Synthesis and structure elucidation of benzoylated deoxyfluoropyranosides

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Synthesis and Structure Elucidation of

Benzoylated Deoxyfluoropyranosides

Aslan M. Esmurziev ^{a b}, Nebojsa Simic ^a, Bård Helge Hoff ^a& Eirik

Sundby ^b

^aNorwegian University of Science and Technology , Høgskoleringen

5, NO-7491, Trondheim , Norway

^bSør-Trøndelag University College , E.C. Dahls gate 2, 7004 ,

Trondheim , Norway

Published online: 13 Dec 2010.

To cite this article: Aslan M. Esmurziev , Nebojsa Simic , Bård Helge Hoff & Eirik Sundby (2010)

Synthesis and Structure Elucidation of Benzoylated Deoxyfluoropyranosides, Journal of Carbohydrate

Chemistry, 29:7, 348-367, DOI: 10.1080/07328303.2010.540055

To link to this article: http://dx.doi.org/10.1080/07328303.2010.540055

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Journal of Carbohydrate Chemistry, 29:348–367, 2010

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ISSN: 0732-8303 print / 1532-2327 online

DOI: 10.1080/07328303.2010.540055

Synthesis and Structure

Elucidation of Benzoylated

Deoxyﬂuoropyranosides

Aslan M. Esmurziev,¹Nebojsa Simic,²Ba˚ rd Helge Hoff,²

and Eirik Sundby³

¹Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491

Trondheim, Norway; and Sør-Trøndelag University College, E.C. Dahls gate 2, 7004

Trondheim, Norway

²Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491

Trondheim, Norway

³Sør-Trøndelag University College, E.C. Dahls gate 2, 7004 Trondheim, Norway

Benzoylated deoxyﬂuoropyranosides have been synthesized, starting with protected,

unprotected, or ﬂuorinated precursors. Fluorination of eight derivatives was compared

using DAST and Deoxo-Fluor as reagents. Deoxo-Fluor was found to be especially

useful in the ﬂuorination of methyl 2,3,4-O-tribenzoyl α-D-mannopyranoside and β-

D-glucopyranoside, resulting in better yields and avoiding the 1,6-methoxy migration

experienced with DAST for one derivative. The two reagents gave comparable yields

in the ﬂuorination of other methyl pyranosides, conﬁrming Deoxo-Fluor as a safer al-

ternative to DAST. Methyl α-D-mannopyranoside underwent ﬂuorination to yield the

4,6-diﬂuorotalopyranoside and the corresponding cyclic sulﬁte. The NMR spectroscopic

properties of 11 benzoyl deoxy-ﬂuoropyranosides are reported.

Keywords Deoxyﬂuorosugars; Diethylaminosulfur triﬂuoride; Bis-(2-methoxyethyl)

aminosulfur triﬂuoride; DAST; Deoxo-Fluor; Benzoyl pyranosides; ¹⁹F NMR

INTRODUCTION

Fluorinated molecules have found widespread applications in the ﬁeld of

medicinal chemistry.^[1,2]Also, ﬂuorinated carbohydrates have found their

use among others as biocompatible surfactants,^[3,4]mechanistic probes,^[5–7]

positron-emitting radiopharmaceuticals,^[8,9]potential anticancer agents,^[10–13]

and building blocks for other bioactive compounds.^[14–16]As compared to their

natural derivatives, ﬂuorinated carbohydrates have altered hydrogen bonding

Received February 25, 2010; accepted November 10, 2010.

Address correspondence to Ba˚rd H. Hoff, Department of Chemistry, Norwegian Univer-

sity of Science and Technology (NTNU) NO-7491, Norway. E-mail: bhoff@chem.ntnu.no

348

Benzoylated Deoxyﬂuoropyranosides

349

abilities and metabolic stability. ¹⁹F NMR opens new possibilities for tracking

distribution, transport, and metabolism of drug derivatives.

Although some unprotected carbohydrates can be ﬂuorinated in decent

yield, most often protection and deprotection schemes are utilized. Having the

options of employing different protecting groups is of importance depending on

the following chemical steps. Esters are often employed, and in terms of molec-

ular mass and cost, the acetate ester is preferred. On the other hand, using

aromatic esters allows for a higher stability, the avoidance/reduction of acyl

migration, and the ability to analyze compounds by UV spectroscopic meth-

ods. Diethylaminosulfur triﬂuoride (DAST) is a commonly used reagent for the

conversion of hydroxyl groups into ﬂuorinated derivatives.^[17,18]Also, partly

benzoylated carbohydrates have been ﬂuorinated with this reagent.^[6,19–23]

However, there are hazards connected to the use of DAST, and a safer alterna-

tive, bis-(2-methoxyethyl)aminosulfur triﬂuoride (Deoxo-Fluor), has been de-

veloped.^[24–26]As part of our effort to prepare building blocks for bioactive com-

pounds, a series of benzoylated deoxy-ﬂuoropyranosides have been synthesized

and characterized. The use of DAST and Deoxo-Fluor has also been compared

in ﬂuorination of various hexapyranosides.

RESULTS AND DISCUSSION

Synthesis of Methyl 2,3,4-tri-O-benzoyl-6-deoxy-6-

ﬂuoro-pyranosides

As monoﬂuorination of unprotected carbohydrates can be problem-

atic, the 6-deoxy-6-ﬂuorohexapyranosides were targeted by ﬂuorination of

the methyl 2,3,4-tri-O-benzoylpyranosides (4a–e). These were obtained by

two different routes: compounds 4a–c were synthesized by Candida ru-

gosa lipase (CRL)-catalyzed hydrolysis of the corresponding tetrabenzoates,

2a–c, as previously reported,^[27]while 4d–e were obtained by a trityla-

tion/benzoylation/detritylation protocol (Sch. 1).

The methyl 2,3,4-tri-O-benzoylhexapyranosides 4a–e were then subjected

to ﬂuorination using DAST in dichloromethane, THF and diglyme, and Deoxo-

Fluor in THF. The degree of conversion obtained under the various conditions

is shown in Table 1. The galacto derivatives 4a–b were ﬂuorinated very slowly,

giving a maximum of 14% conversion using DAST in dichloromethane. No im-

provement was observed using Deoxo-Fluor. In ﬂuorination of structurally re-

lated methyl 2,3,4-tribenyl D-galactopyranoside, Tashiro et al.^[28]also obtained

a cyclic 3,6-ether byproduct. This was not seen in reaction of 4a–b. The low de-

gree of conversion for 4a–b is most likely due to steric hindrance imposed by

the benzoyl groups.

A.M. Esmurziev et al.

350

OMe

O

F

N

F

N

S

F

S

F

O

BzO

F

Deoxo-Fluor

DAST

OBz

BzO

OBz

6d

O

BzO

OMe

BzCl/

pyridine

CRL

BzO

OBz

OH

F

2a-c

DAST or

Deoxo-Fluor

O

HO

OMe

BzO

OMe

BzO

OMe

OH

1a-e

OBz

4a-e

OBz

5a-e

OTr

O

1. TrCl /

pyridine

2. BzCl

FeCl₃

BzO

OMe

BzO

OBz

3d-e

Scheme 1: Route to 5a–e, α-D-galactopyranoside (a), β-D-galactopyranoside (b),

α-D-glucopyranoside (c), β-D-glucopyranoside (d), α-D-mannopyranoside (e).

