The construction of structurally defined carbohydrate polymers is a major area of interest and challenge in modern molecular and chemical biology. For many purposes, glycans are biopolymers of comparable biological complexity to nucleic acids and proteins. Unlike proteins or nucleic acids, glycans are not produced in a linear fashion. The three-dimensional structure of glycans involves extensive branching and stereochemical complexity as a result of the multiple hydroxyl substituents on each monosaccharide unit. A wide variety of chemical and enzymatic strategies are used for the synthesis of glycans. The two general approaches to glycan synthesis are either chemical synthesis using protecting group strategies and stereoselective glycosylations, or enzymatic synthesis using glycosyltransferases, which can provide regioselective assembly in a mild chemical environment. Applications for the synthesis of glycans are critical for the understanding of the role glycans play in biological recognition, immunological response, and disease mechanisms, as homogeneous material in a quantity that can be readily studied is not usually available from natural sources. Developments in automated synthesis and chemoenzymatic strategies have made access to oligosaccharides of great structural complexity a reality, and this has opened the door to understanding the structure-activity relationships of glycans with protein folding, cell adhesion, and in the complex interactions between host and pathogen in infectious diseases.
Synthetic chemistry of glycans is one of the most complex synthetic targets. Glycan synthesis is complicated due to both regioselectivity and stereoselectivity required for the synthesis. There are more than one hydroxyl groups on each monosaccharide unit which have nearly the same reactivity, thus the regioselectivity becomes more important in sugar chemistry than in peptide or nucleic acid chemistry. The new stereocenter created during the formation of a glycosidic linkage makes the formation of glycosidic linkages a stereoselective process in which one has to control the stereochemistry to form either an alpha or beta linkage. The result is that saccharides have a high degree of structural diversity in terms of branching and linkage, which affect the activity of a glycan. Synthesis of glycans relies on the activation of a sugar donor molecule, most often sugar nucleotides in enzymatic synthesis, or thioglycosides in chemical synthesis, and a combination of protecting group cycles or glycosyltransferase specificity to direct synthesis of the target glycan. This is essential to acquire pure glycan standards for functional glycomics studies.
Fig. 1 The chemical biology study of homogeneous N-glycans.1,5
Glycan synthesis has become a major area of investigation in contemporary biological research. By offering methods to study the functions of glycans in biological systems, where they are not merely 'decorative' carbohydrates but act as informational elements in controlling protein function and cell-cell communication. Glycans are especially important in biological systems as post-translational modifications; both N-linked glycosylation and O-linked glycosylation of proteins can affect folding pathways, protein conformation and stability, and can also protect against proteolytic degradation, thus controlling the half-life of proteins in the extracellular milieu . The complex architectures on cell surfaces, from oligosaccharides to branched polysaccharides, are also used as recognition elements in a variety of roles such as cell-cell adhesion, pathogen recognition and immune modulation . A key bottleneck in understanding the role of glycans is the difficulty in accessing defined structures; natural sources of glycans are commonly a mixture of structures that cannot be separated from one another. Synthesizing glycans provides a route to study how different carbohydrate epitopes interact with lectins, such as C-type lectins, which are involved in cell activation and pathogen recognition . The preparation of glycan mimetics and glycoconjugates has been also useful in applications to infectious disease, inflammatory disorders and cancer, which may use glycan synthesis to provide functional groups for targeting specific glycan recognition processes with defined changes in glycan structures in these settings.
