Synthesis of novel 1-N-iminosugars from chiral nonracemic bicyclic lactams

Article abstract of DOI:10.1016/j.tetlet.2004.04.121

This communication reported the synthesis of novel C-6 substituted isofagomine analogues from easily accessible chiral nonracemic bicyclic lactams. These azasugars have potentially very interesting structure and are difficult to obtain by other methods.

Full text of DOI:10.1016/j.tetlet.2004.04.121

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4903–4906
Synthesis of novel 1-N-iminosugars from chiral
nonracemic bicyclic lactams
a
b
b,
Juan Xie,a, Tatyana Guveli, Severine Hebbe and Luc Dechoux
*
*
€
ꢀ
aStructure et Fonction des Molꢀecules Bioactives (UMR CNRS 7613), Equipe Chimie des Glucides,
Case courrier 179, Universitꢀe P. et M. Curie, 4 place Jussieu, 75005 Paris, France
bLaboratoire de Synthꢁese Asymꢀetrique (UMR CNRS 7611), Case courrier 47,
Universitꢀe P. et M. Curie, 4 place Jussieu, 75005 Paris, France
Received 19 March 2004; revised 21 April 2004; accepted 21 April 2004
Available online 8 May 2004
Abstract—This communication reported the synthesis of novel C-6 substituted isofagomine analogues from easily accessible chiral
nonracemic bicyclic lactams. These azasugars have potentially very interesting structure and are difficult to obtain by other
methods.
Ó 2004 Elsevier Ltd. All rights reserved.
Polyhydroxylated piperidines such as 1-deoxynojiri-
mycin and isofagomine are strong inhibitors of glyco-
sidases, presumably by mimicking the transition state of
enzymatic glycoside cleavage.1 These compounds are
now finding clinical applications as anti-HIV,2 antican-
cer,3 antidiabetic agents4 or in the treatment of Gaucher
disease.5 The promising therapeutic potential of imino-
sugars has led to increased interest and demand.
Homologues, N-substituted, deoxygenated, and a num-
ber of other 1-deoxynojirimycin and isofagomine
derivatives have been synthesized during the last few
years.6 Most of the syntheses start from carbohydrates
and in general require numerous steps to reach a specific
target. The development of efficient and general proce-
dures for their synthesis is still an area of great interest,
not only for the synthesis of natural products, but also
for that of chemically modified analogues.
priate bicyclic lactam template.8 However, to the best of
our knowledge, no isofagomine analogue has ever been
prepared from chiral bicyclic lactam.1;9 Subsequent to
our preceding stereocontrolled synthesis of new bicyclic
lactams,10 we envisaged the preparation of 1-N-imino-
sugars A (Fig. 1) as stereoisomers or derivatives of
isofagomine from chiral bicyclic lactam 1. As shown in
the retrosynthesis (Scheme 1), the target molecule A is
accessible from the dihydroxylated lactam B, which
could be obtained from 1, via unsaturated compound C.
In this paper, we report the development of this strategy
with methyl substituted lactam 1 (R ¼ Me).
We started the synthesis from the bicyclic lactam 1a,
obtained stereoselectively from (S)-phenylglycinol 6,10c
by introducing an unsaturation using the mild selenox-
ide syn-elimination method (Scheme 2). Treatment of
the anion of 1a with PhSeBr led to a mixture of mono-
selenide 2 and di-selenide 3. The ratio 2/3 was dependant
Recently, chiral nonracemic bicyclic lactams derived
from homochiral b-aminoalcohols have found wide
applications in the asymmetrical synthesis of substituted
heterocycles.7 Several iminosugars have been prepared
in a rapid and efficient way by employing the appro-
OH
OH
OH
NH
HO
HO
HO
HO
R
NH
HO
HO
NH
Keywords: Isofagomine; 1-N-Iminosugars; Chiral bicyclic lactams.
