Synthesis of new N-substituted 3,4,5-trihydroxypiperidin-2-ones from d-ribono-1,4-lactone

Article abstract of DOI:10.1016/j.carres.2010.07.005

d-Ribono-1,4-lactone was treated with ethylamine in DMF to afford N-ethyl-d-ribonamide 8a in quantitative yield. Using this reaction procedure, N-butyl, N-hexyl, N-dodecyl, N-benzyl, N-(3-methyl-pyridinyl)-, N-(2-hydroxy-ethyl)-, and N-(2-cyano-ethyl)-d-r

Full text of DOI:10.1016/j.carres.2010.07.005

Carbohydrate Research 345 (2010) 1983–1987
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis of new N-substituted 3,4,5-trihydroxypiperidin-2-ones
from D-ribono-1,4-lactone
*
Céline Falentin-Daudre, Daniel Beaupère, Imane Stasik-Boutbaiba
Laboratoire des Glucides, UMR 6219. Université de Picardie Jules Verne, 33 Rue Saint-Leu, F-80039 Amiens, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 April 2010
Received in revised form 17 June 2010
Accepted 4 July 2010
Available online 6 August 2010
D
-Ribono-1,4-lactone was treated with ethylamine in DMF to afford N-ethyl-
quantitative yield. Using this reaction procedure, N-butyl, N-hexyl, N-dodecyl, N-benzyl, N-(3-methyl-
pyridinyl)-, N-(2-hydroxy-ethyl)-, and N-(2-cyano-ethyl)- -ribonamides 8b–h were obtained in quantita-
tive yield. Bromination of the amides 8a–e with acetyl bromide in dioxane followed by acetylation gave
2,3,4-tri-O-acetyl-5-bromo-5-deoxy-N-ethyl, N-butyl, N-hexyl, N-dodecyl, and N-benzyl- -ribonamides
D-ribonamide 8a in
D
D
9a–e in 40–54% yields. To obtain 2,3,4-tri-O-acetyl-5-bromo-5-deoxy-N-(3-methyl-pyridinyl)-, N-(2-
hydroxy-ethyl)-, and N-(2-cyano-ethyl)-9f–h, the bromination is necessary before the amidation
reaction. Treatment of the bromoamides 9a–h with NaH in DMF followed by methanolysis affords
Keywords:
Azasugars
D-Ribono-1,4-lactone
N-alkyl-D-ribono-1,5-lactams 12a–h in quantitative yield.
N-Alkyl-
D
-ribonamides
Ó 2010 Elsevier Ltd. All rights reserved.
N-Alkyl-
D
-ribono-1,5-lactams
1. Introduction
However, only a few reports have appeared on the synthesis of
N-substituted aldonolactams. Except works of Diez,16,17 there
have been no reports of the synthesis of these derivatives from
The discovery of the glycosidase inhibitor activity of the natural
product polyhydroxylated piperidine1 and pyrrolidine2 alkaloids such
as nojirimycin 1, 1-deoxynojirimycin (DNJ) 23a, and 2,5-dihydroxy-
methyl-3,4-dihydroxy-pyrrolidine (DMDP)3b 3 (Fig. 1) manifests the
spectacular development of azasugars (or iminosugars) as pyrroli-
dine, piperidine, azepane, and glyconolactam derivatives. These com-
pounds are known to be potent glycosidase inhibitors4,5 having
interesting antidiabetic,6 anticancer,7 and anti-HIV properties.8
Aldonolactams, for example 4, 5 (Fig.1), have been reported as
having interesting biological activities9a, such as inhibition of gly-
cosidase activity9b–d, cancer cell metastasis10, and inflammation.11
D-ribonolactone.
In view of the high potential of N-alkylated azasugars and in the
continuation of our interest in the synthesis of azasugars, in preli-
minary work we have synthesized some N-alkyl-D-ribono-1,5-lac-
tams.18 We are now reporting in this work two efficient
strategies for the synthesis of new azasugar analogs: N-alkyl-
3,4,5-trihydroxypiperidin-2-ones, for example, with terminal-
functionalized N-alkyl chains. This work may open up possible
opportunities for novel applications.
Earlier we reported the synthesis of 5-amino-5-deoxy-
D-pen-
2. Results and discussion
tonolactams from unprotected -pentono-1,4-lactones in 60–83%
D
overall yield. Thus, unprotected pentonolactone can be trans-
formed to its azido derivative, whose hydrogenation yields the cor-
responding 3,4,5-trihydroxylactam by spontaneous lactamisation
reaction of aminolactone.12
In general, N-alkylated azasugars were demonstrated to be
stronger glycosidase inhibitors than the corresponding non-alkyl-
ated derivatives.1e,g,13 For example, N-butyl-1-deoxy-nojirimycin
6 (Fig. 1) was identified as the most active anti-HIV agent without
significant cytotoxicity13 and also active against Gaucher disease.14
Miglitol 7 is a potent sucrase inhibitor15 and antidiabetic drug in
the market since1996.
In first, for the synthesis of N-ethyl-
strategy given in the Scheme 1. We have used
as starting materials. -Ribono-1,4-lactone was treated with ethyl-
amine (1.1 equiv) in DMF for 1 h at room temperature to afford the
D
-ribonolactam, we tried the
D
-ribono-1,4-lactone
D
N-ethyl-
D
-ribonamide 8a in quantitative yield. (Scheme 1) Treat-
ment of
D-ribono-1,4-lactone with butyl, hexyl, dodecyl, benzyl,
(3-methyl-pyridinyl)-, (2-hydroxy-ethyl)-, and (2-cyano-ethyl)-
amines gave quantitatively the corresponding N-alkyl- -ribona-
D
mides 8b–h. Bromination of the amide 8a by the system SOBr2 in
DMF or PPh3/CBr4 in pyridine led, after acetylation, to the epoxide
80a (Scheme 2).
Epoxide 80a was then treated with NaH in DMF. Monitoring the
reaction by TLC and NMR spectra analysis of the crude product
showed that epoxide 80a was present as the only product and no
* Corresponding author. Tel.:+33 3 22 82 75 66; fax: +33 3 22 82 75 60.
E-mail address: imane.stasik@u-picardie.fr (I. Stasik-Boutbaiba).
