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Review

Advances in the Synthesis of Lignan Natural Products

by
Xianhe Fang
and
Xiangdong Hu
*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi’an 710127, China
*
Author to whom correspondence should be addressed.
Molecules 2018, 23(12), 3385; https://doi.org/10.3390/molecules23123385
Submission received: 7 November 2018 / Revised: 17 December 2018 / Accepted: 18 December 2018 / Published: 19 December 2018
(This article belongs to the Special Issue Lignans)
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Abstract

:
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.

1. Introduction

Lignans are a family of secondary metabolites widely distributed in plants and human food sources. The story of lignans can traced back to 1942, when Harworth introduced the term for the first time to describe this family [1]. It is known that lignans have remarkable ecological functions in plants, providing protection against herbivores and microorganisms [2,3,4,5,6,7]. The consumption of foods rich in lignans has potential to decrease of risk of cancers [8,9,10,11]. During its long research history, this family has exhibited attractive pharmacological activities [12,13,14,15,16,17,18,19], such as antibacterial [20], antiviral [21,22,23,24], antitumor [25,26,27], antiplatelet [28,29], phosphodiesterase inhibition [30,31], 5-lipoxygenase inhibition [32,33,34], HIV reverse transcription inhibition [35,36,37], cytotoxic [38], antioxidant [39], immunosuppressive [40] and antiasthmatic properties [31].
Lignan compounds have dimeric structures formed through a β,β′-linkage between two phenylpropane units with different degrees of oxidation on the side-chain and variable substitution patterns on the phenyl ring. Traditionally, lignans are divided into two classes: classical lignans and neolignans. It should be noted that the term lignan in the literature refers to classical lignans in most cases. Regarding the classification of classical lignans, four different types are reported. The first one arranged classical lignans into three subgroups: acyclic lignan derivatives, arylnaphthalene derivatives and dibenzocyclooctadiene derivatives [41]. The second type includes six subgroups: dibenzylbutanes, dibenzylbutyrolactones, arylnaphthalenes, dibenzocyclooctadienes, substituted tetrahydrofurans and 2,6-diarylfurofurans [9,14]. The third one is comprised of eight subgroups: furofurans, furans, dibenzylbutanes, dibenzylbutyrolactones, aryltetralins, arylnaphthalenes, dibenzocyclooctadienes and dibenzylbutyrolactols [8,42,43,44,45]. The fourth one includes seven subgroups of lignan scaffolds: cyclobutanes, tetrahydrofurans, furofurans, dibenzylbutanes, aryltetralins, cycloheptenes and dibenzocyclooctadienes [46].
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.

2. 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.
The synthesis of the acyclic lignan derivative (±)-paulownin (Scheme 1) was accomplished by Angle and coworkers in 2008 [52]. The key step is a formal [3 + 2]-cycloaddition between silyl ether 1 and aldehyde 2 in the presence of BF3OEt2 and 2,6-di-tert-butyl-4-methylphenol (DBMP), generating aryl tetrahydrofuran 3. After oxidation and removal of the protecting group, the resulting product 4 was connected with imidate 5, generating lactone 6. The synthesis of (±)-paulownin was finished through photocyclization under a medium-pressure Hanovia lamp [53].
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.
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.
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 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 t-butyldimethylsilyl (TBS) protecting groups, the synthesis of (±)-fragransin A2 and (±)-odoratisol was achieved. Through the same strategy, Jahn and coworkers completed the synthesis of (±)-galbelgin, (±)-grandisin, (±)-galbacin, (±)-veraguensin, and (±)-beilschmin B.
A Ni-catalyzed cyclization/cross-coupling strategy was developed and applied for the synthesis of (±)-kusunokinin, (±)-dimethylmetairesinol, (±)-bursehernin and (±)-yatein by Giri and coworkers in 2018 (Scheme 8) [64]. Ligand 48 was used for the Ni-catalyzed cyclization/cross-coupling between iodide 46 and aryl zinc reagent 47 followed by Jones oxidation, generating lactone 49 readily. Compound 49 was then connected with bromide 50 in a good diastereoselective manner, completing the synthesis of (±)-kusunokinin. The syntheses of (±)-dimethylmetairesinol, (±)-bursehernin and (±)-yatein were accomplished using the same protocol.

