The reaction of pyranoside 2-uloses with DAST revised. Synthesis of 1-fluoro-ketofuranosyl fluorides and their reactivity with alcohols

Article abstract of DOI:10.1016/S0040-4020(01)00620-2

We have reinvestigated the reaction of α-pyranosides-2-uloses 13, 14, 19 and 24 with DAST and shown that the 1,2-difluorinated compounds 17, 18 and 25 are produced by a ring-contraction reaction. The reaction of 18 with benzyl alcohol gives the tri-benzyl derivative 26 or compound 27, depending on the reaction conditions. Treating 17 with 2-naphthol produced the spiranic compounds 29-31. The reaction of 17 with bis(trimethylsilyl)uracil produced the mononucleoside 28, which preserves the fluorine atom in the more substituted carbon.

Full text of DOI:10.1016/S0040-4020(01)00620-2

TETRAHEDRON
Pergamon
Tetrahedron 57 52001) 6733±6743
The reaction of pyranoside 2-uloses with DAST revised.
Synthesis of 1-¯uoro-ketofuranosyl ¯uorides and their reactivity
with alcohols
a
a,p
a
a
Mohamed L. Aghmiz, Yolanda Dõaz, Gour Hari Jana, M. Isabel Matheu, Raouf Echarri,
a
Â
Sergio Castillon and M. Luisa Jimeno
a,p
b
Â
a
Â
Departament de Quõmica, Universitat Rovira I Virgili, Pza. Imperial Tarraco 1, 43005 Tarragona, Spain
 Â
Centro de Quõmica Organica `Manuel Lora Tamayo', CSIC, C/Juan de la Cierva 3, 28006 Madrid, Spain
b
Received 22 February 2001; revised 17 May 2001; accepted 30 May 2001
AbstractÐWe have reinvestigated the reaction of a-pyranosides-2-uloses 13, 14, 19 and 24 with DAST and shown that the 1,2-di¯uorinated
compounds 17, 18 and 25 are produced by a ring-contraction reaction. The reaction of 18 with benzyl alcohol gives the tri-benzyl derivative
26 or compound 27, depending on the reaction conditions. Treating 17 with 2-naphthol produced the spiranic compounds 29±31. The
reaction of 17 with bis5trimethylsilyl)uracil produced the mononucleoside 28, which preserves the ¯uorine atom in the more substituted
carbon. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
of uloses 1 and 3, Scheme 1).7 This is usually achieved by
forming trans-fused bicycles. When the anomeric sub-
stituent is axial, such as in ulose 5 5Scheme 2) or the
molecule is conformationally ¯exible, rearrangements
usually occur.5,7
Diethylaminosulfur tri¯uoride 5DAST) has been widely
used in the ¯uorination of sugars.1 The reaction is usually
carried out starting from alcohols and involves inversion of
con®guration. However, there are some cases in which the
con®guration is retained,2 and others that involve 1,2-migra-
tion.3 Over the last ten years we have studied the reaction of
uloses with DAST and established the structural require-
ments for obtaining gem-di¯uoro carbohydrates4 without
secondary reactions.5±9 Thus, for 2-uloses the anomeric
substituent must be equatorial and the conformational
mobility must be restricted 5see, for instance, di¯uorination
Recently, Cabrera-Escribano et al.10 showed that treatment
with DAST of 2-hydroxy-pyranoside 7, whose anomeric
substituent and 2-hydroxyl group are in relative trans
diaxial disposition, affords compounds 8a/8b, which is
generated by a 1,2-migration with concomitant stereo-
selective ¯uorination of the anomeric position. However,
when these substituents are cis 59) the reaction leads to
Scheme 1.
Keywords: carbohydrates; uloses; ¯uorination; diethylaminosulfur tri¯uoride; glycosylation; spiroacetals.
Corresponding authors. Tel.: 134-977-558151; fax: 134-977-559563; e-mail: ydiaz@quimica.urv.es; Tel.: 134-977-559556; fax: 134-977-559563;
e-mail: castillon@quimica.urv.es
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020501)00620-2

6734
M. L. Aghmiz et al. / Tetrahedron 57 62001) 6733±6743
Scheme 2.
the ring-contraction products 10a/10b. There is a similar
ring contraction in the reaction of 2-O-tri¯yl-pyranosides
11 with conventional nucleophilic ¯uorination reagents,
and this leads to products 12a/12b.11 In compounds 9 and
11 the leaving groups 5OSF2NEt2 and OTf) are equatorial
and the ring contraction reaction takes place independently
of the con®guration of the anomeric position. Other ring-
contraction reactions have also been observed in the reac-
tion of partially protected carbohydrates with DAST.12 In a
very recent review, Dax et al. systematized the reactions that
can take place in the ¯uorination of the various positions of
with diagnostic value, with which we can differentiate
between ring contraction products 5Scheme 3) and 1,2
migration products 5Schemes 2 and 3).
We had explored the reaction of 2-uloses 13, 14 and 19 with
DAST to obtain products which we initially assigned to
structures 15, 16 and 20, as a result of a 1,2-migration and
2
di¯uorination.5,7 However, the JH1,F values for these
5Scheme 4) compounds were identical to those of
compounds 10 and 12 but very different from those of
compounds 6 and 8 5Schemes 2 and 3). Actually, Dax'
review anticipated the suspicion of these compounds to be
2
the sugar ring.12 The JH1,F values are spectroscopic data
Scheme 3.
Scheme 4.

M. L. Aghmiz et al. / Tetrahedron 57 62001) 6733±6743
6735
Table 1. Selected spectroscopic 1H- and 13C NMR data, d 5ppm) and J 5Hz), for compounds 17, 18, 21 and 25
2JH1,F1
3JH1,F2
3JH3,F2
3JH3,H4
4JH4,F2
4JH1,H3
d C1
d C2
1JC2,F2
2JC2,F1
1JC1,F1
2JC1,F2
2JC3,F2
3JC5,F2
17aa
17ab
17ba
17bc
18a
18b
21a
21b
25e
64.4
64.4
63.4
64.4
63.6
63.8
63.8
63.5
62.4
0.6
±
2.3
2.0
±
2.0
1.6
1.8
1.2
10.6
12
2.0
0.8
109.1
110.7
109.5
110.3
106.8
107.1
105.4
105.3
106.2
112.1
113.6
112.2
113.6
112.2
112.4
112.3
234.8
234.8
236.8
236.8
237.3
237.3
211.7
32.0
26.5
32.4
31.3
28.2
34.0
32.3
223.8
223.8
223.8
224.3
222.8
224.9
224.7
225.3
224.2
45.4
46.2
45.8
45.7
45.4
45.1
45.0
43.8
46.2
19.8
19.8
20.4
19.4
19.4
19.7
20.4
20.6
20.2
6.0
6.4
1.2
1.1
11.4
14.1
14.1
20.4
2.4
2.8
2.4
d
d
d
±
110.3
±
223.3
±
25.8
10.2
a/b denotes major and minor epimers at C-1 517a/17b, 18a/18b and 21a/21b ratios are 2:1, 3:1 and 2:1, respectively).
CDCl3.
a
b
C6D6, JF1,OMeˆ1.6 Hz, JF2,Meˆ0.4 Hz, JCH35iPr),Fˆ1.5 Hz.
c
C6D6, JOCH3,F1ˆ1.6 Hz, JC3,F1ˆ1.1 Hz.
d
3JC4,F2ˆ1.6 Hz.
e
For the minor isomer, signals are not detected.
ring contracted products.12 All these facts prompted us to
reconsider the structural elucidation of the products
obtained from reaction of uloses 13, 14 and 19 with DAST.
To determine the con®guration at C-2 we considered 3JH3,F2
and JC3,F2, because they are reported to depend on the
2
relative con®guration of the carbon atoms involved in the
coupling.13 In the bibliography there is a wide range of
values for vicinal F/H coupling constants. In furanosyl
3
¯uorides, values of JH2,F1 are .15 Hz for a trans relation-
2. Results and discussion
ship and ,8 Hz for a cis relationship.13±16 For both isomers
of compounds 17, 18 and 21, the coupling constants
3JH3,F2ˆ10±14 Hz 5see Table 1) are closer to trans than to
cis values. The presence of strong electronegative atoms at
C-1 may explain these small values. Actually, the structure
of natural nucleoside nucleocidine is very related to that of
compounds 17 and 18, and 2,3-isopropylidene derivatives
with a H3,F4 trans disposition have 3JH,F coupling constants
of the same order of those observed for 17 and 18 5Fig. 1).17
All these data suggest that F-2/H-3 have a trans relationship
in these compounds.
