Alkene-containing molecules and their derivatives play a major role in medicine, food and energy production, as well as materials research and polymer science. In most applications, particularly in medicine, alkenes are needed in isomerically pure form. Numerous methods have been developed for the synthesis of 1,2-disubstituted alkenes over the past decades. While strategies for stereoselective preparation of olefins have been the subject of substantial interest, methods relating to synthesis of tetrasubstituted alkenes are still an open challenge that could impact construction of many bioactive compounds containing such moieties, especially those that are catalytic. What is more, the small number of available protocols are often not highly selective or broadly applicable.
The goal of the proposed studies is to introduce a practical, scalable, modular and highly stereoselective synthesis of a large assortment tetrasubstituted alkenes from readily available Cu-based catalysts, nitriles, allenes, and a commercially available diboron compound. The tetrasubstituted alkene products will contain readily modifiable functional groups, such as a ketone (e.g. enantioselective reduction), and a boronate moiety (e.g. catalytic cross-coupling), thus offering direct access to a larger collection of otherwise difficult-to-prepare and much sought-after derivatives. The applicability of the approach will be highlighted by a concise and practical gram-scale stereoselective synthesis of two important bioactive compounds. The first will be neocurcumenol, a natural product with anti-inflammatory properties, and the second will be acolbifene, currently in third phase clinical trials for treatment of breast cancer. Equally important, the versatility of the catalytic strategy will allow for facile preparation of host of related analogues – entities that might display superior pharmacological properties and cannot be synthesized easily by the available methods.
