Synthesis and Lipophilicity of Trifluorinated Analogues of Glucose

Article Cite This: J. Org. Chem. 2019, 84, 8509−8522

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Synthesis and Lipophilicity of Trifluorinated Analogues of Glucose Jacob St-Gelais, Megan Bouchard, Vincent Denavit, and Denis Giguère* Département de Chimie, Université Laval, PROTEO, RQRM, 1045 Avenue De la Médecine, Québec City, Quebec, Canada G1V 0A6

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S Supporting Information *

ABSTRACT: In this work, we have developed synthetic routes for novel trifluorinated glucopyranose analogues using a Chiron approach. This strategy used inexpensive levoglucosan as a starting material, and we achieved a microwave glycosylation method as a key step. All analogues adopted standard 4 C1 glucopyranose conformations, and a gauche−gauche conformation for the fluoromethyl group (C5−C6 linkage) was ascertained for congeners with a fluorine atom at C-6. Finally, the lipophilicity of trifluorinated glucose analogues was assessed with a log P determination method based on 19F NMR spectroscopy.

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INTRODUCTION Fluorinated carbohydrates have been applied in studies of lectin−carbohydrate interactions or as mechanistic probes.1 These applications have highlighted the importance of the substitution of one hydroxyl group for a fluorine atom in carbohydrates and paved the way for further relevant synthetic strategies to provide biochemical probes for in vivo magnetic resonance imaging2 and 18F-positron-emitting tomography for cancer diagnosis.3 In addition, fluorine atoms on pyran rings have a limited impact on conformation4 and may increase protein−carbohydrate affinity.5 This increase in affinity can be explained by hydrophobic desolvation and electrostatic interactions through polarized C−F bonds.6 Attractive biological properties of mono- and polyfluorinated 7 D-glucopyranoses triggered wide interest in their preparation. For example, 3-deoxy-3-fluoroglucopyranose was used as a molecular probe,8 whereas its fluorine-18 counterpart has been revealed as an efficient tracer.9 Sanofi-Aventis also developed and explored the biological potential of the 4-deoxy-4fluoroglucopyranose candidate since it is a part of a sodium− glucose transporter inhibitor SAR7226.10 In addition, analogues of 4-fluoroglucopyranose were evaluated as efficient transporters in human erythrocytes11 and in biochemical investigations.12 These successful applications clearly indicated that this class of carbohydrates could be considered as a valuable biological tool and opened the doors to the investigation of polyfluorinated glucopyranose analogues. In that context, creative synthetic approaches were proposed over the years and led to some intricate analogues presented in Figure 1a, some of which have intriguing and promising properties. Recently, the group of Linclau prepared 2,3-dideoxy-2,3-difluoroglucose 113 and 3,4dideoxy-3,4-difluoroglucose 2.14 This is part of their ongoing work related to the preparation of heavily fluorinated carbohydrates similar to compound 315 as a binder of uridine diphospho-galactopyranose mutase from Mycobacterium tuberculosis.5 Also, the group of Cerny included the preparation of 2,4-dideoxy-2,4-difluoroglucose 4 as part of their synthetic program related to the study of the reactivity of 1,6© 2019 American Chemical Society

Figure 1. Known polyfluorinated D-glucose analogues 1−8.

anhydrohexopyranose derivatives.16 In 2009, the group of Withers prepared and investigated difluorosugar fluorides 5 and 6 analogues of glucose as inactivators of the β-glucosidase from Agrobacterium sp.17 Interestingly, they were shown to bind to the enzyme active site reversibly as competitive inhibitors. In the footsteps of these promising examples, the potential of such analogues has led to sustained and growing research efforts toward the design of more heavily fluorinated glycomimetics. In this context, the group of DiMagno prepared hexafluorinated pyranose 7, which was shown to cross the erythrocyte membrane 10 times faster than D-glucose.18 Although in a less efficient way, the 2,3,4-trideoxy-2,3,4-trifluoroglucose analogue 8, whose synthesis was first proposed by O’Hagan, also showed this property.19 Moreover, further investigations differentiated the efficiency of the transport, with the α-anomer being preferred over the β-anomer. Recently, analogue 8 attracted intense synthetic efforts from several groups, including a Chiron approach20 that led to a set of 2,3,4-trideoxy-2,3,4-trifluorohexose congeners, along with two similar but independent innovative approaches by the group of Linclau21 and our Received: March 20, 2019 Published: June 13, 2019 8509

DOI: 10.1021/acs.joc.9b00795 J. Org. Chem. 2019, 84, 8509−8522

Article

The Journal of Organic Chemistry Scheme 1. Retrosynthetic Analysis of Trifluorinated Glucose Analogues 8−11 from Levoglucosan 12

group.22 For our part, the flexibility of the strategy allowed the synthesis of a range of fluorinated carbohydrates, enabling the determination of their lipophilicity. The relative stereochemistry of multivicinal fluorine atoms has a strong effect on the molecules’ log P value. Accordingly, we used a log P determination method developed by the group of Linclau, based on 19F NMR spectroscopy.23 For their part, they showed that there are large lipophilicity variations within a same family of fluorinated carbohydrates. Also, they were the first to report the log P of 2,3,4-trideoxy-2,3,4-trifluoroglucose 8 (−0.17),23 and this was later on corroborated by us (log P value of −0.18).20 Modulation of a heterocycle’s lipophilicity is a constant challenge,24 and the introduction of a fluorine atom can be a fruitful strategy to optimize the properties of bioactive compounds.25 Fluorination often introduces a dipole moment and increases the hydrophobic surface.26 In preliminary communications, we already reported the preparation and lipophilicity of 2,3,4-trideoxy-2,3,4-trifluoroglucose (8, Figure 1).20 In this article, we wish to report on our ongoing research in this area. Discussions will include the synthetic pathways to generate trifluorinated glucopyranose analogues, along with the determination of the members’ corresponding lipophilicity to determine the influence of the position of the fluorine atom on the log P value. As part of our program related to the synthesis of fluorinated carbohydrates,20,27 our attention was turned toward the synthesis and lipophilicity evaluation of various trifluorinated D-glucose analogues: 2,3,4-trideoxy-2,3,4-trifluoroglucose 8, 2,4,6-trideoxy-2,4,6-trifluoroglucose 9, 3,4,6-trideoxy-3,4,6-trifluoroglucose 10, and 2,3,6-trideoxy-2,3,6-trifluoroglucose 11 (Scheme 1). We aimed to develop synthetic routes that start with inexpensive starting materials, make minimal use of protection/deprotection cycles, and do not require tedious purifications. Scheme 1 shows our retrosynthetic analysis of fluorinated glucose analogues 8−11 from commercially available 1,6-anhydro-β-D-glucopyranose (levoglucosan) 12. The latter allowed us to avoid preliminary protection of the O-6 and anomeric positions and could straightforwardly afford scalable fluorinated glucose analogues. Compound 9 could be easily generated from 1,6-anhydro-3-O-benzyl-2,4-dideoxy-2,4difluoro-β-D-glucopyranose 13 following acetolysis and fluorination at C-6. Correspondingly, 3,4,6-trideoxy-3,4,6-trifluoroglucose 10 could be accessible from 1,6-anhydro-2-O-benzyl3,4-dideoxy-3,4-difluoro-β-D-glucopyranose 1414 following the same key steps. As for compounds 8 and 11, they could arise from the common intermediate 1,6-anhydro-4-O-benzyl-2,3dideoxy-2,3-difluoro-β-D-glucopyranose 15.13 Fluorination at

C-4 followed by an acetolysis could lead to compound 8. The latter compound was prepared according to slight modifications of the previously published procedure.20 Similarly, an acetolysis followed by fluorination at C-6 could provide product 11. Difluorinated analogues 13−15 could emerge from levoglucosan 12 through epoxide opening using potassium hydrogen difluoride or classical nucleophilic deoxyfluorination.

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RESULTS AND DISCUSSION The synthesis of 2,4,6-trifluoroglucose analogue 9 was initiated with the known 1,6-anhydro-2,4-di-O-p-toluenesulfonyl-β-Dglucopyranose 16, accessible in one step from levoglucosan (Scheme 2).28 We used our previously described one-pot fourScheme 2. Synthesis of 2,4,6-Trideoxy-2,4,6trifluoroglucopyranose 9a

a

Reagents and conditions: (a) KHF2 (4 equiv), TBAF·3H2O (8 equiv), 180 °C, 24 h, 60%; (b) NaH (1.5 equiv), BnBr (1.5 equiv), TBAI (0.25 equiv), dimethylformamide (DMF), 0 °C to room temperature (rt), 16 h, 94%; (c) TESOTf (0.1 equiv), Ac2O (excess), 0 °C to rt, 1 h, 94%, α/β = 6.5:1; (d) AllylOTMS (10 equiv), TMSOTf (1 equiv), CH3CN, microwave heating, 90 °C, 0.75 h, 20% for 19 and 61% for 20, α/β = 1:1; (e) 1 M NaOMe, CH2Cl2/MeOH, rt, 1 h; (f) DAST (3 equiv), 2,4,6-collidine (6 equiv), CH2Cl2, microwave heating, 100 °C, 1 h, 95% over two steps; (g) HCl (37% in water), H2O/acetone, 70 °C, 16 h, 85%, α/β = 7:3 in acetone-d6. AllylOTMS = allyloxytrimethylsilane, DAST = diethylaminosulfur trifluoride, TBAF = tetrabutylammonium fluoride, TBAI = tetrabutylammonium iodide, TESOTf = triethylsilyl trifluoromethanesulfonate, and TMSOTf = trimethylsilyl trifluoromethanesulfonate. 8510

DOI: 10.1021/acs.joc.9b00795 J. Org. Chem. 2019, 84, 8509−8522

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The Journal of Organic Chemistry Table 1. Synthesis of Difluorinated Glucoside 19 and 20 from Glucose Analogue 18

yield (%)a entry b

1 2b 3 4 5 6 7 8 9

temperature (°C)

time

Lewis acid (equiv)

conversiona (%)

85 85 100 100 100 100 100 90 90

15 h 15 h 25 min 25 min 25 min 25 min 45 min 45 min 45 min

TMSOTf (1) TMSOTf (5) TMSOTf (1) BF3·OEt2 (1) TESOTf (1) TMSOTf (0.5) TMSOTf (0.5) TMSOTf (0.5) TMSOTf (1)

85 95 90 0 72 54 68 58 95

19

20

14 8

25 38 56

3 3 8 3 20

44 44 56 43 61

a

Conversions were determined by 19F NMR analysis of the crude mixture after workup. bConventional heating was used instead of microwave heating.

applicable when allyl alcohol was used as the nucleophile or when compound 13 was considered as the substrate. With the challenging glycosylation successfully completed through an unusual microwave heating procedure, the next hurdle, involving fluorination at C-6, was addressed. Deprotection of the acetyl group under basic conditions was followed by diethylaminosulfur trifluoride (DAST)-mediated deoxofluorination in a high 95% yield over two steps. This result contrasted with our previous DAST-mediated deoxofluorination at C-6 on 2,3,4-trifluoro-2,3,4-trideoxy-β-D-galactopyranoside.20 In that instance, arabino-hex-5-enopyranoside derivative was isolated as the elimination product, which is not the case here.34 Finally, compound 21 was fully deprotected under acidic conditions to furnish 2,4,6-trideoxy-2,4,6-trifluoroglucopyranose 9 in 85% yield (α/β = 7:3 in acetone-d6). Interesting features can be addressed upon closer inspection of the nuclear magnetic resonance (NMR) spectra of trifluorinated glucoside 21 (Figure 2). This compound was isolated as a mixture of anomers (α/β = 1:1), and using twodimensional NMR, it was possible to assign all crucial NMR signals.35 First of all, we can show that the pyran ring adopts the 4 C1 conformation. The anomeric configuration of each compound was determined by examining the coupling constant of H-1 [1H NMR (500 MHz, chloroform-d): 4.58 (dd, 3JH1−H2 = 7.5 Hz, 3JH1−F2 = 3.1 Hz, 4JH1−H3 = 0.3 Hz) for 21β and 5.09 (t, 3 JH1−H2 = 3JH1−F2 = 3.5 Hz) for 21α]. Moreover, both conformers prefer a gauche−gauche (GG) conformation for the fluoromethyl group (C5−C6 linkage) in solution (CDCl3).36 This was confirmed after analysis of the 19F NMR spectrum (470 MHz, chloroform-d). The fluorine at C-6 has a chemical shift of −234.2 ppm (21β) and −235.5 ppm (21α) with, among others, a coupling constant 3JF6−H5 of 22.7 Hz (21β) and 26.2 Hz (21α), corresponding to the antiperiplanar relation with H-5 (Figure 2a). We next turned our attention to the synthesis of 3,4,6trideoxy-3,4,6-trifluoroglucopyranose 10 (Scheme 3). The known Cerny epoxide 22 was treated with a neat mixture of KHF2 and TBAF·3H2O allowing formation of compound 23 as the sole isomer in 52% yield (81% based on the recovered starting material).14 Then, fluorination at C-3 with retention of the configuration was possible via triflate 24 and treatment with Et3N·3HF. It is worth mentioning that the group of Linclau

step process to transform bis-tosylate 16 into 1,6-anhydro-2,4dideoxy-2,4-difluoroglucopyranose 17 in a 60% yield.20 This neat procedure allowed us to generate a multigram-scale of the valuable difluorinated intermediate 17. Benzylation of the free O-3 hydroxyl group generated compound 13 in high yield, and triethylsilyl triflate-catalyzed acetolysis provided the desired diacetylated 18 in 94% yield (α/β = 6.5:1).29 At this point, to successfully fluorinate at C-6, we protected the anomeric position. Our initial experiments involved the installation of an O-aryl group using a phase transfer reaction via a glucosyl bromide. This strategy was first opted to avoid destabilization of the positively charged oxocarbenium center located on the fluorinated pyran core when using a classical glycosylation strategy.30 Unfortunately, this method failed, and we were compelled to use a traditional glycosylation method with Lewis acids as activators. Efforts toward this end are presented in Table 1.31 We first used 1 or 5 equiv of trimethylsilyl trifluoromethanesulfonate (TMSOTf) (entries 1 and 2) with fluorinated glucosyl donor 18 at 85 °C for 15 h using conventional heating. Low conversions were observed based on 19F NMR analysis of the crude mixture after workup. Consequently, to achieve the maximal conversion of the starting material, we opted to perform the crucial glycosylation step using microwave heating. This methodology is known to potentially increase reaction rates in certain cases, and only a handful of research groups reported this technique in glycosylation reactions.32 Also, glycosylation with microwave heating using acetyl glycosyl donors is underexploited33 and represents an interesting challenge with our fluorinated glucosyl donor. We first opted for microwave heating at 100 °C for 25 min with TMSOTf as an activator (entry 3). We were delighted to isolate the desired compound 20 in 56% yield, along with 8% of debenzylated side product 19. Evaluation of various Lewis acids (BF3·OEt2, entry 4 and triethylsilyl trifluoromethanesulfonate (TESOTf), entry 5) resulted in either no conversion or lower yields, respectively. Then, decreasing the amount of the activator to 0.5 equiv gave a lower conversion (entry 6). Therefore, we increased the reaction time to 45 min (entry 7) and decreased the temperature to 90 °C to avoid decomposition (entry 8). We finally increased the number of equivalents of Lewis acid to 1 (entry 9), and we managed to isolate the desired product 20 in 61% yield, along with 20% yield of unprotected intermediate 19. Finally, it is important to point out that this optimized glycosylation was not 8511

DOI: 10.1021/acs.joc.9b00795 J. Org. Chem. 2019, 84, 8509−8522

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Figure 2. Proposed conformation and NMR spectra of trifluorinated glucoside 21: α-anomer = blue; β-anomer = green. (a) Proposed conformation for both anomers; arrows designate key coupling constants. (b) 1H NMR (500 MHz, chloroform-d) spectrum. (c) 19F NMR (470 MHz, chloroform-d) spectrum.

