Advances in the Synthesis of Lignan Natural Products

Lignans comprise a family of secondary metabolites existing widely in plants and also in human food sources. As important components, these compounds play remarkable roles in plants’ ecological functions as protection against herbivores and microorganisms. Meanwhile, foods rich in lignans have revealed potential to decrease of risk of cancers. To date, a number of promising bioactivities have been found for lignan natural products and their unnatural analogues, including antibacterial, antiviral, antitumor, antiplatelet, phosphodiesterase inhibition, 5-lipoxygenase inhibition, HIV reverse transcription inhibition, cytotoxic activities, antioxidant activities, immunosuppressive activities and antiasthmatic activities. Therefore, the synthesis of this family and also their analogues have attracted widespread interest from the synthetic organic chemistry community. Herein, we outline advances in the synthesis of lignan natural products in the last decade.

The synthesis of lignans and their analogues is an active field in the synthetic organic chemistry community. Tremendous synthetic efforts on this family have been well documented by reviews [9][10][11][12][13][14]41,[47][48][49][50][51]. In recent years, several nice reviews have outlined progress of particular topics related to the synthesis of furofuran lignans [48], arylnaphthalene lactone analogues [47] and aryltetralin glycosides [49]. The present review will focus on the papers on the synthesis of lignans published from 2008-2018. In order to avoid unnecessary duplication, we will not discuss works already presented in previous reviews.
For the convenience of introduction of advances in the synthesis of lignans, we discuss three subgroups in present review, namely, acyclic lignan derivatives, dibenzocyclooctadiene derivatives and arylnaphthalene derivatives.

Advances in the Synthesis of Acyclic Lignan Derivatives
In the last decade, synthetic progress in acyclic lignan derivatives is related to lignans featuring dibenzyl tetrahydrofuran, dibenzylbutyrolactone, and diphenyltetrahydrofuranfurofuran skeletons. Scheme 1. Synthesis of (±)-paulownin. Adapted from Angle et al. [52].
In 2011, Barker and coworkers reported the total synthesis of (+)-galbelgin (Scheme 2) [54]. A stereoselective aza-Claisen rearrangement developed in their lab [55] afforded a reliable access to the original two stereocenters in chiral amide 8. The subsequent nucleophilic addition from 11, reduction, hydroxyl protection and double bond oxidative cleavage led to the formation of aldehyde Scheme 1. Synthesis of (±)-paulownin. Adapted from Angle et al. [52].
In 2011, Barker and coworkers reported the total synthesis of (+)-galbelgin (Scheme 2) [54]. A stereoselective aza-Claisen rearrangement developed in their lab [55] afforded a reliable access to the original two stereocenters in chiral amide 8. The subsequent nucleophilic addition from 11, reduction, hydroxyl protection and double bond oxidative cleavage led to the formation of aldehyde 10. The second nucleophilic addition from 11 afforded 12 with four adjacent stereocenters established. Methoxymethyl (MOM) group deprotection and cyclization completed the synthesis of (+)-galbelgin. The synthesis of lignans and their analogues is an active field in the synthetic organic chemistry community. Tremendous synthetic efforts on this family have been well documented by reviews [9][10][11][12][13][14]41,[47][48][49][50][51]. In recent years, several nice reviews have outlined progress of particular topics related to the synthesis of furofuran lignans [48], arylnaphthalene lactone analogues [47] and aryltetralin glycosides [49]. The present review will focus on the papers on the synthesis of lignans published from 2008-2018. In order to avoid unnecessary duplication, we will not discuss works already presented in previous reviews.
For the convenience of introduction of advances in the synthesis of lignans, we discuss three subgroups in present review, namely, acyclic lignan derivatives, dibenzocyclooctadiene derivatives and arylnaphthalene derivatives.

Advances in the Synthesis of Acyclic Lignan Derivatives
In the last decade, synthetic progress in acyclic lignan derivatives is related to lignans featuring dibenzyl tetrahydrofuran, dibenzylbutyrolactone, and diphenyltetrahydrofuranfurofuran skeletons. Scheme 1. Synthesis of (±)-paulownin. Adapted from Angle et al. [52].
In 2011, Barker and coworkers reported the total synthesis of (+)-galbelgin (Scheme 2) [54]. A stereoselective aza-Claisen rearrangement developed in their lab [55] afforded a reliable access to the original two stereocenters in chiral amide 8. The subsequent nucleophilic addition from 11, reduction, hydroxyl protection and double bond oxidative cleavage led to the formation of aldehyde Scheme 2. Synthesis of (+)-galbelgin. Adapted from Barker et al. [54]. She and coworkers reported the total synthesis of beilschmin A and gymnothelignan N in 2014 (Scheme 3) [56]. Alcohol 14 was prepared by hydroxyl protection of chiral amide 13 and subsequent reduction. Aldehyde 16 was obtained after homologation and reduction. The nucleophilic addition of 17 and oxidation afforded ketone 18. Dibenzyl tetrahydrofurans 20 was obtained after a highly stereoselective introduction of a methyl group, deprotection and reduction. The synthesis of beilschmin A was finished after the methylation. Inspired by a biosynthetic proposal from She's group, the challenging seven-membered ring skeleton in gymnothelignan N was constructed by an oxidative Friedel-Crafts reaction of compound 20 using phenyliodonium diacetate (PIDA) as the oxidant, finally affording gymnothelignan N. She and coworkers reported the total synthesis of beilschmin A and gymnothelignan N in 2014 (Scheme 3) [56]. Alcohol 14 was prepared by hydroxyl protection of chiral amide 13 and subsequent reduction. Aldehyde 16 was obtained after homologation and reduction. The nucleophilic addition of 17 and oxidation afforded ketone 18. Dibenzyl tetrahydrofurans 20 was obtained after a highly stereoselective introduction of a methyl group, deprotection and reduction. The synthesis of beilschmin A was finished after the methylation. Inspired by a biosynthetic proposal from She's group, the challenging seven-membered ring skeleton in gymnothelignan N was constructed by an oxidative Friedel-Crafts reaction of compound 20 using phenyliodonium diacetate (PIDA) as the oxidant, finally affording gymnothelignan N. Scheme 4. Bioinspired synthesis of (±)-tanegool and (±)-pinoresinol. Adapted from Lump et al. [46].
