New stereocontrolled transformations in the imidazolosugar series

Article abstract of DOI:10.1016/S0040-4039(01)02320-6

The isomeric imidazolopyrrolidinose 1, imidazolopiperidinose 2 and imidazoloazepanose 3, potential glycosidase inhibitors, were obtained in several steps from D-glucose.

Full text of DOI:10.1016/S0040-4039(01)02320-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1089–1092
New stereocontrolled transformations in the
imidazolosugar series
Kamil Weinberg,a Stefan Jankowski,a Didier Le Nouenb and Andrzej Frankowskia,*
aInstitute of Organic Chemistry, Technical University of Lodz, ul. Zwirki 36, 90-924 Lodz, Poland
bEcole Nationale Supe´rieure de Chimie, Universite´ de Haute-Alsace, 3 rue Alfred Werner, 68093 Mulhouse, France
Received 17 October 2001; revised 28 November 2001; accepted 5 December 2001
Abstract—The isomeric imidazolopyrrolidinose 1, imidazolopiperidinose 2 and imidazoloazepanose 3, potential glycosidase
inhibitors, were obtained in several steps from
D-glucose. © 2002 Elsevier Science Ltd. All rights reserved.
Imidazolosugars as potential glycosidase inhibitors
have been a subject of interest for several research
groups.1–6 The only known natural imidazolosugar–
nagstatine is an effective inhibitor of N-acetylamino-b-
Thus, benzylation of 6a and 6b resulted in the forma-
tion of the compounds 7a and 7b which, after removing
acid-labile protecting groups, gave imidazolyl-pentoses
8a and 8b, each as a mixture of anomers. Subsequent
reduction of 8a and 8b yielded imidazolyl-pentitols 9a
and 9b, respectively, which were then tritylated to form
the ditrityl derivatives 10a and 10b (Scheme 1).
D
-glucosaminidase of bovine kidney.7,8 We present
herein the synthesis of three new isomeric imidazolo-
sugars of the structures 1, 2 and 3 (Fig. 1), potential
glycosidase inhibitors.
Phenylmethanesulphonylation of the OH groups in 10a
and successive removal of the trityl groups by acid
hydrolysis afforded the imidazolyl-pentitol 11a. The
same reaction sequence starting from 10b gave the
imidazolyl-pentitol 11b and the imidazolo-manno-pipe-
ridinose 12 in a 2:1 ratio (Scheme 2).
This synthesis is based on stereocontrolled transforma-
tions of two epimeric dibenzylditritylimidazolyl-penti-
tols 10a and 10b which were obtained in several steps
from dialdofuranose 4, a compound readily available
from
D
-glucose.9
The two epimeric imidazolosugars 6a and 6b were
prepared in a 3:5 ratio by nucleophilic addition of the
5-lithiated derivative of 2-t-butyldimethylsilyl-1-
dimethylsulphamoylimidazole (5)10 to dialdofuranose 49
according to the Kurihara procedure.11 These two
diastereomers were separated by flash chromatography
and hence subjected to analogous reaction sequences.
Under treatment with NaNH2 the compound 11a rear-
ranged to the tricyclic structure 13,14 which was consec-
utively catalytically debenzylated and the resulting
aldehyde was immediately reduced to produce the imi-
dazolopyrrolidinose 1.14 Imidazolopiperidinose 12,
treated with NaNH2, underwent a trans-elimination
reaction to provide its unsaturated derivative 14,14
which was catalytically debenzylated and reduced to
give the imidazolopiperidinose 2.14 When the imida-
zolyl-pentitol 11b was treated with NaNH2, the cyclisa-
tion and elimination reaction sequence led to the
dibenzyl unsaturated imidazoloazepanose 15.14 Cata-
lytic debenzylation and reduction of 15 resulted in the
formation of the imidazoloazepanose 314 (Scheme 3).
The stereochemical outcome of the above reactions
proves the configurations at the newly occurring chiral
centre of the two epimeric adducts 6a and 6b. Thus, we
believe the strong base promotes the SN2 type cyclisa-
tion of 11a to afford the imidazolopiperidinose 16
Figure 1.
