Nucleophilic additions and redox reactions of polyhydroxypyrroline N-oxides on the way to pyrrolidine alkaloids: Total synthesis of radicamine B

Article abstract of DOI:10.1055/s-2007-991059

Nucleophilic addition of aryl Grignard reagents to (2R,3R,4R)-3,4- bis(benzyloxy)-2-(benzyloxymethyl)-3,4-dihydro-2H-pyrrole 1-oxide afford straightforwardly trihydroxylated pyrrolidine alkaloids. Organometallic additions take place with complete anti sel

Full text of DOI:10.1055/s-2007-991059

LETTER
2651
Nucleophilic Additions and Redox Reactions of Polyhydroxypyrroline
N-Oxides on the Way to Pyrrolidine Alkaloids: Total Synthesis of Radicamine B
Nucleophilic
A
e
dditions to
d
Pyrroline
N
r
-Oxideso Merino,*a Ignacio Delso,a,b Tomas Tejero,a Francesca Cardona,b Andrea Goti*b
a
Laboratorio de Sintesis Asimetrica, Departamento de Quimica Organica, Instituto de Ciencia de Materiales de Aragon,
Universidad de Zaragoza, CSIC, 50009 Zaragoza, Aragon, Spain
Fax +34(976)762075; E-mail: pmerino@unizar.es
b
Dipartimento di Chimica Organica ‘Ugo Schiff’ and HeteroBioLab, Università di Firenze, Associated with ICCOM-CNR,
Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
Fax +39(055)4573531; E-mail: andrea.goti@unifi.it
Received 5 July 2007
reported.8 However, due to the relative configuration of
the three contiguous stereocenters in 5, only the all-trans
pyrrolidines are accessible. In the search of structural
analogues of pyrrolidines 1–4 we embarked in a study
Abstract: Nucleophilic addition of aryl Grignard reagents to
(2R,3R,4R)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-3,4-dihydro-
2H-pyrrole 1-oxide afford straightforwardly trihydroxylated
pyrrolidine alkaloids. Organometallic additions take place with
complete anti selectivity. In order to gain access to all four dia- aimed at preparing all the possible 2-aryl polyhydrox-
stereomers with different configuration at C-2 and C-5, an oxida-
tion–reduction protocol is developed. The high selectivity observed
in the nucleophilic addition reaction allowed preparation of natural
radicamine B in only two steps and high chemical yield.
ylated pyrrolidines 6 with different configurations at C-
2 and C-5 in a stereoselective fashion (Scheme 1).
BnO
OBn
HO
OH
Ar-M
Key words: alkaloids, nucleophilic additions, oxidations, nitrones,
pyrrolidines
Ar
*
*
N
O
N
H
M = Li, MgBr
Ar = aryl
BnO
HO
5
6
A great deal of research has been devoted to the synthesis
of natural and synthetic polyhydroxylated pyrrolidines in
search of highly active and efficient glycosidase inhibi-
tors,1 which could serve as therapeutic agents for a variety
of carbohydrate-mediated diseases.2 2-Aryl pyrrolidines
such as radicamines A and B (1 and 2), codonopsinine (3),
and codonopsine (4) belong to a particular class of natural
polyhydroxylated pyrrolidines that can be found in
plants.3 Recently, we communicated our results on nu-
cleophilic addition reactions to mono- and dihydroxylated
cyclic nitrones and their application to the synthesis of
(–)-codonopsinine.4
Scheme 1
In this communication we report our preliminary results
on the preparation of four diastereomeric 2-aryl pyr-
rolidines via arylmagnesium bromide addition to 5, regio-
selective oxidation of the obtained cyclic hydroxylamines
and further stereoselective reduction of the resulting
nitrones. In addition, the synthesis of radicamine B start-
ing from 5, in order to obtain the natural enantiomer,7 is
described.
The stereoselective addition of phenylmagnesium bro-
mide to 5 took place with complete selectivity to afford
hydroxylamine 7 in 92% yield. As expected, the Grignard
reagent reacted with the cyclic nitrone on the less hin-
dered opposite face of the C-2 substituent and in an anti-
periplanar manner to the vicinal OBn group. The all-trans
configuration in 7 was confirmed by NOE correlations.