We reacted uloses 13, 14 and 19 with DAST. Structures of
the products obtained were unequivocally established by
1H- and 13C NMR spectroscopy, using one- and two-dimen-
sional techniques. The methodology used involved the full
assignment of the 1H spectra by gCOSY, TOCSY and
NOESY experiments and the 13C spectra by gHSQC, and
gHMBC experiments. Relevant 1H- and 13C spectra data are
gathered in Table 1. Thus, d ,106±110 ppm 51JC,F
2
,223 Hz, JC,Fˆ44 Hz) for C-1 and d ,112±114 ppm
2
51JC,F ,236±241 Hz, JC,Fˆ28±34 Hz) for C-2 indicate
that a ¯uorine atom is bonded to each of these carbons.
The C-3, the OMe carbon and the carbon of one of the
isopropylidene methyl groups appear as doublets with
coupling constants of 19.8, 1.5, 1.5 Hz, respectively. 19F
NMR spectra also support the presence of two neighboring
¯uorine atoms in secondary and tertiary carbons with
similar environments. However, these data are compatible
with 1,2-migration products 15, 16 and 20, as well as with
the ring contraction products 17, 18 and 21 5Scheme 4).
The values of 2JC3,F2ˆ19±21 Hz for compounds 17, 18 and
21 agree with a gauche or syn relationship of the ¯uorine
atom relative to the electronegative substituent 5the oxygen)
on C-3, i.e. a trans H-3/F-2 relationship.13,18 This value
con®rms the C-2 con®guration of compounds 17, 18 and 21.
3
For the C-1 con®guration, the small JH1,F2 values for all
isomers of compounds 17, 18 and 21 indicate a preferred
rotameric disposition with a gauche H-1/F-2 arrangement.
Besides, the high value of JC1,F2.40 Hz, also for all
2
The 2JH1,F values of these products were 62±65 Hz, which is
as expected for ring-contraction products. Moreover, the
gHMBC experiment, with which we can detect protons
and carbons separated by two or three bonds, shows that
there is a correlation between H-1 and OCH3 517), or H-1
and CH2Ph 518, 21), which con®rms a ®ve-membered struc-
ture for these compounds.
isomers of compounds 17, 18 and 21, suggest an anti orien-
tation of F-2 and the electronegative group 5OMe) bonded to
C-1. The small differences in the values of JC2,F1 for the
major and minor isomers in 17, 18 and 21 do not allow,
however, the assignation of the con®guration at C-1 for
each of the isomers.
Figure 1.

6736
M. L. Aghmiz et al. / Tetrahedron 57 62001) 6733±6743
Scheme 5.
2.1. Mechanistic considerations
observed may be due to an equilibrium process between
intermediates such that the ring contraction takes place
faster from the intermediate resulting from the attack of
¯uorine from the bottom, or through epimerization of the
®nal product 5Scheme 5).
The reaction of 2-OH unprotected pyranosides with DAST
depends on the stereochemisty at positions 1 and 2 and has
the following general trends: 5a) when 2-OH is axial, the
substitution or elimination reaction takes place inde-
pendently if the anomeric group is equatorial or axial;
however, in the latter case 1,2-migration usually competes.
5b) When 2-OH is equatorial substitution competes with
ring contraction and 1,2-migration. Ring contraction is
favored when the anomeric group is cis and in 3,4-O-iso-
propyledene derivatives and, in general, it is restricted in
4,6-O-benzyledene derivatives. 1,2-Migration may take
place when the anomeric substituent is trans to the 2-OH.
Compound 3 5Scheme 1) produced the di¯uoroderivative 4
when treated with DAST. We considered that ulose 24 and
its precursor, alcohol 22 5Scheme 6), were good models for
con®rming the structural requirements for ring-contraction
and 1,2-migration in the reaction with DAST. Effectively,
the reaction of alcohol 22 with DAST led to the glycosyl
¯uoride 23, which resulted from a 1,2-migration 5JH1,F
,52 Hz, see Schemes 2 and 3). However, the reaction of
ulose 24 with DAST led to the ring-contraction product 25.
Spectroscopic data of 25 agree with those of ring-
contraction products 17, 18 and 21 5Table 1).
The reaction of 2-uloses with DAST is more complex. It
involves at least two reactions and all the processes
mentioned above can compete.
2.2. Reactivity of di¯uorinated compounds with alcohols
In the case of compound 1, the di¯uorination product may
be justi®ed by the initial attack of ¯uorine from both sides of
the carbonyl group. The ring-contraction product, which
might be the result of ¯uorine attacking from the top of
the ring 5leaving group equatorial), is probably limited by
the presence of the 4,6-O-benzylidene group. A similar
explanation must also account for compound 3. In
compound 5, whose anomeric group is axial, the con®gu-
ration at position 2 is due to 1,2-migration taking place ®rst.
We had studied the reactivity of the di¯uorinated
compounds with alcohols. Actually, we showed that those
compounds behaved as 1,2-dielectrophilic synthons when
allowed to react with benzyl alcohol or naphthol deriva-
tives.19±22 As we corrected the structure of starting di¯uori-
nated compounds, we revised the structure of glycosylation
products. Also, we reinvestigated the more signi®cant
reactivity of di¯uoroderivatives 17 and 18.
In compounds 13, 14 5whose main conformation is 4C1) and
19, ¯uorine is expected to attack initially from the upper
side. However, this would lead to ring contraction products
having a con®guration at C-2 that it is not the actually
obtained in compounds 17, 18 and 21. The stereochemistry
Therefore, when compound 18 was treated with a 10-fold
excess of benzyl alcohol in the presence of Cp2HfCl2/
AgOTf 5di¯uorinated sugar/alcohol/Cp2HfCl2/AgOTf ratioˆ
1:10:1:2) at 2508C in dry dichloromethane, compound 26
was obtained in a 66% yield 5Scheme 7).
Scheme 6.

M. L. Aghmiz et al. / Tetrahedron 57 62001) 6733±6743
6737
Scheme 7. a: di¯uorinated sugar/benzyl alcohol/Cp2HfCl2/AgOTf ratioˆ1/10/1/2, DCM, 2508C±rt; b: di¯uorinated sugar/benzyl alcohol/Cp2HfCl2/AgOTf
ratioˆ1/2/1/2, DCM, 2508C±rt.
Scheme 8. a: sugar/bis5trimethylsilyl)uracil/Cp2HfCl2/AgOTf ratioˆ1/2/1/2, benzene, rt; b: sugar/6-bromo-2-naphthol/Cp2HfCl2/AgOTf ratioˆ1/1.7/1/2,
DCM, 2508C±rt.
Treatment of 18 with two equivalents of benzyl alcohol
under similar conditions produced compound 27 in 70%
yield. A similar reaction of 17 with an excess of 6-bromo-
b-naphthol led to a 1:1.3:1.9 mixture of compounds 29, 30
and 31 in an overall yield of 47%23 5Scheme 8).
unequivocally assigned by one- and two-dimensional
experiments 5gCOSY, TOCSY, NOESY, gHSQC and
gHMBC). Relevant 13C NMR data are collected in Table 2.
Compounds 26±31 keep the same sugar backbone of their
di¯uorinated precursors, including the isopropylidene
group.24 There are no ¯uorine atoms, except for compound
28, which has only one.
We extended our study of the glycosylation reaction to the
synthesis of nucleoside analogues. When compound 17 was
allowed to react with bis5trimethylsilyl)uracil in the
presence of Cp2HfCl2/AgOTf, the nucleoside analogue 28
was obtained as a mixture in 85% yield with excellent
stereoselectivity 587:13), and from which we were able to
isolate the major isomer in pure form. Interestingly, only
one ¯uorine atom was substituted in the presence of bis-
5trimethylsilyl)uracil.
