Synthesis of 2,3,4-Trideoxy-2,3,4-trifluoroglucose

Lucas Quiquempoix, Zhong Wang, Jérôme Graton, Peter G. Latchem, Mark
Light, Jean-Yves Le Questel, Bruno Linclau

► To cite this version:

Lucas Quiquempoix, Zhong Wang, Jérôme Graton, Peter G. Latchem, Mark Light, et al.. Synthesis of 2,3,4-Trideoxy-2,3,4-trifluoroglucose. Journal of Organic Chemistry, 2019, 84 (9), pp.5899-5906. 10.1021/acs.joc.9b00310 . hal-02419527

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# Synthesis of 2,3,4-Trideoxy-2,3,4-trifluoroglucose

Lucas Quiquempoix,† Zhong Wang,† Jérôme Graton,‡,∥ Peter G. Latchem,† Mark Light,† Jean-Yves Le Questel,‡,∥ and Bruno Linclau*,†,∥

†School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, United Kingdom

‡CEISAM UMR CNRS 6230, Faculté des Sciences et des Techniques, Université de Nantes 2, rue de la Houssinière-BP 92208, 44322 Nantes Cedex 3, France

### 5 Supporting Information

**ABSTRACT:** There is an increasing interest in investigating how polyfluorination of carbohydrates modifies their physical and biological properties. An example that has caught much attention is 2,3,4-trideoxy-2,3,4-trifluoroglucose. Four syntheses of this compound have been reported, which are either low yielding or long (13 or more steps). We report a 6-step synthesis of 2,3,4-trideoxy-2,3,4-trifluoroglucose starting from levoglucosan. The solution-phase structure of an intermediate, 1,6-anhydro-2,4-dideoxy-2,4-difluoroallose, features a rare example of a bifurcated F···H(O)···F hydrogen bond and is compared to its crystal structure.

<figure><img src="image_2.png" /></figure>

The synthesis of compounds containing multiple stereogenic CHF centers has become a topic of great interest. Seminal work has emanated from the O'Hagan group, first with acyclic multivinical fluorinated alkane chains,¹,² and later with cyclic examples with 1,2,3,4,5,6-hexafluorinated cyclohexane as the highlight.³⁻⁵ Next to alkane fluorination, investigations have also focused on replacing multiple heteroatoms with fluorines. A notable example is the synthesis of a polyfluorinated analogue of the natural product danicalipin A by the Carreira group, in which the organochlorine groups were replaced by organofluorines.⁶ Carbohydrate deoxyfluorination, in which alcohol groups are replaced by fluorines, is well-investigated.⁷⁻⁹ Starting from levoglucosan (1,6-anhydro-glucose), the group of Cerny already produced dideoxy-difluorinated carbohydrates in the early seventies.¹⁰,¹¹ The first systematic biological activity and anomeric reactivity studies of dideoxy-difluorinated carbohydrates were reported by Withers et al.¹²,¹³ The first syntheses of 2,3,4-trideoxy-2,3,4-trifluorinated carbohydrate derivatives (glucose and galactose) were reported by Lukacs in 1989,¹⁴ but it is again the O'Hagan group who first synthesized, using a different synthetic strategy, fully deprotected 2,3,4-trideoxy-2,3,4-trifluoroglucose **1** (Chart 1).¹⁵,¹⁶ Very recently, the Giguère group published an impressive synthetic effort achieving the synthesis of many

2,3,4-trifluorinated carbohydrates, as well as a 2,3,4,6-tetradeoxy-2,3,4,6-tetrafluorinated glycoside.¹⁷

Investigations of how such fluorination motifs modify physical and biological properties of carbohydrates are of great interest. In addition, deoxyfluorination of carbohydrates has great potential for NMR-based investigations of protein-carbohydrate interactions.¹⁸⁻²⁰ O'Hagan showed that the exchange of **1** through erythrocyte membranes was slightly slower than that of glucose¹⁵ (and much slower than the corresponding hexafluorinated analogue).²¹,²² We have shown that the lipophilicity of **1** is about 3 orders of magnitude higher than that of glucose.²³ This was confirmed by the Giguère group,¹⁷ who additionally demonstrated the influence of sugar trifluorination stereochemistry on the lipophilicity.

The synthesis of polyfluorinated substrates is a challenging undertaking, especially toward upscaling to produce sufficient quantities. Hence, improving the pioneering syntheses of key molecules has been a focus. The original synthesis of *all-cis* 1,2,3,4,5,6-hexafluorocyclohexane has been superseded by Glorius' stereoselective reduction of hexafluorobenzene.²⁴ Instead of the original de novo approaches to 2,3,4-trideoxy-2,3,4-trifluoroglucose **1**¹⁵,¹⁶ and based on the Lukacs synthesis of 1,6-di-O-acetyl-2,3,4-trideoxy-2,3,4-trifluoroglucose **6** (*Scheme* 1),¹⁴ Giguère's team achieved a scaleable synthesis of **1** (*Scheme* 1).¹⁷ In both cases, the 4-OH group of **3** was inverted after conversion to the corresponding triflate, using NaOBz (Lukacs), and by a Lattrell-Dax reaction (Giguère), to arrive at the corresponding difluorinated galactosan **4**. The subsequent deoxyfluorination reaction was achieved by DAST

<figure><img src="image_3.png" /><figcaption>**Chart 1.** 2,3,4-Trideoxy-2,3,4-trifluoroglucose **1**</figcaption></figure>

Received: January 30, 2019

Published: March 14, 2019

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# Synthesis of 2,3,4-Trideoxy-2,3,4-trifluoroglucose

Lucas Quiquempoix,† Zhong Wang,† Jérôme Graton,‡,∥ Peter G. Latchem,† Mark Light,† Jean-Yves Le Questel,‡,∥ and Bruno Linclau*,†,∥

†School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, United Kingdom

‡CEISAM UMR CNRS 6230, Faculté des Sciences et des Techniques, Université de Nantes 2, rue de la Houssinière-BP 92208, 44322 Nantes Cedex 3, France

### 5 Supporting Information

**ABSTRACT:** There is an increasing interest in investigating how polyfluorination of carbohydrates modifies their physical and biological properties. An example that has caught much attention is 2,3,4-trideoxy-2,3,4-trifluoroglucose. Four syntheses of this compound have been reported, which are either low yielding or long (13 or more steps). We report a 6-step synthesis of 2,3,4-trideoxy-2,3,4-trifluoroglucose starting from levoglucosan. The solution-phase structure of an intermediate, 1,6-anhydro-2,4-dideoxy-2,4-difluoroallose, features a rare example of a bifurcated F···H(O)···F hydrogen bond and is compared to its crystal structure.

<figure><img src="image_3.png" /></figure>

The synthesis of compounds containing multiple stereogenic CHF centers has become a topic of great interest. Seminal work has emanated from the O'Hagan group, first with acyclic multivicinal fluorinated alkane chains,¹,² and later with cyclic examples with 1,2,3,4,5,6-hexafluorinated cyclohexane as the highlight.³⁻⁵ Next to alkane fluorination, investigations have also focused on replacing multiple heteroatoms with fluorines. A notable example is the synthesis of a polyfluorinated analogue of the natural product danicalipin A by the Carreira group, in which the organochlorine groups were replaced by organofluorines.⁶ Carbohydrate deoxyfluorination, in which alcohol groups are replaced by fluorines, is well-investigated.⁷⁻⁹ Starting from levoglucosan (1,6-anhydro-glucose), the group of Cerny already produced dideoxy-difluorinated carbohydrates in the early seventies.¹⁰,¹¹ The first systematic biological activity and anomeric reactivity studies of dideoxy-difluorinated carbohydrates were reported by Withers et al.¹²,¹³ The first syntheses of 2,3,4-trideoxy-2,3,4-trifluorinated carbohydrate derivatives (glucose and galactose) were reported by Lukacs in 1989,¹⁴ but it is again the O'Hagan group who first synthesized, using a different synthetic strategy, fully deprotected 2,3,4-trideoxy-2,3,4-trifluoroglucose **1** (Chart 1).¹⁵,¹⁶ Very recently, the Giguère group published an impressive synthetic effort achieving the synthesis of many

2,3,4-trifluorinated carbohydrates, as well as a 2,3,4,6-tetradeoxy-2,3,4,6-tetrafluorinated glycoside.¹⁷

Investigations of how such fluorination motifs modify physical and biological properties of carbohydrates are of great interest. In addition, deoxyfluorination of carbohydrates has great potential for NMR-based investigations of protein-carbohydrate interactions.¹⁸⁻²⁰ O'Hagan showed that the exchange of **1** through erythrocyte membranes was slightly slower than that of glucose¹⁵ (and much slower than the corresponding hexafluorinated analogue).²¹,²² We have shown that the lipophilicity of **1** is about 3 orders of magnitude higher than that of glucose.²³ This was confirmed by the Giguère group,¹⁷ who additionally demonstrated the influence of sugar trifluorination stereochemistry on the lipophilicity.

The synthesis of polyfluorinated substrates is a challenging undertaking, especially toward upscaling to produce sufficient quantities. Hence, improving the pioneering syntheses of key molecules has been a focus. The original synthesis of *all-cis* 1,2,3,4,5,6-hexafluorocyclohexane has been superseded by Glorius' stereoselective reduction of hexafluorobenzene.²⁴ Instead of the original de novo approaches to 2,3,4-trideoxy-2,3,4-trifluoroglucose **1**¹⁵,¹⁶ and based on the Lukacs synthesis of 1,6-di-O-acetyl-2,3,4-trideoxy-2,3,4-trifluoroglucose **6** (*Scheme* 1),¹⁴ Giguère's team achieved a scaleable synthesis of **1** (*Scheme* 1).¹⁷ In both cases, the 4-OH group of **3** was inverted after conversion to the corresponding triflate, using NaOBz (Lukacs), and by a Lattrell-Dax reaction (Giguère), to arrive at the corresponding difluorinated galactosan **4**. The subsequent deoxyfluorination reaction was achieved by DAST

<figure><img src="image_4.png" /><figcaption>**Chart 1.** 2,3,4-Trideoxy-2,3,4-trifluoroglucose **1**</figcaption></figure>

Received: January 30, 2019

Published: March 14, 2019

<figure><img src="image_5.png" /></figure>
<figure><img src="image_5.png" /><figcaption>**Scheme 2.** Unselective Deoxyfluorination of 4<sup>a</sup></figcaption></figure>

<figure><img src="image_6.png" /></figure>

(Lukacs) or by a 2-step fluoride displacement (Giguère). Finally, acetolysis to cleave the 1,6-anhydrobridge and deprotection gave **1** in 13 overall steps.

As part of a research program investigating GLUT-1-mediated erythrocyte membrane exchange of fluorinated carbohydrates,<sup>25</sup> we required **1** in >100 mg quantities. However, in our hands, the DAST-mediated deoxyfluorination according to Lukacs<sup>14</sup> led to an inseparable mixture of trifluorinated levoglucosan **5a** and levoglactosan **7** (*Scheme 2*) in a 7:3 ratio. Slower addition of DAST at 0 °C did lead to a much improved 97:3 ratio but in a much lower 50% yield (not shown). Combined with the unattractive length of this synthesis, investigations were subsequently initiated toward a shorter route for **1**.

The formation of the galactose isomer can be understood by a 2-step mechanism, in which expulsion of the leaving group is aided by neighboring group participation of the endocyclic oxygen to form an intermediate akin to **9**. Subsequent fluoride attack then leads to the formation of the C-4 stereocenter with retention of the configuration. The participation of 1,6-anhydrosugar endocyclic oxygens in nucleophilic substitution reactions has been investigated by the group of Karban.<sup>26</sup> We have not observed a fluoride attack at C-5 leading to a ring-contracted product, which is not unprecedented for retentive 4-OH deoxyfluorinations.<sup>26</sup> For such cases, the involvement of an S<sub>N</sub>1 mechanism has also been suggested as a possible explanation.<sup>26</sup>

Interestingly, the equivalent DAST-mediated deoxyfluorination of 1,6-anhydro-2,3-difluorolevotalosan **10** (*Scheme 3*) was reported to occur with a clean retention of configuration,<sup>17</sup> despite the presence of the antiperiplanar C2–F bond with the endocyclic oxygen. In such a case, this could be expected to cause a reduction of the oxygen polarizability and, thus, its capacity for anchimeric assistance to form an epoxonium-like intermediate **12**. However, this reaction was conducted at 100

°C in a microwave reactor, which may have forced this process to dominate.

To open the 1,6-anhydrobridge, the mixture of **5a** and **7** was treated with BCl<sub>3</sub>. To our delight, this conversion proceeds in excellent yield to give a mixture of the target compound **1** and 2,3,4-trideoxy-2,3,4-trifluorogalactose **8**. These are separable, albeit only via multiple preparative HPLC runs. Recrystallization of each pyranose followed by X-ray analysis allowed unambiguous confirmation of their relative stereochemistry, and the structure of **1**, also reported by O'Hagan (CSD code, CUTVIX),<sup>15</sup> is shown side-by-side to the novel structure of **8**.

In designing a new, shorter synthesis which also would circumvent unselective deoxyfluorination, we were attracted by a publication from Pacak et al, who reported that treatment of **13** (*Scheme 4a*)<sup>27,28</sup> with KHF<sub>2</sub> in ethylene glycol leads to the difluorinated **14a** as the only isolable product in 5% yield (not shown).<sup>10,11</sup> Pleasingly, optimization of this reaction, which involved the addition of KF and working under more concentrated conditions, improved this to a 54% yield of **14a** on a multigram scale. Lower yields were obtained under rigorous exclusion of moisture.

Then, inspired by a report by Barford et al.,<sup>29</sup> who achieved fluoride introduction starting from tosylate **15** by in situ epoxide formation under essentially the same conditions (*Scheme 4b*), this process was successfully repeated from the known ditosylate **17** (*Scheme 4c*), which was obtained from levoglucosan **2** in 82% yield (not shown),<sup>27,28</sup> to give **14a** in 55% yield. While this article was in preparation, this remarkable transformation was reported by Giguère,<sup>17</sup> who used 8 equiv of TBAF·3H<sub>2</sub>O as the extra fluoride source, in neat conditions at 180 °C, to obtain a slightly higher yield of 60% (multigram scale).

Finally, the plan called for direct deoxyfluorination of **14a** to give the desired **5a**. Deoxyfluorination of 3-OH groups of 1,6-anhydroglucose derivatives with retention of configuration is well-precedented (see examples **14b–14f**, *Scheme 4d*),<sup>14,17,30–34</sup> which has also been explained by neighboring group participation, now with a suitable group at the C-2 or C-4 position. This mechanism is not expected to take place with antiperiplanar fluorine substituents; however, should an S<sub>N</sub>1 mechanism take place, the retentive deoxyfluorination of **14a** may be successful. Unfortunately, we have not been able to find conditions to form **5a** in this way (*Scheme 4e*), with <sup>19</sup>F

<figure><img src="image_7.png" /><figcaption>**Scheme 3.** Deoxyfluorination of 1,6-Anhydro-2,3-dideoxy-2,3-difluorotalose 10<sup>17</sup></figcaption></figure>

<footnote><sup>a</sup>Thermal ellipsoids are drawn at the 50% probability level.</footnote>
<figure><img src="image_6.png" /><figcaption>Scheme 2. Unselective Deoxyfluorination of 4<sup>a</sup></figcaption></figure>

<figure><img src="image_7.png" /></figure>

(Lukacs) or by a 2-step fluoride displacement (Giguère). Finally, acetolysis to cleave the 1,6-anhydrobridge and deprotection gave **1** in 13 overall steps.

As part of a research program investigating GLUT-1-mediated erythrocyte membrane exchange of fluorinated carbohydrates,<sup>25</sup> we required **1** in >100 mg quantities. However, in our hands, the DAST-mediated deoxyfluorination according to Lukacs<sup>14</sup> led to an inseparable mixture of trifluorinated levoglucosan **5a** and levoglactosan **7** (*Scheme* 2) in a 7:3 ratio. Slower addition of DAST at 0 °C did lead to a much improved 97:3 ratio but in a much lower 50% yield (not shown). Combined with the unattractive length of this synthesis, investigations were subsequently initiated toward a shorter route for **1**.

The formation of the galactose isomer can be understood by a 2-step mechanism, in which expulsion of the leaving group is aided by neighboring group participation of the endocyclic oxygen to form an intermediate akin to **9**. Subsequent fluoride attack then leads to the formation of the C-4 stereocenter with retention of the configuration. The participation of 1,6-anhydrosugar endocyclic oxygens in nucleophilic substitution reactions has been investigated by the group of Karban.<sup>26</sup> We have not observed a fluoride attack at C-5 leading to a ring-contracted product, which is not unprecedented for retentive 4-OH deoxyfluorinations.<sup>26</sup> For such cases, the involvement of an S<sub>N</sub>1 mechanism has also been suggested as a possible explanation.<sup>26</sup>

Interestingly, the equivalent DAST-mediated deoxyfluorination of 1,6-anhydro-2,3-difluorolevotalosan **10** (*Scheme* 3) was reported to occur with a clean retention of configuration,<sup>17</sup> despite the presence of the antiperiplanar C2–F bond with the endocyclic oxygen. In such a case, this could be expected to cause a reduction of the oxygen polarizability and, thus, its capacity for anchimeric assistance to form an epoxonium-like intermediate **12**. However, this reaction was conducted at 100

°C in a microwave reactor, which may have forced this process to dominate.

