Stereoselective synthesis of N-galactofuranosyl amides

Article abstract of DOI:10.1016/j.carres.2010.12.020

α- or β-Galactofuranosyl (Galf) amides can be synthesized with high stereoselectivity by traceless Staudinger ligation starting from unprotected β-galactofuranosyl azide or tetra-O-acetyl-β- galactofuranosyl azide, respectively. The resulting Galf amides

Full text of DOI:10.1016/j.carres.2010.12.020

Carbohydrate Research 346 (2011) 465–471
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Stereoselective synthesis of N-galactofuranosyl amides
⇑
Filippo Nisic, Anna Bernardi
Dipartimento di Chimica Organica e Industriale and CISI, Universita’ degli Studi di Milano, Via Venezian 21, I-20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
a
- or b-Galactofuranosyl (Galf) amides can be synthesized with high stereoselectivity by traceless Stau-
Received 29 November 2010
Received in revised form 23 December 2010
Accepted 23 December 2010
Available online 31 December 2010
dinger ligation starting from unprotected b-galactofuranosyl azide or tetra-O-acetyl-b-galactofuranosyl
azide, respectively. The resulting Galf amides are hitherto unknown molecules, with interesting potential
as inhibitors of mycobacterial growth.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Glycosyl amides
Glycosyl azides
Glycomimetics
Neoglycoconjugates
Staudinger ligation
Stereoselective synthesis
1. Introduction
2. Results and discussion
The arabinogalactan constituent of mycobacterial cell walls
contains a galactan polymer made of galactose residues in the fura-
nose form, Galf. The Galf residues are created by bacterial mutases
which convert UDP-galactopyranose into UDP-galactofuranose and
are essential for the viability of mycobacteria.1 The furanose form
The starting galactofuranosyl azide 2 was prepared in 90% yield
from known penta-O-acetyl-galactofuranose 117 using TMSN3 and
SnCl4 (Scheme 1). Zemplén deacetylation afforded the unprotected
Galf-azide 3, whose anomeric b configuration was established by
NOE difference experiments, which showed a clear correlation be-
tween protons H1 and H3.
of D-galactose is unknown in mammals and UDP-galactopyranose
(UDPG) mutase has become an interesting target for the develop-
ment of drugs against the many pathogens which contain Galf,
most prominently Mycobacterium tuberculosis. UDPG mutase inhib-
itors have been reported and shown to block mycobacterial
growth.2–8 Furthermore, simple galactofuranosyl derivatives in
low micromolar concentration have been shown to inhibit bacte-
rial growth9,10 with a mechanism which has not been fully
elucidated.
We have been interested for some time in the opportunities
offered by glycosyl amides as mimics of natural glycosides11,12 and
have been developing synthetic methodologies for the preparation
of glycosyl amides from glycosyl azides based on the traceless Stau-
dinger ligation.13–15 In this paper, we describe a simple stereoselec-
tive synthesis of Galf amides in both anomeric configurations
starting from a common azide precursor. The resulting compounds
may be of interest in the generation of new antibacterial leads, or
as inhibitors of galactofuranosidases and galactofuranosyltransfe-
rases.1,16
Initial studies focused on the functionalization of 2 using stan-
dard methodology, such as catalytic hydrogenation followed by
in situ acetylation (Scheme 2). However, anomerization of the
intermediate glycosyl amine is fast and a mixture of epimers was
obtained. Similarly, reaction of 2 and Ph3P generated an imino-
phosphorane that epimerized at the anomeric position before
reacting with acylating agents, such as pentafluorophenyl valero-
ate (C4H9COPFP, Scheme 2).18 These results are consistent with
previous observations by our group13–15,18 and others19 working
on pyranosyl azides.
On the contrary, following our previously established proto-
col,13–15 traceless Staudinger ligation of 2 with 2-diphenylphos-
phanyl-phenyl valeroate (4a) in a 98:2 N,N-dimethylacetamide
(DMA)–1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU)
solvent mixture (4 h, 70 °C) followed by treatment with water
afforded the corresponding galactofuranosyl amide 5a in 60%
yield as a single anomer (Scheme 3). The structure and anomeric
One Referee remarked that many physical and spectral data of the compounds
described in this paper are also indicative of their anomeric configuration. All the
Referee’s observations are reported in the Supplementary data. We are grateful to this
reviewer for his/her comments.
⇑
Corresponding author. Tel.: +39 0250314092.
E-mail address: anna.bernardi@unimi.it (A. Bernardi).
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.12.020

466
F. Nisic, A. Bernardi / Carbohydrate Research 346 (2011) 465–471
OAc
N3
N3
H1
CH3O-Na+
dry CH3OH
AcO
AcO
HO
O
O
TMSN3,SnCl4
CH2Cl2 dry
O
HO
AcO
AcO
AcO
AcO
HO
H3
OAc
H
OAc
H
H
OH
1
2
3
Scheme 1. Synthesis of Galf-azide 2 and 3.
N3
AcO
O
H2, Pd/C
or
AcO
O
NHCOR
AcO
AcO
Ac2O
AcO
AcO
PPh3
OAc
H
OAc
H
2
C4H9COPFP
Scheme 2. Derivatization of 2 with conventional methods leads to mixtures of epimers at the anomeric position.
NHCOC4H9
c
NHCOC4H9
H1
AcO
HO
H3
O
O
AcO
AcO
HO
HO
a, b
N3
RO
O
+
OAc
OH
H
H
RO
RO
R = OAc
5a
6a
2
OR
H
PPh2
R = H
O
3
HO
O
O
HO
HO
NHCOC4H9
OH
4a
a, b
H
7a
a) 70°C, 4h, DMA:DMPU 98:2; b) H2O, 2 h, 70°C; c) 0.05M MeO-Na+, MeOH.
Scheme 3. Stereodivergent synthesis of furanosyl amides 5a and 7a by ligation of 2 and 3.
configuration of 5a were confirmed by NMR after deacetylation
(cat. NaOMe in MeOH) to yield the unprotected amide 6a
(Scheme 4). The chemical shift of C4 in 6a at 83.6 ppm is diagnostic
for the furanose form, and NOESY experiments (CD3OD at
400 MHz) showed the expected crosspeak between protons H1
and H3.
Surprisingly, ligation of unprotected Galf-azide 3 with 4a affor-
ded, under similar conditions, amide 7a with the opposite anomeric
configuration (Scheme 3). The structure of 7a was confirmed by the
C4 chemical shift (84.4 ppm) and by the absence of crosspeaks be-
tween protons H1 and H3 in the NOESY spectrum (CD3OD; H1, and
H3 of 7a are isochronous in D2O at 400 MHz).
