Synthesis of Biologically Relevant Biflavanoids – A Review

REVIEW

Synthesis of Biologically Relevant Biflavanoids – A Review

by Mohammed Rahman, Muhammad Riaz, and Umesh R. Desai*

Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, School ofPharmacy, Virginia Commonwealth University, 410 N. 12th Street, Suite 542, Richmond, VA 23298-0540,

USA (phone: þ1(804)828-7328; fax: þ1(804)827-3664; e-mail: [email protected])

Recent investigations show that naturally occurring biflavanoids possess anti-inflammatory,anticancer, antiviral, antimicrobial, vasorelaxant, and anticlotting activities. These activities have beendiscovered from the small number of biflavanoid structures that have been investigated, although thenatural biflavanoid library is likely to be large. Structurally, biflavanoids are polyphenolic moleculescomprised of two identical or non-identical flavanoid units conjoined in a symmetrical or unsymmetricalmanner through an alkyl or an alkoxy-based linker of varying length. These possibilities introducesignificant structural variation in biflavanoids, which is further amplified by the positions of functionalgroups – hydroxy, methoxy, keto, or double bond – and stereogenic centers on the flavanoid scaffold. Incombination, the class of biflavanoids represents a library of structurally diverse molecules, whichremains to be fully exploited. Since the time of their discovery, several chemical approaches utilizingcoupling and rearrangement strategies have been developed to synthesize biflavanoids. This reviewcompiles these synthetic approaches into nine different methods including Ullmann coupling ofhalogenated flavones, biphenyl-based construction of biflavanoids, metal-catalyzed cross-coupling offlavones, Wessely–Moser rearrangements, oxidative coupling of flavones, Ullmann condensation withnucleophiles, nucleophilic substitutions for alkoxy biflavanoids, and dehydrogenation-based or hydro-genation-based synthesis. Newer, more robust synthetic approaches are necessary to realize the fullpotential of the structurally diverse class of biflavanoids.

1. Introduction. – Biflavanoids, the small polyphenolic molecules more commonlyreferred to as biflavonoids, are gaining increasing recognition as modulators ofphysiological and pathological responses. Biflavanoids occur in many fruits, vegetables,and plants. Since the time Furukawa extracted leaves of maidenhair tree,Ginko bilobaL, to obtain a yellow pigment, which later proved to be a biflavonoid (II-4’,I-5,II-5,II-7-tetrahydroxy-I-4’,I-7-dimethoxy[I-3’,II-8]-biflavone) and given the name ginkgetin (7c ;Fig. 1) [1], the number of biflavanoids isolated and characterized from nature keepsgrowing [2–15]. Biflavanoids have been found to possess interesting biologicalactivities including anti-inflammatory [16–31], anticancer [32–36], antiviral [37–40],antimicrobial [41–47], vasorelaxant [48] [49], anticlotting [50], and other activities[40] [51–53]. Another property with potential applicability is the anti-oxidant propertyof biflavanoids, although their potency appears to be lower than that of mono-flavanoids despite of the presence of nearly double the number of phenolic OH groups[54]. Finally, biflavanoids may inhibit metabolic enzymes. At least one biflavanoid,amentoflavone, has been found to inhibit a human cytochrome P450 enzyme with

CHEMISTRY & BIODIVERSITY – Vol. 4 (2007) 2495

C 2007 Verlag Helvetica Chimica Acta AG, ZFrich

nanomolar potency, suggesting that the determinants of pharmaceutical activity mayalso impede their usage [55].

Of the large number of biflavanoids that are suggested to exist in nature, only acouple of dozen natural biflavanoids have been explored for biological activity studies.The most studied biflavanoids include ginkgetin (7c), isoginkgetin, amentoflavone,morelloflavone, robustaflavone (8b), hinokiflavone (18a), and ochnaflavone (Fig. 1).Each of these biflavanoids is based on an essentially identical 5,7,4’-trihydroxy-flavanoid parent structure, except for the difference in the nature and position of theinter-flavanoid linkage. The resulting range of biological activities in this group ofbiflavanoids is fairly similar with potencies, e.g., anticancer [32–36], antiviral [37–40],and antimicrobial [41–47], in the low-to-mid micromolar range.

The anti-inflammatory activity of biflavanoids has been studied in sufficient detailat a molecular level. Amentoflavone, ginkgetin (7c), ochnaflavone, and morelloflavone

CHEMISTRY & BIODIVERSITY – Vol. 4 (2007)2496

Fig. 1. Structures of biologically important biflavanoids. These biflavanoids, isolated from nature, havebeen the earliest molecules studied for biological activity. See text for details.

have been shown to inhibit phospholipase A2 and cyclooxygenase-2, resulting indecreased biosynthesis of prostaglandins, the key mediators of inflammation[7] [16] [18] [19] [27] [29] [31]. In addition, the biflavanoids also suppress activation ofnuclear factor–kB to down-regulate the synthesis of inducible nitric oxide synthase[14] [20] [21] [23]. Thus, biflavanoids are likely to be effective anti-inflammatory agentsin a number of disorders, including cancer.

Structurally, biflavanoids are polyphenolic molecules comprised of two identical ornon-identical flavanoid units conjoined in a symmetrical or unsymmetrical mannerthrough an alkyl- or an alkoxy-based linker of varying length (Fig. 2). The variationspossible in the parent flavanoid units, coupled with the large number of permutationspossible in the position and nature of the inter-flavanoid linkage, introduce significantstructural diversity in biflavanoids. This diversity is further amplified by variablypositioned functional groups, e.g., OH, MeO, C¼O groups, or C¼C bonds, andstereogenic centers on the flavanoid scaffold. In combination, the class of biflavanoidsrepresents a library of some 20,000 diverse molecules, each of which is capable ofmultiple H-bonding and hydrophobic interactions. Not all of these have been found toexist in nature as yet. However, in an age that values structural diversity, the theoreticallibrary of biflavanoids spans a wide range of configurational and conformational spacesuggesting that possibilities of interesting biological activity are strong.

Despite the large number of structural opportunities embedded in biflavanoids,only two reviews have appeared on this interesting class of natural products. The first,by Geiger and Quinn, was published in 1975, and then expanded later in 1982. Thereview focused on naturally occurring biflavanoids, with little emphasize on theirsynthesis [56]. Later, Locksley reviewed biflavanoids with a particular emphasis ontheir analytical aspects [57]. It is expected that the availability of a greater number ofbiflavanoids, synthetic or natural, will greatly improve the range and potency ofbiological activity.

Several synthetic approaches including coupling and rearrangement strategies havebeen used to synthesize biflavanoids. This review compiles these reactions into ninedifferent methods: a) Ullmann coupling of halogenated flavones; b) construction of

Fig. 2. Basic scaffold of flavanoids and biflavanoids. The bicyclic ring system is identified as rings A andB, while the unicyclic ring is named ring C. The two monomeric units in biflavanoids are identified usingRoman numerals I and II. The numbering of positions in each case begins with the ring containing the O-

atom. Note that positions 9 and 10 refer to C-atoms at the fusion point.


biflavanoids via biphenyls; c) metal-catalyzed cross-coupling of flavones; d) Wessely–Moser rearrangements; e) phenol oxidative coupling of flavones; f) Ullmanncondensation of flavone salts and halogenated flavones; g) nucleophilic substitutions;h) dehydrogenation of biflavanones into biflavones; and i) hydrogenation of biflavonesinto biflavanones. Although the authors have tried to be as comprehensive as possible,some loss is inevitable.

