Stereo-controlled approach to pyrrolidine iminosugar C-glycosides and 1,4-dideoxy-1,4-imino-l-allitol using a d-mannose-derived cyclic nitrone

Article abstract of DOI:10.1016/j.tetlet.2009.09.139

Intramolecular N-alkylation of 2,3-O-isopropylidene-5-O-methanesulfonyl-6-O-t-butyldimethylsilyl-d-mannofuranose-oxime 7 afforded a five-membered cyclic nitrone 9, which on N-O bond reductive cleavage followed by deprotection of -OTBS and acetonide functi

Full text of DOI:10.1016/j.tetlet.2009.09.139

Tetrahedron Letters 50 (2009) 6906–6908
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereo-controlled approach to pyrrolidine iminosugar C-glycosides and
1,4-dideoxy-1,4-imino-L-allitol using a D-mannose-derived cyclic nitrone
c
Omprakash P. Bande a, Vrushali H. Jadhav a, Vedavati G. Puranik b, Dilip D. Dhavale a, , Marco Lombardo
*
a Department of Chemistry, Garware Research Centre, University of Pune, Pune 411 007, India
b Centre for Material Characterization, National Chemical Laboratory, Pune 411 008, India
c Dipartimento di Chimica ‘G. Ciamician’, Università di Bologna, via Selmi 2, 40126 Bologna, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Intramolecular N-alkylation of 2,3-O-isopropylidene-5-O-methanesulfonyl-6-O-t-butyldimethylsilyl-
mannofuranose-oxime 7 afforded a five-membered cyclic nitrone 9, which on N–O bond reductive cleav-
age followed by deprotection of –OTBS and acetonide functionalities gave 1,4-dideoxy-1,4-imino- -allitol
(DIA) 3. Addition of allylmagnesium chloride to nitrone 9 afforded -allylated product 10a in high diaste-
reoselectivity providing an easy entry to N-hydroxy-C1- -allyl-substituted pyrrolidine iminosugar 4a
D-
Received 7 August 2009
Revised 22 September 2009
Accepted 24 September 2009
Available online 27 September 2009
L
a
a
after removal of protecting group, while N–O bond reductive cleavage in 10a afforded C1-
idine iminosugar 4b.
a-allyl-pyrrol-
Keywords:
Cyclic nitrone
Iminosugars
Enzyme inhibitors
Pyrrolidine
Ó 2009 Elsevier Ltd. All rights reserved.
Enantiopure five-membered hydroxylated cyclic nitrones are
precursors of chiral pyrrolidine, pyrrolizidine, and indolizidine imi-
nosugars by exploiting 1,3-dipolar cycloaddition,1 1,3-addition of
organometallics,2 and SmI2-mediated reductive coupling reactions.3
Amongst iminosugars, five-membered pyrrolidine compounds such
as reported earlier.10 Treatment of 5 with mesyl chloride in the
presence of triethyl amine in CH2Cl2 afforded mesylated product
611 in 98% yield (Scheme 1). Debenzoylation of 6 using potassium
carbonate in methanol afforded a mixture of hemiacetals (a/b ano-
mers = 3:1) which on treatment with hydroxylamine hydrochlo-
ride and sodium bicarbonate in methanol–water at room
temperature for 2 h afforded a mixture of syn- and anti-oxime
7.12 In the subsequent step, reaction of oxime 7 with hydroxyl-
amine hydrochloride13 and sodium bicarbonate in methanol–
water at reflux for 12 h afforded five-membered cyclic nitrones 8
and 9 in the ratio of 2:8. The structure of five-membered nitrone
as 2,5-dideoxy-2,5-imino-
dideoxy-2,5-imino- -glycero-
are selective inhibitors of
- and b-glucosidases.4 The 1,4-dideoxy-
1,4-imino- -allitol (DIA) 3 is a moderately good inhibitor of human
liver -mannosidase and a weak inhibitor of -fucosidase, N-
acetyl-b- -hexosaminidase, and b-
-mannosidase.5 In addition,
D
-mannitol (DMDP) 1 (Fig. 1) and 2,5-
D
D
-manno-heptitol (homo DMDP) 2
a
L
a
-D
a-L
D
D
much interest is now focused on C1-alkyl, vinyl, and allyl-substi-
tuted pyrrolidine and piperidine iminosugars6,7 which were found
to be more selective inhibitors of glycosidases. In particular, the
C1-allylated iminosugars have found significant importance due to
the synthetic versatility of the C@C bond (as a precursor for further
functionalities) and its use in the synthesis of neoglycoconjugates
and C-disaccharides.7 As a part of our efforts in use of nitrones to-
ward the synthesis of iminosugars,8 we now report the intramolec-
OH
OH
HO
HO
HO
OH
HO
HO
OH
OH
N
H
1
N
H
2
OH
ular N-alkylation of
five-memberedcyclicnitrone9thatwasexploitedinthesynthesisof
D
-mannose-derived oxime 79 in the synthesis of
OH
OH
HO
DIA 3 and the hitherto unknown C1-a-allylated pyrrolidine imino-
sugars 4a and 4b.
