Methyl phenylalaninate

The efficiency of this method was demonstrated by the elegant two-step synthesis of aspartame [87], Protection of the a-amino group and activation of the a-carboxylic group are accomplished in only one step Deprotection of the amino functionality occurs during aminolysis, such as with methyl phenylalaninate (H-Phe-OMe in equation 15)... 

The geometric isomers 464 and 467 of 5(47/)-oxazolones prepared from acetophenones can be separated. Alternatively, the mixture can be isomerized under the appropriate reaction conditions to obtain the pure of (Z) or ) isomer. Each isomer can be converted to a pair of enantiomers 466 and 469 (only one enantiomer shown) (Scheme 7.152). The p-methyl phenylalanine analogues thus obtained are constrained phenylalanines and the effect of incorporation of a p-MePhe or p-MeTyr residue on the biological properties of H-Tyr-Tic-Phe-Phe-NH2 (TIPP, where Tic = l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) a delta opioid receptor antagonist, has been studied. ... 

Among the methods described for the synthesis of the key intermediate 4-(chloromethyl)-L-phenylalaninej123-125 direct chloromethylation of a protected l-phenylalanine followed by deprotection represents the simplest procedure. 126 This intermediate is converted into the 4-sulfomethyl derivative which is then used to prepare the /V -/ert-butyloxycarbonyl-4-(sulfo-methyl)phenylalanine monosodium salt l2S and the related Fmoc derivative. 126 ... 

Figure 17. Schematized structure of a chiral crown ether type CSP used for chromatographic resolution or methyl phenylalaninate hydrochloride. Reprinted with permission from ref 122b.

C6Hs (Forts.) ch2—c6h5 ch3 konz. HC1/ H3C-COOH (1 2) 95° 5 h ch3 hsc6-ch2-c-cooh NH 2-Methyl-phenylalanin 50 230 (Subl.) 1... 

Die Ausbeuten der einzelnen Reaktionsschritte sollen ausgezeichnet sein1. a-Methyl-phenylalanin-mcthylamid1 ... 

Das entsprechende (S)-a-Methyl-phenylalanin wird analog aus dem (3R,4S,rS)-f -Lactam erhalten1. 

FIGURE 10 Effect of temperature on enantiomeric resolution on antibiotic CSPs. (a) k, a, and Rs for proglumide (O), 5-methyl-5-phenylhydantoin ( ) and iV-corbyl-DL-pheny-lalanine (x) on Chirobiotic V column using acetonitrile-1 % triethylammonium acetate buffer (10 90, v/v) as the mobile phase and (b) separation of enantiomers of /1-methyl phenylalanine on the Chirobiotic T column using water-methanol (10 90, v/v) as the mobile phase at (A) 1°C, (B) 20°C, (C) 50°C. 1 = erythro-L 2 = erythro-D 3 = threo-L 4 = threo-D. (From Refs. 1 and 22.)... 

Whilst the use of Taddol as an asymmetric phase-transfer catalyst for asymmetric Michael reactions was only moderately successful, it was much more enantioselec-tive in catalyzing alkylation reactions. For this study, Belokon and Kagan employed alanine derivatives lib and 16a-c as substrates, and investigated their alkylation with benzyl bromide under solid-liquid phase-transfer conditions in the presence of 10 mol % of Taddol to form a-methyl phenylalanine, as shown in Scheme 8.8. The best results were obtained using the isopropyl ester of N-benzylidene alanine 16b as substrate and sodium hydroxide as the base. Under these conditions, (R)-a-methyl phenylalanine 17 could be obtained in 81% yield and with 82% ee [19]. Under the same reaction conditions, substrate 16b reacted with allyl bromide to give (R)-Dimethyl allylglycine in 89% yield and with 69% ee, and with (l-naphthyl)methyl chloride to give (R)-a-methyl (l-naphthyl)alanine in 86% yield and with 71% ee [20]. 

Scheme 8.16 Use of Ni(salen) complexes in the synthesis of a-methyl phenylalanine.

