Asymmetric Synthesis of All-Carbon α-aryl Quaternary Carbonyl Compounds By Palladium-catalyzed Asymmetric Allylic Alkylation (Pd-AAA) and Their Application to the Synthesis of Biologically Important 3,3′-disubstituted Oxindole and α-disubstituted Quaternary β-lactone Frameworks
Date of Award
Doctor of Philosophy
M. Mahmun Hossain
M. Mahmun Hossain, Alexander Arnold, Mark Dietz, Arsenio A. Pacheco, Xiaohua Peng
3, 3′-disubstituted Oxindole, All-carbon Quaternary Carbonyl Compounds, Asymmetric Allylic Alkylation, Asymmetric Catalysis, Palladium, Α-disubstituted Quaternary Β-lactone
The development of catalytic, enantioselective methods for the construction of all-carbon quaternary stereocenters is an outstanding achievement in the recent history of organic chemistry. The palladium-catalyzed asymmetric allylic alkylation (Pd-AAA) reaction has played a key role in creating such stereocenters and has allowed researchers to synthesize a vast number of biologically potent natural products. However, synthetic methodologies to access compounds containing α-aryl groups to the quaternary carbon stereocenters are still rare. The increasing appearance of these all-carbon α-aryl quaternary stereocenters in a growing number of biologically active natural products and pharmaceutical agents creates a pressing need for the ability to construct this important motif enantioselectively.
In this endeavor, a set of acyclic all-carbon α-aryl quaternary stereocenter has been synthesized via intermolecular Palladium catalyzed Asymmetric Allylic Alkylation (Pd-AAA). Here hydroxyacrylate was used as an unprecedented nucleophilic counterpart instead of the widely used ketonic substrate. This produced a very rare all-carbon quaternary aldehydes with good to excellent yields (75–99%) and enantioselectivities ranges between 75–94%. This methodology is not only limited to produce aldehydes, as an analogous ketone with a quaternary α-carbon center has also been synthesized successfully.
Using this methodology, chiral 3,3′-disubstituted oxindole moiety was produced with high yield (80%) and enantioselectivity (82%) from o-nitrophenylhydroxyacrylate in three simple steps. The oxindole framework bearing a tetrasubstituted carbon stereocenter at 3-position is a privileged heterocyclic motif that constructs the core of a large family of bioactive natural products and a series of pharmaceutically active compounds. An intensive research has been conducted to synthesize 3,3′-disubstituted oxindole which resulted in a fair amount of methods to produce such an important moiety. However, to the best of our knowledge, all of the reported methodologies so far have used pre-formed oxindole ring itself or a highly specialized compound as a prochiral starting material to produce asymmetry. Another application of this method includes the synthesis of chiral α-disubstituted quaternary β-lactone from the parent phenylhydroxyacrylate in high yield (87%) and enantioselectivity (94%). β-lactones have recently emerged as important synthetic targets due to their occurrence in a variety of natural products, their utility as versatile synthetic intermediates, and their use as monomers for the preparation of biodegradable polymers.
Asad, Md. Sharif Al, "Asymmetric Synthesis of All-Carbon α-aryl Quaternary Carbonyl Compounds By Palladium-catalyzed Asymmetric Allylic Alkylation (Pd-AAA) and Their Application to the Synthesis of Biologically Important 3,3′-disubstituted Oxindole and α-disubstituted Quaternary β-lactone Frameworks" (2015). Theses and Dissertations. 989.