Synlett 2017; 28(15): 1929-1933
DOI: 10.1055/s-0036-1588480
cluster
© Georg Thieme Verlag Stuttgart · New York

Product Selectivity in KAHA Ligations: Ester vs. Amide Formation with Cyclic Hydroxylamines

Florian Rohrbachera, Simon Baldaufa, Thomas G. Wucherpfenniga, Jeffrey W. Bode*a, b
  • aLaboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland   Email: bode@org.chem.ethz.ch
  • bInstitute of Transformative Bio-Molecules (WPI–ITbM), Nagoya University, Chikusa, Nagoya 464-8602, Japan
This work was supported by the Swiss National Science Foundation (150073, 169451)
Further Information

Publication History

Received: 30 April 2017

Accepted after revision: 04 June 2017

Publication Date:
19 July 2017 (eFirst)

Published as part of the Cluster Recent Advances in Protein and Peptide Synthesis

Abstract

Cyclic hydroxylamines form esters instead of the expected amides as major product upon reaction with α-ketoacids. In this report, we document a systematic investigation into the effect of the hydroxylamine structure and the solvent mixture on the product ratio of amides vs. ester in the KAHA ligation. We show that the ratio is almost exclusively determined by the structure of the hydroxylamine, with only minor contributions from the reaction solvent or the structure of the α-ketoacid.

Supporting Information

 
  • References and Notes

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  • 2 Dawson PE. Muir TW. Clark-Lewis I. Kent SB. Science 1994; 266: 776

    • Other amide-forming ligations include the serine/threonine ligation (a) and the traceless Staudinger ligation (b):
    • 3a Zhang Y. Xu C. Lam HY. Lee CL. Li X. Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 6657
    • 3b Kleineweischede R. Hackenberger CP. R. Angew. Chem. Int. Ed. 2008; 47: 5984
  • 4 Pattabiraman VR. Ogunkoya AO. Bode JW. Angew. Chem. Int. Ed. 2012; 51: 5114
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  • 6 Pusterla I. Bode JW. Nat. Chem. 2015; 7: 668
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  • 8 Pusterla I. Bode JW. Angew. Chem. Int. Ed. 2012; 51: 513
  • 9 Chéron N. Ramozzi R. Kaïm LE. Grimaud L. Fleurat-Lessard P. J. Org. Chem. 2012; 77: 1361
  • 10 General Procedure for KAHA Ligations Ketoacid (1.00–2.00 equiv) and hydroxylamine (1.00–2.00 equiv) were dissolved in 8:2 DMSO/H2O (20–100 mM) and heated to 60 °C for 12 h. Reaction progress was monitored by analytical HPLC (Shiseido Capcell Pak UG80 C18 column (4.6 × 250 mm), heated to 60 °C, 30–70% MeCN in 20 min). The crude reaction was directly purified by preparative HPLC (Shiseido Capcell Pak MGII C18 column, 20 × 250 mm, r.t., 40–90% MeCN with 0.1% TFA in 20 min, flow rate 10 mL/min). Typical Analytical Data N-(3-Hydroxypropyl)-3-(4-nitrophenyl)propanamide (Amide-24) 1H NMR (600 MHz, CDCl3): δ = 8.14–8.10 (m, 2 H, CH), 7.38–7.34 (m, 2 H, CH), 6.07 (br s, 1 H, NH), 3.54 (t, J = 5.6 Hz, 2H, CH2), 3.37 (q, J = 6.1 Hz, 2 H, CH2), 3.13 (br s, 1 H, OH), 3.07 (t, = 7.5 Hz, 2 H, CH2), 2.53 (t, J = 7.5 Hz, 2 H, CH2), 1.66–1.59 (m, 2 H, CH2). 13C NMR (150 MHz, CDCl3): δ = 172.4 (CO), 148.8 (C), 146.7 (CNO2), 129.4 (CH), 123.9 (CH), 59.6 (CH2), 37.5 (CH2), 36.7 (CH2), 32.1 (CH2), 31.4 (CH2). ESI-HRMS: m/z calcd for C12H17N2O4 [M + H]+: 253.1183; found: 253.1183. 3-{[3-(4-Nitrophenyl)propanoyl]oxy}propan-1-aminium 2,2,2-trifluoroacetate (Ester-24) 1H NMR (600 MHz, (D3C)2SO): δ = 8.19–8.14 (m, 2 H, CH), 7.73 (br s, 3 H, NH3 +), 7.56–7.51 (m, 2 H, CH), 4.06 (t, J = 6.3 Hz, 2 H, CH2), 3.00 (t, J = 7.5 Hz, 2 H, CH2), 2.82 (t, J = 7.4 Hz, 2 H, CH2), 2.73 (t, J = 7.5 Hz, 2 H, CH2), 1.88–1.80 (m, 2 H, CH2). 13C NMR (150 MHz, (D3C)2SO): δ = 171.9 (CO), 157.9 (q, J = 32.0 Hz, CF3 COO), 148.9 (C), 146.1 (CNO2), 129.7 (CH), 123.5 (CH), 117.36 (q, J = 301 Hz, CF3), 61.3 (CH2), 36.2 (CH2), 34.1 (CH2), 29.9 (CH2), 26.3 (CH2). ESI-HRMS: m/z calcd for C12H17N2O4 [M + H]+: 253.1183; found: 253.1186.