One-Pot, Highly Stereoselective Synthesis of Dithioacetal-α,α-Diglycosides

A one-step access to dithioacetal-α,α-diglycosides is reported. The synthetic strategy is based on the thioacetalization of aldehydes or ketones via highly stereoselective ring-opening of 1,6 anhydrosugars with bis(trimethylsilyl)sulfide.


Introduction
Carbohydrates are a major class of inspiring structures for the design of biologically active compounds. These densely functionalized chiral molecules represent also a prolific source of useful building blocks and molecular tools for asymmetric synthesis. Moreover, their relative structural complexity has been a fertile ground for accidental discoveries in organic synthesis [1]. In this context, we have recently reported a molecular Lego approach for the synthesis of functionalized cyclic and acyclic neo-oligosaccharides [2]. Our strategy was based on the linkage of bifunctional building blocks by Cu(I)-catalyzed azide−alkyne cycloaddition, the reducing end of the sugars being activated as a glycosyl azide and masked as a 1,6-anhydro sugar [2,3]. To explore the interest of thiol-click chemistry for such modular strategies [4,5], we needed to synthesize thioglycoside 1 (Scheme 1). In a first attempt, (TMS) 2 S ring-opening of 1,6-anhydro sugar 2 mediated by TMSOTf following Zhu's protocol [6] did not lead to the desired α-glucosyl thiol 1 (Scheme 1). Much to our surprise, dithioacetal-α,α-diglucoside 3 was obtained as the major product in low yields and as a single diastereomer. We assumed that the unexpected formation of dithioacetal 3 was due to the accidental presence of traces of acetone in the reaction mixture. Dithioacetal diglycosides have almost no precedent in the literature [7,8]. These compounds may be viewed as analogues of trehalose (4), a biologically relevant nonreducing disaccharide found in microorganisms, bacteria, plants and invertebrates [9][10][11]. Examples of related diglycoside acetals designed for asymmetric synthesis, molecular imaging or for their biological interest have been described in the literature [12,13]. Chemistry wise, we were also attracted by the efficiency of this highly stereoselective process in which the formation of multiple C-S single bonds generates an original thiodisaccharide analogue in one step. In this communication, we wish to report our preliminary exploration of the synthetic scope of this TMSOTf-mediated one-pot reaction leading to dithioacetal diglycosides via 1,6-anhydro sugar ring-opening.

Optimization of the Reaction Conditions
Exploration of the synthetic scope of the one-pot process was first performed with 1,6-anhydro-D-glucose 5a [14] using benzaldehyde as the model carbonyl partner (Table 1). The choice of benzaldehyde was guided by mechanistic considerations as we anticipated that this non-enolisable carbonyl compound offered a good equilibrium between reactivity, stability and low volatility. According to the tentative mechanism proposed in Figure 1, TMSOTf is expected to play a double role in the formation of the dithioacetal product. In the first step, TMSOTf promotes the highly diastereoselective (TMS) 2 S ring-opening of anhydrosugar A following a S N 2-type mode [6]. In a second step, addition of the resulting α-thioglycoside B to the TMSOTf-activated carbonyl compound affords the stabilized α-thio carbocation D via thioacetal C [15][16][17][18]. The subsequent interception of this carbocation by a second molecule of α-thioglycoside B affords the dithioacetal-α,α-diglycoside E after aqueous work-up. According to Zhu's optimized conditions [6], 1.4 equiv. of (TMS) 2 S were used in refluxing dichloromethane and the quantity of TMSOTf was increased from 0.4 equiv. to stoichiometric quantity to take into account the activation of the carbonyl compound according to our tentative mechanism ( Figure 1). The reaction was performed in hermetically sealed tubes to avoid solvent evaporation. First attempts to obtain dithioacetal 6a by introducing benzaldehyde at the beginning of the reaction led to unidentified degradation products. To avoid possible inhibition of the first step of the process, i.e., the formation of the key thioglycoside intermediate B, the carbonyl partner was added subsequently after conversion of anhydrosugar 5a to the corresponding thioglycoside derivative. After several assays performed in the absence of benzaldehyde, we found that a complete conversion of the starting material into thioglycoside 7 could be achieved after 2 h when 1.1 equiv. of TMSOTf were used. Various experimental parameters were then examined for the second step. In a first attempt made at room temperature using 0.5 equiv. of benzaldehyde, the desired dithioacetal 6a was obtained in 13% yield, the major product being the unconverted thioglycoside 7 (entry 1, Table 1). To increase the conversion of 5a to 6a, the amount of benzaldehyde was doubled and the temperature reduced to avoid possible degradation. Following these conditions, the yield of the one-pot process could be doubled to 27% at −15 • C and increased to 45% at −30 • C (entries 2-3, Table 1). The yield was further improved to 60% by adding 4Å molecular sieves [18] in the reaction mixture to avoid any possible inhibition of the thioacetalization reaction by traces of water in the reaction mixture (entry 4, Table 1). It was anticipated that the presence of water may facilitate the in situ hydrolysis of the glucosyl silyl sulfide intermediate B to the corresponding less reactive thiol (Figure 1) [19]. The addition of more equivalents of benzaldehyde at −78 • C in the presence of 4Å molecular sieves led to a clean reaction mixture as judged on TLC. However, no improvement of the reaction yields was observed (entries 5-7, Table 1).

