Accepted Manuscript Minireview Recent Developments in β-C-Glycosides: Synthesis and Applications Krishnamoorthy Lalitha, Kumarasamy Muthusamy, Y. Siva Prasad, Praveen Kumar Vemula, Subbiah Nagarajan PII: DOI: Reference:
S0008-6215(14)00370-X http://dx.doi.org/10.1016/j.carres.2014.10.008 CAR 6856
To appear in:
Carbohydrate Research
Received Date: Revised Date: Accepted Date:
2 September 2014 11 October 2014 16 October 2014
Please cite this article as: Lalitha, K., Muthusamy, K., Siva Prasad, Y., Vemula, P.K., Nagarajan, S., Recent Developments in β-C-Glycosides: Synthesis and Applications, Carbohydrate Research (2014), doi: http:// dx.doi.org/10.1016/j.carres.2014.10.008
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Recent Developments in β-C-Glycosides: Synthesis and Applications† Krishnamoorthy Lalitha,a Kumarasamy Muthusamy,a Y. Siva Prasad,a Praveen Kumar Vemula,b Subbiah Nagarajan*,a
a
Organic Synthesis Group, Department of Chemistry and the Centre for Nanotechnology and
Advanced Biomaterials, School of SASTRA University, Thanjavur - 613401, Tamil Nadu, INDIA Fax: 04362264120; Tel: 04362304270; E-mail: [email protected]. b
Technologies for the advancement of Science, Institute for Stem Cell Biology and Regenerative
Medicine (inStem), National Centre for Biological Sciences, UAS-GKVK post, Bellary Road, Bangalore 560065, India.
*Corresponding author: Organic Synthesis Group, Department of Chemistry and the Centre for Nanotechnology and Advanced Biomaterials, School of Chemical and biotechnology, SASTRA University, Thanjavur - 613401, Tamil Nadu, INDIA Fax: 04362264120; Tel: 04362304270; E-mail: [email protected]. †This article is dedicated to Prof. George John, The City College of New York, New York, NY 10031, USA.
1
Highlights C-Glycoside often rely on green chemistry and facile methodology for their synthesis. Snapshot on different methodology available for C-glycoside synthesis has been discussed. Glycosides are commonly used as pharmacophores, biomaterials and green surfactants. C-Glycosides are considered to be as best alternative for O-, N-, S- glycosides. Other applications of C-glycoside are biomolecules, green surfactants and self-assembled soft-materials.
2
Abstract In the last few years, considerable progress has been made in the synthesis of C-glycosides. Despite its challenging chemistry, due to its versatility, C-glycosides play a pivotal role in developing novel materials, surfactants and bioactive molecules. In this review, we present snapshots of various synthetic methodologies developed for C-glycosides in the recent years and the potential application of C-glycosides derived from β-C-glycosidic ketones.
Graphical abstract
Keywords: C-Glycosides, β-C-Glycosidic ketone, Biomolecules, Green surfactants, Self-assembly
3
1.
Introduction
In carbohydrate chemistry, a glycoside is an organic molecule in which sugar is bound to a noncarbohydrate moiety. Glycosides play several important roles in living organisms such as regulation of plant growth, cardiac muscle stimulant, and the primary function as the source of energy for organisms. Generally glycosides can be linked by an O-, N-, S- and C-glycosidic bonds. Intriguingly, C-glycosides are resistant to both acidic and enzymatic hydrolysis, where the other types of glycosides are unstable under hydrolytic conditions. S-glycosides are also known to be resistant towards enzymatic hydrolysis, but on acidic hydrolysis it leads to the formation of free thiols with offensive odour. C-Glycosides were considered as a stable pharmacophores and known to be used in the synthesis of enzyme inhibitors1 and drug molecules for certain viral diseases such as human immunodeficiency virus (HIV), hepatitis virus B and herpes viruses.2,3 Biological activities of the carbohydrate moiety stood up because of its mien at the interface of the cell and its surroundings in bacteria, parasites, viruses, tumors and numerous other targets. This has led to the development of a vaccine by conjugating the carbohydrate with immunogenic carrier proteins using carbohydrate specific immune response concept. For example, a fully synthetic glycoconjugate vaccine has been developed against Haemophilus influenzae type b.4 In the field of material science, carbohydratebased surfactants represent an increasingly important class of non-ionic surfactants/neutral surfactant such as alkyl polyglucosides (APGs) and sorbitan esters (trade names SPAN® and Tween®) which possess a number of favourable attributes including desirable detergent properties and low toxicity.5 However, carbohydrate-based surfactants generally incorporate either base-labile ester linkages (SPAN®, Tween®, and MGEs), or acid-labile O–glycosidic linkages (APGs) into their structures.6 The instability of these functionalities limits the application of carbohydrate-based surfactants in cosmetics, toiletries, agrochemicals and lubricants.7-9 One potential way to address this issue is to replace O-glycosidic linkage with a more stable C-glycoside linkage. In this review we discuss a decade of research focused on the synthesis of C-glycosides10 and their applications (Figure 1). 4
Insert Figure 1 2.
Synthesis of C-glycosides
2.1 Cross-Coupling approach Aryl-C-glycosides have an aryl ring directly connected to the sugar core that confers their stability towards the enzymatic and chemical hydrolysis. Consequently these molecules are of prodigious significance in medicinal chemistry. Moreover, the aryl ring in aryl-C-glycosides provides them an adequate intracellular lifetime to allow trafficking to the nucleus, where they bind to DNA thus forming stable complexes. They also possess antibacterial, antitumor, and antifungal activities and are potent enzyme inhibitors.11,12
Figure 2. Cross-Coupling approach for the synthesis of C-glycosides. A number of approaches including Heck, Suzuki, Stille and Negishi-type reactions have been developed for the synthesis of C-glycosides employing glycals as key starting materials (Figure 2). Glycals can be attached with aryl moiety involving Heck coupling reaction under different experimental conditions.13-33 Matsuda and co-workers reported the synthesis of indolocarbazole natural product 1, a potential checkpoint kinase 1 inhibitor, comprising Heck reaction followed by a 6-π electron cyclization (Scheme 1).34 5
Scheme 1. Synthesis of C-glycosylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones. Another interesting route for the synthesis of C-glycosides includes the Suzuki cross coupling, which involves the reaction between aryl/vinyl-boronic acids or organoboranes and aryl/vinyl halides or triflates catalysed by palladium complexes.16,17,29,30 35-42 Halogenated glycals or stannyl-glycals act as potential substrate in Stille coupling with organostannanes or organohalides to afford Cglycosides.29,42-47 Li et al., described a new approach towards the synthesis of unusual disaccharide derivatives by connecting two monosaccharides.
