(1R)-2,3,4,6-Tetra-O-benzyl-1-C-allyl-1-deoxy-1-C-(2-thiazolyl)-d-galactopyranose

Abstract

We have previously reported that thiazolylketol acetates, synthesized by the addition of 2-lithiothiazole to sugar lactones followed by acetylation, are efficient glycosyl donors affording O-, N-, P-, and C-glycosides. After the first example of C-glycosidation recently described by us, we report here on the unexpected outcome of the reaction of a thiazolylketol acetate with allyltrimethylsilane in the presence of trimethylsilyl triflate. The obtained intermediate, an intramolecular N-thiazolium salt, could be stereoselectively converted into the desired allyl C-thiazolylketoside.

1. Introduction

The C-glycosides are the stable isosteres of the naturally occurring O-glycosides because the presence of a carbon instead of an oxygen atom at the anomeric position leads to glycosides that are not hydrolyzed by acids or glycosidases. Therefore, the C-glycosides can be used instead of the corresponding oxygen-linked glycoconjugates when more stable sugar derivatives are required for biological or pharmacological studies. To this end, a large number of synthetic methodologies were developed during the last forty years [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19], although most of them were exploited only for the preparation of alkyl and aryl C-aldosides. In fact, the synthetic approaches to C-ketosides were barely explored, probably because the stereoselectivity at the anomeric position is difficult to predict and control.

The d-galacto configured thiazolylketol acetate 2 (Scheme 1), prepared from d-galactonolactone 1 as described [20], and the other pyranose and furanose analogues [21], allowed to efficiently synthesise O-, N-, and P-glycosides of the corresponding ulose (3 and 5) or ulosonic acid (4 and 6) derivatives through stereoselective glycosylation, thiazole-to-formyl conversion, and formyl reduction or oxidation [21]. Despite these good results, the first C-glycosylation of the thiazolylketol acetates—the reaction of 2 with trimethylsilyl cyanide in the presence of TMSOTf to give the C-uloside 7 (Scheme 1)—was reported by us three decades after the disclosure of the glycosyl donor 2 [22]. Aiming to gain access to more complex C-glycoside derivatives, we have envisaged the reaction of thiazolylketol acetate 2 with another well-known carbon nucleophile, namely the allyltrimethylsilane. However, contrary to the C-glycosidation carried out with more common glycosyl donors, i.e., lacking the thiazole moiety [23,24], we observed the formation of an intramolecular N-thiazolium salt from which the target allyl C-glycoside could be obtained upon treatment with tetrabutylammonium fluoride.

2. Results and Discussion

The thiazolylketol acetate 2 was treated with 10 equiv. of commercially available allyltrimethylsilane in the presence of trimethylsilyl triflate (TMSOTf) and 4 Å powdered molecular sieves for 5 h at room temperature. Then, the reaction mixture was neutralized by adding triethylamine and filtered through a pad of Celite to give the intramolecular N-thiazolium salt 11 in almost quantitative yield instead of the expected allyl C-glycoside 10 (Scheme 2). The structure of 11 could be established by NMR analysis since its proton spectrum showed the signal of the trimethylsilyl group at 0.18 ppm (singlet, 9 H) while the signals of the thiazole hydrogens were significantly shifted downfield (doublets, 8.52 and 8.04 ppm) due to the positive charge onto the heterocycle (Figure S1). Moreover, in the ¹³C-NMR spectrum was present a quartet at 120.8 ppm with a large coupling constant (320 Hz) typical of the trifluoromethanesulfonate (triflate) anion (Figures S2 and S3). The presence of the triflate anion was confirmed by the signal at 78.7 ppm in its ¹⁹F-NMR spectrum (Figure S4). Therefore, after the addition of the anomeric oxycarbenium ion 8 to the alkene leading to the carbocation 9, the latter did not form the new double bond through release of the trimethylsilyl cation as expected (Scheme 2, red arrows) but underwent the intramolecular attack of the thiazole nitrogen to form 11, a rather stable salt featuring a fused five-member ring (Scheme 2, blue arrows).

Fortunately, we found that upon reaction of the crude N-thiazolium salt 11 with tetrabutylammonium fluoride in THF at 50 °C for 2 h, compound 10 could be recovered in 96% overall yield after column chromatography. As already observed for the O-, N-, P-, and C-glycosidation of the d-galacto-configured thiazolylketol acetate 2 [21,22], the allyl C-glycoside 10 was obtained as a single α-d (axial) anomer. The anomeric configuration was proved by the positive nuclear Overhauser effect (nOe) between one of the -CH₂- hydrogens of the allyl group and the axially oriented H-3 and H-5 protons of the pyranose ring, which adopts the usual ⁴C₁ conformation (Figure S5). Irradiation of the signal at 2.85 ppm showed a significant increase of the signals at 3.88 ppm (H-3) and 3.93 ppm (H-5), besides the obvious effect on the geminal hydrogen at 3.60 ppm.

