ABSTRACTThis dissertation consists of an account focused on the development of spiroketal: a key pharamacophoric unit for the drug discovery. Chapter I is further subdivided into three sections: the first section discusses the development of a novel diastereoselective protocol for the synthesis of mono-bromospiroketal. The development of this methodology builds on our previously developed concepts of HalA and NAAA utilizing the potent power of a weakly nucleophilic ketone towards halo-functionalization and further entrapment of the carbocation through a pendant alcohol. Fine tuning the protection on the alcohol was instrumental in the development of a highly diastereoselective process. The second section is dedicated to the asymmetric development of the same reaction which delves deep into the development of a new class of Brønsted acidic catalyst. This acccount portrays a structure-guided approach for the optimization of VANOL-derived imidodiphosphorimidates as catalysts for the halonium-ion-induced spiroketalization reaction. Fine tuning of the catalyst active site, alongside enhanced acidity, were required to achieve high catalytic activity for the spiroketalization reaction. A wide range of substrates were well tolerated yielding halogenated spiroketals in high yields, diastereoselectivities, and enantioselectivities. The third section is dedicated to the development of benzannulated spiroketals through desymmetrization. Initial attempts were successful in the development of a highly diastereoselective protocol. Current efforts are focused on the development of an asymmetric variant utilizing our previously developed VANOL/VAPOL based catalyst.Chapter II describes an application of the previously discovered methodology towards the total synthesis of the natural product Obtusin. The enabling role of the protecting group on the nucleophilic oxygen atom presents a unique discovery that can improve the reaction outcome. Chapter III depicts the development of three independent methodologies from a critical observation during the mono-bromospiroketalization reaction. Variation of reaction condition enables the shifting of the equilibrium either towards the formation of macrocyclic ether or towards the formation of double anomeric or single anomeric products leading to the generation of cores that are biologically active. A wide range of substrates were well tolerated yielding halogenated macrocyclic ethers and spiroketals in high yields and excellent diastereoselectivities.
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