2. Nomenclature of Biflavanoids. – The rapid growth in literature on biflavanoidsled to various systems of naming these compounds. To rationalize and standardize thenomenclature, Locksley proposed some general rules [57]. He advocated that thegeneric name GbiflavanoidH be used in place of GbiflavonylH and others to describe thefamily. In this nomenclature, the term GbiflavanoidH has been adopted in preference toGbiflavonoidH, as it more accurately reflects the saturated system as being the parentsystem. The ending GoidH may then be modified to cover specific types of homogeneousflavanoid dimers, such as biflavanone, biflavone, biflavan, and others, while, for mixedsystems, the description Gflavanone– flavoneH should be used. This system generallyfollows the IUPAC recommendations. Locksley also standardized the nomenclature ofthe rings and the positions on rings. Each monomer unit is assigned a Roman numeral Iand higher in a sequential manner. The inter-monomer linkage is identified using aRoman numeral, which corresponds to the flavanoid unit, and an Arabic numeral,which corresponds to the position of the linkage. The two numerals for both theflavanoid monomers constituting the dimer are coupled with a hyphen and enclosedwithin square brackets. This represents the inter-monomer linkage. The numbering ofsubstituent groups on the monomeric units follows the IUPAC system for flavones, inwhich the three rings are referred to A, B, and C (Fig. 2).

Some examples will clarify the use of LocksleyHs system. Biflavonoid 16b(Table 5)1), also called hexamethylmorelloflavone, would be named as I-3’,II-3’,I-5,II-5,I-7,II-7-hexamethoxyflavanone-[I-3,II-8]-flavone under the Locksley rule, whileamentoflavone 7o would be named I-4’,II-4’,I-5,II-5,I-7,II-7-hexahydroxy[I-3’,II-8]-biflavone. Hinokiflavone (18a ; Table 6), whose flavone units are linked through an O-atom, would be named II-4’,I-5,II-5,I-7,II-7-pentahydroxy[I-4’-O-II-6]-biflavone, whilethe biflavonyl-oxyalkane 29a (Fig. 3 and Table 7) would be named I-3,II-3,I-7,II-7-tetrahydroxy[I-8-OCH2O-II-8]-biflavone.

IUPAC has also devised its own system of nomenclature for biflavanoids. Forexample, hexamethylmorelloflavone (16b) would be called 5,7,5’,7’-tetramethoxy-2,2’-bis(4-methoxyphenyl)-2,3-dihydro[3,8’]bichromenyl-4,4’-dione in the IUPAC nomen-clature, while amentoflavone (7o) would be named 8-[5-(5,7-dihydroxy-4-oxo-4H-chromen-2-yl)-2-hydroxyphenyl]-5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one.Likewise, hinokiflavone (18a) would be named 6-[4-(5,7-dihydroxy-4-oxo-4H-chro-men-2-yl)phenoxy]-5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one. The funda-mental difference between the Locksley system and the IUPAC system is the referenceskeleton. Whereas the IUPAC system considers the majority of biflavanoids as


1) To ease cataloging and retrieval, biflavanoids have been numbered in sequence according to theirentry in the Tables, rather than in the text. Tables 1–9 have been arranged in the approximate orderof complexity of the biflavanoid structure.

derivatives of the chromene structure, theLocksley system uses the flavanoid structure.Thus, for oxyalkyl-linked biflavanoids, e.g., 29a (Fig. 3), the IUPAC system has tochange its reference skeleton, and this introduces considerable complexity innomenclature. It is important to mention that very few scientists utilize either of thesystems, primarily because common names, e.g., amentoflavone, cupressuflavone, andagathisflavone, are easier. These names, however, are limited because they contain nostructural descriptors. The Locksley system is intuitive, logical, and structure-explicit,and hence is adopted here.

3. Methods for Biflavanoid Synthesis. – 3.1. Ullmann Coupling of HalogenatedFlavones. Ullmann coupling, named after Fritz Ullmann, is a reaction of aryl halidemediated by elemental copper. A typical example of Ullmann reaction is the couplingof 1-chloro-2-nitrobenzene with Cu-bronze alloy to yield 2,2’-dinitro-1,1’-biphenyl(Scheme 1,a). The Ullmann reaction has been classified into two major categories; theGclassicH coupling reaction of aryl halides to give symmetrical biaryls (Scheme 1,a and b)and the GmodifiedH reaction involving Cu-catalyzed coupling of aryl halide and anucleophile, e.g., a phenoxide or an amine (Scheme 1,c). The modified Ullmannreaction is covered in Method F (below).

The classical Ullmann reaction has received the most attention in the synthesis ofbiflavanoids. However, a major drawback of the reaction is the requirement oftemperature in the region 260–3008, which results considerable resinification and pooryields. Nakazawa and Ito investigated the effect of various solvents on the coupling of

Fig. 3. Structure of biflavanoid 29a

Scheme 1. Classical and Modified Ullmann Coupling



Table 1. C�C-Linked Symmetrical Biflavones. The asterisk (*) indicates site of linkage.

RI/II-3 RI/II-5 RI/II-6 RI/II-7 RI/II-8 RI/II-2’ RI/II-3’ RI/II-4’ RI/II-5’ RI/II-6’ Methods References

[I-3,II-3]-Linked

1a [– ]* H H H H H H H H H A, E, H [58–61]1b [– ]* MeO H MeO H H H MeO H H E, B [62] [63]1c [– ]* MeO H MeO H H H H H H B [62] [64]1d [– ]* OH H MeO H H H H H H B [64]1e [– ]* MeO/OH H MeO H H H H H H B [64]1f [– ]* H H H H H H MeO H H E, H [60]1g [– ]* H Me H H H H H H H E, H [60]1h [– ]* H Me H H H H MeO H H E, H [60]

[I-5,II-5]-Linked

2a H [–]* MeO H H H H H H H A [65]

[I-6,II-6]-Linked

3a H H [–]* H H H H H H H A, B [58] [61] [66]3b H H [–]* MeO H H H H H H A, B [65] [67] [68]3c PhCO H [–]* MeO H H H H H H A [67]3d PhCO H [–]* H H H H H H H A, B [66]3e H H [–]* MeO H H H MeO H H A, B [65] [69]3f H MeO [–]* MeO H H H MeO H H B [45] [70] [71]3g H H [–]* H H H H MeO H H A [61]3h H MeO [–]* MeO H H H H H H B [67]3i H OH [–]* MeO H H H H H H B [67]3j H tosyl�O [–]* MeO H H H H H H B [67]3k H OH [–]* OH H H H OH H H C [57]

[I-7,II-7]-Linked

5a H H H [–]* H H H H H H A [58] [61]5b H OH H [–]* H H H H H H C [72]5c H H H [–]* H H H MeO H H A [58] [61]

[I-8,II-8]-Linked

6a H H/MeO H MeO [–]* H H H H H B [73]6b H H H MeO [–]* H H MeO H H A, B [69] [74]6c H H H H [–]* H H OH H H A [74]6d H H H MeO [–]* H H H H H A [67] [74]6e H H H OH [–]* H H H H H A [74]6f H MeO H MeO [–]* H H MeO H H A, B, D [69] [75 �85]6g H OH H MeO [–]* H H MeO H H A, B [75] [78] [80] [82] [83]6h H H H H [–]* H H H H H A [58] [61]6i PhCOO H H MeO [–]* H H H H H A [67]6j H OH H OH [–]* H H OH H H A, H [80] [81] [86]6k OH MeO H MeO [–]* H H MeO H H B [87]6l AcO MeO H MeO [–]* H H MeO H H B [87]6m H MeO H MeO [–]* H H H H H A, B, D [63] [79] [80] [88] [89]6n H OH H MeO [–]* H H OH H H A [80]6o H OH/MeO H MeO [–]* H H OH H H A [80]6p MeO MeO H MeO [–]* H H MeO H H A [90]6q OH OH H OH [–]* H H OH H H A [90]6r H OH H MeO [–]* H H H H H A [88]6s H AcO H MeO [–]* H H H H H A [88]

monoflavones, and determined that DMF and DMSO worked best giving yields of ca.30% [97].

