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This grant seeks to develop and exploit ligand scaffold optimization as a novel strategy for improving catalyst efficiency. The overall goal of this proposal is to develop methodologies which allow for scaffold optimization and use it to design, prepare, and evaluate focused libraries of new chiral ligands for use in catalytic asymmetric synthesis. The specific aims are to (i) carry out mechanistic studies to improve our understanding of the current generation of self-assembled ligands (SALs), (ii) evaluate new, complementary structural motifs and metal coordination geometries for the preparation self-assembled ligands and catalyst systems, (iii) evaluate the use of boracycles as an alternative motif for self-assembled ligands, and (iv) generate diverse ligand scaffold libraries via click chemistry.

Progress has been made on several of the specific aims, particularly, specific aim iv. Following up on a 2008 Organic Letters communication, a full paper comparing the results obtained using two different ligating groups with a series click-connected ligand scaffolds is in preparation. Publication is delayed somewhat as we work to grow crystals suitable for structure determination. At present the crystals are too small for structure determination. Computational studies carried out by our collaborator, Prof. Libbie Pelter (Purdue Calumet University), indicate that the proposed structure in Figure 1 is too strained to function in the reaction. Thus, obtaining a structure of this successful Click-Connected catalyst scaffold is of particular importance in understanding the role of the catalyst scaffold.

Figure 1. Structural studies on a successful Click-Connected catalyst are underway.

In addition, new studies carried out by Mr. Nathan Thacker and Mr. Kaz Toyama, graduate students in the UNL Chemistry departments, assisted by summer undergraduate research student, Mr. Jeffrey O'Neill (Purdue Calumet University), have obtained promising preliminary results on efforts to exploit scaffold optimization in the preparation of bifunctional organocatalysts. Using bifunctional catalysts for dual activation involves positioning two functional groups to independently activate the substrate and reagent, for example, both an electrophile and a nucleophile. This strategy is common in nature, used for example by the class II metal-dependant aldolases. Scaffold optimization affords the opportunity to vary the shape of the chiral substrate/reagent pocket and thereby moderate the reactivity and enantioselectivity of the catalyst.  While the catalysts are not yet optimized and only modest levels of enantioselectivity have been achieved to data, preliminary data obtained in the past year, particularly the wide variation in the rate of reaction as a function of catalyst scaffold, indicate that click-connected scaffolds can be used to develop effective catalysts exploiting dual activation in the oxy-Michael reaction shown below.

Figure 2. The design and first generation bifunctional dual activation catalysts for the oxy-Michael reaction exploiting the ability to generate diverse catalyst scaffold libraries for scaffold optimization.

In the proposal it was noted that preliminary experiments had been carried out on the combination of the chiral, homoleptic complex (SS,SS)-27 with the sterically encumbered tetramethyl-box derivative 25a (R¹ = H) and the unsubstituted-box derivative 25b (R² = H). Remarkably, ¹H NMR analysis had indicated both combinations undergo facile exchange with high selectivity for formation of the heteroleptic complexes (i.e., 28a (R = Me) and 28b (R = H). We had proposed to characterize and crystallize the new heteroleptic complexes in order to better understand the origin of their large thermodynamic preference. This past summer, an undergraduate, Ms. Kirsten Johnson from neighboring Nebraska Wesleyan University, was supported under this grant to work on this aspect of the proposal. Kirsten, now in her senior year, continues to work part time on the project in an effort to grow x-ray quality crystals for structure determination. Kirsten is in the process of preparing applications for graduate study.

Figure 3.  Alternative structural motifs that apparently also direct heteroleptic self-assembly are under investigation.