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DOI: 10.1055/a-2595-1603
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Emerging Trends in Organic Chemistry: A Focus on India

Organocatalyzed Glycosylation for the Stereoselective Synthesis of O/C-Glycosides

Shashiprabha Dubey
a   Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P.O. Box 173, Lucknow, 226 031, India
b   Academy of scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
,
Pintu Kumar Mandal  ∗
a   Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P.O. Box 173, Lucknow, 226 031, India
b   Academy of scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
› Author Affiliations

The authors gratefully acknowledge financial support by the Science and Engineering Research Board (SERB), DST, Govt. of India (Grant No. CRG/2022/003936). S. D. thanks to the Science and Engineering Research Board (SERB), DST, Govt. of India for the research fellowships.
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Abstract

Oligosaccharides play a pivotal role in biological systems and support immune function due to their unique sugar structures. For a better understanding of the biochemical processes, it is essential to need pure and structurally well-defined oligosaccharides. Even though there has been significant progress in the synthesis of oligosaccharides, the efficient and stereoselective synthesis of glycosidic bonds through chemical glycosylation remains a challenging task for chemists. Organocatalysis is an exciting field in chemistry that utilizes small organic molecules as catalysts to accelerate chemical reactions under substoichiometric conditions. These catalysts offer advantages like environmentally friendly conditions, high selectivity, and efficiency for synthesizing complex molecules. In the last few years, organocatalyzed glycosylation has significantly progressed in carbohydrate chemistry particular to the stereoselective synthesis of oligosaccharides. This personal account describes the organocatalytic glycosylation methodologies developed by our group for activation of trichloroacetimidate donor and glycal substrates resulting in the specific formation of α- or β-glycosidic bonds.

1 Introduction

2 Trichloroacetimidate Donor

3 Glycals

4 Conclusion


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Key words

organocatalysis - glycosylation - catalyst - stereoselectivity - oligosaccharides

Biographical Sketches

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Pintu Kumar Mandal obtained his PhD in 2009 at the Jadavpur University, Kolkata. He pursued his postdoctoral research in the laboratory of Professor W. Bruce Turnbull at the University of Leeds, Leeds. He was selected as a Newton International Fellow (RSC, 2009–2011) at the University of Leeds, UK. Then, he moved to the Georgia State University, Atlanta, USA to work with Professor Peng George Wang. He returned back to India in May, 2013 and held a Scientist position, currently holds the position of Principal Scientist at CSIR-CDRI, Lucknow. His research interests include the efficient chemical synthesis of biologically relevant O-, C-glycosides and catalytic stereoselective glycosylation and functionalization.

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Shashiprabha Dubey received her MSc from the University of Allahabad in 2020. She is currently working as a Project-JRF under the supervision of Dr. Pintu Kumar Mandal. Her research focused on organocatalyzed stereoselective glycosylation.

1

Introduction

Organocatalysis has been well established and documented[1] for the challenging transformations in various branches of synthetic chemistry with an emphasis on the advancement of a new approach to proficiently make manifold chiral molecules with excellent regio-, chemo-, and enantioselective control. Because of their effectiveness, operational simplicity, selectivity, readily available, low toxicity, and environmentally favorable qualities organocatalysts find extensive use in various fields. In the pharmaceutical industry, they are essential for asymmetric synthesis and drug discovery, making it easier to create enantiomerically pure compounds.[2] In agriculture, organocatalysts aid in the environmentally friendly synthesis of agrochemicals and green insecticides. They are also crucial for synthesizing biodegradable polymers and nanomaterials in material science. Organocatalysts are crucial to green chemistry since they facilitate sustainable and solvent-free processes.[3]

In carbohydrate chemistry, glycosylation is the process by which a carbohydrate is attached through its anomeric carbon to aglycones via glycosidic linkages. Glycosidic bonds can either be O-linked, C-linked, N-linked, or S-linked. On the basis of linkages, glycosyl compounds are classified into O-glycosides, C-glycosides, N-glycosides (known as glycosylamine), and S-glycosides (known as thioglycoside).

