Biotransformations in the Preparation of Compounds Labeled with Carbon and Hydrogen Isotopes

Abstract

Biotransformations are selective chemical modifications of molecules by biological entities ranging from isolated enzymes (cell-free systems) to intact organisms 1 . In particular cases they are exploited by the chemical and pharmaceutical industries for production of chemicals; this approach can be especially advantageous for structurally complex compounds 2 . Preparative biotransformations have been used on a laboratory scale by radiochemists to prepare isotopically labeled compounds 3 necessary for drug development and other applications in the life sciences. Their synthetic use for isotope labeling includes:. selective modifications of individual functional groups; . synthesis of structurally complex molecules from less complex isotopically labeled precursors; . synthesis of key intermediates for reconstitution approaches to labeled compounds (see Chapter 10).Enzymes are proteins able to catalyze reactions with very high regio-and/or stereoselectivities under mild conditions. Those enzymes combining low substrate specificity (broad applicability) with high product selectivity are of optimal suitability for organic synthesis. Further increase of structural variety and stability by protein-and mediumengineering 4 has extended their synthetic applicability significantly and made them important tools in organic synthesis. The broad scope of their synthetic use is documented in numerous papers, reviews and textbooks 5 . Although successful in particular applications, biotransformations are less common in isotopic labeling.As the complexity of the biological system varies from highly purified enzymes to whole cell-containing systems, so do some of the practical dimensions of the experiments vary. Therefore this chapter is organized accordingly.In one-step biotransformations particularly, isolated enzymes have distinctive advantages, since they can be used simply, almost like any chemical reagent, and -importantly for isotopic labeling -they do not result in any isotope dilution. Since a large number of enzymes are commercially available, many types of reactions can be carried out.Examples of the use of isolated enzymes in isotopic labeling include N-or O-acylations, hydrolyses, redox reactions and group transfer reactions. Most of them aim for applications such as racemate resolution, catalysis of reactions and synthesis of enantiomerically pure molecules. Optical Resolutions via DerivativesDespite the availability of several chemical strategies for diastereo-and enantioselective syntheses in isotopic labeling (see Chapter 11), kinetic racemate resolution remains a major application of enzymes in the chemistry of isotopically labeled compounds. Depending on the molecular entity, different possibilities have been described for achieving enantioselective differentiation through either derivatization (e.g. N-acyl formation and cleavage, O-acyl formation and cleavage) or selective degradation (e.g. redox reactions). N-Acyl Formation: Enzymatically catalyzed N-acylation of racemates is used for preparative synthesis of ...