Our interest in targets containing substituted tetrahydropyran units inspired the development of a new methodology involving a one pot, highly diastereoselective Sc(III)-catalyzed synthesis of 2,6-cis-disubstituted tetrahydropyran rings. We demonstrated the powerful bond-forming ability of this strategy in our syntheses of neopeltolide and (–)-exiguolide, in which the key bond-forming steps involved concurrent formation of the pyran ring and closure of the macrocycle. This method was further modified to a Prins-type Maitland-Japp reaction, enabling the synthesis of okilactomycin. Biological studies were performed on both neopeltolide and (–)-exiguolide, revealing interesting mechanistic insights of these potential chemotherapeutics.
Carbene Catalysis: Bakkenolides and Protoilludanes
Our interest in transformations facilitated by N-heterocyclic carbenes (NHCs) has inspired us to apply NHC catalysis to the synthesis of complex and biologically-relevant terpene natural products. Using carbene catalysis, facile construction of the hydrindane core of the bakkenolides was accomplished with high levels of selectivity on multigram scale. Further processing of this intermediate afforded bakkenolides I, J, and S. A similar apporach was applied in our recent synthesis of the protoilludanes. Treatment of a linear unsaturated aldehyde with a chiral carbene catalyst afforded the desired annulated product with excellent efficiency, again on multigram scale. This key intermediate was carried on to give echinocidin B and D, isovelleral, and armillaridin.
Complementary to our interest in forming highly functionalized pyranones, we have also pursued the catalytic asymmetric synthesis of benzopyranones, the core structures of flavonoids. This class represents a broad collection of plant secondary metabolites that possess a diverse array of biological activity and medicinal applications, particulary as anti-cancer therapeutics. We sought to mimic the biosynthesis of these compounds using a bifunctional H-bonding/ Brønsted base catalyst as a small molecule analog of the enzyme chalcone isomerase. This strategy was demonstrated using simple alkylidene malonates and then extended to the synthesis of (–)-deguelin, (–)-isosilybin A, and the abyssinone family of natural products.
Alstonine has recently been identified as the major component of a plant-based treatment used in Nigeria by traditional healers to treat psychotic disorders. However, the scarcity and lack of purity from natural sources, as well as the uncertainty regarding its exact mechanism of action drove our interest in the asymetric synthesis of these natural products. The related trans diastereomer, serpentine, exhibits anticancer and antimalarial properties, and there have been limited efforts at elucidating its mechanism of action. We have recently accomplished the first enantioselective total syntheses of alstonine and serpentine with a novel cooperative H-bond donor/enanmine catalysis reaction as the key step. These scalable syntheses will allow for further study of the biological activity of these unique alkaloids.