Glycosides play numerous vital roles in living organisms, including antioxidant,[4] anti-inflammatory,[4] antihypertensive,[5] and antidiabetic activities.[6] The growing interest in carbohydrate-based drug discovery and biomedical research and a deeper understanding of glycan-mediated biological processes have created a significant demand for structurally defined glycans. On account of their eminence, the diversification of glycosyl compounds has drawn significant attention in the realm of carbohydrate chemistry. Despite this, there has been great advancement in the chemical synthesis of complex oligosaccharides, with numerous elegant syntheses documented in recent years.[7] However, to date, no universal glycosylation protocol exists that reliably yields high stereoselectivity levels.

In general, traditional reaction conditions are often harsh, which results in reduced chemo-, stereo-, and sometimes also regiocontrol, particularly as chemical complexity in the substrates increases. Additionally, to achieve high levels of reactivity and selectivity the promoter/activator, solvent, reaction temperature, and reagent concentration must be optimized.

Furthermore, the stereoselective synthesis of oligosaccharides has also been accomplished with the use of transition-metal catalysis, which has proven to be more effective than conventional glycosylations. However, they have several drawbacks, such as the high cost of catalyst synthesis and the possibility of metal toxicity to the end products.

Moreover, organocatalyzed reactions offer a better operational simplicity and mild route to target molecules without the need of expensive transition metals or harsh reagents as catalysts, avoiding the potential toxicity and environmental problems associated with conventional methods. Organocatalysis has emerged as the most thriving field in the recent 20 years providing an attractive method to synthesize complex structures including oligosaccharides.[8] Although it has a long history, scientists have recently become interested in applying small organic molecules as chiral catalysts in carbohydrate chemistry for stereoselective glycosylation reactions.[9] Throughout the past few decades, several noteworthy studies have been conducted in this field. For example, Pápai et al.,[10] Eric N. Jacobsen,[11] and E. M. McGarrigle[12] published an intriguing report that focused on Schreiner’s thiourea as a potential organocatalyst for a highly stereoselective synthesis of glycoside. The organocatalyst Schreiner's thiourea, formerly known as N,N′-bis[3,5-bis(trifluoromethyl)phenyl]thiourea introduced by Wittkopp and Schreiner[13] possesses privileged catalytic properties and is well-known for its ability to improve stereoselectivity in various chemical reactions, most notably glycosylation. The catalytic activity of thiourea compounds is generally associated with the ability to form strong double hydrogen bonds with substrates, which can favorably preorganize and activate the reacting partners.[14] It can also act as Brønsted bases and Brønsted acids to promote organic transformations.[15] It can activate substrates and steer the course of reactions towards specific stereoisomers by forming strong hydrogen bonds due to its structural characteristics, which include the presence of electron-withdrawing trifluoromethyl groups and rigid structure.

Further, Schmidt et al.[16] and Galan et al.[17] have found synergistic catalysis for the synthesis of O-glycosides. Following an aryl thiourea-catalyzed reaction, Toshima et al.[18] demonstrated stereocontrolled photoinduced glycosylation of α-glycosyl trichloroacetimidates. Soon after, Galan,[19] Takao,[20] and their co-workers published a special report on the bifunctional catalyst based on hydrogen-bonding-assisted catalysis for high stereoselective facile glycosylation of 2-nitro-glycal setting a new standard in this area. The Loh group[21] then reported on strain-release stereoselective and stereospecific furano- and pyranosylation using a multicatalytic system with ultralow thiourea.

Inspired by this theme, our group has also enlisted various organocatalytic glycosylation methods for synthesizing O-/C-/N-glycosides with high control of regio- and stereoselectivity that have broad pharmaceutical importance. Although the Banik group[22] previously published a review on this topic in 2022, covering the developments up to 2021, a personal account remains valuable for insight into our group’s work. Our group has also contributed various methodologies to the field of organocatalyzed stereoselective glycosylation (Scheme [1]). Building on our ongoing interest in organocatalyzed glycosylation strategies, we present here a personal account focusing on the organocatalyzed direct glycosylation reaction of trichloroacetimidate donor or various glycals with nucleophiles to provide a stereoselective synthesis of O-/C-/N-glycosides.

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Scheme 1 A schematic representation of the organocatalytic glycosylation of trichloroacetimidate donor A and glycal B by our group

# 2

Trichloroacetimidate Donor

Trichloroacetimidates are versatile glycosyl donors and have played crucial roles in numerous ground-breaking syntheses of biologically relevant oligosaccharides. Because they are reactive and easily prepared from the corresponding lactol precursors with trichloroacetonitrile, they can be quickly activated with a catalytic amount of Lewis acid.

