Preparation and reactivity of some 3-deoxy-D-altronic acid derivatives

Article abstract of DOI:10.1081/CAR-100103954

3-Amino-3-deoxy-2,4,5,6-tetra-O-methyl-D-altronic acid hydrochloride was the key intermediate in the preparation of poly[(2S,3R)-2-methoxy-3-(D-erythro-trimethoxypropyl)propanamide], a chiral nylon 3 analog. We now describe an alternative synthetic route

Full text of DOI:10.1081/CAR-100103954

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PREPARATION AND REACTIVITY OF SOME 3-DEOXY-D-
ALTRONIC ACID DERIVATIVES
María de Gracia García-Martín a , María Violante de Paz Báñez b & Juan A. Galbis c
a Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia ,
Universidad de Sevilla , Sevilla, 41012, Spain
b Departamento de Ingeniería Química, Química Física y Química Orgánica , Universidad
de Huelva , Huelva, 21071, Spain
c Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia ,
Universidad de Sevilla , Sevilla, 41012, Spain
Published online: 16 Aug 2006.
To cite this article: María de Gracia García-Martín , María Violante de Paz Báñez & Juan A. Galbis (2001) PREPARATION
AND REACTIVITY OF SOME 3-DEOXY-D-ALTRONIC ACID DERIVATIVES, Journal of Carbohydrate Chemistry, 20:2, 145-157, DOI:
10.1081/CAR-100103954
To link to this article: http://dx.doi.org/10.1081/CAR-100103954
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J. CARBOHYDRATE CHEMISTRY, 20(2), 145–157 (2001)
PREPARATION AND REACTIVITY OF SOME
3-DEOXY-D-ALTRONIC ACID DERIVATIVES
María de Gracia García-Martín1, María Violante de Paz Báñez,2
and Juan A. Galbis1,*
1Departamento de Química Orgánica y Farmacéutica,
Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain
2Departamento de Ingeniería Química,
Química Física y Química Orgánica, Universidad de Huelva,
21071 Huelva, Spain
ABSTRACT
3-Amino-3-deoxy-2,4,5,6-tetra-O-methyl-D-altronic acid hydrochloride was
the key intermediate in the preparation of poly[(2S,3R)-2-methoxy-3-(D-ery-
thro-trimethoxypropyl)propanamide], a chiral nylon 3 analog. We now
describe an alternative synthetic route to this amino acid and the unexpected
reactivity of some of its 3-deoxy derivatives. Attempts to open the 3-azido-3-
deoxy-tri-O-methyl (or O-benzyl)-D-altrono-1,5-lactone intermediates gave
mixtures of products, mostly, ꢀ,ꢁ-unsaturated carbonyl compounds.
INTRODUCTION
Poly(ꢁ-peptide)s, which can be envisaged as nylon 3 derivatives, are able to
adopt regular folded structures stabilized by intramolecular hydrogen bonds with
features very similar to the ꢀ-helix characteristic of poly(ꢀ-peptide)s. Recently, it
has been demonstrated1–3 that not only main chain substitution but also the consti-
tution and position of the substituents are determinant for the conformation
adopted by poly(ꢁ-peptide)s and more specifically for the type of helix that they
may form. On the other hand, synthetic polymers containing carbohydrate units in
*Corresponding author.
145
Copyright © 2001 by Marcel Dekker, Inc.
www.dekker.com

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GARCIA-MARTIN, DE PAZ BÁÑEZ, AND GALBIS
Scheme 1.
the main chain are considered as a new type of polymeric material4 due to their
potential as biodegradable and biocompatible materials useful for medical
applications.
We have recently described the preparation of 3-amino-3-deoxy-2,4,5,6-
tetra-O-methyl-D-altronic acid hydrochloride (2) through the 3-acetamido-3-de-
oxy-2,4,6-tri-O-methyl-D-altrono-1,5-lactone (1)5. This aminoaldonic acid was
transformed into the corresponding ꢁ-lactam, (3S,4R)-3-methoxy-4-(D-erythro-
trimethoxypropyl)azetidine-2-one (3), which was further polymerized by anionic
ring-opening polymerization to give poly[(2S,3R)-2-methoxy-3-(D-erythro-
trimethoxypropyl)propanamide] (4), a chiral nylon 3 analog (Scheme 1)5. Due to
increasing interest in enantiomerically pure ꢁ-amino acids, we tried some alterna-
tive approaches to the preparation of O-benzyl and O-methyl derivatives of the 3-
amino-3-deoxy-D-altronic acid. Thus, we attempted to prepare the aminoaldonic
acid 2 by opening the lactone ring of 3-azido-3-deoxy-2,4,6-tri-O-methyl-D-al-
trono-1,5-lactone (13) which is a precursor of 1, but complex mixtures of products,
mainly ꢀ,ꢁ-unsaturated carbonyl compounds, were formed. Likewise, the 3-azido-
3-deoxy-2,4,6-tri-O-benzyl-D-altrono-1,5-lactone (10) behaved in a similar way.
We now describe an alternative synthetic route to the amino acid 2, the preparation
of lactones 10 and 13 and some other derivatives, and some results on their chem-
ical reactivity.
RESULTS AND DISCUSSION
Per-O-benzylation of 5 to obtain 6 (Scheme 2) was carried out with benzyl
bromide in the presence of sodium hydride in DMF (92%). The O-methyl group of
6 was hydrolyzed with 4M hydrochloric acid in acetonitrile at 85°C, and the tri-O-