The NMR spectra of compound 26 showed the presence of
three benzyl groups and two acetalic carbon atoms 5apart
from the isopropylidene group) attributed to C-1 5tertiary,
100.7 ppm) and C-2 5quaternary, 106.8 ppm). gHMBC
correlations con®rmed the presence of two benzyl groups
bonded to C-1 and one to C-2. The con®guration at C-1 and
C-2 was established by NOESY experiments 5Fig. 2).
2.3. Structural elucidation of compounds 26±31
The NMR spectra for 27 show the following features: C-2
5quaternary, 107.7 ppm) is acetalic, C-1 571.8 ppm) is a
tertiary carbon bonded to one oxygen, and there are two
benzyl groups. The protons of one of the benzylic groups
1H- and 13C NMR spectra of compounds 26±31 were
Table 2. Selected spectroscopic 13C NMR data, d 5ppm) for compounds 26,
27, 28, 29, 30 and 31 5CDCl3)
2
show a Jˆ11.1 Hz and correlate with C-1 in the gHMBC
C1
C2
C3
C4
C5
C10
C20
C100
C200
spectrum, whereas the ones of the other benzyl group show
a 2Jˆ15.3 Hz, which indicates that they are part of a cycle25
and correlate with C-1 in the HMBC spectrum. Moreover,
one aromatic quaternary carbon 5134 ppm) shows an
HMBC correlation with H-1 54.5 ppm) and with protons
of the endocyclic benzyl CH2 group. All these data indicate
that the benzyl group at C-2 has undergone a Friedel±Crafts
26 100.7 106.8 84.7 79.2 71.3
27
28
71.8 107.7 84.3 80.2 72.9
83.6 112.5 80.7 77.2 71.6
62.6
29 106.2
92.6 83.3 79.3 72.2 154.9 114.2
30
31
42.8 118.1 84.3 78.6 71.8 153.2 119.2 152.1 115.8
42.3 118.9 83.9 78.4 72.0 153.2 118.1 153.8 115.4

6738
M. L. Aghmiz et al. / Tetrahedron 57 62001) 6733±6743
Figure 2.
cyclization involving C-1. The con®guration at C1 and C2
was established by NOESY experiments.
show that C-2 5118.1 and 118.9 ppm, respectively) is
acetalic and quaternary and C-1 542.8 and 42.3 ppm, respec-
tively) is a tertiary carbon not bonded to oxygen. The
presence of eleven protons in the aromatic region 5one of
which is due to an OH group) indicates the presence of two
naphthol units, one of them bonded to C-1 via its Ca, and
the other one cyclized via its oxygen and its Ca. All these
data are consistent with the spiroacetal structures proposed
and show that compounds 30 and 31 are epimers at C-2, as
con®rmed by NOESY experiments.
NMR data for compounds 29±31 were comparatively
studied. Compound 29 shows the following features: one
naphthol unit, an OMe group, a tertiary acetalic carbon
attributed to C-1, and a quaternary nonacetalic carbon corre-
sponding to C-2. The gHMBC correlation between H-1 and
two aromatic carbons at 154.9 ppm 5C-10) and 114.3 ppm
5C-20) indicates that the naphthol unit bonded to C-1 via its
oxygen has undergone an electrophilic substitution and is
bonded to C-2 via its Ca. The con®guration at C-1 and C-2
was established by NOESY experiments.
The spectra of compound 28 show the presence of one
¯uorine atom at C-2 5112.5 ppm), and an OMe group and
a uracil moiety bonded to C-1 583.6 ppm). Con®guration of
3
The spectra for compounds 30 and 31 are very similar and
C-2 is determined by the values of J3,Fˆ12.8 Hz and
Scheme 9.

M. L. Aghmiz et al. / Tetrahedron 57 62001) 6733±6743
6739
2JC3,Fˆ21.9 Hz, which indicate a trans disposition between
H-3 and ¯uorine, and by a NOEenhancement in H 3 when H1
was irradiated.
using silica gel 60 A CC 56±35 mm). Band separation was
monitored by UV. TLC plates were prepared with Kieselgel
60 PF254. Solvents for chromatography were distilled at
atmospheric pressure prior to use. Reaction solvents were
puri®ed and dried by using standard procedures.
2.4. Mechanistic consideration of the reaction of
di¯uorinated compounds with alcohols
3.1. Synthesis of di¯uorocarbohydrate 17
Scheme 9 shows a possible mechanism to explain how
compounds 26±31 are formed. The reaction starts with the
abstraction of ¯uorine at C1, followed by acetal formation to
give 32 5Rˆmethyl, benzyl, R0ˆbenzyl, naphthyl). A trans-
acetalization can be produced at this stage to give the inter-
mediate 33. The activation of the ¯uorine in 32 produces the
oxonium cation 34, from which compound 26 5RˆR0ˆ
benzyl) is formed by the attack by a second molecule of
benzyl alcohol on the exo face. An intramolecular
Friedel±Crafts reaction from 34 5Rˆmethyl, R0ˆbenzyl
or 6-bromo-2-naphthyl) gives the spiro compounds 27 or
29. Compounds 30 and 31 are probably formed from 35.
A series of processes must be involved, including OR0
migration, the attack by a second molecule of R0OH,
isomerization, the departure of an R0OH molecule and
Friedel±Crafts cyclization. However, the sequence of
events cannot be precised.
DAST 50.54 ml, 4 mmol) was added dropwise at room
temperature to a solution of ulose 13 50.202 g, 1 mmol) in
dichloromethane 55 ml). After 8 h, the reaction mixture was
poured into a cold saturated aqueous NaHCO3 solution, the
organic layer was separated and the aqueous layer was
extracted with CH2Cl2. The combined organic layers
were dried with MgSO4 and evaporated to give a crude
oil, which was chromatographed 5ethyl acetate/hexaneˆ
1:4) to produce compound 17 50.161 g, 72%) as a dia-
stereoisomeric mixture.
3.1.1. Spectroscopic data of 17a 0maj) extracted from the
spectrum of mixture. 1H NMR 5C6D6, 400 MHz) d 5.08 5d,
1H, J1,F1ˆ64.4 Hz, H1), 4.74 5dd, 1H, J3,F2ˆ12.0 Hz, J3,4ˆ
6.0 Hz, H3), 4.06±4.18 5m, 2H, H5a, H5b), 3.68 5ddd, 1H,
J4,5aˆ10.4 Hz, J4,3ˆ6.0 Hz, J4,5bˆ4.4 Hz, H4), 3.06 5d, 3H,
JMe,F1ˆ1.6 Hz, OCH3), 1.57 5s, 3H, CH3), 1.14 5d, 3H,
JMe,F2ˆ0.4 Hz, CH3). 13C NMR 5C6D6, 100 MHz) d 115.8
5C5CH3)2), 113.6 5dd, J2,F2ˆ234.8 Hz, J2,F1ˆ26.5 Hz, C2),
110.7 5dd, J1,F1ˆ223.8 Hz, J1,F2ˆ45.8 Hz, C1), 80.4 5d,
J3,F2ˆ20.4 Hz, C3), 79.3 5C4), 73.0 5d, J5,F2ˆ1.2 Hz, C5),
57.8 5OCH3), 26.8 5CH3), 26.3 5d, JMe,F2ˆ1.5 Hz, CH3).
In conclusion, the reaction of a-pyranside-2-uloses 13, 14,
19 and 24 with DAST gives 2,5-anhydro-1,2-di¯uoro-
furanoses 17, 18, 21 and 25, respectively, as a result of a
ring-contraction reaction with concomitant entry of ¯uorine
at positions 1 and 2. These 2,5-anhydro-1,2-di¯uoro sugars
behave like 1,2-dielectrophilic synthons. Therefore, they
react with benzyl alcohol or naphthols to give products of
¯uorine substitution 526) or spiroacetalic compounds result-
ing from ¯uorine substitution and intramolecular Friedel±
Crafts reaction 527, 29±31). Isomerization is also possible
under the reaction conditions. When 1,2-di¯uorosugar 17
was allowed to react with bis5trimethylsilyl)uracil, ¯uoro-
nucleoside 28 was obtained due to the substitution of one
¯uorine atom.