3. 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].
Based on a double organocuprate oxidation strategy, Spring and coworkers reported the total synthesis of (±)-deoxyschizandrin in 2012 (Scheme 10) [67]. Symmetrical 1,3-diene 58 was prepared by the homo-coupling of alkenyl iodide 57 through a mild metalation, magnesio-cuprate transmetalation and subsequent oxidation using 61 as the oxidant [68]. Subsequent hydrogenation afforded 59 as a mixture of two diastereoisomers. After iodination, the expected iodide 60 was obtained. The synthesis of (±)-deoxyschizandrin was completed by an intramolecular organocuprate oxidation process, including metalation, magnesio-cuprate transmetalation and oxidation with 61.
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 PdCl2(PPh3)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(OtBu)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.
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.
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].

4. 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].
In 2009, Deng and coworkers reported an asymmetric total synthesis of (−)-plicatic acid (Scheme 14) [73]. The enantioselective epoxidation of trisubstitued olefin 85 was applied for the introduction of the original chiral stereocenters. Excellent enantioselectivity was obtained from the application of chiral (S,S)-TADOOH 86. Intramolecular Friedel-Crafts reaction of 87 formed the six-membered ring of 88 effectively. Subsequent silylation and intramolecular Barbier reaction under SmI2/NiI2 conditions afforded a diastereoselective access to diol 90. After Fleming-Tamao- Kumada oxidation [74,75], 91 was furnished. The synthesis of (−)-plicatic acid was completed following hydration and global debenzylation.
The stereoselective aza-Claisen rearrangement strategy developed by Barker and coworkers was not only effective for asymmetric synthesis of (+)-galbelgin (Scheme 2), but also for asymmetric synthesis of (−)-cyclogalgravin, and (−)-pycnanthulignenes A and B (Scheme 15) [54]. Through the aza-Claisen rearrangement strategy, alcohol 9 (Scheme 2) was prepared and submitted to hydroxyl protection and double bond oxidation, generating aldehyde 92. The addition from aryllithium 11 gave compound 93. The synthesis of (−)-cyclogalgravin was achieved through cyclization. Employing same protocol, Barker’s group also finished an asymmetric synthesis of (−)-pycnanthulignenes A and B.
In 2012, Hong and coworkers reported the enantioselective total synthesis of (+)-galbulin using an organocatalytic asymmetric Michael-Michael-aldol cascade (Scheme 16) [76]. Under the promotion of Jørgensen-Hayashi catalyst 96, ketoaldehyde 97 was readily prepared from the asymmetric Michael-Michael-aldol cascade of 94 and 95. Compound 99 was produced by reduction, oxidation and epoxidation treatments of 97. Following epoxide ring-opening and aromatization, compound 101 was obtained. The synthesis of (+)-galbulin was finally accomplished through selective methylation and dehydroxylation processes.
Peng and coworkers reported in 2013 the synthesis of sacidumlignan A employing Ueno-Stork radical cyclization and skeletal rearrangement strategy (Scheme 17) [77]. Alcohol 103 was connected with ethyl propenyl ether in the presence of bromine, readily generating 104. The Ueno-Stork radical cyclization of 104 was enabled by Bu3SnH and AIBN.
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 BH3·SMe2 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.
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.
Hajra and coworkers reported the enantioselective total synthesis of (−)-podophyllotoxin and natural analogues in 2017 (Scheme 23) [84]. The L-proline-catalyzed asymmetric cross aldol reaction between 6-bromopiperonal 128 and aldehyde 129 introduced original stereocenters with excellent diastereoselectivity and excellent stereoselectivity at gram scale. Lactone 130 was obtained after reduction, lactonization and TBS protection operations. Z-Benzylidene lactone 132 was prepared through an aldol reaction between 130 and aldehyde 131, and subsequent elimination. The intramolecular Heck reaction between trisubstituted Z-alkene motif and the bulky bromoarene motif in 132 happened smoothly, generating compound 133 in good yields. Notably, under different hydrogenation conditions, three stereoselective pathways of 133 led to the synthesis of (−)-podophyllotoxin, (−)-picropodophyllin, (+)-isopicropodophyllin, respectively. Meanwhile, the synthesis of (+)-isopicropodophyllone was achieved through the oxidation of (+)-isopicropodophyllin. The synthesis of (−)-isopodophyllotoxin can be accomplished through a TBS deprotection and reductive Heck reaction process from 132.
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.
Peng and coworkers reported the total synthesis of (−)-podophyllotoxin and four natural analogues using a Ni-catalyzed reductive cascade in 2018 (Scheme 25) [87]. The asymmetric conjugated addition of 141 to chiral α,β-unsaturated amide 140 introduced the first stereocenter. Enol ether 144 was obtained after subsequent reduction, oxidation, acetal formation and elimination. β-Bromoacetal 145 was produced using 2,4,4,6-tetrabromo-2,5-cyclohexadienone (TBCD). With the application of the Ni-catalyzed reductive cascade [88], both 146 and 147 were produced in moderate yields. After the hydration and oxidation of 146, the synthesis of (+)-deoxypicropodophyllin was accomplished. (+)-Isodeocypodophyllotoxin can be synthesized from the epimerization at C9a of (+)-deoxypicropodophyllin under basic conditions. With the radical bromination under visible-light irradiation [89], and further oxidation treatments, the synthesis of (−)-epipodophyllotoxin and (−)-podophyllotoxone was achieved in a stepwise fashion. The stereoselective reduction of (−)-podophyllotoxone using l-Selectride gave (−)-podophyllotoxin. Additionally, compound 147 can be transformed into Meyer’s 150 intermediate for synthesis of (−)-picropodophyllin and (−)-picropodophyllone through three regular operations [90].
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.
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.
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.
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 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.