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147
benzyl derivative 8 was obtained in a 75% yield. Oxidation of 8 with pyridinium
chlorochromate (PCC) in dichloromethane afforded a good yield (56%) of the cor-
responding 3-azido-3-deoxy-tri-O-benzyl-1,5-D-altrono-lactone (10). However,
attempts to oxidize 8 with dimethyl sulfoxide-acetic anhydride (1:1) gave rise to a
complex mixture of products, from which 6% of the ꢀ,ꢁ-unsaturated lactone 9
could be isolated. The latter compound could have been formed by ꢁ-elimination
of the azido group from the preformed lactone 10.
In a similar way, PCC oxidation of 12 gave the lactone 13 (Scheme 3). Open-
ing of lactones 10 and 13 with methyl iodide as described previously 5–7 was un-
successful. Under those conditions very complex mixture of products were formed,
most of them showing (TLC) intense absorbance under UV light which, together
with the NMR data, indicated the presence of conjugated unsaturated systems.
We could verify that these compounds, having a ꢁ-azido carbonyl system,
suffered ꢁ-elimination of the azido group under basic conditions, even with bases
as weak as triethylamine. The driving force for this process could be the high sta-
bility of the ꢀ,ꢁ-unsaturated carbonyl system and the favorable entropic factor.
The ꢁ-elimination of benzoate and benzyl groups from 1,5-aldonolactones8, 9 and
1,5-aldonolactams10 respectively, had been reported to give the corresponding
ꢀ,ꢁ-unsaturated derivatives. Earlier studies from our laboratory also described11
the ꢁ-elimination of the methoxy group at C-3 of 2,3,4-tri-O-methyl-D-xylono (and
L-arabinono)-1,5-lactones.
We also undertook the opening of lactone 13 under acidic conditions
(Scheme 3). Its reaction with camphorsulfonic acid in dry methanol at room tem-
perature for 7 h, afforded 14 in 94% yield, whereas reaction of 13 with methyl or-
thoformate in methanol, in the presence of sulfuric acid at 50°C, afforded only a
35% yield of 14. When trifluoromethanesulfonic acid was used instead of sulfuric
acid, 14 was isolated in 59% yield.

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GARCIA-MARTIN, DE PAZ BÁÑEZ, AND GALBIS
We tried the methylation of OH-5 of 14 by several different methods. Com-
pound 14 was recovered unaltered after treatment with diazomethane in diethyl
ether in the presence of silica gel for 6 days, whereas when 14 was treated with
sodium hydride/methyl iodide in dry DMF, ꢁ-elimination reactions took place, and
unsaturated compounds 15 and 17–19 were isolated in 20%, 18%, 33% and 28%
yields, respectively. However, treatment of 14 with methyl iodide and silver oxide
under different conditions gave the desired product 16 in moderate to low yields.
Most of these experiments produced 16 along with lactone 13, ꢀ,ꢁ-unsaturated lac-
tone 15 and, in some cases, other unsaturated compounds. The reduction of the
azido group at C-3 of 16 took place easily with hydrogen and 10% Pd/C, and the
intermediate methyl 3-amino-3-deoxy-2,4,5,6-tetra-O-methyl-D-altronate was hy-
drolyzed with 4M hydrochloric acid to give 3-amino-3-deoxy-2,4,5,6-tetra-O-
methyl-D-altronic acid hydrochloride (2).
In order to prevent elimination reactions, the azido groups of 6 and 11 were
reduced with hydrogen in the presence of 10% Pd/C in methanol, and the amino
compounds 7 and 20 were obtained in good yields. Hydrolysis of the methyl gly-
coside 20 (Scheme 4) with 4M hydrochloric acid-acetonitrile gave 21 in 85% yield,
and the amino group was protected as N-benzyloxycarbonyl derivative to give 22.
Oxidation of 22 with PCC in dichloromethane yielded lactone 23 (87%). However,
treatment of 23 with methyl iodide, under the conditions known5–7 to open the

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149
lactone ring with methylation of OH-5, gave the cyclic urethane 24 (60%). The for-
mation of 24 could be explained as nucleophilic attack by the free OH-5, of the
corresponding open chain derivative, on the carbonyl of the N-protecting group,
with displacement of the benzyloxy group.
In conclusion, due to the easy elimination of the azido group at C-3 of lactone
13, attempts to open the lactone ring under basic conditions did not give good
yields of 16, the precursor of the amino acid 2, but mixtures of ꢀ,ꢁ-unsaturated car-
bonyl compounds were obtained instead. However, compound 16 was obtained in
low to moderate yield, in two steps, by treatment of 13 with camphorsulfonic acid,
then methylation of OH-5 of 14, under mild conditions, with silver oxide and
methyl iodide. Alternatively, as we have already described5 the amino acid 2 was
prepared from the acetamido lactone 1. Lactones 13 and 1 were both easily ob-
tained from 12.
EXPERIMENTAL
General Methods. Chemicals were all used as purchased from the Aldrich
Chemical Co. Solvents were dried and purified, when necessary, by appropriate
standard procedures. Melting points are uncorrected. Optical rotations were mea-
sured at 20 ꢂ 5°C with a Bellingham & Standley Inc., P20 polarimeter (5-cm cell).
TLC was performed on Silica Gel 60 F254 (Merck) with detection by UV light or
charring with sulfuric acid and flash column chromatography with Silica Gel 60
(230–400 mesh, Merck). Elemental analyses were determined in the Microanaly-
sis Laboratories at the Universidad Complutense de Madrid. FT IR spectra: films
or KBr discs. NMR spectra: chemical shifts are reported as parts per million down
field from tetramethylsilane. MS were recorded on a Kratos MS80RFA instrument

