refer to number of species chemically mvestlgated

obtained by derivatlzatlon (sometimes not possible due to the scarcity of material), although often synthesis IS necessary

The synthesis of xanthones has been revlewed [l&9]. The standard method is the Grover, Shah and Shah condensation between an ortho-oxygenated benzolc acid and a reactive phenol m the presence of phosphorous oxychlorlde and zinc chlonde [16] A recent vanation of this method uses methylsulphonic acid and phosphorous pentoxide m place of the above reagents [17]. Alter- natively, benzophenones, prepared by Friedel-Crafts acylation [18], may be converted to xanthones by dehy- drative or oxldatlve cyclizatlon. Two other methods have appeared recently. The nucleophihc addltlon of salicyhc acid denvatlves to p-benzoqumones has been used to prepare a series of 1,4(or 5,8)-dlhydroxyxanthones [19], and 3-hydroxyxanthone has been prepared in 50% yield

by a cycloaddltion reactlon between a dlene and a benzopyranone [20]

Mono-oxygenated xunthones. Two mono-oxygenated xanthones (1 and 2, Table 2) have recently been isolated from seven species 4-Hydroxyxanthone also occurs in Guttlferae. These compounds are now known to occur in eight genera from three subfamihes. Notable 1s their absence from Clusloldeae (> 50 species investigated).

Dioxygenated xanthones The majority of the recently isolated dioxygenated xanthones (Table 3) are from spe- cies of the Hypencoldeae, reflecting the recent interest m this subfamily Dloxygenated xanthones are however, also common m species of Calophyllum, Mammea and Mesua and found in all subfamilies 1,7-Dlhydroxyxan- thone (4), has now been Isolated from 40 species of Guttlferae The 2,5-dloxygenation pattern of xanthones 5 and 10 IS new from nature

Xanthones from Guttlferae

Table 2 Mono-oxygenated xanthones

969

2-Hvdroxvxanthonefl)

CalophyLlum zeylantcum Kosterm.[21]

Hypertcum baleartcum L. [22]

Hypertcum canartensis L. [24]

Hypertcum ertcotdes L. [25]

Hypertcum mysorense [26.27]

Vtsmta guaramtrangae Huber [ZS]

2-lathoxvxanthone(21

Caratpa pstdtfolta Ducke [29]

Hypertcum mysorense [27]

Vtsmta guaramtrangae Huber [28]

*First reported occurrence m nature tFlrst reported occurrence in Guttlferae.

Table 3 Dioxygenated xanthones

1.5-DibvdroxvxanthoneC31

CalophyLLum zeylanicum Kosterm.[Bl]

Garctnta xanthochymus Hook. f. [30]

1.7-DihvdroxvxanthoneC4IfEuxanthonel

Bonnetta strtcta (Nees) Ness & Mart.[31]

CaLophyllum zeylantcum Kosterm.[21]

Carctnta indtca Choisy [50]

Garcinta xanthochymus Hook. f.[30]

HaplocLathra uerttctlLata Ducke[29]

Hypericum

Hypertcum

Hypertcum

Hypertcum

baleartcum L. [22]

canartensls L. [24]

ertcotdes L. [25]

mysorense [26.27]]

Kahurea tomentosa Ducke [29]

Vtsmta guarantrangae Huber [ZS]

2.5-Dihvdroxvxanthonef51

*Hypertcum canartensts L. [24]

2.3-DImethoxvxanthonal6l.

*Hypertcum mysorense [27.32-J

I-Hvdtoxv-7-¤ethoxvxanthonef71

Bonnetta stricta (Nees) Ness Mart. [31]

HaplocLathra paniculata (Mart.) Benth. [33]

Haploclathra uerttctLLata Ducke[29]

Hypertcum mysorense [26]

Mahurea tomentosa Ducke [29]

Vtsmta guaramirangae Huber [28]

2-Hvdroxv-1-methoxvxanthone[f%I*

Vismta guaramirangae Huber [28]

2-Hvdroxv-3-methoxvxanthone(91

*HyperCcum mysorense [ZS]

2-Hvdroxv-5-methoxvxanthoneflOl_

*Hypertcum androsaemum L. [34]

Nypertcum canartensts L. [24]

3-Hvdroxv-P-methoxvxanthonefllk

Hypericum androsaemum L. [34]

Hypericum balearicun L. 1223

Psorospermum febrtfugum Sprach [36]

Vtsrta guaramtrangae Huber [28]

Trioxygenated xanthones. Twenty trioxygenated xan- (17), 1,4,7- (19) and 2,3,5- (27), and xanthones 33 and 34 thones, of which nine are new natural products, are are the first trimethoxyxanthones from the Guttlferae. shown in Table 4. Novel oxygenation patterns are 1,5,8- Two 1,2,Strioxygenated xanthones (12 and 14) have been

970 G J BENNETT and H-H LEE

Table 4 Trloxygenated xanthones

*Carc~nn xanrhochymus Hook f c301

1.3-Dihvdroxv-2-methoxvxanthonell3)

1.5-Dihvdroxv-2-aethoxyxanthonell4)

*Carc~n~u xanthochymus Hook. f c301

1.5-Dihvdroxv-3-methoxvxanthone~l5~

Garcinia ranthochymus Hook f.[30]

Haploctathra Lieantha (Benth ) Benth C361

Haploclathra paniculata (Mart ) Benth [33]

Vismia guaram~rangae Huber [28]

1.5-Dihvdroxv-6-methoxvxanthone(l6r

* rouomtta excelsa Andrade-Lima et

G Marlz [37]

1.5-Dihvdroxv-8-methoxvxanthone(l7)_

*VLsmia guarnmirangae Huber [28]

1.6-Dihvdroxy-5-lethoxyxanthone/ls) ‘IBuchanoxanthone)

Calophyllum zeyZanLcum Kosterm [21]

Touomita excelsa Andrade-L.lma et G Marlz [37]

1.7-Dihvdroxv-4-rethoxvxanthonefl91

*VtsmCa guaram~rangne Huber [28]

1.7-Dihvdroxy-6-methoxvxanthonef201

*Touomita excelsa Andrade-Lima et G Marlz [37]

1.7-Dihvdroxv-8-=ethoxvxanthone[21)

Bonnetia stricta (Nees) Ness & Mart [31]

Haploclathra [leantha (Benth ) Benth. [36]

HapLoclathra panicuLata (Mart ) Benth. [33]

5.6-Dihvdroxv-1-lethoxvxanthone[221

*Touomtta excelsa Andrade-Lima et G.Mariz [373

Benth

1.3.5-Trihvdroxvxanthonef301

Carcinia xanthochymus Hook. f

1.3.7-Trihvdroxvxanthonef31)_ /Gentisein)

Haploclathra paniculata (Mart Benth

Hypericum degentf Bornm. [41]

1.6.7-Trihvdroxyxanthonef32)

Ptntonia instgnis Mart [29]

t Haploclathra paniculata (Mart

Benth

2.3.4-Tri=ethoxvxanthone[34)

*Hypericum ericoides L c251

I-Hvdroxv-3.5-dilethoxvxanthonel23)

HapLoclathra pantculata (Mart ) Benth [33]

1-Hvdroxv-6.7-dimethoxvxanthone[24)_

Hypericum mysorense [26]

l-Hydroxv-7.8-dimethoxyxanthone(251

Haploclathra pan~culata (Mart ) Bench [33]

2-Hydroxv-3,4-diaethoxvxanthone(26)

Hypericum canarLensis L 1241

Hypericum sampson~t Hance [39]

KteLmeyera rubiflora Camb c4o1

*Kielmeyera spec~oso St.Hlll [40]

3-Hvdroxy-2.5-dilethoxvxanthonel27)

*Hypericum androsaemum L c341

4-Hvdroxv-2.3-dilethoxyxanthone0

Cara~pa grand~fLora Mart. [29]

5-Hvdroxy-1.3-di=ethoxyxanthone[29)

Haploclathra panlculata (Mart.)

‘c331

c3o1

1 t-331

1 c331

reported from Garcinia xanthochymus, but their physlcal wood of Tovomita excelsa, were assigned a l,S,&dihy- data have not been pubhshed.

Three of the four xanthones isolated from the trunk droxymethoxy structure [37]. Two of these (l&18) were known compounds, whereas the I-methoxy structure (22)

Xanthones from Guttlferae

Table 5. Tetra- and pentaoxygenated xanthones

971

1.3-Dihvdroxv-5.6-dimethoxvxanthone iLeiaxanthone)(35)

‘Haploclathra Lieantha (Benth ) Benth [36]

1.5-Dihvdroxv-6.7-dimethoxvxanthone

I36)

Caraipa grandLfLora Mart c291

Caraipa pstdifolla Ducke [29]

Caraipa ualioi Paula [29]

TouomLta brasiliensis Walp c421

1.6-Dihvdroxv-5.7-dilethoxvxanthoxvxanthone

(37)

Hypericum canariensis L [24]

I.?-Dihvdroxv-3.8-dimethoxvxanthone

t’ [Gentiaculein)(381

HapLocLathra Lieantha (Benth ) .Benth [36]

HapLocLathra paniculata (Mart ) Benth. [33]

2.5-Dihvdroxv-1,6-dimethoxvxanthone

G!.zQ

*Garcinia thaaiteslt Pierre [43]

3.7-Dihvdroxv-1,8-dimethoxvxanthone

(40)

*HapLocLathra pan~culata (Mart.) Benth [33]

3.8-Dihvdroxv-1.7-dimethoxvxanthone 17

t HapLocLathra panLcuLata (Mart.)

