The selective manipulation of hydroxyl groups in di- and polyols is a frequently encountered problem in organic synthesis. Such processes are often tedious and/or moderate yielding, and often necessitate multistep protection / deprotection sequences. Applying boron–diol interactions previously exploited in molecular recognition and based on methods previously developed in our research group, we have developed two classes of chemical transformations: 1. Regioselective sulfonylations of carbohydrate derivatives catalyzed by a borinic ester, providing access to the corresponding mono-tosylates in high yields; 2. Selective monoalkylations and monosulfonylations of structurally diverse 1,2- and 1,3-diol substrates.

To address the issue of unnecessary functional group transformations in synthesis, the direct functionalization of carbon-hydrogen (C―H) bonds presents itself as an efficient and atom economical process. In particular, palladium(II)-catalyzed oxidative functionalization of arene C–H bonds were investigated to yield intermolecular and intramolecular arylations. Kinetic studies and characterization of bimetallic palladium(II) complexes led to the discovery of two other palladium(II)-catalyzed processes: arene hydroxylation and selective chlorination of anilides. Realizing the potential of biocatalysis and of transition-metal catalysis, we marriaged these two fundamentally different methods to access complex molecules in rapid and step economical ways and chose popular synthetic target, 6-deoxyerythronolide B to showcase the efficiency of these stereoselective reactions. To form the 14-membered lactone, we employed a transition-metal catalyzed ring-closing metathesis. Two different fragments were assembled via traditional and reliable aldols, oxidations and reductions, crotylations and protective group chemistry.

Since recognizing the significance of reversible oxidative addition of palladium into aryl halides in the synthesis of 2-bromo-indoles, the Lautens group has focused on unusual carbon-halogen reductive eliminations. These efforts led to the discovery of the novel palladium-catalyzed inter- and intramolecular carbohalogenation reaction – the formal addition of an sp2 carbon–iodide bond across an alkene. One current research direction is utilizing a range of aryl halides and pseudohalides as starting materials for carbohalogenation chemistry. This thesis describes complementary research, focusing on the expansion of functional group scope. Carbohalogenation has been developed to synthesize novel products including heteroaromatic compounds and 7-membered rings. Polyunsaturated aryl iodide substrates were investigated with the goal of performing domino carbohalogenation. Ultimately, the successful halogen exchange process was combined with domino carbohalogenation in an efficient halogen-exchange domino reaction. Additionally, preliminary studies on enantioselective carbohalogenation, and functionalization of the neopentyl iodide products are also discussed.

The development of a palladium-catalyzed intramolecular carboesterification of unactivated olefins is described. Olefin difunctionalization is a powerful tool for adding complexity to a molecule, and this formal [3+2] cycloaddition generates highly functionalized fused ring systems. Initially discovered by Dr. Yang Li in our group, it was found that when propiolic acids with a pendant terminal olefin were treated with 1 mol % Pd(MeCN)2Cl2, 3 equivalents of copper (II) chloride, and 3 equivalents of lithium chloride in acetonitrile at 50 °C, cyclization occurred in up to 90% yield. The optimization of this reaction and the extension to propiolamides and propargyl alcohols is described in this thesis. A mechanism involving a novel palladium-carboxylate species is proposed. Preliminary investigations into the synthesis of chiral sulfoxide pincer ligands are also described. The nucleophilic aromatic substitution of 1,3-dibromobenzene and 2,6-dichloropyridine with various thiols, followed by oxidation of the sulfides to sulfoxides is investigated as a route to the desired proligands.

scyllo-Inositol is currently in phase II clinical trials as a therapeutic for Alzheimer’s disease (AD). Previous work from our lab has shown that scyllo-inositol prevents Ab1-42 fibril formation instead leading to the formation of small Ab oligomers in vitro. To further understand the molecular details of Ab-scyllo-inositol binding interactions, a library of scyllo-inositol derivatives was prepared. A sequence of protecting group transformations afforded a hydroxylamine functionalized scyllo-inositol. Subsequent oxime formation with aromatic aldehydes generated a novel class of inositol derivatives in good yield and high purity. The effects of these compounds on the Ab aggregation cascade were evaluated by a biotin-avidin Ab1-42 oligomer assay and atomic force microscopy (AFM). Preliminary plate assay data indicated that several of these derivatives increased peptide oligomerization and the corresponding AFM images showed altered fibril formation. These results suggested that this class of scyllo-inositol derivatives is active in the Ab aggregation cascade.