A key design principle of glycan synthesis is the control of glycosidic bond formation, which requires activation of the glycosyl donor, enhancement of the nucleophilicity of the acceptor, and careful attention to stereochemical parameters to control anomeric configuration. This is true both in chemical and enzymatic approaches to synthesis, with a common theme being the activation of sugar donors. Activation of monosaccharide units to high-energy nucleoside diphosphate sugars is a biological requirement to provide substrates for glycosyltransferases, and a commonly used strategy for chemical glycosylation reactions. This activation not only changes the electronic properties of the anomeric center, making it susceptible to attack by hydroxyl groups on the growing oligosaccharide chain, but also provides the thermodynamic driving force for the coupling reaction to proceed. In chemical synthesis, regioselective protection of hydroxyl groups is another key design principle: protection with orthogonal protecting groups masks certain functional groups while leaving others available to react, and helps to prevent uncontrolled polymerization. Stereochemical control of glycosidic bond formation is perhaps the most difficult design challenge of glycan synthesis: in every glycosylation reaction, a new α- or β-anomeric glycosidic bond is created, and the stereochemical outcome of the reaction must be controlled by neighboring group participation from the C-2 substituent, solvent effects, and the inherent reactivity of various glycosylation promoters. In enzymatic synthesis, the stereochemical challenge is obviated by the regio- and stereo-specificity of Leloir glycosyltransferases in aqueous environments, although other issues such as enzyme stability, substrate specificity, and cost of sugar nucleotide donors present challenges in this approach. A more recent development is the hybrid chemoenzymatic synthesis, where chemically synthesized cores are elaborated enzymatically, allowing for the production of complex, multi-antennary structures not easily accessible with either strategy alone.
Chemical synthesis of glycans can be divided into solution- and solid-phase strategies. The major difference between the two approaches is that in solution synthesis, each monosaccharide addition requires isolation, typically by column chromatography, whereas solid-phase synthesis typically does not require intermediate purification. A solution-phase synthesis has the advantage that reagent and protecting group conditions can be carefully optimized at each step; a solid-phase synthesis has the advantages of fast, automated repeat cycles but generally requires that each step be nearly quantitative with no side reactions (this can be a challenge since each coupling also needs to be stereoselective). Both approaches typically involve the use of orthogonal protecting groups, to allow individual hydroxyl groups to be deprotected in a controlled fashion, as well as the use of glycosyl donors of variable reactivity and a directing group to control stereoselectivity of the anomeric reaction. Recently there has been a move away from linear stepwise synthesis to convergent synthesis. This has been approached in terms of one-pot "programmed synthesis" in which two or more donors with reactivity that has been pre-adjusted by protecting group chemistry (using electronic effects to provide chemoselectivity) are successively activated in the same reaction mixture without purification. A second approach is to integrate the construction of the carbon backbone and glycosylation, as in reductive glycosylation strategies. Capping procedures to acetylate the unreacted hydroxyls are often used in automated solid-phase syntheses as an error-proofing step to cut off incomplete sequences, while also saving reagents. The general strategy in all cases is to obtain perfect regioselectivity and stereoselectivity and to minimize the number of steps. This is often accomplished by the use of the most appropriate participating group, solvent, and promoter for each coupling.
Fig. 2 Chemical strategies for the construction of β-d-mannosidic bonds in complex-type N-glycans.2,5
Protecting groups are part of the approach required to functionalize carbohydrates selectively because it allows the chemist to selectively deprotect different positions on the carbohydrate to address it selectively. The key to successful orthogonal protecting group chemistry is that each protecting group must be removed selectively by a different mechanism, without affecting the other protecting groups in place. This could be removal by acid or base catalysis, hydrogenolysis, photolysis, fluorolysis, or other means. It also means that a given protecting group can be installed and deprotected anywhere in the synthetic route, as long as the conditions used to install and remove it do not affect the other protecting groups in place. A protecting group that remains in place for the whole synthetic route is called a permanent protecting group. A common permanent protecting group is the benzyl ether, since benzyl ethers are quite stable under most conditions and can be removed under hydrogenolysis conditions. Permanent protecting groups are also used to help dissolve the sugar in an organic solvent. Temporary protecting groups are those that are removed during the synthetic route, and these protecting groups need to be more reactive than the permanent protecting groups. They need to be removed in the presence of the other protecting groups in place on the molecule. This can be accomplished if the temporary protecting group is removed by an acid or base that does not remove any of the other protecting groups, or if it has a silyl group that is removed under silyl-specific conditions. Silyl ethers, esters, and carbonates are common temporary protecting groups. A protecting group can affect the reactivity of the glycosyl donor to which it is attached. Electron withdrawing groups make the anomeric carbon less reactive, and electron donating groups make it more nucleophilic. If there is a participating protecting group at C-2, a 1,2-trans glycosidic bond may be formed preferentially, if the reaction goes through the open chain acyloxonium ion intermediate. A modern development is cyclic bifunctional protecting groups, e.g. diacetals, that can protect a trans-diequatorial diol and constrain the conformation, thus affecting the glycosylation. Visible-light absorbing photolabile protecting groups have also been developed that can be used to spatially control deprotection.
