Azlactone intermediate

Acetic anhydride is added to 3-fluorobenzaldehyde, N-acetyl glycine, and anhydrous sodium acetate in ethyl acetate. The reaction mixture is heated to 80 °C. After completion of the reaction, the mixture is cooled, water is added, and the resultant precipitate is filtered and washed. The crude azlactone intermediate is then treated with aqueous sodium hydroxide followed by acidification. The resultant precipitate is filtered, washed, and dried to provide the N-acetyl dehydro-3-fluorophenylalanine in 70% yield from the aldehyde on a 50 kg scale. 

N-Acetyl-3-fluorophenylalanine is charged into a reactor and following pH adjustment and solvent exchange with water, Amano L-acylase (5% by weight) is added. The reaction is stirred at 35— 10 °C until the biotransformation is complete. The mixture is then acidified and filtered. The filtrate is basified and concentrated. The resultant product solution is subjected directly to the Boc protection step. 

Methanol is added to the crude aqueous solution of 3-fluorophenylalanine, followed by a solution of di-t-butylcarbonate in methanol. Following this addition, the reaction is acidified and the resultant precipitate filtered and dried to provide the N-BOC-(S)-3-fluorophenylalanine in 99% ee and 98% purity by HPLC analysis (70% yield from N-acetyl-3-fluorophenylalanine). 

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Synthesis of dehydrotryptophan The amino acid tryptophan was first synthesised by Erleiuneyer s method via the dehydrotiyptophan intermediate. Ellinger et al. reacted indole-3-caibaldehyde 66 with the glycine derivative hippuric acid 67, after which hydrolysis of the azlactone intermediate 68 afforded the dehydrotiyptophan intermediate 69 [85] (Scheme 12.18). 

The azlactones of a-benzoylaminocinnamic acids have traditionally been prepared by the action of hippuric acid (1, Ri = Ph) and acetic anhydride upon aromatic aldehydes, usually in the presence of sodium acetate. The formation of the oxazolone (2) in Erlenmeyer-Plochl synthesis is supported by good evidence. The method is a way to important intermediate products used in the synthesis of a-amino acids, peptides and related compounds. The aldol condensation reaction of azlactones (2) with carbonyl compounds is often followed by hydrolysis to provide unsaturated a-acylamino acid (4). Reduction yields the corresponding amino acid (6), while drastic hydrolysis gives the a-0X0 acid (5). ... 

Saturated azlactones such as 18 and 29a, whose preparation is discussed in parts 2, b and 3 of this section, are useful intermediates for the synthesis of a variety of j8,j8-disubstituted alanines (32). ... 

The preparation of the less stable isomer (53b) of the oxazolone 53a involves a rather tedious procedure. It has been reported that 53a is rapidly isomerized to 53b in 48% hydrobromic acid saturated with gaseous HBr. In this way four azlactones have been converted into their isomers.It has been established, moreover, that the isomerization is radical-initiated and does not involve a carbonium ion intermediate. The isomerization can be reversed by pyridine. ... 

Azlactones like 6 are mainly used as intermediates in the synthesis of a-amino acids and a-keto acids. The Erlenmeyer-Pldchl reaction takes place under milder conditions than the Perkin reaction. 

In subsequent studies,22 Sheehan et al. demonstrated that the action of diisopropylcarbodiimide on penicilloate 24, prepared by protection of the free primary amino group in 23 with trityl chloride (see Scheme 6b), results in the formation of the desired -lactam 25 in a very respectable yield of 67 %. In this most successful transformation, the competing azlactonization reaction is prevented by the use of a trityl group (Ph3C) to protect the C-6 amino function. Hydrogenolysis of the benzyl ester function in 25, followed by removal of the trityl protecting group with dilute aqueous HC1, furnishes 6-aminopenicillanic acid (26), a versatile intermediate for the synthesis of natural and unnatural penicillins. 

Scheme 6. Azlactonization of intermediate 5 (a) and synthesis of 6-aminopenicillanic acid (b).