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GARCIA-MARTIN, DE PAZ BÁÑEZ, AND GALBIS
equipped with a combined EI-CI source. HRMS (EI. 70 eV) were taken with
10000.
3-Amino-3-deoxy-2,4,5,6-tetra-O-methyl-D-altronic acid hydrochloride
(2). A solution of 16 (0.025 g, 0.086 mmol) in methanol (1 mL) was stirred with
10% Pd/C (3 mg) for 2 h under a hydrogen atmosphere. The suspension was fil-
tered through diatomaceous earth and the solution concentrated to dryness. The
residue was purified by flash-column chromatography (ethyl acetate) to give a
compound (0.022 g, 97%) that was identified as methyl 3-amino-3-deoxy-2,4,5,6-
tetra-O-methyl-D-altronate, according to the following data: IR 3420, 1630 (NH2),
1750 cmꢃ1 (CO ester); 13C NMR (CDCl3, 50 MHz), ꢄ 170.74 (C-1), 81.24, 78.23,
77.64 (C-2/C-4/C-5), 69.82 (C-6), 59.80, 59.16, 58.60, 57.65 (4 OCH3), 54.32 (C-
3), 52.45 (COOCH3). The above compound was treated with 4M HCl (2 mL) at
room temperature for 5 days, then concentrated. The residue was treated with light
petroleum to give a solid which was identified as the previously described 25
(0.024 g, 93%).
Methyl 3-azido-3-deoxy-2,4,6-tri-O-benzyl-ꢀ-D-altro-hexopyranoside
(6). To sodium hydride (60%) (0.12 g, 3.05 mmol) washed with pentane (20 mL
ꢅ 3) under argon atmosphere, a solution of 55 (0.13 g, 0.61 mmol) in dry DMF (7
mL) was added dropwise with stirring at 0°C. The mixture was stirred at this tem-
perature for 1 h, then benzyl bromide (0.24 mL, 2.05 mmol) was added and stirring
was continued at room temperature overnight. Methanol (2.5 mL) was added drop-
wise and the mixture was stirred for 1 h, then the reaction mixture was poured into
a mixture of CHCl3 (50 mL) and aq NaHCO3 satd solution (25 mL). The organic
phase was washed with brine (25 mL), dried (anhydrous MgSO4) and concen-
trated. The yellowish residue was purified by flash-column chromatography (1:2
diethyl ether-light petroleum) to give the title compound as an oil (0.28 g, 92%);
[ꢀ]D ꢆ52° (c 1.3, dichloromethane); IR 3030 (Ph), 2100 (N3), 747, 701 cmꢃ1 (Ph);
1H NMR (CDCl3, 200 MHz), ꢄ 7.35–7.25 (m, 15 H, 3 Ph), 4.69 (d, 1 H, J1,2 1.9 Hz,
H-1), 4.68–4.46 (6 H, 3 OCH2Ph), 4.12–3.96 (m, 3 H, H-4, H-6, H-6ꢇ), 3.83 (ddd,
1 H, J2,3 4.7, J3,4 3.4, J1,3 0.6 Hz, H-3), 3.68 (m, 1 H, H-5), 3.63 (dd, 1 H, H-2),
3.38 (s, 3 H, OCH3); 13C NMR (CDCl3, 50 MHz), ꢄ 137.99, 137.48, 137.31,
128.33, 128.28, 128.19, 128.08, 127.82, 127.64 (Ph), 99.89 (C-1), 77.64 (C-2),
73.35 (OCH2Ph), 72.65 (C-4), 72.43, 72.24 (2 OCH2Ph), 69.06 (C-6), 67.91 (C-5),
59.08 (C-3), 55.34 (OCH3); MS (CI): m/z 462 (M ꢆ H- N2)ꢆ, 430 (M - N2 -
OCH3)ꢆ, 91 (Ph-CH2)ꢆ.
Anal. Calcd for C28H31N3O5: C, 68.69; H, 6.38; N, 8.58. Found: C, 68.39; H,
6.28; N, 8.35.
Methyl 3-amino-3-deoxy-2,4,6-tri-O-benzyl-ꢀ-D-altro-hexopyranoside
(7). A solution of 6 (0.45 g, 0.93 mmol) in methanol (3 mL) was stirred with 10%
Pd/C for 4–5 h at room temperature under a hydrogen atmosphere, at atmospheric
pressure. The mixture was diluted with methanol, filtered on diatomaceous earth
and concentrated. Purification of the residue by flash-column chromatography
(ethyl acetate) afforded the corresponding amino derivative 7 (0.42 g, 98%) as an

