Bioinspired Syntheses of Dimeric Hydroxycinnamic Acids (Lignans) and Hybrids, Using Phenol Oxidative Coupling as Key Reaction, and Medicinal Significance Thereof

Lignans are mainly dimers of 4-hydroxycinnamic acids (HCAs) and reduced analogs thereof which are produced in Nature through phenol oxidative coupling (POC) as the primary C-C or C-O bond-forming reaction under the action of the enzymes peroxidases and laccases. They present a large structural variety and particularly interesting biological activities, therefore, significant efforts has been devoted to the development of efficient methodologies for the synthesis of lignans isolated from natural sources, analogs and hybrids with other biologically interesting small molecules. We summarize in the present review those methods which mimic Nature for the assembly of the most common lignan skeleta by using either enzymes or one-electron inorganic oxidants to effect POC of HCAs and derivatives, such as esters and amides, or cross-POC of pairs of HCAs or HCAs with 4-hydrocycinnamyl alcohols. We, furthermore, provide outlines of mechanistic schemes accounting for the formation of the coupled products and, where applicable, indicate their potential application in medicine.


Introduction
CinA and its 4-hydroxysubstituted derivatives (HCAs), namely CouA, CafA, FerA and SinA, form an important family of natural products ubiquitous in the plant kingdom generally known as cinnamates [1]. Cinnamates are derived biogenetically from ShiA through the intermediacy of the amino acid Phe (Scheme 1).

Scheme 1.
Outline of the biosynthetic route to naturally occurring cinnamates and selected reduced derivatives. HCAs and derivatives are powerful natural antioxidants, abundantly found in a variety of foods and drinks, which could be therefore used for the prevention and/or therapy of oxidative stress-associated diseases, like atherosclerosis, inflammatory injury and cancer [2,3]. The side chain of cinnamates is biogenetically further reduced thus leading to a variety of reduced derivatives such as the corresponding aldehydes (e.g., p-coumaraldehyde), alcohols (e.g., ConAl) and alkenes (e.g., isoeugenol). All these compounds are coined as phenylpropanoids and form the C6-C3 class of ShiA metabolites [1].
Interestingly, these phenypropanoid compounds are further dimerized or polymerized in Nature and thus provide access to two further families of natural products also widely distributed in plants, collectively coined as lignans and lignin, respectively. Lignans are mainly dimeric in Nature and are produced biosynthetically by the dimerization of HCAs and their reduced derivatives HCAls. The role of lignans in plants seems to be primarily plant defense [4]. Lignin is a high molecular weight complex polymer, derived from the polymerization of phenylpropanoid alcohols (called monolignols), such as ConAl. Lignin constitutes an integral part of the secondary cell walls of plants conferring mechanical strength to the cell wall and, by extension, to plant as a whole.
Dimerization of phenolic compounds in Nature is effected using POC as key reaction, which allows the connection of the monomers through the formation of new C-C or C-O bonds. Although this concept had been long recognized, it was the seminal investigation by Barton and Cohen on the structure of Pummerer's ketone, produced by the ferricyanide-mediated POC of p-cresol in alkaline solution, which established the relation of such reactions in the laboratory with biosynthetic pathways [5]. This concept was applied in the elegant biomimetic two-steps synthesis of (±)-usnic acid by Barton and coworkers using the POC of methylphloracetophenone as key step for the assembly of the skeleton (Scheme 2) [6].

Scheme 2.
Barton's biomimetic synthesis of usnic acid based on POC as key step. The primary bond connecting the two monomers is shown in blue and bolded and the secondary one in red and bolded.
actually formed in a particular POC depends on the stereoelectronic effects operating in the phenoxide radical, the oxidant or oxidant system and the reaction conditions. The most abundant structures in lignans are constructed by primary 8-8', 8-5' and 8-Ο-4' bonds. Coupling at position 5 is only possible when this position is unoccupied. On the other hand, coupling between O atoms or between C atoms both in position 1 (1-1' coupling) have not been observed in lignans because in the former case it would create a highly unstable peroxy dimer, whereas in the latter case it could not be effected due to steric hindrance because both monomers bear a propanoid side chain in position 1 [15]. Many lignans are produced in Nature in optically pure form, while others are produced as mixtures of enantiomers. Even different plants may produce the same lignan but with different enantiomeric composition [16]. The multitude of the pharmacological properties of lignans has been recently summarized [17], and include antioxidant, anti-inflammatory, antitumor and anti-HIV activities to name a few. Taking into consideration the many potential applications of lignans in medicine, a variety of synthetic methods have been devised which allow ease access to natural lignans and derivatives suitable for structure-activity relationship studies [18][19][20].
This review presents an overview of the application of POC on HCAs and derivatives, such esters and amides, as a key reaction in the efficient assembly of the skeleton of the most abundant lignan structures in nature and of analogs of potential medicinal interest. Particular attention is paid to POCs in which the anticipated regioisomer is being produced in significant excess to unwanted other regioisomers and oligomers. Interestingly, although a large array of oxidants, inorganic and enzymes, have been already developed for performing POC [21], a few of them have been proved particularly useful in producing regioselectively and/or stereoselectively the desired lignan isomer or an appropriate key intermediate.
Dilactones substituted by halogens in the aromatic ring have been synthesized by either applying POC to appropriately halogenated CinAs [31,32] or by direct halogenation of acetylated dilactones [33]. Such halogen substituted dilactones like 1e and 1f have been used for the synthesis of lignans of the CL5a subtype, e.g., of galbelgin (13a) and grandisin (13b) (Scheme 9), through acid mediated rearrangement which however takes a different route (Scheme 10) than the one depicted in Scheme 7, precisely due to the presence of the halogen [33].   The presence of halogen is such dilactones may, in some other cases and depending on the reaction conditions, serve to produce aryltetralins, such as 15a and 15b (Scheme 11), with different oxygenation pattern than normal, by blocking the normal ring closure position [18].

