Chapter 1. Mannich-type Reactions of Cyclic Nitrones: Syntheses of (–)-Lobeline and (–)-Sedinone.Piperidine is a very common structural motif of numerous classes of alkaloids and important pharmaceuticals. A particularly common structural feature found in these molecules is the presence of a beta-aminocarbonyl or beta-aminoalcohol moiety. We have developed an enantioselective Mannich-type addition of methyl ketones to nitrones producing the resulting hydroxylamines with high yields and enantioslectivity. The substrate scope of this reaction is broad and includes different 2,3,4-substituted and heterocyclic nitrones, as well as different electron rich- and -deficient acetophenones and alkyl methyl ketones. Additionally, we developed a nitrone variant of Robinson-Schöpf reaction that further expanded the scope to 5- and 7-membered ring and acyclic nitrones, albeit in racemic format. The combination of two developed methodologies provided a powerful tool for the unified approach towards total synthesis of two 2,6-disubstituted piperidine alkaloids: (–)-lobeline and (–)-sedinone. Chapter 2. Enantiospecific Total Synthesis of Chilocorine C. Chilocorine C is a very structurally unique defensive hexacyclic alkaloid that was isolated from ladybug beetles (Coccinellidae). It belongs to a class of “dimeric alkaloids” and is present as a minor component in Chilocorus cacti. We have successfully completed the first total synthesis of chilocorine C via a convergent strategy. Our overall approach includes a carefully orchestrated sequence with several chemoselective transformations, including a specifically designed cascade that accomplishes nine distinct chemical reactions in one-pot, can smoothly forge that domain and ultimately enable a 15-step, 11-pot enantiospecific synthesis of the natural product. Mechanistic studies, density functional theory calculations, and the delineation of several other unsuccessful approaches highlight its unique elements. Chapter 3. Enantiospecific Total Synthesis of Dankasterone B. Dankasterone B represents a unique biologically active cystostatic steroid that was isolated from Halichondria sponge-derived fungus Gymnascella dankaliensis. Structurally, it contains a very rare 13(14→8)abeo-8-ergostane steroid core, that is believed to be a result of a 1,2-migration of the C13–C14 bond to the C8 position. We have successfully accomplished a 20 step total synthesis of dankasterone B as well as the formal total synthesis of dankasterone A and periconiastone A, starting from commercially available (R)-carvone using a convergent strategy. Our synthesis combines several unique elements like Zweifel olefination, diastereospecific intramolecular Heck reaction, diastereoselective Claisen rearrangement to install the ergosterol sidechain and SmI2-promoted late-stage 6-exo-trig cyclization.



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