N-glycosylation of 2,3-dideoxyfuranose derivatives having difluoromethylene-phosphonate and -phosphonothioate functionality at the 3α-position

Article abstract of DOI:10.1055/s-2002-34218

TiCl₄-Mediated N-glycosylation of 2,3-dideoxyribofunanosides having a difluoromethylene-phosphonate or -phosphonothioate functional group at the 3α-position with silylated pyrimidines was examined. The phosphonate functional was a good directin

Full text of DOI:10.1055/s-2002-34218

LETTER
1657
N-Glycosylation of 2,3-Dideoxyfuranose Derivatives Having Difluoro-
methylene-phosphonate and -phosphonothioate Functionality at the 3 -Position
N
-Glycosylation
e
of 2,3-D
i
t
deoxyfu
s
ranose
D
u
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
E-mail: yokomatu@ps.toyaku.ac.jp
Received 3 August 2002
BzO
BzO
BzO
T(TMS)2
Abstract: TiCl4-Mediated N-glycosylation of 2,3-dideoxyribo-
funanosides having a difluoromethylene-phosphonate or -phospho-
nothioate functional group at the 3 -position with silylated
pyrimidines was examined. The phosphonate functional was a good
directing group to induce -N-glycosylation for -N3-pyrimidine-
nucleotide analogue 13 in high diastereoselectivity. The phospho-
nothioate was an effective functional group to give -N1-pyrimi-
dine-nucleotide analogues 18a–c with good diastereoselectivity.
The nucleotide analogue 18a was transformed to the difluorometh-
ylenephosphonate analogue 20 of thymidine-3′-phosphate by oxi-
dation with MCPBA, followed by aqueous work-up.
T
T
O
O
O
OEt
TiCl4
CH2P(X)(OEt)2
CH2P(O)(OH)2
CH2P(S)(OEt)2
X=S
X=O
3
1a
1b
2 (92% de)
BzO
O
S
P
OEt
OEt
Key words: nucleotide analogues, N-glycosylations, neighbour-
ing-group effects, phosphorus, fluorine
A
Scheme 1
Since the discovery of certain sugar-modified nucleosides
and nucleotides having potential antiviral and antitumor
effects, many useful strategies for modification of natural-
ly occurring nucleosides and nucleotides have been de-
vised in the search for novel nucleotide analogues having
significant biological activity.1 Replacement of 3 - or 5 -
phosphate moiety of naturally occurring nucleotides with
metabolically stable methylenephosphonate functional
group has been introduced to synthesize novel nucleotide
analogues which act as a pseudoterminator of poly-
merase-catalyzed RNA-synthesis2 or as important compo-
nents of antisense oligonucleotides having increased
resistance to nuclease.3
With a view to obtaining metabolically stable nucleotide
analogues which act as a mimic for the naturally occurring
nucleotides, replacement of the phosphate moiety with a
difluoromethylenephosphonic acid would be a good tac-
tic.4 Many , -difluoromethylenephosphonate derivatives
have been studied as a potential enzyme inhibitor and as a
useful probe for elucidation of biochemical processes.5
Methods for synthesis of 5 -deoxy-5 -difluoromethylene-
phosphonate nucleotide analogues 4 have been devel-
oped.6 However, to the best of our knowledge, methods
for stereoselective synthesis of 2 ,3 -dideoxy-3 -difluoro-
methylenephosphonate nucleotide analogues of general
structure 5 have not been developed.7 In this paper, we re-
port stereoselective synthesis of 2 ,3 -dideoxy-3 -
difluoromethylenephosphonate nucleotide analogues by
the phosphnothioate-assisted N-glycosylation with pyr-
imidine bases as an extension of our previous work
(Figure 1).
In the synthesis of a series of metabolically stable 2 ,3 -
dideoxynucleotide analogues having a methylenephos-
phonate functionality at the 3 -position, previously, we
have pursued Lewis acid-mediated N- and C-glycosyla-
tion of 2,3-dideoxyfuranose derivatives 1a,b possessing a
methylenephosphonate or methylenephosphonothioate
functionality.8 In the N-glycosylation with the phospho-
nothioate 1a, the phosphonothioate functional group ef-
fectively participates in forming the bicyclic cationic
intermediate A to give the -nucleotide analogue 2 stereo-
selectively (92% de) under the modified Vorbrüggen
conditions (Scheme 1).8a,9 The nucleotide analogue 2
was transformed to the phosphonic acid analogue 3 of
thymidin-3 -phosphate through exchanging the phos-
phonothioate functionality to phosphonic acid.