18
Although the dilactones 1a and 1d from the dehydrodimerization of the FerA and SinA respectively, are readily available through FeCl3-mediated POC [23], the corresponding dilactone 1g from the dehydrodimerization of CafA cannot be obtained using this one-electron oxidant. However, Kumada and coworkers reported that this transformation can be effected either enzymatically or non-enzymatically, using CuCl2 as the oxidant, in 64% yield [35]. On the other hand, Jin and coworkers demonstrated that all three dilactones may be obtained using a single oxidant, namely Ag2O, in yields however ranging from 14% to 34% [36]. In the case of FerA, a FerA trimer (19) was also isolated and characterized (Scheme 14). Evaluation of the antioxidant activity of monomers and dimers showed that the most potent were the ones bearing adjacent phenolic functionalities, that is CafA and dilactone 1g and that dimerization results in remarkable enhancement of activity. Scheme 13. Plausible mechanisms for the conversion of the dilactone 1a to arylnaphtalene 17 on treatment with NaOH first and then HCl.
Dilactones 1a and 1d have been also obtained electrochemically by the anodic oxidation of FerA and SinA, respectively, in MeOH along with NLs of the asatone (20)-and isoasatone (21)-types (Scheme 15) [37]. Interestingly, at low concentrations of HCAs only the NLs were formed. These later compounds are plausibly formed through the Diels-Alder reaction of the cyclohexadienones 22, which are obtained through two single-electron oxidations of the corresponding phenolates (Scheme 16) [37].
Interestingly HCAs, such as FerA, can be cross-coupled with the corresponding allylic alcohol (ConAl, 23) to give the anticipated heterodimer, that is monolactone 24. This compound is, however, formed in mixture with the homodimers, that is the dilactone 1a and furofuran lignan pinoresinol (25) (Scheme 17) [38]. The latter was actually isolated as the corresponding diacetate 26. Monolactone 24, isolated from the reaction mixture through CC, is a potent germination inhibitor. Dilactones of the general type 1 can be also obtained by the so-called non-POC of electronic rich aromatics [21], e.g., of ACAs. Thus, treatment of ACAs with thallium(III) trifluoroacetate in CH2Cl2/CF3CO2H in the presence of BF3.Et2O produced the corresponding dilactones 27 (Scheme 18) in yields ranging from 12% to 54%, based on recovered starting material [39]. Lactone 27a has been partially reduced with DIBAL by Pelter and coworkers in order to prepare the lignan 4,8-dihydroxysesamin (28) [25]. Alternatively, CoF3 may be used for such dimerizations. Although the reactions are slower and less consumption of starting materials and poorer yields are observed with this reagent, its use is associated with several advantages over Th(OCOCF3)3. For example, POC may also be performed with CoF3 but not with Th(OCOCF3)3. Accordingly, CoF3-mediated dehydrodimerization of FerA produced dilactone 1a in 20% yield. The non-POC concept was further exploited by Mori and coworkers in the dehydrodimerization of the N-(3,4,5-trimethoxycinnamoyl)-L-Pro (29). This resulted in the stereoselective assembly of the skeleton of lignans of the 2,6-diarylfurofuran (CL6) subtype, such as yangambin (31a) and caruilignan A (31b) (Scheme 19) with a variety of pharmacological activities [40]. The method involved oxidation of the electron-rich aromatic ring of compound 29 with PbO2/TFA/Celite in CH2Cl2 at −78 °C to the corresponding benzylic cation radical which, through a cyclic radical, was dimerized and finally hydrolyzed to give furanofuranone 30 in 64% yield and e.e. >95% [40]. L-Pro acted as the chiral auxilliary inducing chirality in the dimerization step. Intermediate 30 was then readily transformed to the desired final products 31a and 31b.

Syntheses of Lignans Based on the Key Intermediate Dialkyl 1,2-dihydro-1-arylnaphthalene-2,3dicarboxylate
Treatment of Me-Sin (32) with FeCl3·6H2O in acetone-water produced a mixture of compounds, the major component of which was the tetralol 33a. This compound was obtained in 61% yield following crystallization. The other components of the reaction mixture were separated with CC from the residue of the mother liquid. These included the dimethyl trans-1,2-dihydro-1-arylnaphthalene-2,3-dicarboxylate (dimethyl thomasidioate, 9a), lactone 34, and the diastereomer 33b received in mixture with a quantity of unprecipitated 33a. This mixture was first methylated and then rechromatographed to provide pure methyl ether 33c (Scheme 20) [30]. Compound 33a was dehydrated to arylnaphthalene 9a under treatment with perchloric acid in acetic acid. However, this conversion could not be effected under the acidic conditions (FeCl3, pH ca. 2) of the POC experiment described above. This indicates that the 4-hydroxyarylnaphthalenes 33a and 33b are formed through a different mechanism (Scheme 21) than the one producing the dehydrated product 9a [29]. Interestingly, CAN-mediated POC of 32 produced a similar product mixture to that from FeCl3-mediated POC, whereas the use of potassium ferricyanide in acetone-water produced dimethyl thomasidioate (9a) in 16% yield as the only fluorescent compound under UV irradiation. On the other hand, treatment of 32 with silver carbonate produced a complex reaction mixture of non-fluorescent products.

Scheme 21.
Outline of the plausible mechanisms for the formation of products 33a,b and 9a from POC of Me-Sin. Similarly, 5-Br or -I substituted Me-Fer (35a and b) can be directly converted to dihalogenated aryl dihydronaphthalenes (36a and 36b) in 23% and 75% crude yields respectively, through POC, by using FeCl3 as one-electron oxidant. Dimer 36b was further used in a synthesis of (±)-isolariciresinol dimethyl ether 37 (Scheme 22) [32].

HO
Setälä and coworkers also obtained the aryldihydronaphthalene 9a, in 41% yield, directly through POC of Me-Sin (32) but using hydrogen peroxide as oxidant and the enzyme HRP as catalyst at pH 4 in acetone-water. In earlier work, the authors had observed that in low pH-values the formation of oligomers/polymers is suppressed, thus favouring higher yields of the desired dimers. Interestingly, when the same reaction was performed in aqueous methanol dimer 9a was produced in only 14% yield, the main product (49% yield) being a mixture of the spiro dimers 38a and 38b (Schemes 23 and 24) [41]. This mixture failed to produce the aryldihydronaphthalene 9a upon attempted acid-mediated dienone-phenol rearrangement, which however led to the isomeric aryldihydronaphthalene 39 (Scheme 25). Thus, dimers 38 cannot be intermediates in the formation of 9a.  Bunzel and coworkers synthesized dimethyl thomasidioate (9a) from SinA in a two-steps one-pot sequence involving treatment of SinA with acetyl chloride in methanol followed by treatment of the thus obtained in situ Me-Sin (32) with aqueous FeCl3 . 6H2O. That way, the dimer 9a was obtained in 52% yield. Finally, saponification of diester 9a with 2M NaOH produced ThoA (8)  Neudorffer and coworkers electrochemically generated the phenoxy radical from Et-Sin (40), in acetonitrile containing lithium perchlorate as the supporting electrolyte and a stoichiometric amount of tetramethylammonium hydroxide, which led to the synthesis of diethyl thomasidioate (41) in 42% yield (Scheme 27), along with 12% unreacted ester 40 [43].

