Synthesis of Dipeptides by Boronic Acid Catalysis

Abstract

We have found that a boronic acid catalyzed amidation of an N-hydroxy amino acid methyl ester with amino acid tert-butyl esters gave N-hydroxy dipeptide derivatives in good yields without any racemization. The protecting groups on the nitrogen atom could be easily removed by heterogeneous hydrogenation conditions.

Key words

N-hydroxy amino acid esters - amidation - boronic acid ­catalysis - N-hydroxy dipeptides - substrate-controlled reaction

• References and Notes

• 1 Hiroaki Tsuji, Department of Chemistry, College of Humanities & Sciences, Nihon University, Sakurajosui, Setagaya-ku, Tokyo 156-8550, Japan. Following e-mail address is also active: [e-mail].
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Examples of catalytic synthesis of dipeptides with base catalyst:
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With boronic acid analogues:
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With Ru catalyst:
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• 7 Catalytic synthesis of cyclic peptides from β-amino alcohols, see: Gnanaprakasam B. Balaraman E. Ben-David Y. Milstein D. Angew. Chem. Int. Ed. 2011; 50: 12240
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For a review, see:
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For N-hydroxy amino acids for peptide synthesis, see:
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• 14 As a preliminary experiment, we also examined the reaction of N-hydroxyphenylalanine methyl ester (95:5 er) with l-Ala-OMe under our catalyst system to give the desired dipeptide in 58% yield (95:5 dr). This result clearly shows that our catalyst system would be applicable to the other N-hydroxy amino acid methyl esters.
• 15 The activation of the ester group through internal H-bonding interaction is also possible, see ref. 12. We excluded out this possibility because dichlorophenylborane also catalyzed the reaction of 4 with 6a at 100 °C to give 7a in 49% yield.
• 16 Boronic acid catalyzed amidation reaction of hydroxy group containing substrates, see: Yamashita R. Sakakura A. Ishihara K. Org. Lett. 2013; 15: 3654
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• 18 General Procedure for the Boronic Acid Catalyzed Amidation Reaction: Typical Procedure for the Reaction of (2S)-Methyl 2-(benzylhydroxyamino)propanoate (4) with H-l-Ala-Ot-Bu (6a) (2S)-Methyl 2-(benzylhydroxyamino)propanoate (4, 52.3 mg, 0.25 mmol, 1.0 equiv), H-l-Ala-Ot-Bu (6a, 108.9 mg, 0.75 mmol, 3.0 equiv), and 3,4,5-trifluorophenylboronic acid (5.3 mg, 0.03 mmol, 12 mol%) were charged into an oven-dried test tube equipped with a magnetic stir bar. The test tube was sealed with a rubber septum and refilled with N₂. Toluene (1 mL, 0.25 M) was added to the test tube, and the reaction mixture was stirred at 100 °C for 18 h. The resulting mixture was allowed to cool to r.t., and then sat. NaHCO₃ solution (1 mL) was added. The aqueous phase was extracted with CH₂Cl₂ (3 × 3 mL). The combined organic extracts were washed with brine (1 × 3 mL) and dried over Na₂SO₄. After removal of the solvent, the resulting crude mixture was purified by silica gel column chromatography (hexane/EtOAc = 7:3, 65:35) to give the desired product 7a (53.6 mg, 0.166 mmol, 66% yield, 95:5 dr) as a yellow oil. IR (neat): 3364, 2981, 1732, 1649, 1518, 1453, 1368, 1148, 748, 697 cm^–1. ¹H NMR (400 MHz, CDCl₃, major diastereomer): δ = 7.42–7.28 (m, 5 H), 7.09 (d, J = 7.2 Hz, 1 H), 5.40 (br s, 1 H), 4.53 (qd, J = 7.2, 7.2 Hz, 1 H), 4.00 (d, J = 13.2 Hz, 1 H), 3.83 (d, J = 13.6 Hz, 1 H), 3.46 (q, J = 6.8 Hz, 1 H), 1.46 (s, 9 H), 1.41 (d, J = 6.8 Hz, 3 H), 1.40 (d, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.8, 172.6, 137.2, 129.4, 128.3, 127.4, 82.1, 66.4, 60.6, 48.0, 27.9, 18.4, 13.9. [α]_D ²⁴ +11.88 (c 1.01, CHCl₃). HLPC conditions: DAICEL CHIRALPACK IC, hexane/i-PrOH = 4:1, flow rate = 1 mL/min, λ = 207 nm, retention time; t _R (major) = 8.75 min, t _R (minor) = 14.19 min. HRMS (ESI⁺): m/z calcd for C₁₇H₂₆N₂O₄Na [M + Na]⁺: 345.1785; found: 345.1774.