A practical synthesis of sugar-derived cyclic nitrones: Powerful synthons for the synthesis of iminosugars

Article abstract of DOI:10.1055/s-0029-1219189

Sugar-derived cyclic nitrones were synthesized from the corresponding aldoses through an efficient and practical procedure involving a seven-step reaction sequence in good to excellent overall yield (10-42%). This synthetic strategy, requiring only inexpe

Full text of DOI:10.1055/s-0029-1219189

488
LETTER
A Practical Synthesis of Sugar-Derived Cyclic Nitrones: Powerful Synthons
for the Synthesis of Iminosugars
Sugar-DerivedCyclic
N
u
itrone
s
-Bao Wang,a,b Mu-Hua Huang,a Yi-Xian Li,a,b Pei-Xin Rui,a Xiang-Guo Hu,a,b Wei Zhang,a,b Jia-Kun Su,a,b Zhao-
Lan Zhang,a,b Jian-She Zhu,a,b Wei-Hua Xu,a Xian-Qing Xie,a Yue-Mei Jia,*a Chu-Yi Yu*a
a
Beijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute
of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. of China
Fax +86(10)82616433; E-mail: yucy@iccas.ac.cn
Graduate University of The Chinese Academy of Sciences, Beijing 100049, P. R. of China
b
Received 28 October 2009
Methods for the synthesis of cyclic nitrones13 include ox-
Abstract: Sugar-derived cyclic nitrones were synthesized from the
idation of hydroxylamines,14 amines15 and imines,16 con-
corresponding aldoses through an efficient and practical procedure
densation of ketones with hydroxylamines,17 and N-
involving a seven-step reaction sequence in good to excellent over-
alkylation of oximes.18 Among the existing methods, N-
all yield (10–42%). This synthetic strategy, requiring only inexpen-
sive reagents, is easy to perform and hence suitable for large-scale alkylation of oximes is the most widely used strategy for
preparations.
the formation of the nitrone functionality due to the rela-
tive ease with which the regio- and stereoselectivity in-
volved in the transformation can be controlled. A number
of methods have been developed for the synthesis of sug-
ar-derived cyclic nitrones18,19 from the readily available
sugar hemi-acetals. In these approaches the key steps in-
clude addition of O-silylated hydroxylamine or
H2NOTHP to the hemi-acetal to form the O-protected
oxime, followed by mesylation of the exposed OH, and
then intramolecular N-alkylation of the oxime. The draw-
backs associated with these procedures are that large
amounts of side-products are commonly formed from the
reaction and tedious work-up procedures are required;
hence, these procedures are not suitable for large-scale
preparations. In our earlier work we have tried to improve
the synthetic procedure12b by using the Wittig reaction to
open the cyclic sugar hemi-acetal ring; this was relatively
easy to work-up but was still not suitable for large-scale
preparations due to critical reaction conditions. Goti’s
one-pot procedure18d using NH2OH instead of NH2–
OSiR3 provided a shortened synthetic route, but its overall
yield was poor. Herein, we report an improved procedure
for the synthesis of cyclic nitrones from sugar hemi-ace-
tals that is based on our previous method. The key im-
provement was the use of NH2OMe instead of the Wittig
reagent to open the hemi-acetal ring.
Key words: sugar-derived cyclic nitrones, synthesis, iminosugars,
nitrones
Iminosugars,1 the ‘nitrogen-in-the-ring’ analogues of pyr-
anoses and furanoses, have attracted considerable atten-
tion from synthetic organic chemists due to their
remarkable biological activities.2 A number of iminosug-
ars, both synthetic and naturally occurring, have been
shown to be selective and potent inhibitors of glycosidas-
es, glycosyltransferases or other carbohydrate processing
enzymes.3 Furthermore, an increasing number of imino-
sugar family members have exhibited great potential as
pharmaceuticals.1a,2c Although great effort has been ex-
pended and numerous synthetic procedures have been de-
veloped for the synthesis of iminosugars,4 efficient
methods for the rapid generation of iminosugars with the
structural diversity necessary for in-depth structure–activ-
ity studies are still lacking. Among the existing approach-
es, synthetic methods based on sugar-derived cyclic
nitrones have emerged as a potentially powerful strategy
for the diversity-oriented synthesis of iminosugars due to
the reactivity of the nitrone functionality.
Nitrones have been shown to be very diverse synthetic in-
termediates for the construction of structurally complex
molecules5,6 because they are capable of undergoing a va-
riety of synthetically useful reactions, such as: 1,3-dipolar
cycloadditions,7 nucleophilic additions,8,9 and pinacol-
type coupling reactions, etc.10 Enantiomerically pure
polyfunctional cyclic nitrones, which have been widely
used in the synthesis of various natural and biologically
