Palladium-catalyzed C-C coupling: efficient preparation of new 5-thio-β-d-xylopyranosides as oral venous antithrombotic drugs

Article abstract of DOI:10.1016/j.tetlet.2009.04.050

First examples of a Suzuki and Stille cross-coupling reaction to prepare derivatives of pyridinyl 5-thio-β-d-xylopyranosides are described. Some of these compounds are orally active in an animal model of venous thrombosis.

Full text of DOI:10.1016/j.tetlet.2009.04.050

Tetrahedron Letters 50 (2009) 3872–3876
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed C–C coupling: efficient preparation of new
5-thio-b-D-xylopyranosides as oral venous antithrombotic drugs
*
M. Bondoux, L. Mignon, K. Ou, P. Renaut, D. Thomas, V. Barberousse
Laboratoires Fournier, A Solvay Pharmaceuticals Company, 50 rue de Dijon, 21121 Daix, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 January 2009
Revised 8 April 2009
Accepted 14 April 2009
Available online 17 April 2009
First examples of a Suzuki and Stille cross-coupling reaction to prepare derivatives of pyridinyl 5-thio-b-
D
-xylopyranosides are described. Some of these compounds are orally active in an animal model of
venous thrombosis.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
5-Thioxylopyranosides
Antithrombotic
Glycosaminoglycan
Suzuki
Stille
Coupling reactions
S
O
HO
HO
Thromboembolic disorders are a major cause of morbidity and
mortality in industrialized countries. The prophylaxis of these dis-
orders is largely managed by intravenous heparin therapy or by
oral warfarin therapy. The drawbacks of heparin therapy are the
mode of administration and the high hemorrhagic risk. The draw-
backs of warfarin therapy are the delay of their action, the risk in
bleeding and the interactions with numerous drugs representing
serious problems.
O
O
HO
HO
N
N
OH
OH
1
2
S
CN
HO
S
HO
HO
O
CN
In our search for new orally active antithrombotic drugs with-
out such serious side effects, we developed a lead-finding program
HO
HO
N
OH
O
N
based on the hypothesis that b-D-xylopyranosides might be effec-
tive antithrombotic drugs1–4 since they induce the biosynthesis
of glycosaminoglycans in cell culture, as demonstrated by Oka-
yama,5 Schwarz,6 and others. We previously reported2–4 that 5-
4
3
S
thio-b-D-xylopyranosides were more potent than their 5-oxo ana-
HO
O
HO
logs and therefore we focused on the former. Within these series,
Odiparcil (Chart 1) was evaluated in clinical trials in patients7 for
the prevention of venous thromboembolism (VTE), particularly fol-
lowing orthopedic surgery (e.g., knee or hip arthroplasty) with
some preliminary proof of principle.
OH
Me
O
Odiparcil
O
Our plans focused on the elucidation of structural analogs of
Odiparcil. Previously1–4 we investigated aromatic aglycons and
studied heteroaromatic moieties. Particularly, pyridine derivatives
were assessed since these new chemical entities could induce (i)
improved pharmacokinetic profiles, with much better solubility
Chart 1.
properties and (ii) improved activity with novel interactions
between the target and the nitrogen atom. This led us to prepare
5-thio-b-D-xylopyranosides containing pyridine moieties and led
* Corresponding author.
to the discovery of lead compound 1 (Chart 1) which shows prom-
E-mail address: veronique.barberousse@solvay.com (V. Barberousse).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.050

