Relative Reactivity Values Research Articles

Unraveling the promoter effect and the roles of counterion exchange in glycosylation reaction.

The stereoselectivity of glycosidic bond formation continues to pose a noteworthy hurdle in synthesizing carbohydrates, primarily due to the simultaneous occurrence of SN1 and SN2 processes during the glycosylation reaction. Here, we applied an in-depth analysis of the glycosylation mechanism by using low-temperature nuclear magnetic resonance and statistical approaches. A pathway driven by counterion exchanges and reaction byproducts was first discovered to outline the stereocontributions of intermediates. Moreover, the relative reactivity values, acceptor nucleophilic constants, and Hammett substituent constants (σ values) provided a general index to indicate the mechanistic pathways. These results could allow building block tailoring and reaction condition optimization in carbohydrate synthesis to be greatly facilitated and simplified.

Toward an Improved Triterpene 3-O-Glucuronidation: The Systematic Determination of the Relative Reactivities of Glucuronyl Donors and Acceptors.

3-O-β-Glucuronide triterpenes are plant-derived compounds. Some of them have been used as herbal medicine and in pharmaceuticals, such as chikusetsu saponins and Quillaja saponins. However, the demand for these materials has remained largely a challenge owing to their natural scarcity and low-yielding purification process. Therefore, a chemical triterpene 3-O-glucuronidation was conducted in this study to alleviate the surging demand on natural source. Various glucuronyl imidate donors and oleanane-type triterpene acceptors were synthesized, and the relative reactivity values (RRV) and acceptor nucleophilic constants (Aka) were systematically measured to study their influence on glucuronidation yield. As a result, applying donors in higher RRV value generally improved the production of 3-O-glucuronide triterpenes. Meanwhile, a bulky pivaloyl group was an ideal 2-O-protection to provide β-selectivity and prevented side reactions, including orthoester formation and acyl-transfer reaction. Collectively, a positive correlation was observed between reactive donors/acceptors and improved glucuronidation yields. These findings offered insights on the influence of donors' and acceptors' reactivities on 3-O-β-glucuronide triterpenes synthesis, and this knowledge would help to access saponins of interest to address future needs.

Threshold of Thioglycoside Reactivity Difference Is Critical for Efficient Synthesis of Type I Oligosaccharides by Chemoselective Glycosylation

Synthesis of type I LacNAc (Galβ1 → 3GlcNAc) oligosaccharides usually suffers from low yields. We herein report the efficient synthesis of type I LacNAc oligosaccharides by chemoselective glycosylation. With 16 relative reactivity values (RRVs) measured thiotoluenyl-linked disaccharide donors and acceptors, chemoselective glycosylations were investigated to obtain optimal conditions. In these reactions, the RRV difference between the donors and acceptors had to be more than 6311 to obtain type I LacNAc tetrasaccharides in 72-86% yields, with minimal occurrence of aglycon transfer. The threshold of RRV difference was further applied to plan the synthesis of longer glycans. Because it is challenging to measure the RRVs of tetrasaccharides, anomeric proton chemical shifts were utilized to predict the corresponding RRVs, which consequently explained the outcome of glycosylations for the synthesis of type I LacNAc hexasaccharides. The result supported the idea that elongation of glycan chains has to proceed from the reducing to the nonreducing end for a better yield.

Mapping Mechanisms in Glycosylation Reactions with Donor Reactivity: Avoiding Generation of Side Products.

The glycosylation reaction, which is key for the studies on glycoscience, is challenging due to its complexity and intrinsic side reactions. Thioglycoside is one of the most widely used glycosyl donors in the synthesis of complex oligosaccharides. However, one of the challenges is its side reactions, which lower its yield and limits its efficiency, thereby requiring considerable effort in the optimization process. Herein, we reported a multifaceted experimental approach that reveals the behaviors of side reactions, such as the intermolecular thioaglycon transformation and N-glycosyl succinimides, via the glycosyl intermediate. Our mechanistic proposal was supported by low temperature NMR studies that can further be mapped by utilizing relative reactivity values. Accordingly, we also presented our findings to suppress the generation of side products in solving this particular problem for achieving high-yield glycosylation reactions.

Hierarchical and Programmable One-Pot Oligosaccharide Synthesis.