active nitrogen-containing compounds,6,9,11,12 are espe-
cially valuable in organic synthesis. Therefore, the search
for efficient and practical synthetic approaches toward cy-
clic nitrones is of ongoing interest.
The synthesis of five-membered cyclic nitrones was first
investigated (Scheme 1). Sugar hemi-acetals 2,3,5-tri-O-
benzylfuranoses 1 were prepared through the reported
method from the corresponding aldoses in three steps.20a
Compound 1 was treated with O-methylhydroxylamine
hydrochloride in the presence of pyridine to form O-meth-
yl oxime ether 2. The exposed hydroxy group was then
mesylated to produce the oxime ether 3. Hydrolysis of 3
by using an aqueous solution of formaldehyde (37%) in
THF, catalyzed by TsOH, afforded aldehyde 4. Treatment
of 4 with hydroxylamine hydrochloride resulted in the for-
mation of the desired nitrone 5 (Scheme 1, Table 1). It is
remarkable that this seven-step synthesis was virtually all
conducted as a one-pot synthesis where only basic work-
SYNLETT 2010, No. 3, pp 0488–0492
1
2.
0
2.
2
0
1
0
Advanced online publication: 11.01.2010
DOI: 10.1055/s-0029-1219189; Art ID: W17209ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Sugar-Derived Cyclic Nitrones
489
up was required between each step of the reaction se- 7, 8, and 9 were used directly in the subsequent reaction
quence, i.e. the crude intermediates 1, 2, 3, and 4 were without further purification. While the overall yields were
used directly in the next step of reaction without further generally good to excellent, there was one exception in the
purification. Only the final products, nitrones 5, were sub- case of the synthesis of 10c, where the overall yield was
jected to further purification by column chromatography only 10% over the seven steps, based on D-ribose
(5a and 5b) or recrystallization (5c and 5d). The synthesis (Table 1, entry 7).
was carried out on a multi-gram scale, producing up to
100 g of nitrones in good to excellent overall yields (23–
OH
O
OH
O
OH
NOMe
OBn
OH
35% in seven steps based on the aldoses, or 36–40% in
i
ii
ref.
BnO
four steps based on the sugar hemi-acetals 1; Table 1).21
OBn
BnO
OH
HO
OBn
OBn
HO
BnO
BnO
aldose
OH
6
O
O
7
OH
OH
–O
N+
NOMe
ref.
i
ii
OMs
OMs
O
NOMe
OBn
iv
iii
OH
OBn
HO
BnO
BnO
OBn
2
aldose
1
BnO
OBn
BnO
BnO
OBn
O–
N
OBn
OBn
OBn
10
BnO
BnO
OMs
BnO
OMs
9
8
NOMe
O
iv
6a 2,3,4-tri-O-benzyl-D-arabinopyranose
6b 2,3,4-tri-O-benzyl-L-arabinopyranose
6c 2,3,4-tri-O-benzyl-D-ribopyranose
6d 2,3,4-tri-O-benzyl-D-xylopyranose
iii
BnO
OBn
BnO
OBn
BnO
OBn
4
5
3
1a 2,3,5-tri-O-benzyl-D-arabinofuranose
1b 2,3,5-tri-O-benzyl-L-arabinofuranose
1c 2,3,5-tri-O-benzyl-D-ribofuranose
1d 2,3,5-tri-O-benzyl-D-xylofuranose
Scheme 2 Reagents and conditions: (i) for 7a, 7b, and 7c:
H2NOMe·HCl, pyridine, CH2Cl2, r.t.; for 7d: H2NOMe·HCl, NaCO3,
EtOH–H2O, reflux; (ii) MsCl, Et3N, CH2Cl2, 0 °C; (iii) TsOH, aq
HCHO (37%), THF, r.t.; (iv) NH2OH·HCl, NaHCO3, EtOH–H2O
(4:1), r.t., 24 h, then 40 °C.
Scheme 1 Reagents and conditions: (i) pyridine, NH2OMe·HCl; (ii)
Et3N, MsCl CH2Cl2; (iii) p-TsOH, aq HCHO (37%), THF; (iv)
NH2OH·HCl, NaHCO3, H2O, MeOH, r.t. to 60 °C.
The relatively poor overall yield of 10c resulted from the
poor yield of the final cyclization step; in this case the in-
termediate oxime 11c (Figure 1) could also be isolated.
Attempts to improve the yield of 10c by optimizing the re-
agents and reaction conditions, unfortunately failed. It is
worth mentioning that hemi-acetal 6d, which was derived
from D-xylose, reacted poorly with MeONH2·HCl in the
presence of pyridine in CH2Cl2 at room temperature.
However, when the reaction was conducted at reflux in
EtOH–H2O, in the presence of Na2CO3, the desired oxime
ether 7d was obtained in 92% yields.
The procedure was then successfully extended to the syn-
thesis of six-membered cyclic nitrones (Scheme 2). Sugar
hemi-acetals 2,3,4-tri-O-benzyl-pyranose 6 were pre-
pared through the reported method from the correspond-
ing aldoses in three steps.20b Cyclic nitrones 10 were
prepared following the procedure described above in good
to excellent overall yields (10–42% in seven steps based
on the aldoses, or 14–54% in four steps based on the sugar
hemi-acetals 6; Table 1). The synthesis of 10 was found to
be as robust as the synthesis of 5 in that it was performed
on multi-gram scale and that all the crude intermediates 6,
Table 1 Synthesis of Sugar-Derived Cyclic Nitrones
Entry
1
Starting material
D-arabinose
Cyclic nitronea
Yield (%)b
–
HO
O
BnO
O
OH
23
N
5a
(38)c
+
OH
HO
BnO
BnO
OBn
OBn
–
O
N+
HO
O
32
OH
2
3
L-arabinose
D-ribose
5b
5c
(38)c
HO
OH
BnO
–
HO
O
BnO
O
30
N+
OH
(36)c
HO
OH
OBn
BnO
Synlett 2010, No. 3, 488–492 © Thieme Stuttgart · New York

