Synthesis and Structural Characteristics of all Mono- And Difluorinated 4,6-Dideoxy- d - Xylo-hexopyranoses

pubs.acs.org/joc

Article

Synthesis and Structural Characteristics of all Mono- and

Diﬂuorinated 4,6-Dideoxy‑^D-xylo-hexopyranoses

David E. Wheatley, Clement Q. Fontenelle, Ramakrishna Kuppala, Robert Szpera, Edward L. Briggs,

Jean-Baptiste Vendeville, Neil J. Wells, Mark E. Light, and Bruno Linclau *

Cite This: J. Org. Chem. 2021, 86, 7725 −7756

Read Online

sı

*

Metrics & More

Article Recommendations

Supporting Information

ACCESS

ABSTRACT: Protein−carbohydrate interactions are implicated in

many biochemical/biological processes that are fundamental to life and

to human health. Fluorinated carbohydrate analogues play an

important role in the study of these interactions and ﬁnd application

as probes in chemical biology and as drugs/diagnostics in medicine.

The availability and/or eﬃcient synthesis of a wide variety of

ﬂuorinated carbohydrates is thus of great interest. Here, we report a

detailed study on the synthesis of monosaccharides in which the

hydroxy groups at their 4- and 6-positions are replaced by all possible

mono- and diﬂuorinated motifs. Minimization of protecting group use was a key aim. It was found that introducing electronegative

substituents, either as protecting groups or as deoxygenation intermediates, was generally beneﬁcial for increasing deoxyﬂuorination

yields. A detailed structural study of this set of analogues demonstrated that dideoxygenation/ﬂuorination at the 4,6-positions caused

very little distortion both in the solid state and in aqueous solution. Unexpected trends in α/β anomeric ratios were identiﬁed.

Increasing ﬂuorine content always increased the α/β ratio, with very little diﬀerence between regio- or stereoisomers, except when

4,6-diﬂuorinated.

Withers reported that the aﬃnity of 1,2-dideoxy-1,2-diﬂuori-

nated glucoses analogues toward glycogen phosphorylase was

higher than that of the respective monoﬂuorinated derivatives.⁹

The 1,2-dideoxy-1,2-diﬂuorinated mannoses as well as 1,2-

dideoxyglucose all have a much weaker binding aﬃnity. The

importance of the presence of ﬂuorine substitution, and the

stereochemistry of the C−F groups, points to eﬀects such as

hydrogen bonding or dipolar interactions. The diﬀerence

between the monoﬂuorinated and diﬂuorinated motifs points

to a hydrophobic desolvation eﬀect, and the combination of

these eﬀects has aptly been coined “polar hydrophobicity”.^15,24

Other examples include a 2,3,4-trideoxy-2,2,3,3,4,4-hexaﬂuori-

nated hexose and 2,3,4-trideoxy-2,3,4-triﬂuorinated hexo-

ses,^15,24which have been shown to cross the erythrocyte

membrane through GLUT-1 transporter protein. Our group

has shown that 2,3-dideoxy-2,2,3,3-tetraﬂuorinated Galp-UDP

and Galf-UDP derivatives have a higher aﬃnity for galactose

mutase than the parent galactose based derivatives.^25,26Hence,

the study of polyﬂuorinated sugars is of interest.

INTRODUCTION

■

Incorporation of ﬂuorine into bioactive molecules is common

in the drug discovery process due to the ability of ﬂuorine to

modulate various chemical and physical properties.¹⁻³In the

context of carbohydrates, ﬂuorination enhances enzymatic and

hydrolytic stabilities of glycosides by destabilizing the

oxonium-type intermediates through which they typically

degrade.^4,5This has found application in, for example, the

development of mechanism-based inhibitors.^6,7Another

important application of ﬂuorine incorporation in carbohy-

drates is as a probe to study the interaction of individual

hydroxyl groups with proteins,^8,9and deoxyﬂuorination has

also been shown to modulate other interactions, such as C−

H···π.^10,11Increasingly, the ﬂuorine atom is introduced to serve

as an NMR label to probe glycan−protein binding

interactions¹²or to investigate sugar membrane transport.¹³⁻¹⁶

The modulation in carbohydrate lipophilicity upon deoxo-

ﬂuorination reactions has also been reported.¹⁷⁻²⁰Finally, the

use of ¹⁸F for PET imaging is another important application,

with 2-deoxy-2-ﬂuoroglucose being one of the most important

PET radiopharmaceuticals, seeing use as a generic tumor tracer

and to study glucose metabolism.^21,22However, many other

sugars have also been applied in this area.²¹⁻²³Hence, the

synthesis and investigation of ﬂuorinated carbohydrates is of

great interest.

Received: April 6, 2021

Published: May 24, 2021

There have been a number of vicinal diﬂuorinated

dideoxysugars reported. In a landmark study, the group of

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

7725

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

In virtually all of the above examples, the ﬂuorine atom(s)

replaced one or more hydroxyl groups, but in principle,

ﬂuorination of deoxysugars at the position of the natural

deoxygenation is also of interest. Deoxygenated sugars occur

widely in nature and are an important class of sugars found in

plants, fungi, and microorganisms.^27,28Consequently, their

synthesis and conformational analysis have received much

attention,^27,29,30and ﬂuorination at the 6-position of common

6-deoxysugars such as ^L-fucose has been reported.³¹⁻³⁵

Dideoxygenated sugars are less common, but 2,6-dideoxy-

and 3,6-dideoxysugars are important constituents of bioactive

compounds including macrolide antibiotics and cardiac

glycosides (e.g., digitoxose), which without the sugar group

have reduced or no bioactivity. Their synthesis³⁶⁻⁴⁴and

conformational analysis⁴⁵continue to be the subject of much

study. Hexoses with dideoxygenation at the 4- and 6-positions

are rarer sugars yet have been reported to play key roles in

macrolide antibiotic pharmacokinetics, pharmacodynamics,

and molecular target recognition.⁴⁶⁻⁴⁹Thorson et al. recently

described an elegant approach for the synthesis of all eight

possible 2,3-diastereomers of 4,6-dideoxyhexoses in enantio-

merically pure form from a single natural product source.⁵⁰

The best known 4,6-dideoxysugar in nature is chalcose (Figure

1), which is an essential constituent of lankamycin and the

Figure 2. 4,6-Dideoxygenated target structures.

sequence to give ^D-1b as the pure β-anomer.⁵⁹Synthesis of the

4-deoxy-4-ﬂuorinated fucose derivatives proved to be low-

yielding: a ﬂuoride displacement on the mesylate derived from

quinovose derivative 12 (Scheme 1b) led to 13 in 25% yield.

The 4-deoxy-4-ﬂuoro-^D-fucoside D-2b was then obtained by

two further protecting group manipulations.⁶⁰DAST ﬂuorina-

tion was attempted on the ^D-quinovose derivative 14 (Scheme

1c) but aﬀorded none of the expected 4-deoxy-4-ﬂuorofuco-

side 17. Instead, a very low yield of the quinovose derivative 15

was obtained, with 5-ﬂuoroaltrofuranoside 16 as the major

product.⁶¹The retention and rearrangement were both

explained by the displacement of the leaving group by the

ring oxygen leading to a 4,5-epoxonium derivative (not

shown), which was then opened by ﬂuoride anion mainly at

C-5, leading to 16. Our group has reported that DAST

treatment of unprotected methyl quinovoside 18 (Scheme 1d)

did lead to the corresponding 4-deoxy-4-ﬂuorofucose deriva-

tive 19, albeit in a low yield.⁶²In contrast, deoxyﬂuorination

with DAST at the 4-position of ^L-fucose derivatives to give

quinovose derivatives was more successful (Scheme 1e): 20−

22 were converted to 23−25 with the desired inversion of

conﬁguration in reasonable to good yield.^63,64It was reported

that in the reaction of 21 a workup with NaOH resulted in the

recovery of 42% of starting material, which was attributed to

hydrolysis of unreacted aminosulﬁte intermediate (not

shown).⁶⁴Starting from 22, the byproduct 26 was also

isolated, the formation of which was explained by an

elimination followed by glycal hydroﬂuorination.⁵⁹Depro-

tection of 25 gave 4-deoxy-4-ﬂuoro-^L-quinovose (4,6-dideoxy-

4-ﬂuoro-^L-glucose) L-3a.⁵⁹

Figure 1. Naturally occurring 4,6-dideoxyhexoses.

chalcomycin macrolide antibiotics, which without chalcose do

not show bioactivity.⁵¹⁻⁵³The nonmethylated 4,6-dideoxy-D-

xylo-hexopyranose has been found as part of the macrolide

neutramycin. Finally, desosamine is an amino-4,6-dideoxy

sugar also found as part of many macrolide antibiotics

including erythromycin, oleandromycin, mycinamycin, methy-

mycin/pikromycin, and megalomycin.^{27,28,54−56}The biosyn-

thesis of deoxysugars typically starts from common mono-

saccharides through deoxygenation reactions, which for

dideoxygenated sugars is still subject to much research.^28,57

As part of our interest in the synthesis and applications of

ﬂuorinated dideoxygenated carbohydrates, so far at the 2,3-

and 3,4- positions, we report here the synthesis of a library of

ﬂuorinated 4,6-dideoxy-^D-xylo-hexopyranoses comprising the

three possible monoﬂuorinated derivatives 1−3 (Figure 2), the

two possible 4,6-diﬂuorinated stereoisomers 4 and 5, and the

two possible geminal diﬂuorides 6 and 7. The emphasis was on

eﬃcient syntheses minimizing the use of protecting groups.

While most of these targets are novel or have not yet been

described in the ^D-form, there is precedence for the

introduction of many of these ﬂuorination motifs. An overview

is given in Schemes 1 and 2. Withers and co-workers

synthesized 10 (Scheme 1a) from the 4-deoxyglucose 8

derivative by direct ﬂuorination with diethylaminosulfur

triﬂuoride (DAST), which gave yields below 20% after a

tedious puriﬁcation.⁵⁸A three-step, one-pot protection strategy

leading to the 2,3-O-acetylated derivative 11 allowed for a

greater ﬂuorination yield of 66%, but due to the protection/

deprotection steps, overall a similar 22% yield for 11 from 8

was obtained. Compound 11 was then converted in a two-step

In general, the synthesis of the starting substrates mentioned

in Scheme 1 requires several steps. While 4-deoxyglucose is

commercially available, it is relatively expensive and its

synthesis relies on the reduction of 2,3,6-protected 4-halo or

4-thiocarbonyl glucoside derivatives.^9,65,66The synthesis of 12

was achieved via NBS-induced ring-opening of the 4,6-O-

benzylidene-protected derivative of methyl-α-^D-glucopyrano-

side, followed by THP ether protection and LiAlH₄reduction

of the resultant 6-bromo derivative. The quinovose derivative

14 was prepared by reduction of the corresponding 2,3-di-O-

7726

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Scheme 1. Overview of Previous Syntheses of Monoﬂuorinated 4,6-Dideoxyhexose Sugars

Scheme 2. Overview of the Syntheses of Diﬂuorinated 4,6-Dideoxyhexose Sugars

7727

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

a

Scheme 3. Routes toward 4- and 6-Deoxygalactoside Derivatives Using the BDA Protecting Group

a

TIPST = triisopropylsilanethiol.

benzyl 6-O-tosyl precursor,⁶⁷ultimately derived from the same

benzylidene-protected glucoside as 12 (not shown). Con-

versely, 20−22 were eﬃciently obtained from either methyl or

ethyl thiofucoside or fucose itself. However, given ^D-fucose is

much more expensive, access to ^D-2/3 is less straightforward.

The synthesis of methyl 4,6-diﬂuorogalacto and -glucosides

is well described (Scheme 2). Direct diaminosulfur triﬂuoride

(DAST) treatment of methyl α-^D-glucopyranoside 27 leads to

the 4,6-dideoxy-4,6-diﬂuorogalactoside 28 in relatively high

yield (Scheme 2a).^68,69The corresponding sulfuryl chloride

mediated chlorination leading to the dichlorogalactoside 29

has also been reported, obtained in 45% yield from 27.^70,71In

both cases, all alcohols are thought to be activated for

nucleophilic attack by ﬂuoride or chloride, but the axial

anomeric substituent repels the approach of the nucleophile at

the 3-position, and the presence of the more electron-

withdrawing anomeric acetal group slows down attack at the

2-position. The primary 6-position reacts ﬁrst, then the 4-

position, and once the axial ﬂuoride/chloride is installed at the

4-position, it then additionally hinders S_N2 reaction at the 2-

position.^68,72As an alternative to the DAST-mediated

deoxyﬂuorination, Szarek and co-workers eﬀected the double

displacement of bis-triﬂate 30 (Scheme 2b) with tris-

(dimethylamino)sulfonium diﬂuorotrimethylsilicate (TASF),

accessing benzyl-protected methyl 4,6-dideoxy-4,6-diﬂuoro-β-

D-galactoside 31 in 39% yield.⁷³However, routes toward the

gluco-conﬁgured analogue are more circuitous. 4,6-Dideoxy-

4,6-diﬂuoroglucoside 35 (Scheme 2c) is prepared by a

sequential ﬂuorination from 2,3-protected galactoside: starting

from the 2,3,6-tribenzoate 32, accessible in one step from

methyl α-^D-galactopyranoside,⁷⁴ﬂuorination at the 4-position

of 32 gives the glucose derivative 33 in excellent yield.^75,76

Benzoate hydrolysis then gives methyl 4-deoxy-4-ﬂuoro α-D-

glucopyranoside 34,⁷⁷which can then be selectively ﬂuorinated

at the primary 6-OH, again in excellent yield to give 35.⁷⁷

Direct dideoxydiﬂuorination has been widely applied. From

the 2,3-diacetate 36 (Scheme 2d) a moderate yield of 38 was

reported,⁵⁸but on the equivalent dibenzoate 37, an high yield

of 39 was obtained.⁷⁵Two-step anomeric acetylation of 38

then gave the triacetate 5b as the β-anomer. More recently,

̀

Giguere and co-workers reported a 1,6-anhydrosugar-based

route toward 5a (Scheme 2e).²⁰This approach begins from

known ﬂuorinated levoglucosan derivative 40, itself prepared in

ﬁve steps from levoglucosan.⁷⁸

Benzylation of the free hydroxyl to obtain 41 preceeds Lewis

acid catalyzed ring-opening and concomitant acetolysis,

aﬀording an anomeric mixture of 42. In order to access the

6-OH selectively, the anomeric acetate was ﬁrst transformed

́

into allyl glycoside 43, allowing selective Zemplen depro-

tection and deoxyﬂuorination of the 6 position, furnishing 44.

Global deprotection using BCl₃unmasks 4,6-dideoxy-4,6-

diﬂuoroglucose 5a in 48% overall yield from 40.

Finally, it is relevant to mention that 4,6-dideoxygenated

6,6,6-triﬂuorinated sugars have been synthesized by the group

of Qing, based on a de novo synthesis using Sharpless

dihydroxylation chemistry (not shown).⁷⁹

RESULTS AND DISCUSSION

■

Introduction of 4,6-Dideoxy-6-ﬂuoro Substitution. To

avoid the use of 4-deoxyglucose as starting material (cf.

Scheme 1), it was decided to devise a new synthesis of 4,6-

dideoxy-6-ﬂuoro-^D-xylo-hexopyranoside sugars. Our initial

approach was based on the selective protection of the

equatorial 2- and 3-OH groups of methyl α-^D-galactopyrano-

side 45 (Scheme 3) to give the most stable butanediacetal ring

appendage (BDA).^80,81In the ﬁrst instance, a mixture of 2,3-

protected BDA isomers is obtained;⁸²however, the use of BF₃·

OEt₂with prolonged reaction timesfollowed by meticulous

chromatographyled to the BDA-protected galactoside

46.⁸²⁻⁸⁴This was followed by selective protection of the 6-

position as silyl ether 47. Tin-free reductive deoxygenation of

the corresponding thiocarbonate 48 using triethylsilane and

7728

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

benzoyl peroxide led to 49, and TBDMS removal ﬁnally gave

the 4-deoxy-^D-xylo-hexopyranoside derivative 55. This sub-

strate was also obtained by an alternative route based on a

deoxygenation protocol developed by Dang and co-workers of

sugar-based 2-phenyl-1,3-dioxolane rings under radical con-

ditions.⁸⁵They reported that radical chain redox rearrange-

ment of methyl 4,6-O-benzylidene-α-^D-galactopyranoside with

the (commercially available) triisopropylsilanethiol (TIPST)

reagent, using only 5 mol % of TIPST and 0.5 equiv of di-tert-

butyl peroxide, gives a 40:60 mixture of 4-O-benzoyl-6-deoxy-

and 6-O-benzoyl-4-deoxy- derivatives, regardless of the nature

of the alcohol protecting groups at the 2- and 3-position

(acetyl or methyl). The required 4,6-benzylidene substrate 50

was synthesized from 45 as reported.⁸²The BDA diaster-

eomers were now easily separated. From 50, application of the

Dang methodology aﬀorded 52 and 53 in 91% combined yield

on a 7 g scale, and it was shown to occur with the expected

regioselectivity (ratio 52 (6-deoxy):53 (4-deoxy) = 42:58).

The inseparable mixture was treated with sodium methoxide to

oﬀer the now separable 6-deoxy and 4-deoxy galactosides 54

and 55 in 37% and 54% yield, respectively. Finally,

deoxoﬂuorination of 55 using a modiﬁed procedure by Wagner

et al. that employed DAST and 2,4,6-collidine under

microwave irradiation⁸⁶successfully aﬀorded the desired 56

in excellent yield.

In our hands, the number of equivalents of DAST could be

reduced from 6 to 3 without observing any decrease in yield.

Pleasingly, applying the deoxychlorination reaction using

conditions developed by Minnaard et al.⁸⁸followed the

expected regioselectivity as observed for the 4,6-dideoxydi-

ﬂuorination (cf. Scheme 2) to give the 4-chloro-6-ﬂuoroga-

lactose derivative 60 in 60% yield. The galacto stereochemistry

was conﬁrmed by ¹H NMR analysis, in which H4 was found to

3

appear as a doublet of doublets, with J_H4−H33.7 Hz and

³J_H4−H51.2 Hz, indicative of two ax−eq couplings. Finally,

reduction of the chloride with tributyltin hydride initiated by

AIBN in reﬂuxing toluene smoothly aﬀorded the desired 4,6-

dideoxy-6-ﬂuoro derivative 10 in 88% yield. Therefore, the 4,6-

dideoxy-6-ﬂuoro motif could be introduced via a new three-

step operation in 37% overall yield, without the use of

protecting groups.

Introduction of 4,6-Dideoxy-4-ﬂuoro Substitution (4-

Deoxy-4-ﬂuoro Fucose Stereochemistry). As shown in

Scheme 1, attempted deoxyﬂuorination on the ^D-quinovose

derivative 14 did not lead to the expected 4-deoxy-4-

ﬂuorofucoside product 17,⁶¹but when the 2 and 3-positions

were unprotected, a low 22% yield was obtained.⁶²We

presumed that the nonreacting alcohol groups at the 2- and 3-

positions are converted to the strongly electron-withdrawing

aminodiﬂuorosulﬁte intermediates by the DAST reagent,

which may have minimized rearrangement reactions. Hence,

introduction of an electron-withdrawing group at the 6-

position was proposed to further enhance the deoxyﬂuorina-

tion yield (Scheme 6). Selective primary tosylation of α-^D-

glucopyranoside 27 was achieved at low temperature, as

position 2 was found to slowly react at room temperature.

Pleasingly, deoxyﬂuorination of 6-O-tosylated 61 resulted in

a markedly improved 49% yield of the corresponding 4-ﬂuoro-

6-tosyl product 62. However, the subsequent reduction of

tosylate 62 proved capricious; the reaction did not progress at

0 °C, and carrying out the reaction with LiAlH₄at reﬂux

resulted in the isolation of ^D-19 in only 4% yield. Without a 4-

OH group, reduction via an oxetane intermediate is not

possible, which could be the reason for the reaction failure.

These harsh conditions also lead to the formation of an

anhydro byproduct 63, isolated in 16% yield. This outcome

can be rationalized by deprotonation of the 3-OH proton and

subsequent displacement of the 6-OTs upon ring inversion to

As a curiosity, the reduction of the benzylidene acetal of the

2,3-butane diacetal diastereomer 51 (Scheme 4) proceeded

Scheme 4. Reduction of the Benzylidene Acetal of the 2,3-

Protected BDA Minor Diastereomer 51

with the opposite regioselectivity. The 6-deoxygenated product

57 was now obtained as the major isomer in an 80:20 ratio.

The origin for this reversal in reduction regiochemistry is

unclear but will be related to the diﬀerent butanediacetal ring

conformation of 50 and 51.

89

1

the C₄chair form. Replacement of LiAlH₄with LiBEt₃H at

0 °C resulted in a much improved 67% yield of 63, at the

expense of complete suppression of the desired reduction to ^D-

19.

While this process was easily conducted on scale, a shorter,

protecting group free route was also developed (Scheme 5),

inspired by a successful deoxychlorination example at the 4-

position of N-Cbz-protected methyl 6-aminoglucoside^70,71

Hence, to achieve 4-deoxyﬂuorination with an electron-

withdrawing group at the 6-position, we applied the

deoxychlorination/reduction strategy previously employed for

the 4,6-dideoxy-6-ﬂuoro derivative 10 (cf. Scheme 5). Initially,

Appel conditions⁹⁰accessed methyl 6-chloro-6-deoxy-D-

glucopyranoside 64 in 64% yield; however, we were drawn

to a little-used procedure published by Long in 1969, which

87

with SO₂Cl_2.Hence, it was envisioned to introduce the 4-

Cl group directly on a 6-deoxy-6-ﬂuoroglucose derivative.

Starting from methyl ^D-glucoside 27, selective monoﬂuorina-

tion at the most reactive 6-position was achieved by Card’s

method⁷⁶to give the 6-ﬂuoro derivative 59 in excellent yield.

Scheme 5. Introduction of the 4,6-Dideoxy-6-ﬂuoro Substitution

7729

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Scheme 6. Introduction of the 4,6-Dideoxy-4-ﬂuoro Substitution (Fucose Stereochemistry)

Scheme 7. Introduction of the 4,6-Dideoxy-4-ﬂuoro Substitution (Quinovose Stereochemistry)

used 2 equiv of methanesulfonyl chloride as the chloride

source, bypassing the need to use hepatotoxic CCl₄.⁹¹In our

hands, this aﬀorded 64 in near-quantitative yield. Subsequent

deoxyﬂuorination with DAST furnished 65 in 47% yield,

possessing the desired 4-ﬂuoro-6-chloro motif. Finally,

application of the Bu₃SnH/AIBN reduction in reﬂuxing

toluene would aﬀord the desired deoxygenated product ^D-19,

this time in a much improved 70% yield (31% over three

steps).

Introduction of 4,6-Dideoxy-4-ﬂuoro Substitution (4-

Deoxy-4-ﬂuoroquinovose Stereochemistry). In contrast

to dideoxyﬂuorination of unprotected methyl α-^D-glucopyrano-

side 27 leading to the 4,6-dideoxy-4,6-diﬂuorogalactose

derivative in good yield (cf. Scheme 2), subjecting methyl α-

D-galactopyranoside 45 to these conditions leads to a mixture

of regioisomers. This mirrors the low-yielding monoﬂuorina-

tion of 45 in which the 6-deoxy-6-ﬂuorogalactose derivative

could only be obtained in yields ranging from 20 to 25%,⁹²

compared to 60 to 70% for the corresponding process from the

methyl glucoside 27 leading to 6-deoxy-6-ﬂuoroglucose (not

shown).⁷⁶Hence, a direct deoxyﬂuorination strategy from

unprotected methyl α-^D-fucoside was not attempted. Instead,

an approach involving protection of the alcohols at the 2- and

3-position was pursued. As shown in Scheme 1, Lindhorst et al.

successfully deoxyﬂuorinated the 1,2,3-tribenzoylated ^L-fuco-

side 22.⁵⁹However, the high cost of D-fucose prevented us

from using the same strategy, and a synthesis from methyl α-^D-

galactopyranoside 45 was carried out (Scheme 7) which was

converted to the known methyl 2,3-di-O-benzoyl-α-^D-galacto-

pyranoside 37 in three steps.⁹³Deoxygenation was envisioned

product easily puriﬁed by column chromatography to give the

bromide 66 in 85% yield. However, radical reduction of 66

with Bu₃SnH led to a 1:1.5 mixture of the desired 2,3-

dibenzoyl compound 67 and the migrated 2,4-dibenzoyl

isomer 68. This observation is consistent with a study by

Roslund, Leino, and co-workers, who reported on the fast

migration of benzoyl esters between positions 3 and 4.⁹⁵

Instead, direct deoxyﬂuorination of 66 (7 g scale) using

DAST in reﬂuxing CH₂Cl₂gave the bromoﬂuorosugar 69 in

67% yield, consistent with the yield obtained by Lindhorst et

al. on their fucose intermediate (cf. 22 → 25, Scheme 1).⁵⁹

Inversion of stereochemistry was determined by NMR analysis

and was also unambiguously conﬁrmed by X-ray crystallo-

graphic analysis of a single crystal (Figure 3). The bromide

Figure 3. Crystal structure of methyl 4,6-dideoxy-2,3-di-O-benzoyl-6-

bromo 4-ﬂuoro-α-^D-glucopyranoside 69 (benzoyl protecting groups

have been removed for clarity).

group could now be reduced on large (8 g) scale without any

risk of benzoyl migration to yield 76% of the deoxyﬂuorosugar

70. Subsequent alcohol deprotection was easily performed with

sodium methoxide to oﬀer methyl 4-deoxy-4-ﬂuoro-α-^D-

quinovoside 71 in 79% yield. Direct conversion of 69 into

71 by treatment with LiAlH₄was not successful. Starting from

45, application of the MsCl mediated deoxychlorination

procedure, followed by C4-deoxyﬂuorination, and chloride

reduction may result in an even higher yield for the

via selective 6-bromination using an Appel reaction to give 66.

94

́

Adapting protocols from Cleophax and co-workers, 1 equiv

of CBr₄was used to avoid any overhalogenation at OH-4. For

large-scale reactions (3 g), precipitation and ﬁltration of most

of the triphenylphosphine oxide with Et₂O aﬀorded a crude

7730

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Scheme 8. 4,6-Dideoxy-4-ﬂuoro Substitution (Quinovose Stereochemistry) Using BDA Protection

Scheme 9. Introduction of 4,6-Dideoxy-4,6-diﬂuoro Substitution (Glucose Stereochemistry)

Scheme 10. Introduction of 4,6-Dideoxy-4,4-diﬂuoro and -6,6-diﬂuoro Substitution

deoxyﬂuorination reaction, given the higher electronegativity

of Cl over Br, but was not attempted.

out a number of times in our group and when conducted on

large scale once led to a violent runaway reaction despite no

external heating. It was suspected that the poor solubility of 27

in DAST played a role, and when solid particles remain present

after the mixture is allowed to warm to room temperature,

local heating of this exothermic reaction at the interface may

lead to excessive HF evolution. Hence, given this safety risk, a

safer reaction procedure was developed by simply using

dichloromethane as reaction solvent, leading to a 46% yield on

5 g scale (not shown).

Introduction of 4,6-Dideoxy-4,6-diﬂuoro Substitution

(Glucose Stereochemistry). As shown in Scheme 2, the

synthesis of methyl 4,6-diﬂuoro-^D-glucoside 39 involving the

dibenzoate 37 had been reported by Esmurziev et al.⁷⁵In our

hands (Scheme 9), dideoxydiﬂuorination to give 39 was

achieved in 76% yield on 9 g scale, which aﬀorded the desired

4,6-diﬂuoroglucoside 35 upon deprotection with sodium

methoxide also in 71% yield (25% overall).

A shorter synthesis was also investigated (Scheme 8) based

on the previously mentioned selective BDA protection of

methyl α-^D-galactopyranoside 45 (cf. Scheme 3 above) leading

to 46. At−40 °C, it was possible to selectively tosylate the 6-

OH of 46 to give 72; conducting the reaction at room

temperature gave an inseparable mixture of mono- and

ditosylated products. Subsequent hydride displacement of 72

gave ^D-fucose derivative 54. Unfortunately, DAST-mediated

deoxygenation was much less eﬃcient compared to that of 66

(cf. Scheme 7), giving 73 in only 37% yield. Because of this

drastic loss of yield in the ﬁnal ﬂuorination step, the approach

using the 2,3-di-O-benzoyl-protected galactoside 37 is the

preferred route for the synthesis.

Introduction of 4,6-Dideoxy-4,6-diﬂuoro Substitution

(Galactose Stereochemistry). The conversion of 27 to 28,

as reported in the literature⁶⁹(cf. Scheme 2), has been carried

7731

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Table 1. Hydrolysis of the Methyl Glycosides to Free Dideoxyﬂuorosugars 1a−7a

a

b

Synthesized according to ref 68. Residual TFA in the isolated reducing sugar derivative, relative to the product.

As above, the use of the BDA protecting group to directly

work with the initial diastereomeric mixture⁸²of 2,3-BDA-

protected galactosides obtained upon protection of 45.

Introduction of 4,6-Dideoxy-4,4-diﬂuoro and -6,6-

Diﬂuoro Substitution. The alcohols 54 and 55 (Scheme 10),

obtained as a separable mixture in four steps from methyl α-^D-

galactopyranoside 45 as discussed above (cf. Scheme 3), were

identiﬁed as precursors to introduce 4,6-dideoxy-4,4- and -6,6-

diﬂuorosubstitution. The alcohol groups of 54 and 55 were

quantitatively oxidized with Dess−Martin periodinane to give

75 and 79, which were then treated with 6 equiv of DAST to

give the gem-diﬂuorinated products 76 and 80 in good yields.

The deoxyﬂuorination of 75 led to two ﬂuoroalkene by-

products 77 and 78 in 12% and 10% isolated yield,

respectively, likely resulting from concomitant E2-elimination

of H-3 or H-5 of the putative intermediate 81 by ﬂuoride.

Given that the reaction was conducted in nonpolar CH₂Cl₂,

involvement of the possible intermediate 82, which features a

degree of stabilization by the ﬂuorine atom,^96,97is unlikely. No

carbenium ion mediated rearrangement products were isolated.

Hence, C4-deoxoﬂuorination gives a better yield than the C4-

deoxyﬂuorination of 54 to 73 (cf. Scheme 8). C4-

Deoxoﬂuorination with an electron-withdrawing C6-substitu-

ent was not attempted, given the obvious risk for an

elimination side reaction.

protect the galactoside positions 2 and 3 (46, cf Scheme 3)

provided a means to avoid the three-step preparation of the

deoxyﬂuorination substrate 37. However, deoxyﬂuorination of

46 proved capricious with yields of 74 capped around 30%

even when using a large molar excess of DAST (up to 6 equiv)

and an elevated reaction temperature. As observed before, the

less electron-withdrawing nature of the BDA group probably

results in a more electron-rich sugar ring leading to

rearrangement side reactions. The best yield was again

obtained using the modiﬁed conditions reported by Wagner

et al.⁸⁶Up to 600 mg of diol 46 was treated with 3 equiv of

both DAST and 2,4,6-collidine in 1,2-dichloroethane and

heated at 100 °C under microwave irradiation for 6 min,

yielding 47% of the desired compound 74. Hydrolysis of the

BDA protecting group in 4 M HCl in reﬂuxing THF gave

methyl glycoside 35 in 61% yield, with 9% of recovered

starting material, but with TFA/H₂O, an improved 76% yield

of 35 was obtained. Therefore, 35 could be obtained in a three-

step synthesis from 45 in a 25% overall yield. Comparison of

the two methods shows that, while the double deoxyﬂuorina-

tion of the benzoate-protected derivative 35 is clearly superior

to that of the BDA derivative 46, the overall yields of the

diﬀerent processes are very similar. In addition, the overall

yield of the BDA approach will be higher if one is content to

Deprotection and Access to the Reducing or

Peracetylated Sugars. In order to obtain the fully

7732

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

́

Table 2. Acetolysis/Zemplen Deprotection Strategy to Obtain Free Dideoxyﬂuorosugars 1a−7a

a

b

Synthesized according to ref 68. Starting from 73/76/80, the BDA protecting group was ﬁrst removed using TFA/H₂O (9:1) at rt for 5 min,

c

d

followed by evaporation. 13% of peracetylated open form sugar (5c) was also isolated. 7% of peracetylated open form sugar (6c) was also

isolated.

deprotected reducing ﬂuorinated sugars, the methyl glycosides

were treated with a 1:1 mixture of triﬂuoroacetic acid and

water while heating at reﬂux (Table 1).⁹²The reaction time

required highly depended on the ﬂuorination pattern with the

4-deoxysugars being the fastest (entries 1 and 7), followed by

the 6-deoxymonoﬂuorosugars (entries 2 and 3) and the

diﬂuorosugars (entries 4−6). As expected,⁴hydrolysis was the

slowest when an equatorial ﬂuorine was present. For 74, 76,

and 80, TLC analysis indicated fast removal of the BDA

protecting group under these conditions. The yields were good

to excellent for the three monoﬂuorosugars 10, ^D-19, and 71

(entries 1−3), but as these required more polar eluents during

chromatographic puriﬁcation, it was diﬃcult to remove

residual TFA to a satisfactory level even after extensive

evaporation or treatment with K₂CO₃. Therefore, further

puriﬁcation by peracetylation and column chromatography,

Given the moderate yields and the diﬃcult removal of

residual TFA, it was decided to achieve anomeric deprotection

by a direct acetolysis reaction using acetic anhydride as solvent

and either sulfuric acid or TMSOTf⁹⁸as catalyst (Table 2).

Excellent yields of 82−89% were obtained for monoﬂuorinated

substrates 1b and 2b using TMSOTf (entries 1 and 2), while

4,6-diﬂuoro- products 4b and 5b were aﬀorded in slightly

lower 74 and 69% yields (entries 4 and 5).

When these conditions were applied to the BDA-protected

4,6-diﬂuorinated methyl glycoside 74, a complex mixture was

obtained from which compound 5b could only be obtained in

14−18% yield.

Consequently, substrates 73, 76, and 80 were ﬁrst treated

with TFA/H₂O (9:1) for 5 min at room temperature followed

by evaporation to dryness. The crude mixtures were then

subjected to the acetolysis conditions (H₂SO₄) to give the

triacetylated derivatives 3b, 6b, and 7b in 57%, 48%, and 71%

yield, respectively (entries 3, 6, and 7). It should be noted that,

in the case of 5b and 6b, byproducts in the acetylation

reactions were isolated in non-negligible yields of 13% and 7%,

respectively. These were identiﬁed as the pentaacetylated open

forms 5c and 6c of the parent reducing sugars (Figure 4)

Presumably the 5-OH group has a signiﬁcantly reduced

nucleophilicity due to the electron-withdrawing nature of the

́

followed by Zemplen deprotection, aﬀorded the pure sugar

derivatives 1a−3a in 53, 58, and 75% yield, respectively (not

shown). In contrast, compounds 4a−6a could be obtained in

moderate to good yields with less than 1% residual TFA. The

preparation of 4a was attempted from both the methyl

glycoside 35 and the BDA-protected derivative 74 (entry 5),

with the former approach giving the highest yield.

7733

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

sugars 1a−7a in good to excellent yields with straightforward

puriﬁcation. Hence, the acetolysis strategy proved the method

of choice to cleave the methyl glycosides.

Structural Characteristics and Anomer Preferences.

Pleasingly, various monosaccharides proved crystalline, with all

reducing sugars crystallizing as the α-anomer. Their crystal

structures are given in Table 3, next to the crystal structures of

α-^D-glucopyranose 83 and α-L-fucopyranose 84 (shown in the

D-conﬁguration to facilitate comparison) as reference struc-

tures. Based on the Cremer−Pople parameters,⁹⁹with

azimuthal angles θ and radii Q approaching 0° and 0.57 Å,

respectively, all structures are very close to a ⁴C₁conformation

Figure 4. Structure of the acetolysis byproducts of 4,6-dideoxy-4,6-

diﬂuoro-^D-glucose and 4,6-dideoxy-4,4-diﬂuoro-D-xylo-hexose.

proximal ﬂuorine substituents, causing a small amount of the

open-chain form to exist as part of the solution equilibrium.

́

Although not attempted, Zemplen deprotection of these

byproducts is expected to return 5a and 6a.

