Selective Cyclization Reaction Research Articles

Mechanism and origins of cobalt-catalyzed ligand-controlled regiodivergent C-H functionalization of aldehydes with enynes.

The influence of the P-M-P bite angle in diphosphine ligands on selectivity has been observed in various catalytic reactions. A better understanding of the ligand bite angle concept is important for the rational design of efficient catalytic systems. In the present work, the mechanism of cobalt-catalyzed C-H functionalization of aldehydes with enynes and how the diphosphine ligands alter regioselectivity were investigated by density functional theory (DFT) calculations. The catalytic cycle is initiated by the oxidative cyclization of enynes rather than the oxidative addition of aldehydes. Regioselectivity arises from competing σ-bond metathesis and migratory insertion steps, in which the steric effects of diphosphine ligands are the dominant factors influencing the activation barriers. The calculations indicate that σ-bond metathesis is more challenging and its feasibility is highly dependent on the ligand bite angle. The improved mechanistic understanding will enable further design of transition-metal-catalyzed selective cyclization reactions.

A rational entry to cyclic polymers via spontaneous and selective cyclization reactions

This focus review describes the status quo of synthetic routes to cyclic compounds and cyclic polymers via spontaneous cyclization processes using (1) rotaxane chemistry and (2) dynamic covalent chemistry. Systems with rotaxane-based structures undergo spontaneous and selective cyclization of two self-complementary molecules and a macromolecular rotaxane switch, where the relative position of each component can be controlled, which results in a topology change from linear to cyclic. Systems based on dynamic covalent chemistry use exchange reactions of bis(2,2,6,6-tetramethylpiperidin-1-yl)disulfide (BiTEMPS) units that behave as stable linkages at r.t. and exchange disulfide bonds upon heating. Controlling the dynamic nature of BiTEMPS-based low-molecular-weight compounds and polymers thus provides cyclic topologies via spontaneous and selective cyclization processes. This focus review describes the synthetic routes to cyclic compounds and cyclic polymers via spontaneously occurring cyclization processes using (1) rotaxane chemistry and (2) dynamic covalent chemistry. Systems with rotaxane-based structures proceed via the spontaneous and selective cyclization of two self-complementary molecules and a macromolecular rotaxane switch, which results in a topology change from linear to cyclic. Systems based on dynamic covalent chemistry use exchange reactions of bis(2,2,6,6-tetramethylpiperidin-1-yl)disulfide (BiTEMPS) units. Controlling the dynamic nature of BiTEMPS-based molecules provides cyclic topologies via spontaneously and selectively occurring cyclization processes.

Synthesis of Enantioenriched Tetra-ortho-3,3′-substituted Biaryls by Small-Molecule-Catalyzed Noncanonical Polyketide Cyclizations

The arene-forming aldol condensation is a fundamental reaction in the biosynthesis of aromatic polyketides. Precisely controlled by the polyketide synthases, the highly reactive poly-β-carbonyl substrates are diverged into numerous aromatic natural products by selective cyclization reactions; a fascinating biosynthetic strategy that sparked our interest to investigate atroposelective aldol condensations. In this Account, we contextualize and highlight the ability of small-molecule catalysts to selectively convert noncanonical hexacarbonyl substrates in a double arene-forming aldol condensation resulting in the atroposelective synthesis of tetra-ortho-3,3′-substituted biaryls. The hexacarbonyl substrates were obtained by a fourfold ozonolysis enabling a late-stage introduction of all carbonyl functions in one step. Secondary amine catalysts capable of forming an extended hydrogen-bonding network triggered the noncanonical polyketide cyclization in order to form valuable biaryls in high yields and with stereocontrol of up to 98:2 er.1 Biosynthesis of Aromatic Polyketides2 Rotationally Restricted Aromatic Polyketides3 3,3′-Substituted Binaphthalenes in Catalysis4 Stereoselective Synthesis of Atropisomers5 Synthesis of Enantioenriched Tetra-ortho-3,3′-Substituted Biaryls by the Atroposelective Arene-Forming Aldol Condensation6 Conclusion

Catalyst-Dependent Chemoselectivity in the Dirhodium-Catalyzed Cyclization Reactions Between Enodiazoacetamide and Nitrosoarene: A Theoretical Study.