Scheme 27. Electrochemical POC of Et-Sin (40).
When the corresponding Et-Fer (42) was subjected to anodic electrolysis under the above described reaction conditions, the corresponding dimer 43 was obtained in 15% yield along with 28% of unreacted ester 42 and three additional dimers. These included one lignan 44 of the bis(arylmethylene)succinic acid type in 8% yield, one neolignan 45 of the dihydrobenzofuran type in 13% and one oxyneolignan 46 with an β-O-4 bond in 10% (Scheme 28) [43].
Zoia and coworkers developed an enantioselective biomimetic approach to synthesize ThoA (8) [44]. They subjected amides 47a-c of SinA with chiral amines, such as (S)-Phe ethyl ester, (S)-methylbenzylamine and (S)-2-phenyloxazolidinone, the latter acting as chiral auxiliaries, to POC using hydrogen peroxide as oxidant and HRP as catalyst in a dioxane-water, buffered at pH 4, solution.
The amides were obtained from the coupling of SinA and the corresponding amines in 40%-50% yields. Although POC of Me-Sin with this system produced a racemic mixture of the dimethyl trans-thomasidioates 9a and 9a' in 70% yield, the presence of the chiral auxilliaries secured the creation of mixtures of the corresponding two diastereomeric bisamides I and II (48a-c) of trans-ThoA with d.e. in the range of 40%-70%. The total yields (both diastereomers) of the thus obtained chiral amides of ThoA (8) were in the range 40%-60% (Scheme 29). Interestingly, best d.e. (70%) was obtained with (S)-2-phenyloxazolidinone, as the chiral auxilliary, whereas best yield (60%) with (S)-Phe ethyl ester, as the chiral auxilliary. Amides I (48a-c) could be hydrolyzed to ThoA (8) with LiOOH in THF-H2O in 10%-60% yields, the highest one obtained with the amide (48a-I) from (S)-2-phenyloxazolidinone. Computational methods showed that enantio-and diastereoselectivity are controlled by the β-β oxidative coupling step and the stability of the reactive conformation of the intermediate quinonemethide, respectively [44].  46 Cilliers and Singleton subjected CafA to oxidation with O2 in an alkaline (KOH) aqueous solution (pH 8.5). Although POC on free HCAs usually leads to dilactones 1, in this case, a mixture of mainly dimeric products (see also Sections 3.1 and 3.3) and unreacted CafA was obtained, the main component of which was caffeicin E (49), that is a lignan of the substituted 1,2-dihydronaphthalene (CL3) type (Scheme 30) [45].
Maeda and coworkers reported that POC of the HCA methyl ester 51, readily derived from the coumarin daphnetin 50, mediated by iron(III) chloride heptahydrate in aqueous acetone solution, gave 1,2-dihydronaphthalene 52 in 16% yield (Scheme 31) and 41% recovery of starting material [46]. Changing the oxidant to silver oxide or potassium hexacyanoferrate(III) in the presence of Na2CO3, resulted in very low yields (1%-5%) of 52, isolated as the corresponding tetra-acetate (53), along with other dimeric products. Compound 52 was shown to be a potent inhibitor of lipid peroxidation. In an earlier study, the same authors obtained the isomeric 1,2-dihydronaphalene, isolated as the corresponding tetra-acetate 56, as the main product from POC of methyl ester 55 using either silver oxide (28%), or potassium hexacyanoferrate/sodium acetate (20%) or sodium carbonate (13%), as the oxidant [47]. Ester 55 was readily obtained from the coumarin esculetin (54). Αgata and coworkers isolated from Rabdosia japonica Hara a CafA tetramer, which they named rabdosiin (57). The aboveground part of this plant is used in Japan as a common household medicine for gastrointestinal disorders, called "emeiso". Compound is a diester (hybrid) of the lignan 58 of dihydronaphthalene type with the 1R,2S configuration and the (R)-α-hydroxyacid 59. In order to prove its structure, this research group subjected Me-Caf (60) into POC using FeCl3 as the oxidant. That way, they obtained racemic lignan 61 in 55% yield. Rabdosiin is thought to be biogenetically produced through the oxidative coupling of two molecules of (R)-(+)-RosA (62) in a way analogous to the dehydrodimerization of Me-Caf towards the lignan skeleton 61 (Scheme 32) [48,49]. (−)-Rabdosiin and particularly its monopotassium and monosodium salts have potent anti-HIV activity [50]. It has been also found to be a strong inhibitor of DNA topoisomerases I and II [51]. Interestingly, natural rabdosiin has been isolated in both diastereomeric forms, namely the (−)-(1R,2S) and the (+)-(1S,2R) forms, although in both diastereomers the Dpl ester groups are R.
The same research group subjected the ester 64 of SinA with methyl (R)-mandelate into POC, using a similar method to that used by Wallis to dehydrodimerize the corresponding Me-Sin, and obtained three main products, namely two 1,2-trans-thomasidioate esters 65 and 66 in 53 and 23% yields and one 1,2-cis diastereomer 67 in 8% yield. It is therefore evident that chiral esters of HCAs lead to diastereoselective production of coupled-cyclized dimers (Scheme 34) [52]. Scheme 32. POC of Me-Caf (60) using FeCl3 as oxidant and the structures of rabdosiin (57) and RosA (62).   It should be noted that syntheses of the methyl and butyl esters 68 and 69 of both enantiomers (R)-(+)(62)-and (S)-(−)(62a)-RosA have been published by Reimann and Pflug [53] and Huang and coworkers [54], respectively ( Figure 1). Esters 69a and 69b showed interesting antioxidant and antitumour activity [54]. (R)-(+)-RosA has been recently shown to be a potent inhibitor against snake venom [55]. Interestingly, oligomerization of RosA in nature produces complex NLs isolated from the Indinesian plant Helictora isora possessing mild inhibitory activity against the avian myeloblastosis virus, such as helicterins A (70a) and B (70b), helisorin (71) and helisterculin A (72) (Figure 1). Syntheses for such compounds have been recently disclosed by Snyder and Kontes [56].
Examples of recently reported interesting natural products of the ester (depsides) or the amide type containing the lignan dihydronaphthalene nucleus are the mono-ester 73 of caffeicin E, named SalA-R and the tris(tyramide) thoreliamide C (74) (Figure 2), the latter also incorporating a β-O-4 bond, isolated from Origanum dictamnus L. by Exarchou and coworkers [57] and from Mitrephora thorelii by Ge and coworkers [58], respectively. Daquino and coworkers subjected Me-Caf (60) and CAPE (75) to various oxidants and studied the products of the oxidative coupling reactions [59]. Ester 75 is a natural product contained in propolis with anti-inflammatory, antioxidant and antitumour activity [60]. Thus, POC of CAPE using MnO2 as oxidant in CH2Cl2 produced an unusual lignan 76 of the benzo[kl]xanthene type and the dihydronaphthalene 78 in 48% and 16.5% yields, respectively, along with residual CAPE (Scheme 35). Highest yield (72%) in 76 was obtained when CHCl3 was used as the solvent, whereas highest yield (23.7%) in 78 was obtained with n-hexane/CH2Cl2 (1:1) as the solvent. Under analogous reaction conditions and using CHCl3 as the solvent, Me-Caf gave the corresponding products 77 and 79 in 51% and 7% yields, respectively. CAPE was also oxidatively dimerized in the presence of Mn(OAc)3 in CHCl3 and produced, with 89% conversion, 76 and 78 in 71% and 22% yields, respectively. This then appears to be the best method to synthesize dimer 76. On the contrary, CafA itself failed to produce the natural benzoxanthene lignan mongolicumin (80) in satisfactory yield (<10%) under these reaction conditions. However, lignan 80 could be obtained from dimer 77 through partial alkaline hydrolysis, acid-mediated cyclization and finally mild basic hydrolysis in 40% overall yield based on CafA as starting material. Benzoxanthenes have shown potential antitumour activity and, because of their strong fluorescence, may be of considerable interest in the design of new fluorescent probes for biomedical applications [59]. The proposed, by the authors, mechanism for the formation of benzoxanthane lignans 76 and 77 is outlined in Scheme 36.
It should be noted that Maeda and coworkers isolated a benzoxanthene lignan (81a), as the corresponding triacetate (81b) during the POC of the methyl ester 55 (Scheme 37), in particular when the oxidant used was silver oxide, along with the dihydronaphthalene 56 and other compounds [47]. Formation of compound 81a may be also explained with a similar mechanism to that outlined in Scheme 36. Both compounds (56 and 81b) showed potent inhibition of lipid peroxidation. Scheme 37. POC of ester 55 utilizing Ag2O as the oxidant. Stretched structures are used, in the proposed mechanism outlining formation of product, for the sake of drawing clearly electron movement and for avoiding overcrowding of groups.
Asymmetric syntheses of aryltetralin lignans attract considerable interest due to the fact that the clinically important antitumor drugs Etoposide and Teniposide are derived from the natural lignan podophyllotoxin (82) (Scheme 38) [61].
Taking into consideration the fact that podophyllotoxin is biosynthesized by the oxidative cyclisation of a lignan of the dibenzylbutyrolactone (CL2) type, such as matairesinol (83) or yatein (84) (Scheme 38) [62], attempts were made to effect such cyclizations using laboratory reagents. They were, however, unsuccessful as they invariably lead to the formation of an eight-membered ring rather than the anticipated six-membered ring [19]. Interestingly, Cambie and coworkers managed to cyclize yatein (84) by non-POC with formation of the six-membered ring, thus producing deoxyisopodophyllotoxin (85), using thallium(III) oxide as oxidant in TFA (Scheme 39) [63].