Higher reactivity was observed in ﬂuorination of 4c. The use of DAST in

dichloromethane gave a 54% conversion. This could be increased to 91% by

applying a 1-h reﬂuxing period at the end of the reaction. The use of Deoxo-

Fluor led to a comparable 88% conversion. In ﬂuorination of 4a–c, the 6-deoxy-

6-ﬂuoroderivatives, 5a–c, were the only products in each case. However, in

line with that reported by Lin et al.,^[19]DAST ﬂuorination of methyl 2,3,4-tri-

O-benzoyl-β-D-glucopyranoside (4d) gave rise to both 5d and the migration

Table 1: Degree of conversion (%)^ain ﬂuorination of 4a–e in various solvents using

DAST (4 eq) and Deoxo-Fluor (4 eq)

DAST

Deoxo-Fluor

b

Substrate CH₂Cl₂CH₂Cl₂

THF Di-glyme Product THF THF^bProduct

4a

4b

4c

4d

4e

14

12

14

10

91

<1

5a

5b

13

7

88

85

77

13

9

5a

5b

5c

5d

5e

54

41

<1

5c

88

74^c

60

>99^d

5d + 6d

>99

78

e)

62

5e

^aConv. by HPLC.

^bReﬂuxed for 1 h after standard reaction.

^cProducts: 5d, 41%; 6d, 33%.

^dProducts: 5d, 38%; 6d, 62%.

^eNot performed.

Benzoylated Deoxyﬂuoropyranosides

351

product 6d. A reﬂuxing period at the end of the reaction increased the amount

of the rearrangement product further to 62%. A mechanistic rationale for this

migration has been proposed,^[19,29,30]where the glycosidic oxygen acts as a nu-

cleophile on the RO-SF₂NEt₂intermediate, possibly assisted by the carbonyl

oxygen situated at C-2 (Sch. 2).

Et₂NF₂SO

MeO

OMe

OBz

F

BzO

O

BzO

O

F^-

O

+

O

Ph

O

OBz

O

OBz

Ph

Scheme 2: Possible mechanism for the C-1 to C-6 methoxy migration.

In contrast, the use of Deoxo-Fluor gave 5d as the only product. Full con-

version to 5d was obtained when applying a reﬂuxing period at the end of

the reaction. The reason why Deoxo-Fluor does not cause this migration is

not understood. However, DFT calculations have indicated that the increased

stability of Deoxo-Fluor as compared to DAST is due to coordination of the

ether oxygen with the sulphur atom of the reagent.^[24]Possibly, such a coor-

dination could also be present in the RO-SF₂N(CH₂CH₂OCH₃)₂intermediate,

both shielding C-6 toward nucleophilic attack from oxygen at C-1 and increas-

ing the strength of the susceptible C-O bond. Deoxo-Fluor also proved to be the

best ﬂuorinating agent for the synthesis of 5e from 4e (77% conv.). Fluorina-

tion of 4e with DAST in dichloromethane gave 60% conversion.

Synthesis of Other Benzoylated Deoxy-ﬂuoropyranosides

We continued to compare the performance of DAST and Deoxo-Fluor

in ﬂuorination of other methyl pyranosides. Methyl 2,3,6-tri-O-benzoyl-α-

D–galactopyranoside (7a), obtained by abrupt benzoylation of 1a, was ﬂuori-

nated using DAST and Deoxo-Fluor (Sch. 3). The product 8c has been prepared

previously using DAST.^[20,21]

F

OBz

OH

O

DAST

or

CRL

DAST

or

F

OMe

F

OMe

HO

OMe

HO

BzO

OMe

Deoxo-Fluor

BzO

OBz

BzO

OBz

BzO

OBz

Deoxo-Fluor

OBz

10c

8c

7a

9a

Scheme 3: Synthesis of methyl 2,3,6-tri-O-benzoyl-4-deoxy-4-ﬂuoro-α-D-glucopyranoside (8c)

and methyl 2,3-di-O-benzoyl-4,6-dideoxy-4,6-diﬂuoro-α-D-glucopyranoside (10c) using DAST

or Deoxo-Fluor.

A.M. Esmurziev et al.

352

Fluorination of 7a with DAST and Deoxo-Fluor using 2.5 equivalents of

ﬂuorinating agent gave a 67% and 65% conversion, respectively. The degree

of conversion for both systems could be improved to 90% by addition of a sec-

ond portion of reagent after 6 h reaction time. The reaction of 7a with DAST

was run in a 23.3 mmol scale, giving 72% isolated yield of 8c. Further, from

7a, Candida rugosa lipase-catalyzed hydrolysis gave 9a, which was submit-

ted to DAST and Deoxo-Fluor ﬂuorination (Sch. 3). The diﬂuorinated α-D-

glucopyranoside 10c was obtained in 74% and 72% isolated yield, respectively,

indicating very similar reactivity for the two reagents. No other ﬂuorinated

byproducts were observed.

DAST ﬂuorination of methyl α-D-mannopyranoside (1e) to yield methyl

4,6-dideoxy-4,6-diﬂuoro-α-D-talopyranoiside (11f) has been reported.^[21,31]

The preparation of methyl 4,6-dideoxy-4,6-diﬂuoro-2,3-di-O-benzoyl-α-

D–talopyranoside (10f) was attempted using both DAST and Deoxo-Fluor

followed by benzoylation without isolation of 11f (Sch. 4). In both cases 9

equivalents of ﬂuorinating agent was used and a similar low 26% isolated

yield of 10f was obtained.

OH

F

O

DAST

BzCl

HO

OMe

F

OMe

F

OMe

F

OMe

or

Pyridine

Deoxo-Fluor

OH

HO

OH

BzO

OBz

O

S

1e

11f

10f

12f

O

Scheme 4: Synthesis of methyl 2,3-di-O-benzoyl-4,6-dideoxy-4,6-diﬂuoro-α-D–talopyranoside

(10f) and the structure of the byproduct 12f.

The reasons for the loss in yield were investigated by isolation of

11f. However, in addition to 11f,^[31]another diﬂuorinated carbohydrate was

isolated. NMR spectroscopy conﬁrmed this to be a methyl 4,6-dideoxy-

diﬂuorotallopyranoside, but with higher shift values for H-1, H-2, and H-3 as

compared to 11f. Whereas compound 11f underwent benzoylation to afford 10f

(77% isolated yield), the unknown compound failed to react under similar con-

ditions. Based on previous reports on ﬂuorination of inositol derivatives using

and a characteristic IR band at 1215 cm⁻¹a cyclic sulﬁte was the

[32,33]

SF₄

,

most likely candidate structure. The presence of sulphur was conﬁrmed by

ICP-MS, and a reaction of 11f with thionyl chloride gave a compound with the

same chemical and spectroscopic properties, thus conﬁrming the structure 12f.

The mechanism of formation is expected to follow that outlined for SF₄.^[33]

We were also interested in obtaining the benzoylated 2-deoxy-2-ﬂuoro-

and 3-deoxy-3-ﬂuoro-D-gluco derivatives as building blocks for bioactive com-

pounds. Methylation and benzoylation of commercially available 3-deoxy-3-

ﬂuoro-D-glucose was attempted as shown in Scheme 5. To avoid the isolation

Benzoylated Deoxyﬂuoropyranosides

353

OH

OBz

OH

OBz

1. MeOH/H⁺

O

BzCl

+

HO

OH

BzO

OMe

BzO

OBz

HO

OH

BzO

OBz

Pyridine

2, BzCl/pyridine

F

OH

F

OBz

F

OBz

F

13d

14d

15d

BzCl/pyridine

Scheme 5: Synthesis of benzoylated 3-deoxy-3-ﬂuoro- and 2-deoxy-2-ﬂuoro-

D-glucopyranoside.

of the intermediate methyl glucoside, benzoylation was performed on the crude

reaction product. This, however, gave a mixture of the β-anomer 13d (12% iso-

lated yield) and the tetrabenzoate 14d (3%). Both the low yield and formation

of the β-anomer 13d correspond with results for synthesis of the corresponding

acetates.^[34]

Attempts to prepare methyl 3,4,6-tri-O-benzoyl-2-deoxy-2-ﬂuoro-

D–glucopyranoside were also made by the two-step route shown in Scheme

5, but were unsuccessful. Due to the low efﬁciency in forming the methyl

glycosides, it was considered more useful to prepare the corresponding tetra-

benzoates 14 and 15 by benzoylation (Sch. 5). Crystallization gave 48% and

51% isolated yield of the β-anomers 14d and 15d, respectively. We were not

able to purify the α-anomers present in the mother liquor.

