Synthesis of stereoregular poly-O-methyl-d- and l-polygalactonamides as nylon 6 analogues

Article abstract of DOI:10.1016/j.tetasy.2004.11.061

Conveniently activated dimers: (pentachlorophenyl 6-(6′-(tert- butoxycarbonylamino)-6′-deoxy-2′,3′,4′, 5′-tetra-O-methyl-d-galactonamide)-6-deoxy-2,3,4,5-tetra-O-methyl-d- galactonate) 7 and its analogue in the l-series 16, were prepared, respectively, fr

Full text of DOI:10.1016/j.tetasy.2004.11.061

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 97–103
Synthesis of stereoregular poly-O-methyl-D- and
L-polygalactonamides as nylon 6 analogues
Carmen L. Romero Zaliz and Oscar Varela*
´ ´ ´
CIHIDECAR-CONICET. Departamento de Quımica Organica, Facultad de CienciasExactasy Naturales, Pabello n II,
Ciudad Universitaria, 1428-Buenos Aires, Argentina
Received 25 October 2004; accepted 24 November 2004
Abstract—Conveniently activated dimers:(pentachlorophenyl 6-(6 0-(tert-butoxycarbonylamino)-60-deoxy-20,30,40,50-tetra-O-
methyl-D-galactonamide)-6-deoxy-2,3,4,5-tetra-O-methyl-D-galactonate) 7 and its analogue in the L-series 16, were prepared, respec-
tively, from 6-amino-6-deoxy-D- and L-galactonic acid derivatives 5 and 14. Upon release of the amino function of 7 under acidic
conditions, polymerization was conducted in a non-polar (CHCl3) or a polar solvent (DMF) affording poly(6-amino-6-deoxy-
2,3,4,5-tetra-O-methyl-D-galactonic acid) 11. Similarly, polymerization in DMF from 16 gave the polygalactonamide 18 (L-series).
The polyamides were characterized by IR and NMR spectroscopies. The latter technique was also employed for establishing the
conformation of 11 in CDCl3 solution. Molecular weights (about 11,000) were estimated by viscosimetry and size exclusion chro-
matography. Polygalactonamides 11 and 18 were highly hygroscopic and soluble in a variety of organic solvents, including chloro-
form. The thermal behavior of the polyamides was also studied.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1.Introduction
polyamides relies upon the existence of a C2 axis of sym-
metry in the starting sugar-derived monomers; otherwise
the occurrence of regioisomerism during the polycon-
densation leads to aregic polymers.15 In contrast, AB-
type polyaldonamides are stereoregular regardless of
the configuration of the monomer. This kind of polyam-
ide has been prepared by polycondensation of amino
acids derived from pentoses16 and hexoses.17 Among
the varied applications of sugar amino acids,18 6-ami-
no-6-deoxyaldonic acids can be considered as conve-
nient monomers for the construction of hydroxylated
In recent years, the synthesis of polyamides more hydro-
philic and degradable than the industrial nylons has
attracted considerable attention. Biodegradable polymers
are in general environmentally friendly1 and have found
biomedical applications, such as in medical devices2 and
in controlled delivery of drugs.3 For the preparation of
these promising materials, renewable natural resources
are being employed. The degradation products of poly-
mers made of natural occurring building blocks are usu-
ally non-toxic and can be metabolized properly by living
tissues.4,5 Considering this point of view, carbohydrates
stand out as highly convenient precursors of polymers
that contain several stereocenters in the main chain.6,7
Thus, polyhydroxylated analogues of nylon 6,6 and re-
lated compounds have been prepared by condensation
of diamines with aldaric acid derivatives.6,8 In this
way, stereoregular9,10 and non-stereoregular polyaldara-
mides11–13 have been prepared. Also, derivatives of 1,6-
diamino-1,6-dideoxy-D-mannitol and L-iditol have been
employed for the synthesis of regioregular linear poly-
amides.14 The stereoregularity of these AABB-type
analogues of nylon 6. We have recently reported19
a
straightforward route to 6-amino-6-deoxy-2,3,4,5-tetra-
O-methyl-D- and L-galactonic acids, which was an
improvement of a synthesis previously described by
us.20 Herein we report the use of derivatives of these
sugar amino acids as precursors of well-defined, enantio-
merically pure, and stereoregular polygalactonamides.
2.Results and discussion
The convenient building block 6-azido-6-deoxy-2,3,4,5-
tetra-O-methyl-D-galactonic acid 1 was readily prepared
starting from D-galactono-1,4-lactone.19 Catalytic
hydrogenation of the azide function of 1 in the presence
of di-tert-butyldicarbonate (Boc2O) afforded 2, the
*
Corresponding author. Tel.:+54 11 4576 3346; fax:+54 11 4576
3352; e-mail: varela@qo.fcen.uba.ar
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.061

98
C. L. Romero Zaliz, O. Varela / Tetrahedron: Asymmetry 16 (2005) 97–103
OMe OMe
OMe OMe
OMe OMe
HCl (g)
EtOAc
OC Cl
OH (Boc) O
OR
6
5
2
HCl.H N
BocHN
N
3
2
H /Pd
2
OMe OMe O
OMe OMe O
OMe OMe O
t
1
4
2 R = H (Boc = Bu OCO)
C Cl OH,
6
5
DCC, EtOAc
3 R = C Cl
6
5
OMe OMe
OC Cl
6
5
HCl.H N
2
OMe OMe O
5
i
Pr NEt, DMF
O
OMe OMe
OMe OMe
H
N
BocHN
OR
OMe OMe
OMe OMe O
6 R = H
C Cl OH,
6
5
7 R = C Cl
DCC, EtOAc
6
5
Scheme 1.