19F NMR 5C6D6, 376.4 MHz) d 2124.3 5td, JF2,H3
12.0 Hz, JF2,F1ˆJF2,H5ˆ4.6 Hz, F2), 2145.2 5dd, JF1,H1
64.4 Hz, JF1,F2ˆ4.6 Hz, F1).
ˆ
ˆ
3.1.2. Spectroscopic data of 17b 0min) extracted from the
spectrum of mixture. H NMR 5C6D6, 400 MHz) d 5.03
1
5dd, 1H, J1,F1ˆ64.4 Hz, J1,F2ˆ2.0 Hz, H1), 4.81 5dd, 1H,
J3,F2ˆ11.4 Hz, J3,4ˆ6.4 Hz, H3), 4.06±4.18 5m, 2H, H5a,
H5b), 3.62 5ddd, 1H, J4,5aˆ10.0 Hz, J4,3ˆ6.4 Hz, J4,5b
ˆ
4.4 Hz, H4), 3.03 5d, 3H, JMe,F1ˆ1.6 Hz, OCH3), 1.59 5s,
3H, CH3), 1.16 5d, 3H, JMe,F2ˆ0.4 Hz, CH3). 13C NMR
5C6D6, 100 MHz) d 115.8 5C5CH3)2), 113.6 5dd, J2,F2
236.8 Hz, J2,F1ˆ31.3 Hz, C2), 110.3 5dd, J1,F1ˆ224.3 Hz,
ˆ
3. Experimental
J1,F2ˆ45.7 Hz, C1), 80.2 5dd, 1H, J3,F2ˆ19.4 Hz, J3,F1
ˆ
Melting points are uncorrected. Optical rotations were
measured at 258C in 10 cm cells. 1H- and 13C NMR spectra
were recorded on a Varian INOVA-400 and VARIAN
Unity-400 spectrometers operating at 399.93 MHz 51H)
and 99.98 MHz 513C), respectively, using CDCl3 as solvent
at 308C with TMS as internal standard. 19F spectra were
recorded either on a Varian Gemini 300 MHz spectrometer
operating at 282.3 MHz or on a Varian 400 MHz spectro-
meter operating at 376.4 MHz, using CDCl3 as solvent at
1.1 Hz, C3), 79.1 5C4), 73.0 5d, J5,F2ˆ1.1 Hz, C5), 58.5 5d,
JMe,F1ˆ0.2 Hz, OCH3), 26.8 5d, JMe,F2ˆ1.5 Hz, CH3), 26.3
5CH3). 19F NMR 5C6D6, 376.4 MHz) d 2125.2 5td, JF2,F1
JF2,H3ˆ11.4 Hz, JF2,H5ˆ5.3 Hz, F2), 2144.4 5dd, JF1,H1
64.4 Hz, JF1,F2ˆ11.4 Hz, F1).
ˆ
ˆ
3.2. Synthesis of di¯uorocarbohydrate 18
1
308C. Monodimensional H-, 13C- and 19F spectra were
DAST 50.53 ml, 3.9 mmol) was added dropwise at room
temperature to a solution of ulose 14 50.5 g, 1.8 mmol) in
anhydrous benzene 55 ml). After 24 h, standard work-up as
described for synthesis of 17 rendered a crude oil that
was puri®ed by column chromatography 5ethyl acetate/
hexaneˆ1:2) to give a diastereoisomeric mixture of com-
pound 18 50.420 g, 78%) as a colorless oil.
obtained using standard conditions. Homonuclear 2D
spectra 5COSY, TOCSY and NOESY) were acquired in
the phase-sensitive mode. Elemental analyses were deter-
mined at the Servei de Recursos Cienti®cs 5Universitat
Rovira I Virgili). Flash column chromatography was
performed using silica gel 60 A CC 540±63 mm). Prepara-
tive layer chromatography was performed on silicagel 60.
Radial chromatography was performed on 1, 2 or 4 mm
plates of silica gel, depending on the amount of product.
Medium-pressure chromatography 5MPLC) was performed
3.2.1. Spectroscopic data of 18a 0maj) extracted from the
spectrum of mixture. 1H NMR 5CDCl3, 400 MHz) d 7.38±
7.12 5m, 5H, Ph), 5.27 5dd, 1H, J1,F1ˆ63.6 Hz, J1,F2ˆ0.9 Hz,

6740
M. L. Aghmiz et al. / Tetrahedron 57 62001) 6733±6743
H1), 4.91 5m, 1H, CH2Ph), 4.83 5m, 1H, H3), 4.78 5m, 1H,
H4), 4.72 5m, 1H, CH2Ph), 4.22 5m, 1H, H5a), 4.12 5m, 1H,
J5b,F2ˆ4.6 Hz, H5b), 1.52 5s, 3H, CH3), 1.32 5s, 3H, CH3).
13C NMR 5CDCl3, 100 MHz) d 135.7 5CAr), 129.0±128.0
NMR 5CDCl3, 282.3 MHz) d 2144.4 5dd, JF1,H1ˆ63.5 Hz,
JF1,F2ˆ7.0 Hz, F1), 2119.00 5m, F2).
3.4. Synthesis of glycopyranosyl ¯uoride 23
5CAr), 115.4 5C5CH3)2), 112.2 5dd, J2,F2ˆ237.3 Hz, J2,F1
ˆ
28.2 Hz, C2), 106.8 5dd, J1,F1ˆ222.8 Hz, J1,F2ˆ45.4 Hz,
C1), 79.3 5d, J3,F2ˆ19.4 Hz, C3), 78.3 5C4), 72.4 5C5), 71.6
5CH2Ph), 25.9 5CH3), 25.6 5CH3). 19F NMR 5CDCl3,
A solution of alcohol 22 50.118 g, 0.3 mmol) in dry DCM
52 ml) was treated with DAST 50.3 ml, 0.360 g, 2.2 mmol)
dropwise under argon atmosphere at room temperature and
the resulting mixture was stirred for a period of 4 h and then
re¯uxed for 3 h. After cooling and standard work up, the
crude residue was puri®ed over silica gel chromatography in
ethyl acetate/hexaneˆ1:9 to give compound 23 50.060 g,
49%) as a 1:1 anomeric mixture 5colorless oil).
282.3 MHz) d 2123.5 5m, F2), 2143.7 5dd, JF1,H1
63.6 Hz, JF1,F2ˆ3.1 Hz, F1).
ˆ
3.2.2. Spectroscopic data of 18b 0min) extracted from the
spectrum of mixture. 1H NMR 5CDCl3, 400 MHz) d 7.45±
7.20 5m, 5H, Ph), 5.32 5dd, 1H, J1,F1ˆ63.8 Hz, J1,F2ˆ2.0 Hz,
H1), 4.88 5m, 1H, CH2Ph), 4.84 5m, 1H, H3), 4.78 5m, 1H,
H4), 4.66 5m, 1H, CH2Ph), 4.22 5m, 1H, H5a), 4.10 5m, 1H,
J5b,F2ˆ4.7 Hz, H5b), 1.52 5s, 3H, CH3), 1.31 5s, 3H, CH3).
13C NMR 5CDCl3, 100 MHz) d 135.1 5CAr), 129.0±128.0
3.4.1. Spectroscopic data of 23a 0b) extracted from the
spectrum of mixture. 1H NMR 5CDCl3, 400 MHz) d 7.40±
7.20 5m, 5H, Ph), 5.20 5dd, 1H J1,Fˆ52.4 Hz, J1,2ˆ6.3 Hz,
H1), 4.84 5d, 1H, Jˆ11.4 Hz, OCH2Ph), 4.78 5d, 1H, Jˆ
5CAr), 116.5 5C5CH3)2), 112.4 5dd, J2,F2ˆ237.3 Hz, J2,F1
ˆ
11.4 Hz, OCH2Ph), 3.94 5td, 1H, J3,2ˆJ3,4ˆ10.2 Hz, J3,F
ˆ
34.0 Hz, C2), 107.1 5dd, J1,F1ˆ224.9 Hz, J1,F2ˆ45.1 Hz,
C1), 79.2 5d, 1H, J3,F2ˆ19.7 Hz, C3), 78.3 5C4), 72.5 5C5),
71.8 5CH2Ph), 25.9 5CH3), 25.6 5CH3). 19F NMR 5CDCl3,
0
0.9 Hz, H3), 3.67 5dq, 1H, J5,4ˆ9.6, J5,6ˆ6.0 Hz, H5) 3.60
5ddd, 1H, J2,Fˆ13.7 Hz, J2,3ˆ10.4 Hz, J2,1ˆ6.0 Hz, H2),
3.54 5t, 1H, J4,3ˆJ4,5ˆ10 Hz, H4), 3.25 5s, 3H, OMe), 3.22
5s, 3H, OMe), 1.85±1.36 5m, 8H, 5CH2)4), 1.33 5d, 3H,
J6,5ˆ6.0 Hz, H6). 13C NMR 5CDCl3, 100 MHz) d 138.2
282.3 MHz) d 2123.3 5td, JF2,F1ˆJF2,H3ˆ13.0 Hz, JF2,H5
ˆ
5.3 Hz, F2), 2141.6 5dd, JF1,H1ˆ63.8 Hz, JF1,F2ˆ13.0 Hz,
F1).
