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Synthesis 2024; 56(06): 890-905
DOI: 10.1055/a-2066-1659
review
Emerging Trends in Glycoscience

Recent Advances in the Synthesis and Application of C-2-Formyl Glycals

Aditi Arora‡
a   Bioorganic Laboratory, University of Delhi, 110021 Delhi, India
,
Sumit Kumar‡
a   Bioorganic Laboratory, University of Delhi, 110021 Delhi, India
b   Visiting Research Scholar, Department of Chemistry and Environmental Science, Medgar Evers College, The City University of New York, Brooklyn, NY 11225, USA
,
Vinod Khatri
c   T. D. L. Govt. College for Women, Murthal-131027, Haryana, India
,
Ashok K. Prasad
a   Bioorganic Laboratory, University of Delhi, 110021 Delhi, India
,
Rajni Johar Chhatwal∗
d   Maitreyi College, Department of Chemistry, University of Delhi, 110021 Delhi, India
,
Sandeep Kumar  ∗
a   Bioorganic Laboratory, University of Delhi, 110021 Delhi, India
e   Acharya Narendra Dev College, Department of Chemistry, University of Delhi, 110019 Delhi, India
› Author Affiliations

We are appreciative to the Institute of Eminence at the University of Delhi for helping to strengthen research and development through financial support. The Council of Scientific and Industrial Research (CSIR), New Delhi, India, has awarded Sumit Kumar and Aditi Arora a Junior Research Fellowship (JRF) and they are grateful to CSIR.
› Further Information
 
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Abstract

C-2-Formyl glycals have sustained interest in carbohydrate chemistry as they afford valuable chiral building blocks for many biological-, pharmaceutical-, and industrial-based important molecules. Basically, C-2-formyl glycals are a class of carbohydrates incorporating an α,β-unsaturated aldehyde. Therefore in many organic reactions, the C-2-formyl glycals can serve as an α,β-unsaturated aldehyde core. In this review, we have compiled a literature survey covering the period 2013–2022, on the synthesis of C-2-formyl glycals and further discuss their importance for the synthesis of many medicinal, supramolecular, biological, organic, and material chemistry based molecules.

1 Introduction

2 Synthesis of C-2-Formyl Glycals

2.1 Vilsmeier–Haack Formylation

2.2 By Consecutive Cyclization

2.3 XtalFluor‑E Based Synthesis

3 Applications of C-2-Formyl Glycals

3.1 C-2-Formyl Glycals as a Synthons

3.2 Anticancer

3.3 Anti-inflammatory

3.4 Antimicrobial

3.5 Glycosidase Inhibitors

3.6 Miscellaneous

4 Conclusion and Future Aspects


#

Key words

C-2-formyl glycals - α,β-unsaturated aldehyde - carbohydrate - Vilsmeier–Haack reaction - biological activity - glycosides

Biographical Sketches

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Aditi Arora obtained her Honours Degree from Miranda House, University of Delhi in 2018. She completed her Master’s in Organic Chemistry from Department of Chemistry, University of Delhi in 2020. She was a Gold Medalist during her Master’s. At present, she is pursuing Ph.D. from Department of Chemistry, University of Delhi. Her research interests include design and synthesis of carbohydrate and coumarin modified molecules.

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Sumit Kumar obtained his Master’s Degree in Organic Chemistry from Department of Chemistry, University of Delhi in 2020 and Honours Degree from Kirori mal College, University of Delhi in 2018. He is pursuing Ph.D. from Department of Chemistry, University of Delhi. His research interests include design and synthesis of sugar-modified heterocyclic motifs of therapeutic importance. He is currently a visiting Research Scholar at Medgar Evers College, City University of New York (CUNY) in the Chemistry and Environmental Science Department.

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Dr. Vinod Khatri studied Chemistry at Kurukshetra University, Kurukshetra Haryana and received his Ph.D. from the University of Delhi under the supervision of Professor Ashok K. Prasad. After his Ph.D. in 2017, he joined IISER Mohali as National Postdoctoral Fellow (DST-SERB) and worked on metal-catalyzed reactions on carbohydrates. In 2018, he joined as an Assistant Professor in the Department of Higher Education Haryana. He worked as postdoctoral fellow at the Freie University Berlin, Germany for one year with Dr. Sumati Bhatia in 2021. His research interests are C-glycosides, sugar-based copolymers, and multivalent glycoconjugates.

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Late Professor Ashok K. Prasad (1961–2023) obtained his Ph.D. from the Department of Chemistry, University of Delhi, in 1990 in the area of synthesis of bioactive polyphenolic natural products. After spending about a decade as a post-doctoral fellow/visiting scientist at the University of Southern Denmark, the Max Planck Institute for Molecular Physiology (Germany), Sapienza University Rome (Italy), and the University of Massachusetts Lowell (USA), Professor Prasad joined the Department of Chemistry, University of Delhi, as Reader in 2001 and subsequently became Professor in 2009. He was the Head of the Chemistry Department and Dean of Science Faculty, University of Delhi from 2021-2023. He has published more than 300 research papers in journals of international repute. His research interest were in the areas of nucleic acid chemistry, biotransformations, natural product chemistry, and synthesis of bioactive heterocyclic compounds.