Reaction Scope
We then tested the one-pot reaction on a series of aldehydes under the optimized conditions to evaluate its synthetic scope ( Table 2). The influence of electron-withdrawing and electron-donating substituents on the aromatic aldehyde moiety was explored with benzaldehyde analogues. The presence of a para-methoxy group did not improve the efficiency of the process whereas substitution with a trifluoromethyl group was found to strongly decrease the yield of the reaction (entries 2-3). We were pleased to see that the one-pot synthesis of dithioacetal glycosides could be performed with enolizable aliphatic aldehydes, however in lower yields compared to benzaldehyde (entries 4-5). Not surprisingly, the modest yields obtained with pivaladehyde compared to linear aldehydes suggested that the thioacetalization process was sensitive to steric hindrance (entry 6). The experimental conditions were found to be compatible with allyl protecting groups (entry 7).
The one-pot synthesis of dithioketal-α,α-diglycosides were explored with cyclic and acyclic ketones (Scheme 2). The expected lowest reactivity of ketones compared to aldehydes resulted in lower yields. Application of optimal conditions for the synthesis of 6 afforded acceptable yields only for cyclobutanone giving 8b in 31% yield. Under these conditions, no desired products or poor conversions were obtained with cyclohexanone and 3-pentanone. After extensive optimization with cyclohexanone we founded that large excess of TMS 2 S (2.5 equiv.) is required and that the cyclohexanone have to be present from the beginning of the reaction. With these conditions we are delighted to obtain compound 8a with 45% yield. The application of these conditions with 3-pentanone afforded 8c in poor yield showing the less reactivity of acyclic ketone for this one-pot process. It is noteworthy that the 1 H NMR spectra of dithioketal glycosides 8 obtained from ketones are much simpler than those generated from aldehydes. In 8, the two sugars moieties are magnetically equivalent. One signal is thus observed for the two anomeric protons which appear as a doublet with a vicinal coupling constant of~5 to 6 Hz. In contrast, two distinct doublets are observed for the anomeric protons in 6 (J~5 to 6 Hz). In the case of compounds 6, the two pyranose moieties are not magnetically equivalent. Tietze et al. have reported a similar observation for related diglycosides acetals [12].

General Procedure for the Synthesis of Diglycoside Thioacetals 6
Molecular sieves 4Å (80 mg) were added to a tube. A solution of anhydroglucose 5 (1 equiv., 0.233 mmol) in CH 2 Cl 2 (1 mL) was added via cannula to the flask. Bis (trimethylsilyl) sulfide (1.4 equiv., 58.3 mg, 0.0613 mL, 0.327 mmol) followed by trimethylsilyl trifluoromethane sulfonate (1.1 equiv., 57 mg, 0.0466 mL, 0.257 mmol) were added to the mixture. The tube was sealed and the medium was stirred at 60 • C. After 2 h of reaction, a solution of the corresponding aldehyde (1 equiv., 0.233 mmol) in 0.3 mL of CH 2 Cl 2 was added at −30 • C. The reaction was stirred for 1 h 30 min. The mixture was warmed up to r.t. and washed with saturated aqueous NaHCO 3 (50 mL). The aqueous layer was extracted with CH 2 Cl 2 (3 × 50 mL). The organic layers were combined and washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude obtained was purified by flash column chromatography (Petroleum Ether/EtOAc) to afford compounds 6.