Asymmetric Centers Research Articles

Copper-Catalyzed Highly Enantioselective 1,4-Protoboration of Terminal 1,3-Dienes

Copper-Catalyzed Highly Enantioselective 1,4-Protoboration of Terminal 1,3-Dienes

Phosphorus Compounds of Natural Origin: Prebiotic, Stereochemistry, Application

Organophosphorus compounds play a vital role as nucleic acids, nucleotide coenzymes, metabolic intermediates and are involved in many biochemical processes. They are part of DNA, RNA, ATP and a number of important biological elements of living organisms. Synthetic compounds of this class have found practical application as agrochemicals, pharmaceuticals, bioregulators, and othrs. In recent years, a large number of phosphorus compounds containing P-O, P-N, P-C bonds have been isolated from natural sources. Many of them have shown interesting biological properties and have become the objects of intensive scientific research. Most of these compounds contain asymmetric centers, the absolute configurations of which have a significant effect on the biological properties of the products of their transformations. This area of research on natural phosphorus compounds is still little-studied, that prompted us to analyze and discuss it in our review. Moreover natural organophosphorus compounds represent interesting models for the development of new biologically active compounds, and a number of promising drugs and agrochemicals have already been obtained on their basis. The review also discusses the history of the development of ideas about the role of organophosphorus compounds and stereochemistry in the origin of life on Earth, starting from the prebiotic period, that allows us in a new way to consider this most important problem of fundamental science.

Synthesis of pyrano[3,2-c]quinoline derivatives using catalyst prepared from L-proline and p-toluenesulfonic acid

This research prepared new generation of ionic liquid (Deep eutectic solvent, DES) from L-proline and p-toluenesulfonic acid. The ionic liquid has an asymmetric center in its structure because the original amino acid has an asymmetric center. Subsequently, the ionic liquid was studied catalytic activity in reactions of quinoline[3,2-c]pyrano derivatives synthesis. Conditions affecting the reaction and rate of the two products were also investigated. The results of the reaction conditions showed that aprotic polar solvents gave better yields and the best reaction conditions were: temperature: 50oC, time: 2 h, catalytic amount: 35% mol . The ratios of two product isomers showed that the reaction always forms a mixture of two diastereomers and the trans products were synthesized with moderate enantiomeric excess (40% for four derivatives) compared with the cis products. In addition, the results on catalytic reuse also showed that the catalyst had good usability without significant decreasing activity. When benzaldehyde and aniline were changed with their derivates bearing donating electron group (-CH3), the reaction yields slightly decrease. However, benzaldehyde bearing withdrawing electron group (-F) gave moderate yield.

Nonlinear Rocking Behavior of Irregular Anchored Rigid Bodies: Influence of Main Parameters and Anchoring Effectiveness

ABSTRACT The rocking response of anchored rigid bodies with irregular geometry is evaluated, incorporating the non-linearity of restrainers. A parametric analysis is performed, introducing the concept of Probability Reduction Spectra (PRS) to identify the influence of the main parameters into the rocking response as a function of the fundamental frequencies (excitation/body). The results allow identifying the conditions where anchoring systems are more suitable for different types of excitations. Restrainers have a better performance for slender bodies under impulsive motions (near source) with any eccentricity up to the center of geometry. For seismic excitations, from far or intermediate-depth sources, it is evident a PRS’ band where anchorage is effective. Independently of the kind of excitation, bodies with low and/or asymmetric center of mass could suddenly overturn under abrupt peak intensities after anchorage failure.

Stereoselective and Stereospecific Triflate‐Mediated Intramolecular Schmidt Reaction: Ready Access to Alkaloid Skeletons**

AbstractThe stereoselectivity and stereospecificity of the triflate‐mediated intramolecular Schmidt reaction of substituted 3‐(1‐azidocyclohexyl)propanol derivatives leading to octahydro‐1H‐pyrrolo[1,2‐a]azepine, the structural skeleton of several important families of alkaloids such as the Stemona alkaloids, has been examined. The reaction involves an initial intramolecular SN2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2‐shift/N2‐elimination followed by hydride‐mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicyclic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process, leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro‐1H‐pyrrolo[1,2‐a]azepine. The origin of the stereoselectivity is rationalized based on theoretical calculations. The concise synthesis of (−)‐(cis)‐3‐propylindolizidine and (−)‐(cis)‐3‐butyllehmizidine, two alkaloids found in the venom of workers of the ant Myrmicaria melanogaster, is reported.

