Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000083.xml
Synlett 2017; 28(15): 1929-1933
DOI: 10.1055/s-0036-1588480
DOI: 10.1055/s-0036-1588480
cluster
Product Selectivity in KAHA Ligations: Ester vs. Amide Formation with Cyclic Hydroxylamines
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 (online)
![](https://www.thieme-connect.de/media/synlett/201715/lookinside/thumbnails/st-2017-w0309-c_10-1055_s-0036-1588480-1.jpg)
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
- Supporting information for this article is available online at https://doi.org/10.1055/s-0036-1588480.
- Supporting Information
-
References and Notes
- 1 Bode JW. Fox RM. Baucom KD. Angew. Chem. Int. Ed. 2006; 45: 1248
- 2 Dawson PE. Muir TW. Clark-Lewis I. Kent SB. Science 1994; 266: 776
- 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
- 5 Wucherpfennig TG. Rohrbacher F. Pattabiraman VR. Bode JW. Angew. Chem. Int. Ed. 2014; 53: 12244
- 6 Pusterla I. Bode JW. Nat. Chem. 2015; 7: 668
- 7 Rohrbacher F. Deniau G. Luther A. Bode JW. Chem. Sci. 2015; 6: 4889
- 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, J = 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.
Other amide-forming ligations include the serine/threonine ligation (a) and the traceless Staudinger ligation (b):