57th Annual Report on Research 2012 Under Sponsorship of the ACS Petroleum Research Fund

Under the auspice of American Chemical Society Petroleum Research Fund (ACS PRF), we have made some important progresses in the area of enantioselective catalysis of oxidative cyclization reactions by small organic molecule cooperative catalysis.

Selective catalysis of triene cyclizations has been a challenge for synthetic chemists.  The cyclized products contain unique functional groups, and they are often difficult to access by other means.  One possible Stetter cyclization product, a densely-functionalized cyclopentenone, is of particular importance, since it contains a quaternary stereogenic center and an adjacent conjugated diene.  Chiral N-heterocyclic carbenes (NHCs) belong to a class of privileged Lewis bases in asymmetric organocatalysis. Although a few impressive examples of NHC catalysis with low catalyst loadings have been reported, most intramolecular Stetter cyclizations with activated olefins require relatively high catalyst loadings ( ≥10 mol %).  We have developed highly enantioselective Stetter cyclizations to densely functionalized cyclopentenones.  We also discovered that a catalytic amount of external acetic acid could stabilize the active NHC catalyst, which enables efficient reactions with low catalyst loadings (down to 2.5 mol %).

During the initial catalyst screen, we were surprised to discover that catalytic efficiency of NHCs seemed to depend crucially on the Brønsted base and acid co-catalysts.  To our surprise, well-established reaction conditions for intramolecular Stetter cyclizations were ineffective in this system: NHC catalyst barely achieved a single turnover, in the presence of strong non-nucleophilic bases, including KHMDS and KOt-Bu.  Neither organic bases, nor K₂CO₃ could effectively turn over the catalytic cycle.  The incomplete conversion under these conditions suggests that the integrity of the catalyst was largely compromised, a finding rarely reported in the literature.

The aforementioned Brønsted bases are capable of generating sufficient quantities of NHC through deprotonation.  However, the data suggest the decomposition of active catalyst significantly compromises the reaction efficiency.  For this reason, we explored carboxylates that have much weaker Brønsted basicity, which emerge as uniquely effective reagents.  A catalytic amount (20 mol % each) of NaOAc and triazolium salt co-catalyzed a highly enantioselective reaction with excellent efficiency (97% ee and 85% yield within 5 h).  Although NaOBz provided less impressive rate acceleration compared to that of NaOAc, the same ee was observed in each case.  These data suggest that carboxylates are likely involved in the rate-determining step (RDS), but not in the enantioselectivity-determining step in the catalytic cycle.

Under optimized conditions, a variety of (2E, 4Z, 6E) trienes with different steric and electronic properties were studied.  We applied 5 mol % of catalyst for most substrates so that most reactions can complete within 40 h.  Electron-withdrawing and moderately-donating groups on the aromatic region  were well tolerated, and cyclopentenones were isolated with excellent yields and ees (92–96% yield, 98–99% ee).  The presence of strong electron-donating groups retarded the reaction rate, but the isolated yields were minimally affected (75% and 87% yield, 99% ee).  The introduction of an additional alkyl group was tolerated (up to 94% yield, >99% ee) and the cyclization efficiency of substrates with large substituents was maintained as well.

In summary, we have developed a highly enantioselective Stetter cyclization of a conjugated triene to access highly functionalized cyclopentenones with low catalyst loadings (down to 2.5 mol %).  The substrate scope for this method is general and the cyclization products are synthetically useful.  Through mechanistic studies, we discovered that AcOH co-catalyst is crucial in preventing active NHC catalyst decomposition and facilitating the NHC turnover.  The design and discovery of other robust catalytic systems enabled by cooperative catalysis is underway.

Two graduate students particiated in this research and they learned enormously about organic synthesis, physical organic chemistry, catalysis, molecular design and modeling, and asymmetric synthesis and separation techniques.  Both of them defended their MS Theses in May on this topic.  This project has set the firm foundation of studying catalytic enantioselective reactions (either by small organic molecule or metal-ligand complex catalysts) in our lab and at Georgia State University.  We really appreciate the general support from ACS PRF.