Synthesis of 6-amino-6-deoxy-d-gulono-1,6-lactam and l-gulono-1,6-lactam derived from corresponding 5,6-O-sulfinyl hexono-1,4-lactones

Article abstract of DOI:10.1016/j.tet.2006.05.017

Syntheses of 6-amino-6-deoxy-2,3-O-isopropylidene-d-gulono- and l-gulono-1,6-lactams 3 and 4 from corresponding glycono-1,4-lactones are described. Activation of the primary hydroxyl group requires 5,6-cyclic sulfite intermediate to obtain 6-azido-6-deoxy

Full text of DOI:10.1016/j.tet.2006.05.017

Tetrahedron 62 (2006) 7455–7458
Synthesis of 6-amino-6-deoxy-D-gulono-1,6-lactam and
L-gulono-1,6-lactam derived from corresponding
5
,6-O-sulfinyl hexono-1,4-lactones
*
Laurent Gireaud, Ludovic Chaveriat, Imane Stasik, Anne Wadouachi and Daniel Beaupere
`
Laboratoire des Glucides UMR 6219, Universite´ de Picardie Jules Verne, 33 Rue Saint-Leu, F-80039 Amiens, France
Received 22 February 2006; revised 3 May 2006; accepted 10 May 2006
Available online 9 June 2006
Abstract—Syntheses of 6-amino-6-deoxy-2,3-O-isopropylidene-D-gulono- and L-gulono-1,6-lactams 3 and 4 from corresponding glycono-
1,4-lactones are described. Activation of the primary hydroxyl group requires 5,6-cyclic sulfite intermediate to obtain 6-azido-6-deoxy
derivatives, which are cyclized after reduction.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
described an improved synthesis of 6-amino-6-deoxy-D-gal-
actono- and D-mannono-1,6-lactams 1 and 2 via correspond-
ing 6-bromo-6-deoxy-1,4-lactones (Fig. 1).
5
Intracyclic nitrogen-based sugar analogues named azasugars
or iminosugars have been discovered as natural products.
These compounds have been of considerable interest be-
cause many of them show specific inhibition against glyco-
sidases and glycosyltransferases, being potential therapeutic
H
N
H
N
HO
HO
HO
HO
O
O
1
agents for viral, proliferative and metabolic diseases. Thus,
these properties have stimulated intensive work directed on
their synthesis, usually towards the five- and six-member
iminosugars.
OH
OH
OH
OH
1
2
Figure 1.
Nevertheless, only few reports have appeared on the synthe-
sis of seven-member iminosugars (polyhydroxyazepanes),
which have also been shown to possess potent inhibitory
2
In previous work, we have shown the usefulness of cyclic
sulfites for stereoselective N-glycosylation, O-glycosylation
activities. In some of those reported, they have often been
obtained in admixture with their corresponding six-member
ring derivatives, requiring separation.
6
3
and C-glycosylation reactions of hexoses and pentoses. In
the continuation of our interest in the synthesis of aza-
5
,7
sugars, we now describe a synthetic route to 6-amino-6-
deoxy-D- and L-gulono-1,6-lactams 3 and 4 (Fig. 2) from
D- and L-gulono-1,4-lactones involving 5,6-cyclic sulfite as
activating group of the primary hydroxyl.
Polyhydroxyheptonolactams have been reported as tetra-
hydroxycaprolactam derived, potentially useful monomers
for the preparation of novel oligomeric and polymeric
4
a
materials.
Polyhydroxyheptonolactams are also precursors of poly-
hydroxyazepanes, and have been described from protected
lactones as starting materials. Our group has recently
H
N
H
N
O
O
O
O
4
O
O
HO
HO
Keywords: D-Gulono-1,4-lactone; L-Gulono-1,4-lactone; 5,6-O-Sulfinyl-
1,4-lactone; 6-Amino-6-deoxy-D-gulonolactam; 6-Amino-6-deoxy-L-gulo-
nolactam.
HO
HO
3
4
*
Corresponding author. Tel.: +33 3 22 82 75 27; fax: +33 3 22 82 75 60;
e-mail: anne.wadouachi@u-picardie.fr
Figure 2.