Benth [33]

5.6-Dihvdroxv-1.3-dimethoxvxanthone fFerrxanthonelf421

HapLocLathra Lteantha (Benth ) Benth. [36]

*Hesua ferrea L. [23]

2-Hvdroxv-5.6.7-trimethoxvxanthone (43)

*Hypericum erLcotdes L c251

3-Hvdroxv-1.2.4-trimethoxvxanthone

I44)

*Psorospermum febrLfugum Sprach [35]

3-Hvdroxv-1.5.6-trimethoxvxanthone (45)

HapLocLathra lieantha (Benth ) Benth [36]

7-Hvdroxv-1.3.8-trimethoxvxanthone JAnthaxanthone)(46)

*HapLocLathra Lieantha (Benth ) Benth [36]

1.3.5.6-Tetrahvdroxvxanthonel471

Hyperrcum androsaemum L c341

1.3.6.7-Tetrahvdroxvxanthone[481 /Norathvrioll

Cratorylum prunLfLorum Kurz CL301

CarcLnLa mangostana L. [46]

Hypericum androsaemum L. [34]

Hypericum aucherL Jaub et Sprach. [47]

1.3.5-Trihvdroxy-6-methoxvxanthone

149)

HaplocLathra lLeantha (Benth ) Benth. [36]

1.5.6-Trihvdroxv-3-methoxvxanthone

w

‘Hypertcum androsaemum L. [34]

l-7.8-Trihvdroxv-6-methoxvxanthone

(51)

*Archytaea multiflora Benth. [31]

2.4.5-Trihvdroxv-1-methoxvxanthone I_

*Garctnia mangostana L. [83]

3.8-Dihvdroxv-1.2.4-trilethoxvxanthone(531

*Psorospermum Febrifugum Sprach c351

was new. An unambiguous synthesis of 22 has been completed by the methylation of 1-hydroxy-5,6-diben- zyloxyxanthone followed by debenzylation, and the prod- uct shown to be different from the.natural compound [38]. 4,5-Dlhydroxy-3-methoxyxanthone IS suggested as a likely alternatlve structure

The sodmm acetate induced shifts m the UV spectrum of a 2,3,4-hydroxydlmethoxyxanthone from Kielmeyera species, led to the assignment of the more acidic 3-

hydroxy structure. However, the 13C NMR spectrum has indicated that both methoxy groups are di-ortho-substi- tuted and that therefore the structure should be 2- Hydroxy-3,4-dlmethoxyxanthone (26) [40]. Conse- quently, the structure of a xanthone from Hypericum canarlensn should also be revised to 26, as in Table 4.

Ten xanthones have been isolated from the roots of Vismia quaramirangae [28] Based mainly on ‘H NMR spectroscopy, one of the three new xanthones was as-

972 G J BENNETT and H -H LEE

signed the structure of 1,7-dlhydroxy-4-methoxy- xanthone (19X rather than the 2-methoxy alternative that was indicated by a positive Gibbs test. Two para- dloxygenated analogues also gave positive Gibbs tests, suggesting that this test IS unrehable m certain cases

thone (53, Table 5) IS related to 44 from the same plant, and brings the total number known to five

Alkylated xanthones

Tetraoxygenated xnnthones The newly Isolated tet- raoxygenated xanthones are shown m Table 5. In the first mvestlgatlons of the genus Haploclathra, three species have yielded 17 different xanthones [29, 33, 361. These include four 1,3,5,6- and four 1,3,7,8_tetraoxygenated xanthones, the latter being common in the Gentianaceae Xanthone 35 has been synthesized [44] and shown to be identical to a compound from Centaur-turn lmarlfolium, but to differ somewhat from the Haploclathra xanthone.

Several unusual oxygenation patterns have been found. The stem bark and timber of Garcmla thwaltesl ylelded 2,5-dlhydroxy-1,6-dlmethoxyxanthone (39), and the structure of 2-hydroxy-5,6,7-trimethoxyxanthone (43), isolated from Hyperlcum erzcotdes [24], has been con- firmed by synthesis (Scheme 1) [45] A 1,2,4,5_tetraoxy- genated xanthone, BR-xanthone-B (SZ), has been Isolated from the fruit of Garcrma mangostuna.

Alkylated xanthones in Guttlferae are usually mono- or dl-C,-substituted The C, group may be 3-methylbut- 2-enyl (as m 54), or less often l,l-dimethylprop-2-enyl (as m 89), and these are frequently cyclized with ortho hydroxyls giving 2,2_dimethylpyrano (or dihydropyrano), 2,2,3_trimethylfurano (possible artefacts), or rarely 2- lsopropenyldihydrofurano compounds Occasionally, hydroxylatlon or hydration of the side chain occurs C,, substltuents, m which two prenyl groups are Joined together, Include geranyl (as m 112) and lavandulyl (as in 115)

The oxygenation patterns of alkylated xanthones are less diverse than m the unalkylated compounds Four patterns predominate: 1,3,5-, 1,3,7-, 1,3,5,6-, and 1,3,6,7- Di- and pentaoxygenated compounds are rare.

The mcluslon of Archytaea (Bonnetlaceae) in the sub- family Klelmeyeroideae IS supported by the lsolatlon of a 1,6,7,8_tetraoxygenated xanthone (51) from Archytaea multrjiora [31] This oxygenation pattern IS only known in other three species, two of which belong to this subfamdy

Pentaoxygenated xanthones. These compounds are rare m the Guttiferae but common m the Gentlanaceae The new compound, 3,8-dlhydroxy-1,2,4-tnmethoxyxan-

Mono-C,-trloxygenuted xunthones Fractlonatlon of the cytotoxic ethanol extract of the roots of Psoros- permumfebrfigum led to the lsolatlon of the antl-leuk- aemlc xanthones, psorospermm (57, Table 6) and its chlorohydrm (58) [Sl, 521. Their ready mterconverslon suggested a possible artefact Tandem mass spectrometry has confirmed that psorospermm IS a natural product, while the posslblhty that 58 IS an artefact has not been rigorously excluded [53] The other derivatives (59-61), show no anti-leukaemlc properties The absolute stereo- chemistry of psorospermm has been determined as

1

Reagents ( I ) AlC13 / ether, ( II) Me,NOH / reflux, ( ~1) H,, Pd / C

Scheme I

Xanthones from Guttlferae 913

Table 6 Mono-C,-tnoxygenated xanthones

w (56) 6-Deoxviacareubin

CaLophyLlum zeylantcum Kosterm.[21]

OH

0 OMe

0 OH

1

(57)

(59)

(59)

(60)

(61)

(62)

3, e R= 7.s 0 ; PSOrOSDerriU (2.R.3.R)

4. Me

R= ‘r<

(2.R.3.S) OH

CH,Cl

r"

e R=

OH (2.R.3.R)

CH,OH

R = Me

Y

: 3’ .a’-DeOXvD SOTOSD‘ZrliI,

I

R=

l<o

""H (5-O-Methyl)

Me

*Psorospermum febrifugum Sprach. C51.52.541

Rheediachro-enoxanthone

Rheedia brastliensis (Mart.) Pl. and Tr.[58]

*Rheedia gardnerlana Pl. and Tr.[59]

(63) RI = H. R2 = OH: Hvmericanarin

*Hypericum canariensis L. [24]

(64) R, = OH, R, = H; livperxanthone

*Hypericum sampsonit Hance [39]

2’R,3’R by an ORD, ‘H NMR and TLC comparison with Progress towards a total synthesis of psorospermm has analogous epoxides denved from rotenone [54]. been made by the enantioselective preparation of the

A stereoselective synthesis of 5-methyl-( -!-)-2’R,3’S- 2’R,3’R-dlhydrobenzofuran (66) [56] A synthesis of the psorospermin (65) has been completed and 1s shown m 5-methyl-1’,2’-dehydro derivative of 3’,4’-deoxypsoro- part in Scheme 2 [55]. The final step in the synthesis spermm (60) has also been reported [57]. involves two consecutive displacements, producing a Rheediachromenoxanthone (62) and hyperxanthone racemlc mixture of the 2R’,3’S and 2’S,3’R epoxides (65). (64) appear to be derived from tetraoxygenated xan-

974 G J. BENNETT and H -H LFE

Reagents ( I) Os04/Na104, dioxane / Hz0 (11) PIlsP=C(Me)CO,Et.

benzene (m) LlAIH./THF (IV) MCPBA, CH2C12 (v) MsCL/py

(VI) H,.Pd/C (vu) KO’Bu

OMe

Me0

66

Scheme 2

thones by nuclear reduction at the 3- and l-pontions respectively In fact, 64 occurs with the expected precur- sor, toxyloxanthone B (82) m Hyperuzum sampsonu The unusual 4,6,7- (or 2,3,5-?) oxygenation pattern of hyperi- canarm (63) IS otherwlse only known in 27 from Hyper- icum androsaemum. The structures of 63 and 64 are supported by significantly different physical data

Dl-C,-trroxygenated xanthones Garcmone A from Garcima mangostana was asslgned a novel 1,3,6-tnhy- droxy structure (68, Table 7), an oxygenation pattern unknown m the Guttiferae However, the synthetic sub- stance, prepared by the prenylatlon of 1,3,6-trlhydroxy- xanthone, showed httle similarity with the natural com- pound [66].

