Asymmetric multicomponent [C+NC+CC] synthesis of highly functionalized pyrrolidines catalyzed by silver(I)

[reaction: see text] Highly functionalized pyrrolidines are obtained in a single chemical step via a mild, efficient, and selective Ag(I)-catalyzed asymmetric [C+NC+CC] coupling process. Oppolzer's camphorsultam enables the desired reaction cascade and provides a reliable means to control the developing stereochemistry and purify the products. This three-component reaction provides unprecedented access to structurally diverse pyrrolidines for both target- and diversity-oriented syntheses.     

Asymmetric [C + NC + CC] coupling entry to the naphthyridinomycin natural product family: formal total synthesis of cyanocycline A and bioxalomycin β2

A full account of our [C + NC + CC] coupling approach to the naphthyridinomycin family of natural products is presented, culminating in formal total syntheses of cyanocycline A and bioxalomycin β2. The key complexity-building reaction in the synthesis involves the Ag(I)-catalyzed endo-selective [C + NC + CC] coupling of aldehyde 7, (S)-glycyl sultam 8, and methyl acrylate (9) to provide the highly functionalized pyrrolidine 6, which was carried forward to an advanced intermediate (compound 33) in Fukuyama's synthesis of cyanocycline A. Since cyanocycline A has been converted to bioxalomycin β2, this constitutes a formal synthesis of the latter natural product as well. The multicomponent reaction-based strategy reduces the number of steps previously needed to assemble these complex molecular targets by one-third. This work highlights the utility of the asymmetric [C + NC + CC] coupling reaction in the context of a complex pyrrolidine-containing target and provides an illustrative guide for its application to other synthesis problems. The synthesis also fueled collaborative biological and biochemical research that identified a unique small molecule inhibitor of cell migration (compound 30).     

C+NC+CC] coupling-enabled synthesis of influenza neuramidase inhibitor A-315675

An efficient synthesis of the neuramidase inhibitor A-315675 is reported. The fully functionalized pyrrolidine core of the target is assembled in one pot via an exo-selective asymmetric [C+NC+CC] coupling reaction.     

Organocatalytic asymmetric multi-component [C+NC+CC] synthesis of highly functionalized pyrrolidine derivatives

The highly chemo- and enantioselective organocatalytic [C+NC+CC] coupling process between aldehydes, dialkyl 2-aminomalonates and α,β-unsaturated aldehydes is presented. The reaction gives access to highly functionalized pyrrolidine derivatives in good yields with >10:1 dr and 90-98% ee.     

DFT study on [4+2] and [2+2] cycloadditions to [60] fullerene

The functionalisation of C₆₀ fullerene with 2,3-dimethylene-1,4-dioxane (I) and 2,5-dioxabicyclo [4.2.0]octa-1(8),6-diene (II) was investigated by the use of density functional theory calculations in terms of its energetic, structural, field emission, and electronic properties. The functionalisation of C₆₀ with I was previously reported experimentally. The I and II molecules are preferentially attached to a C—C bond shared and located between two hexagons of C₆₀ via [4+2] and [2+2] cycloadditions bearing reaction energies of ?15.9 kcal mol^?1 and ?72.4 kcal mol^?1, respectively. The HOMO-LUMO energy gap and work function of C₆₀ are significantly reduced following completion of the reactions. The field electron emission current of the C₆₀ surface will increase after functionalisation of either the I or II molecule.     

Highly Regio-, Diastereo-, and Enantioselective Synthesis of Tetrahydroazepines and Benzo[b]oxepines through Palladium-Catalyzed [4+3] Cycloaddition Reactions

A novel Pd⁰-catalyzed asymmetric [4+3] annulation reaction of two readily accessible starting materials has been developed for building seven-membered heterocyclic architectures. The potential [3+2] side pathway could be suppressed though fine tuning of the conditions. A broad scope of cycloaddition donors and acceptors participated in the transformation with excellent chemo-, regio-, diastereo-, and enantioselectivtities, leading to valuable tetrahydroazepines and benzo[b]oxepines.     

Cobalt(II)-Catalyzed C(sp3)−C(sp3) Coupling for the Direct Stereoselective Synthesis of 2-Deoxy-C-Glycosides from Glycals

We report a ligand-controlled Co^II-catalyzed C(sp³)−C(sp³) coupling hydroalkylation for direct and β-selective synthesis of 2-deoxy-C-glycosides from glycals. This reaction proceeds by a radical pathway for alkyl halide activation and is β-selective through ligand control. This approach may inspire the development of further stereoselective coupling reactions with potential application in the field of carbohydrates.     

Asymmetric Total Synthesis of Hasubanan Alkaloids: Periglaucines A–C,N,O-Dimethyloxostephine and Oxostephabenine

We report herein the asymmetric total synthesis of periglaucines A–C, N,O-dimethyloxostephine and oxostephabenine. The key strategies used include: 1) a Rh^I-catalyzed regio- and diastereoselective Hayashi-Miyaura reaction to connect two necessary fragments; 2) an intramolecular photoenolization/Diels–Alder (PEDA) reaction to construct the highly functionalized tricyclic core skeleton bearing a quaternary center; 3) a bio-inspired intramolecular Michael addition and transannular acetalization to generate the aza[4.4.3]propellane and the tetrahydrofuran ring.     

