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Open Access Publications from the University of California

Reaction Discovery Using Nickel Catalysis and Total Syntheses of Indolactam Alkaloids

  • Author(s): Fine Nathel, Noah Frederick
  • Advisor(s): Garg, Neil K
  • et al.

Transition metal-catalyzed cross-coupling reactions are useful tools to assemble carbon–carbon (C–C) and carbon–heteroatom (C–X) bonds. Traditionally, electrophilic halides and pseudohalides have been cross-coupled to their nucleophilic counterparts with palladium. Recently, however, the implementation of nickel as a catalyst for cross-coupling reactions has enabled the use of less reactive cross-coupling partners, such as carbamates, sulfamates, and amides. This dissertation describes the development of nickel-catalyzed cross-couplings of untraditional electrophiles to forge carbon–heteroatom (C–X) bonds. Additionally, the total syntheses of four indolactam alkaloids, indolactam V, pendolmycin, lyngbyatoxin A, and teleocidin A-2, using both a key distortion-controlled indolyne reaction and palladium-catalyzed sp2–sp3 C–C bond construction, are described.

Chapters one and two describe the development of nickel-catalyzed amination reactions of aryl electrophiles to form carbon–nitrogen (C–N) bonds. The amination reaction of aryl carbamates to form aryl amines is discussed. Subsequently, the development of green cross-couplings of aryl sulfamates and chlorides to similarly form aryl amines is reported.

Chapter three introduces a means to accomplish a controlled cine substitution. This two-step process is comprised of a carbamate-directed ortho-lithiation/functionalization of an arene, followed by a nickel-catalyzed reductive deoxygenation of the directing group. This sequence provides a new strategy for synthesis and complements the more commonly employed ipso substitution in arene functionalization.

Chapter four concerns the utility of amides as electrophilic cross-coupling partners. These traditionally unreactive moieties are activated by nickel and coupled to alcohols to form acyl C¬–O bonds. This study suggests that amides may serve as useful building blocks to construct C–X and C–C bonds.

Chapter five describes the total syntheses of (–)-indolactam V and its C7-substituted natural product derivatives, (–)-pendolmycin, (–)-lyngbyatoxin A, and (–)-teleocidin A-2. The C4–N linkage is constructed with a distortion-controlled indolyne functionalization. The total synthesis of (–)-indolactam V provides a platform for the divergent syntheses of the other three natural products via a palladium-catalyzed cross-coupling to functionalize C7 and introduce a quaternary center.

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