The stem bark of Garcmla quadrfarta produces xan- thone 69, which shows a rare prenylation, para, rather than ortho to a hydroxyl group. 6-Deoxy-y-mangostm (70) has been isolated from the seed arils of Garcinza mangostana fruit and IS a possible biosynthetic precursor

to mangostm (70; R, = Me, R, = OH), the major metab- olite from the same plant (see Biosynthesis).

The stem bark of Calophyllum walker1 contains xan- thones 74 and 7678 The hydroxymethyl group in thwal- teslxanthanol (77) was located by mild acetylatlon Shielding of H-3” was observed, while H-3’ was un- affected [65]. The 2-lsopropenyldlhydrofuran group of 78 IS otherwise only known (without the hydroxy) m 3’,4’- deoxypsorospermin (60) The cts configuration of 78 was asslgned from the 6 Hz couplmg between the 2” and 3” protons The 3” proton was also coupled to H-6 and strongly deshlelded, suggestmg that It IS almost m the same plane as the xanthone nucleus

Mono-C,-tetrahydroxyxanthones Xanthone 79 (Table 8) IS the second 1,3,5,8-tetra-oxygenated xanthone from G. mangostana, the other bemg gartanm (79; R, =H, R, =prenyl). This oxidation pattern IS otherwise unknown m the Guttiferae but common m the Gentianaceae Three 2-prenyl-3-methoxyxanthones (54. 55, and 79) have been

Xanthones from Guttlferae 975

Table 7 Dl-C,-tnoxygenated xanthones

(67) R, = OH, Rz = H. CDesoxvKartanin

RheedCa brasiliensis (Mart.) Pl. and Tr

Rheedia gardnerLana Pl and Tr

(68) RI = H. R, = OH: Garcinone &

*Carcinia mangostana L. [61]

(69) 4.8-Dif3rmethylbut-2-envlj-1.3.5-

trihvdroxvxanthone

*Garcinta quadrifaria Bail1 ex Pierre [62]

(70) R,=R,=H; 6-Deoxv-T-¤angostin

*CaLophyLLum thoaitesi Pl. and Tr

Garcinta mangostana L [49]

(71) R,=H. R,=Me: Calcocalabaxanthone 16-Deoxvraneostin)

CalophyLlum bracteatum Thw. [63]

*CalophylLum calaba var.calaba L

C631

[63.64]

0 OH

(72) ‘frapezifolixanthone

CaLophylLum calaba var. calaba L [63j

Rob (73) ;;c:; ._;;;-=-;;, c4g, Calophyllum calaba var. calaba L.[643

Calophyllum zeylanicum Kosterm.[Bl]

(74) R = H ; Deaethylcalabaxanthone

*Calophyllum walkeri Wight [SS]

Garclnta mangostana L. [49]

Pl.and Tr.[63]

976 G J BENNETT and H-H LEE

Table 7 Conmued

‘1 (76) R = Me; Thraitesixanthone

Calophyllum walker-t Wlght [65]

(77) R = CH,OH. Thraitesixanthonol

*Calophyllum walker-L Wight [65]

y.2I_ (78)

*Calophyllum walker-L Wlght [65]

Table 8 Mono-C,-tetraoxygenated xanthones -

0.H R,

H

0 OH

HoJc)IYKk

(79) R, = Me, R2 = H

1.5.STrihvdroxv-3-methow-2-

p

* Car-CirlLQ mangostana L cf371

(80) 1.3.6.7-Tetrahvdroxv-8-(3-

methvlbut-2-envl)xanthone

*Hypericum androsaemum L [34]

(El) Jacareubin

Calophyllum zeyZanLcum Kosterm [213

(82) Toxvloxanthone B

t HyperLcum nndrosaemum L II341

Hypertcum sampsonir Hance [39]

found in Garcrnza mangostana The 3-methoxy group prevents further prenylatlon m the 4-posItIon, however

Toxyloxanthone B (82), first found from the Moraceae,

the presence of a methylatmg enzyme does not preclude has been Isolated from Hyperlcum androsaemum together

4-prenylatlon as IS shown by the presence of 67 m the with its probable blogenetlc precursor (80)

DA’,-tetraoxyqenated xanthones While the xan- same plant thones m this category (Table 9) are more numerous than

Xanthones from Guttlferae 977

Table 9 DK,-tetraoxygenated xanthones

(83) Xanthone I&

*Vtsnia gutneensts (L.) Choisy [68]

OH

(84) 7-PrenvlMcereubin

*Rheedta gardnertana Pl.and Tr.[60]

OH R

(85) R = 3-Methylbut-2-enyl; Xanthone Ei

*Vismia gutneensts (L.) Choisy [SS]

(86) R = l,l-Dimethylprop-2-enyl;

Racluraxanthone

Garctnta oualtfolta 0

t Rheedia benthaatana P

Rheedia brasiLtensts

iv. [69]

. and Tr.[70]

( i

Mart.) l.and Tr.[581

Rheedia gardnertana PI. and Tr.[59]

0 OH

(87) Pvranojacereubin

Rheedta brastltensts (Mart.) Pl.and Tr.[58]

*Rheedta gardnertana Pl.and Tr.[GO]

dH

0 OH

(88) Rheediaxanthone h

*Garctnta denstuenia Engl. [71]

Garctnta staudttt Engl. [62]

Rheedta benthaniana Pl. and Tr. [703

Rheedta brastltensts (Mart ) Pl. and Tr. [58]

Rheedta gardnertana Pl. and Tr. [59]

(89) Rheediaxanthone B

*Rheedta benthnmiana Pl. and Tr. [701

Rheedia brastltensis (Mart.) Pl. and Tr. [58]

Rheedta gardneriana Pl and Tr. [591

978 G J BENNETT and H-H LEE

Table 9 Contwmd

0 /

(91) Rheediaxanthone C

*Rheedia benthamiana Pl. and Tr

Rheedia brasiliensis (Mart ) Pl and Tr

Rheedia gnrdnertana Pl. and Tr

c701

;ztJ ?

(92) *Rheedia brasiliensrs (Mart.) Pl.and Tr [58]

AH cg3) *Rheedta brasiliensts (Mart.)

Pl.and Tr [SS]

0 OH

(94) *Rheedia brasiliensis (Mart ) Pl and Tr.[58]

0 OH

(95) RI= Me. R, = H: lanplexanthone

*Touomita mangle G Maritz [73]

\ (96) Garcinone B

*Garcinin mangostana L [61.147]

Xanthones from Gutnferae

Table 9 Contmued

979

(97) *carcinta mQngostQnQ L. [74]

(98) 3’.4’-Dihydro 93; J-Isomanvostin

*Carcinia mangostana

(99) R = H; Garcinone C

*Carctnia mangostana

(100) R = Me: Garcinone D *

Carctnta mangostana

L. [49]

L. [61]

L. [75]

(101) 3’.4’-Dihydro 96; 3-Isoraneostin Hvdrate

*Garcinia mangostana L. [49]

H

\

(102) R = -C=CHMe,: 1-Isoranvostin

(103) R = -CH,C(OH)Me, : 1-Isomaneostin Hydrate

*Garcinia mangostana L. [49]

(104) BR-xan thone-A

*CarcCnia mangostana L. [SJ]

the monoprenylated compounds, there is little structural variation This IS due m part to the fact that most of these xanthones have been Isolated from only a few species of the closely allied genera Garcwa and Rheedia. Dia- lkylated xanthones, especially dlpyrano compounds, give rise to doubly-charged Ions in their mass spectra due to the simultaneous loss of two alkyl fragments [SS]. Apart from macluraxanthone (86), which is known from a Moraceae species, all the xanthones in Table 9 are new natural products.

A dipyranoxanthone from Garcinta densivenia was originally assigned the linear structure of pyranojacereu- bm (87) on the basis of the size of the diamagnetic shift of H-4’ upon 0-acetylation [71]. Subsequently, when a similar compound was isolated from Rheedia gardneriana and the two compounds compared, the structure of the G. densivenla xanthone was revised to that of rheediaxan- thone A (88), and the new compound assigned the structure of pyranojacereubm (87) [60]. This example serves to highlight the problem of differentiating between substituents at the 2- and 4-positions. Upon acetylation, H-4’ of 87 was deshielded by 60.26 (expected -60.30), compared to 60.19 for H-4’ of 88 [60].

