Synthesis of novel polyhydroxylated pyrrolidine-triazole/-isoxazole hybrid molecules

Article abstract of DOI:10.1039/c4ob01934b

A straightforward synthesis of novel, 2-heterocyclyl polyhydroxylated pyrrolidines is described. Stereocontrolled additions of nucleophiles to cyclic nitrones generated the corresponding 2,3-trans adducts, allowing the synthesis of the corresponding pyrrolidines via key intermediates bearing an alkyne and a nitrile oxide. Three hybrid systems, including a pyrrolidine with two isoxazoles and one triazole, are efficiently prepared via 1,3-dipolar cycloaddition. Biological testing of the product alkaloids showed that subtle structural variations have drastic effects on their inhibitory activities against glucosidases. This journal is

Full text of DOI:10.1039/c4ob01934b

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Synthesis of novel polyhydroxylated pyrrolidine–
triazole/-isoxazole hybrid molecules†
Cite this: DOI: 10.1039/c4ob01934b
Cheng-Kun Lin,a Li-Wei Cheng,b Huang-Yi Li,a Wen-Yi Yuna and
Wei-Chieh Cheng*a,b
A straightforward synthesis of novel, 2-heterocyclyl polyhydroxylated pyrrolidines is described. Stereo-
controlled additions of nucleophiles to cyclic nitrones generated the corresponding 2,3-trans adducts,
allowing the synthesis of the corresponding pyrrolidines via key intermediates bearing an alkyne and a
nitrile oxide. Three hybrid systems, including a pyrrolidine with two isoxazoles and one triazole, are
efficiently prepared via 1,3-dipolar cycloaddition. Biological testing of the product alkaloids showed that
subtle structural variations have drastic effects on their inhibitory activities against glucosidases.
Received 12th September 2014,
Accepted 9th December 2014
DOI: 10.1039/c4ob01934b
www.rsc.org/obc
Introduction
A new class of polyhydroxylated pyrrolidines, in which an aryl
moiety is directly attached at the C-2 position of the pyrrol-
idine ring with a specific 2,3-trans configuration, was recently
discovered.1 The large variety of biological activities exhibited
by molecules containing the 2-aryl pyrrolidine skeleton
suggests that this motif is a privileged scaffold with potential
use in combinatorial chemistry for drug discovery.2 Members
of this class including (–)-codonopsinol, radicamine A, and
radicamine B have been isolated from plants known for their
utility as diuretics, antidotes, hemostats and carcinostatic
agents and for the treatment of liver diseases.3 They have also
been found to inhibit various glycosidases, especially α-gluco-
sidases, and some synthetic 2-aryl pyrrolidines were found to
exhibit better inhibitory potency than natural alkaloids against
Fig. 1 Examples of bioactive 2-aryl polyhydroxylated pyrrolidines and
the identification of cyclic nitrone 1 as a key intermediate for their
synthesis.
glycosidases. This interesting biological activity has motivated dine and a heterocycle, to form a hybrid molecule and increase
the development of various methods for their synthesis.4
the molecular diversity.
In a previous study,4a we reported an efficient preparation
Based on our literature search, a nucleophilic addition of
of 2-aryl polyhydroxylated pyrrolidine alkaloids, in which excel- organometallic reagents to cyclic nitrons has been reported,7
lent diastereoselectivity was achieved using a stereocontrolled but the direct use of heterocyclic lithium reagents7e is not prac-
addition of Grignard reagents to cyclic nitrones, and the five- tical for our further diversity. In contrast, isoxazoles and 1,2,3-
membered chiral cyclic nitrone 1 and its enantiomer are key triazoles can be accessed via a 1,3-dipolar cycloaddition of
intermediates (Fig. 1). Inspired by many biomolecules contain- alkynes with nitrile oxides and azides, respectively, and the
ing a five-membered heterocycle such as a triazole or isox- high yield and regioselectivity of this ring formation step make
azole,5,6 we are curious whether we can develop a new chemical it a good choice for the efficient conjugation of two diverse
method to combine two scaffolds, a polyhydroxylated pyrroli- fragments or even two molecules.8 Therefore, we decided to
install the desired functional groups such as an alkyne and a
nitrile oxide on a pyrrolidine skeleton first and then undergo
a heterocyclic ring formation with a concomitant increase in
molecular diversity.
aGenomics Research Center, Academia Sinica, 128, Section 2, Academia Road,
Taipei, 11529, Taiwan. E-mail: wcheng@gate.sinica.edu.tw; Fax: (+886)2-2789-8771
bDepartment of Chemistry, National Cheng Kung University, 1, University Road,
To the best of our knowledge, however, the synthesis
Tainan City, 701, Taiwan
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
of hybrid molecules containing both
a polyhydroxylated
pyrrolidine and a functionalized triazole or isoxazole remains
NMR spectra for new compounds. See DOI: 10.1039/c4ob01934b
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Scheme 1 General approaches towards the synthesis of polyhydroxy-
lated pyrrolidine heterocycle hybrid molecules.
Scheme 3 Synthesis of 2-triazolyl- and 2-isoxazolyl polyhydroxylated
pyrrolidines 10 and 13 from alkyne 8. Reagents and conditions: (a)
TMSCuC–Li, THF, −78 °C, 1.5 h, 89%, (b) i. Zn, HOAc, DCM, rt, 24 h, ii.
