Novel 2-aryl-3,4,5-trihydroxypiperidines: Synthesis and glycosidase inhibition

Article abstract of DOI:10.1016/j.cclet.2013.06.027

Three pairs of novel 2-aryl-3,4,5-trihydroxypiperidines (6-8 and their enantiomers), the piperidine analogues of the pyrrolidine alkaloids radicamine A and radicamine B, were prepared from six-membered cyclic nitrones through a concise two-step procedure, i.e., Grignard reagent addition and deprotection. These novel polyhydroxylated piperidine iminosugars were assayed against 10 types of enzymes. Only compound 8 exhibited weak inhibition (IC₅₀ 1080 μmol/L) against β-galactosidase from rat intestinal lactases.

Full text of DOI:10.1016/j.cclet.2013.06.027

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CCLET-2658; No. of Pages 5
Chinese Chemical Letters xxx (2013) xxx–xxx
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Chinese Chemical Letters
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Original article
Novel 2-aryl-3,4,5-trihydroxypiperidines: Synthesis and glycosidase
inhibition
Hui Zhao a, Wu-Bao Wang a, Shinpei Nakagawa b, Yue-Mei Jia a, Xiang-Guo Hu a,
a,
George W.J. Fleet c, Francis X. Wilson d, Robert J. Nash e, Atsushi Kato b, , Chu-Yi Yu
*
*
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, China
b Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
c Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
d Summit PLC, 91, Milton Park, Abingdon, Oxon OX14 4RY, UK
e Phytoquest Limited, IBERS, Plas Gogerddan, Ceredigion, Aberystwyth SY23 3EB, Wales, UK
A R T I C L E I N F O
A B S T R A C T
Article history:
Three pairs of novel 2-aryl-3,4,5-trihydroxypiperidines (6–8 and their enantiomers), the piperidine
analogues of the pyrrolidine alkaloids radicamine A and radicamine B, were prepared from six-
membered cyclic nitrones through a concise two-step procedure, i.e., Grignard reagent addition and
deprotection. These novel polyhydroxylated piperidine iminosugars were assayed against 10 types of
Received 19 May 2013
Received in revised form 6 June 2013
Accepted 17 June 2013
Available online xxx
enzymes. Only compound 8 exhibited weak inhibition (IC50 1080
mmol/L) against b-galactosidase from
rat intestinal lactases.
Keywords:
ß 2013 Atsushi Kato and Chu-Yi Yu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All
2-Aryl polyhydroxylated piperidine
Iminosugars
rights reserved.
Radicamine mimics
Glycosidase inhibitors
1. Introduction
[5g,6,7] because they are capable of undergoing a variety of
synthetically useful transformations, such as 1,3-dipolar cycload-
Iminosugars, also referred to as azasugars, iminocyclitols, or
polyhydroxylated alkaloids, have attracted considerable attention
due to their intriguing biological properties [1]. These ‘‘nitrogen-
in-the-ring’’ analogues of pyranoses and furanoses are potent
inhibitors of glycosidases and other glycosyl processing enzymes,
and have potential as pharmaceuticals [1,2]. Polyhydroxylated
pyrrolidines carrying an aromatic substituent on the iminosugar
ring are a rare class of iminosugars found in nature (Fig. 1) [3];
these alkaloids exhibit antihypertensive pharmacological activity
without influencing the central nervous system in animal tests.
Many methods have been developed to access these alkaloids [4a],
and a number of derivatives have been synthesized [5]. In contrast,
2-aryl polyhydroxylated piperidines have not yet been isolated
from nature; in view of this, this paper reports the synthesis and
glycosidase inhibition profile of a number of aryl piperidine
analogues.
ditions [8], nucleophilic additions [9,10], and pinacol-type
coupling reactions [11].
In the context of our interest in the synthesis of bioactive
azasugars [4k,12], we have developed a practical method to
synthesize a series of five- and six-membered polyhydroxylated
cyclic nitrones on a large scale [13], which are versatile synthons in
the construction of novel iminosugars [14]. As a part of our
continuing interest in the synthesis of iminosugar analogues,
herein we report the synthesis of 2-aryl polyhydroxylated
piperidine iminosugars (compounds 6–8, and ent-(6–8), Fig. 2)
from a pair of enantiomeric six-membered polyhydroxylated cyclic
nitrones 12 and ent-12, and their glycosidase inhibitory activity.
