L-Tyrosine Hydrazide

[7662-51-3]  · C8H13N3O2  · L-Tyrosine Hydrazide  · (MW 195.24)

(resolution of carboxylic acids and amino acids1)

Physical Data: crystalline solid; mp 196-198 °C; [a]25D +76° (c 4.2, 1N HCl).

Solubility: slightly sol cold methanol or ethanol; readily sol hot methanol or ethanol.

Form Supplied in: the free base (98% purity) is available from several commercial sources. No additional purification before use is required.

Preparative Methods: the synthesis of L-tyrosine hydrazide from L-tyrosine has been described.2 D-Tyrosine hydrazide has been obtained by resolution of DL-tyrosine hydrazide with Cbz-L-proline.3

Handling, Storage, and Precautions: the free base is stable in amber bottles, at room temperature, for indefinite periods of time. No special handling precautions have been described.

Introduction.

L-Tyrosine hydrazide (L-Tyr-NHNH2) (1) is useful in the resolution of simple carboxylic acids and amino acid derivatives. It often forms highly crystalline salts with these compounds, which yield diastereomerically pure salts in just one or two recrystallizations. The yields of resolved acids tend to be high, and in many cases both enantiomers can be obtained from the same operation (the more soluble diasteromeric salt that remains in the mother liquors is often quite pure). The tyrosine hydrazide can be recovered without appreciable loss of optical activity.

Resolution of Carboxylic Acids.

A variety of racemic monofunctional carboxylic acids have been resolved with chiral a-amino acid hydrazides, including L-Tyr-NHNH2 and L-leucine hydrazide, which produce mandelic acid analogs with greater than 99% ee.4 Other examples of resolutions of simple carboxylic acids have appeared in the patent literature (eq 1).5

Resolution of Cyclic Amino Acid Derivatives.

L-Tyr-NHNH2 has been used many times in the resolution of all types of N-functionalized amino acids. The high crystallinity of the salts formed has been found to be a great advantage in situations where many other common resolving agents have failed. As indicated above, multiple recrystallizations of the diastereomeric salts formed by L-Tyr-NHNH2 are rarely necessary to obtain amino acids of high optical purity. In most cases, D-a-amino acid derivatives form less soluble salts with L-Tyr-NHNH2 than the corresponding L-a-amino acid derivatives. One of the earliest works in this area was the resolution of (±)-Cbz-proline (eq 2).3 (±)-Cbz-Alanine and (±)-Cbz-isoleucine (eq 3) have also been resolved.3 In all cases, the unnatural D-a-amino acids are obtained. This procedure also allows the isolation of D-tyrosine hydrazide by resolution of (±)-Tyr-NHNH2 with Cbz-L-proline.3 Most other amino acids resolved with L-tyrosine hydrazide also have their amino group protected as the Cbz derivative. For example, both enantiomers of azetidine-2-carboxylic acid are readily available, in high yield and about 100% ee, after one single crystallization of the racemate with L-Tyr-NHNH2 (eq 4).6 Similarly, both enantiomers of pipecolic acid are obtained by resolution of (±)-N-Cbz-pipecolic acid with L-Tyr-NHNH2 (eq 5).7

Resolution of Acyclic Amino Acid Derivatives.

D-Homoserine is readily available by resolution of (±)-N-Cbz-homoserine (eq 6).8 Both enantiomers of threo-2-amino-3,4-dihydroxybutyric acids are available via a similar resolution with L-Tyr-NHNH2.9 N-Cbz-derivatives of amino dicarboxylic acids, such as a-aminosuberic acid, have been resolved with D-Tyr-NHNH2. In this case, the L-amino acid derivatives crystallize preferentially with the resolving agent.10 Finally, tetrazole analogs of a-amino acids have also been resolved with L-Tyr-NHNH2. For example, racemic tetrazole analogs of N-protected alanine, leucine, phenylalanine, and valine are resolved with L-Tyr-NHNH2 to yield, except for the phenylalanine analog, the D-enantiomers (eq 7).11


1. All chemical yields indicated for resolution steps represent the % of the theoretical amount of pure enantiomer. For a review of resolving agents used for acids and amino acids, see: Wilen, S. H. In Tables of Resolving Agents and Optical Resolutions; Eliel, E., Ed.; Univ. of Notre Dame Press: Notre Dame, 1972.
2. Curtius, T.; Donselt, W. JPR 1917, 95, 349.
3. Vogler, K.; Lanz, P. HCA 1966, 49, 1348.
4. Jap. Patent 01 221 345 (CA 1990, 112, 118 459r).
5. Manoury, P.; Obitz, D.; Peynot, M.; Frost, J. Eur. Pat. Appl. 364 327, 1990 (CA 1990, 113, 191 392p).
6. Rodebaugh, R. M.; Cromwell, N. H. JHC 1969, 6, 993.
7. Balaspiri, L.; Penke, B.; Petres, J.; Kovacs, K. M 1970, 101, 1177.
8. Curran, W. V. Prep. Biochem. 1981, 11, 269.
9. Okawa, K.; Hori, K.; Hirose, K.; Nakagawa, Y. BCJ 1969, 42, 2720.
10. Hase, S.; Kiyoi, R.; Sakakibara, S. BCJ 1968, 41, 1266.
11. Grzonka, Z.; Liberek, B. T 1971, 27, 1783.

Juan C. Jaen

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



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