TBAF, THF, rt, 2 h, iii. Boc2O, Et3N, DCM, rt, 2 h, 81% over three steps
from 7, (c) 2-azidoanisole, CuSO4, Na ascorbate, t-BuOH, H2O, rt, 14 h,
88%, (d) H2, Pd(OH)2/C, MeOH, HCl, rt, 12 h, 90%, (e) N-hydroxy-4-
methylbenzimidoyl chloride 11, Et3N, DCM, rt, 12 h, 70%, (f) BCl3, DCM,
−78 °C, 4 h, 73%.
incompletely explored. Herein, we report a new approach for
the installation of an alkynyl and oxime group at the C-2
position of the pyrrolidine ring from a chiral cyclic nitrone
(Scheme 1). These alkynes and oximes are then elaborated
to give functionalized or substituted isoxazole or triazole via
1,3-dipolar cycloadditon. Novel polyhydroxylated pyrrolidine
heterocycle hybrid molecules were prepared using this
method, and their inhibitory activities against glycosidases
were studied.
conditions12 and the key alkyne 8 was successfully obtained in
81% yield from 7 over three steps. With this 1,3-dipolarophile
8 in hand, the copper(I)-catalyzed 1,2,3-triazole ring formation
between 2-azidoanisole and 8 was performed as a model reac-
tion to generate the single adduct 9 in good yield (88%) with
excellent regioselectivity.13 Catalytic hydrogenation [Pd(OH)2/
H2] of 9 under acidic conditions delivered C-2-triazolyl poly-
Results and discussion
As illustrated in Scheme 2, the synthesis of the desired alkyne
6 commenced with the elaboration of enantiopure tri-O-benzyl
cyclic nitrone 1, readily available from D-arabinose.9 Nucleo-
philic addition of ethynyl lithium to cyclic nitrone 1 gave only
a single 2,3-trans adduct 2 in good yield (90%), which under-
went a copper catalyzed ‘click’ reaction with azidobenzene.
Unexpectedly, a mixture of the triazolyl cyclic nitrones 3 and 4
was obtained, presumably by copper-mediated oxidation.10
Cleavage of the N–O bond of 2 using Zn/AcOH conditions gave
vinyl pyrrolidine 5 instead of the desired alkynyl pyrrolidine 6
(Scheme 2).11
1
hydroxylated pyrrolidine 10 in good yield (90%). The H NMR
spectrum of 10 showed a characteristic peak at 8.3 ppm,
corresponding to the methine proton on the triazole ring.
Attempts to react 8 with 4-methylbenzaldehyde oxime and
bleach14 under biphasic conditions were unsatisfactory due
to the poor yield (<30%). In contrast, treatment of 8 with
N-hydroxy-4-methylbenzimidoyl chloride (11), prepared by the
treatment of 4-methylbenzaldehyde oxime with N-chloro-
succinimide (NCS) under basic homogeneous conditions,15
afforded 12 in good yield (70%) as a single adduct with excel-
lent regioselectivity. After global deprotection of 12 by treat-
ment with BCl3 in CH2Cl2 at −78 °C,16 the C-2-isoxazolyl
polyhydroxylated pyrrolidine 13 was obtained in 73% yield.
Notably, catalytic hydrogenation [Pd(OH)2/H2] of 12 did not
give 13, presumably because the isoxazole ring of 12 was labile
These problems required our synthetic strategy to be re-
designed (Scheme 3). Fortunately, the TMS-masked acetylene
moiety in 7 was found to withstand the Zn/AcOH reductive
1
under these conditions.17 In the H NMR spectrum of 13, the
characteristic peak corresponding to the methine proton on
the isoxazole ring was observed at 6.82 ppm.
Next, our attention turned to the development of a new
route to the preparation of another type of C-2-isoxazolyl poly-
hydroxylated pyrrolidine (Scheme 4). N-protected aldehyde 15
(2,3-trans configuration)18 was obtained from cyclic nitrone 1
in an overall yield of 54% over four steps via the selective
addition of vinylmagnesium bromide, reduction of the N–O
bond, N-Boc protection, and ozonolysis. Compound 15 was
reacted with hydroxylamine hydrochloride in the presence of
Scheme 2 Attempts for the preparation of the alkyne and triazoles.
Reagents and conditions: (a) HCuC–Li, THF, 0 °C, 3 h, 90%, (b) PhN3,
CuSO4, Na ascorbate, t-BuOH, H2O, rt, 14 h, 50%, (c) Zn, HOAc, rt, 3 h.
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Table 1 Inhibitory activities of synthesized alkaloids against
glucosidasesa
IC50 (μM)
Compound
α-Glucosidaseb
β-Glucosidasec
10
13
18
20
21
22
23
24
26
27
1.4 0.1
5.8 0.6
1.6 0.2
NId
59
NI
NI
50
75
NI
39
7
1.1 0.2
0.2 0.01 (Ki = 67 nM)e
6.5 0.4
5
6
72
1.4 0.1
15
1.3 0.02
6
2
1
6.3 0.5
8
Scheme 4 Synthesis of the regioisomeric 2-isoxazolyl polyhydroxy-
lated pyrrolidine 18 from oxime 16. Reagents and conditions: (a) (i) Vinyl
MgBr, THF, 0 °C, 2 h, (ii) Zn, HOAc, rt, 14 h, (iii) Boc2O, Et3N, DCM, rt,
2 h, (iv) O3, MeOH, −78 °C, 10 min, 54% over four steps; (b) NaOMe,
NH2OH-HCl, MeOH, rt, 2 h, 90%; (c) NaOCl, Et3N, DCM, H2O, 1-bromo-
4-ethynylbenzene, 0 °C, 12 h, 72%; (d) BCl3, DCM, −78 °C, 4 h, 65%.
