This dissertation is concerned with the stereospecific transformations of α-amino-β-diazonium intermediates. The mechanism of the Brønsted acid-catalyzed aza-Darzens reaction is explored by charting the stereochemical outcome of the triflic acid-promoted conversion of trans-triazolines to cis-aziridines. These experiments are consistent with the intermediacy of an α-diazonium-β-amino ester intermediate. However, the behavior of an α-diazo imide is used to demonstrate that this intermediate, commonly invoked in reactions of diazoalkane addition reactions to imines, may not be as universal as previously believed.
Our mechanistic investigations led to development of a new diastereoselective reaction. We devised a conceptually new approach to syn-1,2-aminoalcohols that involves Brønsted acid activation of an imine and novel α-diazo imide. After initial C–C bond formation between azomethine and diazoalkane, a latent nucleophilic oxygen terminates the addition reaction by cyclization to the diazo carbon. The net result is a highly diastereoselective and efficient equivalent to a glycolate Mannich reaction. Exploration of the enantioselective variant of this reaction uncovered new copper(I)-catalyzed pathways for diazo imide–azomethine reactions.
Based on the efficient and diastereoselective formal anti-aminohydroxylation of α,β-unsaturated imides and investigations of the mechanism of trans-triazoline fragmentation that was developed in the Johnston group, the first study of substrate-controlled diastereoselection in a double [3+2] dipolar cycloaddition of benzyl azide with α,β-unsaturated imides was investigated. Using a strong Brønsted acid (triflic acid) to activate the electron deficient imide π-bond, high diastereoselection was observed provided that a 1,1,3,3-tetraisopropoxydisiloxanylidene group (TIPDS) is used to restrict the conformation of the central 1,3-anti diol. This development provides a basis for a stereocontrolled approach to the aminopolyol core of (+)-zwittermicin A using a bidirectional synthesis strategy. The masked aminopolyol core was functionalized and coupled with the isonitrile fragment in a Passerini reaction to provide the complete carbon skeleton of (+)-zwittermicin A.