Recent Advances in Polyphenol Research

Plant polyphenols are secondary metabolites that constitute one of the most common and widespread groups of natural products. They are crucial constituents of a large and diverse range of biological functions and processes, and provide many benefits to both plants and humans. Many polyphenols, from their structurally simplest representatives to their oligo/polymeric versions, are notably known as phytoestrogens, plant pigments, potent antioxidants, and protein interacting agents.

This sixth volume of the highly regarded Recent Advances in Polyphenol Research series is edited by Heidi Halbwirth, Karl Stich, Véronique Cheynier and Stéphane Quideau, and is a continuance of the series’ tradition of compiling a cornucopia of cutting-edge chapters, written by some of the leading experts in their respective fields of polyphenol sciences. Highlighted herein are some of the most recent and pertinent developments in polyphenol research, covering such major areas as:

• Chemistry and physicochemistry
• Biosynthesis, genetics & metabolic engineering
• Roles in plants and ecosystems
• Food, nutrition & health
• Applied polyphenols

This book is a distillation of the most current information, and as such, will surely prove an invaluable source for chemists, biochemists, plant scientists, pharmacognosists and pharmacologists, biologists, ecologists, food scientists and nutritionists.  

• Language: English
• Publisher: Wiley
• Release date: Jan 11, 2019
• ISBN: 9781119427919

Book preview

Contributors

Anna K.F. Albertson

Department of Chemistry, McGill University, Montreal, Québec, Canada

Andrew C. Allan

Plant & Food Research, University of Auckland, Auckland, New Zealand

Pierre‐Marie Allard

Bioactive Natural Products Unit, School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland

Serge Antonczak

Institute of Chemistry of Nice, University of Nice‐Sophia Antipolis, Nice, France

Chahinez Aouf

SPO SPIRAL, INRA Montpellier SupAgro, UMR 1083, Montpellier, France

Nicolas Barber‐Chamoux

Department of Cardiology, INSERM, UMR 766, Clermont‐Ferrand University Hospital, Clermont‐Ferrand, France

Guillaume Billerach

SPO SPIRAL, INRA Montpellier SupAgro, UMR 1083, Montpellier, France

Frédéric Bourgaud

Plant Advanced Technologies, Vandoeuvre, France

Sonam Chouhan

Natural Product Laboratory, Division of Biochemistry, Faculty of Basic Sciences, Sher‐e‐Kashmir University of Agricultural Sciences and Technology of Jammu, Jammu, India

Victor de Freitas

Faculty of Science, University of Porto, Porto, Portugal

Julien Diharce

Institute of Organic and Analytical Chemistry, University of Orléans, Orléans, France

Eric Dubreucq

SPO SPIRAL, INRA Montpellier SupAgro, UMR 1083, Montpellier, France

Léonor Duriot

Plant Advanced Technologies, Vandoeuvre, France

Richard V. Espley

Plant & Food Research, University of Auckland, Auckland, New Zealand

Hélène Fulcrand

SPO SPIRAL, INRA Montpellier SupAgro, UMR 1083, Montpellier, France

Carole Gavira

Plant Advanced Technologies, Vandoeuvre, France

Sanjay Guleria

Natural Product Laboratory, Division of Biochemistry, Faculty of Basic Sciences, Sher‐e‐Kashmir University of Agricultural Sciences and Technology of Jammu, Jammu, India

Alain Hehn

Agronomy and Environment Laboratory, INRA, University of Lorraine, Vandoeuvre, France

Dirk Hölscher

Max Planck Institute for Chemical Ecology, Jena; University of Kassel, Witzenhausen, Germany

Mattheos A.G. Koffas

Department of Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, USA

Miwa Kubo

Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan

Romain Larbat

Agronomy and Environment Laboratory, INRA, University of Lorraine, Vandoeuvre, France

Jean‐Philip Lumb

Department of Chemistry, McGill University, Montreal, Québec, Canada

Benoit Mignard

Plant Advanced Technologies, Vandoeuvre, France

Dragan Milenkovic

Human Nutrition Unit, INRA, UMR 1019, University of Clermont Auvergne, Clermont‐Ferrand, France

Laurent‐Emmanuel Monfoulet

Human Nutrition Unit, INRA, UMR 1019, University of Clermont Auvergne, Clermont‐Ferrand, France

Christine Morand

Human Nutrition Unit, INRA, UMR 1019, University of Clermont Auvergne, Clermont‐Ferrand, France

Ryosuke Munakata

Agronomy and Environment Laboratory, INRA, University of Lorraine, Vandoeuvre, France

Alexandre Olry

Agronomy and Environment Laboratory, INRA, University of Lorraine, Vandoeuvre, France

Emerson Ferreira Queiroz

Bioactive Natural Products Unit, School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland

Ludwig Ring

Biotechnology of Natural Products, Technical University Munich, Freising, Germany

Laurent Rouméas

SPO SPIRAL, INRA Montpellier SupAgro, UMR 1083, Montpellier, France

Claus Schneider

Department of Pharmacology, Vanderbilt University, Nashville, USA

Wilfried Schwab

Biotechnology of Natural Products, Technical University Munich, Freising, Germany

Kathy E. Schwinn

Plant & Food Research, Palmerston North, New Zealand

Kanika Sharma

Natural Product Laboratory, Division of Biochemistry, Faculty of Basic Sciences, Sher‐e‐Kashmir University of Agricultural Sciences and Technology of Jammu, Jammu, India

Chuankui Song

Biotechnology of Natural Products, Technical University Munich, Freising, Germany

Brenda S.J. Winkel

Department of Biological Sciences, Virginia Tech, Blacksburg, USA

Jean‐Luc Wolfender

Bioactive Natural Products Unit, School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland

