Lipid analogs of the nodulation factors using the ugi/passerini multicomponent reactions: Preliminary studies on the carbohydrate monomer

Article abstract of DOI:10.3987/COM-07-S(U)60

Treament of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-isocyano-β-D-gluco-pyranose and the corresponding β-allyl glycoside with octanal and acetic acid provide the Passerini products in excellent yields whereas the corresponding Ugi transformation in the presence of i-propylamine proceeded with much lower efficiency. This work represents a preliminary investigation on a project directed towards the modification of the lipid moiety of the nodulation factors.

Full text of DOI:10.3987/COM-07-S(U)60

HETEROCYCLES, Vol. 73, 2007
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HETEROCYCLES, Vol. 73, 2007, pp. 891 - 901. © The Japan Institute of Heterocyclic Chemistry
Received, 5th August, 2007, Accepted, 1st October, 2007, Published online, 2nd October, 2007. COM-07-S(U)60
LIPID ANALOGS OF THE NODULATION FACTORS USING THE
UGI/PASSERINI MULTICOMPONENT REACTIONS: PRELIMINARY
STUDIES ON THE CARBOHYDRATE MONOMER
Nathalie Grenouillat, Boris Vauzeilles, and Jean-Marie Beau*
Université Paris-Sud 11, Institut de Chimie Moléculaire et des Matériaux associé
au CNRS, Laboratoire de Synthèse de Biomolécules, 91405 Orsay Cedex, France,
Fax: (+33) 1-6985-3715. E-mail: jmbeau@icmo.u-psud.fr
Abstract – Treament of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-isocyano-β-D-gluco-
pyranose and the corresponding β-allyl glycoside with octanal and acetic acid
provide the Passerini products in excellent yields whereas the corresponding Ugi
transformation in the presence of i-propylamine proceeded with much lower
efficiency. This work represents a preliminary investigation on a project directed
towards the modification of the lipid moiety of the nodulation factors.
Carbohydrates and glycoconjugates have proven to be very important molecules in biology because they
are involved in numerous cellular communication events.1 The synthesis of carbohydrate derivatives has
become a fundamental research area, in which a rapid access to molecular diversity is one of the
promising strategies for the discovery of bioactive compounds.1,2 Within this context, isocyanide-based
multicomponent reactions such as the Passerini3 or Ugi4 reactions are attractive solutions since they
require the synthesis of relatively simple precursors that can rapidly lead to a highly diverse range of
derivatives which can be screened for biological activity.5
We decided to focus on the reaction of the peracetylated derivatives of 2-isocyanoglucose with either an
α-acetyl or a β-allyl group on the anomeric position. This work represents a preliminary investigation on
a project directed towards the modification of the lipid moiety of the nodulation factors (Nod Factors)
such as the following lipo-chitooligosaccharide 1. The structure of 1 is typical of a class of glycolipids
secreted by rhizobia.6 They are essential signaling molecules initiating symbiosis with legumes, resulting
in the formation of rhizobia-infected nodules on plant roots in which the atmospheric nitrogen is fixed.7
Structure-activity relationships have shown that a structural modification of the lipid unit induces a

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HETEROCYCLES, Vol. 73, 2007
variation in the biological activity in alfalfa (Medicago sativa) roots.8 The chemistry described here is
somewhat complementary to Ziegler’s studies,9 which involved 1-isocyanoglucose, and
2-isocyanoglucose with an anomeric β-acetyl group.10
OAc
O
OH
O
NHAc
NHAc
OH
H
O
H
O
HO
HO
O
O
O
O
H
O
OH
O
OSO3
-
NH
NHAc
O
1
Figure
Glucosamine hydrochloride 2 was reacted with methyl formate in the presence of sodium methoxide,
leading to the quantitative formation of N-formyl glucosamine11 which appears, on the NMR timescale, as
a mixture of anomers and rotamers around the amide bond (approx. 9/1 trans vs. cis amide). This
intermediate was transformed, with acetic anhydride and pyridine, into the corresponding peracetate 3,
which was isolated in the form of its α anomer12 in a 60% overall yield. Dehydration with phosphorus
oxychloride afforded the corresponding isocyanide 412 in 68% yield.
