Fluorination of 2-hydroxy-hexopyranosides by DAST: Towards formyl C-glycofuranosides from equatorial-2-OH methyl hexopyranosides

Article abstract of DOI:10.1016/j.tetasy.2003.11.034

Reaction of diversely configured and substituted, unbranched methyl D-hexopyranosides with the DAST in dichloromethane or acetonitrile led to normal substitution products and/or rearranged fluoro compounds (ring-contracted 2,5-anhydro-1-fluoro-1-O-methylhexitol derivatives, 2-methoxy-D-hexopyranosyl fluorides, and, for some 3-azido substrates, rearranged 2-azido-3-fluoro-D-hexopyranosides). When the reaction was performed in acetonitrile, the solvent participation as a nucleophile (Ritter reaction) was observed in one case. For a 2,4-unprotected 3-azido substrate, 2,3-dehydration and fluorination at C(4), the latter with epimerization, took place. ¹⁹F/¹H and ¹⁹F/¹³C coupling constant values were systematically applied to discriminate between isomeric structures for fluorinated products, and for some, previously described, coming from five 3-branched-chain D- or L-hexopyranosides, thus discarding the previously reported structural assignment. From the synthetic point of view, the most outstanding result was the preparation of 2,5-anhydro-1-fluoro-1-O- methylhexitols, showing a latent formyl group functionality, a transformation, which was achieved in one case. A rationalization for the formation of the different types of product is also proposed.

Full text of DOI:10.1016/j.tetasy.2003.11.034

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 429–444
Fluorination of 2-hydroxy-hexopyranosides by DAST: towards
formyl C-glycofuranosides from equatorial-2-OHmethyl
hexopyranosides
Yolanda Vera-Ayoso, Pastora Borrachero, Francisca Cabrera-Escribano,*
ꢀ
Ana T. Carmona and Manuel Gomez-Guillen
ꢀ
Departamento de Quꢀımica Orgꢀanica ‘Profesor Garcꢀıa Gonzꢀalez’, Facultad de Quꢀımica, Universidad de Sevilla,
Apartado de Correos No. 553, E-41071 Sevilla, Spain
Received 14 October 2003; accepted 26 November 2003
Abstract—Reaction of diversely configured and substituted, unbranched methyl
methane or acetonitrile led to normal substitution products and/or rearranged fluoro compounds (ring-contracted 2,5-anhydro-
1-fluoro-1-O-methylhexitol derivatives, 2-methoxy- -hexopyranosyl fluorides, and, for some 3-azido substrates, rearranged
2-azido-3-fluoro- -hexopyranosides). When the reaction was performed in acetonitrile, the solvent participation as a nucleophile
D-hexopyranosides with the DAST in dichloro-
D
D
(Ritter reaction) was observed in one case. For a 2,4-unprotected 3-azido substrate, 2,3-dehydration and fluorination at C(4), the
latter with epimerization, took place. 19F/1H and 19F/13C coupling constant values were systematically applied to discriminate
between isomeric structures for fluorinated products, and for some, previously described, coming from five 3-branched-chain D- or
L
-hexopyranosides, thus discarding the previously reported structural assignment. From the synthetic point of view, the most
outstanding result was the preparation of 2,5-anhydro-1-fluoro-1-O-methylhexitols, showing a latent formyl group functionality, a trans-
formation, which was achieved in one case. A rationalization for the formation of the different types of product is also proposed.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
kinds of rearrangement promoted by this fluorinating
agent. These reactions take place with or without ring
contraction, depending primarily on the substrate, and
constitute a convenient route to branched-chain glycosyl
fluorides and 2,5-anhydro-1-fluoro-1-O-methylhexitols,
as well as conformationally constrained cyclic fluori-
nated glycos-b-amino acids.
The role of organofluorine compounds, and in particu-
lar fluorocarbohydrates, in different branches of indus-
try and medicine1 has inspired great efforts to develop
new, mild reagents2;3 and methods4 for regioselective
fluorination, as well as to establish5 the mechanistic
features governing the corresponding or alternative
reaction paths.
We report herein our findings on the reactions of DAST
with a series of unbranched methyl 2-hydroxy-hexo-
pyranosides. The extension of the above methodol-
ogy12–15 to unbranched methyl 1,2-trans-diequatorial-
and 1,2-cis-glycopyranosides allowed us to prepare a
series of 2,5-anhydro-1-fluoro-1-O-methylhexitols (A)
(Scheme 1), and to gain a better understanding of the
structural requirements for each type of rearrangement
path. Compounds of type A contain a masked aldehyde
function, and the quantitative transformation into the
corresponding formyl C-glycofuranoside B was achieved
in one case. The mild conditions under which these ring-
contraction reactions take place, highlight this kind of
rearrangement promoted by DAST as a convenient
method to generate a furanose-based anomeric C-formyl
Among a large number of strategies to introduce fluo-
rine into carbohydrates, diethylaminosulphur trifluoride
(DAST) is known to be a useful reagent for the direct
replacement of a hydroxyl group by fluorine.6–9 How-
ever, unusual reactions caused by the action of DAST
have also been described.5;9–11 Over the last few years we
have studied the reaction of 3-branched-chain hexo-
pyranosides (and hexo-1-thiopyranosides) of the
L
D- and
- series with DAST, and reported12–15 three different
* Corresponding author. Tel: +34-95-4557150; fax: +34-95-4624960;
e-mail: fcabrera@us.es
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.11.034

430
Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 15 (2004) 429–444
O
R
HO
OMe
O
O
DAST
R
R
CHO
OMe
F
H
O
OMe
R
A
B
HO
Scheme 1. General ring-contraction reaction of 2-equatorial-hydroxy 1,2-cis and 1,2-trans glycopyranosides, promoted by DAST, and transfor-
mation of the product into 2,5-anhydro-aldehydo-furanose (Ôformyl C-glycofuranosideÕ), as formulated for the -series of sugars.
D
group. This provides a route to acid-stable C-glycofur-
anosides (C-oligosaccharides16 and C-glycoconju-
gates17;18), using compounds of type B or their synthetic
equivalents A as building blocks in standard coupling
reactions with nucleophiles.
authors indicated that, for this kind of rearrangement,
only an equatorial arrangement of the HO-2 group
(activated by DAST), irrespective of the specific ano-
meric configuration, appears to be essential. The cou-
2
pling constant J1;F values are spectroscopic data with a
diagnostic value, useful for differentiating between ring-
contracted products (2J1;F 63–68 Hz) and 1,2-migration
products (2J1;F 48–54 Hz).5
In a previous paper,14 we demonstrated that the bran-
ched-chain 2-hydroxy-hexopyranoside 1, whose ano-
meric substituent and the 2-hydroxyl group are in a
trans-diaxial arrangement, when treated with DAST,
affords a mixture of compounds 2a and 2b (Scheme 2),
which are generated through a 1,2-migration with con-
comitant stereoselective fluorination at the anomeric
position. When these substituents are cis, as is the case
for 3 or 5, the reaction leads to the ring-contracted
products 4a and b or 6a and b, respectively. Other
examples of similar ring contractions have been
reported9 by Dax et al. in a recent review, where those
We had found14 that the reaction of the branched-chain
2-hydroxy-hexopyranosides 7–11 gives rise to products
for which the structures 12–17 (Scheme 3) were initially
2
assigned. However, the J1;F values observed for these
compounds (except for 12) were in conflict with the
spectral data described above (see Scheme 2) and those
deduced and later published5 by Dax et al. All these
facts prompted us to reconsider the structural assign-
ment for the products obtained from 7–11.
OMe
Me
F
Me
O
Me
O
Me
MeO
Me
MeO
i
Me
MeO
O
F
+
OMe
OMe
NO2
NO2
NO2
OH
1.3 :1
1
2a
2JH,F = 53.1 Hz
2b
2JH,F = 54.0 Hz
OMe
F
OMe
H
H
Me
Me
Me
OMe
F
ii
Me
MeO
O
O
O
Me
MeO
Me
MeO
+
OH
NO2
NO2
NO2
3 : 1
3
4a
4b
2JH,F = 64.4 Hz
2JH,F = 64.3 Hz
Ph
Ph
O
O
O
iii
O
O
O
O2N
O2N
Me
HO
Me
OMe
OMe
F
H
5
6a,b
2.5 : 1 epimeric mixture
2JH,F = 64.1 (major) and
65.0 Hz (minor)
Scheme 2. Some antecedents14 of reactions of 3-branched-chain substrates with DAST, showing two types of rearrangement depending upon the
relative 1,2-configuration. (i) DAST, CH2Cl2, rt; 58% global yield. (ii) DAST, CH2Cl2, rt; 70% global yield. (iii) DAST, diglyme, rt; 95% from
converted substrate.

Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 15 (2004) 429–444
431
(a)
F
F
H
Me
OMe
+
Me
O
Me
O
Me
O
F
HO
HO
i
F
HO
i
F
O
OMe
OH
OMe
+
HO
12
(30%)
OH
ref. 14
NO2
NO2
O2N
NO2
F
OMe
7
45a,b
1.4 : 1 (37%)
13
12 (30%)
F
(b)
H
Me
OMe
Me
O
F
Me
i
i
O
O
O
O
O
OMe
OH
Ph
O
Ph
O
Ph
O
ref. 14
NO2
O2N
14
NO2
OMe
8
46a,b
1.2 : 1 (25%;a 42%b)
(c)
F
H
Me
OMe
F
Me
Me
O
TBDPSO
HO
O
TBDPSO
TBDPSO
HO
i
i
O
OMe
OH
HO
O2N
NO2
NO2
ref. 14
OMe
9
15
47a,b
2.7 : 1 (25%)
(d)
Ph
O
Ph
O
Ph
O
O
O
O
O
O
ii
O
ii
F
O2N
O2N
O2N
SPh
HO
ref. 14
Me
Me
SPh
Me
SPh
F
H
48 (9.5%;a 16%b)
10
16
(e)
SPh
H
F
Me
Me
Me
SPh
O
F
SPh
ii
O
O
O
O
O
ii
O
O
Ph
Ph
O
OH
Ph
NO2
NO2
11
NO2
17
ref. 14
49 (34%;a 48%b)
Scheme 3. Structural reassignment for the products obtained14 in the fluorination of the five substrates 7–11. (i) DAST (5 mol equiv), CH2Cl2; reflux
(2 h). (ii) DAST (5 mol equiv), CH2Cl2, 0 ꢁC (0.5 h) fi reflux (1–3 h). aIsolated; bfrom converted substrate.
2. Results
6-O-tert-butyl-diphenylsilyl derivative 29. Another sub-
strate, the methyl 3,6-dideoxy-a-D-hexopyranoside 30,
The opening of the 1,3-dioxane ring of methyl 3-O-
benzyl-4,6-O-benzylidene-a-D-glucopyranoside or its
was prepared according to a published procedure.29
Branched-chain substrates 7–11 were obtained as pre-
viously described.13;14;30
b anomer19 by treatment with sodium cyanoborohydride20
led to compounds 1821;22 and 1919;21;23 (from the a ano-
mer) or 2024 and 21 (from the b anomer), which were
separated in each case by column chromatography. To
our knowledge, compound 21 has not previously been
described but is now completely characterized (see
Experimental). The anomeric methyl 3-azido-4,6-O-
Treatment of 18 or 20 with DAST (5 mol equiv) in
dichloromethane at reflux for 1.5–2.0 h afforded the
epimeric, ring-contracted difluoro products 31a and b, in
40–41% overall yields (79% or 65% from converted
substrate, starting from 1 or 3, respectively). When this
epimeric mixture was treated with aqueous trifluoro-
acetic acid, almost quantitative transformation into the
benzylidene-
D
-glucopyranosides 22 and 23 were pre-
pared as described in the literature,25 as well as their
respective,
D
-altro configured isomers 2426 and 25.27 By
2,5-anhydro-4-fluoro-aldehydo-D-talose derivative 32
occurred (Scheme 4).
treatment of the 4,6-O-deprotected compound 26,28
derived from 24, with tert-butyl-chloro-diphenylsilane,
we prepared the substrate 27. Similarly, deprotection of
When the methyl 3-azido-4,6-O-benzylidene-D-gluco-
pyranoside derivatives 22 and 23 were treated with
DAST in dichloromethane for 6–8 h, no reaction was
25 afforded the methyl b-
D
-altropyranoside derivative
28, which was characterized and transformed into its

