Straightforward synthesis of derivatives of D- and L-galactonic acids as precursors of stereoregular polymers

Article abstract of DOI:10.1016/S0957-4166(03)00588-3

High yielding routes for the synthesis of selectively protected derivatives of D- and L-galactonic acids, having free OH or NH₂ groups at the C-6 position, are reported. The successful direct per-O-methylation of galactonic acid derivatives from the corresponding galactono-1,4-lactones was developed as a key step of the sequence. For example, 6-azido-6-deoxy-L-galactono-1,4-lactone 16 was converted into the potassium salt and methylated (NaH, DMSO, MeI) to the methyl ester of the 2,3,4,5-tetra-O-methyl derivative 12. Compound 16 was readily prepared by bromination at C-6 of L-galactonolactone 1 and isopropylidenation; followed by substitution of bromine by azide and removal of the protecting groups. Hydrolysis of the methyl ester of 12 and hydrogenation of the azide led to the tetra-O-methyl derivative of the 6-amino acid 18 with 52% overall yield from 1. The same sequence applied to D-galactonolactone 19 led to the enantiomeric amino acid 25 with a 47% overall yield.

Full text of DOI:10.1016/S0957-4166(03)00588-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2579–2586
Straightforward synthesis of derivatives of
D
- and -galactonic
L
acids as precursors of stereoregular polymers
Carmen L. Romero Zaliz and Oscar Varela*
CIHIDECAR-CONICET, Departamento de Qu´ımica Orga´nica, Facultad de Ciencias Exactas y Naturales, Pabello´n II,
Ciudad Universitaria, 1428 Buenos Aires, Argentina
Received 19 May 2003; accepted 15 July 2003
Abstract—High yielding routes for the synthesis of selectively protected derivatives of
or NH2 groups at the C-6 position, are reported. The successful direct per-O-methylation of galactonic acid derivatives from the
corresponding galactono-1,4-lactones was developed as a key step of the sequence. For example, 6-azido-6-deoxy- -galactono-1,4-
lactone 16 was converted into the potassium salt and methylated (NaH, DMSO, MeI) to the methyl ester of the 2,3,4,5-tetra-O-
methyl derivative 12. Compound 16 was readily prepared by bromination at C-6 of -galactonolactone 1 and isopropylidenation;
D- and L-galactonic acids, having free OH
L
L
followed by substitution of bromine by azide and removal of the protecting groups. Hydrolysis of the methyl ester of 12 and
hydrogenation of the azide led to the tetra-O-methyl derivative of the 6-amino acid 18 with 52% overall yield from 1. The same
sequence applied to
© 2003 Elsevier Ltd. All rights reserved.
D-galactonolactone 19 led to the enantiomeric amino acid 25 with a 47% overall yield.
the solid state affording materials of improved mechan-
ical properties.11 Our already mentioned synthesis of
1. Introduction
the per-O-methyl-
methyl
seven steps (30% overall yield). A key intermediate of
D
-galactonic acid derivative,9 from
Effective utilization of renewable natural resources as
precursors of polymers and organic chemicals has
recently become of interest since long-term access to
fossil materials is expected to become increasingly
difficult. In particular, carbohydrates have been
employed as a source of optically active condensation
polymers, which carry in their chains diverse function-
alities.1,2 Novel technological and biomedical applica-
tions have been found for such polymers that, in
addition, are usually environmentally compatible.3,4
Carbohydrate-based polyamides5,6 have been prepared
by polycondensation of amino acids derived from
pentoses7 and hexoses.8 We have reported recently the
preparation of 6-amino-6-deoxy-2,3,4,5-tetra-O-methyl-
6-O-tosyl-a-
D
-galactopyranoside,
involved
the sequence was methyl 6-azido-6-deoxy-2,3,4-tri-O-
methyl-a-D-galactopyranoside, which was converted
into a lactone by hydrolysis of the glycoside followed
by oxidation of the anomeric center. While searching
for a more direct route to
D- and L-galactonic acid
derivatives, alternative procedures were also explored
starting from the respective aldonolactones. Herein we
report the results of these investigations.