Jian Zha

Department of Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, USA

Preface

Polyphenols are secondary metabolites that are widely distributed in the plant kingdom and characterized by a large diversity of chemical structures. As supported by the international academic society Groupe Polyphénols, which organizes the biennial International Conference on Polyphenols (ICP), the term polyphenol should be exclusively used for plant secondary metabolites derived from the phenylpropanoid and/or polyketide pathway(s), featuring more than one phenolic ring and being devoid of any nitrogen‐based functional group (www.groupepolyphenols.com/the‐society/why‐bother‐with‐polyphenols). Several thousand structures have been isolated and characterized from plants so far, ranging from quite simple phenolic molecules to highly polymerized compounds with molecular weights of more than 30 000 Da. As a result of the huge diversity of structures, polyphenols possess diverse physicochemical properties. Over the years, scientists from all over the world have been fascinated by these molecules, trying to shed light on their chemistry, properties and physiological relevance in plants, humans and ecosystems. In addition, there is increasing interest in the valorization of polyphenols obtained as natural by‐products from, for example, the lignocellulose industry or agroindustrial waste streams for use as bioactive substances in dietary supplements and functional food, additives in food and cosmetic products to mediate antioxidant activity, natural coloration or flavours, and as raw materials for emerging products such as multifunctional polymer coatings or antibacterial packaging.

The book series Recent Advances in Polyphenol Research started in 2008 upon the occasion of the 24th ICP in Salamanca, Spain. The content of the first volume was mostly based on review articles written by plenary lecturers of the previous ICP, which had taken place in Winnipeg, Canada. Since then, this flagship publication of the Groupe Polyphénols has been released every two years to provide the reader with authoritative updates on various topics of polyphenol research written by ICP plenary lecturers and invited expert contributors.

This sixth volume of the series presents chapters representing a distillation of the topics covered during the 28th ICP, which was organized and hosted by the Technische Universität Wien in July 2016 in Vienna, Austria. This beautiful setting is represented on the cover by a photo of the dome of the stunning Art Nouveau church by Otto Wagner in Vienna. Participants were given a chance to visit this church in person during one of the social events organized during the conference.

Five main topics of the polyphenol sciences were selected for the scientific programme of this memorable ICP 2016 edition.

Chemistry and Physicochemistry, covering structures, reactivity, organic synthesis, molecular modelling, fundamental aspects, chemical analysis, spectroscopy, molecular associations, and interactions of polyphenols.

Biosynthesis, Genetics and Metabolic Engineering, covering molecular biology, genetics, enzymology, gene expression and regulation, trafficking, biotechnology, horticultural science, and molecular breeding related to polyphenols.

Roles in Plants and Ecosystems, covering plant growth and development, biotic and abiotic stress, resistance, ecophysiology, sustainable development, valorization, plant environmental system, forest chemistry, and lignin and lignan.

Food, Nutrition and Health, covering food ingredients, nutrient components, functional food, mode of action, bio‐availability and metabolism, food processing, influence on food and beverage properties, cosmetics, antioxidant activity of polyphenols.

Applied Polyphenolics, covering new findings on sources of isolated and standardized polyphenolic fractions and novel epigenetic polyphenol mechanisms, as well as industrial implementations of newly gleaned knowledge on polyphenols.

The 13 chapters of this volume highlight advances in our understanding of (i) polyphenol biosynthesis with a focus on (sub)cellular distribution and organization of the pathways, novel genes and transcription factors, (ii) bioactive and dietary compounds with a focus on health and taste, (iii) innovative sources of polyphenol compounds and their characterization and (iv) emerging products such as thermosetting polymers.

The conference was attended by 272 scientists from 40 countries, with 209 paper contributions, comprising 55 oral communications and 154 poster presentations.

The sixth volume of Recent Advances in Polyphenol Research contains chapters from 13 invited conference speakers and expert contributors. The support and assistance of the Groupe Polyphénols, the BachBERRY group, several Austrian academic associations and foundations, notably the Technische Universität Wien, the City of Vienna and the Vienna Convention Bureau, and several private sponsors are gratefully acknowledged, as the great success of the 28th International Conference on Polyphenols would not have been possible without their contributions. As a final note, the editors would also like to deeply thank all of the plenary, communication and poster presenters for the quality of their contributions, from basic science to more applied fields, and all of the attendees.

Heidi Halbwirth

Karl Stich

Véronique Cheynier

Stéphane Quideau

Acknowledgements

The editors wish to thank all the members of the Groupe Polyphénols Board Committee (2016–2018) for their guidance and assistance throughout this project.

Groupe Polyphénols Board 2016–2018

Dr Luc Bidel

Dr Catherine Chèze

Professor Victor de Freitas

Professor M. Teresa Escribano

Professor Kazuhiko Fukushima

Dr Sylvain Guyot

Professor Ann E. Hagerman

Professor Heidi Halbwirth

Professor Amy Howell

Dr Stefan Martens

Dr Fulvio Mattivi

Professor Stéphane Quideau

Professor Jess Reed

Dr Erika Salas

Professor Kathy Schwinn

Dr David Vauzour

Professor Kristiina Wähälä

1

The Lignans: A Family of Biologically Active Polyphenolic Secondary Metabolites

Anna K.F. Albertson and Jean‐Philip Lumb

Department of Chemistry, McGill University, Montreal, Québec, Canada

1.1 Introduction

Nature has long served as an important source of therapeutics, and lignans represent a large class of pharmacologically active compounds (Cunha et al. 2012). This family of molecules demonstrates a wide range of biological activities, which plants use as a front‐line chemical defence against pathogens (Figure 1.1). Additionally, the anticancer, antimiotic, antiangiogenesis and antiviral properties possessed by lignans have made them appealing drug candidates, as well as starting points for drug discovery. Lignans currently employed for healthcare include (−)‐podophyllotoxin (1), a treatment for warts, and its derivatives (−)‐etoposide (2) and (−)‐teniposide (3), two potent chemotherapeutic agents (Liu et al. 2007). Other members of this class with promising biological activities include (+)‐gomisin J (4) and (+)‐pinoresinol (5). Due to the established benefits of the lignans, both their biosynthesis and synthetic strategies to access them have been areas of extensive research.

