Recent Progress in the Synthesis and Glycosylation of Rare Sugars

This Short Review is dedicated to Professor Erick M. Carreira on the occasion of his 60^th birthday.

Abstract

Out of 42 naturally occurring monosaccharides, only seven are abundant in Nature (glucose, galactose, mannose, fructose, xylose, ribose, and l-arabinose), while the others have been classified as ‘rare sugars’. Fungi and bacteria use a wide range of monosaccharides, in contrast to mammals, reflected in their glycosylated metabolites, as well as the cellular machineries that are involved in their sugar metabolism. Recognition of the microbiome’s impact on human health has led to increased interest in microbial glycans, as they often mediate interaction between host and microbes. Efficient access to rare sugars and oligosaccharides is necessary to study their roles in Nature, which can provide new pharmacological leads. Furthermore, it enables the synthesis of bioactive glycosylated natural products and congeners. This short review highlights recent progress in the synthesis and the efficient, site- and stereoselective glycosylation of rare sugars. Finally, it provides a recent example where synthetic access to rare sugars has enabled biochemical studies to better understand and interfere with processes in Nature.

1 Introduction

2 Synthesis of Rare Sugars

2.1 Syntheses from Renewable Feedstock

2.2 De Novo Syntheses

3 Glycosylation

3.1 Catalyst-Controlled Glycosylation

3.2 One-Pot Iterative Oligosaccharide Synthesis in Solution

4 Application in Biochemical Research

5 Conclusion

Key words

carbohydrates - rare sugars - oligosaccharides - glycosylation - catalysis - photochemistry

1

Introduction

Glycans play crucial roles in various biological processes including signaling and immune response.[1] While the set of monosaccharides used by mammals is comparatively small,[2] the fungal and bacterial glycome are extremely diverse.[3] [4] This diversity can be seen, among others, in the wealth of bioactive glycosylated natural products.[5] Beyond impacting physicochemical properties, sugars are often essential for bioactivity. In the case of amphotericin, for example, bioactivity is lost upon cleavage[6] and affected by modifications of rare sugar mycosamine.[7] Similarly, the trisaccharide in potent cytotoxic agent calicheamicin targets the compound to the DNA site where double strand cleavage occurs.[8] [9] [10] Appreciation of the importance of saccharides in secondary metabolites has generated efforts to glycodiversify bioactive natural products such as vancomycin.[11] [12] In addition, recognition of the microbiome importance in human health has spurred interest in understanding the interactions between host and microbes, which are often mediated by microbial glycans.[13] [14] [15] The chemical synthesis of rare sugar glycans has been lagging. However, innovations in recent years have led to efficient syntheses of diverse sugars, as well as progress in stereoselective glycosylation. These advancements are further enabling glycodiversification, leading to a broader wealth of accessible bioactive compounds, and ultimately to a better understanding of the role of sugars.

Nicole Hauser(2^nd from the left) pursued her Ph.D. in the group of Prof. Erick M. Carreira at ETH Zürich, focusing on the total synthesis of natural products. After graduation, she joined Prof. Mohammad R. Seyedsayamdost’s group at Princeton University to explore the biochemistry associated with enzymes. Nicole started her independent career as tenure track assistant professor at Aarhus University in Denmark in June 2023, where her research aims to address synthetic challenges by using enzymes. From right to left: Marvin Wenninger obtained his Ph.D. in total synthesis from the University of Tübingen, Megan Eg Larsen is pursuing a chemical project in the group, and Martin Lyngsøe Poulsen is the group’s first Ph.D. student.

In this short review, we will first discuss progress in the chemical synthesis of rare sugar pyranoses both focusing on methods that use renewable feedstock as well as de novo syntheses. Amino sugars and furanoses will not be covered. Second, a resume on recent progress in catalyst-controlled glycosylation reactions and one-pot oligosaccharide syntheses that featured rare sugars will be presented. Finally, we will highlight a recent example where synthetic access to rare sugar derivatives has driven biochemical research.

2

Synthesis of Rare Sugars

2.1

Syntheses from Renewable Feedstock

Scheme 1 (A) Synthesis of rare sugars from spectinomycin (1). (B) A range of d-4,6-dideoxy sugars and d-4,5,6-trideoxy sugars was synthesized by ‘sugar pirating’.

Only seven out of the naturally occurring 42 sugars have not been classified as rare sugars (glucose, galactose, mannose, fructose, xylose, ribose, and l-arabinose).[16] Conventional syntheses of rare sugars both from scratch and from abundant sugars often require many steps that encompass redox manipulations and functional group interconversions. Recent trends have focused on the use of feedstock chemicals for efficient access to rare sugars.

As illustrated in Scheme [1]A, Thorson and co-workers utilized a ‘sugar-pirating’-strategy to synthesize d-deoxy sugars from commercially available spectinomycin (1).[17] The cis-cisoid-trans fused tricyclic natural product was sequentially Boc-protected and subjected to diastereoselective ketone reduction with NaBH₄ to access 3′-α-hydroxy intermediate 2 in 90% yield and >10:1 d.r. over two steps (Scheme [1]A). Alternatively, Rh-C-catalyzed hydrogenation,[18] followed by Boc-protection delivered 3′-β-hydroxy intermediate 3 in 89% yield and >10:1 d.r. Subsequent stereoselective 2′-hemiacetal reduction, or sequential C3 O-methylation or Barton–McCombie deoxygenation and hemiacetal reduction afforded glycosides 4. Acid hydrolysis finally provided deoxy sugars 5–11 in 4 to 6 steps and overall yields between 12% and 58%. In total, Thorson and co-workers efficiently synthesized 11 rare deoxy sugars from spectinomycin (1), including 4,6-dideoxy- and 3,4,6-trideoxypyranoses (Scheme [1]B).

