Fragmentation of carbohydrate anomeric alkoxyl radicals: New synthesis of chiral 1-fluoro-1-halo-1-iodoalditols

Article abstract of DOI:10.1002/chem.200800734

A new general methodology for the synthesis of 1,1,1-trihaloalditols by starting from l,5-anhydro-2-deoxyhex-1-enitol derivatives (glycals) is described. The halogens are introduced sequentially in each of the three different steps of the process. The fluorine is introduced in the first step by electrophilic fluorination of the starting glycal; next, hydroxyhalogenation of the resulting vinyl fluoride allows the addition of any halogen (F, Cl, Br or I) at will, and finally, an iodine atom is inserted through an alkoxyl radical fragmentation reaction. This methodology allows the preparation of diverse types of 1,1,1-trihalogenated compounds (R-CF₂I, R-CFI₂, R-CFClI and R-CFBrI) under mild conditions compati ble with sensitive substituents. In some cases, the diastereomeric mixtures generated from R-CFClI and R-CFBrI can be chromatographically separated, and their configuration determined by X-ray crystallographic analysis. The synthetic usefulness of these compounds has been preliminarily assessed by examining the reactivity of the fluorinated radical generated by rupture of the C-I bond.

Full text of DOI:10.1002/chem.200800734

DOI: 10.1002/chem.200800734
Fragmentation of Carbohydrate Anomeric Alkoxyl Radicals:
New Synthesis of Chiral 1-Fluoro-1-halo-1-iodoalditols
Cosme G. Francisco,[a] Concepción C. Gonzµlez,*[a] Alan R. Kennedy,[b]
Nieves R. Paz,[a] and Ernesto Suµrez*[a]
Abstract: Anew general methodology
for the synthesis of 1,1,1-trihaloalditols
by starting from 1,5-anhydro-2-deoxy-
hex-1-enitol derivatives (glycals) is de-
scribed. The halogens are introduced
sequentially in each of the three differ-
ent steps of the process. The fluorine is
introduced in the first step by electro-
philic fluorination of the starting
glycal; next, hydroxyhalogenation of
the resulting vinyl fluoride allows the
addition of any halogen (F, Cl, Br or I)
at will, and finally, an iodine atom is in-
serted through an alkoxyl radical frag-
mentation reaction. This methodology
allows the preparation of diverse types
ble with sensitive substituents. In some
cases, the diastereomeric mixtures gen-
ꢀ
ꢀ
erated from R CFClI and R CFBrI
can be chromatographically separated,
and their configuration determined by
X-ray crystallographic analysis. The
synthetic usefulness of these com-
pounds has been preliminarily assessed
by examining the reactivity of the fluo-
rinated radical generated by rupture of
ꢀ
of 1,1,1-trihalogenated compounds (R
ꢀ
ꢀ
ꢀ
R
CF2I, R CFI2, R CFClI and
CFBrI) under mild conditions compati-
Keywords: alditols asymmetric
·
synthesis · carbohydrates · halogens ·
radical reactions
ꢀ
the C I bond.
Introduction
metabolic processes,[4] and the difluoromethylene functional-
ity is known to be isostere and isopolar to an oxygen
atom.[5] The introduction of a gem-difluoromethyl group
into bioactive compounds can enhance or alter their activity
dramatically.
The field of fluoroorganic chemistry has received considera-
ble attention in recent decades. Extensive research has al-
ready been carried out into the incorporation of one or sev-
eral fluorine atoms into organic substrates, which can lead
to profound effects on the physical, chemical and biological
properties of the molecules,[1] as exemplified by the growing
number of pharmaceutical and plant protection agents that
have fluorine incorporated in their structure.[2]
Recently, fluorinated carbohydrates[6] (fluorosugars) have
attracted increased attention from organic chemists. The ac-
tivity of fluorosugars is mostly attributed to the replacement
of a hydroxyl group by fluorine in a carbohydrate residue,
which causes electronic effects on neighbouring groups with
minimal steric perturbation to the original structure or con-
formation. Only a few gem-difluorinated sugars have been
reported,[7] which is probably due to the shortcomings of the
existing synthetic methods. Therefore novel and efficient
methods to introduce the gem-difluoromethyl group into
sensitive molecules are still required.
In recent years, we have developed the synthesis of 1-
deoxy-1-halo-1-iodoalditols based on the anomeric alkoxyl
radical fragmentation (ARF)[8] of 2-deoxy-2-halo-glycofura-
noses and pyranoses. The glycopyran-1-O-yl and glycofuran-
1-O-yl radicals were easily generated by reaction of 2-halo-
carbohydrate anomeric alcohols with hypervalent iodine re-
agents in the presence of molecular iodine or bromine. Sub-
Among them, gem-difluoro compounds have become a
significant area of research[3] since CH2/CF2 transposition
has been recognised as a valuable tool in the blockage of
[a] Prof. C. G. Francisco, Dr. C. C. Gonzµlez, N. R. Paz,
Prof. Dr. E. Suµrez
Instituto de Productos Naturales y Agrobiología del C.S.I.C.
Carretera de La Esperanza 3
38206 La Laguna Tenerife (Spain)
Fax : (+34)922-260-135
E-mail: ccgm@ipna.csic.es
esuarez@ipna.csic.es
[b] Dr. A. R. Kennedy
WestCHEM Department of Pure and Applied Chemistry
University of Strathclyde
ꢀ
sequently, alkoxyl-radical-driven fragmentation of the C1
C2 bond afforded a C2 radical that could be trapped inter-
molecularly by halogen atoms from the medium. In this
Glasgow, G1 1XL (UK)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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Chem. Eur. J. 2008, 14, 6704 – 6712

FULL PAPER
way, 1,1-dihaloalditols with one less carbon atom than the
starting sugar were obtained in good yields.[9] 1,1-Dihaloal-
kanes are versatile compounds in organic synthesis and have
ꢀ
attracted much interest as intermediates in C C bond-form-
ing reactions.[10]
With these results in hand, we turned our attention to a
general protocol for the synthesis of 1,1,1-trihaloalditols by
starting from a glycal as outlined in Scheme 1, in which the
halogens are introduced sequentially in each of the three
different steps of the process. The fluorine is introduced in
the first step by electrophilic fluorination; next, hydroxyha-
logenation of the vinyl fluoride allows the addition of any
halogen and finally, the iodine is inserted through a radical
ARF reaction.
Scheme 2. Synthesis of 1,5-anhydro-2-deoxy-2-fluoro-hex-1-enitols. R=
CH2OAc, CH3, H. Method A: a) i) Selectfluor (1.5 equiv), nitromethane,
15 h; ii) MgBr2 (2 equiv), reflux, 1 h; c) Et3N (3 equiv), acetonitrile,
reflux, 1.5 h. Method B: b) i) Selectfluor (1.5 equiv), nitromethane/H2O,
RT, 6 h, then reflux 0.5 h; ii) Ac2O, pyridine; iii) HBr/HOAc, Ac2O, 2 h ;
c) Et3N (3 equiv), acetonitrile, reflux, 1 h.
Scheme 1. Synthesis of 1,1,1-trihaloalditols. R=Protective group, R1 =
CH2OAc, CH3, H; X=F, Cl, Br, I.
This methodology should prove useful in the synthesis of
a number of fluorinated 1,1,1-trihaloalditols of the general
tion of the anomeric bromide obtained from this reaction
with triethylamine in acetonitrile afforded the required vinyl
fluoride. By following this methodology (method A), we
were able to prepare substrates 1, 5 and 11, which are de-
rived from d-galactal,[20] l-fucal and l-arabinal, respectively.
When method Awas used, vinyl fluorides derived from d-
glucal[20,21] 9 and l-rhamnal 10 resulted in mixtures that
were difficult to separate. Asomewhat different sequence
(method B) was required in these two cases, as exemplified
by the reaction of d-glucal. The hex-enitol was also treated
with Selectfluor, but in aqueous nitromethane to afford the
mano and gluco-derived fluorohydrin mixtures, which were
separated after acetylation. Subsequent substitution of the
anomeric acetyl group in the gluco derivative by bromide
with HBr/HOAc, followed by elimination of the HBr with
triethylamine (TEA), gave the desired vinyl fluorides in
good yields.