2. Results and discussion
D
-galactonic acid as a precursor of a stereoregular
For the synthesis of a selectively protected derivative of
6-amino-6-deoxy-L-galactonic acid we first selected the
polyamide.9 The open-chain monomers of the galacto
configuration are particularly interesting as they prefer-
entially adopt a planar zigzag conformation in solu-
tion,10 which is expected to favor the polycondensation
reactions. Furthermore, it has been reported that the
zigzag conformation of the galactaryl units of poly-
galactaramides induces an alignment of the chains in
azide 5 as a key intermediate (Scheme 1). We success-
fully employed the enantiomer of 5 as a precursor of
the target amino acid in the
D
-series.9 The starting
material 5,6-O-isopropylidene-L-galactono-1,4-lactone
2 was obtained from 1 following the procedure
described for the acetonation of
D
-galactonolactone.12
The next step of the sequence involved the opening of
the lactone ring and the methylation of the alcohol
functions. It is known that the alkylation of aldonolac-
* Corresponding author. Tel.: 54-11-4576-3346; fax: 54-11-4576-3346;
e-mail: varela@qo.fcen.uba.ar
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00588-3

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C. L. Romero Zaliz, O. Varela / Tetrahedron: Asymmetry 14 (2003) 2579–2586
Scheme 1.
tones and aldonic acids in the presence of strong bases
is difficult, as usual isomerizations and eliminations are
produced.13,14 As a result per-O-alkylated aldonolac-
tones were prepared by the classical method of hydroly-
sis of alkylated glycosides followed by oxidation,8,15 or
by means of specific reagents16 or procedures.17 How-
ever, we could only succeed in the per-O-methylation of
derivatives of aldonic acids by opening the lactone ring
previous to the addition of the methylation reagent.
Thus, treatment of 2 with a methanolic solution of
KOH afforded the potassium salt of the aldonic acid.
The opening of the lactone was evidenced by the 13C
NMR spectrum of the salt, which showed a strong
upfield shifting of the C-4 resonance compared with the
same signal in 2. The dried potassium salt, dissolved in
dimethylsulfoxide (DMSO) was methylated with methyl
iodide in the presence of sodium hydride to give the
methyl ester of the methylated aldonic acid derivative 3.
This reaction proved to be quite general as when
applied to other aldonolactone derivatives (as discussed
later) it gave, in all cases, good yields of the methylated
product.
Due to the difficulties in the preparation of 4, we
attempted an alternative strategy (Scheme 2) for the
synthesis of the 6-amino-6-deoxyhexonolactone ana-
logue of 5. In this case, a good leaving group at C-6 of
1 was introduced in the first stages of the sequence.
Thus, the 6-bromo derivative 8 was prepared via the
6-O-trityl lactone 6, or directly from 1 by the procedure
described by Pedersen et al.18 Tritylation of 1 under
standard conditions afforded 6 as a crystalline product
(93% yield), which was quantitatively acetylated to 7.
This compound was also prepared (85% yield) by a
one-pot tritylation and acetylation of 1.19 Treatment of
7 with hydrogen bromide in methylene chloride led to
8. Alternatively, bromination of 1 with HBr–acetic acid
and further acetylation rendered 8 (62% yield).18 Unfor-
tunately, the bromide substitution in 8 by azide was
unsuccessful, as extensive decomposition of the starting
material occurred under different reaction conditions.
As the 6-O-trityl derivative 6 could be readily prepared
from 1, it was selected as the starting material for the
synthesis of 12 (Scheme 3), a direct precursor of the
desired amino acid. Methylation of 6, under the condi-
tions described for 2, led to 9 in 80% yield. Removal of
the trityl group of 9 with boron trifluoride–ethyl ether-
ate afforded 10. Compound 10 itself can be seen as the
monomer precursor of a stereoregular polyester, as
successful polymerization of the lactones of substituted
o-hydroxyacids has recently been reported.20 On the
other hand, for the synthesis of 12, the free hydroxyl
Compound 3 was subjected to acid hydrolysis for the
removal of the isopropylidene group and to promote
the 1,5-lactonization of the resulting 5-hydroxy acid.
However, the NMR spectra of the product showed that
only partial lactonization had taken place, even upon
prolonged drying. The crude mixture of hydrolysis was
tosylated to give a low yield of the expected monotosyl
derivative of the 1,5-lactone 4. The poor yield was
consistent with the fact that 4 reverted partially to the
5-hydroxy acid during chromatographic purification.
1
group of 10 was tosylated to afford 11. The H NMR
spectrum of 11 showed the signals of H-6 and H-6% at
Scheme 2.

C. L. Romero Zaliz, O. Varela / Tetrahedron: Asymmetry 14 (2003) 2579–2586
2581
Scheme 3.
low field, due to the deshielding effect of the tosylate.
The large value for J3,4 and the smaller ones for J2,3 and
J4,5 indicated, as expected for a derivative having
galacto configuration,10 a planar zigzag conformation
for the backbone chain of 11.
istic of the 3,6-anhydro ring. The fragment of the
lateral chain (m/z 103, 6%) was also observed. The
structure of 13 was confirmed chemically by the simple
heating of a toluene solution of the tosylate 11, which
led to the anhydro sugar 13, in 92% yield. The rather
unusual cyclization of 11, suggested the attack of the
methoxy group at C-3 to C-6, with nucleophilic dis-
placement of the tosylate and subsequent O-
demethylation.