anhydro-4-O-benzyl-2,3-dideoxy-2,3-difluoro-β-D-glucopyranose 15.13 Scheme 4 summarizes an alternative method to prepare intermediate 15 as compared to our previously described protocol.20 The synthesis was initiated with Cerny’s epoxide 29 generated from levoglucosan in four steps.37 Compound 29 was subjected to KHF2/KF in ethylene glycol allowing access to product 30 in 83% yield.38 Then, for the next step, we evaluated the possibility of avoiding toxic and sensitive deoxofluorinating reagents. Consequently, fluorination at C-3 was achieved with retention of the configuration upon exposure to Et3N·3HF on the triflate intermediate 31. As a result, 2,3dideoxy-2,3-difluoroglucose analogue 1513 was isolated in a high 95% yield over two steps, presumably via neighboring group participation of the benzyloxy at C-4.39 This transformation furnished only the product with retention of the configuration without formation of any other rearrangement byproducts. A titanium tetrachloride-mediated benzyl deprotection generated 31, and subsequent epimerization using a Lattrell−Dax strategy allowed the isolation of compound 33 in 95% yield over two

reported this deoxyfluorination step using Deoxo-Fluor providing product 14 in 67% yield with concomitant formation of a rearrangement byproduct.14 Interestingly, the strategy proposed here allowed only the formation of the product with retention of the configuration without any observable rearrangement byproducts. Subsequently, triethylsilyl triflate (TESOTf)catalyzed acetolysis of the 1,6-anhydro bridge in 1414 provided compound 25 in 63% yield (α/β = 22:3). Then, glycosylation with allyloxytrimethylsilane using our optimized conditions gave compound 26 in 48% yield (α/β = 1:1). Deoxyfluorination at C6 was achieved with a deprotection of the acetyl group under basic conditions, followed by treatment with DAST. Trifluoroglucose analogue 28 (85% yield over two steps) was finally deprotected under acidic conditions allowing formation of product 10 in 66% (α/β = 3:1 in acetone-d6). To complete our set of trifluorinated glucose analogues, we next focused on the synthesis of 2,3,4-trideoxy-2,3,4-trifluoroglucopyranose 8 and 2,3,6-trideoxy-2,3,6-trifluoroglucopyranose 11. Both products have the common precursor 1,68512

DOI: 10.1021/acs.joc.9b00795 J. Org. Chem. 2019, 84, 8509−8522

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The Journal of Organic Chemistry

oglucopyranose 11, which is summarized in Scheme 5. Thus, a TESOTf-catalyzed acetolysis generated compound 37 (92%

Scheme 3. Synthesis of 3,4,6-Trideoxy-3,4,6trifluoroglucopyranose 10a

Scheme 5. Synthesis of 2,3,6-Trideoxy-2,3,6trifluoroglucopyranose 11a

a

Reagents and conditions: (a) TESOTf (0.1 equiv), Ac2O (excess), 0 °C to rt, 1 h, 92%, α/β = 17:1; (b) AllylOTMS (10 equiv), TMSOTf (3 equiv), CH3CN, microwave heating, 90 °C, 0.75 h, 44%, α/β = 1:1.7; (c) 1 M NaOMe, CH2Cl2/MeOH, rt, 1 h; (d) DAST (3 equiv), 2,4,6-collidine (6 equiv), CH2Cl2, microwave heating, 100 °C, 1 h, 85% over two steps, α/β = 1:1.7; (e) HCl (37% in water), H2O/ acetone, 70 °C, 16 h, 66%, α/β = 3:2 in acetone-d6. AllylOTMS = allyloxytrimethylsilane, DAST = diethylaminosulfur trifluoride, TESOTf = triethylsilyl trifluoromethanesulfonate, and TMSOTf = trimethylsilyl trifluoromethanesulfonate.

a

Reagents and conditions: (a) KHF2 (1.5 equiv), TBAF·3H2O (3 equiv), 180 °C, 3 h, 52% (81% brsm); (b) Tf2O (1 M in CH2Cl2, 2 equiv), pyridine (10 equiv), 0 °C to rt, 1 h; (c) Et3N·3HF (15 equiv), 80 °C, 24 h, 80% over two steps; (d) TESOTf (0.1 equiv), Ac2O (excess), 0 °C to rt, 1 h, 63%, α/β = 22:3; (e) AllylOTMS (10 equiv), TMSOTf (1 equiv), CH3CN, microwave heating, 90 °C, 0.75 h, 48%, α/β = 1:1; (f) 1 M NaOMe, CH2Cl2/MeOH, rt, 6 h; (g) DAST (3 equiv), CH2Cl2, microwave heating, 100 °C, 1 h, 85% over two steps, α/β = 1:1; (h) HCl (37% in water), H2O/acetone, 70 °C, 16 h, 66%, α/β = 3:1 in acetone-d6. AllylOTMS = allyloxytrimethylsilane, brsm = based on the recovered starting material; DAST = diethylaminosulfur trifluoride, TBAF = tetrabutylammonium fluoride, TESOTf = triethylsilyl trifluoromethanesulfonate, Tf2O = trifluoromethanesulfonic anhydride, and TMSOTf = trimethylsilyl trifluoromethanesulfonate.

yield, α/β = 17:1), and the latter was subjected to our microwave glycosylation generating glucoside 38 in 44% yield (α/β = 1:1.7). Deoxyfluorination at C-6 was accomplished following the same strategy as described above: removal of the acetyl group, followed by DAST-mediated deoxofluorination (39, 85% yield, α/β = 1:1.7), and finally global deprotection under acidic conditions. 2,3,6-Trideoxy-2,3,6-trifluoroglucopyranose 11 was isolated in a satisfactory 66% yield (α/β = 3:2 in acetone-d6) and represented the final targeted member of our set of organofluorine analogues. The lipophilicities of carbohydrate analogues are known to be difficult to predict. This also holds true for fluorinated carbohydrates. The quantification of the impact of deoxyfluorination on a carbohydrate scaffold is not trivial, and the group of Linclau started to tackle this problem by developing a log P determination method based on 19F NMR spectroscopy.23 To

steps. Activation of the hydroxyl group at C-4 as triflate permitted a nucleophilic fluorination with inversion of the configuration upon exposure to TBAF·3H2O. Subsequent acetolysis and global deprotection under acidic conditions generated 2,3,4-trideoxy-2,3,4-trifluoroglucopyranose 8.40 The 2,3-difluoroglucose analogue 15 represented the ideal precursor for the preparation of 2,3,6-trideoxy-2,3,6-trifluor-

Scheme 4. Synthesis of 2,3,4-Trideoxy-2,3,4-trifluoroglucopyranose 8a

Reagents and conditions: (a) KHF2 (7 equiv), KF (6 equiv), ethylene glycol, 200 °C, 4 h, 83%; (b) Tf2O (1 M in CH2Cl2, 1.5 equiv), pyridine (3 equiv), 0 °C to rt, 0.5 h; (c) Et3N·3HF (15 equiv), Et3N (45 equiv), 80 °C, 24 h, 95% over two steps; (d) TiCl4 (1.1 equiv), CH2Cl2, 0 °C, 0.5 h, 66%; (b) Tf2O (2 equiv), pyridine (3 equiv), CH2Cl2, 0 °C, 0.5 h; (e) TBANO2 (3 equiv), CH3CN, microwave heating, 100 °C, 3 h, 95% over two steps; (f) TBAF·3H2O (1.5 equiv), CH2Cl2, rt, 18 h; (g) Ac2O (30 equiv), H2SO4 (10 equiv), 0 °C to rt, 18 h, then NaOAc (20 equiv), rt, 0.3 h, 63% over three steps, α/β = 5:1; (h) HCl (37% in water), H2O/acetone, rt, 3 h, quant., α/β = 5:1 in acetone-d6. Deoxo-Fluor = bis(2methoxyethyl)aminosulfur trifluoride, TBAF = tetrabutylammonium fluoride, TBANO2 = tetrabutylammonium nitrite, and Tf2O = trifluoromethanesulfonic anhydride. a

8513

DOI: 10.1021/acs.joc.9b00795 J. Org. Chem. 2019, 84, 8509−8522

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The Journal of Organic Chemistry investigate the influence of the position of a fluorine atom on a carbohydrate scaffold, we used Linclau’s method to determine the log P of trifluorinated glucose analogues. Briefly, the method measures the distribution between n-octanol and water relative to an internal reference. After shaking the mixture of a trifluorinated glucose analogue and reference between the phases, an aliquot of each of the settled phases is analyzed by 19F NMR. The integration ratio of trifluoroglucose to reference (known log P) in each phase is cross-correlated allowing the log P to be determined. First, the conformation of a molecule can have a strong impact on its lipophilicity. Glucose analogues 8−11 adopt standard 4C1like conformations, and this was confirmed using NMR analysis.35 Also, in deuterated acetone, these compounds have similar anomeric ratios, with the α anomer being favored (the β anomer is usually preferred for D-glucopyranose).41 Interestingly, the conformation of the hydroxymethyl or fluoromethyl groups (C5−C6 linkage) can also impact the lipophilicity. As such, all glucose analogues with a fluorine atom at C-6 adopt a GG conformation for both anomers. This information could be extracted from the 19F NMR spectrum (470 MHz, acetone-d6) of compounds 9−11 (coupling constant between F-6 and H-5): 9α: J = 27.2 Hz; 9β: J = 24.1 Hz; 10α: J = 24.2 Hz; 10β: J = 24.5 Hz; 11α: J = 27.8 Hz; 11β: J = 24.9 Hz.41 The GG conformation can be explain by hyperconjugation effects.25a The σ*CF orbital is aligned with the adjacent C−H bond at C-5, which can donate electron density into the σ*CF orbital.42 Among all fluorinated candidates, analogues with a fluorine atom at C-6 were the most hydrophilic as compared to 2,3,4trifluoroglucopyranose 8 (log P = −0.18) (Figure 3). Moreover,

C-6 position adopted a gauche−gauche conformation and were more hydrophilic than 2,3,4-trifluoroglucopyranose. The synthetic preparation of carbohydrate analogues could generate useful tools to deepen investigations on the use of intriguing fluorine-containing carbohydrates and to underscore their relevance to biology.

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EXPERIMENTAL SECTION

General Information. All reactions were carried out under an argon atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. Methylene chloride (CH2Cl2) was distilled from CaH2 and tetrahydrofuran was distilled from Na/benzophenone immediately before use. Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous materials, unless otherwise stated. Reagents were purchased with the highest commercial quality available and used without further purification, unless otherwise stated. Reactions were monitored by thin-layer chromatography carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as a visualizing agent and charring with a solution of 3 g of PhOH and 5 mL of H2SO4 in 100 mL of EtOH, followed by heating with a heat gun. SiliaFlash P60 40−63 μm (230−400 mesh) was used for flash column chromatography. Reactions that required heating were performed using an oil bath, unless otherwise stated. NMR spectra were recorded with an Agilent DD2 500 MHz spectrometer and calibrated using a residual undeuterated solvent (chloroform-d: 1H δ = 7.26 ppm, 13C δ = 77.16 ppm) as an internal reference. Calibration of 19F NMR was performed using hexafluorobenzene, which have been measured at −162.29 ppm compared to the chemical shift of the reference compound CFCl3. Coupling constants (J) are reported in hertz (Hz), and the following abbreviations were used to designate multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, m = multiplet, and br = broad. Assignments of NMR signals were made by homonuclear [correlated spectroscopy (COSY)] and heteronuclear (heteronuclear single quantum coherence (HSQC), Heteronuclear multiple bond correlation, heteronuclear nuclear Overhauser effect, 19F c2HSQC) two-dimensional correlation spectroscopy. Infrared spectra were recorded using an ABB Bomem MB-Series Arid Zone FT-IR MB-155 spectrometer. The absorptions are given in wavenumbers (cm−1). Microwave heating was conducted in a Biotage Initiator Classic apparatus with sealed reaction vessels using an internal probe. Highresolution mass spectra (HRMS) were recorded with an Agilent 6210 LC time-of-flight mass spectrometer in electrospray mode. Either protonated molecular ions [M + nH]n+, sodium adducts [M + Na]+, or ammonium adducts [M + NH4]+ were used for empirical formula confirmation. Optical rotations were measured with a JASCO DIP-360 digital polarimeter and are reported in units of 10−1 (deg cm2 g−1). 1,6-Anhydro-3-O-benzyl-2,4-deoxy-2,4-fluoro-β-D-glucopyranose (13). To a stirred solution of known compound 1720 (153 mg, 0.9222 mmol) in dry dimethylformamide (7 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil) (55 mg, 1.3833 mmol, 1.5 equiv) under an argon atmosphere. Benzyl bromide (164 μL, 1.3833 mmol, 1.5 equiv) and tetrabutylammonium iodide (85 mg, 0.2305 mmol, 0.25 equiv) were then added, and the mixture was stirred at room temperature overnight. The mixture was diluted in H2O (60 mL) and extracted with CH2Cl2 (3 × 25 mL). The combined organic phases were washed with aqueous 1 M HCl solution (25 mL) and a saturated aqueous NaHCO3 solution (25 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude oil was purified by flash column chromatography (silica gel, EtOAc/ hexanes, 1:9−1:1) to give 13 as a white amorphous solid (221 mg, 0.8669 mmol, 94% yield); Rf = 0.61 (silica, EtOAc/hexanes, 2:3); [α]D25 = −50.9 (c 0.4, CHCl3); IR [attenuated total reflection (ATR), ZnSe] ν 2978, 2916, 1342, 972, 910, 872, 787 cm−1; 1H NMR (500 MHz, chloroform-d) δ: 7.39−7.30 (m, 5H, Ar), 5.57 (dt, 3JH1−H2 = 4.8 Hz, 4JH1−H3 = 4JH1−H5 = 1.3 Hz, 1H, H-1), 4.74 (ddq, 3JH5−F4 = 12.9 Hz, 3 JH5−H6a = 5.9 Hz, 3JH5−H6b = 3JH5−H4 = 4JH5−H1 = 1.5 Hz, 1H, H-5), 4.72 (d, 2JCH2aPh−CH2bPh = 11.9 Hz, 1H, CH2aPh), 4.66 (d, 2JCH2bPh−CH2aPh = 11.8 Hz, 1H, CH2bPh), 4.46 (dm, 2JH4−F4 = 46.2 Hz, 1H, H-4), 4.37

Figure 3. Lipophilicities of trifluorinated glucopyranose analogues 8− 11 and 2,3,4-trideoxy-2,3,4-trifluorohexopyranose analogues 40−43.20

2,4,6-trifluoroglucopyranose 9 (log P = −0.64) is more lipophilic than 3,4,6-trifluoroglucopyranose 10 and 2,3,6trifluoroglucopyranose 11, which have comparable log P values (−0.42 and −0.47 respectively). Finally, all substituents on a glucopyranose scaffold are oriented equatorially as compared to other hexopyranoses. As such, the lipophilicity of our set of trifluorinated glucose aligned well with other 2,3,4-trideoxy2,3,4-trifluorohexopyranose analogues 40−4320 (Figure 3).

