A rapid synthesis of 2-Aryl polyhydroxylated pyrrolidines

Article abstract of DOI:10.1055/s-0029-1258085

Friedel-Crafts-type reaction of electron-rich aromatic compounds with polyhydroxylated cyclic nitrones catalyzed by Brnsted acid afforded 2-aryl polyhydroxylated pyrrolidines in good to excellent yields with high diastereoselectivity under mild conditions.

Full text of DOI:10.1055/s-0029-1258085

LETTER
1609
A Rapid Synthesis of 2-Aryl Polyhydroxylated Pyrrolidines
Synthesis
i
of 2-A
r
a
yl Polyhyd
-
roxylate
K
d
Pyrrolidines un Su,a,b Yue-Mei Jia,a Ruirui He,c Pei-Xin Rui,a Nanyin Han,c Xihui He,c Junfeng Xiang,a Xin Chen,c
Jinghua Zhu,c 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 Chinese Academy of Sciences, Beijing 100049, P. R. of China
b
c
School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. of China
Received 7 April 2010
Though many elegant synthetic procedures have already
been developed for the synthesis of 2-aryl iminosugars,
there still lacks of efficient methods for the rapid genera-
tion of 2-aryl iminosugars with structural diversities
which is essential for in-depth structure–activity study. In
this context, we decided to examine the direct arylation of
polyhydroxylated cyclic nitrones via the Friedel–Crafts-
type reactions which, we envisage, might provide an effi-
cient method for the synthesis of compound libraries of
2-aryl iminosugars, because polyhydroxylated cyclic ni-
trones have recently emerged as potentially powerful syn-
thons for iminosugars synthesis.5
Abstract: Friedel–Crafts-type reaction of electron-rich aromatic
compounds with polyhydroxylated cyclic nitrones catalyzed by
Brønsted acid afforded 2-aryl polyhydroxylated pyrrolidines in
good to excellent yields with high diastereoselectivity under mild
conditions.
Key words: 2-aryl polyhydroxylated pyrrolidines, iminosugars,
Brønsted acid, polyhydroxylated cyclic nitrones, Friedel–Crafts
reaction
Iminosugars (polyhydroxylated alkaloids) have attracted
considerable attention for their remarkable biological ac-
tivities and potential as pharmaceuticals.1 Polyhydroxy-
lated pyrrolidines carrying an aromatic substituent on the
iminosugar ring, that is, 2-aryl polyhydroxylated pyrro-
lidines, are a rare class of alkaloids found in nature
(Figure 1).2 Due to their intriguing molecular structures
and important biological activities, many efforts have
been made in developing synthetic methods for these al-
kaloids.3
O–
N+
O–
N+
O–
N+
BnO
BnO
OBn
BnO
OBn
BnO
OBn
6
7
8
Figure 2 Polyhydroxylated cyclic nitrones
The synthesis and biological evaluation of 2-aryl polyhy-
droxylated pyrrolidines have hence become an area of in-
terest, and a number of derivatives had been synthesized
for the purpose of searching for new biologically active
molecules.4
While the greatest interest associated with nitrones has
been focused on the study of 1,3-dipolar cycloaddition re-
actions,6 numerous reactions with nucleophiles7 also mer-
it attention. Apart from organometallics, electron-rich
aromatic compounds could also be used in the reactions
with nitrones. The Friedel–Crafts alkylation of nitrones
was first reported by Banerji in 1982,8 and further ex-
plored by Vallée and others.9 In view of their exquisite
and special chemical reactivity and stereochemistry in
comparison with those of other usual nitrones, an explor-
atory study on the Friedel–Crafts reaction of polyhydrox-
ylated cyclic nitrones with electron-rich aromatic
compounds would be of significance for developing a new
synthetic method of 2-aryl iminosugars, as well as for a
better understanding of the nitrone chemistry.
