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Natural Lactones and Lactams

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Contents

Preface XIII List of Contributors XV

1 Tetronic Acids 1 Dimitris Georgiadis 1.1 Introduction 1 1.2 Natural Occurrence, Biological Activities, and Biosynthesis 1 1.3 5-Ylidene Tetronic Natural Products 6 1.3.1 Pulvinic Acids and Pulvinones 6 1.3.2 Agglomerins 11 1.3.3 Tetronomycin 13 1.3.4 Stemofoline Alkaloids 13 1.3.5 Variabilin 17 1.3.6 Tetrodecamycin 17 1.4 5-Monosubstituted Tetronic Natural Products 19 1.4.1 Carlic, Carlosic, Carolic, Carolinic, and Viridicatic Acids 19 1.4.2 RK-682 20 1.4.3 Massarilactone B 21 1.4.4 Annularins F, G, and H 21 1.4.5 Palinurin 23 1.4.6 Pesthetoxin 24 1.4.7 Rotundifolides A and B 24 1.5 5-Disubstituted Tetronic Natural Products 25 1.5.1 5-Dialkyl Tetronic Natural Products 25 1.5.1.1 Vertinolide 25 1.5.1.2 Papyracillic Acid B 26 1.5.1.3 Bisorbibutenolide 26 1.5.2 5-Spirotetronic Natural Products 29 1.5.2.1 Spirotetronic Antibiotics 29 1.5.2.2 Ircinianin and Wistarin 35 1.5.2.3 Stemonamine Alkaloids 35 1.5.2.4 Abyssomicins 37 1.6 5-Unsubstituted Tetronic Natural Products 41 VI Contents

1.6.1 Tetronasin 41 1.7 Conclusions 42 References 43

2 Recent Advances in the Field of Naturally Occurring 5,6-Dihydropyran-2-ones 51 Juan Alberto Marco and Miguel Carda 2.1 Introduction 51 2.2 Synthetic Methodologies for 5,6-Dihydropyran-2-ones 52 2.2.1 Lactonization of Substituted δ-Hydroxy Acid Derivatives 52 2.2.2 Oxidation of Substituted Dihydropyran Derivatives 53 2.2.3 Ring-Closing Metathesis 54 2.2.4 Miscellaneous Methods 54 2.3 Formation of Stereogenic Centers inside the Dihydropyrone Ring 55 2.3.1 Use of Chiral Precursors 56 2.3.1.1 Carbohydrate and Related Precursors 56 2.3.1.2 Chiral Hydroxy Acids 58 2.3.1.3 Chiral Epoxides 60 2.3.1.4 Other Chirons 62 2.3.2 Asymmetric (Enantioselective) Reactions 64 2.3.2.1 Asymmetric (Enantioselective) Sharpless Epoxidations or Dihydroxylations 64 2.3.2.2 Asymmetric Aldol-Type Reactions 68 2.3.2.3 Asymmetric Allylations 69 2.3.2.4 Asymmetric Carbonyl Reductions 71 2.3.2.5 Asymmetric Alkylations 72 2.3.2.6 Asymmetric Epoxide Hydrolysis 73 2.3.2.7 Asymmetric Cycloadditions 74 2.3.2.8 Other Asymmetric Methods 75 2.4 Pharmacological Properties of Pyrones 78 2.5 Biosynthetic Formation of Pyrones 79 2.6 Syntheses of Natural 5,6-Dihydropyran-2-ones Reported during the Period from 2006 to the First Half of 2012 91 References 91

3 β-Lactams 101 Girija S. Singh and Siji Sudheesh 3.1 Introduction 101 3.1.1 Biosynthesis of Penicillin and Cephalosporin 102 3.2 Monocyclic β-Lactams 103 3.2.1 Biosynthesis of Nocardicin A 104 3.2.2 Synthetic Approaches to Construct β-Lactam Ring 105 3.2.2.1 Cycloaddition Reactions 106 3.2.2.2 Cyclization Reactions 115 3.2.2.3 Miscellaneous Approaches 118 Contents VII

3.2.3 Biological Activity of Monocyclic 2-Azetidinones 119 3.3 Penams 121 3.3.1 Synthetic Approaches to Penam Skeleton 121 3.3.2 Biological Activity of Penams 122 3.4 Cephalosporins 124 3.4.1 Synthetic Approaches to Cephalosporin Skeleton 125 3.4.2 Biological Activity of Cephalosporins 128 3.5 Clavulanic Acid 130 3.5.1 Synthetic Approaches to Clavam Skeleton 131 3.5.2 Biological Activity of Clavams 132 3.6 Carbapenems 133 3.6.1 Synthetic Approaches to Carbapenem Skeleton 134 3.6.2 Biological Activity of Carbapenems 136 3.7 Spiro-Fused β-Lactams 137 3.7.1 Occurrence and Structure of Chartellines 137 3.7.2 Total Synthesis of Chartelline C 137 3.7.3 Biological Activity of Spiro-Fused β-Lactams 140 3.8 Summary 140 References 141

4 α-Alkylidene-γ-andδ-Lactones and Lactams 147 Łukasz Albrecht, Anna Albrecht, and Tomasz Janecki 4.1 Introduction 147 4.2 Occurrence, Biosynthesis, and Biological Activities of α-Alkylidene γ-andδ-Lactones and Lactams 148 4.2.1 α-Alkylidene-γ-Lactones 148 4.2.2 α-Alkylidene-δ-Lactones 152 4.2.3 α-Alkylidene-γ-andδ-Lactams 153 4.3 Recent Advances in the Synthesis of α-Alkylidene-γ-andδ-Lactones and Lactams 153 4.3.1 Cyclization of 2-Alkylidene-4-(5-)Hydroxyalkanoates and 2-Alkylidene-4-(5-)Aminoalkanoates in the Synthesis of α-Alkylidene-γ-andδ-Lactones and Lactams 154 4.3.1.1 Organometallic Reagents Derived from 2-Bromomethylacrylic Acid and Its Derivatives in the Synthesis of 2-Alkylidene- 4-Hydroxyalkanoates and 2-Alkylidene-4-Aminoalkanoates 155 4.3.1.2 Application of Allylboronates in the Synthesis of 2-Alkylidene- 4-Hydroxyalkanoates and 2-Alkylidene-4-Aminoalkanoates 156 4.3.1.3 Baylis–Hillman Alcohol Derivatives in the Synthesis of α-Alkylidene γ-andδ-Lactones and Lactams 161 4.3.1.4 Ring-Opening Reactions in the Synthesis of 2-Alkylidene- 4-Hydroxyalkanoates and 4-Aminoalkanoates 167 4.3.2 Construction of α-Alkylidene-γ-andδ-Lactone and Lactam Rings via Intramolecular Morita–Baylis–Hillman Reaction 168 VIII Contents

