The Efficient Preparation of Di- and Tripeptides by Coupling N-(Cbz- or Fmoc-α-aminoacyl)benzotriazoles with Unprotected Amino Acids

Alan R. Katritzky; Parul Angrish; Kazuyuki Suzuki

doi:10.1055/s-2006-926287

PAPER

The Efficient Preparation of Di- and Tripeptides by Coupling N-(Cbz- or Fmoc-α-aminoacyl)benzotriazoles with Unprotected Amino Acids

Alan R. Katritzky*, Parul Angrish, Kazuyuki Suzuki
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
Fax: +1(352)3929199; e-Mail: katritzky@chem.ufl.edu;

Abstract

All articles of this category

Abstract

N-(Cbz- or Fmoc-α-aminoacyl)benzotriazoles 2 and N-protected peptidoylbenzotriazoles 6 are coupled in aqueous acetonitrile solution with free amino acids or dipeptides to prepare: (i) 22 chirally pure dipeptides 5a-v (in an average yield of 82%) from N-(Cbz- or Fmoc-α-aminoacyl)benzotriazoles 2 and unprotected amino acids, (ii) five chiral tripeptides 7a-e (in an average yield of 75%) from N-protected peptidoylbenzotriazoles 6 and unprotected amino acids, (iii) one chiral tripeptide 7g (62%) from N-(Cbz- or Fmoc-α-aminoacyl)benzotriazole 2a and the free dipeptide 8. In all, N-(Cbz- or Fmoc-α-aminoacyl)benzotriazole derivatives of 17 of the 20 naturally occurring amino acids were used, including those containing the following unprotected side chain functionalities: alcoholic -OH (Ser), indole -NH (Trp), imidazole -NH, phenolic -OH (Tyr), -CONH₂ (Gln, Asn), -SH (Cys), -CO₂H (Glu, Asp), and -S-S (Cystine). Support for the complete retention of chirality was obtained by parallel experiments involving d-Ala, l-Ala, and dl-Ala for the preparation of di- and tripeptides. This and other evidence for chiral integrity was supported by NMR and HPLC analyses.

Key words

N-(protected α-aminoacyl)benzotriazole - acylating reagent - dipeptides - N-Cbz-peptidoylbenzotriazole - tripeptides

Full Text

References

<A NAME="RM02505SS-1A">1a</A> Gross M. Meienhofer J. The Peptides Academic Press; New York: 1979.

<A NAME="RM02505SS-1B">1b</A> Goodman M. Felix A. Moroder L. Toniolo C. Synthesis of Peptides and Peptidomimetics, In Science of Synthesis Vol. E22a and E22b: Georg Thieme Verlag; Stuttgart, New York: 2001.

<A NAME="RM02505SS-1C">1c</A> Sheppard RC. Amino-acids, Peptides, and Proteins Vol. 10: The Chemical Society; London: 1977.

<A NAME="RM02505SS-1D">1d</A> Bodanszky M. Klausner YS. Ondetti MA. Peptide Synthesis 2nd ed.: John Wiley and Sons; New York: 1976.

<A NAME="RM02505SS-1E">1e</A> Wipf P. Chem. Rev. 1995, 95: 2115

<A NAME="RM02505SS-1F">1f</A> Humphrey JM. Chamberlin AR. Chem. Rev. 1997, 97: 2243

<A NAME="RM02505SS-1G">1g</A> Fletcher MD. Campbell MM. Chem. Rev. 1998, 98: 763

<A NAME="RM02505SS-2">2</A> Hegarty AF. McCarthy DG. J. Am. Chem. Soc. 1980, 102: 4537

<A NAME="RM02505SS-3A">3a</A> Schmidt U. Utz R. Lieberknecht A. Griesser H. Potzolli B. Bahr J. Wagner K. Fischer P. Synthesis 1987, 236

<A NAME="RM02505SS-3B">3b</A> Hofmann K. Haas W. Smithers MJ. Zanetti G. J. Am. Chem. Soc. 1965, 87: 631

<A NAME="RM02505SS-4">4</A> Gagnon P. Huang X. Therrien E. Keillor JW. Tetrahedron Lett. 2002, 43: 7717

<A NAME="RM02505SS-5">5</A> Bauer H. Staab KH. Schneider KM. Azolides in Organic Synthesis and Biochemistry John Wiley and Sons Ltd; New York: 1998.

<A NAME="RM02505SS-6">6</A> Gross H. Bilk L. Tetrahedron 1968, 24: 6935

<A NAME="RM02505SS-7A">7a</A> Katritzky AR. He H.-Y. Suzuki K. J. Org. Chem. 2000, 65: 8210

<A NAME="RM02505SS-7B">7b</A> Katritzky AR. Yang H. Zhang S. Wang M. Arkivoc 2002, (xi): 39

<A NAME="RM02505SS-7C">7c</A> Katritzky AR. Yang B. Semenzin D. J. Org. Chem. 1997, 62: 726

<A NAME="RM02505SS-7D">7d</A> Katritzky AR. Wang M. Yang H. Zhang S. Akhmedov NG. Arkivoc 2002, (viii): 134

<A NAME="RM02505SS-7E">7e</A> Katritzky AR. Wang M. Zhang S. Arkivoc 2001, (ix): 19

<A NAME="RM02505SS-8A">8a</A> Katritzky AR. Pastor A. J. Org. Chem. 2000, 65: 3679

<A NAME="RM02505SS-8B">8b</A> Katritzky AR. Abdel-Fattah AAA. Wang M. J. Org. Chem. 2003, 68: 4932

<A NAME="RM02505SS-8C">8c</A> Katritzky AR. Abdel-Fattah AAA. Wang M. J. Org. Chem. 2003, 68: 1443

<A NAME="RM02505SS-8D">8d</A> Katritzky AR. Suzuki K. Singh SK. He H.-Y. J. Org. Chem. 2003, 68: 5720

<A NAME="RM02505SS-8E">8e</A> Katritzky AR. Suzuki K. Singh SK. Croat. Chem. Acta 2004, 77: 175

<A NAME="RM02505SS-9A">9a</A> Katritzky AR. Pastor A. Voronkov MV. J. Heterocycl. Chem. 1999, 36: 777

<A NAME="RM02505SS-9B">9b</A> Katritzky AR. Denisko OV. Fang Y. Zhang L. Wang Z. Arkivoc 2001, (xi): 41

<A NAME="RM02505SS-10A">10a</A> Katritzky AR. Suzuki K. Singh SK. Synthesis 2004, 2645

<A NAME="RM02505SS-10B">10b</A> Katritzky AR. Angrish P. Hür D. Suzuki K. Synthesis 2005, 397

<A NAME="RM02505SS-11A">11a</A> Fredrich J. Young EA. J. Med. Chem. 1964, 44: 820

<A NAME="RM02505SS-11B">11b</A> Fredrich J. Young EA. Bowen DO. J. Med. Chem. 1965, 56: 274

<A NAME="RM02505SS-11C">11c</A> Kunz H. Buchholz M. Chem. Ber. 1979, 112: 2145

<A NAME="RM02505SS-11D">11d</A> Iwamura M. Hodota C. Ishibashi M. Synlett 1991, 35