New Developments in Metal-Mediated Heterocycle Synthesis

Abstract

This thesis describes the development of new metal-mediated chemical reactions which enable the rapid construction of stereocontrolled heterocycles. The reactions proceed by functionalizing olefins to form a ring, a carbon-heteroatom bond, a carbon-carbon bond or carbon-hydrogen bond, and 1-2 stereocenters with high selectivity. This strategy is especially attractive for generating libraries of new compounds simply by exchanging the coupling partners. Three new methods are described below for the formation of guanidines, sulfamides, and tetrahydrofurans. Cyclic guanidines are prevalent motifs in a wide array of pharmaceuticals and natural products. In addition, the synthetic community has exhibited a strong interest in utilizing silver as a catalyst for the formation of heterocycles. For these reasons, a new method was developed which accomplishes the silver-catalyzed hydroamination reaction of tosyl-protected guanidines onto unactivated olefins. This intramolecular cyclization reaction proceeds using catalytic amounts of silver (15-20%) in the presence of atmospheric oxygen and one equivalent of strong base. The cyclic guanidines are constructed in high yields (up to 98%). Sterically congested quaternary centers can be formed by cyclization onto 1,1-disubstitued alkenes. Also, bicyclic guanidines are formed in high yields (using 40 mol% AgNO3). Sulfamides are present in a variety of biologically active compounds and often serve as isosteres for ureas in the medicinal chemist's toolbox. Due to their biological and synthetic importance, an asymmetric synthesis of cyclic sulfamides was developed showcasing the ability of the Pd-catalyzed carboamination reaction for rapidly generating a diverse set of compounds in high yield and enantioselectivity. The new asymmetric method utilized Pd2(dba)3 and the commercially available chiral ligand (S)-Siphos-PE for high enantio-induction. Transformations of electron-neutral or electron-rich aryl bromides provided the highest levels of asymmetric induction whereas use of electron-poor electrophiles resulted in lower selectivity. The presence of water in the reaction had a remarkable influence on yield, improving the yield by up to 45%. The possible influence of competing syn and anti aminopalladation pathways prompted a mechanistic study by deuterium labeling studies which showed that the predominant mechanistic pathway occurred by syn aminopalladation. This asymmetric reaction has also been applied to the synthesis of 6-membered cyclic sulfamides, although geminal substitution is required in the homoallyl backbone for effective cyclization. This carboamination reaction proceeds in good yields and high enantioselectivity (up to 94% yield, up to 96% ee). A Pd-catalyzed desymmetrization reaction which operates under anti aminopalladation conditions was also examined. Asymmetric induction is achieved using axially chiral ligands with electron-rich phosphines, and hopefully, further manipulation of the ligand will improve enantioselectivity. Tetrahydrofurans bearing substituents at the C2 position are prominent motifs present in many biologically active compounds. Early developments in the Wolfe group described the racemic palladium-catalyzed alkoxylation reaction which formed the heterocyclic ring along with a C–O bond, a C–C bond, and 1-2 stereocenters with high diastereoselectivity. Conversely, a palladium-catalyzed enantioselective alkoxylation reaction remained elusive even though the racemic reaction was described in 2004. The realization of an enantioselective alkoxylation reaction employed a new chiral ligand with a TADDOL backbone. The asymmetric carboalkoxylation reaction proceeds in moderate to good yields (54%-85%) and moderate to good enantiomeric ratios (68:32 to 95:5). High enantioselectivity was obtained for alcohols bearing bulky substituents geminal to the alcohol.