Compound 7a was fully characterized as the 1,2-cis isomer after
acetylation to 8a (Scheme 4), by the presence of crosspeaks
between protons H1 and H4 in the NOESY spectrum (CDCl3 at
400 MHz).
The reason for this selectivity switch is not completely under-
stood at present, but the anomeric inversion must derive from a
ring-opening process occurring after the azide reduction step, pre-
sumably from the b-iminophosphorane 9 to afford the phosphin-
immine 10 (Scheme 5). From this open-chain intermediate, the
ring closure step could be biased by the unprotected hydroxy
group at position 2, which can trap the
and enforce formation of the (1,2-cis)
consistent with our previous observation that
sylamides are formed as by-products in the ligation of unprotected
-glucopyranosyl azide with phosphines 4a, and that the amount
a
-iminophosphorane 11
-anomers. This result is
-N-glucofurano-
a
a
a
of furanose by-product increases with the reaction temperature.14
In this case, ring opening of the intermediate iminophosphorane,
which is favored at high temperatures, leads to an open-chain 2-
hydroxy phosphinimine, which follows the same path as 10. If this
is the case, the retention of configuration observed with the tetra-
O-acetyl azide 2 is even more puzzling. Indeed, as it was observed
for pyranosyl azides,15 the acetylated substrate is expected to un-
dergo ring-opening even more easily than 3, due to the electron
withdrawing property of the protecting groups, and thus to afford
H
H1
HO
O
4 RO
O
Ac2O, DMAP
Pyridine
AcO
AcO
HO
HO
NHCOC4H9
OH
NHCOC4H9
OAc
H
H
7a
8a R = OAc
Scheme 4. Acetylation of 7a and NOESY characterization of 8a.

F. Nisic, A. Bernardi / Carbohydrate Research 346 (2011) 465–471
467
N3
HO
O
HO
HO
PAr3
N
OH
H
HO
H
O
N2
HO
O
3
+
HO
HO
N
PAr3
HO
HO
PPh2
OH
H
OH
H
O
10
9
O
β-iminophosphorane
phosphinimmine
4a
H
H
R
HO
HO
O
H
HO
O
O
H
HO
HO
HO
HO
O
HO
HO
N
O
N
N
O
O
H
H
O
PAr3
H
H
P
P
Ar3
Ph
Ph
11
α-iminophosphorane
R
H
Ph2P
H
O
HO
HO
O
O
H2O
HO
HO
HO
HO
OH
+
O
N
NHCOR
OH
O
H
H
P
Ph
7a
Ph
α-galactofuranosyl amide
HO
1,2 CIS
Scheme 5. Proposed mechanism for the anomeric epimerization of 3.
NHCOR'
NHCOR'
HO
AcO
O
O
HO
HO
AcO
AcO
a, b
c
N3
RO
O
OH
OAc
5a-f
H
H
RO
RO
R= Ac
6a-f
2
OR
H
+
PPh2
R= H
O
R'
3
HO
O
O
HO
HO
NHCOR'
OH
4a-g
R' = -(CH2)3CH3
R' = -CH2CH(CH3)2
a, b
H
4a
4b
7a-g
4c R' = -CH=C(CH3)2
4d
R' = -(CH2)14CH3
4e R' = -(CH2)6CH3
4f
4g
R' = -CH2CH(CH3)(CH2)2CH=C(CH3)2
R' = -Ph
a) 70°C, 4h, DMA:DMPU 98:2; b) H2O, 2 h, 70°C; c) 0.05M MeO-Na+, MeOH.
Scheme 6. Traceless Staudinger ligation of 2 and 3 with phosphines 4a–g.

468
F. Nisic, A. Bernardi / Carbohydrate Research 346 (2011) 465–471
at least partial racemization. The exclusive formation of the
a-(1,2-
enzymes.1,16 Further studies are in progress to analyze the activity
trans) anomer may indicate that, in the absence of a directing ef-
fect of a free 2-OH group, trans ring closure of the phosphinimine
is favored, possibly for steric reasons.
of galactofuranosyl amides against Galf-containing pathogens.
3. Experimental
3.1. General
To explore the scope of this reaction and confirm its stereo-
chemical outcome, 2 and 3 were subjected to traceless ligation
with a series of phosphines 4a–g (Scheme 6). To facilitate purifica-
tion from the phosphinoxide byproduct, amides 5a–f obtained
from tetra-O-acetyl azide 2 were not directly isolated. Anomeric
configurations and diastereomeric distributions were analyzed by
1H NMR spectroscopy on the crude reaction mixtures, which were
then deacetylated to afford the corresponding deprotected amides
6a–f. The latter were finally isolated and purified by flash chroma-
tography on silica gel. The deprotection step was found to be crit-
ical to preserve configurational integrity of the anomeric carbon.
Although 0.05 M NaOMe in MeOH solutions and short contact
times (45 min) were used successfully, the use of more concen-
trated (0.1 M) solutions caused anomeric epimerization. This pro-
cess likely occurs via NaOMe-induced deprotonation of the
amide nitrogen, which allows ring opening to occur with a process
similar to that described in Scheme 5 for iminophosphorane 9.
Longer chain amides, such as 4d–f, appeared to be more stable to
basic conditions. Products from the Staudinger ligation of the
unprotected Galf-azide 3 were isolated by water extraction from
the crude reaction mixtures and purified by silica gel chromatogra-
phy. Anomeric ratios were evaluated on the crude by 1H NMR
spectroscopy.
Solvents were dried by standard procedures: dichloromethane,
methanol, N,N-diisopropylethylamine, and triethylamine were
dried over calcium hydride; N,N-dimethylacetamide (DMA), 1,3-
dimethyltetrahydro-2(1H)pyrimidinone (DMPU), chloroform, and
pyridine were dried over activated molecular sieves. Reactions
requiring anhydrous conditions were performed under nitrogen.
