De novo synthesis of racemic 4-deoxy-4,4-difluoro- and 2,4-dideoxy-2,4,4- trifluorohexosides

Article abstract of DOI:10.1002/ejoc.201100565

A range of racemic 4-deoxy-4,4-difluorinated carbohydrates were prepared by using a diversity-oriented de novo synthesis starting with three commercially available two-carbon building blocks. A common gem-difluorinated glycal was prepared in 35 % yield in

Full text of DOI:10.1002/ejoc.201100565

FULL PAPER
DOI: 10.1002/ejoc.201100565
De Novo Synthesis of Racemic 4-Deoxy-4,4-difluoro- and 2,4-Dideoxy-2,4,4-
trifluorohexosides
Guy T. Giuffredi,[a] Bruno Bernet,[b] and Véronique Gouverneur*[a]
Keywords: Carbohydrates / Fluorine / Synthetic methods / Combinatorial chemistry / Gold
A range of racemic 4-deoxy-4,4-difluorinated carbohydrates
were prepared by using a diversity-oriented de novo synthe-
sis starting with three commercially available two-carbon
building blocks. A common gem-difluorinated glycal was
prepared in 35% yield in seven steps, from which five dif-
ferent 4-deoxy-4,4-difluoro- and 4-deoxy-2,4,4-trifluoro-
hexopyranosides were accessed using well-established func-
tional group manipulations.
desired probes. Herein we present a diversity-oriented ap-
proach towards a series of novel racemic 4,4-difluorinated
hexopyranosides.
Introduction
Nature relies on weak interactions such as hydrogen
bonds to construct complex supramolecular architectures;
this is best illustrated with the three-dimensional structures
of enzymes or nucleic acids. Inspired by these systems,
chemists have exploited non-covalent interactions to ad-
vance synthesis and catalysis as well as the field of selective
molecular recognition.[1] The growing prevalence of fluori-
nated pharmaceuticals,[2] agrochemicals,[3] and materials[4]
in our daily life underscores the need to further understand
the effects of fluorine substitution for archetypical mole-
cules.[5] Various groups have studied the ability of the C–F
bond to engage in hydrogen bonding both in the solid state
and in solution.[6] NMR spectroscopy has unveiled the exis-
tence of C–F···H–X hydrogen bonds between carbon-
bound fluorine and intramolecular H-bond donors.[7–9] For
these investigations, carbohydrate-derived 1,3-diaxial and
1,2-cis-fluoroalcohols are ideal probes by virtue of their ri-
gid ring structure (Figure 1a).[7,8] No information is avail-
able on the effect of gem-difluorination on C–F···H–O
bonding, so we initiated a study aimed at accessing repre-
sentative 4-deoxy-4,4-difluorohexopyranosides (Ϯ)-1 and
(Ϯ)-2 for interrogation using NMR spectroscopy (Fig-
ure 1b). A comparative study with the corresponding mono-
fluorinated structural analogs[10] will allow us to gain fur-
ther insight into the strength and persistence of C–F···H–O
bonding in these systems. Currently, such investigations are
hampered by the lack of efficient synthetic routes to the
Figure 1. (a) Previously observed C–F···H–O bonds in fluorinated
carbohydrates;[7,8] (b) fluorinated carbohydrates (Ϯ)-1 and (Ϯ)-2 as
novel probes to investigate the effect of geminal fluorination on C–
F···H–O.
The installation of a difluoromethylene group at a late
stage is synthetically challenging. Electrophilic fluorination
allows for the preparation of 2,2-difluoro sugars from 2-
fluoroglycals only,[11] and nucleophilic fluorination of
carbonyl groups with diethylaminosulfur trifluoride
(DAST)[12] can suffer from side reactions resulting from
neighboring group participation, migration, or elimi-
nation.[13] Alternatively, gem-difluorinated monosaccha-
rides can be prepared by de novo synthesis, whereby the
highly functionalized molecular core is assembled from
small building blocks, one of them featuring the key difluo-
romethylene motif.[14,15] Hitherto, only two racemic de novo
syntheses of 4-deoxy-4,4-difluorohexosides have been re-
[a] Chemistry Research Laboratory, University of Oxford,
Oxford OX1 3TA, United Kingdom
Fax: +44-1865-275-644
E-mail: veronique.gouverneur@chem.ox.ac.uk
[b] Laboratorium für Organische Chemie, ETH Zürich,
Wolfgang Pauli-Strasse 10, 8093 Zürich, Switzerland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100565.
Eur. J. Org. Chem. 2011, 3825–3836
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. T. Giuffredi, B. Bernet, V. Gouverneur
FULL PAPER
ported. In 1993, Taguchi and co-workers described the syn- tatively difluorinated terminal ynone (Ϯ)-3. This three-step
thesis of 4-deoxy-4,4-difluoro-threo-hexopyranosides in synthesis of (Ϯ)-3 is a significant improvement (65% overall
eight steps with an overall yield of 16%, featuring a Diels– yield) over the previously reported preparation (9% overall
Alder reaction as the key cyclization step.[15c] More recently, yield[16e]).
Percy and co-workers described the synthesis of 4-deoxy-
4,4-difluoromannoses and -alloses in six steps with overall
yields of up to 17%, applying a ring-closing metathesis re-
action as their key step.[15a] Based on our past experience
on the development of novel fluorination reactions[16] and
the synthesis of fluorinated carbohydrate analogs,[17] we
conceive a robust de novo synthesis of a range of novel
racemic 4-deoxy-4,4-difluorohexopyranosides starting with
three commercially available two-carbon precursors. We
have demonstrated that dihydropyranone (Ϯ)-4 is accessible
Scheme 2. Preparation of ynone (Ϯ)-3. Reagents and conditions:
(i) Zn dust, CuCl, BF3·OEt2, THF/Et2O, 0 °C to r.t., 16 h, 77%;
(ii) NHMeOMe·HCl, AlMe3, THF, –78 °C to r.t., 1 h, (Ϯ)-8 (85%),
(Ϯ)-9 (9%); (iii) ethynylmagnesium bromide, THF, 0 °C, 5 h, quan-
titative.
by a four-step protocol with a 6-endo-dig gold-catalyzed cy-
clization of ynone (Ϯ)-3 as the key reaction (Scheme 1).[16e]
In addition, Taguchi and co-workers reported that stereose-
lective reduction of (Ϯ)-4 under Luche conditions leads to
key cis-glycal (Ϯ)-cis-5.[15c] With these two precedents, we
surmise that a subsequent diversity-oriented functionaliza-
tion of (Ϯ)-cis-5 by electrophilic additions to the enolic
double bond should give access to a range of diversely sub-
stituted racemic 4-deoxy-4,4-difluorohexopyranosides in-
clusive of the desired methyl α-d/l-talopyranosides (Ϯ)-1
and (Ϯ)-2.
Treatment of (Ϯ)-3 with four successive portions of
gold(III) chloride (2.5 mol-%) afforded the corresponding
5,5-difluoro-5,6-dihydropyran-4-one (Ϯ)-4 in 75% yield
after 2 d (Table 1, Entry 1).[16e] The use of gold(I) chloride
also required four additions (2.5 mol-% portions), but the
yield was reduced to 67% (Table 1, Entry 2). When chloro-
(triphenylphosphane)gold(I) (1 mol-%) and silver triflate
(2 mol-%) were used (Table 1, Entry 3), starting material
(Ϯ)-3 was completely consumed within 1 h and (Ϯ)-4 was
isolated in 49% yield. The yield was raised to 63–66% upon
treatment with (SIPr)AuCl[18] [SIPr = 1,3-bis(2,6-diisopro-
pylphenyl)imidazolin-2-ylidene] (1 mol-%) and silver triflate
(2 mol-%) at room temperature or 0 °C (Table 1, Entries 4
and 5). The highest yield (87%) was obtained with 1 mol-%
of the Gagosz catalyst[19] (Ph3PAuNTf2) (Table 1, Entry 6).
Table 1. Cyclization of (Ϯ)-3.
Scheme 1. Synthetic plan.
Entry
Catalyst
Time
[h]
Yield
[%]
Results and Discussion
1
2
3
4
5
6
10 mol-% AuCl3
10 mol-% AuCl
1 mol-% Ph3PAuCl / 2 mol-% AgOTf
1 mol-% (SIPr)AuCl / 2 mol-% AgOTf
1 mol-% (SIPr)AuCl / 2 mol-% AgOTf 1 (0 °C)
1 mol-% Ph3PAuNTf2 24
48
48
1
75
67
49
63
66
87
Optimization of the Preparation of the Key Intermediate:
syn-Glycal (؎)-cis-5
1
Our study commenced with the preparation of ynone
(Ϯ)-3 from three two-carbon building blocks (Scheme 2).
The use of rigorously dried solvents led to an improvement
in the previously reported Reformatsky reaction of ethyl
Taguchi and co-workers described the reduction of dihy-
bromodifluoroacetate (6) with (benzyloxy)acetaldehyde. β- dropyranone (Ϯ)-4 under Luche conditions (cerium chlo-
Hydroxy ester (Ϯ)-7 was delivered in 77% yield after 16 h ride heptahydrate and sodium borohydride) and obtained
at room temperature (ref.[16e] 57%). To ensure selective (Ϯ)-cis-5 and (Ϯ)-trans-5 in 81% yield as a 94:6 cis/trans
monoaddition of the Grignard reagent, Weinreb amide (Ϯ)- mixture.[15c] In our hands, the selectivity of this reaction
8 was prepared in 85% yield by treating ester (Ϯ)-7 with dropped to 90:10 and the yield to 60% (Table 2, Entry 1).
N,O-dimethylhydroxylamine hydrochloride.[16e] Demethyl- A complex mixture of products was observed when (Ϯ)-4
ated (Ϯ)-9 was formed as a side product (9% yield). Ad- was treated with l-Selectride. The highest diastereoselectiv-
dition of ethynylmagnesium bromide to (Ϯ)-8 gave quanti- ity (cis/trans = 92:8) was observed upon reduction with di-
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Racemic 4-Deoxy-4,4-difluoro- and 2,4-Dideoxy-2,4,4-trifluorohexosides
isobutylaluminum hydride (DIBAL) in dichloromethane yield was improved to 80% when the reaction was carried
(63% yield; Table 2, Entry 2), and the highest yield of out with a stoichiometric amount of osmium tetroxide and
81% with DIBAL in toluene (cis/trans = 87:13; Table 2, En- tetramethylethylenediamine (TMEDA) in dichloromethane
try 3).
at –78 °C. Acetylation of (Ϯ)-11 delivered triacetate (Ϯ)-12
in 96% yield as a 3:1 α/β mixture. The anomers of (Ϯ)-12
were assigned by the upfield shift for H–C(1) of the β-d/l-
anomers and its large J(1,2) coupling of 8.5 Hz, but could
not be separated by silica gel chromatography. Treatment of
(Ϯ)-11 with 2,2-dimethoxypropane and TsOH·H2O in ace-
tone gave isopropylidene acetal (Ϯ)-13 in 63% yield. The
structure of (Ϯ)-13 was confirmed by X-ray analysis; only
d-13 is depicted in Scheme 4.
Table 2. Reduction of pyranone (Ϯ)-4.
Entry
Reagent
Solvent
Yield [%] cis/trans
1
2
3
NaBH4/CeCl3·7H2O
DIBAL
MeOH
CH2Cl2
toluene
60
63
81
90:10
92:8
87:13
Synthesis of 4-Deoxy-4,4-difluoro-D/L-mannopyranoses
DIBAL
In attempts to obtain 4-deoxy-4,4-difluoro-d/l-manno-
pyranoses, glycal (Ϯ)-cis-5 was treated with meta-chloroper-
benzoic acid (m-CPBA) in water. This reaction delivered,
after subsequent acetylation, an anomeric mixture of gluco-
configured triacetate (Ϯ)-12 as the only isolable product
(16%) (Scheme 5). However, when performing the oxi-
dation with m-CPBA in methanol, methyl α-d/l-mannopyr-
anoside (Ϯ)-1 was obtained in 41% yield, along with 28%
of β-d/l-gluco isomer (Ϯ)-14, evidencing the intermediate
formation of epimeric 1,2-epoxides. Diastereoisomers (Ϯ)-
1 and (Ϯ)-14 were easily separated by silica gel chromatog-
raphy. The α-d/l-manno configuration of (Ϯ)-1 is evidenced
by a small J(1,2) value (1.6 Hz) and by the downfield shift
of H-3 (3.78–3.68 ppm) and H-5 (δ =3.90 ppm). Crystalli-
zation of (Ϯ)-1 from ethyl acetate and hexane gave crystals
suitable for X-ray analysis, which confirmed the α-d/l-
manno configuration of (Ϯ)-1; only d-1 is depicted in
Scheme 5.
Hydroxyglycals (Ϯ)-cis-5 and (Ϯ)-trans-5 could not be
separated by silica gel chromatography. Therefore, a 92:8
mixture of (Ϯ)-cis-5/(Ϯ)-trans-5 was transformed into pival-
ates (Ϯ)-cis-10/(Ϯ)-trans-10 by treatment with pivaloyl
chloride in pyridine. Chromatography on silica gel gave (Ϯ)-
cis-10 (75% yield), a mixture of (Ϯ)-cis-10 and (Ϯ)-trans-
10 (24% yield), and a pure sample of trans-10 (Scheme 3).
Deprotection of (Ϯ)-cis-10 with 1,8-diazabicycloundec-7-
ene (DBU) proceeded quantitatively to afford pure (Ϯ)-cis-
5. With pure syn-glycal (Ϯ)-cis-5 in hand, we started the
diversity-oriented functionalization.