TheUllmann reaction has been used to synthesize symmetrical biflavones with [I-3,II-3], [I-5,II-5], [I-6,II-6], [I-7,II-7], [I-8,II-8], [I-3’,II-3’], and [I-4’,II-4’] linkages[58] [65–67] [74–80] [88] [89] [91]. Interestingly, cupressuflavone hexamethyl ether(6f), a symmetrical biflavanoid (Table 1), was prepared in 33% yield [57] [106] twoyears before the isolation of the parent biflavanoid, cupressuflavone (6j) by Seshadriand co-workers from Rhus succedanea [81]. The Ullmann synthesis of cupressuflavone(6j ; Table 1) has been recently revisited by Zhang et al. to improve its yields [78](Scheme 2).

Scheme 2. Synthesis of Cupressubiflavone Hexamethylether and Cupressubiflavone from IodoDerivativeof Apigenin by Ullmann Reaction

i) Cu/DMF, reflux. ii) AlCl3.


Table 1 (cont.)

RI/II-3 RI/II-5 RI/II-6 RI/II-7 RI/II-8 RI/II-2’ RI/II-3’ RI/II-4’ RI/II-5’ RI/II-6’ Methods References

[I-3’,II-3’]-Linked

9a H H H MeO H H [–]* H H MeO B [91]9b H H H MeO H H [–]* MeO H H B [91]9c H H H H H MeO [–]* MeO H H B [91]9d H H H H H H [–]* MeO H MeO B [91]9e H H H H H H [–]* H H H A [58] [61]9f H H H H H H [–]* H H MeO A, B [66]9g H H H H H H [–]* MeO H H A, B [66]9h H H H MeO H H/MeO [–]* MeO H MeO/H B [92]9i H MeO H MeO H H [–]* MeO MeO H A [90]9j H OH H OH H H [–]* OH OH H A [90]

[I-4’,II-4’]-Linked

10a H H H H H H H [–]* H H A [58] [61]10b OH H H H H MeO H [–]* MeO H E [93]10c AcO H H H H MeO H [–]* MeO H E [93]10d H H H H H MeO H [–]* MeO H B [92]10e H H H MeO H MeO H [–]* MeO H B [92]


Table2.

C�C-L

inkedUnsym

metricalBiflavo

nes.The

asterisk

(*)indicatessite

oflin

kage.

RI-3

RI-5

RI-6

RI-7

RI-3’

RI-4’

RI-5’

RII-5

RII-6

RII-7

RII-8

RII-3’

RII-4’

RII-5’

Metho

dsReferen

ces

[I-3,II-3’]-Linke

d

3l[–

]*MeO

HMeO

HMeO

HMeO

HMeO

H[–

]*MeO

HE

[94]

[I-6,II-8]-Linke

d

4aH

MeO

[–]*

MeO

HMeO

HMeO

HMeO

[–]*

HMeO

HB,D

,H[77][85][95][96]

4bH

H[–

]*MeO

HMeO

HH

HMeO

[–]*

HMeO

HB

[69]

4cH

OH

[–]*

OH

HOH

HOH

HOH

[–]*

HOH

HB,H

[95]

[I-3’,II-8]-Linke

d

7aH

BnO

HMeO

[–]*

MeO

HBnO

HBnO

[–]*

HBnO

HA

[97][98]

7bH

BnO

HMeO

[–]*

MeO

HBnO

HBnO

[–]*

HBnO

HA

[97][98]

7cH

OH

HMeO

[–]*

MeO

HOH

HOH

[–]*

HOH

HA

[97][98]

7dH

MeO

HMeO

[–]*

MeO

HMeO

HMeO

[–]*

HMeO

HA,B

,C,H

[99–10

3]7e

HMeO

HMeO

[–]*

i PrO

Hi PrO

Hi PrO

[–]*

Hi PrO

HC

[100

]7f

HOH

HMeO

[–]*

OH

HOH

HOH

[–]*

HOH

HC

[100

]7g

HMeO

HMeO

[–]*

MeO

Hi PrO

Hi PrO

[–]*

Hi PrO

HC

[100

]7h

HOH

HMeO

[–]*

MeO

HOH

HOH

[–]*

HOH

HC

[100

]7i

HMeO

HMeO

[–]*

MeO

Hi PrO

Hi PrO

[–]*

HMeO

HC

[100

]7j

HOH

HMeO

[–]*

MeO

HOH

HOH

[–]*

HMeO

HC

[100

]7k

HH

HOH

[–]*

OH

OH

HH

OH

[–]*

OH

OH

OH

H[104

]7l

HH

HMeO

[–]*

MeO

MeO

HH

H[–

]*MeO

MeO

MeO

H[104

]7m

HH

HMeO

[–]*

MeO

HH

HOH

[–]*

MeO

MeO

HH

[105

]7n

HH

HMeO

[–]*

MeO

HH

HMeO

[–]*

MeO

MeO

HH

[105

]7o

HOH

HMeO

[–]*

MeO

HOH

HH

[–]*

HMeO

HA

[99]

7pH

MeO

HMeO

[–]*

MeO

HMeO

HMeO

[–]*

MeO

MeO

HA

[90]

[I-3’,II-6]-Linke

d

8aH

HH

MeO

[–]*

MeO

HMeO

[–]*

CF

2HO

HH

CF

2HO

HC

[106

]8b

HOH

HOH

[–]*

OH

HOH

[–]*

OH

HH

OH

HC

[107

]8c

HMeO

HMeO

[–]*

MeO

HMeO

[–]*

MeO

HH

MeO

HB

[103

]

Symmetrical biflavanoids with linkages other than 3, 5, 6, 7, 8, 3’, and 4’ have notbeen synthesized because it is difficult to introduce halogen atoms on these C-atoms.Typically, the bromo- and iodo-flavones have been found to yield biflavones under theUllmann conditions. The chloro-flavones are unreactive because of the higherelectronegativity of the Cl substituent, which makes the formation of C�Cu�Clbonds more difficult. Although the coupling of iodo-flavones is expected to be higher


Table 3. C�C-Linked Symmetrical Biflavanones. The asterisk (*) indicates site of linkage.

RI/II-2 RI/II-3 RI/II-5 RI/II-6 RI/II-7 RI/II-3’ RI/II-4’ Methods References

[I-2,II-2]-Linked

11a [ – ]* H H H H H H E [108–112]11b [ – ]* H H Me H H H E [110]

[I-3,II-3]-Linked

12a H [–]* H H H H H C, E [59] [60] [113] [114]12b H [–]* H H H H MeO C, E [60] [113] [114]12c H [–]* H Me H H H E [60] [113]12d H [–]* H Me H H MeO E [60] [113]12e H [–]* H H H MeO MeO E [113]12f H [–]* H Me H MeO MeO E [113]12g H [–]* H H MeO H MeO C [114]12h H [–]* MeO H MeO H MeO C [114]12i H [–]* OH H MeO H MeO C [114]12j H [–]* OH H OH H OH C [114]12k H [–]* MeO H MeO H H I [64]

[I-6,II-6]-Linked

13a H H MeO [–]* MeO H MeO B [45] [70]13b H OH MeO [–]* MeO H MeO B [71]

Table 4. C�C-Linked Unsymmetrical Biflavanones. The asterisk (*) indicates site of linkage.

