Endo Approach Research Articles

Novel Bicyclic P,S-Heterocycles via Stereoselective hetero-Diels-Alder Reactions of Thiochalcones with 1-Phenyl-4H-phosphinin-4-one 1-Oxide.

Thiochalcones undergo cycloaddition reactions in THF solution at 60 °C with the synthetically unexplored 1-phenyl-4H-phosphinin-4-one 1-oxide in a highly regio- and stereoselective manner, yielding hitherto unknown bicyclic P,S-heterocycles containing fused thiopyran and phosphinine rings. The stereochemical structures of two of the obtained (4+2)-cycloadducts were unambiguously assigned by means of the X-ray single-crystal analysis. Based on these assignments, a concerted mechanism of the hetero-Diels-Alder reaction via the preferred endo approach of the heterodiene from the less hindered P=O side of the phosphininone molecule is postulated to explain the established rac-(4RS,8SR,9SR,10SR)-configured (4+2)-cycloadducts isolated as major products.

Regio- and stereoselectivity of the [3+2] cycloaddition of nitrones with methyl-acetophenone: A DFT investigation

A theoretical study of the regio- and stereoselectivities of the [3 + 2] cycloaddition reactions of nitrones with substituted alkene (methyl acetophenone) is investigated using density functional theory (DFT) and carried out at B3LYP/6-311+G(d,p) level. The reactivity of these cycloadditions is rationalized by FMO model, activation energy calculations, and philicity indexes. The electronic populations have been calculated from natural orbital, which based on charges by using NBO analysis, MK and CHelpG electrostatic population. The four possible pathways, fused and bridged regioisomeric modes, and the two stereoisomeric approaches endo and exo for the cycloaddition reactions are analyzed and discussed. Analysis of TS geometries and bond lengths demonstrate that these reactions follow a one-step mechanism with asynchronous transition states. The activation energy indicated a favored endo approach along the four reaction pathways.

Computational exploration of the 1,3‐dipolar cycloaddition reaction of 7‐isopropylidenebenzonorbornadiene with nitrile oxide and cyclic nitrone derivatives

AbstractThe synthesis of isoxazolidine and isoxazole derivatives, versatile building blocks for the construction of a wide range of complex heterocyclic architectures in synthetic organic and medicinal chemistry, is efficiently achieved via the 1,3‐dipolar cycloaddition reaction (1,3‐DC). Herein, we report an extensive theoretical study on the peri‐, regio‐, stereo, and enantio‐selectivities of 1,3‐DC of 7‐isopropylidenebenzonorbornadiene with nitrile oxide and cyclic nitrone derivatives using density functional theory calculations. Acetophenone‐substituted nitrile oxide periselectively adds across the endocyclic olefinic bond of the dipolarophile to furnish the exo‐cycloadduct as the major product, a reaction that has a rate constant of 1.88 × 109 s−1. The endo approach of this periselective path is the closest competing pathway with a rate constant of 4.59 × 107 s−1. Different substituents on the nitrile oxide do not affect the peri‐ and stereo‐selectivity of the reaction. Diethyl ether solvation has no substantial effect on the energetic patterns observed in the gas phase computation. Also, we report a novel 1,3‐DC between cyclic nitrone derivatives and 7‐isopropylidenebenzonorbornadiene as an efficient way to generate isoxazolidine derivatives. Even though the reactions of the cyclic nitrone derivatives have slightly higher activation barriers than the acyclic nitrile oxide derivatives, the former is more enantioselective than the latter. Whereas electron‐donating groups (EDGs) on the cyclic nitrone favor the formation of the exo‐cycloadduct, electron‐withdrawing groups (EWGs) favor the formation of the endo‐cycloadduct. Both 1,3‐dipoles add across the dipolarophile via a concerted asynchronous mechanism.