Suzuki cross coupling reaction of exo-glycal,
accompanied by hydrogenated deprotection under Pd(OH)2/C, H2 condition lead to the formation of disaccharide derivative. In this case stereoselective hydroboration of exo-glycal confers the βconfiguration of the C-disaccharides.48 C-glycoside can also be synthesised by Negishi coupling reaction of an organozinc compound and an organic halide, catalysed by nickel or palladium complexes. In addition to glycals, glycosyl halides can also be used as starting materials for Negishi cross coupling reaction (Scheme 2).11, 49-51
6
Scheme 2. Synthesis of C-glycoside by Negishi cross coupling approach. Hayashi and co-workers developed an asymmetric synthesis of optically active cis- and trans-2-aryl6-methylpyrans from commercially available tetra-O-acetyl-D-glucopyranosyl bromide. The reaction proceeds by two important steps: one involves the direct arylation in the absence of any organometallic reagents, and the other include deoxygenation at the C-3 position followed by inversion of configuration at the C-2 position (Scheme 3).52
Scheme 3. Synthesis of 2-aryl-3-hydroxy-6-(hydroxymethyl)pyrans. 2.2 Additions of allylsilanes The Ferrier reaction encompasses a nucleophilic substitution reaction along with an allylic shift in a glycal lead to the formation of C-glycosides.
Wide variety of carbon nucleophiles such as
allylsilanes, allyl-, alkyl-, aryl-, and alkynyl metal reagents, TMSCN, isonitriles, enol derivatives, and aromatics are able to react with Ferrier cation of glycal to give C-glycosides. These types of reactions are usually carried out in the presence of Lewis acids, including TMSOTf, BF3.OEt2 or 7
SnCl4.53-71 Recent exploitations in the use of promoters for the Ferrier rearrangement of O-, N-, Cand S-nucleophiles with glycals has been reviewed elsewhere.72,73 In 1982, Kishi and co-workers74 studied highly stereoselective approaches to α- and βglycopyranosides. They described the stereochemical control of the nucleophilic addition to the oxonium ion derived from tetra-O-benzyl-D-pyranose derivatives. The oxonium ion consents nucleophiles from the α-axial side due to the anomeric effect from the oxygen in the ring. Treatment of 2,3,4,6-tetra-O-benzyl-D-glucopyranose with allyltrimethylsilane and BF3.OEt2 in acetonitrile furnished the product with high stereoselectivity. Horton et al.75 have reported the synthesis of 3(2,3,4,6-tetra-O-acetyl-α,β-D-glucopyranosyl) propene 8 and 9 in 23% combined yield with α:β ratio 5:1 (Scheme 4).76
Scheme 4. Synthesis of allyl C-glycosides. Nucleophilic addition of allyltrimethylsilanes, alkynyltrimethylsilanes, silyl cyanides etc. at the anomeric carbon of glycals with simultaneous loss of a substituent at C-3 yielded the corresponding C-glycosides.77 This lead to double bond migration to give 2,3-unsaturated sugars which could act as useful chiral substrate for further manipulation in organic synthesis. Danishefsky et al. reported the nucleophilic addition of glycal acetates with allyltrimethylsilanes in the presence of equimolar amounts of TiCl4 as a Lewis acid.78 Nicolaou and co-workers manifested the stereoselective allylation at the C-1 position in 1-alkylglucal 10 using TiCl4 to obtain compound 11 (Scheme 5).79 Under this reactive conditions, selective formation of C-glycoside was favored at lower temperature 8
and yield of the reaction was dependent on the reaction medium. Yadav et al. have also contributed in this field by using several Lewis acids, such as molecular iodine, InBr3, Bi(OTf)3, LiBF4, Sc(OTf)3 and phosphomolybdic acid supported on silica gel. 80-85
Scheme 5. Stereoselective allylation of 1-alkylglucal. Similar to allylsilanes, alkenylsilanes can also be used for the related transformation. Silylacetylenes were found to be reactive enough to generate the corresponding C-glycosides (Scheme 6). Ferrier type alkynylation of glucals using activated alkynes viz allyltrimethylsilane as nucleophile in the presence of ZrCl4, HClO4-SiO2, Er(OTf)3, TMSOTf, AuCl3 or Zeolite lead to the formation of expected products in excellent yield with very good α-selectivity.13, 73, 86-94
Scheme 6. Ferrier type alkynylation of glucals using activated alkynes. Mukherjee and co-workers lately manifested a stereoselective C-glycosylation reaction between glycal 14 and unactivated alkynes 15 in the presence of copper triflate and ascorbic acid to afford the corresponding C-glycosides 16 (Scheme 7).95
9
Scheme 7 - Stereoselective C-glycosylation of glycal using unactivated alkynes. 2.3 Radical addition method Similar to cross coupling approach and addition of allylsilanes, radical addition between highly electrophilic radicals (fluorinated or unfluorinated) and 2-benzyloxyglucal or galactal opens a new path for the synthesis of C-glycosides (Scheme 8).96-105 The formation of both α and β anomers 18 and 19 is the major drawback of this methodology.
