Natural Lactones and Lactams

Synthesis, Occurrence and Biological Activity

Tomasz Janecki

• Publisher: Wiley-VCH
• Year: 2013
• Print ISBN:
  9783527334148
• eBook ISBN:
  9783527666935
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Organic Chemistry

While there are numerous books on heterocycles and natural products, this text fills the need for an up-to-date summary focusing on recently developed and improved synthetic methods for the preparation of the most important classes of lactones and lactams - all in one volume.
Comprehensive in its coverage, this book also provides readers with a brief description of the occurrence and biological or pharmaceutical activity of the compounds, and each chapter deals with a certain class of lactones or lactames to enable quick access to the information needed.
A valuable resource for organic chemists, biochemists and medicinal chemists in academia and industry wanting to learn about successful synthetic routes leading to important natural products and use this as inspiration for their own work in the lab.

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) with enol structure 1 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.

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

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 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].

Scheme 1.2 Biosynthesis of pulvinic acids (16) and pulvinones (14).

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 depolarization 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 aglycon (tetronolide) that features a trans-decalin system and a tetronate moiety spiro linked with a cyclohexene ring and two sugar side chains heavily responsible 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 memb...

Table of contents

• Cover
• Related Titles
• Title Page
• Copyright
• Preface
• List of Contributors
• Chapter 1: Tetronic Acids
• Chapter 2: Recent Advances in the Field of Naturally Occurring 5,6-Dihydropyran-2-ones
• Chapter 3: β-Lactams
• Chapter 4: α-Alkylidene-γ- and δ-Lactones and Lactams
• Chapter 5: Medium-Sized Lactones
• Chapter 6: Macrolactones
• Chapter 7: Resorcylic Acid Lactones
• Chapter 8: Cyclic Peptides
• Index