OAc
O
OH
1. MeONa, HCO2Me, MeOH
2. Ac2O, Pyr.
O
AcO
AcO
HO
HO
OH
60%
HCOHN
NH3Cl
OAc
3
2
OAc
O
POCl3, Et3N, CH2Cl2
AcO
AcO
68%
CN
OAc
4
Scheme 1
The reaction of isocyanide 4 under Passerini conditions with ocatanal and acetic acid appeared to be
sluggish and required 2 equiv. of both the aldehyde and the acid to reach completion. After 24 h, the
expected products 5 were isolated in an 87% overall yield, as an equimolar mixture of the two possible
diastereomers. It should be noted that all of these experiments were run under an inert atmosphere, since
in the presence of air, a noticeable amount of aldehyde was oxidized to the corresponding acid which
could take part in the reaction leading to an undesired side-product. The Passerini products 5 were
deacetylated in moderate yield (39%) to the α-hydroxy amide 7 (α:β ratio of 3:1). Hydroxylated lipids
have been found as N-substituents of D-glucosamine in the structurally diverse Nod factors.13
The poor reactivity of isocyanide 4 appeared more obvious in the Ugi reaction, where conversion was
very slow and only an 11% yield of the expected products 6 was achieved. Once again, no

HETEROCYCLES, Vol. 73, 2007
893
stereoselectivity was observed and an equimolar mixture of both diastereomers was isolated. Addition of
zinc chloride seemed to accelerate the reaction, but led to the concomitant formation of byproducts
including the Passerini products, as observed by TLC analysis.
OAc
O
OAc
O
O
O
O
O
AcO
AcO
AcO
AcO
NH
OH
OH
11%
2
HN
HN
4
OAc
OAc
O
O
87%
*
N
(27% based on
recovered 4)
*
O
MeONa, MeOH
5
6
OH
O
O
O
HO
HO
OH
39%
HN
O
OH
7
Scheme 2
In order to test whether the poor reactivity of the isocyanide was due to the presence of the anomeric α
acetate and to better mimic the structure of the Nod Factors, we decided to perform these reactions on an
allyl β-glycoside. The β-allyl glycoside of N-acetyl glucosamine 8, available in one step by anomeric
O-alkylation of N-acetyl-D-glucosamine,14 was first deacetylated (90%) by treatment in refluxing aqueous
barium hydroxide, and the resulting amine was isolated in the form of its sulfuric acid salt. Formylation in
methanol in the presence of sodium methoxide failed due to the poor solubility of the amine, but could be
achieved in 80% yield in water in the presence of sodium hydrogencarbonate. Peracetylation (Ac2O,
pyridine, 83%) provided the N-formyl derivative 9 which was dehydrated (POCl3, Et3N) to the
corresponding isocyanide 10 in 72% yield.
1. Ba(OH) H O, 110°C; H SO
2
2,
2. HCO Me, H O, NaHCO
2
4
OH
OAc
O
2
3. Ac O, Pyr.
2
3
O
O
NHAc
HO
HO
2
AcO
AcO
O
60%
NH
O
8
9
OAc
O
POCl Et N, CH Cl
2
3,
3
2
AcO
AcO
O
72%
CN
10
Scheme 3

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HETEROCYCLES, Vol. 73, 2007
The reaction of 10 under Passerini conditions afforded the expected products 11 as an equimolar mixture
of diastereomers and did not show any appreciable increase in reactivity as compared to isocyanide 4.
This was confirmed by the slow reaction of 10 under Ugi’s conditions. After one week of reaction in the
presence of zinc chloride, which in this case led to a clean reaction, 26% of the expected mixture of
diastereomers 12 was isolated.
OAc
O
OAc
O
O
O
O
O
AcO
AcO
AcO
AcO
O
O
OH
86%
NH
OH
HN
2
HN
10
O
O
ZnCl
26%
2
*
*
O
N
11
12
O
O
Scheme 4
With both isocyanides 4 and 10 in this study, the Ugi reaction proceeded significantly slower with a low
yield than did the corresponding Passerini reaction, which provided the expected condensation products
in excellent yields. In the present form it is clear that future synthetic work on more complex
carbohydrates should be focused on the Passerini solution to provide structurally diverse α-hydroxy
amide products for biological testing. Although not relevant to our study, the chirality of isocyanides 4
and 10 had no influence on the stereochemical outcome of both reactions, as stated many times in the past
with chiral isocyanides.5
EXPERIMENTAL
All air sensitive reactions were carried out under argon atmosphere. Solvents were purified by distillation
just prior to use or dried by standard methods. Dichloromethane was distilled from phosphorous
pentoxide. Thin layer chromatography was performed on Merck 60F254 sheets with detection by UV and
by charring with 5% ethanolic H2SO4. Silica gel SDS 60 ACC 35-70 µm was used for flash column
chromatography. NMR spectra were taken on Brücker AC 200 and AC 250 spectrometers. For the allyl
group, the following lettering was used for the protons: -CHdHd’CHa=CHbHc, with Ha and Hb in a Z
relationship. Optical rotations were measured at 589 nm on a Perkin Elmer 341 polarimeter. Melting
points (uncorrected) were measured on a Büchi 510 apparatus. Infrared spectra were taken on a Brücker
IFS-66 Fourier transform spectrometer (KBr). Mass spectra were taken on a ThermoFinnigan Mat 95,
with Electrospray ionization in the positive mode of detection (ESI+). Elemental analyses were performed
at the CNRS, Gif sur Yvette, France.

