A sequential one-pot strategy for the synthesis of triterpenoid saponins in ionic liquid [emim][OTf]

Abstract

1-Ethyl-3-methylimidazolium trifluoromethanesulfonate ([emim][OTf]) is an efficient co-solvent and co-promoter for one-pot sequential glycosylation with the combined use of thioglycosides and trichloroacetimidates (or N-phenyltrifluoroacetimidates) donors at room temperature. One-pot glycosylation is efficient for the synthesis of triterpenoid saponins with the combined use of N-phenyltrifluoroacetimidate donors and 2-methyl-5-tert-butylphenyl (Mbp) thioglycoside donors in [emim][OTf].

Introduction

Triterpenoid saponins are glycosylated secondary metabolites that exist widely in terrestrial plants and some marine organisms and present a broad spectrum of well-defined biological and pharmacological activities.^1–5 Attracted by these interesting biological activities, several research groups have reported on the synthesis of many oleanane-type triterpenoid saponins.^6–8 Notably, the development of a ‘one-pot sequential glycosylation’ strategy has greatly facilitated the synthesis of this kind of glycoconjugate with complicated sugar moieties.^9,10 Recently, we completed the synthesis of several natural and non-natural triterpenoid saponins by adopting the ‘one-pot sequential glycosylation’ strategy with the combined use of 2-methyl-5-tert-butylphenyl (Mbp) thioglycosides and trichloroacetimidates as donors (equation (1) in Scheme 1).^11–13 Although this strategy is efficient for the assembly of saccharides onto aglycones, there are some drawbacks, such as low reaction temperatures (−78 ^oC), the use of an environmentally toxic and volatile organic solvent (CH₂Cl₂) and the need for molecular sieves as dehydrating agents (4 Å MS).

Scheme 1.

One-pot sequential glycosylation with the combined use of thioglycosides and trichloroacetimidates (or N-phenyltrifluoroacetimidates) donors in [emim][OTf] at room temperature.

Ionic liquids (ILs) are a class of solvents which are quite different from traditional organic solvents due to their high polarity with poorly coordinating ion pairs, which usually results in improved accelerating effects in chemical reactions. ¹⁴ ILs are often fluid at room temperature and have a low vapour pressure. They have been widely applied as green replacements for organic solvents. ¹⁵ In particular, ILs have had many applications in oligosaccharide synthesis as green solvents and catalysts.^16–19 Recently, Galan et al. ²⁰ reported the successful application of [bmim][OTf] as a mild promoter in ambient three-component reactivity-based one-pot glycosylation reactions. In the light of these research findings, and in conjunction with our interest in searching for a general, efficient and green glycosylation strategy, we report in this article the use of [emim][OTf] ¹⁸ as co-solvent and co-promoter for one-pot sequential glycosylation with the combined use of thioglycosides and trichloroacetimidates (or N-phenyltrifluoroacetimidates) donors at room temperature (equation (2) in Scheme 1).

Experimental

Commercial reagents were all analytically or chemically pure and used without further purification unless specified. All anhydrous solvents were dried and redistilled prior to use in the usual way. Thin-layer chromatography (TLC) was performed on precoated E. Merck Silica Gel 60 F254 plates. Flash column chromatography was performed on silica gel (200–300 mesh, Qingdao, China). Optical rotations were determined with a Perkin–Elmer Model 241 MC polarimeter. 1H NMR and 13C NMR spectra were taken on a JEOL JNM-ECP 600 spectrometer with tetramethylsilane as the internal standard, and chemical shifts are recorded in δ values. Mass spectra were recorded on a quadrupole timeof- flight (Q-TOF) global mass spectrometer.