5. 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.

Funding

This research was funded by National Natural Science Foundation of China (21772153), and the Key Science and Technology Innovation Team of Shaanxi Province (2017KCT-37).

Conflicts of Interest

The authors declare no conflict of interest.

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Molecules 23 03385 sch001 550
Scheme 1. Synthesis of (±)-paulownin. Adapted from Angle et al. [52].
Scheme 1. Synthesis of (±)-paulownin. Adapted from Angle et al. [52].
Molecules 23 03385 sch001
Molecules 23 03385 sch002 550
Scheme 2. Synthesis of (+)-galbelgin. Adapted from Barker et al. [54].
Scheme 2. Synthesis of (+)-galbelgin. Adapted from Barker et al. [54].
Molecules 23 03385 sch002
Molecules 23 03385 sch003 550
Scheme 3. Synthesis of beilschmin A and gymnothelignan N. Adapted from She et al. [56].
Scheme 3. Synthesis of beilschmin A and gymnothelignan N. Adapted from She et al. [56].
Molecules 23 03385 sch003
Molecules 23 03385 sch004 550
Scheme 4. Bioinspired synthesis of (±)-tanegool and (±)-pinoresinol. Adapted from Lump et al. [46].
Scheme 4. Bioinspired synthesis of (±)-tanegool and (±)-pinoresinol. Adapted from Lump et al. [46].
Molecules 23 03385 sch004
Molecules 23 03385 sch005 550
Scheme 5. Asymmetric synthesis of (−)-bursehernin. Adapted from MacMillian et al. [60].
Scheme 5. Asymmetric synthesis of (−)-bursehernin. Adapted from MacMillian et al. [60].
Molecules 23 03385 sch005
Molecules 23 03385 sch006 550
Scheme 6. Asymmetric synthesis of ent-fragransin C1. Adapted from Soorukram et al. [61].
Scheme 6. Asymmetric synthesis of ent-fragransin C1. Adapted from Soorukram et al. [61].
Molecules 23 03385 sch006
Molecules 23 03385 sch007 550
Scheme 7. Bioinspired synthesis of seven acyclic lignans. Adapted from Jahn et al. [63].
Scheme 7. Bioinspired synthesis of seven acyclic lignans. Adapted from Jahn et al. [63].
Molecules 23 03385 sch007
Molecules 23 03385 sch008 550
Scheme 8. Synthesis of four acyclic lignans. Adapted from Giri et al. [64].
Scheme 8. Synthesis of four acyclic lignans. Adapted from Giri et al. [64].
Molecules 23 03385 sch008
Molecules 23 03385 sch009 550
Scheme 9. Asymmetric synthesis of (+)-isoschizandrin. Adapted from Lin and Xu et al. [65].
Scheme 9. Asymmetric synthesis of (+)-isoschizandrin. Adapted from Lin and Xu et al. [65].
Molecules 23 03385 sch009
Molecules 23 03385 sch010 550
Scheme 10. Synthesis of (±)-deoxyschizandrin. Adapted from Spring et al. [67].
Scheme 10. Synthesis of (±)-deoxyschizandrin. Adapted from Spring et al. [67].
Molecules 23 03385 sch010
Molecules 23 03385 sch011 550
Scheme 11. Synthesis of five dibenzocyclooctadienes lignans. Adapted from RajanBabu et al. [69].