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151
oil; [ꢀ]D ꢆ58° (c 1.86, dichloromethane); IR 3382, 1606 (NH2), 746, 701 cmꢃ1
(Ph); 1H NMR (CDCl3, 500 MHz), ꢄ 7.40–7.20 (m, 15 H, 3 Ph), 4.72 (d, 1 H, J1,2
1.8 Hz, H-1), 4.62 (d, 1H, J 12.1 Hz, OCH2Ph), 4.60 (d, 1H, J 12.1 Hz, OCH2Ph),
4.58 (d, 1H, J 12.1 Hz, OCH2Ph), 4.56 (d, 1H, J 12.1 Hz, OCH2Ph), 4.52 (d, 1H, J
11.4 Hz, OCH2Ph), 4.43 (d, 1H, J 11.4 Hz, OCH2Ph), 3.97 (ddd, 1 H, J4,5 9.5, J5,6
2.4, J5,6ꢇ 5.3 Hz, H-5), 3.82 (dd, 1 H, J3,4 3.8 Hz, H-4), 3.77 (dd, 1 H, J6,6ꢇ 10.7 Hz,
H-6), 3.73 (dd, 1 H, H-6ꢇ), 3.62 (dd, 1 H, J2,3 3.8 Hz, H-2), 3.39 (s, 3 H, OCH3),
3.37 (t, 1 H, H-3); 13C NMR (CDCl3, 125 MHz), ꢄ 138.33, 138.05, 137.93, 128.37,
128.26, 127.84, 127.77, 127.67 (Ph), 100.26 (C-1), 77.63 (C-2), 73.45 (OCH2Ph),
73.08 (C-4), 72.06 (OCH2Ph), 71.43 (OCH2Ph), 69.79 (C-6), 66.69 (C-5), 55.21
(OCH3), 49.30 (C-3); MS (CI): m/z 464 (M ꢆ H)ꢆ, 432 (M - OCH3)ꢆ, 91 (Ph-
CH2)ꢆ.
Anal. Calcd for C28H33NO5: C, 72.55; H, 7.18; N, 3.02. Found: C, 72.53; H,
7.11; N, 2.74.
3-Azido-3-deoxy-2,4,6-tri-O-benzyl-ꢀ,ꢁ-D-altro-hexopyranose (8).
A
solution of 6 (2.17 g, 4.44 mmol) in a 3:5 mixture of 4M HCl-acetonitrile (80 mL)
was heated at 85°C for 4 days. The organic layer was washed with aq NaHCO3 satd
solution (15 mL ꢅ 3) and the aqueous solution extracted with Cl3CH (75 mL ꢅ 3).
The combined organic solutions were dried (anhydrous MgSO4) and concentrated
to dryness. The residue was purified by flash-column chromatography (2:1 diethyl
ether-light petroleum) giving a small amount of the starting material 6 (0.18 g,
8%), and 8 as an oil (1.45 g, 75%); [ꢀ]D ꢆ14° (c 1.4, dichloromethane); IR 3425
(OH), 3030 (Ph), 2110 (N3), 742, 699 cmꢃ1 (Ph); 13C NMR (CDCl3, 50 MHz), ꢄ
137.99–137.28, 128.67–127.61 (Ph) 92.94, 91.20 (C-1ꢀ/C-1ꢁ), 78.15, 77.63 (C-
2ꢀ/C-2ꢁ), 73.54, 73.19, 72.45, 72.14 (OCH2Ph), 74.29, 72.78, 72.65, 67.58 (C-
4ꢀ,ꢁ/C-5ꢀ,ꢁ), 68.96 (C-6ꢀ and C-6ꢁ), 59.79, 59.33 (C-3ꢀ/C-3ꢁ); MS (CI): m/z
340 (M - OCH2Ph - N2)ꢆ, 91 (Ph-CH2)ꢆ.
Anal. Calcd for C27H29N3O5: C, 68.19; H, 6.15; N, 8.84. Found: C, 67.82; H,
6.26; N, 8.68.
3-Deoxy-2,4,6-tri-O-benzyl-D-erythro-hex-2-enono-1,5-lactone (9).
A
solution of 8 (0.12 g, 0.25 mmol) in 1:1 dry Me2SO-acetic anhydride (4 mL) was
stirred at room temperature under an argon atmosphere for 2 days. The mixture was
poured into iced H2O (15 mL) containing Et3N (1 mL) and extracted with diethyl
ether (20 mL ꢅ 3). The organic solution was dried (anhydrous MgSO4) and con-
centrated to dryness. TLC of the residue showed a complex mixture of products
and flash-column chromatography (1:5 ethyl acetate-light petroleum, containing
1% of Et3N) afforded the title compound as an oil (0.007 g, 6%); IR 3030 (Ph),
1
1744 (CO lactone), 1640 (CꢈC), 736, 690 cmꢃ1 (Ph); H NMR (CDCl3, 500
MHz), ꢄ 7.34–7.24 (m, 15 H, Ph), 5.63 (d, 1 H, J3,4 4.1 Hz, H-3), 4.89, 4.86 (2d,
each 1 H, J 12.1 Hz, CH2Ph), 4.58–4.46 (m, 6 H, H-4, H-5, 2CH2Ph), 3.73 (dd, 1
H, J5,6 3.9, J6,6ꢇ 10.7 Hz, H-6), 3.65 (dd, 1 H, J5,6ꢇ 4.7 Hz, H-6ꢇ); 13C NMR (CDCl3,
125 MHz), ꢄ 159.37 (C-1), 144.02 (C-2),137.41–127.34 (Ph), 110.16 (C-3),
79.74/69.34 (C-4/C-5), 73.54 (C-6), 71.11, 70.33, 68.28 (3 OCH2Ph); MS (CI): m/z
339 (M - C7H7)ꢆ, 181 (C7H7 C7H6)ꢆ, 91 (C7H7)ꢆ.

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GARCIA-MARTIN, DE PAZ BÁÑEZ, AND GALBIS
3-Azido-3-deoxy-2,4,6-tri-O-benzyl-D-altrono-1,5-lactone (10). A solu-
tion of 8 (0.16 g, 0.34 mmol) in dry CH2Cl2 (12 mL) was stirred with 3Å molecu-
lar sieves (0.15 g) for a few minutes, then pyridinium chlorochromate (0.36 g, 1.68
mmol) was added. The mixture was stirred at room temperature in the dark for 2
days, then diluted with diethyl ether, filtered through a column of silica gel G con-
taining CaSO4 (10%), and concentrated to give 10 as a colorless oil (0.1 g, 56%);
[ꢀ]D ꢃ44° (c 0.68, dichloromethane); IR 3031 (Ph), 2110 (N3), 1748 (CꢈO lac-
tone), 742, 699 cmꢃ1 (Ph); 1H NMR (CDCl3, 500 MHz), ꢄ 7.60–7.25 (m, 15 H, 3
Ph), 5.12 (d, 1 H, J 11 Hz, OCH2Ph), 4.74 (d, 1 H, J 11 Hz, OCH2Ph), 4.72 (d, 1
H, J 11.6 Hz, OCH2Ph), 4.66 (d, 1 H, J 11.6 Hz, OCH2Ph), 4.60 (d, 1 H, J 12 Hz,
OCH2Ph), 4.58 (m, 1 H, H-5), 4.52 (d, 1 H, J 12 Hz, OCH2Ph), 4.36 (d, 1 H, J2,3
8.7 Hz, H-2), 4.20 (dd, 1 H, J3,4 3.2 Hz, H-3), 4.15 (dd, 1 H, J4,5 4.1 Hz, H-4), 3.69
(dd, 1 H, J5,6 4.1, J6,6ꢇ 10.9 Hz, H-6), 3.65 (dd, 1 H, J5,6ꢇ 3.1 Hz, H-6ꢇ); 13C NMR
(CDCl3, 125 MHz), ꢄ 168.37 (C-1), 136.69, 128.44, 128.31, 128.11, 127.95,
127.83, 127.59 (Ph), 78.15 (C-5), 74.46 (C-2), 73.86 (C-4 and OCH2Ph), 73.54,
72.90 (2 OCH2Ph), 68.66 (C-6), 60.01 (C-3); MS (CI): m/z 181 (C7H7C7H6)ꢆ, 91
(Ph-CH2)ꢆ.
Anal. Calcd for C27H27N3O5: C, 68.49; H, 5.75; N, 8.87. Found: C, 68.27; H,
5.76; N, 8.61.
3-Azido-3-deoxy-2,4,6-tri-O-methyl-D-altrono-1,5-lactone (13). Com-
pound 13 was prepared from 125 (1.2 g, 4.86 mmol) by the same procedure de-
scribed for 10, and obtained as a colorless oil (1.1 g, 92%); [ꢀ]D ꢃ29° (c 1.17,
dichloromethane); IR 2112 (N3), 1752 cmꢃ1 (CO lactone); 1H NMR (CDCl3, 200
MHz), ꢄ 4.51 (q, 1 H, J5,6 ꢈ J5,6ꢇ 3.5 Hz, H-5), 4.15 (dd, 1 H, J3,4 3.0 Hz, H-3), 4.03
(d, 1 H, J2,3 9.2 Hz, H-2), 3.75 (t, 1 H, J4,5 3.3 Hz, H-4), 3.58 (d, 2 H, H-6, H-6ꢇ),
3.66, 3.49, 3.36 (s, each 3 H, OCH3); 13C NMR (CDCl3, 50 MHz), ꢄ 168.59 (C-1),
77.47 (C-5), 77.00 (C-4), 76.92 (C-2), 71.76 (C-6), 59.71 (C-3), 60.21, 59.72,
58.45 (3 OCH3); MS (CI): m/z 246 (M ꢆ H)ꢆ.
Anal. Calcd for C9H15N3O5: C, 44.08; H, 6.16; N, 17.14. Found: C, 44.11; H,
6.04; N, 17.07.
Methyl 3-azido-3-deoxy-2,4,6-tri-O-methyl-D-altronate (14). A solution
of lactone 13 (0.16 g, 0.65 mmol) in dry MeOH (10 mL) containing camphorsul-
fonic acid (6 mg) was stirred at room temperature for 6 h. The solution was then
stirred with IRA 400 (HO-) resin for 10 min. The mixture was diluted with diethyl
ether (20 mL), the resin was filtered off and the solution concentrated. The result-
ing syrup was purified by chromatography as usual (2:3 ethyl acetate-light
petroleum) to give the title compound as a colorless oil (0.17 g, 94%); [ꢀ]D ꢃ44°
1
(c 0.7, dichloromethane); IR 3488 (OH), 2114 (N3), 1747 cmꢃ1 (CO ester); H
NMR (CDCl3, 200 MHz), ꢄ 4.17 (d, 1 H, J2,3 4.2 Hz, H-2), 3.91 (m, 1 H, H-5), 3.81
(s, 3 H, COOCH3), 3.64 (dd, 1 H, J3,4 7.9 Hz, H-3), 3.53 (d, 2H, H-6, H-6ꢇ), 3.41
(dd, 1 H, J4,5 7.1 Hz, H-4), 3.51, 3.47, 3.41 (3s, each 3 H, OCH3); 1H (Me2SO-d6,
200 MHz), ꢄ 5.19 (d, 1 H, JOH,5 5 Hz, OH), 4.16 (d, 1 H, J2,3 3.6 Hz, H-2), 3.91 (m,
1 H, H-5), 3.70 (s, 3 H, COOCH3), 3.64 (dd, 1 H, J3,4 9.2 Hz, H-3), 3.40 (m, 1 H,