Scheme 3. Preparation of pure syn-glycal (Ϯ)-cis-5. Reagents and
conditions: (i) PivCl, pyridine, 0 °C to r.t., 16 h, 75% of (Ϯ)-cis-5,
24% of (Ϯ)-cis-5/(Ϯ)-trans-5, and a sample of pure (Ϯ)-trans-5;
(ii) DBU, MeOH, r.t., 16 h, Ͼ95%.
Synthesis of 4-Deoxy-4,4-difluoro-D/L-glucopyranoses
Dihydroxylation of (Ϯ)-cis-5 under the standard Upjohn
conditions (OsO4, NMO) led to a 1:1 anomeric mixture of
gluco-configured triol (Ϯ)-11 in 75% yield (Scheme 4). The
Scheme 5. Synthesis and X-ray analysis of 4-deoxy-4,4-difluoro-α-
d/l-mannopyranoside (Ϯ)-1. Reagents and conditions: (i) 1. m-
CPBA, H2O, 0 °C to r.t., 16 h; 2. Ac2O, pyridine, r.t., 16 h, 16%;
(ii) m-CPBA, MeOH, 0 °C to r.t., 16 h, (Ϯ)-1 (41%), (Ϯ)-14 (28%).
Synthesis of 2,4-Dideoxy-4,4-difluoro-
hexopyranosides
D/L-threo-
Scheme 4. Synthesis of 4-deoxy-4,4-difluoro-d/l-glucopyranoses
(Ϯ)-12 and (Ϯ)-13 and X-ray structure of isopropylidene acetal
(Ϯ)-13. Reagents and conditions: (i) OsO4, TMEDA, CH2Cl2,
–78 °C, 16 h, 80%; (ii) Ac2O, DMAP, pyridine, r.t., 16 h, 96%;
(iii) CMe2(OMe)2, TsOH.H2O, acetone, r.t., 63%.
Treatment of (Ϯ)-cis-5 with HCl in methanol and chro-
matographic separation on silica gel delivered methyl 2,4-
dideoxy-4,4-difluoro-α-d/l-hexopyranoside (Ϯ)-α-15 and
its β-d/l-anomer (Ϯ)-β-15 in 83 and 10% yield, respectively
Eur. J. Org. Chem. 2011, 3825–3836
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G. T. Giuffredi, B. Bernet, V. Gouverneur
FULL PAPER
(Scheme 6). Hydrogenation of (Ϯ)-α-15 delivered diol (Ϯ)- chromatography allowed partial separation of the anomers,
16 in quantitative yield. X-ray crystal analysis of (Ϯ)-16 affording 42% of pure (Ϯ)-β-19 and 15% of pure (Ϯ)-α-
confirmed the structural assignment; only d-16 is depicted 19. Single-crystal analysis of major β-d/l anomer (Ϯ)-β-19
in Scheme 6.
allowed unambiguous structural assignment; only d-β-19 is
depicted in Scheme 7. The pyranosyl ring of crystalline d-β-
19 adopts a S conformation with a pseudoequatorial ester
5
moiety and an axial benzyloxymethyl group. 4-Deoxy-4,4-
difluoro-d/l-allopyranoses should be accessible by applying
the conditions of Percy and co-workers[15a] to (Ϯ)-β-19.
Synthesis of 2,4-Dideoxy-2,4,4-trifluoro-D/L-hexopyranoses
Following procedures reported by Wong and Dax,[20] flu-
orination of glycal (Ϯ)-cis-5 was attempted using Se-
lectfluor in a mixture of nitromethane and water at room
temperature (Scheme 8). Only trace amounts of trifluorin-
ated products were formed within 16 h; prolonged reaction
times of up to 5 d did not lead to a satisfactory conversion.
At 60 °C, the reaction went to completion within 16 h when
using 1.2 equiv. of Selectfluor in a 1:5 mixture of nitrometh-
ane/water. A 3:2 mixture of α/β-d/l-glucopyranose (Ϯ)-20
(α/β = 2:1) and α-d/l-mannopyranose (Ϯ)-21 was identified
by 19F NMR spectroscopy of the crude mixture. Acetyl-
ation of the crude product and chromatographic separation
on silica gel delivered α/β-d/l-glucopyranosyl acetates (Ϯ)-
22 (α/β = 2:1) and α-d/l-mannopyranosyl acetate (Ϯ)-23 in
55 and 38% yield, respectively. Inspired by the work of Dax
and co-workers,[20b] pivaloylated glycal (Ϯ)-cis-10 was
treated with Selectfluor to improve the diastereoselectivity.
19F NMR spectroscopic analysis of the crude product indi-
cated a 5:1 ratio of (Ϯ)-24 (α/β = 3:1)/(Ϯ)-25. Acetylation
and chromatographic separation delivered (Ϯ)-26 (α/β =
3:1) and (Ϯ)-27 in 53 and 15% yield, respectively.
Scheme 6. Synthesis and X-ray analysis of 2,4-dideoxy-4,4-di-
fluoro-α-d/l-threo-hexopyranoside (Ϯ)-16. Reagents and condi-
tions: (i) 37% HCl, THF/MeOH, 40 °C, 20 h, (Ϯ)-α-15 (83%), (Ϯ)-
β-15 (10%); (ii) H2, 10% Pd/C, MeOH, r.t., 3 h, Ͼ95%.
Synthesis towards 4-Deoxy-4,4-difluoro-D/L-allopyranoses
Percy and co-workers reported that the dihydroxylation
of 2,3-unsaturated (Ϯ)-17 delivers 4-deoxy-4,4-difluoro-β-
d/l-allopyranoside (Ϯ)-18 in good yields (Scheme 7).[15a] To
assess the ability of (Ϯ)-cis-5 to engage in SN2Ј substitution
under standard Mitsunobu conditions, (Ϯ)-cis-5 was
treated with para-nitrobenzoic acid, diisopropyl azodicar-
boxylate (DIAD), and triphenylphosphane. This transfor-
mation led to a 2:1 mixture of desired α/β-d/l-hex-2-enopy-
ranosides (Ϯ)-β-19/(Ϯ)-α-19 in 89% yield. Silica gel
Scheme 8. Synthesis of 2,4,4-trifluoro-d/l-hexopyranoses (Ϯ)-20–
27. Reagents and conditions: (i) Selectfluor, MeNO2/H2O (1:5),
80 °C, 16 h; (ii) Ac2O, DMAP, pyridine, CH2Cl2, r.t., 16 h, (Ϯ)-22
(55%, α/β = 2:1), (Ϯ)-23 (38%), (Ϯ)-26 (53%, α/β = 3:1), (Ϯ)-27
(15%).
To get direct access to 2,4,4-trifluorinated methyl α-d/l-
mannopyranoside (Ϯ)-2, glycal (Ϯ)-cis-5 was treated with
Selectfluor in a 1:3 mixture of nitromethane/methanol for
16 h at 60 °C (Scheme 9). Silica gel chromatography gave
the desired mannopyranoside (Ϯ)-2 in 19% yield together
with the gluco-anomers (Ϯ)-α-28 (14%) and (Ϯ)-β-28
Scheme 7. Synthesis of anomeric hex-2-enopyranosides (Ϯ)-β-19
and (Ϯ)-α-19 and X-ray structure of (Ϯ)-β-19. Reagents and condi-
tions: (i) p-NO2BzOH, PPh3, DIAD, toluene, r.t., 24 h, (Ϯ)-β-19
(42%), (Ϯ)-α-19 (15%).
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Racemic 4-Deoxy-4,4-difluoro- and 2,4-Dideoxy-2,4,4-trifluorohexosides
in deuterated solvents using Bruker DPX400, AV400, and AV500
spectrometers. 13C NMR spectra were recorded in deuterated sol-
vents using Bruker DPX400, AV400, and AV500 spectrometers
with a carbon-13 cryoprobe. 19F spectra (both with and without
proton decoupling) were recorded with Bruker AV400 and AV500
(35%). The α-d/l-manno configuration of (Ϯ)-2 is evi-
denced by a small J(1,2) value (1.6 Hz), the downfield shift
of H-3 (δ = 4.17–4.01 ppm) and H-5 (δ = 4.10 ppm), a large
3J(H-3,F) (27 Hz), and a distinctly smaller 3J(H-1,F)
(9 Hz).
1
spectrometers. H and 13C NMR spectra are reported as chemical
shifts (δ) in parts per million (ppm) relative to the solvent peak
using the Bruker internal referencing procedure (edlock). 19F NMR
spectra are referenced relative to CFCl3 in CDCl3. The following
abbreviations are used to describe multiplicities, s = singlet, d =
doublet, t = triplet, q = quartet, br. = broad, m = multiplet. Low-
and high-resolution mass spectra were recorded with a Bruker
MicroTof spectrometer using positive or negative electrospray ion-
ization (ESI+/ESI–). IR spectra were recorded as thin films on
NaCl plates, neat or in solution in CHCl3 or CH2Cl2 with a Bruker
Tensor 27 FTIR spectrometer. Absorptions are measured in wave-
numbers (cm–1) and only peaks of interest are reported.
Scheme 9. Synthesis of 2,4-dideoxy-2,4,4-trifluorohexopyranosides
(Ϯ)-2, (Ϯ)-α-28, and (Ϯ)-β-28. Reagents and conditions: (i) Se-
lectfluor, MeNO2/MeOH (1:3), 80 °C, 16 h, (Ϯ)-2 (19%), (Ϯ)-α-28
(14%), (Ϯ)-β-28 (35%).
The 19F NMR spectra of trifluorides (Ϯ)-2 and (Ϯ)-28
exhibit characteristic J(F,F) couplings. Besides the large
2J(Fax-4,Feq-4) of 250 Hz, (Ϯ)-2 shows 1FJ(F-2,Fax-4) of
Ethyl (؎)-4-(Benzyloxy)-2,2-difluoro-3-hydroxybutanoate [(؎)-
7]:[16e] A suspension of zinc dust (0.40 g, 6.0 mmol) and copper(I)
chloride (60 mg, 0.6 mmol) in freshly dried diethyl ether/tetra-
hydrofuran (4:1) (12.5 mL) was vigorously stirred for 1 h at room
temperature and treated with ethyl bromodifluoroacetate (0.25 mL,
2.0 mmol), freshly prepared benzyloxy acetaldehyde (0.31 mL,
2.2 mmol), and boron trifluoride diethyl ether (0.27 mL, 2.2 mmol).
The suspension was stirred overnight and filtered through Celite,
and the solvents were evaporated. Purification by column
chromatography on silica gel (hexane/EtOAc, 85:15 to 80:20) af-
forded alcohol (Ϯ)-7 (0.42 g, 77%) as a colorless oil. Rf = 0.31
(hexane/EtOAc, 75:25). 1H NMR (400 MHz, CDCl3): δ = 7.40–
7.29 (m, 5 H, Ph), 4.56 (s, 2 H, CH2Ph), 4.30–4.20 (m, 1 H, 3-H),
4.24 (q, J = 7.1 Hz, 2 H, OCH2Me), 3.98 (br. d, J = 6.1 Hz, 1 H,
OH), 3.72 (dd, J = 10.1, 4.6 Hz, 1 H, 4-HA), 3.68 (dd, J = 10.1,
4
20 Hz (see ref.[10,21]) and J(F-2,Feq-4) of 3 Hz (bent W ar-
rangement), whereas (Ϯ)-α-28 and (Ϯ)-β-28 show 4J(F-
2,Feq-4) of 14 Hz (flat W arrangement; see ref.[22]) and 4J(F-
2,Fax-4) of 3 Hz (bent W arrangement).
Conclusions
In summary, we have implemented a diversity-oriented
de novo synthesis of a range of different 4-deoxy-4,4-di-
fluoro-d/l-hexoses. Key glycal (Ϯ)-cis-5 was synthesized in
seven steps as a single diastereomer with a vastly improved
overall yield of 35%. By using the Gagosz catalyst for the
6.1 Hz, 1 H, 4-HB), 1.25 (t, J = 7.1 Hz, 3 H, Me) ppm. 13C NMR
2
gold-catalyzed cyclization reaction, we were able to lower (101 MHz, CDCl3): δ = 163.2 [t, J(C,F) = 32 Hz, C=O], 137.3 (C
1
of Ph), 128.7, 128.2, 128.0 (5 CH of Ph), 113.8 [dd, J(C,F) = 257,
the catalyst loading (from 10 to 1 mol-%), to raise the yield
(from 75 to 87%), and to avoid sequential addition of the
catalyst. Glycal (Ϯ)-cis-5 successfully delivered five different
gem-difluorinated hexose analogs in good yield by using
well-established functionalization reactions. With the excep-
tion of the 4,4-difluoroglucosides and the 4,4-difluoro-
mannosides, the di- and trifluorinated carbohydrates re-
ported herein are novel. Amongst them, target methyl α-d/
l-talopyranosides (Ϯ)-1 and (Ϯ)-2 were accessed in eight
steps with an overall yield of 14 and 7%, respectively. NMR
spectroscopic investigations of (Ϯ)-1 and (Ϯ)-2 to elucidate
the strength and persistence of intramolecular C–F···H–O
bonds are currently ongoing in our laboratory and will be
reported in due course.
254 Hz, CF2], 73.9 (CH2Ph), 70.9 [dd, 2J(C,F) = 26, 25 Hz, C-3],
3
67.9 [t, J(C,F) = 3 Hz, C-4], 63.2 (OCH2Me), 13.0 (Me) ppm. 19F
2
NMR (376 MHz, CDCl3): δ = –115.2 [ddd, J(F,F) = 263 Hz, J =
8, 6 Hz, 1 F], –120.0 [ddd, 2J(F,F) = 263 Hz, J = 13, 4 Hz, 1 F]
+
ppm. HRMS (ESI): calcd. for C18H22F2NaO4 [M + Na]+
297.0909; found 297.0898.