R4
OR2
N
R1
R3
HO
OH
(–)-codonopsinine (1) R1 = Me, R2 = R4 = Me, R3 = H
(–)-codonopsine (2) R1 = Me, R2 = R4 = Me, R3 = OMe
radicamine A (3) R1 = CH2OH, R2 = Me, R3 = OH, R4 = H.
radicamine B (4) R1 = CH2OH, R2 = R3 = R4 = H
OMe
Me
N
O-Benzyl-protected polyhydroxylated cyclic nitrones 6–
8, which were prepared following the reported procedures
(Figure 2),10 were chosen for the investigation. In our ini-
tial study, indole 9a was employed in the model reaction
with cyclic nitrones, not only because it is fairly electron
rich, but also because the indole nucleus has been found
in myriad alkaloids and biologically active heterocycles.11
Thus, the reaction of indole with nitrone 6 was performed
in methanol at ambient temperature in the presence of
HO
OMe
HO
OH
codonopsinol (5)
Figure 1 Examples of 2-aryl polyhydroxylated pyrrolidines
SYNLETT 2010, No. 11, pp 1609–1616
x
x
.x
x
.2
0
1
0
Advanced online publication: 11.06.2010
DOI: 10.1055/s-0029-1258085; Art ID: W05310ST
© Georg Thieme Verlag Stuttgart · New York

1610
J.-K. Su et al.
LETTER
HCl, which was generated by addition of acetyl chloride or dr = 80:20, determined by 1H NMR of crude mixture of
to methanol (10% v/v) at 0 °C. As anticipated, the desired products) in 4 hours.
2-(1H-indol-3-yl)-pyrrolidine 10 was formed in good
yield (84%) and moderate diastereoselectivity (trans/cis
Table 1 Reaction of Electron-Rich Aromatics with Cyclic Nitrones
O–
N+
OH
N
R
R
Ar
AcCl, MeOH, 0 °C to r.t.
+
ArH
BnO
OBn
BnO
OBn
6
R = BnOCH2
9a–k
10–27
7, 8 R = H
Entry
Nitrone
ArH
Time (h)
Major product
Yield (%)a
(drb)
OH
NH
H
N
N
96
(98:2)
1
6
4
BnO
BnO
OBn
9a
10
OH
H
N
NH
N
97
(95:5)
2
3
7
8
4
4
BnO
OBn
OBn
9a
11
OH
N
H
N
NH
93
(95:5)
BnO
9a
12
H
N
H
N
OH
N
93
(99:1)
4
5
6
6
4
4
BnO
OMe
MeO
BnO
BnO
OBn
9b
9c
13
H
NH
OH
N
N
93
(95:5)
BnO
OBn
OMe
OMe
14
OH
N
NH
NH
95
(98:2)
6
7
6
6
4
4
BnO
OMe
OBn
OBn
BnO
BnO
OMe
OMe
15
9d
9e
OH
N
NH
NH
OMe
95
(97:3)
BnO
16
H
H
N
OH
N
N
91
(92:8)
8
6
8
BnO
F
F
BnO
OBn
9f
17
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LETTER
Synthesis of 2-Aryl Polyhydroxylated Pyrrolidines
1611
Table 1 Reaction of Electron-Rich Aromatics with Cyclic Nitrones (continued)
O–
N+
OH
N
R
R
Ar
AcCl, MeOH, 0 °C to r.t.
+
ArH
BnO
OBn
BnO
OBn
6
R = BnOCH2
9a–k
10–27
7, 8 R = H
Entry
Nitrone
ArH
Time (h)
Major product
Yield (%)a
(drb)
H
N
H
N
OH
N
81
(92:8)
9
6
72
BnO
NO2
NO2
BnO
18
OBn
9g
OH
HN
HN
N
91
(87:13)
10
11
12
13
14
15
6
7
8
6
6
7
8
12
12
168
8
BnO
9h
BnO
19a
OBn
OH
HN
HN
N
88c
(73:27)
9h
BnO
OBn
20a–b
OH
HN
HN
N
89c
(73:27)
9h
BnO
OBn
21a–b
OH
N
S
S
73d
(57:43)
BnO
9i
BnO
OBn
22a
OH
N
OH
OH
93
(99:1)
BnO
HO
OBn
OH
BnO
9j
9j
23
OH
N
OH
OH
84
(93:7)
12
HO
OBn
OH
BnO
24
HO
OH
OH
N
OH
84e
16
6
12
BnO
(99:1)
HO
OBn
HO
OH
BnO
9k
25
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1612
J.-K. Su et al.
LETTER
Table 1 Reaction of Electron-Rich Aromatics with Cyclic Nitrones (continued)
O–
N+
OH
N
R
R
Ar
AcCl, MeOH, 0 °C to r.t.
