Applications of chiral guanidine organocatalysts in asymmetric transformations probing structure activity relationships of artificial enzyme active sites and development of metal -free oxidative cyclization reactions

The common theme throughout this research was the search for new tools and routes to effect useful chemical transformations. During these investigations we utilized a several distinctly different approaches. First, a wide variety of organocatalysts were synthesized and applied to epoxide and aziridine ring openings. The organocatalysts served as efficient, albeit non-stereoselective catalysts of the ring opening. However, several novel chiral guanidine organocatalysts were capable of asymmetric induction in the aza-Henry reaction. A number of structural modifications were examined, revealing a unique enhancement in stereoselectivity for an ethylene-linked bisguanidine. Furthermore, the major enantiomeric form of the β-nitroamine products could be selectively reversed when a bisguanidine was used instead of a monoguanidine. In collaboration with other researchers, we examined the substrate specificity and selectivity of artificial enzymes. A series of compounds was synthesized to probe structure activity relationships and explore the scope of catalyzable reactions. Our efforts aided studies of the properties of the synthesized enzymes and also aided the use of these enzymes for more challenging chemical transformations. In addition to our efforts in catalysis, we have developed a broadly applicable, high yielding oxyamination reaction of alkenes promoted by Brønsted acids. Under these conditions the acid is incorporated into the cyclized products providing an overall aminohydroxylation of the alkene. Multiple ring sizes were formed generating pyrrolidines, piperidines, and azepanes with a general preference for endo cyclization. This highly endo selective aminohydroxylation provides an alternative synthetic route to useful nitrogen-containing heterocycles. This system also exhibits an unusual preference for endo ring closure in contrast to existing exo selective methods. Consequently we propose in situ formation of an aziridinium ion is responsible for both the endo and anti selectivity of the process

Computational Design of Enone-Binding Proteins with Catalytic Activity for the Morita–Baylis–Hillman Reaction

The Morita–Baylis–Hillman reaction forms a carbon–carbon bond between the α-carbon of a conjugated carbonyl compound and a carbon electrophile. The reaction mechanism involves Michael addition of a nucleophile catalyst at the carbonyl β-carbon, followed by bond formation with the electrophile and catalyst disassociation to release the product. We used Rosetta to design 48 proteins containing active sites predicted to carry out this mechanism, of which two show catalytic activity by mass spectrometry (MS). Substrate labeling measured by MS and site-directed mutagenesis experiments show that the designed active-site residues are responsible for activity, although rate acceleration over background is modest. To characterize the designed proteins, we developed a fluorescence-based screen for intermediate formation in cell lysates, carried out microsecond molecular dynamics simulations, and solved X-ray crystal structures. These data indicate a partially formed active site and suggest several clear avenues for designing more active catalysts