Amidation of (؎)-7: A suspension of N,O-dimethylhydroxylamine
hydrochloride (2.93 g, 30 mmol) in tetrahydrofuran (40 mL) was
cooled to 0 °C, treated dropwise with trimethylaluminum (2 m in
toluene, 15 mL, 30 mmol), allowed to reach room temperature
leading to a transparent solution. This solution was cooled to
–78 °C, treated with a solution of (Ϯ)-7 (2.74 g, 10 mmol) in tetra-
hydrofuran (10 mL), stirred for 15 min at –78 °C and for 1 h at
0 °C, and diluted with 1.5 m HCl (30 mL). The aqueous mixture
was extracted with ethyl acetate (3ϫ30 mL). Combined organic
layers were dried with magnesium sulfate, filtered, and concen-
trated. Purification by column chromatography on silica gel (hex-
ane/EtOAc, 30:70 to 70:30) afforded amide (Ϯ)-8 (2.46 g, 85%) and
side product (Ϯ)-9 (0.26 g, 9%).
Experimental Section
General: All reactions requiring anhydrous conditions were con-
ducted in dried apparatus under an inert atmosphere of argon or
nitrogen. Solvents were dried and purified before use according to
standard procedures. All reactions were monitored by TLC using
Merck Kiesegel 60 F254 plates. Visualizations of the reaction com-
ponents was achieved by using UV fluorescence (254 nm) and
KMnO4 stain. Column chromatography was carried out over
Merck silica gel C60 (40–60 μm) or by using a Biotage SP4 auto-
mated chromatography system using commercially available Bio-
(؎)-4-(Benzyloxy)-2,2-difluoro-3-hydroxy-N-methoxy-N-methyl-
butanamide [(؎)-8]:[16e] Colorless solid. Rf = 0.35 (hexane/EtOAc,
50:50); m.p. 65 °C. 1H NMR (400 MHz, CDCl3): δ = 7.36–7.26 (m,
5 H, Ph), 4.58 (d, J = 12.0 Hz, 1 H, CHAPh), 4.54 (d, J = 12.0 Hz,
3
1 H, CHBPh), 4.45 [dddd, J(H,F) = 15.4, 8.7 Hz, J = 6.1, 4.5 Hz,
1 H, 3-H], 3.76 (dd, J = 10.2, 4.4 Hz, 1 H, 4-HA), 3.72 (s, 3 H,
OMe), 3.68 (dd, J = 10.4, 6.3 Hz, 1 H, 4-HB), 3.29 (br. s, 1 H, OH),
3.17 (br. s, 3 H, NMe) ppm. 13C NMR (101 MHz, CDCl3): δ =
1
tage SNAP cartridges KP-sil. All H NMR spectra were recorded
Eur. J. Org. Chem. 2011, 3825–3836
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3829

G. T. Giuffredi, B. Bernet, V. Gouverneur
FULL PAPER
161.3 (m, C=O), 137.5 (C of Ph), 128.4, 127.9, 127.8 (5 CH of Ph),
2J(F,F) = 282 Hz, J = 14, 2 Hz, 1 F] ppm. HRMS (ESI): calcd. for
115.6 [dd, 1J(C,F) = 259, 257 Hz, CF2], 73.6 (CH2Ph), 71.0 [dd, C13H12F2NaO3 [M + Na]+ 277.0652; found 277.0647.
2J(C,F) = 26, 24 Hz, C-3], 68.3 [dd, 3J(C,F) = 5, 2 Hz, C-4], 62.0
+
Reduction of (؎)-4: A solution of hex-2-en-ulose (Ϯ)-4 (2.2 g,
8.6 mmol) in dichloromethane (19 mL) was cooled to –78 °C,
treated dropwise with diisobutylaluminum hydride (1 m in hexane,
13 mL), stirred for 30 min at –78 °C, and treated with saturated
aqueous potassium sodium tartrate solution (5 mL). The emulsion
was warmed to room temperature and extracted with diethyl ether
(3 ϫ 5 mL). Combined organic layers were washed with brine
(10 mL), dried with magnesium sulfate, filtered, and concentrated
in vacuo. Purification by column chromatography on silica gel
(hexane/EtOAc, 85:15 to 75:25) afforded an 92:8 mixture of (Ϯ)-
cis-5 and (Ϯ)-trans-5 (1.4 g, 63%) as a colorless oil.
(OMe), 33.0 (NMe) ppm. 19F NMR (376 MHz, CDCl3): δ = –113.8
[d, 2J(F,F) = 270 Hz, 1 F], –117.2 [dd, 2J(F,F) = 270 Hz, J = 11 Hz,
1 F] ppm. HRMS (ESI): calcd. for C13H17F2NNaO4 [M + Na]+
+
312.1018; found 312.1014.
(؎)-4-(Benzyloxy)-2,2-difluoro-3-hydroxy-N-methoxybutanamide
[(؎)-9]: Colorless solid. Rf = 0.23 (hexane/EtOAc, 50:50); m.p.
93 °C. IR (CHCl ): ν = 3176 (O-H/N–H), 1688 (C=O) cm–1. 1H
˜
3
NMR (400 MHz, CD3OD): δ = 7.38–7.24 (m, 5 H, Ph), 4.54 (s, 2
H, CH2Ph), 4.37–4.26 (m, 1 H, 3-H), 3.72 (dd, J = 10.3, 4.2 Hz, 1
H, 4-HA), 3.70 (s, 3 H, OMe), 3.61 (dd, J = 10.3, 7.1 Hz, 1 H, 4-
2
HB) ppm. 13C NMR (101 MHz, CD3OD): δ = 161.3 [t, J(C,F) =
Pivaloylation of (؎)-cis-5 and (؎)-trans-5: Pivaloyl chloride
(2.4 mL, 20 mmol) was added to a solution of glycals (Ϯ)-cis-5/
(Ϯ)-trans-5 92:8 (0.51 g, 2.0 mmol) in pyridine (20 mL). The solu-
tion was stirred overnight at 0 °C, warmed to room temperature,
and treated carefully with saturated aqueous NaHCO3 solution
(5 mL). The aqueous phase was extracted with dichloromethane
(3 ϫ 5 mL). Combined organic layers were washed with brine
(15 mL), dried with magnesium sulfate, filtered, and concentrated
in vacuo. The two diastereomers could be partially separated by
column chromatography on silica gel (hexane/EtOAc, 97:3 to 92:8)
to afford an analytical sample of (Ϯ)-trans-10, a mixture of (Ϯ)-
cis-10 and (Ϯ)-trans-10 (0.17 g, 24%), and (Ϯ)-cis-10 (0.51 g, 75%).
28 Hz, C=O], 138.2 (C of Ph), 128.4, 128.0, 127.8 (5 CH of Ph),
1
2
116.2 [t, J(C,F) = 256 Hz, CF2], 73.5 (CH2Ph), 70.1 [t, J(C,F) =
24 Hz, C-3], 68.9 [t, 3J(C,F) = 3 Hz, C-4], 63.4 (OMe) ppm. 19F
2
NMR (376 MHz, CD3OD): δ = –119.1 [dd, J(F,F) = 263 Hz, J =
10 Hz, 1 F], –122.6 [dd, 2J(F,F) = 263 Hz, J = 11 Hz, 1 F] ppm.
+
HRMS (ESI): calcd. for C12H15F2NNaO4 [M + Na]+ 298.0861;
found 298.0859.
(؎)-6-(Benzyloxy)-4,4-difluoro-5-hydroxyhex-1-yn-3-one [(؎)-3]:[16e]
A solution of amide (Ϯ)-8 (1.74 g, 6.0 mmol) in tetrahydrofuran
(12 mL) was cooled to 0 °C, treated with ethynylmagnesium bro-
mide (0.5 m in tetrahydrofuran, 36 mL, 18 mmol), stirred at 0 °C
for 1 h, and poured into cold 1 m HCl (30 mL). The aqueous phase
was extracted with diethyl ether (3ϫ20 mL). Combined organic
layers were washed with brine (50 mL), dried with magnesium sul-
fate, filtered, and concentrated. Purification through a short pad
of silica gel (3 cm; hexane/EtOAc, 32:68) gave ynone (Ϯ)-3 (1.55 g,
Ͼ95%) as a yellowish oil. Important: Ynone (Ϯ)-3 is very sensitive
to silica gel (no product was obtained from acidic silica gel). Rf =
0.30 (hexane/Et2O, 50:50). 1H NMR (400 MHz, CDCl3): δ = 7.42–
7.30 (m, 5 H, Ph), 4.56 (s, 2 H, CH2Ph), 4.41–4.29 (m, 2 H, 2 6-
H), 3.77–3.67 (m, 1 H, 5-H), 3.59 (s, 1 H, CϵCH), 3.13 (br. d, J =
4.7 Hz, 1 H, OH) ppm. 13C NMR (101 MHz, CDCl3): δ = 176.0
[dd, 2J(C,F) = 35, 33 Hz, C=O], 136.9 (C of Ph), 128.6, 128.1, 127.9
1,5-Anhydro-6-O-benzyl-2.4-dideoxy-4,4-difluoro-3-O-pivaloyl-D/L
-
threo-hex-1-enitol [(؎)-cis-10]: Colorless oil. Rf = 0.27 (hexane/
EtOAc, 92:8). IR (neat): ν = 1738 (C=O), 1647 (C=C) cm–1. 1H
˜
NMR (500 MHz, CDCl3): δ = 7.40–7.29 (m, 5 H, Ph), 6.48 (br. d,
J = 6.0 Hz, 1 H, 1-H), 5.45 [tdd, 3J(H,F) = 8.5 Hz, J = 3.8, 1.6 Hz,
4
1 H, 3-H], 4.83 [td, J(H,F) = 6.3 Hz, J = 6.3, 3.2 Hz, 1 H, 2-H],
4.65 (d, J = 12.0 Hz, 1 H, CHAPh), 4.60 (d, J = 12.0 Hz, 1 H,
CHBPh), 4.46–4.36 (m, 1 H, 5-H), 3.88 (dd, J = 11.0, 8.5 Hz, 1 H,
6-HA), 3.82 [dt, J = 11.0, 1.7 Hz, 4J(H,F) = 1.7 Hz, 1 H, 6-HB],
1.19 (s, 9 H, CMe3) ppm. 13C NMR (126 MHz, CDCl3): δ = 177.1
(C=O), 145.2 (C-1), 137.3 (C of Ph), 128.5, 127.9, 127.8 (5 CH of
Ph), 114.9 [dd, 1J(C,F) = 254, 247 Hz, C-4], 97.8 [d, 3J(C,F) =
1
(5 CH of Ph), 114.3 [dd, J(C,F) = 258, 256 Hz, CF2], 85.7 (C-2),
2
2
3 Hz, C-2], 76.0 [t, J(C,F) = 27 Hz, C-5], 73.7 (CH2Ph), 65.9 [dd,
78.0 (C-1), 73.7 (CH2Ph), 70.3 [dd, J(C,F) = 27, 25 Hz, C-5], 67.5
3J(C,F) = 7, 2 Hz, C-6], 64.4 [dd, 2J(C,F) = 33, 19 Hz, C-3], 38.9
(CMe3), 26.9 (CMe3) ppm. 19F NMR (376 MHz, CDCl3): δ =
[t, 3J(C,F) = 3 Hz, C-6] ppm. 19F NMR (376 MHz, CDCl3): δ =
–115.1 [dd, 2J(F,F) = 265 Hz, J = 8 Hz, 1 F], –120.4 [dd, 2J(F,F) =
265 Hz, J = 13 Hz, 1 F] ppm. HRMS (ESI–): calcd. for
2
2
–110.9 [dd, J(F,F) = 258 Hz, J = 6 Hz, 1 F], –126.4 [dt, J(F,F) =
258 Hz, J = 10 Hz, 1 F] ppm. HRMS (ESI): calcd. for
C13H11F2O3 [M – H]– 253.0676; found 253.0680.
+
C18H22F2NaO4 [M + Na]+ 363.1378; found 363.1387.
