Control of ditryptophan cross-linking: dihydrotryptophan as a tryptophan precursor in peptide synthesis

J Pept Res. 1999 Apr;53(4):465-74. doi: 10.1034/j.1399-3011.1999.00044.x.

Abstract

In neat trifluoroacetic acid, tryptophan side chains cross-link to form a diastereomeric mixture of tryptophan dimers. Convergent oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) converts tryptophan dimers to ditryptophan. Since cross-link formation is under thermodynamic control, there has been no simple way of controlling the regiochemistry of the cross-linking process when more than one tryptophan side chain is present. Here, we show that dihydrotryptophan (Dht) can be incorporated into peptides as a tryptophan precursor, which reforms tryptophan upon treatment with DDQ. Dihydrotryptophan was prepared as a mixture of gammaS and gammaR diastereomers and the indoline nitrogen was protected with a Cbz group. The resulting amino acid, Nalpha-BOC-Dht(Cbz)-OH, was then incorporated into peptides as a mixture of diastereomers. Dht was resistant to tryptophan cross-linking in neat trifluoroacetic acid and was converted back to tryptophan during convergent oxidation of tryptophan dimers. While Dht is useful for control of ditryptophan regiochemistry and as a potential tryptophan analog, it is not a general strategy for Trp protection since DDQ is unlikely to be compatible with easily oxidized amino acids such as cysteine.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acylation
  • Cross-Linking Reagents / chemistry*
  • Oxidation-Reduction
  • Peptides / chemical synthesis*
  • Tryptophan / analogs & derivatives*
  • Tryptophan / chemistry*

Substances

  • Cross-Linking Reagents
  • N(epsilon)-carbobenzyloxy-gamma-delta(1)-dihydrotryptophan
  • Peptides
  • Tryptophan