Scheme 8. Addition of ethyl bromodifluoroacetate to 2-benzyloxyglucal. 2.4 Knoevenagel condensation The transformation of β-C-glycosidic ketone, bio-based precursor obtained by the reaction of partially protected/unprotected sugars with acetylacetone in water, into C-glycosides is of particular 10
interest in carbohydrate chemistry due to its mild reaction conditions. The first one-step procedure for the synthesis of was reported by Gonzalez and co-workers reported the simple procedure for the preparation of C-glycosides directly by the reaction of unprotected carbohydrates with the nucleophile derived from malonate derivative in the presence of water, considered to be a green solvent.8,9 Subsequently, Rodrigues et al. has further developed this green protocol to a wide range of 1,3-diketone in alkaline aqueous media, which lead to the exclusive formation of β-Cglycosides.106 Knoevenagel condensation between the formyl group of unprotected sugar with active methylene group of 1,3-diketone is the key step for both the reactions. This could be a more soaring strategy for the synthesis of C-glycosides and most adept choice for cross coupling, addition of allylsilanes and radical addition methods. A facile one-step synthesis of C-glycosides from unprotected sugars involving Horner-WadsworthEmmons reaction in water or under solvent-free conditions has been reported.12-14,107-111
However,
most of these method led to β-C-pyranosides as the main products. Recently Wang et al. developed a stereoselective procedure for the preparation of ketone β-C-pyranosides 21 and ketone β-Cfuranosides 22 upon condensation of pentane-2,4-dione with various unprotected sugars 20 in presence of sodium carbonate in water. At 90 ºC, the ketone β-C-pyranoside 21 was obtained in excellent yields (up to 97%) in short reaction time. In contrast, at 10 ºC, the ketone C-furanosides, 24 were the main products obtained in 83-97% yields (Scheme 9).112
11
Scheme 9. Synthesis of β-C-glycosides.
3.
Application of β-C-glycosidic ketones
3.1 Synthesis of sugar based macrolides The pharmacological properties of macrocycles originates from their structural complexity, rigidity and ability to form stable, inter- and intramolecular hydrogen bonding.113-116 In this context several research groups focused on the synthesis of carbohydrate based macrocycles that can form extensive hydrogen bonding networks.117-121 Biologically active macrolides such as kendomycin, bryostatin, spongistatine, rapamycin and clicktophycin inspires the synthesis of macrocyclic glycoconjugates, which in turn derived from β-C-glycosidic ketones. The synthetic strategy for structurally unique and diverse macrocyclic glycoconjugates is based on three scaffolds: (i) polyfunctional pyran skeleton derived from monosaccharides; (ii) 1,4-disubstituted triazoles and (iii) 1,4,5-trisubstituted triazoles. Glycopyranosyl butanone 25 was obtained by aldol condensation of β-C-glycosidic ketones with a number of substituted aromatic aldehydes.122,123 Further one-pot chemoselective tosylation of primary hydroxyl group (C-6) followed by acetylation of secondary hydroxyl groups (C-2, C-3 and 12
C-4) furnished 6’-O-(tosyl)-tri-O-acetyl-β-D-glycopyranosyl aryl butenones 26 in good yield. The tosyl derivative 26 reacted with sodium azide in DMF at 80 ºC to afford the corresponding 6’-azido derivative, which further underwent Cu-catalysed alkyne-azide cycloaddition with alkynyltosylates to furnish tosyloxytriazoles 27. These triazole derivatives subsequently underwent azidation to afford 6’,4’’-azidoalkyl, triazolyl-β-D-glucopyranose derivatives. Finally tetrabutyammonium hydrogen sulfate prompted intramolecular cycloaddition reaction of azide and alkenone afforded macrocyclic glycoconjugates 28 and subsequent acetyl hydrolysis furnished compounds 29 (Scheme-10).124
n n
n
Scheme 10. Synthesis of macrocyclic glycoconjugates. Concise synthesis of ethylene glycol derivative having different functional group at either ends of the 13
chain, which could form supramolecular structure is a major challenge. The most important application of such molecules are for the treatment of neurodegenerative disorders, injuries of central nervous system and as engineering biomaterials.125-127 A class of C-disaccharides bearing different linking units such as triethylene glycol (TEG), substituted alkyl and alryl moiety was synthesised involving aldol condensation of β-C-glycosidic ketones (30) with TEG-dialdehydes, aromatic dialdehyde (isophthalaldehyde) and heterocyclic dialdehyde (thiophene-2,3-dicarbaldehyde). The resulted α-,β-unsaturated-β -C-glycosidic ketones could undergo Michael addition with another molecule of β-C-glycosidic ketone to give the substituted alkyl ketone linked C-disaccharide derivatives (31-34). In this reaction, the solvent ratio and equivalents of β-C-glycosidic ketones determined the nature of the product formation (Scheme 11).128
Scheme 11. Synthesis of ether-, substituted alkyl- and aryl-linked C-disaccharides. 3.2 Synthesis of spirooxindoles Intermolecular cycloaddition reactions of azomethine ylides with dipolarophiles derived from α-,βunsaturated ketones and acetylenic moiety lead to a number of interesting heterocyclic compounds. These complex molecules are useful for the construction of diverse chemical libraries of drug-like 14
molecules.129-133 One-pot reaction of various α-,β-unsaturated β-C-glycosidic ketones 35 derived from β-C-glycosidic ketone with the azomethine-ylide derived from isatin (1H-indole-2,3-dione) and sarcosine (N-methylglycine), afforded sugar substituted monospirooxindole-pyrrolidines 36. Similarly, compound 35 on reaction with azomethine ylide derived from isatin and L-proline resulted in the formation of monospirooxindole-pyrrolizidines 37. Ether linked dispiro compounds 38 and 39 can also be synthesized using the above discussed strategy. The formation of endo-transition state governs the regioselectivity of this reaction. Cycloaddition reaction of anti-ylide and double bond of
