Cl^–···H–N Interaction Assisted Addition of Sulfonamides to Enol Ethers: Synthesis of 2-Deoxy and 2,6-Dideoxy Sulfonamido Glycosides

Abstract

The strained/frustrated electrostatic interactions between the ion pair of TTBPy⁺X^– increases the reactivity in both the ions, resulting in the activation of a third molecule like sulfonamides (aromatic/­aliphatic) via hydrogen bonding. This intriguing weak-interactions-based reactivity has been utilized to develop an organocatalytic synthesis of 2-deoxy-sulfonamido-glycosides from glycals. The sulfonamidoglycosylation of glycals using a catalytic amount of 2,4,6-tri-tert-butylpyridinium salts proceeded stereoselectively to provide N-glycosides in good to high yields. This process was demonstrated with l-rhamnal and d-galactal. Besides, IR spectroscopic studies explain that the hindered protonated pyridine cannot behave as a cationic Brønsted acid as is generally perceived.

2,4,6-Tri-tert-butylpyridine (TTBPy)[1] and other sterically strained pyridine analogues 2,6-di-tert-butylpyridine (DTBP), 2,6-di-tert-butyl 4-methylpyridine (DTBMP), and 2,4,6-tri-tert-butylpyrimidine (TTBP) are known for their unique reactivity in various organic reactions. Considering the inductive effects caused by the presence of tert-butyl groups in these molecules, these are expected to be more basic than pyridine and lutidine. In contrast, the observed aqueous pK _a value of TTBPy is about ca. 2 units lesser (pK _a of TTBPy = 3.4) than expected that is attributed to the poor solvation of the protonated pyridinium cation. The steric bulk at ortho positions of the 2,6-disubstituted pyridines block the cationic site from solvation making the entity unstable. These sterically bulky molecules that can differentiate between Brønsted acids and Lewis acids have found application as proton-trapping agents.[2] The non-nucleophilic basic character of TTBPy has been exploited in various organic transformations, e.g., in characterizing the concentration of acylium ions in aromatic acylation reactions,[3] in the synthesis of indole triflones[4] along with its recently found utility as Lewis base in frustrated Lewis pair in the presence of B(C₆F₅)₃ that can heterolytically cleave H₂.[5] Also, Ye and coworkers observed an interesting anomeric stereoswitch in stereoselective glycosylation of 2,3-oxazolidinone thioglycoside in the presence and absence of 2,4,6-tri-tert-­butylpyrimidine.[6] [7] Due to the complete shielding of the cationic [N–H]⁺ site by the bulky ortho-tert-butyl groups, the [N–H]⁺···Cl^– distance is found to be unusually longer (3.10 Å) even in the solid state.[8] We hypothesized that due to the weakening of the cation–anion interactions in the sterically bulky TTBPy salts owing to the steric bulk, the anions show increased reactivity in organic solvents and can activate any third molecule, which we call as frustrated Brønsted pair reactivity.[9] The mild activation conditions have been exploited in the stereoselective synthesis of O- and S-glycosylation reactions from glycals.[9] [10] In this work we show the ability of the TTBPy·HCl salt to activate the aliphatic and aro­matic sulfonamides via frustrated Brønsted pair catalysis to synthesize the biologically important 2-deoxysulfonamidoglycosides.

Sulfonamides are known to possess a broad spectrum of biological activities. Several sulfonamides have appeared as useful therapeutics for the treatment of cancer and chemotherapy. E7010, E7070, T138067, and ABT-751 are found to be the inhibitors of tumor cell proliferation and some of them are under clinical evaluation as potential drugs.[11] The mechanism of antitumor activity of some of these compounds has been studied in detail and was found that they inhibit microtubule assembly by binding to tubulin at the colchicine binding site.[12] Sulfonamides possessing a free sulfonamido moiety act as strong carbonic anhydrase inhibitors.[13] In addition, hypoglucemic sulfonamides are used in the treatment of some forms of diabetes as well.[14] [15] Despite the significance, the literature on the synthesis of sulfonamido glycosides is scarce.[16,17] Danishefsky’s group synthesized 2-iodo glycosylsulfonamides 4aa by reacting glycals with benzene sulfonamide 2a in the presence of iodonium di-sym-collidine (Scheme [1, a])[18] and were used in the synthesis of oligosaccharides as well. The direct synthesis of 2-deoxyglycosylsulfonamides from benzyl-­protected glycals (1a,b) has been achieved by P. A. Colinas et al., using catalytic amounts of triphenylphosphine hydrobromide (Scheme [1, b]).[19] It was observed that a change of Brønsted acid to camphor sulfonic acid leads to lower yields of the product. Use of strong Lewis acids like BF₃·Et₂O[20] or strong acid source like HClO₄·SiO₂ [21] [22] provides access to 2,3-unsaturated N-glycosylsulfonamides. Recently, Pedersen and coworkers have developed a self-promoted glyco­sylation method to synthesize 2-oxy-β-N-glycosyl sulfonyl amides.[23] Given the significance of the sulfonamides, it is important to develop other milder methods for the direct synthesis of 2-deoxysulfonamidoglycosides.