HO
(HO)2(O)PF2C
B
B
O
O
CF2P(O)(OH)2
OH OH
4
5
Figure 1
First, we examined N-glycosylation of the glycosyl donor
12 having the difluoromethylenephosphonate functional-
ity (Scheme 3). The glycosyl donor 12 was readily pre-
pared from 1,2-O,O-isopropylidene-(R)-glyceraldehyde 6
as shown in Scheme 2. Horner–Emmons–Wadsworth
reaction of 6 with tert-butyl diethylphosphonoacetate
Synlett 2002, No. 10, Print: 01 10 2002.
Art Id.1437-2096,E;2002,0,10,1657,1660,ftx,en;U05502.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1658
T. Murano et al.
LETTER
gave the unsaturated ester 7 in 80% yield. Reaction
between 7 and diethyl (lithiodifluoromethyl)phos-
phonate10 at –78 °C in THF gave the Michael adduct 8 in
81% yield as a 1:1 mixture of diastereoisomers. Treatment
of the mixture with concentrated HCl in EtOH at 25 °C re-
producibly gave the trans-lactone 911 as the sole product
in 50% yield. Under the conditions, the (3R,4S)-diastere-
oisomer of 8 was rapidly lactonized, but the (3S,4S)-dias-
tereoisomer decomposed during the reaction.12 The
relative stereochemistry of 9 was deduced by a NOESY-
experiment, which showed a strong correlation between
H-3 and the methylene protons to the hydroxyl. Reduc-
tion of 10 with BH3 THF in THF at 0 °C gave the lactol
11 in 80% yield without affecting the phosphonate func-
tional group. The lactol 11 was transformed to an anomer-
ic mixture of 1-ethoxy derivative 12 ( : = 1:1) in 95%
yield on treatment with triethyl orthoformate in EtOH in
the presence of a catalytic amount of ammonium nitrate.
TBDPSO
TBDPSO
O
H
O
O
TiCl4 / T(TMS)2
CH2Cl2 / 0 °C
Me
OEt
N
(EtO)2(O)PCF2
N
H
CF2P(O)(OEt)2
O
(90% de)
12
13
Scheme 3
H
H
O
TBDPSO
H
O
H
H
N
H
N
R
O
H
Me
R=CF2P(O)(OEt)2
Figure 2 NOESY-correlations of 13
O
O
a
O
b
O
examined N-glycosylation of the phosphonothioate ana-
logues 16 and 17 with bis-trimethylsilylpyrimidines
(Scheme 4 and Table 1). The glycosyl donors 16 and 17
were prepared from the lactone 10. Thionylation of 10
with Lawesson’s reagent in refluxing toluene gave the
phosphonothioate 14 in 80% yield, which was trans-
formed to an anomeric mixture of 1-ethoxy derivative 16
( : = 1:1) via the lactol 15 in good overall yield (76%) in
an analogous manner to that of synthesis of 12. The lactol
15 was also transformed to an anomeric mixture of 1-ace-
toxy derivative 17 ( : = 1:1) by the standard protocol
(Ac2O, pyridine). The previous results of Lewis acid-me-
diated N-glycosylation of non-fluorinated glycosyl donor
1a with (T(TMS)2) revealed that TiCl4 was the best Lewis
acid to induce the high stereoselectivity and yield.8a Then,
1-ethoxy derivative 16 was treated with T(TMS)2 in the
presence of TiCl4 in CH2Cl2 at 0 °C for 3 hours. In con-
trast to N-glycosylation of the phosphonate analogue 12,
the desired -N-glycosylation proceeded with a good dia-
stereoselectivity ( : = 89:11) to give -N1-nucleotide an-
alogue 18a in 93% yield (entry 1). The relative
stereochemisty of 18a and the site of glycosylation on the
pyrimidine were confirmed on the basis of the NOESY-
experiments. The diagnostic NOESY-correlations are de-
picted in Figure 3. Under the same conditions, bis-tri-
methylsilyluracil [U(TMS)2] reacted with 16 to give 18b
in 63% yield with comparable diastereoselectivity (entry
2). However, significant decrease in diastereoselectivity
was observed in the reaction with bis-trimethylsilyl-5-
fluorouracil [5-FU(TMS)2] (entry 3). The 1-acetoxy de-
rivative 17 seems to be less potent as a glycosyl donor
than 1-ethoxy derivative16; the reaction of 17 with
T(TMS)2 under the same conditions resulted in a signif-
icant loss of the diastereoselectivity and yield (entries 1
vs. 4). A similar trend was observed for the reaction with
U(TMS)2 (entries 2 vs. 5).