Selected biologically active lignan natural products.

Figure 1.1 Selected biologically active lignan natural products.

In addition to their varied biological activities, lignans comprise a vast array of structurally distinct skeletons (Figure 1.2), including 6‐ and 8‐membered carbocycles (6, 7), linear dibenzylbutanes (8), and diversely oxidized tetrahydrofurans (9–11). Remarkably, their biosynthesis originates from a regio‐ and stereoselective, oxidative coupling of relatively simple monolignols (propenyl phenols) (12), to form the key 8–8 bond that serves to characterize all lignan natural products. Subsequent transformations, including cyclization and oxidation of the parent scaffold, convert the initially formed dimer to various family members, imparting unique functionalities. While this blueprint has served as a key source of inspiration for decades of biomimetic synthetic approaches to the lignans, issues of selectivity in the oxidative coupling have led researchers to alternative, target‐oriented routes, which are often specific for an individual structural class. In this review, we summarize these recent efforts from 2009 to 2016, and provide an overview of contemporary research efforts interrogating the lignans. Previous reviews on this subject cover 2000–2004 (Saleem et al. 2005), 2005–2008 (Pan et al. 2009), and 2009–2015 (Teponno et al. 2016).

Structural classes of lignans.

Figure 1.2 Structural classes of lignans.

1.2 Biosynthesis of Lignans

Due to their biological activity and fundamental importance to plant biology, significant efforts have been made to elucidate lignan biosynthesis (Suzuki and Umezawa 2007; Umezawa 2009; Petersen et al. 2010). Lignans originate from cinnamic acids, which are themselves biosynthesized from phenylalanine (Scheme 1.1). The shikimate pathway, which produces several aromatic amino acids including phenylalanine (16), is preceded by the synthesis of shikimic acid (15) from phosphoenolpyruvate (13) and erythrose‐4‐phosphate (14). The conversion of phenylalanine to cinnamic acid (17) is carried out by phenylalanine ammonia‐lyase (PAL). Substitution of the aromatic ring is performed by cinnamate hydroxylases (C4H and C3H), to access coumaric acid (18) and caffeic acid (19). The methyl ether found in ferulic acid (20) is installed by caffeic acid O‐methyltransferase (CAOMT). Several additional steps convert the carboxylic acid to the primary alcohol, affording coniferyl alcohol (21). This propenyl phenol undergoes an oxidative coupling, the first step in the biosynthesis of pinoresinol (5). The oxidative coupling has been extensively investigated (Hapiot et al. 1994; Gavin and Huai‐Bing 1997; Halls et al. 2004; Pickel et al. 2010), and involves a unique mechanism, starting with a one‐electron oxidation of the phenol, believed to be carried out by a laccase. Two phenoxyl radicals (22) are then proposed to combine in the presence of a dirigent protein to form a bis‐para‐quinone methide (23), which undergoes subsequent cyclization to provide the furofuran 5.

Biosynthesis of (+)-pinoresinol.

Scheme 1.1 Biosynthesis of (+)‐pinoresinol.

Several dirigent proteins have been isolated, including those that are selective for either enantiomer of pinoresinol. They display a unique ability to control the regio‐ and stereoselectivity of phenoxyl C–C coupling, despite not having any oxidative activity themselves. This has led to a biosynthetic proposal that requires an exogenous oxidant, followed by diffusion of the phenoxyl radicals into the dirigent protein’s active site. In their absence, the oxidative coupling of coniferyl alcohol leads to a complex mixture (Scheme 1.2), from which pinoresinol is isolated in only trace quantities. The first crystal structure of such proteins was obtained from a pea plant, Pisum sativum (Figure 1.3), affording (+)‐pinoresinol (Kim et al. 2015). While it was not co‐crystallized with the substrate, several aspects of the protein are consistent with the proposed biosynthesis. A trimer structure was determined, which was observed to have six conserved residues in the proposed active site with other proteins that produce (+)‐pinoresinol. These include arginine and aspartic acid residues that are on opposite sides of the pocket but are sufficiently close to co‐ordinate to the phenolic and primary hydroxylic oxygens of the oxidized substrate. However, since several loops surrounding the potential binding cavity were not resolved in the structure, alternative modes of substrate binding and coupling could not be confirmed.

(a) Main coupling pathways for oxidative coupling of coniferyl alcohol. (b) Atom labelling of coniferyl alcohol. (c) Calculated spin density for atoms contributing most to coniferyl radical. (d) Conversion of radical-coupled products to neolignans.

Scheme 1.2 (a) Main coupling pathways for oxidative coupling of coniferyl alcohol. (b) Atom labelling of coniferyl alcohol. (c) Calculated spin density for atoms contributing most to coniferyl radical. (d) Conversion of radical‐coupled products to neolignans.

Crystal structure of dirigent protein from Pisum sativum.

Figure 1.3 Crystal structure of dirigent protein from Pisum sativum.

While the exact mechanistic steps involved in the dimerization have not been conclusively determined, it is now accepted that the dirigent protein is critical for controlling selectivity during the oxidative coupling. This is readily apparent from numerous studies on the free radical coupling of monolignols (Table 1.1). In the presence of various oxidants, coniferyl alcohol rarely forms pinoresinol but instead affords dimers arising from radical coupling at carbon 8 with carbon 5 and oxygen 4 (Scheme 1.2a and b), along with extensive polymerization and decomposition. Attempts at directly mimicking the biosynthetic pathway by employing laccases (Wan et al. 2007; Lu and Miyakoshi 2012) (Table 1.1, entries 1–4) and peroxidases (Chioccara et al. 1993; Mitsuhashi et al. 2008; Matsutomo et al. 2013) (entries 5–7) afford mixtures that vary significantly depending on the specific enzyme used, as well as the method of isolation and purification of the oxidase. Due to the sensitivity of the enzymes, temperature and pH play a large role in the product distribution. More traditional synthetic oxidants, such as peroxides (Dellagreca et al. 2008) (entry 8) and metal salts (Brežný and Alföldi 1982; Vermes et al. 1991; Kasahara et al. 2006; Lancefield and Westwood 2015) (entries 9–12), have been utilized and suffer from similar challenges with regioselectivity and decomposition.