After successfully utilizing the bulky pyridine catalysis for O- and S-glycocosylation reactions,[8] [9] [10] here, in the current work, we present this mild and unique anion-based-activation catalyzed synthesis of 2-deoxy glycosylsulfonamides in a highly efficient and stereoselective fashion. Our attempts started by using 3,4,6-tri-O-(p-methylbenzyl)-d-galactal (1c) and ortho-toluenesulfonamide (2c) as starting materials and the chloride salt 3a as the catalyst in dichloroethane as the solvent. The reaction between 1c and 2c led to no conversion under 5 mol% of the catalyst even at 40 °C. However, we found that the sulfonamidoglycosylation proceeded smoothly at 40 °C when 20 mol% of the catalyst 3a were used along with 1.5 equiv of the sulfonamide. The product 4cc was obtained in 75% yield and with an anomeric ratio of 1:3.4 in favor of β-isomer. To decipher the roles of cation and anion in the current bulky pyridinium catalysis, we then performed the experiments by varying the anions of the catalyst. The reactions were performed with TTBPy salts of bromide, iodide, triflate, and BAr^F ₄ as anions the results of which are tabulated in Table [1]. When galactal 1c was treated with o-toluenesulfonamide in the presence of 20 mol% of various salts, it was observed that the bromide salt gave the product in a lower yield of 66% after 24 h, relative to the chloride salt (Table [1], entry 2). A further drop in yields of the product was observed with iodide and triflate salts under the same reaction conditions (41% and 46% respectively, Table [1], entries 6 and 7). Intriguingly, no conversion is observed when the anion is switched to a weakly coordinating BAr^F ₄. These studies clearly demonstrate the criticality of anions under the current transformation. The more weakly coordinating the anion is, the lesser reactive is the catalyst. Furthermore, no reaction was observed when polar solvents like DMF or DMSO were used (Table [1], entries 3 and 4, respectively). Again, these experiments showcase the significance of the nonpolar solvents in the current transformation. The polar solvents in which the individual ions are stabilized would remove any kind of strain or frustration within the ion pair and hence cannot catalyze the transformation. With the optimized conditions in hand,[24] various sugar glycals have been subjected to the conditions to provide the corresponding 2-deoxysulfonamides. The protocol has been tested with various substituted benzene sulfonamides 2b–e by reacting them with O-TBDMS-, O-TIPDS-, O-Bn-, and O-(p-MeBn)-protected rhamnal and galactal donors 1c–g where products 4 are obtained in good yields with moderate to good stereoselectivity (Scheme [2]).

Table 1 Optimization of Reaction Conditions

Entry	Catalyst	mol%	Solvent	Time	Yield (%)	Selectivity (α:β)a
1	3a	5	DCE	24 h	–	–
2	3a	20	DCE	24 h	75	1:3.4
3	3a	20	DMF	24 h	–	–
4	3a	20	DMSO	24 h	–	–
5	3b	20	DCE	24 h	66	1:3
6	3c	20	DCE	2 d	41	1:3
7	3d	20	DCE	2 d	46	1:3
8	3e	20	DCE	2 d	–	–

^a Anomeric selectivities were determined by ¹H NMR analysis.