490
W.-B. Wang et al.
LETTER
Table 1 Synthesis of Sugar-Derived Cyclic Nitrones (continued)
Entry
4
Starting material
D-xylose
Cyclic nitronea
Yield (%)b
–
HO
HO
O
BnO
O
O
N+
35
OH
5d
(40)c
HO
OH
BnO
OBn
–
O
N+
42
OH
5
6
7
8
D-arabinose
L-arabinose
D-ribose
10a
10b
10c
10d
(52)c
BnO
BnO
BnO
OBn
HO
OH
OBn
–
O
HO
HO
HO
N+
O
O
O
35
OH
(43)c
OBn
OBn
HO
HO
HO
OH
OBn
–
O
N+
10
OH
(14)c
OH
OBn
–
O
N+
34
OH
D-xylose
(54)c
BnO
OBn
OH
OBn
a Compounds 10a, 10b, and 10c are novel compounds.
b Method A: Isolated overall yields in seven steps based on the corresponding aldoses.
c Method B: Overall four-step yield based on the corresponding sugar hemi-acetals 1 or 6 are shown in brackets.
Acknowledgment
OH
N
MsO
BnO
This work was supported by The National Natural Science Founda-
tion of China (No. 20672117), The National Basic Research Pro-
gram of China (No. 2009CB526511), The Ministry of Science and
Technology and the Ministry of Health of the P. R. of China (No.
2009ZX09501-006), and The Chinese Academy of Sciences.
OBn
OBn
11c
Figure 1 Structure of compound 11c
References and Notes
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quence. The merits of this new procedure are that it is: (a)
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Method A: Compounds 1 and 6 were prepared from the
corresponding aldoses (90 g 0.6 mol) in three steps
according to the literature20 and were used directly in the
next step without further purification. NH2OMe·HCl (55.12
g, 0.66 mol, 1.1 equiv) and Et3N (91.9 mL, 0.66 mol, 1.1
equiv) were added to a solution of crude compound 1 or 6
(crude product prepared from 0.6 mol aldose) in anhydrous
CH2Cl2 (300 mL). The reaction reached completion after
vigorous stirring for about 12 h. The reaction mixture was
then concentrated in vacuo and the resulting mixture was
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and the aqueous phase was extracted with EtOAc (3 × 150
mL). The combined organic phases were dried with
anhydrous Na2SO4 and filtered, the filtrate was concentrated
in vacuo to give the crude product 2 or 7, which was used
directly in the next step of reaction without further
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purification. To an ice-cooled solution of 2 or 7 in Et3N (91.9
mL, 0.66 mol, 1.1 equiv) and CH2Cl2 (300 mL), was added
methanesulfonyl chloride (51.08 mL, 0.66 mol, 1.1 equiv)
slowly, and the mixture was allowed to warm gradually to
r.t. After 1 h, the reaction mixture was quenched by addition
of H2O (200 mL). The organic phase was separated and the
aqueous phase was extracted with EtOAc (3 × 150 mL). The
combined organic phases were dried over anhydrous
MgSO4. After filtration, the solvent was removed in vacuo to
give crude product 3 or 8 as a yellow oil, which was used
directly in the next step without further purification. To a
well-stirred solution of 3 or 8 in THF (400 mL), p-TsOH
(114 g, 0.6 mol) and aq HCHO (37%, 150 mL) were added
subsequently. After stirring for 36 h, the reaction was
neutralized with sat. aq NaHCO3. EtOAc (600 mL) was
added to the reaction mixture, the organic phase was
separated and the aqueous phase was extracted with EtOAc
(3 × 150 mL). The combined organic phases were dried with
anhydrous Na2SO4. After filtration, the filtrate was
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concentrated in vacuo, the resulting crude product 4 or 9 was
used directly in the next step of reaction without further
purification. A solution of NH2OH·HCl (93.15 g, 1.35 mol)
and NaHCO3 (113.4 g, 1.35 mol) in H2O (150 mL) was
added to the solution of crude 4 or 9 in EtOH (600 mL)
dropwise. The reaction mixture was stirred at r.t. for 12 h
and then stirred at about 60 °C until TLC showed the
reaction to have reached completion. The solvents were
removed in vacuo and the residue was dissolved in EtOAc
Synlett 2010, No. 3, 488–492 © Thieme Stuttgart · New York