M. Bondoux et al. / Tetrahedron Letters 50 (2009) 3872–3876
3873
ising pharmacological profile.8 We first determined the influence
of the heteroatom of the osidic ring and the influence of the ano-
meric configuration by synthesizing the 5-oxo analog of compound
In this type of chemistry the critical step is the glycosylation
step between the glycosyl donor and the pyridinol. As a strict b-
configuration of the glycosidic bond is required for the biological
1 (2) and the
a
-analog 3 of another active compound (48). As pre-
activity2, the chromatographic separation of both the
a and b epi-
viously observed with other aglycon series2–4, compounds 29 and
mers, generated during the reaction, represents a serious limitation
to the method. Thus, we developed chemical synthetic routes
based on Suzuki and Stille coupling reactions (Scheme 1) which
had never been reported for 5-thiosugars. As illustrated below, this
chemistry allowed for parallel synthesis, thereby resulting in in-
creased efficiency. Using the Suzuki and Stille coupling reactions,
we have prepared a large number of novel compounds that avoid
the glycosylation reaction for each compound (Scheme 1). This
type of strategy has been utilized to prepare several nucleo-
sides11–13 and pyranosides.14,15 Because of the high affinity of pal-
ladium for sulfur and of the vulnerability of acetate-protecting
groups for basic conditions, it was not clear whether the Suzuki
and Stille cross-coupling reactions could be applied to these pro-
tected thioglycosides.
310 are inactive. Therefore we focused our syntheses on 5-thio-b-
D
-xylopyranosides.
We first investigated compounds with small substituents such
as halogens, cyano, nitro, alkyl, or trifluoromethyl groups8 on the
pyridine ring. The preparation of such derivatives was relatively
straightforward using several commercially available aglycons
but biological results were rather disappointing. We therefore
decided to switch our synthetic efforts to bicyclic aglycons or to
acylated pyridines in order to explore the targeted binding site.
Therefore, a robust synthetic protocol was needed in order to pre-
pare numerous xylopyranosides for the structure–activity relation-
ship studies.
Glycosylation
HO
S
R
S
R
AcO
Suzuki, Stille reactions
reaction
AcO
AcO
O
O
S
N
AcO
N
AcO
AcO
N
OAc
R
+
OAc
Br
OAc
R'
X
X
Scheme 1. General pathway.
OR"
S
R
AcO
O
B
AcO
N
OR"
OAc
X = Br, I
+
X
Pathway A
R'
S
R
AcO
O
AcO
N
OAc
S
R
B
R'
AcO
AcO
O
Br
N
Pathway B
OAc
+
R"O
R'
OR"
Scheme 2. Suzuki cross-coupling reactions.
Table 1
Suzuki cross-coupling reactions: search for optimal base and catalyst
OH
B
S
AcO
S
O
Br
NC
RO
AcO
O
OH
OAc
+
RO
CN
OR
N
N
516
6
7: R = Ac
8: R = H
Entry
Boronic acid derivative (equiv)
Base
CsF (2 equiv)
Catalyst
Solvent
Timea (min)
Yieldb (%)
1
2
3
4
5
1.2
1.2
1.2
2
PS-PPh3-Pdc (0.05 equiv)
PS-PPh3-Pd (0.05 equiv)
PS-PPh3-Pd (0.05 equiv)
DMEd/CH3OH
DME/CH3OH
DME/CH3OH
DME/H2O
30
30
30
20
30
48
39
14
65
57f
MP-Carbonatec (2 equiv)
PL-HCO3 MR-Resine (2 equiv)
Na2CO3 (1.5 equiv)
Cs2CO3 (2 equiv)
Pd(dppf)Cl2ꢀCH2Cl2 (0.1 equiv)
2
PS-PPh3-Pd (0.05 equiv)
DME/CH3OH
a
All the experiments have been performed under microwave heating at 120 °C.
Yield in isolated 7.
Commercially available at Argonaut Technologies.
Dimethoxyethane.
Commercially available at Polymer Laboratories.
Yield in isolated 8.
b
c
d
e
f

