Rhodium(I)-Catalyzed Stereoselective Carbocyclization Reactions with 1,6-Chloroenynes Containing 1,1-Disubstituted Olefins and Total Synthesis of (–)-Fraxinellonone
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Authors
Ylagan, Ridge Michael P
Date
2024-06-12
Type
thesis
Language
eng
Keyword
Rhodium , Transition Metal Catalysis , Pauson-Khand Reaction , 1,6-Enyne , 1,6-Chloroenyne , Enantioselective , Stereoselective , Total Synthesis , Fraxinellonone , Density Functional Theory , [2+2+2] , Cyclopentenone , Cyclohexenone
Alternative Title
Abstract
The transition metal-catalyzed higher order [m+n+o] carbocyclization reaction is an important class of reaction that affords elaborate carbocycles in a highly convergent manner. More specifically, the carbocyclization reactions of 1,6-enynes with unsaturated components is one of the most popular approaches. However, the development of carbocyclization is limited by the low reactivity of highly substituted olefins as reacting component. This thesis focuses on the development of rhodium-catalyzed stereoselective carbocyclization reactions with 1,6-chloroenynes containing 1,1-disubstituted olefins to address the limitation.
Chapter 1 introduces the transition metal-catalyzed higher order [m+n+o] carbocyclization reaction and followed by a focused review of examples using 1,6-enynes containing 1,1-disubstituted olefins, as these processes afford quaternary stereogenic centers. The review is divided into: Pauson-Khand reaction (“PKR”) and [(2+2)+2] carbocyclization reaction with alkynes and alkenes as exogenous component. This review focuses on seminal examples of the above-mentioned substrates to highlight limitations and thereby set the stage for the work completed in Chapter 2-4.
Chapter 2 highlights the development of an enantioselective rhodium-catalyzed Pauson-Khand reaction with 1,6-chloroenynes containing 1,1-disubstituted olefins. Following a review of the historical development of the PKR, our work with 1,6-chloroenynes containing 1,1-disubstituted olefins is discussed. A DFT calculation study on the enantiodetermining transition state of key examples revealed that the stereoelectronic profile of alkynyl chloride enables excellent PK reactivity and enantioselectivity.
Chapter 3 illustrates the development of an enantioselective rhodium-catalyzed [2+2+2] carbocyclization reaction with 1,6-chloroenynes containing 1,1-disubstituted olefins and ethoxyacetylene as ketene equivalent. The chapter first delineates the historical development of the metal-catalyzed [2+2+2] carbocyclization reactions and followed by our approach for the construction of enantioenriched bicyclohexenones. Lastly, our concise total synthesis of the limonoid (–)-fraxinellonone is described.
Chapter 4 describes the construction of [6,5]-bicyclopentenones using an enantioselective rhodium-catalyzed PKR. Future directions to develop this methodology are included.
In summary, this thesis presents a compelling case that incorporating alkynyl chloride in the 1,6-enyne expands the scope of enantioselective rhodium-catalyzed carbocyclization reaction with [5,5]-, [5,6]-, and [6,5]-ring scaffold. We anticipate that these observations will expand the scope of current carbocyclization reactions and facilitate the discovery of new carbocyclization reactions. Hence, 1,6-chloroenyne serves as a conceptual “Universal Alkyne”.