Squaramides (3,4-diaminocyclobutene-1,2-diones) are known to be strong hydrogen bond donors, and recently have been demonstrated to show unusual responses to anions and the potential to adopt secondary structures. In the first part of the project, a small molecule version of a fluorene-based poly(squaramide) was synthesized to gain insights into the mechanism of the “turn-on” fluorescence response of the polymer in the presence of mono-basic phosphate anions. In the second part, mono and dipyridyl squaramides are examined. Pyridyl squaramides were discovered to form strong intramolecular hydrogen bonds, making the folding process more favorable than their urea counterparts. They are particularly interesting as their urea analogues are capable of taking up helical conformations when folded. The folding properties of these pyridyl squaramides in a range of solvents, and the influence of added anions on the folding process, are described herein.

The selective manipulation of hydroxyl groups in di- and polyols is a frequently encountered problem in organic synthesis. Such processes are often tedious and/or moderate yielding, and often necessitate multistep protection / deprotection sequences. Applying boron–diol interactions previously exploited in molecular recognition and based on methods previously developed in our research group, we have developed two classes of chemical transformations: 1. Regioselective sulfonylations of carbohydrate derivatives catalyzed by a borinic ester, providing access to the corresponding mono-tosylates in high yields; 2. Selective monoalkylations and monosulfonylations of structurally diverse 1,2- and 1,3-diol substrates.

To address the issue of unnecessary functional group transformations in synthesis, the direct functionalization of carbon-hydrogen (C―H) bonds presents itself as an efficient and atom economical process. In particular, palladium(II)-catalyzed oxidative functionalization of arene C–H bonds were investigated to yield intermolecular and intramolecular arylations. Kinetic studies and characterization of bimetallic palladium(II) complexes led to the discovery of two other palladium(II)-catalyzed processes: arene hydroxylation and selective chlorination of anilides. Realizing the potential of biocatalysis and of transition-metal catalysis, we marriaged these two fundamentally different methods to access complex molecules in rapid and step economical ways and chose popular synthetic target, 6-deoxyerythronolide B to showcase the efficiency of these stereoselective reactions. To form the 14-membered lactone, we employed a transition-metal catalyzed ring-closing metathesis. Two different fragments were assembled via traditional and reliable aldols, oxidations and reductions, crotylations and protective group chemistry.

Since recognizing the significance of reversible oxidative addition of palladium into aryl halides in the synthesis of 2-bromo-indoles, the Lautens group has focused on unusual carbon-halogen reductive eliminations. These efforts led to the discovery of the novel palladium-catalyzed inter- and intramolecular carbohalogenation reaction – the formal addition of an sp2 carbon–iodide bond across an alkene. One current research direction is utilizing a range of aryl halides and pseudohalides as starting materials for carbohalogenation chemistry. This thesis describes complementary research, focusing on the expansion of functional group scope. Carbohalogenation has been developed to synthesize novel products including heteroaromatic compounds and 7-membered rings. Polyunsaturated aryl iodide substrates were investigated with the goal of performing domino carbohalogenation. Ultimately, the successful halogen exchange process was combined with domino carbohalogenation in an efficient halogen-exchange domino reaction. Additionally, preliminary studies on enantioselective carbohalogenation, and functionalization of the neopentyl iodide products are also discussed.

We have described two important classes of palladium-catalyzed reactions for the synthesis of heterocycles and carbocycles: tandem Pd-catalyzed reactions of gem-dibromoolefins and domino Pd-catalyzed reactions via an ortho C−H functionalization. Chapter 1 describes the tandem Pd-catalyzed reaction of gem-dibromoolefins via an intramolecular direct arylation and an intermolecular Suzuki-Miyaura cross-coupling. A number of aromatic carbocycles were synthesized by this method. Chapter 2 describes the tandem Pd-catalyzed reactions of β,β-dibromoenamides via an intramolecular C−O bond formation and an intermolecular Suzuki-Miyaura cross-coupling. Depending on the substituent on the nitrogen of β,β-dibromoenamides, either aromatic heterocycles or acyclic compounds can be synthesized. Chapter 3 and 4 describe the domino Pd-catalyzed reactions via an ortho C−H functionalization of aryl iodides. 2-Pyrrole substituted phenyl iodides were coupled with alkyl bromides in the presence of norbornene to provide aromatic tetracyclic compounds through three C−C bond formations (Chapter 3). However, the reaction between 2-methyl substituted phenyl iodides and the alkyl bromides in the presence of norbornene provided tetrasubstituted helical alkenes with the norbornene incorporated in the final product through four C−C bond formations (chapter 4). In Chapter 5, detailed mechanistic studies including kinetic and NMR studies were described for the regioselective C−H functionalization of 2-pyrrole substituted phenyl iodides. The studies provided advanced and important understanding of the mechanism, and a rationale for the high regioselectivity.