Asymmetric Total Synthesis of Hasubanan Alkaloids: Periglaucines A–C,N,O-Dimethyloxostephine and Oxostephabenine

We report herein the asymmetric total synthesis of periglaucines A–C, N,O-dimethyloxostephine and oxostephabenine. The key strategies used include: 1) a Rh^I-catalyzed regio- and diastereoselective Hayashi-Miyaura reaction to connect two necessary fragments; 2) an intramolecular photoenolization/Diels–Alder (PEDA) reaction to construct the highly functionalized tricyclic core skeleton bearing a quaternary center; 3) a bio-inspired intramolecular Michael addition and transannular acetalization to generate the aza[4.4.3]propellane and the tetrahydrofuran ring.     

One-Pot Synthesis of Benzodiazepines through RuII-Catalyzed Regioselective [5+2] Annulation of N-Aryl Amidines with Alkynyl Cyclobutyl Acetates

A highly efficient strategy to construct benzo[d][1,3]diazepines via selective C−H bond activation of N-aryl amidines and coupling with alkynyl cyclobutyl acetates was achieved successfully by Ru^II-catalyzed [5+2] cyclization. This protocol features excellent regioselectivity, wide substrate tolerance, mild reaction conditions, which might be potentially applied in the discovery of lead compounds for the developing new drugs.     

Pd(II)-catalyzed aliphatic Claisen rearrangements of acyclic allyl vinyl ethers

Palladium (II)-catalyzed [3,3] sigmatropic rearrangement of acyclic allyl vinyl ethers delivers 2,3-anti disubstituted pentenal Claisen adducts with high diastereoselectivity. Reaction conditions for circumventing allyl vinyl ether cleavage that had previously plagued catalyzed rearrangement of α-unsubstituted vinyl ether substrates are described. Merging Pd(II) catalysis with the facile access to the Claisen substrates afforded by Ir(I)-catalyzed olefin isomerization provides an expedient procedure for realizing asymmetric anti-selective Claisen rearrangements.     

Development of Chiral Spiro Phosphoramidites for Rhodium-Catalyzed Enantioselective Reactions

A series of 1,1′-spirobiindane-7,7′-diol ( SPINOL ) analogues bearing a 2,2′-dimethyl-, cyclopentyl-, or cyclohexyl-fused ring were synthesized, and their distinct structural features were elucidated by X-ray crystallography. On the basis of these scaffolds, chiral monophosphoramidite ligands 6 a – m were synthesized, which demonstrated excellent enantioselectivity in Rh^I-catalyzed asymmetric hydrogenation of a dehydro amino acid methyl ester. Ligands 6 a – m were also successfully applied in the Rh^I-catalyzed enantioselective [4+2] cycloaddition of α,β-unsaturated imines with isocyanates, which afforded the corresponding pyrimidinones in good yields (60–92 %) with high enantioselectivities (75–92 % ee).     

A density functional theory study of the stereoselectivity of Cu(OTf)2-catalyzed [3+2] cycloaddition of trifluoromethylated N-acylhydrazones and isoprene: A concerted asynchronous mechanism

Here we employ density functional theory calculations to systematically investigate the underlying mechanism of Cu(OTf)₂-catalyzed [3+2] cycloaddition reactions in the synthesis of CF₃-substituted pyrazolidines. About eight possible initial configurations of the [3+2] reaction is considered, and all relevant reactants, transition states, and products are optimized. Based on these structures, internal reaction coordinate paths, and wavefunction analysis results, we conclude that the Cu(OTf)₂-catalyzed [3+2] cycloaddition follows a concerted asynchronous mechanism. The C N bond forms immediately after the formation of the C C bond. Among the eight reaction paths, the energy barrier for the [3+2] reaction that leads to the CF₃-substituted syn-pyrazolidine is the lowest, ∼5.4 kcal/mol, which might result in the diastereoselectivity that is observed in the experiment. This work not only gives the detailed mechanism of the Cu(OTf)₂-catalyzed [3+2] cycloaddition but can also be helpful for the future designation of Cu(OTf)₂-based cycloaddition processes.     

RhodiumIII/SilverI Relay Catalyzed C—H Aminomethylation with Imine Equivalents and Lewis Acid Catalyzed [4+2] Cycloaddition of Indoles with Triarylhexahydrotriazine†

A Rh^III/Ag^I relay‐catalyzed C(sp²)—H coupling of indoles with triarylhexahydrotriazine (THT) is reported in this context. Upon merging Rh^III‐catalyzed C(sp²)—H bond activation and silver promoted THT dissociation, an efficient indole's C3 aminomethylation protocol is uncovered, providing C3 aminomethyl indoles in good yields and exhibiting potential applications for the synthesis of complicated bioactive compounds. We revealed the C3‐selectivity of this reaction through a detailed mechanistic investigation. Meanwhile, during the examination of the reaction conditions, we discovered another [4+2] cycloaddition pathway to afford tetrahydro‐indolo[3,2‐c]quinoline scaffold products via silver or Lewis acid catalysis.     