2. Experimental
General procedure for the synthesis compounds 6–8 and ent-
(6–8): A solution of the cyclic six-membered nitrone 12 or ent-12
(1.0 mmol) in THF (10 mL) was cooled to 0 8C and aryl Grignard
reagents (5.0 mmol) in THF (5 mL) was added under an inert N2
atmosphere. The mixture was kept at this temperature for 2 h, and
then quenched by adding saturated aqueous NH4Cl solution
(15 mL). The aqueous phase was extracted with EtOAc (3 ꢀ 10 mL),
the combined extracts were dried (MgSO4) and concentrated under
Nitrones have been shown as very versatile synthetic inter-
mediates for the construction of structurally complex molecules
* Corresponding authors.
E-mail addresses: kato@med.u-toyama.ac.jp (A. Kato), yucy@iccas.ac.cn
(C.-Y. Yu).
1001-8417/$ – see front matter ß 2013 Atsushi Kato and Chu-Yi Yu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.06.027
Please cite this article in press as: H. Zhao, et al., Novel 2-aryl-3,4,5-trihydroxypiperidines: Synthesis and glycosidase inhibition, Chin.
Chem. Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.06.027

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H. Zhao et al. / Chinese Chemical Letters xxx (2013) xxx–xxx
CH
3
H
CH
CH
3
H
N
OCH
3
3
HO
OCH
HO
OCH
OCH
3
OH
3
3
N
N
N
N
H C
3
H C
H C
3
3
OCH
3
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
(-)-Codonopsine (5)
Radicamine A (1)
(-)-Codonopsinine (3)
Radicamine B (2)
(+)-Codonopsinine (4)
Fig. 1. Radicamines and related natural compounds.
reduced pressure. The residue was purified by flash column
chromatography (silica gel, petroleum ether/EtOAc = 15/1) to give
the addition compound. Aqueous HCl (6 mol/L, 1.0 mL) was added
to the suspension of the addition product (0.23 mmol) and Pd/C
(40 mg) in CH3OH (20 mL), then the mixture was subjected to
hydrogenation under H2 atmosphere for 24 h. The catalyst was
filtered and washed with methanol (5 mL). The filtrate was
neutralized by adding NH3ꢁH2O, then concentrated, the residue
was purified by ion exchange resin to give the target product 6–8 or
ent-(6–8).
H-2), 2.93 (dd, 1H, J1 = 1.91 Hz, J2 = 14.35 Hz, H-6e), 2.76 (d, 1H,
J = 14.17 Hz, H-6a); 13C NMR (75 MHz, D2O):
139.2, 128.9, 128.2,
d
127.9 (Ph–C), 74.5 (C-4), 72.0 (C-3), 69.2 (C-5), 64.7 (C-2), 49.0 (C-
6); HRMS (EI), m/z, 210.11245; [M+H]+ (C11H16NO3 calcd.
210.11247).
