Efficient synthesis of multifunctional furanoid C-glycoamino acid precursors

Article abstract of DOI:10.1016/j.tetasy.2004.12.024

Ready access to constrained, multifunctionalized, hydrolytically stable amino acids has been established by the synthesis of their direct precursors using 2,5-anhydro-3-azido-3-deoxy-d-altrose (a 'formyl azido-C-glycofuranoside') , or its readily availabl

Full text of DOI:10.1016/j.tetasy.2004.12.024

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 889–897
Efficient synthesis of multifunctional furanoid C-glycoamino
acid precursors
Yolanda Vera-Ayoso, Pastora Borrachero, Francisca Cabrera-Escribano* and
´ ´
Manuel Gomez-Guillen
´ ´
Departamento de Quımica Organica ‘Profesor Garcıa Gonzalez’, Facultad de Quımica, Universidad de Sevilla,
´
Apartado de Correos No. 553, E-41071 Sevilla, Spain
´
´
Received 26 November 2004; accepted 15 December 2004
Abstract—Ready access to constrained, multifunctionalized, hydrolytically stable amino acids has been established by the synthesis
of their direct precursors using 2,5-anhydro-3-azido-3-deoxy-D-altrose (a Ôformyl azido-C-glycofuranosideÕ), or its readily available,
stable synthetic equivalent [(1R) and (1S)-2,5-anhydro-3-azido-4,6-O-benzylidene-3-deoxy-1-fluoro-1-O-methyl-D-altritol], as novel
molecular scaffolds.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
for two applications: as novel artificial proteins to study
the factors governing protein folding and stability,12 and
as chemically defined immunogens for vaccine develop-
ment.13,14 Enhanced activities of peptide inhibitors
were also obtained through multivalent peptide assem-
bly.15–20 Several types of cyclic molecules (cyclic pep-
tides, calix[4]arenes, cholic acid, and carbohydrates,
among others)21–24 have been used as templates for mul-
tivalent assembly, and it seems to be that the topology of
multivalent peptides can be controlled by the defined
spatial orientation of the functionalities on the rigid
scaffold core.25
The structural control of molecular assemblies using
peptide chains, which possess stereogenic centers and
hydrogen bonding sites, is considered to be a useful ap-
proach to artificial highly-ordered systems.1 Protein sec-
ondary structure such as a-helices, b-sheets, and b-turns
are important in inducing the three-dimensional struc-
ture and biological activity of proteins. Relatively short
oligomers of b- and c-amino acids, especially those of
conformationally restricted systems, have been shown
to adopt ordered secondary structures.2,3 In particular,
Fleet et al.4,5 have reported a number of peptidomimet-
ics and unnatural biopolymers adopting interesting sec-
ondary structures because of the carbohydrate-derived
tetrahydrofuran systems they contain. On their hand,
the SeebachÕs6,7 and GellmanÕs8–11 groups have found
that b-peptides are able to adopt defined three-dimen-
sional structures similar to those of natural peptides.
The unnatural b-peptide backbone is resistant to prote-
olysis,2 in contrast to a-amino acid backbone.
On the basis of our previous experience with formyl
nitro- and azido-C-glycofuranosides,26–28 we recently
started a project based on exploiting the potential of
these readily available compounds for the synthesis of
hydrolytically stable glycoamino acids (GAAs).
GAAs,29–31 which are carbohydrates bearing both an
amino group and a carboxyl group, are ideal building
blocks32 to generate peptidomimetics because of their
rigidity and multifunctionality. These compounds may
be (a) inserted in appropriate sites of small peptides,
providing the specific three-dimensional structures re-
quired for bonding to their receptors,33,34 (b) connected,
furnishing peptide-bond linked carbohydrates35 (carbo-
peptoids), or (c) exploited as templates for multivalent
peptide assembly. We now propose the use of formyl
azido-C-glycofuranosides I, readily available from their
synthetic equivalents II (Fig. 1), as molecular scaffolds
On the other hand, template-assembled multivalent pep-
tides have found wide applications in recent years. This
kind of molecules, in which several copies of a certain
peptide are attached to a cyclic core, has been developed
*
Corresponding author. Tel.: +34 95 455 7150; fax: +34 95 462
4960; e-mail: fcabrera@us.es
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.12.024

890
Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 16 (2005) 889–897
and a 1:3.3 mixture (73%) of the ring contracted, re-
HO
HO
O
O
arranged (1R)- and (1S)-2,5-anhydro-1-fluoro-1-O-
methyl-D-altritol derivatives 10a and 10b (Scheme 1).
Separation of these epimers was achieved by column
chromatography. This reaction is a new example of
the DAST-mediated rearrangement previously observed
in other equatorial-2-OH glycopyranosides.26 The H(1)/
F coupling constant values observed for 10a and 10b
(J = 68 Hz for 10a, and J = 63 Hz for 10b) are in the
range observed38 for ring-contracted products (J = 63–
68 Hz). Assignment of configuration to these epimers
was made on the basis of the H(2)/F coupling constant
value (J = 11.5 Hz for 10a, J = 3.1 Hz for 10b, suggest-
ing39 the H(2)/F gauche relationship in both cases, as
an anti one would lead to a J value of ꢀ20 Hz), and
the C(2)/F coupling constant value, lower for 10a
(J = 11.5 Hz) than for 10b (J = 32.7 Hz), in agreement39
with the F/ring O gauche and anti relationships, respec-
tively. This stereochemical difference has no effect in the
subsequent synthetic transformations to which the dia-
stereomeric 10a/10b mixture was subjected, leading to
products that lack stereogenic character at C(1).
CHO
OMe
H
N3
N3
F
I
II
Figure 1. ‘Formyl azido-C-glycofuranosideÕ scaffolds.
for C-glycoamino acids or precursors, that is, com-
pounds 1–4 (Fig. 2), which are rigid and multifunction-
alized compounds that may serve as differently shaped
(AB, A-spacer-B, AB2, and A2B) templates for attaching
peptides.
AcO
AcO
RO
RO
O
O
H
N
COOH
N3
N3
COOR
2 (R = Et, H)
1 (R = Ac, H)
AB template
A-Spacer-B template
N3
HO
HOOC
HO
O
COOH
O
O
Ph
O
Ph
a
O
O
O
O
COOH
N3
+
N3
N3
HO
OMe
9 (20%)
N3
OMe
3
4
8
AB2 template
A2B template
Figure 2. Azido-C-glycocarboxylic acids.
HO
HO
O
O
Ph
Ph
O
O
O
O
O
b
H
+
+
R
S
(83%)
N3
N3
N3
We describe herein the synthesis of one member of series
I, the 2,5-anhydro-3-azido-3-deoxy-D-altrose 5, and the
high-yielding preparation of 4,6-di-O-acetyl-2,5-anhy-
dro-3-azido-D-altronic acid 1 (R = Ac)36 and 4,6-di-O-
acetyl-2,5-anhydro-1-arylamino-3-azido-1,3-dideoxy-D-
altritol 2 (R = Et). The precursors 6 and 7 of compounds
3 and 4 have also been successfully obtained. Com-
pound 5 provides three points of diversification, indi-
cated by bold arrows in the formula, with orthogonal
chemical reactivity.
CHO
F
OMe
H
H
F
OMe
(1/3.3)
5
10a,b (73%)
d
c
(93%)
(94%)
e
AcO
AcO
HO
HO
AcO
AcO
O
O
O
(90%)
OMe
OMe
11
OMe
OMe
12
N3
CHO
N3
N3
13
Scheme 1. Reagents and conditions: (a) DAST, MeCN, reflux
(12 min). (b) PTSA, acetone, rt (1 h). (c) MeOH, PTSA, rt (1 h). (d)
i. MeOH, PTSA, rt (1 h); ii. Ac2O, Py, 0 ꢁC. (e) 9:1 TFA/H2O, rt (1 h).
