Improved synthesis of 6-amino-6-deoxy-D-galactono-1,6-lactam and D-mannono-1,6-lactam from corresponding unprotected D-hexono-1,4-lactones

Article abstract of DOI:10.1016/j.tet.2003.12.062

Regioselective bromination of unprotected D-galactono-1,4-lactone and D-mannono-1,4-lactone with PPh₃/CBr₄ led to 6-bromo-6-deoxy derivatives. These intermediates were treated with LiN ₃ and hydrogenated to give 6-amino-6-deoxy-D-galactono-1,6-lactam (8) and 6-amino-6-deoxy-D-mannono-1,6-lactam (13) in 74 and 67% overall yield, respectively.

Full text of DOI:10.1016/j.tet.2003.12.062

Tetrahedron 60 (2004) 2079–2081
Improved synthesis of 6-amino-6-deoxy-D-galactono-1,6-lactam
and D-mannono-1,6-lactam from corresponding unprotected
D-hexono-1,4-lactones
*
Ludovic Chaveriat, Imane Stasik, Gilles Demailly and Daniel Beaupere
`
´
Laboratoire des Glucides, Universite de Picardie Jules Verne, 33 Rue Saint-Leu, F-80039 Amiens, France
Received 16 September 2003; revised 18 November 2003; accepted 24 December 2003
Abstract—Regioselective bromination of unprotected D-galactono-1,4-lactone and D-mannono-1,4-lactone with PPh3/CBr4 led to 6-bromo-
6-deoxy derivatives. These intermediates were treated with LiN3 and hydrogenated to give 6-amino-6-deoxy-D-galactono-1,6-lactam (8) and
6-amino-6-deoxy-D-mannono-1,6-lactam (13) in 74 and 67% overall yield, respectively.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
flexibility of the seven-member ring, therefore increasing
the formation of hydrogen bonds to make contact with the
enzyme.
The discovery of the glycosidase inhibitor activity of the
natural product nojirimycin 1 initiated the synthesis of
various polyhydroxylated piperidine and pyrrolidine deriva-
tives (azasugars).1 This group of inhibitors is potentially
useful for treating metabolic disorders such as diabetes,2
cancer3 and AIDS.4 Seven-member azasugars
(polyhydroxyazepanes 2, 3, 4) have also shown to possess
potent inhibitory activities.5 (Fig. 1) The hydroxyl groups,
in azepanes, adopt different spatial disposition due to the
However, only a few reports have appeared on the synthesis
of seven-member iminosugars. In some of those reported
they have been obtained in admixture with their correspond-
ing six-member ring derivatives, requiring separation.6
The use of protected D-galactono-1,4-lactone and
D-mannono-1,4-lactone for preparing the corresponding
lactams 87 and 138 has been described. The title compounds
were obtained in 54 and 27% overall yield, respectively.
In the continuation of our interest in the synthesis of
azasugars,9 we now describe a direct and improved
synthetic route to 6-amino-6-deoxy-D-1,6-galactonolactam
(8) and 6-amino-6-deoxy-D-mannono-1,6-lactam (13) from
unprotected D-galactono-1,4-lactone and D-mannono-1,4-
lactone, in three steps.
2. Results and discussion
The selective bromination of the primary hydroxyl group in
D-galactono-1,4-lactone (5) using triphenylphosphine
(PPh3)-carbon tetra-bromide (CBr4) in pyridine gave the
6-bromo-6-deoxy-D-galactono-1,4-lactone (6) in 82% yield
as the key starting material for the synthesis of lactam 8. The
introduction of an azide function at the C-6 position was
achieved using lithium azide (LiN3) to give 6-azido-6-
deoxy-D-galactono-1,4-lactone (7) in 91% yield. A one-pot
procedure for the azidation of (5), was attempted: either by
using a mixture of PPh3–CBr4 and lithium azide in (DMF)
Figure 1. Examples of azasugars.
