Peptides and peptidoaldehydes as substrates for the Pictet–Spengler reaction

Abstract

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.

Synthesis of rigid tryptophan mimetics by the diastereoselective Pictet-Spengler reaction ofβ3-homo-tryptophan derivatives with chiralα-amino aldehydes

“…The reactions with D‐amino aldehydes were totally selective, and only cis diastereoisomer was formed. The comparison of these results with the study conducted under the same conditions with α ‐Trp derivatives and L‐amino and D‐amino aldehydes shows that the ratio of cis/trans diastereoisomers is very similar . These and our previous results showed that the ratio of cis/trans diastereomers depended on the stereogenic centre of amino aldehyde.…”

“…The pseudo 10‐membered ring often, but not always, is formed by an intramolecular hydrogen bond between the CO of the first residue ( i ) and the NH of the fourth residue ( i + 3 ). According to literature and our previous study , it is considered that disubstituted 6‐membered rings in tetrahydro‐ β ‐carboline can induce β ‐turns. Such structures are more commonly found in trans isomers; therefore, we speculate that it is possible that trans analogs 6a‐h and 7a‐4 can have the ability to form β ‐turns.…”

“…α-Amino aldehydes protected by a benzyloxycarbonyl group (Z), were prepared with good yields via the Ferentz-Castro procedure [36] and used instantly without purification to avoid racemization. The PS cyclizations of different L-β 3 -homo-tryptophan derivatives with L-α-amino and D-α-amino aldehydes were performed in the presence of 5 equivalents of TFA and at low temperature to avoid racemization of chiral amino aldehydes (Scheme 1) [17,24,[37][38][39]. The reaction was stirred at À40°C for the first 5 h, and then stirring was continued at room temperature overnight.The ratio of stereoisomers was determined by 1 H NMR spectra of the crude mixture after the reaction.…”

The Pictet-Spengler Reaction Updates Its Habits

“…N-substituted aryl ethylamines 20 [27,31,35,36,39,40], allene-containing-tryptophan 21 [42], trifluoromethylated precursors 22 [55], and spirocyclic lactams embodying Trp 23 [56] were the most interesting amine substrates. Conversely, isatins 24 [44][45][46], enaminone 25 [52], (S)-2,3-Oisopropylidene-L-glyceraldehyde 26 [53], pyridoxal 27 [60], L/D-amino aldehydes 28 [57,63], and 11 C-labeled formaldehyde 29 [58] were the most notable carbonyl components (Figure 1). We wish to highlight few papers concerning the P-S cyclization of THIQs [32][33][34][35][36] and THBCs [38,43,51,55].…”

“…Chiral catalysts derived from BINOL [40,44,45] and SPINOL [49] (phosphoric acids and thiourea derivatives) stand out among the usual Brønsted acids: TFA [35,42,47,57], HCl [58], 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) [59], 2,4,6-trichloro-1,3,5-triazine (TCT) [54], H 2 SO 4 [50], MeSO 3 H [52], TsOH [58], and mild catalysts, such as phosphate buffer [30,39] and microwave irradiation [61].…”