To open the 1,6-anhydrobridge, the mixture of **5a** and **7** was treated with BCl<sub>3</sub>. To our delight, this conversion proceeds in excellent yield to give a mixture of the target compound **1** and 2,3,4-trideoxy-2,3,4-trifluorogalactose **8**. These are separable, albeit only via multiple preparative HPLC runs. Recrystallization of each pyranose followed by X-ray analysis allowed unambiguous confirmation of their relative stereochemistry, and the structure of **1**, also reported by O'Hagan (CSD code, CUTVIX),<sup>15</sup> is shown side-by-side to the novel structure of **8**.

In designing a new, shorter synthesis which also would circumvent unselective deoxyfluorination, we were attracted by a publication from Pacak et al, who reported that treatment of **13** (*Scheme* 4a)<sup>27,28</sup> with KHF<sub>2</sub> in ethylene glycol leads to the difluorinated **14a** as the only isolable product in 5% yield (not shown).<sup>10,11</sup> Pleasingly, optimization of this reaction, which involved the addition of KF and working under more concentrated conditions, improved this to a 54% yield of **14a** on a multigram scale. Lower yields were obtained under rigorous exclusion of moisture.

Then, inspired by a report by Barford et al.,<sup>29</sup> who achieved fluoride introduction starting from tosylate **15** by in situ epoxide formation under essentially the same conditions (*Scheme* 4b), this process was successfully repeated from the known ditosylate **17** (*Scheme* 4c), which was obtained from levoglucosan **2** in 82% yield (not shown),<sup>27,28</sup> to give **14a** in 55% yield. While this article was in preparation, this remarkable transformation was reported by Giguère,<sup>17</sup> who used 8 equiv of TBAF·3H<sub>2</sub>O as the extra fluoride source, in neat conditions at 180 °C, to obtain a slightly higher yield of 60% (multigram scale).

Finally, the plan called for direct deoxyfluorination of **14a** to give the desired **5a**. Deoxyfluorination of 3-OH groups of 1,6-anhydroglucose derivatives with retention of configuration is well-precedented (see examples **14b–14f**, *Scheme* 4d),<sup>14,17,30–34</sup> which has also been explained by neighboring group participation, now with a suitable group at the C-2 or C-4 position. This mechanism is not expected to take place with antiperiplanar fluorine substituents; however, should an S<sub>N</sub>1 mechanism take place, the retentive deoxyfluorination of **14a** may be successful. Unfortunately, we have not been able to find conditions to form **5a** in this way (*Scheme* 4e), with <sup>19</sup>F

<figure><img src="image_8.png" /><figcaption>Scheme 3. Deoxyfluorination of 1,6-Anhydro-2,3-dideoxy-2,3-difluorotalose 10<sup>17</sup></figcaption></figure>

<footnote><sup>a</sup>Thermal ellipsoids are drawn at the 50% probability level.</footnote>
<figure><img src="image_8.png" /><figcaption>**Scheme 4.** Synthesis of 2,4-Dideoxy-2,4-difluorolevoglucosan 14a, and Its Unsuccessful Deoxyfluorination to 5a</figcaption></figure>

NMR analysis indicating that the 3-OH group does not react with DAST.

Hence, it was decided to first effect 3-OH inversion (Scheme 5). Oxidation of 14a gave a mixture of the ketone 18 and its hydrate 20, which was immediately followed by borohydride reduction. While reduction of the corresponding (non-fluorinated) 2,4-dideoxy pyranulose 19 under similar conditions resulted in a 56:44 ratio of equatorial/axial attack,³⁵ reduction of 18 predominantly gave the desired axial attack to give the levoallosan derivative 21. Axial attack is sterically hindered by the anhydro bridge, but for 18, borohydride attack is also hindered by the two axial fluorine groups. Unsurprisingly, reaction with the bulky L-selectride, which selectively reduces cyclohexanones with an axial α-fluorine through axial

attack,³⁶ was extremely sluggish. With NaBH₄ in Et₂O, the reaction was not fully selective, and 4–15% of levoglucosan 14a was formed (not shown). This was separable from 21, but given 14a does not react under deoxyfluorination conditions, separation is not necessary at this stage. However, reduction with NaBH₄ in EtOH³⁷ did lead to virtually complete selectivity, leading to 21 in an excellent yield. DAST-mediated deoxyfluorination of 21 only led to trace amounts of 5a, while fluoride substitution of triflate 22a with Et₃N·3HF also did not lead to appreciable conversions. Pleasingly, successful conversion to give 5a was achieved with the use of nonafluorobutyl sulfonyl fluoride (NfF)³⁸ in the presence of Et₃N·3HF as the external fluoride source, which proceeds via the corresponding nonaflate 22b. Given the volatility of 5a, for which a crystal structure could be obtained, this reaction required execution in a sealed tube. Finally, BCl₃-mediated opening of the 1,6-anhydro bridge gave the desired 1 in excellent yield.

The ¹H NMR spectrum of 21 (CDCl₃) displays a very defined doublet of triplets for the alcohol group (Figure 1).

<figure><img src="image_9.png" /><figcaption>**Figure 1.** Coupling constants of the alcohol hydrogen before and after fluorine decoupling.</figcaption></figure>

Fluorine decoupling simplifies the signal to a 12.4 Hz doublet (³Jₖ₃-OH), a magnitude consistent with an antiperiplanar alignment, and the triplet was assigned as $^{11}J_{OH...F}$ couplings to F-2 and F-4, each measuring at ±2.2 Hz. Hence, this indicates that, in solution, the O–H bond is positioned in between the two C–F bonds, with hydrogen bonding to the fluorine atoms, possibly as a so-called “bifurcated hydrogen bond”. While it has been calculated that there is no enthalpic advantage to form such a three-center interaction, it has been

<figure><img src="image_10.png" /><figcaption>**Scheme 5.** Successful Synthesis of 2,3,4-Trideoxy-2,3,4-trifluoroglucose 1ᵃ</figcaption></figure>

<footnote>ᵃThermal ellipsoids are drawn at the 50% probability level. One out of four conformations is shown for 21.</footnote>
<figure><img src="image_9.png" /><figcaption>**Scheme 4.** Synthesis of 2,4-Dideoxy-2,4-difluorolevoglucosan 14a, and Its Unsuccessful Deoxyfluorination to 5a</figcaption></figure>

NMR analysis indicating that the 3-OH group does not react with DAST.

Hence, it was decided to first effect 3-OH inversion (Scheme 5). Oxidation of 14a gave a mixture of the ketone 18 and its hydrate 20, which was immediately followed by borohydride reduction. While reduction of the corresponding (non-fluorinated) 2,4-dideoxy pyranulose 19 under similar conditions resulted in a 56:44 ratio of equatorial/axial attack,³⁵ reduction of 18 predominantly gave the desired axial attack to give the levoallosan derivative 21. Axial attack is sterically hindered by the anhydro bridge, but for 18, borohydride attack is also hindered by the two axial fluorine groups. Unsurprisingly, reaction with the bulky L-selectride, which selectively reduces cyclohexanones with an axial α-fluorine through axial

attack,³⁶ was extremely sluggish. With NaBH₄ in Et₂O, the reaction was not fully selective, and 4–15% of levoglucosan 14a was formed (not shown). This was separable from 21, but given 14a does not react under deoxyfluorination conditions, separation is not necessary at this stage. However, reduction with NaBH₄ in EtOH³⁷ did lead to virtually complete selectivity, leading to 21 in an excellent yield. DAST-mediated deoxyfluorination of 21 only led to trace amounts of 5a, while fluoride substitution of triflate 22a with Et₃N·3HF also did not lead to appreciable conversions. Pleasingly, successful conversion to give 5a was achieved with the use of nonafluorobutyl sulfonyl fluoride (NfF)³⁸ in the presence of Et₃N·3HF as the external fluoride source, which proceeds via the corresponding nonaflate 22b. Given the volatility of 5a, for which a crystal structure could be obtained, this reaction required execution in a sealed tube. Finally, BCl₃-mediated opening of the 1,6-anhydro bridge gave the desired 1 in excellent yield.

The ¹H NMR spectrum of 21 (CDCl₃) displays a very defined doublet of triplets for the alcohol group (Figure 1).

<figure><img src="image_10.png" /><figcaption>**Figure 1.** Coupling constants of the alcohol hydrogen before and after fluorine decoupling.</figcaption></figure>

Fluorine decoupling simplifies the signal to a 12.4 Hz doublet (³Jₖ₃-OH), a magnitude consistent with an antiperiplanar alignment, and the triplet was assigned as $^{11}$JₐOH...F couplings to F-2 and F-4, each measuring at ±2.2 Hz. Hence, this indicates that, in solution, the O–H bond is positioned in between the two C–F bonds, with hydrogen bonding to the fluorine atoms, possibly as a so-called “bifurcated hydrogen bond”. While it has been calculated that there is no enthalpic advantage to form such a three-center interaction, it has been

<figure><img src="image_11.png" /><figcaption>**Scheme 5.** Successful Synthesis of 2,3,4-Trideoxy-2,3,4-trifluoroglucose 1ᵃ</figcaption></figure>

<footnote>ᵃThermal ellipsoids are drawn at the 50% probability level. One out of four conformations is shown for 21.</footnote>
suggested that this type of interaction “would become favorable if both acceptors occurred in the same molecule and were rigidly held in the proper arrangement”.³⁹ Density functional theory calculations (IEF-PCM/B97-D3BJ/6-311++G(2d,p) level of theory in chloroform, see the Supporting Information) showed this conformation as the only one being populated (99%), with two OH···F distances (values around 2.45 Å) shorter than the sum of the H and F van der Waals radii (2.57 Å) and typical of hydrogen-bond interaction. The interaction energies ($E^{(2)}_{n→σ*}$) computed from NBO analysis⁴⁰ indicated very weak charge transfers (0.67 and 0.63 kJ mol⁻¹) from the fluorine atoms lone pairs to the hydroxyl antibonding orbital, which is in line with the values previously encountered in such OH···F interactions.⁴¹ In addition, calculation of coupling constants within this IMHB conformer led to a $^3J_{H,OH}$ value of 13.5 Hz and two $^{h1}J_{OH...F}$ values of -1.6 and -1.4 Hz, close to the experimental values (12.4 and ±2.2 Hz); whereas the non-IMHB conformers exhibit couplings very far from the experimental data. To the best of our knowledge, there are very few examples involving an alcohol (phenol) donor and two C–F acceptors, either intermolecular (*syn*-2,4-difluoroadamantane)⁴² or intramolecular (e.g., 2-(trifluoromethyl)phenol).⁴³ We believe there also is only one example of a 5-membered $^{h1}J_{OH...F}$ coupling in the literature (4.6 Hz), reported by Bernet also on an 1,6-anhydrosugar derivative.⁴⁴

The weak OH···F hydrogen bond⁴⁵⁻⁴⁷ does not play an important role in the overall combination of interactions that determine crystal packings. The known crystal structure of **14a** (CSD code, ADFGLP) has attracted interest in that its crystal packing does not include any intermolecular hydrogen bonding between the alcohol group and the fluorine atoms, despite the availability of two C–F acceptors in a small molecule.⁴⁸ In this context, we were delighted to be able to obtain single crystals of **21** (*Scheme* 5). Its unit cell is quite complex, containing 8 independent molecules, which differ in their OH orientation, including structures with either an antiperiplanar (as shown in *Scheme* 5) or a synperiplanar orientation between the O–H and alcohol C–H bonds. Like in **14a**, the packing is clearly dominated by intermolecular hydrogen bonding, in which two different chains can be distinguished (see the *Supporting Information* for details), and not by intramolecular OH···F hydrogen bonding.

In conclusion, we have achieved a short, 6-step synthesis of 2,3,4-trideoxy-2,3,4-trifluoroglucose **1** from levoglucosan in 24% overall yield. The key transformations involved a selective difluorination of 2,4-di-O-tosyl levoglucosan **17** and the deoxyfluorination of 2,4-dideoxy-2,4-difluorolevoallosan **21**. A rare F···H(O)···F bifurcated hydrogen bond was observed in solution for **21**, but although this particular conformation was also present in the crystalline state, the crystal packing of this compound was clearly dominated by intermolecular O–H···O hydrogen bonding.

## ■ EXPERIMENTAL SECTION

**Computational Details.** To provide further evidence of the occurrence of a bifurcated hydrogen bond in **21**, density functional theory calculations were performed by using the A.03 version of the Gaussian 16 program.⁴⁹ Following the methodology used in our previous work on the levoglucosan series,⁴¹ the geometries of the various structures have been optimized at the IEF-PCM/B97-D3BJ/6-311++G(2d,p) level of theory in chloroform. Frequency calculation of the various energetic minima were then carried out at the same level of theory, allowing for the calculations of the corresponding Gibbs free energies and of the Boltzmann distribution.

IMHB interactions were analyzed through AIM topological analysis of the IEF-PCM/B97-D3BJ/6-311++G(2d,p) wave functions with the AIM2000 program.⁵⁰ The complementary contribution of charge transfer between the acceptor lone pair(s) electrons and the $σ^*$ donor antibonding orbital was estimated through natural bond orbital (NBO) analyses.⁴⁰ The NBO method was applied at the IEF-PCM/B97-D3BJ/6-311++G(2d,p) level in CHCl₃ to provide the corresponding interaction energies ($E^{(2)}_{n→σ^*}$) evaluated from second-order perturbation theory, using the NBO 6.0 program.⁵¹

The spin-spin coupling constants (*J*) were then estimated from the previous optimized geometries by using the gauge-invariant atomic orbital (GIAO) method. The hybrid B97-2 functional and the pcJ-2 basis set, specifically designed for the calculation of these NMR parameters,⁵² were used.

**General Synthesis Conditions.** All air/moisture sensitive reactions were carried out under an inert atmosphere (Ar), in dried glassware. Dry CH₂Cl₂, THF, MeOH, and hexane were bought from commercial suppliers and used as received. TLC was performed on aluminum-precoated plates coated with silica gel 60 with an F254 indicator, visualized under UV light (254 nm), and/or by staining with KMnO₄ (10% aq.). Flash column chromatography was performed with Sigma-Aldrich 60 silica gel (40–63 µm). Preparative HPLC was carried out using a Biorad Bio-Sil D 90-10 column (250 mm × 22 mm at 15 mL min⁻¹). High-resolution MS samples were analyzed using a Maxis (Bruker Daltonics, Bremen, Germany) mass spectrometer equipped with a time-of-flight (TOF) analyzer. Samples were introduced to the mass spectrometer via a Dionex Ultimate 3000 autosampler and uHPLC pump and eluted in 5 min at 0.6 mL min using a gradient of 20% acetonitrile (0.2% formic acid) to 100% acetonitrile (0.2% formic acid) through an Acquy UPLC BEH C18 (Waters) 1.7 µm, 50 mm × 2.1 mm column. High-resolution mass spectra were recorded using positive ion electrospray ionization. ¹H, ¹⁹F, and ¹³C NMR spectra were recorded at room temperature on a Bruker Ultrashield 400 or 500 MHz spectrometer. ¹H and ¹³C chemical shifts (*δ*) are quoted in ppm relative to residual solvent peaks as appropriate. ¹⁹F spectra were externally referenced to CFCl₃. The coupling constants (*J*) are given in Hertz (Hz). The NMR signals were designated as follows: *s* (singlet), *d* (doublet), *t* (triplet), *q* (quartet), *quin* (quintet), *sxt* (sextet), *spt* (septet), *m* (multiplet), or a combination of the above. For all compounds, detailed peak assignment was performed through the combined use of HSQC and COSY NMR experiments.