The remainder of the vinyl fluorides 3, 4, 7 and 8 were
prepared from the 2-deoxy-2-fluoro-d-arabino-hex-1-enitol
derivative 1. Hydrolysis of acetate groups with K2CO3/
MeOH yielded the triol 2.[19a] Treatment with NaH and MeI
or BnBr gave 3 and 4 in moderate yields. Reaction of 1 with
dimethoxypropane and subsequent protection of 6 with
benzyl bromide or dinitrobenzoyl chloride afforded models
7 and 8.
ꢀ
structure R CFIX (X=F, Cl, Br, I). 1,1-Difluoro-1-iodoaldi-
tols can be obtained when X=F.[11] These compounds may
be of interest as building blocks to introduce a gem-difluoro-
methylene group in target polyhydroxylated chiral mole-
cules. This reaction can also provide useful access to 1,1-
diiodo-1-fluoroalditols when X=I.[12] 1,1-Diiodoalkanes are
a valuable class of organic compounds that are extensively
useful in organic synthesis.[13] Finally, an alditol with three
different halogen atoms can also be obtained when X=Br
or Cl.[14] Chiral 1,1,1-trihaloalkanes constitute an interesting
group of organic compounds that includes chiral trihalome-
thanes, which is one of the smallest chiral molecules and has
been the subject of several studies that deal with important
physical and chemical aspects of chirality.[15]
Until now, there appears to be no general methodology
directed towards the synthesis of asymmetric carbon atoms
that bear three different halogen atoms.[16] For example, one
of the simplest compounds of this type is bromochloro-
fluoromethane, which was first synthesised at the end of the
1800s.[17] Almost a century elapsed before the enantiomers
would be even partially resolved and the absolute configura-
tion assigned.[16d,e,18]
Results and Discussion
In previous communications we have described some pre-
liminary results,[11,14] and now we report the full details of
these experiments and their extension to a number of new
models.
Synthesis of 2-deoxy-2-fluoro-hex-1-enitols: Vinyl fluorides
1–11 (DNBz=3,5-dinitrobenzoyl) used in this study were
synthesised from the corresponding 2-deoxy-hex-1-enitol
(glycals) by following the protocols outlined in Scheme 2.
Glycals were treated with Selectfluor in dry nitromethane
by using magnesium bromide as a nucleophile.[19] Elimina-
We have synthesised 2,2-dihalohydrins 12–39 from 2-
deoxy-2-fluoro-hex-1-enitols 1–11 as outlined in Table 1. Di-
fluorohydrins
(42–76%),[22] chlorofluorohydrins (40–
75%),[21] bromofluorohydrins (55–82%)[23] and fluoroiodo-
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E. Suµrez et al.
Table 1. Synthesis of 1,1,1-trihaloalditols.[a]
ed to extend and delineate the
scope of our general protocol,
particularly in regard to the in-
fluence of the stereochemistry
of the saccharide on the stereo-
selectivity of the radical reac-
tion.
The ARF reactions were per-
formed under the conditions
stated in the table, with (diace-
toxyiodo)benzene (DIB) and
iodine in CH2Cl2 at room tem-
perature and irradiation with
two 80 W tungsten filament
lamps. The reactions proceeded
smoothly with complete con-
sumption of the starting materi-
al and without isomerisation of
the adjacent stereogenic centre.
No side products were detected
in the crude reaction mixtures,
even in those with moderate
yields.
The first three models shown
in entries 1–16 of Table 1 illus-
trate the transformation of 2-
deoxy-2-fluoro-2-halo-galacto-
pyranose derivatives 12–27 into
1-deoxy-1-fluoro-1-halo-1-iodo-
arabinitols 40–55,[28] with one
carbon atom less than the start-
ing material, which proceeded
in moderate to good yields. The
yields of benzyl-protected car-
bohydrates (entries 6–8, 13 and
14) are significantly smaller
(compare, for example, en-
tries 3 with 7 and 13). This may
be attributable to intermolecu-
lar reactions since it has been
reported that alkoxyl radicals
generated under DIB/I2 condi-
tions can be used to deprotect
benzyl ethers in carbohydrate
substrates.[30]
Entry
Substrate[b]
Product
Yield [%] (dr)[c]
1
2
3
4
5
6
7
8
12: R=Ac, X=F
13: R=Ac, X=Cl
14: R=Ac, X=Br
15: R=Ac, X=I
16: R=Me, X=F
17: R=Bn, X=F
18: R=Bn, X=Br
19: R=Bn, X=I
40: R=Ac, X=F
41: R=Ac, X=Cl
42: R=Ac, X=Br
43: R=Ac, X=I
44: R=Me, X=F
45: R=Bn, X=F
46: R=Bn, X=Br
47: R=Bn, X=I
75
67 (1:1)
60 (1:1)
81
57
33
46 (1:1)
58
9
20: X=F
21: X=Cl
22: X=Br
23: X=I
48 X=F
76
10
11
12
49: X=Cl
50: X=Br
51: X=I
79 (1:1)
72 (1:1)
79
13
24: R=Bn, X=Br
25: R=Bn, X=I
26: R=DNBz, X=Cl
27: R=DNBz, X=Br
A
46 (3:2)
55
76 (3:2)
66 (2:1)
14[d]
15[e]
16[f]
A
AHCTREUNG
17
18
19
20
28: X=F
29: X=Cl
30: X=Br
31: X=I
56: X=F
57: X=Cl
58: X=Br
59: X=I
71
60 (1:1)
71 (1:1)
75
21
22
23
24
32: X=F
33: X=Cl
34: X=Br
35: X=I
60: X=F
61: X=Cl
62: X=Br
63: X=I
82
70 (1:1)
80 (1:1)
83
25
26
27
28
36: X=F
37: X=Cl
38: X=Br
39: X=I
64: X=F
65: X=Cl
66: X=Br
67: X=I
77
84 (1:1)
65 (1:1)
94
As might be expected, nei-
ther the chloro (entries 2 and
10) nor bromo (entries 3, 7 and
11) series of mixed trihaloaldi-
tols exhibited any significant
diastereoselectivity, and in the
great majority of cases, they
were obtained as inseparable
[a] All reactions were performed in dry CH2Cl2 (50 mLmmolꢀ1) under irradiation with two 80 W tungsten fila-
ment lamps at room temperature for 1 h and contained 1.5 mmol (diacetoxyiodo)benzene (DIB) and 1.5 mmol
I2 per mmol of substrate. [b] The great majority of dihalohydrins are mixtures at C1 and/or C2, the composi-
tion of each one is specified in the Supporting Information section. [c] Isolated yield. [d] The reaction was
completed in 0.5 h. [e] DNBz=3,5-dinitrobenzoyl. [f] The reaction was completed in 0.75 h.
hydrins (66–94%)[21c,24] were prepared by treatment with Se-
lectfluor,[16,25] N-chlorosuccinimide,[26] N-bromoacetamide[27]
and N-iodosuccinimide,[28] respectively. Encouraged by the
ease of construction of these mixed dihalohydrins, we decid-
equimolecular mixtures of diastereomers. Notwithstanding,
from more sterically demanding substrates (entries 13, 15
and 16), compounds 52, 54 and 55 were obtained with a
slight but significant level of diastereoselection.
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Carbohydrate Anomeric Alkoxyl Radicals
FULL PAPER
3
Although the diastereomeric mixture 52 could be separat-
ed by careful chromatography, unfortunately the crystals ob-
tained of (S)-52 were not suitable for X-ray analysis. We
prepared 3,5-dinitrobenzoates 54 and 55 (entries 15 and 16)
with the aim to eventually establish the absolute configura-
tion at C1 by X-ray crystallography. The diastereomeric mix-
tures could be separated by chromatography and their struc-
and JF,H coupling constants, particularly in the S isomers
(327 and 14.6 Hz for (S)-54 and 314 and 20.7 Hz for (S)-55,
respectively), which may be attributable to substituent ef-
fects and/or conformational changes in solution.[34] Even
more surprising is the small but significant difference ob-
3
served in the JH,H coupling constant between the protons at
C3 and C4 (5.3 Hz for (S)-54 and 2.9 Hz for (S)-55), most
probably due to the flexible nature of the isopropylidene
ring in solution.