No significant change in stereoselectivity was observed when the protecting group is changed from silyl to benzyl and p-methylbenzyl on rhamnose based donors. p-Methylbenzyl-protected galactal donor reacted with sulfonamide acceptor 2c and 2d to provide respective glycosylated compound 4cc and 4cd with 75% and 66% yield, respectively. Aliphatic sulfonamide 2e also smoothly coupled to 1e and 1g to give expected products 4ee and 4ge, with 72% and 75% yield, respectively, and in favour of β-stereoselectivity. All of these donors gave β-glycosylsulfonamide as the major isomer irrespective of the sulfonamide acceptor used. The stereochemistry of the products have been confirmed by NOE analysis and also the coupling constants. When the signal for the anomeric proton of 4ee [25] at 4.80 ppm was irradiated, an enhancement in the signal at 3.35 ppm corresponding to H-5 was observed suggesting the cis relation between the sulfonamide group and the C5-methyl group (refer to the Supporting Information for details).

Interestingly, when 3,4-di-O-tert-butyldiphenylsilyl-l-rhamnal (1h) was reacted with p-tolylsulfonamide under the reaction conditions, it surprisingly led to stereoswitch and gave the α-product as the major anomer (α:β = 6:1). Later, the coupled products of 1h with other sulfonamides have also been prepared (Scheme [3]). In all the cases, the sulfonamidoglycosides 5ha–e were obtained with excellent stereoselectivity ratios ranging from 6:1 to 16:1 favoring α-isomer. The stereochemistry of the products has been again confirmed by NOE analysis. The irradiation of the signal for H-1 at 5.40 ppm for the compound 5he [26] led to an enhancement of the signal for the C-5 methyl doublet at 1.31 ppm confirming the α-stereochemistry of the glycosylsulfonamide (refer to the Supporting Information for details). In order to understand the mechanism, a few control experiments were performed. Firstly, the reaction between the rhamnal and the methylsulfonamide when performed in the absence of the catalyst did not lead to any conversion, suggesting the importance of the catalyst (Scheme [4], eq. 1). We are aware that the catalyst 3a cannot behave as a cationic Brønsted acid as the steric crowding on the ortho position of the pyridinium does not allow the proton transfer to the glycal (Figure [1, a])[10] suggesting a unique mechanism for this transformation.

Also, a few solid-state IR studies were performed. Unlike other pyridines, the protonated [TTBPyH]⁺ gives a sharp signal at 3346 cm^–1 for the N–H stretch in the IR spectrum indicating the inability of the N–H proton to involve in any H bonding. When the IR spectrum was recorded with a 1:1 mixture of TTBPy·HCl with p-toluene sulfonamide (2b), no change was observed for the N–H stretch of the bulky pyridinium species demonstrating the sulfonamide is not involved in any interaction with the cationic species (Figure [2, a]). However, the intensity of the stretch corresponding to the NH₂ doublet of the sulfonamide is significantly decreased indicating some interaction with the bulky pyridine salt presumably with the anion. Also, the reaction did not proceed under the optimized reaction conditions when performed in dark (Scheme [4], eq. 2). In addition, no product formation was observed in the presence of a radical-trapping agent TEMPO (Scheme [4], eq. 3). These experiments suggest the possible involvement of a frustrated radical pair (FRP) species in the current transformation akin to the recent of observation of radicals in the FLP catalysis.[27] When an ESR spectrum was recorded with a 1:1 mixture of 3a and 2d at rt, the spontaneous generation of a mild ESR signal having g value 2.03 was observed (Figure [2, b]). The signal is not conclusive and provides only little evidence towards the involvement of any radical species under the reaction conditions. However, the IR experiments, along with the control experiments and the optimization studies with various salts, point to an anion-directed activation similar to the O- and S-glycosylation reactions.[9] [10] The anions associated with the sterically bulky 2,4,6-tri-tert-butylpyridinium, due to the strain within the ion pair is imparted with unusual reactivity and can polarize the N–H bond of the sulfonamido group. The thus mildly acidic N–H proton protonates the glycals forming an oxocarbenium ion which undergoes a nucleophilic addition leading to the observed N-glycosylated products (Figure [1, b]). The applicability of current mild catalysis for the sulfonamidoglycosylation protocol towards large-scale synthesis was also investigated. We were delighted to find that 1 g of di-O-TBDPS-protected l-rhamnal 1h was reacted with glycosyl sulfonamide acceptor 2d in the presence of 20 mol% of 3a in DCE at 40 °C and afforded the corresponding sulfonamidoglycoside 5hd in 62% yield with α-selectivity (Scheme [5, a]). Also, N-alkylation of one of the derivatives (5hd) has been performed to showcase the utility of these sulfonamidoglycosides towards further transformations. The compound 5hd when reacted with iodomethane in the presence of sodium hydride in DMF as a solvent provided the corresponding N-methyl adduct 6a in an excellent 91% yield (Scheme [5, b]).

