3,3-Dichloro-1,2-diphenylcyclopropene (CPICl)-Mediated Synthesis of N^α-Protected Amino Acid Azides and α-Ureidopeptides

Abstract

Rapid synthesis of acid azides via in situ generation of acid chlorides using CPICl as chlorinating agent from the corresponding N^α-protected amino acids is described. Also the conversion of acid azides into ureidopeptides through the Curtius rearrangement under ultrasonication is delineated. The mildness of the protocol renders the acid-sensitive substrates to afford the corresponding amino acid azides and ureidopeptides in good yields. Diphenylcyclopropenone has also been recovered from the reaction mixture and reused.

Keywords

N^α-protected amino acids - CPICl - acid chlorides - acid azides - Curtius rearrangement - ureidopeptides

• References and Notes

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• 24 General Procedure for the Synthesis of N ^α-Boc/Cbz/Fmoc-Ureidopeptides 5 Oxalyl chloride (1.0 equiv) was added to a solution of diphenylcyclopropenone (1.1 equiv) in CH₂Cl₂ at r.t. After gas evolution had ceased, a solution of N^α-protected amino acid (1.0 equiv) and DIPEA (2.2 equiv) in CH₂Cl₂ was added at –15 °C followed by stirring for 5 min, TMSN₃ (1.5 equiv) was added to the reaction mixture. After stirring for an additional 5–10 min, toluene was added to the reaction mixture which was subjected to ultrasonication at 45 °C for about 20 min followed by addition of amino acid methyl ester, and the ultrasonication was continued until completion of the reaction. The solvent was removed in vacuo. The residue was washed with citric acid (10%) and NaHCO₃ (10%) solutions and triturated 2–3 times with Et₂O (5 mL) and filtered. The solid obtained was then recrystallized using DMSO–H₂O (8:2). The diphenylcyclopropenone was also recovered from ether layer and reused.
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• 26 The possibility of the epimerization for the two epimeric ureidopeptides was analyzed through ¹H NMR spectroscopy, which were prepared from Boc-(l)-Phe-OH and optically pure (R)-(+)- and (S)-(–)-1-phenylethylamine using the present method. The ¹H NMR spectra of Boc-(l)-Phe-Ψ(NHCONH)-(R)-(+)-1-phenylethylamine (5k) and Boc-(l)-Phe-Ψ(NHCONH)-(S)-(–)-1-phenylethylamine (5l) contained the (R)- and (S)-1-phenylethylamine methyl group doublet at δ = 1.28, 1.30 and 1.25, 1.27 ppm, respectively. Whereas Boc-(l)-Phe-Ψ(NHCONH)-(R,S)-(±)-1-phenylethylamine (5k + 5l) contained two separate doublets at δ = 1.25, 1.27, 1.28, 1.30 ppm for (R,S)-(±)-1-phenylethylamine methyl groups (Figure 1). This clearly indicates that the present protocol is free of epimerization.
• 27 Selected Spectroscopic Data
  Fmoc-Ile-N₃ (2a)²³ Yield 94%; mp 152 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.88–0.92 (m, 3 H), 1.02–1.37 (m, 5 H), 1.87–1.99 (m, 1 H), 4.45–4.49 (m, 2 H), 4.54 (d, J = 6.3 Hz, 2 H), 5.14 (s, 1 H), 7.29–7.80 (m, 8 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 11.62, 15.10, 25.71, 30.03, 47.57, 55.82, 67.09, 120.49, 125.76, 127.67, 128.29, 141.58, 144.27, 156.63, 180.03. HRMS: m/z calcd for C₂₁H₂₂N₄NaO₃: 401.1590; found: 401.1596 [M + Na]⁺. (Z)-Ala-Ψ[NH-CO-NH]-Gly-OMe (3h)²³ Yield 91%; mp 141–143 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.40 (d, J = 7.7 Hz, 3 H), 3.57 (s, 3 H), 4.45 (d, J = 6.5 Hz, 2 H), 5.13 (s, 2 H), 5.01–5.06 (m, 1 H), 5.66 (br, 1 H), 6.50 (br, 2 H), 7.22–7.38 (m, 5 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 21.56, 41.23, 51.49, 59.78, 64.94, 127.43, 127.61, 128.57, 137.22, 155.07, 156.28, 171.75. HRMS: m/z calcd for C₁₄H₁₉N₃NaO₅: 332.1222; found: 332.1225 [M + Na]⁺. Boc-Ser(Bn)-Ψ[NH-CO-NH]-Gly-OMe (5j)²⁴ Yield 87%; mp 133 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.34 (s, 9 H), 3.44–3.48 (m, 2 H), 3.62 (s, 3 H), 3.84 (d, J = 6.9 Hz, 2 H), 4.49 (s, 2 H), 4.94–4.97 (m, 1 H), 5.78 (br, 1 H), 6.48 (br, 1 H), 6.54 (br, 1 H), 7.26–7.38 (m, 5 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 28.63, 45.51, 53.56, 71.57, 76.61, 77.45, 78.77, 126.61, 127.36, 128.53, 138.14, 156.38, 157.25, 171.35. HRMS: m/z calcd for C₁₈H₂₇N₃NaO₆: 404.1798; found: 404.1797 [M + Na]⁺.