Hydrogen-bond-directed enantioselective decarboxylative Mannich reaction of β-ketoacids with ketimines: application to the synthesis of anti-HIV drug DPC 083.

The decarboxylative Mannich reaction (DMR) of b-ketoacids with imines has emerged as a very important tool for the synthesis of natural products and biologically active compounds. The elegant work of Robinson on the total synthesis of ( )-tropinone represents the first practical example of utilizing the DMR as a key step in organic synthesis. Herbert and co-workers and Mangla and Bhakuni then developed a similar decarboxylative Mannich condensations of b-ketoacids with D-pyrroline and D-piperideine for the synthesis of biologically relevant alkaloids, such as septicine, phenanthroindolizidines, and cryptopleurine. Despite these notable achievements, little progress has been made in the development of an asymmetric version for this important reaction. Recently, the group of Tian developed a chiralauxiliary-based method in which b-ketoacids undergo highly diastereoselective decarboxylative Mannich transformation with optically active 2-(tert-butanesulfinyl-imino)glyoxylates, and Lu and co-workers described a catalytic asymmetric DMR of b-ketoacids with aldimines to afford b-amino ketones with a maximum of ee value of 83%. However, all such studies have focused on the aldimine-based electrophiles. In contrast, the use of ketimines as the electrophilic acceptors for the decarboxylative Mannich reactions of bketoacids still remains a formidable challenge and there has been no report in the literature, to date, of such a potentially useful transformation. The obvious benefits that hydrogen-bonding catalysis can offer in asymmetric synthesis have been recognized in recent years. Aunique characteristic of hydrogen-bonding catalysis is that the catalyst not only activates the reaction partners through hydrogen-bond interactions, but also positions them in close proximity with the desired relative geometry, and as such, the reaction is often facilitated in a synergistic manner, a manner similar to that of enzymatic catalysis. Herein, we report the results of our efforts in developing a hydrogenbond-directed enantioselective decarboxylative Mannich reaction of b-ketoacids by employing cyclic N-acyl ketimines as the electrophilic acceptor (Figure 1). This new reaction was cooperatively promoted by saccharide-based bifunctional organocatalysts. The catalysts contain a tertiary amine and thiourea moieties which simultaneously activate the substrates and are responsible for excellent overall stereochemical control. The potential application of this catalytic asymmetric decarboxylative Mannich reaction was further exemplified in a highly enantioselective synthesis of the antiHIV drug DPC 083.