Retention Of Configuration Research Articles

Theoretical study of water-assisted reaction between methane and nitrosonium cation

The water-assisted reaction between CH4 and NO+ has been studied employing post Hartree–Fock and density functional theory methods. Two reaction pathways were considered: (i) a frontside NO+ attack on the C–H bond of methane with retention of configuration and (ii) a backside attack with inversion of configuration. The first pathway leads to a thermodynamically more favorable hydrate of N-protonated nitrosomethane, and the second one leads to its O-protonated isomer. The catalytic effect of a single water molecule is expressed in decreasing the activation energy for the elementary step by about a factor of two for the frontside mechanism and by a factor of four to five for the backside one when compared with the calculated literature data on water-free methane nitrosation. The combination of the activation strain model of reactivity and the energy decomposition analysis reveals that the activation barriers are largely determined by the relative stability of the termolecular reactant complexes. The crucial factor that stabilizes these complexes comes from the electrostatic attraction. The catalytic effect of the key water molecule is decreased with introduction of additional one or two explicit water molecules, which form a coordinate O→N bonding with NO+. On the contrary, an additional water molecule hydrogen bonded to the key catalytic water molecule enhances the catalytic effect.

Natural Product Synthesis by Intramolecular Alkylidene Carbene C−H Insertion

AbstractDirect functionalization of unactivated C−H bonds is of increasing importance in organic synthesis. Of the many methods that have been developed, intramolecular alkylidene C−H insertion, proceeding with retention of absolute configuration, is among the most versatile. This Review explores all examples of the use of intramolecular alkylidene C−H insertion in natural product synthesis.

Stereoselective Transesterification of P-Chirogenic Hydroxybinaphthyl Phosphinates.

The substitution reaction of phosphinates with a binaphthyloxy group at the phosphorus atom with lithium alkoxides proceeded with good to high efficiencies to give P-chirogenic phosphinates with a high enantiomeric ratio. As alcohols, primary, secondary, and tertiary alcohols could be used, and the use of tert-butyl alcohol yielded the products with a higher enantiomeric ratio. A substrate with two different alkyl groups on the phosphorus atom could also participate in the substitution reaction to give the corresponding products in good yields with excellent selectivity. The molecular structures of one of the substrates and the corresponding products, determined by X-ray analyses, proved that the substitution reaction at the phosphorus atom proceeded with inversion of the absolute configuration. The usefulness of the reaction was demonstrated by using it to prepare a drug candidate for Duchenne muscular dystrophy. Finally, thionation of the resulting phosphinates was carried out to form P-chirogenic phosphinothioates.

Synthesis of C4‐Acyl‐tetrofuranosides and C5‐Acyl‐pentopyranosides Enabled by the Liebeskind‐Srogl Cross‐Coupling Reaction

AbstractAn efficient and versatile protocol for the synthesis of C4‐acyl‐tetrofuranosides and C5‐acyl‐pentopyranosides has been established via the Liebeskind‐Srogl cross‐coupling reaction of various uronic acid‐derived thioesters and a wide range of arylboronic acids. Distinctive features of this transformation include mild reaction conditions, broad substrate scopes, impressive compatibility with a wide array of functional groups, and retention of stereochemical configurations. Dapagliflozin‐derived thioester is also amenable to this transformation, demonstrating the potential of this strategy in the late‐stage modifications of the active pharmaceuticals.

Catalytic Asymmetric Chlorination of Isoxazolinones

AbstractOrganic compounds featuring a chlorine substituted stereocenter are frequently found in nature and are interesting for pharmaceutical applications and as synthetic building blocks. Catalytic methods to generate such stereocenters by C,H bond functionalization are still relatively rare. Here we report the first catalytic asymmetric chlorination of isoxazolinones, a synthetically and biologically interesting class of heterocycles, which can be considered as precursors for β‐aminoacids. The title reaction was catalyzed with high enantioselectivity by a planar chiral ferrocene based palladacycle in high to excellent yields. It is showcased that the products are valuable for post‐synthetic transformations. An SN2 reaction proceeded with smooth inversion of the absolute configuration. The substitution product could then be transformed into an α‐azido β‐aminoacid derivative via a reductive, diastereoselective ring opening.