1H, 13C and 31P NMR spectra were recorded at 400 MHz on a Bruker
AVANCE-400 instrument. Chemical shifts (d) for 1H and 13C spectra
are expressed in ppm relative to internal Me4Si as standard. Signals
were abbreviated as s, singlet; br s, broad singlet; d, doublet; t,
triplet; q, quartet; m, multiplet. Mass spectra were obtained with
a Bruker ion-trap Esquire 3000 apparatus (ESI ionization) and FT-
ICR Mass Spectrometer APEX II & Xmass software (Bruker Dalton-
ics)—4.7 Magnet. Thin layer chromatography (TLC) was carried out
with pre-coated Merck F254 silica gel plates. Flash chromatography
(FC) was carried out with Macherey-Nagel Silica Gel 60 (230–400
mesh). The syntheses of o-diphenylphosphinophenol and of phos-
phines 4a–c have been described.13
3.2. 2-Diphenylphosphanylphenyl palmitate (4d)
The results of this screening are collected in Table 1. Transfer of
linear aliphatic (4a,d,e), branched aliphatic (4b,f), unsaturated
(4c,f), and aromatic (4g) amide chains was performed with uni-
form results. All reactions gave the expected products in moderate
yields. As previously reported for unprotected glycopyranosyl
azides,14 microwave irradiation was found to accelerate the liga-
tion of 3 (entries 7 and 11). The stereoselectivity was complete,
as determined by the 1H NMR spectra of the crude reaction mix-
tures. In all cases, b-anomers were obtained from the tetra-O-acet-
Dry triethylamine (1.1 equiv) and palmitoyl chloride (1.1 equiv)
were added, at room temperature and under nitrogen, to a solution
of o-diphenylphosphinophenol (1 equiv) in dry CH2Cl2 (0.1 M). The
reaction mixture was stirred at room temperature and monitored
by TLC (90:10 hexane–EtOAc) until disappearance of the o-diphe-
nylphosphinophenol (ca. 1 h). The solvent was then evaporated un-
der reduced pressure and the residue was diluted with EtOAc and
washed with 5% aqueous NaHCO3 and water. The organic layer was
dried over Na2SO4 and concentrated. The compound was purified
by flash chromatography (hexane–EtOAc 95:5) yield = 85%. 1H
NMR (400 MHz, CDCl3, 25 °C): d = 7.42–7.28 (m, 11H, Ph), 7.18–
7.08 (m, 2H), 6.82–6.76 (m, 1H), 2.23 (t, J = 7.2, J = 8 Hz, 2H, CH2),
1.48 (t, J = 7.2, J = 6.8 Hz, 2H, CH2), 1.41–1.17 (m, 24H, 12 ꢀ CH2),
0.88 (t, J = 6.8 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3, 25 °C):
d = 171.8, 134.3, 134.1, 133.9, 129.2, 126.2, 122.8, 35.2, 34.3, 32.2,
29.9, 29.8, 29.6, 29.4, 29.3, 29.1, 24.7, 22.9, 14.3; 31P NMR
(161 MHz, CDCl3): d = ꢁ14.3 ppm [oxide 31P = +27.3 ppm].
yl azide 2 and a-anomers from the unprotected azide 3.
While further studies are clearly needed to clarify the mecha-
nism of this intriguing reaction, the results described herein repre-
sent the first reported synthesis of Galf amides. Notably, both
isomers can be obtained with excellent selectivity from a common,
easily available precursor. The chemical synthesis of Galf deriva-
tives has been recently reviewed1,16,20 and the interest in these
molecules is currently increasing for their potential as antibacterial
agents and as useful core structures for targeting Galf recognizing
Table 1
Ligation of 2 and 3 with phosphines 4a–ga
Entry
Azide
Phosphine
R
Product
a
/bb
Yields
1
2
3
4
5
6
7
8
9
10
11
12
13
2
2
2
2
2
2
3
3
3
3
3
3
3
4a
4b
4c
4d
4e
4f
4a
4b
4c
4d
4e
4f
–(CH2)3CH3
–CH2CH(CH3)2
–CH@C(CH3)2
–(CH2)14CH3
–(CH2)6CH3
–CH2CH(CH3)(CH2)2CH@C(CH3)2
–(CH2)3CH3
–CH2CH(CH3)2
–CH@C(CH3)2
–(CH2)14CH3
–(CH2)6CH3
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
2:98
P1:99
2:98
60
53
48
60
56
51
60
57
51
55
63
56
62
P1:99
P1:99
P1:99
P99:1c
P99:1
P99:1
P99:1
P99:1c
P99:1
P99:1
–CH2CH(CH3)(CH2)2CH@C(CH3)2
–Ph
4g
7g
a
Unless otherwise stated, all reactions were performed in 98:2 DMA–DMPU mixtures for 4 h at 70 °C. Water was then added and the solution was stirred for additional 2 h
at 70 °C before work up.
b
1H NMR spectroscopic ratio of the anomeric protons in the crude.
Reaction performed under microwave irradiation: 30 min, 70 °C.
c

F. Nisic, A. Bernardi / Carbohydrate Research 346 (2011) 465–471
469
3.3. 2-Diphenylphosphanylphenyl caprylate (4e)
solution of o-diphenylphosphinophenol
temperature and under argon, to a solution of 1,2,3,5,6-penta-O-
acetyl-b- -galactofuranose 1 (500 mg, 1.28 mmol, 1 equiv) in dry
D
A
(126.2 mg,
CH2Cl2 (2.56 mL, 0.5 M). The reaction mixture was stirred at room
temperature and the reaction was monitored by TLC (6:4 hexane–
EtOAc). After 24 h CH2Cl2 was added and the solution was washed
with saturated Na2CO3 and then with water. The organic layer was
dried over Na2SO4, filtered, and evaporated under reduced pres-
sure. The crude product was purified by flash chromatography
using 60:40 hexane–EtOAc as the eluent to afford the product in
0.45 mmol, 1 equiv), caprylic acid (77.9 mg, 0.54 mmol, 1.2 equiv)
and N,N-dimethylaminopyridine (5.5 mg, 0.045 mmol, 0.1 equiv)
in dry CH2Cl2 was added, at room temperature and under argon,
to a solution of N,N0-dicyclohexylcarbodiimide (130.1 mg, 0.63
mmol, 1.4 equiv) in dry CH2Cl2 (total volume: 4.5 mL, 0.1 M). The
mixture was stirred at room temperature for 1 h, monitoring by
TLC (90:10 hexane–EtOAc). The reaction mixture was filtered and
washed with CH2Cl2. The crude product was purified by flash chro-
matography using 90:10 hexane–EtOAc as the eluent to afford the
product in 90% yield. 1H NMR (400 MHz, CDCl3, 25 °C): d = 7.45–
7.26 (m, 11H, Ph), 7.20–7.07 (m, 2H), 6.83–6.78 (m, 1H), 2.25 (t,
J = 7.6 Hz, 2H, CH2), 1.49 (t, J = 7.2 Hz, 2H, CH2), 1.36–1.19 (m, 8H,
4 ꢀ CH2), 0.89 (t, J = 6.8 Hz, CH3); 13C NMR (100 MHz, CDCl3,
25 °C): d = 171.8, 135.9, 134.7, 134.3, 134.1, 130.1, 129.2, 128.8,
128.7, 126.2, 122.8, 34.2, 33.8, 31.8, 29.2, 29.1, 24.7, 22.8, 14.3 (CH3).
90% yield. ½a 2D5
ꢂ
ꢁ11.5 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3,
25 °C): d = 5.42 (s, 1H, H-1), 5.40–5.35 (m, 1H, H-5), 5.05 (dd,
J2,3 = 5.2, J3,4 = 2.8 Hz, 1H, H-3), 4.95 (t, J3,4 = 2.8 Hz, 1H, H-4),
0
0
4.39–4.32 (m, 2H, H-2, H-6), 4.19 (dd, J5,6 = 6.8, J6,6 = 11.6 Hz, 1H,
H-60), 2.16 (s, 3H, OAc), 2.14 (s, 3H, OAc), 2.12 (s, 3H, OAc), 2.06
(s, 3H, OAc); 13C NMR (100 MHz, CDCl3, 25 °C): d = 170.6, 170.1,
169.9, 169.7, 94.3 (C-1), 82.2 (C-2), 81.1 (C-4), 76.5 (C-3), 69.4
(C-5), 62.5 (C-6), 20.9–20.7 (4 ꢀ OAc). ESI-MS: m/z 396.2 [M+Na]+.