Table 1.1 Synthetic oxidative couplings of coniferyl alcohol.

a Yields based on theoretical yield of 50%.

These issues of selectivity result from delocalization of the phenoxyl radical, which places partial spin density at carbons 1, 3, 5, 8 and oxygen 4 (Scheme 1.2c) (Sangha et al. 2012). Although the calculated spin density at carbons 1 and 3 is higher than at other carbons, steric factors and the inability to restore aromaticity make coupling at these positions unlikely. Calculated enthalpic values show that 8–O–4, 8–8, and 8–5 dimers are 5–20 kcal mol−1 more stable than the 5–O–4, 5–5, and 8–1 dimers. The 8–5 and 8–O–4 linkages allow for rearomatization by nucleophilic attack of the para‐quinone methide (Scheme 1.2d). Intramolecular cyclization by the phenol in the 8–5 dimer and an external nucleophilic attack on the 8–O–4 dimer provide the core structures of the neolignan class of molecules. The 8–O–4 linkage is the most thermodynamically favourable, which is consistent with experimental studies. Additionally, this coupling is the predominant interunit linkage observed in lignin, the plant polymer synthesized from the oxidation of monolignols. The ability of plants to form other linkages in both the polymer and the lignans is thus likely to result from factors controlling the orientation of the radicals during coupling. Without the dirigent protein to position the phenoxyl radicals appropriately, controlling selectivity remains a significant challenge.

The C–C linkage adjoining two units of coniferyl alcohol is conserved in all the lignan natural products, with subsequent transformations of this core structure leading to downstream derivatives (Scheme 1.3). These steps have been carefully studied for the biosynthesis of (+) or (−)‐podophyllotoxin (1), which begins from (+) or (−)‐pinoresinol (5) by reduction to the benzylfuran lariciresinol (24), followed by further reduction to secoisolariciresinol (25) (Suzuki and Umezawa 2007). A dehydrogenase is proposed to convert the diol into the corresponding lactone, matairesinol (26). Several additional steps, which are supported by enzymatic studies, lead to the formation of yatein (27). Recently, the dioxygenase responsible for transforming yatein into deoxypodophyllotoxin (28) was isolated (Lau and Sattely 2015). Hydroxylation of the aryltetralin affords podophyllotoxin (1).

Biosynthetic pathway for conversion of pinoresinol to podophyllotoxin.

Scheme 1.3 Biosynthetic pathway for conversion of pinoresinol to podophyllotoxin.

1.3 Synthetic Approaches to Lignans and Derivatives

Due to the challenges in the direct biomimicry of lignan natural products, alternative synthetic routes to this class of molecules have been developed. The efficiency of the biosynthetic pathway has been exploited by limiting the sites of coupling in the oxidation of propenyl phenols. Bio‐inspired approaches have also been explored that access a key intermediate that provides access to several lignan structural cores. However, the majority of synthetic strategies have relied on targeting a specific skeletal class, and so are not transferable to other types of lignans. Conceptually, the pathways for different structural classes often follow similar approaches in terms of the order of creating the central core and installing the aromatic rings. However, since they are synthetically different transformations, this review will separate the works described herein by the singular class of lignans being accessed.

1.3.1 Biomimetic and Bio‐Inspired Approaches

The regioselectivity issues associated with the oxidative coupling of the monolignols have led to the development of substrates that limit the sites of dimerization and subsequent transformations. A tert‐butyl blocking group at the 5 position of ethyl ferulate (29) is one such example (Scheme 1.4) (Hou et al. 2006; Wang et al. 2006). This eliminates any possibility of coupling at this site, while the steric bulk adjacent to the phenolic oxygen prevents the 8–O–4 dimerization that is often the major product of oxidation of propenyl phenols. Use of the ethyl ester of ferulic acid inhibits any intramolecular cyclization that would quench the para‐quinone methides formed in the oxidation. Alternatively, a proton‐transfer from C8 to restore aromaticity, facilitated by the alkaline reaction conditions, affords the diene 30. Hydrogenation and removal of the blocking group gives a mixture of diastereomers of the dibenzylbutane class of lignans.

Synthesis of dibenzylbutanes 31–32.

Scheme 1.4 Synthesis of dibenzylbutanes 31–32.

With this work as a starting point, the same ethyl ferulate substrate was employed to synthesize other lignan cores under similar oxidative conditions (Scheme 1.5) (Li et al. 2014b). By utilizing iron(III) chloride as the oxidant, which generates HCl over the course of the reaction, 30 cannot be formed. Instead, with H2O serving as an external nucleophile, the 2,5‐diaryltetrahydrofurans 33 and 34 can be obtained. Treatment of this intermediate with acid afforded aryldihydronaphthalene 35, as opposed to the desired 36, due to the steric bulk of the tert‐butyl group. By using the same diene intermediate 30 as Hou, the arylnaphthalene 38 could be obtained by removal of the tert‐butyl group and Lewis acid‐catalysed cyclization. Saponification and amidation provided the natural product (±)‐canabisin D (41).

Synthesis of 2,5-diaryltetrahydrofurans 33–34 and aryldihydronaphthalenes 35, 38–39, 41.

Scheme 1.5 Synthesis of 2,5‐diaryltetrahydrofurans 33–34 and aryldihydronaphthalenes 35, 38–39, 41.