Finally, all of the peracetylated pyranoses were then

4

́

subjected to standard Zemplen deprotection, aﬀording free

(θ = 0° and Q = 0.57 Å represent the ideal values for a C₁

Table 3. Crystal Structures with Structural Data

a

b

Older database structures do not retain atom coordinate standard deviations, and thus, these cannot be calculated for the CP parameters. http://

6ring.bio.nrc.ca. Structure from Mostad et al.¹⁰²Structure from Longchambon et al.¹⁰³Obtained from an incomplete hydrolysis reaction of 76:

c

d

e

see the Experimental Section for details.

7734

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Figure 5. Comparison of ¹⁹F NMR (470 MHz, D₂O) spectra of all synthesized 4,6-dideoxysugars 1a−7a. Inset: Signals for 6a and 7a (CF₂region).

conformation). The average ring dihedrals are between 56.3°

and 58.2°, so very close to the ideal angle of 60° and very

similar to the values for α-glucopyranose (56.7°) and α-

fucopyranose (58.5°). The closeness to a ⁴C₁chair structure is

also apparent from their respective Whitﬁeld linear combina-

tion of idealized IUPAC shapes,¹⁰⁰which in all cases is clearly

dominated by the ⁴C₁chair conformation, and from the

Woods¹⁰¹BFMP system, in which the three possible “d”

reference planes all show very little distortion (all <5°, most

<3°). As expected for small deviations, the Cremer−Pople

meridian angles φ, indicating the distortion from the chair

conformation, vary considerably, even between close ana-

logues. This is also seen with the BFMP method: the ⁰d₃plane

is the best-ﬁt plane for 4 of the 7 ﬂuorinated structures, and the

⁴d₁plane for the remaining three. α-Glucopyranose 83 and α-

fucopyranose 84 show the ⁰d₃plane and the ²d₅plane as their

best BFMP ﬁt. While 5a, the direct 4,6-diﬂuorinated analogue

of glucose, has the same best ﬁt plane as glucose, this is not the

case for fucose and its 4-deoxyﬂuorinated analogue. Interest-

ingly, the reducing ﬂuorosugars 2a and 6a do not have the

same best ﬁt plane as their methyl glycoside derivatives 19 and

its much higher ³J_H5−F6value ( 27 Hz vs 14 Hz). Without a

substituent at the 4-position as in 1a, the J_H5−F6value is an

intermediate 22 Hz.

3

The dispersion of the ﬂuorine resonances of sugar

derivatives 1a−7a is shown in Figure 5. Some interesting

trends can be observed. The F4 resonances of the galacto-

conﬁgured compounds 2a and 4a are upﬁeld (lower chemical

shift) compared to those of the corresponding glucose

analogues 3a and 5a, which can be explained by deshielding

of the equatorial F by the antiperiplanar endocyclic C5−O5

bond¹⁰⁶and shielding of the axial ﬂuorine from hyper-

conjugation by the antiperiplanar C3−H3 and C5−H5

bonds.¹⁰⁷The ¹⁹F chemical shift values of the monodeoxy-

ﬂuorinated 4-deoxy-4-ﬂuoroglucose 87^5,108and -galactose

92¹⁰⁹show the same trend (not shown). Similarly, for the

4,4-diﬂuorinated 6a, the equatorial ﬂuorine is deshielded

compared to the axial ﬂuorine substituent.

Conversely, the F6 resonance of the galacto-conﬁgured 4a is

downﬁeld compared to that of the glucose analogue 5a, with a

smaller chemical shift diﬀerence. We suggest that this is

consistent with the explanation given above for the F4

resonances: for 5a, as reported above, the C5−C6 gg

conformation featuring antiperiplanar C5−H5 and C6−F6

bonds is the most populated, leading to enhanced shielding of

the “axial” C6−F6 by the C5−H5 bond. For 4a, the gt/tg

conformations will be the most populated, within the latter a

deshielding eﬀect from the antiperiplanar C5−O5 group takes

place. The combined eﬀects on F4 and F6 then explain the

much larger chemical shift diﬀerence between F4 and F6 for 5a

compared to 4a. The same trend is observed for 6-deoxy-6-

ﬂuoroglucose and 6-deoxy-6-ﬂuorogalactose: the F6 resonance

of the galacto-conﬁgured analogue (−229.9/−229.8 ppm) is

downﬁeld compared to that of the glucose analogue (−235.6/

−234.9 ppm).

4

0

76: in both cases, a shift from d₁to d₃is observed. In

contrast, the methyl glucoside structures 19, 71, and 76, which

diﬀer in ﬂuorination stereochemistry/number at C4, all have

the same best ﬁt plane (⁰d₃). On the whole, this analysis clearly

shows that 4,6-dideoxygenation combined with monoﬂuorina-

tion at C4 or at C6, diﬂuorination at C4, or diﬂuorination at

C4 and C6 does not cause appreciable ring distortion, even

with diﬀerent C4 stereochemistry. Regarding the C5−C6

conformation, α-^D-glucose α-83 crystallized in the gt-

conformation, while its 4,6-diﬂuorinated analogue 5a crystal-

lized as the gg-conformer.

The ⁴C₁chair conformation is also apparent from the

solution-phase NMR data, including vicinal coupling constants

between C2 and F4 (³J_C2−F4, Table S2) and small eﬀects such

The inﬂuence of the anomeric conﬁguration on the ﬂuorine

resonances, albeit a smaller eﬀect, is also apparent: for all

equatorial F4 substituents, including that of the 4,4-

diﬂuorinated 6a, the chemical shift is upﬁeld (lower chemical

shift) for the β-anomer compared to the α-anomer, while for

the axial F4 substituents it is the other way around: the α-

as the Altona−Haasnoot rules,^104,105as illustrated for J_H2−H3

3

in Table S3 for α- and β-4-ﬂuorinated gluco- and galacto-

conﬁgured analogues. The higher population of the C5−C6 gg-

conformer for the 4,6-diﬂuorinated glucose derivative 5a

compared to the galactose derivative 4a was clearly exposed by

7735

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Table 4. Relative Proportions of α/β Anomers at Equilibrium in D₂O

a

Ratios as reported by Murphy et al.¹¹⁰

anomer displays the upﬁeld resonance. The published chemical

shift data for monodeoxyﬂuorinated 4-deoxy-4-ﬂuoroglucose

87^5,108and -galactose 92¹⁰⁹also show this trend. In the study

of a series of ﬂuorinated glucose derivatives (equatorial ﬂuorine

substituents), Giguere had noted that the ¹⁹F resonances for

the β-anomers occur at lower ﬁeld than these of the α-

anomers, except for F4,²⁰and our data are consistent with this.

For F6, in all cases the α-anomer does display an upﬁeld

chemical shift, regardless of C4 stereochemistry. We have no

explanation for this observation, although for the 6-ﬂuorinated

compounds, it is noted that the ³J_H5−F6values of the α-anomer

are always larger than those of the β-anomer, which suggests a

larger shielding of F6_α, consistent with a lower chemical shift.

Next, the anomeric ratio of the reducing sugars 1a−7a was

analyzed. Samples were prepared in duplicate to a concen-

tration of 64 μmol of substrate in D₂O (0.75 mL) and

reached equilibrium. The time taken for equilibration was

typically 1 d or less, but samples were left to further equilibrate

for at least 3 d. The anomeric ratios were then obtained by ¹⁹

F

quantitative integration (qNMR), and the corresponding

−ΔG° (−ΔG°_obs) values were then calculated from K_eq

according to eq 1.

[α]

[β]

K_eq

=

= e^−ΔG°/RT

(1)

The data are listed in Table 4, which is augmented with the

data for a number of nonﬂuorinated “parent” sugars and a

number of monodeoxyﬂuorinated sugars for comparison, and

the ratios are discussed using Figures 6 and 7.

There is a clear correlation between the number of ﬂuorines

and the anomeric ratio, as illustrated in Figure 6 for all 4,6-

dideoxygenated derivatives. The parent 4,6-dideoxygenated 86,

synthesized from methyl 4,6-dideoxy-4,6-dichloro-galactopyr-

1

monitored by H NMR until the ratio of anomers at 25 °C

7736

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

anomeric ratio on the C4-conﬁguration is discussed using

Figure 7.

In all cases, it can be seen from Figure 7 that OH → F

exchange leads to an increase in α-anomer population. Murphy

already showed that this was the case for monodeoxyﬂuorina-

tion of glucose and galactose at both the 4- and 6-positions

(compare 83 with 87 and 88 and compare 92 with 90 and

91).¹¹⁰Here, it can be seen that monodeoxyﬂuorination of 87

and 88 to 5a and of 90 and 91 to 4a also leads to such an

increase. Equally, 4-deoxyﬂuorination of quinovose (89 to 3a)

and fucose (84 to 2a) leads to an increase in (α/β)-anomer

ratio.

In general, galactose-conﬁgured derivatives display a lower

α-anomer population compared to their respective glucose-

conﬁgured diastereomers, with approximately the same free

energy diﬀerence. However, this does not hold when the 6-

position is unsubstituted: quinovose 89 and fucose 84 have the

same anomeric ratio, as have their respective 4-deoxyﬂuori-

nated derivatives 2a and 3a.

This was further explored by correlating the free energy

change upon anomerization with chemical shift data of H3 and

H5, which were shown by Murphy to be correlated.¹¹⁰The

chemical shift data utilized in the Murphy analysis are the

chemical shift diﬀerences of (H3 + H5) of the derivatives with

the (H3 + H5) chemical shift values of their parent sugars.

Although the subtraction of the chemical shift values of the

parent sugar derivatives does not change any correlation

coeﬃcients, it does facilitate comparison of the relative eﬀect

of the ﬂuorination upon anomer ratio between diﬀerent series.

In this regard, the anomeric ratios of the “parent” pyranoses 4-

deoxyglucose 93 (Table 4, entry 2), fucose 84 (entry 5),

quinovose 89 (entry 7), galactose (92), glucose (83), and 4-

Figure 6. Free energy change corresponding to anomeric inversion of

4,6-dideoxygenated mono- and diﬂuorinated sugar derivatives (D₂O,

less negative ΔG° value equals higher α-anomer population).

deoxy-4-ﬂuoroglucose (87) were also determined by ¹H or ¹⁹

F

qNMR, while the data for 6-deoxy-6-ﬂuoroglucose (88), 4-

deoxy-4-ﬂuorogalactcose (90), and 6-deoxy-6-ﬂuorogalactcose

(91) were taken from the Murphy report.

In Figure 8, the plot of ΔG°_obsvs the sum of the chemical

shift values of all sugar derivatives involved (the 4,6-

dideoxygenated xylo-hexopyranose derivatives α-86 and α-

1a−α-7a, the nonﬂuorinated C4- or C6-deoxygenated sugars

α-84, α-89, and α-93, the parent glucose and galactose α-83

and α-92, and the C4/C6 monodeoxyﬂuorinated sugars α-87

and α-88−α-90) are shown. There is clearly no correlation

Figure 7. Comparison (dotted line) of the anomeric ratio

diﬀererences (expressed as their corresponding anomerization free

energy change) between glucose and their corresponding galactose

derivatives (D₂O, less negative ΔG° value equals higher α-anomer

population). *These values were taken from ref 100.

anose 29 (cf. Scheme 2) via tin-mediated radical reduction and

subsequent acetolysis to deprotect the anomeric position,

followed by global Zemplen deprotection (not shown),⁸⁸has

by far the lowest anomeric ratio, and monoﬂuorination at the

4- (2a, 3a) or 6-position (1a) leads to an increase in α-anomer

population. Geminal diﬂuorination at these positions leads to a

further increase (6a, 7a). For these derivatives, there is very

little or no diﬀerence between ﬂuorination at the 4- and 6-

positions. With diﬂuorination present at the 4-and 6-positions,

the anomeric ratio is further increased. The dependence of the

Figure 8. Plot of ΔG°_obsvs chemical shift values of 1a−7a and 83, 84,

and 86−93. Values for 88, 90 and 91 taken from ref.¹¹⁰Only the α-

anomers are shown; the data for the β-anomers is given in the

Supporting Information (Figure S1).

7737

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

observed for the data set at a whole (red trendline), with little

correlation observed for the ﬂuorinated 4,6-dideoxygenated

xylo-hexopyranose derivatives α-1a-α-7a (green trendline).

However, the trendline of sugars having C4-gluco stereo-

chemistry (83, 89, 88, 3a, 87, 5a, orange) shows an improved

correlation coeﬃcient, which is even higher for the C4-galacto

conﬁgured compounds (92, 84, 90, 2a, 91, 4a, blue).

observation is that the 4,4-diﬂuorinated compound 6a

correlates well with both the quinovo and fuco series.

We were also interested if the 4,6-diﬂuorinated derivatives

4a and 5a would correlate with Murphy’s previously published

gluco and galacto series. Figure 10 shows that when the values

of 4a and 5a are added to this larger data set, it can be seen

that an excellent ﬁt is obtained.

Further dissection of these data revealed that categorizing

the set by both the presence/absence of substitution at C6, and

by stereochemistry at C4, aﬀords excellent correlations for

three of the four series, as shown in Figure 9A. Only the gluco-

Figure 10. ΔG°_obsvs chemical shift diﬀerencefor compounds 4a and

5a superimposed onto the Murphy¹⁰⁰data. Trendlines have been

calculated with and without compounds 4a and 5a. For compounds

83, 87, and 92, we have used our experimental values. Only the α-

anomers are shown, and a fully annotated plot and the data for the β-

anomers are given in the Supporting Information (Figures S4 and S5).

CONCLUSION

■

The synthesis of a series of 4,6-dideoxygenated monosacchar-

ides with all possible mono- and diﬂuorination motifs at these

positions has been achieved, and their structural characteristics

investigated. While the 4,6-dideoxy-4,6-diﬂuorinated galactose

derivative was obtained via a modiﬁcation of Somawardhana’s

excellent direct regioselective bis-deoxyﬂuorination of methyl-

α-^D-glucopyranoside,^68,69the synthesis of other known targets

was reinvestigated and typically improved with regards to

overall yield and/or number of syntetic steps. In all cases, the

starting materials were cheap/nonexpensive methyl-α-^D-gluco

or -galactopyranoside.

The use of protecting groups was avoided in the synthesis of

the 4,6-dideoxy-6-ﬂuoro- and the 4,6-dideoxy-4-ﬂuoro-^D-

fucose derivative by exploiting selective deoxychlorination

methodology at either the 4- or the 6-position. In the latter

case, the chloride served as protecting group to allow selective

deoxyﬂuorination at the 4-position before reduction to the

deoxy moiety. The use of an eﬃcient yet old and rarely used 6-

deoxychlorination method,⁹¹avoiding the use of Appel

conditions (CCl₄, PPh₃), added to the synthetic eﬃciency on

larger scale. For glucose stereochemistry, as in 4-deoxy-4-

ﬂuoro-^D-quinovose, protection of the 2,3-positions was still

required, with the benzoate protecting group being superior

over the BDA protecting group in terms of deoxyﬂuorination

yield, but with the latter allowing a shorter synthesis in similar

overall yield (or higher yield if the use of 2,3-BDA isomers is

tolerated). Hence, there is a clear tendency for the

deoxyﬂuorination yields to be higher when electron-with-

drawing groups are present, which is attributed to the

decreased availability of the ring oxygen lone pairs to initiate

ring contraction side reactions. The synthesis of the novel

Figure 9. Plots of (A) ΔG°_obsvs chemical shift values of 1a−7a and

83, 84, and 86−93 and (B) ΔG°_obsvs chemical shift diﬀerence of 1a−

7a and 83, 84, and 86−93 from the “parent” pyranose. Trendlines

have been calculated for the four diﬀerent parent series (Glu, Gal,

Quin, and Fuc) and for the whole data set. Values for 88, 90, and 91

taken from ref110. Only the α-anomers are shown; the data for the β-

anomers are given in the Supporting Information (Figure S2).

conﬁgured series has a correlation coeﬃcient of less than 0.9,

with the galacto, fuco, and quinovo series having coeﬃcients

greater than 0.96. Figure 9B shows the same correlations, but

now the chemical shift values of H3 and H5 of the parent

hydroxylated compounds (galactose 92, glucose 83, fucose 84,

and quinovose 89) are subtracted from the sum of the H3 and

H5 chemical shifts of the corresponding analogues, according

to the Murphy analysis. This indicates the relative eﬀect of the

substitution on the anomeric ratio, and in accord with

Murphy’s observation, a given chemical shift change causes a

higher α/β ratio for galacto-conﬁgured derivatives (with a very

pronounced eﬀect in the fucose series). An unexpected

7738

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

otherwise noted. All reported solvent mixtures are volume measure-

ments. 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 (CDCl₃7.27 and 77.0 ppm; CD₃OD

3.31 and 49.15 ppm; acetone-d₆2.05 and 29.32 ppm; D₂O 4.64 ppm).

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. Structural assignments were made with

additional information from gCOSY, gHSQC, and gHMBC experi-

ments. ACD/Laboratories (2020.1.2, v S15S41) was used for

processing spectral data. IR spectra were recorded in the range

4000−500 cm⁻¹on Thermo Scientiﬁc Nicolet iS5 as ﬁlms or solids,

and absorption peaks are given in cm⁻¹. Optical rotations were

collected on an Optical Activity PolAAr 2001 machine. Samples of

reducing sugar derivatives were allowed to equilibrate for 24 h before

optical rotation measurement. HRMS spectra were obtained on a

Bruker Daltonics MaXis time-of-ﬂight (TOF) mass spectrometer.

Low resolution electrospray mass spectra were recorded with a Waters

Acquity TDQ mass tandem quadrupole mass spectrometer.

geminal diﬂuorinated derivatives was also achieved with 2,3-

BDA protection. The deoxoﬂuorination yields were excellent

overall, although deoxoﬂuorination of the C4-ketone also gave

rise to two regioisomeric elimination side products.

Anomeric deprotection using aqueous TFA proceeded in all

cases, although, predictably, it was lower yielding with

substrates with an increased ﬂuorine content. The use of

acetolysis conditions followed by Zemplen deprotection was

also successful, with similar overall yields.

Seven crystal structures were obtained of methyl anomers

and reducing sugars, involving ﬁve ﬂuorination motifs. A

comparison involving Cremer−Pople, Whitﬁeld, and Woods

BFMP parameters clearly indicated that these ﬂuorination

4

motifs did not cause appreciable C₁-chair distortion, at least

not more than their corresponding hydroxylated sugars. The

chair conformation was also apparent from NMR analysis in

aqueous solution. The ﬂuorine chemical shifts of all sugars

showed nice dispersion between −196 and −235 ppm (C−F

groups) and −116 and −139 ppm (CF₂groups), and their

relative chemical shift values, including that of the 6-

ﬂuorinated compounds, could be explained by the extent of

“axial” disposition of the C−F bond. There is also a consistent

chemical shift diﬀerence whether the anomeric position is α- or

β-conﬁgured, for which we have no explanation yet.

The anomeric ratios in aqueous solution were quantiﬁed

using a qNMR protocol. In all cases, the α/β-ratio increased

with increasing ﬂuorine content. Surprisingly, there is very little

diﬀerence in anomeric ratio between regioisomers. Equally

surprising is the dependence on C4-stereochemistry: with 4,6-

diﬂuorination, the gluco-conﬁgured sugar has a higher α-

anomer content, which was also observed for the monodeoxy-

ﬂuorinated derivatives: both 4- and 6-deoxyﬂuoroglucose show

a higher α/β-ratio than the corresponding 4- and 6-

deoxyﬂuorogalactose derivatives. In all these cases, the

anomeric ratio diﬀerence is very similar compared to that of

glucose and galactose. However, the anomeric ratio of 4-

deoxyﬂuorofucose and 4-deoxyﬂuoroquinovose is the same.

The anomeric ratios and the sum of the H3 and H5 chemical

shift values according to Murphy’s method¹¹⁰show good to

excellent correlations when taking into account both the extent

of deoxygenation and stereochemistry present at C4. There is

also an excellent ﬁt of the two 4,6-diﬂuorinated sugars with

Murphy’s data.

General Procedure A for the Deprotection of Methyl

Glycosides. A solution of methyl glycoside (1 equiv) in TFA/H₂O

(1:1, 0.3 M) was heated to 110 °C and stirred for the noted time. The

reaction was cooled to rt and concentrated in vacuo. Puriﬁcation by

chromatography (MeOH/CH₂Cl₂) aﬀorded the reducing sugars 1a−

7a.

General Procedure B for the Acetolysis of Protected Sugars.

To a solution of protected sugar (1 equiv) in Ac₂O (20 equiv) was

cooled to 0 °C. TMSOTf (0.1−0.2 equiv) or H₂SO₄(1−5 equiv) was

added, and the reaction allowed to warm to rt and stirred for 16 h.

The reaction was diluted with EtOAc and then quenched by the slow

addition of satd NaHCO_3(aq). The phases were separated, and the

organic layer washed with satd NaHCO_3(aq). The combined aqueous

layers were re-extracted with EtOAc, and then the combined organic

phases were washed with brine, dried (MgSO₄), and concentrated in

vacuo. Puriﬁcation by chromatography (EtOAc/hexane or EtOAc/

petroleum ether) aﬀorded the acetylated sugars 1b−7b.

́

General Procedure C for the Zemplen Deprotection of

Acetylated Sugars. To a solution of acylated sugar (1 equiv) in

MeOH (0.2 M) was added NaOMe (0.3 equiv). The reaction was

stirred for 2 h and then neutralized by the addition of Amberlite

IR120 H-form ion-exchange resin (pH 7). The resin was then ﬁltered

oﬀ, and the beads were washed with MeOH. The ﬁltrate was

concentrated in vacuo. Puriﬁcation by chromatography (MeOH/

CH₂Cl₂or MeOH/EtOAc) aﬀorded the reducing sugars 1a−7a.

4,6-Dideoxy-6-ﬂuoro-^D-xylo-hexopyranose (1a). From 1b. Using

general procedure C with 1b (140 mg, 0.48 mmol), puriﬁcation by

chromatography (5% MeOH/CH₂Cl₂) aﬀorded 1a as an oﬀ-white

powder (57 mg, 0.35 mmol, 73%).

These sugars will be useful as building blocks for

glycorandomization of aglycones leading to bioactive com-

pounds including macrolide antibiotics for screening stud-

ie,^57,111−114or as probes for enzymatic and biosynthethesis

studies.¹¹⁵

From 10. Using general procedure A with 10 (500 mg, 2.78 mmol)

for 90 min, puriﬁcation by chromatography (8−10% MeOH/

CH₂Cl₂) aﬀorded 1a as a colorless solid (383 mg, 2.31 mmol,

83%) with 18% TFA by ¹⁹F NMR: mp (postcolumn) 144−145 °C;

[α]²_D⁴+75.7 (c 0.27, MeOH); IR (neat) 3351 (br), 2933 (w), 1446

(w), 1067 (s), 1009 (s), 978 (s), 832 (s) cm⁻¹; ¹H NMR (500 MHz,

CD₃OD, 45/55 α/β) δ 5.15 (1H, d, J = 3.7 Hz, H_1α), 4.44 (1H, d, J =

7.7 Hz, H_1β), 4.42 (1H, ddd, J = 47.4, 10.0, 3.2 Hz, H_6aβ), 4.39 (1H,

ddd, J = 47.7, 9.9, 3.3 Hz, H_6aα), 4.38 (1H, ddd, J = 47.8, 10.0, 5.5 Hz,

H_6bβ), 4.35 (1H, ddd, J = 47.8, 9.9, 5.1 Hz, H_6bα), 4.27−4.17 (1H, m,

H_5α), 3.90 (1H, ddd, J = 11.4, 9.4, 5.2 Hz, H_3α), 3.76 (1H, ddddd, J =

19.9, 11.9, 5.5, 3.2, 2.1 Hz, H_5β), 3.61 (1H, ddd, J = 11.5, 9.0, 5.2 Hz,

H_3β), 3.28 (1H, dd, J = 9.4, 3.7 Hz, H_2α), 3.04 (1H, dd, J = 9.0, 7.7

Hz, H_2β), 1.91 (1H, ddd, J = 12.6, 5.0, 2.3 Hz, H_4(eq)α), 1.89 (1H,

ddd, J = 12.6, 5.2, 2.0 Hz, H_4(eq)β), 1.43 (1H, dt, J = 12.7, 11.7 Hz,

H_4(ax)β), 1.42 (1H, td, J = 12.4, 11.6 Hz, H_4(ax)α) ppm; ¹H NMR (500

MHz, D₂O, α/β 33:67) δ 5.14 (1H, d, J = 3.7 Hz, H_1α), 4.46 (1H, d, J

= 7.8 Hz, H_1β), 4.43 (1H, ddd, J = 46.9, 10.4, 2.4 Hz, H_6aβ), 4.41 (1H,

ddd, J = 46.9, 10.5, 2.6 Hz, H_6aα), 4.33 (1H, ddd, J = 47.4, 10.5, 5.2

EXPERIMENTAL SECTION

■

4-Deoxy-D-glucose (93), L-fucose (84), D-quinovose (89), D-glucose

(83), ^D-galactose (92), and 4-deoxy-4-ﬂuoro-D-glucose (87) were

commercially available and used as received.

General Conditions. All air/moisture sensitive-reactions were

carried out under an inert atmosphere (Ar or N₂) in dried glassware.

Dry CH₂Cl₂, THF, MeOH, and MeCN were purchased from

commercial suppliers and used as received. In all cases, heating of

reaction mixtures was achieved by aluminum heating blocks using a

thermostat. 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) or

H₂SO₄/EtOH + 0.4% (w/v) N-(1-naphthyl)ethylenediamine dihy-

drochloride, followed by brief heating. Flash column chromatography

was performed with Sigma-Aldrich 60 silica gel (40−63 μm) unless

7739

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Hz, H_6bα), 4.32 (1H, ddd, J = 47.6, 10.4, 5.8 Hz, H_6bβ), 4.14 (1H,

ddddd, J = 23.9, 12.4, 5.2, 2.6, 2.4 Hz, H_5α), 3.83 (1H, br ddd, J =

11.3, 9.7, 5.2 Hz, H_3α), 3.79 (1H, dddt, J = 21.6, 12.1, 5.7, 2.3 Hz,

H_5β), 3.62 (1H, ddd, J = 11.4, 9.4, 5.2 Hz, H_3β), 3.32 (1H, dd, J = 9.7,

3.8 Hz, H_2α), 3.02 (1H, dd, J = 9.4, 7.9 Hz, H_2β), 1.87 (1H, br dddd, J

= 12.8, 5.2, 2.3, 0.3 Hz, H_4(eq)α), 1.84 (1H, br ddd, J = 12.9, 5.2, 2.1

Hz, H_4(eq)β), 1.39 (1H, td, J = 12.6, 11.4 Hz, H_4(ax)α), 1.37 (1H, dt, J =

4-Deoxy-4-ﬂuoro-^D-fucose (2a). From 2b. Using general proce-

dure C with 2b (270 mg, 0.92 mmol), puriﬁcation by chromatography

(5% MeOH/CH₂Cl₂) aﬀorded 2a as a colorless solid (123 mg, 0.74

mmol, 80%).

From ^D-19. Using general procedure A with D-19 (500 mg, 2.78

mmol) for 3.5 h, puriﬁcation by chromatography (8−10% MeOH/

CH₂Cl₂) aﬀorded 2a as a colorless solid (383 mg, 2.31 mmol, 83%)

with 22% residual TFA (¹⁹F NMR integration): mp (postcolumn)

183−185 °C; [α]²_D⁵+67.9 (c 0.48, MeOH); IR (neat) 3334 (br), 2937

1

12.6, 11.9 Hz, H_4(ax)β) ppm; H{¹⁹F} NMR (500 MHz, CD₃OD) δ

5.15 (1H, d, J = 3.6 Hz, H_1α), 4.43 (1H, d, J = 7.7 Hz, H_1β), 4.42 (1H,

dd, J = 9.9, 3.1 Hz, H_6aβ), 4.39 (1H, dd, J = 9.9, 3.3 Hz, H_6aα), 4.37

(1H, dd, J = 9.8, 5.5 Hz, H_6bβ), 4.35 (1H, dd, J = 9.9, 5.0 Hz, H_6bα),

4.22 (1H, ddt, J = 12.2, 5.1, 2.7 Hz, H_5α), 3.90 (1H, ddd, J = 11.4, 9.4,

5.1 Hz, H_3α), 3.76 (1H, dddd, J = 11.9, 5.4, 3.2, 2.1 Hz, H_5β), 3.61

(1H, ddd, J = 11.5, 9.0, 5.2 Hz, H_3β), 3.28 (1H, dd, J = 9.4, 3.7 Hz,

H_2α), 3.04 (1H, dd, J = 9.1, 7.7 Hz, H_2β), 1.91 (1H, ddd, J = 12.5, 5.1,

2.2 Hz, H_4(eq)α), 1.89 (1H, ddd, J = 12.6, 5.3, 2.0 Hz, H_4(eq)β), 1.43

(1H, dt, J = 12.6, 11.8 Hz, H_4(ax)β), 1.42 (1H, td, J = 12.3, 11.5 Hz,

H_4(ax)α) ppm; ¹H{¹⁹F} NMR (500 MHz, D₂O) δ 5.14 (1H, d, J = 3.7

Hz, H_1α), 4.46 (1H, d, J = 7.9 Hz, H_1β), 4.43 (1H, dd, J = 10.4, 2.4

Hz, H_6aβ), 4.41 (1H, dd, J = 10.4, 2.5 Hz, H_6aα), 4.33 (1H, dd, J =

10.3, 5.2 Hz, H_6bα), 4.32 (1H, dd, J = 10.4, 5.8 Hz, H_6bβ), 4.14 (1H,

ddt, J = 12.3, 5.1, 2.4 Hz, H_5α), 3.83 (1H, ddd, J = 11.4, 9.7, 5.1 Hz,

H_3α), 3.79 (1H, ddt, J = 12.0, 5.8, 2.3 Hz, H_5β), 3.62 (1H, ddd, J =

11.5, 9.2, 5.2 Hz, H_3β), 3.32 (1H, dd, J = 9.7, 3.7 Hz, H_2α), 3.02 (1H,

dd, J = 9.2, 7.9 Hz, H_2β), 1.87 (1H, br ddd, J = 12.8, 5.2, 2.3 Hz,

H_4(eq)α), 1.84 (1H, ddd, J = 12.9, 5.2, 2.1 Hz, H_4(eq)β), 1.39 (1H, br q,

J = 12.4 Hz, H_4(ax)α), 1.37 (1H, dt, J = 12.4, 11.9 Hz, H_4(ax)β) ppm;

¹³C{¹H} NMR (126 MHz, CD₃OD) δ 98.6 (C_1β), 94.8 (C_1α), 86.2

(d, J_C−F= 171.2 Hz, C_6α), 85.8 (d, J_C−F= 171.9 Hz, C_6β), 78.2 (C_2β),

75.7 (C_2α), 72.2 (C_3β), 72.1 (d, J_C−F= 18.9 Hz, C_5β), 68.6 (C_3α), 67.9

(C_5α), 35.4 (d, J_C−F= 6.2 Hz, C_4αor C_4β), 35.3 (d, J_C−F= 6.2 Hz, C_4α

or C_4β) ppm; ¹³C{¹H} NMR (126 MHz, D₂O) δ 96.1 (C_1β), 92.7

(C_1α), 85.0 (d, J_C−F= 167.6 Hz, H_6α), 84.7 (d, J_C−F= 167.9 Hz, C_6β),

1

(w), 1419 (w), 1076 (s), 1033 (s), 960 (s) cm⁻¹; H NMR (500

MHz, CD₃OD, α/β 50:50) δ 5.11 (1H, d, J = 3.6 Hz, H1α), 4.51

(1H, br ddt, J = 50.7, 2.7, 0.4 Hz, H_4α), 4.452 (1H, br ddd, J = 50.3,

3.0, 0.4 Hz, H_4β), 4.445 (1H, dd, J = 7.7, 1.1 Hz, H_1β), 4.19 (1H, dq, J

= 29.8, 6.8 Hz, H_5α), 3.85 (1H, ddd, J = 29.3, 10.2, 2.7 Hz, H_3α), 3.73

(1H, dq, J = 27.4, 6.5 Hz, H_5β), 3.69 (1H, dd, J = 10.2, 3.7. 0.9 Hz,

H_2α), 3.55 (1H, ddd, J = 29.5, 9.9, 3.0 Hz, H_3β), 3.43 (1H, ddd, J =

9.9, 7.8, 1.5 Hz, H_2β), 1.29 (3H, dd, J = 6.6, 0.6 Hz, H_6β), 1.23 (3H,

1

dd, J = 6.7, 0.6 Hz, H_6α) ppm; H NMR (500 MHz, D₂O, α/β:

34:66) δ 5.10 (1H, d, J = 3.7 Hz, H_1α), 4.57 (1H, br dd, J = 50.1, 2.8

Hz, H_4α), 4.50 (1H, br dd, J = 49.9, 2.9 Hz, H_4β), 4.49 (1H, dd, J =

7.9, 1.1 Hz, H_1β), 4.13 (1H, dq, J = 30.7, 6.7 Hz, H_5α), 3.80 (1H, ddd,

J = 29.9, 10.4, 2.7 Hz, H_3α), 3.76 (1H, dq, J = 28.5, 6.6 Hz, H_5β), 3.67

(1H, ddd, J = 10.4, 3.7, 1.3 Hz, H_2α), 3.60 (1H, ddd, J = 30.3, 10.1,

2.8 Hz, H_3β), 3.35 (1H, ddd, J = 10.1, 7.9, 1.4 Hz, H_2β), 1.17 (3H, dd,

J = 6.6, 0.6 Hz, H_6β), 1.13 (3H, dd, J = 6.7, 0.6 Hz, H_6α) ppm;

¹H{¹⁹F} NMR (500 MHz, CD₃OD) δ 5.11 (1H, d, J = 3.7 Hz, H_1α),

4.51 (1H, dt, J = 2.7, 0.4 Hz, H_4α), 4.453 (1H, br d, J = 2.8 Hz, H_4β),

4.452 (1H, d, J = 7.7 Hz, H_1β), 4.19 (1H, br q, J = 6.6 Hz, H_5α), 3.85

(1H, dd, J = 10.2, 2.7 Hz, H_3α), 3.73 (1H, br q, J = 6.6 Hz, H_5β), 3.69

(1H, dd, J = 10.2, 3.7 Hz, H_2α), 3.55 (1H, dd, J = 9.8, 2.7 Hz, H_3β),

3.43 (1H, dd, J = 9.9, 7.6 Hz, H_2β), 1.29 (3H, d, J = 6.6 Hz, H_6β), 1.23

(3H, d, J = 6.7 Hz, H_6α) ppm; ¹H{¹⁹F} NMR (500 MHz, D₂O) δ 5.10

(1H, d, J = 3.7 Hz, H_1α), 4.57 (1H, br d, J = 2.7 Hz, H_4α), 4.51 (1H,

br d, J = 2.9 Hz, H_4β), 4.49 (1H, d, J = 8.0 Hz, H_1β), 4.13 (1H, q, J =

6.7 Hz, H_5α), 3.80 (1H, dd, J = 10.4, 2.7 Hz, H_3α), 3.76 (1H, q, J = 6.6

Hz, H_5β), 3.67 (1H, dd, J = 10.4, 3.9 Hz, H_2α), 3.60 (1H, dd, J = 10.0,

2.8 Hz, H_3β), 3.36 (1H, dd, J = 10.0, 7.9 Hz, H_2β), 1.17 (3H, d, J = 6.6

Hz, H_6β), 1.13 (3H, d, J = 6.7 Hz, H_6α) ppm; ¹³C{¹H} NMR (126

MHz, CD₃OD) δ 98.4 (C_1β), 94.32 (C_1α), 94.26 (d, J_C−F= 180.7 Hz,

C_4α), 93.4 (d, J_C−F= 181.4 Hz, C_4β), 74.0 (d, J_C−F= 18.6 Hz, C_3β),

73.7 (C_2β), 70.6 (d, J_C−F= 18.8 Hz, C_5β), 70.4 (d, J_C−F= 2.2 Hz, C_2α),

70.2 (d, J_C−F= 18.4 Hz, C_3α), 66.1 (d, J_C−F= 18.8 Hz, C_5α), 16.5 (d,

75.7 (C_2β), 72.9 (C_2α), 70.8 (d, J_C−F= 18.6 Hz, C_5β), 70.1 (d, J_C−F

=

0.7 Hz, C_3β), 67.1 (d, J_C−F= 18.1 Hz, C_5α), 66.7 (d, J_C−F= 0.7 Hz,

C_3α), 32.72 (d, J_C−F= 6.7 Hz, C_4α), 32.69 (d, J_C−F= 6.9 Hz, C_4β)

ppm; ¹⁹F NMR (470 MHz, CD₃OD) δ −229.7 (td, J = 47.6, 20.0 Hz,

F_6β), −230.9 (td, J = 47.7, 21.8 Hz, F_6α) ppm; ¹⁹F NMR (470 MHz,

D₂O) δ −227.6 (td, J = 47.3, 21.6 Hz, F_6β), −228.9 (td, J = 47.4, 24.0

Hz, F_6α) ppm; ¹⁹F(¹H} NMR (470 MHz, CD₃OD) δ −229.7 (s, F_6β),

−230.9 (s, F_6α) ppm; ¹⁹F(¹H} NMR (470 MHz, D₂O) δ −227.7 (s,

F_6β), −229.0 (s, F_6α) ppm; HRMS (ES⁺) for C₆H₁₁FNaO₄[M + Na]⁺

calcd 189.0534 found 189.0534.