4.3.3 Methods Involving α-Dialkoxyphosphoryl-γ-andδ-Lactones and Lactams as Key Intermediates 172 4.3.3.1 Methods Involving Cyclic α,β-Unsaturated Precursors 172 4.3.3.2 Methods Involving 2-Dialkoxyphosphoryl 4-(5-)Hydroxy or 4-(5-)Aminoalkanoates as Key Intermediates 174 4.3.3.3 α-Diethoxyphosphoryl-δ-Lactones in the Synthesis of 3-Methylene-3,4-Dihydrocoumarins 182 4.3.3.4 Annulation of the Lactone Frameworks via Carbon–Carbon Bond-Forming Reactions 184 4.3.4 β-Elimination Reaction in the Synthesis of α-Alkylidene-γ-Lactones or γ-Lactams 184 4.3.5 Oxidation of 3-Alkylidenetetrahydrofuranones in the Synthesis of α-Alkylidene-γ-Lactones 186 4.3.6 Miscellaneous Methods for the Preparation of α-Alkylidenelactones and Lactams 187 4.4 Conclusions 188 References 188

5 Medium-Sized Lactones 193 Isamu Shiina and Kenya Nakata 5.1 Introduction 193 5.1.1 Natural Eight- and Nine-Membered Lactones 193 5.1.2 Lactonization Methods 194 5.1.2.1 Corey–Nicolaou S-Pyridyl Ester Lactonization Method 195 5.1.2.2 Mukaiyama Onium Salt Method 195 5.1.2.3 Masamune Thioester Activation Method 197 5.1.2.4 Yamaguchi Mixed-Anhydride Method 198 5.1.2.5 Mitsunobu Alcohol Activation Method 199 5.1.2.6 Keck–Steglich DCC/DMAP·HCl Activation Method 199 5.1.2.7 Shiina Benzoic Anhydride Method 200 5.2 Total Synthesis of Eight-Membered Lactones 203 5.2.1 Cephalosporolide D 203 5.2.1.1 Shiina Total Synthesis (1988) 203 5.2.1.2 Buszek Total Synthesis (2001) 204 5.2.1.3 Rao Total Synthesis (2010) 204 5.2.1.4 Sabitha Total Synthesis (2011) 205 5.2.2 Octalactins A and B 205 5.2.2.1 Buszek Total Synthesis (1994) 205 5.2.2.2 Clardy Total Synthesis (1994) 206 5.2.2.3 Holmes Total Synthesis (2004) 207 5.2.2.4 Shiina Total Synthesis (2004) 207 5.2.2.5 Andrus Formal Total Synthesis (1996) 208 5.2.2.6 Hatakeyama Synthesis of the Lactone Moiety (1998) 209 5.2.2.7 Garcia Synthesis of the Lactone Moiety (1998) 210 Contents IX

5.2.2.8 Buszek Alternative Synthesis of Octalactin A (2002) 210 5.2.2.9 Cossy Synthesis of the Lactone Moiety (2005) 211 5.2.2.10 Hulme Partial Synthesis (1997) 211 5.2.3 Solandelactones A–H 212 5.2.3.1 Martin Total Synthesis of Solandelactone E (2007) 212 5.2.3.2 White Total Synthesis of Solandelactones E and F (2007) 213 5.2.3.3 Pietruszka Total Synthesis of Solandelactones A–H (2008) 213 5.2.3.4 Aggarwal Total Synthesis of Solandelactones E (2010) and F (2012) 214 5.2.3.5 Datta Synthesis of the Lactone Moiety (1988) 214 5.2.3.6 Mohapatra Synthesis of the Lactone Moiety (2003) 215 5.3 Total Synthesis of Nine-Membered Lactones 215 5.3.1 Halicolactone 215 5.3.1.1 Wills Total Synthesis (1995) 216 5.3.1.2 Takemoto–Tanaka Total Synthesis (2000) 216 5.3.1.3 Kitahara Total Synthesis (2002) 216 5.3.1.4 Tang Total Synthesis (2009) 217 5.3.1.5 Pietruszka Total Synthesis (2010) 218 5.3.1.6 Datta Formal Synthesis (1998) 218 5.3.2 Griseoviridin 219 5.3.2.1 Meyers Total Synthesis (2000) 219 5.3.3 2-Epibotcinolide 219 5.3.3.1 Shiina Total Synthesis (2006) 220 5.3.3.2 Chakraborty Synthesis of the Lactone Moiety (2006) 222 5.4 Conclusions 222 References 223

6 Macrolactones 229 Gangavaram V. M. Sharma and Venkata Ramana Doddi 6.1 Introduction 229 6.1.1 Classiﬁcation of Macrolides 231 6.1.1.1 ‘‘Polyoxo’’ Macrolides 232 6.1.1.2 Polyene Macrolides 232 6.1.1.3 Ionophoric Macrolides 233 6.1.1.4 Ansamycin Macrolides 233 6.1.1.5 Other Macrolides 234 6.1.2 Macrolactones as Chemical Signals (Semiochemicals) 235 6.1.3 Macrolactones as Musks 236 6.2 General Methods for the Synthesis of Macrolactones 236 6.3 Synthesis of Macrolides 241 6.3.1 Synthesis of Patulolide C 241 6.3.2 Synthesis of Balticolide 242 6.3.3 Synthesis of Oximidine II 243 6.3.4 Synthesis of Ripostatin B 245 6.3.5 Synthesis of Azamacrolides 247 X Contents

