Configurationally Stable Biaryl Analogues of 4-(Dimethylamino)pyridine:  A Novel Class of Chiral Nucleophilic Catalysts

A short synthetic approach toward a novel class of chiral nucleophilic catalysts, the dissymmetry of which stems from restricted rotation about an Ar−Ar bond, has been developed. The key steps of the synthesis include preparation of a nucleophilic 1-methyl-2-pyrrolino[3,2-<i>c</i>]pyridine core <b>16</b> by <i>ortho</i>-lithiation and creation of the biaryl axes via Suzuki cross-coupling reactions. Comparative HPLC studies of racemization for configurationally labile biaryls <b>31</b>, <b>38</b>, and <b>43</b> containing 1-methyl-2-pyrrolino[3,2-<i>c</i>]pyridine, 4-(dimethylamino)pyridine, and 4-(1-pyrrolidino)pyridine cores, respectively, have demonstrated that a pyrrolidino substituent <i>ortho</i> to the biaryl axis is optimal for slowing Ar−Ar rotation. Biaryls containing all three cores have been shown to retain DMAP-like catalytic activity in the acylation of a hindered alcohol. Biaryls <b>55</b> and <b>56</b>, which are configurationally stable at ambient temperature, have also been prepared via modification of configurationally labile derivatives. Compounds <b>55</b> and <b>56</b> in optically pure form should provide a useful starting point for studies on catalytic asymmetric acyl transfer using atropisomeric analogues of DMAP.