3.7. Synthesis of b-D-galactofuranosyl azide (3)
3.4. 2-Diphenylphosphanylphenyl citronellate (4f)
A solution of NaOMe 0.1 M in dry methanol (320
0.5 equiv) was added, at room temperature and under nitrogen, to
a solution of 2,3,5,6-tetra-O-acetyl-b- -galacto-furanosyl azide 2
lL, 0.32 mmol,
A
solution of the o-diphenylphosphinophenol (127.8 mg,
0.46 mmol, 1 equiv), the citronellic acid (93.6 mg, 0.55 mmol,
1.2 equiv) and N,N-dimethylaminopyridine (5.5 mg, 0.046 mmol,
0.1 equiv) in dry CH2Cl2 was added, at room temperature and under
argon, to a solution of N,N0-dicyclohexylcarbodiimide (132.1 mg,
0.64 mmol, 1.4 equiv) in dry CH2Cl2 (total volume: 4.6 mL, 0.1 M).
The mixture was stirred at room temperature for 1 h, monitoring
by TLC (90:10 hexane–EtOAc). The reaction mixture was filtered
and washed with CH2Cl2. The crude product was purified by flash
chromatography using 95:5 hexane–EtOAc as the eluent to afford
the product in 75% yield. 1H NMR (400 MHz, CDCl3, 25 °C):
d = 7.45–7.27 (m, 11H, Ph), 7.21–7.08 (m, 2H), 6.84–6.78 (m, 1H),
5.07 (t, J = 7.2, J = 6.8 Hz, 1H, CH), 2.25 (dd, J = 5.6, JHa–Hb = 15.3 Hz,
1H, Ha, CH2), 2.06 (dd, J = 8.4, JHa–Hb = 15.3 Hz, 1H, Hb, CH2), 1.99–
1.79 (m, 3H, CH–CH2), 1.68 (s, 3H, CH3), 1.60 (s, 3H, CH3), 1.27–
1.12 (m, 2H, CH2), 0.89 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3,
25 °C): d = 171.2, 153.2, 153.1, 136, 135.9, 134.3, 134.1, 133.9,
131.9, 131.8, 131.7, 130.1, 129.2, 128.8, 128.7, 126.2, 124.5, 122.7,
41.5, 36.9, 29.9, 25.6, 19.8, 17.9; 31P NMR (161 MHz, CDCl3):
d = ꢁ14.9 ppm [oxide 31P = +27.3 ppm].
D
(238 mg, 0.64 mmol, 1 equiv) in dry MeOH (6.4 mL, 0.1 M). The
mixture was stirred at room temperature. After 1 h TLC monitoring
(eluents: hexane–EtOAc 50:50 and CHCl3–MeOH 80:20) showed
total consumption of the starting material, Amberlyst IRA 120 H+
resin was added. The mixture was stirred for 30 min (pH 3). The re-
sin was filtered and washed with MeOH, the solvent was removed
under reduced pressure. The product, isolated in quantitative yield,
was used without further purification. ½a D25
ꢂ
ꢁ153 (c 1, MeOH). 1H
NMR (400 MHz, D2O, 25 °C): d = 5.31 (d, J1,2 = 2.8 Hz, 1H, H-1),
4.06 (ABX system, part A dd, J2,3 = 4, J3,4 = 10 Hz 1H, H-3), 4.01
(ABX system, part B, dd, J3,4 = 10.4, J4,5 = 4.4 Hz, 1H, H-4), 3.94
(ABX system, part X, dd, J1,2 = 2.8, J2,3 = 3.6 Hz, 1H, H-2), 3.80–
0
3.73 (ddd, J4,5 = 4.4, J5,6 = 7.2, J5,6 = 4.8 Hz, 1H, H-5), 3.64 (dd,
0
0
0
J5,6 = 4.8, J6,6 = 11.6 Hz, 1H, H-6), 3.57 (dd, J5,6 = 7.2, J6,6 = 11.6 Hz,
1H, H-60); 13C NMR (100 MHz, D2O, 25 °C): d = 95.3 (C-1), 84.2 (C-
4), 80.6 (C-2), 76.4 (C-3), 70.7 (C-5), 62.6 (C-6). ESI-MS: m/z
228.07 [M+Na]+. NOESY (400 MHz, D2O, 25 °C): contact between
H-1/H-3.
3.5. 2-Diphenylphosphanylphenyl benzoate (4g)
3.8. General procedure for stereoselective ligation of 2 and 3 in
DMA:DMPU mixtures
Dry pyridine (27 lL, 0.34 mmol, 1.2 equiv), benzoic anhydride
(76.6 mg, 0.34 mmol, 1.2 equiv), and N,N-dimethylaminopyridine
(3.4 mg, 0.028 mmol, 0.1 equiv) were added, at room temperature
and under argon, to a solution of o-diphenylphosphinophenol
(78.6 mg, 0.28 mmol, 1 equiv) in dry CH2Cl2 (1.87 mL, 0.15 M). The
solution was stirred for 3 h and then concentrated in vacuo. The res-
idue was dissolved in EtOAc and washed with 5% aqueous NaHCO3
and water. The organic layer was dried over Na2SO4 and concen-
trated. The product was purified by flash chromatography using
95:5 hexane–EtOAc as the eluant. Quantitative yield. 1H NMR
(400 MHz, CDCl3, 25 °C): d = 7.81–7.78 (m, 2H), 7.46 (m, 1H), 7.37
(td, J = 7.6, 1.5 Hz, 1H), 7.32–7.23 (m, 13H, Ph), 7.12 (dd, J = 7.6 Hz,
1H), 6.82 (ddd, J = 9.8, 4.2, 2.6 Hz, 1H); 13C NMR (100 MHz, CDCl3,
25 °C): d = 164.3, 152.9 (d, J = 17 Hz), 135.5 (d, J = 10 Hz), 134.6,
134.2, 133.6, 133.4, 131.7 (d, J = 11 Hz), 130.7 (d, J = 15 Hz), 130.2,
129.9, 129.2, 129.1, 128.6, 128.5, 128.3, 128.1, 126.2, 122.6; 31P
NMR (161 MHz, CDCl3): d = ꢁ14.3 ppm [oxide 31P = +27.3 ppm].
The phosphine (1.2 equiv) was added, at room temperature, to a
0.1 M solution of azide 2 or 3 (1 equiv) in 98:2 N,N-dimethylacet-
amide–DMPU. The solution was stirred for 4 h at 70 °C, then water
was added and the mixture was stirred for an additional 2 h at the
same temperature. The solvent was evaporated under reduced
pressure, and the residue was purified as indicated below for each
compound.