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CONCLUSIONS In this study, the synthesis of a family of trifluorinated analogues of D-glucopyranose was accomplished using a Chiron approach. The versatility of this strategy allowed a rapid access to heavily fluorinated carbohydrates. The lipophilicities were measured, and it was determined that analogues with a fluorine atom at the 8514

DOI: 10.1021/acs.joc.9b00795 J. Org. Chem. 2019, 84, 8509−8522

Article

The Journal of Organic Chemistry

diamond) ν 2951, 1744, 1367, 1232, 1032, 993, 739 cm−1; 1H NMR (500 MHz, chloroform-d) δ: 7.41−7.28 (m, 10H, Ar-α/β) 5.93 (dddd, J = 17.3, 10.4, 6.3, 5.3 Hz, 1H, OAll-α), 5.92 (dddd, J = 17.1, 10.4, 6.3, 5.1 Hz, 1H, OAll-β), 5.35 (dq, J = 17.2, 1.6 Hz, 1H, OAll-α), 5.34 (dq, J = 17.2, 1.6 Hz, 1H, OAll-β), 5.27 (dq, J = 10.4, 1.3 Hz, OAll-α), 5.25 (dq, J = 10.4, 1.4 Hz, 1H, OAll-β), 5.06 (t, 3JH1−H2 = 3JH1−F2 = 3.5 Hz, 1H, H-1α), 4.85−4.78 (m, 4H, CH2Ph-α/β), 4.56 (dd, 3JH1−H2 = 7.8 Hz, 3JH1−F2 = 2.9 Hz, 1H, H-1β), 4.48 (ddd, 2JH4−F4 = 50.0 Hz, 3JH4−H5 = 9.7 Hz, 3JH4−H3 = 8.2 Hz, 1H, H-4β), 4.45 (dddd, 2JH2−F2 = 49.0 Hz, 3 JH2−H3 = 9.2 Hz, 3JH2−H1 = 4.0, 4JH2−F4 = 0.6 Hz, 1H, H-2α), 4.44 (ddd, 2 JH4−F4 = 49.7 Hz, 3JH4−H5 = 10.2 Hz, 3JH4−H3 = 8.6 Hz, 1H, H-4α), 4.40 (dt, 2JH6a−H6b = 12.4 Hz, 4JH6a−F4 = 2.9 Hz, 3JH6a−H5 = 2.3 Hz, 1H, H6aβ), 4.37 (ddt, J = 13.1, 5.3, 1.5 Hz, 1H, OAll-β), 4.36 (dt, 2JH6a−H6b = 12.4 Hz, 3JH6a−H5 = 4JH6a−F4 = 2.1 Hz, 1H, H-6aα), 4.33 (dt, 2JH2−F2 = 50.1 Hz, 3JH2−H3 = 8.6 Hz, 3JH2−H1 = 7.7 Hz, 1H, H-2β), 4.27 (ddd, 2 JH6b−H6a = 12.4 Hz, 3JH6b−H5 = 4.4 Hz, 4JH6b−F4 = 1.6 Hz, 1H, H-6bα), 4.24 (ddt, J = 13.0, 5.3, 1.5 Hz, 1H, OAll-α), 4.23 (ddd, 2JH6b−H6a = 12.2 Hz, 3JH6b−H5 = 5.2 Hz, 4JH6b−F4 = 1.6 Hz, 1H, H-6bβ), 4.16 (ddt, J = 13.0, 6.1, 1.3 Hz, 1H, OAll-β), 4.14 (dddd, 3JH3−F4 = 15.2 Hz, 3JH3−F2 = 12.6 Hz, 3JH3−H2 = 9.8 Hz, 3JH3−H4 = 8.6 Hz, 1H, H-3α), 4.10 (ddt, J = 13.0, 6.1, 1.3 Hz, 1H, OAll-α), 4.03 (dtdd, 3JH5−H4 = 9.9 Hz, 3JH5−H6b = 3 JH5−F4 = 4.4 Hz, 3JH5−H6a = 2.4 Hz, 4JH5−H1 = 0.4 Hz, 1H, H-5α), 3.81 (tt, 3JH3−F4 = 3JH3−F2 = 15.8 Hz, 3JH3−H4 = 3JH3−H2 = 8.6 Hz, 1H, H-3β), 3.64 (dddd, 3JH5−H4 = 9.8 Hz, 3JH5−H6b = 5.2 Hz, 3JH5−F4 = 2.9 Hz, 3 JH5−H6a = 2.3 Hz, 1H, H-5β), 2.10 (s, 6H, COCH3 α/β); 13C{1H} NMR (126 MHz, chloroform-d) δ 170.77, 170.75 (2C, 2 × COCH3-α/ β), 133.3 (1C, OAll-β), 133.1 (1C, OAll-α), 137.9, 137.5, 128.57, 128.55, 128.2, 128.14, 128.07, 128.0 (10C, Ar-α/β), 118.6 (1C, OAllα), 118.4 (1C, OAll-β), 99.3 (dd, 2JC1−F2 = 22.9 Hz, 4JC1−F4 = 0.9 Hz, 1C, C-1β), 95.2 (dd, 2JC1−F2 = 20.8 Hz, 4JC1−F4 = 1.1 Hz, 1C, C-1α), 91.9 (dd, 1JC2−F2 = 188.9 Hz, 3JC2−F4 = 9.4 Hz, 1C, C-2β), 89.6 (dd, 1 JC2−F2 = 193.6 Hz, 3JC2−F4 = 9.1 Hz, 1C, C-2α), 89.10 (dd, 1JC4−F4 = 185.4 Hz, 3JC4−F2 = 8.7 Hz, 1C, C-4α), 89.09 (dd, 1JC4−F4 = 185.9 Hz, 3 JC4−F2 = 9.1 Hz, 1C, C-4β), 80.1 (t, 2JC3−F2 = 2JC3−F4 = 18.8 Hz, 1C, C3β), 77.9 (t, 2JC3−F2 = 2JC3−F4 = 18.5 Hz, 1C, C-3α), 75.0 (t, 4JCH2Ph−F2 = 4 JCH2Ph−F4 = 1.3 Hz, 1C, CH2Ph-α), 74.5 (t, 4JCH2Ph−F2 = 4JCH2Ph−F4 = 1.5 Hz, 1C, CH2Ph-β), 71.3 (d, 2JC5−F4 = 24.3 Hz, 1C, C-5β), 70.5 (s, 1C, C-6β), 69.1 (s, 1C, C-6α), 67.1 (d, 2JC5−F4 = 24.3 Hz, 1C, C-5α), 62.3 (s, 1C, C-6β), 62.2 (s, 1C, C-6α), 20.93, 20.91 (2C, 2 × COCH3-α/β); 19 F NMR (470 MHz, chloroform-d) δ: −196.5 (ddddd, 2JF4−H4 = 49.8 Hz, 3JF4−H3 = 15.4 Hz, 3JF4−H5 = 4.3 Hz, 4JF4−H6a = 2.1 Hz, 4JF4−H6b = 1.7 Hz, 1F, F-4α), −197.4 (ddt, 2JF2−H2 = 50.1 Hz, 3JF2−H3 = 15.5 Hz, 3 JF2−H1 = 4JF2−F4 = 2.9 Hz, 1F, F-2β), −197.7 (ddq, 2JF4−H4 = 49.5 Hz, 2 JF4−H3 = 15.5 Hz, 3JF4−H6a = 3JF4−H6b = 4JF4−F2 = 2.4 Hz, 1F, F-4β), −200.6 (ddd, 2JF2−H2 = 48.9 Hz, 2JF2−H3 = 13.0 Hz, 2JF2−H1 = 2.1 Hz, 1F, F-2α); HRMS calcd for C18H26F2NO5 [M + NH4]+ 374.1774, found 374.1776. 1-O-Allyl-3-O-benzyl-2,4,6-trideoxy-2,4,6-trifluoro-α/β-Dglucopyranose (21). To a solution of 20 (70 mg, 0.1964 mmol) in CH2Cl2/MeOH (2 mL, 4:1) was added dropwise a methanolic 1 M NaOMe solution, until pH was ≈9. The mixture was stirred at room temperature for 1 h and then neutralized to pH ≈ 7 with an acidic resin. The mixture was filtered and concentrated under reduced pressure to afford the deacetylated 20 as a colorless oil (61.5 mg, 0.1956 mmol, 100% yield). To a solution of 20 (48 mg, 0.1525 mmol) in CH2Cl2 (2.55 mL) were added 2,4,6-collidine (0.122 mL, 0.9163 mmol, 6 equiv) and diethylaminosulfur trifluoride 1 M in CH2Cl2 (0.458 mL, 0.4581 mmol, 3 equiv). The mixture was heated in a microwave reactor at 100 °C for 1 h. After cooling, the reaction mixture was quenched with water (15 mL). The mixture was extracted with CH2Cl2 (3 × 15 mL). The combined organic phases were successively washed with a saturated aqueous NaHCO3 solution (15 mL) and an aqueous 1 M HCl solution (15 mL). The organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography (silica gel, EtOAc/ hexanes, 0:100−3:7) to give 21 as an anomeric mixture (α/β 1:1) as a thick yellow oil (45.8 mg, 0.1451 mmol, 95% yield); Rfα = 0.65 (silica, EtOAc/hexanes, 2:3); Rfβ = 0.64 (silica, EtOAc/hexanes, 2:3); [α]D25 =

(dm, 2JH2−F2 = 46.3 Hz, 1H, H-2), 3.99 (dt, 2JH6b−H6a = 7.7 Hz, 3JH6b−H5 = 4JH6b−H4 = 1.2 Hz, 1H, H-6b), 3.83 (ttt, 3JH3−F2 = 3JH3−F4 = 19.6 Hz, 3 JH3−H4 = 3JH3−H2 = 2.2 Hz, 4JH3−H5 = 4JH3−H1 = 1.4 Hz, 1H, H-3), 3.77 (dddt, 2JH6a−H6b = 7.7 Hz, 3JH6a−H5 = 5.9 Hz, 4JH6a−F4 = 4.2 Hz, 4JH6a−H4 = 1.1 Hz, 1H, H-6a); 13C{1H} NMR (126 MHz, chloroform-d) δ: 137.0, 128.8, 128.3, 127.9 (6C, Ar), 99.4 (d, 2JC1−F2 = 29.9 Hz, 1C, C1), 89.2 (dd, 1JC4−F4 = 182.7 Hz, 3JC4−F2 = 6.2 Hz, 1C, C-4), 76.1 (t, 2 JC3−F2 = 2JC3−F4 = 28.4 Hz, 1C, C-3), 87.1 (dd, 1JC2−F2 = 182.8 Hz, 3 JC2−F4 = 5.1 Hz, 1C, C-2), 74.3 (d, 2JC5−F4 = 22.4 Hz, 1C, C-5), 73.0 (s, 1C, CH2Ph), 64.6 (d, 3JC6−F4 = 9.6 Hz, 1C, C-6); 19F NMR (470 MHz, chloroform-d) δ: −180.6 (dddd, 2JF4−H4 = 46.5 Hz, 3JF4−H3 = 18.3 Hz, 3 JF4−H5 = 13.0 Hz, 4JF4−H6a = 4.2 Hz, 1F, F-4), −187.1 (ddd, 2JF2−H2 = 46.4 Hz, 3JF2−H3 = 19.6 Hz, 3JF2−H1 = 4.8 Hz, 1F, F-2); HRMS calcd for C13H18F2NO3 [M + NH4]+ 274.1249, found 274.1262. 1,6-Di-O-acetyl-3-O-benzyl-2,4-dideoxy-2,4-difluoro-α/β-Dglucopyranose (18). To a stirred solution of 13 (432 mg, 1.686 mmol) in acetic anhydride (Ac2O) (9 mL) at 0 °C were added two drops of triethylsilyl trifluoromethanesulfonate (≈20−30 μL, cat) under an argon atmosphere. After 1 h, a saturated aqueous NaHCO3 solution (30 mL) was added and the mixture was stirred for 30 min. The reaction mixture was extracted with EtOAc (3 × 25 mL). The combined organic phases were washed with a saturated aqueous NaHCO3 solution (2 × 25 mL) and brine (25 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude oil was purified by flash column chromatography (silica gel, EtOAc/hexanes, 1:9−1:1) to give 18 as an anomeric mixture (α/β 6.5:1) as a yellowish amorphous solid (568 mg, 1.585 mmol, 94% yield); Rf = 0.47 (silica, EtOAc/hexanes, 2:3); [α]D25 = 72.2 (c 0.7, CHCl3); IR (ATR, diamond) ν 2954, 1744, 1371, 1213, 1026, 932, 739 cm−1; only the α anomer has been attributed in 1H NMR and 13C NMR; 1H NMR (500 MHz, chloroform-d) δ: 7.41−7.30 (m, 5H, Ar), 6.35 (t, 3JH1−H2 = 3JH1−F2 = 3.5 Hz, 1H, H-1), 5.72 (dd, 3JH1−H2 = 8.2 Hz, 3 JH1−F2 = 3.3 Hz, 1H, H-1β) 4.84 (s, 2zH, CH2Ph), 4.59 (dddd, 2JH2−F2 = 47.9 Hz, 3JH2−H3 = 9.2 Hz, 3JH2−H1 = 4.1 Hz, 5JH2−H5 = 0.6 Hz, 1H, H2), 4.51 (ddd, 2JH4−F4 = 49.9 Hz, 3JH4−H5 = 10.1 Hz, 3JH4−H3 = 8.6 Hz, 1H, H-4), 4.34 (dt, 2JH6a−H6b = 12.4 Hz, 3JH6a−H5 = 4JH6a−F4 = 2.1 Hz, 1H, H-6a), 4.27 (ddd, 2JH6b−H6a = 12.4 Hz, 3JH6b−H5 = 4.4 Hz, 4JH6b−F4 = 1.7 Hz, 1H, H-6b), 4.10 (ddt, 3JH3−F4 = 15.1 Hz, 3JH3−F2 = 12.9 Hz, 3 JH3−H4 = 3JH3−H2 = 8.9 Hz, 1H, H-3), 4.05 (dtdd, 3JH5−H4 = 9.4 Hz, 3 JH5−F4 = 3JH5−H6b = 4.5 Hz, 3JH5−H6a = 2.3 Hz, 5JH5−H2 = 0.5 Hz, 1H, H5), 2.19, 2.09 (6H, 2 × COCH3); 13C{1H} NMR (126 MHz, chloroform-d) δ: 170.7, 168.8 (2C, 2 × COCH3), 137.6, 128.6, 128.2, 128.0 (6C, Ar), 88.6 (dd, 2JC1−F2 = 22.9 Hz, 4JC1−F4 = 1.3 Hz, 1C, C-1), 88.53 (dd, 1JC2−F2 = 193.8 Hz, 3JC2−F4 = 9.5 Hz, 1C, C-2), 88.46 (dd, 1 JC4−F4 = 185.4 Hz, 3JC4−F2 = 9.3 Hz, 1C, C-4), 77.6 (t, 2JC3−F2 = 2JC3−F4 = 18.6 Hz, 1C, C-3), 74.9 (t, 4JCH2Ph−F2 = 4JCH2Ph−F4 = 1.6 Hz, 1C, CH2Ph), 61.8 (s, 1C, C-6), 21.0, 20.9 (2C, 2 × COCH3); 19F NMR (470 MHz, chloroform-d) δ: −197.1 (dddt, 2JF4−H4 = 49.6 Hz, 3JF4−H3 = 15.0 Hz, 3JF4−H5 = 3.8 Hz, 4JF4−H6a = 4JF4−H6b = 2 Hz, 1F, F-4α), −198.1 (ddp, J = 49.7, 15.6, 2.2 Hz, 1F, F-4β), −199.2 (ddt, J = 50.5, 15.4, 3.0 Hz, 1F, F-2β), −201.3 (ddd, 2JF2−H2 = 48.1 Hz, 3JF2−H3 = 12.7 Hz, 3 JF2−H1 = 2.0 Hz, 1F, F-2α); HRMS calcd for C17H24F2NO6 [M + NH4]+ 376.1566, found 376.1571. 6-O-Acetyl-1-O-allyl-3-O-benzyl-2,4-dideoxy-2,4-difluoro-α/ β-D-glucopyranose (20). To a stirred solution of 18 (151 mg, 0.4216 mmol) in dry acetonitrile (4.2 mL) were added allyloxytrimethylsilane (0.710 mL, 4.216 mmol, 10 equiv) and trimethylsilyl trifluoromethanesulfonate (TMSOTf) (0.76 mL, 0.4216 mmol, 1 equiv) under an argon atmosphere. The mixture was heated in a microwave reactor at 90 °C for 45 min. After cooling, the reaction mixture was quenched with water (30 mL). The mixture was extracted with CH2Cl2 (3 × 25 mL). The combined organic phases were successively washed with a saturated aqueous NaHCO3 solution (25 mL) and an aqueous 1 M HCl solution (25 mL). The organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography (silica gel, EtOAc/ hexanes, 0:100−1:1) to give 20 as an anomeric mixture (α/β 1:1) as a colorless oil (79.7 mg, 0.2237 mmol, 53% yield); Rf = 0.53 (silica, EtOAc/hexanes, 2:3); [α]D25 = 34.8 (c 0.6, CHCl3); IR (ATR, 8515