J

_C−F= 5.5 Hz, C_6β), 16.3 (d, J_C−F= 6.0 Hz, C_6α) ppm; ¹³C{¹H} NMR

(126 MHz, D₂O) δ 95.9 (C_1β), 92.9 (d, J_C−F= 177.4 Hz, C_4α), 92.21

(C_1α), 92.15 (d, J_C−F= 179.1 Hz, C_4β), 71.7 (d, J_C−F= 18.4 Hz, C_3β),

71.6 (d, J_C−F= 0.7 Hz, C_2β), 69.4 (d, J_C−F= 18.4 Hz, C_5β), 68.08 (d,

1,2,3-Tri-O-acetyl-4,6-dideoxy-6-ﬂuoro-^D-xylo-hexopyranoside

(1b). Using general procedure B with 10 (500 mg, 2.78 mmol) and

TMSOTf (0.1 equiv) puriﬁcation by chromatography (25% EtOAc/

petroleum ether) aﬀorded 1b as a colorless oil (720 mg, 2.46 mmol,

89%): IR (neat) 2963 (w), 1746 (s), 1371 (m), 1219 (s), 1069 (m),

930 (m) cm⁻¹; ¹H NMR (400 MHz, CDCl₃, α/β 64:33) δ 6.37 (1H,

d, J = 3.6 Hz, H_1α), 5.68 (0.5H, d, J = 8.0 Hz, H_1β), 5.32 (1H, td, J =

10.9, 5.1 Hz, H_3α), 5.12−5.00 (2H, m, H_2α, H_2β, H_3β), 4.48 (0.5H,

ddd, J = 47.3, 10.0, 3.6 Hz, H_6aβ), 4.45 (1H, ddd, J = 47.4, 10.1, 3.4

Hz, H_6aα), 4.44 (0.5H, ddd, J = 46.8, 10.4, 4.4 Hz, H_6bβ), 4.40 (1H,

ddd, J = 47.1, 10.2, 4.4 Hz, H_6bα), 4.29−4.14 (1H, m, H_5α), 3.92

(0.5H, ddddd, J = 19.7, 12.0, 4.5, 3.5, 2.2 Hz, H_5β), 2.25 (1H, ddd, J =

12.8, 5.2, 2.4 Hz, H_4(eq)α), 2.20 (0.5H, ddd, J = 13.1, 5.0, 2.2 Hz,

H_4(eq)β), 2.15 (3H, s, COCH_3α), 2.11 (1.5H, s, COCH_3β), 2.06 (3H,

s, COCH_3α), 2.05 (3H, s, 2 × COCH_3β), 2.03 (3H, s, COCH_3α),

1.81−1.69 (1.5H, m, H_4(ax)α, H_4(ax)β) ppm; ¹³C{¹H} NMR (101 MHz,

CDCl₃) δ 170.3 (CO_α), 170.2 (CO_β), 169.9 (CO_α), 169.6 (CO_β),

J_C−F= 18.1 Hz, C_3α), 68.06 (d, J_C−F= 2.2 Hz, C_2α), 65.2 (d, J_C−F

=

18.6 Hz, C_5α), 14.9 (d, J_C−F= 5.5 Hz, C_6β), 14.8 (d, J_C−F= 5.7 Hz,

C_6α) ppm; ¹⁹F NMR (470 MHz, CD₃OD) δ −219.5 (dt, J = 50.2,

28.5 Hz, F_4β), −222.7 (dt, J = 50.9, 29.6 Hz, F_4α) ppm; ¹⁹F NMR

(470 MHz, D₂O) δ −218.2 (1F, br dtd, J = 49.7, 29.3, 0.7 Hz, F_4β),

−221.1 (1F, br dtd, J = 50.1, 30.7, 1.1 Hz, F_4α) ppm; ¹⁹F(¹H} NMR

(470 MHz, CD₃OD) δ −219.5 (0.4F, s, F_4β), −222.7 (1F, s, F_4α)

ppm; ¹⁹F(¹H} NMR (470 MHz, D₂O) δ −218.2 (s, F_4β), −221.1 (s,

F_4α) ppm; HRMS (ES⁺) for C₆H₁₁FNaO₄[M + Na]⁺calcd 189.0534

found 189.0536.

1,2,3-Tri-O-acetyl-4-deoxy-4-ﬂuoro-^D-fucopyranoside (2b).

Using general procedure B with ^D-19 (128 mg, 0.71 mmol) and

TMSOTf (0.1 equiv), puriﬁcation by chromatography (20% EtOAc/

hexane) aﬀorded 2b as a colorless oil (170 mg, 0.58 mmol, 82%). IR

(neat) 2987 (w), 1735 (s), 1367 (m), 1208 (s), 1069 (s), 927 (s)

cm⁻¹; ¹H NMR (400 MHz, CDCl₃, α/β 91/9)δ 6.34 (1H, d, J = 3.6

Hz, H_1α), 5.68 (0.1H, dd, J = 8.3, 0.7 Hz, H_1β), 5.38 (1H, ddd, J =

10.9, 3.6, 1.1 Hz, H_2α), 5.27 (1H, ddd, J = 26.3, 10.9, 2.5 Hz, H_3α),

5.00 (0.1H, ddd, J = 27.3. 10.4, 3.7 Hz, H_3β), 4.74 (1H, dd, J = 50.1,

2.5 Hz, H_4α), 4.66 (0.1H, dd, J = 49.8, 2.7 Hz, H_4β), 4.17 (1H, dq, J =

28.5, 6.6 Hz, H_5α), 3.87 (0.1H, dq, J = 25.8, 6.6 Hz, H_5β), 2.14 (3H, s,

OAc_α), 2.13 (3H, s, OAc_α), 2.12 (0.3H, s, OAc_β), 2.11 (0.3H, s,

OAc_β), 2.05 (0.3H, s, OAc_β), 2.03 (OAc_α), 1.38 (0.3H, d, J = 6.6 Hz,

H_6β), 1.32 (3H, d, J = 6.6 Hz, H_6α) (H_2βnot resolved) ppm; ¹³C{¹H}

169.1 (CO_β), 169.0 (CO_α), 92.1 (C_1β), 90.1 (C_1α), 83.7 (d, J_C−F

=

174.6 Hz, C_6α), 83.3 (d, J_C−F= 174.6 Hz, C_6β), 71.05 (d, J_C−F= 21.3

Hz, C_5β), 71.03 (C_2β), 70.5 (C_3β), 70.0 (C_2α), 68.6 (d, J_C−F= 20.5 Hz,

H_5α), 67.2 (C_3α), 31.1 (d, J_C−F= 6.6 Hz, C_4α), 30.9 (d, J_C−F= 5.9 Hz,

C_4β), 21.0 (COCH_3α), 20.89 (COCH_3α), 20.86 (COCH_3β), 20.8

(COCH_3β), 20.7 (COCH_3β), 20.6 (COCH_3α) ppm; ¹⁹F NMR (376

MHz, CDCl₃) δ −230.3 (td, J = 46.8, 19.1 Hz, F_6β), −230.8 (td, J =

46.8, 20.8 Hz, F_6α) ppm; ¹⁹F(¹H} NMR (376 MHz, CDCl₃) δ −230.4

(0.5F, s, F_6β), −230.9 (s, F_6α) ppm; HRMS (ES⁺) for C₁₂H₁₇FNaO₇

[M + H]⁺calcd 315.0851 found 315.0855.

7740

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

NMR (101 MHz, CDCl₃) δ 170.5 (CO_α), 169.7 (CO_α), 169.23

(CO_β), 169.22 (CO_β), 169.0 (CO_α), 91.9 (C_1β), 89.8 (C_1α), 89.1 (d,

The mixture was stirred for 16 h. The reaction was diluted with

CH₂Cl₂(10 mL) and quenched by the addition of satd NaHCO_3(aq)

(20 mL). The phases were separated, and the aqueous phase extracted

with CH₂Cl₂(3 × 20 mL). the combined organic layers were dried

(MgSO₄) and concentrated in vacuo. Puriﬁcation by chromatography

(20% EtOAc/hexane) aﬀorded 3b as a colorless oil (24 mg, 0.08

mmol, 57%, α/β 76:24): IR (neat) 3655 (w), 2981 (m), 1749 (s),

1369 (m), 1208 (s), 1031 (s), 943 (m), 899 (m) cm⁻¹;¹H NMR (400

MHz, CDCl₃,) δ 6.24 (1H, t, J = 3.4 Hz, H_1α), 5.71 (1H, d, J = 8.3

Hz, H_1β), 5.55 (1H, ddd, J = 13.1, 10.4, 8.8 Hz, H_3α), 5.32 (1H, ddd, J

= 14.0, 9.6, 9.0 Hz, H_3β), 5.06 (1H, ddd, J = 9.7, 8.4, 0.5 Hz, H_2β),

5.01 (1H, ddd, J = 10.3, 3.8, 0.9 Hz, H_2α), 4.17 (1H, ddd, J = 50.0,

9.4, 9.1 Hz, H_4β), 4.15 (1H, ddd, J = 49.3, 9.7, 9.1 Hz, H_4α), 4.09−

4.00 (1H, m, H_5α), 3.75 (1H, dqd, J = 9.8, 6.1, 2.5 Hz, H_5β), 3.05

(3H, s, OAc_α), 2.11 (6H, s, OAc_α, OAc_β), 2.09 (3H, s, OAc_β), 2.04

(3H, OAc_β), 2.02 (3H, s, OAc_α), 1.40 (3H, dd, J = 6.2, 1.4 Hz, H_6β),

1.36 (3H, dd, J = 5.9, 1.3 Hz, H_6α) ppm; ¹³C{¹H} NMR (101 MHz,

CDCl₃) δ 169.94 (CO_α), 169.93 (CO_β), 169.8 (CO_α), 169.4 (CO_β),

169.00 (CO_α), 168.96 (CO_β), 91.7 (d, J_C−F= 187.1 Hz, C_4α), 91.5

(C_1β), 91.3 (d, J_C−F= 187.8 Hz, C_4β), 88.9 (d, J_C−F= 1.5 Hz, C_1α),

72.6 (d, J_C−F= 20.5 Hz, C_3β), 70.50 (d, J_C−F= 8.1 Hz, C_2β), 70.48 (d,

J_C−F= 186.3 Hz, C_4α), 71.8 (d, J_C−F= 18.3 Hz, C_3β), 70.3 (d, J_C−F=

19.1 Hz, C_5β), 68.4 (d, J_C−F= 18.3 Hz, C_3α), 67.7 (C_2β), 67.4 (d, J_C−F

= 19.1 Hz, C_5α), 66.1 (d, J_C−F= 2.2 Hz, C_2α), 20.9 (OAc_α), 20.81

(OAc_β), 20.79 (OAc_α), 20.7 (OAc_β), 20.6 (OAc_β), 20.5 (OAc_α), 15.6

(2 × C, d, J_C−F= 5.9 Hz, C_6α, C_6β) ppm (one CO_βand C_4βnot

observed); ¹⁹F NMR (376 MHz, CDCl₃) δ −217.5 (0.1F, dt, J = 50.3,

26.9 Hz, F_4β), −219.8 (1F, dt, J = 50.3, 27.7 Hz, F_4α) ppm; ¹⁹F(¹H}

NMR (376 MHz, CDCl₃) δ −217.6 (s, F_4β), −219.9 (s, F_4α) ppm;

HRMS (ES⁺) for C₁₂H₁₇FNaO₇[M + Na]⁺calcd 315.0851 found

315.0850.

4-Deoxy-4-ﬂuoro-^D-quinovose (3a). From 3b. Using general

procedure C with 3b (292 mg, 1.00 mmol), puriﬁcation by

chromatography (5% MeOH/CH₂Cl₂) aﬀorded 3a as a colorless

solid (150 mg, 0.90 mmol, 90%).

From 71. Using general procedure A with 71 (500 mg, 2.78 mmol)

for 17 h, puriﬁcation by chromatography (8−10% MeOH/CH₂Cl₂

aﬀorded 3a as a colorless solid (438 mg, 2.64 mmol, 95%) with 13%

residual TFA (¹⁹F NMR integration): mp (postcolumn) 117−119 °C;

[α]²_D⁵+38.6 (c 0.49, MeOH); IR (neat) 3343 (br), 2937 (w), 1373

1

(m), 1089 (s), 998 (s) cm⁻¹; H NMR (500 MHz, CD₃OD, α/β

J_C−F= 24.2 Hz, C_5β), 69.7 (d, J_C−F= 20.5 Hz, C_3α), 69.3 (d, J_C−F= 8.8

50:50) δ 5.03 (1H, t, J = 3.7 Hz, H_1α), 4.48 (1H, d, J = 7.8 Hz, H_1β),

4.05−3.97 (1H, m, H_5α), 3.87 (1H, ddd, J = 50.8, 9.5, 8.7 Hz, H_4β),

3.83 (1H, ddd, J = 13.2, 9.4, 8.7 Hz, H_3α), 3.82 (1H, ddd, J = 53.2,

9.3, 8.7 Hz, H_4α), 3.56 (1H, ddd, J = 15.4, 9.4, 8.7 Hz, H_3β), 3.54 (1H,

dqd, J = 9.5, 6.1, 2.4 Hz, H_5β), 3.40−3.35 (1H, m, H_2α), 3.15 (1H,

ddd, J = 9.4, 7.8, 0.8 Hz, H_2β), 1.29 (3H, dd, J = 6.2, 1.4 Hz, H_6α),

Hz, C_2α), 67.5 (d, J_C−F= 23.5 Hz, C_5α), 20.9 (OAc_α), 20.80 (OAc_β),

20.78 (OAc_α), 20.7 (OAc_β), 20.6 (OAc_β), 20.5 (OAc_α), 17.2 (C_6α),

17.1 (C_6β) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −197.1 to −197.4

(m, F_4α), −198.9 (br dd, J = 50.3, 13.9 Hz, F_4β) ppm; ¹⁹F(¹H} NMR

(376 MHz, CDCl₃) δ −197.3 (1F, s, F_4α), −199.0 (0.29F, s, F_4β)

ppm; HRMS (ES+) for C₁₂H₁₇FNaO₇, calcd 315.0851, found

315.0852.

1

1.23 (3H, dd, J = 6.2, 1.2 Hz, H_6β) ppm; H NMR (500 MHz, D₂O,

α/β 34:66) δ 5.03 (1H, t, J = 3.6 Hz, H_1α), 4.52 (1H, d, J = 8.0 Hz,

H_1β), 3.99−3.91 (1H, m, H_5α), 3.92 (1H, ddd, J = 50.4, 9.5, 8.9 Hz,

H_4β), 3.91 (1H, ddd, J = 52.6, 9.6, 8.7 Hz, H_4α), 3.77 (1H, dddd, J =

15.3, 9.8, 8.8, 0.5 Hz, H_3α), 3.60 (1H, ddd, J = 15.3, 9.5, 8.8 Hz, H_3β),

3.58 (1H, dqd, J = 9.5, 6.2, 2.5 Hz, H_5β), 3.44 (1H, ddd, J = 9.8, 3.9,

0.9 Hz, H_2α), 3.15 (1H, ddd, J = 9.6, 8.0, 0.9 Hz, H_2β), 1.18 (3H, dd, J

= 6.2, 1.5 Hz, H_6β), 1.15 (3H, dd, J = 6.0, 1.1 Hz, H_6α) ppm; ¹H{¹⁹F}

NMR (500 MHz, CD₃OD) δ 5.03 (1H, d, J = 3.7 Hz, H_1α), 4.49 (1H,

d, J = 7.8 Hz, H_1β), 4.05−3.97 (1H, m, H_5α), 3.87 (1H, dd, J = 9.4, 8.8

Hz, H_4β), 3.85−3.79 (2H, m, H_3α, H_4α), 3.56 (1H, dd, J = 9.4, 8.8 Hz,

H_3β), 3.54 (1H, dq, J = 9.4, 6.1 Hz, H_5β), 3.40 (1H, m, H_2α), 3.16

(1H, dd, J = 9.4, 7.8 Hz, H_2β), 1.29 (3H, d, J = 6.1 Hz, H_6β), 1.23

(3H, d, J = 6.3 Hz, H_6α) ppm; ¹H{¹⁹F} NMR (500 MHz, D₂O) δ 5.03

(1H, d, J = 3.9 Hz, H_1α), 4.52 (1H, d, J = 8.0 Hz, H_1β), 3.98−3.88

(3H, m, H_4α, H_4β, H_5α), 3.78 (1H, dd, J = 9.8, 8.6 Hz, H_3α), 3.60 (1H,

dd, J = 9.6, 8.9 Hz, H_3β), 3.58 (1H, dq, J = 9.5, 6.2 Hz, H_5β), 3.44

(1H, dd, J = 9.8, 3.9 Hz, H_2α), 3.15 (1H, J = 9.5, 8.0 Hz, H_2β), 1.18

(3H, d, J = 6.2 Hz, H_6β), 1.15 (3H, d, J = 5.9 Hz, H_6α) ppm; ¹³C{¹H}

NMR (126 MHz, CD₃OD) δ 98.2 (d, J_C−F= 1.4 Hz, C_1β), 96.8 (d,

4,6-Dideoxy-4,6-diﬂuoro-^D-galactose (4a). From 4b. Using

general procedure C with 4b (729 mg, 2.35 mmol), puriﬁcation by

chromatography (10% MeOH/CH₂Cl₂) aﬀorded 4a as a white

powder (337 mg, 1.83 mmol, 78%).

From 28. Using general procedure A with 28 (1.93 g, 9.74 mmol),

puriﬁcation by chromatography (5−8% MeOH/CH₂Cl₂) aﬀorded 4a

as a pale yellow solid (1.40 g, 7.60 mmol, 78%) with <1% TFA (¹⁹F

NMR integration): mp (postcolumn) 172−174 °C; [α]²_D⁵+ 75.0 (c

0.64, MeOH); IR (neat) 3402 (br), 2978 (w), 1411 (w), 1148 (m),

1099 (s), 1019 (s), 924 (m) cm⁻¹; ¹H NMR (500 MHz, CD₃OD, α/

β 58/42) δ 5.18 (1H, d, J = 3.7 Hz, H_1α), 4.76 (1H, br dd, J = 51.2,

2.7 Hz, H_4α), 4.70 (1H, br dd, J = 51.0, 2.8 Hz, H_4β), 4.58 (1H, ddd, J

= 46.1, 9.5, 5.7 Hz, H_6aβ), 4.57 (1H, ddd, J = 46.1, 9.5, 5.7 Hz, H_6aα),

4.523 (1H, dddd, J = 47.5, 9.5, 6.7, 1.2 Hz, H_6bβ), 4.518 (1H, dd, J =

7.7, 1.2 Hz, H_1β), 4.47 (1H, dddd, J = 47.5, 9.5, 6.7, 1.3 Hz, H_6bα),

4.31 (1H, br dddd, J = 30.5, 13.2, 6.7, 5.7 Hz, H_5α), 3.92 (1H, dddd, J

= 28.2, 12.6, 6.7, 5.7 Hz, H_5β), 3.88 (1H, ddd, J = 29.3, 10.2, 2.7 Hz,

H_3α), 3.73 (1H, ddd, J = 10.2, 3.7, 1.1 Hz, H_2α), 3.60 (1H, ddd, J =

29.5, 10.0, 2.8 Hz, H_3β), 3.48 (1H, ddd, J = 10.0, 7.7, 1.5 Hz, H_2β)

ppm; ¹H NMR (500 MHz, D₂O, α/β 40:60) δ5.20 (1H, d, J = 3.7 Hz,

H_1α), 4.81 (1H, br dd, J = 50.8, 2.8 Hz, H_4α), 4.74 (1H, br dd, J =

50.4, 2.8 Hz, H_4β), 4.56 (1H, dd, J = 7.9, 1.0 Hz, H_1β), 4.50 (1H,

dddd, J = 47.5, 10.1, 7.2, 1.0 Hz, H_6bβ), 4.28 (1H, dddd, J = 31.6, 17.2,

6.9, 4.0 Hz, H_5α), 3.96 (1H, ddddd, J = 29.1, 11.3, 7.2, 4.1, 3.8 Hz,

H_5β), 3.84 (1H, ddd, J = 29.5, 10.4, 2.8 Hz, H_3α), 3.73 (1H, ddd, J =

10.4, 3.8, 1.2 Hz, H_2α), 3.65 (1H, ddd, J = 29.9, 10.0, 2.8 Hz, H_3β),

3.42 (1H, ddd, J = 9.9, 8.1, 1.3 Hz, H_2β) ppm; H_6aα, H_6bαand H_6aβare

J

_C−F= 181.9 Hz, C_4α), 96.2 (d, J_C−F= 182.2 Hz, C_4β), 93.6 (d, J_C−F=

1.7 Hz, C_1α), 76.3 (d, J_C−F= 8.3 Hz, C_2β), 75.9 (d, J_C−F= 17.9 Hz,

C_3β), 73.8 (d, J_C−F= 7.9 Hz, C_2α), 72.9 (d, J_C−F= 17.6 Hz, C_3α), 70.6

(d, J_C−F= 24.7 Hz, C_5β), 65.7 (d, J_C−F= 24.1 Hz, C_5α), 17.9 (C_6αand

C_6b(bs)) ppm; ¹³C{¹H} NMR (126 MHz, D₂O) δ 95.7 (C_1β), 94.5

(d, J_C−F= 179.8 Hz, C_4α), 94.1 (d, J_C−F= 180.0 Hz, C_4β), 91.8 (C_1α),

73.8 (d, J_C−F= 8.8 Hz, C_2β), 73.6 (d, J_C−F= 17.9 Hz, C_3β), 71.1 (d,

J_C−F= 8.1 Hz, C_2α), 70.9 (d, J_C−F= 17.6 Hz, C_3α), 69.3 (d, J_C−F= 24.8

1

Hz, C_5β), 64.8 (d, J_C−F= 24.3 Hz, C_5α), 16.36 (C_6β), 16.34 (C_6α)

ppm; ¹⁹F NMR (470 MHz, CD₃OD) δ −197.5−197.7 (m, F_4α),

−199.3 (ddquin, J = 50.8, 15.4, 1.4 Hz, F_4β) ppm; ¹⁹F NMR (470

MHz, D₂O) δ −119.2−196.4 (m, F_4α), −198.2 (app ddspt, J = 50.4,

15.4, 1.4 Hz, F_4β) ppm; ¹⁹F(¹H} NMR (470 MHz, CD₃OD) δ −197.6

(s, F_4α), −199.3 (s, F_4β) ppm; ¹⁹F(¹H} NMR (470 MHz, D₂O) δ

−196.3 (s, F_4α), −198.3 (s, F_4β) ppm; HRMS (ES⁺) for C₆H₁₁FNaO₄

[M + Na]⁺calcd 189.0534 found 189.0538.

1,2,3-Tri-O-acetyl-4-deoxy-4-ﬂuoro-^D-quinovopyranoside (3b).

To 73 (42 mg, 0.14 mmol) was added a solution of TFA/H₂O

(9:1, 0.5 mL). The colorless mixture was stirred for 10 min, over

which time it turned bright yellow. The solution was concentrated in

vacuo and redissolved in Ac₂O (0.27 mL, 2.80 mmol). The solution

was cooled to 0 °C, and concd H₂SO₄(10 μL, 0.14 mmol) was added.

obscured by the residual solvent peak. H{¹⁹F} NMR (500 MHz,

CD₃OD) δ 5.18 (1H, d, J = 3.6 Hz, H_1α), 4.76 (1H, br d, J = 2.7 Hz,

H_4α), 4.70 (1H, dd, J = 2.8, 0.5 Hz, H_4β), 4.58 (1H, dd, J = 9.5, 5.3

Hz, H_6aβ), 4.57 (1H, dd, J = 9.5, 5.7 Hz, H_6aα), 4.523 (1H, dd, J = 9.5,

6.8 Hz, H_6bβ), 4.519 (1H, d, J = 7.7 Hz, H_1β), 4.47 (1H, dd, J = 9.5,

6.9 Hz, H_6bα), 4.31 (1H, br dd, J = 6.7, 5.7 Hz, H_5α), 3.92 (1H, dd, J =

6.8, 5.3 Hz, H_5β), 3.87 (1H, dd, J = 10.2, 2.7 Hz, H_3α), 3.73 (1H, dd, J

= 10.2, 3.7 Hz, H_2α), 3.60 (1H, dd, J = 9.9, 2.8 Hz, H_3β), 3.48 (1H,

dd, J = 9.9, 7.7 Hz, H_2β) ppm; ¹H{¹⁹F} NMR (500 MHz, D₂O) δ 5.20

(1H, d, J = 3.7 Hz, H_1α), 4.81 (1H, br d, J = 2.7 Hz, H_4α), 4.75 (1H,

br d, J = 2.7 Hz, H_4β), 4.58 (1H, ddd, J = 10.3, 4.1, 1.8 Hz, H_6bα), 4.56

(1H, d, J = 8.0 Hz, H_1β), 4.50 (1H, dd, J = 10.2, 7.1 Hz, H_6bβ), 4.28

(1H, dd, J = 7.0, 4.1 Hz, H_5α), 3.96 (1H, dd, J = 7.2, 4.1 Hz, H_5β),

3.84 (1H, dd, J = 10.4, 2.8 Hz, H_3α), 3.74 (1H, dd, J = 10.4, 3.7 Hz,

7741

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

H_2α), 3.65 (1H, dd, J = 10.0, 2.8 Hz, H_3β), 3.42 (1H, dd, J = 10.0, 7.9

Hz, H_2β) ppm; H_6aαand H_6aβare obscured by the residual solvent

peak. ¹³C{¹H} NMR (101 MHz, CD₃OD) δ 98.6 (C_1β), 94.4 (C_1α),

91.4 (dd, J_C−F= 179.7, 5.9 Hz, C_4α), 90.5 (dd, J_C−F= 180.1, 6.2 Hz,

C_4β), 82.9 (dd, J_C−F= 168.0, 6.6 Hz, C_6α), 82.6 (dd, J_C−F= 168.7, 5.9

(1H, dd, J = 7.9, 0.5 Hz, H_1β), 4.24 (1H, dt, J 50.9, 8.8 Hz, H_4β), 4.22

(1H, dt, J 50.9, 8.7 Hz, H_4α), 4.03−4.13 (1H, m, H_5α), 3.92 (1H, dt, J

16.3, 9.3 Hz, H_3α), 3.60−3.64 (1H, m, H_5β), 3.65 (1H, dddd, J = 16.3,

9.5, 8.7, 0.8 Hz, H_3β), 3.38 (1H, ddd, J 9.6, 3.7, 0.9 Hz, H_2α), 3.17

(1H, ddd, J 9.3, 7.8, 0.7 Hz, H_2β) ppm; ¹H NMR (500 MHz, D₂O, α/

β 45:55) δ 5.12 (1H, t, J = 3.5 Hz, H_1α), 4.67−4.48 (4H, m, H_6α,

H_6β), 4.59 (1H, dd, J = 8.0, 0.5 Hz, H_1β), 4.28 (2H, ddd, J = 50.7,

10.1, 8.9 Hz, H_4α, H_4β), 4.06 (1H, dddddd, J = 28.0, 10.1, 4.1, 3.6, 1.8,

0.5 Hz, H_5α), 3.87 (1H, dt, J = 15.9, 9.3 Hz, H_3α), 3.75 (1H, ddddd, J

= 25.8, 10.0, 3.9, 2.6, 2.1 Hz, H_5β), 3.70 (1H, dddd, J = 15.7, 9.6, 8.8,

0.8 Hz, H_3β), 3.46 (1H, ddd, J = 9.9, 3.8, 0.9 Hz, H_2α), 3.17 (1H, ddd,

J = 9.6, 8.0, 0.9 Hz, H_2β) ppm; ¹H{¹⁹F} NMR (500 MHz, CD₃OD) δ

5.11 (1H, d, J = 3.7 Hz, H_1α), 4.52−4.62 (4H, m, H_6aα+ H_6bα+ H_6aβ

+ H6_bβ), 4.54 (1H, d, J = 7.9 Hz, H_1β), 4.24 (1H, t, J = 8.8 Hz, H_4β),

4.22 (1H, t, J = 8.8 Hz, H_4α), 4.08 (1H, ddd, J = 10.2, 3.8, 1.5 Hz,

H_5α), 3.92 (1H, t, J = 9.3 Hz, H_3α), 3.68 (1H, ddd, J = 10.0, 4.1, 1.8

Hz, H_5β), 3.65 (1H, t, J = 9.0 Hz, H_3β), 3.38 (1H, dd, J = 9.6, 3.7 Hz,

Hz, C_6β), 73.8 (C_2β), 73.5 (d, J_C−F= 17.6 Hz, C_3β), 73.3 (dd, J_C−F

=

22.7, 17.6 Hz, C_5β), 70.5 (d, J_C−F= 2.2 Hz, C_2α), 69.8 (d, J_C−F= 18.3

Hz, C_3α), 69.0 (dd, J_C−F= 23.1, 18.0 Hz, C_5α) ppm; ¹³C{¹H} NMR

(126 MHz, D₂O) δ 96.1 (C_1β), 92.4 (C_1α), 90.3 (dd, J_C−F= 177.3, 7.0

Hz, C_4α), 89.3 (dd, J_C−F= 178.0, 7.3 Hz, C_4β), 82.4 (dd, J_C−F= 166.7,

6.0 Hz, C_6α), 82.0 (dd, J_C−F= 166.7, 5.7 Hz, C_6β), 71.8 (dd, J_C−F

=

20.9, 17.3 Hz, C_5β), 71.6 (C_2β), 71.3 (d, J_C−F= 18.1 Hz, C_3β), 68.1 (d,

J

_C−F= 2.2 Hz, C_2α), 67.70 (dd, J_C−F= 20.6, 17.3 Hz, C_5α), 67.69 (d,

_C−F= 17.6 Hz, C_3α) ppm; ¹⁹F NMR (470 MHz, CD₃OD) δ −219.1

(1F, dddq, J = 51.2, 29.5, 28.2, 1.2 Hz, H_4β), −222.0 (1F, dddq, J =

51.1, 30.5, 29.3, 1.0 Hz, F_4α), −232.5 (1F, ddd, J = 47.5, 46.1, 12.4

Hz, F_6β), −232.6 (1F, dddd, J = 47.6, 46.8, 13.5, 0.6 Hz, F_6α) ppm;

¹⁹F NMR (470 MHz, D₂O) δ −217.0 (1F, dtq, J = 50.4, 29.7, 1.1 Hz,

1

H_2α), 3.17 (1H, dd, J = 9.3, 7.8 Hz, H_2β) ppm; H{¹⁹F} NMR (500

F_4β), 219.4 (1F, ddddd, J = 50.8, 31.6, 29.3, 3.6, 0.7 Hz, F_4α), −230.6

(1F, dddd, J = 57.9, 45.4, 15.3, 2.5 Hz, F_6β), −230.8 (1F, dddd, J =

47.6, 45.4, 17.2, 3.9 Hz, F_6α) ppm; ¹⁹F(¹H} NMR (470 MHz,

CD₃OD) δ −219.0 (1F, s, F_4β), −221.9 (1F, s, F_4α), −232.3 (1F, s,

F_6β), −232.5 (1F, s, F_6α) ppm; ¹⁹F(¹H} NMR (470 MHz, D₂O) δ

−216.9 (1F, d, J = 2.5 Hz, F_4β), −219.2 (1F, d, J = 3.9 Hz, F_4α),

−230.4 (1F, d, J = 2.5 Hz, F_6β), −230.7 (1F, d, J = 3.9 Hz, F_6α) ppm;

HRMS (ES⁺) for C₆H₁₀F₂NaO₄[M + Na]⁺calcd 207.0439, found

207.0439. Spectroscopic data corresponds with the literature.¹¹⁶

1,2,3-Tri-O-acetyl-4,6-dideoxy-4,6-diﬂuoro-D-galactopyranoside

(4b). Using general procedure B from 28 (1.50 g, 8.15 mmol) and

H₂SO₄(5 equiv), puriﬁcation by chromatography (25% EtOAc/

petroleum ether) aﬀorded 4b as an oﬀ-yellow amorphous solid (1.87

g, 6.03 mmol, 74%): mp (postcolumn) 91−92 °C; IR (neat) 2981

(w), 1746 (s), 1374 (s), 1209 (s), 1010 (s), 899 (s) cm⁻¹; Data for

the major (α) anomer: ¹H NMR (400 MHz, CDCl₃, α/β 98:2) δ 6.40

(1H, d, J = 3.6 Hz, H₁), 5.41 (1H, ddd, J = 10.9, 3.6, 1.2 Hz, H₂), 5.30

(1H, ddd, J = 26.2, 10.9, 2.5 Hz, H₃), 5.02 (1H, dd, J = 50.3, 2.3 Hz,

H₄), 4.58 (1H, ddd, J = 46.1, 9.4, 6.6 Hz, H_6a), 4.54 (1H, dddd, J =

46.2, 9.4, 6.1, 1.2 Hz, H_6b), 4.29 (1H, dddd, J = 28.9, 10.9, 6.6, 6.1 Hz,

H₅), 2.17 (3H, s, OAc), 2.14 (3H, s, OAc), 2.04 (3H, s, OAc) ppm;

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 170.3 (CO), 169.6 (CO), 168.7

MHz, D₂O) δ 5.12 (1H, d, J = 3.9 Hz, H_1α), 4.60 (1H, dd, J = 11.0,

3.5 Hz, H_6aα), 4.59 (1H, d, J = 8.0 Hz, H_1β), 4.59 (1H, dd, J = 10.9,

2.0 Hz, H_6aβ), 4.55 (1H, dd, J = 10.9, 3.2 Hz, H_6bβ), 4.54 (1H, dd, J =

11.0, 1.1 Hz, H_6bα), 4.28 (2H, dd, J = 10.0, 8.9 Hz, H_4α, H_4β), 4.06

(1H, dddd, J = 10.0, 3.5, 1.8, 0.5 Hz, H_5α), 3.87 (1H, dd, J = 9.9, 8.8

Hz, H_3α), 3.75 (1H, ddd, J = 10.0, 3.9, 2.0 Hz, H_5β), 3.70 (1H, dd, J =

9.6, 8.8 Hz, H_3β), 3.46 (1H, dd, J = 9.9, 3.8 Hz, H_2α), 3.17 (1H, dd, J

= 9.6, 8.0 Hz, H_2β) ppm; ¹³C NMR (101 MHz, CD₃OD) δ 98.4 (d,

J_C−F= 1.5 Hz, C_1β), 94.0 (d, J_C−F= 1.8 Hz, C_1α), 90.2 (dd, J_C−F

=

182.3, 7.3 Hz, C_4α), 89.9 (dd, J_C−F= 181.9, 7.3 Hz, C_4β), 83.1 (d, J_C−F

= 173.1 Hz, C_6α), 82.7 (d, J_C−F= 172.4 Hz, C_6β), 76.0 (d, J_C−F= 8.8

Hz, C_2β), 75.9 (d, J_C−F= 18.0 Hz, C_3β), 73.7 (dd, J_C−F= 24.2, 18.3

Hz, C_5β), 73.4 (bd, J_C−F= 8.1 Hz, C_2α), 72.9 (d, J_C−F= 17.2 Hz, C_3α),

69.3 (dd, J_C−F= 23.8, 18.0 Hz, C_5α) ppm; ¹³C{¹H} NMR (126 MHz,

D₂O) δ 96.0 (d, J_C−F= 1.2 Hz, C_1β), 92.0 (d, J_C−F= 1.4 Hz, C_1α), 88.1

(dd, J_C−F= 180.5, 7.2 Hz, C_6α), 87.9 (dd, J_C−F= 180.8, 7.3 Hz, C_6β),

81.6 (d, J_C−F= 168.3 Hz, C_4α), 81.4 (d, J_C−F= 168.6 Hz, C_4β), 73.6

(d, J_C−F= 17.9 Hz, C_3β), 73.4 (d, J_C−F= 8.8 Hz, C_2β), 71.7 (dd, J_C−F

=

24.3, 17.9 Hz, C_5β), 70.9 (d, J_C−F= 18.1 Hz, C_3α), 70.8 (d, J_C−F= 8.3

Hz, C_2α), 67.6 (dd, J_C−F= 24.1, 17.4 Hz, C_5α) ppm; ¹⁹F NMR (470

MHz, CD₃OD) δ −199.6 to −199.4 (1F, m, F_4α, a dd, J = 51.0, 16.2

was observed), −201.4 to −201.2 (1F, m, F_4β, a dd, J = 51.0, 16.2 Hz

was observed), −236.6 (1F, td, J = 47.7, 25.0 Hz, F_6β), −237.3 (1F,

td, J = 47.8, 26.9 Hz, F_6α) ppm; ¹⁹F NMR (470 MHz, D₂O) δ −198.5

(1F, ddddtd, J = 50.8, 15.8, 4.0, 3.1, 1.7, 0.8 Hz, F_4α), −200.6 (1F,

ddddt, J = 50.8, 15.7, 3.6, 1.8, 0.7 Hz, F_4β), −235.2 (1F, td, J = 47.1.