+
1,5-Anhydro-6-O-benzyl-2.4-dideoxy-4,4-difluoro-
en-3-ulose [(؎)-4]:[16e] Triphenylphosphanegold(I) bis(trifluorome-
thanesulfonyl)imidate (3.8 mg, 0.005 mmol, 1 mol-%) was added to erythro-hex-1-enitol [(؎)-trans-10]: Colorless crystals. Rf = 0.35
D/L-glycero-hex-2-
1,5-Anhydro-6-O-benzyl-2.4-dideoxy-4,4-difluoro-3-O-pivaloyl-D/L
-
a solution of ynone (Ϯ)-3 (127 mg, 0.50 mmol) in dichloromethane
(5 mL). The mixture was stirred for 24 h at room temperature and
filtered through Celite. Evaporation of the filtrate and purification
(hexane/EtOAc, 92:8); m.p. 57 °C. IR (CH Cl ): ν = 1732 (C=O),
˜
2 2
1
1645 (C=C) cm–1. H NMR (500 MHz, C6D6): δ = 7.34 (m, 2 H,
2 H of Ph), 7.25 (m, 2 H, 2 H of Ph), 7.19 (m, 1 H, 1 H of Ph),
by column chromatography on silica gel (hexane/EtOAc, 80:20) 6.23 (dd, J = 6.0, 1.0 Hz, 1 H, 1-H), 5.60–5.54 (m, 1 H, 3-H), 4.76
4
3
gave pyranone (Ϯ)-4 (110 mg, 87%) as a colorless oil. Rf = 0.34
(hexane/Et2O, 60:40). H NMR (400 MHz, CDCl3): δ = 7.46 (d, J
[q, J = J(H,F) = 5.7 Hz, 1 H, 2-H], 4.51 [ddt, J(H,F) = 26.5 Hz,
1
3
J = 7.3, 1.9, J(H,F) = 1.9 Hz, 1 H, 5-H], 4.36 (dd, J = 12.0 Hz, 1
= 6.1 Hz, 1 H, 1-H), 7.42–7.30 (m, 5 H, Ph), 5.61 [ddd, J = 5.8 Hz,
4J(H,F) = 3.0, 2.9 Hz, 1 H, 2-H], 4.65–4.47 (m, 1 H, 5-H), 4.64 (d,
J = 12.1 Hz, 1 H, CHAPh), 4.61 (d, J = 12.1 Hz, 1 H, CHBPh),
H, CHAPh), 4.34 (dd, J = 12.0 Hz, 1 H, CHBPh), 3.99 (dt, J =
11.0, 1.9 Hz, 1 H, 6-HA), 3.84 (dd, J = 11.0, 7.3 Hz, 1 H, 6-HB),
1.19 (s, 9 H, CMe3) ppm. 13C NMR (126 MHz, C6D6): δ = 176.4
4.01 (dd, J = 11.4, 2.8 Hz, 1 H, 6-HA), 3.96 (dd, J = 11.4, 6.8 Hz, (C=O), 147.3 (C-1), 138.3 (C of Ph), 128.6, 127.9, 127.8 (5 CH of
1 H, 6-HB) ppm. 13C NMR (101 MHz, CDCl3): δ = 179.6 [t,
2J(C,F) = 25 Hz, C-3], 163.6 (C-1), 136.9 (C of Ph), 128.6, 128.1,
Ph), 117.2 [dd, 1J(C,F) = 254, 249 Hz, C-4], 97.2 [d, 3J(C,F) =
4 Hz, C-2], 73.7 (CH2Ph), 73.6 [dd, 2J(C,F) = 30, 24 Hz, C-5], 66.8
127.8 (5 CH of Ph), 108.3 [t, 1J(C,F) = 255 Hz, C-4], 104.9 [t, (C-6), 63.7 [dd, 2J(C,F) = 37, 31 Hz, C-3], 38.7 (CMe3), 27.0
3J(C,F) = 2 Hz, C-2], 80.7 [t, 2J(C,F) = 28 Hz, C-5], 73.9 (CH2Ph), (CMe3) ppm. 19F{1H} NMR (376 MHz, C6D6): δ = –121.5 (d, J =
3
65.8 [t, J(C,F) = 4 Hz, C-6] ppm. 19F NMR (376 MHz, CDCl3): 259 Hz, 1 F), –123.2 (d, J = 259 Hz, 1 F) ppm. HRMS (ESI): calcd.
δ = –122.4 [ddd, 2J(F,F) = 282 Hz, J = 16, 2 Hz, 1 F], –123.2 [ddd,
for C18H22F2NaO4 [M + Na]+ 363.1378; found 363.1374.
+
3830
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3825–3836

Racemic 4-Deoxy-4,4-difluoro- and 2,4-Dideoxy-2,4,4-trifluorohexosides
Preparation of Pure (؎)-cis-5 from (؎)-cis-10: 1,8-Diazabicycloun-
dec-7-ene (0.039 mL, 0.26 mmol) was added to a solution of pival-
ate (Ϯ)-cis-10 (47 mg, 0.13 mmol) in methanol (1 mL). The solu-
tion was stirred at room temperature overnight and the solvents
were then evaporated. Purification by chromatography on silica gel
(hexane/EtOAc, 85:15 to 75:25) gave hydroxyglycal (Ϯ)-cis-5
(33 mg, Ͼ95%) as a colorless oil. Rf = 0.27 (hexane/EtOAc, 75:25).
2.7 Hz, 0.75 H, 1α-H], 5.81 (d, J = 8.5 Hz, 0.25 H, 1β-H), 5.61
[ddd, 3J(H,F) = 19.6, 4.7 Hz, J = 10.7 Hz, 0.75 H, 3α-H], 5.40 [ddd,
3J(H,F) = 19.6, 5.4 Hz, J = 10.1 Hz, 0.25 H, 3β-H], 5.27–5.22 (m,
0.25 H, 2β-H), 5.21 (dd, J = 10.7, 3.5 Hz, 0.75 H, 2α-H), 4.62 (d, J
= 12.3 Hz, 0.75 H, CHAPhα), 4.62 (d, J = 12.0 Hz, 0.25 H,
CHAPhβ), 4.55 (d, J = 12.3 Hz, 0.75 H, CHBPhα), 4.53 (d, J =
3
12.0 Hz, 0.25 H, CHBPhβ), 4.30 [ddd, J(H,F) = 24.6 Hz, J = 6.9,
IR (neat): ν = 3406 (O-H), 1650 (C=C) cm–1. 1H NMR (400 MHz, 2.8 Hz, 0.75 H, 5α-H], 4.01 [ddd, 3J(H,F) = 23.0 Hz, J = 6.9,
˜
CDCl3): δ = 7.41–7.29 (m, 5 H, Ph), 6.45 (d, J = 6.0 Hz, 1 H, 1- 2.8 Hz, 0.25 H, 5β-H], 3.92–3.90 (m, 0.25 H, 6β-HA), 3.90 (dd, J =
H), 4.96–4.84 (m, 1 H, 2-H), 4.64 (d, J = 11.8 Hz, 1 H, CHAPh),
4.61 (d, J = 11.8 Hz, 1 H, CHBPh), 4.38–4.21 (m, 2 H, 3–H and 5-
H), 3.92 (d, J = 4.4 Hz, 2 H, 6-H), 2.83 (br. s, 1 H, OH) ppm. 13C
11.0, 2.2 Hz, 0.75 H, 6α-HA), 3.73 (dd, J = 11.0, 6.9 Hz, 0.25 H,
6β-HB), 3.70 (dd, J = 11.4, 6.9 Hz, 0.75 H, 6α-HB), 2.18 (s, 2.25 H,
OAcα), 2.16 (s, 2.25 H, OAcα), 2.14 (s, 0.75 H, OAcβ), 2.13 (s, 0.75
NMR (101 MHz, CDCl3): δ = 144.5 (C-1), 137.0 (C of Ph), 128.6, H, OAcβ), 2.04 (s, 0.75 H, OAcβ), 2.02 (s, 2.25 H, OAcα) ppm. 13C
1
128.4, 127.6 (5 CH of Ph), 116.1 [dd, J(C,F) = 251, 249 Hz, C-4], NMR (126 MHz, CDCl3; α/β = 3:1): δ = 169.5 (C=O2α), 169.4
3
2
101.1 [d, J(C,F) = 4 Hz, C-2], 75.3 [t, J(C,F) = 28 Hz, C-5], 73.9
(C=O2α and β), 169.0 (C=O2β), 168.7 (C=O2β), 168.6 (C=O2α), 137.5
(Cβ of Ph), 137.4 (Cα of Ph), 128.5–127.7 (5 CHα and β of Ph), 116.3
(CH2Ph), 66.8 [dd, 3J(C,F) = 6, 2 Hz, C-6], 64.6 [dd, 2J(C,F) = 30,
21 Hz, C-3] ppm. 19F NMR (376 MHz, CDCl3): δ = –110.0 [br. d, [t, J(C,F) = 254 Hz, C-4α], 115.9 [t, J(C,F) = 255 Hz, C-4β], 91.4
1
1
2J(F,F) = 254 Hz, 1 F, Feq], –129.0 [br. d, 2J(F,F) = 254 Hz, 1 F, (C-1β), 88.8 (C-1α), 74.9 [dd, 2J(C,F) = 29, 23 Hz, C-5β], 73.7
+
Fax] ppm. HRMS (ESI): calcd. for C13H14F2NaO3 [M + Na]+
(CH2Phα), 73.6 (CH2Phβ), 72.1 [dd, 2J(C,F) = 28, 23 Hz, C-5α],
279.0803; found 279.0802.
70.2 [dd, 2J(C,F) = 22, 19 Hz, C-3β], 69.5 [d, 3J(C,F) = 4 Hz, C-
3
3
2β], 68.4 [d, J(C,F) = 8 Hz, C-2α], 66.7 [d, J(C,F) = 5 Hz, C-6β],
66.3 [dd, 2J(C,F) = 22, 19 Hz, C-3α], 66.0 [d, 3J(C,F) = 5 Hz, C-
6α], 20.8 (Meα), 20.7 (Meβ), 20.4 (Meα and β), 20.3 (Meα and β) ppm.
6-O-Benzyl-4-deoxy-4,4-difluoro-α/β-D/L-xylo-hexopyranose [(؎)-
11]: A solution of glycal (Ϯ)-cis-5 (53 mg, 0.20 mmol) and tetra-
methylethylene diamine (33 μL, 0.22 mmol) in dichloromethane
(20 mL) was cooled –78 °C, treated with osmium tetroxide (53 mg,
0.21 mmol), and stirred for 16 h at –78 °C. After evaporation, a
solution of the residue in methanol (5 mL) and concentrated HCl
(0.1 mL) was stirred for 2 h. Evaporation and purification by col-
umn chromatography on silica gel (hexane/EtOAc, 15:85 to 10:90)
gave a 3:1 anomeric mixture of (Ϯ)-11 (46 mg, 80%) as a white
19F NMR (376 MHz, CDCl3; α/β = 3:1): δ = –116.3 [d, J(F,F) =
2
251 Hz, 0.75 F, 4α-Feq], –118.6 [dd, 2J(F,F) = 251 Hz, J = 6 Hz,
0.25 F, 4β-Feq], –130.5 [dt, 2J(F,F) = 251 Hz, J = 22 Hz, 0.25 F, 4β-
2
Fax], –131.5 [ddd, J(F,F) = 251 Hz, J = 24, 20 Hz, 0.75 F, 4α-Fax]
ppm. HRMS (ESI): calcd. for C19H22F2NaO8 [M + Na]+
+
439.1175; found 439.1162.
solid. R = 0.24 (hexane/EtOAc, 14:86). IR (CH Cl ): ν = 3378 (O-
˜
f
2
2
6-O-Benzyl-4-deoxy-4,4-difluoro-1,2-O-isopropylidene-α-D/L
-
H) cm–1. 1H NMR (500 MHz, [D6]DMSO; α/β = 3:1): δ = 7.39–
7.29 (m, 5 H, Ph), 7.00 (d, J = 6.5 Hz, 0.25 H, 1-OHβ), 6.86 (d, J
= 4.7 Hz, 0.75 H, 1-OHα), 5.72 (d, J = 6.5 Hz, 0.25 H, 3-OHβ),
5.64 (d, J = 6.3 Hz, 0.75 H, 3-OHα), 5.37 (d, J = 6.5 Hz, 0.25 H,
2-OHβ), 5.06 (dd, J = 6.9, 1.3 Hz, 0.75 H, 2-OHα), 5.05–5.01 (m,
0.75 H, 1α-H), 4.54–4.52 (m, 0.25 H, 1β-H), 4.52 (s, 0.5 H,
CH2Phβ), 4.51 (s, 1.5 H, CH2Phα), 4.18 [ddd, 3J(H,F) = 26.2 Hz, J
= 7.6, 2.2 Hz, 0.75 H, 5α-H], 3.95 [ddd, 3J(H,F) = 25.0 Hz, J = 7.6,
2.2 Hz, 0.25 H, 5β-H], 3.83–3.70 (m, 1.75 H, 3α-H, 6α-HA and 6β-
HA), 3.60 [ddd, 3J(H,F) = 21.6 Hz, J = 10.0, 7.6 Hz, 0.25 H, 3β-
H], 3.54 (dd, J = 10.4, 7.9 Hz, 1 H, 6α-HB and 6β-HB), 3.38 (m,
0.75 H, 2α-H), 3.14–3.08 (m, 0.25 H, 2β-H) ppm. 13C NMR
(126 MHz, [D6]DMSO; α/β = 3:1): δ = 138.0 (C of Ph), 128.3,
xylo-hexopyranose [(؎)-13]: A solution of triols (Ϯ)-11 (85 mg,
0.29 mmol) in acetone/2,2-dimethoxypropane (1:1, 1.2 mL) was
treated with TsOH·H2O (6 mg, 0.03 mmol) and stirred at room
temperature overnight. After the addition of Amberlite-400 IR 93
(OH– form), filtration, evaporation, and purification by column
chromatography (hexane/EtOAc, 80:20 to 70:30) gave isopropylid-
ene acetal (Ϯ)-13 (60 mg, 63%) as a white solid. Rf = 0.52 (hexane/
1
EtOAc, 67:33); m.p. 89 °C. IR (CH Cl ): ν = 3398 (O-H) cm–1. H
˜
2
2
NMR (400 MHz, CDCl3): δ = 7.41–7.25 (m, 5 H, Ph), 5.66 (d, J
= 4.6 Hz, 1 H, 1-H), 4.67 (d, J = 12.1 Hz, 1 H, CHAPh), 4.60 (d,
J = 12.1 Hz, 1 H, CHBPh), 4.35 (dd, J = 9.0, 4.4 Hz, 1 H, 2-H),
4.30–4.13 (m, 2 H, 3-H, 5-H), 3.87 (dd, J = 11.0, 3.6 Hz, 1 H, 6-
4
HA), 3.82 [dt, J = 10.3, 6.7 Hz, J(H,F) = 6.7 Hz, 1 H, 6-HB], 2.90
1
127.7, 127.5 (5 CH of Ph), 119.2 [t, J(C,F) = 251 Hz, C-4α], 118.7
(br. s, 1 H, 3-HO), 1.59 (s, 3 H, Me), 1.38 (s, 3 H, Me) ppm. 13C
NMR (126 MHz, CDCl3): δ = 137.4 (C of Ph), 128.5, 127.9, 127.1
(5 CH of Ph), 116.9 [dd, 1J(C,F) = 254, 252 Hz, C-4], 110.4 (CMe2),
[t, 1J(C,F) = 250 Hz, C-4β], 96.5 [d, 4J(C,F) = 13 Hz, C-1β], 92.2
[d, 4J(C,F) = 11 Hz, C-1α], 73.3 (m, C-2β), 72.3 (CH2Phβ), 72.3
(CH2Phα), 71.9 (m, C-3β and C-5β), 70.4 (C-2α), 69.1 (m, C-3α),
3
96.3 (C-1), 75.2 [d, J(C,F) = 3 Hz, C-2], 73.6 (CH2Ph), 70.9 [dd,
2
3
68.0 [dd, J(C,F) = 28, 23 Hz, C-5α], 66.4 [d, J(C,F) = 6 Hz, C-6α
and β] ppm. 19F{H} NMR (376 MHz, [D6]DMSO; α/β = 3:1): δ =
–115.0 (d, J = 244 Hz, 0.75 F, Feq-4α), –117.8 (d, J = 243 Hz, 0.25
F, Feq-4β), –133.5 (br. dd, J = 243, 23 Hz, 0.25 F, Fax-4β), –134.8
(dtt, J = 244, 24, 6 Hz, 0.75 F, Fax-4α) ppm. HRMS (ESI): calcd.