6.3.6 Synthesis of (+)-Acutiphycin 247 6.3.7 Synthesis of Archazolid A 250 6.3.8 Synthesis of Epothilone B 251 6.3.9 Synthesis of Batatoside L 252 6.4 Synthesis of Macrodiolides 252 6.4.1 Synthesis of Verbalactone 254 6.4.2 Synthesis of Acremodiol 255 6.4.3 Synthesis of Amphidinolide X 257 6.4.4 Synthesis of Marinomycin A 258 6.5 Synthesis of Macrotriolides 260 6.5.1 Synthesis of Macrosphelides A and E 261 6.5.2 Synthesis of Macrosphelides C and F 262 6.5.3 Synthesis of Macrosphelides G and I 263 6.5.4 Synthesis of Macrosphelide M 266 6.6 Conclusions and Perspectives 267 Abbreviations 267 References 269

7 Resorcylic Acid Lactones 273 Carmela Napolitano and Paul V. Murphy 7.1 Introduction – A Historical Perspective 273 7.2 Biosynthesis 277 7.3 Chemical Synthesis 277 7.3.1 Zearalenone 279 7.3.2 Radicicol 285 7.3.3 Pochonins 292 7.3.4 RALs with cis-Enone Groups 295 7.3.5 Aigialomycin D 303 7.3.6 Other RALs 309 7.4 Conclusion and Outlook 315 References 315

8 Cyclic Peptides 321 Srinivasa Rao Adusumalli, Andrei K. Yudin, and Vishal Rai 8.1 Introduction 321 8.2 Synthesis of Natural Lactones and Lactams 332 8.2.1 Cyclocinamide A 332 8.2.2 Biphenomycin B 333 8.2.3 Antillatoxin 336 8.2.4 Halipeptins 338 8.2.5 Largazole 340 8.2.6 Dendroamide A 342 8.2.7 Chondramide C 346 8.2.8 Cyclocitropsides 346 8.2.9 Sanguinamide B 349 Contents XI

8.2.10 Apratoxin A 349 8.2.11 Thiocillin I 351 8.2.12 Lagunamide A 353 8.2.13 Kapakahines 356 8.2.14 Chloptosin 357 8.3 Conclusion 359 References 361

Index 371

XIII

Preface

Lactones and lactams are one of the best recognized classes of natural products. They can be found in many natural sources and have very diversified structure with the ring size varying from 4-membered up to 60-membered. The synthesis and chemistry of natural lactones and lactams have been extensively studied in many laboratories for a long time. The main reason for the enormous interest in these two classes of compounds arises from the fact that lactone or lactam moiety is present in a vast number of natural and synthetic compounds displaying a wide spectrum of desired biological properties. Moreover, this moiety is usually crucial for their activity. The most important application of the lactones and lactams is in the pharmaceutical industry. Currently, plenty of drugs containing these structural motifs, such as β-lactams, macrolactones, dihydropyran-2-ones or tetronic acids are used in medicinal treatment of inflammation, cancer, malaria and many other diseases. Many others are on different steps of medicinal trials. Well known are also the odorant properties of many lactones which are used in fine and functional perfumery. Musk odorants which are macrolactones or relatively simple γ-and δ-lactones like whisky, wine or Aerangis lactones are the best known examples. The second important reason for the great attention given by chemists to natural lactones and lactams is their attractiveness as chiral building blocks which are frequently used in organic synthesis. Taking all these facts into consideration, it is really surprising that, to the best of my knowledge, any comprehensive compilation dedicated to this group of natural products has not been published so far. I believe that this book fills this gap, at least to some extent. The lactone or lactam structural motif can be found in so many natural products that it was not possible to include all of them in this book. Consequently, the selection which had to be made is, to a great extent, the arbitral decision of the editor proceeded by discussions with college chemists. The content of this book is therefore arguable and one can imagine somewhat different choice of subjects. One of the first things I had to do when starting the edition of this book was to get in touch with and secure the cooperation of the undisputable experts in specific and sometime narrow groups of lactones or lactams. Although it was a challenge in a few cases, the list of contributors to this book shows clearly that this undertaking has been successively accomplished. The book is organized in eight chapters devoted to different classes of natural lactones and lactams and I believe that all main groups are included. The only really XIV Preface

big class which is not discussed in this book are coumarins but fortunately many reviews devoted to the occurrence, biological activity and synthesis of this class of compounds have recently been published (see A. Yu. Fedorov, A. V. Nyuchev and I. P. Beletskaya Chemistry of Heterocyclic Compounds 2012, 48, 166, and references cited therein). All contributors to this book were asked to include in their chapters a general overview as well as information about the occurrence and biological activity of the speciﬁc class of lactones and/or lactams. However, the main part of each contribution is dedicated to the general and most recent synthetic methods leading to each class of compounds. The authors were encouraged to adhere to this general scheme, however their own ideas on the content of the chapter and personal style were fully honored. I would like to thank all the authors and coauthors of the individual chapters for their excellent and timely contributions. Also, I would like to give special acknowl- edgments to the Wiley-VCH editorial staff, in particular to Anne Brennfuehrer who inspired me to take up the challenge of developing this book and guided me through all the steps of the editorial process and to Lesley Belﬁt who took care of all the technical aspects of book preparation.