2.1.1

Site-Selective Epimerization Reactions

Epimerization is conventionally achieved by S_N2 displacement of an activated hydroxy group or by stepwise oxidation and reduction. Waymouth and Chung and Minnaard, de Vries, and co-workers independently reported Pd-catalyzed C3-selective oxidation of unprotected methyl glycosides[19] and minimally protected methyl and phenyl glucosides and phenyl thioglucoside, respectively.[20] Using Waymouth’s (neocuproine)PdOAc catalyst 13,[21] Minnaard, de Vries, and co-workers selectively oxidized unprotected α-glucose 12 and α-N-acetylglucosamine at C3 (Scheme [2]A).[22] 3-Keto α-glucose 15 was reduced by NaBH₄ to afford allose (17) in 54% yield over 2 steps. Reduction with LS-Selectride (16) yielded higher selectivity (92:8 vs. 68:32) but rendered product isolation more tedious. C3-Selective oxidation was rationalized by catalyst chelation through vicinal bis-equatorial hydroxyls, which allows selective oxidation of secondary over primary alcohols, as well as increased nucleophilicity and basicity of C3–OH compared to other secondary hydroxy groups.[23] In a combined experimental and computational study featuring carba-glucosides, Witte, Minnaard, Bickelhaupt, and co-workers revealed that the ring oxygen plays a crucial role in the observed C3-selectivity.[24] Oxidation proceeds via Pd coordination, followed by rate-determining β-hydride elimination through a four-membered transition state with buildup of positive charge at carbon. The ring oxygen polarizes C1 and C5 through inductive effects and consequently disfavors the buildup of positive charge at vicinal carbon atoms, thus rendering C3 the favored site for oxidation. β-Glucose underwent oxidation both at the anomeric position and C3, followed by rearrangement to bislactone under the reaction conditions. For successful selective transformation, the use of DMSO as solvent was critical as it suppresses mutarotation to β-glucose.

Scheme 2 (A) C3-Oxidation of α-glucose and reduction to allose catalyzed by neocuproine Pd catalyst. (B) Selective one-pot isomerization of 1,2-trans to 1,2-cis diols catalyzed by Ru(II) in the presence of methylboronic acid. Wilkinson’s catalyst (20) was generally preferred with equatorial, and Shvo’s (25) with axial γ-C substituents. Generally, epimerization occurs adjacent to axial substituents (green).

Tang and co-workers developed a one-pot method to selectively access rare sugars by epimerization of 1,2-trans- to 1,2-cis-diols (Scheme [2]B).[25] They harnessed Wilkinson’s catalyst (20) and Shvo’s catalyst (25) to transform unprotected pyranoses and disaccharides, and identified MeB(OH)₂ (26) as optimal chelating agent that drives the reaction to cis product.[26] Wilkinson’s catalyst (20) performed well on saccharides with equatorial γ-C substitution such as methyl galactoside 18, which was transformed to guloside 21 in 54% yield. Similarly, unprotected methyl glucoside (19) underwent selective epimerization to mannoside 22 in 83% yield. In contrast, Shvo’s catalyst (25) was preferred with axial substitution at γ-C. In the presence of 25, l-rhamnose derivative 23 and 2-deoxyglucoside 24 underwent selective epimerization to afford 6-deoxy-l-altroside 27 in 85% yield and 2-deoxy-α-d-ribohexoside 28 in 63% yield, respectively. As a rule of thumb, epimerization selectively occurs at C–OH with an adjacent axial substituent, proposedly via intermediates shown in Scheme [2]B.

Nature uses radical intermediates to invert stereocenters in glycans, thus converting abundant into rare sugar motifs.[27] These intermediates have a long history in carbohydrate chemistry, as exemplified by Giese’s rearrangement of anomeric radicals to 2-deoxy sugars.[28] Progress in photoredox catalysis has led to numerous applications in glycochemistry, which were highlighted in recent reviews.[29] [30] Among others, it has enabled the conversion of minimally or unprotected abundant sugars into rare sugars (see also Section 2.1.2).

Wendlandt and co-workers explored the photocatalyzed synthesis of rare sugars via selective epimerization of naturally abundant monosaccharides and glycans.[31] [32] Their initial site-selective carbohydrate epimerization reaction proceeded through two consecutive hydrogen atom transfer (HAT) steps, thus driving a photocatalytic, non-equilibrium epimerization through a radical-mediated transformation. They utilized 4-CzIPN (30), quinuclidine (31), adamantane-1-thiol (32), and tetrabutylammonium p-chlorobenzoate (33) in MeCN–DMSO at room temperature under blue light irradiation to achieve selective epimerization of a range of minimally protected or unprotected monosaccharides (Scheme [3]A).[31]

Scheme 3 (A) One-pot C3-epimerization of methyl α-d-glucoside and 2-deoxyglucose. Isolated yields are provided in brackets. (B) The reaction proceeds through two sequential, independent HATs firstly to the quinuclidinium radical and secondly from adamantane-1-thiol.

For example, methyl α-d-glucoside (19) was selectively transformed into alloside 34 by C3-epimerization, thus displaying orthogonal reactivity to Tang’s conditions.[25] 2-Deoxyglucose (29) underwent site-selective epimerization to afford 35 in 55% yield, which is particularly interesting because C3-epimerization of 2-deoxy sugars cannot be realized through alternative, enolization-based isomerization. Furthermore, the glucoside motif of a di- and a trisaccharide were C3-epimerized under the optimized conditions. In contrast, C2-selectivity was observed with methyl β-arabinoside, methyl β-galactoside, and methyl β-fucoside (not shown). Yields were generally moderate to good and site-selectivities high in most instances; however, it appears that site-selectivity can be hard to predict. As a general trend, vicinal cis-diols were obtained. Mechanistic studies suggested that initial hydrogen atom abstraction (HAA) by the electrophilic quinuclidinium radical cation is irreversible. In the final step, thiol 32 diastereoselectively donates a hydrogen atom to the glycosyl radical (Scheme [3]B). Intriguingly, the use of alkanethiols was critical in these transformations, as no other H atom donor gave conversion of starting material. C3-Selective HAA, for example with glucoside, is in accordance with selective oxidation reactions reported by Waymouth and Minnaard.[19] [20] [22] [33] Computational studies using density functional theory (DFT) indicated that the transition state leading to C3–H abstraction is stabilized by C–H···O hydrogen bonding between electron-deficient α-hydrogens of the quinuclidinium cation and the non-bonding electrons of a cis-1,3-axial oxygen.[34]

Wendlandt and co-workers also investigated the selective epimerization at carbohydrate carbons with axial secondary hydroxyls.[32] Building on previously observed kinetic reaction control, they reasoned that sterically hindered HAA reagents would selectively cleave more accessible, equatorial C–H bonds. Indeed, subjecting methyl α-d-galactoside (36) to tetrabutylammonium decatungstate (TBADT, 1 mol%) in the presence of 4,4′-dimethoxydiphenyl disulfide (37; 10 mol%) and tetrabutylammonium dibutyl phosphate (20 mol%) in MeCN at room temperature yielded methyl α-d-glucoside (19) in 55% yield upon irradiation with 390 nm light (Scheme [4]A).[35]

Scheme 4 (A) TBADT selectively catalyzed C4-epimerization of unprotected pyranosides such as methyl α-d-galactoside in the presence of 4,4′-dimethoxydiphenyl disulfide and tetrabutylammonium dibutyl phosphate. (B) Unprotected monosaccharides were selectively epimerized in aqueous solution in the presence of NaDT and sodium dibutyl phosphate. (C) Double and triple epimerization of anhydrosugars to afford anhydroidose.