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.07.005

1984
C. Falentin-Daudre et al. / Carbohydrate Research 345 (2010) 1983–1987
OH
HO
Br
OH
O
H
O
H
i)
O
O
N
N
HO
N
OH
R
HO
O
HO
HO
HO
OH
OH
N
ii)
11
HO
OH
OH
OH
HO
3
HO
4
OH
1 R=OH
f R= H2C
2 R=H
OAc
O
OH
H
g R= -(CH2)2OH
h R= -(CH2)2CN
Br
OH
NHR
N
N
N
OAc OAc
O
HO
HO
HO
9f-h
HO
Scheme 3. Reagents and conditions: (i) SOBr2/DMF (1.1 equiv)/DMF; (ii) (a) RNH2
(1 equiv) /DMF, (b) Ac2O/pyridine, rt.
OH
HO
OH
7
OH
5
HO
6
Figure 1. Examples of azasugars.
the compounds 8f–h and due to the difficulties in the preparation
of
2,3,4-tri-O-acetyl-5-bromo-5-deoxy-N-(3-methyl-pyridinyl)-,
trace of the target 2,3,4-tri-O-acetyl-N-ethyl-D-ribono-1,5-lactam
was obtained.
However, treatment of the amide 8a with acetyl bromide in
dioxane for 16 h, at room temperature, followed by acetylation
N-(2-O-acetyl-ethyl)-, and (2-cyano-ethyl)-D-ribonamides (9f–h)
we attempted an alternative strategy.
D
-Ribono-1,4-lactone was treated withSOBr2 inDMF toafford the
5-bromo-5-deoxy-D
-ribono-1,4-lactone 11 in 95% yield.19 Treat-
gave the 2,3,4-tri-O-acetyl-5-bromo-5-deoxy-N-ethyl-D-ribona-
ment of the compound 11 with, (3-methyl-pyridinyl)-, (2-hydroxy-
ethyl)-, and (2-cyano-ethyl)-amines, in DMF at room temperature,
gave, after acetylation, the corresponding 2,3,4-tri-O-acetyl-5-bro-
mo-5-deoxy-N-(3-methyl-pyridinyl)-, (2-O-acetyl-ethyl)-, and (2-
cyano-ethyl)-
2,3,4-Tri-O-acetyl-5-bromo-5-deoxy-N-ethyl-
was then treated with NaH in DMF, for 1 h, affording the desired
2,3,4-tri-O-acetyl-N-ethyl- -ribono-1,5-lactam. Methanolysis of 2,3,4-
tri-O-acetyl-N-ethyl- -ribono-1,5-lactam with sodium methoxide
in methanol, led according to NMR spectroscopy, to N-ethyl- -rib-
ono-1,5-lactam 12a in quantitative yield. (Scheme 4) The mass
spectrum of compound 12a showed a diagnostic peak at m/z 198
(M+Na)+. The title compound was identified by elemental analysis
and NMR spectra which showed, in particular, a signal of a second
methylene group at 49.9 ppm corresponding to –HN–CH2.
mide 9a which was isolated in 51% yield. In this case, no trace of
the undesired epoxide was detected. We propose that this result
can be explained by the presence of the acetate protecting group
at C-4 position.
Bromination of the amides 8b–e with acetyl bromide in dioxane
followed by acetylation gave 2,3,4-tri-O-acetyl-5-bromo-5-deoxyl-
N-butyl, N-hexyl, N-dodecyl, and N-benzyl-D-ribonamides 9b–e in
40–54 % yields.
On the other hand, treatment of the amides derivatives 8f–h by
the same bromination system, acetyl bromide in dioxane, followed
by acetylation gave the 1,2,3,4-tetra-O-acetyl-N-(3-methyl-pyridi-
D-ribonamides 9f–h (Scheme 3).
D
-ribonamide 9a
D
D
D
nyl-), N-(2-O-acetyl-ethyl)-, and N-(2-cyano-ethyl)-D-ribonamides
10f–h as the only products, in quantitative yield. (Scheme 1) No
trace of the attempted 2,3,4-tri-O-acetyl-5-bromo-5-deoxy-N-al-
kyl-D-ribonamides 9f–h was obtained.
Using this method, N-butyl, N-hexyl, N-dodecyl, N-benzyl, N-(3-
In the case of compounds 8f–h, in all instances and under differ-
ent bromination conditions: heating, use of more equivalents of
acetyl bromide and use of other mildly more polar solvents instead
of dioxane as Et2O, DME or THF to dissolve the compounds 8f–h,
the bromination remained unsuccessful. Using of the acetyl bro-
mide in a more polar solvents (DMF and CH3CN) gave a mixture
of products. To prevent this failure owed to the insolubility of
methyl-pyridinyl)-, N-(2-hydroxy-ethyl)-, and N-(2-cyano-ethyl)-
ribono-1,5-lactams 12b–h were obtained in good yields (Scheme 4).
From 12h, the N-(2-carboxy-ethyl)- -ribono-1,5-lactam 12i
D-
D
was obtained by acid hydrolysis (HCl 20%) in 96% yield.
In summary, we have reported an efficient synthesis of novel N-
alkyl-D-ribono-1,5-lactams which were synthesized in four steps in
39–54% overall yields from unprotected D-ribono-1,4-lactone.
O
HO
OH
3. Experimental
3.1. General
a R= Ethyl
O
i)
b R= Butyl
c R= Hexyl
d R= Dodecyl
e R= Benzyl
HO
O
NHR
OH
OH
8a-h
HO
OH
N
f R=
H2C
Melting points were determined on a Buchi 535 apparatus and
are uncorrected. Optical rotations were measured with a JASCO
DIP-370 digital polarimeter, using a sodium lamp (k = 589 nm) at
g R= -(CH2)2OH
h R= -(CH2)2CN
ii)
OAc
OAc
O
O
Br
AcO
NHR
NHR
OAc
9a-e
OAc
OAc
OAc
10f-h
OAc
O
Br
NHR
Scheme 1. Reagents and conditions: (i) RNH2/DMF, rt; (ii) (a) CH3COBr/Dioxane, rt,
(b) Ac2O/pyridine, rt.
a R= Ethyl
OAc
OAc
9a-h
b R= Butyl
c R= Hexyl
d R= Dodecyl
e R= Benzyl
i)
Et
R
N
N
H2C
f R=
HN
O
OH
g R= -(CH2)2OH
h R= -(CH2)2CN
O
i)
HO
O
O
HO
NHEt
i R= -(CH2)2COOH
ii)
OH
OH
HO
12a-h
OH
AcO
OAc
8a
8'a
Scheme 2. Reagents and conditions: (i) (a) SOBr2 in DMF or PPh3/CBr4 in pyridine,
(b) Ac2O/pyridine, rt.