α,β-unsaturated β-C-glycosidic ketones, to give the corresponding expected cycloaddition products 41. The possible repulsive force exerted between the carbonyl groups of oxindole and the sugarderived dipolarophiles rules out the syn-ylide formation (Scheme 12).134-136
15
16
Scheme 12. Synthesis of sugar-based spiro compounds and the proposed mechansim.134 Computational studies reveal that the formation of complex 2 is more preferred than complex 1 because of the possible H-bonding interactions between carbonyl and NH groups of azomethineylide with free hydroxyl groups at C-2 and C-3 positions of sugar-derived dipolarophile (Scheme 12). These results argue that the [3+2]-cycloaddition reaction is more feasible by forming the favoured complex 2. 3.3 Synthesis of nucleoside analogues Naturally occurring nitrogen heterocyclics show several interesting biological activities such as inhibition of dihydrofolate reductase, anti-bacterial and anti-leukaemic activity, to mention a few.137,138 Analogues of nucleosides were synthesized by the condensation of α,β-unsaturated-C-βglycosidic ketones 35 with 6-amino-1,3-dimethyluracil. The optimized condition was the use of
17
sodium ethoxide catalyst in THF/ EtOH (3:1) solvent mixture at room temperature to achieve high yield (Scheme 13).139
Scheme 13. Synthesis of pyrido[2,3-d]pyrimidine-C-β -D-glycosides. 3.4 Synthesis of sugar substituted cyclic oligopyrroles Cyclic oligopyrroles with sugar substitution on the meso-like and β -pyrrolic carbons are rather rare.140,141 A simple two step procedure was used for the preparation of symmetric calix[4]pyrrole containing a chiral moiety. Acid catalysed condensation of pyrrole with ketone derivative 30 resulted in the formation of respective dipyrrolyl derivative 41 and subsequent acid catalysed MacDonald [2+2] reaction with ketone leads to calix[4]pyrrole. These self-assembled solvated chiral systems act as scaffolds and/or chiral inductors. The synthesis started with the preparation of sugar coupled dipyrrolyl derivative 41 involving the reaction of pyrrole and acetylated carbohydrate ketone in an aprotic solvent in the presence of trifluoroacetic acid, which subsequently reacted with acetone in DCM under acidic conditions to afford the expected products 42-44 as an inseparable mixture of diastereoisomers 5,10-cis and 5,10-trans calix[4]pyrrol-5,10-diyl-bis-D-glycero-D-gulo-heptitols (Scheme 14).142
18
Scheme 14. Synthesis of calix[4]pyrrole as a mixture of diastereoisomers.
Scheme 15. Synthesis of monosubstitutedcalix[4]pyrrole. 19
To improve the yield of cyclisation and to avoid the formation of inseparable mixture of diastereomers, experiment was conducted using unprotected carbohydrate derivative (Scheme 15). Here, there was no risk of hydrolysis of ester protective groups at sugar moiety while using methane sulfonic acid as a catalyst. β-C-glycosidic ketone reacted with pyrrole in dry methanol in the presence of methanesulfonic acid to furnish the expected unprotected dipyrrylnonitol 45 (Scheme 15) which further underwent condensation with acetone under same reaction conditions resulted in monosubstituted calix[4]pyrrole 47. The disubstituted derivative was not observed under this experimental condition. 3.5 Morita-Baylis-Hillman reaction Morita-Baylis-Hillman (MBH) reaction[143-146] appeared to be one of the most important reactions and its applications has received growing interest since the mid 1990’s. In addition, MBH ring closing reactions offer opportunities and provide challenges in designing various biologically interesting substrates. The MBH reaction of sugar substituted methyl ketones viz, protected and partially protected β-C-glycosidic ketones, aliphatic and aromatic methyl ketones with ophthaldialdehyde 48 leads to the formation of inden-1-ol derivative 49 (Scheme 16).147 For sugar substituted methyl ketones, moderate yield (53-85 %) was obtained in CHCl3 solvent with a catalytic amount of pyrrolidine at room temperature. Indanones and indenols are effective tubulin polymerization inhibitors and also been used for the treatment of Alzheimer's disease.148-150
Scheme 16. Synthesis of sugar-linked inden-1-ol derivatives. 3.6 MCR reaction for biphenyl methyl-C-β-D-glycosides Mishra and co-workers developed a facile and eco-friendly synthesis of biphenyl methyl β -C20
glycosides in aqueous medium.151 Multicomponent one-pot reaction of unprotected β-C-glycosidic ketones with aromaticaldehyde and malononitrile in the presence of K2CO3 in aqueous medium leads to the formation of biphenyl methyl-C-β-D-glycosides. The methodology developed is quite economical, eco-friendly and doesn’t require any protection or deprotection strategy. This procedure was further extended to obtain related products starting from partially protected sugar derivatives, aromatic aldehydes and malononitrile in the presence of pyrrolidine in THF (Scheme 17).152
Scheme 17. Synthesis of biphenyl methyl β-C-glycosides. 3.7 Synthesis of IBCG, lac operon promoter Genetic engineering calls for a tight regulation system to control the expression of the introduced exogenous genes, and it is generally achieved via inducible gene expression systems.154-156 Isopropyl-
β-D-thiogalactopyranoside (IPTG) is routinely used as an inducer of the lac operon in bacterial systems for in vitro studies to induce the expression of exogenously induced genes.156,157 This sugar analogue binds to lac repressor to activate the gene transcription machinery (Figure 3).158
Insert Figure 3 When IPTG solution is used as the lac operon inducer in animals, IPTG undergoes decomposition and expels an unpleasant thiol smell. To overcome this instability, Liu et al. synthesized a new lac inducer, isobutyl-β -C-galactoside (IBCG), 55, a C-glycoside analogue of IPTG and the methodology established is superior than the previously reported procedures using Lewis acid promoted reaction between galactosepentaacetate and methallyltrimethylsilane or by Grignard reaction between bromoacetogalactose and excess isobutylmagnesium bromide.159 Replacement of the S-glycosidic bond by a C-glycosidic bond renders the resulting molecule much more stable and it showed equal
21
gene induction ability.