Keywords: D-galactono-1,4-lactone; D-mannono-1,4-lactone; 6-Bromo-6-
deoxy-D-hexono-1,4-lactones; Seven-member azasugars; 6-Amino-6-
deoxy-D-galactono; D-mannono-1,6-lactams.
*
Corresponding author. Tel.: þ33-3-22-82-75-66; fax: þ33-3-22-82-75-
60; e-mail address: imane.stasik@sc.u-picardie.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.12.062

2080
L. Chaveriat et al. / Tetrahedron 60 (2004) 2079–2081
Scheme 1. Conditions: (a) PPh3, CBr4; (b) LiN3; (c) H2, Pd/C.
to give compound 7 but in only 11% yield, or by using
Mitsunobu reaction (PPh3-diethyl azodicarboxylate-
diphenylphosphoryl azide in DMF) to give 7 in 40% yield.
3. Experimental
3.1. General
Catalytic hydrogenation of 7 over palladium on charcoal
(10%), at room temperature, produced quantitatively the
desired 6-amino-6-deoxy-D-galactono-1,6-lactam (8)
(Scheme 1).
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
(l¼589 nm) at 24 8C. 1H and 13C NMR spectra were
recorded in D2O, in MeOD or in DMSO-d6. Me4Si was used
as an internal standard on a Bruker 300 MHz spectrometer.
D-mannono-1,4-lactone was used as the key starting
material for the synthesis of lactam 13 (Scheme 2). For
synthesis of D-mannono-1,4-lactone (10), which was not
commercially available, we have used two procedures.
First, we have hydrogenated the double bound of
D-isoascorbic acid as describe in literature8 but the yield
of this reaction was lower than 50%. In a second time
oxidation, of D-mannose (9), using bromine and barium
carbonate in water10 afforded a mixture of D-mannono-1,4-
lactone (10) and D-mannono-1,5-lactone. Isolation of
compound 10 was very difficult and lead to substantially
lower yield.
Thin-layer chromatography (TLC) was performed on
E. Merck glass plates silica gel sheets (SilicaGel F254) and
visualised under UV light and/or stained with phospho-
molybdic acid-aqueous H2SO4 solution. Column chroma-
tography was carried out on silica gel (E. Merck 230–400
mesh). All solvents were distilled before use.
3.1.1. 6-Bromo-6-deoxy-D-galactono-1,4-lactone (6). To a
solution of D-galactono-1,4-lactone (5) (10 g, 56.2 mmol) in
pyridine (200 mL) was added triphenylphosphine (30 g,
2 equiv.) and carbon tetra-bromide (3£6 g, 1 equiv.) at
20 min intervals. The mixture was stirred, under an inert
atmosphere, at room temperature for 18 h. Methanol was
added and the solution was kept for 10 min at room
temperature and concentrated in vacuo. The toluene
(50 mL) was added to the crude material. After concen-
tration, the residue was diluted with water and washed with
CH2Cl2. The water extracts were concentrated in vacuo and
the obtained residue was chromatographed on silica gel.
Elution with EtOAc–hexanes (9:1) to give 6 (11.2 g, 82%)
as white solid: Rf 0.6 (EtOAc–MeOH 9:1); mp 126–
127 8C; [a]2D4 2100 (c 1.0, H2O). Anal. calcd % for
C6H9BrO5: C, 29.90; H, 3.76; Br, 33.15. Found % C, 30.4;
However, when sodium hydrogencarbonate was used
instead of barium carbonate, D-mannono-1,4-lactone (10)
was isolated in quantitative yield.
Treatment of D-mannono-1,4-lactone (10) with PPh3–CBr4
in pyridine gave the 6-bromo-6-deoxy-D-mannono-1,4-
lactone (11) in 69% yield. The reaction of the brominated
derivative 11 with LiN3 afforded the 6-azido-6-deoxy-D-
mannono-1,4-lactone (12) in 98% yield. Hydrogenation of
12 with H2–Pd/C produced quantitatively 6-amino-6-
deoxy-D-mannono-1,6-lactam (13) (Scheme 2).