N-Boc derivative of the corresponding amine (Scheme
1). The carboxylic acid group of 2 was converted into
the pentachlorophenyl ester by dicyclohexylcarbodi-
imide (DCC)-promoted condensation with pentachloro-
phenol. The ester group of the resulting derivative 3
was suitably activated for the polycondensation, and
the amine was deprotected from the N-Boc derivative
by hydrolysis with a saturated solution of hydrogen
chloride in EtOAc. The hydrochloride derivative 4 was
obtained as a crystalline product that showed NMR
spectral data in full agreement with the proposed struc-
ture. Thus, the 13C NMR spectrum of 4 exhibited the
resonances for the carbons bonded to oxygen (76.5–
80.3 ppm), the four signals for the methoxyl carbons
(59.0–61.0 ppm) and the signals of the aromatic carbons
of pentachlorophenyl. The resonances of the carbonyl
and methylene (CH2–N) carbons appeared at 167.7
and 39.8 ppm, respectively.
plished when linear dimers of the repeating unit were
employed as precursors of polymers.16,17 Therefore,
the active ester 3, having the amino group protected,
was allowed to react with 6-amino-6-deoxy-2,3,4,5-tet-
ra-O-methyl-D-galactonic acid 5, which was prepared
by hydrogenation of 1 followed by alkaline hydrolysis
of the methyl ester.19 As the resulting dimeric carboxylic
acid 6 was quite difficult to purify, it was converted
directly into the pentachlorophenyl ester 7, by condens-
ation with pentachlorophenol using DCC as coupling
reagent. As the sequence 1!3!7 took place with a
low overall yield (18%), an alternative procedure for
the synthesis of 7 from 1 was attempted.
Compound 1 was esterified with pentachlorophenol to
give 8 (Scheme 2). The active ester of 8 reacted with
the amino acid 5 to afford dimeric 6-(60-azido-60-
deoxy-20,30,40,50-tetra-O-methyl-D-galactonamide)-6-
deoxy-2,3,4,5-tetra-O-methyl-D-galactonic acid
9 in
The polymerization of 4, upon releasing of the amino
group from the hydrochloride with N,N-diisopropyleth-
ylamine (DIPEA) was unsuccessful, as TLC examina-
tion of the reaction mixture showed several spots.
Also, the 13C NMR spectrum of the product was rather
complex, and suggested the formation of oligomers. In
fact, linear21 and cyclic oligomers22,23 and lactams16,17,24
have been reported to be formed in the polycondensa-
tion of sugar-derived amino acids. However, successful
polymerizations of such amino acids have been accom-
good yield (62% from 1). The 1H NMR spectrum
(500 MHz) of 9 allowed a first order analysis; the assign-
ments were confirmed by 2D COSY H,H experiments.
The coupling constant values for the protons of the
chain are indicative that both units in the dimer 9 are
found in the extended planar zigzag conformation, and
shows only some conformational instability for the
C-5–C-6 (and C-50–C-60) bonds, according to the aver-
0
aged values observed for J5,6a, J5,6b, J5 ,6 a, J5 ,6 b. Anal-
0
0
0
ogous open-chain derivatives having the galacto
O
OMe OMe
O
OMe OMe
OMe OMe
OMe OMe
OMe OMe
H
N
H
N
(Boc)2O
H2/Pd
OR
Pri2NEt
DMF
BocHN
OR
+ 5
N3
OH
N3
OMe OMe
6 R = Boc
OMe OMe O
C6Cl5OH,
DCC, EtOAc
OMe OMe
OMe OMe O
OMe OMe O
C6Cl5OH,
DCC, EtOAc
9
1 R = H
8 R = C6Cl5
7 R = C6H5
OMe OMe
O
OMe OMe
OMe OMe
HCl3 or DMF
Pri2NEt
H
N
HCl (g),
EtOAc
N
H
HCl.H2N
OC6Cl5
OMe OMe O
OMe OMe
OMe OMe O
n
11
10
Scheme 2.

C. L. Romero Zaliz, O. Varela / Tetrahedron: Asymmetry 16 (2005) 97–103
99
configuration usually adopt the planar zigzag form,
which is free of 1,3-parallel interactions.25
Mark-Howink equation (g = 2.9 · 10À4 M0.78) reported
for nylon 6.26
Catalytic hydrogenation of the azide function of 9 in the
presence of di-tert-butyldicarbonate gave the N-Boc
derivative 6. The carboxylic acid group of 6 was acti-
vated with DCC and condensed with pentachlorophenol
to afford the pentachlorophenyl ester 7, in an over-
all yield higher than that in the previous route (40%
from 1).