Scheme 4. Reagents and conditions: (i) (a) NaH/DMF, rt, (b) MeONa/MeOH, rt; (ii)
20% HCl, 80 °C.

C. Falentin-Daudre et al. / Carbohydrate Research 345 (2010) 1983–1987
1985
24 °C. 1H and 13C NMR spectra were recorded in Me2SO-d6, CDCl3,
or in pyridine-d5. Me4Si was used as an internal standard on a Bru-
ker 300 MHz spectrometer. Mass spectra were recorded on a Q-
TOF Global mass spectrometer. Thin-layer chromatography (TLC)
was performed on E. Merck glass plates silica gel sheets (Silica
Gel F254) and stained with phosphomolybdic acid–aq H2SO4 solu-
tion. Column chromatography was carried out on silica gel (E.
Merck 230–400 mesh). All solvents were purified in a conventional
manner.
155 °C; 1H NMR (300 MHz, Me2SO-d6): d 8.51 (s, 1H), 8.44 (d, 1H,
J = 4.8 Hz), 8.27 (t, 1H), 8.27 (t, 1H), 7.70 (d, 1H), 7.33 (dd, 1H),
4.34 (d, 2H), 4.14 (d, 2H, J = 3.3 Hz), 3.65 (m, 2H), 3.55 (dd, 1H);
3.40 (dd, 1H), 13C NMR (75 MHz, Me2SO-d6): d 172.9, 148.7,
147.9, 135.2, 135.1, 123.4, 74.3, 73.3, 72.2, 63.6, 39.9; ESIMS: m/z
[M+Na]+, calcd: 279, found: 279 Anal. Calcd for C12H18N2O5: C,
53.33; H, 6.71; N, 10.36. Found: C, 53.23; H, 6.63; N, 1045.
3.1.1.7. N -(2-Hydroxy-ethyl)-D-ribonamide (8g). Compound 8g
(285 mg, 100%) as a white solid; ½a D20
ꢀ
+35 (c 0.24, H2O); mp 118–
3.1.1. General procedure for preparation of N-alkyl-
D
-
120 °C; 1H NMR (300 MHz, Me2SO-d6): d 7.58 (t, 1H), 4.06 (d, 2H,
J = 4.6 Hz), 3.65 (m, 2H), 3.55 (dd, 1H,), 3.40 (m, 2H), 3.38 (dd,
1H), 3.29 (m, 2H), 13C NMR (75 MHz, Me2SO-d6): d 173.0, 74.3,
73.3, 72.2, 63.7, 60.2, 41.4; ESIMS: m/z [M+Na]+, calcd: 209, found:
209 Anal. Calcd for C7H15NO6: C, C, 40.19; H, 7.23; N, 6.70. Found:
C, 40.01; H, 7.35; N, 6.62.
ribonamide (8a–h)
To a stirred solution of D-ribono-1,4-lactone (200 mg, 1.35 mmol)
in DMF was added alkylamine (1.1 equiv). The solution was kept for
1 h at room temperature. The reaction mixture was then concen-
trated to give quantitatively 8a–h.
3.1.1.1. N-Ethyl-
D
-ribonamide (8a). Compound 8a (260 mg, 100%)
ꢀ
3.1.1.8. N -(2-Cyano-ethyl)-D-ribonamide (8h). Compound 8h
as a white solid: ½a D20
+41 (c 0.24; H2O); mp 58–60 °C; 1H NMR
(294 mg, 100%) as a white solid; ½a D20
ꢀ
+28 (c 0.23, H2O); mp 139–
(300 MHz, Me2SO-d6) d 4.24 (d, 1H, J = 3.1 Hz), 3.87 (m, 2H),
3.71 (dd, 1H, J = 3.0 Hz, J = 12.0 Hz), 3.58 (dd, 1H, J = 6.1 Hz,
J = 12.0 Hz), 3.16 (q, 2H). 1.05 (t, 3H); 13C NMR (75 MHz, Me2SO-
d6) d 172.6, 74.3, 73.2, 72.4, 63.6, 33.5, 15.2; ESIMS: m/z [M+Na]+,
calcd: 216, found: 216. Anal. Calcd for C7H15NO5: C, 43.52; H,
7.83; N, 7.25. Found: C, 43.41; H, 7.78; N, 7.10.
140 °C; 1H NMR (300 MHz, Me2SO-d6): d 7.95 (t, 1H), 4.07 (d, 2H,
J = 3.2 Hz), 3.64 (m, 2H), 3.55 (dd, 1H), 3.38 (m, 1H), 3.29 (m,
2H), 2.64 (t, 1H, J = 6.6 Hz), 13C NMR (75 MHz, Me2SO-d6): d
173.4, 119.7, 74.3, 73.4, 71.9, 63.6, 60.2, 35.0, 17.8; ESIMS: m/z
[M+Na]+, calcd: 241, found: 241 Anal. Calcd for C8H14N2O5: C,
44.03; H, 6.47; N, 12.84. Found: C, 44.15; H, 6.35; N, 12.74.
3.1.1.2. N-Butyl-
D
-ribonamide (8b). Compound 8b (300 mg, 100%)
ꢀ
3.1.2. General procedure for preparation of 2,3,4-tri-O-acetyl-5-
as a white solid; ½a D20
+14 (c 0.20, H2O); mp 99–101 °C; 1H NMR
bromo-5-deoxy-N-alkyl-D-ribonamide (9a–e)
(300 MHz, Me2SO-d6): d 7.58 (t, 1H,), 4.02 (d, 1H, J = 3.8 Hz), 3.57
(m, 2H), 3.55 (dd, 1H), 3.37 (dd, 1H); 3.08 (m, 2H), 1.41 (m, 2H,),
1.27 (m, 2H), 0.88 (t, 3H), 13C NMR (75 MHz, Me2SO-d6): d 172.9,
74.2, 73.2, 72.4, 63.6, 38.3, 31.7, 20, 14.2; ESIMS: m/z [M+Na]+, calcd:
244, found: 244. Anal. Calcd for C9H19NO5: C, 48.86; H, 8.66; N, 6.33.