3.8.1. N-Pentanoyl-b-D-galactofuranosylamide (6a)
The compound was purified by flash chromatography (CHCl3–
MeOH 80:20) yield = 60%. ½a D25
ꢂ
ꢁ17.9 (c 0.2, MeOH). 1H NMR
(400 MHz, CD3OD, 25 °C): d = 5.38 (d, J1,2 = 5.2 Hz, 1H, H-1), 4.14
(t, J2,3 = 5.8, J3,4 = 6.4 Hz, 1H, H-3), 3.95 (t, J1,2 = 5.2, J2,3 = 5.8 Hz,
1H, H-2), 3.90 (dd, J3,4 = 6.4, J4,5 = 2.8 Hz, 1H, H-4), 3.68–3.63 (m,
1H, H-5), 3.62–3.57 (m, 2H, H-6, H-60), 2.22 (t, J = 7.4 Hz, 2H,
CH2), 1.71–1.54 (m, 2H, CH2), 1.48–1.32 (m, 2H, CH2), 0.95 (t,
J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CD3OD, 25 °C): d = 177.4,
85.5 (C-1), 83.6 (C-4), 81.1 (C-2), 77.5 (C-3), 72.7 (C-5), 64.4 (C-
6), 37.1 (CH2), 28.9 (CH2), 23.5 (CH2), 14.3 (CH3). FT-ICR (ESI) calcd
for C11H21N1O6 [M+Na]+ 286.12611, found 286.12586. NOESY
(400 MHz, D2O, 25 °C): contact between H-1/H-3.
3.6. 2,3,5,6-Tetra-O-acetyl-b-D-galactofuranosyl azide (2)
Trimethylsilyl azide (238
lL, 1.79 mmol, 1.4 equiv) and SnCl4
(45 L, 0.384 mmol, 0.3 equiv) were added in sequence, at room
l

470
F. Nisic, A. Bernardi / Carbohydrate Research 346 (2011) 465–471
3.8.2. N-(3-Methylbutanoyl)-b-
D
-galactofuranosylamide (6b)
3.8.7. N-Pentanoyl-a-D-galactofuranosylamide (7a)
The compound was purified by flash chromatography (CHCl3–
The compound was purified by flash chromatography (CHCl3–
MeOH 85:15) yield = 53%. ½a D25
ꢂ
ꢁ24.5 (c 1, MeOH). 1H NMR
MeOH 80:20) yield = 60%. ½a D25
ꢂ
+18.1 (c 1, MeOH). 1H NMR
(400 MHz, CD3OD, 25 °C): d = 5.40 (d, J1,2 = 5.2 Hz, 1H, H-1), 4.15
(t, J2,3 = 5.8, J3,4 = 6.4 Hz, 1H, H-3), 3.97 (t, J1,2 = 5.2, J2,3 = 5.8 Hz,
1H, H-2), 3.92 (dd, J3,4 = 6.4, J4,5 = 2.8 Hz, 1H, H-4), 3.71–3.65 (m,
1H, H-5), 3.63–3.58 (m, 2H, H-6, H-60), 2.35 (d, J = 7.2 Hz, 2H,
CH2), 1.01 (d, J = 6.4 Hz, 3H, CH3), 0.97 (d, J = 6 Hz, 3H, CH3); 13C
NMR (100 MHz, CD3OD, 25 °C): d = 176.6, 85.6 (C-1), 83.7 (C-4),
81.2 (C-2), 77.5 (C-3), 72.7 (C-5), 64.4 (C-6), 46.5 (CH2), 22.9
(CH3), 22.7 (CH3). FT-ICR (ESI) calcd for C11H21N1O6 [M+Na]+
286.12611, found 286.12584.
(400 MHz, CD3OD, 25 °C): d = 5.69 (d, J1,2 = 4.4 Hz, 1H, H-1), 4.13
(t, J2,3 = 3.4, J3,4 = 3.6 Hz, 1H, H-3), 3.88 (dd, J1,2 = 4.4, J2,3 = 3.4 Hz,
1H, H-2), 3.80 (dd, J3,4 = 3.6, J4,5 = 3 Hz, 1H, H-4), 3.74 (ddd,
0
J4,5 = 3, J5,6 = 6, J5,6 = 6.8 Hz, 1H, H-5), 3.62 (dd, J5,6 = 6,
0
0
0
J6,6 = 11.6 Hz, 1H, H-6), 3.57 (dd, J5,6 = 6.8, J6,6 = 11.6 Hz, 1H, H-
60), 2.29 (t, J = 7.6 Hz, 2H, CH2), 1.64–1.56 (m, 2H, CH2), 1.43–1.32
(m, 2H, CH2), 0.95 (t, J = 7.4 Hz, 3H, CH3); 13C NMR (100 MHz,
CD3OD, 25 °C): d = 176.7, 84.4 (C-4), 82.2 (C-1), 78.5 (C-3), 77.4
(C-2), 73 (C-5), 64.3 (C-6), 37 (CH2), 28.9 (CH2), 23.5 (CH2), 14.3
(CH3). FT-ICR (ESI) calcd for C11H21N1O6 [M+Na]+ 286.12611, found
286.12597.
3.8.3. N-3-Methyl-2-butenoyl-b-D-galactofuranosylamide (6c)
The compound was purified by flash chromatography (CHCl3–
MeOH 85:15) yield = 48%. ½a D25
ꢂ
ꢁ27.8 (c 0.2, MeOH). 1H NMR
3.8.8. N-(3-Methylbutanoyl)-a-D-galactofuranosylamide (7b)
The compound was purified by flash chromatography (CHCl3/
(400 MHz, CD3OD, 25 °C): d = 5.74 (s, 1H, CH), 5.41 (d, J1,2 = 5.6 Hz,
1H, H-1), 4.15 (t, J2,3 = 5.8, J3,4 = 6.4 Hz, 1H, H-3), 3.96 (t, J1,2 = 5.6,
J2,3 = 5.8 Hz, 1H, H-2), 3.90 (dd, J3,4 = 6.4, J4,5 = 2.8 Hz, 1H, H-4),
3.68–3.63 (m, 1H, H-5), 3.61–3.57 (m, 2H, H-6, H-60), 2.15 (s, 3H,
CH3), 1.89 (s, 3H, CH3); 13C NMR (100 MHz, CD3OD, 25 °C):
d = 170.2, 154.3, 119.3 (CH), 85.4 (C-1), 83.4 (C-4), 81.1 (C-2), 77.5
(C-3), 72.8 (C-5), 64.4 (C-6), 27.5 (CH3), 20.3 (CH3). FT-ICR (ESI) calcd
for C11H21N1O6 [M+Na]+ 284.11046, found 284.11027.
