An efficient, scalable synthesis of the molecular transporter octaarginine via a segment doubling strategy

[reaction: see text]. Short oligomers of arginine function as remarkably efficient molecular transporters of drugs and probe molecules into cells and tissue. Currently, these compounds are prepared on resin through a unidirectional solid-phase synthesis. To extend the utility of these compounds for therapeutic and research applications, a scalable solution-phase synthesis of Arg8 (1) has been developed on the basis of a segment doubling strategy that proceeds in 13 steps and 28% overall yield from 4, including a novel one-step perdeprotection-perguanidinylation reaction.     

An efficient route to polynitrogen-fused tricycles via a nitrene-mediated N-N bond formation under microwave irradiation

The synthesis of unprecedented fused azaheterocyclic ring systems is described. Tricycles with either a central pyrazole or a triazole ring were obtained via a nitrene-mediated reaction of nitro bis(hetaryl) derivatives in the presence of triethylphosphite. The cyclization proceeded with complete chemoselectivity for the desired N-N bond formation and was completed within minutes under microwave activation. The key nitro bicycles were synthesized using either Stille couplings or aromatic nucleophilic substitution.     

An efficient approach to the synthesis of 3-vinylidene tetrahydropyrans via Prins-type cyclization

Lewis acid-catalyzed intramolecular reactions of oxocarbenium ions with propargylsilanes are described. The results obtained indicate that trimethylsilyl trifluoromethanesulfonate (TMSOTf) efficiently catalyses cyclization leading to the corresponding 3-vinylidene tetrahydropyrans in high yield as single isomers.     

An efficient approach to dihydrofurocoumarins via palladium-catalyzed annulation of 1,3-dienes by o-iodoacetoxycoumarins

The palladium-catalyzed annulation of 1,3-dienes by o-iodoacetoxycoumarins provides an efficient method for the synthesis of biologically interesting dihydrofurocoumarins. The presence of the acetyl group on the phenolic oxygen and the use of silver carbonate as a base are crucial for this process. This reaction is very general and regio- and stereoselective, and a wide variety of terminal, cyclic, and internal 1,3-dienes can be utilized. Derivatization of the annulation products provides an efficient approach to numerous analogues of natural products.     

An efficient approach to the stereoselective synthesis of 2,6-disubstituted dihydropyrans via stannyl-Prins cyclization

A general method has been developed for the stereoselective construction of 2,6-disubstituted dihydropyrans based on the Lewis acid-catalyzed intramolecular reactions of oxocarbenium ions with vinylstannanes. This novel methodology was applied to the enantioselective total synthesis of (−)-centrolobine.     

Cobalt-catalyzed, room-temperature addition of aromatic imines to alkynes via directed C-H bond activation

A quaternary catalytic system consisting of a cobalt salt, a triarylphosphine ligand, a Grignard reagent, and pyridine has been developed for chelation-assisted C-H bond activation of an aromatic imine, followed by insertion of an unactivated internal alkyne that occurs at ambient temperature. The reaction not only tolerates potentially senstitive functional groups (e.g., Cl, Br, CN, and tertiary amide), but also displays a unique regioselectivity. Thus, the presence of substituents such as methoxy, halogen, and cyano groups at the meta-position of the imino group led to selective C-C bond formation at the more sterically hindered ortho positions. Under acidic conditions, the hydroarylation products of dialkyl- and alkylarylacetylenes underwent cyclization to afford benzofulvene derivatives, while those of diarylacetylenes afforded the corresponding ketones in moderate to good yields. A mechanistic investigation into the reaction with the aid of deuterium-labeling experiments and kinetic analysis has indicated that oxidative addition of the ortho C-H bond is the rate-limiting step of the reaction. The kinetic analysis has also shed light on the complexity of the quaternary catalytic system.     

A DDQ-promoted metal-free cross-coupling of 1,3-diarylpropynes with hydroxyl via Sp C-H bond activation to form C-O bond

A metal-free coupling reaction between 1,3-diarylpropynes and alcohols/phenols/acids via propargylic sp³ C-H bonds activation and C-O bond formation reaction promoted by DDQ was realized. The reaction afforded series of propargyl ethers, propargyl esters and propargyl ketals.     