Catalytic hydrogenation using Pearlman’s catalyst in
HCl–MeOH furnished deoxyradicamine hydrochloride
(8) in quantitative yield (Scheme 2).9
HO
OH
HO
OH
R1
R
Me
N
N
H
HO
Me
OR2
OMe
radicamine A (1), R1 = OH; R2 = Me
radicamine B (2), R1 = R2 = H
codonopsinine (3), R = H
codonopsine (4), R = OMe
Figure 1
More recently, Gurjar5 and Yu6 independently reported
that radicamines A and B would be easily accessible by a
stereoselective addition of a suitable aryl organometallic
derivative to the cyclic nitrone 5,7 which can be easily pre-
pared from either D-arabinose or L-xylose, as previously
BnO
OBn
HO
OH
Cl–
ii
i
5
100%
92%
N
N
H2
BnO
OH
HO
8
7
Scheme 2 Reagents and conditions: i) PhMgBr, THF, 0 °C; ii) H2,
5 atm, Pd(OH)2–C, HCl–MeOH, r.t.
SYNLETT 2007, No. 17, pp 2651–2654
1
6
.1
0
.
2
0
0
7
Advanced online publication: 25.09.2007
DOI: 10.1055/s-2007-991059; Art ID: G23207ST
© Georg Thieme Verlag Stuttgart · New York

2652
P. Merino et al.
LETTER
In order to have an access to other diastereomeric deoxy- yield of nitrone 13 being at a low temperature (TEMPO,
radicamines, we studied an oxidation–reduction protocol –80 °C). Under these conditions, a mixture of nitrones 10
that had been recently employed successfully in our labo- and 13 was obtained in 3:1 ratio, respectively (23% isolat-
ratories with different pyrrolidines.10 Thus, hydroxyl- ed yield for 13). This result was expected on the basis of
amine 7 was oxidized with TEMPO at 0 °C and a 6.7:1 the above-mentioned antiperiplanar effect of OBn, now
mixture of regioisomeric nitrones 9 and 10, respectively, effective on the hydrogen atom at C-2 which is trans to the
was obtained in quantitative yield (Scheme 3).
vicinal OBn group. After separation by radial chromatog-
raphy, the nitrone 10 was re-used in the reduction reac-
tion, while nitrone 13 was employed in the following step.
The reduction of nitrone 13 was more difficult than for
nitrone 9, probably due to the steric shield presented by
the phenyl to the preferred face for hydride attack. Boron-
derived hydrides (e.g., NaBH4 and L-selectride) resulted
unreactive. As for 10, the reduction of nitrone 13 was suc-
cessfully achieved upon treatment with an excess (4.0
equiv) of DIBAL-H in THF at –80 °C, which furnished a
mixture of hydroxylamines 12 and 14 in 10:90 ratio, re-
spectively, and 90% total yield.
BnO
OBn
BnO
OBn
i or ii
+
7
N
N
BnO
BnO
O
O
9
10
Scheme 3 Reagents and conditions: i) TEMPO, 0 °C, 3 h (100%,
9:10, 6.7:1); ii) MnO2, 80 °C, 30 min (90%, 9:10, 1:1).
The observed regiochemistry was in good agreement with
the previously proposed model.11 Accordingly, oxidation
should occur preferentially by abstraction of the hydrogen
a to the nitrogen atom which can be oriented in an anti-
periplanar conformation with respect to the b-alkoxy
group in the intermediate nitrosonium species. Indeed,
such an orientation allows a stabilizing sC–H → s*C–O
electron-donating hyperconjugative interaction to be ef-
fective. This conformation may only be achieved by the
side chain at C-5 (Figure 2, model A), thus leading to 9 as
the major regioisomer, in spite of the supposed higher sta-
bility of the conjugated nitrone 10.12 On the other hand,
10
9
90%
OBn
ii
BnO
96%
OBn
i
BnO
N
N
BnO
BnO
OH
OH
(ds > 95%)
(ds = 92%)
11
12
90%
OBn
iii
13
when the oxidation reaction was carried out with MnO2
BnO
OBn
BnO
at 80 °C in chloroform as the solvent, an equimolar mix-
ture of nitrones 9 and 10 was obtained. These observations
account for a loss of selectivity of the reaction at higher
temperatures.
ii
10
+
90%
N
N
O
BnO
OH
BnO
14 (ds = 90%)
13
13:10 = 1:3
H5
H5
OBn
Scheme 4 Reagents and conditions: i) L-selectride, THF, –80 °C;
ii) DIBAL-H, THF, –80 °C; iii) TEMPO, –80 °C, 48 h.
