Influence of remote carbamate protective groups on the ß-selectivity in rhamnosylations.

In this work, we present the synthesis of a series of L-thiorhamnosyl donors containing O-carbamate protective groups and the study of their influence on the selectivity in rhamnosylations. It is found that a carbamate on the C-4 position increased the ß selectivity compared with carbamates on the C2 or C3 positions, respectively, and when no carbamate group was installed. In addition it is found that the observed ß selectivity was greater when the 4-O carbamate had less electron withdrawing groups on the nitrogen. The influence of using triflic acid catalysis was studied as well and it was found to lower the ß-selectivity. In addition a new efficient one step synthesis of selectively 2,4-O-benzylated rhamnosides was established using phase transfer catalysis.

CO2 complexation with cyclodextrins.

Carbon dioxide (CO2) emissions from industrial processes, power generation, and transportation contribute significantly to global warming and climate change. Carbon capture and storage (CCS) technologies are essential to reduce these emissions and mitigate the effects of climate change. Cyclodextrins (CDs), cyclic oligosaccharides, are studied as potential CO2 capture agents due to their unique molecular structures and high selectivity towards CO2. In this paper we have investigated binding efficiency of a number of cyclodextrins towards CO2. It is found that the crystal structure of α-cyclodextrin with CO2 has a 1:1 stoichioimetry and that a number of simple and modified cyclodextrins bind CO2 in water with a Kg of 0.18-1.2 bar-1 (7-35 M-1) with per-O-methyl α-cyclodextrin having the highest CO2 affinity.

Substrate specific closed-loop optimization of carbohydrate protective group chemistry using Bayesian optimization and transfer learning.

A new way of performing reaction optimization within carbohydrate chemistry is presented. This is done by performing closed-loop optimization of regioselective benzoylation of unprotected glycosides using Bayesian optimization. Both 6-O-monobenzoylations and 3,6-O-dibenzoylations of three different monosaccharides are optimized. A novel transfer learning approach, where data from previous optimizations of different substrates is used to speed up the optimizations, has also been developed. The optimal conditions found by the Bayesian optimization algorithm provide new insight into substrate specificity, as the conditions found are significantly different. In most cases, the optimal conditions include Et3N and benzoic anhydride, a new reagent combination for these reactions, discovered by the algorithm, demonstrating the power of this concept to widen the chemical space. Further, the developed procedures include ambient conditions and short reaction times.

Switchable product selectivity in dehydration of N-acetyl-d-glucosamine promoted by choline chloride-based deep eutectic solvents.

Herein, we report choline chloride-based deep eutectic solvents (DESs) promoted conversion of N-acetyl-d-glucosamine (GlcNAc) into nitrogen-containing compounds, i.e., 3-acetamido-5-(1',2'-dihydroxyethyl) furan (Chromogen III) and 3-acetamido-5-acetylfuran (3A5AF). The binary deep eutectic solvent choline chloride-glycerin (ChCl-Gly), was found to promote the dehydration of GlcNAc to form Chromogen III, which reaches a maximum yield of 31.1%. On the other hand, the ternary deep eutectic solvent, choline chloride-glycerol-B(OH)3 (ChCl-Gly-B(OH)3), promoted the further dehydration of GlcNAc into 3A5AF with a maximum yield of 39.2%. In addition, the reaction intermediate, 2-acetamido-2,3-dideoxy-d-erythro-hex-2-enofuranose (Chromogen I), was detected by in situ nuclear magnetic resonance (NMR) techniques when promoted by ChCl-Gly-B(OH)3. The experimental results of the 1H NMR chemical shift titration showed ChCl-Gly interactions with α-OH-3 and α-OH-4 of GlcNAc, which is responsible for promoting the dehydration reaction. Meanwhile, the strong interaction between Cl- and GlcNAc was demonstrated by 35Cl NMR.

Glycosyl Formates: Glycosylations with Neighboring-Group Participation.

Protected 2-O-benzyolated glycosyl formates were synthesized in one-step from the corresponding orthoester using formic acid as the sole reagent. Glucopyranosyl, mannopyranosyl and galactopyranosyl donors were synthesized and their glycosylation properties studied using model glycosyl acceptors of varied steric bulk and reactivity. Bismuth triflate was the preferred catalyst and KPF6 was used as an additive. The 1,2-trans-selectivities resulting from neighboring-group participation were excellent and the glycosylations were generally high-yielding.

Vessel effects in organic chemical reactions; a century-old, overlooked phenomenon.