Results and discussion

In this research using the ionic liquid 1, the trichloroacetimidate donors (2–6), N-phenyltrifluoroacetimidate donors (7–9), thioglycoside donors (10–14) and aglycone acceptors (15–18) were used as shown in Scheme 2. In initial experiments, glycosyl trichloroacetimidates 2 ¹⁴ , 3 ¹³ , 4 ¹³ , and 5 ¹¹ were selected as donors in conjunction with 2-methyl-5-tert-butylphenyl (Mbp) thioglycoside 10 ¹¹ and aglycone 15 ¹¹ as model acceptors to investigate the sequential one-pot glycosylation strategy in the ionic liquid 1 at room temperature. The results are summarized in Table 1. Using ionic liquid 1 as solvent in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and N-iodosuccinimide (NIS) at room temperature, we obtained the glycosylation products in 23%–43% yields (Table 1, entries 1–4). By increasing the amount of the acid catalyst (TMSOTf) (from 0.1 equiv. to 0.2 equiv.), we obtained 2a in 51% yield (Table 1, entry 5). Interestingly, the glycosylation product 2a was obtained in 14% yield without the presence of TMSOTf (Table 1, entry 6), which demonstrated [emim][OTf] 1 could activate the trichloroacetimidate donor 2 in the absence of the acidic promoter (TMSOTf). When the solvent ionic liquid 1 was changed to 1 with CH₂Cl₂ as co-solvent (1: CH₂Cl₂, V:V 9:1), the sequential one-pot glycosylation was run with an increased yield (21%; compare entry 6 with entry 9 in Table 1). Substitution of CH₂Cl₂ for [emim][OTf] 1 led to a decreased yield (8%) (Table 1, entry 7). We presumed that the degradation of imidate 2 in CH₂Cl₂ at room temperature with the presence of TMSOTf was more rapid than that in [emim][OTf] 1 (compare entry 5 with entry 7 in Table 1). In addition, experiments performed in a 9:1 1/CH₂Cl₂ co-solvent with the presence of 0.2 equiv. TMSOTf evidenced that the addition of TMSOTf catalyst is favourable to activate the trichloroacetimidate donor (Table 1, entries 8 and 10). Thus, 0.2 equiv. TMSOTf and NIS as promoters at room temperature in 1 and CH₂Cl₂ (90% V/V) co-solvent emerged as an optimized protocol for sequential one-pot glycosylation with the combined use of thioglycosides and trichloroacetimidates donors.

Scheme 2.

Ionic liquid 1, trichloroacetimidate (2–6), N-phenyltrifluoroacetimidate (7–9), thioglycoside (10–14) donors and aglycone acceptors (15–18) used in this research.

Table 1.

One-pot glycosylation of different glycosyl trichloroacetimidates 2–5, Mbp thioglycoside 10 and aglycone 15 in ionic liquid 1.

Entry a	Donor	Acceptor 1	Acceptor 2	Promoter	Solvent b	Reaction time	Product	Yield (%) c
1	2	10	15	0.1 equiv. TMSOTf → NIS	1	2 h → 1 h	2a	43
2	3	10	15	0.1 equiv. TMSOTf → NIS	1	2 h → 1 h	3a	36
3	4	10	15	0.1 equiv. TMSOTf → NIS	1	2 h → 1 h	4a	31
4	5	10	15	0.1 equiv. TMSOTf → NIS	1	2 h → 1 h	5a	23
5	2	10	15	0.2 equiv. TMSOTf → NIS	1	2 h → 1 h	2a	51
6	2	10	15	No promoter → NIS	1	1 h → 1 h	2a	14
7	2	10	15	0.2 equiv. TMSOTf → NIS	CH2Cl2	1 h → 1 h	2a	8
8	2	10	15	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	1 h → 1 h	2a	61
9	2	10	15	No promoter → NIS	1 + CH2Cl2	2 h → 1 h	2a	21
10	3	10	15	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	3a	59

a

All reactions were performed at room temperature.

b

The ratio of co-solvent 1 and CH₂Cl₂ was 9:1 (V: V).

c

Yield refers to the isolated product by silica gel column chromatography.

To test the scope and limitations of the reaction, a wide range of trichloroacetimidate donor 6, N-phenyltrifluoroacetimidate donors (7–9), thioglycosides (11–14) and aglycone acceptors (16–18) were applied in the sequential one-pot glycosylation with 0.2 equiv. TMSOTf and NIS as promoters at room temperature in 1 with CH₂Cl₂ (90% V/V) as co-solvent, and the results are listed in Table 2. Under the optimized conditions, the sequential one-pot glycosylation reactions were carried out with good yields (Table 2). To our delight, the reactions with the use of N-phenyltrifluoroacetimidate donors (7–9) gave glycosylated products in higher yields, which represents a slight increase when compared to the same reactions with the use of trichloroacetimidate donors (2, 3 and 6; Table 2). This result implies that the N-phenyltrifluoroacetimidate donor degraded slowly in 1 with CH₂Cl₂ as the co-solvent at room temperature with the catalysis of TMSOTf. It should be noted that glycosylation yields with the combined use of N-phenyltrifluoroacetimidate donors (7–9) and Mbp thioglycosides (10 and 12) are typically higher in comparison to the corresponding glycosylation reactions with the combined use of N-phenyltrifluoroacetimidate donors (7–9) and thioglycoside donors (11 and 13–14; Table 2, entries 4–5, 18–19 and 4–7, 20–23).