MeOH 80:20) yield = 57%. ½a D25
ꢂ
+33.4 (c 1, MeOH). 1H NMR
(400 MHz, CD3OD, 25 °C): d = 5.72 (d, J1,2 = 4.4 Hz, 1H, H-1), 4.16
(t, J2,3 = 3.2, J3,4 = 3.6 Hz, 1H, H-3), 3.92 (dd, J1,2 = 4.4, J2,3 = 3.2 Hz,
1H, H-2), 3.84 (dd, J3,4 = 3.6, J4,5 = 3.2 Hz, 1H, H-4), 3.78 (ddd,
0
0
J4,5 = 3.2, J5,6 = 5.6, J5,6 = 6.8 Hz, 1H, H-5), 3.65 (dd, J5,6 = 5.6, J6,6
=
11.2 Hz, 1H, H-6), 3.61 (dd, J5,6 = 6.8, J6,6 = 11.2 Hz, 1H, H-60),
2.18 (d, J = 6.4 Hz, 2H, CH2), 2.16–2.08 (m, 1H, CH), 1.01 (d,
J = 2.4 Hz, 3H, CH3), 0.99 (d, J = 2.4 Hz, 3H, CH3); 13C NMR
(100 MHz, CD3OD, 25 °C): d = 176, 85.6 (C-4), 84.5 (C-1), 82.2 (C-
3), 77.4 (C-2), 73 (C-5), 64.3 (C-6), 46.5 (CH2), 27.3 (CH), 22.9
(CH3). FT-ICR (ESI) calcd for C11H21N1O6 [M+Na]+ 286.12611, found
286.12591.
0
0
3.8.4. N-Palmitoyl-b-D-galactofuranosylamide (6d)
The compound was purified by flash chromatography (CHCl3–
MeOH 90:10) yield = 60%. ½a D25
ꢂ
ꢁ37.3 (c 1, MeOH). 1H NMR
(400 MHz, CD3OD, 25 °C): d = 5.40 (d, J1,2 = 5.2 Hz, 1H, H-1), 4.15
(t, J2,3 = 6, J3,4 = 6 Hz, 1H, H-3), 3.96 (t, J1,2 = 5.2, J2,3 = 5.6 Hz, 1H,
H-2), 3.93 (dd, J3,4 = 6.4, J4,5 = 2.8 Hz, 1H, H-4), 3.70–3.65 (m, 1H,
H-5), 3.63–3.58 (m, 2H, H-6, H-60), 2.24 (t, J = 8 Hz, 2H, CH2), 1.63
(m, 2H, CH2), 1.41–1.25 (m, 24H, 12 ꢀ CH2), 0.92 (t, J = 6.8 Hz,
3H, CH3); 13C NMR (100 MHz, CD3OD, 25 °C): d = 177.1, 85.7 (C-
1), 83.8 (C-4), 81.2 (C-2), 77.6 (C-3), 72.8 (C-5), 64.4 (C-6), 37.4,
33.2, 30.9, 30.7, 30.6, 30.4, 26.8, 23.8, 14.6 (CH3). FT-ICR (ESI) calcd
for C22H43N1O6 [M+Na]+ 440.29826; found 440.29844.
3.8.9. N-(3-Methyl-2-butenoyl)-a-D-galactofuranosylamide (7c)
The compound was purified by flash chromatography (CHCl3–
MeOH 85:15) yield = 51%. ½a D25
ꢂ
+30.2 (c 0.8, MeOH). 1H NMR
(400 MHz, CD3OD, 25 °C): d = 5.86 (s, 1H, CH), 5.77 (d, J1,2 = 4 Hz,
1H, H-1), 4.17 (t, J2,3 = 3.2, J3,4 = 3.6 Hz, 1H, H-3), 3.94 (dd, J1,2 = 4,
J2,3 = 3.2 Hz, 1H, H-2), 3.85 (br t, J3,4 = 3.6, J4,5 = 3.2 Hz, 1H, H-4),
0
3.79 (ddd, J4,5 = 3.2, J5,6 = 6, J5,6 = 6.8 Hz, 1H, H-5), 3.68 (dd,
0
0
0
J5,6 = 6, J6,6 = 11.2 Hz, 1H, H-6), 3.62 (dd, J5,6 = 6.8, J6,6 = 11.2 Hz,
1H, H-60), 2.20 (s, 3H, CH3), 1.94 (s, 3H, CH3); 13C NMR (100 MHz,
CD3OD, 25 °C): d = 169.5, 154.2, 119.4 (CH), 84.4 (C-4), 82.1 (C-1),
78.7 (C-3), 77.5 (C-2), 73.1 (C-5), 64.4 (C-6), 27.4 (CH3), 20.3
(CH3). FT-ICR (ESI) calcd for C11H21N1O6 [M+Na]+ 284.11046; found
284.11044.
3.8.5. N-Capryloyl-b-D-galactofuranosylamide (6e)
The compound was purified by flash chromatography (CHCl3–
MeOH 85:15) yield = 56%. ½a D25
ꢂ
ꢁ50.4 (c 0.9, MeOH). 1H NMR
(400 MHz, CD3OD, 25 °C): d = 5.42 (d, J1,2 = 5.2 Hz, 1H, H-1), 4.17
(t, J2,3 = 5.8, J3,4 = 6.4 Hz, 1H, H-3), 3.98 (t, J1,2 = 5.2, J2,3 = 5.8 Hz,
1H, H-2), 3.95 (dd, J3,4 = 6.4, J4,5 = 2.8 Hz, 1H, H-4), 3.73–3.68 (m,
1H, H-5), 3.65–3.59 (m, 2H, H-6, H-60), 2.28 (t, J = 7.2, J = 8 Hz,
2H, CH2), 1.65 (m, 2H, CH2), 1.47–1.27 (m, 8H, 4 ꢀ CH2), 0.94 (t,
J = 6.8 Hz, 3H, CH3); 13C NMR (100 MHz, CD3OD, 25 °C): d = 177.1,
85.4 (C-1), 83.6 (C-4), 81 (C-2), 77.3 (C-3), 72.6 (C-5), 64.2 (C-6),
37.2, 32.8, 30.2, 30.1, 26.7, 23.6, 14.4 (CH3). FT-ICR (ESI) calcd for
3.8.10. N-Palmitoyl-
The compound was purified by flash chromatography (CHCl3/
MeOH 90:10) yield = 55%.
+9 (c 1, MeOH). 1H NMR
a-D-galactofuranosylamide (7d)
½ ꢂ
a 2D5
(400 MHz, CD3OD, 25 °C): d = 5.74 (d, J1,2 = 4 Hz, 1H, H-1), 4.18 (t,
J2,3 = 3.2, J3,4 = 3.6 Hz, 1H, H-3), 3.94 (dd, J1,2 = 4, J2,3 = 3.2 Hz, 1H,
H-2), 3.85 (br t, J3,4 = 3.6, J4,5 = 2.8 Hz, 1H, H-4), 3.79 (ddd,
C
14H27N1O6 [M+Na]+ 328.17306, found 328.17317.