RI-5 RI-6 RI-7 RI-4’ RII-5 RII-7 RII-8 RII-4’ Methods References

[I-6,II-8]-Linked

14a OH [–]* OH OH OH OH [–]* OH B [95]14b MeO [–]* MeO MeO MeO MeO [–]* MeO B [95]

Table 5. C�C-Linked Flavanone–Flavone Dimers. The asterisk (*) indicates site of linkage.

RI-3 RI-5 RI-7 RI-4’ RII-3 RII-5 RII-7 RII-8 RII-4’ Methods References

[I-3,II-3]-Linked

15a [ – ]* MeO MeO H [–]* MeO MeO H H I [64]

[I-3,II-8]-Linked

16a [ – ]* H H MeO H MeO MeO [–]* MeO I [115]16b [ – ]* MeO MeO MeO H MeO MeO [–]* MeO B [116]

yielding than that of the bromo-flavones, this is not observed because of a slightlyhigher level of reductive dehalogenation.

TheUllmann reaction was also studied for synthesis of the unsymmetrical biflavoneginkgetin (7c). Condensation of the two iodinated flavones using activated Cu powderin DMF unexpectedly resulted in only the symmetrical I-8,II-8-coupled product.However, omission of the solvent completely changed the course of the reaction andthe I-3’,II-8-coupled ginkgetin (7c) was obtained in 21% overall yield [97] (Scheme 3).Hexamethyl and tetramethyl ethers, 7d and 7o (Table 2), respectively, of amento-flavone, which have the I-3’,II-8 linkage, were the first unsymmetrical biflavonessynthesized by Nakazawa and Ito using the Ullmann reaction [97] [99]. Following thisinitial success, a number of unsymmetrical biflavanoids were synthesized [99] [119].However, the overall yields remained low because of the competing symmetricalcoupling as well as due to resinification that accompanies the high temperatureconditions.

3.2. Synthesis of Biflavones via 1,1’-Biphenyls. Mathai et al. first introduced thisapproach of utilizing a 1,1’-biphenyl skeleton to the synthesis of biflavones [66] [91].4,4’-Dimethoxy-3,3’-diformyl-1,1’-biphenyl (34) was condensed with 2-hydroxyaceto-


Table 6. Monoether-Linked Symmetrical and Unsymmetrical Biflavones. The asterisk (*) indicates site oflinkage.

RI-5 RI-7 RI-3’ RI-4’ RII-5 RII-6 RII-7 RII-8 RII-4’ Methods References

[I-3’-O-II-4’]-Linked

17a MeO MeO [-O-]* MeO MeO H MeO H [-O-]* B [117]

[I-4’-O-II-6]-Linked

18a OH OH H [-O-]* OH [-O-]* OH H OH F [96] [118]18b MeO MeO H [-O-]* MeO [-O-]* MeO H MeO F [96] [118]18c MeO MeO NO2 [-O-]* MeO [-O-]* MeO H MeO F [118]18d MeO MeO NH2 [-O-]* MeO [-O-]* MeO H MeO F [118]18e MeO MeO AcNH [-O-]* MeO [-O-]* MeO H MeO F [118]18f OH MeO H [-O-]* OH [-O-]* MeO H MeO F [118]18g AcO MeO H [-O-]* AcO [-O-]* MeO H MeO F [118]18h AcO AcO H [-O-]* AcO [-O-]* AcO H AcO F [118]

[I-4’-O-II-8]-Linked

19a MeO MeO H [-O-]* MeO H MeO [-O-]* MeO F [76] [118] [119]19b OH OH H [-O-]* OH H OH [-O-]* OH F [118] [119]19c MeO MeO NO2 [-O-]* MeO H MeO [-O-]* MeO F [118]19d MeO MeO NH2 [-O-]* MeO H MeO [-O-]* MeO F [118]19e MeO MeO AcNH [-O-]* MeO H MeO [-O-]* MeO F [118]19f OH MeO H [-O-]* OH H MeO [-O-]* MeO F [118]19g AcO MeO H [-O-]* AcO H MeO [-O-]* MeO F [118]

[I-4’-O-II-4’]-Linked

20a H H NO2 [-O-]* H H H H [-O-]* F [120] [121]20b H H NH2 [-O-]* H H H H [-O-]* F [120] [121]20c H H H [-O-]* H H H H [-O-]* F [120] [121]20d MeO MeO MeO [-O-]* MeO H MeO H [-O-]* B [117]

phenone (35) in the presence of ethanolic KOH to give the bichalconyl derivative 36,which, on refluxing with SeO2 in amyl alcohol gave the symmetrical 3’,3’-biflavonylderivative 9f (Table 1) [66] (Scheme 4). Several scientists have followed the Mathaiapproach to synthesize a number of biflavanoids including 9h (Table 1), with a varietyof modification, requiring less reaction time, higher yields, and easier separations[69] [70] [75] [82] [83] [89] [92] [95].

The biphenyl precursor is a key intermediate in this synthetic approach and is oftenthe most difficult step. For example, 3,3’-diacetyl-2,2’,4,4’,6,6’-hexamethoxy-1,1’-biphenyl (38) was obtained by Ullmann coupling in only 3% yield (Scheme 5).Alternatively, 2,2’,4,4’,6,6’-hexamethoxy-1,1’-biphenyl (40) was prepared in 60% yieldby Ullmann coupling of 2-iodo-1,3,5-trimethoxybenzene 39. Friedel–Craft acylation of40 gave the required biphenyl 38 in good overall yields. Using this key intermediate,racemic 6f (Table 1) was successfully synthesized [75] [88].


Table 7. Diether-Linked Symmetrical Biflavones. The asterisk (*) indicates site of linkage.

RI/II-3 RI/II-6 RI/II-7 RI/II-8 RI/II-2’ RI/II-3’ RI/II-4’ n Methods References

[I-3-O(CH2)nO-II-3]-Linked

21a [-n-]* Cl H H H H H 2 G [122]21b [-n-]* Cl H H H H H 3 G [122]21c [-n-]* Cl H H H H H 4 G [122]21d [-n-]* Cl H H H H H 5 G [122]21e [-n-]* H H H H H MeO 1 G [123]21f [-n-]* H H H H H MeO 4 G [124]21g [-n-]* Me H H H H H 4 G [124]21h [-n-]* Me H H H H MeO 4 G [124]21i [-n-]* Me H H H H MeO 2 G [124]21j [-n-]* H MeO H H H H 1 G [125]21k [-n-]* H H H H H MeO 1 G [125]21l [-n-]* H H H H H H 1 G [126]21m [-n-]* H H H H H MeO 1 G [126]21n [-n-]* MeO H H H H H 1 G [126]21o [-n-]* Me H H H H MeO 1 G [126]21p [-n-]* H H H H MeO MeO 1 G [126]21q [-n-]* Me H H H MeO MeO 1 G [126]


27a H [-n-]* H H H H H 1 G, J [127] [128]


28a H H [-n-]* H H H H 1 G [129]28b MeO H [-n-]* H H H H 1 G [129]


29a MeO H MeO [-n-]* H H H 1 G [128]

[I-2’-O(CH2)nO-II-2’]-Linked

30a H H H H [-n-]* H H 1 G [128]

[I-4’-O(CH2)nO-II-4’]-Linked

31a H H H H H H [-n-]* 1 G [128]


Table 8. Diether-Linked Unsymmetrical Biflavones. The asterisk (*) indicates site of linkage.