This article presents a general experimental protocol for programmable one-pot oligosaccharide synthesis and demonstrates how to use Auto-CHO software for generating potential synthetic solutions. The programmable one-pot oligosaccharide synthesis approach is designed to empower fast oligosaccharide synthesis of large amounts using thioglycoside building blocks (BBLs) with the appropriate sequential order of relative reactivity values (RRVs). Auto-CHO is a cross-platform software with a graphical user interface that provides possible synthetic solutions for programmable one-pot oligosaccharide synthesis by searching a BBL library (containing about 150 validated and >50,000 virtual BBLs) with accurately predicted RRVs by support vector regression. The algorithm for hierarchical one-pot synthesis has been implemented in Auto-CHO and uses fragments generated by one-pot reactions as new BBLs. In addition, Auto-CHO allows users to give feedback for virtual BBLs to keep valuable ones for further use. One-pot synthesis of stage-specific embryonic antigen 4 (SSEA-4), which is a pluripotent human embryonic stem cell marker, is demonstrated in this work.

Hierarchical and programmable one-pot synthesis of oligosaccharides

The programmable one-pot oligosaccharide synthesis method was designed to enable the rapid synthesis of a large number of oligosaccharides, using the software Optimer to search Building BLocks (BBLs) with defined relative reactivity values (RRVs) to be used sequentially in the one-pot reaction. However, there were only about 50 BBLs with measured RRVs in the original library and the method could only synthesize small oligosaccharides due to the RRV ordering requirement. Here, we increase the library to include 154 validated BBLs and more than 50,000 virtual BBLs with predicted RRVs by machine learning. We also develop the software Auto-CHO to accommodate more data handling and support hierarchical one-pot synthesis using fragments as BBLs generated by the one-pot synthesis. This advanced programmable one-pot method provides potential synthetic solutions for complex glycans with four successful examples demonstrated in this work.

Importance of C−N Bond Rotation in N-Acyl Oxazolidinones in their SmI2-Promoted Coupling to Acrylamides

A detailed mechanistic investigation was undertaken to determine the dominating factors of the postelectron transfer steps in the SmI(2)-promoted carbon-carbon bond forming reaction between N-acyl oxazolidinones and acrylamides. Competition experiments were performed by reacting two N-acyl oxazolidinones with a limiting amount of N-t-butyl acrylamide, and from the product distribution, the relative reactivity values (RV) for a series of N-acyl oxazolidinones were then calculated against N-pivaloyl oxazolidinone as the reference. An almost linear correlation was obtained for the simple alkyl N-acyl oxazolidinones when ln RV was plotted against the activation barriers for C-N bond rotation (s-trans to s-cis) obtained by DFT calculations, implying that C-N bond rotation from the s-trans to s-cis conformation is one of the essential parameters controlling the reactivity. These results were substantiated by other competition experiments carried out for the corresponding imide derivatives, where rotation is not necessary for obtaining bidentate coordination and where no such correlation as described above was observable. The finding that the reactivity of the simple N-acyl oxazolidinones for these SmI(2)-mediated transformations correlates with the activation barriers for C-N bond rotation may have implications for other useful synthetic organic reactions involving similar substrates. Finally, these studies were extrapolated to understanding the poor reactivity of N-acyl oxazolidinones, as those derived from Evans chiral auxiliaries, with N-tert-butyl acrylamide. These couplings appear to be dominated by the activation energy for addition because of arising syn-pentane interactions in the transition-state for C-C bond formation. We demonstrate that the addition of Lewis acids can have a beneficial effect on the coupling yields.

Thio-arylglycosides with various aglycon para-substituents: a probe for studying chemical glycosylation reactions.

Three series of thioglycosyl donors differing only in their respective aglycon substituents within each series have been prepared as representatives of typical glycosyl donors. The relative anomeric reactivities of these donors were quantified under competitive glycosylation conditions with various reaction time, promoters, solvents and acceptors. Over three orders of magnitude reactivity difference were generated by simple transformation of the para-substituent on the aglycon with methanol as the acceptor, while chemoselectivities became lower with carbohydrate acceptors. Excellent linear correlations were attained between relative reactivity values of donors and sigma(p) values of the substituents in the Hammett plots. This indicates that the glycosylation mechanism remains the same over a wide range of reactivities and glycosylation conditions. The negative slopes of the Hammett plots suggested that electron donating substituents expedite the reactions and the magnitudes of slopes can be rationalized by neighboring group participation as well as electronic properties of the glycon protective groups. Within the same series of donors, less nucleophilic acceptors gave smaller slopes in their Hammett plots. This is consistent with the notion that acceptor nucleophilic attack onto the reactive intermediate is part of the rate limiting step of the glycosylation reaction.

