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

Abstract

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.

Continuous Flow Chemistry: A Novel Technology for the Synthesis of Marine Drugs

“…On the other hand, avoiding expensive metal catalysts is also a challenge in industrial synthesis. In this regard, a chemoenzymatic process has recently been developed for the preparation of optically pure alcohol (45), a precursor of the building block (44) in the preparation of the C14-C19 intermediate (42) of eribulin (Scheme 12) [57]. Scheme 10.…”

“…The enzyme packed in the reactor could be used continuously for 1 week, maintaining a productivity of 1.12 mM/h/g. Finally, both compounds were treated and isolated properly to produce the desired pure alcohol (S)-45 with a 90% overall yield and >99% e.e (Scheme 14) [57]. Scheme 14.…”

“…The higher concentration of AZAs in the matrix extract led to a four-step purification process with recoveries of 75% for AZA1 (57) and 70% of AZA2 (58), that is, a 1.5 increment compared with the extraction from shellfish. This study was carried out on six successive culture lots (1200 L harvested in total) and obtained 9.3 mg of AZA1 (57) and 2.2 mg of AZA2 (58) of >95% purity in 12 days (8 days of culture, 1 day of filtration, and 3 days of extractions), showing that the obtention of AZA1 and −2 in photobioreactors has been possible.…”

Continuous Flow Synthesis of Anticancer Drugs

“…The separation of racemic products via chiral chromatography is not viable on scale. However, a considerable amount of recent work highlights the possibility to use enzymes for dynamic kinetic resolutions of racemates in a continuous fashion [52,53,101].…”

“…To provide a greener and more effective strategy for the synthesis of alcohol (S)-50, Ghosh et al [101] developed an enzymatic resolution of the racemic mixture in flow mode.…”