Łod´ z,´ May 2013 Tomasz Janecki XV

List of Contributors

Srinivasa Rao Adusumalli Venkata Ramana Doddi Indian Institute of Science CSIR-Indian Institute of Education and Research (IISER) Chemical Technology Bhopal Organic and Biomolecular Department of Chemistry Chemistry Division Bhopal 462 023 Tarnaka Uppal Road Madhya Pradesh Hyderabad 500 007 India India

Łukasz Albrecht Dimitris Georgiadis Lodz University of Technology National and Kapodistrian Institute of Organic Chemistry University of Athens Z˙ eromskiego 116 Department of Chemistry 90-924 Łod´ z´ Laboratory of Organic Chemistry Poland Panepistimiopolis Zografou 15771 Athens Anna Albrecht Greece Lodz University of Technology Institute of Organic Chemistry Tomasz Janecki Department of Chemistry Lodz University of Technology Z˙ eromskiego 116 Department of Chemistry 90-924 Łod´ z´ Institute of Organic Chemistry Poland Z˙ eromskiego 116 90-924 Łod´ z´ Miguel Carda Poland Universidad Jaume I Departamento de Qu´ımica Juan Alberto Marco Inorganica´ y Organica´ Universidad de Valencia Castellon´ Departamento de Qu´ımica Spain Organica´ Burjassot Valencia 46100 Spain XVI List of Contributors

Paul V. Murphy Isamu Shiina National University of Ireland Tokyo University of Science Galway Department of Applied Chemistry School of Chemistry Faculty of Science University Road 1-3 Kagurazaka Galway Shinjuku-ku Ireland Tokyo 162-8601 Japan Kenya Nakata Shimane University Girija S. Singh Department of Chemistry University of Botswana Graduate School of Science and Chemistry Department Engineering Private Bag: 0022 1060 Nishikawatsu-cho Gaborone Matsue Botswana Shimane 690-8504 Japan Siji Sudheesh University of Botswana Carmela Napolitano Chemistry Department National University of Ireland Private Bag: 0022 Galway Gaborone School of Chemistry Botswana University Road Galway Andrei K. Yudin Ireland University of Toronto Davenport Research Laboratories Vishal Rai Department of Chemistry Indian Institute of Science 80 St. George Street Education and Research (IISER) Toronto, Ontario M5S 3H6 Bhopal Canada Department of Chemistry Bhopal 462 023 Madhya Pradesh India

Gangavaram V. M. Sharma CSIR-Indian Institute of Chemical Technology Organic and Biomolecular Chemistry Division Tarnaka Uppal Road Hyderabad 500 007 India 1

1 Tetronic Acids Dimitris Georgiadis

1.1 Introduction

Tetronic acids belong to the class of 4-hydroxybutenolides that are characterized by a 4-hydroxy-2(5H)-furanone ring, as it can be seen in the generic structure of Scheme 1.1 [1]. This type of ﬁve-membered vinylogous acids can be met in two main tautomeric forms (1 and 2)withenolstructure1 being the one that predominates. Tetronic acid is a substructural element of many natural products of various classes such as alkaloids, terpenes, macrolides, and tannins. Two well-known natural products of this class are ascorbic acid (3) and penicillic acid (4). In many cases, its presence in natural products is connected with a wide range of signiﬁcant biological properties and, therefore, the synthesis of these compounds has attracted synthetic interest for more than a century. In the following section, a synopsis of the natural occurrence, biological activities, and biosynthetic considerations of tetronic acid natural products will be attempted and a more thorough analysis of the synthetic strategies toward such compounds will be presented. Categorization of tetronic structures is based on 5-position’s substitution and discussion on synthetic routes toward these compounds will be limited on total syntheses with main focus to the construction of tetronic ring.

1.2 Natural Occurrence, Biological Activities, and Biosynthesis

A large group of tetronic natural products isolated from numerous fungi, molds, and lichens are pulvinic acids (16) and their decarboxylated analogs, pulvinones (14) [2]. The ﬁrst pulvinic derivative was isolated by Berbet in 1831 from the lichen Cetraria vulpina, whereas the ﬁrst pulvinone was isolated by Gill in 1973 by the mushroom Boletus elegans [3]. Pulvinic dimers such as norbadione A (from bolete Xerocomus badius [4]) and sclerocitrin (from puffball Scleroderma citrinum [5]) have also been isolated and they have been biosynthetically linked with the dimerization of xerocomic acid by an ingenious mechanism proposed

Natural Lactones and Lactams: Synthesis, Occurrence and Biological Activity, First Edition. Edited by Tomasz Janecki. © 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA. 2 1 Tetronic Acids

HO HO OH MeO 4 3 O 5 2 1 HO O O O O O O O Me HO O 1 2 HO Generic structures Ascorbic acid (3) Penicillic acid (4) of a tetronic acid

Scheme 1.1 Generic structure of a tetronic acid and structures of ascorbic acid (3)and penicillic acid (4).

by Steglich et al. [5]. Vulpinic acid and analogs have displayed anti-inflammatory, antipyretic, and analgesic properties, but several of these compounds are cytotoxic [6]. Norbadione A, di-O-methyl atromentic acid, and derivatives exhibit marked antioxidant and radioprotective properties [7], whereas variegatic and xerocomic acids are inhibitors of cytochrome P450 enzymes [8]. In addition, norbadione A acts as a strong Cs2+ chelator and has been studied for applications in 137Cs decontamination [9]. Biosynthetically, pulvinic acids and pulvinones are related to terphenylquinones (9 and 10) and grevillins (11), two isomeric classes of natural products that stem from the dimerization of arylpyruvates 7 that directly connects them with the shikimate pathway (Scheme 1.2) [2a]. This was supported by feeding experiments that established l-phenylalanine and l-tyrosine as essential building blocks for their biosynthesis [10] as well as the identification of the atromentin’s gene cluster that delineated the biogenetic relation of tyrosine with 10 [11]. 3-Acyl tetronic acids are probably the biologically most interesting class of tetronic acid natural products. For example, tetronasin [12], an ionophore antibiotic produced from Streptomyces longisporoflavus, is used as an animal-feed supplement and interferes with the selective permeation of ions across lipid bilayers causing depolar- ization of the membrane and death [13]. This molecule tends to bind metal ions by using its 3-acyl-tetronic moiety. RK-682, a simple 3-palmitoyl-5-hydroxymethylene tetronic acid isolated from various Actinomycetes and Streptomycetes sources [14], is a potent inhibitor of HIV-1 protease [14a] and various protein tyrosine kinases and phosphatases [14b] (including VHR and cdc25B) by acting as a phosphate mimic. In 2010, Sun et al. [15] reported the full reconstruction of RK-682 biosynthesis by using recombinant enzymes via a pathway that shares many common features with that of spirotetronate antibiotics that will be discussed later. Indications from feeding/NMR (nuclear magnetic resonance) experiments have shown that the biosynthesis of relevant agglomerins [16] may follow a similar pathway that is based on the incorporation of a glyceryl unit into the tetronic ring [17]. On the contrary, in 1962, an alternative route has been proposed by Bentley et al. [18] for the biosynthesis of 3-acyl tetronic acids isolated from molds (carlic, carolic, and carlosic acids) that involves enzymatic acylation of γ-methyl tetronic derivatives derived from C4-dicarboxylic acids. A group of tetronic acid natural products with challenging structural patterns from both synthetic and biosynthetic viewpoints and interesting antibiotic and antitumor properties are the spirotetronic natural products. Tetrocarcin A (TCA) is produced by Micromonospora chalcea NRRL 11289 and possesses a polycyclic 1.2 Natural Occurrence, Biological Activities, and Biosynthesis 3