One of the most intriguing aspects of synthetic chemistry is the interplay of numerous dependent and independent variables en route to achieve a successful, high-yielding chemical transformation. The experienced synthetic chemist will probe many of these variables during reaction development and optimization, which will routinely involve investigation of reaction temperature, solvent, stoichiometry, concentration, time, choice of catalyst, addition sequence or quenching conditions just to name some commonly addressed variables. Remarkably, little attention is typically given to the choice of reaction vessel material as the surface of common laboratory borosilicate glassware is, incorrectly, assumed to be chemically inert. When reviewing the scientific literature, careful consideration of the vessel material is typically only given during the use of well-known glass-etching reagents such as HF, which is typically only handled in HF-resistant, polyfluorinated polymer vessels. However, there are examples of chemical transformations that do not involve such reagents but are still clearly influenced by the choice of reaction vessel material. In the following review, we wish to condense the most significant examples of vessel effects during chemical transformations as well as observations of container-dependent stability of certain molecules. While the primary focus is on synthetic organic chemistry, relevant examples from inorganic chemistry, polymerization reactions, atmospheric chemistry and prebiotic chemistry are also covered.

Slow glycosylation: Activation of trichloroacetimidates under mild conditions using lithium salts and the role of counterions.

Glycosylations were carried out with the two glycosyl donors 4-O-acetyl-2,3-O-isopropylidene-1-O-trichloroacetimidoyl-α-l-rhamnopyranose and 2,3,4-tri-O-benzyl-1-O-trichloro-acetimidoyl-α-l-rhamnopyranose in combination with the two alcohols 1-adamantanol and l-menthol as model glycosyl acceptors. As catalysts, the five lithium salts LiNTf2, LiI, LiClO4, LiPF6 and LiOTf were investigated. We demonstrated that both lithium and the respective counterions are playing a role in the activation of trichloroacetimidate glycosyl donors at rt. Under these very mild conditions, the glycosylations are slow and completed in two to eight days. Depending on the counterion, the rate and yield of the reaction differs; however, the selectivity of all investigated lithium salts is deficient.

Stereoselective O-Glycosylations by Pyrylium Salt Organocatalysis.

Despite many years of invention, the field of carbohydrate chemistry remains rather inaccessible to non-specialists, which limits the scientific impact and reach of the discoveries made in the field. Aiming to increase the availability of stereoselective glycosylation chemistry for non-specialists, we have discovered that several commercially available pyrylium salts catalyze stereoselective O-glycosylations of a wide range of phenols and alkyl alcohols. This catalytic reaction utilizes trichloroacetimidates, an easily accessible and synthetically proven electrophile, takes place under air and only initiates when all three reagents are mixed, which should provide better reproducibility by non-specialists. The reaction exhibits varying degrees of stereospecificity, resulting in ß-selective glycosylations from α-trichloroacetimidates, whilst an α-selective glycosylation proceeds from ß-trichloroacetimidates. A mechanistic study revealed that the reaction likely proceeds via an SN 2-like substitution on the protonated electrophile.

Interactions between PAMAM-NH2 and 6-Mercaptopurine: Qualitative and Quantitative NMR studies.

Despite being used as an anti-leukemic drug, the poor solubility of 6-mercaptopurine (6-MP) limits its use in topical and parenteral applications. Dendrimers are commonly used as drug carriers to improve their solubility in aqueous solution. In this work, the interactions between 6-MP and the amine-terminated poly(amidoamine) dendrimers (PAMAM-NH2 ) were investigated by various NMR technology. The chemical shift titrations disclosed that the 6-MP interacted with the surface of PAMAM-NH2 mainly through electrostatics. The determination of diffusion coefficient and relaxation measurements further confirmed the presence of interactions in 6-MP/PAMAM-NH2 complexes. In addition, the encapsulation of 6-MP within the cavity of PAMAM-NH2 was revealed through nuclear Overhauser effect spectroscopy and Saturation Transfer Double Difference analysis. Finally, the binding strength (H-8 is 100% and H-2 is 70%) of 6-MP to PAMAM-NH2 was quantitatively expressed using epitope maps. This study provides a systematic methodology for qualitative and quantitative studies of the interactions between dendrimers and drug molecules in general.

Carbohydrate-Derived Metal-Chelator-Triggered Lipids for Liposomal Drug Delivery.