HO
HO
O
N3
CHO
When the 10a,b mixture was treated in acetone with p-
toluenesulfonic acid (PTSA) at room temperature for
1 h, usual work-up led to the crude aldehydo-sugar 5
in 83% yield, pure enough to be used for further trans-
formation, but unstable to be purified by column chro-
5
HOOC
BnO
N3
HO
O
O
OMe
OMe
OMe
OMe
N3
N3
1
matography. Crude product 5 showed in its H NMR
6
7
spectrum a signal at d 9.51 ppm, assigned to the formyl
proton. The same 10a,b mixture was transformed, by the
action of PTSA and methanol, into the 4,6-O-deprotec-
ted dimethyl acetal 11 in high yield (93%), the structure
of which being deduced from its high-resolution mass
spectrum and the appearance of signals for two methyl
2. Results and discussion
The known37 methyl 3-azido-4,6-O-benzylidene-3-
deoxy-a-D-allopyranoside 8, treated with diethylamino-
sulfur trifluoride (DAST) in refluxing acetonitrile for
12 min, gave a mixture of the 2-enopyranoside 9 (20%)
1
groups in its H and 13C NMR spectra. When the fore-
going reaction was performed without purifying the
product, and this was subjected to standard acetylation

Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 16 (2005) 889–897
891
conditions, the 4,6-di-O-acetyl derivative 12 (94% after
column chromatography) was obtained, thus corrobo-
rating the presence of two hydroxyl groups in 11 and,
hence, in 5. Treatment of 12 with 9:1 trifluoroacetic
acid/water afforded 90% of crude 13, a sample of which
was purified by column chromatography and showed in
chloride in pyridine at ꢁ25 ꢁC, the 6-O-tosyl 15 and
the 4,6-di-O-tosyl 16 derivatives were obtained in 60%
and 10% yields, respectively. The latter is the 4,6-di-O-
tosyl derivative, as evidenced by the MS and NMR spec-
tra (four doublets, each for two protons, at d 7.59, 7.52,
7.41, and 7.32 ppm), while the unique tosyl group of the
former is located at O-6, giving rise to a broadening of
the C(4)H signal by the additional coupling with the hy-
droxyl proton, and to the expected shift of this signal to
lower d value (4.36 ppm) in comparison with that of 16
(4.94 ppm). Compound 15, treated with sodium azide in
dimethylformamide at 110 ꢁC for 3 h, led to the 3,6-
diazido compound 6 (95% yield after column chroma-
tography), whose structure was confirmed by its high-
resolution MS and the absence of aromatic signals in
its NMR spectra; 6 is a precursor of 2,5-anhydro-3,6-
diazido-3,6-dideoxy-D-altronic acid 4.
1
its H NMR spectrum the formyl proton signal as a
doublet (J 1.5 Hz) at d 9.63 ppm, as well as the two
acetyl proton singlets at d 2.17 and 2.11 ppm, and in
its 13C NMR spectrum, three carbonyl carbon signals
(d 199.2 ppm for the aldehydic one; 170.6 and
170.3 ppm for the two ester carbonyl carbons).
Scheme 2 shows the synthesis of AB and A-spacer-B
templates. Hydrolysis of 12 with 9:1 trifluoroacetic acid
(TFA)/water, followed by oxidation with aqueous
sodium dichromate/sulfuric acid (JonesÕ reagent), gave
the 4,6-di-O-acetyl-b-azido acid 1 in 65% yield (Scheme
2). Reductive amination of 13 was achieved starting
from 12 as above and treating crude 13 with ethyl p-ami-
nobenzoate and sodium triacetoxy-borohydride, to give
4,6-di-O-acetyl-2,5-anhydro-3-azido-1,3-dideoxy-1-[(4-
ethoxycarbonylphenyl)amino]-D-altritol (2, R = Et, 47%
after column chromatography) accompanied by 34% of
the primary alcohol 14. Last product may be useful for
obtaining an additional amount of 1 by oxidation with
JonesÕ reagent. Compound 1 showed in the 13C NMR
spectrum three carbonyl carbon signals, among them
that of highest d value (172.0 ppm) being assigned to
TsO
HO
TsO
TsO
O
O
a
10a,b
+
OMe
OMe
15 (60%)
OMe
OMe
16 (10%)
N3
N3
b
(95%)
N3
O
HO
OMe
OMe
N3
1
the carboxyl carbon. The H NMR spectrum of com-
pound 2 showed two doublets at d 7.78 and 6.71 ppm,
each for two aromatic protons, two signals for the two
C(1) diastereotopic protons at d 3.57 and 3.40 ppm,
and a broad signal at d ꢀ 5.6 ppm assigned to the amine
proton, as well as the typical quartet/triplet signal tan-
dem for the O-ethyl protons of an ester; corresponding
signals in the 13C NMR spectrum and the high-resolu-
tion mass spectrum corroborated the proposed struc-
ture. Compound 14 had NMR spectra showing a
broad OH-proton signal at d ꢀ 1.95 ppm and signals
for the two C(1) protons (doublet at d 3.82 ppm) and
for the C(1) nucleus (d 62.0 ppm), but lacking any signal
assignable to aromatics.
6
Scheme 3. Synthesis of an AB2 template precursor. Reagents and
conditions: (a) i. MeOH, PTSA, rt (1 h); ii. TsCl, Py, ꢁ25 ꢁC (2.5 h).
(b) NaN3, DMF, 110 ꢁC (3 h).
The A2B template precursor 7 was prepared as shown in
Scheme 4. In order to make possible the selective oxida-
tion of the primary alcohol at C-6, a 1:3.3 mixture of
10a,b was first transformed into 11 as seen above and,
without further purification, treated with the 2,2,6,6-
tetramethylpiperidine-N-oxyl radical (TEMPO)/KBr/
NaClO system in ethyl acetate, and aqueous NaClO2
as the terminal oxidant,40 to give, after methylation with
trimethylsilyl-diazomethane, the desired methyl uronate
17 in poor yield (24%); its spectral data (mainly MS and
NMR) corroborated this structure: the novel methyl
ester function gave rise to a singlet at d 3.78 ppm for the
three methyl protons, as well as an ester carbonyl signal
at 171.6 ppm and an additional methyl carbon signal at
52.6 ppm. Alternatively, crude 11 was treated with tert-
butyl-diphenyl-chlorosilane to obtain the 6-O tert-butyl-
diphenylsilyl derivative 18 in good yield, high-resolution
MS of which evidenced the presence of a unique tert-
butyl-diphenylsilyl (TBDPS) protecting group and one
free-remaining OH group in the molecule, corroborated
by its NMR spectra. Conventional benzylation of 18
with benzyl chloride/potassium hydroxide in toluene
afforded, after column chromatography, 80% of the ex-
pected 2,5-anhydro-3-azido-4-O-benzyl-6-O-(tert-butyl-
diphenylsilyl)-3-deoxy D-altrose dimethyl acetal 19 and
19% of the 4,6-di-O-benzyl derivative 20. High-resolu-
tion mass spectrum (HRMS) of 19 and the appearance,
AcO
O
AcO
c
COOH
a
N3
(65%)
1
12
AcO
AcO
AcO
AcO
b
O
O
H
+
N
OH
N3
N3
14 (34%)
COOR
2 R = Et (47%)
Scheme 2. Synthesis of AB and A-spacer-B templates. Reagents and
conditions: (a) i. 9:1 TFA/H2O, rt (1 h); ii. JonesÕ reagent, ꢁ30 ꢁC!rt
(1 h). (b) i. 9:1 TFA/H2O, rt (1 h); ii. 4-H2N–C6H4–CO2Et, NaB-
H(OAc)3, DCE, rt (18 h). (c) JonesÕ reagent, ꢁ30 ꢁC!rt (1 h).