Electrochemical approaches for the oxidative coupling of monolignols have also been developed, providing a greener synthetic pathway to these dimers. Proline derivatives of cinnamic acids, such as 42, served as precursors to bislactone 43 via dimerization in the presence of a platinum electrode (Scheme 1.6) (Mori et al. 2016). Reduction afforded the linear tetraol 44, which underwent spontaneous cyclization upon selective mesylation of the primary alcohols, to give (+)‐yangambin (45) in high enantiomeric excess. Similar synthetic routes provided access to other furofuran natural products, including (+)‐sesamin (46) and (+)‐eudesmin (47).

Synthesis of (+)-yangambin (45), (+)-sesamin (46) and (+)-eudesmin (47).

Scheme 1.6 Synthesis of (+)‐yangambin (45), (+)‐sesamin (46) and (+)‐eudesmin (47).

While syntheses that target a specific lignan class have proven to be very efficient and diversifiable for their intended target, few strategies have demonstrated suitably flexible access to natural products of more than one lignan family, as is the case in lignan biosynthesis itself. While mimicking the proposed biosynthesis continues to suffer from issues of regio‐ and chemoselectivity, it has nevertheless served as a source of inspiration to convert a single starting material into multiple lignan natural targets. A bio‐inspired method utilizing a 1,4‐diarylbutane‐1,4‐diol intermediate was developed to access the 2,5‐di‐aryl‐THF and aryltetralin classes (Scheme 1.7) (Barker and Rye 2009). Treatment of the mono‐protected diol with methanesulfonyl chloride and triethylamine allows for the formation of the para‐quinone methide intermediate. Depending on the protecting group on the remaining alcohol, two pathways can occur. A MOM group can be cleaved under the reaction conditions, leading to a 5‐exo‐trig cyclization and providing the 2,5‐diaryltetrahydrofuran class of lignans. However, the TBS protecting group is more stable to the conditions, forcing a 6‐exo‐trig carbocyclization, driven by the oxygen‐bearing substituent in the meta‐position. Upon elimination of the corresponding silanol, an aryldihydronaphthalene is obtained.

Reaction pathways in the divergent synthesis of 2,5-diaryltetrahydrofurans and aryldihydronaphthalenes.

Scheme 1.7 Reaction pathways in the divergent synthesis of 2,5‐diaryltetrahydrofurans and aryldihydronaphthalenes.

The asymmetrical synthesis of the key dibenzylbutane intermediate began with accessing chiral amide 49 from (S)‐α‐methylbenzylamine (48) over six steps (Scheme 1.8) (Rye and Barker 2011). Addition of the desired aryl lithium species installed the first aromatic ring, providing ketone 51. A series of straightforward manipulations that included reduction of the ketone, protection of the alcohol and oxidation of the terminal alkene to the aldehyde set the stage for the addition of a second aryl group to provide 54. Mesylation of the resulting benzylic alcohol led to an in situ cyclization, providing the tetrahydrofuran lignan (+)‐galbelgin (55).

Synthesis of (+)-galbelgin (55).

Scheme 1.8 Synthesis of (+)‐galbelgin (55).

To access the aryldihydronaphthalenes, alcohol 52 was silylated and similar oxidation conditions of the alkene 56 gave aldehyde 57 (Scheme 1.9). This intermediate was then arylated with different aryl halides and treatment of the resulting dibenzylbutanes with MsCl afforded (−)‐cyclogalgravin (58) and (−)‐pycnanthulignene B (60). Similar transformations were carried out, followed by deprotection of the MOM group, to provide (−)‐pycnanthulignene A (62).

Synthesis of (-)-cyclogalgravin (58), (-)-pycnanthulignene B (60), and (-)-pycnanthulignene A (62).

Scheme 1.9 Synthesis of (−)‐cyclogalgravin (58), (−)‐pycnanthulignene B (60), and (−)‐pycnanthulignene A (62).

A method inspired by lignan biosynthesis that exploits the versatility of the bis‐para‐quinone methide as a divergent intermediate from which to access all the lignan classes has also been developed (Scheme 1.10) (Albertson and Lumb 2015). As an alternative to the oxidative coupling, a photochemical [2+2]‐cycloaddition was employed to form the key carbon–carbon bond. The solid‐state photochemical transformation of the para‐nitrophenol ester of ferulic acid (20) afforded a single diastereomer of the corresponding cyclobutane, which was subsequently reduced to the diol (63). This intermediate underwent oxidative ring opening with iron(III) chloride to provide (±)‐tanegool (66), a natural product previously isolated (Macías et al. 2004) but not synthesized. The oxidation is presumed to go through a similar para‐quinone methide intermediate (64) as the one proposed in the biosynthetic pathway to pinoresinol (23). However, due to the stereochemistry of the cyclobutane, only one tetrahydrofuran ring can form, to avoid a trans‐fused 5,5 ring system. The use of H2O as a solvent also provides a nucleophile to quench the second para‐quinone methide (66). With this proof of concept, an epimeric cyclobutane (67) was synthesized and under identical oxidation conditions, (±)‐pinoresinol (5) was obtained.

Synthesis of (±)-tanegool (66) and (±)-pinoresinol (5).

Scheme 1.10 Synthesis of (±)‐tanegool (66) and (±)‐pinoresinol (5).

1.3.2 Dibenzylbutyrolactones

Approaches to the dibenzylbutyrolactone lignans have long been available, and hinge on two general routes (Scheme 1.11). Capitalizing on the facile nature of α‐alkylation of the lactone has focused on methods for accessing the β‐substituted benzyl‐butyrolactone. A particular advantage of this approach is the ability to readily access differentially substituted aryl substituents. Alternatively, work has also been done on the formation of the dibenzylbutane core via methods beyond oxidative coupling, followed by conversion to the lactone.

General methods for the synthesis of dibenzylbutyrolactones.

Scheme 1.11 General methods for the synthesis of dibenzylbutyrolactones.