Stereoselective and Stereospecific Triflate-Mediated Intramolecular Schmidt Reaction: Ready Access to Alkaloid Skeletons*.

The stereoselectivity and stereospecificity of the triflate‐mediated intramolecular Schmidt reaction of substituted 3‐(1‐azidocyclohexyl)propanol derivatives leading to octahydro‐1H‐pyrrolo[1,2‐a]azepine, the structural skeleton of several important families of alkaloids such as the Stemona alkaloids, has been examined. The reaction involves an initial intramolecular SN2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2‐shift/N2‐elimination followed by hydride‐mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicyclic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process, leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro‐1H‐pyrrolo[1,2‐a]azepine. The origin of the stereoselectivity is rationalized based on theoretical calculations. The concise synthesis of (−)‐(cis)‐3‐propylindolizidine and (−)‐(cis)‐3‐butyllehmizidine, two alkaloids found in the venom of workers of the ant Myrmicaria melanogaster, is reported.

Koshland’s model as a method for the analysis of enzymatic deracemization reactions

Koshland’s four-point location model is applied to consider some enzymatic reactions of deracemization. The sequen-tial model is a theory describing the cooperativity of protein subunits. It postulates that the conformation of the protein changes with each binding of a ligand, thus sequentially changing its affinity to ligands at adjacent binding sites. When the substrate binds to the active site of one subunit of the enzyme, the remaining subunits are activated. The possibility of the alternative binding of both substrates and products of the enzymatic reaction can be assessed on the basis of the known data on the structure of all four substituents at the chiral atom and their correspondence to the ligand specificity of the corresponding subsets of the enzyme. The made theoretical conclusions were tested by the example of the enzymatic deracemization of some hydroxyphosphonic acids. The replacement of ethoxyl groups at the phosphorus atom by isopropoxy groups and an increase in the volume of the substituent led to a significant increase in the enantiomeric excess of the hydrolysis product of hydroxyphosphonate. Hence, the conclusion is drawn that the key criterion for the efficient or inefficient passage of the reaction is the ratio of the sizes and the degree of hydrophobicity of the corresponding substituents at the asymmetric reaction center.

New Isomalabaricane-Derived Metabolites from a Stelletta sp. Marine Sponge.

In continuation of our studies on a Vietnamese collection of a Stelletta sp., sponge we have isolated two new isomalabaricane triterpenoids, stellettins Q and R (1 and 2), and four new isomalabaricane-derived nor-terpenoids, stellettins S-V 3–6, along with previously known globostelletin N. Among them, compound 3 contains an acetylenic fragment, unprecedented in the isomalabaricane family and extremely rare in other marine sponge terpenoids. The structures and absolute configurations of all new compounds were established by extensive NMR, MS, and ECD analyses together with quantum-chemical modeling. Additionally, according to obtained new data we report the correction in stereochemistry of two asymmetric centers in the structures of two known isomalabaricanes, 15R,23S for globostelletin M and 15S,23R for globostelletin N.

Computational 1 H and 13 C NMR of the trimeric monoterpenoid indole alkaloid strychnohexamine: Selected spectral updates.

Very large trimeric indole alkaloid strychnohexamine, with empirical formula C59 H60 N6 O (66 second-row atoms and 60 protons), has been subjected to the state-of-the-art computation of the 1 H and 13 C nuclear magnetic resonance (NMR) chemical shifts of its configurational isomers at each of the 14 asymmetric centers. Several spectral reassignments and corrections of 1 H and 13 C NMR spectra of this alkaloid were suggested based on the PBE0/pcSseg-2//pcseg-2 calculation of its NMR chemical shifts. Thus, all pairs of diastereotopic protons were assigned together with four aromatic carbon resonances of C-9 and C-11, C-9″, and C-11″. In addition, the unassigned chemical shifts of carbon C-23″ and proton at C-3' in, accordingly, 13 C and 1 H NMR spectra were predicted.

