Passerini multicomponent reaction of protected α-aminoaldehydes as a tool for combinatorial synthesis of enzyme inhibitors

Abstract

Three-component Passerini condensation of N-Boc-a-aminoaldehydes with various isocyanides and carboxylic acids leads, after Boc-deprotection/transacylation, to complex peptide-like structures containing an a-hydroxy-b-aminoacid unit or, after oxidation, an a-oxo-b-aminoacid unit.Isocyanide employing multicomponent reactions have emerged as very powerful tools for the combinatorial synthesis of various pharmacologically important derivatives. 1 Of the two classical reactions belonging to this family, the Ugi condensation has been more widely studied and used in the generation of chemical libraries. On the other hand, the Passerini reaction, although older, has been employed less in combinatorial chemistry. 2 The reasons for this lower success are associated with the fact that a four-component condensation (Ugi) introduces a higher degree of diversity than a three-component one (Passerini). Moreover, the two amide bonds that link the components in Ugi adducts are more suitable for the synthesis of peptidomimetics, than the combination of one ester and one amide bond produced in the Passerini reaction. Finally, intramolecular variants declass the Passerini process to a twocomponent reaction, making it less suited for combinatorial chemistry.In this work we show that, when protected a-aminoaldehydes are employed in Passerini condensation, a simple rearrangement of the reaction products allows an easy combinatorial entry to peptide-like structures, making this old methodology more valuable, particularly in the field of peptidomimetics and enzyme inhibitors.The general strategy is depicted in Scheme 1 and involves condensation of N-Boc protected a-aminoaldehydes 1 with various isocyanides and various carboxylic acids, followed by one-pot Boc deprotection and acyl migration. This two step protocol gives rise to complex peptide-like substances 3 possessing a central a-hydroxy-b-aminoacid unit. This type of monomer has been widely used in the synthesis of enzyme inhibitors. 3 Moreover, a simple oxidation will produce oligopeptides 4 containing an a-oxo-b-aminoacid unit, which is an even more attractive structure, thanks to its similarity with protease transition state. 4 Only two examples of Passerini reactions involving protected a-aminoaldehydes have been reported previously. 5 In one case, however, 5a the carboxylic component was not retained during course of the synthesis; in the other case the yields were low and no further manipulation of the condensation adduct was attempted. 5b

Asymmetric Multicomponent Reactions (AMCRs): The New Frontier

“…[91] A comprehensive study of the Passerini reaction has been performed with the a-aminoaldehydes 57 derived from natural amino acids. [92] The results were very homogeneous, independently of the carboxylic acid or isocyanide reagents used, and the aldehyde side chain was found to have little influence on the diastereoselectivity (Scheme 23). This strategy has been applied to the solid-phase synthesis of different oligopeptides by using a supported isocyanide and a chiral phenylalaninal derivative; the diastereoselectivity was appreciably lower than for the reaction in solution.…”

Coupling Isocyanide-Based Multicomponent Reactions with Aliphatic or Acyl Nucleophilic Substitution Processes

“…51 In addition, complete retention of configuration at the stereogenic center of the aldehyde was observed. Also enantiomerically pure isocyanoacetates 52,53 or isocyanoacetamides 54 can be used in this reaction.…”

A New Highly Convergent Entry to Densely Functionalized Aziridines Based on the Ugi Reaction

“…The formation of 15 from 11 is puzzling: while oxygen to nitrogen acyl migrations are quite frequent in the manipulation of Passerini products [11], the transamidation in Ugi derivatives is expected to be kinetically and thermodynamically disfavored (at least under basic conditions). Although such a process is documented under acid conditions with aromatic amides or on N-acylprolinols [12], the same behavior under neutral and even basic conditions is less intelligible.…”