Metal-catalyzed Cycloisomerization Research Articles

Metal-Catalyzed Cascade Reactions between Alkynoic Acids and Dinucleophiles: A Review

Cascade reactions provide a straightforward access to many valuable compounds and reduce considerably the number of steps of a synthetic sequence. Among the domino and multicomponent processes that involve alkynes, the cascade reaction between alkynoic acids and C-, N-, O- and S-aminonucleophiles stands out as a particularly powerful tool for the one-pot construction of libraries of nitrogen-containing heterocyclic compounds with scaffold diversity and molecular complexity. This reaction, based on an initial metal-catalyzed cycloisomerization that generates an alkylidene lactone intermediate, was originally catalyzed by gold(I) catalysts, along with silver salts or Brönsted acid additives, but other alternative metal catalysts have emerged in the last decade as well as different reaction media. This review examines the existing literature on the topic of metal-catalyzed cascade reactions of acetylenic acids and dinucleophiles and discusses aspects concerning substrate/catalyst ratio for every catalyst system, nature of the aminonucleophile involved and substrate scope. In addition, alternative solvents are also considered, and an insight into the pathway of the reaction and possible intermediates is also provided.

Construction of Diverse Polycyclic Structures via Group 9 Metal-Catalyzed Cycloisomerization of 1,6-Diyne Derivatives

Construction of Diverse Polycyclic Structures via Group 9 Metal-Catalyzed Cycloisomerization of 1,6-Diyne Derivatives

Sequencing palladium-catalyzed cycloisomerization cascades in a synthesis of the gelsemine core.

Transition metal-catalyzed cycloisomerization is a powerful strategy for the construction of cyclic organic molecules, and the use of palladium catalysts can deliver a wide range of monocyclic and bicyclic products. However, applications of cycloisomerizations in complex target synthesis in which more than one cycloisomerization process is deployed in a cascade context are rare. Here we report investigations of the relative rates of two different types of ene-ynamide cycloisomerization that form fused and spirocyclic rings, and use of these results to design a sequence-controlled cascade cycloisomerization that prepares the tetracyclic core of gelsemine in a single step. Crucial to this work was an evaluation of the kinetics of each cycloisomerization in competition experiments, which revealed a key influence of the ynamide electron-withdrawing group on the cycloisomerization reaction.

Synthesis of Proposed Structure of Aaptoline B via Transition Metal-Catalyzed Cycloisomerization and Evaluation of Its Neuroprotective Properties in C. Elegans

A concise synthesis of the proposed structure of aaptoline B, a pyrroloquinoline derived from a marine sponge, was accomplished. A key feature of this synthesis is the versatile transition metal-catalyzed cycloisomerization of N-propargylaniline to construct a quinoline skeleton. However, the spectral data of the synthesized aaptoline B did not agree with those of previous studies. The structure of the synthesized aaptoline B was confirmed using a combined 2D NMR analysis. Furthermore, we assessed the possible neuroprotective potential of aaptoline B using the C. elegans model system. In this study, aaptoline B significantly improved the viability and the morphology of dopaminergic neurons of nematodes under MPP+ exposure conditions. We also found that MPP+-induced motor deficits in nematodes were efficiently restored by aaptoline B treatment. Our findings demonstrate the neuroprotective effects of aaptoline B against MPP+-induced dopaminergic neuronal damage. Further studies are underway to explain its pharmacological mechanism.