‘Cooperative catalysis’ which involves combining co-catalysts with organocatalysts is a fascinating area that improves catalytic activity and selectivity. Various reports have exhibited that the Brønsted acid and a hydrogen-bond donor, such as thiourea, can be combined to enhance the catalytic activity of the acid and achieve higher yields, reaction rates, and occasionally enantiocontrol.[23] In this regard, Schmidt and co-workers[24] discovered that Schreiner’s thiourea and an achiral Brønsted acid [bis(4-nitrophenyl)phosphate] might work together to catalyze the glycosylation of suitably protected trichloroacetimidate glycosyl donors. Similarly, we developed a highly β-stereoselective glycosylation method for the production of O-glycosides through the activation of glycosyl trichloroacetimidate donor using an environmentally benign N-benzoylglycine/thiourea cooperative catalyst with excellent yield at room temperature (Scheme [2]).[25a] This method has many advantages, including the good binding ability of environmentally sustainable N-benzoylglycine amino acid derivative with the soft Lewis basic moiety of the thiourea, which enriches the hydrogen-bonding capacity of the catalyst allowing the activation of trichloroacetimidate donor.

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Scheme 2 Schreiner’s thiourea/N-benzoylglycine-catalyzed O-glycosylation

The cooperative behavior of N-benzoylglycine with Schreiner’s thiourea as a co-catalyst has a significant impact on the stereoselectivity and reaction rate. The N-benzoylglycine has a pK a value of around 3.6, which further lowers the acidic character of the thiourea catalyst. It was anticipated that in the presence of thiourea as a co-catalyst, the N-benzoylglycine would function cooperatively and have a significant impact on reactivity and stereoselectivity in the glycosylation process.

Using the perbenzylated galactosyl trichloroacetimidate donor 2, various acceptors such as aliphatic, aromatic, and sugar alcohols efficiently form high β-selective O-glycosides in satisfactory yields (Scheme [2]).

It is noteworthy that the stereoselectivity of the reaction to form the corresponding glycosides decreases with increasing steric hindrance in the aromatic acceptor, due to decreasing nucleophilicity of the acceptor hydroxyl group. Similarly, the α-anomer was detectable and the reaction rate and significant preference for β-product production reduced as the alcohols changed from primary to secondary. This approach can also be applied for 1,2:3,4-di-O-isopropylidene-d-galactose as sugar acceptor, furnishing the corresponding β-selective disaccharide 3i as a major product.

Next, the substrate scope of the glycosyl donor was examined, and we observed a variety of sugars with various protecting groups engaged successfully leading to the desired glycoside product in good yields with high β-selectivity. After exploring the substrate scope our focus was shifted toward the mechanism of the reaction. For this, we carried out some additional NMR studies which demonstrate that there are increased shifts of the aryl protons of thiourea due to hydrogen-bond-mediated interaction between the catalyst and co-catalyst involving the shifts of the –NH and –OH signals and the shifts of the proton signals of bis(trifluoromethyl)phenylthiourea residues.

Next, we wanted to check whether the similar methodology was applicable to synthesizing β-stereoselective l-rhamnopyranoside with rhamnosyl trichloroacetimidate donor. The distant picololyl groups integrated into the glycosyl donor are essential in determining the predominance of β-stereoselectivity because of their direct hydrogen-bond-assisted aglycone delivery. Encouraged by the above studies, we next sought to explore the application of the synergistic catalyst system consisting of N-benzoylglycine/thiourea promoter system for β-stereoselective l-rhamnopyranosylations using rhamnosyl trichloroacetimidate (Scheme [3]).[25b] It was found that β-selectivity was enhanced by employing a highly reactive 2-O-picolyl-substituted glycosyl trichloroacetimidate donor rather than the perbenzylated α-l-rhamnopyranosyl trichloroacetimidate. Subsequently, the synthetic utility of a cooperative catalytic system was explored by evaluating a series of l-rhamnosyl trichloroacetimidate donor bearing 2-pyridinecarbonyl (Pico) groups at the C2 and C3 positions. Different acceptors including aliphatic, aromatic, and secondary alcohols along with glycosyl alcohols were used and afforded the corresponding product in excellent yield with varying degree of anomeric selectivity. Moreover, excellent yields of glycoside products with good β-stereoselectivity were obtained with less sterically hindered primary and secondary alcohols. Interestingly, alcohol such as cyclopropylmethanol and propan-2-ol produced excellent β-stereoselectivity rhamnoside in 82% and 77% yields, respectively.