3. Materials and Methods

Anhydrous CH₂Cl₂ (99.8%), anhydrous THF (99.9%), allyltrimethylsilane (98%), trimethylsilyl triflate (99%), triethylamine (99%), tetrabutylammonium fluoride trihydrate (98%), acetic acid (99.99%), powdered 4 Å molecular sieves (5 μm average particle size), and Celite were purchased from Sigma-Aldrich (Saint-Quentin-Fallavier, France). The reactions were monitored by TLC on silica gel 60 F₂₅₄ (Merck, Molsheim, France) with detection by charring with sulfuric acid. Flash column chromatography was performed on silica gel 60 (40–63 μm, Merck). Optical rotations were measured at 20 ± 2 °C in the stated solvent; [α]_D values are given in deg mL g⁻¹ dm⁻¹. ¹H NMR (300 and 400 MHz), ¹³C NMR (75 and 100 MHz), and ¹⁹F NMR (282 MHz) spectra were recorded in CDCl₃ at room temperature with a Varian Gemini 300 MHz and a Bruker Avance 400 MHz spectrometer. In the ¹H NMR spectra reported below, the n and m values quoted in geminal or vicinal proton–proton coupling constants J_n,m refer to the number of the corresponding sugar protons. FT-IR spectra were recorded using a Perkin Elmer Spectrum 3 instrument equipped with an ATR accessory. High-resolution mass spectrometry (Waters Micromass Q-TOF, Waters Corp., Milford, MS, USA) analyses were carried out at the “Laboratoire de Mesures Physiques” (University of Montpellier).

(1R)-2,3,4,6-Tetra-O-benzyl-1-C-allyl-1-deoxy-1-C-(2-thiazolyl)-d-galactopyranose (10)

A mixture of 2 (500 mg, 0.75 mmol), activated 4 Å powdered molecular sieves (0.50 g), and anhydrous CH₂Cl₂ (7.5 mL) was stirred at room temperature under a nitrogen atmosphere for 10 min, then allyltrimethylsilane (1.20 mL, 7.50 mmol) and trimethylsilyl triflate (140 μL, 0.75 mmol) were added. The mixture was stirred at room temperature for 5 h, then diluted with triethylamine (0.30 mL) and CH₂Cl₂ (50 mL), filtered through a pad of Celite, and concentrated to afford crude 11. A solution of the latter and nBu₄NF·3H₂O (2.37 g, 7.50 mmol) in anhydrous THF (7.5 mL) was stirred at 50 °C for 2 h, then cooled to room temperature, diluted with acetic acid (2 mL), and concentrated. The residue was eluted from a column of silica gel with 8:1 cyclohexane-AcOEt to give 10 (467 mg, 96%) as a colorless syrup; [α]_D = −7.9 (c = 0.8, CHCl₃). ¹H NMR (400 MHz): δ 7.77 (d, 1H, J = 4.0 Hz, Th), 7.40–7.26 (m, 21H, 4 Ph, Th), 5.69 (dddd, 1H, J = 5.6, 8.0, 10.2, 17.2 Hz, CH=CH₂), 5.17 (dddd, 1H, J = 1.0, 1.5, 2.0, 17.2 Hz, 1 H of CH=CH₂), 5.08 and 4.67 (2 d, 2H, J = 12.0 Hz, PhCH₂), 5.02 (dddd, 1H, J = 1.0, 1.0, 2.0, 10.2 Hz, 1 H of CH=CH₂), 4.77 (s, 2H, PhCH₂), 4.54 and 4.48 (2 d, 2H, J = 11.6 Hz, PhCH₂), 4.54 and 4.25 (2 d, 2H, J = 10.4 Hz, PhCH₂), 4.10 (dd, 1H, J_3,4 = 2.8, J_4,5 = 0.8 Hz, H-4), 4.06 (d, 1H, J_2,3 = 9.6 Hz, H-2), 3.93 (ddd, 1H, J_5,6a = 7.6, J_5,6b = 5.2 Hz, H-5), 3.88 (dd, 1H, H-3), 3.77 (dd, 1H, J_6a,6b = 9.2 Hz, H-6a), 3.63 (dd, 1H, H-6b), 3.60 (dddd, 1H, J = 1.0, 1.5, 5.6, 14.8 Hz, 1 H of CH₂-CH=), and 2.85 (dddd, 1H, J = 1.0, 1.0, 8.0, 14.8 Hz, 1 H of CH₂-CH=). ¹³C NMR (100 MHz): δ 174.7 (C), 141.9 (CH), 139.3 (C), 138.6 (C), 138.5 (C), 138.1 (C), 132.8 (CH), 128.45 (CH), 128.42 (CH), 128.3 (CH), 128.23 (CH), 128.20 (CH), 127.83 (CH), 127.77 (CH), 127.6 (CH), 127.51 (CH), 127.47 (CH), 127.35 (CH), 127.29 (CH), 119.9 (CH), 118.0 (CH₂), 82.2 (CH), 82.1 (C), 81.0 (CH), 75.9 (CH₂), 74.6 (CH), 74.4 (CH₂), 73.6 (CH₂), 72.8 (CH₂), 71.6 (CH), 68.8 (CH₂), and 33.4 (CH₂). FT-IR (cm⁻¹): 3088, 3064, 3030, 2917, 2868, 1496, 1453, 1361, 1093, 992, 913, 731, and 694. HRMS (ESI/Q-TOF): m/z calcd. for C₄₀H₄₂NO₅S [M+H]⁺ 648.2778, found 648.2780.

4. Conclusions

The allyl C-thiazolylketoside 10 constitutes a versatile building block since it is bearing two orthogonal functional groups. In fact, while the thiazole ring can be easily converted into a formyl group, which is then reduced or oxidized, the allyl moiety is a suitable substrate for the well-known dihydroxylation (leading to a vicinal diol) [25,26,27] or cross-metathesis (affording longer chain derivatives) reactions [28,29]. Moreover, it is expected that all the above-mentioned transformations will take place, leaving unaltered the configuration of the starting material 10 due to the quaternary nature of the anomeric carbon.