* Corresponding author. Fax: +48 42 6365530; e-mail: andfrank@
ck-sg.p.lodz.pl
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02320-6

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K. Weinberg et al. / Tetrahedron Letters 43 (2002) 1089–1092
Scheme 1. Reagents and conditions: (a) 2-t-butyldimethylsilyl-1-dimethylsulphamoylimidazole (5), BuLi, THF, −70°C, 78%; (b)
BnBr, NaH, DMF, rt; (c) 1.5N HCl, THF, reflux, 8a: 65% (two steps), 8b: 60% (two steps); (d) NaBH4, MeOH, 0°C“rt, 9a: 88%,
9b: 87%; (e) TrCl, Py, DMAP, 80°C, 10a: 56%, 10b: 48%.
Scheme 3. Reagents and conditions: (a) NaNH2, DMF, rt, 13:
Scheme 2. Reagents and conditions: (a) BnSO2Cl, Py,
56%, 14: 84%, 15: 85%; (b) H2/Pd/C, EtOH, rt, 1: 81%, 2:
−30°C“rt; (b) 6N HCl, THF, reflux, 11a: 70% (two steps);
35%, 3: 24%.
11b: 34%, 12: 18% (two steps).
tion of phenylmethanesulphonic acid residue (Scheme
5).
(Scheme 4). The rearrangement of 16 into 13 involves
piperidine ring contraction, relying on the departure of
the equatorial phenylmethanesulphonate group from
C-7 and the 1,2-migration of the antiperiplanar [C-8/C-
8a] bond, assisted by an attack of the alcoholate ion at
C-9 on C-8, which is possible only in the boat confor-
mation of the piperidine ring. The formation of 13 as
only one isomer with the S-configuration at C-8 sug-
gests both the above processes are simultaneous
(Scheme 4). The epimeric imidazolopiperidinose 12,
however, in the same reaction conditions yields the
trans-elimination product 14, thanks to the hydrogen
atom at C-8 in 12 which is situated anti towards the
leaving group.
The trans stereochemistry of the elimination reactions
converting 12 into 14 and 11b into 15 proves the
R-configuration on the carbon atom adjacent to the
imidazole ring in both 12 and 11b.
The configuration of 13 and the boat conformation of
its pyranose ring (Scheme 3) were deduced by nuclear
Overhauser effect (NOE) measurements. Thus, irradia-
tion of H-9 generated nuclear Overhauser enhancement
at H-9% (26%) and H-5 (6%). When H-9% was irradiated,
a 22% NOE at H-9, 8% NOE at H-8 and 4% at H-5
were observed. Irradiation of H-7 gave enhancement of
H-8 (3%) and H-6 (8%). The irradiation of H-6 led only
to NOE enhancement of the proton H-7 (10%). The
experimental results were confirmed by molecular mod-
elling with the SYBYL 6.5 software from TRIPOS Inc.
The conversion of the imidazolyl-pentitol 11b into the
imidazoloazepanose 15 in basic conditions proceeds
probably via the epoxide 17 (compare Lohray et al.13),
with seven-membered ring closing and trans-elimina-

K. Weinberg et al. / Tetrahedron Letters 43 (2002) 1089–1092
1091
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Ohishi, H.; Yoneda, R.; Kurihara, T. J. Org. Chem. 1996,
61, 4405–4411.
Scheme 4. Proposed course of rearrangement of 16 into 13.
12. Karplus, M. J. Am. Chem. Soc. 1963, 85, 2870–2876.
13. Lohray, B. B.; Jayamma, Y.; Chatterjee, M. J. Org.
Chem. 1995, 60, 5958–5960.
14. All new compounds gave satisfactory NMR and MS
spectroscopy data. The most important data are listed
below.