Celebrating Professor Barry M. Trost's 80th Birthday

Celebrating Professor Barry M. Trost's 80^th Birthday

Bifunctionalized allenes. Part XXII. Coinage metal-catalyzed cycloisomerization of phosphorylated 3-(α- or β-hydroxyalkyl)allenes to 2-phosphoryl-2,5-dihydrofurans or 2-phosphoryl-5,6-dihydro-2H-pyrans

The present paper discusses the coinage metal-catalyzed cycloisomerization reaction of phosphorylated 3-(α- or β-hydroxyalkyl)allenes. 3-(α- or β-Hydroxyalkyl)-allenylphosphonates and -allenyl phosphine oxides were smoothly converted into the 2-phosphoryl-2,5-dihydrofurans or 2-phosphoryl-5,6-dihydro-2Н-pyrans by using 5 mol % of coinage metal salts as catalyst in 5-endo-trig or 6-endo-trig cycloisomerization, respectively. Experimental conditions such as the type of the solvent, the reaction temperature, the mol % and the type of the catalyst and its influence on the yields and the reaction time of the cycloisomerization reaction of the phosphorylated 3-(α- or β-hydroxyalkyl)allenes were optimized.

Selectivity in Transition Metal-catalyzed Cyclizations: Insights from Experiment and Theory.

Transition metal-catalyzed cycloisomerization reactions offer a powerful tool for the synthesis of complex cyclic organic molecules from acyclic precursors. In addition to ring formation, these processes can result in the generation of new stereocentres at the site of ring formation; understanding the origins of stereoselectivity enables the use of cycloisomerization chemistry in synthesis, and promotes the design of new reactions. In this article, some recent developments from our groups in regio- and stereoselective cycloisomerization reactions are discussed. Alongside experimental observations, crucial to developing a robust understanding of selectivity has been the use of computation to explore theoretical reaction pathways, which provides an exceptional level of insight into selectivity. In its most valuable form, this correlation between experiment and theory enables the design of improved catalyst systems exhibiting both enhanced reactivity, and selectivity.

Combination of Metal-Catalyzed Cycloisomerizations and Biocatalysis in Aqueous Media: Asymmetric Construction of Chiral Alcohols, Lactones, and γ-Hydroxy-Carbonyl Compounds

The combination of the metal-catalyzed cycloisomerization of alkynes containing a tethered nucleophile as substituent in aqueous media (followed by the spontaneous hydrolysis, hydroalkoxylation, or aminolysis of the transiently formed five-membered heterocycles) with the subsequent enantioselective ketone bioreduction (mediated by KREDs) has been achieved. The overall transformations, which formally involve a three-step one-pot reaction, provide a variety of enantiopure valuable molecules (e.g., 1,4-diols, lactones, and γ-hydroxy-carbonyl compounds (carboxylic acids, esters, and amides)) with high conversions and enantioselectivities and under mild reaction conditions, disclosing the concept of integrated metal-catalyzed cycloisomerizations of alkynes and enzymatic catalysis in water.

Cycloisomerization between Aryl Enol Ether and Silylalkynes under Ruthenium Hydride Catalysis: Synthesis of 2,3-Disubstituted Benzofurans.

Metal-catalyzed cycloisomerization reactions of 1,n-enynes have become conceptually and chemically attractive processes in the search for atom economy, which is a key subject of current research. However, metal-catalyzed cycloisomerization between aryl enol ether and silylalkynes has not been developed. The ruthenium hydride complex catalyzed cycloisomerization between aryl enol ether and silylalkynes is reported to give benzofurans having useful functional groups, vinyl and trimethylsilylmethyl, on the 2- and 3-positions, respectively.

Metal-catalyzed cycloisomerization as a powerful tool in the synthesis of complex sesquiterpenoids.

Covering: up to 2015Sesquiterpenoids are consistently attracting the interest of the scientific community due to their promising clinical profile as therapeutic agents. Cycloisomerization of enynes and dienes is a powerful tool in the hands of organic chemists to access them. In the last 20 years the field has witnessed remarkable advances, especially by revealing the capability of platinum and gold complexes to initiate such reactions. Nowadays, cycloisomerizations continue to enrich our knowledge with atom-economical routes and impressive cascades to reach more complex molecules. The current review covers the basic mechanistic aspects of metal catalysis in cycloisomerization reactions and their progress to the synthesis of selected complex sesquiterpenoids.

