Stereoselective access to 2-deoxy-2-trifluoromethyl sugar mimetics by trifluoromethyl-directed 1,2-trans glycosylation

Abstract

Fluorinated carbohydrate mimetics are valuable molecular fragments in contemporary Glycoscience. Available synthetic protocols are mainly restricted to the preparation of ‘standard’ monofluorinated derivatives, whereas their more complex C(sp³)–CF₃ congeners remain virtually underdeveloped. A protocol for accessing a series of previously uncharted 2-deoxy-2-trifluoromethyl-D-hexopyranosides from D-glycals is disclosed. The stereoselectivity of the glycosylation step, which is mainly governed by a combination of electronic and more dominant steric factors, revealed a pronounced substrate control rendering 1,2-trans glycosides as a result of the configuration of the CF₃ moiety at C-2. The synthetic utility of this approach was demonstrated in the preparation of 2-CF₃-glycoconjugates of natural origin, including disaccharides, cholesterol analogs, amino acids, and sphingosine/phytosphingosine derivatives.

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Introduction

There is growing interest in the preparation of carbohydrate mimetics that overcome some of the limitations, such as short lifetimes and low absorption properties (reduced hydrophobicity), typically associated with drugs based on natural carbohydrates.¹ Among them, F-glycomimetics,² resulting from the bioisosteric replacement of H and OH by F,³ and particularly those featuring polyfluoroalkyl groups (R_F),⁴ such as CF₃ ⁵ (CH₃ isoster) and C₂F₅,⁶ have recently attracted considerable interest (Fig. 1A).⁷ However, although the preparation of CF₃-containing active principal ingredients (APIs) has been long appreciated in MedChem due to the beneficial properties such polyfluorinated groups impart (e.g., enhanced lipophilicity and metabolic/oxidative stability),⁸ CF₃-glycosides remain largely underrepresented^9,10 in Glycoscience compared to their monofluorinated congeners. Interestingly, the latter are widely used as inhibitors of glycosidases,¹¹ lectin ligands,¹² building blocks to construct synthetic (glyco)peptides/proteins^13–15 for carbohydrate vaccine design,¹⁶ as well as radiotracers for imaging applications (e.g., [¹⁸F]FDG).¹⁷

Fig. 1 (A) 2-Fluorinated-hexopyranosides and selected drugs containing F and CF₃ groups. Hits obtained with the Reaxys database. (B) Physical properties of F vs. CF₃ groups (top). Calculated Electrostatic potential surfaces (EPS), van der Waals volume (blue), and dipole moment (magnitude and vector, red) (bottom) (see the ESI† for details). (C) Selectivity control in 2-deoxyglycosides bearing temporary (X = I, Br, SPh, SePh) and permanent (X = F, CF₃) C2-directing groups.

We hypothesise the unique properties³ of the CF₃ group, with similar polarity but larger steric constraints compared to those of the F atom; will likely influence metabolism, distribution, uptake, and therapeutic potential in CF₃-monosaccharides (Fig. 1B, top). This trend is also supported by calculations of electrostatic potential surface (EPS), van der Waals volume, and dipole moment (magnitude and vector) for 2-CF^manno,gluco₃vs. 2-F^manno,gluco hexopyranoses (Fig. 1B, bottom and Figs. S1–S4, ESI†).^18,19 Moreover, CF₃ moieties may confer conformational constraints and enzymatic stability as well as privileged imaging potential (increased sensitivity in ¹⁹F-MRI and possibility to access [¹⁸F]-derivatives for PET imaging).^17,20 Readily available trifluoroacetamides (NHC(O)CF₃) and trifluoroacetoxy (OC(O)CF₃) groups are the closest-art and the most frequent motifs among C(sp²)(O)CF₃-containing glycosides.^9,21 Unfortunately, other CF₃-sugars are only limited to α-C(sp³)–CF₃ alcohols resulting from 1,2-nucleophilic addition of TMSCF₃ to carbonyls²² and, more recently, C(sp²)–CF₃-glycals produced by photoredox²³/electrochemical²⁴ radical additions or via cross-couplings of CuCF₃ with 2-iodoglycals.⁵ Besides its remarkable biophysical properties, F has also proven an efficient steering group for the stereoselective preparation of 2-deoxy-2-fluoroglycosides.²⁵ In this case, the high 1,2-anti selectivity results from the preferred conformation of the oxocarbenium ion in the transition state reminiscent to half-chair geometries that are favoured by the high electronegativity of F. The energy of the transition state is minimized when the nucleophile trajectory is aligned with the orbital, consistent with the Felkin–Anh–Eisenstein model for 1,2-stereoinduction.²⁵ This contrasts with the stereoselectivity observed in similar examples using larger temporary C-2-directing groups such as halogens²⁶ and chalcogens²⁷ in which the 1,2-trans stereoselectivity is mainly governed by steric (Pauli) factors (Fig. 1C).²⁸ Removal of these groups affords the corresponding 2-deoxyglycosides.²⁹

