L-Aspartic Acid1

(L)

[56-84-8]  · C4H7NO4  · L-Aspartic Acid  · (MW 133.10) (D)

[1783-96-6] (DL)

[617-45-8]

(chiral reagent used in diastereoselective alkylations2 and as a ligand for LiAlH4 in asymmetric reductions3 of enones)

Physical Data: (S)-(+),4a [a]20D +25°, mp >300 °C (dec.); (R)-(-),4a [a]20D -24°, mp >300 °C; (±) mp 325-348 °C (dec.).

Solubility: sol in acid and alkali; sol water (1 g/222.2 mL at 20 °C), forming supersaturated solutions easily; insol alcohol.

Form Supplied in: commercially available as a white solid in racemic and optically pure forms.4

Diastereoselective Alkylations.

Esters derived from L-aspartic acid have been alkylated at both the a- and b-positions (eq 1).1,2 b-Alkylations have been more widely used. The amino acid moiety is responsible for the diastereoselection in the b-alkylation process.

Alkylation of cyclic derivatives of L-aspartic acid (1) occurs exclusively at the b-position with good to excellent diastereoselection. One application is the synthesis of chiral b-dicarbonyl equivalents.5 Equivalents of either enantiomer can be prepared depending on whether the alkylation is performed on a lactone (eq 2) or an oxazoline (eq 3).

The most commonly used cyclic derivatives of L-aspartic acid are b-lactams (eq 4).6 For example, excellent regioselectivity and diastereoselectivity are observed in the alkylation of the dianion of (3). Other compounds related to (3) have been prepared from L-aspartic acid7 and used in highly diastereoselective alkylations en route to a variety of natural and nonnatural products8 including b-lactams,9 g-lactams,10 and dihydroisocoumarin derivatives.11

Asymmetric Reductions.

Asymmetric reductions of prochiral ketones to optically active secondary alcohols have been extensively studied.3 The most common method involves the use of chiral unidentate or bidentate ligands in conjunction with Lithium Aluminum Hydride. However, an (S)-aspartic acid derived tridentate ligand has been shown to be very effective in certain cases, presumably due to the rigidity of aluminum complex (4) (eqs 5-7).12

Unfortunately, the complete enantiofacial differentiation of cyclohexenone (eq 7) appears to be an isolated case, as reaction with 3-methylcyclohexenone afforded the corresponding (S)-cyclohexanol in only 28% ee. In the absence of a general trend for the outcome of these reductions, the scope of this method seems limited at this point, as opposed to (S)-BINAL-H mediated reductions (see Lithium Aluminum Hydride and subsequent articles).


1. (a) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis; Wiley: New York, 1987; Chapter 7. (b) Greenstein, W. Chemistry of the Amino Acids; Wiley: New York, 1961; Vol. 3, Chapter 23.
2. Seebach, D.; Wasmuth, D. AG(E) 1981, 20, 971.
3. Nishizawa, M.; Noyori, R. COS 1991, 8, Chapter 1.7.
4. (a) Harada, K. BCJ 1964, 37, 1383. (b) For syntheses of DL-aspartic acid, see Dunn, M. S.; Smart, B. W. OCS 1963, 4, 55.
5. McGarvey, G. J.; Hiner, R. N.; Matsubara, Y.; Oh, T. TL 1983, 24, 2733.
6. Reider, P. J.; Grabowski, E. J. J. TL 1982, 23, 2293.
7. Labia, R.; Morin, C. CL 1984, 1007.
8. (a) Nordlander, J. E.; Payne, M. J.; Njoroge, F. G.; Vishwanath, V. M.; Han, G. R.; Laikos, G. D.; Balk, M. A. JOC 1985, 50, 3619. (b) Baldwin, J. E.; North, M.; Flinn, A. TL 1987, 28, 3167.
9. (a) Salzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G.; Bouffard, F. A. JACS 1980, 102, 6163. (b) Salzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G. TL 1980, 21, 1193.
10. Baldwin, J. E.; Adlington, R. M.; Gollins, D. W.; Schofield, C. J. T 1990, 46, 4733.
11. Broady, S. D.; Rexhausen, J. E.; Thomas, E. J. CC 1991, 708.
12. (a) Sato, T.; Gotoh, Y.; Fujisawa, T. TL 1982, 23, 4111. (b) Sato, T.; Gotoh, Y.; Wakabayashi, Y.; Fujisawa. T. TL 1983, 24, 4123.

Alyx-Caroline Guével

The Ohio State University, Columbus, OH, USA



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