Peptidomimetics Passerini reactions

Most attempts to construct diastereoselective variants of the Passerini reaction have met with a certain degree of failure. Undoubtedly, the numerous uncertainties of the reaction mechanism have contributed to these difficulties. The usual low levels of control for the Passerini reaction have also impeded efforts to establish empirical trends in the diastereofacial selectivity. This is exemplified in the construction of peptidomimetics, a class of molecules which has stimulated numerous applications of the Passerini reaction, where the diastereoselectivity is typically in the range of 1 1 to 4 1, A survey of results of the diastereofacial selectivity of carbonyl addition does not consistently follow a clear trend of either the Felkin-Anh or chelation-controlled models of carbonyl addition. ... 

Many protease/peptidase inhibitor peptidomimetics include a-ketoamide moieties as key bioactive functionalities and the Passerini reaction provides a facile entry for their preparation through the oxidation of a-hydroxy amides. Researchers at Schering-Plough have utilized this strategy to synthesize a variety of a macrocyclic a-ketoamides towards the development of Hepatitis C virus (HCV) NS3 protease inhibitors. Aldehyde 56 was treated with allylisocyanide and acetic acid to give a-acyloxyamide... 

A potentially useful synthetic extension in this area of research has been the Passerini reaction-amine deprotection-acyl migration (PADAM) sequence, first conceived as a tool for giving access to peptide-like structures [40] and mainly developed by Banfi, Riva, and coworkers [2a]. In this sense, PADAM sequence has been employed for the synthesis of interesting peptidomimetics since the resulting a-ketoamide scaffolds are useful for drug discovery [41] or in the synthesis of enzyme inhibitors [42], and this amplifies the scope of this valuable multicomponent process [43] (Fig. 8.4). 

The sequential use of the organocatalytic a-amination of aldehydes by azodicar-boxylates with another process has provided a useful tool for the synthesis of complex molecules. Thus, the combination of the amination of linear aldehydes catalyzed by (5)-proline (20) and the Passerini reaction allowed the rapid access to norstatine based peptidomimetics albeit with low diastereoselectivities (36-98% yield, up to 4 1 dr) [27]. Moreover, the enantioselective synthesis of y-amino-a,P-unsaturated esters can be performed via the sequential a-amination-Homer-Wadsworth-Emmons olefination of aldehydes catalyzed by (5)-proline (20,10mol%) affording the expected products in high yields and enantioselectivities (85-90% yield, ee 92-99%) [28]. 

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