0
J4,5 = 2.8, J5,6 = 6, J5,6 = 6.8 Hz, 1H, H-5), 3.67 (dd, J5,6 = 6,
0
0
0
J6,6 = 11.2 Hz, 1H, H-6), 3.63 (dd, J5,6 = 6.8, J6,6 = 11.2 Hz, 1H, H-
60), 2.33 (t, J = 7.2 Hz, 2H, CH2), 1.68 (br t, J = 7.2 Hz, 2H, CH2),
1.44–1.28 (m, 24H), 0.96 (t, J = 6.8 Hz, 3H, CH3); 13C NMR
(100 MHz, CD3OD, 25 °C): d = 176.7, 84.4 (C-4), 82.2 (C-1), 78.5
(C-3), 77.4 (C-2), 73 (C-5), 64.4 (C-6), 37.3, 33.2, 30.9, 30.8, 30.6,
30.4, 26.8, 23.9, 14.6 (CH3). FT-ICR (ESI) calcd for C22H43N1O6
[M+Na]+ 440.29826, found 440.29797.
3.8.6. N-Citronelloyl-b- -galactofuranosylamide (6f)
D
The compound was purified by flash chromatography (CHCl3–
MeOH 90:10) yield = 51%. ½a D25
ꢂ
ꢁ55.8 (c 0.9, MeOH). 1H NMR
(400 MHz, CD3OD, 25 °C): d = 5.45 (d, J1,2 = 5.2 Hz, 1H, H-1), 5.16
(t, J = 6.8 Hz, 1H, CH) 4.20 (t, J2,3 = 5.6, J3,4 = 6.2 Hz, 1H, H-3), 4.01
(t, J1,2 = 5.2, J2,3 = 5.6 Hz, 1H, H-2), 3.97 (dd, J3,4 = 6.2, J4,5 = 2.8 Hz,
1H, H-4), 3.71 (ddd, J4,5 = 2.8, J = 6, J = 6.8 Hz, 1H, H-5), 3.68–3.63
(m, 2H, H-6, H-60), 2.29 (dd, J = 13.6, J = 6 Hz, 1H, Ha, CH2), 2.18–
1.98 (m, 4H), 1.73 (s, 3H, CH3), 1.67 (s, 3H, CH3), 1.48–1.40 (m,
1H), 1.33–1.22 (m, 1H), 1.01 (d, J = 6.4 Hz, 3H, CH3); 13C NMR
(100 MHz, CD3OD, 25 °C): d = 176.6, 132.4, 125.7, 85.7 (C-1), 83.8
(C-4), 81.2 (C-2), 77.6 (C-3), 72.8 (C-5), 64.4 (C-6), 44.9, 38.1,
30.9, 26.6, 26, 19.9, 17.9. FT-ICR (ESI) calcd for C16H29N1O6
[M+Na]+ 354.18871, found 354.18866.
3.8.11. N-Capryloyl-a-D-galactofuranosylamide (7e)
The compound was purified by flash chromatography (CHCl3–
MeOH 85:15) yield = 63%. ½a D25
ꢂ
+12.2 (c 1, MeOH). 1H NMR
(400 MHz, CD3OD, 25 °C): d = 5.68 (d, J1,2 = 4.4 Hz, 1H, H-1), 4.12
(t, J2,3 = 3.6, J3,4 = 3.2 Hz, 1H, H-3), 3.87 (dd, J1,2 = 4.4, J2,3 = 3.6 Hz,
1H, H-2), 3.79 (t, J3,4 = 3.2, J4,5 = 2.8 Hz, 1H, H-4), 3.73 (ddd,
0
J4,5 = 2.8, J5,6 = 6, J5,6 = 6.8 Hz, 1H, H-5), 3.61 (dd, J5,6 = 6,

F. Nisic, A. Bernardi / Carbohydrate Research 346 (2011) 465–471
471
J6,6 = 11.2 Hz, 1H, H-6), 3.57 (dd, J5,6 = 6.8, J6,6 = 11.2 Hz, 1H, H-60),
2.27 (t, J = 7.2 Hz, 2H, CH2), 1.62 (br t, J = 7.2 Hz, 2H, CH2), 1.40–
1.24 (m, 8H, 4 ꢀ CH2), 0.91 (t, J = 6.4, J = 7.2 Hz, 3H, CH3); 13C
NMR (100 MHz, CD3OD, 25 °C): d = 176.7, 84.4 (C-4), 82.2 (C-1),
78.5 (C-3), 77.3 (C-2), 72.9 (C-5), 64.3 (C-6), 37.3 (CH2), 33.0,
30.4, 30.3 (3 ꢀ CH2), 26.8 (CH2), 23.8 (1 ꢀ CH2), 14.6 (CH3). FT-
1H, H-4), 2.23 (t, J = 7.6 Hz, 2H, CH2), 2.18 (s, 3H, OAc), 2.12 (s,
3H, OAc), 2.10 (s, 3H, OAc), 2.05 (s, 3H, OAc), 1.61–1.56 (m, 2H,
CH2), 1.41–1.32 (m, 2H, CH2), 0.92 (t, J = 7.6 Hz, 3H, CH3); 13C
NMR (100 MHz, CDCl3, 25 °C): d = 176.7, 173, 170.7, 169.8, 169.1,
79.9 (C-1), 79.7 (C-4), 76.7 (C-3), 75.1 (C-2), 70.3 (C-5), 62.9 (C-
6), 36.7 (CH2), 29.9 (CH2), 22.5 (CH2), 21.1–20.8 (4 ꢀ OAc), 14.3
(CH3). NOESY (400 MHz, CDCl3, 25 °C): contact between H-1/H-4.
0
0
0
ICR (ESI) calcd for
328.17314.
C
14H27N1O6 [M+Na]+ 328.17306, found
Acknowledgments
3.8.12. N-Citronelloyl-a-D-galactofuranosylamide (7f)
The compound was purified by flash chromatography (CHCl3–
This work was supported by Universita’ degli Studi di Milano
(PUR2008) and by Comune di Milano (Convenzione 55/2008).
The HRMS spectra have been obtained from CIGA (Centro Interdi-
partimentale Grandi Apparecchiature, Universita’ degli Studi di
Milano).