1
a IC50 and Ki values were measured in triplicates. b From Bacillus
stearothermophilus. c From almonds. d No inhibition (less than 50%
inhibition at 400 μM). e Competitive inhibition.
compounds 10, 18, 20 and 21 showed significant inhibitory
selectivity between α-glucosidase and β-glucosidase. Also, 21
and 22, which are similar in overall structure but have
different heterocyclic rings, had very different biological activi-
ties: against α-glucosidase (Bacillus), the former, with an isox-
azole ring, was approximately 30-fold more potent (IC50
=
0.2 μM) than the latter, with a triazole ring (IC50 = 6.5 μM).
However, two types of regioisomeric isoxazoles, 20 and 24,
showed a similar inhibitory potency of α-glucosidase; their
IC50 values were 1.1 and 1.4 μM, respectively. Compound 21
was the most potent inhibitor with a Ki value of 67 nM against
α-glucosidase (Bacillus) (Fig. 3). For comparison purposes, 26
(vs. 20 or 24) and 27 (vs. 21) were prepared with an alkyl chain
instead of a heterocyclic ring between the pyrrolidine and sub-
stituent moieties. Obviously, 20 and 24 showed much better
activity (>10-fold) than 26 against α-glucosidase. The inhibitory
activity of 21 was approximately 6.5-fold higher than that of
Fig. 2 Examples of the synthesized hybrid molecules. The specified
yield refers to the overall yield from the corresponding alkyne 8 or 27 against α-glucosidase. Notably, though 26 and 27 had
oxime 16.
moderate inhibition activity against α- and β-glucosidases, they
dramatically lost their selectivity to distinguish α- and β-gluco-
sidases, possibly due to their flexible alkyl spacer. In contrast,
our molecules containing a heterocyclic ring exhibited not
sodium methoxide to give oxime 16 (90%), which was treated
with bleach and 1-bromo-4-ethynylbenzene to afford isox-
azole 17 (72%) via in situ generation of the corresponding
nitrile oxide and 1,3-dipolar cycloaddition at low temperature.
To avoid dehalogenation during palladium-catalyzed hydro-
genation, deprotection of 17 was performed using BCl3 to give
1
pyrrolidine 18. In the H NMR spectrum of 18, the character-
istic peak for the methine proton on the isoxazole ring was
observed at 6.9 ppm, which is much more similar to the
chemical shift of the methine proton in 13 than 10.
Several different polyhydroxylated pyrrolidine-heterocycle
hybrid molecules were synthesized using these conditions
(Fig. 2), and their inhibitory activity against glucosidases was
studied (Table 1).
Biological evaluation
Inhibitory potency and selectivity was found to depend on the
type of heterocyclic ring and its substituents. For example, Fig. 3 Lineweaver–Burk double reciprocal plots of compound 21.
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only inhibitory potency but also selectivity between α- and Synthesis
β-glucosidases.
(2R,3R,4R)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-
dihydro-2H-pyrrole 1-oxide (1). The cyclic nitrone 1 was pre-
pared as a white solid in an overall yield of 56% over five steps
following the known method. 1H NMR (600 MHz, CDCl3) δ
Conclusions
In summary, general and flexible synthetic routes to isoxazolyl 3.73 (dd, J = 2.9, 10.2 Hz, 1H), 4.02 (br, 1H), 4.05 (dd, J = 5.0,
and triazolyl polyhydroxylated pyrrolidines have been develo- 10.2 Hz, 1H), 4.35 (t, J = 3.2 Hz, 1H), 4.50–4.53 (m, 5H), 4.60
ped via protected pyrrolidines bearing an alkyne or oxime (d, J = 12 Hz, 1H), 4.64 (br, 1H), 6.90 (s, 1H), 7.27–7.36 (m,
moiety at the C-2 position as key intermediates. A [3 + 2] cyclo- 15H); 13C NMR (150 MHz, CDCl3) δ 137.6, 137.2, 137.1, 132.8,
addition reaction between alkynes and azides or nitrile oxides 128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 82.7, 80.3,
conveniently generates structurally diverse adducts in excellent 77.5, 73.5, 71.9, 71.6, 66.0; HRMS: calculated for [C26H27NO4 +
yields and regioselectivities. The nature of the heterocyclic H]+ 418.2044, found 418.2049.
ring and its substituents was found to have a profound effect
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-((benzyloxy)methyl)-2-
on inhibitory potency and glycosidase selectivity. This general ((trimethylsilyl)ethynyl) pyrrolidin-1-ol (7). Compound
1
and flexible chemistry should allow easy access to more struc- (5.0 g, 12.0 mmol) was dissolved in anhydrous tetrahydrofuran
turally and stereogenically diverse polyhydroxylated pyrrol- (10 mL) and then ((trimethylsilyl)ethynyl)lithium (3 equiv.)
idine-heterocycle hybrid molecules, and therefore allow for was added dropwise at −78 °C under argon. After stirring for
more comprehensive studies of their biological functions in 1.5 h, the reaction mixture was quenched with a saturated
the future.