A di‑iron(III) μ-oxido complex as catalyst precursor in the oxidation of alkanes and alkenes

The oxido-bridged diiron(III) complex [Fe2(μ-O)(μ-OAc)(DPEAMP)2](OCH3) (1), based on a new unsymmetrical ligand with an N4O donor set, viz. [2-((bis(pyridin-2-ylmethyl)amino)methyl)-6-((ethylamino)methyl)-4-methylphenol (HDPEAMP)], has been prepared and characterized by spectroscopic methods and X-ray crystallography. The crystal structure of the complex reveals that each Fe(III) ion is coordinated by three nitrogen and three oxygen donors, two of which are the bridging oxido and acetate ligands. Employing H2O2 as a terminal oxidant, 1 is capable of oxidizing a number of alkanes and alkenes with high activity. The catalytic oxidation of 1,2-dimethylcyclohexane results in excellent retention of configuration. Monitoring of the reaction of 1 with H2O2 and acetic acid in the absence of substrate, using low-temperature UV–Vis spectroscopy, suggests the in situ formation of a transient Fe(III)2-peroxido species. While the selectivity and nature of oxidation products implicate a high-valent iron-oxido complex as a key intermediate, the low alcohol/ketone ratios suggest a simultaneous radical-based process.

Free‐Radical Epimerization of d‐ into l‐C‐(Glycosyl)methanol Compounds Using 1,5‐Hydrogen Atom Transfer Reaction

AbstractA simple epimerization of C‐(α‐d‐Glyp)methanol into C‐(β‐l‐Glyp)methanol compounds is described. The radical sequence involved homolytic cleavage of the C5−H bond by 1,5‐hydrogen atom transfer promoted by the 1’‐O‐yl radical and subsequent hydride addition with inversion of configuration. This methodology allows the preparation of rare C‐(β‐l‐Idop)‐, C‐(β‐l‐Altp)‐, C‐(β‐l‐Gulp)‐, C‐(β‐l‐Allp)methanol glycosides starting from carbohydrates of the d‐series. It can also be applied to transform l‐ into d‐configured C‐glycosyl compounds, as illustrated by the formation of C‐(β‐d‐6dGulp)‐ and C‐(β‐d‐6dAltp)methanol from readily accessible l‐rhamno and l‐fuco analogs, respectively. In further development of this procedure compounds with C‐(β‐l‐Araf)‐ and C‐(β‐l‐5dRibf)methanol structures have also been synthesized. The alkoxyl radicals were generated by reaction of the corresponding N‐alkoxyphthalimides with nBu3SnH(D) and in comparative terms, by visible light‐photocatalysis using the Hantzsch ester/fac‐Ir(ppy)3 procedure. The influence of the sugar ring conformation and the electronegativity of the substituents on the stereochemical outcome will be addressed.

SN2 Reactions with an Ambident Nucleophile: A Benchmark Ab Initio Study of the CN- + CH3Y [Y = F, Cl, Br, and I] Systems.

We characterize the Walden-inversion, front-side attack, and double-inversion SN2 pathways leading to Y– + CH3CN/CH3NC and the product channels of proton abstraction (HCN/HNC + CH2Y–), hydride-ion substitution (H– + YH2CCN/YH2CNC), halogen abstraction (YCN–/YNC– + CH3 and YCN/YNC + CH3–), and YHCN–/YHNC– complex formation (YHCN–/YHNC– + 1CH2) of the CN– + CH3Y [Y = F, Cl, Br, and I] reactions. Benchmark structures and frequencies are computed at the CCSD(T)-F12b/aug-cc-pVTZ level of theory, and a composite approach is employed to obtain relative energies with sub-chemical accuracy considering (a) basis-set effects up to aug-cc-pVQZ, (b) post-CCSD(T) correlation up to CCSDT(Q), (c) core correlation, (d) relativistic effects, and (e) zero-point energy corrections. C–C bond formation is both thermodynamically and kinetically more preferred than N–C bond formation, though the kinetic preference is less significant. Walden inversion proceeds via low or submerged barriers (12.1/17.9(F), 0.0/4.3(Cl), −3.9/0.1(Br), and −5.8/–1.8(I) kcal/mol for C–C/N–C bond formation), front-side attack and double inversion have high barriers (30–64 kcal/mol), the latter is the lower-energy retention pathway, and the non-SN2 electronic ground-state product channels are endothermic (ΔH0 = 31–92 kcal/mol).

