Chiral Substrates Research Articles

Disposable Plasmonics: Plastic Templated Plasmonic Metamaterials with Tunable Chirality.

Development of low-cost disposable plasmonic substrates is vital for the applicability of plasmonic sensing. Such devices can be made using injection-molded templates to create plasmonic films. The elements of these plasmonic films are hybrid nanostructures composed of inverse and solid structures. Tuning the modal coupling between the two allows optimization of the optical properties for nanophotonic applications.

Rhodium-catalyzed [5 + 2 + 1] cycloaddition of ene-vinylcyclopropanes and CO: reaction design, development, application in natural product synthesis, and inspiration for developing new reactions for synthesis of eight-membered carbocycles.

Practical syntheses of natural products and their analogues with eight-membered carbocyclic skeletons are important for medicinal and biological investigations. However, methods and strategies to construct the eight-membered carbocycles are limited. Therefore, developing new methods to synthesize the eight-membered carbocycles is highly desired. In this Account, we describe our development of three rhodium-catalyzed cycloadditions for the construction of the eight-membered carbocycles, which have great potential in addressing the challenges in the synthesis of medium-sized ring systems. The first reaction described in this Account is our computationally designed rhodium-catalyzed two-component [5 + 2 + 1] cycloaddition of ene-vinylcyclopropanes (ene-VCPs) and CO for the diastereoselective construction of bi- and tricyclic cyclooctenones. The design of this reaction is based on the hypothesis that the C(sp(3))-C(sp(3)) reductive elimination of the eight-membered rhodacycle intermediate generated from the rhodium-catalyzed cyclopropane cleavage and alkene insertion, giving Wender's [5 + 2] cycloadduct, is not easy. Under CO atmosphere, CO insertion may occur rapidly, converting the eight-membered rhodacycle into a nine-membered rhodacycle, which then undergoes an easy C(sp(2))-C(sp(3)) reductive elimination process and furnishes the [5 + 2 + 1] product. This hypothesis was supported by our preliminary DFT studies and also served as inspiration for the development of two [7 + 1] cycloadditions: the [7 + 1] cycloaddition of buta-1,3-dienylcyclopropanes (BDCPs) and CO for the construction of cyclooctadienones, and the benzo/[7 + 1] cycloaddition of cyclopropyl-benzocyclobutenes (CP-BCBs) and CO to synthesize the benzocyclooctenones. The efficiency of these rhodium-catalyzed cycloadditions can be revealed by the application in natural product synthesis. Two eight-membered ring-containing natural products, (±)-asterisca-3(15),6-diene and (+)-asteriscanolide, have been synthesized using the [5 + 2 + 1] cycloaddition as the key step. In the latter case, excellent asymmetric induction was obtained using a chiral substrate. The efficiency of the [5 + 2 + 1] reaction was further demonstrated by the synthesis of four sesquiterpene natural products, (±)-pentalenene, (+)-hirsutene, (±)-1-desoxyhypnophilin, and (±)-hirsutic acid C, containing linear or branched triquinane skeletons utilizing the tandem or stepwise [5 + 2 + 1] cycloaddition/aldol reaction strategy. With the success of [5 + 2 + 1] cycloaddition in natural product synthesis, application of the [7 + 1] and benzo/[7 + 1] cycloadditions in target- and function-oriented syntheses can be envisioned.

A Highly Effective Ruthenium System for the Catalyzed Dehydrogenative Cyclization of Amine-Boranes to Cyclic Boranes under Mild Conditions.