Scheme 18. Synthesis of IBCG, lac operon promoter. The crude β-C-glycosidic ketone 51 undergoes per-TMS-silylation reaction leading to the formation of per-silyl substituted β-C-glycosidic ketone 53 which is more soluble in hexane and could be easily extracted from the reaction mixture. The Wittig reaction of compound 53 proceeded well and resulted in the formation of compound 54 in high yield, which was converted into IBCG 55 in two additional steps (Scheme 18). IBCG precursor 52 can also be synthesised by direct protection of sugar hydroxyl group using acetyl chloride or benzylchloride followed by Wittig reaction. The yield isolated by using this synthetic strategy was too low (
S0008-6215(14)00370-X http://dx.doi.org/10.1016/j.carres.2014.10.008 CAR 6856
To appear in:
Carbohydrate Research
Received Date: Revised Date: Accepted Date:
2 September 2014 11 October 2014 16 October 2014
Please cite this article as: Lalitha, K., Muthusamy, K., Siva Prasad, Y., Vemula, P.K., Nagarajan, S., Recent Developments in β-C-Glycosides: Synthesis and Applications, Carbohydrate Research (2014), doi: http:// dx.doi.org/10.1016/j.carres.2014.10.008
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Recent Developments in β-C-Glycosides: Synthesis and Applications† Krishnamoorthy Lalitha,a Kumarasamy Muthusamy,a Y. Siva Prasad,a Praveen Kumar Vemula,b Subbiah Nagarajan*,a
a
Organic Synthesis Group, Department of Chemistry and the Centre for Nanotechnology and
Advanced Biomaterials, School of SASTRA University, Thanjavur - 613401, Tamil Nadu, INDIA Fax: 04362264120; Tel: 04362304270; E-mail: [email protected]. b
Technologies for the advancement of Science, Institute for Stem Cell Biology and Regenerative
Medicine (inStem), National Centre for Biological Sciences, UAS-GKVK post, Bellary Road, Bangalore 560065, India.
*Corresponding author: Organic Synthesis Group, Department of Chemistry and the Centre for Nanotechnology and Advanced Biomaterials, School of Chemical and biotechnology, SASTRA University, Thanjavur - 613401, Tamil Nadu, INDIA Fax: 04362264120; Tel: 04362304270; E-mail: [email protected]. †This article is dedicated to Prof. George John, The City College of New York, New York, NY 10031, USA.
1
Highlights C-Glycoside often rely on green chemistry and facile methodology for their synthesis. Snapshot on different methodology available for C-glycoside synthesis has been discussed. Glycosides are commonly used as pharmacophores, biomaterials and green surfactants. C-Glycosides are considered to be as best alternative for O-, N-, S- glycosides. Other applications of C-glycoside are biomolecules, green surfactants and self-assembled soft-materials.
2
Abstract In the last few years, considerable progress has been made in the synthesis of C-glycosides. Despite its challenging chemistry, due to its versatility, C-glycosides play a pivotal role in developing novel materials, surfactants and bioactive molecules. In this review, we present snapshots of various synthetic methodologies developed for C-glycosides in the recent years and the potential application of C-glycosides derived from β-C-glycosidic ketones.
Graphical abstract
Keywords: C-Glycosides, β-C-Glycosidic ketone, Biomolecules, Green surfactants, Self-assembly
3
1.
Introduction
In carbohydrate chemistry, a glycoside is an organic molecule in which sugar is bound to a noncarbohydrate moiety. Glycosides play several important roles in living organisms such as regulation of plant growth, cardiac muscle stimulant, and the primary function as the source of energy for organisms. Generally glycosides can be linked by an O-, N-, S- and C-glycosidic bonds. Intriguingly, C-glycosides are resistant to both acidic and enzymatic hydrolysis, where the other types of glycosides are unstable under hydrolytic conditions. S-glycosides are also known to be resistant towards enzymatic hydrolysis, but on acidic hydrolysis it leads to the formation of free thiols with offensive odour. C-Glycosides were considered as a stable pharmacophores and known to be used in the synthesis of enzyme inhibitors1 and drug molecules for certain viral diseases such as human immunodeficiency virus (HIV), hepatitis virus B and herpes viruses.2,3 Biological activities of the carbohydrate moiety stood up because of its mien at the interface of the cell and its surroundings in bacteria, parasites, viruses, tumors and numerous other targets. This has led to the development of a vaccine by conjugating the carbohydrate with immunogenic carrier proteins using carbohydrate specific immune response concept. For example, a fully synthetic glycoconjugate vaccine has been developed against Haemophilus influenzae type b.4 In the field of material science, carbohydratebased surfactants represent an increasingly important class of non-ionic surfactants/neutral surfactant such as alkyl polyglucosides (APGs) and sorbitan esters (trade names SPAN® and Tween®) which possess a number of favourable attributes including desirable detergent properties and low toxicity.5 However, carbohydrate-based surfactants generally incorporate either base-labile ester linkages (SPAN®, Tween®, and MGEs), or acid-labile O–glycosidic linkages (APGs) into their structures.6 The instability of these functionalities limits the application of carbohydrate-based surfactants in cosmetics, toiletries, agrochemicals and lubricants.7-9 One potential way to address this issue is to replace O-glycosidic linkage with a more stable C-glycoside linkage. In this review we discuss a decade of research focused on the synthesis of C-glycosides10 and their applications (Figure 1). 4
Insert Figure 1 2.
Synthesis of C-glycosides
2.1 Cross-Coupling approach Aryl-C-glycosides have an aryl ring directly connected to the sugar core that confers their stability towards the enzymatic and chemical hydrolysis. Consequently these molecules are of prodigious significance in medicinal chemistry. Moreover, the aryl ring in aryl-C-glycosides provides them an adequate intracellular lifetime to allow trafficking to the nucleus, where they bind to DNA thus forming stable complexes. They also possess antibacterial, antitumor, and antifungal activities and are potent enzyme inhibitors.11,12
Figure 2. Cross-Coupling approach for the synthesis of C-glycosides. A number of approaches including Heck, Suzuki, Stille and Negishi-type reactions have been developed for the synthesis of C-glycosides employing glycals as key starting materials (Figure 2). Glycals can be attached with aryl moiety involving Heck coupling reaction under different experimental conditions.13-33 Matsuda and co-workers reported the synthesis of indolocarbazole natural product 1, a potential checkpoint kinase 1 inhibitor, comprising Heck reaction followed by a 6-π electron cyclization (Scheme 1).34 5
Scheme 1. Synthesis of C-glycosylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones. Another interesting route for the synthesis of C-glycosides includes the Suzuki cross coupling, which involves the reaction between aryl/vinyl-boronic acids or organoboranes and aryl/vinyl halides or triflates catalysed by palladium complexes.16,17,29,30 35-42 Halogenated glycals or stannyl-glycals act as potential substrate in Stille coupling with organostannanes or organohalides to afford Cglycosides.29,42-47 Li et al., described a new approach towards the synthesis of unusual disaccharide derivatives by connecting two monosaccharides.
