Abstract
Chiral fluorolactam derivatives bearing a fluorine atom at a stereogenic centre were synthesized by a combination of selective direct fluorination using fluorine gas and a biochemical amidase cyclisation process.
Highlights
Enzyme catalysed reaction of functional fluoromalonate building blocks, prepared using fluorine gas, has been used for the first time for the enantioselective synthesis of a pharmaceutically important chiral fluorolactam derivative
Inspection of each stage of the synthetic route shows that most waste is generated in the key enantioselective fluorination stage because, NFSI is synthesised by reaction of the corresponding sulfonamide with fluorine gas,[16] which must be taken into account when calculating process mass intensity (PMI) measurements, and loss of material due to the low ee and subsequent resolution
We assumed that all solvent used in the HPLC resolution was recycled and the waste generated in the multi-step synthesis of the palladium catalyst was not included in the PMI calculation
Summary
Enzyme catalysed reaction of functional fluoromalonate building blocks, prepared using fluorine gas, has been used for the first time for the enantioselective synthesis of a pharmaceutically important chiral fluorolactam derivative. Green metrics packages allow a holistic comparison between potential synthetic reaction pathways using a mixture of quantitative and qualitiative assessment criteria.[10] Calculations of total process mass intensity (PMI) enables the synthetic chemist to compare the environmental effect of competing synthetic strategies from common starting materials, aiding the selection of the final preparative route.[11]
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