1
tures were confirmed by H, 13C NMR spectroscopies includ-
ing DEPT, COSY, HMQC and HMBC experiments. Crystal-
lisation of the minor isomers (S)-54 and (S)-55 from n-
hexane/EtOAc provided colourless crystals suitable for X-
ray studies, which permitted the determination of the C1
stereochemistry as stated (Figure 1).[31]
Next, the reaction was examined with other types of car-
bohydrates to test the generality and applicability of this
methodology. Models derived from d- and l-arabino-hexo-
pyranoses (entries 17–24) and l-erythro-pentopyranoses (en-
tries 25–28) were used, and the results are summarised in
Table 1. As can be observed, the reaction worked very well
for all halogen atoms, and the 1,1,1-trihaloalditols 56–67
were obtained in good yields. As well as in the examples of
low steric demand discussed before, the radical fragmenta-
tion occurs with low diastereoselectivity and trihaloalditols
were obtained as equimolecular mixtures of isomers that
were difficult to separate by chromatography.
It is necessary to remark that all of the trihaloalditols ob-
tained were quite stable and could be purified by chroma-
tography over silica gel and handled without special precau-
tions apart from avoiding overexposure to light or heat and
can be kept for months in the freezer without significant de-
composition. The synthetic usefulness of these compounds
as building blocks for the preparation of organofluorine
compounds has been preliminarily assessed, and the results
are summarised in Scheme 3.[35] We were particularly inter-
ested in the reactivity of the fluorinated radical generated
Figure 1. The X-ray structure of (S)-54 showing the anti relationships be-
ꢀ
ꢀ
tween the C1 F and C2 O bonds.
Some features of the X-ray crystal structures of (S)-54
ꢀ
ꢀ
and (S)-55 deserve brief comment. The F C1 bond exhibits
by rupture of the C I bond. The reductive deiodination of
ꢀ
a nearly antiperiplanar relationship with the C2 O bond
compound 40 with tributyltin hydride/2,2ꢁ-azobisisobutyroni-
trile (AIBN) led to 1,3,4-tri-O-acetyl-5-deoxy-5,5-difluoro-2-
O-formyl-d-arabinitol (68) in excellent yield.[36] Radical in-
termolecular allylation was also possible by following the
Keck and Yates protocol.[37] Reaction of difluoroiodo com-
pound 48 and diiodofluoro compound 43 with allyltributyl
stannane in the presence of AIBN gave the expected allyl
with a F-C1-C2-O dihedral angle of 174.6 and 171.88, respec-
tively. This is quite surprising considering the stereoelec-
tronic preference of two vicinal electronegative atoms to
adopt a gauche in favour of an anti conformation. This coun-
terintuitive gauche effect seems to be quite general and has
been the subject of numerous synthetic and theoretical stud-
ies, particularly with oxygen
and fluorine atoms.[32] Further-
more, as a consequence of this
anti conformation, in both iso-
mers (S)-54 and (S)-55 the vol-
uminous iodine atom is point-
ing towards the acetal ring
plane in an apparently energeti-
cally disfavoured arrangement.
The conformation of the acetal
ring in the crystalline structure
was determined as O3T3 with
very similar phase angles for
both isomers (P=103.4 for (S)-
54 and 106.58 for (S)-55).[33]
Other highlighted features of
Scheme 3. a) Bu3SnH (5 equiv), AIBN (0.4 equiv), PhH (30 mL), reflux, 0.5 h; b) allyltributylstannane
(5 equiv), AIBN (0.4 equiv), PhH (30 mL), reflux, 40 min; c) Grubbs catalyst [(PCy3)2Cl2Ru=CHPh]
compounds 54 and 55 are the
1
differences between the JF,C (0.1 equiv), CH2Cl2 (40 mL), RT, 1 h.
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6707

E. Suµrez et al.
compound 69 and diallyl compound 70 in good yields.[38]
Ring-closing metathesis (RCM) of compound 70 provided
the tertiary fluoride compound 71 in 90% yield.[39]
Generalprocedure for the synthesis of 2-deoxy-2,2-bromofuloropyrano-
ses: Asolution of the corresponding 2-deoxy-2-fluoro-hex-1-enitol
(1 mmol) in THF (20 mL) and H2O (5 mL), which contained freshly crys-
tallised N-bromoacetamide (1.5 mmol) was stirred at room temperature
for 1–7.5 h. The mixture was then poured into H2O and extracted with
EtOAc. The organic layer was dried and concentrated in vacuo. Column
chromatography of the residue (hexanes/EtOAc mixtures) afforded the
required bromofluorohydrin compounds.
Conclusion
Generalprocedure for the synthesis of 2-deoxy-2,2-ful oroiodopyranoses
Asolution of the corresponding 2-deoxy-2-fluoro-hex-1-enitol (1 mmol)
:
We believe that the reported methodology will be of interest
because it permits the facile preparation of mono- or gem-
difluorinated chiral building blocks for incorporation into
important complex target molecules. Also, we report for the
first time on the chromatographic resolution of diastereoiso-
meric mixtures of 1-bromo or 1-chloro-1-deoxy-1-fluoro-1-
iodo-alkanes of this type, and the determination of their ab-
solute configuration by X-ray crystallographic analysis. In
summary, the ARF reaction of 2-fluoro-2-halohydrins de-
rived from carbohydrates provides a good method of prepar-
ing 1,1,1-trihaloalditols with one carbon atom less than the
original carbohydrate and offers special advantages, such as
ready accessibility of the starting material, experimental
simplicity, good yields and mild conditions that are compati-
ble with the stability of the protective groups most common-
ly used in carbohydrate chemistry. Further exploration of
the synthetic potential of these compounds is currently
under investigation in our laboratory.
in THF (10 mL) and H2O (5 mL), which contained N-iodosuccinimide
(2 mmol) was stirred at room temperature (without light exposure) for 1–
4 h. The mixture was diluted with EtOAc, poured into H2O and extracted
with EtOAc. The organic layer was washed with aq Na2S2O3, dried and
concentrated in vacuo. Column chromatography of the residue (hexanes/
EtOAc mixtures) afforded the required fluoroiodohydrin compounds.
Generalprocedure for the ARF reaction : Asolution of the dihalohydrins
(1 mmol) in CH2Cl2 (50 mL), which contained (diacetoxyiodo)benzene
(1.5 mmol) and I2 (1.5 mmol) was irradiated with two 80 W tungsten-fila-
ment lamps at room temperature. The mixture was then poured into
H2O and extracted with CH2Cl2. The organic layer was washed with aq
Na2S2O3, dried and concentrated in vacuo. Column chromatography of
the residue (hexanes/EtOAc mixtures) afforded the halo-fluoro-iodine
compounds. No special precautions needed to be taken to exclude light
during workup and chromatography, and these compounds could be
stored indefinitely under N2 at ꢀ208C in the dark.
1,3,4-Tri-O-acetyl-5-deoxy-5,5-difluoro-2-O-formyl-5-iodo-d-arabinitol
(40): Oil (75%); [a]D =+23.4 (c=0.73); 1H NMR: d=2.05 (s, 3H), 2.14
(s, 3H), 2.18 (s, 3H), 3.91 (dd, J=7.4, 11.7 Hz, 1H), 4.31 (dd, J=5.0,
11.7 Hz, 1H), 5.19 (ddd, J=8.6, 3JF,H =6.1, 11.1 Hz, 1H), 5.52 (dddd, J=
1.0, 2.1, 5.0, 7.4 Hz, 1H), 5.61 (dd, J=2.1, 8.6 Hz, 1H), 8.00 ppm (brs,
1H); 13C NMR: d=20.5 (CH3), 20.6 (CH3), 20.8 (CH3), 61.6 (CH2), 67.3
1
(CH), 68.2 (CH), 72.5 (dd, 2JF,C =24.4, 24.4 Hz; CH), 100.4 (dd, JF,C
=
314.3, 314.3 Hz; C), 159.7 (CH), 168.3 (C), 169.1 (C), 170.3 ppm (C);
19F NMR: d=ꢀ46.3 (dd, 3JF,H =9.8, 2JF,F =197.3 Hz, 1F), ꢀ50.8 ppm (dd,
3JF,H =13.8, 2JF,F =197.3 Hz, 1F); IR: n˜ =1762, 1736, 1230, 1198 cmꢀ1; MS
(70 eV, EI): m/z (%): 407 (<1) [MꢀOCOH]+, 393 (3), 325 (33), 283
(100), 263 (86); HRMS (EI): m/z: calcd for C11H14F2IO6: 406.9803
[MꢀOCOH]+; found: 406.9802; elemental analysis calcd (%) for
C12H15F2IO8 (452.15): C 31.88, H 3.34; found: C 31.95, H 3.31.
