Efficient synthesis of new N-alkyl-d-ribono-1,5-lactams from d-ribono-1,4-lactone

Article abstract of DOI:10.1016/j.tetlet.2009.07.026

d-Ribono-1,4-lactone was treated with ethylamine in DMF to afford N-ethyl-d-ribonamide 9a in quantitative yield. Bromination of amide 9a by the system SOBr₂ in DMF or PPh₃/CBr₄ in pyridine led, after acetylation, to epoxid

Full text of DOI:10.1016/j.tetlet.2009.07.026

Tetrahedron Letters 50 (2009) 5364–5366
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis of new N-alkyl-D-ribono-1,5-lactams from
D-ribono-1,4-lactone
*
Céline Falentin, Daniel Beaupère, Gilles Demailly, Imane Stasik
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:
D
-Ribono-1,4-lactone was treated with ethylamine in DMF to afford N-ethyl-D-ribonamide 9a in quanti-
Received 26 May 2009
Revised 2 July 2009
Accepted 6 July 2009
Available online 10 July 2009
tative yield. Bromination of amide 9a by the system SOBr2 in DMF or PPh3/CBr4 in pyridine led, after acet-
ylation, to epoxide 7. However, treatment of amide 9a with acetyl bromide in dioxane followed by
acetylation gave 2,3,4-tri-O-acetyl-5-bromo-5-deoxyl-N-ethyl-
D-ribonamide 10a. Methanolysis of 10a,
with sodium methoxide, afforded the N-ethyl- -ribonolactam 11a in 51% overall yields. Using this
D
method, N-butyl, N-hexyl, N-dodecyl, and N-benzyl-
(48–53%).
D
-ribonolactams 11b–e were obtained in good yields
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Azasugars
D-Ribono-1,4-lactone
N-Alkyl-
N-Alkyl-
D
-ribonamides
D-ribono-1,5-lactams
The discovery of the glycosidase inhibitor activity of the natural
product nojirimycin 1 initiated the synthesis of various polyhydr-
oxylated pyrrolidine, piperidine, azepane, and lactam derivatives
(azasugars).1 This group of inhibitors is potentially useful for treat-
ing metabolic disorders such as diabetes,2 cancer,3 and AIDS.4
Aldonolactams have been reported to have interesting biologi-
cal activities such as inhibition of glycosidase activity.5 For exam-
ple, compounds 2 and 3 have been reported as potentially useful
for treating cancer cell metastasis,6 and inflammation (Fig. 1).7
for the synthesis of new azasugar analogues namely N-alkyl-D-rib-
onolactams: N-ethyl, N-butyl, N-hexyl, N-dodecyl, and N-benzyl-D-
ribonolactams.
At first, for the synthesis of N-ethyl-
the strategy given in Scheme 1. We have used
D
-ribonolactam, we tried
-ribono-1,4-lactone
D
as the starting material via the 5-bromo-5-deoxy-D-ribono-1,4-lac-
tone (6) as the intermediate.13
The treatment of brominated derivative 6 with ethylamine
(1.2 equiv) in DMF at room temperature for 1 h gave after acetyla-
tion epoxide 7 as the only product, in quantitative yield. No trace of
Earlier we reported the synthesis of 5-amino-5-deoxy-
D-pen-
tonolactams from unprotected
overall yields.
Thus, unprotected pentonolactone can be transformed to its azi-
do derivative, whose hydrogenation yields the corresponding
3,4,5-trihydroxylactam by spontaneous lactamization of the
aminolactone.8
In general, the N-alkylated derivatives were found to be stron-
ger glycosidase inhibitors than the corresponding nonalkylated
derivatives.5,9 For example, the N-butyl 1-deoxynojirimycin 4 or
miglitol 5 has been shown to possess potent inhibitory activity of
glycosidase enzymes.10
However, only a few reports have appeared on the synthesis of
N-substituted aldonolactams. Except for the work of Diez,11,12
there have been no reports of the synthesis of these derivatives.