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Dr. Rajni Johar Chhatwal obtained her B.Sc. and M.Sc. degrees from Kurukshetra University, Kurukshetra in 1993 and 1995, respectively. Then Dr Chhatwal earned her Ph.D. from Guru Jambeshwar University in 2005. Her area of interest is the spectral, structural elucidation and co-ordination abilities of tin and aluminum with triphenyl oxo propoxide to yield starting material triphenyl tin (IV) aluminum (III) oxo propoxide compound. Currently, Dr Chhatwal is an Associate Professor in Maitreyi­ College, University of Delhi.

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Dr Sandeep Kumar obtained his Ph.D. from the Department of Chemistry, University of Delhi, India in February 2022 under the supervision of Prof. Ashok Kumar Prasad in the field of nucleosides and carbohydrate chemistry. His research interest lies in the synthesis of modified nucleosides and sugar-based heterocyclic molecules for therapeutic applications. Dr Kumar secured All India Rank 14 in CSIR-JRF and thereafter awarded SPM (Shyama Prasad Mukherjee) Fellowship during his Ph.D. Dr Kumar has been DST-INSPIRE Fellow during graduation and post-graduation. Also, Dr Kumar is recipient of many meritorious fellowships from Haryana Government and Kurukshetra University. He has published around twenty research papers in internationally reputed journals such as New Journal of Chemistry, Carbohydrate Research, Beilstein Journal of Organic Chemistry, Journal of Organic Chemistry etc. Currently, Dr Kumar is an Assistant Professor in the Department of Chemistry, Acharya Narendra Dev College, University of Delhi.

1

Introduction

In biological systems, carbohydrates play a crucial part in essential life activities and are essential building blocks.[1] Natural carbohydrates have played a significant role in the complete synthesis of a variety of compounds over the past few decades. They are affordable, easily accessible, and endowed with a richness of stereochemical and functional properties.[2] But the potential of carbohydrates as chiral building blocks depends on the creation of useful critical intermediates that can satisfy these conditions. It is well known that adding an α,β-unsaturated carbonyl system increases the adaptability of sugar nuclei as stereochemical templates; Fraser-Reid’s synthesis and use of alkyl hex-2-enopyranose-4-uloses is a trailblazing example in this regard.[3]

Glycals, a type of sugar enol ether, have a double bond between C-1 and C-2 of pyranose or furanose sugars inside the ring.[4] Glycal is a generic term, although individual sugar derivatives have more specific names. For example, a glycal made from glucose is called a glucal, whereas a glycal made from galactose is called a galactal, and so on. Since their initial discovery and synthesis by Fischer and Zach in 1913, glycols have been widely used as a crucial precursor for the synthesis of numerous biologically significant compounds.[5] Glycals, 1,2-unsaturated sugar derivatives, are adaptable building blocks for diversity-oriented synthesis (DOS), which produces novel structural features as well as natural products.

Due to their ability to conduct a range of chemical reactions in a chemo-, stereo-, and regioselective manner, C-2-formyl glycals, a class of carbohydrates with an, α,β-unsaturated carbonyl group, have attracted significant attention from organic chemists in recent years. They are desirable intermediates in synthetic organic chemistry because they have a conjugated enal group, inherent chirality, and synthetic flexibility.[6] C-2-Formyl glycals have uses in medical, biological, supramolecular, and material chemistry in addition to their interest in synthetic chemistry.[7] As demonstrated in the synthesis of sugar β-amino acids,[8] iminosugars,[9] prospective anticancer,[10] anti-inflammatory chemicals,[11] as well as other significant intermediates,[12] C-2-formyl glycals are adaptable synthons in organic chemistry. The synthesis of acyclo-C-nucleosides can be carried out using a variety of C-2-formyl glycal building blocks.[13] The research on recent developments in the synthesis of C-2-formyl glucal and their applications reported after 2013 is compiled in this study.


# 2

Synthesis of C-2-Formyl Glycals

There are several ways to make C-2-formylated glycals,[14] [15] [16] but the Vilsmeier–Haack reaction[17] is still the most used method, which can be attributed to its ease of use, low cost of reagents, easy access to glycals with a variety of functionalities, moderate to good formylation product yields, and suitability for large-scale synthesis (Scheme [1]).[18]

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Scheme 1 Synthesis of C-2-formyl glycals

However, this reaction uses POCl3, a reagent that reacts aggressively with water and is extremely poisonous and corrosive. Since 2013, several methods have been reported to produce C-2-formyl glycals.

2.1

Vilsmeier–Haack Formylation

In 1991, Ramesh and Balasubramanian[18] used a Vilsmeier–Haack reaction of glycals with DMF and POCl3 to create C-2-formyl glycals in an efficient and simple manner. C-2-Formyl glycals 2a–f were produced by treating a solution of glycals 1a–f in DMF with POCl3 at 0 °C and at room temperature for 4–9 h, followed by base hydrolysis (Scheme [1]). The Vilsmeier–Haack one-step direct formylation of glycals has since been utilized by numerous research groups worldwide.[19] [20] [21] [22]


# 2.2

By Consecutive Cyclization

3-Deoxy-C-2-formyl glycals 4a–c were produced following consecutive cyclization by Lin and co-workers.[23] A solution of 3-deoxy-β-enaminals 3a–h in AcOH was stirred at 80 °C for 20 min, then purification by silica gel column chromatography (EtOAc/hexane 1:4) gave 3-deoxy-C-2-formyl glycals 4a–c in good yields (95–97%) (Scheme [2]).