ExperimentalSection
Generalmethods : Melting points were determined with a hot-stage appa-
ratus and are uncorrected. Optical rotations were measured at the
sodium line at ambient temperature in CHCl3 solutions. IR spectra were
recorded in CCl4 solutions unless otherwise stated. NMR spectra were
determined at 400 MHz for 1H, 100.6 MHz for 13C in CDCl3 and
376.5 MHz for 19F in CDCl3 unless otherwise stated, in the presence of
TMS as an internal standard. Mass spectra were determined at 70 eV.
Merck silica gel 60 PF (0.063–0.2 mm) was used for column chromatogra-
phy. Circular layers of 1 mm of Merck silica gel 60 PF254 were used on a
Chromatotron for centrifugally assisted chromatography. Commercially
available reagents and solvents were of analytical grade or were purified
by standard procedures prior to use. All reactions involving air or mois-
ture-sensitive materials were carried out under a nitrogen atmosphere.
TLC plates were visualised by spraying with a solution of 0.5% vanillin
in H2SO4/EtOH (4:1) and heating until development of colour.
1,3,4-Tri-O-acetyl-5-deoxy-5-fluoro-2-O-formyl-5,5-diiodo-d-arabinitol
(43): Crystalline solid (81%); m.p. 103–1048C (n-hexane/EtOAc); [a]D =
+14.4 (c=0.16); 1H NMR (500 MHz): d=2.03 (s, 3H), 2.13 (s, 3H), 2.18
(s, 3H), 3.88 (dd, J=7.4, 11.7 Hz, 1H), 4.31 (dd, J=4.8, 11.7 Hz, 1H),
2
5.24 (dd, J=7.4, JF,H =7.4 Hz, 1H), 5.51–5.55 (m, 2H), 8.00 ppm (s, 1H);
13C NMR (125.7 MHz): d=20.6 (CH3), 20.8 (CH3), 21.1 (CH3), 27.8 (d,
2
1JF,C =325.1 Hz; C), 61.8 (CH2), 67.8 (CH), 70.9 (CH), 76.8 (d, JF,C
=
8.8 Hz; CH), 159.8 (CH), 168.4 (C), 169.2 (C), 170.3 ppm (C); 19F NMR:
d=ꢀ69.8 ppm (s, 1F); IR: n˜ =1760, 1736, 1370, 1230, 1196 cmꢀ1; MS
(70 eV, EI): m/z (%): 501 (<1) [MꢀOAc] +, 433 (<1), 331 (14), 263
(100); HRMS (EI): m/z: calcd for C10H12FI2O6: 500.8707 [MꢀOAc] +
;
Generalprocedure for the synthesis of 2-deoxy-2,2-difuloropyranoses
:
found: 500.8710; elemental analysis calcd (%) for C12H15FI2O8 (560.05):
C 25.72, H 2.70; found: C 25.89, H 2.73.
F-TEDA-BF4 (Selectfluor) (1.5 mmol) was added to a solution of the cor-
responding 2-deoxy-2-fluoro-hex-1-enitol (1 mmol) in nitromethane
(10 mL) and H2O (2 mL) and the mixture was stirred at room tempera-
ture until the disappearance of the starting material was observed by
TLC (15 h). The mixture was then heated to reflux for 0.5 h, poured into
brine and extracted with EtOAc. The organic layer was dried and con-
centrated in vacuo. Column chromatography of the residue (hexanes/
EtOAc mixtures) afforded the required difluorohydrin compounds.
5-Deoxy-5,5-difluoro-2-O-formyl-5-iodo-1,3,4-tri-O-methyl-d-arabinitol
(44): Oil (57%); [a]D =+9.0 (c=0.10); 1H NMR: d=2.98 (ddd, J=7.9,
3JF,H =6.0, 8.7 Hz, 1H), 3.41 (s, 3H), 3.52 (s, 3H), 3.53 (dd, 5JF,H =0.8,
1.3 Hz, 3H), 3.58 (d, J=6.7 Hz, 2H), 3.63 (dd, J=2.3, 7.9 Hz, 1H), 5.42
(dddd, J=1.0, 2.3, 6.7, 6.7 Hz, 1H), 8.14 ppm (d, J=1.0 Hz, 1H);
4
13C NMR: d=59.0 (CH3), 60.8 (d, 5JF,C =1.6 Hz; CH3), 61.2 (d, JF,C
=
2.7 Hz; CH3), 69.6 (CH2), 70.6 (CH), 79.4 (d, 3JF,C =4.3 Hz; CH), 84.8
General procedure for the synthesis of 2-deoxy-2,2-chlorofluoropyrano-
ses: Asolution of the corresponding 2-deoxy-2-fluoro-hex-1-enitol
(1 mmol) in THF (20 mL) and H2O (10 mL), which contained N-chloro-
succinimide (2 mmol) was heated at 508C for 6–12 h. The mixture was
then poured into H2O and extracted with EtOAc. The organic layer was
dried and concentrated in vacuo. Column chromatography of the residue
(hexanes/EtOAc mixtures) afforded the required chlorofluorohydrin
compounds.
(dd, 2JF,C =19.4, 20.0 Hz; CH), 107.9 (dd, 1JF,C =316.6, 322.4 Hz; C),
3
2
160.1 ppm (CH); 19F NMR: d=ꢀ41.7 (dd, JF,H =8.8, JF,F =200.9 Hz, 1F),
ꢀ47.1 ppm (dd, 3JF,H =7.8, 2JF,F =200.9 Hz, 1F); IR: n˜ =2937, 1728, 1175,
1224 cmꢀ1; MS (70 eV, EI): m/z (%): 353 (1) [MꢀCH3]+, 291 (6), 265 (8),
195 (5), 163 (8), 147 (100); HRMS (EI): m/z: calcd for C8H12F2IO5:
352.9698 [MꢀCH3]+; found: 352.9699; elemental analysis calcd (%) for
C9H15F2IO5 (368.12): C 29.36, H 4.11; found: C 29.47, H 4.09.
6708
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 6704 – 6712

Carbohydrate Anomeric Alkoxyl Radicals
FULL PAPER
3
1,3,4-Tri-O-benzyl-5-deoxy-5,5-difluoro-2-formyl-5-iodo-d-arabinitol(45) :
Crystalline solid (46%); m.p. 52.5–53.68C (n-hexane/EtOAc); [a]D =
ꢀ38.5 (c=0.14); 1H NMR: d=3.44 (ddd, J=7.1, 3JF,H =7.1, 8.2 Hz, 1H),
3.60 (dd, J=6.9, 9.8 Hz, 1H), 3.64 (dd, J=5.8, 9.8 Hz, 1H), 4.02 (dd, J=
2.6, 7.1 Hz, 1H), 4.47 (d, J=11.8 Hz, 1H), 4.51 (d, J=11.8 Hz, 1H), 4.53
(d, J=10.8 Hz, 1H), 4.57 (d, J=10.8 Hz, 1H), 4.76 (d, J=10.6 Hz, 1H),
4.87 (d, J=10.6 Hz, 1H), 5.47 (dddd, J=0.8, 2.6, 5.8, 6.9 Hz, 1H), 7.25–
19F NMR: d=ꢀ67.7 ppm (d, JF,H =22.9 Hz, 1F); IR: n˜ =3030, 2931, 1735,
1455, 1383, 1218, 1172, 1110 cmꢀ1; MS (70 eV, EI): m/z (%): 518/516
(<1) [M]+, 503/501 (1/1), 460/458 (<1), 273 (1), 227/225 (11/11), 183/181
(12/14), 91 (100); HRMS (EI): m/z calcd for C16H1979BrFIO5: 515.9445
[M]+; found: 515.9449; elemental analysis calcd (%) for C16H19BrFIO5
(517.13): C 37.16, H 3.70; found: C 37.15, H 3.84.
