t-Leucine t-Butyl Ester1

(D)

[61169-85-5]  · C10H21NO2  · t-Leucine t-Butyl Ester  · (MW 187.32) (L)

[31556-74-8] (DL)

[99285-38-8]

(chiral auxiliary used in asymmetric alkylations,1 1,2-additions,2 and 1,4-additions3 of aldehyde and ketone derived Schiff bases)

Physical Data: D,4a [a]20D -56°; bp 90-91 °C/21 mmHg. L,4a [a]20D +51.7° (92.3% ee); bp 87-89 °C/18 mmHg.

Solubility: sol hexanes, benzene.

Preparative Methods: prepared by esterification of t-leucine with Isobutene and conc Sulfuric Acid (under pressure).4 Typical yields are 62-64% and 12-14% of recovered amino acid. t-Leucine itself is commercially available in racemic and optically pure forms. It can also be prepared by oxidation of pinacolone to trimethylpyruvic acid, followed by oxime formation and zinc reduction. Resolution of the N-formyl derivative of t-leucine has been carried out using brucine.4a

Handling, Storage, and Precautions: none.

Asymmetric Alkylations.

The use of nitrogen derivatives of carbonyl compounds (imines, imides, amides, sultams, oxazolines) is often the most efficient procedure for achieving a-alkylations.1 Chiral auxiliaries bearing heteroatoms in a 1,2-relationship appear to work best, as they have chelation sites for the metal cation. High levels of asymmetric induction can thus be achieved due to the system rigidity. Cyclic ketones have been alkylated via the lithiated enamine formed from L-t-leucine t-butyl ester (eq 1).5 High enantiomeric excesses and predictability of absolute configuration make this method attractive.

1,2-Additions.

The imine prepared from L-t-leucine t-butyl ester and benzaldehyde has been used to prepare D-phenylglycine in 96.5% ee via a diastereoselective hydrocyanation.2 A rigid five-membered ring transition state involving hydrogen bonding between nitrogen and carbonyl oxygen has been proposed. Attack of cyanide ion from the opposite side of the bulky t-butyl group accounts for the stereochemical outcome (eq 2).

1,4-Additions.

Asymmetric Michael additions1 of Grignard reagents can be performed on a,b-unsaturated aldimines3a derived from either enantiomer of t-leucine t-butyl ester (eq 3).

Similarly, malonate anions3b,c add to aldimines with reasonably high enantioselectivity. The new asymmetric center, however, has the opposite absolute configuration to that shown in eq 3. A chelated aldimine of (E) geometry is the proposed intermediate for this reversal of stereoselection (eq 4).

Cyclic aldimines can also be used, and subsequent alkylation of the magnesioenamine intermediate achieved with good to excellent diastereoselectivity.3d,e,f Cis or trans products can be obtained, depending on the procedure chosen (eq 5).

A few natural product syntheses feature the use of both acyclic6 and cyclic7,8 aldimines of either enantiomer of t-leucine t-butyl ester. Kinetic resolution of racemic aldehydes has also been achieved using L-t-leucine t-butyl ester.8

For the three types of reactions presented above, t-leucine t-butyl ester has been shown to be the most efficient amino acid derivative. It is often mentioned that valine t-butyl ester affords lower enantioselectivities. Work-up procedures allow recovery of reusable optically pure auxiliary.


1. (a) Ager, D. J.; East, M. B. T 1992, 48, 2803 and references cited therein. (b) ApSimon, J. W.; Lee Collier, T. T 1986, 42, 5157. (c) Tomioka, K.; Koga, K. In Asymmetric Synthesis; Academic: New York, 1983; Vol. 2. (d) Coppola, G. M.; Schuster, H. F. In Asymmetric Synthesis; Wiley: New York, 1987; Chapter 4.
2. Yamada, S.; Hashimoto, S. CL 1976, 921.
3. (a) Hashimoto, S.; Yamada, S.; Koga, K. JACS 1976, 98, 7450. (b) Hashimoto, S.; Komeshima, N.; Yamada, S.; Koga, K. TL 1977, 2907. (c) Yamada, S.; Komeshima, N.; Yamada, S.; Koga, K. CPB 1979, 27, 2437. (d) Hashimoto, S.; Kogen, H.; Tomioka, K.; Koga, K. TL 1979, 3009. (e) Kogen, H.; Tomioka, K.; Hashimoto, S.; Koga, K. TL 1980, 4005. (f) Kogen, H.; Tomioka, K.; Hashimoto, S.; Koga, K. T 1981, 37, 3951.
4. (a) Hashimoto, S.; Yamada, S.; Koga, K. CPB 1979, 27, 771. (b) Roeske, R. W. CI(L) 1959, 1121.
5. (a) Hashimoto, S.; Koga, K. TL 1978, 573. (b) Hashimoto, S.; Koga, K. CPB 1979, 27, 2760.
6. (a) Whittaker, M.; McArthur, C. R.; Leznoff, C. C. CJC 1985, 63, 2844. (b) Muraoka, O.; Fujiwara, N.; Tanabe, G.; Momose, T. TA 1991, 2, 357.
7. (a) Tomioka, K.; Masumi, F.; Yamashita, T.; Koga, K. TL 1984, 25, 333. (b) Tomioka, K.; Masumi, F.; Yamashita, T.; Koga, K. T 1989, 45, 643.
8. (a) Paquette, L. A.; Macdonald, D.; Anderson, L. G.; Wright, J. JACS 1989, 111, 8037. (b) Paquette, L. A.; Macdonald, D.; Anderson, L. G. JACS 1990, 112, 9292. (c) Snider, B. B.; Yang, K. TL 1989, 30, 2465. (d) Snider, B. B.; Yang, K. JOC 1990, 55, 4392.

Alyx-Caroline Guével

The Ohio State University, Columbus, OH, USA



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