Conversion of Amides into Esters by the Nickel-Catalyzed Activation of Amide C-N Bonds

The amide function is ubiquitous in natural compounds as well as in man-made molecules and materials. It is generally very stable and poorly reactive owing to its resonance-stabilized C–N group that imparts a planar geometry to amides. In contrast, carboxylic esters are generally reactive under a variety of mild conditions; therefore, it is not surprising that a number of direct methods are available to the chemist for converting esters into amides (amino-de-alkoxylation reaction) but very few for achieving the opposite transformation. Recently, Professors Neil Garg and Ken Houk from the University of California, Los Angeles (UCLA, USA) reported in Nature a groundbreaking method for converting amides into esters with a high degree of efficiency

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC

Harnessing Heterocyclic Arynes &amp; Amides as Synthetic Building Blocks

This dissertation describes the study of two synthetic building blocks, heterocyclic arynes and amides, and their applications in synthetic organic chemistry. Heterocyclic arynes are highly reactive intermediates that act as electrophilic arene surrogates. In contrast, amides are tradionally considered to be robust functional groups. However, recently the acyl–nitrogen bond of amides have been activated under mild transition metal-catalysis to act as acyl electrophiles and form C–heteroatom and C–C bonds.Chapter One reviews the field of heterocyclic arynes from a historial perspective with an emphasis on pyridyne and indolyne methodologies. Moreover, this chapter highlights the use of pyridynes, indolynes, and related strained intermediates in the synthesis of natural products.Chapter Two describes the total syntheses of (–)-indolactam V and its C7-substituted natural product derivatives, (–)-pendolmycin, (–)-lyngbyatoxin A, and (–)-teleocidin A-2. The C4–N linkage is constructed with a distortion-controlled indolyne functionalization. The total synthesis of (–)-indolactam V provides a platform for the divergent syntheses of the other three natural products via a palladium-catalyzed cross-coupling to functionalize C7 and introduce a quaternary center.Chapter Three pertains to accessing two new oxacyclic strained intermediates, the 4,5-benzofuranyne and the 3,4-oxacyclohexyne. In situ trapping of these intermediates affords an array of heterocyclic scaffolds and the experimentally-determined ratio of regioisomers are consistent with predictions made using the distortion/interaction model. In addition, oxygen-containing strained intermediates were found to provide access to greater selectivities from trapping experiments compared to their corresponding nitrogen-containing counterparts. Chapter Four illustrates the synthesis of six new indole-based conjugated trimers and their photophysical properties. These conjugated trimers are generated using highly reactive indolyne intermediates in the presence of a palladium catalyst. In addition, this reactivity could provide access to a variety of trimeric cores, which could have further applications in new materials.Chapter Five depicts the activation of the carbon–nitrogen bond of amides under nickel catalysis and the utility of amides as electrophilic acyl cross-coupling partners. We first investigated the conversion of amides to esters, which is a challenging and underdeveloped transformation. Density functional theory calculations provide insight into the thermodynamics and catalytic cycle of the amide-to-ester transformation. This report provides a way to harness amides as synthons and has led to the further use of amides in the construction of carbon–heteroatom or carbon–carbon bonds under nickel-catalysis

Expanding the Strained Alkyne Toolbox: Generation and Utility of Oxygen-Containing Strained Alkynes

We report synthetic methodology that permits access to two oxacyclic strained intermediates, the 4,5-benzofuranyne and the 3,4-oxacyclohexyne. In situ trapping of these intermediates affords an array of heterocyclic scaffolds by the formation of one or more new C-C or C-heteroatom bonds. Experimentally determined regioselectivities were consistent with predictions made using the distortion/interaction model and were also found to be greater compared to selectivities seen in the case of trapping experiments of the corresponding N-containing intermediates. These studies demonstrate the synthetic versatility of oxacyclic arynes and alkynes for the synthesis of functionalized heterocycles, while further expanding the scope of the distortion/interaction model. Moreover, these efforts underscore the value of harnessing strained heterocyclic intermediates as a unique approach to building polycyclic heteroatom-containing frameworks

Expanding the Strained Alkyne Toolbox: Generation and Utility of Oxygen-Containing Strained Alkynes

We report synthetic methodology that permits access to two oxacyclic strained intermediates, the 4,5-benzofuranyne and the 3,4-oxacyclohexyne. In situ trapping of these intermediates affords an array of heterocyclic scaffolds by the formation of one or more new C–C or C–heteroatom bonds. Experimentally determined regioselectivities were consistent with predictions made using the distortion/interaction model and were also found to be greater compared to selectivities seen in the case of trapping experiments of the corresponding <i>N</i>-containing intermediates. These studies demonstrate the synthetic versatility of oxacyclic arynes and alkynes for the synthesis of functionalized heterocycles, while further expanding the scope of the distortion/interaction model. Moreover, these efforts underscore the value of harnessing strained heterocyclic intermediates as a unique approach to building polycyclic heteroatom-containing frameworks

Total syntheses of indolactam alkaloids (−)-indolactam V, (−)-pendolmycin, (−)-lyngbyatoxin A, and (−)-teleocidin A-2

We report the total syntheses of (-)-indolactam V and the C7-substituted indolactam alkaloids (-)-pendolmycin, (-)-lyngbyatoxin A, and (-)-teleocidin A-2. The strategy for preparing indolactam V relies on a distortion-controlled indolyne functionalization reaction to establish the C4-N linkage, in addition to an intramolecular conjugate addition to build the conformationally-flexible nine-membered ring. The total synthesis of indolactam V then sets the stage for the divergent synthesis of the other targeted alkaloids. Specifically, late-stage sp2-sp3 cross-couplings on an indolactam V derivative are used to introduce the key C7 substituents and the necessary quaternary carbons. These challenging couplings, in addition to other delicate manipulations, all proceed in the presence of a basic tertiary amine, an unprotected secondary amide, and an unprotected indole. Thus, our approach not only enables the enantiospecific total syntheses of four indolactam alkaloids, but also serves as a platform for probing complexity-generating and chemoselective transformations in the context of alkaloid total synthesis

Conjugated Trimeric Scaffolds Accessible from Indolyne Cyclotrimerizations: Synthesis, Structures, and Electronic Properties

We report the design and synthesis of a new class of indole-based conjugated trimers. The targeted compounds are accessed from <i>in situ</i> generated, highly reactive indolyne intermediates using Pd-catalyzed cyclotrimerization reactions. By harnessing three indolyne isomers, six isomeric indole trimers are accessible, none of which have been previously synthesized. Using computational analysis, we describe the structural and photophysical properties of these unique compounds. This study showcases the use of indolynes in transition metal-catalyzed reactions, while providing access to a new class of conjugated trimers, including highly bent heteroaromatic compounds. Computations indicate that, despite differences in planarity between the molecules, the photophysical properties of each trimer are derived from the <i>N</i>-methylindole building block. Excited state behavior follows predicable patterns