The thermal behavior of polyamide 11 was investigated
by differential scanning calorimetry (DSC) and thermo-
gravimetric analysis (TGA). The thermogram for the
first heating cycle of 11 (obtained from DMF) showed
two endotherms at 138 and 187 ꢁC. These two transi-
tions may be attributed to the melting of populations
of crystallites differing in size, a rather common phe-
nomenon among polyamides that crystallize from solu-
tion.27 Additionally, when the sample was heated to
160 ꢁC, slowly cooled to room temperature and sub-
jected to a second cycle of heating, a single endotherm
at 187 ꢁC (DH = 72.6 J/g) was observed. The width of
the peak was considerably narrow (12 ꢁC) indicating a
low degree of microstructural heterogeneity. However,
no such endotherm was observed when the sample was
heated to 210 ꢁC, cooled and slowly heated again, sug-
gesting that some decomposition takes place at the melt-
ing temperature. This was confirmed by TGA, which
showed that the onset of decomposition started at
170 ꢁC and finished at 275 ꢁC, with a weight loss of 18%.
Hydrolysis of the N-Boc protecting group of 7 with a
saturated solution of hydrogen chloride in EtOAc affor-
ded the hydrochloride derivative 10. The polymerization
of 10 was conducted in both chloroform and DMF as
solvents, and DIPEA was employed to release the amino
group from the hydrochloride salt and as a catalyst of
the polycondensation. The resulting polymers were puri-
fied by evaporation of the reaction solvents, dissolution
in dichloromethane and precipitation with dry ethyl
ether. Polyamides 11 obtained from CHCl3 or DMF
exhibited identical NMR and IR spectra. The 1H
NMR spectrum showed four singlets of methoxyl
groups, and the signals of the hydrogens of the chain
could be readily assigned with the aid of homonuclear
2D COSY experiments. The full assignment of the spec-
trum was necessary to conduct structural studies, as dis-
cussed later. The 13C NMR spectrum of 11 showed at
higher field the signal of C-6 bonded to nitrogen that,
as expected for a methylene carbon, appeared with in-
verse phase in the DEPT experiment. The signals of
the carbons bonded to oxygen appeared between 81.4
and 77.7 ppm, and the methoxyl carbons between 60.3
and 57.6 ppm; whereas C-1 (carbonyl of amide) reso-
nates at 171.4 ppm. The IR spectrum of 11 exhibited
the characteristic amide absorption bands at 3419 (NH
stretch), 1661 (amide I) and 1529 cmÀ1 (amide II).
In order to obtain a polygalactonamide enantiomeric of
11, the polymerization of 6-amino-6-deoxy-2,3,4,5-tetra-
O-methyl-L-galactonic acid 14 was conducted. The same
route as that described for the synthesis of 11 was fol-
lowed. Thus, condensation of 14 with the pentachloro-
phenyl ester 13 gave the dimeric acid 15 (Scheme 3).
Reduction of the azide function of 15 in the presence
of di-tert-butyldicarbonate, followed by esterification
with pentachlorophenol gave 17 (42% from 13). After
removal of the N-Boc protecting group with HCl/
EtOAc, the resulting dimeric amino acid hydrochloride
was polymerized in a DMF solution containing DIPEA,
to give the polygalactonamide 18. This polyamide
showed identical IR and NMR spectra as 11. The
molecular weight and thermal behavior of 18 and 11
were also similar (Table 1). As expected, the specific
rotation of 18 was almost identical in absolute value
and opposite in sign compared to that of 11. Further-
more, as observed for other stereoregular chiral poly-
amides,15 11 and 18 displayed a much higher absolute
value of specific rotation compared with their respective
precursors 7 and 17.
Comparative data for polyamides 11, synthesized by
polycondensation in CHCl3 or DMF, are shown in
Table 1. The use of DMF resulted in a better yield of
11, which may be attributed to the formation of longer
polymer chains in such a solvent. Oligomeric products,
probably formed in CHCl3 could remain soluble during
the precipitation of 11 from a CH2Cl2 solution upon
addition of ethyl ether, lowering the yield. In agreement
with this explanation, molecular weights estimated by
size exclusion chromatography (SEC) were similar for
both purified polymers. Also, a comparable value of
molecular weight (Mv = 10,000) was calculated from
the intrinsic viscosity of 11 (DMF) by applying the
Polyamides 11 and 18 were highly hygroscopic solids,
and soluble in organic solvents, such as chloroform,
DMF and DMSO as well as in common polyamide sol-
vents, like formic acid and dichloroacetic acid. Solubility
in chloroform is remarkable as this behavior is unusual
in conventional nylons, but it is rather common for
stereoregular polyamides containing stereocenters in
the chain.16,17,28 As the solubility of chiral polyamides
in chloroform has been attributed to the formation of
ordered helical structures stabilized by intramolecular
hydrogen bonds,29 we decided to investigate the confor-
mation of 11 in CDCl3 solution by NMR spectroscopy.
The chemical shift of amide protons are sensitive to
hydrogen bonding formation, which results in a shifting
of the signal to higher frequencies. In a non-polar org-
anic solvent, such as chloroform, model amides have
Table 1. Some data for polygalactonamides 11 and 18
Polyamide Polymerization Yieldb (%) [a]D
Mw
Tm
c
solventa
11
11
18
DMF
CHCl3
DMF
89
61
85
+72.0 11,000 187
+71.5 11,500 187
À72.2 10,500 180
a Polymerizations were conducted under the same conditions (20 ꢁC for
8 days).
b Isolated yield of the polyamide from the respective dimeric precursor.
c Determined by SEC.