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Scheme 2 Synthesis of 3-deoxy-C-2-formyl glycals
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Scheme 3 Synthesis of C-2-formyl glycals

# 2.3

XtalFluor‑E Based Synthesis

The most used method is still the Vilsmeier–Haack reaction because it provides a straightforward route to adding a formyl group to the C-2 position from widely available precursors. POCl3, a reagent that reacts strongly with water and is extremely poisonous and corrosive, is used in this reaction. In order to synthesize C-2-formyl glycals with diverse functional groups, Paquin and co-workers[24] described alternative conditions for the Vilsmeier–Haack formylation in which POCl3 was replaced by XtalFluor-E ([Et2NSF2]BF4),[25] [26] [27] a less toxic and more hydrolytically stable reagent. Formylation yields were often found to be lower for the glucal series than the galactal series,[24] which was attributed to electronic and steric effects of the C-4 protecting group on the C=C bond due to its proximity to the incoming Vilsmeier–Haack reagent in the pseudoequatorial position.[28]

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Scheme 4 Unexpected formylation outcomes and formylation of a disaccharide glycal
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Scheme 5 Stereoselective synthesis of 1,2-annulated sugars from sugar-derived a dienone via a domino double-Michael addition reaction

Treatment of glycals 5a–k with XtalFluor-E in DMF gave C-2-formyl glycals 6a–k in 11–90% yields (Scheme [3]).[24] 3,4-Di-OBn-6-OTBS glucal 5n was reacted with XtalFluor-E under similar conditions and gave, unexpectedly, formyl formate glucal 7 as well as formate glucal 8 by formylation at C-6 (Scheme [4]A). Similar results were obtained using XtalFluor-E with 3,4-di-OPMB-6-OTr glucal 5o, which gave formyl formate glucal 10 in 22% yield together with C-2-formyl glucal 6o in 12% yield (Scheme [4]B). Finally, disaccharide glycal 11 using standard Vilsmeier–Haack conditions,[29] gave the C-2-formyl lactal 12 in 37% yield, in contrast using XtalFluor-E gave C-2-formyl lactal 12 in 56% yield (Scheme [4]C).[24]


#
# 3

Applications of C-2-Formyl Glycals

3.1

C-2-Formyl Glycals as Synthons

1,2-Annulated sugars are a biologically significant class of molecules.[30] The traditional methods for their synthesis are multistep and thus improved methods are being developed for their synthesis. The Vankar group[31] reported a highly stereoselective and mild technique for the synthesis of 1,2-annulated sugars via a domino methodology with double-Michael addition reactions. The sugar-obtained dienone 14 was synthesized by the reaction of C-2-formyl galactal 13 at 0 °C to room temperature with vinylmagnesium bromide using dry THF as the solvent; the hydroxyl group in the resultant product was oxidized via IBX to give dienone 14 in 63% yield (2 steps). The dienone 14 was then treated with differently substituted 1,3-diones in the presence of MeONa as a base in MeOH/THF (5:1) as solvent at 0 °C to room temperature to yield the resultant 1,2-annulated sugars 15a–d as single diastereomers (Scheme [5]).

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Scheme 6 Synthesis of substituted pyrroles via azomethine ylide cycloaddition reaction of C-2-formyl glycals with substituted α-amino acids
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Scheme 7 Synthesis of sugar-substituted pyrrole derivatives via reaction of C-2-formyl glycals and N-alkyl-glycine ethyl esters

The pyrrole moiety is an integral part of many natural products[32] [33] and acyclo-C-nucleosides are known for their significant biological activity.[34,35] Reddy and Reddy[36] first reported the synthesis of sugar-based pyrrole molecules via the electrocyclic reaction of azomethine ylides obtained via condensing C-2-formyl glycals 16 with α-amino acids 17. A series of eight pyrrole derivatives, 18a–h were obtained in good yields by using three differently substituted glycals and a variety of cyclic and acyclic amino acids (Scheme [6]). The scope of this synthesis was also examined with N-alkyl-glycine ethyl esters 19 and gave pyrroles 20a–d (Scheme [7]).

Proline is a special five-membered cyclic amino acid in which the nitrogen-bearing carbon is linked to the COOH group.[37] In particular, it is crucial for intracellular signaling and molecular recognition. Proline-rich motifs found in numerous signaling cascades are found in modular protein domains including WW (rsp5-domain) as well as SH3 (Src homology 3).[38] The Vankar group[39] used C-2-formyl glycals as a starting point to create four different kinds of O-benzyl-protected proline derivatives (Scheme [8]). Using a previously described method,[40] [41] N-Boc-amino alcohols 21a,b and 22a,b were prepared from the corresponding C-2-formyl-d-glucal 6a and C-2-formyl-d-galactal 6b metabolites. These N-Boc-amino alcohols 21a,b and 22a,b were oxidized with Jones reagent in acetone to give N-Boc-amino acids 23a,b and 24a,b, and these were deprotected with TFA to give tri-O-benzyl-NH-proline derivatives 25a,b and 26a,b, which are helpful synthons in the synthesis of various nitrogen heterocycles and organocatalysts.[42] [43]

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Scheme 8 Synthesis of tri-O-benzyl-NH-proline derivatives from d-glycals

C-2-Formyl glycals and primary amines were successfully combined to produce good to outstanding yields of β-enaminals by Lin and co-workers.[23] β-Enaminals are adaptable synthetic building blocks that have undergone intensive research for the synthesis of a number of significant compounds, including pyrroles,[44] isoxazoles,[45] and quinolones,[46] and others.[47] Michael addition[48] was performed on C-2-formyl glycals of d-glucals or d-galactals 27a–d in MeOH for 10 min using primary amines 28a–c (1.1 equiv), such as benzylamine (28a), n-butylamine (28b), and n-octylamine (28c) to give β-enaminals 29a–k with good selectivity in 87–95% yields (ratio E/Z isomers 85:15–93:7) (Table [1]).

