New meta-Terphenyl-Derived Primary Amines in Asymmetric Catalysis

Abstract

In this dissertation, two distinct asymmetric reaction types are described: [5 + 2] pyrylium cycloadditions and aldehyde α-functionalizations. Both reactions are mediated by simple, organic primary amine catalysts bearing bulky meta-terphenyl moieties. The main text of this thesis is divided into five chapters outlining the relevant background and the original research. Chapter 1 provides a thorough historical overview of [5 + 2] oxidopyrylium cycloadditions and related asymmetric [3 + 2] cycloadditions. Early discoveries of intermolecular and intramolecular processes, asymmetric precedents, and pertinent frontier molecular orbital considerations are examined. The application of these transformations to the synthesis of natural products and bioactive compounds is also discussed. In Chapter 2, a new method for effecting catalytic enantioselective intramolecular [5 + 2] cycloadditions based on oxidopyrylium intermediates is presented. The development and employment of a dual catalyst system—consisting of a chiral m-terphenyl-containing primary aminothiourea and a second achiral thiourea—are described. Experimental evidence points to a new type of cooperative catalysis with each species being necessary to generate a reactive pyrylium ion pair that undergoes subsequent cycloaddition with high enantioselectivity. Chapter 3 details the successful expansion of the enantioselective [5 + 2] methodology to intermolecular reactions. Highly enantioselective intermolecular [5 + 2] cycloadditions of pyrylium ion intermediates with electron-rich alkenes are promoted by the same dual catalyst system as in Chapter 2. The observed enantioselectivity is highly dependent on the substitution pattern of the 5π component, and the basis for this effect is analyzed in detail using experimental and computational evidence. The resultant 8-oxabicyclo[3.2.1]octane derivatives possess a scaffold common in natural products and medicinally active compounds and are also versatile chiral building blocks for further manipulations. Several stereoselective complexity-generating transformations of the 8-oxabicyclooctane products are described. In Chapter 4, we transition into a literature survey of catalytic asymmetric α-functionalizations of α-branched aldehydes. First, the challenges associated with the efficient functionalization of such substrates, relative to their unbranched counterparts, are detailed. This introduction is followed by a comprehensive overview of catalytic, enantioselective α-heterofunctionalizations: aminations, oxygenations, sulfenylations, and fluorinations. Advantages and drawbacks to previously described methods are analyzed in detail. Chapter 5 recounts our own contributions to this area. A new chiral m-terphenyl-containing primary amine catalyst for the asymmetric α-hydroxylation and α-fluorination of α-branched aldehydes is reported. The products of the title transformations are isolated in high yields and exceptional enantioselectivities within short reaction times. Both processes can be performed at high concentrations and on gram scale. The remarkable similarity between the procedures, combined with computational evidence, implies a possible general catalytic mechanism for α-functionalizations. Promising initial results for α-amination and α-chlorination support this hypothesis.