Glycosylation reactions are manifold, and have been historically grouped in different classes according to their activation/departure modes, stereocontrol strategies and their convergence potential. Classical glycosyl halides have set the stage for stereoselective synthesis, their reactivity being tuned with heavy metal promoters. Activation modes in Lewis acid catalysis was first established for the anomeric trichloroacetimidates donors. Thioglycosides have become the cornerstone of glycosylation platforms, being bench-stable and able to be used as donor or acceptor with activation by thiophilic reagents for uni- or bi-directional elongation. Reductive glycosylation provided a highly orthogonal approach that combines C-C bond formation and glycosylation in the same step, with a sugar silane reagent carrying a C-2 hydride that participates in transition metal-catalyzed reductive coupling with a carbonyl compound to form an alcohol nucleophile, which in turn is captured by an internal glycosyl donor attached to the same silicon anchor, achieving bond formation and glycosylation in a tandem sequence that obviates the need for an independent and linear C-C bond formation followed by a late glycosylation step. The same C-C bond formation and glycosylation tandem was achieved with one-pot sequential reactions with multiple donors that are preprogrammed with different reactivity. Donors and acceptors can be combined and their activation/reaction is conducted in one reaction vessel without intermediate purification. In this system, the reactivity gradient between different donors is electronically tuned, e.g. by modifying the protecting groups. Donor preactivation approaches, on the other hand, form reactive anomeric species that are stable enough to have acceptors added in a second step.
Synthetic approaches to glycans have been faced with several challenges. First, the structure of glycans themselves is such that they are not linear polymers as is the case for proteins and nucleic acids, but have multiple hydroxyl groups with similar nucleophilicity, making it difficult to control reactivity at each position without an appropriate choice of protecting groups to direct reactivity to the desired position. This reliance on protecting groups, however, results in a large number of additional steps which add to the overall complexity of the synthesis. The additional deprotection steps required once the target protective group strategy has been realized further decreases the synthetic efficiency and results in large amounts of wasted materials. Furthermore, each glycosylation reaction results in a new chiral center at the anomeric position that must be controlled so that the desired α or β linkage is obtained. Methods for this transformation are still not universal, especially for 1,2-cis glycosidic linkages and sterically hindered anomeric quaternary centers. In addition, the building blocks needed for the assembly of glycans still pose a challenge. Rare sugars and unstable sugars, like furanoses, must still be accessed by indirect routes which can prove to be difficult. For example, d-galactofuranose is conformationally locked and results in a decreased nucleophilicity of the acceptor. Other factors such as insolubility and aggregation of partially assembled structures on a solid support are other common challenges, leading to shielding of reactive groups and incomplete couplings. These issues can also arise when synthesizing in solution, as the purification of highly polar intermediates with similar chromatographic properties can be a time and resource-intensive process. As a result of these challenges, the syntheses of complex glycans can require long reaction times, result in poor overall yields, and often result in limited scalability that only allows them to be obtained in academic quantities and not the amounts needed for drug development.
Control of stereochemistry at the anomeric center is probably the most challenging aspect of glycan assembly. Since the α or β configuration of glycosidic bonds determines the 3D orientation of carbohydrate epitopes, they play a crucial role in recognition processes. The stereochemical ratio at the anomeric position is the result of electronic directing effects, steric hindrance, and the reaction medium and is, in general, not easily predicted. Directing effects of a 2-acyl substituent are a highly effective method of enforcing 1,2-trans anomeric configuration as the cyclic acyloxonium ion intermediate acts as a neighboring group. On the other hand, 1,2-cis glycosidic linkages are not accessible by this method. Non-participating 2-ether protecting groups lead, in general, to anomeric mixtures since the anomeric effect is not strong enough to overcome the thermodynamic preference and significant experimental development of the promoter, solvent, and temperature is required to achieve reasonable stereoselectivity. Glycosides without a C-2 hydroxyl group (or 2-deoxy sugars in general) are particularly challenging since this stereocontrol element is not available and the stereochemical integrity of 2-deoxy glycosides is generally lower and the donors more labile. Glycosides with a quaternary center at C-2 position represent another case of poor stereoselective access. In these systems, significant steric strain at the anomeric center disfavors the transition state required to reach the desired stereochemistry. Solvent polarity has a similar effect on stereochemical control at the anomeric center. Ethereal solvents lead to predominantly α-products, but more polar solvents have been reported to enhance the amount of β-anomer, although it is substrate dependent and no general trends can be given. Accurate predictive models to determine stereochemical ratios of glycosylation from first principles are not yet available.