Found: C, 48.76; H, 8.60; N, 6.25.
To a stirred solution of N-alkyl-D-ribonamide (8a–e) (1.29 mmol)
in 1,4-dioxane (3 mL) was added acetyl bromide (1.1 equiv). The
solution was kept overnight at room temperature. The solvent
was removed in vacuo and the residue was treated with acetic anhy-
dride in pyridine for 1 h. The reaction mixture was then concen-
trated and the toluene (50 mL) was added to the crude material.
After concentration, the residue was diluted with CH2Cl2 and
washed with water. The CH2Cl2 extracts were dried, filtered, and
concentrated. Column chromatography (7:3 cyclohexane/EtOAc)
of the residue afforded 2,3,4-tri-O-acetyl-5-bromo-5-deoxy-N-al-
3.1.1.3. N -Hexyl-D-ribonamide (8c). Compound 8c (335 mg,
100%) as a white solid; ½a D20
ꢀ
+23 (c 0.22, H2O); mp 88–90 °C; 1H
NMR (300 MHz, Me2SO-d6): d 7.59 (t, 1H), 4.02 (d, 1H, J = 4.2 Hz),
3.63 (m, 2H), 3.56 (dd, 1H), 3.37 (dd, 1H); 3.07 (d, 2H), 1.42–1.26
(m, 6H), 0.87 (t, 3H), 13C NMR (75 MHz, Me2SO-d6): d 173.6, 74.9,
73.3, 72.9, 63.6, 38.6, 31.5–26.5, 22.5, 14.4; ESIMS: m/z [M+Na]+,
calcd: 272, found: 272. Anal. Calcd for C11H23NO5: C, 52.99; H,
9.30; N, 5.62;. Found: C, 52.87; H, 9.21; N, 5.71.
kyl-D-ribonamide 9a–e.
3.1.2.1. 2,3,4-Tri-O-acetyl-5-bromo-5-deoxy-N -ethyl-D-ribona-
mide 9a. Compound 9a (250 mg, 51%) as a colorless syrup: ½a D20
ꢀ
ꢁ3 (c 0.33; CHCl3); 1H NMR (300 MHz, CDCl3) d 6.13 (t, 1H), 5.50
(m, 3H), 3.71 (dd, 1H), 3.50 (dd, 1H), 3.36 (q, 2H), 2.13–2.10 (s,
9H). 1.19 (t, 3H), 13C NMR (75 MHz, CDCl3) d 169.7–169.4, 165.4,
71.9, 71.8, 69.1, 34.3, 31.4, 20.8, 20.7, 20.6, 14.8; ESIMS: m/z
[M+Na]+ calcd: 404, found: 404. Anal. Calcd for C13H20BrNO7: C,
40.85; H, 5.27; Br, 20.91; N, 3.66. Found: C, 40.64; H, 5.30; Br,
20.82; N, 3.53.
3.1.1.4. N -Dodecyl-D-ribonamide (8d). Compound 8d (450 mg,
100%) as a white solid; ½a D20
ꢀ
+18 (c 0.28, MeOH); mp 128–130 °C;
1H NMR (300 MHz, Me2SO-d6): d 7.59 (t, 1H), 4.02 (d, 2H,
J = 4.6 Hz), 3.63 (m, 2H), 3.55 (dd, 1H), 3.38 (dd, 1H); 3.06 (m,
2H), 1.44–1.26 (m, 10H), 0.88 (t, 3H), 13C NMR (75 MHz, Me2SO-
d6): d 172.7, 74.3, 73.1, 72.4, 63.6, 38.7, 31.8–26.8, 22.6, 14.4;
ESIMS: m/z [M+Na]+, calcd: 356, found: 356 Anal. Calcd for
3.1.2.2. 2,3,4-Tri-O-acetyl-5-bromo-5-deoxy-N -butyl-D-ribona-
C17H35NO5: C, 61.23; H, 10.58; N, 4.20. Found: C, 61.12; H, 10.62;
mide 9b. Compound 9b (252 mg, 54%) as a colorless syrup: ½a D20
ꢀ
N, 4.32.
+4 (c 0.33; CHCl3); 1H NMR (300 MHz, CDCl3) d 6.14 (t, 1H), 5.75
(d, 2H, J = 3.1 Hz), 5.50 (m, 3H), 3.70 (dd, 1H), 3.49 (dd, 1H), 3.39
(m, 2H), 1.53 (m, 2H), 1.31 (m, 2H), 2.16–2.06 (s, 9H). 0.95 (t,
3H), 13C NMR (75 MHz, CDCl3) d 169.6, 169.4, 165.4, 69.1, 39.2,
31.6, 20.8, 20.7, 20.6, 13.7; ESIMS: m/z [M+Na]+ calcd: 433, found:
433. Anal. Calcd for C15H24BrNO7: C, 43.91; H, 5.90; Br, 19.48; N,
3.41. Found: C, 43.81; H, 5.95; Br, 19.40; N, 3.31.
3.1.1.5. N -Benzyl-D-ribonamide (8e). Compound 8e (345 mg,
100%) as a white solid; ½a D20
ꢀ
+22 (c 0.29, H2O); mp 102–104 °C;
1H NMR (300 MHz, Me2SO-d6): d 8.12 (t, 1H), 4.13 (d, 1H,
J = 3.7 Hz), 3.64 (m, 2H), 3.55 (dd, 1H), 3.40 (dd, 1H); 4.32 (d,
2H), 7.31 (m, 5H), 13C NMR (75 MHz, Me2SO-d6): d 172.7, 139.7,
128.6, 127.6, 127.1, 74.4, 73.3, 72.3, 63.7, 42.2, 31.8–26.8, 22.6,
14.4; ESIMS: m/z [M+Na]+, calcd: 278, found: 278 Anal. Calcd for
3.1.2.3. 2,3,4-Tri-O-acetyl-5-bromo-5-deoxy-N -hexyl-D-ribona-
C12H17NO5: C, 56.46; H, 6.71; N, 5.49. Found: C, 56.36; H, 6.62;
mide 9c. Compound 9c (210 mg, 48%) as a colorless syrup: ½a D20
ꢀ
N, 5.52.
