Butane-2,3-diacetal-desymmetrized glycolic acid - A new building block for the stereoselective synthesis of enantiopure α-hydroxy acids

Article abstract of DOI:10.1002/1521-3773(20010803)40:15<2906::AID-ANIE2906>3.0.CO;2-5

According to a chiral memory protocol, a chiral glycolic acid equivalent, the butane-2,3-diacetal-desymmetrized glycolate 2, is obtained from chiral 3-halopropane-1,2-diols 1. Compound 2 is a new and effective building block for the synthesis of mono- and

Full text of DOI:10.1002/1521-3773(20010803)40:15<2906::AID-ANIE2906>3.0.CO;2-5

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3
78C) and the mixture was filtered in a UltraFree MC 30000 MWCO
a result of this feature, a range of synthesis methods has
centrifugal filtration unit (Millipore) at 3500 g for 7 min at 378C. The
concentration of free substrate in the filtrate was quantified by ICP-MS and
the bound fraction was calculated as % bound ˆ ([total]-[free])/[total].
The proton T (longitudinal NMR relaxation time) value of water was
1
measured at 20 MHz at 24 and 378C by inversion recovery on a Brucker
[4±11]
appeared over the years.
A commonly adopted strategy is
the a-alkylation of chiral glycolic acid equivalents.[
Following our earlier reports using dispiroketal desymmetri-
zation for this purpose, we here report the design, prepara-
tion, and alkylation reactions of a new chiral glycolic acid
12, 13]
Minispec; the data were obtained in PBS or with 4.5% HSA by using 0 ±
0 mm of the Gd3 complex. The relaxivity (r
‡
) was determined from the
versus the sample concentration.
4
1
equivalentÐthe butane-2,3-diacetal-desymmetrized glycolate
slope of the plot of 1/T
1
[14]
1.
Our synthetic plan relied on a chiral memory procedure[15]
Received: March 19, 2001 [Z16799]
whereby the chirality of a readily available 3-halopropane-1,2-
diol 2 would be used to fix the chirality of the butane diacetal
group in the stereoselective protection step.[ It was envis-
aged that the alkyl halide product 3 would undergo ready
elimination of hydrogen halide to form the exo-methylene
[
[
[
1] P. Caravan, J. J. Ellison, T. J. McMurry, R. B. Lauffer, Chem. Rev. 1999,
16]
99, 2293.
2] R. B. Lauffer, D. J. Parmelee, S. Dunham, H. S. Ouellet, R. P. Dolan,
S. Witte, T. J. McMurry, R. C. Walovich, Radiology 1998, 207, 529.
3] Another strategy to improve the rotational correlation times and the
relaxivity of the contrast agent consists of using polymer and
dendrimer conjugates, although no such drugs have been reported
to be at an advanced development stage.
[17]
enol ether, which, after oxidative cleavage, would yield the
facially desymmetrized glycolate 1 (Scheme 1).
[
4] a) A. Y. Louiem, M. M. Huber, E. T. Ahrens, U. Rothbacher, R.
Moats, R. E. Jacobs, S. Fraser, T. J. Meade, Nat. Biotechnol. 2000, 18,
O
O
OH
BDA
protection
3
7
21; b) R. A. Moats, S. E. Frazer, T. J. Meade, Angew. Chem. 1997, 109,
50; Angew. Chem. Int. Ed. Engl. 1997, 36, 726. Other recent examples
elimination
O
O
X
O
O
X
3
‡
of the Gd -based MRI-targeted contrast agents and sensors are:
O
oxidative
cleavage
O
O
OH
c) W.-h. Li, S. E. Fraser, T. J. Meade, J. Am. Chem. Soc. 1999, 121,
1413; d) G. Lemieux, K. J. Yarema, C. L. Jacobs, C. R. Bertozzi, J. Am.
Chem. Soc. 1999, 121, 4278; e) R. Bhorade, R. Weissleder, T.
Nakakoshi, A. Moore, C.-H. Tung, Bioconjugate Chem. 2000, 11,
1
3
2
Scheme 1. Synthetic strategy for the development of a BDA-desymme-
trized glycolate equivalent (BDA ˆ butane diacetal).
301; f) M. P. Lowe, D. Parker, Chem. Commun. 2000, 707.