The nucleophilic substitution of the tosylate group of
11 by sodium azide, under different reaction conditions
gave moderate yields (ꢀ50%) of the expected azide
derivative 12. In all instances, a by-product was isolated
with its proportion in the reaction mixture increasing
when the reactions were conducted at higher tempera-
The formation of the by-product 13 lowered the yield
of the azide derivative 12, a key intermediate to the
target molecule and so another route (Scheme 4) for the
synthesis of 12 starting from 1, was attempted. Treat-
ment of 1 with 32% HBr in acetic acid afforded the
corresponding 6-bromo-6-deoxy derivative, which was
employed crude for the next step. The traces of acids
(HBr and AcOH) present in the crude product, cata-
lyzed the acetonation with 2,2-dimethoxypropane, to
give the di-O-isopropylidene derivative 14 in 99% yield
from 1. The methanol released during the reaction from
the acetonation reagent produced the simultaneous for-
mation of the methyl ester, as observed for analogous
isopropylidenation of aldonolactones.23,24 Substitution
of the bromide of 14 by sodium azide readily took place
to give the 6-azido-6-deoxy product 15 in 87% yield.
Removal of the ketal protecting groups by acid hydrol-
ysis led to 16 (93% yield).
1
tures and for longer times. The H NMR spectrum of
this by-product showed only four methyl groups
instead of the expected five; one of them was assigned
to the methyl ester because of its characteristic chemical
shift (l 3.76 in CDCl3). The spectral data suggested the
formation of a 3,6-anhydro bridge and so the by-
product was formulated as 13. In accordance with the
structure proposed, the NMR spectrum of the product
showed the C-6 resonance at low field, as observed for
1,4-anhydrogalactitol, which possesses as 13 an 1,4-
anhydro ring.21 Also, both compounds exhibited the
resonances for all of the other ring carbons at low field.
The mass spectrum of the by-product supported the
structural assignments. Similar to per-O-methylated
3,6-anhydro-
-galactitol,22 the mass spectrum of 13
D
showed a diagnostic peak at m/z 131 (63%), character-
Scheme 4.

2582
C. L. Romero Zaliz, O. Varela / Tetrahedron: Asymmetry 14 (2003) 2579–2586
Per-O-methylation of 16, by the procedure described
above for similar aldonolactone derivatives, afforded 12
in 77% yield. Hydrolysis of the ester function of 12
under alkaline conditions led to the acid derivative 17.
The last step of the sequence, the hydrogenation of 17,
afforded the target compound 18, in crystalline form.
The corresponding enantiomer 25 was also obtained
tal polarimeter at 25°C. Nuclear magnetic resonance
(NMR) spectra were recorded with a Bruker AC 200 or,
when indicated, with a Bruker AMX 500 instrument, in
CDCl3 solutions (tetramethylsilane as internal standard)
1
unless otherwise indicated. For those fully assigned H
NMR spectra, 2D COSY experiments were conducted.
For the assignment of the 13C NMR spectra, DEPT
techniques were employed. Electron impact-mass spec-
tra (EI-MS) were performed with a Shimadzu QP 5000
mass spectrometer, operating at 70 eV.
from
D
-galactono-1,4-lactone 19 by using the same
procedure (Scheme 5).
In summary, we have reported alternative procedures
for the synthesis of derivatives of
straightforward route has been developed to prepare,
starting from the - and the -galactonolactones 1 and
L
-galactonic acid. A
3.2. Methyl 5,6-O-isopropylidene-2,3,4-tri-O-methyl-L-
galactonate 3
L
D
19, the respective v-aminoacid derivatives 18 and 25, in
52 and 47% overall yield. The key step of the synthesis
was the successful direct methylation of the aldonolac-
tones to afford the corresponding esters of per-O-
methyl aldonic acids. These bifunctional compounds are
useful monomers for the construction of optically
active, stereoregular AB-type polyamides. Also, the
intermediate 15 would render, upon hydrogenation, a
precursor of a similar polyamide having protecting
groups that could be readily removed by hydrolysis.
Different properties (i.e. solubility) should be expected
for the resulting polymer. Furthermore, the v-hydroxy-
acid derivative 10 constitutes a potentially useful precur-
sor for the synthesis of a stereoregular polyester or
co-polyester.