Suzuki cross coupling reaction of exo-glycal,
accompanied by hydrogenated deprotection under Pd(OH)2/C, H2 condition lead to the formation of disaccharide derivative. In this case stereoselective hydroboration of exo-glycal confers the βconfiguration of the C-disaccharides.48 C-glycoside can also be synthesised by Negishi coupling reaction of an organozinc compound and an organic halide, catalysed by nickel or palladium complexes. In addition to glycals, glycosyl halides can also be used as starting materials for Negishi cross coupling reaction (Scheme 2).11, 49-51
6
Scheme 2. Synthesis of C-glycoside by Negishi cross coupling approach. Hayashi and co-workers developed an asymmetric synthesis of optically active cis- and trans-2-aryl6-methylpyrans from commercially available tetra-O-acetyl-D-glucopyranosyl bromide. The reaction proceeds by two important steps: one involves the direct arylation in the absence of any organometallic reagents, and the other include deoxygenation at the C-3 position followed by inversion of configuration at the C-2 position (Scheme 3).52
Scheme 3. Synthesis of 2-aryl-3-hydroxy-6-(hydroxymethyl)pyrans. 2.2 Additions of allylsilanes The Ferrier reaction encompasses a nucleophilic substitution reaction along with an allylic shift in a glycal lead to the formation of C-glycosides.
Wide variety of carbon nucleophiles such as
allylsilanes, allyl-, alkyl-, aryl-, and alkynyl metal reagents, TMSCN, isonitriles, enol derivatives, and aromatics are able to react with Ferrier cation of glycal to give C-glycosides. These types of reactions are usually carried out in the presence of Lewis acids, including TMSOTf, BF3.OEt2 or 7
SnCl4.53-71 Recent exploitations in the use of promoters for the Ferrier rearrangement of O-, N-, Cand S-nucleophiles with glycals has been reviewed elsewhere.72,73 In 1982, Kishi and co-workers74 studied highly stereoselective approaches to α- and βglycopyranosides. They described the stereochemical control of the nucleophilic addition to the oxonium ion derived from tetra-O-benzyl-D-pyranose derivatives. The oxonium ion consents nucleophiles from the α-axial side due to the anomeric effect from the oxygen in the ring. Treatment of 2,3,4,6-tetra-O-benzyl-D-glucopyranose with allyltrimethylsilane and BF3.OEt2 in acetonitrile furnished the product with high stereoselectivity. Horton et al.75 have reported the synthesis of 3(2,3,4,6-tetra-O-acetyl-α,β-D-glucopyranosyl) propene 8 and 9 in 23% combined yield with α:β ratio 5:1 (Scheme 4).76
Scheme 4. Synthesis of allyl C-glycosides. Nucleophilic addition of allyltrimethylsilanes, alkynyltrimethylsilanes, silyl cyanides etc. at the anomeric carbon of glycals with simultaneous loss of a substituent at C-3 yielded the corresponding C-glycosides.77 This lead to double bond migration to give 2,3-unsaturated sugars which could act as useful chiral substrate for further manipulation in organic synthesis. Danishefsky et al. reported the nucleophilic addition of glycal acetates with allyltrimethylsilanes in the presence of equimolar amounts of TiCl4 as a Lewis acid.78 Nicolaou and co-workers manifested the stereoselective allylation at the C-1 position in 1-alkylglucal 10 using TiCl4 to obtain compound 11 (Scheme 5).79 Under this reactive conditions, selective formation of C-glycoside was favored at lower temperature 8
and yield of the reaction was dependent on the reaction medium. Yadav et al. have also contributed in this field by using several Lewis acids, such as molecular iodine, InBr3, Bi(OTf)3, LiBF4, Sc(OTf)3 and phosphomolybdic acid supported on silica gel. 80-85
Scheme 5. Stereoselective allylation of 1-alkylglucal. Similar to allylsilanes, alkenylsilanes can also be used for the related transformation. Silylacetylenes were found to be reactive enough to generate the corresponding C-glycosides (Scheme 6). Ferrier type alkynylation of glucals using activated alkynes viz allyltrimethylsilane as nucleophile in the presence of ZrCl4, HClO4-SiO2, Er(OTf)3, TMSOTf, AuCl3 or Zeolite lead to the formation of expected products in excellent yield with very good α-selectivity.13, 73, 86-94
Scheme 6. Ferrier type alkynylation of glucals using activated alkynes. Mukherjee and co-workers lately manifested a stereoselective C-glycosylation reaction between glycal 14 and unactivated alkynes 15 in the presence of copper triflate and ascorbic acid to afford the corresponding C-glycosides 16 (Scheme 7).95
9
Scheme 7 - Stereoselective C-glycosylation of glycal using unactivated alkynes. 2.3 Radical addition method Similar to cross coupling approach and addition of allylsilanes, radical addition between highly electrophilic radicals (fluorinated or unfluorinated) and 2-benzyloxyglucal or galactal opens a new path for the synthesis of C-glycosides (Scheme 8).96-105 The formation of both α and β anomers 18 and 19 is the major drawback of this methodology.