Synthesis of a Positional Scanning Library of Pentamers of N-Alkylglycines Assisted by Microwave Activation and Validation via the Identification of Trypsin Inhibitors

A positional scanning library of 625 N-alkylglycine pentamers has been synthesized on solid-phase, employing a set of 10 commercially available primary amines as a source of chemical diversity. The iterative synthetic steps were carried out in tea bags and accelerated by using microwave assisted organic synthesis (MAOS). The reactivity study of the primary amines used as diversity sources led to determine their relative reactivity values and equireactivity factors, which were applied to the library synthesis to ensure comparable concentrations of all final oligomers in the mixtures. This library was validated by the screening, deconvolution, and identification of trypsin inhibitors. These compounds are of potential interest for controlling the intracellular transport of TRPV1 channel.

Photocatalytic Oxidation of Alkanes with Dioxygen by Visible Light and Copper(II) and Iron(III) Chlorides: Preference Oxidation of Alkanes over Alcohols and Ketones

Abstract Visible light irradiation of alkanes in acetonitrile with CuCl2 and FeCl3 catalysts under atmospheric dioxygen gave the corresponding alcohols and ketones effectively; in these reactions, the total selectivity of the products did not decrease so much with increase of alkane conversion. For example, cyclohexanol and cyclohexanone were formed with ca. 70% selectivity at 50% conversion, because overoxidation of the products took place more slowly than cyclohexane oxidation. The relative reactivity values of cycloalkanes increased as their ring-sizes decreased. In the oxidation of hexane, the reactivity ratio of C1-/C2-/C3-H was found to be 1.0/1.4/1.8 with CuCl2 and 1.0/4.6/6.6 with FeCl3, respectively. Toluene and diphenylmethane were more reactive than cyclohexane with FeCl3, as expected, whereas the alkane was oxidized faster than the benzylic compounds in the separate reaction with CuCl2. Moreover, the alkane oxidation could be comparably performed by sunlight instead of an artificial lamp.

A New Reactivity‐Based One‐Pot Synthesis of N‐Acetyllactosamine Oligomers.

Poly-N-acetyllactosamine oligomer is a type-2 glycan core from which a number of important bioactive glycoconjugates are assembled in vivo. Development of an effective synthesis of N-acetyllactosamine oligomers will therefore provide a new chemoenzymatic entry to this class of complex saccharides. This paper describes the design and synthesis of thioglycoside building blocks, determination of their relative reactivity values, and demonstration of their use in the programmable one-pot synthesis of various N-acetyllactosamine oligomers. Through a combination of segment condensation, the strategy allows for the preparation of larger oligosaccharides with minimal protecting group manipulation, as illustrated in the synthesis of an octasaccharide in a very short period of time.

A new reactivity-based one-pot synthesis of N-acetyllactosamine oligomers.

Poly-N-acetyllactosamine oligomer is a type-2 glycan core from which a number of important bioactive glycoconjugates are assembled in vivo. Development of an effective synthesis of N-acetyllactosamine oligomers will therefore provide a new chemoenzymatic entry to this class of complex saccharides. This paper describes the design and synthesis of thioglycoside building blocks, determination of their relative reactivity values, and demonstration of their use in the programmable one-pot synthesis of various N-acetyllactosamine oligomers. Through a combination of segment condensation, the strategy allows for the preparation of larger oligosaccharides with minimal protecting group manipulation, as illustrated in the synthesis of an octasaccharide in a very short period of time.

