Rhodium-Catalyzed Enantioselective Coupling Reactions of Arylboronic Acids with Olefins - Synthesis of 1,1,2-Triarylethanes for the Treatment of Pulmonary Diseases
Final Report Abstract
The funded project dealt with enantioselective rhodium-catalyzed domino transformations of arylboronic acids with alkynylcyclohexadienones. Domino reactions are a powerful means to construct complex structures starting from relatively simple starting materials since several bonds are generated in a single sequence in one pot. These processes are highly attractive from the perspective of synthetic efficiency, financial cost-savings and the reduction of environmental impact, since time-consuming work-up and purification steps are reduced significantly. The project was based on a mechanism published by Lee (2006) which proposed the 1,1-addition of a Rh‒aryl complex to an alkyne resulting in endo-cyclic double bonds after a subsequent intramolecular cyclization. We designed a similar starting material and wanted to develop a method for the synthesis of fused heterocycles in a domino process, generating two carbon‒carbon bond and two stereocenters in one sequence. However, during our work we discovered ‒ first for our own starting materials and later for Lee's substrates ‒ that this mechanism is not operative which was also proven by an X-ray structure of our product as well as fragmentation experiments with Lee's products. The actual mechanism proceeds via a 1,2-addition of Rh‒aryl complex to the alkyne, thereby generating exo-cyclic double bonds after the subsequent intramolecular cyclization. This discovery finally led to the retraction of Lee's publication (2012). After a thorough optimization of the reaction conditions, which involved the development of new chiral diene ligands, we were able to obtain the respective fused heterocycles in moderate to good yields (up to 74%) and ee's (up to 90% ee). This domino transformation is remarkable insofar, that it generates two carbon‒carbon bonds and two stereocenters in one domino sequence which results in the desymmetrization of the cyclohexadienone moiety. Since the starting materials are easily available from cheap precursors (phenol and propargyl alcohols) the overall process efficiently generates high complexity from very simple building blocks.
