Chemical Synthesis of Nucleoside Analogues

Pedro Merino

• Publisher: Wiley
• Year: 2013
• Print ISBN: 9781118007518
• eBook ISBN: 9781118498101
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Biochemistry
• Index: Biological Sciences

Compiles current tested and proven approaches to synthesize novel nucleoside analogues

Featuring contributions from leading synthetic chemists from around the world, this book brings together and describes tested and proven approaches for the chemical synthesis of common families of nucleoside analogues. Readers will learn to create new nucleoside analogues with desired therapeutic properties by using a variety of methods to chemically modify natural nucleosides, including:

• Changes to the heterocyclic base
• Modification of substituents at the sugar ring
• Replacement of the furanose ring by a different carbo- or heterocyclic ring
• Introduction of conformational restrictions
• Synthesis of enantiomers
• Preparation of hydrolitically stable C-nucleosides

Chemical Synthesis of Nucleoside Analogues covers all the major classes of nucleosides, including pronucleotides, C-nucleosides, carbanucleosides, and PNA monomers which have shown great promise as starting points for the synthesis of nucleoside analogues. The book also includes experimental procedures for key reactions related to the synthesis of nucleoside analogues, providing a valuable tool for the preparation of a number of different compounds.

Throughout the book, chemical schemes and figures help readers better understand the chemical structures of nucleoside analogues and the methods used to synthesize them. Extensive references serve as a gateway to the growing body of original research studies and reviews in the field.

Synthetically modified nucleosides have proven their value as therapeutic drugs, in particular as antiviral and antitumor agents. However, many of these nucleoside analogues have undesirable side effects. With Chemical Synthesis of Nucleoside Analogues as their guide, researchers have a new tool for synthesizing a new generation of nucleoside analogues that can be used as therapeutic drugs with fewer unwanted side effects.

Chapter 1: Biocatalytic Methodologies for Selective Modified Nucleosides

Miguel Ferrero, Susana Fernández and Vicente Gotor

Departamento de Química Orgánica e Inorgánica y Instituto Universitario de Biotecnología de Asturias, Universidad de Oviedo, Oviedo, Asturias, Spain

1.1 Introduction

Nucleosides are fundamental building blocks of biological systems that are widely used as therapeutic agents to treat cancer, fungal, bacterial, and viral infections.¹ Since the latter 1980s, nucleoside analogues have been investigated with renewed urgency in the search for agents effective against the human immunodeficiency virus (HIV) and to use as a more effective treatment for other viral infections. This has resulted in an explosion of synthetic activity in the field of nucleosides, and consequently, extensive modifications have been made to both the heterocyclic base and the sugar moiety to avoid the drawbacks shown by nucleosides or analogues in certain applications.

The intense search for clinically useful nucleoside derivatives has resulted in a wealth of new approaches to their synthesis, and most important, their enantioselective synthesis. Thus, especially for organic chemists, biocatalytic methods have been recognized as practical procedures in the nucleoside area.² For the manipulation of protecting groups, the use of biocatalysts in organic synthesis has become an attractive alternative to conventional chemical methods, due to their simple feasibility and high efficiency. In general, these catalysts are inexpensive and satisfy increasingly stringent environmental constraints. Due to these advantages, biocatalyzed reactions are playing an increasing role primarily in the preparation of nonracemic chiral biologically active compounds not only in the laboratory but also in industrial production, in which enzyme-catalyzed chemical transformations are in great demand in the pharmaceutical and chemical industries.³ In addition, enzyme-catalyzed reactions are less hazardous, less polluting, and less energy consuming than are conventional chemistry-based methods.

The synthetic potential of enzymes related to nucleoside synthesis has been applied profusely, especially since the introduction of organic solvent methodology. It is our aim in this chapter to cover the literature of the last decade or so relative to nucleosides with selected examples because of special significance. Our desire is to show a range of examples that cover nucleoside analogue syntheses through enzymatic procedures and to summarize and offer an easily accessible visual reference review. Due to the vastness of the bibliographic material related to nucleosides, we do not cover other enzymatic processes, such as preparation of nucleoside antibiotics using microorganisms,⁴ nucleoside syntheses mediated by glycosyl transfer,⁵ or halogenation enzymes.⁶

Most enzymatic reactions, just like those included here, are performed by a small number of biocatalysts. With the passing of time, their nomenclature has changed in an effort to unify criteria and to refer to a given enzyme by only one name. Table 1.1 lists the enzymes mentioned in this review, sorted alphabetically. These are cited as in the original papers to facilitate checking the original work, together with their corresponding new denominations.

Table 1.1 Enzymes Commonly Used in Biocatalytic Processes Shown in This Review

Accepted Name (Abbreviation)

Other Denominations

Adenosine deaminase (ADA) Adenylate deaminase (AMPDA) 5′-adenylic acid deaminase, AMP deaminase Candida antarctica lipase A (CAL-A) lipase A Candida antarctica lipase B (CAL-B) Novozym-435, SP-435, lipase B Candida rugosa lipase (CRL) Candida cylindracea lipase (CCL) ChiroCLEC BL Lipase M (from Mucor javanicus) Lipozyme Mucor miehei lipase, Lipozyme IM Pseudomanas cepacia lipase (PSL) Pseudomonas sp. lipase, Pseudomonas fluorescens lipase (PFL), PCL, lipase P, lipase PS, LPS, amano PS, amano lipase PS Burkholderia cepacia Pig liver esterase (PLE) Porcine pancreas lipase (PPL) Subtilisin Thermomyces lanuginosa lipase (TL IM) Lipozyme TL IM

To simplify the schemes, Figure 1.1 collects the common abbreviations of nucleoside bases, their protected version used in this chapter, and their structures.

