Distinct conformational preferences of prolinol and prolinol etherenamines in solution revealed by NMR

Abstract

Enamines, which are key intermediates in organocatalysis derived from aldehydes and prolinol or Jørgensen–Hayashi-type prolinol ether catalysts, were investigated conformationally in different solvents by means of NMR spectroscopy, in order to provide an experimental basis for a better understanding of the origin of stereoselection. For all of the enamines studied, surprisingly strong conformational preferences were observed. The enamines of the diarylprolinol (ether) catalysts were found to exclusively exist in the s-trans conformation due to the bulkiness of the pyrrolidine α-substituent. For prolinol enamines, however, a partial population of the s-cis conformation in solution was also evidenced for the first time. In addition, for all of the enamines studied, the pyrrolidine ring was found to adopt the down conformation. Concerning the exocyclic C–C bond, the sc-exo conformation, stabilized by CH/π interactions, is exclusively observed in the case of diarylprolinol ether enamines. In contrast, diarylprolinol enamines adopt the sc-endo conformation, allowing for an OH⋯N hydrogen bond and a CH/π interaction. A rapid screening approach for the different conformational enamine features is presented and this was applied to show their generality for various catalysts, aldehydes and solvents. Thus, by unexpectedly revealing the pronounced conformational preferences of prolinol and prolinol ether enamines in solution, our study provides the first experimental basis for discussing the previously controversial issues of s-cis/s-trans and sc-endo/sc-exo conformations. Moreover, our findings are in striking agreement with the experimental results from synthetic organic chemistry. They are therefore expected to also have a significant impact on future theoretical calculations and synthetic optimization of asymmetric prolinol (ether) enamine catalysis.