Development of New C-C/C-N Bonds: Formation of Highly Substituted Centers in Diarylheptanoids and Indole Alkaloids

Natural products display a vast array of chemical groups and atoms in different spatial arrangements providing novel chemical space, and they remain one of the best sources of potential drug candidates and leads. We concentrated on two classes of natural products, calyxins and 3,3’-pyrrolidinyl-spirooxindole natural products, that have intriguing architecture scaffolds and promising biological activity.

Containing all-carbon tertiary centers, calyxins are a subclass of diarylheptanoid natural products. Inspired by the capability and advantages of titanocene chemistry to construct carbon−carbon bonds, we sought to develop a titanocene-catalyzed method to access calyxin diarylheptanoids. We developed a catalytic protocol for the synthesis of all-carbon tertiary centers that allows for the mild generation of a propargyl organometallic that proceeds with a high degree of regioselectivity in the carbonyl addition event. Our protocol utilizes a combination of catalytic titanocene and stoichiometric Zn dust to facilitate the metallation of readily prepared propargylic acetates.

Containing all-carbon quaternary spirocenters, 3,3’-pyrrolidinyl-spirooxindole cores are found in many spirooxindole products and exhibits a range of biological activity. Our approach focuses on assembling the quaternary carbon spirocenter in a single, convergent approach through two sequential bond formations. We envisioned this occurring through a [4+1]-cycloaddition pathway. Sequential bond formations for the constructing quaternary carbon center from the Kukhtin-Ramirez redox condensation of 1,2-dicarbonyls and trivalent phosphorus were examined. This method was applied in the synthesis of bis-spirocyclopropyl oxindoles, which show promising cytotoxicity towards human breast and brain cancer cell lines. We also evaluated various nitrogen containing 1,3-heterodiene components for the construction of 3,3’-pyrrolidinyl-spirooxindole cores, and aryl imines in the presence of BF₃OEt₂ facilitated addition of the phosphonium enolates followed by N-alkylation to give the corresponding aziridines in modest yields.

We demonstrated the use of diazooxindoles in a Rh(II)-catalyzed, formal [4+1]-cycloaddition toward the construction of spirooxindole pyrrolones employing vinyl isocyanates as 1,3-heterodiene surrogates. The method exhibits good tolerance to a diverse array of functional groups and substitution patterns across each component, and unsaturated spiro-γ-lactams are amenable to further synthetic manipulations pertinent to target directed synthesis. The intermediacy of a cyclopropyl isocyanate enables ring expansion to the corresponding 5-membered N-heterocycle to occur under comparably milder conditions than previously established photochemical and thermal rearrangements of cyclopropylimines.

Through the use of a chiral rhodium(II)-catalyst, enantioselective cyclopropanation of diazooxindole and vinyl isocyanate was achieved, and through further functionalization by hydrogenation and hydrosilylation reduction protocols the chiral spirooxindole pyrrolone was accessed. Preliminary investigation into palladium-catalyzed [4+1]-cycloaddition to provide 3,3’-pyrrolidinyl-spirooxindole cores is also reported herein.