Reports: UR651152-UR6: A Computational Exploration of the Stereoselective Synthesis of Substituted Pyrrolidines

Maria C. Milletti, PhD, Eastern Michigan University

The goal of this funded research project is to investigate the stereospecific synthesis of substituted pyrrolidines from a computational perspective in order to inform and guide the choice of experimental conditions leading to maximum stereoselectivity.  The synthetic pathway under consideration is the tandem aza-Cope – Mannich reaction, an efficient method to the formation of a variety of substituted pyrrolidines that can serve as asymmetric organocatalysts.

During this first year of the grant we have explored

  1. the Lewis-acid catalyzed ring-opening reaction of variously-substituted oxazolidines to produce the initial iminium cation intermediate;
  2. the influence of substituent size on the energetics of the aza-Cope – Mannich reaction;
  3. the potential erosion of stereoselectivity through C-C bond rotations of the iminium cation intermediates preceding and following the aza-Cope rearrangement step of the reaction.

We investigated these key aspects of the synthesis by considering how the choice of Lewis acid and oxazolidine substituents alters our conclusions.  Specifically, we have used three iminium cation substituents with varying steric and electronic characteristics, as well as comparing more- or less-heavily substituted carbonyl groups in the pyrrolidine product.

Results obtained to date are as follows:

  1. Lewis acid coordination to both nucleophilic centers of the oxazolidine ring leads to epimerization and subsequent erosion of stereoselectivity.  Therefore, it is preferable to use catalytic rather than stoichiometric amounts of acid catalyst.  In addition, the electron withdrawing ability of substituents affects the charge distribution of the 5-member ring and has an impact on the oxazolidine’s ability to epimerize and form the desired iminium cation intermediate.
  2. Substituent size appears to be an important factor in determining the product stereoselectivity.  Substituents that are less bulky and less electron donating lead to a loss of stereoselectivity by decreasing the difference in thermodynamic stability among intermediate stereoisomers and the difference in activation energies for the rate-determining step.
  3. In addition, iminium cation intermediates with smaller, less electron-donating substituents experience a loss of stereoselectivity due to lower activation barriers to C-C bond rotation.

During the second year of the grant, we plan to continue our investigation of the effect of substituents’ steric and electronic characteristics on the energy profile of the aza-Cope – Mannich reaction and product distribution of stereoisomers.

In addition, we will model the reaction using chiral Lewis acids to see if they impart a particular conformation to key intermediates.

This project is in collaboration with one of my colleagues at Eastern Michigan University, Prof. Harriet Lindsay, who is carrying out the experimental work.  The grant has allowed me to make significant progress on the project by giving me the opportunity to hire student researchers.  Prof. Lindsay and I believe that by next summer we will have enough data to submit a grant proposal to NSF to secure continued funding for this joint project.

In addition, financial support from this grant provided my students with the opportunity to present their results at the ACS Central Regional meeting in May of this year and at the ACS Fall National Meeting in August.  This was a tremendous opportunity for them, as this was the first time they had presented their work to other chemists.  Participation at both events gave them confidence in their abilities to do research at a professional level and they have begun to consider graduate school as an option after graduation.

Attendance at the ACS National meeting also gave them an opportunity to hear about areas of chemistry other than our own computational field.  They talked to recruiters from several companies and one of them is going to pursue an internship with NASA next summer.

The increased activity in my lab has also been an excellent recruiting tool and two new students joined our research group this fall.  I am sure that this academic year will be a very productive one.