The experimental availability of any glycan synthesis method is often hampered by stepwise losses and limited purification power. A series of protecting group operations (installation, retention and orthogonal deprotection) for each synthetic step is a potential source of side reactions, such as acyl migration, elimination reactions or unwanted anomeric deprotection, that decrease the amount of recovered material at each step. The longer the synthetic sequence, the lower the final yield and the more difficult and expensive becomes its preparation at multigram scale, even if it can be feasible at the laboratory scale. The purification of the target glycan is difficult to achieve as the oligosaccharide grows in size since the polarity of the unfinished sequences is very similar to that of the target molecule. The problem of incomplete stereoselectivity of many glycosylation reactions is often one of the main sources of impurities, since low amounts of the wrong anomeric form are difficult to separate from the expected isomer and can often co-elute with the desired compound, requiring several recycles of purification. Another problem is the aggregation on the solid support, that can occur when a new sugar unit is attached to the glycan chain, causing it to fold on the resin itself. The steric hindrance can hide the last hydroxyl group and prevent its reaction even if the donor is in excess. In order to be soluble in aprotic and non-polar organic solvents, many late-stage intermediates are difficult to work with if they are too polar and require polar protic solvents. This limits the reaction conditions (temperature, acid concentration) that can be used, and can often lead to the accelerated decomposition of the glycosyl donor. Last but not least, any unavoidable impurity in the starting monosaccharide building blocks is often a source of side coupling that will propagate through the whole sequence and create additional impurities that are inseparable from the final product. All of these issues require a comprehensive characterization of each step, that in many cases still does not stop the unavoidable loss of yield that chemical glycan synthesis suffers from. In that way, methodologies with shorter sequences and higher convergency have been constantly developed.
The design and chemical synthesis of glycans is also an important technology in the pharmaceutical and biotechnology industries. Chemical synthesis allows for the preparation of structurally well-defined carbohydrates which can be used to probe the functions of glycans in complex systems or in drug development and can also be used to generate defined glycans that can be attached to proteins in order to produce pharmaceuticals. Having well-defined and homogeneous glycans is crucial for studying structure-activity relationships to determine which structural features of glycans are important for interactions with proteins such as glycoprotein stability, antibody recognition and lectin binding, as the glycans available from natural sources are complex mixtures. In the pharmaceutical industry, glycan synthesis is used to produce glycoprotein-based therapeutics with defined and optimized pharmacological properties, for example, certain glycoforms of a protein therapeutic can be designed to improve serum half-life and effector functions and/or reduce antigenicity. It is also now common to use chemical synthesis in order to access rare monosaccharide derivatives, such as fluorinated sugars, which can be used as probes or inhibitors to determine the mechanisms of enzymes and binding of glycans to proteins and receptors. Synthetic glycans are also used in the preparation of glycoconjugate vaccines, where pathogen-associated carbohydrate antigens can be coupled to protein carriers that are immunogenic in order to produce a protective antibody response. Chemical synthesis is also routinely used in combination with enzymatic synthesis in biotechnology, such as in glycoengineering approaches that modify cell surface glycocalyx or biosimilar production in which a glycosylation pattern that matches the reference product is required. It is also now possible to produce antibody-drug conjugates where the glycan of an antibody can be modified to act as a site-specific anchor for a payload to be attached, thereby improving the therapeutic index while maintaining the integrity of the antibody.