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1,3,4,6-Tetra-O-acetyl-2-deoxy-2-formamido-α−D-glucopyranose (3)12
Glucosamine hydrochloride (1.00 g) was added to 10.0 mL of a sodium methoxide solution (0.48 mol/L,
MeOH), followed by 1.00 mL of methyl formate (16.6 mmol). After being stirred at rt for 2 h, the
reaction mixture was diluted with 2 mL of MeOH, warmed at 40°C for 4 h, and stirred overnight at rt.
The residue was concentrated and purified by flash chromatography over silica gel (EtOAc / MeOH /
water 4:1:1) giving 961 mg (99%) of a white solid of 2-deoxy-2-formamido-D-glucopyranose11: mp
1
133°C; IR (cm-1) : 3305 / 2993 / 2940 / 2890 / 1632 / 1564 / 1396 / 1322; H NMR (250 MHz, D2O) δ
(ppm) : (two sets of signals due to the presence of the α / β anomers) 8.21 / 8.15 (2 s, 0.8 H, CHOtrans),
8.01 / 7.99 (2 s, 0.2 H, CHOcis), 5.25 (d, H-1αcis, J1α,2 3.4 Hz), 5.21 (d, H-1αtrans, J1α,2 3.4 Hz), 4.75 (d,
H-1βtrans, J1β,2 8.3 Hz), 4.57 (d, H-1βcis, J1β,2 8.3 Hz), 4.00 – 3.33 (m, 6 H, H-2, H-3, H-4, H-5, 2 H-6);13C
NMR (62.5 MHz, D2O) δ (ppm) : 167 (CHOcis), 166 (CHOtrans), 97 (C-1βtrans and cis), 93 (C-1αtrans and cis), 78 /
76 / 72 (C-3cis, C-4cis, C-5cis), 74 / 73 / 72 (C-3trans, C-4trans, C-5trans), 63 (C-6cis), 62 (C-6trans), 58 (C-2cis), 55
(C-2trans); MS(ESI+) m/z: 230.1 [M + Na]+; HRMS(ESI+) calcd. for C7H13NO6Na([M+Na]+): 230.0641;
found m/z 230.0644.
Pyridine (4.80 mL, 60 mmol) and acetic anhydride (2.80 mL, 30 mmol) were added to 930 mg (4.49
mmol) of the preceding N-formyl derivative, and the reaction mixture was stirred at rt for 2 h. After
concentration, the oily residue was taken in CH2Cl2 and washed with aqueous HCl (0.1 N). Drying
(Na2SO4) and concentration of the organic layer gave 1.43 g of an orange foam which was recristallized
from Et2O yielding 1.02 g (61%) of 3 as a white solid. 3: [αD]20 +88 (c 0.675, CHCl3); mp 131°C; IR
589
(cm-1) : 3402 / 2969 / 1746 / 1697 / 1508 / 1380 / 1225; 1H NMR (250 MHz, CDCl3) δ (ppm) : 8.11 (s, 0.8
H, CHOtrans), 7.99 (d, 0.2 H, CHOcis, J 11,2 Hz), 6.18 (d, 1 H, H-1α, J1α,2 3.4 Hz), 5.87 (d, 0.8 H, NHtrans
,
JNH,2 8.8 Hz), 5.86 (m, 0.2 H, NHcis), 5.27 / 5.18 (m, 2 H, H-3 et H-4), 4.54 (ddd, 0.8 H, H-2trans, J2,3 9.8
Hz), 3.76 (m, 0.2 H, H-2cis), 4.24 / 4.03 (2 dd, 2 H, H-6a,b, Ja,b 12.7 Hz, J6a,5 3.9 Hz and J6b,5 2.4 Hz), 4.00
13
(m, 1 H, H-5), 2.16 / 2.06 / 2.03 / 2.02 (4 s, 12 H, CH3CO); C NMR (62.5 MHz, CDCl3) δ (ppm) : (two
sets of signals due to the presence of two slow equilibrating trans / cis rotamers of the formamide) 172 /
171 / 169 / 168 (4 CH3CO), 161 (CHO), 90 (C-1α), 70 / 69 / 67 (C-3, C-4, C-5), 61 (2 C-6), 50 (C-2), 21 /
20 (4 CH3CO); MS (ESI+) m/z: 398.1 [M + Na]+; HRMS (ESI+) calcd. for C15H21NO10Na ([M+Na]+):
398.1063; found m/z 398.1060.