In conclusion, the work described here provides a strategy for the stereoselective synthesis of both α- and β-­sulfonamidoglycosides. The preparation is high yielding and effective for gram-scale synthesis. We have successfully showcased the utility of the sterically bulky 2,4,6-tri-tert-butylpyridinium salts in activating sulfonamides, thus synthesizing the biologically important class of compounds, 2-deoxy and 2,6-dideoxy sulfonamidoglycosides. Interestingly, the observed catalytic activity also seems to be influenced by the counterion of the catalyst. IR studies reiterate the fact that the sterically protected N–H proton of pyridinium is not involved in H-bonding interactions, which signifies the unique anion-assisted polarization of N–H bond leading to the protonation of glycals thereby catalyzing the reaction. Besides, the application of the sulfonamidoglycosides has been shown by synthesizing the corresponding N-alkylated product.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank the Central Instrumentation Facility of IIT Guwahati and North East Centre for Biological Sciences and Healthcare Engineering (NECBH), IIT Guwahati.

• References and Notes

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• 24 General Method to Synthesize Sulfonamidoglycosides from GlycalsGlycal (0.082–0.161 mmol, 1.0 equiv) and glycosyl sulfonamide acceptor (0.123–0.240 mmol, 1.5 equiv) was taken in a round-bottomed flask (10 mL). The flask was then filled with dry DCE, and catalyst TTBPy·HCl (20 mol%) was added to it. The mixtures were stirred at 40 °C in a sealed flask until the reaction was determined to be complete by either TLC or NMR analysis of the crude material. The reaction mixture was quenched by water (20 mL for 0.082 mmol) and it was extracted with DCM (3 × 15 mL for 0.082 mmol), dried over Na₂SO₄, and concentrated in vacuo and purified by silica gel column chromatography (Merck 60–120 mesh, 7 gm) followed by HPLC purification (using HPLC-grade acetonitrile solvent, flow rate 5 mL/min) for some of the compounds.
• 25 3,4-O-(Tetraisopropyldisiloxane-1,3-diyl)-l-erythro-hexapyranosyl-2,6-dideoxy-α,β-l-rhamnopyranosyl Methanesulfonamide (4ee)According to general method, a solution of glycosyl donor 3,4-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-1,2,6-trideoxy-l-arabino-1-hexenopyranose 1e (50 mg, 0.134 mmol, 1.0 equiv) and glycosyl sulfonamide acceptor 2e (19 mg, 0.200 mmol, 1.5 equiv) in dry DCE at 40 °C was treated with 2,4,6-tri(tert-butyl)pyridinium