aqueous solution of ammonium chloride, extracted with ethyl
acetate (15 mL × 3), dried over anhydrous magnesium sulfate,
and concentrated. The crude product was purified by column
chromatography (20% ethyl acetate in hexanes, silica gel) to
give the title compound 7 (5.6 g, 89%) as a colorless oil. 1H
NMR (600 MHz, CDCl3) δ 0.18 (s, 9H), 3.35 (q, J = 4.3 Hz, 1H),
Experimental
General information
All solvents and reagents were obtained commercially and 3.69 (qd, J = 4.4, 10.2 Hz, 2H), 3.94 (dd, J = 2.7, 6.4 Hz, 1H),
used without further purification. 1H NMR spectra were 4.10 (t, J = 2.7 Hz, 1H), 4.23 (d, J = 2.7 Hz, 1H), 4.44–4.66 (m,
recorded on a Bruker AVANCE 600 spectrometer in deuterium 6H), 5.20 (br, 1H), 7.22–7.34 (m, 15H); 13C NMR (150 MHz,
solvents such as chloroform-d (δ = 7.24), methanol-d4 (δ = CDCl3) δ 138.3, 138.2, 137.6, 128.6, 128.5, 128.4, 128.3, 128.0,
3.31), and deuterium oxide (δ = 4.81) at ambient temperature. 127.99, 127.92, 127.8, 127.7, 86.5, 82.9, 73.6, 72.2, 72.0, 69.5,
13C NMR spectra were recorded with a Bruker AVANCE 600 68.0, 62.8, 0.2; HRMS: calculated for [C31H37NO4Si + H]+
spectrometer and were assigned according to chloroform-d (δ = 516.7153, found 516.7141.
77.0 ppm of the central line). Chemical shifts are given in ppm
(2R,3R,4R,5R)-tert-Butyl-4-bis(benzyloxy)-5-((benzyloxy)-
(δ) and coupling constants (J) are given in Hz. The splitting methyl)-2-ethynylpyrrolidine -1-carboxylate (8). Zinc dust
patterns are reported as s (singlet), d (doublet), t (triplet), q (2.75 g, 10 equiv.) was suspended in acetic acid (10 mL). The
(quartet), m (multiplet), and dd (double of doublets). High mixture was stirred at room temperature for 15 min, after
resolution mass spectra were recorded using a Bruker Dal- which the color of the solution turned brown. A solution of
tonics BioTOF III spectrometer (ESI-MS). Analytical HPLC compound 7 (2.18 g, 4.23 mmol) in dichloromethane (10 mL)
spectra were recorded at 220 nm using a HITACHI L-2450 was added. After stirring at room temperature for 24 h, acetic
equipped with a photodiode array detector and a Mightysil acid was removed under reduced pressure, and the solution
column (ZORBOX XDB-C-18, 2.1 × 50 mm, 5 μm) eluted with a was adjusted to pH = 7 with saturated sodium bicarbonate
gradient from 90% H2O/10% CH3OH to 10% H2O/90% CH3OH aqueous solution and filtered through a pad of celite. The fil-
with a flow rate = 0.2 mL min−1. Flash column chromato- trate was washed with ethyl acetate, dried over anhydrous mag-
graphy was carried out using
a Merck Kieselgel Si60 nesium sulfate, and concentrated to give the crude product,
(40–63 μm). IR spectra were recorded with a Thermo Nicolet which was treated with tetrabutylammonium fluoride (1 M
380. Optical rotations were measured with a Perkin-Elmer solution in tetrahydrofuran, 4.9 mL, 1.17 equiv.). The mixture
Model 341 polarimeter. Thin-layer chromatography (TLC) was stirred at room temperature for 2 h. The reaction mixture
plates visualized by exposure to ultraviolet light at 254 nm was concentrated and purified by column chromatography
and/or immersion in a staining solution (phosphomolybdic (33% ethyl acetate in hexanes, silica gel) to give the pyrrolidine
acid, ninhydrin, or potassium permanganate) followed by (1.5 g, 92%) as a colorless oil. The pyrrolidine (1.50 g,
heating on a hot plate. Ozonolysis was performed on an ozone 3.51 mmol) was reacted with di-tert-butyl dicarbonate
generator (Fischer Technology OZ 502/10). Reactions were (1.11 mL, 1.3 equiv.) in dichloromethane (7 mL) in the pres-
monitored by analytical thin-layer chromatography (TLC) in ence of triethylamine (660 μL) at room temperature. After stir-
silica gel 60 F254 plates and visualized under UV (254 nm) and ring for 2 h, water was added to the reaction mixture, followed
by staining with p-anisaldehyde or acidic ninhydrin or phos- by extraction with dichloromethane, dried over anhydrous
phomolybdic acid. Concentration refers to rotary evaporation.
magnesium sulfate, and concentrated. The crude mixture was
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purified by column chromatography (10% ethyl acetate in
(2R,3R,4R,5S)-5-(Hydroxymethyl)-2-(3-(p-tolyl)isoxazol-5-yl)-
hexanes, silica gel) to give the title compound 8 (1.63 g, 88%) pyrrolidine-3,4-diol (13). A mixture of compound 8 (60 mg,
as a colorless oil; 1H NMR (600 MHz, CDCl3; rotamers were 0.12 mmol), N-hydroxy-4-methylbenzimidoyl chloride 11 (1 M
observed) δ 1.45 + 1.50 (ss, 9H), 2.36 + 2.42 (ss, 1H), 3.45 (t, J = solution in dichloromethane, 150 μL, 3 equiv.), and triethyl-
9.6 Hz, 1H), 3.75 + 3.92 (dd dd, J = 3.6, 8.4 Hz, J = 3.6, 8.4 Hz, amine (20 μL, 1.17 equiv.) in dichloromethane (3 mL) was
1H), 4.12–4.29 (m, 3H), 4.40–4.67 (m, 7H), 7.20–7.37 (m, 15H); stirred at room temperature for 12 h. The mixture was evapor-
13C NMR (150 MHz, CDCl3; rotamers were observed) δ 154.1 + ated and then water was added. The aqueous layer was
153.6, 138.6 + 138.3, 138.0 + 138.9, 137.2, 128.6, 128.5, 128.4, extracted with ethyl acetate (10 mL × 3). The combined organic
128.1, 127.9, 127.8, 127.7, 127.6, 86.4 + 85.3, 82.9, 81.6 + 81.5, layer was dried over anhydrous magnesium sulfate, and con-
80.8, 80.7, 80.6, 73.1, 72.3, 71.8, 71.7, 71.6, 71.2, 71.0, 68.7 + centrated. The crude mixture was dissolved in dry dichloro-
68.3, 62.8 + 62.5, 54.6 + 54.0, 28.5; HRMS: calculated methane under an argon atmosphere at −78 °C. Boron
[C33H37NO5 + H]+ 528.2672, found 528.2672.