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Scheme 3 N-Benzoylglycine/thiourea cooperative catalyzed stereoselective synthesis of β-l-rhamnopyranosides

However, all the above reported work used a co-catalyst along with catalyst to activate glycosyl imidate donors. Varga, Pápai, and co-workers elucidated the computational studies that Brønsted acid based activation mode of thiourea offers a direct and more convenient approach to catalyze the glycosylation reaction. Further, the detailed experimental studies were reported by McGarrigle and co-workers using thiouracil as Brønsted acid. Inspired by this concept, very recently (2024), we reported thiouracil-catalyzed α-selective O-glycosylations employing easily accessible glycosyl trichloroacetimidate donors 2 without the requirement of any co-catalyst or additive (Scheme [4]).[25c] Delightfully, we observed that a good range of acceptors including saccharides, amino acids, and different primary alcohols including 1-adamantanemethanol, piperonyl alcohol, 2-adamantanol, 1-adamantanol, and N-(tert-butoxycarbonyl)-d-serine methyl ester afforded moderate to excellent yields of the desired products with great α-selectivity. Notably, the l-menthol acceptor (73% α:β = 10:1) gave a lower yield, and both acid-sensitive isopropylidene-protected glycosyl acceptor and thioglycoside acceptors were well accepted. A variety of imidate donors derived from galactose, mannose, rhamnose, 6-O-acetyl-2,3,4-tri-O-benzyl-α-d-galactopyranose, and 2,3,4-tri-O-benzyl-6-O-(tert-butyldiphenylsilyl)-α-d-galactopyranose containing a bulky TBDPS protecting group at the 6-position were merged with various glycosyl acceptors in good efficiency to furnish the desired glycosides in predominantly α-stereoselectivity.

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Scheme 4 Thiouracil-catalyzed α-selective O-glycosylations with glycosyl trichloroacetimidate donors

We further tried to investigate this approach for the one-pot synthesis of trisaccharide after discovering that thioglycosides are inert under the current organocatalytic conditions (Scheme [5]). Initially, the glucose α-imidate donor 2a was reacted with a thioglycoside acceptor 7 under the standard conditions to afford the coupled disaccharide as an intermediate. Thereafter, the glycosyl acceptor 8 was added to the same pot to react with the disaccharide intermediate in the presence of NIS and catalytic amount of TMSOTf, providing the trisaccharide 9 with 57% yield.

Based on NMR investigations, we suggest that the catalyst first takes up the H-bond from the alcohol substrate and forms a catalyst-acceptor complex A (Scheme [5]). It is this catalyst–alcohol complex (RO–Cat–H) A that interacts with the trichloroacetimidate 2a and undergoes proton transfer, leading to the formation of oxocarbenium ion intermediate B. The anomeric effect, chairlike transition state, and steric hindrance would facilitate the acceptor to α-face attack of the oxocarbenium ion intermediate, resulting in the desired α-glycosides 6.

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Scheme 5 One-pot synthesis of trisaccharide and plausible mechanism

Aryl-C-glycosides are distinct structural motifs that represent a class of saccharides or glycoconjugates that are metabolically stable and widely found in pharmaceuticals and biologically relevant natural products. The conjugation of five-membered nitrogen heterocycles, such as indoles, to the anomeric carbon of sugars, directly connected through a C–C bond, produces indole-C-glycosides, a significant heteroaryl subclass of C-glycoside. In this regard, Chen and co-workers[26] reported the formation of indole C-glycosides via ortho-directed C–H glycosylation promoted by palladium catalyst using glycosyl chloride as a donor. Therefore, it was very desirable to investigate direct and sufficient stereoselective methods for 3-indolyl-C-glycosides. Keeping this encumbrance in mind, we explored the synthesis of 3-indolyl-C-glycosides 10 employing catalytic amounts of tris(pentafluorophenyl)borane B(C6F5)3 or BCF catalyzed with the utility of glycosyl imidate donors 2 (Scheme [6]). [25d] When glycosyl donor and glycosyl acceptor reacted in a 1.2:1 molar ratio with 10 mol% of B(C6F5)3 at –10° C, the desired C-glycoside was obtained in excellent yield within 15 min with exclusively β-selectivity. Indoles having electron-donating substituents (such as methyl and methoxy) as well as an electron-withdrawing group (CO2Me) at the 5-position and 2-position of the indole ring were well assimilated to effect the C3-glycosylation in a highly facile fashion. Further, we also extended the protocol to include a variety of glycosyl donors bearing protecting groups such as peracetyl, perbenzyl, disaccharides glycosyl, and l-arabinopyranose α-imidate donors. In general, all the reactions proceeded smoothly to provide the desired products with good yield and β-stereoselectivity. On the other hand, the peracetylated rhamnosyl imidate produced 74% α-selective glycoside. Additionally, a 77% yield of the α-selective product was obtained from the reaction of substituted indoles with picoloyl protected rhamnosyl trichloroacetimidate (Scheme [6]). The isopropylidene-protected mannofuranosyl imidate was subjected to establish reaction conditions with substituted indole to give their corresponding C-glycosides in 68% yield with moderate selectivity (α:β = 1:4).

