Chapter 3: Stereoselective Synthesis of 2,3-dideoxy glycosides via anomeric C-Glycosylation.
C-Glycosylation is of great significance in the synthesis of optically active compounds, in particular, interest due to their worth as key intermediates for assembling biologically active molecules. It allows the introduction of carbon chains into sugar chiron and the use of sugar nuclei as chiral pools as well as carbon sources.8 C-glycosides are resourceful chiral building blocks for the construction of many biologically interesting polyether natural products such as palytoxin, spongistatin, halichondrin, etc.9 Ferrier reaction is a well-known reaction it is the most basic and key reaction of carbohydrates.10 Several reagent systems have been established to construct the C-glycosides.11 Developing new methods using nontoxic reagent systems is always required However, we developed A new approach for preparing 2,3-unsaturated C-glycosides by using Zn(OTf)2 as Lewis acid catalyst (Scheme 3).
Table 4 Standardization of Ferrier C-Glycosylation conditions
Scheme 3: Zn(OTf)2 catalyzed C-glycosylation.
Reaction conditions: All reactions were performed with glucal (1.0 equiv.), acceptor (1.2 equiv.) in 1,2-dichloroethane, 10 mol% of Zn(OTf)2 used at 40 oC, ? : ?? ratios were examined by 1H NMR.
Our study began with the conversion of glucal (1) to Allyl 4, 6-O-acetyl Glycoside 3a. On the reaction of Glycal 1a with allyl trimethyl silane 2a and 10 mol% Zn(OTf)2. Initially, the reaction done in DCM at room temperature gives a 54% yield in 16h, better yields obtained by increasing temperature to 40 oC. The further reaction is done for improving the yield in DCE solvent at a 40 oC reaction was completing within 1h affords desired product with a 96% yield.
Figure 3: Scope of C- Glycosylation of glycals using a wide range of nucleophiles.
The stereochemistry of newly formed stereocenters in compound 3a was correlated by spectroscopic analysis and compared with literature data. This method was elaborated by using a range of acceptors including trimethylsilyl cyanide 2b, triethyl silane 2c, trimethylsilylazide 2d give the corresponding glucosides as an inseparable mixture of isomers, Furthermore, the silyl ether 2e and ?-keto ester 2f were successfully reacted with glycal affords the desired product. Next, we examined the glycosylation of heterocycles such as furan 2g resulted in the mixture (1:1) of the corresponding C-3 and C-1 epimers and thiophene 2h. glycosides which are synthesized using acceptors 2a-2h are tabulated (Figure 3).
Scope of the reaction was further illustrated with different types of Glycals like Galactal (1c), Rhamnal (1d), Xylal (1e), and Arabinal (1f) with wide range of acceptors like Allyl TMS 2a, Trimethylsilylcyanide 2b, Triethylsilane 2c, Trimethylsilylazide 2d, silyl enol ether 2e, and thiophene 2h. Performed respectively under zinc mediated C-Glycosylation to obtain the desired glycosides (3-27) with good yield and high anomeric selectivity. The synthetic utility of the present method was further extended to disaccharide D-Lactal (1g) and is tabulated. Next, Glycosylation reaction was performed using activated alkyne acceptors to access C-alkynylated sugars. These chiral sugar derivatives transformed in to various glycoconjugates, different Glycals Glucal (1a), Galactal (1c), Rhamnal (1d), Xylal (1e), Arabinal (1f), and D-Lactal (1g) were successfully glycosylated with Phenyl (trimethylsilyl)acetylene under present reagent system at ambient temperature to generate C-1 alkynylated Glycosides 28-32 with high anomeric selectivity are tabulated (Figure 4).
Figure 4: Stereoselective Synthesis of C-Alkynylated Glycosides.
After successful synthesizing the C-glycosides of various glycals on reacting with Silylated nucleophiles we extended to study of C-alkylation by using AlMe3 as model acceptor. A solution of AlMe3 (2.0 M in hexane, 1.5 equiv.) on reacting with glucal 1a (1.0 equiv.) in DCE solvent at 0 ?C in the presence of Zn(OTf)2 (10 mol%) for 1h affords desired product in 94% yield with 80 : 20, ????? mixture. Similarly, Galactal (1c), Xylal (1e), Arabinal (1f), and D-Lactal (1g) are successfully converted into C-alkylated derivatives.
Reaction condition: All reactions were performed with glycal (1.0 equiv.), acceptor (1.5 equiv.) in 1,2-dichloroethane, 10 mol% of Zn(OTf)2 used at 0 oC, Isolated and unoptimized yields, ? : ?? ratios were examined by 1H NMR spectroscopy.
Figure 4: Stereoselective Synthesis of C-Alkylation.