25.9 Hz, F_6β), −235.8 (1F, dddd, J = 47.6, 46.8, 27.9, 0.7 Hz. F_6α)

ppm; ¹⁹F(¹H} NMR (470 MHz, CD₃OD) δ −199.5 (1F, s, F_4α),

−201.3 (1F, s, F_4β), −236.6 (1F, s, F_6β), −237.4 (1F, s, F_6α) ppm;

¹⁹F(¹H} NMR (470 MHz, D₂O) δ −198.4 (1F, s, F_4α), −200.5 (1F, s,

F_4β), −235.1 (1F, s, F_6β), −235.7 (1F, s, F_6α) ppm; MS (ESI+) 207.3

[M + Na]⁺. Physical and spectroscopic values are consistent with the

literature.²⁰

1,2,3-Tri-O-acetyl-4,6-dideoxy-4,6-diﬂuoro-D-glucopyranoside

(5b) and 1,1,2,3,5-Penta-O-acetyl-4,6-dideoxy-4,6-diﬂuoro-^D-glu-

cose (5c). Using general procedure B with 35 (506 mg, 2.55 mmol)

and H₂SO₄(3 equiv), puriﬁcation by chromatography (20−50%

EtOAc/hexane) aﬀorded ﬁrst 5b as a colorless oil (543 mg, 1.75

mmol, 69%) and then the peracetylated open chain form 5c as a white

powder (135 mg, 0.33 mmol, 13%).

Data for 5b. IR (neat) 2970 (w), 1712 (s), 1372 (m), 1225 (s),

1013 (s), 913 (m) cm⁻¹; ¹H NMR (400 MHz, CDCl₃, α/β 88:12) δ

6.32 (1H, t, J = 3.3 Hz, H_1α), 5.74 (1H, d, J = 8.3 Hz, H_1β), 5.62 (1H,

app dt, J = 13.8, 9.7 Hz, H_3α), 5.39 (1H, dddd, J = 14.8, 9.5, 8.9, 0.6

Hz, H_3β), 5.07 (1H, ddd, J = 9.4, 8.3, 0.4 Hz, H_2β), 5.02 (1H, ddd, J =

10.3, 3.7, 0.9 Hz, H_2α), 4.76−4.50 (6H, m, H_4α, H_4β, H_6α, H_6β), 4.08

(1H, dddt, J = 26.5, 10.3, 4.2, 2.2 Hz, H_5α), 3.82 (1H, ddtd, J = 25.4,

10.0, 3.0, 2.0 Hz, H_5β), 2.18 (3H, s, OAc_α), 2.11 (3H, s, OAc_α), 2.11

(3H, s, OAc_β), 2.10 (3H, s, OAc_β), 2.04 (3H, s, OAc_β), 2.02 (3H, s,

OAc_α) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.74 (CO_α),

169.69 (CO_β), 169.5 (CO_α), 169.1 (CO_β), 168.7 (CO_β), 168.6

(CO_α), 91.4 (C_1β), 88.8 (C_1α), 85.2 (dd, J_C−F= 187.1, 8.1 Hz, C_4α),

(CO), 89.5 (C₁), 85.9 (dd, J_C−F= 185.6, 5.1 Hz, C₄), 79.9 (dd, J_C−F

170.2, 6.6 Hz, C₆), 69.5 (dd, J_C−F= 25.3, 18.7 Hz, C₅), 67.7 (d, J_C−F

=

17.6 Hz, C₃), 66.1 (d, J_C−F= 2.2 Hz, C₂), 20.8 (OAc), 20.7 (OAc),

20.5 (OAc) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −219.6 (1F, dt, J =

50.3, 27.7 Hz, F₄), −232.4 (1F, td, J = 46.4, 11.3 Hz, F₆) ppm;

¹⁹F(¹H} NMR (376 MHz, CDCl₃) δ −219.8 (1F, s, F₄), −232.5 (1F,

1

s, F₆) ppm; Selected data for the minor (β) anomer: H NMR (400

MHz, CDCl₃) δ 5.73 (1H, dd, J = 8.3, 0.9 Hz, H₁) ppm; ¹⁹F NMR

(376 MHz, CDCl₃) δ −217.6 (1F, dt, J = 50.3, 27.7 Hz, F₄) ppm;

¹⁹F(¹H} NMR (376 MHz, CDCl₃) δ −217.8 (1F, s, F₄) ppm; HRMS

(ES⁺) for C₁₂H₁₆F₂NaO₇[M + Na]⁺calcd 333.0756 [M + H]⁺found

333.0755.

4,6-Dideoxy-4,6-diﬂuoro-^D-glucose (5a). From 5b. Using general

procedure C with 5b (413 mg, 1.33 mmol), puriﬁcation by

chromatography (10% MeOH/CH₂Cl₂) aﬀorded 5a as a white

powder (158 mg, 0.86 mmol, 65%).

From 35. Using general procedure A with 35 (1.03 g, 5.20 mmol)

for 60 h, puriﬁcation by chromatography (3−6% MeOH/CH₂Cl₂)

aﬀorded 5a as a white powder (650 mg, 3.53 mmol, 68%) with <1%

TFA (¹⁹F NMR integration).

From 74. Using general procedure A with 74 (130 mg, 0.42 mmol)

for 36 h, puriﬁcation by chromatography (4−8% MeOH/CH₂Cl₂)

aﬀorded 5a as an oﬀ-white solid (42 mg, 0.23 mmol, 55%) with <1%

TFA (¹⁹F NMR integration): mp (postcolumn) 117−119 °C; [α]²_D⁴

+53.5 (c 0.91, MeOH), lit.²⁰+48.2 (c 1.0, MeOH); IR (neat) 3355

(br. s), 3288 (br. s), 2958 (w), 1149 (s), 1130 (s), 1081 (s), 1054 (s)

1

cm⁻¹; H NMR (500 MHz, CD₃OD, α/β 64:36) δ 5.11 (1H, t, J =

3.5 Hz, H_1α), 4.61 (1H, ddt, J = 47.8, 10.4, 2.0 Hz, H_6aβ), 4.59 (1H,

dddd, J = 47.5, 10.4, 3.7, 1.7 Hz, H_6aα), 4.56 (1H, dddd, J = 47.5, 10.4,

4.1, 1.8 Hz, H_6bβ), 4.543 (1H, ddt, J = 48.1, 10.4, 1.7 Hz, H_6bα), 4.542

7742

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

85.0 (dd, J_C−F= 187.4, 7.7 Hz, C_4β), 80.1 (d, J_C−F= 176.1 Hz, C_6α),

79.9 (d, J_C−F= 176.1 Hz, C_6β), 72.7 (dd, J_C−F= 24.2, 18.3 Hz, C_5β),

72.3 (d, J_C−F= 19.8 Hz, C_3β), 70.3 (dd, J_C−F= 23.5, 18.3 Hz, C_5α),

69.9 (d, J_C−F= 8.1 Hz, C_2β), 69.4 (d, J_C−F= 19.8 Hz, C_3α), 68.7 (d,

J_C−F= 8.1 Hz, C_2α), 20.6 (OAc_α), 20.5 (OAc_α), 20.4 (OAc_β), 20.3

(OAc_β), 20.2 (OAc_α) (One OAc_βsignal not resolved) ppm; ¹⁹F NMR

(376 MHz, CDCl₃) δ −199.3 (1F, br dd, J = 50.3, 13.8 Hz, F_4α),

−200.9 (1F, br dd, J = 51.2, 14.8 Hz, F_4β), −236.8 (1F, td, J = 46.8,

25.4 Hz, F_6β), −237.1 (1F, td, J = 46.8, 26.5 Hz, F_6α) ppm; ¹⁹F(¹H}

NMR (376 MHz, CDCl₃) δ −199.1 (1F, s, F_4α), −200.75 (1F, s, F_4β),

−236.7 (1F, s, F_6β), −237.0 (1F, s, F_6α) ppm; HRMS (ES+) for

C₁₂H₁₆F₂NaO₇[M + Na]⁺calcd 333.0756, found 333.0761.

Spectroscopic data corresponds with the literature.^58,117

248.0 Hz, C_4β), 98.2 (C_1β), 94.0 (C_1α), 75.4 (d, J_C−F= 8.2 Hz, C_2β),

74.5 (t, J_C−F= 20.4 Hz, C_3β), 72.7 (d, J_C−F= 7.3 Hz, C_2α), 71.6 (t,

J_C−F= 20.0 Hz, C_3α), 70.9 (dd, J_C−F= 30.4, 24.1 Hz, C_5β), 66.0 (dd,

J

_C−F= 30.0, 24.5 Hz, C_5α), 12.2 (d, J_C−F= 5.5 Hz, C_6β), 12.0 (d, J_C−F

= 5.6 Hz, C_6α) ppm; ¹³C{¹H} NMR (126 MHz, D₂O) δ 118.4 (t, J_C−F

= 249.6 Hz, C_4α), 117.9 (t, J_C−F= 249.8 Hz, C_4β), 95.7 d, J_C−F= 1.0

Hz, C_1β), 91.9 (br s, C_1α), 73.1 (d, J_C−F= 8.1 Hz, C_2β), 72.2 (t, J_C−F

=

20.7 Hz, C_3β), 70.3 (d, J_C−F= 7.4 Hz, C_2α), 69.54 (dd, J_C−F= 30.6,

24.2 Hz, C_5β), 69.54 (t, J_C−F= 20.2 Hz, C_3α), 64.9 (dd, J_C−F= 29.8,

24.3 Hz, C_5α), 10.7 (d, J_C−F= 5.3 Hz, C_6β), 10.6 (d, J_C−F= 5.5 Hz,

C_6α) ppm; ¹⁹F NMR (471 MHz, CD₃OD) δ −118.8 (1F, br ddd, J =

245.9, 6.1, 2.1 Hz, F_4α(eq)), −121.3 (1F, dd, J = 246.1, 6.6 Hz, H_4β(eq)),

−139.5 (1F, dt, J = 246.1, 21.6 Hz, F_4β(ax)), −141.3 (1F, dddd, J =

245.9, 23.6, 20.6, 1.1 Hz, H_4α(ax)) ppm; ¹⁹F NMR (470 MHz, D₂O) δ

−117.6 (1F, dddd, J = 245.3, 6.1, 2.5, 0.7 Hz, F_4α(eq)), −120.0 (1F, br

dd, J = 245.3, 6.3 Hz, F_4β(eq)), −137.4 (1F, br dt, J = 245.3, 21.9 Hz,

F_4β(ax)), −138.9 (1F, dddd, J = 245.3, 23.6, 21.1, 1.4 Hz, F_4α(ax)) ppm;

¹⁹F(¹H} NMR (471 MHz, CD₃OD) δ −118.8 (1F, d, J = 245.9 Hz,

Data for 5c: mp (postcolumn) 111−113 °C; [α]²_D⁵−12.3 (c 0.55,

CHCl₃); IR (neat) 2947 (w), 1738 (s), 1370 (m), 1215 (s), 1011

(m), 963 (s) cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 6.94 (1H, br d, J

= 4.6 Hz, H₁), 5.50 (1H, ddd, J = 5.7, 4.6, 0.7 Hz, H₂), 5.46 (1H, ddd,

J = 27.5, 5.7, 2.0 Hz, H₃), 5.03 (1H, ddd, J = 47.4, 8.9, 1.8 Hz, H₄),

5.05−4.94 (1H, m, H₅), 4.64 (1H, ddt, J = 46.7, 10.8, 2.6 Hz, H_6a),

4.61 (1H, ddt, J = 47.7, 10.8, 2.2 Hz, H_6b), 2.11−2.09 (15H, m, 5 ×

CH₃) ppm; ¹H{¹⁹F} NMR (500 MHz, CDCl₃) δ 6.94 (1H, d, J = 4.4

Hz, H₁), 5.50 (1H, dd, J = 5.8, 4.6 Hz, H₂), 5.45 (1H, dd, J = 5.8, 2.1

Hz, H₃), 5.04 (1H, dd, J = 9.0, 2.2 Hz, H₄), 5.00 (1H, dt, J = 8.8, 2.4

Hz, H₅), 4.64 (1H, dd, J = 10.8, 2.6 Hz, H_6a), 4.62 (1H, dd, J = 10.8,

2.4 Hz, H_6b), 2.19−2.09 (15H, m, 5 × CH₃) ppm; ¹³C{¹H} NMR

(126 MHz, CDCl₃) δ 169.7 (CO), 169.6 (CO), 169.5 (CO), 168.1 (2

× CO), 87.2 (dd, J_C−F= 181.1, 6.1 Hz, C₄), 85.9 (C₁), 80.4 (dd, J_C−F

F

_4α(eq)), −121.9 (1F, d, J = 246.1 Hz, F_4β(eq)), −139.5 (1F, d, J =

246.1 Hz, F_4β(ax)), −141.3 (1F, d, J = 245.9 Hz, F_4α(ax)) ppm; ¹⁹F(¹H}

NMR (470 MHz, D₂O) δ −117.6 (1F, d, J = 245.3 Hz, F₄(eq)_α),

−120.0 (1F, d, J = 245.3 Hz, F₄(eq)_β), −137.4 (1F, d, J = 245.3 Hz,

F₄(ax)_β), −138.9 (1F, d, J = 245.3 Hz, F₄(ax)_α) ppm; HRMS (ES+)

for C₆H₁₀F₂NaO₄calcd 207.0439, found 207.0444.

1,2,3-Tri-O-acetyl-4,6-dideoxy-4,4-diﬂuoro-^D-xylo-hexopyrano-

side (6b) and 1,1,2,3,5-Penta-O-acetyl-4,6-dideoxy-4,4-diﬂuoro-^D-

xylo-hexose (6c). A solution of 76 (448 mg, 1.43 mmol) in THF/

H₂O (9:1, 5 mL) was stirred for 5 min, then concentrated in vacuo.

The brown residue was then redissolved in Ac₂O (2.7 mL), and

cooled to 0 °C. concd H₂SO₄(80 μL, 1.43 mmol) was added, and the

reaction warmed to rt and stirred for 48 h. The reaction was diluted

with EtOAc (20 mL) and quenched by the slow addition of satd

NaHCO_3(aq)(20 mL). The phases were separated, and the aqueous

layer was extracted with EtOAc (3 × 20 mL). The combined organic

layers were washed with brine (50 mL), dried (MgSO₄), and

concentrated in vacuo. Puriﬁcation by chromatography (Biotage

Isolera One, 10 g KP-Sil, gradient 0−15% EtOAc/cyclohexane)

aﬀorded ﬁrst 6b as a colorless oil (212 mg, 0.68 mmol, 48%) and then

the peracetylated open chain form 6c as a white powder (41 mg, 0.10

mmol, 7%).

= 174.3, 2.6 Hz, C₆), 70.1 (d, J_C−F= 3.1 Hz, C₂), 68.0 (dd, J_C−F

=

60.6, 18.7 Hz, C₅), 66.7 (d, J_C−F= 17.2 Hz, C₃), 20.7 (CH₃), 20.54 (2

× CH₃), 20.46 (CH₃), 20.4 (CH₃) ppm; ¹⁹F NMR (470 MHz,

CDCl₃) δ −209.4 (1F, br ddd, J = 46.1, 27.2, 7.5 Hz, F₄), −237.7 (1F,

br td, J = 47.2, 25.8 Hz, F₆) ppm; ¹⁹F(¹H} NMR (470 MHz, CDCl₃)

δ −209.5 (1F, d, J = 1.1 Hz, F₄), −237.8 (1F, d, J = 1.1 Hz, F₆) ppm;

HRMS (ES⁺) for C₁₆H₂₂F₂NaO₁₀[M + H]⁺calcd 435.1073 found

435.1076.

4,6-Dideoxy-4,4-diﬂuoro-^D-xylo-hexopyranose (6a). From 6b.

Using general procedure C with 6b (192 mg, 0.52 mmol), puriﬁcation

by chromatography (5% MeOH/EtOAc) aﬀorded 6a as a white

amorphous solid (113 mg, 0.61 mmol, 97%).

From 76. Using general procedure A with 76 (325 mg, 1.04 mmol)

for 21 h, puriﬁcation by chromatography (5% MeOH/CH₂Cl₂) and

further puriﬁcation by recrystallization (Et₂O) aﬀorded 6a as colorless

needles (116 mg, 0.63 mmol, 61%) with <1% TFA (¹⁹F NMR

integration): mp (Et₂O) 135−145 °C; [α]²_D⁴+80.4 (c 0.72, MeOH);

IR (neat) 3347 (br), 2942 (w), 1441 (w), 1246 (w), 1048 (s), 978

Data for 6b: IR (neat) 2999 (w), 1755 (s), 1371 (m), 1205 (s),

1061 (s), 938 (m) cm⁻¹; ¹H NMR (400 MHz, CDCl₃, α/β 87:13) δ

6.32 (1H, dd, J = 3.6, 2.5 Hz, H_1α), 5.75 (1H, dd, J = 8.4, 0.8 Hz,

H_1β), 5.59 (1H, ddd, J = 19.8, 10.7, 4.5 Hz, H_3α), 5.37 (1H, ddd, J =

19.7, 10.2, 5.0 Hz, H_3β), 5.23 (1H, ddd, J = 10.2, 8.3, 1.5 Hz, H_2β),

5.19 (1H, ddd, J = 10.7, 3.7, 1.3 Hz, H_2α), 4.16 (1H, dq, J = 22.3, 6.4

Hz, H_5α), 3.87 (1H, dq, J = 21.2, 6.4 Hz, H_5β), 2.18 (3H, s, COCH_3α),

2.17 (3H, s, COCH_3α), 2.15 (3H, s, COCH_3β), 2.21 (3H, s,

COCH_3β), 2.04 (3H, s, COCH_3β), 2.02 (3H, s, COCH_3α), 1.37 (3H,

d, J = 6.4 Hz, H_6β), 1.33 (3H, d, J = 6.4 Hz, H_6α) ppm; ¹³C{¹H} NMR

(101 MHz, CDCl₃) δ 169.7 (CO_α), 169.6 (CO_β), 169.4 (CO_α), 169.0

(CO_β), 168.9 (CO_β), 168.7 (CO_α), 116.4 (dd, J_C−F= 253.1, 251.6 Hz,

C_4α), 115.9 (dd, J_C−F= 254.6, 252.4 Hz, C_4β), 91.4 (d, J_C−F= 1.5 Hz,

C_1β), 88.9 (C_1α), 71.1 (dd, J_C−F= 30.1, 25.0 Hz, C_5β), 70.4 (dd, J_C−F

= 22.0, 19.1 Hz, C_3β), 69.6 (d, J_C−F= 8.1 Hz, C_2β), 68.6 (d, J_C−F= 7.3

Hz, H_2α), 68.1 (dd, J_C−F= 29.3, 25.0 Hz, C_5α), 67.6 (d, J_C−F= 22.0,

19.1 Hz, C_3α), 20.6 (COCH_3α), 20.7 (COCH_3β), 20.48 (COCH_3α),

20.45 (COCH_3β), 20.38 (COCH_3β), 20.35 (COCH_3α), 11.3 (d, J_C−F

= 5.9 Hz, C_6α) ppm (C_6βobscured by C_6α); ¹⁹F NMR (376 MHz,

CDCl₃) δ −117.2 (1F, br d, J = 249.7 Hz, F_4(eq)α), −119.6 (1F, br dd,

J = 249.7, 4.3 Hz, F_4(eq)β), −133.8 (1F, dt, J = 249.7, 20.8 Hz, F_4(ax)β),

−135.0 (1F, dt, J = 249.7, 20.8 Hz, F_4(ax)α) ppm; ¹⁹F(¹H} NMR (376

MHz, CDCl₃) δ −117.2 (1F, d, J = 249.7 Hz, F_4(eq)α), −119.6 (1F, d,

J = 249.7 Hz, F_4(eq)β), −133.8 (1F, d, J = 249.7 Hz, F_4(ax)α), −135.0

(1F, d, J = 249.7 Hz, F_4(ax)α) ppm; HRMS (ES⁺) for C₁₂H₁₆F₂NaO₇

[M + Na]⁺calcd 333.0756 found 333.0754.

1

(s), 926 (m), 859 (m) cm⁻¹; H NMR (500 MHz, CD₃OD, α/β

60:40) δ 5.09 (1H, t, J = 3.1 Hz, H_1α), 4.55 (1H, dd, J = 7.9, 0.9 Hz,

H_1β), 4.17 (1H, dq, J = 23.6, 6.5 Hz, H_5α), 3.93 (1H, ddd, J = 20.6,

10.0, 6.5 Hz, H_3α), 3.75 (1H, dq, J = 22.2, 6.3 Hz, H_5β), 3.67 (1H,

ddd, J = 20.7, 9.8, 6.6 Hz, H_3β), 3.56 (1H, ddd, J = 10.0, 3.7, 1.6 Hz,

H_2α), 3.23 (1H, ddd, J = 9.8, 7.9, 2.0 Hz, H_2β), 1.26 (3H. br d, J = 6.3

Hz, H_6β), 1.21 (3H, br d, J = 6.5 Hz, H_6α) ppm; ¹H NMR (500 MHz,

D₂O, α/β 39:61) δ 5.11 (1H, br dd, J = 3.8, 2.5 Hz, H_1α), 4.60 (1H,

dd, J = 8.1, 1.0 Hz, H_1β), 4.16 (1H, dq, J = 24.2, 6.5 Hz, H_5α), 3.91

(1H, ddd, J = 20.7, 10.2, 6.2 Hz, H_3α), 3.80 (1H, dq, J = 23.0, 6.3 Hz,

H_5β), 3.75 (1H, ddd, J = 20.8, 10.0, 6.3 Hz, H_3β), 3.59 (1H, ddd, J =

10.2, 3.8, 1.7 Hz, H_2α), 3.29 (1H, ddd, J = 10.0, 8.0, 2.0 Hz, H_2β), 1.16

(3H, d, J = 6.4 Hz, H_6β), 1.13 (3H, d, J = 6.5 Hz, H_6α) ppm; ¹H{¹⁹F}

NMR (500 MHz, CD₃OD) δ 5.09 (1H, d, J = 3.7 Hz, H_1α), 4.55 (1H,

d, J = 7.9 Hz, H_1β), 4.17 (1H, q, J = 6.5 Hz, H_5α), 3.93 (1H, d, J =

10.0 Hz, H_3α), 3.75 (1H, q, J = 6.4 Hz, H_5β), 3.67 (1H, d, J = 9.8 Hz,

H_3β), 3.56 (1H, dd, J = 10.0, 3.7 Hz, H_2α), 3.32 (1H, dd, J = 9.8, 7.9

Hz, H_2β), 1.26 (3H, d, J = 6.4 Hz, H_6β), 1.21 (3H, d, J = 6.5 Hz, H_6α)

1

ppm; H{¹⁹F} NMR (500 MHz, D₂O) δ 5.11 (1H, d, J = 3.7 Hz,

H_1α), 4.60 (1H, d, J = 8.0 Hz, H_1β), 4.16 (1H, q, J = 6.5 Hz, H_5α),

3.91 (1H, d, J = 10.2 Hz, H_3α), 3.80 (1H, q, J = 6.5 Hz, H_5β), 3.75

(1H, d, J = 9.9 Hz, H_3β), 3.59 (1H, dd, J = 10.2, 3.8 Hz, H_2α), 3.29

(1H, dd, J = 9.9, 8.0 Hz, H_2β), 1.16 (3H, d, J = 6.5 Hz, H_6β), 1.13

(3H, d, J = 6.5 Hz, H_6α) ppm; ¹³C{¹H} NMR (126 MHz, CD₃OD) δ

120.1 (dd, J_C−F= 250.7, 248.9 Hz, C_4α), 119.4 (dd, J_C−F= 251.6,

Data for 6c: mp (postcolumn) 114−116 °C; [α]²_D⁵−23.4 (c 0.47,

CHCl₃); IR (neat) 2968 (w), 1759 (s), 1743 (s), 1374 (s), 1127 (s),

1044 (s), 979 (s) cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.86 (1H, d, J

= 5.4 Hz, H₁), 5.70 (1H, dd, J = 5.4, 2.7 Hz, H₂), 5.62−5.50 (1H, m,

7743

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

H₃), 5.09 (1H, ddq, J = 14.4, 9.7, 6.5 Hz, H₅), 2.13 (3H, s, CH₃), 2.11

(3H, s, CH₃), 2.09 (3H, s, CH₃), 2.07 (3H, s, CH₃), 2.06 (3H, s,

CH₃), 1.31 (3H, d, J = 6.5 Hz, H₆) ppm; ¹³C{¹H} NMR (101 MHz,

CDCl₃) δ 169.5 (CO), 169.21 (CO), 169.16 (CO), 168.13 (CO),

168.05 (CO), 119.5 (t, J_C−F= 251.6 Hz, C₄), 86.0 (C₁), 67.3 (C₂),

66.2 (dd, J_C−F= 33.0, 29.3 Hz, C₅), 65.5 (dd, J_C−F= 31.5, 27.9 Hz,

C₃), 20.8 (CH₃), 20.52 (CH₃), 20.49 (CH₃), 20.45 (CH₃), 20.4

(CH₃), 12.1 (t, J_C−F= 2.9 Hz, C₆) ppm; ¹⁹F NMR (376 MHz,

CDCl₃) δ −120.6 (1F, ddd, J = 277.4, 15.6, 10.4 Hz, F_4a), −121.3

(1F, ddd, J = 277.4, 13.9, 10.4 Hz, F_4b) ppm; ¹⁹F(¹H} NMR (376

MHz, CDCl₃) δ −120.6 (1F, d, J = 277.4 Hz, F_4a), −121.3 (1F, d, J =

277.4 Hz, F_4b) ppm; HRMS (ES⁺) for C₁₆H₂₂F₂NaO₁₀[M + H]⁺

calcd 435.1073 found 435.1080.

11.4 Hz, F_6aα), −130.5 (1F, ddd, J = 287.9, 54.9, 10.9 Hz, F_6bβ),

−130.7 (1F, ddd, J = 286.5, 54.7, 12.2 Hz, F_6bα) ppm; ¹⁹F(¹H} NMR

(470 MHz, CD₃OD) δ −128.9 (1F, d, J = 290.0 Hz, F_6aβ), −129.1

(1F, d, J = 289.0 Hz, F_6aα), −132.5 (1F, d, J = 290.0 Hz, F_6bβ), −132.7

(1F, d, J = 289.0 Hz, F_6bα) ppm; ¹⁹F(¹H} NMR (470 MHz, D₂O) δ

−129.8 (1F, d, J = 287.9 Hz, F_6aβ), −130.1 (1F, d, J = 286.5 Hz, F_6aα),

−130.5 (1F, d, J = 287.9 Hz, F_6bβ), −130.8 (1F, d, J = 286.5 Hz, F_6bα

)

ppm; HRMS (ES-) for C₆H₉F₂O₄[M − H]⁻calcd 183.0474, found

183.0475.

1,2,3-Tri-O-acetyl-4,6-dideoxy-6,6-diﬂuoro-^D-xylo-hexopyrano-

side (7b). A solution of 80 (1.15 g, 3.68 mmol) in TFA/H₂O (9:1, 12

mL) was stirred for 5 min and then concentrated in vacuo. The

residue was redissolved in Ac₂O (6.95 mL) and cooled to 0 °C.

Concentrated H₂SO₄(0.20 mL, 3.68 mmol) was added, and then the

reaction was warmed to rt and stirred for 24 h. The solution was

diluted with EtOAc (30 mL) and quenched by the slow addition of

satd NaHCO_3(aq)(30 mL). The phases were separated, and the

aqueous layer was extracted with EtOAc (3 × 30 mL). The combined

organic phases were washed with brine (100 mL), dried (MgSO₄),

and concentrated in vacuo. Puriﬁcation by chromatography (Biotage

Isolera One, 20% EtOAc/cyclohexane) aﬀorded 7b as a colorless oil

(809 mg, 2.61 mmol, 71%): IR (neat) 2971 (w), 1742 (s), 1370 (m),

4,6-Dideoxy-6,6-diﬂuoro-^D-xylo-hexopyranose (7a). From 7b.

Using general procedure C with 7b (726 mg, 2.34 mmol), puriﬁcation

by chromatography (8% MeOH/CH₂Cl₂) aﬀorded 7a as an oﬀ-white

powder (257 mg, 1.40 mmol, 60%).

From 80. Using general procedure A with 80 (280 mg, 0.90 mmol)

for 3 h, puriﬁcation by chromatography (8−10% MeOH/CH₂Cl₂)

aﬀorded 7a as a colorless solid (85 mg, 0.46 mmol, 51%): mp

(postcolumn)118−119 °C; [α]²_D⁵+46.7 (c 0.61, MeOH); IR (neat)

3300 (br), 2941 (w), 1428 (w), 1025 (s), 993 (s), 861 (m) cm⁻¹; ¹H

NMR (500 MHz, CD₃OD, α/β 56:44) δ 5.79 (1H, td, J = 55.6, 3.8

Hz, H_6β), 5.75 (1H, td, J = 55.7, 3.7 Hz, H_6α), 5.17 (1H, d, J = 3.6 Hz,

H_1α), 4.46 (1H, d, J = 7.7 Hz, H_1β), 4.16 (1H, br tddd, J = 12.0, 10.0,

3.5, 2.6 Hz, H_5α), 3.89 (1H, ddd, J = 11.4, 9.4, 5.1 Hz, H_3α), 3.75 (1H,

br ddddd, J = 12.0, 10.7, 10.4, 3.8, 2.2 Hz, H_5β), 3.61 (1H, ddd, J =

11.5, 9.1, 5.1 Hz, H_3β), 3.29 (1H, dd, J = 9.4, 3.6 Hz, H_2α), 3.06 (1H,

dd, J = 9.1, 7.7 Hz, H_2β), 2.00 (1H, br dd, J = 11.9, 4.6 Hz, H_4α(eq)),

1.99 (1H, ddt, J = 12.7, 5.0, 1.7 Hz, H_4β(eq)), 1.50 (1H, app q, J = 12.1

1

1210 (s), 1057 (s), 917 (s) cm⁻¹; H NMR (400 MHz, CDCl₃, α/β

85:15) δ 6.38 (1H, d, J = 3.6 Hz, H_1α), 5.81 (1H, ddd, J = 56.0, 54.5,

3.4 Hz, H_6β), 5.75 (1H, ddd, J = 56.0, 54.4, 3.4 Hz, H_6α), 5.68 (1H, d,

J = 7.6 Hz, H_1β), 5.32 (1H, ddd, J = 11.4, 10.4, 5.3 Hz, H_3α), 5.05

(1H, dd, J = 10.3, 3.6 Hz, H_2α), 4.23−4.11 (1H, m H_5α), 3.97−3.85

(1H, m, H_5β), 2.35 (1H, ddd, J = 12.7, 5.1, 2.4 Hz, H_4(eq)α), 2.33−

α

β

2.26 (1H, m, H_4(eq)β), 2.17 (3H, s, OCH₃_β), 2.12 (3H, s, OCH₃_β),

α

2.07 (3H, s, OCH₃), 2.06 (3H, s, OCH₃), 2.06 (3H, s, OCH₃),

α

1

2.04 (3H, s, OCH₃), 1.78 (1H, app q, J = 12.5 Hz, H_4(ax)α) (H_2β,H_3β,

Hz, H_4β(ax)), 1.46 (1H, app q, J = 12.1 Hz, H_4α(ax)) ppm; H NMR

H_4(ax)βobscured by major anomer) ppm; ¹³C NMR (101 MHz,

(500 MHz, D₂O, α/β 39:61) δ 5.780 (1H, td, J = 54.8, 3.3 Hz, H_6β),

5.776 (1H, td, J = 54.8, 3.1 Hz, H_6α), 5.17 (1H, d, J = 3.7 Hz, H_1α),

4.49 (1H, d, J = 7.9 Hz, H_1β), 4.14 (1H, app qt, J = 12.0, 2.6 Hz, H_5α),

3.83 (1H, ddd, J = 11.4, 9.7, 5.2 Hz, H_3α), 3.80 (1H, tddd, J = 11.8,

10.9, 3.1, 2.2 Hz, H_5β), 3.63 (1H, ddd, J = 11.4, 9.3, 5.2 Hz, H_3β), 3.35

(1H, dd, J = 9.8, 3.7 Hz, H_2α), 3.05 (1H, dd, J = 9.3, 7.9 Hz, H_2β),

2.00 (1H, br ddd, J = 12.7, 5.1, 2.4 Hz, H_4(eq)α), 1.98 (1H, br ddd, J =

12.6, 5.2, 2.0 Hz, H_4(eq)β), 1.44 (1H, dt, J = 12.7, 11.8 Hz, H_4(ax)β),

CDCl₃) δ 170.2 (CO_α), 169.9 (CO_α), 168.8 (CO_α), 113.8 (dd, J_C−F

=

245.0, 242.1 Hz, C_6α), 92.0 (C_1β), 89.8 (C_1α), 70.8 (C_2β), 69.9 (C_2α),

69.7 (C_3β), 68.9 (dd, J_C−F= 28.6, 26.4 Hz, H_5α), 66.5 (C_3α), 28.3 (dd,

α

J_C−F= 4.4, 2.9 Hz, C_4α), 20.9 (OCH₃), 20.82 (OCH₃), 20.76

β

α

(OCH₃), 20.6 (OCH₃), 20.5 (OCH₃) (C_5β, C_4βand one OCH₃

unresolved) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −127.1 (1F, ddd, J

= 293.0, 53.8, 6.9 Hz, F_6aβ), −127.3 (1F, ddd, J = 293.0, 55.5, 8.7 Hz,

F_6aα), −132.2 (1F, ddd, J = 293.0, 55.5, 12.1 Hz, F_6bβ), −132.6 (1F,

ddd, J = 293.0, 55.5, 13.9 Hz, F_6bα) ppm; ¹⁹F(¹H} NMR (376 MHz,

CDCl₃) δ −127.2 (1F, d, J = 293.0 Hz, F_6aβ), −127.4 (1F, d, J = 293.0

Hz, F_6aα), −132.2 (1F, d, J = 293.0 Hz, F_6bβ), −132.6 (1F, d, J = 293.0

Hz, F_6bα) ppm; HRMS (ES⁺) for C₁₂H₁₆F₂NaO₇[M + Na]⁺calcd

333.0756, found 333.0753.

