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Org. Synth. 2002, 78, 220

DOI: 10.15227/orgsyn.078.0220

SYNTHESIS OF AMINO ACID ESTER ISOCYANATES: METHYL (S)-2-ISOCYANATO-3-PHENYLPROPANOATE

[ Benzenepropanoic acid, α-isocyanato-, methyl ester, (S) ]

Submitted by James H. Tsai, Leo R. Takaoka, Noel A. Powell, and James S. Nowick¹ .

Checked by Adam Charnley and Steven Wolff.

1. Procedure

A 250-mL, three-necked, round-bottomed flask is equipped with a mechanical stirrer and charged with 100 mL of methylene chloride , 100 mL of saturated aqueous sodium bicarbonate , and 5.50 g (25.5 mmol) of L-phenylalanine methyl ester hydrochloride (Note 1). The biphasic mixture is cooled in an ice bath and stirred mechanically while 2.52 g (8.42 mmol) of triphosgene (Note 2) is added in a single portion. The reaction mixture is stirred in the ice bath for 15 min and then poured into a 250-mL separatory funnel. The organic layer is collected, and the aqueous layer is extracted with three 15-mL portions of methylene chloride . The combined organic layers are dried (MgSO₄), vacuum filtered, and concentrated at reduced pressure using a rotary evaporator to give a colorless oil. The oil is purified by Kugelrohr distillation (130°C, 0.05 mm) to afford 5.15 g (98%) of methyl (S)-2-isocyanato-3-phenylpropanoate as a colorless oil (Notes 3-6).

2. Notes

1. L-Phenylalanine methyl ester hydrochloride was purchased from Bachem California Inc.

2. Triphosgene was purchased from Aldrich Chemical Company, Inc.

3. The product has the following properties: [α]_D ²⁵ −83.8° (neat); IR (CHCl₃) cm⁻¹: 2260, 1747 ; ¹H NMR (400 MHz, CDCl₃) δ: 3.03 (dd, 1 H, ABX pattern, J_AB = 13.8, J_BX = 7.8), 3.16 (dd, 1 H, ABX pattern, J_AB = 13.6, J_AX = 4.8), 3.81 (s, 3 H), 4.27 (dd, 1 H, J = 7.8, 4.6), 7.18-7.21 (m, 2 H), 7.27-7.36 (m, 3 H) ; ¹³C NMR (125 MHz, CDCl₃) δ: 39.6, 52.8, 58.3, 126.7, 127.2, 128.4, 129.1, 135.4, 170.7 . Anal. Calcd for C₁₁H₁₁NO₃: C, 64.38; H, 5.40; N, 6.83. Found: C, 64.18; H, 5.40; N, 6.70.

4. The yield is typically 4.97-5.15 g (95-98%).

5. The submitters previously reported an optical rotation of [α]_D ²² +71.9° (neat) for methyl (S)-2-isocyanato-3-phenylpropanoate .² This value does not match the current value of [α]_D ²⁵ −83.8° (neat) and is in error. The origin of this discrepancy involves the path length of the polarimeter cell. With a 5-cm cell, a correct α value of −48.15° is obtained. If a 10-cm cell is used, a spurious positive α value is obtained, which gives rise to a erroneous positive value of [α]_D.

6. The optical purity of the product was determined to be >99.5% by trapping with (S)-1-phenylethylamine and ¹H NMR analysis of the resulting urea adduct, as described in reference 2.

Handling and Disposal of Hazardous Chemicals

The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.

These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.

3. Discussion

This procedure provides a convenient, rapid, high yielding route to amino acid ester isocyanates.. It is based upon procedures the submitters have previously reported for the preparation of both amino acid ester isocyanates² and peptide isocyanates.³^,⁴ These procedures use either triphosgene or a solution of phosgene in toluene as a one-carbon electrophile and either pyridine or aqueous sodium bicarbonate as a base. The current procedure uses triphosgene and sodium bicarbonate to minimize the hazard and toxicity of the reagents and waste products. These mild reaction conditions are superior to alternative methods for the preparation of amino acid ester isocyanates, which include refluxing the amino acid ester hydrochloride in toluene for several hours while purging with gaseous phosgene,⁵ or treating the amino acid ester hydrochloride with di-tert-butyl dicarbonate and 4-dimethylaminopyridine (DMAP).⁶

Amino acid ester isocyanates are produced cleanly by this method and can often be used without purification. If desired, volatile amino acid ester isocyanates, such as the title compound, can be purified to analytical purity by Kugelrohr distillation. The amino acid ester isocyanates generated by this method are formed without detectable racemization (>99.5% ee); the enantiomeric purity of the isocyanates can be checked by trapping with (S)-1-phenylethylamine, followed by ¹H NMR analysis of the resulting urea adducts.² If this method is used to generate isocyanates of peptides, then efficient stirring is necessary to prevent epimerization of the peptide isocyanates.³, ⁴

Amino acid ester isocyanates are useful synthetic building blocks, precursors to peptides and azapeptides,⁷^,⁸ chiral derivatizing agents,⁹^,¹⁰ and reagents for the preparation of chiral chromatographic media.¹¹^,¹² (S)-2-Isocyanato-3-phenylpropanoate (phenylalanine methyl ester isocyanate) has been used as a building block for 1,2,4-triazine azapeptides,⁸ and inhibitors of thermolysin¹³ and human leukocyte elastase (HLE).¹⁴

References and Notes

Department of Chemistry, University of California Irvine, Irvine, CA 92697-2025. This work was supported by the National Institutes of Health (Grant GM-49076). J.S.N. thanks the following agencies for support in the form of awards: The National Science Foundation (Presidential Faculty Fellow Award), the Camille and Henry Dreyfus Foundation (Teacher-Scholar Award), and the Alfred P. Sloan Foundation (Alfred P. Sloan Research Fellowship).
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Nowick, J. S.; Holmes, D. L.; Noronha, G.; Smith, E. M.; Nguyen, T. M.; Huang, S.-L.; Wang, E. H. J. Org Chem. 1998, 63, 9144 (Addition and correction for Ref. 3).
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Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

Methyl (S)-2-isocyanato-3-phenylpropanoate:
Benzenepropanoic acid, α-isocyanato-, methyl ester, (S)- (9); (40203-94-9)

L-Phenylalanine methyl ester hydrochloride:
L-Phenylalanine methyl ester, hydrochloride (9); (7524-50-7)

Triphosgene:
Carbonic acid, bis(trichloromethyl) ester (8,9); (32315-10-9)

Notes

References/EndNotes

Article Compounds

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