Similarly, fully unprotected mono- and oligosaccharides were epimerized in acetone–H₂O (1:1) with sodium decatungstate (NADT, 1 mol%), sodium dibutyl phosphate and 4,4'-diaminodiphenyl disulfide (39). For example, epimerization of d-fructose (38) yielded l-sorbose (40) in 54% yield (Scheme [4]B). Subjecting 1,6-anhydrosugars 41 and 44 to the reaction conditions was envisioned to effect multiple epimerization reactions, thus serving as viable route to access idose derivatives. Indeed, two and three sequential stereocenter inversions were observed for anhydromannose (41) and anhydroglucose (44), yielding anhydroidose (43) in 54% and 40% yield, respectively, in the presence of disulfide 42 (Scheme [4]C). In addition, di- and trisaccharides were selectively single or double axial-to-equatorial epimerized. Mechanistic studies supported site-selective HAA by excited state tungstate catalyst, followed by stereoselective hydrogen atom donation by the thiol derived from disulfide 37, 39, or 42.

Scheme 5 (A) Increased acidity of triphenylsilanethiol leads to coupled, reversible HAT steps and thermodynamic reaction control, in contrast to independent, irreversible HAT with adamantane-1-thiol. (B) Thermodynamic reaction control was applied to transform l-digitoxose or d-anhydrogalactose.

An interesting change in mechanism was observed when adamantane-1-thiol (32) was replaced with triphenylsilanethiol in the Ir-catalyzed conversion of cis-cyclohexane-1,2-diol into the trans-1,2-diol (Scheme [5]A).[36] Quinuclidine (31) acted as a base to afford silanethiolate, which was oxidized by the photocatalyst over the parent thiol. The resulting thiyl radical thus acted as HAA and the thiol as H atom donor, rendering both steps microscopically reversible. This mechanism is distinct from the one using adamantane-1-thiol (32), which features independent, irreversible HAT steps. Triphenylsilanethiol thus leads to a thermodynamic equilibrium mixture of the two products rather than kinetic product distribution. Subjecting l-digitoxose (45) or d-anhydrogalactose (46) to the optimized reaction conditions afforded l-olivose (48) in 73% yield and d-anhydrogulose (49) in 82% yield, respectively (Scheme [5]B).

2.1.2

Site-Selective Deoxygenations

In 2021, Wendlandt and co-workers reported the photocatalytic synthesis of 2-deoxy- and 4-deoxy-2-keto sugars by transition-metal-promoted reductive dehydration.[37] Utilizing their optimized conditions (4-CzlPN (30), quinuclidine (31) as the HAT mediator,[31] Mn(OAc)₂·4H₂O, Bu₄NOAc, and blue LED) they prepared, among others, 2-deoxy-keto sugar 51 in 50% yield from methyl l-rhamnoside 50 (Scheme [6], Path A). Redox-active Mn salts were identified as crucial additives, giving high conversion of starting material and minimal overoxidation of the radical intermediate. While unprotected rhamnose or thioglycoside failed to undergo redox-isomerization, methyl glycosides and anhydrosugars with axial vicinal C–OH were isomerized in moderate yields. For example, anhydrogalactose 46 was selectively transformed into keto sugar 53 in 48% yield (Scheme [7]A). d-Anhydromannose 41 selectively afforded C4-deoxygenated keto sugar 55 in 52% yield.

Scheme 6 Synthesis of a 2-deoxy-keto sugar from unprotected l-rhamnoside (Path A) utilizing 4-CzlPN, and from C2–OBz rhamnoside (Path B) utilizing an Ir photocatalyst.

The versatile keto sugar intermediate provides efficient access to various rare sugars in short sequences of steps, thus adding value to the transformation despite only moderate yields. Both anhydro-keto sugars 46 and 41 were transformed into aminosugars 54 and 56 through a reductive amination sequence in 22% and 23% yield, respectively, over three steps (Scheme [7]A). The ketone in 51 was further reduced to yield deoxy sugars 57 and 58 using DIBAL-H, respectively borane–ammonia complex with (R)-CBS-catalyst (Scheme [7]B). These sequences proved more efficient than previous syntheses. Furthermore, l-mycaroside 59 and l-ristosamine glycoside 60 were accessed in excellent yields by Grignard addition (2 steps, prior 5 steps) and by oxime reduction (3 steps, prior 6 steps), respectively. Additional protocols for 3-keto sugar derivatizations of minimally protected substrates were further reported by Minnaard and co-workers.[38]

Scheme 7 (A) Synthesis of amino sugars via 3-keto sugars accessed through 1,2-radical migration. (B) 2-Deoxy-keto glycosides are versatile intermediates.

Also in 2021, Taylor and co-workers presented an alternative photocatalytic approach to access a large number of rare l-α-sugars.[39] Utilizing iridium-based photocatalyst 47 along with quinuclidine (31), tetrabutylammonium 4-chlorobenzoate (33), and potassium hydrogen carbonate, they achieved the conversion of several O-acylated sugars into the corresponding deoxy-keto sugars via 1,2-acyloxy migration of an intermediately formed dioxolane (Scheme [6], path B). Highest yields were obtained with pivalate or benzoate esters: for example, C2-benzoylated rhamnoside 52 was transformed into 51 in 71% yield. In contrast to Wendlandt’s method, Taylor’s enabled deoxy-keto sugar formation irrespective of the configuration at the vicinal carbon. While the yields were significantly higher compared to Wendlandt and co-workers’ (>52% compared to >36% overall), at least one additional step was necessary to synthesize the corresponding esters. As shown in Scheme [8], the procedure developed by Taylor and co-workers tolerates the TBS protecting group (62 and 67), as well as C6–O acylated carbohydrates (63, 68, 70). Furthermore, it is applicable to disaccharides, such as β-galactopyranosyl disaccharide 68, which was converted into the corresponding deoxy-keto sugar in 83% yield (Scheme [8]B, starting disaccharide is shown). In contrast β-pyranoside-derived esters 69 and 70 afforded products in lower yields due to decreased reactivity of the β-anomer (27% for β-anomer 71 compared to 67% for α-anomer 64 and 36% for β-anomer 72 compared to 87% for α-anomer 66, Scheme [8]C). Low yields were obtained with C3–O acylated pyranosides, which were poorly reactive under optimized conditions, as well as aryl glycosides and aryl thioglycosides, which was rationalized by competitive oxidation of electron-rich aryls.