In 2015, Lump and coworkers reported a bioinspired total synthesis of (±)-tanegool and (±)-pinoresinol (Scheme 4) using [2 + 2] photodimerization and oxidative ring-opening as key steps [46]. The synthesis started with the esterification of ferulic acid. The resulting product 22 went through [2 + 2] photodimerization and reduction, generating diol 23 smoothly. The synthesis of (±)-tanegool through the expected oxidative ring-opening of 23 was achieved under different oxidative conditions. Moreover, synthesis of (±)-pinoresinol was also accomplished. Using the same strategy, trans-diester 26 was prepared from cis-diester 25. Reduced product 27 was submitted to an oxidative ring-opening treatment using FeCl 3 ·6H 2 O as the oxidant, finishing the synthesis of (±)-pinoresinol through an oxidative ring opening and two 5-exo-trig cyclization pathway.
In 2017, Soorukram and coworkers reported the asymmetric synthesis of ent-fragransin C 1 (Scheme 6) [61]. Ketone 36 was produced by the nucleophilic addition of the aryllithium species generated from 35 to chiral Weinreb amide 34. The following stereoselective reduction led to the formation of alcohol 37. After hydroxyl protection, double bond oxidative cleavage and nucleophilic addition from aryllithium 39, compound 40 was furnished in good diastereoselectivity. Followed by the deprotection and cyclization treatments, the tetrahydrofuran ring in 41 was established. Finally, the synthesis of ent-fragransin C 1 was accomplished through debenzylation under hydrogenation conditions. reduction. Aldehyde 16 was obtained after homologation and reduction. The nucleophilic addition of 17 and oxidation afforded ketone 18. Dibenzyl tetrahydrofurans 20 was obtained after a highly stereoselective introduction of a methyl group, deprotection and reduction. The synthesis of beilschmin A was finished after the methylation. Inspired by a biosynthetic proposal from She's group, the challenging seven-membered ring skeleton in gymnothelignan N was constructed by an oxidative Friedel-Crafts reaction of compound 20 using phenyliodonium diacetate (PIDA) as the oxidant, finally affording gymnothelignan N. Scheme 4. Bioinspired synthesis of (±)-tanegool and (±)-pinoresinol. Adapted from Lump et al. [46].
In 2015, Lump and coworkers reported a bioinspired total synthesis of (±)-tanegool and (±)-pinoresinol (Scheme 4) using [2 + 2] photodimerization and oxidative ring-opening as key steps [46]. The synthesis started with the esterification of ferulic acid. The resulting product 22 went through [2 + 2] photodimerization and reduction, generating diol 23 smoothly. The synthesis of (±)-tanegool through the expected oxidative ring-opening of 23 was achieved under different oxidative conditions. Moreover, synthesis of (±)-pinoresinol was also accomplished. Using the same strategy, trans-diester 26 was prepared from cis-diester 25. Reduced product 27 was submitted to an Scheme 4. Bioinspired synthesis of (±)-tanegool and (±)-pinoresinol. Adapted from Lump et al. [46]. oxidative ring-opening treatment using FeCl3·6H2O as the oxidant, finishing the synthesis of (±)-pinoresinol through an oxidative ring opening and two 5-exo-trig cyclization pathway. As powerful synthetic tools, photoredox-catalyzed tranformations have received considerable attention in recent decades [57][58][59]. In 2015, MacMillian and coworkers developed an enantioselective α-alkylation of aldehydes using a combination of photoredox catalysis and enamine catalysis and achieved the asymmetric synthesis of (−)-bursehernin through this strategy (Scheme 5) [60]. Using Ru(bpy)3Cl2, chiral amine 33 and a compact fluorescent lamp (CFL) light source, the α-alkylation of aldehyde 28 with bromonitrile 29 generated chiral aldehyde 30 in excellent yields and excellent enantioselectivity. Subsequent reduction and cyclization afforded lactone 31. The synthesis of (−)-bursehernin was achieved by a highly stereoselective alkylation between 31 and bromide 32. In 2017, Soorukram and coworkers reported the asymmetric synthesis of ent-fragransin C1 (Scheme 6) [61]. Ketone 36 was produced by the nucleophilic addition of the aryllithium species generated from 35 to chiral Weinreb amide 34. The following stereoselective reduction led to the formation of alcohol 37. After hydroxyl protection, double bond oxidative cleavage and nucleophilic addition from aryllithium 39, compound 40 was furnished in good diastereoselectivity.Followed by the deprotection and cyclization treatments, the tetrahydrofuran ring in 41 was established. Finally, the synthesis of ent-fragransin C1 was accomplished through debenzylation under hydrogenation conditions.
