Phenylglycine, synthesis

Dondoni A, Perrone D, Semola T (1995) Synthesis of Taxol and Taxotere Side chains by 2-(Trimethylsilyl)thiazole Based Homologation of L-Phenylglycine. Synthesis 181... 

It is an important dyestuffs intermediate. It condenses with chloroethanoic acid to give phenylglycine-o-carboxylic acid for the synthesis of indigo. It can be diazotized and used as a first component in azo-dyes it condenses also with chloroanthraquinones to give intermediates for anthraquinone dyes. 

Chloroacetic acid can be esterified and aminated to provide useful chemical intermediates. Amphoteric agents suitable as shampoos have been synthesized by reaction of sodium chloroacetate with fatty amines (4,5). Reactions with amines (6) such as ammonia, methylamine, and trimethylamine yield glycine [66-40-6J, sarcosine [107-97-17, and carhoxymethyltrimethylammonium chloride, respectively. Reaction with aniline forms /V-phenylglycine [103-01 -5] a starting point for the synthesis of indigo (7). 

Amino acid separations represent another specific application of the technology. Amino acids are important synthesis precursors - in particular for pharmaceuticals -such as, for example, D-phenylglycine or D-parahydroxyphenylglycine in the preparation of semisynthetic penicillins. They are also used for other chiral fine chemicals and for incorporation into modified biologically active peptides. Since the unnatural amino acids cannot be obtained by fermentation or from natural sources, they must be prepared by conventional synthesis followed by racemate resolution, by asymmetric synthesis, or by biotransformation of chiral or prochiral precursors. Thus, amino acids represent an important class of compounds that can benefit from more efficient separations technology. 

An efficient stereoselective Strecker synthesis of phenylglycine has been achieved using the tert-butyl ester tm-leucine as the chiral auxiliary. Its benzaldimine reacts with hydrogen cyanide in hexane at — 23 °C to furnish the ( )-diastereomer with the excellent diastereoselectivity of >98 254. 

The synthesis of a-amino acids by reaction of aldehydes or ketones with ammonia and hydrogen cyanide followed by hydrolysis of the resulting a-aminonitrile is called the Strecker synthesis. Enzymatic hydrolysis has been applied to the kinetic resolution of intermediate a-aminonitriles [90,91]. The hydrolysis of (rac)-phenylglycine nitrile... 

Denis, J.N., Corres, A., Greene, A.E. (1991) Direct, Highly Efficient Synthesis from (S)-(-F)-Phenylglycine of the Taxol and Taxotere Side Chains. Journal of Organic Chemistry, 56, 6939-6942. 

Corey and Ishihara29 report the synthesis of a new bis(oxazoline). This catalyst effects Diels-Alder reaction via a tetracoordinated metal complex. Ligand (.S )-8I is synthesized from (iS )-phenylglycine, as depicted in Scheme 5-25. Treatment of 81 with Mgl2 L gives a dark solution of complex 82, which can be utilized as a Diels-Alder reaction catalyst. Thus, reaction of cyclopentadiene with 71 in the presence of 82 yields product 72a with an enantiomeric ratio of over 20 1 (Scheme 5-26). 

Phenyl formate, physical properties, 6 292t Phenyl glycidyl ether (PGE), 10 376 AT-Phenylglycine, 1 138 9 279 AT-Phenylglycinonitrile, 3 174 Phenylhydrazine synthesis, 13 573 Phenylhydrazone cleavage, microwaves in, 16 562... 

The synthesis of indigo was much more difficult than that of alizarin (6.2) [43]. In 1865 von Baeyer first attempted to obtain indigo by reductive dimerisation of isatin (6.116) he finally achieved a seven-step synthesis from phenylglycine via isatin in 1878. Many syntheses have been developed subsequently for indigo, but very few of these have achieved industrial importance. 

The synthesis of indigo by means of alkaline fusion of phenylglycine... 

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

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. ... 

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)... 

Cefadroxil Cefadroxil, [6/ -[6a,7)3(7 )]]-3-methyl-8-oxo-7-[[amino(4-hydroxyphenyl) acetyl]amino]-5-thia-l-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (32.1.2.14), is an analog of cephalexin and differs only in the presence of a hydroxyl group in the fourth position of the phenyl ring of phenylglycine, and is synthesized by a scheme analogous to the scheme of cephradin synthesis [90-96],... 

