The specific aims of this proposal are: 1) to develop novel routes to enatio-enriched piperidine derivatives through the discovery of new asymmetric catalytic reactions, and 2) to establish general strategies for the preparation of a variety of chiral piperidine motifs commonly found in biologically active alkaloid products. The piperidine structural motif is a common feature in a large number of medicinally relevant alkaloid natural and unnatural products. Consequently piperidine-derived molecules are believed to hold significant therapeutic potential. To date, this structural feature is frequently accessed via intramolecular Mannich-type cyclizations of iminium ions; however, there is currently no catalyst capable of promoting this reaction in an enantioselective fashion. Recent work in the Jacobsen laboratory has shown that chiral thiourea catalysts can activate N-alkylimines and N-acyliminium ions towards a number of asymmetric processes. It is proposed that such catalysts could be exploited for enantioselective Mannich- type cyclizations. A variety of known and novel thiourea catalysts will be prepared and screened for their ability to promote enantioselective intramolecular Mannich-type reactions of allylsilane- and vinylsilane- derived N-acyliminium ions or N-alkylimines. The modular nature of the thiourea catalysts will allow for systematic catalyst optimization. Upon identification of a successful catalyst for this transformation, the substrate scope and mechanism will be further explored. In light of the abundance of piperidine-derived biologically active molecules, the development of a catalytic asymmetric intramolecular Mannich-type cyclization would be of significance to both the biological and chemical communities. Relevance: The continuing effort to improve public health by the discovery of improved, affordable therapies for common diseases requires new, innovative methods for the preparation of small molecule drugs. The methods development described in this proposal would contribute a valuable tool to the academic and industrial communities for the efficient synthesis known biologically active molecules, or, potentially, for the discovery of new, previously unknown small molecule drugs. ? ? ?
| Reisman, Sarah E; Doyle, Abigail G; Jacobsen, Eric N (2008) Enantioselective thiourea-catalyzed additions to oxocarbenium ions. J Am Chem Soc 130:7198-9 |