+2 (c 0.37; CHCl3); 1H NMR (300 MHz, CDCl3) d 6.16 (t, 1H), 5.76
(d, 2H, J = 3.0 Hz), 5.51 (m, 2H), 3.69 (dd, 1H), 3.48 (dd, 1H,), 3.31
(m, 2H), 2.17–2.05 (s, 9H), 1.52–1.31 (m, 6H), 0.89 (t, 3H), 13C
NMR (75 MHz, CDCl3) d 169.6, 169.5, 169.4, 165.4, 71.9, 71.8,
3.1.1.6. N-(3-Methyl-pyridinyl)-D-ribonamide (8f). Compound 8f
(365 mg, 100%) as a white solid; ½a D20
ꢀ
+20 (c 0.26, H2O); mp 153–

1986
C. Falentin-Daudre et al. / Carbohydrate Research 345 (2010) 1983–1987
69.1, 39.4, 29.5–22.5, 20.8–20.5, 14.0; ESIMS: m/z [M+Na]+ calcd:
461, found: 461. Anal. Calcd for C17H28BrNO7: C, 46.58; H, 6.44;
Br, 18.23; N, 3.20. Found: C, 46.65; H, 6.31; Br, 18.36; N, 3.28.
171.5–169.1, 165.9, 71.8, 69.1, 62.8, 39.1, 31.4, 20.8–20.7; ESIMS:
m/z [M+Na]+ calcd: 462, found: 462. Anal. Calcd for C14H19BrN2O7:
C, 41.29; H, 4.70; Br, 19.62; N, 6.88. Found: C, 41.18; H, 4.81; Br,
19.52; N, 6.85.
3.1.2.4. 2,3,4-Tri-O-acetyl-5-bromo-5-deoxy-N-dodecyl-D-ribon-
amide 9d. Compound 9d (157 mg, 40%) as a colorless syrup: ½a D20
ꢀ
3.1.4. General procedure for preparation
+6 (c 0.23; CHCl3); 1H NMR (300 MHz, CDCl3) d 6.13 (t, 1H), 5.77 (d,
1H, J = 3.0 Hz), 5.52 (m, 2H), 3.70 (dd, 1H), 3.50 (dd, 1H), 3.41 (m,
2H), 2.13–2.09 (s, 9H), 1.54–1.28 (m, 20H, J = 6.3 Hz), 0.90 (t, 3H),
13C NMR (75 MHz, CDCl3) d 169.5–169, 165.4, 72.1, 69.1, 39.5,
31.9–22.7, 20.8–20.6, 14.1; ESIMS: m/z [M+Na]+ calcd: 545, found:
545. Anal. Calcd for C23H40BrNO7 : C, 52.87; H, 7.72; Br, 15.29; N,
2.68. Found: C, 52.77; H, 7.83; Br, 15.38; N, 2.62.
N-Alkyl-D-ribono-1,5-lactam (12a–h): To a stirred solution of
9a–h (0.367 mmol) in DMF (2.5 mL) was added NaH (1 equiv).
The reaction mixture was stirred at room temperature for 1 h
and NaH (1 equiv) was then added. After 1 h, the solvent was re-
moved in vacuo and the obtained residue was chromatographed
on silica gel. Elution with (7:3, (AcOEt/cyclohexan) gave 2,3,4-tri-
O-acetyl-N-alkyl-
2,3,4-tri-O-acetyl-N-alkyl-
D
-ribono-1,5-lactam. To a solution of the obtained
-ribono-1,5-lactam (0.365 mmol) in
D
3.1.2.5. 2,3,4-Tri-O-acetyl-5-bromo-5-deoxy-N-benzyl-
D
-ribona-
MeOH (7.5 mL) was added NaOMe (1 M) in MeOH (1.1 mL). The
mixture was stirred for 1 h at room temperature. After concentra-
tion, the residue was diluted with water and washed with CH2Cl2.
The water extracts were combined. The acidic resin (Amberlite IR-
120 H+) was added and the suspension was stirred for 5 min. The
resin was then removed by filtration. The filtrate was concentrated
under reduced pressure to give quantitatively the desired N-alkyl-
mide 9e. Compound 9e (228 mg, 52%) as a colorless syrup: ½a D20
ꢀ
+43 (c 0.22; CHCl3); 1H NMR (300 MHz, CDCl3) d 7.37–7.29 (m,
5H), 5.86 (d, 1H, J = 3.1 Hz), 5.54 (m, 1H), 4.52 (d, 1H, J = 1.9 Hz),
4.50 (d, 1H), 3.72 (dd, 1H), 3.51 (d, 1H, J = 11.6 Hz), 2.20–2.08 (s,
9H), 13C NMR (75 MHz, CDCl3) d 169.8–169.7, 165.6, 135.6, 72.4,
69.0, 43.3, 31.5, 20.8–20.6, 14.8; ESIMS: m/z [M+Na]+ calcd: 467,
found: 467. Anal. Calcd for C18H22BrNO7: C, 48.66; H, 4.99; Br,
17.99; N, 3.15. Found: C, 48.58; H, 5.03; Br, 17.86; N, 3.21.
D-ribono-1,5-lactam (12a–h).
3.1.4.1. N-Ethyl-D-ribono-1,5-lactam 12a. Compound 12a (65 mg)
3.1.3. General procedure for preparation of 2,3,4-tri-O-acetyl-5-
as colorless solid; ½a D20
ꢀ
+22 (c 0.24; H2O); mp 143–145 °C; 1H NMR
bromo-5-deoxy-N-alkyl-
D
-ribonamide 9f–h
(300 MHz, pyridine-d5) d 4.87 (m, 1H), 4.44 (m, 2H), 3.93 (dd, 1H),
3.48 (dd, 1H), 3.33 (q, 2H), 1.03 (t, 3H),. 13C NMR (75 MHz, pyri-
dine-d5) d 171.0, 72.1, 70.6, 65.8, 49.9; 41.7, 11.9; ESIMS: m/z
[M+Na]+ calcd: 198, found: 198. Anal. Calcd for C7H13NO4: C,
47.99; H, 7.48; N, 8.00. Found: C, 48.2; H, 7.45; N, 7.89.
