Arylglycine

Synthetic utility of stereoselective alkylations in natural product chemistry is exemplified by the preparation of optically active 2-arylglycine esters (38). Chirally specific a-amino acids with methoxyaryl groups attached to the a-carbon were prepared by reaction of the dimethyl ether of a chiral bis-lactam derivative with methoxy arenes. Using SnCl as the Lewis acid, enantioselectivities ranging from 65 to 95% were obtained. 

Significantly, the acidic conditions for release of the amino acid derivatives from the chiral template gives access to arylglycines, even those carrying electron-withdrawing substituents, e.g., a chlorine atom, which arc prone to ready racemization under basic conditions. 

The standard synthesis of sydnones (Section 5.03.9.2) has benefited from the use of A,./V,iV, iV -tetrabromobenzene-1,3-disulfonamide (TBBDS) as an efficient promoter of the one-pot conversion of various iV-arylglycines to sydnone products <2006H(68)2343>. Conversion of A-arylglycines to sydnones was achieved in 85 to 95% yield using a combination of NaN02 and AczO in CH2C12 promoted by TBBDS, under mild and neutral conditions. 

Aryl chlorothioformates, 23 628 Aryl complexes, zirconium, 26 655 Aryl ethers, uses for, 70 581 2-Arylglycine esters, 72 166 Aryl halide amination, 9 278 Aryl halides, reaction with carbon monoxide, 5 11 Arylhydrazines, 9 270 Arylmethane dyes, 9 503... 

The reactions of the 5-oxazolanes 14 with aryllead triacetates are examples of the typical arylation of heterocycles by which products 15 are formed. After hydrolysis and decarboxylation, heterocyclic compounds 15 are converted to the arylglycines 16 in yields of 81-93% (Equation (5)).33... 

This reaction occurs not only in bicyclic lactams, but also in monobac-tams. Indeed, intramolecular nucleophilic amino attack has also been observed in an arylglycine-substituted monobactam (Fig. 5.8,b) [84b], However, ampicillin (see below, 5.43, Fig. 5.14), which also carries an a-amino side chain in the 6/3-position, does not exhibit such an enhanced rate. This difference in reactivity has been attributed to the steric hindrance of both the geminal Me groups and H-C(3), which impedes the attack by the a-amino group at the /3-face [84a], In contrast, penicillins with an amino substituent in the 6/3-acylamido side chain show an intermolecular reaction resulting in the formation of oligomers (see Sect. 5.2.5). 

Fig. 5.8. An a-amino group in the acylamido side chain off)-lactams increases the rate of degradation in alkaline media by favoring an intramolecular nucleophilic reaction yielding piper-azine-2,5-dione products (e.g., 5.31 and 5.33). a) a-(2-Amino-2-phenylacetyl)cephalosporins b) arylglycine-substituted monobactams c) 6a-epiampicitlin (5.32). 

Since the early review on sydnones by Stewart (192) and the subsequent coverage by Potts (1), several new applications of these remarkably stable mesoionic heterocycles have been described. In particular, the synthesis of pyrazoles from sydnones has been pursued by several groups. Badachikar et al. (193) prepared several new potential antibacterials (297) from the appropriate sydnones 296, which were synthesized in the standard fashion by the cyclodehydration of the corresponding A-nitroso-A-arylglycine. 

With Arenetricarbonylmanganese Complexes Preparation of Arylglycine Derivatives... 

The Pd-catalyzed amidocarbonylation was used for the synthesis of a-arylglycines that are antimicrobial agents and enzyme inhibitors.Thus, iV-acyl-a-arylglycines and other iV-acyl-a-amino acids were synthesized in highly efficient and economical manner under the standard conditions. In a similar manner, an advanced intermediate for the synthesis of antiepileptic Levetiracetam 7, iV-acetyl-a-aminobutyric acid 6, was synthesized in high yield from propanal and acetamide (Equation (1)). ... 

The enantioselective amination of iV-acyl oxazolidinones has been studied as part of a general approach to the synthesis of arylglycines. In this case, the enolization is initiated by a chiral magnesium bis(sulfonamide) complex. The oxazolidinone imide enolates are generated using catalytic conditions (10 mol% of magnesium complex) and treated in situ with BocN=NBoc to provide the corresponding hydrazide. 20 mol% of iV-methyl-p-toluensulfonamide are added to accelerate the reaction (equation 117). 

