Organometallic Reactions Development, Mechanistic Studies and Synthetic Applications

The present dissertation describes the research performed at the Technical University of Denmark and The Scripps Research Institute in the period March 2006 – May 2009. The four different topics are not interlinked and can be read independently of each other. The first project describes a mechanistic study of the Barbier allylation of benzaldehydes with six different metals (Zn, In, Sb, Sn, Bi and Mg) in aqueous media.

The mechanism of the allylation was investigated by means of Hammett plots and the secondary deuterium kinetic isotope effect. It was found that all metals except magnesium form a discrete allylmetal species and the rate-determining step is the polar addition to the carbonyl. For magnesium data indicates that the selectivity-determining step is generation of the radical anion of the benzaldehyde.

The second project discusses a concise and enantiopure total synthesis of (+)-pancratistatin from renewable resources by means of methodology developed in the Madsen group. The key step comprises a one-pot zinc-mediated fragmentation of a functionalized carbohydrate and consecutive allylation. The third project was performed in the laboratories of Professor Phil Baran and consisted of the successful total synthesis of the cyclophane cavicularin, which contains a bent aromatic moiety.

The pivotal step in the synthesis embodied a pyrone-alkyne Diels-Alder cycloaddition with CO2-extrusion to deliver the bent aromatic residue. The fourth project involved further development of the conditions previously discovered in the Madsen group for the direct coupling of alcohols and amines to amides under dihydrogen liberation.

The goal was to synthesize isolatable ruthenium catalysts and two 18-electron complexes capable of performing the reaction in excellent yields were prepared and characterized. Furthermore, it was found that several metathesis catalysts were found to be effective in the amidation.