RI-3 RI-6 RI-7 RI-4’ RII-6 RII-7 RII-8 RII-2’ RII-4’ n Methods References


22a [-n-]* H MeO H [-n-]* H H H H 1 G [130]22b [-n-]* H H MeO [-n-]* H H H H 1 G [130]


23a [-n-]* H H H H [-n-]* H H H 1 G [131]23b [-n-]* H H MeO H [-n-]* H H H 1 G [130] [131]23c [-n-]* Me H H H [-n-]* H H H 1 G [131]23d [-n-]* Me H MeO H [-n-]* H H H 1 G [131]23e [-n-]* H MeO H H [-n-]* H H H 1 G [130]


24a [-n-]* H MeO H H H [-n-]* H H 1 G [130]24b [-n-]* H H MeO H H [-n-]* H H 1 G [130]

[I-3-O(CH2)nO-II-2’]-Linked

25a [-n-]* H MeO H H H H [-n-]* H 1 G [130]25b [-n-]* H H MeO H H H [-n-]* H 1 G [130]

[I-3-O(CH2)nO-II-4’]-Linked

26a [-n-]* H MeO H H H H H [-n-]* 1 G [130]26b [-n-]* H H MeO H H H H [-n-]* 1 G [130]

Table 9. Diether-Linked Symmetrical Biflavanones. The asterisk (*) indicates site of linkage.

RI-7 RI-4’ RII-7 RII-4’ n Methods References


32a [-n-]* H [-n-]* H 1 G [129]33a [-n-]* OH [-n-]* OH 1 G [129]

Scheme 3. Synthesis of Ginkgetin by Ullmann Coupling

i) Cu, neat, reflux. ii) 10% H3PO4, AcOH, 1108.

Enantioselective synthesis of biflavanoids 6f and 6j has also been reported [84].The chirality of biflavones is due to the atropisomerism of the biflavone moiety. Asshown in Scheme 6, chiral tetra-ether 45 was first prepared through sequentialintroduction of 2-iodo-3,5-dimethoxyphenol moieties on the erythrytyl skeleton 41. Inthis process, the second Mitsunobu reaction (conversion of 44 to 45) is low-yieldingbecause of steric hindrance. Also, it is interesting to note that simultaneousintroduction of two molecules of 2-iodo-3,5-dimethoxyphenol on 41 failed miserably.Treatment of 45 with BuLi, followed by the addition of CuCN/TMEDA led to the in


Scheme 4. Synthesis of Biflavonoid 9f

Scheme 5. Synthesis of 1,1’-Biphenyls, the Precursors of Biflavanoids

situ formation of a higher-order cyanocuprate intermediate, which gave 46 uponexposure to dry O2 at �788 in 75% yield. This process induces chirality in biphenyl 46,which is converted to biphenol 50 in four steps (Scheme 6). The diastereoisomeric


Scheme 6. Synthesis of Biflavonoids 6f and 6j

i) (t-Bu)Me2SiCl (TBDMSCl), 1H-Imidazole, DMF. ii) 2-Iodo-3,5-dimethoxyphenol, diethyl azodicar-boxylate (DEAD), Bu3P. iii) BuNF. iv) 2-Iodo-3,5-dimethyloxyphenol, DEAD, Bu3P. v) BuLi, CuCN/N,N,N’,N’-tetramethylethylenediamine (TMEDA) 1 :3, dry O2. vi) 10% Pd/C, H2. vii) TsCl, Py, 08. viii)NaI, acetone. ix) Activated Zn-powder, EtOH. x) (S)-a-Methoxy-a-(trifluoromethyl)phenylacetylchloride, 4-(dimethylamino)pyridine (DMAP), Et3N. xi) Ac2O, Py. xii) TiCl4, benzene. xiii) p-Anis-aldehyde, KOH, cat. benzyl(triethyl)ammonium chloride (TEBACl), EtOH/H2O 3 :2. xiv) I2, DMSO.

xv) BCl3, CH2Cl2.

excess of 50 was found to be 81% by an examination of 1H-NMR spectra of thecorresponding (S)-MosherHs ester 51. Diacetate 52, synthesized from 50, underwent aTiCl4-promoted Friedel–Crafts rearrangement to afford 53 in 94% yield. Followingaldol reaction with p-anisaldehyde, bichalcone 54was obtained in 80% yield, which wascyclized to biflavanoid 6f using I2/DMSO in 60% yield. Selective demethylation of 6fwith BCl3 in CH2Cl2 at 08 gave (þ)-6j in 84% yield. The absolute configuration of thesynthetic (þ)-6j ([a]22D ¼ þ76.6 (EtOH)) was found to be (R) [84].

A similar approach has been used to synthesize biflavanoids 3f and 13a (Tables 1and 3) in four steps from benzyl 4-iodo-3,5-dimethoxyphenyl ether (55 ; Scheme 7).Compound 55 was subjected to the Ullmann coupling to give 4,4’-(dibenzyloxy)-2,2’,6,6’-tetramethoxy-1,1’-biphenyl (56), which on Hoesch reaction yielded 4,4’-dihydroxy-3,3’-diacetyl-2,2’,6,6’-tetramethoxybiphenyl (57). Aldol condensation withp-anisaldehyde, followed by oxidative cyclization with SeO2, gave I-6,II-6-biapigenin3f. In contrast, bichalcone 58 in refluxing alcoholic H3PO4 for three weeks gave 6,6’’-binarigenin hexamethyl ether 13a [70] [95].

Scheme 7. Synthesis of Biflavanoids 3f and 13a

i) Ullmann coupling. ii) Hoesch reaction (MeCN, ZnCl2), HCl. iii) p-Anisaldehyde, base. iv) SeO2,dioxane. v) H3PO4.


[I-3,II-3]-Biflavones 1b and 1c (Table 1) have also been synthesized using thebiphenyl precursor approach. Friedel–Crafts acylation of 59with succinyl chloride gavebutane-1,4-dione 60 in 65% yield, which, on selective demethylation with BCl3, gave 61in 98% yield. Esterification of 61 with either benzoyl or anisoyl chloride afforded ester62a and 62b, respectively, which, on Baker–Venkataraman rearrangement, gavephenols 63a (90% yield) and 63b (89% yield), respectively. Acid-catalyzed ring closureof the phenols yielded [I-3,II-3]-biflavones 1b and 1c in yields of 95 and 88%,respectively [62] (Scheme 8). This appears to be the best-yielding synthesis ofbiflavones and open up a novel route to the synthesis of sterically hindered [I-3,II-3]-linked biflavanoids.

Only one biflavonoid containing an oxymethylene linker has been synthesized usingthe biphenyl precursor approach, although it is expected to work with many similarsystems. Quinacetophenone 64 was methylenated with CH2I2 in the presence of K2CO3

to obtain 65, which was condensed with benzoic anhydride to yield [I-6,II-6]-bis(flavonyloxy)methane 27a (Table 7) in good yields (Scheme 9) [127].

[I-4’,II-4’]-Linked biflavonyl ethers 20d and 17a (Table 6) have also beensynthesized by building upon the biphenyl structure. Dicarboxylic acid 66 wasesterified with 2’-hydroxy-4’6’-dimethoxyacetophenone to obtain 67, which, on heatingat 1208 under basic conditions for 10 min, underwent rearrangement to 68. Cyclization

Scheme 8. Synthesis of Biflavonoids 1b and 1c

i) Succinyl chloride (Friedel–Crafts reaction). ii) BCl3. iii) Benzoyl chloride and anisoyl chloride, Py. iv)Baker–Venkatraman rearrangement. v) AcOH, H2SO4.


of 68 under strongly acidic conditions gave 17a. An identical procedure was followedfor synthesizing 20d [117] (Scheme 10).

