Chiral a-amino acids

The complex obtained from commercially available chiral a-amino acids (AA) with Cu + ion induces asymmetry in the Diels-Alder reaction of 31 (R = H) with 32. By using 10% Cu(II)-AA (AA = L-abrine) the cycloaddition occurs e/iJo-stereoselectively in 48 h at 0°C with high yield and with acceptable enantioselectivity ee = 1A%). This is the first example of enantioselective Lewis-acid catalysis of an organic reaction in water [9b]. 

In recent years, the catalytic asymmetric hydrogenation of a-acylamino acrylic or cinnamic acid derivatives has been widely investigated as a method for preparing chiral a-amino acids, and considerable efforts have been devoted for developing new chiral ligands and complexes to this end. In this context, simple chiral phosphinous amides as well as chiral bis(aminophosphanes) have found notorious applications as ligands in Rh(I) complexes, which have been used in the asymmetric hydrogenation of a-acylamino acrylic acid derivatives (Scheme 43). 

The pharmaceutical industry has been giving increased attention to homogeneous asymmetric hydrogenation for the synthesis of chiral molecules due to significant improvements in this technology (1). We recendy synthesized a chiral a-amino acid intermediate using Et-DuPhos-Rh catalyst, obtaining enantiomeric pmities (EP) of... 

DIPAMP-Rh complex to give the corresponding chiral a-amino acid derivative in over 98% ee. The chiral product has been used for the synthesis of (S)-(-)-ac-romelobic acid [88]. Hydrogenation of a tetrahydropyrazine derivative catalyzed by a PHANEPHOS-Rh complex at -40"C gives an intermediate for the synthesis of Crixivan in 86% ee [82a]. Hydrogenation of another tetrahydropyrazine carboxamide derivative catalyzed by an (R)-BINAP-Rh catalyst leads to the chiral product in 99% ee [89]. 

SYNTHESIS AND APPLICATION OF DIAMINO FERRIPHOS AS A LIGAND FOR ENANTIOSELECTIYE Rh-CATALYSED PREPARATION OF CHIRAL a-AMINO ACIDS... 

These are converted into chiral a-amino acids (5) on hydrogenation with Raney nickel. 

Chiral a-amino acids from imines derived from (S)-menthone... 

The method was successfully employed with enolizable esters, including chiral a-amino acid esters and peptides, and no trace of racemization/epimerization at the a carbon was detected. 

The asymmetric transamination from chiral a-amino acids 1021 and amino acid derivatives (57) (esters 86,103), amino alcohols 104 ) to carbonyl functions in prochiral substrates (58) (a-keto acids 102), a-keto esters 86,103), ketones 103b d) was described... 

The chiral lactone alcohol derivative (178)181) can be readily prepared from natural (S)-glutamic acid, the cheapest chiral a-amino acid. Lactone (178) was alkylated to yield optically active 3-substituted lactone alcohol derivatives, (179) and (180), which were intermediates in the stereoselective synthesis of various natural products 182). 

Chiral a-amino acids The lithium anion of the N-protected glycine amides 3, prepared by reaction of the pyrrolidine with [bis(methylthio)methylene]glycyl pivalic anhydride (DMAP), is alkylated with high diastereoselectivity. The (S)-amino acid (5) is obtained on acid hydrolysis. 

The rhodium-chiral phosphine catalyzed asymmetric hydrogenation of protected enam-ides, and other unsaturated amino acid derivatives (equation 85), gave almost 100% ee of the corresponding chiral a-amino acid derivative343,344. 

The sequence of Ugi-4CR + hydrolysis of the amino substituent has been employed in the stereoselective synthesis of chiral a-amino acid derivatives, by using a chiral amine component. Then the chiral template was covalently bound in close proximity to the newly synthesized chiral center. The amine residue of the product must be removable under mild conditions to avoid decomposition of the desired product. Chiral a-ferrocenylamines have been employed with some success [34], but the most useful auxiliaries were carbohydrate amines [35]. 

Electrophilic amination is a general entry to chiral a-amino acids or functionalized P-amino and P-hydroxy a-amino acids with an anti stereochemistry. The chiral enolate technology has been applied for the obtaining of C-N bond-forming reactions with stereochemical control. 

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-. ... 

Llewellyn DB, Arndtsen BA (2005) Synthesis of a library of chiral a-amino acid-based borate counteranions and their application to copper catalyzed olefin cyclopropanation. Tetrahedron Asymmetry 16 1789-1799 Makino T, Baba N, Oda J, Inouye Y (1977) Asymmetric reduction of alpha, beta-unsaturated iminuum salt with A-glucopyranosyl-l,4-dihydronicotin-amides. Chemlnd 1977 277-278... 

When azomethine ylides are generated by condensation of aldehydes with chiral a-amino acids, the stereogenic center of the latter is lost in the planar 1,3-dipole structure. To achieve diastereoselection in the addition to Ceo, an additional chiral element is therefore needed. An optically pure azomethine ylide was generated by reaction of (+)-2,3-0-isopropylidene-D-glyceraldehyde with... 

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]. 

Resolution of Carboxylic Acids. A variety of racemic monofunctional carboxylic acids have been resolved with chiral a-amino acid hydrazides, including L-1Vr-NHNH2 andL-leucine hydrazide, which produce mandelic acid analogs with greater than 99% ee. Other examples of resolutions of simple carboxylic acids have appeared in the patent literature (eq 1). ... 

Recently, Steckhan and coworkers [485,486] have reported that anodic methoxyla-tion of chiral 5-methyl- and 5-chloromethyl-2-oxazolidinones followed by Lewis acid-catalyzed allylation provides 4-allyl products highly diastereoselectively. Similarly, anodic methoxylation of cyclic dipeptides and dipeptolides derived from chiral a-amino acid [487] or a-hydroxy acid [488] provides useful chiral synthetic building blocks, as in Eq. (64). a-Alkoxylation of lactic amide derivatives was also reported [489]. However, the diasteros-electivity was low. 

The synthesis of chiral a-amino acids starting from a-keto acids by means of a transamination has been reported by NSC Technologies [115]. In this process, L-aspartate serves as the amino donor. The substrate specificity is broad, allowing the conversion of numerous keto acid substrates. 

Carboxylic acids. Primary alcohols are oxidized to acids (secondary alcohols to ketones) using catalytic amount of CrOj and excess HjIOg in wet MeCN. By this procedure there is very little racemization of the products bearing a chirality center adjacent to the emerging carbonyl group. Therefore this method is useful for the preparation of chiral a-amino acids. 

Amines. Chiral a-amino acids are obtained from cyanohydrins via a Mitsunobu reaction employing A-f-butoxycarbonyl-A-(2-trimethylsilyl)ethylsulfonamide as the nucleophile. The a-aminonitrile derivatives thus generated are hydrolyzed with acid. By means of an intramolecular displacement (3-hydroxy acids are transformed into (3-amino acids. Thus, subjecting the derived 0-benzylhydroxamides to Mitsunobu reaction conditions leads to (3-lactams which are readily processed (LiOH H, Pd/C). 

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