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H-4), 3.45 (dd, 1 H, J5,6 5.9, J6,6ꢇ 9.5 Hz, H-6), 3.34 (dd, 1 H, J5,6ꢇ 5.5 Hz, H-6ꢇ),
3.38, 3.36, 3.25 (3s, each 3 H, OCH3); 13C NMR (CDCl3, 50 MHz), ꢄ 170.94 (C-
1), 80.32 (C-2), 79.47 (C-6), 72.90 (C-4), 70.41 (C-5), 62.50 (C-3), 59.43, 59.08,
58.98 (3 OCH3), 52.21 (COOCH3).
Anal. Calcd for C10H19N3O6: C, 43.22; H, 6.90; N, 15.16. Found: C, 43.22;
H, 6.87; N, 15.07.
Treatment of lactone 13 with trimethyl orthoformate: Isolation of 14.
Method a): A solution of lactone 13 (0.05 g, 0.2 mmol) in methanol (0.2 mL) con-
taining trimethyl orthoformate (0.04 mL, 0.4 mmol) and concentrated H2SO4 (1.1
ꢉL, 2.0 ꢅ 10ꢃ3 mmol), was heated at 50°C for 14 h. The solution was concentrated
and the residue was solved in ethyl acetate (15 mL), washed with aq NaHCO3 satd
solution, dried (anhydrous MgSO4) and concentrated. Flash-column chromatogra-
phy of the residue (1:1 ethyl acetate-light petroleum) gave 14 (0.02 g, 35%).
Method b): Lactone 13 (0.05 g, 0.2 mmol) was solved in a solution of 0.11 M
trifluoromethanesulfonic acid in methanol (0.06 mL) and trimethyl orthoformate
(45ꢉL, 0.4 mmol) was added. The mixture was stirred at room temperature
overnight, then work-up as described for a) afforded 14 (0.03 g, 59%).
Treatment of 14 with MeI/NaH: Isolation of methyl 2,4,6-tri-O-methyl-
D-erythro-(Z)-2-hexenoate (17), methyl 2,4,5,6-tretra-O-methyl-D-erythro-(Z)-
2-hexenoate (18), and methyl 2,4,5,6-tetra-O-methyl-D-erythro-(E)-2-
hexenoate (19). To sodium hydride (60%) (0.02 g, 0.58 mmol) washed with
pentane (15 mL ꢅ 3) under an argon atmosphere, was added dropwise a solution
of 14 (0.1 g, 0.36 mmol) in dry DMF (5 mL). The mixture was stirred at room tem-
perature for 10 min, then MeI (75 ꢉL, 1.2 mmol) was added and stirring was con-
tinued under the same conditions for 6 h. The reaction mixture was diluted with
CH2Cl2 (20 mL) and the organic solution was washed with 0.5 M HOAc:NaOAc
(pH 4.74) (10 mL ꢅ 2), then with H2O (10 mL) and dried (anhydrous Na2SO4).
The solvent was evaporated under reduced pressure and the residue (0.17 g)
showed a complex mixture of products on TLC. Flash-column chromatography of
this residue using 1:5 to 2:3 ethyl acetate-light petroleum, afforded the following
fractions: 15 (0.015 g, 20%), 17 (0.014 g, 18%), 18 (0.03 g, 33%), and 19 (0.025
g, 28%).
Compound 17: IR 3507 (OH), 3080 (CꢈC-H), 1651 (CꢈC), 1728 cmꢃ1 (CO
ester); 1H NMR (CDCl3, 200 MHz), ꢄ 6.10 (d, 1 H, J3,4 9.4 Hz, H-3), 4.24 (dd, 1
H, J4,5 5.0 Hz, H-4), 3.88 (bm, 1H, H-5), 3.79 (s, 3 H, COOCH3), 3.46 (dd, 1H, J5,6
4.2, J6.6ꢇ 9.8 Hz, H-6), 3.35 (dd, 1H, J5,6ꢇ 6.8 Hz, H-6ꢇ), 3.69, 3.36, 3.29 (3s, each
3 H, OCH3); 13C NMR (CDCl3, 50 MHz), ꢄ 163.29 (C-1), 149.19 (C-2), 123.20
(C-3), 75.7, 71.9 (C-4/C-5), 73.01 (C-6), 60.08, 59.13, 56.96 (3 OCH3), 52.96
(COOCH3); MS (FAB): m/z 257 (M ꢆ Na)ꢆ.
Compound 18: IR 3144 (CꢈC-H), 1657 (CꢈC), 1728 cmꢃ1 (CO ester); 1H
NMR (CDCl3, 200 MHz), ꢄ 6.10 (d, 1 H, J3,4 9.4 Hz, H-3), 4.32 (dd, 1 H, J4,5 3.7
Hz, H-4), 3.77 (s, 3 H, COOCH3), 3.50ꢃ3.30 (m, 3H, H-5, H-6, H-6ꢇ), 3.68, 3.45,
3.33, 3.27 (4s, each 3 H, OCH3); 13C NMR (CDCl3, 50 MHz), ꢄ 163.40 (C-1),

