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Article

Cooperatively Catalyzed Activation of Thioglycosides with Iodine and Iron(III) Trifluoromethanesulfonate

by
Ashley R. Dent
,
Aidan M. DeSpain
and
Alexei V. Demchenko
*
Department of Chemistry, Saint Louis University, 3501 Laclede Ave, St. Louis, MO 63103, USA
*
Author to whom correspondence should be addressed.
Molecules 2025, 30(15), 3058; https://doi.org/10.3390/molecules30153058
Submission received: 14 June 2025 / Revised: 17 July 2025 / Accepted: 18 July 2025 / Published: 22 July 2025
(This article belongs to the Special Issue Contemporary Synthetic Glycoscience: A Theme Issue Dedicated to the Memory of Hans Paulsen)
Browse Figure
Versions Notes

Abstract

Reported herein is a further expansion of the cooperatively catalyzed Koenigs–Knorr glycosylation reaction, known as “the 4K reaction”. It has been discovered that molecular iodine, along with a metal salt and an acid additive, can activate thioglycosides. Previous mechanistic studies showed the interaction of the anomeric sulfur with thiophilic iodine; this complex is stable until the halophilic metal salt and the acid additive are added. This new avenue has allowed for the investigation of halophilic promoters that would not activate thioglycosides without iodine. Presented herein is the recent discovery of iron(III) triflate as an efficient activator of thioglycosides via the 4K reaction pathway.

1. Introduction

Carbohydrates are a vital class of molecules that are found profusely throughout nature. Due to their fundamental significance, it is of the utmost importance that carbohydrates be synthesized efficiently. The most central aspect to carbohydrate synthesis is the glycosylation reaction; however, it continues to be the most difficult and demanding aspect as well [1]. While nature effortlessly achieves glycosylation reactions via an enzymatic mechanism, chemical glycosylation itself remains onerous [2,3,4,5,6,7,8]. Paulsen’s statement written in 1982, “Although we have now learned to synthesize oligosaccharides, it should be emphasized that each oligosaccharide synthesis remains an independent problem, whose resolution requires considerable systematic research and a good deal of know-how. There are no universal reaction conditions for oligosaccharide syntheses” [2], is still current and very topical even now, many decades later – especially in relation to the synthesis of challenging linkages and targets. This article is dedicated to the late Professor Hans Paulsen (1922–2024), whose seminal publications on glycosylation, oligosaccharide synthesis, and building block reactivity have given enormous inspiration to the authors.
Early glycosylation reactions were performed by Michael [9], Fischer [10], and Koenigs/Knorr [11], making use of simple glycosyl halides or hemiacetals (Fischer). Although these simple glycosyl donors were appropriate for simple glycoside synthesis, the overall efficiency remained limited in scope and needed improvement. With classical Koenigs–Knorr reaction conditions [11,12,13], a glycosyl bromide donor is reacted with a glycosyl acceptor in the presence of silver(I) oxide or carbonate. Unfortunately, this reaction can be slow—particularly with unreactive bromides, such as those equipped with benzoyl protecting groups. Recently, we determined that a catalytic amount of a Lewis acid added to the Ag(I)-promoted glycosylation dramatically increases reaction rates and yields [14]. This has since been named “the 4K reaction” [15].
Thioglycosides are among the most common building blocks used in carbohydrate chemistry. For glycosylation, thioglycosides can be activated by the use of electrophilic or thiophilic promotors [16]. Among these, organosulfur compounds [17,18,19,20,21,22], halogen-based reagents [23,24,25,26,27,28], and photo-activators [29,30,31,32] are among the most popular. Activation with metal salts is also known [33]. Early work by Ferrier, who used mercury(II) salts for the activation of phenylthio glycosides [34], was complemented by Pohl, who used Ph3Bi(OTf)2 [35,36], and Sureshan [37] and Zhu [38], who used Au(III) salts. Our group previously reported the use of palladium(II) bromide [39], copper(II) bromide [40], and FeCl3 [41].
Our lab also recently demonstrated that thioglycosides can be activated using molecular iodine along with a metal salt and an acid additive under the 4K reaction conditions [42]. While initial studies were aimed at silver sulfate, a recent expansion explored bismuth(III) triflate as an activator while listing other viable metal salts [43]. Presented herein is the discovery that iron(III) triflate is also a viable reagent for the 4K reaction with thioglycosides.