We recently disclosed a new ruthenium-catalyzed dehydrogenative cyclization process (CDC) of diamine-monoboranes leading to cyclic diaminoboranes. In the present study, the CDC reaction has been successfully extended to a larger number of diamine-monoboranes (4-7) and to one amine-borane alcohol precursor (8). The corresponding NB(H)N- and NB(H)O-containing cyclic diaminoboranes (12-15) and oxazaborolidine (16) were obtained in good to high yields. Multiple substitution patterns on the starting amine-borane substrates were evaluated and the reaction was also performed with chiral substrates. Efforts have been spent to understand the mechanism of the ruthenium CDC process. In addition to a computational approach, a strategy enabling the kinetic discrimination on successive events of the catalytic process leading to the formation of the NB(H)N linkage was performed on the six-carbon chain diamine-monoborane 21 and completed with a (15) N NMR study. The long-life bis-σ-borane ruthenium intermediate 23 possessing a reactive NHMe ending was characterized in situ and proved to catalyze the dehydrogenative cyclization of 1, ascertaining that bis σ-borane ruthenium complexes are key intermediates in the CDC process.

Dimeric TADDOL Phosphoramidites in Asymmetric Catalysis: Domino Deracemization and Cyclopropanation of Sulfonium Ylides.

A gold-catalyzed asymmetric cyclopropanation of unactivated olefins with sulfonium ylides in the presence of a bimetallic catalyst with a novel dimeric TADDOL-phosphoramidite ligand is reported. This transformation allows a rare gold-catalyzed dynamic deracemization of chiral racemic substrates, where the same catalyst is responsible for several synergistic tasks in solution. The products are useful building blocks in synthesis and enable expeditious access to natural products.

Stereoselectivity of phosphotriesterase with paraoxon derivatives: a computational study

The bacterial enzyme phosphotriesterase (PTE) exhibits stereoselectivity toward hydrolysis of chiral substrates with a preference for the Sp enantiomer. In this work, docking analysis and two explicit-solvent molecular dynamics (MD) simulations were performed to characterize and differentiate the structural dynamics of PTE bound to the Sp and Rp paraoxon derivative enantiomers (Rp-1 and Sp-1) hydrolyzed with distinct catalytic efficiencies. Comparative analysis of the molecular trajectories for PTE bound to Rp-1 and Sp-1 suggested that substrate binding induced conformational changes in the loops near the active site. After 100 ns of MD simulation, the Zn β2+ metal ion formed hexacoordinated- and tetracoordinated geometries in the Sp-1-PTE and Rp-1-PTE ensembles, respectively. Simulation results further showed that the hydrogen bond between Asp301 and His254 occurred with a higher probability after Sp-1 binding to PTE (47.5%) than that after Rp-1 binding (22.2%). These results provide a qualitative and molecular-level explanation for the 10 orders of magnitude increase in the catalytic efficiency of PTE toward the Sp enantiomer of paraoxon.

Installation of the imidazole ring on chiral substrates via allylic substitution

Allylic substitution of chiral allylic picolinate (1 equiv) with the copper reagents derived from 2-lithio-1-alkylimidazoles (2 equiv), CuBr·Me2S (1 equiv) and MgBr2 (3 equiv) afforded imidazole derivatives possessing a chiral allylic chain at the C2 position stereo- and regioselectively. The chiral imidazoles thus produced were transformed into [chiral imidazolium]+[NTf2]– in good yields. Similarly, the 2-pyridyl derivative with a chiral side chain was synthesized.

ChemInform Abstract: Synthesis of Hydantoins and Dihydrouracils via Thermally‐Promoted Cyclization of Ureidoacetamides.

Abstract The synthesis of hydantoins and dihydrouracils from ureidoacetamides has been carried out at high temperature in glycol solvents. A series of substrates were prepared and examined to determine the effect of substrate structure, N -acyl substitution (X), and solvent on the course of the reaction. A dramatic effect was observed when using ureidoacetamides (e.g., X= N -methyl- N -phenyl), which led to higher yields, faster reaction times, and lower racemization of chiral substrates. The rate of racemization of a chiral hydantoin in the presence of dibenzylamine and N -methyl aniline has also been determined. The thermal cyclization methodology has been applied to the preparation of a complex hydantoin.

Rational design of a fluorescent sensor to simultaneously determine both the enantiomeric composition and the concentration of chiral functional amines.