Geo-Electrical Detection of Impermeable Membranes in the Subsurface

In this paper, we have investigate looking ahead capabilities of electrical resistivity tomography (ERT) for a soil penetrating tool with electrodes. In our case study, the desired detection resolution (10 to 20 cm at a depth of at least 6 m) was much higher than what can be achieved from classical surface ERT measurements. Therefore, we designed a logging-type tool, that can be pushed into the ground. Our target was a buried PVC membrane which acts as an electrical insulator. In this phase, we performed numerical simulations and laboratory measurements. The methodology is based on a two-step approach. First, we calculate the background resistivity of the tool’s path is determined by inversion of near-looking electrode configurations. Next, the theoretical response (kernel) of the far-looking configurations is calculated for different membrane positions. The root mean square (RMS) error between the kernel and the measurements is minimized to detect the membrane. If the membrane is within sensing reach, the RMS has a minimum for the kernel corresponding to the true membrane position. If no minimum in RMS is found, the membrane is not within sensing reach and the tool can be pushed closer to the membrane. The laboratory tests comprised measurements in a tank filled with either water or saturated sand or saturated sand with clay slabs and chunks. The laboratory results were successful in pinpointing the position of the membrane with an accuracy of 10 to 20 cm, depending on the dimension of the tool and the distance from the membrane.

Nucleophilic Substitution at Heteroatoms-Identity Substitution Reactions at Phosphorus and Sulfur Centers: Do They Proceed in a Concerted (SN2) or Stepwise (A-E) Way?

The mechanisms of three selected identity substitution reactions at phosphorus and sulfur occurring with stereospecific inversion have been investigated using density functional theory (DFT). The first identity reaction between methoxyl anion and methyl ethylphenylphosphinate 1 reported in 1963 has been shown to proceed in a stepwise fashion according to the addition–elimination (A–E) mechanism involving formation of a pentacoordinate phosphorus intermediate (TBI-1). In contrast, the results of DFT studies of the identity chloride exchange reaction in (ethoxy)ethylphosphonochloridothionate 3 in acetone solution provided evidence that it proceeds synchronously according to the classical Ingold’s SN2-P mechanism. DFT calculations of the methoxyl–methoxy exchange reaction at sulfur in methyl p-toluenesulfinate 4 catalyzed by trifluoroacetic acid in methanol revealed that it proceeds stepwise (A–E mechanism), involving the formation of the high-coordinate sulfurane intermediate. In both identity transesterification reactions, 1 and 4, the transiently formed trigonal bipyramidal intermediates with the two methoxyl groups occupying apical positions (TBI-1 and TBI-4) have higher free energy barriers for the Berry-type pseudorotation than those for direct decomposition to starting phosphinate and sulfinate ensuring stereospecific inversion of configuration at the phosphinyl and sulfinyl centers. Thus, the DFT method proved its usefulness in the distinction between both mechanisms that are often indistinguishable by kinetic measurements.

Pyrene-Fused [7]Helicenes Connected Via Hexagonal and Heptagonal Rings: Stereospecific Synthesis and Chiroptical Properties.

In this manuscript, we portrayed a stereospecific synthesis of C2- and C1-symmetric pyrene-fused [7]helicene compounds 1 and 2, respectively. Compounds 1 and 2 were synthesized via a one-pot Suzuki coupling-C-H activation and two-step Suzuki coupling-Scholl reaction, respectively, with complete retention of configuration. The synthesized molecules differ in the fusing mode of [7]helicene units with pyrene via six- and seven-membered rings for 1 and 2, respectively. There was a significant difference in the functional properties and enantiomerization barrier of both compounds because of their distinct molecular symmetry as well as fusing mode to pyrene moiety. The heptagon-containing molecule 2 showed remarkable photophysical and chiroptical properties with commendable configurational stability compared to 1 and pristine [7]helicene as well as its [5]helicene congener.