5CAr), 128.3, 5CHAr), 127.6 5CHAr), 109.4 5d, J1,F
ˆ
ˆ
213.2 Hz, C1), 98.4 5Cacetal), 98.2 5Cacetal), 78.9 5d, J2,F
23.2 Hz, C2), 74.4 5OCH2Ph), 71.9 5d, J3,Fˆ12.2 Hz, C3),
70.8 5C4), 70.5 5d, J5,Fˆ5.5 Hz, C5), 48.8 5OMe), 46.7
5OMe), 27.0 5CH2), 26.9 5CH2), 21.4 5CH2), 21.3 5CH2),
16.7 5C6). 19F NMR 5CDCl3, 282.3 MHz) d 2139.6 5dd,
JH1,Fˆ51.8 Hz and JH2,Fˆ13.5 Hz).
3.3. Synthesis of di¯uorocarbohydrate 21
DAST 50.14 ml, 1 mmol) was added dropwise to a solution
of compound 19 50.048 g, 0.13 mmol)) in anhydrous
CH2Cl2 51 ml). After 24 h, standard work up gave an oil,
which was puri®ed by preparative thin layer chroma-
tography 5ethyl acetate/hexaneˆ1:7), to yield the di¯uoro
compound 21 50.029 g, 61%) as an diastereoisomeric
mixture.
3.4.2. Spectroscopic data for 23b 0a) extracted from
spectrum of mixture. 1H NMR 5CDCl3, 400 MHz): d
7.38±7.26 5m, 5H, Ph), 5.50 5dd, 1H, J1,Fˆ52.8 Hz, J1,H2
ˆ
2.8 Hz, H1), 4.86 5m, 2H), 4.29 5t, 1H, J3,2ˆJ3,4ˆ10.4 Hz,
H3), 3.5±3.7 5m, 3H, H2, H4, H5), 3.22 5s, 3H, OCH3), 3.21
5s, 3H, OCH3), 2.20±1.47 5m, 8H, 5CH2)4), 1.26 5d, 3H,
J6,5ˆ6.4 Hz, H6). 13C NMR 5CDCl3, 100 MHz) 138.1,
128.3, 127.7, 127.4, 105.2 5d, J1,Fˆ226.7 Hz, C1), 96.7
5Cacetal), 96.5 5Cacetal), 76.3 5d, Jˆ23.5 Hz, C2), 74.4
5OCH2Ph), 71.2, 69.9, 68.0 5d, Jˆ2.1 Hz), 46.7 5OMe),
46.5 5OMe), 27.0 5CH2), 26.9 5CH2), 21.35CH2), 21.2
5CH2), 16.6 5C6). 19F NMR 5CDCl3, 282.3 MHz): 2146.65
5dd, JH1,Fˆ51.8 Hz, JH2,Fˆ22.9 Hz).
3.3.1. Spectroscopic data of 21a 0maj) extracted from the
spectrum of mixture. 1H NMR 5CDCl3, 400 MHz) d 8.00±
7.25 5m, 10H, HAr), 5.34 5dd, 1H, J1,F1ˆ63.8 Hz, J1,F2
ˆ
1.6 Hz, H1), 5.24 5dd, 1H, J4,3ˆ5.4 Hz, J4,5ˆ4.8 Hz, H4),
4.95 5d, 1H, JABˆ12.0 Hz, CH2Ph), 4.73 5dd, 1H, JAB
ˆ
ˆ
12.0 Hz, JH,F1ˆ1.7 Hz CH2Ph), 4.32 5dd, 1H, J3,F2
14.1 Hz, J3,4ˆ5.4 Hz, H3), 4.22 5m, 1H, J5,6ˆ6.8 Hz, J5,4ˆ
4.8 Hz, H5), 3.45 5s, 3H, OCH3), 1.48 5d, 3H, J6,5ˆ6.8 Hz,
H6). 13C NMR 5CDCl3, 100 MHz) d 165.6 5CO), 133.5±
128.0 512CAr), 112.3 5dd, J2,F2ˆ211.7 Hz, J2,F1ˆ32.3 Hz,
C2), 105.4 5dd, J1,F1ˆ224.7 Hz, J1,F2ˆ45.0 Hz, C1), 82.9
5d, J3,F2ˆ20.4 Hz, C3), 80.7 5C4), 79.6 5d, J5,F2ˆ2.4 Hz,
C5), 71.0 5CH2Ph), 58.4 5d, JMe,F2ˆ2.4 Hz, OCH3), 19.4
5C6). 19F NMR 5CDCl3, 282.3 MHz) d 2140.89 5dd,
JF1,H1ˆ63.8 Hz, JF1,F2ˆ9.0 Hz, F1), 2119.15 5m, F2).
3.5. Synthesis of the ulose 24
A mixture of alcohol 22 50.197 g, 0.5 mmol), PCC 50.431 g,
2.0 mmol), sodium acetate 50.164 g, 2.0 mmol) and
Ê
4 A activated molecular sieves 51.0 g) was placed in a light-
protected ¯ask under argon atmosphere and DCM 55 ml)
was added. After 1 h, the solvent was evaporated to dryness
and the residue was puri®ed by column chromatography in
chloroform to afford pure product 24 50.150 g, 77%).
3.3.2. Spectroscopic data of 21b 0min) extracted from the
spectrum of mixture. 1H NMR 5CDCl3, 400 MHz) d 8.00±
7.25 5m, 10H, HAr), 5.33 5dd, 1H, J1,F1ˆ63.5 Hz, J1,F2
ˆ
1.8 Hz, H1), 5.22 5dd, 1H, J4,3ˆ5.0 Hz, J4,5ˆ4.3 Hz, H4),
4.23 5dd, 1H, J3,F2ˆ14.1 Hz, J3,4ˆ5.0 Hz, H3), 4.23 5m,
1H, J5,6ˆ6.8 Hz, J5,4ˆ4.3 Hz, H5), 3.45 5s, 3H, OCH3),
1.47 5d, 3H, J6,5ˆ6.8 Hz, H6). 13C NMR 5CDCl3,
100 MHz) d 165.6 5CO), 133.5±128.0 5CAr), 5C2) not
observed, 105.3 5dd, J1,F1ˆ225.3 Hz, J1,F2ˆ43.8 Hz, C1),
3.5.1. Compound 24. [a]Dˆ279.0 5cˆ0.45, CDCl3); IR
1
1727 cm21 5nCO) H NMR 5CDCl3, 400 MHz) d 7.26±
7.29 5m, 5H, Ph), 4.93 5d, 1H, Jˆ10.4 Hz, H3), 4.78 5s,
1H, H1), 4.69 5d, 1H, Jˆ11.8 Hz, CH2Ph), 4.53 5d, 1H, Jˆ
11.8 Hz, CH2Ph), 4.22 5m, 1H, H5), 3.67 5t, 1H, J4,3ˆ
J4,5ˆ10.4 Hz, H4), 3.16 5s, 3H, OCH3), 3.12 5s, 3H,
OCH3), 1.82±1.30 5m, 8H, 5CH2)4), 1.23 5d, 3H,
83.2 5d, J3,F2ˆ20.6 Hz, C3), 80.8 5C4), 79.7 5d, J5,F2
ˆ
2.8 Hz, C5), 70.81 5CH2Ph), 58.5 5OCH3), 19.3 5C6). 19F

M. L. Aghmiz et al. / Tetrahedron 57 62001) 6733±6743
6741
J6,5ˆ6.4 Hz, H6). 13C NMR 5CDCl3, 100 MHz) d 195.6
5CO), 136.2, 128.5, 128.3, 128.2, 99.4 5C1), 99.1 5Cacetal),
98.5 5Cacetal), 74.3 5C4), 73.4 5C3), 70.1 5OCH2Ph), 66.9 5C5),
47.3 5OCH3), 46.6 5OCH3), 26.9 5CH2), 26.8 5CH2), 21.2
52CH2), 16.1 5C6). Anal. Calcd. for C21H28O7: C, 64.28; H,
7.14. Found; C, 64.18; H, 7.43.
afford compound 26 50.101 g, 66%) as a colorless oil.
