[27719-98-8]  · C9H12N2O  · (S)-1-Amino-2-hydroxymethylindoline  · (MW 164.208)

(stereospecific synthesis of a-substituted a-amino acids from a-keto acids1)

Physical Data: mp 81.5-82.7 °C (racemate).

Solubility: readily sol methanol, ethanol; insol hexane, ether.

Preparative Methods: 2-hydroxymethylindoline is resolved with (S)-(+)-Mandelic Acid to give (S)-(+)-2-hydroxymethylindoline, which is then nitrosated and reduced to produce (S)-(1) (eq 1).1 (R)-(1) is also available by a similar procedure.

Purification: recrystallization from methanol/ether.

Handling, Storage, and Precautions: the reagent is very air sensitive. Store under nitrogen or argon at -20 °C. Use in a fume hood.

The enantiospecific synthesis of natural and unnatural a-amino acids has been reviewed.2 Some of the most successful approaches involve the stereoselective hydrogenation of chiral dehydroamino acid derivatives. Many of these transformations are equivalent to the stereoselective reductive amination of a-keto acids (eq 2).3 For example, catalytic reduction of the imines of a-keto acids with chiral a-methylbenzylamine gives a-substituted a-amino acids with 12-80% ee (eq 3).4

Compound (1) and its enantiomer provide a variation on the same theme of stereospecific reductive amination. In this case, reduction of a chiral cyclic hydrazone (derived from an a-keto acid and (1)) with Aluminum Amalgam in wet DME proceeds with high stereoselectivity. Reductive cleavage of the N-N bond and ester hydrolysis complete the procedure, which produces a-amino acids with high optical purity (eq 4).1 The source of chirality is recovered by conversion of the resulting indoline-2-methanol back into (1).1

Related reagents that have been used successfully for these purposes include (2) and (3).1,5 In general, (3) appears to generate product with higher enantiomeric purity than either (1) or (2).

Other chiral amine reagents that have been used to effect similar stereospecific reductive aminations include 1,2-diamines6 and 1,2-amino alcohols (eq 5).7,8

Stereospecific reduction of chiral diketopiperazine derivatives from proline and a-keto acids also provide a versatile route to a-amino acids (eq 6).9,10 The selectivity of the reduction is highly dependent on the nature of the RŽ group on the nitrogen atom.

A related synthetic approach involves the biomimetic transamination of a-keto acids with chiral pyridoxamine analogs (eq 7)11 or achiral pyridoxamine analogs in the presence of a chiral ligand.12,13

Related Reagents.


1. Corey, E. J.; McCaully, R. J.; Sachdev, H. S. JACS 1970, 92, 2476.
2. (a) Haemers, A.; Mishra, L.; Van Assche, I.; Bollaert, W. Pharmazie 1989, 44, 97. (b) Asymmetric Synthesis, Chiral Catalysis; Morrison, J. D. Ed.; Academic: Orlando, 1985; Vol. 5.
3. Babievskii, K. K.; Latov, V. K. RCR 1969, 38, 456.
4. (a) Harada, K.; Matsumoto, K. JOC 1967, 32, 1794. (b) Hiskey, R. G.; Northrop, R. C. JACS 1961, 83, 4798.
5. Corey, E. J.; Sachdev, H. S.; Gougoutas, J. Z.; Saenger, W. JACS 1970, 92, 2488.
6. Meric, R.; Vigneron, J. P. TL 1974, 15, 2059.
7. Jiao, X. Y.; Chen, W. Y.; Hu, B. F. SC 1992, 22, 1179.
8. Vigneron, J. P.; Kagan, H.; Horeau, A. TL 1986, 9, 5681.
9. Bycroft, B. W.; Lee, G. R. CC 1975, 988.
10. Poisel, H.; Schmidt, U. CB 1973, 106, 3408.
11. Zimmerman, S. C.; Breslow, R. JACS 1984, 106, 1490.
12. Deschenaux, R.; Bernauer, K. HCA 1984, 67, 373.
13. Bernauer, K.; Deschenaux, R.; Taura, T. HCA 1983, 66, 2049.

Juan C. Jaen

Parke-Davis Pharmaceutical Research, Ann Arbor, MI, USA

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