Chemoenzymatic Process For The Preparation Of (S)-7-((Tert-Butyldiphenylsilyl)Oxy)Hept-1-Yn-4-Ol In A Continuous Packed-Bed Reactor, A Key Intermediate For Eribulin Synthesis

A practical chemoenzymatic process has been developed for the preparation of optically pure (S)-7-((tert-butyldiphenylsily)oxy)hept-l-yn-4-ol, (S)-4. This was prepared via enantioselective acylation of racemic homopropargylic alcohol (+/-)-4 catalyzed by Amano lipase from Pseudomonas fluorescens. The acylation reaction was studied in a packed-bed reactor (PBR) for the production of optically pure alcohol (S)-4 in a continuous mode. The estimated kinetic parameters were V-max 3.46 (+/- 0.17) mM/h/g and apparent K-m value, K-m,K-app = 582.10 (+/- 29.10) mM (correlation coeff. r = 0.96). At a substrate concentration of 100 mg/mL (272 mM) and a flow rate of 0.1 mL/min, both the isomers are obtained in >95% theoretical yield and > 99% e.e. at steady state in a PBR with 3.6 g enzyme. The advantage of this protocol is that the enzyme can be recycled many times. Finally, this was converted to (R)-tert-butyl((4-chloro-6-iodohept-6-en-1-yl)oxy)diphenylsilane, 3, which is the key building block for the synthesis of the C14-C19 intermediate of eribulin.