Scheme 8 (A) Ir-catalyzed deoxy-keto sugar synthesis tolerates silyl protecting groups, as well as acylation at C6–O. (B) A variety of C2–O benzoylated methyl glycosides were converted in high yields under photocatalytic conditions. (C) Methyl β-glycosides afforded lower yields compared to α-glycosides.

Ngai and co-workers developed a mechanistically similar transformation of C2–O acylated α-bromopyranosides 73 (Scheme [9]).[40] In the presence of Pd(0), ester 73 underwent 1,2-acyloxy migration under blue light irradiation to afford intermediates with C2 radical character. These were harnessed to access 2-deoxyglycosyl esters 74 in 56–95% yield with high α- and excellent C1/C2-selectivity in most cases. By changing base and solvent, 2-deuterioglycosyl esters (in THF-d ₈ as solvent), or 2-iodo-2-deoxyglycosyl esters (from α-iodoglycosides, with Cs₂CO₃ in t-BuOH) could be generated (not shown). Mechanistic studies suggested the following pathway: photoexcitation of Pd(0) → Pd(0)* provides access to organometallic intermediates with radical character, enabling acyloxy migration. Radical clock, crossover, and substituent effect experiments supported a concerted mechanism. Reductive elimination to the 2-deoxy sugar in case of glycosyl bromides, or atom transfer to the 2-iodo-2-deoxy sugar in case of glycosyl iodides regenerates the Pd(0) catalyst. The Pd(0) source was found to be critical, and only Pd(PPh₃)₄ gave satisfactory results.

Scheme 9 C2–O Acylated glycosyl halides undergo 1,2-acyloxy migration upon treatment with Pd(PPh₃)₄ under light irradiation, to afford 2-deoxyglycosyl esters.

Scheme 10 Two-step C4-deoxygenation of a glucoside and an alloside by pyrrolidinopyridine-catalyzed chemo- and site-selective toluoylation, followed by SmI₂–HMPA-mediated reduction.

Ueda, Kawabata, and co-workers reported a two-step protocol for C4-deoxygenation of pyranoses enabled by site-selective toluoylation (Scheme [10]).[41] They had previously reported that pyrrolidinopyridine catalyst 76 chemo- and site-selectively functionalized unprotected β-glucosides at C4–OH using isobutyric anhydride in low polarity solvent.[42] [43] Glucoside 75 was C4–O acylated using toluic anhydride in CHCl₃–2,4,6-collidine (9:1), whereas alloside 79 required toluoyl chloride in the presence of pivalic acid and Hünig’s base in CHCl₃. While site-selectivities were very high, separation of the desired 77 and 80 from mono-acylated side products required HPLC purification. Subsequent SmI₂–HMPA-mediated reduction following a protocol by Lam and Markó[44] [45] afforded C4-deoxygenated glucoside 78 and alloside 81 in moderate yields due to competing deacylation.

In 2024, Chi and co-workers reported site-selective C–O bond cleavage by a conceptually similar ‘tagging-editing’ approach of unprotected sugars.[46] Their protocol complements methods for C2- and C4-deoxygenations as it allows for deoxygenation at C3 and C6. C3-Selective formation of photoredox active ester 85 from glucoside 19 was accomplished by transient protection of C6–OH and C4–OH with boronic acid 83 in the presence of pre-catalyst 82 [47] and Hantzsch ester derivative 84 (Scheme [11]A). Exposure to photocatalyst 30 under blue light irradiation resulted in C–O cleavage to afford a C3 radical, which reacted with HAT donor adamantane-1-thiol (32) to provide 86 in 85% yield over two steps. C3-Deoxygenation of both α- and β-glucosides, phenyl β-thiogalactoside, and C6–OH protected α-mannosides gave >80% yield in most cases. In the absence of boronic acid 83, selective C6–OH acylation of glucosides, galactosides, and mannosides, such as 22, was achieved, thus providing access to 6-deoxy sugars, such as 88, through C6–O acylated intermediate 87 in 58–75% yield under otherwise similar reaction conditions (Scheme [11]B). By combining two acylation steps with subsequent C–O cleavage as shown in Scheme [11]C, five 3,6-dideoxy sugars were synthesized in only three steps. Natural and medicinal products and disaccharides were also modified by ‘tagging-editing’ sequences. In addition, C3-alkylation was enabled by adding an alkene in the photoredox step under slightly modified conditions (not shown). This modular strategy provides rapid access to building blocks, as demonstrated by over 60 synthesized substrates. A selection of 3-deoxy-, 6-deoxy-, and 3,6-dideoxy sugars thus accessed are depicted in Scheme [11]D.

Scheme 11 (A) C3-Selective acylation of unprotected glycosides using a photoactive Hantzsch ester derivative to set the stage for photocatalytic C3-deoxygenation. (B) In the absence of 2,6-dimethoxyphenylboronic acid, selective C6-deoxygenation was achieved. (C) Combining two acylation steps with a photocatalytic deoxygenation step gave access to 3,6-dideoxy sugars. (D) Scope of 3-, 6-, and 3,6-deoxy sugars synthesized by tagging-editing sequences.

