Amino acid derivatives, formation

Cl3CCH20C0-0-succinimidyl, 1 N NaOH or 1 N Na2C03, dioxane, 77-96% yield/ This method does not result in oligopeptide formation when used to prepare amino acid derivatives. 

For the separation of amino acids, the applicability of this principle has been explored. For the separation of racemic phenylalanine, an amphiphilic amino acid derivative, 1-5-cholesteryl glutamate (14) has been used as a chiral co-surfactant in micelles of the nonionic surfactant Serdox NNP 10. Copper(II) ions are added for the formation of ternary complexes between phenylalanine and the amino acid cosurfactant. The basis for the separation is the difference in stability between the ternary complexes formed with d- or 1-phenylalanine, respectively. The basic principle of this process is shown in Fig. 5-17 [72]. 

Tin(Il) shows considerable affinity towards nitrogen, therefore is expected to activate the imino group. The diastereoselective addition of tin(II) enolates derived from thioesters 1 to x-imino-esters 2 is reported12. This reaction proceeds smoothly to afford. vi w-/j-amino acid derivatives 3 (d.r. 95 5) in good yields. Lithium, magnesium, and zinc enolates do not react while titanium enolates give the adducts in low yield with preferential formation of the anti-isomer. 

Like the Strecker synthesis, the Ugi reaction also involves a nucleophilic addition to an imine as the crucial step in which the stereogenic center of an a-amino acid derivative is formed4. The Ugi reaction, also denoted as a four-component condensation (A), is related to the older Passerini reaction5 (B) in an analogous fashion as the Strecker synthesis is to cyanohydrin formation. In both the Ugi and the Passerini reaction, an isocyanide takes the role of cyanide. 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

The main application of the enzymatic hydrolysis of the amide bond is the en-antioselective synthesis of amino acids [4,97]. Acylases (EC 3.5.1.n) catalyze the hydrolysis of the N-acyl groups of a broad range of amino acid derivatives. They accept several acyl groups (acetyl, chloroacetyl, formyl, and carbamoyl) but they require a free a-carboxyl group. In general, acylases are selective for i-amino acids, but d-selective acylase have been reported. The kinetic resolution of amino acids by acylase-catalyzed hydrolysis is a well-established process [4]. The in situ racemization of the substrate in the presence of a racemase converts the process into a DKR. Alternatively, the remaining enantiomer of the N-acyl amino acid can be isolated and racemized via the formation of an oxazolone, as shown in Figure 6.34. 

In 1995, and regrettably missed in last year s review, Klotgen and Wiirthwein described the formation of the 4,5-dihydroazepine derivatives 2 by lithium induced cyclisation of the triene 1, followed by acylation <95TL7065>. This work has now been extended to the preparation of a number of l-acyl-2,3-dihydroazepines 4 from 3 <96T14801>. The formation of the intermediate anion and its subsequent cyclisation was followed by NMR spectroscopy and the stereochemistry of the final product elucidated by x-ray spectroscopy. The synthesis of optically active 2//-azepines 6 from amino acids has been described <96T10883>. The key step is the cyclisation of the amino acid derived alkene 5 with TFA. These azepines isomerise to the thermodynamically more stable 3//-azepines 7 in solution. 

The Heck reaction has proven to be an extremely useful method for the formation of C-C bond at a vinyl carbon centre. There are numerous reported examples of enantioselctive Pd catalyzed C-C bond forming reactions.10"13 Surprisingly, reports of Heck transformations using amino acid based phosphine, phosphinite ligands are rare. Recently Gilbertson reported a proline derived phosphine-oxozoline ligand in a catalytic asymmetric Heck reaction.5 In this paper we present some novel amino acids derived ligands as part of a catalytic system for use in asymmetric Heck reactions. 

In this context, also mentionable are several publications by the groups of Dlaz-de-Villegas [242], Guarna [243], Kunz [244] and Waldmann [245], which describe the formation of six-membered azaheterocycles via treatment of an imine with an appropriate substituted diene. For instance, as described by Waldmann and coworkers, reaction of the enantiopure amino acid-derived imines 2-452 with Danishefsky s diene 2-453 in the presence of equimolar amounts of a Lewis acid provided diastereomeric enaminones 2-456 and 2-457 (Scheme 2.105) [245a]. 