Absolute Stereochemical Determination of Organic Molecules through Induction of Helicity in Host-Guest Complexes.

Stereochemistry is a fundamental molecular property with important ramifications for structure, function, and activity of organic molecules. The basic building blocks of living organisms (amino acids and sugars) exhibit a precisely selected set of molecular handedness that has evolved over millions of years. The absolute stereochemistry of these building blocks is manifested in the structure and function of the cell machinery (e.g., enzymes, proteins, etc.), which are essential components of life. In the many chemical subdisciplines, molecular stereochemistry is exceedingly important and is often a strong determinant of structure and function. Besides its biological implications, the centrally important role of stereochemistry in many disciplines of chemistry and related fields has led to tremendous effort and activity, highlighted by the success in stereoselective syntheses of a host of functionalities. In the present climate, it is often the difficulty of assigning absolute stereochemistry as opposed to synthesis, which has become a nontrivial challenge, requiring the attention of the community. There will not be a general solution to this problem, as each system will have its own unique requirements and challenges; however, the need for rapid, routine, and microscale analysis is apparent. This is especially true with parallel and high-throughput arrays for screening conditions and catalysts, generating a large number of samples that require analysis.In this Account, we summarize our contribution to this field through the development of molecular receptors for sensing molecular asymmetry. These methodologies strive to unambiguously assign the absolute configuration of asymmetric center(s). To accomplish this task, our laboratory has designed a variety of host molecules, bearing various binding elements, to form stable complexes with chiral molecules (guests). During this complexation event, the stereochemistry of a target molecule induces a supramolecular chirality (i.e., helicity) within the host system. The design of the host system is such that the helicity of the host/guest complex can be observed and assigned via Exciton Coupled Circular Dichroism (ECCD), a nonempirical technique for identifying handedness, which is correlated back to the absolute stereochemistry of the bound chiral molecule. Taking advantage of the high sensitivity of chiroptical techniques (in terms of the required amount of sample for analysis) and fast response time, these methodologies offer a microscale, rapid, and nonempirical solution for assignment of absolute stereochemistry.The first part of this Account describes application of porphyrin tweezers as reporters of chirality for the absolute stereochemical determination of various classes of organic molecules. This methodology is suitable to report the absolute configuration of organic molecules that contain two binding elements (nitrogen or oxygen based functionalities). In the second part, host systems that do not require two sites of attachment to form ECCD active complexes will be described. This enables the absolute stereochemical assignment of challenging chiral molecules with functional groups lacking routine techniques for analysis.

Different Inductive Effects of Praziquantel Racemate and its Enantiomers on the Enzyme CYP3A4 Mediated by Pregnane X Receptor and its Variants.

Praziquantel (PZQ), which possesses an asymmetric center, is classified as a pyrazinoisoquinoline and has been the mainstay in the treatment of schistosomiasis since 1980. PZQ undergoes a pronounced first-pass metabolism in the liver through the CYP450 system which could be mediated by nuclear receptors. The purpose of this study was to investigate the possible different induction effects of CYP3A4 by PZQ racemate and enantiomers via the pregnane X receptor (PXR) and the effect of PXR polymorphism on the induction potency of PZQs. The dual-luciferase reporter gene systems constructed in HepG2 cells were used to measure the abilities of PZQs to induce CYP3A4 expression mediated by PXR. The mRNA and protein levels of CYP3A4 were evaluated by polymerase chain reaction (PCR) and western blotting, respectively. In HepG2 cells transfected with PXRwt, PXR158, PXR163, PXR370 or PXR403 expression plasmids, PZQ racemate and its enantiomers up-regulated the luciferase activity in a concentration-dependent manner, while reaching saturation after transfected with PXR379 expression plasmids. The mRNA and protein expression of CYP3A4 was effectively activated in PXR-transfected HepG2 cells. The induction ability of CYP3A4 mediated by PXR activation by PZQ racemate and its enantiomers were statistically different between the same PXR group and different PXR groups. The enantioselective induction effects of PZQs on CYP3A4 were related to the enantioselective activations of PXR by PZQs and were influenced by the PXR gene polymorphism. These findings provide a basis for further understanding the enantiomeric metabolism and the variable efficacy of PZQs.

