Development and Study of Novel Catalytic Reactions to Efficiently Address Synthetic Challenges: Enantioselective Multicomponent Synthesis of Homoallylic Amines and Site-Selective Debenzylation of Mono- and Disaccharides

Abstract

Dissertation Advisor: Professor Eric N. Jacobsen Elisabetta Ronchi Development and Study of Novel Catalytic Reactions to Efficiently Address Synthetic Challenges: Enantioselective Multicomponent Synthesis of Homoallylic Amines and Site-Selective Debenzylation of Mono- and Disaccharides Abstract In Chapter 1, we detail the development of an aryl-pyrrolidino-thiourea and silyl triflate co-catalyzed multicomponent synthesis of enantioenriched homoallylic amines from acetals, allylsilanes and BocNH2. The reaction exhibits excellent chemo- and enantioselectivity across a broad substrate scope. In addition, we investigated the nature of the molecular recognition responsible for the high enantioselectivities observed. Through a combination of mechanistic experiments and computational modelling we identified an anchoring H-bonding interaction between the catalyst amide and the iminium ion and an enantiodifferentiating dispersive interaction between the substrate and the aryl portion of the catalyst. This contrasts with what has been observed in previous reports using similar catalysts, where more electrostatic interactions (i.e. cation-π interactions) were identified, highlighting the ability of this scaffold to stabilize transition states and control enantioselectivity via a variety of mechanisms. In Chapter 2, we describe preliminary results in the development of an asymmetric nucleophilic debenzylation reaction. Building on precedent from our laboratory where TMSBr was used to open oxetanes via catalyst-controlled anion delivery, we extend this strategy to effect the dealkylations of unhindered ethers using TMSI in conjunction with a dual HBD with modest levels of enantioselectivity. After this proof of principle, we attempted to apply this strategy to the site selective debenzylation of carbohydrates, as carbohydrates play major roles in a variety of biological processes, but their selective synthesis remains challenging. Our efforts, however, were unsuccessful due to compatibility issues between the strong acids required for nucleophilic dealkylation of carbohydrates and our catalysts. In Chapter 3, we describe the development and initial optimization of an alternative approach to the address the synthetic challenges of selective debenzylations of carbohydrates. We hypothesized that Mn(salen) complexes, catalysts which are widely used in catalytic oxidations and are known for their excellent spatial recognition properties, could site-selectively deprotect complex carbohydrates via benzylic C–H oxidation followed by hemiacetal breakdown. Using an inexpensive, commercially available Mn(salen) catalyst, we successfully demonstrated both the reactivity and the selectivity of this deprotection strategy on a series of mono- and disaccharide substrates, accessing valuable synthetic intermediates which would otherwise require lengthy synthetic sequences.