H
H
N
Ph
H2
O
BnO
N
O
OBn
Bn
Ph
Bn
Catalytic hydrogenation of the diastereomeric hydroxyl-
amines 11, 12, and 14 as described above for 7, in acidic
methanol using the Pearlman’s catalyst, afforded, after
filtration of the catalyst and evaporation of the solvent,
pure 15, 16, and 17, respectively, in quantitative yield
(Scheme 5). Compounds 15–17 were isolated and charac-
terized as the corresponding hydrochlorides14 and thus all
possible diastereomers at C-2 and C-5 of pyrrolidines 6
(Ar = Ph) were obtained.
O
O
BnO
A
Figure 2 Model for oxidation of 7 showing electron-donating
hyperconjugative effect sC–H → s*C–O
.
Reduction of 9 with L-selectride in THF at –80 °C afford-
ed hydroxylamine 11 as the only isomer in 96% yield
(Scheme 4). The reduction of 10 proved to be more diffi-
cult since after treatment with either NaBH4, L-selectride
or LiAlH4 for 24 hours only the starting material was
recovered. Gratifyingly, treatment of 10 with the more
coordinating DIBAL-H, provided an 8:92 mixture of
hydroxylamines 7 and 12, respectively, in 90% yield.
After chromatographic purification, hydroxylamine 12
was isolated in 81% yield. In both cases the major product
resulted from delivery of hydride to the less-hindered
face, in an antiperiplanar manner to the vicinal benzyloxy.
The oxidation of 12 gave, in all cases, nitrone 10 as the
major compound, the best conditions for maximizing the
11
12
14
100%
OH
100%
OH
i
i
100%
OH
i
HO
HO
HO
Cl
Cl
Cl
N
N
N
H2
H2
H2
HO
HO
HO
15
17
16
Scheme 5 Reagents and conditions: i) H2 (5 atm), Pd(OH)2–C,
HCl–MeOH, r.t.
Synlett 2007, No. 17, 2651–2654 © Thieme Stuttgart · New York

LETTER
Nucleophilic Additions to Pyrroline N-Oxides
2653
Having shown that a phenyl group at C-2 of the pyrrol-
idine ring can be efficiently introduced, we targeted the
natural radicamine B. The synthesis of that compound is
straightforward and has been achieved in two steps from
nitrone 5 as depicted in Scheme 6. The addition of 4-ben-
zyloxyphenylmagnesium bromide15 to 5 took place with
complete selectivity affording hydroxylamine 18. The ste-
reochemical outcome of the reaction is explained well by
invoking a Felkin–Anh-type transition-state model with
attack of the nucleophile from the less hindered face.4,16
Acknowledgment
We thank for their support of our programs: the Spanish Ministry of
Science and Education (MEC. Madrid, Spain), FEDER Program
and the Government of Aragon (Zaragoza, Spain) and MiUR
(Italy). One of us (I.D.) also thanks Gobierno de Aragon and the
Socrates/Erasmus exchange program for grants.
References and Notes
(1) (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645. (b) Watson, A.
A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J.
Phytochemistry 2001, 56, 265. (c) Asano, N. Curr. Top.
Med. Chem. 2003, 3, 471. (d) Ayad, T. Y.; Genisson, Y.;
Baltas, M. Curr. Org. Chem. 2004, 8, 1211. (e) de Melo, E.
B.; Domes, A. da S.; Carvalho, I. Tetrahedron 2006, 62,
10277. (f) Caines, M. E. C.; Hancock, S. M.; Tarling, C. A.;
Wrodnigg, T. M.; Stick, R. V.; Stütz, A. E.; Vasella, A.;
Withers, S. G.; Strynadka, N. C. J. Angew. Chem. Int. Ed.
2007, 46, 4474.