1
Compound 26: [a]Dˆ251.3 5cˆ0.97, CHCl3), H NMR
5CDCl3, 400 MHz), d 7.33±7.08 5m, 15H, Ph), 4.96 5d,
1H, JABˆ12.1 Hz, CH2Ph), 4.90 5s, 1H, H1), 4.76 5d, 1H,
JABˆ12.0 Hz, CH2Ph), 4.75 5dd, 1H, J4,3ˆ5.8 Hz, J4,5a
ˆ
4.0 Hz, H4), 4.75 5d, 1H, JABˆ12.3 Hz, CH2Ph), 4.72 5d,
1H, JABˆ12.1 Hz, CH2Ph), 4.62 5d, 1H, JABˆ12.3 Hz,
CH2Ph), 4.61 5d, 1H, JABˆ12.0 Hz, CH2Ph), 4.51 5d, 1H,
J3,4ˆ5.8 Hz, H3), 3.95 5d, 1H, J5b,5aˆ10.5 Hz, H5b), 3.79
5dd, 1H, J5a,5bˆ10.5 Hz, J5a,4ˆ4.0 Hz, H5a), 1.33 5s, 3H,
CH3), 1.21 5s, 3H, CH3). 13C NMR 5CDCl3, 100 MHz), d
138.1 5CAr), 137.0 5CAr), 136.9 5CAr), 127.8±125.8
515CHAr), 111.3 5C5CH3)2), 106.8 5C2), 100.7 5C1), 84.7
5C3), 79.2 5C4), 71.3 5C5), 71.0 5CH2Ph), 68.9 5CH2Ph),
64.5 5CH2Ph), 25.3 5CH3), 23.9 5CH3). Anal. Calcd for
C29H32O6: C, 73.08; H, 6.76. Found: C, 73.04, H, 6.79.
3.6. Synthesis of di¯uorocarbohydrate 25
A solution of ketone 24 50.100 g, 0.25 mmol) in dry DCM
54 ml) was treated with DAST 50.7 ml, 0.84 g, 5.2 mmol)
under argon atmosphere and the mixture was re¯uxed
for 16 h. After cooling and the standard work up, the residue
was chromatographed on silica gel in ethyl acetate/
hexaneˆ1:9 to ethyl acetate/hexaneˆ1:1 to give compound
25 as a diastereoisoeric mixture 50.020 g, 19% yield,
conversion 50%) and unreacted ketone 24 50.050 g).
3.8.2. Synthesis of compound 27. Ratio 18/PhCH2OH 1:2.
The general procedure was followed with Cp2HfCl2
50.120 g, 0.32 mmol), AgOTf 50.166 g, 0.64 mmol) and
3.6.1. Spectroscopic data for 25a 0maj) extracted from
spectrum of mixture. 1H NMR 5CDCl3, 400 MHz) d 7.28±
7.26 5m, 5H, Ph), 5.32 5dd, 1H, J1,F1ˆ62.4 Hz, J1,F2ˆ1.2 Hz,
H1), 4.90 5d, 1H, Jˆ12.9 Hz, OCH2Ph) 4.68 5dd, 1H,
Jˆ12.0 Hz, JCH2,F1ˆ1.2 Hz, OCH2Ph), 4.32 5dd, 1H,
J3,F2ˆ20.4 Hz, J3,4ˆ10.2 Hz, H3), 4.14±3.97 5m, 2H, H4,
H5), 3.15 5s, 3H, OMe), 3.05 5s, 3H, OMe). 1.95±1.40 5m,
8H, 5CH2)4), 1.33 5d, 3H, J6,5ˆ6 Hz, H6). 13C NMR 5CDCl3,
100 MHz) d 136.6, 128.4, 128.2, 127.9, 110.3 5dd,
Ê
4A molecular sieves 50.320 g), benzyl alcohol 50.69 g,
0.64 mmol) and compound 18 50.050 g, 0.17 mmol) for
90 min. Standard work up gave a crude oil which was
puri®ed by column chromatography 5ethyl acetate/hexaneˆ
2:3) to produce compound 27 50.046 g, 70%) as a colorless
oil. Compound 27: [a]Dˆ2149.6 5cˆ0.84, CHCl3), 1H
NMR 5CDCl3, 400 MHz), d 7.41±7.03 5m, 9H, Ph), 4.96
5dd, 1H, J4.3ˆ6.2 Hz, J4,5aˆ3.8 Hz, H4), 4.89 5d, 1H,
J2,F2ˆ223.3 Hz, J2,F1ˆ25.8 Hz, C2), 106.2 5dd, J1,F1
ˆ
0
0
0
J1a ,1b ˆ15.3 Hz, H1a ), 4.82 5d, 1H, J3,4ˆ6.2 Hz, H3), 4.76
224.2 Hz, J1,F2ˆ46.2 Hz, C1), 100.4 5Cacetal), 99.8 5Cacetal),
74.9 5d, J5,F2ˆ2.4 Hz, C5), 72.9 5d, J4,F2ˆ1.6Hz, C4), 71.6
5OCH2Ph), 70.3 5d, J3,F2ˆ20.2 Hz, C3), 46.7 5OMe), 46.6
0
0
5d, 1H, JABˆ11.1 Hz, CH2Ph), 4.75 5d, 1H, J1b ,1a ˆ15.3 Hz,
0
H1b ), 4.64 5d, 1H, JABˆ11.1 Hz, CH2Ph), 4.50 5s, 1H, H1),
5OMe), 27.3 5CH2), 27.2 5CH2), 21.3 52CH2), 18.9 5C6). 19
F
4.00 5d, 1H, J5b,5aˆ10.2 Hz, H5b), 3.92 5dd, 1H, J5a,4
ˆ
3.8 Hz, J5a,5bˆ10.2 Hz, H5a), 1.49 5s, 1H, CH3), 1.39 5s,
1H, CH3). 13C NMR 5CDCl3, 100 MHz), d 138.2 5CAr),
134.0 5CAr), 130.9 5CAr), 130.2 5CHAr), 128.5 5CHAr),
128.4 5CHAr), 128.1 5CHAr), 127.5 5CHAr), 126.3 5CHAr),
124.2 5CHAr), 112.7 5C5CH3)2), 107.7 5C2), 84.3 5C3), 80.2
NMR 5CDCl3, 282.3 MHz) d 2118.9 5m, F2), 2144.3 5dd,
JF1,H1ˆ62.4 Hz, JF1,F2ˆ6.0 Hz, F1).
3.7. General procedure for the reaction of
di¯uorocarbohydrates 17 and 18 with alcohols
0
5C4), 72.9 5C5), 71.8 5C1), 70.8 5CH2), 62.6 5C1 ), 26.4 5CH3),
25.1 5CH3). Anal. Calcd for C22H24O5: C, 73.08; H, 6.76.
Found: C, 73.04, H, 6.79.
A mixture of Cp2HfCl2 50.5 mmols), AgOTf 51 mmol) and
Ê
powered 4 A molecular sieves 5440 mg) in dichlorometane
51.5 ml) was stirred for 10 min. at room temperature. The
alcohol 51 mmol) in dichlorometane 50.5 ml) was then
added and, after 5 minutes at room temperature, the mixture
was cooled to 2508C. Di¯uoride 17 or 18 50.5 mmol) was
then added and the temperature was left to reach room
temperature. When the reaction was ®nished, the reaction
mixture was poured into a saturated aqueous NaHCO3 solu-
tion, and ®ltered through a Celite pad. The organic layer was
separated and the aqueous layer extracted with CH2Cl2
53£10 ml). The combined layers were dried 5MgSO4) and
evaporated. The crude oil was puri®ed by ¯ash or thin-layer
chromatography.