The synthesis of an AB2 template precursor is summa-
rized in Scheme 3. When crude 11, obtained from
10a,b as indicated above, was made to react with tosyl

892
Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 16 (2005) 889–897
MeOOC
HO
molecular scaffolds with a 2,5-anhydro-sugar frame-
O
work. Their potential for both structural and functional
diversification has been demonstrated by the synthesis of
various unusual C-glycoamino acid precursors that may
act as key structure-inducing templates in generating
folded, hydrolytically stable peptidomimetics.
OMe
N3
OMe
a
(24%)
TBDPSO
HO
17
b
c
O
10a,b
(82%)
OMe
OMe
N3
18
4. Experimental
4.1. General
TBDPSO
BnO
BnO
BnO
O
O
+
Solvents were purified and dried by standard proce-
dures. TLC was performed on silica gel plates (DC-
Alufolien F254, E. Merck); detection of compounds
was accomplished with UV light (254 nm) and by char-
ring with H2SO4 or an anisaldehyde reagent. Preparative
column chromatography was carried out using silica gel
(E. Merck, 0.063–0.200 mm or 0.040–0.063 mm). Melt-
ing points were recorded on a Gallenkamp MFB-595
apparatus and are uncorrected. A Perkin–Elmer 241
MC polarimeter was used for the measurement of opti-
cal rotations. Infrared spectra were obtained for films on
a FTIR Bomem Michelson MB-120 spectrophotometer.
1H NMR spectra (300 or 500 MHz) and 13C NMR spec-
tra (75.4 or 125.7 MHz) were recorded with a Bruker
AMX-300 or a Bruker AMX-500 spectrometer, using
the solvent peak as internal reference; chemical shifts
(d) are expressed in parts per million from TMS;
coupling constants (J), in hertz. Assignments were
confirmed by decoupling, homonuclear 2D COSY
correlated spectra, and heteronuclear 2D correlated
(HETCOR) spectra. HRCIMS (150 eV) experiments
were performed with a Micromass AutoSpecQ instru-
ment with a resolution of 10,000 (5% valley definition),
and HRFABMS was performed on a VG AutoSpec
spectrometer (Fisons Instruments) (30 keV).
OMe
OMe
OMe
OMe
N3
19 (80%)
N3
20 (19%)
d
(98%)
HOOC
BnO
HO
BnO
e
O
O
(98%)
OMe
OMe
OMe
OMe
N3
21
N3
7
Scheme 4. Synthesis of an A2B template precursor. Reagents and
conditions: (a) i. MeOH, PTSA, rt (1 h); ii. TEMPO/KBr/NaClO; iii.
NaClO2; iv. TMSCHN2/hexane. (b) i. MeOH, PTSA, rt (1 h); ii.
TBDPSCl, DCM/Py, DMAP, rt (15 h). (c) BnCl, KOH, toluene, 90 ꢁC
(45 min). (d) TBAF/THF 1 M, THF, rt (3 h). (e) TCCA/TEMPO,
NaBr, acetone, aq NaHCO3, rt (45 min).
in its NMR spectra, of two doublets (Jgem = 12.0) at d
4.81 and 4.65, each for one proton, assigned to the benz-
yl methylenic protons, and the corresponding methyl-
enic carbon signal at d 73.3 ppm, confirmed that 19
was the 4-O-benzyl derivative. The side product 20
had HRMS and NMR spectra congruent with the ab-
sence of any TBDPS group and the presence of two benz-
yl groups in the molecule. Pure 19 was 6-O-deprotected
by the action of tetrabutylammonium fluoride, affording
compound 21 in almost quantitative yield. The spectral
properties of 21 were in agreement with the expected
loss of the TBDPS group (HRMS m/z values corre-
sponding to the molecular formula, NMR signals for
only one phenyl group). Finally, oxidation of 21 with
trichloroisocyanuric acid, promoted by the TEMPO
radical, led to 2,5-anhydro-3-azido-4-O-benzyl-3-
deoxy-D-altruronic acid dimethylacetal 7 in 98% yield.
Again, the HRMS and the NMR spectra corroborated
the structure of the product; thus, the carboxylic group
gave rise to the appearance of a 13C signal at d
175.4 ppm, while the remaining 4-O-benzyl group origi-
nated aromatic signals and two doublets, at d 4.77 and
4.71 ppm (J 11.7 Hz), for the methylene diastereotopic
protons, as expected.
4.2. Preparation of (1R)- and (1S)-2,5-anhydro-3-azido-
4,6-O-benzylidene-3-deoxy-1-fluoro-1-O-methyl-D-altri-
tols, 10a and 10b
To a solution of methyl 3-azido-4,6-O-benzylidene-3-
deoxy-a-D-allopyranoside37 (103.7 mg, 0.338 mmol) in
acetonitrile (6.2 mL), cooled at 0 ꢁC, DAST (223 lL,
1.69 mmol) was added dropwise. The mixture was re-
fluxed for 12 min and then the solvent was evaporated
under vacuum. The residue was treated with dichloro-
methane and poured into a cold, saturated aqueous
sodium hydrogen carbonate solution (50 mL). The
phases were separated and the organic layer was washed
1
with brine, dried (Na2SO4), and concentrated. The H
NMR spectrum of the crude product showed the pres-
ence of a 1:3.3 10a/10b diastereomeric mixture. Column
chromatography (10:1!6:1 gradient, hexane/ethyl ace-
tate) gave pure 2-enopyranoside 9 (19.6 mg, 20%) as a
white crystalline product, 10a (18.9 mg, 18%) as an
amorphous solid, and 10b (57.6 mg, 55%) as white crys-
talline compound.
3. Conclusion
In summary, a DAST-promoted rearrangement ob-
served in a hexose-derived azido-2-equatorial-hydroxy
glycopyranoside, involving ring contraction under
remarkably mild conditions, leads to a new class of
Methyl 3-azido-4,6-O-benzylidene-2,3-dideoxy-a-D-ery-
thro-hex-2-enopyranoside, 9. Mp 112–114 ꢁC; Rf 0.47
23
(4:1 hexane/ethyl acetate); ½aꢂ ¼ þ7:90 (c 0.83, ace-
D

Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 16 (2005) 889–897
893
tone); IR mmax 2116 (N3) and 1651 cmꢁ1 (C@C); 1H
NMR (500 MHz, CD3COCD3) d 7.51–7.34 (m, 5H,
Ph), 5.77 (s, 1H, CH–Ph), 5.31 (dd, 1H, J1,2 = 3.0,
J2,5 = 2.0, H-2), 5.03 (dd, 1H, J1,5 = 1.0, H-1), 4.58–
then neutralized with triethylamine. The organic solvent
was evaporated under vacuum and the residue purified
by column chromatography (10:1 dichloromethane/
methanol) to give pure 11 (35 mg, 93%) as an oil; Rf
25
0
4.55 (m, 1H, H-5), 4.29 (dd, 1H, J6,6 = 8.7, J5,6 = 3.2,
0.51 (10:1 dichloromethane/methanol); ½aꢂ ¼ þ58:5 (c
D
H-6), 3.96–3.89 (m, 2H, H-4 and H-60), and 3.39 (s,
3H, OMe); 13C NMR (125.7 MHz, CD3COCD3) d
138.8 (C-3), 138.5–127.0 (Ph), 111.9 (C-2), 102.6 (CH–
Ph), 97.3 (C-1), 75.8 (C-5), 69.5 (C-6), 65.0 (C-4), and
55.8 (OMe); FABHRMS: m/z 312.0955 (calcd for
C14H15N3O4+Na+: 312.0960).