CO2But
CHO
6
7
HO
O
O
d
O
O
c
CO2But
CF2P(O)(OEt)2
CF2P(O)(OEt)2
9
8
SPDBTO
SPDBTO
O
O
e
O
OX
CF2P(O)(OEt)2
CF2P(O)(OEt)2
10
11 X=H
12
f
X=Et
Scheme 2 Reagents and conditions: (a) (EtO)2P(O)CH2CO2-t-Bu,
NaH, THF, 80%; (b) LiCF2P(O)(OEt)2, THF, –78 °C, 81%; (c) concd
HCl, EtOH, 50%; (d) TBDPSCl, imidazole, DMF, 85%; (e)
BH3 THF, THF, 0 °C, 80%; (f) CH(OEt)3, cat. NH4NO2, EtOH,
80 °C, 95%.
N-Glycosylation of 12 with bis-trimethylsilylthymine
T(TMS)2 was carried out at 0 °C in CH2Cl2 in the presence
of TiCl4. The reaction gave the -N3-nucleotide analogue
13 of a high diastereomeric excess (90% de) in 42% yield.
In this reaction, T(TMS)2 reacted with 12 preferably at the
N3-nitorogen of the pyrimidine from -face of the glyco-
syl donor.9c The site of glycosylation on the pyrimidine
could be assigned by characteristic downfield shift ( =
6.83, t, J = 7.7 Hz) of the anomeric proton as well as a
strong correlation between N1-H and H-6 in the NOESY
spectrum (Figure 2). -Configuration of 13 was assigned
on the basis of the observed NOESY-relay correlations
among protons in the sugar moiety depicted in Figure 2.
With the results of N-glycosylation of 12 having a difluo-
romethylenephosphonate functionality in mind, we next
Synlett 2002, No. 10, 1657–1660 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
N-Glycosylation of 2,3-Dideoxyfuranose Derivatives
1659
T(TMS)2 in the presence of TiCl4 kinetically produces
the -N3-nucleotide analogue 19 with poor diastereoselec-
tivity, which isomerizes to the thermodynamically more
stable -N1-nucleotide analogue 18a with good diastereo-
selectivity under the conditions.
TBDPSO
Lawesson's reagent
toluene / 110 °C
O
BH3•THF / 0 °C
O
10
CF2P(S)(OEt)2
O
14
R
NH
TBDPSO
TBDPSO
O
TBDPSO
O
N
O
H
O
O
TiCl4 / T(TMS)2
OX
TiCl4 / B(TMS)2
CH2Cl2 / 0 °C
Me
17
N
CH2Cl2 / –40 °C
CF2P(S)(OEt)2
(EtO)2(S)PF2C
CF2P(S)(OEt)2
N
O
H
15
X=H
16 X=Et
X=Ac
18a-c
(β:α = 34:66)
19
17
TiCl4 / T(TMS)2
17
18a (β:α = 88:12)
Scheme 4
CH2Cl2 / –40 to 0 °C
Scheme 5
Table 1 N-Glycosylation of 16 and 17 with Silylated Pyrimidines in
the Presence of TiCl4
The nucleotide analogue 18a ( : = 89:11) thus obtained
was converted to the difluoromethylenephosphonate ana-
logue 20 of thymidine-3 -phosphate in 64% yield by oxi-
dation with MCPBA (5.0 equiv), followed by aqueous
work-up. Diastereomerically pure 20 could be isolated
Entrya Glycosyl Baseb
donor
18
R
Yield Ratio
( : )c
1
2
3
4
5
16
16
16
17
17
T(TMS)2
U(TMS)2
5-FU(TMS)2
T(TMS)2
U(TMS)2
18a
18b
18c
18a
18b
Me
H
93
64
84
72
52
89:11
87:13
76:24
70:30
84:16
by
preparative
HPLC
[Inertsil
(GL-science),
F
hexane:EtOAc = 1:1, Scheme 6].
