Synthesis of rigid tryptophan mimetics by the diastereoselective Pictet-Spengler reaction of ß³-homo-tryptophan derivatives with chiral α-amino aldehydes.

The Pictet-Spengler (PS) cyclizations of ß(3)-hTrp derivatives as arylethylamine substrates were performed with L-α-amino and D-α-amino aldehydes as carbonyl components. During the PS reaction, a new stereogenic center was created, and the mixture of cis/trans 1,3-disubstituted 1,2,3,4-tetrahydro-ß-carbolines was obtained. The ratio of cis/trans diastereomers depends on the stereogenic centre of used amino aldehyde and the size of substituents. It was confirmed by 1H and 2D NMR (ROESY) spectra. The conformations of cyclic products were studied by 2D NMR ROESY spectra. Products of the PS condensation after removal of protecting group(s) can be incorporated into a peptide chain as tryptophan mimetics with the possibility of the ß-turn induction.

Peptides and peptidoaldehydes as substrates for the Pictet-Spengler reaction.

The Pictet-Spengler (PS) reaction was performed with various types of substrates: H-Trp-OMe and dipeptides with N-terminal Trp as arylethylamine components and Z-protected amino aldehydes and peptidoaldehydes as carbonyl components. We found that the C-terminal part of Trp derivatives did not have any influence on the stereoselectivity of the reaction and the results are the same for simple esters of Trp and dipeptides. On the contrary, the selectivity of the PS reaction with peptidoaldehydes with L configuration of the C-terminus residue is totally different from that obtained with simple L-amino aldehydes. It allows us to obtain cis stereoisomers, which cannot be isolated from the reaction with amino aldehydes. But the utility of the peptidoaldehydes as substrates for the PS reaction is reduced by the side formation of enamides which decrease the yield of cyclization.