Pentaerythrityltetramine scaffolds for solid-phase combinatorial chemistry.
Straightforward synthesis for two pentaerythrityltetramine precursors, 2,2-bis(azidomethyl)propane-1,3-diamine (1) and 2-[N-(allyloxycarbonyl)aminomethyl]-2-azidomethylpropane-1,3-diamine (2), has been described. Both propane-1,3-diamines have been attached by reductive amination to a solid-supported backbone amide linker derived from 4-(4-formyl-3,5-dimethoxyphenoxy)butyric acid. The presence of the two methoxy substituents on the linker is essential to avoid cross-linking between two linkers. The remaining free primary amino group of the propane-1,3-diamine moiety may then be selectively acylated with an appropriately protected amino acid using conventional N,N-dicyclohexylcarbodiimide/1-hydroxybenzotriazole (DCC/HOBt) activation without any interference by the secondary amino function. The latter group may be subsequently acylated by an anhydride method. Sequential reduction of the azido group and removal of the allyloxycarbonyl protection from 2 allow further coupling of two different amino acids, and hence, this handle may be utilized in construction of branched structures containing four different amino acids or peptides. Solid-supported 1 may, in turn, be used for the synthesis of similar constructs containing two identical branches. It is worth noting that no acid-labile protecting groups are required in this approach, and hence, this dimension may be saved for the cleavage of the linker. The applicability of the scaffolds to library synthesis has been demonstrated by preparation of 11 pentaerythrityl-branched tetra- and octapeptides.
Virta
Pasi
P
Department of Chemistry, University of Turku, FIN-20014 Turku, Finland. pasi.virta@utu.fi
Leppänen
Marika
M
Lönnberg
Harri
H
D000588:Amines / Q000737:chemistry*; D000596:Amino Acids / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques; D006571:Heterocyclic Compounds / Q000138:chemical synthesis*; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis; D010084:Oxidation-Reduction; D011409:Propylene Glycols / Q000737:chemistry*
D000588:Amines; D000596:Amino Acids; D006571:Heterocyclic Compounds; D009842:Oligopeptides; D011409:Propylene Glycols; C008783:pentaerythritol