Phenylglycine amide

Asymmetric Strecker Synthesis of a-Amino Acids via a Crystallization-Induced Asymmetric Transformation Using (/Q-Phenylglycine Amide as Chiral Auxiliary... 

Diastereoselective Slrecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an In situ crystallization-induced asymmetric transformation, whereby one diastereomer selecliveiy precipitates and can be isolated in 76-33% yield and dr > gsti. The diastereomeilcaily pure a-amino nitrtie obtained from pivaidehyde (R, = t-Bu, Rj = H) was converted in three steps to (S)-tert-leucine in 73% yieid and >98% ee. 

In this paper, the firsi two examples of the use of (fO-phenylglycine amide in asy mniciric Sircckei leactioits are presciiicd. Pbaldchydc and. 4-dimelhoxyphenyliiccioae... 

A statement that points out that further examples of this reaction are under investigation using (R)-phenylglycine amide with different... 

The asymmetric Strecker reaction of (R)-phenylglycine amide 1, pivaldehyde 2, and HCN generated in situ from NaCN and AcOH was studied (Table 1). Amino nitriles (R,S)-3 and (R,R)-3 were obtained in 80% yield in a ratio of 65 35 by stirring an equimolar mixture of 1 (as AcOH salt) with 2 and NaCN in MeOH overnight at room temperature, followed by evaporation of the solvent (entry 1). The diastereo-meric ratio (dr) of (R,S)-3 and (R,R)-3 was determined by NMR on the basis of the relative integration between the t-Bu signals at 1.05 ppm for (R,S)-3 and 1.15 ppm for (R,R)-3. 

Table 1. Asymmetric Strecker Reactions of (R)-Phenylglycine Amide 1 and Pivaldehyde 2...

In summary, (R)-phenylglycine amide 1 is an excellent chiral auxiliary in the asymmetric Strecker reaction with pivaldehyde or 3,4-dimethoxyphenylacetone. Nearly diastereomerically pure amino nitriles can be obtained via a crystallization-induced asymmetric transformation in water or water/methanol. This practical one-pot asymmetric Strecker synthesis of (R,S)-3 in water leads to the straightforward synthesis of (S)-tert-leucine 7. Because (S)-phenylglycine amide is also available, this can be used if the other enantiomer of a target molecule is required. More examples are currently under investigation to extend the scope of this procedure. ... 

To present the take-home message of the current work Present-active In summary, (R)-phenylglycine amide 1 is an excellent chiral auxiliary in the asymmetric Strecker reaction with pivaldehyde or 3,4-dimethoxyphenyl-acetone. (From Boesten et al.. 2001)... 

Diastereoselective Strecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an in situ crystallization-induced asymmetric transformation, whereby one diastereomer selectively precipitates and... 

R)-Phenylglycine amide I is an excellent chiral auxiliary in the asymmetric Strecker reaction of pivaldehyde 2. In water at 70 °C, the (R,S)-3 product was isolated in 93% yield and dr > 99/1. Work is underway to convert (R,S)-3 to (S)-tert-leucine and thereby complete the asymmetric Strecker reaction. 

R)-Phenylglycine amide 1 is an excellent chiral auxiliary in the asymmetric Strecker reaction of pivaldehyde 2. 

Overview. To solve these problems, we present the first example of a crystallization-induced asymmetric transformation using optically pure (R)-phenylglycine amide 1 as a chiral auxiliary. The (R,S)-3 diastereomer precipitates out of solution in 76-93% yield with a diastereomeric ratio (dr) > 99/1. (106 words)... 

Because of its anticipated easy removal via catalytic hydrogenolysis, we decided to see the application of (R)-phenylglycine amide as a chiral auxiliary in asymmetric synthesis. (Adapted from Boesten et ah, 2001)... 

The asymmetric Strecker reaction of (R)-phenylglycine amide 1, pyvaldehyde 2, and FICN generated in situ from NaCN and AcOH was studied. (From... 

A two-step approach, involving repeated use of the same enzyme, has been reported for the resolution of rac-l-phenylethylamine 56a (Scheme 2.34). Penicillin acylase, from Alcaligenes faecalis, was initially used in aqueous medium with (R)-phenylglycine amide 67 as the acyl donor. Under these conditions, the enzyme catalyzed the enantioselective acylation of 56a at pH 10-11. The product amide 68 was insoluble, and was collected and re-exposed to the enzyme at pH below 7.5. This resulted in the cleavage of the phenylglycinyl substituent. Excellent conversions, E values and enantiomeric excesses were achieved [36]. 

PGA D-Phenylglycine amide PGME D-Phenylglycine methyl ester PhAc Phenylacetic acid... 

The use of phenylglycine amide (3) for the preparation of amino acids is discussed in Chapter 25. 

The high-yield synthesis of the racemate via a Strecker synthesis is elegantly combined with the asymmetric transformation process. Addition of the resolving agent (S)-mandelic acid results in the formation of both diastereoisomeric salts. In the presence of benzaldehyde these salts are in equilibrium with the Schiff base, which racemizes readily. The low solubility of the diastereoisomeric salts (in apolar solvents) eventually allows obtainment of a >95% yield of the (/f) (.S )-salt in more than 99% diastereoisomeric excess. After decomposition of this salt by hydrochloric acid, pure (Ah-phenylglycine amide is obtained, and the resolving agent can be recycled. 

As a second example, we recently used the readily available (W)-phenylglycine amide as a Chirality Transfer reagent (see Chapter 25).43 In this case, a Strecker reaction is performed on pivaldehyde under equilibrium conditions resulting in two covalent diastereoisomeric products (Scheme 7.9). The lower solubility of the (.S. /H-diastereoisomer results in transformation of the (R,/H-diastereoisomer into the (.S. /H-diastereoisomer in 93% yield and >99% diastereoselectivity. 

Enantiopure Amines by Chirality Transfer Using (/ )-Phenylglycine Amide... 

Enantiopure (/D-phenylglycine amide [abbreviated ( )-PGA] (1) has become readily accessible at DSM as a result of its application on industrial scale as a key intermediate in enzymatic routes for the preparation of fS-lactam antibiotics (Scheme 25.1).10... 

Either (S)-specific aminopeptidase catalyzed hydrolysis of racemic PGA11 or crystallization-induced asymmetric transformation of racemic PGA with (.S l-mandelic acid as resolving agent12 can be used to prepare (R)-PGA. As a result of its ready availability on large scale within DSM, we envisaged the application of (R)-PGA for the production of enantiomerically pure amine functionalized compounds using the chirality transfer concept. Obviously, (S)-phenylglycine amide is also available and can be used for the preparation of the opposite enantiomer of the amines described. 

FIGURE 25.2 Chirality transfer routes of (R)-PGA [( )-phenylglycine amide] toward a-amino acids, homoal-lylamines, and amines. 

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