1
Overall yields for the transformation of unprotected
D-galactono and D-mannono-1,4-lactones into correspond-
ing 6-amino-6-deoxy-D-hexono-1,6-lactams are 74 and
67%, respectively.
H, 3.70; Br 33.02; H NMR (300 MHz, MeOD) d 4.42 (d,
1H, J¼8.4 Hz), 4.32 (m, 2H), 3.98 (m, 1H), 3.62 (dd, 1H,
J¼6.9, 10.3 Hz), 3.50 (dd, 1H, J¼6.7, 10.2 Hz). 13C NMR
(75 MHz, MeOD) d 174.9, 80.3, 74.7, 73.8, 69.0, 32.5.
Scheme 2. Conditions: (a) Br2, H2O, NaHCO3; (b) PPh3, CBr4; (c) LiN3; (d) H2, Pd/C.

L. Chaveriat et al. / Tetrahedron 60 (2004) 2079–2081
2081
3.1.2. 6-Azido-6-deoxy-D-galactono-1,4-lactone (7). A
stirred solution of 6-bromo-6-deoxy-D-galactono-1,4-lac-
tone (6) (1 g, 4.15 mmol) in DMF (10 mL) was treated with
lithium azide (20% in H2O) (12 mL, 1.3 equiv.) and set
aside at 80 8C for 1 h. The mixture was poured into ice-
water (15 mL) and the product extracted with ethyl acetate.
The organic layer was concentrated in vacuo and the
obtained residue was chromatographed on silica gel. Elution
with EtOAc–hexanes (7:3) to give 7 (0.74 g, 91%) as
yellow oil: Rf 0.7 (EtOAc–MeOH 9:1); [a]2D4 265 (c 1.0,
MeOH). Lit.7 [a]D23 270.6 (c 1.0, MeOH); 1H NMR
(300 MHz, MeOD) d 4.40 (d, 1H, J¼8.8 Hz), 4.27 (dd,
1H, J¼8.2, 8.8 Hz), 4.11 (dd, 1H, J¼2.8, 8.1 Hz), 3.91 (m,
1H), 3.51 (dd, 1H, J¼7.7, 12.7 Hz), 3.41 (dd, 1H, J¼5.0,
12.7 Hz); 13C NMR (75 MHz, MeOD) d 175.0, 80.8, 74.6,
73.6, 68.5, 53.4.
azide, as in case of 6 gave 12 (0.58 g, 98%) as yellow oil: Rf
0.6 (EtOAc–MeOH 9:1); [a]2D4 þ20 (c 1.0, MeOH). Anal.
calcd % for C6H9N3O5: C, 35.47; H, 4.47. Found % C,
35.42; H, 4.42; 1H NMR (300 MHz, MeOD) d 4.68 (d, 1H,
J¼4.5 Hz), 4.57 (dd, 1H, J¼2.7, 4.4 Hz), 4.52 (dd, 1H,
J¼2.7, 8.9 Hz), 4.15 (m, 1H), 3.55 (dd, 1H, J¼2.2,
12.8 Hz), 3.39 (dd, 1H, J¼4.9, 12.8 Hz). 13C NMR
(75 MHz, MeOD) d 176.6, 79.2, 71.3, 69.6, 67.4, 54.2.
3.1.7. 6-Amino-6-deoxy-D-mannono-1,6-lactam (13).
Compound 12 (0.3 g, 1.48 mmol) in ethanol was treated
with palladium on charcoal and then hydrogenated for 18 h,
as in case of 7, to give 13, in quantitative yield, as white
solid: Rf 0.4 (EtOAc–MeOH 3:2); mp 150–152 8C; [a]D24
þ47 (c 1.0, H2O). Anal. calcd % for C6H11NO5: C, 40.68;
1
H, 6.26. Found % C, 40.60; H, 6.12; H NMR (300 MHz,
D2O) d 4.71 (d, 1H, J¼5.6 Hz), 3.98 (m, 2H), 3.74 (m, 1H),
3.52 (dd, 1H, J¼6.8, 13.4 Hz), 2.84 (m, 1H). 13C NMR
(75 MHz, D2O) d 175.9, 75.1, 72.2, 75.1, 68.8, 67.4, 39.7.