In the continuation of our interest in the synthesis of azasugars,
we are now reporting in this preliminary work an efficient strategy
D
-pentono-1,4-lactones in 60–83%
the intermediate 5-bromo-5-deoxy-N-ethyl-
tained (Scheme 1). In the literature,11,12 a similar intermediate was
obtained but in two steps: when 5-bromo or 5-iodo-5-deoxy- -rib-
D-ribonamide was ob-
D
ono-1,4-lactone was treated by leucine derivatives using Et3N as
OH
OH
H
NH
N
NH
O
HO
HO
O
HO
HO
HO
OH
OH
OH
HO
OH
1
2
3
OH
OH
N
N
HO
HO
HO
HO
OH
OH
4
5
* Corresponding author. Tel.: +33 3 22 82 75 66; fax: +33 3 22 82 75 60.
E-mail address: imane.Stasik@sc.u-picardie.fr (I. Stasik).
Figure 1. Examples of azasugars.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.026

C. Falentin et al. / Tetrahedron Letters 50 (2009) 5364–5366
5365
Table 1
Yields of 10b–e and 11b–e
HO
O
Br
O
ref.13
O
O
Product
Yield (%)
54
½ ꢀ
a 2D0
i
X )
6
HO
OH
HO
OH
OAc
O
OH
i)
O
Br
Br
Br
NHBu
(c 0.33; CHCl3) +4
(c 0.37; CHCl3) +2
(c 0.23; CHCl3) +6
(c 0.22; CHCl3) +43
(c 0.16; H2O) +7
NHR
Et
Et
OAc
OAc
O
OH
OH
N
HN
ii)
X
O
10b
AcO
AcO
O
O
OAc
8a
7
AcO
OAc
OAc
48
40
52
98
NHC6H11
Scheme 1. Reagents: (i) (a) EtNH2, DMF; (b) Ac2O, HClO4; (ii) NaH, DMF.
OAc
OAc
10c
the base the only product obtained was the brominated amide
which was converted to epoxide by treatment with K2CO3.
Epoxide 714 was then treated with NaH in DMF. Monitoring the
reaction by TLC and NMR spectra analysis of the crude product
showed that epoxide 7 was present as the only product and no
OAc
O
Br
NHC12H23
OAc
OAc
10d
trace of the target 2,3,4-tri-O-acetyl-N-ethyl-
(8) was obtained.
D-ribono-1,5-lactam
OAc
O
Due to the difficulties in the preparation of 2,3,4-tri-O-acetyl-N-
ethyl- -ribono-1,5-lactam 8 owing to the formation of epoxide 7
we attempted an alternative strategy.
-Ribono-1,4-lactone was treated with ethylamine in DMF for
1 h at room temperature to afford the N-ethyl-
-ribonamide 9a15
in quantitative yield. Treatment of -ribono-1,4-lactone with butyl,
hexyl, dodecyl, and benzylamine gave quantitatively the corre-
sponding N-alkyl ribonamides 9b–e. Bromination of amide 9a by
the system SOBr2 in DMF or PPh3/CBr4 in pyridine led also, after
acetylation, to epoxide 7.
Br
NHBn
D
OAc
N
OAc
10e
D
D
Bu
D
O
HO
HO
HO
OH
11b
However, treatment of amide 9a with acetyl bromide in dioxane
for 16 h, at room temperature, followed by acetylation gave the
C6H11
N
2,3,4-tri-O-acetyl-5-bromo-5-deoxy-N-ethyl-
which was isolated in 51% yield. Bromoamide 10a was then treated
with NaH in DMF, for 1 h, affording 2,3,4-tri-O-acetyl-N-ethyl-
ribonolactam. Methanolysis of 2,3,4-tri-O-acetyl-N-ethyl- -ribono-
lactam with sodium methoxide in methanol, led according to NMR
spectroscopy, to N-ethyl-
-ribonolactam 11a17 in quantitative
yield. The mass spectrum of compound 11a showed a diagnostic
peak at m/z 198 (M+Na)+. The title compound was identified by ele-
mental analysis and NMR spectra which showed, in particular, a
signal of a second methylene group at 49.9 ppm corresponding to
–HN–CH2 (Scheme 2).
D
-ribonamide 10a16
O
HO
HO
HO
99
99
98
(c 0.10; H2O) +64
(c 0.10; H2O) +19
(c 0.11; H2O) ꢁ10
D
-
OH
11c
D
C
12H23
D
N
O
HO
HO
OH
11d
Using this method, N-butyl, N-hexyl, N-dodecyl, and N-benzyl-
-ribonolactams (11b–e) were obtained in good yields (Table 1).