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GARCIA-MARTIN, DE PAZ BÁÑEZ, AND GALBIS
148.67 (C-2), 123.83 (C-3), 82.1, 75.2 (C-4/C-5), 71.80 (C-6), 60.02, 59.15, 58.81,
57.14 (4 OCH3), 52.10 (COOCH3); MS (FAB): m/z 271 (M ꢆ Na)ꢆ.
Compound 19: 1H NMR (CDCl3, 200 MHz), ꢄ 6.08 (d, 1 H, J3,4 9.0 Hz, H-
3), 4.78 (dd, 1 H, J4,5 2.9 Hz, H-4), 3.80 (s, 3 H, COOCH3), 3.55-3.35 (m, 3H, H-
5, H-6, H-6ꢇ), 3.62, 3.49, 3.31, 3.29 (4s, each 3 H, OCH3); 13C NMR (CDCl3, 50
MHz), ꢄ 163.34 (C-1), 148.08 (C-2), 109.52 (C-3), 82.60, 76.32 (C-4/C.5), 72.32
(C-6), 59.04, 58.69, 56.84, 55.51 (4 OCH3), 52.17 (COOCH3); MS (FAB): m/z 271
(M ꢆ Na)ꢆ.
Treatment of 14 with MeI/Ag2O. a) Isolation of 3-deoxy-2,4,6-tri-O-
methyl-D-erythro-hex-2-enono-1,5-lactone (15). To a solution of 14 (0.08 g,
0.3 mmol) in dry THF (1 mL) was added silver oxide (0.076 g, 0.33 mmol) and MeI
(0.04 mL, 6 mmol) and the mixture was stirred at room temperature under argon
for 5 h. The mixture was diluted with acetonitrile and the suspension was filtered
through diatomaceous earth. The filtrate was concentrated and the residue was pu-
rified by flash-column chromatography (1:5 to 1:3 ethyl acetate-light petroleum) to
give 15 (0.052 g, 87%) as an oil; [ꢀ]D ꢆ84° (c 2.0, dichloromethane); IR 3073
(CꢈCH), 1753 (CꢈO lactone), 1655 cmꢃ1 (CꢈC); 1H NMR (CDCl3, 200 MHz),
ꢄ 5.65 (d, 1 H, J3,4 4.1 Hz, H-3), 4.45 (dt, 1 H, J4,5 6.1 Hz, H-5), 4.23 (dd, 1 H, H-
4), 3.64 (dd, 1 H, J5,6 4.1, J6,6ꢇ 10.7 Hz, H-6), 3.55 (dd, 1 H, J5,6ꢇ 4.6 Hz, H-6ꢇ),
3.67, 3.41, 3.37 (3s, each 3 H, OCH3); 13C NMR (CDCl3, 50 MHz), ꢄ 159.47 (C-
1), 145.21 (C-2), 107.21 (C-3), 79.42, 71.16 (C-4/C-5), 70.81 (C-6), 59.44, 56.62,
55.57 (3 OCH3); HRMS (EI) Calcd for C9H14O5 : 202.084124. Found:
202.084455.
b) Isolation of methyl 3-azido-3-deoxy-2,4,5,6-tetra-O-methyl-D-al-
tronate (16). A solution of 14 (0.06 g, 0.21 mmol) in dry acetonitrile (1 mL) was
stirred with silver oxide (0.23 g, 0.42 mmol) and MeI (0.6 mL, 2.74 mmol) at 60°C
for 60 h. A complex mixture of compounds was observed (TLC) and after work-
ing up as usual, the following compounds were isolated: 13 (0.014 g, 13%), 15
(0.05 g, 58%) and 16 (0.02 g, 17%) as a colorless oil; [ꢀ]D ꢃ33° (c 1.2,
1
dichloromethane); IR 2112 (N3), 1755 cmꢃ1 (CO ester); H NMR (CDCl3, 200
MHz), ꢄ 4.09 (d, 1 H, J2,3 3.6 Hz, H-2), 3.77 (s, 3 H, COOCH3), 3.73 (dd, 1 H, J3,4
9.2 Hz, H-3), 3.66-3.40 (m, 4 H, H-4, H-5, H-6, H6ꢇ), 3.47, 3.44, 3.42, 3.34 (4s,
each 3 H, OCH3); 13C NMR (CDCl3, 50 MHz), ꢄ 171.00 (C-1), 80.45, 79.95, 78.21
(C-2/ C-4/ C-5), 71.26 (C-6), 62.77 (C-3), 59.57, 59.06, 59.05, 58.42 (4 OCH3),
52.10 (COOCH3); MS (CI): m/z 247 (M ꢆ H - COOCH3)ꢆ, 232 (M - COOCH3)ꢆ,
101 (C5H9O2)ꢆ.
Anal. Calcd for C11H21N3O6: C, 45.36; H, 7.27; N, 14.42. Found: C, 45.30;
H, 7.01; N, 14.24.
c) A solution of 14 (0.11 g, 0.41 mmol) in dry acetonitrile (1 mL) was stirred
with silver oxide (0.19 g, 0.8 mmol) and MeI (1.3 mL, 20.7 mmol) at room tem-
perature for 7 days. Work- up as usual afforded 16 (23%) and 13 (21%).
d) To a solution of 14 (0.4 g, 1.4 mmol) in dry acetonitrile (7.5 mL) were
added Dowex 50 ꢅ 8 resin (0.29 g, 1.44 meq Hꢆ), molecular sieves 3 Å (0.4 g),