Based on a tandem nucleophilic addition/Ru-catalyzed isomerization/SET oxidation/radical dimerization strategy [62], Jahn and coworkers reported a bioinspired total synthesis of multiple lignans in 2018 (Scheme 7) [63]. Using bromide 42 as the substrate, a smooth unprecedented tandem 1,2-nucleophilic addition/Ru-catalyzed isomerization/SET oxidation/radical dimerization afforded 1,4-diketone 43 with acceptable diastereoselectivity. After the reduction, three different treatments of 43 led to the formation of 44 and 45 in varied ratios. With the removal of double Scheme 5. Asymmetric synthesis of (−)-bursehernin. Adapted from MacMillian et al. [60]. oxidative ring-opening treatment using FeCl3·6H2O as the oxidant, finishing the synthesis of (±)-pinoresinol through an oxidative ring opening and two 5-exo-trig cyclization pathway. As powerful synthetic tools, photoredox-catalyzed tranformations have received considerable attention in recent decades [57][58][59]. In 2015, MacMillian and coworkers developed an enantioselective α-alkylation of aldehydes using a combination of photoredox catalysis and enamine catalysis and achieved the asymmetric synthesis of (−)-bursehernin through this strategy (Scheme 5) [60]. Using Ru(bpy)3Cl2, chiral amine 33 and a compact fluorescent lamp (CFL) light source, the α-alkylation of aldehyde 28 with bromonitrile 29 generated chiral aldehyde 30 in excellent yields and excellent enantioselectivity. Subsequent reduction and cyclization afforded lactone 31. The synthesis of (−)-bursehernin was achieved by a highly stereoselective alkylation between 31 and bromide 32. In 2017, Soorukram and coworkers reported the asymmetric synthesis of ent-fragransin C1 (Scheme 6) [61]. Ketone 36 was produced by the nucleophilic addition of the aryllithium species generated from 35 to chiral Weinreb amide 34. The following stereoselective reduction led to the formation of alcohol 37. After hydroxyl protection, double bond oxidative cleavage and nucleophilic addition from aryllithium 39, compound 40 was furnished in good diastereoselectivity.Followed by the deprotection and cyclization treatments, the tetrahydrofuran ring in 41 was established. Finally, the synthesis of ent-fragransin C1 was accomplished through debenzylation under hydrogenation conditions.

Advances in Synthesis of Dibenzocyclooctadiene Serivatives
Dibenzocyclooctadiene derivative lignans feature a particular eight-membered ring containing

Advances in Synthesis of Dibenzocyclooctadiene Serivatives
Dibenzocyclooctadiene derivative lignans feature a particular eight-membered ring containing a chiral biaryl axis. Members of this subgroup possess various substitution patterns with two aryl rings and different stereocenters on the aliphatic bridge.
In 2010, an interesting Ni-catalyzed enantioselective Ullmann coupling of bis-ortho-substituted arylhalides was developed and applied to the asymmetric synthesis of (+)-isoschizandrin by Lin and coworkers (Scheme 9) [65]. With the application of chiral ligand 56, the Ni-catalyzed enantioselective Ullmann coupling of bromide 51 gave the axial chiral biaryl dial 52 with acceptable enantioselectivity. Aldehyde 55 was prepared after monoprotection, Wittig reaction and deprotection operations. The synthesis of (+)-isoschizandrin was accomplished according to Molander's cyclization protocol [66].
In 2010, an interesting Ni-catalyzed enantioselective Ullmann coupling of bis-ortho-substituted arylhalides was developed and applied to the asymmetric synthesis of (+)-isoschizandrin by Lin and coworkers (Scheme 9) [65]. With the application of chiral ligand 56, the Ni-catalyzed enantioselective Ullmann coupling of bromide 51 gave the axial chiral biaryl dial 52 with acceptable enantioselectivity. Aldehyde 55 was prepared after monoprotection, Wittig reaction and deprotection operations. The synthesis of (+)-isoschizandrin was accomplished according to Molander's cyclization protocol [66],.
In 2013, the RajanBabu group reported a general synthetic approach to multiple dibenzocyclooctadienes lignans via an interesting borostannylative cyclization (Scheme 11) [69].
In the presence of PdCl 2 (PPh 3 ) 2 and [B-Sn] reagent 70, chiral diynyl precursor 62 was converted into dibenzocyclooctadiene 64 through a borostannylative cyclization and a subsequent acidification process [70]. The Subsequent hydrogenation afforded 65 as the major product. After the deprotection and oxidation, the general intermediate 66 was prepared. The synthesis of (−)-ananolignan C was achieved through two successive diastereoselective reductions of 66. Meanwhile, the synthesis of (−)-ananolignan B was accomplished from the treatment of 66 with LiAl(O t Bu)3H and subsequent acetylation. The stereoselective hydrogenation of (−)-ananolignan B led to the formation of (−)-ananolignan D. The following configuration inversion of the hydroxyl group and actylation led to the synthesis of (−)-ananolignan F. In addition, (−)-interiotherin C can also be formed through the esterification of 69 and angeloyl chloride 71. Scheme 12. Synthesis of another three dibenzocyclooctadienes lignans. Adapted from RajanBabu et al., [69].