DOI: 10.1021/acs.joc.9b00795 J. Org. Chem. 2019, 84, 8509−8522

Article

The Journal of Organic Chemistry 28.7 (c 0.9, CHCl3); IR (ATR, diamond) ν 2922, 1456, 1086, 1028, 1005, 739, 696 cm−1; the anomeric mixture has been separated for NMR characterization; 1H NMR (500 MHz, chloroform-d) δ: 7.41− 7.28 (m, 10H, Ar-α/β), 5.93 (dddd, J = 17.2, 10.4, 6.1, 5.2 Hz, 1H, OAll-α), 5.92 (dddd, J = 17.2, 10.4, 6.3, 5.1 Hz, 1H, OAll-β), 5.36 (dq, J = 17.2, 1.6 Hz, 1H, OAll-α), 5.34 (dq, J = 17.2, 1.6 Hz, 1H, OAll-β), 5.26 (dq, J = 10.4, 1.3 Hz, 1H, OAll-α), 5.25 (dq, J = 10.4, 1.3 Hz, 1H, OAll-β), 5.09 (t, 3JH1−H2 = 3JH1−F2 = 3.5 Hz, 1H, H-1α), 4.84 (d, 2 JCH2aPh−CH2bPh = 11.7 Hz, 1H, CH2aPh-β), 4.83 (d, 2JCH2aPh−CH2bPh = 11.5

3

JOH−H3 = 4.7 Hz, 1H, OH-3α), 4.91 (td, 3JH1−H2 = 3JH1−OH = 7.1 Hz, JH1−F2 = 2.6 Hz, 1H, H-1β), 4.63 (ddt, 2JH6a−F6 = 47.7 Hz, 2JH6a−H6b = 10.6 Hz, 3JH6a−H5 = 4JH6a−F4 = 1.8 Hz, 1H, H-6aβ), 4.62 (dddd, 2JH6b−F6 = 47.7 Hz, 2JH6b−H6a = 10.7 Hz, 3JH6b−H5 = 3.8 Hz, 4JH6b−F4 = 1.7 Hz, 1H, H-6bα), 4.58 (dddd, 2JH6b−F6 = 47.5 Hz, 2JH6b−H6a = 10.6 Hz, 3JH6b−H5 = 4.6 Hz, 4JH6b−F4 = 1.8 Hz, 1H, H-6bβ), 4.58 (ddt, 2JH6a−F6 = 48.0 Hz, 2 JH6a−H6b = 10.6 Hz, 3JH6a−H5 = 4JH6a−F4 = 1.8 Hz, 1H, H-6aα), 4.38− 4.18 (m, 4H, H-2α; H-3α; H-4α/β), 4.15 (dddddd, 3JH5−F6 = 26.5 Hz, 3 JH5−H4 = 10.0 Hz, 3JH5−F4 = 4.6 Hz, 3JH5−H6b = 3.9 Hz, 3JH5−H6a = 1.8 Hz, 4 JH5−H3 = 0.6 Hz, 1H, H-5α), 4.08−3.98 (m, 1H, H-3β), 4.01 (ddd, 2 JH2−F2 = 52.1 Hz, 3JH2−H3 = 9.0 Hz, 3JH2−H1 = 7.6 Hz, 1H, H-2β), 3.84 (ddddd, 3JH5−F6 = 24.5 Hz, 3JH5−H4 = 10.0 Hz, 3JH5−H6b = 4.4 Hz, 3JH5−F4 = 2.8 Hz, 3JH5−H6a = 1.8 Hz, 1H, H-5β); 13C{1H} NMR (126 MHz, acetone-d6) δ: 95.4 (d, 2JC1−F2 = 22.0 Hz, 1C, C-1β), 94.2 (dd, 1JC2−F2 = 185.8 Hz, 3JC2−F4 = 9.2 Hz, 1C, C-2β), 90.91 (dd, 2JC1−F2 = 21.6 Hz, 4 JC1−F4 = 1.5 Hz, 1C, C-1α), 90.86 (dd, 1JC2−F2 = 189.5 Hz, 3JC2−F4 = 8.9 Hz, 1C, C-2α), 89.4 (dt, 1JC4−F4 = 182.4 Hz, 3JC4−F2 = 3JC4−F6 = 8.1 Hz, 1C, C-4α), 89.3 (dt, 1JC4−F4 = 183.3 Hz, 3JC4−F2 = 3JC4−F6 = 7.3 Hz, 1C, C-4β), 82.33 (dd, 1JC6−F6 = 171.9 Hz, 3JC6−F4 = 8.7 Hz, 1C, C-6α), 82.32 (dd, 1JC6−F6 = 172.0 Hz, 3JC6−F4 = 9.3 Hz, 1C, C-6β), 73.6 (t, 2JC3−F2 = 2 JC3−F4 = 19.4 Hz, 1C, C-3β), 72.8 (ddd, 2JC5−F6 = 23.8 Hz, 2JC5−F4 = 18.6 Hz, 4JC5−F2 = 0.8 Hz, 1C, C-5β), 70.5 (t, 2JC3−F2 = 2JC3−F4 = 19.2 Hz, 1C, C-3α), 68.4 (ddd, 2JC5−F6 = 23.8 Hz, 2JC5−F4 = 18.3 Hz, 4JC5−F2 = 1.2 Hz, 1C, C-5α); 19F NMR (470 MHz, acetone-d6) δ: −199.4 (br dd, 2 JF4−H4 = 49.8 Hz, 3JF4−H3 = 16.5 Hz, 1F, F-4α), −200.1 (ddt, 2JF2−H2 = 52.5 Hz, 3JF2−H3 = 13.6 Hz, 3JF2−H5 = 4JF2−F4 = 3.3 Hz, 1F, F-2β), −201.1 (br dd, 2JF4−H4 = 50.1 Hz, 3JF4−H3 = 16.3 Hz, 1F, F-4β), −201.6 (dd, 2 JF2−H2 = 49.9 Hz, 3JF2−H3 = 12.6 Hz, 1F, F-2α), −235.2 (td, 2JF6−H6a = 2 JF6−H6b = 47.4 Hz, 3JF6−H5 = 24.1 Hz, 1F, F-6β), −235.9 (td, 2JF6−H6a = 2 JF6−H6b = 47.8 Hz, 3JF6−H5 = 27.2 Hz, 1F, F-6α); HRMS calcd for C6H8F3O3 [M − H]− 185.0431, found 185.0430. 1,6-Anhydro-2-O-benzyl-4-deoxy-4-fluoro-β-D-glucopyranose (23). In a round-bottom flask with the known compound 2243 (129 mg, 0.5507 mmol) were added TBAF·3H2O (521 mg, 1.6521 mmol, 3 equiv) and KHF2 (64.5 mg, 0.8260 mmol, 1.5 equiv). The mixture was heated at 180 °C for 3 h. After cooling to rt, the reaction mixture was diluted with water (30 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic phases were washed with a saturated aqueous NaHCO3 solution (25 mL) and an aqueous 1 M HCl solution (25 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography (silica gel, EtOAc/hexanes, 3:7−1:1) to give 23 as a pale-yellow amorphous solid (72.5 mg, 0.2864 mmol, 52% yield) and starting material 22 (37.4 mg, 0.8260 mmol, 29%). The spectroscopic data derived from compound 23 match those reported in the literature.14 1,6-Anhydro-2-O-benzyl-3,4-dideoxy-3,4-difluoro-β-D-glucopyranose (14). To an ice-cold stirred solution of 23 (59 mg, 0.2321 mmol) in CH2Cl2 (2 mL) were added pyridine (186 μL, 2.321 mmol, 10 equiv) and a 1 M solution of trifluoromethanesulfonic anhydride in CH2Cl2 (0.464 mL, 0.4641 mmol, 2 equiv). The mixture was stirred for 5 min at 0 °C before warming at room temperature for 55 min. The reaction mixture was quenched with water (10 mL). The mixture was extracted with CH2Cl2 (3 × 10 mL), and the combined organic phases were successively washed with a saturated aqueous NaHCO3 solution (20 mL) and aqueous 1 M HCl solution (20 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude triflate 24 was used for the next step without further purification. To the crude 24 was added triethylamine trihydrofluoride (0.572 mL, 3.4808 mmol, 15 equiv), and the mixture was heated at 80 °C for 24 h and then cooled to room temperature. The reaction mixture was quenched with water (15 mL). The mixture was extracted with CH2Cl2 (3 × 15 mL), and the combined organic phases were successively washed with a saturated aqueous NaHCO3 solution (20 mL) and aqueous 1 M HCl solution (20 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel, EtOAc/hexanes, 3:20−1:1) to give 14 as a pale-yellow 3

Hz, 1H, CH2aPh-α), 4.82 (d, 2JCH2bPh−CH2aPh = 11.6 Hz, 1H, CH2bPh-β), 4.81 (d, 2JCH2bPh−CH2aPh = 11.2 Hz, 1H, CH2bPh-α), 4.68−4.57 (m, 2H, H-6α), 4.67 (ddt, 2JH6a−F6 = 47.0 Hz, 2JH6a−H6b = 10.4 Hz, 3JH6a−H5 = 4 JH6a−F4 = 2.0 Hz, 1H, H-6aβ), 4.59 (dddd, 2JH6b−F6 = 47.1 Hz, 2JH6b−H6a = 10.4 Hz, 3JH6b−H5 = 4.6 Hz, 4JH6b−F4 = 1.8 Hz, 1H, H-6bβ), 4.58 (dd, 3 JH1−H2 = 7.5 Hz, 3JH1−F2 = 3.1 Hz, 4JH1−H3 = 0.3 Hz, 1H, H-1β), 4.49 (ddd, 2JH4−F4 = 50.3 Hz, 3JH4−H5 = 10.2 Hz, 3JH4−H3 = 8.6 Hz, 1H, H4β), 4.49 (ddd, 2JH4−F4 = 50.4 Hz, 3JH4−H5 = 10.2 Hz, 3JH4−H3 = 8.5 Hz, 1H, H-4α), 4.46 (dddd, 2JH2−F2 = 48.8 Hz, 3JH2−H3 = 9.3 Hz, 3JH2−H1 = 3.9 Hz, 4JH2−F4 = 0.7 Hz, 1H, H-2α), 4.40 (ddt, J = 12.9, 5.1, 1.4 Hz, 1H, OAll-β), 4.34 (ddd, 2JH2−F2 = 50.1 Hz, 3JH2−H3 = 8.6 Hz, 3JH2−H1 = 7.7 Hz, 1H, H-2β), 4.25 (ddt, J = 12.9, 5.3, 1.5 Hz, 1H, OAll-α), 4.17 (ddt, J = 12.9, 6.3, 1.3 Hz, 1H, OAll-β), 4.16 (ddt, 3JH3−F4 = 15.7 Hz, 3JH3−F2 = 12.6 Hz, 3JH3−H4 = 3JH3−H2 = 9.0 Hz, 1H, H-3α), 4.11 (ddt, J = 13.0, 6.1, 1.4 Hz, 1H, OAll-α), 3.97 (dddtd, 3JH5−F6 = 26.2 Hz, 3JH5−H4 = 10.1 Hz, 3 JH5−H6b = 4.5 Hz, 3JH5−F4 = 2.8 Hz, 3JH4−H6a = 1.8 Hz, 1H, H-5α), 3.83 (ttd, 3JH3−F4 = 3JH3−F2 = 15.8 Hz, 3JH3−H4 = 3JH3−H2 = 8.6 Hz, 4JH3−H1 = 0.6 Hz, 1H, H-3β), 3.63 (ddddd, 3JH5−F6 = 22.8 Hz, 3JH5−H4 = 9.7 Hz, 3 JH5−H6b = 4.8 Hz, 3JH5−F4 = 3.1 Hz, 3JH4−H6a = 1.8 Hz, 1H, H-5β); 13 C{1H} NMR (126 MHz, chloroform-d) δ: 138.0, 128.4, 128.02, 128.02 (6C, Ar-α), 137.5, 128.6, 128.14, 128.12 (6C, Ar-β), 133.3 (1C, OAll-β), 133.0 (1C, OAll-α), 118.6 (1C, OAll-α), 118.4 (1C, OAll-β), 99.2 (dd, 2JC1−F2 = 23.4 Hz, 4JC1−F4 = 1.3 Hz, 1C, C-1β), 95.3 (dd, 2 JC1−F2 = 20.9 Hz, 4JC1−F4 = 1.0 Hz, 1C, C-1α), 91.8 (dd, 1JC2−F2 = 189.1 Hz, 3JC2−F4 = 9.3 Hz, 1C, C-2β), 89.5 (dd, 1JC2−F2 = 193.6 Hz, 3JC2−F4 = 9.1 Hz, 1C, C-2α), 88.1 (ddd, 1JC4−F4 = 185.2 Hz, 3JC4−F2 = 9.0 Hz, 3 JC1−F6 = 7.4 Hz, 2C, C-4α/β), 81.0 (d, 1JC6−F6 = 175.1 Hz, 2C, C-6α/ β), 80.0 (t, 2JC3−F2 = 2JC3−F4 = 18.7 Hz, 1C, C-3β), 77.8 (t, 2JC3−F2 = 2 JC3−F4 = 18.2 Hz, 1C, C-3α), 74.9 (t, 4JCH2Ph−F2 =, 4JCH2Ph−F4 = 1.5 Hz, 1C, CH2Ph-α), 74.4 (t, 4JCH2Ph−F2 =, 4JCH2Ph−F4 = 1.6 Hz, 1C, CH2Ph-β), 72.4 (dd, 2JC5−F4 = 24.2 Hz, 2JC5−F6 = 18.9 Hz, 1C, C-5β), 70.4 (1C, OAll-β), 69.1 (1C, OAll-α), 68.3 (dd, 3JC5−F4 = 24.4 Hz, 3JC5−F6 = 17.7 Hz, 1C, C-5α); 19F NMR (470 MHz, chloroform-d) δ: −196.7 (dd, 2 JF4−H4 = 50.2 Hz, 3JF4−H3 = 15.9 Hz, 1F, F-4α), −197.5 (ddt, 2JF4−H4 = 49.9 Hz, 3JF4−H3 = 15.5 Hz, 3JF4−H5 = 4JF4−F2 = 2.5 Hz, 1F, F-4β), −197.8 (ddt, 2JF2−H2 = 50.3 Hz, 2JF2−H3 = 16.2 Hz, 3JF2−H1 = 4JF2−F4 = 2.5 Hz, 1F, F-2β), −200.8 (dd, 2JF2−H2 = 48.6 Hz, 2JF2−H3 = 12.7 Hz, 1F, F-2α), −234.2 (td, 2JF6−H6a = 2JF6−H6b = 47.0 Hz, 3JF6−H5 = 22.7 Hz, 1F, F-6β) −235.5 (td, 2JF6−H6a = 2JF6−H6b = 47.0 Hz, 3JF6−H5 = 26.2 Hz, 1F, F-6α); HRMS calcd for C16H23F3NO3 [M + NH4]+ 334.1625, found 334.1625. 2,4,6-Trideoxy-2,4,6-trifluoro-α/β-D-glucopyranose (9). To a stirred solution of 21 (63.8 mg, 0.202 mmol) in water/acetone (4 mL, 1:1) was added an aqueous hydrochloric acid solution (37%) (8 mL), and the mixture was heated at 70 °C overnight. After cooling, the reaction mixture was dried over an air stream. The dried crude was dissolved in acetone, and silica gel was added and concentrated under reduce pressure. The resulting dry-pack was purified by flash column chromatography (silica gel, MeOH/CH2Cl2, 0:100−3:7). After column chromatography, the product was then dissolved in acetone/MeOH (1:1) and stirred with activated coal for 30 min. The mixture was filtered through celite and concentrated under reduced pressure to give 9 as an anomeric mixture (α/β, 7:3) as a thick yellow oil (31.9 mg, 0.1714 mmol, 85% yield); Rf = 0.28 (silica, MeOH/CH2Cl2, 1:19); [α]D25 = 48.6 (c 0.4, MeOH); IR (ATR, diamond) ν 3356, 2962, 1636, 1366, 1057, 995, 771 cm−1; 1H NMR (500 MHz, acetone-d6) δ: 6.39 (d, 3JOH−H1 = 6.9 Hz, 1H, OH-1β), 6.24 (dd, 3JOH−H1 = 4.7 Hz, 4JOH−F2 = 1.0 Hz, 1H, OH-1α), 5.38 (dt, 3JH1−H2 = 3JH1−OH = 4.6 Hz, 3JH1−F2 = 3.3 Hz, 1H, H-1α), 5.25 (d, 3JOH−H3 = 5.0 Hz, 1H, OH-3β), 5.11 (d, 8516