Me
H
O
O
N
Me
NH
Me
TBDPSO
NH
O
TBDPSO
a All reactions were carried out at 0 °C for 3 h in the presence of 5.0
equiv of TiCl4 in CH2Cl2.
O
N
O
O
MCPBA / CH2Cl2
aq. NaHCO3
1)
b Prepared in situ from bis-trimethylsilylacetamide (2.0 equiv) and the
base (2.0 equiv) in the solvent.
2)
CF2P(S)(OEt)2
CF2P(O)(OEt)2
c Determined by 1H NMR (400 MHz, CDCl3).
18a
20
Scheme 6
O
Me
NH
In summary, we have developed an efficient method for
the stereoselective synthesis of novel 2 ,3 -dideoxyribo-
nucleotide analogues, in which the difluoromethylene-
phosphonate functionality is incorporated to the 3 -
position as a phosphate isostere.
H
H
TBDPSO
N
O
O
H
R=CF2P(S)(OEt)2
H
H
R
H
Acknowledgement
Figure 3 NOESY-correlations of 18a
This work was supported in part by Grants-in-Aid for Scientific
Research (C) (to S. S) and for Encouragement of Young Scientists
(to T. M) from the Ministry of Education, Culture, Sports, Science
and Technology of Japan.
The reactivity of the TiCl4-mediated N-glycosylation of
1-acethoxy derivative 17 with T(TMS)2 was significantly
affected by the reaction temperature.13 On reaction of 17
with T(TMS)2 (2 equiv) in CH2Cl2 in the presence of TiCl4
(5 equiv) at –40 °C for 3 hours, T(TMS)2 reacted at the N3-
nitrogen to give a 66:34 mixture of -N3-nucleotide ana-
logue 19 and the corresponding -anomer in 72% yield.
However, when the reaction was carried out at –40 ºC for
3 hours, and was quenched after being stirred at 0 °C for
an additional 3 hours, -N1-nucleotide analogue 18a
( : = 88:12) was produced in 78% yield (Scheme 5). The
results may suggest that the N-glycosylation of 17 with
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Synlett 2002, No. 10, 1657–1660 ISSN 0936-5214 © Thieme Stuttgart · New York

1660
T. Murano et al.
LETTER
127.6, 120.1 (dt, JCP = 216.2 Hz, JCF = 263.7 Hz), 110.3,
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42.3 (dt, JCP = 14.4 Hz, JCF = 20.7 Hz), 29.9, 26.8, 19.3, 16.4
(d, JCP = 5.2 Hz), 12.9. 19F NMR (376 MHz, CDCl3,
benzotrifluoride): = –47.1 (1 F, dd, JFF = 300.9 Hz,
JFP = 105.7 Hz), –58.5 (1 F, ddd, JFF = 300.9 Hz, JFP = 111.5
Hz, JFH = 26.1 Hz). 31P NMR (162 MHz, CDCl3): = 6.77
(dd, JPF = 105.7, 111.5 Hz). MS (EI): m/z = 593 [M+ – t-Bu].
HRMS (EI): m/z calcd for C27H32N2O7F2PSi [M+ – t-Bu]:
593.1697. Found: 593.1697. Anal. Calcd for
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(6) (a) Blackburn, G. M.; Guo, M.-J. Tetrahedron Lett. 1993,
34, 149. (b) Matulic-Adamic, J.; Usman, N. Tetrahedron
Lett. 1994, 35, 7193. (c) Matulic-Adamic, J.; Haeberli, P.;
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(7) (a) Lequeux, T. P.; Percy, J. M. Synlett 1995, 361. (b) Butt,
A. H.; Percy, J. M.; Spencer, N. S. Chem. Commun. 2000,
1691.
C31H41N2O7F2PSi: C, 57.22; H, 6.35; N, 4.30. Found: C,
56.61; H, 6.35; N, 4.22.