Modular, Metal-Catalyzed Cycloisomerization Approach to Angularly Fused Polycyclic Aromatic Hydrocarbons and Their Oxidized Derivatives.

Palladium-catalyzed cross-coupling reactions of 2-bromobenzaldehyde and 6-bromo-2,3-dimethoxybenzaldehyde with 4-methyl-1-naphthaleneboronic acid and acenaphthene-5-boronic acid gave corresponding o-naphthyl benzaldehydes. Corey-Fuchs olefination followed by reaction with n-BuLi led to various 1-(2-ethynylphenyl)naphthalenes. Cycloisomerization of individual 1-(2-ethynylphenyl)naphthalenes to various benzo[c]phenanthrene (BcPh) analogues was accomplished smoothly with catalytic PtCl2 in PhMe. In the case of 4,5-dihydrobenzo[l]acephenanthrylene, oxidation with DDQ gave benzo[l]acephenanthrylene. The dimethoxy-substituted benzo[c]phenanthrenes were demethylated with BBr3 and oxidized to the o-quinones with PDC. Reduction of these quinones with NaBH4 in THF/EtOH in an oxygen atmosphere gave the respective dihydrodiols. Exposure of the dihydrodiols to N-bromoacetamide in THF-H2O led to bromohydrins that were cyclized with Amberlite IRA 400 HO(-) to yield the series 1 diol epoxides. Epoxidation of the dihydrodiols with mCPBA gave the isomeric series 2 diol epoxides. All of the hydrocarbons as well as the methoxy-substituted ones were crystallized and analyzed by X-ray crystallography, and these data are compared to other previously studied BcPh derivatives. The methodology described is highly modular and can be utilized for the synthesis of a wide variety of angularly fused polycyclic aromatic hydrocarbons and their putative metabolites and/or other derivatives.

Bifunctionalized Allenes. Part XVI. Synthesis of 3-Phosphoryl-2,5-dihydrofurans by Coinage Metal-Catalyzed Cyclo-isomerization of Phosphorylated α-Hydroxyallenes.

Phosphorylated α-hydroxyallenes 1 and 2 were smoothly converted into the corresponding 2,5-dihydrofurans 3 and 4 in an 5-endo-trig cycloisomerization reaction by using 5 mol % of coinage metal salts as catalyst. Experimental conditions such as the type of the solvent, the reaction temperature, the mol % and the type of the catalyst were optimized. This mild and efficient cyclization method can be applied to dimethyl 1-hydroxyalkyl-alka-1,2-dienephosphonates 1 and 2-diphenylphosphinoyl-2,3-dien-1-ols 2a–c and 3-diphenylphosphinoyl-3,4-dien-2-ols 2d,e, furnishing 3-phosphorylated 2,5-dihydrofurans 3 and 4 in very good yields.

ChemInform Abstract: 1,2‐Boryl Migration Empowers Regiodivergent Synthesis of Borylated Furans.

A regioselective transition metal-catalyzed cycloisomerization reaction of boron-containing alkynyl epoxides toward C2- and C3-borylated furans has been developed. It was found that the copper catalyst as well as the gold catalyst with more basic triflate counterion favor boryl migration toward C3-borylated furans, whereas employment of the cationic gold hexafluoroantimonate affords C2-borylated furan via a formal 1,2-hydrogen shift.

ChemInform Abstract: A Versatile Synthetic Platform Based on Bicyclo[4.1.0]heptenes

AbstractReview: 79 refs.

1,2-boryl migration empowers regiodivergent synthesis of borylated furans.

A regioselective transition metal-catalyzed cycloisomerization reaction of boron-containing alkynyl epoxides toward C2- and C3-borylated furans has been developed. It was found that the copper catalyst as well as the gold catalyst with more basic triflate counterion favor boryl migration toward C3-borylated furans, whereas employment of the cationic gold hexafluoroantimonate affords C2-borylated furan via a formal 1,2-hydrogen shift.

