Passerini reaction/amine deprotection/acyl migration

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). 

S. Fame, T. Hjehngaard, S. P. Roche, D. J. Aitken, Org. Lett. 2009, 11, 1167-1170. Passerini reaction-amine deprotection-acyl migration peptide assembly efficient formal synthesis of cyclotheonamide C. 

More recently, Aitken and coworkers described a short and convergent formal total synthesis of cyclotheonamide C using a process that involves a Passerini reaction, amine deprotection, and an acyl migration (PADAM sequence. Scheme 22) [90]. The key linear pentapeptide 22e is obtained by a Passerini reaction of isocyanide a, Fmoc-amino aldehyde b, and Boc-dipeptide acid e followed by Fmoc removal and consequently 0,N-acyl migration [91]. The macrocyclization was achieved with TBTU and HOBt after Boc and fBu removal in good yield (52%) to furnish intermediate f. 

In this context, and more recently, an interesting application of this methodology has been described by Faure, Aitken, and coworkers. Thus, they applied PADAM methodology (three-component Passerini reaction-amine deprotection-0,N-acyl migration) as key synthetic step of the linear pentapeptide intermediate in the formal total synthesis of cyclotheonamide C 54, a potent inhibitor of serine protease such as thrombin belonging to a family of cyclic pentapeptides with potential biological activities (Scheme 8.19) [47]. 

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