100
C. L. Romero Zaliz, O. Varela / Tetrahedron: Asymmetry 16 (2005) 97–103
O
OMe OMe
OMe OMe
OMe OMe
OMe OMe
H
N
i
Pr NEt
2
OR
OH
OH
N
+
3
N
H N
2
3
DMF
OMe OMe
OMe OMe O
OMe OMe O
OMe OMe O
15
C Cl OH,
6
5
12 R = H
13 R = C Cl
14
DCC, EtOAc
6
5
O
OMe OMe
OMe OMe
OMe OMe
H
N
1) HCl (g), EtOAc
i
(Boc) O
2
1
2
N
H
R HN
OR
2) DMF, Pr NEt
2
H /Pd
2
OMe OMe O
OMe OMe
2
OMe OMe O
1
n
18
16 R = Boc, R = H
C Cl OH,
DCC, EtOAc
6
5
1
2
17 R = Boc, R = C H
6
5
Scheme 3.
6´
N
shown molecular shifts around 6 ppm for non-hydro-
gen-bonded NH protons and around 8 ppm for
amide–amide H-bonded NH protons.30 For example,
NH bonds of carbopeptoids engaged in hydrogen-bond-
H
6
H
H
H
MeO
OMe
O
H
H
1
H
ing showed dNH higher than 8 ppm.31 In the H NMR
O
OMe
Me
MeO
N
H
6´
H
spectrum of 11, recorded in CDCl3 at 25 ꢁC, the amide
proton resonates at 7.17 ppm. Interestingly, this signal
was strongly deshielded (d 8.02) when the spectrum
was recorded in DMSO-d6 indicating that any intra-
molecular hydrogen bonding in the polyamide should
be weak enough to be disrupted by the polar solvent.
As the temperature dependence of the amide proton
chemical shift can be employed as a tool for detecting
hydrogen bonding,32 variable temperature NMR exper-
iments were conducted for polyamide 11. From the plot
of the amide proton chemical shift as a function of tem-
perature, the reduce temperature constant (ÀDd/DT)
was calculated. The small value obtained (ÀDd/
DT = 2.1 ppb/K) indicated a small change in the NH
protons chemical environment with temperature.30 All
these results seem to indicate that the amide proton of
11 experiences little or no amide–amide hydrogen
bonding.
H
MeO
H
6
H
6
2O
3
H
4
5
H
OMe
H
H
MeO
N
Scheme 4. Correlations observed in the NOESY spectrum of 11.
the other methylene proton (H-60) which is oriented al-
most perpendicularly to the carbonyl plane, is the more
shielded proton in the spectrum of 11. Moreover, the
coupling constant values for the amide proton clearly
indicated that this proton adopts an antiperiplanar dis-
position with respect to H-6 (J = 7.5 Hz), whereas is
gauche to H-60 (J = 2.9 Hz). The mentioned shielding
and deshielding effects detected for the polyamide 11
were not observed in monomeric precursors such as 3
and 4.
Further structural information was obtained from the
NOESY spectrum of 11, which showed cross-peaks for
the NH proton with many other protons of the hydro-
carbon backbone. Particularly interesting were the
cross-peaks between NH–H-2 and NH–H-4. Among
all the possible rings that can be formed by hydrogen
bonding between the amide proton and the methoxy
groups, the five-membered ring, which involves the
methoxy group at C-2 of the adjacent residue, is in a bet-
ter agreement with the detected NOEs (Scheme 4). The
formation of the hydrogen-bonded five-membered ring
promotes an arrangement of the polyamide chain that
brings closer in space H-2, H-4, H-5, and H-60 to the
NH proton, justifying the NOEs observed. In such an
arrangement, according to the coupling constants mea-
sured, each repeating unit of 11 maintains basically the
extended zigzag conformation found for open-chain
derivatives of galactose.25 Additionally, the conform-
ation proposed for 11 accounts for the deshielding of
H-6, which is shifted at an even higher frequency than
H-2 (vicinal to the carbonyl). As depicted in Scheme 4,
H-6 is located in the same plane of the carbonyl and
experiences its anisotropic deshielding effect. In contrast,
3.Conclusions
Herein we report the synthesis of dimers of per-O-
methyl-6-amino-6-deoxy-D- and L-galactonic acids.