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155
silver oxide (0.33 g, 1.44 mmol) and MeI (1.8 mL, 28.8 mmol). The mixture was
heated, with stirring under argon, at 80°C for 10 h. During this time, more silver
oxide (0.33 g, 1.44 mmol) and MeI (0.36 mL, 7.75 mmol) were added, then the
mixture was diluted with acetonitrile (5 mL) and stirring was continued at 30°C
overnight. Work-up as usual gave 16 (24%) and 13 (20%).
Methyl 3-amino-3-deoxy-2,4,6-tri-O-methyl-ꢀ-D-altro-hexopyranoside
(20). Compound 20 was obtained from 11 (0.36 g, 1.38 mmol) as described
above for the preparation of 7 and obtained as a colorless oil (0.30 g, 93%); [ꢀ]D
1
ꢆ98° (c 1.63, dichloromethane); IR 3440, 1632 cmꢃ1 (NH2); H NMR (CDCl3,
500 MHz), ꢄ 4.55 (bs, 1 H, H-1), 3.90-3.75 (m, 2 H, H-3, H-5), 3.65 (dd, 1 H, J5,6
2.5, J6,6ꢇ 10.4 Hz, H-6), 3.57 (dd, 1 H, J5,6ꢇ 5.6, H-6ꢇ), 3.60ꢃ3.50 (m, 1 H, H-4),
3.45-3.35 (m, 1 H, H-2), 3.29, 3.28, 3.26, 3.23 (4s, each 3 H, OCH3), 1.8 (bs, 2 H,
NH2); 13C NMR (CDCl3, 125 MHz), ꢄ 99.32 (C-1), 79.60 (C-4), 74.35 (C-2), 72.05
(C-6), 65.73 (C-5), 59.35, 57.84, 56.60, 54.98 (4 OCH3), 48.05 (C-3); MS (CI): m/z
236 (M ꢆ H)ꢆ, 204 (M - OCH3)ꢆ, 172 (M - CH3OH - OCH3)ꢆ; HRMS (EI) Calcd
for C10H21NO5 : 235.1414. Found: 235.1418.
3-Amino-3-deoxy-2,4,6-tri-O-methyl-ꢀ,ꢁ-D-altro-hexopyranose (21).
A
solution of 20 (0.5 g, 2.2 mmol) in a 5:1 mixture of 4M HCl-acetonitrile (20 mL)
was heated at 80°C for 2 h. The mixture was concentrated to dryness and ex-
tracted with CH2Cl2 (20 mL). The extract was washed with aq NaHCO3 satd so-
lution (10 mL ꢅ 2), dried (anhydrous MgSO4) and concentrated to dryness. The
residue (0.45 g) was purified by flash-column chromatography (10:1 CH2Cl2-
MeOH) to give 21 as a solid (0.40 g, 85%), mp 174°C (dec.); [ꢀ]D ꢃ73° (c 0.52,
1
dimethyl sulfoxide); IR 3413, 1665 cmꢃ1 (NH2); H NMR (Me2SO-d6, 500
MHz), ꢀ anomer: ꢄ 5.00 (bs, 1 H, H-1), 4.36 (bs, 1 H, OH), 4.12 (ddd, 1 H, J
2.4, J 5.0, J 6.0 Hz, H-5), 4.05 (m, 1 H, H-3), 3.55 (m, 1 H, H-4), 3.36 (m, 2 H,
H-6, H-6ꢇ), 3.30 (dd, 1 H, J 2.5, J 5.0 Hz, H-2); ꢁ anomer: ꢄ 4.85 (bs, 1 H, H-
1), 4.05 (m, 1 H, H-3), 4.01 (bs, 1 H, OH), 3.77 (ddd, 1 H, J 2.4, J 4.5, J 9.0 Hz,
H-5), 3.55 (m, 1 H, H-4), 3.36 (m, 2 H, H-6, H-6ꢇ), 3.27 (dd, 1 H, J 1.9, J 4.2
Hz, H-2); ꢀ and ꢁ anomers: ꢄ 3.46, 3.45, 3.37, 3.36, 3.35, 3.34 (6s, each 3 H,
OCH3); 13C NMR (Me2SO-d6, 125 MHz), ꢀ anomer: ꢄ 92.12 (C-1), 78.30 (C-2),
74.64 (C-4), 71.55 (C-6), 67.03 (C-5), 57.95 (C-3); ꢁ anomer: ꢄ 91.22 (C-1),
78.57 (C-2), 74.54 (C-4), 72.15 (C-5), 71.48 (C-6), 57.14 (C-3); ꢀ and ꢁ
anomers: ꢄ 59.07, 58.99, 58.14, 57.95, 57.53, 57.14 (6 OCH3).
Anal. Calcd for C9H19NO5: C, 48.84; H, 8.66; N, 6.33. Found: C, 49.12; H,
8.30; N, 6.51.
3-(Benzyloxycarbonyl)amino-3-deoxy-2,4,6-tri-O-methyl-ꢀ,ꢁ-D-altro-
hexopyranose (22). To a cold solution (0ꢈn5°C) of 21 (0.26 g, 1.17 mmol) in
aq NaHCO3 satd solution (10 mL), benzyloxycarbonyl chloroformate (0.25 mL,
2.0 mmol) was added dropwise with stirring. The mixture was stirred at room tem-
perature overnight, then H2O was added (10 mL) and the mixture was extracted
with CHCl3 (25 mL ꢅ 3). The organic solution was washed with brine (25 mL),

