Chemoenzymatic Chiral Synthesis Of Cyhalofop-butyl

Cyhalofop-butyl is an aryloxyphenoxypropionate herbicide listed in1992with excellent herbicidal properties and low toxicity. The only effective type ofCyhalofop-butyl is the (R)-isomer. How to highly enantioselectivity synthesisbiological active (R)-isomer is a key problem. Previous synthetic procedures havebeen developed for the production of racemic or optically active CyB, but, as far aswe know, none of them imply the use of biocatalysts to overcome the low yield, theracemization and environmental impact caused by these conventional chemicalsynthetic procedures mentioned above, although some biotransformation had beenused for the transesterification of various compounds due to more highlyenantioselective and eco-friendly.A Novozym435(the only enzyme that catalyzed the transesterification ofCyhalofop-ethyl and n-butanol)-mediated transesterification approach combinedwith chemical synthesis of adequate intermediates to carry out the total synthesis of(R)-Cyhalofop-butyl was, for the first time, developed in this paper. Meanwhile, theeffects of some main variables on the Novozym435-meidated transesterificationapproach in organic solvents, co-solvent mixtures, IL-containing medium and freesolvent were examined and the the catalytic performances exhibited by Novozym435in different media were characterized. On this basis, a novel and highlychemoenzymatic synthesis of Cyhalofop-butyl based on Novozym435mediatedtransesterification was established.The best reaction system among all selected media was free solvent. The totalyield and enantiomeric purity of Cyhalofop-butyl by this chemo-enzymaticsynthesis in this system were61.2%and>99%, respectively;16.1%and21%higher than that of the traditional way.The best neat organic solvent, co-solvent mixtures or IL-containing mixtureswere found to be acetonitrile, acetonitrile-toluene (50:50, v/v) and C4M I m· P F6-acetonitrile (10:90, v/v) for the Novozym435-mediated transesterification ofCyhalofop-ethyl with respect to the initial rate, the maximum substrate conversionand the enantioselectivity.The influence law of the acyl donors’ structure on the Novozym 435-mediated transesterification of Cyhalofop-ethyl in each selected reactionmedium was the same. The initial rate and the maximum substrate conversiondecreased with increasing chain length of the acyl donor except for n-butylpropionate, while e.e. of the product was all above99%. n-butanol gave the highestinitial rate and conversion in all selected acyl donors.In acetonitrile, acetonitrile-toluene (50:50, v/v), C4MIm·PF6-acetonitrile(10:90, v/v) and free solvent, both the initial rate and the maximum substrateconversion of the Novozym435-mediated transesterification of Cyhalofop-ethylwere influenced by many variables and their effect on the initial rate and themaximum substrate conversion varied with the reaction medium, while theenantioselectivity of the reaction remained almost unchanged and was constantlyhigher than99%within the scope examined. In the case of the enzymatictransesterification of Cyhalofop-ethyl with n-butanol, the optimal initial wateractivity (aw), the Cyhalofop-ethyl concentration, reaction temperature and shakingrate were0.11,300mmol/L,45C and200r/min in acetonitrile;0.11,300mmol/L,45C and200r/min in acetonitrile-toluene (50:50, v/v);0.11,300mmol/L,45Cand200r/min in C4MIm·PF6-acetonitrile (10:90, v/v);0.11,600mmol/L,40C and200r/min in free solvent, under which the initial rate, the maximum substrateconversion and the reaction time were459.5mmol/L·h,81.7%and2h inacetonitrile;347.9mmol/L·h,82.8%and2h in acetonitrile-toluene (50:50, v/v);437.1mmol/L·h,83.6%and2h in C4MIm·PF6-acetonitrile (10:90, v/v);477.8mmol/L·h,98.2%and6h in free solvent. Meanwhile, under which the relativeactivity was66.5%,90.4%,94.5%and41.2%, repesctively, when Novozym435was reused after6batches.This study not only enriches our knowledge of enzymatic transesterification,nonaqueous enzymology, even green chemistry, but also provides a novel andefficient route of Cyhalofop-butyl, thus lay a foundation for industrial applications.