NMR Spectroscopy

The NMR assignments of the compounds 5a–e, 8c, 10c, 10f, 13d, 14d, and

15d were based on the data obtained from 1D ¹H, ¹³C, and ¹⁹F and various 2D

experiments. Spin systems and connectivity in the pyranose ring and in the

aromatic systems were identiﬁed by DQF-COSY, HMQC, and HSQC-TOCSY

experiments. The connectivity between the pyranose ring and benzoyl groups

was identiﬁed in HMBC spectra from long-range correlations between protons

H-2, H-3, H-4, and H-6, the corresponding carbonyl-, and its directly attached

aromatic carbon (Fig. 1).

F

OBz

6

O

5

H

2

4

H

OR

O

OBz

1

HMBC

H

3

H

Figure 1: HMBC correlations revealing connectivity between the pyranoside and benzoyl

groups.

A.M. Esmurziev et al.

354

The ¹H and ¹³C chemical shifts are given in the Experimental section; the

1

resolved H-¹H and ¹⁹F-¹H coupling constants and the ¹⁹F chemical shifts are

given Table 2.

¹H NMR data of the pyranose part of 5c corresponded with that published

previously.^{[35] 1}H NMR of 5d has been reported, but not assigned,^[19]while in

the case of 8c, previously reported shifts for protons at C-6, C-1, and C-2 have

1

to be revised.^[20,21]The H chemical shift of H-1 depended on the anomeric

conﬁguration and the conﬁguration at C-2. For the α-anomers 5a, 5c, 8c, and

10c, the H-1 signal resided at higher ppm values than for their β-anomers.

The coupling constants between H-1 and H-2 are also of diagnostic value. In

the case of 13d, both the H-1 shift value and the coupling between H-1 and

H-2 enabled assignment of stereochemistry as β-conﬁgured.

The ²J_HFcouplings for 6-deoxy-6-ﬂuoroderivatives 5a–e, 10c, and 10f were

in the range of 45.6 to 47.5 Hz, while when the ﬂuorine was situated at C-2,

C-3, and C-4, slightly higher coupling values were observed (50.3–52.0 Hz).

The ¹³C NMR data for 5c corresponded with that reported^[35]; data for 8c

has not been found, while in the case of 5d,^[19]assignment has not been pro-

vided. The C-1 and the methoxy carbon shifts are strong indicators of anomeric

conﬁguration, and the α-anomers had lower shift values than the β-anomers

for both signals. The chemical shifts of C-6 in the 6-deoxy-6-ﬂuoropyranosides

were only slightly affected by structural variation and appeared from 80.7 to

1

81.7 ppm. The J_CFcoupling constants varied from 169.6 to 193.2 Hz depend-

ing on the position of the ﬂuorine and pyranose structure. Among others, the

¹J_CFcoupling constants at C-6 depended on the stereochemistry at C-4 and

were higher for 5c–e and 10c than for 5a–b and 10f.

The ¹⁹F NMR data of 8c corresponded well with those reported,^[20,21]while

reference data for the other compounds have not been published. The shifts for

the ﬂuorine at C-6 varied from −230.50 to −236.15 ppm, while the ﬂuorines at

C-2, C-3, and C-4 resided from −195.53 to −200.19. The ¹⁹F-¹H coupling con-

stants were in good agreement with those observed from the ¹H 1D spectrum.

CONCLUSION

Eleven deoxy-ﬂuoro benzoyl pyranosides, eight of which are new chemical

entities, have been synthesized and characterized by high-ﬁeld NMR spec-

troscopy. The use of DAST and Deoxy-Fluor was compared in the ﬂuorina-

tion of eight different carbohydrate derivatives and in most cases the reagents

gave similar yields. Surprisingly, in reaction of methyl α-D-mannopyranoside,

a cyclic sulﬁte was discovered as the major byproduct using both reagents.

The use of Deoxy-Fluor was found to be superior for the ﬂuorination of methyl

2,3,4,-tribenzoyl-β-D-glucopyranoside, avoiding a 1,6-migration experienced

with DAST. Moreover, with Deoxy-Fluor, as compared to DAST, ﬂuorination

355

A.M. Esmurziev et al.

356

of carbohydrates can be performed with good conversion in nonchlorinated sol-

vents (THF) with a less hazardous reagent.

EXPERIMENTAL

General

Methyl α-D-mannopyranoside (1e) was prepared by a known method,^[36]

while 1a–d, DAST, and Deoxo-Fluor were purchased from Sigma-Aldrich. Ben-

zoyl chloride and pyridine were from Fluka. 2-Deoxy-2-ﬂuoro-D-glucose and

3-deoxy-3-ﬂuoro-D-glucose were from Toronto Research Chemicals Inc. The

compounds 2a–c, 4a–c, and 9a were prepared as described previously.^[27,37]

Solvents were from VWR and were used as received, except for CH₂Cl₂, which

was dried over CaCl₂. Column chromatography was performed using silica gel

60A from Fluka (pore size 40–63 µm). Candida rugosa lipase (type VII, ≥700

units/mg solid) was from Sigma-Aldrich.

Analysis

The HPLC system consisted of an Agilent 1100 series quaternary pump,

Agilent 1100 series variable wavelength UV detector (200–315 nm), and ther-

mostated column compartment. Conversion was analyzed on a Supelcosil C18

column (5-µm particle size, 25 cm) at 254 nm, eluting with a mixture of deion-

ized water containing TFA (0.01%) and MeOH (30:70, vol.-%). Melting points

were determined by a Mettler FP 5 melting point apparatus and are uncor-

rected. Optical rotations were measured using the sodium D line at 589 nm on

a Perkin-Elmer 243 B polarimeter.

NMR Spectroscopic Methods

1

Unless otherwise stated, H and ¹³C NMR data were recorded using a

Bruker Avance 600 spectrometer operating at a proton frequency of 600.18

MHz with a 5-mm triple-resonance cryo probe equipped with a z-gradient. The

samples containing a solution of 20 mg of substances in CDCl₃were measured

at 298 K with TMS as reference standard. The ¹⁹F NMR data were recorded

with a Bruker Avance 500 spectrometer using hexaﬂuorobenzene as reference

standard. Pulse sequences from the Bruker user library were used. The ac-

1

quisition details for the 1D H and ¹³C NMR, HMQC, HSQC-TOCSY, HMBC,

1

and H,¹H DQF-COSY were as described previously.^[37]470 MHz ¹⁹F 1D: π/2

pulse for ¹⁹F 15.0 µs, spectral width 100 kHz, acquisition time 0.35 s, relax-

ation delay 1.0 s. 470 MHz ¹⁹F 1D with proton BB decoupling: π/2 pulse for

¹⁹F 15.0 µs, spectral width 94.3 kHz, acquisition time 0.66 s, WALTZ proton

decoupling during acquisition, relaxation delay 1.0 s. In order to distinguish

Benzoylated Deoxyﬂuoropyranosides

357

close resonances for some of the compounds, additional experiments were run

to obtain higher resolution.