0.46, dichloromethane); IR mmax 2102 cmꢁ1 (N3); 1H
NMR (500 MHz, CDCl3) d 4.54 (d, 1H, J1,2 = 7.0, H-
1), 4.38 (br dd, 1H, J3,4 = J4,5 = 6.3, H-4), 4.16 (dd,
1H, J2,3 = 4.3, H-3), 4.11 (dd, 1H, H-2), 3.86 (dd, 1H,
0
0
J6,6 = 12.5, J5,6 = 2.8, H-6), 3.79 (ddd, 1H, J5,6 = 3.3,
H-5), 3.66 (dd, 1H, H-60), 3.49 and 3.48 (each s, each
3H, 2OMe), and 2.66 (br s, 1H, HO-4); 13C NMR
(125.7 MHz, CDCl3) d 103.8 (C-1), 82.5 (C-5), 78.7 (C-
2), 71.9 (C-4), 66.0 (C-3), 61.7 (C-6), and 55.4 and
54.6 (2OMe); FABHRMS: m/z 256.0922 (calcd for
C8H15N3O5+Na+: 256.0910).
Compound 10a: Rf 0.42 (4:1 hexane/ethyl acetate);
25
D
½aꢂ ¼ ꢁ72:0 (c 0.60, acetone); IR mmax 2108 (N3),
982 cmꢁ1 (CF); 1H NMR (500 MHz, CD3COCD3) d
7.52–7.37 (m, 5H, Ph), 5.69 (s, 1H, CH–Ph), 5.28 (dd,
1H, J1,F = 68.0, J1,2 = 7.2, H-1), 4.66 (dd, 1H,
2
0
J2,3 = J3,4 = 4.6, H-3), 4.47 (dd, 1H, J6,6 = 8.6,
4.5. Preparation of 4,6-di-O-acetyl-2,5-anhydro-3-
azido-3-deoxy-D-altrose dimethyl acetal, 12
3
J5,6 = 3.5, H-6), 4.22 (ddd, 1H, J2,F = 11.5, H-2), 3.96
(dd, 1H, J4,5 = 9.2, H-4), 3.88–3.84 (m, 2H, H-5 and
4
H-60), and 3.61 (d, 3H, JOMe,F = 1.2, OMe); 13C
To a solution of 50 mg (0.162 mmol) of the diastereo-
meric mixture 10a,b in methanol (1.5 mL), p-toluene-
sulfonic acid (6 mg, 0.032 mmol) was added. The
mixture was stirred at room temperature for 1 h, then
neutralized with triethylamine, and concentrated. The
residue, without purification, was dissolved in anhy-
drous pyridine (1 mL), cooled at 0 ꢁC and treated with
acetic anhydride (1 mL). The reaction mixture was stir-
red at room temperature for 20 h and then evaporated
under vacuum. Purification of the residue by column
chromatography (2:1 ether/hexane) gave pure 12
NMR (125.7 MHz, CD3COCD3) d 138.4–127.3 (m,
Ph), 112.4 (d, J1,F = 220.0, C-1), 102.8 (CH–Ph), 81.9
1
2
(C-4), 80.1 (d, J2,F = 23.9, C-2), 71.8 (C-6), 71.0 (C-5),
3
62.1 (d, J3,F = 6.3, C-3), and 57.4 (OMe); CIHRMS:
m/z 310.1208 (calcd for C14H17FN3O4+H+: 310.1203).
Compound 10b: Rf 0.40 (4:1 hexane/ethyl acetate); mp
24
D
132–136 ꢁC; ½aꢂ ¼ ꢁ61:0 (c 0.75, acetone); IR mmax
2108 (N3), 949 cmꢁ1 (CF); 1H NMR (500 MHz,
CD3COCD3) 7.52–7.36 (m, 5H, Ph), 5.69 (s, 1H, CH–
2
Ph), 5.36 (dd, 1H, J1,F = 62.6, J1,2 = 7.0, H-1), 4.70
(48.2 mg, 94%) as an oil; Rf 0.57 (1:1 hexane/ethyl ace-
24
(dd, 1H, J2,3 = J3,4 = 4.3, H-3), 4.46 (dd, 1H,
0
tate); ½aꢂ ¼ þ57:5 (c 0.52, dichloromethane); IR mmax
D
3
J6,6 = 8.6, J5,6 = 3.5, H-6), 4.24 (ddd, 1H, J2,F = 3.1,
H-2), 3.98 (dd, 1H, J4,5 = 9.3, H-4), 3.86–3.82 (m, 2H,
2108 (N3), 1746 (C@O), 1229 (C–O), 1121 cmꢁ1 (C–O–
C); 1H NMR (500 MHz, CDCl3) d 5.14 (dd, 1H,
J4,5 = 8.5, J3,4 = 5.0, H-4), 4.55 (d, 1H, J1,2 = 7.5, H-1),
4.40 (dd, 1H, J2,3 = 4.7, H-3), 4.30 (dd, 1H,
4
H-5 and H-60), and 3.58 (d, 3H, JOMe,F = 1.5, OMe);
13C NMR (125.7 MHz, CD3COCD3) d 138.4–127.3
(m, Ph), 111.9 (d, J1,F = 215.0, C-1), 102.8 (CH–Ph),
1
0
J6,6 = 12.0, J5,6 = 3.0, H-6), 4.25 (ddd, 1H,
0
2
82.0 (C-4), 79.5 (d, J2,F = 32.7, C-2), 71.8 (C-6), 71.1
(C-5), 61.7 (C-3), 57.4 (OMe); CIHRMS: m/z 310.1204
J5,6 = 4.0 Hz, H-5), 4.11 (dd, 1H, H-60), 4.10 (dd, 1H,
H-2), 3.46 and 3.44 (each s, each 3H, 2OMe), and 2.16
and 2.07 (each s, each 3H, 2COMe); 13C NMR
(125.7 MHz, CDCl3) d 170.9 and 170.5 (2C@O), 103.1
(C-1), 78.8 (C-2), 77.1 (C-5), 73.8 (C-4), 63.5 (C-3),
63.2 (C-6), 55.7 and 54.0 (2OMe), and 21.0 and 20.6
(2COMe); FABHRMS: m/z 340.1136 (calcd for
C12H19N3O7+Na+: 340.1121).
(calcd for C14H17FN3O4+H+: 310.1203).
4.3. Preparation of 2,5-anhydro-3-azido-3-deoxy-D-
altrose, 5
To a solution of 50 mg (0.162 mmol) of the diastereo-
meric mixture 10a,b in acetone (1.5 mL), p-toluenesulf-
onic acid (12 mg, 0.064 mmol) was added. The
solution was allowed to stand at room temperature for
1 h and then neutralized with triethylamine. The mixture
was evaporated under vacuum to give a residue, extrac-
tion of which with dichloromethane gave 25 mg (83%)
of chromatographically homogeneous crude 5, pure
enough to be used for further transformation, but un-
stable to be purified by column chromatography.
4.6. Preparation of 4,6-di-O-acetyl-2,5-anhydro-3-azido-
3-deoxy-D-altrose, 13
Dimethylacetal 12 (111 mg, 0.299 mmol) was dissolved
in a 9:1 trifluoroacetic acid/water mixture (3.1 mL) and
the solution was allowed to stand at room temperature
for 1 h. The reaction mixture was poured into an ice-
water mixture (100 mL) and extracted with dichlorome-
thane (4 · 20 mL). The combined organic layers were
washed with saturated aqueous sodium hydrogen car-
bonate, brine, and dried (Na2SO4). Evaporation of the
solvent under reduced pressure afforded crude 13
(85.5 mg, 90%) as a chromatographically homogeneous
oil, pure enough for further transformations without
purification. An analytical sample of 13 was obtained
after column chromatography (4:1 hexane/ethyl acetate)
4.4. Preparation of 2,5-anhydro-3-azido-3-deoxy-D-
altrose dimethyl acetal, 11
To a solution of 50 mg (0.162 mmol) of the diastereo-
meric mixture 10a,b in methanol (1.5 mL), p-toluene-
sulfonic acid (6 mg, 0.032 mmol) was added. The
mixture was stirred at room temperature for 1 h and

894
Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 16 (2005) 889–897
of the crude product; Rf 0.37 (4:1 hexane/ethyl acetate);
dride (93.0 mg, 0.441 mmol). The reaction mixture was
stirred at room temperature until total consumption
(18 h) of 13. The mixture was then diluted with satu-
rated aqueous sodium hydrogen carbonate (25 mL)
and the aqueous layer was extracted with ethyl acetate
(3 · 20 mL). The combined organic layers were dried
(Na2SO4), and concentrated under reduced pressure.