Saturated 2-vinyl-5(47Z)-oxazolones have been widely used as intermediates for the synthesis of polymeric compounds that will be described in Section 7.3.2.9. Apart from these polymerization reactions, the Diels-Alder reactions of 4-sub-stituted-2-vinyl-5(47/)-oxazolones 134 with cyclopentadiene are reported to give norbomenyl oxazolones 135 that are useful to prepare norbornenyl functionalized resins by azlactone ring-opening addition reactions (Scheme 7.39). 

A simple two-step synthesis of 4-arylthieno[3,2-c]pyridine-6-carboxylic acids has recently been presented by Eweiss (Scheme 74) (B-81MI31703). The condensation of thiophene-2-carbaldehyde with an N -aroylated a-amino acid yields a thienylidene azlactone (281) which on treatment with AICI3 is converted to a thieno[3,2-c]pyridine (283). A nitrilium ion (282) resulting from a vinyl-oxygen fission is probably involved as an intermediate. Sandberg s method already mentioned in the previous section has also been applied to the synthesis of thieno[3,2-c]pyridines (Scheme 75). 

One of the oldest methods for the preparation of DHAs is the ring opening of unsaturated azlactones by attack of a nucleophile on the carbonyl group. Several methods for the synthesis of unsaturated azlactones (Azl) have been developed over the years and the chemistry of these important intermediates has been reviewed/1,2 Following are the methods of their synthesis that have remained in use during the last few decades. 

The preparation of the first unsaturated azlactone was reported in 1883 by Plochl/40 who condensed benzaldehyde with hippuric acid in presence of acetic anhydride. This approach was later used by Erlenmeyer/41 who extended the procedure to include other aldehydes and also established the usefulness of azlactones as intermediates in the synthesis of DHAs. The method involves the condensation of an A-acylglydne 4 with aldehydes and ketones in the presence of acetic anhydride and anhydrous sodium acetate (Scheme 2)J41 t5l Other catalysts such as copper(II) acetate/46 lead acetate/47,48 potassium carbonate/49 or potassium hydrogen carbonate 50 have also been used. The reaction proceeds via formation of an azlactone 5, which then condenses with the appropriate aldehyde or ketone to give unsaturated azlactone 6. Reaction of 6 with a nucleophile such as OH, OR, or NHR leads to the corresponding A-acyl-DHA derivatives 7. Reaction with the sodium salt of an amino acid gives a DHA containing dipeptide acid. 51 ... 

Oxazolones are attacked by a variety of electrophiles at C(4) these reactions, which require the presence of bases, proceed through the enolate anions (197). This type of anion adds to carbonyl compounds, a key step in the Erlenmeyer synthesis of unsaturated azlactones (equation 35) (see Section 4.18.4.3.4). The anions are intermediates in the formation of the amides (198) when oxazolones are treated with enamines (Scheme 15) (71JCS(C)598>. 

Bergmann s synthesis (1926) is still used to prepare unsaturated azlactones containing only alkyl substituents. It consists of the treatment of a-alkyl a- (a-halogenoacyl)amino acids with acetic anhydride and it involves the isomerization of an intermediate 2-methylene-5(2H)-oxazolone. An example is given in equation (153). 

Chromatography) (equation 82). These complexes are used as enantioselective nucleophilic catalysts for reactions such as the rearrangements of O-acylated azlactones, oxindoles, and benzofuranones, and the kinetic resolution of secondary alcohols via acylation. X-ray crystal structures have been obtained for iV-acylated derivatives of (366), allowing for characterization of a likely intermediate along the catalytic pathway. 

This method has also been applied to unsymmetrical acyclic allyl esters. The reaction of an azlactone with a geminal diacetate substrate gave access to an advanced intermediate for the synthesis of sphingofungin F. ... 

In a similar fashion, the activation of azlactones with Lewis acids gives intermediate munchnones which can then be trapped with imines or alkenes to yield 2-imidazolines 92 or A -pyrrolines 93 respectively, with high diastereos-electivities (Scheme 20) <2002OL3533, 2004JA12776>. 

Azlactone A five-membered ring compound, which is a useful synthetic intermediate, also called 5-oxazolone. 

Dakin-West reaction. Reaction of a-amino acids with acetic anhydride in the presence of base to give a-acetamido ketones. The reaction occurs via the intermediate azlactone. 

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