The resulting product is, however, an N-substituted oxazolidine amino acid, but this can easily be removed by either reductive or oxidative (Fig. 7) procedures. These and similar reactions can be used to prepare y-hydroxy-a-amino acids, arylglycines, a-alkyl-a-amino acids, and a variety of nonproteinogenic dipeptides (Fig. 7). The review by Muzart (58) is an excellent source of further information on the use of Cr compounds in organic synthesis. 

Several reports have employed a more traditional approach where the use of enantio-pure chiral amino auxiliaries, that, after the successful Strecker reaction, can be chemically modified to yield the free amino acids. For example, Chakraborty and co-workers have reported the highly diastereoselective addition of trimethylsilyl cyanide to a variety of a-phenylglycinol-derived benzaldimines [16]. (S)-a-Methylbenzylamine has been used as a chiral auxiliary for the asymmetric Strecker reaction [17]. (R)-Phenylglycinol has been utilized as a chiral auxiliary from the asymmetric Strecker reaction products of aldehydes in the synthesis of a,a-disubstituted amino acids [18]. (R)- and (S)-2-Amino-2-phenylethanol were used as chiral auxiliaries in the synthesis of optically pure a-arylglycines [19]. 

In a radically different approach, Alper has discovered that Me-DuPhos may be used in the synthesis of a-amino acids through a palladium-catalyzed double carbohydroamination whereby aryl iodides 74 can be converted to the corresponding arylglycine amides 75 in the presence of excess primary amine (Scheme 13.27).72... 

A catalytic approach to the synthesis of arylglycines was proposed by Evans and coworkers using enantioselective amination of iV-acy 1 oxazolidinones [54], Metallo-bis(sulfonamide) complexes derived from chiral diamines are potential chiral catalysts. The magnesium-bis(sulfonamide) complex 109 was generated by treating (S,S)-bis(sulfonamide) 108 with dimethylmagnesium in dichloromethane (Scheme 50). 

Jacobs WA, Heidelberger M (1919) Aromatic arsenic compounds. II. The amides and alkylamides of N-arylglycine arsonic acids. J Am Chem Soc 41 1809-1821... 

Other reports for the boron-Mannich reaction include the synthesis of aminophenol derivatives,561 a-arylglycines,576 a growth hormone secretagogue NN703,577 a polyhydroxyindolizine alkaloid uniflorine A,578 and cyclic ct-amino acids.579 The reaction has been applied to solution-phase reactions580 and the solid-phase reaction581-585 for the synthesis of libraries of peptides, a-amino acids, and bicyclic diketopiperazines. The reactions were accelerated by the irradiation of microwave.586... 

Cyclization of the anilide 213 using TiCU produced the 3-chloro-substituted oxindole 214 (Equation 69), whereas a similar reaction induced by BF3-OEt2 gave the corresponding methoxy-substituted derivative <1998T4889>. Lewis acids have also been used in an approach to indole-2-carboxylates based on cyclization of (Z)-A(A -dimethyl-aminopropenoates derived by exposure of A -arylglycinates to DMEDMA <2006SL749>. 

In summary, the stereoselective formation of the a-azido carboximides (S)-7 by means of electrophilic azide transfer to the JV-acyloxazolidinones 5 leads to a new class of very versatile protected amino acids which can be easily tranformed into free amino acids (or peptides). This methodology, in contrast to the preparation of a-amino acids by means of alkylation of chiral glycine enolates9, also provides access to arylglycines and hindered amino acid derivatives such as tcrt-alkylglycines. 

Hydrogenation of the azide moiety readily provides the amine using Palladium on Carbon and H2 or Tin(II) Chloride. This methodology has been extended to the synthesis of arylglycines (eq 26). ... 

By replacing the amides of ehloracetic acid by carbamide or its jS-alkyl or aryl derivatives in the reaction described in the preceding section, the carbamides and substituted carbamides of the arylglycine-arsinic acids may be obtained these have the general formula ... 

Aromatic azines may be reduced in aprotic media in the presence of carbon dioxide to amino acids thus ArCR=N-N=CRAr can be reduced (R=H) in MeCN saturated with CO2 at —1.7 to —2.0 V (SCE) to A-arylideneamino-2-arylglycines or at —2.1 to —2.2 V to A-unsubstituted arylglycines [50]. 

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