Table 2.

One-pot glycosylation of different glycosyl trichloroacetimidates 2–5 (N-phenyltrifluoroacetimidate donors (7–9)), thioglycoside donors (11–14) and aglycone acceptors (16–18) in ionic liquid 1 and CH₂Cl₂ (90% V/V) as co-solvent.

Entry a	Donor	Acceptor 1	Acceptor 2	Promoter	Solvent b	Reaction time	Product	Yield (%) c
1	2	10	16	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	6a	43
2	3	10	16	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	7a	36
3	5	10	16	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	8a	31
4	7	10	15	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	2a	52
5	7	10	16	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	6a	56
6	7	11	15	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	2a	49
7	7	11	16	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	6a	51
8	8	10	15	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	3a	51
9	8	11	15	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	3a	56
10	8	10	16	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	7a	35
11	8	11	16	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	7a	61
12	6	12	17	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	9a	42
13	6	12	18	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	10a	44
14	6	13	17	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	9a	39
15	6	13	18	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	10a	41
16	6	14	17	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	9a	37
17	6	14	18	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	10a	32
18	9	12	17	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	9a	61
19	9	12	18	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	10a	65
20	9	13	17	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	9a	60
21	9	14	17	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	9a	59
22	9	13	18	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	10a	57
23	9	14	18	0.2 equiv. TMSOTf → NIS	1 + CH2Cl2	2 h → 1 h	10a	53

a

All reactions were performed at room temperature.

b

The ratio of co-solvent 1 and CH₂Cl₂ was 9:1 (V: V).

c

Yield refers to the isolated product by silica gel column chromatography.

Taken together, our experimental results demonstrated that one-pot convergent approaches for glycosylation of triterpenoid saponins in the ionic liquid 1 with CH₂Cl₂ as co-solvent at room temperature was feasible. Although, the yields for the one-pot glycosylation are moderate, the multiple glycosylation steps can be achieved in a single reaction thus avoiding purification between individual steps.

Conclusion

In conclusion, we have shown the applicability of the ionic liquid 1 and CH₂Cl₂ (90% V/V) as co-solvent for the one-pot glycosylation with the combined use of thioglycosides and trichloroacetimidates (or N-phenyltrifluoroacetimidates) donors at room temperature, which avoid the usual glycosylation conditions with low reaction temperature (−78 ^oC) and the need for molecular sieve dehydrating agents (4Å MS). Furthermore, we have found that glycosylation yields with the combined use of N-phenyltrifluoroacetimidate donors and Mbp thioglycosides are typically higher in comparison to the corresponding glycosylation reactions with the combined use of trichloroacetimidates donors and thioglycosides.

Synthesis of 1-ethyl-3-methylimidazolium trifluoromethanesulfonate ([emim][OTf])

Freshly distilled ethyl trifluoromethanesulfonate (8.95 g, 0.05 mol) was dropped slowly into magnetically stirred N-methylimidazole (4.00 g, 0.05 mol) at 0 °C over a period of 6 h. Stirring was continued for 12 h at 30 °C to complete the reaction. Finally the excess of ethyl trifluoromethanesulfonate (0.27 g, 0.0015 mol) was evaporated at 0.01 mbar and 25 °C. The product (12.7 g, 0.05 mol, quantitative yield) was obtained as a clear and colourless liquid.

General procedure for the preparation of triterpenoid saponins 2a–10a by one-pot sequential glycosylation

The glycosyl trichloroacetimidates 2–6 (or N-phenyltrifluoroacetimidate donors 7–9) (2.1 equiv.) and thioglycosides 10–14 (1.5 equiv.) were dissolved in 1, CH₂Cl₂, or 1-CH₂Cl₂ (1 mL), and TMSOTf was added. After the reaction was stirred at room temperature for 2.5 h, saponin acceptors 15–18 (1 equiv.), and NIS (2 equiv.) were added. The reaction was stirred at room temperature until TLC showed complete conversion of the donor. The reaction mixture was performed by the addition of water and extraction of the product with CH₂Cl₂. The organic layer was concentrated and the residue was purified by silica gel column chromatography.