Synthetic complex glycans are of interest as therapeutics, and as such are a strong motivation to develop new methods in the chemical glycosciences. The glycoform of a therapeutic is directly linked to both the activity and safety of the drug. For example, the N-linked glycan attached to the invariant Fc domain of monoclonal antibodies regulates antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Glycoengineered antibodies with altered glycoforms such as low core fucosylation have been shown to more effectively target cancer cells and lead to greater patient responses. Other therapeutic proteins that can be conjugated with complex glycans are cytokines. The complex glycan modification of interleukin-18 has been shown to improve physiochemical characteristics of the protein without changing potency, and complex glycan modified interferon-alpha-2a has shown good bioactivity in vivo. It was also shown that insulin with N-glycans had less tendency to form oligomers and fibrils, and still preserved signaling through its receptor, a clear benefit for shelf life in formulation. Antibody drug conjugates can also be made using chemical methods, with the N-glycosylation site on the Fc domain being the point of conjugation for the drug payload. This is advantageous because the site is highly conserved and the N-glycan can be removed to provide homogeneous conjugation while lysine-based conjugation strategies are prone to heterogeneity. In addition to conjugation to proteins, carbohydrate antigens with sialylated Lewis epitopes have been attached to protein scaffolds to target dendritic cell-specific lectins in vaccine development, allowing for enhanced antigen presentation to T-cells. Homogeneous glycoforms of synthetic glycans are easily generated and so the structure of carbohydrates can be directly correlated with biological activity in the design of drug candidates.
Chemical synthesis is also a powerful tool for glycoengineering efforts to remodel biological systems and create improved biotherapeutics. For example, synthetic glycans have been used to confirm that recombinant production systems generate equivalent glycosylation for biosimilar proteins, as required by regulatory authorities for market approval. Synthetic glycan precursors can also be metabolically loaded into living cells for real-time remodeling of the glycocalyx, to study the effects of glycans on cell adhesion, signaling, and receptor internalization. Chemoenzymatic synthesis of activated sugar nucleotides containing rare monosaccharide analogs, such as fluorinated fucose derivatives, has also provided NMR probes for studying glycan-receptor interactions. For glycosylating cells, chemical synthesis enables site-selective glycosylation using enzyme-coupled transglycosylation with sugar oxazoline donors. As recombinant therapeutic proteins can be produced in non-glycosylating systems such as bacterial hosts, chemical synthesis can also enable post-expression glycan installation. For example, glycoengineering has been used to create homogeneous glycoforms of an antibody with defined sialylation patterns to discover that α-2,6-linked sialic acid residues on complex-type biantennary N-glycans produce optimal anti-inflammatory activity. Enzymatic remodeling can also be integrated with chemical synthesis to install different glycan structures at distinct glycosylation sites within the same protein, to create asymmetrical glycoforms with improved receptor binding and effector function.
Recent innovations and trends in carbohydrate synthesis are already paving the way to a future where the seemingly irreconcilable notions of biological relevance and ease of access start to converge. A first major trend is the growing acceptance of strategies based on the liberation of complex glycans from large scale naturally-occurring sources followed by labeling with removable functionalities and purification to homogeneous gram-scale materials, bypassing the step-by-step assembly that has so far limited throughput. This approach, also known as "reverse synthesis", will free the researcher from protracted de novo synthesis but still provide chemically defined material for functional interrogation. A second trend is the extension of chemoenzymatic assembly strategies beyond rudimentary 'hybrid' protocols to more ambitious one-pot multienzyme (OPME) cascades combining salvage pathway enzymes with glycosyltransferases displaying substrate promiscuity, allowing direct elaboration of inexpensive monosaccharide building blocks into complex glycan epitopes without the isolation of intermediates. A strong move in this direction will likely be represented by process intensification where flow chemistry platforms combining rapid reaction cycles with inline purification capabilities can compress synthetic timelines into days rather than weeks. Artificial intelligence will likely play a major role in speeding up synthesis design, by making accurate predictions of protective group schemes and glycosylation conditions directly from structural databases, alleviating the empirical effort otherwise required. Finally, biocatalytic 'building block factories' where engineered microbes are used to produce activated sugar donors and, perhaps more importantly, a set of orthogonally protected monosaccharides will further democratize access to starting materials. Together, these developments are expected to begin to move glycan synthesis away from an esoteric craft to a standardized scalable technology available to non-specialists, and significantly narrow the gap between synthetic capacity and the overwhelmingly unexplored glycospace that dominates the biology of recognition.