(3 + 2) cycloaddition reaction of 7-isopropylidenebenzonorbornadiene and diazomethane derivatives: A theoretical study

The ability to synthesize targeted molecules hinges on detailed mechanistic insight of the reaction. The 1,3-dipolar cycloaddition reaction between diazomethane derivatives and 7-isopropylidenebenzonorbornadiene have been extensively studied using density functional theory (DFT) at the M06–2X/6-311G(d,p) level of theory in order to delineate the peri-, regio-, and stereo-selectivities of the reaction. The diazomethane is shown to periselectively add across the endocyclic olefinic bond of the 7-isopropylidenebenzonorbornadiene and stereoselectively in the exo fashion, yielding the exo-cycloadduct as the major product, with a rate constant of 3.83 × 104 s−1. The endo approach of this periselective path is the closest competing pathway with a rate constant of 8.78 × 101 s−1. Neither electron-donating groups (R = methyl, ethyl, amine, cyclopropyl) nor electron-withdrawing groups (R = cyano, nitro, carbonyl) on the diazomethane alters the peri- and stereo-selectivity of the reaction. However, the substituents do have an effect on whether the addition follow normal or inverse electron demand mechanisms. EDGs favor a normal electron demand mechanism while EWGs favor an inverse electron demand 1,3-dipolar cycloaddition reaction. While EDGs-substituted diazomethane derivatives behave as nucleophiles in reactions with 7-isopropylidenebenzonorbornadiene, EWGs-substituted diazomethane derivatives behave as electrophiles. The 1,3-dipole adds across the dipolarophile via a concerted asynchronous mechanism, but a stepwise diradical mechanism has been ruled out. The selectivities observed in the title reaction are kinetically controlled. Analysis of the nucleophilic Parr function (PK−) at the different reaction sites in the dipolarophile indicates that the diazomethane adds across the atomic centers with highest NBO and Mulliken atomic spin densities.

Enhanced Endo's approach for evaluating free-surface Green's function with application to wave-structure interactions

The Green function of the diffraction-radiation theory of time-harmonic waves under a moderate water depth is considered. The paper presents a newly developed enhanced algorithm based on Endo's approach, which employs a direct Gauss-Laguerre quadrature in the calculation of the principal value integrations. This methodology was firstly originated from Endo (1983), and had been subsequently improved by Liu et al. (2008) and Shan et al. (2019). Unfortunately, the latest version of Endo's approach still has two fatal problems with (1) incredibly large or small values at some “weird frequencies”, and (2) nonsense values in the high-frequency region under a large depth. The present algorithm proposes special techniques for the removal of the singularities at these “weird frequencies”, and provides special treatments to avoid exceeding hardware's limitation when the input parameter k0h is overlarge. The developed algorithm is thereafter tested against a variety of sea conditions, via a comparison with Newman's polynomial algorithm (Newman, 1985), certifying its good accuracy in various circumstances. By carrying out a benchmark test on the DeepCwind semisubmersible, through a comparison with Shan's algorithm (Shan et al., 2019) and the commericial software Hydrostar®, the cause of the occurrence of the “weird frequencies” is found, in association with other important findings. The computations demonstrate that the present enhanced algorithm is free from the preceding problems and is sufficiently accurate to compute wave loads in practice.

Comparison of Bypass and Endovascular Intervention for Popliteal Occlusion with the Involvement of Trifurcation for Critical Limb Ischemia

The aim of this study is to analyze the technical aspects and outcomes of the treatment of occlusion of the popliteal artery with the involvement of the trifurcation treated with a bypass (open) and endovascular (endo) approach. Overall, 108 consecutive procedures were enrolled retrospectively. Patients were evaluated in 2 groups: the endo group (65 patients) and the open group (43 patients). Primary outcome were MALE (major adverse limb events), amputation-free survival, and early mortality (until 30days). Secondary outcome was overall survival in 3years. Inclusion criteria were Rutherford 4 and 5 and occlusion of the popliteal artery with the involvement of trifurcation and, at least, 1 infrapopliteal artery of runoff. Technical success was achieved in 100% of patients in the open and 96.9% of patients in the endo group. Freedom from MALE was 73.5% and 68.5% for 1 and 3years respectively for the endo group, and 84.3% and 77.2% respectively for the open group (P=0.413). Considering the total number of major reinterventions executed until 3years, the reinterventions was statistically more performed in the endo compared to the open group (P=0.0459). Amputation-free survival for the endo group in 30days, 1year, and 3years was 93.7%, 79.3%, and 66.0%, respectively, and the amputation-free survival for the open group was 88.4%, 77.4%, and 64.3% (P=0.726). Early mortality was 9.3% for the open group and 1.5% for the endo group (P=0.060). In 3years, the overall survival was 75.1% in the open group and 84.3% in the endo group. In 3years, follow-up endovascular treatment of occlusion of the popliteal artery with the involvement of the trifurcation has similar time freedom from MALE comparedto open approach. Overall and amputation-free survival was not different betweenthe groups besides more reinterventions in patients who underwent endovascular approach.

