Asymmetric alkylation of enantiomeric tetrahydroisoquinolyl oxazolines was achieved with 96-97% diastereoselectivity. Removal of the oxazoline chiral auxiliary and further transformations provide a straightforward synthesis of the two synthetic intermediates that were previously synthesized by resolution, and which comprise a formal synthesis of berbamunine by Ullman coupling.

A convenient method for construction of polycyclic fused nitrogen-containing heterocycles has been developed. The methodology involves palladium-catalyzed intermolecular carbopalladation-annulation cascade reaction of haloaryl heterocyclic derivatives with different alkynes under relatively mild reaction conditions. Thus, the palladium-catalyzed cascade cyclization of bromophenyl derivatives of indolizine and indole with alkynes afforded tetracycles, possessing a newly formed fused six-membered ring. The reaction of 3-(2-iodobenzyl)-indoles with a variety of alkynes afforded polycyclic compounds with fused seven-membered rings. Annulation with unsymmetrical alkynes exhibited varied regioselectivity. Overall, this approach allows for quick and efficient assembly of polycyclic derivatives of indole and indolizine from easily available precursors.

Noncovalent interactions play an essential role in biological and chemical processes. In the main chain of common protein secondary structures, the lone pair (n) of a carbonyl oxygen is delocalized into the antibonding orbital (π*) of the subsequent carbonyl group. Herein, experimental and computational data reveal that this n→π* interaction can be attenuated by the inductive electron withdrawal of one or two α-fluoro groups in the donor. The steric effect of three α-fluoro groups, however, overcomes the inductive withdrawal. These data evoke a means to modulate the n→π* interaction in peptides, proteins, and other systems.

Porphobilinogen synthase (PBGS) catalyzes the first common step in the biosynthesis of the essential heme, chlorophyll and vitamin B(12) heme pigments. PBGS activity is regulated by assembly state, with certain oligomers exhibiting biological activity and others either partially or completely inactive, affording an innovative means of allosteric drug action. Pseudomonas aeruginosa PBGS is functionally active as an octamer, and inactive as a dimer. We have identified a series of compounds that stabilize the inactive P. aeruginosa dimer by a computational prescreen followed by native PAGE gel mobility shift analysis. From those results, we have prepared related thiadiazoles and evaluated their ability to regulate P. aeruginosa PBGS assembly state.

A series of novel imidazobenzodiazepine analogs of the lead chiral ligand SH-053-2'F--CH (), an α2/α3/α5 (Bz)GABA (A)ergic receptor subtype selective ligand, which reversed PCP-induced prepulse inhibition (PPI) of acoustic startle, were synthesized. These chiral ()-CH ligands are targeted for the treatment of schizophrenia and depression. These new ligands were designed by modifying the liable ester functionality in to improve the metabolic stability, cytotoxicity, and activity as compared to . Based on the data to date, the most promising ligands are the -cyclopropyl amide GL-I-55 () and the methyl bioisostere GL-I-65 (). The metabolic stability, cytotoxicity and locomotor effects are described in this report. Based on these results, and are the most promising for further pharmacology.

Bicyclo[1.1.1]pentane (BCP) has received substantial interest in the field of synthetic chemistry recently for its potential use as a benzene isostere in medicinal chemistry. Whereas bicyclo[2.2.2]octane (BCO) has also been used as a bioisostere of benzene, the condensation of BCP-amine with nadic anhydride is significantly easier than that of BCO-amine. Analyses of the geometries and the frontier molecular orbitals of these amines suggest that the low steric hindrance and high intrinsic nucleophilicity of BCP-amine together contribute to its exceptional reactivity.

This Highlight accounts for a recent phenomenon in which a series of novel ynamide structural analogues have emerged and caught the attention of the synthetic community. Preparations and reactions of these ynamide variants are delineated here to demonstrate their accessibility as well as their reactivity. This Highlight should help reveal that these unique N-containing alkynes can become highly versatile building blocks in organic syntheses.