Syntheses of Lignans Based on the Key Intermediate Dialkyl Bis(arylmethyle-ne)succinate
Sarkanen and Wallis subjected cinnamate ester 95 into POC coupling using alkaline potassium ferricyanide as oxidant and obtained a mixture of the bisquinonemethides 96a and 96b, in the ratio 65:35, in 72% yield. These compounds can be tautomerized to the same dimethyl bis(arylmethylene)succinate (44a), whereas upon catalytic hydrogenation they are transformed to the corresponding diarylbutanes 97a and 97b. Furthermore, diesteres 97a and 97b could be converted to the corresponding diastereomeric tetrahydrofurans 98a and 98b upon reduction with LAH, followed by acid-mediated ring closure with dehydration (Scheme 42) [64].
It should be noted that the diethyl bis(arylmethylene)succinate 44 (Scheme 28) was identified by Neudorffer and coworkers as the minor product of the electrochemical POC of Et-Fer [43]. On the other hand, Bunzel and coworkers synthesized diethyl bis(arylmethylene)succinate 44b through POC of Et-Sin, using Mn(OAc)3.2H2O as oxidant in pyridine (Scheme 43) [42]. They isolated its corresponding diacetate 44c in 85% yield. From this compound, free acid 44d was obtained, in a two-step saponification, however in low yield (30%) along with unsaponified diester 44b.
Wang and coworkers subjected Et-Fer (42) into an alkanine potassium ferricyanide-mediated POC in PhH-H2O to obtain the corresponding diethyl bis(aryl-methylene)succinate 44e, however as a minor product of the reaction in only 9% yield (Scheme 44). The main product of the reaction was the benzofuran 99 which was obviously formed through the alternative primary β-5 coupling [65].

9%
When, however, they blocked the position 5 by a tert-butyl group, they succeeded to synthesize the β-β' coupling product 44f in excellent yield from the Et-Fer derivative 100 (Scheme 45). That way, alternative dimerizations involving position C-5 or even O-4, due to steric hindrance, can be avoided.   Moon and coworkers recently isolated a novel cytotoxic lignan from the seeds of Trichosanthes kirilowii, identified it as the monoester of (−)-(2R,3R)-secoisolariciresinol with FerA and designated it as hanultarin (105). This compound and the already known diester 1,4-O-diferuloyl-secoisolariciresinol (106) (Figure 3), also isolated from the seeds, showed comparable cytotoxic effects to cisplatin against several cancer cell lines [67]. Lee and coworkers synthesized, with other than the POC route, for the first time the above compounds and analogs and evaluated their cytotoxicity against several cancer cell lines [68]. They found that, although neither FerA nor secoisolariciresinol are cytotoxic, their conjugation leads to cytotoxic hybrids with the most potent being the diferuloyl ester 106 of secolariciresinol. They also proposed that the observed cytotoxic effect might originate from the inhibitory effect of the polymerization of actin or microtubule fibers. It is interesting to note that amides of the bis(arylmethylene)succinic acid have been isolated from plants. For example, Ma and coworkers isolated from the seeds of Hyoscyamus niger four lignanamides, that is hyoscyamide (107), cannabisin G (108), cannabisin D (109) and grossamide (110) (Figure 4) [69]. Hyoscyamide and cannabisin G are dimers of (Z)-and (E)-N-feruloyltyramine, respectively. On the other hand, grossamide and cannabisin D are bistyramides of dimers of FerA of the benzofuran neolignan and the arylnaphtalene lignan types, respectively. Grossamide and cannabisins D and G showed moderate cytotoxicity in cultured LNCaP human prostate cancer cells. Tomosaka and coworkers also isolated cannabisin G (108), along with (±)-lyoniresinol (11a) (Scheme 8), from the root bark of Berberis vulgaris L. Although both compounds exhibited antioxidant activity in a hydroxyl radical-scavenging assay, only canabbisin G showed cytoprotective activity in cultured MCF-7 cells modulated by hydrogen peroxide [70]. Li and coworkers have recently published a concise synthesis of cannabisin G using as key reaction the alkaline ferricyanide-mediated oxidative dimerization of ethyl 5-(t-butyl)ferulate (100) [71].

Syntheses of Lignans Based on the Key Intermediate 3,4-Disubstituted 2,5-Di-aryltetrahydrofuran
As outlined above (Scheme 9), lignans of the 2,5-diaryltetrahydrofuran (CL5a) type can be obtained indirectly through acid-mediated rearrangement of halogenated bilactones (e. g., 1e, 1f). However, Ahmed and coworkers also managed to obtain directly such a compound through POC of suitable halogenated HCAs, such as 111, using FeCl3 as oxidant in the presence of hydrochloric acid in low concentration. That way, they isolated the tetrahydrofuran intermediate 112 in 13% yield, along with unreacted starting material (Scheme 47).