Unprecedented Synthesis of 4‐Ylidene (3 S)‐3‐hydroxy‐1‐aryl (alkyl)‐pyrrolidine‐2,5‐diones Based on 1,3‐Dipolar Cycloaddition of a Sugar‐derived Nitrone to N‐Substituted Maleimides

Abstract1,3‐Dipolar cycloaddition of a sugar‐based nitrone to differently N‐substituted maleimides afforded mixtures of isoxazolidine‐based cycloadducts. The obtained predominant cycloadducts displayed three new contiguous stereogenic centers placing the protons in syn and anti‐relationship, respectively at the fused bond, and for H5 and H6. This was explained by an endo approach of the maleimide derivatives to the Si‐face of the nitrone reacting in its Z‐form. The mCPBA‐mediated oxidative cleavage N−O bond of the isoxazolidine occurred almost quantitatively to afford unprecedented sugar nitrones. Their pyrolysis under thermal or microwave activation led to new 4‐ylidene (3 S)‐3‐hydroxy‐1‐aryl (alkyl)‐pyrrolidine‐2,5‐diones.

A molecular electron density theory study of Diels‐Alder reaction between Danishefsky's diene and (2E)‐3‐phenyl‐2‐(trifluoromethyl) acrylonitrile

AbstractThe Diels‐Alder reaction between Danishefsky's diene (DD 4) and (2E)‐3‐phenyl‐2‐(trifluoromethyl) acrylonitrile (EPTA 5) at 393 K in the presence of toluene has been studied using the molecular electron density theory at the M06‐2X/6‐31G(d,p) computational level. The calculated relative Gibbs free energies indicated that the studied reaction takes place in a complete regioselective and stereoselective manner in which the most nucleophilic center of DD 4 is attacked by the most electrophilic center of EPTA 5 passing through the stationary point of TS2n. It was shown that the TS2n affords the corresponding cycloadduct of CA2n as the unique product in excellent agreement with the experimental outcomes. On the other hand, a great destabilizing steric repulsion between methoxy moiety of DD 4 and the trifluoromethyl moiety of EPTA 5 along the exo stereoselective approach is responsible for the predominance of the endo approach over the exo one. The nucleophilic and electrophilic Parr functions at the reactive sites of the DD 4 and EPTA 5 have been used to explain the regioselectivity of the Diels‐Alder reaction. According to the electron localization function analysis of the intrinsic reaction coordinate profile of the energetically most preferred TS2n, a nonconcerted two‐stage one‐step molecular mechanism has been proposed. The mechanism indicated the formation of C1C6 single bond through coupling of C1 to C6 and subsequent C4C5 single bond through coupling of C4 to C5 at cycloadduct CA2n.

Synthesis of 7-norbornenols via Diels–Alder cycloadditions of cyclopentadienol generated by decomposition of ferrocenium cation

Ferrocenium hexafluorophosphate, Cp2FePF6, was determined to be a convenient source of cyclopentadienol when stirred open to air in a mixture of acetonitrile and water. The cyclopentadienol was intercepted via Diels–Alder reaction with a variety of dienophiles to afford cycloadducts having 7-norbornenol cores. Reactions were stereoselective, producing single diastereomers from endo approach of the dienophile syn to the OH substituent of the cyclopentadienol.