As shown in the two examples described here, formation of the benzene nucleus by trimerization of alkynes is usually catalyzed by a Co-complex. However, Und-heim and coworkers [276] have recently shown that a Ru "-complex can also be used. Reaction of the triyne 6/4-9, which was prepared from SchollkopPs bislactim ether 6/4-8 [277] with Grubbs I catalyst 6/3-13, led to 6/4-10 in an excellent yield of 90%. Hydrolysis of 6/4-10 gave the desired as-indacene-bridged bis(a-amino acid) derivative 6/4-11 (Scheme 6/4.3). 

Importantly, it was demonstrated that no significant racemization occurred in the course of peptide formation. Furthermore, the complete coupling of difficult peptide sequences could be accomplished within a few minutes, and it was determined that peptide fragments have higher reactivity than single amino acid derivatives under microwave irradiation conditions. However, the exact reaction temperature during the irradiation period was not determined. 

Reaction with chelating agents. Such reactions have been used primarily for partial dealumination of Y zeolites. In 1968, Kerr (8,21) reported the preparation of aluminum-deficient Y zeolites by extraction of aluminum from the framework with EDTA. Using this method, up to about 50 percent of the aluminum atoms was removed from the zeolite in the form of a water soluble chelate, without any appreciable loss in zeolite crystallinity. Later work (22) has shown that about 80 percent of framework aluminum can be removed with EDTA, while the zeolite maintains about 60 to 70 percent of its initial crystallinity. Beaumont and Barthomeuf (23-25) used acetylacetone and several amino-acid-derived chelating agents for the extraction of aluminum from Y zeolites. Dealumination of Y zeolites with tartaric acid has also been reported (26). A mechanism for the removal of framework aluminum by EDTA has been proposed by Kerr (8). It involves the hydrolysis of Si-O-Al bonds, similar to the scheme in Figure 1A, followed by formation of a soluble chelate between cationic, non-framework aluminum and EDTA. 

FIGURE 2.14 Peptide-bond formation from chlorides of A-alkoxycarbonylamino acids. N-9-Fluorenylmethoxycarbonylamino-acid chlorides.41 The base is NaHCO, Na2C03, or a tertiary amine. The reaction is carried out in a one- or two-phase system. The latter is used to try to suppress formation of the 2-alkoxy-5(4//)-oxazolone that is generated by the action of the base on the acid chloride. The method is applicable primarily to Fmoc-amino-acid derivatives that do not have acid-sensitive protecting groups on their side chains. 

J Kovac, GL Mayers, RH Johnson, RE Cover, UR Ghatak. Racemization of amino acid derivatives. Rate of racemization and peptide bond formation of cysteine active esters. J Org Chem 35, 1810, 1970. 

The amidocarbonylation of aldehydes provides highly efficient access to N-acyl a-amino acid derivatives by the reaction of the ubiquitous and cheap starting materials aldehyde, amide, and carbon monoxide under transition metal-catalysis [1,2]. Wakamatsu serendipitously discovered this reaction when observing the formation of amino acid derivatives as by-products in the cobalt-catalyzed oxo reaction of acrylonitrile [3-5]. The reaction was further elaborated to an efficient cobalt- or palladium-catalyzed one-step synthesis of racemic N-acyl a-amino acids [6-8] (Scheme 1). Besides the range of direct applications, such as pharmaceuticals and detergents, racemic N-acetyl a-amino acids are important intermediates in the synthesis of enantiomeri-cally pure a-amino acids via enzymatic hydrolysis [9]. 

The formation of DNP or dansyl amino acid derivatives followed by chromatography or electrophoresis is a useful technique in certain circumstances. The preparation of DNP derivatives may be indicated when the sample for analysis contains a variety of other substances, removal of which would be complicated, leading possibly to considerable analytical errors. However, the derivative formation and extraction is time consuming and itself can introduce inaccuracies into the analysis and should be used only when it offers an advantage over the separation of untreated amino acids. 

One may, therefore, assume that the lactam metabolites formed are rather resistant to hydrolytic degradation and do not contribute significantly to the formation of the co-amino acid derivatives. This is in line with the observation that substituted pyrrolidin-2-ones are generally resistant to metabolic hydrolysis (see Sect. 5.3). 

Fig. 5.26. Metabolism of the piperidine ring according to the mechanism in Fig. 5.23. Diphen-idol (5.97) and DN-9893 (5.73) yield both amino acid and lactam metabolites [177], Phencyclidine (5.98) yields only the amino acid derivative steric hindrance at the N-atom appears to impede formation of the lactam metabolite [190].

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