2.1.3

Site-Selective C–H Oxidation

l-Hexoses are less prevalent in Nature than d-hexoses. Nevertheless, they are present in several bioactive natural products and medicines, such as cytotoxic glycopeptide antibiotic bleomycin A₂, or glycoysaminoglycans heparin and heparan sulfate. Synthetic access to various l-hexoses and 6-deoxy-l-hexoses has been enabled both through de novo syntheses, as well as from feedstock carbohydrates. The latter strategies encompass conversion of d-sugars by epimerization or head-to-tail inversion, as well as transformation of l-sugars by homologation of short-chained carbohydrates, rearrangements of l-hexoses, and reduction of commercially available l-lactones.[48] In an elegant orthogonal approach, Pedersen, Bols, and co-workers succeeded in synthesizing all l-hexoses from commercially available l-fucose and l-rhamnose. Inspired by Simmons and Hartwig’s alcohol-directed C–H oxidation,[49] they employed a sequence of Ir-catalyzed dehydrogenative C4–O silylation, site-selective C6–H silylation, and Fleming–Tamao oxidation to access various methyl glycosides and thioglycosides.[50] [51] Subjecting methyl l-rhamnoside 96 to diethylsilane in the presence of catalytic [Ir(cod)OMe]₂ afforded silyl ether 97, which underwent Ir-catalyzed dehydrogenative silylation in the presence of tetramethylphenanthroline ligand 98 and H₂-acceptor norbornene. Fleming–Tamao oxidation of oxasilolane 99 was followed by acetylation to afford fully protected l-mannoside 101 in 82% over 4 steps without purification of intermediates (Scheme [12]A).[50] Similarly, protected l-fucoside was converted into fully protected l-galactoside in 67% yield (not shown). Application of the same synthetic strategy to more versatile phenyl thioglycosides required increased catalyst loading in the C–H activation step and further optimization of oxidation conditions to minimize protodesilylation.[51] Phenyl thioglycosides of all 8 l-hexoses were thus synthesized in moderate to good yields over 4 steps. For example, thioglycoside 102 was converted into l-guloside 103 in 53% over 4 steps (Scheme [12]B).

Scheme 12 (A) Methyl l-rhamnoside was converted into protected l-mannoside through a sequence of Ir-catalyzed silyl ether formation, Ir-catalyzed C–H activation, and Fleming–Tamao oxidation. Subsequent acylation facilitated product isolation. (B) The same synthetic strategy was applied to access synthetically versatile thioglycosides such as an l-guloside. Increased catalyst loading for C–H-silylation and optimization of oxidation conditions were crucial to achieve moderate to good yields for all l-thiohexosides.

2.2

De Novo Syntheses

De novo synthesis can provide an advantage over synthesis from natural feedstock for accessing both d- and l-sugars, as well as non-natural analogues. This section aims to highlight recently reported methods and sequences that can be harnessed to access several rare sugars. Lowary and co-workers commenced their synthesis of 3,6-dideoxy sugars d-abequose (113), d-paratose (114), and d-tyvelose (110) with asymmetric reduction of 2-acetylfuran (104) followed by Achmatowicz rearrangement (Scheme [13]).[52] They then followed Tang’s protocol for dynamic kinetic resolution using Birman’s tetramisole 108 to selectively form α- or β-glycoside 109 or 111 from pyranone 107.[53] β-Glycosyl ester 111 was stereospecifically glycosylated with PMBOH under Tsuji–Trost conditions, followed by Michael addition of BnOH to diastereoselectively introduce the C2 substituent in 112. Subsequent ketone reduction afforded equatorial C4–OH with moderate selectivity under all conditions tried, resulting in an inseparable mixture of diastereoisomers. Benzoylation allowed for diastereoisomer separation and afforded protected d-paratose in 85% yield, while Mitsunobu reaction inverted the C4 stereocenter in 61% yield. Global deprotection finally led to 3,6-dideoxy sugars 114 and 113. A similar sequence of steps transformed α-glycoside 109 into d-tyvelose (110). Overall, these syntheses required 9 steps starting from 2-acetylfuran (104) due to protecting group manipulations and stereocenter inversions, necessitated by moderately selective reductions, or undesired stereochemical outcome.

Scheme 13 Synthetic route to 3,6-dideoxypyranosides through a dihydropyran intermediate.

Guo, Tang, and co-workers synthesized a range of rare sugars through dynamic kinetic redox isomerization of Achmatowicz rearrangement products (Scheme [14]A).[54] Iridium catalysts were uniquely suited to provide cis-lactone 116 from lactol 115. With [Ir(cod)Cl]₂ in 1,2-dichloroethane at 50 °C, a 3:1 cis/trans ratio was obtained, reflecting the equilibrium ratio of hemiacetal 116 and thus indicating that equilibration was slower than isomerization. The addition of catalytic 2,6-dichlorobenzoic acid accelerated equilibration between the hemiacetals and led to >20:1 d.r. in CHCl₃ at room temperature. The method gave high NMR yields and consistently high d.r. for a range of hemiacetals differing in C6 substituent. Key intermediate 116 was then divergently modified towards a variety of 2,6-dideoxy sugars as well as 2,3,6-trideoxy sugars, such as 117, in 2–5 steps. The corresponding trans-diastereoisomers were synthesized from dihydropyran 118, which was obtained from 116 by sequential C4-inversion under Mitsunobu conditions and hydrolysis.

Scheme 14 (A) Ir-catalyzed redox isomerization of Achmatowicz products to access a range of rare sugars. (B) An efficient stereodivergent strategy amenable to the synthesis of all stereoisomers of 2,3,6-trideoxypyranosides starting from 2-acetylfuran was developed via sequential enantioselective reduction, Achmatowicz reaction, stereodivergent glycosylation, and catalyst-controlled tandem reduction.

Zhao, Tang, and co-workers further completed de novo syntheses of all stereoisomers of 2,3,6-trideoxypyranosides starting from 2-acetylfuran (104) (Scheme [14]B).[55] Based on reports by O’Doherty and co-workers,[56] [57] [58] a sequence of Noyori asymmetric hydrogenation and stereoselective Achmatowicz­ rearrangement furnished dihydropyran 120, which was stereodivergently glycosylated through Tsuji–Trost Pd-π-allyl intermediates to afford 121 and 122. Dihydropyrans 121 and 122 were then subjected to tandem reduction by Rh-catalyzed transfer hydrogenation to yield both possible C4-epimers, for example 123 and 124 from 121, in high yields simply by switching configuration at DPEN ligand 119. The sequence of steps was also applied to dihydropyran enantiomer 107. It was further iteratively used for de novo syntheses of 2,3,6-trideoxy di- and trisaccharides (not shown).

