Racemic azlactones

It is mentioned in Section II, C, 1 that iV -benzoyl-D-alanine cyclizes in 100% sulfuric acid to. give an azlactone which racemizes very slowly. ... 

Oxazolones (azlactones) are a form of activated lactones, so they are included in this section. CAL-B is an effective catalyst for the DKR of various racemic four-substituted-5 (4H)-oxazolones, in the presence of an alcohol, yielding optically active N-benzoyl amino acid esters as illustrated in Figure 6.24 [40]. Enantioselective biotransformations of lactides [72,73] and thiolactones ]74] have also been reported. 

Moreover, it is possible to open racemic azlactones by acyl bond cleavage to form protected amino acids in a dynamic kinetic resolution process. As azlactones suffer a fast racemization under the reaction conditions, eventually all starting material is converted [115]. 

Liang J, Ruble JC, Fu GC (1998) Dynamic kinetic resolutions catalyzed by a planar-chiral derivative of DMAP enantioselective synthesis of protected a-amino acids from racemic azlactones. J Org Chem 63 3154—3155... 

Scheme 6.89 Proposed mechanistic picture for the asymmetric alcoholytic DKR of racemic aziactones promoted by bifunctional (thio)urea catalysts 64, 77, and 78 (A) hydrogen-bonded azlactone-64 complex supported by NMR methods (B).

Scheme 6.90 Chiral N-benzoyl-protected a-amino acid allyl esters obtained from 64- and 78-catalyzed asymmetric DKR of racemic azlactones derived from racemic natural nonnatural a-amino acids.

Compared to the chemo-catalyzed kinetic resolution of alcohols, there are few reports of similar reactions for amines. Building on other work, one elegant example from Berkessel uses bifunctional organocatalysts to enantioselectively hydrolyze a racemic azlactone, and the dynamic kinetic resolution (DKR) is achieved by in-situ acid-catalyzed racemization of the azlactone under mild conditions to give product N-acylarnino esters in, for example, 72% ee and 96% conversion with phenylalanine [6]. 

Protected amino acids with either a free amino or carboxyl function can usually be prepared by proven methods or are even commercially available. Therefore stages (i) - (iii) may be considered as simple routine nowadays, although great care must be taken that the protected starting materials are pure enantiomers. The reactions that cause most trouble are in stages (iv), (v) and (vii). In these stages an activated carboxyl group is involved and the chiral centre adjacent to it is at peril from racemization. A typical reaction which causes epimerization is azlactone formation. With acids or bases these cyclization products may reversibly enolize and racemize. Direct racemization of amino acids has also been observed. 

The best preventive measure against racemization in critical synthetic steps (e.g. fragment condensation, see p. 239) is to use glycine (which is achiral) or proline (no azlactone) as the activated carboxylic acid component. The next best choice is an aliphatic monoamino monocarboxylic acid, especially with large alkyl substituents (valine, leucine). Aromatic amino acids (phenylalanine, tyrosine, tryptophan) and those having electronegative substituents in the /7-position (serine, threonine, cysteine) are, on the other hand, most prone to racemization. Reaction conditions that inhibit azlactone formation and racemization are non-polar solvents, a minimum amount of base, and low temperature. If all precautions are taken, one still has to reckon with an average inversion of 1 % per condensation reaction. This means, for example, that a synthetic hectapeptide contains only 0.99100 x 100% = 37% of the fully correct diastereomer (see p. 233 f.). 

In 1970 Steglich and Hofle reported that 4-dimethylaminopyridine (DMAP) and 4-(pyrrolidino)pyridine (PPY) are excellent catalysts for isomerization of O-acyl azlactones E to their C-acylated isomers F [79-81], In this rearrangement, a new quaternary stereocenter is generated (Scheme 13.41). Clearly, DMAP or PPY afford the rearrangement products F in the racemic form. 

The planar chiral DMAP derivative 79a proved successful also in the dynamic kinetic resolution of racemic azlactones by ring-opening with alcohols (Scheme... 

