Isocyanides are a very special class of organic compounds, which may behave as acyl anion equivalents. However, with very few exceptions, isocyanides do not react with carbonyl compounds in the absence of an acid. In this chapter, all reactions of a carbonyl compound or an acetal with an isocyanide are considered. These are processes that frequently, but not invariably, result in the incorporation of an acid residue in the final product. In the classic Passerini reaction, discovered in 1921 by Mario Passerini, the acid is always a carboxylic acid and the products alpha‐acyloxy amides. A more recent variation, which is often referred to as the Passerini reaction as well, employs a variety of mineral (H+) or Lewis acids (LA) to afford alpha‐hydroxy amides. These compounds may also be formed in the presence of carboxylic acids such as formic acid or trifluoracetic acid. Interactions of isocyanides with carbonyl compounds and some protic or Lewis acids can also lead to a large variety of products other than alpha‐hydroxy amides, including several heterocyclic systems. These Passerini‐type reactions are discussed. Acetals can also react with isocyanides in the presence of Lewis acids. The usual products are alpha‐alkoxy amides.
The classic Passerini reaction is one of the oldest multicomponent reactions and is the first based on isocyanides to be discovered. This method is experiencing a growing interest. Its scope has been expanded by employing bifunctional substrates able to undergo secondary reactions. In this way, a larger variety of products can be synthesized and complex biologically active substances can be accessed quickly. Modifications that form products different from alpha‐acyloxy amides or alpha‐hydroxy amides, especially those leading to heterocycles, may find useful applications in synthesis.
A highly diastereoselective Ugi reaction involving a chiral cyclic imine, two enantiomerically pure isocyanides and various carboxylic acids was employed for the synthesis of polyfunctionalized pyrrolidines. Both chiral substrates have been efficiently prepared by chemoenzymatic methodologies from readily available achiral substrates. This highly convergent approach can find an application in the fragment-based drug discovery process.
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.
This account summarizes the results of studies carried out by the authors during the last 10 years aimed at expanding the utility of the venerable Passerini and Ugi reactions. Particular emphasis is given to efforts that focus on coupling these processes with post-condensation, intramolecular, aliphatic nucleophilic substitution and acyl nucleophilic substitution reactions. The methodologies developed in these investigations serve as the basis for short sequences for the preparation of a diverse number of interesting drug-like structures.
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.
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