NIH SuRE Project – Abstract
Heterocycles account for more than 50% of all known organic compounds. Their rich activities in
biological systems are important for pharmaceuticals and natural products. Among the top 200 brand
name drugs, over 75% are heterocyclic compounds. In nature, heterocycles are active components for
defense, communication, and reproduction. Low regioselectivities, low stereo-/enantioselectivities,
lengthy synthetic sequences, and low overall yields in most multi-step syntheses make it extremely
challenging to provide sufficient quantities of desired bioactive heterocycles for therapeutic purposes.
This NIH SuRE proposal aims to develop and utilize highly selective metal catalyzed carbon carbon
bond formation reactions that will lead to efficient synthesis of novel selenium, sulfur, and oxygen-
containing heterocycles with rich biological activities. This proposal also aims to develop
multicomponent coupling processes for rapid generation of functionality and complexity in heterocycles,
a new selective merged asymmetric conjugate addition-acylation as well as a merged conjugate
addition-oxidation strategy that will lead to the synthesis of new classes of bioactive selenium, sulfur-
containing heterocycles. The proposed new C-C bond formations and multicomponent reactions will
provide new opportunities for complex novel heterocycle synthesis. The metal-catalyzed conjugate
addition of nucleophiles onto polyenic Michael acceptors is one of the most attractive and powerful C-C
bond forming strategies for synthesis of relevant molecules, as it provides opportunity for sequential
generation of two or more stereogenic centers in a straightforward fashion. The multicomponent
reactions enabled by direct trapping of metal enolates could provide powerful transformations for the
formation of multiple C-C bonds and chiral centers in a single pot. The resultant versatile heterocyclic
subunits and trapping of the metal enolates in situ will provide excellent opportunities for new innovative
approaches for novel complex heterocyle synthesis and drug discovery. Further elaboration of this
chemistry will likely allow the first enantioselective synthesis of very important classes of heterocycles
such as biselenoflavonoids, bithioflavonoids and bioactive biflavonoids, potential small molecule
therapeutics for Alzheimer’s disease. This SuRE project is expected to significantly enhance and
expand the research capacity towards a sustainable research excellence at WSSU, a HBCU.