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Scheme 6 Tris(pentafluorophenyl)borane-catalyzed stereoselective C-glycosylation of indoles with glycosyl trichloroacetimidates

Next, we proposed a plausible mechanism (Scheme [6]) based on control experiments and some previous literature reports. We postulated that firstly there is the formation of acceptor–activator adduct B via interaction of indole A in the presence of BCF, which further promotes the perbenzylated α-glucosyl imidate which leads to an acid–base type reaction with BCF adduct and furnishes β-selective glycosides 10.


# 3

Glycals

Glycals are a class of 1,2-unsaturated sugar derivatives that serve as useful starting materials for diversity-oriented synthesis (DOS) and useful building blocks in organic synthesis. Glycals are chiral synthons that are of great interest in glycobiology and carbohydrate chemistry due to their potential applications in glycosylation processes. Glycals are most commonly used as starting materials in the synthesis of 2-deoxy glycosides, as they provide a readily accessible platform to introduce the necessary modifications at the C-2 position to create the ‘deoxy’ feature of the sugar molecule.

2-Deoxyglycosides are a significant class of carbohydrates found in a variety of bioactive compounds,[27] including landomycin A, digitoxin, and jadomycin B. Additionally, 2-deoxy-d-glucose (2-DG) and its derivatives have also been considered as a potential polypharmacological agent for COVID-19 treatment.[28] Catalyzing the direct addition of an alcohol to a glycal is the most atom-efficient route to 2-deoxyglycosides. Over the past few years, numerous chemists have made exceptional contributions to the synthesis of 2-deoxysugar using various organocatalysts.[29] The most remarkable study was reported by Galan and McGarrigle et al.[29a] by exploring the involvement of Schreiner’s thiourea catalysis and the combination of thiourea with a proper enantiomer of a strong chiral Brønsted acid. Inspired by the aforementioned report, in 2023, our group reported that l-prolinethioamide catalyzes direct stereoselective glycosylation of glycal donors 11 with alcohols to access 2-deoxyglycosides 12 with high α-selective under mild reaction conditions (Scheme [7]).[30a] l-Prolinethioamide is an efficient organocatalyzed readily available, has high efficiency, and operates under mild reaction conditions.

From the screening of various l-proline-derived catalysts, it was discovered that the thioamides produced the highest yield with full stereoselective glycosylation. As an organocatalyst, prolinethioamide derivatives have a significant impact on the yield and stereoselectivity of the glycosylation reaction. Since prolinethioamide derivatives have a greater capacity to delocalize the negative charge of the C=S bond as the thioamide group would establish a stronger hydrogen bond with the acceptor than the amide group thus efficiently facilitate the glycosylation reaction.

Notably, none of the reactions showed the presence of a 2,3-unsaturated Ferrier product. Excellent axial selectivities were observed for various glycal donors, such as glucal, galactal, and rhamnal, with the use of suitable protecting groups, such as the benzyl, bulky silyl ethers, as well as derivatives with a cyclic protecting group like 3,4-O siloxane significantly improved the stereoselectivity (from 24:1.8 to α only). Unfortunately, disarming the donor with the acetate protecting group only produced the rearranged product instead of the desired product. This is probably because the reactivity of the donor may be diminished by the presence of a deactivating group, such as at C-3, which is close to the reactive double bond.

