Synthetic Methods for Biologically Active Molecules: Exploring the Potential of Bioreductions

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


Table of Contents:
Preface

DEVELOPMENT OF SUSTAINABLE BIOCATALYTIC REDUCTION PROCESSES FOR ORGANIC CHEMISTS
Introduction
Biocatalytic Reductions of C=O Double Bonds
Biocatalytic Reductions of C=C Double Bonds
Biocatalytic Reductions of Imines to Amines
Biocatalytic Reductions of Nitriles to Amines
Biocatalytic Deoxygenation Reactions
Emerging Reductive Biocatalytic Reactions
Reaction Engineering for Biocatalytic Reduction Processes
Summary and Outlook

REDUCTASES: FROM NATURAL DIVERSITY TO ESTABLISHED BIOCATALYSIS AND TO EMERGING ENZYMATIC ACTIVITIES
Reductases: Natural Occurrence and Context for Biocatalysis
Emerging Cases of Reductases in Biocatalysis
Concluding Remarks

SYNTHETIC STRATEGIES BASED ON C=C BIOREDUCTIONS FOR THE PREPARATION OF BIOLOGICALLY ACTIVE MOLECULES
Introduction
Bioreduction of Alpha,Beta-Unsaturated Carbonyl Compounds
Bioreduction of Nitroolefins
Bioreduction of Alpha,Beta-Unsaturated Carboxylic Acids and Derivatives
Bioreduction of Alpha,Beta-Unsaturated Nitriles
Concluding Remarks

SYNTHETIC STRATEGIES BASED ON C=O BIOREDUCTIONS FOR THE PREPARATION OF BIOLOGICALLY ACTIVE MOLECULES
Introduction
Synthesis of Biologically Active Compounds through C=O Bioreduction
Other Strategies to Construct Biologically Active Compounds
Summary and Outlook

PROTEIN ENGINEERING: DEVELOPMENT OF NOVEL ENZYMES FOR THE IMPROVED REDUCTION OF C=C DOUBLE BONDS
Introduction
The Protein Engineering Process and Employed Mutagenesis Methods
Examples of Rational Design of Old Yellow Enzymes
Evolving Old Yellow Enzymes (OYEs)
Conclusions and Perspectives

PROTEIN ENGINEERING: DEVELOPMENT OF NOVEL ENZYMES FOR THE IMPROVED REDUCTION OF C=O DOUBLE BONDS
Introduction
Detailed Characterization of PAR
Detailed Characterization of LSADH
Engineering of PAR for Increasing Activity in 2-Propanol/Water Medium
Application of Whole-Cell Biocatalysts Possessing Mutant PARs and LSADH
Engineering of Beta-Keto Ester Reductase (KER) for Raising Thermal Stability and Stereoselectivity
New Approach for Engineering or Obtaining Useful ADHs/Reductases

SYNTHETIC APPLICATIONS OF AMINOTRANSFERASES FOR THE PREPARATION OF BIOLOGICALLY ACTIVE MOLECULES
Introduction
Applications
Challenges
Future Research Needs
Conclusions

STRATEGIES FOR COFACTOR REGENERATION IN BIOCATALYZED REDUCTIONS
Introduction: NAD(P)H as the Universal Reductant in Reduction Biocatalysis
The Most Relevant Cofactor Regeneration Approaches - and How to Choose the Most Suitable One
Coupling the Reduction Reaction to a Regeneration Reaction Producing a Valuable Compound
Avoiding NAD(P)H: Does it Also Mean Avoiding the Challenge?
Conclusions

SOLVENT EFFECTS IN BIOREDUCTIONS
Introduction
Solvent Systems for Biocatalytic Reductions
Solvent Control of Enzyme Selectivity
Concluding Remarks

APPLICATION OF IN SITU PRODUCT REMOVAL (ISPR) TECHNOLOGIES FOR IMPLEMENTATION AND SCALE-UP OF BIOCATALYTIC REDUCTIONS
Introduction
Process Requirements for Scale-Up
Bioreduction Process Engineering
In situ Product Removal
Biocatalyst Format
Selected Examples
Future Outlook
Conclusions

BIOREDUCTIONS IN MULTIENZYMATIC ONE-POT AND CASCADE PROCESSES
Introduction
Coupled Oxidation and Reduction Reactions
Consecutive and Cascade One-Pot Reductions
Cascade Processes, Including Biocatalyzed Reductive Amination Steps
Other Examples of Multienzymatic Cascade Processes, Including Bioreductive Reactions

DYNAMIC KINETIC RESOLUTIONS BASED ON REDUCTION PROCESSES
Introduction
Cyclic Compounds
Acyclic Alpha-Substituted-Beta-Keto Esters and 2-Substituted-1,3-Diketones
Acyclic Ketones and Aldehydes
Conclusions

RELEVANT PRACTICAL APPLICATIONS OF BIOREDUCTION PROCESSES IN THE SYNTHESIS OF ACTIVE PHARMACEUTICAL INGREDIENT
Introduction
Ketoreductases
Ene Reductases
Others
Bioreduction-Supported Processes
Outlook

Index


About the Author :
Elisabetta Brenna received her laurea (1989) and PhD (1993) in chemistry from the University of Milan. In 1996, she became Assistant Professor at Politecnico di Milano, where she is now Associate Professor. Her main scientific interests are the enzyme-mediated synthesis of the single enantiomers of chiral biologically active compounds, and the use of the SNIF NMR technique for tracing back the synthetic history of active pharmaceutical ingredients and synthetic flavourings. She is author of more than 120 publications in international journals.