To a solution of 212 (1.00 g, 4.59 mmol) in dry MeOH
(10 mL) was added dropwise and with stirring a 30%
solution of KOH in MeOH. When the solution became
slightly alkaline (pH ꢀ7.5) the solvent was evaporated
under reduced pressure. The resulting solid potassium
salt of the
L-galactonic acid derivative was dried in
vacuum and then dissolved in dimethylsulfoxide
(DMSO, 7 mL). The solution was externally cooled (ice
bath) after which it was added to a suspension of NaH
(1.7 g) in DMSO (10 mL). After 30 min of stirring at
room temperature, the mixture was cooled (ice bath)
and methyl iodide (2.60 mL) was slowly added with
vigorous stirring. When the addition was finished, the
reaction mixture was stirred at room temperature for 2
h at which point TLC (5:1 hexane–EtOAc) showed a
major product (Rf 0.70) with no starting material being
detected. Upon addition of MeOH, the mixture was
neutralized with acetic acid, diluted with water (30 mL)
and extracted with CH2Cl2 (3×80 mL). The organic
extract was dried over MgSO4 and then concentrated.
Column chromatography purification of the residue
afforded 3 (0.72 g, 56%) as an oil, [h]D=+10.2 (c 1.0,
3. Experimental
3.1. General methods
Melting points were determined with a Fisher–Johns
apparatus and are uncorrected. Analytical thin-layer
chromatography (TLC) was performed on Silica Gel 60
1
CHCl3); H NMR l 4.22 (ddd, 1H, J4,5=4.8, J5,6=6.2,
J5,6%=8.0 Hz, H-5), 4.03 (d, 1H, J2,3=2.2 Hz, H-2), 4.01
(dd, 1H, J6,6%=8.0 Hz, H-6), 3.81 (t, 1H, H-6%), 3.80 (s,
3H, CO2CH3), 3.65 (dd, 1H, J3,4=9.1 Hz, H-3), 3.48,
3.47, 3.33 (3s, 9H, 3 OCH3), 3.34 (dd, 1H, H-4), 1.42,
1.37 (2s, 6H, C(CH3)2); 13C NMR l 171.7, 108.5, 82.3,
79.2, 79.1, 76.8, 66.1, 60.7, 60.1, 58.6, 51.8, 26.3, 25.7.
Anal. calcd for C13H24O7: C, 53.40; H, 8.28. Found: C,
53.73; H, 8.42.
F
254 (E. Merck) aluminum-supported plates (layer thick-
ness 0.2 mm). Visualization of the spots was effected by
exposure to UV light or by charring with a solution of
5% (v/v) sulfuric acid in EtOH, containing 0.5% p-
anisaldehyde. Column chromatography was carried out
with Silica Gel 60 (230–400 mesh, E. Merck). Optical
rotations were measured with a Perkin–Elmer 343 digi-
Scheme 5.

C. L. Romero Zaliz, O. Varela / Tetrahedron: Asymmetry 14 (2003) 2579–2586
2583
3.3. 2,3,4-Tri-O-methyl-6-O-tosyl-
L
-galactono-1,5-lac-
3.6. 6-Bromo-6-deoxy-2,3,5-tri-O-acetyl-L-galactono-
1,4-lactone 8
tone 4
A solution of 3 (0.14 g, 0.48 mmol) in 5% aqueous HCl
was heated at 50°C for about 1 h, while the solvent was
slowly evaporated by adjusting the pressure in the
rotatory evaporator. The residue obtained upon addi-
tion of water and further concentration revealed by
TLC the consumption of the starting material. The
resulting syrup was dried and dissolved in pyridine (0.7
mL) after which tosyl chloride (0.15 g, 0.78 mmol) was
added to the solution. The mixture was stirred at room
temperature for 3 h, diluted with water (20 mL) and
extracted with CH2Cl2 (3×30 mL). The extract was
dried and concentrated and the resulting syrup purified
by column chromatography with mixtures of hexane–
EtOAc of increasing polarity (from 5:1 to 1:1). From
the column, was isolated the oil 4 (0.036 g, 20%);
Hydrogen bromide was bubbled through an externally
cooled (ice bath) solution of 7 (0.50 g, 0.92 mmol) in
dry CH2Cl2 (12.5 mL). The reaction was monitored by
TLC (1:1 hexane–EtOAc) and showed a gradual con-
version of 7 (Rf 0.66) into a more polar product (Rf
0.57). When the conversion was complete, the solution
was concentrated and the residue purified by column
chromatography using hexane–EtOAc (from 5:1 to 4:1)
to give 8 (0.17 g, 51%); mp 100°C; [h]D=+9.2 (c 0.8,
CHCl3). Lit.18 mp 100–101°C; [h]D=−10.1, for the
enantiomer.
Alternatively, the bromide 8 was prepared by bromina-
tion and acetylation of 1, following the procedure
described by Pedersen18 for the enantiomer of 1.