Scheme 48.
Outline of the proposed mechanism for the formation of the 2,5-diaryltetrahydrofuran lignan 112 by POC of HCA 111.

Synthesis of NLs of the Benzofuran Type-Formation of β-5 Bond as the Key Step
Cilliers and Singleton treated an alkaline aqueous solution of CafA with O2 and identified a series of POC products designated as caffeicins. One of them, designated caffeicin F (115), is a neolignan of the 2,3-dihydrobenzofuran (NL1) type [45]. Although no relative stereochemistry is provided for 115, the coupling constant between protons 2 and 3 (J = 7.2 Hz) indicates a trans configuration ( Figure 5).

30%
The same reaction could be performed using either an excess of iodosylbenzene in the presence of Mn(III)TPPOAc as catalyst or a stoichiometric amount of iodosylbenzene with MnTTPCl or even excess H2O2 with MnTPPCl to obtain benzofuran 116 in 22%, 36% and ca. 25% yields, respectively.

Scheme 50.
Outline of the proposed mechanism for the formation of the neolignan 116 and the oxyneolignan 117.
Compounds 116 and 117 are thought to be formed through the common intermediate 118 which is intercepted either intramolecularly from the adjacent hydroxyl group or intermolecularly from methanol (Scheme 50).
Maeda and coworkers reported that POC of the HCA methyl ester 51, mediated by silver oxide in benzene-acetone, produced the benzofuranoid dimer 119a as the main product, isolated as its corresponding triacetate 119b in 15% yield (Scheme 51) [46] and 21% recovery of starting material as the corresponding diacetate. No such product was isolated by using either potassium hexacyanoferrate(III)/Na2CO3 or ferric chloride as oxidant. Compound 119b exhibited potent inhibition of lipid peroxidation both in rat brain homogenate and rat liver microsomes. In earlier studies, the same authors synthesized the benzofuranoids 116 and 121 from Me-Fer (42a) and its regioisomer 120, respectively, and converted the former into the lignin schizotenuin D (122) and related compounds with potent inhibitory effects on lipid peroxidation [73,74]. The common structural characteristic of all starting materials used in these POCs producing benzofuranoid NLs is that their 5 position is unhindered. Βolzacchini and coworkers subjected the amide 123 of FerA with ethyl (S)-alaninate, used as chiral auxilliary, to POC employing HRP-H2O2 as oxidant system in dioxane-aqeous buffer pH 3. That way, a mixture of the two diastereomeric benzofuranoid dimers 124 and 125 was obtained in 70% yield and d.e. 65%, which could be separated by silica gel FCC (Scheme 52) [75]. It should be reminded that, without a chiral auxilliary, the oxidant system HRP-H2O2 produces racemic mixtures. The major diastereomer had the 2S,3S absolute stereochemistry, as this was shown by LiOOH-mediated hydrolysis, esterification with diazomethane, reduction with LiBH4 and finally identification with the known 2S,3R stereoisomer 126 of dehydrodiconiferyl alcohol. Scheme 52. Diastereoselective POC of ferulamide 123 using HRP-H2O2.
Ralph and coworkers developed a simple and cheap method for the preparation of diethyl diferulate 45 (Scheme 28), in gram quantities and in reasonable yields (ca. 50% yield), from Et-Fer (42) utilizing the biomimetic HRP-H2O2 system in an aqueous acetate buffer pH 4.0 [76].
Considering the natural neolignan 3',4-di-O-methylcedrusin (139) with known inhibitory activity of cell proliferation as lead compound, Pieters and coworkers synthesized a series of 19 related dihydrobenzofuran lignans and benzofurans, suitable for SARS, by utilizing a biomimetic reaction sequence involving as key reaction the POC of p-coumaric (127), caffeic (60) or ferulic (42a) acid methyl esters with silver oxide in anhydrous PhH-acetone. The anticipated dihydrobenzofurans 128, 115 and 116 were obtained in 23%-50% yields. Compound 116 was O-methylated giving the diferulate analog 129. This compound was oxidized with DDQ to the corresponding benzofuran 130, which was then catalytically reduced leading to benzofuran analog 131. On the other hand, dihydrobenzofurans 115-116 and 128-129 were catalytically reduced giving analogs 132-135, which were further reduced with LAH leading to the diols 136-139. Furthermore, catalytic hydrogenation of 135 caused opening of the dihydrofuran ring giving alcohol 140 (Scheme 53). All synthesized compounds were tested for potential anticancer activity in 60 human tumor cell lines. The dihydrobenzofuran dimer 115 from Me-Caf was the most potent. It should be noted that the two enantiomers of racemic 115 were separated by chiral HPLC and that the 2R,3R enantiomer was the more active one. Furthermore, the two enantiomers of racemic neolignan 129 were also separated in order to obtain 3',4-di-O-methylcedrusin (139), with the 2R,3S assigned configuration, a minor constituent of the traditional medicament "dragon's blood". Surprisingly, no activity was exhibited by this particular compound. Leukemia cell lines and breast cancer lines were relatively more sensitive to the cytotoxic dihydrobenzofuran NLs. These studies established that the NLs of the dihydrobenzofuran type form a new group of antimitotic and potential antitumor agents which inhibit tubulin polymerization [77]. Carunchio and coworkers subjected FerA to POC using the enzyme laccase in EtOH-aqueous buffer pH 6.0 and the reaction was monitored by HPLC-MS. They identified the two main products initially formed as the benzofuranoid dimer 141 and the β-O-4 coupling product 142 (Scheme 54) [78]. They also found that enzymatic activity is inhibited by dipeptides of the type Gly-X due to the formation of complexes with Cu(II), known to play a central role in the laccase, single electron transfer, reaction mechanism. Scheme 54. Dimers from laccase-mediated POC of FerA.
A dihydrobenzofuran dimer, namely compound 45 was also isolated by Neudorffer and coworkers, as the second most abundant compound (13% yield) of the mixture obtained by the electrochemical POC of Et-Fer (Scheme 28) [43].
Kuo and Wu reported a biomimetic multistep synthesis of salvinal (143) [79], a benzofuranoid NL isolated from the root of Salvia miltiorrhizae Bunge, whose aqueous extracts have been extensively used in Asia in the treatment of cardiovascular disorders and cancer. Salvinal is a novel Adenosine A1 receptor ligand and a novel microtubule inhibitor with antimitotic activity in multidrug-sensitive and -resistant human tumor cells [80]. Key step in the synthesis of salvinal was POC of Me-Fer by ferric chloride in aqueous acetone (Scheme 55) producing the known dihydrobenzofuran dimer 116 in 34% yield. Rakotondramanana and coworkers subjected Me-Fer (42a) to POC using Ag2O as oxidant in toluene-acetone (2:1) and obtained as the main product the known dihydrobenzofuran 116 in 45% yield, along with the corresponding β-Ο-4 dimer 144 in 5% yield. Compound 116 was protected with the TBDMS group and then selectively reduced to produce alcohol 145. This compound, upon esterification with the gallic acid derivative 146 and finally deprotection gave the dihydrobenzofuran-gallic acid hybrid 147 (Scheme 56) [81]. Biological evaluation of these compounds for potential antiatherogenic, antiplasmodial and cytotoxic activities showed that dimer 144 presented the best antiatherogenic effect (antioxidant activity and cytoprotective effect) whereas dihydrobenzofuran 116 exhibited the best activity against murine P388 leukemia cells. On the other hand, hybrid 147 showed a very good antiplasmodial potency coupled also with an antioxidant one.