Corey and Ishihara s synthesis of phe-box ligand 29 began with the trifluoro-acetyl derivative of (5)-phenylglycine 26. Treatment of 26 with methylmagnesium iodide, as shown in Figure 9.7, followed by potassium hydroxide in methanol afforded amino alcohol 27 in 88% yield (2 steps).This was then acylated with dimethylmalonyl dichloride 24 and triethylamine followed by cyclization using methanesulfonic acid at reflux to afford phe-box ligand 29 in 78% yield. 

The most versatile lithium amides in regard to accessibility and asymmetric induction in deprotonation and elimination reactions arc lithium bis(l-phenylethyl)amide, lithium 2,2-dimethyl-A -[1 -pheny 1-2-0-piperidinyliethyljpropylamide and lithium 2,2-dimethyl-A-[2-(4-methyl-l-piperazinyl)-l-phenylethyl]propylamide. 1-Phenylethylamine and phenylglycine, which serve as educts for the synthesis of these bases, are commercially available at modest prices in both enantiomeric forms. Relevant preparative procedures can be found in the Appendix. 

For the enantioselective synthesis of a-alkyl-a-phenylglycines the enolates 2, derived from (S)-3,6-dihydro-3-phenyl-2i/-l,4-oxazin-2-ones, 1, were alkylated91. (S)-l is available from an (S)-a-hydroxy acid (R1 = i-Pr, C6H5, Bn) and racemic phenylglycine in five steps. The yields of the alkylation step are around 90%, but the diastereoselectivity is strongly dependent on R1. 

Acylation of 6-APA with an amino acid leads to a compound that bears some resemblance to a dipeptide. The coupling product with D-phenylglycine shows an enhanced antibacterial spectmm, possibly as a result of a better fit to the cell wall cross-hnking enzyme. The compound also shows improved oral absorption. One synthesis starts with the acylation of 6-APA with the acid chloride (3-3) from D-2-azidophenylacetic acid. Catalytic reduction of the product (3-4) affords ampicillin (3-5) [4]. An analogous scheme leads to amoxycillin (3-6), a widely used dmg that is reasonably well absorbed on oral administration. 

The key sequence in a somewhat involved stereospecihc total synthesis of a carbacephem starts by preparation of a chiral auxiliary. It is interesting to note that nitrogen is the only atom from this molecule retained in the hnal product. Constmction of this moiety starts with the formation of the carbethoxy derivative (37-2) from L(- -)-phenylglycine (37-1). Selective reduction of the free carboxyl group with borane. THF leads to the hydroxycarbamate (37-3). In a one-pot sequence, this is first cyclized to the corresponding oxazolidinone (37-4) by means of sodium hydride and then alkylated with ethyl bromoacetate (37-5). Saponification of the side chain then affords the chiral acetic acid (37-6). The carboxyl group is then activated by conversion to its acid chloride (37-7). 

An efficient synthesis of P-lactam with D-phenylglycine or its derivatives as a side chain can be accomplished only by using a kinetically controlled approach via acyl group transfer from an activated side chain donor, and D-phenylglycine can be used as ester, usually methyl (PGM) or ethyl (PGE), or as amide (PGA). As a... 

Synthesis of R-(-)-3,5-dinitrobenzoyI-vacuum oven overnight at 110... 

Phenylglycine derivatives are key intermediates in the synthesis of vancomycin. 81-85 This amino add is also very useful for incorporation into oxazolidinones as a chiral aux-iliaryt45,47 48 53 86 87 and for modulating bioactivities of peptides and peptidomimeticsJ85,88 There are several possible approaches to the synthesis of phenylglycines, including the Strecker reaction and the Evans electrophilic azidation reaction.181 ... 

The chiral Strecker reaction has been used in an effective synthesis of the substituted phenylglycine 46 (Scheme 17)J81 a-Phenylglycinol was used as the chiral amine supply. 

Scheme 17 Synthesis of a Substituted Phenylglycine via the Chiral Strecker Reaction ...

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