Figure 1.1 Pyrimidine and purine bases, their more common protected versions used in this review, and their abbreviations.

1.2 Transformations on the sugar moiety

Modification of nucleosides via enzymatic acylation has been one of the most extensively used methodologies over recent years, since in some cases a simple acylation of one of the hydroxyl groups in a nucleoside can result in an increase in their biological activity compared with that of the unmodified derivative.⁷

1.2.1 Enzymatic Acylation/Hydrolysis

An interesting family of nucleoside analogues is that of the amino sugar nucleosides, since they possess anticancer, antibacterial, and antimetabolic activities.⁸ Gotor, Ferrero, and co-workers have synthesized, through short and convenient syntheses, pyrimidine 3′,5′-diamino analogues of thymidine (T),⁹ 2′-deoxyuridine (dU),⁹ 2′-deoxycytydine (dC^Bz),¹⁰ (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU, Brivudin),¹¹ and the purine 3′,5′-diamino analogue of 2′-deoxyadenosine (dA^Bz).¹⁰ Regioselective protection of one of the primary amino groups situated in the 3′- or 5′-position is a very difficult task, since traditional chemical methods do not distinguish between them, and moreover, there are other reactive points on the molecule, such as the nitrogen atoms on the bases. They report the regioselective enzymatic acylation of the amino groups in the sugar moiety of pyrimidine and purine 3′,5′-diaminonucleosides.^{9, 12} This enzymatic strategy made it possible for the first time to regioselectively synthesize N^3′- or N^5′-acylated pyrimidine and purine 3′,5′-diamino nucleoside derivatives by means of a very simple and convenient procedure using immobilized Pseudomonas cepacia lipase (PSL-C) or Candida antartica lipase B (CAL-B) as a biocatalyst, respectively (Scheme 1.1).

Scheme 1.1

Although oxime esters are good acylating agents in regioselective enzymatic acylations of nucleosides,¹³ nonactivated esters such as alkyl esters are used since amines are much more nucleophilic than alcohols, and they react nonenzymatically with oxime esters. To confer versatility to this enzymatic reaction, other acyl moieties besides acetyl, such as formyl, alkyl, alkenyl, or aryl, are introduced.

An efficient new approach to the synthesis of oligonucleotides via a solution-phase H-phosphonate coupling method has been reported.¹⁴ It is particularly suitable when multikilogram quantities of oligonucleotides are required and is an alternative method of choice to traditional solid-phase synthesis. The key building blocks for solution-phase oligonucleotide synthesis are 3′- and/or 5′-protected nucleosidic monomers. Among the limited protecting groups available, the levulinyl group is frequently chosen to protect the 3′- and/or 5′-hydroxyl of the nucleosides, since this group is stable to coupling conditions and can be cleaved selectively without affecting other protecting groups in the molecule. Until recently, the preparation of these building blocks has been carried out through several tedious chem...

Table of contents

• Cover
• Title Page
• Copyright
• Dedication
• Contributors
• Foreword
• Preface
• Chapter 1: Biocatalytic Methodologies for Selective Modified Nucleosides
• Chapter 2: Nucleosides Modified at the Base Moiety
• Chapter 3: Chemical Synthesis of Acyclic Nucleosides
• Chapter 4: Phosphonated Nucleoside Analogues
• Chapter 5: Chemical Syntheses of Nucleoside Triphosphates
• Chapter 6: Mononucleotide Prodrug Synthetic Strategies
• Chapter 7: Synthesis of C-Nucleosides
• Chapter 8: Methodologies for the Synthesis of Isomeric Nucleosides and Nucleotides of Antiviral Significance
• Chapter 9: Synthesis of Conformationally Constrained Nucleoside Analogues
• Chapter 10: Synthesis of 3′-Spiro-Substituted Nucleosides: Chemistry of TSAO Nucleoside Derivatives
• Chapter 11: l-Nucleosides
• Chapter 12: Chemical Synthesis of Carbocyclic Analogues of Nucleosides
• Chapter 13: Uncommon Three-, Four-, and Six-Membered Nucleosides
• Chapter 14: Recent Advances in Synthesis and Biological Activity of 4′-Thionucleosides
• Chapter 15: Recent Advances in the Chemical Synthesis of Aza-Nucleosides
• Chapter 16: Stereoselective Methods in the Synthesis of Bioactive Oxathiolane and Dioxolane Nucleosides
• Chapter 17: Isoxazolidinyl Nucleosides
• Chapter 18: Synthetic Studies on Antifungal Peptidyl Nucleoside Antibiotics
• Chapter 19: Chemical Synthesis of Conformationally Constrained PNA Monomers
• Index