Ester active derivatives of the dimers were successfully
polymerized in solvents of different polarity. The result-
ing polygalactonamides 11 and 18 were fully character-
ized. They were enantiomerically pure compounds (no
isomerization occurred during the polymerizations)
and soluble in a variety of solvents, including chloro-
form. Studies on the conformation of 11 in CDCl3 solu-
tion by NMR spectroscopy provided no evidence of
secondary structures formed by amide–amide hydrogen
bonding. Instead, a weak intramolecular hydrogen bond
seems to be formed between the amide proton and the
methoxy group at C-2. In contrast, amide–amide hydro-
gen bonding was detected for linear oligomers of isopro-
pylidene derivatives of 6-amino-6-deoxy-D-galactonic
acid.23 These oligomers adopt a rigid structure compara-
ble to the b-sheet of peptides; whereas a diasteromeric
D-allonate showed no formation of ordered structures.21
These results demonstrate that the solution conforma-

C. L. Romero Zaliz, O. Varela / Tetrahedron: Asymmetry 16 (2005) 97–103
101
tion of polyaldonamides is strongly influenced by the
stereochemistry and substitution pattern of the constitu-
ent sugar amino acids.
the residue chromatographed in a silica gel column
(5:1 hexane–EtOAc) to afford crystalline 3 (0.24 g,
37%), mp 101 ꢁC; [a]D = À3.7 (c 1.3, CHCl3); 1H
NMR
d 4.91 (br s, 1H, NH), 4.41 (d, 1H,
J2,3 = 1.7 Hz, H-2), 4.10 (dd, 1H, J3,4 = 8.9 Hz, H-3),
3.64, 3.54, 3.50, 3.49 (4s, 12H, 4OCH3), 3.60–3.50 (m,
3H, H-4,5,6), 3.41 (m, 1H, H-60); 13C NMR d 168.0
(C-1), 156.0 (NHCO), 144.0, 132.2, 131.9, 127.4 (C-aro-
matic), 80.1, 79.6 (C-2,3,4,5), 77.7 (C (CH3)3), 60.8, 60.2,
59.1, 57.6 (OCH3), 39.7 (C-6), 28.4 (C(CH3)3). Anal.
Calcd for C21H28O8NCl5:C, 42.02; H, 4.72. Found:C,
42.12; H, 4.76.
4.Experimental
4.1. 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 F254 (E. Merck) aluminum-supported plates (layer
thickness 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 car-
ried out with Silica Gel 60 (230–400 mesh, E. Merck).
Optical rotations were measured with a Perkin-Elmer
343 digital polarimeter at 25 ꢁC. Nuclear magnetic reso-
nance (NMR) spectra were recorded with a Bruker
AMX 500 instrument (1H 500 MHz, 13C 125.3 MHz),
in CDCl3 solutions (tetramethylsilane as internal stan-
dard) unless otherwise indicated. For those fully as-
4.3. Pentachlorophenyl 6-amino-6-deoxy-2,3,4,5-tetra-O-
methyl-D-galactonate hydrochloride 4
A solution of 3 (0.19 g, 0.32 mmol) in dry EtOAc
(2.2 mL) was added to a saturated solution of hydrogen
chloride in EtOAc (5.8 mL). After stirring overnight at
room temperature, the mixture was concentrated to
afford 4 as a crystalline hygroscopic product (0.16 g,
95%). The solid was recrystallized from MeOH–diethyl
1
ether, mp 122–123 ꢁC; [a]D = À4.8 (c 0.8, CHCl3); H
NMR (DMSO-d6) d 8.11 (br s, 2H, NH2), 4.45 (d, 1H,
J2,3 = 2.3 Hz, H-2), 3.94 (dd, 1H, J3,4 = 8.6 Hz, H-3),
1
signed H NMR spectra, 2D COSY experiments were
conducted and for the assignment of the 13C NMR spec-
tra, DEPT techniques were employed. Size exclusion
chromatography (SEC) was performed at room temper-
ature with a Waters apparatus equipped with a Waters
2414 refractive index detector and Styragel HR
(7.8 · 300 mm) Waters columns, using THF as mobile
phase. To make polyamides soluble in this solvent, they
were trifluoroacetylated by the method of Schulz et al.33
The flow rate was 1 mL minÀ1. Calibration was based
on polystyrene standards. Melting points were deter-
mined by DSC using a Shimadzu DSC-50, calibrated
with alumina. Samples of about 2–3 mg were heated at
a rate of 10 ꢁC minÀ1 and cooled to room temperature.
The peak temperatures were taken as melting points.
Thermogravimetric analysis (TGA) was conducted in a
Shimadzu TGA-51. IR spectra (films) were recorded
with a Nicolet 510P FT-IR spectrometer.
3.73 (ddd, 1H, J4,5 = 3.0, J5,6 = 4.0, J5,6 = 7.6 Hz, H-
5), 3.58 (dd, 1H, H-4), 3.52, 3.44, 3.43, 3.40 (4s, 12H,
0
0
OCH3), 3.12 (m, 1H, J6,6 = 13.3 Hz, H-6), 3.00 (m,
1H, H-60); 13C NMR (DMSO-d6) d 168.0 (C-1), 143.6,
131.4, 131.0, 127.0 (C-aromatic), 79.4, 79.3, 78.8, 76.8
(C-2,3,4,5), 60.1, 58.7, 58.5, 58.3 (OCH3), 39.2 (C-6).
Anal. Calcd for C16H21O6NCl6ÆH2O:C, 35.81; H, 3.96.
Found:C, 35.35; H, 4.26.
