Modified Dakin-West reaction

A special application of heteroaromatic acylation via a modified Dakin-West reaction leads to a-fluoro ketone derivatives [50] (equation 30) Such fluoro ketones have been successfully used as enzyme inhibitors in modern bioorganic chemistry [5, 6]... 

Scheme 32 Synthesis of 1-Oxoethylene Peptides using a Modified Dakin-West Reaction 72-73 ...

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 ... 

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. 

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). 

Several different routes have been found which lead to imidazo[5,l-c][l,4]oxazines. Treatment of the imidazoledicarboxylic acid (667) with acetic anhydride afforded (668). The initial steps of this transformation presumably involve a modified Dakin-West reaction (66JOC806). 

The synthesis of ketomethylene pseudopeptide analogues was accomplished by L. Cheng et al., and their biological activity as thrombin inhibitors was tested. These analogues were prepared through a modified Dakin-West reaction under mild conditions and in almost quantitative yield. The required anhydride was prepared from monomethyl succinate, and a large excess of it was mixed with the tripeptide substrate in pyridine in addition to triethylamine and catalytic amounts of DMAP. The reaction mixture was heated for one hour at 40-50 °C. 

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). 

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. 

A Dakin-West reaction on plant scale is demonstrated by elaboration of a modified procedure avoiding uncontrolled release of carbon dioxide. It seems to be generally accepted that the mechanism involves dehydrative formation of an azlactone (oxazolinone), which is then C-acylated (in equilibria with G-acylation), undergoes ring-opening hydrolysis, and then decarboxylates to form the acylamino ketone. Pyrimidine ring formation is achieved in a simple one-pot reaction, which is followed by a simple isomerization. Laboratory experiments had made clear that the mechanism... 

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. 

A synthetic route via the Dakin-West acylation reaction followed by a hydrolysis step was first reported for the preparation of p-acylamino a-oxo esters from acylamino acidsJ10l This method was later modified and adapted for the synthesis of peptide a-oxo esters, a-oxo acids, and a-oxoamides (Scheme 2).[1A5111... 

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