Date of Award
Doctor of Philosophy
Levi M. Stanley
The prevalence of nitrogen heterocycles in medicinally important compounds has, for years, inspired synthetic chemists for developing strategies to form new heterocyclic scaffolds and methods that streamline the syntheses of complex heterocycles. Giving into the cause, this dissertation primarily focuses on development of transition-metal catalyzed hydroacylation of alkenes as a platform for enantioselective synthesis of multiple classes of polycyclic nitrogen heterocycles.
Development of catalytic, enantioselective intramolecular hydroacylation of N-vinylindole-2-carboxaldehydes that occur in the presence of a readily accessible rhodium catalyst and form chiral, non-racemic 2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ones in high yields and enantioselectivities has been described. The dihydropyrroloindolone products can be readily transformed to dihydropyrroloindoles that are core structures present in a variety of natural products and biologically relevant compounds. This methodology could be extended to hydroacylations of N-allylindole- and N-allylpyrrole-2-carboxaldehydes in construction of six-membered rings that generated 7,8-dihydropyrido[1,2-a]indol-9(6H)ones and 6,7-dihydroindolizin-8(5H)-ones in moderate to high yields with excellent enantioselectivities. In contrast to many alkene hydroacylations that form six-membered rings, these endo-selective annulative processes occur in the absence of ancillary functionality to stabilize the acylrhodium(III) hydride intermediate.
Our protocol for rhodium-catalyzed hydroacylation of N-vinylindole-2-carboxaldehyde could be leveraged for installation of stereochemical triad in 2,3-dihydro-1H-pyrrolo[1,2-a]-indole core of putative structure of yuremamine. The enantioselective model synthesis was achieved in 39% overall yield and 96% ee over 5 steps. An enantioselective synthesis of a densely functionalized dihydropyrroloindolone that maps onto the putative structure of yuremamine is demonstrated in 26% yield and 97% ee over 8 steps.
Additionally, exo-selective nickel- and NHC-catalyzed hydroacylations could be coupled with catalytic enantioselective -(hetero)arylation reactions in a sequential synthetic strategy to form a wide variety of nitrogen-containing heterocyclic ketones bearing -chiral quaternary stereogenic centers. Exo-selective, intramolecular Ni-catalyzed hydroacylations of N-homoallylindole- and N-homoallylpyrrole-2-carboxaldehydes form -substituted six-membered heterocyclic ketones in up to 95% yield, while N-heterocyclic carbene (NHC)-catalyzed hydroacylations of N-allylindole- and N-allylpyrrole-2-carboxaldehydes form -substituted five-membered heterocyclic ketones in up to 99% yield. The racemic five- and six-membered products of Ni- and NHC-catalyzed hydroacylation reactions are readily transformed into heterocyclic ketones containing an -chiral quaternary stereogenic center by enantioselective Ni-catalyzed -arylation and -heteroarylation reactions. The identity of the precatalyst for Ni-catalyzed -(hetero)arylation is dictated by the identity of the –substituted heterocyclic ketone starting material. -(Hetero)arylations of six-membered heterocyclic ketones occur at 65-85 ÃÂ°C in the presence of a catalyst generated in situ from Ni(COD)2 and (R)-BINAP or (R)-DIFLUORPHOS. -(Hetero)arylation of five-membered heterocyclic ketones must be conducted at room temperature in the presence of an [((R)-BINAP)Ni(2-NC-Ph)] precatalyst or a catalyst generated in situ from Ni(COD)2, (R)-DIFLUORPHOS and benzonitrile.
Finally, studies on Ni2P nanocrystal catalyzed hydrogenation of phenylacetylene have been reported. The model reaction is studied with both hollow and solid Ni2Ps in two different solvents (1,4-dioxane and 1-propanol). Recycling studies in both solvents demonstrated increase in catalytic activity of Ni2P nanocrystals over reaction cycles. Structural characterization of recycled Ni2P nanocrystals via powder XRD, TEM and XPS analyses revealed reduction in size of hollow nanoparticles along with the formation of Ni(II) species after hydrogenation reactions. Systematic characterization of Ni2P nanocrystals isolated after each reaction throughout the lifetime of recycling study (in both 1,4-dioxane and 1-propanol) has been demonstrated.
Ghosh, Avipsa, "Transition Metal-Catalyzed Alkene Hydroacylation as a Platform for Enantioselective Synthesis of Polycyclic Nitrogen Heterocycles" (2016). Graduate Theses and Dissertations. 15919.