1,6-Anhydro-2,3,4-trideoxy-2,3,4-trifluoroglucose **5a** and 1,6-Anhydro-2,3,4-trideoxy-2,3,4-trifluorogalactose **7** from **4** (*Scheme* 2). To a solution of 1,6-anhydro-2,3-dideoxy-2,3-difluorogalactose 4¹⁴,¹⁷ (100 mg, 0.60 mmol) in dry CH₂Cl₂ (2.3 mL) at 0 °C was added DAST (0.24 mL, 1.96 mmol) dropwise. The resulting mixture was stirred at rt under argon for 24 h, until TLC indicated full consumption of the starting material. The reaction mixture was quenched by carefully adding sat. aq. NaHCO₃ (5 mL) at 0 °C, and the resulting aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were combined, dried over MgSO₄, and filtered, and the solvent was slowly evaporated under controlled reduced pressure (600 mbar). Purification by column chromatography (pentane/CH₂Cl₂: 80:20 to 50:60) afforded 92 mg (0.50 mmol, 83%) of an inseparable mixture of diastereoisomers trifluoro levoglucosan **5a** and levoglactosan **7** (*dr* 69:31) as a white solid. ¹H NMR (400 MHz, CDCl₃, *δ*): 5.62 (1H, br. s, H₁(Glc)), 5.54 (1H, m, *J* = 5.1, 1.5 Hz is observed, H₁(Gal)), 5.02 (1H, m, *J* 47.7 Hz is observed, H₃(Gal)), 4.93–4.59 (5H, m), 4.57 (1H, m, *J* 44.7, 14.9, 1.5 Hz is observed, H₄(Glc)), 4.43 (1H, m, *J* 45.5, 14.9, 1.5 Hz is observed, H₂(Glc)), 4.34 (1H, br. d, *J* 8.1 Hz, H₆endo(Gal)), 3.96 (1H, br. dd, *J* 8.1, 1.0 Hz, H₆endo(Glc)), 3.74–3.89 (2H, m, H₆exo(Glc,Gal)) ppm. ¹⁹F NMR (376 MHz, CDCl₃, *δ*): −188.0 (m, *J* 45.1, 15.6, 12.1, 3.5 Hz is observed, F₄(Glc)), −191.1 (dquin, *J* 41.6, 13.8 Hz, F₃(Glc)), −193.6 (m, *J* 45.1, 3.5 Hz is observed, F₂(Glc)), −195.5 (ddd, *J* 44.6, 16.0, 8.7 Hz, F₄(Gal)), −208.8 (m, *J* 46.8, 24.3, 15.6 Hz is observed, F₃(Gal)), −209.0 (br. d, *J* 43.4 Hz, F₂(Gal)) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃, *δ*): −188.0 (d, *J* 12.1 Hz, F₄(Glc)), −191.1 (t, *J* 12.1 Hz, F₃(Glc)), −193.6
suggested that this type of interaction “would become favorable if both acceptors occurred in the same molecule and were rigidly held in the proper arrangement”.³⁹ Density functional theory calculations (IEF-PCM/B97-D3BJ/6-311++G(2d,p) level of theory in chloroform, see the Supporting Information) showed this conformation as the only one being populated (99%), with two OH...F distances (values around 2.45 Å) shorter than the sum of the H and F van der Waals radii (2.57 Å) and typical of hydrogen-bond interaction. The interaction energies ($E^{(2)}_{n→σ*}$) computed from NBO analysis⁴⁰ indicated very weak charge transfers (0.67 and 0.63 kJ mol⁻¹) from the fluorine atoms lone pairs to the hydroxyl antibonding orbital, which is in line with the values previously encountered in such OH...F interactions.⁴¹ In addition, calculation of coupling constants within this IMHB conformer led to a $^3J_{H,OH}$ value of 13.5 Hz and two $^{h1}J_{OH...F}$ values of -1.6 and -1.4 Hz, close to the experimental values (12.4 and ±2.2 Hz); whereas the non-IMHB conformers exhibit couplings very far from the experimental data. To the best of our knowledge, there are very few examples involving an alcohol (phenol) donor and two C–F acceptors, either intermolecular (*syn*-2,4-difluoroadamantane)⁴² or intramolecular (e.g., 2-(trifluoromethyl)phenol).⁴³ We believe there also is only one example of a 5-membered $^{h1}J_{OH...F}$ coupling in the literature (4.6 Hz), reported by Bernet also on an 1,6-anhydrosugar derivative.⁴⁴

The weak OH...F hydrogen bond⁴⁵⁻⁴⁷ does not play an important role in the overall combination of interactions that determine crystal packings. The known crystal structure of **14a** (CSD code, ADFGLP) has attracted interest in that its crystal packing does not include any intermolecular hydrogen bonding between the alcohol group and the fluorine atoms, despite the availability of two C–F acceptors in a small molecule.⁴⁸ In this context, we were delighted to be able to obtain single crystals of **21** (*Scheme* 5). Its unit cell is quite complex, containing 8 independent molecules, which differ in their OH orientation, including structures with either an antiperiplanar (as shown in *Scheme* 5) or a synperiplanar orientation between the O–H and alcohol C–H bonds. Like in **14a**, the packing is clearly dominated by intermolecular hydrogen bonding, in which two different chains can be distinguished (see the *Supporting Information* for details), and not by intramolecular OH...F hydrogen bonding.

In conclusion, we have achieved a short, 6-step synthesis of 2,3,4-trideoxy-2,3,4-trifluoroglucose **1** from levoglucosan in 24% overall yield. The key transformations involved a selective difluorination of 2,4-di-O-tosyl levoglucosan **17** and the deoxyfluorination of 2,4-dideoxy-2,4-difluorolevoallosan **21**. A rare F...H(O)...F bifurcated hydrogen bond was observed in solution for **21**, but although this particular conformation was also present in the crystalline state, the crystal packing of this compound was clearly dominated by intermolecular O–H...O hydrogen bonding.

## ■ EXPERIMENTAL SECTION

**Computational Details.** To provide further evidence of the occurrence of a bifurcated hydrogen bond in **21**, density functional theory calculations were performed by using the A.03 version of the Gaussian 16 program.⁴⁹ Following the methodology used in our previous work on the levoglucosan series,⁴¹ the geometries of the various structures have been optimized at the IEF-PCM/B97-D3BJ/6-311++G(2d,p) level of theory in chloroform. Frequency calculation of the various energetic minima were then carried out at the same level of theory, allowing for the calculations of the corresponding Gibbs free energies and of the Boltzmann distribution.

IMHB interactions were analyzed through AIM topological analysis of the IEF-PCM/B97-D3BJ/6-311++G(2d,p) wave functions with the AIM2000 program.⁵⁰ The complementary contribution of charge transfer between the acceptor lone pair(s) electrons and the $σ^*$ donor antibonding orbital was estimated through natural bond orbital (NBO) analyses.⁴⁰ The NBO method was applied at the IEF-PCM/B97-D3BJ/6-311++G(2d,p) level in CHCl₃ to provide the corresponding interaction energies ($E^{(2)}_{n→σ^*}$) evaluated from second-order perturbation theory, using the NBO 6.0 program.⁵¹

The spin-spin coupling constants (*J*) were then estimated from the previous optimized geometries by using the gauge-invariant atomic orbital (GIAO) method. The hybrid B97-2 functional and the pcJ-2 basis set, specifically designed for the calculation of these NMR parameters,⁵² were used.

**General Synthesis Conditions.** All air/moisture sensitive reactions were carried out under an inert atmosphere (Ar), in dried glassware. Dry CH₂Cl₂, THF, MeOH, and hexane were bought from commercial suppliers and used as received. TLC was performed on aluminum-precoated plates coated with silica gel 60 with an F254 indicator, visualized under UV light (254 nm), and/or by staining with KMnO₄ (10% aq.). Flash column chromatography was performed with Sigma-Aldrich 60 silica gel (40–63 µm). Preparative HPLC was carried out using a Biorad Bio-Sil D 90-10 column (250 mm × 22 mm at 15 mL min⁻¹). High-resolution MS samples were analyzed using a Maxis (Bruker Daltonics, Bremen, Germany) mass spectrometer equipped with a time-of-flight (TOF) analyzer. Samples were introduced to the mass spectrometer via a Dionex Ultimate 3000 autosampler and uHPLC pump and eluted in 5 min at 0.6 mL min using a gradient of 20% acetonitrile (0.2% formic acid) to 100% acetonitrile (0.2% formic acid) through an Acquity UPLC BEH C18 (Waters) 1.7 µm, 50 mm × 2.1 mm column. High-resolution mass spectra were recorded using positive ion electrospray ionization. ¹H, ¹⁹F, and ¹³C NMR spectra were recorded at room temperature on a Bruker Ultrashield 400 or 500 MHz spectrometer. ¹H and ¹³C chemical shifts (*δ*) are quoted in ppm relative to residual solvent peaks as appropriate. ¹⁹F spectra were externally referenced to CFL₃. The coupling constants (*J*) are given in Hertz (Hz). The NMR signals were designated as follows: *s* (singlet), *d* (doublet), *t* (triplet), *q* (quartet), *quin* (quintet), *sxt* (sextet), *spt* (septet), *m* (multiplet), or a combination of the above. For all compounds, detailed peak assignment was performed through the combined use of HSQC and COSY NMR experiments.

1,6-Anhydro-2,3,4-trideoxy-2,3,4-trifluoroglucose **5a** and 1,6-Anhydro-2,3,4-trideoxy-2,3,4-trifluorogalactose **7** from **4** (*Scheme* 2). To a solution of 1,6-anhydro-2,3-dideoxy-2,3-difluorogalactose 4¹⁴,¹⁷ (100 mg, 0.60 mmol) in dry CH₂Cl₂ (2.3 mL) at 0 °C was added DAST (0.24 mL, 1.96 mmol) dropwise. The resulting mixture was stirred at rt under argon for 24 h, until TLC indicated full consumption of the starting material. The reaction mixture was quenched by carefully adding sat. aq. NaHCO₃ (5 mL) at 0 °C, and the resulting aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were combined, dried over MgSO₄, and filtered, and the solvent was slowly evaporated under controlled reduced pressure (600 mbar). Purification by column chromatography (pentane/CH₂Cl₂: 80:20 to 50:60) afforded 92 mg (0.50 mmol, 83%) of an inseparable mixture of diastereoisomers trifluoro levoglucosan **5a** and levoglactosan **7** (*dr* 69:31) as a white solid. ¹H NMR (400 MHz, CDCl₃, *δ*): 5.62 (1H, br. s, H₁(Glc)), 5.54 (1H, m, *J* = 5.1, 1.5 Hz is observed, H₁(Gal)), 5.02 (1H, m, *J* 47.7 Hz is observed, H₃(Gal)), 4.93–4.59 (5H, m), 4.57 (1H, m, *J* 44.7, 14.9, 1.5 Hz is observed, H₄(Glc)), 4.43 (1H, m, *J* 45.5, 14.9, 1.5 Hz is observed, H₂(Glc)), 4.34 (1H, br. d, *J* 8.1 Hz, H₆endo(Gal)), 3.96 (1H, br. dd, *J* 8.1, 1.0 Hz, H₆endo(Glc)), 3.74–3.89 (2H, m, H₆exo(Glc,Gal)) ppm. ¹⁹F NMR (376 MHz, CDCl₃, *δ*): −188.0 (m, *J* 45.1, 15.6, 12.1, 3.5 Hz is observed, F₄(Glc)), −191.1 (dquin, *J* 41.6, 13.8 Hz, F₃(Glc)), −193.6 (m, *J* 45.1, 3.5 Hz is observed, F₂(Glc)), −195.5 (ddd, *J* 44.6, 16.0, 8.7 Hz, F₄(Gal)), −208.8 (m, *J* 46.8, 24.3, 15.6 Hz is observed, F₃(Gal)), −209.0 (br. d, *J* 43.4 Hz, F₂(Gal)) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃, *δ*): −188.0 (d, *J* 12.1 Hz, F₄(Glc)), −191.1 (t, *J* 12.1 Hz, F₃(Glc)), −193.6
(d, J 12.1 Hz, F₂(Glc)), -195.5 (d, J 15.6 Hz, F₄(Gal)), -208.8 (dd, J 15.6, 3.5 Hz, F₃(Gal)), -209.0 (d, J 5.2 Hz, F₂(Gal)) ppm.

### 2,3,4-Trideoxy-2,3,4-trifluoro-D-glucopyranose 1 and 2,3,4-Trideoxy-2,3,4-trifluoro-D-galactopyranose 8 from the Mixture of 5a and 7 (Scheme 2).
To a solution of the mixture of 5a/7 (89 mg, 0.53 mmol) in CH₂Cl₂ (3.6 mL) at 0 °C was added BCl₃ (1 M in CH₂Cl₂, 2.2 mL, 2.2 mmol) dropwise. The resulting mixture was stirred at rt for 2 h before being quenched with water (5 mL). The organic solvent was then removed under reduced pressure, and the resulting aqueous phase was stirred for an additional 1 h at rt. The remaining water was evaporated to give a brown dense oil, which was then purified by column chromatography (pentane/acetone 90:10 to 60:40) to afford 90 mg (0.48 mmol, 91%) of a "pure" mixture of **1** and **8**. Complete separation of the two diastereoisomers could be achieved via repeated HPLC separations (pentane/acetone 70:30).

Data for 2,3,4-trideoxy-2,3,4-trifluoro-D-glucopyranose **1** (white solid): R<sub>f</sub> 0.12 (pentane/EtOAc 60:40). mp 98-100 °C (CHCl<sub>3</sub>/acetone), lit<sup>15</sup> 103-105 °C (CHCl<sub>3</sub>). [α]<sub>D</sub>+28.0 for α/β 0.30:1.00 (c 0.99, CD<sub>3</sub>OD, 21 °C), lit<sup>15</sup>+40.1 for α/β 1.0:9.8 (c 1.15, THF-d<sub>8</sub>, 22 °C). IR (neat) 3367 (m, br.), 3111 (m, br.), 2961 (m), 1032 (s), 995 (s) cm<sup>-1</sup>. <sup>1</sup>H NMR (500 MHz, CDCl<sub>3</sub>, δ): 5.49 (1H, br, q, J = 3.1 Hz, H<sub>1α</sub>), 5.09 (1H, dddd, J = 55.0, 16.6, 14.0, 8.4, 7.9 Hz, H<sub>3α</sub>), 4.92 (1H, br, dd, J = 7.6, 3.0 Hz, H<sub>1β</sub>), 4.82 (1H, dddt, 53.1, 16.5, 15.9, 8.3 Hz, H<sub>3β</sub>), 4.66 (1H, m, a doublet with J = 50.4 Hz can observed, H<sub>4β</sub>), 4.64 (1H, dddd J = 50.9, 15.1, 9.9, 8.3 Hz, H<sub>4α</sub>), 4.53 (1H, dddd, J = 49.8, 12.9, 8.9, 3.9 Hz, H<sub>2α</sub>), 4.35 (1H, dddd, J = 50.9, 14.5, 8.1, 7.6 Hz, H<sub>2β</sub>), 4.13 (1H, ddq, J = 9.8, 4.4, 2.5 Hz, H<sub>5α</sub>), 4.03-3.73 (4H, m, H<sub>6,6α</sub> + H<sub>6,6β</sub>), 3.63-3.57 (1H, m, H<sub>5β</sub>), 3.34 (1H, br, s, OH<sub>1α</sub>), 1.84 (1H, br, s, OH<sub>6α</sub> ppm. <sup>1</sup>H<sup>19</sup>F NMR (500 MHz, CDCl<sub>3</sub>, δ): 5.49 (1H, br, d, J = 3.6 Hz, H<sub>1α</sub>), 5.09 (1H, t, J = 8.5 Hz, H<sub>3α</sub>), 4.92 (1H, d, J = 7.7 Hz, H<sub>1β</sub>), 4.82 (1H, t, J = 8.3 Hz, H<sub>3β</sub>), 4.67 (1H, dd, J = 9.8, 8.3 Hz, H<sub>4β</sub>), 4.64 (1H, dd, J = 9.3, 8.3 Hz, H<sub>4α</sub>), 4.53 (1H, dd, J = 8.8, 3.8 Hz, H<sub>2α</sub>), 4.35 (1H, dd, J = 8.3, 7.7 Hz, H<sub>2β</sub>), 4.13 (1H, dd, J = 9.9, 4.2, 2.4 Hz, H<sub>5α</sub>), 4.03-3.74 (4H, m, H<sub>6,6α</sub> + H<sub>6,6β</sub>), 3.60 (1H, ddd, J = 9.8, 4.7, 2.4 Hz, H<sub>5β</sub>), 3.34 (1H, br, s, OH<sub>1α</sub>), 1.84 (1H, br, s, OH<sub>6α</sub> ppm. <sup>19</sup>F NMR (471 MHz, CDCl<sub>3</sub>, δ): -195.1 to -195.4 (m, a doublet of quintets with J = 53.2, 13.6 Hz is observed, F<sub>3β</sub>), -199.3 to -199.6 (m, a doublet of triplets with J = 50.9, 14.4 Hz is observed, F<sub>2α</sub> or F<sub>4α</sub>), -200.0 (dddt, J = 50.9, 15.9, 13.0, 2.9 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -200.6 to -200.9 (m, a doublet of triplets with J = 50.7, 14.5 Hz is observed, F<sub>2β</sub> or F<sub>4β</sub>), -201.0 to -201.30 (m, a doublet of quintets with J = 54.9, 13.5 Hz is observed, F<sub>3α</sub>), -201.5 (dtd, J = 49.9, 13.6, 2.0 Hz, F<sub>2α</sub> or F<sub>4α</sub> ppm. <sup>19</sup>F<sup>1</sup>H NMR (471 MHz, CDCl<sub>3</sub>, δ): -195.3 (t, J = 12.9 Hz, F<sub>3β</sub>), -199.4 (dd, J = 12.9, 2.1 Hz, F<sub>2α</sub> or F<sub>4α</sub>), -200.0 (dd, J = 13.6, 2.9 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -200.8 (dd, J = 12.5, 2.5 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -201.1 (t, J = 12.9 Hz, F<sub>2α</sub> or F<sub>4α</sub>), -201.5 (dd, J = 12.9, 2.1 Hz, F<sub>2α</sub> or F<sub>4α</sub> ppm. The spectral dispersion in CD<sub>3</sub>OD is superior. <sup>1</sup>H NMR (500 MHz, CD<sub>3</sub>OD, δ): 5.33 (1H, q, J = 3.5 Hz, H<sub>1α</sub>), 4.97 (1H, dddt, J = 56.0, 17.0, 13.8, 8.6 Hz, H<sub>3α</sub>), 4.88 (1H, dddt, J = 54.3, 16.8, 15.9, 8.4 Hz, H<sub>3β</sub>), 4.82 (1H, dd, J = 7.7, 2.8 Hz, H<sub>1β</sub>), 4.68-4.49 (2H, m, H<sub>4α</sub> + H<sub>4β</sub>), 4.49 (1H, ddddd, J = 50.4, 13.2, 8.9, 3.8, 0.4 Hz, H<sub>2α</sub>), 4.21 (1H, ddt, J = 51.5, 15.1, 8.3 Hz, H<sub>2β</sub>), 4.02-3.96 (1H, m, H<sub>5α</sub>), 3.84 (1H, dq, J = 12.4, 2.0 Hz, H<sub>6β</sub>), 3.78 (1H, dq, J = 12.4, 2.0 Hz, H<sub>6α</sub>), 3.73 (1H, ddd, J = 12.4, 4.1, 1.8 Hz, H<sub>6α</sub>), 3.70 (1H, ddd, J = 12.4, 4.7, 2.0 Hz, H<sub>6β</sub>), 3.62-3.56 (1H, m, H<sub>5β</sub> ppm. <sup>1</sup>H<sup>19</sup>F NMR (500 MHz, CD<sub>3</sub>OD, δ): 5.33 (1H, d, J = 3.8 Hz, H<sub>1α</sub>), 4.96 (1H, br, t, J = 8.4 Hz, H<sub>3α</sub>), 4.88 (1H, t, J = 8.4 Hz, H<sub>3β</sub>), 4.82 (1H, d, J = 7.7 Hz, H<sub>1β</sub>), 4.59 (1H, dd, J = 9.8, 8.3 Hz, H<sub>4β</sub>), 4.58 (1H, dd, J = 9.9, 8.2 Hz, H<sub>4α</sub>), 4.49 (1H, dd, J = 9.0, 3.8 Hz, H<sub>2α</sub>), 4.21 (1H, t, J = 8.1 Hz, H<sub>2β</sub>), 3.99 (1H, br, ddd, J = 9.8, 4.1, 2.3 Hz, H<sub>5α</sub>), 3.84 (1H, dd, J = 12.4, 2.1 Hz, H<sub>6β</sub>), 3.79 (1H, dd, J = 12.4, 2.1 Hz, H<sub>6α</sub>), 3.73 (1H, dd, J = 12.4, 4.1 Hz, H<sub>6α</sub>), 3.70 (1H, dd, J = 12.4, 4.7 Hz, H<sub>6β</sub>), 3.59 (1H, ddd, J = 9.8, 4.7, 2.1 Hz, H<sub>5β</sub> ppm. <sup>19</sup>F NMR (471 MHz, CD<sub>3</sub>OD, δ): -196.9-197.2 (m, a doublet of quintets with J = 54.4, 13.6 Hz is observed, F<sub>3β</sub>), -200.7 to -201.0 (m, a doublet of triplets with J = 51.5, 14.3 Hz is observed, F<sub>2α</sub> or F<sub>4α</sub>), -201.7 (dddt, J = 51.5, 15.7, 12.9, 2.9 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -202.4 to -202.8 (2F, m, F<sub>3α</sub> and F<sub>2β</sub> or F<sub>4β</sub>), -203.1 (dtd, J = 50.0, 13.6, 2.1 Hz, F<sub>2α</sub> or F<sub>4α</sub>) ppm. <sup>19</sup>F<sup>1</sup>H NMR (471 MHz, CD<sub>3</sub>OD, δ): -197.1 (t, J = 12.9 Hz, F<sub>3β</sub>), -200.9 (dd, J = 12.2, 2.1 Hz, F<sub>2α</sub> or F<sub>4α</sub>), -201.7