By harnessing the inherent enolate chemistry available in this class of natural products, a racemic synthesis of (±)‐yatein (27) was developed (Scheme 1.12) (Trazzi et al. 2010). The method began with a Morita–Baylis–Hillman coupling to provide 69, following silyl protection, which is subsequently elaborated to lactone 71 by reduction of the ester, hydrolysis of the nitrile and in situ cyclization. Desilylation and dehydroxylation then provided lactone 72, which is diastereoselectively alkylated with benzyl bromide 73 to complete the synthesis of (±)‐yatein (27).

Synthesis of (±)-yatein (27).

Scheme 1.12 Synthesis of (±)‐yatein (27).

An approach for the synthesis of (±)‐5′‐methoxyyatein (77) proceeded in a similar manner (Scheme 1.13) (Amancha et al. 2010). Cyano ester 74 was synthesized in five steps, setting the stage for a tandem L‐proline catalysed Knoevenagel condensation/hydrogenation, to afford a mixture of inseparable racemic diastereomers of cyano lactone 75. Diastereoselective benzylation of the mixture with 73, with the expected approach of the electrophile from the sterically less hindered face, and reductive decyanation then provided the natural product.

Synthesis of (±)-5′-methoxyyatein (77).

Scheme 1.13 Synthesis of (±)‐5′‐methoxyyatein (77).

An enantioselective synthesis of this class of lignans utilizing this general approach has also been demonstrated (Scheme 1.14) (Hajra et al. 2013). By employing chiral oxazolidinone 78, the first aldol reaction could be conducted with high levels of diastereocontrol, providing a convenient means to set the stereochemistry of the first benzyl group. Silylation and saponification afforded carboxylic acid 82, which was selectively reduced to alcohol 83. Cyclization to the corresponding lactone, and selective benzylation and desilylation then provided (−)‐7′‐(S)‐hydroxyarctigenin (85).

Synthesis of (-)-7′-(S)-hydroxyarctigenin (85).

Scheme 1.14 Synthesis of (−)‐7′‐(S)‐hydroxyarctigenin (85).

Chiral catalysts have also been employed to form the benzylbutyrolactone core enantioselectively. For example, merging photoredox and organocatalysis affected an asymmetrical α‐alkylation of aldehyde 86 (Scheme 1.15) (Welin et al. 2015). Subsequent reduction of the aldehyde and lactonization provided the butyrolactone 90, which was subsequently converted into (−)‐bursehernin (92) by diastereoselective alkylation with 91.

Synthesis of (-)-bursehernin (92).

Scheme 1.15 Synthesis of (−)‐bursehernin (92).

An alternative approach to the dibenzylbutyrolactone class of lignans relies on formation of the dibenzylbutane backbone, followed by installation of the lactone. This strategy was utilized in the enantioselective synthesis of (−)‐hinokinin (98) (Scheme 1.16) (Zhou et al. 2015). The first stereoselective conjugate addition was followed by a cascade anion‐oxidative hydroxylation and oxygen anion cyclization, to install butyrolactonimidate 96. Removal of the chiral sulfinyl moiety and Krapcho decarboxylation afforded lactone 97, which was converted to the natural product through a series of straightforward synthetic manipulations.

Synthesis of (-)-hinokinin (98).

Scheme 1.16 Synthesis of (−)‐hinokinin (98).

1.3.3 Arylnaphthalenes and Aryltetralins

Synthetic strategies directed towards the six‐membered carbocyclic cores of arylnaphthalene and aryltetralin lignans have been extensively developed (Sellars and Steel 2007). One of the most common approaches has been to introduce the decalin unit early in the synthesis, and then append the second aryl ring in a later stage. This approach was elegantly employed in the asymmetrical synthesis of (−)‐podophyllotoxin (1) (Scheme 1.17) (Ting and Maimone 2014). Treatment of cyclobutanol 99 with strong base afforded the corresponding ortho‐quino‐dimethane, which was trapped in situ by a Diels–Alder cycloaddition with enamide 100. Subsequent reduction of the ester and protection of the resulting diol as a cyclic acetal afforded tetrahydronaphthalene 102, which underwent diastereoselective C–H arylation. This introduces the cis relationship between the carbonyl at C1 and the aryl substituent at C2 found in podophyllotoxin, which is notoriously difficult to install (Yu et al. 2017). Deprotection of the acetal and subsequent lactonization then completed the total synthesis.

Synthesis of (-)-podophyllotoxin (1).

Scheme 1.17 Synthesis of (−)‐podophyllotoxin (1).

The synthesis of the arylnaphthalenes chimensin (110) and taiwanin C (111) was approached in a similar manner (Scheme 1.18) (He et al. 2014). The naphthalene core was formed first by the Blaise reaction between aryl nitrile 106 and the zinc enolate of 107 to afford 108, which underwent a 6‐π electrocyclization to install the naphthalene lactone. Conversion of the aniline to the iodide set the stage for a Suzuki coupling to install the aryl substituents of chimensin (110) and taiwanin C (111).

Synthesis of chimensin (110) and taiwanin C (111).

Scheme 1.18 Synthesis of chimensin (110) and taiwanin C (111).

The synthesis of the naphthalene lactone of justicidin B (115) in a two‐step route from malonic diester 112 has also been developed (Scheme 1.19) (Hayat et al. 2015). Upon treatment with base, a Knoevenagel condensation provided butenolide 113, which was further cyclized to 114 at elevated temperatures. Conversion of the resulting naphthol to the triflate, followed by Suzuki coupling, installed the final aryl substituent and completed the synthesis of justicidin B (115).

Synthesis of justicidin B (115).

Scheme 1.19 Synthesis of justicidin B (115).

A complementary approach to the aryltetralins involves the preparation of a linear precursor, possessing the necessary complement of substituents, followed by a late‐stage cyclization to install the six‐membered carbocycle of the aryltetralin or aryldihydronaphthalene lignans. For example, a one‐pot cascade composed of a conjugate addition/allylation reaction was developed for this class of compounds (Scheme 1.20) (Wu et al. 2009). The chiral oxazolidine 116 served to control the relative stereochemistry of the conjugate addition, as well as the allylation, via lithium enolate 118. Oxidative cleavage of the double bond, followed by an L‐proline‐mediated aldol cyclization, closed the six‐membered ring of the aryltetralin, before a series of straightforward steps completed the total synthesis of (+)‐podophyllotoxin (1).