(2) (a) Stütz, A. E. Iminosugars as Glycosidase Inhibitors:
Nojirimycin and Beyond; Wiley-VCH: Weinheim, 1999.
(b) Compain, P.; Martin, O. R. Iminosugars: From Synthesis
to Therapeutic Applications; Wiley: Chichester, 2007, in
press.
BnO
OBn
i
5
92%
N
BnO
OH
18
ii 100%
OBn
HO
OH
HO
OH
Cl
iii
99%
N
N
H
H2
HO
radicamine B (2)
HO
OH
OH
2 · HCl
(3) (a) Shibano, M.; Tsukamoto, D.; Masuda, A.; Tanaka, Y.;
Kusano, G. Chem. Pharm. Bull. 2001, 49, 1362.
Scheme 6 Reagents and conditions: i) 4-BnOC6H4MgBr, THF,
0 °C; ii) H2 (5 atm), Pd(OH)2–C, HCl–MeOH, r.t.; iii) Dowex 5WX8-
200, NH4OH (1 N).
(b) Shibano, M.; Tsukamoto, D.; Kusano, G. Heterocycles
2002, 57, 1539. (c) Chandrasekar, S.; Jagadeshwar, V.;
Prakash, S. J. Tetrahedron 2005, 46, 3127. (d) Haddad, M.;
Larcheveque, M. Synlett 2003, 274. (e) Toyao, A.; Tamura,
O.; Tagaki, H.; Ishibashi, H. Synlett 2003, 35. (f) Severino,
E. A.; Correia, C. R. D. Org. Lett. 2000, 2, 3039. (g) See
also ref. 5 and 6.
Natural radicamine B was obtained in only one additional
step consisting of catalytic hydrogenation in HCl–MeOH
in the presence of 10 mol% Pearlman’s catalyst. By using
this catalyst [Pd(OH)2–C], instead of those previously
(4) Goti, A.; Cicchi, S.; Mannucci, V.; Cardona, F.; Guarna, F.;
Merino, P.; Tejero, T. Org. Lett. 2003, 5, 4235.
5
reported (PdCl2 and Pd–C6), radicamine B was isolated
as the corresponding hydrochloride in high overall yield
(92%, 2 steps, Scheme 6).17 Although isolation of radi-
camine B (2) as hydrochloride is justified by its higher
stability, the free amine was obtained by elution through a
ion-exchange column (Dowex 5WX8-200) with 1 N
NH4OH. Synthesized radicamine B (2) showed identical
physicochemical data to those reported for the natural
compound3a,17 and for the enantiomer,5,6,17 in the last case
with exception of the opposite sign of optical rotation.
(5) Gurjar, M. K.; Borhade, R. G.; Puranik, V. G.; Ramana, C.
V. Tetrahedron Lett. 2006, 47, 6979.
(6) Yu, C.-Y.; Huang, M.-H. Org. Lett. 2006, 8, 3021.
(7) In their original papers, appeared during the preparation of
this manuscript, Gurjar (ref. 5) and Yu (ref. 6) reported the
synthesis of the enantiomers of the natural products since
they started from ent-5, synthesizing ent-1 and ent-2. Indeed,
Yu et al. (ref. 6) revised the configuration of both natural
radicamines A and B as those given in Figure 1.
(8) (a) Cardona, F.; Faggi, E.; Liguori, F.; Cacciarini, M.; Goti,
A. Tetrahedron Lett. 2003, 44, 2315. (b) Carmona, A. T.;
Whigtman, R. H.; Robina, I.; Vogel, P. Helv. Chim. Acta
2003, 86, 3066. (c) Desvergnes, S.; Py, S.; Vallée, Y. J. Org.
Chem. 2005, 70, 1459. (d) Cicchi, S.; Marradi, M.; Vogel,
P.; Goti, A. J. Org. Chem. 2006, 71, 1614. (e) Revuelta, J.;
Cicchi, S.; Goti, A.; Brandi, A. Synthesis 2007, 485.