[
5] a) D. L. Eaton, B. E. Malloy, S. P. Tsai, W. Henzel, D. Drayna, J. Biol.
Chem. 1991, 266, 21833; b) L. Bajzar, R. Manuel, M. E. Nesheim, J.
Biol. Chem. 1995, 270, 14477; c) M. E. Nesheim, Fibrinolysis Proteol-
ysis 1999, 13, 72.
6] T. Peters, Jr., All About Albumin: Biochemistry, Genetics and,
Medical Applications, Academic Press, San Diego, 1996.
7] R. B. Lauffer, T. J. McMurry, S. Dunham, D. Scott, D. J. Parmelee, S.
Dumas, WO-A 97/36619 [Chem. Abstr. 1997, 127, 316334.
8] S. Aime, M. Chiaussa, G. Digilio, E. Gianolio, E. Terreno, J. Biol.
Inorg. Chem. 1999, 4, 66.
The initial route employed (S)-3-bromopropane-1,2-diol 4
available by the Jacobsen dynamic hydrolytic resolution of
epibromohydrin ) as starting material. Treatment with
butane-2,3-dione (1.1 equiv) in methanol in the presence of
trimethyl orthoformate (2.1 equiv) and camphorsulfonic acid
(
[
[
[
[
[18]
(
CSA; 0.1 equiv) at reflux for two hours lead to the BDA-
protected alkyl bromide 5 as a single diastereomer in 84%
yield (Scheme 2). To a solution of this material in THF at 08C
was added an excess (1.2 equiv) of potassium hexamethyldi-
silazide (KHMDS), which on warming to room temperature
overnight, effected a smooth elimination to the desired exo-
methylene enol ether 6 in 85% yield. Ozonolysis under
standard conditions, followed by triphenyl phosphaine work-
up, gave the desired building block 1 in 69% yield as a
colorless solid. Recrystallization of this material from diethyl
ether/hexanes afforded 1 in >99% ee as determined by chiral
GC.
9] R. B. Lauffer, T. J. Brady, EP-A 222,886 B1 [Chem. Abstr. 1990, 113,
94083.
[
10] L. Bajzar, J. Morser, M. E. Nesheim, J. Biol. Chem. 1996, 271, 16603.
Butane-2,3-Diacetal-Desymmetrized Glycolic
AcidÐA New Building Block for the
Stereoselective Synthesis of Enantiopure
a-Hydroxy Acids**
This route was readily modified to allow synthesis on a
multigram scale. Thus, the commercially available and
relatively cheap (S)-3-chloropropane-1,2-diol[ 7 was used
as the starting material. Standard BDA protection of this
compound under the identical conditions described for 5 gave
the crude BDA adduct 8 which was treated with an excess of
potassium tert-butoxide in THF at reflux for 30 minutes.
Ozonolysis with a dimethyl sulfide (DMS) workup afforded
the crude glycolate product as a colorless solid, which on
recrystallization from diethyl ether/hexanes gave enantiomer-
ically pure 1 in 56% yield over the three steps (Scheme 2).
With multigram quantities of enantiopure 1 available,
alkylation reactions were investigated. Initial methylation
studies with lithium hexamethyldisilazide (LHMDS) and
methyl iodide revealed a strong dependence of the crude
Elena Díez, Darren J. Dixon, and Steven V. Ley*
19]
Of the many classes of functional groups and motifs present
in biologically and pharmacologically important compounds,
mono- or dialkylated a-hydroxy acids occur commonly.[ As
1±3]
[
*] Prof. Dr. S. V. Ley, Dr. E. Díez, Dr. D. J. Dixon
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge CB2 1EW (UK)
Fax : (‡ 44)1223-336-442
E-mail: svl1000@cam.ac.uk
[
**] We thank the EU (Marie Curie Fellowship to E.D.), the EPSRC (to
D.J.D.), the Novartis Research Fellowship (to S.V.L.), and Pfizer
Gobal Research and Development, Groton, USA, for financial
support.
2906
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1433-7851/01/4015-2906 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2001, 40, No. 15

COMMUNICATIONS
OH
OH
to the principle attack of the lithium enolate of 1 on the alkyl
halide and not through any secondary enhancement effect.