(2R,3R,4R,5R)-tert-Butyl 3,4-bis(benzyloxy)-5-((benzyloxy)- added dropwise at the same temperature. The reaction mixture
trichloride (1 M solution in hexanes, 1.8 mL, 15 equiv.) was
methyl)-2-(1-(2-methoxy phenyl)-1H-1,2,3-triazol-4-yl)pyrroli- was allowed to warm to 0 °C and stirred for 4 h. The reaction
dine-1-carboxylate (9). To a solution of compound 8 (60 mg, mixture was quenched with methanol, and concentrated. The
0.11 mmol) and 2-azidoanisole (0.5M solution in tert-butyl crude mixture was purified by column chromatography (10%
methyl ether, 0.29 mL, 1.09 equiv.) in tert-butanol (2 mL) was methanol in dichloromethane, silica gel) to give the title com-
added copper(II) sulfate pentahydrate (2.8 mg, 0.1 equiv.), pound 13. [α]2D0 +11.90 (c 0.13 in MeOH); IR (neat): 3313 (br),
sodium ascorbate (2.2 mg, 0.1 equiv.), and water (1 mL). The 2955 (m), 2924 (s), 1612 (m), 1403 (s) cm–1; 1H NMR (600 MHz,
mixture was stirred at 40 °C for 12 h. The mixture was then CD3OD) δ 2.39 (s, 3 H), 3.16–3.18 (m, 1H), 3.66 (dd, J = 5.2,
diluted with water and extracted with ethyl acetate (10 mL × 3). 11.2 Hz, 1H), 3.70 (dd, J = 4.5, 11.2 Hz, 1H), 4.01 (t, J = 5.0 Hz,
The combined organic layers were dried over anhydrous mag- 1H), 4.16 (t, J = 5.8 Hz, 1H), 4.34 (d, J = 6.5 Hz, 1H), 6.82 (s,
nesium sulfate, and concentrated. The crude mixture was puri- 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H); 13C
fied by column chromatography (10% ethyl acetate in hexanes, (150 MHz, CD3OD) δ 174.7, 163.9, 141.8, 130.8, 127.9, 127.5,
silica gel) to give the title compound 9 (69 mg, 88%) as a 101.1, 77.3, 73.7, 66.6, 63.7, 60.6, 21.5; HRMS: calculated for
1
yellow oil. H NMR (600 MHz, CDCl3; rotamers were observed) [C15H18N2O4 + H]+ 291.1267, found 291.1262.
δ 1.23 + 1.40 (ss, 1H), 3.64 (m, 1H), 3.66 + 3.37 (ss, 1H), 3.98
(2R,3R,4R,5R)-tert-Butyl
3,4-bis(benzyloxy)-5-((benzyloxy)-
(dd, J = 4.2, 8.8 Hz, 1H), 4.17 + 4.18 (ss, 1H), 4.24 + 4.26 (ss, methyl)-2-((hydroxyimino)methyl)pyrrolidine-1-carboxylate
1H), 4.35–4.63 (m, 6 H), 4.65 + 4.75 (dd, J = 5.1 Hz, J = 11.7 Hz, (16). Compound 1 (2 g, 5 mmol) was dissolved in tetrahydro-
1H), 5.27 + 5.34 (ss, 1H), 6.89–7.15 (m, 7H), 7.24–7.39 (m, 13 furan (20 mL) and then vinyl magnesium bromide (1 M solu-
H), 7.58 + 7.22 (dd br, J = 1.3, 7.9 Hz, 1H), 7.82 + 7.86 (ss, 1H); tion in tetrahydrofuran, 14 mL, 3 equiv.) was added dropwise
13C NMR (150 MHz, CDCl3; rotamers were observed) δ 154.3, at 0 °C under an argon atmosphere. After 14 h, the reaction
151.5, 148.6, 138.8, 137.8, 137.7, 130.2, 129.9, 128.7, 128.64, mixture was quenched with saturated ammonium chloride
128.60, 128.5, 128.4, 128.0, 127.9, 127.8, 127.76, 127.73, 126.6, aqueous solution, extracted with dichloromethane (20 mL × 3),
125.9, 125.6, 124.2, 121.3 + 121.2, 112.4 + 112.2, 87.0 + 86.6, dried over anhydrous magnesium sulfate, and concentrated.
84.9 + 83.6, 82.6 + 80.3, 73.3, 71.9 + 71.8, 71.1, 68.9 + 68.3, 63.9 The crude mixture was purified by column chromatography
+ 63.5, 61.3 + 60.6, 56.0 + 55.8, 28.6 + 28.3; HRMS: calculated (25% ethyl acetate in hexanes, silica gel) to give the hydroxyl-
for [C40H44N4O6 + H]+ 676.3261, found 676.3251.
amine (1.91 g, 90%) as a brown solid. A mixture of the hydroxy-
(2R,3R,4R,5R)-5-(Hydroxymethyl)-2-(1-(2-methoxyphenyl)- lamine (170 mg, 0.38 mmol) and zinc dust (248 mg, 10 equiv.)
