This review describes the remarkable transition in the manufacture of β‐lactam antibiotics, which is driven by the desire to reduce or eliminate the production of waste and the dependence on organic solvents. To this effect, traditional chemical procedures are gradually being replaced by biotransformations. The β‐lactam antibiotics industry has led the way in the introduction of biocatalysis in the fine chemicals industry by replacing the chemical multi‐step process for the penicillin nucleus 6‐aminopenicillanic acid (6‐APA) by an enzymatic one in the early 1990's. Recently, bioprocesses have been developed for the synthesis of the cephalosporin nucleus, 7‐aminodeacetoxycephalosporanic acid (7‐ADCA) from a penicillin precursor and will shortly be commercialized. Thirty years of research have now resulted in viable enzymatic procedures for coupling the β‐lactam nuclei with D‐phenylglycine side‐chains. The necessary adaptations in the synthesis of the side‐chain donors have likewise resulted in more efficient procedures. 1 Introduction 2 Semi‐Synthetic β‐Lactam Antibiotics: Industrial Production Prior to 1985 3 Biocatalytic Synthesis of β‐Lactam Nuclei 3.1 6‐Aminopenicillanic Acid 3.2 7‐Aminodeacetoxycephalosporanic Acid 4 Biocatalytic Routes to Side‐Chains 4.1 Synthesis of the Side‐Chain Building Blocks 4.2 Synthesis of Activated Side‐Chain Donors 5 Enzymatic Coupling of the Side‐Chains to the β‐Lactam Nuclei 5.1 Chemical Procedures 5.2 Enzymatic Coupling 5.3 Practical Procedures for Enzymatic Coupling6 Conclusion and Future Outlook

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A truly catalytic procedure is described for the esterification of a-amino acids, thereby circumventing the formation of stoichiometric quantities of salts associated with conventional procedures. The acid form of ultrastable zeolite Y (H-USY), a naphtha cracking catalyst, acted as a solid acid catalyst in the reaction of several a-amino acids with methanol at 100-130 °C (15-20 bar). For example, L-phenylalanine afforded the methyl ester in 83% yield after 20 h at 100 °C. Based on the (unlikely) participation of all the Al atoms of the zeolite this corresponded to a turnover number of 180. The ester product was partially racemised (52% ee). Phenylglycine, p-hydroxyphenylglycine and homophenylalanine were similarly converted to their methyl esters. The H-USY catalyst could be recycled albeit with decreased activity after each cycle owing to the adsorption of water (formed in the reaction). Its activity was completely restored, however, after calcination.

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The hydration of d-phenylglycine nitrile to the corresponding amide, mediated by nitrile hydratase-containing microorganisms, was studied. Batch and fed-batch reactions were compared with regard to degradation and racemisation of the chemically labile substrate. A batch process gave satisfactory results and at up to 25 mM d-phenylglycine nitrile (d-1), d-phenylglycine amide was obtained in 94% yield with 92% ee using an immobilised Rhodococcus sp. (NOVO SP 361). The enzyme could be reused, although it slowly lost its activity. When the concentration of d-phenylglycine nitrile was increased to 100 mM in a batch reaction rapid decomposition of the substrate was observed and d-phenylglycine amide was obtained in only 37% yield. A fed-batch reaction afforded an improved yield, although the decomposition of the substrate could not be avoided completely. Lowering the temperature stabilised the substrate, and a fed-batch reaction at 5 °C resulted in a 96% yield of d-phenylglycine amide with 95% ee. A number of other whole-cell hydratase/amidase systems also hydrated d-1 in nearly quantitative yield and >94% ee. Moreover, the ee was further increased to >99% upon prolonged reaction times with minimal loss in yield due to the action of the l-specific amidase that is present in these biocatalysts.

A cascade of two enzymatic transformations is employed in a one-pot synthesis of cephalexin. The nitrile hydratase (from R. rhodochrous MAWE)-catalyzed hydration of D-phenylglycine nitrile to the corresponding amide was combined with the penicillin G acylase (penicillin amidohydrolase, E.C. 3.5.1.11)-catalyzed acylation of 7-ADCA with the in situ-formed amide to afford a two-step, one-pot synthesis of cephalexin. D-Phenylglycine nitrile appeared to have a remarkable selective inhibitory effect on the penicillin G acylase, resulting in a threefold increase in the synthesis/hydrolysis (S/H) ratio. 1,5-Dihydroxynaphthalene, when added to the reaction mixture, cocrystallized with cephalexin. The resulting low cephalexin concentration prevented its chemical as well as enzymatic degradation; cephalexin was obtained at 79% yield with an S/H ratio of 7.7.