Doctor of Philosophy

dissertationPalladium-catalyzed alkene difunctionalization reactions represent a powerful methodology for the construction of diverse carbon-carbon and carbon-heteroatom bonds. The success of these transformations requires the effective stabilization of alkyl- Pd intermediates generated following migratory insertion of an alkene. Stabilization of Pd-intermediates helps to prevent side reactions, thus enabling the formation of desired difunctionalization products in high selectivity. Chapter 1 examines distinctive methods used for the interception of alkyl-Pd intermediates and the strategies associated with minimizing byproduct formation. The Sigman laboratory has been interested in alkene difunctionalization reactions that take advantage of the unique reactivity of n-allyl/benzyl stabilized intermediates in order to generate significant molecular complexity from simple starting materials. Chapter 2 details the development of the Pd-catalyzed 1,4-difunctionalization of the commodity chemical 1,3-butadiene, which affords difficult to access skipped polyene products. This transformation regioselectively functionalizes the two terminal alkenes of 1,3-butadiene by means of a a ^ n ^ a isomerization of cationic Pd-intermediates. The utility of the 1,4-difunctionalization of 1,3-butadiene is highlighted by the synthesis of a highly functionalized skipped triene-containing fragment of ripostatin A. Chapter 3 describes an advancement of the 1,4-difunctionalization reaction, namely using isoprene as the 1,3-diene substrate to generate skipped diene-containing terpenoid products. This method presents an added challenge resulting from the use of a 1,3-diene with two inequivalent alkenes that can contribute to complex isomeric product mixtures as the result of unselective alkene insertion. Through the use of pyridineoxazoline- type ligands, good site selectivity of alkene insertion has been achieved. Mechanistic studies that combine design of experiments with systematic multiparameter ligand modulation ultimately suggest that the electronic asymmetry and steric properties of the ligand are critical to the observed enhancement in site selectivity of alkene insertion. The development of a 1,3-difunctionalization of terminal alkenes using 1,1- disubstituted vinyl triflates and boronic acids is discussed in Chapter 4. This transformation is realized using a novel difunctionalization strategy, and generates a new C(sp2)-C(sp2) double bond as well as a C(sp3)-C(sp2) bond. Dependent on the boronic acid coupling partner, the reaction affords skipped diene or allylic arene products stereoand regioselectively

Palladium-Catalyzed 1,3-Difunctionalization Using Terminal Alkenes with Alkenyl Nonaflates and Aryl Boronic Acids

A Pd-catalyzed 1,3-difunctionalization of terminal alkenes using 1,1-disubstituted alkenyl nonaflates and arylboronic acid coupling partners is reported. This transformation affords allylic arene products that are difficult to selectively access using traditional Heck cross-coupling methodologies. The evaluation of seldom employed 1,1-disubstituted alkenyl nonaflate coupling partners led to the elucidation of subtle mechanistic features of π-allyl stabilized Pd-intermediates. Good stereo- and regioselectivity for the formation of 1,3-addition products can be accessed through a minimization of steric interactions that emanate from alkenyl nonaflate substitution

Hybrid Enzymatic and Organic Electrocatalytic Cascade for the Complete Oxidation of Glycerol

We demonstrate the complete electrochemical oxidation of the biofuel glycerol to CO₂ using a hybrid enzymatic and small-molecule catalytic system. Combining an enzyme, oxalate oxidase, and an organic oxidation catalyst, 4-amino-TEMPO, we are able to electrochemically oxidize glycerol at a carbon electrode, while collecting up to as many as 16 electrons per molecule of fuel. Additionally, we investigate the anomalous electrocatalytic properties that allow 4-amino-TEMPO to be active under the acidic conditions that are required for oxalate oxidase to function

Mechanism and Selectivity in the Pd-Catalyzed Difunctionalization of Isoprene

The three-component coupling of isoprene, an alkenyl triflate, and styrenylboronic acid catalyzed by a palladium pyrox complex affords access to skipped dienes from simple chemical feedstocks. Unfortunately, the transformation proceeds with only moderate selectivity and yields. The reaction mechanism and factors responsible for the resulting regioselectivity were elucidated using M06/SDD/6-311++G­(d,p) + SMD calculations. Distortion of the palladium coordination sphere in the transition structure of the migratory insertion step is found to control the 4,1- vs 1,<i>x</i>-selectivity. The calculated ΔΔ<i>G</i>^⧧ of 1.0 kcal/mol for this step is in excellent agreement with the experimentally observed selectivity of 1:9.9 disfavoring the 4,1-product. The transmetalation was found to be the regioselectivity determining step for the formation of the 1,2- vs 1,4-addition products. Systematic conformational searches for the transmetalation transition structure revealed a series of steric interactions between the <i>t</i>-Bu substituent on the ligand and the substrates in the model system that are balanced by additional repulsive interactions between the substrates and the pyridyl portion of the ligand. The combination of these effects leads to the low to moderate 1,2- vs 1,4-selectivity in the experimentally studied system

Cu-Mediated C–H ¹⁸F‑Fluorination of Electron-Rich (Hetero)arenes

This communication describes a method for the nucleophilic radiofluorination of electron-rich arenes. The reaction involves the initial C­(sp²)–H functionalization of an electron-rich arene with MesI­(OH)­OTs to form a (mesityl)­(aryl)­iodonium salt. This salt is then used in situ in a Cu-mediated radiofluorination with [¹⁸F]­KF. This approach leverages the stability and availability of electron-rich arene starting materials to enable mild late-stage radiofluorination of toluene, anisole, aniline, pyrrole, and thiophene derivatives. The radiofluorination has been automated to access a 41 mCi dose of an ¹⁸F-labeled nimesulide derivative in high (2800 ± 700 Ci/mmol) specific activity