2J(C,F) = 32, 25 Hz, C-5], 69.2 [dd, 2J(C,F) = 31, 22 Hz, C-3],
66.7 [d, 3J(C,F) = 8 Hz, C-6], 26.4, 25.5 (CMe2) ppm. 19F NMR
(376 MHz, CDCl3): δ = –100.0 [ddd, 2J(F,F) = 258 Hz, J = 15,
2
8 Hz, 1 F, Feq], –123.7 [ddt, J(F,F) = 258 Hz, J = 19, 4 Hz, 1 F,
Fax] ppm. HRMS (ESI): calcd. for C16H20F2NaO5 [M + Na]+
+
for C13H16F2NaO5 [M + Na]+ 313.0858; found 313.0859.
+
353.1171; found 353.1172.
1,2,3-Tri-O-acetyl-6-O-benzyl-4-deoxy-4,4-difluoro-α/β-
D/L-
xylo-hexopyranose [(؎)-12]: A solution of triols (Ϯ)-11 (43 mg, m-CPBA Oxidation of (؎)-cis-5: A solution of 3-chloroperbenzoic
0.15 mmol) and acetic anhydride (1.8 mL, 15 mmol) in pyridine
(6 mL) was treated with 4-(dimethylamino)pyridine (2 mg,
0.03 mmol) and stirred at room temperature overnight. Evapora-
tion and purification by chromatography on silica gel (hexane/
acid (741 mg, 4.3 mmol) in methanol (2 mL) was added to a solu-
tion of glycal (Ϯ)-cis-5 (360 mg, 1.4 mmol) in methanol (10 mL) at
0 °C. The solution was stirred for 6 h at 0 °C, treated dropwise with
saturated aqueous NaHCO3 solution (6 mL), stirred overnight at
EtOAc, 85:15 to 65:35) afforded a 3:1 α/β mixture of triacetates room temperature, and extracted with dichloromethane
(Ϯ)-12 (60 mg, 96%) as a colorless oil. Rf = 0.29 (hexane/EtOAc, (3 ϫ 10 mL). Combined organic layers were washed with brine
75:25). IR (neat): ν = 1763 (C=O)cm–1 1H NMR (500 MHz, (20 mL), dried with magnesium sulfate, filtered, and concentrated.
.
˜
CDCl3; α/β = 3:1): δ = 7.33 (m, 5 H, Ph), 6.42 [t, J ≈ 5J(H,F) ≈
Purification by column chromatography on silica gel (hexane/
Eur. J. Org. Chem. 2011, 3825–3836
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3831

G. T. Giuffredi, B. Bernet, V. Gouverneur
FULL PAPER
EtOAc, 60:40 to 30:70) afforded (Ϯ)-1 (175 mg, 41%) and (Ϯ)-14
(118 mg, 28%).
Methyl 6-O-Benzyl-2,4-dideoxy-4,4-difluoro-β-D/L-threo-hexo-
pyranoside [(؎)-β-15]: Colorless oil. Rf = 0.27 (hexane/EtOAc,
60:40). IR (neat): ν = 3426 (O-H) cm–1 1H NMR (400 MHz,
.
˜
Methyl 6-O-Benzyl-4-deoxy-4,4-difluoro-α-D/L-lyxo-hexopyranoside
[(؎)-1]: Rf = 0.18 (hexane/EtOAc, 60:40); m.p. 45 °C. IR (CH2Cl2):
CDCl3): δ = 7.40–7.26 (m, 5 H, Ph), 4.66 (d, J = 11.9 Hz, 1 H,
CHAPh), 4.58 (d, J = 11.9 Hz, 1 H, CHBPh), 4.54 (br. d, J =
9.2 Hz, 1 H, 1-H), 4.01–3.85 (m, 2 H, 3-H, 6-HA), 3.81–3.70 (m, 2
H, 5-H, 6-HB), 3.28 (s, 3 H, OMe), 2.33–2.26 (m, 1 H, 2-Heq), 1.84
(td, J = 12.2, 9.6 Hz, 1 H, 2-Hax) ppm. 13C NMR (126 MHz,
CDCl3): δ = 137.8 (C of Ph), 128.5, 127.8, 127.7 (5 CH of Ph),
117.2 [dd, 1J(C,F) = 253, 249 Hz, C-4], 100.2 (C-1), 74.0 [dd,
ν = 3409 (O-H) cm–1. 1H NMR (500 MHz, [D8]THF): δ = 7.27–
˜
7.19 (m, 4 H, 4 H of Ph), 7.15 (tt, J = 7.2, 1.6 Hz, 1 H, 1 H of
Ph), 4.61 [t, J = 5J(H,F) = 1.6 Hz, 1 H, 1-H], 4.52 (d, J = 12.2 Hz,
1 H, CHAPh), 4.50 (d, J = 9.2 Hz, 1 H, 3-OH), 4.49 (d, J = 12.2 Hz,
3
1 H, CHBPh), 4.02 (J = 6.2 Hz, 1 H, 2-OH), 3.90 [ddd, J(H,F) =
25.4 Hz, J = 8.1, 2.0 Hz, 1 H, 5-H], 3.80 [ddd, J = 10.7, 1.8 Hz,
4J(H,F) = 0.8 Hz, 1 H, 6-HA], 3.78–3.68 (m, 2 H, 2-H, 3-H), 3.60
(dd, J = 10.8, 7.8 Hz, 1 H, 6-HB), 3.30 (s, 3 H, OMe) ppm. 13C
NMR (126 MHz, CDCl3): δ = 137.7 (C of Ph), 128.4, 127.8, 127.4
(5 CH of Ph), 118.0 [t, 1J(C,F) = 252 Hz, C-4], 100.5 (C-1), 73.6
(CH2Ph), 70.7 [d, 3J(C,F) = 7 Hz, C-2], 69.2 [dd, 2J(C,F) = 28,
23 Hz, C-5], 67.2 [dd, 2J(C,F) = 20, 18 Hz, C-3], 66.2 [d, 3J(C,F) =
5 Hz, C-6], 55.6 (OMe) ppm. 19F NMR (376 MHz, CDCl3): δ =
–115.2 [d, 2J(F,F) = 254 Hz, 1 F, Feq], –129.3 [dt, 2J(F,F) = 254 Hz,
2
2J(C,F) = 28, 23 Hz, C-5], 73.8 (CH2Ph), 68.2 [t, J(C,F) = 22 Hz,
3
3
C-3], 67.0 [d, J(C,F) = 4 Hz, C-6], 56.9 (OMe), 37.3 [d, J(C,F) =
6 Hz, C-2] ppm. 19F NMR (376 MHz, CDCl3): δ = –123.6 [d,
2J(F,F) = 243 Hz, 1 F, Feq], –137.5 [dt, 2J(F,F) = 243 Hz, J = 21 Hz,
+
1 F, Fax] ppm. HRMS (ESI): calcd. for C14 H1 8F2NaO4
[M + Na]+ 311.1065; found 311.1066.
Methyl 2,4-Dideoxy-4,4-difluoro-α-D/L-threo-hexopyranoside [(؎)-
16]: A suspension of (Ϯ)-α-15 (40 mg, 0.14 mmol) and Pd/C (10%,
16 mg, 0.015 mmol) in tetrahydrofuran (1 mL) was put under a hy-
drogen atmosphere by three evacuation–hydrogen pressure cycles,
stirred for 5 h at room temperature, and filtered through Celite, and
the solvents were evaporated. Purification by column chromatog-
raphy on silica gel (hexane/EtOAc, 25:75) gave diol (Ϯ)-16 (26 mg,
Ͼ95 %) as a white solid. Rf = 0.38 (hexane/EtOAc, 25:75). 1H
NMR (400 MHz, CDCl3): δ = 4.78 (br. s, 1 H, 1-H), 4.11 [dddd,
3J(H,F) = 20.6, 6.1 Hz, J = 11.8, 5.8 Hz, 1 H, 3-H], 3.92 (dd, J =
11.9, 1.8 Hz, 1 H, 6-HA), 3.83 [ddd, 3J(H,F) = 24.6 Hz, J = 7.9,
2.6 Hz, 1 H, 5-H], 3.74 (dd, J = 11.8, 7.9 Hz, 1 H, 6-HB), 3.40 (s,
3 H, OMe), 3.30 (br. s, 2 H, 2 OH), 2.10 [dddd, J = 13.1, 5.6,
1.2 Hz, 4J(H,F) = 3.4 Hz, 1 H, 2-Heq], 1.89 [td, J = 12.7 Hz,
4J(H,F) = 3.5 Hz, 1 H, 2-Hax] ppm. 13C NMR (126 MHz, CDCl3):
δ = 119.5 [dd, 1J(C,F) = 251, 247 Hz, C-4], 99.4 (C-1), 72.2 [dd,
+
J = 25 Hz, 1 F, Fax] ppm. HRMS (ESI): calcd. for C14H18F2NaO5
[M + Na]+ 327.1015; found 327.1016.
Methyl 6-O-Benzyl-4-deoxy-4,4-difluoro-β-D/L-xylo-hexopyranoside
[(؎)-14]: R = 0.16 (hexane/EtOAc, 60:40). IR (CH Cl ): ν = 3317
˜
f
2
2
1
(O-H) cm–1. H NMR (500 MHz, CDCl3): δ = 7.34 (m, 5 H, Ph),
4.65 (d, J = 12.0 Hz, 1 H, CHAPh), 4.57 (d, J = 12.0 Hz, 1 H,
CHBPh), 4.30 (d, J = 7.9 Hz, 1 H, 1-H), 3.97 (br. d, J = 10.1 Hz,
1 H, 6-HA), 3.86–3.72 (m, 3 H, 3-H, 5-H, and 6-HB), 3.61 (s, 3 H,
OMe), 3.62–3.55 (m, 1 H, 2-H), 3.04 (br. s, 1 H, OH), 3.00 (br. s,
1 H, OH) ppm. 13C NMR (126 MHz, CDCl3): δ = 137.6 (C of Ph),
128.5, 127.8, 127.7 (5 CH of Ph), 117.1 [dd, 1J(C,F) = 253, 251 Hz,
C-4], 103.0 (C-1), 74.1 [dd, 2J(C,F) = 29, 23 Hz, C-5], 73.8
(CH2Ph), 73.0 (m, C-2, C-3), 65.5 [d, 3J(C,F) = 5 Hz, C-6], 57.4
(OMe) ppm. 19F NMR (376 MHz, CDCl3): δ = –119.9 [dd, 2J(F,F)
= 248 Hz, J = 7 Hz, 1 F, Feq], –134.4 [dt, 2J(F,F) = 248 Hz, J =
21 Hz, 1 F, Fax] ppm. HRMS (ESI): calcd. for C14H18F2NaO5+ [M
+ Na]+ 327.1015; found 327.1017.
2
2J(C,F) = 28, 23 Hz, C-5], 66.4 [t, J(C,F) = 21 Hz, C-3], 59.6 [d,
3J(C,F) = 6 Hz, C-6], 55.4 (OMe), 37.3 [d, 3J(C,F) = 7 Hz, C-2]
2
ppm. 19F NMR (376 MHz, CDCl3): δ = –118.3 [br. dt, J(F,F) =
243 Hz, J = 3 Hz, 1 F, Feq], –137.9 [ddd, 2J(F,F) = 243 Hz, J = 24,
+
Acid-Catalyzed Addition of Methanol to (؎)-cis-5: A solution of
glycal (Ϯ)-cis-5 (176 mg, 0.69 mmol) in tetrahydrofuran/methanol
(7:2, 9 mL) was treated with concentrated hydrochloric acid
(0.16 mL, 2.0 mmol), heated to 40 °C for 6 h, diluted with diethyl
ether (10 mL), washed with saturated aqueous NaHCO3 solution
(3ϫ5 mL), dried with magnesium sulfate, filtered, and concen-
trated. Purification by column chromatography (hexane/EtOAc,
67:33 to 34:66) gave (Ϯ)-α-15 (165 mg, 83%) and (Ϯ)-β-15 (19 mg,
10%).