Synthesis of (+)-podophyllotoxin (1).

Scheme 1.20 Synthesis of (+)‐podophyllotoxin (1).

In a synthesis of the sacidumlignans, the six‐membered carbocycle of the aryltetralin core was constructed from tertiary alcohol 124 (Scheme 1.21) (Rout and Ramana 2012). Oxidative cleavage of the double bond, followed by lactonization and oxidation, provided diaryl‐lactone 125, whose α‐alkylation with methyl triflate proceeded with high diastereoselectivity. Reduction of the lactone and selective deoxygenation of the tertiary alcohol provided primary alcohol 127. Oxidation to the aldehyde allowed for an acid‐catalysed intramolecular Friedel–Crafts cyclization to afford 128. Deprotection then provided (−)‐sacidumlignan B (129), whereas a one‐pot oxidation deprotection sequence afforded sacidumlignan A (130).

Synthesis of (-)-sacidumlignan B (129) and sacidumlignan A (130).

Scheme 1.21 Synthesis of (−)‐sacidumlignan B (129) and sacidumlignan A (130).

A similar approach to this class of lignans began with an Ueno‐Stork cyclization of primary alkyl bromide 131 to provide diaryl‐tetrahydrofuran 132 (Scheme 1.22) (Peng et al. 2013). Subsequent oxidative cyclization afforded the lactone and α‐methylation proceeded with high levels of diastereocontrol to give 133. Reduction of the lactone generated the linear diol 134. A three‐step sequence of selective protection, deoxygenation and deprotection was then used to remove the tertiary alcohol and provide 135. Oxidation of the primary alcohol to the aldehyde and Friedel–Crafts cyclization afforded (±)‐cyclogalgravin (58), which was used as a precursor to additional family members (136–142) by selective manipulation of the styrenyl double bond.

Synthesis of (±)-cyclogalgravin (58) and aryltetralins 136–142.

Scheme 1.22 Synthesis of (±)‐cyclogalgravin (58) and aryltetralins 136–142.

A conceptually distinct approach to this family of lignans by linking the two aryl groups together via a novel one‐pot oxidative [3,3] rearrangement/Friedel–Crafts arylation has also been described (Scheme 1.23) (Reddel et al. 2014). By using aryl hydrazone 143, simple arene coupling partners could be introduced to make a small family of benzhydryl derivatives, in high yields and with complete transfer of chirality. A sequence of oxidative alkene cleavage and Wittig olefination was used to convert 147 to the corresponding methyl enol ether. This intermediate was then used to access tetralone natural products (−)‐8′‐epi‐aristoligone (138) and the aryldihydronaphthalene (−)‐cyclogalgavrin (58). Using this route, a small library of differentially functionalized derivatives (60, 149–151) was prepared, highlighting the versatility of the methodology.

Synthesis of aryldihydronaphthalenes 56, 60 and aryltetralins 138, 149–151.

Scheme 1.23 Synthesis of aryldihydronaphthalenes 56, 60 and aryltetralins 138, 149–151.

Formation of arylnaphthalenes via a conceptually distinct cyclization of bis‐acetylenes has also received significant attention. For example, a Garratt‐Braverman reaction of bis‐propargyl ether 152 was employed for the synthesis of this class of compounds (Scheme 1.24) (Mondal et al. 2011). Initial studies afforded mixtures of products (153–156) upon treatment of 152 with potassium tert‐butoxide, due to a lack of control in the cyclization. In the presence of base, 152 provides bis‐allene 157, which can rearrange to the diradical furan 158. These radicals have resonance character on the carbons of the aromatic rings, such as 159. Upon radical recombination, the furan aryl decalin core 160 is obtained and proton transfers restore aromaticity, yielding the desired arylnaphthalene 153. However, other resonance structures exist for the diradical intermediate (161–163), which lead to alternative cyclization products (164–166).

Initial Garratt–Braverman studies for synthesis of arylnaphthalenes 153–156.

Scheme 1.24 Initial Garratt–Braverman studies for synthesis of arylnaphthalenes 153–156.

Following these initial studies, approaches were developed to limit the product distribution by modifying the electronics of one aromatic ring to make it electron‐poor. Such a donor–acceptor system allowed for increased radical nucleophilicity at the carbon α to the donating ring. This biased the cyclization to install the electron‐rich ring as the appended ring on the naphthalene core. This was demonstrated by utilizing bis‐propargyl ether 167, which placed a benzoyl group in the para‐position (Scheme 1.25). Under the reaction conditions, the benzoyl group is cleaved, and a subsequent methylation of the free phenol provides 168 and 169. The challenge of a non‐symmetrical substitution pattern on the aryl ring was removed by using ether 170, which gave 171 as a single isomer. Oxidation of these isofurans to the corresponding lactones provided the natural products taiwanin C (111) and justicidin E (172), as well as several non‐natural derivatives.

Synthesis of taiwanin C (111) and justicidin E (172).

Scheme 1.25 Synthesis of taiwanin C (111) and justicidin E (172).

A similar approach, starting from bis‐propargyl ether 173, was also developed (Scheme 1.26) (Kudoh et al. 2013). Upon exposure to Triton B, an intramolecular anionic Diels–Alder reaction was used to synthesize cyclic acetal 174, which served as a precursor to arylnaphthalene lactone natural products justicidin B (115) and retrojusticidin B (175). A similar route using alternatively substituted aromatic rings was used to complete the synthesis of phyllamycin C (176) and phyllamycin A (177).

Synthesis of arylnaphthalenes 115, 175–177.

Scheme 1.26 Synthesis of arylnaphthalenes 115, 175–177.