Table 1 The Michael Addition of C-2-Formyl Glycals with Primary Amines

Substrate

R1

R2

R3

R4

Product

R5

Yield (%)

27a

OBn

H

OBn

OBn

29a

n-Oct

87

27a

OBn

H

OBn

OBn

29b

n-Bu

95

27a

OBn

H

OBn

OBn

29c

Bn

91

27b

OMe

H

OMe

OMe

29d

n-Oct

91

27b

OMe

H

OMe

OMe

29e

Bn

91

27c

OPent

H

OPent

OPent

29f

n-Oct

93

27c

OPent

H

OPent

OPent

29g

n-Bu

92

27c

OPent

H

OPent

OPent

29h

Bn

90

27d

H

OBn

OBn

OBn

29i

n-Oct

87

27d

H

OBn

OBn

OBn

29j

n-Bu

90

27d

H

OBn

OBn

OBn

29k

Bn

91

Due to their exceptional enzymatic activities[49] and olefin­ metathesis,[50] biologically important molybdenum compounds have drawn a lot of interest for their higher oxidation state. Maiti and co-workers reported high-valent MoVI-ONO complexes that can be used for general oxidative cyclization catalysis as well as selectivity for ubiquitous heterocyclic motifs that are widely generated, such as their chiral analogues (chiral benzimidazoles).[51] MoVI (HL) is a promising catalyst for the development of excellent selectivity, benign, straightforward, and general oxidative cyclization processes. To illustrate the versatility of this benign synthetic approach, they used MoO2(HL)(H2O)DMF as a catalyst for the cyclocondensation and oxidation of C-2-formyl glycals 6a,b with o-phenylenediamine 30 at room temperature, which gave a direct synthesis of valuable glycal-based chiral benzimidazoles 31a,b (Scheme [9]).

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Scheme 9 Synthesis of chiral benzimidazoles

In medicinal chemistry and drug discovery, C-aryl glycosides are important molecules for the development of antibiotics, anticancer medications, and antidiabetic medicines.[52] [53] Messaoudi and co-workers,[54] reported the arylation of 2,3-glycals with various aryl iodides in a regio- and diastereoselective manner. The Pd(OAc)2/AsPh3 precatalytic system worked well across a range of substituted 2,3-glycals to give C-2-aryl glycosides with perfect diastereoselectivity. However, the C-2-formyl benzylated pseudoglucal 32 gave reversed reactivity in favor of the C-3-aryl glycoside 34 in 60% yield as a single stereoisomer (Scheme [10]).

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Scheme 10 Synthesis of C-aryl glycosides

# 3.2

Anticancer

According to a World Health Organization (WHO) assessment, by 2030 there are expected to be 26 million new instances of cancer and 17 million cancer-related deaths annually. Cancer is one of the main causes of death worldwide.[55] Coumarins and pyrano[3,2-c]pyranones are key structural components of many natural compounds.[56] Sagar and co-workers[57] synthesized a series of twenty novel sugar-fused pyrano[3,2-c]pyranones 36a–j and 37a–j using C-2-formyl galactal 6b and C-2-formyl glucal 6a as starting substrates (Scheme [11]). The reaction was carried out under microwave conditions using toluene/AcOH as the solvent system. The synthesized compounds were also analyzed for their anticancer activities against MCF-7 (breast), MDA-MB-231 (breast), and HepG2 (liver) cancer cell lines; three carbohydrate-coupled pyrano[3,2-c]pyranones have micromolar anticancer action. According to cellular uptake experiments, the addition of the carbohydrate moiety to the 4-hydroxycoumarin derivatives 35a–j improves their uptake by breast cancer cells, which in turn increases their potential to suppress cell development as compared to the precursor 4-hydroxycoumarin compounds.

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Scheme 11 Synthesis of pyrano[3,2-c]pyranones from a C-2-formyl galactal and a C-2-formyl glucal

Many bioactive natural compounds contain the significant structural pyrano[3,2-c]quinolone motif.[58] In 2018, Sagar and co-workers[59] reported the synthesis of pyrano[3,2-c]quinolones. A library of twenty-three novel compounds, 39a–k and 40a–k were synthesized starting from C-2-formyl galactal 6b and C-2-formyl glucal 6a (Scheme [12]). The reaction involved short reaction times and it was a green approach. N-Methyl-substituted carbohydrate-fused pyrano[3,2-c]quinolone 42 was also synthesized using this protocol (Scheme [12]). The compounds so obtained were examined for their anticancer activities against MCF-7 (breast) and HepG2 (liver) cancer cells. The chosen library members exhibited low micromolar (3.53–9.68 M) and specific antiproliferative efficacy. These results on carbohydrate-fused pyrano[3,2-c]quinolone derivatives should lead to the discovery of new anticancer therapeutic candidates.

