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
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.
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