ent-6: ½a 2D0
ꢃ 17:14 (c 1.05, CH3OH); mp: 198–199 8C; IR (KBr,
ꢂ
cmꢃ1): 3352, 3278 (br s), 2954 (m), 2882 (m), 1516 (s), 1249 (vs),
1184 (m), 1070 (s), 1031 (m), 820 (m), 742 (m); 1H NMR (300 MHz,
D2O):
d 7.27 (d, 2H, J = 8.40 Hz, Ph–), 6.93 (d, 2H, J = 8.40 Hz, Ph–),
3.96–4.03 (m, 1H, H-5), 3.75–3.82 (m, 4H, H-3, CH3O–), 3.56 (dd,
1H, J1 = 3.30 Hz, J2 = 9.60 Hz, H-4), 3.30 (d, 1H, J = 9.90 Hz, H-2),
2.94 (d, 1H, J = 14.41 Hz, H-6e), 2.76 (d, 1H, J = 13.80 Hz, H-6a); 13
C
6: ½a 2D0
ꢂ
þ 18:06 (c 1.55, CH3OH); mp: 204–205 8C; IR (KBr,
cmꢃ1): 3472 (m), 3426 (s), 3356 (s), 3279 (vs), 2959 (m), 2922 (m),
2905 (m), 2883 (m), 1613 (m), 1517 (vs), 1384 (m), 1249 (s), 1057
NMR (75 MHz, D2O): d 158.5, 132.2, 129.1, 114.2 (Ph–C), 74.6 (C-4),
(s), 1030 (vs), 820 (m), 742 (m); 1H NMR (300 MHz, D2O):
d
7.28 (d,
72.1 (C-3), 69.4 (C-5), 64.1 (C-2), 55.4 (CH3O–), 49.0 (C-6); HRMS
(ESI-MS): m/z 240.12302 [M+H]+ (C12H18NO4 requires:
240.12303).
2H, J = 8.31 Hz, Ph–), 6.94 (d, 2H, J = 8.34 Hz, Ph–), 3.99–4.01 (m,
1H, H-5), 3.78 (t, 1H, J = 9.75 Hz, H-3), 3.76 (s, 3H, CH3O–), 3.57
(dd, 1H, J1 = 2.79 Hz, J2 = 9.42 Hz, H-4), 3.35 (d, 1H, J = 9.99 Hz, H-
2), 2.96 (d, 1H, J = 14.29 Hz, H-6e), 2.80 (d, 1H, J = 14.30 Hz, H-6a);
ent-7: ½a 2D0
ꢃ 22:5 (c 0.80, CH3OH), mp: 227–228 8C, IR (KBr,
ꢂ
cmꢃ1): 3293 (br s), 1614 (s), 1599 (m), 1520 (vs), 1447 (s), 1407
(s), 1256 (s), 1179 (m), 1134 (m), 1084 (s), 833 (m); 1H NMR
13C NMR (75 MHz, D2O):
d 158.5, 132.1, 129.2, 114.3 (Ph–C), 74.6
(C-4), 72.1 (C-3), 69.3 (C-5), 64.1 (C-2), 55.4 (CH3O–), 49.0 (C-6);
HRMS (ESI-MS), m/z 240.12302 [M+H]+ (C12H18NO4 calcd.
240.12303).
(300 MHz, D2O): d 7.19 (d, 2H, J = 7.80 Hz, Ph–), 6.80 (d, 2H,
J = 7.80 Hz, Ph–), 3.95–4.03 (m, 1H, H-5), 3.78 (t, 1H, J = 9.60 Hz,
H-3), 3.57 (d, 1H, J = 7.20 Hz, H-4), 3.33 (d, 1H, J = 9.90 Hz, H-2),
2.96 (d, 1H, J = 13.80 Hz, H-6e), 2.79 (d, 1H, J = 13.80 Hz,
H-6a); 13C NMR (75 MHz, D2O):
d 155.8, 130.4, 129.4, 115.8
7: ½a 2D0
þ 20:74 (c 1.35, CH3OH); mp: 233–234 8C; IR (KBr,
ꢂ
cmꢃ1): 3366 (br s), 2918 (m), 1637 (m), 1496 (m), 1455 (m), 1145
(m), 1091 (s), 866 (m), 761 (s), 701 (m); 1H NMR (300 MHz, D2O):
d
(Ph–C), 74.4 (C-4), 71.7 (C-3), 69.0 (C-5), 64.0 (C-2), 48.8 (C-6);
HRMS (ESI-MS): m/z 226.10748 [M+H]+ (C11H16NO4 calcd.
226.10738).