1H-1,2,3-triazol-4-yl)pyrrolidine-3,4-diol (10). A mixture of in acetic acid (3 mL) was stirred at room temperature over-
compound 9 (68 mg, 0.1 mmol), concentrated hydrochloric night. The reaction mixture was filtered through a pad of celite
acid (5 drops), and Pd(OH)2 (5 mg, 0.01 equiv.) in methanol and the filtrate was neutralized with saturated sodium bicar-
(4 mL) was stirred at room temperature under hydrogen. bonate aqueous solution, and extracted with dichloromethane
After 12 h, the reaction mixture was filtered through a pad (5 mL × 3). The combined organic layers were dried over anhy-
of celite and concentrated. The crude product was purified drous magnesium sulfate, concentrated, and then reacted
by column chromatography (10% methanol in dichloro- directly with di-tert-butyl dicarbonate (437 μL, 5 equiv.) and tri-
methane, silica gel) to give the title compound 10 (28 mg, ethylamine (265 μL, 5 equiv.) in dichloromethane (4 mL) at
90%) as a white solid. [α]D20 +10.16 (c 0.16 in MeOH); IR (neat): room temperature. After stirring for 2 h, water (20 mL) was
3313 (br), 2934 (m), 1658 (m), 1475 (m) cm–1; 1H NMR added to the reaction mixture, which was then extracted with
(600 MHz, CD3OD) δ 3.27 (dd, J = 6.1, 10.4 Hz, 1H), 3.70 (dd, dichloromethane, dried over anhydrous magnesium sulfate,
J = 3.7, 11.3 Hz, 1H), 3.76 (dd, J = 4.0, 11.3 Hz, 1H), 3.90 (s, and concentrated to give a crude tert-butoxycarbonyl-protected
3H), 3.97 (t, J = 6.5 Hz, 1H), 4.27 (t, J = 6.1 Hz, 1H), 4.30 (d, J = product. After the ozonolysis of the crude tert-butoxycarbonyl-
7.3 Hz, 1H); 13C NMR (150 MHz, CD3OD) δ 153.4, 148.5, 132.1, protected product in methanol (20 mL) at −78 °C for 10 min,
127.5, 126.8, 126.2, 122.2, 113.9, 83.5, 79.4, 65.2, 63.2, 59.3, the crude aldehyde was reacted with hydroxylamine hydrochlo-
56.7; HRMS: calculated for [C14H18N4O4 + H]+ 307.1401 found ride (132 mg, 5 equiv.) and sodium methoxide (5.4 M solution
307.1402.
in methanol, 352 μL, 5 equiv.) for 2 h. The solvent was evapor-
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ated, and after the addition of water, the aqueous layer was 126.9, 99.4, 83.6, 79.5, 65.2, 63.4, 59.8; HRMS: calculated
extracted with ethyl acetate (5 mL × 3). The combined organic [C14H16N2O4 + H]+ 276.1110, found 276.1111.
layers were dried over anhydrous magnesium sulfate, concen-
(2R,3R,4R,5R)-2-(5-(4-Chlorophenyl)isoxazol-3-yl)-5-(hydroxy-
trated, and purified by column chromatography (25% ethyl methyl)pyrrolidine-3,4-diol (20). The title compound 20 was
acetate in hexanes, silica gel) to give compound 16 (112 mg, synthesized by the procedure described for the preparation of
54% over four steps) as a white solid. 1H NMR (600 MHz, compound 16 in 53% yield over three steps. [α]2D0 +9.76 (c 0.04
CDCl3; rotamers were observed) δ 1.47 (s, 13H), 3.61 + 3.69 (m, in MeOH); IR (neat): 3307 (br), 2924 (m), 1613 (m), 1466 (m)
1H), 3.67 (m, 1H), 4.02 (m, 1H), 4.03–4.37 (m, 3H), 4.44 (m, cm–1; 1H NMR (600 MHz, CD3OD) δ 3.18–3.20 (m, 1H), 3.67
1H), 4.47–4.80 (m, 9H), 5.12 + 5.24 (dd, J = 4.8, 5.2 Hz), 6.75 + (dd, J = 5.8, 11.2 Hz, 1H), 3.73 (dd, J = 3.9, 11.2 Hz, 1H), 3.93 (t,
6.76 (ss, 1H), 7.31–7.51 (m, 23H), 8.99 + 9.10 (ss, 1H), 9.45 + J = 6.5 Hz, 1H), 4.13 (t, J = 6.4 Hz, 1H), 4.17 (d, J = 7.3 Hz, 1H),
9.49 (ss, 1H); 13C NMR (150 MHz, CDCl3; rotamers were 7.51–7.53 (m, 2H), 7.81–7.83 (m, 2H); 13C NMR (150 MHz,
observed) δ 154.2, 153.2, 154.0, 153.9, 152.4, 152.3, 150.8, CD3OD) δ 170.4, 167.4, 137.5, 130.6, 128.5, 127.6, 99.9, 83.6,
150.7, 138.6, 138.5, 138.3, 138.2, 137.9, 137.8, 137.6, 137.5, 79.4, 65.2, 63.4, 59.8; HRMS: calculated for [C14H15ClN2O4
137.3, 137.2, 128.6, 128.5, 128.47, 128.44, 128.41, 128.3, 128.0, H]+ 311.0720, found 311.0711.