In summary, we developed a highly efficient method for incorporated anomeric C-glycosidic linkages in 2,3 unsaturated glycosides and should potentially give rise to a large number of pseudo-oligosaccharides and glycoconjugates.
Chapter 4: Sulfonium iodate salt promoted the vicinal bifunctionalization of glycal.
2-Deoxy sugars and their derivatives are important synthetic intermediates for constructing several valuable glycoconjugates12 and natural products.13 Due to limited amounts of these molecules can be isolated from natural sources, it is critical to developing efficient tools for the stereoselective synthesis of oligosaccharides to extensively study their structure and activity relationship for the discovery of effective therapeutic agents. Because of their pharmacological properties, the stereoselective preparation of 2-deoxy sugars has gained considerable attention and remains a challenging task.14 Hypervalent iodine as an environmentally benign and valuable oxidizing agent has led to the development of greener and more attractive alternatives to toxic metal oxidants.15
In our research, we reported a simple, efficient, method developed for the synthesis of 2-deoxy-2-iodo glycosides and glycoconjugates using sulfonium-salt reagent system. Me3SI(OAc)2 which prepared from Me3SI and PhI(OAc)2, promotes the glycal into 2-deoxy-2-iodo-?-manopyranoside and 2-deoxy-2-iodo-?-glucopyranoside (Scheme 4).
Table 4 Standardization for iodoacetoxylation of glycal a
Scheme 4: Sulfonium salt mediated vicinal bifunctionalization
a. Reaction conditions: Glucal (1.0 equiv.), solvent (1 mL), 25 °C., b. Isolated yield after column chromatography, c. Diastereomeric ratios were determined by 1H NMR spectroscopy, d. Reactions were carried out in one pot.
Initially, our study began for the iodoacetoxylation of glucal 1a (1.0 equiv.) with sulfonium salt 3a (1.1 equiv.) under an inert atmosphere. The reaction was checked in different solvent Acetic acid gives the better result within 10 min in 92% yield with 78: 22, ???? ratio, at the same time better yields are obtained in one-pot condition with 98% yield with 80: 20, ???? ratio. Further optimization in the one-pot condition under different solvents doesnt provide any improvement in selectivity.
After successful by functionalization of next this method was elaborated with various glycals and the results are summarized (Figure 5).
Figure 5: One-pot iodoacetoxylation of glycals
Motivated by these results we next studied the viability of Sulfonium salt reagent with a wide range of carboxylic acids to get structurally diverse glycoconjugates (Scheme 5). Me3SI(OAc)2 on reacting with benzoic acid forms iodobenzoate salt with formula Me3SI(OBz)2 which successfully converts glucal into 2-Iodo-2-deoxyglycosyl benzoate with good yield and selectivity.
Scheme 5: Sulfonium salt promoted one-pot iodo carboxylation.
Next, we studied this protocol with sterically divorced carboxylic acids having aromatic, alicyclic, aliphatic and heterocyclic compounds are successfully transformed into corresponding glycoconjugates are summarized (Figure 6)
Figure 6: Substrate scope of various carboxylic acids
By encouraging the above results we next focused to promote the haloazidation of glycals. Which are the precursors to the synthesis of 2-aminosugars through 2-deoxyglycosyl azide intermediates. We Optimized initially azidoiodination of glucal on reacting with Sulfonium salt and TMSN3 (3 equiv.) in DCM which affords a mixture of glycosyl azides 46 (42% yield) and glycosyl acetates 6 (36% yield) after 24 h at room temperature, better yield was observed when the amount of TMSN3 (5 equiv.) increased. By changing the azide source to NaN3 (3.0 equiv.), the reaction performed well in acetonitrile solvent gives the desired product with improved yield of 96% (Scheme 7). After successful optimization, we extended this protocol to promote haloazidation of different glycals.
Scheme 7: One-pot iodo azidation of glucal.
We next observed sulfonium salt promoted one-pot alkoxylation by using methanol as a nucleophile reacts with glucal converts into 2-iodo-2-deoxyglycoside 51 in 94 % yield with 84: 16, ???? mixture.
Scheme 8: One-pot alkoxyiodination of glucal.
Further, we demonstrated the synthesis of 1,2-cohalogenation of cyclic enol ethers and alkenes by using sulfonium salt, which bifunctionlize the alkenes into iodocarboxylation, iodoacetoxylation and iodoazidation with excellent yield and good selectivity.
Scheme 9: One-pot vicinal bifunctionalisation of alkenes
In summary, we developed a new reagent system for the vicinal functionalization glycal into one pot glycoconjugates in a stereocontrolled manner. The new sulfonium reagent is conveniently generated in situ under metal-free conditions. The transformation is run at ambient temperature under mild reaction conditions.