Synthetic Methods for Biologically Active Molecules E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 634

Veröffentlichungsjahr: 2013

Beschreibung

This useful reference focuses on the currently available toolbox of bio-catalysed reductions of C=O, C=C and formal C=N bonds to show which transformations can be reliably used in manufacturing processes and which still require improvements.

Following an introductory chapter, chapters 2-4 present the synthetic strategies that are currently available for the reduction of C=C and C=O bonds and for reductive amination, by means of whole-cell catalysts and isolated enzymes. Chapters 5-7 go on to describe the improvements achieved thus far, illustrating the current versatility of enzymes in organic synthesis. Chapters 8-12 present the improvements brought about by the optimization of reaction conditions, and the use of particular synthetic sequences. The final chapter describes practical applications of bio-reductions for the synthesis of active pharmaceutical ingredients.

With its excellent and comprehensive overview, this book will be of great interest to those working in academia and industry.


From the contents:
* Development of Sustainable Biocatalyzed Reduction Processes for Organic Chemists
* Reductases: From Natural Diversity to Biocatalysis and Emerging Enzymatic Activities.
* Synthetic Strategies Based on C=C Bioreductions
* Synthetic Strategies Based on C=O Bioreductions
* Development of Novel Enzymes for the Improved Reduction of C=C Double Bonds
* Development of Novel Enzymes for the Improved Reduction of C=O Double Bonds
* Synthetic Applications of Aminotransferases
* Strategies for Cofactor Regeneration in Biocatalyzed Reductions
* Effects of Solvent System and Substrate Loading in Bioreduction
* Perspectives in the Use of In-Situ Product Removal (ISPR) Techniques in Bioreductions
* Multi-Enzymatic Cascade Reactions Based on Reduction Processes
* Relevant Practical Applications of Bioreduction Processes in the Synthesis of Active Pharmaceutical Ingredients

Leseprobe

Contents

Cover

Related Titles

Title Page

Copyright

Preface

List of Contributors

Chapter 1: Development of Sustainable Biocatalytic Reduction Processes for Organic Chemists

1.1 Introduction

1.2 Biocatalytic Reductions of C=O Double Bonds

1.3 Biocatalytic Reductions of C=C Double Bonds

1.4 Biocatalytic Reductions of Imines to Amines

1.5 Biocatalytic Reductions of Nitriles to Amines

1.6 Biocatalytic Deoxygenation Reactions

1.7 Emerging Reductive Biocatalytic Reactions

1.8 Reaction Engineering for Biocatalytic Reduction Processes

1.9 Summary and Outlook

References

Chapter 2: Reductases: From Natural Diversity to Established Biocatalysis and to Emerging Enzymatic Activities

2.1 Reductases: Natural Occurrence and Context for Biocatalysis

2.2 Emerging Cases of Reductases in Biocatalysis

2.3 Concluding Remarks

References

Chapter 3: Synthetic Strategies Based on C=C Bioreductions for the Preparation of Biologically Active Molecules

3.1 Introduction

3.2 Bioreduction of α,β-Unsaturated Carbonyl Compounds

3.3 Bioreduction of Nitroolefins

3.4 Bioreduction of α,β-Unsaturated Carboxylic Acids and Derivatives

3.5 Bioreduction of α,β-Unsaturated Nitriles

3.6 Concluding Remarks

References

Chapter 4: Synthetic Strategies Based on C=O Bioreductions for the Preparation of Biologically Active Molecules

4.1 Introduction

4.2 Synthesis of Biologically Active Compounds through C=O Bioreduction

4.3 Other Strategies to Construct Biologically Active Compounds

4.4 Summary and Outlook

References

Chapter 5: Protein Engineering: Development of Novel Enzymes for the Improved Reduction of C=C Double Bonds

5.1 Introduction

5.2 The Protein Engineering Process and Employed Mutagenesis Methods

5.3 Examples of Rational Design of Old Yellow Enzymes

5.4 Evolving Old Yellow Enzymes (OYEs)

5.5 Conclusions and Perspectives

References

Chapter 6: Protein Engineering: Development of Novel Enzymes for the Improved Reduction of C=O Double Bonds