3.3.Metal-Catalyzed Cross-Coupling of Flavones. Although several metal-catalyzedcross-coupling reactions are being used to form C�C bonds, the synthesis ofbiflavanoids has primarily involved Stille coupling and Suzuki coupling only, both ofwhich utilize the exquisite ability of Pd to cross-couple aryl groups. Stille, the father ofcoupling reactions with organostannanes, synthesized symmetrical [I-7,II-7]-biflavone5b (Table 1) by cross-coupling of flavone triflate 72 with 0.5 equiv. of distannane [72](Scheme 11). Flavone triflates have been found to cross-couple with a variety oforganostannanes under neutral conditions in the presence of LiCl and a Pd0 catalyst.The technique tolerates various functional groups including alcohol, ester, nitro, acetal,ketone, and aldehyde. The concentration of hexamethylditin determines whether anaryl(trimethyl)stannane or a symmetrical biaryl is formed. Echavarren and Stillestandardized all Pd-catalyzed cross-coupling reactions with organostannanes into two

Scheme 10. Synthesis of Biflavonoids 17a and 20d

i) SO2Cl2, 2’-Hydroxy-4,6-dimethoxyacetophenone. ii) Py, KOH, heat. iii) AcOH, H2SO4.


Scheme 9. Synthesis of Biflavonoid 27a

methods involving the use of Pd(PPh3)4 or PdCl2(PPh3)2 in either dioxane or DMF,respectively [72].

Suzuki coupling, which utilizes arylboronic acids, has also been used to synthesizebiflavanoids 7e–7j [100] (Scheme 12). Two approaches have been devised to synthesizebiflavones. In the first approach, flavone-boronic acids were synthesized, followed bytheir catalytic coupling with appropriate iodoflavones. Thus, flavone-8-boronic acids 76and 77 were prepared by lithiation of iodoflavones 73 and 74 at �788, followed byreaction with (MeO)3B. Partial solubility of iodoflavone 75 at �788 limits successfullithiation. Another problem with this approach is the catalytic coupling of boronic acids76 and 77with 3’-iodoflavones 78 and 79 in which competitive protodeboronation of theboronic acid moiety occurs resulting in lower yields. However, the yield of the coupledproducts, biflavones 7e–7j (Table 2) could be improved to nearly 90% through use ofexcess boronic acid derivatives [100] (Scheme 12).

Scheme 11. Synthesis of Biflavanoid 5b

Scheme 12. Synthesis of Biflavonoids 7d and 7f–7j

i) BuLi, (MeO3)B. ii) K2CO3, Pd(TPP)4 (TPP¼ triphenylphosphine). iii) BCl3/CH2Cl2.


Alternatively, instead of direct coupling of the two flavone rings, the second flavonering could be built after the Suzuki coupling of a benzeneboronic acid, as exemplified inthe synthesis of 7d (Table 2 and Scheme 13) [117]. Thus, boronic acid 80 was coupledwith iodoflavone 78, followed by Lewis-acid catalyzed acylation of 81 with p-methoxycinnamic acid. In the course of acylation, regioselective demethylation of thediorthosubstituted MeO group occurred to give chalcone 82, from which the secondflavone ring of [I-3’,II-8]-biflavone 7d was built through a standard oxidativecyclization reaction [100] (Scheme 13).

The Suzuki coupling was also exploited to synthesize 8a from iodoflavone 88 andboronate ester 93 [106] [107] (Scheme 14). In this convergent process, 88 and 93 weresynthesized independently in five and three steps, respectively, by employing tradi-tional reactions. An interesting aspect of these reactions was the chemoselective 4’-O-and 7-O-geminal-difluoromethylenation of 85 to give 86 using HCF2Cl under basicconditions, which did not difluoroalkylate the strongly H-bonded 5-OH group.Regioselective iodination, followed by methylation of 86, gave 88 in good yields. Anearly identical set of reactions, i.e., acylation, aldol condensation, iodination, andmethylation, led to the synthesis of 93 in good yields. The final Pd(Ph3P)4-catalyzedcross-coupling of 88 and 93 under standard Suzuki conditions gave the unsymmetrical[I-3’,II-6]-biflavone 8a in 33% yield.

The synthesis of robustaflavone (8b ; Table 2) was attempted by both Stille andSuzuki couplings [107]. Apigenin 7,4’-dimethyl ether 95 was regioselectively iodinatedusing Tl-assisted iodination. This appears to be the only method for the preparation of6-iodoapigenin derivatives and is likely to be the most only efficient method for thesynthesis of 6-halogenated flavones. The other coupling partner necessary for Stille andSuzuki couplings, i.e., 99 and 100, respectively, was prepared from 3’-iodoapigenintrimethyl ether 98. Whereas the 3’-stannane 100 repeatedly failed to couple with 97under several different Stille conditions, Suzuki coupling between boronate 99 and

Scheme 13. Synthesis of Biflavonoid 7d

i) K2CO3, Pd(TPP)4. ii) 4-MeO�C6H4�CH¼CH�COOH, BF3 ·Et2O. iii) I2, DMSO, H2SO4.


iodide 97worked successfully to give robustaflavone hexamethyl ether 8b in reasonablygood yields [107] (Scheme 15).

The exact reasons why Stille coupling failed, where Suzuki coupling succeeded arenot clear. Transmetallation from Sn to Pd is the rate-limiting step in Stille couplings.Because the iodide 97 is particularly reactive toward oxidative addition, which is mademore feasible by the presence of two electron-donating MeO groups, reduction of thearyl iodide occurs much faster than transmetallation. In contrast, transmetallation fromB to Pd in Suzuki coupling is rapid, and oxidative addition is generally the rate-limitingstep [107].

3.4. Wessely–Moser Rearrangements. The Wessely–Moser rearrangement occursfrequently in monoflavanoids and is characterized by the reorganization of 5,7,8-substituents to a 5,6,7-substitution pattern under acidic conditions (Scheme 16). In thisprocess, the heterocyclic ring of the monoflavanoid undergoes acid-catalyzed ringopening, followed by recyclization with either of the two ortho-OH groups to give anequilibrium mixture of the two substitution patterns.

Nakazawa showed that HI in Ac2O can convert the C(4’)�O�C(8) isomer ofhinokiflavone pentamethyl ether into the natural C(4’)�O�C(6) hinokiflavone via theWessely–Moser rearrangement [118]. Later, Seshadri and co-workers, who had



i) 1. ClCH2CN/ZnCl2/HCl; 2. H2O. ii) 1. 4-Hydroxybenzaldehyde, NaOH; 2. HCl. iii) HCF2Cl/NaOH.iv) AgOAc/I2. v) MeI/K2CO3. vi) 1. ClCH2CN/ZnCl2/HCl; 2. H2O. vii) 3-Iodo-4-methoxybenzaldehyde,NaOH. viii) MeI/K2CO3. ix) Bis(pinacolato)diboran (pinacol¼2,3-dimethylbutane-2,3-diol), PdCl2-

(dppf) (dppf¼diphenylphosphinoferrocene), MeI/K2CO3. x) Pd(TPP)4.

previously reported an incorrect linkage of the natural product, hinokiflavone,established that the same rearrangement had occurred during the course of theirUllmann reaction [96]. Likewise, Pelter et al. treated (þ)-cupressuflavone hexamethylether 6f with HI at 130–1408 for 8 h, followed by permethylation to give a mixture of(� )-agithisflavone hexamethyl ether 4a (Table 2) and (� )-cupressuflavone hexa-methyl ether 6f in a ratio of 3 :2 (w/w) [63] (Scheme 17). This equilibrium conversion


Scheme 15. Synthesis of Biflavonoid 8b

i) BBr3. ii) TlOAc, I2. iii) Me2SO4. iv) Bis(pinacolato)diboran, PdCl2, K2CO3. v) (SnMe3)2, Pd(TPP)4.vi) Pd(TPP)4, DMF/H2O, NaOH.

