Phenylalanine derivatives, asymmetric alkylation

The alkylation of ( )-spirolactones (34a) and (34b) with higher diastereoface selectivity has been modelled by geometry-optimized ab initio 4-31G calculations which suggest that approach of the electrophile occurs at an angle of ca 80° to the plane of the enolate and with some displacement away from the oxygen linked to the metal ion.41 Asymmetric a-methylation of phenylalanine derivatives has been achieved with 82% ee and retention of configuration in the absence of any external chiral source.42... 

Since the stereochemistry of the newly created quaternary carbon center was apparently determined in the second alkylation process, the core of this method should be applicable to the asymmetric alkylation of aldimine Schiffbase 42 derived from the corresponding a-amino adds. Indeed, di-alanine-, phenylalanine- and leucine-derived imines 42 (R1 = Me, CH2Ph, i-Bu) can be alkylated smoothly under similar conditions, affording the desired non-coded amino acid esters 43 with excellent asymmetric induction, as exemplified in Table 5.7 [19]. 

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]. 

Amino acid-derived primary-tertiary diamine catalysts have been used extensively in aldol reactions. Lu and Jiang [34] documented a direct asymmetric aldol reaction between acetone and a-ketoesters catalyzed by an L-serine-derived diamine 17. Sels et al. [35] found that several primary amino acid-based diamines (18) were efficient catalysts for the syn-aldol reaction of linear aliphatic ketones with aromatic aldehydes. Luo and Cheng utilized L-phenylalanine-derived diamine catalyst 15a for the enantioselective syn-aldol reaction of hydroxyl ketones with aromatic aldehydes [36]. Moreover, a highly enantioselective direct cross aldol reaction of alkyl aldehydes and aromatic aldehydes was realized in the presence of 15a (Scheme 3.8) [37]. Very recently, the same group also achieved a highly enantioselective cross-aldol reaction of acetaldehyde [38]. Da and coworkers [39] discovered that catalyst 22, in combination with 2,4-dinitrophenol, provided good activation for the direct asymmetric aldol reaction (Scheme 3.9). 

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]. 

The use of iso-Nobin derivatives 27 as asymmetric phase-transfer catalysts for the alkylation of substrate 11a was also investigated [30], The N-acylated derivatives 27c and 27d were again found to be the most enantioselective catalysts and, under identical conditions to those employed for Nobin (see Scheme 8.13), were only slightly less enantioselective than Nobin 24. Thus, catalyst 27d generated phenylalanine in 70% yield and with 92% ee, compared to a 90% yield with 97% ee obtained with Nobin 24, both after an 8- to 9-min reaction time in DCM. However, whereas when Nobin was used as the catalyst, the (R)-enantiomcr of the catalyst generated (R)-amino acids, the use of the (S)-enantiomers of catalysts 27b-d gave (R)-amino acids. 

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. 

L-a-Amino-esters, via Schiff s bases of ajS-unsaturated aldehydes and 1,4-addition of Grignard reagents, have provided asymmetric syntheses of j8-disubstituted aldehydes (43) (60—100% optical yields). Two groups have independently described the asymmetric a-alkylation of ketones [(44) (45)], utilizing imines of a-amino-acid derivatives (L-proline and D-phenylalanine). 

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