O OH Ar Ar Ar Ar O O OH OH O OH O OH H Oxidation Dimerization + NH2 OH Ar O OH O HO O O O Ar Ar 8 Ar Ar 5: Ar = Ph 7 6: Ar = (p-OH)Ph 9: Polyporic acid (Ar = Ph) 11: Grevillins 10: Atromentin [Ar = (p-OH)Ph] Oxidation Ar OH HO O O HO Ar OH O OH Ar Ar CO2H HO Ar Ar O CO2H Ar Ar OH − HO Ar O O CO2 OH O HO Ar 15 14 O 13 12 HO O 16

Scheme 1.2 Biosynthesis of pulvinic acids (16) and pulvinones (14). 4 1 Tetronic Acids

aglycon (tetronolide) that features a trans-decalin system and a tetronate moiety spiro linked with a cyclohexene ring and two sugar side chains heavily respon- sible for their biological activity [19]. TCA-induced apoptosis in tumor cells [20] can be mediated by (i) antagonizing the mitochondrial functions of proteins of the Bcl-2 family (natural apoptosis inhibitors) in HeLa cells [20a], (ii) activating the caspase-dependent cell death pathway via endoplasmic reticulum stress in lymphomas [20b,c], and (iii) inhibiting the phosphorylation of factors involved in phosphatidylinositol 3-kinase/Akt signaling in human breast cancer cells [20d]. On bioassay using experimental mouse models, TCA exhibited remarkable antitumor activities without signiﬁcant myelosuppression and associated nephrotoxicity [21]. Arisostatins A and B, two tetrocarcins of similar biological properties, have been isolated in 2000 from Micromonospora sp. TP-A0316 [22]. Recent results have indicated that arisostatin A induces apoptosis in HN-4 cells by mediating loss of mitochondrial transmembrane potential, release of cytochrome C into cytosol and generation of reactive oxygen species [23]. More than 60 structurally related compounds have been reported from strains of various Gram-positive bacteria (Actinomycetes) and nearly all of them possess antibacterial and antitumor activities. Well-known examples include the ﬁrst member to be discovered in this family, chlorothricin [24], as well as kijanimicin [25], lobophorins A–F [26], MM46115 [27], and versipelostatin [28]. Chlorothricin acts as an inhibitor of pyruvate carboxylase

that catalyzes the anaplerotic CO2 fixation on synthetic media and it is able to inhibit cholesterol biosynthesis via the mevalomalonate pathway [29]. Kijanimicin has a broad spectrum of antimicrobial activity against Gram-positive bacteria, anaerobes, and the malaria parasite Plasmodium falciparum and also shows antitumor activity [25, 30]. Interestingly, lobophorins A and B exhibit anti-inflammatory and not antibiotic properties, based on experiments performed in the PMA-induced mouse ear edema model [26a]. Versipelostatin down-regulates the expression of GRP78, a molecular chaperone in the endoplasmic reticulum that plays an important role as a surviving factor in solid tumors because of its acquisition of a resistant mechanism against both chemotherapy and hypoglycemic stress [28, 31]. Later, it was demonstrated that versipelostatin can specifically inhibit the activation of the unfolded protein response (UPR), in response to glucose deprivation [31]. The result of versipelostatin action is enhanced sensitivity to glucose deprivation with enhanced cell death after exposure to the drug in the glucose-deprived state. Another group of structurally related spirotetronate macrolides lacking the decalin core include spirotetronic tetramers quartromicins [32], spirohexenolides [33], and abyssomicins [34]. Spirohexenolide A displays strong cytotoxicity in the NCI-60 cell line and low toxicity in mice [33], whereas quartromicins exhibit antiviral activity against herpes simplex virus type 1, influenza virus type A, and HIV [32]. Natural atropoisomers abyssomicin C and atrop-abyssomicin C display significant antibiotic activity against a variety of Gram-positive bacteria, including methicillin- and vancomycin-resistant Staphylococcus aureus strains, with the second being the most active [34a, 35]. These molecules are the first natural products able to inhibit the p-aminobenzoic acid (pABA), a constituent of the folate pathway, by covalently 1.2 Natural Occurrence, Biological Activities, and Biosynthesis 5 binding to aminodesoxychorismate synthase via a Michael addition of a cysteine nucleophile [36]. Initial results from feeding experiments complemented by the identification of the gene clusters [37] of chlorothricin [37a], kijanimicin [37b], TCA [37c], abyssomicin [37d], and quartromicin [37e] as well as the related non-spiro tetronates tetronomycin [38] and RK-682 [15] have contributed to the elucidation of a rea- sonable biosynthetic route for the tetronate moiety (Scheme 1.3). In particular, a polyketide unit (19), synthesized by a module type I polyketide synthase (PKS), and a glycerol derived 3-carbon unit bound to an acyl carrier protein, ACP (glyceryl- S-ACP, 18) are combined to form the tetronate moiety. The latter is synthesized by an FkbH-like glyceryl-S-ACP synthase that catalyzes d-1,3-bisphosphoglycerate dephosphorylation and transfer to ACP. In the case of RK-682, the formation of the C–C and C–O bonds of the tetronic ring seems to be mediated by the action of the same synthase, but it is not clear in what order and whether this is also the case for other tetronic natural products. In the case of kijanimicin and TCA, an FAD- dependent oxidoreductase has been suggested to be involved in the dehydration and subsequent intramolecular (or intermolecular, in the case of quartromicins) Diels–Alder reaction, but it is still not clear whether such processes are catalyzed or spontaneous (e.g., a similar gene was not found in the case of abyssomicin). It should be noted that similar Diels–Alder reactions have been proposed for the biosynthesis of spirotetronic sesterterpenes ircinianin and wistarin [39]. In this case, the unprecedented occurrence of both wistarin enantiomers in nature may imply that this process is enzyme catalyzed. Finally, feeding/NMR experiments with versipelostatin imply the intermediacy of a glycerol unit in its biosynthesis, although no genetic data are still available [40].

