DAKIN - WEST Acylation

DAKIN WEST Acylation An acylative decartxixylation of o-amino acids or o-thio acids. 

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. 

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... 

There are two approaches to the production of peptide a-oxo derivatives (1) the Dakin-West acylation directly from N-protected peptides (Section 15.1.5.1), and (2) oxidation of N-protected peptidyl a-substituted carboxylic acid derivatives (Section 15.1.5.2), which are prepared from N-protected peptides or nonpeptidyl intermediates. The oxidation approach has a synthetic advantage over the Dakin-West acylation as there can be retention of configuration in the final product, but it can be tedious to perform and, in some cases, it requires particular care. 

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... 

Scheme 2 Synthesis of Peptide a-Oxo Esters, a-Oxo Acids, and a-Oxoamides via the Dakin-West Acylation Reaction1 -2 "1...

OAKIN Oxidation 84 DAKIN WEST Acylation 84 DANHEISER Annulation 85 DANISHEFSKY Sitytoxydenes 66 DARAPSKI Ammoacid synthesis 87 DARZENS-NENITZESCU Acylation 87 DAR2fENS Epoxide synthesis 88 DAVIDSON Oxazola synthesa 89 OELEPINEAMehydeoxidalion 89 DAVIS Oxidizing reagent 90 Decker 127... 

DAKIN WEST Acylation An acylative decarboxylation of a-amino acids or a-thio acids. 

DAKIN Oxidation 84 DAKIN - WEST Acylation 84 OANHEISER Annulation 85 DANISHEFSKY Silyloxydlenes 86 DARAPSKI Amtroaeid synthesis 87 DARZENS - NENITZESCU Acylation 87 DARZENS Epoxide synthesis 88 DAVIDSON Oxszole synthesis 89 DELEPINE Aldehyde oxidation 69 DAVIS Oxidzstg reagent 90 Decker 127... 

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]... 

When an a-amino acid is treated with an anhydride in the presence of pyridine, the carboxyl group is replaced by an acyl group and the NH2 becomes acylated. This is called the Dakin-West reaction The mechanism involves formation of an oxazolone. The reaction sometimes takes place on carboxylic acids even when an amino group is not present. A number of N-substituted amino acids, RCH-(NHR )COOH, give the corresponding N-alkylated products. 

A-Acyl AAs, when transformed into a-acylaminoketones by the Dakin-West reaction, react with arylhydrazines, arylsulfonylhydrazines, or some primary amines to give the corresponding ketimines which undergo cyclodehydration with POCI3/PCI5 or TPP (Scheme 21) (78LA1916). 

Verwendet man zur Acylierung Carbonsaureanhydridc/Py ridi n, so besteht die Gefahr, daB das 4-Acyl-oxazolinon zum a-Acylamino-keton gespalten wird (Dakin-West-Reaktion) 96>. So liefern die 4-Acyl-oxazoli-none beim Erwarmen mit Eisessig/Pyridin (96> vgl. auch 171)) oder was-serfreier Oxalsaure in guten Ausbeuten a-Acylamino-ketone. 

N-Acyl-1.4-dihydro-pyridyl]-oxazolinone (98) und 4-Acyl-A2-oxazolinone (85) konnten NMR-spektroskopisch auch als Zwischenstufen der klassischen Dakin-West-Reaktion 50> nachgewiesen werden 170>. 

All three isomerizations discussed above seem to occur by analogous mechanistic pathways similar to the mechanism formulated for the Dakin-West reaction [82]. Deacylation of the starting material H by catalyst G affords, in a fast and reversible step (Scheme 13.47, step I), an acylpyridinium/enolate ion-pair I. From this ion pair, enantioselective C-acylation proceeds in the rate-determining and irreversible second step, furnishing the C-acylated product J (Scheme 13.47, step II). 

Several reactions are occurring in this step that have been elucidated by others (1). First, an a-ketoester is the initial condensation product of an N-acyl-aminoacid and an alkyl oxalyl chloride via a Dakin-West reaction. Second, at reflux temperatures isomeric enol esters are formed that directly condense with hydrazine to form a triazinone intermediate followed by the second ring closure. Other purines have been prepared in an analogous reaction pathway (2). 

When primary amines react with a-acylaminoketones the resulting Schiff bases can be cyclized in the presence of phosphoryl chloride, phosphorus pentachloride, or triphenylphosphine and triethylamine in hexachloroethane to give 1-substituted imidazoles (11) (Scheme 2.1.4). The starting a-acyl-aminocarbonyls are readily prepared from a-amino acids by reduction with sodium amalgam [31, 32] or by the Dakin-West reaction [33, 34], which is most conveniently conducted in the presence of 4-(AUV-dimethylamino)pyridine (DMAP) as an acylation catalyst [35 37]. 

Gerencevic, N., Prostenik, M. n-Acyl amino acids in the Dakin-West reaction replacements of the acyl groups. Bulletin Scientifique, Section A Sciences Naturelles, Techniques et Medicales (Zagreb) 1970, 15,158. 

Knorr, R Staudinger, G. K. Mechanism of the Dakin-West reaction. II. Kinetics and mechanisms of the Dakin-West reaction of N-acylated secondary amino acids. Chem. Ber. 1971,104, 3621-3632. 

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%. 

It is also superior to pyridine as a catalyst for C-acylation, for example in the Dakin-West reaction.3 This reaction is the conversion of a-amino acids into a-acylamino ketones by reaction with acid anhydrides catalyzed by a base (usually... 

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