This account describes the historical development of the coupling of γ,δ-unsaturated Fischer carbene complexes and -alkynylbenzaldehydes, which directly affords hydrophenanthrene ring systems in a process where each reactant contributes five carbons to the newly-formed bicyclo[4.4.0]decane ring system. The process has been termed net [5+5] cycloaddition. Use of the reaction to produce various medicinally important natural products and/or their parent ring systems is discussed.

Bioassay-guided fractionation of the extract of Jamaican marine sponge sp. followed by preparative TLC and HPLC yielded several known methyl ester cyclic peroxides (), known plakortides (), known bicyclic lactone () and new cyclic peroxide acids (). The chemical structures were elucidated by extensive interpretation of their spectroscopic data. These natural products showed remarkable in vitro cytotoxicity against several cancer cell lines.

Alkoxide-directed metal-centered intermolecular [2+2+2] annulation is shown to chemo-, regio-, and stereoselectively engage two polyunsaturated substrate in productive cyclization chemistry. This annulation process is unique in the field, revealing that it is possible to selectively engage three of five π-systems residing in the coupling partners in initial [2+2+2] reaction, and demonstrating that one of the two remaining π-systems (the TMS-alkyne) can ultimately serve to simply generate a new metallacyclopentene of great potential value in additional metallacycle-mediated coupling chemistry.

The plant-derived compounds furfuryl alcohol and itaconic anhydride are known to undergo a Diels-Alder reaction at room temperature and in bulk to efficiently give an alkene-containing lactone carboxylic acid. Reported here is the conversion of this substance to a variety of derivatives via hydrogenation, epoxidation, or halolactonization reactions. Most notable is the formation of a set of three related acrylate or methacrylate esters (see graphical abstract) produced by direct acylative ring opening of ether bonds using Sc(OTf) and (meth)acrylic anhydride. These esters are viewed as promising candidates for use as biorenewable monomers in reversible addition-fragmentation chain transfer (RAFT) polymerization reactions.

This article describes the development of microwave-assisted oxyanionic 5-exo-dig cyclization-Claisen rearrangement sequence as a convenient "one-pot" route to a variety of seven-membered carbocyclic ring systems. This process was used as the key transformation for the construction of several natural products, including frondosins A, B, and C.

There has been increasing use of hypervalent iodine reagents in the field of nucleoside chemistry. Applications span: (a) synthesis of nucleoside analogues with sulfur and seleno sugar surrogates, (b) synthesis of unusual carbocyclic and ether ring-containing nucleosides, (c) introduction of sulfur and selenium into pyrimidine bases of nucleosides and analogues, (d) synthesis of isoxazole and isoxazoline ring-containing nucleoside analogues, (e) involvement of purine ring nitrogen atoms for remote C-H bond oxidation, and (f) metal-catalyzed and uncatalyzed synthesis of benzimidazolyl purine nucleoside analogues by intramolecular C-N bond formation. This review offers a perspective on developments involving the use of hypervalent iodine reagents in the field of nucleoside chemistry that have appeared in the literature in the 2003-2017 time frame.

Allylic azides are underutilized in organic synthesis when compared to other organic azides or other allylic functionality. This is likely because allylic azides rearrange at room temperature, resulting in a potentially complex mixture of azides. This rearrangement has been termed the Winstein rearrangement. Understanding the mechanism and basic principles governing the allylic azide equilibrium may aid in developing applications for these molecules based on either alkene or azide functionalization. Presented herein is a compilation of the key observations regarding the nature of the allylic azide rearrangement. Mechanistic considerations are explicitly addressed with key examples from the literature.

