Gold® complexes enantioselective aldol reaction

Gold(I)-Catalyzed Aldol Reaction. In 1986 an elegant enantioselective and diastereoselective synthesis of dihydrooxazolines was reported, using the aldol reaction of an aldehyde with an a-isocyanoacetate ester (formally a Knoevenagel reaction) using a cationic gold(I) complex of (1) (eq 1). ... 

The gold(I) complex is prepared in situ by the reaction of (1) with bis(cyclohexyl isocyanide)gold(I) tetrafluoroborate (2), typically in anhydrous dichloromethane. The dihydrooxazolines obtained provide a ready access to enantiomerically pure p-hydroxy-a-amino acid derivatives. High diastereo- and enantios-electivity are generally maintained with a wide variety of substituted aldehydes, and a-isocyanoacetate esters. N,N-Dimethyl-a-isocyanoacetamides and a-keto esters have been substituted for the a-isocyanoacetate ester and aldehyde component, respectively, sometimes with improved stereoselectivity. The effect of both the central and planar chirality of (1) on the diastereo- and enantioselectivity of the gold(I)-catalyzed aldol reaction has been studied. The modification of the terminal di-alkylamino group of (1) can lead to improvements in the stereos-... 

Table 3. Diastereo- and enantioselective aldol reaction of methyl isocyanoacetate (27) with tildehydes catalyzed by chiral ferrocenylphosphine 86c gold(I) complex.

Ito and coworkers found that chiral ferrocenylphosphine-silver(I) complexes also catalyze the asymmetric aldol reaction of isocyanoacetate with aldehydes (Sch. 26) [51]. It is essential to keep the isocyanoacetate at a low concentration to obtain a product with high optical purity. They performed IR studies on the structures of gold(I) and silver(I) complexes with chiral ferrocenylphosphine 86a in the presence of methyl isocyanoacetate (27) and found significant differences between the iso-cyanoacetate-to-metal coordination numbers of these metal complexes (Sch. 27). The gold(I) complex has the tricoordinated structure 100, which results in high ee, whereas for the silver(I) complex there is an equilibrium between the tricoordinated structure 101 and the tetracoordinated structure 102, which results in low enantioselectivity. Slow addition of isocyanoacetate 27 to a solution of the silver(I) catalyst and aldehyde is effective in reducing the undesirable tetracoordinated species and results in high enantioselectivity. 

Silver(i) complex coordinated with the ferrocenylbisphosphine ligand 8g is also effective as a catalyst for the asymmetric aldol reaction of isocyanoacetate when the isocyanoacetate is kept in low concentration in the reaction system (Scheme 2-58) [82], Thus, by the slow addition of isocyanoacetate over a period of 1 h to a solution of aldehyde and the silver catalyst, iranj-oxazolines are formed in 80—90% ee, the enantioselectivity being only a little lower than that observed in the gold(i)-catalyzed... 

Table 11 Enantioselectivity and Diastereoselectivity in the Aldol Reactions of Methyl Isocyanoacetate Under Catalysis by Chiral Ferrocenylphosphine-Gold Complexes (equation 22)...

One of the earliest examples of an asymmetric catalytic aldol reaction in which the enolate component is generated in situ in the presence of an aldehyde is to be found in the pioneering work by Hayashi and Ito. In 1986, these investigators reported enantioselective addition reactions of a-isocyanoacetate to aldehydes catalyzed by chiral gold complexes (Scheme 4.23 see also Scheme 4.3) [18, 40). Several features of the catalyst and the process are important to note (1) the isocyanoester is a C-H acid (pfC 13), which is significantly further acidified upon its chelation to the Au center, (2) the presence of the tertiary amine in the ligand likely assists the enolization event, and (3) turnover of the... 

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