In this context, we were intrigued on the behaviour of the CF₃ group when placed at the C-2 position of a glycosyl donor, and whether the presence of such an electron-withdrawing and bulky unit may impart stabilizing/destabilizing interactions at the nearby oxocarbenium ion (e.g., nF → 2pC interactions),³⁰ affecting the stereochemical outcome of the glycosylation reaction. Thus, here we report the development of a synthetic route (including a detailed study of the glycosylation reaction) to access new C(sp³)–CF₃-(glyco)architectures. In particular, it would be interesting to comparatively determine if the electronic factors that govern the stereochemical outcome of the glycosylation of 2-deoxy-2-fluoro-glycosides are also operating in the case of 2-deoxy-2-CF₃-derivatives (Fig. 1C, X = CF₃). We anticipate the development of synthetic methods such as the one described in this study will establish the basis for successfully approaching further studies in complex fluorinated glycomimetics.

Results and discussion

Synthesis of glycosyl donors

In light of this, a strategy for the preparation of 2-CF₃-glycosyl donors was envisaged from commercially available D-glucals as precursors (Scheme 1A). In our previous work, we reported the synthesis of 3a by iodination of D-glucal 1a to 2a (64% via dehydrative elimination)³¹ followed by selective trifluoromethylation using CF₃H-derived CuCF₃ (80%).⁵ This trifluoromethylation process required the use of a glovebox and manipulation of gaseous reagents. Herein, the overall synthetic sequence was improved by using first a more efficient iodination protocol (79% for 2a; 59% for 2b)³² and second, the use of a trifluoromethylation system (TMSCF₃/KF/CuBr) that permits readily scalable synthesis and employs simpler reaction setup to access valuable 2-CF₃-glycals (98% for 3a; 93% for 3b). Next, functionalization of the double bond was attempted, but the 2-CF₃-alkene proved reluctant to undergo electrophilic additions, including halogenation, H⁺-mediated hydration, hydroboration, and epoxidation (Scheme S2, ESI†). Polyfluorinated alkenes and aromatic compounds are likely to reverse the natural polarity of such π-systems, making them prone to nucleophilic attacks.³³ Nonetheless, structural examination of 3a,b advises a push–pull effect between the electron-donating oxygen of the enol ether and the electron-withdrawal of the CF₃ group that in combination with its steric bulkiness, renders this double bond considerable unreactive (Scheme S2, ESI†). To our delight, hydroxymercuration of 3a using Hg(OTFA)₂ followed by reductive demercuration with NaBH₄ afforded a 1 : 1.6 mixture of gluco4a and manno5a pyranoses in 90% yield that after acetylation yielded chromatographically separable 4b (35%) and 5b (46%) (Scheme S3, ESI†). Collectively, the detection of only α-anomers indicates that similarly to 2-F, 2-CF₃ reinforces the anomeric effect.³⁴O-Benzyl protecting groups in 1-O-acetyl-pyranoses 4b and 5b were removed under hydrogenolysis conditions and subsequent acetylation afforded products 4c and 5c in good overall yields (up to 80%). Same reaction sequence starting from parent 1-OH-pyranoses 4a and 5a resulted in detrimental anomerization to afford inseparable α/β mixtures of gluco4c and manno5c pyranoses. Direct hydroxymercuration-reduction of 2-CF₃-tri-O-acetyl-D-glucal 3b proved inefficient and 4b was obtained in a poor 34% yield along with unidentified rearrangement byproducts. Analysis of 4c by X-ray diffraction† indicated that typical ⁴C₁ conformation is adopted in the solid state despite the presence of the sterically demanding CF₃ group. ¹H and ¹³C NMR data showed that the same geometry is also conserved in solution for both gluco and manno derivatives as determined by diagnostic ¹J_C1–H1 and ³J_H,H coupling constants and key NOE contacts (Scheme 1B and Fig. S141, ESI†).