Research progress of chiral ligand exchange stationary phases in the enantiomer resolution

The structure of chiral drugs contains at least one asymmetric center. When the enantiomers act on the human body, they are recognized by chiral receptors and enzymes in vivo, which will show different physiological effects and even adverse reactions. Therefore, it is very important for the development of chiral pharmacy to obtain chiral enantiomers with a single configuration by racemic resolution. Some general impurities will be introduced in the production of chiral drugs, thus the detection of impurities is also a crucial step in the quality control of chiral medicines. The chiral ligand exchange stationary phase has a strong recognition effect on enantiomer analytes with multiple chelating sites, and is very suitable for the separation and control of biological samples such as amino acids. In this work, the development of chiral ligand exchange stationary phases in enantiomeric resolution is reviewed, which is expected to provide a basis for the quality control of complex chiral drug components.

Biocatalytic approaches for enantio and diastereoselective synthesis of chiral β-nitroalcohols.

Chiral β-nitroalcohols find significant application in organic synthesis due to the versatile reactivity of hydroxyl and nitro functionalities attached to one or two vicinal asymmetric centers. They are key building blocks of several important pharmaceuticals, bioactive molecules, and fine chemicals. With the growing demand to develop clean and green methods for their synthesis, biocatalytic methods have gained tremendous importance among the existing asymmetric synthesis routes. Over the years, different biocatalytic strategies for the asymmetric synthesis of β-nitroalcohol stereoisomers have been developed. They can be majorly classified as (a) kinetic resolution, (b) dynamic kinetic resolution, (c) Henry reaction, (d) retro-Henry reaction, (e) asymmetric reduction, and (f) enantioselective epoxide ring-opening. This review aims to provide an overview of the above biocatalytic strategies, and their comparison along with future prospects. Essentially, it presents an enzyme-toolbox for the asymmetric synthesis of β-nitroalcohol enantiomers and diastereomers.

Metal-Catalyzed Intermolecular Hydrofunctionalization of Allenes: Easy Access to Allylic Structures via the Selective Formation of C–N, C–C, and C–O Bonds

Following a strong regain of interest over the past 20 years in the chemistry of allenes, this "forgotten" family of unsaturated molecules is undergoing a renaissance. In this context, the metal-catalyzed hydrofunctionalization of allenes is nowadays one of the most studied transformations. The latter is of great interest because it opens a way to produce selectively functionalized allylic structures. These motifs are important in synthesis, particularly for the formation of asymmetric centers. Hydrofunctionalization of allenes is also a totally atom economical strategy, avoiding generation of any waste, to produce allylic functionalized structures. Compared to the main pathway to obtain the latter (aka Tsuji-Trost allylic substitution), metal-catalyzed hydrofunctionalization does not require the prefunctionalization of starting material with a leaving group. This review presents a state of the art exploration of all existing transition metal-catalyzed methods allowing the selective intermolecular hydrofunctionalization of allenes with N-H, C-H, and O-H nucleophiles or electrophiles.

Prorocentroic Acid, a Neuroactive Super-Carbon-Chain Compound from the Dinoflagellate Prorocentrum hoffmannianum.

Prorocentroic acid (PA) was isolated from the dinoflagellate Prorocentrum hoffmannianum. Relative configurations for its 35 asymmetric centers were determined by analysis of NMR data including heteronuclear couplings and quantum mechanical calculations. PA was tested by using murine cortical neurons grown on microelectrode arrays. Long-term exposure to subtoxic concentrations induced a significant reorganization of neuronal signaling, mainly by changes in the bursting activity. The observed effects could be due to the activation of a plasticity process.