Compounds which contain a 1,1,2-trimethyldihydro- furan nng are possible artefacts due to the ease with which the parent l,l-di~ethylallyl group cychzes with an

ortho-hydroxyl. Rheediaxanthone B (89) and xanthones 90 and 94 are optically active and should therefore be true natural products; however rheediaxanthone C (91), al- though also optically active, is thought to be an artefact of 89 [70].

Nine of the xanthones in Table 9 were isolated from Rheedta brasiliensls and are biogenetically closely related (eg. 92-94). The location of the methoxyl in manglexan- thone (95) was confirmed by its 13C NMR chemical shift (> S60), indicating di-ortho-substitution [70]. Therefore 95 is apparently different from tovopyrifolic A (95; R, = H, R, = Me) which IS found m the same genus [76].

During the last eight years an equal number of papers have described new xanthones from Garcinia mangostana. Those shown in Table 9 all contain the 1,3,6,7-tetra- oxygenation pattern and are cychzed or hydrated deriva- tives of the major metabolite, mangostin (70; R, = Me, R, = OH) or y-mangostm (70) R, = H, R, =OH). The chromanoxanthones (98 and 101-104) had been syn- theslsed previously by the p-toluenesulphonic acid cata- lysed cyclization of mangostin [77]. Whereas this reagent gave both linear and angular chroman rings, methanolic HCl gives only the linear product [78].

Dlmethylmangostin (106), which may be selectively demethylated to give the natural mangostins, has been synthesized by Lee (Scheme 3) [79]. The problem of

980 G J BENNETT and H -H LEE

186 R = Me

187 R = H

Reagents (I) TFAA/CH2C12 (n)H2,Pd/C (ui) CH2N2 (IV) Me.,NOH/py (v) BC’L~/CHICl,

(n) Mel/K#ZO, (vu) McCOCI/K&YOB (viu) LlCL/DMF (XI) KO’Bu/DMSO

Scheme 3

selective prenylation m the 2- and 8-posltions was over- come by the preparation of the dichromanoxanthone (105). Ring openmg was accomphshed with boron trl- chloride to give a dlchlorlde which underwent dehydro- chlormatlon with hthmm chloride m DMF, producing 106 AlternatIvely, treatment of the dichloride with pot- assmm-t-butoxlde m DMSO gave p-mangostm (107)

Trr-C,-tetraoxygenated xanthones. Five xanthones of this type are now known, and the two new ones are shown m Table 10. The structure of garcmone E (108) 1s tenta- tive, and based mainly on the formation of a tnchromano compound with methanohc HCl [78]

The novel ring B substltutlon pattern of nervosaxan- thone (109) was suggested by the deshlelded methylene of one of the prenyl groups, placmg It peri to the carbonyl, and the ‘H NMR resonance of the single aromatic pro- ton [72] The arrangement of the 2- and 4-substltuents was determined by an ‘H NMR study of the tn- and tetra-acetates

Dl-C,-pentaoxygenated xanthones The first natural examples of thn type are xanthones V, (110) and V,, (111) (Table 10) from Vismla qumeensts They are the 7-meth- oxy derlvatlves of xanthones V, (83) and V,, (85) (Table 9) Together these constitute the only occurrences of prenylated xanthones m the genus Vtsmla

More complex xanthones. Garcrma pyr$era shows a link with G. cowa and G. rubrn by producing 8-geranyl- 1,3,6,7_tetraoxygenated xanthones (112-l 14; Table 11) [72] The optically active maculatoxanthone (115) IS the first xanthone with a lavandulyl side chain, although this arrangement is found m three benzophenones-tovo- phenones A and B (141,142) and xanthochymol (144). Calozeyloxanthone (116) contams a novel C,, arrange- ment, presumably a cychzed geranyl group

Calophyllum wightuznum produces a palmltic acid clathrate which yielded a xanthone named wightlanone [81]. A .5,5-diprenyl structure was proposed. However, on comparison [21], it was found to be identical with a sample of zeyloxanthanone (117) isolated from Calo- phyllum zeylumcum Gamboglc acid (118) has been re- isolated from Garcrma hanburyl together with a new derivative, neo-gamboglc acid (119) [82]

Xanthone glycosrdes

The C-glucosylxanthones, mangiferm (120; Table 12) and lsomangiferm (121) have been found m several spe- cies of Hyperrcum and Cratoxylum prumforum but are not known In the rest of the famdy. The taxonomic significance of thrs will be discussed later There are only two examples of 0-glycosldes in Guttlferae (122, 123), although neither has been properly characterized Both 0- and C-glycosylxanthones are common m the Gentlan- aceae [2]

Xanthonohgnoids

Kielcorm was first isolated from Klelmeyera species, and Its structure has been defined as a racemate of the two 5,6-trans isomers (124) [SS] It has recently been isolated from several Hypericum species and Vtsmia guaramlran- gae. The other xanthonohgnolds m Table 13 also have the trnns configuration and are optically inactive.

BIogenetIcally, xanthonohgnolds are thought to be formed by the coupling of a cmnamyl alcohol with an ortho-dlhydroxyxanthone Klelcorm and 2.3,4-(or 5,6,7)- trloxygenated xanthones co-occur m Hypericum caly- cmum and H. ertcoldes as well as m three Ktelmeyera

Xanthones from Guttlferae

Table 10 Trl-C,-tetraoxygenated and Dl-C,-pentaoxygenated xanthones

981

(108) Garcinone E

*Carctnta nangostana I,. [78]

(109) Uervosaxanrhone

*Garctnta neruosa Miq. [72]

0 OH

(110) Xanthone E

*Vtsmta gutneensts (L.) Choisy [683

(111) Xanthons $,,

*Vtsmta gutneensts (L.) Choisy [68)

species. The 1,5,6,7_tetraoxygenated candensins A and C Benzophenones (125, 126) are found alongside similarly substituted xan- thones in the two Cararpa species and H. canariensls

Benzophenones are of interest as they have been Impli-

Furthermore, syringaresmol (129), a likely precursor to cated in xanthone biosynthesis. Simple benzophenones

the C& moiety of candensins A and C, has been isolated are rare m the Guttiferae. They have been found in the

as the diacetate from Vtsmra quaramirangae. heartwood of five species (Table 14t_usually with anal-

Klelcorin (124) has been synthesized by two different ogous xanthones. For example, maclurm (134) occurs

routes [91,92] One involves the blomlmetic coupling of with 1,3,6,7-tetrahydroxyxanthone (48) in Garcinia

2-methoxy-3,4_dihydroxyxanthone (130, Scheme 4) and mangostana, with 48 and 1,3,5,6-tetrahydroxyxanthone in

comferyl alcohol (131) [91] crs-Klelcorin (124, 5,6-crs) Symphonia globulifera and with xanthochymol (144) in

was a mmor product. Garcmra xanthochymus.

Candensinb and hyperlcorin from Hyperlcum canar- lenses and H. mysore&- respectively, have been assigned the same structure (127) and their ohvslcal data comnare

Prenylated benzophenones

reasonably well. An isomer of kielcorin, named kielcbrin These compounds shown in Table 15, may be divided B has been ldentlfied in Kielmeyera corlacea and tenta- into two groups, true benzophenones (M-142) and those tlvely assigned structure 128. with reduced A rings, the so-called polyisoprenylated

982 G J BENNETT and H-H LEE

Table I1 More complex xanthones

(1121 R = H. Rubraxanthone

(113) R = 3-Methyl-2-butenyl:*Iscoranin

(114) R = 3-Methyl-4-hydroxy-2-butenyl;

*Isocoranol

Garctnta pyrtfera Ridl. [72] H

(116) Calozevloxanthone

* Calophyllum zeylantcum Kosterm.[21]

(117) Zevloxanthonone /liahtianone)

Calophyllum aightiagnum T Anders [811

*Garctnia hanburyi Hook f [827

benzophenones (143-148) Of the former group, five Garclnia /da, shows broad antlmicroblal actlvlty [102] contam unsubstituted B rings, and therefore have no There has been some controversy regardmg the struc- known xanthone analogues. The vlsmlaphenones tures of the four closely related compounds contaimng a (136-139) have been synthesized by the prenylatlon of blcyclononene motety (144-147). The X-ray determined suitably substituted benzophenones [98-1001. Tovo- structures of xanthochymol (144) and lsoxanthochymol phenones A and B (141, 142) contam the rare lavandulyl (146) are shown m Table 15 Cambogm (147) was shown side chain, aqd koianone (143) from the edible fruit of to be the antipode of the latter and cambogmol (145),

Xanthones from Guttlferae

Table 12. Xanthone glycosldes

983

(120) R,=B-D-Glucopyranosyl, R,=H:

Cratoxylum pruntflorus Kurz. [130]

Hypericum aucheri Jaub et Sprach 1471

Hypertcum barbatum Jack [S4]

Hypericum botssieri Petrovic [85]

'Hypericum humifusum L. [SS]

Hypertcum maculatum Crantz [84]

Hypericum rocheli Griseb. and Schenk. [SS]

Hypericum rumeltacum Boiss [84]

Hypertcum sampsonii Hance [39]

&

(121) R,=H. Rs+-D-Glucopyranosyl;

Isomaneiferin

Cratoxylum pruntflorum Kurz. [130]

Hypericum boissieri Petrovic [85]

Hypertcum hirsutum [87]

Hypericum rochelt Griseb and Schenk [85]

tHypericum sampsonii Hance [39]

(122) R,.=R,=H; 1.3.6.7-Tetrahvdroxv-

0-alucosvlxanthone

Garctnta mangos.tana L. [46]

(123) 1.6.7-Trihvdroxvxanthone- 7-0-alvcoside

Platonta CnsignCs Mart. [29]

(Gly: unidentified sugar)

OH

f” OMe

Me0

HO

OMe

0

OMe

OH

OH

129

Ad’ ffie~conn I24 )

C6Hb ( + CIS. luelconn )

I30 HOTO\, 6Me

131

Scheme 4

which can be prepared from cambogm, was assigned the structure of the enantlomer of xanthochymol with a shlfted double bond [ 1061.