432
Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 15 (2004) 429–444
(a)
OBn
O
OH
O
Ph
O
O
Na (CN)BH3
O
R'
HO
BnO
BnO
BnO
+
R'
R'
BnO
HO
HO
HO
R
R
R
R = OMe, R' = H;
R' = H, R = OMe
18 R = OMe, R' = H;
20 R' = H, R = OMe
19 R = OMe, R' = H;
21 R' = H, R = OMe
(b)
OBn
O
HO
BnO
79%a
DAST
CH2Cl2,
reflux, 2h
HO
OMe
18
F
F
OBn
O
OBn
O
TFA / H2O
92%b
BnO
BnO
CHO
OMe
F
H
32
OBn
O
65%a
31a,b
1.9 :1
HO
BnO
2JH4,F: 53.9 Hz
OMe
HO
2JH1,F: Major epimer, 64.4 Hz;
minor epimer, 66.1 Hz
2JH4,F: Major epimer, 54.6 Hz;
minor epimer, 54.6 Hz
20
HMBC: C1/OCH3; H1/OCH3
Scheme 4. (a) Preparation of substrates 18 and 20, and their respective regioisomers 19 and 21; (b) fluorination of 18 and 20 by the DAST reagent,
and hydrolysis of the product 31a,b to the C-formyl derivative 32. aYield from converted substrate; bisolated yield.
F
OH
O
Ph
Ph
F
O
O
DAST
O
O
O
O
+
N3
N3
N3
MeCN, reflux,
6h
HO
OMe
33(25%a)
2JH2,F: 48.2 Hz
OMe
OMe
F
H
22
34a,b (63%a)
(69%a)
2JH1,F: Major epimer, 67.0 Hz;
minor epimer,
F
OTBDPS
O
66.0 Hz
N3
35a,b
2JH4,F: Major epimer, 54.5 Hz;
minor epimer, 54.5 Hz
(60%a)
OMe
F
H
1.2 :1
OMe
O
F
OH
O
Ph
Ph
O
O
DAST
O
O
O
OMe
+
N3
N3
N3
MeCN, reflux,
15 h
HO
23
F
OMe
36(66%a)
F
H
34a,b (32%a)
2JH1,F: 49.5 Hz
Scheme 5. Fluorination of 22 and 23, and transformation of product 34a,b into the 6-O-protected derivative 35a,b. aYield from converted substrate.
observed. When acetonitrile was used as the solvent at
reflux for 6 h (Scheme 5), the a- -glycoside 22 gave,
after column chromatography, the 2-inverted fluoro
compound 33 (23% yield, 25% from converted sub-
strate) and the 1-epimeric mixture of 1,4-difluoro, ring-
contracted products 34a and b (57% overall yield; 63%
from converted substrate), indicating an extensive loss
of the benzylidene protecting group during the reaction.
Characterization of 34a and b was achieved by prepa-
ration of its 6-O-tert-butyl-diphenylsilyl derivative 35a
and b, also obtained as an epimeric mixture. In contrast
with 22, its b anomer 23, under the same conditions,
D

Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 15 (2004) 429–444
433
except for heating for 15 h, was transformed into the 1,2-
rearranged compound 36 (40%; 66% from converted
substrate) and the same epimeric mixture of 4,6-O-de-
protected compounds 34a and b (20%; 32% from con-
verted substrate).
A different course of the reaction was observed when
starting from the 4-O-deprotected compound 27, derived
from 24 through 26 [Scheme 7, (a)]. In this case, fluorina-
tion with DAST in dichloromethane at reflux for 2 h led to
1
a 1:1 mixture (by H NMR) of the two 4-fluoro-2,3-
dehydrated 4-epimers 42 and 43, in 77% overall yield.
Preparative TLC made possible the separation of the epi-
mers, which could thus be characterized. It is noteworthy
thatthereactionof27withDASTinacetonitrileaffordeda
complex mixture of polar and non-fluorinated products.
The 4,6-di-O-protected methyl 3-azido-a-
D
- and b-D-
altropyranoside derivatives 24 and 25 behaved differ-
ently (Scheme 6) under fluorination conditions similar to
those applied to 22 and 23 (DAST in refluxing aceto-
nitrile, but for 1–1.5 h). Starting from 24, three pyr-
anosic, monofluorinated products were obtained (37, 38
and 39, in 56%, 29% and 14% yields, respectively), two
of them showing rearranged substitution patterns; from
The reactions of compounds 29 and 30 with DAST were
also investigated. The former, the b anomer of 27, did
not react with DAST in dichloromethane at reflux and,
when the solvent was acetonitrile, a complex mixture of
non-fluorinated products was obtained [Scheme 7, (b)].
25, the 2,3-rearranged methyl b-D-altropyranoside
derivative 40 and the non-fluorinated 2,3 rearranged
product 41 (formed by solvent participation in a Ritter
reaction) were obtained (31% and 42% yield from con-
verted substrate, respectively). In an attempt to fluori-
nate the b-D-altropyranoside derivative 25 with DAST
in dichloromethane at reflux for 2 h, no reaction oc-
curred, as seen for 22 and 23.
The latter, a methyl 3,6-dideoxy-2,4-unprotected-a-D-
hexopyranoside, on treatment with DAST in dichlo-
romethane at reflux for 1 h, afforded an unstable
difluoro compound that could not be completely char-
acterized, in low yield (up to 32%), for which we ten-
tatively propose the structure 44 [Scheme 2, (c)].
OH
O
Ph
Ph
Ph
Ph
Ph
F
O
O
O
F
O
DAST
O
O
O
O
O
O
O
+
+
F
N3
MeCN, reflux,
OMe
1h
OMe
N3
OMe
N3
N3
OMe
38(29%a)
39(14%a)
24
37(56%a)
OH
O
N3
O
N3
Ph
Ph
O
O
O
DAST
O
O
O
O
+
OMe
OMe
OMe
MeCN, reflux,
1.5 h
N3
F
NHAc
25
40(23%a)
41(32%a)
Scheme 6. Fluorination of 24 and 25. aIsolated yield.
(a)
OTBDPS
O
F
OH
O
OH
O
TBDPSO
F
HO
HO
TBDPSO
O
TBDPS-Cl
Py-DMAP
DAST
HO
+
CH2Cl2, reflux,
2 h (77%a)
N3
OMe
N3
OMe
N3
OMe
N3
OMe
42
26
43
27
(1 : 1)b
(b)
OH
O
OH
O
TBDPSO
HO
HO
TsOH
TBDPS-Cl
Py-DMAP
DAST
HO
no reaction
25
OMe
OMe
diverse
conditions
N3
N3
28
29
(c)
HO
H F
Me
H
O
H
DAST
O
OMe
Me
CH2Cl2, reflux
1h
H
F
H
HO
H
OMe
30
44, tentative (32%c)
Scheme 7. (a) Preparation of substrate 27 and its fluorination with DAST; (b) preparation of substrate 29 and its attempted fluorination with DAST,
c
showing no reaction; (c) fluorination of substrate 30. aGlobal yield; bseparation of products was achieved by preparative TLC; isolated yield.

434
Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 15 (2004) 429–444
A spectral reinvestigation of the products obtained from
the branched-chain substrates 7–11 led us to conclude
that a structural reassignment was necessary. Thus, the
correct structures of the products are as follows (Scheme
F), which should give rise31 to a 3JC4;F ꢀ 8 Hz; similarly,
3
the low value of JC3;F (2.4 Hz) (for 36) confirms the
gauche C(3)/F relationship.
3): (a) from 7, the expected 4,6-difluoro-b-
L
-hexopyr-
For compounds 37, 38 and 39, coming from 24 (Scheme
6), the highest 19F/1H and 19F/13C coupling constant
values were measured on the signals of C(2)H and C(2)
for 37, C(1)H and C(1) for 38, and C(3)H and C(3) for
39, indicating the respective fluorination site. For 37, the
anoside 12 (correctly assigned before14) and the epimeric
mixture of ring-contracted 1,6-difluoro-hexitol deriva-
tives 45a and b; (b) from 8, the mixture of 4,6-di-O-
protected 2,5-anhydro-1-fluoro-hexitol derivatives 46a
and b; (c) from 9, the mixture of 6-O-protected 2,5-an-
hydro-1-fluoro-hexitol derivatives 47a and b; (d) from
3
low J3;4 value (2.9 Hz) suggests the equatorial arrange-
ment of the C(3)H, since C(4)H is axial, while the
absence of splitting of the C(4) signal (3JC4;F ꢀ 0 Hz ) is
again in agreement with the axial orientation of the F
10, the 2-phenylthio-b-D-glucopyranosyl fluoride deriv-
ative 48; and (e) from 11 (enantiomer of 10), 49 (the b-
enantiomer of 48).
L-
3
3
atom at C(2); this and the low values of J1;2 and J2;3
(1.0 and 2.8 Hz, respectively) agree with the equatorial
arrangement of C(2)H and C(1)H. For 38, the 3J1;2 value
(7.3 Hz) indicates a trans-diaxial relationship between
3
3
these protons, and the J2;3 and J3;4 values (3.2 and
5.8 Hz) agree with an equatorial arrangement of C(3)H.
3. Discussion
3
3
3
For 39, the high J2;3, J3;4 and J4;5 values (9.0, 9.7 and
12.1 Hz, respectively) show the trans-diaxial relationship
Structures for the foregoing new products 31–43 coming
from unbranched hexopyranosides were assigned mainly
on the basis of their high-resolution mass spectrometric
3
between the respective protons, while the low J1;2 value
(3.4 Hz) indicates the equatorial orientation of the
anomeric proton. For both products 38 and 39, the 3JC;F
values (9.8 and 8.3 Hz) measured, respectively, in the
C(3) and C(1) signals are indicative of the equatorial
arrangement of the F atom, thus corroborating the
foregoing assignments.
1
data and H and 13C NMR spectra. In particular, the
19F/1H and 19F/13C coupling constant values were of
diagnostic application. Compounds 31a and b (Scheme
4) and 35a and b (and their immediate precursor 34a and
b) (Scheme 5) contained one fluorine atom at the C(4)
ring position (2JH4;F 54.5–54.6 Hz) and a second fluorine
atom at C(1), whose coupling constant with the geminal
proton––2JH1;F values of 64–67 Hz, in the range (63–
68 Hz) observed5 for analogous compounds––indicated
an exo-cyclic position; consequently, these products
must have a ring-contracted structure. For 31a and b,
heteronuclear multiple bond correlations (HMBC) were
observed: On the one hand, between C(1) and the me-
thyl protons and on the other, between C(1)H and the
methyl carbon nucleus, thus corroborating the assign-
ment. The structure of 2,5-anhydro-4-fluoro-aldehydo-
Of the two products obtained from 25, only 40 contains
one fluorine atom at C(3), as evidenced by the mass
spectrum and the J values observed in the NMR spectra,
the highest ones being observed in the C(3) signal (1JC3;F
181.0 Hz) and in the C(3)H signal (2JH3;F 49.7 Hz); the
second product 41 has an acetamido group instead of
the fluorine atom, as a consequence of solvent partici-
pation (Ritter reaction). For 40 and 41, the substituent
orientation pattern is the same––equatorial at C(1) and
axial at C(2) and C(3)––in agreement with the vicinal
coupling constant values observed in the respective
D
-talose derivative 32 was easily assigned to the
3
3
3
hydrolysis product of 31a and b from the d value of the
emerging C(1)H (doublet, 9.68 ppm) and carbonyl C(1)
signals (singlet, 199.6 ppm) observed, as well as from the
high-resolution, electron-impact mass spectrum (HRE-
IMS).
proton signals: for 40, J1;2 1.7, J2;3 3.7 and J3;4 1.7 Hz
4
(and, to identify the signal correspondence, JH1;F 2.7,
3JH2;F 7.5 and JH3;F 49.7 Hz; JC2;F 26.4, JC3;F 181.0,
2
2
1
2JC4;F 16.3 and JC5;F 2.5 Hz); for 41, J1;2 1.2, J2;3 3.0
3
3
3
3
and J3;4 4.5 Hz. For the latter product, the presence of
an acetamido group is evidenced from the acetyl protons
signal (singlet at d 2.03 ppm), the amino proton signal
(broad, d 5.71 ppm), and the carbonyl 13C signal
(d 171.5 ppm). The axial arrangement of the F atom at
C(3) of 40 was confirmed by the absence of splitting of
the C(1) signal.
Compound 33, also obtained from 22 (Scheme 5), is a
methyl 2-fluoro-a-D-hexopyranoside derivative, as
deduced from the JH2;F and JC2;F values (48.2 and
180.0 Hz, respectively), whilst its isomer 36, obtained as
2
1
the major product from 23, must be a 2-O-methyl-a-D-
hexopyranosyl fluoride, since the highest 19F/1H and
19F/13C coupling constant values were found for the
1H and 13C nuclei at the 1-position (2JH1;F 49.5 Hz; 1JC1;F
225.4 Hz). Both isomers 33 and 36 showed low proton/
proton 3J values between C(1)H, C(2)H, and C(3)H
The products 42 and 43 obtained from 27 [Scheme 7, (a)]
are 4-epimeric 4-fluoro-a-D-hex-2-enopyranoside deriv-
atives, as deduced from HRMS and NMR data. For 42,
the ethylenic proton signal (at d 5.58 ppm) must be
assigned to C(2)H, since it is split by the coupling with
the anomeric proton (3J1;2 3.5 Hz), and the 13C signals at
134.0 and 114.4 ppm correspond to the two ethylenic
carbon atoms C(3) and C(2), respectively, the former
showing a two-bond coupling with fluorine (2JC3;F
13.6 Hz). The position of the fluorine atom at C(4) is
3
(3J1;2 1.7 and 1.5 Hz; J2;3 2.3 and 3.3 Hz) and high ones
between the remaining pairs of pyranosic vicinal protons
(3J3;4 10.6 and 9.9 Hz; 3J4;5 9.0 and 9.9 Hz), so that C(3)H
must have the axial orientation, but C(2)H and C(1)H
the equatorial one. For 33, the absence of splitting of the
C(4) signal is in agreement with a gauche C(4)/F rela-
tionship31 (axial F), and not with an anti one (equatorial
1
deduced from the J values found (2JH4;F 51.5 and JC4;F

Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 15 (2004) 429–444
435
1
173.6 Hz). Compound 43 gave rise to H and 13C spec-
tra, respectively, similar to those of its isomer, the most
outstanding difference being that observed between the
3J4;5 values (8.8 and 2.0 Hzfor 42 and 43, respectively),
indicating that the orientation of C(4)H must be axial
for 42 and equatorial for 43.
the anomeric b-configuration was easily assigned from
3
the J1;2 value (8.2 Hz), while the low C(2) d value
(59.6 ppm) was according to the presence of a phenyl-
thio group at this position.
The findings described here for unbranched substrates
led to the conclusion that a simplified correlation
between structure and mechanistic pattern in the fluo-
rination reaction, such as that described for branched-
chain derivatives in our earlier article,14 is no longer
possible. Thus, the anomers 18 and 20, both having the
HO group at C(2) equatorially oriented, led (Scheme 4)
to the same epimeric pair of ring-contracted products
31a and b, in agreement with earlier observations32
indicating that when the leaving group at C(2) is equa-
torial, the ring-contraction reaction takes place
irrespective of the relative 1,2 configuration of the sub-
strate.
Structure 44 is tentatively assigned to the product
obtained from 30, since only the 1H and 13C NMR
spectra could be registered. The presence of one fluorine
atom at each position 1 and 2 was evidenced from the d
values observed for C(1)H, C(2)H, C(1), and C(2) (5.26,
4.44, 112.1 and 91.7 ppm, respectively), and, more sig-
nificantly, from the JH;F and JC;F values: thus, the value
2
of JH1;F1 (65.5 Hz) is in the range (63–68 Hz) charac-
teristic5 of the presence of a fluorine atom and an alkoxy
group at a terminal, exo-cyclic position, also in agree-
4
ment with the long-range coupling JF1;OMe (1.5 Hz),
3
3
while the JH1;F2 and JH2;F1 values (7.0 and 9.1 Hz,
respectively) indicate a vicinal relationship between the
two fluorine atoms in the molecule, corroborated by the
high values of J measured in the C(1) and C(2) signals
The formation of 34a,b occurs, after extensive 4,6-O-
deprotection in the course of the reaction, through a
mechanism involving ring-oxygen anchimeric assistance
to the departure of the leaving group from C(2), similar
to that proposed9;12;14;32 for other ring-contractions,
followed by difluorination.
(1JC1;F1 219.6 Hz, JC2;F2 173.0 Hz, JC1;F2 28.3 Hz, JC2;F1
1
2
2
25.8 Hz), as well as in the C(3) signal (2JC3;F2 20.4 Hz).
In the light of the foregoing structural study of the
products obtained from unbranched methyl 2-hydroxy-
hexopyranosides, as well as of literature precedents5;31 of
assignments based on the 19F/1H and 19F/13C coupling
constant values observed for related compounds, a
structural reassignment for the products obtained from
the 3-branched-chain substrates 7–11 (Scheme 3) was
The formation of 37 and 38 from 24 may be explained,
as in similar cases,11;14 by a scheme involving the an-
chimeric assistance of the axial methoxy group to the
departure of the leaving group [Scheme 8, (a)], the
attack of fluoride on C(2) leading to 37 with retained
configuration, and on C(1) affording the rearranged
made. A common 2,5-anhydro-1-fluoro-1-O-methyl-
mannitol derivative pattern was assigned to the 1-epi-
L
-
b-D-hexopyranosyl fluoride 38. The formation of the
minor product 39 may be explained assuming the an-
chimeric assistance of the azido group, which might also
lead to 37. However, formation of 40 and 41, both
showing the azido group axially arranged at C(2) and
the new substituent, F or NHAc, at C(3) with axial
orientation again, seems to indicate [Scheme 8, (b)] a
first mechanistic step of azido-assisted departure of the
leaving group, a second step of equilibration of the
intermediate cation to a carbocation at C(3), which
might lose a proton from the vicinal C(2), and a third
step, in which the conjugated addition of the nucleophile
(fluoride or acetonitrile) on the less-hindered face of the
double bond would lead to 40 or, through a Ritter-type
reaction, to 41; the trans-diaxial orientation of the C(2)
and C(3) substituents for both compounds might also
result from a dipole repulsion effect.
meric pairs 45a and b, 46a and b, and 47a and b obtained
2
from 7, 8, and 9, respectively, since the JH1;F values
measured (64.2, 64.0; 65.0, 64.0; 65.4, 64.0 Hz, respec-
tively) are in agreement with the previous observations
cited above, but very different from those found for
glycosyl fluorides. Moreover, we found in our reinves-
tigation that all of these products showed Cð1Þ/OCH3
and C(1)H/OCH3 heteronuclear multiple bond correla-
tions (HMBC), indicating three bonds between the
corresponding atoms and, therefore, that the fluorine
atom and the methoxy group are substituents at C(1).
1
Another feature of the H NMR spectra of these com-
pounds is the higher chemical shift value observed for
the C(2)H signal of the 2,5-anhydro-hexitol structure
(d range: 4.62–4.82 ppm; for example,14 4a, 4b and 6a
and b) in comparison with a glycopyranosyl fluoride
structure (d range: 3.66–4.05 ppm; for instance,14 2a and
2b). It is noteworthy that the new structures 46a and b
assigned to the compounds obtained as a mixture from 8
correspond to the respective enantiomers of 6a and b
(Scheme 2), as corroborated by the respectively identical
1H and 13C NMR spectra,14 in spite of the non-enan-
tiomeric relationship between the respective substrates 8
The formation of the unsaturated sugar derivatives 42
and 43 from 27 may be considered a normal b-elimi-
nation process, but the conditions used here are different
(dichloromethane as the solvent) from those used in the
foregoing examples (acetonitrile); this might be the
reason why no nucleophilic addition to the a,b-unsatu-
rated azide was observed, rather an allylic SN1 reaction.
That is, 27 might first undergo the departure of the
leaving group from C(2)- assisted again by the methoxy
or the azido group- followed by the loss of a proton
from C(3) to form a b-elimination intermediate product,
from which the departure of the leaving group from C(4)
might become easier, since the remaining carbocation
(b-
mers (as obtained from the enantiomers 10 and 11),
L
-) and 5 (a-D-). Products 48 and 49, being enantio-
showed identical 1H and 13C NMR spectra, respectively,
2
in which the JH1;F1 value (50.9 Hz) agreed with the
reassigned glycosyl fluoride structure, confirmed in our
reinvestigation by the observed HMBC H-2/(SPh)Cipso
;

436
Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 15 (2004) 429–444
(a)
Ph
O
O
O
:F
37 + 38
OSF2NEt2
O
Ph
O
O
N3
DAST
O
Me
24
N3
OMe
Ph
O
O
O
:F
39 + 37
OMe
N
N
N
OSF2NEt2
H
O
(b)
Ph
Ph
O
O
O
OMe
Ph
O
O
O
O
OMe
O
DAST
OMe
H
25
N
N
N3
O
N3
N
:F
Ph
40
- H+
O
OMe
O
H
N3
41
MeCN
(Ritter)
Scheme 8. (a) Rationalization proposed for the formation of 37, 38 and 39 from 24; (b) proposal for the formation of 40 and 41 from 25.
would be allylic; all of this is in agreement with the fact
that two epimers, 42 and 43 are formed.
cyclic sulphonium ion intermediate, a process that might
be a consequence of the higher nucleophilicity of the
sulphur of phenylthio group in comparison with the ring
oxygen; later attack of fluoride at C(1) would open this
ring, leading to the 1,2-diequatorial product.
The product obtained from 30, tentatively formulated as
44, might have been formed like similar compounds14 by
ring-oxygen participation pushing out the leaving group
from C(4), requiring in this case the adoption of the 1C4
conformation by the pyranose ring, and the opening of
the cyclic oxonium ion formed as intermediate by attack
of the fluoride on C(1), followed by a standard SN2
reaction of a second fluoride on C(2); since all this
involves inversion of the configuration of C(4) and C(2),
4. Conclusion
The methyl 2-hydroxy-hexopyranosides that we have
used as substrates for this study react with DAST
showing the following general trends: (a) When the
HO-2 is equatorial, a five-membered ring-contracted
product––the synthetic equivalent of a Ôformyl C-
glycofuranosideÕ––is obtained, even when starting from
4,6-O-benzylidene derivatives. Nevertheless, for this
rigidified trans-decalin-type system, when the 1,2
substituents have a trans-diequatorial arrangement,
nucleophilic substitution by fluoride or 1,2-aglycon
migration strongly competes with the ring-contraction
process. (b) When the HO-2 is axial, nucleophilic
substitution, elimination reaction, or 1,2-neighbouring
group migration can take place; however, no ring-
contracted product was detected by us in any case. As a
consequence, a convenient and ready access to Ôformyl
C-glycofuranosidesÕ, starting from equatorial-2-OH
methyl hexopyranosides, is established.
the
D-arabino configuration was assigned.
The reformulated (as ring-contracted) products 45a and
b, 47a and b, coming from the 3-branched-chain, 1,2-
trans-diequatorially substituted compounds 7–9, were
assumed to be formed by a mechanistic pathway similar
to that proposed9;12;14;32 for ring contractions. It is
noteworthy that the 4,6-O-benzylidene substrate 8, as
well as 514 (Scheme 2), led to ring-contracted products,
thus refuting a generalization of the stated9 principle,
which establishes that 4,6-O-benzylidene hexopyrano-
sides of the trans-decalin type containing an equatorial
HO group at C(2) cannot undergo ring-contraction
reactions.
For their part, the enantiomeric 4,6-O-benzylidene-1-
thio-a-glucopyranoside derivatives 10 and 11 follow a
pathway involving 1,2-migration of the phenylthio
group with retention of configuration at C(2) but
inversion at C(1). These results may be explained only if
the departure of the leaving group occurs before the
migration of the phenylthio group, which could lead to a
A different behaviour is observed for phenyl 1-thio-
hexopyranosides, since a 2-phenylthio-glycopyranosyl
fluoride is obtained, irrespective of the C(1)/C(2) con-
figurational relationship, probably due to the higher
nucleophilicity of sulphur.

Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 15 (2004) 429–444
437
The systematic use of 19F/1H and 19F/13C coupling
constant values and heteronuclear multiple bond cor-
relation (HMBC) technique led to a structural reas-
signment for the fluorinated products 45–49, previously
borohydride (0.650 g, 10.3 mmol) and molecular sieve
ꢁ
(3 A). After 30 min stirring, HCl/Et2O was added until
gas evolution stopped. The reaction mixture was kept
for 5 min at room temperature and then diluted with
dichloromethane. The organic layer was washed with
water and saturated aqueous sodium hydrogen car-
bonate. After drying over Na2SO4, the organic layer was
concentrated and the residue was subjected to column
chromatography (1:1 fi 5:1 gradient, ether/hexane) to
give 18 (0.19 g, 62%) and 19 (0.11 g, 38%).
reported,14 coming from five 3-branched-chain
-hexopyranosides.
D- or
L
5. Experimental
25
Compound 18 had ½aŠ ¼ +78.2 (c 0.93, CH2Cl2) [lit.21:
D
25
D
5.1. General
½aŠ ¼ +79.2 (c 3.50, CHCl3)].
25
D
Hexane and ether were distilled from sodium prior to
use. TLC was performed on silica gel plates (DC-
Compound 19 had ½aŠ ¼ +98.4 (c 0.91, CH2Cl2) [lit.21:
25
½aŠ ¼ +101.3 (c 0.545, CHCl3)].
D
Alufolien F254, E. Merck, or Alugram Sil G/UV254
,
Macherey-Nagel), and preparative TLC on Kieselgel 60
F254 DC-Platten 105715 HR; detection of compounds
was accomplished with UV light (254 nm) and by char-
ring with H2SO4 and an anisaldehyde reagent. Silica gel
60 (E. Merck, 230–400 mesh) was used for column
chromatography. Solutions were concentrated under
diminished pressure at <40 ꢁC. Melting points were
determined on a Gallenkamp MFB-595 apparatus and
are uncorrected. A Perkin–Elmer 241 MC polarimeter
was used for the measurement of optical rotations. IR
spectra (neat or on a KBr disc) were obtained on a
FTIR Bomem Michelson MB-120 spectrophotometer.
1H NMR spectra (300 and 500 MHz) and 13C NMR
spectra (75.4 and 125.7 MHz) were recorded with a
Bruker AMX-300 or an AMX-500 spectrometer;
chemical shifts (d) are expressed in ppm from TMS;
coupling constants (J), in Hz. Assignments were con-
firmed by decoupling, homonuclear 2D COSY corre-
lated spectra, heteronuclear 2D correlated (HETCOR)
spectra, heteronuclear 1D single quantum coherence
(HSQC) spectra, differential NOE and 1D NOESY
experiments. Heteronuclear multiple bond correlation
(HMBC) experiments were acquired in the same con-
ditions that HSQC corresponding experiments and
optimized for long range coupling of 7 Hz. EI mass
spectra (70 eV) were measured with a Kratos MS-
80RFA instrument, with an ionizing current of 100 lA,
an accelerating voltage of 4 kV, and a resolution of
10,000 (10% valley definition). Fast-atom bombardment
mass spectrometry (FABMS) was performed on the
same instrument; ions were produced by a beam of
xenon atoms (6–7 keV) using a matrix consisting of
m-nitrobenzyl alcohol or thioglycerol and NaI as salt.
HREIMS (70 eV) and HRCIMS (150 eV) experiments
were performed with a Micromass AutoSpecQ instru-
ment with a resolution of 10,000 (5% valley definition).
HRFABMS was performed on a VG AutoSpec spec-
trometer (Fisons Instruments) (30 keV).
5.3. Methyl 3,6-di-O-benzyl-b-
and methyl 3,4-di-O-benzyl-b-
D
-glucopyranoside,24 20,
-glucopyranoside, 21
D
To a solution of methyl 3-O-benzyl-4,6-O-benzylidene-
b-
-glucopyranoside19 (0.23 g, 0.62 mmol) in dry THF
(8.7 mL) was added sodium cyanoborohydride (0.50 g,
D
ꢁ
7.97 mmol) and molecular sieve (3 A). After 30 min of
stirring, HCl/Et2O was added until gas evolution stop-
ped. The reaction mixture was kept for 5 min at room
temperature and then diluted with dichloromethane.
The organic layer was washed with water and saturated
aqueous sodium hydrogen carbonate. After drying over
Na2SO4, the organic layer was concentrated and the
residue subjected to column chromatography (1:1 fi 5:1
gradient, ether/hexane) to give 20 (0.14 g, 61%) and 21
(0.04 g, 19%).
25
Compound 20 had ½aŠ ¼ )23.0 (c 0.73, CH2Cl2) [lit.24:
D
24
D
½aŠ ¼ )29.5 (c 0.76, CHCl3)].
22
D
Compound 21: Syrup; Rf 0.47 (ether); ½aŠ ¼ À5:8 (c
1.2, acetone); IR (film) mmax 3306 (OH) and 1127,
1053 cmÀ1 (C–O–C); 1H NMR (500 MHz, CDCl3)
d 7.40–7.12 (m, 10H, 2 Ph), 4.87 and 4.83 (2d, 2H,
0
JH;H ¼ 11:3, CH2Ph), 4.83 and 4.62 (2d, 2H,
0
JH;H ¼ 10:8, CH2Ph), 4.18 (d, 1H, J1;2 ¼ 7:5, H-1), 3.84
0
(dd, 1H, J6;6 ¼ 12:0, J5;6 ¼ 2:3, H-6), 3.69 (dd, 1H,
J5;6 ¼ 4:0, H-60), 3.56 (m, 2H, H-3 and H-4), 3.51 (3H,
0
OMe), 3.45 (dd, 1H, J2;3 ¼ 8:0, H-2), 3.35 (m, 1H, H-5),
2.44 (s, 1H, HO-2) and 1.98 (s, 1H, HO-6); 13C NMR
(127.5 MHz, CDCl3) d 138.4–127.8 (MHz, 2 Ph), 103.7
(C-1), 84.2 (C-3), 77.4 (C-4), 75.3, 75.1 and 75.0 (C-5
and 2 C2 Ph), 74.6 (C-2), 61.8 (C-6) and 57.3 (OMe).
HREIMS: m=z 374.1722 (calcd for C21H26O6: 374.1729).
5.4. Methyl 3-azido-6-O-tert-butyl-diphenylsilyl-3-deoxy-
a-D-altropyranoside, 27
5.2. Methyl 3,6-di-O-benzyl-a-
D
-glucopyranoside,21;22 18
-glucopyranoside,19;21;23 19
Dry pyridine (250 lL) and 4-(dimethylamino)pyridine
(DMAP, 0.010 g) were added to a solution of methyl
and methyl 3,4-di-O-benzyl-a-
D
3-azido-3-deoxy-a-
D
-altropyranoside9
(26, 0.340 g,
To a solution of methyl 3-O-benzyl-4,6-O-benzylidene-
a-
-glucopyranoside19 (0.298 g, 0.801 mmol) in dry
tetrahydrofuran (11 mL) was added sodium cyano-
1.56 mmol) in dry dichloromethane (2.5 mL) and the
mixture then stirred under argon and cooled at 0 ꢁC.
tert-Butyl-chloro-diphenylsilane (550 lL, 2.43 mmol)
D

438
Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 15 (2004) 429–444
25
D
was then added to the mixture, which was allowed to
warm to room temperature. After 72 h, the reaction was
quenched by adding 1 M HCl until neutral pH (1 mL)
and the mixture was shaken with dichloromethane
(3 · 15 mL). The combined organic layers were dried
over Na2SO4 and concentrated to a syrup, which was
subjected to column chromatography (1:1 hexane/ethyl
hexane/ethyl acetate); ½aŠ ¼ )58.2 (c 0.78, acetone); IR
(film) mmax 3308 (OH), 2110 (N3) and 704 cmÀ1 (CSi); 1H
NMR (300 MHz, CD3COCD3) d 7.81–7.38 (m, 10H,
2Ph), 4.93 (d, 1H, J1;2 ¼ 1:6, H-1), 4.44 (d, 1H,
0
J4;OH ¼ 3:7, HO-4), 4.01 (dd, 1H, J6;6 ¼ 10:7, J5;6 ¼ 2:9,
H-6), 3.96–3.79 (m, 4H, H-3, H-4, H-5 and H-60), 3.74
(dd, 1H, J2;3 ¼ 4:4, H-2), 3.50 (s, 3H, OMe), and 1.05 (s,
9H, CMe3); 13C NMR (125.7 MHz, CD3COCD3)
d 136.5–128.5 (m, Ph), 100.7 (C-1), 76.4, 70.4 and 65.6
(C-3, C-4 and C-5), 65.0 (C-6), 63.4 (C-2), 56.7 (OMe),
27.1 (CMe3), and 19.9 (CMe3); HRFABMS: m=z
480.1932 (calcd for C23H31N3O5Si+Na: 480.1931).
acetate) to give 27 (0.660 g, 92%); syrup; Rf 0.42 (2:1
25
hexane/ethyl acetate); ½aŠ ¼ +35.7 (c 0.9, acetone); IR
D
(film) mmax 3310 (OH), 2110 (N3) and 702 cmÀ1 (CSi); 1H
NMR (300 MHz, CD3COCD3) d 7.79–7.38 (m, 10H,
2Ph), 4.65 (d, 1H, J2;OH ¼ 5:1, HO-2), 4.60 (d, 1H,
J1;2 ¼ 2:4, H-1), 4.27 (d, 1H, J4;OH ¼ 6:1, HO-4), 4.12
(ddd, 1H, J4;5 ¼ 7:9, J3;4 ¼ 4:0, H-4), 4.01–3.84 (m, 4H,
H-2, H-5, H-6 and H-60), 3.80 (dd, 1H, J2;3 ¼ 4:6, H-3),
3.37 (s, 3H, OMe), and 1.05 (s, 9H, CMe3); 13C NMR
(125.7 MHz, CD3COCD3) d 136.5–128.3 (MHz, Ph),
102.9 (C-1), 72.5 (C-5), 70.2 (C-2), 66.4 (C-4), 65.1 (C-6),
64.6 (C-3), 55.3 (OMe), 27.2 (CMe3), and 19.8 (CMe3);
5.7. (1R and 1S)-2,5-Anhydro-3,6-di-O-benzyl-4-deoxy-
1,4-difluoro-1-O-methyl-D-talitols, 31a,b
(a) From 18: DAST (177 lL, 1.33 mmol) was dropped
into a solution of compound 18 (0.100 g, 0.267 mmol) in
dry dichloromethane (5 mL) at 0 ꢁC under argon. After a
few minutes, the cooling bath was removed and the
mixture heated to reflux for 1.5 h. After dilution with
iced saturated aqueous sodium hydrogen carbonate
(75 mL), the aqueous layer was extracted with dichloro-
methane (3 · 30 mL). The combined organic layers were
washed with brine (60 mL), dried over Na2SO4, and
concentrated to afford, after column chromatography
(1:10 ether/hexane), unreacted starting material 18
(0.050 g, indicating 50% of conversion) and a 1.3:1.0 (by
1H NMR) epimeric mixture 31a,b (0.040 g, 40%, corre-
sponding to 79% yield from converted substrate); syrup;
Rf 0.45 (1:1 ether/hexane); IR (film) mmax 1127, 1053 (C–
O–C) and 991 cmÀ1 (CF); HRCIMS: m=z 379.1714
(calcd for C21H24F2O4+H: 379.1721).
HRFABMS:
m=z
480.1933
(calcd
for
C23H31N3O5Si+Na: 480.1931).
5.5. Methyl 3-azido-3-deoxy-b-
D
-altropyranoside, 28
p-Toluenesulphonic acid (0.082 g, 0.434 mmol) was
added to a solution of methyl 3-azido-4,6-O-benzylid-
ene-3-deoxy-b-D
-altropyranoside8 (1.33 g, 4.33 mmol) in
1:1 methanol/dioxane (44 mL). The mixture was heated
at 85 ꢁC for 2 h, neutralized with triethylamine and
concentrated. The residue was subjected to column
chromatography (1:4 hexane/ethyl acetate) to give 28
(0.920 g, 97%); syrup; Rf 0.43 (ethyl acetate);
23
½aŠ ¼ À124:4 (c 0.57, acetone); IR (film) mmax 3313
D
(OH) and 2108 cmÀ1 (N3); 1H NMR (300 MHz,
CD3SOCD3, at 363 K) d 4.88 (d, 1H, JHO;4 ¼ 4:0, HO-4),
4.78 (d, 1H, J1;2 ¼ 2:0, H-1), 4.37 (d, 1H, JHO;2 ¼ 5:5,
Major epimer: 1H NMR (500 MHz, CD3COCD3)
2
d 7.39–7.33 (m, 10H, 2 Ph), 5.33 (dd, 1H, J1;F ¼ 66:1,
2
0
HO-2), 4.18 (dd, 1H, JHO;6 ¼ JHO;6 ¼ 5:7, HO-6), 3.81–
J1;2 ¼ 3:0, H-1), 5.22 (ddd, 1H, J4;F ¼ 54:6, J3;4 ¼ 3:2,
0
3.79 (m, 1H, H-4), 3.68–3.60 (m, 3H, H-3, H-5 and H-6),
J4;5 ¼ 2:3, H-4), 4.72 and 4.63 (2d, 2H, JH;H ¼ 11:9,
0
3.59–3.56
(m,
1H,
H-2),
3.51
(ddd,
1H,
CH2Ph), 4.57 and 4.54 (2d, 2H, JH;H ¼ 12:0, CH2Ph),
J6 ;OH ¼ J6 ;5 ¼ 5:5, J6;6 ¼ 11:0, H-60), and 3.42 (s, 3H,
OMe); 13C NMR (75.8 MHz, CD3SOCD3, at 363 K)
99.0 (C-1), 75.8 (C-5), 68.0 (C-4), 65.1 (C-2), 61.8 (C-3),
61.4 (C-6), and 55.5 (OMe); HRCIMS: m=z 220.0930
(calcd for C7H13N3O5+H: 220.0933).
4.38 (ddd, 1H, J3;F ¼ 23:0, J2;3 ¼ 7:3, J3;4 ¼ 3:7, H-3),
3
0
0
0
4.22 (dddd, 1H, 3J5;F ¼ 29:8, J5;6 ¼ J5;6 ¼ 6:2, H-5), 4.00
0
3
0
(ddd, 1H, J2;F ¼ 12:0, H-2), 3.77 (dd; 1H, J6;6 ¼ 9:9,
H-6), 3.62 (ddd, 1H, 4J6 ;F ¼ 2:1, H-60), and 3.54 (d, 3H,
0
4JOMe;F ¼ 1:2,
OMe);
13C
139.5–128.5 (m, Ph), 113.4 (d,
NMR
(127.5 MHz,
CD3COCD3)
d
1JC1;F ¼ 220:0, C-1), 91.0 (d, JC4;F ¼ 189:8, C-4), 81.0
1
2
2
5.6. Methyl 3-azido-6-O-tert-butyl-diphenylsilyl-3-deoxy-
b-
(d, JC2;F ¼ 24:5, C-2), 80.6 (d, JC5;F ¼ 17:6, C-5), 79.5
2
D
-altropyranoside, 29
(d, JC3;F ¼ 16:2, C-3), 73.8 and 72.7 (CH2Ph), 68.3 (d,
3JC6;F ¼ 10:3, C-6), and 57.4 (s, OMe). HMBC correla-
tions: C-1/OCH3 and H-1/OCH3.
Dry pyridine (145 lL), 4-(dimethylamino)pyridine
(DMAP, 0.006 g), and tert-butyl-diphenyl-chlorosilane
(360 lL, 1.38 mmol) were added at 0 ꢁC, under argon, to
Minor epimer: 1H NMR (500 MHz, CD3COCD3)
2
a stirred solution of methyl 3-azido-3-deoxy-b-
D
-altro-
d 7.39–7.33 (m, 10H, 2Ph); 5.30 (dd, 1H, J1;F ¼ 64:4,
2
pyranoside (28, 0.201 mg, 0.919 mmol) in dry CH2Cl2
(1.5 mL). The mixture was then allowed to warm to
room temperature. After 72 h, the reaction was quen-
ched by adding 1 M HCl until neutral pH (1 mL) after
which the mixture was shaken with dichloromethane
(3 · 15 mL). The combined organic layers were dried
over Na2SO4 and concentrated to a syrup, which was
subjected to column chromatography (1:1 hexane/ethyl
acetate) to give 29 (0.382 g, 87%); syrup; Rf 0.38 (2:1
J1;2 ¼ 3:7, H-1), 5.22 (ddd, 1H, J4;F ¼ 54:6, J3;4 ¼ 3:2,
0
J4;5 ¼ 2:3, H-4), 4.72 and 4.63 (2d, 2H, JH;H ¼ 11:9,
0
CH2Ph), 4.57 and 4.54 (2d, 2H, JH;H ¼ 12:0, CH2Ph),
3
4.37 (ddd, 1H, J3;F ¼ 23:0, J2;3 ¼ 7:3, J3;4 ¼ 3:6, H-3),
4.22 (dddd, 1H, 3J5;F ¼ 29:8, J5;6 ¼ J5;6 ¼ 6:2, H-5), 4.00
0
3
0
(ddd, 1H, J2;F ¼ 12:0, H-2), 3.77 (dd, 1H, J6;6 ¼ 9:9,
H-6), 3.62 (ddd, 1H, 4J6 ;F ¼ 2:1, H-60), and 3.54 (d, 3H,
0
4JOMe;F ¼ 1:2,
OMe);
13C
139.5–128.5 (m, Ph), 112.8 (d,
NMR
(127.5 MHz,
CD3COCD3)
d

Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 15 (2004) 429–444
439
1
1JC1;F ¼ 218:7, C-1), 91.0 (d, JC4;F ¼ 189:8, JC1;F, C-4),
with DAST (236 lL, 1.79 mmol). After a few minutes,
the cooling bath was removed and the mixture heated to
reflux for 6 h. The solvent was then evaporated and the
residue treated with dichloromethane and iced saturated
aqueous sodium hydrogen carbonate. The aqueous layer
was extracted with dichloromethane (3 · 30 mL). The
combined organic layers were washed with brine, dried
over Na2SO4 and concentrated to afford, after column
chromatography (1:5 fi 1:3 gradient, ether/hexane), the
monofluoro compound 33 (0.025 g, 23%; corresponding
to 25% from converted substrate) and a mixture of the
unreacted starting material 22 and (1R and 1S)-2,5-
2
2
80.9 (d, JC2;F ¼ 26:9, C-2), 80.4 (d, JC5;F ¼ 17:6, C-5),
2
79.6 (d, JC3;F ¼ 16:2, C-3), 73.8 and 72.7 (CH2Ph), 68.3
3
(d, JC6;F ¼ 10:3, C-6), and 57.4 (s, OMe). HMBC cor-
relations: C-1/OCH3 and H-1/OCH3.
(b) From 20: DAST (165 lL, 1.24 mmol) was dropped to
a solution of compound 20 (0.093 g, 0.249 mmol) in dry
dichloromethane (4.8 mL) at 0 ꢁC under argon. After a
few minutes, the cooling bath was removed and the
mixture heated to reflux for 2 h. After dilution with iced
saturated aqueous sodium hydrogen carbonate (70 mL),
the aqueous layer was extracted with dichloromethane
(3 · 30 mL). The combined organic layers were washed
with brine (70 mL), dried over Na2SO4, and concen-
trated, to afford, after column chromatography (1:8
ether/hexane), unreacted starting material (0.037 g,
indicating 60% of conversion) and a 1.9:1.0 (by 1H
NMR) epimeric mixture 31a and b (0.039 g, 41%, cor-
responding to 65% yield from converted substrate).
anhydro-3-azido-3,4-dideoxy-1,4-difluoro-1-O-methyl-D-
talitols 34a and b (0.055 g, in the ratio 1:4.5 22:34 by 1H
NMR, indicating 91% of conversion and 63% yield of
34a and b from converted substrate). In order to isolate
and characterize the ring-contracted products, the above
mixture 22 and 34, dissolved in dichloromethane
(330 lL) and dry pyridine (33 lL), was treated with
DMAP (1.5 mg) and tert-butyl-chloro-diphenylsilane
(75 lL) under the conditions indicated above to prepare
compound 27. Column chromatography (1:1 ether/
hexane) of the resulting reaction mixture afforded a
fraction containing only the epimers 35a and b (0.050 g,
1.2:1 by 1H NMR) and a second fraction contain-
ing unreacted mixture 22 and 34 (0.020 g, 1:1 by
1H NMR).
5.8. 2,5-Anhydro-3,6-di-O-benzyl-4-deoxy-4-fluoro-alde-
hydo-D-talose, 32
A sample of (1R and 1S)-2,5-anhydro-3,6-di-O-benzyl-
4-deoxy-1,4-difluoro-1-O-methyl- -talitols 31a and b
D
(0.100 g, 265 mmol) was treated at room temperature
with 9:1 trifluoroacetic acid/water (2 mL) for 1 h. The
mixture was poured onto ice-water (100 mL) and
extracted with dichloromethane (3 · 20 mL). The com-
bined organic layers were washed with saturated aque-
ous sodium hydrogen carbonate, dried over Na2SO4,
and concentrated, to afford pure 32 (0.835 g, 92%) as a
syrup. The analytical sample, obtained by column
Compound 33: Solid; mp: 56–60 ꢁC; Rf 0.44 (1:3 ether/
22
hexane); ½aŠ ¼ +60.8 (c 0.53, acetone); IR (KBr) mmax
D
2108 (N3) and 980 cmÀ1 (CF); 1H NMR (300 MHz,
CD3COCD3) d 7.49–7.36 (m, 5H; Ph), 5.81 (s, 1H, CH-
Ph), 4.91 (dd, 1H, 3J1;F ¼ 7:8, J1;2 ¼ 1:7, H-1), 4.78 (ddd,
2
1H, J2;F ¼ 48:2, J2;3 ¼ 2:3, H-2), 4.27 (dd, 1H,
0
J6;6 ¼ 11:7, J5;6 ¼ 1:7, H-6), 4.12 (ddd, 1H, J3;4 ¼ 10:6,
4
3
J4;5 ¼ 9:0, J4;F ¼ 1:6, H-4), 3.92 (ddd, J3;F ¼ 29:0,
H-3), 3.89–3.83 (MHz, 2H, H-5 and H-60), and 3.44 (s,
3H, OMe); 13C NMR (75.8 MHz, CD3COCD3) d 138.8–
chromatography (3:1 ether/hexane), had Rf 0.54 (ether);
22
D
½aŠ ¼ +29.6 (c 1.02, acetone); IR (film) mmax 1728 (CO),
1128, 1051 (C–O–C), and 988 cmÀ1 (CF); 1H NMR
2
127.2 (Ph), 102.5 (CH-Ph), 99.5 (d, JC1;F ¼ 31:0, C-1),
(500 MHz, CDCl3) d 9.68 (d, 1H, J1;2 ¼ 1:5, CHO),
1
89.8 (d, JC2;F ¼ 180:0, C-2), 74.6 (C-4), 69.2 (C-6), 64.9
2
7.35–7.24 (m, 10H, 2 Ph), 4.99 (ddd, J4;F ¼ 53:9,
2
(C-5), 59.7 (d, JC3;F ¼ 16:6), and 55.7 (OMe); HRC-
J3;4 ¼ 3:4, J4;5 ¼ 2:3, H-4), 4.70 and 4.63 (2d,
IMS: m=z 310.1207 (calcd for C14H16FN3O4+H:
310.1203).
0
0
JH;H ¼ 11:8, CH2Ph), 4.59 and 4.53 (2d, JH;H ¼ 12:0,
CH2Ph), 4.42 (ddd, J2;3 ¼ 8:4, 4J2;F ¼ J2;CHO ¼ 0:7, H-2),
3
0
4.22 (dddd, J5;F ¼ 28:9, J5;6 ¼ J5;6 ¼ 6:3, H-5), 4.10
Epimeric mixture 35a and b (69% from converted sub-
strate 34a and b): Syrup; Rf 0.49 (1:9 ether/hexane); IR
(film) mmax 2110 (N3), 990 (CF) and 704 cmÀ1 (CSi);
HRCIMS: m=z 462.2030 (calcd for C23H29F2N3O3Si+H:
462.2024).
3
0
(ddd, J3;F ¼ 22:3, H-3), 3.77 (dd, J6;6 ¼ 9:9, H-6), and
3.71 (ddd, J6 ;F ¼ 2:2, H-60); NOE contacts (1D NO-
4
0
ESY): H-5, H-4, H-3; 13C NMR (125.7 MHz, CDCl3)
d 199.6 (CHO), 137.8–127.8 (Ph), 89.5 (d, 1JC4;F ¼ 192:6,
2
C-4), 83.8 (C-2), 80.2 (d, JC5;F ¼ 23:5, C-5), 78.7 (d,
2JC3;F ¼ 16:8, C-3), 73.7 and 72.7 (CH2Ph), and 67.1 (d,
3JC6;F ¼ 10:8, C-6); HREIMS: m=z 344.1431 (calcd for
C20H21FO4: 344.1424).
Major epimer: 1H NMR (500 MHz, CD3COCD3)
2
d 7.72–7.43 (m, 10H, 2 Ph), 5.44 (dd, 1H, J1;F ¼ 67:0,
J1;2 ¼ 3:5, H-1), 5.17 (ddd, 1H, 2J4;F ¼ 54:5,
3
J3;4 ¼ J4;5 ¼ 4:5, H-4), 4.51 (ddd, 1H, J3;F ¼ 22:0,
J2;3 ¼ 6:0, H-3), 4.24 (ddd, 1H, 3J5;F ¼ 19:5,
J5;6 ¼ J5;6 ¼ 4:5, H-5), 4.00 (ddd, 1H, 3J2;F ¼ 15:5, H-2),
0
5.9. Methyl 3-azido-4,6-O-benzylidene-2,3-dideoxy-2-
3.84 (dd, 2H, J6 and 6 ;F ¼ 3:0, H-6 and H-60), 3.61 (d, 3H,
0
fluoro-a-
anhydro-3-azido-6-O-tert-butyl-diphenylsilyl-3,4-dide-
oxy-1,4-difluoro-1-O-methyl- -talitols, 35a and b
D
-mannopyranoside, 33, and (1R and 1S)-2,5-
4JOMe;F ¼ 1:5, OMe), and 1.05 (s, 9H, CMe3); 13C
D
NMR(127.5 MHz, CD3COCD3) d 136.3–128.7 (m, 2Ph),
1
1
112.0 (d, JC1;F ¼ 220:3, C-1), 97.3 (d, JC4;F ¼ 186:0,
2
2
A
solution of methyl 3-azido-4,6-O-benzylidene-3-
-glucopyranoside25 22 (109 mg, 0.355 mmol)
C-4), 83.2 (d, JC5;F ¼ 24:7, C-5), 82.7 (d, JC2;F ¼ 20:5,
2
3
deoxy-a-
D
C-2), 66.2 (d, JC3;F ¼ 25:3, C-3), 63.7 (d, JC6;F ¼ 4:9,
C-6), 57.6 (OMe), 27.1 (CMe3), and 19.7 (CMe3).
in dry acetonitrile (6.5 mL), cooled at 0 ꢁC, was treated