This was implemented by using substoichiometric quantities
of base. Table 1 shows the results for the alkylation of 1 with a
range of alkyl halides using 0.95 equivalents of LHMDS and
excess electrophile in THF at � 78 to � 308C.
Br
Cl
OH
OH
4
7
a
a
Table 1. Monoalkylations of glycolate 1.
O
O
O
O
O
O
O
O
Br
Cl
a) LHMDS, THF, _78˚C
O
O
O
O
R
O
O
b) RX (3 equiv), _78 → _30˚C
O
O
O
O
c) AcOH (2 equiv), _78˚C → RT
8
1
11–18
5
Entry
1
RX
d.r.
10:1[a]
Product
Yield (conv.)
64%
b
d
OMe
11
Cl
Br
O
O
O
2
3
10:1[b]
15:1
12[c]
13[d]
85% (97%)
61% (87%)
CN
O
O
O
O
I
O
O
O
4
18:1[a]
14[d,e]
92%
Br
6
6
O
c
e
5
6
21:1
60:1
15
57%
I
4
9% over
56% over
three steps
O
three steps
Br
16[c,d]
89% (96%)
O
O
Br
O
17[e]
7
8
> 99:1
96%
O
1
Br
Scheme 2. Synthesis of BDA-desymmetrized glycolic acid from 1-halo-
propane-2,3-diols. a) MeCOCOMe (1.1 equiv), CSA (0.1 equiv),
18[d]
> 99:1
84% (91%)
CH(OMe)
8C !RT; c) O
d) tBuOK (2.0 equiv), THF, reflux, 2 h; e) O
788C, then DMS (2.0 equiv), � 788C !RT.
3
(2.1 equiv), MeOH, reflux, 2 h; b) KHMDS (1.2 equiv), THF,
, CH Cl (1.1 equiv), � 788C !RT;
, � 788C, then PPh
, CH Cl /MeOH (1:1),
0
3
2
2
3
[a] > 99:1 after column chromatography. [b] > 99:1 after recrystallization.
[c] Configuration determined by single-crystal X-ray determination.
[d] Configuration determined by NOE experiments. [e] Configuration
determined by specific rotation comparison after deprotection.
3
2
2
�
diastereomeric ratio (d.r.) on the equivalents of base used.
Thus, with 1.05 equivalents of LHMDS, 9 and 10 were
afforded in an excellent 70:1 ratio, alongside a small amount
In general, the selectivity of the alkylation improved with
increasing size of the electrophile and the reactions gave good
to excellent chemical yields of the alkylated products even
with less reactive alkyl halides such as ethyl and butyl iodide.
With bulky halides such as benzyl bromide and 2-(bromome-
thyl)naphthalene, no minor diastereomer could be detected
within the crude reaction mixture. NOE experiments on the
major diastereomeric products suggested the newly intro-
duced alkyl group was located in an equatorial position and
therefore the newly formed stereogenic center was of the (R)-
configuration. Single-crystal X-ray determination of nitrile 12
and the allylated product 16 confirmed the stereochemical
outcome. This suggested attack of the alkyl halide on the
enolate carbon atom was occurring from the side opposing the
(
ꢀ10%) of dimethylated material. However, with 0.90 equiv-
alents of LHMDS, the same products 9 and 10 were formed in
the ratio of 9:1 with a yield of 84% at 93% conversion
(Scheme 3).
Encouraged by these initial results we examined the
alkylation reactions of 1 further. However, care was taken
to ensure that the observed selectivity in the reactions was due
O
O
O
a or b
O
O
O
O
O
+
O
O
O
O
O
O
O
1,3-related axial methoxy group.
1
9
10
Further alkylation reactions of the monoalkylated products
leading to the dialkylated products were also very effective. In
the first case, successive treatment of the benzylated product
conditions a:
conditions b:
9:10 = 70:1
9:10 = 9:1
Scheme 3. Lithium enolate methylations of 1. a) LHMDS (1.05 equiv),
THF, � 788C, 10 min, then MeI (3.0 equiv), � 78 ! � 308C over 2 h, then
AcOH (2.0 equiv); b) LHMDS (0.9 equiv), THF, � 788C, 10 min, then MeI
1
7 in THF at � 788C with LHMDS (1.1 equiv) and methyl
iodide (3.0 equiv) afforded the two diastereomers 19 and 20 in
(
3.0 equiv), � 78 ! � 308C over 2 h, then AcOH (2.0 equiv).
the ratio of 3:1 and in combined yield of 82% after separation
Angew. Chem. Int. Ed. 2001, 40, No. 15
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by column chromatography. In a complimentary study the
methylated glycolate product 9 was treated with LHMDS and
then benzyl bromide. These conditions afforded 20 as the only
Table 2. Deprotection of mono- and dialkylated BDA-glycolates.