2. Results and Discussion

Ferric or iron(III) salts are formed from iron, the second most abundant metal on earth. Iron salts tend to be naturally abundant, inexpensive, and relatively benign. After preliminary optimization of the reaction conditions, we identified I2 (1.5 equiv), Fe(OTf)3 (1.5 equiv), and TfOH (0.2 equiv) in the presence of molecular sieves (3 Å) in 1,2-dichloroethane (DCE) as the most promising combination of reagents. I2 and Fe(OTf)3 without TfOH, or Fe(OTf)3 and TfOH without I2, will form the product too, but at much slower rates and lower yields. Reactions in the absence of Fe(OTf)3 did not proceed for unreactive thioglycosides. Scaling back the amounts of I2 and Fe(OTf)3 to 1.0 equiv led to a loss in yield and decrease in reaction rates. All glycosylations with less-reactive per-O-benzoylated (disarmed) glycosyl donors were performed at rt, whereas reactions with all other, more reactive glycosyl donors were performed at −30 °C. Standard primary glycosyl acceptor 1 and secondary glycosyl acceptor 2 (Figure 1) were chosen to investigate the scope of this reaction.
The results of glycosylation reactions are shown in Table 1. The glycosidation of per-O-benzoylated (disarmed) glucosyl donor 3 with 6-OH acceptor 1 produced disaccharide 4 in 16 h in 96% yield (entry 1). Glycosidation of 3 with 2-OH acceptor 2 produced disaccharide 5 in 24 h in 87% yield (entry 2). Other classes of thioglucosides were explored to further expand the scope. Thus, the glycosidation of α-ethylthio glycoside 6 with 6-OH acceptor 1 gave disaccharide 4 in 30 h in 92% yield (entry 3). The glycosidation of phenylthio or tolylthio glycosyl donors 7 or 8 with 6-OH acceptor 1 gave disaccharide 4 in 30 h in 90–95% yield (entries 4–5). These disaccharides all exhibit complete β-selectivity due to the participation of the neighboring benzoyl protecting group at C-2. The glycosidation of per-O-benzylated glucosyl donor 9 with 6-OH acceptor 1 was faster as these donors are known to be more reactive (armed) [44]. Disaccharide 10 was formed in 16 h in 86% yield (α:β = 1:1.5, entry 6). The glycosidation of 9 with 2-OH acceptor 2 formed disaccharide 11 in 16 h in 73% yield (α:β = 1.0:1, entry 7). Poor stereoselectivity was due to lack of the stereocontrolling factors.
We then looked into reactions of galactosyl donors. The glycosidation of per-O-benzoylated galactosyl donor 12 with 6-OH acceptor 1 produced disaccharide 13 in 16 h in 96% yield (entry 8). The glycosidation of 12 with 2-OH acceptor 2 produced disaccharide 14 in 24 h in 89% yield (entry 9). These disaccharides all exhibit complete β-selectivity due to the participation of the neighboring benzoyl protecting group at C-2. The glycosidation of per-O-benzylated galactosyl donor 15 with 6-OH acceptor 1 formed disaccharide 16 in 16 h in 92% yield (β-only, entry 10). The glycosidation of 15 with 2-OH acceptor 2 formed disaccharide 17 in 16 h in 79% yield (α:β = 1.6:1, entry 11). The poor stereoselectivity of 17 was due to the lack of stereocontrolling factors.
The glycosidation of per-O-benzoylated mannosyl donor 18 with 6-OH acceptor 1 produced disaccharide 19 in 84% yield in 24 h (entry 12). The glycosidation of 18 with 2-OH acceptor 2 produced disaccharide 20 in 24 h in 85% yield (entry 13). These disaccharides all exhibit complete α-selectivity due to the participation of the neighboring benzoyl protecting group at C-2. The glycosidation of per-O-benzylated mannosyl donor 21 with 6-OH acceptor 1 formed disaccharide 22 in 16 h in 81% yield (α:β = 1:4, entry 14). The glycosidation of 21 with 2-OH acceptor 2 formed disaccharide 23 in 16 h in 70% yield (α:β = 1:1.2, entry 15).
We then investigated whether these new reaction conditions would work well in combination with the remote benzoyl groups for galactosyl donors to achieve α-selectivity [45,46]. The glycosidation of galactosyl donor 24 with 6-OH acceptor 1 produced disaccharide 25 in 16 h in 78% yield with complete α-selectivity (entry 16). Finally, we investigated the application of this methodology to a mannosyl donor equipped with the superarming protecting group pattern [47]. The glycosidation of this mannosyl donor 26 with 6-OH acceptor 1 formed disaccharide 27 in 16 h in 79% yield with complete α-selectivity (entry 17).
Undoubtedly, our studies have demonstrated that I2/Fe(OTf)3/TfOH-catalyzed 4K reactions are swift and high yielding. Poor stereocontrol in the case of 2-O-benzylated glycosyl donors is not uncommon, and while α-galactosylation could be effectively achieved by using remote benzoyl groups (vide infra), we have not yet determined how to improve the stereoselectivity of glucosylation. To gain a stereocontrolling mode with glucosyl donors, in the past we demonstrated that bismuth(III)-promoted 4K reactions are compatible with the H-bond-mediated Aglycone Delivery (HAD) pathway [43]. The HAD reaction is based on glycosyl donors’ O-picoloyl (Pico) protecting group. These donors provide high or even complete syn-selectivities in respect to Pico [48]. The 4K reaction conditions developed herein, however, were found to be incompatible with 4-O-Pico-substituted building blocks. This is because ferric salts are known to be effective reagents for the removal of Pico groups [49].