(5S)-1-O-Benzyl-5-bromo-5-deoxy-5-fluoro-2-O-formyl-3,4-O-isopropyl-
idene-5-iodo-d-arabinitol(( S)-52): Crystalline solid (18%); m.p. 84.0–
85.38C (n-hexane/EtOAc); [a]D =+14.0 (c=0.10); 1H NMR: d=1.44 (s,
3H), 1.65 (s, 3H), 3.69 (d, J=5.3 Hz, 2H), 4.54 (d, J=11.9 Hz, 1H), 4.59
(d, J=11.9 Hz, 1H), 4.65 (dd, J=5.0, 6.2 Hz, 1H), 4.66 (dd, J=6.2,
3JF,H =16.7 Hz,1H), 5.69 (dddd, J=1.1, 5.0, 5.3, 5.3 Hz, 1H), 7.30–
7.37 ppm (m, 5H), 8.07 ppm (brs, 1H); 13C NMR (125.7 MHz): d=25.4
(CH3), 26.3 (CH3), 60.3 (d, 1JF,C =325.9 Hz; C), 67.8 (CH2), 68.3 (CH),
73.4 (CH2), 75.6 (CH), 86.2 (d, 2JF,C =23.3 Hz; CH), 110.4 (C), 127.7 (2”
CH), 127.9 (CH), 128.5 (2”CH), 137.5 (C), 159.9 ppm (CH); 19F NMR:
d=ꢀ67.6 ppm (brs, 1F); IR: n˜ =3030, 2938, 1735, 1383, 1218, 1172,
1112 cmꢀ1; MS (70 eV, EI): m/z (%): 518/516 (<1) [M]+, 503/501 (1/1),
460/458 (<1), 285 (<1), 273 (2), 227/225 (10/10), 91 (100); HRMS (EI):
m/z: calcd for C16H1981BrFIO5: 517.9424 [M]+; found: 517.9427; elemental
analysis calcd (%) for C16H19BrFIO5 (517.13): C 37.16, H 3.70; found: C
37.47, H 3.34.
7.39 (m, 15H), 8.00 ppm (dd, J=0.8, 0.8 Hz, 1H); 13C NMR: d=67.2
3
(CH2), 70.9 (CH), 73.3 (CH2), 74.6 (CH2), 75.1 (CH2), 77.1 (d, JF,C
=
4.3 Hz; CH), 82.8 (dd, 2JF,C =19.3, 20.3 Hz; CH), 104.4 (dd, 1JF,C =324.5,
366.4 Hz; C), 127.8 (2”CH), 127.9 (CH), 128.0 (CH), 128.1 (2”CH),
128.3 (CH), 128.4 (2”CH), 128.46 (4”CH), 128.5 (2”CH), 136.3 (C),
2
137.2 (C), 137.4 (C), 160.2 ppm (CH); 19F NMR: d=ꢀ40.9 (d, JF,F
=
183.5 Hz, 1F), ꢀ46.4 ppm (d, 2JF,F =183.5 Hz, 1F); IR: n˜ =3018, 2930,
1727, 1455, 1178, 1115 cmꢀ1; MS (70 eV, EI): m/z (%): 505 (1) [MꢀBn]+,
399 (1), 309 (1), 271 (1), 91 (100); HRMS (EI): m/z calcd for
C20H20F2IO5: 505.0324 [MꢀBn]+; found: 505.0347; elemental analysis
calcd (%) for C27H27F2IO5 (596.41): C 54.37, H 4.56; found: C 54.14, H
4.40.
1,3,4-Tri-O-benzyl-5-deoxy-5-fluoro-2-formyl-5,5-diiodo-d-arabinitol(47) :
1
Oil (58%); [a]D =ꢀ11.2 (c=0.34); H NMR: d=3.62 (dd, J=1.1, 6.4 Hz,
2H), 3.78 (dd, J=5.6, 3JF,H =8.5 Hz, 1H), 4.07 (dd, J=2.9, 5.6 Hz, 1H),
4.44 (d, J=11.9 Hz, 1H), 4.49 (d, J=11.9 Hz, 1H), 4.57 (d, J=11.1 Hz,
1H), 4.78 (d, J=10.9 Hz, 1H), 4.86 (d, J=11.1 Hz, 1H), 5.06 (d, J=
10.9 Hz, 1H), 5.51 (ddd, J=2.6, 6.4, 6.4 Hz, 1H), 7.26–7.43 (m, 15H),
5-Deoxy-1-O-benzyl-5-fluoro-2-O-formyl-3,4-O-isopropylidene-5,5-
diiodo-d-arabinitol(53) : Oil (55%); [a]D =+4.9 (c=0.51); H NMR: d=
1
1.45 (s, 3H), 1.65 (s, 3H), 3.66 (dd, J=5.5, 9.8 Hz, 1H), 3.69 (dd, J=6.7,
9.8 Hz, 1H), 4.56 (d, J=11.9 Hz, 1H), 4.58 (d, J=11.9 Hz, 1H), 4.64 (dd,
J=6.1, 3JF,H =22.6 Hz, 1H), 4.72 (dd, J=3.3, 6.1 Hz, 1H), 5.61 (m, 1H),
7.29–7.36 (m, 5H), 8.05 ppm (brs, 1H); 13C NMR (125.7 MHz): d=22.3
(d, 1JF,C =335.5 Hz; C), 25.4 (CH3), 26.5 (CH3), 67.8 (CH2), 68.3 (CH),
73.3 (CH2), 74.7 (CH), 87.3 (d, 2JF,C =20.7 Hz; CH), 109.9 (C), 127.7 (2”
CH), 127.8 (CH), 128.4 (2”CH), 137.6 (C), 159.9 ppm (CH); 19F NMR:
d=ꢀ74.1 ppm (s, 1F); IR: n˜ =3018, 2935, 1732, 1549, 1383, 1215,
1170 cmꢀ1; MS (70 eV, EI): m/z (%): 564 (<1) [M]+, 549 (<1), 273 (11),
229 (22), 91 (100); HRMS (EI): m/z: calcd for C16H19FI2O5: 563.9306
[M]+; found: 563.9297; elemental analysis calcd (%) for C16H19FI2O5
(564.13): C 34.07, H 3.39; found: C 34.18, H 3.02.
7.96 ppm (s, 1H); 13C NMR: d=36.6 (d, 1JF,C =328.5 Hz; C), 67.6 (CH2),
2
71.3 (CH), 73.2 (CH2), 74.1 (CH2), 75.7 (CH2), 78.2 (CH), 88.6 (d, JF,C
=
17.7 Hz; CH), 127.8–128.6 (15”CH), 136.6 (C), 137.3 (C), 137.5 (C),
3
160.3 ppm (CH); 19F NMR: d=ꢀ64.1 ppm (d, JF,H =6.2 Hz, 1F); IR: n˜ =
3067, 3033, 2929, 1732, 1456, 1172, 1098 cmꢀ1; MS (70 eV, EI): m/z (%):
613 (1) [MꢀBn]+, 507 (1), 303 (1), 289 (1), 254 (4), 181 (12), 91 (100);
HRMS (EI): m/z: calcd for C20H20FI2O5: 612.9384 [MꢀBn]+; found:
612.9378; elemental analysis calcd (%) for C27H27FI2O5 (704.32): C 46.02,
H 3.87; found: C 46.02, H 4.05.