Two related pigments, namely garcinol and isogarcinol were isolated from Garc~ma indica [107] Garcinol was assigned the structure of cambogmol(145), however, their UV spectra m ethanol differed significantly, and It was suggested that camboginol lacked the extended con- Jugatlon m the cyclohexane rmg. The UV spectrum of cambogmol was repeated m cyclohexane and shown to be compatible with the orlgmally proposed structure. A solvent-dependent UV spectrum had already been noted for xanthochymol [lOS] Ultimately, the X-ray crystal structure of lsogarcmol mdlcated Its Identity with cam- bogm (147), and the formation of lsogarcmol from gar- cinol, as well as physlcal data, suggest that the latter is ldentlcal to cambogmol (145) [ 11 I]

A related compound, nemorosonol, isolated from the fruits of CIusu~ nemorosa has been assigned the tncyclode- cane structure (148). It IS suggested that the various polylsoprenylated benzophenones may orlginate from a common precursor (150, R = prenyl or 2+sopropenylhex- 4-enyl) by cyclizatlon between C-l and C-6 to form the bicychc compounds and C-10-C-l and C-6-C-7 to form 148.

Sarothrahn (149) from Hypericum Japomcum has antI- mlcroblal properties, and IS closely related to other fihcmic acid derivatives (which lack a benzoyl group) found m this and other Hyperxum species. Three other

984 G J BENNETT and H-H LEF

Table 13 Xanthonohgnolds

(124) Ri=H. R,=H. R,=H. R+=Me.

Kielcorin

Hypericum androsaeaum L C34.881

Hypericum calycinum L II=31

Hyperrcum canar~ens~s L c241

Hyperrcum ericotdes L [SQ]

Hypericum maculatum Crantz [SS]

Hypericum perforatum L. [ES]

Vismla guaramtrangae Huber [ZS]

(126) RI=OH. Rz=OMe. RzJ=H. R+=Me,

Candensin C

Hypericum canariensLs L [24]

*vlsrnla guaram~rangae Huber [28]

(127) R,=H. Rz=OMe. Ra=H. Ra=Me.

Candensin n 1HvDericorinl

* HyperLcum canariensis L [24]

HyperLcum mysorense [90]

(125) Ri=OH. Rz=H. R,=OMes R4=H

Candensin h

Cariapa grandiflora Mart II291

CaraLpa ualor Paula [29]

VLsmia guaramLrangae Hubcr [2S]

(128) Kielcorin B

*Kielmeyera cortacea Mart. [91]

prenylated benzophenones (bromanone, cluslanone, and Isolated from G. quaeszta, and on the basis of Its conver- marupone) were mentloned m the earher review Cl]. slon to a xanthone and 13C NMR evidence, Its structure

Fmally, one other compound of interest is hermionic has been revised to the diphenylether (149) [113]. Decar- acid. Orlgmally Isolated from Garcznta hermonit, and boxylated hermlonic acid (150) and its demethyl denva- assigned a dlphenyl structure [l], it has now been re- tive (IS), named quaesltol were also isolated [114].

Xanthones from Guttlferae 985

Table 14 Benzophenones

2.3’-Dihydroxv-4.6-dimethoxvbenzor&?mone

ALlanbLachCa floribunda Oliv. [93]

Garctnta xanthochyaus Hook. f [30]

Symphonta globultfera L. [94]

HOtiH (135) 2.3’.4.5’.6-Pentahvdroxvbenzoohenone

Carctnta pedunculata Roxb. [95]

Biogenetically, these compounds appear to be very close- ly related to xanthones.

CHEMOTAXONOMY

Recent reviews have outlined the principles of chemo- taxonomy and the taxonomic importance of various classes of secondary metabolites [115-1171. As xan- thones occur widely m only a few, unrelated families of higher plants, their potential taxonomic value is restricted to within these few families. This sectlon will examme the dlstributlon of xanthones within the Guttiferae.

The oxygenation pattern is the most vanable structural feature of Guttiferae xanthones, and almost forty differ- ent patterns are known. The major oxygenation patterns are shown at the top of Table 16, grouped mainly according to B-ring oxygenation. The number of species m which xanthones with each oxygenation pattern occur 1s gtven for various subdivisions of the family (cf Table 1).

It can be seen from Table 16 that the varlatlon of xanthone oxygenation pattern is of some systematic significance. Some oxygenation patterns appear through- out the family, while others are restricted to certain plant groups. Clearly, the first three of the six subfamilies each produce xanthones with a different range of oxygenation patterns, suggesting that there are different biogenetic constramts on the species of each group. A similar or somewhat narrower range of oxygenation patterns is shown by the tribes or genera of each of these subfamllies. This overall picture may become clearer as more plants are studied.

A species from a particular genus generally does not contain the whole range of oxygenated xanthones found

in the genus. Some species appear not to synthesize xanthones, e.g. Calophyllum macrocarpum. This plant accumulates a C,J, compound, 3,4_dihydroxybenzalde- hyde, perhaps, it is suggested, due to the absence of a key enzyme [SS]. Slmllarly, some species appear to produce only benzophenones, or only simple rather than pre- nylated xanthones

At first sight, such wide variations within a genus may appear to suggest that xanthones are of little taxonomlc value at this level; however, when considered with other taxonomlc characters, xanthones may be useful in aiding infra-genenc classifications. For example, closely related species of Calophyllum have many xanthones m common.

The xanthone distribution within each subfamily will now be examined in more detad. Besides xanthones, the Guttiferae contain a wide variety of other metabolites many of which are also of taxonomlc value and these will be mentloned briefly.

Kielmeyerordeae

The species of this South American subfamdy are characterized by an abundance of simple oxygenated xanthones The two tribes, Kielmeyereae and Caraipeae, show rune oxygenation patterns m common (Table 16). Several rather umque patterns containing 7,8-oxy- genatlon are evident, and interestingly, xanthones with 6,7-dloxygenated B-rings have not been found. Simple 1,3,5_trioxygenated xanthones are common only in this subfamily, and perhaps related to this 1s the rare occur- rence of prenylated xanthones. Prenylation is absent in the Caraipeae tribe, but three prenylated xanthones have been found in species of the Kielmeyereae tribe. Two of

986 G J BENNFTT and H-H LEE

these xanthones are very cominon III Culophyllum species. A further difference between the two tribes IS that

xanthones without l-oxygenation are common only m the Klelmeyereae tribe Slmllarly, xanthonohgnolds, which otherwlse only occur m the Hyperlcoldeae sub- family, are 5,6,7-trloxygenated m Kzelmeyern species but 1,5,6,7_tetraoxgenated m Cararpu speclea.

Remarkably. the two genera of the Caralpeae tribe, so far have no oxygenation patterns m common (Carazpa: 7-, 1,3,7-, 1,5,6,7-, 5,6,7- and 1,6,7&oxygenatlon, and Haploclathra: 1,7-, 1,3,5-, 1,3,5,6-. 1,3,7,8- and 1,7,8-oxy- genation).

For a long time a morphologtcal hnk has been recog- nised between the Klelmeyeroldeae and the family Bon- netiaceae (Bonnetlo and Archytaea genera), and Hutchm- son has even grouped the two together as a single family [ 1181. However, the Bonnetlaceae have also been classl- fied as a tribe m Theaceae [119], a related family m which xanthones have not been found The xanthones that have recently been isolated from two Bonnetlaceae species show the characterlstlc oxldatlon patterns of the Keel-

meyeroldeae [31], and have led one taxonomist to sub- merge the Bonnetlaceae into this subfamily [13].