Zhang and coworkers performed radical coupling reactions between equimolar quantities of Et-Fer (42) and ConAl in the presence of HRP and H2O2-urea complex as oxidant in acetone-aqueous buffer pH 5.0. They isolated and characterized a series of cross-coupled products, two of which (148 in 6.4% yield and 149, as the corresponding acetate 149a, in 1.5% yield) ( Figure 6) were NLs of the dihydrobenzofuran type, along with a series of homo-coupled products [82]. Homodimers of the same type, such as dehydrodiconniferyl alcohol 150 and diethyl dehydrodiferulate 45, were also identified in the reaction mixture. Subbaraju and coworkers synthesized the neolignan tiruneesiin (151) in racemic form using as key reaction the POC of Me-Fer (42a) with Ag2O in dry PhH-acetone, which produced dihydrobenzofuran 116 in 29% yield. Catalytic hydrogenation of the double bond, LAH-mediated reduction of the ester functions, followed by O-benzylation of the aromatic hydroxyl, bisacetylation of the aliphatic hydroxyl groups and finally catalytic hydrogenolysis afforded (±)-151 in 12.6% total yield (Scheme 57) [83]. It should be noted that tiruneesiin, identified in Justicia neesii Ramamoorthy as the (−)-151 enantiomer, belongs to the group of dihydrobenzofuranoid NLs, which are known to be inhibitors of tubulin polymerization [77]. Antus and coworkers have shown that Ag2O-mediated POC of Et-Caf (152) leads to the dihydrobenzofuran 153 as the main product isolated as its corresponding triacetate (153a), which was used for the synthesis of the NL Americanin-D (154) [84]. When a mixture of 152 and ConAl (23) was treated with either silver oxide or silver carbonate in benzene-acetone, the cross-coupled product 155 was isolated in 6%-8% yield, along with other dimers [85]. Compound 155 was used by the same research group as starting material for the synthesis of racemic cedrusin (156) (Scheme 58) [86]. On the other hand, the same research group oxidatively dimerized Me-Fer (42a) with Ag2O in benzene-acetone to obtain dihydrobenzofuran 116 in 38% yield. This compound was employed as starting material for the synthesis of racemic balanophonin (157) and its corresponding methyl ester 158 [87] as well as the monomethyl ether 159 of cedrusin [86] (Scheme 59). It should be noted that the NL (−)-balanophonin and its corresponding methyl ester were isolated from Balanophora japonica Mikino and Ziziphus jujuba Mill, respectively, and showed significant PGI2 inducing effect, whereas (+)-cedrusin and its monomethyl ether were isolated from Cedrus deodara and Euconomia ulmoides Oliv., respectively. The latter plant has been applied in China as hypotensive drug. Daquino and coworkers subjected CAPE (75) into POC using Ag2O as oxidant in CH2Cl2 and obtained the corresponding dihydrobenzofuran 160 in 58% yield (Scheme 60) [59] when a ratio of CAPE:Ag2O = 1:2 was used. Interestingly, when POC was repeated in the presence of Mn(ACAC)2 no dihydrobenzofuran was formed, the main product being the benzoxanthene lignan 76 in 54% yield.
Bruschi and coworkers oxidized Evans' 2-oxazolidinone amides (161-164) of FerA utilizing either HRP-H2O2 in dioxane or acetone/aqueous buffer pH 3.5 or Ag2O in CH2Cl2 as oxidants and obtained the corresponding diastereomeric dihydrobenzofurans 165-172. These compounds were further reduced with LiBH4 to the corresponding known enantiomeric dihydrodiconiferyl alcohols 173 and 174 (Scheme 61). The major enantiomer was identified in each case and the e.e. was calculated. Best enantioselectivities (e.e. 59%-62%) were secured with HRP-H2O2 in acetone-aqueous buffer as the oxidant system and (R)-and (S)-5-phenyl-2-oxazolidinones as the chiral auxiliaries [88]. Arrieta-Baez and Stark subjected pairs of HCAs in cross-POC utilizing H2O2 in combination with either APP or HRP, as the oxidant systems in a phosphate buffer (pH 6.1) and studied the formation of products from cross-coupling and dimerization reactions. They found that only the mixtures of CafA and FerA and of CafA and SinA produced cross-coupled products in addition to dimerization products. In combinations of CouA and any of the other HCAs, dimerization products were only observed from the other HCAs but not CouA. Also, from the mixture FerA and SinA dimerization products were only observed from SinA. Both enzymes produced identical major products. The various major products formed were isolated by HPLC and identified. They had predominantly β-β γ-lactone (175-176) and β-5 benzofuran molecular frameworks (177-178) and one of them (179) was of the oxyneolignan 1,4-benzodioxane type (Figure 7) [89].  comparable results. Cross-coupling products, along with homodimers, were essentially obtained in 12%-24% yields from the combinations of 32 with 60 and of 32 with 42a. They were predominantly of the benzofuran type (181-182). In one case, a 1,4-benzodioxane product (183) was also formed in 9% yield. The combination of 60 and 42a produced as main product in 32% yield the homodimer benzofuran 116 from 42a. Homodimers obtained were either of the benzofuran (116) or the dihydronaphthalene (184) type (Figure 8) [90].   On the other hand, the combination of amides 180 and 181 produced mainly a benzofuran type cross-coupled product 185 in 27% and two homodimers, one of the benzofuran type (186) and the other of the dihydronaphthalene type (187) in 6 and 15% yields, respectively (Scheme 63). Product 185 was a mixture of diastereomers with a d.e. evaluated to be 38%. Interestingly, conjugation of NLs of the benzofuran type with other natural products can lead to hybrids with interesting biological properties, such as the dihydrobenzofuran-gallic acid hybrid 147 (Scheme 56) mentioned above. Other worth mentioning such hybrids are the so called schizotenuins A (188), C1 (189) and C2 (190) (Figure 9) which were isolated by Matsuta and coworkers from the terrestrial part of Schizonepeta tenuifolia BRIQ. This plant has been used in traditional Chinese medicines as anti-inflammatory crude drug. Hybrids 188-190 are actually the diester and the two possible monoesters of the benzofuran 192 (CafA dimer) with DplA and act by inhibiting the 3α-hydroxysteroid dehydrogenase. Compound 192 was prepared from the fully protected dihydrobenzofuran 191, readily available using Ag2O-mediated POC of Me-Fer (42a) as key reaction, by DDQ-mediated oxidation, followed by deprotection steps (Scheme 64) [73].  L.), has a similar benzofuranoid substructure. It had been previously synthesized enzymatically from coumaroylagmatine (195) using cell free extracts from the shoots of barley seedlings [92].
Another interesting, naturally occurring, dihydrobenzofuranoid hybrid is (+)-LitA (197) (Figure 10), in particular because of its potent and non-toxic anti-HIV activity that results from inhibition of HIV-1 integrase [93]. Several total syntheses of 197 have been already reported [93][94][95][96][97]. This compound can be considered as a hybrid of the (2S,3S)-dimer 201 of CafA with (R)-DplA. Dimer 201 could be assembled in nature through the unusual coupling (β-2) of the C-centered radicals 198 and 199, followed by the usual Michael addition on the p-quinonemethide intermediate 200. Alternatively, LitA might be considered as the product (hybrid) of cross-POC between RosA and CafA, involving the same type of C-C bond formation as key step for the assembly of the molecular skeleton.  Figure 10. The structure of (+)-LitA (197) and outline of plausible mechanism for the formation of core dihydrobenzofuranoid structure by either POC of CafA or cross-POC of CafA with RosA.
RosA and LitA along with dimers and trimers of the former, in which the monomeric units are joined through dihydrobenzofuran moieties, were isolated and identified by Ly and coworkers from the methanol exctract of dried leaves of Celastrus hindsii Benth a species of the Celastraceae family, which is used in Vietnam as traditional medicine for treating ulcers, tumors and inflammation. These compounds showed antioxidative activity whose effectiveness could be correlated to the number of the phenolic hydroxyl groups in each molecule [98]. One of the dimers, namely LitA-B (202) may be considered as a hybrid of neolignan 201 with two molecules of DplA ( Figure 11). It is thought of being formed in nature through POC coupling of two molecules of RosA. LitA-B is also a potent and nontoxic inhibitor of HIV-1 replication. The pharmaceutically interesting acids RosA, LitA and LitA-B have been also found in some other plants [98].  Another example of a dihydrobenzofuranoid hybrid is thoreliamide A (203) (Figure 12) which has been isolated in optically inactive form from the stems of the plant Mitrephora thorelii (Annonaceae) by Ge and coworkers [58]. This natural product may be considered as the hybrid of the unusual dihydrobenzuran 204 with two molecules of tyramine. Compound 204 might arise from cross-POC of FerA and SinA or HFeA with further functional group elaboration on the aromatic SinA/HFeA side of the molecule.