1

1.43 (1H, td, J = 12.5, 11.6 Hz, H_4(ax)α) ppm; H{¹⁹F} NMR (500

MHz, CD₃OD) δ 5.80 (1H, d, J = 3.8 Hz, H_6β), 5.75 (1H, d, J = 3.8

Hz, H_6α), 5.17 (1H, d, J = 3.6 Hz, H_1α), 4.46 (1H, d, J = 7.7 Hz, H_1β),

4.16 (1H, dddd, J = 12.3, 3.6, 2.4, 0.5 Hz, H_5α), 3.89 (1H, ddd, J =

11.4, 9.4, 5.1 Hz, H_3α), 3.75 (1H, ddd, J = 12.0, 3.8, 2.2 Hz, H_5β), 3.61

(1H, ddd, J = 11.5, 9.1, 5.1 Hz, H_3β), 3.29 (1H, dd, J = 9.4, 3.6 Hz,

H_2α), 3.06 (1H, dd, J = 9.1, 7.7 Hz, H_2β), 1.995 (1H, br ddd, J = 12.5,

5.1, 2.6 Hz, H_4α(eq)), 1.985 (1H, br ddd, J = 12.5, 5.1, 2.2 Hz, H_4β(eq)),

1.50 (1H, app q, J = 12.1 Hz, H_4β(ax)), 1.46 (1H, app q, J = 12.1 Hz,

H_4α(ax)) ppm; ¹H{¹⁹F} NMR (500 MHz, D₂O) δ 5.783 (1H, d, J = 3.2

Hz, H_6β), 5.779 (1H, d, J = 2.7 Hz, H_6α), 5.17 (1H, d, J = 3.7 Hz,

H_1α), 4.49 (1H, d, J = 7.9 Hz, H_1β), 4.14 (1H, dt, J = 12.3, 2.7 Hz,

H_5α), 3.83 (1H, ddd, J = 11.4, 9.8, 5.1 Hz, H_3α), 3.80 (1H, ddd, J =

11.8, 3.1, 2.2 Hz, H_5β), 3.63 (1H, ddd, J = 11.5, 9.3, 5.2 Hz, H_3β), 3.35

(1H, dd, J = 9.7, 3.7 Hz, H_2α), 3.05 (1H, dd, J = 9.2, 8.0 Hz, H_2β),

2.00 (1H, ddd, J = 12.7, 4.9, 2.2 Hz, H_4(eq)α), 1.98 (1H, ddd, J = 12.8,

5.1, 2.1 Hz, H_4(eq)β), 1.44 (1H, dt, J = 12.6, 12.0 Hz, H_4(ax)β), 1.42

(1H, td, J = 12.4, 11.8 Hz, H_4(ax)α) ppm; ¹³C{¹H} NMR (101 MHz,

CD₃OD) δ 117.1 (t, J_C−F= 241.2 Hz, C_6α), 116.5 (t, J_C−F= 241.5 Hz,

Methyl 4,6-Dideoxy-6-ﬂuoro-α-^D-xylo-hexopyranoside (10). This

is a known compound;⁵⁸however, no characterization data have been

described. To a solution of 60 (2.37 g, 11.0 mmol) in toluene (80

mL) was added Bu₃SnH (7.40 mL, 27.5 mmol) and AIBN (200 mg,

0.88 mmol). The reaction mixture was reﬂuxed at 115 °C for 16 h and

then concentrated in vacuo to aﬀord a yellow oil. Puriﬁcation by

chromatography (10% K₂CO₃/silica,¹¹⁸10% MeOH/CH₂Cl₂)

aﬀorded 10 as an oﬀ-white powder (1.75 g, 9.71 mmol, 88%): mp

(postcolumn) 104−106 °C; [α]²_D⁴+157.6 (c 0.49, MeOH); IR (neat)

3300 (br), 2941 (w), 1430 (w), 1118 (m), 1026 (s), 927 (m) cm⁻¹;

¹H NMR (400 MHz, CDCl₃) δ 4.84 (1H, d, J = 3.9 Hz, H₁), 4.45

(1H, ddd, J = 47.1, 9.9, 3.8 Hz, H_6a), 4.41 (1H, ddd, J = 47.6, 9.9, 5.1

Hz, H_6b), 4.02 (1H, ddddd, J = 20.8, 12.0, 5.1, 3.6, 2.5 Hz, H₅), 3.89

(1H, dddd, J = 11.5, 9.3, 5.1, 2.1 Hz, H₃), 3.44 (3H, s, OCH₃), 3.42

(1H, td, J = 9.8, 3.9 Hz, H₂), 2.52 (1H, d, J = 2.5 Hz, 3-OH), 2.09

(1H, d, J = 10.3 Hz, 2-OH), 1.98 (1H, ddd, J = 12.8, 5.1, 2.1 Hz,

H_4(eq)), 1.53 (1H, app q, J = 12.2 Hz, H_4(ax)) ppm; ¹³C{¹H} NMR

(101 MHz, CDCl₃) δ 99.7 (C₁), 84.6 (d, J_C−F= 173.1 Hz, C₆), 74.2

(C₂), 68.7 (C₃), 67.0 (d, J_C−F= 20.5 Hz, C₅), 55.5 (OCH₃), 32.9 (d,

J_C−F= 6.6 Hz, C₄) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −228.4

(ddd, J = 47.6, 47.2, 20.8 Hz, F₆) ppm; ¹⁹F(¹H} NMR (376 MHz,

CDCl₃) δ −228.4 (s, F₆) ppm; HRMS (ES⁺) C₇H₁₃FNaO₄[M +

Na]⁺calcd 203.0690 found 203.0691.

C_6β), 98.8 (C_1β), 94.8 (C_1α), 78.0 (C_2β), 75.5 (C_2α), 72.3 (t, J_C−F

=

25.9 Hz, C_5β), 71.7 (C_3β), 68.2 (t, J_C−F= 25.8 Hz, C_5α), 68.0 (C_3α),

33.1 (t, J_C−F= 3.1 Hz, C_4α), 33.0 (t, J_C−F= 3.0 Hz, C_4β) ppm;

¹³C{¹H} NMR (126 MHz, D₂O) δ 115.0 (t, J_C−F= 241.2 Hz, C_6α),

114.4 (t, J_C−F= 241.4 Hz, C_6β), 96.4 (C_1β), 92.9 (C_1α), 75.7 (C_2β),

72.9 (C_2α), 70.5 (t, J_C−F= 24.6 Hz, C_5β), 69.7 (C_3β), 66.9 (t, J_C−F

=

24.0 Hz, C_5α), 66.2 (C_3α), 31.1−31.0 (m, C_4α, C_4β) ppm; ¹⁹F NMR

(470 MHz, CD₃OD) δ −128.8 (1F, ddd, J = 290.0, 55.4, 10.0 Hz,

F_6aβ), −129.0 (1F, ddd, J = 289.0, 55.7, 10.4 Hz, F_6aα), −132.5 (1F,

dddd, J = 290.0, 55.8, 11.1, 1.1 Hz, F_6bβ), −132.6 (1F, ddd, J = 289.0,

55.9, 12.0 Hz, H_6bα) ppm; ¹⁹F NMR (470 MHz, D₂O) δ −129.7 (1F,

ddd, J = 287.9, 54.7, 11.8 Hz, F_6aβ), −130.0 (1F, ddd, J = 286.5, 54.7,

Methyl 4-Deoxy-4-ﬂuoro-α-^D-fucopyranoside (D-19). From 62. A

solution of 62 (414 mg, 1.18 mmol) in THF (6 mL) was cooled to 0

7744

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

°C. A solution of LiAlH₄(1 M in THF, 4.27 mL, 4.72 mmol) was

added dropwise, turning the light brown solution colorless. The

reaction was heated to 80 °C and stirred for 3 h. The reaction was

cooled to rt and quenched by the slow addition of satd Rochelle’s

salt_(aq)(10 mL). The emulsion was diluted with EtOAc (10 mL) and

stirred for 2 h. The phases were separated, and the aqueous phase was

extracted with EtOAc (3 × 10 mL). The combined organic layers

were washed with brine (50 mL), dried (MgSO₄), and concentrated

in vacuo. Puriﬁcation by chromatography (50−100% EtOAc/hexane

then 2% MeOH/EtOAc) aﬀorded ﬁrst 63 as a colorless oil (33 mg,

0.19 mmol, 16%) followed by ^D-19 as a white solid (7 mg, 0.04 mmol,

4%).

From 65. to a solution of 65 (1.78 g, 8.27 mmol) in toluene (40

mL) was added AIBN (543 mg, 3.31 mmol) and Bu₃SnH (4.45 mL,

16.5 mmol). The yellow solution was heated to 120 °C and stirred for

16 h, before being cooled to rt. The mixture was concentrated in

vacuo and the yellow residue dissolved in MeCN (50 mL). The

organic phase was washed with hexane (3 × 50 mL) and then

concentrated in vacuo to yield an oﬀ-white solid. Puriﬁcation by

chromatography (10% acetone/hexane) aﬀorded ^D-19 as a white solid

(1.04 g, 5.77 mmol, 70%): mp (postcolumn) 141−143 °C; [α]_D²⁵

+165.6 (c 0.40, CHCl₃), lit. (enantiomer)⁶²[α]_D²⁵−191.2 (c 1.0,

MeOH); IR (neat) 3472 (m), 3428 (m), 2934 (w), 1452 (w), 1345

(m), 1105 (m), 1017 (s), 993 (s), 956 (s) cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ 4.81 (1H, d, J = 3.2 Hz, H₁), 4.59 (1H, dd, J = 50.6, 2.7 Hz,

H₄), 3.94 (1H, dq, J = 29.7, 6.7 Hz, H₅), 3.88−3.78 (2H, m, H₂, H₃),

3.44 (3H, s, OCH₃), 2.58 (1H, s, 3-OH), 2.27 (1H, d, J = 7.8 Hz, 2-

OH), 1.33 (3H, d, J = 6.7 Hz, H₆) ppm; ¹³C{¹H} NMR (101 MHz,

F₄), −231.0 (1F, s, F₆) ppm. These NMR data correspond to the data

in the literature.^68,69

Methyl 4,6-Dideoxy-4,6-diﬂuoro-α-D-glucopyranoside (35).

From 39. To a solution of 39 (6.52 g, 16.0 mmol) in MeOH/

CH₂Cl₂(1:1, 100 mL) was added NaOMe in MeOH (25% w/w, 10

drops). The mixture was stirred for 16 h. The reaction was neutralized

by the addition of 4 M HCl_(aq)(pH 7). The solution was

concentrated in vacuo to aﬀord a yellow oil. Puriﬁcation by

chromatography (3−8% MeOH/CH₂Cl₂) aﬀorded 35 as a white

crystalline solid (2.24 g, 11.3 mmol, 71%).

From 74. A solution of 74 (859 mg, 2.75 mmol) in TFA/H₂O

(9:1, 10 mL) was stirred for 5 min at rt and then concentrated in

vacuo. Puriﬁcation by chromatography (5% MeOH/CH₂Cl₂) aﬀorded

35 as a brown oil (414 mg, 2.09 mmol, 76%, including 8 mol % of

TFA): mp 80−83 °C, lit.⁷⁷93−94 °C (EtOAc/hexane); [α]²_D¹+142.2

(c 0.23, CHCl₃), lit.⁷⁷[α]_D+142.0 (c 1.02 CHCl₃); IR (neat) 3379

1

(br), 2919 (w), 1456 (w), 1015 (s), 900 (m) cm⁻¹; H NMR (400

MHz, acetone-d₆) δ 4.70 (1H, t, J = 3.5 Hz, H₁), 4.61 (3H, m, H₆+

OH, a coupling constant of 49.8 Hz [doublet] was observed for H₆),

4.25 (1H, ddd, J = 51.2, 10.1, 8.7 Hz, H₄), 3.78−4.02 (3H, m, H₃, H₅,

1

OH), 3.40−3.46 (1H, m, H₂), 3.38 (3H, s, OCH₃) ppm; H NMR

(400 MHz CDCl₃) δ 4.82 (1H, t, J = 3.6 Hz, H₁), 4.65 (2H, dm, a

coupling constant of 47.2 Hz [doublet] was observed, H₆), 4.38 (1H,

ddd, J = 51.0, 10.3, 8.7 Hz, H₄), 3.99 (1H, dt, J = 15.7, 9.1 Hz, H₃),

3.89 (1H, ddq, J = 26.0, 10.0, 3.2 Hz, H₅), 3.59 (1H, td, J = 9.1, 3.6

Hz, H₂), 3.48 (3H, s, OCH₃), 2.82 (1H, br s, 3-OH), 2.28 (1H, br d, J

= 9.1 Hz, 2-OH) ppm; ¹³C{¹H} NMR (101 MHz, acetone-d₆) δ

100.9 (d, J_C−F= 1.5 Hz, C₁), 89.8 (dd, J_C−F= 182.3, 8.1 Hz, C₄), 82.5

(d, J_C−F= 172.0 Hz, C₆), 73.04 (C₂), 73.00 (d, J_C−F= 25.3 Hz, C₃),

69.1 (dd, J_C−F= 24.6, 19.1 Hz, C₅), 55.7 (OCH₃) ppm; ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 99.0 (C₁), 87.9 (dd, J_C−F= 183.4, 7.3 Hz,

C₄), 81.0 (d, J_C−F= 174.6 Hz, C₆), 72.9 (d, J_C−F= 17.6 Hz, C₃), 71.9

(d, J_C−F= 8.1 Hz, C₂), 68.2 (dd, J_C−F= 23.5, 18.3 Hz, C₅), 55.8

(OCH₃) ppm; ¹⁹F NMR (376 MHz, acetone-d₆) δ −198.3 (1F, br dd,

CDCl₃) δ 99.4 (C₁), 91.8 (d, J_C−F= 181.9 Hz,C₄), 70.3 (d, J_C−F

=

18.3 Hz, C₃), 69.5 (d, J_C−F= 2.2 Hz, C₂), 65.2 (d, J_C−F= 19.1 Hz,

C₅), 55.7 (OCH₃), 15.8 (d, J_C−F= 5.1 Hz, C₆) ppm; ¹⁹F NMR (376

MHz, CDCl₃), δ −221.9 (dt, J = 50.6, 29.7 Hz, F₄) ppm; ¹⁹F(¹H}

NMR (346 MHz, CDCl₃) δ −221.8 (s, F₄) ppm; HRMS (ES⁺) for

C₇H₁₃FNaO₄[M + Na]⁺calcd 203.0690 found 203.0688. Physical

and spectroscopic data are consistent with the enantiomer.⁶²

J = 51.2, 16.5 Hz, F₄), −235.5 (1F, td, J = 48.2, 26.5 Hz, F₆) ppm; ¹⁹

F

Methyl 4,6-Dideoxy-4,6-diﬂuoro-α-D-galactopyranoside (28). A

suspension of 27 (5.00 g, 25.7 mmol) in CH₂Cl₂(25 mL) under Ar

was cooled to 0 °C. DAST (20.4 mL, 154.2 mmol) was added

dropwise. The solution was allowed to slowly warm to rt and stirred

for 90 h. The solution was cooled to 0 °C and quenched by the slow

addition of MeOH (60 mL) and addition of silica powder (6 mL).

The mixture was stirred for 30 min over which time it warmed to rt.

The mixture was concentrated in vacuo. Puriﬁcation by chromatog-

raphy (10−25% acetone/CH₂Cl₂) aﬀorded 28 as a white powder

(2.33 g, 11.76 mmol, 46%). [α]²_D¹+166.6(c 0.53, EtOH), lit.⁶⁹[α]²_D²

+282.9 (EtOH); IR (neat) 3357 (br), 2953 (w), 1350 (w), 1191 (m),

1097 (s), 1056 (s), 913 (s) cm⁻¹; ¹H NMR (400 MHz, acetone-d₆) δ

4.81 (1H, br dd, J = 51.2, 2.7 Hz, H₄), 4.76 (1H, d, J = 3.2 Hz, H₁),

4.62 (1H, ddd, J = 46.0, 9.5, 4.9 Hz, H_6a), 4.52 (1H, dddd, J = 47.8,

9.5, 7.1, 1.1 Hz, H_6b), 4.21 (1H, d, J = 4.2 Hz, 3-OH), 4.09 (1H, br

dddd, J = 30.4, 14.4, 7.1, 4.8 Hz, H₅), 3.85 (1H, dddd, J = 29.0, 10.0,

6.1, 2.7 Hz, H₃), 3.77−3.70 (2H, m, H₂and 2-OH), 3.38 (3H, s,

OCH₃) ppm; ¹H NMR (400 MHz, CDCl₃) δ 4.89 (1H, d, J = 3.3 Hz,

H₁), 4.85 (1H, dd, J = 50.9, 2.3 Hz, H₄), 4.63 (1H, ddd, J = 46.1, 9.5,

6.0 Hz, H_6a), 4.58 (1H, dddd, J = 46.8, 9.5, 6.5, 1.0 Hz, H_6b), 4.07

(1H, ddt, J = 30.1, 12.6, 6.5 Hz, H₆), 3.94−3.78 (2H, m, H₂and H₃),

3.48 (3H, s, OCH₃), 2.43 (1H, br s, 2-OH or 3-OH), 2.13 (1H, br d, J

= 6.4 Hz, 2-OH or 3-OH) ppm; ¹³C{¹H} NMR (101 MHz, acetone-

NMR (376 MHz, CDCl₃) δ −199.2 (1F, br dd, J = 51.0, 15.7 Hz, F₄),

−235.5 (1F, td, J = 47.2 26.0 Hz, F₆) ppm; ¹⁹F(¹H} NMR (376 MHz,

acetone-d₆) δ −198.3 (1F, s, F₄), −235.5 (1F, s, F₆) ppm; HRMS

(ES⁺) for C₇H₁₂F₂NaO₄[M + Na]⁺calcd 221.0596 found 221.0594.

NMR data in acetone d₆correspond to literature data.⁷⁷

Methyl 2,3-Di-O-benzoyl-4,6-dideoxy-4,6-diﬂuoro-α-D-glucopyr-

anoside (39). A suspension of 37⁹³(8.90 g, 22.1 mmol) in CH₂Cl₂

(10 mL) was cooled to −40 °C. DAST (25.5 mL, 193 mmol) was

added, and the mixture was stirred for 24 h, over which time it was

allowed to reach rt. The mixture was diluted with CH₂Cl₂(70 mL)

and cooled to 0 °C. The reaction was quenched by the addition of

MeOH (20 mL), warmed to rt, and stirred for 2 h. The solution was

washed with satd NaHCO_3(aq)(100 mL), H₂O (100 mL), and brine

(100 mL), dried (MgSO₄), and concentrated in vacuo to aﬀord a

yellow oil. Puriﬁcation by chromatography (0−20% EtOAc/hexane)

aﬀorded 39 as a colorless foam (6.84 g, 16.8 mmol, 76%): [α]_D²¹

+154.6 (c 0.53, CHCl₃, lit.⁷⁵[α]_D²²+29.4, c 2.0, CHCl₃);IR (neat)

2958 (w), 1723 (s), 1602 (w), 1452 (m), 1270 (s), 1025 (s), 918 (m)

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.05−7.95 (4H, m, Ar_H),

7.57−7.49 (2H, m, Ar_H), 7.44−7.35 (4H, m, Ar_H), 6.11 (1H, dt, J =

14.4, 9.3 Hz, H₃), 5.21−5.14 (2H, m, H₁, H₂), 4.77 (1H, ddd, J =

50.7, 9.9, 9.1 Hz, H₄), 4.83−4.64 (2H, m, H₆), 4.20−4.05 (1H, m,

H₅), 3.47 (3H, s, OCH₃) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

165.8 (CO), 165.6 (CO), 133.5 (Ar_C), 133.3 (Ar_C), 129.9 (Ar_C),

129.8 (Ar_C), 129.3 (Ar_C), 128.9 (Ar_C), 128.5 (Ar_C), 128.4 (Ar_C), 97.0

(C₁), 86.0 (dd, J_C−F= 187.4, 7.7 Hz, C₄), 80.8 (d, J_C−F= 175.3 Hz,

C₆), 71.3 (d, J_C−F= 7.3 Hz, C₂), 70.4 (d, J_C−F= 20.5 Hz, C₃), 68.0

(dd, J_C−F= 23.1, 18.7 Hz, C₅), 55.8 (OCH₃) ppm; ¹⁹F NMR (376

MHz, CDCl₃) δ −197.9 (1F, br dd, J = 49.4, 17.7 Hz, H₄), −235.9

(1F, ddd, J = 48.6, 46.8, 26.0 Hz, F₆) ppm; ¹⁹F(¹H} NMR (376 MHz,

CDCl₃) δ −198.0 (1F, s, F₄), −235.9 (1F, s, F₆) ppm; LRMS (ESI+)

407.4 [M + H]⁺. NMR data correspond to literature data.⁷⁵

d₆) δ 100.7 (C₁), 90.3 (dd, J_C−F= 179.7, 6.6 Hz, C₄), 82.2 (dd, J_C−F

=

167.3, 6.6 Hz, C₆), 69.6 (d, J_C−F= 2.9 Hz, C₂), 69.2 (d, J_C−F= 17.6

Hz, C₃), 68.5 (33, J_C−F= 22.0, 17.6 Hz, C₅), 55.2 (OCH₃) ppm;

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 99.3 (C₁), 88.6 (dd, J_C−F

181.6, 5.5 Hz, C₄), 81.0 (dd, J_C−F= 169.5, 6.6 Hz, C₆), 69.8 (d, J_C−F

=

17.6 Hz, C₃), 69.6 (d, J_C−F= 2.9 Hz, C₂), 67.9 (dd, J_C−F= 23.8, 18.0

Hz, C₅), 55.9 (OCH₃) ppm; ¹⁹F NMR (376 MHz, acetone-d₆) δ

−220.0 (1F, dtt, J = 20.3, 29.5, 5.2 Hz, F₄), −230.2 (1F, td, J = 46.8,

15.6 Hz, F₆) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −221.3 (1F, dt, J =

51.2, 29.9 Hz, F₄), −231.2 (1F, td, J = 46.8, 12.1 Hz, F₆) ppm;

¹⁹F(¹H} NMR (376 MHz, acetone-d₆) δ −219.9 (1F, s, F₄), −230.1

(1F, s, F₆) ppm; ¹⁹F(¹H} NMR (376 MHz, CDCl₃) δ −221.2 (1F, s,

Methyl 6-O-tert-Butyldimethylsilyl-2,3-O-((2′R,3′R)-2′,3′-dime-

thoxybutane-2′,3′-diyl)-α-^D-galactopyranoside (47). To a solution

of 46⁸⁰(8.80 g, 28.5 mmol) in DMF (100 mL) was added imidazole

7745

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(85.6 mmol, 5.82 g). The solution was cooled to 0 °C, and TBDMSCl

(4.73 g, 31.4 mmol) was added portionwise. The mixture was stirred

for 15 min at this temperature, warmed to rt, and stirred for 1 h. The

reaction was quenched by the addition of H₂O (4 mL). The mixture

was extracted with Et₂O and pentane (9:1, 2 × 100 mL). The

combined organic phases were washed with H₂O and brine, dried

(MgSO₄), and concentrated in vacuo. Puriﬁcation by chromatography

(20−30% EtOAc/petroleum ether) aﬀorded 47 as a colorless solid

(10.1 g, 23.9 mmol, 84%): mp (postcolumn) 112−114 °C; [α]_D²⁷

−39.3 (c 0.36, CHCl₃); IR (neat) 3474 (br, w), 2951 (m), 2856 (w),

1.52 (1H, app q, J = 11.9 Hz, H₄(ax)), 1.35 (3H, s, C(CH₃)^BDA), 1.30

(C(CH₃)^BDA), 0.90 (9H, s, C(CH₃)₃), 0.072 (3H, s, SI(CH₃)), 0.068

(3H, s, Si(CH₃)) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 100.2

(C(CH₃)^BDA), 99.5 (C(CH₃)^BDA), 98.4 (C₁), 71.0 (C₂), 69.1 (C₅),

65.9 (C₆), 63.7 (C₃), 54.8 (OCH₃), 47.9 (OCH₃^BDA), 47.8

(OCH₃^BDA), 32.5 (C₄), 25.9 (C(CH₃)₃), 18.4 (C(CH₃)₃), 17.9

(C(CH₃)^BDA), 17.8 (C(CH₃)^BDA), −5.3 (Si(CH₃)), −5.4 (Si(CH₃))

ppm; HRMS (ES⁺) for C₁₉H₃₈NaO₇Si [M + Na]⁺calcd 429.2279

found 429.2285.

Mixture of Methyl 4-O-Benzoyl-2,3-O-((2′R,3′R)-2′,3′-dimethox-

ybutane-2′,3′-diyl)-α-^D-fucopyranoside (52) and Methyl 6-O-

Benzoyl-4-deoxy-2,3-O-((2′S,3′S)-2′,3′-dimethoxybutane-2′,3′-

diyl)-α-^D-xylo-hexopyranoside (53). To a solution of 50⁸²(7.00 g,

17.7 mmol) in chlorobenzene (26.5 mL) were added triisopropylsi-

lane thiol (0.190 mL, 0.883 mmol) and di-tert-butyl peroxide (1.61

mL, 8.83 mmol). The reaction mixture was heated at reﬂux for 1.5 h

before being cooled down to rt. The mixture was concentrated in

vacuo. Puriﬁcation by chromatography (40% Et₂O/petroleum ether)

aﬀorded an inseparable mixture of 52 and 53 as a colorless oil (6.39 g,

16.1 mmol, 91%, 52/53 42:58): HRMS (ES+) for C₂₀H₂₈NaO₈,[M +

Na]⁺calcd 419.1676, found 419.1676.

1

1472 (w), 1376 (w), 1255 (w), 1119 (s), 1037 (s) cm⁻¹; H NMR

(400 MHz, CDCl₃) δ 4.80 (1H, d, J = 3.6 Hz, H₁), 4.21 (1H, dd, J =

10.3, 3.6 Hz, H₂), 4.06 (1H, dd, J = 10.3, 3.1 Hz, H₃), 4.04−4.01 (1H,

m, H₄), 3.90 (1H, dd, J = 12.4, 8.4 Hz, H_6a), 3.84−3.77 (2H, m, H₅,

H_6b), 3.42 (3H, s, OCH₃), 3.27 (3H, s, OCH₃^BDA), 3.25 (3H, s,

OCH₃^BDA), 2.56 (1H, t, J = 1.1 Hz, 4-OH), 1.34 (3H, s, C(CH₃)^BDA),

1.32 (3H, s, C(CH₃)^BDA), 0.91 (9H, s, C(CH₃)₃), 0.10 (6H, s,

Si(CH₃)₂) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 100.11

(C(CH₃)^BDA), 100.09 (C(CH₃)^BDA), 98.3 (C₁), 70.7 (C₅), 67.9 (C₄),

66.5 (C₃), 65.2 (C₂), 62.5 (C₆), 55.0 (OCH₃), 47.92 (OCH₃^BDA),

47.89 (OCH₃^BDA), 25.9 (C(CH₃)₃), 18.3 (C(CH₃)₃), 17.8 (C-

(CH₃)^BDA), 17.7 (C(CH₃)^BDA), −5.5 (Si(CH₃)₂) ppm; HRMS (ES⁺)

for C₁₉H₃₈NaO₈Si [M + Na]⁺calcd 445.2228 found 445.2240.

Methyl 6-O-tert-Butyldimethylsilyl-4-O-phenoxythiocarbonyl-

2,3-O-((2′R,3′R)-2′,3′-dimethoxybutane-2′,3′-diyl]-α-^D-galactopyr-

anoside (48). To a solution of 47 (9.16 g, 21.7 mmol) and DMAP

(6.62 g, 54.3 mmol) in MeCN (12 mL) was added O-phenyl

chlorothionoformate (3.90 mL, 28.0 mmol). The mixture was stirred

for 15 h. The mixture was concentrated in vacuo, and the residue was

redissolved in Et₂O (150 mL) and washed with H₂O (3 × 100 mL).

The organic layer was dried (MgSO₄) and concentrated in vacuo.

Puriﬁcation by chromatography (10−15% EtOAc/petroleum ether)

aﬀorded 48 as a colorless foam (10.3 g, 18.4 mmol, 85%): [α]²_D⁷−13.6

(c 0.44, CHCl₃); IR (neat) 2951 (w), 2856 (w), 1490 (w), 1369 (w),

1

Selected data for 52: H NMR (400 MHz, CDCl₃) δ 8.14−8.09

(2H, m, Ar_H), 7.61−7.55 (1H, m, Ar_H), 7.51−7.42 (2H, m, Ar_H), 5.40

(1H, dd, J = 3.1, 1.0 Hz, H₄), 4.86 (1H, d, J = 3.3 Hz, H₁), 4.33 (1H,

dd, J = 10.6, 3.3 Hz, H₂), 4.28 (1H, dd, J = 10.6, 3.3 Hz, H₃), 4.25−

4.14 (1H, m, H₅), 3.46 (3H, s, OCH₃), 3.29 (3H, s, OCH₃^BDA), 3.26

(3H, s, OCH₃^BDA), 1.33 (3H, s, (C(CH₃)^BDA), 1.21 (3H, d, J = 6.6

Hz, H₆), 1.15 (3H, s, (C(CH₃)^BDA) ppm; ¹³C{¹H} NMR (101 MHz,

CDCl₃) δ 166.7 (CO), 132.9 (Ar_C), 130.5 (Ar_C), 130.0 (Ar_C), 128.3

(Ar_C), 100.1 (C(CH₃)^BDA), 99.8 (C(CH₃)^BDA), 98.6 (C₁), 72.3 (C₄),

65.8 (C₅), 65.7 (C₂), 64.9 (C₃), 55.3 (OCH₃), 48.0−47.8 (2 ×

OCH₃^BDA), 17.8 (C(CH₃)^BDA), 17.6 (C(CH₃)^BDA), 16.3 (C₆) ppm;

1

Selected data for 53: H NMR (400 MHz, CDCl₃) δ 8.09−8.04

(2H, m, Ar_H), 7.61−7.55 (1H, m, Ar_H), 7.51−7.42 (2H, m, Ar_H), 4.82

(1H, d, J = 3.4 Hz, H₁), 4.39 (2H, d, J = 4.9 Hz, H₆), 4.25−4.14 (2H,

m, H₃, H₅,), 3.74 (1H, dd, J = 10.2, 3.6 Hz, H₂), 3.43 (3H, s, OCH₃),

3.29 (3H, s, OCH₃^BDA), 3.28 (3H, s, OCH₃^BDA), 1.95 (1H, ddd, J =

12.3, 4.8, 2.2 Hz, H_4(eq)), 1.73 (1H, app q, J = 12.0 Hz, H_4(ax)), 1.36

(3H, s, (C(CH₃)^BDA), 1.31 (3H, s, (C(CH₃)^BDA) ppm; ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 166.3 (CO), 133.1 (Ar_C), 129.9 (Ar_C),

129.7 (Ar_C), 128.4 (Ar_C), 100.3 (C(CH₃)^BDA), 99.7 (C(CH₃)^BDA),

98.6 (C₁), 70.7 (C₂), 66.5 (2 × C, C₅, C₆), 63.4 (C₃), 55.0 (OCH₃),

48.0−47.8 (2 × OCH₃^BDA), 32.2 (C₄), 17.9 (C(CH₃)^BDA), 17.8

(C(CH₃)^BDA) ppm;

1

1277 (m), 1198 (s), 1115 (s), 1037 (s) cm⁻¹; H NMR (400 MHz,

CDCl₃) δ 7.49−7.39 (2H, m, Ar_H), 7.31−7.26 (1H, m, Ar_H), 7.16−

7.12 (2H, m, Ar_H), 5.97 (1H, dd, J = 3.3, 1.1 Hz, H₄), 4.80 (1H, d, J =

3.6 Hz, H₁), 4.28 (1H, dd, J = 10.5, 3.3 Hz, H₃), 4.08 (1H, dd, J =

10.5, 3.6 Hz, H₂), 4.08−4.04 (1H, m, H₅), 3.79 (1H, dd, J = 10.3, 6.5

Hz, H_6a), 3.70 (1H, dd, J = 10.3, 6.9 Hz, H_6b), 3.44 (3H, s, OCH₃),

3.28 (3H, s, OCH₃^BDA), 3.25 (3H, s, OCH₃^BDA), 1.34 (3H, s,

C(CH₃)^BDA), 1.29 (3H, s, C(CH₃)^BDA), 0.91 (9H, s, C(CH₃)₃), 0.10

(3H, s, Si(CH)₃), 0.09 (3H, s, Si(CH₃)) ppm; ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 194.6 (CS), 153.5 (Ar_C), 129.4 (Ar_C), 126.3 (Ar_C),

121.8 (Ar_C), 100.2 (C(CH₃)^BDA), 100.0 (C(CH₃)^BDA), 98.2 (C₁),

78.8 (C₄), 70.3 (C₅), 66.8 (C₂), 65.3 (C₃), 61.5 (C₆), 55.3 (OCH₃),

48.1 (OCH₃^BDA), 48.0 (OCH₃^BDA), 25.9 (C(CH₃)₃), 18.3 (C(CH₃)₃),

17.8 (C(CH₃)^BDA), 17.7 (C(CH₃)^BDA), −5.36 (Si(CH₃)), −5.49

(Si(CH₃)) ppm; HRMS (ES⁺) for C₂₆H₄₂NaO₉SSi [M + Na]⁺calcd

581.2211 found 581.2220.

Methyl 2,3-O-((2′R,3′R)-2′,3′-dimethoxybutane-2′,3′-diyl)-α-^D-

fucopyranoside (54) and Methyl 4-Deoxy-2,3-O-((2′R,3′R)-2′,3′-

dimethoxybutane-2′,3′-diyl)-α-^D-xylo-hexopyranoside (55). From

the 42:58 mixture of benzoates 52/53 obtained above: to a solution

of 52/53 (7.56 g, 19.1 mmol) in MeOH (75 mL) was added a

solution of NaOMe (25 wt %, 0.65 mL, 2.86 mmol). The mixture was

stirred at rt for 16 h. A further portion of NaOMe (25 wt %, 0.65 mL,

2.86 mmol) was added, and the reaction was stirred at rt for a further

4 h then at 50 °C for 2.5 h. The reaction was neutralized with

Amberlite IR120-H⁺and then ﬁltered and concentrated in vacuo.

Puriﬁcation by chromatography (40−70% EtOAc/petroleum ether)

aﬀorded a ﬁrst fraction containing unreacted 52 (900 mg, 2.27 mmol,

12%), a second fraction containing mainly 54 but contaminated with

a small amount of 55, and a third fraction containing pure 55 as an

oﬀ-white amorphous solid (2.99 g, 10.2 mmol, 54%). Unreacted 52

was resubmitted to deprotection using 1 equiv of MeONa and heating

at 60 °C for 3 h to reach completion. This was combined with the

impure fraction and puriﬁed by chromatography (30−60% EtOAc/

petroleum ether) to give pure 54 as a colorless oil (2.07 g 7.08 mmol,

37%).

Methyl 6-O-tert-Butyldimethylsilyl-4-deoxy-2,3-O-((2′R,3′R)-

2′,3′-dimethoxybutane-2′,3′-diyl)-α-^D-xylo-hexopyranoside (49).

A mixture of 48 (5.89 g, 10.9 mmol) and Et₃SiH (60 mL) was

brought to reﬂux. Benzoyl peroxide (526 mg, 2.17 mmol) was added,

and the reaction was heated under reﬂux for 30 min. A further portion

of benzoyl peroxide (526 mg, 2.17 mmol) was added and the reﬂux

continued for a further 1.5 h. The reaction was cooled to rt and the

Et₃SiH removed in vacuo. The crude residue was dissolved in CH₂Cl₂

(100 mL) and washed with 1 M NaOH (2 × 100 mL) and brine (100

mL). The organic layer was dried (MgSO₄) and concentrated in

vacuo. Puriﬁcation by chromatography (8−10% EtOAc/petroleum

ether) aﬀorded 49 as an amorphous white solid (2.73 g, 6.71 mmol,

62%): mp (postcolumn) 77−78 °C; [α]²_D⁷−53.6 (c 0.79, CHCl₃); IR

(neat) 2952 (w), 2857 (w), 1463 (w), 1375 (w), 1253 (w), 1196 (w),

1

1121 (s), 1085 (s), 1037 (s) cm⁻¹; H NMR (400 MHz, CDCl₃) δ

Synthesis of 54 from 72: To a solution of 72 (1.51 g, 3.26 mmol)

in DMSO (20 mL) was added NaBH₄(270 mg, 7.18 mmol). The

suspension was heated to 120 °C for 3 h and then cooled to 0 °C. The

reaction was quenched by the slow addition of 2 M HCl (10 mL),

warmed to rt, and diluted with H₂O (20 mL). The aqueous phase was

extracted with Et₂O (5 × 40 mL), and the combined organic extracts

4.77 (1H, d, J = 3.4 Hz, H₁), 4.15 (1H, ddd, J = 11.8, 10.1, 4.8 Hz,

H₃), 3.86 (1H, dddd, J = 11.4, 5.9, 5.1, 2.2 Hz, H₅), 3.69 (1H, dd, J =

10.4, 5.9 Hz, H_6a), 3.68 (1H, dd, J = 10.1, 3.4 Hz, H₂), 3.58 (1H, dd, J

= 10.4, 5.1 Hz, H_6b), 3.40 (3H, s, OCH₃), 3.28 (3H, s, OCH₃^BDA),

3.26 (3H, s, OCH₃^BDA), 1.90 (1H, ddd, J = 12.4, 4.8, 2.2 Hz, H₄(eq)),

7746

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

were dried (MgSO₄) and concentrated in vacuo. Puriﬁcation by

chromatography (20% EtOAc/hexane) aﬀorded 54 as a colorless oil

(809 mg, 2.77 mmol, 80%).

mmol) in chlorobenzene (4 mL) were added triisoproylsilane thiol

(28 μL, 0.13 mmol) and di-tert-butyl peroxide (0.24 mL, 1.32 mmol).