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Scheme 12 Synthesis of pyrano[3,2-c]quinolones from C-2-formyl galactal and 2-C-formyl glucal

# 3.3

Anti-inflammatory

A bioactive glycolipid found in a marine sponge called α-GalCer offers therapeutic potential for autoimmune disorders, cancer, and microbial infections.[60] The semi-invariant T-cell receptor (TCR) of invariant natural killer T (iNKT) cells is stimulated by the binding of α-GalCer to CD1d on antigen-presenting cells (APCs), and the resulting α-GalCer-CD1d complex causes the production of signaling molecules known as cytokines that start cellular communication. The balance between the release and activity of these cytokines with opposite activity is crucial in numerous disorders. These cytokines are classed as pro- or anti-inflammatory.[61] As a result of these cytokines’ subsequent activation of immune cells, such as neutrophils, dendritic cells, and macrophages, immunological responses are further modified.[62] [63]

Neurodegenerative disorders develop and advance in large part as a result of microglial activation. Anti-inflammatory drugs that regulate microglial activation could therefore be used as possible treatments for neurodegenerative illnesses. Park and co-workers designed and synthesized α-galactosylceramide (α-GalCer) analogues to have anti-inflammatory actions on activated microglia (Scheme [13]).[64] They evaluated 25 α-GalCer analogues biologically, and they found an intriguing preliminary structure-activity link in the inhibitory effect of these compounds on NO release and TNF-α (TNF = tumor necrosis factor) generation in lipopolysaccharide (LPS) stimulated BV2 microglial cells. The α-GalCer analogues 55d and 55e reduced the phosphorylation of p38 MAPK and the DNA binding activities of NF-κB and AP-1, according to the molecular mechanisms.

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Scheme 13 Synthesis of α-GalCer analogues

# 3.4

Antimicrobial

Malaria is a potentially fatal mosquito-borne illness that is brought on by an apicomplexan parasite of the species Plasmodium. Malaria continues to be a severe public health issue, especially in the high transmission regions of Sub-Saharan­ Africa, Southeast Asia, and Latin America, where over 219 million hospital cases and nearly a million fatalities occur yearly.[65] Global needs for new antimalarial therapies have increased due to the threat that rising antimalarial drug resistance poses to the control of the illness. New chemical libraries and innovative screening techniques are needed to find novel malaria therapeutics.

Similar to this, new antibacterial and antiviral drugs should be created with chemical properties that are distinctly different from those of existing agents due to the rapid development of drug resistance. Using their divergent synthesis method,[66] Park and co-workers[21] created a concentrated library of carbohybrids based on 2-aminopyrimidines. The carbohybrid scaffolds 57, which contain a variety of heterocyclic moieties, were synthesized by the condensation of C-2-formyl glycals 56a and 56b with dinucleophiles and subsequent ring opening (pyrimidine, pyrazolopyrimidine, and pyrazole). Sequential changes of functional groups through mesylation, trityl deprotection, and azide replacement allowed the synthesis of carbohybrids 58, 59, and 60, respectively, with distinct appendages. In order to obtain analogues 61, 62, and 63, the primary hydroxyl group in 60 was modified through tritylation, benzylation, and mesylation respectively (Scheme [14]). They improved the substrate molecule to yield 58aA and 61aA, as potent antimalarial prospects with selective indices as well as rapid acting properties against the main asexual parasite types, based on in vitro biological studies. Moreover, these lead compounds showed good pharmacokinetic characteristics and quick in vivo effectiveness.

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Scheme 14 Synthesis of carbohybrid-based molecular frameworks
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Scheme 15 Synthesis of diversified C-nucleosides

Because formyl sugars have both electron-donating as well as electron-withdrawing properties, the molecule is more vulnerable to attack by a nucleophile. Bari and co-workers[67] synthesized a variety of C-nucleosides 64–69 by reactions with N,N-dinucleophiles using a similar strategy (Scheme [15]). A novel methodology was utilized for the synthesis of pyrazole-acyclo-C-nucleoside 64 by reacting formyl-bearing sugar 6a with cyanoethylhydrazine in refluxing ethanol. A mixture of 6a and 2-hydrazino-4-phenylthiazole was stirred in refluxing ethanol, however even after a longer reaction period, no ring change could be seen; instead, formation of hydrazone 65 was observed. Treating formyl-bearing sugar 6a with pentafluorophenylhydrazine in refluxing ethanol gave 66 in high yield. Reaction of C-2-formyl glycal 6a and thiosemicarbazide gave semicarbazone 67 in good yield, while its reaction with 3-methyl-5-amine-1H-pyrazole in refluxing ethanol produced 68. Sugar 6a was treated with hydrazinopyridine to give N-2-pyridyl-pyrazole 69.

Three viral, two fungal as well as five bacterial strains were tested against seven nucleoside analogues, including one starting material. C-Nucleosides showed no discernible antiviral impact. The majority of the synthetic chemicals tested against two fungal and five bacterial strains were active­. Compounds 66, 67, and 69 exhibited moderate cytotoxicity­ against Candida albicans and Cryptococcus neoformans, while compound 6a displayed activity against Acinetobacter baumannii.

