Organocatalyzed Enantioselective Synthesis of α-Amino Acid Esters, β-Hydroxycarbonyl Compounds, Pyrano[2,3-b] Pyrans and α-Amino Acid Derivatives




Konda, Swapna

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Performing asymmetric transformations is one of the most challenging areas of organic chemistry. Most importantly, within a chiral surrounding, two enantiomeric biologically active agents often behave differently. Therefore, to develop an enantioselective synthesis of the desired enantiomer in an asymmetric transformation is highly desirable in medicinal chemistry as well as in the pharmaceutical industry. Over the last fifteen years the field of organocatalysis has grown from a small collection of unique or unusual chemical reactions to a thriving area of research with a very broad scope of reactions, and a typical reactivities and selectivities. It has now become a well established approach for asymmetric organic synthesis. This dissertation describes the highly enantioselective synthesis of versatile synthetic intermediates in the synthesis of a multitude of important chiral compounds. The organocatalysts used in this study are bifunctional and are capable of activation both the nucleophile and the electrophile simultaneously and frequently demonstrate superior reactivity and stereoselectivity. This dissertation work demonstrates that cinchona alkaloid-derived thioureas are superior organocatalysts for the synthesis of enantiomerically enriched biologically active molecules, such as α-amino acid esters or α-hydroxy acid esters and β-hydroxy carbonyl compounds. Organocatalysis is currently one of the fastest growing fields of research in organic chemistry. Catalysis by metal free organic molecules has been known in organic chemistry for more than 100 years, but its full potential was recognized only until the 21st century. Today, the most applications of organocatalysts are in asymmetric reactions. Development of new chiral catalysts is normally based on the structural tuning of known catalysts and on the synthesis of catalyst libraries. Catalyst development is a time consuming and complex process. The prediction of catalyst properties such as selectivity and reactivity is very difficult and the substrate scope of any given catalyst is usually narrow. Most of the reported organocatalysts have the reaction center moiety and the stereocontrolling moiety in the same molecule connected by covalent bonds. This design is highly effective in achieving stereocontrol, but is disadvantageous for the modification and fine tuning of catalyst structures. The aim of the thesis is to bridge the gaps in the catalyst synthesis, which is suitable for high throughput screening. We designed target organocatalyst in a simplified way, it is synthesized in-situ from the self-assembly of the precatalyst modules (proteogenic α-aminoacids and cinchona alkaloid derivatives) through ionic interactions. Enantioselectivity and reactivity may be fine-tuned to a substrate or specific reaction by simply replacing the modules, without the need of synthesizing new chiral catalysts.


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Asymmetric Organocatalysis