1
[h]D=−32.7 (c 0.8, CHCl3); H NMR l 7.79, 7.36 (2d,
4H, J=8.4 Hz, H-aromatic), 4.40 (ddd, 1H, J4,5=1.8,
3.7. Methyl 2,3,4,5-tetra-O-methyl-6-O-trityl-L-galacto-
nate 9
J5,6=7.5, J5,6%=5.9 Hz, H-5), 4.22 (dd, 1H J6,6%=9.9 Hz,
H-6), 4.08 (dd, 1H, H-6‘), 3.98 (d, 1H, J2,3=9.5 Hz,
H-2), 3.92 (t, 1H, J3,4=2.2 Hz, H-4), 3.54 (dd, 1H,
H-3), 3.66, 3.52, 3.51, (3s, 9H, OCH3), 2.45 (s, 3H,
ArCH3); 13C NMR l 168.9, 145.5, 132.1, 130.0, 128.0,
81.6, 78.8, 75.7, 73.1, 66.3, 61.1, 61.0, 58.5, 21.7. Anal.
calcd for C16H22O8S.0.5H2O: C, 50.12; H, 6.06; S, 8.35.
Found: C, 50.49; H, 5.95; S, 8.17.
To a solution of 6 (1.00 g, 2.38 mmol) was slowly
added 30% KOH in MeOH with stirring. When the
alkalinity of the solution (pH ꢀ7.5) persisted for about
30 min, the solvent was evaporated to afford the solid
potassium salt (13C NMR (DMSO-d6) l 175.6, 144.3,
128.8, 128.4, 127.6, 126.9, 126.7, 85.7, 72.1, 71.8, 70.4,
68.9, 65.7). The dried solid was then dissolved in anhy-
drous DMSO (6.5 mL), and to this cooled solution (ice
bath) was added a suspension of NaH (1.15 g) in
DMSO (10 mL). The mixture was stirred at room
temperature for 30 min, cooled to 0°C and methyl
iodide (1.75 mL) added. After 2 h of vigorous stirring
at room temperature, MeOH was added carefully to the
suspension, which was then neutralized with acetic acid,
diluted with water and extracted with CH2Cl2 (3×80
mL). The extract was dried over MgSO4 and concen-
trated to afford a syrup that was subjected to column
chromatography with 5:1 hexane–EtOAc. Compound 9
was isolated as a colorless oil (0.96 g, 80%); [h]D=−5.1
3.4. 6-O-Trityl-L-galactono-1,4-lactone 6
To a suspension of 1 (1.0 g, 5.61 mmol) in anhydrous
pyridine (8.4 mL) was added triphenylmethyl chloride
(trityl chloride, 1.87 g, 6.72 mmol). The mixture was
maintained in the dark with occasional stirring, at
room temperature for 48 h. The solvent was evaporated
and the residue purified by column chromatography
with EtOAc–hexane (from 1:1 to 3:1) to afford crys-
talline 6 (2.20 g, 93%), mp 77–78°C, [h]D=−22.4 (c 1.2,
CHCl3); 1H NMR (DMSO-d6) l 7.26–7.42 (m, 15H,
H-aromatic), 6.08 (d, 1H, J=6.6 Hz, disappeared on
deuteration, OH), 5.48 (d, 1H, J=5.3 Hz, OH), 5.28 (d,
1H, J=6.6 Hz, OH), 4.34–4.08 (m, 3H), 3.81 (bq, 1H),
3.10 (dd, 1H, J=6.3, J=8.6 Hz), 2.93 (bt, 1H, J=8.4
Hz); 13C NMR (DMSO-d6) l 174.5, 143.6, 128.2, 127.8,
127.0, 86.0, 79.4, 73.8, 72.1, 65.8, 63.9. Anal. calcd for
C25H24O6: C, 71.41; H, 5.75. Found: C, 71.48; H, 5.86.
1
(c 1.0, CHCl3); H NMR l 7.49–7.20 (m, 15H), 4.00 (d,
1H, J=2.0 Hz, H-2), 3.81 (s, 3H), 3.79 (dd, 1H, J=2.0,
J=9.3 Hz), 3.61–3.45 (m, 3H), 3.47 (s, 3H), 3.38 (s,
3H), 3.34 (s, 3H), 3.22 (dd, 1H), 3.21 (s, 3H); 13C NMR
l 172.1, 143.9, 128.8, 128.6, 128.5, 127.8, 127.1, 127.0,
87.2, 80.6, 79.3, 78.8, 78.5, 62.0, 60.6, 59.8, 58.5, 58.3,
51.8. Anal. calcd for C30H36O7.H2O: C, 68.39; H, 7.29.
Found: C, 68.61; H, 7.28.
