Chiral compounds, Amino acids

Perindopril (A), an orally active pharmaceutical for the treatment of hypertension, is an important commercial target compound that has a cyclic a-amino acid as an intermediate in its synthetic route. The bicyclic a-amino acid building block is synthesized by reduction of the chiral indoline-2-carboxylic acid (B, R=R =H) shown in Figure 1.4. This chiral cyclic amino acid has so far proven very difficult to synthesize in a highly enantioselective manner using chiral hydrogenation. 

Oxazolones (73), the saturated azlactones, have been studied intensively (B-57MI41801, B-57MI41802, 65AHC(4)75,69MI41800,77AHC(21)175). They show carbonyl and C=N absorptions in the 1820 and 1660 cm-1 regions, respectively. Azlactones derived from chiral a-amino acids, e.g. compound (74), can be obtained in optically active forms which racemize easily. The derived salts (75 R2 = H, Me or Ph) likewise exhibit optical activity they show intense carbonyl bands at 1890-1880 and C=N+ absorptions at ca. 1650 cm-. ... 

In 1872 the simplest a,a-disubstituted amino acid (2-aminoisobutyric acid, Aib) was described [3]. In 1908 the first optically active representative of this class of compounds, (/ )-2-ethylala-nine (D-isovaline), was isolated by microbial racemic resolution [4]. Synthetic chemists have therefore been interested in the enantiopure synthesis of a-alkylated a-amino acids for some time. Their powerful methods for the construction of chiral a-amino acids can in some cases also be used for the synthesis of the a-alkylated derivatives which has been the topic of recent reviews [5]. 

An interesting group of chiral carriers are those formed by species that utilize interactions between transported enantiomer and transition metal complexes. For instance, such a compound, acting as an additional chiral ligand for the copper central cation, is able to recognize an amino acid Cu(II) complex present in the feed phase. This double chiral carrier-amino acid-Cu (II) complex becomes diastereoisomeric and can be transported through a... 

Alternate routes to chiral a-amino acids and a-amino alcohols that apparently proceed with somewhat higher diasteroselectivity involve the reactions of achiral a-chloronitroso compounds with chiral enolates or of chiral a-chloronitroso compounds with achiral enolates (see section on the animation with nitroso compounds in Comparison with Other Methods), but they have not been applied nearly as frequently as the animations described above. 

Piperazinediones are the keto forms of 2,5-dihydroxy-3,6-dihydropyrazines, and many 2,5-piperazinedione derivatives have been found in nature. Numerous synthetic investigations for these compounds <83H(20)1407, 93AHC(57)186> have been carried out, particularly in an approach to the total synthesis of the antibiotic bicyclomycin <85JA3253> and the synthesis of chiral a-amino acids known as the Schollkopf-Hartwig bislactim ether method. Direct introduction of a substituent on... 

This chapter considers the results received from enantioselective electrochemical reactions mainly from hydrogenations on metal (Pt, Ni), graphite, and Hg cathodes modified with chiral compounds (polyamino acids, alkaloids, and amino alcohols). Enantioselectivities of hydrogenation reactions were not effective, ee values did not exceed 50%, except in the cases of dehydrohalogenation and oxidation, from which optical yields reached above 90%. 

This reaction was first reported by Schollkopf in 1979. It is a synthesis of an unnatural nonproteinogenic amino acid from the lithiated enolate equivalent of a simple amino acid (e.g., glycine, alanine and valine), which involves the diastereoselective alkylation of the lithiated bis-lactim ether of an amino acid with an electrophile or an Aldol Reaction or Michael Addition to an o ,jS-unsaturated molecule and subsequent acidic hydrolysis. Therefore, the intermediate of the bis-lactim ether prepared from corresponding amino acids is generally referred to as the Schollkopf bis-lactim ether, " Schollkopf chiral auxiliary, Schollkopf reagent, or Schollkopf bis-lactim ether chiral auxiliary. Likewise, the Schollkopf bis-lactim ether mediated synthesis of chiral nonproteinogenic amino acid is known as the Schollkopf bis-lactim ether method, Schollkopf bis-lactim method, or Schollkopf methodology. In addition, the reaction between a lithiated Schollkopf bis-lactim ether and an electrophile is termed as the Schollkopf alkylation, while the addition of such lithiated intermediate to an Q ,j8-unsaturated compound is referred to as the Schollkopf-type addition. ... 

Organic chemists speak of a chiral pool, which comprises those naturally occurring compounds that are readily available as a single enantiomer and capable of being used as starting materials for the enantioselective synthesis of other chiral molecules. Amino acids are well represented in the chiral pool. All except glycine have at least one chirality center and, although L-amino acids are more abundant and less expensive than their D-enantiomers, both are available. 

Chiral a-amino acids, a-methyl amino acids and ahphatic or aromatic a-hydroxycarboxylic acids, chiral iV-alkyl, iV-carbamyl, and iV-formyl amino acids, dipeptides and heterocyclic compounds... 

The primary goal of this book is to summarize synthetic approaches to non-a-amino acids, particularly those amino acids that are key synthetic intermediates or important compounds in their own right Achiral amino carboxylic acids are discussed throughout and special attention is focused on both chiral nonracemic and chiral racemic amino acids in chapter five, emphasizing the diastereoselcctivity and/or enantioselectivity of each synthetic process. Having such synthetic information collected in one place will, it is hoped, facilitate current research and stimulate new research in this important area. 

Chiral -amino acids are an important class of building blocks for the synthesis of biologically active compounds. Among them, chiral cyclic -amino acids are currently of much interest because of a recent finding that peptides composed of... 

Because of their occurrence in many biologically active compounds, chiral a-amino acids are among the most important targets for asymmetric synthesis. A wide variety of methods have been developed, in addition to the two included in this section, and these are described in a recent monograph.0 1... 

Further work on the preparation of chiral a-amino-acids reported in the past year (see also the section on asymmetric hydrogenation) includes an extension of the utility of anions derived from lactim ethers (228) in the synthesis of such compounds by condensations with aldehydes and ketones chiral inductions are somewhat lower than in the alkylations of (228) reported previously (4, 320). Enzyme-mediated hydrolysis of 5(4H)-oxazolones by chymotrypsin or subtilisin gives a-acylamino-acids with good enantiomeric enrichments, especially if the substrate carries bulky substituents. Schiff s bases of a-amino-esters can be enriched enantiomerically to an extent of up to 70% by sequential deprotonation with a chiral lithium amide and protonation with an optically pure tartaric acid. ... 

The tetrahydrophthalic ester of prednisolone, an anti-inflammatory drug, consists of two diastereoisomers. Olszewska et al. [66] describes the effect of addition of an optically active compound (amino acids, cyclodextrins, camphosulfonic acid) on the capacity ratios, k, and separation factors of these diastereoisomers by TLC. They used both mobile phases containing a chiral additive and stationary phases impregnated with an optically active compound, for example, silica gel plates impregnated with amino acids. The best resolution was obtained by impregnation of the stationary phase with o-camphosulfonic acid and copper acetate, and use of dichloromethane-isopropanol (90+10, v/v) as mobile phase. The addition of chiral compound to the mobile phase had less effect on the resolution of diastereoisomers. 

---