3.1.3. 6-Amino-6-deoxy-D-galactono-1,6-lactam (8). A
solution of compound 7 (0.35 g, 1.72 mmol) in ethanol
(8 mL) was treated with palladium on charcoal (10%,
0.035 g) and then hydrogenated for 18 h at room tempera-
ture. The mixture was filtered through a layer of celite and
the filtrate was concentrated in vacuo to give 8 as white
solid: Rf 0.4 (EtOAc–MeOH 3:2); mp 168–170 8C; [a]D24
213 (c 1.0, H2O). Lit.7 [a]D25 216.3 (c 1.0, H2O); mp 175–
176 8C; 1H NMR (300 MHz, D2O) d 4.43 (d, 1H,
J¼9.3 Hz), 3.91 (m, 1H), 3.71 (m, 2H), 3.50 (dd, 1H,
J¼4.6, 15.8 Hz), 3.21 (dd, 1H, J¼2.9, 15.8 Hz); 13C NMR
(75 MHz, D2O) d 176.4, 73.3, 69.1, 40.6.
Acknowledgements
`
We thank the Ministere de la Recherche and the Conseil
Regional de Picardie for financial support.
´
References and notes
3.1.4. D-mannono-1,4-lactone (10). To a solution of
D-mannose (9) (5 g, 2.8 mmol) and sodium hydrogencarbo-
nate (3.35 g, 4 mmol) in distilled water (50 mL) cooled at
0 8C, bromine (3£1 mL, 58.5 mmol) was added at 20 min
intervals. The reaction mixture was stirred at this tempera-
ture for 1 h and then for 4 days at room temperature. Sodium
thiosulfate was added to destroy the excess of bromine and
the solvent was removed in vacuo to give a white solid. The
obtained solid was chromatographed on silica gel. Elution
with EtOAc–MeOH (9:1) and recrystallized from
2-propanol to give quantitatively compound 10 as white
solid: Rf 0.5 (EtOAc–MeOH 7:3); mp 145–146 8C; [a]D24
þ53 (c 1.0, H2O). Lit.11 mp 151 8C; [a]D20 þ51.2 (c 2, H2O);
1H NMR (300 MHz, DMSO-d6) d 4.55 (d, 1H, J¼4.6 Hz),
4.50 (dd, 1H, J¼2.7, 4.6 Hz), 4.31 (dd, 1H, J¼8.9, 2.8 Hz),
3.96 (m, 1H), 3.80 (dd, 1H, J¼2.8, 11.7 Hz), 3.67 (dd, 1H,
J¼5.1, 11.7 Hz); 13C NMR (75 MHz, DMSO-d6) d 177.1,
78.6, 71.2, 69.8, 68.5, 63.2.
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3.1.5. 6-Bromo-6-deoxy-D-mannono-1,4-lactone (11).
Reaction of 10 (2.15 g, 12 mmol) with triphenylphosphine
and carbon tetra-bromide in pyridine, as in case of 5 gave 11
(2 g, 69%) as white solid: Rf 0.44 (EtOAc–MeOH 9:1); mp
136–137 8C; [a]D24 þ55 (c 1.0, H2O). Lit.12 mp 136–
139 8C; [a]2D0 þ54.7 (c 1.1, H2O). 1H NMR (300 MHz,
MeOD) d 4.61 (d, 1H, J¼4.6 Hz), 4.47 (dd, 1H, J¼2.7,
4.6 Hz), 4.32 (dd, 1H, J¼2.7, 9.0 Hz), 4.13 (m, 1H), 3.75
(dd, 1H, J¼2.8, 11.6 Hz), 3.63 (dd, 1H, J¼5.1, 11.6 Hz).
13C NMR (75 MHz, MeOD) d 177.3, 80.6, 71.8, 70.1, 67.5,
37.4.
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