3. Materials and Methods

3.1. General Methods

Column chromatography was performed on silica gel 60 (70–230 mesh); reactions were monitored by TLC on Kieselgel 60 F254. The compounds were detected by examination under UV light and by charring with 5% sulfuric acid in methanol. Solvents were removed under reduced pressure at <40 °C. ClCH2CH2Cl (1,2-DCE) was distilled from CaH2 directly prior to application. Molecular sieves (3 Å) used for reactions were first crushed and then activated in vacuo at 390 °C directly prior to application. Optical rotations were measured on a “Jasco P-2000” polarimeter (Jasco Corporation, Tokyo, Japan). 1H NMR spectra were recorded in CDCl3 at 400 or 700 MHz. 13C{1H} NMR spectra were recorded in CDCl3 at 101 or 175 MHz. The 1H NMR chemical shifts and the 13C{1H} NMR chemical shifts were referenced to CDCl3 (δH = 7.26, δC = 77.00 ppm). Structural assignments were made with additional information from COSY experiments. Compound ratios were determined by comparing the integration intensities of the relevant signals in their 1H NMR spectra. See Supplementary Materials for NMR spectra of all compounds. Accurate mass spectrometry determinations were performed using an Agilent 6230 ESI TOF LCMS mass spectrometer (Agilent, Santa Clara, CA, USA).