Metal–Indolizine Zwitterion Complexes as a New Class of Organometallic Material: a Spectroscopic and Theoretical Investigation

Indolizine zwitterion coordinated metal species have been commonly proposed as intermediates in the mechanisms of metal-catalyzed cycloisomerization of propargylic pyridines for indolizines. Yet, it is only recently that the first metal–indolizine complexes have been isolated by our group. Considering from the perspective of molecular materials, the π-interaction between the dπ(M) and the π-system of the indolizine skeleton in the electronic ground or excited states may allow charge delocalization and offer functionalities for optoelectronic applications. We herein report the synthesis and spectroscopic and theoretical investigations on two classes of Ru–indolizine zwitterion complexes. The synthetic strategy employed, i.e., cycloisomerization of propargylic pyridines, represents a general preparation method for stable metal–indolizine complexes. Indolizine zwitterions in this work have been found to exhibit strong trans effect. Spectroscopic studies on these complexes reveals the tunability of the π*(indolizine) level and its impact on the luminophores nearby. Overall, indolizine zwitterion represents a new class of organometallic ligand with high potential in the design of functional molecular electronic/photonic elements.

A Versatile Synthetic Platform Based on Bicyclo[4.1.0]heptenes

Bicyclo[4.1.0]heptenes, which are readily accessible molecules via the transition metal-catalyzed cycloisomerization of 1,6-enynes, and have served as useful building blocks in organic synthesis. These molecules can undergo a variety of ring-opening reactions given that the release of the cyclopropyl ring strain (27.5 kcal/mol) may serve as a thermodynamic driving force for reactions, and the double bond within the skeleton can afford the kinetic opportunity to initiate the ring-opening via a coordination to a metal species. Even though the chemistry of the cyclopropyl group has been widely explored in organic chemistry, less attention has been paid to the chemistry of bicyclo[4.1.0]heptenes. However, during the past 5 years, we have been engaged in the exploration of the chemistry of bicyclo[4.1.0]heptenes. This review describes the chemistry developed in our laboratory. Depending upon the position, number, and identity of the substituent(s), the identity of the tether group, and the nature of the catalytic system, bicyclo[4.1.0]heptenes can undergo a variety of transformations. Our studies have revealed the reaction patterns of bicyclo[4.1.0]heptenes which include thermal reactions, nucleophilic addition, and rhodium-catalyzed reactions, that can proceed both with and without opening of the cyclopropyl ring. The chemistry described in this review can be used to produce a variety of new compounds such as 2,4-pentadienals, 3-methylene-4-vinylcyclohex-1-enes, bicyclo[3.2.2]nonadienes, 1,6,7,9a-tetrahydrocyclohepta[c] pyrans and -pyridines, hexahydroisoquinolines, 4-oxa-6-azatricyclo[3.3.0.02,8]octanes, and heterotricyclo[3.3.1.02,8]nonanes.

Synthesis of [5]Helicenes with a Substituent Exclusively on the Interior Side of the Helix by Metal-catalyzed Cycloisomerization

[5]Helicenes with a substituent exclusively oriented toward the interior curvature of the helix are synthesized by metal-catalyzed cycloisomerization. In addition, novel azulene-fused helicenes have been found through cycloisomerization studies. These [5]helicenes shows a high enough configurationally stability to allow resolution by HPLC on a chiral stationary phase.

ChemInform Abstract: Transition Metal‐Catalyzed Carbocyclization of Nitrogen and Oxygen‐Tethered 1,n‐Enynes and Diynes: Synthesis of Five or Six‐Membered Heterocyclic Compounds

AbstractReview: 228 refs.

Synthesis of a novel chemotype via sequential metal-catalyzed cycloisomerizations

Sequential cycloisomerizations of diynyl o-benzaldehyde substrates to access novel polycyclic cyclopropanes are reported. The reaction sequence involves initial Cu(I)-mediated cycloisomerization/nucleophilic addition to an isochromene followed by diastereoselective Pt(II)-catalyzed enyne cycloisomerization.