3,4-Di-O-acetyl-1,5-dideoxy-5,5-difluoro-2-O-formyl-5-iodo-l-arabinitol
(48): Crystalline solid (76%); m.p. 76.5–788C (n-hexane/EtOAc); [a]D =
ꢀ14.9 (c=0.22); 1H NMR: d=1.23 (d, J=6.2 Hz, 3H), 2.16 (s, 3H), 2.17
(s, 3H), 5.18 (ddd, J=8.8, 3JF,H =6.0, 11.2 Hz, 1H), 5.32 (dddd, J=2.1,
6.2, 6.2, 6.2 Hz, 1H), 5.42 (dd, J=2.1, 8.8 Hz, 1H), 7.96 ppm (s, 1H);
13C NMR: d=16.1 (CH3), 20.5 (CH3), 20.7 (CH3), 66.9 (CH), 71.1 (CH),
(5R)-5-Chloro-5-deoxy-1-O-(3,5-dinitrobenzoyl)-5-fluoro-2-O-formyl-3,4-
O-isopropylidene-5-iodo-d-arabinitol(( R)-54): Crystalline solid (46%);
m.p. 120.4–122.08C (hexane/EtOAc); [a]D =+30 (c=0.05); 1H NMR: d=
1.48 (s, 3H), 1.66 (s, 3H), 4.55 (dd, J=2.4, 6.1 Hz, 1H), 4.58 (dd, J=6.8,
11.9 Hz, 1H), 4.71 (dd, J=6.1, 3JF,H =24.4 Hz, 1H), 4.79 (dd, J=3.7,
11.9 Hz, 1H), 5.81 (ddd, J=2.4, 3.7, 6.8 Hz, 1H), 8.10 (s, 1H), 9.13 (d,
J=2.1 Hz, 2H), 9.23 ppm (dd, J=2.1, 2.1 Hz, 1H); 13C NMR (C6D6): d=
25.2 (CH3), 26.1 (CH3), 66.0 (CH2), 67.2 (CH), 74.0 (d, 1JF,C =324.5 Hz;
C), 74.9 (CH), 86.6 (d, 2JF,C =20.7 Hz; CH), 110.5 (C), 122.5 (CH), 128.8
(2”CH), 132.5 (C), 148.3 (2”C), 159.6 (CH), 162.3 ppm (C); 19F NMR:
d=ꢀ66.7 ppm (s, 1F); IR: n˜ =3102, 2929, 1737, 1549, 1461, 1342,
1273 cmꢀ1; MS (70 eV, EI): m/z (%): 563/561 (5/15) [MꢀCH3]+, 483 (18),
385 (9), 295/293 (3/7), 293 (7), 195 (100); HRMS (EI): m/z: calcd for
72.8 (dd, 2JF,C =23.0, 24.0 Hz; CH), 100.8 (dd, 1JF,C =314.0, 318.0 Hz; C),
2
159.9 (CH), 168.2 (C), 169.4 ppm (C); 19F NMR: d=ꢀ46.0 (d, JF,F
=
192.0 Hz, 1F), ꢀ50.7 ppm (dd, 3JF,H =13.4, 2JF,F =192.0 Hz, 1F); IR: n˜ =
2940, 1760, 1731, 1371, 1201, 1170 cmꢀ1; MS (70 eV, EI): m/z (%): 267
(14) [MꢀI]+, 249 (16), 225 (100), 205 (91); HRMS (EI): m/z: calcd for
C10H13F2O6: 267.0680 [MꢀI]+; found: 267.0692; elemental analysis calcd
(%) for C10H13F2IO6 (394.11): C 30.48, H 3.32; found: C 30.68, H 3.14.
3,4-Di-O-acetyl-1,5-dideoxy-5-fluoro-2-O-formyl-5,5-diiodo-l-arabinitol
(51): Crystalline solid (79%); m.p. 90–918C (n-hexane/EtOAc); [a]D =
ꢀ16.9 (c=0.42); 1H NMR: d=1.23 (d, J=6.4 Hz, 3H), 2.17 (s, 3H), 2.19
C15H1235ClFIN2O10
:
560.9209 [MꢀCH3]+; found: 560.9212; elemental
3
(s, 3H), 5.23 (dd, J=8.0, JF,H =6.0 Hz, 1H), 5.30–5.35 (m, 2H), 7.95 ppm
analysis calcd (%) for C16H15ClFIN2O10 (576.66): C 33.33, H 2.62, N 4.86;
found: C 33.49, H 2.52, N 4.84.
1
(s, 1H); 13C NMR: d=16.4 (CH3), 20.9 (CH3), 21.1 (CH3), 28.7 (d, JF,C
=
324.0 Hz; C), 67.4 (CH), 74.0 (CH), 76.8 (d, 2JF,C =24.0 Hz; CH), 160.0
(CH), 168.2 (C), 169.4 ppm (C); 19F NMR: d=ꢀ69.1 ppm (s, 1F); IR:
n˜ =2991, 1759, 1730, 1370, 1199, 1171 cmꢀ1; MS (70 eV, EI): m/z (%): 457
(<1) [MꢀOCOH]+, 287 (11), 273 (6), 205 (100); HRMS (EI): m/z: calcd
for C9H12FI2O4: 456.8809 [MꢀOCOH]+; found: 456.8800; elemental anal-
ysis calcd (%) for C10H13FI2O6 (502.02): C 23.93, H 2.61; found: C 23.93,
H 2.31.
(5S)-5-Chloro-5-deoxy-1-O-(3,5-dinitrobenzoyl)-5-fluoro-2-O-formyl-3,4-
O-isopropylidene-5-iodo-d-arabinitol(( S)-54): Crystalline solid (30%);
m.p. 134.5–135.58C (hexane/EtOAc); [a]D =0 (c=0.15); 1H NMR: d=
1.48 (s, 3H), 1.68 (s, 3H), 4.56 (dd, J=5.3, 6.1 Hz, 1H), 4.58 (dd, J=6.6,
3
12.0 Hz, 1H), 4.78 (dd, J=3.9, 12.0 Hz, 1H), 4.88 (dd, J=6.1, JF,H
=
14.6 Hz, 1H), 5.90–5.93 (m, 1H), 8.16 (brs, 1H), 9.14 (d, J=2.1 Hz, 2H),
9.24 ppm (dd, J=2.1, 2.1 Hz, 1H); 13C NMR (C6D6): d=25.1 (CH3), 26.3
(CH3), 65.6 (d, 3JF,C =3.2 Hz; CH), 67.0 (CH2), 76.29 (d, 1JF,C =314.8 Hz;
C), 76.3 (CH), 86.2 (d, 2JF,C =24.7 Hz; CH), 111.2 (C), 122.2 (CH), 128.8
(2”CH), 132.4 (C), 148.3 (2”C), 159.4 (CH), 162.2 ppm (C); 19F NMR:
d=ꢀ68.0 ppm (brs, 1F); IR: n˜ =3102, 2939, 1740, 1548, 1343, 1275,
1173 cmꢀ1; MS (70 eV, EI): m/z (%): 563/561 (4/13) [MꢀCH3]+, 483 (24),
385 (7), 295/293 (2/6), 195 (100); HRMS (EI): m/z: calcd for
(5R)-1-O-Benzyl-5-bromo-5-deoxy-5-fluoro-2-O-formyl-3,4-O-isopropyl-
idene-5-iodo-d-arabinitol(( R)-52): Oil (28%); [a]D =+12.7 (c=0.49);
1H NMR: d=1.44 (s, 3H), 1.63 (s, 3H), 3.68 (d, J=6.1 Hz, 2H), 4.54 (d,
J=11.9 Hz, 1H), 4.55 (dd, J=6.1, 3JF,H =23.4 Hz, 1H), 4.58 (d, J=
11.9 Hz, 1H), 4.67 (dd, J=3.4, 6.1 Hz, 1H), 5.58 (ddd, J=3.4, 6.1, 6.1 Hz,
1H), 7.29 ꢀ7.36 (m, 5H), 8.05 ppm (s, 1H); 13C NMR (125.7 MHz): d=
25.4 (CH3), 26.3 (CH3), 59.6 (d, 1JF,C =333.7 Hz; C), 67.9 (CH2), 68.2
(CH), 73.3 (CH2), 74.3 (CH), 86.4 (d, 2JF,C =17.2 Hz; CH), 109.9 (C),
127.7 (2”CH), 127.9 (CH), 128.5 (2”CH), 137.5 (C), 159.9 ppm (CH);
C15H1235ClFIN2O10
:
560.9209 [MꢀCH3]+; found: 560.9213; elemental
analysis calcd (%) for C16H15ClFIN2O10 (576.66): C 33.33, H 2.62, N 4.86;
found: C 33.51, H 2.52, N 4.74.
Chem. Eur. J. 2008, 14, 6704 – 6712
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6709

E. Suµrez et al.
(5R)-5-Bromo-5-deoxy-1-O-(3,5-dinitrobenzoyl)-5-fluoro-2-O-formyl-3,4-
O-isopropylidene-5-iodo-d-arabinitol(( R)-55): Crystalline solid (44%);
m.p. 128.7–130.38C (n-hexane/EtOAc); [a]D =+19.3 (c=0.14); H NMR:
(dd, 3JF,H =10.0, 2JF,F =188.1 Hz, 1F); IR: n˜ =1767, 1736, 1203, 1161 cmꢀ1
;
MS (70 eV, EI): m/z (%): 349 (36) [MꢀOCOH]+, 267 (9), 225 (97), 205
(100); HRMS (EI): m/z: calcd for C9H12F2IO4: 348.9748 [MꢀOCOH]+;
found: 348.9737; elemental analysis calcd (%) for C10H13F2IO6 (394.11):
C 30.48, H 3.32; found: C: 30.53, H 3.30.