+
127.9, 127.8, 127.7, 127.68, 127.65, 127.59, 127.56, 127.4, 85.9,
(2R,3R,4R,5R)-2-(5-(2-Bromophenyl)isoxazol-3-yl)-5-(hydroxy-
84.7, 84.6, 83.3, 82.4, 82.2, 81.1, 80.7, 80.67, 80.63, 73.1, 71.64, methyl)pyrrolidine-3,4-diol (21). The title compound 21 was
71.62, 71.60, 71.2, 71.1, 71.0, 70.9, 68.5, 67.9, 63.3, 63.1, 63.0, synthesized by the procedure described for the preparation of
62.7, 62.6, 59.2, 59.1, 28.5, 28.4; HRMS: calculated for compound 16 in 50% yield over three steps. [α]2D0 −7.10 (c 0.18
[C32H38N2O6 + H]+ 547.2730, found 547.2731.
in MeOH); IR (neat): 3317 (br), 2925 (m), 1601 (s), 1435 (s) cm−1
;
(2R,3R,4R,5R)-2-(5-(4-Bromophenyl)isoxazol-3-yl)-5-(hydroxy- 1H NMR (600 MHz, CD3OD) δ 3.18–3.21 (m, 1H), 3.67 (dd,
methyl)pyrrolidine-3,4-diol (18). A mixture of the oxime 16 J = 5.8, 11.3 Hz, 1H), 3.75 (dd, J = 4.0, 11.3 Hz, 1H), 3.94 (t, J =
(700 mg, 1.3 mmol) and 4-bromo-1-ethynylbenzene (1 g, 4.2 6.5 Hz, 1H), 4.15 (t, J = 7.1 Hz, 1H), 4.22 (d, J = 7.1 Hz, 1H),
equiv.) in dichloromethane (6 mL) was stirred at 0 °C, and 7.12 (s, 1H), 7.38 (td, J = 1.7, 8.1 Hz, 1H), 7.50 (td, J = 1.0,
then a mixture of bleach (18 mL, 12 equiv.) and water (26 mL) 7.7 Hz, 1H), 7.77 (dd, J = 1.0, 8.1 Hz, 1H), 7.81 (dd, J = 1.7,
was added dropwise. The reaction mixture was warmed to 7.7 Hz, 1H); 13C NMR (150 MHz, CD3OD) δ 169.5, 166.8, 135.6,
room temperature. After 12 h, the reaction mixture was 132.8, 131.4, 129.8, 129.2, 122.2, 104.1, 83.6, 79.5, 65.2, 63.4,
quenched with saturated ammonium chloride aqueous solu- 59.9; HRMS: calculated for [C14H15BrN2O4 + H]+ 355.0215,
tion, extracted with dichloromethane, dried over anhydrous found 355.0210.
magnesium sulfate, and concentrated. The crude product
(2R,3R,4R,5R)-2-(1-(2-Bromophenyl)-1H-1,2,3-triazol-4-yl)-5-
without purification was directly used in the next step. The (hydroxymethyl) pyrrolidine-3,4-diol (22). The title compound
crude material was dissolved in dichloromethane (80 mL) at 22 was synthesized by the procedure described for the prepa-
−78 °C and then boron trichloride (20 mL, 15 equiv.) was ration of compound
8 in 64% yield over three steps.
added dropwise under an argon atmosphere. After stirring for [α]2D0 +12.72 (c 0.12 in MeOH); IR (neat): 3318 (br), 2923 (m),
4 h, the mixture was quenched with methanol. Solvents were 1493 (s) cm–1; 1H NMR (600 MHz, CD3OD) δ 3.26 (br, 1H), 3.71
removed under reduced pressure and the residue was purified (br, 1H), 3.77 (br, 1H), 3.96 (br, 1H), 4.27 (br, 1H), 4.32 (br,
by column chromatography (10% methanol in dichloro- 1H), 7.50–7.53 (m, 1H), 7.57–7.60 (m, 2H), 7.86 (d, J = 8.2 Hz,
methane) to give the title compound 18 (218 mg, 47%) as a 1H), 8.27 (s, 1H); 13C NMR (150 MHz, CD3OD) δ 149.2, 138.1,
white solid. [α]2D0 +17.05 (c 0.13 in MeOH); IR (neat): 3305 (br), 135.2, 133.1, 130.1, 129.7, 126.3, 120.2, 83.7, 79.6, 65.2, 63.3,
3124 (m), 2919 (m), 1610 (s), 1465 (s) cm–1; 1H NMR (600 MHz, 59.4; HRMS: calculated for [C13H15BrN4O3 + H]+ 355.0328,
CD3OD) δ 3.18–3.20 (m, 1H), 3.67 (dd, J = 5.8, 11.2 Hz, 1H), found 355.0377.
3.74 (dd, J = 3.9, 11.2 Hz, 1H), 3.93 (t, J = 6.7 Hz, 1H), 4.13 (t,
(2R,3R,4R,5R)-2-(1-(2-Hydroxyethyl)-1H-1,2,3-triazol-4-yl)-5-
J = 6.7 Hz, 1H), 4.18 (d, J = 7.3 Hz, 1H), 4.6 (s, 1H), 6.90 (s, 1H), (hydroxymethyl)pyrrolidine-3,4-diol (23). The title compound
7.67 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 8.2 Hz, 2H); 13C NMR 23 was synthesized by the procedure described for the prepa-
(150 MHz, CD3OD) δ 170.5, 167.4, 133.6, 128.6, 127.9, 125.6, ration of compound
8 in 71% yield over three steps.
100.0, 83.6, 79.4, 65.2, 63.4, 59.8; HRMS: calculated for [α]2D0 +37.16 (c 0.22 in MeOH); IR (neat): 3285 (br), 2949 (m),
[C14H15BrN2O4 + H]+ 356.1839, found 356.1829.