DOI: 10.1021/acs.joc.9b00795 J. Org. Chem. 2019, 84, 8509−8522

Article

The Journal of Organic Chemistry

9.9 Hz, 3JH4−H3 = 8.3 Hz, 1H, H-4β), 4.49 (dddd, 2JH4−F4 = 51.3 Hz, 3 JH4−F3 = 15.0 Hz, 3JH4−H5 = 10.1 Hz, 3JH4−H3 = 8.1 Hz, 1H, H-4α), 4.48 (dd, 3JH1−H2 = 7.8 Hz, 4JH1−H5 = 0.6 Hz, 1H, H-1β), 4.42 (dq, 2JH6a−H6b = 12.1 Hz, 3JH6a−H5 = 4JH6a−F3 = 5JH6a−F4 = 1.8 Hz, 1H, H-6aα), 4.39 (ddt, J = 12.7, 5.2, 1.5 Hz, 1H, OAll-β), 4.35 (dq, 2JH6a−H6b = 12.3 Hz, 3 JH6a−H5 = 4JH6a−F3 = 5JH6a−F4 = 1.9 Hz, 1H, H-6aβ), 4.26 (ddd, 2JH6b−H6a = 11.9 Hz, 3JH6b−H5 = 4.8 Hz, 4JH6b−F4 = 1.4 Hz, 1H, H-6bα), 4.24 (ddd, 2 JH6b−H6a = 12.2 Hz, 3JH6b−H5 = 5.1 Hz, 4JH6b−F4 = 1.5 Hz, 1H, H-6bβ), 4.15 (ddt, J = 12.9, 5.1, 1.4 Hz, 1H, OAll-β), 4.15 (ddt, J = 12.7, 6.3, 1.2 Hz, 1H, OAll-α), 4.02−3.96 (m, 1H, H-5α) 3.99 (ddt, J = 12.9, 6.4, 1.3 Hz, 1H, OAll-α), 3.63−3.59 (m, 1H, H-5β), 3.58 (dddd, 3JH2−F3 = 12.4 Hz, 3JH2−H3 = 9.2 Hz, 3JH2−H1 = 3.8 Hz, 4JH2−F4 = 0.7 Hz, 1H, H-2α), 3.54 (ddd, 3JH2−F3 = 14.5 Hz, 3JH2−H3 = 8.7 Hz, 3JH2−H1 = 7.8 Hz, 1H, H2β), 2.11, 2.10 (6H, 2 × COCH3-α/β); 13C{1H} NMR (126 MHz, chloroform-d) δ: 170.74, 170.70 (2C, 2 × COCH3-α/β), 137.7 (1C, OAll-β), 137.6 (1C, OAll-α), 133.5, 133.1, 128.7, 128.5, 128.25, 128.24, 128.13, 128.08 (10C, Ar-α/β), 118.8 (1C, OAll-α), 118.1 (1C, OAll-β), 101.6 (dd, 3JC1−F3 = 11.7 Hz, 4JC1−F4 = 1.1 Hz, 1C, C-1β), 96.1 (d, 3JC1−F3 = 9.6 Hz, 1C, C-1α), 94.1 (dd, 1JC3−F3 = 187.9 Hz, 2JC3−F4 = 18.6 Hz, 1C, C-3β), 92.5 (dd, 1JC3−F3 = 185.1 Hz, 2JC3−F4 = 17.9 Hz, 1C, C-3α), 87.4 (dd, 1JC4−F4 = 186.7 Hz, 2JC4−F3 = 18.4 Hz, 1C, C-4β), 87.3 (dd, 1JC4−F4 = 186.7 Hz, 2JC4−F3 = 19.6 Hz, 1C, C-4α), 79.2 (dd, 2JC2−F3 = 17.8 Hz, 3JC2−F4 = 7.3 Hz, 1C, C-2β), 76.5 (dd, 2JC2−F3 = 16.4 Hz, 3 JC2−F4 = 6.9 Hz,1C, C-2α), 74.8, 73.5 (2C, 2 × CH2Ph-α/β), 70.9 (1C, OAll-β), 70.1 (dd, 2JC5−F4 = 23.5 Hz, 3JC5−F3 = 8.4 Hz, 1C, C-5β), 69.0 (1C, OAll-α), 66.6 (dd, 2JC5−F4 = 23.5 Hz, 3JC5−F3 = 7.2 Hz, 1C, C-5α), 62.23 (d, 3JC6−F4 = 1.6 Hz, 1C, C-6β), 62.15 (d, 3JC6−F4 = 1.6 Hz, 1C, C6α), 20.94, 20.91 (2C, 2 × COCH3-α/β); 19F NMR (470 MHz, chloroform-d) δ: −193.3 (dq, 2JF3−H3 = 52.0 Hz, 3JF3−F4 = 3JF3−H4 = 3 JF3−H2 = 14.1 Hz, 1F, F-3β), −197.4 (dqd, 2JF3−H3 = 54.3 Hz, 3JF3−F4 = 3 JF3−H4 = 3JF3−H2 = 13.6 Hz, 4JF3−H1 = 3.6 Hz, 1F, F-3α), −197.8 (ddddd, 2 JF4−H4 = 51.3 Hz, 3JF4−H3 = 16.4 Hz, 3JF4−F3 = 13.7 Hz, 4JF4−H6a = 1.9 Hz, 4 JF4−H6b = 1.4 Hz, 4JF4−H2 = 0.7 Hz 1F, F-4α), −199.4 (ddddd, 2JF4−H4 = 51.2 Hz, 3JF4−H3 = 16.9 Hz, 3JF4−F3 = 14.1 Hz, 4JF4−H6a = 1.8 Hz, 4JF4−H6b = 1.5 Hz, 1F, F-4β); HRMS calcd for C18H26F2NO5 [M + NH4]+ 374.1774, found 374.1795. 1-O-Allyl-2-O-benzyl-3,4,6-trideoxy-3,4,6-trifluoro-α/β-Dglucopyranose (28). To a solution of 26 (24 mg, 0.0671 mmol) in CH2Cl2/MeOH (0.7 mL/4:1) was added dropwise a methanolic 1 M NaOMe solution, until pH was ≈ 9. The mixture was stirred at room temperature for 6 h and then neutralized to pH ≈ 7 with an acidic resin. The mixture was filtered and concentrated under reduced pressure to afford 27 as a colorless oil (21 mg, 0.0668 mmol, 99% yield). To a solution of 27 (21 mg, 0.0668 mmol) in CH2Cl2 (1.1 mL) were added 2,4,6-collidine (0.054 mL, 0.403 mmol, 6 equiv) and diethylaminosulfur trifluoride (0.027 mL, 0.201 mmol, 3 equiv). The mixture was heated in a microwave reactor at 100 °C for 1 h. After cooling, the reaction mixture was quenched with water (15 mL). The mixture was extracted with CH2Cl2 (3 × 15 mL). The combined organic phases were successively washed with a saturated aqueous NaHCO3 solution (15 mL) and an aqueous 1 M HCl solution (15 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography (silica gel, EtOAc/hexanes, 0:100−3:7) to give 28 as an anomeric mixture (α/β 1:1) as a thick yellow oil (18 mg, 0.0569 mmol, 85% yield); Rf = 0.73 (silica, EtOAc/hexanes, 2:3); [α]D25 = −4.2 (c 0.2, CHCl3); IR (ATR, diamond) ν 2932, 1720, 1458, 1157, 1095, 1018, 741 cm−1; 1H NMR (500 MHz, chloroform-d) δ: 7.44− 7.28 (m, 10H, Ar-α/β), 5.93 (dddd, J = 17.2, 10.5, 6.1, 5.2 Hz, 1H, OAll-β), 5.90 (dddd, J = 17.2, 10.4, 6.3, 5.1 Hz, 1H, OAll-α), 5.35 (dq, J = 17.2, 1.6 Hz, 1H, OAll-β), 5.34 (dq, J = 17.2, 1.6 Hz, 1H, OAll-α), 5.25 (dq, J = 10.3, 1.3 Hz, 1H, OAll-β), 5.24 (dq, J = 10.4, 1.4 Hz, 1H, OAll-α), 5.00 (ddtd, 2JH3−F3 = 54.5 Hz, 3JH3−F4 = 17.1 Hz, 3JH3−H4 = 3 JH3−H2 = 8.7 Hz, 4JH3−H5 = 1.0 Hz, 1H, H-3α), 4.88 (d, 2JCH2aPh−CH2bPh =

oil (47.6 mg, 0.1858 mmol, 80% yield). The spectroscopic data derived from compound 14 match those reported in the literature.14 1,6-Di-O-acetyl-2-O-benzyl-3,4-dideoxy-3,4-difluoro-α/β-Dglucopyranose (25). To a stirred solution of 14 (74.4 mg, 0.290 mmol) in acetic anhydride (2 mL) at 0 °C were added two drops of triethylsilyl trifluoromethanesulfonate (≈20−30 μL, cat) under an argon atmosphere. The mixture was allowed to cool down to room temperature, and after 1 h, a saturated aqueous NaHCO3 solution (15 mL) was added to the mixture. After 30 min of stirring, the reaction mixture was extracted with EtOAc (3 × 15 mL). The combined organic phases were washed with a saturated aqueous NaHCO3 solution (2 × 15 mL) and brine (15 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude oil was purified by flash column chromatography (silica gel, EtOAc/hexanes, 1:9−1:1) to give 25 as an anomeric mixture (α/β 22:3) as a colorless oil (65 mg, 0.1822 mmol, 63% yield); Rf = 0.51 (silica, EtOAc/hexanes, 2:3); [α]D25 = 50.3 (c 0.2, CHCl3); IR (ATR, diamond) ν 2928, 1744, 1371, 1217, 1109, 1016, 739 cm−1; only the α anomer has been attributed in 1H NMR and 13C NMR; 1H NMR (500 MHz, chloroform-d) δ: 7.39−7.29 (m, 5H, Ar), 6.28 (q, 3JH1−H2 = 4JH1−F3 = 4 JH1−H5 = 3.5 Hz, 1H, H-1), 5.61 (d, 3JH1−H2 = 8.2 Hz, 1H, H-1β), 4.92 (dddd, 2JH3−F3 = 53.9 Hz, 3JH3−F4 = 16.1 Hz, 3JH3−H2 = 9.2 Hz, 3JH3−H4 = 8.5 Hz, 1H, H-3), 4.72 (d, 2JCH2aPh−CH2bPh = 12.0 Hz, 1H, CH2aPh), 4.69 (d, 2JCH2bPh−CH2aPh = 12.0 Hz, 1H, CH2bPh), 4.56 (dddd, 2JH4−F4 = 51.2 Hz, 3JH4−F3 = 14.8 Hz, 3JH4−H5 = 10.1 Hz, 3JH4−H3 = 8.4 Hz, 1H, H-4), 4.35 (dq, 2JH6a−H6b = 12.4 Hz, 3JH6a−H5 = 4JH6a−F4 = 5JH6a−F3 = 2.0 Hz, 1H, H-6a), 4.26 (ddd, 2JH6b−H6a = 12.5 Hz, 3JH6b−H5 = 4.4 Hz, 4JH6b−F4 = 1.7 Hz, 1H, H-6b), 4.05 (dtd, 3JH5−H4 = 10.1 Hz, 3JH5−H6b = 3JH5−F4 = 4.5 Hz, 3JH5−H6a = 2.3 Hz, 1H, H-5), 3.71 (dddd, 3JH2−F3 = 12.4 Hz, 3JH2−H3 = 9.3 Hz, 3JH2−H1 = 3.9 Hz, 4JH2−F4 = 0.7 Hz, 1H, H-2), 2.17, 2.09 (6H, 2 × COCH3); 13C{1H} NMR (126 MHz, chloroform-d) δ: 170.6, 168.9 (2C, 2 × COCH3), 137.0, 128.8, 128.4, 128.1 (6C, Ar), 92.0 (dd, 1 JC3−F3 = 187.0 Hz, 2JC3−F4 = 18.4 Hz, 1C, C-3), 89.5 (dd, 3JC1−F3 = 10.4 Hz, 4JC1−F4 = 1.5 Hz, 1C, C-1), 86.8 (dd, 1JC4−F4 = 186.6 Hz, 2JC4−F3 = 18.7 Hz, 1C, C-4), 75.4 (dd, 2JC2−F3 = 17.2 Hz, 1JC2−F4 = 7.5 Hz, 1C, C2), 73.4 (d, 4JCH2Ph−F3 = 1.0 Hz, 1C, CH2Ph), 68.8 (dd, 2JC5−F4 = 23.7 Hz, 3JC5−F3 = 7.0 Hz, 1C, C-5), 61.8 (1C, C-6), 21.1, 20.9 (2C, 2 × COCH3); 19F NMR (470 MHz, chloroform-d) δ: −192.7 (dq, J = 52.3, 13.6 Hz, 1F, F-3β), −197.9 (dqd, 2JF3−H3 = 53.6 Hz, 3JF3−F4 = 3JF3−H4 = 3 JF3−H2 = 14.6 Hz, 4JF3−H1 = 3.6 Hz, 1F, F-3α), −198.5 (dtddd, 2JF4−H4 = 51.1 Hz, 3JF4−F3 = 3JF4−H3 = 14.6 Hz, 3JF4−H5 = 4.0, 4JF4−H6a = 2.4 Hz, 4 JF4−H6b = 1.6 Hz, 1F, F-4α), −199.8 (dt, J = 51.1, 14.6 Hz, 1F, F-4β); HRMS calcd for C17H24F2NO6 [M + NH4]+ 376.1566, found 376.1562. 6-O-Acetyl-1-O-allyl-2-O-benzyl-3,4-dideoxy-3,4-difluoro-α/ β-D-glucopyranose (26). To a stirred solution of 25 (61.8 mg, 0.172 mmol) in dry acetonitrile (1.7 mL) were added allyloxytrimethylsilane (0.290 mL, 1.72 mmol, 10 equiv) and trimethylsilyl trifluoromethanesulfonate (0.031 mL, 0.172 mmol, 1 equiv) under an argon atmosphere. The mixture was heated in a microwave reactor at 90 °C for 45 min. After cooling, the reaction mixture was quenched with water (15 mL). The mixture was extracted with CH2Cl2 (3 × 15 mL). The combined organic phases were successively washed with a saturated aqueous NaHCO3 solution (15 mL) and an aqueous 1 M HCl solution (15 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography (silica gel, EtOAc/hexanes, 0:100−2:3) to give 26 as an anomeric mixture (α/β 1:1) as a colorless thick oil (29.5 mg, 0.08279 mmol, 48% yield); Rf = 0.62 (silica, EtOAc/hexanes, 2:3); IR (ATR, diamond) ν 2924, 1744, 1366, 1234, 1095, 1026, 741 cm−1; 1 H NMR (500 MHz, chloroform-d) δ: 7.39−7.27 (m, 10H, Ar-α/β), 5.93 (dddd, J = 17.2, 10.5, 6.1, 5.2 Hz, 1H, OAll-β), 5.91 (dddd, J = 17.0, 10.4, 6.4, 5.2 Hz, 1H, OAll-α), 5.35 (dq, J = 17.3, 1.6 Hz, 1H, OAllβ), 5.34 (dq, J = 17.2, 1.6 Hz, 1H, OAll-α), 4.98 (dddd, 2JH3−F3 = 54.4 Hz, 3JH3−F4 = 16.5 Hz, 3JH3−H2 = 9.3 Hz, 3JH3−H4 = 8.1 Hz, 1H, H-3α), 4.87 (d, J = 11.3 Hz, 1H, CH2aPh), 4.83 (d, J = 12.5 Hz, 1H, CH2aPh), 4.81 (q, 3JH1−H2 = 4JH1−F3 = 4JH1−H5 = 3.4 Hz, 1H, H-1α), 4.76 (d, J = 11.3 Hz, 1H, CH2bPh), 4.66 (ddt, 2JH3−F3 = 52.1 Hz, 3JH3−F4 = 17.0 Hz, 3 JH3−H2 = 3JH3−H4 = 8.5 Hz, 1H, H-3β), 4.64 (d, J = 12.3 Hz, 1H, CH2bPh), 4.53 (dddd, 2JH4−F4 = 51.2 Hz, 3JH4−F3 = 14.5 Hz, 3JH4−H5 =