Effects of Chemical Mechanism Uncertainties on the Reactivity Quantification of Volatile Organic Compounds Using a Three-Dimensional Air Quality Model

Accurate quantification of the ozone-forming potential, termed reactivity, of volatile organic compounds (VOCs) is critical for correctly assessing the impacts of emissions on air quality. As reactivity-based regulations are being more carefully considered for urban ozone control strategies, the uncertainties in the ability to quantify reactivity are gaining importance. This study utilized a three-dimensional air quality model to examine the uncertainty in reactivity quantification resulting from a set of reaction rate constant uncertainties. A previous study identified the set of rate constants that were most critical for single-cell model ozone predictions. With the detailed airshed model, uncertainties in rate constants for aldehyde photolysis, nitric acid formation, and decomposition of peroxy acetyl nitrate (PAN) and peroxy propionyl nitrate plus higher PAN analogues (PPN) exhibited the greatest impact on relative compound reactivity values. For the compounds and reactions examined, the combined responses to 2σ changes in reaction rate constants were approximately 15% of the predicted relative reactivity values, with the reactivities of ethylbenzene and toluene exhibiting the greatest response. The choice of reactivity quantification measures and the air quality models used had a greater impact on relative reactivity predictions than did the rate constant uncertainties.

Effect of positively charged ions on the “molecular” hydrogen yield in the radiolysis of aqueous solutions

The radiolytic hydrogen yield G H 2 from deaerated aqueous solutions of metal ions has been investigated. In Ni 2+, Co 2+ and Zn 2+ solutions G H 2 was constant and no solute concentration effect was observed. In Cd 2+, Cu 2+, Pb 2+ and acidic Hg 2+ solutions G H 2 decreased with increasing solute concentration and the order of the efficiency of the metal ions in reducing the hydrogen yields is Cd 2+<Cu 2+<Pb 2+<Hg 2+. The fact that all these metal ions are good scavengers for the reducing species leads to the conclusion that e aq - or H atoms are not the main precursors of H 2. Homogeneous kinetics was used to express the dependence of G H 2 on solute concentration. The rate-determining step is considered to be the first-order dispppearance of H - produced by the reaction of subexcitation electrons with water as proposed by Platzman. The chemical reactivity of the above ions towards H - is shown to be governed by the rate of substitution of H - on the aquated metal ion and the relative reactivity values found agreement with Eigen's values for lingad substitution. It was also shown that a small part (≈ 10 per cent) of the H 2 may be produced by the reaction of H atoms with the reduced form of the metal ion M +.

Directive effects in benzylic hydrogen atom abstraction—I : Radical bromination by 4-bromo-2,4,6-tri-tert-butyl-2,5-cyclohexadienone

Relative reactivity values in benzylic bromination of alkylbenzenes and benzyl type ethers by 4-bromo-2,4,6-tri-t-butyl-2,5-cyclohexadienone (BTBC) have been measured by intermolecular competition with benzhydryl methyl ether as reference standard at 40° in CCl 4 are compared with results found for N-bromosuccinimide (NBS). The reactivity values for m- and p-substituted XC 9H 4CH 2OMe relative to this standard toward BTBC show a polar effect with ϱ = −0·43 correlated by σ + constants; a result identical to that found for NBS (ϱ = −0·45) carried out in CH 2Cl 2. The identical ϱ-values and other data support the suggestion that atomic Br is the main H-abstracting species in benzylic bromination using BTBC.

Directive effects in benzylic hydrogen atom abstraction—II : Radical chlorination by sulphuryl chloride

Relative reactivity values for benzaldehyde, deoxybenzoin, alkylbenzenes and cyclohexane toward sulphuryl chloride have been measured at 40° in carbon tetrachloride. The values (per α-H atom) for ethylbenzene, cumene and diphenylmethane, and that for cyclohexane relative to toluene are found to be significantly different from those reported for photochlorination under similar conditions, α-Chlorination of substituted toluenes relative to cyclohexane and of substituted ethylbenzenes relative to m-chlorobenzaldehyde by sulphuryl chloride in dilute CCl 4 solution at 40° has been measured and the results show a polar effect with ϱ-values of −0·56 and −0·49, respectively, correlated by σ constants. Although the relative reactivity data for alkylbenzenes can probably be interpreted as evidence for H abstraction mainly by the chlorosulphinyl radical the reaction constant ϱ found for the toluene system cannot be utilised to identify the principal H-abstracting species. Nevertheless, abstraction by the “π-complexed” Cl atom has been ruled out under the condition studied.