OH O O− P PKS ACP ACP S O O O O SH S O O OH O HO O OH 19 O − HO O P O − OH PO 3 4 20 17 OH 18

O O O O

O HO HO O

22 21

Scheme 1.3 Biosynthetic route toward spirotetronates. 6 1 Tetronic Acids

1.3 5-Ylidene Tetronic Natural Products

1.3.1 Pulvinic Acids and Pulvinones

The representative examples of this family, as shown in Figure 1.1, are pulvinic acids (X = OH), vulpinic acids (X = OMe), and pulvinones (analogs lacking carboxyl or ester group). These compounds constitute a large group of 5-arylidenetetronates and can be extracted from lichenous and higher fungal sources [2a]. Since the pioneering synthesis of vulpinic acid (24) by Volhard in 1894 [41], the total synthesis of many members of this family has been described (Figure 1.1). From 1894 (Volhard’s syntheses of 23 and 24) until the early 1970s, hydrolysis (for pulvinic acids) or methanolysis (for vulpinic acids) of dilactones of type 38 was the main synthetic strategy (Scheme 1.4) [42]. Volhard’s dilactone approach was based on the condensation of diethyl oxalate and phenyl acetonitrile and subsequent acidic hydrolysis and dehydration [41]. Asano and Kameda [43] and Akermak [44] extended the methodology for unsymmetrical dilactones by the successive use of different aryl acetonitriles in the condensation step, but the ﬁnal formation of two = pulvinic isomers (39 and 40,Ar1 Ar2) after dilactone opening was unavoidable. Alternative routes to access dilactones 38 have also been developed [45], with the most important being the biosynthetically inspired oxidative rearrangement of aryl hydroxyquinones such as polyporic acid 9 [45b,c] or atromentin 10 [45a]. Among the various conditions used for this oxidation, Moore’s protocol [dimethyl

R3 R4 Pulvinic acid (23): R1−7 = H, X = OH Vulpinic acid (24): R1−7 = H, X = OMe Atromentic acid (25): R , , , , = H, R , = X = OH R2 1 2 4 5 7 3 6 Pinastric acid (26): R1−5,7 = H, R6 = X = OMe X Leprapinic acid (27): R − = H, R = X = OMe R 2 7 1 1 Variegatic acid (28): R , , = H, R , , , = X = OH O 1 2 5 3 4 6 7 O Xerocomic acid (29): R1,2,4,5 = H, R3,6,7 = X = OH O OH Gomphidic acid (30): R1,2,4 = H, R3,5,6,7 = X = OH Rhizocarpic acid (31): R − = H, X = PheOMe 1 7 − Calycin (32): R2−7 = H, R1 = X = −O Epanorin (33): R1−7 = H, X = LeuOMe (34)R1,2,4,5,7 = H, R3,6 = X = OMe R R 5 7 (35)R1,5,7 = H, R2,4 = Cl, R3,6 = X = OMe R6

HO O O HO HO OH OMe CO2H O O HO O O O O O O O HO2C OH

HO OH Norbadione A (37) Methyl bovinate (36) OH

Figure 1.1 Structures of naturally occurring pulvinic acids. 1.3 5-Ylidene Tetronic Natural Products 7 sulfoxide/acetic anhydride (DMSO/Ac2O)] was and still is the most widely used (i.e., Steglich’s synthesis of methyl bovinate (36) in 2008 [46]). Dilactone strategy has been the basis for the total synthesis of a variety of pulvinic/vulpinic acids, such as atromentic (25) [42a], pinastric (26) [42b,c], leprapinic (27) [42d], variegatic (28) [42e], xerocomic (29) [42f], gomphidic (30) [42g], rhizocarpic (31) [42h] acids, calycin (32) [44], and epanorin (33) [42h]. Nevertheless, with the only exception of Moore’s synthesis of vulpinic acid based on the thermal rearrangement of azidoquinone 41 to pulvinonitrile 42 followed by hydrolysis (Scheme 1.4) [47], no regiospeciﬁc methods have been reported during 80 years after Volhard’s introduction of dilactone strategy.

O O X (CO2Et)2, EtONa Hydrolysis OH (1) conc. H2SO4, O (Ar = Ar , Ref. 41) (X = OH) Ar1 CN 1 2 AcOH, H2O Ar 1 Ar1 Methanolysis (2) Ac O Ar2 + (CO2Et)2, EtONa or NaH 2 Ar2 (X = OMe) O Ar2 CN O 2 steps, (Ar1 = Ar2, Ref. 43,44) O 38 O 39 10, Ref. 45a) O /HCl (for H2 2 , AcOH (Ref. 45b) + Pb(OAc)4 2O (Ref. 45c) DMSO, Ac O O O O O Ar1 OH Ar Ph N3 1 O Ar , = Ph Δ, EtOH Ph 1 2 Ar2 HO Ar Ph HCl, HO 2 HO Ph (65%) MeOH (95%) HO O X O O NC 9 or 10 41 42 40

Scheme 1.4 Pulvinic acid synthesis from dilactones 38 and azidoquinone 41.