* Corresponding authors. Tel.: +33-1-44275893; fax: +33-1-44275513
(J.X.); tel./fax: +33-1-44272620 (L.D.); e-mail addresses: xie@ccr.
jussieu.fr; dechoux@ccr.jussieu.fr
OH
1-deoxynojirimycin
isofagomine
1-N-iminosugars A
Figure 1. Structure of natural and target iminosugars.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.121

4904
J. Xie et al. / Tetrahedron Letters 45 (2004) 4903–4906
MeO C
MeO C
MeO C
2
2
2
OH
R
N
R
N
R
N
HO
O
O
O
HO
HO
R
HO
NH
Ph
Ph
Ph
O
O
O
A
1
B
C
Scheme 1. Retrosynthesis of iminosugars A.
PhSe
PhSe
O
CO2Me
Me
CO2Me
Me
CO2Me
Me
ref. 10c
H2N
PhSe
O
a
OH
Ph
+
O
N
O
N
N
O
O
Ph
Ph
Ph
6
1a
2
3
b
CO2Me
CO2Me
Me
O
O
N
Me
O
N
OH
Ph
Ph
5
4
Scheme 2. Reagents and conditions: (a) (i) LiHMDS (1.2 equiv), THF, )78 °C, 1 h; (ii) PhSeBr (1.5 equiv), )78 to )50 °C, 0.5 h; 2: 40%, 3: 29%;
(b) mCPBA (2.3 equiv), THF, )15 °C, 0.5 h or 3 equiv NaIO4, THF, rt, 15 h, 50%.
CO2Me
Me
CO2Me
Me
on the quantity of base and PhSeBr: the best result (2/
3 ¼ 40/29) was obtained using 1.2 equiv LiHMDS and
1.5 equiv PhSeBr. Subsequent periodate or mCPBA
oxidation of 2 followed by benzeneselenenic acid elimi-
nation, produced however the pyridone 5, instead of the
desired a,b-unsaturated molecule 4. The instability of
a,b-unsaturated bicyclic lactams with similar structures
and their spontaneous transformation into the corre-
sponding pyridone as a minor product has recently been
observed.11
ref. 10a
H2N
+
OH
O
O
N
N
O
N
O
O
Ph
ent-6
1c
Ph
Ph
1b
Ph
a
CH2OBn
Me
O
CH2OBn
Me
O
O
N
N
7c
7b
38 %
Ph
30 %
To avoid this side reaction, we decided to reduce first the
ester function, which could be the cause of this elimi-
nation reaction. Furthermore, in order to obtain several
stereoisomers of 1-N-iminosugars A, the synthesis was
started with 1b,c (stereoisomers of 1a), which are readily
accessible from (R)-phenylglycinol ent-6 as a mixture of
cis and trans diastereomers (1b/1c ¼ 55/45).10a Reduc-
tion of the ester function with LiAlH4 gave primary
alcohols, which were protected as benzyl ethers 7b,c. At
this stage, the two diastereomers 7b and 7c were easily
separated by silica gel chromatography. The required
unsaturated lactams 8b and 8c were prepared separately
by phenylselenenylation followed by oxidative elimina-
tion with mCPBA (Scheme 3).
b
b
c
CH2OBn
Me
O
CH2OBn
Me
O
O
O
N
8c
8b
Ph
Ph
31 %
44 %
c
OH
N
OH
N
CH2OBn
Me
O
HO
O
HO
O
CH2OBn
Me
O
12
Dihydroxylation with OsO4 cat./Ba(ClO3)2 furnished
9b
9c
Ph
Ph
9b13 and 9c13 as single stereoisomers in 51% and 79%
yields, respectively. Consequently, the same exo-facial
diastereoselectivity was obtained with the two diastero-
isomers 8b and 8c. This stereoselectivity has already
been observed in the dihydroxylation of analogous
unsaturated lactams.8a;9g These results suggest that the
51 %
79 %
Scheme 3. Reagents and conditions: (a) (i) LiAlH4 (1 equiv), THF,
0 °C to rt, 5 h; (ii) NaH (1.4 equiv), THF, 0 °C, BnBr (1.5 equiv), 24 h;
(b) (i) LiHMDS (1.4 equiv), PhSeBr (1.5 equiv), THF, )78 °C; (ii)
mCPBA (3 equiv), CH2Cl2, rt, 1 h 30; (c) OsO4 (0.28 equiv), Ba(ClO3)2
(1.5–3 equiv), THF/H2O (2:1), 4 d.