In Table 16 this subfamdy has been divided mto two groups: Calophyllum and MesualMammea. Both groups contam a similar range of simple xanthones, and show the same common oxygenation patterns (1,5-, 1,7- and 1,5,6-), but there IS a clear dlstmctlon, m that the latter group shows an almost total absence of prenylated xanthones. Only two are known from a species of Knyea (= Mesuu)

Cl1 The 180 species of Calophyllum are found mainly from

India to New Gumea [120] The genus appears to be the most homogeneous m the famtly as far as xanthone dlstrlbutlon IS concerned. Almost all the 21 xanthonc- containing species show both simple and prenylated xanthones Jacareubin (81) occurs m 17 of these species (and with 6-deoxyjacareubm (56) m 1 l), and IS therefore classed as a taxonomlc marker for the genus [ 1211 This

Table 15 Prenylated benzophenones

(136) R, = H. Rz = Me. Vismiaphenone A

*Vtsmia decrpLens Schlecht-Cham [96]

itsaia guara~~~rrangae Huber [ZS]

(137) R, = Me. R, = H; VismiaDhenone C

*Vismta guaramirangae Huber [28]

0 OH

(138) Vismiaphenone B

Clusia elLLpttctfoltn Cuatr. [97]

*Vtsmta decipfens Schlecht-Cham [96]

H

(139) IsovismiaDhenone B

Clusia eLlipticiFolLn Cuatr. [97]

*Vtsnia decipLens Schlecht-Cham [96]

0 OH

(140) *Clus~a elLtptLcLfoZia Cuatr. [97]

Xanthones from Guttlferae 987

Table 15 Contrnued

(141) TovoDhenone c

*Tovoa~ta mangle C.Maritz [loll

(142) Tovonhenone B

*Touomita mangle G.Maritz [loll

dH

(144) R = 3-Methylbut-3-enyl

Xanthochvmol

Garcinta mannii Ollv. [lo33

Garcinla ovalifolla Oliv C691

Garcinia polyantha 011~. [72)

Garctnta staudii Engl. [62]

Garctnia xishuanbannanensis Y H.Ll Cl043

Rheedta madrunno (HBK) Pl and Tr [105]

(145) R = 3-Methylbut-2-enyl

“enantiomer” of 144

CamboeinollGarcinoll

*Garcinta cambogta Desr.[106.108]

Garctnla hulllensrs [109]

Garcinia indica Choisy [107.111(

988 G J BENNETT and H-H LEE

Table 15 Contrnued -

(146) Isoxanthochymol (147) Enantlomer of 146

GarcLnia ouelifolia Oliv [‘=I Camboain(Isoearcino1)

Garcinia polyantha 011~ 1721 *Carctnia cambogla Desr [lOS]

Garcrnia xLs.huanbannanensLs Garclnra lndtca Choosy [107.111j Y H LI [104]

(148) Nemorosonol

Clusla nemorosa G F.W Meyer [llO]

OH 0

Saro thral in

Hyperrcum Japonicum Thunb cl=1

umformtty may be a reflectron of the rather narrow geographtc range, and close relattonshtp of many of the spectes mvesttgated

Interestmgly, the xanthone content of Calophyllum spectes often vartes greatly wtth the part of the plant. For example, the three xanthones found m the bark of C zeylamcum, were not found in the umber, whtch contam- ed seven other xanthones [Zl] Thts phenomenon, as well as the structural slmtlartttes of many of the xanthones, makes the chemtcal compartson of Calophyllum spectes dtfficult

In a recent revtew of the genus [120], Stevens equated C. zeylanrcum (now C lankaensd [21]) wtth C. trapezfol- Iurn. They do in fact have seven xanthones m common, and only differ in that they each produce two xanthones not found m the other [2 1, 1221 A posstble geographtcal vartatton IS suggested m C. walkerr [65] A plant from Indta yielded four xanthones that were not found m the Srt Lankan plant of the same name, however, the bark of the latter was not thoroughly mvesttgated [123] Stgnifi- cant dtfferences have also been found m two vartettes of C calahu [63,64, 1241

Tab

le

16.

The

&

stri

butlo

n*

of s

impl

e an

d al

kyla

ted

xant

hone

s an

d re

late

d m

etab

ohte

s in

the

G

uttif

erae

- O

xyge

natio

n pa

ttern

s

Sub/

amrl

y/T

rrbe

f’

57

11

(No

of s

peci

es)

5 7

Kie

lmey

erea

e (9

)

Car

alpe

ae

(7)

{ Bon

nelr

acea

e (2

)

Cal

ophy

llum

(2

1)

Mes

ua,

Mam

mea

(1

0)

Clu

siea

e (1

0)

Gar

cvna

(2

9)

5 4

1 2 1

23

8 14

34

7 6

Rhe

edla

et

c (6

)

Mor

onob

olde

ae

(4)

Lor

oste

mol

deae

(2

)

Cra

toxy

leae

(2

)

Hyp

erlc

eae

(18)

Vls

mie

ae

(5)

5 5

3 2 2

4 4

1 2

1 1

1 1

32

33

53

75

5 6

6 2

2

21 1

1 1

1

1

1 1

1 1

1 1

13

1

1

1 1

Sim

ple

xant

hone

s A

lkyl

ated

xa

ntho

nes

15

56

6 11

1

5 1

1 3 1 1

1 1

61

51

17

1 O

ther

sj

1

36

75

63

78

6 3

67

6 77

8

7 5

7 7

8 8

61

33

1 12

378

3

4 12

2

1

1 1)

1 1

21 1

5 1

2 1 1

1 21

2 1

1237

8 14

14

18

24

, 15

2

1 37

, 13

567

1 12

35

1 13

45,

345?

[3

8]

4 15

6

125,

12

45,

1256

, 13

47,

1357

2 3

3 1

3

2 1

25,2

35,

2567

147,

15

8, 5

678,

1

1567

8

1 1

3 3

7 5 6

3 1

2 8n

2 3

2 2 1 1

1 O

ther

4 X

GII

X

U

WI

3 6 7

3 3

5 13

58

1 12

8 3

1 16

7 2

0 5 r

1 12

5,

1256

1

2 2

2

1567

1

3 23

5.

367

9 7

1

1356

7 1

2

*Num

bers

m

Tab

le

refe

r to

nu

mbe

r of

spe

cies

m

whi

ch

xant

hone

s w

ith

the

part

icul

ar

oxyg

enat

ion

have

be

en

foun

d.

IGen

era

m w

hich

se

vera

l pl

ants

ha

ve

been

ex

amin

ed

are

sepa

rate

d fr

om

the

rest

of

the

su

bfan

nly

or

trib

e (c

f T

able

1)

$The

se

mm

or

oxyg

enat

ion

patte

rns,

ap

art

from

on

e,

have

be

en

foun

d m

one

sp

ecie

s;

2,5-

dlox

ygen

atlo

n fo

und

m t

wo

spec

ies

§1,5

-Dlo

xyge

natlo

n an

d 1,

6,7-

tnox

ygen

atlo

n fo

und

m e

ight

an

d tw

o sp

ecie

s re

spec

tivel

y,

rem

aind

er

foun

d in

one

sp

ecie

s

JIX

G,

xant

hone

gl

ycos

ides

, X

L,

xant

hohg

nold

s,

BZ

, si

mpl

e an

d pr

enyl

ated

be

nzop

heno

nes

IInc

lude

s th

ree

spec

ies

whi

ch

cont

am

xant

hone

s w

ith

redu

ced

B-r

ing

990 G J BENNETT and H-H LEE

Neoflavonotds (and other 4-substttuted coumarms) and chromones occur m many CalophyUum spectes [125,126].

Clusrodeae

Generally xanthones occur less frequently m the Clus- rodeae than m the precedmg subfamthes, and the range of

major oxygenatton patterns IS rather restncted. Xan- thones m wfuch I-oxygenatton IS absent are not known, but several umque oxygenatton patterns contammg 2- and 4-oxygenatton occur Spectes of both trtbes produce prenylated benzophenones, often as the maJor metab- ohtes, but otherwtse the tribes show little m common.

In the Clusreae tribe. xanthones and benzophenones occur in Tuuomztu spectes, but the large, poorly-studted Clusla genus has so far not yrelded any xanthones. Recently, Delle Monache and co-workers have begun to study a number of C’lusra species [ 1 lo]

The Garcmeae trtbe IS drvrded mto two groups in ‘Table 16 Gmcma and RiieedS~a/Pentaphakmyrnum/Alrcln- hlackza. The tribe appears fatrly homogeneous, wtth each group showmg a stmrlar range of sample and prenylated xanthones

Xanthones have been found m about half the Garcmzu species studted Btffavonotds occur m almost aIf species and benzophenones m 11 Waterman and co-workers have systematically exammed several Garcmra spectes from troprcal Afrrca The subsequent chemotaxonomrc revrew of the genus shows that m certam cases xanthone structure correlates well with the mfra-genertc class& catron [ 127)

Three species from the sectron Rheedropsrs of the genus have been Investigated, and each contams prenylated xanthones wrth 1,3,.5,6-tetraoxygenation as well as xan- thochymol(l44) The benzophenones cambogm (147) and cambogmol(l45) occur m two species from the Gamogm section, and the two species which produce gambogrc actd (118) and other xanthones with reduced B-rmgs are from the sectron Hebradendron X-Geranylated xan- thones are only known m three Garcwa species, two of which belong to sectton Oxycarpus It has been suggested that the thud spectes, whtch has so far not been asstgned to a sectron, may also go here [72] Such correlations were not found m many other secttons, but as only 10% of Garczmu spectes have been studred tt IS perhaps too early to tell