Column chromatography (1:1 ether/hexane) of the resi-
due afforded pure 4,6-di-O-acetyl-2,5-anhydro-3-azido-
1,3-dideoxy-1-(4-ethoxycarbonyl-phenylamino)-D-altri-
tol (2, 62.5 mg, 47%) and 4,6-di-O-acetyl-2,5-anhydro-3-
azido-3-deoxy-D-altritol (14, 32.5 mg, 34%).
26
½aꢂ ¼ þ40:9 (c 0.49, dichloromethane); IR mmax 2114
D
(N3), 1742 (C@O), 1233 and 1125 cmꢁ1 (C–O); 1H
NMR (500 MHz, CDCl3) d 9.63 (d, 1H, JCHO,2 = 1.5,
CHO), 4.31 (dd, 1H, J3,4 = 5.0, J4,5 = 7.0, H-4), 4.69
(dd, 1H, J2,3 = 5.0, H-3), 4.46 (dd, 1H, H-2), 4.45 (m,
0
1H, H-5), 4.39 (dd, 1H, J5,6 = 3.2, J6,6 = 12.2 Hz, H-
6), 4.15 (dd, 1H, J5,6 = 4.2, H-60), and 2.17 and 2.11
0
(each s, each 3H, 2COMe); 13C NMR (125.7 MHz,
CDCl3) d 199.2 (CHO), 170.6 and 170.3 (2COMe),
82.7 (C-2), 78.8 (C-5), 73.8 (C-4), 63.3 (C-3), 63.1 (C-
6), and 20.9 and 20.5 (2COMe); CIHRMS: m/z
272.0892 (calcd for C10H13N3O6+H+: 272.0883).
26
Compound 2: Rf 0.39 (10:1 ether/hexane); ½aꢂ ¼ ꢁ6:8
D
4.7. Preparation of 4,6-di-O-acetyl-2,5-anhydro-3-azido-
3-deoxy-D-altronic acid, 1
(c 0.42, dichloromethane); IR mmax 3376 (NH), 2110
(N3), 1746 and 1699 (C@O), 1279, 1231, 1177, and
1
1113 cmꢁ1 (C–O); H NMR (300 MHz, CD3COCD3) d
7.78 (d, 2H, J2 ,3 = 8.7, aromatic H-30), 6.71 (d, 2H, aro-
matic H-20), 5.81 (br dd, 1H, J1a,NH ꢃ J1b,NH = 5.6,
NH), 5.38 (dd, 1H, J4,5 = 6.7, J3,4 = 5.2, H-4), 4.61
0
0
Compound 12 (111 mg, 0.299 mmol) was dissolved in a
9:1 trifluoroacetic acid/water mixture (3.1 mL) and the
solution was allowed to stand at room temperature for
1 h. The reaction mixture was poured into ice-water
(100 mL) and extracted with dichloromethane
(4 · 20 mL). The combined organic layers were succes-
sively washed with saturated sodium hydrogen carbon-
ate and brine, then dried (Na2SO4), and concentrated.
The residue (crude 13) was dissolved in ether (2.3 mL)
and cooled at ꢁ30 ꢁC. This solution was treated with
aqueous sodium dichromate/sulfuric acid (JonesÕ re-
agent, 3.6 mL, 2.35 mmol) and the temperature was
allowed to rise the ambient. The organic solvent was
evaporated under reduced pressure and the residue
was filtered through a silica gel path by using
ether (100 mL) and then ethyl acetate (150 mL) as
(dd,
1H,
J2,3 = 4.4,
H-3),
4.43
(td,
1H,
J1a,2 = J1b,2 = 6.6, H-2), 4.28–4.21 (m, 2H, H-5 and H-
6), 4.25 (q, 2H, J = 7.1, CH3CH2O), 4.13 (dd, 1H,
J6,6 = 12.5, J5,6 = 6.2, H-60), 3.57 (ddd, 1H,
J1a,1b = 13.4, H-1a), 3.40 (ddd, 1H, H-1b), 2.13 and
2.00 (2s, each 3H, 2COMe), and 1.31 (t, 3H,
CH3CH2O); 13C NMR (75.4 MHz, CD3COCD3) d
170.8 and 170.7 (2COMe), 166.8 (ArCOOEt), 153.3–
112.2 (Ph), 78.4 (C-2 and C-5), 75.8 (C-4), 64.5 (C-6),
64.0 (C-3), 60.4 (CH3CH2O), 43.9 (C-1), 20.6 and 20.3
(2COMe), and 14.7 (CH3CH2O); CIHRMS: m/z
420.1644 (calcd for C19H24N4O7: 420.1645).
0
0
eluents, to give pure 1 (44 mg, 65%); Rf 0.37 (4:1 ether/
Compound 14: Rf 0.40 (1:4 hexane/ethyl acetate);
26
D
26
acetone); ½aꢂ ¼ þ40:2 (c 0.50, dichloromethane); IR
½aꢂ ¼ þ19:4 (c 0.72, dichloromethane); IR mmax 3306
D
mmax 3300 (OH), 2120 (N3), 1746 (C@O), 1231 and
1119 cmꢁ1 (C–O); 1H NMR (500 MHz, CDCl3) 5.19
(dd, 1H, J3,4 = 5.0, J4,5 = 8.0, H-4), 4.77 (d, 1H,
J2,3 = 4.5, H-2), 4.69 (dd, 1H, H-3), 4.45 (ddd, 1H,
(OH), 2108 (N3), 1227 and 1119 cmꢁ1 (C–O); 1H
NMR (300 MHz, CDCl3) d 5.22 (dd, 1H, J4,5 = 7.3,
J3,4 = 5.2, H-4), 4.41 (dd, 1H, J2,3 = 4.8, H-3), 4.32
0
(dd, 1H, J6,6 = 11.7, J5,6 = 3.0, H-6), 4.30–4.21 (m,
0
J5,6 = 2.8, J5,6 = 4.0, H-5), 4.39 (dd, 1H, J6,6 = 12.5,
H-6), 4.15 (dd, 1H, H-60), and 2.18 and 2.10 (each s,
each 3H, 2COMe); 13C NMR (125.7 MHz) d 172.0
(COOH), 170.7 and 170.4 (2C OMe), 78.3 and 78.2
(C-2 and C-5), 73.2 (C-4), 62.8 and 62.7 (C-3 and C-
6), and 20.9 and 20.4 (2COMe); CIHRMS: m/z
288.0836 (calcd for C10H13N3O7+H+: 288.0832).
2H, H-2 and H-5), 4.11 (dd, 1H, J5,6 = 4.2, H-60), 3.82
0
0
(d, 2H, J1 and 1 ,2 = 6.0, H-1 and H-10), 2.19 and 2.12
0
(each s, each 3H, 2COMe), and 1.95 (br s, 1H, OH);
13C NMR (75.4 MHz, CDCl3) d 170.8 and 170.5
(2COMe), 79.7 and 77.3 (C-5 and C-2), 74.3 (C-4),
63.6 (C-6), 62.5 (C-3), 62.0 (C-1), and 20.9 and 20.5
(2COMe); CIHRMS: m/z 274.1026 (calcd for
C10H15N3O6+H+: 274.1039).
