Amino acid esters Schiff bases

Simple esters cannot be allylated with allyl acetates, but the Schiff base 109 derived from o -amino acid esters such as glycine or alanine is allylated with allyl acetate. In this way. the o-allyl-a-amino acid 110 can be prepared after hydrolysis[34]. The Q-allyl-o-aminophosphonate 112 is prepared by allylation of the Schiff base 111 of diethyl aminomethylphosphonates. [35,36]. Asymmetric synthesis in this reaction using the (+ )-A, jV-dicyclohex-ylsulfamoylisobornyl alcohol ester of glycine and DIOP as a chiral ligand achieved 99% ec[72]. 

Parmar et al have developed a method for resolving racemic mixtures of a variety of natural and nonnatural amino acids using the ethyl ester of the amino acid protected at the amino position hy the formation of a Schiff base with an aromatic aldehyde such as /)-chlorobenzaldehyde. Both chymotrypsin and Lip such as porcine Lip gave good yields of the L-amino acid which precipitates out of solution as the amino acid ester released from the imine is cleaved by the hydrolase. 

Racemic a-amino acid esters have been converted to single enantiomers by condensing them with 2-hydroxypinan-3-one (91), and then diastereoselectively protonating the resultant chiral Schiff base. ... 

Another possible mechanism for the racemization of amino acid esters involves the in situ, transient, formation of Schiff s bases by reaction of the amine group of an amino acid ester with an aldehyde. Using this approach, DKR of the methyl esters of proline 5 and pipecolic acid 6 was achieved using lipase A from C. ant-arclica as the enantioselective hydrolytic enzyme and acetaldehyde as the racemiz-ing agent (Scheme 2.4). Interestingly, the acetaldehyde was released in situ from vinyl butanoate, which acted as the acyl donor, in the presence of triethylamine. The use of other reaction additives was also investigated. Yields of up to 97% and up to 97% e.e. were obtained [6]. 

Figure 2.6 By resolution of df-amino acid esters under conditions of dynamic resolution 100% of a single enantiomer may be produced. Using catalytic amounts of pyiidoxyl-5-phosphate, which forms a Schiff s base with the ester and not the acid, the unreacted D-ester may be racemised in situ and for instance L-tyrosin has been obtained in 97% ee and 95% yield.

It is well over 40 years since Pfeiffer discovered that certain reactions of a-amino acid esters, in particular, ester exchange, racemization and oxygenation, are effected very readily when their Schiff bases with salicylaldehyde are complexed to a transition metal ion (most notably Cu11). The Schiff bases result from a condensation reaction between a reactive carbonyl group and the amino group of the amino acids. Snell and his co-workers43 were also one of the first to point out that similar reactions also occurred if pyridoxal was used instead of salicylaldehyde, and that there is a close analogy with pyridoxal phosphate-promoted enzymic reactions of a-amino acid metabolism. Since then much work has been due on these and other similar systems and their reactivities. 

A number of studies have been carried out on the ligand reactivities of the metal complexes of Schiff bases derived from amino acid esters and carbonyl compounds. Ester exchange reactions were first reported by Pfeiffer et a/.492 and extended by other investigators.493 496... 

LLB, LiOH, and H2O promoted the direct aldol reaction of glycinate Schiff bases 12 with aldehydes 3, providing access to p-hydroxy-a-amino acid esters 13 (Scheme 4,bottom) [7],... 

On the basis of this achievement, different types of catalysts have been designed and evaluated with aromatic aldimine Schiff bases of a-amino acid esters (mainly alaninate), and these are summarized in Table 4.5. 

Calcagni, A., Rossi, D., and Lucerne, G., a-Hydroxymethylation of Schiff bases derived from a-amino acid esters, Synthe.si.s. 445, 1981. 

Enantioselectiveprotonation. French chemists have reported a new method for obtaining optically active a-amino acids A racemic a-amino acid ester is converted into the racemic Schiff base 2. This is deprotonated with LDA to the anion 3, which is then protonated with an optically active acid such as 1. The optically active Schiff base 2 is formed with an enantiomeric ratio as high as 80 20. The enantiomeric ratios are dependent largely on the structure of the diacyltartarlc acid. 