11.2 Hz, 1H, CH2aPh-β), 4.83 (d, 2JCH2aPh−CH2bPh = 12.2 Hz, 1H, CH2aPh-α), 4.83 (q, 3JH1−H2 = 4JH1−F3 = 4JH1−H5 = 3.4 Hz, 1H, H-1α), 4.76 (d, 2JCH2bPh−CH2aPh = 11.3 Hz, 1H, CH2bPh-β), 4.77−4.47 (m, 7H, H-3β; H-4α/β; H-6α/β), 4.64 (d, 2JCH2bPh−CH2aPh = 12.2 Hz, 1H, 8517

DOI: 10.1021/acs.joc.9b00795 J. Org. Chem. 2019, 84, 8509−8522

Article

The Journal of Organic Chemistry CH2bPh-α), 4.50 (d, 3JH1−H2 = 7.7 Hz, 1H, H-1β), 4.42 (ddt, J = 12.8, 5.2, 1.5 Hz, 1H, OAll-β), 4.16 (ddt, J = 12.8, 6.1, 1.5 Hz, 1H, OAll-β), 4.16 (ddt, J = 12.7, 5.1, 1.5 Hz, 1H, OAll-α), 4.00 (ddt, J = 13.0, 6.4, 1.3 Hz, 1H, OAll-α), 3.91 (dddddt, 3JH5−F6 = 26.9 Hz, 3JH5−H4 = 10.4 Hz, 3 JH5−F4 = 4.6 Hz, 4JH5−H1 = 2.8 Hz, 4JH5−F3 = 2.0 Hz, 3JH5−H6a = 5JH5−H2 = 1.0 Hz, 1H, H-5α), 3.59 (dddtt, 3JH5−F6 = 23.5 Hz, 3JH5−H4 = 9.9 Hz, 3 JH5−F4 = 4.0 Hz, 3JH5−H6a = 4JH5−H3 = 2.7 Hz, 3JH5−H6b = 4JH5−F3 = 1.1 Hz, 1H, H-5β), 3.58 (dddd, 3JH2−F3 = 12.2 Hz, 3JH2−H3 = 9.4 Hz, 3JH2−H1 = 3.9 Hz, 5JH2−H5 = 0.7 Hz, 1H, H-2α), 3.55 (ddd, 3JH2−F3 = 14.6 Hz, 3 JH2−H3 = 8.7 Hz, 3JH2−H1 = 7.8 Hz, 1H, H-2β); 13C{1H} NMR (126 MHz, chloroform-d) δ: 137.5 (1C, OAll-β), 137.4 (1C, OAll-α), 133.3, 132.9, 128.5, 128.4, 128.13, 128.10, 128.0, 127.9 (10C, Ar-α/β), 118.6 (1C, OAll-β), 118.0 (1C, OAll-α), 101.5 (dd, 3JC1−F3 = 11.6 Hz, 4JC1−F4 = 1.5 Hz, 1C, C-1β), 96.1 (dd, 3JC1−F3 = 10.4 Hz, 4JC1−F4 = 1.5 Hz, 1C, C-1α), 93.9 (dd, 1JC3−F3 = 188.0 Hz, 2JC3−F4 = 18.8 Hz, 1C, C-3β), 92.3 (dd, 1JC3−F3 = 185.3 Hz, 2JC3−F4 = 18.2 Hz, 1C, C-3α), 86.2 (ddd, 1JC4−F4 = 186.1 Hz, 2JC4−F3 = 18.4 Hz, 3JCJC5−F64−F6 = 7.1 Hz, 1C, C-4), 86.1 (ddd, 1JC4−F4 = 186.6 Hz, 2JC4−F3 = 19.0 Hz, 3JC4−F6 = 7.6 Hz, 1C, C-4), 80.7 (d, 1JC6−F6 = 175.4 Hz, 2C, C-6α/β), 79.0 (dd, 2JC2−F3 = 17.9 Hz, 3 JC2−F4 = 7.5 Hz, 1C, C-2β), 76.3 (dd, 2JC2−F3 = 16.5 Hz, 3JC2−F4 = 7.2 Hz, 1C, C-2α), 74.7 (1C, CH2Ph-β), 73.4 (d, 4JCH2Ph−F3 = 1.5 Hz, 1C, CH2Ph-α), 71.1 (ddd, 2JC5−F6 = 23.7 Hz, 2JC5−F4 = 19.1 Hz, 3JC5−F3 = 8.1 Hz, 1C, C-5β), 70.6 (1C, OAll-β), 68.9 (1C, OAll-α), 67.6 (ddd, 2JC5−F6 = 23.7 Hz, 2JC5−F4 = 18.0 Hz, 3JC5−F3 = 7.1 Hz, 1C, C-5α); 19F NMR (470 MHz, chloroform-d) δ: −193.3 (dqt, 2JF3−H3 = 51.5 Hz, 3JF3−F4 = 3 JF3−H4 = 3JF3−H2 = 14.2 Hz, 4JF3−H5 = 4JF3−H1 = 1.0 Hz, 1F, F-3β), −197.6 (dqt, 2JF3−H3 = 54.8 Hz, 3JF3−F4 = 3JF3−H4 = 3JF3−H2 = 14.6 Hz, 4 JF3−H1 = 4JF3−H5 = 2.0 Hz, 1F, F-3α), −198.2 (dddt, 2JF4−H4 = 51.5 Hz, 3 JF4−H3 = 16.8 Hz, 3JF4−F3 = 13.3 Hz, 3JF4−H5 = 4JF4−H6a = 3.2 Hz, 1F, F4α), −199.6 (dddd, 2JF4−H4 = 50.6 Hz, 3JF4−H3 = 16.1 Hz, 3JF4−F3 = 14.1 Hz, 3JF4−H5 = 3.1 Hz, 1F, F-4β), −234.8 (td, 2JF6−H6a = 2JF6−H6b = 46.9 Hz, 3JF6−H5 = 23.5 Hz, 1F, F-6β), −236.1 (td, 2JF6−H6a = 2JF6−H6b = 47.4 Hz, 3JF6−H5 = 27.1 Hz, 1F, F-6α); HRMS calcd for C16H23F3NO3 [M + NH4]+ 334.1625, found 334.1640. 3,4,6-Trideoxy-3,4,6-trifluoro-α/β-D-glucopyranose (10). To a stirred solution of 28 (13.6 mg, 0.0429 mmol) in water/acetone (0.43 mL, 1:1) was added an aqueous hydrochloric acid solution (37%) (0.86 mL), and the mixture was heated at 70 °C overnight. After cooling, the reaction mixture was dried over an air stream. The dried crude was dissolved in acetone, silica gel was added, and the mixture was concentrated under reduce pressure. The resulting dry-pack was purified by flash column chromatography (silica gel, MeOH/CH2Cl2, 0:100−3:7). After column chromatography, the product was dissolved in acetone/MeOH (1:1) and stirred with activated coal for 30 min. The mixture was filtered through celite and concentrated under reduced pressure to give 10 as a anomeric mixture (α/β, 3:1) as a thick yellow oil (9.6 mg, 0.0516 mmol, 66% yield); Rf = 0.27 (silica, MeOH/CH2Cl2, 1:20); [α]D25 = 52.2 (c 0.2, CHCl3); IR (ATR, diamond) ν 3348, 2962, 1636, 1366, 1057, 995, 771 cm−1; only the α anomer has been attributed in 1H NMR and 13C NMR; 1H NMR (500 MHz, acetone-d6) δ: 6.15 (dd, 3JOH1−H1 = 4.6 Hz, 4JOH1−H2 = 1.1 Hz, 1H, OH-1), 5.22 (p, 3 JH1−OH1 = 3JH1−H2 = 4JH1−F3 = 4JH1−H5 = 3.7 Hz, 1H, H-1), 4.77 (ddtd, 2 JH3−F3 = 54.9 Hz, 3JH3−F4 = 17.0 Hz, 3JH3−H4 = 8.7 Hz, 4JH3−H5 = 0.5 Hz, 1H, H-3), 4.70 (ddd, J = 10.7, 3.8, 2.0 Hz, 1H, H-1β), 4.74−4.54 (m, 2H, H-6), 4.55 (dddd, 2JH4−F4 = 52.0 Hz, 3JH4−F3 = 14.8 Hz, 3JH4−H5 = 10.1 Hz, 2JH4−H3 = 8.2 Hz, 1H, H-4), 4.40 (d, 3JOH2−H2 = 8.2 Hz, 1H, OH-2), 4.17 (dddddt, 3JH5−F6 = 27.1 Hz, 3JH5−H4 = 10.0 Hz, 3JH5−F4 = 4.4 Hz, 4JH5−H1 = 3.5 Hz, 3JH5−H6 = 1.9 Hz, 3JH5−H6 = 4JH5−H3 = 0.8 Hz, 1H, H-5), 3.69 (ddddt, 3JH2−F3 = 12.4 Hz, 3JH2−H3 = 9.1 Hz, 3JH2−OH2 = 8.5 Hz, 3JH2−H1 = 3.8 Hz, 4JH2−OH1 = 4JH2−F4 = 0.7 Hz, 1H, H-2); 13 C{1H} NMR (126 MHz, acetone-d6) δ: 97.5 (dd, 3JC1−F3 = 11.8 Hz, 4 JC1−F4 = 1.7 Hz, 1C, C-1β), 94.1 (dd, 1JC3−F3 = 182.9 Hz, 2JC3−F4 = 17.4 Hz, 1C, C-3), 93.7 (dd, 3JC1−F3 = 10.5 Hz, 4JC1−F4 = 1.5 Hz, 1C, C-1), 87.6 (ddd, 1JC4−F4 = 183.7 Hz, 2JC4−F3 = 18.3 Hz, 3JC4−F6 = 8.1 Hz, 1C, C-4), 82.2 (dd, 1JC6−F6 = 172.5 Hz, 3JC6−F4 = 1.3 Hz, 1C, C-6), 71.5 (dd, 2 JC2−F3 = 16.7 Hz, 3JC2−F4 = 7.1 Hz, 1C, C-2), 68.1 (ddd, 2JC5−F6 = 23.2 Hz, 2JC5−F4 = 18.4 Hz, 3JC5−F3 = 7.2 Hz, 1C, C-5); 19F NMR (470 MHz, acetone-d6) δ: −195.4 (dq, J = 52.9, 14.8, 14.4 Hz, 1F, F-3β), −199.1

(dddddd, 2JF4−H4 = 51.9 Hz, 3JF4−H3 = 16.4 Hz, 3JF4−F3 = 14.0 Hz, 3JF4−H5 = 3.9 Hz, 4JF4−H6 = 3.4 Hz, 4JF4−H2 = 0.6 Hz, 1F, F-4α), −200.96 (dqd, 2 JF3−H3 = 54.7 Hz, 3JF3−F4 = 3JF3−H4 = 3JF4−H2 = 13.9 Hz, 4JF3−H1 = 3.3 Hz, 1F, F-3α), −201.01 (dt, J = 51.1, 17.1, 14.8 Hz, 1F, F-4β), −235.5 (td, J = 47.7, 47.1, 24.5 Hz, 1F, F-6β), −236.1 (td, 2JF6−H6a = 2JF6−H6b = 47.6 Hz, 3JF4−H5 = 24.2 Hz, 1F, F-6α); HRMS calcd for C6H8F3O3 [M − H]− 185.0431, found 185.0438. 1,6-Anhydro-4-O-benzyl-2-deoxy-2-fluoro-β-D-glucopyranose (30). To a stirred solution of known compound 2937 (1.1 g, 4.75 mmol) in ethylene glycol (10 mL, 0.46 M) were added KHF2 (2.2 g, 28.5 mmol, 6 equiv) and KF (1.66 g, 28.5 mmol, 6 equiv). The mixture was heated at 180 °C for 4 h. After cooling to rt, the reaction mixture was quenched with an aqueous 5% K2CO3 solution (75 mL) and stirred for 5 min. The mixture was then extracted with CHCl3 (5 × 75 mL), and the combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude oil was purified by flash column chromatography (silica gel, acetone/CHCl3, 1:19−1:9) to give 30 as a pale-yellow amorphous solid (1.00 g, 3.93 mmol, 83% yield). The spectroscopic data derived from compound 30 match those reported in the literature.13 1,6-Anhydro-4-O-benzyl-2,3-dideoxy-2,3-difluoro-β-D-glucopyranose (15). To an ice-cold stirred solution of 30 (574 mg, 2.258 mmol) in CH2Cl2 (20 mL) were added pyridine (0.55 mL, 6.773 mmol, 3 equiv) and a 1 M solution of trifluoromethanesulfonic anhydride in CH2Cl2 (3.39 mL, 3.386 mmol, 1.5 equiv). The mixture was stirred for 5 min at 0 °C, and the reaction mixture was allowed to warm at room temperature for 25 min. The reaction mixture was quenched with water (15 mL). The mixture was extracted with CH2Cl2 (3 × 15 mL), and the combined organic phases were successively washed with a saturated aqueous NaHCO3 solution (30 mL) and aqueous 1 M HCl solution (30 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude triflate 31 was used for the next step without further purification. To the crude 31 were added triethylamine trihydrofluoride (5.52 mL, 33.86 mmol, 15 equiv) and triethylamine (16.5 mL, 3 times Et3N·3HF). The mixture was heated at 80 °C for 24 h and then cooled to room temperature. The reaction mixture was quenched with water (15 mL). The mixture was extracted with CH2Cl2 (3 × 15 mL), and the combined organic phases were successively washed with a saturated aqueous NaHCO3 solution (20 mL) and an aqueous 1 M HCl solution (20 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel, Et2O/CH2Cl2, 1:19) to give 15 as a pale-yellow oil (550 mg, 2.149 mmol, 95% yield). The spectroscopic data derived from compound 15 match those reported in the literature.13 2,3,4-Trideoxy-2,3,4-trifluoro-α/β-D-glucopyranose (8). To a stirred solution of 3620 (12.1 mg, 0.04478 mmol) in water (0.450 mL) at room temperature was added an aqueous hydrochloric acid solution (37%) (1 mL). The mixture was stirred at room temperature for 1 h and then evaporated with a gentle air flow. The obtained yellow crude was purified by flash column chromatography (silica gel, EtOAc/hexanes, 4:1) to give pure product 8 (α/β, 5:1) as a colorless thick oil (8.3 mg, 0.04478 mmol, 100% yield). The spectroscopic data derived from compound 8 match those reported in the literature.19 1,6-Di-O-acetyl-4-O-benzyl-2,3-dideoxy-2,3-difluoro-α/β-Dglucopyranose (37). To a stirred solution of 15 (281 mg, 1.098 mmol) in acetic anhydride (6 mL) at 0 °C were added two drops of triethylsilyl trifluoromethanesulfonate (≈20−30 μL, cat) under an argon atmosphere. The mixture was allowed to cool down to room temperature, and after 1 h, a saturated aqueous NaHCO3 solution (30 mL) was added to the mixture. After 30 min of stirring, the reaction mixture was extracted with EtOAc (3 × 25 mL). The combined organic phases were washed with a saturated aqueous NaHCO3 solution (2 × 25 mL) and brine (25 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude oil was purified by flash column chromatography (silica gel, EtOAc/hexanes, 1:9−1:1) to give 37 as an anomeric mixture (α/β 17:1) as a colorless oil (361 mg, 1.009 mmol, 92% yield); Rf = 0.40 (silica, EtOAc/hexanes, 2:3); [α]D25 = 108.4 (c 0.4, CHCl3); IR (ATR, diamond) ν 3034, 1740, 1371, 1215, 1066, 933, 750 cm−1; only the α anomer has been 8518