Scheme 16. Wessely–Moser Rearrangement

represented the first preparation of a member of the agathisflavone family. Benzene-induced 1H-NMR solvent shifts were used to verify the linkage positions inagathisflavone and cupressuflavone [63] [77].

3.5. Phenol Oxidative Coupling of Flavones. In view of the success achieved insynthesizing natural products by oxidative coupling of phenolic monomers using one-electron oxidizing agents, flavanoid chemists have also attempted to synthesizebiflavanoids according to a similar strategy. Further, oxidative coupling of mono-flavanoids provides a unique route because it is likely to follow the natural biosyntheticprocess. Also, this approach can work on an unprotected polyphenol skeleton, unlikeseveral other synthetic approaches that require the use of protection–deprotectionstrategies.

Apigenin (101) was subjected to oxidative coupling using alkaline potassiumferricyanide to produce two biflavanoids, 3l and 1b (Tables 1 and 2), with [I-3’,II-3] and[I-3,II-3] linkages [94] (Scheme 18). The investigators suggested that these inter-flavone linkages arise due to coupling of two radicals. Though these inter-flavonelinkages have not been encountered in nature thus far, it is likely that they will befound. Coupling of mesomeric radicals does not explain the formation of the naturalbiflavones that possess inter-flavone linkages at C(6) and C(8) of the A ring. Electron-spin-resonance studies show that delocalization of an unpaired electron at theC(4’)�OH group in apigenin 101 occurs only in the B and C ring [94]. Thus, the radicalgenerated on C(4’)�OH group of apigenin 101 through oxidative coupling candelocalize to C(3’), C(1’), or C(3). This delocalized radical then attacks the electronrich C(6)- and C(8)-atoms of ring A resulting in the electrophilic substitution, ratherthan electron pairing.

Other investigators have suggested that radical generation on the A ring of apigeninis possible when OH groups at C(4’) and C(7) are protected with Me groups. Aplausible proof of this hypothesis is the oxidative dimerization of apigenin-4’,7-dimethyl ether 102 with FeCl3 in boiling dioxane that gives a [I-6,II-6]-coupledbiflavone 3k (Table 1) in 6% yield [57] (Scheme 19). Like flavones, oxidativedimerization of flavanones has been found to produce biflavanones [59] [60].

Electrochemical reduction of flavone 103 using a H-type cell and glass-filterdiaphragm equipped with a series of electrodes and supporting electrolytes, including



i) HI, Ac2O, heat.

H2SO4 or TsOH, yielded two dimers, racemic and meso forms of 2,2’-biflavanone 11a(Table 3), and a reduced monomer, flavanone 104 [108] (Scheme 20). Yields in theelectrochemical reduction were largely affected by the nature of electrodes and thesupporting electrolytes, as well as the reaction temperatures. Electrolytic coupling ofa,b-unsaturated carbonyl compounds have two primary modes of dimerization thatinclude coupling at the b-C- or at the a-C-atom. Often b,b-coupling is major reactionoutcome. Interestingly, although flavone 103 has a Ph substituent at C(2), coupling atthe b-position was still the major mode. The proposed mechanism of the electro-chemical reduction of flavone 103 is as shown in Scheme 21.

Protonation of flavone 103, followed by electrochemical reduction, is likely to give aflavon-2-yl radical 107. This radical is proposed to react with monomer 103 to give aradical intermediate, which is further electrochemically reduced to give 2,2-linked


Scheme 18. Synthesis of Biflavonoids 3l and 1b

i) Alkaline K3Fe(CN)6, Me2SO4.

Scheme 19. Synthesis of Biflavonoid 3k

i) FeCl3 in boiling dioxane.

biflavanone 11a (Table 3). The coupling between 107 and 103 could either besymmetrical or unsymmetrical, resulting in either racemic or meso products.Alternatively, radical 107 may undergo protonation and one-electron reduction togive the reduced mono-flavonoid 104, which is a by-product of the reaction(Scheme 21) [108].

In a manner similar to electrochemical reduction, photolysis of flavone 103 using254- or 306-nm UV light in the presence of an electron-donating amine, e.g., Et3N, inMeCN readily produces racemic and meso-[I-2,II-2]-biflavanone 11a and reducedflavanone 104 (Scheme 20). The yield of 11a is dependent on the molar ratio ofsubstrate to amine, the type of amine and solvent, and the irradiation source [109](Scheme 20).

The proposed mechanism of this photolysis is also depicted in Scheme 21, as it issimilar to that of electrochemical reduction. Photolysis of flavone 103 with electron-donor Et3N undergoes a dominant pathway of single-electron transfer (SET) toproduce an exciplex 105 or contact-ion radical pair 106, followed by the proton transferto yield a contact-ion radical in a cage. This radical has a structure similar to that of 107,except for its location in a cage with an associated amine. After escaping out of the cage,radical 107 follows a process described above in case of electrochemical reduction toyield racemic or meso-11a. The photolytic process also affords reduced by-productflavanone 104 through enol 112 (Scheme 21) [109].

3.6. Ullmann Condensation with Flavone Salts. This is a modified Ullmann reactionwhich involves the Cu-catalyzed coupling of a halogenated flavone with a nucleophilicflavone salt, thereby providing a hetero-atom-linked biflavanoid in a single step. Thereactivity of the halogen atom for Ullmann condensation could be enhanced byintroducing an electron-withdrawing NO2 group ortho to the halogen atom. Thus,flavones 151 and 152 were successfully coupled under the modifiedUllmann conditionsin 85% yield using DMSO as the high boiling solvent. Reductive elimination of the NO2

group produced the C(4’)�O�C(8)-linked biflavanoid 19a (Table 6) (Scheme 22)[118]. Likewise, the synthesis of the isomeric C(4’)�O�C(6)-linked biflavanoid,hinkoflavone pentamethyl ether 18b (Table 6), was also accomplished by thismethodology from the flavones 151 and 153 (Scheme 23). The synthesis of 18b and19a provided the conclusive proof that hinokiflavone has C(4’)�O�C(6) linkage,rather than the C(4’)�O�C(8) linkage [118]. The resolution of poor reactivity of halo-


Scheme 20. Synthesis of Biflavanoid 11a

i) Electrochemical reduction using MeOH/H2SO4. ii) Photolysis (300 nm), Et3N, MeCN.


Sche

me21.Mecha

nism

ofBiflavano

idFo

rmationthroug

hElectrochem

ical

Reductio

n,an

dCou

plingor

Pho

tolysisin

thePresenceof

Amines

flavones in Ullmann condensation using the NO2-group strategy paved the way for thesynthesis of several other biflavanoids, e.g., 20a–20c (Table 6) [120] [121].

Nakazawa has further shown that Wessely–Moser rearrangement (Method D)could convert the C(4’)�O�C(8)-linked 19a to a C(4’)�O�C(6)-linked 18a [118].These findings were confirmed by Seshadri and co-workers [119]. They studied thepossible rearrangement of C(4’)�O�C(8)-linked biflavonyl ether under severalconditions including heating with activated Cu-bronze in the presence and absenceof a base. In each case, the flavone underwent demethylation, except in the presence ofa base where it underwent the Wessely–Moser rearrangement [96].

3.7. Nucleophilic Substitution. Methylenation of a phenolic group is a commonnatural process, often encountered in lignan, alkaloid, and flavanoid biosynthesis.Mono-methylenation is straightforward when only two symmetrical OH groups are tobe alkylated; however, when the scaffold contains several OH groups, numerous


Scheme 22. Synthesis of 19a

i) Ullmann conditions. ii) H3PO4. iii) HI/Ac2O.