Synthesis

Methyl 2,3,4-tri-O-benzoyl-β-D-glucopyranoside (4d)^[38]

Methyl β-D-glucopyranoside (1d) (1.00 g, 5.15 mmol) was ﬁrst converted

to methyl 2,3,4-tri-O-benzoyl-6-trityl-β-D-glucopyranoside (3d) by tritylation

and benzoylation according to the procedure of Ding et al.^[39]This resulted in

an oil that crystallized from EtOH giving 1.25 g (1.67 mmol, 32%) of 3d as a

white solid, mp. 115–116^◦C, [α]_D²²= −12.2^◦(c 1.0, CHCl₃). H NMR (CDCl₃,

1

400 MHz) δ: 7.97 (m, 2 H, Ar), 7.82 (m, 2 H, Ar), 7.70 (m, 2 H, Ar), 7.51–7.29

(m, 9 H, Ar), 7.16 (m, 8 H, Ar), 7.09 (m, 7 H, Ar), 5.79 (t, J = 9.6, 1 H, H-3),

5.63 (t, J = 9.6, 1 H, H-4), 5.54 (dd, J_2,3= 9.6, J_2,1= 8.0, 1 H, H-2), 4.72 (d,

J_1,2= 8.0, 1 H, H-1), 3.85 (m, 1 H, H-5), 3.62 (s, 3 H, OCH₃), 3.35 (dd, J_5,6a

= 2.5, J_6a,6b= 10.7, 1 H, H-6_a), 3.26 (dd, J_5,6b= 5.1, J_6b,6a= 10.7, 1H, H-6_b).

¹³C NMR (CDCl₃, 100 MHz) δ: 166.1, 165.4, 164.9, 143.9 (3 C), 133.3, 133.25,

133.2, 130.0 (2 C), 129.92 (2 C), 129.8 (2 C), 129.7, 129.5, 129.3, 129.1 (2 C),

128.7 (6 C), 128.4 (2 C), 128.3 (2 C), 127.9 (6 C), 127.0 (3 C), 102.1 (C-1), 86.8

(O-CPh₃), 74.0 (C-5), 73.4 (C-3), 72.2 (C-2), 69.6 (C-4), 62.6 (C-6), 56.9 (O-CH₃).

Compound 3d (1.00 g, 1.34 mmol) was detritylated using FeCl₃·6H₂O in

CH₂Cl₂according to the procedure described by Ding et al.^[40]This gave a white

foam, which was puriﬁed by silica gel column chromatography (toluene/EtOAc,

1/1) and then crystallized from pentane/CHCl₃to give 450 mg (0.89 mmol, 66%)

of 4d as white solid, mp. 79–80^◦C, [α]_D²²= −8.4^◦(c 1.1, CHCl₃), lit.^[38]−6.6^◦(c

1

1.1, CHCl₃). H NMR (CDCl₃) and ¹³C NMR (CDCl₃) corresponded with data

reported previously.^[27,38]

Methyl 2,3,4-tri-O-benzoyl-α-D-mannopyranoside (4e)^[41,42]

Methyl α-D-mannopyranoside (2.00, 10.30 mmol) was converted to methyl

2,3,4-tri-O-benzoyl-6-trityl-α-D-mannopyranoside (3e)^[40,43]as described for

4d. This gave 2.70 g (3.61 mmol, 35%) of 3e as a white solid, mp. 113–114^◦C,

lit.^[43]110–120^◦C, [α]²_D²= −90.5^◦(c 1.0, CHCl₃), lit.^[40]−45^◦(c 2.0, CHCl₃). H

1

NMR (CDCl₃, 400 MHz) δ: 8.15 (m, 2 H, Ar), 7.83 (m, 2 H, Ar), 7.73 (m, 2 H,

Ar), 7.61 (m, 1 H, Ar), 7.51–7.38 (m, 10 H, Ar), 7.30 (m, 3 H, Ar), 7.18–7.06 (m,

10 H, Ar), 6.02 (t, J = 10.2, 1H, H-4), 5.77 (dd, J_3,2= 3.3, J_3,4= 10.2, 1 H, H-3)

5.68 (m, 1 H, H-2), 5.03 (d, J = 1.5, 1 H, H-1), 4.17 (m, 1 H, H-5), 3.55 (s, 3

H, OCH₃), 3.40 (dd, J_5,6a= 2.5, J_6a,6b= 10.5, 1 H, H-6_a), 3.29 (dd, J_5,6b= 4.9,

J_6b,6a= 10.5, 1 H, H-6_b). ¹³C NMR (CDCl₃, 100 MHz) δ: 165.8, 165.7, 165.2,

143.9 (3C), 133.6, 133.2, 133.1, 130.1 (2 C), 129.9 (2 C), 129.8 (2 C), 129.7,

129.5, 128.8 (2 C), 128.77 (6 C), 128.4 (2 C), 128.3 (2 C), 127.8 (6 C), 127.0 (3

A.M. Esmurziev et al.

358

C), 98.7 (C-1), 86.8 (O-CPh₃), 70.9 (C-2), 70.7 (C-3), 70.4 (C-5), 67.2 (C-4), 62.5

(C-6), 55.4 (O-CH₃).

Detritylation of 3e (2.50 g, 3.34 mmol) was performed as described for 3d to

give 4e, 1.31 g (2.59 mmol, 77%) as a white solid, mp. 69–70^◦C, [α]_D²²= −127.5^◦

(c 0.5, CHCl₃), lit.^[27]−126.0^◦(c 0.5, CHCl₃), lit.^[38]−154^◦(c 1.1, CHCl₃). NMR

corresponded with that reported previously.^[27]

Methyl 2,3,4-tri-O-benzoyl-6-deoxy-6-ﬂuoro-α-D-galactopyranoside (5a)

DAST (106 µL, ∼129 mg, ∼0.80 mmol) was added drop-wise to a solution

of 4a (100 mg, 0.20 mmol) and DMAP (50 mg, 0.40 mmol) in dry CH₂Cl₂(2

mL) at −25^◦C under argon. After 12 h the reaction mixture was allowed to

slowly warm to rt and stirred overnight. The reaction mixture was then cooled

to 0^◦C and methanol (0.3 mL) was added to quench the reaction. The resulting

solution was further diluted with CH₂Cl₂(5 mL) and washed with saturated

NaHCO₃(3 × 5 mL) and water (5 mL), and the combined aqueous phase was

back-extracted once with CH₂Cl₂(5 mL). The organic phases were washed once

more with water (10 mL), dried over MgSO₄, and concentrated under vacuum.

The residue was puriﬁed by silica gel column chromatography (toluene/EtOAc,

9/1) to give 10 mg (0.02 mmol, 10%) of compound 5a as a colorless foam; [α]_D²²

1

= +78.1^◦(c 0.7, CHCl₃). H NMR (CDCl₃, 600 MHz) δ: 8.07 (m, 2 H, Ar), 7.98

(m, 2 H, Ar), 7.79 (m, 2 H, Ar), 7.62 (m, 1 H, Ar), 7.52 (m, 1 H, Ar), 7.48 (m, 2 H,

Ar), 7.43 (m, 1 H, Ar), 7.38 (m, 2 H, Ar), 7.24 (m, 2 H, Ar), 5.96 (m, 1 H, H-3),

5.94 (m, 1 H, H-4), 5.67 (dd, 1 H, H-2), 5.32 (d, 1 H, H-1), 4.57 (m, 2 H, H-6_ab),

4.52 (m, 1 H, H-5) 3.50 (s, 3 H, OCH₃). ¹³C NMR (CDCl₃, 150 MHz) δ: 166.08,

165.58, 165.50, 133.63, 133.41, 133.18, 129.92 (2 C), 129.86 (2 C), 129.69 (2

C), 129.14, 129.10, 129.03, 128.66 (2 C), 128.44 (2 C), 128.27 (2 C), 97.57 (C-

1), 81.72 (d, J = 171.2, C-6), 69.26 (C-2), 69.02 (d, J = 6.6, C-4), 68.23 (C-3),

67.65 (d, J = 23.0, C-5), 55.79 (OCH₃). HRMS (ESI): 509.1619 (calcd 509.1606,

M+H⁺).

