Thesis advisor: Amir H. Hoveyda / Abstract Chapter 1: Development of Efficient and Kinetically E-Selective Cross-Metathesis to Generate Alkenyl Halides We have devised a broadly applicable strategy to achieve kinetically E-selective cross-metathesis to generate a valuable set of E-alkenyl chlorides and fluorides in high efficiency. The synthetic utility was demonstrated through several concise syntheses of E-alkenyl chloride and fluoride precursors to biologically active molecules. The design principles delineated in this study are expected to initiate a wider range of efficient and kinetically controlled E-selective olefin metathesis processes where there is a diminished preference for the E isomer such as macrocyclic ring-closing metathesis. Chapter 2: Development of Efficient and Kinetically E-Selective Macrocyclic Ring-Closing Metathesis We devised a strategy to achieve high E selectivity in ring-closing metathesis to afford E-macrocyclic alkenes of various ring sizes regardless of the associated thermodynamic preferences. The key findings revealed that E-alkenylB(pin), widely recognized for its broad use in catalytic cross-coupling chemistry, possesses the appropriate steric and electronic attributes to serve as a suitable cross-partner in ring-closing metathesis with Mo alkylidenes. Synthetic utility was demonstrated through ring-closing metathesis at a late stage of a multi-step route. The investigation described herein offers a practical solution to a compelling problem in olefin metathesis, further elevating the utility of this widely used transformation. Chapter 3: Stereoselective Synthesis of E- and Z-Trisubstituted Alkenes by Combining Stereoretentive Catalytic Cross-Metathesis and Catalytic Cross-Coupling We introduced a general solution to a longstanding and compelling problem in olefin metathesis: a broadly applicable strategy for the reliable and efficient synthesis of acyclic E- and Z-trisubstituted alkenyl halides. Complications resulted from the formation of an unstable methylidene species or less reactive disubstituted alkylidene complexes can be addressed by utilizing a stereo-defined E- or Z-trisubstituted alkene and a 1,2-disubstituted olefin as substrates. By merging two central catalytic transformations in organic synthesis, cross-coupling and CM, various E- or Z-trisubstituted alkenyl chloride and bromides were readily accessed by the same catalytic system without the need for directing groups. The synthetic utility of the present protocol was demonstrated through several concise and efficient synthesis of biologically active natural products/synthetic precursors. Notably, the E- or Z-trisubstituted alkenyl halides prepared by CM may be readily converted to other trisubstituted olefins with complete retention of stereochemical purity by means of a second cross-coupling reaction. Based on the new findings, we revisited previously unaddressed problems and establish that readily available isoprenoid alkenes can serve as a suitable surrogate for unhindered terminal alkenes in CM. Chapter 4: In situ Protection/Deprotection for Catalytic Olefin Metathesis in the Presence of Polar Protic Functional Groups We demonstrated that protic groups such as alcohols and carboxylic acids that are problematic with high-oxidation-state alkylidenes could be effectively masked in situ prior to CM reactions by an appropriate borane reagent. The commercial sample of alkenes that are usually contaminated with protic impurities could be ‘purified’ in situ by a sub-stoichiometric amount of pinacolborane. Deprotection of the in situ boron-based protecting group proceeded under mild conditions and could be performed in the same vessel. The one-pot protection/cross-metathesis/deprotection of alcohol and carboxylic acid-containing alkenes described herein is likely to have an impact on the diversity of organic molecules that can be prepared in a laboratory setting. / Thesis (PhD) — Boston College, 2018. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.