Rhodium-Catalyzed Carbocyclizations of Alkylidenecyclopropanes with Allenes and Carbon Monoxide: Stereoselective Construction of Six- and Seven-Membered Rings
Negru, Elena Daniela
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This thesis is divided in the following manner: Chapter 1 offers a short introduction, Chapter 2 describes the higher-order rhodium-catalyzed semi-intermolecular [(3+2)+2] carbocyclizations of alkylidenecyclopropanes (ACPs) with allenes, Chapter 3 highlights our results with respect to the rhodium-catalyzed semi-intermolecular [(3+2)+1] carbocyclizations of ACPs and carbon monoxide, while Chapter 4 covers the conclusions and future recommendations. Section 2.1 provides an introduction into the metal-catalyzed carbocyclizations, followed by a description of three-carbon synthon utilized in higher-order carbocyclizations. Section 2.2 particularly focuses on the reactivity of ACPs towards different transition metals to provide three-carbon surrogates in this type of cycloadditions. Section 2.3 describes the metal-catalyzed cycloaddition reactions that employ allenes as exogenous two-carbon π-components, and concomitantly highlight the challenges associated with controlling chemo-, regio- and stereoselectivity for these processes. The development of the rhodium-catalyzed [(3+2)+2] carbocyclization of alkyne-tethered ACPs is discussed in Section 2.4, which includes the optimization studies, the scope with respect to both substrates and also a plausible reaction mechanism, which accounts for the exclusive formation a single geometrical and regioisomer. Section 2.5 describes the isolation of the key rhodacycle intermediate and its application towards the development of a highly enantioselective [(3+2)+2] carbocyclization of alkene-tethered ACPs and allenes. We were able to isolate the corresponding cyclic adduct in 90:10 enantiomeric ratio and excellent regio- and diastereoselectivity. Chapter 3 commences with an introduction to the Pauson–Khand reaction (PKR) and continues with the description of the intra- and intermolecular [3+2+1] carbocyclization reactions (Section 3.1). The following section details our efforts towards the development of the diastereoselective rhodium-catalyzed [(3+2)+1] carbocyclization of alkenylidenecyclopropanes and carbon monoxide. In collaboration with Prof. M.-H. Baik’s group, we employed high-level DFT calculations, which were supported by experimental studies, in order to construct a reliable hypothesis and demonstrate the scope for this reaction. All reactions afforded the six-membered bicycles in excellent yield and diastereoselectivity. Finally, Section 3.3 describes an extension of this [(3+2)+1] carbocyclization reaction by employing alkyne-tethered ACPs to construct substituted bicyclic phenols. Overall, the methodologies described in this thesis have the potential of being utilized as key steps in the synthesis of important natural products (e.g. guaianolides).