Scheme 8. Addition of ethyl bromodifluoroacetate to 2-benzyloxyglucal. 2.4 Knoevenagel condensation The transformation of β-C-glycosidic ketone, bio-based precursor obtained by the reaction of partially protected/unprotected sugars with acetylacetone in water, into C-glycosides is of particular 10
interest in carbohydrate chemistry due to its mild reaction conditions. The first one-step procedure for the synthesis of was reported by Gonzalez and co-workers reported the simple procedure for the preparation of C-glycosides directly by the reaction of unprotected carbohydrates with the nucleophile derived from malonate derivative in the presence of water, considered to be a green solvent.8,9 Subsequently, Rodrigues et al. has further developed this green protocol to a wide range of 1,3-diketone in alkaline aqueous media, which lead to the exclusive formation of β-Cglycosides.106 Knoevenagel condensation between the formyl group of unprotected sugar with active methylene group of 1,3-diketone is the key step for both the reactions. This could be a more soaring strategy for the synthesis of C-glycosides and most adept choice for cross coupling, addition of allylsilanes and radical addition methods. A facile one-step synthesis of C-glycosides from unprotected sugars involving Horner-WadsworthEmmons reaction in water or under solvent-free conditions has been reported.12-14,107-111
However,
most of these method led to β-C-pyranosides as the main products. Recently Wang et al. developed a stereoselective procedure for the preparation of ketone β-C-pyranosides 21 and ketone β-Cfuranosides 22 upon condensation of pentane-2,4-dione with various unprotected sugars 20 in presence of sodium carbonate in water. At 90 ºC, the ketone β-C-pyranoside 21 was obtained in excellent yields (up to 97%) in short reaction time. In contrast, at 10 ºC, the ketone C-furanosides, 24 were the main products obtained in 83-97% yields (Scheme 9).112
11
Scheme 9. Synthesis of β-C-glycosides.
3.
Application of β-C-glycosidic ketones
3.1 Synthesis of sugar based macrolides The pharmacological properties of macrocycles originates from their structural complexity, rigidity and ability to form stable, inter- and intramolecular hydrogen bonding.113-116 In this context several research groups focused on the synthesis of carbohydrate based macrocycles that can form extensive hydrogen bonding networks.117-121 Biologically active macrolides such as kendomycin, bryostatin, spongistatine, rapamycin and clicktophycin inspires the synthesis of macrocyclic glycoconjugates, which in turn derived from β-C-glycosidic ketones. The synthetic strategy for structurally unique and diverse macrocyclic glycoconjugates is based on three scaffolds: (i) polyfunctional pyran skeleton derived from monosaccharides; (ii) 1,4-disubstituted triazoles and (iii) 1,4,5-trisubstituted triazoles. Glycopyranosyl butanone 25 was obtained by aldol condensation of β-C-glycosidic ketones with a number of substituted aromatic aldehydes.122,123 Further one-pot chemoselective tosylation of primary hydroxyl group (C-6) followed by acetylation of secondary hydroxyl groups (C-2, C-3 and 12
C-4) furnished 6’-O-(tosyl)-tri-O-acetyl-β-D-glycopyranosyl aryl butenones 26 in good yield. The tosyl derivative 26 reacted with sodium azide in DMF at 80 ºC to afford the corresponding 6’-azido derivative, which further underwent Cu-catalysed alkyne-azide cycloaddition with alkynyltosylates to furnish tosyloxytriazoles 27. These triazole derivatives subsequently underwent azidation to afford 6’,4’’-azidoalkyl, triazolyl-β-D-glucopyranose derivatives. Finally tetrabutyammonium hydrogen sulfate prompted intramolecular cycloaddition reaction of azide and alkenone afforded macrocyclic glycoconjugates 28 and subsequent acetyl hydrolysis furnished compounds 29 (Scheme-10).124
n n
n
Scheme 10. Synthesis of macrocyclic glycoconjugates. Concise synthesis of ethylene glycol derivative having different functional group at either ends of the 13
chain, which could form supramolecular structure is a major challenge. The most important application of such molecules are for the treatment of neurodegenerative disorders, injuries of central nervous system and as engineering biomaterials.125-127 A class of C-disaccharides bearing different linking units such as triethylene glycol (TEG), substituted alkyl and alryl moiety was synthesised involving aldol condensation of β-C-glycosidic ketones (30) with TEG-dialdehydes, aromatic dialdehyde (isophthalaldehyde) and heterocyclic dialdehyde (thiophene-2,3-dicarbaldehyde). The resulted α-,β-unsaturated-β -C-glycosidic ketones could undergo Michael addition with another molecule of β-C-glycosidic ketone to give the substituted alkyl ketone linked C-disaccharide derivatives (31-34). In this reaction, the solvent ratio and equivalents of β-C-glycosidic ketones determined the nature of the product formation (Scheme 11).128
Scheme 11. Synthesis of ether-, substituted alkyl- and aryl-linked C-disaccharides. 3.2 Synthesis of spirooxindoles Intermolecular cycloaddition reactions of azomethine ylides with dipolarophiles derived from α-,βunsaturated ketones and acetylenic moiety lead to a number of interesting heterocyclic compounds. These complex molecules are useful for the construction of diverse chemical libraries of drug-like 14
molecules.129-133 One-pot reaction of various α-,β-unsaturated β-C-glycosidic ketones 35 derived from β-C-glycosidic ketone with the azomethine-ylide derived from isatin (1H-indole-2,3-dione) and sarcosine (N-methylglycine), afforded sugar substituted monospirooxindole-pyrrolidines 36. Similarly, compound 35 on reaction with azomethine ylide derived from isatin and L-proline resulted in the formation of monospirooxindole-pyrrolizidines 37. Ether linked dispiro compounds 38 and 39 can also be synthesized using the above discussed strategy. The formation of endo-transition state governs the regioselectivity of this reaction. Cycloaddition reaction of anti-ylide and double bond of
α,β-unsaturated β-C-glycosidic ketones, to give the corresponding expected cycloaddition products 41. The possible repulsive force exerted between the carbonyl groups of oxindole and the sugarderived dipolarophiles rules out the syn-ylide formation (Scheme 12).134-136
15
16