A fluorescent molecular probe, a 1,1'-bi-2-naphthol (BINOL)-based bis(naphthylimine) compound (R)-4, is designed to exhibit very different fluorescent responses at two emission wavelengths toward a variety of chiral functional amines including diamines, amino alcohols, and amino acids. At one emission wavelength (λ1), it shows high sensitivity toward the substrates, and at another wavelength (λ2), it shows high enantioselectivity. This is the first rational design of such a dual responsive fluorescent sensor which can be used to simultaneously determine both the concentration and the enantiomeric composition of functional chiral amines by one fluorescent measurement. This strategy is potentially generally applicable for the construction of sensors for rapid assay of structurally diverse chiral substrates. When (R)-4 is treated with various chiral functional amines in the presence of Zn(OAc)2, its 2-naphthylamine units are displaced off to show large fluorescent enhancement at λ1 = 427 nm (I1) due to the restored emission of 2-naphthylamine. The combination of the remaining chiral binaphthyl unit with the chiral substrates leads to highly enantioselective fluorescent enhancement at λ2 > 500 nm (I2). Since I1 is only concentration dependent but independent of the chiral configuration, it allows the determination of the substrate concentration. The highly enantioselective I2 allows the determination of the enantiomeric composition. Thus, using one fluorescent probe with one fluorescent measurement, both the concentration and the enantiomeric composition are determined. The dual responsive mechanism of (R)-4 is studied by using various spectroscopic methods including fluorescence, UV-vis, NMR, and mass analyses.

Electrochemistry and Chirality in Bibenzimidazole Systems

A detailed electrochemical study has been carried out on 1,1’-bibenzo[d]imidazoles and the corresponding mono- and bibenzimidazolium salts, and compared to benzimidazole and benzimidazolium moiety models, and to 2,2’-bibenzo[d]imidazole constitutional isomers. The voltammetric experiments, supported by theoretical calculations and structural diffractometric characterizations, evidence how both electrochemical and chiral properties of bibenzimidazole systems depend on the torsional barrier between the two moieties, which determines at the same time the effective conjugation and communication between symmetrical redox centres, and the possibility of obtaining the molecule in two inherently chiral enantiomers that are configurationally stable at room temperature. In particular, the 1,1’-bibenzimidazole scaffold appears very promising for perspective development of inherently chiral substrates that may be used as additives, or supporting electrolytes, or ionic liquids. In fact, the high torsional angle granted by the 1,1’ connectivity results both in an energy barrier high enough to yield permanently stable enantiomers at room temperature, and in low effective conjugation between the two moieties, affording a very large operating window. The effect of single and double alkylation has also been considered. A preliminary enantiorecognition test, achieved performing the electrooligomerization of enantiopure 2,2’-bi[2-(5,2’-bithienyl)]3,3’-bithianaphthene in the presence of either the (R)- or the (S)- enantiomer of a 1,1’-bibenzimidazolium salt, has shown interesting results.

High-throughput enantiopurity analysis using enantiomeric DNA-based sensors.

Distinguishing between the two enantiomers of a molecule is a challenging task due to their nearly identical physical properties. Time-consuming chromatography methods are typically required for this task, which greatly limits the throughput of analysis. Here we describe a fluorescence-based method for the rapid and high-throughput analysis of both small-molecule enantiopurity and concentration. Our approach relies on selective molecular recognition of one enantiomer of the target molecule using a DNA aptamer, and the ability of aptamer-based biosensors to transduce the presence of a target molecule into a dose-dependent fluorescence signal. The key novel aspect of our approach is the implementation of enantiomeric DNA biosensors, which are synthesized from D- and L-DNA, but labeled with orthogonal fluorophores. According to the principle of reciprocal chiral substrate specificity, these biosensors will bind to opposite enantiomers of the target with equal affinity and selectivity, enabling simultaneous quantification of both enantiomers of the target. Using the previously reported DNA biosensor for L-tyrosinamide (L-Tym), we demonstrate the ability to rapidly and accurately measure both enantiopurity and concentration for mixtures of L- and D-Tym. We also apply our enantiomeric biosensors to the optimization of reaction conditions for the synthesis of D-Tym and provide mathematical modeling to suggest that DNA biosensors having only modest binding selectivity can also be used for fluorescence-based enantiopurity measurement. This research provides a generalizable method for high-throughput analysis of reaction mixtures, which is anticipated to significantly accelerate reaction optimization for the synthesis of high-value chiral small molecules.