Scheme 1 (A) Synthesis of 2-deoxy-2-trifluoromethyl-D-hexopyranoses of gluco and manno configurations and (B) conformational analysis. Reagents and conditions: (a) 1a,b (1 equiv.), NIS (1.2 equiv.), AgNO₃ (0.2 equiv.), dry MeCN, reflux, 1 h (for 1a) up to 4 h (for 1b). (b) 2a,b (1 equiv.), CuCF₃ (2 equiv.), 1 : 1 (v/v) DMF/DMI, 40 °C, 17 h and 50 °C, 16 h. (c) (i) 3a,b (1 equiv.), Hg(OTFA)₂ (1.5 equiv.), 3 : 1 THF/H₂O, 0 °C to rt, 36 h; (ii) NaBH₄ (6.3 equiv.), H₂O, 0 °C, 20 min. (d) Ac₂O (3.6 equiv.), pyridine, rt, 15 h. (e) H₂ (1 atm), 10% Pd/C, MeOH, rt, 16 h. ^fThis yield corresponds to a pure analytical sample obtained after a tedious fractional crystallization process. Prior column chromatography of the crude reaction afforded an inseparable mixture of 1 : 1.6 4a/5a in 90% yield. ^gYield over three steps from 3a (for 4b, 5b) and 3b (for 4c). Isolated yields given for all compounds unless otherwise indicated (see the ESI† for details). DMF = N,N-dimethylformamide, DMI = 1,3-dimethyl-2-imidazolidinone, TFA = trifluoroacetic acid, THF = tetrahydrofuran. ORTEP drawing of 4c with thermal ellipsoids drawn at the 50% probability level (H atoms omitted for clarity).

After optimizing the preparation of 2-CF₃-pyranoses, the synthesis of suitable glycosyl donors was further examined (Scheme 2A and Scheme S4, ESI†). We first explored the preparation of trichloroacetimidate 5a-OTCA by reacting 5a with DBU and Cl₃CN, but the poor yields obtained (48%) and the need of purification reduced its synthetic utility.

Scheme 2 (A) Synthesis of glycosyl bromide donors and (B) screening of glycosylation solvents and conformational analysis. Reagents and conditions: ^aYield and selectivity determined by ¹⁹F NMR of the crude reaction mixture using 1,4-difluorobenzene as internal standard unless otherwise indicated. ^bReactions performed at 0.1 M concentration. ^cYield over two steps from 4c. ^dPoor solubility of AgOTf observed (see the ESI† for details). MS = molecular sieves, THF = tetrahydrofuran, NR = no reaction. ORTEP drawing of 7β with thermal ellipsoids drawn at the 50% probability level (H atoms omitted for clarity).

Reacting 5b with BF₃·OEt₂ and thiophenol in CH₂Cl₂ afforded thioglycoside donor 5b-SPh in a very low 23% isolated yield (Scheme S4, ESI†). Notably, reaction of pyranoses 4–5b,c with HBr in AcOH delivered glycosyl bromides (4–5b,c)-Br in almost quantitative yields (Scheme 2A). Glycosyl bromides proved to be stable, and they were directly used as glycosyl donors in subsequent glycosylation reactions without further purification.