4.8. Preparation of 4,6-di-O-acetyl-2,5-anhydro-3-azido-
1,3-dideoxy-1-(4-ethoxycarbonyl-phenylamino)-D-altritol,
2, and 4,6-di-O-acetyl-2,5-anhydro-3-azido-3-deoxy-D-
altritol, 14
4.9. Preparation of 2,5-anhydro-3-azido-3-deoxy-6-O-(4-
toluenesulfonyl)-D-altrose dimethyl acetal, 15, and 2,5-
anhydro-3-azido-3-deoxy-4,6-di-O-(4-toluenesulfonyl)-D-
altrose dimethyl acetal, 16
Compound 12 (100 mg, 0.315 mmol) was dissolved in a
9:1 trifluoroacetic acid/water mixture (2.7 mL) and the
solution was allowed to stand at room temperature for
1 h. The reaction mixture was poured into ice-water
(100 mL) and extracted with dichloromethane
(4 · 20 mL). The combined organic layers were succes-
sively washed with saturated sodium hydrogen carbon-
ate and brine, then dried (Na2SO4), and concentrated.
The residue (crude 13) was dissolved in 1,2-dichloro-
ethane (3.1 mL) and treated with ethyl 4-aminobenzoate
(72.1 mg, 0.437 mmol) and sodium triacetoxyborohy-
To a solution of 61.3 mg (0.198 mmol) of the diastereo-
meric mixture 10a,b in methanol (1.8 mL), p-toluene-
sulfonic acid (7.3 mg, 0.037 mmol) was added. The
mixture was stirred at room temperature for 1 h, then
neutralized with triethylamine, and concentrated. The
residue, without purification, was dissolved in anhy-
drous pyridine (1 mL), cooled at ꢁ25 ꢁC, and treated
with a solution of tosyl chloride (115 mg, 0.603 mmol)
in anhydrous pyridine (1 mL) at 0 ꢁC. The reaction mix-
ture was stirred at ꢁ25 ꢁC for 2.5 h, then diluted with

Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 16 (2005) 889–897
895
water (1 mL), the temperature was allowed to rise the
ambient, and the reaction mixture was extracted with
dichloromethane (3 · 20 mL). The combined organic
layer was dried (Na2SO4) and concentrated under re-
duced pressure. Column chromatography of the residue
(4:1 2:1 gradient, hexane/ethyl acetate) gave pure 2,5-
anhydro-3-azido-3-deoxy-4,6-di-O-(4-toluenesulfonyl)-
D-altrose dimethyl acetal (16, 10.5 mg, 10%) and 2,5-
anhydro-3-azido-3-deoxy-6-O-(4-toluenesulfonyl)-D-al-
trose dimethyl acetal (15, 46 mg, 60%), both as oils.
(125.7 MHz, CDCl3) d 103.0 (C-1), 81.5 (C-5), 78.2 (C-
2), 72.7 (C-4), 65.9 (C-3), 55.2 and 53.1 (2OMe), and
51.6 (C-6); FABHRMS: m/z 281.0970 (calcd for
C8H14N6O4+Na+: 281.0974).
4.11. Preparation of methyl 2,5-anhydro-3-azido-3-deoxy-
D-altruronate dimethyl acetal, 17
To a solution of 61 mg (0.197 mmol) of the diastereo-
meric mixture 10a,b in methanol (1.8 mL), p-toluene-
sulfonic acid (15 mg, 0.08 mmol) was added. The
mixture was stirred at room temperature for 1 h, then
neutralized with triethylamine, and concentrated. The
residue, without purification, was dissolved in ethyl ace-
tate (300 lL). To this solution, 39 lL of 0.5 M KBr and
2,2,6,6-tetramethylpiperidine-N-oxyl radical (TEMPO,
0.6 mg, 0.004 mmol) were added. The mixture was
cooled at 5 ꢁC, treated with a 10% aqueous sodium
hypochlorite (800 lL, 1.04 mmol) dropwise, and stirred
at room temperature for 30 min. Then, 25% aqueous so-
dium chlorite (1.1 mL) was added. After 30 min at room
temperature, the organic phase was separated, and the
remaining aqueous phase was extracted with ethyl ace-
tate (2 · 15 mL). The aqueous layer was acidified with
1 M HCl and then extracted with ethyl acetate
(3 · 20 mL). The combined organic extracts were
washed with brine (40 mL), dried (Na2SO4), and con-
centrated under reduced pressure. The residue was dis-
solved in 1:1 methanol/acetonitrile (1mL) and treated
with 400 lL of 2 M trimethylsilyl-diazomethane in hex-
ane. After 2 h at room temperature, the solvents were
evaporated under reduced pressure and the residue
was purified by column chromatography (40:1
dichloromethane/methanol) to give pure 17 (12 mg,
Compound 15: Rf 0.50 (1:1 hexane/ethyl acetate);
25
½aꢂ ¼ þ36:8 (c 0.83, dichloromethane); IR mmax 3308
D
(OH), 2112 (N3), 1360 and 1177 (SO2), 1119 cmꢁ1 (C–
O–C); 1H NMR (500 MHz, CDCl3) d 7.78 and 7.34
(each d, each 2H, J ꢃ 8.5, aromatic protons), 4.49 (d,
1H, J1,2 = 6.5, H-1), 4.36 (br dd, 1H, J3,4 ꢃ J4,5 = 6.0,
0
H-4), 4.20 (dd, 1H, J6,6 = 11.0, J5,6 = 3.0, H-6), 4.15
(dd, 1H, J5,6 = 3.0, H-60), 4.14 (dd, 1H, J2,3 = 4.0 Hz,
0
H-3), 4.09 (dd, 1H, H-2), 3.90 (ddd, 1H, H-5), 3.45
and 3.40 (each s, each 3H, 2OMe), and 2.45 (s, 3H,
ArMe); 13C NMR (125.7 MHz) d 145.1–128.0 (Ph),
103.1 (C-1), 80.2 (C-5), 78.5 (C-2), 72.2 (C-4), 68.8 (C-
6), 65.4 (C-3), 55.3 and 53.6 (2OMe), and 21.8 (ArMe);
FABHRMS: m/z 410.0984 (calcd for C15H21N3O7S+
Na+: 410.0998).
Compound 16: Rf 0.60 (1:1 hexane/ethyl acetate);
24
½aꢂ ¼ þ52:0 (c 0.52, dichloromethane); IR mmax 2114
D
(N3), 1362 and 1177 (SO2), 1121 cmꢁ1 (C–O–C); 1H
NMR (500 MHz, CDCl3) d 7.59 and 7.52 (each d, each
2H, J ꢃ 9, aromatic protons), 7.41 and 7.32 (each d,
each 2H, aromatic protons), 4.94 (dd, 1H, J4,5 = 8.0,
J3,4 = 5.0, H-4), 4.47 (d, 1H, J1,2 = 7.5, H-1), 4.15 (dd,
1H, J2,3 = 3.7, H-3), 4.09 (m, 2H, H-5 and H-6), 3.98
0
24%) as an oil; Rf 0.51 (10:1 dichloromethane/metha-
20
D
0
(dd, 1H, H-2), 3.86 (d, 1H, J6,6 = 10.5 Hz, H-6 ), 3.40
nol); ½aꢂ ¼ þ19:7 (c 0.68, dichloromethane); IR mmax
and 3.31 (each s, each 3H, 2OMe), 2.48 and 2.44 (each
s, each 3H, 2 ArMe); 13C NMR (125.7 MHz, CDCl3)
d 146.3–128.1 (2Ph), 102.5 (C-1), 78.4 (C-2), 76.7 (C-
5), 76.4 (C-4), 67.4 (C-6), 63.5 (C-3), 55.3 and 53.0
(OMe), and 21.9 and 21.8 (2 ArMe); FABHRMS: m/z
564.1071 (calcd for C22H27N3O9S2+Na+: 564.1086).