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.017

7456
L. Gireaud et al. / Tetrahedron 62 (2006) 7455–7458
2
. Results and discussion
compound has already been described in the literature for
structures with cis-relationship between the 3-OH group
and the side chain at C-4. This anhydridation was observed
by heating 6-bromo-6-deoxy-D-mannono and D-idono-1,4-
We first selected the D-gulono-1,4-lactone as starting mate-
rial. D-Gulono-1,4-lactone was subjected to bromination,
with the intention to prepare 6-bromo-6-deoxy-D-gulono-
8
lactone.
1
,4-lactone, by using carbon tetrabromide–triphenylphos-
5
phine system in pyridine. In spite of many attempts with
other solvents such as DMF or higher temperatures, we
never obtained the 6-bromo-6-deoxy derivative. With this re-
agent, D-gulono-1,4-lactone gave a 3,6-anhydro derivative 5
Therefore, we turned to the cyclic sulfite as activating group.
5,6-Cyclic sulfite derivative 8 of D-gulono-1,4-lactone was
obtained from 2,3-O-isopropylidene-D-gulono-1,4-lactone
9
7, which was synthesized in two steps from commercial
(
70%). This reaction applied to L-gulono-1,4-lactone gave
D-gulono-1,4-lactone (Scheme 2). Sulfinylation of 7 by thio-
nyl chloride in THF in the presence of pyridine afforded 5,6-
cyclic sulfite D-gulono-1,4-lactone 8 in 99% in 5–10 min.
Treatment of 8 with sodium azide in DMF gave the corre-
sponding 6-deoxy-6-azido compound 9 in 93% yield. The
one-pot reduction of the azido group and subsequent N-het-
erocyclization was realized by catalytic hydrogen transfer
with ammonium formate as hydrogen donor and palladium
the same result, the 3,6-anhydro compound 6 was isolated
in only 38% yield, in this case more starting lactone was
retrieved (Scheme 1). The formation of 3,6-anhydro
OH
HO
O
O
HO
(i)
O
O
O
70%
ꢀ
10
on charcoal (10%) as catalyst in ethyl acetate at 70 C.
The 6-amino-6-deoxy-D-gulono-1,6-lactam 3 was isolated
in 92% yield.
HO
OH
O
O
OH
OH
5
D-gulono-1,4-lactone
OH
O
HO
This strategy was also applied to the L-gulono-1,4-lactone.
2,3-O-Isopropylidene-L-gulono-1,4-lactone 10 was prepared
as described in the literature. Sulfinylation of 10 was quan-
HO
(i)
O
O
68%
9
HO
OH
titative. Then azidation of 11 afforded the product 12 in 95%
yield. The reduction–cyclization steps by catalytic hydrogen
transfer produced 6-amino-6-deoxy-L-gulono-1,6-lactam 4
in 84% yield from 12 (Scheme 3).
6
L-gulono-1,4-lactone
Scheme 1. (i) Conditions: PPh
3
, CBr , pyridine.
4
O
S
O
OH
O
OH
O
(i)
O
O
HO
HO
Ref 9
O
O
O
9
9%
HO
OH
O
O
O
O
D-gulono-1,4-lactone
7
8
H
N
OH
O
O
O
O
(
ii)
N3
(iii)
O
O
9
3%
92%
HO
O
HO
9
3
Scheme 2. (i) Conditions: SOCl
2
, pyridine, THF; (ii) NaN
3
, DMF; (iii) Pd/C (10%), HCO
2
NH
4
, EtOAc.
O
OH
OH
S
O
O
O
O
(i)
O
HO
Ref 9
HO
O
O
O
quant.
HO
OH
O
O
O
O
L-gulono-1,4-lactone
10
11
H
N
OH
O
O
O
O
(
ii)
N3
(iii)
84%
O
9
5%
HO
O
O
HO
4
12
Scheme 3. (i) Conditions: SOCl
2
, pyridine, THF; (ii) NaN
3
, DMF; (iii) Pd/C (10%), HCO
2
NH
4
, EtOAc.