Sagar, Singh, and co-workers[68] tested two series of carbohydrate-fused pyrano[3,2-c]pyranone carbohybrids against Plasmodium falciparum. These hybrids were made by combining C-2-formyl galactal 6b and C-2-formyl glucal 6a with various freshly synthesized 4-hydroxycoumarins 35a–j (Scheme [11]). With the help of a growth inhibition assay on the P. falciparum 3D7 strain and a SYBR green-based fluorescence assay, the antimalarial activity of these carbohybrids was identified. By using a hemocompatibility experiment, it was shown that carbohybrid 36b, which had the strongest antimalarial activity, also had hemolytic activity. With an IC50 value of 5.861 M and highest growth inhibitory capacity against Plasmodium, C-2-formyl galactal fused pyrano[3,2-c]pyranone carbohybrid 36b showed no toxicity against HepG2 cells or hemolysis of erythrocytes. Compared to uninfected erythrocytes, parasitized erythrocytes showed a greater absorption of this carbohybrid molecule. These results demonstrate that the fusion of a carbohydrate group to the 4-hydroxycoumarin precursor produced pyrano-pyranone derivatives with improved solubility, uptake, and selectivity.


# 3.5

Glycosidase Inhibitors

Iminosugars are a significant class of chemicals with intriguing structural features and significant biological effects, particularly as glycosidase inhibitors,[69] making them crucial candidates for organic synthesis. Numerous naturally occurring or manufactured 5-, 6-, and 7-membered compounds have been described in the literature as effective glycosidase inhibitors, among them are monocyclic iminosugars.[70] 2,5-Dihydroxymethyl-3,4-dihydroxypyrrolidine (DMDP), codonopsinine, 1,4-dideoxy-1,4-imino-d-arabinitol (DAB), and radicamine A are well-known pyrrolidine-based examples of 5-membered iminosugars that act as inhibitors.[71] Freshly obtained (–)-steviamine from the leaves of Stevia rebaudiana was found to be a potent-galactosidase inhibitor (IC50 = 35 M, rat intestinal lactase).[72]

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Scheme 16 Synthesis of keto-formates and monocyclic azasugars

In order to synthesize four novel compounds, the Vankar group[40] developed a new method for the construction of pyrrolidine azasugars from C-2-formyl glycals, for example the dihydroxymethyl dihydroxypyrrolidines 79a and 79b (Scheme [16]) and 84a and 84b (Scheme [17]). This methodology has the potential for the synthesis of other pyrrolidine azasugars. Further, four new steviamine analogues 92a, 92b, 95a, and 95b (Scheme [18]) were developed using the key procedures of aza-Michael addition and ring-closing metathesis. Steviamine analogue 95a was found to be a good and selective β-mannosidase inhibitor, whereas the other steviamine analogues showed affinity toward galactosidases. All of the compounds synthesized were tested for glycosidase inhibition against six commercially available enzymes.

The synthesis of monocyclic azasugars 79a and 79b started from 3,4,6-tri-O-benzyl-d-glucal, which was modified into the vinyl aldehyde 6a using the Vilsmeier–Haack reaction (Scheme [16]). NaBH4 was then used to reduce 6a in methanol, resulting in the corresponding allylic alcohol 70a.[73] The primary hydroxyl group in alcohol 70a was protected with trityl chloride with Et3N as the base to give trityl ether 71a in 92% yield. OsO4 and NMO were then used to dihydroxylate the olefin moiety, producing a mixture of diols 72a (dr = 5.5:1) in nearly quantitative yield. Treatment of 72a with sodium metaperiodate introduced in small amounts over a period of 2 h, followed by vigorous stirring at room temperature for 3 h gave 73a in 74% yield. The 3,4,6-tri-O-benzyl-d-C-2-formyl galactal 6b was transformed into ketoformate 73b utilizing an identical set of synthetic procedure. After employing NaBH4 in methanol to reduce compound 73a, the diols 74a and 74b were obtained in 1.8:1 ratio. The diols were chromatographically separated, and then at 0 °C, mesyl chloride was added along with Et3N and a catalytic quantity of DMAP to give dimesylates 75a and 75b, which were treated with neat benzylamine to give pyrrolidines 76a and 76b by double nucleophilic displacement. Pyrrolidines 76a and 76b were detritylated using trifluoroacetic acid (3 equiv) in dichloromethane at 0 °C to give alcohols 77a and 77b that were fully deprotected using Pd(OH)2/C under a pressure of 1 atm H2, in acidic medium for 2 d to give 79a [74] and 79b [75] in 10.4% and 8.4% overall yields, respectively, from C-2-formyl glucal.

Starting from 73b reduction with NaBH4 produced a 1.3:1 mixture of the diols 80a and 80b (Scheme [17]). Using the same route as given in Scheme [16] gave pyrrolidines 84a and 84b in 9.5% and 10.6% overall yields, respectively, from d-galactal.