Density functional theory study of the regio and stereoselectivity in 1,3-dipolar cycloddition reactions between N-methyl methylenenitrone and fluorinated dipolarophiles

A DFT study of the reactivity, regio-, and stereoselectivity of 1,3-dipolar cycloaddition of N-methyl-methylenenitrone 1 with (E and Z)-2,4-diethoxy-5-(perfluoroprop-1-en-1-yl)pyrimidine 2E, 2Z and (E and Z)-(perfluoroprop-1-en-1-yl)benzene, 3E, 3Z in the gas phase and in toluene, has been carried out by using density functional theory (DFT)-based reactivity indices and activation energy calculations at B3LYP/6-31G (d) level of theory. Four reactive channels associated with the 5- and 4-regio and endo and exo stereoselective approach modes of the pyrimidine or phenyl group of these fluorinated vinyls relative to nitrone 1 have been explored and characterized. IRC calculations show that these cycloadditions follow an asynchronous concerted mechanism with a low polar character, displaying 5-regioselectivity and it is found that the endo pathway is preferred, therefore the formation of product with 5-regio and endo pathway is dominant. Also, DFT-based reactivity indices clearly predict the experimental regiochemistry.

DFT interpretations for cycloadditions of an electron deficient C-aryl-N-phenyl nitrone

1,3-dipolar cycloaddition reactions of an electron deficient C-aryl-N-phenyl nitrone to benzylidene derivatives (with different electrophilicities) have been analyzed by density functional theory calculations. The transition states corresponding to the endo and exo approaches along the feasible regioisomeric reaction channels have been located for each cycloaddition. The reactions follow a concerted mechanism with asynchronous transition states. The asynchronicity along the regiochemical reaction modes depends on the β-carbon electrophilicities of the olefins. The regio and stereochemistries predicted from the calculated activation energy barriers (with solvent and higher basis set corrections) of the located transition states are in conformity with the experimental results. The local electrophilicities, softness matching indices and the interaction energies were then calculated to analyze how well these reactivity parameters can interpret the regioselectivities of such reactions. The electronic populations at the reactive sites computed from electrostatic potential-driven atomic charges provided correct and consistent predictions for each theoretical model contrary to the natural orbital based charges.

DFT study of the mechanism and stereoselectivity of the 1,3-dipolar cycloaddition between pyrroline-1-oxide and methyl crotonate

A theoretical study of the regio- and stereoselectivities of the 1,3-dipolar cycloaddition reaction between methyl crotonate and pyrroline-1-oxide has been carried out using density functional theory (DFT) at the B3LYP/6-31G(d) level of theory. The reaction has been followed by performing transition state optimization, calculations of intrinsic reaction coordinate and activation energies; the molecular mechanism of the reactions is concerted and asynchronous. The regio- and exo/endo-selectivity have been explained in terms of frontier molecular orbital interactions, local and global electrophilicity and nucleophilicity indices and an analysis of the Wiberg bond indices in the transition state. The FMO analysis and DFT-based reactivity indices showed that the regioselectivity of this reaction is controlled by the HOMOdipole–LUMOdipolarophile interaction. The activation parameters indicated favoured endo approach along the meta-pathway in agreement with the experimental results. The molecular mechanism of the 1,3-dipolar cycloaddition reaction between pyrroline-1-oxide and methyl crotonate is theoretically investigated by DFT method at the B3LYP/6-31G* level. The transition states corresponding to the possible stereoisomeric pathways along regioisomeric reaction channels were searched, localized and optimized. The cycloaddition is favored along the reaction channel with the meta-endo adduct as major diastereomer in agreement with experiment.

Organocatalytic Enantioselective Cycloaddition Reactions of Dienamines with Quinones

Matching catalyst and substrate: Organocatalytic cycloaddition between dienamines and 1,4-benzo- or 1,4-naphthoquinones affords biologically interesting dihydronaphtho- and dihydroanthraquinone core structures. The enantioselectivity of this new reaction is ensured by a steric shielding catalyst and carefully selecting substrates that greatly favor the endo approach (see scheme) due to electrostatic interactions in the zwitterionic intermediate.

