Role of heteroatom chelation in addition and reduction reactions

The ability to control stereochemistry through transition metal chelation has been under investigation since Cram's seminal work in the 1950's. Chelation-control can bring about organization in the transition state or intermediate of a reaction. Due to the high degree of order in a chelated transition state or intermediate, high diastereoselectivities and enantioselectivities are observed in the product distribution. The research presented herein focuses in two areas: (1) The ability of lanthanides, in particular samarium diiodide (Sml2), to promote chelation-control in the reduction of â-hydroxyketones, and (2) The ability of fluorine to act as a template for chelation-control synthesis.

Since 1980, the use of lanthanides, especially samarium diiodide, has found a unique role in synthetic organic chemistry. Although Sml2 has been shown to mediate a variety of organic transformations, the mechanistic details on how these reactions occur is still under investigation. The reduction of â-hydroxyketones using Sml2 has recently been discovered as an efficient method to synthesize anft-l,3-diols in high yields and diastereoselectivities. This research investigates the mechanistic details of this efficient reduction of â-hydroxyketones. The role of substrate, solvent, and proton source has been investigated to determine the optimal conditions for reduction of â-hydroxyketones with high diastereoselectivity.

The second part of this work focuses on the ability of fluorine to act as a template for chelation-control synthesis. Fluorine containing organics have become of importance to medicinal chemists and the pharmaceutical industry. The introduction of fluorine into a pharmaceutical agent has been shown to have dramatic increases in the biological activity in comparison to the non-fluorinated analogue. Although these molecules display increased biological activity, the synthesis of fluorine containing substrates is extremely difficult and costly. The focus of this project was to determine the ability of electronegative fluorine to interact with a Lewis acid and promote a chelated transition state or intermediate. Our investigations have shown that fluorine can chelate to lithium and titanium containing Lewis acids to yield reduction and addition to pendant a-carbonyls in high yields and diastereoselectivities. Excellent diastereoselectivity was observed in the reduction and addition reactions of a - and â-fluoroketones providing products through a chelated intermediate or transition state. This study provides evidence that fluorine is an excellent facilitator for chelation-controlled synthesis..