To a stirred solution of 5-bromo-5-deoxy-
D-ribono-1,4-lactone
(200 mg, 0.917 mmol) in DMF (2 mL) was added (3-methyl-pyrid-
inyl)-, (2-hydroxy-ethyl)-, or (2-cyano-ethyl)-amines (1.1 equiv).
The solution was kept for 2 h at room temperature. The solvent
was removed in vacuo and the residue was treated with Ac2O
(2 mL) in the presence of perchloric acid (two drops). After
30 min at 0 °C, under an inert atmosphere, the reaction was neu-
tralized by the addition of saturated solution of sodium hydrogen-
carbonate The solution was concentrated and the residue was
diluted with CH2Cl2 and washed with water. The extracts were
dried, filtered, and concentrated under reduced pressure. Column
chromatography (6:4 cyclohexane/EtOAc) of the residue afforded
3.1.4.2. N-Butyl-D-ribono-1,5-lactam 12b. Compound 12b (66 mg)
as colorless syrup; ½a D20
ꢀ
+7 (c 0.16; H2O); 1H NMR (300 MHz, pyri-
dine-d5) d 5.95 (t, 1H), 5.64 (m, 1H), 5.59 (d, 1H, J = 3.1 Hz), 5.07
(dd, 1H), 4.67 (dd, 1H), 4.54 (m, 2H), 2.61 (m, 2H), 2.34 (m, 2H),
1.90 (t, 3H). 13C NMR (75 MHz, pyridine-d5) d 172.3, 73.2, 71.9,
51.6., 47.6; 30.1, 21.1, 14.8; ESIMS: m/z [M+Na]+ calcd: 226, found:
226. Anal. Calcd for C9H17NO4: C, 53.19; H, 8.43; N, 6.89. Found: C,
53.01; H, 8.51; N, 6.92.
2,3,4-tri-O-acetyl-5-bromo-5-deoxy-N-alkyl-
D-ribonamide 9f–h.
3.1.3.1. 2,3,4-Tri-O-acetyl-5-bromo-5-deoxy-N-(3-methyl-pyrid-
inyl)-D-ribonamide 9f. Compound 9f (170 mg, 40%) as a colorless
3.1.4.3. N-Hexyl-D-ribono-1,5-lactam 12c. Compound 12c (71 mg)
as colorless syrup; ½a D20
ꢀ
+64 (c 0.10; H2O); 1H NMR (300 MHz, pyr-
syrup: ½a 2D0
ꢀ
+59 (c 0.35; CHCl3); 1H NMR (300 MHz, CDCl3) d 8.54
idine-d5) d 5.99 (t, 1H), 5.63 (m, 1H), 5.60 (d, 1H, J = 3.1 Hz), 5.11
(dd, 1H), 4.70 (dd, 1H), 4.55 (m, 2H), 2.67–2.23 (t, 3H), 1.90 (t,
3H). 13C NMR (75 MHz, pyridine-d5) d 171.8, 72.6, 71.3, 66.5,
51.1, 47.4, 34.5–27.0, 23.1, 14.5; ESIMS: m/z [M+Na]+ calcd: 254,
found: 254. Anal. Calcd for C11H21NO4: C, 57.12; H, 9.15; N, 6.06.
Found: C, 57.24; H, 9.02; N, 6.13.
(m, 2H), 7.69 (d, 1H), 7.58 (t, 1H), 7.29 (dd, 1H), 5.49 (m, 3H),
3.69 (dd, 1H), 3.50 (dd, 1H), 3.49 (d, 2H, J = 11.6 Hz), 2.16–2.06
(s, 9H). 13C NMR (75 MHz, CDCl3) d 169.6–169.2, 166.2, 149,
135.7, 135.6, 123.7, 71.9, 69.1, 40.8, 31.4, 20.8, 20.7, 20.6, 14.8;
ESIMS: m/z [M+Na]+ calcd: 307, found: 307. Anal. Calcd for
C17H21BrN2O7: C, 45.86; H, 4.75; Br, 17.95; N, 6.29. Found: C,
45.77; H, 4.84; Br, 17.99; N, 6.36.
3.1.4.4. N-Benzyl-D-ribono-1,5-lactam 12e. Compound 12e (70 mg)
as colorless syrup; ½a D20
ꢀ
ꢁ10 (c 0.11; H2O); 1H NMR (300 MHz, pyr-
3.1.3.2.
2,3,4-Tri-O-acetyl-5-bromo-5-deoxy-N-(2-O -acetyl-
idine-d5) d 9.07–8.70(m, 5H), 6.34 (m, 1H), 6.29 (t, 1H), 6.15 (d, 1H,
J = 5.2 Hz), 5.95 (s, 1H), 5.36 (dd, 1H), 5.03 (dd, 1H). 13C NMR
(75 MHz, pyridine-d5) d 173.4, 138.9, 130.2–128.8, 73.7, 72.4,
67.4, 51.6, 45.9; ESIMS: m/z [M+Na]+ calcd: 260, found: 260. Anal.
Calcd for C12H15NO4: C, 60.75; H, 6.37; N, 5.90. Found: C, 60.75; H,
6.37; N, 5.90.
ethyl)-D-ribonamide 9g. Compound 9g (163 mg, 39%) as a color-
less syrup: ½a 2D0
ꢀ
ꢁ2 (c 0.44; CHCl3); 1H NMR (300 MHz, CDCl3) d
6.60 (t, 1H), 5.49 (m, 3H), 3.69 (dd, 1H), 3.60 (m, 2H), 3.49 (dd,
1H), 4.21 (t, 2H), 2.21–2.10 (s, 12H). 13C NMR (75 MHz, CDCl3) d
171.5–169.1, 165.9, 71.8, 69.1, 62.8, 39.1, 31.4, 20.8–20.7, 14.8;
ESIMS: m/z [M+Na]+ calcd: 462, found: 462. Anal. Calcd for
C
15H22BrNO9: C, 40.92; H, 5.04; Br, 18.15; N, 3.18. Found: C,
3.1.4.5. N-(3-Methyl-pyridinyl)-D-ribono-1,5-lactam 12f. Com-
40.81; H, 5.09; Br, 18.01; N, 3.25.