21 Hz, 1 F, Fax] ppm. HRMS (ESI): calcd. for C7H12F2NaO4 [M
+ Na]+ 221.0596; found 221.0596.
SN2Ј-Addition of 4-Nitrobenzoic Acid to (؎)-cis-5: A mixture of tri-
phenylphosphane (1.10 g, 4.1 mmol), diisopropyl azodicarboxylate
(1.24 mL, 4.2 mmol), and 4-nitrobenzoic acid (0.68 g, 4.1 mmol) in
tetrahydrofuran (5 mL) was added dropwise to a solution of glycal
(Ϯ)-cis-5 (0.38 g, 1.5 mmol) in toluene (30 mL) at 0 °C. The mix-
ture was stirred at room temperature for 24 h and diluted with a
1:1 mixture of dichloromethane (30 mL) and saturated aqueous
NaHCO3 solution (30 mL). The layers were separated, and the
aqueous phase was extracted with dichloromethane. The combined
organic layers were dried with magnesium sulfate, filtered, and con-
centrated. Purification by column chromatography on silica gel
(hexane/EtOAc, 90:10 to 85:15) gave (Ϯ)-α-19 (90 mg, 15%), a mix-
ture of (Ϯ)-α-19 and (Ϯ)-β-19 (192 mg, 32 %), and (Ϯ)-β-19
(260 mg, 42%).
Methyl 6-O-Benzyl-2,4-dideoxy-4,4-difluoro-α-D/L-threo-hexo-
pyranoside [(؎)-α-15]: Colorless oil. Rf = 0.44 (hexane/EtOAc,
60:40). IR (neat): ν = 3427 (O-H) cm–1 1H NMR (400 MHz,
.
˜
CDCl3): δ = 7.40–7.27 (m, 5 H, Ph), 4.87 (br. s, 1 H, 1-H), 4.66 (d,
J = 12.0 Hz, 1 H, CHAPh), 4.57 (d, J = 12.0 Hz, 1 H, CHBPh),
4.21 [ddt, 3J(H,F) = 20.0, 6.0 Hz, J = 12.0, 6.0 Hz, 1 H, 3-H], 4.03
3
[ddd, J(H,F) = 25.3 Hz, J = 7.8, 2.5 Hz, 1 H, 5-H], 3.94 (br. d, J
= 10.8 Hz, 1 H, 6-HA), 3.72 (dd, J = 10.8, 7.7 Hz, 1 H, 6-HB), 3.40
(s, 3 H, OMe), 2.21 [dddd, J = 13.0, 5.4, 1.0 Hz, 4J(H,F) = 3.3 Hz,
6-O-Benzyl-2,3,4-trideoxy-4,4-difluoro-1-O-(4-nitrobenzoyl)-α-D/L-
4
1 H, 2-Heq], 1.90 [td, J = 13.0 Hz, J(H,F) = 3.4 Hz, 1 H, 2-Hax] glycero-hex-2-enopyranose [(؎)-α-19]: Colorless solid. Rf = 0.45
ppm. 13C NMR (126 MHz, CDCl3): δ = 139.9 (C of Ph), 128.4,
(hexane/EtOAc, 80:20); m.p. 101 °C. IR (CH Cl ): ν = 1730 (C=O),
˜
2 2
1
1
127.7, 127.6 (5 CH of Ph), 117.9 [dd, J(C,F) = 251, 249 Hz, C-4], 1607 (C=C) cm–1. H NMR (500 MHz, CDCl3): δ = 9.14 (dt, J =
2
97.9 (C-1), 73.6 (CH2Ph), 69.4 [dd, J(C,F) = 28, 23 Hz, C-5], 66.6 9.1, 2.2 Hz, 2 H, 2 H of C6H4), 8.83 (dt, J = 8.8, 1.9 Hz, 2 H, 2 H
[d, 3J(C,F) = 4 Hz, C-6], 65.9 [t, 2J(C,F) = 21 Hz, C-3], 55.2 (OMe), of C6H4), 7.41–7.30 (m, 5 H, Ph), 6.68 [t, J = J(H,F) = 3.2 Hz, 1
5
3
3
36.2 [d, J(C,F) = 6 Hz, C-2] ppm. 19F NMR (376 MHz, CDCl3):
H, 1-H], 6.34 (dd, J = 10.1, 3.5 Hz, 1 H, 2-H), 6.24 [t, J(H,F) =
δ = –120.8 [br. d, J(F,F) = 242 Hz, 1 F, Feq], –140.0 [ddd, J(F,F) 9.8 Hz, J = 9.8 Hz, 1 H, 3-H], 4.64 (d, J = 12.0 Hz, 1 H, CHAPh),
2
2
3
= 242 Hz, J = 25, 20 Hz, 1 F, Fax] ppm. HRMS (ESI): calcd. for
4.56 (d, J = 12.0 Hz, 1 H, CHBPh), 4.51 [ddt, J(H,F) = 21.9 Hz,
C14H18F2NaO4 [M + Na]+ 311.1065; found 311.1064.
J = 7.5 Hz, J(H,F) = J = 2.9 Hz, 1 H, 5-H], 3.99 (dd, J = 11.4,
+
3
3832
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3825–3836

Racemic 4-Deoxy-4,4-difluoro- and 2,4-Dideoxy-2,4,4-trifluorohexosides
2.8 Hz, 1 H, 6-HA), 3.76 (dd, J = 11.0, 7.6 Hz, 1 H, 6-HB) ppm.
13C NMR (126 MHz, CDCl3): δ = 163.3 (C=O), 150.9 (CNO2),
10.5, 4.8 Hz, J = 10.5 Hz, 0.67 H, 3α-H], 5.60–5.43 (m, 0.33 H, 3β-
2
H), 4.74 [ddd, J(H,F) = 49.0 Hz, J = 10.0, 3.8 Hz, 0.67 H, 2α-H],
2
137.6 (C of Ph), 134.6 (C of C6H4), 131.0 (2 CH of C6H4), 130.9 4.61 (d, J = 12.1 Hz, 1 H, CHAPh), 4.55 [dt, J(H,F) = 50.9 Hz, J
3
[t, J(C,F) = 8.6 Hz, C-2], 128.4, 127.7, 127.6 (5 CH of Ph), 126.4
≈ 8.8 Hz, 0.33 H, 2β-H], 4.53 (d, J = 11.9 Hz, 0.33 H, CHBPhβ),
2
[dd, J(C,F) = 32, 26 Hz, C-3], 123.7 (2 CH of C6H4), 112.6 [dd,
4.53 (d, J = 12.1 Hz, 0.67 H, CHBPhα), 4.25 [ddd, 3J(H,F) = 25 Hz,
1J(C,F) = 246, 236 Hz, C-4], 88.6 (C-1), 73.6 (CH2Ph), 72.5 [dd,
J = 6.8, 2.7 Hz, 0.67 H, 5α-H], 4.03 [ddd, J(H,F) = 22.8 Hz, J =
3
3
2J(C,F) = 32, 25 Hz, C-5], 66.3 [d, J(C,F) = 6 Hz, C-6] ppm. 19F
6.9, 2.7 Hz, 0.33 H, 5β-H], 3.89 (br. d, J = 11.1 Hz, 1 H, 6-HA),
3.70 (dd, J = 11.1, 6.9 Hz, 0.33 H, 6β-HB), 3.67 (dd, J = 11.1,
6.8 Hz, 0.67 H, 6α-HB), 2.21 (s, 3 H, OAc), 2.20 (s, 2 H, OAcα),
2.19 (s, 1 H, OAcβ) ppm. 13C NMR (126 MHz, CDCl3; α/β = 2:1):
δ = 169.4 (C=Oα), 169.1 (C=Oβ), 168.5 (C=Oα), 168.4 (C=Oβ),
137.4 (C of Phβ), 137.4 (C of Phα), 128.5–127.0 (5 CH of Ph), 116.5
[ddd, 1J(C,F) = 256, 254 Hz, 3J(C,F) = 11 Hz, C-4α], 116.1 [td,
1J(C,F) = 254 Hz, 3J(C,F) = 11 Hz, C-4β], 90.8 [d, 2J(C,F) = 24 Hz,
2
NMR (376 MHz, CDCl3): δ = –109.6 [ddd, J(F,F) = 238 Hz, J =
22, 2 Hz, 1 F], –113.5 [ddd, 2J(F,F) = 238 Hz, J = 9, 2 Hz, 1 F]
ppm. HRMS (ESI): calcd. for C20H17F2NNaO6 [M + Na]+
+
428.0916; found 428.0917.
6-O-Benzyl-2,3,4-trideoxy-4,4-difluoro-1-O-(4-nitrobenzoyl)-β-D/L
glycero-hex-2-enopyranose [(؎)-β-19]: Colorless solid. Rf = 0.39
(hexane/EtOAc, 80:20); m.p. 85 °C. IR (CH Cl ): ν = 1740 (C=O),
-
˜
2
2
2
1
C-1β], 89.0 [d, J(C,F) = 22 Hz, C-1α], 87.6 [dd, J(C,F) = 192 Hz,
1607 (C=C) cm–1. H NMR (500 MHz, CDCl3): δ = 8.26 (dt, J =
8.8, 1.9 Hz, 2 H, 2 H of C6H4), 8.20 (dt, J = 8.8, 1.9 Hz, 2 H, 2 H
of C6H4), 7.39–7.30 (m, 5 H, Ph), 6.65 (br. s, 1 H, 1-H), 6.30 (dd,
J = 10.7, 1.6 Hz, 1 H, 2-H), 6.24–6.17 (m, 1 H, 3-H), 4.55 (d, J =
12.0 Hz, 1 H, CHAPh), 4.52 (d, J = 12.0 Hz, 1 H, CHBPh), 4.33
1
3J(C,F) = 7 Hz, C-2β], 85.5 [dd, 1J(C,F) = 195 Hz, J(C,F) = 7 Hz,
3
C-2α], 74.8 [dd, 2J(C,F) = 28, 23 Hz, C-5β], 73.7 (CH2Phα), 73.6
(CH2Phβ), 71.8 [dd, 2J(C,F) = 27, 23 Hz, C-5α], 70.1 [dt, J(C,F) =
2
22, 20 Hz, C-3β], 68.2 [dt, 2J(C,F) = 21, 20 Hz, C-3α], 65.8 [d,
3J(C,F) = 5 Hz, C-6α], 65.6 [d, J(C,F) = 4 Hz, C-6β], 20.8 (Meα),
3
3
[dtd, J(H,F) = 13.0, 7.6 Hz, J = 7.6, 3.5 Hz, 1 H, 5-H], 3.89 [ddd,
J = 11.4, 4.7 Hz, J(H,F) = 1.3 Hz, 1 H, 6-HA], 3.82 (dd, J = 11.0,
20.7 (Meβ), 20.4 (Me) ppm. 19F NMR (376 MHz, CDCl3; α/β =
4
2
4
2:1): δ = –115.7 [br. dd, J(F,F) = 253 Hz, J(F,F) = 13 Hz, 0.67 F,
4α-Feq], –117.9 [ddd, J(F,F) = 252 Hz, J(F,F) = 13 Hz, J = 5 Hz,
0.33 F, 4β-Feq], –129.8 [dtd, J(F,F) = 252 Hz, J = 21 Hz, J(F,F)
8.2 Hz, 1 H, 6-HB) ppm. 13C NMR (126 MHz, CDCl3): δ = 162.9
(C=O), 150.8 (CNO2), 137.4 (C of Ph), 134.4 (C of C6H4), 132.6
[t, 3J(C,F) = 10 Hz, C-2], 131.1 (2 CH of C6H4), 128.4, 127.8, 127.5
(5 CH of Ph), 126.0 [t, 2J(C,F) = 29 Hz, C-3], 123.6 (2 CH of
C6H4), 112.9 [dd, 1J(C,F) = 241, 238 Hz, C-4], 89.6 (C-1), 75.4 [dd,
2
4
2
4
2
= 3 Hz, 0.33 F, 4β-Fax], –130.8 [dtd, J(F,F) = 253 Hz, J = 22 Hz,
4J(F,F) = 2 Hz, 0.67 F, 4α-Fax], –203.8 [dtt, J = 51, 13, 3 Hz, 4J(F,F)
= 13, 3 Hz, 0.33 F, 2β-F], –205.4 [dddd, J = 49 Hz, 4J(F,F) = 13 Hz,
J = 12 Hz, 4J(F,F) = 2 Hz, 0.67 F, 2α-F] ppm. HRMS (ESI): calcd.
3
2J(C,F) = 31, 26 Hz, C-5], 73.5 (CH2Ph), 67.1 [d, J(C,F) = 4 Hz,
2
C-6] ppm. 19F NMR (376 MHz, CDCl3): δ = –100.8 [ddd, J(F,F)
+
for C17H19F3NaO6 [M + Na]+ 399.1026; found 399.1023.
= 283 Hz, J = 12, 7 Hz], –109.2 [ddd, 2J(F,F) = 283 Hz, J = 13,
+
5 Hz] ppm. HRMS (ESI): calcd. for C20H17F2NNaO6 [M + Na]+
1,3-Di-O-acetyl-6-O-benzyl-2,4-dideoxy-2,4,4-trifluoro-α-D/L
-
lyxo-hexopyranose [(؎)-23]: Colorless oil. Rf = 0.22 (hexane/
428.0916; found 428.0916.
EtOAc, 80:20). IR (neat): ν = 1766 (C=O) cm–1 1H NMR
.