3.2. Synthesis of Building Blocks

Methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (1) was synthesized as reported previously, and its analytical data was in accordance with that previously described [50].
Methyl 3,4,6-tri-O-benzyl-α-D-glucopyranoside (2) was synthesized as reported previously, and its analytical data was in accordance with that previously described [50].
Ethyl 2,3,4,6-tetra-O-benzoyl-1-thio-β-D-glucopyranoside (3) was synthesized as reported previously, and its analytical data was in accordance with that previously described [51].
Ethyl 2,3,4,6-tetra-O-benzoyl-1-thio-α-D-glucopyranoside (6) was synthesized as reported previously, and its analytical data was in accordance with that previously described [51].
Phenyl 2,3,4,6-tetra-O-benzoyl-1-thio-β-D-glucopyranoside (7) was synthesized as reported previously, and its analytical data was in accordance with that previously described [52].
Tolyl 2,3,4,6-tetra-O-benzoyl-1-thio-β-D-glucopyranoside (8) was synthesized as reported previously, and its analytical data was in accordance with that previously described [53].
Ethyl 2,3,4,6-tetra-O-benzyl-1-thio-β-D-glucopyranoside (9) was synthesized as reported previously, and its analytical data was in accordance with that previously described [54].
Ethyl 2,3,4,6-tetra-O-benzoyl-1-thio-β-D-galactopyranoside (12) was synthesized as reported previously, and its analytical data was in accordance with that previously described [51].
Ethyl 2,3,4,6-tetra-O-benzyl-1-thio-β-D-galactopyranoside (15) was synthesized as reported previously, and its analytical data was in accordance with that previously described [55].
Ethyl 2,3,4,6-tetra-O-benzoyl-1-thio-β-D-mannopyranoside (18) was synthesized as reported previously, and its analytical data was in accordance with that previously described [51].
Ethyl 2,3,4,6-tetra-O-benzyl-1-thio-β-D-mannopyranoside (21) was synthesized as reported previously, and its analytical data was in accordance with that previously described [56].
Ethyl 3,4,-di-O-benzoyl-2,6-di-O-benzyl-1-thio-β-D-galactopyranoside (24) was synthesized as reported previously, and its analytical data was in accordance with that previously described [45].
Ethyl 2-O-benzoyl-3,4,6-tri-O-benzyl-1-thio-β-D-mannopyranoside (26) was synthesized as reported previously, and its analytical data was in accordance with that previously described [57].