1616 (m), 1425 (m) cm–1; H NMR (600 MHz, D2O) δ 3.26–3.28
1
(2R,3R,4R,5R)-5-(Hydroxymethyl)-2-(5-phenylisoxazol-3-yl)- (m, 1H), 3.72 (dd, J = 6.2, 11.8 Hz, 1H), 3.78 (dd, J = 4.3,
pyrrolidine-3,4-diol (19). The title compound 19 was syn- 11.8 Hz, 1H), 3.99–4.01 (m, 3H), 4.25 (d, J = 8.3 Hz, 1H), 4.30
thesized by the procedure described for the preparation of (t, J = 8.3 Hz, 1H), 4.55–4.56 (m, 2H), 8.0 (s, 1H); 13C NMR
compound 16 in 49% yield over three steps. [α]2D0 +11.43 (c 0.12 (150 MHz, D2O) δ 146.1, 124.2, 80.8, 76.9, 61.8, 61.6, 60.1, 55.9,
in MeOH); IR (neat): 3310 (br), 2927 (m), 1610 (m), 1463 (s) 52.5; HRMS: calculated [C9H16N4O4 + Na]+ 267.1069, found
1
cm–1; H NMR (600 MHz, CD3OD) δ 3.21 (br, 1H), 3.67 (dd, J = 267.1061.
5.8, 11.2 Hz, 1H), 3.74 (dd, J = 3.2, 11.2 Hz, 1H), 3.94 (t, J =
(2S,3R,4R,5R)-2-(3-(4-Chlorophenyl)isoxazol-5-yl)-5-(hydroxy-
6.4 Hz, 1H), 4.15 (t, J = 6.4 Hz, 1H), 4.18 (d, J = 6.9 Hz, 1H), methyl)pyrrolidine-3,4-diol (24). The title compound 24 was
6.86 (s, 1H), 7.46–7.51 (m, 3H), 7.82 (d, J = 7.6 Hz, 1H); 13C synthesized by the procedure described for the preparation of
NMR (150 MHz, CD3OD) δ 171.7, 167.1, 131.6, 130.4, 128.9, compound 8 in 54% yield over three steps. [α]2D0 +8.03 (c 0.11
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in MeOH); IR (neat): 3311 (br), (m), 2925 (m), 1633 (s), 1463 (s)
cm–1; 1H NMR (600 MHz, CD3OD) δ 3.16–3.18 (m, 1H), 3.66
(dd, J = 5.4, 11.2 Hz, 1H), 3.73 (dd, J = 3.8, 11.2 Hz, 1H), 3.91 (t,
J = 6.7 Hz, 1H), 4.21 (t, J = 6.4 Hz, 1H), 4.26 (d, J = 6.8 Hz, 1H),
6.81 (s, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.81 (d, J = 8.6 Hz, 2H);
13C NMR (150 MHz, CD3OD) δ 175.7, 163.0, 137.3, 130.4,
129.5, 129.2, 100.9, 83.1, 79.3, 65.2, 63.0, 60.2, 50.0; HRMS:
calculated [C14H15ClN2O4 + H]+ 311.0720, found 311.0721.
(2R,3R,4R,5S)-5-(Hydroxymethyl)-2-(3-undecylisoxazol-5-yl)-
pyrrolidine-3,4-diol (25). The title compound 25 was syn-
thesized by the procedure described for the preparation of
compound 8 in 47% yield over three steps. [α]2D0 +15.23 (c 0.14
in MeOH); IR (neat): 3329 (br), 2929 (m), 1622 (s), 1459 (s)
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cm−1 1H NMR (600 MHz, CD3OD) δ 0.90 (t, J = 6.8 Hz, 3H),
;
1.29–1.34 (br, 18H), 1.65–1.68 (m, 2H), 2.65 (t, J = 7.4 Hz, 1H),
3.30–3.32 (m, 1H), 3.65 (dd, J = 5.5, 11.4 Hz, 1H), 3.71 (dd, J =
3.8, 11.4 Hz, 1H), 3.89 (t, J = 6.6 Hz, 1H), 4.15 (t, J = 6.5 Hz,
1H), 4.18 (d, J = 7.1 Hz, 1H), 6.32 (s, 1H); 13C NMR (150 MHz,
CD3OD) δ 174.1, 165.8, 102.7, 82.8, 79.0, 64.9, 62.8, 59.7, 33.3,
30.9, 30.8, 30.7, 30.6, 30.4, 29.5, 23.9, 14.7; HRMS: calculated
[C19H34N2O4 + H]+ 355.2597, found 355.2584.
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Assay for glycosidase inhibitory activity19
The inhibitory activities of α-glucosidase from Bacillus stearo-
thermophilus (Sigma, G3651) and β-glucosidase from almonds
(Sigma, G0395) were determined by measuring the absorbance
of 4-nitrophenol at 405 nm. To evaluate the inhibition against
α-glucosidase, the reaction mixture consisted of 10 μL of
enzyme (1 U mL−1), 20 μL of a synthesized molecule, 50 μL of
100 mM sodium phosphate buffer (pH 6.8) and 20 μL of
15 mM 4-nitrophenyl-α-D-glucopyranoside. To evaluate the inhi-
bition against β-glucosidase, the reaction mixture consisted of
10 μL of enzyme (1 U mL−1), 20 μL of a synthesized molecule,
45 μL of 100 mM sodium citrate buffer (pH 5.2) and 25 μL of
4 mM 4-nitrophenyl-β-D-glucopyranoside. After incubating at
37 °C for 30 minutes, 100 μL of 0.5 M glycine buffer (pH 10.2)
was added to the reaction mixture to stop the reaction. The
concentration of inhibitors required for inhibiting 50% of gly-
cosidase activity under the assay conditions was defined as the
IC50 value. The IC50 value was measured graphically by a plot
of percent inhibition versus log of the test compound. The Km
value was determined using Michaelis–Menten kinetics.
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Acknowledgements
We thank the Ministry of Science and Technology and the
Academia Sinica for financial support.
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