Rhee and co-workers synthesized stereochemically distinct 4-deoxy and 4,6-dideoxy sugars via Pd-catalyzed hydroalkoxylation of allenes.[59] For example, reaction of allene 126 with commercially available homoallylic alcohol 125 afforded acetals 128 and 130 by simply switching configuration of Trost ligand 127 (Scheme [15]). Subsequent olefin metathesis with Grubbs-I catalyst yielded cyclic acetals 129 and 131, which were converted into 4,6-dideoxyalloside 132 and 4,6-dideoxymannoside 133, respectively. More recently, Seo and Rhee used Ru catalyst 134 to convert 129 into 135 by olefin migration (Scheme [15]).[60] Analogous to observations made by Grubbs and co-workers,[61] 134 was formed in situ by thermal decomposition of 138, which was derived from Grubbs-II catalyst and ethyl vinyl ether. Cyclic acetal 135 was dihydroxylated to d-digitoxoside 136, which was further elaborated into d-olivoside 137 by a sequence of Mitsunobu reaction and acyl hydrolysis. The method was further applied to access di- and trisaccharides of 2,6-dideoxy and 2-deoxy sugars.

Scheme 15 A sequence consisting of enantioselective Pd-catalyzed allene hydroalkylation and Grubbs metathesis for the synthesis of unsaturated cyclic acetals, which were converted into 4,6-dideoxy sugars. Olefin isomerization using an in situ generated Ru catalyst further enabled access to 2,6-dideoxyglycosides.

Inspired by reports by Seo and Rhee,[62] [63] Bennett and co-workers developed a gold(I)-catalyzed cyclization of homopropargyl orthoesters 139 and 143, accessible from methyl (R)- and (S)-lactate, respectively, in 6 steps, to access 2,6-dideoxy sugars (Scheme [16]).[64] Using AuSbF₆, JackiePhos (144), as well as 2,6-di-tert-butylpyrimidine (DTBP) as acid scavenger in MeCN in the presence of 4 Å MS afforded naphthylmethyl- or benzyl-protected enones 140 and 145 in 90% and 71% yield, respectively. These were converted into l-digitoxoside 141, naphthylmethyl-protected l-olivose 142, d-boivinoside 146, and orthogonally protected d-oliose 147 in 2–3 additional steps and good yields. Naphthylmethyl-protected enone 140 was further converted into l-ristosamine and l-saccharosamine (not shown).

Li, Huang, Hong, and co-workers devised a route to all possible stereoisomers of 3,6-dideoxy sugars from TBS-protected methyl lactate by an olefin cross-metathesis/isomerization approach (Scheme [17]).[65] One-pot reduction/Grignard addition of TBS-protected l-methyl lactate 148 afforded a 5:1 mixture of anti/syn allylic alcohols 149 and 150. Subsequent cross-metathesis of alcohol 149 using 3 mol% Grubbs-II catalyst at room temperature afforded allyl alcohol 151, which was concentrated in vacuo, before subjecting it to an additional 5 mol% Grubbs-II catalyst at 40 °C to effect isomerization to silyl ether 152. The resulting E/Z isomers 152 were transformed into 3,6-dideoxy sugars l-paratose (153) and l-ascarylose (154) by a sequence of Upjohn dihydroxylation and TBS deprotection. Using minor syn-alcohol 150 or starting from TBS-protected d-methyl lactate, all seven naturally occurring 3,6-dideoxy sugars, as well as a non-natural diastereoisomer were accessible in only five steps from methyl lactate.

Scheme 16 Synthesis of various 2,6-dideoxy sugars via Au(I)-catalyzed cycloisomerization of orthoesters.

Scheme 17 Synthesis of l-paratose and l-ascarylose from TBS-protected l-methyl lactate enabled by Grubbs olefin metathesis/isomerization.

Galan, Willis, and co-workers applied a Prins cyclization strategy to access orthogonally protected 2,4- and 2,6-dideoxyglycosides via silyltetrahydropyran intermediates (Scheme [18]).[66] α-Benzyldimethylsilyl acetal 156 was reacted with secondary homoallylic alcohol 155, derived from (S)-glycidol by benzyl protection and CuI-catalyzed vinylmagnesium bromide addition, to afford silyltetrahydropyran 157. Inspired by reports by Trost and Donohoe,[67] [68] [69] 157 was subjected to two-step Fleming–Tamao oxidation and acetylation to yield 158. Alternatively, tetrahydropyran 157 was deprotected, followed by Mitsunobu inversion at C3 to provide 159. Sequential Fleming–Tamao oxidation and acetylation yielded 160 in good yield. In addition, orthogonally protected 2,6-dideoxyglycosyl ester 163 was accessed from 162 following an analogous sequence. Carbamate 162 was synthesized from penta-1,4-dien-3-ol (161) via Sharpless asymmetric epoxidation, Mitsunobu reaction, carbamoylation, and DIBAL-H-mediated epoxide opening.

Scheme 18 A sequence of Prins cyclization and Fleming–Tamao oxidation was used to access 2,4-dideoxyglycosyl esters and a 2,6-dideoxy sugar.

3

Glycosylation

Stereoselective glycosylation and oligosaccharide synthesis are long-standing challenges in organic chemistry. The presence of several similarly reactive hydroxyl groups, the stereochemical complexity and the installation of a new stereogenic center upon glycosylation conventionally require extensive use of protecting groups and optimization of reaction conditions for every glycosyl donor/acceptor couple.[70] Recent comprehensive reviews highlighted strategies for 2-deoxyglycosylations, which are particularly challenging due to the absence of a C2 directing group that is often harnessed to achieve high degrees of stereoselectivity.[71] [72] [73] Herein, we focus on catalyst-controlled glycosylations, as well as iterative one-pot glycosylation methods that were applied to rare sugars.