OH
N
H
N
R
The required 1-O-benzoyl-2,3-O-isopropylidene-6-O-t-butyldi-
methylsilyl- -mannofuranose 5 was prepared from -mannose
OH
OH
a-
D
D
3
4a, R = OH,
4b, R = H,
* Corresponding author. Tel.: +91 20 25691727; fax: +91 20 2569 1728.
E-mail address: ddd@chem.unipune.ernet.in (D.D. Dhavale).
Figure 1. Iminosugars and analogues.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.139

O. P. Bande et al. / Tetrahedron Letters 50 (2009) 6906–6908
6907
8 was established by the spectral data and the single crystal X-ray
analysis14 (Fig. 2).
bond reductive cleavage and reduction of C@N bond in nitrone 9
(or a mixture of 8 and 9) by hydrogenation (H2/10% Pd/C in meth-
anol) followed by cleavage of 2,3-O-isopropylidene functionality
and desilylation with TFA–H2O (9:1), afforded 3 in good yield.
The spectral and analytical data18 were found to be in agreement
with structure 3 which was further confirmed by converting it into
known hydrochloride salt (MeOH–HCl). Thus, treatment of DIA 3
with MeOH–HCl gave hydrochloride salt 3a. The spectral and ana-
lytical data of 3a were found to be in consonance with those repor-
The 1H and 13C NMR data15 of nitrone 9 were found to be nearly
identical to those of 8 (slight difference in the d and J values), indi-
cating formation of five-membered nitrone 9 whose structure was
confirmed in subsequent steps by single crystal X-ray analysis
(vide supra). The formation of nitrone 9 probably involves in situ
generation of an epoxide by intramolecular SN2 displacement of
C5-mesyl group by C4-hydroxyl group. The intramolecular 5-exo-
tet epoxide ring opening by nucleophilic attack of the nitrogen
atom (from the side opposite to epoxide ring) afforded nitrone 9
as a major product, as expected on the basis of Baldwin rules,16
with inversion of configuration at C4 and C5 (Scheme 1). No trace
of six-membered nitrone derived from the less favored 6-endo-tet
ring closure mode was observed. Under reflux conditions, migra-
tion of the t-butyldimethylsilyl (TBS) group from primary (C6) to
secondary (C5) hydroxyl functionality occurred,17 affording nitrone
8 as a minor product.
ted5b {mp 110–112 °C, ½a 2D0
ꢀ
ꢁ26.0 (c 1.0, H2O), [lit5b mp 112–
113 °C, ½a 2D0
ꢁ24.6 (c 1.12, H2O)]}.