In 1975, Pattenden et al. reported the first regiospecific synthesis of permethylated pulvinic acids 46 [48] and pulvinones 45 [49] by condensation of 44 with aroyl formates and aryl aldehydes, respectively, followed by dehydration (Scheme 1.5). Interestingly, Pattenden’s pioneering work allowed the first total synthesis of naturally occurring pulvinones, first isolated from natural sources in 1973 [3b] but

O O O (1) Ar2COX, LAH O LICA, −78 °C O O Ar Ar Ar1 1 1 (2) p-TsOH, reflux (X = H) Ar2 O MeO or P2O5 (X = CO2Me) MeO MeO X 43 44 45: X = H 46: X = CO2Me O O Ph O 230 °C Ph Ph HO O O Ph 47 48

Scheme 1.5 Syntheses of pulvinic derivatives by Pattenden and Claisen. 8 1 Tetronic Acids

already produced by Claisen in 1895 [50] from the thermal rearrangement of a symmetrical trione (47 → 48, Scheme 1.5). In 1984, Ramage et al. [51] have demonstrated that dioxolane phosphorane 49 can lead to pulvinic acids and pulvinones after olefination with α-ketoesters or aldehydes, respectively, and Claisen condensation with arylacetic esters (Scheme 1.6). In the case of pulvinic acids [51b], regiospecificity can be controlled by proper choice of ester groups, as this was outlined in the synthesis of xerocomic acid (29). Ramage’s protocol was also used for the synthesis of multicolanic acid [51c], a tetronic metabolite found in Penicillium multicolor, which was previously synthesized by Pattenden via maleic anhydride chemistry [52]. In 2007, Bruckner’s group modified Ramage’s protocol by using similar phosphonates in order to replace the olefination step by a Horner–Wadsworth–Emmons (HWE) reaction [53].

Li+ O t-BuO O − Ar O Ar C HCO t-Bu, 1 2 2 O Ar1 OH − ° 78 C to r.t. OO OMe H OO Ar2 toluene, OO toluene, Ar1 80 °C 80 °C O O Ar1 O Ar1 Ar = (p-OBn)Ph O PPh 51 1 O 3 H O Ar = [3,4-di(OBn)]Ph 49 52 2 50 OMe + Li− Ar2C HCO2Me, −78 °C to r.t. (1) H2, Pd/C O (2) TFA, O anisole Ar2 Ar1 HO (29) (60%) 53 Ar1 = (p-OBn)Ph H2, Pd/C Ar2 = [3,4-di(OBn)]Ph (60%) 3′,4′,4-Trihydroxypulvinone (54)

Scheme 1.6 Syntheses of 29 and 54 by Ramage.

Working independently, Gill and Pattenden employed benzylacyloins (55)as synthetic precursors to obtain grevillins (58, pulvinic acids biosynthetic progenitors) and pulvinones 45, (Scheme 1.7). Synthesis of pulvinones by Gill [54] was based on a previous report by Smith’s group [55] and relies on the condensation of unsymmetrical bis-benzyl acyloins with carbonyldiimidazole. Similar condensation of 55 with oxalyldiimidazole (Gill’s method [54]) or esteriﬁcation with ethyloxalyl chloride followed by Dieckmann condensation (Pattenden’s method [56]) led to grevillins (58) that rearrange to quinones 59 [57], affording pulvinic acids after application of Moore’s protocol [45c]. In 1985, Campbell et al. [58] employed a Dieckmann condensation strategy to the synthesis of pulvinones. By this route, Campbell prepared tetronic acid 61 that can be either transformed to phosphorane 62 and utilized in Wittig reactions or condensed with arylaldehydes that can afford pulvinones after dehydration. The ﬁrst route led Steglich’s group in 2000 to the total synthesis of aurantricholides A (65) and B (66), two minor pigments of toadstool Tricholoma aurantium [59], whereas 1.3 5-Ylidene Tetronic Natural Products 9

(1) Me SO , 2 4 Ar1 Ar1 Ar1 K CO (1) LDA (1) ClCOCO Et, Et N 2 3 2 3 O OH (2) NBS, hv, HO O (2 equiv.) O (2) DBU reflux (2) O=C(imid)2 or O (3) DBU OH (1) LDA (2 equiv.) O O (2) (COimid) 2 Ar 45 Ar2 56 Ar2 55 2 57

Ar1 Ar1 (3) DBU (1) CH N O OH 2 2 O OH (4) BBr (2) Br2, AcOH EtONa 3

HO O O O Ar 2 Ar2 58 59

Scheme 1.7 Use of benzylacyloins in the synthesis of pulvinic derivatives. the second one was used for the total synthesis of pulverolide (69), a pigment isolated from Pulveroboletus ravenelii, by Yang et al. [60] in 2010 (Scheme 1.8).

O − MeO OH Br + O O OEt Ph3P MeO MeO OMe 63 + Ar Ar1 O 1 EtONa, r.t. HO MeO O Ar1 (Ar = Ph, 62%) OMe O (Ar = (p-OMe)Ph, 29%) O O 62 64

EtONa (1) Me2SO4, K2CO3 (quant.) (2) NBS, AIBN (86%) (1) hv (3) PPh3 (2) BBr O 3 OH Ar OEt t-BuOK HO O O (68%) Ar1 Ar O O 1 O O O HO 60 61 Aurantricholide A (65): Ar = Ph, (80%) OBn Aurantricholide B (66): Ar = (p-OH)Ph, (56%) MeO O LDA 67 OH Ph OBn OH O OH ° MeO MW, 245 C, O NH OAc 4 O Ph MeO O OH OH 68 O Pulverolide (69), (80%)

Scheme 1.8 Total syntheses of aurantricholides A and B and pulverolide.

