A practical
chemoenzymatic process has been developed for the preparation
of optically pure (S)-7-((tert-butyldiphenylsilyl)oxy)hept-1-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,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.
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