6.1 Introduction

6.2 Detailed Characterization of PAR

6.3 Detailed Characterization of LSADH

6.4 Engineering of PAR for Increasing Activity in 2-Propanol/Water Medium

6.5 Application of Whole-Cell Biocatalysts Possessing Mutant PARs and LSADH

6.6 Engineering of β-Keto Ester Reductase (KER) for Raising Thermal Stability and Stereoselectivity

6.7 New Approach for Engineering or Obtaining Useful ADHs/Reductases

References

Chapter 7: Synthetic Applications of Aminotransferases for the Preparation of Biologically Active Molecules

7.1 Introduction

7.2 Applications

7.3 Challenges

7.4 Future Research Needs

7.5 Conclusions

References

Chapter 8: Strategies for Cofactor Regeneration in Biocatalyzed Reductions

8.1 Introduction: NAD(P)H as the Universal Reductant in Reduction Biocatalysis

8.2 The Most Relevant Cofactor Regeneration Approaches – and How to Choose the Most Suitable One

8.3 Coupling the Reduction Reaction to a Regeneration Reaction Producing a Valuable Compound

8.4 Avoiding NAD(P)H: Does It Also Mean Avoiding the Challenge?

8.5 Conclusions

References

Chapter 9: Solvent Effects in Bioreductions

9.1 Introduction

9.2 Solvent Systems for Biocatalytic Reductions

9.3 Solvent Control of Enzyme Selectivity

9.4 Concluding Remarks

References

Chapter 10: Application of In situ Product Removal (ISPR) Technologies for Implementation and Scale-Up of Biocatalytic Reductions

10.1 Introduction

10.2 Process Requirements for Scale-Up

10.3 Bioreduction Process Engineering

10.4 In situ Product Removal

10.5 Biocatalyst Format

10.6 Selected Examples

10.7 Future Outlook

10.8 Conclusions

References

Chapter 11: Bioreductions in Multienzymatic One-Pot and Cascade Processes

11.1 Introduction

11.2 Coupled Oxidation and Reduction Reactions

11.3 Consecutive and Cascade One-Pot Reductions

11.4 Cascade Processes Including Biocatalyzed Reductive Amination Steps

11.5 Other Examples of Multienzymatic Cascade Processes, Including Bioreductive Reactions

References

Chapter 12: Dynamic Kinetic Resolutions Based on Reduction Processes

12.1 Introduction

12.2 Cyclic Compounds

12.3 Acyclic α-Substituted-β-Keto Esters and 2-Substituted-1,3-Diketones

12.4 Acyclic Ketones and Aldehydes

12.5 Conclusions

References

Chapter 13: Relevant Practical Applications of Bioreduction Processes in the Synthesis of Active Pharmaceutical Ingredients

13.1 Introduction

13.2 Ketoreductases

13.3 Ene Reductases

13.4 Others

13.5 Bioreduction-Supported Processes

13.6 Outlook

Acknowledgments

References

Index

Related Titles

Whittall, J., Sutton, P.W. (eds.)

Practical Methods for Biocatalysis and Biotransformations 2

2012

ISBN: 978-1-119-99139-7

Cossy, J., Arseniyadis, S. (eds.)

Modern Tools for the Synthesis of Complex Bioactive Molecules

2012

ISBN: 978-0-470-61618-5

Drauz, K., Gröger, H., May, O. (eds.)

Enzyme Catalysis in Organic Synthesis

Third, Completely Revised and Enlarged Edition

2012

ISBN: 978-3-527-32547-4

Yeh, W., Yang, H., McCarthy, J.R.

Enzyme Technologies

Metagenomics, Evolution, Biocatalysis and Biosynthesis

2010

ISBN: 978-1-118-12503-8

Loos, K. (ed.)

Biocatalysis in Polymer Chemistry

2011

ISBN: 978-3-527-32618-1

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Preface

Since the last decade, chemical industry has been showing a continuous and urgent need for the development of sustainable manufacturing processes, with the reduction of greenhouse gas emission and waste output and replacement of toxic and/or dangerous reagents. Process chemists have turned their attention to the employment of enzyme catalysis in the development of synthetic procedures, especially for the preparation of high-value products in the life science area, such as biologically active molecules and active pharmaceutical ingredients. Efforts have been devoted to optimize biotechnological tools for organic synthesis and to investigate the efficiency and the substrate specificity of biocatalyzed reactions in order to make them a first choice in practical synthetic applications.

