Date of Award

Fall 2015

Degree Type

Dissertation

Degree Name

PhD. Chemistry

Department

Chemistry and Biochemistry

Advisor

John R. Sowa Jr., Ph.D

Committee Member

David Sabatino, Ph.D

Committee Member

Cecilia Marzabadi, Ph.D

Committee Member

Nicholas Snow, Ph.D

Keywords

Asymmetric Transfer Hydrogenation, Allylic Alcohol, Ruthenium, Reaction Method

Abstract

This dissertation highlights the developments and optimization of a new reaction method that transforms racemic secondary allylic alcohols into optically active secondary alcohols. The key step in this methodology occurs through a ruthenium catalyzed tandem isomerization and asymmetric transfer hydrogenation reaction. This reaction is a one pot, two-step process, which utilizes the unique ability of a transition metal catalyst to effect a combined reduction of the C-C double bond and the carbonyl group in a selected class of secondary allylic alcohols.

With a-vinyl benzyl alcohol as substrate, the optimal catalyst for this reaction was generated in situ from a di-μ-chlorobis[(p-cymene)chlororuthenium (II)] complex and the chiral ligand (S,S)-TsDPEN in the presence of potassium hydroxide as a base to afford yields of up to 97% and up to 93% enantiomeric excess (ee) for the desired chiral secondary benzyl alcohol.

Moreover, a series of substituted a-vinyl benzyl alcohols with electron-donating groups (EDG) and electron withdrawing groups (EWG) were tested under the optimized asymmetric transfer hydrogenation (ATH) conditions in order to explore their effects on chemical reactivity. Interestingly, the ortho-methyl substituent in a-vinyl tolyl alcohol and the sterically encumbered internal alkene in trans-1,3-diphenyl-2-propen-1-ol had the most adverse effects on chemical reactivity (77-86% yields) and enantioselectivities (30-40% ee). Both EWG and EDG at the para-positions were found to be well tolerated and exhibited good product yields (>80%) and enantioselectivities (>90%) underscoring the influence of steric crowding on the reactivity of starting materials.

The mechanism for the isomerization and ATH reaction was proposed to proceed through the transposition of the allylic double bond to generate a carbonyl compound. This reactive intermediate was then reduced to the corresponding chiral secondary alcohol through a metal-ligand bifunctional pathway.

Taken altogether, this thesis describes an important development in the isomerization and ATH reaction of the challenging secondary allylic alcohols. This discovery is not only an essential contribution to this broad reaction class but also in its application towards the synthesis of important targets, such as the LTD4 antagonist currently marketed as SingulairTM.

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