Enantioselective Synthesis of Chiral 2-Nitroallylic Amines via Cooperative Cation-Binding Catalysis.

Chiral allylic amines are valuable building blocks for biologically important compounds and natural products. In this study, we present the use of cooperative cation-binding catalysis as an efficient method for synthesizing chiral allylic amines. By utilizing a chiral oligoEG and potassium fluoride as a cation-binding catalyst and base, respectively, a wide range of biologically relevant chiral 2-nitroallylic amines are obtained with excellent enantioselectivities (up to >99 % ee) through the organocatalytic asymmetric aza-Henry-like reaction of ß-monosubstituted and ß,ß-disubstituted nitroalkenes with α-amidosulfones as imine precursors. Extensive experimental studies are presented to illustrate plausible mechanisms. Preliminary use of a chiral 2-nitroallylic amine as a Michael acceptor demonstrated its potential application for diversity-oriented synthesis of bioactive compounds.

Biomimetic Catalytic Retro-Aldol Reaction Using a Cation-Binding Catalyst: A Promising Route to Axially Chiral Biaryl Aldehydes.

Here we describe a biomimetic catalytic retro-aldol reaction of racemic α-substituted ß-hydroxy ketones utilizing a chiral oligoEG cation-binding catalyst as a type-II aldolase mimic. Our investigation of various aldol substrates has demonstrated that our biomimetic retro-aldol protocol enables rapid access to highly enantiomerically enriched aldols with a selectivity factor (s) of up to 70. Additionally, we have demonstrated the synthetic strategy's feasibility for accessing diverse and valuable axially chiral aldehydes.

Kinetic Resolution of ß-Hydroxy Carbonyl Compounds via Enantioselective Dehydration Using a Cation-Binding Catalyst: Facile Access to Enantiopure Chiral Aldols.

A practical and highly enantioselective nonenzymatic kinetic resolution of racemic ß-hydroxy carbonyl (aldol) compounds through enantioselective dehydration process was developed using a cation-binding Song's oligoethylene glycol (oligoEG) catalyst with potassium fluoride (KF) as base. A wide range of racemic aldols was resolved with extremely high selectivity factors ( s = up to 2393) under mild reaction conditions. This protocol is easily scalable. It provides an alternative approach for the syntheses of diverse biologically and pharmaceutically relevant chiral aldols in enantiomerically pure form. For example, racemic gingerols could participate in this kinetic resolution with superb efficiency ( s > 240), affording both enantiomerically pure gingerols and corresponding shogaols simultaneously in a single step. The dramatic effectiveness of such kinetic resolution process can be ascribed to systematic cooperative hydrogen-bonding catalysis in a densely confined supramolecular chiral cage in situ generated from the chiral catalyst, substrate, and KF.

"On Water'' Promoted Ullmann-Type C-N Bond-Forming Reactions: Application to Carbazole Alkaloids by Selective N-Arylation of Aminophenols.

The Ullmann-type cross coupling of a variety of aromatic, aliphatic amines with aryl halides is reported using a CuI-based catalytic system in combination with an easily accessible prolinamide ligand in aqueous media. The method is mild and tolerant to air, moisture, and a wide range of functional groups, providing a novel way to access a variety of aminated products. Secondary amines like heteroaromatic amines and nucleobases have also been used, affording the corresponding coupling products in good to excellent yields. Moreover, this method has been employed for chemoselective C-N arylation of aminophenols and further utilized for the synthesis of carbazole natural products, avoiding the protection and deprotection steps.

Asymmetric Synthesis of α-Fluoro-ß-Amino-oxindoles with Tetrasubstituted C-F Stereogenic Centers via Cooperative Cation-Binding Catalysis.

Biologically relevant chiral 3,3-disubstituted oxindole products containing a ß-fluoroamine unit are obtained in high yields and with excellent stereoselectivity (up to 99% ee, dr >20:1 for syn) through the organocatalytic direct Mannich reaction of 3-fluoro-oxindoles as fluoroenolate precursors and α-amidosulfones as the bench-stable precursors of sensitive imines by using a chiral oligoethylene glycol and KF as a cation-binding catalyst and base, respectively. This protocol can be easily scaled without compromising the asymmetric induction. Furthermore, this protocol was also successfully extended to generate tetrasubstituted C-Cl and C-Br stereogenic centers.

