Biotransformation for l-ephedrine production

Abstract

l-ephedrine is widely used in pharmaceutical preparations as a decongestant and anti-asthmatic compound. One of the key intermediates in its production is l-phenylacetylcarbinol (l-PAC) which can be obtained either from plants (Ephedra sp.), chemical synthesis involving resolution of a racemic mixture, or by biotransformation of benzaldehyde using various yeasts.

In the present review, recent significant improvements in the microbial biotransformation are assessed for both fed-batch and continuous processes using free and immobilised yeasts. From previous fed-batch culture data, maximal levels of l-PAC of 10–12 gl⁻¹ were reported with yields of 55–60% theoretical based on benzaldehyde. However, recently concentrations of more than 22 gl⁻¹ have been obtained using a wild-type strain of Candida utilis. This has been achieved through optimal control of yeast metabolism (via microprocessor control of the respiratory quotient, RQ) in order to enhance substrate pyruvate production and induce pyruvate decarboxylase (PDC) activity. Processes involving purified PDC have also been evaluated and it has been demonstrated that l-PAC levels up to 28 gl⁻¹ can be obtained with yields of 90–95% theoretical based on the benzaldehyde added. In the review the advantages and disadvantages of the various strategies for the microbial and enzymatic production of l-PAC are compared.

In view of the increasing interest in microbial biotransformations, l-PAC production provides an interesting example of enhancement through on-line control of a process involving both toxic substrate (benzaldehyde) and end-product (l-PAC, benzyl alcohol) inhibition.