Enantiopure Alcohols by Combining Enzymatic Resolution with in-situ Racemisation

Dr R. Broxterman, DSM, Netherlands

This presentation concerned the development of an industrial process based on work carried out by Professor J-E. Bäckvall in Stockholm on the dynamic kinetic resolution of secondary alcohols. Typically this involves acylating one enantiomer of a racemic mixture in the presence of an enzyme and an organometallic catalyst (to racemise and recycle the off-enantiomer by oxidation / reduction). In this way yields up to 100% are theoretically possible as opposed to a maximum 50% in the absence of the organometallic catalyst.

There were 3 issues to tackle from an industrial perspective – the acyl donor (4-chlorophenyl acetate was used by Bäckvall), the racemisation catalyst, and the amount of biocatalyst required. In the optimised process immobilised Candida Antarctica lipase (Novozyme 435 ®) is used as biocatalyst, ruthenium complex (7) is used, in place of the "SHVO" catalyst (8), for racemisation in toluene as solvent. Isopropenyl acetate, isopropyl acetate or isopropyl butyrate can be used as the acyl donor depending on the ester required.

The by-product from isopropenyl acetate (acetone) has to be removed as it is formed by distillation to avoid “transfer oxidation” of the product and potassium carbonate (0.2mol%) is also required to neutralise any acetic acid formed, as this forms an inactive ruthenium acetate complex. Under these conditions yields over 90% and ee’s >98% are achievable using either aromatic or aliphatic alcohols as substrates and this technology has been demonstrated on scale.