Proline- and thioproline-derived enamines: The theoretical study of torsional and ring-puckering conformations

Proline and its derivatives catalyze Mannich and aldol reactions by forming enamine with ketone substrates. The conformations of such enamine play an important role in stereochemistry of the final products. In this study, the conformational features of proline- and thioproline-derived enamine which are derived from the reaction of cyclohexanone with (S)-proline and (R)-thioproline, respectively, are investigated theoretically using B3LYP and MP2. For proline-derived enamine, two ring-puckering conformations i.e. up (u) and down (d) puckered of pyrrolidine ring were located as minima. The conversion from d to u puckered conformation occurs via an envelop transition state requires 1.7 and 4.0 kcal/mol for syn and anti forms at MP2 level. The barriers of the rotation of Csp2N bond leading to syn and anti conformations are 3.8 and 4.3 kcal/mol for d and u ring-puckered forms, respectively. For thioproline-derived enamine, apart from the u and d puckered conformations of thiazolidine ring, a down and envelop (de) ring conformation was found as the global minimum. The barriers of the Csp2N bond rotation of d and u puckered ring are 3.5 and 4.3 kcal/mol, similar to the corresponding conformations of proline-derived enamine. The barriers of the ring puckering change from d to u are 0.7 and 4.1 kcal/mol for syn and anti form, respectively. An interesting characteristic of the de ring conformation is its small Csp2N bond rotation barrier of 2.3 kcal/mol.