L. Gireaud et al. / Tetrahedron 62 (2006) 7455–7458
7457
In summary, we have described an access to 6-amino-
-deoxy-D- and L-gulono-1,6-lactam derived 3 and 4 from
(3 mL). The filtrate was concentrated to give a yellow syrup,
which was purified by flash chromatography on silica gel
(EtOAc). The 5,6-O-sulfinyl derivative 8 was isolated as
a mixture of endo/exo diastereoisomers (1.2 g, 99%) as a
6
corresponding 2,3-O-isopropylidene-hexono-1,4-lactones.
Attempts at 6-bromination of D- and L-gulono-1,4-lactones
were unsuccessful. The azidation was efficient with a 5,6-
cyclic sulfite as an alternative intermediate. Overall yields
for the sulfinylation, azidation and reduction–cyclization
are 84 and 80%, respectively, for the D- and L-isomers 3 and 4.
colourless syrup. R 0.46 (hexane–EtOAc 1:1), endo/exo
f
1
mixture H NMR (CDCl , 300 MHz) d 5.16 (dd, 2H, H-1,
3
H-3), 4.87 (m, 7H), 4.53–4.31 (2 dd, 4H, H-6 endo/exo),
1.40 (s, 3H, CH ), 1.38 (s, 6H, 2CH ), 1.31 (s, 3H, CH ).
3
3
3
1
3
C NMR (CDCl , 75 MHz) d 173.4 (C-1), 115.4 (C-iso),
3
82.1, 81.0 (C-4), 79.7, 79.0 (C-2), 76.0 (C-3), 75.8 (C-5),
68.5, 67.7 (C-6), 26.8, 25.8 (2CH3).
3. Experimental
3
.1. General
3.1.4. 6-Azido-6-deoxy-2,3-O-isopropylidene-D-gulono-
lactone (9). To a solution of compound 8 (1 g, 3.78 mmol)
in DMF (10 mL) was added sodium azide (369 mg,
All chemicals were purchased from Aldrich or Acros
France). Carbon tetrabromide furnished by Aldrich was
ꢀ
(
1.5 equiv). The mixture was heated at 80 C for 24 h
sublimed before use. Melting points were determined on
a B u¨ chi 535 apparatus and are uncorrected. Optical rotations
were determined with a Jasco Dip 370 electronic micro-
under argon atmosphere. After evaporation of DMF under
reduced pressure, the residue was purified by flash chroma-
tography on silica gel (acetone) to furnish 9 (920 mg, 93%)
as a syrup. R 0.7 (hexane–EtOAc 1:1), [a] ꢁ31 (c 1,
ꢀ
1
polarimeter (10 cm cell) at 24 C. H NMR spectra were
recorded on a Bruker 300 WB spectrometer at 300 MHz
and C NMR spectra were recorded at 75 MHz.
f
D
1
CHCl ), H NMR (CDCl , 300 MHz) d 4.97 (d, 1H, H-2,
3
3
1
3
J2,3¼5.32 Hz), 4.87 (dd, 1H, H-3, J ¼3.45 Hz), 4.61 (dd,
3,4
1
H, H-4, J ¼7.2 Hz), 4.08 (m, 1H, H-5, J ¼5.5 Hz),
4,5 5,6a
Thin layer chromatography (TLC) was performed on Merck
glass plates silica gel 60 F254 stained with phosphomolybdic
acid–H SO reagent in ethanol. Column chromatography
3.52 (dd, 1H, H-6a, J
J5,6b¼3.1 Hz), 1.42 (s, 3H, CH ), 1.32 (s, 3H, CH ).
¼13.06 Hz), 3.42 (dd, 1H, H-6b,
6a,6b
1
3
C
NMR (CDCl , 75 MHz) d 175.2 (C-1), 114.1 (C-iso), 81.1
3
3
2
4
3
was carried out on silica gel (Merck, 230–400 mesh). All
solvents were distilled before use.
(C-4), 77.0 (C-2), 76.3 (C-3), 70.2 (C-5), 53.0 (C-6), 26.1,
25.0 (2CH3).
3
.1.1. 3,6-Anhydro-D-gulono-1,4-lactone (5). A solution of
3.1.5. 2,3-O-Isopropylidene-D-gulono-1,6-lactam (3).
