(SP-4-4)-[(S)-[o-(1-Benzyl-2-pyrrolidinecarboxamido)-a-phenylbenzylidene]glycinato(2-)-N,N,N,O1]nickel

[96293-17-3]  · C27H25N3NiO3  · (SP-4-4)-[(S)-[o-(1-Benzyl-2-pyrrolidinecarboxamido)-a-phenylbenzylidene]glycinato(2-)-N,N,N,O1]nickel  · (MW 498.20)

(used in asymmetric alkylations,1 1,2-additions,2 and 1,4-additions3 to prepare a-amino acids)

Alternate Name: nickel(II) nitrate-(S)-o-(benzylprolylamino)benzophenone-glycine

Physical Data: diamagnetic, mp 208-212 °C.

Solubility: sol CHCl3; insol MeOH.

Form Supplied in: not commercially available; prepared as a red solid.1

Preparative Method: prepared by condensation of (S)-o-[(N-benzylprolyl)amino]benzophenone (BBP) with glycine in the presence of nickel(II) nitrate in methanol.1

Purification: purified by sequential chromatography over silica gel and Sephadex LH-20, or by dry flash chromatography.1

Handling, Storage, and Precautions: care should be taken in applying samples to purified Sephadex. The addition of basic media can present an explosion hazard.

Alkylations.

The high kinetic stability of the NiII-BBP-glycine complex (1) permits alkylation and halogenation of its derived enolate. Alkylations mediated by powdered alkali in DMF, MeCN, or aqueous acetone have proven superior, though other methods are known (eq 1).1 Substituents introduced in this fashion kinetically and thermodynamically prefer the face opposite the N-benzyl group. Consequently, the (S)-proline derived complex instills high (S) selectivity in alkylation products. Electrophilic bromination at this site licenses subsequent attack by nucleophiles (eq 2).5 Electrophilic attack at nitrogen frequently precludes the use of free glycine in this synthesis. The title reagent solves this problem through protection of the amino group as its Schiff's base.6 Chromatographic separation of the alkylated complexes followed by acidic hydrolysis liberates a-amino acids of high optical purity. As a consequence, (1) has been used as a chiral building block for fluorinated phenylalanines and pharmaceutically important radiolabeled amino acids.1,7,8

1,2-Additions.

Increased C-H acidity (pKa = 18.8 in DMSO) facilitates condensation of the complex with aldehydes and ketones, while the use of free glycine is generally problematic.9,10 The stereochemical outcome at the a-carbon parallels those of alkyl halide alkylations.11 Thus the NiII-BBP-glycine complex provides a route to asymmetric aldols and anti b-substituted a-aminobutanoic acids (eqs 3 and 4).

1,4-Additions.

Glycine complex (1) undergoes asymmetric conjugate addition to a,b-unsaturated esters, nitriles, aldehydes, and ketones.3 Judicious selection of alkene leads to (S)-glutamic acids, though vigorous conditions (concd HCl, 100 °C) are employed for hydrolysis. The high levels of enantioselectivity achieved by this method have culminated in an asymmetric synthesis of proline derivatives (eq 5).4

Related Reagents.

Other conceptually related materials used for asymmetric amino acid synthesis include benzophenone imines derived from a-amino esters, a-amino esters temporarily protected as the derived acetals, and bislactim ethers.12


1. (a) Belokon, Y. N.; Bakhmutov, V. I.; Chernoglazova, N. I.; Kochetkov, K. A.; Vitt, S. V.; Garbalinskaya, N. S.; Belikov, V. M. JCS(P1) 1988, 305. (b) Belokon, Y. N.; Sagyan, A. S.; Djambaryan, S. M.; Bakhmutov, V. I.; Belikov, V. M. T 1988, 44, 5507.
2. Belokon, Y. N.; Bulychev, A. G.; Vitt, S. V.; Struchkov, Y. T.; Batsanov, A. S.; Timofeeva, T. V.; Tsyryapkin, V. T.; Ryzhov, M. G.; Lysova, L. A.; Bakmutov, V. I.; Belikov, V. M. JACS 1985, 107, 4252.
3. Belokon, Y. N.; Bulychev, A. G.; Rhyzhov, M. G.; Vitt, S. V.; Batsanov, A. S.; Struchkov, Y. T.; Bakhmutov, V. I.; Belikov, V. M. JCS(P1) 1986, 1865.
4. Belekon, Y. N.; Bulychev, A. G.; Pavlov, V. A.; Feorova, A. B.; Tsyryapkin, V. A.; Bakhmutov, V. A.; Belikov, V. M.; JCS(P1) 1988, 2075.
5. Belokon, Y. N.; Popkov, A. N.; Chernoglazova, N. I.; Saporovska, M. B.; Bakhmutov, V. I.; Belikov, V. M. CC 1988, 1336.
6. (a) Gillard, R. D.; Laurie, S. H., Price, D. C.; Phipps, D. A.; Seik, C. F.; JCS(D) 1974, 1385. (b) Phipps, D. A. J. Mol.. Catal. 1979, 5, 81.
7. Kukhar, V. P.; Belokon, Y. N.; Soloshonok, V. A.; Svistunova, N. Y.; Rozhenko, A. B.; Kuz'mina, N. A. S 1993, 117.
8. Fasth, K. J.; Langstrom, B. ACS 1990, 44, 1990.
9. Ogata, Y.; Kawasaki, A.; Suzuki, H.; Kojoh, H. JOC 1973, 38, 3031.
10. (a) Erlenmeyer, E. B 1892, 3445. (b) Erlenmeyer, E.; Frustuck, E. LA 1895, 36, 284. (c) Forster, M. O.; Kao, K. A.; JCS 1926, 1943. (d) Bolhofer, W. A.; JACS 1954, 76, 1322. (f) Shaw, K. N.; Fox, S. N. JACS 1953, 75, 3417.
11. Belokon, Y. N.; Maleyev, V. I.; Vitt, S. V.; Ryzhov, M. G.; Kondrashov, Y. D.; Golubev, S. N.; Vauchskii, Y. P.; Kasika, A. I.; Novikova, M. I.; Krsutskii, P. A.; Yurchenko, A. G.; Dubchak, I. L.; Shklover, V. E.; Struchkov, T. T.; Bakhmutov, V. I.; Belikov, V. M.; JCS(D) 1985, 17.
12. For a review identifying modern reagents used in a-amino acid synthesis, see T 1988, 44, 5253.

David G. Young

The Ohio State University, Columbus, OH, USA



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