3.1

Catalyst-Controlled Glycosylation

While it is hard to imagine that there will be a one-for-all solution for stereoselective glycosylation, catalyst-control holds promise in broad applicability. Pedersen and co-workers investigated pyrylium salt 166 as organocatalyst in search for general nucleophilic activation under operationally simple conditions (Scheme [19]).[74] They found 166 to catalyze glycosylation of glucosyl α-trichloroacetimidates with a range of both aliphatic and aromatic nucleophiles in high to excellent yields favoring β-linked disaccharides. For galactosylation, highest yields and β-selectivities were obtained in toluene at –78 °C to room temperature. For example, α-164 afforded 1,6-β-linked disaccharide 168 in 98% yield upon coupling with methyl glucoside acceptor 165. In addition, perbenzylated galactosyl and 4,6-benzylidene-protected mannosyl α-trichloroacetimidate donors yielded 1,6-disaccharides with methyl glucoside in good to high yields. Challenging 2-deoxyglucosyl donor 170 required electron-withdrawing acetate and conformationally restrictive 4,6-benzylidene protecting groups to undergo 1,6-galactosylation with acceptor 171 and afforded a 1:3 α/β ratio of glycoside 172. Changing the catalyst to pyrylium salt 167, invertive glycosylation of glucosyl and galactosyl β-trichloroacetimidates was accomplished to obtain 1,6-α-disaccharides such as 169. Glucals did not undergo glycosylation under the optimized conditions. Based on mechanistic studies, Pedersen and co-workers propose that pyrylium catalysts 166 and 167 increase nucleophile acidity through complexation, thus simultaneously facilitating leaving group protonation and increasing nucleophilicity.

Scheme 19 Pyrylium salts were harnessed for invertive 1,6-glycosylation of glycosyl trichloroacetimidates. A challenging 2-deoxyglucosyl trichloroacetimidate underwent glycosylation with a galactoside, albeit affording the corresponding disaccharide at lower α/β ratio.

Jacobsen and co-workers extended the concept of thiourea catalyst controlled glycosylations[75] [76] [77] [78] to the regio- and stereoselective glycosylation of minimally protected sugars (Scheme [20]).[79] Under optimized conditions, thiourea 175, bearing electron-rich arene substituents, catalyzed the coupling of permethylated d-galactosyl phosphate 173 with a range of unprotected methyl glycosides, for example methyl β-l-fucoside (174). Disaccharide 176 was thus synthesized in 70% yield with high 1,2- over 1,3-selectivity and >20:1 β/α. In contrast, α-configured acceptors afforded significantly lower or even inverted 1,2- to 1,3-selectivities.

The nature of the anomeric substituent impacted selectivity to a lesser extent. Utilizing thiourea catalyst 179 and mannosyl phosphate 177, highly selective mannosylation of various acceptors was accomplished. Among them, α-galactoside 178 was C2–O mannosylated with a preference of 13:1 over C3. Mechanistic investigations indicated that selective catalysts accelerate the glycosylation step and that carbohydrate C–H/catalyst-π interactions determine 1,2- vs. 1,3-selectivity.

Scheme 20 Highly 1,2- and β-selective glycosylation of a variety of minimally protected acceptors utilizing thiourea catalysts with glycosyl phosphate donors.

Taylor and co-workers built on earlier success in the site-selective glycosylation of unprotected 1,2-diols,[26] as well as β-selective glycosylation of peracetylated 2-deoxy sugar halides with partially protected donors.[80] They utilized oxaboraanthracene-derived 183 to catalyze stereo- and site-selective coupling of in situ formed mesyl glycosides with a number of partially protected pyranosides and furanosides (Scheme [21]).[81] The addition of 1,2,2,6,6-pentamethylpiperidine (PMP) and methanesulfonic anhydride in CH₂Cl₂ at room temperature afforded anomeric mixtures of mesyl glycosides favoring α-configuration (6.3:1 up to >20:1 for pyranoses under equilibrium conditions). Subsequent addition of glycosyl acceptors and 183 (10 mol%) afforded high yields and moderate to high β-selectivities in the absence of C2 directing groups. For example, galactosyl donor 181 and glucosyl donor 182 afforded disaccharide 185 in 71% yield with 8:1 β/α selectivity and disaccharide 186 in 78% yield with 9:1 β/α selectivity, respectively, upon coupling with thiomannoside 184. ‘Armed’ benzyl, PMP- and benzylidene-protected glucose, galactose, and arabinose reacted with 2,3,4-triolglycosides exclusively at C3 with up to >19:1 β/α selectivity. The catalyzed reaction overrides substrate-inherent α-selectivity, albeit with unsatisfactory β-selectivity in a few cases. For example, glycosylation of perbenzylated 2-deoxyglucose 187 with thiomannoside 184 in the absence of catalyst yielded disaccharide 188 favoring α-configuration (5.1:1 α/β), whereas in the presence of borinic acid 183, β-configuration (1:2.3 α/β) was slightly favored. Mechanistic studies suggested that both catalyzed and uncatalyzed reactions occur by associative mechanisms, and that epimerization at the anomeric center is catalyzed by MsO^–. In the absence of catalyst, the higher reactivity of minor β-mesylate results in α-selective glycosylation under Curtin–Hammett control. The catalyst selectively accelerates the displacement of α-mesylate, thus favoring β-product to an extent that most of the α-product derives from competing uncatalyzed S_N2-type displacement. Catalyst-induced acceleration is hypothesized to derive from the bulkiness of the borinic acid, which favors 1,2-trans product. In line with observed MsO^– catalyzed epimerization of glycosyl mesylate intermediate, slow addition increased β-selectivity.

Scheme 21 Borinic acid catalyzed glycosylation led to exclusive 1,3- and predominantly β-selectivity, overriding inherent substrate selectivity in some cases.

3.2

One-Pot Iterative Oligosaccharide Synthesis in Solution

Scheme 22 One-pot iterative glycosylation by fine-tuning the reactivity of silyl protecting groups. Key to success of fluoride migration catalysis is the ability of the borane catalyst to abstract and re-deliver fluoride, thus activating both donor and acceptor.