Scheme 12. Synthesis of sugar-based spiro compounds and the proposed mechansim.134 Computational studies reveal that the formation of complex 2 is more preferred than complex 1 because of the possible H-bonding interactions between carbonyl and NH groups of azomethineylide with free hydroxyl groups at C-2 and C-3 positions of sugar-derived dipolarophile (Scheme 12). These results argue that the [3+2]-cycloaddition reaction is more feasible by forming the favoured complex 2. 3.3 Synthesis of nucleoside analogues Naturally occurring nitrogen heterocyclics show several interesting biological activities such as inhibition of dihydrofolate reductase, anti-bacterial and anti-leukaemic activity, to mention a few.137,138 Analogues of nucleosides were synthesized by the condensation of α,β-unsaturated-C-βglycosidic ketones 35 with 6-amino-1,3-dimethyluracil. The optimized condition was the use of
17
sodium ethoxide catalyst in THF/ EtOH (3:1) solvent mixture at room temperature to achieve high yield (Scheme 13).139
Scheme 13. Synthesis of pyrido[2,3-d]pyrimidine-C-β -D-glycosides. 3.4 Synthesis of sugar substituted cyclic oligopyrroles Cyclic oligopyrroles with sugar substitution on the meso-like and β -pyrrolic carbons are rather rare.140,141 A simple two step procedure was used for the preparation of symmetric calix[4]pyrrole containing a chiral moiety. Acid catalysed condensation of pyrrole with ketone derivative 30 resulted in the formation of respective dipyrrolyl derivative 41 and subsequent acid catalysed MacDonald [2+2] reaction with ketone leads to calix[4]pyrrole. These self-assembled solvated chiral systems act as scaffolds and/or chiral inductors. The synthesis started with the preparation of sugar coupled dipyrrolyl derivative 41 involving the reaction of pyrrole and acetylated carbohydrate ketone in an aprotic solvent in the presence of trifluoroacetic acid, which subsequently reacted with acetone in DCM under acidic conditions to afford the expected products 42-44 as an inseparable mixture of diastereoisomers 5,10-cis and 5,10-trans calix[4]pyrrol-5,10-diyl-bis-D-glycero-D-gulo-heptitols (Scheme 14).142
18
Scheme 14. Synthesis of calix[4]pyrrole as a mixture of diastereoisomers.
Scheme 15. Synthesis of monosubstitutedcalix[4]pyrrole. 19
To improve the yield of cyclisation and to avoid the formation of inseparable mixture of diastereomers, experiment was conducted using unprotected carbohydrate derivative (Scheme 15). Here, there was no risk of hydrolysis of ester protective groups at sugar moiety while using methane sulfonic acid as a catalyst. β-C-glycosidic ketone reacted with pyrrole in dry methanol in the presence of methanesulfonic acid to furnish the expected unprotected dipyrrylnonitol 45 (Scheme 15) which further underwent condensation with acetone under same reaction conditions resulted in monosubstituted calix[4]pyrrole 47. The disubstituted derivative was not observed under this experimental condition. 3.5 Morita-Baylis-Hillman reaction Morita-Baylis-Hillman (MBH) reaction[143-146] appeared to be one of the most important reactions and its applications has received growing interest since the mid 1990’s. In addition, MBH ring closing reactions offer opportunities and provide challenges in designing various biologically interesting substrates. The MBH reaction of sugar substituted methyl ketones viz, protected and partially protected β-C-glycosidic ketones, aliphatic and aromatic methyl ketones with ophthaldialdehyde 48 leads to the formation of inden-1-ol derivative 49 (Scheme 16).147 For sugar substituted methyl ketones, moderate yield (53-85 %) was obtained in CHCl3 solvent with a catalytic amount of pyrrolidine at room temperature. Indanones and indenols are effective tubulin polymerization inhibitors and also been used for the treatment of Alzheimer's disease.148-150
Scheme 16. Synthesis of sugar-linked inden-1-ol derivatives. 3.6 MCR reaction for biphenyl methyl-C-β-D-glycosides Mishra and co-workers developed a facile and eco-friendly synthesis of biphenyl methyl β -C20
glycosides in aqueous medium.151 Multicomponent one-pot reaction of unprotected β-C-glycosidic ketones with aromaticaldehyde and malononitrile in the presence of K2CO3 in aqueous medium leads to the formation of biphenyl methyl-C-β-D-glycosides. The methodology developed is quite economical, eco-friendly and doesn’t require any protection or deprotection strategy. This procedure was further extended to obtain related products starting from partially protected sugar derivatives, aromatic aldehydes and malononitrile in the presence of pyrrolidine in THF (Scheme 17).152
Scheme 17. Synthesis of biphenyl methyl β-C-glycosides. 3.7 Synthesis of IBCG, lac operon promoter Genetic engineering calls for a tight regulation system to control the expression of the introduced exogenous genes, and it is generally achieved via inducible gene expression systems.154-156 Isopropyl-
β-D-thiogalactopyranoside (IPTG) is routinely used as an inducer of the lac operon in bacterial systems for in vitro studies to induce the expression of exogenously induced genes.156,157 This sugar analogue binds to lac repressor to activate the gene transcription machinery (Figure 3).158
Insert Figure 3 When IPTG solution is used as the lac operon inducer in animals, IPTG undergoes decomposition and expels an unpleasant thiol smell. To overcome this instability, Liu et al. synthesized a new lac inducer, isobutyl-β -C-galactoside (IBCG), 55, a C-glycoside analogue of IPTG and the methodology established is superior than the previously reported procedures using Lewis acid promoted reaction between galactosepentaacetate and methallyltrimethylsilane or by Grignard reaction between bromoacetogalactose and excess isobutylmagnesium bromide.159 Replacement of the S-glycosidic bond by a C-glycosidic bond renders the resulting molecule much more stable and it showed equal
21
gene induction ability.
Scheme 18. Synthesis of IBCG, lac operon promoter. The crude β-C-glycosidic ketone 51 undergoes per-TMS-silylation reaction leading to the formation of per-silyl substituted β-C-glycosidic ketone 53 which is more soluble in hexane and could be easily extracted from the reaction mixture. The Wittig reaction of compound 53 proceeded well and resulted in the formation of compound 54 in high yield, which was converted into IBCG 55 in two additional steps (Scheme 18). IBCG precursor 52 can also be synthesised by direct protection of sugar hydroxyl group using acetyl chloride or benzylchloride followed by Wittig reaction. The yield isolated by using this synthetic strategy was too low (
