In this project funded by the Chemical Synthesis Program of the Chemistry Division, Professor Patrick J. Walsh of the Department of Chemistry at the University of Pennsylvania will examine general methods for the chelation-controlled addition of organometallic reagents to alpha or beta silyloxy and alpha or beta halo aldehydes, ketones, and aldimimes. These substrates typically do not chelate. The central hypothesis of this project is that Cram-chelation can be achieved with substrates that strongly resist chelation by employing mild nucleophiles in combination with zinc Lewis acids. There are three specific objectives: 1. Developing chelation-controlled additions to chiral alpha and beta silyloxy aldehydes and ketones; 2. Assessing the ability of zinc reagents to chelate alpha or beta halo aldehydes and ketones; 3. Assessing the ability of zinc reagents to chelate alpha or beta halo imines and to promote Cram chelation additions.
The project could lead to general methods for highly diastereoselective additions to alpha or beta substituted aldehydes, ketones, and aldimines. These methods are highly useful for the preparation of a large number of substructures commonly seen in biologically important molecules, including syn-1,2- and anti-1,3-diols, syn-1,2-halo hydrins, cis-epoxides and allylic epoxides, and anti-1,2-amino alcohols. The successful results of this work could positively impact the pharmaceutical, agrochemical, and specialty chemical industries. In addition, this project will provide excellent training of students, including those from groups historically underrepresented in the sciences.