In summary, we have reported an efficient synthesis of novel N-
Bn
N
D
O
alkyl-
D-ribono-1,5-lactams which were synthesized in four steps in
OH
48–53% overall yields from unprotected
D-ribono-1,4-lactone.
11e
Acknowledgments
HO
OH
O
O
i)
We thank the Ministère de la Recherche, the Conseil Régional de
Picardie, and the CNRS for financial support.
O
HO
Br
NHR
OH
OH
9a-e
HO
OH
References and notes
ii)
a R= Ethyl
R
b R= Butyl
c R= Hexyl
d R= Dodecyl
e R= Benzyl
OAc
N
O
1. Bols, M. Acc. Chem. Res. 1998, 31, 1–8.
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iii)
O
HO
NHR
OAc
OAc
HO
11a-e
OH
10a-e
Scheme 2. Reagents and conditions: (i) RNH2/DMF, rt; (ii) (a) CH3COBr/dioxane, rt;
(b) Ac2O/pyridine, rt; (iii) (a) NaH/DMF, rt; (b) MeONa/MeOH, rt.

5366
C. Falentin et al. / Tetrahedron Letters 50 (2009) 5364–5366
5. (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) Fleet, G. W. J.; Ramsden, N. G.; Witty, D. R. Tetrahedron 1989, 45,
319–326; (c) Stütz, Arnold E. In Iminosugars as Glycosidase Inhibitors:
Nojirimycin and Beyond; Wiley-VCH: New York, 1999; pp 93–111.
6. 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.
kept for 1 h at room temperature. The reaction mixture was then concentrated
to give quantitatively 9a (260 mg) as a white solid: ½a D20
þ 41 (c 0.24; H2O); mp
ꢀ
58–60 °C; 1H NMR (300 MHz, D2O) 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,
J = 9.0 Hz). 1.05 (t, 3H, J = 9.0 Hz); 13C NMR (75 MHz, D2O) 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.
16. Typical synthesis procedure and spectral data of representative compound 2,3,4-tri-
7. Tsuruoka, T.; Yuda, Y.; Nakabayashi, A.; Katano, K.; Sezaki, M.; Kondo, S. JP
63216867 A2, 1988.
8. Bouchez, V.; Stasik, I.; Beaupère, D.; Urzan, R. Tetrahedron Lett. 1997, 38, 7733–
7736.
9. (a) Elbein, A. D. FASEB J. 1991, 5, 3055–3063; (b) Asano, N.; Nash, R. J.;
Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645–1680; (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.
10. (a) Platt, F. M.; Neises, G. R.; Dwek, R. A.; Butters, T. D. J. Biol. Chem. 1994, 269,
8362–8365; (b) 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; (c)
Markad, S. D.; Karanjule, N. S.; Sharma, T.; Sabharwal, S. G.; Dhavale, D. D.
Bioorg. Med. Chem. 2006, 14, 5535–5539.
O-acetyl-5-bromo-5-deoxy-N-ethyl-
ethyl- -ribonamide (9a) (250 mg, 1.29 mmol) in 1,4-dioxane (3 mL) was added
acetyl bromide (105 L, 1.1 equiv). The solution was kept overnight at room
temperature. The solvent was removed in vacuo and the residue was treated
with acetic anhydride in pyridine for 1 h. The reaction mixture was then
concentrated 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-
D-ribonamide(10a):Toastirredsolutionof N-
D
l
deoxy-N-ethyl-
D
-ribonamide 10a (0.250 g, 51%) as a colorless syrup: ½a D20
ꢁ 3 (c
ꢀ
0.33; CHCl3); 1H NMR (300 MHz, CDCl3) d 5.50 (m, 3H), 3.71 (dd, 1H, J = 3.0 Hz;
J = 6.0 Hz), 3.50 (dd, 1H, J = 6.0 Hz, J = 12.0 Hz), 3.36 (q, 2H, J = 6.0 Hz), 2.13-2.10
(s, 9H). 1.19 (t, 3H, J = 6 Hz), 13C NMR (75 MHz, CDCl3) d 169.7, 169.6, 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.
