Development of Orthogonal Catalytic Click Processes That Forge Functional Linkages

Abstract

Chapter One: Development of a New Catalytic Click Reaction Involving Nitriles and Allenes (CuPDF)Catalytic click reactions, although small in number, have made a profound impact on chemistry research, including the fields of drug discovery, biological chemistry, and materials science. What is much needed are additional catalytic reactions that bring about the union of commonly occurring and robust functional groups, are mutually orthogonal to those that exist and offer a function other than connecting two fragments. We have developed a catalytic click process that connects a nitrile and a monosubstituted allene in the presence of commercially available B2(pin)2 and a readily accessible Cu(I) complex. The modification stage involves alkene isomerization by base and condensation with a hydrazine and both processes are performed in situ. The resulting linkages contain a robust diazaborinine that is fluorescent. We demonstrate that the click process, which we have named copper(I)-catalyzed phenoxydiazaborinine formation (CuPDF) is mutually orthogonal to copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) as well as sulfur-fluorine exchange (SuFEx). These click reactions can therefore be used for efficient synthesis of sequence-defined oligomers that may contain modifiable linkages and peptide-drug conjugates. For applications in aqueous media, we have also developed, copper(I)- and palladium-catalyzed quinoline formation (Cu/PdQNF). These latter processes generate fluorescent connectors as well. Chapter Two: Development of a Catalytic Click Reaction Involving Ketones and Allenes (CuAKA) We have developed another click reaction, this time bringing about the union of a ketone and, similar to CuPDF, a monosubstituted allene and B2(pin)2. We label this click reaction copper(I)-catalyzed allene–ketone addition or CuAKA. As a consequence of shared reactants, identifying catalysts that would allow CuAKA and CuPDF to be mutually orthogonal was at the center of our investigations. Our studies resulted in the identification of copper(I) complexes that can be used to perform a click reaction on a nitrile or a ketone. Furthermore, we found that mutual orthogonality can be achieved between CuAKA and CuAAC using an amino phosphine–Cu(I) catalyst. Computational and kinetics studies were performed that shed light on the origins of catalyst-controlled chemoselectivity. Importantly, similar to CuPDF, CuAKA can be performed in aqueous media. Chapter Three: Preparation of Multi-drug Conjugates with Mutually Orthogonal Click Reactions We show that with CuAAC, CuPDF and CuAKA, three mutually orthogonal click processes can be efficiently merged to assemble complex molecules efficiently with no protection/deprotection needed. With CuAKA, similar to CuAAC and CuPDF, being also orthogonal to SuFEx, a four-armed core molecule may be used in a similar fashion. A central finding in this part of study was the discovery that CuAKA, similar to CuAAC but unlike CuPDF, can be used to link molecules that contain acidic protons, such as phenol or a carboxylic acid moieties. Chapter Four: Controlled Rupture of CuAKA-Generated Linkages A distinct attribute of CuAKA is that it forms a linkage that is cleavable under mild aqueous oxidative conditions. We show that the tertiary hydroxy group accelerates the oxidation of the nearby C–B bond within the connector to generate a -hydroxy ketone that undergoes a retro-aldol reaction to effect rupture. We show that an aryl linker between the ketone and the carrier molecule, such a bile acid or a cell-penetrating peptide (CPP) may be used to achieve the steric and electronic parameters that are needed for optimal clicking and clipping rates. To demonstrate applicability, we used CuAKA was used for efficient linking of camptothecin, an anti-cancer agent with low selectivity, to a ketone attached to unprotected penetratin, a CPP. The ensuing release of the payload proceeded readily in a 68 mM aqueous solution of hydrogen peroxide at 37 °C with control experiments indicating that a proximal lysine residue accelerates the retro-aldol reaction.