Bifunctional Cinchona alkaloid thiourea catalyzed highly efficient, enantioselective aza-Henry reaction of cyclic trifluoromethyl ketimines: synthesis of anti-HIV drug DPC 083.

The aza-Henry reaction is a powerful method for C C bond formation. Moreover, the versatile nitro group can be conveniently transformed into a variety of new functional groups, which are highly valuable in the preparation of related analogues in drug discovery. In recent years, significant efforts have been directed toward the development of catalytic asymmetric aza-Henry reactions. However, the electrophilic substrates have been largely confined to imines derived from aldehydes. The development of an efficient protocol for an enantioselective aza-Henry reaction of ketimines to generate a chiral quaternary center remains elusive because of the lower reactivity of ketimines and difficulties in enantiofacial discrimination. To our knowledge, to date, there has been only one report, by Feng and co-workers, of a chiral N,N’dioxide copper complex (20 mol %) catalyzed asymmetric aza-Henry reaction between acyclic ketimines and nitromethane; this reaction proceeded with good enantioselectivities (71–96 % ee) but generally in poor yields (21–70%). Dihydroquinazolinones, as an important class of heterocyclic compounds are characterized by their broad spectrum of intriguing biological properties, such as antiviral and antiobesity activities, and their use in the treatment of cardiovascular diseases and pain. Notably, among these compounds, drug candidates DPC 083 and DPC 961, bearing a chiral trifluoromethyl moiety, are potent HIV-1 nonnucleoside reverse transcriptase inhibitors (Scheme 1). It is believed that the trifluoromethyl motif plays a pivotal role in the bioactivity. Accordingly, efficient approaches to valuable chiral molecular architectures with sites for functional group diversification are of considerable synthetic and biological importance. Furthermore, catalytic enantioselective syntheses of DPC 083 and DPC 961 are needed. Given the important challenge of the construction of a functionalized quaternary stereogenic center in the dihydroquinazolinone scaffolds, significant efforts have been made but with limited success. The approaches reported to date mainly rely on chiral auxiliaries to control the stereoselectivity. An atom-economical catalytic enantioselective process is more attractive but, to our knowledge, such a method giving a useful level of enantioselectivity (> 90% ee) is an unmet synthetic issue. Herein, we report a novel highly efficient organocatalytic enantioselective aza-Henry reaction for the preparation of the enantioenriched trifluoromethyl dihydroquinazolinones. Notably, a highly efficient hydrogen-bond-mediated enantioselective addition of nitroalkanes to ketimines has been achieved for the first time under mild reaction conditions in high yields using as low as 1 mol% catalyst loading. Furthermore, we also observed that the trifluoromethyl group is critical for not only biological activity, but also for chemical reactivity. Finally, the highly enantioselective synthesis of DPC 083 has been achieved using the aza-Henry reaction as a key step. We envisioned that a catalytic enantioselective aza-Henry reaction could be realized by the reaction of 2(1H)-quinazolinones 1 with versatile nitroalkanes to generate chiral dihydroquinazolinones (Table 1). Accordingly, our investigation began with the model reaction between trifluoromethylquinazolin-2(1H)-one (1a ; 1.0 equiv) and nitromethane (2a ; 2.0 equiv) in the presence of quinine (4a ; 10 mol%) as the catalyst in CH2Cl2 at room temperature (Table 1, entry 1). [11]