Synthesis of other three lignans was reported by RajanBabu and coworkers in the same paper (Scheme 12) [69]. Oxidative cleavage of the right-bottom double bond of 64 was applied for the formation of ketone 72. Diol 74 was obtained from the debenzylation and methyllithium 1,2-addition of 72. After hydroxyl oxidation, diastereoselective reduction and benzoyl protection steps, compound 76 was obtained. Starting from 76, synthesis of schizanrin F was achieved by TBS deprotection, oxidation, diastereoselective reduction and acetylation process. Starting from diol 74 again, compound 78 can be prepared by TBS deprotection, oxidation and double diastereoselective reduction. Finally, the synthesis of kadasuralignan B and tiegusanlin D was accomplished through acetylation and benzoylation of 78, respectively. Scheme 11. Synthesis of five dibenzocyclooctadienes lignans. Adapted from RajanBabu et al. [69].
The Subsequent hydrogenation afforded 65 as the major product. After the deprotection and oxidation, the general intermediate 66 was prepared. The synthesis of (−)-ananolignan C was achieved through two successive diastereoselective reductions of 66. Meanwhile, the synthesis of (−)-ananolignan B was accomplished from the treatment of 66 with LiAl(O t Bu) 3 H and subsequent acetylation. The stereoselective hydrogenation of (−)-ananolignan B led to the formation of (−)-ananolignan D. The following configuration inversion of the hydroxyl group and actylation led to the synthesis of (−)-ananolignan F. In addition, (−)-interiotherin C can also be formed through the esterification of 69 and angeloyl chloride 71.
Synthesis of other three lignans was reported by RajanBabu and coworkers in the same paper (Scheme 12) [69]. Oxidative cleavage of the right-bottom double bond of 64 was applied for the formation of ketone 72. Diol 74 was obtained from the debenzylation and methyllithium 1,2-addition of 72. After hydroxyl oxidation, diastereoselective reduction and benzoyl protection steps, compound 76 was obtained. Starting from 76, synthesis of schizanrin F was achieved by TBS deprotection, oxidation, diastereoselective reduction and acetylation process. Starting from diol 74 again, compound 78 can be prepared by TBS deprotection, oxidation and double diastereoselective reduction. Finally, the synthesis of kadasuralignan B and tiegusanlin D was accomplished through acetylation and benzoylation of 78, respectively. The Subsequent hydrogenation afforded 65 as the major product. After the deprotection and oxidation, the general intermediate 66 was prepared. The synthesis of (−)-ananolignan C was achieved through two successive diastereoselective reductions of 66. Meanwhile, the synthesis of (−)-ananolignan B was accomplished from the treatment of 66 with LiAl(O t Bu)3H and subsequent acetylation. The stereoselective hydrogenation of (−)-ananolignan B led to the formation of (−)-ananolignan D. The following configuration inversion of the hydroxyl group and actylation led to the synthesis of (−)-ananolignan F. In addition, (−)-interiotherin C can also be formed through the esterification of 69 and angeloyl chloride 71. Scheme 12. Synthesis of another three dibenzocyclooctadienes lignans. Adapted from RajanBabu et al., [69].
Synthesis of other three lignans was reported by RajanBabu and coworkers in the same paper (Scheme 12) [69]. Oxidative cleavage of the right-bottom double bond of 64 was applied for the formation of ketone 72. Diol 74 was obtained from the debenzylation and methyllithium Scheme 12. Synthesis of another three dibenzocyclooctadienes lignans. Adapted from RajanBabu et al. [69]. In 2018, a mild and asymmetric synthetic route to (−)-gymnothelignan L was developed by She and coworkers through a Suzuki-Miyaura coupling and a bioinspired desymmetric transannular Friedel-Crafts cyclization strategy (Scheme 13) [71]. Iodide 80 was obtained from iodination of compound 79. The Suzuki-Miyaura coupling of 80 and arylboronic acid 84 formed biphenyl compound 81, which was transformed into 82 using DIBAL-H as the reducing agent. Under acidic conditions, a bioinspired desymmetric transannular Friedel-Crafts cyclization of 82 occurred readily, generating 83. After removal of the benzyl protecting group, the synthesis of (−)-gymnothelignan L was completed. At almost the same time, a similar strategy was applied in total synthesis (−)-gymnothelignan V by Soorukram and coworkers [72]. In 2018, a mild and asymmetric synthetic route to (−)-gymnothelignan L was developed by She and coworkers through a Suzuki-Miyaura coupling and a bioinspired desymmetric transannular Friedel-Crafts cyclization strategy (Scheme 13) [71]. Iodide 80 was obtained from iodination of compound 79. The Suzuki-Miyaura coupling of 80 and arylboronic acid 84 formed biphenyl compound 81, which was transformed into 82 using DIBAL-H as the reducing agent. Under acidic conditions, a bioinspired desymmetric transannular Friedel-Crafts cyclization of 82 occurred readily, generating 83. After removal of the benzyl protecting group, the synthesis of (−)-gymnothelignan L was completed. At almost the same time, a similar strategy was applied in total synthesis (−)-gymnothelignan V by Soorukram and coworkers [72].

Advances in the Synthesis of Arylnaphthalene Derivatives
In the literature, the arylnaphthalene derivative lignan subgroup includes arylnaphthalenes and aryltetralins. Structurally, these lignans have a substituted naphthalene core. It should be mentioned that, due to their excellent biological characters, several clinically used antitumor drugs are derived from the well-known member, podophyllotoxin, and its glycosides [49].

Advances in the Synthesis of Arylnaphthalene Derivatives
In the literature, the arylnaphthalene derivative lignan subgroup includes arylnaphthalenes and aryltetralins. Structurally, these lignans have a substituted naphthalene core. It should be mentioned that, due to their excellent biological characters, several clinically used antitumor drugs are derived from the well-known member, podophyllotoxin, and its glycosides [49].