Antinociceptive ligand HZ-166 is a GABA α2/α3 receptor subtype-selective potentiator. It has been shown to exhibit anxiolytic-like effects in rodent and rhesus monkeys, as well as reduced sedative/ataxic liabilities. In order to improve the metabolic stability of HZ-166, the ethyl ester moiety was bioisosterically replaced with 2,4-disubstituted oxazoles and oxazolines. The new analogs of HZ-166 were synthesized, characterized, and evalutated for their biological activity and docked in the human full-length heteromeric α1β3γ2L GABA receptor subtype CyroEM structure (6HUO). Importantly no sedation nor ataxia was observed on the rotorod for LKG-I-70 () or KPP-III-51 () at 100 and 120 mg/kg, respectively. These was also no loss of righting response for either ligand.

Herein is described the strategy to debrominate different aryl bromides selectively, using polymethylhydrosiloxane (PMHS) which tolerates a variety of functional groups. Key elements of this approach include the use of catalytic Pd(OAc) and the correct equivalents of polymethylhydrosiloxane (PMHS), in conjunction with aqueous KF. The present reaction process provides a strategic tool for the synthesis of a number of medicinally important molecules.

Fluorescent amino acids are powerful biophysical tools as they can be used in structural or imaging studies of a given protein without significantly perturbing its native fold or function. Here, we have synthesized and characterized 7-(dimethylamino)acridon-2-ylalanine (Dad), a red-shifted derivative of the genetically-incorporable amino acid, acridon-2-ylalanine. Alkylation increases the quantum yield and fluorescence lifetime of Dad relative to a previously published amino acid, 7-aminoacridon-2-ylalanine (Aad). These properties of Dad make it a potentially valuable protein label, and we have performed initial testing of its ability to be genetically incorporated using an evolved aminoacyl tRNA synthetase.

A series of 4-[(triazolyl)methoxy]phenyl analogs of the phenoxyphenyl-substituted thiirane SB-3CT was evaluated for its ability to inhibit gelatinases, members of the matrix metalloproteinase family of enzymes. The triazole segment of these inhibitors was assembled using the Meldal-Sharpless copper-catalyzed Huisgen dipolar cycloaddition of an azide and a terminal alkyne. While these triazole derivatives possessed fair activity as gelatinase inhibitors, an intermediate used in the dipolar cycloaddition, 4-(propargyloxy)phenyl derivative , showed very good activity (>50% inhibitory activity following a 3 h pre-incubation of at a concentration of 3 μM) as an inhibitor of human matrix metalloproteinase-2.

The prevalence of stereochemically complex amines in natural products, pharmaceuticals and other bioactive compounds, coupled with the challenges inherent in their preparation, has inspired our work to develop new and versatile methodologies for the synthesis of amine-containing stereotriads ('triads'). The key step is a highly chemo-, regio-, and stereoselective transition-metal catalyzed nitrene transfer reaction that transforms one of the cumulated double bonds of an allene precursor into a bicyclic methyleneaziridine intermediate. This account summarizes our strategies to rapidly elaborate such intermediates into stereochemically rich, densely functionalized amine triads, nitrogen heterocycles, aminated carbocycles and other useful synthetic building blocks.

Herein, we describe the synthesis of a novel bis-1,2,3-triazole ligand which contains an internal N-alkylated 2,2'-bipyrrolidine linker. By using simple starting materials, the ligand could be generated in good yield through several synthetic steps. To investigate the potential for the application of this ligand in transition metal catalysis, we generated a bis-Au(I) complex in nearly quantitative yield and examined its reactivity in the context of alkyne hydration. Both alkyl and aryl terminal alkynes could be efficiently converted to their corresponding ketones in nearly quantitative yields with only 1% catalyst loading under mild conditions.

Nitrogen-centered radicals are reactive intermediates that can function in the formation of new C-N bonds or enable the formation of other bonds through their ability to abstract hydrogen atoms to generate carbon radical intermediates. Methods for the generation of nitrogen-centered radicals have traditionally involved application of radical initiators and propagators such as peroxides, AIBN and tin hydrides. More recently, approaches to nitrogen-centered radicals involving copper catalysis have been developed. In the transformations summarized herein, the copper catalyst either oxidizes or reduces the nitrogen-centered radical precursor. Some of these methods have been developed as catalytic enantioselective using chiral copper complexes.