A short, two-step approach to the synthesis of diazepane or diazocane systems, based on a Ugi multicomponent reaction followed by a subsequent intramolecular SN2 reaction was studied. 1-sulfonyl tetrahydrobenzo[e]-1,4-diazepin-1-ones 1 were obtained in very high yield through a Ugi multicomponent reaction followed by Mitsunobu cyclization. On the other hand, aliphatic 1-sulfonyl 1,4-diazepan-5-ones 2 could be obtained employing different cyclization conditions (sulfuryl diimidazole). A similar approach toward diazocane rings using hydroxamates as nucleophiles was less successful, affording only O-cyclized adducts or unexpected side products. A mechanistic explanation of the observed outcomes is proposed.
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
This paper describes the synthesis of a bicyclic beta-amino acid scaffold in both pure enantiomeric forms and its application as chiral auxiliary in an intramolecular version of the Ugi multicomponent reaction (U-5C-4CR) to prepare alpha-amino acid derivatives of both D- and L-series in a straightforward and very stereoselective manner. The mild conditions required for the Ugi condensation and for the removal of the chiral auxiliary make this method very attractive to prepare a wide range of differently structured N-alkylated and unalkylated amino acid derivatives.
Research progress is often promoted by unexpected results that open the way to new scenarios. In this communication, an unprecedented condensation of arylacetic acids and isocyanides and the unusual base-mediated rearrangement of the resulting products to give two novel classes of polysubstituted pyrrolones and pyrrolidinediones are reported.
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