Date of Award
Open Access Dissertation
Chemistry and Biochemistry
Sheryl L. Wiskur
The work contained herein focuses on the methodology and design of new reactions for the production of stereoenriched compounds. The primary focus of research discussed is kinetic resolution, a classic and powerful methodology for the separation of a single enantiomer from a racemic mixture. In 2011, a silylation-based resolution catalyzed by a chiral isothiourea produced synthetically useful selectivity factors for mono-functional secondary alcohols. In chapter 2, this methodology was subsequently expanded to include α-hydroxy lactones with selectivity factors up to 100. This study resulted in the most selective reaction reported to date for the aforementioned silylation-based resolution. In addition to lactones, α-hydroxy lactams, amides and esters were resolved with synthetically useful enantioselectivity. This is notably the first successful non-enzymatic resolution of hydroxy lactams ever reported.
In an effort to remove chromatography completely from the kinetic resolution process, an alternate polymer-supported version of the reaction was studied. The successful use of polymer-bound triphenylsilyl chloride to eliminate chromatographic purification steps is contained in Chapter 3. The polymer-supported reagent was utilized to produce useful selectivities for the resolution of benzylic alcohols and α-hydroxy lactones. The polymer-bound silyl source was also successfully recycled without loss in enantioselectivity.
In Chapter 4, our attempts to elucidate the mechanism of the kinetic resolution via reaction progress kinetic analysis will be demonstrated. Preliminary results of this investigation suggest the reaction is very sensitive to silyl chloride concentration. This finding suggests a more complex reaction than our previous hypothesis. Additionally, a stereoenriched silyl chloride was tested in the silylation reaction. The overall inversion of stereochemistry observed in these experiments does not support our previously proposed double inversion mechanism. Results of the kinetic studies and chiral probe reactions will be utilized to propose a plausible mechanistic cycle for the silylation reaction.
Finally, research to expand silylation-based resolutions to include an asymmetric borane Lewis acid catalyzed silicon-oxygen coupling will be highlighted. A variety of stereogenic at silicon silanes were prepared and tested in the reaction. The low diastereoselectivity of these reactions does not support the ability to affect resolution of racemic alcohols via this method. The reaction was further complicated by reactivity that appeared substrate-dependent. The results of the silicon-oxygen coupling kinetic resolution of substrates to include secondary alcohols and propargylic alcohols will be discussed in Chapter 5.
Clark, R. W.(2015). A Silylation-Based Kinetic Resolution of Hydroxy Lactones and Lactams with Subsequent Mechanistic Investigations. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/3662