Compound 18a: [ ]D20 +30.2 (c 1.3, CHCl3) for a sample of
78% de. 1H NMR (400 MHz, CDCl3): = 8.07 (1 H, br s),
7.71–7.62 (4 H, m), 7.49–7.34 (7 H, m), 6.19 (1 H, t, J = 6.8
Hz), 4.46–4.40 (1 H, m), 4.31–4.17 (4 H, m), 4.16–4.08 (1
H, m), 3.84 (1 H, dd, J = 2.4, 11.6 Hz), 3.68–3.50 (1 H, m),
2.82–2.72 (1 H, m), 2.21–2.11 (1 H, m), 1.56–1.53 (3 H, m),
1.36 (32 H, t, J = 7.0 Hz), 1.34 (3 H, t, J = 7.0 Hz), 1.11 (9
H, s). 13C NMR (100 MHz, CDCl3): = 163.9, 150.3, 135.5,
135.2, 135.0, 133.1, 132.3, 130.0 (2 carbons), 127.9 (2
carbons), 120.9 (dt, JCP = 176.5 Hz, JCF = 268.4 Hz), 111.3,
84.5, 78.9, 64.9 (d, JCP = 6.7 Hz), 64.5, 41.5 (dt, JCP = 16.6
Hz, JCF = 20.4 Hz), 33.1, 26.9, 19.4, 16.1 (d, JCP = 5.7 Hz),
11.9. 19F NMR (376 MHz, CDCl3, benzotrifluoride):
=
–50.3 (1 F, ddd, JHF = 13.1 Hz, JFF = 289.5 Hz, JFP = 110.6
Hz), –54.7 (1 F, ddd, JHF = 21.9 Hz, JFF = 289.5 Hz,
JFP = 107.7 Hz). 31P NMR (162 MHz, CDCl3): = 74.9 (dd,
J
PF = 107.7 Hz, 110.6 Hz). MS (EI): m/z = 609 [M+ – t-Bu],
541 [M+ – thymine]. Anal. Calcd for C31H41N2O6F2PSSi: C,
55.84; H, 6.20; N, 4.20. Found: C, 55.65; H, 6.14; N, 4.01.
Compound 20: [ ]D20 +34.0 (c 1.0, CHCl3). 1H NMR (400
MHz, CDCl3): = 8.24 (1 H, br s), 7.71–7.61 (4 H, m), 7.48–
7.33 (6 H, m), 6.19 (1 H, t, J = 6.9 Hz), 4.48–4.42 (1 H, m),
4.35–4.21 (4 H, m), 4.16–4.08 (1 H, m), 3.84 (1 H, dd,
J = 2.5, 11.6 Hz), 3.46–3.25 (1 H, m), 2.85–2.73 (1 H, m),
2.24–2.12 (1 H, m), 1.54 (3 H, s), 1.38 (6 H, t, J = 7.1 Hz),
1.10 (9 H, s). 13C NMR (100 MHz, CDCl3): = 163.9, 150.3,
135.5, 135.4, 135.2, 133.1, 132.3, 130.0 (2 carbons), 127.9
(2 carbons), 119.9 (dt, JCP = 214.3 Hz, JCF = 263.3 Hz),
111.3, 84.5, 78.5, 64.9 (d, JCP = 6.8 Hz), 64.8 (d, JCP = 7.0
Hz), 64.6, 42.3 (dt, JCP = 15.0 Hz, JCF = 20.2 Hz), 32.7, 26.9,
19.4, 16.3 (d, JCP = 5.2 Hz), 11.9. 19F NMR (376 MHz,
CDCl3, benzotrifluoride): = –51.1 (1 F, ddd, JHF = 14.5 Hz,
(8) (a) Yokomatsu, T.; Sada, T.; Shimizu, T.; Shibuya, S.
Tetrahedron Lett. 1998, 39, 6299. (b) Yokomatsu, T.; Sada,
T.; Shimizu, T.; Shibuya, S. Heterocycles 2000, 52, 515.
(9) Reviews for N-glycosylation in the synthesis of nucleosides
and nucleotides: (a) Vorbüggen, H. Acc. Chem. Res. 1995,
28, 509. (b) Wilson, L. J.; Hager, M. W.; El-Kattan, Y. A.;
Liotta, D. C. Synthesis 1995, 1465. (c) Vorbrüggen, H.;
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Lett. 1992, 33, 1839. (b) Berkowitz, D. B.; Eggen, M.; Shen,
Q.; Shoemarker, R. J. Org. Chem. 1996, 61, 4666.