Glycosylation reaction

Next, preliminary glycosylation reactions were attempted using anomeric acetates 4b, 5b, trichloroacetimidate 5a-OTCA, and thioglycoside 5b-SPh as donors (Scheme S5, ESI†). While the reaction of anomeric acetates showed no conversion using common promoters (0.1–4 equiv. TMSOTf or 3 equiv. BF₃·OEt up to 72 h at room temperature) for both manno and gluco configurations (Scheme S5, entries 1–3, ESI†), trichloroacetimidate 5a-OTCA afforded expected product 6a in a good combined 69% yield and 38 : 62 α/β ratio (Scheme S5, entry 4, ESI†). In contrast, activation of 5b-SPh with the NIS/TfOH³⁵ system only started when temperatures above −35 °C where reached, affording 6a (73%) in a 58 : 42 α/β ratio along with hydrolysis byproducts (∼27%) (Scheme S5, entry 5, ESI†). In summary, the preparation of thioglycoside and trichloroacetimidates resulted problematic, delivering low isolated yields of 5a-OTCA and 5b-SPh, required additional purification steps, and are not applicable to gluco configurations. Moreover, glycosylation of these donors offered substantial hydrolysis, poor 1,2-trans control of the CF₃ group (5a-OTCA), required higher activation temperatures (5b-SPh) that compromise good stereoselectivities for general application of this protocol or showed no reactivity (4b and 5b). Next, we focused our attention towards the glycosylation of easily accessible glycosyl bromides (Scheme 2B),³⁶ which showed smooth activation at very low temperatures. Thus, CF^gluco₃4c-Br was selected as a model substrate and 1,2 : 3,4-di-O-isopropylidene-α-D-galactopyranose as the acceptor with 4 Å MS and silver triflate (AgOTf) as the promoter (Scheme 2B). Preliminary tests showed the importance of conducting the reaction at very low temperature (ca. −80 °C), in particular for gluco configuration, due to the propensity of 2-CF₃-glucosyl bromides to undergo elimination processes to the parent 2-CF₃-D-glucal (5–20%). Solvent screening showed that reactions in THF afforded low yields and the selectivity was poor (Scheme 2B, entry 1). When using acetonitrile at −40 °C, excellent β-selectivities were obtained, albeit with lower yield (Scheme 2B, entry 2). Using either CH₂Cl₂ or toluene, the selectivity was similar, affording 7β as the major isomer, yet in CH₂Cl₂, the yield was eroded, probably due to solubility issues with AgOTf (Scheme 2B, entries 3 vs. 4). In this case, no surface effects on selectivity were detected. Finally, best yield and selectivities were obtained in a 1 : 1 (v/v) CH₂Cl₂/toluene mixture (Scheme 2B, entry 5). Treatment of 7β under these optimized glycosylation conditions discarded anomerization of final 2-CF₃-glycosides during the reaction. Similarly to their hexopyranose precursors and the resulting glycosyl donors (Schemes 1B and 2A), glycosylation products also maintain the same ⁴C₁ conformation both in the solid state (X-ray for 7β)† and in solution (Scheme 2B and Fig. S5 and S142, ESI†). This observation suggests that a priori, 2-deoxy-2-CF₃-glycoside analogs of natural products could be designed to maintain molecular recognition events (unless key specific interactions are operative at C-2) by biological entities, validating our starting hypothesis (F^δ− → CF₃^δ−).

