Enzymic preparation of (3R-cis)-3-(acetyloxy)-4-phenyl-2-azetidinone: a taxol side-chain synthon.

Abstract

A key chiral intermediate [(3R-cis)-3-(acetyloxy)-4-phenyl-2-azetidinone (2)] for the semi-synthesis of paclitaxel (taxol; 5), an anti-cancer compound, was prepared by an enzymic process. The stereoselective enzymic hydrolysis of cis-3-(acetyloxy)-4-phenyl-2-azetidinone (1) to the corresponding (S)-(-)-alcohol (3) was carried out using various lipases. Lipase PS-30 (Pseudomonas cepacia) and BMS (Bristol-Myers Squibb) lipase (Pseudomonas sp. SC13856) catalysed hydrolysis of the undesired enantiomer of racemic compound 1, producing the (S)-(-)-alcohol (3) and the desired (R)-(+)-acetate (2). Reaction yields of > 96% and optical purities of > 99.5% were obtained. For a very efficient enzyme source (BMS lipase), a lipase fermentation using Pseudomonas sp. SC13856 was developed. In a fed-batch process using soybean oil, the fermentation resulted in 1500 units of extracellular lipase activity/ml. Crude BMS lipase (1.7 kg, containing 140,000 units/g) was recovered from the filtrate by ethanol precipitation. BMS lipase and commercially available lipase PS-30 were independently immobilized on Accurel polypropylene. These immobilized lipases were re-used (ten cycles) without loss of enzyme activity, productivity or optical purity of the product. The enzymic reaction process was scaled up to 75 and 150 litres using immobilized BMS lipase and lipase PS-30 respectively. From the reaction mixture, compound 2 was isolated in 88-90 mol% yield and 99.5% optical purity. A purity of 99.9 (area %) was demonstrated by g.c. for isolated compound 2.

• Authors: R N Patel, A Banerjee, R Y Ko, J M Howell, W S Li, F T Comezoglu, R A Partyka, F T Szarka
• Journal: Biotechnology and applied biochemistry (Biotechnol Appl Biochem) Vol. 20 Issue 1 Pg. 23-33 (08 1994) ISSN: 0885-4513 [Print] United States
• PMID: 7917063 (Publication Type: Journal Article)

Chemical References

• 3-(acetyloxy)-4-phenyl-2-azetidinone
• Antineoplastic Agents
• Azetidines
• Enzymes, Immobilized
• Lipase
• Paclitaxel

Topics

• Antineoplastic Agents (chemical synthesis)
• Azetidines (chemical synthesis)
• Catalysis
• Enzymes, Immobilized
• Lipase
• Molecular Structure
• Paclitaxel (chemical synthesis)
• Pseudomonas (enzymology)
• Stereoisomerism