Desymmetrization of meso [3.2.1]oxabicyclic systems using metal-catalysed asymmetric intramolecular C-H insertion

Diazoketone derivatives of meso 8-oxabicyclo[3.2.1]octen-3-ones were desymmetrized by an intramolecular C-H insertion mediated by chiral copper and dirhodium catalysts to generate oxatricyclic systems with up to 5 contiguous stereogenic centres and 50% ee.     

A facile enantioselective synthesis of (+)-rolipram via C-H insertion process

Rolipram, (±)-4-(3-cyclopentyloxyl-4-methoxylphenyl)-2-pyrrolidinone,is known as a potent and selective inhibitor of phosphodiesterase type IV(PDE IV)1.In fact, although both enantiomers are active, the levorotatory isomer, for which several synthesis has been recently reported2, has proved to be the most active one. Hashimoto and Jung have repored rolipram,s synthesis via intramolecular C-H insertion reaction of α-methoxylcarbonyl-α-diazoacetamide and α-phenylsulfonyl-α-diazoacetamid…     

Catalytic asymmetric synthesis of a 1-deoxy-1,1-difluoro-D-xylulose

[reaction: see text] A new route, of potential strategic importance, to a difluorosugar analogue has been developed. Key steps included a Stille coupling and a highly regio- and enantioselective dihydroxylation of a highly substituted diene. Protecting groups were chosen to enhance the reactivity of the disubstituted allylic fragment in the AD reaction and allow deprotection under orthogonal conditions.     

Total synthesis of (+)-lithospermic acid by asymmetric intramolecular alkylation via catalytic C-H bond activation

The total synthesis of (+)-lithospermic acid is described. The efficient synthesis features an asymmetric alkylation via C-H bond activation to assemble the dihydrobenzofuran core of the natural product. This was accomplished via a chiral imine-directed C-H bond functionalization and represents the first application of this C-H activation method to natural product synthesis. Furthermore, a challenging deprotection of a late-stage permethylated lithospermic acid was achieved.     

Direct synthesis of chiral 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines via a catalytic asymmetric intramolecular aza-Friedel-Crafts reaction

The direct asymmetric intramolecular aza-Friedel-Crafts reaction of N-aminoethylpyrroles with aldehydes catalyzed by a chiral phosphoric acid represents the first efficient method for the preparation of medicinally interesting chiral 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines with high yields and high enantioselectivities. This strategy has been shown to be quite general toward various aldehydes and pyrrole derivatives.     

A concise synthesis of (±)-pregabalin via intramolecular C-H insertion of N-cumyl á-diazoacetamide

Pregabalin 1 (3-aminomethyl-5-methyl hexanoic acid) is a potent anticonvulsant related to the inhibitory neurotransmitter γ-aminobutyric acid (GABA).1 In preclinical trials of anticonvulsant activity, pregabalin is three to ten times more potent than gabapentin. Therefore, pregabalin can be used for the potential treatment of several central nervous system (CNS) disorders including epilepsy, neuropathic pain, anxiety and social phobia. Many synthetic routes have been developed to prepare p…     

Catalytic asymmetric synthesis of stable oxetenes via Lewis acid-promoted [2+2] cycloaddition

A highly enantioselective and atom-economical [2 + 2] cycloaddition of various alkynes with trifluoropyruvate using a dicationic (S)-BINAP-Pd catalyst has been established. This is the first enantioselective synthesis of stable oxetene derivatives, whose structure has been clarified by X-ray analysis. This catalytic process offers a practical synthetic method for oxetene derivatives (catalyst loading: up to 0.1 mol %), which can serve as novel chiral building blocks for pharmaceuticals and agrochemicals and can also be transformed into a variety of enantiomerically enriched CF(3)-substituted compounds with high stereoselectivity.     

Palladium-catalyzed synthesis of 2-substituted benzothiazoles via a C-H functionalization/intramolecular C-S bond formation process

Catalytic synthesis of 2-substituted benzothiazoles from thiobenzanilides was achieved in the presence of a palladium catalyst through C-H functionalization/C-S bond formation. This method features the use of a novel catalytic system consisting of 10 mol % of Pd(II), 50 mol % of Cu(I), and 2 equiv of Bu4NBr that produced variously substituted benzothiazoles in high yields with good functional group tolerance.     