This book is intended to describe the state of the art of these efforts for the advantage of both the academic and the industrial audience. The book will focus on the current available toolbox of biocatalyzed reductions of C=O, C=C, and formal C=N double bonds, in order to show (i) which are the reliable biocatalyzed transformations to be used by organic chemists involved in the development of manufacturing processes, and (ii) which are the biotransformations still requiring improvements and investigations. Bioreductions have been chosen as the main topic of the book, because of their widespread applications in organic synthesis and their versatility in the creation of stereogenic centers in chiral molecules.

Chapters 1 and 2 will give an overview of the advantages of enzyme-catalyzed reductions and of the efforts devoted to investigate the emerging enzyme-reducing capabilities. Chapters 3 and 4 will present the synthetic strategies that are currently available for the reduction of C=C and C=O double bonds by means of whole-cell catalysts and isolated enzymes. Chapters 5 and 6 will describe the improvements achieved up to now for these two kinds of bioreduction by manipulation of the enzymes, according to the different approaches of protein engineering. These chapters will show the versatility that is currently possible in adapting the enzymes to the requests of organic synthesis. Chapter 7 will give a survey of the application of the process of enzymatic reductive amination catalyzed by transaminases for the preparation of chiral amines.

Chapters 8–12 will present the improvements brought about by the optimization of reaction conditions (e.g., the choice of the cofactor regeneration system, the nature of the solvent, and the employment of in situ product removal technologies) and the use of particular synthetic procedures (e.g., multienzymatic one-pot and cascade reactions or dynamic kinetic resolution methods).

Finally, Chapter 13 will describe the actual practical applications of bioreductions for the synthesis of important types of biologically active molecules.

Elisabetta Brenna

Politecnico di Milano

Dipartimento di Chimica

Materiali ed Ingegneria Chimica

Milano

Italy

List of Contributors

Elisabetta Brenna

Politecnico di Milano

Via Mancinelli 7

20131 Milano

Italy

Aníbal Cuetos

University of Oviedo

Departamento de Química Orgánica e Inorgánica

c/Julian Claveria 8

33006 Oviedo

Spain

Pablo Domínguez de María

RWTH Aachen University

Institut für Technische und Makromolekulare Chemie (ITMC)

Worringer Weg 1

52074 Aachen

Germany

Alba Díaz-Rodríguez

University of Oviedo

Departamento de Química Orgánica e Inorgánica

c/Julian Claveria 8

33006 Oviedo

Spain

Elena Fernández-Álvaro

GlaxoSmithKline

Diseases of the Developing World Medicines Development Campus

Parque Tecnológico de Madrid

c/Severo Ochoa, 2

28760 Tres Cantos

Spain

Erica E. Ferrandi

Istituto di Chimica del Riconoscimento Molecolare, CNR

Via Mario Bianco 9

20131 Milano

Italy

Francesco G. Gatti

Politecnico di Milano

Dipartimento di Chimica

Materiali e Ingegneria Chimica “Giulio Natta”

Via Mancinelli 7

20131 Milano

Italy

Mélanie Hall

University of Graz

Department of Chemistry

Organic and Bioorganic Chemistry

Heinrichstraße 28

8010 Graz

Austria

Frank Hollmann

Delft University of Technology

Department of Biotechnology

Julianalaan 136

2628BL Delft

The Netherlands

Nobuya Itoh

Toyama Prefectural University

Biotechnology Research Center and

Department of Biotechnology

Kurokawa 5180

Imizu

Toyama 939-0398

Japan

Dimitris Kalaitzakis

University of Crete

Department of Chemistry

Heraklion-Voutes Campus

Heraklion

71003 Crete

Greece

Sanjay Kamat

Hospira Inc.