˜
Preparation of 6-O-Benzyl-2,4-dideoxy-2,4,4-trifluoro-α/β-D/L-xylo-
hexopyranose [(؎)-20] and 6-O-Benzyl-2,4-dideoxy-2,4,4-trifluoro-α-
D/L-lyxo-hexopyranose [(؎)-21] by Fluorination of (؎)-cis-5: A solu-
tion of Selectfluor (0.42 g, 1.2 mmol) and glycal (Ϯ)-cis-5 (0.26 g,
1.0 mmol) in nitromethane/water (3:16, 19 mL:16 mL) was heated
to 60 °C overnight and to 90 °C for 30 min. The mixture was cooled
to room temperature, and the aqueous phase was extracted with
diethyl ether (3ϫ20 mL). Combined organic layers were dried with
magnesium sulfate, filtered, and concentrated to afford (Ϯ)-α-20/
(Ϯ)-β-20/(Ϯ)-21 = 3:1:2. Rf = 0.38 (hexane/EtOAc, 66:34). 19F{1H}
NMR [376 MHz, CDCl3; (Ϯ)-α-20/(Ϯ)-β-20/(Ϯ)-21 = 3:1:2]: δ =
[(Ϯ)-α-20] –115.7 (dd, J = 254, 13 Hz, 0.5 F, Feq-4), –130.8 (d, J =
254 Hz, 0.5 F, Fax-4), –205.5 (d, J = 13 Hz, 0.5 F, F-2); [(Ϯ)-β-20]
–117.9 (dd, J = 252, 13 Hz, 0.17 F, Feq-4), –129.8 (d, J = 252 Hz,
0.17 F, Fax-4), –203.8 (d, J = 13 Hz, 0.17 F, F-2); [(Ϯ)-21] –115.5
(d, J = 252 Hz, 0.33 F, Feq-4), –128.5 (dd, J = 252, 21 Hz, 0.33 F,
Fax-4), –205.3 (d, J = 21 Hz, 0.33 F, F-2) ppm.
(500 MHz, CDCl3): δ = 7.39–7.29 (m, 5 H, Ph), 6.34 [br. d, 3J(C,F)
3
= 7.1 Hz, 1 H, 1-H], 5.40 [dddd, J(H,F) = 28.3, 22.5, 5.4 Hz, J =
3.1 Hz, 1 H, 3-H], 4.78 [br. d, 2J(H,F) = 48 Hz, 1 H, 2-H], 4.64 (d,
J = 12.0 Hz, 1 H, CHAPh), 4.55 (d, J = 12.0 Hz, 1 H, CHBPh),
4.25 [ddd, 3J(H,F) = 24.2 Hz, J = 7.1, 2.2 Hz, 1 H, 5-H], 3.95 (dd,
J = 11.2, 2.2 Hz, 1 H, 6-HA), 3.76 (dd, J = 11.2, 7.1 Hz, 1 H, 6-
HB), 2.25 (s, 3 H, OAc), 2.18 (s, 3 H, OAc) ppm. 13C NMR
(126 MHz, CDCl3): δ = 169.6, 167.8 (C=O), 137.5 (C of Ph), 128.5,
1
127.9, 127.7 (5 CH of Ph), 115.3 [dd, J(C,F) = 259, 249 Hz, C-4],
3
89.9 [d, 2J(C,F) = 32 Hz, C-1], 85.7 [dd, 1J(C,F) = 188 Hz, J(C,F)
= 8 Hz, C-2], 73.8 (CH2Ph), 72.8 [dd, 2J(C,F) = 28, 23 Hz, C-5],
2
3
66.4 [dt, J(C,F) = 23, 17 Hz, C-3], 60.1 [d, J(C,F) = 6 Hz, C-6],
20.8 (Me), 20.5 (Me) ppm. 19F NMR (376 MHz, CDCl3): δ =
–115.5 [br. d, 2J(F,F) = 252 Hz, 4-Feq], –128.6 [dq, 2J(F,F) =
252 Hz, 1FJ(F,F) = 22 Hz, J = 22 Hz, 4-Fax], –205.3 [ddtd, J = 49,
28, 22 Hz, 1FJ(F,F) = 22 Hz, J = 7 Hz, 2-F] ppm. HRMS (ESI):
+
calcd. for C17H19F3NaO6 [M + Na]+ 399.1026; found 399.1017.
Acetylation of (؎)-20/(؎)-21: A solution of (Ϯ)-α-20/(Ϯ)-β-20/(Ϯ)-
21 (3:1:2, 170 mg, 0.58 mmol), acetic anhydride (0.16 mL,
1.7 mmol), pyridine (0.14 mL, 1.7 mmol) and 4-(dimethylamino)
pyridine (4 mg, 0.03 mmol) in dichloromethane (0.6 mL) was
stirred overnight at room temperature, and the solvents were then
evaporated. Purification by column chromatography on silica gel
(hexane/EtOAc, 85:15 to 60:40) afforded (Ϯ)-22 (α/β = 2:1; 113 mg,
55%) and 23 (90 mg, 38%).
Preparation of 6-O-Benzyl-2,4-dideoxy-2,4,4-trifluoro-3-O-pivaloyl-
α/β-D/L-xylo-hexopyranose [(؎)-24] and 6-O-Benzyl-2,4-dideoxy-
2,4,4-trifluoro-3-O-pivaloyl-α-D/L-lyxo-hexopyranose [(؎)-25] by
Electrophilic Fluorination of (؎)-cis-10: A solution of Selectfluor
(0.58 g, 1.6 mmol) and glycal (Ϯ)-cis-10 (0.46 g, 1.4 mmol) in nitro-
methane/water (1:5, 24 mL) was heated to 60 °C overnight and to
90 °C for 30 min. The mixture was cooled to room temperature and
extracted with diethyl ether (3ϫ20 mL). Combined organic layers
were dried with magnesium sulfate, filtered, and evaporated to af-
ford (Ϯ)-α-24/(Ϯ)-β-24/(Ϯ)-25 = 9:3:2. Rf = 0.16 (hexane/EtOAc,
1,3-Di-O-acetyl-6-O-benzyl-2,4-dideoxy-2,4,4-trifluoro-α/β-D/L
xylo-hexopyranose [(؎)-22]: Colorless oil. Rf = 0.64 (hexane/
EtOAc, 66:34). IR (neat): ν = 1766 (C=O) cm–1
-
.
1H NMR 73:17). 19F{1H} NMR [376 MHz, CDCl3; (Ϯ)-α-24/(Ϯ)-β-24/(Ϯ)-
(500 MHz, CDCl3; α/β = 2:1): δ = 7.38–7.26 (m, 5 H, Ph), 6.51 25 = 9:3:2]: δ = [(Ϯ)-α-24] –115.8 (dd, J = 250, 13 Hz, 0.64 F, 4-
˜
[dd, J = 3.2 Hz, 3J(H,F) = 2.3 Hz, 0.67 H, 1α-H], 5.88 [dd, J =
8.1 Hz, J(H,F) = 3.1 Hz, 0.33 H, 1β-H], 5.69 [dtd, J(H,F) = 20,
Feq), –131.8 (d, J = 250 Hz, 0.64 F, 4-Fax), –204.0 (d, J = 13 Hz,
0.64 F, 2-F); [(Ϯ)-β-24] –118.2 (dd, J = 250, 13 Hz, 0.21 F, 4-Feq),
3
3
Eur. J. Org. Chem. 2011, 3825–3836
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3833

G. T. Giuffredi, B. Bernet, V. Gouverneur
FULL PAPER
–130.1 (d, J = 250 Hz, 0.21 F, 4-Fax), –202.6 (d, J = 13 Hz, 0.21 F,
2-F); [(Ϯ)-25] –115.9 (d, J = 249 Hz, 0.14 F, 4-Feq), –128.9 (dd, J
= 249, 21 Hz, 0.14 F, 4-Fax), –206.7 (d, J = 21 Hz, 0.14 F, 2-F)
ppm.
2
2
(CH2Ph), 72.9 [dd, J(C,F) = 29, 23 Hz, C-5], 66.3 [dt, J(C,F) =
22, 17 Hz, C-3], 66.1 [d, 3J(C,F) = 6 Hz, C-6], 39.2 (CMe3), 26.9
(CMe3), 20.8 (Me) ppm. 19F{1H} NMR (376 MHz, CDCl3): δ =
–115.8 (dd, J = 252, 2 Hz, 1 F, 4-Feq), –128.8 (dd, J = 252, 21 Hz,
1 F, 4-Fax), –205.9 (dd, J = 21, 2 Hz, 1 F, 2-F) ppm. HRMS (ESI):
Acetylation of (؎)-24/(؎)-25: A solution of crude (Ϯ)-α-24/(Ϯ)-β-
24/(Ϯ)-25 (9:3:2, 0.46 g, 1.4 mmol) and acetic anhydride (1.4 mL,
14 mmol) in pyridine (33 mL) was treated with 4-(dimethylamino)-
pyridine (12 mg, 0.10 mmol), and stirred overnight, and the sol-
vents were evaporated. Purification by column chromatography on
silica gel (hexane/EtOAc, 90:10 to 60:40) gave (Ϯ)-26 (α/β = 5:1;
0.30 g, 53%), a mixture of (Ϯ)-26 and (Ϯ)-27 (95 mg, 17%), and
(Ϯ)-27 (84 mg, 15%).
calcd. for C19H22F2NaO8 [M + Na]+ 441.1495; found 441.1494.
+
Fluorination of (؎)-cis-5 in Methanol: A solution of Selectfluor
(0.71 g, 2.0 mmol) and glycal (Ϯ)-cis-5 (0.26 g, 1.0 mmol) in nitro-
methane/methanol (3:10, 13 mL) was heated to 60 °C for 16 h and
to 90 °C for 30 min. The mixture was cooled to room temperature,
diluted with water (30 mL), and extracted with diethyl ether
(3ϫ20 mL). Combined organic layers were dried with magnesium
sulfate, filtered, and concentrated. Purification by column
chromatography on silica gel (hexane/EtOAc, 87:13 to 60:40) af-
forded (Ϯ)-α-28 (42 mg, 14%), (Ϯ)-2 (57 mg, 19%), and (Ϯ)-β-28
(107 mg, 35%).
1-O-Acetyl-6-O-benzyl-2,4-dideoxy-2,4,4-trifluoro-3-O-pivaloyl-α/β-
D/L-xylo-hexopyranose [(؎)-26]: Colorless oil. Rf = 0.55 (hexane/
EtOAc, 80:20). IR (CH Cl ): ν = 1754 (C=O) cm–1 1H NMR
.
˜
2
2
(500 MHz, CDCl3; α/β = 5:1): δ = 7.41–7.30 (m, 5 H, Ph), 6.56
[dd, J = 3.8 Hz, 3J(H,F) = 2.2 Hz, 0.83 H, 1α-H], 5.93 [dd, J =
8.0 Hz, 3J(H,F) = 3.3 Hz, 0.17 H, 1β-H], 5.72 [dtd, 3J(H,F) = 21.1,
10.1, 4.9 Hz, J = 10.1 Hz, 0.83 H, 3α-H], 5.42–5.26 (m, 0.17 H, 3β-
H), 4.81 [dddd, 3J(H,F) = 48.8 Hz, J = 10.0, 3.9 Hz, 4J(H,F) =
1.3 Hz, 0.83 H, 2α-H], 4.66 (d, J = 11.9 Hz, 0.17 H, CHAPhβ), 4.66
(d, J = 12.1 Hz, 0.83 H, CHAPhα), ca. 4.68–4.48 (m, 0.17 H, 2β-H),
4.58 (d, J = 12.0 Hz, 1 H, CHBPh), 4.29 [ddd, 3J(H,F) = 24.4 Hz, J
= 6.9, 2.9 Hz, 0.83 H, 5α-H], 4.07 [ddd, 3J(H,F) = 22.8 Hz, J = 6.8,
2.9 Hz, 0.17 H, 5β-H], 3.93 [ddd, J = 11.4, 2.9 Hz, 4J(H,F) =
1.1 Hz, 1 H, 6-HA], 3.76 (dd, J = 10.5, 6.8 Hz, 0.17 H, 6β-HB), 3.72
(dd, J = 11.3, 6.9 Hz, 0.83 H, 6α-HB), 2.26 (s, 0.51 H, OAcβ), 2.25
(s, 2.49 H, OAcα), 1.33 (s, 9 H, CMe3) ppm. 13C NMR (126 MHz,
CDCl3; α/β = 5:1): δ = 177.2 (C=O of Pivα), 176.7 (C=O of Pivβ),
168.5 (C=O of Acβ), 168.5 (C=O of Acα), 137.4 (C of Phα), 137.4
(C of Phβ), 128.5–127.8 (5 CH of Ph), 116.5 [td, 1J(C,F) = 255 Hz,
Methyl 6-O-Benzyl-2,4-dideoxy-2,4,4-trifluoro-α-D/L-lyxo-hexo-
pyranoside [(؎)-2]: Colorless oil. Rf = 0.49 (hexane/EtOAc, 67:33).
