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Synlett 2006(11): 1774-1776  
DOI: 10.1055/s-2006-944203
LETTER
© Georg Thieme Verlag Stuttgart · New York

Cyclizations of α-Keto Ester Modified Aspartic Acids in Peptides

Wolfgang Seufert, Antoine Fleury, Bernd Giese*
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax: +41(61)2670976; e-Mail: bernd.giese@unibas.ch;
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Publication History

Received 20 April 2006
Publication Date:
04 July 2006 (online)

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Abstract

Aspartic acid peptides with α-keto ester modification can cyclize to form γ-lactam derivatives. This reaction represents an easy access to conformationally restricted peptidomimetics.

Key words

α-keto ester - cyclizations - γ-lactams - diastereoselec­tivity - peptidomimetics

    References and Notes

  • 1 Obkircher M. Seufert W. Giese B. Synlett  2005,  1182 
    Thieme Connect
  • To our knowledge, such a cyclization of an amide group into an α-keto ester under basic conditions has been described only with β-lactams leading to six-membered rings:
  • 4a Bryan DB. Hall RF. Holden KG. Huffman WF. Gleason JG. J. Am. Chem. Soc.  1977,  99:  2353 
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  • 7 A similar cyclization under acidic conditions has been described recently: Takeuchi Y. Nagao Y. Toma K. Yoshikawa Y. Akiyama T. Nishioka H. Abe H. Harayama T. Yamamoto S. Chem. Pharm. Bull.  1999,  47:  1284 
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  • 9a Freidinger RM. Veber DF. Perlow DS. Brooks JR. Saperstein R. Science  1980,  210:  656 
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2

During this reaction at least four different products were formed, with 5 only as a minor component.

3

General Cyclization Procedure. The α-keto ester modified aspartic acid peptides 6-9 were dissolved in 20 mL CH2Cl2. After addition of 2 mL Et3N, the solution was stirred for 30 min at r.t. The solvents were evaporated and the residue purified by column chromatography yielding γ-lactams 10-13 as mixture of two diastereomers.
Spectroscopic Data for cis -13 (R ¹ = H) as an Example.
1H NMR (500 MHz, CDCl3): δ = 0.93 (d, J = 6.9 Hz, 3 H), 1.03 (d, J = 6.6 Hz, 3 H), 1.45 (s, 9 H), 2.14 (dd, J = 13.5, 9.3 Hz, 1 H), 2.74 (dsept, J = 9.6, 6.7 Hz, 1 H), 3.01 (dd, J = 13.5, 8.9 Hz, 1 H), 3.48 (s, 3 H), 3.63 (d, J = 9.7 Hz, 1 H), 3.83-3.86 (m, 2 H), 4.53 (m, 1 H), 4.99 (s, 1 H), 5.08 (d, J = 12.3 Hz, 1 H), 5.12 (d, J = 12.3 Hz, 1 H), 5.34 (br t, 1 H), 7.06 (d, J = 5.7 Hz, 1 H), 7.30-7.37 (m, 5 H). 13C NMR (126 MHz, CDCl3): δ = 20.1 (CH3), 21.0 (CH3), 27.8 (CH), 28.4 (CH3), 39.5 (CH2), 44.2 (CH2), 50.3 (CH), 53.6 (CH3), 61.1 (CH), 67.3 (CH2), 80.5 (C), 86.5 (C), 128.5 (CH), 128.6 (CH), 128.7 (CH), 135.4 (C), 156.2 (C), 169.7 (C), 170.5 (C), 171.5 (C), 171.5 (C). MS (ESI): m/z (%) = 560 (2) [M + K]+, 544 (100) [M + Na]+, 488 (2) [M - t-Bu + Na]+. Anal. Calcd for C25H35N3O9: C, 57.57; H, 6.76; N, 8.06. Found: C, 57.62; H, 6.75; N, 8.01.

5

The cis and trans refer to the relative configuration of the amine and the hydroxy substituent. Assignment of the diastereomers was made on the basis of NOESY experiments.

6

DFT calculations (B3LYP) indicate that the cis diastereomer A is thermodynamically slightly more stable than the trans diastereomer B. Only in the cis isomer A does an H bond (1.9 Å) between the OH and the benzyl ester exist.

8

The preferred formation of trans products under slightly acidic conditions was also observed with peptides 6 and 9. Not only acidic silica gel but also acetic acid could be used.