Scheme 11. Synthesis of five dibenzocyclooctadienes lignans. Adapted from RajanBabu et al. [69].
Molecules 23 03385 sch011
Molecules 23 03385 sch012 550
Scheme 12. Synthesis of another three dibenzocyclooctadienes lignans. Adapted from RajanBabu et al. [69].
Scheme 12. Synthesis of another three dibenzocyclooctadienes lignans. Adapted from RajanBabu et al. [69].
Molecules 23 03385 sch012
Molecules 23 03385 sch013 550
Scheme 13. Bioinspired asymmetric synthesis of (-)-gymnothelignan L. Adapted from She et al. [71].
Scheme 13. Bioinspired asymmetric synthesis of (-)-gymnothelignan L. Adapted from She et al. [71].
Molecules 23 03385 sch013
Molecules 23 03385 sch014 550
Scheme 14. Asymmetric synthesis of (−)-plicatic acid. Adapted from Deng et al. [73].
Scheme 14. Asymmetric synthesis of (−)-plicatic acid. Adapted from Deng et al. [73].
Molecules 23 03385 sch014
Molecules 23 03385 sch015 550
Scheme 15. Asymmetric synthesis of (−)-cyclogalgravin. Adapted from Barker et al. [54].
Scheme 15. Asymmetric synthesis of (−)-cyclogalgravin. Adapted from Barker et al. [54].
Molecules 23 03385 sch015
Molecules 23 03385 sch016 550
Scheme 16. Enantioselective synthesis of (+)-galbulin. Adapted from Hong et al. [76].
Scheme 16. Enantioselective synthesis of (+)-galbulin. Adapted from Hong et al. [76].
Molecules 23 03385 sch016
Molecules 23 03385 sch017 550
Scheme 17. Synthesis of sacidumlignan A. Adapted from Peng et al. [77].
Scheme 17. Synthesis of sacidumlignan A. Adapted from Peng et al. [77].
Molecules 23 03385 sch017
Molecules 23 03385 sch018 550
Scheme 18. Synthesis of (±)-cyclogalgravin and (±)-galbulin. Adapted from Peng et al. [78].
Scheme 18. Synthesis of (±)-cyclogalgravin and (±)-galbulin. Adapted from Peng et al. [78].
Molecules 23 03385 sch018
Molecules 23 03385 sch019 550
Scheme 19. Synthesis of justicidin B and retrojusticiding B. Adapted from Argade et al. [79].
Scheme 19. Synthesis of justicidin B and retrojusticiding B. Adapted from Argade et al. [79].
Molecules 23 03385 sch019
Molecules 23 03385 sch020 550
Scheme 20. Synthesis of arylnaphthalene derivative lignans. Adapted from Shia et al., 2015 [80].
Scheme 20. Synthesis of arylnaphthalene derivative lignans. Adapted from Shia et al., 2015 [80].
Molecules 23 03385 sch020
Molecules 23 03385 sch021 550
Scheme 21. Synthesis of arylnaphthalene lignans. Adapted from Narender et al. [81].
Scheme 21. Synthesis of arylnaphthalene lignans. Adapted from Narender et al. [81].
Molecules 23 03385 sch021
Molecules 23 03385 sch022 550
Scheme 22. Synthesis of seven arylnaphthalene lignans. Adapted from Ham et al. [83].
Scheme 22. Synthesis of seven arylnaphthalene lignans. Adapted from Ham et al. [83].
Molecules 23 03385 sch022