Methyl 2,3,4-tri-O-benzoyl-6-deoxy-6-ﬂuoro-β-D-galactopyranoside (5b)

Compound 5b was synthesized as described for 5a, starting with 4b

(100 mg, 0.20 mmol) giving 9 mg (0.02 mmol, 9%) of a colorless oil; [α]_D²²

=

+146.0^◦(c 0.5, CHCl₃). H NMR (CDCl₃, 600 MHz) δ: 8.06 (m, 2 H, Ar), 7.97

(m, 2 H, Ar), 7.78 (m, 2 H, Ar), 7.62 (m, 1 H, Ar), 7.52 (m, 1 H, Ar), 7.48 (m,

2 H, Ar), 7.43 (m, 1 H, Ar), 7.39 (m, 2 H, Ar), 7.24 (m, 2 H, Ar), 5.91 (dd, 1

H, H-4), 5.78 (dd, 1 H, H-2), 5.58 (dd, 1 H, H-3), 4.75 (m, 1 H, H-1), 4.62 (m,

2 H, H-6_ab), 4.26 (m, 1 H, H-5), 3.62 (s, 3 H, OCH₃). ¹³C NMR (CDCl₃, 150

MHz) δ: 165.58, 165.53, 165.32, 133.69, 133.32, 133.29, 130.01 (2 C), 129.80 (2

C), 129.77 (2 C), 129.30, 128.82, 128.68, 128.64 (2 C), 128.39 (2 C), 128.31 (2

C), 102.42 (C-1), 81.17 (d, J = 172.4, C-6), 72.27 (d, J = 23.0, C-5), 71.65 (C-3),

1

Benzoylated Deoxyﬂuoropyranosides

359

69.61 (C-2), 67.93 (d, J = 6.6, C-4), 57.38 (OCH₃). HRMS (ESI): 509.1612 (calcd

509.1606, M+H⁺).

Methyl 2,3,4-tri-O-benzoyl-6-deoxy-6-ﬂuoro-α-D-glucopyranoside (5c)^[35]

DAST (190 µL, ∼232 mg, ∼1.44 mmol) was added drop-wise to a solution

of 4c^[27](180 mg, 0.36 mmol) and DMAP (100 mg, 0.80 mmol) in dry CH₂Cl₂

(3 mL) at −25^◦C. After stirring under argon for 12 h, the reaction mixture was

allowed to warm to ambient temperature, stirred overnight, and reﬂuxed for

1 h. The mixture was then cooled to 0^◦C and methanol (0.5 mL) was added

to quench the reaction. The reaction mixture was then diluted with CH₂Cl₂

(10 mL) and washed with saturated NaHCO₃(3 × 10 mL) and water (10 mL),

and the aqueous phase was back-extracted once with CH₂Cl₂(10 mL). The

combined organic phases were washed once with water (15 mL), dried over

MgSO₄, and concentrated under vacuum. The residue was crystallized twice

from MeOH to give 135 mg (26.55 mmol, 75%) as a white solid, mp. 143–144^◦C,

(lit.^[35]145–146^◦C), [α]²_D²= +46.8^◦(c 1.5, CHCl₃), lit.^[35]+52.7^◦(c 1, CHCl₃).

¹H NMR (CDCl₃, 600 MHz) δ: 7.97 (m, 4 H, Ar), 7.87 (m, 2 H, Ar), 7.54 (m, 1

H, Ar), 7.52 (m, 1 H, Ar), 7.43 (m, 1 H, Ar), 7.38 (m, 4 H, Ar), 7.29 (m, 2 H, Ar),

6.19 (t, 1 H, H-3), 5.56 (t, 1H, H-4), 5.28 (m, 1 H, H-2), 5.27 (m, 1 H, H-1), 4.59

(dd, 2 H, H-6_ab), 4.27 (ddt, 1 H, H-5), 3.49 (s, 3H, (OCH₃). ¹³C NMR (CDCl₃, 150

MHz) δ: 165.80, 165.77, 165.29, 133.56, 133.41, 133.16, 129.94 (2 C), 129.88 (2

C), 129.67 (2 C), 129.12, 128.99, 128.74, 128.49 (2 C), 128.44 (2 C), 128.31 (2

C), 97.04 (C-1), 81.50 (d, J = 175.6, C-6), 71.92 (C-2), 70.25 (C-3), 68.55 (d, J =

6.6, C-4), 68.55 (d, J = 19.8, C-5), 55.74 (OCH₃).

Methyl 2,3,4-tri-O-benzoyl-6-deoxy-6-ﬂuoro-β-D-glucopyranoside (5d)^[19]

Deoxo-Fluor in THF (50%, 350 µL, 0.81 mmol) was added drop-wise to a so-

lution of 4d (100 mg, 0.20 mmol) in THF (1 mL) at −25^◦C. After stirring under

argon for 12 h, the reaction mixture was allowed to warm to ambient tem-

perature, stirred overnight, and reﬂuxed for 1 hour. The reaction mixture was

cooled to 0^◦C and methanol (0.5 mL) was added to quench excess of the reagent.

The reaction mixture was then diluted with CH₂Cl₂(5 mL) and washed with

saturated NaHCO₃(3 × 5 mL) and water (5 mL), and the aqueous phases

were back-extracted once with CH₂Cl₂(5 mL). The combined organic phases

were washed once with water (10 mL), dried over MgSO₄, and concentrated

under vacuum. The residue was puriﬁed by silica gel column chromatography

(toluene/EtOAc, 9/1) to give an oil, which was crystallized twice from MeOH to

give 74 mg (0.15 mmol, 74%) of a white solid, mp. 64–65^◦C, [α]_D²²= −1.6^◦(c 1.0,

CHCl₃). ¹H NMR (CDCl₃, 600 MHz) δ: 7.96 (m, 2 H, Ar), 7.94 (m, 2 H, Ar),7.82

(m, 2 H, Ar), 7.52 (m, 2 H, Ar), 7.42 (m, 1 H, Ar), 7.38 (m, 4 H, Ar), 7.28 (m, 2

H, Ar), 5.91 (t, 1 H, H-3)_,5.51 (m, 1 H, H-4), 5.50 (m, 1 H, H-2), 4.76 (d, 1 H,

H-1), 4.62 (dd, 2 H, H-6_ab), 4.05 (qt, 1 H, H-5), 3.58 (s, 3H, OCH₃). ¹³C NMR

(CDCl₃, 150 MHz) δ: 165.79, 165.24, 165.10, 133.62, 133.28, 133.25, 129.85 (4

A.M. Esmurziev et al.

360

C), 129.75 (2 C), 129.23, 128.72, 128.63, 128.50 (2 C), 128.36 (2 C), 128.31 (2

C), 101.94 (C-1), 81.56 (d, J = 175.6, C-6), 73.22 (d, J = 19.8, C-5), 72.76 (C-3),

71.66 (C-2), 68.83 (d, J = 7.7, C-4), 57.20 (OCH₃).