Also of interest IS the apparent geographtcal varlatton of tetraoxygendtton patterns [ 1271 African Garcmm spe- cues contam 1,3,5,6- (and no 1,3,6,7-) tetraoxygenated xanthones, whereas Astan species, apart from one, show only 1,3,6,7-tetraoxygenatton. Some xanthones from Afrr- can Garczmu also occur m species of the related South American genus, Kheedla. whtch so far has also yielded only 1,3,5,6-tetraoxygenated xanthones

The Moronbordeae subfamtly IS rather small, and the four mvesttgattons so far have produced xanthones srmt- lar to those m the Clusrodeae The Lorostemotdeae sub- family contains only two species from which one preny- lated xanthone has been Isolated

Hyperrcoldeae

Thts subfamtly of three tribes IS closely related to the rest of the Gutttferae [ 128, 1291, although tt IS somettmes classed as a separate famtly, the Hypencaceae [IZJ The

followmg evtdence supports such a relattonshtp Preny- lated xanthones, have been found m all three tribes of the Hypertcotdeae, and although they have unique struc- tures, they are stmtlar to those found m other subfamrhes (e g 63,80) The presence of xanthones with 7,8- and 5,6,7-oxygenation and xanthonohgnotds shows a link wtth the Ktelmeyerotdeae subfamtly, and two benzophen- ones (138, 139) from Vlsmra dwrpwns also occur in a specres of Clusra

LJnhke the rest ofthe family, the Hypertcordeae contam C-glucosylxanthones. They have been found m several species of Hyperlcum [84,85] and Cratovylum prunifol- rum [130], and occur wrth both sample and prenylated xanthones, as well as flavonotds As rt appears that these glycostdes may be btogenetrcally dtfferent from the xan- thones rn the rest of the family (see Btosynthests), their presence should not be regarded as evtdence of ‘xan- thones’ to support the mcluston of the subfamtly m the Guttiferae Interestmgly. sample xanthones wrth 6,7-oxy- genated B-rmgs are unusually common m Hyperlcum species They occur wtth the stmtiarfy substnuted gly- costdes and may be bmgenettcally related

A chemotaxonomtc survey of the Hyperrcum genus has recently appeared Cl3 11 In addttton to xanthones, many flavonords and other phloroglucmol dertvattves have been found Vismur species produce prenylated anthra- nords and other anthracene dertvattves (vtsmlones) [ 1321 Stmrlar metabohtes also occur m Psorospermum species

CL331

BIOSYNTHESIS

The charactertstrc oxygenatron patterns of xanthones from htgher plants were recogmsed early on as bemg due to a mtxed shtkrmate-acetate btogenests [53 Along these lmes vartous biosynthetrc pathways were proposed [7,8, IO] and these have been reviewed [l J

Early btosynthetrc studies were hmtted to the 1,3,7- trtoxygenated xanthones of Gentlana luteu (Genttana- ceae) [134, 1351 The results Indicated that the xanthone nucleus was formed from acetate (rmg A) and a C,C, umt derived from phenylalanme The partrctpatton of an mtermedtate benzophenone (152) was demonstrated by the mcorporatton of trttrated 152 [135]

The first study on the btosynthesrs of xanthones m the Gutttferae has recently been reported [136] Cmnamtc acid, benzotc actd, m-hydroxybenzotc actd and the ben- zophenone (152) as well as malomc acid were effictent precursors to mangostm (153) m Garcmla mangosrana, tmplymg the pathway depicted m Scheme 5

Furthermore, the labelled benzophenone (152) was stgmficantly mcorpordted into 8-desoxygartamn (67) and gartanm (79, R, =H, R, =prenyl) m the same plant These findmgs, coupled wtth the earher studies on Gcn- trana lutea, Indicate the mvolvement of benzophenone 152 m the btosynthests of xanthones with four different oxygenatton patterns (1,3,5-. 1.3,7-, 1,3,6,7- and 1,3,5,8-k and suggest that tt may be an mtertnedtate m the bto- synthesis of most higher plant xanthonrs

The proposed drrect m-hydroxylatton of benzoate (Scheme 5) was suggested, m part, by the poor mcorpor- atron of p-substrtuted precursors Earlter btosynthettc proposals, such as the choice of maclurm (134) as a umversal xanthone precursor [IO] and the Idea of spuo- dteneone intermediates [7], were formulated wrth the assumptton that shrkrmate derrvatrves were necessartfy

Xanthones from Guttlferae 991

AI

1% R’ = CO,H, R2 = Me

151b R’ = H, R2 = Me

151C R’ = RZ = H

3x Malonyl CoA

OH

153

Scheme 5.

152

oxygenated in the p-posltion. As It now appears that xanthone blosynthesls may not involve such slnkimate derivatives, the earlier proposals require re-evaluation.

Of the various modes of xanthone formatlon proposed to date, phenol oxldative coupling [137, 138-J can most neatly account for the large variety and co-occurrence of oxgenated xanthones [S] Carpenter et al, postulated the oxidative coupling of a series of suitably hydroxylated benzophenones to account for the major xanthone oxy- genation patterns [8]. This suggestion is compatible with the new biosynthetic results, as the benzophenones all require the meta- or 3’-oxygenation for oxidative coup- ling, and may be derived from benzophenone 152. For example, the oxidatlve coupling of 152 can give 1,3,5- and 1,3,7-trthydroxyxanthones (Scheme 6, Route A) and maclunn (134), which may be formed by the 4’-hydroxy- lation of 152, can produce 1,3,5,6- and 1,3,6,7-tetrahy- droxyxanthones (Route B)

An alternative to the view that xanthones are formed from a series of benzophenones, is the proposal of Rezende and Gottlieb that the xanthone oxygenation pattern is modified after initial xanthone formation from a single benzophenone-maclurm (134) [lo]. The ‘pn-

motive’, maclurin-derived 1,3,5,6- and 1,3,6,7-tetraoxy- genated xanthones could lead to all other oxygenation patterns by successive nuclear oxidations and/or reduc- tions. For example, the reduction of the 6-position of these xanthones would give 1,3,5- and 1,3,7-trioxygenated xanthones (Scheme 6, Route C).

In view of the recent biosynthetic studies, the 1,3,5- and 1,3,7-trioxygenated xanthones appear more sulted to occupy the positions of ‘primitive’ xanthones, as they are clearly more likely to be formed by the direct oxidative coupling of benzophenone 152 (Scheme 6, Route A), than by a three-step route via maclurm (134) (Route B + Route C). The 1,3,5,6- and 1,3,6,7_tetraoxygenated xanthones may alternatively be formed by the &oxygenation of the 1,3,5- and 1,3,7-tnoxygenated xanthones (Scheme 6, Route D)

Similar nuclear oxldations/reductlons of the trioxygen- ated xanthones, can lead to the major oxygenation patterns of Guttiferae xanthones, as illustrated in Scheme 7 It can be seen that the most common oxygenation patterns (particularly 1,3,5-, 1,3,7-, 1,7-, 1,5-, and 7-) are more directly accessible from 152 than from maclurin (134) in the earlier proposal.

992 G J BENNFTT and H-H LFE

Scheme 6

Benzophenone

152

Oxldatwe couphng

/ \

1,3,5 ( 33 )* 1,3.7 ( 26 )

A i L J i L

1,2,3.5 ( 6 ) 1,s ( 29 ) 1,3,5,6 ( 35 1 1,3.6,7 ( 25 ) I ,7 ( 42 ) 1.3.7,s ( 3 )

14w I/ 01

i,2,5 ( 2 ) 5 (5 ) 1,5,6(22) I ,6.7 ( 7 ) 7( 18) 1.7.8(8)

/

2SC-2) 1,2,5,6(2) 5,6(2) 1,5,6,7,(7) 6.7(7) 1,6.7,8 ( 4 ) 7,8(4)

5,6,7( 11) 6.78 ( 3 )

*No of species that produce xanthones wth each oxygenation pattern

Scheme 7

The dIscusston so far has centred on the four predoml- always found ortho to an oxygen function 2-Prenylatlon nant oxygenation patterns of prenylated xanthones, but IS the most common, but is only found m the presence of avolded the Issue of prenylatlon Prenylatlon IS almost 1,3-dloxygenatlon, suggestmg perhaps that the prenyl

Xanthones from Guttlferae 993

group mhtbtts reduction of the 3-hydroxyl, which ts very often absent m simple xanthones

Monoprenylatton occurs less often m the 4-, 8-, or 7- postttons. A second prenyl group frequently occurs m the 4- or 8-positions 2,4-Diprenylatton IS associated wtth 1,3,5-, 1,3,5,6,- or 1,3,5,8-oxygenatton, but mterestmgly, not known wtth 1,3,7- or 1,3,6,7-oxygenation, and 2,8- dtprenylation ts hmtted to 1,3,7- and 1,3,6,7-oxygenatton patterns

As wtth oxygenatton, there 1s little evidence to suggest whether prenylatton occurs at the benzophenone or xanthone stage, although the latter 1s preferred, e.g. ref [139] 2-Prenyl-1,3,5-trthydroxyxanthone has been pos- tulated as a precursor to 6-deoxyjacareubin (56) and jacareubm (81) [ 1401, a route mvolvmg 6-oxygenation at the xanthone stage, and m keeping wtth Scheme 7 These three xanthones are found together m four Calophyllum species. Similarly, 2-prenyl-1,3,7-trihydroxyxanthone could lead to mangostm (153) vta 6-deoxy-y-mangostm (70). The alternative, that 153 and 70 derive from two benzophenones, 1s less attractive, as it does not mdtcate such a close relationship between these co-occurring xanthones It can be seen that a series of modtfications (oxygenation, further prenylation, cyclizatton etc ) to the two basic 2-prenylxanthones can produce over 40, or about half of the known prenylated xanthones.