Endovascular-first approach is not associated with worse amputation-free survival in appropriately selected patients with critical limb ischemia

Endovascular interventions for critical limb ischemia are associated with inferior limb salvage (LS) rates in most randomized trials and large series. This study examined the long-term outcomes of selective use of endovascular-first (endo-first) and open-first strategies in 302 patients from March 2007 to December 2010. Endo-first was selected if (1) the patient had short (5-cm to 7-cm occlusions or stenoses in crural vessels); (2) the disease in the superficial femoral artery was limited to TransAtlantic Inter-Society Consensus II A, B, or C; and (3) no impending limb loss. Endo-first was performed in 187 (62%), open-first in 105 (35%), and 10 (3%) had hybrid procedures. The endo-first group was older, with more diabetes and tissue loss. Bypass was used more to infrapopliteal targets (70% vs 50%, P = .031). The 5-year mortality was similar (open, 48%; endo, 42%; P = .107). Secondary procedures (endo or open) were more common after open-first (open, 71 of 105 [68%] vs endo, 102 of 187 [55%]; P = .029). Compared with open-first, the 5-year LS rate for endo-first was 85% vs 83% (P = .586), and amputation-free survival (AFS) was 45% vs 50% (P = .785). Predictors of death were age >75 years (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.7-6.6; P = .0007), end-stage renal disease (ESRD) (HR, 3.4; 95% CI, 2.1-5.6; P < .0001), and prior stroke (HR, 1.6; 95% CI, 1.03-2.3; P = .036). Predictors of limb loss were ESRD (HR, 2.5; 95% CI, 1.2-5.4; P = .015) and below-the-knee intervention (P = .041). Predictors of worse AFS were older age (HR, 2.03; 95% CI, 1.13-3.7; P = .018), ESRD (HR, 3.2; 95% CI, 2.1-5.11; P < .0001), prior stroke (P = .0054), and gangrene (P = .024). At 5 years, endo-first and open-first revascularization strategies had equivalent LS rates and AFS in patients with critical limb ischemia when properly selected. A patient-centered approach with close surveillance improves long-term outcomes for both open and endo approaches.

Asymmetric Diels–Alder reaction with &gt;C=P– functionality of the 2-phosphaindolizine-η1-P-aluminium(O-menthoxy) dichloride complex: experimental and theoretical results

The Diels–Alder reaction of the 2-phosphaindolizine-η1-P-aluminium(O-menthoxy) dichloride complex with dimethylbutadiene was investigated experimentally and computationally. The >C=P– functionality of the complex reacts with 2,3-dimethylbutadiene with complete diastereoselectivity to afford [2 + 4] cycloadducts. Calculation of the model substrate, 3-methoxycarbonyl-1-methyl-2-phosphaindolizine-P-aluminium(O-menthoxy) dichloride (7a), at the DFT (B3LYP/6-31+G*) level reveals that the O-menthoxy moiety blocks the Re face of the >C=P– functionality, due to which the activation barrier of the Diels–Alder reaction of 7a with 1,3-butadiene, involving its attack from the Si face, is lower. It is found that in this case, the exo approach of the diene is slightly preferred over the endo approach.

Endocardial Electrogram Characteristics of Epicardial Ventricular Arrhythmias

While most ventricular arrhythmias (VA) can be ablated successfully using an endocardial (endo) approach, epicardial (epi) mapping and ablation is sometimes required. There may be suggestive clues on the surface electrocardiogram; however, identification of an epi origin of VA with certainty remains problematic. All patients referred for ablation of ventricular tachycardia or frequent ventricular ectopy from June 2007 to July 2011 were evaluated. Patients with completed endo and epi electroanatomical activation maps of an epi VA were included (n = 10). Bipolar electrograms (EGMs) in the area of earliest endo activation were analyzed and compared to the area of early epi activation. An EGM component was characterized as far field if it was monophasic and there was inability to capture. We identified 3 characteristics from endo mapping that consistently indicated need for epi ablation: (1) Diffusely early activation (>2 cm(2) region of sites with equally earliest activation within 10 milliseconds). (2) Sequence of a far-field EGM followed by a near-field EGM in the region of earliest endo activation. (3) Inability to capture the far-field component of the earliest EGM (stim-QRS < egm-QRS time) or reproduce morphological features of the VA complex with stimulation at the earliest endo site of activation. The presence of a diffusely early area of activation and inability to capture a far-field endo EGM indicates that epi ablation may be needed to eliminate a VA.

