A-trifluoromethyl ketones

The first substrate analogue inhibitors of FAAH were reported in 1994. The anandamide analogues prepared represented three elasses of putative transition-state inhibitors a-trifluoromethyl ketones, a-ketoesters and a-ketoamides [62], In the initial sereening studies, it was found that the trifluoromethyl ketone eompounds tested were effeetive inhibitors of AEA hydrolysis. A selected set of a-keto esters also inhibited hydrolysis, while a-keto amides were ineffective. In particular, arachidonyl trifluoromethyl ketone (32), gave almost 100% inhibition of anandamide hydrolysis. A detailed investigation of the structural requirements for FAAH inhibition with a-trifluoromethyl ketones has been carried out by Roger and co-workers [63]. 

Perfiuoroolefins, 0-substituted, from a-trifluoromethyl ketones, 48,119 Periodate oxidation of thioanisole, 46, 78... 

The procedure illustrates a fairly general method for the preparation of -substituted perfiuoroolefins. The method has been applied to the synthesis of 2-cyclohexyl- (70%), 2-benzyl- (61%), and 2-(/>-fluorophenyl)perfluoropropenes (67%), and it is probably applicable to any a-trifluoromethyl ketone. Olefins containing a perfluoroalkyl group other than trifluoromethyl can be prepared by the same procedure by the substitution of lithium chlorodifluoroacetate for sodium chlorodifluoroacetate.7 Other routes to / -substituted perfiuoroolefins are not general or convenient. Routes to perfiuoroolefins generally yield the a-substi-tuted olefin rather than the /3-substituted olefin. 

It is interesting to note that when the dicarbonyl partner is a trifluoromethyl-ketone derivative, the dehydration is not observed and the corresponding hexahydropyrimidine s are obtained in good yields [70,80-82], regardless of the reaction conditions involving various catalytic systems, different medium, and thermal activation modes (Scheme 14 and Table 1). The different observations based on the isolation of these hydroxylated products allowed to corroborate the acyliminium ion mechanism [62]. 

Replacement of the hydroxamic acid moiety of SAHA by an alternative chelator has been the subject of several studies. Suzuki and Miyata et al. have shown that replacement of the hydroxamic acid of SAHA with a free thiol moiety does not affect the enzymatic HDAC inhibition capability of the compound [57]. Furthermore, replacement of the hydroxamic acid of SAHA by a trifluoromethyl ketone was investigated by Frey et al. (Fig. 8) [58]. The activated ketone is readily hydrated to form the vicinal diol, a structural feature known to bind to zinc-dependent proteases [59]. The in vitro evaluation was done on a partially purified HDAC preparation consisting largely of HDAC 1 and HDAC2 [60], exhibiting an IC50 of 6.7 xM. 

Fig. 8 The hydroxamic acid in SAHA replaced by a trifluoromethyl ketone - IC50S in the micromolar range (reference data for SAHA not given). (Abbott Laboratories)...

Scheme 6 Synthesis of a Trifluoromethyl Ketone by Reaction of an Organometallic Reagent with a Simple Fluorinated Aldehyde 281...

The data in Table 3 suggest that the nature of enantiodifferentiation in the hydrogenation of a,(X,a-trifluoromethyl ketones is only partly similar to that of a-ketoester hydrogenation. Apparently, the OH group of CD has some role in enantioselection during... 

The Pt-cinchonidine system is a promising catalyst for the enantioselective hydrogenation of a,a,a-trifluoromethyl ketones to the corresponding alcohols. The ee varies in a broad range between 5 and 90 %, depending on the chemical nature of the R group in the general structure F3C-CO-R. The remarkable differences may be well explained by steric and electronic effects. 

Charpentier-Morize and coworkers have developed conditions for the cycloalkylation of y-aryl-a-trifluoromethyl ketones selectively to either the cycloalkene (33) or the cycloalkyl chloride (34 Scheme 12) by varying the catalyst. 

Support for an even more remote electrostatic effect on the mechanism is supplied by the studies of Jackson and Fersht (1993). They mutated charged residues on the surface of Subtilisin BPN, that are 13-15A from the active site, to either neutral or oppositely charged residues. The effect of those mutations on the inhibition constant, Ki, of a trifluoromethyl ketone, was compared for wt and mutated subtilisin. The mutations were Asp-36 (located on a surface loop outside the active site cleft and separated from His-64 by about 15-16A) to Gin, and of Asp-99 (about 12-13A from His-64) to Ser and to Lys. The active site of subtilisin includes Ser-221, His-64 and Asp-32. 

Trifluoromethylation. Zinc enolates generated from enol silyl ethers on treatment with Et2Zn react with CF3I in the presence of (Ph3P)3RhCl to provide a-trifluoromethylated ketones. ... 

A related asymmetric autocatalytic reaction (addition of a lithium acetylide to a trifluoromethyl ketone catalysed by product) has been applied to the synthesis of a... 

Scheme 14 Synthesis of a-trifluoromethyl ketones from olefins [46]...

In analogy to the addition of a trifluoromethyl group to a double bond, Akita and co-workers reported the formation of quaternary a-trifluoromethyl ketones by oxidation of the intermediate using DMSO under photoredox catalysis (Scheme 14) [46]. 

Li L, Chen Q-Y, Guo Y (2014) Synthesis of a-trifluoromethyl ketones via the Cu-catalyzed trifluoromethylation of silyl enol ethers using an electrophilic trifluoromethylating agent. J Org Chem 79 5145-5152. doi 10.1021/jo500713f... 

Tomita R, Yasu Y, Koike T, Akita M (2014) Cranbining photoredox-catalyzed trilluoro-methylation and oxidation with DMSO facile synthesis of a-trifluoromethylated ketones from aromatic alkenes. Angew Chem Int Ed 53 7144—7148. doi 10.1002/anie.20I403590... 

The reaction of (5)-(trifluoromethyl)diphenylsulfonium triflate with Na2S204 or H0CH2S02Na under suitable conditions can generate the CF3 radical without further reduction. Various styrenes react with (5)-(trifluoromethyl)diphenylsulfonium triflate in the presence of H0CH2S02Na-2H20 or Na2S204, furnishing a-trifluoromethylated ketones (eq 4). ... 

Scheme 24 Access to 4-Fluoropyrimidines from a-chloro-a -trifluoromethyl ketones...

In a recent drug discovery programme, Boehringer Ingelheim wished to carry out an asymmetric aldol reaction on a trifluoromethyl ketone. Lewis acid catalysed aldol reaction gave no desired product due to the low Lewis... 

Seheme 14.76 Asymmetric acetate aldol reaction with a trifluoromethyl ketone. ... 

Scheme 13. MBH reaction of a-acetylenic a-trifluoromethyl ketones Vinylmetalation of Fluoro-carbonyls...

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