It had been suggested that mangiferm (120) was bio- genettcally related to flavonotds [S, 1411, due to its occurrence m some plants m the presence, or apparently in place of C-glucosylflavones [142], rather than with other xanthones Pujita and Inoue have conducted a thorough study on the biosynthesis of mangtferm (120) and tsomangtferin (121) m Anemarrhena asphodeloides (Ltliaceae) [143, 1441. The results mdtcate that the xan- thone nucleus 1s mdeed formed from a flavonotd-type C,C, precursor (p-hydroxycinnamate) coupled with two malonates (Scheme 8) The labelled benzophenones, tri- flophenone (154) and maclurm (134) were significantly

fy-ycooH “ON

120 & 121

2x c

Malonyl CoA

2.6’&4-6’ *

Oxldative couphng

incorporated mto 120, whereas labelled 1,3,6,7_tetrahy- droxyxanthone was not, suggesting that the glucosylation occurs at the maclurm stage, and that both 120 and 121 are formed by the oxtdative coupling of 3-glucosylmac- lurm (156)

Interestingly, mangtferin (120) has recently been found together wtth 3-C-glucosyhrtflophenone (155) m two ferns (Hypodematwm) [145], and with the 1,3,7-xanthone analogue of 155 m Gentiana lactea [146].

PHARMACOLOGY

Probably the most important development m thts area has been the tdenttfication of the cytotoxtc xanthone psorospermm (57) [Sl, 52,541 It shows significant in uwo acttvtty m P338 leukaemta, colon (C6) and mammary (CD) tumobr systems [ 1481. Synthetic studies on psoros- permin are m progress [55-573 (see earlier), and anal- ogues are bemg prepared and tested for simtlar activity [149-J.

Mangtferm (120) has been the subject of several studies. Anti-mflammatory [lSO], antihepatoxtc [151] and antt- viral (herpes) [ 1521 properties have been reported. Man- gtferm has also been shown to cause the in ultra activation of the lymphocytes of tumour-bearing rats [153].

In contrast to mangtferm (120), which is reported to be a CNS sttmulant [ 1541, mangostin (153) and several of tts dertvatives [155] as well as xanthones from Calophyllum mophyllum and Mesua ferrea [ 1561 produce CNS depres- sion in rats and mice. Many of these xanthones, especially mangostin, exhibit significant anti-inflammatory proper- ttes at doses of 50 mg/kg [155,156]. They have no analgestc or anttpyrettc effect, but mangostm shows antt- ulcer acttvtty The interference of mangostm with inflam- matory and tmmunopathologtcal responses has been further studted [ 1571. The synthetic 3,6-dt-O-glucosyl- mangostm produces myocardial sttmulatton and a rise in blood pressure m dogs [ 155, 1581.

OH

C I ) 3’. oxldatlon (II ) 3 glucosylation

156

Scheme 8

994 C J BF~NFTT and H-H LEF

More xanthones have been tested for zn cltrn mhlbrtlon ofmonoamme oxldases (MAO’s) [159] Two compounds, I-hydroxy-3,8-dlmethoxyxanthone and 1,3-dlhydroxy- 7,&dimethoxyxanthone (swertmm) were Identified as the most effective mhlbltors of type A MAO. but were weak type B MAO inhlbltors In another study 1,5,8- tnhydroxy-3-methoxyxanthone also showed selective type A mhibltlon [146] A number of xanthones also mhlblt xanthme oxldase [160] 1,3,6,7_Tetrahydroxyxan- thone was the most potent of the compounds tested

tlon between 13C NMK chemical shifts of C-4b and C-7 of various 1,3-oxygenated xanthones and tuberculosis mhlbltlon [ 1651. Three potent xanthones were Identified, of which gentlsem (31) was the most active

C0NCL.I SIOY

Several prenylated xanthones possess significant an- timlcrobiafproperties Mangostln shows broad-spectrum antibacterraf activity, mcl’udihg the inhibition ot”penic& hn-resistant strams of Staphylococcus uweus, as well as antifungal propertles [161; lhZ] Xanthones from Culn- phybn mophyllum, particularly 6-deoxyjacareubm (56) andjacareubm (81) [163], and the benzophenoncs kolan- one (143) [102] and garcmol (145) [109] also exhibit antJmJCJ’Obla~ propertles

In conclusion, the Guttlferae produce a wide variety of both simple and prenylated xanthones The growmg Interest in thesecompounds IS shown by the large number Isolated durmg the last eight years An attempt has been made in this review to correl&e xanthone structure with the ciasslcar taxonomic divisions ot-the Ciluttiterae. The new results on xanthone biosynthesis support the Idea of a common_ benimphermne precursor_ ahh<zugh forth!% studies are stilt required Lastly, the pharmacology of xanthones has been summarlred, mdicatmg their poten- teal as medlcmal agents

A tuberculostatlc effect has been noted m many natural A(XnoM.lrdqementc---The authors are grateful to Dr G M

and synthetic xanthones [I 641. A quantltatrve structure- Kltanov for his commumcatlons, and one of us (GJB) thanks the actlvlty relatlonshlp (QSAR) study has found a correla- NatIonal IJnrverslty of Slngdpore for the awdrd of a scholarship

APPENDIX

SpecIea-compound Index

Xanthones except (rrrrl)-xanthollgnold, ( [-glycoslde ( \-benzophenone

(132), (133)

51

4,l 21

71

71~ 73

70, 75

74, 76-78

117

1, 3 4, 18, 56, 73, 81, 116

28, 36. (125) - 2.36

36, (125)

(13CGO)

(148) 48. jl20}, (JZI) (145) (147)

88

118, 119

(145)

4, (145), (147)

(143) 48. 52. 54. 55, 68, 70, 73, 74. 79. 96-104 108. jl22).

(134) (144) 109

86, (144), (146)

(135) 90. (144), (146) 112~114 69

[IS1 a *]

88. (144)

39

3, 4. 12, 14, 15. 30, (134)

(l44), (146)

Xanthones from Gutttferae 995

APPENDIX Contmued

15, 21,35,38,42,45,46,49

7, 15, 21, 23, 25, 29, 31, 33, 38, 40, 41

4, 7 10, 11, 27, 47, 48, SO, 80, 82, (124) - 48, {120) 1, 4, 11

(1201 {lZOl> (1211 (124) 1, 5, 10, 26, 37, 63, (124), (126), (127) --- 31

1, 4, 34, 43, (124) {121} -

(1201 (149) 115, {120}, (124) 1, 2, 4, 6, 7, 924, (127) - (124) - (1201, {121}

11201 26,64,82, { 120}, { 121)

Haploclathra lreantha (Benth.) Benth

H panrculata (Mart) Benth H vertrcrllata Ducke

Hyper~cum androsaemum L

H aucherl Jaub et Sprach

H balearuxm L H barbatum Jack

H bolsslerl Petrovic

H calycmum L H canartensts L H. degenu Bornm

H errcoldes L

H hvsutum H hum&urn L H. Japomcum Thunb

H maculatum Crantz H mysorense H perforatum L H rocheh Grlseb and Schenk H rumehacum Botss

H sampsonu Hance Klelmeyera corlacea Mart.

K rublflora Camb

K speclosa St Hill Mahurea tomentosa Ducke

Mesua ferrea L

Platoma msrgms Mart.

Psorospermum febrlfugum Sprach

Rheedla benthamtana PI and Tr

R. brasdlensls (Mart ) PI and Tr

R gardnerlana PI and Tr

R madrunno (HBK) PI

Symphoma globullfera L Touomlta brasllrensls Walp

T excelsa Andrade-Ltma & G Marttz

T mangle G Marttz

Vlsmra declplens Schlect-Cham

V guaramvangae Hubcr

V aumeensts (L ) Chotsv

(128) - 26 26

4, 7 42

32, { 123) 11,44,53,5741

86,88,89,91 62,67, 8694

62, 67, 84, 8691

(144) (134) 36

16, 18, 20, 22 95, (141), (142)

(136), (MU, (139) 1, 2, 4, 7, 8, 11, 13, 15, 17, 19, (1%126), (136), (137) -- 83,85, 110, 111

REFERENCES

L SultaubaW~ M u s (LSKl) TetJddran 36,143 2 Hostettmann, K and Wagner, H (1977) Phytochemtstry 16,

821 3 Rtchardson,P M (1983)Brochem.Syst EcoL11,371,(1984)

rbrd 12, 1

4. &r&,. A I, Batdas, I., Ht.ubeck., I Q, &t~psou_, T I acd.

We%tetman,P.W (l_Wfi!.J ctwm s~,PerkurTr~ t@x

5 Roberts, J C (1961) Chem Reo 61, 591

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