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Scheme 17 Synthesis of monocyclic azasugars

In order to decrease the nucleophilicity of the amine group and facilitate subsequent reactions, compounds 83a and 83b (Scheme [17]) were initially transformed into Boc amines (Scheme [18]). Treatment of 83a and 83b with Pd(OH)2/C at a pressure of 1 atm H2 for 1 h efficiently removed the benzyl group from the amine functionality without disrupting any of the benzylic ethers that were also present in the molecule.[76] In order to protect the crude amine as the tert-butylcarbamate, it was treated with Boc2O in presence of Na2CO3, yielding 85a and 85b. The free primary alcohol was then oxidized using CrO3/Py/Ac2O,[77] and the resultant aldehyde was subjected to Wittig olefination using methyltriphenylphosphonium bromide and KOtBu to give alkenes 86a and 86b. The Boc-protection in 86a and 86b was removed using trifluoroacetic acid in dichloromethane for 8 h at room temperature to give free amines 87a and 87b. The aza-Michael reaction of free amines 87a and 87b with crotonaldehyde was examined under various conditions, but even under reflux, the addition of bases, such KOtBu or NaH, did not improve conversion. For this reaction, the Zn/NH4Cl system[78] resulted in superior yields of aldehydes, shorter reaction time, with a clean reaction profile. Since the aldehydes produced by the reaction were unstable, they were quickly transformed using methyltriphenylphosphonium bromide and KOtBu into dienes 88a/89a and 88b/89b.

The mixture of dienes 88a and 89a underwent a smooth ring-closing metathesis reaction with Grubbs’ 2nd generation catalyst (6 mol%) in the presence of p-TsOH (2 equiv), in refluxing toluene, producing the products 90a and 90b in a ratio of 1:1 and a total 52% yield over 4 steps (Scheme [18]). The steviamine analogues 91a and 91b were then produced in 70% and 64% yields, respectively, via one-pot double bond reduction and deprotection of benzyl groups using Pd(OH)2/C in 10% HCl/MeOH under 1 atm pressure of H2. The free hydroxyl groups in steviamine analogues 91a and 91b were protected as the acetates using Ac2O/pyridine (1:1) for 8 h to produce 92a and 92b for stereochemistry experiments (Scheme [18]).

In order to produce the ring-closed products 93a and 93b in a ratio of 1.4:1 and a total yield of 48% over 4 stages, the other combination of the dienes 88b and 89b was subjected to ring-closing metathesis (Scheme [18]). Steviamine analogues 94a and 94b were then obtained after hydrogenation. To conduct stereochemical research, acetates 95a and 95b were again synthesized from 94a and 94b, respectively.

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Scheme 18 Synthesis of steviamine analogues
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Scheme 19 Synthesis of sugar-furan fused molecules

Synthetic chemists have long been interested in the synthesis of annulated sugars, which is a significant field of study in the development of contemporary drugs. The Vankar group[19] produced oxa-oxa (5,6 as well as 6,6) annulated sugars from C-2-formyl galactal employing iodocyclization as a critical step. When the thus obtained compounds were evaluated against commercially available enzymes for their ability to inhibit glycosidase, it became clear that the sugar-furan molecules are strong, selective inhibitors. The intended 1,2-annulated sugars were synthesized starting from vinyl aldehyde 6b. The addition of vinylmagnesium bromide to vinyl aldehyde 6b at 0 °C in dry THF followed by protection of the hydroxyl group with benzyl bromide and sodium hydride gave benzyl ether 96 in two steps in 58% yield (Scheme [19]). Regioselective dihydroxylation of the terminal C=C bond in 96 with OsO4/NMO gave a mixture of diols, which was then subjected to oxidative cleavage using sodium metaperiodate in a THF/H2O (1:1) at room temperature to produce the corresponding aldehyde 97a/b. Reduction of the aldehyde group in 97a/b with NaBH4 in methanol gave diastereomeric alcohols 98; iodocyclization of primary alcohols 98 using N-iodosuccinimide[79] in DCM at room temperature gave the 6-endo-iodocyclized products 99a and 99b. The major isomer 99b was subjected to radical-mediated deiodination utilizing a catalytic system of n-Bu3SnCl with AIBN in toluene/tBuOH (1:1) at 80 °C for 1 h to give the intended product 100 in 65% yield. Product 100 was protected using Pd(OH)2/C in MeOH under 1 atm H2 for 4 h to give the furan-fused sugar 101 in 81% yield.

Aldehyde 97b and freshly prepared n-butylmagnesium bromide were then reacted to generate the crude alcohol which was further subjected to iodocyclization to give furan-fused sugar derivative 102 (Scheme [20]). Furan-fused sugar 102 underwent radical deiodination to give 103 followed by hydrogenation to give annulated sugar derivative 104 in two steps. Annulated sugar derivative 104 was treated with Ac2O/Et3N (1:1) in the presence of DMAP for 6 h to give peracetylated 105.

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Scheme 20 Synthesis of a butyl-substituted sugar-furan fused molecule
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Scheme 21 Synthesis of a sugar-pyran-fused molecule
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Scheme 22 Synthesis of 3-deoxy C-2-methylene C-glycoside derivatives

Similarly, the sugar-pyran annulated molecule 111 was also synthesized (Scheme [21]). C-2-Formyl galactal 6b was treated with allylmagnesium bromide followed by protection with benzyl bromide to give 106 as a mixture of α- and β-isomers in 1:0.9 ratio. This mixture of 106 underwent the same series of reactions as those previously described in Scheme [19]; dihydroxylation, followed by oxidative cleavage, and further reduction by NaBH4 to produce a diastereomeric mixture of the primary alcohols as 107a/b. The isomer 107a, which was obtained from this combination of 107a/b, underwent a similar series of reactions to Scheme [19], including radical deiodination, followed by hydrogenation as well as iodocyclization, to produce the sugar-pyran fused molecule 110. According to research on glycosidase inhibition, sugar-furan and n-butyl-substituted sugar-furan molecules were found to be the most potent and highly selective inhibitors.