Advances in the Synthesis of Arylnaphthalene Derivatives
In the literature, the arylnaphthalene derivative lignan subgroup includes arylnaphthalenes and aryltetralins. Structurally, these lignans have a substituted naphthalene core. It should be mentioned that, due to their excellent biological characters, several clinically used antitumor drugs are derived from the well-known member, podophyllotoxin, and its glycosides [49].  [74,75], 91 was furnished. The synthesis of (−)-plicatic acid was completed following hydration and global debenzylation.
The same year, Peng and coworkers also reported the total synthesis of (±)-cyclogalgravin and (±)-galbulin (Scheme 18) [78]. Cyclic acetal 108 was obtained from Ueno-Stork radical cyclization of 107. Diol 110 was prepared by an oxidation, methylation and reduction process. Subsequent selective hydroxyl protection, dehydroxylation, deprotection and oxidation led to the generation of aldehyde 111. Next an intramolecular Friedel-Crafts reaction was applied for the synthesis of (±)-cyclogalgravin. The synthesis of (±)-galbulin was readily achieved by the stereoselective hydrogenation of (±)-cyclogalgravin.
In 2013, Argade and coworkers reported a novel strategy to construct arylnaphthalene frameworks via Pd-promoted [2 + 2 + 2] cyclization (Scheme 19), which enabled the synthesis of justicidin B and retrojusticiding B [79]. Through a Pd-promoted [2 + 2 + 2] cyclization process, aryne precursor 112 was connected with diene 113, generating arylnaphthalene 114. After the regioselective hydrolysis of the ester group, the synthesis of justicidin B was achieved through a chemoselective reduction of the acid group using BH3 . SMe2 and subsequent lactonization. Meanwhile, the synthesis of retrojusticidin B was achieved through the reduction of 115 and subsequent lactonization. The resulting 105 was submitted to a skeletal rearrangement, affording arylnaphthalene 106. The synthesis of sacidumlignan A was achieved after benzyl deprotection.
The same year, Peng and coworkers also reported the total synthesis of (±)-cyclogalgravin and (±)-galbulin (Scheme 18) [78]. Cyclic acetal 108 was obtained from Ueno-Stork radical cyclization of 107. Diol 110 was prepared by an oxidation, methylation and reduction process. Subsequent selective hydroxyl protection, dehydroxylation, deprotection and oxidation led to the generation of aldehyde 111. Next an intramolecular Friedel-Crafts reaction was applied for the synthesis of (±)-cyclogalgravin. The synthesis of (±)-galbulin was readily achieved by the stereoselective hydrogenation of (±)-cyclogalgravin.
In 2013, Argade and coworkers reported a novel strategy to construct arylnaphthalene frameworks via Pd-promoted [2 + 2 + 2] cyclization (Scheme 19), which enabled the synthesis of justicidin B and retrojusticiding B [79]. Through a Pd-promoted [2 + 2 + 2] cyclization process, aryne precursor 112 was connected with diene 113, generating arylnaphthalene 114. After the regioselective hydrolysis of the ester group, the synthesis of justicidin B was achieved through a chemoselective reduction of the acid group using BH 3 ·SMe 2 and subsequent lactonization. Meanwhile, the synthesis of retrojusticidin B was achieved through the reduction of 115 and subsequent lactonization. Shia and coworkers reported in 2015 the synthesis of three arylnaphthalene derivative lignans using a Mn(III)-mediated free radical cyclization cascade (Scheme 20) [80]. Knoevenagel condensation of α-cyano ester 116 with aldehyde 117 and subsequent reduction was applied for the generation of α-cyano ester 118. The following oxidative free radical cyclization cascade enabled by Mn(OAc)3 afforded access to compound 119. The synthesis of retrojusticidin B was accomplished after decyanation and aromatization operations. Using the same strategy, the synthesis of justicidin E and helioxanthin was completed. Scheme 21. Synthesis of arylnaphthalene lignans. Adapted from Narender et al. [81]. Shia and coworkers reported in 2015 the synthesis of three arylnaphthalene derivative lignans using a Mn(III)-mediated free radical cyclization cascade (Scheme 20) [80]. Knoevenagel condensation of α-cyano ester 116 with aldehyde 117 and subsequent reduction was applied for the generation of α-cyano ester 118. The following oxidative free radical cyclization cascade enabled by Mn(OAc) 3 afforded access to compound 119. The synthesis of retrojusticidin B was accomplished after decyanation and aromatization operations. Using the same strategy, the synthesis of justicidin E and helioxanthin was completed. Shia and coworkers reported in 2015 the synthesis of three arylnaphthalene derivative lignans using a Mn(III)-mediated free radical cyclization cascade (Scheme 20) [80]. Knoevenagel condensation of α-cyano ester 116 with aldehyde 117 and subsequent reduction was applied for the generation of α-cyano ester 118. The following oxidative free radical cyclization cascade enabled by Mn(OAc)3 afforded access to compound 119. The synthesis of retrojusticidin B was accomplished after decyanation and aromatization operations. Using the same strategy, the synthesis of justicidin E and helioxanthin was completed. In 2015, Narender and coworkers reported an interesting Ag-promoted radical addition/ cyclization process for the construction of highly substituted α-naphthol skeletons (Scheme 21) and the synthesis of three arylnaphthalene lignans [81]. Through the Ag-promoted radical addition/cyclization between ketoester 120 and aryl propiolate 121, polysubstituted arynaphthol 122 was readily prepared. The synthesis of diphyllin was