UC Irvine

Hydrofunctionalization, which is defined as the addition of a hydrogen atom and another fragment to a degree of unsaturation, is an attractive method for transforming unsaturated hydrocarbons to value-added molecules. We developed Rh-, Pd-, and Cu-H catalysts that are capable of coupling both heteroatom and carbon nucleophiles to unsaturated hydrocarbons. The judicious choice of transition metal source (e.g., transition metal and counterion), bisphosphine ligand, and reaction conditions all play a role in selectively accessing one stereoisomeric product when many other outcomes exist.In Chapter 1, we develop an enantioselective Rh-catalyzed addition of thiols to 1,3-dienes. The use of Rh(cod)2SbF6 and a bisphosphine ligand allows for the synthesis of allylic sulfides with high regio- and enantiocontrol. The catalyst loading can be lowered to 0.1 mol% and an array of functional groups are compatible. By matching the bisphosphine ligand to the 1,3-diene’s substitution pattern, we can transform a wide-range of 1,3-dienes (e.g., cyclic, disubstituted, and butadiene) into chiral sulfide building blocks. In Chapter 2, we investigate the mechanism of the enantioselective 1,3-diene hydrothiolation (Chapter 1) and determine the fundamental steps that govern regioselectivity. Guided by these insights, we then develop a complementary hydrothiolation to provide access to homoallylic sulfides. It is now possible for allylic and homoallylic sulfides to be synthesized in a regiodivergent manner by simply switching the Rh source. Mechanistic investigations shed light on the origin of the high regioselectivity observed for both hydrothiolations. In Chapter 3, we showcase an enantioselective Pd-catalyzed 1,3-diene hydro- phosphinylation. This method allows for complementary access to chiral tertiary phosphine oxides. Secondary phosphine oxides and 1,3-dienes can be coupled in high yields, regioselectivities, and enantioselectivities. Mechanistic studies suggest that the reaction proceeds through a reversible 1,3-diene hydrometallation followed by an irreversible C–P reductive elimination. In Chapter 4, we found that Rh-H catalysis offers an approach to novel α-amino acids (α- AAs). Alkynes and α-nitroesters couple to form allylic α-AA precursors under mild conditions. We apply this method to the synthesis of an α,α-disubstituted α-amino ester. Moreover, initial mechanistic studies suggest that the isomerization of the alkyne starting material to an allene intermediate is reversible and occurs before C–C bond formation. In Chapter 5, we report preliminary results for an enantioselective Cu-catalyzed olefin hydroacylation. This hydroacylation couples activated acyl electrophiles with a,b-unsaturated carbonyls to afford enantioenriched 1,3-dicarbonyls. The identity of the acyl electrophile has a pronounced effect on enantioselectivity. Future efforts are needed to (1) expand the scope of this transformation and (2) understand the step(s) that control enantioselectivity.