215 North Field Drive, Bldg. H3-3N

Lake Forest

IL 60045

USA

Selin Kara

Delft University of Technology

Department of Biotechnology

Julianalaan 136

2628BL Delft

The Netherlands

Sabrina Kille

Max-Planck-Institut für Kohlenforschung

Kaiser-Wilhelm-Platz 1

45470 Mülheim an der Ruhr

Germany

and

Department of Chemistry

Philipps-University Marburg

Hans-Meerwein-Strasse

35032 Marburg

Germany

Iván Lavandera

University of Oviedo

Departamento de Química Orgánica e Inorgánica

c/Julian Claveria 8

33006 Oviedo

Spain

Yoshihide Makino

Toyama Prefectural University

Biotechnology Research Center and

Department of Biotechnology

Kurokawa 5180

Imizu

Toyama 939-0398

Japan

Daniela Monti

Istituto di Chimica del Riconoscimento Molecolare, CNR

Via Mario Bianco 9

20131 Milano

Italy

Abraham R. Mártin-García

Universidad de Sonora

Departamento de Ingeniería Química y Metalurgia

Blvd. Luis Encinas y Rosales S/N

Hermosillo

Sonora 83000

México

Yan Ni

East China University of Science and Technology

State Key Laboratory of Bioreactor Engineering

Laboratory of Biocatalysis and Synthetic Biotechnology

Meilong Road 130

Shanghai 200237

China

Sachin Pannuri

Agennix Ag

101 College Road East

Princeton

NJ 08540

USA

Fabio Parmeggiani

Politecnico di Milano

Dipartimento di Chimica

Materiali e Ingegneria Chimica “Giulio Natta”

Via Mancinelli 7

20131 Milano

Italy

Manfred T. Reetz

Max-Planck-Institut für Kohlenforschung

Kaiser-Wilhelm-Platz 1

45470 Mülheim an der Ruhr

Germany

and

Department of Chemistry

Philipps-University Marburg

Hans-Meerwein-Strasse

35032 Marburg

Germany

Alessandro Sacchetti

Politecnico di Milano

Dipartimento di Chimica

Materiali e Ingegneria Chimica “Giulio Natta”

