Boron-Mediated Semireduction of Alkynoic Acid Derivatives
| dc.contributor.author | Grams, Robert Justin | en |
| dc.contributor.committeechair | Santos, Webster L. | en |
| dc.contributor.committeemember | Lowell, Andrew Nesemann | en |
| dc.contributor.committeemember | Bevan, David R. | en |
| dc.contributor.committeemember | Carlier, Paul R. | en |
| dc.contributor.department | Chemistry | en |
| dc.date.accessioned | 2022-10-23T06:00:17Z | en |
| dc.date.available | 2022-10-23T06:00:17Z | en |
| dc.date.issued | 2021-04-30 | en |
| dc.description.abstract | Organoboron compounds are commonly used precursors for a variety of reactions in organic synthesis as is exemplified by the Suzuki-Miyaura cross-coupling, which is ubiquitous in industry and academia. Additionally, the Chan-Evans-Lam cross-coupling, lithiation-homologation, allylboration, and many other reactions rely on boron to achieve otherwise difficult chemical transformations. Thus, developing novel methods towards the regio- and/or stereoselective installation of boron into organic molecules remain important for designing new drugs. Boron reagents are also useful in chemical transformations that do not ultimately install a boron moiety on the organic molecule. We have developed several methods that achieve the trans-selective borylation or semireduction of internal alkynes, a process dominated by transition metals and often results in incomplete (E)-stereoselectivity. This dissertation describes three novel uses of a diboron reagent or pinacolborane that reduce propiolic acid derivates selectively to (E)-alkenes and one method that installs pinacolatoboron yielding exclusively (E)-β-borylacrylamides. We investigated the trans-selective hydroboration of primary and secondary propiolamides as reports in the literature accomplish trans-hydroboration via transition metal catalysis, which are limited in substrate scope. We discovered that addition of n-butyllithium to propiolamide and pinacolborane exclusively yields (E)-β-borylacrylamides in good to excellent yield. During the reaction, deprotonation of the amide with a strong base generates an alkoxide that coordinates to pinacolborane and forms a boronate complex. Upon warming to room temperature, a hydride transfer is directed to the α-carbon generating a β-carbanion that subsequently captures boron. Workup protonates the amide, furnishing the (E)-β-borylacrylamide product. As a follow-up from the trans-hydroboration of propiolamides described above, we developed a complementary semireduction of primary and secondary propiolamides. In this reaction, addition of catalytic amounts of potassium tert-butoxide to propiolamides generates an alkoxide that coordinates to pinacolborane and rapidly produces (E)-cinnamamides in 35 – 96% yield and >99:1 E:Z stereoselectivity. This reaction effectively reduces an internal alkyne to afford a product with trans geometry. A deuterium labeling study provided mechanistic insight for the transformation suggesting that the β-proton in the products is derived from the amide nitrogen of the propiolamide. Further, we demonstrated the utility of this reaction by augmenting the total synthesis of FK866, a potent nicotinamide mononucleotide adenyltransferase (NMNAT) inhibitor, and isolated the cinnamamide product in good yield with >99:1 E:Z stereoselectivity. Using a similar strategy, we investigated the ability of bis(pinacolato)diboron and base to mediate the α-borylation of propiolic acids. We observed the formation of a semireduced product, i.e., cinnamic acid. In the presence of a crown ether and cesium carbonate, propiolic acid is deprotonated and activates bis(pinacolato)diboron. Subsequent α-borylation and β-carbon protonation affords a highly unstable α-boronic acid derivative that undergoes rapid protodeborylation yielding predominantly (E)-cinnamic acids. The dual role of the carboxylate in activating the diboron reagent and directing α-borylation was unprecedented and is the first transition metal-free method to reduce propiolic acids to (E)-cinnamic acids. In contrast with boron activation from in situ generated alkoxide, an alternative approach is using phosphine catalysts—a major interest in the development of transition metal-free methodology. As such, we investigated the ability of phosphines to mediate the borylation of primary and secondary propiolamides. Surprisingly, we observed an efficient semireduction of primary and secondary propiolamides to their respective (E)-cinnamamides in the presence of catalytic n-tributylphosphine and stoichiometric pinacolborane. We surveyed the scope and reactivity of substrates bearing N-substitutions, electron-rich or deficient aryls, and aliphatics using optimized reaction conditions and produced a library of (E)-cinnamamides in 31 – 98% yield with >99:1 E:Z stereoselectivity. Deuterium labeling studies suggest that hydrogens on the α- and β-carbon come from pinacolborane and the amide hydrogen, respectively. We also trapped and characterized a key intermediate using tris(pentafluorophenyl)borane that supports a mechanism wherein the phosphine catalyst activates the propiolamide by conjugate addition. | en |
| dc.description.abstractgeneral | Boron reagents are ubiquitous in chemical reactions utilized in industry and academia. There are many transformations involving the conversion of a boron group into a different functional group. Thus, designing new chemical reactions that install boron onto organic molecules is critical to increasing access to novel drugs, polymers, and other consumables. Modern boron chemistry strives towards transition metal-free chemical reactions to reduce the use of costly, low abundance transition metals, such as palladium and platinum, that are also implicated in environment and human toxicity. This dissertation discusses four novel reactions that rely on the unique reactivity of boron. Three of these methods involve the semireduction of alkynes to alkenes, i.e., a carbon-carbon triple or double bond, respectively. The other method involves the addition of boron and hydrogen to an alkyne producing an unprecedented molecule with potential for subsequent chemical modification or conversion to a drug. Each of the reactions reported in this dissertation were optimized without transition metals and the products are potentially useful in organic synthesis or in the design of pharmaceuticals or in other industries. | en |
| dc.description.degree | Doctor of Philosophy | en |
| dc.format.medium | ETD | en |
| dc.identifier.other | vt_gsexam:30143 | en |
| dc.identifier.uri | http://hdl.handle.net/10919/112256 | en |
| dc.publisher | Virginia Tech | en |
| dc.rights | In Copyright | en |
| dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | en |
| dc.subject | hydroboration • methodology • propiolamide • semireduction • alkynoic acid | en |
| dc.title | Boron-Mediated Semireduction of Alkynoic Acid Derivatives | en |
| dc.type | Dissertation | en |
| thesis.degree.discipline | Chemistry | en |
| thesis.degree.grantor | Virginia Polytechnic Institute and State University | en |
| thesis.degree.level | doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |
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