Preparation Of Chiral Fluorinated Alcohols Under Biocatalysis

Fluorinated alcohols with chirality exist widely in drugs and other bioactive ingredients.These structures can be efficiently synthesized by asymmetric catalytic reduction of prochiral fluoroketones.Compared with the traditional chemical reduction methods,biocatalytic reduction method has the advantages of high selectivity,less side reactions,mild conditions,environmentally friendly.However,most of the studies focus on the asymmetric reduction reaction of trifluoromethyl ketones,there are few studies on biocatalytic asymmetric reduction reaction of difluoromethyl ketones.On the other hand,the introduction of difluoromethyl group can significantly improve the physiological and biochemical properties of bioactive ingredients.Difluoromethyl groups are also commonly found in the structure of drugs and pesticides.Therefore,it is of great importance to develop the asymmetric reduction of difluoromethyl ketone to obtain the corresponding chiral fluoroalcohols under biocatalysis.In this thesis,we developed an asymmetric reduction of halo-difluorophenone compounds to produce chiral halo-difluorophenethanols by using ketoreductase K234 as a biocatalyst.This method features excellent enantioselectivity,high conversion,simple process,and mild reaction conditions.Under the optimal conditions,we investigated the substrate scope,various iodo-difluoroacetophenone underwent the enantioselective reduction to produce the target molecules with high efficiencies.Bromo-difluoroacetophenone,chloro-difluoroacetophenone and trifluoromethyl ketone can also participate in the reaction without any difficulties.Several chiral fluoroalcohols were obtained by this method,which showed good substrate adaptability.The biocatalytic reduction of fluoroketone can also proceed without coenzyme.This method further reduces the cost of the reaction by reducing the use of expensive coenzymes.α-halogenated-α,α-diflurone and trifluoromethyl ketone all obtained excellent conversion and enantioselectivity in the absence of coenzyme NADP.Subsequently,the reactivity of chiral iododifluoroalcohol obtained by biocatalytic reduction was studied.When iododiflurone was reduced,the reactivity was dramatically reduced and the target product was still not obtained after the hydroxyl group was protected.To understand the reason of this result,we carried out Gaussian calculation.The results showed that the dissociation energy of C-I bond increased significantly after the reduction of carbonyl group, which is difficult to form free radicals to participate in the addition reactions with unsaturated system.