Asymmetric gold-aldol reaction

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... 

The gold(I) complex of a chiral ferrocenylphosphine complex promotes asymmetric aldol reactions of a-isocyanocarboxylates to form chiral oxazolines in high diastereo- and enantio-selectivities (Scheme 52).225,226 In these reactions, the analogous silver(I) ferrocenylphosphine complex also works well. 

Asymmetric Aldol Reactions with a Chiral Ferrocenylphosphine-Gold( I) Complex... 

Scheme 3-30. Gold(I) complex-catalyzed asymmetric aldol reactions.

Asymmetric aldol reaction. In the presence of a gold(I) complex (1) and a chiral ferrocenylphosphine (2), various aldehydes react with methyl isocyanoacetate... 

The gold catalyst has provided some very important achievements in chemistry in general, such as the asymmetric aldol reaction of aldehydes with isocyanoacetates reported by Ito, Sawamura and Hayashi [12,176]. The use of chiral ferrocenylpho-sphine gold (I) complexes allowed them to obtain enantiomerically-pure oxazo-lines. 

B1.2. GOLD-CATALYZED ASYMMETRIC ALDOL REACTION OF cc-ISOCYANOCARBOXYLATES... 

In 1986 Ito, Sawamura, and Hayashi [4] reported that gold(I) complexes prepared from cationic gold complex 1 and chiral ferrocenylphosphine ligands (2) bearing a tertiary amino group at the terminal position of a pendant chain are effective catalysts for asymmetric aldol reaction of... 

TABLE 8B1.1. Gold-Catalyzed Asymmetric Aldol Reaction of Isocyanoacetate 3a with Aldehydes (Scheme 8B1.1)"... 

Figure 8B1.1. Proposed transition-state model of the gold-catalyzed asymmetric aldol reaction.

The usefulness of the gold-catalyzed aldol reaction was demonstrated by application of the method to the asymmetric synthesis of the important membrane components D-erythro and ffereo-sphingosines, and their stereoisomers (Scheme 8B1.2) [13], and MeBmt, an unusual amino acid in the immunosuppressive undecapeptide cyclosporine (Scheme 8B1.3) [14]. 

TABLE 8B1.3. Asymmetric Aldol Reaction of Isocyanoacetate 3b with Functionalized Aldehydes in the Presence of Gold(I) Catalyst Containing Ligand 2a (Scheme 8B1.1) 1... 

It is interesting that aldol-type condensation of tosylmethyl isocyanide (16) with aldehydes is catalyzed by the silver catalyst more stereoselectively than that catalyzed by the gold catalyst under the standard reaction conditions (Scheme 8B1.9) [26], Elucidation of the mechanistic differences between the gold and silver catalysts in the asymmetric aldol reaction of 16 needs further study. Oxazoline 17 can be converted to optically active a-alkyl-p-(A-methyl-amino)ethanols. 

Cobb, A.J.A., Shaw, D.M., Longbottom, D.A., Gold, J.B. and Ley, S.V. (2005) Organocatalysis with proline derivatives improved catalysts for the asymmetric Mannich, nitro-Michael and aldol reactions. Org. Biomol. Chem., 3, 84. 

Worth mentioning are chiral gold complexes [20d, e] as well as chiral quaternary ammonium fluorides [21], which are used successfully as catalysts in the asymmetric aldol reaction. 

The gold(I)-catalyzed asymmetric aldol reaction with the chiral ligand R)- S)-(1) has been applied in the synthesis of o-erythro-and /lireo-sphingosines (eq 11). The D-eo lIiw-sphingosine can be prepared from the three isomer by inversion of the C-3 hydroxyl group. 

Optically active ferrocenylbisphosphines, (/J)-N,iV-dimethyl-l-[(5)-1, 2-bis(diphenylphosphino)ferrocenyIJethylamine [(/J)-(5)-BPPFA] and its derivatives, are efficient chiral bisphos-phine ligands for rhodium-catalyzed asymmetric hydrogenation, palladium-catalyzed asymmetric allylic substitution reactions, and gold-catalyzed asymmetric aldol-type reactions of a-isocyano carboxylates. ... 

Gold and Silver-Catalyzed Asymmetric Aldol Reactions of a-Isocyanocarboxylates... 

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. 

The gold-catalyzed aldol reaction has been successfully applied to the asymmetric synthesis of (l-aminoalkyl)phosphonic acids, phosphonic analogs of a-amino acids (Scheme 2-57) [80, 81]. The reaction of (isocyanomethyl)phosphonates 65 with... 

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... 

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