Thermal and Sc(OTf)3 catalyzed 1,3-dipolar cycloaddition of open-chain nitrones to α,β-unsaturated lactones: combined experimental and computational studies

The stereoselectivity of 1,3-dipolar cycloaddition reactions of C-phenyl open-chain nitrones and α,β-unsaturated γ- and δ-lactones was investigated under thermal and catalytic conditions. It was found that under thermal conditions, the endo approach of the reactants was preferred leading to the thermodynamic product. In the presence of Sc(OTf)3 the exo adduct was obtained in high yield and selectivity. The energies of the cycloaddition reactions were investigated by means of molecular orbital calculations at the B3LYP/6-31+G(d,p) and MP3/6-31+G(d,p) theory level. Different reaction channels and reactant approaches, fitting the individual regio- and stereochemical preferences, are discussed. The computational results were compared with the corresponding experimental data and found to be in good agreement.

Cycloaddition of homochiral dihydroimidazoles: A 1,3-dipolar cycloaddition route to optically active pyrrolo[1,2-a]imidazoles

N-Alkylation of optically active 1-benzyl-4-phenyl-4,5-dihydroimidazole with active alkyl halides and treatment of the so-formed 4,5-dihydroimidazolium ions with DBU in the presence of a range of electron-deficient alkene dipolarophiles, constitutes a 'one-pot' cascade terminating in a 1,3-dipolar cycloaddition reaction that affords optically active pyrrolo[1,2-a]imidazoles. Three bonds of the so-formed pyrrolidine moiety are constructed in this cascade. The cycloaddition follows an endo approach of dipole and dipolarophile with anti geometry of the dipole and facial selectivity derived from the phenyl substituent. Inter- and intramolecular cycloaddition modes are observed.

Theoretical Study on Hetero‐Diels–Alder Reaction of Butadiene with Benzaldehyde Catalyzed by Chiral InIII Complexes

AbstractThe mechanism of the hetero‐Diels–Alder reaction of butadiene with benzaldehyde catalyzed by chiral N,N′‐dioxide/In(OTf)3 complexes was studied theoretically by using density functional theory (DFT) and model system. The computational results indicate that the catalyzed reaction proceeded through a concerted mechanism via a highly zwitterionic transition state. The lowest energy barrier was 11.8 kJ mol–1, which is 63.0 kJ mol–1 lower than that of the uncatalyzed reaction. The results indicate that the endo approach is advantageous over the exo approach, because exo transitions states suffer from more steric hindrance than the endo transitions states as a result of interactions among the substrates, the trifluoromethanesulfonic group and the R4 groups of the ligand. The (S) configuration was observed predominantly over the (R) form, because there is no distinguishable repulsion between butadiene and the exo amino side or the endo amino side of the ligand. Besides, the interactions between the terminal hydrogen atoms of butadiene and the oxygen atoms of the trifluoromethanesulfonic group make the structure more stable. Thus, the experimental results were explained well by calculation of the chiral N,N′‐dioxide/In(OTf)3 complex catalyzed hetero‐Diels–Alder reaction at the molecular level.

1,3-Dipolar cycloadditions of azomethine ylides with chiral acrylates derived from methyl ( S)- and ( R)-lactate: diastereo- and enantioselective synthesis of polysubstituted prolines

The 1,3-dipolar cycloaddition of acrylates derived from methyl ( R)- and ( S)-lactate, as chiral dipolarophiles, with glycine and alanine derived azomethine ylides is described for the first time. By using the corresponding silver metallo-azomethine ylides polysubstituted endo-prolines were obtained with high diastereo- and enantioselectivity. The process occurs at room temperature in toluene with 10 mol % of AgOAc by using either KOH or Et 3N as bases, also in substoichiometric amounts. Under these mild reaction conditions, enantiomerically enriched polysubstituted prolines resulting from an endo approach were obtained in general in high yields and de (86–99%). The absolute configuration of the resulting prolinates can be determined on the basis of X-ray diffraction analysis.