Aiming to analyze the directing effect of the CF₃ on the stereoselectivity of the glycosylation reaction, donors with different 2-CF₃-configuration and electronically different protecting groups were examined (Table 1). To facilitate direct comparison of the stereodirecting value of CF₃vs. F, isopropanol was chosen as nucleophile following seminal reports by Gilmour.²⁵Gluco-CF₃ glycosyl donors favoured formation of β-products, whereas α-glycosides were preferred in manno-CF₃ donors (Table 1, entries 1–4). The best selectivities obtained resulted from the combination of OAc-protecting groups with CF^manno₃5c-Br (95 : 5 α/β) and OBn groups with CF^gluco₃4b-Br (3 : 97 α/β). We first evaluated the role of the concentration (0.05 vs. 0.1 M)³⁷ and stoichiometry (1 : 1, 1 : 2, and 1 : 15 donor/acceptor molar ratio),³⁸ which are critical parameters for the glycosylation outcome (Table S1, entries 1–4, ESI†).³⁹ Only little yield (except in the case of using 1 equiv. of acceptor where more byproducts are detected) and selectivity differences were found in reactions conducted at different reaction concentrations or with increased acceptor stoichiometry that suggests a more S_N1-like dissociative mechanism. The use of promoters bearing non-nucleophilic counter ions such as AgBF₄ ⁴⁰ and AgSbF₆ (unable to provide OTf to the reaction medium) afforded similar selectivities that those with AgOTf, which strongly suggests that anomeric triflates are not likely responsible for the selectivity observed (Table S1, entries 1–4 vs. 5 and 6, ESI†). Our findings are in line with the results obtained in the glycosylation of 2-fluorosugars, yet in this case, trichloroacetimidates were used as glycosyl donors.²⁵ Remarkably, the role of the leaving group in the stereoselectivity seems important (CF^manno₃5a-OTCA; 38 : 62 α/β ratio; Scheme S5, ESI†) vs. (CF^manno₃5b-SPh; 58 : 42 α/β ratio; Scheme S5, ESI†) vs. (CF^manno₃5b-Br, 79 : 21 α/β; Table 1, entry 4).³⁹ Reactions using α-Br/SPh as leaving groups seem to be placed closer to the S_N1 end of the glycosylation mechanistic continuum, proceeding via a common oxocarbenium ion/solvent-separated ion pair (SSIP) species. Small differences in selectivity may be attributed to slightly different activation temperatures (−80 °C for Br vs. −35 °C for SPh).⁴¹ Attempts to shed light on putative reactive intermediates were performed by ¹⁹F and ¹H variable temperature (VT)-NMR experiments⁴² with bromide 4c-Br using our optimized reaction conditions but no intermediates were detected under preactivation conditions (preferred to detect transient intermediates). Subsequent addition of the nucleophile (iPrOH) delivered a complex mixture of signals from which only traces of final glycosylation product 10 could be observed. This result is in line with that using only 1 equiv. of acceptor in which increased amounts of byproducts are detected (Table S1, entry 3, ESI†). On the other hand, as expected,^42,43 a more biased S_N2-like scenario with a larger contribution of α-contact ion pair (CIP) species or even α-anomeric triflates from 5a-OTCA to tentatively rationalize the increased β-selectivity is invoked.⁴⁴ Thus, for the sake of a more accurate comparison (F vs. CF₃), 2-deoxy-2-fluoroglycosyl bromides 8–9a,b-Br¹⁴ were synthetized from 8–9a,b and submitted to the same reaction conditions of the present study. Stereoselectivities in 2-deoxy-2-fluoro derivatives 14–16 were similar to those of trifluoromethylated analogs 10–12 (Table 1, entries 1–3 vs. 5–7). However, inversion of the selectivity was observed in the OBn-manno-sugars 13 and 17 (Table 1, entry 4 vs. 8). Limited stereoselective control was also detected for OBn-manno derivatives in previous works,²⁵ due to mismatched effects between protecting groups and the 2-fluoro substituent. Stereoselectivity in 2-deoxy-2-fluorosugars is rationalized by the Felkin-Anh-Eisenstein 1,2-induction model (Fig. 1C, X = F) in which stereoselective control is reinforced or diminished depending on the electronic nature of protecting groups (due to electrostatic and hyperconjugative interactions).⁴⁵ The higher α-stereoselectivity observed in CF^manno₃vs. F^manno OBn-derivatives may arise from a higher contribution of the steric control, which is reminiscent to that observed with methyl groups in substitution reactions of acyclic α-methyl-β-alkoxy acetals via electrostatically stabilized oxocarbenium ion intermediates.⁴⁶ Next, the effect of the acceptor nucleophilicity was examined with donor CF^gluco₃4c-Br. No remarkable differences were observed when isopropanol and ethanol were used as acceptors and high 1,2-trans stereoselectivities were again obtained (Table 1, entry 1 vs. 9). On the other hand, lower or even inverted (1,2-cis) stereoselectivities were found when larger/weaker nucleophilic tert-butyl alcohol and trifluoroethanol were used as acceptors as they require donors with substantial oxocarbenium ion character and are engaged in dissociative S_N1-like reactions (Table 1, entries 10 and 11).⁴⁷ The increased steric hindrance of the acceptor may disfavour its approach by the top face due to steric (Pauli) repulsions with protecting groups (Fig. 2, middle). Results are compatible with a Curtin-Hammett scenario, where ΔG^‡II increases energy more than ΔG^‡I for bulky and/or weak nucleophiles (Fig. 2, bottom).

Fig. 2 Stereoselectivity rationalization of the glycosylation step in D-manno (top) and D-gluco series (middle). Analysis of the glycosylation of D-gluco donors with small alcohols possessing different stereoelectronic properties as acceptors (bottom).

Table 1 Effect of pyranose configuration, C-2 substituent, protecting groups, and acceptor nucleophilicity in the glycosylation reaction^a