1
1: [h]D −16 (c 0.3, MeOH); H NMR (D2O) l: 3.43 (ddd,
1H, J 5.1, 6.2, 6.6 Hz, H-5), 3.85 (dd, 1H, J 6.2, 11.3 Hz,
H-9), 3.90 (dd, 1H, J 6.6, 12.4 Hz, H-8), 4.00 (dd, 1H, J
5.1, 11.3 Hz, H-9%), 4.22 (dd, 1H, J 3.7, 12.4 Hz, H-8%),
4.50 (dt, 1H, J 3.7, 6.6 Hz, H-7), 4.61 (1H, t, J 6.6 Hz,
H-6), 7.24 (s, 1H, H-1), 8.61 (s, 1H, H-3); 13C NMR
(D2O) l: 45.0 (C-5), 58.2 (C-8), 58.3 (C-9), 65.5 (C-7),
75.0 (C-6), 111.6 (C-1), 127.0 (C-3), 134.6 (C-7a); FAB
MS: 185 ([M+H]+); HRMS: calcd for [M+H]+
(C8H13N2O3) 185.0926, found 185.0926
Scheme 5. Proposed course of the seven-membered ring clos-
ing in 17.
The configuration at C-8 in compound 2 was assigned
on the basis of the ROE signal between H-6 and H-8 in
the ROESY spectrum. The ROE signal between H-7
and H-9 was helpful in the configuration assignment at
C-9 for compound 3.
2: [h]D −32 (c 0.35, MeOH); 1H NMR (D2O) l: 1.86
(ddd, 1H, J 7.5, 8.75, 13.0 Hz, H-7), 2.32 (ddd, 1H, J 3.0,
5.75, 13.0 Hz, H-7’), 3.78 (dd, 1H, J 4.25, 12.25 Hz, H-9),
3.97 (dd, 1H, J 3.5, 12.25 Hz, H-9%), 4.03 (ddd, 1H, J 3.5,
4.25, 6.5 Hz, H-5), 4.12 (ddd, 1H, J 3.0, 6.5, 8.75 Hz,
H-6), 4.89 (1H, dd, J 5.75, 7.5 Hz, H-8), 6.95 (s, 1H,
H-1), 7.73 (s, 1H, H-3); 13C NMR (D2O) l: 35.9 (C-7),
60.2 (C-9), 60.3 (C-8), 61.0 (C-5), 64.0 (C-6), 124.0 (C-1),
131.2 (C-3), 143.0 (C-8a); FAB MS: 185 ([M+H]+);
HRMS: calcd for [M+H]+ (C8H13N2O3) 185.0926, found
185.0923
The configuration at C-6 in 3 can be deduced from the
analysis of vicinal coupling constants. The proton H-6
occupies the pseudo-equatorial position, corresponding
to the R-configuration, because its vicinal coupling
constants with the pseudo-axial H-5 and H-7 (0 and
1.75 Hz, respectively) correspond to HꢀCꢀCꢀH torsion
angles close to 90°.12
1
3: [h]D −17 (c 0.4, MeOH); H NMR (D2O) l: 2.03 (ddd,
1H, J 10.5, 10.75, 12.5 Hz, H-8), 2.14 (ddd, 1H, J 3.0,
4.0, 12.5 Hz, H-8%), 3.99 (d, 1H, J 15.0 Hz, H-5), 4.06
(ddd, 1H, J 1.75, 4.0, 10.75 Hz, H-7), 4.15 (dd, 1H, J
1.75, 6.5 Hz, H-6), 4.37 (dd, 1H, J 6.5, 15.0 Hz, H-5%),
4.89 (dd, 1H, J 3.0, 10.5 Hz, H-9), 6.95 (s, 1H, H-1), 7.73
(s, 1H, H-3); 13C NMR (D2O) l: 35.8 (C-8), 45.3 (C-5),
61.6 (C-9), 66.9 (C-7), 69.4 (C-6), 120.6 (C-1), 126.8
(C-3), 134.1 (C-9a); FAB MS: 185 ([M+H]+); HRMS:
calcd for [M+H]+ (C8H13N2O3) 185.0926, found 185.0929
Acknowledgements
This work was supported by the State Committee for
Scientific Research (Grant 3T09A09817). The authors
also wish to thank Professor J. Streith and Dr. T.
Tschamber for fruitful discussions.