O
R2
R2
R1
3
R O
1
O
R1
observable diastereomeric product by H NMR spectroscopy.
OH
O
The diastereoselectivities in the dialkylation studies clearly
depend on the relative sizes of the attached alkyl group and
the attacking electrophile (Scheme 4).
O
O
O
21–25
[
20]
Entry BDA
Condi- Product
glycolate tions[a]
Yield
Ph
O
O
O
OH
OH
OH
O
a or b
Ph
O
O
O
O
R
O
+
O
21[b]
iPrO
MeO
1
2
14
17
A
B
77%
OiPr
O
O
O
O
O
O
O
R = Bn, 17
R = Me, 9
19
20
conditions a, 19:20 = 3:1, 82%
conditions b, 19:20 = 1:99, 93%
22[c]
quant.
Scheme 4. Dialkylations of monoalkylated BDA-glycolates. a) R ˆ Bn,
LHMDS (1.1 equiv), THF, � 788C, 10 min, then MeI (3.0 equiv),
O
�
78 !08C over 2 h, then AcOH (2.0 equiv); b) R ˆ Me, LHMDS
(
1.1 equiv), THF, � 788C, 10 min, then BnBr (3.0 equiv), � 78 !08C over
3
4
5
18
20
20
B
C
D
23
MeO
MeO
HO
95%
87%
85%
2
h, then AcOH (2.0 equiv).
O
Removal of the BDA protecting group was easily accom-
HO
Me
plished for both the mono- and dialkylated products through
acid-mediated hydrolysis or transesterification (Table 2). For
entries 1, 2, and 5, the absolute configuration of the products
was confirmed as (R) through comparison of the specific
rotations of compounds 21, 22, and 25, respectively, with those
24
O
HO
Me
[
21]
25[d]
reported in the literature.
Derivatization of 23 as the (R)- and (S)-Mosherꢁs esters
confirmed the enantiopurity as >98% ee, suggesting that no
racemization was occurring in either the alkylation or the
deprotection steps. In addition, this derivatization confirmed
O
[
(
1
3
[
a] Conditions: A) TMSCl in iPrOH (0.5m), reflux; B) TMSCl in MeOH
0.5m), 15 min, RT; C) TMSCl in MeOH (0.5m), reflux; D) TFA/H
2
0 (9:1),
0 min, RT. [b] 21: [a]3
.21, CHCl
2
ˆ ‡10.0 (c ˆ 3.12, CHCl
20
D
ˆ ‡11.0, (c ˆ
D
3
) (ref. [21]: [a]
[
22]
the stereochemistry as (R).
32
3
)). [c] 22: [a]
ˆ � 7.6, (c ˆ 2.0, CHCl
D
ˆ ‡6.4 (c ˆ 1.82, CHCl
3
) (ref. [21] for S-isomer:
20
32
D
a]
D
3
)). [d] 25: [a]
ˆ ‡12.8 (c ˆ 1.66, dioxane)
Received: April 2, 2001 [Z16888]
ref. [21]: [a]2
0
ˆ ‡13.2 (c ˆ 1.51, dioxane)).
(
D
[
[
[
1] G. M. Coppola, H. F. Schuster, a-Hydroxy Acids in Enantioselective
Synthesis, VCH, Weinheim, 1997.
2] Y. Murakami, Y. Oshima, Y. Yasumoto, Bull. Jpn. Soc. Sci. Fish. 1982,
[12] a) H. Yu, C. E. Ballard, B. Wang, Tetrahedron Lett. 2001, 42, 1835;
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2
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[
[
[
[
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Burk, C. S. Kalberg, A. Pizzano, J. Am. Chem. Soc. 1998, 120, 4345;
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8] See: T. Ooi, T. Miura, K. Takaya, H. Ichikawa, K. Maruoka,
Tetrahedron 2001, 57, 867, and references therein.