7.16 (d, 2H, J = 8.06 Hz, Ph–), 6.77 (d, 2H, J = 8.07 Hz, Ph–), 3.97 (s,
1H, H-5), 3.76 (t, 1H, J = 9.67 Hz, H-3), 3.53 (dd, 1H, J1 = 2.78 Hz,
J2 = 9.43 Hz, H-4), 3.30 (d, 1H, J = 9.99 Hz, H-2), 2.93 (d, 1H,
J = 14.08 Hz, H-6e), 2.76 (d, 1H, J = 14.17 Hz, H-6a); 13C NMR
ent-8: ½a 2D0
ꢃ 24:52 (c 1.55, CH3OH); mp: 99–100 8C; IR (KBr,
ꢂ
cmꢃ1): 3349 (br s), 3060 (w), 2917 (m), 1602 (m), 1454 (m), 1339
(m), 1240 (m), 1091 (s), 865 (s), 761 (m), 701 (s); 1H NMR
(75 MHz, D2O): d 155.8, 130.4, 129.4, 115.8 (Ph–C), 74.4 (C-4), 71.7
(C-3), 69.0 (C-5), 64.0 (C-2), 48.8 (C-6); HRMS (ESI-MS), m/z
(300 MHz, D2O): d 7.33–7.36 (m, 5H, Ph–), 3.69–3.98 (m, 1H, H-5),
226.10719 [M+H]+ (C11H16NO4 calcd. 226.10738).
3.77 (t, 1H, J = 9.60 Hz, H-3), 3.55 (dd, 1H, J1 = 3.00 Hz, J2 = 9.60 Hz,
H-4), 3.32 (d, 1H, J = 9.90 Hz, H-2), 2.92 (dd, 1H, J1 = 1.50 Hz,
J2 = 14.41 Hz, H-6e), 2.74 (d, 1H, J = 14.41 Hz, H-6a); 13C NMR
8: ½a 2D0
þ 25:33 (c 1.45, CH3OH); mp: 106–107 8C; IR (KBr,
ꢂ
cmꢃ1): 3366 (br s), 2918 (m), 1640 (m), 1496 (m), 1453 (m), 1145
(m), 1091 (s), 761 (s), 701 (s); 1H NMR (300 MHz, D2O):
d
7.23–7.38
(75 MHz, D2O): d 139.5, 128.9, 128.2, 127.9 (Ph–C), 74.6 (C-4), 72.1
(m, 5H, Ph–), 3.98 (m, 1H, H-5), 3.78 (t, 1H, J = 9.76 Hz, H-3), 3.55
(dd, 1H, J1 = 2.93 Hz, J2 = 9.46 Hz, H-4), 3.34 (d, 1H, J = 10.00 Hz,
(C-3), 69.3 (C-5), 64.8 (C-2), 49.0 (C-6); HRMS (ESI-MS), m/z
210.11246 [M+H]+ (C11H16NO3 calcd. 210.11247).
OH
OH
OH
HO
OH
HO
OH
HO
OH
N
H
N
H
N
H
MeO
HO
8
7
6
OH
OH
OH
HO
OH
HO
OH
HO
OH
N
H
N
H
N
H
MeO
HO
ent-6
ent-8
ent-7
Fig. 2. 2-Aryl polyhydroxylated piperidine iminosugars.
Please cite this article in press as: H. Zhao, et al., Novel 2-aryl-3,4,5-trihydroxypiperidines: Synthesis and glycosidase inhibition, Chin.
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H. Zhao et al. / Chinese Chemical Letters xxx (2013) xxx–xxx
3
OBn
OBn
OH
BnO
OBn
BnO
OBn
HO
OH
a
b
N
N
O
N
H
OH
R'
R'
6-8
ent-6-8
12
ent-12
13a-15a
ent-13a-15a
Scheme 1. Reagents and conditions: (a) Grignard reagents, THF, ice-bath, 2 h, 68%–82%; (b) H2, Pd–C, 6 mol/L HCl, CH3OH, 89%–97%.
Table 1
The addition of nitrones with aryl Grignard reagents.
OBn
OBn
OBn
BnO
OBn
BnO
OBn
BnO
OBn
R'
MgBr
R'
3
2
+
N
N
N
O
o
THF, 0
C
OH
OH
R'
12
13a-15a
13b-15b
ent-12
ent-13b-15b
ent-13a-15a
Entry
R0
Product
Yield (%)a
Trans:cisb
1
2
3
4
5
6
MeO–
13a
14a
15a
73
74
68
81
77
82
90:10
92:8
BnO–
H–
87:13
89:11
91:9
MeO–
BnO–
H–
ent-13a
ent-14a
ent-15a
85:15
a
Combined isolated yields after column chromatography.