Compounds 2a-8a displayed the same chemical–physical characteristics already reported in the literature by our laboratory.^22–24 The preparation of glycosyl trichloroacetimidate 6, N-phenyltrifluoroacetimidate donor 9 and thioglycosides 12–14 has not been published in the literature, but are described in the supporting information.

3β-O-Acetyl oleanolate 28-O-2,3,4,6-tetra-O-acetyl-α-D-galacopyranosyl-(1→6)-2,3,4-tri-O-benzoyl-β-D-glucopyranosyl-(1→6)-2,4-O-acetyl-3-benzyl-β-D-glucopyranoside (9a)

${[\alpha ]}_D^{22}$  + 26.1 (c 1.21, CHCl₃); m.p. 168–171 ^oC. IR (KBr) ν_max 2941, 1738, 1448, 1256, 1097 and 705 cm^-1.

¹H NMR (CDCl₃, 600 MHz): δ = 7.31–7.94 (m, 20H, Ph-H), 5.79 (t, J = 9.6 Hz, 1H, H-3″), 5.56 (t, J = 9.6 Hz, 1H, H-4″), 5.48 (dd, J = 9.6, 7.8 Hz, 1H, H-2″), 5.42 (dd, J = 9.2, 3.6 Hz, 1H, H-3″′), 5.40 (d, J = 7.7 Hz, 1H, H-1′), 5.35 (dd, J = 11.0, 3.2 Hz, 1H, H-2″′), 5.24 (t, J = 3.2 Hz, 1H, H-12), 5.08-5.14 (m, 3H, H-2′, H-3′, H-4′), 5.00 (d, J = 8.3 Hz, 1H, H-1″), 4.95 (d, J = 12.4 Hz, 1H, PhCHH), 4.92 (d, J = 3.6 Hz, 1H, H-1″′), 4.79 (d, J = 12.4 Hz, 1H, PhCHH), 4.47 (t-like, J = 8.3, 7.3 Hz, 1H, H-3), 4.25 (d, J = 11.5 Hz, 1H, H-6″′-1), 4.15 (t-like, J = 7.3, 5.9 Hz, 1H, H-4″′), 4.05 (dd, J = 11.5, 4.6 Hz, 1H, H-6′-1), 4.00 (dd, J = 12.1, 5.0 Hz, 1H, H-6″-1), 3.95 (m, 2H, H-3″′, H-5″′), 3.81 (m, 1H, H-5″), 3.70–3.74 (m, 2H, H-5′, H-6″-2), 3.51–3.55 (m, 2H, H-6′-2, H-6″′-2), 2.74 (dd, J = 13.3, 4.1 Hz, 1H, H-18), 2.13, 2.04, 2.00, 1.96, 1.95, 1.86, 1.85 (s each, 3H each, CH₃CO × 7), 1.08, 0.89, 0.87, 0.86, 0.84, 0.84, 0.65 (s each, 3H each, CH₃ × 7).

¹³C NMR (CDCl₃, 150 MHz): δ = 170.6 (C-28), 171.2, 170.6, 170.5, 170.4, 170.3, 169.9, 169.3, 165.9, 165.3, 165.1, 143.2 (C-13), 138.7, 133.8, 133.5, 130.0, 129.9, 128.8, 128.7, 128.6, 128.5, 127.8, 127.6, 126.5, 122.8 (C-12), 101.1 (C-1″′), 96.6 (C-1″), 91.7 (C-1′), 81.1 (C-3), 80.9, 74.6, 73.7, 73.2, 72.4, 71.2, 69.4, 68.4, 68.2, 67.7, 66.9, 66.6, 62.2, 62.1, 55.5, 47.6, 46.9, 45.9, 41.8, 41.1, 39.5, 38.3, 37.9, 37.1, 33.9, 33.2, 33.0, 31.9, 30.8, 29.9, 28.2, 27.9, 25.8, 23.7, 23.6, 23.5, 22.9, 21.5, 21.0, 20.9, 20.7, 18.4, 17.1, 16.9, 15.6.