Methyl 2,3,4-tri-O-benzoyl-6-deoxy-6-ﬂuoro-α-D-mannopyranoside (5e)

Compound 5e was prepared as described for 5d, starting with 4e (100 mg,

0.20 mmol). Puriﬁcation by silica gel column chromatography (toluene/EtOAc,

9/1), followed by crystallization from MeOH gave 64 mg (0.13 mmol, 64%) of

a white solid, mp. 67–68^◦C, [α]_D²²= −154.3^◦(c 1.0, CHCl₃). H NMR (CDCl₃,

1

600 MHz) δ: 8.10 (m, 2 H, Ar), 7.97 (m, 2 H, Ar), 7.83 (m, 2 H, Ar), 7.61 (m, 1

H, Ar), 7.53 (m, 1 H, Ar), 7.49 (m, 2 H, Ar), 7.43 (m, 1 H, Ar), 7.39 (m, 2 H, Ar),

7.26 (m, 2 H, Ar), 5.91 (m, 1 H, H-3), 5.89 (m, 1 H, H-4), 5.68 (m, 1 H, H-2), 5.01

(bs, 1 H, H-1), 4.63 (m, 2 H, H-6_ab), 4.27 (m, 1 H, H-5), 3.54 (s, 3 H, OCH₃). ¹³

C

NMR (CDCl₃, 150 MHz) δ: 165.53, 165.49, 165.42, 133.56 (2 C), 133.19, 129.93

(2 C), 129.80 (2 C), 129.73 (2 C), 129.24, 129.03, 128.84, 128.63 (2 C), 128.50 (2

C), 128.30 (2 C), 98.66 (C-1), 81.70 (d, J = 174.5, C-6), 70.34 (C-2), 69.82 (C-3),

69.58 (d, J = 19.8, C-5), 66.24 (d, J = 6.6, C-4), 55.62 (OCH₃). HRMS (ESI):

509.1611 (calcd 509.1606, M+H⁺).

2,3,4-Tri-O-benzoyl-1-deoxy-1-ﬂuoro-6-methyl-β-D-glucopyranoside (6d)^[19]

Compound 6d was obtained according to the procedure described for 5c,

starting with 4d (50 mg, 0.10 mmol) and DAST (52 µL, ∼64 mg, ∼0.40

mmol) in dry CH₂Cl₂(1 mL). Puriﬁcation by silica gel column chromatogra-

phy (toluene/EtOAc, 9.5/0.5) gave 19 mg (0.04 mmol, 38%) of 6d. The structure

1

of compound 6d was veriﬁed by comparing H NMR to that reported previ-

ously.^[19]

Methyl 2,3,6-tri-O-benzoyl-4-deoxy-4-ﬂuoro-α-D-glucopyranoside (8c)^[20,21]

using DAST

Compound 8c was synthesized as described for 5a starting with 7a

(11.80 g, 23.30 mmol) and DAST (7.5 mL, ∼9.2 g, ∼56 mmol). After 6 h re-

action time a second portion of DAST (7.5 mL, ∼9.2 g, ∼56 mmol) was added.

This resulted in a syrup, which, upon crystallization from EtOH, gave 8.50 g

(16.72 mmol, 72%) of a white solid, mp. 140–141^◦C (lit.^[21]139–141^◦C), [α]²_D²

=

+101^◦(c 1.5, CHCl₃). ¹H NMR (CDCl₃, 600 MHz) δ: 8.10 (m, 2 H, Ar), 8.02 (m,

2 H, Ar), 7.98 (m, 2 H, Ar), 7.60 (m, 1 H, Ar), 7.52 (m, 2 H, Ar), 7.49 (m, 2 H,

Ar), 7.39 (m, 2 H, Ar), 7.38 (m, 2 H, Ar), 6.13 (m, 1 H, H-3), 5.20 (dd, 1 H, H-2),

5.17 (m, 1 H, H-1), 4.77 (m, 1 H, H-4), 4.62 (ddd, 1 H, H-6_a), 4.72 (m, 1 H, H-6_b),

4.32 (m, 1 H, H-5), 3.47 (s, 3H, OCH₃). ¹³C NMR (CDCl₃, 150 MHz) δ: 166.16,

165.85, 165.58,133.51, 133.32, 133.30, 129.96 (2 C), 129.80 (2 C), 129.73 (2 C),

129.65, 129.27, 128.83, 128.52 (2 C), 128.47 (2 C), 128.39 (2 C), 96.88 (C-1),

Benzoylated Deoxyﬂuoropyranosides

361

87.36 (d, J = 187.7, C-4), 71.36 (d, J = 7.7, C-2), 70.45 (d, J = 19.8, C-3), 67.10

(d, J = 23.0, C-5), 62.57, 55.69 (OCH₃).

Methyl 2,3,6-tri-O-benzoyl-4-deoxy-4-ﬂuoro-α-D-glucopyranoside (8c)^[20,21]

using Deoxo-Fluor

Compound 8c was synthesized using Deoxo-Fluor (50% in THF, 415 µL,

∼215 mg, ∼0.97 mmol) and 7a (200 mg, 0.39 mmol) at −25^◦C for 12 h followed

by stirring overnight in ambient temperature. Workup was performed as for 5d

and crystallization from EtOH gave 90 mg (0.18 mmol, 45%) of a white solid.

Physical and spectroscopic properties were identical to that obtained using

DAST.

Methyl 2,3-di-O-benzoyl-4,6-dideoxy-4,6-diﬂuoro-α-D-glucopyranoside (10c)

using DAST

Compound 10c was synthesized as described for 5a, starting with 9a^[27]

(100 mg, 0.25 mmol) and DAST (300 µL, ∼366 mg ∼2.3 mmol) to give 75 mg

(0.18 mmol, 74%) of the product as a colorless oil, [α]²_D²= +29.4^◦(c 2.0, CHCl₃).

¹H NMR (CDCl₃, 600 MHz) δ: 8.01 (m, 2 H, Ar), 7.97 (m, 2 H, Ar), 7.52 (m, 2

H, Ar), 7.38 (m, 4 H, Ar), 6.10 (m, 1 H, H-3), 5.18 (d, 1 H, H-1), 5.16 (m, 1 H,

H-2), 4.76 (dt, 1 H, H-4), 4.73 (m, 2 H, H-6_ab), 4.11 (m, 1 H, H-5), 3.46 (s, 3 H,

OCH₃). ¹³C NMR (CDCl₃, 150 MHz) δ: 165.78, 165.58, 133.48, 133.32, 129.95

(2 C), 129.80 (2 C), 129.26, 128.84, 128.45 (2 C), 128.39 (2 C), 97.04 (C-1), 86.01

(dd, J = 187.7, 7.7, C-4), 80.75 (d, J = 174.5, C-6), 71.31 (d, J = 7.7, C-2), 70.39

(d, J = 19.8, C-3), 68.02 (dd, J = 23.0, 17.6, C-5), 55.81 (OCH₃). HRMS (ESI):

429.1136 (calcd 429.1126, M+Na⁺).

Methyl 2,3-di-O-benzoyl-4,6-dideoxy-4,6-diﬂuoro-α-D-glucopyranoside (10c)

using Deoxo-Fluor

Compound 10c was synthesized using Deoxo-Fluor as described for 5d

starting with 9c (100 mg, 0.25 mmol) and Deoxo-Fluor (50% in THF, 960

µL, ∼498 mg ∼2.25 mmol). Puriﬁcation by silica gel column chromatography

(toluene/EtOAc, 9/1) gave 73 mg (0.18 mmol, 72%) of 10c as colorless oil.

Methyl 2,3-O-dibenzoyl-4,6-dideoxy-4,6-diﬂuoro-α-D-talopyranoside (10f)

using DAST

The ﬂuorination was performed as described for 5a starting with methyl

α-D-mannopyranoside (100 mg, 0.51 mmol) and DAST (610 µL, ∼740 mg

∼4.6 mmol). The reaction mixture was freeze dried to give 108 mg of methyl

4,6-dideoxy-4,6-diﬂuoro-α-D-talopyranoside (11f) as yellowish oil. Crude 11f

was dissolved in dry pyridine (2 mL) and cooled to −10^◦C. Benzoyl chloride

(1.46 g, 10.39 mmol) was added drop-wise and the mixture was allowed to reach

rt. After 3 d the reaction mixture was cooled to 0^◦C, and saturated NaHCO₃

(2 mL) was added. The mixture was then extracted with CHCl₃(2 × 10 mL)

A.M. Esmurziev et al.

