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Synlett 2014; 25(07): 1001-1005
DOI: 10.1055/s-0033-1340864
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© Georg Thieme Verlag Stuttgart · New York

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

Nageswara Rao Panguluri
109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar Veedhi, Bangalore University, Bangalore 560 001, India   Fax: +91(80)22292848   Email: hariccb@gmail.com   Email: hariccb@hotmail.com   Email: sureshbabuvommina@rediffmail.com
,
M. Samarasimhareddy
109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar Veedhi, Bangalore University, Bangalore 560 001, India   Fax: +91(80)22292848   Email: hariccb@gmail.com   Email: hariccb@hotmail.com   Email: sureshbabuvommina@rediffmail.com
,
C. Madhu
109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar Veedhi, Bangalore University, Bangalore 560 001, India   Fax: +91(80)22292848   Email: hariccb@gmail.com   Email: hariccb@hotmail.com   Email: sureshbabuvommina@rediffmail.com
,
Vommina V. Sureshbabu*
109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar Veedhi, Bangalore University, Bangalore 560 001, India   Fax: +91(80)22292848   Email: hariccb@gmail.com   Email: hariccb@hotmail.com   Email: sureshbabuvommina@rediffmail.com
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Further Information

Publication History

Received: 05 December 2013

Accepted after revision: 04 February 2014

Publication Date:
14 March 2014 (online)

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Abstract

Rapid synthesis of acid azides via in situ generation of acid chlorides using CPICl as chlorinating agent from the corresponding Nα-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

Nα-protected amino acids - CPICl - acid chlorides - acid azides - Curtius rearrangement - ureidopeptides

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    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
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  • 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 Nα-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.
  • 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]+.