+
ArH
BnO
OBn
BnO
OBn
6
R = BnOCH2
9a–k
10–27
7, 8 R = H
Entry
17
Nitrone
ArH
Time (h)
Major product
Yield (%)a
(drb)
HO
OH
OH
HCl
OH
88e
(99:1)
N
7
12
HO
OBn
HO
OH
OH
BnO
9k
26
HO
OH
OH
N
OH
81e
18
8
12
(99:1)
HO
OBn
HO
BnO
9k
27
a Isolated overall yield.
b Determined by 1H NMR.
c Inseparable mixture.
d Reaction conditions: AcCl (2 equiv), MeOH (5mL), 0 °C to r.t.
e In diluted solvent, 0 °C.
When the reaction was conducted in the presence of the selectivity (>92:8; Table 1, entries 1–9), although 5-
reduced amount of HCl, that is, addition of AcCl (0.5% fluoro-indole 9f and 5-nitro-indole 9g, with electron-with-
v/v) to the reaction solution, while maintaining the reac- drawing groups, required longer reaction time for full
tion temperature first at 0 °C then slowly warmed to room conversion (Table 1, entry 8 and 9). However, despite
temperature in an argon atmosphere, the reaction afforded moderate to high reaction yields, both pyrrole and
the trans isomer of the hydroxylamine 10 in 96% isolated thiophene displayed moderate diastereoselectivity
yield with high diastereoselectivity (dr = 98:2; Table 1, (Table 1, entries 10 or 13; dr 87:13 for pyrrole, 57:43 for
entry 1).
thiophene, determined by 1H NMR).
The scope and limitation of this reaction were then exam-
ined. It was found that a variety of electron-rich aromatics
underwent this Friedel–Crafts-type reaction smoothly,
producing the desired products in good to excellent yields
with high diastereoselectivity (Table 1). Various indole
derivatives 9b–g worked well and exhibited high diastereo-
Figure 4 X-ray structure of 26, partial H atoms bonded to C atoms
have been omitted for clarity
Figure 3 X-ray structure of 19b
Synlett 2010, No. 11, 1609–1616 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Aryl Polyhydroxylated Pyrrolidines
1613
Attempts to apply this method in the synthesis of natural were achieved in the reactions of indole 9a or resorcinol
products codonopsinol (3) and radicamines A (4) failed 9j with 7 or 8 (Table 1, entries 2, 3, 15). Once again, the
due to the relatively poor nucleophilicity of the 1,2- reaction of pyrrole 9h with either 7 or 8 resulted in good
dimethoxybenzene and guaiacol. However, both resorci- yields but poor diastereoselectivity (Table 1, entries 11
nol (9j) and phloroglucinol (9k) were good substrates for and 12: dr = 73:27, determined by 1H NMR).
the reaction, resulting in the corresponding hydroxyl-
amines 23 and 25 in excellent yield and with high dia-
stereoselectivity (Table 1, entry 14 and 16). All the
Catalytic hydrogenation of some of the O-benzyl cyclic
hydroxyamines 10–27 afforded the deprotected 2-aryl
pyrrolidines 28–39. The use of the Pd/C–AcOH system
for the debenzylation resulted in efficient benzyl group
hydrogenolysis while avoided reduction of the aromatic
heterocycles at the same time (Table 2, entries 1–6, 8). As
was expected, the hydrogenation of the relatively more
complicated substrate, 5-nitroindole derivate 18, resulted
structures of the products 10–27 were determined by
NMR (1H NMR, 13C NMR, and NOE measurements), IR,
MS, and the structures of the hydroxylamines 19b
(Table 1, the minor isomer of entry 10) and 26 were fur-
ther confirmed by X-ray crystal structures. (Figure 3,
Figure 4).12
in a complex mixture of products (Table 2, entry 7).
Reactivities of the cyclic nitrones 7 and 8 were found to
be similar to that of cyclic nitrone 6. For example, good to
excellent yields and high diastereoselectivity (dr >93:7)
Table 2 Debenzylation of N-Hydroxypyrrolidines
OH
H
N
N
R
Ar
R
Ar
Pd/C, H2
BnO
OBn
HO
OH
28–39
R = H, BnOCH2
R = H, HOCH2
Entry
1
Reactant
Product
Isolated yield (%)
H
N
OH
N
NH
HO
H
N
85a
BnO
BnO
OBn
HO
OH
OH
10
28
H
N
H
N
OH
N
HO
H
N
2
80a
BnO
OMe
OMe
NH
BnO
OBn
OBn
HO
13
29
H
OH
N
N
HO
H
N
3
4
5
82a
79a
81a
BnO
BnO
OMe
OMe
HO
OH
OH
14
30
OH
N
NH
HO
NH
H
N
BnO
OMe
OMe
OBn
OBn
HO
BnO
31
15
H
OH
N
N
OMe
NH
HO
H
N
OMe
BnO
BnO
HO
OH
16
32
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1614
J.-K. Su et al.