ꢀ
Targeting toward pyrrolidine iminosugar C-glycosides, we ex-
plored the 1,3-addition of allylmagnesium chloride to nitrone 9
(Scheme 2). This reaction in THF at 0–25 °C for 2.5 h afforded C1-
a
-allylated N-hydroxy pyrrolidine iminosugar 10a and its C1-epi-
mer 10b in the ratio 92:08, respectively, as evident from the 1H
NMR spectrum of crude product. Our attempts to separate the mix-
ture by column chromatography were unsuccessful. However,
The utility of nitrone 9 was first demonstrated in the synthesis
of the known pyrrolidine iminosugar DIA 3. Thus, one pot N–O
crystallization with hexane/ethyl acetate (9:1) gave pure a-allylat-
ed diastereomer 10a in 75% yield.19 The absolute configuration at
newly generated C1-stereocenter in 10a was firmly established
as 1R based on the single crystal X-ray analysis20 (Fig. 3) which also
confirms the structure of five-membered cyclic nitrone 9.21
In the next step, reaction of 10a with TFA–H2O (9:1) at 0–25 °C
for 6 h afforded N-hydroxylated pyrrolidine C-glycoside 4a in 88%
yield.22 Alternatively, 10a was subjected to N–O bond reductive
cleavage using Zn–acetic acid which on treatment with TFA–H2O
RO
O
OBz
a
TBSO
D-Mannose
H
O
O
5 R=H
6 R=Ms
b
(9:1) at 0–25 °C gave C1-
In conclusion, we have reported a new chiral cyclic nitrone 9
from -mannose in 34% overall yield and demonstrated its utility
a
-allylated pyrrolidine C-glycoside 4b.23
c
D
OH
OH
N
MsO
O
OH
N
5
in the synthesis of DIA 3. In addition, we have reported our preli-
minary results on the 1,3-addition of allylmagnesium chloride to
nitrone 9 which was found to be highly stereoselective. The result-
4
TBSO
d
TBSO
1
H
H
6
O
O
O
O
ing C1-a-allyl-substituted pyrrolidine is easily converted into C-
7
OH
N
HO
H
O
N
R1O
H
HO
H
b
TBSO
a
N
RO
HO
4a
9
e
H
O
O
O
O
OH
HO
3
10a
8 R = H, R1 = TBS
9 R = TBS, R1 = H
f
3a = 3.HCl
c
Scheme 1. Reagents and conditions: (a) Ref. 10; (b) MsCl, Et3N, DCM, 3 h, 98%; (c)
(i) K2CO3, MeOH, 25 °C, 0.5 h, 98%, (ii) hydroxylamine hydrochloride, NaHCO3,
MeOH–H2O, rt for 3 h, 90%; (d) hydroxylamine hydrochloride, NaHCO3, MeOH–H2O,
reflux for 12 h, 80% in the 2:8 ratio; (e) (i) H2, Pd/C, 12 h, (ii) TFA, H2O, (9:1), 0–25 °C,
6 h, 75%; (f) MeOH, HCl, 25 °C, 2 h. 98%.
4b
Scheme 2. Reagents and conditions: (a) allylmagnesium chloride, THF, 0–25 °C,
75%; (b) TFA–H2O, 9:1 ratio, 0–25 °C, 6 h, 80%; (c) (i) Zn, MeOH–acetic acid 20:1
ratio, reflux 3 h, (ii) TFA–H2O, 9:1 ratio, 0–25 °C, 6 h, 82%.
Figure 2. ORTEP diagram of compound 8.
Figure 3. ORTEP diagram of compound 10a.

6908
O. P. Bande et al. / Tetrahedron Letters 50 (2009) 6906–6908
1.38 (s, 3H), 1.56 (s, 3H), 3.11 (s, 3H), 3.91 (dd, J = 12.0, 4.2 Hz, 1H), 4.12 (dd,
J = 12.0, 1.8 Hz, 1H), 4.51 (dd, J = 7.5, 3.3 Hz, 1H), 4.82–4.89 (m, 2H), 4.94 (dd,
J = 6.0, 3.3 Hz, 1H), 6.39 (s, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.58 (t, J = 7.5 Hz, 2H),
7.98 (d, J = 8.7 Hz, 1H); 13C NMR (75 MHz, CDCl3): d ꢁ5.5, ꢁ5.3, 18.2, 25.0, 25.7
(s), 26.1, 38.6, 62.4, 78.9(s), 80.0, 84.8, 100.8, 113.3, 128.3(s), 129.1 (s), 133.4,
164.5. Anal. Calcd for C23H36NO9SSi: C, 53.47; H, 7.03. Found: C, 53.53; H, 7.23.
12. Selected data of major syn oxime 7: 1H NMR (300 MHz, CDCl3): d 0.04 (s, 3H),
0.06 (s, 3H), 0.81 (s, 9H), 1.27 (s, 3H), 1.44 (s, 3H), 3.01 (s, 3H), 3.71 (br d,
J = 6.9 Hz, 1H), 3.99 (dd, J = 12.3, 3.6 Hz, 1H), 4.08 (dd, J = 12.3, 2.4 Hz, 1H), 4.30
(br s, 1H, exchangeable with D2O), 4.38–4.48(m, 1H), 4.53 (d, J = 7.8 Hz, 1H),
5.18 (dd, J = 7.8, 3.9 Hz, 1H), 6.95 (d, J = 3.9 Hz, 1H), 9.25(br s, 1H, exchangeable
with D2O); 13C NMR (75 MHz, CDCl3): d ꢁ5.2, ꢁ5.0, 18.6, 24.4, 25.8, 26.2(s),
38.2, 63.0, 66.7, 721, 76.7, 82.3, 109.4, 151.6. Anal. Calcd for C16H33NO8SSi: C,
44.94; H, 7.78. Found: C, 44.63; H, 7.98. The 1H and 13C NMR spectrum showed
additional signals (ꢂ15%) corresponding to other isomer.
glycosided pyrrolidine iminosugars 4a and 4b. The present ap-
proach is general and is useful for the synthesis of a variety of
C1-alkyl, vinyl, and aryl glycosides of pyrrolidine iminosugars.