HRMALDIMS: m/z calcd for C₉₀H₁₁₀O₂₈Na [M + Na⁺]: 1661.7076; found: 1661.7097.

3,23-O-isopropylidene hederagenin 28-O-2,3,4,6-tetra-O-acetyl-α-D-galacopyranosyl-(1→6)-2,3,4-tri-O-benzoyl-β-D-glucopyranosyl-(1→6)-2,4-O-acetyl-3-benzyl-β-D-glucopyranoside (10a)

[α]_D²² + 15.6 (c 1.12, CHCl₃); mp 156–158 ^oC. IR (KBr) ν_max 3061, 2939, 1739, 1438, 1375, 1257, 1087 and 714 cm⁻¹.

¹H NMR (Acetone-d₆, 600 MHz): δ = 6.98–8.24 (m, 20H, Ph-H), 6.35 (t, J = 9.6 Hz, 1H, H-3″), 5.96 (t, J = 9.6 Hz, 1H, H-4″), 5.89 (t, J = 9.7 Hz, 1H, H-4′), 5.71 (t, J = 9.6 Hz, 1H, H-3′), 5.63 (d, J = 8.2 Hz, 1H, H-1′), 5.59 (dd, J = 9.7, 8.3 Hz, 1H, H-2′), 5.44 (dd, J = 9.6, 3.7 Hz, 1H, H-3″′), 5.39 (d, J = 7.8 Hz, 1H, H-1″), 5.36 (t, J = 3.8 Hz, 1H, H-4″′), 5.34 (d, J = 3.2 Hz, 1H, H-1″′), 5.27 (d, J = 11.0 Hz, 1H, H-6″′-1), 5.10 (d, J = 11.9 Hz, 1H, PhCHH), 5.05 (d, J = 11.9 Hz, 1H, PhCHH), 4.73–4.76 (m, 1H, H-5′), 4.30–4.33 (m, 2H, H-2″′, H-6″′-2), 4.16 (dd, J = 12.1, 3.0 Hz, 1 H, H-6″-1), 4.06 (dd, J = 12.0, 5.4 Hz, 1H, H-6′-1), 3.98–4.02 (m, 3H, H-5″, H-5″′, H-6″-2), 3.91–3.95 (m, 2H, H-23), 3.84 (dd, J = 12.0, 2.3 Hz, 1H, H-6′-2), 3.80 (m, 1H, H-2″), 3.57 (dd, J = 12.0, 4.6 Hz, 1H, H-3), 2.84 (d, J = 13.1 Hz, 1H, H-18), 2.12, 2.11, 2.08, 1.97, 1.95, 1.82 (s each, 3H each, CH₃CO × 6), 1.19, 1.14, 1.01, 0.96, 0.90, 0.69 (s each, 3H each, CH₃ × 6).

¹³ C NMR (Acetone-d₆, 150 MHz): δ = 176.0 (C-28), 170.8, 170.7, 170.6, 170.5, 170.4, 170.3, 166.2, 166.1, 165.9, 165.6, 165.2, 161.3, 144.1 (C-13), 134.9, 134.6, 134.5, 134.3, 130.9, 130.7, 130.5, 130.4, 130.3, 130.2, 130.1, 130.0, 129.9, 129.8, 129.6, 129.5, 129.4, 129.1, 128.7, 128.3, 123.4, (C-12), 101.2 (C-1′), 99.3 ((CH₃)₂ CO), 97.2 (C-1″), 97.1 (C-1″′), 91.0, 89.6, 80.9, 78.4, 77.9, 75.1, 74.5, 74.1, 73.5, 72.3, 72.1, 71.5, 69.5, 69.0, 68.9, 68.5, 67.7, 67.4, 66.4, 62.5, 51.9, 48.4, 47.5, 46.5, 42.4, 41.9, 40.4, 39.6, 38.0, 37.4, 34.3, 33.3, 31.3, 28.6, 26.3, 24.3, 24.0, 23.9, 20.9, 20.8, 20.7, 20.6, 20.5, 19.7, 18.3, 17.5, 17.0, 14.6, 12.9.

HRMALDIMS: m/z calcd for C₉₁H₁₁₂O₂₈Na [M + Na⁺]: 1675.7232; found: 1675.7256.