J. Xie et al. / Tetrahedron Letters 45 (2004) 4903–4906
4905
stereoselectivity is not governed by the stereogenic cen-
References and notes
ter bearing the methylenebenzyloxy group but by the
more remote phenyl- and methyl-bearing stereocenters
(stereocenters which define the exo and endo faces).
1. Bols, M. Acc. Chem. Res. 1998, 31, 1.
2. Ratner, L.; Heyden, N. V.; Dedera, D. Virology 1999, 181,
180, and references cited therein.
3. Gross, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W.
Clin. Cancer Res. 1995, 1, 935.
The reduction of lactams 9b and 9c with BH3ÆMe2S
furnished the easily separable piperidines 10b,b0 and
10c,c0, but with low diastereoselectivities (de <10% in the
two cases as determined by 1H NMR of the crude
mixtures) (Scheme 4). These results contrast with
the high facial selectivity (retention of configuration at
C-6) generally observed during the reduction of analo-
gous bicyclic lactams.8a;c;d;10b The lack of stereoselecti-
vity in the reduction of the hydroxylated bicyclic
lactams 9b and 9c could be explained by a competitive
precomplexation14 of the borane by one of the two
hydroxyl groups. Finally, hydrogenolysis of piperidines
10b and 10c with Pd(OH)2 in methanol led to the
expected analogues of isofagomine 11b13 and 11c13 in
good yields.
4. (a) Anzeveno, P. B.; Creemer, L. J.; Daniel, J. K.; King,
C.-H. R.; Liu, P. S. J. Org. Chem. 1989, 54, 2539; (b)
Balfour, J. A.; McTavish, D. Drugs 1993, 46, 1025.
5. Butters, T. D.; Dxek, R. A.; Platt, F. M. Chem. Rev. 2000,
100, 4683.
6. (a) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M.
Chem. Rev. 2002, 102, 515; (b) Iminosugars as Glycosidase
€
Inhibitors-Nojirimycin and Beyond; Stutz, A., Ed.; Wiley-
VCH: Weinheim, 1999; (c) van den Berg, R. J. B. H. N.;
Donker-Koopman, W.; van Boom, J. H.; Aerts, H. M. F.
G. Bioorg. Med. Chem. 2004, 12, 891.
7. (a) Meyers, A. I.; Brengel, G. P. Chem. Commun. 1997, 1;
(b) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56,
9843; (c) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.;
Bosch, J. J. Org. Chem. 2003, 68, 1919.
8. (a) Meyers, A. I.; Andres, C. J.; Resek, L. E.; Woodall,
C. C.; McLaughlin, M. A.; Lee, P. H.; Price, D. A.
Tetrahedron 1999, 52, 8931; (b) Meyers, A. I.; Andres, C.
J.; Resek, L. E.; McLaughlin, M. A.; Woodall, C. C.; Lee,
P. H. J. Org. Chem. 1996, 61, 2586; (c) Meyers, A. I.;
Price, D. A.; Andres, C. J. Synlett 1997, 533; (d) Meyers,
A. I.; Price, D. A. Chirality 1998, 10, 88.
In summary, synthesis of novel 1-N-iminosugars has
been developed from the easily available bicyclic lactams
1. These compounds constitute the first examples of
analogues of isofagomine substituted on the C-6 posi-
tion, which are difficult to obtain by other methods so
far reported. The methodology reported therein should
provide access to other new C-6 substituted 1-N-imino-
sugars as potential glycosidase inhibitors.