3.8. Methyl 2,3,4,5-tetra-O-methyl-L-galactonate 10
3.5. 2,3,5-Tri-O-acetyl-6-O-trityl-L-galactono-1,4-lac-
tone 7
Boron trifluoride–ethyl etherate (0.2 mL) and MeOH
(0.6 mL) were added to a solution of 9 (0.75 g, 1.48
mmol) in CH2Cl2 (40 mL). The solution was stirred at
room temperature for 1 h, when TLC revealed com-
plete consumption of starting 9. The mixture was
diluted with CH2Cl2 (20 mL) and washed with water
(50 mL). The organic layer was dried over MgSO4 and
concentrated. The resulting syrup was purified by
column chromatography (9:1 EtOAc–hexane) to give
Compound 1 (1.00 g, 2.38 mmol) was tritylated as
described previously and to the crude mixture acetic
anhydride was added dropwise, while stirring. After 5 h
of stirring at room temperature, the mixture was con-
centrated to a solid residue, which crystallized from a
5:1 hexane–EtOAc to give 7 (2.61 g, 85%); mp 75–77°C;
[h]D=+35.0 (c 0.9, CHCl3); lit.19 [h]D=−38.7 for the
1
1
enantiomer. The H and 13C NMR spectra of 7 were
oily 10 (0.27 g, 70%); [h]D=−10.5 (c 0.9, CHCl3); H
NMR l 4.01 (d, 1H, J=2.0 Hz), 3.87–3.79 (m, 3H),
identical to those reported for the enantiomer.19

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C. L. Romero Zaliz, O. Varela / Tetrahedron: Asymmetry 14 (2003) 2579–2586
3.81 (s, 3H), 3.51–3.42 (m, 2H), 3.49, 3.48, 3.47, 3.35
(4s, 12H); 13C NMR l 172.0, 81.0, 80.0, 79.4, 79.1,
61.4, 60.5, 59.7, 58.5, 58.0, 51.8. Anal. calcd for
C11H22O7: C, 49.61; H, 8.30. Found: C, 50.03; H, 7.97.
45 (100). Anal. calcd for C10H18O6: C, 51.27; H, 7.75.
Found: C, 51.03; H, 7.40.
Compound 13 was also prepared starting from 11 (78
mg, 0.18 mmol). A solution of 11 in toluene (1 mL) was
heated at 80°C for 16 h, when TLC (EtOAc) showed
complete conversion of the starting material (Rf 0.77)
into 13 (Rf 0.62). The mixture was concentrated and the
residue purified by column chromatography (2:1 hex-
ane–EtOAc) to afford the oil 13 (40 mg, 92%), which
showed the same spectral and physical properties as
those described previously.
3.9. Methyl 2,3,4,5-tetra-O-methyl-6-O-tosyl-L-galacto-
nate 11
To a solution of 10 (0.10 g, 0.38 mmol) in CH2Cl2 (1
mL) and pyridine (0.1 mL) was added tosyl chloride
(0.11 g, 0.57 mmol). The mixture was stirred at room
temperature for 6 h, when TLC (EtOAc) revealed the
complete consumption of the starting material (Rf
0.66). Water (30 mL) was added to the reaction mixture
followed by extraction with CH2Cl2 (3×50 mL). The
organic extract was dried over MgSO4 and concen-
trated. Chromatographic purification of the residue
using 2:1 hexane–EtOAc as solvent gave 11 (0.134 g,
85%); [h]D=−14.3 (c 0.8, CHCl3); 1H NMR l 7.81, 7.36
3.10.2. Synthesis of 12 starting from 6-azido-6-deoxy-L-
galactono-1,4-lactone 16. Compound 16 (0.69 g, 3.39
mmol) was treated with 30% solution of KOH in
MeOH, as described for the preparation of 3 and 9.
The resulting salt was dried, dissolved in DMSO (6
mL), slowly added to a suspension of NaOH (1.20 g) in
DMSO (8.6 mL) and then cooled to 0°C (ice-bath). The
mixture was vigorously stirred for 20 min, and upon the
dropwise addition of methyl iodide (2.3 mL), was
stirred at room temperature for 2.5 h. The usual work-
up of the reaction mixture, followed by chromato-
graphic purification (5:1 hexane–EtAcO), led to 12
(0.76 g, 77%). Compound 12 gave the same physical
and spectral properties as the product described in
Section 3.10.1.
(2d, 4H, J=8.2 Hz, H-aromatic), 4.26 (dd, 1H, J5,6
=
6.1, J5,6%=10.1 Hz, H-2), 3.80 (s, 3H, CO2CH3), 3.77
(dd, 1H, J3,4=9.3 Hz, H-3), 3.61 (dt, 1H, J4,5=2.0 Hz,
H-5), 3.46, 3.40, 3.35, 3.29 (4s, 12H, 4 OCH3), 3.42 (dd,
1H, H-4), 2.45 (s, 3H, ArCH3); 13C NMR l 171.8,
145.0, 132.6, 129.9, 127.9, 85.1, 80.4, 78.9, 78.4, 77.3,
68.0, 60.7, 69.6, 68.8, 68.4, 51.9, 21.6. Anal. calcd for
C18H28O9S: C, 51.42; H, 6.71. Found: C, 51.21; H, 6.71.