Liposomes are versatile three-dimensional, biomaterial-based frameworks that can spatially enclose a variety of organic and inorganic biomaterials for advanced targeted-delivery applications. Implementation of external-stimuli-controlled release of their cargo will significantly augment their wide application for liposomal drug delivery. This paper presents the synthesis of a carbohydrate-derived lipid, capable of changing its conformation depending on the presence of Zn2+ : an active state in the presence of Zn2+ ions and back to an inactive state in the absence of Zn2+ or when exposed to Na2 EDTA, a metal chelator with high affinity for Zn2+ ions. This is the first report of a lipid triggered by the presence of a metal chelator. Total internal reflection fluorescence microscopy and a single-liposome study showed that it indeed was possible for the lipid to be incorporated into the bilayer of stable liposomes that remained leakage-free for the fluorescent cargo of the liposomes. On addition of EDTA to the liposomes, their fluorescent cargo could be released as a result of the membrane-incorporated lipids undergoing a conformational change.

Reactivity, Selectivity, and Synthesis of 4-C-Silylated Glycosyl Donors and 4-Deoxy Analogues.

A method for introducing dimethylphenylsilyl at the 4-position in carbohydrates has been developed. Two C-silylated glycosyl donors were prepared via levoglucosenone, starting from cellulose. The glycosylation properties were studied using three glucoside acceptors, a 3-OH, 4-OH, and 6-OH. Compared with the 4-deoxy variant, it was found that the anomeric selectivity was influenced more by the C-2 substituents orientation than the silyl in the 4-position. In general, the reactivity of these donors was higher than the corresponding 4-deoxy-analogue, albeit a competition experiment showed that the introduction of a C-Si increases the relative reactivity by a modest factor of around two.

Easy access to a carbohydrate-based template for stimuli-responsive surfactants.

In this paper we describe the synthesis of a new carbohydrate-based building block functionalized with azido or amino groups on the 2 and 4 positions. The building block can be synthesized in anomerically pure form in only five scalable steps starting from commercially available levoglucosan. It was shown that the building block could undergo alkylations under strongly basic conditions. The building block with azido groups could furthermore take part in CuAAC reactions, generating derivatives with ester or carboxylic acid functionalities. In addition, the anomeric mixture of the building block was used for the synthesis of a molecule that could act as an emulsifier only in the presence of Zn2+ ions.

α-Selective glycosylations using glycosyl N-(ortho-methoxyphenyl)trifluoroacetimidates.

Six N-(o-methoxyphenyl)trifluoroacetimidate glycosyl donors have been synthesized and their role as glycosyl donors has been investigated. The donors were synthesized with complete ß-selectivity, except in one case, and were found to be stable. When Bi(OTf)3, Fe(OTf)2, and Zn(OTf)2 were employed as catalysts, the glycosylations were found to be highly α-selective in Et2O. The selectivity and reaction rate changed with a change in the acceptor reactivity.

Conformationally Switchable Glycosyl Donors.

Glycosyl donors functionalized with 2,2'-bipyridine moieties on the 3-OH and 6-OH or the 2-OH and 4-OH undergo a conformational change when forming 1:1 complexes with Zn2+ ions. The pyranoside ring of the zinc complexes adopted axial-rich skew boat conformations. The reactivities of the two glycosyl donors were investigated by performing a series of glycosylations in the presence or absence of Zn2+ ions. These glycosylations suggested a decrease in reactivity when binding Zn2+. The conformational effect of binding Zn2+ was therefore studied using a third glycosyl donor, unable to undergo conformational changes when binding Zn2+. From competition experiments, it was observed that the binding-induced conformational change increased the reactivity slightly compared to the glycosyl donor unable to undergo a conformational change.

Self-promoted and stereospecific formation of N-glycosides.

A stereoselective and self-promoted glycosylation for the synthesis of various N-glycosides and glycosyl sulfonamides from trichloroacetimidates is presented. No additional catalysts or promoters are needed in what is essentially a two-component reaction. When α-glucosyl trichloroacetimidates are employed, the reaction resulted in the stereospecific formation of the corresponding ß-N-glucosides in high yields at ambient conditions. On the other hand, when equatorial glucosyl donors were used, the stereospecificity decreased and resulted in a mixture of anomers. By NMR-studies, it was concluded that this decrease in stereospecificity was due to an, until now, unpresented anomerization of the trichloroacetimidate under the very mildly acidic conditions. The mechanism and kinetics of the glycosylations have been studied by NMR-experiments, which gave an insight into the activation of trichloroacetimidates, suggesting an SNi-like mechanism involving ion pairs. The scope of glycosyl donors and sulfonamides was found to be very broad including popular N-protective groups and common glycosyl donors of various reactivity. Peracetylated GlcNAc trichloroacetimidate could be used without the need for any promotors or additives and a tyrosine side chain was glycosylated as an N-glycosyl carbamate. The N-carbamates and the N-sulfonyl groups functioned as orthogonal protective groups of the N-glycoside and hence allowed further N-functionalization without risking mutarotation of the N-glycoside. The N-glycosylation was also performed on a gram scale, without a drop in stereoselectivity nor yield.