11. Piro, J.; Rublralta, M.; Giralt, E.; Diez, A. Tetrahedron Lett. 1999, 40, 4865–4868.
12. Piro, J.; Forns, P.; Blanchet, J.; Bonin, M.; Micouin, L.; Diez, A. Tetrahedron:
Asymmetry 2002, 13, 995–1004.
13. Bouchez, V.; Stasik, I.; Beaupère, D.; Uzan, R. Carbohydr. Res. 1997, 300, 139–
142.
17. Typical synthesis procedure and spectral data of representative compound N-ethyl-
D
-ribonolactam (11a): To a stirred solution of 10a (140 mg, 0.367 mmol) in DMF
14. Synthesis procedure and spectral data of 2,3-di-O-acetyl-4,5-anhydro-N-ethyl-
D
-
(2.5 mL) was added NaH (1 equiv). The reaction mixture was stirred at room
temperature for 1 h and a second portion of NaH (1 equiv) was added. After 1 h,
the solvent was removed in vacuo and the residue was chromatographed on
silica gel. Elution with (7:3, (AcOEt–cyclohexane) gave 2,3,4-tri-O-acetyl-N-
ribonamide (7): To a stirred solution of 5-bromo-5-deoxy- -ribono-1,4-lactone
D
(200 mg, 0.95 mmol) in DMF (2 mL) was added ethylamine (1.1 equiv). The
solution was kept for 1 h at room temperature. The solvent was removed in
vacuo and the residue was treated with acetic anhydride in the presence of
perchloric acid for 1 h. After concentration, the residue was diluted with
CH2Cl2 and washed with water. The CH2Cl2 extracts were dried, filtered and
concentrated. Column chromatography (8:2 EtOAc:cyclohexane) of the residue
ethyl-
D-ribonolactam. To a solution of the obtained 2,3,4-tri-O-acetyl-N-ethyl-
D
-ribonolactam (110 mg, 0.365 mmol) in 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 concentration, 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
afforded 2,3-di-O-acetyl-4,5-anhydro-N-ethyl-D-ribonamide (7) (0.233 g, 90%)
as a white solid: ½a D20
ꢀ
ꢁ 46 (c 0.22; CHCl3); mp 75–77 °C; 1H NMR (300 MHz,
CDCl3) d 5.43 (t, 1H, J = 9.0 Hz), 5.36 (m, 1H, J = 6.0 Hz), 4.41 (d, 1H, J = 6.1 Hz),
4.23 (dd, 1H, J = 3.0 Hz), 3.95 (dd, 1H, J = 9.3.0 Hz), 3.31 (q, 2H, J = 6.1 Hz), 2.16–
2.13 (s, 6H). 1.17 (t, 3H, J = 6 Hz), 13C NMR (75 MHz, CDCl3) d 168.7, 169.9,
169.6, 79.9, 73.9, 71.0, 70.6.1, 33.8, 20.6, 20.6, 14.7; ESIMS: m/z [M+Na]+ calcd:
282, found:282. Anal. Calcd for C11H17NO6: C, 50.96; H, 6.61; N, 5.40. Found: C,
50.88; H, 6.53; N, 5.32.
give quantitatively the desired N-ethyl-D-ribonolactam (11a): (65 mg) as a
colorless solid; ½a D20
ꢀ
þ 22 (c 0.24; H2O); mp 143–145 °C; 1H NMR (300 MHz,
pyridine-d5) d 4.87 (m, 1H), 4.44 (m, 2H), 3.93 (dd, 1H, J = 3.6 Hz, J = 10.5 Hz),
3.48 (dd, 1H, J = 6.3 Hz, J = 10.5 Hz), 3.33 (q, 2H, J = 7.2 Hz), 1.03 (t, 3H,
J = 7.2 Hz),. 13C NMR (75 MHz, pyridine-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.
15. Typical synthesis procedure and spectral data of representative compound N-ethyl-
D-ribonamide (9a): To
a stirred solution of D-ribono-1,4-lactone (200 mg,
1.35 mmol) in DMF (2 mL) was added ethylamine (1.1 equiv). The solution was