9. For recent synthesis of azasugars, see: (a) Ichikawa, Y.;
Igarashi, Y.; Ichigawa, M.; Suhara, Y. J. Am. Chem. Soc.
1998, 120, 3007; (b) Jensen, H. H.; Lohse, A.; Petersen, B.
€
O.; Duus, J. O.; Bols, M. J. Chem. Soc., Perkin Trans. 1
2000, 667; (c) Uldall Hansen, S.; Bols, M. J. Chem. Soc.,
Perkin Trans. 1 2000, 911; (d) Pandey, G.; Kapur, M.
Tetrahedron Lett. 2000, 41, 8821; (e) Liang, X.; Lohse, A.;
Bols, M. J. Org. Chem. 2000, 65, 7432; (f) Pandey, G.;
Kapur, M. Synthesis 2001, 8, 1263; (g) Amat, M.; Llor, N.;
Huguet, M.; Molins, E.; Espinosa, E.; Bosch, J. Org. Lett.
2001, 3, 3257; (h) Pandey, G.; Kapur, M. Org. Lett. 2002,
4, 3883; (i) Patil, N. T.; John, S.; Sabharwal, S. G.;
Dhavale, D. D. Bioorg. Med. Chem. 2002, 10, 2155; (j)
Han, H. Tetrahedron Lett. 2003, 44, 1567; (k) Pandey, G.;
Kapur, M.; Klan, M. I.; Gaikwad, S. M. Org. Biomol.
Chem. 2003, 1, 3321; (l) Ostrowski, J.; Altenbach, H.-J.;
Wischnat, R.; Brauer, D. J. Eur. J. Org. Chem. 2003, 1104.
10. (a) Agami, C.; Dechoux, L.; Hebbe, S. Tetrahedron Lett.
OH
N
OH
N
HO
CH2OBn
HO
CH2OBn
a
9b
+
Me
OH
Me
OH
Ph
10b
Ph
10b' 30%
34%
b
OH
HO
HO
CH2OH
Me
ꢀ
2002, 43, 2521; (b) Agami, C.; Dechoux, L.; Menard, C.;
Hebbe, S. J. Org. Chem. 2002, 67, 7573; (c) Agami, C.;
Dechoux, L.; Hebbe, S. Tetrahedron Lett. 2003, 44, 5311.