Scheme 23. Synthesis of 18a

i) Ullmann conditions. ii) H3PO4. iii) HI/Ac2O.

competing reactions make the reaction challenging [129]. Nucleophilic substitutionreactions have been most commonly used to produce dialkyl-linked biflavones andbiflavanones. The procedure involves refluxing monohydroxy-flavones in acetonesolution with alkyl diiodide or dibromide in the presence of K2CO3 to producebiflavonyloxyalkanes. This method has produced symmetrical bis(flavonyloxy)-methanes 21e, 21j–21q, 27a, 28a, 28b, 29a, 30a, and 31a (Table 7)[50] [51] [125] [128] [129], and the symmetrical biflavanyloxymethanes 32a and 32b(Table 9) [125]. Thus, the flavanoid skeletons have been linked in positions 3, 6, 7, 8, 2’and 4’. An illustrative example of these reactions is the synthesis of biisoflavone 156(Table 7) as shown in Scheme 24. Finally, despite its simplicity, attempts to isolate [I-5-OCH2O-II-5]-bis(flavonyloxy)methanes from techochrysin, apigenin dimethyl ether,and galangin dimethyl ether were unsuccessful due to extensive resinification [129].

An interesting nucleophilic substitution reaction was utilized by Seshadri and co-workers to synthesize diflavonylmethane 159 (Scheme 25). Reaction of resacetophe-none (157) with CH2I2 under alkaline conditions gave the C-methylenated product 158,which could be converted to biflavanoid 159 [129].

In contrast to the symmetrical molecules discussed above, unsymmetrical dialkoxy-biflavanoids are more challenging, although unsymmetrical bis(flavonyloxy)methanes22a, 22b, 23a–23e, 24a, 24b, 25a, 25b, and 27a (Tables 8 and 9) [128] [130] [131] havebeen synthesized starting from two different hydroxy-flavones. In nearly all cases, amixture of three compounds, two symmetrical products and one unsymmetricalproduct, was observed. However, when 7-methoxyflavanol was used, only twocompounds were obtained, of which the unsymmetrical bis(flavonyloxy)methane 22a

Scheme 24. Synthesis of Biisoflavone 156

i) CH2I2, K2CO3.

Scheme 25. Synthesis of Bisflavonylmethane 159

i) CH2I2, EtONa. ii) PhCl, K2CO3, then H2SO4, AcOH.


was the major product. Interestingly, the symmetrical [I-3,II-3]-bis(flavonyloxy)-methane was not formed. Competition at the initial nucleophilic displacement stage,where the phenoxide ion reacts with CH2I2 to yield the intermediate iodomethylderivative, governs the rate of the reaction. The predominance of the phenoxide ion,and its iodomethyl derivative, is based on the acidity of the OH groups [130].

Higher-ordered alkoxy-biflavanoids 21i and 21f–21h (Table 7) were synthesized byheating the appropriate flavanol with 1,4-dibromobutane or 1,2-dibromoethane in thepresence of anhydrous K2CO3 until the solution gave a negative FeCl3 test. Thesebis(flavonyloxy)alkanes were recrystallized in 20–30% yield [124]. An alternativemethod involving a phase-transfer catalyst, Bu4NI, has been used in the synthesis ofbis(flavonyloxy)alkanes 21a–21d (Table 7) from appropriate 1,n-dibromoalkanes.Instead of long reaction times in the previous case, the synthesis here was completein 1 h. The use of Bu4NI is a new introduction to this nucleophilic substitution, whichappears to solubilize K2CO3 in acetone, thereby speeding up the reaction and givinghigher yields (45–60%) [122]. 27a (Table 7) is the only bis(flavonyloxy)methane thathas been synthesized both by this method and Method B.

3.8. Dehydrogenation of Biflavanones into Biflavones. Dehydrogenation of thesaturated biflavanoid ring system to the a,b-unsaturated system is an attractive way togenerate analogs for structure–activity studies and has also been used to characterizenatural biflavanoids. Most work on the conversion of biflavanone to biflavone has beenconducted on [I-3,II-3]-dimers. Dehydrogenation is typically achieved with eitherFentonHs reagent, alkaline potassium ferricyanide, SeO2, or N-bromosuccinimide(NBS).

The oxidation of 4-(hydroxyimino)flavan 160 with SeO2 in aqueous dioxane gaveflavane 165, which, on oxidative dimerization, resulted in the formation of the [I-3,II-3]-biflavone 12a. Dehydrogenation with NBS gave biflavone 1a (Scheme 26) [59].Likewise, flavanone hydrazones have also been oxidized with SeO2 in aqueous dioxaneto produce flavones, which, on oxidative coupling and dehydrogenation using NBS,generate [I-3,II-3]-biflavones 1a and 1f–1h [60] (Scheme 26). NBS is the favoredreagent for dehydrogenation of 14a and 14b (Table 4) to synthesize 4a and 4c,respectively [95]. It has also been used to synthesize 6j [86]. Alternatively,dehydrogenation of semicarpetin and galluflavanone was achieved with I2 and AcOKin AcOH under reflux to generate 7d [101], and 7k and 7l (Scheme 27) [104].

3.9. Hydrogenation of Biflavone into Biflavanone. The reverse of dehydrogenation,i.e., hydrogenation, is also a useful strategy for rapid generation of analogs. However, incontrast to dehydrogenation, hydrogenation can be controlled to generate mono- anddihydrogenated biflavanoids, thereby affording greater structural diversity. Whencatalytic hydrogenation of biflavone 1e was performed at 808 in glacial AcOH for 4 h,monohydrogenated 15a was obtained almost exclusively, while prolonging the reactiontime to 12 h led to both 15a and 12k (Scheme 28). Unfortunately, the overall yield inthis process is not very attractive (ca. 37%). As would be expected, it was possible toobtain 12k from 15a by extended hydrogenation [64]. The reason that hydrogenation of1e is difficult is because the double bond is fully substituted. Li and co-workersexperimented with several hydrogenating conditions including Pd/C-EtOH, Pd/C-AcOEt, PtO2/EtOH, PtO2/AcOEt, Raney-Ni, TiCl3, and Pd/C-NH4COO/MeOH, butnone of the conditions gave high yields [64].


4. Conclusions. – The discovery of several biological activities associated withnatural biflavanoids has greatly increased the need for rapid synthesis of thesemolecules. Since the time of their discovery, a number of synthetic approaches have


Scheme 26. Synthesis of I-3,II-3 Biflavanones and Biflavones

i) SeO2, aq. dioxane. ii) SeO2 in dioxane, reflux. iii) N-Bromosuccinimide (NBS).

Scheme 27. Dehydrogenation of Biflavanones

i) I2, AcOK, AcOH.

been devised, although a majority of the reported strategies focus on preparing a selectgroup of biflavanoid structures. Thus, symmetrical biflavanoids are obtained throughUllmann coupling, while their unsymmetrical counterparts are synthesized using Stilleor Suzuki coupling. Likewise, the synthesis of diether- or alkyl-linked biflavanoidsappears to utilize nucleophilic substitution approach, while electrochemical orphotochemical approaches have been devised to prepare the sterically hindered[I-2,II-2]-linked structures. A significant concern with these approaches is the yield ofsynthesis. Further, a robust approach that rapidly generates a large number ofbiflavanoids for structure–activity studies is highly desirable. Yet, the currentapproaches have yielded a large number of structurally diverse biflavanoids. Furtherimprovement in the synthetic strategies is expected to result in the discovery of morepotent biflavanoids.

This work was supported by grants from the National Heart, Lung, and Blood Institute (RO1HL069975 and R41 HL081972) and the American Heart Association National Center (EIA 0640053N).

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Received March 5, 2007


Synthesis of Biologically Relevant Biflavanoids – A Review

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