finished under known reductive-lactonization conditions [82]. The synthesis of justicidin A was then achieved through methylation of diphyllin. The synthesis of taiwanin E was also accomplished. using a Mn(III)-mediated free radical cyclization cascade (Scheme 20) [80]. Knoevenagel condensation of α-cyano ester 116 with aldehyde 117 and subsequent reduction was applied for the generation of α-cyano ester 118. The following oxidative free radical cyclization cascade enabled by Mn(OAc)3 afforded access to compound 119. The synthesis of retrojusticidin B was accomplished after decyanation and aromatization operations. Using the same strategy, the synthesis of justicidin E and helioxanthin was completed. In 2015, Narender and coworkers reported an interesting Ag-promoted radical addition/cyclization process for the construction of highly substituted α-naphthol skeletons (Scheme 21) and the synthesis of three arylnaphthalene lignans [81]. Through the Ag-promoted radical addition/cyclization between ketoester 120 and aryl propiolate 121, polysubstituted arynaphthol 122 was readily prepared. The synthesis of diphyllin was finished under known reductive-lactonization conditions [82]. The synthesis of justicidin A was then achieved through methylation of diphyllin. The synthesis of taiwanin E was also accomplished. In 2017 Ham and coworkers reported the synthesis of seven arylnaphthalene derivative lignans based on a strategy involving Hauser-Kraus annulation and Suzuki-Miyaura cross-coupling (Scheme 22) [83]. In the presence of LiHMDS, the Hauser-Kraus annulation between cyanophthalide 123 and γ-crotonolactone 124 and subsequent protection treatment gave arylnaphthalene 125. The synthesis of diphllin was finished by the subsequent Suzuki-Miyaura cross-coupling of 126 and potassium aryltrifluoroborate 127. Justicidin A was produced by the methylation of diphllin. The syntheses of taiwannin E, chinensinaphthol justicidin C, justicidin D and cilinaphthalide B were also finished.
Czarnocki and coworkers reported in 2018 the total synthesis of (+)-epigalcatin using a photocyclization process under continuous flow UV irradiation conditions (Scheme 24) [85]. Diester 134 was condensed with aldehyde 120 at basic conditions, affording E,E-bisbenzylidenesuccinic acid 135. Through an amidation process, L-prolinol was introduced in amide 136 as a chiral auxiliary. Eight-membered ring compound 137 was prepared via following hydrolysis and macrolactonization. Under continuous flow irradiation with UV light, the photocyclization of 137 furnished 138 smoothly [86]. Remove of the chiral auxiliary, hydrogenation of the double bond and simultaneous reduction of formyl group led to the formation of ester 139. The synthesis of (+)-epigalcatin was achieved through subsequent reductive transformations of the methyl ester of 139 into a methyl group via three steps. Scheme 23. Synthesis of (−)-podophyllotoxin and three natural analogues. Adapted from Hajra et al. [84].
Czarnocki and coworkers reported in 2018 the total synthesis of (+)-epigalcatin using a photocyclization process under continuous flow UV irradiation conditions (Scheme 24) [85]. Diester 134 was condensed with aldehyde 120 at basic conditions, affording E,E-bisbenzylidenesuccinic acid 135. Through an amidation process, L-prolinol was introduced in amide 136 as a chiral auxiliary. Eight-membered ring compound 137 was prepared via following hydrolysis and macrolactonization. Under continuous flow irradiation with UV light, the photocyclization of 137 furnished 138 smoothly [86]. Remove of the chiral auxiliary, hydrogenation of the double bond and simultaneous reduction of formyl group led to the formation of ester 139. The synthesis of (+)-epigalcatin was achieved through subsequent reductive transformations of the methyl ester of 139 into a methyl group via three steps. Scheme 23. Synthesis of (−)-podophyllotoxin and three natural analogues. Adapted from Hajra et al., [84].
The Ni-catalyzed cyclization/cross-coupling has been verified as a suitable strategy for not only the synthesis of multiple acyclic lignan derivatives (Scheme 8) but also the synthesis of (±)-dimethylretrodendrin and (±)-collinusin (Scheme 26) by Giri and coworker [64]. Lactone 49 was obtanied from the Ni-catalyzed cyclization/cross-coupling process (Scheme 8). The stereoselective aldol reaction between 49 and aldehyde 117 and following intramolecular Friedel-Crafts reaction led to the formation of (±)-dimethylretrodendrin. In the presence of 153, the Ni-catalyzed cyclization/cross-coupling of 46 and 151 and following oxidation gave lactone 152. The synthesis of (±)-collinusin was completed by subsequent intramolecular nucleophilic addition and dehydration. Scheme 27. Synthesis of sevanol. Adapted from Belozerova et al. [91].
In 2018, Belozerova and coworkers reported the synthesis of sevanol via an oxidative dimerization strategy (Scheme 27) [91]. Chiral ester 156 was prepared by esterification of acid 154 and chiral alcohol 155. After the removal of two MOM protecting groups of 156, compound 157 was submitted to FeCl3-promoted oxidative dimerization, affording sevanol after the hydrolysis of all three ester groups.
Aria and coworkers reported total synthesis of (±)-isolariciresinol using a tandem Michael-aldol reaction in 2018 (Scheme 28) [92]. Alcohol 160 was obtained as a diastereomeric mixture from the tandem Michael-aldol reaction of dithiane 158, lactone 124 and aldehyde 159 under basic conditions. After the cleavage of the dithiane substituent and TBS, the following cyclization furnished 162 as the major product.