The ratio was determined by isolation of two isomers.
b
Table 2
Catalytic hydrogenation of the Grignard addition products.
OBn
OH
BnO
OBn
HO
OH
Pd/C, H
2
N
N
H
MeOH, r.t., 24 h
OH
R'
R
13a-15a
6-8
ent-6-8
ent-13a-15a
Entry
Reactant
R
Product
Yield (%)a
1
2
3
4
5
6
13a
MeO
HO
H
6 (MeO–)
7 (HO–)
97
94
92
91
89
90
14a
15a
8 (H–)
ent-13a
ent-14a
ent-15a
MeO
HO
H
ent-6 (MeO–)
ent-7 (HO–)
ent-8 (H–)
a
Isolated yield purified by ion exchange resin.
3. Results and discussion
by 1H-NMR data (13a: J2–3(trans) = 9.69 Hz for example) or by COSY
and NOESY spectra (see the Supporting information) (compound 8
for example: the NOE interactions between H-2/H-6a, H-2/H-5,
and H-2/H-4, indicated that H-2, H-6a, H-5, and H-4 were on the
same side of the ring).
Catalytic hydrogenation of the analogues 13a, 14a and 15a
catalyzed by 10% Pd–C afforded the deprotected 2-aryl piperidine
iminosugars 6, 7, 8 (Table 2).
Our synthesis started from the enantiomeric six-membered
cyclic nitrones 12 and ent-12 (Scheme 1), prepared from arabinose
according to the reported procedures [13]. The addition of aryl
Grignard reagents to the nitrone 12 gave compounds 13–15 with
high 2,3-trans-selectivity (Table 1), although not as high as with
the corresponding five-membered cyclic nitrones [4k], which
gave exclusively trans-products. The results are summarized in
Table 1. The configurations of the products were determined either
The three enantiomeric piperidines were obtained similarly;
ent-12 was treated with the above three aryl Grignard reagents to
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H. Zhao et al. / Chinese Chemical Letters xxx (2013) xxx–xxx
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give the protected addition products ent-(13a–15a), which were
converted, as described above, to the targeted compounds ent-(6–
8) respectively (Scheme 1, Tables 1 and 2).
The piperidine analogues of radicamine A and B were assayed as
potential glycosidase inhibitors against 10 different enzymes. All
the compounds tested exhibited weaker inhibition than radica-
mine A and B [3c] of
similarities. 8 showed weak glycosidase inhibition of
dase (IC50 1080 mol/L) isolated from rat intestinal lactases. The
three pairs of compounds had no inhibition of -mannosidase,
while ent-(6–8) had better inhibition of -fucosidase from bovine
kidney than compounds 6–8. However, compounds 6–8 were more
potent than their enantiomers in inhibiting -galactosidase from
coffee beans and -galactosidase from rat intestinal lactase. To
a
-glucosidase in spite of their structural
b
-galactosi-
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b
a
-L
a
b
study the effect of the size of the heterocyclic ring on glycosidase
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In summary, we have synthesized three enantiomeric pairs of
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Grignard reagents to six-membered cyclic nitrones. Bioassay
results indicated that these compounds exhibited no or only
very weak inhibition of any of the glycosidases tested and are a
much weaker class of inhibitors than the corresponding
pyrrolidines.
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Acknowledgments
Financial support from National Basic Research Program of
China (Nos. 2012CB822101 and 2011CB808603), and the Natural
Science Foundation of China (Nos. 21272240 and 21102149) is
gratefully acknowledged.
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[(2S 3S,4R)-3,4-dihydroxypyrrolidin-2-yl]-5-methylfuran-4-carboxylic acid deri-
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Appendix A. Supplementary data
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Chem. Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.06.027

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Please cite this article in press as: H. Zhao, et al., Novel 2-aryl-3,4,5-trihydroxypiperidines: Synthesis and glycosidase inhibition, Chin.
Chem. Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.06.027