1,3,4,6-Tetra-O-acetyl-2-deoxy-2-isocyano-α-D-glucopyranose (4)12
Triethylamine (6.5 mL, 46 mmol) was added under an argon atmosphere to a solution of 3 (500 mg, 1.33
mmol) in anhydrous CH2Cl2 (20 mL), followed by dropwise addtion of POCl3 (1.0 mL, 10.7 mmol) at
0°C. The reaction mixture was stirred for 2 h at rt under slightly positive argon pressure, and after dilution
with CH2Cl2, washed with a saturated NaHCO3 solution, dried (Na2SO4) and concentrated. The residue

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HETEROCYCLES, Vol. 73, 2007
was purified by flash chromatography over silica gel (cyclohexane / EtOAc 2:1), and crystallized from
CH2Cl2 / hexane yielding 323 mg (68%) of a white solid. 4: [αD]20 +149 (c 0.375, CHCl3); mp 113°C;
589
IR (cm-1) : 2977 / 2156 / 1768 / 1390 / 1221; 1H NMR (250 MHz, CDCl3) δ (ppm) : 6.39 (d, 1 H, H-1α,
J1α,2 3.4 Hz), 5.53 (dd, 1 H, H-3, J3,2 10.7 Hz and J3,4 9.7 Hz), 5.01 (dd, 1 H, H-4, J4,5 ~ J4,3), 4.28 (dd, 1 H,
H-6a, Ja,b 12.4 Hz and J6a,5 3.6 Hz), 4.12 – 4.00 (m, 2 H, H–5 and H-6b), 3.97 (dd, 1 H, H-2), 2.20 / 2.08 /
2.03 / 2.00 (4 s, 12 H, CH3CO); 13C NMR (62.5 MHz, CDCl3) δ (ppm) : 171 / 170 / 169 / 168 (4 CH3CO),
162 (CN), 88 (C-1α), 70 / 69 / 67 (C-3, C-4, C-5), 61 (C-6), 55 (C-2), 21 / 20 (4 CH3CO); MS(ESI+) m/z:
380,1 [M + Na]+; HRMS(ESI+) calcd. for C15H19NO9Na ([M+Na]+): 380,0958; found m/z 380,0954.
1,3,4,6-Tetra-O-acetyl-2-deoxy-2-(N-2-acetoxy-nonanoyl)-amino-α-D-glucopyranose (5)
Isocyanide 4 (50 mg, 140 µmol) was dissolved in CH2Cl2 (0.5 mL), and octanal (50 µL, 320 µmol) and
acetic acid (20 µL, 340 µmol) were added under an argon atmosphere. After stirring for 24 h at rt, the
reaction mixture was concentrated and purified by flash chromatography over silica gel (cyclohexane /
EtOAc 2:1), yielding 66.5 mg (87%) of a slightly yellowish solid. 5: mp 101°C; IR (cm-1) : 3323 / 2928 /
2858 / 1751 / 1685 / 1529 / 1436 / 1371 / 1224 / 1043; 1H NMR (250 MHz, CDCl3) δ (ppm) : 6.20 / 6.15
(2 d, H-1α for both stereomers, J1α,2 3.9 Hz), 6.19 (d, NH, JNH,2 12.7 Hz), 5.30 – 5.12 (m, 2 H, H-3 and
H-4), 4.99 – 4.89 (m, 1 H, CH2-CH-CO), 4.44 – 4.29 (m, 1 H, H-2), 4.23 (m, 1 H, H-6a), 4.06 – 3.92 (m,
2 H, H-5 and H-6b), 2.16 – 1.99 (10 s, 15 H, 5 CH3CO for both diastereomers), 1.70 (m, 2 H,
13
CO-CH-CH2-CH2), 1.30 – 1.10 (m, 10 H, 5 CH2), 0.83 (t, 3 H, CH3, J 6.0 Hz); C NMR (62.5 MHz,
CDCl3) δ (ppm) : 172 - 168 (12 signals, 6 CO for both diastereomers), 90 (2 signals, C-1α for both
diastereomers), 74 (CH2-CH-CO), 70 / 69 / 67 (6 signals, C-3, C-4, C-5 for both diastereomers), 61 (C-6),
51 (2 signals, C-2 for both diastereomers), 32 - 22 (5 CH2), 21 (10 signals, 5 CH3CO for both
diastereomers), 14 (CH3); MS (ESI+) m/z: 545.2 [M + Na]+; HRMS (ESI+) calcd. for C25H39NO12Na
([M+Na]+): 568.2370; found m/z 568.2371; Anal. Calcd. for C25H39NO12: C, 55.04; H, 7.21; N, 2.57; O,