4.4. Pentachlorophenyl 6-(60-(tert-butoxycarbonyl)amino-
60-deoxy-20,30,40,50-tetra-O-methyl-D-galactonamide)-6-
deoxy-2,3,4,5-tetra-O-methyl-D-galactonate 7
To a stirred solution of 3 (0.22 g, 0.37 mmol) in dry
DMF (3 mL), 6-amino-6-deoxy-2,3,4,5-tetra-O-methyl-
D-galactonic acid 5 (0.11 g, 0.37 mmol) in dry DMF
(2 mL) and N,N-diisopropylethylamine (DIPEA,
0.12 mL) were added. After 24 h, the reaction mixture
was concentrated to give syrupy 6-(60-(tert-butoxycar-
bonylamino)-60-deoxy-20,30,40,50-tetra-O-methyl-D-gala-
ctonamide)-6-deoxy-2,3,4,5-tetra-O-methyl-D-galactonic
acid 6 (0.15 g, 70%). To a solution of crude 6 (0.15 g,
0.26 mmol) in dry EtOAc (13 mL), pentachlorophenol
(0.08 g; 0.30 mmol) and DCC (0.02 g; 0.30 mmol) were
added. The reaction was stirred at room temperature
for 16 h, when TLC (EtOAc) showed complete conver-
sion of the starting material (Rf 0.0) into a main spot
(Rf 0.51). Column chromatography (1:3 hexane–EtOAc)
afforded 7 (0.15 g, 70%) as a white foam; [a]D = +9.2 (c
1.0, CHCl3); IR m (cmÀ1) 3502 (OH), 3365 (NH), 2939,
2831 (CH), 1764 (CO), 1720 (NCOO), 1671 (amide I),
1522 (amide II), 1107 (COC); 1H NMR d 7.12 (dd,
1H, JNH,6a = 7.5, JNH,6b = 3.5 Hz, NH), 4.89 (br s, 1H,
NHBoc), 4.42 (d, 1H, J2,3 = 1.8 Hz, H-2), 4.11 (dd,
1H, J3,4 = 8.9 Hz, H-3), 4.02 (ddd, 1H, J5,6a = 6.4,
4.2. Pentachlorophenyl 6-(tert-butoxycarbonyl)amino-6-
deoxy-2,3,4,5-tetra-O-methyl-D-galactonate 3
To a suspension of 6-azido-6-deoxy-2,3,4,5-tetra-O-
methyl-D-galactonic acid19 1 (0.35 g, 1.26 mmol) in
EtOAc (3 mL) was added methanol until complete dis-
solution. Upon addition of di-tert-butyldicarbonate
((Boc)2O, 0.32 g, 1.40 mmol) the mixture was hydroge-
nated at room temperature and 45 psi in the presence
of 10% Pd–C (10 mg) for 5 h. The catalyst was filtered
and the filtrate concentrated to give syrupy 6-(tert-
butoxycarbonyl)amino-6-deoxy-2,3,4,5-tetra-O-methyl-
D-galactonic acid (2, 0.38 g). Crude 2 (0.38 g) dissolved
in EtOAc (7 mL) was treated with pentachlorophenol
(0.41 g, 1.48 mmol) and dicyclohexylcabodiimide
(DCC, 0.31 g, 1.48 mmol). The solution was stirred at
room temperature for 16 h, when TLC (5:1 hexane–
EtOAc) showed that the starting compound (Rf 0.0)
was transformed into a less polar product (Rf 0.20).
The mixture was filtered, the filtrate concentrated, and
0
0
J6a,6b = 14.0 Hz, H-6a), 3.90 (d, 1H, J2 3 = 1.6 Hz, H-
0
20), 3.83 (dd, 1H, J3 4 = 9.0 Hz, H-30), 3.64 (ddd, 1H,
J4,5 = 2.4, J5,6b = 5.2 Hz, H-5), 3.63, 3.58, 3.50 (·3),
0

102
C. L. Romero Zaliz, O. Varela / Tetrahedron: Asymmetry 16 (2005) 97–103
3.48, 3.45, 3.37 (6s, 24H, OCH3), 3.57 (dd, 1H, H-4),
3.52–3.36 (m, 5H, H-40,50,60a,60b,6b), 1.45 (s, 9H,
C(CH3)3); 13C NMR d 171.6, 168.0 (CO), 156.0 (CON-
HBoc), 144.0, 132.3, 131.9, 127.4 (aromatic), 81.6, 80.7,
80.6, 80.3, 80.2, 79.6, 78.0, 77.6 (C-2,20,3,30,4,40,5,50),
60.9, 60.5, 60.2, 60.1, 59.1, 59.0, 57.8, 57.6 (OCH3),
40.0, 38.9 (C-6, 60), 28.4 (C(CH3)3). Anal. Calcd for
C30H47O13N2Cl5:C, 44.70; H, 5.69; N, 3.36; Cl, 21.28.
Found:C, 44.40; H, 5.54; N, 3.24; Cl, 21.73.
H-4), 3.43 (dd, 1H, H-60b), 3.42 (dd, 1H, H-40), 3.35
(dd, 1H, H-6b); 13C NMR d 175.0, 171.7 (CO), 81.4,
80.8, 80.7, 80.5, 79.0, 78.9, 77.3 (C-2,20,3,30,4,40,5,50),
60.8, 60.6, 60.5, 60.0, 59.1, 58.7, 58.5, 57.6 (OCH3),
50.6 (C-60), 38.7 (C-6). Anal. Calcd for C20H38O11N4:
C, 47.05; H, 7.50; N, 10.97. Found:C, 47.12; H, 7.61;
N, 10.87.