Molecules 23 03385 sch023 550
Scheme 23. Synthesis of (−)-podophyllotoxin and three natural analogues. Adapted from Hajra et al. [84].
Scheme 23. Synthesis of (−)-podophyllotoxin and three natural analogues. Adapted from Hajra et al. [84].
Molecules 23 03385 sch023
Molecules 23 03385 sch024 550
Scheme 24. Synthesis of (+)-epigalcatin. Adapted from Czarnocki et al. [85].
Scheme 24. Synthesis of (+)-epigalcatin. Adapted from Czarnocki et al. [85].
Molecules 23 03385 sch024
Molecules 23 03385 sch025 550
Scheme 25. Synthesis of (−)-podophyllotoxin and four natural analogues. Adapted from Peng et al. [87].
Scheme 25. Synthesis of (−)-podophyllotoxin and four natural analogues. Adapted from Peng et al. [87].
Molecules 23 03385 sch025
Molecules 23 03385 sch026 550
Scheme 26. Synthesis of (±)-dimethylretrodendrin and (±)-collinusin. Adapted from Giri et al. [64].
Scheme 26. Synthesis of (±)-dimethylretrodendrin and (±)-collinusin. Adapted from Giri et al. [64].
Molecules 23 03385 sch026
Molecules 23 03385 sch027 550
Scheme 27. Synthesis of sevanol. Adapted from Belozerova et al. [91].
Scheme 27. Synthesis of sevanol. Adapted from Belozerova et al. [91].
Molecules 23 03385 sch027
Molecules 23 03385 sch028 550
Scheme 28. Synthesis of (±)-isolariciresinol. Adapted from Aria et al. [92].
Scheme 28. Synthesis of (±)-isolariciresinol. Adapted from Aria et al. [92].
Molecules 23 03385 sch028
Molecules 23 03385 sch029 550
Scheme 29. Synthesis of (±)-ovafolinins A and B. Adapted from Barker et al. [93].
Scheme 29. Synthesis of (±)-ovafolinins A and B. Adapted from Barker et al. [93].
Molecules 23 03385 sch029
Molecules 23 03385 sch030 550
Scheme 30. Asymmetric synthesis of (+)-ovafolinins A and B. Adapted from Barker et al. [93].
Scheme 30. Asymmetric synthesis of (+)-ovafolinins A and B. Adapted from Barker et al. [93].
Molecules 23 03385 sch030
Molecules 23 03385 sch031 550
Scheme 31. Asymmetric synthesis of (+)-ovafolinins A and B. Adapted from Hu et al., 2018 [94].
Scheme 31. Asymmetric synthesis of (+)-ovafolinins A and B. Adapted from Hu et al., 2018 [94].
Molecules 23 03385 sch031

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MDPI and ACS Style

Fang, X.; Hu, X. Advances in the Synthesis of Lignan Natural Products. Molecules 2018, 23, 3385. https://doi.org/10.3390/molecules23123385

AMA Style

Fang X, Hu X. Advances in the Synthesis of Lignan Natural Products. Molecules. 2018; 23(12):3385. https://doi.org/10.3390/molecules23123385

Chicago/Turabian Style

Fang, Xianhe, and Xiangdong Hu. 2018. "Advances in the Synthesis of Lignan Natural Products" Molecules 23, no. 12: 3385. https://doi.org/10.3390/molecules23123385

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