35.19. Found: C, 55.15; H, 7.47; N, 2.36; O, 35.25.
1,3,4,6-Tetra-O-acetyl-2-deoxy-2-[N-2-(N-acetyl-N-isopropylamino)-nonanoyl]-amino-α-D-gluco-
pyranose (6)
Isocyanide 4 (50 mg, 140 µmol) was dissolved in CH2Cl2 (0.5 mL), and octanal (25 µL, 160 µmol), an
isopropylamine solution (140 µL, 10 % v/v, 163 µmol, CH2Cl2), and an acetic acid solution (100 µL,
10 % v/v, 160 µmol, CH2Cl2) were added. After stirring for 12 h at rt, the reaction mixture was
concentrated and the resulting oily residue was purified by flash chromatography over silica gel
(cyclohexane / EtOAc 2:1), yielding 9.0 mg (11%) of the expected product 6 and 29.5 mg of recovered
starting material (59%). 6: IR (cm-1) : 3423 / 2930 / 2857 / 1750 / 1674 / 1622 / 1543 / 1433 / 1372 / 1223

HETEROCYCLES, Vol. 73, 2007
897
/ 1020; 1H NMR (250 MHz, CDCl3) δ (ppm) : 8.39 / 8.13 (2 d, 1 H, NH for both diastereomers, JNH,2 9.3
Hz), 6.17 / 6.13 (2 d, H-1α for both diastereomers, J1α,2 3.9 Hz), 5.40 – 4.88 (m, 2 H, H-3 and H-4), 4.39
(m, 1 H, H-2), 4.27 – 3.85 (m, 4 H, H-5, H-6a,b, (CH3)2-CH-N), 3.61 / 3.51 (2 t, 1 H, CO-CH-CH2, J 7.3
Hz), 2.24 – 1.96 (10 s, 15 H, 5 CH3CO for both diastereomers), 1.69 (m, 2 H, CO-CH-CH2-CH2), 1.27 –
1.19 (m, 10 H, 5 CH2), 1.13 (m, 6 H, (CH3)2-CH-N), 0.84 (m, 3 H, CH3); MS (ESI+) m/z: 609.3 [M +
Na]+; HRMS(ESI+) calcd. for C28H46N2O11Na ([M+Na]+): 609.2999; found m/z 609.3002.
2-Deoxy-2-N-(2-hydroxynonanoyl)-amino-D-glucopyranose (7)
A solution of sodium methoxide (0.1 M, 0.5 mL, 50 µmol, MeOH) was added to 25 mg of 5 (46 µmol)
and the reaction mixture was stirred overnight at rt, then neutralized with Amberlite IR 120 H+ resin,
filtrated, concentrated and purified by silica gel chromatography (CH2Cl2 / MeOH 10:1), yielding product
1
7 as a white solid (6 mg, 39 %). 7: H NMR (250 MHz, D2O) δ (ppm) :5.09 (2 d, 0.6 H, H-1α for both
diastereomers, J1α,2 2.9 Hz), 4.66 (2 d, 0.4 H, H-1β for both diastereomers, J1β,2 9.0 Hz), 4.02 (m, 1 H,
CO-CH(OH)-CH2-CH2), 4.00 – 3.30 (m, 6 H, H-2, H-3, H-4, H-5, H-6a,b), 1.74 / 1.61 (2 m, 2 H,
CO-CH(OH)-CH2-CH2), 1.50 – 1.20 (m, 10 H, 5 CH2), 0.89 (t, 3 H, CH3, J 6.6 Hz); 13C NMR (62.5 MHz,
D2O) δ (ppm) :177 (CO), 93 (C-1α), 73 - 72 (C-3, C-4, C-5, CH2-CH(OH)-CO), 63 (C-6), 55 (C-2), 35 -
36 (CH2-CH(OH)-CO), 33 - 24 (5 CH2), 14 (CH3); MS(ESI+) m/z: 358.1 [M + Na]+; HRMS(ESI+) calcd.
for C15H29NO7Na ([M+Na]+): 358.1842; found m/z 358.18450.