4.7. Conversion of 9 into 7
4.5. Pentachlorophenyl 6-azido-6-deoxy-2,3,4,5-tetra-O-
methyl-D-galactonate 8
To a suspension of 9 (0.58 g, 1.14 mmol) in EtOAc
(6 mL) was added MeOH dropwise until complete disso-
lution. The mixture was hydrogenated at room temper-
ature and 45 psi for 10 h in the presence of Boc2O
(0.28 g, 1.25 mmol) and 10% Pd–C (20 mg). The catalyst
was filtered off and the filtrate concentrated to afford 6
(0.58 g) as a colorless syrup, which was dissolved in
dry EtOAc (8.5 mL) and treated with pentachlorophe-
nol (0.27 g, 1.08 mmol) and DCC (0.20 g, 1.08 mmol)
as described above. After chromatographic purification,
compound 7 (0.56 g, 60%) was obtained as a white
foam, which showed the same physical and spectral
properties as the product already reported.
To a solution of 1 (0.46 g, 1.70 mmol) in dry EtOAc
(10 mL), pentachlorophenol (0.60 g; 2.40 mmol) and
DCC (0.44 g, 2.40 mmol) were added and the mixture
was stirred at room temperature. After 16 h, TLC
(10:1 hexane–EtOAc) showed total conversion of the
starting material (Rf 0.0) into a less polar product (Rf
0.34), the solid formed was filtered off and washed with
EtOAc. The filtrate and washings were combined, con-
centrated, and chromatographed (10:1 hexane–EtOAc)
to give 8 (0.78 g, 88%) as white crystals, mp 84 ꢁC,
1
[a]D = À20.3 (c 1.0, CHCl3); H NMR d 4.41 (d, 1H,
J2,3 = 1.8 Hz, H-2), 4.09 (dd, 1H, J3,4 = 8.9 Hz, H-3),
4.8. Poly(6-amino-6-deoxy-2,3,4,5-tetra-O-methyl-D-
galactonic acid) 11
0
3.68 (dd, 1H, J5,6 = 6.1, J6,6 = 12.1 Hz, H-6), 3.64,
3.55, 3.54, 3.51 (4s, 12H, OCH3), 3.60 (ddd, 1H,
0
J4,5 = 2.1, J5,6 = 6.4 Hz, H-5), 3.58 (dd, 1H, H-4), 3.48
A saturated solution of hydrogen chloride in dry EtOAc
(9 mL) was added to a solution of 7 (0.62 g, 0.75 mmol)
in dry EtOAc. After stirring at room temperature for
16 h the solution was concentrated to give 10 as a foam;
1H NMR d 8.36 (br s, 3H, NHþ3 ), 7.31 (br s, 1H,
CONH), 4.41 (d, 1H, J2,3 = 1.5 Hz, H-2), 4.10 (dd,
1H, J3,4 = 8.9 Hz, H-3), 4.02 (m, 1H, H-6a), 3.87 (br s,
(dd, 1H, H-60); 13C NMR d 168.0 (CO), 143.9, 132.2,
131.9, 127.4 (C-aromatic), 80.0, 79.6, 79.0, 78.7
(C-2,3,4,5), 60.9, 60.0, 59.1, 58.5 (OCH3), 50.6 (C-6).
Anal. Calcd for C16H18O6N3Cl5:C, 36.56; H, 3.45; N,
7.99; Cl, 33.73. Found:C, 36.78; H, 3.47; N, 7.93; Cl,
33.71.
1H, H-20), 3.81 (br d, 1H, J3 ,4 = 7.5 Hz, H-30), 3.63–
3.23 (m, 7H, H-4,5,6b,40,50,60a,60b), 3.63, 3.58, 3.55,
3.51, 3.50, 3.49, 3.41, 3.40 (8s, 24H, OCH3); 13C NMR
d 171.3, 168.0 (C-1,10), 143.9, 132.3, 131.9, 127.4 (C-aro-
matic), 81.4, 81.0, 80.7, 80.6, 80.1, 79.5, 77.5, 76.5 (C-
2,3,4,5,20,30,40,50), 60.9, 60.6, 60.3, 60.1, 59.4, 59.1,
58.8, 57.8 (OCH3), 39.7, 38.9 (C-6,60). Compound 10
was dissolved in dry DMF (0.78 mL) and DIPEA
(0.19 mL) was added. The solution was stirred for 8 days
at room temperature under Ar atmosphere. When the
mixture became viscous, an additional portion of dry
DMF (0.8 mL) was injected in order to facilitate the stir-
ring. The solvents were then evaporated under dimin-
ished pressure and the residue was dissolved in
dichloromethane (1 mL). Addition of dry ethyl ether
(1.5 mL) afforded 11 (0.33 g, 89%) as a white solid;
[a]D = +72.0 (c 0.9, CHCl3); [g]DCA 0.38 dL/g; Mw
11,000 (GPC); IR (cmÀ1) 3419 (NH), 2941, 2838 (CH),
1661 (amide I), 1529 (amide II), 1100 (COC); 1H
0
0
4.6. 6-(60-Azido-60-deoxy-20,30,40,50-tetra-O-methyl-D-
galactonamide)-6-deoxy-2,3,4,5-tetra-O-methyl-D-galac-
tonic acid 9
A solution of 5 (0.42 g, 1.48 mmol) in dry DMF (10 mL)
and DIPEA (0.52 mL) was added to a solution of 8