362

and the organic phase was washed with saturated NaHCO₃(3 × 15 mL) and

water (15 mL), dried over MgSO₄, and concentrated under vacuum to give yel-

low oil. Puriﬁcation by silica gel column chromatography (toluene/EtOAc, 9/1),

followed by two crystallizations from EtOH, gave 57 mg (0.14 mmol, 27%) of

a yellow amorphous solid, which melted when handled, [α]²_D²= −16.4^◦(c 1.0,

1

CHCl₃). H NMR (CDCl₃, 600 MHz) δ: 8.15 (m, 2 H, Ar), 7.93 (m, 2 H, Ar),

7.60 (m, 1 H, Ar), 7.51 (m, 1 H, Ar), 7.48 (m, 2 H, Ar), 7.34 (m, 2 H, Ar), 5.53

(m, 1 H, H-3), 5.52 (m, 1 H, H-2), 5.03 (dd, 1 H, H-4), 5.01(bs, 1 H, H-1), 4.73

(m, 2 H, H-6_ab), 4.31 (m, 1 H, H-5), 3.50 (s, 3H, OCH₃). ¹³C NMR (CDCl₃,

150 MHz) δ: 165.91, 165.33, 133.48, 133.41, 130.09 (2 C), 129.90 (2 C), 129.54,

129.04, 128.51 (2 C), 128.43 (2 C), 99.19 (C-1), 84.95 (dd, J = 190.7, 6.3, C-

4), 81.26 (dd, J = 169.9, 7.1, C-6), 67.99 (C-2), 67.90 (dd, J = 23.6, 18.5, C-5),

66.69 (d, J = 15.9, C-3), 55.63 (OCH₃). HRMS (ESI): 429.1132 (calcd 429.1126,

M+Na⁺).

Methyl 2,3-O-dibenzoyl-4,6-dideoxy-4,6-diﬂuoro-α-D-talopyranoside (10f)

using Deoxo-Fluor

Compound 10f was synthesized as described for 5d starting with methyl

α-D-mannopyranoside (100 mg, 0.51 mmol) and Deoxo-Fluor (50% in THF,

1.95 mL, ∼1.02 g ∼4.6 mmol). Benzoylation and puriﬁcation as described above

gave 55 mg (0.14 mmol, 26%) of 10f.

Methyl 2,3-O-dibenzoyl-4,6-dideoxy-4,6-diﬂuoro-α-D-talopyranoside (10f) from

11f

To a stirred solution of 11f (50 mg, 0.26 mmol) in pyridine (2 mL)

at −10^◦C was added benzoyl chloride (0.70 g, 4.99 mmol). After addi-

tion the mixture was reacted for 3 d at rt. Then the mixture was cooled

to 0^◦C, and saturated NaHCO₃(2 mL) was added. The mixture was ex-

tracted with CHCl₃(2 × 10 mL), washed with saturated NaHCO₃(3 ×

10 mL) and water (10 mL), dried over MgSO₄, and concentrated under vac-

uum to give yellow oil. Puriﬁcation by silica gel column chromatography

(toluene/EtOAc, 9/1), followed by two crystallizations from EtOH, gave 78 mg

(0.19 mmol, 74%) of a yellow amorphous solid 10f. The spectroscopic properties

corresponded with that described above.

Isolation of methyl 4,6-dideoxy-4,6-diﬂuoro-α-D-talopyranoside 2,3-cylic sulﬁte

(12f) and methyl 4,6-dideoxy-4,6-diﬂuoro-α-D-talopyranoside (11f)^[21,31]

using DAST

Compound 12f: To a stirred solution of methyl α-D-mannopyranoside (800

mg, 4.12 mmol) in anhydrous CH₂Cl₂(25 mL) at −20^◦C was added DAST (2.5

mL, 20 mmol). After adding of DAST the mixture was stirred for 2 h at rt.

Then the mixture was cooled and quenched with MeOH (10 mL). The resulting

mixture was concentrated under reduced pressure. Upon addition of MeOH

Benzoylated Deoxyﬂuoropyranosides

363

(5 mL) and water (20 mL) a white solid precipitated, which was separated

by ﬁltration. This procedure was repeated twice and the combined solid was

recrystallized from MeOH/water to give 270 mg (1.11 mmol, 27%) of 12f as a

white solid, mp. 122.5–123.0^◦C, [α]_D²²= +3.8^◦(c 1.0, CHCl₃). ¹H NMR (CDCl₃,

600 MHz) δ: 5.21 (bs, 1 H, H-1), 5.01 (dt, J = 23.8, 4.5, 1 H, H-3,), 4.76 (bd, J =

4.9, 1-H, H-2), 4.66 (dd, J = 49.5, 4.5, 1 H, H-4), 4.63 (m, 2 H, H-6_ab), 4.07 (m,

J = 28.9, 13.7, 6.1, 1 H, H-5), 3.48 (s, 3 H, OCH₃). ¹³C NMR (CDCl₃, 150 MHz)

δ: 96.50 (C-1), 81.48 (dd, J = 170.8, 6.1, C-4), 80.84 (dd, J = 188.5, 6.1, C-6),

76.10 (d, J = 17.1, C-3), 73.67 (C-2), 65.25 (dd, 24.3, 18.2, C-5), 55.83 (O-CH₃).

¹⁹F NMR (CDCl₃, 470 MHz) δ: −231.87 (dt, J = 46.0, 13.8), −210.38 (m) HRMS

(ESI): 245.0289 (calcd 245.0290, M+H⁺). Compound 11f: Concentration of the

mother liquor followed by silica gel column chromatography (CHCl₃/MeOH,

9/1) yielded 390 mg (1.97 mmol, 48%) of 11f as colorless crystals, mp. 88–89^◦C,

lit.^[21]90–92^◦C. [α]²_D²= +96.2^◦(c 1.0, CHCl₃), lit.^[31]101.9 (c 1.02 MeOH). H

1

NMR (CDCl₃, 600 MHz) δ: 4.88 (bs, 1 H, H-1), 4.80 (m, J = 50.5, 1.4, 1 H, H-4),

4.63 (m, J = 46.8, 2 H, H-6_a,b), 4.08 (m, 1 H- H-5, J = 31.9, 19.3, 6.1), 3.83 (m,

J = 31.6, 3.0, 1 H, H-3), 3.79 (m, 1 H, H-2), 3.43 (s, O-CH₃). ¹³C NMR (CDCl₃,

150) δ: 101.53 (C-1), 90.05 (dd, J = 178.0, 6.1, C-4), 81.27 (dd, J = 169.7, 7.2,

C-6), 69.86 (C-2), 67.40 (dd, 23.8, 18.2, C-5), 65.27 (d, J = 16.6, C-3), 55.55

(O-CH₃). ¹⁹F NMR (CDCl₃, 470 MHz) δ: −231.71 (dt, J = 46.0, 13.8), −216.73

(m).

Methyl 4,6-dideoxy-4,6-diﬂuoro-α-D-talopyranoside 2,3-cylic sulﬁte (12f) from

11f

The synthesis was done essentially as described by Lohray et al.^[44]To a

solution of 11f (20 mg, 0.1 mmol) in dry CCl₄(1 mL) was added SOCl₂(20 µL,

0.25 mmol) and triethylamine (35 µL, 0.25 mmol). The mixture was reﬂuxed

for 45 min, then cooled to rt, diluted with CHCl₃(3 mL), and washed with

NaHCO₃(3 × 5 mL) and water (5 mL). Drying over MgSO₄and concentration

in vacuum gave 21 mg of yellow oil. Crystallization from MeOH (0.2 mL) and

water (0.5 mL) gave 11 mg (0.04 mmol, 44%) of a white solid with identical

NMR spectroscopic properties as for 12f described above.