3325 (OH), 2110 (N3), 1732 (C@O), and 1202 and
1119 cmꢁ1 (C–O–C); 1H NMR (500 MHz, CDCl3) d
4.55 (d, 1H, J1,2 = 6.0, H-1), 4.50 (dd, 1H,
J3,4 = J4,5 = 5.5, H-4), 4.34 (d, 1H, H-5), 4.31 (dd, 1H,
J2,3 = 5.5, H-2), 4.23 (dd, 1H, H-3), 3.78 (s, 3H,
COOMe), and 3.49 and 3.48 (each s, each 3H, two acetal
OMe); 13C NMR (125.7 MHz, CDCl3)
d 171.6
4.10. Preparation of 2,5-anhydro-3,6-diazido-3,6-dide-
oxy-D-altrose dimethyl acetal, 6
(COOMe), 103.0 (C-1), 81.6 (C-5), 79.2 (C-2), 75.4 (C-
4), 64.4 (C-3), 55.5 and 54.3 (two acetal OMe), and
52.6 (COOMe); CIHRMS: m/z 262.1037 (calcd for
C9H15N3O6+H+: 262.1039).
To a solution of 44 mg (0.114 mmol) of 15 in N,N-
dimethylformamide (1 mL), sodium azide (32 mg,
0.492 mmol) was added. The mixture was heated at
110 ꢁC under reflux for 3 h. After evaporation of the sol-
vent, the residue was extracted with ethyl acetate
(30 mL). The extract was washed with water
(3 · 20 mL), dried (Na2SO4), and concentrated, and
the residue was purified by column chromatography
(2:1 hexane/ethyl acetate) to give 6 (27.8 mg, 95%) as
4.12. Preparation of 2,5-anhydro-3-azido-6-O-(tert-butyl-
diphenylsilyl)-3-deoxy-D-altrose dimethyl acetal, 18
p-Toluenesulfonic acid (11.4 mg, 0.058 mmol) was
added to solution of the diastereomeric mixture 10a,b
(96 mg, 0.311 mmol) in methanol (2.8 mL). The mixture
was stirred at room temperature for 1 h, then neutral-
ized with triethylamine, and concentrated. The residue,
without purification, was dissolved in anhydrous
dichloromethane (1 mL) under argon atmosphere, and
anhydrous pyridine (100 lL) and 4-(dimethyl-
amino)pyridine (4 mg) were added to that solution.
The mixture was cooled at 0 ꢁC and treated with tert-
butyl-diphenyl-chlorosilane (248 lL, 0.944 mmol). The
reaction mixture was stirred at room temperature for
an amorphous solid; Rf 0.53 (1:3 hexane/ethyl acetate);
22
½aꢂ ¼ þ117:4 (c 0.74, dichloromethane); IR mmax 2106
D
(N3), 1120 cmꢁ1 (C–O–C); 1H NMR (500 MHz, CDCl3)
d 4.56 (d, 1H, J1,2 = 6.5, H-1), 4.31 (br m, 1H, H-4), 4.18
(m, 2H, H-2 and H-3), 3.89 (ddd, 1H, J4,5 = 7.5,
0
0
J5,6 ꢃ J5,6 = 3.5, H-5), 3.65 (dd, 1H, J6,6 = 13.5, H-6),
3.47 and 3.43 (each s, each 3H, 2OMe), 3.29 (dd, 1H,
H-60), and 2.59 (br s, 1H, OH); 13C NMR

896
Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 16 (2005) 889–897
15 h, then neutralized with 1 M HCl, dried (Na2SO4),
and concentrated under reduced pressure. Column chro-
matography of the residue (5:1 hexane/ethyl acetate)
HRMS: m/z 584.2551 (calcd for C31H39N3O5Si+Na+:
584.2557).
gave pure 18 (120.4 mg, 82%) as an oil; Rf 0.43 (2:1 hex-
Compound 20: Rf 0.54 (2:1 hexane/ethyl acetate);
25
D
28
ane/ethyl acetate); ½aꢂ ¼ þ33:3 (c 0.63, dichlorome-
½aꢂ ¼ þ61:4 (c 0.69, dichloromethane); IR mmax 2106
D
thane); IR mmax 3295 (OH), 2108 (N3), 1115 and 1055
(C–O–C), 706 cmꢁ1 (CSi); 1H NMR (300 MHz, CDCl3)
7.69–7.38 (m, 10H, 2Ph), 4.55 (d, 1H, J1,2 = 6.6, H-1),
4.55 (m, 1H, H-4), 4.20 (dd, 1H, J2,3 ꢃ J3,4 = 4.8, H-3),
4.18 (dd, 1H, H-2), 3.83 (m, 3H, H-5, H-6, and H-60),
3.49 and 3.46 (each s, each 3H, 2OMe), and 1.06 (s,
9H, CMe3); (300 MHz, CD3COCD3): d 7.76–7.40 (m,
10H, 2Ph), 4.77 (m, 2H, H-4 and OH), 4.49 (d, 1H,
J1,2 = 7.2, H-1), 4.15 (dd, 1H, J2,3 ꢃ J3,4 = 3.8, H-3),
4.10 (dd, 1H, H-2), 3.90 (m, 2H, H-5, H-6), 3.78 (dd,
(N3), 1119 and 1067 cmꢁ1 (C–O–C); 1H NMR
(500 MHz, CD3COCD3) d 7.45–7.31 (m, 10H, 2Ph),
4.76 and 4.63 (each d, each 1H, Jgem = 12.0, CH2Ph),
4.55 and 4.50 (each d, each 1H, Jgem = 12.0, CH2Ph),
4.48 (d, 1H, J1,2 = 8.0, H-1), 4.43 (dd, 1H, J4,5 = 8.0,
J3,4 = 4.5, H-4), 4.30 (dd, 1H, J2,3 = 4.0, H-3), 4.03–
4.01 (m, 2H, H-2 and H-5), 3.66 (dd, 1H, J5,6 = 3.0,
J6,6 = 11.0, H-6), 3.55 (dd, 1H, J5,6 = 4.0, H-60), and
3.40 and 3.36 (each s, each 3H, 2OMe); 13C NMR
(125.7 MHz, CD3COCD3) d 139.6–128.2 (m, 2Ph),
104.3 (C-1), 81.0 (C-4), 80.7 and 79.6 (C-5 and C-2),
73.7 and 73.3 (2CH2Ph), 70.0 (C-6), 64.0 (C-3), and
55.1 and 53.7 (2OMe); FABHRMS: m/z 436.1851 (calcd
for C22H27N3O5+Na+: 436.1848).
0
0
1H, J6,6 = 11.7, J5,6 = 3.9, H-60), 3.41 and 3.40 (each
s, each 3H, 2OMe), 1.03 (s, 9H, CMe3); 13C NMR
(75.4 MHz, CDCl3) d 135.8–127.9 (m, 2Ph), 103.5 (C-
1), 83.1 (C-5), 78.8 (C-2), 73.0 (C-4), 66.1 (C-3), 63.8
(C-6), 55.3 and 53.7 (2OMe), 27.0 (CMe3), and 19.4
(CMe3); (75.4 MHz, CD3COCD3) d 136.5–128.6 (m,
2Ph), 104.5 (C-1), 83.0 (C-5), 79.3 (C-2), 73.3 (C-4),
67.2 (C-3), 64.4 (C-6), 55.1 and 53.7 (2OMe), 27.1
(CMe3), and 19.8 (CMe3); FABHRMS: m/z 494.2101
(calcd for C24H33N3O5Si+Na+: 494.2087).