hydrochloride catalyst (8 mg, 0.0268 mmol, 20 mol%) and stirred for 24 h to get the product 4ee as a colourless oil. R_f = 0.4 in 20% EtOAc/hexane, eluent 7% EtOAc in hexane, amount 45 mg, yield 72%. Selectivity α:β = 1:12.5. ¹H NMR (400 MHz, CDCl₃): δ = 5.35 (dd, J = 9.2, 3.3 Hz, 1 H), 4.79 (td, J = 11.1, 1.9 Hz, 1 H), 3.74 (ddd, J = 11.2, 8.1, 5.3 Hz, 1 H), 3.34 (dq, J = 12.3, 6.1 Hz, 1 H), 3.19 (t, J = 8.5 Hz, 1 H), 3.10 (s, 3 H), 2.22 (ddd, J = 12.8, 5.2, 1.9 Hz, 1 H), 1.58 (dd, J = 23.9, 11.3 Hz, 1 H), 1.29 (d, J = 5.8 Hz, 3 H), 1.08–0.92 (m, 28 H). ¹³C NMR (101 MHz, CDCl₃): δ = 80.3, 79.2, 74.1, 73.9, 43.5, 39.7, 31.0, 30.4, 29.8, 18.2, 17.7, 17.5, 17.4, 17.4, 17.4, 17.3, 17.2, 17.2, 13.2, 13.0, 12.9, 12.4, 12.3. HRMS (ESI-QTOF): m/z calcd for C₁₉H₄₁O₆NSSi₂Na [M + Na] ⁺: 490.2091; found: 490.2099. [α]_D ²² –10 (c 0.40, CHCl₃).
• 26 3,4-Di-O-tert-butyldiphenylsilyl-2,6-dideoxy-α,β-l-rhamnopyranosyl Methanesulfonamide (5he)According to general method, a solution of glycosyl donor 3,4-di-O-tert-butyldiphenylsilyl-l-rhamnal 5h (50 mg, 0.082 mmol, 1.0 equiv) and glycosyl sulfonamide acceptor 2e (12 mg, 0.126 mmol, 1.5 equiv) in dry DCE at 40 °C was treated with 2,4,6-tri(tert-butyl)pyridinium hydrochloride catalyst (5 mg, 0.0164 mmol, 20 mol%) and stirred for 24 h to get the product 5he as a colourless oil. R_f = 0.4 in 20% EtOAc/hexane, eluent 7% EtOAc in hexane, amount 41 mg, yield 70%. Selectivity α:β = 7: 1. ¹H NMR (600 MHz, CDCl₃): δ = 7.52 (dd, J = 11.7, 4.6 Hz, 4 H), 7.46–7.45 (m, 1 H), 7.43–7.34 (m, 8 H), 7.31–7.23 (m, 6 H), 5.38 (td, J = 10.7, 1.6 Hz, 1 H), 4.90 (d, J = 10.6 Hz, 1 H), 4.03 (d, J = 1.6 Hz, 1 H), 3.92 (q, J = 7.3 Hz, 1 H), 3.49 (d, J = 2.8 Hz, 1 H), 3.10 (s, 3 H), 1.87–1.83 (m, 1 H), 1.60 (d, J = 13.1 Hz, 1 H), 1.29 (d, J = 7.4 Hz, 3 H), 0.98 (s, 9 H), 0.93 (s, 9 H). ¹³C NMR (151 MHz, CDCl₃): δ = 135.9, 135.8, 135.7, 135.7, 133.8, 133.2, 133.1, 133.0, 130.1, 129.9, 129.9, 128.0, 127.9, 127.8, 127.8, 127.7, 76.0, 73.1, 71.3, 70.7, 43.6, 34.3, 27.0, 26.9, 19.3, 19.1, 16.8. HRMS (ESI-QTOF): m/z calcd for C₃₉H₅₁O₅NSSi₂NH₄ [M + NH₄] ⁺: 719.3370; found: 719.3374. [α]_D ²² –29 (c 0.80, CHCl₃).
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Corresponding author

Publication History

Received: 28 May 2022

Accepted after revision: 05 July 2022

Accepted Manuscript online:
05 July 2022

Article published online:
04 August 2022

© 2022. Thieme. All rights reserved

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Rüdigerstraße 14, 70469 Stuttgart, Germany