Selective synthesis of spiro[4,5]trienyl acetates via an intramolecular electrophilic ipso-iodocyclization process

A general and efficient intramolecular electrophilic ipso-iodocyclization of para-unactivated arylalkynes has been developed for the synthesis of spiro[4,5]trienyl acetates. In the presence of NIS (N-iodosuccimide) and HOAc, para-unactivated arylalkynes, including N-arylpropiolamides and phenyl 3-phenylpropiolate, underwent the intramolecular electrophilic ipso-iodocyclization smoothly in moderate to good yields.     

The synthesis of baclofen and GABOB via Rh(II) catalyzed intramolecular C-H insertion of α-diazoacetamides

The synthesis of baclofen and GABOB is reported via hydrolysis of the corresponding N-tert-butyl γ-lactams, which were obtained from Rh(II) catalyzed intramolecular C-H insertion of α-diazoacetamides.     

Catalytic asymmetric synthesis of chromenes and tetrahydroquinolines via sequential allylic alkylation and intramolecular Heck coupling

Highly enantioselective synthesis of chiral chromenes and tetrahydroquinolines is achieved by combining asymmetric copper-catalyzed allylic substitution with Grignard reagents and an efficient intramolecular Heck reaction. Moreover, the exocyclic double bond formed in the cyclisation was subjected to RCM, hydroboration and hydrogenation illuminating the synthetic versatility of these heterocycles.     

Catalytic asymmetric synthesis of spirocyclobutyl oxindoles and beyond via [2+2] cycloaddition and sequential transformations

Efficient asymmetric synthesis of a collection of small molecules with structural diversity is highly important to drug discovery. Herein, three distinct types of chiral cyclic compounds were accessible by enantioselective catalysis and sequential transformations. Highly regio- and enantioselective [2+2] cycloaddition of (E)-alkenyloxindoles with the internal C C bond of N-allenamides was achieved with N,N′-dioxide/Ni(OTf)₂ as the catalyst. Various optically active spirocyclobutyl oxindole derivatives were obtained under mild conditions. Moreover, formal [4+2] cycloaddition products occurring at the terminal C C bond of N-allenamides, dihydropyran-fused indoles, were afforded by a stereospecific sequential transformation with the assistance of a catalytic amount of Cu(OTf)₂. In contrast, performing the conversion under air led to the formation of γ-lactones via the water-involved deprotection and rearrangement process. Experimental studies and DFT calculations were performed to probe the reaction mechanism.

Three distinct types of chiral cyclic compounds were accessible by catalytic asymmetric synthesis of spirocyclobutyl oxindoles via [2+2] cycloaddition and sequential transformations.     

Rhenium-catalyzed synthesis of naphthalene derivatives via insertion of aldehydes into a C-H bond

A rhenium complex, [ReBr(CO)₃(THF)]₂, catalyzed reactions of aromatic ketimines and aldehydes with dienophiles, followed by dehydration, to give naphthalene derivatives in good to excellent yields. This reaction proceeds via C-H bond activation, insertion of an aldehyde, intramolecular nucleophilic cyclization, reductive elimination, elimination of aniline and Diels-Alder reaction. After dehydration, naphthalene derivatives were formed.     

N,N-dimethylformamide-mediated sodium reduction of trans-3,3'-benzo[c]thienylidene-1,1'-dithione and trans-3,3'-benzo[c]selenonylidene-1,1'-dithione

[reaction: see text] The synthesis of stable methylthio-capped biisothianaphthene and biisoselenophene derivatives has been achieved using DMF-mediated sodium reduction of cyclic thiocarbonyl compounds.     

Silver catalyzed intramolecular cyclization for synthesis of 3-alkylideneoxindoles via C-H functionalization

A novel protocol for the preparation of various 3-alkylideneoxindoles via a silver-catalyzed aromatic C-H functionalization has been developed. The process is simple, environmentally conscious, and avoids the use of abundant bases, oxidants, or other additives.     

Convenient synthesis of 1,1′-H-spiro[indoline-3,3′-piperidine]

The spirocyclic indoline ring system represents an important scaffold for the discovery of novel therapeutics. Herein, we describe the synthesis of 1,1′-H-spiro[indoline-3,3′-piperidine] using an intramolecular palladium-catalyzed α-arylation reaction.