The mixture was heated to 140 °C for 1.5 h and then cooled to rt.

The mixture was concentrated in vacuo. Puriﬁcation by chromatog-

raphy (40% Et₂O/petroleum ether) aﬀorded an inseparable mixture

of 57 and 58 as a colorless oil (868 mg, 2.19 mmol, 83%, 57/58

80:20): HRMS (ES+) for C₂₀H₂₈NaO₈,[M + Na]⁺calcd 419.1676,

found 419.1686.

Synthesis of 55 from 49: To 49 (2.69 g, 6.62 mmol) was added a

solution of TBAF in THF (1 M, 7.90 mL, 7.90 mmol). The mixture

was stirred for 1 h. The THF was removed in vacuo, and the residue

redissolved in CH₂Cl₂(100 mL) and washed with satd NH₄Cl_(aq)

(150 mL), brine (150 mL), dried (MgSO₄), and concentrated in

vacuo. Puriﬁcation by chromatography (60−70% EtOAc/petroleum

ether) aﬀorded 55 as an oﬀ-white amorphous solid (1.65 g, 5.64

mmol, 85%).

1

Selected data for 57: H NMR (400 MHz, CDCl₃) δ 8.18−8.11

(2H, m, Ar_H), 7.62−7.53 (1H, m, Ar_H), 7.49−7.40 (2H, m, Ar_H), 5.50

(1H, br d, J = 2.6 Hz, H₄), 4.89 (1H, d, J = 3.4 Hz, H₁), 4.80 (1H, dd,

J = 11.7, 3.1 Hz, H₃), 4.66 (1H, dd, J = 11.7, 3.4 Hz, H₂), 4.12 (1H, br

q, J = 6.6 Hz, H₅), 3.46 (3H, s, OCH₃), 3.41 (3H, s, OCH₃^BDA), 2.95

(3H, s, OCH₃^BDA), 1.35 (3H, s, C(CH₃)^BDA), 1.30 (3H, s,

C(CH₃)^BDA), 1.16 (3H, d, J = 6.6 Hz, H₆) ppm; ¹³C{¹H} NMR

(101 MHz, CDCl₃) δ 165.8 (CO), 133.2 (Ar_C), 129.9 (Ar_C), 129.8

(Ar_C), 128.4 (Ar_C), 101.5 (C(CH₃)^BDA), 101.4 (C(CH₃)^BDA), 99.1

(C₁), 72.0 (C₄), 68.8 (C₂), 67.8 (C₃), 65.5 (C₅), 55.5 (OCH₃), 48.4

(OCH₃^BDA), 48.1 (OCH₃^BDA), 19.1 (C(CH₃)^BDA), 19.0 (C(CH₃)^BDA),

16.3 (C₆) ppm;

Data for 54: [α]²_D⁷−42.7 (c 0.66, CHCl₃, lit.¹¹⁹(enantiomer):

[α]²_D²+40, c 1.0 CHCl₃); IR (neat) 3489 (br), 2938 (w), 2833 (w),

1

1453 (w), 1369 (m), 1115 (s), 1030 (s), 999 (s) cm⁻¹; H NMR

(400 MHz, CDCl₃) δ 4.76 (1H, d, J = 3.6 Hz, H₁), 4.16 (1H, dd, J =

10.5, 3.6 Hz, H₂), 4.07 (1H, dd, J = 10.5, 3.2 Hz, H₃), 3.96 (1H, qd, J

= 6.7, 1.0 Hz, H₅), 3.76 (1H, dd, J = 3.2, 1.0 Hz, H₄), 3.41 (3H, s,

OCH₃), 3.26 (3H, s, OCH₃^BDA), 3.24 (3H, s, OCH₃^BDA), 1.33 (3H, s,

CH₃^BDA), 1.31 (3H, s, CH₃^BDA), 1.31 (3H, d, J = 6.6 Hz, H₆) ppm;

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 100.10 (C(CH₃)^BDA), 100.07

1

(C(CH₃)^BDA), 98.3 (C₁), 70.4 (C₄), 66.6 (C₃), 66.2 (C₅), 65.0 (C₂),

55.1 (OCH₃), 47.9 (2 × OCH₃^BDA), 17.8 (C(CH₃)^BDA), 17.7

(C(CH₃)^BDA), 16.1 (C₆) ppm; HRMS for C₁₃H₂₄NaO₇[M + Na]⁺

calcd 315.1414 found 315.1416. NMR data correspond to literature

(of enantiomer).¹¹⁹

Selected data for 58: H NMR (400 MHz, CDCl₃) δ 8.07−8.02

(2H, m, Ar_H), 7.62−7.53 (1H, m, Ar_H), 7.49−7.40 (2H, m, Ar_H), 4.85

(1H, d, J = 3.3 Hz, H₁), 4.60 (1H, dt, J = 11.1, 4.7 Hz, H₃), 4.40−4.32

(2H, m, H₆), 4.06 (1H, dd, J = 11.1, 3.4 Hz, H₂), 3.43 (3H, s, OCH₃),

3.40 (3H, s, OCH₃^BDA), 3.34 (3H, s, OCH₃^BDA), 2.10 (1H, ddd, J =

12.3, 4.6, 2.1 Hz, H_4(eq)), 1.50 (1H, app q, J = 11.7 Hz, H_4(ax)), 1.38

(3H, s, C(CH₃)^BDA), 1.37 (3H, s, C(CH₃)^BDA) ppm; ¹³C{¹H} NMR

(101 MHz, CDCl₃) δ 166.3 (CO), 133.1 (Ar_C), 129.8 (Ar_C), 129.6

(Ar_C), 128.4 (Ar_C), 101.6 (C(CH₃)^BDA), 101.4 (C(CH₃)^BDA), 99.0

(C₁), 73.8 (C₂), 66.5 (C₆), 66.2 (C₃), 66.1 (C₅), 55.2 (OCH₃), 48.1

(OCH₃^BDA), 48.0 (OCH₃^BDA), 34.2 (C₄), 18.9 (C(CH₃)^BDA) ppm

(one (C(CH₃)^BDA) signal not observed).

Data for 55: mp 64−66 °C (postcolumn); [α]²_D⁷−53.1 (c 0.78,

CHCl₃); IR (neat) 3511 (br, w), 2934 (w), 2879 (w), 1446 (w), 1375

(m), 1221 (m), 1114 (s), 1020 (s) cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ 4.79 (1H, d, J = 3.6 Hz, H₁), 4.17 (1H, ddd, J = 11.7, 10.1,

5.0 Hz, H₃), 3.93 (1H, ddt, J = 12.0, 6.2, 2.9 Hz, H₅), 3.68 (1H, dd, J

= 10.1, 3.6 Hz, H₂), 3.67 (1H, dd, J = 11.5, 3.3 Hz, H_6a), 3.59 (1H,

dd, J = 11.5, 6.6 Hz, H_6b), 3.42 (3H, s, OCH₃), 3.271 (3H, s,

OCH₃^BDA), 3.268 (3H, s, OCH₃^BDA), 1.79 (1H, ddd, J = 12.4, 4.9, 2.4

Hz, H_4(eq)), 1.61 (1H, app q, J = 12.0 Hz, H_4(ax)), 1.35 (3H, s,

C(CH₃)^BDA), 1.29 (3H, s, C(CH₃)^BDA) ppm; ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 100.2 (C(CH₃)^BDA), 99.6 (C(CH₃)^BDA), 98.5 (C₁),

70.9 (C₂), 68.9 (C₅), 65.3 (C₆), 63.3 (C₃), 55.0 (OCH₃), 47.89

(OCH₃^BDA), 47.85 (OCH₃^BDA), 31.6 (C₄), 17.9 (C(CH₃)^BDA), 17.8

(C(CH₃)^BDA) ppm; HRMS (ES⁺) for C₁₃H₂₄NaO₇[M + Na]⁺calcd

315.1414 found 315.1416.

Methyl 4,6-Dideoxy-4-chloro-6-ﬂuoro-α-^D-galactopyranoside

(60). A solution of 59⁷⁶(610 mg, 3.11 mmol) in CH₂Cl₂(10 mL)

and pyridine (3 mL) was cooled to −78 °C. SO₂Cl₂(1.05 mL, 13.0

mmol) was added, and the mixture was stirred for 30 min at this

temperature and a further 90 min during which time it was allowed to

warm to rt. The reaction was then cooled to 0 °C, a solution of NaI

(930 mg, 6.20 mmol) in MeOH/H₂O (1:1, 6 mL) was added, and the

resulting orange mixture stirred at rt for 30 min. The mixture was then

concentrated in vacuo and the residue dissolved in CHCl₃. The

organic phase was washed with satd NaHCO_3(aq)(30 mL) and the

aqueous phase re-extracted with CHCl₃(3 × 30 mL). The combined

organic phases were dried (MgSO₄) and concentrated in vacuo to

aﬀord a brown solid. Puriﬁcation by chromatography (Biotage Isolera

One, 5−9% MeOH/CH₂Cl₂) aﬀorded 60 as a pale orange solid (400

mg, 1.86 mmol, 60%): mp (postcolumn) 133−134 °C; [α]²_D⁷+205.2

(c = 0.97, CHCl₃); IR (neat) 3419 (br), 2917 (w), 1456 (w), 1347

(m), 1093 (w), 1011 (s), 886 (m) cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ 4.88 (1H, d, J = 3.9 Hz, H₁), 4.60 (1H, ddd, J = 47.0, 9.7,

6.7 Hz, H_6a), 4.57 (1H, ddd, J = 46.1, 9.7, 5.3 Hz, H_6b), 4.42 (1H, dd,

J = 3.7, 1.2 Hz, H₄), 4.29 (1H, dddd, J = 12.7, 6.7, 5.3, 1.2 Hz, H₅),

4.01 (1H, ddd, J = 9.8, 6.5, 3.7 Hz, H₃), 3.86 (1H, td, J = 9.5, 3.9 Hz,

H₂), 3.48 (3H, s, OCH₃), 2.55 (1H, d, J = 6.9 Hz, 3-OH), 2.17 (1H,

d, J = 9.4 Hz, 2-OH) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 99.3

(C₁), 82.5 (d, J_C−F= 170.2 Hz, C₆), 69.8 (C₃), 69.4 (C₂), 67.9 (d,

Methyl 4,6-Dideoxy-6-ﬂuoro-2,3-O-((2′R,3′R)-2′,3′-dimethoxy-

butane-2′,3′-diyl)-α-^D-xylo-hexopyranoside (56). Into a microwave

vial was added a solution of 55 (100 mg, 0.342 mmol) in 1,2-

dichloroethane (0.7 mL). 2,4,6-Collidine (54.7 μL, 0.411 mmol) and

DAST (50.3 μL, 0.411 mmol) were then added, and the vial was

sealed and placed in a microwave reactor. The reaction mixture was

irradiated for 4 min at 100 °C, cooled to rt, quenched with MeOH,

and then concentrated in vacuo. Puriﬁcation by chromatography (20%

EtOAc/hexane) aﬀorded 56 as a pale-yellow oil (81 mg, 0.275 mmol,

80%): [α]²_D⁴−14.8 (c 0.39, CHCl₃); IR (neat) 2950 (w), 1374 (w),

1

1117 (s), 1036 (s), 884 (m) cm⁻¹; H NMR (400 MHz, CDCl₃) δ

4.81 (1H, d, J = 3.4 Hz, H₁), 4.43 (1H, ddd, J = 47.3, 9.9, 3.6 Hz,

H_6a), 4.40 (1H, ddd, J = 47.6, 9.9, 5.1 Hz, H_6b), 4.18 (1H, ddd, J =

11.7, 10.2, 5.0 Hz, H₃), 4.06 (1H, ddddd, J = 20.8, 12.0, 5.1, 3.6, 2.9

Hz, H₅), 3.71 (1H, dd, J = 10.1, 3.5 Hz, H₂), 3.42 (3H, s, OCH₃),

3.27 (3H, s, OCH₃^BDA), 3.26 (3H, s, OCH₃^BDA), 1.83 (1H, ddd, J =

12.4, 4.9, 2.5 Hz, H_4(eq)), 1.65 (1H, app q, J = 12.1 Hz, H_4(ax)), 1.35

(3H, s, CH₃^BDA), 1.29 (3H, s, CH₃^BDA) ppm; ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 100.2 (C(CH₃)^BDA), 99.6 (C(CH₃)^BDA), 98.6 (C₁),

84.7 (d, J_C−F= 173.1 Hz, C₆), 70.6 (C₂), 67.2 (d, J_C−F= 19.8 Hz, C₅),

63.2 (C₃), 55.1 (OCH₃), 47.90 (OCH₃^BDA), 47.86 (OCH₃^BDA), 30.8

(d, J_C−F= 6.6 Hz, C₄), 17.84 (C(CH₃)^BDA), 17.75 (C(CH₃)^BDA) ppm;

¹⁹F NMR (378 MHz, CDCl₃) δ −228.3 (td, J = 46.8, 20.8 Hz, F₆)

J

_C−F= 24.2 Hz, C₅), 61.7 (d, J_C−F= 5.1 Hz, C₄), 55.8 (OCH₃) ppm;

¹⁹F NMR (376 MHz, CDCl₃) δ −229.9 (ddd, J = 47.0, 46.1, 12.7 Hz,

F₆) ppm; ¹⁹F(¹H} NMR (376 MHz, CDCl₃) δ −229.9 (s, F₆) ppm;

HRMS (ES⁺) for C₇H₁₂³⁵ClFNaO₄[M + Na]⁺calcd 237.0300 found

237.0300.

Methyl 4-Deoxy-4-ﬂuoro-6-O-tosyl-α-^D-galactopyranoside (62).

To a solution of 61¹²⁰(3.00 g, 8.61 mmol) in CH₂Cl₂(16 mL) was

added DAST (3.98 mL, 30.1 mmol). The dark brown solution was

then heated to 50 °C and stirred for 16 h. The reaction was cooled to

0 °C and quenched by the addition of MeOH (50 mL). The solution

was concentrated in vacuo to aﬀord a dark yellow oil. Puriﬁcation by

chromatography (80−100% EtOAc/hexane) aﬀorded 62 as an oﬀ-

yellow amorphous solid (1.42 g, 4.06 mmol, 49%): mp (postcolumn)

99−100 °C; [α]²_D⁵+75.5 (c 0.6, CHCl₃); IR (neat) 3364 (br), 2922

ppm; ¹⁹F(¹H} NMR (378 MHz, CDCl₃) δ −228.1 (s, F₆) ppm;

HRMS (ES⁺) for C₁₃H₂₃FNaO₆[M + H]⁺calcd 317.1371 found

317.1376.

Mixture of Methyl 4-O-Benzoyl-2,3-O-((2′S,3′S)-2′,3′-dimethox-

ybutane-2′,3′-diyl)-α-^D-fucopyranoside (57) and Methyl 6-O-

Benzoyl-4-deoxy-2,3-O-((2′S,3′S)-2′,3′-dimethoxybutane-2′,3′-

diyl)-α-^D-xylo-hexopyranoside (58). To a solution of 51 (1.05 g, 2.64

7747

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(w), 1598 (w), 1450 (w), 1356 (s), 1173 (s), 1093 (m), 983 (s)

(s), 927 (m) cm⁻¹; ¹H NMR (500 MHz, CD₃OD) δ 4.80 (1H, ddd, J

= 50.7, 2.8, 0.9 Hz, H₄), 4.75 (1H, d, J = 3.0 Hz, H₁), 3.95 (1H, dddt,

J = 28.6, 7.8, 6.0, 0.7 Hz, H₅), 3.82 (1H, ddd, J = 28.5, 10.2, 2.6 Hz,

H₃), 3.75 (1H, ddd, J = 10.2, 3.6, 1.8 Hz, H₂), 3.73 (1H, dd, J = 11.1,

6.0 Hz, H_6a), 3.64 (1H, ddd, J = 11.1, 7.8, 1.3 Hz, H_6b), 3.43 (3H, s,

OCH₃) ppm; ¹H{¹⁹F} NMR (500 MHz, CD₃OD) δ 4.80 (1H, br d, J

= 2.2 Hz, H₄), 4.75 (1H, d, J = 3.6 Hz, H₁), 3.94 (1H, ddt, J = 7.8, 6.0,

0.7 Hz, H₅), 3.82 (1H, dd, J = 10.2, 2.6 Hz, H₃), 3.75 (1H, dd, J =

10.3, 3.7 Hz, H₂), 3.73 (1H, dd, J = 11.1, 6.0 Hz, H_6a), 3.64 (1H, dd, J

= 11.1, 7.6 Hz, H_6b), 3.43 (3H, s, OCH₃) ppm; ¹³C{¹H} NMR (126

MHz, MeOD₄) δ 101.7 (C₁), 91.3 (d, J_C−F= 181.2 Hz, C₄), 71.2 (d,

1

cm⁻¹; H NMR (400 MHz, CDCl₃) δ 7.80 (2H, dt, J = 8.4, 2.0 Hz,

2H, Ar_H), 7.38−7.34 (2H, m, Ar_H), 4.76 (1H, dd, J = 51.5, 2.6 Hz,

H₄), 4.78 (1H, d, J = 3.4 Hz, H₁), 4.17 (2H, d, J = 6.4 Hz, H₆), 4.02

(1H, dt, J = 29.1, 6.4 Hz, H₅), 3.82 (1H, dddd, J = 27.8, 10.0, 6.2, 2.7

Hz, H₃), 3.81−3.73 (1H, m, H₂), 3.40 (3H, s, OCH₃), 3.01 (1H, d, J

= 6.1 Hz, 3-OH), 2.60 (1H, d, J = 8.9 Hz, 2-OH), 2.46 (s, 3H,

ArCH₃) ppm; ¹³C NMR (101 MHz, CDCl₃) δ 145.2 (Ar_c), 132.4

(Ar_c), 130.0 (Ar_c), 128.0 (Ar_c), 99.3 (C₁), 88.7 (d, J_C−F= 181.9 Hz,

C₄), 69.4 (d, J_C−F= 16.1 Hz,C₃), 69.3 (C₂), 67.3 (d, J_C−F= 18.3 Hz,

C₅), 67.3 (d, J_C−F= 6.6 Hz, C₆), 55.9 (OCH₃), 21.7 (ArCH₃) ppm;

¹⁹F NMR (376 MHz, CDCl₃) δ −221.2 (ddd, J = 50.3, 29.5, 27.7 Hz,

J_C−F= 17.9 Hz, C₅), 70.10 (d, J_C−F= 2.4 Hz, C₂), 70.06 (d, J_C−F

=

17.9 Hz, C₃), 50.1 (OCH₃), 43.0 (d, J_C−F= 6.7 Hz, C₆) ppm; ¹⁹F

NMR (470 MHz, MeOD₄) δ −222.5 (dtquin, J = 50.7, 28.4, 0.9 Hz,

F₄) ppm; ¹⁹F(¹H) NMR (470 MHz, MeOD₄), δ −222.5 (s, F₄) ppm;

HRMS (ES⁺) for C₇H₁₂³⁵ClFNaO₄[M + Na]⁺calcd 237.0300, found

237.0304.

F₄) ppm; ¹⁹F(¹H} NMR (376 MHz, CDCl₃) δ −221.0 (s, F₄) ppm;

HRMS: (ES⁺) for C₁₄H₁₉FNaO₇S [M + Na]⁺calcd. 373.0728 found

373.0735.

Methyl 3,6-Anhydro-4-deoxy-4-ﬂuoro-β-^D-galactopyranoside

(63). A solution of 62 (472 mg, 1.35 mmol) in THF (7 mL) was

cooled to 0 °C. LiBEt₃H (1 M in THF, 4.05 mL, 4.05 mmol) was

added dropwise, and the reaction was stirred at 0 °C for 2 h. The

reaction was quenched by the addition of EtOAc (10 mL) and satd aq

Rochelle’s salt (20 mL) and stirred vigorously for 5 min. The phases

were separated, and the aqueous phase was extracted with EtOAc (3

× 20 mL). The combined organic layers were washed with brine (50

mL), dried (MgSO₄), and concentrated in vacuo to yield a pale-yellow

oil. Puriﬁcation by chromatography (50% EtOAc/hexane) aﬀorded

the title compound as a colorless oil (160 mg, 0.90 mmol, 67%): [α]_D²⁵

+26.5 (c 0.39, CHCl₃); IR (neat) 3364 (br), 2922 (w), 1598 (w),

Methyl 2,3-Di-O-benzoyl-6-deoxy-6-bromo-α-^D-galactopyrano-

side (66). A solution of 37 (3.00 g, 7.45 mmol) in pyridine (100

mL) was cooled to 0 °C. PPh₃(3.91 g, 14.9 mmol) and CBr₄(2.47 g,

7.45 mmol) were added, and the reaction was heated to 60 °C for 1.5

h. The reaction was cooled to rt and then quenched by the addition of

MeOH (10 mL), and stirred for 10 min. The reaction mixture was

concentrated in vacuo to aﬀord an orange oil. The residue was then

taken up and triturated in Et₂O (3 × 100 mL). The precipitate was

dried in vacuo to aﬀord a white solid. Puriﬁcation by chromatography

(25−50% EtOAc/petroleum ether) aﬀorded 66 as a white solid (2.93

g, 6.30 mmol, 85%): mp (postcolumn) 47−49 °C; [α]²_D⁴+161.7 (c

0.71, CHCl₃); IR (neat) 3494 (br), 2934 (w), 1714 (s), 1451 (m),

1

1450 (w), 1356 (s), 1173 (s), 1093 (m), 983 (s) cm⁻¹; H NMR

(400 MHz, CDCl₃) δ 5.34 (1H, dd, J = 51.7, 2.1 Hz, H₄), 4.72 (1H,

d, J = 2.6 Hz, H₁), 4.56 (1H, dd, J = 14.6, 5.4 Hz, H₃), 4.49 (1H, q, J

= 3.0 Hz, H₅), 4.14 (1H, dd, J = 10.5, 1.7 Hz, H_6a), 4.03 (1H, dt, J =

10.5, 3.2 Hz, H_6b), 4.03−3.98 (1H, m, H₂), 3.55 (3H, s, OCH₃), 2.61

(1H, d, J = 1.3 Hz, 2-OH) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

96.7 (C₁), 90.1 (d, J_C−F= 190.7 Hz, C₄), 78.5 (d, J_C−F= 16.8 Hz, C₃),

74.7 (d, J_C−F= 23.5 Hz,C₅), 70.8 (d, J_C−F= 8.8 Hz, C₂), 69.2 (C₆),

57.3 (OCH₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −202.3 (dd, J =

52.0, 13.9 Hz,F₄) ppm; ¹⁹F(¹H} NMR (376 MHz, CDCl₃) δ −202.4

(s, F₄) ppm. HRMS could not be obtained.

Methyl 6-Chloro-6-deoxy-α-^D-glucopyranoside (64). Adapting

the method of Uzan et al.,¹²¹to a suspension of 27 (10.0 g, 51.4

mmol) in DMF (100 mL) was added methanesulfonyl chloride (7.96

mL, 103 mmol). The reaction was heated to 70 °C and stirred for 24

h. The reaction was cooled to rt and concentrated in vacuo.

Puriﬁcation by chromatography (2−5% MeOH/EtOAc) aﬀorded

64 as a white powder (10.4 g, 48.9 mmol, 95%): mp (postcolumn)-

114−116 °C, lit.¹²²111−112 °C (EtOH/EtOAc); [α]²_D⁵+148.5 (c

0.66, MeOH, lit.¹²²[α]_D+151, MeOH); IR (neat) 3401 (m, br),

2918 (w), 2838 (w), 1434 (w), 1341 (m), 1144 (m), 1044 (w), 955

(m) cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 5.22 (1H, d, J = 5.9 Hz,

4-OH), 4.92 (1H, d, J = 5.1 Hz, 1H, 3-OH), 4.84 (1H, d, J = 6.4 Hz,

2-OH), 4.56 (1H, d, J = 3.7 Hz, H₁), 3.85 (1H, dd, J = 11.6, 2.1 Hz,

H_6a), 3.68 (1H, dd, J = 11.6, 6.2 Hz, H_6b), 3.52 (1H, ddd, J = 9.5, 6.2,

2.0 Hz, H₅), 3.42−3.33 (1H, m, H₃), 3.28 (3H, s, OCH₃), 3.20 (1H,

ddd, J = 9.8, 6.3, 3.7 Hz, 1H, H₂), 3.06 (1H, ddd, J = 9.7, 8.7, 5.9 Hz,

H₄) ppm; ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 99.8 (C₁), 73.1

(C₃), 71.8 (C₂), 71.23 (C₄or C₅), 71.21 (C₄or C₅), 54.5 (OCH₃),

45.6 (C₆) ppm; HRMS: (ES⁺) for C₇H₁₃³⁵ClNaO₅[M + Na]⁺

calcd.235.0344 found 235.0342. Physical and spectroscopic character-

istics correspond to the literature.¹²²

1

1268 (s), 1070 (s), 706 (s) cm⁻¹; H NMR (400 MHz, CDCl₃) δ

8.04−7.94 (4H, m, Ar_H), 7.57−7.48 (2H, m, Ar_H), 7.43−7.34 (4H, m,

Ar_H), 5.74 (1H, dd, J = 10.6, 3.1 Hz, H₃), 5.63 (1H, dd, J = 10.6, 3.6

Hz, H₂), 5.18 (1H, d, J = 3.6 Hz, H₁), 4.49 (1H, br t, J = 3.2 Hz, H₄),

4.23 (1H, app t, J = 6.9 Hz, H₅), 3.64 (1H, dd, J = 10.2, 7.0 Hz, H_6a),

3.59 (1H, dd, J = 10.2, 7.2 Hz, H_6b), 3.49 (3H, s, OCH₃), 2.26 (1H, d,

J = 3.6 Hz, 4-OH) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 166.1

(CO), 165.6 (CO), 133.5 (Ar_C), 133.3 (Ar_C), 129.83 (Ar_C), 129.76

(Ar_C), 129.3 (Ar_C), 129.2 (Ar_C), 128.5 (Ar_C), 128.4 (Ar_C), 97.6 (C₁),

70.9 (C₃), 69.9 (C₅), 68.7 (C₂), 68.3 (C₄), 55.7 (OCH₃), 29.7 (C₆)

ppm; HRMS (ES⁺) for C₂₁H₂₁⁷⁹BrNaO₇[M + Na]⁺calcd 487.0363

found 487.0367.

Mixture of Methyl 2,3-Di-O-benzoyl-α-^D-fucopyranoside (67)

and Methyl 2,4-Di-O-benzoyl-α-^D-fucopyranoside (68). To a

solution of 66 (2.63 g, 5.63 mmol) in toluene (100 mL) were

added Bu₃SnH (2.29 mL, 8.48 mmol) and AIBN (0.046 g, 0.28

mmol). The reaction mixture was heated to 70 °C for 16 h and then

concentrated in vacuo to aﬀord a yellow oil. Puriﬁcation by

chromatography (10% K₂CO₃/silica w/w,¹¹⁸35−50% EtOAc/

petroleum ether) aﬀorded an inseparable mixture of 67 and 68 as a

white solid (1.34 g, 3.47 mmol, 62%, 67/68 1:1.5).

1

Selected data for 67: H NMR (400 MHz, CDCl₃) δ 8.19−8.13

(3H, m, Ar_H), 8.12−8.08 (3H, m, Ar_H), 8.03−7.97 (4H, m, Ar_H),

7.64−7.56 (3H, m, Ar_H), 7.56−7.43 (8H, m, Ar_H), 7.42−7.34 (4H, m,

Ar_H), 5.71 (1H, dd, J = 10.8, 3.1 Hz, H₃), 5.62 (1H, dd, J = 10.8, 3.8

Hz, H₂), 5.12 (1H, d, J = 3.3 Hz, H₁), 4.28−4.19 (1H, m H₅), 4.15

(1H, br d, J = 2.1 Hz, H₄), 3.43 (3H, s, OCH₃), 1.37 (3H, d, J = 6.6

Hz, H₆) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 166.9 (CO),

166.7 (CO), 166.1 (CO), 165.8 (CO), 133.42 (Ar_c), 133.36 (Ar_c),

133.3 (Ar_c), 133.2 (Ar_c), 130.0 (Ar_c), 129.9 (Ar_c), 129.8 (Ar_c), 129.7

(Ar_c), 129.54 (Ar_c), 129.45 (Ar_c), 129.43 (Ar_c), 129.40 (Ar_c), 128.6

(Ar_c), 128.43 (Ar_c), 128.42 (Ar_c), 128.4 (Ar_c), 97.5 (C₁), 71.6 (C₃),

70.8 (C₄), 68.9 (C₂), 65.4 (C₅), 55.5 (OCH₃), 16.0 (C₆) ppm. NMR

data correspond to literature (enantiomer).¹²³

Methyl 4,6-Dideoxy-6-chloro-4-ﬂuoro-α-D-galactopyranoside

(65). A solution of 64 (20.0 g, 94.1 mmol) in CH₂Cl₂(200 mL)

was cooled to 0 °C. DAST (32.5 mL, 246 mmol) was added

dropwise. The yellow mixture was heated to 50 °C and stirred for 16

h. The reaction was cooled to rt and poured into a vigorously stirred

solution of satd aq NaHCO₃(400 mL) and stirred for 30 min. The

mixture was then concentrated in vacuo to aﬀord an orange-colored

solid. Puriﬁcation by chromatography (70% EtOAc/hexane) aﬀorded

65 as ﬂuﬀy white needles (9.45 g, 44.0 mmol, 47%): mp 153−154 °C

(postcolumn); [α]²_D⁵+160.4 (c 0.38, CHCl₃); IR (neat) 3331 (m, br),

2937 (w), 2848 (w), 1455 (w), 1363 (w), 1137 (m), 1047 (s), 992

1

Selected data for 68: H NMR (400 MHz, CDCl₃) δ 5.57 (1H,

dd, J = 3.4, 1.0 Hz, H₄), 5.36 (1H, dd, J = 10.4, 3.7 Hz, H₂), 5.13 (1H,

d, J = 3.7 Hz, H₁), 4.49 (1H, dd, J = 10.5, 3.5 Hz, H₃), 3.45 (3H, s,

OCH₃), 1.26 (3H, d, J = 6.6 Hz, H₆) ppm (resonances for the

benzoate protecting groups, and for C5, of 67 and 68 overlapped);

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 97.7 (C₁), 74.3 (C₄), 72.3 (C₂),

67.5 (C₃), 65.0 (C₅), 55.6 (OCH₃), 16.3 (C₆) ppm (resonances for

7748

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

the benzoate protecting groups of 67 and 68 overlapped). NMR data

correspond to literature (enantiomer).¹²⁴

F₄) ppm; ¹⁹F(¹H} NMR (471 MHz, CD₃OD) δ −197.59 (s, F₄) ppm;

HRMS (ES+) for C₇H₁₃FNaO₄[M + Na]⁺calcd 203.0690, found

203.0685.

Methyl 2,3-Di-O-benzoyl-4,6-dideoxy-4-ﬂuoro-6-bromo-α-D-glu-

copyranoside (69). A solution of 66 (7.30 g, 15.7 mmol) in CH₂Cl₂

(200 mL) was cooled to 0 °C. DAST (6.50 mL, 47.0 mmol) was

added, and the mixture was heated to 50 °C. The mixture was stirred

for 24 h and then cooled to rt. The reaction was quenched by the

addition of MeOH (30 mL) and then concentrated in vacuo. The

residue was redissolved in CH₂Cl₂(100 mL), then washed with satd

NaHCO_3(aq)(2 × 100 mL) and H₂O (100 mL), then dried (MgSO₄)

and concentrated in vacuo to aﬀord a brown solid. Puriﬁcation by

chromatography (30% EtOAc/petroleum ether) aﬀorded 69 as an oﬀ-

white solid (4.92g, 10.5 mmol, 67%): mp (postcolumn) 126−127 °C;

[α]²_D⁴+56.5 (c 0.68, CHCl₃); IR (neat) 2935 (w), 1723 (s), 1451

(m), 1272 (s), 1106 (s), 707 (s) cm⁻¹; ¹H NMR (400 MHz, CDCl₃)

δ 8.04−7.97 (4H, m, Ar_H), 7.56−7.50 (2H, m, Ar_H), 7.43−7.36 (4H,

m, Ar_H), 6.15−6.03 (1H, m, H₃), 5.20−5.15 (2H, m, H₁, H₂), 4.66

(1H, dt, J = 50.9, 9.5 Hz, H₄), 4.17 (1H, dddd, J = 9.7, 6.1, 3.6, 2.7

Hz, H₅), 3.79 (1H, dt, J = 11.4, 2.0 Hz, H_6a), 3.65 (1H, ddd, J = 11.4,

5.8, 0.6 Hz, H_6b), 3.49 (3H, s, OCH₃) ppm; ¹³C{¹H} NMR (101

MHz, CDCl₃) δ 165.8 (CO), 165.5 (CO), 133.5 (Ar_C), 133.3 (Ar_C),

129.9 (Ar_C), 129.8 (Ar_C), 129.2 (Ar_C), 128.8 (Ar_C), 128.44 (Ar_C),

Methyl 6-O-p-Toluenesulfonyl-2,3-O-((2′R,3′R)-2′,3′-dimethoxy-

butane-2′,3′-diyl)-α-^D-galactopyransoside (72). A solution of 46

(3.39 g, 11.0 mmol) in pyridine (30 mL) was cooled to −40 °C. TsCl

(2.52 g, 13.2 mmol) was added portionwise, and the reaction stirred

for 6 h. The reaction was quenched by the addition of MeOH (20

mL), and warmed to rt. The mixture was concentrated in vacuo.

Puriﬁcation by chromatography (35% EtOAc/hexane) aﬀorded 72 as

an amorphous white solid (3.05 g, 6.59 mmol, 60%): mp

(postcolumn)67−69 °C; [α]²_D⁷−27.6 (c 0.53, CHCl₃); IR (neat)

3458 (br), 2947 (w), 2835 (w), 1449 (w), 1359 (m), 1083 (s), 1036

(s), 977 (s) cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.84−7.78 (2H, m,

Ar_H), 7.38−7.31 (2H, m, Ar_H), 4.74 (1H, d, J = 3.4 Hz, H₁), 4.26

(1H, dd, J = 10.5, 5.3 Hz, H_6a), 4.19 (1H, dd, J = 10.5, 7.2 Hz, H_6b),

4.11 (1H, dd, J = 10.4, 3.4 Hz, H₂), 4.07−4.00 (2H, m, H₃and H₅),

3.96−3.91 (1H, m, H₄), 3.38 (3H, s, OCH₃), 3.25 (3H, s, OCH₃^BDA),

3.22 (3H, s, OCH₃^BDA), 2.45 (3H, s, ArCH₃), 2.31 (1H, br t, J = 1.4

Hz,4-OH), 1.32 (3H, s, CH₃^BDA), 1.29 (3H, s, CH₃^BDA) ppm;

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 144.9 (Ar_C), 132.8 (Ar_C), 129.8

(Ar_C), 128.0 (Ar_C), 100.19 (C(CH₃)^BDA), 100.18 (C(CH₃)^BDA), 98.2

(C₁), 68.8 (C₆), 68.4 (C₅), 67.6 (C₄), 65.8 (C₃), 64.9 (C₂), 55.3

(OCH₃), 48.0 (OCH₃^BDA), 47.9 (OCH₃^BDA), 21.6 (ArCH₃), 17.72

(C(CH₃)^BDA), 17.65 (C(CH₃)^BDA) ppm; HRMS (ES⁺) for

C₂₀H₃₀NaO₁₀S [M + Na]⁺calcd 485.1452 found 485.1460.

128.38 (Ar_C), 97.0 (C₁), 89.0 (d, J_C−F= 188.5 Hz, C₄), 71.3 (d, J_C−F

=

7.3 Hz, C₂), 70.1 (d, J_C−F= 19.8 Hz, C₃), 67.8 (d, J_C−F= 23.5 Hz,

C₅), 55.8 (OCH₃), 31.4 (C₆) ppm; ¹⁹F NMR (376 MHz, CDCl₃)

δ−196.9 (dd, J = 51.2, 13.0 Hz, F₄) ppm; HRMS (ES+) for

C₂₁H₂₀⁷⁹BrFNaO₆[M + Na]⁺calcd 489.0320, found 489.0316.