Stereoretentive and regioselective selenium-catalyzed intermolecular propargylic C-H amination of alkynes.

Herein we report an intermolecular propargylic C–H amination of alkynes. This reaction is operationally convenient and requires no transition metal catalysts or additives. Terminal, silyl, and internal alkynes bearing a wide range of functional groups can be aminated in high yields. The regioselectivity of amination for unsymmetrical internal alkynes is strongly influenced by substitution pattern (tertiary > secondary > primary) and by relatively remote heteroatomic substituents. We demonstrate that amination of alkynes bearing α-stereocenters occurs with retention of configuration at the newly-formed C–N bond. Competition experiments between alkynes, kinetic isotope effects, and DFT calculations are performed to confirm the mechanistic hypothesis that initial ene reaction of a selenium bis(imide) species is the rate- and product-determining step. This ene reaction has a transition state that results in substantial partial positive charge development at the carbon atom closer to the amination position. Inductive and/or hyperconjugative stabilization or destabilization of this positive charge explains the observed regioselectivities.

Amine-catalyzed site- and stereo-selective coupling of epoxy amines and carbon dioxide to construct oxazolidinones

NEt3catalyzed the cycloaddition of epoxy amine and CO2, which generated oxazolidinones. Reactions of chiral epoxy amine achieved 100% configuration inversion, enabling the synthesis of linezolid. DFT studies show that NEt3acted as a nucleophile.

Stereochemical course of cobalamin-dependent radical SAM methylation by TokK and ThnK.

Complex carbapenems are important clinical antibiotics for difficult-to-treat infections. An essential step in the biosyntheses of these natural products is stereospecific methylation at C6 and subsequent alkylations by cobalamin-dependent radical SAM methylases such as TokK and ThnK. We have prepared isotopically labeled substrates in a stereospecific manner and found that both homologous enzymes selectively abstract the 6-pro-S hydrogen, followed by methyl transfer to the opposite face to give the (6R)-methyl carbapenam product proceeding, therefore, by inversion of absolute configuration at C6. These data clarify an unexpected ambiguity in the recently solved substrate-bound crystal structure of TokK and have led to a stereochemically complete mechanistic proposal for both TokK and ThnK.

Synthesis, Antiproliferative and Anti-MDR Activity of Lathyrane Diterpene Derivatives Based on Configuration Inversion Strategy

Synthesis, Antiproliferative and Anti-MDR Activity of Lathyrane Diterpene Derivatives Based on Configuration Inversion Strategy

Doped Nanostructured Manganese Ferrites: Synthesis, Characterization, and Magnetic Properties

Nanocrystalline aluminum-doped manganese ferrite was synthesized by facile thermal treatment method. Nanostructure-doped ferrite with crystalline size that ranged between 3.71 and 6.35 nm was characterized via X-ray diffraction (XRD), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and vibrating-sample magnetometry (VSM). The Scherrer and Williamson-Hall hypothesis techniques were utilized to determine lattice constants and strain. Various types of structural properties including octahedral and tetrahedral site radius, bond lengths and angles, hopping parameter, oxygen positional parameters, site bonds, and edge lengths were determined from XRD spectrum analysis. Discrepancy in the hypothetically expected angle indicates improvement of A-B superexchange intercommunication. Furthermore, magnetic-hysteresis (M-H) and XPS analysis support the claim of enhancement. The presence of the ionic nature of iron and manganese in ferrite is FeII, FeIII, MnII, and MnIV as revealed by the results of XPS. Moreover, XPS assists in an excellent way to understand the properties such as configuration, chemical nature, and average inversion degree of doped ferrite samples. The spin noncollinearity and exquisite interaction amid the sublattice are responsible for the decrease in the saturation and remnant magnetization determined from the hysteresis loop at ambient temperature with maximum magnetic field of 1.8 T.

