Four-component condensation (Ugi reaction) at high pressure: novel synthesis of peptides containing very bulky α,α-disubstituted glycines

Synthesis of Tripeptides Containing α,α-Diphenylglycine by the Modified Ugi Reaction

“…8 However, tripeptides, in the middle of which Dph is contained, such as 7 , were found to be hardly obtained by these coupling methods, particularly in the cases when the AAs are bulky. On the other hand, removal of an N -benzyl group by catalytic hydrogenolysis from the tripeptide containing an N -benzyl-Dph residue obtained in the previous study 4 gave a sluggish reaction and complicated by-products.…”

“…Takashi Yamada,* Yuichiro Omote, Yoshinori Yamanaka, Toshifumi Miyazawa, Shigeru Kuwata Previously we revealed that using high pressure conditions can effectively accelerate sluggish peptide-bond formation on sterically crowded substrates. 11 Hence, in this study the above reactions were also performed at high pressure, 0.9 GPa (9 kbar), using a stainless steel high pressure apparatus 4 . However, the yields at high pressure did not exceed those at atmospheric pressure (Table 1).…”

“…1,2 In order to overcome these difficulties, we recently applied high pressure conditions (9 kbar) to the Ugi reaction, 3 particularly to the modified Ugi reaction in which Schiff's bases prepared from amine and ketone components were used, and, thereby, we succeeded in synthesizing tripeptides containing the α,α -diisopropylglycine (Dip) residue. 4 α , α -Diphenylglycine (Dph), one of the DSGs, is of interest as a very crowded, aromatic amino acid; α,α -dibenzylglycine (Dbz) is also of interest. 5,7 Although Dph is commercially available, the only Dph-containing peptide so far reported is a Dph-Gly segment.…”

Multicomponent Cascade Reactions of Unprotected Ketoses and Amino Acids – Access to a Defined Configured Quaternary Stereogenic Center

“…3 Moreover, to avoid side reactions, ketones were transformed into the corresponding imines in a separate step. 4 Also few multicomponent reactions of unprotected amino acids with aldehydes and isocyanides were reported. 5 Reports on multicomponent reactions of ketones and unprotected amino acids are rare.…”

Ugi Reaction on α-Phosphorated Ketimines for the Synthesis of Tetrasubstituted α-Aminophosphonates and Their Applications as Antiproliferative Agents

“…In addition, the use of ketones or ketimines as substrates in such reactions, in order to generate structures bearing tetrasubstituted carbons, entails additional obstacles, since the inherent steric factors observed in these systems enhance the difficulty level in these synthetic methodologies [ 23 ]. In addition, the use of acyclic ketones typically requires preformation of the imine intermediate in a separate step, and the yields of the Ugi are often modest [ 24 , 25 , 26 ].…”