1
d=1.49 (s, 3H), 1.67 (s, 3H), 4.58 (dd, J=6.5, 11.8 Hz, 1H), 4.61 (dd, J=
3
1.9, 6.1 Hz, 1H), 4.77 (dd, J=3.9, 11.8 Hz, 1H), 4.80 (dd, J=6.1, JF,H
=
25.6 Hz, 1H), 5.83 (ddd, J=1.9, 3.9, 6.5 Hz, 1H), 8.08 (s, 1H), 9.15 (d,
J=2.1 Hz, 2H), 9.24 ppm (dd, J=2.1, 2.1 Hz, 1H); 13C NMR: d=25.5
(CH3), 26.3 (CH3), 55.9 (d, 1JF,C =331.7 Hz; C), 65.8 (CH2), 67.4 (CH),
74.8 (CH), 86.9 (d, 2JF,C =20.0 Hz; CH), 110.7 (C), 122.6 (CH), 129.6 (2”
CH), 133.2 (C), 148.7 (2”C), 159.8 (CH), 162.2 ppm (C); 19F NMR: d=
ꢀ69.3 ppm (brs, 1F); IR: n˜ =3111, 2950, 1738, 1550, 1343, 1275, 1175,
1154 cmꢀ1; MS (70 eV, EI): m/z (%): 607/605 (9/9) [MꢀCH3]+, 483 (27),
437/435 (7/7), 385 (11), 195 (100); HRMS (EI): m/z: calcd for
2,3-Di-O-acetyl-1,5-dideoxy-1-fluoro-4-O-formyl-1,1-diiodo-l-arabinitol
(63): Oil (83%); [a]D =ꢀ52.8 (c=1.0); 1H NMR: d=1.30 (d, J=6.4 Hz,
3H), 2.13 (s, 3H), 2.26 (s, 3H), 5.02 (dddd, J=6.4, 6.4, 6.4, 7.2 Hz, 1H),
5.51 (dd, J=2.0, 3JF,H =18.0 Hz, 1H), 5.92 (dd, J=2.0, 7.2 Hz, 1H),
8.00 ppm (s, 1H); 13C NMR: d=15.8 (CH3), 20.8 (CH3), 20.9 (CH3), 26.7
(d, 1JF,C =327.8 Hz; C), 68.1 (CH), 70.2 (CH), 77.1 (d, 2JF,C =21.2 Hz;
CH), 159.6 (CH), 168.9 (C), 169.4 ppm (C); 19F NMR: d=ꢀ70.2 ppm (d,
3JF,H =17.4 Hz, 1F); IR: n˜ =2939, 1764, 1736, 1371, 1202, 1166 cmꢀ1; MS
(70 eV, EI): m/z (%): 457 (1) [MꢀOCOH]+, 287 (5), 249 (4), 205 (100);
HRMS (EI): m/z: calcd for C9H12FI2O4: 456.8809 [MꢀOCOH]+; found:
456.8813; elemental analysis calcd (%) for C10H13FI2O6 (502.02): C 23.93,
H 2.61; found: C 24.00, H 2.53.
C15H1279BrFIN2O10
:
604.8704 [MꢀCH3]+; found: 604.8721; elemental
analysis calcd (%) for C16H15BrFIN2O10 (621.11): C 30.94, H 2.43, N 4.51;
found: C 30.95, H 2.46, N 4.26.
(5S)-5-Bromo-5-deoxy-1-O-(3,5-dinitrobenzoyl)-5-fluoro-2-O-formyl-3,4-
O-isopropylidene-5-iodo-d-arabinitol(( S)-55): Crystalline solid (22%);
m.p. 142.7–143.88C (n-hexane/EtOAc); [a]D =ꢀ21.0 (c=0.10); 1H NMR:
d=1.49 (s, 3H), 1.69 (s, 3H), 4.57 (dd, J=6.6, 11.7 Hz, 1H), 4.64 (ddd,
J=2.9, 6.4, 4JF,H =0.8 Hz, 1H), 4.77 (dd, J=4.0, 11.7 Hz, 1H), 4.90 (dd,
J=6.4, 3JF,H =20.7 Hz, 1H), 5.88 (ddd, J=2.9, 4.0, 6.6 Hz, 1H), 8.10 (s,
1H), 9.16 (d, J=2.1 Hz, 2H), 9.24 ppm (dd, J=2.1, 2.1 Hz, 1H);
13C NMR: d=25.5 (CH3), 26.4 (CH3), 57.2 (d, 1JF,C =326.7 Hz; C), 65.5
(CH2), 67.2 (CH), 76.1 (CH), 86.6 (d, 2JF,C =21.3 Hz; CH), 111.4 (C),
122.7 (CH), 129.6 (2”CH), 133.2 (C), 148.7 (2”C), 159.7 (CH),
162.2 ppm (C); 19F NMR: d=ꢀ70.6 ppm (brs, 1F); IR: n˜ =3098, 2984,
1740, 1550, 1342, 1275, 1175 cmꢀ1; MS (70 eV, EI): m/z (%): 607/605 (7/7)
[MꢀCH3]+, 483 (15), 437/435 (6/6), 385 (13), 195 (100); HRMS (EI): m/
z: calcd for C15H1281BrFIN2O10: 606.8684 [MꢀCH3]+; found: 606.8685; el-
emental analysis calcd (%) for C16H15BrFIN2O10 (621.11): C 30.94, H
2.43, N 4.51; found: C 31.06, H 2.41, N 4.48.
2,3-Di-O-acetyl-4-deoxy-4,4-difluoro-1-O-formyl-4-iodo-d-erythritol(64) :
Oil (77%); [a]D =ꢀ17.5 (c=0.27); H NMR (500 MHz): d=2.08 (s, 3H),
1
2.20 (s, 3H), 4.29 (dd, J=6.2, 12.4 Hz, 1H), 4.47 (dd, J=2.4, 12.4 Hz,
1H), 5.42 (ddd, J=6.2, 3JF,H =7.6, 13.2 Hz, 1H), 5.50 (ddd, J=2.4, 6.2,
6.2 Hz, 1H), 8.03 ppm (s, 1H); 13C NMR (125.7 MHz): d=20.6 (2”CH3),
60.7 (CH2), 68.4 (CH), 74.4 (dd, 2JF,C =21.4, 24.5 Hz; CH), 98.6 (dd,
1JF,C =314.3, 320.4 Hz; C), 160.1 (CH), 168.2 (C), 169.4 ppm (C);
19F NMR: d=ꢀ48.7 (dd, 3JF,H =9.2, 2JF,F =192.8 Hz, 1F), ꢀ51.1 ppm (dd,
3JF,H =13.8, 2JF,F =192.8 Hz, 1F); IR: n˜ =2940, 1762, 1737, 1371, 1228,
1201, 1168 cmꢀ1; MS (70 eV, EI): m/z (%): 335 (1) [MꢀOCOH]+, 321
(1), 253 (9), 211 (97), 191 (100); HRMS (EI): m/z: calcd for C8H10F2IO4:
334.9592 [MꢀOCOH]+; found: 334.9600; elemental analysis calcd (%)
for C9H11F2IO6 (380.08): C 28.44, H 2.92; found: C 28.64, H 2.73.