Furthermore, the Dieckmann condensation strategy has also been employed in the synthesis of pulvinic acids [61]. Interestingly, 30 years after the ﬁrst relevant report by Weinstock et al. [61a], the group of Le Gall [61b] presented a versatile route for that purpose. Le Gall improved the synthesis of tetronic acid 61, previously prepared by Campbell et al. [58], by devising a tandem transesteriﬁcation/Dieckmann 10 1 Tetronic Acids

OH (1) LDA O (1) NaOH CO Me (2) NIS, AcOH Cl (1) MeO C 2 OH (2) CO Me OH 2 2 t-BuOK (2.2 equiv.) (3) PdCl 2(PPh3)2 OH MeO2C 2M Na CO MeO DMF, rt XO DCC, DMAP 2 3 Ar Ar Ar 26 Cl (2) LHMDS O 35 O (X = OMe, 90%) O O (3) (CF CO) O, Et N Ph B (3) (CF CO) O, 70 3 2 3 O 3 2 O O pyridine (57%) (X = OH, 53%) 71 61 (4) hv, toluene (Ar = (p-OMe)Ph) (40%)

(1) Pd(OAc)2, Cy2NMe. Et4NBr

O I O OH OCH2CF3 BnO 73 (1) t-BuOK, DMF OCH2CF3 O O (2) CF CH OLi O O 3 2 BnO (2) Cy NMe,2 rt HO − ° O (3) DCC, DMAP 75 O BCl3, 78 C O 72 O HO (60%) (41%) Aspulvinone B (76), O O 74

Scheme 1.9 Total syntheses of aspulvinone B and pulvinic acids 26 and 35. 1.3 5-Ylidene Tetronic Natural Products 11 condensation and offered the first total synthesis of 35 after application of Patten- den’s arylidenation (Scheme 1.9) [48a]. Moreover, Le Gall et al. [61c] demonstrated that the use of aryl acetates of dimethyl tartrate can lead to tetronic acid 71 that can be coupled by aryl groups after iodination and Suzuki coupling reaction, thus affording pinastric acid (26). Recent reports on improved pulvinone synthesis based on Dieckmann condensation have also appeared [62] with that of Bruckner’s¨ group succeeding on the total synthesis of several naturally occurring aspulvinones (i.e., aspulvinone B, Scheme 1.9) [62a]. Bruckner¨ introduced aryl groups of aspulvinones before the Dieckmann condensation by using a Heck reaction to 2-acetoxyacrylate 72 and subsequent esterification with arylacetic acids. In 1991, Pattenden exploited the inherent regioselectivity of nucleophilic addi- tions on β-methoxy maleic anhydrides to prepare gomphidic acid (30)bytwo different routes (Scheme 1.10) [63]. The first one involves an HWE reaction between phosphonate 80 and aryl pyruvate 81 [63b], and the second one is based on a Reformatsky-type reaction of 77 with zinc enolates derived from aryl acetate 79 [63c].

O O O (1) NaH O 1. LDA, ZnCl2 (1) MsCl O O Ar2 O − ° − ° Ar (MeO) P(O)ONa (2) DBN 78 C to 60 C 1 2 Ar1 81 CO Me Ar1 OH H 2 30 30 reflux (3) hv Ar2 2. Ar2 O O (2) hv MeO P (3) TMSI, EtOH (4) TMSI, EtOH 79 CO2Me (21%) MeO HO 77 OMe CO2Me (Ar = (p-OMe)Ph) MeO (Ar2 = (p-OMe)Ph) (49%) 78 2 (27%) (Ar1 = 3,4,5(OMe)3Ph) 80 (14%)

Scheme 1.10 Total syntheses of gomphidic acid by Pattenden.

In a series of reports, Langer’s group studied the synthesis of pulvinic acids via a TMSOTf-catalyzed [3+2] cyclization of 1,3-bis-(trimethylsilyloxy)-1,3-dienes (e.g., 83) with oxalyl chloride followed by Suzuki coupling of product triflates (Scheme 1.11) [64]. Langer’s versatile method was applied to the synthesis of almost all natural pulvinic acids (e.g., xerocomic acid 29), including norbadione A(37) by Le Gall et al. [65]. In a modification of Langer’s protocol, Mioskowski dimerized simple silyl ketene acetals (e.g., 85) to obtain symmetrical pulvinic acids via an uncatalyzed reaction with (COCl)2 (Scheme 1.11) [66]. In 2006, Le Gall et al. [67] presented a conceptually different approach for the synthesis of pulvinic acids, starting from commercial tetronic acid 87 (Scheme 1.12). The protocol involves application of Pattenden’s arylidenylation by aroyl formates, iodination, and aryl coupling by Suzuki reaction. The utility of Le Gall’s method was exemplified by the synthesis of vulpinic (24) and pinastric (26) acid.

1.3.2 Agglomerins

Agglomerins constitute a group of 3-acyl-5-methylidene tetronic acids with antibiotic activity [16]. Synthetic efforts toward agglomerins started by Ley and coworkers 12 1 Tetronic Acids

OTf O O TMSO OTMS (1) TMSCl, Et3N, r.t. − ° MeO O MeO (2) LDA, THF, 78 C (1) (COCl)2, TMSOTf, MeO MeO (3) TMSCl, −78 °C to r.t. −78 °C to r.t. O O MeO B(OH)2 OMe OMe Xerocomic (2) Tf O, pyridine, 2 acid (29) −78 °C to −10 °C MeO (1) Pd(PPh3)4, K3PO4, reflux ° OR OR (2) TMSI, 55 C OR (R = Me, 22% from 82) 82 83 84

O O O (1) PdCl (PPh ) , (1) Cl 2 3 2 Cl Na2CO3 MeO O (2) AcOH (1 equiv.) O OTMS B Pyrrolidine (3) Me SI 25 3 Norbadione A (37) TMSO (2) DBU, MeOH B O (R = Bn) (3) conc. HCl OO (4) 0.5N NaOH (12% from 86) 85 (60%) 86

Scheme 1.11 Application of Langer’s chemistry to the synthesis of pulvinic derivatives.