Synthesis of Oxyneolignans of the Ether Type-Formation of β-O-4 Bond as the Key Step
As we noted above, Carunchio and coworkers subjected FerA to POC using the enzyme laccase and identified two main products initially formed, a benzofuranoid dimer 141 and the β-O-4 coupling product 142 (Scheme 54) [78]. The latter product is an example of the NL3 subtype of NLs ( Figure 13). Οn the other hand, Neudorffer and coworkers isolated the oxyneolignan ether 46 (Scheme 28 and Figure 13) in 10% yield, among other lignans, from the reaction mixture of the electrochemical POC of Et-Fer [43]. Furthermore, Rakotondramanana and coworkers isolated the corresponding dimethyl ester 144 (Scheme 56 and Figure 13) in very low yield, along with the dihydrobenzofuranoid FerA dimer 116, from the Ag2O-mediated POC of Me-Fer [81]. Cross (e.g., 205a,b)-and homo (206a,b and 46)-coupling products (Figure 14) of the β-Ο-4 ether type from the cross-POC of Et-Fer and ConAl (23) were isolated and/or identified, among other lignans, by Zhang and coworkers [82]. Compounds 205 and 206 are obviously formed through interception of the p-benzoquinonoid intermediates 207 by water.
Lu and coworkers subjected Et-Fer in POC utilizing the complex CuCl(OH)-TMEDA as catalyst and oxygen as oxidant in acetonitrile and obtained a mixture composed of β-O-4, 8-5, 8-8 (cyclic and noncyclic) and 5-5 coupled dehydrodiferulates, from which the β-O-4 dimer 46 was obtained through FCC along with the β-5 (dihydrobenzofuranoid) dimer 45 (the structure of dimers 45 and 46 can be seen in Scheme 28). Crystallization of the mixture resulted to pure crystalline 45 and left 46 in mother liquor. From the latter, pure dimer 46 was obtained through simple treatment of mother liquor with TBAF, which converted the remaining dimer 45 to a noncyclic β-5 dimer, and finally rechromatography [99]. Lu and Foo isolated from Salvia officinalis (Sage), a popular herb which has been used since ancient times for its health giving properties and for treating all kinds of ailments, in addition to RosA two compounds, namely the known SalA-K (209) and a novel cyclobutane derivative named sagerinic acid (210) (Figure 15) [101]. The former might be formed by cross-POC of RosA with CafA during which the primary β-Ο-4 bond is formed, followed by a stereoselective interception of the derived p-benzoquinone intermediate by water. In the latter, the two RosA units may be first connected by a Cβ-Cβ bond through POC, probably followed by an intramolecular Michael addition to create the second C-C bond with ring closure and finally reduction of the intermediate o-benzoquinone formed. From the same plant, Lu and coworkers isolated another novel CafA trimer, which they named sagecoumarin (211) (Figure 15), and methyl melitrate A (212) and proposed that MelA-A, its ester 212 and 211 are all synthesized from SalA-K [102].
Another SalA, namely SalA-B (213) (Figure 15) has been isolated from Salvia miltiorrhiza Bge, a well-known Chinese medicine for treating and preventing aging diseases for throusands of years, and has been shown to present interesting cardiovascular effects [103] and to be a potential chemoprotective agent for head and neck squamous cell cancer [104]. SalA-B is structurally related to LitA.  , an endemic plant of Crete which was considered by ancient Greeks as Panacea and used in many cases for its healing effects, in addition to a new dihydronaphthalene hybrid SalA-R (73, Figure 2), RosA and MelA-A three new hybrids 213-215 of dimeric CafA, with an unusual connection (β-Ο-3), and DplA ( Figure 16). Interestingly, SalA-S (215) was the most potent antioxidant, followed by RosA, in the DPPH assay used [57].

