Development of New Catalysts and Concepts for Enantioselective Synthesis of Amines and Alcohols

Abstract

Chapter 1: Ag-Catalyzed Enantioselective Vinylogous Mannich Reactions of Ketoimines Few catalytic methods have been reported for the enantioselective synthesis of N-substituted quaternary carbon stereogenic centers, typically the low reactivity of the electrophilic partner cannot be overcome. Herein, a silver-based catalyst is described which promotes highly site-, diastereo-, and enantioselective additions of siloxyfurans to ansidine-derived ketoimino esters. Mechanistic investigations, undertaken to elucidate the nature of the active silver-phosphine complex, supported the proposed origin for the anti-selective Mannich-type additions. Chapter 2: New Catalysts for the Enantioselective Cu-Catalyzed Additions of Allyl Groups to Phosphinoylaldimines The deficiencies in modern organic synthesis regarding the preparation of chiral molecules bearing amines, despite their incredible significance, are addressed. The development of a new method and catalyst for the preparation of enantiomerically enriched allyl-substituted alpha-chiral amines is described. Copper based catalysts bearing chiral C1-symmetric N-heterocyclic carbenes promote reactions between diphenylphosphinoyl aldimines and allyl boronic acid pinacol ester affording the homoallylic amines with high levels of efficiency and selectivity. Furthermore, the mechanistic rationale describing the selectivity patterns of the designed catalysts is analyzed. Chapter 3: NHC-Cu-Catalyzed Enantioselective Propargyl Group Additions to Phosphinoylaldimines The copper complex of a chiral N-heterocyclic carbene is found to be uniquely effective at promoting highly selective reactions of a commercially available allenylboron reagent and diphenylphosphinoyl aldimines. The enantiomerically enriched homopropargylic amines are exclusively afforded within an hour in the presence of as low as 0.25 mol % catalyst. The utility of the method is further demonstrated through the elaboration of the appended alkyne to difficult-to-access functionalities, highlighted by the synthesis of a key fragment for the preparation of the aza-epothilones, macrocyclic lactams which exhibit acute cytotoxicity. Chapter 4: Metal-Free Catalysts for Enantioselective Synthesis of Allenic Carbinols A metal-free catalyst, unique in structure and mechanism, is developed to address the remaining deficiencies in allyl addition chemistry, an area dominated by metal catalysis. The key organizational and enabling feature of the catalyst is a proton, a simple point charge which affects the facility of the C-C bond formation through electrostatic interactions. The unique alpha-selectivity delivered by the boron-based catalyst, a product of a catalytic cycle characterized by two gamma-selective allyl transfer processes, allows for the unprecedented synthesis of enantiopure allenyl-substituted tertiary alcohols. Moreover, the described transfomations can be performed in a matter of minutes with ˂0.5 mol % catalyst.