Difluoroalkyl ketones

Most peptidyl a,a-difluoroalkyl ketones are actually extended chains based on statone, rather than simple difluoromethyl ketones. The statone derivatives are based on pepstatin, which is an extremely potent peptide inhibitor of aspartic proteases. The difluoro derivatives of statone take advantage of both the electronegativity of fluorine and the potential for additional interactions between the protease and structures on the leaving group side of the inhibitor. 15 This dual nature is part of what makes a,a-difluoroalkyl ketones effective inhibitors of aspartyl proteases as well as serine proteases. There are three main methods of synthesizing peptidyl a,a-difluoroalkyl ketones (1) the Reformatsky reaction with peptide aldehydes (Section 15.1.4.2.1), (2) a modified Dakin-West reaction (Section 15.1.4.2.2), and (3) a Henry nitro-aldol condensation (Section 15.1.4.2.3). 

Scheme 3 Synthesis of Peptide a,a-Difluoroalkyl Ketones from Peptide Aldehydes by a Reformatsky Reaction 181...

Table 4 a,a-Difluoroalkyl Ketones Synthesized by the Reformatsky Method120-21-2 1... 

The second most prevalent method for synthesizing a,a-difluoroalkyl ketones is a modification of the Dakin-West acylation reaction. This method utilizes difluoroacetic anhydride to form an anhydride with the chosen amino acid, which rapidly cyclizes and activates the a-carbon, where acylation then occurs. Although this method has been used to synthesize many a,a-difluoroalkyl ketones (Table 5)J7A25 261 the modified Dakin-West reaction has primarily been used in the synthesis of trifluoromethyl ketones. Since the syntheses of a,a-difluoroalkyl and trifluoromethyl ketones are identical, the details of this method will be discussed in Section 15.1.4.3.1. 

Similar to the Dakin-West procedure previously mentioned, the Henry nitro-aldol condensation reaction is most widely used to synthesize trifluoromethyl ketones, although there are many examples of a,a-difluoroalkyl ketones synthesized by this method (Table 6)JU 12271 The method for a,a-difluoroalkyl and trifluoromethyl ketone synthesis is identical except for the final oxidation although fluoroalkyl and a,a-difluoroalkyl ketones are easily oxidized by the Sarett method (Cr03/pyridine),[12 the corresponding trifluoromethyl ketones can only be oxidized under basic conditions (0.3 M NaOH) with KMn04Jul Also, in some of the syntheses of a,a-difluoroalkyl ketones, the nitro alcohol intermediate was protected by si-lylation with /ert-butylchlorodimethylsilane. The silyl group was later removed by TosOH prior to oxidation. The full details of this method are given in Section 15.1.4.3.2. 

One of the most widely used methods for the synthesis of peptidyl fluoromethyl ketones is a modified Dakin-West acylation procedure. Although this reaction is primarily used for the synthesis of trifluoromethyl ketones (see Scheme 4), it is also frequently used to synthesize fluoroalkyl (Section 15.1.4.1.4), difluoroalkyl (Section 15.1.4.2.2), and perfluoroalkyl ketones. This method is extremely versatile however, there are several drawbacks. First, as noted in Section 15.1.4.1.2, several of the reagents used in the Dakin-West acylation are... 

In this section the synthesis of fluoroalkyl (Section 15.1.4.1.3), a,a-difluoroalkyl (Section 15.1.4.2.3), and trifluoromethyl- and perfluoroalkyl ketones are discussed collectively. The second most widely used method for synthesizing peptide fluoromethyl ketones is the Henry nitro-aldol condensation reaction, which involves the use of (3-nitro alcohols to build the fluoromethyl ketones. As with the modified Dakin-West procedure, the Henry reaction has also been used to synthesize mono-, di-, tri-, and extended fluoromethyl ketones, making it another extremely versatile synthetic method.19 12 19 27 29 33 341 However, similar to the Dakin-West procedure, the products of the Henry reaction are not chiral, since an achiral carbanion is involved in the crucial carbon bond forming step. 

Difluoroalkyl Fluoridothiocarhonates from a-(Trihalomethyl)sulfanyI Ketones... 

In the reaction of a-(trihalomcthyl)sulfanyl ketones with hydrogen fluoride,, -difluoroalkyl fluoridothiocarhonates 14 are obtained instead of the expected trifluoromethyl sulfides.The reaction is thought to proceed via an initial chlorine-fluorine exchange reaction followed by rearrangement into the /i-difluorinated product. 

Difluoroalkyl sulfinylmethyl ketones have been prepared in enantiomerically pure form from (+)-(f )-methyl p-tolyl sulfoxide in high yield (eq 12). The ketone function was then reduced with complete diastereoselectivity. 

Tetrahedral transition state analogues of ester and amide substrates are known to function as efficient enzyme inhibitors of hydrolytic enzymes such as serine and aspartyl proteases as well as metalloproteinases (see Fig. 1.24) [141-144], Although ketals of alkyl or aryl ketones are usually not stable, those of difluroalkyl or trifluoromethyl ketones have considerable stability, as exemplified by their facile formations of the corresponding stable hydrates [145, 146]. Therefore, substrate analogues, containing difluoroalkyl or trifluoromethyl ketone moiety in appropriate positions, have been studied as effective transition state inhibitors of hydrolytic enzymes [141, 147-150],... 

Bannwarth P, Gree D, Gree R (2010) Synthesis of new difluoroalkyl propargyUc ketones and their use for the preparation of fluorinated heterocycles. Tetrahedron Lett 51 2413-2415... 

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