2,3-Di-O-acetyl-4-deoxy-4-fluoro-1-O-formyl-4-diiodo-d-erythritol(67)
:
Oil (94%); [a]D =ꢀ20.0 (c=0.23); 1H NMR: d=2.09 (s, 3H), 2.24 (s,
3H), 4.27 (dd, J=6.8, 12.3 Hz, 1H), 4.53 (ddd, J=1.4, 2.8, 12.3 Hz, 1H),
5.46 (dd, J=4.7, 3JF,H =17.2 Hz, 1H), 5.69 (ddd, J=2.8, 4.7, 6.8 Hz, 1H),
8.04 ppm (brs, 1H); 13C NMR (125.7 MHz): d=20.8 (2”CH3), 24.6 (d,
2,3,5-Tri-O-acetyl-1-deoxy-1,1-difluoro-4-O-formyl-1-iodo-d-arabinitol
(56): Crystalline solid (71%); m.p. 70–718C (n-hexane/EtOAc); [a]D =
+38.5 (c=0.15); 1H NMR: d=2.08 (s, 3H), 2.12 (s, 3H), 2.23 (s, 3H),
4.16 (dd, J=5.0, 12.7 Hz, 1H), 4.27 (dd, J=2.9, 12.7 Hz, 1H), 5.17 (dddd,
J=0.8, 2.9, 5.0, 8.5 Hz, 1H), 5.56 (ddd, J=1.8, 3JF,H =10.8, 12.8 Hz, 1H),
5.87 (dd, J=1.8, 8.5 Hz, 1H), 8.01 ppm (d, J=0.8 Hz, 1H); 13C NMR:
d=20.5 (CH3), 20.6 (2”CH3), 61.0 (CH2), 65.8 (CH), 67.8 (CH), 73.6
(dd, 2JF,C =23.0, 23.0 Hz; CH), 97.7 (dd, 1JF,C =317.6, 322.5 Hz; C), 159.2
1JF,C =327.7 Hz; C), 60.9 (CH2), 70.0 (CH), 78.7 (d, 2JF,C =20.2 Hz; CH),
3
160.2 (CH), 168.4 (C), 169.5 ppm (C); 19F NMR: d=ꢀ69.7 ppm (d, JF,H
=
17.5 Hz, 1F); IR: n˜ =1759, 1737, 1371, 1226, 1200, 1170 cmꢀ1; MS (70 eV,
EI): m/z (%): 361 (<1) [MꢀI]+, 254 (22), 191 (100); HRMS (EI): m/z:
calcd for C9H11FIO6: 360.9584 [MꢀI]+; found: 360.9567; elemental analy-
sis calcd (%) for C9H11FI2O6 (487.99): C 22.15, H 2.27; found: C 22.34, H
2.33.
(CH), 168.8 (C), 168.9 (C), 170.4 ppm (C); 19F NMR: d=ꢀ50.6 (dd,
2
3JF,H =12.0, 2JF,F =191.5 Hz, 1F), ꢀ51.2 ppm (dd, 3JF,H =10.0, JF,F
=
191.5 Hz, 1F); IR: n˜ =1766, 1744, 1201, 1150 cmꢀ1; MS (70 eV, EI): m/z
(%): 407 (2) [MꢀOCOH]+, 393 (1), 325 (23), 283 (100), 263 (83); HRMS
(EI): m/z: calcd for C11H14F2IO6: 406.9803 [MꢀOCOH]+; found:
406.9804; elemental analysis calcd (%) for C12H15F2IO8 (452.15): C 31.88,
H 3.34; found: C 31.84, H 3.26.
Acknowledgements
2,3,5-Tri-O-acetyl-1-deoxy-1-fluoro-4-O-formyl-1,1-diiodo-d-arabinitol
(59): Oil (75%); [a]D =+30.0 (c=0.09); 1H NMR: d=2.08 (s, 3H), 2.11
This work was supported by the Investigation programs nos. CTQ2004–
06381/BQU, CTQ2004–02367/BQU and CTQ2007–67492/BQU of the
Ministerio de Educación y Ciencia (Spain) cofinanced with the Fondo
Europeo de Desarrollo Regional (FEDER). N.R.P. thanks the I3P-CSIC
Program for a fellowship.
(s, 3H), 2.27 (s, 3H), 4.17 (dd, J=5.0, 12.4 Hz, 1H), 4.29 (dd, J=2.9,
2
12.4 Hz, 1H), 5.13 (ddd, J=2.9, 5.0, 8.2 Hz, 1H), 5.50 (dd, J=1.4, JF,H
=
18.5 Hz, 1H), 6.15 (dd, J=1.4, 8.2 Hz, 1H), 8.04 ppm (s, 1H); 13C NMR:
d=20.6 (CH3), 20.8 (CH3), 20.9 (CH3), 25.8 (d, 1JF,C =329.9 Hz; C), 61.0
(CH2), 66.8 (CH), 68.7 (CH), 77.2 (d, 2JF,C =19.4 Hz; CH), 159.3 (CH),
168.9 (2”C), 170.4 ppm (C); 19F NMR: d=ꢀ70.7 ppm (d, 3JF,H =9.0 Hz,
1F); IR: n˜ =2978, 1742, 1374, 1239, 1201, 1151 cmꢀ1; MS (70 eV, EI): m/z
(%): 515 (1) [MꢀOCOH]+, 501 (<1), 433 (1), 373 (1), 330 (10), 263
(100); HRMS (EI): m/z: calcd for C11H14FI2O6: 514.8864 [MꢀOCOH]+;
found: 514.8884; elemental analysis calcd (%) for C12H15FI2O8 (560.05):
C 25.74, H 2.70; found: C 25.80, H 2.56.
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2,3-Di-O-acetyl-1,5-dideoxy-1,1-difluoro-4-O-formyl-1-iodo-l-arabinitol
(60): Syrup (82%); [a]D =ꢀ51.1 (c=0.62); 1H NMR: d=1.28 (d, J=
6.4 Hz, 3H), 2.13 (s, 3H), 2.23 (s, 3H), 5.05 (dddd, J=6.4, 6.4, 6.4,
3
6.4 Hz, 1H), 5.56 (ddd, J=2.0, JF,H =10.0, 12.0 Hz, 1H), 5.64 (dd, J=2.0,
6.4 Hz, 1H), 8.00 ppm (s, 1H); 13C NMR: d=15.9 (CH3), 20.5 (CH3),
20.6 (CH3), 67.2 (CH), 69.3 (CH), 73.5 (dd, 2J(CH)=21.8, 24.5 Hz; CH),
98.2 (dd, 1JF,C =314.6, 315.1 Hz; C), 159.6 (CH), 168.8 (C), 169.3 ppm
(C); 19F NMR: d=ꢀ50.4 (dd, 3JF,H =8.8, 2JF,F =188.1 Hz, 1F), ꢀ51.1 ppm
6710
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 6704 – 6712

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[31] CCDC-679904 ((S)-54) and 219090 ((S)-55) contain the supplemen-
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paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
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Crystaldata and structure refinements
Compound (S)-54: C16H15ClFIN2O10; Mt =576.65; monoclinic; space
group=C2; a=29.7995(13), b=6.5809(3), c=10.4310(3) ꢂ; b=
96.422(2)8; Z=4;
(MoKa)=0.71073 ꢂ; FACHTRE(UNG 000)=1136; T=123(2) K; colourless crystal,
V=2032.76(15) ꢂ3;
1calcd =1.884 mgcmꢀ3
;
m
A
[15] a) J. Crassous, F. Monier, J.-P. Dutasta, M. Ziskind, C. Daussy, C.
Grain, C. Chardonnet, ChemPhysChem 2003, 4, 541–548; b) I.
Novak, D. B. Li, A. W. Potts, J. Phys. Chem. A 2002, 106, 465–468;
c) J. Crassous, A. Collet, Enantiomer 2000, 5, 429–438; d) C.
0.18”0.18”0.07 mm, collected reflections 21338. The structure was
solved by direct methods, all hydrogen atoms were refined aniso-
tropically by using full-matrix least-squares-based F2 to give R1 =
0.0367, wR2 =0.0688 for 4857 independently observed reflections
Chem. Eur. J. 2008, 14, 6704 – 6712
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6711

E. Suµrez et al.
(jFo j>2s
C
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4984, and references therein. For a review on NMR spectra of fluo-
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Compound (S)-55: C16H15BrFIN2O10; Mt =621.11; monoclinic; space
group=C2; a=29.7108(8), b=6.5966(2), c=10.5583(3) ꢂ; b=
97.414(1)8; Z=4;
V=2052.02(10) ꢂ3;
1calcd =2.010 mgcmꢀ3
;
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m
A
0.30”0.12”0.05 mm; collected reflections 19723. The structure was
solved by direct methods, all hydrogen atoms were refined aniso-
tropically by using full-matrix least-squares-based F2 to give R1 =
0.0329, wR2 =0.0606 for 4534 independently observed reflections
(jFo j>2s
U
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[34] It has been demonstrated that JF,H coupling constants are highly
Received: April 16, 2008
sensitive to dihedral angles and substituent effects, see C. Thibau-
Published online: June 23, 2008
6712
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Chem. Eur. J. 2008, 14, 6704 – 6712