(11) Spectroscopic data for selected new compounds:
Compound 9: [ ]D20 +13.8 (c 1.0, CHCl3). 1H NMR (400
MHz, CDCl3): = 4.90–4.83 (1 H, m), 4.38–4.23 (4 H, m),
4.00 (1 H, dd, J = 2.6, 12.5 Hz), 3.72 (1 H, dd, J = 2.9, 12.5
Hz), 3.40–3.22 (1 H, m), 2.85 (2 H, d, J = 8.4 Hz), 2.56 (1 H,
br s), 1.40 (6 H, t, J = 7.1 Hz). 13C NMR (100 MHz, CDCl3):
= 175.1, 119.1 (dt, JCP = 215.4 Hz, JCF = 263.0 Hz), 78.6
(d, JCP = 4.0 Hz), 65.2 (d, JCP = 7.1 Hz), 65.0 (d, JCP = 7.1
Hz), 63.0, 40.1 (dt, JCP = 15.8 Hz, JCF = 21.0 Hz), 20.3, 16.0
(d, JCP = 5.2 Hz). 19F NMR (376 MHz, CDCl3, benzo-
trifluoride): = –54.49 (1 F, dd, JHF = 4.9 Hz, JPF = 105.2
Hz), –54.54 (1 F, JHF = 5.8 Hz, JPF = 105.2 Hz). 31P NMR
(162 MHz, CDCl3): = 5.76 (t, JPF = 105.2 Hz). MS (EI):
m/z = 303 [M+ + 1], 285 [M+ – OH], 271 [M+ – CH2OH].
IR(film): 3247, 2988, 1789, 1645 cm–1. Anal. Calcd for
C10H17O6F2P: C, 39.74; H, 5.67. Found: C, 39.43; H, 5.66.
Compound 13: [ ]D20 +60.4 (c 1.3, CHCl3). 1H NMR (400
MHz, CDCl3): = 9.56 (1 H, d, J = 5.6 Hz), 7.74–7.62 (4 H,
m), 7.48–7.31 (6 H, m), 6.91 (1 H, dd, J = 1.1, 5.6 Hz), 6.83
(1 H, t, J = 7.7 Hz), 4.90–4.83 (1 H, m), 4.34–4.19 (4 H, m),
4.02–3.94 (1 H, m), 3.82–3.74 (1 H, m), 3.64–3.45 (1 H, m),
3.02 (1 H, ddd, J = 8.4, 12.4, 12.4 Hz), 2.59–2.48 (1 H, m),
1.89 (3 H, d, J = 1.1 Hz), 1.37 (3 H, t, J = 7.1 Hz), 1.36 (3 H,
t, J = 7.1 Hz), 1.07 (9 H, s). 13C NMR (100 MHz, CDCl3):
= 163.9, 152.6, 135.6, 135.5, 135.0, 133.4, 133.1, 129.6,
JFF = 302.9 Hz, JPF = 106.8 Hz), –54.0 (1 F, ddd, JHF = 21.5
Hz, JFF = 302.9 Hz, JPF = 106.8 Hz).
31P NMR (162 MHz, CDCl3): = 6.31 (t, JPF = 106.8 Hz).
MS (EI): m/z = 593 [M+ – t-Bu]. HRMS (EI): m/z calcd for
C27H32N2O7F2PSi [M+ – t-Bu]: 593.1697. Found: 593.1672.
(12) Percy et al. reported that the diol i, in situ prepared
stereoselectively from the corresponding olefin by OsO4-
catalyzed dihydroxylation, was not readily cyclized to the
cis-lactone ii under the conditions.7b They were never able to
isolate more than 11% of ii. The results are consistent with
our findings (Scheme 7).
OH
HO
O
O
HO
CO2Et
CF2P(O)(OEt)2
(EtO)2(O)PF2C
i
ii
Scheme 7
(13) The 1-ethoxy derivative 16 did not react with T(TMS)2 in the
presence of TiCl4 at –40 °C and the lactol 15 was recovered
in 80% yield.
Synlett 2002, No. 10, 1657–1660 ISSN 0936-5214 © Thieme Stuttgart · New York