Lactams, resolution with enzymes

An efficient procedure for the large-scale preparation of (lSy2S)-trans-2-methoxycyclohexanol ((+)-102), a key intermediate in the synthesis of a new class of tricyclic jS-lactam antibiotics (104), has been developed by Glaxo Wellcome [96]. The key step of the synthesis was the enzyme-catalyzed resolution of rac-102 with immobilized Candida antarctica B lipase (Scheme 31). Novo 435 was used for the asymmetric acylation of rac-102 and provided direct access to the important alcohol (+)-102 in good yield and high optical purity. The enzyme exhibited excellent stability and retained about half of its initial activity after nine cycles of use. This process is now operating on a manufacturing scale. 

Based on the structural similarities of amino acid amides with ACL, we predicted that ACL racemase catalyzed the racemization of not only the cyclic amino lactam compounds but also amino acid amides. We soon discovered that ACL racemase from Achromobacter obae catalyzed the racemization of amino acid amides, such as 2-aminobutyramide and alanine amide [22], A previous study demonstrated that D-alanine was produced efficiently from L-alanine amide by a dynamic kinetic resolution reaction when the enzyme was used together with DAP from O. anthropi [23]. It had previously been unclear whether ACL racemase catalyzed the racemization of simple amino acid amides. 

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