This process relies on rapid base-induced racemization of the azlactone and rate-limiting ring opening by the alcohol nucleophile. In this process the DMAP derivative 79a acts as both Bronsted-basic and as nucleophilic catalyst. With 2-propanol as reagent enantiomeric excesses up to 78% were achieved for the product amino acid esters [87]. 

Type II Alcoholative KR of Racemic Anhydrides, Azlactones, /V-Car boxy an hydrides, Dioxolanediones and N-Acyloxazolodinethiones... 

This process proceeds as a DKR [13, 190] because the DMAP catalyst promotes not only the asymmetric alcoholysis of the azlactone but also its racemization under the reaction conditions the N-benzoyl a-amino acid ester product does not racemize under these conditions. Johannsen has also screened chiral DMAP 21 (Fig. 8.4) for this transformation, but obtained poorer yields and selectivities [102],... 

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-. ... 

With racemic a-alkylated amino acids an enzymatic racemate resolution is possible. There are several methods to access racemic a-alkylated amino acids in high yields [38]. Different microorganisms have been applied, and the products are obtained in very high enantiomeric purities [39]. Because a-alkylated amino acids are used as building blocks for different active substances, methods for the synthesis of large quantities have been developed, especially in industry [40]. Other effective racemic resolution techniques have been described recently. Disubstituted azlactones of type 28 can react with the phenylalanine derivative 29 [41]. The diastereo-mers of the protected dipeptide 30 are then separated. The easy access of compounds of type 28, together with the optimized reagent 29, ensures... 

Scheme 6. Synthesis of optically pure a,a-disubstituted amino acids by treatment of racemic azlactones 28 with 29 and subsequent diastereomer separation of 30.

The reaction of azlactones or a Meldrum s acid derivative with 2-phenylbut-3-ene-2-yl acetate, in the presence of the racemic ligand and a palladium source has provided a new method for controlling alkene geometry. By varying the reaction conditions excellent selectivities for either or Z geometry could be obtained. " ... 

Overheating in the acid solution causes cyclization of the amide oxygen atom on to the carboxy lic acid. This reaction happens only because of the formation of a five-membered ring, an azlactone. These compounds are particularly dreaded by amino acid chemists because they racemize easily b . enolization and the enol is an aromatic compound. 

Solvent selection can markedly influence the product ratios of a reaction. In the catalytic asymmetric aminohydroxylation of styrene, the ratio of the acetamide products rose from 0.9 1 to 6.1 1 when the reaction was run in aqueous acetonitrile instead of aqueous n-PrOH (Figure 4.11) [34]. Solvent polarity can influence asymmetric induction, particularly during peptide coupling. When the racemic azlactone 15 was condensed with L-lysine methyl ester (16, Figure 4.12), the D,L-product predominated in relatively nonpolar solvents, and the L,L-product predominated in polar solvents and at lower temperatures [35]. 

Acetic anhydride reacts with an a-amino acid in the expected way, under mild conditions, to give the N-acetyl derivative, but also to set up an equilibrium with the carboxy group to form a mixed anhydride. More vigorous conditions promote the cyclisation of the mixed anhydride to the oxazol-5(4H)-one (the azlactone in Figure 4.1), which undergoes racemisation via the oxazole tautomer under the reaction conditions. Hydrolysis at the end of the process gives the racemised amino acid, so the net result is useful in the conversion of a natural L-amino acid into its D-enantiomer through racemisation, followed by resolution of the racemate (Chapter 6). 

In this chapter, we attempt to review the current state of the art in the applications of cinchona alkaloids and their derivatives as chiral organocatalysts in these research fields. In the first section, the results obtained using the cinchona-catalyzed desymmetrization of different types of weso-compounds, such as weso-cyclic anhydrides, meso-diols, meso-endoperoxides, weso-phospholene derivatives, and prochiral ketones, as depicted in Scheme 11.1, are reviewed. Then, the cinchona-catalyzed (dynamic) kinetic resolution of racemic anhydrides, azlactones and sulfinyl chlorides affording enantioenriched a-hydroxy esters, and N-protected a-amino esters and sulftnates, respectively, is discussed (Schemes 11.2 and 11.3). 

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