Methyl 2,4,6-tri-O-benzoyl-3-deoxy-3-ﬂuoro-β-D–glucopyranoside (13d)

3-Deoxy-3-ﬂuoro-D-glucose (200 mg, 1.10 mmol) was dissolved in

HCl·MeOH (1 mL, 0.5 N) and reﬂuxed for 3 d. Then, the reaction mixture was

concentrated and submitted to the same treatment once more to give 237 mg

of colorless oil. The crude mixture was then dissolved in dry pyridine (2 mL)

and cooled to 0^◦C, followed by drop-wise addition of benzoyl chloride (1.46 g,

10.4 mmol). The reaction mixture was warmed to rt and stirred for 3 d. The

reaction mixture was then cooled to 0^◦C, treated with saturated NaHCO₃(5

mL), and extracted with CHCl₃(4 × 10 mL). The organic phases were washed

A.M. Esmurziev et al.

364

with water (20 mL) and concentrated under vacuum. TLC indicated two prod-

ucts that were separated by silica gel column chromatography (toluene/EtOAc,

9.5/0.5). This gave 22 mg (0.04 mmol, 3%) of 14d, and after two crystalliza-

tions from EtOH 70 mg (0.14 mmol, 13%) of 13d, white solid, mp. 146–147^◦C,

[α]²_D²= −17.4^◦(c 0.5, CHCl₃). ¹H NMR (CDCl₃, 600 MHz) δ: 8.08 (m, 2 H, Ar),

8.03 (m, 2 H, Ar), 8.01 (m, 2 H, Ar), 7.59 (m, 1 H, Ar), 7.58 (m, 1 H, Ar), 7.54

(m, 1 H, Ar), 7.45 (m, 2 H, Ar), 7.42 (m, 2 H, Ar), 7.39 (m, 2 H, Ar), 5.66 (m, 1

H, H-4), 5.48 (m, 1 H, H-2), 4.96 (dt, 1 H, H-3), 4.66 (m, 1 H, H-6_b), 4.64 (d, 1

H, H-1), 4.47 (dd, 1 H, H-6_a), 4.02 (m, 1 H, H-5), 3.52 (s, 3 H, OCH₃). ¹³C NMR

(CDCl₃, 150 MHz) δ: 166.17, 164.95, 164.92, 133.62, 133.40, 133.20, 129.93 (2

C), 129.92 (2 C), 129.73 (2 C), 129.50, 129.38, 128.91, 128.51 (2 C), 128.44 (2C),

128.39 (2 C), 101.37 (d, J = 10.7, C-1), 91.79 (d, J = 191.3, C-3), 71.99 (d, J =

18.7, C-2), 71.10 (d, J = 7.7, C-5), 69.73 (d, J = 18.7, C-4), 62.96 (d, J = 1.6,

C-6), 57.12 (OCH₃). HRMS (ESI): 509.1611 (calcd 509.1612, M+H⁺).

1,3,4,6-Tetra-O-benzoyl-3-deoxy-3-ﬂuoro-β-D–glucopyranoside (14d)

3-Deoxy-3-ﬂuoro-D-glucose (70 mg, 0.38 mmol) was dissolved in dry pyri-

dine (1 mL) and cooled to −10^◦C. Benzoyl chloride (220 mg, 1.57 mmol) was

added drop-wise and the mixture was stirred at rt. After 3 d the reaction mix-

ture was cooled, diluted with saturated NaHCO₃(0.5 mL), and extracted with

CHCl₃(4 × 10 mL). The organic phases were then washed with saturated

NaHCO₃(3 × 10 mL) and water (10 mL), dried over MgSO₄, and concentrated

under vacuum. The resulting oil was crystallized twice from MeOH to give 111

mg (0.19 mmol, 49%) of compound 14d as a white solid, mp. 231–232^◦C, [α]_D²²

1

= +9.6^◦(c 1.0, CHCl₃). H NMR (CDCl₃, 600 MHz) δ: 8.04 (m, 2 H, Ar), 8.02

(m, 6 H, Ar), 7.58 (m, 1 H, Ar), 7.54 (m, 2 H, Ar), 7.53 (m, 1 H, Ar), 7.43 (m,

2 H, Ar), 7.40 (m, 4 H, Ar), 7.39 (m, 2 H, Ar), 6.18 (d, 1 H, H-1), 5.84 (m, 1 H,

H-2), 5.81 (m, 1 H, H-4), 5.11 (dt, 1 H, H-3), 4.66 (dd, 1 H, H-6_b), 4.46 (dd, 1 H,

H-6_a), 4.26 (m, 1 H, H-5). ¹³C NMR (CDCl₃, 150 MHz) δ: 166.09, 164.89, 164.84,

164.61, 133.94, 133.72, 133.62, 133.16, 130.21 (2 C), 129.96 (2 C), 129.89 (2 C),

129.82 (2 C), 129.43, 128.82, 128.76, 128.56 (4 C), 128.50 (2 C), 128.36 (2 C),

128.27, 91.95 (d, J = 11.0, C-1), 91.64 (d, J = 193.2, C-3), 72.12 (d, J = 6.6, C-

5), 70.87 (d, J = 19.8, C-2), 69.02 (d, J = 19.8, C-4), 62.47 (C-6). HRMS (ESI):

621.1542 (calcd 621.1531, M+Na⁺).

1,3,4,6-Tetra-O-benzoyl-2-deoxy-2-ﬂuoro-β-D–glucopyranoside (15d)

Compound 15d was synthesized as described for 14d, starting with 2-

deoxy-2-ﬂuoro-D-glucose (70 mg, 0.38 mmol). This gave after crystallization

from MeOH 118 mg (0.20 mmol, 52%) of compound 15d as a white solid, mp.

169–170^◦C, [α]_D²²= +23.7^◦(c 1.0, CHCl₃). H NMR (CDCl₃, 600 MHz) δ: 8.12

1

(m, 2 H, Ar), 8.00 (m, 2 H, Ar), 7.99 (m, 2 H, Ar), 7.92 (m, 2 H, Ar), 7.61 (m,

1 H, Ar), 7.53 (m, 1 H, Ar), 7.52 (m, 1 H, Ar), 7.51 (m, 1 H, Ar), 7.46 (m, 2 H,

Ar), 7.38 (m, 2 H, Ar), 7.37 (m, 2 H, Ar), 7.35 (m, 2 H, Ar), 6.28 (dd, 1 H, H-1),

Benzoylated Deoxyﬂuoropyranosides

365

5.97 (m, 1 H, H-3), 5.71 (t, 1 H, H-4), 4.91 (ddd, 1 H, H-2), 4.62 (dd, 1 H, H-6_b),

4.46 (dd, 1 H, H-6_a), 4.34 (m, 1 H, H-5). ¹³C NMR (CDCl₃, 150 MHz) δ: 166.03,

165.47, 165.15, 164.44, 133.97, 133.63, 133.51, 133.11, 130.22 (2 C), 129.88 (4

C), 129.78 (2 C), 129.47, 128.82, 128.56 (2 C), 128.53, 128.50 (2 C), 128.45 (2 C),

128.36, 128.34 (2 C), 91.98 (d, J = 24.2, C-1), 88.64 (d, J = 192.1, C-2), 73.03

(d, J = 19.8, C-3), 72.98 (C-5), 68.62 (d, J = 6.6, C-4), 62.58 (C-6). HRMS (ESI):

621.1549 (calcd 621.1531, M+Na⁺).

ACKNOWLEDGMENTS

NTNU is acknowledged for use of NMR facilities, Anders Jahres Foundation

for ﬁnancial support, and Anders Brunsvik for HRMS.

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Synthesis and structure elucidation of benzoylated deoxyfluoropyranosides

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