LETTER
Table 2 Debenzylation of N-Hydroxypyrrolidines (continued)
OH
N
H
N
R
Ar
R
Ar
Pd/C, H2
BnO
OBn
HO
OH
28–39
R = H, BnOCH2
R = H, HOCH2
Entry
6
Reactant
Product
Isolated yield (%)
H
N
H
N
OH
N
HO
H
N
79a
BnO
F
F
BnO
OBn
OBn
HO
OH
17
33
H
N
OH
N
7
–
0a
BnO
NO2
BnO
19a
OH
N
HO
HN
HN
H
N
8
9
77a
BnO
HO
OH
BnO
OBn
OBn
34
19a
OH
HCl
OH
N
HO
OH
H
N
95b
BnO
OH
OH
BnO
HO
OH
23
35
OH
HCl
OH
N
OH
H
N
10
11
12
13
96b
92b
97b
93b
OH
OH
HO
BnO
OBn
HO
OH
24
36
HO
OH
HCl
OH
N
HO
OH
H
N
BnO
OH
OH
HO
OH
BnO
OBn
25
37
HO
HO
OH
OH
HCl
HCl
OH
H
N
N
OH
OH
HO
BnO
OBn
HO
OH
38
26
HO
OH
OH
N
HCl
OH
H
N
OH
OH
HO
OH
BnO
OBn
27
39
a Reagents and conditions: Pd/C 20%, AcOH, 35 °C.
b Reagents and conditions: Pd/C 10%, MeOH, r.t.
Synlett 2010, No. 11, 1609–1616 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Aryl Polyhydroxylated Pyrrolidines
1615
Kodzhimatov, O. K.; Ashurmetov, O. J. Nat. Med. 2008, 62,
236.
Finally, it is worth mentioning that treatment of highly ac-
tive phloroglucinol 9k with nitrones 6–8 in diluted reac-
tion solution at 0 °C afforded [1+1] adducts as major
products (dr = 99:1, Table 1, entries 16–18). Treatment of
1 equivalent of phloroglucinol 9k with 2 equivalents of ni-
trone resulted in the formation of [1+2] adducts, that is,
the 2,4-disubstituted phloroglucinols 40 and 41 as the ma-
jor products, with only a trace amount of the correspond-
ing [1+3] adducts being detected (Scheme 1).
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HO
OH
O–
N+
OH
HO
BnO
1) 9k (1 equiv),
AcCl, MeOH,
83–87%
H
N
H
N
2) Pd/C, H2,
93–94%
OH
HO
OH
BnO
OBn
HO
OH
(2 equiv)
40
6
HO
OH
O–
N+
1) 9k (1 equiv),
AcCl, MeOH,
83–87%
H
H
N
N
2) Pd/C, H2,
93–94%
OH
HO
OH
BnO
OBn
HO
OH
41
(2 equiv)
7
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Scheme 1 The synthesis of 2,4-disubstituted phloroglucinols
In summary, the Brønsted acid promoted F–C reaction of
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thesis of the 2-aryl iminosugars. The method is capable of
diversity-oriented synthesis of compound library of 2-aryl
iminosugars, which is essential for the structure–activity
study of this special class of iminosugars.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work is supported by The National Natural Science Foundation
of China (No. 20672117), The National Basic Research Program of
China (No. 2009CB526511), The Ministry of Science and Techno-
logy and the Ministry of Health of the P. R. of China (No.
2009ZX09501-006), and The Chinese Academy of Sciences.
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LETTER
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(12) The crystal structures of 19b and 26 have been deposited at
the Cambridge Crystallographic Data Centre and allocated
the deposition numbers CCDC 756237 and 756238,
respectively.
Synlett 2010, No. 11, 1609–1616 © Thieme Stuttgart · New York