Allyl 3,4,6-tri-O-acetyl-2-deoxy-2-formamido-β-D-glucopyranoside (9)
An aqueous solution (1 mL) of 814 (25 mg, 96 µmol) was treated with barium dihydroxide (61 mg, 193
µmol). The mixture was refluxed for 3 h, then aqueous sulfuric acid (2 M) was added until pH 2. After
filtration and concentration, the sulfate salt of allyl 2-amino-2-deoxy-β-D-glucopyranoside was obtained
1
as a white solid (26 mg, 90%) which was used without further purification. H NMR (200 MHz, D2O) δ
(ppm) : 5.97 (m, 1 H, Ha), 5.36 (dddd, 1 H, Hc, JHc,Ha 17.2 Hz and JHc,Hb ~ JHc,Hd ~ JHc,Hd’ 1.6 Hz), 5.30
(dddd, 1 H, Hb, JHb,Ha 10.2 Hz and JHb,Hd ~ JHb,Hd’ 1.6 Hz), 4.78 (d, 1 H, H-1β, J1β,2 8.4 Hz), 4.40 (dddd, 1 H,
Hd, JHd,Hd’ 12.5 Hz and JHd,Ha 5.6 Hz), 4.21 (dddd, 1 H, Hd’, JHd’,Ha 6.6 Hz), 3.92 (dd, 1 H, H-6a, J6a,6b 12.3
Hz and J6a,5 2.0 Hz), 3.73 (dd, 1 H, H-6b, J6b,5 5.1 Hz), 3.67 (dd, 1 H, H-3, J3,4 8.4 Hz and J3,2 10.6 Hz),
13
3.58 - 3.36 (m, 2 H, H-4 and H-5), 2.83 (dd, 1 H, H-2); C NMR (62.5 MHz, D2O) δ (ppm) : 135
(-OCH2-CH=CH2), 121 (-OCH2-CH=CH2), 101 (C-1β), 77 / 75 / 71 (C-3, C-4 and C-5), 72
(-OCH2-CH=CH2), 62 (C-6), 57 (C-2); MS(ESI+) m/z: 220.2 [M + H]+.
Sodium hydrogencarbonate (10 mg, 119µmol) and methyl formate (20 µL, 324 µmol) were addedto a
solution of the preceding ammonium salt (20 mg, 66 µmol) in water (0.3 mL). After 24 and 36 h at rt

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HETEROCYCLES, Vol. 73, 2007
other portions of NaHCO3 (2x10 mg, 2x119 µmol) and methyl formate (2x20 µL, 2x324 µmol) were
added. The reaction mixture was concentrated after 48 h (total) and purified by flash chromatography
over silica gel (EtOAc / MeOH / water 3:1:1), followed by passing through a column of Dowex H+
(50Wx8), yielding after concentration 14 mg (80%) of allyl 2-deoxy-2-formamido-β-D-glucopyranoside
as white solid: 1H NMR (250 MHz, D2O) δ (ppm) : 8.18 (s, 0.7 H, CHOtrans), 7.97 (s, 0.3 H, CHOcis), 5.90
(m, 1 H, Ha), 5.33 / 5.22 (2 m, 2 H, Hb and Hc), 4.60 (d, H-1βtrans, J1β,2 8.4 Hz), 4.56 (d, H-1βcis), 4.33 /
4.15 (2 m, 2 H, Hd and Hd’), 3.90 (dd, 1 H, H-6a, J6a,6b 12.2 Hz and J6a,5 1.8 Hz), 3.80 – 3.65 (m, 1.7 H,
H-6b and H-2trans), 3.60 - 3.40 (m, 3 H, H-3, H-4 and H-5), 3.21 (dd, 0.3 H, H-2cis, J2,3 8.5 Hz); 13C NMR
(62.5 MHz, D2O) δ (ppm) : (two sets of signals due to the presence of two trans / cis rotamers of the
formamide with slow equilibrium) 170 (CHOcis), 166 (CHOtrans), 134 (-OCH2-CH=CH2), 120
(-OCH2-CH=CH2), 101 (C-1β), 77 (C-5), 75 / 72 (C-3, C-4), 73 (-OCH2-CH=CH2), 62 (C-6), 60 (C-2cis),
56 (C-2trans); MS(ESI+) m/z: 517.2 [2M + Na]+; 270.1 [M + Na]+; HRMS(ESI+) calcd. for C10H17NO6Na
([M+Na]+): 270.0954; found m/z 270.0943.