Methyl 2,3-Di-O-benzoyl-4-deoxy-4-ﬂuoro-α-^D-quinovopyrano-

side (70). To a solution of 69 (7.88 g, 16.9 mmol) in toluene (200

mL) were added Bu₃SnH (6.83 mL, 25.4 mmol) and AIBN (139 mg,

0.85 mmol). The reaction was heated to 115 °C and stirred for 10 h.

The mixture was cooled to rt and then concentrated in vacuo to yield

a yellow oil. Puriﬁcation by chromatography (10% K₂CO₃/silica,¹¹⁸

10−50% EtOAc/petroleum ether) aﬀorded 70 as a colorless oil (5.00

g, 12.9 mmol, 76%): [α]²_D⁷+154.4 (c 0.51, CHCl₃); IR (neat) 2936

(w), 1724 (s), 1451 (m), 1273 (s), 1095 (s), 1027 (m), 986 (m)

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.04−7.96 (4H, m, Ar_H),

7.55−7.49 (2H, m, Ar_H), 7.43−7.35 (4H, m, Ar_H), 6.03 (1H, ddd, J =

13.6, 10.2, 9.2 Hz, H₃), 5.15 (1H, ddd, J = 10.2, 3.7, 0.8 Hz, H₂), 5.08

(1H, t, J = 3.4 Hz, H₁), 4.33 (1H, dt, J = 50.9, 9.5 Hz, H₄), 4.07 (1H,

dqd, J = 9.5, 6.2, 3.9 Hz, H₅), 3.44 (3H, s, OCH₃), 1.43 (3H, dd, J =

6.2, 0.9 Hz, H₆) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 165.9

(CO), 165.7 (CO), 133.4 (Ar_C), 133.2 (Ar_C), 130.0 (Ar_C), 129.8

(Ar_C), 129.5 (Ar_C), 129.0 (Ar_C), 128.43 (Ar_C), 128.35 (Ar_C), 96.8

(C₁), 92.4 (d, J_C−F= 187.1 Hz, C₄), 71.8 (d, J_C−F= 8.1 Hz, C₂), 70.5

(d, J_C−F= 20.5 Hz, H₃), 64.8 (d, J_C−F= 23.5 Hz, C₅), 55.5 (OCH₃),

17.2 (C₆) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −196.0 (dd, J = 50.3,

13.9 Hz, F₄) ppm; HRMS (ES+) for C₂₁H₂₁FNaO₆, [M + Na]⁺calcd

411.1214, found 411.1219.

Methyl 4-Deoxy-4-ﬂuoro-α-^D-quinovopyranoside (71). To a

solution of 70 (1.23 g, 3.16 mmol) in MeOH (50 mL) was added

NaOMe in MeOH (25% v/v, 0.22 mL, 0.95 mmol). The reaction

mixture was stirred at rt for 1 h and was then neutralized with

Amberlite IR-120 (H⁺) resin and ﬁltered. The ﬁltrate was

concentrated in vacuo to aﬀord a brown oil. Puriﬁcation by

chromatography (15−100% EtOAc/petroleum ether) aﬀorded 71 as

a white amorphous solid (451 mg, 2.50 mmol, 79%): mp

(postcolumn) 99−100 °C; [α]_D²⁵+169.0 (c 1.0, MeOH); IR

(neat)3425 (br), 2936 (w), 1450 (m), 1001 (s) cm⁻¹; ¹H NMR

(500 MHz, CD₃OD) δ 4.60 (1H, t, J = 3.5 Hz, H₁), 3.84 (1H, ddd, J

= 49.4, 9.5, 8.7 Hz, H₄), 3.80−3.72 (2H, m, H₃, H₅), 3.41 (1H, dd, J =

9.5, 3.8 Hz, H₂), 3.40 (3H, s, OCH₃), 1.26 (3H, dd, J = 6.2, 1.4 Hz,

H₆) ppm; ¹H{¹⁹F} NMR (500 MHz, CD₃OD) δ 4.60 (1H, d, J = 3.9

Hz, H₁), 3.84 (1H, dd, J = 9.4, 8.6 Hz, H₄), 3.77 (1H, dd, J = 9.4, 8.6

Hz, H₃), 3.76 (1H, dqd, J = 9.4, 6.1, 0.5 Hz, H₅), 3.41 (1H, dd, J =

9.6, 3.9 Hz, H₂), 3.40 (3H, s, OCH₃), 1.26 (3H, d, J = 6.1 Hz, H₆)

ppm; ¹³C{¹H} NMR (101 MHz, CD₃OD) δ 100.9 (d, J_C−F= 2.0 Hz

C₁), 96.3 (d, J_C−F= 182.0 Hz, C₄), 73.2 (d, J_C−F= 8.0 Hz, C₂), 72.8

(d, J_C−F= 8.0 Hz, C₃), 65.9 (d, J_C−F= 24.0 Hz, C₅), 55.6 (OMe), 17.5

(C₆) ppm; ¹⁹F NMR (471 MHz, CD₃OD) δ −197.6 to −197.8 (m,

Methyl 4-Deoxy-4-ﬂuoro-2,3-O-((2′R,3′R)-2′,3′-dimethoxybu-

tane-2′,3′-diyl)-α-^D-quinovopyranoside (73). To a solution of 54

(100 mg, 0.342 mmol) in anhydrous 1,2-dichloroethane (0.7 mL)

were added 2,4,6-collidine (54.7 μL, 0.411 mmol, 1.2 equiv) and

DAST (50.3 μL, 0.411 mmol, 1.2 equiv), and the vial was placed in a

microwave. The reaction mixture was irradiated for 6 min at 100 °C,

cooled to rt, quenched with MeOH, and then concentrated under

vacuum. Column chromatography (10% EtOAc/hexane) aﬀorded 73

as a light brown powder (37 mg, 0.126 mmol, 37%): mp

(postcolumn)121−123 °C; [α]²_D⁴−92.7 (c 0.64, CHCl₃); IR (neat)

1

2986 (w), 1371 (m), 1131 (s), 1028 (s), 997 (s), 885 (s) cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 4.68 (1H, t, J = 3.6 Hz, H₁), 4.25−4.14

(1H, m, H₃), 4.13 (1H, dt, J = 50.5, 9.1 Hz, H₄), 3.89−3.71 (2H, m,

H₂and H₅), 3.43 (3H, s, OCH₃), 3.30 (3H, s, OCH₃^BDA), 3.26 (3H,

s, OCH₃^BDA), 1.35 (3H, s, CH₃^BDA), 1.33 (3H, s, CH₃^BDA), 1.32 (3H,

dd, J = 6.2, 1.2 Hz, H₆) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

100.0 (C(CH₃)^BDA), 99.3 (C(CH₃)^BDA), 97.6 (d, J_C−F= 1.5 Hz, C₁),

92.0 (d, J_C−F= 184.9 Hz, C₄), 68.0 (d, J_C−F= 8.1 Hz, C₂), 67.4 (d,

J

_C−F= 18.3 Hz, C₃), 65.6 (d, J_C−F= 24.2 Hz, C₅), 55.1 (OCH₃), 48.0

(OCH₃^BDA), 47.9 (OCH₃^BDA), 17.7 (C(CH₃)^BDA), 17.6 (C(CH₃)^BDA),

17.3 (C₆) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −199.0 (br dd, J =

15.6, 50.5 Hz, F₄) ppm; ¹⁹F(¹H} NMR (376 MHz, CDCl₃) δ −199.1

(s, F₄) ppm; HRMS (ES⁺) for C₁₃H₂₃FNaO₆[M + Na]⁺calcd

317.1371 found 317.1375.

Methyl 4,6-Dideoxy-4,6-diﬂuoro-2,3-O-((2′R,3′R)-2′,3′-dime-

thoxybutane-2′,3′-diyl)-α-^D-glucopyranoside (74). Into a micro-

wave vial was added a solution of 46 (600 mg, 1.95 mmol) in 1,2-

dichloroethane (2.6 mL). 2,4,6-Collidine (0.79 mL, 5.94 mmol) and

DAST (0.73 mL, 5.94 mmol) were added, and the vial wassealed and

placed in a microwave reactor. The mixture was irradiated at 100 °C

for 8 min. The reaction was cooled to rt and then quenched by the

addition of MeOH. The solution was concentrated in vacuo.

Puriﬁcation by chromatography (silica, 10−20% EtOAc/petroleum

ether) and subsequent recrystallization of the resultant brown oil

(EtOAc/hexane) aﬀorded 74 as ﬁne yellow needles (285 mg, 0.92

mmol, 47%): mp (EtOAc/hexane) 123−125 °C; [α]²_D⁷−76.9 (c 0.28,

CHCl₃); IR (neat) 3352 (br, w), 2981 (m), 1462 (w), 1384 (w),

1

1116 (s), 1005 (s), 936 (m), 884 (m) cm⁻¹; H NMR (400 MHz,

CDCl₃) δ 4.78 (1H, t, J = 3.4 Hz, H₁), 4.65 (1H, dddd, J = 47.2, 10.4,

3.6, 1.7 Hz, H_6a), 4.62 (1H, ddt, J = 47.4, 10.4, 2.0 Hz, H_6b), 4.55

(1H, ddd, J = 52.1, 9.7, 9.2 Hz, H₅), 4.28 (1H, dt, J = 15.5, 9.6 Hz,

H₃), 3.97−3.83 (1H, m, H₅), 3.78 (1H, ddd, J = 10.3, 3.6, 1.1 Hz,

H₂), 3.46 (3H, s, OCH₃), 3.31 (3H, s, OCH₃^BDA), 3.27 (3H, s,

OCH₃^BDA), 1.36 (3H, s, C(CH₃)^BDA), 1.33 (3H, s, C(CH₃)^BDA) ppm;

7749

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 100.0 (C(CH₃)^BDA), 99.5

Data for 78: IR (neat) 2951 (w), 1734 (w), 1379 (s), 1138 (s),

1038 (s), 996 (s) cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.86 (1H, dd,

J = 2.6, 1.1 Hz, H₁), 4.78 (1H, app dquin, J = 9.5, 2.2 Hz, H₃), 4.07

(1H, ddd, J = 9.5, 2.7. 0.4 Hz, H₂), 3.48 (3H, s, OCH₃), 3.31 (3H, s,

OCH₃^BDA), 3.26 (3H, s, OCH₃^BDA), 1.81 (3H, dd, J = 4.8, 2.1 Hz,

H₆), 1.37 (3H, s, CH₃^BDA), 1.35 (3H, s, CH₃^BDA) ppm; ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 138.7 (d, J_C−F= 245.8 Hz, C₄), 135.0 (d,

J_C−F= 31.6 Hz, C₅), 100.8 (C(CH₃)^BDA), 100.0 (C(CH₃)^BDA), 98.4

(C₁), 68.1 (d, J_C−F= 6.6 Hz, C₂), 61.9 (d, J_C−F= 19.1 Hz, C₃), 56.1

(OCH₃), 47.98 (OCH₃^BDA), 47.96 (OCH₃^BDA), 17.8 (C(CH₃)^BDA),

17.7 (C(CH₃)^BDA), 12.7 (C₆) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ

−169.4 (br dd, J = 5.2, 3.5 Hz, F₄) ppm; ¹⁹F(¹H} NMR (376 MHz,

CDCl₃) δ −169.5 (s, F₄) ppm; HRMS (ES⁺) for C₁₃H₂₁FNaO₆[M +

Na]⁺calcd 315.1214 found 315.1215.

Methyl 4,6-Dideoxy-6,6-diﬂuoro-2,3-O-((2′R,3′R)-2′,3′-dime-

thoxybutane-2′,3′-diyl)-α-^D-xylo-hexopyranoside (80). To a solu-

tion of 55 (2.70 g, 9.24 mmol) in CH₂Cl₂(100 mL) was added

Dess−Martin periodinane (4.31 g, 10.2 mmol). The mixture was

stirred at rt for 1 h. The reaction mixture was diluted in CH₂Cl₂(50

mL) and washed with a saturated solution of NaHCO₃and Na₂S₂O₃

(1:1, 150 mL). The aqueous layer was extracted with CH₂Cl₂(2 × 75

mL), and the combined organic layers were washed with a saturated

solution of NaHCO₃/Na₂S₂O₃(1:1, 120 mL), dried (MgSO₄), and

concentrated in vacuo to aﬀord aldehyde 79 as a colorless oil (2.68 g,

9.24 mmol) which was used without further puriﬁcation.

(C(CH₃)^BDA), 97.9 (d, J_C−F= 1.5 Hz, C₁), 85.6 (dd, J_C−F= 184.5, 7.7

Hz, C₄), 81.1 (d, J_C−F= 174.6 Hz, C₆), 68.9 (dd, J_C−F= 23.8, 18.0 Hz,

C₅), 67.5 (d, J_C−F= 8.1 Hz, C₂), 67.4 (d, J_C−F= 17.6 Hz, C₃), 55.5

(OCH₃), 48.0 (OCH₃^BDA), 47.9 (OCH₃^BDA), 17.63 (C(CH₃)^BDA),

17.60 (C(CH₃)^BDA) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −200.6

(1F, br dd, J = 52.0, 15.6 Hz, F₄), −235.2 (1F, td, J = 47.3, 26.9 Hz,

F₆) ppm; ¹⁹F(¹H} NMR (376 MHz, CDCl₃) δ −200.5 (1F, s, F₄),

−235.1 (1F, s, F₆) ppm; HRMS (ES⁺) for C₁₃H₂₂F₂NaO₆[M + Na]⁺

calcd 335.1277 found 335.1282.

Methyl 4,6-Dideoxy-4,4-diﬂuoro-2,3-O-((2′R,3′R)-2′,3′-dime-

thoxybutane-2′,3′-diyl)-α-^D-xylo-hexopyranoside (76), Methyl 4,6-

Dideoxy-4-ﬂuoro-2,3-O-((2′R,3′R)-2′,3′-dimethoxybutane-2′,3′-

diyl)-α-^D-erythro-hex-3-enopyranoside (77), and Methyl 4,6-

Dideoxy-4-ﬂuoro-2,3-O-((2′R,3′R)-2′,3′-dimethoxybutane-2′,3′-

diyl)-α-^L-threo-hex-4-enopyranoside (78). To a solution of 54 (2.07

g, 7.08 mmol) in CH₂Cl₂(70 mL) was added Dess−Martin

periodinane (3.90 g, 9.21 mmol). The mixture was stirred for 90

min. The mixture was diluted with CH₂Cl₂(30 mL) and washed with

a saturated solution of NaHCO₃and Na₂S₂O₃(1:1, 100 mL). The

layers were separated, and the aqueous layer was extracted with

CH₂Cl₂(2 × 50 mL). The combined organic layers were washed with

a saturated solution of NaHCO₃and Na₂S₂O₃(1:1, 80 mL), dried

(MgSO₄), and concentrated in vacuo to aﬀord aldehyde 75 as a

colorless syrup (2.06 g, 7.08 mmol, 100%), which was used without

further puriﬁcation.

To a solution of 79 (2.68 g, 9.24 mmol) in CH₂Cl₂(26 mL) was

added DAST (4.53 mL, 36.9 mmol). The solution was then stirred at

25 °C for 3.5 h. The mixture was diluted with CH₂Cl₂(120 mL) and

cooled to 0 °C, and then the reaction was quenched by slow addition

of satd NaHCO_3(aq)(75 mL). The phases were separated, and the

aqueous phase was extracted with CH₂Cl₂(2 × 75 mL). The

combined organic layers were dried (MgSO₄) and then concentrated

in vacuo. Puriﬁcation by chromatography (25% Et₂O/petroleum

ether) aﬀorded 80 as a light yellow amorphous solid (2.23 g, 7.14

mmol, 77%): mp (postcolumn) 103−104 °C; [α]²_D⁷−60.4 (c 0.56,

CHCl₃); IR (neat) 2949 (w), 1449 (w), 1377 (w), 1117 (m), 1063

To a solution of 75 (2.06 g, 7.08 mmol) in CH₂Cl₂(20 mL) was

added DAST (5.20 mL, 42.5 mmol). The solution was warmed to

40°c and stirred for 16 h. The mixture was cooled to rt and diluted

with CH₂Cl₂. The reaction was quenched by the addition of satd

NaHCO_3(aq). The layers were separated, and the aqueous phase was

extracted twice with CH₂Cl₂. The combined organic layers were

washed with satd NaHCO_3(aq), dried (MgSO₄), and concentrated in

vacuo. Puriﬁcation by chromatography (20−50% EtOAc/petroleum

ether) aﬀorded ﬁrst compound 78 as a white gummy solid (248 mg,

0.85 mmol, 12%), then 76 as a pale-yellow oil (1.45 g, 4.64 mmol,

66%), and ﬁnally 77 as a colorless oil (207 mg, 0.71 mmol, 10%). The

byproducts 77 and 78 could not be obtained free of residual

impurities.

1

(s), 1027 (s), 965 (s) cm⁻¹; H NMR (400 MHz, CDCl₃) δ 5.72

(1H, td, J = 55.6, 4.2 Hz, H₆), 4.83 (1H, d, J = 3.4 Hz, H₁), 4.17 (1H,

ddd, J = 11.8, 10.2, 4.8 Hz, H₃), 4.06−3.93 (1H, m, H₅), 3.72 (1H,

dd, J = 10.2. 3.6 Hz, H₂), 3.44 (3H, s, OCH₃), 3.29 (3H, s,

OCH₃^BDA), 3.27 (3H, s, OCH₃^BDA), 2.03−1.94 (1H, m, H_4(eq)), 1.71

(1H, app q, J = 12.1 Hz, H_4(ax)), 1.36 (3H, s, CH₃^BDA), 1.30 (3H, s,

Data for 76: [α]²_D⁴−82.0 (c 0.57, CHCl₃); IR (neat) 2948 (w),

1

1453 (w), 1371 (m), 1109 (s), 1022 (s), 987 (s), 919 (s) cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 4.76 (1H, t, J = 3.2 Hz, H₁), 4.27 (1H,

ddd, J = 20.5, 10.6, 6.0 Hz, H₃), 3.99 (1H, ddd, J = 10.5, 3.6, 1.6 Hz,

H₂), 3.94 (1H, dq, J = 22.7, 6.5 Hz, H₅), 3.45 (3H, s, OCH₃), 3.30

(3H, s, OCH₃^BDA), 3.27 (3H, s, OCH₃^BDA), 1.37 (3H, s, CH₃^BDA),

1.35 (3H, s, CH₃^BDA), 1.31 (3H, d, J = 6.5 Hz, H₆) ppm; ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 117.0 (dd, J_C−F= 255.3, 250.9 Hz, C₄),

99.98 (C(CH₃)^BDA), 99.96 (C(CH₃)^BDA), 97.8 (C₁), 67.2 (C₂), 66.2

(dd, J_C−F= 19.8, 18.3 Hz, C₅), 66.1 (dd, J_C−F= 30.1, 24.5 Hz, C₃),

55.6 (OCH₃), 48.1 (OCH₃^BDA), 48.0 (OCH₃^BDA), 17.62 (C-

(CH₃)^BDA), 17.55 (C(CH₃)^BDA), 11.3 (d, J_C−F= 5.9 Hz, C₆) ppm;

¹⁹F NMR (376 MHz, CDCl₃) δ −120.38 (1F, dt, J = 242.8, 3.5 Hz,

F_4(eq)), −138.82 (1F, dt, J = 242.8, 21.7 Hz, F_4(ax)) ppm; ¹⁹F(¹H}

NMR (376 MHz, CDCl₃) δ −120.37 (1F, d, J = 242.8 Hz, F_4(eq)),

−138.82 (1F, d, J = 242.8 Hz, F_4(ax)) ppm; HRMS (ES⁺) for

C₁₃H₂₂F₂NaO₆[M + Na]⁺calcd 335.1277 found 335.1280.

CH₃^BDA) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 114.9 (t, J_C−F

=

242.8 Hz, C₆), 100.3 (C(CH₃)^BDA), 98.7 (C(CH₃)^BDA), 98.7 (C₁),

70.5 (C₂), 67.7 (t, J_C−F= 26.4 Hz, C₅), 62.7 (br s, C₃), 55.3 (OCH₃),

47.94 (OCH₃^BDA), 47.92 (OCH₃^BDA), 28.6 (t, J_C−F= 3.3 Hz, C₄), 17.8

(C(CH₃)^BDA), 17.7 (C(CH₃)^BDA) ppm; ¹⁹F NMR (376 MHz, CDCl₃)

δ −127.0 (1F, ddd, J = 289.6, 55.5, 8.7 Hz, F_6a), −130.8 (1F, ddd, J =

289.6, 55.5, 10.4 Hz, F_6b) ppm; ¹⁹F(¹H} NMR (376 MHz, CDCl₃) δ

−127.1 (1F, d, J = 289.6 Hz, F_6a), −130.9 (1F, d, J = 289.6 Hz, F_6b)

ppm; HRMS (ES⁺) for C₁₃H₂₂F₂NaO₆[M + Na]⁺calcd 335.1277

found 335.1272.

Methyl 4,6-Dideoxy-4,4-diﬂuoro-α-^D-xylo-hexopyranoside (85).

To a solution of 76 (700 mg, 2.24 mmol) in H₂O (40 mL) was added

Dowex 50 × 8 H⁺(20 mL). The reaction was heated to 100 °C and

stirred for 5 h. The mixture was ﬁltered and concentrated in vacuo.

The residue was redissolved in TFA/H₂O (9:1, 2.5 mL) and heated

to 75 °C for 22 h. Monitoring by TLC indicated an incomplete

reaction, so a further portion of H₂O (0.75 mL) was then added, and

the mixture heated to 100 °C for a further 7 h. The mixture was

concentrated in vacuo. Puriﬁcation by chromatography (40% acetone/

petroleum ether aﬀorded ﬁrst unreacted methyl glycoside 85 as a light

brown solid, then 300 mg of slightly impure 6a. These were both

further puriﬁed by recrystallization (Et₂O) to aﬀord 85 as a crystalline

white solid (61 mg, 0.31 mmol, 14%), and the corresponding

reducing sugar 6a as a crystalline white solid (142 mg, 0.77 mmol,

34%): mp 130−131 °C; [α]²_D¹+89.3 (c 0.2, CHCl₃); IR (neat) 3418

(br), 2923 (w), 1354 (w), 1230 (m), 1097 (s), 1021 (s), 988 (s)

Data for 77: IR (neat) 2951 (w), 1745 (w), 1377 (m), 1152 (s),

1051 (s), 959 (s) cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.82 (1H, dd,

J = 4.4, 1.3 Hz, H₁), 4.53 (1H, ddd, J = 7.6, 4.3, 3.3 Hz, H₂), 4.44

(1H, qt, J = 6.6, 3.5 Hz, H₅), 3.52 (3H, s, OCH₃), 3.37 (3H, s,

OCH₃^BDA), 3.34 (3H, s, OCH₃^BDA), 1.42 (3H, s, CH₃^BDA), 1.38 (3H,

s, CH₃^BDA), 1.32 (3H, dd, J = 6.6, 1.7 Hz, H₆) ppm; ¹³C{¹H} NMR

(101 MHz, CDCl₃) δ 142.5 (d, J_C−F= 259.7 Hz, C₄), 123.0 (d, J_C−F

=

6.6 Hz, C₃), 100.5 (C(CH₃)^BDA), 99.6 (C(CH₃)^BDA), 97.0 (C₁), 63.3

(d, J_C−F= 1.5 Hz, C₂), 63.0 (d, J_C−F= 27.1 Hz, C₅), 56.0 (OCH₃),

48.9 (d, J_C−F= 1.5 Hz, OCH₃^BDA), 48.5 (OCH₃^BDA), 17.7

(C(CH₃)^BDA), 17.6 (C₆), 17.3 (C(CH₃)^BDA) ppm; ¹⁹F NMR (376

MHz, CDCl₃) δ −152.1 (1F, br t, J = 5.2 Hz, F₄) ppm; ¹⁹F(¹H} NMR

(376 MHz, CDCl₃) δ −152.1 (s, F₄) ppm; HRMS (ES⁺) for

C₁₃H₂₁FNaO₆[M + Na]⁺calcd 315.1214 found 315.1217.

1

cm⁻¹; H NMR (500 MHz, CDCl₃) δ 4.80 (1H, t, J = 3.3 Hz, H₁),

3.97 (1H, dddd, J = 19.7, 9.8, 5.8, 5.3 Hz, H₃), 3.93 (1H, dqd, J =

7750

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

23.2, 6.4, 0.5 Hz, H₅), 3.73 (1H, dddd, J = 9.8, 9.3, 3.9, 1.7 Hz, H₂),

3.47 (3H, s, OCH₃), 2.46 (1H, d, J = 5.1 Hz, 3-OH), 2.29 (1 H, d, J =

H_6aβ), 3.69 (1H, dd, J = 12.4, 2.3 Hz, H_6aα), 3.69 (1H, dddd, J = 10.0,

5.6, 2.3, 0.6 Hz, H_5α), 3.61 (1H, dd, J = 12.4, 5.6 Hz, H_6bα), 3.57 (1H,

dd, J = 12.4, 5.8 Hz, H_6bβ), 3.57 (1H, ddd, J = 9.8, 9.2, 0.3 Hz, H_3α),

3.38 (1H, dd, J = 9.8, 3.8 Hz, H_2α), 3.34 (1H, dd, J = 9.3, 8.9 Hz,

H_3β), 3.32 (1H, ddd, J = 9.6, 5.7, 2.2 Hz, H_5β), 3.26 (1H, dd, J = 9.8,

9.2 Hz, H_4α), 3.25 (1H, dd, J = 9.7, 9.0 Hz, H_4β), 3.09 (1H, dd, J =

9.3, 8.0 Hz, H_2β) ppm; ¹³C{¹H} NMR (126 MHz, D₂O) δ 95.9 (C_1β),

92.1 (C_1α), 75.9 (C_5β), 75.7 (C_3β), 74.1 (C_2β), 72.7 (C_3α), 71.44

(C_2α), 71.40 (C_5α), 69.60 (C_4α), 69.56 (C_4β), 60.7 (C_6β), 60.5 (C_6α)

ppm.

1

9.0 Hz, 2-OH), 1.32 (3H, d, J = 6.5 Hz, H₆) ppm; H{¹⁹F} NMR

(500 MHz, CDCl₃) δ 4.80 (1H, d, J = 3.8 Hz, H₁), 3.97 (1H, dd, J =

9.8, 5.3 Hz, H₃), 3.93 (1H, q, J = 6.5 Hz, H₅), 3.73 (1H, ddd, J = 9.8,

9.1, 3.8 Hz, H₂), 3.47 (3 H, s, OCH₃), 2.46 (1H, d, J = 5.5 Hz, 3-

OH), 2.29 (1H, d, J = 9.1 Hz, 2-OH), 1.32 (3H, d, J = 6.5 Hz, H₆)

ppm; ¹³C NMR (126 MHz, CDCl₃): δ 117.7 (t, J_C−F= 251.5 Hz, C₄),

98.9 (d, J_C−F= 1.0 Hz, C₁), 71.67 (d, J_C−F= 6.7 Hz, C₂), 71.65 (t,

J_C−F= 20.0 Hz, C₃), 65.3 (dd, J_C−F= 29.7, 24.7 Hz, C₅), 55.9 (OCH₃),

11.4 (d, J_C−F= 5.5 Hz, C₆) ppm; ¹⁹F NMR (471 MHz, CDCl₃) δ

−118.1 (1F, ddd, J = 246.2, 6.1, 2.0 Hz, F_4(eq)), −139.7 (1F, ddd, J =

246.4, 22.5, 20.7 Hz, F_4(ax)) ppm; ¹⁹F(¹H} NMR (471 MHz, CDCl₃)

δ −118.1 (1F, d, J = 246.4 Hz, F_4(eq)), −139.7 (1F, d, J = 246.0 Hz,

F_4(ax)) ppm; HRMS (ESI+) for C₇H₁₂F₂NaO₄[M + Na]⁺calcd

221.0601, found 221.0594.

1

L-Fucose (L-84): H NMR (500 MHz, D₂O, α/β 31:69) δ 5.05

(1H, d, J = 4.0 Hz, H_1α), 4.40 (1H, d, J = 7.9 Hz, H_1β), 4.05 (1H, qdd,

J = 6.6, 1.1, 0.6 Hz, H_5α), 3.71 (1H, dd, J = 10.5, 3.4 Hz, H_3α), 3.67−

3.65 (1H, m, H_4α), 3.66 (1H, qd, J = 6.5, 1.1 Hz, H_5β), 3.61 (1H, dd, J

= 10.4, 4.0 Hz, H_2α), 3.60 (1H, ddd, J = 3.6, 1.0, 0.2 Hz, H_4β), 3.49

(1H, dd, J = 10.0, 3.6 Hz, H_3β), 3.30 (1H, ddd, J = 10.3, 7.9, 0.3 Hz,

H_2β), 1.10 (3H, d, J = 6.5 Hz, H_6β), 1.06 (3H, d, J = 6.5 Hz, H_6α)

ppm; ¹³C{¹H} NMR (126 MHz, D₂O) δ 96.2 (C_1β), 92.2 (C_1α), 72.9

(C_2β), 71.9 (C_4α), 71.6 (C_2β), 71.4 (C_4β), 70.9 (C_5β), 69.2 (C_3α), 68.1

(C_2α), 66.3 (C_5α), 15.5 (2 × C, C_6α, and C_6β) ppm. (ca 4% of

furanose form is also present). Data correspond to literature data.¹²⁸

4,6-Dideoxy-^D-xylo-hexopyranose (86). Using general procedure

C with 92 (220 mg, 0.80 mmol), puriﬁcation by chromatography

(10% MeOH/CH₂Cl₂) aﬀorded 82 as a white powder (101 mg, 0.68

mmol, 86%): mp (postcolumn) 143−146 °C, lit.¹²⁵134−136 °C.

Et₂O/MeOH; [α]²_D⁵+47.0 (c 0.61, MeOH), [α]²_D¹+33.9 (c 0.33,

H₂O), lit.¹²⁶[α]_D²⁰+34 (c 1, H₂O); IR (neat) 3315 (br), 2971 (w),

1

4-Deoxy-4-ﬂuoro-D-glucose (87): H NMR (500 MHz, D₂O, α/β

1

2923 (w), 1443 (w), 1045 (s), 815 (s) cm⁻¹; H NMR (500 MHz,

43:57) δ 5.09 (1H, t, J = 3.5 Hz, H_1α), 4.54 (1H, d, J = 7.9 Hz, H_1β),

4.19 (2H, ddd, J = 51.0, 10.0, 8.9 Hz, H_4α+ H_4β), 3.91−3.85 (1H, m,

H_5α), 3.84 (1H, dddd, J = 15.7, 9.8, 8.8, 0.3 Hz, H_3α), 3.74 (1H, dt, J

= 12.5, 2.2 Hz, H_6aβ), 3.69 (1H, dt, J = 12.5, 2.4 Hz, H_6aα), 3.67 (1H,

ddd, J = 15.8, 9.5, 8.7 Hz, H_3β), 3.65 (1H, ddd, J = 12.6, 4.5, 1.8 Hz,

H_6bα), 3.61 (1H, ddd, J = 12.6, 5.3, 1.8 Hz, H_6bβ), 3.55 (1H, ddt, J =

9.8, 5.2, 2.5 Hz, H_5β), 3.43 (1H, ddd, J = 9.9, 3.8, 0.8 Hz, H_2α), 3.14

CD₃OD, α/β 49:51) δ 5.08 (1H, d, J = 3.8 Hz, H_1α), 4.39 (1H, d, J =

7.8 Hz, H_1β), 4.14 (1H, dqdd, J = 11.4, 6.3, 2.2, 0.3 Hz, H_5α), 3.84

(1H, ddd, J = 11.4, 9.4, 5.0 Hz, H_3α), 3.63 (1H, dqd, J = 11.5, 6.2, 2.0

Hz, H_5β), 3.55 (1H, ddd, J = 11.4, 9.0, 5.2 Hz, H_3β), 3.25 (1H, dd, J =

9.4, 3.7 Hz, H_2α), 3.01 (1H, dd, J = 9.0, 7.8 Hz, H_2β), 1.94 (1H, ddd, J

= 12.8, 4.9, 2.2 Hz, H_4(eq)α), 1.92 (1H, ddd, J = 12.8, 5.2, 2.0, 0.3 Hz,

H_4(eq)β), 1.31 (1H, dt, J = 12.8, 11.4 Hz, H_4(ax)β), 1.25 (1H, dt, J =

12.7, 11.5 Hz, H_4(ax)α), 1.21 (3H, d, J = 6.2 Hz, H_6β), 1.14 (3H, d, J =

6.3 Hz, H_6α) ppm; ¹³C{¹H} NMR (126 MHz, CD₃OD) δ 98.4 (C_1β),

94.7 (C_1α), 78.3 (C_2β), 75.8 (C_2α), 72.4 (C_3β), 69.3 (C_5β), 68.8 (C_3α),

64.8 (C_5α), 42.5 (C_4α), 42.3 (C_4β), 21.52 (C_6α), 21.50 (C_6β) ppm; ¹H

NMR (500 MHz, D₂O, α/β 27:73) δ 5.06 (1H, d, J = 3.8 Hz, H_1α),

4.40 (1H, d, J = 7.9 Hz, H_1β), 4.02 (1H, dqdd, J = 11.8, 6.2, 2.2, 0.5

Hz, H_5α), 3.75 (1H, ddd, J = 11.5, 9.8, 5.0 Hz, H_3α), 3.62 (1H, dqd, J

= 11.3, 6.2, 2.0 Hz, H_5β), 3.55 (1H, ddd, J = 11.5, 9.2, 5.3 Hz, H_3β),

3.29 (1H, dd, J = 9.8, 3.8 Hz, H_2α), 2.98 (1H, dd, J = 9.3, 7.9 Hz,

H_2β), 1.91 (dddt, J = 12.9, 5.0, 2.3, 0.5 Hz, H_4(eq)α), 1.88 (1H, ddd, J

= 13.0, 5.2, 2.0 Hz, H_4(eq)β), 1.24 (dt, J = 13.0, 11.5 Hz, H_4(ax)β),

1.26−1.17 (1H, m, H_4(ax)α), 1.08 (3H, d, J = 6.3 Hz, H_6β), 1.05 (3H,

d, J = 6.3 Hz, H_6α) ppm; ¹³C{¹H} NMR (126 MHz, D₂O) δ 95.9

(C_1β), 92.6 (C_1α), 78.0 (C_2β), 73.2 (C_2α), 70.4 (C_3β), 68.6 (C_5β), 66.9

(C_3α), 64.6 (C_5α), 40.0 (C_4α), 39.9 (C_4β), 19.87 (C_6α), 19.85 (C_6β)

ppm; MS (ESI+) 171.4 [M + Na]⁺. Spectroscopic data corresponds

with the literature.⁵⁰

1

(1H, ddd, J = 9.4, 8.2, 0.9 Hz, H_2β) ppm; H{¹⁹F} NMR (500 MHz,

D₂O) δ 5.09 (1H, d, J = 3.9 Hz, H_1α), 4.54 (1H, d, J = 8.0 Hz, H_1β),

4.19 (2H, dd, J = 9.8, 8.8 Hz, H_4α+ H_4β), 3.88 (1H, ddd, J = 9.9, 4.5,

2.6 Hz, H_5α), 3.84 (1H, dd, J = 9.9, 8.8 Hz, H_3α), 3.74 (1H, dd, J =

12.4, 2.1 Hz, H_6aβ), 3.69 (1H, dd, J = 12.7, 2.6 Hz, H_6aα), 3.67 (1H,

dd, J = 9.5, 8.9 Hz, H_3β), 3.65 (1H, dd, J = 12.6, 4.7 Hz, H_6bα), 3.61

(1H, dd, J = 12.3, 5.2 Hz, H_6bβ), 3.55 (1H, ddd, J = 9.7, 5.2, 2.4 Hz,

H_5β), 3.43 (1H, dd, J = 9.9, 3.8 Hz, H_2α), 3.14 (1H, dd, J = 9.6, 8.0

Hz, H_2β) ppm; ¹³C{¹H} NMR (126 MHz, D₂O) δ 95.9 (d, J_C−F= 1.4

Hz, C_1β), 91.9 (d, J_C−F= 1.4 Hz, C_1α), 89.1 (d, J_C−F= 179.8 Hz, C_4α),

89.0 (d, J_C−F= 180.0 Hz, C_4β), 73.7 (d, J_C−F= 17.6 Hz, C_3β), 73.7 (d,

J

_C−F= 8.6 Hz, C_2β), 73.3 (d, J_C−F= 24.3 Hz, C_5β), 71.0 (d, J_C−F= 17.6

Hz, C_3α), 70.9 (d, J_C−F= 8.1 Hz, C_2α), 68.9 (d, J_C−F= 23.8 Hz, C_5α),

60.1 (C_6β), 59.9 (C_6α) ppm; ¹⁹F NMR (470 MHz, D₂O) δ −198.2

(app dddtdt, J = 50.8, 15.7, 3.9, 2.2, 1.8, 0.8 Hz, F_4α), −200.2 (app

ddqt, J = 50.8, 15.7, 2.2, 1.8, 0.8 Hz, F_4β) ppm; ¹⁹F(¹H} NMR (470

MHz, D₂O) δ −198.3 (1F, s, F_4α), −200.3 (1F, s, F_4β) ppm.

