Rigorous Conformational Analysis of Pyrrolidine Enamines with Relevance to Organocatalysis

Abstract

It has been suggested that the origin of regio-and stereoselectivity in Michael additions of pyrrolidine enamines is achieved by thermodynamic rather than kinetic control through distinct conformational preferences of the enamines. We assess this proposal by elaboration of a computational protocol that warrants sufficient accuracy. The small energy differences between the conformers necessitate a high accuracy of the electronic structure method which, in addition, must allow for computationally feasible calculations of a large number of conformers. Our protocol is based on density functional theory which we validated against explicitly correlated coupled cluster theory. The results are in agreement with the available experimental data, but illustrate that conformational preferences determined for one enamine are not readily transferable to other types of enamines. We found that an appropriate conformational sampling is inevitable to arrive at meaningful conclusions. Most prominently, s-cis and strans conformers are similarly stable for aldehyde-and ketone-derived enamines. The regio-and stereoselectivity in Michael additions of pyrrolidine-derived enamines can not be explained by pronounced stability differences of the enamine isomers and conformers in general, disproving the thermodynamic-control hypothesis. The elucidation of the origin of regio-and stereoselectivity requires further theoretical investigations of the elementary steps of Michael additions.

Conformational Properties of a Peptidic Catalyst: Insights from NMR Spectroscopic Studies

“…DMSO, DMF, acetonitrile, CDCl 3 ). 25,[54][55][56][57][58] In contrast, a detailed conformational analysis of an enamine derived from an acidic proton-containing catalyst in a protic solvent has so far remained elusive. 59,23 Thus, analysis of the conformation of 1-En was expected to be challenging.…”

“…Comparison of the NOE-derived H1/p-Hα and H2/p-Hδ 1 /Hδ 2 distances with pure s-cis and s-trans enamine structures that were generated computationally suggests a s-trans:s-cis conformer ratio of approximately 70:30. 27, 55,58 Backbone conformation of the enamine 1-En ' . Next we explored whether the structural features observed for 1 are still intact in enamine 1-En ' .…”

Synthesis of 6,12-Disubstituted Methanodibenzo[b,f][1,5]dioxocins: Pyrrolidine Catalyzed Self-Condensation of 2′-Hydroxyacetophenones

“…Although the details of the mechanisms involved require full clarification, the absence of similar dioxocin products when employing other cyclic secondary amines, such as indoline, morpholine and tetrahydroquinoline, using our hydrosilylation protocol, suggests that an enamine is likely to be involved. Pyrrolidine derived enamines are known to be more reactive that other cyclic amines [46,47], and the protocol for reductive amination from 2′-hydroxyacetophenone and this amine starts with iminium formation at room temperature under neat conditions [48]. Moreover, the same amine was previously reported to promote the formation of 4-chromanones from 2′-hydroxyacetophenones and aliphatic aldehydes and ketones [49].…”

Design of A Metabolically Stable Tritium‐Tracer of the PI3Kδ‐Inhibitor CDZ173 (Leniolisib) as a Tool to Study Liver Metabolites

“…The activation barrier for cis‐trans isomerism for this compound was found to be Δ G 298 ‡ = 80.4 kJmol −1 in solution and Δ G 298 ‡ = 71.4 kJmol −1 in the gas phase, while the pseudorotational barrier in pyrrolidine was calculated to be 0.6 kJmol −1 ab initio taking into account that the nitrogen inversion of the pyrrolidine ring is of little importance in N ‐trifluoroacetyl pyrrolidine . On the other side, we consider the ab initio conformational analysis of Reiher and Seebach on C(2′)‐substituted pyrroldines, where the pyrrolidine nitrogen is bound to a sp 2 ‐hydridized carbon . These authors calculated that UP‐ and DOWN ring conformers of pyrrolidine are both significantly populated when a Boltzmann distribution is in equilibrium.…”