pound 12f (72 mg) as colorless syrup; ½a D20
ꢀ
+44 (c 0.10; H2O); 1H
NMR (300 MHz, pyridine-d5)
d 8.57 (s, 1H), 7.69 (d, 1H,
3.1.3.3. 2,3,4-Tri-O-acetyl-5-bromo-5-deoxy-N -(2-cyano-ethyl)-
J = 9.0 Hz), 7.50 (dd, 1H), 7.34 (dd, 1H), 6.10 (d, 1H, J = 7.7 Hz),
6.07 (m, 2H), 5.25 (dd, 1H), 4.89 (d, 1H, J = 12 Hz), 4.40 (d, 1H,
J = 14.7 Hz), 13C NMR (75 MHz, pyridine-d5) d 173.4, 149.2, 149.1,
136.2, 131.3, 123.6, 73.9, 71.6, 67.1, 52.0, 48.8; ESIMS: m/z
D
-ribonamide 9h. Compound 9h (160 mg, 40%) as a colorless syr-
up: ½a 2D0
ꢀ
ꢁ2 (c 0.44; CHCl3); 1H NMR (300 MHz, CDCl3) d 6.60
(t, 1H), 5.49 (m, 3H), 4.21 (t, 2H), 3.69 (dd, 1H), 3.60 (m, 2H),
3.49 (dd, 1H), 2.21–2.10 (s, 12H), 13C NMR (75 MHz, CDCl3) d

C. Falentin-Daudre et al. / Carbohydrate Research 345 (2010) 1983–1987
1987
[M+Na]+ calcd: 261, found: 261. Anal. Calcd for C11H14N2O4: C,
55.46; H, 5.92; N, 11.76. Found: C, 55.38; H, 6.02; N, 11.67.
2. (a) Welter, A.; Jadot, J.; Dardenne, G.; Marlier, M.; Casimir J. Phytochem. 1976,
747–749; (b) Card, P. J.; Hitz, W. D. J. Org. Chem. 1985, 50, 891–893; (c) Fleet, G.
W. J.; Smith, P. W. Tetrahedron 1987, 43, 971–978; (d) Dondoni, A.; Giovannini,
P. P.; Perrone, D. J. Org. Chem. 2002, 67, 7203–7214; (e) Thompson, D. K.;
Hubert, C. N.; Wightman, R. H. Tetrahedron 1993, 49, 3827–3840.
3. (a) Bols, M. Acc. Chem. Res. 1998, 31, 1–8; (b) Dhavale, D. D.; Matin, M. M.;
Sharma, T.; Sabharwal, S. G. Biorg. Med. Chem. 2003, 11, 3295–3305.
4. (a) Ishida, N.; Kumagai, K.; Niida, T.; Hamamoto, K.; Shomura, T. J. Antibiot.
1967, 20, 62–65; (b) Niwa, T.; Inouye, S.; Tsuruoka, T.; Koaze, Y.; Niida, T. Agric.
Biol. Chem. 1970, 34, 966–968; (c) Koyama, M.; Sakamura, S. Agric. Biol. Chem.
1974, 38, 1111–1112.
3.1.4.6. N-(2-Hydroxy-ethyl)-D-ribono-1,5-lactam 12g. Compound
12g (58 mg) as colorless syrup; ½a D20
ꢀ
+11 (c 0.21; H2O); 1H NMR
(300 MHz, pyridine-d5) d 4.18 (t, 1H), 4.05 (m, 2H), 3.83 (dd, 1H),
3.64 (m, 2H), 3.57 (t, 2H), 13C NMR (75 MHz, pyridine-d5) d 178.4,
72.6, 70.6, 68.7, 62.3, 49.6, 46.7; ESIMS: m/z [M+Na]+ calcd: 214,
found: 214. Anal. Calcd for C7H13NO5: C, 43.98; H, 6.85; N, 7.33.
Found: C, 43.87; H, 6.93; N, 7.25.
5. Evans, S. V.; Hayman, A. R.; Fellows, L. E.; Shing, T. K. M.; Derome, A. E.; Fleet, G.
W. J. Tetrahedron Lett. 1985, 26, 1465–1468.
6. (a) Anzeveno, P. B.; Creemer, L. J.; Daniel, J. K.; King, C. H. R.; Liu, P. S. J. Org.
Chem. 1989, 54, 2539–2542; (b) Robinson, K. M.; Begovic, M. E.; Rhinehart, B. L.;
Heineke, E. W.; Ducep, J. B.; Kastner, P. R.; Marshall, F. N.; Danzin, C. Diabetes
1991, 40, 825–830.
7. (a) Spearman, M. A.; Jameson, J. C.; Wright, J. A. Exp. Cell Res. 1987, 168, 116–
126; (b) Tsukamoto, K. T.; Uno, A.; Shrimada, S.; Imokaw, G. Clin. Res. 1989, 37A,
722–725.
8. Fleet, G. W. J.; Karpas, A.; Dwek, R. A.; Fellows, L. E.; Tyms, A. S.; Petursson, S.;
Namgoong, S. K.; Ramsden, N. G.; Smith, P. W.; Son, J. C.; Wilson, F.; Witty, D.
R.; Jacob, G. S.; Rademacher, T. W. FEBS Lett. 1988, 237, 128–132; (a) Khanna, I.
K.; Mueller, R. A.; Weier, R. M.; Stealey, M. A. U.S. Patent 5216168, 1993; (b)
Karpas, A.; Fleet, G. W.; Dwek, R. A.; Petursson, S.; Namgoong, S. K.; Ramsden,
N. G.; Jacob, G. S.; Rademacher, T. W. Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 9229–
9233; (c) Montefiori, D. C.; Robinson, W. E.; Mitchel, W. M. Proc. Natl. Acad. Sci.
U.S.A. 1988, 85, 9248–9252.
