A-Substituted amino acid derivatives

Asymmetric Alkylation Leading to a-Substituted Amino Acid Derivatives... 

In the literature, a variety of methodologies have been reported for the asymmetric synthesis of quaternary a-amino acids. [3] Among these methods, Seebach s self-regeneration of stereocenters [5] for the preparation of a-substituted amino acid derivatives (Scheme 3) was most attractive to us. The principal reasons are the ready availability of the required chiral imidazolidinones (up to 90% ds), the stability of the corresponding enolates at higher temperature (up to 0 C), and the predictability of the stereochemical outcome. 

Riordan and Stammer (335, 336) employed o-chloranil to oxidize saturated A -oxazolinones, and obtained dioxinones. Treatment of the latter with nucleophiles such as CH3O", PhNH2 or PhCH2SH afforded a-substituted amino acid derivatives, possibly by addition to the acylimine in equilibrium with the quinone adduct. Use of a non-nucleophilic base coupled with scavenging of the phenolic hydroxy groups by etherification made possible the isolation of acylenamino acid derivatives. 

A functionalized amino acid derivative has been synthesized by alkylation of a heteroatom-substituted Jt-allyl intermediate (Scheme 8E.27) [146], The alkylation of a Schiif base, which forms a 2-aza-7t-allyl intermediate, furnishes the malonate adduct with 85% ee despite the epimerizable nature of the newly generated stereogenic center. 

The use of aza-annulation reagent 347 was also applied to the reaction with p-enamino amide substrates (eq. 76).9 Treatment of 379 with 347 led to formation of the A-substituted and A-unsubstituted amino acid derivatives 380, and the unsubstituted substrate produced superior yields. 

The concept of intramolecular alkylation of AT-substituted amino acid derivatives via 1,5-diradicals also turned out to be an excellent system for studying the different stereochemical course of spinisomers as discussed in Section 6.2.2. Thus, the a-ketoester 9, which contains an alanine moiety, was prepared. In contrast to aryl ketones, a-ketoesters are not completely converted into the triplet state after photochemical excitation. Upon addition of either a triplet quencher (naphthalene) or a triplet sensitizer (benzophenone), each of the two spin states may be forced (Scheme 3, Table 1). The chiral center at the d-position with respect to the keto carbonyl group raises the question whether a memory effect of chirality may be observed during the cyclization. The results summarized in Table 1 amply demonstrate the specific properties of spinisomeric biradicals. In the presence of naphthalene, which probably acts not only as a triplet quencher but also as a singlet sensitizer, the chiral information of the reactant 9 is almost entirely conserved in the helical diradical 10 because of its very short lifetime. In contrast, the addition of benzophenone results in almost complete racemization, and also the cis/trans selectivity is... 

Asymmetric amino acid synthesis via diastereoselective alkylation of the lithiated bis-lactim ether (derived from L-Val and Gly or Ala) by an electrophile. Subsequent acid hydrolysis liberates L-Val-OCH3 and the (7 -a-substituted amino acid ester. When the bis-lactim is generated from D-Val, the fl -enantiomer forms ... 

Studies to date indicate that transaminases are specific for L-amino acids and a-keto acids. Peptides and other derivatives of amino acids, such as amides and A -substituted amino acids, are not active. Recently it has been reported that E. coli extracts catalyze a transamination reaction between adenine and a-ketoglutaric acid. ... 

Cyclic carbonates react with isocyanates in the presence of catalysts to give oxazolidi-nones with elimination of carbon dioxide The catalysts sometimes cause trimerization of the isocyanate. Carbonates derived from a-hydroxy carboxylic-, a-mercapto carboxylic and a-A-substituted amino acids react with isocyanates with elimination of carbon dioxide to give five-membered ring [3+2] adducts. ... 

Other electrophiles, such as Michael acceptors, can also be involved in the a-alkylation step. This has been exploited in the conjugate addition of enantiopure lithium amides 60 to unsaturated esters 61, followed by trapping of the resulting enolate with alkylidene malonates. This constitutes a useful methodology for the asymmetric synthesis of p-amino-a-substituted carboxylic acid derivatives 62 (Scheme 11.24) [65]. 