Fluoride Anions in Self-Assembled Chiral Cage for the Enantioselective Protonation of Silyl Enol Ethers.

The potential of Song's chiral oligoethylene glycols (oligoEGs) as catalysts was explored in the enantioselective protonation of trimethylsilyl enol ethers in combination with alkali metal fluoride (KF and CsF) and in the presence of a proton source. Highly enantioselective protonations of various silyl enol ethers of α-substituted tetralones were achieved, producing chiral α-substituted tetralones in full conversion and with up to 99% ee. The established protocol was successfully extended to the synthesis of biologically relevant chiral α-substituted chromanone and thiochromanone derivatives.

Organocatalytic Asymmetric Synthesis of Chiral Dioxazinanes and Dioxazepanes with in Situ Generated Nitrones via a Tandem Reaction Pathway Using a Cooperative Cation Binding Catalyst.

Heterocyclic skeletons play major roles in pharmaceuticals and biological processes. Cycloaddition reactions are most suitable synthetic tools to efficiently construct chemically diverse sets of heterocycles with great structural complexity owing to the simultaneous or sequential formation of two or more bonds, often with a high degree of selectivity. Herein, we report an unprecedented formal cycloaddition of N-Boc-N-hydroxy amido sulfones as the nitrone precursors with terminal-hydroxy α,ß-unsaturated carbonyls in the presence of Song's chiral oligoethylene glycol as a cation-binding catalyst and KF as a base to afford a wide range of highly enantio- and diastereo-enriched six-membered dioxazinane and seven-membered dioxazepane heterocycles. In this process, nitrones as well as terminal-hydroxy α,ß-unsaturated carbonyls serve as "amphiphilic" building units, and the reaction proceeds through a tandem pathway sequence of oxa-Mannich reaction/oxa-Michael reaction/tautomerization/protonation. The cation-binding catalysis in a densely confined chiral space in situ formed by the incorporation of potassium salt is the key to this successful catalysis. This strategy opens a new pathway for the asymmetric synthesis of diverse heterocyclic skeletons of great complexity.

Selective recognition of c-MYC G-quadruplex DNA using prolinamide derivatives.

Herein we report the design, synthesis, biophysical and biological evaluation of triazole containing prolinamide derivatives as selective c-MYC G-quadruplex binding ligands. A modular synthetic route has been devised for prolinamide derivatives using a copper(i) catalyzed azide-alkyne cycloaddition (CuAAC). The Förster resonance energy transfer (FRET) melting assay indicates that prolinamide trimers can significantly stabilize G-quadruplex structures over duplex DNA compared to prolinamide dimers. The fluorescent intercalator displacement (FID) assay shows that a trimer with prolinamide side chains at the para-position of the benzene ring can discriminate between different quadruplex structures and exhibits the highest binding affinity towards the c-MYC G-quadruplex structure. Molecular modeling studies reveal that the prolinamide trimer stacks upon the terminal G-quartet of the c-MYC G-quadruplex. Atomic force microscopy (AFM) analysis reveals that the tris-prolinamide ligand can be used to regulate the assembly of novel supramolecular nanoarchitectures. Further, in vitro cellular studies with human hepatocellular carcinoma (HepG2) cells indicate that the tris-prolinamide derivatives can inhibit cell proliferation and reduce c-MYC expression in cancer cells.

A small molecule peptidomimetic that binds to c-KIT1 G-quadruplex and exhibits antiproliferative properties in cancer cells.