• References and Notes

• 1 Dimroth K, Mach W. Angew. Chem., Int. Ed. Engl. 1968; 7: 460
  CrossrefSearch in Google Scholar
• 2a Brown HC, Kanner B. J. Am. Chem. Soc. 1966; 88: 986
  CrossrefSearch in Google Scholar
• 2b Deutsch E, Cheung NK. V. J. Org. Chem. 1973; 38: 1123
  CrossrefSearch in Google Scholar
• 3 Effenberger F, Eberhard JK, Maier AH. J. Am. Chem. Soc. 1996; 118: 12572
  CrossrefPubMedSearch in Google Scholar
• 4 Xu XH, Liu GK, Azuma A, Tokunaga E, Shibata N. Org. Lett. 2011; 13: 4854
  CrossrefPubMedSearch in Google Scholar
• 5a Jiang C, Blacque O, Fox T, Berke H. Organometallics 2011; 30: 2117
  CrossrefSearch in Google Scholar
• 5b Clark ER, Ingleson MJ. Organometallics 2013; 32: 6712
  CrossrefSearch in Google Scholar
• 6 Boebel TA, Gin DY. Angew. Chem. Int. Ed. 2003; 42: 5874
  CrossrefPubMedSearch in Google Scholar
• 7 Geng Y, Zhang LH, Ye XS. Chem. Commun. 2008; 597
  CrossrefPubMed
• 8 Mukherji A, Kancharla PK. Org. Lett. 2020; 22: 2191
  CrossrefPubMedSearch in Google Scholar
• 9 Mukherji A, Addanki RB, Halder S, Kancharla PK. J. Org. Chem. 2021; 86: 17226
  CrossrefPubMedSearch in Google Scholar
• 10 Ghosh T, Mukherji A, Kancharla PK. Org. Lett. 2019; 21: 3490
  CrossrefPubMedSearch in Google Scholar
• 11 Colinas PA, Núñez NA, Bravo RD. J. Carbohydr. Chem. 2008; 27: 141
  CrossrefPubMedSearch in Google Scholar
• 12a Jordan MA, Wilson L. Nat. Rev. Cancer 2004; 4: 253
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• 12b Yoshimatsu K, Yamaguchi A, Yoshino H, Koyagi N, Kitoh K. Cancer Res. 1997; 57: 3208
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• 13 Abbate F, Casini A, Owa T, Scozzafava A, Supuran CT. Bioorg. Med. Chem. Lett. 2004; 14: 217
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• 14 Supuran CT, Briganti F, Tilli S, Chegwidde WR, Scozzafava A. Bioorg. Med. Chem. 2001; 9: 703
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• 15 Supuran CT, Scozzafava A, Menabuoni L, Mincione F, Briganti F, Mincione G. Eur. J. Pharm. Sci. 1999; 8: 317
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• 16 Liautard V, Pillard C, Desvergnes V, Martin OR. Carbohydr. Res. 2008; 343: 2111
  CrossrefPubMedSearch in Google Scholar
• 17 Colinas PA, Témpera CA, Rodríguez OM, Bravo RD. Synthesis 2009; 4143
  CrossrefPubMed
• 18 Griffith DA, Danishefsky SJ. J. Am. Chem. Soc. 1990; 112: 5811
  CrossrefPubMedSearch in Google Scholar
• 19 Colinas PA, Bravo RD. Org. Lett. 2003; 5: 4509
  CrossrefPubMedSearch in Google Scholar
• 20 Colinas PA, Bravo RD. Carbohydr. Res. 2007; 342: 2297
  CrossrefPubMedSearch in Google Scholar
• 21 Colinas PA, Bravo RD. Mol. Med. Chem. 2007; 62
  Crossref
• 22 Colinas PA, Bravo RD. Tetrahedron Lett. 2005; 46: 1687
  CrossrefPubMedSearch in Google Scholar
• 23 Mała P, Pedersen CM. Eur. J. Org. Chem. 2021; 5685
  CrossrefPubMed