N
H
11b 79 %
ꢀ
11. Amat, M.; Bosch, J.; Hidalgo, J.; Conto, M.; Perez, M.;
Llor, N.; Molins, E.; Miravitlles, C.; Orozco, M.; Lugue,
J. J. Org. Chem. 2000, 65, 7074.
OH
OH
CH2OBn
HO
CH2OBn
Me
a
12. Danishefsky, S.; Schuda, P. F.; Kitakara, T.; Etheredgl, S.
J. J. Am. Chem. Soc. 1977, 99, 6066.
+
9c
N
Me
N
1
13. Selected physical data. Compound 9b: H NMR (CDCl3,
Ph
10c
Ph
10c'
400 MHz): 1.32 (s, 3H, H-9), 2.21 (ddd, 1H, J ¼ 1:2, 4.8,
8.6 Hz, H-8), 2.84 (s, 1H, OH), 3.74 (dd, 1H, J ¼ 5:1,
9.1 Hz, H-10), 3.82 (t, 1H, J ¼ 8:8 Hz, H-10), 3.93 (dd, 1H,
J ¼ 7:3, 8.8 Hz, H-2), 4.00 (d, 1H, J ¼ 3:8 Hz, H-6), 4.49
(dd, 1H, J ¼ 1:5, 3.8 Hz, H-7), 4.55 (t, 1H, J ¼ 9:1 Hz, H-
2), 5.27 (t, 1H, J ¼ 8:1 Hz, H-3), 7.08–7.25 (m, 10H, Ph);
13C NMR (CDCl3): 21.5 (C-9), 46.2 (C-8), 58.4 (C-3), 66.0
(C-7), 66.6 (C-10), 69.8 (C-2), 70.7 (C-6), 73.3 (C-11), 94.6
(C-8a), 125.2, 127.0, 127.6, 128.3, 128.4 (Ph); 137.4, 139.9
(Cipso); 170.0 (CO). Compound 9c: 1H NMR (CDCl3):
1.52 (s, 3H, H-9), 2.80 (dt, 1H, J ¼ 4:8, 8.3 Hz, H-8), 3.25
(s, 1H, OH), 3.51 (dd, 1H, J ¼ 8:6, 9.8 Hz, H-10), 3.74 (dd,
1H, J ¼ 4:6, 9.8 Hz, H-10), 3.90 (dd, 1H, J ¼ 7:4, 8.6 Hz,
OH
OH
22%
32%
b
OH
HO
CH2OH
Me
N
H
11c 81 %
Scheme 4. Reagents and conditions: (a) BH3ÆDMS (6–10 equiv), THF,
0 °C to rt, 1 d; (b) Pd(OH)2 (0.6 equiv), MeOH, rt, 4–6 d.

4906
J. Xie et al. / Tetrahedron Letters 45 (2004) 4903–4906
H-2), 4.25 (d, 1H, J ¼ 3:8 Hz, H-6), 4.40–4.49 (m, 4H, H-
7), 44.3 (C-5), 56.5 (C-8), 60.4 (C-2), 62.6 (C-6), 67.4, 70.3
(C-3,4). Compound 11c: 1H NMR (CD3OD, 400 MHz):
1.19 (d, 3H, J ¼ 6:5 Hz, H-7), 1.45 (tt, 1H, J ¼ 3, 10.5 Hz,
H-5), 2.65 (m, 1H, H-6), 2.71 (dd, 1H, J ¼ 1:5, 14 Hz, H-
2), 2.99 (dd, 1H, J ¼ 2:7, 13.7 Hz, H-2), 3.65 (dd, 1H,
J ¼ 3:2, 5.2 Hz, H-8), 3.70 (dd, 1H, J ¼ 3:7, 6.5 Hz, H-8),
3.82 (m, 1H, H-3), 3.92 (dd, 1H, J ¼ 2:7, 11.2 Hz, H-4);
13C NMR (CD3OD): 20.1 (C-7), 49.8 (C-5), 51.4 (C-2),
53.3 (C-6), 60.8 (C-8), 70.0, 71.8 (C-3,4).
2,7,11), 5.19 (t, 1H, J ¼ 8:1 Hz, H-3), 7.09–7.29 (m, 10H,
Ph); 13C NMR (CDCl3): 27.4 (C-9), 45.5 (C-8), 58.2 (C-3),
67.3 (C-10), 68.7, 68.8 (C-6,7); 69.7 (C-2), 73.5 (C-11), 94.1
(C-8a), 125.2, 127.3, 127.5, 127.8, 128.5, 128.6 (Ph); 137.7,
139.7 (Cipso); 169.4 (CO). Compound 11b: 1H NMR
(CD3OD, 400 MHz): 1.22 (d, 3H, J ¼ 6:8 Hz, H-7), 1.67
(m, 1H, H-5), 2.26 (dd, 1H, J ¼ 3, 13.1 Hz, H-2), 2.30 (m,
1H, H-6), 3.02 (dd, 1H, J ¼ 1:8, 13.1 Hz, H-2), 3.70 (m,
2H, H-3,4), 3.83 (dt, 1H, J ¼ 1:3, 12.1 Hz, H-8), 3.90 (dd,
1H, J ¼ 3:5, 11.8 Hz, H-8); 13C NMR (CD3OD): 17.7 (C-
14. Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19,
356.