(9) Data for 8: [a]D20 +57 (c 1.11, H2O). 1H NMR (400 MHz,
D2O): d = 3.63 (ddd, J = 8.2, 5.5, 4.1 Hz, 1 H, H5), 3.83 (dd,
J = 13.3, 6.3 Hz, 1 H, CH2OH), 3.88 (dd, J = 13.3, 4.5 Hz, 1
H, CH2OH), 4.11 (t, J = 7.5 Hz, 1 H, H4), 4.39 (d, J = 9.9 Hz,
1 H, H2), 4.43 (dd, J = 10.0, 6.9 Hz, 1 H, H3), 7.37–7.47 (m,
5 H, Ar). 13C NMR (100 MHz, D2O): d = 58.1 (CH2OH),
61.9 (C2), 63.2 (C5), 73.7 (C3), 77.5 (C4), 128.3 (Ar), 128.5
(Ar), 130.3 (Ar), 131.3 (Ar). Anal. Calcd for C11H16NO3Cl:
C, 53.77; H, 6.56; N, 5.70. Found: C, 53.92; H, 6.74; N, 5.68.
(10) Marradi, M.; Cicchi, S.; Delso, I.; Rosi, L.; Tejero, T.;
Merino, P.; Goti, A. Tetrahedron Lett. 2005, 46, 1287.
(11) (a) Goti, A.; Cicchi, S.; Fedi, V.; Nannelli, L.; Brandi, A. J.
Org. Chem. 1997, 62, 3119. (b) Cicchi, S.; Goti, A.; Brandi,
A. J. Org. Chem. 1995, 60, 4743.
In conclusion, we have established an efficient oxidation–
reduction protocol for the preparation of unfavorable dia-
stereomers of polyhydroxylated pyrrolidines according to
the more expeditious approach for those compounds, con-
sisting of the nucleophilic addition of an organometallic
reagent to a cyclic nitrone. Taking advantage of the ex-
cellent selectivity offered by polyhydroxylated cyclic
nitrones in nucleophilic addition reactions, natural radi-
camine B has been synthesized, thus demonstrating their
previously assigned revised configuration.6 The synthesis
of other 2-aryl polyhydroxylated pyrrolidines with differ-
ent configurations at the stereogenic centers of the pyr-
rolidine ring is under investigation in our laboratories.
Synlett 2007, No. 17, 2651–2654 © Thieme Stuttgart · New York

2654
P. Merino et al.
LETTER
75.0 (C3), 77.4 (C5), 127.8 (Ar), 128.8 (Ar), 129.1 (Ar),
131.3 (Ar), 132.1 (Ar). Anal. Calcd for C11H16NO3Cl: C,
53.77; H, 6.56; N, 5.70. Found: C, 53.85; H, 6.40; N, 5.45.
(15) Yu, Y.; Singh, S. K.; Liu, A.; Li, T.-K.; Liu, L. F.; LaVoice,
E. J. Bioorg. Med. Chem. 2003, 11, 1475.
(12) Semiempirical calculations (PM3) demonstrated a slightly
higher stability of 15 (DHf = –80.60 kcal/mol), with respect
to 14 (DHf = –79.21 kcal/mol).
(13) Cicchi, S.; Marradi, M.; Goti, A.; Brandi, A. Tetrahedron
Lett. 2001, 42, 6503.
(14) Data for 15: [a]D20 +45 (c 0.41, H2O). 1H NMR (400 MHz,
D2O): d = 3.86–3.96 (m, 3 H, H5, CH2OH), 4.35 (t, J = 3.3
Hz, 1 H, H4), 4.41 (d, J = 5.9 Hz, 1 H, H2), 4.49 (dd, J = 5.9,
3.1 Hz, 1 H, H3), 7.40–7.50 (m, 5 H, Ar). 13C NMR (100
MHz, D2O): d = 56.9 (CH2OH), 62.9 (C2), 67.6 (C5), 74.5
(C3), 79.8 (C4), 128.4 (Ar), 129.4 (Ar), 130.0 (Ar), 132.1
(Ar). Anal. Calcd for C11H16NO3Cl: C, 53.77; H, 6.56; N,
5.70. Found: C, 53.70; H, 6.62; N, 5.79.
(16) Merino, P.; Revuelta, J.; Tejero, T.; Cicchi, S.; Goti, A. Eur.