3.3. Synthesis of Disaccharides

General procedure for glycosidation. A mixture of glycosyl donor (0.05 mmol, 1.1 equiv), glycosyl acceptor (0.045 mmol, 1.0 equiv), and freshly activated molecular sieves (3 Å, 150 mg) in 1,2-dichloroethane (1.0 mL, 0.45 mM) was stirred under argon for 1 h at rt. I2 (0.0675 mmol, 1.5 equiv), Fe(OTf)3 (0.0675 mmol, 1.5 equiv), and TfOH (0.009 mmol, 0.2 equiv) were added, and the resulting mixture was stirred under argon at rt for the time specified in the tables and below. After that, the solids were filtered off through a pad of Celite and washed successively with CH2Cl2. The combined filtrate (~40 mL) was washed with 10% aq. Na2S2O3 (10 mL). The organic phase was separated, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate—hexane or toluene gradient elution) to afford the respective disaccharides in yields and stereoselectivities listed in the tables and below. Anomeric ratios (or anomeric purity) were determined by comparison of the integral intensities of relevant signals in 1H NMR spectra.
Methyl 6-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (4) was obtained from donor 3 [51] (39.0 mg, 0.06 mmol) and acceptor 1 [50] (25.7 mg, 0.055 mmol) under the general glycosidation method as a colorless foam in 16 h in 96% yield (55.4 mg, 0.053 mmol). The title compound was also obtained from donor 6 [51] (24.3 mg, 0.038 mmol) and acceptor 1 (16.0 mg, 0.034 mmol) under the general glycosidation method as a colorless foam in 30 h in 92% yield (32.8 mg, 0.031 mmol). The title compound was also obtained from donor 7 [52] (35.4 mg, 0.051 mmol) and acceptor 1 (21.7 mg, 0.047 mmol) under the general glycosidation method as a colorless foam in 30 h in 90% yield (43.9 mg, 0.042 mmol). The title compound was also obtained from donor 8 [53] (30.6 mg, 0.044 mmol) and acceptor 1 (18.4 mg, 0.04 mmol) under the general glycosidation method as a colorless foam in 30 h in 95% yield (39.1 mg, 0.037 mmol). Analytical data for 4 was in accordance with that previously reported [58].
Methyl 2-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-3,4,6-tri-O-benzyl-α-D-glucopyranoside (5) was obtained from donor 3 [51] (34.0 mg, 0.053 mmol) and acceptor 2 [50] (22.4 mg, 0.048 mmol) under the general glycosidation method as a colorless form in 24 h in 87% yield (43.9 mg, 0.042 mmol). Analytical data for 5 was in accordance with that previously reported [50,58]
Methyl 2,3,4-tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranosyl)-α-D-glucopyranoside (10) was obtained from donor 9 [54] (24.4 mg, 0.042 mmol) and acceptor 1 [50] (17.6 mg, 0.038 mmol) under the general glycosidation method as a colorless form in 16 h in 86% yield (32.0 mg, 0.032 mmol). Analytical data for 10 was in accordance with that previously reported [59].
Methyl 3,4,6-tri-O-benzyl-2-O-(2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranosyl)-α-D-glucopyranoside (11) was obtained from donor 9 [54] (24.8 mg, 0.042 mmol) and acceptor 2 [50] (17.9 mg, 0.039 mmol) under the general glycosidation method as a colorless form in 16 h in 73% yield (27.9 mg, 0.028 mmol). Analytical data for 11 was in accordance with that previously reported [59].
Methyl 6-O-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (13) was obtained from donor 12 [51] (29.1 mg, 0.045 mmol) and acceptor 1 [50] (19.2 mg, 0.041 mmol) under the general glycosidation method as a colorless form in 16 h in 96% yield (41.4 mg, 0.040 mmol). Analytical data for 13 was in accordance with that previously reported [60].