Amadori compounds, N-substituted 1-amino-l-deoxy-2-ketoses e.g. (1) in Scheme 1, formed by reaction of free sugars with the primary amino-groups in free amino acids, peptides or proteins can be determined by g.c. analysis of the A-(carboxymethyl)-amino acid derivatives e.g. (2) released by a protocol involving periodate oxidation of the sugar residue. ... 

The key structural feature of BIRT-377 (1) is the A-aryl-substituted-hydantoin bearing a quaternary stereogenic center. In our retrosynthetic analysis, the hydantoin ring can be synthesized by cyclization of the corresponding acyclic a-substituted amino acid amide (9), which could be derived from (Z>) or (L)-alanine. 

Oxidative cleavage of P-aminoacyl complexes can yield P-amino acid derivatives (320,321). The rhodium(I)-catalyzed carbonylation of substituted aziridines leads to P-lactams, presumably also via a P-aminoacyl—metal acycHc compound as intermediate. The substituent in the aziridine must have 7T or electrons for coordination with the rhodium (322,323). 

However, it was not until the beginning of 1994 that a rapid (<1.5 h) total resolution of two pairs of racemic amino acid derivatives with a CPC device was published [124]. The chiral selector was A-dodecanoyl-L-proline-3,5-dimethylanilide (1) and the system of solvents used was constituted by a mixture of heptane/ethyl acetate/methanol/water (3 1 3 1). Although the amounts of sample resolved were small (2 ml of a 10 inM solution of the amino acid derivatives), this separation demonstrated the feasibility and the potential of the technique for chiral separations. Thus, a number of publications appeared subsequently. Firstly, the same chiral selector was utilized for the resolution of 1 g of ( )-A-(3,5-dinitrobenzoyl)leucine with a modified system of solvents, where the substitution of water by an acidified solution... 

With Sulfur Nucleophiles N-Carboxy-protected aziridine-2-carboxylates react with thiols to give P-mercapto-ot-amino acid derivatives. The reaction is usually catalyzed by BF3 and the yields range from fair to excellent [15, 16, 108-111]. With N-unprotected 3-substituted aziridine-2-carboxylates, the ring-opening with thiols usually takes place with anti stereoselectivity, especially in the case of the C-3 aliphatic substituted substrates. In cases in which C-3 is aromatic, however, the stereoselectivity has been found to be a function of the substitution pattern on the aromatic ring 3-p-methoxy ph eri yl-su bs li In led aziridines 143a (Scheme 3.51) and... 

When /V-arenesulfonyl-a-amino acid derived boranes 13 and 14 are used in substoichiometric amounts in order to mediate enantioselective aldol additions of a,a-dimethyl substituted ketcnc acetal 15, /J-hydroxycarboxylic esters 16 are obtained in enantiomeric excess of 84 to > 99 %3fi. 

An excellent method for the diastereoselective synthesis of substituted amino acids is based on optically active bislactim ethers of cyclodipeptides as Michael donors (Schollkopf method, see Section 1.5.2.4.2.2.4.). Thus, the lithium enolates of bislactim ethers, from amino acids add in a 1,4-fashion to various a,/i-unsaturated esters with high diastereofacial selectivity (syn/anti ratios > 99.3 0.7-99.5 0.5). For example, the enolate of the lactim ether derivative 6, prepared from (S)-valine and glycine, adds in a highly stereoselective manner to methyl ( )-3-phenyl-propenoate a cis/trans ratio of 99.6 0.4 and a syn/anti ratio of 91 9, with respect to the two new stereogenic centers, in the product 7 are found105, los. 

A nomenclature was proposed by Seebach for the description of / -amino acids according to their substitution pattern, and for naming the resulting / -peptides [66, 67]. Enantiomerically pure / -amino acid derivatives with substituents in the 2-or 3-position are thus defined as - and / -amino acids, respectively (abbreviated to H-/ -HXaa-OH and H-/ -HXaa-OH). The corresponding /S-peptides built from these monomers will be named ff - and / -peptides. Similarly, /S -peptides consist of / -amino acid residues with substituents in both the 2- and 3-positions. Finally, peptides built from geminally disubsituted amino acids are referred to as and / -peptides (Fig. 2.6). 

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