Chiral Lewis Acid-catalyzed Isocyanide Alpha-addition Reaction

Catalytic asymmetricα-addtion of isocyanide to polarized multiple bond is a challenging research field, and only few successful examples have been reported so far. Isocyanide-based Passerini three-component and Ugi four-component reactions generate a new chiral center, but how to control the absolute configuration remains an unanswered question.In this thesis, we report our studies on the chiral Lewis acid catalyzed asymmetricα-addtion of isocyanides to aldehydes, especially the Passerini three-component reaction.As a prelude to the development of enantioselective isocyanide-based multicomponent reactions (IMCRs), we first performed massive screening of Lewis acids. We found that SnCl2, Sn(OTf)2, ZnCl2, AlCl3 among others can efficiently catalyze the reaction ofα-isocyanoacetamides and aldehydes to afford 5-aminooxazole in goof to excellent yields. The scope and limitation of this catalytic process was examined and mechanism of the reaction was discussed.We found that [Sn-(R)-Ph-PyBox](OTf)2 catalyzed the condensations betweenα-isocyanoacetamides and chelating aldehydes to provide the corresponding 5-aminooxazole in moderate ee. The reaction outcome turned out to be highly dependent on the reaction temperature and showed an isoinversion effect. We studied the scope of the substrate and found it was limited to the chelating aldehydes. To overome this drawback, we subsequently developed a salen Al (III) catalyzedα-addition ofα-isocyanoacetamides to aldehydes that led to 5-aminooxazole in good yield and enantioselectivity. The conditions are applicable to both aliphatic and aromatic aldehydes, chelating and non-chelating aldehydes. In general, the ee is higher for aliphatic aldehydes than for the aromatic ones. We proposed that a chiral catalyst with only one single coordination site available would be essential for the development of efficient enantioselective isocyanide-basedα-addition reactions.We described an efficient salen Al (III)-catalyzed enantioselective Passerini three-component reaction, Different reaction parameters such as temperature, concentration, and structure of catalyst were examined. Under optimal conditions, a variety of aldehydes, carboxylic acids, and isocyanides participated in the reaction to afford the expectedα-acyloxyamides in good to excellent yield and enantiomeric excess. Many functional groups are tolerated under the catalytic conditions, and can be expoited for further chemical transformations. The importance of the acid structure was noted and the absolute configuration of the Passerini-adduct was determined by comparison with the authentic samples. The chemistry described in this chapter represented the very first example of chiral Lewis acid-catalyzed truly three-component Passerini reaction. The results also laid foundation for the development of catalytic enantioselective Ugi reaction.