A bitter sweet symphony

Oratie uitgesproken door Prof.dr. Jeroen D.C. Codée bij de aanvaarding van het ambt van hoogleraar Organische Chemie aan de Universiteit Leiden op vrijdag 22 september 2023Oratie uitgesproken door Prof.dr. Jeroen D.C. Codée bij de aanvaarding van het ambt van hoogleraar Organische Chemie aan de Universiteit Leiden op vrijdag 22 september 2023Bio-organic Synthesi

Conformational behaviour of mannuronic acid based azasugars

A set of mannuronic acid based iminosugars, comprising the C-5-carboxylic acid, -methyl ester and -amide analogues of 1-deoxymannorjirimicin (DMJ), was synthesized and their pH dependent conformational behavior studied. Under acidic conditions the methyl ester and the carboxylic acid took up an "inverted" 1C4 chair conformation as opposed to the "normal" 4C1 chair at basic pH. This conformational change is explained by the stereoelectronic effects of the ring substituents and it parallels the behavior of the mannuronic acid ester oxocarbenium ion. Because of this solution phase behavior, the mannuronic acid ester azasugar was probed as an inhibitor for a Caulobacter GH47 mannosidase that hydrolyzes its substrates following a reaction itinerary that proceeds through a 3H4 transition state. No binding was observed for the mannuronic acid ester azasugar, but sub-atomic resolution data were obtained for the DMJ-CkGH47 complex, showing two conformations, 3S1 and 1C4, for the DMJ inhibitor

Protecting Group Strategies in Carbohydrate Chemistry

Carbohydrates are the most densely functionalized class of biopolymers in nature. This chapter describes the differences in the reactivity of the various functional groups on a carbohydrate ring and how to exploit these in the design of effective protecting group strategies. It then describes how protecting group effects can be used to control stereoselective transformations and reactivity‐controlled one‐pot synthesis strategies. The chapter highlights applications and strategies in automated synthesis. Different strategies have been developed to automate oligosaccharide assembly based on either solution‐phase synthesis or solid‐phase techniques, and automated solid‐phase synthesizers are now commercially available. Protecting group chemistry can make or break any (oligo)saccharide synthesis effort. The impact of protecting groups on the stereochemical outcome of a glycosylation reaction is best illustrated by the anchimeric assistance that neighboring groups can provide during a glycosylation reaction.Bio-organic Synthesi

Origin of Stereoselectivity in SE2' Reactions of Six-membered Ring Oxocarbenium Ions.

Oxocarbenium ions are key reactive intermediates in organic chemistry. To generate a series of structure-reactivity-stereoselectivity principles for these species, we herein investigated the bimolecular electrophilic substitution reactions (SE2') between allyltrimethylsilane and a series of archetypal six-membered ring oxocarbenium ions using a combined density functional theory (DFT) and coupled-cluster theory approach. These reactions preferentially proceed following a reaction path where the oxocarbenium ion transforms from a half chair (3H4 or 4H3) to a chair conformation. The introduction of alkoxy substituents on six-membered ring oxocarbenium ions, dramatically influences the conformational preference of the canonical 3H4 and 4H3 conformers, and thereby the stereochemical outcome of the SE2' reaction. In general, we find that the stereoselectivity in the reactions correlates to the "intrinsic preference" of the cations, as dictated by their shape. However, for the C5-CH2OMe substituent, steric factors override the "intrinsic preference", showing a more selective reaction than expected based on the shape of the ion. Our SE2' energetics correlate well with experimentally observed stereoselectivity, and the use of the activation strain model has enabled us to quantify important interactions and structural features that occur in the transition state of the reactions to precisely understand the relative energy barriers of the diastereotopic addition reactions. The fundamental mechanistic insight provided in this study will aid in understanding the reactivity of more complex glycosyl cations featuring multiple substituents and will facilitate our general understanding of glycosylation reactions.Bio-organic Synthesi

Mechanistic Investigations into the Application of Sulfoxides in Carbohydrate Synthesis

The utility of sulfoxides in a diverse range of transformations in the field of carbohydrate chemistry has seen rapid growth since the first introduction of a sulfoxide as a glycosyl donor in 1989. Sulfoxides have since developed into more than just anomeric leaving groups, and today have multiple roles in glycosylation reactions. These include as activators for thioglycosides, hemiacetals, and glycals, and as precursors to glycosyl triflates, which are essential for stereoselective β- mannoside synthesis, and bicyclic sulfonium ions that facilitate the stereoselective synthesis of α-glycosides. In this review we highlight the mechanistic investigations undertaken in this area, often outlining strategies employed to differentiate between multiple proposed reaction pathways, and how the conclusions of these investigations have and continue to inform upon the development of more efficient transformations in sulfoxide based carbohydrate synthesis

Developments in the synthesis of mycobacterial phenolic glycolipids

The highly lipophilic outer barrier of mycobacteria, such as M. tuberculosis and M. leprae, is key to their virulence and intrinsic antibiotic resistance. Various components of this mycomembrane interact with the host immune system but many of these interactions remain ill-understood. This review covers several chemical syntheses of one of these components, mycobacterial phenolic glycolipids (PGLs), and outlines the interaction of these PGLs with the human immune system, as established using these well-defined pure compounds.Bio-organic Synthesi