Catalyst screening experiments resulted in the discovery that copper(salen) complex 33 was a highly effective catalyst for the conversion of alanine derivative 16b into (f )-a-methyl phenylalanine 17 under the conditions shown in Scheme 8.16. The presence of just 1 mol% of catalyst 33 was sufficient to induce the formation of compound 17 with up to 92% ee and in >70% yield [33]. Allyl bromide, 1-chloromethylnaphthalene and ethyl iodide also reacted with substrate 16b to give the corresponding (H)-a-methyl a-amino acids in the presence of 2 mol % of complex 33 [34], Complex 33 also catalyzed the asymmetric mono-alkylation of glycine-derived substrate 34 by benzylic or allylic halides, to give (H)-a-amino acid derivatives 35 with 77-81% ee. and in greater than 90% yield, as shown in Scheme 8.17. 

A)-alcohol (7) by Sphingomonas paucimobilis SC 16113 (Fig. 6) (2) the enzymatic resolution of racemic (a-methyl)phenylalanine amide (8) and a-(4-methoxyphenyl)alanine amide (10) by amidase from Mycobacterium neoaurum ATCC 25795 to prepare the corresponding (S)-amino acids (9) and (11), and (3) the asymmetric hydrolysis of methyl-(4-methoxyphenyl)-propanedioic acid, diethyl ester (12), to the corresponding (X)-monoester (13) by pig liver esterase (Fig. 7). 

B. Enzymatic Resolution of Racemic (a-Methyl)phenylalanine Amides... 

The power of this methodology lies in the ability to prepare unnatural amino acid derivatives by asymmetric alkylation of prochiral enolates. Several asymmetric alkylations of the alanine derivative 7, catalysed by the C2-symmetrical quaternary ammonium salt 6d, have been reported these reactions yield unnatural amino acids such as 8 in high enantiomeric excess (Scheme 2) [7]. The chiral salen complex 9 has also been shown to be an effective catalyst for the preparation of a,a-dialkyl a-amino acids [8, 9]. For example, benzylation of the Schiff base 10 gave the a-methyl phenylalanine derivative 11 in 92% ee (Scheme 3) [8]. Similar reactions have been catalysed by the TADDOL 12, and also give a,a-dialkyl a-amino acids in good enantiomeric excess [10]. 

Nitrogen heterocycles such as azirines and aziridines are also used effectively as building blocks for the synthesis of a,a-disubstituted amino acids. The aziridine derivative 33 is prepared in optically pure form by addition of the lithium enolate 32 to the chiral sulfinimide 31 (Scheme 7) [42]. After oxidation of the sulfoxide to the sulfone and subsequent hydration, the a-methylated phenylalanine derivative 34 is obtained in good overall yield. 

A variety of phosphonate analogues of tyrosine phosphate and related structures have been reported. These include L-2,3,5,6-tetrafluoro-4-(phosphono-methyl)phenylalanine (236) which was obtained through alkylation of the... 

In addition, at Ube an analogous process for the enantioselective synthesis of a-methyl phenylalanine has been developed based on an amidase from Pseudomonas fluorescens [IFO 3081] [14]. 

Enzymatic Resolution of Racemic a-Methyl Phenylalanine Amides. The chiral amino acids (22) and (23) (Fig. 6A) are intermediates for the synthesis of (33-receptor agonists (30,31). These are available via the enzymatic resolution of racemic a-methyl phenylalanine amide (24) and a-methyl-4-methoxy-phenylalanine amide (25), respectively, by an amidase from Mycobacterium neoaurum ATCC 25795 (32). Wet cells (10% wt/vol) completed the reaction of amide (24) in 75 min with a... 

Fig. 6. (A) Enantioselective hydrolysis of a-methyl phenylalanine amide (24) and a-methyl-4-hy-droxyphenylalanine amide (25) by amidase. (B) Enantioselective enzymatic hydrolysis of methyl-(4-methoxyphenyl)-propanedioic acid ethyl diester (2Z) to (5)-monoester (26).

Antibiotics closely related to pristinamycin Ia include virginiamycin Sj (6), where the iV-methyl 4-dimethylamino phenylalanine residue is replaced by iV-methyl phenylalanine and vernamycin C (7,=doricin), where the 4-oxo-pipecolic acid residue is replaced by aspartic acid. 

---