(dd, J = 12.9, 2.9 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -202.6 (dd, J = 12.2, 2.9 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -202.7 (t, J = 12.9 Hz, F<sub>3α</sub>), -203.1 (dd, J = 12.9, 2.1 Hz, F<sub>2α</sub> or F<sub>4α</sub>) ppm. To obtain a <sup>13</sup>C NMR spectrum with all carbon atoms clearly visible, acetone-d<sub>6</sub> was used as the solvent (due to the low solubility of **1** in CDCl<sub>3</sub>, we did not obtain a high-quality spectrum). <sup>13</sup>C<sup>1</sup>H NMR (101 MHz, acetone-d<sub>6</sub>, δ): 93.7 (ddd, J = 22.7, 10.3, 1.5 Hz, C<sub>1β</sub>), 92.7 (dt, J = 185.6, 19.8 Hz, C<sub>3β</sub>), 91.2 (ddd, J = 187.8, 17.6, 8.1 Hz, C<sub>2β</sub>), 91.1 (ddd, J = 185.6, 20.5, 19.8 Hz, C<sub>3α</sub>), 90.0 (dd, J = 21.3, 10.3 Hz, C<sub>1α</sub>), 88.0 (ddd, J = 189.3, 14.7, 8.1 Hz, C<sub>2α</sub>), 86.9 (ddd, J = 184.1, 17.6, 8.1 Hz, C<sub>4β</sub>), 86.9 (ddd, J = 182.7, 18.3, 7.3 Hz, C<sub>4α</sub>), 72.6 (dd, J = 23.5, 5.9 Hz, C<sub>5β</sub>), 68.6 (dd, J = 23.5, 5.9 Hz, C<sub>5α</sub>), 60.0 (s, C<sub>6β</sub>), 59.9 (s, C<sub>6α</sub>) ppm. HRMS (ESI-) for C<sub>6</sub>H<sub>8</sub>F<sub>3</sub>O<sub>3</sub> [M-H]<sup>-</sup>: calcd, 185.0426; found, 185.0435. The literature NMR data are reported in CDCl<sub>3</sub> (<sup>1</sup>H NMR without *J* values), otherwise the data above are consistent with the literature.<sup>15</sup>

Data for 2,3,4-trideoxy-2,3,4-trifluoro-D-galactopyranose **8** (while solid): R<sub>f</sub> 0.12 (pentane/EtOAc 60:40). mp 114-116 °C (CHCl<sub>3</sub>/acetone). [α]<sub>D</sub>+62.4 for (c 0.21, CD<sub>3</sub>OD, 21 °C; sample equilibrated for 48h, α/β 1.00:0.64 at time of measurement), lit<sup>17</sup>+58.9 for (c 0.6, MeOH, 25 °C). IR (neat) 3362 (w, br.), 3134 (w, br.), 2961 (w), 1159 (m), 1059 (s) cm<sup>-1</sup>. <sup>1</sup>H NMR (500 MHz, acetone-d<sub>6</sub>, δ): 6.46 (1H, br, d, J = 7.2 Hz, OH<sub>1β</sub>), 6.28 (1H, br, d, J = 4.5 Hz, OH<sub>1α</sub>), 5.47 (1H, q, J = 4.4 Hz, H<sub>1α</sub>), 5.18 (1H, dddd, J = 51.4, 7.6, 3.7, 3.0, 0.7 Hz, H<sub>4α</sub>), 5.19-5.04 (1H, m, H<sub>4β</sub>), 5.13-4.87 (3H, m, H<sub>3α</sub> + H<sub>3β</sub> + H<sub>1β</sub>), 4.86-4.70 (1H, m, a doublet with J = 51.2 Hz is observed, H<sub>2α</sub>), 4.47 (1H, ddddd, J = 52.6, 13.2, 9.1, 7.7, 1.2 Hz, H<sub>2β</sub>), 4.22-4.11 (2H, m, OH<sub>6β</sub> + H<sub>5α</sub>), 4.11 (1H, dd, J = 6.5, 5.1 Hz, OH<sub>6α</sub>), 3.78 (1H, dddd, J = 27.0, 7.5, 5.4, 1.8 Hz, H<sub>5β</sub>), 3.73-3.61 (4H, m, H<sub>6,6α</sub> + H<sub>6,6β</sub>) ppm. <sup>1</sup>H<sup>19</sup>F NMR (500 MHz, acetone-d<sub>6</sub>, δ): 6.46 (1H, d, J = 7.1 Hz, OH<sub>1β</sub>), 6.28 (1H, br, dd, J = 4.5, 0.6 Hz, OH<sub>1α</sub>), 5.47 (1H, t, J = 4.2 Hz, H<sub>1α</sub>), 5.18 (1H, br, d, J = 3.0 Hz, H<sub>4α</sub>), 5.11 (1H, br, d, J = 3.4 Hz, H<sub>4β</sub>), 5.08 (1H, dd, J = 9.5, 2.9 Hz, H<sub>3α</sub>), 4.97 (1H, dd, J = 9.2, 3.2 Hz, H<sub>3β</sub>), 4.88 (1H, t, J = 7.4 Hz, H<sub>1β</sub>), 4.78 (1H, br, dd, J = 9.6, 3.8 Hz, H<sub>2α</sub>), 4.47 (1H, dd, J = 9.2, 7.7 Hz, H<sub>2β</sub>), 4.19 (1H, br, dd, J = 6.1, 5.4 Hz, OH<sub>6β</sub>), 4.16 (1H, br, t, J = 6.9 Hz, H<sub>5α</sub>), 4.10 (1H, dd, J = 6.4, 5.1 Hz, OH<sub>6α</sub>), 3.78 (1H, dd, J = 7.7, 6.0 Hz, H<sub>5β</sub>), 3.75-3.61 (4H, m, H<sub>6,6α</sub> + H<sub>6,6β</sub>) ppm. <sup>13</sup>C<sup>1</sup>H NMR (101 MHz, acetone-d<sub>6</sub>, δ): 94.1 (dd, J = 22.7, 10.3 Hz, C<sub>1β</sub>), 90.9 (dd, J = 184.9, 18.3 Hz, C<sub>2β</sub>), 90.5 (dd, J = 20.5, 9.5 Hz, C<sub>1α</sub>), 89.8 (ddd, J = 188.5, 19.1, 17.6 Hz, C<sub>3β</sub>), 87.9 (ddd, J = 181.2, 16.1, 8.8 Hz, C<sub>4α</sub>), 87.4 (ddd, J = 187.8, 19.1, 17.6 Hz, C<sub>3α</sub>), 87.1 (ddd, J = 181.9, 16.1, 8.8 Hz, C<sub>4β</sub>), 87.0 (ddd, J = 187.8, 17.6, 2.2 Hz, C<sub>2α</sub>), 72.6 (dd, J = 17.6, 5.1 Hz, C<sub>5β</sub>), 68.7 (ddd, J = 19.1, 3.7, 1.5 Hz, C<sub>5α</sub>), 59.3-59.0 (m, C<sub>6α</sub> + C<sub>6β</sub>) ppm. <sup>19</sup>F NMR (471 MHz, acetone-d<sub>6</sub>, δ): -202.7 (dq, J = 47.7, 14.1, 6.4 Hz, F<sub>3β</sub>), -207.7 (dt, J = 52.2, 13.8, 3.6 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -207.9 to -208.1 (m, a doublet with J = 48.6 Hz is observed, F<sub>3α</sub>), -208.7 (dddd, J = 51.5, 13.6, 12.2, 3.6 Hz, F<sub>2α</sub> or F<sub>4α</sub>), -219.5 to -219.8 (m, a doublet of triplets of doublets with J = 51.0, 26.5, 15.7 Hz is observed, F<sub>2β</sub> or F<sub>4β</sub>), -222.3 to -222.6 (m, a doublet of triplets of doublets with J = 52.2, 28.6, 15.1 Hz is observed, F<sub>2α</sub> or F<sub>4α</sub>) ppm. <sup>19</sup>F<sup>1</sup>H NMR (471 MHz, acetone-d<sub>6</sub>, δ): -202.7 (dd, J = 15.0, 13.6 Hz, F<sub>3β</sub>), -207.7 (d, J = 14.3 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -208.0 (dd, J = 15.0, 13.6 Hz, F<sub>3α</sub>), -208.7 (d, J = 13.6 Hz, F<sub>2α</sub> or F<sub>4α</sub>), -219.7 (d, J = 15.0 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -222.5 (d, J = 15.0 Hz, F<sub>2α</sub> or F<sub>4α</sub>) ppm. NMR data match those previously reported.<sup>17</sup>

### 1,6-Anhydro-2,4-dideoxy-2,4-difluoroglucose 14a from 13 (Scheme 4).
To a solution of 13<sup>27,28</sup> (4.04 g, 13.5 mmol) in ethylene glycol (34 mL) were added KHF<sub>2</sub> (6.34 g, 81.2 mmol) and KF (4.72 g, 81.4 mmol). The resulting mixture was stirred for 2 h in a setup left open to the air at 170 °C before being allowed to cool down and loaded onto a silica gel column (CHCl<sub>3</sub>/acetone 70:30), which afforded pure 2,4-difluoro levoglucosan 14a (1.21 g, 7.29 mmol, 54%) as slightly orange crystals. R<sub>f</sub> 0.38 (petroleum ether/acetone 70:30). mp 96-98 °C (chloroform/acetone), lit<sup>53</sup> 99-100 °C (no solvent given). [α]<sub>D</sub>-63.0 (c 0.82, water, 21 °C), lit<sup>11</sup>-62 (c 0.82, water, 20 °C). IR (neat) 3454 (w, br.), 2961 (w), 1038 (s), 1016 (s) cm<sup>-1</sup>. <sup>1</sup>H NMR (500 MHz, CDCl<sub>3</sub>, δ): 5.61 (1H, br, dt, J = 3.8, 1.4 Hz, H<sub>1</sub>), 4.78 (1H, br, dq, J = 12.9, 5.7, 1.3 Hz, H<sub>5</sub>), 4.45 (1H, m, J = 46.4 Hz is observed, H<sub>4</sub>), 4.30 (1H, br, dquin, J = 46.4, 1.3 Hz, H<sub>2</sub>), 4.11 (1H, m, J = 18.0 Hz can be extracted, H<sub>3</sub>), 4.04 (1H, dt, J = 7.8, 0.9 Hz,
(d, J 12.1 Hz, F₂(Glc)), -195.5 (d, J 15.6 Hz, F₄(Gal)), -208.8 (dd, J 15.6, 3.5 Hz, F₃(Gal)), -209.0 (d, J 5.2 Hz, F₂(Gal)) ppm.

### 2,3,4-Trideoxy-2,3,4-trifluoro-D-glucopyranose 1 and 2,3,4-Trideoxy-2,3,4-trifluoro-D-galactopyranose 8 from the Mixture of 5a and 7 (Scheme 2).
To a solution of the mixture of 5a/7 (89 mg, 0.53 mmol) in CH₂Cl₂ (3.6 mL) at 0 °C was added BCl₃ (1 M in CH₂Cl₂, 2.2 mL, 2.2 mmol) dropwise. The resulting mixture was stirred at rt for 2 h before being quenched with water (5 mL). The organic solvent was then removed under reduced pressure, and the resulting aqueous phase was stirred for an additional 1 h at rt. The remaining water was evaporated to give a brown dense oil, which was then purified by column chromatography (pentane/acetone 90:10 to 60:40) to afford 90 mg (0.48 mmol, 91%) of a “pure” mixture of **1** and **8**. Complete separation of the two diastereoisomers could be achieved via repeated HPLC separations (pentane/acetone 70:30).

