Towards Biocatalytic Synthesis of β-Lactam Antibiotics

Abstract

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

Industrial Methods for the Production of Optically Active Intermediates

“…d-Phenylglycine and d-hydroxyphenylglycine, which are incorporated in the side chains of semisynthetic b-lactam antibiotics, are produced in this way. [30] As hydantoins racemize spontaneously at pH > 8, the complete conversion of the racemate into one enantiomer is possible. The rate of racemization is depends on side chain R. If the racemization of the hydantoin is the rate-determining step of the reaction, the reaction can be accelerated significantly by the addition of a racemase (Scheme 9).…”

l-Selective Amidase with Extremely Broad Substrate Specificity fromOchrobactrum anthropiNCIMB 40321

“…Examples of important ␣-hydrogen-␣-amino acids are D-phenylglycine (DPhg) and D-p-hydroxyphenylglycine, which are produced as side chains for the manufacture of semisynthetic ␤-lactam antibiotics such as ampicillin, amoxicillin, and cephalexin (14,53), and D-valine, an intermediate for the pyrethroid insecticide fluvalinate (28). Another frequently used ␣-hydrogen-␣-amino acid is L-tert-leucine, which is used as a building block for a variety of antiviral (e.g., anti-human immunodeficiency virus), antiarthritis, and anticancer drugs under development and as a chiral auxiliary in chemical asymmetric synthesis (5,10).…”

Penicillin acylase-catalyzed synthesis of N-bromoacetyl-7-aminocephalosporanic acid, the key intermediate for the production of cefathiamidine

“…For example, PAs have been used widely for several decades for the industrial production of β-lactam nuclei—6-aminopenicillanic acid (6-APA) and 7-amino-3-deacetoxycephalosporanic acid (7-ADCA) via hydrolysis of penicillin G and cephalosporin G, respectively (Arroyo et al 2003; Wegman et al 2001). In addition, PAs have proven to be excellent catalysts for the N -acylation of β-lactam nuclei via thermodynamically or kinetically controlled strategies, which affords semi-synthetic β-lactam antibiotics such as ampicillin, amoxicillin, cefazolin, and cephalexin (Wegman et al 2001; Volpato et al 2010; Srirangan et al 2013). Currently, the large-scale enzymatic production of many semi-synthetic β-lactam antibiotics such as cephalexin has been realized with PAs as biocatalysts (Wegman et al 2001; Bruggink et al 1998).…”