Methods for the Synthesis of α,α‐Difluoroketones

Abstract

α,α‐Difluoroketones are valuable compounds and can be used as synthetic intermediates for the synthesis of fluorinated molecules, but they also have a direct application in medicinal chemistry, particularly as inhibitors for hydrolytic enzymes. This Microreview will summarize the major methods currently available for the synthesis of α,α‐difluoroketones, highlighting methods involving direct C–F bond formation, as well as those using pre‐difluorinated building blocks.

Enolization rates control mono- versus di-fluorination of 1,3-dicarbonyl derivatives

“…The formation of a hydrate is expected, as diuoroketones are known to form stable tetrahedral adducts. 32 We also observed this peak in our 19 F NMR-monitored synthetic reaction to obtain an authentic sample of 6a, however, upon work-up we did not isolate any 6a-hydrate. In order to further validate our kinetic model ( Fig.…”

“…These include the additions of nucleophilic residues of enzyme active sites to a,a-diuoroketonic compounds, 30,31 which have led to the application of a,a-diuoroketones as enzyme inhibitors. [32][33][34] For example, diuorostatone compounds have been identied as potent inhibitors of HIV-1 protease 35 and of a serine protease in the malaria parasite. 36 Despite the importance of organouorine compounds in the life sciences, very few kinetics studies on uorination reactions are present in the literature and there have been no quantitative studies on the introduction of two uorine atoms to form a diuoromethylene unit.…”

Regioselective Markovnikov hydrodifluoroalkylation of alkenes using difluoroenoxysilanes

“…These studies brought the following to our attention: difluoroenoxysilanes 2 are often more reactive than their nonfluorinated analogs 50 , which are with high nucleophilicity comparable to allylstannanes 58 ; furthermore, to some extent, they are compatible with water 52 and the reaction conditions that include superacids such as HOTf and HClO 4 50 . This suggested to us that 2 could be a promising reagent in developing acid-catalyzed Markovnikov hydrodifluoroalkylation, affording structurally diverse α-branched α,α-difluorinated ketones as fluorinated synthons, as well as interesting targets for medicinal researches 59 .…”

Peptidyl Fluoromethyl Ketones and Their Applications in Medicinal Chemistry

“…d-PFMKs are a class of compounds still little explored due to the complexity of the chemistry concerning the construction of the d-FMK moiety [ 103 , 104 ], which becomes much more challenging when applied to peptidic substrates. One of the most extensive works in this regard has been performed by Imperiali B. and Abeles R.H. in a comparative study on PFMKs as inhibitors of serine proteases [ 105 ].…”