Acknowledgments
O.P.B. is thankful to CSIR, New Delhi, for a Senior Research Fel-
lowship. We gratefully acknowledge the Department of Science
and Technology (DST, New Delhi) for financial support (SR/S1/
OC-21/2005).
References and notes
13. Oxime 7 in the presence of hydroxylamine hydrochloride offered better results
in terms of yields and reproducibility. An analogous observation is reported,
see: Refs. 3 and 9d.
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14. Crystallographic data for compound 8 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication No. CCDC 742578.
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK. Fax: +44 1223 336033. E-mail:
deposit@ccdc.cam.ac.uk.
15. Spectral data for 8: white solid, mp 140–142 °C; ½a D25
ꢀ
+39.29 (c 0.24, CHCl3). IR
(Nujol): 3540–3200, 1728, 1217 cmꢁ1 1H NMR (300 MHz, CDCl3+D2O): d 0.02
;
(s, 3H), 0.06 (s, 3H), 0.81 (s, 9H), 1.33 (s, 3H), 1.40 (s, 3H), 3.67 (dd, J = 11.1,
6.9 Hz, 1H), 3.8 (dd, J = 11.1, 4.8 Hz, 1H), 4.20 (br s, 1H), 4.44 (dd, J = 6.9, 4.8 Hz,
1H), 4.98 (d, J = 6.3 Hz, 1H), 5.10 (d, J = 6.3 Hz, 1H), 6.87 (s, 1H); 13C NMR
(75 MHz, CDCl3+D2O): d ꢁ5.1, ꢁ4.8, 17.9, 25.3(s), 27.3, 64.1, 69.3, 74.7, 79.0,
81.9, 111.6, 133.2. Anal. Calcd for C15H29NO5Si: C, 54.35; H, 8.82. Found: C,
54.53; H, 8.98. Data for 9: white solid, mp = 145–147 °C; ½a D25
ꢀ
+12.5 (c 0.05,
CHCl3); IR (Nujol): 3450–3050, 1725, 1583 cmꢁ1
;
1H NMR (300 MHz,
CDCl3+D2O) d 0.10 (s, 6H), 0.91 (s, 9H), 1.35 (s, 3H), 1.44 (s, 3H), 3.5–3.8 (m,
2H), 4.13 (br s, 1H), 4.33 (dt, J = 6.0, 1.5 Hz, 1H), 4.70 (d, J = 6.3 Hz, 1H), 5.29 (d,
J = 6.3 Hz, 1H), 6.95 (s, 1H); 13C NMR (75 MHz, CDCl3+D2O) d ꢁ5.4, ꢁ5.3, 18.3,
25.6, 25.8 (s), 27.2, 64.2, 68.1, 75.0, 79.0, 81.3, 111.5, 133.2; Anal. Calcd for
C15H29NO5Si: C, 54.35; H, 8.82. Found: C, 54.54; H, 8.60.
3. Desvergnes, S.; Desvergnes, V.; Martin, O. R.; Itoh, K.; Liu, H. W.; Py, S. Bioorg.
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18. Data for 3: thick liquid, ½a D25
ꢀ
ꢁ63.4 (c 0.20, MeOH). IR (neat) 3650–3150 cmꢁ1
;
1H NMR (300 MHz, D2O): d 3.35 (dd, J = 12.9, 2.1 Hz, 1H), 3.46 (dd, J = 12.9,
3.6 Hz, 1H), 3.67 (dd, J = 8.1, 3.3 Hz, 1H), 3.72–3.79 (m, 2H); 1.3 (apperant q,
J = 5.4 Hz, 1H), 4.33–4.40 (m, 1H), 4.42 (dd, J = 8.1, 4.2 Hz, 1H); 13C NMR
(75 MHz, D2O): d 50.0, 61.8, 62.4, 68.6, 70.0, 70.3; Anal. Calcd for C6H13NO4: C,
44.16; H, 8.03. Found: C, 44.30; H, 8.25.