Entry	2-X-pyranose		R	R′	Product yield^b (%)	α/β ratio^b
a General conditions: (1) 2-X-pyranose (1 equiv.), 33 wt% HBr in AcOH, 0 °C to rt, 1–3 h; (2) glycosyl bromide donor (1 equiv.), R'OH (2 equiv.), and AgOTf (2 equiv.) in 1 : 1 (v/v) CH2Cl2/toluene (0.05 M), −80 °C, 3 h unless otherwise indicated. Variable amounts of elimination side-reactions to the parent 2-CF3-D-glucal were detected by ^19F NMR (9–32% in Glc and <10% in Man). b Determined by ^19F NMR analysis of the crude reaction mixture using 1,4-difluorobenzene as internal standard (see the ESI† for details).
1	CF^gluco3	4c	Ac	iPr	10, 61	33 : 67
2	CF^manno3	5c	Ac	iPr	11, 91	95 : 5
3	CF^gluco3	4b	Bn	iPr	12, 72	3 : 97
4	CF^manno3	5b	Bn	iPr	13, 62	79 : 21
5	F^gluco	8a	Ac	iPr	14, 95	24 : 76
6	F^manno	9a	Ac	iPr	15, 84	95 : 5
7	F^gluco	8b	Bn	iPr	16, 78	4 : 96
8	F^manno	9b	Bn	iPr	17, 65	20 : 80
9	CF^gluco3	4c	Ac	Et	18, 78	22 : 78
10	CF^gluco3	4c	Ac	tBu	19, 58	42 : 58
11	CF^gluco3	4c	Ac	CH2CF3	20, 62	72 : 28

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Glycosylation scope

Finally, reaction scope was further examined using a diversity of representative acceptors, including primary and secondary glycosides, amino acids, and lipid aglycones such as cholesterol and sphingosine/phytosphingosine derivatives (Scheme 3). Thus, sequential bromination of 4b, 5b,c and subsequent glycosylation with the primary acceptor 1,2 : 3,4-di-O-isopropylidene-α-D-galactopyranose afforded products 21–23 in good yields (up to 80%) with expected 1,2-trans stereoselectivities (up to 94 : 6 α/β in manno; 6 : 94 α/β in gluco). In most cases, the major anomer was obtained as a single product after chromatographic purification. When the minor isomer was produced to some extent, the epimers could be successfully separated and structurally characterized. Again, analysis of 8, 21–23 by ¹H NMR showed ⁴C₁ conformations dominate in all cases (Fig. S5, ESI†). It should be noted that 2-CF₃-D-glucal byproduct was obtained in variable amounts (10–35%) upon competing elimination process using CF^gluco₃ donors that resulted in reduced overall yields for certain glycosylations. As expected, CF^manno₃ afforded preferably α-glycosides 24 (67%) and 25 (78%) with excellent stereoselectivities (up to 97 : 3 α/β) and slightly better yields when reacted with these secondary alcohols, since elimination side-reactions are significantly less operative from manno-configured donors (<10%). Reaction with biphenyl-2-methanol occurred smoothly with gluco donors to afford β-glycosides and selectivity was slightly benefited using OBn groups (8 : 92 α/β in 26vs. 18 : 82 α/β in 27). In this case, the lower yield obtained for peracetylated biphenyl methyl 27 is caused by the higher amount of elimination (29%) in comparison to the perbenzylated counterpart (11%).

Scheme 3 Glycosylation scope. Reagents and conditions: (a) 4–5b,c (1 equiv.), 33 wt% HBr in AcOH, 0 °C to rt, 4 h. (b) Glycosyl donor (1 equiv.), ROH (2 equiv.), and AgOTf (2 equiv.) in 1 : 1 (v/v) CH₂Cl₂/toluene (0.05 M), −80 °C, 2 h. (c) To facilitate purification, the crude was subjected to acetylation; Ac₂O (6 equiv.), 1 : 1 (v/v) pyridine/CH₂Cl₂, rt, 16 h and the residue purified by flash column chromatography. (d) To facilitate purification, the crude was subjected to Zemplén deacetylation; NaOMe, MeOH, rt, 6 h and the residue purified by flash column chromatography. ^eYield over three steps from 4c. Isolated yields given for all compounds unless otherwise indicated. In parenthesis yield and/or diastereomeric ratio calculated by ¹⁹F NMR of the crude reaction mixture using 1,4-difluorobenzene as internal standard (see the ESI† for details). Variable amounts of elimination side-reactions to the parent 2-CF₃-D-glucal were detected by ¹⁹F NMR (10–35% in Glc and <10% in Man). Boc = tert-butoxycarbonyl.