An efficient non-catalytic, regioselective approach to the synthesis of angularly fused polycyclic systems

A novel approach to the synthesis of partially reduced different ring sizes of PAH analogs with sec.amino and nitrile functionalities is delineated through base-induced ring transformation of 4-sec.amino-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles by a carbanion, generated in situ from cyclopentanone, cyclohexanone, cycloheptanone, and cyclooctanone separately in good yields. An increase in the size of cycloalkanone ring beyond cyclooctanone restricts the ring transformation under analogous reaction conditions possibly due to bulky conformation of higher homologs. The synthetic method provides an efficient general route for the construction of angularly fused partially reduced polycyclic aromatic hydrocarbons: 5-sec.amino-2,3,6,7-tetrahydro-1H-cyclopenta[c]phenanthrene-4-carbonitriles, 6-sec.amino-2,3,4,7,8-pentahydro-1H-benzo[c]phenanthrene-5-carbonitriles, 7-sec.amino-2,3,4,5,8,9-hexahydro-1H-cyclohepta[c]phenanthrene-6-carbonitriles, and 8-sec.amino-2,3,4,5,6,9,10-heptahydro-1H-cycloocta[c]phenanthrene-7-carbonitriles.     

An approach to pancratistatins via ring-closing metathesis: efficient synthesis of novel 1-aryl-1-deoxyconduritols F. cv

Structurally novel cyclitols, 1-aryl-1-deoxyconduritols F, were efficiently prepared from d-xylose, utilizing RCM as a key step. Various aromatic residues were incorporated in the cyclitol skeleton with total stereochemical control, utilizing a diastereoselective aryl cuprate addition to a gamma-alkoxy enoate. The synthetic route establishes a firm foundation for a practical synthesis of the antitumor alkaloid pancratistatin and its aryl analogues. [structure: see text]     

Iridium-catalyzed double incorporation reaction of N-benzylmaleimide to styrene via ortho-C-H bond activation, initiated by precoordination of the double bond of styrene to iridium

Reaction of styrene with N-benzylmaleimide in the presence of [IrCl(cod)]₂ (5 mol %) and bpy (10 mol %) in an autoclave (1 MPa of Ar) at 150 °C for 18 h stereoselectively led to the formation of a new cyclic product. The structure of the product suggests that a novel iridium-catalyzed double incorporation reaction takes place via a metallacyclopentane formed after ortho-C-H activation.     

An efficient route to tetrahydronaphthols via addition of ortho-lithiated stilbene oxides to alpha,beta-unsaturated fischer carbene Complexes

[reaction: see text] A stereoselective/stereospecific synthesis of polysubstituted tetrahydronaphthols based on the Michael addition of ortho-lithiated stilbene oxides to alpha,beta-unsaturated Fischer carbene complexes followed by an unusual cyclization of the corresponding intermediate in a 6-endo-tet mode is described.     

An efficient approach to fused indolines via a copper(I)-catalyzed reaction of sulfonyl azide with 2-ethynylaryl methylenecyclopropane

A cascade reaction of 2-ethynylaryl methylenecyclopropane with sulfonyl azide catalyzed by copper(I) iodide under mild conditions is described, which provides a novel and efficient route for the generation of fused indolines.     

An approach to identifying sequential metabolites of a typical phenylethanoid glycoside, echinacoside, based on liquid chromatography-ion trap-time of flight mass spectrometry analysis

Metabolite identification for the compounds that undergo multiple and sequential metabolism is still a great challenge. Echinacoside (ECH), a typical phenylethanoid glycoside, contains multiple unstable chemical bonds and high reactive functional groups which are susceptible to multiple pathways of degradation and metabolism, leading great difficulties for its metabolite identification. This study proposed a novel approach for rapidly identifying the complicated and unpredictable metabolites of ECH, based on the powerful liquid chromatography hybrid ion trap and time of flight mass spectrometry (LC/MS-IT-TOF) analysis. Four degradation products were rapidly identified via the “fragmentation-degradation” comparisons. Five phase I and phase II metabolites of the degradation products were rapidly characterized via the crossover mass differences comparisons of their quasi-molecular ions with the potential precursors. Four direct phase I and phase II metabolites of the parent compound were identified by the mass differences analysis of the molecular ions between metabolites and the parent compound. Multiple stages of fragmentation patterns were used to confirm the metabolites characterizations. This study provides a novel approach to characterizing the complicated metabolites, and would be widely applicable for the metabolite identification of natural products.     

