Palladium-Catalyzed MBFTs for BRMs

In this last section, the focus shifts to intermolecular palladium-catalyzed MBFTs that are exploited for the synthesis of biologically active molecules. There are several reasons why palladium is one of the most widely employed transition metals. First, it allows facile oxidative insertion and reductive elimination. Second, palladium accepts a broad range of functional groups and its reactivity is heavily influenced by the addition of ligands. Last, by creating asymmetric catalytic complexes, stereoselective reactions are facilitated. Nevertheless, the metal is not commonly used in MBFTs for the synthesis of products that are tested for biologically activity. Therefore, only a few examples will be discussed which provide products that are currently exploited for their biological effect. 

The work of Katsumura offers a great link to the previous section by uniting three components by means of a Stifle coupling/condensation/aza-electrocyclization sequence [41]. Aiming for uleine derivatives, the greatest challenge is to control the 

The highly selective MBFT generates four new bonds - of which three remain after cleaving the auxiliary - and provides the desired product in good yield (75%). Biological tests revealed submicromolar (IC50 = 0.45 pM) activity as an acetylcholine esterase inhibitor for the parent compound uleine. It is therefore expected that derivatives exhibit similar interesting activities. 

With a similar rationale, Cai and coworkers tried to expand the product library by aiming for structural analogs of the widely applied 1,4-benzoxazepines [42]. These seven-membered rings are usually synthesized in a multistep process, but are now available from three simple starting materials in a palladium-catalyzed multicomponent approach. The reaction cascade is initiated by deprotonation and successive ring opening of the electron-poor aziridine 167 by the phenolate 168. Oxidative addition of palladium to the aryl iodide allows isocyanide insertion to furnish 172. Base-induced 

The interesting aspect of this two-bond-forming reaction is the simplicity of its use. The reaction proceeds effortlessly in 18 h under oxygen atmosphere (1 atm), using the relatively inexpensive Pd(OAc)2 (1 mol%) in a renewable solvent (MeTHF) without the need for ligands or bases. The broad range of accepted substrates allow the synthesis of amino-substituted imidazopyridines, benzoxazoles, 

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