Asymmetric Catalysis, Transition metal catalysis, Allylation, Propargylic alkylation, Cooperative catalysis and nonadjacent stereocenter

Abstract

Transition metal catalysis has transformed asymmetric synthesis by enabling precise control of stereocenters, essential for bioactive molecules. This thesis outlines a systematic investigation of stereochemical complexity through transition metal catalysis, progressing from the synthesis of compounds containing an isolated stereocenter to those bearing adjacent and finally non-adjacent stereocenters. The work entails Ir- and Cu-catalyzed reactions, each tailored to address unique stereochemical challenges and molecular architectures. We have developed the first enantioselective C3-allylation of unblocked pyrroles, a transformation long impeded by the innate C2-electrophilicity of pyrrole.[1] By employing a bulky N-silyl protecting group on pyrroles and chiral Ir(I)/(phosphoramidite, olefin) complex as catalyst, this strategy overrides the innate C2-reactivity of pyrroles, delivering C3-allylic pyrroles, bearing an isolated stereocenter, with excellent regio- and enantioselectivity. Moving forward, we explored diastereoselective construction of adjacent stereocenters via a Cu(I)/Brønsted base cooperative catalysis.[2] The doubly enantioconvergent propargylic alkylation of α-cyano carbonyl compounds with ethynyl benzoxazinanones led to acyclic molecules, bearing vicinal quaternary and tertiary stereocenters, with high selectivity while preserving the alkyne functionality for downstream diversification. We subsequently applied this cooperative catalysis concept to the stereodivergent synthesis of adjacent stereocenters using a Cu(I)/Pybox complex and a chiral secondary amine.[3] Through judicious choice of catalyst enantiomers, all four stereoisomers of γ-propargylic α,β-unsaturated aldehydes were selectively accessed, demonstrating independent and orthogonal control over each stereocenter and underscoring the power of cooperative catalysis in achieving stereodivergency. This work expands the frontiers of stereodivergent cooperative catalysis beyond the conventional π-allyl-metal chemistry. Finally, a ligand-controlled Cu-catalyzed propargylic alkylation of vinylogous aza-enamines was developed for the diastereodivergent construction of non-adjacent 1,3-stereocenters, marking the first application of such nucleophiles in transition metal catalysis.[4] This cascade reaction selectively delivers tetrahydroquinoline frameworks remote 1,3-stereocenters, with each diastereomer accessible through ligand permutation. Together, these studies chart a coherent and strategic advancement in asymmetric catalysis, starting from isolated to vicinal, and ultimately to the generation of non-adjacent stereocenters unified by the versatile reactivities of transition metals.