Novel strategies for the synthesis and transformation of nitrogen-containing molecules

Abstract

Over the course of this work, novel strategies for the synthesis and transformation of nitrogen-containing molecules were investigated. In the first research project, a selective nitrogen insertion methodology for the synthesis of γ-lactams from cyclobutanones was explored. Analogies between an aza-Baeyer-Villiger reaction and the corresponding oxygen insertion were identified in terms of regioselectivity and stereospecificity. Consecutively, the mild nature and synthetic applicability of the protocol was demonstrated by exploration of a substrate scope including the transformation of α-substituted cyclobutanones and the gram scale synthesis of 4-phenylpyrrolidin-2-one. During the second research project, a catalytic asymmetric nitrogen incorporation approach was developed based on the previous studies. Chiral phosphoric acids were identified to effectively catalyse the asymmetric condensation between 3-substituted cyclobutanones and amine reagents. The influence of amine substitution and the effect of varying solvents and temperature on the selectivity of the reaction were investigated. Several previously unknown axially chiral cyclobutanone oxime esters were accessed in good enantioselectivities and yields. Application of the developed protocol enabled transformation of substrates bearing versatile aryl and alkyl substituents. Additionally, the reaction of substrates with varying ring sizes, such as cyclopentanones and cyclohexanones, was successfully performed. Following on these results, novel strategies for the conversion of axial-to-point chirality by transformation of the previously formed oxime esters were provided in a third research project. Stereospecific chirality transfer enabled the synthesis of point chiral γ-lactams via Lewis acid-induced ring-expansion rearrangement of axially chiral cyclobutanone oxime esters. Furthermore, the usability of the nitrogen-containing molecules in ring-opening and ring-contraction reactions to obtain chiral nitriles was evaluated. An interesting base-induced rearrangement resulting in the formation of chiral cyclopropane nitriles was discovered. Fine-tuning of the reaction parameters facilitated the highly selective access to cis- and trans-diastereoisomers. Combination with the previously developed asymmetric condensation approach achieved the stereodivergent synthesis of all four cyclo-propane isomers from simple cyclobutanone precursors in a one-pot protocol. Finally, the synthetic utility of the developed methodology was highlighted by the formal synthesis of an FDA-approved drug candidate.