N-O heterocycle compounds play an important role in various fields. Doyle et al. (Cheng et al., 2017) have recently reported an efficient catalyst-controlled selective cyclization reactions of tert-butyldimethylsilyl (TBS)-protected enoldiazoacetamides with nitrosoarenes in which the multifunctionalized products 5-isoxazolones and 1,3-oxazin-4-ones were formed through [3+2]- and [5+1]-cyclizations using Rh2(oct)4 and Rh2(cap)4 as catalysts, respectively. The present work studied the mechanism of the reactions in question and the origins of the catalyst-dependent chemoselectivity by the density functional theory (DFT) calculations at the M06-D3/SMD/6-311+G(d,p)//B3LYP-D3/6-31G(d,p) level of theory. The computed results illustrate the importance of the different dirhodium catalysts to gain diversified N-O heterocycle compounds and suggest the specific interaction between the reactants by the real catalyst model. Meanwhile, it is the steric hindrance and electronic effect of the ligands of dirhodium catalysts that control the reaction mechanism. Furthermore, the other auxiliary theoretical analysis, natural bond orbital calculation and distortion/interaction analysis, make the electronic effects, and steric hindrance more distinct.

Synthesis of 1,2,4-triaza-3,5-diphospholidines

1,2,4-Triaza-3,5-diphospholidines were synthesized by highly selective cyclization reactions between N,N-bis[chloro(phenyl)phosphino]methylamine and 1,2-disubstituted hydrazines. Three examples of molecular structures are discussed against the background of configurational isomers and the potential of the title compounds as versatile cyclic ligands with chelating P–N–P motif.

Brønsted Acid Catalyzed Selective Cyclization Reaction: An Efficient and Facile Synthesis of Polysubstituted Imidazole and Pyrrole Derivatives

An efficient and facile synthesis of 3-(5-aryl-1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazol-4-yl)indolin-2-one and 3-(2,5-diaryl-3-oxo-1,2,3,6-tetrahydropyrrolo[2,3-c]pyrazol-4-yl)indolin-2-one derivatives is reported from the selective cyclization reaction of 3-(2-aryl-2-oxoethylidene)indolin-2-one and 1,3-dimethylurea or 5-amino-2-phenyl-2,4-dihydro-3H-pyrazol-3-one under Bronsted acid conditions. Although there are two carbonyl groups in the substrate, the carbonyl group out of isatin is specially chosen for the cyclization reaction to give the target products. The reported products are new five-membered heterocyclic compounds and the results also show that p-toluenesulfonic acid monohydrate (PTSA·H2O) is an effective catalyst for this synthesis. Therefore, the advantages of this approach are excellent yields, short reaction times, operational simplicity, and good regioselectivity.

ChemInform Abstract: Catalytic Control in Cyclizations: From Computational Mechanistic Understanding to Selectivity Prediction

AbstractReview: 51 refs.

Catalytic Control in Cyclizations: From Computational Mechanistic Understanding to Selectivity Prediction.

This Account describes the use of quantum-chemical calculations to elucidate mechanisms and develop catalysts to accomplish highly selective cyclization reactions. Chemistry is awash with cyclic molecules, and the creation of rings is central to organic synthesis. Cyclization reactions, the formation of rings by the reaction of two ends of a linear precursor, have been instrumental in the development of predictive models for chemical reactivity, from Baldwin's classification and rules for ring closure to the Woodward and Hoffmann rules based on the conservation of orbital symmetry and beyond. Ring formation provides a productive and fertile testing ground for the exploration of catalytic mechanisms and chemo-, regio-, diastereo-, and enantioselectivity using computational and experimental approaches. This Account is organized around case studies from our laboratory and illustrates the ways in which computations provide a deeper understanding of the mechanisms of catalysis in 5-endo cyclizations and how computational predictions can lead to the development of new catalysts for enhanced stereoselectivities in asymmetric cycloisomerizations. We have explored the extent to which several cation-directed 5-endo ring-closing reactions may be considered as electrocyclic and demonstrated that reaction pathways and magnetic parameters of transition structures computed using quantum chemistry are inconsistent with this notion, instead favoring a polar mechanism. A rare example of selectivity in favor of 5-endo-trig ring closure is shown to result from subtle substrate effects that bias the reactant conformation out-of-plane, limiting the involvement of cyclic conjugation. The mode of action of a chiral ammonium counterion was deduced via conformational sampling of the transition state assembly and involves coordination to the substrate via a series of nonclassical hydrogen bonds. We describe how computational mechanistic understanding has led directly to the discovery of new catalyst structures for enantioselective cycloisomerizations. Calculations have revealed that stepwise C-C bond formation and proton transfer dictate the exclusive endo diastereoselectivity of the intramolecular Michael addition to form 2-azabicyclo[3.3.1]nonane skeletons catalyzed by primary amines. These insights have led to development of a highly enantioselective catalyst with higher atom economy than previous generations. This Account also explores transition-metal-catalyzed cycloisomerizations, where our theoretical investigations have uncovered an unexpected reaction pathway in the [5 + 2] cycloisomerization of ynamides. This has led to the design of new phosphoramidite ligands to enable double-stereodifferentiating cycloisomerizations in both matched and mismatched catalyst-substrate settings. Computational understanding of the factors responsible for the regio-, enantio-, and diasterocontrol is shown to generate tangible predictions leading to an acceleration of catalyst development for selective cyclizations.