1

D-Quinovose (89): H NMR (500 MHz, D₂O, α/β 31:69) δ 5.03

1,2,3-Tri-O-acetyl-4,6-dideoxy-D-xylo-hexopyranoside (94).

Using general procedure A with methyl 4,6-dideoxy-α-^D-xylo-

hexopyranoside⁸⁸(565 mg, 3.48 mmol) and TMSOTf (0.2 equiv)

aﬀorded 92 as a light yellow oil (265 mg, 0.97 mmol, 28%): IR (neat)

2979 (w), 1741 (s), 1369 (m), 1212 (s), 1044 (s), 924 (m) cm⁻¹; ¹H

NMR (400 MHz, CDCl₃, α/β 85:15) δ 6.29 (1H, d, J = 3.7 Hz, H_1α),

5.66−5.63 (1H, m, H_1β), 5.27 (1H, ddd, J = 11.5, 10.4, 5.0 Hz, H_3α),

5.02 (1H, dd, J = 10.3, 3.7 Hz, H_2α), 4.13 (1H, dqd, J = 12.0, 6.1, 2.3

Hz, H_5α), 3.81 (1H, dqd, J = 12.2, 6.1, 1.8 Hz, H_5β), 2.22 (1H, ddd, J

= 12.9, 5.1, 2.3 Hz, H_4(eq)α), 2.14 (3H, s, COCH_3α), 2.11 (3H, s,

COCH_3β), 2.05 (3H, s, COCH_3α), 2.05 (3H, s, COCH_3β), 2.04 (3H,

s, COCH_3β), 2.03 (COCH_3α), 1.53 (1H, dt, J = 12.7, 11.7 Hz,

H_4(ax)α), 1.29 (3H, d, J = 6.1 Hz, H_6β), 1.23 (3H, d, J = 6.2 Hz, H_6α)

(H_2β, H_3β, H_4βsignals obscured by major anomer) ppm; ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 170.4 (CO_α), 170.1 (CO_α), 169.3 (CO_α),

92.3 (C_1β), 90.4 (C_1α), 70.4 (C_2α), 67.7 (C_3α), 66.1 (C_5α), 37.7 (C_4α),

37.5 (C_4β), 21.01 (COCH_3α), 20.95 (COCH_3α), 20.65 (COCH_3α),

20.62 (C_6α) (other signals not resolved) ppm; HRMS (ES⁺) for

C₁₂H₁₈NaO₇[M + Na]⁺calcd 297.0945 found 297.0945. Spectro-

scopic characteristics correspond to the literature.¹²⁷

(1H, d, J = 3.8 Hz, H_1α), 4.48 (1H, d, J = 8.0 Hz, H_1β), 3.75 (1H, dqd,

J = 9.7, 6.2, 0.3 Hz, H_5α), 3.51 (1H, dd, J = 9.8, 9.4 Hz, H_3α), 3.39

(1H, dd, J = 9.8, 3.8 Hz, H_2α), 3.35 (1H, dq, J = 9.5, 6.2 Hz, H_5β),

3.28 (1H, t, J = 9.4 Hz, H_3β), 3.10 (1H, dd, J = 9.5, 8.0 Hz, H_2β), 3.01

(1H, t, J = 9.3 Hz, H_4β), 2.99 (1H, t, J = 9.4 Hz, H_4α), 1.14 (3H, d, J =

6.3 Hz, H_6β), 1.11 (3H, d, J = 6.3 Hz, H_6β) ppm; ¹³C{¹H} NMR (126

MHz, D₂O) δ 95.7 (C_1β), 91.9 (C_1α), 75.4 (C_3β), 75.2 (C_4α), 74.9

(C_4β), 74.3 (C_2β). 74.4 (C_3α), 71.9 (C_5β), 71.7 (C_2α), 67.4 (C_5α), 16.7

(2 × C, C_6αand C_6β) ppm. Data correspond to literature data.¹²⁹

1

D-Galactose (92): H NMR (500 MHz, D₂O, α/β 33:67) δ 5.11

(1H, d, J = 3.8 Hz, H_1α), 4.43 (1H, d, J = 7.9 Hz, H_1β), 3.94 (1H,

dddd, J = 7.1, 5.3, 1.2, 0.6 Hz, H_5α), 3.84 (1H, dd, J = 3.2, 1.1 Hz,

H_4α), 3.78 (1H, ddd, J = 3.6, 1.0, 0.3 Hz, H_4β), 3.71 (1H, dd, J = 10.4,

3.3 Hz, H_3α), 3.65 (1H, dd, J = 10.3, 3.7 Hz, H_2α), 3.63 (1H, dd, J =

11.6, 7.9 Hz, H_6aβ), 3.61−3.57 (3H, m, H_6α, H_6bβ), 3.56 (1H, ddd, J =

7.8, 4.4, 1.0 Hz, H_5β), 3.50 (1H, dd, J = 10.0, 3.6 Hz, H_3β), 3.34 (1H,

ddd, J = 10.0, 7.9, 0.3 Hz, H_2β) ppm; ¹³C{¹H} NMR (126 MHz,

D₂O) δ 98.4 (C_1β), 92.3 (C_1α), 75.1 (C_5β), 72.8 (C_3β), 71.8 (C_2β),

70.5 (C_5α), 69.3 (C_4α), 69.1 (C_3α), 68.7 (C_4β), 68.3 (C_2α), 61.2 (C_6α),

61.0 (C_6β) ppm.

1

D₂O NMR Data for Compounds 83−88 (Table 4). D-Glucose (83):

¹H NMR (500 MHz, D₂O, α/β 38:62) δ 5.08 (1H, d, J = 3.8 Hz,

H_1α), 4.50 (1H, d, J = 8.0 Hz, H_1β), 3.75 (1H, dd, J = 12.3, 2.2 Hz,

4-Deoxy-^D-xylo-hexopyranose (93): H NMR (500 MHz, D₂O,

α/β 31:69) δ5.11 (1H, d, J = 3.8 Hz, H_1α), 4.42 (1H, d, J = 7.9 Hz,

H_1β), 3.95 (1H, ddddd, J = 12.1, 6.1, 3.4, 2.3, 0.5 Hz, H_5α), 3.80 (1H,

7751

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

ddd, J = 11.4, 9.7, 5.0 Hz, H_3α), 3.59 (1H, ddd, J = 11.7, 9.2, 5.2 Hz,

H_3β), 3.57 (1H, dddd, J = 11.4, 6.5, 3.3, 1.4 Hz, H_5β), 3.53 (1H, dd, J

= 11.9, 3.3 Hz, H_6aβ), 3.52 (1H, dd, J = 12.0, 3.4 Hz, H_6aα), 3.45 (1H,

dd, J = 11.9, 6.5 Hz, H_6bβ), 3.43 (1H, dd, J = 11.9, 6.1 Hz, H_6bα), 3.31

(1H, dd, J = 9.7, 3.8 Hz, H_2α), 3.00 (1H, dd, J = 9.3, 7.8 Hz, H_2β),

1.84 (1H, dddt, J = 12.8, 5.2, 2.3, 0.5 Hz, H_4(eq)α), 1.82 (1H, dddd, J =

12.8, 5.3, 1.7, 0.3 Hz, H_4(eq)β), 1.29 (1H, br app q, J = 12.1 Hz,

H_4(ax)α), 1.28 (1H, dt, J = 12.9, 11.5 Hz, H_4(ax)β) ppm; ¹³C{¹H} NMR

(126 MHz, D₂O) δ 96.1 (C_1β), 92.7 (C_1α), 76.0 (C_2β), 73.2 (C_2α),

72.5 (C_5β), 70.4 (C_3β), 68.4 (C_5α), 66.9 (C_3α), 63.7 (C_6α), 63.6 (C_6β),

34.2 (2 × C, C_4αand C_4β) ppm. Data correspond to literature data.¹³⁰

Mark E. Light − School of Chemistry, University of

Southampton, Highﬁeld, Southampton SO17 1BJ, U.K.;

orcid.org/0000-0002-0585-0843

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00796

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

ASSOCIATED CONTENT

This project has been funded by the Industrial Biotechnology

Catalyst (Innovate UK, BBSRC, EPSRC, BB/M028941/1) to

support the translation, development, and commercialization

of innovative Industrial Biotechnology processes. We also

thank the EPSRC (core capability EP/K039466/1) for

funding. R.S. thanks the Southampton Excel programme for

a fellowship. Carbosynth and Dextra are thanked for ﬁnancial

support. Julien Malassis is thanked for the crystallization of 19.

■

sı

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c00796.

¹H, ¹³C, ¹⁹F NMR spectra, including 2D data, of all

novel compounds; methodology and qNMR spectra of

compounds 1a−7a and 83, 84, 86, 87, 89, 92, and 93;

crystallographic data of compounds 1a, 2a, 5a, 6a, ^D-19,

69, 71, and 85; coupling constant analyses of 1a−7a and

some acetylated derivatives; companion graphs for

Figures 8−10 showing the β-anomers; tabulated

chemical shift data used to make Figures 8−10 (PDF)

REFERENCES

■

(1) Zhou, Y.; Wang, J.; Gu, Z. N.; Wang, S. N.; Zhu, W.; Acena, J.

L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Next Generation of Fluorine-

Containing Pharmaceuticals, Compounds Currently in Phase II-III

Clinical Trials of Major Pharmaceutical Companies: New Structural

Trends and Therapeutic Areas. Chem. Rev. 2016, 116 (2), 422−518.

(2) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.;

Meanwell, N. A. Applications of Fluorine in Medicinal Chemistry. J.

Med. Chem. 2015, 58 (21), 8315−8359.

Accession Codes

CCDC 1453093, 1473639, 1483644, 1504321, 1520462,

1578049, 1879623, and 2046059 contain the supplementary

crystallographic data for this paper. These data can be obtained

free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by

emailing data_request@ccdc.cam.ac.uk, or by contacting The

Cambridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

(3) Wang, J.; Sánchez-Roselló, M.; Acena, J. L.; del Pozo, C.;

̃

Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in

Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to

the Market in the Last Decade (2001 −2011). Chem. Rev. 2014, 114

(4), 2432−2506.

(4) Namchuk, M. N.; McCarter, J. D.; Becalski, A.; Andrews, T.;

Withers, S. G. The Role of Sugar Substituents in Glycoside

Hydrolysis. J. Am. Chem. Soc. 2000, 122 (7), 1270−1277.

(5) Withers, S. G.; MacLennan, D. J.; Street, I. P. The Synthesis and

Hydrolysis of a Series of Deoxyfluoro-D-Glucopyranosyl Phosphates.

Carbohydr. Res. 1986, 154 (1), 127−144.

AUTHOR INFORMATION

■

Corresponding Author

Bruno Linclau − School of Chemistry, University of

Southampton, Highﬁeld, Southampton SO17 1BJ, U.K.;

orcid.org/0000-0001-8762-0170; Email: bruno.linclau@

soton.ac.uk

(6) Tysoe, C.; Withers, S. G. Fluorinated Mechanism-Based

Inhibitors: Common Themes and Recent Developments. Curr. Top.

Med. Chem. 2014, 14 (7), 865−874.

Authors

(7) Kallemeijn, W. W.; Witte, M. D.; Wennekes, T.; Aerts, J. M. F.

G., Mechanism-Based Inhibitors of Glycosidases: Design and

Applications. In Advances in Carbohydrate Chemistry and Biochemistry;

Horton, D., Ed.; Elsevier, 2014; Vol. 71, pp 297−338.

(8) Lemieux, R. U. The Origin of the Specificity in the Recognition

of Oligosaccharides by Proteins. Chem. Soc. Rev. 1989, 18 (3), 347−

374.

David E. Wheatley − School of Chemistry, University of

Southampton, Highﬁeld, Southampton SO17 1BJ, U.K.;

orcid.org/0000-0002-5075-5554

Clement Q. Fontenelle − School of Chemistry, University of

Southampton, Highﬁeld, Southampton SO17 1BJ, U.K.;

orcid.org/0000-0002-1630-3407

(9) 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.

(10) Santana, A. G.; Jimenez-Moreno, E.; Gomez, A. M.; Corzana,

F.; Gonzalez, C.; Jimenez-Oses, G.; Jimenez-Barbero, J.; Luis Asensio,

J. A Dynamic Combinatorial Approach for the Analysis of Weak

Carbohydrate/Aromatic Complexes: Dissecting Facial Selectivity in

CH/pi Stacking Interactions. J. Am. Chem. Soc. 2013, 135 (9), 3347−

3350.

(11) Jiménez-Moreno, E.; Jimenez-Oses, G.; Gomez, A. M.; Santana,

A. G.; Corzana, F.; Bastida, A.; Jimenez-Barberodef, J.; Asensio, J. L. A

Thorough Experimental Study of CH/pi Interactions in Water:

Quantitative Structure-Stability Relationships for Carbohydrate/

Aromatic Complexes. Chemical Science 2015, 6 (11), 6076−6085.

Ramakrishna Kuppala − School of Chemistry, University of

Southampton, Highﬁeld, Southampton SO17 1BJ, U.K.;

orcid.org/0000-0002-6330-7187

Robert Szpera − School of Chemistry, University of

Southampton, Highﬁeld, Southampton SO17 1BJ, U.K.;

orcid.org/0000-0003-1351-1750

Edward L. Briggs − School of Chemistry, University of

Southampton, Highﬁeld, Southampton SO17 1BJ, U.K.

Jean-Baptiste Vendeville − School of Chemistry, University of

Southampton, Highﬁeld, Southampton SO17 1BJ, U.K.;

orcid.org/0000-0002-5790-6968

Neil J. Wells − School of Chemistry, University of

Southampton, Highﬁeld, Southampton SO17 1BJ, U.K.;

orcid.org/0000-0002-4607-5791

7752

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(12) Arda, A.; Jimenez-Barbero, J. The Recognition of Glycans by

Protein Receptors. Insights from NMR Spectroscopy. Chem. Commun.

2018, 54 (38), 4761−4769.

(31) Burkart, M. D.; Vincent, S. P.; Duffels, A.; Murray, B. W.; Ley,

S. V.; Wong, C. H. Chemo-enzymatic synthesis of fluorinated sugar

nucleotide: Useful mechanistic probes for glycosyltransferases. Bioorg.

Med. Chem. 2000, 8 (8), 1937−1946.

(32) Lee, H.-Y.; Chen, C.-Y.; Tsai, T.-I.; Li, S.-T.; Lin, K.-H.; Cheng,

Y.-Y.; Ren, C.-T.; Cheng, T.-J. R.; Wu, C.-Y.; Wong, C.-H.

Immunogenicity Study of Globo H Analogues with Modification at

the Reducing or Nonreducing End of the Tumor Antigen. J. Am.

Chem. Soc. 2014, 136 (48), 16844−16853.

(33) Allen, J. G.; Mujacic, M.; Frohn, M. J.; Pickrell, A. J.; Kodama,

P.; Bagal, D.; San Miguel, T.; Sickmier, E. A.; Osgood, S.; Swietlow,

A.; Li, V.; Jordan, J. B.; Kim, K.-W.; Rousseau, A.-M. C.; Kim, Y.-J.;

Caille, S.; Achmatowicz, M.; Thiel, O.; Fotsch, C. H.; Reddy, P.;

McCarter, J. D. Facile Modulation of Antibody Fucosylation with

Small Molecule Fucostatin Inhibitors and Cocrystal Structure with

GDP-Mannose 4,6-Dehydratase. ACS Chem. Biol. 2016, 11 (10),

2734−2743.

(34) Dai, Y.; Hartke, R.; Li, C.; Yang, Q.; Liu, J. O.; Wang, L.-X.

Synthetic Fluorinated l-Fucose Analogs Inhibit Proliferation of Cancer

Cells and Primary Endothelial Cells. ACS Chem. Biol. 2020, 15 (10),

2662−2672.

(35) Yang, J.; Fu, X.; Liao, J.; Liu, L.; Thorson, J. S. Structure-Based

Engineering of E. coli Galactokinase as a First Step toward In Vivo

Glycorandomization. Chem. Biol. 2005, 12 (6), 657−664.

(36) Romeo, J. R.; McDermott, L.; Bennett, C. S. Reagent-

Controlled α -Selective Dehydrative Glycosylation of 2,6-Dideoxy

Sugars: Construction of the Arugomycin Tetrasaccharide. Org. Lett.

2020, 22 (9), 3649−3654.

(37) Lee, J.; Kang, J.; Lee, S.; Rhee, Y. H. Flexible Total Synthesis of

11-Deoxylandomycins and Their Non-Natural Analogues by Way of

Asymmetric Metal Catalysis. Angew. Chem., Int. Ed. 2020, 59 (6),

2349−2353.

(38) Yalamanchili, S.; Miller, W.; Chen, X.; Bennett, C. S. Rapid de

Novo Preparation of 2,6-Dideoxy Sugar Libraries through Gold-

Catalyzed Homopropargyl Orthoester Cyclization. Org. Lett. 2019, 21

(23), 9646−9651.

(39) Nogueira, J. M.; Bylsma, M.; Bright, D. K.; Bennett, C. S.

Reagent-Controlled alpha-Selective Dehydrative Glycosylation of 2,6-

Dideoxy- and 2,3,6-Trideoxy Sugars. Angew. Chem., Int. Ed. 2016, 55

(34), 10088−92.

(40) Wang, H.-Y. L.; O’Doherty, G. A. De Novo Synthesis of Deoxy

Sugar via a Wharton Rearrangement. Chem. Commun. 2011, 47 (37),

10251−10253.

(41) Wang, H.-Y. L.; Xin, W.; Zhou, M.; Stueckle, T. A.;

Rojanasakul, Y.; O’Doherty, G. A. Stereochemical Survey of Digitoxin

Monosaccharides. ACS Med. Chem. Lett. 2011, 2 (1), 73−78.

(42) Hoang, K. M.; Lees, N. R.; Herzon, S. B. General Method for

the Synthesis of alpha- or beta-Deoxyaminoglycosides Bearing Basic

Nitrogen. J. Am. Chem. Soc. 2021, 143 (7), 2777−2783.

(43) Ahmed, M. M.; Berry, B. P.; Hunter, T. J.; Tomcik, D. J.;

O’Doherty, G. A. De Novo Enantioselective Syntheses of Galacto-

Sugars and Deoxy Sugars via the Iterative Dihydroxylation of

Dienoate. Org. Lett. 2005, 7 (4), 745−748.

(13) Soueidan, O. M.; Trayner, B. J.; Grant, T. N.; Henderson, J. R.;

Wuest, F.; West, F. G.; Cheeseman, C. I. New Fluorinated Fructose

Analogs as Selective Probes of the Hexose Transporter Protein

GLUT5. Org. Biomol. Chem. 2015, 13 (23), 6511−21.

(14) Potts, J. R.; Hounslow, A. M.; Kuchel, P. W. Exchange of

Fluorinated Glucose Across the Red-Cell Membrane Measured by F-

19-NMR Magnetization Transfer. Biochem. J. 1990, 266 (3), 925−

928.

(15) 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.

(16) 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.

(17) 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 Fluori-

nated Alkanols and Carbohydrates by a New log P Determination

Method. Angew. Chem., Int. Ed. 2016, 55 (2), 674−678.

̀

(18) Denavit, V.; Lainé, D.; St-Gelais, J.; Johnson, P. A.; Giguere, D.

A Chiron Approach Towards the Stereoselective Synthesis of

Polyfluorinated Carbohydrates. Nat. Commun. 2018, 9 (1), 4721.

(19) St-Gelais, J.; Bouchard, M.; Denavit, V.; Giguere, D. Synthesis

and Lipophilicity of Trifluorinated Analogues of Glucose. J. Org.

Chem. 2019, 84 (13), 8509−8522.

́

̂

̀

(20) St-Gelais, J.; Coté, E.; Lainé, D.; Johnson, P. A.; Giguere, D.

Addressing the Structural Complexity of Fluorinated Glucose

Analogues: Insight into Lipophilicities and Solvation Effects. Chem.

- Eur. J. 2020, 26 (59), 13499−13506.

(21) Ribeiro Morais, G.; Falconer, R. A.; Santos, I. Carbohydrate-

Based Molecules for Molecular Imaging in Nuclear Medicine. Eur. J.

Org. Chem. 2013, 2013 (8), 1401−1414.

(22) van der Born, D.; Pees, A.; Poot, A. J.; Orru, R. V. A.;

Windhorst, A. D.; Vugts, D. J. Fluorine-18 Labelled Building Blocks

for PET Tracer Synthesis. Chem. Soc. Rev. 2017, 46 (15), 4709−4773.

(23) Wuest, M.; Trayner, B. J.; Grant, T. N.; Jans, H.-S.; Mercer, J.

R.; Murray, D.; West, F. G.; McEwan, A. J. B.; Wuest, F.; Cheeseman,

C. I. Radiopharmacological Evaluation of 6-Deoxy-6- F-18 Fluoro-D-

fructose as a Radiotracer for PET Imaging of GLUT5 in Breast

Cancer. Nucl. Med. Biol. 2011, 38 (4), 461−475.

(24) Biffinger, J. C.; Kim, H. W.; DiMagno, S. G. The Polar

Hydrophobicity of Fluorinated Compounds. ChemBioChem 2004, 5

(5), 622−627.

(25) N’Go, I.; Golten, S.; Ardá, A.; Canada, J.; Jiménez-Barbero, J.;

̃

Linclau, B.; Vincent, S. P. Tetrafluorination of Sugars as Strategy for

Enhancing Protein-Carbohydrate Affinity: Application to UDP-Galp

Mutase Inhibition. Chem. - Eur. J. 2014, 20 (1), 106−112.

(26) van Straaten, K. E.; Kuttiyatveetil, J. R.; Sevrain, C. M.;

Villaume, S. A.; Jimenez-Barbero, J.; Linclau, B.; Vincent, S. P.;

Sanders, D. A. Structural Basis of Ligand Binding to UDP-

Galactopyranose Mutase from Mycobacterium tuberculosis Using

Substrate and Tetrafluorinated Substrate Analogues. J. Am. Chem. Soc.

2015, 137 (3), 1230−1244.

(44) Ahmed, M. M.; O’Doherty, G. A. De Novo Asymmetric

Syntheses of C-4-Substituted Sugars via an Iterative Dihydroxylation

Strategy. Carbohydr. Res. 2006, 341 (10), 1505−1521.

(45) Vickman, A. E.; Pohl, N. L. B. Probing Deoxysugar

Conformational Preference: A Comprehensive Computational Study

Investigating the Effects of Deoxygenation. Carbohydr. Res. 2019, 475,

17−26.

(27) De Lederkremer, R. M.; Marino, C. Deoxy Sugars: Occurrence

and Synthesis. In Advances in Carbohydrate Chemistry and

Biochemistry; Horton, D., Ed.; Elsevier, 2008; Vol. 61, pp 143−216.

(28) Trefzer, A.; Salas, J. A.; Bechthold, A. Genes and Enzymes

Involved in Deoxysugar Biosynthesis in Bacteria. Nat. Prod. Rep. 1999,

16 (3), 283−299.

(29) Hou, D.; Lowary, T. L. Recent Advances in the Synthesis of 2-

Deoxy-Glycosides. Carbohydr. Res. 2009, 344 (15), 1911−1940.

(30) Kirschning, A.; Jesberger, M.; Schoning, K. U. Concepts for the

Total Synthesis of Deoxy Sugars. Synthesis 2001, 2001 (4), 507−540.

(46) Schlunzen, F.; Zarivach, R.; Harms, J.; Bashan, A.; Tocilj, A.;

̈

Albrecht, R.; Yonath, A.; Franceschi, F. Structural Basis for the

Interaction of Antibiotics with the Peptidyl Transferase Centre in

Eubacteria. Nature 2001, 413 (6858), 814−821.

(47) Borisova, S. A.; Zhang, C.; Takahashi, H.; Zhang, H.; Wong, A.

W.; Thorson, J. S.; Liu, H.-w. Substrate Specificity of the Macrolide-

Glycosylating Enzyme Pair DesVII/DesVIII: Opportunities, Limi-

tations, and Mechanistic Hypotheses. Angew. Chem., Int. Ed. 2006, 45

(17), 2748−2753.

7753

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(48) Zhang, C.; Fu, Q.; Albermann, C.; Li, L.; Thorson, J. S. The In

Vitro Characterization of the Erythronolide Mycarosyltransferase

EryBV and Its Utility in Macrolide Diversification. ChemBioChem

2007, 8 (4), 385−390.

(49) Belousoff, M. J.; Shapira, T.; Bashan, A.; Zimmerman, E.;

Rozenberg, H.; Arakawa, K.; Kinashi, H.; Yonath, A. Crystal Structure

of the Synergistic Antibiotic Pair, Lankamycin and Lankacidin, in

Complex with the Large Ribosomal Subunit. Proc. Natl. Acad. Sci. U.

S. A. 2011, 108 (7), 2717.

(50) Zhang, Y.; Zhang, J.; Ponomareva, L. V.; Cui, Z.; Van Lanen, S.

G.; Thorson, J. S. Sugar-Pirating as an Enabling Platform for the

Synthesis of 4,6-Dideoxyhexoses. J. Am. Chem. Soc. 2020, 142 (20),

9389−9395.

(51) Woo, P. W. K.; Dion, H. W.; Bartz, Q. R. Chemistry of

Chalcose, a 3-Methoxy-4,6-Dideoxyhexose. J. Am. Chem. Soc. 1961, 83

(15), 3352−3353.

(52) Keller-Schierlein, W.; Roncari, G. Stoffwechselprodukte von

Actinomyceten. 33. Mitteilung. Hydrolyseprodukte von Lankamycin:

Lankavose und 4-O-Acetyl-arcanose. Helv. Chim. Acta 1962, 45 (1),

138−152.

(53) Graziani, E. I.; Overk, C. R.; Carter, G. T. Purification,

Structure Determination, and Antimicrobial Activity of Neutramycins

B-G. J. Nat. Prod. 2003, 66 (9), 1149−1153.

(54) Velvadapu, V.; Andrade, R. B. Concise Syntheses of D-

Desosamine, 2-Thiopyrimidinyl Desosamine Donors, and Methyl

Desosaminide Analogues from D-Glucose. Carbohydr. Res. 2008, 343

(1), 145−50.

(55) Zhang, Z.; Fukuzaki, T.; Myers, A. G. Synthesis of D-

Desosamine and Analogs by Rapid Assembly of 3-Amino Sugars.

Angew. Chem., Int. Ed. 2016, 55 (2), 523−527.

(56) Zeng, J.; Wang, R.; Wang, Y.; Zhang, S.; Sun, G.; Liao, Z.;

Meng, L.; Wan, Q. Diversified Synthesis and α -Selective Glyco-

sylation of 3-Amino-2,3,6-trideoxy Sugars. Org. Chem. Front. 2018, 5

(23), 3391−3395.

(57) Thibodeaux, C. J.; Melanco̧ n, C. E.; Liu, H.-w. Natural-Product

Sugar Biosynthesis and Enzymatic Glycodiversification. Angew. Chem.,

Int. Ed. 2008, 47 (51), 9814−9859.

(58) 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.

(59) Lindhorst, T. K.; Thiem, J. Synthesis of 4-Deoxy and 4-Deoxy-

4-Halogeno Derivatives of L-Fucose as Potential Enzyme-Inhibitors.

Carbohydr. Res. 1991, 209, 119−129.

(65) Limberg, G.; Thiem, J. Synthesis of Modified Aldonic Acids

and Studies of Their Substrate Efficiency for Dihydroxy Acid

Dehydratase (DHAD). Aust. J. Chem. 1996, 49 (3), 349−356.

(66) Daranas, A. H.; Shimizu, H.; Homans, S. W. Thermodynamics

of Binding of D-galactose and Deoxy Derivatives thereof to the L-

Arabinose Binding Protein. J. Am. Chem. Soc. 2004, 126 (38), 11870−

11876.

(67) Koto, S.; Morishima, N.; Mori, Y.; Tanaka, H.; Hayashi, S.;

Iwai, Y.; Zen, S. Partially Benzylated Derivatives of 6-Deoxy-D-

glucose. Bull. Chem. Soc. Jpn. 1987, 60 (6), 2301−2303.

(68) Somawardhana, C. W.; Brunngraber, E. G. Stereo- and Regio-

selectivity of Diethylaminosulfur Trifluoride as a Fluorinating Reagent

for Methyl Glycosides. Carbohydr. Res. 1983, 121, 51−60.

(69) Somawardhana, C. W.; Brunngraber, E. G. A One-Step

Synthesis of Methyl 4,6-Dideoxy-4,6-difluoro-alpha-D-galactopyrano-

side. Carbohydr. Res. 1981, 94 (2), C14−C15.

̈

(70) Helferich, B.; Löwa, A.; Nippe, W.; Riedel, H. Uber zwei neue

Derivate von Trehalose und Mannit und uber ein α -Methylglucosid-

̈

dichlorhydrin. Ber. Dtsch. Chem. Ges. B 1923, 56 (5), 1083−1087.

(71) Bragg, P. D.; Jones, J. K. N.; Turner, J. C. The Reaction of

Sulphuryl Chloride with Glycosides and Sugar Alcohols. Part I. Can. J.

Chem. 1959, 37 (9), 1412−1416.

(72) Jennings, H. J.; Jones, J. K. N. Reactions of Sugar

Chlorosulfates: Part V. The Synthesis of Chlorodeoxy Sugars. Can.

J. Chem. 1965, 43 (8), 2372−2386.

(73) Doboszewski, B.; Hay, G. W.; Szarek, W. A. The Rapid

Synthesis of Deoxyfluoro Sugars Using Tris(dimethylamino)-

sulfonium Difluorotrimethylsilicate (TASF). Can. J. Chem. 1987, 65

(2), 412−419.

(74) Reist, E. J.; Spencer, R. R.; Calkins, D. F.; Baker, B. R.;

Goodman, L. Derivatives of 4-Amino-4-deoxy-D-glucose. J. Org.

Chem. 1965, 30 (7), 2312−2317.

(75) Esmurziev, A. M.; Simic, N.; Hoff, B. H.; Sundby, E. Synthesis

and Structure Elucidation of Benzoylated Deoxyfluoropyranosides. J.

Carbohydr. Chem. 2010, 29 (7), 348−367.

(76) Card, P. J. Fluorinated Carbohydrates. Use of DAST in the

Synthesis of Fluorinated Sugars. J. Org. Chem. 1983, 48 (3), 393−395.

(77) Card, P. J.; Reddy, G. S. Fluorinated Carbohydrates. 2.

Selective Fluorination of Glucopyranosides and Mannopyranosides -

Use OF 2-D NMR for Structural Assignments. J. Org. Chem. 1983, 48

(24), 4734−4743.

(78) Fontenelle, C. Q.; Shishmarev, D.; Kuchel, P. W.; Linclau, B.

The Synthesis of 3,4-Dideoxy-3,4-difluoro-D-glucose. Trends Carbo-

hydr. Res. 2017, 9 (1), 28−33.

(79) Wang, B.-L.; Yu, F.; Qiu, X.-L.; Jiang, Z.-X.; Qing, F.-L.

Synthesis of Trifluoromethylated Analogues of β -L-Fucofuranose and

β -L-4,6-Dideoxyxylohexopyranose. J. Fluorine Chem. 2006, 127 (4),

580−587.

(80) Ley, S. V.; Owen, D. R.; Wesson, K. E. Rapid Access to Rare

Natural Pyranosides Using 1,2-Diacetal Protected Intermediates. J.

Chem. Soc., Perkin Trans. 1 1997, No. 19, 2805−2806.

(81) Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.; Foster, A. C.; Ince, S.

J.; Priepke, H. W. M.; Reynolds, D. J. 1,2-diacetals: A New

Opportunity for Organic Synthesis. Chem. Rev. 2001, 101 (1), 53−80.

(82) Fontenelle, C. Q.; Kuppala, R.; Light, M.; Linclau, B. Isolation

and Characterisation of an Unexpected Byproduct in the

Regioselective Butane Diacetal Protection of Alpha-Methyl Galacto-

pyranoside. Carbohydr. Res. 2018, 455, 14−17.

(83) Douglas, N. L.; Ley, S. V.; Osborn, H. M. I.; Owen, D. R.;

Priepke, H. W. M.; Warriner, S. L. Direct Protection of 1,2-Diols from

Alpha-diketones. Synlett 1996, 1996 (8), 793−795.

(84) Montchamp, J. L.; Tian, F.; Hart, M. E.; Frost, J. W. Butane 2,3-

Bisacetal Protection of Vicinal Diequatorial Diols. J. Org. Chem. 1996,

61 (11), 3897−3899.

(85) Dang, H. S.; Roberts, B. P.; Sekhon, J.; Smits, T. M.

Deoxygenation of Carbohydrates by Thiol-Catalysed Radical-chain

Redox Rearrangement of the Derived Benzylidene Acetals. Org.

Biomol. Chem. 2003, 1 (8), 1330−1341.

(60) Aburaki, S.; Yamashita, H.; Ohnuma, T.; Kamachi, H.;

Moriyama, T.; Masuyoshi, S.; Kamei, H.; Konishi, M.; Oki, T.

Synthesis and Antifungal Activity of Pradimicin Derivatives -

Modifications of the Sugar Part. J. Antibiot. 1993, 46 (4), 631−640.

(61) Mori, Y.; Morishima, N. Ring Contraction in the Fluorination

of Methyl 2-O-Benzyl-3,6-Dideoxy-alpha-D-Hexopyranoside and

Methyl 2,3-di-O-Benzyl-6-Deoxy-alpha-D-Hexopyranosides with Di-

ethylaminosulphur trifluoride (DAST). Chem. Pharm. Bull. 1992, 40

(3), 826−828.

(62) Valverde, P.; Delgado, S.; Martínez, J. D.; Vendeville, J.-B.;

̃

Malassis, J.; Linclau, B.; Reichardt, N.-C.; Canada, F. J.; Jiménez-

Barbero, J.; Ardá, A. Molecular Insights into DC-SIGN Binding to

Self-Antigens: The Interaction with the Blood Group A/B Antigens.

ACS Chem. Biol. 2019, 14 (7), 1660−1671.

(63) Ando, T.; Ishida, H.; Kiso, M.; Hasegawa, A. Fluorination of

Methyl 6-Deoxy-1-thiohexopyranosides with Diethylaminosulfur

Trifluoride (DAST), and the Formation of Unexpected Products.

Carbohydr. Res. 1993, 249 (1), 275−280.

(64) Hultin, P. G.; Buffie, R. M. Syntheses of Methyl (4,6-dideoxy-

alpha-L-lyxo-hexopyranosyl)-(1 -> 3)- and (4-Deoxy-4-fluoro-alpha-

L-rhamnopyranosyl)-(1 -> 3)-2-acetamido-2-deoxy-alpha-D-glucopyr-

anosides, Analogs of the Mycobacterial Arabinogalactan Linkage

Disaccharide. Carbohydr. Res. 1999, 322 (1−2), 14−25.

7754

https://doi.org/10.1021/acs.joc.1c00796

J. Org. Chem. 2021, 86, 7725−7756

Article Doi

Synthesis and Structural Characteristics of all Mono- And Difluorinated 4,6-Dideoxy- d - Xylo-hexopyranoses

DOI: 10.1021/acs.joc.1c00796

Source and publish data:

Authors:

Article abstract of DOI:10.1021/acs.joc.1c00796

Full text of DOI:10.1021/acs.joc.1c00796

Products guided by the article

R&D Labs maybe for 1263311-58-5

Relevant to this article

Hot Product