Data for 2,3,4-trideoxy-2,3,4-trifluoro-D-glucopyranose **1** (white solid): R<sub>f</sub> 0.12 (pentane/EtOAc 60:40). mp 98–100 °C (CHCl<sub>3</sub>/acetone), lit<sup>15</sup> 103–105 °C (CHCl<sub>3</sub>). [α]<sub>D</sub> +28.0 for α/β 0.30:1.00 (c 0.99, CD<sub>3</sub>OD, 21 °C), lit<sup>15</sup> +40.1 for α/β 1.0:9.8 (c 1.15, THF-d<sub>8</sub>, 22 °C). IR (neat) 3367 (m, br.), 3111 (m, br.), 2961 (m), 1032 (s), 995 (s) cm<sup>-1</sup>. <sup>1</sup>H NMR (500 MHz, CDCl<sub>3</sub>, δ): 5.49 (1H, br, q, J = 3.1 Hz, H<sub>1α</sub>), 5.09 (1H, ddddd, J = 55.0, 16.6, 14.0, 8.4, 7.9 Hz, H<sub>3α</sub>), 4.92 (1H, br, dd, J = 7.6, 3.0 Hz, H<sub>1β</sub>), 4.82 (1H, dddt, 53.1, 16.5, 15.9, 8.3 Hz, H<sub>3β</sub>), 4.66 (1H, m, a doublet with J = 50.4 Hz can observed, H<sub>4β</sub>), 4.64 (1H, dddd J = 50.9, 15.1, 9.9, 8.3 Hz, H<sub>4α</sub>), 4.53 (1H, dddd, J = 49.8, 12.9, 8.9, 3.9 Hz, H<sub>2α</sub>), 4.35 (1H, dddd, J = 50.9, 14.5, 8.1, 7.6 Hz, H<sub>2β</sub>), 4.13 (1H, ddq, J = 9.8, 4.4, 2.5 Hz, H<sub>5α</sub>), 4.03–3.73 (4H, m, H<sub>6,6α</sub> + H<sub>6,6β</sub>), 3.63–3.57 (1H, m, H<sub>5β</sub>), 3.34 (1H, br, s, OH<sub>1α</sub>), 1.84 (1H, br, s, OH<sub>6α</sub> ppm. <sup>1</sup>H<sup>[19F]</sup> NMR (500 MHz, CDCl<sub>3</sub>, δ): 5.49 (1H, br, d, J = 3.6 Hz, H<sub>1α</sub>), 5.09 (1H, t, J = 8.5 Hz, H<sub>3α</sub>), 4.92 (1H, d, J = 7.7 Hz, H<sub>1β</sub>), 4.82 (1H, t, J = 8.3 Hz, H<sub>3β</sub>), 4.67 (1H, dd, J = 9.8, 8.3 Hz, H<sub>4β</sub>), 4.64 (1H, dd, J = 9.3, 8.3 Hz, H<sub>4α</sub>), 4.53 (1H, dd, J = 8.8, 3.8 Hz, H<sub>2α</sub>), 4.35 (1H, dd, J = 8.3, 7.7 Hz, H<sub>2β</sub>), 4.13 (1H, ddd, J = 9.9, 4.2, 2.4 Hz, H<sub>5α</sub>), 4.03–3.74 (4H, m, H<sub>6,6α</sub> + H<sub>6,6β</sub>), 3.60 (1H, ddd, J = 9.8, 4.7, 2.4 Hz, H<sub>5β</sub>), 3.34 (1H, br, s, OH<sub>1α</sub>), 1.84 (1H, br, s, OH<sub>6α</sub> ppm. <sup>19</sup>F NMR (471 MHz, CDCl<sub>3</sub>, δ): -195.1 to -195.4 (m, a doublet of quintets with J = 53.2, 13.6 Hz is observed, F<sub>3β</sub>), -199.3 to -199.6 (m, a doublet of triplets with J = 50.9, 14.4 Hz is observed, F<sub>2α</sub> or F<sub>4α</sub>), -200.0 (dddt, J = 50.9, 15.9, 13.0, 2.9 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -200.6 to -200.9 (m, a doublet of triplets with J = 50.7, 14.5 Hz is observed, F<sub>2β</sub> or F<sub>4β</sub>), -201.0 to -201.30 (m, a doublet of quintets with J = 54.9, 13.5 Hz is observed, F<sub>3α</sub>), -201.5 (dtd, J = 49.9, 13.6, 2.0 Hz, F<sub>2α</sub> or F<sub>4α</sub> ppm. <sup>19</sup>F<sup>{1H}</sup> NMR (471 MHz, CDCl<sub>3</sub>, δ): -195.3 (t, J = 12.9 Hz, F<sub>3β</sub>), -199.4 (dd, J = 12.9, 2.1 Hz, F<sub>2α</sub> or F<sub>4α</sub>), -200.0 (dd, J = 13.6, 2.9 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -200.8 (dd, J = 12.5, 2.5 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -201.1 (t, J = 12.9 Hz, F<sub>2α</sub> or F<sub>4α</sub>), -201.5 (dd, J = 12.9, 2.1 Hz, F<sub>2α</sub> or F<sub>4α</sub> ppm. The spectral dispersion in CD<sub>3</sub>OD is superior. <sup>1</sup>H NMR (500 MHz, CD<sub>3</sub>OD, δ): 5.33 (1H, q, J = 3.5 Hz, H<sub>1α</sub>), 4.97 (1H, dddt, J = 56.0, 17.0, 13.8, 8.6 Hz, H<sub>3α</sub>), 4.88 (1H, dddt, J = 54.3, 16.8, 15.9, 8.4 Hz, H<sub>3β</sub>), 4.82 (1H, dd, J = 7.7, 2.8 Hz, H<sub>1β</sub>), 4.68–4.49 (2H, m, H<sub>4α</sub> + H<sub>4β</sub>), 4.49 (1H, ddddd, J = 50.4, 13.2, 8.9, 3.8, 0.4 Hz, H<sub>2α</sub>), 4.21 (1H, ddt, J = 51.5, 15.1, 8.3 Hz, H<sub>2β</sub>), 4.02–3.96 (1H, m, H<sub>5α</sub>), 3.84 (1H, dq, J = 12.4, 2.0 Hz, H<sub>6β</sub>), 3.78 (1H, dq, J = 12.4, 2.0 Hz, H<sub>6α</sub>), 3.73 (1H, ddd, J = 12.4, 4.1, 1.8 Hz, H<sub>6α</sub>), 3.70 (1H, ddd, J = 12.4, 4.7, 2.0 Hz, H<sub>6β</sub>), 3.62–3.56 (1H, m, H<sub>5β</sub> ppm. <sup>1</sup>H<sup>[19F]</sup> NMR (500 MHz, CD<sub>3</sub>OD, δ): 5.33 (1H, d, J = 3.8 Hz, H<sub>1α</sub>), 4.96 (1H, br, t = 8.4 Hz, H<sub>3α</sub>), 4.88 (1H, t, J = 8.4 Hz, H<sub>3β</sub>), 4.82 (1H, d, J = 7.7 Hz, H<sub>1β</sub>), 4.59 (1H, dd, J = 9.8, 8.3 Hz, H<sub>4β</sub>), 4.58 (1H, dd, J = 9.9, 8.2 Hz, H<sub>4α</sub>), 4.49 (1H, dd, J = 9.0, 3.8 Hz, H<sub>2α</sub>), 4.21 (1H, t, J = 8.1 Hz, H<sub>2β</sub>), 3.99 (1H, br, ddd, J = 9.8, 4.1, 2.3 Hz, H<sub>5α</sub>), 3.84 (1H, dd, J = 12.4, 2.1 Hz, H<sub>6β</sub>), 3.79 (1H, dd, J = 12.4, 2.1 Hz, H<sub>6α</sub>), 3.73 (1H, dd, J = 12.4, 4.1 Hz, H<sub>6α</sub>), 3.70 (1H, dd, J = 12.4, 4.7 Hz, H<sub>6β</sub>), 3.59 (1H, ddd, J = 9.8, 4.7, 2.1 Hz, H<sub>5β</sub> ppm. <sup>19</sup>F NMR (471 MHz, CD<sub>3</sub>OD, δ): -196.9–-197.2 (m, a doublet of quintets with J = 54.4, 13.6 Hz is observed, F<sub>3β</sub>), -200.7 to -201.0 (m, a doublet of triplets with J = 51.5, 14.3 Hz is observed, F<sub>2α</sub> or F<sub>4α</sub>), -201.7 (dddt, J = 51.5, 15.7, 12.9, 2.9 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -202.4 to -202.8 (2F, m, F<sub>3α</sub> and F<sub>2β</sub> or F<sub>4β</sub>), -203.1 (dtd, J = 50.0, 13.6, 2.1 Hz, F<sub>2α</sub> or F<sub>4α</sub>) ppm. <sup>19</sup>F<sup>{1H}</sup> NMR (471 MHz, CD<sub>3</sub>OD, δ): -197.1 (t, J = 12.9 Hz, F<sub>3β</sub>), -200.9 (dd, J = 12.2, 2.1 Hz, F<sub>2α</sub> or F<sub>4α</sub>), -201.7

(dd, J = 12.9, 2.9 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -202.6 (dd, J = 12.2, 2.9 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -202.7 (t, J = 12.9 Hz, F<sub>3α</sub>), -203.1 (dd, J = 12.9, 2.1 Hz, F<sub>2α</sub> or F<sub>4α</sub>) ppm. To obtain a <sup>13</sup>C NMR spectrum with all carbon atoms clearly visible, acetone-d<sub>6</sub> was used as the solvent (due to the low solubility of **1** in CDCl<sub>3</sub>, we did not obtain a high-quality spectrum). <sup>13</sup>C<sup>{1H}</sup> NMR (101 MHz, acetone-d<sub>6</sub>, δ): 93.7 (ddd, J = 22.7, 10.3, 1.5 Hz, C<sub>1β</sub>), 92.7 (dt, J = 185.6, 19.8 Hz, C<sub>3β</sub>), 91.2 (ddd, J = 187.8, 17.6, 8.1 Hz, C<sub>2β</sub>), 91.1 (ddd, J = 185.6, 20.5, 19.8 Hz, C<sub>3α</sub>), 90.0 (dd, J = 21.3, 10.3 Hz, C<sub>1α</sub>), 88.0 (ddd, J = 189.3, 14.7, 8.1 Hz, C<sub>2α</sub>), 86.9 (ddd, J = 184.1, 17.6, 8.1 Hz, C<sub>4β</sub>), 86.9 (ddd, J = 182.7, 18.3, 7.3 Hz, C<sub>4α</sub>), 72.6 (dd, J = 23.5, 5.9 Hz, C<sub>5β</sub>), 68.6 (dd, J = 23.5, 5.9 Hz, C<sub>5α</sub>), 60.0 (s, C<sub>6β</sub>), 59.9 (s, C<sub>6α</sub>) ppm. HRMS (ESI<sup>-</sup>) for C<sub>6</sub>H<sub>8</sub>F<sub>3</sub>O<sub>3</sub> [M<sup>-</sup> H]<sup>+</sup>: calcd, 185.0426; found, 185.0435. The literature NMR data are reported in CDCl<sub>3</sub> (<sup>1</sup>H NMR without *J* values), otherwise the data above are consistent with the literature.<sup>15</sup>

Data for 2,3,4-trideoxy-2,3,4-trifluoro-D-galactopyranose **8** (while solid): R<sub>f</sub> 0.12 (pentane/EtOAc 60:40). mp 114–116 °C (CHCl<sub>3</sub>/acetone). [α]<sub>D</sub> +62.4 for (c 0.21, CD<sub>3</sub>OD, 21 °C; sample equilibrated for 48h, α/β 1.00:0.64 at time of measurement), lit<sup>17</sup>+58.9 for (c 0.6, MeOH, 25 °C). IR (neat) 3362 (w, br.), 3134 (w, br.), 2961 (w), 1159 (m), 1059 (s) cm<sup>-1</sup>. <sup>1</sup>H NMR (500 MHz, acetone-d<sub>6</sub>, δ): 6.46 (1H, br, d, J = 7.2 Hz, OH<sub>1β</sub>), 6.28 (1H, br, d, J = 4.5 Hz, OH<sub>1α</sub>), 5.47 (1H, q, J = 4.4 Hz, H<sub>1α</sub>), 5.18 (1H, ddddd, J = 51.4, 7.6, 3.7, 3.0, 0.7 Hz, H<sub>4α</sub>), 5.19–5.04 (1H, m, H<sub>4β</sub>), 5.13–4.87 (3H, m, H<sub>3α</sub> + H<sub>3β</sub> + H<sub>1β</sub>), 4.86–4.70 (1H, m, a doublet with J = 51.2 Hz is observed, H<sub>2α</sub>), 4.47 (1H, ddddd, J = 52.6, 13.2, 9.1, 7.7, 1.2 Hz, H<sub>2β</sub>), 4.22–4.11 (2H, m, OH<sub>6β</sub> + H<sub>5α</sub>), 4.11 (1H, dd, J = 6.5, 5.1 Hz, OH<sub>6α</sub>), 3.78 (1H, dddd, J = 27.0, 7.5, 5.4, 1.8 Hz, H<sub>5β</sub>), 3.73–3.61 (4H, m, H<sub>6,6α</sub> + H<sub>6,6β</sub>) ppm. <sup>1</sup>H<sup>[19F]</sup> NMR (500 MHz, acetone-d<sub>6</sub>, δ): 6.46 (1H, d, J = 7.1 Hz, OH<sub>1β</sub>), 6.28 (1H, br, dd, J = 4.5, 0.6 Hz, OH<sub>1α</sub>), 5.47 (1H, t, J = 4.2 Hz, H<sub>1α</sub>), 5.18 (1H, br, d, J = 3.0 Hz, H<sub>4α</sub>), 5.11 (1H, br, d, J = 3.4 Hz, H<sub>4β</sub>), 5.08 (1H, dd, J = 9.5, 2.9 Hz, H<sub>3α</sub>), 4.97 (1H, dd, J = 9.2, 3.2 Hz, H<sub>3β</sub>), 4.88 (1H, t, J = 7.4 Hz, H<sub>1β</sub>), 4.78 (1H, br, dd, J = 9.6, 3.8 Hz, H<sub>2α</sub>), 4.47 (1H, dd, J = 9.2, 7.7 Hz, H<sub>2β</sub>), 4.19 (1H, br, dd, J = 6.1, 5.4 Hz, OH<sub>6β</sub>), 4.16 (1H, br, t, J = 6.9 Hz, H<sub>5α</sub>), 4.10 (1H, dd, J = 6.4, 5.1 Hz, OH<sub>6α</sub>), 3.78 (1H, dd, J = 7.7, 6.0 Hz, H<sub>5β</sub>), 3.75–3.61 (4H, m, H<sub>6,6α</sub> + H<sub>6,6β</sub>) ppm. <sup>13</sup>C<sup>{1H}</sup> NMR (101 MHz, acetone-d<sub>6</sub>, δ): 94.1 (dd, J = 22.7, 10.3 Hz, C<sub>1β</sub>), 90.9 (dd, J = 184.9, 18.3 Hz, C<sub>2β</sub>), 90.5 (dd, J = 20.5, 9.5 Hz, C<sub>1α</sub>), 89.8 (ddd, J = 188.5, 19.1, 17.6 Hz, C<sub>3β</sub>), 87.9 (ddd, J = 181.2, 16.1, 8.8 Hz, C<sub>4α</sub>), 87.4 (ddd, J = 187.8, 19.1, 17.6 Hz, C<sub>3α</sub>), 87.1 (ddd, J = 181.9, 16.1, 8.8 Hz, C<sub>4β</sub>), 87.0 (ddd, J = 187.8, 17.6, 2.2 Hz, C<sub>2α</sub>), 72.6 (dd, J = 17.6, 5.1 Hz, C<sub>5β</sub>), 68.7 (ddd, J = 19.1, 3.7, 1.5 Hz, C<sub>5α</sub>), 59.3–59.0 (m, C<sub>6α</sub> + C<sub>6β</sub>) ppm. <sup>19</sup>F NMR (471 MHz, acetone-d<sub>6</sub>, δ): -202.7 (dq, J = 47.7, 14.1, 6.4 Hz, F<sub>3β</sub>), -207.7 (dt, J = 52.2, 13.8, 3.6 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -207.9 to -208.1 (m, a doublet with J = 48.6 Hz is observed, F<sub>3α</sub>), -208.7 (dddd, J = 51.5, 13.6, 12.2, 3.6 Hz, F<sub>2α</sub> or F<sub>4α</sub>), -219.5 to -219.8 (m, a doublet of triplets of doublets with J = 51.0, 26.5, 15.7 Hz is observed, F<sub>2β</sub> or F<sub>4β</sub>), -222.3 to -222.6 (m, a doublet of triplets of doublets with J = 52.2, 28.6, 15.1 Hz is observed, F<sub>2α</sub> or F<sub>4α</sub>) ppm. <sup>19</sup>F<sup>{1H}</sup> NMR (471 MHz, acetone-d<sub>6</sub>, δ): -202.7 (dd, J = 15.0, 13.6 Hz, F<sub>3β</sub>), -207.7 (d, J = 14.3 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -208.0 (dd, J = 15.0, 13.6 Hz, F<sub>3α</sub>), -208.7 (d, J = 13.6 Hz, F<sub>2α</sub> or F<sub>4α</sub>), -219.7 (d, J = 15.0 Hz, F<sub>2β</sub> or F<sub>4β</sub>), -222.5 (d, J = 15.0 Hz, F<sub>2α</sub> or F<sub>4α</sub>) ppm. NMR data match those previously reported.<sup>17</sup>

### 1,6-Anhydro-2,4-dideoxy-2,4-difluoroglucose 14a from 13 (Scheme 4).
To a solution of 13<sup>27,28</sup> (4.04 g, 13.5 mmol) in ethylene glycol (34 mL) were added KHF<sub>2</sub> (6.34 g, 81.2 mmol) and KF (4.72 g, 81.4 mmol). The resulting mixture was stirred for 2 h in a setup left open to the air at 170 °C before being allowed to cool down and loaded onto a silica gel column (CHCl<sub>3</sub>/acetone 70:30), which afforded pure 2,4-difluoro levoglucosan 14a (1.21 g, 7.29 mmol, 54%) as slightly orange crystals. R<sub>f</sub> 0.38 (petroleum ether/acetone 70:30). mp 96–98 °C (chloroform/acetone), lit<sup>53</sup> 99–100 °C (no solvent given). [α]<sub>D</sub> -63.0 (c 0.82, water, 21 °C), lit<sup>11</sup> -62 (c 0.82, water, 20 °C). IR (neat) 3454 (w, br.), 2961 (w), 1038 (s), 1016 (s) cm<sup>-1</sup>. <sup>1</sup>H NMR (500 MHz, CDCl<sub>3</sub>, δ): 5.61 (1H, br, dt, J = 3.8, 1.4 Hz, H<sub>1</sub>), 4.78 (1H, br, dq, J = 12.9, 5.7, 1.3 Hz, H<sub>5</sub>), 4.45 (1H, m, J = 46.4 Hz is observed, H<sub>4</sub>), 4.30 (1H, br, dquin, J = 46.4, 1.3 Hz, H<sub>2</sub>), 4.11 (1H, m, J = 18.0 Hz can be extracted, H<sub>3</sub>), 4.04 (1H, dt, J = 7.8, 0.9 Hz,
$H_{6endo}$), 3.80 (1H, m, $H_{6exo}$), 2.30 (1H, br, d, $J = 6.1$ Hz, $OH_3$) ppm. $^{13}$C{$^{1}$H} NMR (101 MHz, $CDCl_3$, δ): 99.3 (d, $J = 28.6$ Hz, $C_1$), 89.9 (dd, $J = 181.9$, 5.1 Hz, $C_4$), 88.0 (dd, $J = 184.1$, 4.4 Hz, $C_2$), 74.3 (d, $J = 22.7$ Hz, $C_5$), 69.5 (dd, $J = 29.3$, 27.9 Hz, $C_3$), 64.7 (d, $J = 9.5$ Hz, $C_6$) ppm. $^{19}$F NMR (471 MHz, $CDCl_3$, δ): -183.3 (m, $J = 46.3$, 17.3, 12.8, 4.1, 0.9 Hz, $F_4$), -188.4 (ddd, $J = 46.5$, 18.4, 3.9 Hz, $F_2$) ppm. $^{19}$F{$^{1}$H} NMR (471 MHz, $CDCl_3$, δ): -183.3 (s, $F_4$), -188.4 (s, $F_2$) ppm. HRMS (CI) for $C_6H_9F_2O_3$ [M + H]$^+$: calcd, 167.05143; found, 167.05391. NMR data match those previously reported.¹⁷

**1,6-Anhydro-2,4-dideoxy-2,4-difluoroglucose 14a from 17 (Scheme 4).** Following the same procedure as described just above, 2,4-di-O-tosyl levoglucosan 17<sup>27,28</sup> (8.36 g, 17.8 mmol) was converted into 2,4-difluoro levoglucosan 14a (1.51 g, 9.09 mmol, 55%), obtained pure as a white solid after column chromatography ($CH_2Cl_2$/EtOAc 60:40).