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W.-B. Wang et al.
LETTER
(dd, J = 10.1, 1.6 Hz, 1 H, H-6). 13C NMR (75 MHz,
CDCl3): d = 138.0, 137.4, 137.3, 133.4 (C-2), 128.7, 128.6,
128.4, 128.2, 128.1, 128.0, 127.9, 127.6 (Ph), 83.2 (C-3),
80.6 (C-4), 74.2 (C-5), 73.6, 73.2, 72.5, 64.5 (C-6).
Compound 10a: 88.2 g (42% from 75 g D-arabinose); 94 g
from 181.6 g 6a (52%). Light-yellow oil; [a]D20 –44 (c 1.17,
CHCl3). IR (thin film): 2960 (s), 2925 (s), 2855 (s), 1597
(w), 1454 (m), 1260 (s), 1023 (s), 800 (s), 739 (m), 698 (m)
cm–1. 1H NMR (300 MHz, CDCl3): d = 7.33–7.25 (m, 15 H,
Ph), 7.01 (d, J = 2.9 Hz, 1 H, H-2), 4.94–4.58 (m, 6 H,
PhCH2), 4.31 (d, J = 3.6 Hz, 1 H, H-3), 4.06–3.82 (m, 4 H,
H-6, H-4, H-5). 13C NMR (75 MHz, CDCl3): d = 137.6,
137.3, 128.6, 133.4 (C-2), 128.6, 128.5, 128.2, 128.1, 128.0,
127.9, 127.8 (Ph), 74.6, 73.5, 72.9, 72.8, 72.1, 71.4 (C-3, C-
4, C-5), 60.0 (C-6). TOF-HRMS (ESI+): m/z [M + H]+ calcd
for C26H28NO4: 418.2013; found: 418.2001.
(300 mL) and H2O (200 mL). The organic phase was
separated and the aqueous phase was extracted with EtOAc
(3 × 150 mL). The combined organic phases were dried with
anhydrous Na2SO4. After filtration and concentration in
vacuo, the resulting crude product was either recrystallized
or purified by flash column chromatography (petroleum
ether–EtOAc, 2:1→1:2). Method B: The same procedure as
method A was used with purified compounds 1 and 6 as
starting material. Compound 5a: 129.0 g (23% from 200 g
D-arabinose); 79.4 g from 210.3 g 1a (38%). Yellow oil;
[a]D20 –78 (c 1.08, CH2Cl2) {Lit18d [a]D23 –75.9 (c 0.54,
CH2Cl2)}. IR (thin film): 3030 (w), 2866 (m), 1582 (s), 1496
(w), 1454 (s), 1363 (m), 1095 (s), 737 (s), 697 (s) cm–1. 1H
NMR (300 MHz, CDCl3): d = 7.27–7.14 (m, 15 H, Ph), 6.73
(s, 1 H, H-2), 4.67 (t, J = 2.1 Hz, 1 H, H-3), 4.58–4.38 (m,
6 H, PhCH2), 4.28 (dd, J = 7.6, 4.5 Hz, 1 H, H-4), 4.08–4.03
(m, 1 H, H-5), 3.90 (dd, J = 10.1, 4.3 Hz, 1 H, H-6), 3.73
Synlett 2010, No. 3, 488–492 © Thieme Stuttgart · New York

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