Organic Syntheses Procedure

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Org. Synth. 1985, 63, 171

DOI: 10.15227/orgsyn.063.0171

N-tert-BUTOXYCARBONYL-l-PHENYLALANINE

[L-Phenylalanine, N[(1,1-dimethylethoxy)carbonyl)]-]

Submitted by William J. Paleveda, Frederick W. Holly, and Daniel F. Veber¹.

Checked by Mark A. Sanner, Thomas von Geldern, and Clayton H. Heathcock.

1. Procedure

To a stirred mixture of 16.51 g (0.1 mol) of L-phenylalanine in 60 mL of water and 60 mL of peroxide-free dioxane (Note 1) is added 21 mL of triethylamine. To the resulting solution is added 27.1 g (0.11 mol) of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (Note 2). Solution is obtained during the first hour of stirring. After 3 hr (Note 3) the solution is diluted with 150 mL of water. The resulting turbid solution is extracted with at least four 200-mL portions of ethyl ether (Note 4). The aqueous layer is then acidified to pH 2.5 with cold 2.5 N hydrochloric acid to yield an oily layer. The mixture is extracted with three 100-mL portions of methylene chloride. The combined organic extracts are dried with anhydrous sodium sulfate. After filtration of the sodium sulfate, the filtrate is evaporated under reduced pressure at a bath temperature of 30°C. Hexane is added to the thick oil to turbidity. Crystallization occurs after cooling and stirring the mixture for a short time. More hexane is added in portions until no further crystallization occurs. A total of 200 mL of hexane is required. The mixture is allowed to stand for 1 hr. The white crystalline solid is collected by filtration, washed with three 100-mL portions of hexane, and dried under reduced pressure to yield 21.4–22.0 g (80–83%) of tert-butoxycarbonyl-L-phenylalanine, mp 86–88°C, [α]_D20 −3.6° (HOAc, c 1), [α]₅₄₆20 29.9° [EtOH, c 1) (Note 5).

2. Notes

1. Peroxides are removed from dioxane by its passage through a column of neutral alumina.²

2. 2-(tert-Butoxycarbonyloxyimino)-2-phenylacetonitrile is obtained from Aldrich Chemical Company, Inc., under the trademark "BOC-ON."

3. The reaction is allowed to continue until TLC (Whatman K1F, ethyl acetate–pyridine–acetic acid–water, 10:5:1:3) shows that the unprotected amino acid (R_f 0.4) is no longer present, as evidenced by negative ninhydrin spray.

4. It is imperative that all the by-product is removed at this point; otherwise it will contaminate the product, making crystallization difficult. Each ether extract is spotted on a Whatman K1F plate and the plate viewed under UV light to ascertain that all of the by-product has been extracted. The checkers found that six or seven ether extractions were required to remove the by-product completely.

5. The literature gives melting points ranging from 79–80°C to 84–86°C; the optical rotation is reported as [α]_D25 −0.8° (HOAc, c 4.957), [α]_D20 −4.8° (HOAc, c 1), [α]₅₄₆20 30° (EtOH, c 1).

The spectral properties of tert-butoxycarbonyl-L-phenylalanine are as follows: ¹H NMR (CD₃OD) δ: 1.36 (s, 9 H, t-butyl), 2.87 (dd, 1 H, J = 14.9, H_β), 3.16 (dd, 1 H, J = 14.6, H_β), 4.36 (dd, 1 H, J = 9.6, H_α), 7.26 (s, 5 H, phenyl). In CDCl₃ solution, both carbamate rotamers may be seen in the ¹H NMR spectrum.

3. Discussion

Various reagents have been used for the introduction of the tert-butoxycarbonyl group, including tert-butyl p-nitrophenyl carbonate,³ tert-butyl azidoformate⁴ (no longer commercially available because of its toxic and potentially explosive nature), tert-butyl 2,4,5-trichlorophenyl carbonate,⁵ di-tert-butyl dicarbonate,⁶ and the reagent described herein, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile.⁷ Using the same reagent, the crystalline BOC derivatives of the following amino acids have been prepared in these laboratories in the indicated yields: 7-aminoheptanoic acid (88%), DL-tyrosine (96%), 6-fluoro-DL-tryptophan (87%), 5-methyl-DL-tryptophan (95%), 5-bromo-DL-tryptophan (94%), 5-methoxy-DL-tryptophan (67%), 1-methyl-DL-tryptophan (82%), and 5-fluoro-DL-tryptophan (62%).

References and Notes

Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
Stewart, J. M.; Young, J. D. "Solid Phase Peptide Synthesis," W. H. Freeman & Co.: San Francisco, 1969, p 31.
Anderson, G. W.; McGregor, A. C. J. Am. Chem. Soc. 1957, 79, 6180.
Schwyzer, R.; Sieber, P.; Kappeler, H. Helv. Chim. Acta 1959, 42, 2622.
Broadbent, W.; Morley, J. S.; Stone, B. E. J. Chem. Soc. C 1967, 2632.
Moroder, L.; Hallett, A.; Wünsch, E.; Keller, O.; Wersin, G. Hoppe-Seyler's Z. Physiol. Chem. 1976, 357, 1651.
Itoh, M.; Hagiwara, D.; Kamiya, T. Tetrahedron Lett. 1975, 4393; Bull. Chem. Soc. Jpn. 1977, 50, 718.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

alumina

L-Phenylalanine, N[(1,1-dimethylethoxy)carbonyl)]-

hydrochloric acid (7647-01-0)

ether,
ethyl ether (60-29-7)

sodium sulfate (7757-82-6)

methylene chloride (75-09-2)

dioxane (123-91-1)

L-phenylalanine (63-91-2)

hexane (110-54-3)

triethylamine (121-44-8)

tert-Butyl azidoformate (1070-19-5)

2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (58632-95-4)

ninhydrin (938-24-9)

7-aminoheptanoic acid (929-17-9)

tert-butyl 2,4,5-trichlorophenyl carbonate (16965-08-5)

Di-tert-butyl dicarbonate (24424-99-5)

N-tert-Butoxycarbonyl-L-phenylalanine,
tert-butoxycarbonyl-L-phenylalanine (13734-34-4)

tert-butyl p-nitrophenyl carbonate (13303-10-1)

DL-tyrosine

6-fluoro-DL-tryptophan (7730-20-3)

5-methyl-DL-tryptophan (951-55-3)

5-bromo-DL-tryptophan (6548-09-0)

5-methoxy-DL-tryptophan (28052-84-8)

1-methyl-DL-tryptophan (26988-72-7)

5-fluoro-DL-tryptophan (154-08-5)

Notes

References/EndNotes

Article Compounds

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