**1,6-Anhydro-2,4-dideoxy-2,4-difluoroallose 21 (Scheme 5).** To a round-bottomed flask were added 2,4-difluoro levoglucosan 14a (790 mg, 4.76 mmol) and anhydrous $CH_2Cl_2$ (78.3 mL). The resulting solution was cooled to 0 °C, followed by the addition of TCCA (2.19 g, 9.42 mmol) and TEMPO (40 mg, 0.256 mmol). The reaction mixture was stirred at room temperature for 2 h and monitored by TLC analysis. Upon completion, the mixture was filtered over Celite, dried over $Na_2SO_4$, and concentrated under reduced pressure. The crude mixture was eluted over a pad of silica gel (acetone/$CH_2Cl_2$ 10/90–20/80) to afford a mixture of the 3-uloside **18** and its hydrate form **20**. Following a modified literature procedure,³⁷ this mixture (~4.76 mmol) was dissolved in EtOH (reagent grade, 25 mL), followed by slow addition of a solution of $NaBH_4$ (540 mg, 14.27 mmol) in EtOH (25 mL). The reaction mixture was stirred at room temperature for 2 h and then monitored by $^{19}$F{$^{1}$H} NMR analysis. Upon completion, acetic acid (1 mL) was slowly added to the reaction mixture, and the solvent was then removed by evaporation under reduced pressure. The residue was diluted with water (100 mL) and extracted with EtOAc (100 mL × 7). The combined organic layer was dried over $Na_2SO_4$, filtered, and concentrated. $^{19}$F{$^{1}$H} NMR analysis of the crude mixture indicated that reduction of the ketone was highly diastereoselective (de ≈99%, see the Supporting Information). The crude mixture was purified by flash chromatography (acetone/$CH_2Cl_2$ 10/90) to afford the desired product **21** (670 mg, 4.03 mmol, 85%) as a white solid. An analytical sample of pure **21** was obtained by HPLC ($CH_2Cl_2$/EtOAc 70:30), as a white solid. $R_f$ 0.70 ($CH_2Cl_2$/acetone 70:30). mp 108–110 °C (hexane/$CH_2Cl_2$), lit³⁷ 113–115 °C (EtOAc). [$\alpha$]$_D$ -69.0 (c 1.06, MeOH, 24 °C), lit³⁷ -85 (c 0.6, $CHCl_3$, 23–25 °C). IR (neat) 3265 (m, br.), 2989 (w), 2915 (w), 1339 (m), 1033 (s) cm⁻¹. ¹H NMR (500 MHz, $CDCl_3$, δ): 5.67 (1H, br, t, $J = 2.1$ Hz, $H_1$), 4.90–4.83 (1H, m, $H_5$), 4.68 (1H, m, $J = 48.5$ Hz is observed, $H_4$), 4.57 (1H, m, $J = 49.8$ Hz is observed, $H_2$), 3.92–3.75 (1H, m, $H_{6exo}$), 3.84 (1H, m, $J = 12.4$, 4.2 Hz is observed, $H_3$), 3.72 (1H, br, dt, $J = 8.4$, 1.1 Hz, $H_{6endo}$), 2.73 (1H, dt, $J = 12.4$, 2.3 Hz, $OH_3$) ppm. ¹H{$^{19}$F} NMR (500 MHz, $CDCl_3$, δ): 5.67 (1H, d, $J = 2.6$ Hz, $H_1$), 4.87 (1H, m, $H_5$), 4.68 (1H, br, t, $J = 3.4$ Hz, $H_4$), 4.57 (1H, ddd, $J = 4.1$, 2.8, 1.1 Hz, $H_2$), 3.84 (1H, dt, $J = 12.1$, 4.1 Hz, $H_3$), 3.83 (1H, dd, $J = 8.6$, 5.6 Hz, $H_{6exo}$), 3.72 (1H, dd, $J = 8.4$, 1.0 Hz, $H_{6endo}$), 2.73 (1H, d, $J = 12.4$ Hz, $OH_3$) ppm. $^{13}$C{$^{1}$H} NMR (101 MHz, $CDCl_3$, δ): 98.5 (d, $J = 24.2$ Hz, $C_1$), 88.0 (d, $J = 184.9$ Hz, $C_2$), 86.5 (d, $J = 184.9$ Hz, $C_4$), 73.6 (d, $J = 19.1$ Hz, $C_5$), 63.7 (d, $J = 6.6$ Hz, $C_6$), 62.8 (t, $J = 18.3$ Hz, $C_3$) ppm. $^{19}$F NMR (471 MHz, $CDCl_3$, δ): -204.8 (m, $F_4$), -207.0 (br, dddt, $J = 49.9$, 25.6, 8.9, 2.3 Hz, $F_2$) ppm. $^{19}$F{$^{1}$H} NMR (471 MHz, $CDCl_3$, δ): -204.8 (d, $J = 9.3$ Hz, $F_4$), -207.0 (d, $J = 9.3$ Hz, $F_2$) ppm. HRMS (CI) for $C_6H_9F_2O_3$ [M + H]$^+$: calcd, 167.05143; found, 167.05425.

**1,6-Anhydro-3-O-trifluoromethanesulfonyl-2,4-dideoxy-2,4-difluoroallose 22a (Scheme 5).** To a solution of a 8:92 mixture of 14a/21 (205 mg, 1.23 mmol, 1.13 mmol of 21) in dry $CH_2Cl_2$ (3.2 mL) at 0 °C was added pyridine (0.12 mL, 1.48 mmol). Stirring was continued at 0 °C for 10 min before $Tf_2O$ (0.21 mL, 1.26 mmol) was added. The resulting mixture was allowed to warm to rt and stirred for an additional hour before being filtered through a pad of silica. Solvent was removed under vacuum, and the resulting orange oil was purified by column chromatography (hexane/$CH_2Cl_2$ 80:20 to

60:40), which afforded 218 mg (0.73 mmol, 65%) of compound 22a as a white solid. $R_f$ 0.24 (pentane/$CH_2Cl_2$ 50:50). mp 108–110 °C (pentane/$CH_2Cl_2$). [$\alpha$]$_D$ -50.2 (c 0.52, $CHCl_3$, 22 °C). ¹H NMR (500 MHz, $CDCl_3$, δ): 5.71 (1H, br, t, $J = 2.2$ Hz, $H_1$), 4.95–4.91 (1H, $m, H_5$), 4.90 (1H, m, $J = 24.3$, 3.9 Hz is observed, $H_3$), 4.87 (1H, m, $J = 50.9$ Hz is observed, $H_4$), 4.75 (1H, m, $J = 50.3$ Hz is observed, $H_2$), 3.88 (1H, m, $J = 8.6$, 5.1, 2.2 Hz is observed, $H_{6exo}$), 3.80 (1H, br, dt, $J = 8.9$, 1.0 Hz, $H_{6endo}$) ppm. ¹H{$^{19}$F} NMR (500 MHz, $CDCl_3$, δ): 5.71 (1H, d, $J = 2.8$ Hz, $H_1$), 4.94 (1H, br, dd, $J = 4.8$, 2.7 Hz, $H_5$), 4.90 (1H, t, $J = 3.8$ Hz, $H_3$), 4.88–4.84 (1H, m, $H_4$), 4.76 (1H, m, $J = 3.9$, 2.6, 1.4 Hz is observed, $H_2$), 3.88 (1H, dd, $J = 8.8$, 5.6 Hz, $H_{6exo}$), 3.80 (1H, dd, $J = 8.8$, 0.9 Hz, $H_{6endo}$) ppm. $^{13}$C{$^{1}$H} NMR (101 MHz, $CDCl_3$, δ): 118.3 (q, $J = 319.1$ Hz, $CF_3$), 98.4 (d, $J = 23.5$ Hz, $C_1$), 85.6 (d, $J = 195.1$ Hz, $C_4$), 84.3 (d, $J = 197.3$ Hz, $C_2$), 75.7 (t, $J = 16.9$ Hz, $C_3$), 73.9 (d, $J = 19.1$ Hz, $C_5$), 63.7 (d, $J = 5.9$ Hz, $C_6$) ppm. $^{19}$F NMR (376 MHz, $CDCl_3$, δ): -75.04 (s, $CF_3$), -202.1–-202.5 (m), -204.2 (ddd, $J = 50.3$, 24.3, 10.4 Hz) ppm. $^{19}$F{$^{1}$H} NMR (376 MHz, $CDCl_3$, δ): -75.0 (s, $CF_3$), -202.3 (d, $J = 10.4$ Hz), -204.2 (d, $J = 10.4$ Hz) ppm. HRMS (CI) for $C_6H_8F_3O_2S$ [M + H]$^+$: calcd, 299.00071; found, 299.00012.

**1,6-Anhydro-2,3,4-trideoxy-2,3,4-trifluoroglucose 5a from 21 (Scheme 5).** To a solution of 21 containing 4% of 14a (335 mg, 2.02 mmol, 1.94 mmol of 21) in anhydrous THF (5.7 mL) in a sealed tube reactor were added triethylamine (1.62 mL, 11.6 mmol, 5.8 equiv), $Et_3N·3HF$ (0.63 mL, 3.86 mmol), and $NfF$ (0.65 mL, 3.92 mmol). The resulting mixture was stirred at 90 °C for 4 days before being quenched with sat. aq. $NaHCO_3$ (17 mL). The layers were separated, and the aqueous phase was diluted with water (20 mL) to dissolve the large amount of salts formed during quenching and extracted with $CH_2Cl_2$ (3 × 50 mL). The organic phases were combined, dried over $MgSO_4$, and concentrated under vacuum. Purification by column chromatography (pentane/DCM 90:10 to 50:50) afforded 5a (222 mg, 1.34 mmol, 69%) as a white solid, as well as unreacted 14a (10 mg). $R_f$ 0.64 (pentane/EtOAc 80:20). mp 66–68 °C (hexane/$CH_2Cl_2$). [$\alpha$]$_D$ -53.8 (c 1.30, $CHCl_3$, 24 °C), lit¹⁴ -56.0 (c 1.32, $CHCl_3$, 22 °C). ¹H NMR (400 MHz, $CDCl_3$, δ): 5.62 (1H, br, s, $H_1$), 4.85–4.78 (1H, m, $H_5$), 4.83 (1H, dtquin, $J = 42.5$, 15.2, 1.7 Hz, $H_3$), 4.57 (1H, ddd, $J = 44.7$, 14.9, 1.2 Hz, $H_4$), 4.43 (1H, ddd, $J = 45.5$, 15.2, 1.2 Hz, $H_2$), 3.97 (1H, dd, $J = 8.1$, 1.0 Hz, $H_{6endo}$), 3.90–3.78 (1H, m, $H_{6exo}$) ppm. $^{13}$C{$^{1}$H} NMR (101 MHz, $CDCl_3$, δ): 98.6 (dd, $J = 28.6$, 2.2 Hz, $C_1$), 87.2 (dt, $J = 178.3$, 33.7 Hz, $C_3$), 86.4 (ddd, $J = 182.7$, 31.5, 4.4 Hz, $C_4$), 84.5 (ddd, $J = 182.7$, 27.9, 3.7 Hz, $C_2$), 73.5 (dd, $J = 21.6$, 1.8 Hz, $C_3$), 64.1 (dd, $J = 9.2$, 2.6 Hz, $C_6$) ppm. $^{19}$F NMR (376 MHz, $CDCl_3$, δ): -188.0 (ddtd, $J = 44.8$, 15.7, 10.9, 4.3 Hz, $F_4$), -191.1 (dquin, $J = 42.4$, 14.1 Hz, $F_3$), -193.6 (m, $J = 45.1$ Hz is observed, $F_2$) ppm. $^{19}$F{$^{1}$H} NMR (376 MHz, $CDCl_3$, δ): -188.0 (d, $J = 12.1$ Hz, $F_4$), -191.1 (t, $J = 12.1$ Hz, $F_3$), -193.6 (1F, d, $J = 12.1$ Hz, $F_2$) ppm. $^{13}$C NMR matches the literature data (pyridine $d_5$).¹⁴

**2,3,4-Trideoxy-2,3,4-trifluoro-D-glucopyranose 1 from Pure 5a (Scheme 5).** To a solution of trifluoro levoglucosan 5a (124 mg, 0.74 mmol) in $CH_2Cl_2$ (5.1 mL) at 0 °C was added $BCl_3$ (1 M in $CH_2Cl_2$, 3.1 mL, 3.1 mmol) dropwise. The resulting mixture was stirred at rt for 2 h before being quenched with water (7 mL). DCM was then removed under reduced pressure, and the resulting aqueous phase was stirred for an additional 1 h at rt. The remaining water was evaporated to give a brown dense oil, which was then purified by column chromatography (pentane/acetone 90:10 to 60:40) to afford 119 mg of trifluoroglucose 1 (0.64 mmol, 87%) as a dense clear oil, which solidified upon standing.

## ASSOCIATED CONTENT

### Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b00310.

Copies of NMR spectra; ratio determination for the DAST reaction of 4 and reduction of 18; tables with the relative Gibbs energy and populations of the energetic minima of 21 and discussion about the coupling constant analysis; X-ray data of compounds 1, 5a, 8,
$H_{6endo}$), 3.80 (1H, m, $H_{6exo}$), 2.30 (1H, br, d, $J = 6.1$ Hz, $OH_3$) ppm. $^{13}$C{$^{1}$H} NMR (101 MHz, $CDCl_3$, δ): 99.3 (d, $J = 28.6$ Hz, $C_1$), 89.9 (dd, $J = 181.9$, 5.1 Hz, $C_4$), 88.0 (dd, $J = 184.1$, 4.4 Hz, $C_2$), 74.3 (d, $J = 22.7$ Hz, $C_5$), 69.5 (dd, $J = 29.3$, 27.9 Hz, $C_3$), 64.7 (d, $J = 9.5$ Hz, $C_6$) ppm. $^{19}$F NMR (471 MHz, $CDCl_3$, δ): -183.3 (m, $J = 46.3$, 17.3, 12.8, 4.1, 0.9 Hz, $F_4$), -188.4 (ddd, $J = 46.5$, 18.4, 3.9 Hz, $F_2$) ppm. $^{19}$F{$^{1}$H} NMR (471 MHz, $CDCl_3$, δ): -183.3 (s, $F_4$), -188.4 (s, $F_2$) ppm. HRMS (CI) for $C_6H_9F_2O_3$ [M + H]$^+$: calcd, 167.05143; found, 167.05391. NMR data match those previously reported.¹⁷

**1,6-Anhydro-2,4-dideoxy-2,4-difluoroglucose 14a from 17 (Scheme 4).** Following the same procedure as described just above, 2,4-di-O-tosyl levoglucosan 17<sup>27,28</sup> (8.36 g, 17.8 mmol) was converted into 2,4-difluoro levoglucosan 14a (1.51 g, 9.09 mmol, 55%), obtained pure as a white solid after column chromatography ($CH_2Cl_2$/EtOAc 60:40).