DOI: 10.1021/acs.joc.9b00795 J. Org. Chem. 2019, 84, 8509−8522

Article

The Journal of Organic Chemistry attributed in 1H NMR and 13C NMR; 1H NMR (500 MHz, chloroform-d) δ: 7.40−7.30 (m, 5H, Ar), 6.37 (t, 3JH1−H2 = 3JH1−F2 = 3.5 Hz, 1H, H-1), 5.04 (ddt, 2JH3−F3 = 54.2 Hz, 3JH3−F2 = 13.9 Hz, 3 JH3−H2 = 3JH3−H4 = 8.7 Hz, 1H, H-3), 5.69 (dd, 3JH1−H2 = 8.1 Hz, 3JH1−F2 = 3.0 Hz, 1H, H-1β), 4.89 (dd, 2JCH2aPh−CH2bPh = 11.0 Hz, 4JCH2aPh−F3 = 1.2 Hz, 1H, CH2aPh), 4.67 (dddd, 2JH2−F2 = 49.6 Hz, 3JH2−F3 = 13.4 Hz, 3 JH2−H3 = 9.0 Hz, 3JH2−H1 = 4.1 Hz, 1H, H-2), 4.62 (d, 2JCH2bPh−CH2aPh = 11.0 Hz, 1H, CH2bPh), 4.28 (dd, 2JH6a−H6b = 12.2 Hz, 3JH6a−H5 = 3.7 Hz, 1H, H-6a), 4.24 (dt, 2JH6b−H6a = 12.4 Hz, 3JH6b−H5 = 2.0 Hz, 4JH6b−H4 = 1.5 Hz, 1H, H-6b), 3.91 (dtt, 3JH5−H4 = 10.1 Hz, 3JH5−H6a = 4JH5−F3 = 3.1 Hz, 3JH5−H6b = 4JH5−H3 = 0.7 Hz, 1H, H-5), 3.70 (ddd, 3JH4−F3 = 13.8 Hz, 3 JH4−H5 = 10.2 Hz, 4JH4−H3 = 8.5 Hz, 1H, H-4), 2.15, 2.00 (6H, 2 × COCH3); 13C{1H} NMR (126 MHz, chloroform-d) δ: 170.6, 168.8 (2C, 2 × COCH3), 136.9, 128.8, 128.7, 128.5 (6C, Ar), 94.0 (dd, 1 JC3−F3 = 185.9 Hz, 2JC3−F2 = 18.1 Hz, 1C, C-3), 88.7 (dd, 2JC1−F2 = 22.4 Hz, 3JC1−F3 = 10 Hz, 1C, C-1), 86.8 (dd, 1JC2−F2 = 194.6 Hz, 2JC2−F3 = 18.6 Hz, 1C, C-2), 74.7 (d, 4JCH2Ph−F3 = 3.2 Hz, 1C, CH2Ph), 74.0 (dd, 2 JC4−F3 = 17.2 Hz, 3JC4−F2 = 7.0 Hz, 1C, C-4), 70.2 (dd, 3JC5−F3 = 8.5 Hz, 4 JC5−F2 = 1.4 Hz, 1C, C-5), 62.1 (s, 1C, C-6), 20.75, 20.81 (2C, 2 × COCH3); 19F NMR (470 MHz, chloroform-d) δ: −190.9 (dq, J = 52.1, 13.0 Hz, 1F, F-3β), −195.4 (dqd, 2JF3−H3 = 54.4 Hz, 3JF3−H2 = 3JF3−H4 = 3 JF3−F2 = 13.6 Hz, 4JF3−H5 = 3.5 Hz, 1F, F-3α), −201.0 (dddd, 51.3, 16.0, 13.5, 3.0 Hz, 1F, F-2β), −203.0 (ddd, 2JF2−H2 = 49.5 Hz, 3JF2−H3 = 14.1 Hz, 3JF2−F3 = 12.5 Hz, 1F, F-2α); HRMS calcd for C17H24F2NO6 [M + NH4]+ 376.1566, found 376.1565. 6-Acetyl-1-O-allyl-4-O-benzyl-2,3-dideoxy-2,3-difluoro-α/βD-glucopyranose (38). To a stirred solution of 37 (48 mg, 0.1334 mmol) in dry acetonitrile (9.1 mL) were added allyloxytrimethylsilane (0.224 mL, 1.334 mmol, 10 equiv) and trimethylsilyl trifluoromethanesulfonate (0.724 mL, 0.4002 mmol, 3 equiv) under an argon atmosphere. The mixture was heated in a microwave reactor at 90 °C for 45 min. After cooling, the reaction mixture was quenched with water (15 mL). The mixture was extracted with CH2Cl2 (3 × 15 mL). The combined organic phases were successively washed with a saturated aqueous NaHCO3 solution (15 mL) and an aqueous 1 M HCl solution (15 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography (silica gel, EtOAc/hexanes, 0:100− 1:1) to give 38 as an anomeric mixture (α/β 1:1.7) as a white amorphous solid (21.1 mg, 0.0592 mmol, 44% yield); Rf = 0.60 (silica, EtOAc/hexanes, 2:3); [α]D25 = 68.2 (c 0.5, CHCl3); IR (ATR, diamond) ν 2930, 1732, 1367, 1240, 1024, 955, 750 cm−1; 1H NMR (500 MHz, chloroform-d) δ: 7.4 −7.28 (m, 10H, Ar-α/β), 5.92 (dddd, J = 17.2, 10.4, 6.3, 5.2 Hz, 1H, OAll-β), 5.89 (dddd, J = 17.3, 10.4, 6.1, 5.3 Hz, 1H, OAll-α), 5.33 (dq, J = 17.2, 1.6 Hz, 1H, OAll-β), 5.32 (dq, J = 17.2, 1.6 Hz, 1H, OAll-α), 5.24 (dq, J = 10.4, 1.3 Hz, 1H, OAll-β), 5.23 (dq, J = 10.4, 1.3 Hz, 1H, OAll-α), 5.08 (t, 3JH1−H2 = 3JH1−F2 = 3.6 Hz, 1H, H-1α), 5.07 (ddt, 2JH3−F3 = 54.8 Hz, 3JH3−F2 = 13.9 Hz, 3JH3−H2 = 9.0 Hz, 3JH3−H4 = 8.3 Hz, 1H, H-3α), 4.88 (d, 2JCH2aPh−CH2bPh = 10.9 Hz, 1H, CH2aPh-α), 4.86 (d, 2JCH2aPh−CH2bPh = 11.0 Hz, 1H, CH2aPh-β), 4.77 (ddt, 2JH3−F3 = 52.8 Hz, 3JH3−F2 = 16.7 Hz, 3JH3−H2 = 3JH3−H4 = 8.4 Hz, 1H, H-3β), 4.60 (d, 2JCH2bPh−CH2aPh = 11.2 Hz, 1H, CH2bPh-α), 4.60 (d, 2 JCH2bPh−CH2aPh = 11.0 Hz, 1H, CH2bPh-β), 4.53 (dddd, 2JH2−F2 = 50.1 Hz, 3JH2−F3 = 13.5 Hz, 3JH2−H3 = 8.9 Hz, 3JH2−H1 = 4.0 Hz, 1H, H-2α), 4.52 (ddd, 3JH1−H2 = 7.8 Hz, 3JH1−F2 = 2.8 Hz, 4JH1−F3 = 0.3 Hz, 1H, H1β), 4.39 (dddd, 2JH2−F2 = 51.4 Hz, 3JH2−F3 = 15.3 Hz, 3JH2−H3 = 8.4 Hz, 3 JH2−H1 = 7.7 Hz, 1H, H-2β), 4.37 (ddt, J = 12.8, 5.4, 1.6 Hz, 1H, OAllβ), 4.33−4.20 (m, 4H, H-6α/β), 4.19 (ddt, J = 12.9, 5.2, 1.3 Hz, 1H, OAll-α), 4.15 (ddt, J = 12.9, 6.3, 1.4 Hz, 1H, OAll-β), 4.05 (ddt, J = 13.0, 6.1, 1.4 Hz, 1H, OAll-α), 3.89 (dtt, 3JH5−H4 = 10.1 Hz, 3JH5−H6a = 4 JH5−F3 = 3.5 Hz, 3JH5−H6b = 4JH5−H1 = 0.8 Hz, 1H, H-5β), 3.67 (ddd, 3 JH4−F3 = 13.4 Hz, 3JH4−H5 = 9.9 Hz, 3JH4−H3 = 8.4 Hz, 1H, H-4β), 3.63 (ddd, 3JH4−F3 = 13.4 Hz, 3JH4−H5 = 10.0 Hz, 3JH4−H3 = 8.4 Hz, 1H, H4α), 3.50 (dddd, 3JH5−H4 = 9.9 Hz, 3JH5−H6a = 4.8 Hz, 4JH5−F3 = 2.3 Hz, 3 JH5−H6b = 1.3 Hz, 1H, H-5β); 13C{1H} NMR (126 MHz, chloroformd) δ: 170.74 (1C, COCH3-β), 170.73 (1C, COCH3-α), 137.2, 128.70, 128.5, 128.40 (6C, Ar-β), 137.1, 128.68, 128.6, 128.3 (6C, Ar-α), 133.2

(1C, OAll-β), 133.0 (1C, OAll-α), 118.5 (2C, OAll-α/β), 98.7 (dd, 2 JC1−F2JC1−F2 = 22.8 Hz, 3JC1−F3 = 11.4 Hz, 1C, C-1β), 96.3 (dd, 1JC3−F3 = 186.7 Hz, 2JC3−F2 = 18.5 Hz, 1C, C-3β), 95.3 (dd, 2JC1−F2 = 20.4 Hz, 3 JC1−F3 = 10.2 Hz, 1C, C-1α), 94.3 (dd, 1JC3−F3 = 184.3 Hz, 2JC3−F2 = 18.2 Hz, 1C, C-3α), 90.1 (dd, 1JC2−F2 = 190.3 Hz, 2JC2−F3 = 19.1 Hz, 1C, C-2β), 87.8 (dd, 1JC2−F2 = 194.4 Hz, 2JC2−F3 = 17.9 Hz, 1C, C-2α), 74.9 (dd, 2JC4−F3 = 17.2 Hz, 3JC4−F2 = 6.9 Hz, 1C, C-4β), 74.8 (dd, 2JC4−F3 = 17.0 Hz, 3JC4−F2 = 6.6 Hz, 1C, C-4α), 74.45 (s, 1C, CH2Ph-β), 74.43 (s, 1C, CH2Ph-α), 71.8 (dd, 3JC5−F3 = 9.9 Hz, 4JC5−F2 = 0.9 Hz, 1C, C-5β), 70.6 (s, 1C, OAll-β), 69.0 (s, 1C, OAll-α), 68.1 (dd, 3JC5−F3 = 8.6 Hz, 4 JC5−F2 = 0.9 Hz, 1C, C-5α), 62.54 (s, 1C, C-6β), 62.50 (s, 1C, C-6α), 20.95 (s, 1C, COCH3-β), 20.93 (s, 1C, COCH3-α); 19F NMR (470 MHz, chloroform-d) δ: −190.7 (dq, 2JF3−H3 = 53.0 Hz, 3JF3−F2 = 3JF3−H4 = 3JF3−H2 = 13.7 Hz, 1F, F-3β), −195.3 (dqd, 2JF3−H3 = 54.7 Hz, 3JF3−F2 = 3JF3−H4 = 3JF3−H2 = 13.4 Hz, 4JF3−H5 = 3.2 Hz, 1F, F-3α), −199.6 (dddd, 2JF2−H2 = 51.2 Hz, 3JF2−H3 = 16.2 Hz, 3JF2−F3 = 13.3 Hz, 3JF2−H1 = 2.8 Hz, 1F, F-2β), −202.3 (dt, 2JF2−H2 = 50.1 Hz, 3JF2−H3 = 3JF2−F3 = 13.1 Hz, 1F, F-2α); HRMS calcd for C18H26F2NO5 [M + NH4]+ 374.1774, found 374.1773. 1-O-Allyl-4-O-benzyl-2,3,6-trideoxy-2,3,6-trifluoro-α-D-glucopyranose (39α) and 1-O-Allyl-4-O-benzyl-2,3,6-trideoxy2,3,6-trifluoro-β-D-glucopyranose (39β). To a solution of 38 (81 mg, 0.2280 mmol) in CH2Cl2/MeOH (2.2 mL, 4:1) was added dropwise a methanolic 1 M NaOMe solution, until pH was ≈9. The mixture was stirred at room temperature for 1 h and then neutralized to pH ≈ 7 with an acidic resin. The mixture was filtered and concentrated under reduced pressure to afford the deacetylated 38 as a colorless oil (70.8 mg, 0.2257 mmol, 99% yield). To a solution of the deacetylated compound (71 mg, 0.226 mmol) in CH2Cl2 (3.75 mL) were added 2,4,6-collidine (0.180 mL, 1.351 mmol, 6 equiv) and diethylaminosulfur trifluoride (0.089 mL, 0.676 mmol, 3 equiv). The mixture was heated in a microwave reactor at 100 °C for 1 h. After cooling, the reaction mixture was quenched with water (15 mL). The mixture was extracted with CH2Cl2 (3 × 15 mL). The combined organic phases were successively washed with a saturated aqueous NaHCO3 solution (15 mL) and an aqueous 1 M HCl solution (15 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography (silica gel, EtOAc/hexanes, 0:100−3:7) to give 39 as two pure anomers (α/β 1:1.7) as a thick yellow oil for the α and a white solid for the β (60.7 mg, 0.1912 mmol, 85% yield). 39α: Rf = 0.63 (silica, EtOAc/hexanes, 2:3); IR (ATR, diamond) ν 2932, 1450, 1366, 1111, 1018, 941, 741 cm−1; 1H NMR (500 MHz, chloroform-d) δ: 7.40−7.30 (5H, Ar) 5.89 (dddd, J = 17.2, 10.4, 6.0, 5.2 Hz, 1H, OAll), 5.33 (dq, J = 17.2, 1.6 Hz, 1H, OAll), 5.23 (dq, J = 10.4, 1.3 Hz, 1H, OAll), 5.11 (t, 3JH1−H2 = 3JH1−F2 = 3.6 Hz, 1H, H-1), 5.07 (ddddd, 2 JH3−F3 = 54.7 Hz, 3JH3−F2 = 13.6 Hz, 3JH3−H2 = 9.0 Hz, 3JH3−H4 = 8.2 Hz, 4 JH3−H5 = 0.8 Hz, 1H, H-3), 4.91 (dd, 2JCH2aPh−CH2bPh = 11.0 Hz, 4 JCH2aPh−F3 = 1.2 Hz, 1H, CH2aPh), 4.65 (ddd, 2JH6a−F6 = 46.9 Hz, 2 JH6a−H6b = 10.7 Hz, 3JH6a−H5 = 3.0 Hz, 1H, H-6a), 4.64 (d, 2 JCH2bPh−CH2aPh = 11.1 Hz, 1H, CH2bPh), 4.58 (ddt, 2JH6b−F6 = 48.2 Hz, 2JH6b−H6a = 10.3 Hz, 3JH6b−H5 = 1.8 Hz, 1H, H-6b), 4.54 (dddd, 2 JH2−F2 = 50.1 Hz, 3JH2−F3 = 13.2 Hz, 3JH2−H3 = 8.9 Hz, 3JH2−H1 = 4.2 Hz, 1H, H-2), 4.20 (dddd, J = 13.0, 5.2, 1.7, 1.4 Hz, 1H, OAll), 4.06 (ddt, J = 13.0, 6.0, 1.4 Hz, 1H, OAll), 3.82 (ddddd, 3JH5−F6 = 28.1 Hz, 3JH5−H4 = 10.1 Hz, 3JH5−H6a = 2.9 Hz, 3JH5−H6b 1.5 Hz, 4JH5−H3 = 0.9 Hz, 1H, H-5), 3.74 (ddd, 3JH4−F3 = 13.9 Hz, 3JH4−H5 = 10.1 Hz, 3JH4−H3 = 8.3 Hz, 1H, H-4); 13C{1H} NMR (126 MHz, chloroform-d) δ: 137.4, 128.7, 128.33, 128.31 (6C, Ar), 132.9 (1C, OAll), 118.4 (1C, OAll), 95.5 (dd, 2 JC1−F2 = 20.6 Hz, 2JC1−F3 = 10.1 Hz, 1C, C-1), 94.0 (dd, 1JC3−F3 = 184.5 Hz, 2JC3−F2 = 18.4JC3−F6 = 1.1 Hz, 1C, C-3), 87.8 (dd, 1JC2−F2 = 194.2 Hz, 2JC2−F3 = 17.7 Hz, 1C, C-2), 81.4 (d, 1JC6−F6 = 174.0 Hz, 1C, C-6), 74.9 (d, 4JCH2Ph−F3 = 2.8 Hz, 1C, CH2Ph), 74.6 (dt, 2JC4−F3 = 17.2 Hz, 3 JC4−F2 = 3JC4−F6 = 6.8 Hz, 1C, C-4), 69.3 (ddd, 2JC5−F6 = 18.2 Hz, 3 JC5−F3 = 8.6 Hz, 4JC5−F2 = 1.1 Hz, 1C, C-5), 69.0 (1C, OAll); 19F NMR (470 MHz, chloroform-d) δ: −195.9 (dq, 2JF3−H3 = 54.8 Hz, 3JF3−H2 = 3 JF3−H4 = 3JF3−F2 = 13.1 Hz, 1F, F-3), −202.4 (dt, 2JF2−H2 = 50.4 Hz, 3 JF2−H3 = 3JF2−F3 = 13.2 Hz), −234.9 (td, 2JF6−H6a = 2JF6−H6b = 47.6 Hz, 8519