Iterative one-pot glycosylation is an efficient approach to rapidly build up complexity from monosaccharide building blocks. The main challenge is fine-tuning of reactivities to drive selective formation of the desired product.[82] [83] Montgomery and co-workers developed elegant, so-called fluoride migration catalysis to assemble trisaccharides in one pot.[84] The reactions employ glycosyl fluoride donors and silyl ether acceptors and are catalyzed by B(C₆F₅)₃ in toluene at room temperature. Highest efficiency was achieved with anhydrous catalyst; however, the reaction also occurred with catalyst hydrate and unpurified, ACS grade CH₂Cl₂ in an open flask, thus adding to the practicability of this method. Inspiration was derived from two publications on the observation of a fluoride-rebound mechanism, where a fluoride ion is abstracted by electrophilic triarylborane, followed by redelivery in a catalytic sequence.[85] [86] This observation fueled the hypothesis that electrophilic triarylborane catalysts could activate a glycosyl donor by fluoride abstraction, followed by activation of a silyl ether group by fluoride delivery, thus activating both donor and acceptor in a turnover step. A range of diversely protected saccharides underwent glycosylation under mild conditions with exclusive selectivity for 1,2-trans products through anchimeric assistance of C2–OAc. For example, rhamnosyl fluoride 190 yielded α-disaccharide 192 upon reaction with galactoside 191, whereas glucosylation of fucosyl fluoride 193 with 194 afforded β-disaccharide 195 (Scheme [22]). As expected, stereoselectivities were reduced in the absence of a C2 directing group. The reaction proceeded rapidly for armed, perbenzylated substrates, whereas disarmed acetates required longer reaction times. Mannosyl, galactosyl, and glucosyl fluorides were employed, along with ribose- and xylose-based donors. In addition to silyl ethers, free alcohols could be used as donors, however, catalyst inhibition led to lower reaction rates. Iterative one-pot couplings were accomplished by sequential addition of glycosyl fluorides and fine-tuning of silyl ether reactivity by varying steric encumbrance. For example, mannosyl fluoride 196 was coupled with glucoside 197, followed by glucosyl β-fluoride 198 to afford trisaccharide 199. Similarly, iterative glycosylation of fluoride 200, trimethylsilyl ether 201, and mannosyl fluoride 202 yielded 203. Intermolecular glycosylation thus complements a previously published method by Montgomery and co-workers, where 1,2-cis products are obtained by intramolecular aglycone delivery (IAD) of silyl ether linked monosaccharides.[87] Combining both methods, branched and linear trisaccharides were accessible in 40–50% yields (not shown).

Scheme 23Iterative coupling of partially protected glycosides enabled by Bu₂BOTf for transient protection and thioglycoside activation, followed by nucleophile addition. Stereo- and site-selectivity are determined by the intermediate borate complex.

Chan-Park, Liu, and co-workers accomplished regio- and stereoselective glycosylation of partially protected glycosides by transient protection[88] [89] [90] with Bu₂BOTf, followed by thioglycoside activation and nucleophile addition (Scheme [23]).[91] Partially protected β-thioglucoside, β-thiomannoside, β-thiogalactoside, and β-thioalloside donors underwent reactions with C2–O, C3–O, C4–O, and C6–O unprotected glucose and galactose acceptors. For thioglycoside activation, conventional reagents (Ph₂SO/Tf₂O, NIS/TMSOTf or AgOTf/4-nitrobenzenesulfenyl chloride) were used. A broad range of protecting groups were tolerated under the reaction conditions, such as benzyl, benzoyl, benzylidene, silyl, and acetate. For example, alloside 204 underwent β-selective glucosylation with acceptor 205 in 80% yield under optimized reaction conditions. In situ protection with bulky, electron-withdrawing borate furthermore led to stereoselective glycosylations with free C2–OH (1,2-trans) due to steric effects, and with free C3–OH and C4–OH due to steric and electronic effects.[92] [93] Yields were decreased in the presence of unprotected primary hydroxy groups, and with acetate protecting groups on the donor thioglycoside. Successful selective coupling of two thioglycosides by transient boron protection set the stage for one-pot trisaccharide synthesis from thiogalactoside 207, glucosamine derivative 208, and thiomannoside 209 to afford trisaccharide 210 as single product.

4

Application in Biochemical Research

Access to rare sugars, oligosaccharides, and derivatives in synthetically useful yields are essential to elucidate the plethora of functions that they play in Nature. The relative abundance of 6-deoxy sugars in bacteria compared to mammals, along with their key roles in virulence or viability, renders machineries related to their selective incorporation into glycans interesting antibiotic targets. In 2023, Lupoli and co-workers investigated the enzyme WbbL, from Escherichia coli, that catalyzes transfer of activated l-rhamnose donor 211 to a lipid pyrophosphate acetylglucosamine acceptor (212) in the biosynthesis of O-antigen polysaccharides (Scheme [24]).[94]

Scheme 24 WbbL catalyzes glycosylation of an activated l-rhamnose donor with lipid-bound N-acetylglucosamine, thus establishing the O-antigen motif in lipopolysaccharides. Binding affinities of various rare sugar substrates were evaluated with a soluble enzyme homologue.

These constitute a part of lipopolysaccharides and are required for virulence. In addition to membrane associated WbbL, they expressed and studied soluble, putative similar protein RfbF from Thermus thermophilus that was identified through sequence similarity searches. The latter allowed isothermal titration calorimetry studies to assess binding affinity of both donors and acceptors to the enzyme. Synthetic access to a range of nucleoside diphosphate rare sugars such as dTDP-l-6-deoxytalose (214), dTDP-l-fucose (215), and dTDP-l-mannose (216)[95] [96] enabled structure–affinity studies with soluble RbF, as well as investigation of WbbL substrate scope in enzyme activity studies. Inspired by the observation that l-rhamnose 1-phosphate (217) was a weak binder to soluble RbF, Lupoli and co-workers then evaluated the capacity of known 6-deoxyimino sugar 218 [97] to inhibit enzyme function and thus impact virulence. Indeed, E. coli grown in the presence of 218 featured decreased levels of O-antigen, suggesting that imino sugar 218 could be utilized to impair host infection.

5

Conclusion

Rare sugars are present on many bioactive bacterial and fungal natural products, and play, among others, a role in host–microbiome interaction as part of microbial glycans. Since bacteria and fungi utilize rare sugars that mammals do not, the corresponding metabolic machinery could present a valuable drug target. In order to study their function in Nature, we need to be able to access rare sugars and rare sugar glycosides. Recent years have witnessed the development of a plethora of methods to synthesize rare sugars both from renewable feedstock and through de novo synthesis. In addition to dedicated methods for 2-deoxyglycosylation, several recently developed glycosylation methods have featured rare sugars in their substrate scopes, thus paving the way to efficient rare sugar oligosaccharide synthesis. Site-selective modifications of minimally protected or unprotected carbohydrates have furthermore led to a better understanding of inherent reactivities, which can spur future progress in more efficient, ‘greener’ carbohydrate chemistry.

Conflict of Interest

The authors declare no conflict of interest.

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Publication History

Received: 16 April 2024

Accepted after revision: 02 September 2024

Article published online:
08 October 2024