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Strecker Degradation Of Amino Acids To Ketones

H.L. Slates, D. Taub, C.H. Kuo, N.L. Wendler
J. Org. Chem. 29, 1424 (1964)

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Degradation of alpha-Methyl-3,4-dihydroxyphenylalanine

The transformation of alpha-methyl-DOPA diethyl ether to 3,4-dimethoxyphenylacetone (V) was effected oxidatively with sodium hypochlorite1 in 90% yield. Thus, the total sequence (Chart I) from alpha-methyl-DOPA to 3,4-dimethoxyphenylacetone, consisting of the four steps, acetylation, methylation, hydrolysis, and hypochlorite oxidation, can be effected with a potential overall yield of 90%.

The direct hypochlorite oxidation of alpha-methyl-DOPA itself proceeds in the desired manner to give 3,4-dihydroxyphenylacetone in ca. 50% yield. The latter substance is highly water soluble and sensitive as well to manipulation, although it can be methylated to V in reasonable yield. To a large and competitive extent, however, the direct hypochlorite oxidation of alpha-methyl-DOPA involves nuclear attack as evidenced by accompanying resinification. The use of t-butyl hypochlorite was found to be superior to sodium hypochlorite in this instance and suggests, thereby, that the breakdown reaction to ketone is faster than nuclear involvement. The hypochlorite degradation of the 3-monomethyl ether of alpha-methyl-DOPA to 3-methoxy-4-hydroxyphenylacetone also can be accomplished in at least 60-70% yield.


The oxidative degradation IVV would appear clearly to be initiated by N-chlorination (compare a ⇒ b ⇒ c) inasmuch as the N-acetate derivative III is unchanged under the conditions of hypochlorite oxidation, whereas the latter (III) is oxidized smoothly by lead tetraacetate, a reagent known to attack carboxyl functions.



3,4-Dimethoxyphenylacetone (V) from IV

To a stirred solution, (20-25) of 956 mg. (4.00 mmoles) of alpha-methyl-3,4-dimethoxyphenylalanine (IV) in 25 ml. of water was added 10 ml. of benzene. Sodium hypochlorite solution (14 ml., 0.3 N active chlorine)2 was added dropwise over 20 min. The reaction was followed by spotting aliquots on starch-iodide paper. After each addition of hypochlorite, a negative test was obtained in about 30 sec. At the reaction's completion, a positive test was obtained 5 min. after addition of the last drop of hypochlorite. The layers were separated and the basic aqueous layer was extracted twice with 50% benzene-ether; the combined organic phase was dried over magnesium sulfate and concentrated to dryness in vacuo. The neutral residue (725 mg., 92%) consisted of 3,4-dimethoxyphenylacetone; infrared spectrum was identical with standard; v.p.c. showed it to be 97% pure.

Semicarbazone. The semicarbazone crystallized from ether-chloroform and had m.p. 171-174; mixture melting point was undepressed with an authentic sample of mp 175-176C.

3,4-Dihydroxyphenylacetone (VI)

A. Sodium Hypochlorite

To a stirred solution of 844 mg. (4.00 mmoles) of alpha-methyl-3,4-dihydroxyphenylalanine (I) in 20 ml. of 0.5 M borax buffer (pH 8.5)3 was added 10 ml. of benzene. Nitrogen was bubbled through the solution and 12.0 ml. of 0.34 N sodium hypochlorite solution added dropwise. The red solution was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The latter extract was dried and concentrated to dryness. The residue was triturated with chloroform, the latter suspension filtered, and the filtrate concentrated to dryness in vacuo to give 3,4-dihydroxyphenylacetone, 235 mg (36%), with additional material still in the aqueous mother liquors. Acetylation of a probe (pyridine-acetic anhydride, 25C, 18 hr.) gave 3,4-diacetoxyphenylacetone. The latter was identified as the diacetate by comparison with an authentic sample.

B. t-Butyl Hypochlorite

To a stirred suspension of 844 mg (4.0 mmoles) of alpha-methyl-3,4-dihydroxyphenylalanine in 10 ml. of water (under nitrogen) was added 340 mg. (4.00 mmoles) of sodium bicarbonate. t-Butyl hypochlorite (0.50 g., 4.5 mmoles) in 10 ml. of t-butyl alcohol was added dropwise over 30 min. The deep red reaction mixture was acidified with 5 ml. of 2 N hydrochloric acid and extracted thoroughly with ethyl acetate. Further work-up as in A led to 335 mg. (50%) of 3,4-dihydroxyphenylacetone; infrared spectrum was identical with that of an authentic sample.

3,4-Diacetoxyphenylacetone (XIV) from II

To a stirred solution of 16.85 g. (50 mmoles) of N-acetyl-alpha-methyl-3,4-diacetoxyphenylalanine (II) in 125 ml. of acetonitrile was added 4.00 mL (50 mmoles) of pyridine followed by 22.15 g. (50 mmoles) of lead tetraacetate. The mixture was warmed cautiously to reflux temperature at which point lead acetate precipitated rapidly from solution. The mixture was refluxed gently for 30 min., cooled, filtered, and the filtrate concentrated to dryness. The residue, consisting mainly of the intermediate decarboxylated imine tri-acetate (XIII), was hydrolyzed by heating on the steam bath (90-95) with 15 ml. of acetic acid and 10 ml. of water for 50 min. The mixture was cooled, water was added, and it was extracted with chloroform. The chloroform extract was washed with dilute potassium bicarbonate solution and salt solution, dried over magnesium sulfate, and concentrated to dryness to give 3,4-diacetoxyphenylacetone (XIV), 9.4 g. (75%); bp 145-150C (0.05 mmHg).

The diacetoxy ketone was converted in good yield by the appropriate processes to the corresponding dimethoxyketone V and to the dihydroxy hydantoin and alpha-methyl-DOPA. Similar lead tetraacetate treatment of the N-acetyldimethoxyamino acid IIIc in CH3CN-pyridine led to the dimethoxy ketone V.



  1. For the employment of hypochlorite in the degradation of natural amino acids, see:
    1. K. Langheld, Ber., 42, 392 (1909)
    2. H. P. Dakin Biochem. J., 10, 319 (1916); 11, 79 (1917)
    3. D. D. van Slyke, D. A Mcfayden, and D. Hamilton, J. Biol. Chem., 141, 627 (1941)
    4. I. D. Spenser, J. C. Crowhall, and D. G. Smyth, Chem. Ind. (London), 798 (1956)
  2. Commercial "5%" sodium hypochlorite was used. A 5.00 ml aliquot was added to 2.0 g of potassium iodide in 30ml of 0.5 N hydrochloric acid and the iodine formed titrated vs. 0.1 N sodium thiosulfate; 30.50 ml. of 0.1 N sodium thiosulfate was required.
  3. Borax buffer: 3.1 g. of boric acid in 50 ml. of water, 8.5 ml. of 1 N sodium hydroxide, and enough water to bring the total to 100 ml.