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Development and Design of Transition Metal-Catalyzed Transformations in Macrocyclizations and Carbon–Carbon Bond Formations

  • Author(s): Riedel, Jan Christian
  • Advisor(s): Dong, Vy M
  • et al.

Cyclic peptides have been recognized for their potential to

mimic protein-protein interactions. Traditionally, cyclizations

are carried out at high dilution to suppress competitive

intermolecular reactions, which makes these cyclizations

economically inefficient and hard to perform at scale.

We developed the use of dehydro amino acids as

traceless turn-inducers to enable macrocyclizations at high

concentrations. We demonstrated our strategy in the

total synthesis of dichotomin E at cyclization concentrations as high as 0.1~M. In collaboration with Prof. Rachel Martin, we studied the origin of the turn-inducing effect by CD-spectroscopy, NMR and molecular mechanics simulations.

Inspired by nature’s ability to take a common precursor like geranyl

pyrophosphate and cyclize it into an array of natural products (e.g.,

sabinene, limonene, camphene, and pinene), we expanded the

cycloisomerization chemistry of 2-allyl-4-pentenal derivatives.

We found that cobalt is a competent catalyst in the synthesis of cyclobutanones

over cyclopentanones. We propose a Co(0) active catalyst.

Building on this chemistry, we extended our methodology by

making bicyclic systems. From a symmetrical starting material we affect a desymmetrization and build \textit{trans}-fused hydrindanones selectively.

Using DFT, we studied the mechanism of a rhodium catalyzed cycloisomerization to understand the structure-selectivity relationship between ligand and reaction outcome. A unprecedented induced-fit mechanism has been found operable, and the insights of these studies led to the design and synthesis of new ligands to access new pathways.

Simple unsaturated nitriles play an important role as flavoring agents

and precursors for fine chemicals and polymers. Traditional synthesis

would involve the use of halides and toxic cyanides. We developed

a method that improves previous approaches by using a Cu(II) catalyst

and di-tert-butyl peroxide to generate alkyl radicals from alkylnitriles.

We used unactivated olefins and simple alkylnitriles in a broad reaction

scope through double sp$^{3}$ C--H activation. Internal as well as terminal

olefins are competent coupling partners. We hypothesize, that the high

chemo- and regioselectivity comes from a directing group effect of the nitrile to the copper catalyst.

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