Compound 9 (200 mg, 0.822 mmol) in ethyl acetate
(15 mL) was treated with palladium on charcoal (10%) in
the presence of ammonium formate (10 equiv). The mixture
was heated under argon atmosphere for 18 h, then filtered
through a layer of Celite and concentrated in vacuo to give
D-gulono-1,4-lactone (0.5 g, 2.8 mmol) in pyridine (10 mL)
was treated with triphenylphosphine (1.47 g, 2 equiv) and
carbon tetrabromide (0.93 g, 1 equiv). The mixture was
stirred at room temperature for 2 h, then concentrated
in vacuo and the residue was purified by column chromato-
graphy (EtOAc) to give 5 (0.314 g, 70%) as white solid.
3 as white crystals (165 mg, 92%). R 0.36 (hexane–EtOAc
f
ꢀ
1
R 0.5 (EtOAc–MeOH 9:1), mp 146–147 C, [a] ꢁ5.9
4:6), [a]D ꢁ15.5 (c 0.88, CHCl ), H NMR (CDCl3,
f
D
3
1
(
c 0.4, MeOH), H NMR (MeOD, 300 MHz) d 4.52 (d, 1H,
300 MHz) d 4.9 (d, 1H, H-2, J ¼5.34 Hz), 4.8 (dd, 1H,
2
,3
H-2, J2,3¼4.6 Hz), 4.43 (dd, 1H, H-3, J ¼2.9 Hz), 4.38
3,4
H-3, J3,4¼3.52 Hz), 4.55 (dd, 1H, H-4, J ¼7.28 Hz), 4.15
4,5
(
1
dd, 1H, H-4, J4,5¼7.7 Hz), 4.15 (m, 1H, H-5), 3.78 (dd,
H, H-6a, J5,6a¼4.2 Hz, J ¼11.5 Hz), 3.70 (dd, 1H, H-6b,
(m, 1H, H-5, J ¼4.27 Hz), 3.53 (dd, 1H, H-6a, J
¼
5,6a 6a,6b
12.9 Hz), 3.42 (dd, 1H, H-6b, J ¼1.24 Hz), 1.32 (s, 3H,
5,6b
6a,6b
13
13
J5,6b¼4.9 Hz). C NMR (MeOD, 75 MHz) d 176.4 (C-1),
CH ), 1.22 (s, 3H, CH ). C NMR (CDCl , 75 MHz)
3
3
3
8
5.0 (C-4), 78.7 (C-3), 75.2 (C-2), 74.2 (C-5), 69.9 (C-6).
d 175.2 (C-1), 114.1 (C-iso), 81.1 (C-4), 77.9 (C-2), 77.0
C-3), 70.2 (C-5), 53.5 (C-6), 26.1, 25.0 (2CH ). Anal. Calcd
(
3
3
.1.2. 3,6-Anhydro-L-gulono-1,4-lactone (6). L-Gulono-
for C H O N: C 49.76; H 6.96; N 6.45. Found (%): C 49.71;
9 15 5
1,4-lactone (0.5 g, 2.8 mmol) in pyridine treated with tri-
phenylphosphine (2 equiv) and carbon tetrabromide as
H 6.91; N 6.43.
described above for 5, gave 6 as white solid (0.172 g, 38%).
R 0.5 (EtOAc–MeOH 9:1), mp 150–151 C, [a] +5 (c
0
3.1.6. 2,3-O-Isopropylidene-5,6-O-sulfinyl-L-gulonolac-
tone (11). Reaction of 2,3-O-isopropylidene-L-gulono-1,4-
lactone10 (1 g, 4.61 mmol)inTHF(20 mL), withanhydrous
ꢀ
.5, MeOH), H NMR (MeOD, 300 MHz) d 4.46 (dd, 1H,
f
D
1
9
H-4, J3,4¼6.5 Hz), 4.39 (d, 1H, H-2, J ¼3.1 Hz), 4.32
pyridine (2.4 equiv) and thionyl chloride (1.2 equiv), as in
case of 7, gave quantitatively 11 as a colourless syrup in
2,3
(
dd, 1H, H-3), 4.17 (m, 1H, H-5, J ¼5.0 Hz), 3.82 (d,
4
,5
1
3
2
H, H-6, J5,6¼7.2 Hz).