Via Mancinelli 7

20131 Milano

Italy

Joerg H. Schrittwieser

Delft University of Technology

Department of Biotechnology

Julianalaan 136

2628BL Delft

The Netherlands

Ioulia Smonou

University of Crete

Department of Chemistry

Heraklion-Voutes Campus

Heraklion

71003 Crete

Greece

Gábor Tasnádi

University of Graz

ACIB GmbH c/o

Organic and Bioorganic Chemistry

Heinrichstraße 28

8010 Graz

Austria

Roland Wohlgemuth

Sigma-Aldrich Chemie GmbH

Industriestrasse 25

9470 Buchs

Switzerland

John M. Woodley

Technical University of Denmark

Department of Chemical and Biochemical Engineering

Center for Process Engineering and Technology

Søltofts Plads

2800 Lyngby

Denmark

Jian-He Xu

East China University of Science and Technology

State Key Laboratory of Bioreactor Engineering

Laboratory of Biocatalysis and Synthetic Biotechnology

Meilong Road 130

Shanghai 200237

China

Hui-Lei Yu

East China University of Science and Technology

State Key Laboratory of Bioreactor Engineering

Laboratory of Biocatalysis and Synthetic Biotechnology

Meilong Road 130

Shanghai 200237

China

1

Development of Sustainable Biocatalytic Reduction Processes for Organic Chemists

Roland Wohlgemuth

1.1 Introduction

Among the different factors contributing to a good chemical manufacturing process, the process efficiency and specifically volume–time output in terms of reactor capacity and cycle time, respectively, have been given the largest weight – among the conversion costs, with material cost being the second [1]. Raw materials or intermediates with a higher oxidation state than the target products are often preferred to oxidations on an industrial scale due to process safety and toxicity concerns [2] and therefore have to be transformed in one or more reduction processes to the desired oxidation state; the importance to use as few redox steps as possible in a multistep synthesis has been outlined in the concept of redox economy [3–5]. Nonselective reductions often require additional protection–deprotection steps influencing process economy and leading to waste that scales stoichiometrically with increasing production. Therefore, the reduction of the number of synthetic steps by highly selective and sustainable reduction processes in organic synthesis is of key importance and has influenced the development of reduction processes, reagents, and tools (see Figure 1.1 for route selection in reductions). The variety of reducing agents, from simple molecular hydrogen with chiral or nonchiral catalysts in catalytic hydrogenations to reducing equivalents from inorganic or organic reagents with the required reducing power for the specific reduction, has enabled a large number of selective reduction reactions. The scope of reducing agents has been greatly expanded from the use of hydrogen gas in catalytic hydrogenation, the preparation of nongaseous reducing agents like lithium aluminum hydride and sodium borohydride, to the development of highly selective boranes by HC Brown, representing a milestone of organic synthesis and optically active organoboranes and providing versatile synthetic methodologies for asymmetric reductions of prochiral ketones, whereby the chiral auxiliary is recovered in an easily recyclable form [6–8]. With the growing importance of safety, health, and environment aspects, the nature of the reducing agents, the transition from stoichiometric to catalytic reductions, and the development of sustainable chemistry have received increased attention [9]. Among the many synthetic methodologies available for reduction reactions, biocatalysis [10–20] has become an attractive choice in organic chemistry due to progress in understanding fundamental structure–function relationships and engineering of enzymes, their applications to organic synthesis, and developing novel enzymes to solve synthetic challenges in organic chemistry.

Figure 1.1 Biocatalytic reduction processes and the optimization of the redox state changes and the number of one-pot reaction steps over the synthetic sequence, whereby additional criteria like material costs, yields, and step combinations in one-pot reaction play a role in route selection.

Key advances over the past 10 years have established biocatalysis as a practical, robust, and sustainable methodology in both laboratory and industrial chemical syntheses of bulk and specialty chemicals for a variety of industries [21–22]. The biocatalysts in the BRENDA database [23], which contains functional biochemical and molecular enzyme data and about 62 000 unique fully characterized reactions, can be searched according to EC subclasses for known reduction reactions in various ways. The widely used differentiation between alcohol dehydrogenases and carbonyl reductases or ketoreductases is based on the directional preference, expressed as the ratio of the reaction rate constants for the reduction and the oxidation direction, which have been for the first time reengineered by active site redesign of a parent dehydrogenase into an effectively “one-way” reductase [24]. Ready-to-use biocatalysts in the form of whole cells or isolated enzymes have become practical tools for the organic chemist to perform enzymatic reductions with high selectivity [25].

1.2 Biocatalytic Reductions of C=O Double Bonds

The synthetic applications of the biocatalytic reduction of C=O double bonds are also described in detail in Chapter 4, while Chapter 6 describes the use of protein engineering to develop novel enzymes for the improved reduction of C=O double bonds.

1.2.1 Biocatalytic Reductions of Ketones to Alcohols

The biocatalytic asymmetric reduction of ketones to alcohols has been of great interest to organic chemists over many decades [26–28]. A large range of reactions with an even larger number of ketone substrates carrying a variety of substituent functional groups has been developed. Microbial reduction of phenylglyoxylic acid to mandelic acid by yeast has been found more than a century ago [29]. The investigation of the absolute stereochemical course of hydride transfer to carbonyl groups of decalin derivatives in reductions by microorganisms like Curvularia falcata has led Vladimir Prelog to rationalize these numerous experimental facts by a simple scheme connecting the substrate orientation in the plane of the carbonyl group with the spatial hydride transfer relative to this plane, later called Prelog's rule (), for the absolute configuration of the obtained chiral alcohols [30,31]. Prelog's rule states that the alcohols that were formed by the microbial reductions studied had all the ()-configuration and explains this fact by the pro- hydride transfer from the cofactor to the Re-face of the carbonyl group, a property not only of the microbial reducing agents used but also of the oxidoreductase enzymes [32,33]. The later discoveries of microorganisms and alcohol dehydrogenases, for example, from [34,35], sp., and [36,37], with the pro- hydride transfer from the cofactor to the opposite Si-face of the carbonyl group leading to alcohols with the ()-configuration are described to have anti-Prelog enantioselectivity. The catalytic asymmetric reduction of prochiral cyclohexanones to their corresponding axially chiral ()- and ()-alcohols is a reduction where chiral transition metal catalysts fail, but where excellent enantioselectivity has been achieved with alcohol dehydrogenases and the reversal of enantioselectivity by directed evolution [38].