A P‐Functionalized [3]Ferrocenophane with a Dynamic SPS‐Bridge

AbstractFerrocene‐1,1′‐dithiol reacts with PCl3 and P(NMe2)3 to give [3]ferrocenophanes with SPS‐ansa‐bridges comprising potentially reactive P−Cl and P−N bonds at the central bridge atom. The products were characterized by NMR data and single‐crystal XRD studies. The P‐chloro‐derivative exists both in the solid state and in solution as a mixture of two energetically nearly degenerate conformers with different stereochemical disposition of the ansa‐bridge. Activation parameters for the dynamic equilibration between both isomers in solution were determined by dynamic NMR spectroscopy. Computational studies suggest that the isomerization proceeds via a torsional motion of the bridging SPS‐unit rather than via configuration inversion at the phosphorus atom.

Process Development of the Copper(II)-Catalyzed Dehydration of a Chiral Aldoxime and Rational Selection of the Co-Substrate.

The access towards chiral nitriles remains crucial in the synthesis of several pharmaceuticals. One approach is based on metal‐catalyzed dehydration of chiral aldoximes, which are generated from chiral pool‐derived aldehydes as substrates, and the use of a cheap and readily available nitrile as co‐substrate and water acceptor. Dehydration of N‐acyl α‐amino aldoximes such as N‐Boc‐l‐prolinal oxime catalyzed by copper(II) acetate provides access to the corresponding N‐acyl α‐amino nitriles, which are substructures of the pharmaceuticals Vildagliptin and Saxagliptin. In this work, a detailed investigation of the formation of the amide as a by‐product at higher substrate loadings is performed. The amide formation depends on the electronic properties of the nitrile co‐substrate. We could identify an acceptor nitrile which completely suppressed amide formation at high substrate loadings of 0.5 m even when being used with only 2 equivalents. In detail, utilization of trichloroacetonitrile as such an acceptor nitrile enabled the synthesis of N‐Boc‐cyanopyrrolidine in a high yield of 92 % and with full retention of the absolute configuration.

Silver‐Mediated Conversion of Alcohols to Carbonates with Dialkylazodicarboxylate

AbstractConversion of alcohols to carbonate was observed under the mild conditions of Mitsunobu reaction in presence of silver salt. An investigation is undertaken to explore this unexpected observation, where the presence of DEAD (Diethylazodicarboxylate) and silver salt is essential, while Ph3P is not required. The formation of carbonate is stereospecific, follows with retention of configuration; iso‐propyl carbonate is formed when DIPAD (Diisopropylazodicarboxylate) is used. The method is extended for several examples of alcohols, while it doesn't works for phenols.

Configurational Lability at Tetrahedral Phosphorus: syn/anti‐Isomerization of a P‐Stereogenic Phosphiranium Cation by Intramolecular Epimerization at Phosphorus

AbstractTetrahedral main‐group compounds are normally configurationally stable, but P‐epimerization of the chiral phosphiranium cations syn‐ or anti‐[Mes*P(Me)CH2CHPh][OTf] (Mes*=2,4,6‐(t‐Bu)3C6H2) occurred under mild conditions at 60 °C in CD2Cl2, resulting in isomerization to give a syn‐enriched equilibrium mixture. Ion exchange with excess [NBu4][Δ‐TRISPHAT] (Δ‐TRISPHAT=Δ‐P(o‐C6Cl4O2)3) followed by chromatography on silica removed [NBu4][OTf] and gave mixtures of syn‐ and anti‐[Mes*P(Me)CH2CHPh][Δ‐TRISPHAT]⋅x[NBu4][Δ‐TRISPHAT]. NMR spectroscopy showed that isomerization proceeded with epimerization at P and retention at C. DFT calculations are consistent with a mechanism involving P‐C cleavage to yield a hyperconjugation‐stabilized carbocation, pyramidal inversion promoted by σ‐interaction of the P lone pair with the neighboring β‐carbocation, and ring closure with inversion of configuration at P.