Enesulfonamides as Nucleophiles in Catalytic Asymmetric Reactions

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114190087/ABSTRACT

From Prof. Shu Kobayashi's group at The University of Tokyo, Tokyo, Japan

The recent article in ACIEE EarlyView from the lab of Prof. Kobayashi detailed a novel reaction of enesulfonamide as a nucleophile in nucleophilic addition catalyzed by copper-based Lewis acid in the presence of chiral ligand. Comparison was made with enecarbamate that enesulfonamide is more convenient to make than the enecarbamate the reactions demonstrated here were efficient. The product generated from the addition is sulfonylimine, which could be reduced to either 1,3-amino alcohol or sulfonamide, both of which are medicinally important.

Enesulfonamide can be simply made from condensation of a ketone and a sulfonamide. E- and Z-alkene isomers could be separated by column chromatography.

Most of the examples of enesulfonamide were made from aromatic ketones. But aliphatic ketones were also shown to be feasible to make and to be employed in the reaction. The early example from the study was the addition of p-methoxyphenyl-substituted enesulfonamide, generate from condensation of p-methoxysulfonamide and phenyl ethyl ketone, to ethyl glyoxylate. The product, sulfonylimine, could be hydrolyzed to give ketone. Several hydrolysis conditions were investigated as shown in Table 1.

From the table, the use of too little acid led to decrese in yield and diastereoselectivity of keto ester 7a (entry 1). However, increasing the amount of acid, as in entry 2, both yield and diastereoselectivity improved significantly. Increase in the amount of acid probably prevented formation of enesulfonamide 8a which led to epimerization.

The optimal reaction conditions were screened with different enesulfonamide using ethyl glyoxylate as the reaction partner. General trend: electron-rich aryl substituent on the sulfonyl group is more reactive than electron-poor aryl substituent. The reaction is also stereospecific: Z-enesulfonamide afforded syn-product, and E-enesulfonamide afforded anti-product.

As mentioned before, the sulfonylimine product could be reduced stereoselectively to give a sulfonamide alcohol, as represented in Scheme 2.

Enesulfonamide also added to azodicarboxylate as shown in Equation 2 between sulfonamide (E)-4b and diisopropyl azodicarboxylate. In this case, diamine 11 was used as the chiral ligand.

In summary, a novel method copper-catalyzed enesulfonamide addition to glyoxylate has been developed. The reactions proceeded in high yield and high diastereo- and enantioselectivities, even with catalyst loading as low as 0.2 mol%.