• 24 General Method to Synthesize Sulfonamidoglycosides from GlycalsGlycal (0.082–0.161 mmol, 1.0 equiv) and glycosyl sulfonamide acceptor (0.123–0.240 mmol, 1.5 equiv) was taken in a round-bottomed flask (10 mL). The flask was then filled with dry DCE, and catalyst TTBPy·HCl (20 mol%) was added to it. The mixtures were stirred at 40 °C in a sealed flask until the reaction was determined to be complete by either TLC or NMR analysis of the crude material. The reaction mixture was quenched by water (20 mL for 0.082 mmol) and it was extracted with DCM (3 × 15 mL for 0.082 mmol), dried over Na₂SO₄, and concentrated in vacuo and purified by silica gel column chromatography (Merck 60–120 mesh, 7 gm) followed by HPLC purification (using HPLC-grade acetonitrile solvent, flow rate 5 mL/min) for some of the compounds.
• 25 3,4-O-(Tetraisopropyldisiloxane-1,3-diyl)-l-erythro-hexapyranosyl-2,6-dideoxy-α,β-l-rhamnopyranosyl Methanesulfonamide (4ee)According to general method, a solution of glycosyl donor 3,4-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-1,2,6-trideoxy-l-arabino-1-hexenopyranose 1e (50 mg, 0.134 mmol, 1.0 equiv) and glycosyl sulfonamide acceptor 2e (19 mg, 0.200 mmol, 1.5 equiv) in dry DCE at 40 °C was treated with 2,4,6-tri(tert-butyl)pyridinium hydrochloride catalyst (8 mg, 0.0268 mmol, 20 mol%) and stirred for 24 h to get the product 4ee as a colourless oil. R_f = 0.4 in 20% EtOAc/hexane, eluent 7% EtOAc in hexane, amount 45 mg, yield 72%. Selectivity α:β = 1:12.5. ¹H NMR (400 MHz, CDCl₃): δ = 5.35 (dd, J = 9.2, 3.3 Hz, 1 H), 4.79 (td, J = 11.1, 1.9 Hz, 1 H), 3.74 (ddd, J = 11.2, 8.1, 5.3 Hz, 1 H), 3.34 (dq, J = 12.3, 6.1 Hz, 1 H), 3.19 (t, J = 8.5 Hz, 1 H), 3.10 (s, 3 H), 2.22 (ddd, J = 12.8, 5.2, 1.9 Hz, 1 H), 1.58 (dd, J = 23.9, 11.3 Hz, 1 H), 1.29 (d, J = 5.8 Hz, 3 H), 1.08–0.92 (m, 28 H). ¹³C NMR (101 MHz, CDCl₃): δ = 80.3, 79.2, 74.1, 73.9, 43.5, 39.7, 31.0, 30.4, 29.8, 18.2, 17.7, 17.5, 17.4, 17.4, 17.4, 17.3, 17.2, 17.2, 13.2, 13.0, 12.9, 12.4, 12.3. HRMS (ESI-QTOF): m/z calcd for C₁₉H₄₁O₆NSSi₂Na [M + Na] ⁺: 490.2091; found: 490.2099. [α]_D ²² –10 (c 0.40, CHCl₃).
• 26 3,4-Di-O-tert-butyldiphenylsilyl-2,6-dideoxy-α,β-l-rhamnopyranosyl Methanesulfonamide (5he)According to general method, a solution of glycosyl donor 3,4-di-O-tert-butyldiphenylsilyl-l-rhamnal 5h (50 mg, 0.082 mmol, 1.0 equiv) and glycosyl sulfonamide acceptor 2e (12 mg, 0.126 mmol, 1.5 equiv) in dry DCE at 40 °C was treated with 2,4,6-tri(tert-butyl)pyridinium hydrochloride catalyst (5 mg, 0.0164 mmol, 20 mol%) and stirred for 24 h to get the product 5he as a colourless oil. R_f = 0.4 in 20% EtOAc/hexane, eluent 7% EtOAc in hexane, amount 41 mg, yield 70%. Selectivity α:β = 7: 1. ¹H NMR (600 MHz, CDCl₃): δ = 7.52 (dd, J = 11.7, 4.6 Hz, 4 H), 7.46–7.45 (m, 1 H), 7.43–7.34 (m, 8 H), 7.31–7.23 (m, 6 H), 5.38 (td, J = 10.7, 1.6 Hz, 1 H), 4.90 (d, J = 10.6 Hz, 1 H), 4.03 (d, J = 1.6 Hz, 1 H), 3.92 (q, J = 7.3 Hz, 1 H), 3.49 (d, J = 2.8 Hz, 1 H), 3.10 (s, 3 H), 1.87–1.83 (m, 1 H), 1.60 (d, J = 13.1 Hz, 1 H), 1.29 (d, J = 7.4 Hz, 3 H), 0.98 (s, 9 H), 0.93 (s, 9 H). ¹³C NMR (151 MHz, CDCl₃): δ = 135.9, 135.8, 135.7, 135.7, 133.8, 133.2, 133.1, 133.0, 130.1, 129.9, 129.9, 128.0, 127.9, 127.8, 127.8, 127.7, 76.0, 73.1, 71.3, 70.7, 43.6, 34.3, 27.0, 26.9, 19.3, 19.1, 16.8. HRMS (ESI-QTOF): m/z calcd for C₃₉H₅₁O₅NSSi₂NH₄ [M + NH₄] ⁺: 719.3370; found: 719.3374. [α]_D ²² –29 (c 0.80, CHCl₃).
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