IR (neat): ν = 3402 (O-H) cm–1. 1H NMR (500 MHz, [D ]acetone):
˜
6
δ = 7.42–7.28 (m, 5 H, Ph), 5.16 (d, J = 7.9 Hz, 1 H, OH), 4.98
[dt, 3J(H,F) = 8.4 Hz, J = 1.6 Hz, 5J(H,F) = 1.6 Hz, 1 H, 1-H],
2
4
4.72 [dddd, J(H,F) = 48.5 Hz, J = 6.1 Hz, J(H,F) = 3.1, 1.5 Hz,
1 H, 2-H], 4.66 (d, J = 12.0 Hz, 1 H, CHAPh), 4.62 (d, J = 12.0 Hz,
1 H, CHBPh), 4.17–4.01 (m, 1 H, 3-H), 4.10 [ddd, 3J(H,F) =
25.1 Hz, J = 7.5, 2.5 Hz, 1 H, 5-H], 3.93 [ddd, J = 11.1, 2.4 Hz,
4J(H,F) = 1.1 Hz, 1 H, 6-HA], 3.73 (dd, J = 11.1, 7.8 Hz, 1 H, 6-
HB), 3.47 (s, 3 H, OMe) ppm. 13C NMR (126 MHz, CDCl3): δ =
137.8 (C of Ph), 128.4, 127.8, 127.6 (5 CH of Ph), 116.9 [dd, 1J(C,F)
= 254, 249 Hz, C-4], 97.7 [d, 2J(C,F) = 30 Hz, C-1], 88.4 [dd,
1J(C,F) = 177 Hz, 3J(C,F) = 8 Hz, C-2], 73.8 (CH2Ph), 69.7 [dd,
2
2J(C,F) = 28, 23 Hz, C-5], 67.0 [ddd, J(C,F) = 22, 20, 18 Hz, C-
3], 66.3 [d, 3J(C,F) = 5 Hz, C-6], 55.6 (OMe) ppm. 19F NMR
2
3J(C,F) = 11 Hz, C-4α], C-4β hidden by the noise, 90.9 [d, J(C,F)
2
(376 MHz, [D6]acetone): δ = –116.7 [br. d, J(F,F) = 250 Hz, 1 F,
2
1
= 25 Hz, C-1β], 88.1 [d, J(C,F) = 22 Hz, C-1α], 87.6 [dd, J(C,F)
= 192 Hz, 3J(C,F) = 8 Hz, C-2β], 85.6 [dd, 1J(C,F) = 188 Hz,
3J(C,F) = 7 Hz, C-2α], 74.9 [dd, 2J(C,F) = 28, 22 Hz, C-5β], 73.7
(CH2Phα), 73.6 (CH2Phβ), 71.8 [dd, 2J(C,F) = 27, 23 Hz, C-5α],
70.0 (m, C-3β), 68.0 [dt, 2J(C,F) = 22, 19 Hz, C-3α], 65.8 [d, 3J(C,F)
= 5 Hz, C-6α], 65.7 [d, 3J(C,F) = 4 Hz, C-6β], 39.11 (CMe3α), 39.06
(CMe3β), 26.88 (CMe3α), 26.86 (CMe3β), 20.8 (Meα), 20.7 (Meβ)
ppm. 19F NMR (376 MHz, CDCl3; α/β = 5:1): δ = –115.9 [ddd,
2J(F,F) = 253 Hz, 4J(F,F) = 13 Hz, J = 3 Hz, 0.83 F, 4α-Feq], –118.0
Feq-4], –132.2 [ddt, 2J(F,F) = 250 Hz, J = 25, 20 Hz, h1J(F,F) =
20 Hz, 1 F, Fax-4], –208.4 [ddddd, J = 51, 27 Hz, h1J(F,F) =
19 Hz, J = 9, 3 Hz, 1 F, F-2] ppm. HRMS (ESI): calcd. for
+
C14H17F3NaO4 [M + Na]+ 329.0971; found 329.0969.
Methyl 6-O-Benzyl-2,4-dideoxy-2,4,4-trifluoro-α-D/L-xylo-hexopyr-
anoside [(؎)-α-28]: Colorless oil. Rf = 0.54 (hexane/EtOAc, 67:33).
1
IR (neat): ν = 3403 (O-H) cm–1. H NMR (400 MHz, CDCl ): δ =
˜
3
3
7.40–7.29 (m, 5 H, HPh), 5.02 [t, J = 3.0 Hz, J(H,F) = 3.0 Hz, 1
2
[ddd, J(F,F) = 254 Hz, 4J(F,F) = 13 Hz, J = 5 Hz, 0.17 F, 4β-Feq],
H, 1-H], 4.65 (d, J = 12.1 Hz, 1 H, CHAPh), 4.57 (d, J = 12.1 Hz,
2
4
1 H, CHBPh), 4.50 [dddd, 2J(H,F) = 49.0 Hz, J = 9.7, 3.7 Hz,
–130.0 [dtd, J(F,F) = 253 Hz, J = 21 Hz, J(F,F) = 4 Hz, 0.17 F,
2
4
3
4J(H,F) = 1.7 Hz, 1 H, 2-H], 4.33 [dddt, J(H,F) = 20.0, 12.2 Hz,
4β-Fax], –131.1 [dtd, J(F,F) = 254 Hz, J = 22 Hz, J(F,F) = 3 Hz,
4
3
3
0.83 F, 4α-Fax], –204.1 [0.17 F, dtt, J = 51, 13, 4 Hz, J(F,F) = 13,
J = 9.6, 6.1 Hz, J(H,F) = 6.1 Hz, 1 H, 3-H], 4.10 [ddd, J(H,F) =
25.5 Hz, J = 7.6, 2.7 Hz, 1 H, 5-H], 3.92 [ddd, J = 11.1, 2.4 Hz,
4J(H,F) = 1.1 Hz, 1 H, 6-HA], 3.72 (ddd, J = 11.1, 7.7 Hz, 1 H, 6-
HB), 3.52 (s, 3 H, CH3), 2.32 (d, J = 6.0 Hz, 1 H, OH) ppm. 13C
NMR (126 MHz, CDCl3): δ = 137.6 (CPh), 128.4, 127.8, 127.5
(CHPh), 117.2 [td, 1J(C,F) = 253 Hz, 3J(C,F) = 11 Hz, C-4], 96.8
[d, 2J(C,F) = 20 Hz, C-1], 88.8 [dd, 1J(C,F) = 191 Hz, 3J(C,F) =
8 Hz, C-2], 73.6 (CH2Ph), 69.5 [dd, 2J(C,F) = 22, 20 Hz, C-5], 69.1
4 Hz, 2β-F], –205.9 [0.83 F, dddd, J = 49, 11 Hz, 4J(F,F) = 13, 3 Hz,
2α-F] ppm. HRMS (ESI): calcd. for C20H25F3NaO6 [M + Na]+
+
441.1495; found 441.1489.
1-O-Acetyl-6-O-benzyl-2,4-dideoxy-2,4,4-trifluoro-3-O-pivaloyl-α-D/
L
-lyxo-hexopyranose [(؎)-27]: Colorless solid. Rf = 0.40 (hexane/
EtOAc, 80:20); m.p. 108 °C. IR (CH Cl ): ν = 1753 (C=O) cm–1.
˜
2
2
1H NMR (500 MHz, CDCl3): δ = 7.40–7.29 (m, 5 H, Ph), 6.39 [br.
2
3
[dt, J(C,F) = 27, 23 Hz, C-3], 66.0 [d, J(C,F) = 5 Hz, C-6], 55.9
(CH3) ppm. 19F NMR (376 MHz, CDCl3): δ = –116.8 [ddd, 2J(F,F)
= 250 Hz, 4J(F,F) = 13 Hz, J = 6 Hz, 1 F, 4-Feq], –135.2 [dddd,
2J(F,F) = 250 Hz, J = 25, 21 Hz, 4J(F,F) = 3 Hz, 1 F, 4-Fax], –205.9
[dtd, J = 50, 13 Hz, 4J(F,F) = 13, 3 Hz, 1 F, 2-F] ppm. HRMS
d, 3J(H,F) = 6.4 Hz, 1 H, 1-H], 5.41 [dddd, 3J(H,F) = 28.4, 21.1
2
5.4 Hz, J = 3.2 Hz, 1 H, 3-H], 4.80 [br. d, J(H,F) = 48.6 Hz, 1 H,
2-H], 4.69 (d, J = 12.0 Hz, 1 H, CHAPh), 4.66 (d, J = 12.0 Hz, 1
H, CHBPh), 4.31 [ddd, 3J(H,F) = 23.6 Hz, J = 7.3, 2.5 Hz, 1 H, 5-
H], 4.00 (dd, J = 11.4, 2.5 Hz, 1 H, 6-HA), 3.81 (dd, J = 11.4,
7.2 Hz, 1 H, 6-HB), 2.23 (s, 3 H, OAc), 1.34 (s, 9 H, CMe3) ppm.
13C NMR (126 MHz, CDCl3): δ = 177.3 (C=O of Piv), 167.9 (C=O
of Ac), 137.4 (C of Ph), 128.5, 127.9, 127.8 (5 CH of Ph), 115.3
[td, 1J(C,F) = 259 Hz, 3J(C,F) = 11 Hz, C-4], 90.1 [d, 2J(C,F) =
32 Hz, C-1], 85.7 [dd, 1J(C,F) = 188 Hz, 3J(C,F) = 7 Hz, C-2], 73.8
(ESI): calcd. for C14H17F3NaO4 [M + Na]+ 329.0971; found
+
329.0972.
Methyl 6-O-Benzyl-2,4-dideoxy-2,4,4-trifluoro-β-D/L-xylo-hexo-
pyranoside [(؎)-β-28]: Colorless oil. Rf = 0.43 (hexane/EtOAc,
67:33). IR (neat): ν = 3399 (O-H) cm–1. 1H NMR (500 MHz,
˜
3834
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3825–3836

Racemic 4-Deoxy-4,4-difluoro- and 2,4-Dideoxy-2,4,4-trifluorohexosides
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G. T. Giuffredi, L. E. Jennings, B. Bernet, V. Gouverneur, J.
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2002, 124, 9756–9767; c) H. W. Chen, Z. Zhao, T. M. Hallis,
Z. H. Guo, H. W. Liu, Angew. Chem. 2001, 113, 627; Angew.
Chem. Int. Ed. 2001, 40, 607–610.
a) H. Ferret, I. Déchamps, B. G. Pardo, L. Van Hijfte, J. Cossy,
Arkivoc 2010, viii, 126–159; b) R. P. Singh, J. M. Shreeve, Syn-
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M. I. Matheu, R. Echarri, S. Castillón, M. L. Jimeno, Tetrahe-
dron 2001, 57, 6733–6743.
1,1-Difluoro: a) L. R. Cox, G. A. DeBoos, J. J. Fullbrook, J. M.
Percy, N. S. Spencer, M. Tolley, Org. Lett. 2003, 5, 337–339; b)
2,2-Difluoro: J. A. L. Miles, L. Mitchell, J. M. Percy, K. Singh,
E. Uneyama, J. Org. Chem. 2007, 72, 1575–1587; c) T. Masuda,
S. Shibuya, M. Arai, S. Yoshida, T. Tomozawa, A. Ohno, M.
Yamashita, T. Honda, Bioorg. Med. Chem. Lett. 2003, 13, 669–
673; 3,3-Difluoro: d) X.-H. Xu, Z.-W. You, X. Zhang, F.-L.
Qing, J. Fluorine Chem. 2007, 128, 535–539.
CDCl3): δ = 7.40–7.29 (m, 5 H, Ph), 4.65 (d, J = 12.0 Hz, 1 H,
CHAPh), 4.60 (d, J = 12.0 Hz, 1 H, CHBPh), 4.50 [dd, J = 7.7 Hz,
2
3J(H,F) = 2.7 Hz, 1 H, 1-H], 4.29 [dddd, J(H,F) = 50.5 Hz, J =
[9]
4
9.3, 7.5 Hz, J(H,F) = 1.7 Hz, 1 H, 2-H], 4.10–3.97 (m, 1 H, 3-H),
3.96 (br. d, J = 10.8 Hz, 1 H, 6-HA), 3.82 [ddd, 3J(H,F) = 23.1 Hz,
J = 7.3, 2.4 Hz, 1 H, 5-H], 3.75 [ddd, J = 10.8, 7.3 Hz, h1J(H,F) =
0.5 Hz, 1 H, 6-HB], 3.63 (s, 3 H, OAc), 2.45 (br. s, 1 H, OH) ppm.
13C NMR (126 MHz, CDCl3): δ = 137.4 (C of Ph), 128.6, 128.0,
1
3
127.9 (5 CH of Ph), 117.2 [td, J(C,F) = 253 Hz, J(C,F) = 11 Hz,
2
1
C-4], 100.8 [d, J(C,F) = 23 Hz, C-1], 90.9 [dd, J(C,F) = 188 Hz,
[10]
[11]
3J(C,F) = 8 Hz, C-2], 73.9 (CH2Ph), 72.8 [dd, 2J(C,F) = 28, 23 Hz,
2
3
C-5], 71.9 [dt, J(C,F) = 22, 21 Hz, C-3], 66.4 [d, J(C,F) = 5 Hz,
C-6], 57.4 (OMe) ppm. 19F NMR (376 MHz, CDCl3): δ = –118.9
[ddd, 2J(F,F) = 250 Hz, 4J(F,F) = 13 Hz, J = 7 Hz, 1 F, 4-Feq],
2
4
[12]
–128.8 [dtd, J(F,F) = 250 Hz, J = 20 Hz, J(F,F) = 3 Hz, 1 F, 4-
Fax], –205.9 [dtt, J = 50, 14, 3 Hz, 4J(F,F) = 14, 3 Hz, 1 F, 2-F]
ppm. HRMS (ESI): calcd. for C14H17F3NaO4 [M + Na]+
+
329.0971; found 329.0973.
CCDC-825987 [for (Ϯ)-13], -825988 [for (Ϯ)-16], -825989 [for (Ϯ)-
1], and -825990 [for (Ϯ)-β-19] contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[13]
[14]
Supporting Information (see footnote on the first page of this arti-
1
cle): H, 13C, and 19F NMR spectra of all products.
Acknowledgments
We thank the Berrow Foundation for a scholarship to G. T. G. and
Dr. Amber L. Thompson (Oxford Chemical Crystallography Ser-
vice) for help with crystallographic problems.
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Received: April 21, 2011
Published Online: June 17, 2011
3836
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