A modular synthesis of l-proline derived peptidomimetics has been developed using the Cu(I) catalyzed Huisgen cycloaddition between an azido prolinamide with pyridine and benzene dicarboxamide containing dialkynes. Förster Resonance Energy Transfer (FRET) melting assay provided an initial indication that the pyridyl analogue can stabilize the c-KIT1 quadruplex DNA. A competitive FRET-melting assay and Fluorescent Intercalator Displacement (FID) assay suggest that the pyridyl ligand shows excellent selectivity for c-KIT1 quadruplex over duplex DNA and other investigated G-quadruplexes. Molecular docking studies indicate that the pyridyl ligand can adopt unique conformations upon binding to c-KIT1 quadruplex due to the presence of intramolecular hydrogen bonds. The pyridyl ligand can perturb cell cycle progression and induce necrotic cell death of human hepatocellular liver carcinoma HepG2 cells.

Thiazolidinedione-isatin conjugates via an uncatalyzed diastereoselective aldol reaction on water.

An uncatalyzed aldol reaction of N-substituted thiazolidinediones with isatin derivatives has been developed "on water" to afford a new class of pharmacologically important thiazolidinedione-isatin conjugates in excellent yields and diastereoselectivities. The isatin-thiazolidine conjugate undergoes a catalyst-free stereoselective transfer aldol reaction on water. Single-crystal X-ray studies reveal that the aldol products can self-assemble to form supramolecular DNA "zipper" like structures through intermolecular hydrogen bonds and aromatic π-π interactions.

A fluorescent guanosine dinucleoside as a selective switch-on sensor for c-myc G-quadruplex DNA with potent anticancer activities.

Like likes like! A novel fluorescent C2 -symmetric guanosine-based dinucleoside has been engineered by chemical ligation of two guanosine units with a biocompatible dansyl tag. The nucleoside exhibits high selectivity for c-myc G-quadruplex DNA through fluorescence enhancement over duplex DNA and other promoter G-quadruplexes (see scheme). It stains the nucleus preferentially, arrests the cell cycle at the G2/M phase, inhibits cell growth, and induces apoptosis in A375 cancer cells.

Design and synthesis of an on-off "click" fluorophore that executes a logic operation and detects heavy and transition metal ions in water and living cells.

We have designed and synthesized a novel fluorescent molecular probe using the Cu(i)-catalyzed Huisgen cycloaddition of 1,3-diethynyl-6-fluoroisoquinoline with 1-(2-azidoethyl)pyrrolidine. This water soluble "click" fluorescent chemosensor displays good sensitivity towards heavy and transition metal ions. It shows pronounced fluorescence enhancement and high selectivity for Zn(2+) over other biologically relevant metal ions in water at pH 7.0. The fluorescence response of the bis-triazole derivative in the presence of Zn(2+) is switchable and reversible as a function of pH. The chemosensor also exhibits fluorescence quenching with Fe(2+) and Cu(2+) in water at pH 7.0. A modified YES logic gate property has been proposed using the "turn-on" and "turn-off" behavior of the bis-triazole with Zn(2+) and Fe(2+). The sensor is cell membrane permeable and applicable for intracellular Zn(2+) imaging.

Iron catalyzed highly regioselective dimerization of terminal aryl alkynes.

Iron can catalyze head-to-head dimerization of terminal aryl alkynes to give the corresponding (E) selective conjugated enynes in high yields. A variety of substituted aryl acetylenes underwent smooth dimerization using catalytic FeCl(3) and DMEDA in the presence of KO(t)Bu.

Synthesis of spirocyclic thiazolidinediones using ring-closing metathesis and one-pot sequential ring-closing/cross metathesis.

A novel synthetic route to spirocyclic thiazolidinediones is reported by utilizing ring-closing metathesis (RCM). A selective cross metathesis (CM) of N-allyl azaspiro derivatives with different olefins has been demonstrated to prepare substituted azaspiro-[4.4]nonenediones. The X-ray crystal structure of a spirocyclic thiazolidinedione dimer is described, which has been prepared in two steps from thiazolidinedione using a one-pot sequential ring-closing and self metathesis. Cross metathesis proceeds smoothly with both electron rich and poor olefins. The symmetrical bis-thiazolidinedione spirocyclic system can be used as CM coupling partner with olefins. One-pot sequential RCM-CM has been developed for the synthesis of substituted spirocyclic compounds. The methodology allows a quick access to thia-azaspiro-[4.4]nonene and -[4.5]decene-dione ring systems from readily available starting materials which are not otherwise accessible.