(0.78 g; 1.48 mmol) with stirring. The mixture was stir-
red at room temperature for 16 h, when TLC (EtOAc)
revealed the absence of 8 (Rf 0.75). The solution was
concentrated and the resulting residue was dissolved in
water, made basic (NaHCO3), and extracted with
dichloromethane (3 · 50 mL). The aqueous layer was
acidified to pH 4 with 0.5 M aqueous HCl and extracted
with dichloromethane (3 · 50 mL). The organic extract
was dried (MgSO4) and concentrated to give white crys-
tals. Recrystallization from EtOAc–hexane gave pure 9
(0.62 g, 75%); mp 129 ꢁC; [a]D = +33.7 (c 1.1, CHCl3);
IR m (cmÀ1) 3413 (NH, OH), 2941, 2836 (CH), 2103
(N3), 1733 (CO), 1655 (amide I), 1529 (amide II), 1100
(COC); 1H NMR d 7.18 (dd, 1H, JNH,6a = 7.8,
JNH,6b = 3.6 Hz, NH), 4.05 (d, 1H, J2,3 = 2.1 Hz, H-2),
3.99 (ddd, 1H, J5,6a = 6.4, J6a,6b = 14.1 Hz, H6a), 3.91
0
NMR d 7.17 (dd, 1H, JNH,6 = 7.5, JNH,6 = 2.9 Hz,
0
NH), 4.04 (dd, 1H, J5,6 = 5.8, J6,6 = 14.1 Hz, H-6),
3.88 (d, 1H, J2,3 = 1.3 Hz, H-2), 3.83 (dd, 1H,
J3,4 = 9.0 Hz, H-3), 3.59 (ddd, 1H, J4,5 = 2.3,
0
(dd, 1H, J3,4 = 9.1 Hz, H-3), 3.90 (d, 1H, J2 2 = 1.6 Hz,
0
0
J5,6 = 4.5 Hz, H-5), 3.52, 3.48, 3.45, 3.35 (4s, 12H, 4
H-20), 3.81 (d, 1H, J3 4 = 9.2 Hz, H-30), 3.63 (dd, 1H,
OCH3), 3.42 (dd, 1H, H-4), 3.28 (dd, 1H, H-60); 13C
NMR d 171.4 (C-1), 81.4, 81.1, 80.7, 77.7 (C-2,3,4,5),
60.3 (·2), 59.0, 57.6 (4OCH3), 39.2 (C-6). Anal. Calcd
for C10H19O5N:C, 51.44; H, 8.23; N, 6.00. Found:C,
51.66; H, 8.35; N, 5.85.
0
0
J5,6 a = 6.2, J6 a,6 b = 12.1 Hz, H-60a), 3.60 (ddd,
1H, J4,5 = 2.3, J5,6b = 4.8 Hz, H-5), 3.54 (ddd, 1H,
0
0
0
J4 5 = 2.4, J5 6 b = 5.5 Hz, H-50), 3.53, 3.52, 3.50, 3.49,
3.48, 3.47, 3.42, 3.37 (8s, 24H, 8OCH3), 3.47 (dd, 1H,
0
0
0 0

C. L. Romero Zaliz, O. Varela / Tetrahedron: Asymmetry 16 (2005) 97–103
103
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The same polymerization was conducted starting from
10 (0.30 g, 0.36 mmol) using CHCl3 (0.45 mL) as solvent
and 0.11 mL of N,N-diisopropylethylamine, to afford 11
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The synthesis of 18 from 6-azido-6-deoxy-2,3,4,5-tetra-
O-methyl-L-galactonic acid19 (12) was performed fol-
lowing the sequence depicted in Scheme 3. All the steps
were conducted as described for the preparation of the
analogous intermediates of the D-series (Schemes 1 and
2). Their yields and optical rotations are reported for
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´
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each individual case. The H and 13C spectra of 13–18
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´
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1.1, CHCl3).
4.9.2. 6-(60-Azido-60-deoxy-20,30,40,50-tetra-O-methyl-L-
galactonamide)-6-deoxy-2,3,4,5-tetra-O-methyl-L-galac-
tonic acid 15. Yield 76%; [a]D = À33.4 (c 1.3, CHCl3).
4.9.3. Pentachlorophenyl 6-(60-(tert-butoxycarbonyl-
amino)-60-deoxy-20,30,40,50-tetra-O-methyl-L-galacton-
amide)-6-deoxy-2,3,4,5-tetra-O-methyl-L-galactonate 17.
Yield 55% (from 15); [a]D À9.4 (c 0.8, CHCl3).
´
´
17. Bueno, M.; Galbis, J. A.; Garcıa-Martın, M. G.; de Paz,
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21. Hunter, D. F. A.; Fleet, G. W. J. Tetrahedron: Asymmetry
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Acknowledgements
We are indebted to the University of Buenos Aires
(Projects X108 and X059) and the National Research
Council of Repu´blica Argentina (CONICET) for
financial support. O.V. is a Research Member of
CONICET.
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