C NMR (MeOD, 75 MHz)
endo/exo mixture. R 0.46 (hexane–EtOAc 1:1), endo/exo
f
1
d 173.4 (C-1), 80.4 (C-3), 72.8 (C-6), 72.3 (C-4), 71.4
C-5), 70.0 (C-2).
mixture H NMR (CDCl , 300 MHz) d 5.23 (dd, 1H, H-3),
3
(
4.76 (m, 6H), 4.46–4.35 (2 dd, 4H, H-6 endo/exo), 1.42
(s, 3H, CH ), 1.38 (s, 3H, CH ), 1.28 (s, 3H, CH ), 1.31 (s,
3H, CH3). C NMR (CDCl , 75 MHz) d 173.4 (C-1),
3 3 3
1
3
3.1.3. 2,3-O-Isopropylidene-5,6-O-sulfinyl-D-gulonolac-
tone (8). To a solution of 2,3-O-isopropylidene-D-gulono-
3
115.4 (C-iso), 82.3, 82.1 (C-4), 79.6, 79.1 (C-2), 76.4
(C-3), 75.8 (C-5), 68.5, 67.7 (C-6), 26.9, 26.0 (2CH3).
9
1
,4-lactone 7 (1 g, 4.6 mmol) in THF (20 mL) precooled
ꢀ
to 0 C, were added anhydrous pyridine (2.4 equiv) then
dropwise thionyl chloride (1.2 equiv). The mixture was
3.1.7. 6-Azido-6-deoxy-2,3-O-isopropylidene-L-gulono-
lactone (12). Reaction of 11 (720 mg, 2.724 mmol) with
sodium azide (1.5 equiv) in DMF, as in case of 8, gave 12
ꢀ
dinium salts were filtrated and washed with cooled THF
stirred at 0 C under argon atmosphere for 10 min and pyri-

7458
L. Gireaud et al. / Tetrahedron 62 (2006) 7455–7458
as a colourless syrup (630 mg, 95%). R 0.73 (hexane–
f
2. (a) Poitout, L.; Le Merrer, Y.; Depezay, J. C. Tetrahedron Lett.
1994, 35, 3293–3296; (b) Qian, X.; Moris, F. V.; Wong, C. H.
Bioorg. Med. Chem. Lett. 1996, 6, 1117–1122; (c) Moris,
F. V.; Qian, X. H.; Wong, C. H. J. Am. Chem. Soc. 1996, 118,
7647–7662; (d) Painter, G. F.; Eldridge, P. J.; Falshaw, A.
Bioorg. Med. Chem. 2004, 12, 225–232.
3. (a) Dax, K.; Graigg, V.; Koblinger, B.; St u¨ tz, A. E.
J. Carbohydr. Chem. 1990, 9, 479–499; (b) Lohray, B. B.;
Jayamma, Y.; Chatterjee, M. J. Org. Chem. 1995, 60, 5958–
5960; (c) Poitout, L.; Le Merrer, Y.; Depezay, J. C.
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Poitout, L.; Depezay, J. C.; Dosbaa, I.; Geoffroy, S.; Foglietti,
M. J. Bioorg. Med. Chem. 1997, 5, 519–533.
1
EtOAc 1:1), [a]D +23 (c 1, CHCl ), H NMR (CDCl ,
3
3
3
00 MHz) d 4.9 (d, 1H, H-2, J2,3¼5.34 Hz), 4.9 (dd, 1H,
H-3, J3,4¼3.52 Hz), 4.55 (dd, 1H, H-4, J ¼7.28 Hz), 4.15
4,5
(
m, 1H, H-5, J5,6a¼4.27 Hz), 3.53 (dd, 1H, H-6a,
J6a,6b¼12.9 Hz), 3.42 (dd, 1H, H-6b, J ¼2.98 Hz), 1.42
5,6b
1
3
(
s, 3H, CH ), 1.34 (s, 3H, CH ). C NMR (CDCl ,
3
3
3
75 MHz) d 174.0 (C-1), 114.9 (C-iso), 80.2 (C-4),
76.8 (C-2), 76.3 (C-3), 70.3 (C-5), 52.8 (C-6), 27.1, 26.1
(
2CH3).
