Improved synthesis of the Ni(II) complex of the Schiff base of (S)-2-[N-(N′-benzylprolyl)amino]benzophenone and glycine

Abstract

The environmental impact of a known synthesis of the Ni complex of the Schiff base of (S)-2-[N-(N′-benzylprolyl)amino]benzophenone and glycine was decreased by optimisation of the ratio the starting materials; a new starting material, Ni(NO₃)₂·6NH₃, was evaluated as a nickel source.

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Green Context

The preparation of speciality α-amino acids requires the large-scale manufacture of various chiral glycine and alanine synthons. Nickel complexes have been shown to be particularly effective in achieving high asymmetric induction for the synthesis of α-amino acids but nickel contaminated waste waters present an environmental problem. Here the synthesis of the nickel complex is optimised including the use of a new nickel source. The net result is a reduction in the environmental impact of the process.

JHC

For the preparation of non-coded and/or selectively labelled α-amino acids, several chiral glycine and alanine synthons are manufactured and marketed in bulk quantities. The most important are Seebach′s¹ and Oppolzer′s² derivatives and O′Donnell′s achiral synthon,³ for stereospecific alkylation for which an efficient chiral catalyst has been recently developed.⁴ Ni(II) complexes of Schiff bases of (S)-2-[N-(N′-benzylprolyl)amino]benzophenone (BPB) and α-amino acids achieve high asymmetric induction for the synthesis of α-amino acids⁵ at ambient temperature. The chiral auxilliary BPB is regenerated but excess nickel in the waste water is a potential environmental problem.

The complexes were developed as artificial analogs of pyridoxal 5′-phosphate (PLP)-dependent enzymes.⁶ The central sodium atom of a PLP-dependent enzyme was replaced by nickel in order to form a more stable compound. In spite of the inexpensive and reliable application of these complexes, the fate of the nickel used in their preparation should be carefully controlled. Energy-consuming procedures used for removal of nickel from waste water might significantly increase the cost of α-amino acids production. Nickel from the complexes is easily regenerated when a mixture of an amino acid and nickel chloride (after acidic hydrolysis) is separated on a cation-exchanger. A large amount of metal remains in the methanolic waste solution after preparation of the complexes, due to a two-fold excess of Ni(NO₃)₂·6H₂O used in a standard protocol.^7–9 This excess is necessary in order to shift the equilibrium towards complex formation.

Previous attempts to substitute nickel nitrate with nickel acetate, which bears four molecules of water in the internal coordination sphere instead of six in the nitrate, did not shift the equilibrium towards complex formation.¹⁰

In this work the successful synthetic application of near stochiometric amounts of Ni(NO₃)₂·6H₂O or anhydrous Ni(NO₃)₂·6NH₃† , minimising amount of Ni²⁺ need to be recovered from waste water, is described (Scheme 1).

Scheme 1

Results and discussion

In this work a two-fold excess of glycine instead of five-fold^7–9 was used in order to reduce the amount of nickel chelating amino acid in the waste water.

Experiments did not support the initial hypothesis that anhydrous Ni(NO₃)₂·6NH₃ would shift the equilibrium towards complex formation. Observed yields of complex formation starting from Ni(NO₃)₂·6H₂O were 5–13% higher than the corresponding yields starting from Ni(NO₃)₂·6NH₃ (Table 1).

Table 1 Yields of the Ni(II) complex of Schiff base of BPB and glycine depending on excess of nickel salts

Excess of the nickel salt	2	1.2	1.05
Yield of the complex starting from Ni(NO3)2·6NH3 (%)	64	78	67
Yield of the complex starting from Ni(NO3)2·6H2O (%)	77	88	71

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When a two-fold excess of any nickel salt was used solid precipitate appeared in the reaction mixture after 90 min. With lower excesses of nickel salts no precipitates were observed. Formation of the precipitate is probably responsible for lower yields of the complexes when using a two-fold excess of a nickel salt compared with 1.2-fold. This may be due to absorbtion of BPB by precipitated nickel oxide/hydroxide. Work-up of the homogeneous reaction mixtures obtained with lower excesses of nickel salts is better suited to scale-up as no separation and processing of solid nickel-containing waste is necessery.