ChemInform Abstract: Catalytic Highly Asymmetric 1,5(6)‐Selective Cyclization Reaction of α‐Hydroxyimino Cyclic Ketones: Direct Approach to Ring‐Fused Hydroxyimino Dihydropyrans.

AbstractThe first catalytic asymmetric 1,5(6)‐selective Michael addition/cyclization reaction of α‐hydroxyimino ketones (I) and (IV) with γ,β‐unsaturated α‐keto esters, such as (II) is reported.

Synthesis of Aroylguanidines by an Unexpected Demethylation-Addition Cascade

A simple and efficient method was developed for the synthesis of <i>N</i>-aroyl-<i>N</i>′-arylguanidines under mild conditions by an unexpected demethylation–addition cascade reaction of readily available <i>N</i>-cyanoimidates with aryl amines. Moreover, 1-aryl-2-aminoquinazolin-4(1<i>H</i>)-ones and 2-(arylamino)quinazolin-4(3<i>H</i>)-ones can also be prepared by selective cyclization reactions of (2-fluorobenzoyl)- or (2-nitrobenzoyl)guanidines, respectively. This method provided two attractive strategies for the preparation 2-aminoquinazolinones derivatives from inexpensive reactants.

Catalytic highly asymmetric 1,5(6)-selective cyclization reaction of α-hydroxyimino cyclic ketones: direct approach to ring-fused hydroxyimino dihydropyrans

Herein, we have disclosed a catalytic asymmetric 1,5(6)-selective Michael/cyclization reaction of α-hydroxyimino cyclic ketones with γ,β-unsaturated α-keto esters. Unlike the previous catalytic strategies, this reaction provides a convenient 1,5(6)-selective asymmetric pathway to access synthetically useful ring-fused dihydropyrans. In general, high levels of yield, enantio- and diastereoselectivity (up to 99% yield, >99% ee and >20 : 1 dr) were obtained.

Characterization, Modes of Synthesis, and Pleiotropic Effects of Hypocholesterolemic Compounds - A Review

Studies on the various cholesterol-lowering agents is one of the important areas in clinical research. Identifica- tion and characterization of potential molecules from various sources have been carried out in the past and their relation- ship with the enzymes which are involved in the cholesterol cascade is gaining interest. In this review, we have high- lighted various inhibitors involved in the cholesterol cascade as well as cholesterol-lowering agents, viz., tocotrienol, flavonoids, phytosterols, phytostanols, statins, DADS, and synthetic compounds. The mechanism of action and characteri- zation of these hypocholesterolemic compounds are discussed in this communication. Major natural sources as well as synthetic and biological routes of synthesis of these compounds are reviewed in a concise manner. Especially, various HMG-CoA analogues including statins have been reviewed specifically. In this respect, researchers have identified 2,3- oxidosqualene cyclase-lanosterol synthase (lanosterol syn- thase, oxidosqualene-lanosterol cyclase, lanosterol synthase, 2,3-oxidosqualene-lanosterol cyclase, human lanosterol syn- thase (EC 5.4.99.7)) having a molecular weight of 83 kDa, catalyzing the highly selective cyclization reaction from the substrate 2,3-oxidosqualene (squalene 2,3-epoxide, squalene 2,3-oxide, (S)-squalene-2,3-epoxide, 2,3-epoxisqualene, oxidosqualene) into lanosterol, as an appropriate step for the inhibition of cholesterol biosynthesis (3). Oxidosqualene cyclase inhibitors (OSCI) arrest the downstream of 2,3- oxidosqualene which helps to stimulate epoxysterols to

ChemInform Abstract: Photoinduced Electron Transfer‐Initiated Selective Cyclization Reactions of (Z)‐N‐Benzoyl‐α‐dehydro(1‐naphthyl)alaninamides into 4,5‐Dihydrooxazole Derivatives.

AbstractThe substituent and solvent effects on the title reaction are studied.

Photoinduced Electron Transfer-Initiated Selective Cyclization Reactions of (Z)-N-Benzoyl-α-dehydro(1-naphthyl)alaninamides into 4,5-Dihydrooxazole Derivatives

An investigation was undertaken to gain understanding of substituent and solvent effects on the photoreactivity of the title 1-naphthylalanine N',N'- disubstituted amides [(Z)-1] and the (Z)-1-derived product composition. Results indicated that the photoinduced electron transfer reaction of (Z)-1 in methanol containing triethylamine (TEA) proceeds less efficiently than that of the corresponding 1-naphthylalanine alkyl esters to afford cis-4,5-dihydrooxazoles in preference to the trans-isomers and also the former isomers undergo negligible isomerization to the latter isomers in the presence of TEA. Analysis of solvent effects substantiated that both the polarity of solvent and the ability of solvent to donate proton or to accept electron are major factors for controlling the photoreactivity and product composition ratio.