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North, T. Parsons, V. I. Tararov, Tetrahedron 2001, 57, 771; b) U.
Hanefeld, Y. X. Li, R. A. Sheldon, T. Maschmeyer, Synlett 2000, 1775,
and references therein.
Tetrahedron Lett. 1984; 25, 39;
m) J. DꢁAngelo, O. Pag eÁ s,
J. Maddaluno, F. Dumas, G. Revial, Tetrahedron Lett. 1983, 24,
5869.
[13] a) B. C. B. Bezuidenhoudt, G. H. Castle, S. V. Ley, Tetrahedron Lett.
1994, 35, 7447; b) B. C. B. Bezuidenhoudt, G. H. Castle, J. V. Geden,
S. V. Ley, Tetrahedron Lett. 1994, 35, 7451; c) G. H. Castle, S. V. Ley,
Tetrahedron Lett. 1994, 35, 7455; d) G.-J. Boons, R. Downham, K. S.
Kim, S. V. Ley, M. Woods, Tetrahedron 1994, 50, 7157; e) R. Down-
ham, K. S. Kim, S. V. Ley, M. Woods, Tetrahedron Lett. 1994, 35, 769.
[14] J. S. Barlow, D. J. Dixon, A. C. Foster, S. V. Ley, D. J. Reynolds, J.
Chem. Soc. Perkin Trans. 1 1999, 1627.
[
[
[
[
10] F. F. Huerta, Y. R. S. Laxmi, J.-E. Bäckvall, Org. Lett. 2000, 2, 1037.
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Schreier, J. Org. Chem. 1997, 62, 7841.
[15] a) D. J. Dixon, A. C. Foster, S. V. Ley, D. J. Reynolds, J. Chem. Soc.
Perkin Trans. 1 1999, 1635; b) D. J. Dixon, A. C. Foster, S. V. Ley, D. J.
Reynolds, J. Chem. Soc. Perkin Trans. 1 1999, 1631.
2908
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1433-7851/01/4015-2908 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2001, 40, No. 15

COMMUNICATIONS
[
16] S. V. Ley, D. K. Baeschlin, D. J. Dixon, A. C. Foster, S. J. Ince,
H. W. M. Priepke, D. J. Reynolds, Chem. Rev. 2001, 101, 53, and
references therein.
[
[
[
[
17] H. Orth, Angew. Chem. 1952, 64, 544.
18] M. E. Furrow, S. E. Schaus, E. N. Jacobsen, J. Org. Chem. 1998, 63, 6776.
19] Available from Aldrich in either enantiomeric form.
20] For similar observations in reactions using dispiroketal-desymme-
trized glycolic acid, see; a) G.-J. Boons, R. Downham, K. S. Kim, S. V.
Ley, M. Woods, Tetrahedron 1994, 50, 7157; b) R. Downham, K. S.
Kim, S. V. Ley, M. Woods, Tetrahedron Lett. 1994, 35, 769.
3
2
[
21] Specific rotations: 21: [a]
D
ˆ ‡10.0 (c ˆ 3.12, CHCl
3
32
) (available from
Aldrich, [a]2
0
ˆ ‡11.0, (c ˆ 3.21, CHCl
)); 22: [a]
ˆ ‡6.4 (c ˆ 1.82,
D
3
D
2
0
CHCl
3
) (S isomer: [a]
D
ˆ � 7.6, (c ˆ 2.0, CHCl
3
), F. A. Davis, M. S.
Haque, T. G. Ulatowski, J. C. Towson, J. Org. Chem. 1986, 51, 2402);
2
5: [a]3
D
2
ˆ ‡12.8 (c ˆ 1.66, dioxane) (R-isomer: [a]
20
D
ˆ ‡13.2 (c ˆ
1
.51, dioxane), S.-S. Jew, H.-A. Kim, J.-H. Kim, H.-G. Park, Hetero-
cycles 1997, 46, 65).
[
22] J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95, 512.