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GARCIA-MARTIN, DE PAZ BÁÑEZ, AND GALBIS
dried (anhydrous MgSO4) and concentrated to a residue (0.55 g). Flash-column
chromatography of this residue (1:1 to 4:1 diethyl ether-light petroleum) afforded
22 as a white solid (0.2 g, 50%), mp 106–107°C; [ꢀ]D ꢆ64° (c 0.87,
dichloromethane); IR 3426 (NH and OH), 2990 (Ph), 1683 (NH-CO-O), 762, 695
cmꢃ1 (Ph); 1H NMR (CDCl3, 500 MHz), ꢀ anomer: ꢄ 7.37–7.26 (m, 5 H, Ph), 6.05
(d, 1 H, JNH,3 9.7 Hz, NH), 5.15 (dd, 2H, J 12.3 Hz, CH2-Ph), 5.21 (d, 1 H, J1,2 3.7
Hz, H-1), 4.49 (bd, 1 H, H-3), 4.04 (ddd, 1 H, J4,5 9.7, J5,6 2.2, J5,6ꢇ 7.2 Hz, H-5),
3.67 (dd, 1 H, J6,6ꢇ 10.2 Hz, H-6), 3.54 (dd, 1 H, H-6ꢇ), 3.42 (dd, 1 H, J2,3 1.5 Hz,
H-2), 3.40 (m, 1 H, H-4), 3.44, 3.37, 3.36 (3s, each 3 H, OCH3); 13C NMR (CDCl3,
125 MHz), ꢀ anomer: ꢄ 156.39 (CꢈO), 128.05–136.48 (Ph), 92.32 (C-1), 78.37
(C-4), 73.02 (C-2), 72.44 (C-6), 66.80 (CH2-Ph), 66.39 (C-5), 59.13, 58.05, 57.19
(3 OCH3), 46.20 (C-3); MS (CI): m/z 338 (M - NH3)ꢆ, 248 (M - PhCH2O)ꢆ, 230
(M - PhCH2O - H2O)ꢆ, and 91 (Ph-CH2)ꢆ.
Anal. Calcd for C17H25NO7: C, 57.46; H, 7.09; N, 3.94. Found: C, 57.45; H,
7.05; N, 3.74.
3-(Benzyloxycarbonyl)amino-3-deoxy-2,4,6-tri-O-methyl-D-altrono-1,5-
lactone (23). Compound 22 (0.4 g, 1.13 mmol) was oxidized to lactone 23 as de-
scribed above for the preparation of 10. Lactone 23 was a colorless oil (0.35 g, 87%
yield); [ꢀ]D ꢆ64° (c 0.87, dichloromethane); IR 3420 (NH), 1727 (CO lactone),
745, 699 cmꢃ1 (Ph); 13C NMR (CDCl3, 125 MHz), ꢄ 169.29 (C-1), 155.90 (CꢈO),
135.22, 128.57, 128.28, 128.16 (Ph), 77.87, 76.38, 76.25 (C-2/C-4/C-5), 72.03 (C-
6), 67.12 (CH2-Ph), 59.55, 58.54, 57.82 (3 OCH3), 50.34 (C-3); MS (CI): m/z 354
(M ꢆ H)ꢆ and 91 (Ph-CH2)ꢆ; HRMS (EI) Calcd for C17H23NO7: 353.1468.
Found: 353.1490.
3-Amino-3-deoxy-3,5-N,O-carbonyl-2,4,6-tri-O-methyl-D-altronic acid
(24). To a solution of lactone 23 (0.11 g, 0.31 mmol) in dry THF (3 mL) was
added freshly powdered KOH (0.07 g, 1.27 mmol), 18-crown-6 (8.4 mg, 10%
mol) and MeI (0.07 mL, 1.0 mmol). The mixture was stirred in the dark at room
temperature under argon for 3 h. Then CH2Cl2 (10 mL) was added and the solu-
tion was washed with H2O (5 mL). The aqueous phase was treated with concen-
trated HCl to pH 2, then extracted with CH2Cl2 (15 mL ꢅ 4), dried (anhydrous
MgSO4) and concentrated to a residue (0.03 g). The aqueous phase was concen-
trated to dryness and extracted with MeOH. Evaporation of the methanol solvent
gave a residue which was purified by flash-column chromatography, and the
cyclic urethane 24 was isolated as a white solid (0.05 g, 60%), mp 118°C (dec);
[ꢀ]D ꢃ44° (c 0.69, methanol); IR 3336 (COOH), 1703 cmꢃ1 (CO acid); 1H NMR
(Me2SO-d6, 200 MHz), ꢄ 6.85 (bs, 1 H, NH), 4.25–3.40 (m, 6 H, sugar moiety),
3.33, 3.32, 3.27 (3s, each 3 H, OCH3); 13C NMR (Me2SO-d6, 50 MHz), ꢄ 172.04
(COOH), 154.20 (CO, urethane), 79.28, 77.50, 71.49 (C-2/C-4/C-5), 70.34 (C-
6), 60.06, 59.14, 58.85 (3 OCH3), 57.12 (C-3); MS (CI): m/z 264 (M ꢆ H)ꢆ, 220
(M ꢆ H ꢃ CO2)ꢆ.
Anal. Calcd for C10H17NO7: C, 45.79; H, 6.15; N, 5.34. Found: C, 45.70; H,
6.22; N, 5.20.

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ACKNOWLEDGMENT
We thank the C.I.C.Y.T. (Comisión Interministerial de Ciencia y Tecnología)
of Spain for financial support (Grant MAT99-0578-C02-01).
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Received May 22, 2000
Accepted December 19, 2000

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