DAKIN-WEST Ketone Synthesis

DAKIN-WEST Ketone Synthesis An acylative decarboxylation of a-amino or a-thio acids (see 1st edition). 

Treatment of an a-amino acid with an anhydride in the presence of pyridine, known as the Dakin-West reaction,[1431 gives access to a racemic a-amido ketone.1 44 1451 The mechanism involves formation of an oxazolinone (98)J146 In the modified Dakin-West reaction, the oxazolinone is reacted with an acid chloride (Scheme 33)J136 139] Due to the rapid epimer-ization of the oxazolinones, a diastereomeric mixture of product 99 is obtained. No detailed protocol has been published so far for the modified Dakin-West synthesis applied to (oxomethyleneamino) peptides, but the procedure is adapted from that already reported for (oxomethylene) peptides containing the tp[CO-CH2] link.1147 ... 

Fluoromethyl ketones are one of the most widely used classes of peptidyl a-fluoroalkyl ketones, second only to trifluoromethyl ketones. Peptidyl fluoromethyl ketones are very effective as irreversible inhibitors of cysteine proteases the first reported use of a fluoromethyl ketone compound was the use of Z-Phe-Ala-CH2F as an irreversible inhibitor of cathepsin BJ2,31 Today, many lysine and arginine derivatives have been synthesized as potential inhibitors for trypsin and trypsin-like enzymesJ3 There are four basic methods for the synthesis of peptide fluoromethyl ketones (1) the reaction of HF with peptide diazomethyl ketones (Section 15.1.4.1.1), (2) a halogen-exchange reaction with a chloro-, bromo-, or iodomethyl ketone (Section 15.1.4.1.2), (3) a Henry nitro-aldol condensation reaction (Section 15.1.4.1.3), and (4) a modified Dakin-West acylation reaction (Section 15.1.4.1.4). 

As with the Henry nitro-aldol condensation, the modified Dakin-West acylation is primarily used for synthesis of trifluoromethyl ketones, although there are several examples of its use in the synthesis of fluoromethyl ketones (Table 3).[31314 The modified Dakin-West reaction utilizes fluoroacetic anhydride (or other appropriate anhydrides) to form an anhydride, which then undergoes cyclization, activation of the a-carbon, and acylation at the a-carbon the precise 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... 

Scheme 4 Synthesis of Fluoromethyl Ketones by a Modified Dakin-West Reaction 20 ...

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. 

Unlike the Dakin-West and Henry nitro-aldol methods previously mentioned, the reaction of aldehydes with organometallics has only been used for the synthesis of peptidyl trifluoromethyl ketones. This method, along with the Henry nitro-aldol synthesis, eliminates the use of the toxic reagents required for the Dakin-West synthesis and starts with readily... 

An improved method for the preparation of a series of oxazole-containing dual PPARa/y agonists was reported by A.G. Godfrey et al. The synthesis utilized the Dakin-West reaction which allowed the introduction of a phenyl ketone moiety. This ketone was subsequently converted to the corresponding oxazole using POCI3/DMF. 

The Dakin-West reaction provides a source of V-acyl-a-amino ketones (e.g. 1), which Franzen has exploited for the synthesis of secondary diazo ketones, thereby avoiding the need to use the higher homologs of diazomethane (Scheme 2). The ketoamide (1) is first nitrosated using N2O3 in glacial acetic acid. The oily Af-nitroso derivative is separated and then decomposed with sodium methoxide in methanol to give the diazo ketone (2) yields are about 50-60%. 

The Dakin-West synthesis of a>acylamino ketones16 is closely related to the decarboxylation of a-amino carboxylic acids. Interaction of a carboxylic acid anhydride, e.g., acetic or benzoic anhydride, and an amino acid in the presence of pyridine or some similar base affords the derived a>acylamino ketone by decarboxylation. 

It should be noted that there are several other means by which the key a-aminocarbonyl intermediates of the Gutknecht synthesis may be prepared besides by the reduction of a-oximino ketones. The oxidation of a-aminoalcohols, reduction of a-amino acids and their derivatives, hydrolysis of a-acetamido ketones formed from a-amino acids and acetic anhydride by the Dakin-West reaction, and the reduction of a-azido, a-diazo, and a-nitro ketones all lead to dihydropyrazines by way of a-amino ketones. The Gastaldi synthesis provides an alternate use of a-oximino ketones, to afford dicyano pyrazines. ... 

Khodaei, M.M., Khosropour, A.R. and Fattahpour, R 2005. A modified procedure for the Dakin-West reaction An efficient and convenient method for a one-pot synthesis of P-acetamido ketones using silica sulfuric acid as catalyst. Tetrahedron Lett. 46(12) 2105-2108. 

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