Synthesis of 5-Substituted Thiazolyl Peptides via the Thio-Ugi Reaction

Significance

Based on previous work concerning the synthesis of unsubstituted thiazole amino acids by the reaction of isocyanoacetaldehyde ­acetal with thioacids (U. Kazmaier, S. Ackermann Org. Biomol. Chem. 2005, 3, 3184), the present paper reports the synthesis of 5-substituted thia­zole peptides via a thio-Ugi reaction, involving the combination of thiobenzoic acid 1, isobutyraldehyde or pivaldehyde 2, methyl isocyanoacetate 3 and ammonium hydroxide or benzylamine. The formed peptide acids 4 were then activated as mixed anhydrides and, upon treatment with two equivalents of an acid chloride, led to the formation of the corresponding acetylated hydroxythia­zoles 5. Both organic (acyl chlorides, chloroformates) and inorganic (phosphoryl chloride) chlorides were shown to undergo the cyclization in good to high yields towards products 5. Interestingly, by use of triflic anhydride and changing slightly the conditions, the synthesis of thiazolyl triflates 5 (R^³ = Tf) was achieved albeit in lower yield. The resulting triflates underwent Suzuki, ­Sonogashira, and Stille cross-coupling reactions in good to high yields.