Reports: DNI155734-DNI1: New Chemical Reactions by Engaging Catalytic Ester Enolate Equivalents in Synergistic Catalysis

Thomas N. Snaddon, PhD, Phil, BSc, Indiana University, Bloomington

Overview: This ACS PRF-DNI Award has been used to support a PDRA (Dr. Colin Pearson) to further the development of cooperative catalysis involving C1-ammonium enolates nucleophiles and α-(allyl)palladium electrophiles. As outlined in our original PRF proposal, cooperative catalysis offers many benefits for chemical synthesis that include addressing stereochemical issues that are beyond the reach of single catalyst systems.

In 2016 we disclosed the first direct asymmetric α-allylation of aryl acetic acid esters (J. Am. Chem. Soc. 2016, 138, 5214-5217). Critical to the success of this reaction was the identification and optimization of 'phenolate rebound' as an effective mechanism of catalyst turnover in the nucleophilic cycle.

Utilizing Dr. Pearson's considerable expertise in chemical synthesis, we have used ACS PRF support to broadly investigate the generality of this mechanistic

Previous Investigations (2016): Our efforts were directed toward three areas:

1. The preparation of stereodefined enolates via methods other than deprotonation.

Despite encouraging preliminary data concerning decarboxylative we have found trouble generalizing this. A doctoral student has taken Dr. Pearson's initial observations and is currently working to find a general solution.

2. The effect of Lewis acid catalysts on the stability of C1-ammonium enolates.

Here we have attempted to stabilize -alkyl C1-ammonium enolates with a variety of common Lewis acids in order to preserve their lifetime at room temperature. We have been unsuccessful in the endeavor as the external Lewis acid sequesters the liberated phenol and shuts down Lewis base catalyst turnover.

3. A computational collaboration (With Prof. Peng Liu, Pittsburgh University) to elucidate the critical role X- plays on enantiocontrol.

We have been unable to identify the role played by the nucleofuge (X-) on enantiocontrol.

Current Investigations (2017): Our efforts were directed toward three areas:

4. Decoupling Enantiocontrol from Metal-Centered Reactivity.

Cooperative catalysis provides the opportunity to tune enantiocontrol and metal-based reactivity independently. This is critical as, for example, moving from rigid monodentate P-ligands (for Pd) to a monodentate P-ligand might engineer the required reactivity but limit one's ability to control enantioselectivity. In our system, enantioselectivity continues to be administered by the Lewis base catalyst. In a sense, we get the best of both worlds. We have used this strategy to overcome substrate steric and electronic limitations observed in our initial reaction to permit the use of 2-substituted allyl electrophiles as well as those substituted with silicon. The only differences in each case are the electronic and steric parameters of the P-ligand. In each case, high levels of enantiocontrol are observed.

5. Continued computational collaboration (With Prof. Peng Liu, Pittsburgh University).

In relation to point 4 (above) we have worked closely with Prof. Peng Liu to computationally interrogate many aspects of our cooperative process. This has led us to establish (1) the nature of the bond forming even (2) the nature of enantiocontrol, and (3) a likely operative mechanism.

We are currently in the process of writing two manuscripts that hinge on the support provided by this ACS PRF-DNI award.

Dr. Pearson has also co-authored two other contributions. The first is a submission to The Encyclopedia of Reagents for Organic Synthesis (EROS), and the second is an invited "First Reactions" commentary for ACS Central Science.