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DOI: 10.1055/s-2006-944203
Cyclizations of α-Keto Ester Modified Aspartic Acids in Peptides
Publikationsverlauf
Publikationsdatum:
04. Juli 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
- 1
Obkircher M.Seufert W.Giese B. Synlett 2005, 1182 - 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 -
4b
Aszodi J.Chantot J.-F.Collard J.Teutsch G. Heterocycles 1989, 28: 1061 -
4c
Arnoldi A.Merlini L.Scaglioni L. J. Heterocycl. Chem. 1987, 24: 75 - 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 -
9a
Freidinger RM.Veber DF.Perlow DS.Brooks JR.Saperstein R. Science 1980, 210: 656 -
9b
Freidinger RM. J. Med. Chem. 2003, 46: 5553
References and Notes
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.
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.
6DFT 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.
8The 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.