In the presence of 153, the Ni-catalyzed cyclization/cross-coupling of 46 and 151 and following oxidation gave lactone 152. The synthesis of (±)-collinusin was completed by subsequent intramolecular nucleophilic addition and dehydration.
In 2018, Belozerova and coworkers reported the synthesis of sevanol via an oxidative dimerization strategy (Scheme 27) [91]. Chiral ester 156 was prepared by esterification of acid 154 and chiral alcohol 155. After the removal of two MOM protecting groups of 156, compound 157 was submitted to FeCl 3 -promoted oxidative dimerization, affording sevanol after the hydrolysis of all three ester groups. In the presence of 153, the Ni-catalyzed cyclization/cross-coupling of 46 and 151 and following oxidation gave lactone 152. The synthesis of (±)-collinusin was completed by subsequent intramolecular nucleophilic addition and dehydration. In 2018, Belozerova and coworkers reported the synthesis of sevanol via an oxidative dimerization strategy (Scheme 27) [91]. Chiral ester 156 was prepared by esterification of acid 154 and chiral alcohol 155. After the removal of two MOM protecting groups of 156, compound 157 was submitted to FeCl3-promoted oxidative dimerization, affording sevanol after the hydrolysis of all three ester groups.
Aria and coworkers reported total synthesis of (±)-isolariciresinol using a tandem Michael-aldol reaction in 2018 (Scheme 28) [92]. Alcohol 160 was obtained as a diastereomeric mixture from the tandem Michael-aldol reaction of dithiane 158, lactone 124 and aldehyde 159 under basic conditions. After the cleavage of the dithiane substituent and TBS, the following cyclization furnished 162 as the major product. Aria and coworkers reported total synthesis of (±)-isolariciresinol using a tandem Michael-aldol reaction in 2018 (Scheme 28) [92]. Alcohol 160 was obtained as a diastereomeric mixture from the tandem Michael-aldol reaction of dithiane 158, lactone 124 and aldehyde 159 under basic conditions. After the cleavage of the dithiane substituent and TBS, the following cyclization furnished 162 as the major product.
Ester 163 was prepared from methanolysis of the lactone ring and TBS protection operations. The synthesis of (±)-isolariciresinol was achieved through the subsequent reduction and deprotection treatments. Ester 163 was prepared from methanolysis of the lactone ring and TBS protection operations. The synthesis of (±)-isolariciresinol was achieved through the subsequent reduction and deprotection treatments.
Barker and coworkers reported in 2017 the first total synthesis of (±)-ovafolinins A and B through the acyl-Claisen rearrangement developed in their lab and a cascade cyclization enabled by bulky protecting groups (Scheme 29) [93]. Notably, (±)-ovafolinins A and B have polycyclic skeletons rarely found in lignans. The acyl-Claisen rearrangement between acid chloride 165 and allylic morpholine 166 afforded amide 167 as a single diastereoisomer and in excellent yields. Alcohol 168 was prepared by hydration and reduction. Phenol 169 was introduced through a Mitsunobu reaction. Alcohol 170 was obtained after the oxidative cleavage of the double bond and following reduction. The subsequent t-butyldiphenylsilyl (TBDPS) protection, debenzylation and oxidation led to the formation of compounds 171 and 172 through a cascade cyclization enabled by the TBDPS group. The synthesis of (±)-ovafolinins A and B was achieved after subsequent hydrogenation and deprotection.
Barker and coworkers reported in 2017 the first total synthesis of (±)-ovafolinins A and B through the acyl-Claisen rearrangement developed in their lab and a cascade cyclization enabled by bulky protecting groups (Scheme 29) [93]. Notably, (±)-ovafolinins A and B have polycyclic skeletons rarely found in lignans. The acyl-Claisen rearrangement between acid chloride 165 and allylic morpholine 166 afforded amide 167 as a single diastereoisomer and in excellent yields. Alcohol 168 was prepared by hydration and reduction. Phenol 169 was introduced through a Mitsunobu reaction. Alcohol 170 was obtained after the oxidative cleavage of the double bond and following reduction. The subsequent t-butyldiphenylsilyl (TBDPS) protection, debenzylation and oxidation led to the formation of compounds 171 and 172 through a cascade cyclization enabled by the TBDPS group. The synthesis of (±)-ovafolinins A and B was achieved after subsequent hydrogenation and deprotection. Scheme 28. Synthesis of (±)-isolariciresinol. Adapted from Aria et al. [92].
Ester 163 was prepared from methanolysis of the lactone ring and TBS protection operations. The synthesis of (±)-isolariciresinol was achieved through the subsequent reduction and deprotection treatments. Barker and coworkers reported in 2017 the first total synthesis of (±)-ovafolinins A and B through the acyl-Claisen rearrangement developed in their lab and a cascade cyclization enabled by bulky protecting groups (Scheme 29) [93]. Notably, (±)-ovafolinins A and B have polycyclic skeletons rarely found in lignans. The acyl-Claisen rearrangement between acid chloride 165 and allylic morpholine 166 afforded amide 167 as a single diastereoisomer and in excellent yields. Alcohol 168 was prepared by hydration and reduction. Phenol 169 was introduced through a Mitsunobu reaction. Alcohol 170 was obtained after the oxidative cleavage of the double bond and following reduction. The subsequent t-butyldiphenylsilyl (TBDPS) protection, debenzylation and oxidation led to the formation of compounds 171 and 172 through a cascade cyclization enabled by the TBDPS group. The synthesis of (±)-ovafolinins A and B was achieved after subsequent hydrogenation and deprotection. Scheme 29. Synthesis of (±)-ovafolinins A and B. Adapted from Barker et al. [93].