Methyl 2-O-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyl)-3,4,6-tri-O-benzyl-α-D-glucopyranoside (14) was obtained from donor 12 [51] (24.4 mg, 0.038 mmol) and acceptor 2 [50] (16.1 mg, 0.035 mmol) under the general glycosidation method as a colorless form in 24 h in 89% yield (32.1 mg, 0.031 mmol). Analytical data for 14 was in accordance with that previously reported [61].
Methyl 2,3,4-tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-α/β-D-galactopyranosyl)-α-D-glucopyranoside (16) was obtained from donor 15 [55] (22.3 mg, 0.038 mmol) and acceptor 1 [50] (16.1 mg, 0.035 mmol) under the general glycosidation method as a colorless foam in 16 h in 92% yield (31.5 mg, 0.032 mmol). Analytical data for 16 was in accordance with that previously reported [62].
Methyl 3,4,6-tri-O-benzyl-2-O-(2,3,4,6-tetra-O-benzyl-α/β-D-galactopyranosyl)-α-D-glucopyranoside (17) was obtained from donor 15 [55] (22.3 mg, 0.038 mmol) and acceptor 2 [50] (16.1 mg, 0.035 mmol) under the general glycosidation method as a colorless form in 16 h in 79% yield (27.1 mg, 0.027 mmol). Analytical data for 17 was in accordance with that previously reported [63].
Methyl 6-O-(2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (19) was obtained from donor 18 [51] (24.4 mg, 0.038 mmol) and acceptor 1 [50] (16.1 mg, 0.035 mmol) under the general glycosidation method as a colorless foam in 24 h in 84% yield (30.1 mg, 0.029 mmol). Analytical data for 19 was in accordance with that previously reported [64].
Methyl 2-O-(2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl)-3,4,6-tri-O-benzyl-α-D-glucopyranoside (20) was obtained from donor 18 [51] (21.6 mg, 0.034 mmol) and acceptor 2 [50] (14.2 mg, 0.031 mmol) under the general glycosidation method as a colorless form in 24 h in 85% yield (26.9 mg, 0.026 mmol). Analytical data for 20 was in accordance with that previously reported [65].
Methyl 2,3,4-tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-α/β-D-mannopyranosyl)-α-D-glucopyranoside (22) was obtained from donor 21 [56] (30.4 mg, 0.052 mmol) and acceptor 1 [50] (21.9 mg, 0.047 mmol) under the general glycosidation method as a colorless foam in 16 h in 81% yield (37.5 mg, 0.038 mmol). Analytical data for 22 was in accordance with that previously reported [66].
Methyl 3,4,6-tri-O-benzyl-2-O-(2,3,4,6-tetra-O-benzyl-α/β-D-mannopyranosyl)-α-D-glucopyranoside (23) was obtained from donor 21 [56] (30.5 mg, 0.052 mmol) and acceptor 2 [50] (22.0 mg, 0.047 mmol) under the general glycosidation method as a colorless form in 16 h in 70% yield (32.9 mg, 0.033 mmol). Analytical data for 23 was in accordance with that previously reported [67].
Methyl 6-O-(3,4-di-O-benzoyl-2,6-di-O-benzyl-α-D-galactopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (25) was obtained from donor 24 [45] (27.9 mg, 0.046 mmol) and acceptor 1 [50] (19.2 mg, 0.041 mmol) under the general glycosidation method as a colorless foam in 16 h in 78% yield (32.5 mg, 0.032 mmol). Analytical data for 25 was in accordance with that previously reported [45].
Methyl 6-O-(2-O-benzoyl-3,4,6-tri-O-benzyl-α-D-mannopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (27) was obtained from donor 26 [57] (30.1 mg, 0.05 mmol) and acceptor 1 [50] (21.2 mg, 0.046 mmol) under the general glycosidation method as a colorless foam in 16 h in 79% yield (36.2 mg, 0.036 mmol). Analytical data for 27 was in accordance with that previously reported. [68]