3
.1.8. 2,3-O-Isopropylidene-L-gulono-1,6-lactam (4).
Reaction of 12 (200 mg, 0.822 mmol) in ethyl acetate with
palladium on charcoal (10%) in the presence of ammonium
formate (10 equiv), as in the case of 9, gave 4 as white crys-
tals (150 mg, 84%). R 0.36 (hexane–EtOAc 4:6), [a] +17
4. (a) Long, D. D.; Stetz, R. J. E.; Nash, R. J.; Marquess, D. G.;
Lloyd, J. D.; Winters, A. L.; Asano, N.; Fleet, G. W. J.
J. Chem. Soc., Perkin Trans. 1 1999, 901–908; (b) Joseph,
C. C.; Regeling, H.; Zwanenburg, B.; Chittenden, G. J. F.
Tetrahedron 2002, 58, 6907–6911.
f
D
1
(
c 2.5, CHCl ), H NMR (MeOD, 300 MHz) d 4.3 (d, 1H,
3
H-2, J2,3¼7.8 Hz), 3.9 (dd, 1H, H-3, J ¼4.1 Hz), 3.45
3,4
(
4
1
dd, 1H, H-4, J4,5¼7.28 Hz), 4.15 (m, 1H, H-5, J
¼
5. Chaveriat, L.; Stasik, I.; Demailly, G.; Beaupere, D.
Tetrahedron 2004, 60, 2079–2081.
5,6a
.27 Hz), 3.53 (dd, 1H, H-6a, J6 ¼12.9 Hz), 3.42 (dd,
a,6b
H, H-6b, J ¼1.24 Hz), 1.32 (s, 3H, CH ), 1.22 (s, 3H,
5,6b 3
6. (a) Aouad, M. E.; El Meslouti, A.; Uzan, R.; Beaupere, D.
Tetrahedron Lett. 1994, 35, 6279–6282; (b) El Meslouti, A.;
Beaupere, D.; Demailly, G.; Uzan, R. Tetrahedron Lett. 1994,
35, 3913–3916; (c) Beaupere, D.; El Meslouti, A.; Lelievre,
P.; Uzan, R. Tetrahedron Lett. 1995, 36, 5347–5348; (d)
Roussel, F.; Wadouachi, A.; Beaupere, D. Carbohydr. Lett.
1
3
CH3). C NMR (MeOD, 75 MHz) d 175.2 (C-1), 114.1
(
C-iso), 81.1 (C-4), 77.9 (C-2), 77.0 (C-3), 70.2 (C-5),
3.5 (C-6), 26.1, 25.0 (2CH ). Anal. Calcd for C H O N:
5
3
9 15 5
C 49.76; H 6.96; N 6.45. Found (%): C 49.73; H 6.89;
N 6.40.
2000, 3, 397–404; (e) Benksim, A.; Beaupere, D.; Wadouachi,
A. Org. Lett. 2004, 6, 3913–3915.
7
. Bouchez, V.; Stasik, I.; Beaupere, D.; Uzan, R. Tetrahedron
Lett. 1997, 38, 7733–7736.
References and notes
8
9
. Lundt, I.; Frank, H. Tetrahedron 1994, 50, 13285–13298.
. Fleet, G. W. J.; Ramsden, N. G.; Witty, D. R. Tetrahedron 1989,
1
. (a) Carbohydrate Mimics, Concepts and Methods; Chapleur,
Y., Ed.; Wiley-VCH: Weinheim, 1998; (b) Iminosugars
as Glycosidase Inhibitors; St u¨ tz, A. E., Ed.; Wiley-VCH:
Weinheim, 1999.
45, 319–326.
0. Gla c¸ on, V.; El Meslouti, A.; Uzan, R.; Demailly, G.; Beaupere,
D. Tetrahedron Lett. 1996, 37, 3683–3686.
1