Directed Assembly of Periodic Materials from
Protein and Oligonucleotide-Modified
Nanoparticle Building Blocks**
So-Jung Park, Anne A. Lazarides, Chad A. Mirkin,*
and Robert L. Letsinger*
Figure 1. Schematic representation of DNA-directed assembly of Au
nanoparticles and streptavidin. A) Assembly of oligonucleotide-function-
alized streptavidin and Au nanoparticles (Au ± STV assembly). B) Assem-
bly of oligonucleotide-functionalized Au nanoparticles (Au ± Au assembly).
Note that 1 and 4 have the same DNA sequence.
In 1996 we reported a method for utilizing DNA and its
synthetically programmable sequence recognition properties
to assemble nanoparticles functionalized with oligonucleo-
[
1]
immobilize such molecules onto oligonucleotide-modified
nanoparticles and generate a new class of hybrid particles that
exhibit the high stability of the oligonucleotide-modified
particles but with molecular recognition properties that are
dictated by the surface-immobilized protein or receptor
rather than the DNA. Alternatively, one could functionalize
a protein that has multiple receptor binding sites with
receptor-modified oligonucleotides so that the protein recep-
tor complex could be used as one of the building blocks, in
place of one of the inorganic nanoparticles, in our original
materials assembly scheme. Herein, we use 13-nm gold
particles, streptavidin, and biotinylated DNA to explore these
hypotheses (Figure 1A) and some of the physical and chemical
properties of the resulting new bioinorganic materials.
tides into preconceived architectures (Figure 1B). Since that
initial report, our research group and many others have shown
[
2±8]
that this strategy
and off-shoots of it that rely on protein ±
receptor and antibody ± antigen interactions[9±12] can be used
to generate a wide range of architectures with many unusual
and, in some cases, useful chemical and physical properties.
Since proteins and certain protein receptors can be
functionalized with oligonucleotides, one, in principle, could
[
*] Prof. C. A. Mirkin, S.-J. Park, Prof. A. A. Lazarides
Department of Chemistry
and
Center for Nanofabrication and Molecular Self Assembly
Northwestern University
2
145 Sheridan Road, Evanston, IL 60208-3113 (USA)
The nanoparticle/protein assembly (Figure 1A) reported
herein relies on three building blocks: streptavidin complexed
to four biotinylated oligonucleotides (1 ± STV), oligonucleo-
tide-modified gold nanoparticles (2 ± Au), and a linker
oligonucleotide (3) that has one half of its sequence comple-
mentary to 1 and the other half complementary to 2 (Fig-
ure 1). In a typical experiment, linker DNA (3; 10 mm, 21 mL)
was introduced to a mixture of 2 ± Au (9.7 nm, 260 mL) and 1 ±
STV (1.8 mm, 27 mL), or linker DNA 3 (10 mm, 21 mL) was
premixed with 1 ± STV (1.8 mm, 27 mL) and then the mixture
was added to 2 ± Au (9.7 nm, 260 mL) in 0.3m phosphate-
buffered saline (PBS) solution. Aggregates with similar
properties could be formed by both methods, but premixing
Fax: (‡1)847-467-5123
E-mail: camirkin@chem.nwu.edu
Prof. R. L. Letsinger
Department of Chemistry
Northwestern University
2
145 Sheridan Road, Evanston, IL 60208-3113 (USA)
Fax: (‡1)847-491-2081
E-mail: rletsinger@chem.nwu.edu
[
**] C.A.M. acknowledges DARPA, NSF, ARO, and NIH for support of
this research. R.L.L. acknowledges the NIH. The DND-CAT Syn-
chrotron Research Center is supported by E.I. Dupont de Nemours &
Co., The Dow Chemical Company, the U.S. National Science
Foundation through Grant DMR-9304725, and the State of Illinois
through the Department of Commerce and the Board of Higher
Education Grant IBHE HECA NWU 96. Use of the Advanced
Photon Source was supported by the U.S. Department of Energy,
Basic Energy Sciences, Office of Energy Research under Contract
No. W-31-102-Eng-38.
3
and 1 ± STV facilitates aggregate formation. Since a 13-nm
gold particle is substantially larger than streptavidin (4 Â 4 Â
13, 14]
5
nm),[
a 1:20 molar ratio of Au nanoparticle to strepta-
vidin was used to favor the formation of an extended
polymeric structure rather than small aggregates comprised
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
Angew. Chem. Int. Ed. 2001, 40, No. 15
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
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