Engineering Gold Nanoparticles with DNA Ligands for Selective Catalytic Oxidation of Chiral Substrates

Noble metal nanoparticles are promising materials for heterogeneous enantioselective catalysis because of their high surface-to-volume ratios, large concentrations of highly undercoordinated surface sites, and quantum confinement effects. In this work, we report on the use of DNA as an environment-responsive chiral ligand to engineer the selective catalytic behaviors of glucose oxidase-mimicking gold nanoparticles (AuNPs), with glucose enantiomers as the substrates. DNA can be stimulated externally to switch between random-coiled and multistranded structures (e.g., duplex, i-motif, or G-quadruplex). Random-coiled DNA-capped nanoparticles preferentially catalyze oxidation of l-glucose, and structured DNA-capped nanoparticles show higher activity toward d-glucose. pH-induced selectivity diminishment of DNA-treated AuNPs is also found, further demonstrating the chiral selector effect of DNA ligands. In the end, the selective catalysis of AuNPs allows control of the size enlargement of nanoparticles through s...

Palladium(II)-Catalyzed Highly Enantioselective C–H Arylation of Cyclopropylmethylamines

C-H arylation via a Pd(II)/Pd(IV) catalytic cycle has been one of the most extensively studied C-H activation reactions since the 1990s. Despite the rapid development of this reaction in the past two decades, an enantioselective version has not been reported to date. Herein, we report a Pd(II)-catalyzed highly enantioselective (up to 99.5% ee) arylation of cyclopropyl C-H bonds with aryl iodides using mono-N-protected amino acid (MPAA) ligands, providing a new route for the preparation of chiral cis-aryl-cyclopropylmethylamines. The enantiocontrol is also shown to override the diastereoselectivity of chiral substrates.

Theoretical investigation on SnCl4-catalyzed tandem dimerization/oxy-2-azonia-Cope rearrangements between β,γ-unsaturated ketones and imines

The mechanism of the Lewis acid-catalyzed oxy-2-azonia-Cope rearrangement between β,γ-unsaturated ketones and imines leading to the formation of homoallylic amides and lactams has been theoretically studied using the B3LYP density functional theory methods enhanced with a polarized continuum solvation model. It was predicted that the SnCl 4 -catalyzed tandem dimerization/oxy-2-azonia- Cope rearrangement mechanism is highly preferred over the uncatalyzed version as well as the plausible tandem dimerization/Prins rearrangement mechanism. A two-step pathway was found for the overall reaction, involving the initial nucleophilic dimerization followed by the (3,3)-sig- matropic rearrangement. The latter phase was considered to be the rate-limiting step. Particularly, the transition states account for the experimentally observed stereoselectivities and Z/E selectivities. The high stereoselectivity and Z/E selectivity for the chiral cyclic substrates can be attributed to the relative conformational stabilities of TSs. Moreover, distortion-interaction analysis has been performed in an attempt to quantify the various contributions to the reac- tion transition states, and it revealed that interaction energy E II and distortion energy ∆Ed associated with the forma- tion of the 2COM2 complex are the determining factors to

Cyclic enaminones. Part I: stereocontrolled synthesis using diastereoselective and catalytic asymmetric methods.

Cyclic enaminones are versatile intermediates to construct a variety of azacyclic frameworks and have been widely used in alkaloid synthesis. Here, we summarize three approaches for stereoselective syntheses of cyclic enaminones and their functionalized derivatives. These include chiral substrates (chirons) as starting materials, syntheses employing non-catalytic (stoichiometric) reagents, and catalytic asymmetric methods.

