Project description:Vinyl sulfides react rapidly and efficiently with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to form α,β-unsaturated thiocarbenium ions through oxidative carbon-hydrogen bond cleavage. These electrophiles couple with appended π-nucleophiles to yield sulfur-containing heterocycles through carbon-carbon bond formation. Several nucleophiles are compatible with the procedure, and the reactions generally proceed through readily predictable transition states.
Project description:A sequence consisting of palladium-catalyzed benzamide ortho-arylation/reaction with (CF3CO)2O was developed allowing a convenient one-pot synthesis of ortho-arylated benzonitriles and fluorenone derivatives. The outcome of this transformation is dependent on the amide N-alkyl substituent. Dehydration of ortho-arylated N-cyclohexyl-benzamides by (CF3CO)2O results in efficient production of benzonitriles. In contrast, o-arylated N-propylbenzamides are converted to fluorenone derivatives.
Project description:Spiroacetals can be formed through a one-pot sequence of a hetero-Diels-Alder reaction, an oxidative carbon-hydrogen bond cleavage, and an acid treatment. This convergent approach expedites access to a complex molecular subunit which is present in numerous biologically active structures. The utility of the protocol is demonstrated through its application to a brief synthesis of the actin-binding cytotoxin bistramide A.
Project description:3,5-Dimethylpyrazole was employed as a monodentate directing group for palladium-catalyzed ortho-sp2 C-H arylation with aryl iodides. The reaction shows good functional group tolerance and outstanding selectivity for mono- ortho-arylation. Ozonolysis of ortho-arylated arylpyrazoles gave acylated biphenylamines that were further arylated to afford unsymmetrically substituted 2,6-diarylacetanilides.
Project description:Post-translational modification by the addition of an oxoanion functional group, usually a phosphate group and less commonly a sulfate group, leads to diverse structural and functional consequences in protein systems. Building upon previous studies of the phosphoserine residue (pSer), we address the distinct nature of hydrogen bonding interactions in phosphotyrosine (pTyr) and sulfotyrosine (sTyr) residues. We derive partial charges for these modified residues and then study them in the context of molecular dynamics simulation of model tripeptides and sulfated protein complexes, potentials of mean force for interacting residue pairs, and a survey of the interactions of modified residues among experimental protein structures. Overall, our findings show that for pTyr, bidentate interactions with Arg are particularly dominant, as has been previously demonstrated for pSer. sTyr interactions with Arg are significantly weaker, even as compared to the same interactions made by the Glu residue. Our work sheds light on the distinct nature of these modified tyrosine residues, and provides a physical-chemical foundation for future studies with the goal of understanding their roles in systems of biological interest.
Project description:In this study, chemiresistive anion sensors are developed using carbon nanotube fibers (CNTFs) functionalized with squaramide-based dual-hydrogen bond donors (SQ1 and SQ2) and systematically compared the sensing properties attained by two different functionalization methods. Model structures of the selectors are synthesized based on a squaramide motif incorporating an electron-withdrawing group. Anion-binding studies of SQ1 and SQ2 are conducted using UV-vis titrations to elucidate the anion-binding properties of the selectors. These studies revealed that the chemical interaction with acetate (AcO-) induced the deprotonation of both SQ1 and SQ2. Selectors are functionalized onto the CNTFs using either covalent or non-covalent functionalization. For covalent functionalization, SQ1 is chemically formed on the surface of the CNTFs, whereas SQ2 is non-covalently functionalized to the surface of the CNTFs assisted by poly(4-vinylpyridine). The results showed that non-covalently functionalized CNTFs exhibited a 3.6-fold higher sensor response toward 33.33 mm AcO- than covalently functionalized CNTFs. The selector library is expanded using diverse selectors, such as TU- and CA-based selectors, which are non-covalently functionalized on CNTFs and presented selective AcO--sensing properties. To demonstrate on-site and real-time anion detection, anion sensors are integrated into a sensor module that transferred the sensor resistance to a smartphone via wireless communication.
Project description:We report a chiral-squaramide-catalyzed enantio- and diastereoselective synthesis of ?-allyl amino esters. The optimized protocol provides access to N-carbamoyl-protected amino esters via nucleophilic allylation of readily accessible ?-chloro glycinates. A variety of useful ?-allyl amino esters were prepared, including crotylated products bearing vicinal stereocenters that are inaccessible through enolate alkylation, with high enantioselectivity (up to 97% ee) and diastereoselectivity (>10:1). The reactions display first-order kinetic dependence on both the ?-chloro glycinate and the nucleophile, consistent with rate-limiting C-C bond formation. Computational analysis of the uncatalyzed reaction predicts an energetically inaccessible iminium intermediate, and a lower energy concerted SN2 mechanism.
Project description:The dramatic increase in healthcare cost has become a significant burden to the world. Many patients are denied the accessibility of medication because of the high price of drugs. Total biosynthesis of chiral drug intermediates is an environmentally friendly approach that helps provide more affordable pharmaceuticals. Here we have expanded the natural metabolic capability to biosynthesize a nonnatural amino acid L-homoalanine, which is a chiral precursor of levetiracetam, brivaracetam, and ethambutol. We developed a selection strategy and altered the substrate specificity of ammonium-assimilating enzyme glutamate dehydrogenase. The specificity constant k(cat)/K(m) of the best mutant towards 2-ketobutyrate is 50-fold higher than that towards the natural substrate 2-ketoglutarate. Compared to transaminase IlvE and NADH-dependent valine dehydrogenases, the evolved glutamate dehydrogenase increased the conversion yield of 2-ketobutyrate to L-homoalanine by over 300% in aerobic condition. As a result of overexpressing the mutant glutamate dehydrogenase and Bacillus subtilis threonine dehydratase in a modified threonine-hyperproducing Escherichia coli strain (ATCC98082, DeltarhtA), 5.4 g/L L-homoalanine was produced from 30 g/L glucose (0.18 g/g glucose yield, 26% of the theoretical maximum). This work opens the possibility of total biosynthesis of other nonnatural chiral compounds that could be useful pharmaceutical intermediates.
Project description:Chromenes and isochromenes react quickly with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to form persistent aromatic oxocarbenium ions through oxidative carbon-hydrogen cleavage. This process is tolerant of electron-donating and electron-withdrawing groups on the benzene ring and additional substitution on the pyran ring. A variety of nucleophiles can be added to these cations to generate a diverse set of structures.
Project description:Nitrogen-rich heterocyclic compounds have had a profound effect on human health because these chemical motifs are found in a large number of drugs used to combat a broad range of diseases and pathophysiological conditions. Advances in transition-metal-mediated cross-coupling have simplified the synthesis of such molecules; however, C-H functionalization of medicinally important heterocycles that does not rely on pre-functionalized starting materials is an underdeveloped area. Unfortunately, the innate properties of heterocycles that make them so desirable for biological applications--such as aqueous solubility and their ability to act as ligands--render them challenging substrates for direct chemical functionalization. Here we report that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for the mild (moderate temperature, 50 °C or less), direct and operationally simple formation of medicinally relevant C-C bonds while reacting in a complementary fashion to other innate C-H functionalization methods (Minisci, borono-Minisci, electrophilic aromatic substitution, transition-metal-mediated C-H insertion and C-H deprotonation). We prepared a toolkit of these reagents and studied their reactivity across a wide range of heterocycles (natural products, drugs and building blocks) without recourse to protecting-group chemistry. The reagents can even be used in tandem fashion in a single pot in the presence of water and air.