酸・塩基複合塩を鍵とする高機能触媒の設計および高選択的合成法の開拓

The design of highly functionalized artificial catalysts is very important for practical organic synthesis. We have succeeded in the rational design of high-performance catalysts based on acid-base combined salts. Acid-base combined salt catalysts can be classified into three types: (1) Metal oxide-Lewis base combined salts, (2) Bronsted acid-Bronsted base combined salts, and (3) Lewis acid-Lewis base combined salts. Here we report our recent studies on development of highly selective cyclization reactions for the synthesis of key intermediates of bioactive natural products. Molybdenum(VI) oxide-bis(quinolinolato) complexes (class 1) efficiently catalyze biomimetic dehydrative cyclization of serine, threonine and cysteine derivatives to give oxazolines and thiazolines. Chiral 1, 1'-binaphthyl-2, 2'-diammonium salts (class 2) are useful catalysts for enantioselective Diels-Alder reaction of α-acyloxyacroleins. We also have developed the first enantioselective biomimetic iodocyclization of isoprenoids using a chiral nucleophilic promoter (class 3).

Efficient and Reusable PdCl2(MeCN)2/CuCl2/PEG‐400 System for Cyclization of Alkenyl β‐Keto Esters and Amides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Efficient and Reusable PdCl2(MeCN)2/CuCl2/PEG-400 System for Cyclization of Alkenyl β-Keto Esters and Amides

PEG-400 [poly(ethylene glycol-400)] was found as an effective medium for the PdCl(2)(MeCN)(2)-catalyzed hydroalkylation cyclization of alkenyl beta-keto esters and amides. In PEG-400, no additives such as Me(3)SiCl and Ln(OTf)(3) were required for the complete conversion of alkenyl beta-keto esters. The results also showed that CuCl(2) could promote the reaction. In the presence of PdCl(2)(MeCN)(2), CuCl(2), and PEG-400, various alkenyl beta-keto esters and amides underwent a selective cyclization reaction to give good to excellent yields of the desired six-membered-ring carbocycles. Furthermore, the PdCl(2)(MeCN)(2)/CuCl(2)/PEG-400 system could be recycled and reused five times without any loss of catalytic activity.

Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase

In higher organisms the formation of the steroid scaffold is catalysed exclusively by the membrane-bound oxidosqualene cyclase (OSC; lanosterol synthase). In a highly selective cyclization reaction OSC forms lanosterol with seven chiral centres starting from the linear substrate 2,3-oxidosqualene. Valuable data on the mechanism of the complex cyclization cascade have been collected during the past 50 years using suicide inhibitors, mutagenesis studies and homology modelling. Nevertheless it is still not fully understood how the enzyme catalyses the reaction. Because of the decisive role of OSC in cholesterol biosynthesis it represents a target for the discovery of novel anticholesteraemic drugs that could complement the widely used statins. Here we present two crystal structures of the human membrane protein OSC: the target protein with an inhibitor that showed cholesterol lowering in vivo opens the way for the structure-based design of new OSC inhibitors. The complex with the reaction product lanosterol gives a clear picture of the way in which the enzyme achieves product specificity in this highly exothermic cyclization reaction.

High Yield Synthesis, Separation and Structural Characterization of New [n+n]-Polyazamacrocycles

t-Bu- and isopropyl-substituted aromatic dialdehydes (la-c) and diamines (2a-f) were used to synthesize a series of imine macrocycles (3a-m). The highly selective cyclization reaction resulted either in a [2+2] stoechiometry or in a mixture of different [n+n] cycles, depending on the diamine building block. For some defined macrocycles (3b, 3d, 3e) the structure was elucidated by single crystal X-Ray diffraction that revealed a column-like arrangement of the macrocycles in the solid state. Mixtures of macrocycles were investigated with a combination of MALDI-Tof and analytical GPC which brought significant improvements in the determination of the exact size distribution. Isolated higher homologues of polyimine cycles were made available by preparative GPC for the first time. The possibility to reduce the imine macrocycles quantitatively to their corresponding amine analogues was demonstrated exemplary by the reduction of two pyridine containing cycles (4a-b).

Total synthesis of (+/-)-11 alpha-hydroxyprogesterone by cyclization of a polyunsaturated epoxide.

The total synthesis of a typical 11-hydroxylated steroid, (+/-)-11 alpha-hydroxyprogesterone, was achieved by picric acid-catalyzed tricyclization of a polyunsaturated epoxide appropriately substituted with ketal, hydroxyl, and acetylenic units. This epoxide was prepared by a multistage sequence featuring two successive alkylations of intermediary, monocyclic sulfones. The first sulfone intermediate was obtained by means of a short sequence starting from levulinic acid and diethyl succinate and involving a selective cyclization reaction.