1
13: [h]D −82 (c 1.75, CHCl3); H NMR (CDCl3) l: 3.48
References
(bd, 1H, J 2.5 Hz, H-7), 3.60 (dd, 1H, J 3.25, 11.25 Hz,
H-9), 3.85 (d, 1H, J 11.25 Hz, H-9%), 4.40 (d, 1H, J 3.25
Hz, H-5), 4.51, 4.73 (2d, 2H, J 12 Hz, OBn), 4.54, 4.62
(2d, 2H, J 11.5 Hz, OBn), 4.88 (d, 1H, J 2.5 Hz, H-8),
4.89 (s, 1H, H-6), 6.86 (s, 1H, H-1), 7.19–7.42 (m, 10H,
arom.), 7.51 (s, 1H, H-3); 13C NMR (CDCl3) l: 43.5
1. Frankowski, A.; Seliga, C.; Bur, D.; Streith, J. Helv.
Chim. Acta 1991, 74, 934–940.
2. Burgess, K.; Chaplin, D. A. Heterocycles 1994, 37, 673–
677.
3. Frankowski, A.; Deredas, D.; Le Nouen, D.; Tschamber,
T.; Streith, J. Helv. Chim. Acta 1995, 78, 1837–1842.
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Lett. 1995, 36, 1085–1088.
(C-7), 59.2 (C-5), 63.5 (C-9), 69.5 (OC
6 H2Ph), 70.7
(OCH2Ph), 85.2 (C-6), 98.6 (C-8), 121.2 (C-1), 128.0–
6
129.0 (m, arom.), 131.1 (C-3), 135.2 (C-7a), 138.8, 138.9
(s-arom.); FAB MS: 363 ([M+H]+)

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K. Weinberg et al. / Tetrahedron Letters 43 (2002) 1089–1092
1
14: [h]D +172 (c 0.9, CHCl3); 1H NMR (CDCl3) l:
3.47 (dd, 1H, J 8.75, 11.25 Hz, H-9), 3.60 (dd, 1H, J
5.0, 11.25 Hz, H-9%), 4.24 (dd, 1H, J 1.25, 6.25 Hz,
H-6), 4.41 (ddd, 1H, J 1.25, 5.0, 8.75 Hz, H-5), 4.42,
4.47 (2d, 2H, J 12.25 Hz, OBn), 4.88 (d, 1H, J 6.25,
H-7), 4.95 (s, 2H, OBn), 6.94 (s, 1H, H-1), 7.20–7.40
(m, 10H, arom.), 7.50 (s, 1H, H-3); 13C NMR (CDCl3)
15: [h]D +57 (c 1.5, CHCl3); H NMR (CDCl3+C6D6) l:
3.51 (dd, 1H, J 2.6, 13.2 Hz, H-5), 3.74 (ddd, 1H, J 2.6,
3.1, 9.0 Hz, H-6), 3.83 (dd, 1H, J 9.0, 13.2 Hz, H-5%), 3.88
(dd, 1H, J 3.1, 6.0 Hz, H-7), 4.21, 4.36 (2d, 2H, J 11.5 Hz,
OBn), 4.58, 4.61 (2d, 2H, J 12 Hz, OBn), 4.70 (d, 1H, J
6.0, H-8), 7.00 (s, 1H, H-1), 7.00–7.30 (m, 10H, arom.), 7.46
(s, 1H, H-3); 13C NMR (CDCl3+C6D6) l: 47.9 (C-5) 69.9
l: 60.5 (C-5), 62.8 (C-9) 69.2 (OC
6
H2Ph), 69.3
(C-6), 70.3 (OC6 H2Ph), 71.2 (OC6 H2Ph), 76.4 (C-7), 95.8
(OCH2Ph), 71.2 (C-6), 89.8 (C-7), 124.8 (C-1), 127.5–
6
(C-8), 127.5–129.0 (m, arom.), 131.0 (C-3), 137.7, 139.4
(s-arom.), 138.0 (C-9a), 140.0 (C-1), 147.8 (C-9); FAB MS:
363 ([M+H]+).
129.0 (m, arom.), 138.3 (C-3), 139.2 (C-8a), 140.0 (C-8);
FAB MS: 363 ([M+H]+)