Pyridine (1 mL) and acetic anhydride (0.5 mL) were added to 9 mg of the preceding N-formyl derivative
(37 µmol), and the reaction mixture was stirred at rt overnight, then concentrated and coevaporated
several times with toluene, diluted in CH2Cl2, washed with aqueous HCl (1 M), dried and concentrated,
yielding 12 mg of 9 (83%, white solid). 9: 1H NMR (250 MHz, CDCl3) δ (ppm) : 8.17 (d, 0.6 H, CHOtrans
,
J 1.7 Hz), 8.02 (d, 0.4 H, CHOcis, J 11.3 Hz), 6.00 (m, 1 H, NH), 5.80 (m, 1 H, Ha), 5.40 - 5.00 (m, 4 H,
Hb, Hc, H-3 and H-4), 4.74 (d, 0.6 H, H-1βtrans, J1β,2 8.3 Hz), 4.50 - 4.05 (m, 4.4 H, Hd, Hd’, H-6a,b and
H-1βcis), 3.95 (m, 0,6 H, H-2trans), 3.70 (m, 1 H, H-5), 3.46 (m, 0.4 H, H-2cis), 2.10 – 2.03 (6 s, 9 H,
CH3CO); MS(ESI+) m/z: 396.1 [M + Na]+.
Allyl 3,4,6-tri-O-acetyl-2-deoxy-2-isocyano-β-D-glucopyranoside (10)
A solutionof 9 (226 mg, 605 µmol) in anhydrous CH2Cl2 (15 mL) was treated with triethylamine (3.7 mL,
26.3 mmol) under an argon atmosphere, followed by dropwise addition of POCl3 (700 µL, 7.5 mmol) at
0°C. After 2 h at rt under argon, the reaction mixture was diluted with CH2Cl2, washed with saturated
aqueous NaHCO3, dried and concentrated. The residue was purified by flash chromatography over silica
1
gel (cyclohexane / EtOAc 2:1), yielding 163 mg of a white solid (10, 72%). 10: H NMR (250 MHz,
CDCl3) δ (ppm) : 5.95 (dddd, 1 H, Ha, JHa,Hc 17.1 Hz, JHa,Hb 10.0 Hz, JHa,Hd’ 6.6 Hz and JHa,Hd 5.1 Hz), 5.40
(dddd, 1 H, Hc, JHc,Hb 1.8 Hz, JHc,Hd’ 1.4 Hz and JHc,Hd 1.6 Hz), 5.30 (m, 2 H, Hb and H-3), 4.96 (m, 1 H,
H-4), 4.64 (d, 1 H, H-1β, J1β,2 8.0 Hz), 4.41 (m, 1 H, Hd, JHd,Hd’ 12.8 Hz and JHd,Hb 1.6 Hz), 4.28 (dd, 1 H,
H-6b, J6a,6b 12.3 Hz and J6b,5 4.6 Hz), 4.19 (dddd, 1 H, Hd’, JHd’,Hb 1.4 Hz), 4.13 (dd, 1 H, H-6a, J6a,5 2.4
Hz), 3.74 (ddd, 1 H, H-5, J5,4 10.1 Hz), 3.66 (dd, 1 H, H-2, J2,3 10.5 Hz), 2.12 / 2.09 / 2.04 (3 s, 9 H,

HETEROCYCLES, Vol. 73, 2007
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CH3CO); 13C NMR (62.5 MHz, CDCl3) δ (ppm) : 171 / 170 / 169 (CH3CO), 161 (CN), 133
(-OCH2-CH=CH2), 119 (-OCH2-CH=CH2), 99 (C-1β), 73 / 72 / 67 (C-3 C-4, C-5), 71 (-OCH2-CH=CH2),
61 (C-6), 57 (C-2), 21 / 20 (CH3CO); MS (ESI+) m/z: 378.1 [M + Na]+; HRMS (ESI+) calcd. for
C16H21NO8Na ([M+Na]+): 378.1165; found m/z 378.1165; Anal. Calcd. for C16H21NO8: C, 55.04; H, 5.96;
N, 3.94; O, 36.02. Found: C, 54.03; H, 6.09; N, 3.81; O, 35.86.