3.10. Methyl 6-azido-6-deoxy-2,3,4,5-tetra-O-methyl-
L-
galactonate 12 and methyl 3,6-anhydro-2,4,5-tri-O-
3.11. Methyl 6-bromo-6-deoxy-2,3:4,5-di-O-isopropyli-
dene-L-galactonate 14
methyl-
L
-galactonate 13
3.10.1. Starting from 11. To a solution of 11 (0.12 g,
0.29 mmol) in dry DMF (1.7 mL) was added sodium
azide (0.057 g, 0.87 mmol) with the resulting mixture
heated to 80°C. After 4 h TLC (10:1 hexane–EtOAc)
showed complete conversion of 10 into two main prod-
ucts having Rf 0.76 and 0.62. The mixture was filtered
and the filtrate concentrated. The resulting residue was
purified by column chromatography (5:1 hexane–
EtOAc) to afford compound 12 (0.04 g, 47%); [h]D=
Compound 1 (1.00 g, 5.62 mmol) was dissolved in 32%
HBr in acetic acid (7.5 mL). The solution was stirred at
room temperature for 2 h, when TLC (10:1 EtOAc–
MeOH) showed just a main spot (Rf 0.43) and none of
the starting material 1 (Rf 0.13). MeOH was added
slowly and the solution concentrated. This procedure
was repeated twice in order to remove the acids. The
crude product was dissolved in 2,2-dimethoxypropane
(26 mL) and acetone (2 mL) and the solution stirred for
16 h at room temperature. Monitoring of the mixture
by TLC (5:1 hexane–EtOAc) showed a single spot
having an Rf value of 0.43. The solution was neutral-
ized with concentrated aqueous ammonia and the sol-
vent evaporated. The resulting residue was purified by
column chromatography (10:1 hexane–EtOAc) to give
crystalline 14 (1.97 g, 99%); mp 52°C; [h]D=+7.6 (c 1.0,
1
+4.3 (c 1.4, CHCl3); H NMR l 4.00 (d, 1H, J2,3=2.0
Hz, H-2), 3.81 (s, 3H, CO2CH3), 3.80 (dd, 1H, J3,4=9.3
Hz, H-3), 3.62 (dd, 1H, J5,6=6.4, J6,6%=12.1 Hz, H-6),
3.55 (ddd, 1H, J4,5=2.2, J5,6%=6.5 Hz, H-5), 3.50, 3.49,
3.46 (3s, 9H, 3OCH3), 3.45 (dd, 1H, H-4), 3.42 (dd, 1H,
H-6‘), 3.35 (s, 3H, OCH3); 13C NMR l 171.9, 80.7,
78.9, 78.8, 78.5, 60.8, 59.6, 58.5, 58.4, 51.9, 50.6 (C-6).
Anal. calcd for C11H21O6N3: C, 45.35; H, 7.27; N,
14.43. Found: C, 45.70; H, 7.26; N, 14.09.
1
CHCl3); H NMR l 4.57 (d, 1H, J2,3=5.2 Hz, H-2),
4.39 (dd, 1H, J3,4=7.2 Hz, H-3), 4.23 (ddd, 1H, J4,5
=
6.8, J5,6=4.3, J5,6%=5.2 Hz, H-5), 3.96 (t, 1H, H-4), 3.80
(s, 3H, CO2CH3), 3.64 (dd, 1H, J6,6%=10.9 Hz, H-6),
3.50 (dd, 1H, H-6‘), 1.47, 1.45, 1.41 (3s, 12 H, 2
(CH3)2C); 13C NMR l 171.2, 112.4, 110.1, 79.8, 79.7,
78.6, 77.3, 52.5, 32.8, 27.3, 27.1, 26.0. Anal. calcd for
C13H21O6Br: C, 44.21; H, 5.99; Br, 22.62. Found: C,
44.49; H, 6.02; Br, 22.44.