Automation of glycan synthesis is challenged in ways that are different from peptides and nucleotides. It has been, and still is, complicated by a lack of a general coupling protocol. Additionally, at each synthetic step, the correct stereochemistry for branching points must be chosen. To address the former, platforms have been developed that combine an efficient temperature cycling for faster kinetics and better control of anomeric selectivity with diminished side reactions. Solid phase synthesis has evolved to include robotic capping steps and in-process monitoring with colorimetric assays, making it possible to operate continuously while allowing for some failure of individual coupling steps. Flow-based systems have also become a high-throughput paradigm where the solution-phase reagents are passed through packed-bed reactors with immobilized promoters and catalysts. High coupling efficiencies are possible with a smaller reagent excess and an overall simplified workup. Integration of purification steps have improved as well, such as cartridge-based desalting and "catch-and-release" chromatography that can be operated automatically without any manual intervention that used to create disconnected steps in the synthetic procedures. The challenging final chemical sialylation step has been overcome with a pre-activated donor supply and microfluidic mixing. The difficult 1,2-cis linkages, previously considered a roadblock for automation, can now be achieved with a temperature-controlled cycle exploiting the kinetic anomeric effect. Most importantly, custom coupling sequences can now be programmed into the synthesizer using a modular software interface, without requiring extensive carbohydrate chemistry knowledge, greatly expanding the opportunities for multi-disciplinary use.
Chemical methods are also diversifying the structural space of glycans available for modification, beyond linear oligomers, to more hyperbranched structures or highly functionalized motifs. Glycosynthase engineering, in which hydrolytic enzymes are mutated to create active sites that drive transglycosylation without the requirement for costly sugar nucleotides and instead take activated fluorides or thioglycosides to create targeted linkages, is not only orthogonal to glycosyltransferase and glycosidase action but permits the construction of unnatural S-linked glycosides of potential pharmaceutical value. The orthogonal capture and cleavage reagents, such as 4-aminobenzoic acid based reversible tags, can then be used to isolate and subsequently regenerate free reducing glycans from crude natural sources to serve as starting material for further modification. New strategies for incorporating post-glycosylational modifications are also starting to emerge. For example, enzyme pairs for oxidation followed by transamination reactions, to introduce amino groups in place of the more common hydroxyl groups, can be used to access otherwise rare aminosugars from simple monosaccharide starting materials. Sequential chemoenzymatic methods are also proving especially promising for making glycans with more complex topologies. In such schemes, a chemically synthesized core is decorated in parallel, using glycosyltransferases that accept a broader range of aglycone partners, resulting in complex, asymmetrical multi-antennary glycans inaccessible to enzymatic or chemical synthesis alone. In an orthogonal approach, endoglycoceramidases are repurposed to cleave gangliosides directly from glycoconjugates or lipid extracts, providing a source of complex oligosaccharides scaffolds that can be further modified at the reducing end for later conjugation or elaboration. Overall, these advances are diversifying the synthetic glycans space towards not only length, but also branching, modifications and unnatural linkages.
The historical and technical development of chemical glycan synthesis offers a microcosm in which the dual nature of glycobiology as a basic and translational research area can be readily appreciated. The great chemical and topological diversity inherent in carbohydrate structures has naturally been a driver of continued improvement and innovation in the field of glycan synthesis. This has included the invention of new protecting group chemistries, activation strategies, and stereocontrol methodologies for the purposes of expanding the range of accessible structures. In addition to the natural progression of the field toward more complex structures, increased efforts in chemical glycan synthesis have been provided by the translational need for access to N-glycans and O-linked glycoproteins of defined structure and function. This has allowed for the transformation of what were previously laborious multistep syntheses of small oligosaccharides to more robust platforms for the construction of highly-branched N-glycans and structurally-defined O-linked glycoproteins. An overarching theme of chemical glycan synthesis is that no one approach, be it chemical, enzymatic, or chemoenzymatic, is all encompassing, and that there can be great strategic complementarity between different methodologies. This has been increasingly realized and exemplified in the context of chemoenzymatic glycan synthesis where enzyme promiscuity is leveraged to reduce the chemical synthetic burden for constructing complex structures while retaining chemical precision at key linkages that can be synthetically challenging. In the future, it is likely that chemical glycan synthesis will be improved in both breadth and ease of access through advances in automation and machine learning, process intensification, and the continuous adoption of technologies from other areas of organic synthesis and manufacturing.
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