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Scheme 7 l-Prolinethioamide-catalyzed α-stereoselective synthesis of 2-deoxy glycosides

Interestingly, this method worked well for a variety of alcohol acceptors, carbamate-protected serine amino acid, and phenol of tyrosine amino acid yielding the corresponding α-2-deoxyglycosides.

Moreover, the utility of this method was demonstrated by the synthesis of trehalose-type 1,1′-linked sugar 15 and 16 (Scheme [8]). After exploration of the substrate scope, we carried out a few control experiments and we proposed that the catalyst becomes a stronger acid when its sulfur atom takes up an H-bond from the alcohol acceptor (Scheme [8]). Following interaction with the glycal this H-bonded catalyst–alcohol complex A transfers protons. Second, the produced anion encourages the deprotonation of alcohol to create an activated acceptor (alkoxide RO–). The reactive π-complex is then protonated to create a short-lived pseudo-chair oxocarbenium ion C, which successfully withstands the attack of activated acceptor (alkoxide RO–) to provide the required α-2-deoxyglycoside 12. The α-stereoselectivity can be further understood by considering that the alcohol complex may preferentially coordinate from the lower face and the C–O bond generated before the ion pair has a chance to reorganize.

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Scheme 8 Synthesis of trehalose-type 1,1′-linked sugars and plausible mechanism

Further, we explore an alternative organocatalyst such as monothiophthalimide which is cheap and effective for stereoselective glycosylation. We report a mild organocatalytic method for the direct synthesis of 2-deoxy O/N-glycosides 17 employing monothiophthalimide using glycal donors 11 with α-selectivity (Scheme [9]).[30b] This straightforward procedure exhibits good α-stereoselectivity, a wide range of substrates, high yields, and outstanding tolerance to glycosyl acceptors. A broad range of substrates have been investigated for the potential of monothiophthalimide organocatalyst, which exhibits high tolerance to functional groups and enables the production of biologically significant glycosyl sulfonamides. The interaction between the catalyst glucal donor and acceptor isopropanol was finally seen through controlled experiment research in order to comprehend the mechanistic route. It was discovered that the peaks of the –OH proton interacts with the isopropanol in the presence of monothiophthalimide whereby the monothiophthalimide engages via Brønsted acid/base catalysis like mechanism thus showing the acceptor–activator adduct A forms. On the basis of controlled experiments and some earlier literature reports, a suitable mechanism was proposed as depicted in (Scheme [9]). First, a catalyst–alcohol complex A was formed as a result of the catalyst and alcohol interacting through an H-bond. Additionally, this complex was coordinated with the galactal double bond through the sterically favorable α-face. The galactal double bond further gets polarized, which promotes proton transfer and results in the creation of the short-lived intermediate oxocarbenium and alkoxide (RO–) ions. Ultimately, the desired product 17 is the result of the reaction between the oxocarbenium and alkoxide (RO–) ions.

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Scheme 9 Monothiophthalimide-catalyzed direct α-selective glycosylation of glycal donors

Among various carbohydrate-based synthetic building blocks, glycals have been considered the most versatile chiral synthon. The presence of the 2,3-olefinic moiety in pyran rings, which can be further functionalized into different carbohydrate derivatives and valuable chiral compounds through a variety of complexity-generating processes, makes 2,3-unsaturated C-glycosides particularly appealing. Despite the progress made in the area of high-value 2,3-unsaturated C-glycosides, there are still few studies on its synthesis employing an organocatalyzed system. Inspiring from this, we successfully established an effective and highly stereoselective α-C-glycosylation strategy of glycals to access 2,3-unsaturated allyl-/alkynyl glycosides under mild reaction conditions by employing a catalytic amount of tris(pentafluorophenyl)borane B(C6F5)3 (Scheme [10]).[30c] A diverse spectrum of glycal donors bearing commonly employed protecting groups such as acetyl, methyl, ethyl, benzoyl, benzyl, and allyl served as effective substrates which coupled with allyltrimethylsilane and trimethylsilyl phenylacetylene to achieve the corresponding 2,3-unsaturated allyl- and alkynyl-C-glycosides with good to excellent yields in excellent α-selectivity under the optimized conditions. The reaction demonstrated broad applicability with various allyl/alkynyl nucleophiles, affording the corresponding allyl and alkynyl glycosides in good yields and excellent α-selectivity.