440
Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 15 (2004) 429–444
Minor epimer: 1H NMR (500 MHz, CD3COCD3)
(C-4), 68.3 (C-6), 66.0 (d, 3JC5;F ¼ 2:4, C-5), 60.2 (OMe),
2
3
d 7.72–7.43 (m, 10H, 2 Ph), 5.38 (dd, 1H, J1;F ¼ 66:0,
and 58.5 (d, JC3;F ¼ 2:4, C-3); HRCIMS: m=z 310.1191
J1;2 ¼ 5:5, H-1), 5.16 (ddd, 1H, 2J4;F ¼ 54:5,
(calcd for C14H16FN3O4+H: 310.1203). Epimeric mix-
ture 35a and b had identical properties, respectively, to
those of the product obtained from 22.
3
J3;4 ¼ J4;5 ¼ 4:5, H-4), 4.51 (ddd, 1H, J3;F ¼ 22:0,
J2;3 ¼ 6:0, H-3), 4.24 (ddd, 1H, 3J5;F ¼ 19:5,
J5;6 ¼ J5;6 ¼ 4:5, H-5), 4.00 (ddd, 1H, 3J2;F ¼ 15:5, H-2),
0
3.84 (dd, 2H, J6 and 6 ;F ¼ 3:0, H-6 and H-60), 3.62 (d, 3H,
0
4JOMe;F ¼ 1:5, OMe), and 1.05 (s, 9H, CMe3); 13C NMR
5.11. Methyl 3-azido-4,6-O-benzylidene-2,3-dideoxy-2-
(127.5 MHz, CD3COCD3) d 136.3–128.7 (m, 2Ph), 112.6
fluoro-a-
ene-3-deoxy-2-O-methyl-b-
and methyl 2-azido-4,6-O-benzylidene-2,3-dideoxy-3-flu-
oro-a- -glucopyranoside, 39
D
-altropyranoside, 37, 3-azido-4,6-O-benzylid-
1
1
(d, JC1;F ¼ 219:3, C-1), 97.4 (d, JC4;F ¼ 185:4, C-4),
D
-allopyranosyl fluoride, 38,
2
2
83.0 (d, JC5;F ¼ 24:7, C-5), 82.6 (d, JC2;F ¼ 20:9, C-2),
2
3
66.7 (d, JC3;F ¼ 21:2, C-3), 63.9 (d, JC6;F ¼ 5:4, C-6),
57.7 (OMe), 27.1 (CMe3), and 19.7 (CMe3).
D
DAST (223 lL, 1.69 mmol) was added to a solution of
methyl 3-azido-4,6-O-benzylidene-3-deoxy-a- -altro-
D
5.10. 3-Azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-a-
pyranoside26 24 (0.104 g, 0.337 mmol) in dry acetonitrile
(6.2 mL), and the mixture refluxed for 1 h. The solvent
was evaporated and the residue treated with dichloro-
methane and iced saturated aqueous sodium hydrogen
carbonate (75 mL); the organic layer was washed with
brine, dried and Na2SO4, and concentrated to afford a
crude product. After column chromatography (4:1
hexane/ethyl acetate), three products were isolated: 37
(0.0585 g, 56%), 38 (0.0304 g, 29%), and 39 (0.0149 g,
14%).
D
-mannopyranosyl fluoride, 36, and (1R and 1S)-2,5-
anhydro-3-azido-6-O-tert-butyl-diphenylsilyl-3,4-dide-
oxy-1,4-difluoro-1-O-methyl- -talitols, 35a and b
D
DAST (197 lL, 1.490 mmol) was added to a cooled
solution of 3-azido-4,6-O-benzylidene-3-deoxy-b-
D
-
glucopyranoside 2325 (91.6 mg, 0.298 mmol) in dry
acetonitrile (5.4 mL); after a few minutes, the cooling
bath was removed and the mixture heated to reflux for
15 h. After removing the solvent, the mixture was
treated with dichloromethane and iced saturated aque-
ous sodium hydrogen carbonate and the aqueous layer
extracted with dichloromethane (3 · 30 mL). The com-
bined organic layers were washed with brine, dried over
Na2SO4 and concentrated to afford, after column
chromatography (1:4 fi 1:2 gradient, ether/hexane),
compound 36 (0.037 g, 40%; corresponding to 66% from
converted substrate) and a mixture of unreacted starting
material 23 and (1R and 1S)-2,5-anhydro-3-azido-3,4-
Compound 37: Solid; mp: 112–116 ꢁC; Rf 0.45 (4:1
22
hexane/ethyl acetate); ½aŠ ¼ +40.8 (c1, acetone); IR
D
1
(KBr) mmax 2106 (N3) and 1053 cmÀ1 (CF); H NMR
(500 MHz, CD3COCD3) d 7.51–7.36 (m, 5H, Ph), 5.76
3
(s, 1H, CH-Ph), 4.78 (br d, 1H, J1;F ¼ 11:6, H-1), 4.68
2
(ddd, 1H, J2;F ¼ 43:1, J2;3 ¼ 2:8, J2;1 ¼ 1:0, H-2), 4.40
3
(ddd, 1H, J3;F ¼ 9:6, J3;4 ¼ 2:9, H-3), 4.28 (dd, 1H,
0
J6;6 ¼ 9:6, J5;6 ¼ 4:5, H-6), 4.16–4.11 (m, 2H, H-4 and
H-5), 3.80 (dd, 1H, J6 ;5 ¼ 9:6, H-60), and 3.40 (s, 3H,
0
dideoxy-1,4-difluoro-1-O-methyl-
D
-talitols 34a and b
OMe); 13C NMR (125.7 MHz, CD3COCD3) d 138.8–
(0.048 g, in the ratio 2.7:1 23:34 by 1H NMR, indicating
61% of conversion and 32% yield of 34 from converted
substrate). In order to isolate the ring-contracted prod-
ucts, the above mixture 23 and 34, dissolved in dichlo-
romethane (330 lL) and dry pyridine (33 lL) was treated
with DMAP (1.5 mg) and tert-butyl-chloro-diphenylsi-
lane (75 lL) under the conditions indicated above to
prepare compound 27. Column chromatography (1:1
ether/hexane) of the resulting reaction mixture afforded
a fraction containing only the epimers 35a and b
(0.010 g, 60% from converted substrate 34a and b, epi-
127.2 (m, Ph), 102.7 (CH-Ph), 99.1 (d, 2J1;F ¼ 33:9, C-1),
1
88.5 (d, J1;F ¼ 172:2, C-2), 76.2 (C-4), 69.4 (C-6), 59.7
2
(C-5), 58.2 (d, J2;F ¼ 28:9, C-3), and 55.7 (OMe);
HRCIMS: m=z 310.1196 (calcd for C14H16FN3O4+H:
310.1203).
Compound 38: Amorphous material; Rf 0.39 (4:1 hex-
23
D
ane/ethyl acetate); ½aŠ ¼ )83.5 (c 0.9, acetone); IR
(film) mmax 2103 (N3) and 993 cmÀ1 (CF); 1H NMR
(300 MHz, CD3COCD3) d 7.50–7.36 (m, 5H, Ph), 5.67
2
(s, 1H, CH-Ph), 5.40 (dd, 1H, J1;F ¼ 53:4, J1;2 ¼ 7:3,
1
meric ratio 1.1:1.0 by H NMR) and a second fraction
containing unreacted mixture 23 and 34 (0.040 g, 7:1 by
H-1), 4.68 (dd, 1H, J3;4 ¼ 5:8, J2;3 ¼ 3:2, H-3), 4.30 (dd,
0
1H, J6;6 ¼ 10:0, J5;6 ¼ 4:8, H-6), 3.94–3.84 (m, 2H, H-4
1H NMR).
and H-5), 3.78 (dd, 1H, J5;6 ¼ 10:0, H-60), 3.53 (d, 3H,
0
5JMe;F ¼ 0:7, OMe), and 3.52 (ddd, 1H, J2;F ¼ 12:7,
3
Compound 36: Amorphous material; Rf 0.46 (1:2 ether/
H-2); 13C NMR (75.8 MHz, CD3COCD3) d 138.5–127.1
25
D
1
hexane); ½aŠ ¼ )23.4 (c 0.82, acetone); IR (film) mmax
(m, Ph), 109.1 (d, J1;F ¼ 214:5, C-1), 102.4 (CH-Ph),
2108 (N3) and 978 cmÀ1 (CF); 1H NMR (300 MHz,
80.0 (d, 2J2;F ¼ 21:2, C-2), 77.3 (C-4), 69.0 (C-6), 64.9 (d,
3
CDCl3) d 7.48–7.33 (m, 5H, Ph), 5.65 (s, CH-Ph), 5.60
3J5;F ¼ 5:3, C-5), 61.2 (d, J3;F ¼ 9:8, C-3), and 58.4
2
(d, 1H, J1;F ¼ 49:5, J1;2 ¼ 1:5, H-1), 4.34 (dd, 1H,
(OMe); HRCIMS: m=z 310.1194 (calcd for
C14H16FN3O4+H: 310.1203).
0
J6;6 ¼ 10:1,
J6;5 ¼ 4:6,
H-6),
4.17
(dd,
1H,
0
J3;4 ¼ J4;5 ¼ 9:9, H-4), 3.98 (ddd, 1H, J5;6 ¼ 9:7, H-5),
3.84 (ddd, 1H, J6 ;F ¼ 1:1, H-60), 3.83 (ddd, 1H,
Compound 39: Amorphous material; Rf 0.34 (4:1 hex-
5
0
23
D
J2;3 ¼ 3:3, 4J3;F ¼ 1:6, H-3), 3.69 (ddd, 1H, J2;F ¼ 1:0, H-
ane/ethyl acetate); ½aŠ ¼ +63.2 (c 0.94, acetone); IR
2), and 3.59 (s, 3H, OMe); 13C NMR (125.7 MHz,
(film) mmax 2106 (N3) and 991 cmÀ1 (CF); 1H NMR
(300 MHz, CD3COCD3) d 7.48–7.36 (m, 5H, Ph), 5.70
1
CDCl3) d 136.7–125.9 (m, Ph), 105.1 (d, JC1;F ¼ 225:4,
2
4
C-1), 101.7 (CH-Ph), 78.2 (d, JC2;F ¼ 35:8, C-2), 75.9
(s, 1H, CH-Ph), 4.99 (dd, 1H, J1;F ¼ J1;2 ¼ 3:4, H-1),

Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 15 (2004) 429–444
441
2
4.85 (ddd, 1H, J3;F ¼ 54:9, J3;4 ¼ 9:7, J2;3 ¼ 9:0, H-3),
(OMe), 51.4 (C-3), and 23.7 (COMe); HRCIMS: m=z
349.1509 (calcd for C16H20N4O5+H: 349.1512).
5
0
4.27 (ddd, 1H, J6;6 ¼ 9:0, J5;6 ¼ 3:7, J6;F ¼ 2:1, H-6),
3
3.92 (ddd, 1H, J4;F ¼ 20:0, J4;5 ¼ 12:1, H-4), 3.85–3.80
(m, 2H, H-5 and H-60), 3.73 (ddd, 1H, 3J2;F ¼ 11:3, H-2),
and 3.45 (s, 3H, OMe); 13C NMR (75.8 MHz,
CD3COCD3) d 138.5–127.1 (m, Ph), 102.2 (CH-Ph),
5.13. Methyl 3-azido-6-O-tert-butyl-diphenylsilyl-2,3,4-
trideoxy-4-fluoro-a-
and methyl 3-azido-6-O-tert-butyl-diphenylsilyl-2,3,4-tri-
deoxy-4-fluoro-a- -threo-hex-2-enopyranoside, 43
D
-erythro-hex-2-enopyranoside, 42,
3
1
100.5 (d, J1;F ¼ 8:3, C-1), 89.9 (d, J3;F ¼ 187:2, C-3),
2
80.1 (d, J4;F ¼ 17:4, C-4), 69.1 (C-6), 63.0 (d,
D
3J5;F ¼ 7:6, C-5), 62.7 (d, J2;F ¼ 17:4, C-2), and 55.7
2
(OMe); HRCIMS: m=z 310.1190 (calcd for
C14H16FN3O4+H: 310.1203).
DAST (137 lL, 1.04 mmol) was added to an ice-cooled
solution of methyl 3-azido-6-O-tert-butyl-diphenylsilyl-
3-deoxy-a-D-altropyranoside 27 (0.094 g, 0.207 mmol) in
dry dichloromethane (3.8 mL). After a few minutes, the
cooling bath was removed and the mixture refluxed for
2 h. After dilution with iced saturated aqueous sodium
hydrogen carbonate (70 mL), the aqueous layer was
extracted with dichloromethane (3 · 30 mL). The com-
bined organic layers were washed with brine (70 mL),
dried over Na2SO4, and concentrated to afford, after
column chromatography (10:1 hexane/ethyl acetate), a
5.12. Methyl 2-azido-4,6-O-benzylidene-2,3-dideoxy-3-
fluoro-b-D-altropyranoside, 40, and methyl 3-acetamido-
2-azido-4,6-O-benzylidene-2,3-dideoxy-b-D-altropyrano-
side, 41
DAST (235 lL, 1.69 mmol) was added to a cold solution
of methyl 3-azido-4,6-O-benzylidene-3-deoxy-b-
1
D
-
1:1 mixture (by H NMR) of 42 and 43 (0.070 g, 77%),
which could be separated by TLC (40:1 hexane/ethyl
acetate, 4 runs).
altropyranoside27 25 (0.109 g, 0.355 mmol) in dry aceto-
nitrile (6.5 mL) and the mixture refluxed for 1.5 h. The
solvent was then evaporated and the residue treated with
dichloromethane and iced saturated aqueous sodium
hydrogen carbonate; the organic layer was washed with
brine, dried over Na2SO4, and concentrated to afford a
crude product. Column chromatography (10:1 hexane/
ethyl acetate) led to the separation of the unreacted
starting material 25 (0.026 g, indicating 76% of conver-
sion), the fluoro compound 40 (0.025 g, 23%, corre-
sponding to 31% yield from converted substrate), and
the Ritter reaction product 41 (0.039 g, 32%, corre-
sponding to 42% from converted substrate).
Compound 42: Syrup; Rf 0.45 (10:1 hexane/ethyl ace-
25
D
tate); ½aŠ ¼ )1.8 (c 0.67, acetone); IR (film) mmax 2114
(N3), 978 (CF), and 702 cmÀ1 (CSi); 1H NMR
(300 MHz, CD3COCD3) d 7.76–7.43 (m, 10H, 2 Ph),
2
5.58 (d, 1H, J1;2 ¼ 3:5, H-2), 5.29 (dd, 1H, J4;F ¼ 51:5,
J4;5 ¼ 8:8, H-4), 5.11 (d, 1H, H-1), 4.14 (ddd, 1H,
3
0
J5;6 and 6 ¼ 4:0, J5;F ¼ 13:4, H-5), 3.96 (dd, 2H,
J6 and 6 ;F ¼ 1:4, H-6 and H-60), 3.41 (s, 3H, OMe), and
4
0
1.06 (s, 9H, CMe3); 13C NMR (75.8 MHz, CD3COCD3)
d 136.4–128.6 (m, Ph), 134.0 (d, 2J3;F ¼ 13:6, C-3), 114.4
1
(C-2), 96.5 (C-1), 83.5 (d, J4;F ¼ 173:6, C-4), 70.9 (d,
2J5;F ¼ 24:3, C-5), 63.8 (C-6), 55.9 (OMe), 27.1 (CMe3),
and 19.8 (CMe3); HRCIMS: m=z 442.1968 (calcd for
C23H28FN3O3Si+H: 442.1962).
Compound 40: Amorphous material; Rf 0.56 (4:1 hex-
22
D
ane/ethyl acetate); ½aŠ ¼ )107.3 (c 1.14, acetone); IR
(film) mmax 2112 (N3) and 986 cmÀ1 (CF); 1H NMR
(500 MHz, CD3COCD3) d 7.49–7.34 (m, 5H, Ph), 5.71
4
(s, 1H, CH-Ph), 4.98 (dd, 1H, J1;F ¼ 2:7, J1;2 ¼ 1:7,
Compound 43: Syrup; Rf 0.43 (10:1 hexane/ethyl ace-
25
2
H-1), 4.91 (ddd, 1H, J3;F ¼ 49:7, J2;3 ¼ 3:7, J3;4 ¼ 1:7,
tate); ½aŠ ¼ )4.4 (c 0.60, acetone); IR (film) mmax 2110
D
(N3), 1055 (CF) and 702 cmÀ1 (CSi); 1H NMR
(500 MHz, CD3COCD3) d 7.76–7.44 (m, 10 H, 2 Ph),
5.71 (dd, 1H, J1;2 ¼ 4J2;F ¼ 3:3, H-2), 5.12 (dd, 1H,
0
H-3), 4.31 (dd, 1H, J6;6 ¼ 9:8, J6;5 ¼ 4:4, H-6), 4.21
3
(ddd, 1H, J2;F ¼ 7:5, H-2), 3.89–3.78 (m, 3H, H-4, H-5
and H-60), and 3.55 (s, 3H, OMe); 13C NMR
2
5J1;F ¼ 3:5, H-1), 4.91 (dd, 1H, J4;F ¼ 49:9, J4;5 ¼ 2:0,
(125.7 MHz, CD3COCD3) d 138.7–127.2 (m, Ph), 102.8
1
3
(CH-Ph), 100.9 (C-1), 88.6 (d, J3;F ¼ 181:0, C-3), 75.6
0
H-4), 4.29 (dddd, 1H, J5;F ¼ 30:3, J5;6 ¼ J5;6 ¼ 6:5, H-
2
3
(d, J4;F ¼ 16:3, C-4), 69.3 (C-6), 64.5 (d, J5;F ¼ 2:5,
0
5), 4.00 (dd, 1H, J6;6 ¼ 10:3, H-6), 3.88 (ddd, 1H,
2
J6 ;F ¼ 1:7, H-60), 3.37 (s, 3H, OMe) and 1.06 (s, 9H,
4
C-5), 61.6 (d, J2;F ¼ 26:4, C-2), and 57.4 (OMe);
0
CMe3); 13C NMR (125.7 MHz, CD3COCD3) d 136.7 (d,
HRCIMS: m=z 310.1191 (calcd for C14H16FN3O4+H:
310.1203).
2J3;F ¼ 15:1, C-3), 136.3–128.7 (m, 2Ph), 116.0 (d,
3J2;F ¼ 7:5, C-2), 96.2 (C-1), 82.2 (d, J4;F ¼ 178:5, C-4),
1
71.1 (d, 2J5;F ¼ 17:6, C-5), 62.9 (d, 3J6;F ¼ 7:5, C-6), 55.7
(OMe), 27.1 (CMe3), and 19.7 (CMe3); HRCIMS: m=z
442.1972 (calcd for C23H28FN3O3Si+H: 442.1962).
Compound 41: Syrup; Rf 0.37 (1:1 hexane/ethyl acetate);
24
D
½aŠ ¼ )54.6 (c 0.80, acetone); IR (film) mmax 3304 (NH),
1
2106 (N3), 1695 (CO) and 1353 cmÀ1 (NCO); H NMR
(300 MHz, CDCl3) d 7.50–7.37 (m, 5H, Ph), 5.71 (br,
1H, NH), 5.62 (s, 1H, CH-Ph), 4.75 (d, 1H, J1;2 ¼ 1:2,
H-1), 4.44 (dd, 1H, J2;3 ¼ 3:0, H-2), 4.39 (dd, 1H,
5.14. Reaction of methyl 3,6-dideoxy-a- -xylo-hexopyr-
anoside, 30, with DAST
D
0
J5;6 ¼ 4:9, J6;6 ¼ 10:3, H-6), 4.20 (m, 1H, H-3), 4.05 (dd,
0
1H, J4;5 ¼ 9:9, J3;4 ¼ 4:5, H-4), 3.88 (dd, 1H, J5;6 ¼ 10:0,
H-60), 3.69 (ddd, 1H, H-5), 3.56 (s, 3H, OMe), and 2.03
(s, 3H, COMe); 13C NMR (125.7 MHz, CDCl3) d 171.5
(CO), 129.1–127.7 (m, Ph), 101.8 (CH-Ph), 100.1 (C-1),
73.3 (C-4), 68.9 (C-6), 65.0 (C-5), 59.7 (C-2), 57.2
DAST (410 lL, 3.09 mmol) was added to a solution of
methyl 3,6-dideoxy-a- 30
-xylo-hexopyranoside29
(0.100 g, 0.617 mmol) in dry dichloromethane (4.4 mL)
D
cooled at 0 ꢁC, under argon. After 15 min, the cooling

442
Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 15 (2004) 429–444
3
bath was removed and the mixture refluxed for 1 h. The
solvent was evaporated and the residue treated with
dichloromethane and iced saturated aqueous sodium
hydrogen carbonate (75 mL); the organic layer was
washed with brine, dried over Na2SO4, and concen-
trated to afford a crude product. After column chro-
matography (3:1 to 1:1 gradient hexane/ether), an
almost pure product was isolated to which the tentative
structure of (1R or 1S)-4,5-anhydro-2,3,6-trideoxy-1,2-
J4;5 ¼ 7:0, H-4), 4.78 (dd, 1H, J2;F ¼ 9:1, H-2), 4.61
2
0
(ddd, 1H, J6;F ¼ 47:6, J5;6 ¼ 2:7, J6;6 ¼ 10:7, H-6), 4.51
(ddd, 1H, 2J6 ;F ¼ 46:6, J5;6 ¼ 3:7, H-60), 4.00 (dddd, 1H,
3J5;F ¼ 25:4, H-5), 3.59 (s, 3H, MeO), and 1.70 (d, 3H,
5JMe;F ¼ 1:6, Me-3); NOE contacts (1D NOESY): Me-3,
H-1, H-5; 13C NMR (125.7 MHz, CDCl3) d 110.9 (d,
0
0
1J1;F ¼ 226:3, C-1), 94.9 (C-3), 82.4 (d, J5;F ¼ 20:1, C-
2
1
2
5), 81.6 (d, J6;F ¼ 174:7, C-6), 81.4 (d, J2;F ¼ 25:1, C-
3
2), 76.2 (d, J4;F ¼ 6:3, C-4), 57.5 (MeO), and 13.8
difluoro-1-O-methyl-
D
-arabino-hexitol, 44 (0.0328 g,
(Me-3); HMBC correlations: H-1/OCH3 and C-1/OCH3.
32%) was assigned. Syrup; 1H NMR (500 MHz,
2
1
CD3COCD3) d 5.26 (ddd, 1H, J1;2 ¼ 4:7, J1;F1 ¼ 65:5,
Minor isomer: H NMR (500 MHz, CDCl3) d 5.28 (dd,
3J1;F2 ¼ 7:0, H-1), 4.44 (ddddd, 1H, J2;F2 ¼ 48:5,
1H, J1;2 ¼ 4:6, 2J1;F ¼ 64:0, H-1), 4.92 (d, 1H, J4;5 ¼ 7:8,
H-4), 4.76 (dd, 1H, 3J2;F ¼ 9:2, H-2), ꢀ4.61 (overlapped,
H-6), ꢀ4.51 (overlapped, H-60), 3.97 (m, 1H, H-5), 3.58
2
3J2;F1 ¼ J2;3a ¼ 9:1, J2;3b ¼ 4:0, H-2), 3.57 (d, 3H,
4JOMe;F1 ¼ 65:5, OMe), 2.66–2.63 (m, 1H, H-4), 2.11–
2.08 (m, 1H, H-5), 2.00–1.86 (m, 2H, H-3a and H-3b),
and 1.34 (d, 3H, J5;6 ¼ 7:0, Me-6); 13C NMR
(s, 3H, MeO), and 1.74 (d, 3H, JMe;F ¼ 0:9, Me-3); 13C
5
1
NMR (125.7 MHz, CDCl3) d 110.8 (d, J1;F ¼ 213:7,
1
2
(125.7 MHz, CD3COCD3) d 112.4 (dd, J1;F1 ¼ 219:6,
C-1), 94.0 (C-3), 82.2 (d, J5;F ¼ 22:6, C-5), 81.4 (d,
2J;F2 ¼ 28:3, C-1), 91.7 (dd, J2;F2 ¼ 173:0, J2;F1 ¼ 25:8,
1J6;F ¼ 174:7, C-6), 81.3 (d, J2;F ¼ 21:4, C-2), 76.2 (d,
1
2
2
2
C-2), 57.5 (OMe), 24.2 (d, J3;F2 ¼ 20:4, C-3), 38.2 (d,
3J4;F ¼ 6:3, C-4), 57.4 (MeO), and 13.5 (Me-3); HMBC
correlations: H-1/OCH3 and C-1/OCH3.
3J4;F2 ¼ 3:5, C-4), 30.3 (overlapped with the acetone
signal, C-5), and 14.3 (C-6).
5.15.2. Methyl 3,4,6-trideoxy-4,6-difluoro-3-C-methyl-3-
5.15. Reaction of DAST with the 3-C-methyl-3-nitro
sugar derivatives 7–11. General procedure14
nitro-b- -galactopyranoside, 12. Syrup; Rf 0.25 (1:2 ethyl
L
23
acetate/hexane); ½aŠ ¼ +4.7 (c 0.75, CHCl3); IR (film)
D
mmax 3480 (OH), 1556 and 1352 (NO2), and 1058 cmÀ1
(CF); 1H NMR (500 MHz, CDCl3) d 4.96 (d, 1H,
2J4;F ¼ 47:7, H-4), 4.60 (2ddd, 2H, 2J6;F ¼ 46:1, H-6 and
DAST (660 lL, 5 mmol; or 462 lL, 3.5 mmol, as indi-
cated in each case) was added to a solution of the
respective sugar derivative (1 mmol) in the solvent
indicated in each case, cooled at 0 ꢁC, under argon.
After 15 min, the cooling bath was removed and the
mixture allowed to warm to room temperature or heated
to reflux, under stirring, until either complete transfor-
mation of the substrate or until no further progress of
the reaction was observed (TLC monitoring, 2:1 or 1:1
ether/hexane). The mixture was poured onto iced satu-
rated aqueous sodium hydrogen carbonate (50 mL) and
the aqueous layer extracted with dichloromethane
(2 · 25 mL). The combined organic layers were washed
with brine (25 mL), dried over MgSO4 and concentrated.
Separation and purification of the new products were
achieved by column chromatography or preparative
TLC as indicated below for each substrate.
5
H-60), 4.52 (dd, 1H, J1;2 ¼ 7:9, J1;F ¼ 1:4, H-1), 4.35
4
3
(dd, 1H, J2;F ¼ 1:0, H-2), 4.00 (m, 1H, J5;F ¼ 27:2,
3J5;F ¼ 10:0, H-5), 3.61 (s, 3H, MeO), and 1.72 (d, 3H,
4JMe;F ¼ 1:3, Me-3); 13C NMR (125.7 MHz, CDCl3) d
2
102.2 (C-1), 90.4 (d, J3;F ¼ 17:7, C-3), 89.5 (dd,
3
1
1J4;F ¼ 189:2, J4;F ¼ 4:9, C-4), 79.9 (dd, J6;F ¼ 170:9,
3J6;F ¼ 6:3, C-6), 72.8 (C-2), 70.3 (dd, J5;F ¼ 25:0,
2
2J5;F ¼ 18:4, C-5), 57.4 (MeO), and 10.9 (Me-3); HRC-
IMS m=z 242.0842 (calcd for C8H13F2NO5+H:
242.0840), 210.0575 (calcd for C8H13F2NO5-OCH3:
210.0578).
(b) From methyl 4,6-O-benzylidene-3-deoxy-3-C-methyl-
-glucopyranoside13
3-nitro-b-
L
8
(0.326 g); DAST:
660 lL; solvent: dry dichloromethane (10 mL); temper-
ature: reflux for 2 h. The reaction afforded, after pre-
parative TLC (1:1 ether/hexane), the unreacted starting
material (0.148 g, indicating 59% of conversion) and a
(a) From methyl 3-deoxy-3-C-methyl-3-nitro-b-L-
glucopyranoside13;30 7 (0.237 g); DAST: 660 lL; solvent:
dry dichloromethane (10 mL); temperature: reflux for
2 h. The reaction afforded, after column chromatogra-
phy (1:4, ethyl acetate/hexane), two fractions; the first
1
1.2:1 (by H NMR) syrupy mixture (0.081 g, 25%, cor-
responding to 42% yield from converted substrate) of
the two epimeric compounds 46a and b; IR (film) 1556
and 1352 cmÀ1 (NO2), and 1058 cmÀ1 (CF); HREIMS:
m=z 327.1118 (calcd for C15H18FNO6–F: 327.1124).
1
one consisted of a 1.4:1 (by H NMR) syrupy mixture
(0.089 g, 37%) of the two epimeric compounds 45a
(major) and 45b; IR (film) mmax 3485 (OH), 1551 and
1354 (NO2), and 980 cmÀ1 (CF); HRCIMS: m=z
222.0781 (calcd for C8H13F2NO5–F: 222.0778), 210.0580
(calcd for C8H13F2NO5–OCH3: 210.0578); the other
fraction was pure methyl glycoside 12 (0.071 g, 30%).
5.15.3. (1R and 1S)-4,6-O-Benzylidene-2,5-anhydro-3-
deoxy-1-fluoro-3-C-methyl-1-O-methyl-3-nitro-L-manni-
tols, 46a and b. Major isomer: 1H NMR (500 MHz,
CDCl3) d 7.48–7.36 (m, 5H, Ph), 5.60 (s, 1H, CH-Ph),
5.31 (dd, 1H, J1;2 ¼ 5:0, 2J1;F ¼ 65:0, H-1), 4.66 (dd, 1H,
3
0
5.15.1. (1R and 1S)-2,5-Anhydro-3,6-dideoxy-1,6-diflu-
oro-3-C-methyl-1-O-methyl-3-nitro-
J2;F ¼ 12:5, H-2), 4.59 (dd, 1H, J5;6 ¼ 4:2, J6;6 ¼ 9:8, H-
0
L
-mannitols, 45a and
b. Major isomer: H NMR (500 MHz, CDCl3) d 5.26
6), 4.49 (d, 1H, J4;5 ¼ 9:9, H-4), 3.98 (dd, 1H, J5;6 ¼ 9:8,
1
4
H-60), 3.90 (ddd, 1H, H-5), 3.63 (d, 3H, JMeO;F ¼ 1:3,
2
5
(dd, 1H, J1;2 ¼ 4:5, J1;F ¼ 64:2, H-1), 4.91 (d, 1H,
MeO), and 1.84 (d, 3H, JMe;F ¼ 0:7, Me-3); 13C NMR

Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 15 (2004) 429–444
443
(125.7 MHz, CDCl3) d 136.1–126.3 (Ph), 110.1 (d,
(d) From phenyl 4,6-O-benzylidene-3-deoxy-3-C-methyl-
3-nitro-1-thio-a- 10 (0.403 g);
-glucopyranoside14
3
1J1;F ¼ 222:5, C-1), 102.2 (CH-Ph), 91.7 (d, J3;F ¼ 0:9,
D
2
C-3), 84.6 (C-4), 83.0 (d, J2;F ¼ 23:4, C-2), 72.1 (d,
DAST: 660 lL; solvent: dry dichloromethane (10 mL);
temperature: 0 ꢁC (0.5 h) to reflux (3 h). The reaction
afforded, after preparative TLC (1:1.5 ether/hexane), the
unreacted starting material (0.169 g, indicating 58% of
conversion) and compound 48 (0.038 g, 9.5%, corre-
sponding to 16% yield from converted substrate).
4J5;F ¼ 2:8, C-5), 71.1 (C-6), 57.3 (MeO), and 14.1
(d,4JMe;F ¼ 1:5, Me-3); HMBC correlations: H-1/OCH3
and C-1/OCH3.
Minor isomer: 1H NMR (500 MHz, CDCl3) d 7.48–7.36
(m, 5H, Ph), 5.60 (s, 1H, CH-Ph), 5.35 (dd,
1H,J1;2 ¼ 4:3, 2J1;F ¼ 64:0, H-1), 4.70 (dd, 1H,
3
0
J2;F ¼ 12:4, H-2), 4.59 (dd, 1H, J5;6 ¼ 4:4, J6;6 ¼ 9:8, H-
0
6), 4.48 (d, 1H, J4;5 ¼ 9:7, H-4), 3.96 (dd, 1H, J5;6 ¼ 9:9,
5.15.5.
nitro-2-phenylthio-b-
4,6-O-Benzylidene-2,3-dideoxy-3-C-methyl-3-
-glucopyranosyl fluoride, 48.
H-60), 3.88 (ddd, 1H, H-5), 3.63 (d, 3H, JMeO;F ¼ 1:3,
4
D
MeO), and 1.89 (d, 3H, JMe;F ¼ 1:3, Me-3); 13C NMR
5
Compound 48 showed physical and spectroscopic
properties identical, respectively, to those of 49 [see (e),
next paragraph], except for the rotatory power:
(125.7 MHz, CDCl3) d 136.1–126.3 (Ph), 110.6 (d,
1J1;F ¼ 222:5, C-1), 102.2 (CH-Ph), 91.5 (d, J3;F ¼ 2:8,
3
2
C-3), 84.5 (C-4), 82.8 (d, J2;F ¼ 26:5, C-2), 72.1 (d,
26
½aŠ ¼ )92.3 (C 0.65, acetone).
4J5;F ¼ 2:8, C-5), 71.1 (C-6), 57.5 (MeO), and 14.3
(d,4JMe;F ¼ 2:6, Me-3); HMBC correlations: H-1/OCH3
and C-1/OCH3.
D
(e) From phenyl 4,6-O-benzylidene-3-deoxy-3-C-me-
thyl-3-nitro-1-thio-a-L
-glucopyranoside14 11 (0.403 g);
DAST: 660 lL; solvent: dry dichloromethane (10 mL);
temperature: 0 ꢁC (0.5 h) to reflux (1 h). The reaction
afforded, after preparative TLC (1:1.5, ether/hexane),
unreacted starting material (0.118 g, indicative of 71% of
conversion) and the glycosyl fluoride 49 (0.139 g, 34%,
corresponding to 48% yield from converted substrate)
containing trace amounts of its a-anomer.
(c) From methyl 6-O-tert-butyldiphenylsilyl-3-deoxy-3-
-glucopyranoside13
C-methyl-3-nitro-b-
L
9
(0.476 g);
DAST: 660 lL; solvent: dry dichloromethane (10 mL);
temperature: reflux for 2 h. The reaction afforded, after
preparative TLC (1:1 ether/hexane), a 2.7:1 (by 1H
NMR) syrupy mixture (0.119 g, 25%) of the two epi-
meric compounds 47a and b; IR (film) mmax 3452 (OH),
1553 and 1363 (NO2), 1085 (CF), and 703 (CSi) cmÀ1
;
FABMS: m=z 500 (20, [M+Na]þ); HRFABMS: m=z
500.1879 (calcd for C24H32FNO6Si+Na: 500.1881).
5.15.6. 4,6-O-Benzylidene-2,3-dideoxy-3-C-methyl-3-ni-
tro-2-phenylthio-b-L-glucopyranosyl fluoride, 49. Syrup;
23
Rf 0.54 (1:1 ether/hexane); ½aŠ ¼ +84.5 (c 0.84, acetone);
D
IR (film) mmax 1557 and 1391 (NO2), and 1107 cmÀ1
(CF); 1H NMR (500 MHz, CD3COCD3) d 7.58–7.33 (m,
10H, 2Ph), 5.76 (s, 1H, CH-Ph), 5.75 (dd, 1H,
5.15.4. (1R and 1S)-6-O-tert-Butyldiphenylsilyl-2,5-anhy-
dro-3-deoxy-1-fluoro-3-C-methyl-1-O-methyl-3-nitro-L-
2J1;F ¼ 50:9, J1;2 ¼ 8:2, H-1), 4.48 (d, 1H, J4;5 ¼ 9:2, H-
mannitols, 47a and b. Major isomer: 1H NMR
(500 MHz, CDCl3) d 7.70–7.38 (m, 10H, 2Ph), 5.21 (dd,
1H, J1;2 ¼ 5:4, 2J1;F ¼ 65:4, H-1), 5.12 (d, 1H, J4;5 ¼ 7:2,
2
0
4), 4.39 (dd, H, J6;6 ¼ 9:1, J5;6 ¼ 4:0, H-6), 4.00–3.95
3
(m, 2H, H-5 and H-60), 3.91 (dd, 1H, J2;F ¼ 21, H-2),
3
and 1.87 (s, 3H, Me); NOE contacts: H-1/Me-3, H-1/H-
5 and H-2/H-4; 13C NMR (125.7 MHz, CD3COCD3) d
134.0–127.1 (2Ph), 110.2 (d, 1J1;F ¼ 212:4, C-1), 102.4 (C
H-4), 4.82 (dd, 1H, J2;F ¼ 9:8, H-2), 3.90 (dd, 1H,
0
J5;6 ¼ 3:8, J6;6 ¼ 11:2, H-6), 3.84 (m, 1H, H-5), 3.79 (dd,
1H, J5;6 ¼ 2:9, H-60), 3.57 (d, 3H, JMeO;F ¼ 1:1, MeO),
4
0
3
5
H-Ph), 92.5 (d, J3;F ¼ 7:6, C-3), 81.8 (C-4), 69.0 (C-6),
3.48 (br s, 1H, HO), 1.68 (d, 3H, JMe;F ¼ 0:4, Me-3),
66.3 (d, 3J5;F ¼ 5:0, C-5), 59.6 (d, 2J2;F ¼ 25:1, C-2), and
12.8 (Me); HREIMS m=z 405.1046 (calcd for
C20H20FNO5S: 405.1046); HMBC correlation: H-2/
and 1.09 (s, 9H, t-Bu); 13C NMR (125.7 MHz, CDCl3) d
1
135.6–127.7 (2Ph), 111.2 (d, J1;F ¼ 223:8, C-1), 93.9 (d,
3J3;F ¼ 6:4, C-3), 83.0 (C-5), 81.6 (d, J2;F ¼ 25:6, C-2),
2
(SPh)Cipso
.
77.4 (C-4), 63.1 (C-6), 57.2 (MeO), 26.7 (CMe3), 19.1
(CMe3), and 12.6 (Me-3); HMBC correlations: H-1/
OCH3 and C-1/OCH3.
Minor isomer: 1H NMR (500 MHz, CDCl3) d 7.70–7.38
2
(m, 10H, 2Ph), 5.26 (dd, 1H, J1;2 ¼ 5:2, J1;F ¼ 64:0, H-
1), 5.09 (d, 1H, J4;5 ¼ 7:9, H-4), 4.80 (dd, 1H, 3J2;F ¼ 7:6,
Acknowledgements
0
H-2), 3.93 (dd, 1H, J5;6 ¼ 3:7, J6;6 ¼ 11:3, H-6), 3.84 (m,
1H, H-5), 3.81 (dd, 1H, J5;6 ¼ 2:8, H-60), 3.60 (d, 3H,
We are grateful to the Direccion General de Investi-
ꢀ
0
ꢀ
gacion, Ministerio de Ciencia y Tecnologıa of Spain
4JMeO;F ¼ 1:3, MeO), 3.37 (br s, 1H, HO), 1.73 (d, 3H,
5JMe;F ¼ 0:9, Me-3), and 1.09 (s, 9H, t-Bu); 13C NMR
(125.7 MHz, CDCl3) d 135.6–127.7 (2Ph), 110.8 (d,
1J1;F ¼ 218:7, C-1), 93.5 (C-3), 82.4 (C-5), 81.2 (d,
2J2;F ¼ 29:7, C-2), 77.4 (C-4), 63.0 (C-6), 57.3 (MeO),
26.7 (CMe3), 19.1 (CMe3), and 12.7 (Me-3); HMBC
correlations: H-1/OCH3 and C-1/OCH3.
ꢀ
(grant no. BQU2000-1155), and the Direccion General
ꢀ
ꢀ
ꢀ
de Universidades e Investigacion, Consejerıa de Edu-
cacion y Ciencia of Andalusia (FQM 142), for financial
support. One of us (Y.V.-A.) thanks the Ministerio de
ꢀ
Educacion, Cultura y Deporte of Spain for a post-
graduate fellowship.
ꢀ

444
Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 15 (2004) 429–444
15. Vera-Ayoso, Y.; Borrachero, P.; Cabrera-Escribano, F.;
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