Synthesis of libraries of thiazole, oxazole and imidazole-based cyclic peptides from azole-based amino acids. A new synthetic approach to bistratamides and didmolamides

Abstract

Treatment of a 1 : 1 mixture of the thiazole-based amino acids 8a and 8b with FDPP-i-Pr(2)NEt in CH(3)CN gave a mixture of the cyclic trimers 14, 15, 16 and 17 and the cyclic tetramers 19 and 23 in the ratio 2 : 7 : 5 : 8 : 1 : 1 and in a combined yield of 70%. Separate coupling reactions between the bisimidazole amino acid 45 and the thiazole/oxazole amino acids 43a and 42a in the presence of FDPP-i-Pr(2)NEt led to the bisimidazole based cyclic trimers 55 and 57 respectively (54-57%) and to the cyclic tetramer 56 (8-11%). Similar coupling reactions involving the bisthiazole and bisoxazole amino acids 49 and 47 with the imidazole/oxazole/thiazole amino acids 41a, 42a and 43a gave rise to the library of oxazole, thiazole and imidazole-based cyclic peptides 58, 59, 60, 61, 62, 63, 64 and 65. A coupling reaction between the bisthiazole amino acid 49 and the oxazole amino acid 73 led to an efficient (36% overall) synthesis of bistratamide H (67) found in the ascidian Lissoclinum bistratum. Coupling reactions involving oxazolines with thiazole amino acids were less successful. Thus, a coupling reaction between the phenylalanine-based oxazoline amino acid 71a and either the thiazole amino acid 8a or the bisthiazole amino acid 74 gave only a 2% yield of the cyclic hexapeptide didmolamide A (4) found in the ascidian Didemnum molle. Didmolamide B (68) was obtained in 9% yield from a coupling reaction between 74 and the phenylalanine threonine amino acid 72, using either FDPP or DPPA.

Bistratamides M and N, Oxazole-Thiazole Containing Cyclic Hexapeptides Isolated from Lissoclinum bistratum Interaction of Zinc (II) with Bistratamide K

“…Moreover, the former biological activities could be attributable to the conformational constraints imposed by the heterocycles and their ability to bind metals or intercalate into DNA. Particularly, the antitumor activities and the potential to act as metal ion chelators have made these azole-based cyclic peptides attractive targets for total synthesis and biological evaluation [ 16 ].…”

Design and Synthesis of Selenazole‐Containing Peptides for Cocrystallization with P‐Glycoprotein

“…Corresponding thiazole analogues were also prepared by similar means. [25,26] The homochiral tri- and tetrapeptides were synthesized by one-step cyclization of the respective amino acid units. Other trimeric peptide stereoisomers were synthesized by recursive coupling of corresponding monomeric units and final macrocyclization (Scheme 2).…”

N‐Aryl Imidazole Platforms – Synthesis and Structural Investigation

“…[16,17] Beside the usage of the side chains for molecular recognition, cyclotri-and tetrameric peptides have also been used as ligands for copper(II) complexes. [19,20] The advantage of such imidazole-containing platforms relative to oxazole-and thiazole-containing scaffolds is the presence of the secondary amines, which can be easily alkylated to lead to numerous platforms with different functionalities. [19,20] The advantage of such imidazole-containing platforms relative to oxazole-and thiazole-containing scaffolds is the presence of the secondary amines, which can be easily alkylated to lead to numerous platforms with different functionalities.…”