**1,6-Anhydro-2,4-dideoxy-2,4-difluoroallose 21 (Scheme 5).** To a round-bottomed flask were added 2,4-difluoro levoglucosan 14a (790 mg, 4.76 mmol) and anhydrous $CH_2Cl_2$ (78.3 mL). The resulting solution was cooled to 0 °C, followed by the addition of TCCA (2.19 g, 9.42 mmol) and TEMPO (40 mg, 0.256 mmol). The reaction mixture was stirred at room temperature for 2 h and monitored by TLC analysis. Upon completion, the mixture was filtered over Celite, dried over $Na_2SO_4$, and concentrated under reduced pressure. The crude mixture was eluted over a pad of silica gel (acetone/$CH_2Cl_2$ 10/90–20/80) to afford a mixture of the 3-uloside **18** and its hydrate form **20**. Following a modified literature procedure,³⁷ this mixture (~4.76 mmol) was dissolved in EtOH (reagent grade, 25 mL), followed by slow addition of a solution of $NaBH_4$ (540 mg, 14.27 mmol) in EtOH (25 mL). The reaction mixture was stirred at room temperature for 2 h and then monitored by $^{19}$F{$^{1}$H} NMR analysis. Upon completion, acetic acid (1 mL) was slowly added to the reaction mixture, and the solvent was then removed by evaporation under reduced pressure. The residue was diluted with water (100 mL) and extracted with EtOAc (100 mL × 7). The combined organic layer was dried over $Na_2SO_4$, filtered, and concentrated. $^{19}$F{$^{1}$H} NMR analysis of the crude mixture indicated that reduction of the ketone was highly diastereoselective (de ≈99%, see the Supporting Information). The crude mixture was purified by flash chromatography (acetone/$CH_2Cl_2$ 10/90) to afford the desired product **21** (670 mg, 4.03 mmol, 85%) as a white solid. An analytical sample of pure **21** was obtained by HPLC ($CH_2Cl_2$/EtOAc 70:30), as a white solid. $R_f$ = 0.70 ($CH_2Cl_2$/acetone 70:30). mp 108–110 °C (hexane/$CH_2Cl_2$), lit³⁷ 113–115 °C (EtOAc). [$\alpha$]$_D$ = -69.0 (c 1.06, MeOH, 24 °C), lit³⁷ -85 (c 0.6, $CHCl_3$, 23–25 °C). IR (neat) 3265 (m, br.), 2989 (w), 2915 (w), 1339 (m), 1033 (s) cm⁻¹. ¹H NMR (500 MHz, $CDCl_3$, δ): 5.67 (1H, br, t, $J = 2.1$ Hz, $H_1$), 4.90–4.83 (1H, m, $H_5$), 4.68 (1H, m, $J = 48.5$ Hz is observed, $H_4$), 4.57 (1H, m, $J = 49.8$ Hz is observed, $H_2$), 3.92–3.75 (1H, m, $H_{6exo}$), 3.84 (1H, m, $J = 12.4$, 4.2 Hz is observed, $H_3$), 3.72 (1H, br, dt, $J = 8.4$, 1.1 Hz, $H_{6endo}$), 2.73 (1H, dt, $J = 12.4$, 2.3 Hz, $OH_3$) ppm. ¹H{$^{19}$F} NMR (500 MHz, $CDCl_3$, δ): 5.67 (1H, d, $J = 2.6$ Hz, $H_1$), 4.87 (1H, m, $H_5$), 4.68 (1H, br, t, $J = 3.4$ Hz, $H_4$), 4.57 (1H, ddd, $J = 4.1$, 2.8, 1.1 Hz, $H_2$), 3.84 (1H, dt, $J = 12.1$, 4.1 Hz, $H_3$), 3.83 (1H, dd, $J = 8.6$, 5.6 Hz, $H_{6exo}$), 3.72 (1H, dd, $J = 8.4$, 1.0 Hz, $H_{6endo}$), 2.73 (1H, d, $J = 12.4$ Hz, $OH_3$) ppm. $^{13}$C{$^{1}$H} NMR (101 MHz, $CDCl_3$, δ): 98.5 (d, $J = 24.2$ Hz, $C_1$), 88.0 (d, $J = 184.9$ Hz, $C_2$), 86.5 (d, $J = 184.9$ Hz, $C_4$), 73.6 (d, $J = 19.1$ Hz, $C_5$), 63.7 (d, $J = 6.6$ Hz, $C_6$), 62.8 (t, $J = 18.3$ Hz, $C_3$) ppm. $^{19}$F NMR (471 MHz, $CDCl_3$, δ): -204.8 (m, $F_4$), -207.0 (br, dddt, $J = 49.9$, 25.6, 8.9, 2.3 Hz, $F_2$) ppm. $^{19}$F{$^{1}$H} NMR (471 MHz, $CDCl_3$, δ): -204.8 (d, $J = 9.3$ Hz, $F_4$), -207.0 (d, $J = 9.3$ Hz, $F_2$) ppm. HRMS (CI) for $C_6H_9F_2O_3$ [M + H]$^+$: calcd, 167.05143; found, 167.05425.

**1,6-Anhydro-3-O-trifluoromethanesulfonyl-2,4-dideoxy-2,4-difluoroallose 22a (Scheme 5).** To a solution of a 8:92 mixture of 14a/21 (205 mg, 1.23 mmol, 1.13 mmol of 21) in dry $CH_2Cl_2$ (3.2 mL) at 0 °C was added pyridine (0.12 mL, 1.48 mmol). Stirring was continued at 0 °C for 10 min before $Tf_2O$ (0.21 mL, 1.26 mmol) was added. The resulting mixture was allowed to warm to rt and stirred for an additional hour before being filtered through a pad of silica. Solvent was removed under vacuum, and the resulting orange oil was purified by column chromatography (hexane/$CH_2Cl_2$ 80:20 to

60:40), which afforded 218 mg (0.73 mmol, 65%) of compound 22a as a white solid. $R_f$ = 0.24 (pentane/$CH_2Cl_2$ 50:50). mp 108–110 °C (pentane/$CH_2Cl_2$). [$\alpha$]$_D$ = -50.2 (c 0.52, $CHCl_3$, 22 °C). ¹H NMR (500 MHz, $CDCl_3$, δ): 5.71 (1H, br, t, $J = 2.2$ Hz, $H_1$), 4.95–4.91 (1H, m, $H_5$), 4.90 (1H, m, $J = 24.3$, 3.9 Hz is observed, $H_3$), 4.87 (1H, m, $J = 50.9$ Hz is observed, $H_4$), 4.75 (1H, m, $J = 50.3$ Hz is observed, $H_2$), 3.88 (1H, m, 8.6, 5.1, 2.2 Hz is observed, $H_{6exo}$), 3.80 (1H, br, dt, $J = 8.9$, 1.0 Hz, $H_{6endo}$) ppm. ¹H{$^{19}$F} NMR (500 MHz, $CDCl_3$, δ): 5.71 (1H, d, $J = 2.8$ Hz, $H_1$), 4.94 (1H, br, dd, $J = 4.8$, 2.7 Hz, $H_5$), 4.90 (1H, t, $J = 3.8$ Hz, $H_3$), 4.88–4.84 (1H, m, $H_4$), 4.76 (1H, m, $J = 3.9$, 2.6, 1.4 Hz is observed, $H_2$), 3.88 (1H, dd, $J = 8.8$, 5.6 Hz, $H_{6exo}$), 3.80 (1H, dd, $J = 8.8$, 0.9 Hz, $H_{6endo}$) ppm. $^{13}$C{$^{1}$H} NMR (101 MHz, $CDCl_3$, δ): 118.3 (q, $J = 319.1$ Hz, $CF_3$), 98.4 (d, $J = 23.5$ Hz, $C_1$), 85.6 (d, $J = 195.1$ Hz, $C_4$), 84.3 (d, $J = 197.3$ Hz, $C_2$), 75.7 (t, $J = 16.9$ Hz, $C_3$), 73.9 (d, $J = 19.1$ Hz, $C_5$), 63.7 (d, $J = 5.9$ Hz, $C_6$) ppm. $^{19}$F NMR (376 MHz, $CDCl_3$, δ): -75.04 (s, $CF_3$), -202.1–-202.5 (m), -204.2 (ddd, $J = 50.3$, 24.3, 10.4 Hz) ppm. $^{19}$F{$^{1}$H} NMR (376 MHz, $CDCl_3$, δ): -75.0 (s, $CF_3$), -202.3 (d, $J = 10.4$ Hz), -204.2 (d, $J = 10.4$ Hz) ppm. HRMS (CI) for $C_6H_8F_3O_2S$ [M + H]$^+$: calcd, 299.00071; found, 299.00012.

**1,6-Anhydro-2,3,4-trideoxy-2,3,4-trifluoroglucose 5a from 21 (Scheme 5).** To a solution of 21 containing 4% of 14a (335 mg, 2.02 mmol, 1.94 mmol of 21) in anhydrous THF (5.7 mL) in a sealed tube reactor were added triethylamine (1.62 mL, 11.6 mmol, 5.8 equiv), Et₃N·3HF (0.63 mL, 3.86 mmol), and NfF (0.65 mL, 3.92 mmol). The resulting mixture was stirred at 90 °C for 4 days before being quenched with sat. aq. $NaHCO_3$ (17 mL). The layers were separated, and the aqueous phase was diluted with water (20 mL) to dissolve the large amount of salts formed during quenching and extracted with $CH_2Cl_2$ (3 × 50 mL). The organic phases were combined, dried over $MgSO_4$, and concentrated under vacuum. Purification by column chromatography (pentane/DCM 90:10 to 50:50) afforded 5a (222 mg, 1.34 mmol, 69%) as a white solid, as well as unreacted 14a (10 mg). $R_f$ = 0.64 (pentane/EtOAc 80:20). mp 66–68 °C (hexane/$CH_2Cl_2$). [$\alpha$]$_D$ = -53.8 (c 1.30, $CHCl_3$, 24 °C), lit¹⁴ -56.0 (c 1.32, $CHCl_3$, 22 °C). ¹H NMR (400 MHz, $CDCl_3$, δ): 5.62 (1H, br, s, $H_1$), 4.85–4.78 (1H, m, $H_5$), 4.83 (1H, dtquin, $J = 42.5$, 15.2, 1.7 Hz, $H_3$), 4.57 (1H, ddd, $J = 44.7$, 14.9, 1.2 Hz, $H_4$), 4.43 (1H, ddd, $J = 45.5$, 15.2, 1.2 Hz, $H_2$), 3.97 (1H, dd, $J = 8.1$, 1.0 Hz, $H_{6endo}$), 3.90–3.78 (1H, m, $H_{6exo}$) ppm. $^{13}$C{$^{1}$H} NMR (101 MHz, $CDCl_3$, δ): 98.6 (dd, $J = 28.6$, 2.2 Hz, $C_1$), 87.2 (dt, $J = 178.3$, 33.7 Hz, $C_3$), 86.4 (ddd, $J = 182.7$, 31.5, 4.4 Hz, $C_4$), 84.5 (ddd, $J = 182.7$, 27.9, 3.7 Hz, $C_2$), 73.5 (dd, $J = 21.6$, 1.8 Hz, $C_3$), 64.1 (dd, $J = 9.2$, 2.6 Hz, $C_6$) ppm. $^{19}$F NMR (376 MHz, $CDCl_3$, δ): -188.0 (ddtd, $J = 44.8$, 15.7, 10.9, 4.3 Hz, $F_4$), -191.1 (dquin, $J = 42.4$, 14.1 Hz, $F_3$), -193.6 (m, $J = 45.1$ Hz is observed, $F_2$) ppm. $^{19}$F{$^{1}$H} NMR (376 MHz, $CDCl_3$, δ): -188.0 (d, $J = 12.1$ Hz, $F_4$), -191.1 (t, $J = 12.1$ Hz, $F_3$), -193.6 (1F, d, $J = 12.1$ Hz, $F_2$) ppm. $^{13}$C NMR matches the literature data (pyridine $d_5$).¹⁴

**2,3,4-Trideoxy-2,3,4-trifluoro-D-glucopyranose 1 from Pure 5a (Scheme 5).** To a solution of trifluoro levoglucosan 5a (124 mg, 0.74 mmol) in $CH_2Cl_2$ (5.1 mL) at 0 °C was added $BCl_3$ (1 M in $CH_2Cl_2$, 3.1 mL, 3.1 mmol) dropwise. The resulting mixture was stirred at rt for 2 h before being quenched with water (7 mL). DCM was then removed under reduced pressure, and the resulting aqueous phase was stirred for an additional 1 h at rt. The remaining water was evaporated to give a brown dense oil, which was then purified by column chromatography (pentane/acetone 90:10 to 60:40) to afford 119 mg of trifluoroglucose 1 (0.64 mmol, 87%) as a dense clear oil, which solidified upon standing.

## ASSOCIATED CONTENT

### Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b00310.

Copies of NMR spectra; ratio determination for the DAST reaction of 4 and reduction of 18; tables with the relative Gibbs energy and populations of the energetic minima of 21 and discussion about the coupling constant analysis; X-ray data of compounds 1, 5a, 8,
and 21; and crystal packing discussion for 14a and 21
(PDF)

X-ray crystallographic data for compound 1 (CIF)

X-ray crystallographic data for compound 5a (CIF)

X-ray crystallographic data for compound 8 (CIF)

X-ray crystallographic data for compound 21 (CIF)

■ AUTHOR INFORMATION

Corresponding Author

*E-mail: bruno.linclau@soton.ac.uk

ORCID

Jérôme Graton: 0000-0002-1114-200X

Jean-Yves Le Questel: 0000-0001-5307-2137

Bruno Linclau: 0000-0001-8762-0170

Notes

The authors declare no competing financial interest.

The raw NMR data files are available free of charge at https://doi.org/10.5258/SOTON/D0846.

■ ACKNOWLEDGMENTS

We thank the University of Southampton, the Leverhulme Trust (grant RPG-2015-211), and the European Community (INTERREG IVa Channel Programme, IS:CE-Chem, project 4061) for funding and the EPSRC for a core capability grant (EP/K039466/1). The CCIPL (Centre de Calcul Intensif des Pays de Loire) also is acknowledged for provision of computer time. Prof Philip Kuchel and Dr Dmitry Shishmarev are acknowledged for stimulating discussions.

■ REFERENCES

(1) Hunter, L.; Slawin, A. M. Z.; Kirsch, P.; O'Hagan, D. Synthesis and Conformation of Multi-vicinal Fluoroalkane Diastereoisomers. *Angew. Chem., Int. Ed.* **2007**, *46* (41), 7887–7890.

(2) Hunter, L.; Kirsch, P.; Hamilton, J. T. G.; O'Hagan, D. The Multi-Vicinal Fluoroalkane Motif: an Examination of 2,3,4,5-Tetrafluorohexane Stereoisomers. *Org. Biomol. Chem.* **2008**, *6* (17), 3105–3108.

(3) Keddie, N. S.; Slawin, A. M. Z.; Lebl, T.; Philp, D.; O'Hagan, D. All-cis 1,2,3,4,5,6-Hexafluorocyclohexane Is a Facially Polarized Cyclohexane. *Nat. Chem.* **2015**, *7* (6), 483–488.

(4) Durie, A. J.; Fujiwara, T.; Cormanich, R.; Buhl, M.; Slawin, A. M. Z.; O'Hagan, D. Synthesis and Elaboration of All-cis-1,2,4,5-Tetrafluoro-3-Phenylcyclohexane: A Polar Cyclohexane Motif. *Chem. - Eur. J.* **2014**, *20* (21), 6259–6263.

(5) Durie, A. J.; Slawin, A. M. Z.; Lebl, T.; Kirsch, P.; O'Hagan, D. Synthesis and Structure of all-syn-1,2,3,4-Tetrafluorocyclohexane. *Chem. Commun.* **2011**, *47* (29), 8265–8267.

(6) Fischer, S.; Huwyler, N.; Wolfrum, S.; Carreira, E. M. Synthesis and Biological Evaluation of Bromo- and Fluorodicalipin A. *Angew. Chem., Int. Ed.* **2016**, *55* (7), 2555–2558.

(7) Cheng, Y.; Guo, A. L.; Guo, D. S. Recent Progress in Synthesis and Applications of Fluorinated Carbohydrates. *Curr. Org. Chem.* **2010**, *14* (9), 977–999.

(8) Dax, K.; Albert, M.; Ortner, J.; Paul, B. J. Synthesis of Deoxyfluoro sugars From Carbohydrate Precursors. *Carbohydr. Res.* **2000**, *327* (1–2), 47–86.

(9) Card, P. J. Synthesis of Fluorinated Carbohydrates. *J. Carbohydr. Chem.* **1985**, *4* (4), 451–487.

(10) Pacak, J.; Podesva, J.; Cerny, M. 2,4-Dideoxy-2,4-difluoro-D-glucose. *Chem Ind. 1970*, No. 28, 929.

(11) Pacak, J.; Podesva, J.; Tocik, Z.; Cerny, M. Syntheses with Anhydro Sugars. XI. Preparation of 2-Deoxy-2-fluoro-D-glucose and 2,4-Difluoro-D-glucose. *Collect. Czech. Chem. Commun.* **1972**, *37*, 2589–2599.

(12) Street, I. P.; Armstrong, C. R.; Withers, S. G. Hydrogen Bonding and Specificity. Fluorodeoxy Sugars as Probes of Hydrogen Bonding in the Glycogen Phosphorylase-Glucose Complex. *Biochemistry* **1986**, *25* (20), 6021–6027.

