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Our research in the area of nitrile functionalization set out to examine two parallel lines of inquiry.  At the end of the first year of the funding period, we were able to demonstrate that the alpha-silylation of nitriles proceeds in the absence of the zinc catalyst, which shifted our focus away from developing this reaction and toward exploring the reactivity of these materials. As delineated in the original proposal, we have succeeded in catalyzing the addition of these compounds to aldehydes under several catalytic conditions. In addition, we have continued our exploration of the catalyst-free displacement of alkoxy groups from vinylogous esters, demonstrating wide substrate scope and opening the door to new bond constructions. During the two-year funding period, support from the ACS-PRF has enabled significant advances in two related projects that have, as their over-arching goal, the rapid assembly of complex products from simple starting materials through mechanistically distinct processes.

Our facile synthesis of a-silylnitriles has enabled us to explore their unique reactivity. Initial studies focused on the use of cinchonium acetates wherein the parent alkaloid was alkylated with benzyl chloride. The active catalyst is made by counterion metathesis with AgOAc. This catalyst is reasonably active for the reaction with benzaldehyde in a variety of solvents, providing the a-alkyl-b-hydroxynitrile products in up to 70% yield, albeit with no discernible diastereo-selectivity. Furthermore, chiral HPLC confirmed that both diastereomers of the product were racemic. Use of CuOAc as a catalyst was also explored, and the product was formed in 1-2 days with 20 mol% catalyst. The best reactivity was obtained when CuOAc was combined with the cinchonium catalyst, albeit with no diastereo- or enantio induction. Use of the 9-anthracenyl cinchonium, which has proven invaluable in enhancing the selectivity of the O’Donnel alkylation,[i] did not alter the stereoselectivity. Although the stereoselectivity remains frustratingly low, the reactivity is intriguing and we intend to more fully explore the use of CuOAc in conjunction with a variety of ligands and other additives. The use of a nucleophilic counterion is consistent with our original hypothesis for de-silylation and it is likely that other metal acetates will also provide fruitful avenues for the development of new catalysts.

During the second year of this PRF funding period, we were able to complete an initial study of the direct displacement of alkoxy groups from vinylogous esters. This reaction was discovered during the first year of funding and fit within the general theme of assembling complex molecules from simple starting materials. We were able to demonstrate the generality of this process on over 30 substrates and conduct key experiments that suggest the unique chelation ability of magnesium forms the basis for the reactivity that we observe. In addition, we have explored non-aromatic substrates and begun studies toward a complex alkaloid natural product synthesis that will be conducted in just 5 steps with our new Grignard addition as the key step. The first results are the subject of a preliminary communication that is in the final editing stages for submission to Organic Letters.[ii]

The PRF-G grant from has had a significant impact on the development of two scientists in my group. Young Sam Park, who worked part time on this project and part time on another, was able to complement his training in target-oriented synthesis with basic research in catalysis, which added significant breadth to his skill-set. As a result, he was hired into a basic research position at Samsung’s headquarters in his home country of Korea. The other trainee supported by this grant was Anthony J. “A-J” Brockway. A-J performed all of the experiments in the alkoxide displacement area and has seen the project through to fruition during the funding period. Now, in the third year of his Ph.D. training, he has the skills necessary to work independently on a bold new project, for which his training during the PRF funding period was instrumental.

In summary, we have discovered new reactivity that enables the synthesis of useful organic frameworks from simple starting materials. Research conducted with funds from the PRF has revealed interesting new catalytic reactivity, whereas parallel research during the first half of the funding period has illuminated new direct reactions that offer reactivity that complements transition metal-catalyzed cross-couplings.

REFERENCES

[i] Corey, E. J.; Xu, F.; Noe, M. C. A rational approach to catalytic enantioselective enolate alkylation using a structurally rigidified and defined chiral quaternary ammonium salt under phase transfer conditions. J. Am. Chem. Soc. 1997, 119, 12414-12415.

[ii] Brockway, A. J.; Gonzalez-Lopez, M.; Fettinger, J. C.; Shaw, J. T. Direct displacement of alkoxy groups of vinylogous esters by Grignard reagents. Org. Lett. 2010, submission in progress. [submission draft available on request]