Glycoconjugate vaccines against antimicrobial resistant pathogens

Antimicrobial resistance (AMR) is responsible for the death of millions worldwide and stands as a major threat to our healthcare systems, which are heavily reliant on antibiotics to fight bacterial infections. The development of vaccines against the main pathogens involved is urgently required as prevention remains essential against the rise of AMR. A systematic research review was conducted on MEDLINE database focusing on the six AMR pathogens defined as ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli), which are considered critical or high priority pathogens by the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC). The analysis was intersecated with the terms carbohydrate, glycoconjugate, bioconjugate, glyconanoparticle, and multiple presenting antigen system vaccines.Glycoconjugate vaccines have been successful in preventing meningitis and pneumoniae, and there are high expectations that they will play a key role in fighting AMR. We herein discuss the recent technological, preclinical, and clinical advances, as well as the challenges associated with the development of carbohydrate-based vaccines against leading AMR bacteria, with focus on the ESKAPE pathogens. The need of innovative clinical and regulatory approaches to tackle these targets is also highlighted.Horizon 2020(H2020)861194Bio-organic Synthesi

Controlling Multivalent Binding through Surface Chemistry: Model Study on Streptavidin.

Although multivalent binding to surfaces is an important tool in nanotechnology, quantitative information about the residual valency and orientation of surface-bound molecules is missing. To address these questions, we study streptavidin (SAv) binding to commonly used biotinylated surfaces such as supported lipid bilayers (SLBs) and self-assembled monolayers (SAMs). Stability and kinetics of SAv binding are characterized by quartz crystal microbalance with dissipation monitoring, while the residual valency of immobilized SAv is quantified using spectroscopic ellipsometry by monitoring binding of biotinylated probes. Purpose-designed SAv constructs having controlled valencies (mono-, di-, trivalent in terms of biotin-binding sites) are studied to rationalize the results obtained on regular (tetravalent) SAv. We find that divalent interaction of SAv with biotinylated surfaces is a strict requirement for stable immobilization, while monovalent attachment is reversible and, in the case of SLBs, leads to the extraction of biotinylated lipids from the bilayer. The surface density and lateral mobility of biotin, and the SAv surface coverage are all found to influence the average orientation and residual valency of SAv on a biotinylated surface. We demonstrate how the residual valency can be adjusted to one or two biotin binding sites per immobilized SAv by choosing appropriate surface chemistry. The obtained results provide means for the rational design of surface-confined supramolecular architectures involving specific biointeractions at tunable valency. This knowledge can be used for the development of well-defined bioactive coatings, biosensors and biomimetic model systems

Rational tuning of the reactivity of three-membered heterocycle ring-openings via SN2 reactions

The development of small molecule covalent inhibitors and probes continuously pushes the rapidly evolving field of chemical biology forward. A key element in these molecular tool compounds is the "electrophilic trap" that allows for a covalent linkage with the target enzyme. The reactivity of this entity needs to be well balanced to effectively trap the desired enzyme, while not being attacked by off-target nucleophiles. We here investigate the intrinsic reactivity of substrates containing a class of widely used electrophilic traps, the three-membered heterocycles with an N- (aziridine), P- (phosphirane), O- (epoxide) and S-atom (thiirane) as heteroatom. Using quantum chemical approaches, we studied the conformational flexibility and nucleophilic ring-opening reaction of a series of model substrates, in which these electrophilic traps are mounted on a cyclohexene scaffold (C6H10Y with Y = NH, PH, O, S). It is revealed that the activation energy of the ring-opening reaction does not necessarily follow the trend that is expected from C-Y leaving-group bond strength, but steeply decreases from NH, to PH, to O, to S. We illustrate that the HOMONu-LUMOSubstrate interaction is an all-important factor for the observed reactivity. In addition, we show that the activation energy of aziridines and phosphiranes can be tuned far below that of the corresponding epoxides and thiiranes by the addition of proper electron-withdrawing ring substituents. Our results provide mechanistic insights to rationally tune the reactivity of this class of popular electrophilic traps and can guide the experimental design of covalent inhibitors and probes for enzymatic activity.NWONWO-Rekentijd grant 17569 and 11116Bio-organic Synthesi

An orthogonally protected cyclitol for the construction of nigerose- and dextran-mimetic cyclophellitols

Cyclophellitols are potent inhibitors of exo- and endoglycosidases. Efficient synthetic methodologies are needed to fully capitalize on this intriguing class of mechanism-based enzyme deactivators. We report the synthesis of an orthogonally protected cyclitol from d-glucal (19% yield over 12 steps) and its use in the synthesis of α-(1,3)-linked di- and trisaccharide dextran mimetics. These new glycomimetics may find use as Dextranase inhibitors, and the developed chemistries in widening the palette of glycoprocessing enzyme-targeting glycomimetics.ERC-CoG-726072 “GLYCONTROL”; ERC-2020-SyG-951231 “CARBOCENTRE”Bio-organic Synthesi