Convenient, asymmetric synthesis of enantiomerically pure 2′,6′-dimethyltyrosine (DMT) via alkylation of chiral equivalent of nucleophilic glycine

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For a recent review on χ (chi)-constrained amino acids, see: Gibson, S. E.; Guillo, N.; Tozer, M. J. Tetrahedron 1999, 55, 585.

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A biocatalytic method for preparing (S)-N-acetyl-DMT using α-chymotrypsin has also been reported. Abrash, H. I.; Niemann, C. Biochemistry 1963, 2, 947.

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(b) Williams, R. M. Synthesis of Optically Active α-Amino Acids; Pergamon Press: Oxford, 1989.

For an updated, improved large-scale preparation, see: Belokon’, Yu. N.; Tararov, V. I.; Maleev, V. I.; Savel'eva, T. F.; Ryzhov, M. G. Tetrahedron: Asymmetry 1998, 9, 4249.

For reviews on reactivity, properties and applications of complex (S)-1 in the asymmetric synthesis of α-amino acids, see: (a) Belokon, Yu. N. Janssen Chimica Acta 1992, 10, 4. (b) Belokon, Yu. N. Pure Appl. Chem. 1992, 64, 1917. (c) Kukhar’, V. P.; Resnati, G.; Soloshonok, V. A. In Fluorine-Containing Amino Acids. Synthesis and Properties; Kukhar’, V. P.; Soloshonok, V. A., Eds.; John Wiley & Sons: Chichester, 1994; Chapter 5. (d) Soloshonok, V. A. In Biomedical Frontiers of Fluorine Chemistry; Ojima, I.; McCarthy, J. R.; Welch, J. T., Eds.; ACS Books, American Chemical Society: Washington, DC, 1996; Chapter 2. (e) Soloshonok, V. A. In Enantiocontrolled Synthesis of Fluoro-Organic Compounds: Stereochemical Challenges and Biomedicinal Targets; Soloshonok, V. A. Ed.; John Wiley & Sons: Chichester, 1999; Chapter 7.

For successive papers, see: (a) Soloshonok, V. A.; Avilov, D. V.; Kukhar’, V. P.; Tararov, V. I.; Savel'eva, T. F.; Churkina, T. D.; Ikonnikov, N. S.; Kochetkov, K. A.; Orlova, S. A.; Pysarevsky, A. P.; Struchkov, Yu. T.; Raevsky, N. I.; Belokon’, Yu. N. Tetrahedron: Asymmetry 1995, 6, 1741.

(j) Qiu, W.; Soloshonok, V. A.; Cai, C.; Tang, X.; Hruby, V. J. Tetrahedron 2000, 56, 2577.

(k) Soloshonok, V. A.; Cai, C.; Hruby, V. J. Angew. Chem., Int. Ed. 2000, 39, 2172.

(b) Soloshonok, V. A.; Avilov, D. V.; Kukhar’, V. P. Tetrahedron: Asymmetry 1996, 7, 1547.

(c) Soloshonok, V. A.; Avilov, D. V.; Kukhar’, V. P. Tetrahedron 1996, 52, 12433.

(d) De, B. B.; Thomas, N. R. Tetrahedron: Asymmetry 1997, 8, 2687.

(e) Soloshonok, V. A.; Cai, C.; Hruby, V. J.; Meervelt, L. V.; Mischenko, N. Tetrahedron 1999, 55, 12031.

(f) Soloshonok, V. A.; Cai, C.; Hruby, V. J.; Meervelt, L. V. Tetrahedron 1999, 55, 12045.

(g) Soloshonok, V. A.; Cai, C.; Hruby, V. J. Tetrahedron: Asymmetry 1999, 10, 4265.

(h) Soloshonok, V. A.; Cai, C.; Hruby, V. J. Tetrahedron Lett. 2000, 41, 135.

(i) Soloshonok, V. A.; Cai, C.; Hruby, V. J. Organic Lett. 2000, 2, 747.

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Determined by 1H NMR (500 MHz) on the crude reaction mixture.

As was demonstrated (see Refs. 8 and 9) CD and ORD spectra of Ni(II)-complexes of this type in neutral solutions exhibit two maxima in the region of metal d–d transition (Cotton effects at 450 and 550 nm). In the ORD spectra, the sign of the Cotton effects in this region strictly depends upon a conformation of the polycyclic system of chelate rings. Thus, in the case of complexes containing α-monosubstituted α-amino acid, the pseudoaxial orientation of the amino acid side chain, corresponding to α-l) configuration of α-amino acid, causes a Cotton effect with a positive sign at the 500–700 nm region and a negative sign at 400–450 nm. Consequently, a pseudoequatorial orientation of the amino acid side chain brings about opposite signs of the Cotton effects at 400–450 (positive) and at the 500–700 nm (negative) region. As has been established in numerous studies, this general trend is not influenced by the structure and nature of the α-amino acid side chain, and the configuration of stereogenic centers within it. 1H NMR spectra of the complexes containing α-(l)- and α-(d)-amino acids are also very characteristic, featuring substantial difference in chemical shifts of aromatic and methylene protons of the (N-benzyl)proline moiety.