58th Annual Report on Research 2013 Under Sponsorship of the ACS Petroleum Research Fund

The goal of this funded research project is to investigate the stereospecific synthesis of substituted acyl 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 second year of the grant we have explored the role of the following variables in determining stereoselectivity:

1. the identity of the Lewis acid catalyst;
2. the presence of substituents at the carbinol carbon position of the oxazolidine starting material;
3. the presence of substituents at the vinyl position.

For each of the substrates described below, we map the energy profile for the key steps of the reaction, including coordination of the acid catalyst to the oxazolidine starting material to produce the iminium cation intermediate, a series of C-C bond rotations that lead to the other possible stereoconformers and can interconvert among them, and the rate-determining aza-Cope rearrangement for each of the stereoisomers. A comparison of the activation barriers for these key steps will shed light on the factors that determine the observed stereochemical product ratios and enable us to suggest ways to improve it.

Results obtained to date are described below:

1. We investigated the effect of using a chiral Lewis acid (isopinocampheyldifluoroborane)[1] on product stereoselectivity. The starting material for the reaction is a substituted oxazolidine containing a chiral center. Since it is desirable to be able to select for one of the oxazolidine stereoisomers, we have investigated how the chiral substrate interacts with the chiral acid catalyst. This work is still ongoing, but it appears that selectivity depends on the presence of other bulky substituents on the oxazolidine substrate. Namely, activation barriers to product formation are prohibitively high for one of the oxazolidine stereoisomers only when there are other bulky groups on the substrate. In this case, the chiral catalyst may improve product stereoselectivity. However, the steric bulk of the chiral catalyst we are investigating may in some cases prevent adequate coordination to the oxazolidine nucleophilic center that leads to product formation, thus affecting product yield without improving stereoselectivity.
2. Experimental evidence suggests that the presence of a methyl substituent at the carbinol carbon of the oxazolidine starting material affords markedly increased stereoselectivity.[2] We have mapped the potential energy profile for the first two steps (including the rate-determining step) of the aza-Cope – Mannich reaction for the unsubstituted substrate (leading to a secondary alcohol) and two substituted substrates (leading to tertiary alcohols). In addition, we are investigating any differences in activation barriers to C-C bond rotations that would lead to erosion of stereoselectivity. We have chosen methyl and trifluoromethyl as the substituents in order to discern between steric and electronic effects. This work is ongoing but we hope to conclude this avenue of investigation by the end of the year.
3. A third, new avenue of investigation is the effect of placing a substituent at the vinyl position of the oxazolidine starting material. We have mapped out the energy profile for the key steps in the reaction for the substrate with a phenyl substituent at the vinyl position. Results of the calculations indicate that for this substrate the barriers to C-C bond rotation that can interconvert stereoisomers are small compared to those for the rate determining-step, thus suggesting poor stereoselectivity. In addition, activation barriers for the rate-determining aza-Cope rearrangement step are comparable in size for the boat and chair conformers of the iminium cation intermediate. This is unusual, as in most of the other substrates we have investigated the activation barriers for the boat conformers are much higher than those for the chair conformers. Another unusual feature is that the rearrangement step for all stereoisomers of this substrate is somewhat endothermic, while for most other substrates it is exothermic. Given these anomalies, we are mapping out the reaction energy profile for an identical oxazolidine substrate without the phenyl substituent at the vinyl position. We hope that a comparison of the two substrates will allow us to determine more precisely the electronic/steric effects that give rise to the anomalous behavior of the substituted substrate.

During the third year of the grant we will focus on three areas of inquiry:

1) exploration of the aza-Prins-pinacol mechanism as an alternative to the aza-Cope – Mannich mechanism;

2) continue to investigate whether the use of chiral catalysts can improve product stereoselectivity;

3) the effect of substituents at various positions of the oxazolidine starting material, including an electronegative protecting group at the iminium position and a series of aryl substituents at the carbon adjacent to the nitrogen of the oxazolidine ring.

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 plan to submit a grant proposal to NSF by the end of the year 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 September. Participation at both events gave them confidence in their abilities to do research at a professional level and an opportunity to hear about areas of chemistry other than our own computational field.

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

[1] Vedejs, E. Shapland, P.; J. Org. Chem. 2006, 71, 6666-6669.

[2] Lindsay, H.A. and Pendleton, I., unpublished data, Eastern Michigan University, 2012.