19. Data for compound 10a: white solid, mp 89–91 °C; ½a D25
ꢀ
+2.76 (c 0.11, CHCl3); IR
(neat) 3676–3250 cmꢁ1; 1215, 759; 1H NMR (300 MHz, CDCl3): d 0.05 (s, 6H),
0.09 (s, 9H), 1.25 (s, 3H), 1.50 (s, 3H), 2.30–2.45 (m, 1H), 2.46–2.62 (m, 1H),
2.94 (dd, J = 5.7, 2.7 Hz, 1H), 3.01 (apperent q, J = 6.9 Hz, 1H), 3.04–3.20 (1H,
exchangeable with D2O), 3.67 (dd, J = 10.4, 7.4 Hz, 1H), 3.73 (dd, J = 10.4,
4.8 Hz, 1H), 3.95–4.04 (m, 1H), 4.13 (t, J = 6.9 Hz, 1H), 4.53 (dd, J = 6.9, 5.7 Hz,
1H), 5.04–5.22 (m, 2H), 5.50–5.80 (1H, exchangeable with D2O), 5.80–6.00 (m,
1H); 13C NMR (75 MHz, CDCl3) d ꢁ5.25, ꢁ5.20, 18.3, 25.2, 25.9 (s), 27.2, 35.9,
64.5, 69.2, 72.3, 74.0, 74.8, 79.5, 113.3, 117.1, 134.4; Anal. Calcd for
C18H35NO5Si: C, 57.87; H, 9.44. Found: C, 57.71; H, 9.29.
20. Crystallographic data for compound 10a have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication No.
CCDC 742579. Copies of the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Fax: +44 1223 336033. E-
mail: deposit@ccdc.cam.ac.uk.
21. The observed diastereoselectivity was found to be analogous to earlier report
in which addition of vinylmagnesium chloride to five-membered cyclic nitrone
afforded major product from the face opposite to the 2-O-Bn group, see: Ref.
2a.
22. Data for 4a: thick liquid, ½a D25
ꢀ
+1.7 (c 0.11, MeOH). IR (neat) 3600–3250 cmꢁ1
;
1H NMR (300 MHz, D2O): d 2.38ꢁ2.54 (m, 2H), 2.88 (t, J = 4.2 Hz, 1H), 2.97 (dt,
J = 6.0, 5.7 Hz, 1H), 3.60–3.72(m, 2H), 3.75 (dd, J = 11.7, 3.9 Hz, 1H), 3.93 (quin,
J = 3.9 Hz, 1H), 4.03 (t, J = 5.7 Hz, 1H), 5.04–5.28 (m, 2H); 5.86–6.06 (m, 1H);
13C NMR (75 MHz, D2O): d 34.9, 63.4, 67.7, 70.4, 70.9, 71.0, 75.2, 117.2, 135.0;
Anal. Calcd for C9H17NO5: C, 49.31; H, 7.82. Found: C, 49.59; H, 7.65.
23. Data for 4b: thick liquid, ½a D25
ꢀ
+13.0 (c 0.13, MeOH). IR (Neat) 3770–3050 cmꢁ1
;
1H NMR (300 MHz, D2O): d 2.40ꢁ2.59 (m, 1H), 2.60–2.75 (m, 1H), 3.67 (dt,
J = 9.0, 6.0 Hz, 1H), 3.72–3.79 (m, 3H), 4.05–4.12 (m, 2H), 4.45 (t, J = 5.14 Hz,
1H), 5.25–5.38 (m, 2H), 5.78–5.95 (m, 1H); 13C NMR (75 MHz, D2O): d 33.6,
61.9, 62.7, 64.9, 68.2, 68.9, 73.4, 120.0, 132.0; Anal. Calcd for C9H17NO4: C,
53.19; H, 8.43. Found: C, 53.40; H, 8.31.
10. Francisco, C. G.; Freire, R.; Gonzalez, C. C.; Leon, E.; Riesco-Fagundo, C.; Suarez,
E. J. Org. Chem. 2001, 66, 1861.
11. Spectral data for 6: thick liquid; ½a D25
ꢀ
+48.92 (c 0.32, CHCl3). IR (Nujol): 1728,
1217 cmꢁ1 1H NMR (300 MHz, CDCl3): d 0.01 (s, 3H), 0.06 (s, 3H), 0.80 (s, 9H),
;