Synthesis of Oxyneolignans of the 1,4-Benzodioxane Type-Formation of β-O-4 Bond as the Key Step
As we noted above, Antus and coworkers oxidatively dimerized Et-Caf (152) using Ag2O as oxidant and then acetylated the crude reaction product to obtain pure triacetate 153a in 29% yield following crystallization (Scheme 58). From the mother liquor, the authors isolated through silica gel CC a mixture of the isomeric oxyneolignans 216 and 217 (Figure 17) of the 1,4-benzodioxane NL2 type in 6% yield [84].  The same research group subjected a mixture of Et-Caf (152) and ConAl (23) (molar ratio = 1:1.1) in cross-POC using silver oxide or silver carbonate as oxidant in benzene/acetone (2:1) and obtained a mixture from which the various products were isolated by preparative TLC. Major product of the coupling reaction was the 3-aryl-1,4-benzodioxane derivative 218a, which crystallized out from a mixture with the alternative regioisomer 219a. Both had the trans relative stereochemistry. Their corresponding cis isomers 218b and 219b were also obtained in much lower yields (Scheme 66). Silver carbonate resulted in higher regioselectivity (218a:219a = 25:1) than that obtained with silver oxide (218a:219a = 19:1). On the other hand, the use of hexacyanoferrate(III)/sodium carbonate as oxidizing agent in acetone/water (ca. 1:3) reversed the regioselectivity of the reaction and produced 219a as the major isomer. The cis isomers were also isolated as crystalline compounds in lower yields.
The 218 (a + b):219(a + b) ratio was ca. 1:9 [85]. POC of CafA with O2 in an alkaline (KOH) aqueous solution produced, in addition to caffeicins E and F (see sections 2.2 and 3.1 above), dimeric CafA compounds of the 1,4-benzodioxane type which were named caffeicin A-D. The two substituents of the heterocyclic ring had the cis relative configuration (see e.g., compounds 220 and 221) ( Figure 18) based on 1 H-NMR coupling constants considerations [45]. The cis formed is preferred since the bulky groups are both in the equatorial position with the dioxane ring adopting the boat form.
As mentioned above, when a mixture of CafA and SinA was subjected in cross-POC utilizing H2O2 in combination with either APP or HRP, an oxyneolignan (179) of the 1,4-benzodioxane type was obtained (Figures 7 and 18) in modest yield [89].
The reported coupling constant (J) for protons 7 and 8 was 2.5 Hz. Therefore, the relative stereochemistry in compound 179 should be cis (Figure 18). On the other hand, cross-POC of a pair of Me-Caf and Me-Sin utilizing the HRP-H2O2 oxidant system produced, among other lignans, the 1,4-benzodioxane product 183 in 9% yield (Figure 8) [90]. Based on coupling constant arguments (JH7-H8 = 2.3 Hz), this compound should also have the cis relative stereochemistry (Figure 18).
An interesting optically inactive 1,4-benzodioxane hybrid 222 ( Figure 18) was isolated, along with other lignanamides (see Sections 2.2 and 3.1) from the stems of Mitrephora thorelii [58]. This compound, named thoreliamide B, can be considered as the hybrid of acid 223 and tyramine. The former may then obviously be a cross-POC product of SinAl with CafA. Based on coupling constant arguments (JH7-H8 = 8.0 Hz), this racemic compound should have the trans relative stereochemistry. Figure 18. Structures of oxyneolignans of the 1,4-benzodioxane type.

Synthesis of Other NLs-Formation of β-1 or 5-5 Bond as the Key Step
Setälä and coworkers performed a cross-POC reaction with an equimolar mixture of Me-Sin (32) and alcohol 224, a syringyl lignin model compound, utilizing HRP-H2O2 as oxidant system in acetone-aqueous buffer solution pH 3.5. Acetylation of the crude reaction mixture, followed first by silica gel CC and then by preparative HPLC separation, lead to a ca. 50% recovery of alcohol 224 and the isolation of two products, namely the spiro cross-coupling product 225 in 19% yield and the sinapate dimer 226 in ca. 4% yield (Scheme 67) [105]. Treatment of spiro compound 225 with a catalytic quantity of pTSA monohydrate in methanol gave, with loss of the side chain, a single diastereomer of compound 227, which was isolated in 33% yield as the corresponding peracetate 228.

Conclusions
We have presented in this review an overview of past and recent applications of an old reaction, namely POC, in the bioinspired syntheses of a variety of CLs, and NLs with potential medicinal significance. These involve, in particular, lignans of the dilactone, dihydronaphthalene, bis(aryl-methylene)succinic acid, 1,4-benzodioxane, tetrahydrofuran, dihydrobenzofuran, aryl β-cinnamyl ether, and benzoxanthene subtypes. POC utilizes simple starting materials and experimental procedures and creates in one-pot experiments relatively complex structures often with good yields, which would otherwise require several steps to be assembled. Simple, commercially available or easily synthesized, building blocks, such as naturally occurring HCAs and HCAls and synthetic analogs as well as esters and amides of HCAs, are usually employed. Coupling between the same or different (cross-POC), in some cases, building blocks is effected by the action of one-electron inorganic oxidants or enzymes (peroxidases, usually HRP and less often laccases) as catalysts with H2O2 or O2 as oxidant, which mimic even closer the natural conditions for performing such dehydrodimerizations. Suitable inorganic oxidants have been also used in the so-called non-POC which uses ACAs as starting materials and has been used successfully, for example, in the synthesis of lignans of the isostegane type. Although POC usually produces mixtures of regio-and diastereoisomers and therefore chromatographic techniques are necessary for their separation, it is still a very attractive alternative to other multi-step methodologies, in particularly in cases where a single regioisomer and/or diastereoiosmer is formed as the main product, because of the simplicity in its performance and the fact that creates complex structures in one-pot reactions. The regioselectivity of POC has been improved by selectively blocking positions which could be potentially involved in bond-forming reactions through radical coupling. One such group is the tert-butyl group which is readily introduced and finally removed after the POC reaction. Interestingly, the primary products of POC can be readily transformed through simple reactions in a multitude of other medicinally significant lignans and hybrids. A serious drawback of POC is that it provides the dimers in racemic mixtures, even when enzymes are used as catalysts. However, this problem has been faced with considerable success by subjecting to POC chiral esters or amides of HCAs, readily produced by condensing HCAs with chiral alcohols or amines, e.g., esters of chiral α-amino acids, used as chiral auxilliaries. That way, the thus produced diastereomeric compounds are resolved with chromatographic techniques and, if necessary, the chiral auxilliary is removed, for example, by alkaline hydrolysis or LiOOH-mediated hydrolysis. It is reasonable to assume that POC will continue to be used for the ready assembly of the skeleta of naturally occurring and biologically interesting lignans of several types and that it will be further developed towards the direction of improving its regio-and the stereoselectivity by the thoughtful choice of combinations of substrates, oxidant systems, reaction conditions and chiral auxilliaries.