Erlenmeyer amino acid synthesis

The Erlenmeyer amino acid synthesis962 depends on condensation of an aldehyde with hippuric acid this gives an alkylidene azlactone, which is an intermediate in the synthesis, being converted into an %-amino acid by reduction and hydrolysis. 

The alkylidene azlactones are prepared by boiling hippuric acid, the aldehyde, glacial acetic acid, and sodium acetate under reflux. As a class they are amenable to many types of reaction by hydrolysis with alkali they afford oc-oxo acids, and on oxidation by hydrogen peroxide in alkali they yields the 

Hippuric acid has often been replaced in these reactions by A-acetylglycine Herbst and Shemin,964 for example, used it with benzaldehyde when preparing 4-benzylidene-2-methyl-5-oxazolone in 75% yield. 

Creatinine has also been applied as methylene component Nicolet and Campbell965 thus prepared / -substituted jV-methylalanine derivatives and the condensation of vanillin with creatinine (95% yield) is described in Organic Syntheses.966 

Further, hydantoin,967 thiohydantoin, dioxopiperazine, and rhodanine have all been used in similar condensation, yielding the derived %,/ -unsaturated compounds. 

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Amino acid synthesis from aldehydes and hydantoin (Bergmann), synthesis of serine derivatives (Erlenmeyer) or of y-hydroxyaminoacids (Plochl)... 

ERLENMEYER - PLOCHL - BERGMANN Amino Acid Synthesis... 

Erlenmeyer-Plochl azlactone and amino acid synthesis. Formation of azlactones by intramolecular condensation of acylglycines in the presence of acetic anhydride. The reaction of azlactones with carbonyl compounds followed by hydrolysis to the unsaturated a-acylamino acid and by reduction yields the amino acid drastic hydrolysis gives the a-oxo acid. 

Erdmann (see Volhard-Erdmann Cyclization) Erlenmeyer-Plochl Azlactone and Amino Acid Synthesis Eschenmoser Coupling Reaction Eschenmoser Fragmentation Eschenmoser-Claisen Rearrangement Eschenmoser-Tanabe Fragmentation Eschweiler-Clarke Reaction Etard Reaction... 

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). ... 

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. 

L-Dopa was produced industrially by Hoffrnann-LaRoche, using a modification of the Erlenmeyer synthesis for amino acids. In the 1960s, research at Monsanto focused on increasing the L-Dopa form rather than producing the racemic mixture. A team led by William S. Knowles (1917—) was successful in producing a rhodium-diphosphine catalyst called DiPamp that resulted in a 97.5% yield of L-Dopa when used in the Hoffrnann-LaRoche process. Knowles s work produced the first industrial asymmetric synthesis of a compound. Knowles was awarded the 2001 Nobel Prize in chemistry for his work. Work in the last decade has led to green chemistry synthesis processes of L-Dopa using benzene and catechol. 

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 ... 

Acylaminocarboxylic acids 288 are converted into 5(4//)-oxazolinones 289 by acid anhydrides (Scheme 140). In an extension of this reaction, A-acyl derivatives of glycine 290 react with aldehydes with concomitant cyclization to give azlactones 291 (Scheme 141) this is the basis of the Erlenmeyer synthesis of amino acids. Treatment of amino acid derivatives 292 with PBr3 affords the thiazolidine-2,5-dione 293 (Scheme 142) <1971CB3146>. 

Azlactones 22 are intermediates in the Erlenmeyer synthesis (1893) of cr-amino acids. They are made by the action of acetic anhydride/sodium acetate upon a mixture of A-benzoylglycine (hippuric acid) 21 and benzaldehyde via 2-phenyloxazol-5(4//)-one 20 ... 

The Erlenmeyer azlactone synthesis (Scheme 1.8.5.7) combining a hippuric acid derivative, acetic anhydride and an aldehyde to form a didehydroazlactone. This azlactone approach has been extensively used for the synthesis of amino acids. 59... 

Figure 6.41 Preparation of carbon-14-labeled a-amino acids from aromatic aldehydes via Erlenmeyer s azlactone synthesis...

We recently used L-aminoacylase to provide the amino acids shown in Scheme 8. In these instances either the aldehydes were not available or they performed very poorly in the Erlenmeyer chemistry for enamide synthesis. These resolutions can be integrated very readily into an overall process, where the unwanted isomer can be racemized and recycled by way of treatment with acetic anhydride and racemization via the azalactone. 

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