4. Conclusions

Our previous studies of the 4K reaction with thioglycosides opened a new exciting avenue for discovery of new classes of thioglycoside activators. Previously, we demonstrated that I2/Bi(OTf)3/TfOH cooperatively catalyzed 4K reactions can be swift and efficient. Developed herein is an I2/Fe(OTf)3/TfOH cooperatively catalyzed 4K reaction for the direct activation of conventional thioglycosides. This methodology presents a promising expansion of the 4K reaction, which overall continues to be an exciting avenue for exploration. As demonstrated by several substrates and targets, this method offers new synthetic capabilities. The reaction conditions are relatively mild, and because of that, the glycosylation reactions are much slower than those in the presence of bismuth(III), albeit the product yields were similar.
Regardless of whether bismuth(III) or iron(III) were employed as co-catalysis, the reaction worked with a broad range of substrates, with both armed and disarmed glycosyl donors. In contrast, previously described activations in the presence of FeCl3 alone worked well only for highly reactive, armed and superarmed thioglycoside donors, even in the presence of a large excess. Attempts to substitute Fe(OTf)3 with FeCl3 in the 4K reactions lead to decreased yields due to the accumulation of multiple side products.
It also became apparent that the 4K reactions with ferric triflate are not compatible with the HAD method because ferric salts are known to cleave the picoloyl group that is needed as a stereodirecting handle. Further exploration of the 4K reaction, the search for other effective promoters and catalysts, and application to the manual and automated synthesis of various linkages and glycan targets are currently underway.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules30153058/s1, Figure S1. 1H NMR Spectrum (CDCl3, 400 MHz) of Compound 4; Figure S2. COSY NMR Spectrum (CDCl3, 400 MHz) of Compound 4; Figure S3. 13C NMR Spectrum (CDCl3, 101 MHz) of Compound 4; Figure S4. 1H NMR Spectrum (CDCl3, 400 MHz) of Compound 5; Figure S5. COSY NMR Spectrum (CDCl3, 400 MHz) of Compound 5; Figure S6. 13C NMR Spectrum (CDCl3, 101 MHz) of Compound 5; Figure S7. 1H NMR Spectrum (CDCl3, 400 MHz) of Compound 10; Figure S8. COSY NMR Spectrum (CDCl3, 400 MHz) of Compound 10; Figure S9. 13C NMR Spectrum (CDCl3, 101 MHz) of Compound 10; Figure S10. 1H NMR Spectrum (CDCl3, 400 MHz) of Compound 11; Figure S11. COSY NMR Spectrum (CDCl3, 400 MHz) of Compound 11; Figure S12. 13C NMR Spectrum (CDCl3, 101 MHz) of Compound 11; Figure S13. 1H NMR Spectrum (CDCl3, 400 MHz) of Compound 13; Figure S14. COSY NMR Spectrum (CDCl3, 400 MHz) of Compound 13; Figure S15. 13C NMR Spectrum (CDCl3, 101 MHz) of Compound 13; Figure S16. 1H NMR Spectrum (CDCl3, 400 MHz) of Compound 14; Figure S17. COSY NMR Spectrum (CDCl3, 400 MHz) of Compound 14; Figure S18. 13C NMR Spectrum (CDCl3, 101 MHz) of Compound 14; Figure S19. 1H NMR Spectrum (CDCl3, 400 MHz) of Compound 16; Figure S20. COSY NMR Spectrum (CDCl3, 400 MHz) of Compound 16; Figure S21. 13C NMR Spectrum (CDCl3, 101 MHz) of Compound 16; Figure S22. 1H NMR Spectrum (CDCl3, 400 MHz) of Compound 17; Figure S23. COSY NMR Spectrum (CDCl3, 400 MHz) of Compound 17; Figure S24. 13C NMR Spectrum (CDCl3, 101 MHz) of Compound 17; Figure S25. 1H NMR Spectrum (CDCl3, 400 MHz) of Compound 19; Figure S26. COSY NMR Spectrum (CDCl3, 400 MHz) of Compound 19; Figure S27. 13C NMR Spectrum (CDCl3, 101 MHz) of Compound 19; Figure S28. 1H NMR Spectrum (CDCl3, 400 MHz) of Compound 20; Figure S29. COSY NMR Spectrum (CDCl3, 400 MHz) of Compound 20; Figure S30. 13C NMR Spectrum (CDCl3, 101 MHz) of Compound 20; Figure S31. 1H NMR Spectrum (CDCl3, 400 MHz) of Compound 22; Figure S32. COSY NMR Spectrum (CDCl3, 400 MHz) of Compound 22; Figure S33. 13C NMR Spectrum (CDCl3, 101 MHz) of Compound 22; Figure S34. 1H NMR Spectrum (CDCl3, 400 MHz) of Compound 23; Figure S35. COSY NMR Spectrum (CDCl3, 400 MHz) of Compound 23; Figure S36. 13C NMR Spectrum (CDCl3, 101 MHz) of Compound 23; Figure S37. 1H NMR Spectrum (CDCl3, 400 MHz) of Compound 25; Figure S38. COSY NMR Spectrum (CDCl3, 400 MHz) of Compound 25; Figure S39. 13C NMR Spectrum (CDCl3, 101 MHz) of Compound 25; Figure S40. 1H NMR Spectrum (CDCl3, 400 MHz) of Compound 27; Figure S41. COSY NMR Spectrum (CDCl3, 400 MHz) of Compound 27; Figure S42. 13C NMR Spectrum (CDCl3, 101 MHz) of Compound 27.