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Scheme 23 Epimerization of a α-C-glycoside into a pure β-C-glycoside

# 3.6

Miscellaneous

Natural compounds with extraordinarily high bioactivities are generally obtained from C-branched-C-glycosides, which are in turn produced by several bacteria.[80] In order to synthesize deoxygenated C-2-methylene-C-glycosides 114α, 114β, 116α, and 116β, Sridhar and co-workers[20] developed a generic procedure employing Claisen rearrangement of 2-vinyloxymethyl glycal 113 derivatives (Scheme [22]). Moreover, this technique can also be utilized to synthesize C-2-methylene-α- and β-C-glycosides in a stereoselective manner.

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Scheme 24 Synthesis of C-2-methyl C-glycosides

In addition to this technique, a ZnII-mediated anomerization of the α-C-glycosides was also employed to obtain diastereomerically pure β-C-glycosides from C-2-methylene C-glycoside derivative 114 (Scheme [23]).

The method was further utilized to prepare C-2-methyl-C-glycosides 118 and 119 from deoxysugars by selectively hydrogenating the C-2-methylene functionality in 117 after the generality and stereoselectivity of the reorganization were assessed (Scheme [24]).

It is noteworthy that the majority of these molecules can function as essential building blocks for the production of a vast variety of bioactive natural products. This methodology was further expanded to prepare an advanced intermediate for the synthesis of (–)-brevisamide 124 [81] [82] (Scheme [25]).


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# 4

Conclusion and Future Aspects

Over the past 30 years, C-2-formyl glycals have been utilized as adaptable chiral intermediates. They are desirable substrates for the synthesis of a wide range of organic molecules with functional, stereochemical, structural, and appendage diversity due to the availability of an easy method to incorporate the formyl group through a one-step Vilsmeier­–Haack reaction, their multifunctional architecture, the presence of an enal group with extended conjugation, built-in chirality, and the possibility of synthetic maneuverability to the desired targets. This review has shown that the chemistry of C-2-formyl glycals is not limited to synthetic organic chemistry or carbohydrate chemistry. The few applications in supramolecular and materials chemistry that have been identified are merely the beginning of the era of materials science and are expected to spark more attention. The chemistry of C-2-formyl glycals is anticipated to continue expanding in the future due to their numerous applications. C-2-Formyl glycals have grown in significance as useful precursors for numerous synthetic applications in recent years. It is important to note that numerous research teams have used C-2-formyl glycals for a variety of synthetic transformations, including the production of annulated glycopyranosides, C-glycosides, optically active sugar peroxides, heterocycles, and methylene-valerolactones, among others. The ease with which these variously functionalized carbohydrate intermediates are available is probably going to increase interest in their potential uses in synthetic organic chemistry.

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Scheme 25 Total synthesis of (–)-brevisamide

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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Authors

Rajni Johar Chhatwal
Maitreyi College, Department of Chemistry, University of Delhi
110021 Delhi
India   

Sandeep Kumar
Acharya Narendra Dev College, Department of Chemistry, University of Delhi
110019 Delhi
India   

Publication History

Received: 21 February 2023

Accepted after revision: 30 March 2023

Accepted Manuscript online:
30 March 2023

Article published online:
02 May 2023

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Scheme 1 Synthesis of C-2-formyl glycals
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Scheme 2 Synthesis of 3-deoxy-C-2-formyl glycals
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Scheme 3 Synthesis of C-2-formyl glycals
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Scheme 4 Unexpected formylation outcomes and formylation of a disaccharide glycal
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Scheme 5 Stereoselective synthesis of 1,2-annulated sugars from sugar-derived a dienone via a domino double-Michael addition reaction
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Scheme 6 Synthesis of substituted pyrroles via azomethine ylide cycloaddition reaction of C-2-formyl glycals with substituted α-amino acids
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Scheme 7 Synthesis of sugar-substituted pyrrole derivatives via reaction of C-2-formyl glycals and N-alkyl-glycine ethyl esters
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Scheme 8 Synthesis of tri-O-benzyl-NH-proline derivatives from d-glycals
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Scheme 9 Synthesis of chiral benzimidazoles
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Scheme 10 Synthesis of C-aryl glycosides
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Scheme 11 Synthesis of pyrano[3,2-c]pyranones from a C-2-formyl galactal and a C-2-formyl glucal
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Scheme 12 Synthesis of pyrano[3,2-c]quinolones from C-2-formyl galactal and 2-C-formyl glucal
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Scheme 13 Synthesis of α-GalCer analogues
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Scheme 14 Synthesis of carbohybrid-based molecular frameworks
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Scheme 15 Synthesis of diversified C-nucleosides
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Scheme 16 Synthesis of keto-formates and monocyclic azasugars
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Scheme 17 Synthesis of monocyclic azasugars
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Scheme 18 Synthesis of steviamine analogues
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Scheme 19 Synthesis of sugar-furan fused molecules
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Scheme 20 Synthesis of a butyl-substituted sugar-furan fused molecule
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Scheme 21 Synthesis of a sugar-pyran-fused molecule
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Scheme 22 Synthesis of 3-deoxy C-2-methylene C-glycoside derivatives
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Scheme 23 Epimerization of a α-C-glycoside into a pure β-C-glycoside
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Scheme 24 Synthesis of C-2-methyl C-glycosides
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Scheme 25 Total synthesis of (–)-brevisamide