From the next fractions of the column was isolated the
more polar product (Rf 0.62), which was identified as
the 3,6-anhydro derivative 13 (0.02 g, 24%); [h]D=
1
−50.8 (c 0.7, CHCl3); H NMR (DMSO-d6) l 3.91 (d,
1H, J2,3=5.5 Hz, H-2), 3.81 (ddd, 1H, J4,5=2.0, J5,6
2.5, J5,6%=4.6 Hz, H-5), 3.78 (ddd, 1H, J4,6=0.7, J6,6%
=
=
10.1 Hz, H-6), 3.76 (dd, 1H, J3,4=4.6 Hz, H-3), 3.72
(dd, 1H, H-6‘), 3.69 (ddd, 1H, H-4), 3.67, 3.31, 3.28,
3.24 (4s, 12H, CH3O); 13C NMR (CDCl3) l 170.5, 85.1,
84.7, 83.4, 80.9, 71.4 (C-6), 58.7, 57.5, 56.8, 52.0; EI-
MS: 202 (1%), 175 (6), 143 (5), 131 (63), 104 (12), 101
(45), 99 (58), 75, (22), 73, (44), 71 (57), 59 (20), 58 (25),
3.12. Methyl 6-azido-6-deoxy-2,3:4,5-di-O-isopropyli-
dene-L-galactonate 15
A solution of 14 (1.58 g, 4.36 mmol) and sodium azide
(0.55 g, 8.72 mmol) was stirred at 85°C for 16 h. TLC

C. L. Romero Zaliz, O. Varela / Tetrahedron: Asymmetry 14 (2003) 2579–2586
2585
(5:1 hexane–EtOAc) revealed a single spot (Rf 0.40)
having similar mobility of the starting material (Rf
0.42). However, the color of the spot with the p-
anisaldehyde–H2SO4 reagent was brown for the azide
and black for 13. The mixture was cooled, filtered, and
concentrated to a syrup, which was subjected to chro-
matographic purification (3:1 hexane–EtOAc). Com-
pound 15 (1.20 g, 87%) was isolated as a colorless oil,
[h]D=−30.0 (c 0.8, CHCl3). (Lit.23 [h]D=+30.9 for the
enantiomer). The 1H and 13C NMR spectra were identi-
cal to those reported for the enantiomer.23
The 1H and 13C spectra of 20–25 were identical to those
of the respective analogue in the -series 13–18.
L
3.16.1. Methyl 6-bromo-6-deoxy-2,3:4,5-di-O-isopropyli-
dene-L-galactonate 20. Yield 93%; [h]D=−7.6 (c 1.3,
CHCl3).
3.16.2. Methyl 6-azido-6-deoxy-2,3:4,5-di-O-isopropyli-
dene-L-galactonate 21. Yield 85%; [h]D=+29.4 (c 1.1,
CHCl3).
3.16.3. 6-Azido-6-deoxy-L-galactono-1,4-lactone 22.
Yield 93%; [h]D=−75.8 (c 0.8, CHCl3).
3.13. 6-Azido-6-deoxy-L-galactono-1,4-lactone 16
A solution of 15 (1.00 g, 13.17 mmol) in trifluoroacetic
acid-water (4:1 14 mL) was stirred at room tempera-
ture. After 2.5 h, TLC (EtOAc) showed complete con-
version of 15 into a more polar product (Rf 0.53). The
solution was concentrated and the syrup was chromato-
graphically purified (3:1 EtOAc–hexane) to afford 16
(0.60 g, 93%); [h]D=+65.1 (c 0.8, EtOAc). (Lit.23 [h]D=
−70.3 for the enantiomer). The spectral data of 16 were
identical to those reported for the enantiomer.23
3.16.4. Methyl 6-azido-6-deoxy-2,3,4,5-tetra-O-methyl-
L
-galactonate 23. Yield 74%; [h]D=−2.7 (c 1.4, CHCl3).
3.16.5. 6-Azido-6-deoxy-2,3,4,5-tetra-O-methyl-
L
-galac-
tonic acid 24. [h]D=−8.2 (c 1.0, CHCl3).
3.16.6. 6-Amino-6-deoxy-2,3,4,5-tetra-O-methyl-
L
-galac-
tonic acid 25. Yield 86% (from 23); [h]D=+20.0 (c 0.9,
H2O).
3.14. 6-Azido-6-deoxy-2,3,4,5-tetra-O-methyl-L-galac-
tonic acid 17
Acknowledgements
To a solution of 12 (0.41 g, 1.41 mmol) in MeOH-water
(3:1 4 mL) was added KOH (0.10 g) dissolved in
MeOH (0.3 mL). The mixture was stirred at room
temperature for 3 h, when TLC (1:1 hexane–EtOAc)
showed no starting material 17 (Rf 0.70) remaining. The
solution was diluted with 5% aqueous KOH (30 mL)
and extracted with CH2Cl2 (2×30 mL). The aqueous
phase was acidified (pH 2–3) with 10% aqueous HCl
and extracted with CH2Cl2 (3×50 mL). The organic
extract was dried over MgSO4 and concentrated to
syrupy 17 (0.35 g, 90%). This crude product was pure
enough for the following step. A portion was chro-
matographed (4:1 hexane–EtOAc) to give analytically
pure 17; [h]D=+7.6 (c 0.7, MeOH); lit.9 [h]D=−11 for
Financial support from the University of Buenos Aires
(Project X108) is gratefully acknowledged. O.V. is a
Research Member of the National Research Council of
Repu´blica Argentina (CONICET).
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