A conceptually related intramolecular cyclization was employed, utilizing ester 178 to tether an alkyne and an alkene (Scheme 1.27) (Park et al. 2014). Treatment of 178 with acetic anhydride at elevated temperatures under microwave irradiation provided aryldihydronaphthalene lactone 179 by way of a Diels–Alder cycloaddition. Oxidation to the arylnaphthalene with 2,3‐dichloro‐5,6‐dicyano‐p‐benzoquinone (DDQ) provided the natural product, justicidin E (172). By altering the linkage partners prior to the intramolecular cyclization, the biologically active molecules taiwanin C (111) and daurinol (183) could be prepared selectively.

Synthesis of justicidin E (172), taiwanin C (111), and daurinol (183).

Scheme 1.27 Synthesis of justicidin E (172), taiwanin C (111), and daurinol (183).

A similar tethering strategy was employed in a one‐pot intramolecular dehydro‐Diels–Alder reaction (Scheme 1.28) (Kocsis and Brummond 2014). Inclusion of nitrobenzene allowed for the oxidation of the ester tether of the desired alkene and alkyne to occur in situ, and provided several arylnaphthalene lactone lignans, including justicidin B (115), isojusticidin B (184), taiwanin C (111) and retrohelioxanthin (185).

Synthesis of aryl naphthalene lignans 111, 115, 184–185.

Scheme 1.28 Synthesis of arylnaphthalene lignans 111, 115, 184–185.

A related ester tether was also employed to access various arylnaphthalene lignans (Scheme 1.29) (Kao et al. 2015). In this case, a free radical cyclization was used to convert α‐cyano ester 186 into the corresponding aryldihydronaphthalene lactone 187. Subsequent cleavage of the cyano group and oxidation completed a synthesis of justicidin E (173). Similar synthetic steps were taken to access helioxanthin (188) and retrojusticidin B (175).

Synthesis of justicidin E (173), helioxanthin (188) and retrojusticidin B (175).

Scheme 1.29 Synthesis of justicidin E (173), helioxanthin (188) and retrojusticidin B (175).

In addition to esters, arylnaphthalenes have been synthesized utilizing a variety of tethers, including propargyl ethers (Scheme 1.30) (Gudla and Balamurugan 2011). This intermediate united a benzyl ketone with an aryl acetylene (189), which underwent an intramolecular, sequential electrophilic addition and benzannulation catalysed by a Au(III)‐salt. Subsequent oxidation afforded the corresponding lactones, providing access to the natural products justicidin E (172), taiwanin C (111) and retrojusticidin B (175), as well as several non‐natural analogues.

Synthesis of justicidin E (172), taiwanin C (111) and retrojusticidin B (175).

Scheme 1.30 Synthesis of justicidin E (172), taiwanin C (111) and retrojusticidin B (175).

There has also been significant effort to develop convergent, multibond forming routes for both aryltetralins and arylnaphthalenes. For example, an enantioselective total synthesis of (+)‐galbulin (136) via an organocatalytic domino Michael–Michael‐aldol condensation was developed (Scheme 1.31) (Hong et al. 2012). The aryl dehydrodecalin core was formed in two steps from the cascade reaction of 191 and 192, in the presence of a proline catalyst. The first Michael addition served as a kinetic resolution of the starting racemic mixture of 192 as only the enantiomer leading to transition state 197 proceeded in the reaction, due to steric effects. Acetic acid catalysed the second Michael addition to close the first six‐membered ring and subsequent treatment with para‐toluene sulfonic acid provided the aldol product 200 with high enantioselectivity. With the core aryl decalin structure constructed, a global reduction and selective allylic oxidation afforded primary alcohol 201. The methoxy enone 203 was accessed over two steps via epoxide 202 and elevated temperatures aromatized the cyclohexanone ring to give 204. A final methylation, protection and reduction sequence was conducted to complete the synthesis of (+)‐galbulin (136).

Synthesis of (+)-galbulin (136).

Scheme 1.31 Synthesis of (+)‐galbulin (136).

A complementary coupling reaction of aryl β‐ketoester 205 and arylalkyne 206 was employed to afford arylnaphthalene 207 in a one‐pot process mediated by AgOAc and Na2S2O8 (Scheme 1.32) (Naresh et al. 2015). A subsequent reduction completed a synthesis of diphyllin (207), which could be readily extended to justicidin A (209). The method was further applied to the structurally related natural product taiwanin E (210), as well as several non‐natural analogues.

Synthesis of diphyllin (208), justicidin A (209) and taiwanin E (210).

Scheme 1.32 Synthesis of diphyllin (208), justicidin A (209) and taiwanin E (210).

1.3.4 2,5‐Diaryltetrahydrofurans

Several approaches have been developed for the synthesis of 2,5‐diaryltetrahydrofuran lignans (Scheme 1.33). One such strategy accesses an aryl furan intermediate with subsequent arylation (strategy A). Another method links the two aryl groups through a linear chain, creating functional groups that allow for an intramolecular cyclization to form the furan ring (strategy B). Finally, there have been developments in convergent pathways that bring the two aryl rings together while forming the central five‐membered ring in a single step (strategy C).

General methods for the synthesis of 2,5-diaryltetrahydrofurans.

Scheme 1.33 General methods for the synthesis of 2,5‐diaryltetrahydrofurans.

Using a strategy of nucleophilic lactone‐arylation, an asymmetrical synthesis of (+)‐veraguensin (221) was developed (Scheme 1.34) (Matcha and Ghosh 2010). Beginning from D‐mannitol (211), a sequence of steps to prepare ester 212 was employed, which unified with aldehyde 213 by an aldol reaction. In situ deprotection/oxidation with NaIO4 afforded the corresponding lactol, which was converted into acetal 215 under standard conditions. The terminal alkene was oxidatively cleaved to provide aldehyde 216 which, upon reduction to the primary alcohol, underwent cyclization to lactone 217. Reduction to the diol