J. Org. Chem. 2004, 776.
(17) Data for 2·HCl: [a]D20 +81 (c 0.25, H2O). 1H NMR (400
MHz, D2O): d = 3.57 (ddd, J = 4.0, 6.2, 8.5 Hz, 1 H, H5),
3.81 (dd, J = 6.2, 12.6 Hz, 1 H, CH2OH), 3.86 (dd, J = 4.0,
12.6 Hz, 1 H, CH2OH), 4.08 (t, J = 7.7 Hz, 1 H, H4), 4.31 (d,
J = 10.2 Hz, 1 H, H2), 4.37 (dd, J = 7.5, 10.2 Hz, 1 H, H3),
6.87 (d, J = 8.7 Hz, 2 H, ArH), 7.32 (d, J = 8.7 Hz, 2 H,
ArH). 13C NMR (100 MHz, D2O): d = 58.2 (CH2OH), 61.6
(C2), 62.8 (C4), 73.6 (C3), 77.1 (C5), 116.2 (Ar), 122.9 (Ar),
130.2 (Ar), 157.1 (Ar). Anal. Calcd for C11H16NO4Cl: C,
50.48; H, 6.48; N, 5.63. Found: C, 58.29; H, 6.73; N, 5.80.
Data for 2: [a]D20 +74 (c 0.29, H2O) [Lit. for natural
compound: +72 (c 0.10, H2O);3a Lit. for synthetic
Data for 16: [a]D20 +78 (c 0.54, H2O). 1H NMR (400 MHz,
D2O): d = 3.64 (ddd, J = 8.4, 4.8, 3.5 Hz, 1 H, H5), 3.85 (dd,
J = 12.2, 8.6 Hz, 1 H, CH2OH), 3.95 (dd, J = 12.2, 5.0 Hz, 1
H, CH2OH), 4.11 (dd, J = 3.4, 1.3 Hz, 1 H, H4), 4.37 (dd,
J = 3.3, 1.2 Hz, 1 H, H3), 4.85 (d, J = 3.3 Hz, 1 H, H2), 7.34–
7.40 (m, 5 H, Ar). 13C NMR (100 MHz, D2O): d = 59.4
(CH2OH), 64.8 (C5), 67.5 (C2), 75.9 (C3), 76.6 (C4), 127.5
(Ar), 128.9 (Ar), 129.1 (Ar), 130.3 (Ar). Anal. Calcd for
C11H16NO3Cl: C, 53.77; H, 6.56; N, 5.70. Found: C, 53.88;
H, 6.59; N, 5.83.
enantiomer: –69 (c 0.20, H2O)5 and –72.7 (c 0.17, H2O)6]. 1H
NMR (400 MHz, D2O): d = 2.83–2.91 (m, 1 H, H5), 3.35
(pseudo t, J = 9.9 Hz, 1 H, CH2OH), 3.40–3.56 (m, 3 H,
CH2OH + H4 + H3), 3.73 (pseudo t, J = 7.8 Hz, 1 H, H2), 6.92
Data for 17: [a]D20 +27 (c 0.10, H2O). 1H NMR (400 MHz,
D2O): d = 3.90 (dd, J = 12.0, 8.2 Hz, 1 H, CH2OH), 3.98 (dd,
J = 12.1, 5.1 Hz, 1 H, CH2OH), 3.98–4.06 (m, 1 H, H5),
4.30–4.34 (m, 1 H, H2), 4.46 (dd, J = 4.3, 1.3 Hz, 1 H, H4),
4.81–4.85 (s, 1 H, H3), 7.34–7.43 (m, 5 H, Ar). 13C NMR
(100 MHz, D2O): d = 58.3 (CH2OH), 62.5 (C2), 64.0 (C4),
(d, J = 8.0 Hz, 2 H, ArH), 6.37 (d, J = 8.0 Hz, 2 H, ArH). 13
C
NMR (100 MHz, D2O): d = 62.3 (C2), 63.5 (CH2OH), 63.8
(C4), 78.4 (C3), 82.9 (C5), 116.7 (Ar), 126.1 (Ar), 128.8 (Ar),
165.7 (Ar). Anal. Calcd for C11H15NO4: C, 58.66; H, 6.71; N,
6.22. Found: C, 58.50; H, 6.90; N, 6.31.
Synlett 2007, No. 17, 2651–2654 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.