DOI: 10.1021/acs.joc.9b00795 J. Org. Chem. 2019, 84, 8509−8522

Article

The Journal of Organic Chemistry

1α), 89.3 (dd, 1JC2−F2 = 188.7 Hz, 2JC2−F3 = 15.2 Hz, 1C, C-2α), 82.69 (dt, 1JC6−F6 = 171.5 Hz, 4JC6−F3 = 5JC6−F2 = 1.4 Hz, 1C, C-6β), 82.65 (dt, 1 JC6−F6 = 171.7 Hz, 4JC6−F3 = 2.0 Hz, 5JC6−F2 = 0.6 Hz, 1C, C-6β), 74.5 (ddd, 2JC5−F6 = 18.3 Hz, 3JC5−F3 = 9.0 Hz, 4JC5−F2 = 1.1 Hz, 1C, C-5β), 70.7 (ddd, 2JC5−F6 = 18.0 Hz, 3JC5−F3 = 8.0 Hz, 4JC5−F2 = 1.5 Hz, 1C, C5α), 68.4 (dt, 2JC4−F3 = 18.6 Hz, 3JC4−F2 = 3JC4−F6 = 7.7 Hz, 1C, C-4β), 68.3 (dt, 2JC4−F3 = 18.4 Hz, 3JC4−F2 = 7.9 Hz, 3JC4−F6 = 6.6 Hz, 1C, C4α); 19F NMR (470 MHz, acetone-d6) δ: −195.8 (dq, 2JF3−H3 = 53.3 Hz, 3JF3−H2 = 3JF3−H4 = 3JF3−F2 = 14.2 Hz, 1F, F-3β), −199.8 (dddd, 2 JF2−H2 = 51.9 Hz, 3JF2−H3 = 16.5 Hz, 3JF2−F3 = 13.1 Hz, 3JF2−H1 = 2.7 Hz, 1F, F-2β), −201.1 (dt, 2JF2−H2 = 50.8 Hz, 3JF2−H3 = 3JF2−F3 = 13.6 Hz, 1F, F-2α), −201.4 (dqd, 2JF3−H3 = 55.4 Hz, 3JF3−H2 = 3JF3−H4 = 3JF3−F2 = 13.7 Hz, 4JF3−H5 = 1.7 Hz, 1F, F-3α), −235.1 (td, 2JF6−H6a = 2JF6−H6b = 47.6 Hz, 3JF6−H5 = 24.9 Hz, 1F, F-6β), −235.7 (td, 2JF6−H6a = 2JF6−H6b = 48.0 Hz, 3JF6−H5 = 27.8 Hz, 1F, F-6α); HRMS calcd for C6H8F3O3 [M − H]− 185.0431, found 185.0432. log P Determination Protocol.

3

JF6−H5 = 28.1 Hz, 1F, F-6); HRMS calcd for C16H23F3NO3 [M + NH4]+ 334.1625, found 334.1628; 39β: Rf = 0.61 (silica, EtOAc/ hexanes, 2:3); [α]D25 = 3.5 (c 0.2, CHCl3); IR (ATR, diamond) ν 2932, 1450, 1366, 1111, 1018, 941, 741 cm−1; 1H NMR (500 MHz, chloroform-d) δ: 7.40−7.30 (5H, Ar) 5.93 (dddd, J = 17.2, 10.4, 6.0, 5.2 Hz, 1H, OAll), 5.35 (dq, J = 17.2, 1.6 Hz, 1H, OAll), 5.25 (dq, J = 10.4, 1.3 Hz, 1H, OAll), 4.89 (dd, 2JCH2aPh−CH2bPh = 11.0 Hz, f4JCH2aPh−F3 = 1.2 Hz, 1H, CH2aPh), 4.78 (ddtd, 2JH3−F3 = 52.8 Hz, 3JH3−F2 = 16.8 Hz, 3 JH3−H2 = 3JH3−H4 = 8.4 Hz, 4JH3−H5 = 0.8 Hz, 1H, H-3), 4.64 (ddt, 2 JH6a−F6 = 47.6 Hz, 2JH6a−H6b = 10.3 Hz, 3JH6a−H5 = 1.6 Hz, 1H, H-6a), 4.63 (d, 2JCH2bPh−CH2aPh = 11.1 Hz, 1H, CH2bPh), 4.60 (ddd, 2JH6b−F6 = 47.1 Hz, 2JH6b−H6a = 10.2 Hz, 3JH6b−H5 = 3.8 Hz, 1H, H-6b), 4.55 (dd, 3 JH1−H2 = 7.8 Hz, 3JH1−F2 = 2.8 Hz, 1H, H-1), 4.41 (dddd, 2JH2−F2 = 51.2 Hz, 3JH2−F3 = 15.2 Hz, 3JH2−H3 = 8.3 Hz, 3JH2−H1 = 7.7 Hz, 1H, H-2), 4.40 (ddt, J = 12.9, 5.1, 1.4 Hz, 1H, OAll), 4.17 (ddt, J = 12.9, 6.3, 1.3 Hz, 1H, OAll), 3.74 (ddd, 3JH4−F3 = 13.3 Hz, 3JH4−H5 = 10.0 Hz, 3JH4−H3 = 8.5 Hz, 1H, H-4), 3.46 (dddt, 3JH5−F6 = 25.5 Hz, 3JH5−H4 = 10.0 Hz, 3 JH5−H6b = 3.8 Hz, 3JH5−H6a = 4JH5−F3 = 1.6 Hz, 1H, H-5); 13C{1H} NMR (126 MHz, chloroform-d) δ: 137.2, 128.7, 128.39, 128.35 (6C, Ar), 133.2 (1C, OAll), 118.4 (1C, OAll), 98.7 (dd, 2JC1−F2 = 22.9 Hz, 2JC1−F3 = 11.4 Hz, 1C, C-1), 96.0 (dd, 1JC3−F3 = 187.0 Hz, 2JC3−F2 = 18.4JC3−F6 = 1.1 Hz, 1C, C-3), 90.0 (dd, 1JC2−F2 = 190.1 Hz, 2JC2−F3 = 18.9 Hz, 1C, C2), 81.3 (dd, 1JC6−F6 = 174.3 Hz, 4JC6−F3 = 1.3 Hz, 1C, C-6), 74.8 (d, 4 JCH2Ph−F3 = 2.8 Hz, 1C, CH2Ph), 74.5 (dt, 2JC4−F3 = 17.5 Hz, 3JC4−F2 = 3 JC4−F6 = 7.1 Hz, 1C, C-4), 72.9 (ddd, 2JC5−F6 = 18.8 Hz, 3JC5−F3 = 9.7 Hz, 4JC5−F2 = 1.2 Hz, 1C, C-5), 70.5 (1C, OAll); 19F NMR (470 MHz, chloroform-d) δ: −191.1 (dqd, 2JF3−H3 = 52.7 Hz, 3JF3−H2 = 3JF3−H4 = 3 JF3−F2 = 13.8 Hz, 4JF3−H5 = 1.5 Hz, 1F, F-3), −199.7 (dddd, 2JF2−H2 = 51.2 Hz, 3JF2−H3 = 16.1 Hz, 3JF2−F3 = 13.1 Hz, 3JF2−H1 = 2.9 Hz, 1F, F-2), −233.9 (td, 2JF6−H6a = 2JF6−H6b = 47.4 Hz, 3JF6−H5 = 25.6 Hz, 1F, F-6); HRMS calcd for C16H23F3NO3 [M + NH4]+ 334.1625, found 334.1628. 2,3,6-Trideoxy-2,3,6-trifluoro-α/β-D-glucopyranose (11). To a stirred solution of 39 (25 mg, 0.0787 mmol) in water/acetone (0.8 mL, 1:1) was added an aqueous hydrochloric acid solution (37%) (1.6 mL), and the mixture was heated at 70 °C overnight. After cooling, the reaction mixture was dried over an air stream. The dried crude was dissolved in acetone, silica gel was added, and the mixture was concentrated under reduce pressure. The resulting dry-pack was purified by flash column chromatography (silica gel, MeOH/CH2Cl2, 0:100−3:7). After column chromatography, the product was dissolved in acetone/MeOH (1:1) and stirred with activated coal for 30 min. The mixture was filtered through celite and concentrated under reduced pressure to give 11 as an anomeric mixture (α/β, 3:2) as a thick yellow oil (9.6 mg, 0.0516 mmol, 66% yield); Rf = 0.26 (silica, MeOH/ CH2Cl2, 1:19); [α]D25 = 54.3 (c 0.1, MeOH); IR (ATR, diamond) ν 3348, 2962, 1636, 1366, 1057, 995, 771 cm−1; 1H NMR (500 MHz, acetone-d6) δ: 6.45 (br s, 1H, OH-1β), 6.26 (br s, 1H, OH-1α), 5.42 (t, 3 JH1−H2 = 3JH1−F2 = 3.8 Hz, 1H, H-1α), 5.23 (br s, 1H, OH-4β), 5.16 (br d, 3JOH−H4 = 5.7 Hz, 1H, OH-4α), 4.91 (br dd, 3JH1−H2 = 7.6 Hz, 3JH1−F2 = 2.7 Hz, 1H, H-1β), 4.77 (ddddd, 2JH3−F3 = 55.1 Hz, 3JH3−F2 = 13.5 Hz, 3 JH3−H4 = 9.1 Hz, 3JH3−H2 = 8.5 Hz, 4JH3−H5 = 0.8 Hz, 1H, H-3α), 4.67 (ddd, 2JH6a−F6 = 47.5 Hz, 2JH6a−H6b = 10.3 Hz, 3JH6a−H5 = 4.0 Hz, 1H, H6aα), 4.66 (ddt, 2JH6b−F6 = 48.0 Hz, 2JH6b−H6a = 10.3 Hz, 3JH6b−H5 = 1.6 Hz, 1H, H-6bβ), 4.62 (ddd, 2JH6a−F6 = 47.6 Hz, 2JH6a−H6b = 10.0 Hz, 3 JH6a−H6b = 4.4 Hz, 1H, H-6aβ), 4.70−4.54 (m, 1H, H-3β), 4.59 (ddt, 2 JH6b−F6 = 47.9 Hz, 2JH6b−H6a = 10.3 Hz, 3JH6b−H5 = 1.8 Hz, 1H, H-6bα), 4.51 (dddd, 2JH2−F2 = 50.9 Hz, 3JH2−F3 = 13.0 Hz, 3JH2−H3 = 9.0 Hz, 3 JH2−H1 = 3.9 Hz, 1H, H-2α), 4.21 (dddd, 2JH2−F2 = 52.0 Hz, 3JH2−F3 = 14.5 Hz, 3JH2−H3 = 8.6 Hz, 3JH2−H1 = 7.7 Hz, 1H, H-2β), 3.98 (dddddd, 3 JH5−F6 = 27.5 Hz, 3JH5−H4 = 10.2 Hz, 3JH5−H6a = 4.0 Hz, 3JH5−H6b = 1.7 Hz, 4JH5−F3 = 1.0 Hz, 4JH5−H3 = 0.7 Hz, 1H, H-5α), 3.77−3.67 (m, 2H, H-4α/β), 3.62 (ddddd, 3JH5−F6 = 25.0 Hz, 3JH5−H4 = 10.1 Hz, 3JH5−H6a = 4.4 Hz, 3JH5−H6b = 1.8 Hz, 4JH5−F3 = 1.1 Hz, 1H, H-5β); 13C{1H} NMR (126 MHz, acetone-d6) δ: 96.1 (ddd, 1JC3−F3 = 183.5 Hz, 2JC3−F2 = 17.7 Hz, 4JC3−F6 = 1.0 Hz, 1C, C-3β), 94.7 (dd, 2JC1−F2 = 22.6 Hz, 3JC1−F3 = 11.2 Hz, 1C, C-1β), 94.2 (ddd, 1JC3−F3 = 181.4 Hz, 2JC3−F2 = 17.2 Hz, 4 JC3−F6 = 1.0 Hz, 1C, C-3α), 92.4 (dd, 1JC2−F2 = 186.8 Hz, 2JC2−F3 = 17.5 Hz, 1C, C-2β), 91.2 (dd, 2JC1−F2 = 21.1 Hz, 3JC1−F3 = 10.2 Hz, 1C, C-

(1) To a 10 mL vial containing a stir bar in octanol (2 mL) and water (2 mL) were added trifluoroglucose analogue (5 mg) and 2,2,2trifluoroethanol (10 μL). The mixture was stirred at high speed for 2 h at rt and then left to stand for 24 h. (2) A total of 250 μL of air was filled in a 1 mL disposable syringe. The needle of the syringe was inserted in the octanol phase while releasing a slow and constant air stream without disturbing the biphasic mixture. A total of 500 μL of the octanol phase was taken, and while taking out the needle from the phase, 100 μL was slowly ejected. The needle was then carefully wiped with a dry clean tissue, and one drop of the phase was wasted and the needle was wiped again. A total of 400 μL of the octanol phase was injected in an NMR tube together with 100 μL of acetoned6, and the tube was sealed with a propane torch. The same protocol was applied for the water sample. Briefly, 500 μL of air was filled in a syringe before inserting the needle in the biphasic mixture. A slow and constant air stream was pushed out of the syringe until reaching the water phase.44 In the water phase, all of the air in the syringe was release and 800 μL was taken. While removing the needle from the water phase and passing through the octanol phase, water was slowly and constantly ejected from the syringe (100 μL). The needle was then carefully wiped with a dry clean tissue, and one drop of the phase was wasted and the needle was wiped again. Finally, 400 μL of the phase was injected in an NMR tube together with 100 μL of acetone-d6 and the tube was sealed with a propane torch. When both NMR tubes were cooled to rt, they were shaken up for 1 min prior to the NMR analysis. (3) For the 19F NMR experiments, the spin of the apparatus was removed. For the octanol sample, a pulse delay (D1) of 30 s was set, and for the water phase, a D1 of 60 s was used. The spectral width was set from 30 to −300 ppm, and the number of scans was fixed to 128. Finally, the data was processed using MestReNova 11.0.4 with a processing template similar to that previously described.23

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b00795. 1 H, 13C, 19F, COSY, and HSQC NMR spectra of new compounds; optimization of the glycosylation; and log P determination using 19F NMR (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Denis Giguère: 0000-0003-2209-1428 8520

DOI: 10.1021/acs.joc.9b00795 J. Org. Chem. 2019, 84, 8509−8522

Article

The Journal of Organic Chemistry Notes

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and Université Laval. J.S.-G. thanks PROTEO for a postgraduate fellowship, and M.B. thanks NSERC for an Undergraduate student research award. Finally, the authors would like to thank Drs. Yoann M. Chabre and Paul A. Johnson for proofreading this article and for useful discussions.

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DOI: 10.1021/acs.joc.9b00795 J. Org. Chem. 2019, 84, 8509−8522

Article

The Journal of Organic Chemistry

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DOI: 10.1021/acs.joc.9b00795 J. Org. Chem. 2019, 84, 8509−8522