Taking advantage of the above achievement, Barker and coworkers reported the first asymmetric total synthesis of (+)-ovafolinins A and B (Scheme 30). Starting from acid chloride 165 again, chiral amide 174 was first prepared. Stereoselective allylation and dihydroxylation of the double bond led to the generation of lactone 176. After the reduction and oxidative cleavage of the 1,2-diol motif, lactone 177 was formed by Fétizon oxidation. The introduction of the benzyloxymethyl group and the following reduction led to the formation of 179. After TBDPS protection, Mitsunobu reaction with 181 and debenzylation, alcohol 180 was obtained. Chiral 172 was formed through a cascade cyclization under oxidative conditions. Finally, the first asymmetric synthesis of (+)-ovafolinins A and B was achieved after deprotection operations. Based on optical rotation comparisons between the synthetic samples and the natural compounds, Barker's group demonstrated that natural ovafolinins A and B were both isolated in scalemic mixtures. And the original stereochemical assignment of natural ovafolinin B was corrected. Taking advantage of the above achievement, Barker and coworkers reported the first asymmetric total synthesis of (+)-ovafolinins A and B (Scheme 30). Starting from acid chloride 165 again, chiral amide 174 was first prepared. Stereoselective allylation and dihydroxylation of the double bond led to the generation of lactone 176. After the reduction and oxidative cleavage of the 1,2-diol motif, lactone 177 was formed by Fétizon oxidation. The introduction of the benzyloxymethyl group and the following reduction led to the formation of 179. After TBDPS protection, Mitsunobu reaction with 181 and debenzylation, alcohol 180 was obtained. Chiral 172 was formed through a cascade cyclization under oxidative conditions. Finally, the first asymmetric synthesis of (+)-ovafolinins A and B was achieved after deprotection operations. Based on optical rotation comparisons between the synthetic samples and the natural compounds, Barker's group demonstrated that natural ovafolinins A and B were both isolated in scalemic mixtures. And the original stereochemical assignment of natural ovafolinin B was corrected.  Recently, we developed a new asymmetric synthetic route to (+)-ovafolinins A and B (Scheme 31) [94]. Starting from benzyl syringaldehyde 182, bromide 183 was prepared after reduction and bromination. The diastereoselective alkylation of (S)-Taniguchi lactone 184 introduced two adjacent Scheme 30. Asymmetric synthesis of (+)-ovafolinins A and B. Adapted from Barker et al. [93].
Recently, we developed a new asymmetric synthetic route to (+)-ovafolinins A and B (Scheme 31) [94]. Starting from benzyl syringaldehyde 182, bromide 183 was prepared after reduction and bromination. The diastereoselective alkylation of (S)-Taniguchi lactone 184 introduced two adjacent stereogenic centers in excellent stereoselectivity, affording lactone 185. Subsequent double benzyl protection opened the lactone ring and generated ester 186. Compound 189 was obtained from the reduction and connected with 188 through Mitsunobu reaction. After oxidative cleavage of double bond, aldehyde 190 was obtained. The polycyclic skeleton in 191 was constructed through a double Friedel-Crafts reaction of 190. The synthesis of (+)-ovafolinin B was accomplished through the global debenzylation. And the synthesis of (+)-ovafolinin A was achieved through subsequent benzylic oxidation cyclization enabled by Cu(OAc) 2 . Taking advantage of the above achievement, Barker and coworkers reported the first asymmetric total synthesis of (+)-ovafolinins A and B (Scheme 30). Starting from acid chloride 165 again, chiral amide 174 was first prepared. Stereoselective allylation and dihydroxylation of the double bond led to the generation of lactone 176. After the reduction and oxidative cleavage of the 1,2-diol motif, lactone 177 was formed by Fétizon oxidation. The introduction of the benzyloxymethyl group and the following reduction led to the formation of 179. After TBDPS protection, Mitsunobu reaction with 181 and debenzylation, alcohol 180 was obtained. Chiral 172 was formed through a cascade cyclization under oxidative conditions. Finally, the first asymmetric synthesis of (+)-ovafolinins A and B was achieved after deprotection operations. Based on optical rotation comparisons between the synthetic samples and the natural compounds, Barker's group demonstrated that natural ovafolinins A and B were both isolated in scalemic mixtures. And the original stereochemical assignment of natural ovafolinin B was corrected. Recently, we developed a new asymmetric synthetic route to (+)-ovafolinins A and B (Scheme 31) [94]. Starting from benzyl syringaldehyde 182, bromide 183 was prepared after reduction and bromination. The diastereoselective alkylation of (S)-Taniguchi lactone 184 introduced two adjacent Scheme 31. Asymmetric synthesis of (+)-ovafolinins A and B. Adapted from Hu et al. 2018 [94].

Conclusions
In this review, we have summarized the advances in the synthesis of lignan natural products reported from 2008 to 2018. Synthetic progress in three areas was outlined: acyclic lignan derivatives, dibenzocycooctadiene derivative and arylnaphthalene derivatives. Novel synthetic methodologies had been applied for construction of challenging structures existing in lignan natural products. As the result, many elegant synthetic approaches to lignans had been developed. However, as a long term program, the promising biological features and development of concise synthetic approaches to lignan natural products and their analogues are continuing to attract more and more interest from the pharmaceutical industry and the organic synthesis community.