Allyl 3,4,6-tri-O-acetyl-2-deoxy-2-N-(2-acetoxynonanoyl)-amino-β-D-glucopyranoside (11)
Isocyanide 10 (40 mg, 113 µmol) was dissolved in CH2Cl2 (0.5 mL), and octanal (35 µL, 224 µmol) and
acetic acid (13 µL, 225 µmol) were added. After 36 h of stirring at rt, the reaction mixture was
concentrated and purified by flash chromatography over silica gel (cyclohexane / EtOAc 2:1). The
coupling products 11 were isolated as a white solid (51.5 mg, 86 %). 11: IR (cm-1) : 3330 / 2928 / 2860 /
1750 / 1667 / 1537 / 1460 / 1376 / 1232 / 1048 / 972 / 903; 1H NMR (250 MHz, CDCl3) δ (ppm) : 6.12 /
6.07 (2 d, NH for both diastereomers, JNH,2 9.0 Hz and JNH,2 9.4 Hz), 5.82 (m, 1 H, Ha), 5.35 - 4.96 (m, 5
H, Hb, Hc, H-3, H-4 and CH2-CH-CO), 4.66 / 4.57 (2 d, 1 H, H1β for both diastereomers, J1β,2 8.3 Hz),
4.39 – 3.86 (m, 5 H, Hd, Hd’, H-2, H-6a and H-6b), 3.68 (m, 1 H, H-5), 2.15 – 1.99 (8 s, 12 H, CH3CO
for both diastereomers), 1.75 (m, 2 H, CO-CH-CH2-CH2), 1.32 – 1.15 (m, 10 H, CH2), 0.85 (t, 3 H, CH3, J
6.5 Hz); 13C NMR (62.5 MHz, CDCl3) δ (ppm) : (two sets of signals due to the presence of two
diastereomers) 171 - 169 (5 CO), 133 (-OCH2-CH=CH2), 118 (-OCH2-CH=CH2), 100 (C-1β), 74
(CH2-CH-CO), 72 - 68 (C-3, C-4, C-5), 70 (-OCH2-CH=CH2), 62 (C-6), 54 (C-2), 32 - 22 (6 CH2), 21 (4
CH3CO), 14 (CH3);MS(ESI+) m/z: 566.3 [M + Na]+; HRMS(ESI+) calcd. for C26H41NO11Na ([M+Na]+):
566.2580; found m/z 566.2577; Anal. Calcd. for C26H41NO11: C, 57.45; H, 7.60; N, 2.58; O, 32.38. Found:
C, 57.41; H, 7.69; N, 2.39; O, 32.41.
Allyl
3,4,6-tri-O-acetyl-2-deoxy-2-[N-(2-(N-acetyl-N-isopropylamino)-nonanoyl)-amino-β-D-gluco-
pyraside (12)
Isocyanide 10 (23 mg, 65 µmol) was dissolved in CH2Cl2 (0.4 mL), and octanal (25 µL, 160 µmol),
isopropylamine (15 µL, 175 µmol), and acetic acid (10 µL, 173 µmol) were added. After 1 h, a zinc
chloride solution (140 µL, 1M, 140 µmol, THF) was added and the reaction mixture was stirred at rt for
1 week, concentrated and purified by flash chromatography over silica gel (cyclohexane / EtOAc 2:1).
1
The expected coupling product was isolated as a slightly yellowish solid (10 mg, 26 %). 12: H NMR
(250 MHz, CDCl3) δ (ppm) : 5.87 (m, 1 H, Ha), 5.49 – 5.00 (m, 4 H, Hb, Hc, H-3 and H-4), 4.98 and
4.92 (2 d, 1 H, H-1β for both diastereomers, J1β,2 8.3 Hz), 4.40 – 3.95 (m, 6 H, Hd, Hd’, H-2, H-6a, H-6b
and CO-CH-CH2), 3.80 (m 1 H, (CH3)2-CH-N), 2.44 – 2.40 (2 s, N-CO-CH3 for both diastereomers),
2.09 – 2.02 (6 s, CH3CO for both diastereomers), 1.50 – 1.20 (m, 18 H, CO-CH-CH2-CH2, 5 CH2 and

900
HETEROCYCLES, Vol. 73, 2007
(CH3)2-CH-N), 0.87 (t, 3 H, , CH3, J 6.8 Hz); 13C NMR (62.5 MHz, CDCl3) δ (ppm) : (two sets of signals
due to the presence of two diastereomers) 171 - 169 (5 CO), 133 (-OCH2-CH=CH2), 117
(-OCH2-CH=CH2), 100 (C-1β), 72 (CH2-CH-CO), 71 - 69 (C-3, C-4, C-5), 70 (-OCH2-CH=CH2), 62
(C-6), 54 (C-2), 52 ((CH3)2-CH-N)), 32 - 23 (6 CH2), 23 ((CH3)2-CH-N), 21 (4 CH3CO), 14 (CH3);MS
(ESI+) m/z: 607.3 [M + Na]+; HRMS(ESI+) calcd. for C29H48N2O10Na ([M+Na]+): 607.3207; found m/z
607.3213.
ACKNOWLEDGEMENTS
We are grateful to Rhone-Poulenc SA (Contract n° 041313.00), Aventis CropScience SA and Bayer
CropScience for the financial support of this study.
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