3.9. Reaction of di¯uorocarbohydrate 17 with
uracil0TMS)2
3.9.1. Synthesis of compounds 28. A mixture of Cp2HfCl2
Ê
50.460 mmol), AgOTf 50.92 mmol) and 4 A molecular
sieves in 1.5 ml of benzene was stirred for 10 min under
inert atmosphere. To this reaction mixture, a solution of
bis5trimethylsilyl)uracil 50.92 mmol) in benzene 50.5 ml)
and after 5 min, a solution of compound 17 50.46 mmol)
in benzene 51 ml) was added. The reaction mixture was
stirred for 24 h, then poured into cold saturated aqueous
NaHCO3 solution, and ®ltered through a Cellite pad. The
organic layer was separated and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were
dried over MgSO4 and evaporated. The crude residue was
puri®ed by ¯ash chromatography to afford 0.124 g of 28
585%) as an epimeric 87/13 mixture. A pure sample of the
major isomer was isolated by repetitive chromatography of
a small sample of the mixture to afford a white solid.
3.8. Reaction of di¯uorocarbohydrate 18 with benzyl
alcohol
3.8.1. Synthesis of compound 26. Ratio 18/PhCH2OH 1:10.
The general procedure was followed with Cp2HfCl2
50.124 g, 0.33 mmol), AgOTf 50.171 g, 0.66 mmol) and
Ê
4A molecular sieves 50.300 g), benzyl alcohol 50.350 g,
1
3.3 mmol) and compound 18 50.050 g, 0.17 mmol) for 3 h.
The standard work up gave a crude oil which was puri®ed
by thin layer chromatography 5ethyl acetate/hexaneˆ1:3) to
mpˆ183±1858C; [a]Dˆ153.2 5cˆ0.74, CHCl3); H NMR
5CDCl3, 400 MHz), d 9.70 5bs, 1H, NH), 7.45 5dd, 1H,
0
0
0
0
0
0
J6 ,5 ˆ8.2 Hz, J6 ,Fˆ1.7 Hz, H6 ), 5.72 5d, 1H, J5 ,6
ˆ

6742
M. L. Aghmiz et al. / Tetrahedron 57 62001) 6733±6743
0
00
8.2 Hz, H5 ), 5.61 5d, 1H, J1,Fˆ13.3 Hz, H1), 4.84 5dd, 1H,
115.8 5C2 ), 112.7 5C5CH3)2), 84.3 5C3), 78.6 5C4), 71.8
5C5), 42.8 5C1), 24.3 5CH3), 23.6 5CH3). Anal. Calcd for
C28H22Br2O5: C, 56.21; H, 3.68. Found: C, 55.90, H, 3.64.
J4,5aˆ5.4 Hz, J4,5bˆ2.8 Hz, H4), 4.67 5dd, 1H, J3,4ˆ6.5 Hz,
J3,Fˆ12.8 Hz, H3), 4.19 5m, 1H, J5a,4ˆ5.4 Hz, J5a,5b
ˆ
10.4 Hz, J5a,Fˆ2.8 Hz, H5a), 4.14 5dd, 1H, J5b,5aˆ10.4 Hz,
J5b,4ˆ2.8 Hz, H5b), 3.39 5s, 3H, OCH3), 1.51 5s, 3H, CH3),
1.33 5s, 1H, CH3). 13C NMR 5CDCl3, 100.6 MHz), d 161.9
3.10.3. Compound 31. Mpˆ224±2268C, [a]Dˆ17.1
1
5cˆ1.21, CHCl3), H NMR 5CDCl3, 400 MHz), d 8.36 5d,
00 00
00
00 00
00
0
0
0
0
1H, J4 ,5 ˆ9.3 Hz, H4 ), 7.96 5d, 1H, J7 ,5 ˆ2.1 Hz, H7 ),
5C4 ), 150.3 5C2 ), 139.2 5d, J6 ,Fˆ5.4 Hz, C6 ), 115.4
0
0
0
0
0
0
7.86 5d, 1H, J7 ,5 ˆ2.1 Hz, H7 ), 7.60 5d, 1H, J9 ,10 ˆ
0 00 00 00
5C5CH3)2), 112.5 5d, J2,Fˆ245.1 Hz, C2), 101.9 5C5 ), 83.6
9.0 Hz, H9 ), 7.60 5d, 1H, J9 ,10 ˆ8.7 Hz, H9 ), 7.56 5dd,
5d, J1,Fˆ27.2 Hz, C1), 80.7 5d, J3,Fˆ21.9 Hz, C3), 77.2 5C4),
71.6 5C5), 56.4 5OCH3), 24.9 5CH3), 24.5 5CH3). 19F NMR
5CDCl3, 282.3 MHz), d 2127.8 5t, JF,H1ˆJF,H3ˆ13.0 Hz).
Anal. Calcd for C13H17FN2O6: C, 49.37; H, 5.42. Found:
C, 49.58, H, 5.07.
00 00
00 00
00
0
0
1H, J5 ,4 ˆ9.3 Hz, J5 ,7 ˆ2.1 Hz, H5 ), 7.12 5d, 1H, J10 ,9
ˆ
0
0
0
0
0
0
9 Hz, H10 ), 7.03 5dd, 1H, J5 ,4 ˆ9.3 Hz, J5 ,7 ˆ2.1 Hz, H5 ),
00 00
00
6.98 5d, 1H, J10 ,9 ˆ8.7 Hz, H10 ), 6.63 5s, 1H, OH), 6.43 5d,
0
0
0
1H, J4 ,5 ˆ9.3 Hz, H4 ), 6.15 5s, 1H, H1), 5.02±4.98 5m, 2H,
H3, H4), 4.23 5dd, 1H, J5a,5bˆ10.2 Hz, J5a,4ˆ3.0 Hz, H5a),
13
4.09 5d, 1H, J5b,5aˆ10.2 Hz, H5b), 1.28 5s, 3H, CH3), 0.76
3.10. Reaction of di¯uorocarbohydrate 17 with 6-bromo-
2-naphthol. Synthesis of compounds 29, 30 and 31
00
5s, 3H, CH3). C NMR 5CDCl3, 100 MHz) d 153.8 5C1 ),
0
153.2 5C1 ), 130.2 5C8 ), 129.9 5C8 ), 118.09 5C2 ), 129.7
0
00
0
0
00
00
0
5C7 ), 129.6 5C7 ), 120.7 5C10 ), 128.4 5C9 ), 128.2 5C9 ),
00
A mixture of Cp2HfCl2 50.822 g, 2.16 mmols), AgOTf
Ê
51.113 g, 4.32 mmol) and 4 A molecular sieves 51.9 g) in
00
128.1 5C5 ), 131.06 5C3 ), 124.6 5C4 ), 122.6 5C4 ), 118.9
0
5C2), 127.7 5C3 , 129.2 5C5 , 116.1 5C6 ), 115.9 5C6 ), 115.4
00
00
0
0
0
00
dichloromethane 511 ml) was stirred for 10 min at room
temperature. 6-bromo-2-naphthol 50.820 g, 3.67 mmol) in
dichloromethane 56.5 ml) was then added and, after 5 min
at room temperature, the mixture was cooled to 2508C.
Compound 17 50.486 g, 2.16 mmol) in 11 ml of dichloro-
methane was added and the temperature was then left to
reach room temperature. After the reaction was completed
54 h) standard work up gave a crude oil, which was puri®ed
to afford compound 29 50.131 g, 15%) as a colorless oil, and
compounds 30 50.275 g, 21%) and 31 50.145 g, 11%) as
white solids.
00
0
5C2 ), 112.4 5C5CH3)2), 111.7 5C10 ), 83.9 5C3), 78.4 5C4),
72.0 5C5), 42.3 5C1), 24.4 5CH3), 23.8 5CH3). Anal. Calcd for
C28H22Br2O5: C, 56.21; H, 3.68. Found: C, 55.94, H, 3.83.
Acknowledgements
We thank DGESIC 5PB98-1510) for ®nancial support. We
thank Professor K. Dax 5University of Graz, Austria) for his
interesting suggestions. G. H. J. thanks DGESIC for a post-
doctoral fellowship.