Asymmetric tandem 1,5-hydride shift/ring closure for the synthesis of chiral spirooxindole tetrahydroquinolines.

The direct functionalization of sp(3) C-H bonds through a tandem 1,5-hydride shift/ring closure is described. Various optically active spirooxindole tetrahydroquinoline derivatives bearing contiguous quaternary or tertiary stereogenic carbon centers were readily synthesized. A chiral scandium complex of N,N'-dioxide promoted the reactions in good yields (up to 97%) with excellent diastereoselectivities (>20:1) and enantioselectivities (up to 94% ee). Kinetic isotope effect (KIE) experiments and internal redox reactions of chiral substrates were conducted, and the results provided intriguing information that helped clarify the mechanism of the reaction.

Asymmetric trapping of zwitterionic intermediates by sulphur ylides in a palladium-catalysed decarboxylation-cycloaddition sequence.

Through nearly 50 years of development, sulphur ylides have been established as versatile and powerful reagents for the construction of carbocycles and heterocycles. Despite advances, two important and yet elusive bottlenecks continue to inhibit the advancement of this chemistry: a limited number of reagents with polar groups to react with sulphur ylides, and the wide utilization of chiral auxiliaries or substrates to achieve asymmetric cycloaddition processes in the majority of known reports. Herein, we apply an asymmetric palladium catalysis strategy to the chemistry of sulphur ylides to address these two fundamental problems. We thus achieve an unprecedented decarboxylation-cycloaddition sequence of cyclic allylic esters with sulphur ylides through the enantioselective trapping of Pd-stabilized zwitterionic intermediates by the ylides. As a result, a series of biologically and synthetically important 3-vinyl indolines are rapidly assembled with a high reaction efficiency and stereoselectivity.

ChemInform Abstract: Access to Functionalized Bicyclo[4,3,0]nonenes via Palladium‐Catalyzed Oxidative Cyclization of 2‐Allylcyclohexyl Oximes.

AbstractStarting from the chiral title substrates the synthesis of either bicyclic hydroxyaldehydes or enones bearing aliphatic substituents can be achieved by variation of the catalytic system.

ChemInform Abstract: Nanoceria‐Catalyzed Highly Efficient Procedure for N‐Formylation of Amines at Room Temperature under Solvent‐Free Conditions.

AbstractApplication of a chiral substrate yields the corresponding product without razemization.

Synthesis of hydantoins and dihydrouracils via thermally-promoted cyclization of ureidoacetamides

The synthesis of hydantoins and dihydrouracils from ureidoacetamides has been carried out at high temperature in glycol solvents. A series of substrates were prepared and examined to determine the effect of substrate structure, N-acyl substitution (X), and solvent on the course of the reaction. A dramatic effect was observed when using ureidoacetamides (e.g., X=N-methyl-N-phenyl), which led to higher yields, faster reaction times, and lower racemization of chiral substrates. The rate of racemization of a chiral hydantoin in the presence of dibenzylamine and N-methyl aniline has also been determined. The thermal cyclization methodology has been applied to the preparation of a complex hydantoin.

Darzens reaction rate enhancement using aqueous media leading to a high level of kinetically controlled diastereoselective synthesis of steroidal epoxyketones.

Darzens reactions between halocarbonyls and aldehydes have been carried out in water in the presence of a Li(+)-containing base, a phase-transfer catalyst, and granular polytetrafluoroethylene under mechanical stirring. Reactions using both aromatic and aliphatic aldehydes produced epoxides stereoselectively in good to excellent yields. This is the first time that aliphatic aldehydes with α-H have been used in aqueous Darzens reactions. The Darzens reactions were much faster in water than in organic solvents. This aqueous rate enhancement occurred for Darzens reactions between enantiopure steroidal haloketones and aldehydes, yielding enantiopure spiroepoxides with a high level of kinetically controlled diastereoselectivity. Chromatography was avoided in the purifications of the steroidal spiroepoxides. This is an example of preparing enantiopure epoxyketones via aqueous Darzens reaction using chiral α-haloketone substrates.