Gold(I)‐Catalyzed Divergence in the Preparation of Bicyclic Enol Esters: From Exclusively [3C+2C]‐Cycloaddition Reactions to Exclusive Formation of Vinylcyclopropanes

With the use of benzonitrile‐stabilized Au^I catalyst [Au(IPr)(NCPh)]SbF₆ ( Ic ; IPr=1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene), a spectrum of reactivity is observed for propargyl ester 4 a with cyclic vinyl ethers, ranging from exclusively [3C+2C] cycloaddition reactions to exclusively cyclopropanation depending only on the structure of the substrate. Some initially formed cyclopropanation products rearrange into the corresponding formally [3C+2C] cycloaddition products after treatment with fresh Au^I complex at 80 °C. Vinylcyclopropanes formed from dihydrofuran and dihydropyran resisted such rearrangement, even in the presence of fresh Au^I catalyst at elevated temperature. This study addresses an important mechanistic question concerning whether the five‐membered‐ring products were produced by a direct [3C+2C] cycloaddition reaction or by a sequential cyclopropanation/ring‐expansion reaction. A dual pathway is proposed for the Au^I‐catalyzed reactions between propargyl esters and cyclic vinyl ethers. The different behavior among vinyl cyclic ethers is attributed to the difference in the polarization of the π bond. Highly polarized bonds appear to undergo the cycloaddition reaction whereas less polar π‐bonds produce cyclopropanes.     

Copper-catalyzed synthesis of 5-substituted 1H-tetrazoles via the [3+2] cycloaddition of nitriles and trimethylsilyl azide

The [3+2] cycloaddition between various nitriles and trimethylsilyl azide proceeds smoothly in the presence of a Cu^I catalyst in DMF/MeOH, to give the corresponding 5-substituted 1H-tetrazoles in good to high yields. The reaction most probably proceeds through the in situ formation of a copper azide species, followed by a successive [3+2] cycloaddition with the nitriles.     

Oligonucleotides containing arylacetylene residues: Synthesis and post-synthetic modification via [3+2] cycloaddition

The synthesis of a phosphoramidite reagent for 5′-modification of oligonucleotides by introducing an arylacetylene residue has been described. Using the reaction with 3-(perylen-3-yl)propyl azide as an example, it was shown that the acetylene derivatives of oligonucleotides synthesized using this reagent undergo Cu^I-catalyzed [3+2] dipolar cycloaddition. Fluorescent conjugates were obtained in high yields and characterized by mass spectra. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1220–1226, July, 2006.     

Fine‐Tuning the Reactivity and Stability by Systematic Ligand Variations in CpCoI Complexes as Catalysts for [2+2+2] Cycloaddition Reactions

CpCo^I‐olefin‐phosphite and CpCo^I‐bisphosphite complexes were systematically prepared and their reactivity in [2+2+2] cycloaddition reactions compared with highly active [CpCo(H₂C?CHSiMe₃)₂] ( 1 ). Whereas 1 is an excellent precursor for the synthesis of [CpCo(olefin)(phosphite)] complexes ( 2 a – f ), [CpCo(phosphite)₂] complexes ( 3 a – e ) were prepared photochemically from [CpCo(cod)]. The complexes were evaluated in the cyclotrimerization reaction of diynes with nitriles yielding pyridines. For [CpCo(olefin)(phosphite)], as well as some of the [CpCo(phosphite)₂] complexes, reaction temperatures as low as 50 °C were sufficient to perform the cycloaddition reaction. A direct comparison showed that the order of reactivity for the complex ligands was olefin₂>olefin/phosphite>phosphites₂. The complexes with mixed ligands favorably combine reactivity and stability. Calculations on the ligand dissociation from [CpCo(olefin)(phosphite)] proved that the phosphite is dissociating before the olefin. [CpCo(H₂C?CHSiMe₃){P(OPh)₃}] ( 2 a ) was investigated for the co‐cyclization of diynes and nitriles and found to be an efficient catalyst at rather mild temperatures.     

Enantioselective Ag(I)-catalyzed [3+2] cycloaddition of azomethine ylides using a chiral ferrocene-based phosphine–phosphoramidite ligand having a stereogenic P-center

A series of chiral ferrocene-based phosphine–phosphoramidite ligands (PPFAPhos) have been employed in the Ag(I)-catalyzed asymmetric [3+2] cycloaddition of azomethine ylides with dimethyl maleate. The results showed that the ligand with a stereogenic P-center in the phosphino moiety displayed the best diastereo- and enantioselectivities, in which up to 99% enantiomeric excesses and 99/1 endo/exo selectivities have been achieved.     

Recyclable gallium(III) triflate-catalyzed [4+3] cycloaddition for synthesis of 2,4-disubstituted-3H-benzo[b][1,4]diazepines

Simple and efficient Ga(OTf)₃-catalyzed [4+3] cycloaddition of 1,3-diarylpropynones and o-phenylenediamines is developed for the preparation of 2,4-disubstituted-3H-benzo[b][1,4]diazepines. The reaction has advantages of using a green solvent, generating a minimal amount of waste, and easy catalyst recycle.