Originally devised as a method for the conversion of amino acids or amino acid esters to aldehydes. The Akabori reaction has been modihed for use in the determination of C-terminal amino acids by performing the reaction in the presence of hydrazine and for the production of derivatives useful for mass spectrometric identihcation. See Ambach, E. and Beck, W., Metal-complexes with biologically important ligands. 35. Nickel, cobalt, palladium, and platinum complexes with Schiff-bases of... 

Studies on the transamination reaction between f-butyl esters of optically active amino acids and methyl pyruvate were carried out, as shown in Scheme 7. The resulting iminodicarboxylic acid (16) was partially hydrolyzed and then oxidized with f-butyl hypochlorite to form alanine. The oxidation is a generally applicable one, and the optical purity of alanine is high (50-70%). Similar asymmetric transamination between an (S)-amino acid and ketones was carried out. Catalytic hydrogenation of the Schiff s bases prepared from a-keto acid esters and amino acid esters was carried out, and a substituent and temperature effect observed (de 40-70%). ... 

A variety of reagents have been described for reductive amination, a labelhng reaction based on the attachment of an amino group at the carbonyl group in a reducing sugar under mild acidic conditions. This yields an acid-labile Schiff base (imine derivative), which is subsequently reduced to a stable secondary amine. Frequently applied reagents are 2-aminopyridine (PA), 2-aminoacridone (2-AMAC), and 4-aminobenzene derivatives such as 4-aminobenzoic ethyl ester (ABEE) or aminobenzoic butyl ester (ABBE). 

Tripeptides can be obtained in good yields by reacting primary amines with aldehydes leading to the intermediate Schiff base. Applying pathway (b Scheme 6) with isocyanide amino acid esters and N-pro-tected amino acids, the Ugi reaction occurs s with good yields (equation 37). Asymmetric induction on the new stereogenic centre ( ) is low, but can be enhanced by the use of chiral amines. 

In a similar manner, we synthesized dipeptides (Scheme 6) and their hydroxy analogs (depsipeptide unit) (Scheme 7) starting from the Schiff bases of a-amino acid esters (14). Optically pure dipeptides were synthesized via separation of the two diastereomers of the azido-3-lactam by HPLC as typified in Scheme 8. It turned out that no racemizatlon at all took place during the ring opening... 

Since a 3-lactam derived from the Schiff base of an a-amino acid ester was thus proved to be the synthetic equivalent of dipeptide, we prepared tripeptide and tetrapeptide synthons involving one or two 3-lactams, which were further submitted to hy-drogenolysis to give the corresponding tri- and tetrapeptides (Scheme 9)(16). 

The Schiff bases are obtained in situ by mixing sodium salicyaldehyde (10-30% molar excess) with amino acids or amino acid ester hydrochlorides (10-15 fivnol) in methanol. Spectral measurements are carried out 1-4 hr... 

The recycling of the undesired enantiomer from the enzymatic resolution is of crucial importance particularly on an industrial scale [107]. The classical chemical method consists of the thermal racemization of an amino acid ester at about 150-170°C. Milder conditions can be employed for the racemization of the corresponding amides via intermediate formation of Schiff bases with aromatic aldehydes such as benzaldehyde or salicylaldehyde (Scheme 2.14). More recently, intense research has been devoted to the use of isomerase enzymes (such as amino acid racemases [108]) aiming at the development of dynamic resolution processes. 

Scheme 3.38 DKR of Schiff bases of amino acid esters.

There are various synthetic routes to introduce hydrocarbon long chains into amino acid-based surfactants. For example, a long-chain fatty acyl group is introduced on the amino part of amino acids by using an acid chloride. To obtain amino acid esters or amides, the carbonyl parts of amino acids are reacted with fatty alcohol or amines, respectively. For example, C-alkylation of an amino acid is obtained by the reaction of a-bromo fatty acid with ammonia or by a transmission reaction of the amino part of the amino ester with a stable Schiff base followed by deprotonation with a strong base. This is followed by alkylation with an alkyl halide. N-Alkylation of an amino acid is generally obtained by the reaction of fatty amines with monochloroacetic acid, methyl acrylate, or maleic acid or by the addition of 1,2-epoxy alkane to amino acids. 

Anions derived from Schiff bases of a-amino-acid esters react with various halogenomethanes (CH2BrCI, CH2CIF, CHCIF2) to give the expected a-halo-genomethyl derivatives in (crude) yields of 70—80%. Methods for the preparation of /8-fluoro- and 8, 8-difluoro-a-amino-acids have also been developed. 

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