The presented protocol was applied to the stereoselective synthesis of 2-CF₃-analogs of some relevant natural products. Despite the higher amount of side-elimination reactions using peracetylated glycosyl donors (typically in CF^gluco₃), these were chosen as reactants in the glycosylation scope, mainly due to their higher flexibility for accessing final unprotected derivatives (via Zemplén deacetylation) in comparison to the perbenzylated analogs. Fair yield, although excellent selectivity, was observed in the synthesis of 28 (βGlc(1,6)Glc branch found in yeast and fungi β-glucans) from the mismatched donor 4c-Br (48%, 5 : 95 α/β). Reaction of cholesterol with both gluco and manno epimers afforded 29 and 30 (mimetics of natural cholesteryl glucosides from H. pylori) with good isolated yields (up to 67%) and stereoselectivities (85 : 15 α/β in 29; 21 : 79 α/β in 30) and only minute elimination (10–15%). When using protected L-serine as acceptor, low yield of the desired product 31 (24%) was obtained due to competing elimination process (25%). However, excellent β-selectivity (5 : 95 α/β) was achieved by virtue of the equatorial CF₃ configuration. Unexpectedly, the stereoselective control was completely eroded using a protected azido-sphingosine analog⁴⁸ that reacted with CF^gluco₃4c-Br producing an equimolar anomeric mixture of the desired product 32a (24% by ¹⁹F NMR). Moreover, its problematic purification required the hydrolysis of acetyl groups to obtain 32b in pure form and a poor 17% isolated yield (over three steps from 4c). In stark contrast, when protected azido-phytosphingosine acceptor was reacted with CF^manno₃5c-Br, excellent α-selectivity was obtained (95 : 5 α/β) and 33 (KRN7000 precursor)⁴⁹ was isolated in 64% yield. The same glycosyl donor smoothly reacted with primary and secondary sugar acceptors to afford important αMan(1,6)Man and αMan(1,2)Man epitopes 34 (48%) and 35 (50%), respectively with preferred α-configuration (up to 93 : 7 α/β).

Conclusion

In summary, we have disclosed the unprecedented synthesis and glycosylation of 2-deoxy-2-trifluoromethylsugars that are in turn prepared from readily available D-glycals.

The study of the stereoelectronic properties of the CF₃ group highlighted the selectivity control of glycosylation affording 1,2-trans glycosides. Structural screening indicated that best stereoselectivities are reinforced by the effect of protecting groups (OBn/CF^gluco₃ as β-selective; OAc/CF^manno₃ as α-selective). Glycosylation proved successful for a range of different alcohols including primary and secondary aliphatic-OH, sugars, and complex aglycones. Interestingly, conformational analyses of resulting CF₃-glycosides showed no perturbations in the molecular geometry, which may stimulate the development of new CF₃-sugar mimetics with interesting physicochemical properties (e.g., log P enhancement and/or increased ¹⁹F NMR sensitivity) to complement the applications of traditional F-sugars. Indeed, reaction scope also proved successful for the preparation biologically relevant C(sp³)–CF₃-glycosides including amino acids, cholesterol, and sphingosine/phytosphingosine analogs. Collectively, it has been demonstrated that the method is synthetically useful for accessing novel 2-deoxy-2-CF₃-glycosides bearing aglycones of different structural nature in very high stereoselectivities even when a non-optimal combination of protecting groups and CF₃ configuration is used. We expect this report will help to flourish the field of polyfluoroalkyl sugar chemistry by establishing a new direction of development in glycomimetic design. Further synthetic developments and mechanistic investigations on the role of CF₃ in the stability of the glycosidic bond and the modulation of physicochemical and recognition/processing properties are subjects of ongoing studies in our laboratory.

Author contributions

J.M and I.B. performed all of the experiments. M.B. performed the computational calculations. O.B. supervised the project. O.B. and S.C. were responsible for funding acquisition. All authors contributed to the preparation of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the Spanish Government-MCIU/MCIN, the national agency of investigation-AEI/10.13039/501100011033, and the European Regional Development Fund-ERDF (projects; CTQ2017-90088-R and PID2020-120584RB-I00 to O. B., CTQ2017-89750-R to S. C. FPI Fellowship; PRE2018-085730 to I. B. and FPU Fellowship; FPU19/01969 to M. B.) and the Universitat Rovira i Virgili (Martí i Franquès Research Fellowship Programme; 2012BPURV-67 to J. M.) for financial support. We also thank the ICIQ X-ray diffraction unit for the crystallographic studies and Aria Valaei for preliminary experiments. O. B. was a Ramón y Cajal Fellow (RYC-2015-17705).

References

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2128831 (7β) and 2128832 (4c). For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3qo00274h

‡ Equal contribution.

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