1
3.10.1. Compound 29. [a]Dˆ2113.0 5cˆ0.8, CHCl3), H
0
0
0
NMR 5CDCl3, 400 MHz), d 8.16 5d, 1H, J4 ,5 ˆ9.3 Hz, H4 ),
0
0
0
0
0
References
7.82 5d, 1H, J7 ,5 ˆ2.1 Hz, H7 ), 7.60 5d, 1H, J9 ,10 ˆ9.0 Hz,
0
0
0
0
0
0
H9 ), 7.38 5dd, 1H, J5 ,4 ˆ9.3 Hz, J5 ,7 ˆ2.1 Hz, H5 ), 7.05 5d,
0
0
0
1. 5a) Tsuchiya, T. Adv. Carbohydr. Chem. Biochem. 1990, 48,
91±277. 5b) Hudlicky, M. Org. React. 1988, 35, 513±637.
Â
2. Castillon, S.; Dessinges, A.; Faghih, R.; Lukacs, G.; Olesker,
1H, J10 ,9 ˆ9.0 Hz, H10 ), 5.06 5s, 1H, H1), 4.94 5dd, 1H,
J4,3ˆ5.9 Hz, J4,5aˆ4.2 Hz, H4), 4.72 5d, 1H, J3,4ˆ5.9 Hz,
H3), 4.28 5d, 1H, J5b,5aˆ11.0 Hz, H5b), 3.76 5dd, 1H,
J5a,5bˆ11.0 Hz, J5a,4ˆ4.2 Hz, H5a), 3.47 5s, 3H, OCH3),
1.45 5s, 3H, CH3), 1.19 5s, 3H, CH3); 13C NMR 5CDCl3,
A.; Thang, T. T. J. Org. Chem. 1985, 50, 4913±4917.
3. Nicolaou, K. C.; Ladduwahetty, T.; Randall, J. L.;
Chucholowsky, A. J. Am. Chem. Soc. 1986, 108, 2466±2467.
4. For a review about methods for synthesising gem-di¯uoro-
compounds see: Tozer, M. J.; Herpin, T. F. Tetrahedron
1996, 52, 8619.
0
100 MHz), d 154.9 5C1 ), 130.3 5C8 ), 129.9 5C9 ) 129.6
0
0
0
0
0
0
0
5C3 ), 128.9 5C7 ), 128.1 5C5 ),?126.4 5C4 ), 116.2 5C6 ),
0
0
114.2 5C2 ), 112.2 5C10 ), 111.9 5C5CH3)2), 106.2 5C1),
92.6 5C2), 83.3 5C3), 79.3 5C4), 72.2 5C5), 55.1 5OCH3),
24.5 5CH3), 22.5 5CH3). Anal. Calcd for C19H19BrO5: C,
56.03; H, 4.70. Found: C, 55.85, H, 4.78.
5. El-Laghdach, A.; Echarri, R.; Matheu, M. I.; Barrena, M. I.;
Â
Castillon, S.; Garcõa, J. J. Org. Chem. 1991, 56, 4556±4559.
Â
Â
6. El-Laghdach, A.; Matheu, M. I.; Castillon, S.; Lukacs, G.
3.10.2. Compound 30. Mpˆ204±2068C, [a]Dˆ2177.0
Carbohydr. Res. 1992, 233, C1±C2.
7. Barrena, M. I.; Matheu, M. I.; Castillon, S. J. Org. Chem.
1998, 63, 2184±2188.
1
Â
5cˆ0.3, CHCl3), H NMR 5CDCl3, 400 MHz), d 7.78 5d,
0
0
0
00 00
00
1H, J7 ,5 ˆ2.1 Hz, H7 ), 7.70 5d, 1H, J7 ,5 ˆ2.1 Hz, H7 ),
00
00
00
Â
8. Fernandez, R.; Castillon, S. Tetrahedron 1999, 55, 8497±
Â
7.63 5s, 1H, OH), 7.58 5d, 1H, J9 ,10 ˆ8.7 Hz, H9 ), 7.56
5d, 1H, J9 ,10 ˆ9.0 Hz, H9 ), 7.26 5d, 1H, J10 ,9 ˆ8.7 Hz,
H10 ), 7.13 5d, 1H, J4 ,5 ˆ9.0 Hz, H4 ), 7.10 5d, 1H,
J10 ,9 ˆ9.0 Hz, H10 ), 6.93 5dd, 1H, J5 ,4 ˆ9.0 Hz, J5 ,7
0
0
0
00 00
8508.
 Â
9. Fernandez, R.; Matheu, M. I.; Echarri, R.; Castillon, S.
00
00 00
00
0
0
0
0
0
0
0
ˆ
Tetrahedron 1998, 54, 3523±3532.
10. 5a) Borrachero-Moya, P.; Cabrera-Escribano, F.; Gomez-
0
00 00
00 00
Â
2.1 Hz, H5 ), 6.83 5dd, 1H, J5 ,4 ˆ9.0 Hz, J5 ,7 ˆ2.1 Hz,
00
0
0
0
Â
Guillen, M.; Madrid-Dõaz, F. Tetrahedron Lett. 1997, 38,
Â
H5 ), 6.45 5d, 1H, J4 ,5 ˆ9.0 Hz, H4 ), 5.76 5s, 1H, H1),
5.00±4.90 5m, 2H, H3, H4), 4.10 5dd, 1H, J5a,5bˆ10.8 Hz,
J5a,4ˆ3.3 Hz, H5a), 3.87 5d, 1H, J5b,5aˆ10.8 Hz, H5b), 1.35
1231±1234. 5b) Borrachero, P.; Cabrera-Escribano, F.;
 Â
Carmona, A. T.; Gomez-Guillen, M. Tetrahedron: Asymmetry
5s, 6H, 2CH3). 13C NMR 5CDCl3, 100 MHz), d 153.2 5C1 ),
2000, 11, 2927±2946.
0
00
152.1 5C1 ), 131.5 5C3 ), 130.1 5C8 ), 129.7 5C8 ), 129.5
00
00
0
Â
11. Baer, H. H.; Hernandez-Mateo, F.; Siemsen, L. Carbohydr.
Res. 1989, 187, 67±92.
0
00
0
0
00
5C7 ), 129.1 5C7 ), 129.0 5C5 ), 128.5 5C9 ), 128.1 5C9 ),
00
127.4 5C5 ), 127.4 5C3 ), 126.1 5C4 ), 122.5 5C4 ), 120.0
0
00
0
12. Dax, K.; Albert, M.; Ortner, J.; Paul, B. J. Carbohydr. Res.
2000, 327, 47±86.
00
0
0
5C10 ), 119.2 5C2 ), 118.1 5C2), 116.1 5C6 ), 114.6 5C6 ),
00

M. L. Aghmiz et al. / Tetrahedron 57 62001) 6733±6743
6743
Â
20. Matheu, M. I.; Echarri, R.; Castillon, S. Tetrahedron Lett.
1993, 34, 2361±2364.
21. Echarri, R.; Matheu, M. I.; Castillon, S. Tetrahedron 1994, 50,
13. Penglis, A. A. E. Adv. Carbohydr. Chem. Biochem. 1981, 38,
195±285.
Â
È
14. Csuk, R.; Glanzer, B. I. Adv. Carbohydr. Chem. Biochem.
1988, 46, 73±177.
9125±9134.
22. Matheu, M. I.; Echarri, R.; Domenech, C.; Castillon, S.
Tetrahedron 1996, 52, 7797±7806.
Á
Â
15. Michalik, M.; Hein, M.; Frank, M. Carbohydr. Res. 2000, 327,
185±218.
23. An additional product was obtained in comparison with
previous experiments 5Ref. 22). We realize that the quality
of catalyst used in this work was different.
16. Williamson, K. L.; Li, Y.-F.; Hall, F. H.; Swager, S. J. Am.
Chem. Soc. 1966, 5678±5680.
17. Jenkins, I. D.; Verheyden, J. P. H.; Moffat, J. G. J. Am. Chem.
Soc. 1976, 98, 3346±3357.
24. For comparative purposes with the starting materials, priority
in the numbering has been given to the sugar backbone.
25. Martin, O. R. Carbohydr. Res. 1987, 171, 211.
18. Hall, L. D.; Steiner, P. R.; Pedersen, C. Can. J. Chem. 1970,
48, 1155±1165.
Â
19. Matheu, M. I.; Echarri, R.; Castillon, S. Tetrahedron Lett.
1992, 33, 1093±1096.