0
0
4.14. Preparation of 2,5-anhydro-3-azido-4-O-benzyl-3-
deoxy-D-altrose dimethyl acetal, 21
A solution of 19 (71.8 mg, 0.128 mmol) in dry tetrahy-
drofuran (THF, 5.8 mL) at 0 ꢁC was treated with
256 lL (256 mmol) of 1 M tetrabutylammonium fluo-
ride (TBAF)/THF solution. The mixture was stirred
until TLC indicated total consumption of the starting
material (3 h), then concentrated under reduced pres-
sure. Column chromatography of the residue (1:3 hex-
4.13. Preparation of 2,5-anhydro-3-azido-4-O-benzyl-6-
O-(tert-butyl-diphenylsilyl)-3-deoxy-D-altrose dimethyl
acetal, 19, and 2,5-anhydro-3-azido-4,6-di-O-benzyl-3-
deoxy-D-altrose dimethyl acetal, 20
ane/ethyl acetate) gave pure 21 (40.6 mg, 98%). Rf 0.41
26
D
To a solution of 18 (87.8 mg, 0.186 mmol) in dry toluene
(1.5 mL) powdered potassium hydroxide (100 mg,
1.79 mmol) was added. The mixture was stirred at room
temperature for 30 min, and then a solution of benzyl
chloride (350 lL, 3.06 mmol) in anhydrous toluene
(200 lL) was added. The reaction mixture was heated
at 90 ꢁC for 45 min and then diluted with water
(1 mL). The phases were separated and the aqueous
layer was extracted with dichloromethane (3 · 20 mL).
The combined organic layers were washed with brine
(15 mL), dried (Na2SO4), and concentrated under re-
duced pressure. Column chromatography of the residue
(10:1!4:1 gradient, hexane/ethyl acetate) gave pure 2,5-
anhydro-3-azido-4-O-benzyl-6-O-(tert-butyl-diphenylsil-
yl)-3-deoxy-D-altrose dimethyl acetal 19 (83.6 mg, 80%)
and 2,5-anhydro-3-azido-4,6-di-O-benzyl-3-deoxy-D-al-
trose dimethyl acetal 20 (14.5 mg, 19%), both as oils.
(1:5 hexane/ethyl acetate); ½aꢂ ¼ þ60:2 (c 0.62, dichlo-
romethane); IR mmax 3474 (OH), 2105 (N3), 1109 and
1063 cmꢁ1 (C–O–C); 1H NMR (300 MHz, CDCl3) d
7.39–7.32 (m, 5H, Ph), 4.70 and 4.61 (each d, each 1H,
Jgem = 11.7, CH2Ph), 4.54 (d, 1H, J1,2 = 7.5, H-1), 4.27
(dd, 1H, J4,5 = 8.7, J3,4 = 4.5, H-4), 4.06 (dd, 1H,
0
J2,3 = 4.1, H-3), 4.02 (ddd, 1H, J5,6 = 2.7, J5,6 = 4.0,
H-5), 3.96 (dd, 1H, H-2), 3.88 (dd, 1H, J6,6 = 12.4, H-
0
6), 3.57 (dd, 1H, H-60), and 3.47 and 3.45 (each s, each
3H, 2OMe); 13C NMR (75.4 MHz, CDCl3) d 137.2–
128.1 (m, Ph), 103.7 (C-1), 80.5 (C-5), 79.1 (C-2), 78.8
(C-4), 73.4 (CH2Ph), 63.1 (C-3), 61.5 (C-6), and 55.7
and 54.5 (2OMe); FABHRMS: m/z 346.1376 (calcd for
C15H21N3O5+Na+: 346.1379).
4.15. Preparation of 2,5-anhydro-3-azido-4-O-benzyl-3-
deoxy-D-altruronic acid dimethyl acetal, 7
Compound 19: Rf 0.59 (4:1 hexane/ethyl acetate);
A solution of 21 (32.5 mg, 0.101 mmol) in acetone
(1 mL) was treated with 300 lL of a 15% aqueous so-
dium hydrogen carbonate. To the mixture, cooled at
0 ꢁC, sodium bromide (2.02 mg, 0.0202 mmol), 2,2,6,6-
tetramethylpiperidine-N-oxyl radical (TEMPO, 0.3 mg,
0.002 mmol), and trichloroisocyanuric acid (TCCA,
two portions, each 23.5 mg, 0.101 mmol, over 10 min)
were successively added. The mixture was stirred at
room temperature for 45 min and filtered through a cel-
ite layer. The filtrate was treated with saturated aqueous
sodium carbonate (30 mL) and washed with ethyl
acetate (3 · 25 mL). The aqueous layer was acidified
with 2 M HCl, then extracted with ethyl acetate
(4 · 100 mL). The combined organic extracts were dried
26
½aꢂ ¼ þ21:8 (c 0.64, dichloromethane); IR mmax 2106
D
(N3), 1113 and 1069 (C–O–C), 702 cmꢁ1 (CSi); 1H
NMR (300 MHz, CD3COCD3) d 7.81–7.32 (m, 15H, 3
Ph), 4.81 and 4.65 (each d, each 1H, Jgem = 12.0,
CH2Ph), 4.64 (dd, 1H, J4,5 = 8.1, J3,4 = 4.5, H-4), 4.53
(d, 1H, J1,2 = 7.5, H-1), 4.40 (dd, 1H, J2,3 = 3.0, H-3),
0
4.12 (dd, 1H, H-2), 4.01 (ddd, 1H, J5,6 = J5,6 = 2.7, H-
0
5), 3.81 (dd, 1H, J6,6 = 11.1, H-6), 3.73 (dd, 1H, H6),
3.42 and 3.42 (each s, each 3H, 2OMe), and 1.00 (s,
9H, CMe3); 13C NMR (75.4 MHz, CD3COCD3) d
139.0–128.3 (3Ph), 104.4 (C-1), 81.7 (C-5), 80.1 (C-2),
80.0 (C-4), 73.3 (CH2Ph), 64.3 (C-6), 64.0 (C-3), 55.1
and 53.8 (2OMe), 27.2 (CMe3), and 19.7 (CMe3); FAB-

Y. Vera-Ayoso et al. / Tetrahedron: Asymmetry 16 (2005) 889–897
897
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(Na2SO4), and concentrated under reduced pressure to
give 33.1 mg (98%) of 7; Rf 0.42 (5:1 dichloromethane/
24
D
methanol); ½aꢂ ¼ ꢁ108:2 (c 0.68, dichloromethane);
IR mmax 3295 (OH), 2110 (N3), 1736 (CO), 1111 and
1065 cmꢁ1 (C–O–C); 1H NMR (300 MHz, CDCl3) d
7.39–7.32 (m, 5H, Ph), 4.77 and 4.71 (each d, each 1H,
Jgem = 11.7, CH2Ph), 4.60 (d, 1H, J1,2 = 6.9, H-1), 4.53
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4.08–4.00 (m, 2H, H-2 and H-3), and 3.46 and 3.45 (each
s, each 3H, 2OMe); 13C NMR (75.4 MHz) d 175.4
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79.6 (C-2), 79.1 (C-5), 73.4 (CH2Ph), 63.2 (C-3), and
55.7 and 53.9 (2OMe); FABHRMS: m/z 360.1161 (calcd
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Acknowledgements
We thank the Spanish ÔMinisterio de Ciencia y Tec-
nologıaÕ (Grant BQU2000-1155 and predoctoral
fellowship to Y.V.-A.), the European Commission,
´
Directorate General for Science and Development
´
´
Carmona, A. T.; Gomez-Guillen, M. Tetrahedron: Asym-
metry 2004, 15, 429–444.
´
(FP6-503480), and the ÔJunta de AndalucıaÕ (FQM
142) for financial support.
27. Borrachero, P.; Cabrera-Escribano, F.; Carmona, A. T.;
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Gomez-Guillen, M. Tetrahedron: Asymmetry 2000, 11,
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