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Scheme 10 B(C6F5)3-catalyzed stereoselective synthesis of 2,3-unsaturated C-glycosides

To further demonstrate the utility of this method, we extended the developed methodology to disaccharide such as maltal, which would result in a 75% yield with α-selectivity up to α:β > 10:1. Following that, we applied the optimized procedure to deoxysugar 3,4-di-O-acetyl-l-rhamnal, and the reaction produced the required C-glycoside in an 88% yield with outstanding stereoselectivity (α > 99).

Based on the above results and some earlier literature reports, a suitable mechanism was proposed (Scheme [11]). At the outset, BCF efficiently processes allylic rearrangement, which may function as a Lewis acid to act on deactivated glycals and produce an oxocarbenium ion A. The resulting 2,3-unsaturated C-glycosides with exclusive α-selectivity are then produced by the stereoselective attack of active nucleophiles such as allyltrimethylsilane or trimethylsilylacetylene at C-1 from the α-phase. Due to a favorable anomeric effect and steric effects, the stereochemical results of the products clearly favored an α-face nucleophilic strategy.

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Scheme 11 Proposed mechanism of designed protocol

# 4

Conclusion

It is obvious that advancements in organocatalysis glycosylation have significantly broadened carbohydrate chemistry and in particular the more efficient access to stereoselective diverse complex oligosaccharides. To conclude, we have outlined the various organocatalysis glycosylation strategies to access the stereoselective α- or β-glycosides that our group has previously developed. All of these developed strategies exhibit a wide substrate scope with respect to various glycosyl donors and acceptors, including broad functional group tolerance, and synthetic applicability. In addition, 2-thiouracil and l-prolinethioamide organocatalysis were reported for the first time that activate the glycosyl imidate donor as well as glycal, respectively, without the requirement of any co-catalyst or additive.

Despite the many advances in organocatalysis, the field is still in its infancy, and organocatalysis has enormous potential to be exploited further in the field of stereoselective chemical glycosylation. However, until now, no organocatalysis glycosylation protocol exists that provides consistently high levels of stereoselectivity of different donors. Hence, there is still a need for the development of more effective organocatalyst protocols for glycosylation.

Research on organocatalysis for asymmetric synthesis have demonstrated that these catalysts may be adjusted to provide the best control and reactivity while preserving a wide range of substrates. In order to meet the specific and demanding needs of the glycosylation reaction with high control over chemo-, regio-, and stereoselectivity, it will be necessary to further adapt small organocatalysts. Although a universal glycosylation catalyst may not be achievable, we should be able to create a set of catalysts that will accomplish all required glycosylations. Therefore, many challenges and opportunities remain in this field. We hope that this account will garner significant interest and help in expanding research on this topic.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgement

All the authors are gratefully acknowledged for their invaluable contributions. The authors also acknowledge CSIR-CDRI, Government of India, for infrastructural support. CDRI communication no. 10976.


Corresponding Author

Pintu Kumar Mandal
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension
Sitapur Road, P.O. Box 173, Lucknow, 226 031
India   

Publication History

Received: 18 March 2025

Accepted after revision: 25 April 2025

Accepted Manuscript online:
25 April 2025

Article published online:
16 June 2025

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Scheme 1 A schematic representation of the organocatalytic glycosylation of trichloroacetimidate donor A and glycal B by our group
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Scheme 2 Schreiner’s thiourea/N-benzoylglycine-catalyzed O-glycosylation
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Scheme 3 N-Benzoylglycine/thiourea cooperative catalyzed stereoselective synthesis of β-l-rhamnopyranosides
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Scheme 4 Thiouracil-catalyzed α-selective O-glycosylations with glycosyl trichloroacetimidate donors
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Scheme 5 One-pot synthesis of trisaccharide and plausible mechanism
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Scheme 6 Tris(pentafluorophenyl)borane-catalyzed stereoselective C-glycosylation of indoles with glycosyl trichloroacetimidates
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Scheme 7 l-Prolinethioamide-catalyzed α-stereoselective synthesis of 2-deoxy glycosides
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Scheme 8 Synthesis of trehalose-type 1,1′-linked sugars and plausible mechanism
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Scheme 9 Monothiophthalimide-catalyzed direct α-selective glycosylation of glycal donors
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Scheme 10 B(C6F5)3-catalyzed stereoselective synthesis of 2,3-unsaturated C-glycosides
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Scheme 11 Proposed mechanism of designed protocol