(13) Withers, S. G.; Percival, M. D.; Street, I. P. The Synthesis and Hydrolysis of a Series of Deoxofluoro-alfa-D-glucopyranosyl and Deoxofluoro-alfa-D-glucopyranosyl Phosphates. *Carbohydr. Res.* **1989**, *187* (1), 43–66.

(14) Sarda, P.; Escribano, F. C.; José Alves, R.; Olesker, A.; Lukacs, G. Stereospecific Access to 2,3,4-Trideoxy-2-3,4-trifluoro-D-glucose and D-galactose Derivatives. *J. Carbohydr. Chem.* **1989**, *8* (1), 115–123.

(15) Bresciani, S.; Lebl, T.; Slawin, A. M. Z.; O'Hagan, D. Fluorosugars: Synthesis of the 2,3,4-Trideoxy-2,3,4-trifluoro Hexose Analogues of D-Glucose and D-Altrose and Assessment of Their Erythrocyte Transmembrane Transport. *Chem. Commun.* **2010**, *46* (30), 5434–5436.

(16) Corr, M. J.; O'Hagan, D. Fluorosugars: An Improved Synthesis of the 2,3,4-Trideoxy-2,3,4-trifluoro Hexose Analogue of D-Glucose. *J. Fluorine Chem.* **2013**, *155*, 72–77.

(17) Denavit, V.; Lainé, D.; St-Gelais, J.; Johnson, P. A.; Giguère, D. A Chiron Approach Towards the Stereoselective Synthesis of Polyfluorinated Carbohydrates. *Nat. Commun.* **2018**, *9* (1), No. 4721.

(18) Diercks, T.; Infantino, A. S.; Unione, L.; Jimenez-Barbero, J.; Oscarson, S.; Gabius, H. J. Fluorinated Carbohydrates as Lectin Ligands: Synthesis of OH/F-Substituted N-Glycan Core Trimannoside and Epitope Mapping by 2D STD-TOCSYreF NMR Spectroscopy. *Chem. - Eur. J.* **2018**, *24* (59), 15761–15765.

(19) Arda, A.; Jimenez-Barbero, J. The Recognition of Glycans by Protein Receptors. Insights from NMR Spectroscopy. *Chem. Commun.* (Cambridge, U. K.) **2018**, *54* (38), 4761–4769.

(20) Ribeiro, J. P.; Diercks, T.; Jimenez-Barbero, J.; Andre, S.; Gabius, H. J.; Canada, F. J. Fluorinated Carbohydrates as Lectin Ligands: (19)-F-Based Direct STD Monitoring for Detection of Anomeric Selectivity. *Biomolecules* **2015**, *5* (4), 3177–3192.

(21) Kim, H. W.; Rossi, P.; Shoemaker, R. K.; DiMagno, S. G. Structure and Transport Properties of a Novel, Heavily Fluorinated Carbohydrate Analogue. *J. Am. Chem. Soc.* **1998**, *120* (35), 9082–9083.

(22) Bifinger, J. C.; Kim, H. W.; DiMagno, S. G. The Polar Hydrophobicity of Fluorinated Compounds. *ChemBioChem* **2004**, *5* (5), 622–627.

(23) Linclau, B.; Wang, Z.; Compain, G.; Paumelle, V.; Fontenelle, C. Q.; Wells, N.; Weymouth-Wilson, A. Investigating the Influence of (Deoxy)fluorination on the Lipophilicity of Non-UV-Active Fluorinated Alkanols and Carbohydrates by a New log P Determination Method. *Angew. Chem., Int. Ed.* **2016**, *55* (2), 674–678.

(24) Wiesenfeldt, M. P.; Nairoukh, Z.; Li, W.; Glorius, F. Hydrogenation of Fluoroarenes: Direct Access to all-cis-(Multi)-fluorinated Cycloalkanes. *Science* **2017**, *357* (6354), 908.

(25) Shishmarev, D.; Fontenelle, C. Q.; Kuprov, I.; Linclau, B.; Kuchel, P. W. Transmembrane Exchange of Fluorosugars: Characterization of Red Cell GLUT1 Kinetics Using(19)-F NMR. *Biophys. J.* **2018**, *115* (10), 1906–1919.

(26) Karban, J.; Cisarova, I.; Strasak, T.; Stastna, L. C.; Sykora, J. Skeletal Rearrangements Resulting from Reactions of 1,6:2,3-and 1,6:3,4-Dianhydro-beta-D-hexopyranoses with Diethylaminosulphur Trifluoride. *Org. Biomol. Chem.* **2012**, *10* (2), 394–403.

(27) Cerny, M.; Gut, V.; Pacak, J. Partielle Substitution der 1,6-Anhydro-β-D-glucopyranose. *Collect. Czech. Chem. Commun.* **1961**, 26, 2542–2550.

(28) Rasmussen, T. S.; Jensen, H. H. Synthesis and Glycosidase Inhibitory Activity of Noeurostegine-A New and Potent Inhibitor of beta-Glucoside Hydrolases. *Org. Biomol. Chem.* **2010**, *8* (2), 433–41.

(29) Barford, A. D.; Foster, A. B.; Westwood, J. H.; Hall, L. D.; Johnson, R. N. Studies of Specifically Fluorinated Carbohydrates. 14. Fluorinated Carbohydrates. 12. 4-Deoxy-4-Fluoro-D-Glucose - Improved Synthesis and Glycosyl Fluoride Derivatives. *Carbohydr. Res.* **1971**, *19* (1), 49.
and 21; and crystal packing discussion for 14a and 21
(PDF)

X-ray crystallographic data for compound 1 (CIF)

X-ray crystallographic data for compound 5a (CIF)

X-ray crystallographic data for compound 8 (CIF)

X-ray crystallographic data for compound 21 (CIF)

■ AUTHOR INFORMATION

Corresponding Author

*E-mail: bruno.linclau@soton.ac.uk

ORCID

Jérôme Graton: 0000-0002-1114-200X

Jean-Yves Le Questel: 0000-0001-5307-2137

Bruno Linclau: 0000-0001-8762-0170

Notes

The authors declare no competing financial interest.

The raw NMR data files are available free of charge at https://doi.org/10.5258/SOTON/D0846.

■ ACKNOWLEDGMENTS

We thank the University of Southampton, the Leverhulme Trust (grant RPG-2015-211), and the European Community (INTERREG IVa Channel Programme, IS:CE-Chem, project 4061) for funding and the EPSRC for a core capability grant (EP/K039466/1). The CCIPL (Centre de Calcul Intensif des Pays de Loire) also is acknowledged for provision of computer time. Prof Philip Kuchel and Dr Dmitry Shishmarev are acknowledged for stimulating discussions.

■ REFERENCES

(1) Hunter, L.; Slawin, A. M. Z.; Kirsch, P.; O'Hagan, D. Synthesis and Conformation of Multi-vicinal Fluoroalkane Diastereoisomers. *Angew. Chem., Int. Ed.* **2007**, *46* (41), 7887–7890.

(2) Hunter, L.; Kirsch, P.; Hamilton, J. T. G.; O'Hagan, D. The Multi-Vicinal Fluoroalkane Motif: an Examination of 2,3,4,5-Tetrafluorohexane Stereoisomers. *Org. Biomol. Chem.* **2008**, *6* (17), 3105–3108.

(3) Keddie, N. S.; Slawin, A. M. Z.; Lebl, T.; Philp, D.; O'Hagan, D. All-cis 1,2,3,4,5,6-Hexafluorocyclohexane Is a Facially Polarized Cyclohexane. *Nat. Chem.* **2015**, *7* (6), 483–488.

(4) Durie, A. J.; Fujiwara, T.; Cormanich, R.; Buhl, M.; Slawin, A. M. Z.; O'Hagan, D. Synthesis and Elaboration of All-cis-1,2,4,5-Tetrafluoro-3-Phenylcyclohexane: A Polar Cyclohexane Motif. *Chem. - Eur. J.* **2014**, *20* (21), 6259–6263.

(5) Durie, A. J.; Slawin, A. M. Z.; Lebl, T.; Kirsch, P.; O'Hagan, D. Synthesis and Structure of all-syn-1,2,3,4-Tetrafluorocyclohexane. *Chem. Commun.* **2011**, *47* (29), 8265–8267.

(6) Fischer, S.; Huwyler, N.; Wolfrum, S.; Carreira, E. M. Synthesis and Biological Evaluation of Bromo- and Fluorodicalipin A. *Angew. Chem., Int. Ed.* **2016**, *55* (7), 2555–2558.

(7) Cheng, Y.; Guo, A. L.; Guo, D. S. Recent Progress in Synthesis and Applications of Fluorinated Carbohydrates. *Curr. Org. Chem.* **2010**, *14* (9), 977–999.

(8) Dax, K.; Albert, M.; Ortner, J.; Paul, B. J. Synthesis of Deoxyfluoro sugars From Carbohydrate Precursors. *Carbohydr. Res.* **2000**, *327* (1–2), 47–86.

(9) Card, P. J. Synthesis of Fluorinated Carbohydrates. *J. Carbohydr. Chem.* **1985**, *4* (4), 451–487.

(10) Pacak, J.; Podesva, J.; Cerny, M. 2,4-Dideoxy-2,4-difluoro-D-glucose. *Chem Ind. 1970*, No. 28, 929.

(11) Pacak, J.; Podesva, J.; Tocik, Z.; Cerny, M. Syntheses with Anhydro Sugars. XI. Preparation of 2-Deoxy-2-fluoro-D-glucose and 2,4-Difluoro-D-glucose. *Collect. Czech. Chem. Commun.* **1972**, *37*, 2589–2599.

(12) Street, I. P.; Armstrong, C. R.; Withers, S. G. Hydrogen Bonding and Specificity. Fluorodeoxy Sugars as Probes of Hydrogen Bonding in the Glycogen Phosphorylase-Glucose Complex. *Biochemistry* **1986**, *25* (20), 6021–6027.

(13) Withers, S. G.; Percival, M. D.; Street, I. P. The Synthesis and Hydrolysis of a Series of Deoxofluoro-alfa-D-glucopyranosyl and Deoxofluoro-alfa-D-glucopyranosyl Phosphates. *Carbohydr. Res.* **1989**, *187* (1), 43–66.

(14) Sarda, P.; Escribano, F. C.; José Alves, R.; Olesker, A.; Lukacs, G. Stereospecific Access to 2,3,4-Trideoxy-2-3,4-trifluoro-D-glucose and D-galactose Derivatives. *J. Carbohydr. Chem.* **1989**, *8* (1), 115–123.

(15) Bresciani, S.; Lebl, T.; Slawin, A. M. Z.; O'Hagan, D. Fluorosugars: Synthesis of the 2,3,4-Trideoxy-2,3,4-trifluoro Hexose Analogues of D-Glucose and D-Altrose and Assessment of Their Erythrocyte Transmembrane Transport. *Chem. Commun.* **2010**, *46* (30), 5434–5436.

(16) Corr, M. J.; O'Hagan, D. Fluorosugars: An Improved Synthesis of the 2,3,4-Trideoxy-2,3,4-trifluoro Hexose Analogue of D-Glucose. *J. Fluorine Chem.* **2013**, *155*, 72–77.

(17) Denavit, V.; Lainé, D.; St-Gelais, J.; Johnson, P. A.; Giguère, D. A Chiron Approach Towards the Stereoselective Synthesis of Polyfluorinated Carbohydrates. *Nat. Commun.* **2018**, *9* (1), No. 4721.

(18) Diercks, T.; Infantino, A. S.; Unione, L.; Jimenez-Barbero, J.; Oscarson, S.; Gabius, H. J. Fluorinated Carbohydrates as Lectin Ligands: Synthesis of OH/F-Substituted N-Glycan Core Trimannoside and Epitope Mapping by 2D STD-TOCSY/F NMR Spectroscopy. *Chem. - Eur. J.* **2018**, *24* (59), 15761–15765.

(19) Arda, A.; Jimenez-Barbero, J. The Recognition of Glycans by Protein Receptors. Insights from NMR Spectroscopy. *Chem. Commun.* (Cambridge, U. K.) **2018**, *54* (38), 4761–4769.

(20) Ribeiro, J. P.; Diercks, T.; Jimenez-Barbero, J.; Andre, S.; Gabius, H. J.; Canada, F. J. Fluorinated Carbohydrates as Lectin Ligands: (19)-F-Based Direct STD Monitoring for Detection of Anomeric Selectivity. *Biomolecules* **2015**, *5* (4), 3177–3192.

(21) Kim, H. W.; Rossi, P.; Shoemaker, R. K.; DiMagno, S. G. Structure and Transport Properties of a Novel, Heavily Fluorinated Carbohydrate Analogue. *J. Am. Chem. Soc.* **1998**, *120* (35), 9082–9083.

(22) Bifinger, J. C.; Kim, H. W.; DiMagno, S. G. The Polar Hydrophobicity of Fluorinated Compounds. *ChemBioChem* **2004**, *5* (5), 622–627.

(23) Linclau, B.; Wang, Z.; Compain, G.; Paumelle, V.; Fontenelle, C. Q.; Wells, N.; Weymouth-Wilson, A. Investigating the Influence of (Deoxy)fluorination on the Lipophilicity of Non-UV-Active Fluorinated Alkanols and Carbohydrates by a New log P Determination Method. *Angew. Chem., Int. Ed.* **2016**, *55* (2), 674–678.

(24) Wiesenfeldt, M. P.; Nairoukh, Z.; Li, W.; Glorius, F. Hydrogenation of Fluoroarenes: Direct Access to all-cis-(Multi)-fluorinated Cycloalkanes. *Science* **2017**, *357* (6354), 908.

(25) Shishmarev, D.; Fontenelle, C. Q.; Kuprov, I.; Linclau, B.; Kuchel, P. W. Transmembrane Exchange of Fluorosugars: Characterization of Red Cell GLUT1 Kinetics Using(19)-F NMR. *Biophys. J.* **2018**, *115* (10), 1906–1919.

(26) Karban, J.; Cisarova, I.; Strasak, T.; Stastna, L. C.; Sykora, J. Skeletal Rearrangements Resulting from Reactions of 1,6:2,3-and 1,6:3,4-Dianhydro-beta-D-hexopyranoses with Diethylaminosulphur Trifluoride. *Org. Biomol. Chem.* **2012**, *10* (2), 394–403.

(27) Cerny, M.; Gut, V.; Pacak, J. Partielle Substitution der 1,6-Anhydro-β-D-glucopyranose. *Collect. Czech. Chem. Commun.* **1961**, 26, 2542–2550.

(28) Rasmussen, T. S.; Jensen, H. H. Synthesis and Glycosidase Inhibitory Activity of Noeurostegine-A New and Potent Inhibitor of beta-Glucoside Hydrolases. *Org. Biomol. Chem.* **2010**, *8* (2), 433–41.

(29) Barford, A. D.; Foster, A. B.; Westwood, J. H.; Hall, L. D.; Johnson, R. N. Studies of Specifically Fluorinated Carbohydrates. 14. Fluorinated Carbohydrates. 12. 4-Deoxy-4-Fluoro-D-Glucose - Improved Synthesis and Glycosyl Fluoride Derivatives. *Carbohydr. Res.* **1971**, *19* (1), 49.
(30) Faghih, R.; Escribano, F. C.; Castillon, S.; Garcia, J.; Olesker, A.; Thang, T. T. Chiral Synthons for the Total Synthesis of Fluoro Amino-acids and Fluoro Analogs of Antibiotic Sugars. *J. Org. Chem.* **1986**, *51* (24), 4558–4564.

(31) Horník, Š.; Červenková Šťastná, L.; Cuřínová, P.; Sýkora, J.; Káňová, K.; Hrstka, R.; Císarová, I.; Dračínský, M.; Karban, J. Synthesis and In Vitro Cytotoxicity of Acetylated 3-Fluoro, 4-Fluoro and 3,4-Difluoro Analogs of D-Glucosamine and D-Galactosamine. *Beilstein J. Org. Chem.* **2016**, *12*, 750–759.

(32) Mtashobya, L.; Quiquempoix, L.; Linclau, B. The Synthesis of Mono- and Difluorinated 2,3-Dideoxy-D-glucopyranoses. *J. Fluorine Chem.* **2015**, *171*, 92–96.

(33) Karban, J.; Sykora, J.; Kroutil, J.; Cisarova, I.; Padelkova, Z.; Budesinsky, M. Synthesis of All Configurational Isomers of 1,6-Anhydro-2,3,4-trideoxy-2,3-epimino-4-fluoro-beta-D-hexopyranoses. *J. Org. Chem.* **2010**, *75* (10), 3443–3446.

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(30) Faghih, R.; Escribano, F. C.; Castillon, S.; Garcia, J.; Olesker, A.; Thang, T. T. Chiral Synthons for the Total Synthesis of Fluoro Amino-acids and Fluoro Analogs of Antibiotic Sugars. *J. Org. Chem.* **1986**, *51* (24), 4558–4564.

(31) Horník, Š.; Červenková Šťastná, L.; Cuřínová, P.; Sýkora, J.; Káňová, K.; Hrstka, R.; Císařová, I.; Dračínský, M.; Karban, J. Synthesis and In Vitro Cytotoxicity of Acetylated 3-Fluoro, 4-Fluoro and 3,4-Difluoro Analogs of D-Glucosamine and D-Galactosamine. *Beilstein J. Org. Chem.* **2016**, *12*, 750–759.

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