Application of the Ni(II) complex of the Schiff base of BPB and glycine for asymmetric synthesis of α-amino acids often does not require separation of the complex from unreacted BPB (see, for example, ref. 9). In such cases, in spite of lower yields of the complexes, a 1.05-fold excess of nickel salt might be the best ratio. This will decrease the amount of nickel circulating in the process.

Synthesis of more sterically hindered complexes derived from α-monosubstituted glycines (e.g. proteinogenic α-amino acids) is in progress in order to test the new ratio of the starting compounds under more challenging conditions.

Experimental

General procedure for the synthesis of the glycine complex

2.5 M MeONa/MeOH (8 ml, 20 mmol) was added to a stirred suspension of BPB (500 mg, 1.3 mmol), glycine (195 mg, 2.6 mmol) and the corresponding amount of a nickel salt (Table 1) in dry MeOH (4 ml) under argon at 55 °C. The volume of the reaction mixture was then adjusted to 15 ml with dry MeOH. After stirring at 55 °C for 90 min, the mixture was poured into 10% aqueous citric acid (100 ml), stirred and the resulting precipitate was filtered off and dried in air. The dry precipitate was purified by column chromatography using silica gel (Merck 40/63) eluted with chloroform.‡ Yields of complex formation are given in the Table 1. ¹H and ¹³C NMR data have been reported previously.¹¹

Acknowledgement

The authors are grateful to Dr Nicholas Gillings for linguistic corrections.

Notes and references

1. D. Seebach, A. R. Sting and M. Hoffmann, Angew. Chem., Int. Ed., 1996, 35, 2708.
2. W. Oppolzer, R. Moretti and C. Zhou, Helv. Chim. Acta, 1994, 77, 2363.
3. M. J. O′Donnell, Aldrichim. Acta, 2001, 34, 3.
4. T. Ooi, M. Takeuchi, M. Kameda and K. Maruoka, J. Am. Chem. Soc., 2000, 122, 5228.
5. Y. N. Belokon, Pure Appl. Chem., 1992, 64, 1917.
6. H. C. Dunathan, Adv. Enyzmol. Relat. Areas Mol. Biol., 1971, 79.
7. Y. N. Belokon, V. I. Tararov, V. I. Maleev, T. F. Saveleva and M. G. Ryzhov, Tetrahedron: Asymmetry, 1998, 9, 4249.
8. Y. N. Belokon, V. I. Bakhmutov, N. I. Chernoglazova, K. A. Kochetkov, S. V. Vitt, N. S. Garbalinskaya and V. M. Belikov, J. Chem. Soc., Perkin Trans. 1, 1998, 305.
9. V. A. Soloshonok, D. V. Avilov, V. P. Kukhar, V. I. Tararov, T. F. Saveleva, T. D. Churkina, N. S. Ikonnikov, K. A. Kochetkov, S. A. Orlova, A. P. Pysarevsky, Y. T. Struchkov, N. I. Raevsky and Y. N. Belokon, Tetrahedron: Asymmetry, 1995, 6, 1741.
10. J. Jirman and A. Popkov, Collect. Czech. Chem. Commun., 1994, 59, 2103.
11. A. Popkov, J. Jirman, M. Nádvorník and P. A. Manorik, Collect. Czech. Chem. Commun., 1998, 63, 990.

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Footnotes

† Ni(NO₃)₂·6NH₃ for this work was prepared by bubbling NH₃ gas through a cold methanolic solution of Ni(NO₃)₂·6H₂O and filtering off the resulting precipitate. Aqueous ammonia may be also used instead of NH₃ gas, in this case the content of water in the internal coordinational sphere of Ni(NO₃)₂·6NH₃ will be higher.

‡ As chloroform is known to be a human carcinogen, for preparative applications a gradient elution using CH₂Cl₂ → CH₂Cl₂–Me₂CO = 7∶1 or toluene → toluene–Me₂CO = 2∶1 is strongly recommended.

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