Differential growth and evaluation of band structure of π-SnS for thin-film solar cell applications

Thin-films and nanomaterials with asymmetrical centers are widely used, and a representative example is π-SnS. The cubic phase of SnS is a “thermodynamic metastable” polymorph of SnS that has not been investigated extensively. Maintaining the stability of π-SnS intact and device fabrication are challenging owing to the lack of proper understanding of the nucleation and growth properties. We report a substrate-specific differential growth attribute of π-SnS based on the chemical deposition route. We evaluated the optical properties and band structure of π-SnS and achieved an efficiency of ~ 0.12% for a preliminary thin-film solar cell device.

Status and outlook for acaricide and insecticide discovery.

To guarantee sustainability and progress, the agrochemical industry is faced with several major challenges. Currently, loss of active ingredients due to consumer perception, changing grower needs and ever‐changing regulatory requirements is far higher than the number being introduced into the market. Therefore, there is a need to develop new products that can provide improved efficacy, selectivity and favorable environmental profiles. Strategies to achieve these goals are the search for acaricides and insecticides with new modes of action, or the discovery of novel molecules with activity on the most attractive target sites having resistance breaking properties against pest species. In this context, the introduction of halogen atoms or asymmetric centers into an active ingredient remains an important tool to modulate their properties, but so too is the pro‐pesticide concept. This review gives an overview of agrochemicals launched over the past 8 years, reflects new insights into known mechanisms of action, and describes the status and outlook for acaricide and insecticide discovery.

Effects of restriction of forefoot rocker functions by immobilisation of metatarsophalangeal joints on kinematics and kinetics during walking

ObjectiveThis study was conducted to investigate the effects of restriction of forefoot rocker (FFR) functions by immobilisation of unilateral metatarsophalangeal joints (MPJs) on kinematic and kinetic factors during walking. MethodsEighteen healthy young adults participated in this study. To immobilise the MPJs of the right leg, an aluminium sole plate (AS) was fixed on the sole of the foot. Kinematic and kinetic data were collected while each subject walked at a comfortable speed with the AS and without. ResultsIn the AS condition, the walking speed and contralateral step length were significantly decreased, and an asymmetrical centre of mass (COM) movement was observed. The range of plantarflexion motion and positive work by the ankle joint were decreased markedly during the late stance of the AS limb. In contrast, maximum hip and knee flexion angles in the swing phase of the AS limb and positive work by the bilateral hip joints over the gait cycle were increased. ConclusionsThe results suggested that MPJ immobilisation may result in marked motion limitation of ankle plantarflexion and inhibition of push-off by the ankle joint despite no restrictions on the ankle joint. These changes may interfere with gait speed and a smooth and symmetrical COM shift during walking.

Computational 1H and 13C NMR of strychnobaillonine: On the way to larger molecules calculated at lower computational costs.

The 1H and 13C NMR chemical shifts of strychnobaillonine, a very large dimeric indole alkaloid, consisting of as many as 46 nonhydrogen atoms, were calculated with using the established earlier the most effective computational protocol, PBE0/pcSseg-2//pcseg-2. A very good result was achieved at this level, characterized by the root mean square deviation of only 0.14 ppm for protons and 2.4 ppm for carbons, which enabled the verification of the configurations of its all 13 asymmetrical centers. Essential deviations of the calculated and experimental 1H NMR spectrum of strychnobaillonine were established in several cases, which enabled the performance of some additional NMR assignments and reassignments of the originally proposed structure.

Argentivorous Molecules Exhibiting Highly Selective Silver(I) Chiral Enhancement.

We report the synthesis of chiral tetra-armed cyclens, having an asymmetric center at one side-arm, that show selective chiral enhancement with silver(I). When the chiral ligand forms a silver(I) complex, the side-arms cover the silver(I) incorporated into the cyclen. The asymmetric center controls the conformation of the side-arms in one direction, increasing the molar ellipticity of the CD spectrum. Chiral cyclens substituted with biphenyl groups exhibit large molar ellipticity values with strong exciton coupling effects.