3.1.4.7. N-(2-Cyano-ethyl)-D-ribono-1,5-lactam 12h. Compound
12h (67 mg) as colorless syrup; ½a D20
ꢀ
+18 (c 0.11; H2O); 1H NMR
(300 MHz, pyridine-d5) d 5.92 (t, 1H), 5.62 (m, 2H), 5.25 (dd, 1H),
4.94–4.83 (m, 2H), 4.74 (dd, 1H), 3.95 (t, 2H), 13C NMR (75 MHz,
pyridine-d5) d 173.3, 120, 73.4, 71.9, 67.0, 52.4, 44.5, 16.7; ESIMS:
m/z [M+Na]+ calcd: 223, found: 223. Anal. Calcd for C8H12N2O4: C,
48.00; H, 6.04; N, 13.99. Found: C, 47.95; H, 6.15; N, 14.12.
3.1.5. N-(2-carboxy-ethyl)-
To N-(2-cyano-ethyl)-
D
-ribono-1,5-lactam 12i
D-ribono-1,5-lactam (12h) (240 mg,
0.736 mmol) was added HCl (20%; 5 mL). The reaction mixture
was stirred, for 7 h, at 90 °C. The solution was concentrated and
the residue was diluted with water. The obtained solution was
treated with NaOH (1 M) and stirred for 5 min at room tempera-
ture. The suspension was filtered and the filtrate was concentrated
under diminished pressure to give the desired compound 12i
9. (a) Wang, G.-N.; Reinkensmeier, G.; Zhang, S.-W.; Zhang, J. Z.; Zhang, L.-R.;
Zhang, L.-H.; Butters, T. D.; Ye, X. -S. J. Med. Chem. 2009, 52, 3146–3149; (b)
Platt, F. M.; Neises, G. R.; Dwek, R. A.; Butters, T. D. J. Biol. Chem. 1994, 269,
8362–8365; (c) Block, X.; Lu, X.; Platt, F. M.; Foster, G. R.; Gerlich, W. H.;
Blumberg, B. S.; Dwek, R. A. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 2235–2239; (d)
Markad, S. D.; Karanjule, N. S.; Sharma, T.; Sabharwal, S. G.; Dhavale, D. D.
Bioorg. Med. Chem. 2006, 14, 5535–5539.
10. (a) Tsuruoka, T.; Nakabayashi, S.; Fukuyasu, H.; Ishii, Y.; Tsuruoka, T.;
Yamamoto, H.; Inouye, S.; Kondo, S. EP 328111 A2, 1989; (b) Fleet, G. W. J.;
Ramsden, N. G.; Witty, D. R. Tetrahedron 1989, 45, 319–326.
11. Tsuruoka, T.; Yuda, Y.; Nakabayashi, A.; Katano, K.; Sezaki, M.; Kondo, S. JP
63216867 A2, 1988.
12. Bouchez, V.; Stasik, I.; Beaupère, D.; Urzan, R. Tetrahedron Lett. 1997, 38, 7733–
7736.
13. (a) Fleet, G. W. J.; Ramsden, N. G.; Dwek, R. A.; Rademacher, T. W.; Fellows, L.
E.; Nash, R. J.; Green, D. St. C.; Winchester, B. J. Chem. Soc., Chem. Commun. 1988,
483–485; (b) Elbein, A. D. FASEB J. 1991, 5, 3055–3063; (c) Zhou, J.; Zhang, Y.;
Zhou, X.; Zhou, J.; Zhang, L.-H.; Ye, X.-S.; Zhang, X.-L. Bioorg. Med. Chem. 2008,
16, 1605–1612; (d) Zhang, G.-L.; Chen, C.; Xiong, Y.; Zhang, L.-H.; Ye, J.; Ye, X.-S.
Carbohydr. Res. 2010, 345, 780–786.
(155 mg, 96%), as colorless syrup. ½a D20
ꢀ
+10 (c 0.30; H2O); 1H
NMR (300 MHz, D2O) d 4.37 (d, 1H, J = 3.3 Hz), 4.18 (m, 1H), 3.89
(t, 1H), 3.44–3.28 (m, 2H), 3.11 (dd, 1H), 2.78 (m, 2H),. 13C NMR
(75 MHz, D2O) d 175.0, 174.3, 80.5, 71.4, 65.7, 50.3, 43.4, 29.9;
ESIMS: m/z [M+Na]+ calcd: 242, found: 242. Anal. Calcd for
C8H13NO6: C, 43.84; H, 5.98; N, 6.39. Found: C, 43.75; H, 5.89; N,
6.43.
Acknowledgments
14. (a) Butters, T. D.; Dwek, A.; Platt, F. M. Chem. Rev. 2000, 100, 4683–4696; (b)
Asano, N.; Ishii, S.; Kizu, H.; Ikeda, K.; Yasuda, K.; Kato, A.; Martin, O. R.; Fan, J.
Q. Eur. J. Biochem. 2000, 267, 4179–4186; (c) Cox, T.; Lachmann, R.; Hollak, C.;
Aerts, J.; van Weely, S.; Hrebicek, M.; Platt, F.; Butters, T.; Dwek, R.; Moyses, C.;
Gow, I.; Elstein, D.; Zimran, A. Lancet 2000, 355, 1481–1485.
15. (a) Robinson, K. M.; Rhinehart, B. L.; Begovic, M. E.; King, C. H.; Liu, P. S. J.
Pharmacol. Expt. Ther. 1989, 251, 224–229; (b) Platt, F. M.; Neises, G. R.;
Karlsson, G. B.; Dwek, R. A.; Butters, T. D. J. Biol. Chem. 1994, 269, 27108–27114;
(c) Xu, Y.; Seok-Rye, C.; Mei-Ping, K.; Kung, H. F. Nucl. Med. Biol. 1999, 26, 833–
835.
16. Piro, J.; Rublralta, M.; Giralt, E.; Diez, A. Tetrahedron Lett. 1999, 40, 4865–4868.
17. Piro, J.; Forns, P.; Blanchet, J.; Bonin, M.; Micouin, L.; Diez, A. Tetrahedron:
Asymmetry 2002, 13, 995–1004.
18. Falentin, C.; Beaupere, D.; Demailly, G.; Stasik, I. Tetrahedron Lett. 2009, 50,
5364–5366.
We thank the Ministère de la Recherche, the Conseil Régional de
Picardie and the CNRS for the financial support.
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