MeOH 90:10) yield = 56%. ½a D25
ꢂ
+13.2 (c 1, MeOH). 1H NMR
(400 MHz, CD3OD, 25 °C): d = 5.74 (d, J1,2 = 4 Hz, 1H, H-1), 5.17 (t,
J = 5.8 Hz, 1H, CH) 4.18 (t, J2,3 = 3.4, J3,4 = 3.6 Hz, 1H, H-3), 3.93
(dd, J1,2 = 4, J2,3 = 3.4 Hz, 1H, H-2), 3.85 (dd, J3,4 = 3.6, J4,5 = 3.2 Hz,
0
1H, H-4), 3.79 (ddd, J4,5 = 3.2, J5,6 = 5.6, J5,6 = 6.8 Hz, 1H, H-5),
0
0
3.68 (dd, J5,6 = 5.6, J6,6 = 11.2 Hz, 1H, H-6), 3.63 (dd, J5,6 = 6.8,
Supplementary data
J6,6 = 11.2 Hz, 1H, H-60), 2.34 (dd, J = 13.6, J = 6 Hz, 1H, Ha, CH2),
0
2.18–1.98 (m, 4H), 1.73 (s, 3H, CH3), 1.67 (s, 3H, CH3), 1.48–1.40
(m, 1H), 1.33–1.22 (m, 1H), 0.95 (d, J = 6.8 Hz, 3H, CH3); 13C NMR
(100 MHz, CD3OD, 25 °C): d = 175.9, 132.4, 125.7 (CH), 84.5 (C-4),
82.3 (C-1), 78.5 (C-3), 77.4 (C-2), 73 (C-5), 64.4 (C-6), 44.9, 38.1,
31.7, 26.6, 26, 19.9, 17.9. FT-ICR (ESI) calcd for C16H29N1O6
[M+Na]+ 354.18871, found 354.18864.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2010.12.020.
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3.8.13. N-Benzoyl-
The compound was purified by flash chromatography (CHCl3/
MeOH 85:15) yield = 62%.
+7.9 (c 1, MeOH). 1H NMR
(400 MHz, CD3OD, 25 °C): d = 7.91 (m, 2H, Hortho), 7.60 (m, 1H,
para), 7.53 (m, 2H, Hmeta), 5.94 (d, J1,2 = 4.8 Hz, 1H, H-1), 4.27 (t,
a-D-galactofuranosylamide (7g)
½ ꢂ
a 2D5
H
J2,3 = 4.2, J3,4 = 4.4 Hz, 1H, H-3), 4.13 (t, J1,2 = 4.8, J2,3 = 4.2 Hz, 1H,
H-2), 3.93 (dd, J3,4 = 3.6, J4,5 = 2.8 Hz, 1H, H-4), 3.84 (ddd,
0
J4,5 = 2.8, J5,6 = 5.4, J5,6 = 6.8 Hz, 1H, H-5), 3.70 (dd, J5,6 = 5.6,
0
0
0
J6,6 = 11.2 Hz, 1H, H-6), 3.66 (dd, J5,6 = 6.8, J6,6 = 11.2 Hz, 1H, H-
60); 13C NMR (100 MHz, CD3OD, 25 °C): d = 169.8, 135.4, 133.2,
129.8, 128.6, 84.5 (C-4), 82.7 (C-1), 78.2 (C-3), 77.9 (C-2), 72.7
(C-5), 64.4 (C-6). FT-ICR (ESI) calcd for C13H17N1O6 [M+Na]+
306.09481, found 306.09465.
7. (a) Carlson, E. E.; May, J. F.; Kiessling, L. L. Chem. Biol. 2006, 13, 825–837; (b)
Dykhuizen, E. C.; May, J. F.; Tongpenay, A.; Kiessling, L. L. J. Am. Chem. Soc. 2008,
130, 6706–6707; (c) Dykhuizen, E. C.; Kiessling, L. L. Org. Lett. 2009, 11, 193–
196.
8. Veerapen, N.; Yuan, Y.; Sanders, D. A. R.; Pinto, B. M. Carbohydr. Res. 2004, 339,
2205–2217.
3.8.14. 2,3,5,6-Tetra-O-acetyl-N-pentanoyl-a-D-galactofurano-
sylamide (8a)
9. Owen, D. J.; Davis, C. B.; Hartnell, R. D.; Madge, P. D.; Thomson, R. J.; Chong, A. K.
J.; Coppel, R. L.; von Itzstein, M. Bioorg. Med. Chem. Lett. 2007, 17, 2274–2277.
10. Owen, D. J.; Davis, C. B.; Hartnell, R. D.; Madge, P. D.; Thomson, R. J.; Chong, A.
K. J.; Coppel, R. L.; von Itzstein, M. Carbohydr. Res. 2007, 342, 1773–1780.
11. Timpano, G.; Tabarani, G.; Anderluh, M.; Invernizzi, D.; Vasile, F.; Potenza, D.;
Nieto, P. M.; Rojo, J.; Fieschi, F.; Bernardi, A. ChemBioChem 2008, 12, 1921–
1930.
12. Cheshev, P.; Bernardi, A. Chem. Eur. J. 2008, 14, 7434–7441.
13. Bianchi, A.; Bernardi, A. J. Org. Chem. 2006, 71, 4565–4577.
14. Nisic, F.; Bernardi, A. Carbohydr. Res. 2008, 343, 1636.
15. Nisic, F.; Andreini, M.; Bernardi, A. Eur. J. Org. Chem. 2009, 33, 5744–5751.
16. Peltier, P.; Euzen, R.; Daniellou, R.; Nugier-Chauvin, C.; Ferrières, V. Carbohydr.
Res. 2008, 343, 1897–1923.
Acetic anhydride (10 equiv) and a catalytic amount of N,N-
dimethylaminopyridine were added, at room temperature, to a
solution of 7a (1 equiv) in pyridine dried on molecular sieves
(0.1 M). The solution was stirred for 24 h and then was concen-
trated in vacuo. The residue was dissolved in EtOAc and washed
with aqueous 5% HCl, aqueous 5% NaHCO3 and water. The organic
layer was dried over Na2SO4 and concentrated to give 8a in quan-
titative yield. 1H NMR (400 MHz, CDCl3, 25 °C): d = 6.14 (d,
JNH,1 = 10 Hz, 1H, NH), 6.06 (d, J1,2 = 4.4 Hz, JNH,1 = 10, 1H, H-1),
17. Chittenden, G. J. F. Carbohydr. Res. 1972, 25, 35–41.
0
5.34 (ddd, J4,5 = 6.8, J5,6 = 3.6, J5,6 = 6.8 Hz, 1H, H-5), 5.21 (dd,
18. Bianchi, A.; Bernardi, A. Tetrahedron Lett. 2004, 45, 2231–2234.
19. Kovács, L.; Osz, E.; Domokos, V.; Holzer, W.; Györgydeák, Z. Tetrahedron 2001,
57, 4609–4621.
J1,2 = 4.4, J2,3 = 1.8 Hz, 1H, H-2), 5.07 (dd, J2,3 = 1.8, J3,4 = 3.2 Hz,
0
1H, H-3), 4.38 (dd, J5,6 = 3.6, J6,6 = 12 Hz, 1H, H-6), 4.09 (dd,
20. Completo, C. G.; Lowary, T. L. J. Org. Chem. 2008, 73, 4513–4525.
J5,6 = 6.8, J6,6 = 12 Hz, 1H, H-60), 3.92 (dd, J3,4 = 3.2, J4,5 = 6.8 Hz,
0
0