NMR analysis of the Fischer-Tropsch wastewater: Combination of 1D selective gradient TOCSY, 2D DOSY and qNMR.

The Fischer-Tropsch (FT) process is a practical approach to convert synthesis gas (CO and H2) into hydrocarbons and oxygenates, and these product mixtures are usually well-characterized. However, the analysis of Fischer-Tropsch waste water (FTW) is still somewhat underdeveloped and the exact composition of FTW remains unclear. Herein, various qualitative NMR techniques, especially diffusion-ordered spectroscopy (DOSY) and one dimension (1D) selective gradient total correlation spectroscopy (SelTOCSY) were strategically applied in the analysis of FTW. The NMR results show that the DOSY technique can pseudo-separate most of components in complex mixtures over the diffusion dimension. The SelTOCSY technique is used as a supporting method in the cases where the DOSY technique cannot clearly distinguish overlapped signals. Moreover, the quantitative 1H NMR (qNMR) was further used to quantify the components of the sample. These routine and advanced qualitative and quantitative NMR technique utilized here provide a fast, effective and feasible method for the identification of complex mixtures in FTW, which might be a powerful and fast alternative to gas chromatography or high performance liquid chromatography for FTW research.

Synthesis of α-D-GalpN3-(1-3)-D-GalpN3: α- and 3-O-selectivity using 3,4-diol acceptors.

The motif α-D-GalpNAc-(1-3)-D-GalpNAc is very common in Nature and hence its synthesis highly relevant. The synthesis of its azido precursor has been studied and optimized in terms of steps, yields and selectivity. It has been found that glycosylation of the 3,4-diol acceptor is an advantage over the use of a 4-O-protected acceptor and that both regio- and anomeric selectivity is enhanced by bulky 6-O-protective groups. The acceptors and donors are made from common building blocks, limiting protective manipulations, and in this context, unavoidable side reactions.

Catalytic Glycosylations in Oligosaccharide Synthesis.

Catalytic glycosylation has been a central reaction in carbohydrate chemistry since its introduction by Fischer 125 years ago, but it is only in the past three to four decades that catalytic methods for synthesizing oligosaccharides have appeared. Despite the development of numerous elegant and ingenious catalytic glycosylation methods, only a few are in general use. This review covers all methods of catalytic glycosylation with the focus on the development and application in oligosaccharide synthesis and provide an overview of the scope and limitations of these. The review also includes relevant mechanistic studies of catalytic glycosylations. The future of catalytic glycosylation chemistry is discussed, including specific, upcoming methods and possible directions for the field of research in general.

Silyl-protective groups influencing the reactivity and selectivity in glycosylations.

Silyl groups such as TBDPS, TBDMS, TIPS or TMS are well-known and widely used alcohol protective groups in organic chemistry. Cyclic silylene protective groups are also becoming increasingly popular. In carbohydrate chemistry silyl protective groups have frequently been used primarily as an orthogonal protective group to the more commonly used acyl and benzyl protective groups. However, silyl protective groups have significantly different electronic and steric requirements than acyl and alkyl protective groups, which particularly becomes important when two or more neighboring alcohols are silyl protected. Within the last decade polysilylated glycosyl donors have been found to have unusual properties such as high (or low) reactivity or high stereoselectivity. This mini review will summarize these findings.

On the nature of the electronic effect of multiple hydroxyl groups in the 6-membered ring - the effects are additive but steric hindrance plays a role too.

Research during the last two decades has shown a remarkable directional component of the substituent effects of hydroxy groups, which has a profound effect on the properties of hydroxylated compounds such as carbohydrates. While the epimerisation of a single hydroxyl function is well studied the consequence of multiple epimerisations is more speculative. In this work the effect of three epimerisations was investigated. To this end epimeric 2-phenyl iminoxylitols that have a phenyl group as a conformational anchor and thus hydroxyl groups in the axial or equatorial position, respectively, were synthesized and their pKa and conformation were studied. The results show that the large difference in the electronic effect between the axial and equatorial hydroxyls is partially cancelled by counteracting steric hindrance from 1,3-diaxial interactions. Hydrogen bonding does not appear to play any role in the electronic influence of the hydroxyl groups.