Author Contributions

Conceptualization, A.R.D. and A.V.D.; methodology, A.R.D.; formal analysis, A.R.D.; investigation, A.R.D. and A.M.D.; data curation, A.R.D. and A.M.D.; writing—original draft preparation, A.R.D.; writing—review and editing, A.R.D. and A.V.D.; supervision, A.V.D.; project administration, A.V.D.; funding acquisition, A.V.D. All authors have read and agreed to the published version of the manuscript.

Funding

The authors are indebted to the NSF (CHE-2350461) for support of this work.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data is available from the authors.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 30 03058 g001
Figure 1. Structures of glycosyl acceptors 1 and 2 used in this study.
Figure 1. Structures of glycosyl acceptors 1 and 2 used in this study.
Molecules 30 03058 g001
Table 1. Investigation of the scope of the iron(III) triflate-promoted 4K reaction.
Table 1. Investigation of the scope of the iron(III) triflate-promoted 4K reaction.
Molecules 30 03058 i001
EntryDonorAcceptorProduct, Time, Yield, Ratio α/β
1Molecules 30 03058 i002
3		1Molecules 30 03058 i003
4, 16 h, 96%, β-only
232Molecules 30 03058 i004
5, 24 h, 87%, β-only
3Molecules 30 03058 i005
6		1Molecules 30 03058 i006
4, 30 h, 92%, β-only
4Molecules 30 03058 i007
7		1Molecules 30 03058 i008
4, 30 h, 90%, β-only
5Molecules 30 03058 i009
8		1Molecules 30 03058 i010
4, 30 h, 95%, β-only
6Molecules 30 03058 i011
9		1Molecules 30 03058 i012
10, 16 h, 86%, α:β = 1:1.5
792Molecules 30 03058 i013
11, 16 h, 73%, α:β = 1:1
8Molecules 30 03058 i014
12		1Molecules 30 03058 i015
13, 16 h, 96%, β-only
9122Molecules 30 03058 i016
14, 24 h, 89%, β-only
10Molecules 30 03058 i017
15		1Molecules 30 03058 i018
16, 16 h, 92%, β-only
11152Molecules 30 03058 i019
17, 16 h, 79%, α:β = 1.6:1
12Molecules 30 03058 i020
18		1Molecules 30 03058 i021
19, 24 h, 84%, α-only
13182Molecules 30 03058 i022
20, 24 h, 85%, α-only
14Molecules 30 03058 i023
21		1Molecules 30 03058 i024
22, 16 h, 81%, α:β = 1:4
15212Molecules 30 03058 i025
23, 16 h, 70%, α:β = 1:1.2
16Molecules 30 03058 i026
24		1Molecules 30 03058 i027
25, 16 h, 78%, α-only
17Molecules 30 03058 i028
26		1Molecules 30 03058 i029
27, 16 h, 79%, α-only
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Dent, A.R.; DeSpain, A.M.; Demchenko, A.V. Cooperatively Catalyzed Activation of Thioglycosides with Iodine and Iron(III) Trifluoromethanesulfonate. Molecules 2025, 30, 3058. https://doi.org/10.3390/molecules30153058

AMA Style

Dent AR, DeSpain AM, Demchenko AV. Cooperatively Catalyzed Activation of Thioglycosides with Iodine and Iron(III) Trifluoromethanesulfonate. Molecules. 2025; 30(15):3058. https://doi.org/10.3390/molecules30153058

Chicago/Turabian Style

Dent, Ashley R., Aidan M. DeSpain, and Alexei V. Demchenko. 2025. "Cooperatively Catalyzed Activation of Thioglycosides with Iodine and Iron(III) Trifluoromethanesulfonate" Molecules 30, no. 15: 3058. https://doi.org/10.3390/molecules30153058

APA Style

Dent, A. R., DeSpain, A. M., & Demchenko, A. V. (2025). Cooperatively Catalyzed Activation of Thioglycosides with Iodine and Iron(III) Trifluoromethanesulfonate. Molecules, 30(15), 3058. https://doi.org/10.3390/molecules30153058

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