UC Irvine

Transition-metal catalysis with strained rings offers unique opportunities to unlock challenging bond constructions with implications in drug discovery. Pyrazoles and cyclic tripeptides represent two classes of biologically relevant compounds with distinct synthetic challenges. For pyrazoles, the differentiation of two chemically similar nitrogen atoms can be complicated. Cyclic tripeptides, by contrast, are intrinsically strained, making them a largely underexplored yet promising synthetic target. This dissertation describes efforts toward the regioselective functionalization of pyrazoles and the synthesis of strained cyclic tripeptides.In Chapter 1, we disclose a Cu-catalyzed enantioselective hydroamination of cyclopropenes with pyrazoles. Chiral N-cyclopropyl pyrazoles and structurally related heterocycles are prepared using an earth-abundant copper catalyst, under mild reaction conditions with high regio-, diastereo-, and enantio-control. The nitrogen regioselectivity observed favors the more hindered nitrogen of the pyrazole. Experimental and DFT studies support a unique mechanism that features a 5-centered aminocupration.In Chapter 2, we develop a Cu-catalyzed arylation of pyrazoles with in situ generated arynes. A major challenge in late-stage functionalization is the selective N-arylation of unsymmetric pyrazoles to create a core relevant in blockbuster medicines. Traditional cross-coupling methods usually favor one type of regioisomer and thus, limit late-stage access to alternatives that could speed up drug discovery. Here, we show that copper catalysis harnesses arynes to achieve switchable arylation of pyrazoles. By tuning metallotautomers, we direct N-arylation to either nitrogen atom in a pyrazole, unlocking site-selective control between two similar nitrogen sites. Mechanistic studies reveal how steric and electronic forces guide regioselectivity and turn an unpredictable process into a blue-print for late-stage functionalization of N–N linkages.In Chapter 3, we explore the synthesis of strained cyclic α-tripeptides, an underexplored but highly intriguing class of macrocycles. Conventional cyclization strategies suffer from limited scope and low yields due to dimerization; here, we investigate a photo-induced ring expansion of cyclols to access cyclic tripeptides. Preliminary results demonstrate that titanium catalyst controls radical fragmentation selectivity. The successful synthesis of cyclol intermediates lays the groundwork for future studies to apply the unique photochemical approach to these elusive scaffolds.