A new diastereoselective multicomponent, one-pot strategy for the synthesis of 3-substituted isoindolinones via efficient C-C bond formation

A new three-component reaction among o-phthalaldehyde, N-alkyl/aryl substituted urea, and an aromatic aldehyde has been developed at ambient condition, and a class of isoindolinones with novel C-3 substitution were conveniently synthesized. The general diastereomeric excess as high as over 99% of the products indicated the excellent stereoselectivity posed in this multicomponent reaction.     

An efficient stereoselective synthesis of aminocyclohexenes from 7-azanorbornenes via LiAlH4 mediated tandem double bond migration-ring opening sequence

hNav1.7 had received great interest in the past decade owing to its attractive mechanism of actions in pain processing pathway. More recently, we developed a series of efficacious hNav1.7 inhibitors for analgesic, which were characterized with a novel aminocyclohexene as pharmacophore. Herein, we reported our synthetic efforts to construct the unique scaffold, which can be rapidly accessed from readily available 7-azanorbornenes via an unexpected catalyst-free, LiAlH₄ mediated tandem double bond migration-ring opening sequence. A probable mechanism was proposed to illuminate the good regio- and stereoselectivity.     

Metal-free and efficient approach to 4-thiocyanated 2H-chromenes via TFA-mediated cascade cyclization of 2-propynolphenols

A metal-free, Brønsted acid-mediated cascade cyclization of 2-propynolphenols for efficient synthesis of various 4-thiocyanated 2H-chromenes is developed by using KSCN as the thiocyanated source. This reaction was characterized by readily prepared starting materials, bearing good functional group tolerance and excellent yields. Moreover, the obtained 4-thiocyanated 2H-chromenes could be further derivated to potential bioactive and pharmaceutical molecules.     

An efficient approach to pyrazolo[5,1-a]isoquinolin-2-amines via a silver(I)-catalyzed three-component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, and nitrile

A three-component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, and nitrile catalyzed by silver triflate under mild conditions is reported, which generates pyrazolo[5,1-a]isoquinolin-2-amines in good to excellent yields.     

An efficient low-temperature route to polycyclic isoquinoline salt synthesis via C-H activation with [Cp*MCl2]2 (M = Rh, Ir)

Bi-, tri-, and tetracyclic isoquinoline salts were readily synthesized in excellent yields at room temperature from readily available starting materials after three reaction steps. Aromatic C-H activation was first promoted by sodium acetate with [Cp*MCl2]2 (M = Rh, Ir) at room temperature to form cyclometalated compounds. Dimethylacetylenedicarboxylate was then found to insert into the metal-carbon bonds of the cyclometalated compounds. Finally, the insertion compounds underwent oxidative coupling to form the desired isoquinoline salts and regenerate [Cp*MCl2]2. All of the intermediate compounds following C-H activation, alkyne insertion, and oxidative coupling were fully characterized, including the determination of X-ray structures in several cases, and the results shed light on the overall mechanism. Moreover, it was possible to synthesize the isoquinoline salts from readily available starting materials using one-pot procedures; thus, this work provides a novel, efficient method for metal-mediated synthesis of heterocycles.     

An efficient, economical synthesis of hydroxytyrosol and its protected forms via Baeyer-Villiger oxidation

An efficient and practical preparation of hydroxytyrosol and its orthogonally-protected forms was developed from inexpensive tyrosol. The utilization of Baeyer-Villiger oxidation enables the chemoselective introduction of a phenolic hydroxyl group in good yield.     

An expeditious approach to 1-aminoisoquinolines via an unexpected reaction of 2-alkynylbenzaldoxime, carbodiimide, with bromine

A three-component reaction of 2-alkynylbenzaldoxime, carbodiimide, and bromine provides a novel and efficient approach to functionalized 1-aminoisoquinolines. This unexpected reaction proceeds through electrophilic cyclization, [3+2] cycloaddition, rearrangement and hydrolyzation.