3874
M. Bondoux et al. / Tetrahedron Letters 50 (2009) 3872–3876
Our first target was to obtain xylopyranosides with pyridine
Cs2CO3 as a base, DME/MeOH as solvents (Table 1, entry 5), we sur-
prisingly obtained the unprotected xylopyranosides directly.
Having demonstrated the synthetic utility of the Suzuki coupling
to provide different substituents on the pyridine ring, we turned
our attention to the preparation of various xylopyranosides16 (Ta-
ble 2). This led us to study numerous xylopyranosides in biological
assays and structure–activity relationship studies.
In order to increase the diversity of our library of 5-thio-xylo-
pyranosides we also explored pathway B, starting from aryl halides
(Scheme 3). The new challenge was to synthesize boron derivatives
from 5-thio-xylopyranosides. To our knowledge, these types of
compounds have never been reported. All the experiments were
rings substituted by aryl16 and heteroaryl groups.17 Glycosylations
were performed according to classical methods.8,16,17 Two syn-
thetic pathways were studied (Scheme 2), the boronic moiety
being attached to the phenyl ring (pathway A) or to the pyridinyl
xylopyranoside (pathway B).
In a first series of reactions (pathway A), we used a pyridinyl
xylopyranoside bearing a halide substituent which was combined
with a series of phenyl boronic acid derivatives. Various conditions
were studied using different catalysts and different bases (Table 1)
and microwave heating. The best results were obtained with
Pd(dppf)Cl2ꢀCH2Cl2 as a catalyst and Na2CO3 as a base.18 Using
Table 2
Examples of Suzuki cross-coupling reactions of thioxylosides (pathway A)
OH
B
S
AcO
AcO
X
S
4
O
RO
RO
+
O
R'
5
6
OH
OAc
OR
N
2
R'
N
10
9
7, 11-32
a: R = Ac
b: R = H
Entry
X
Aryl position
R’
Product
Yield (%)
1
2
Br
Br
I
2
2
4
4
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
6
6
4-F
4-OMe
4-F
4-OMe
4-F
4-OMe
2,4-diF
2-Cl, 4-F
3-CN, 4-F
3-F, 4-CN
3-CN
3-OMe
4-OiPr
3,4-diOMe
3,5-diMe, 4-OMe
3-Cl, 4-OMe
4-F, 2-OMe
3-F-4-OiPr
2,6-diF, 4-OMe
3-Me, 4-F
2-Me, 4-F
4-F
11a19
12b20
13a21
14a22
15b23
16a24
17a25
18a26
19a27
20a28
7a29
64
65
47
29
41
80
87
81
66
65
59
77
55
73
52
66
92
82
30
48
72
46
28
3
4a
5
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
6a
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23a
21a30
22a31
23a32
24a33
25a34
26a35
27a36
28a37
29a38
30a39
31b40
32a41
4-OMe
Experimental conditions: Pd(dppf)Cl2ꢀCH2Cl2, Na2CO3, DME/H2O, under microwave heating at 120 °C for 20 min.
a
The used base is MP-carbonate.
S
AcO
AcO
O
Br
OAc
N
516
O
B
i
S
AcO
AcO
O
+
O
OAc
F
F
N
33
S
AcO
AcO
ii
O
O
OAc
+
B
O
F
O
B
N
F
Br
F
O
34
F
Scheme 3. Example of Suzuki cross-coupling reactions (Pathway B). Reagents and conditions: (i) Pd(dppf)Cl2ꢀCH2Cl2, KOAc, DME, 150 °C, 1 h,
Na2CO3, DME, 120 °C, 30 min, waves; Overall yield: 40%.
lwaves; (ii) Pd(dppf)Cl2ꢀCH2Cl2,
l

M. Bondoux et al. / Tetrahedron Letters 50 (2009) 3872–3876
3875
S
S
AcO
AcO
AcO
AcO
Sn(nBu)4
i
O
O
OAc
+
OAc
ii
O
N
N
Br
Ac
36
37
35
Scheme 4. Stille cross-coupling reaction. Reagents and conditions: (i) PdCl2(PPh3)2/CuI/AcN/reflux, 1 h; (ii) HCl, 1 h; Overall yield: 68%.
Table 3
ation of the substituted pyridinols. Preliminary bioassays showed
that some of our new 5-thio-b- -xylopyranosides possess anti-
Some antithrombotic activities
D
R4
N
thrombotic efficacy and should be more fully investigated in pre-
clinical studies.
S
O
R5
R6
HO
HO
OH
References and notes
R2
1. Bellamy, F.; Horton, D.; Millet, J.; Picart, F.; Samreth, S.; Chazan, J. B. J. Med.
Chem. 1993, 36, 898–903.
Product
R2
R4
R5
R6
Activitya (%)
2. Samreth, S.; Barberousse, V.; Bellamy, F.; Horton, D.; Masson, Ph.; Millet, J.;
Renaut, P.; Sepulchre, C.; Theveniaux, J. Trends Recept. Res. 1993, 20, 41–59.
3. Bellamy, F.; Barberousse, V.; Martin, N.; Masson, P.; Millet, J.; Samreth, S.;
Sepulchre, C.; Theveniaux, J.; Horton, D. Eur. J. Med. Chem. 1995, 30, 101s–115s.
4. Samreth, S.; Barberousse, V.; Bellamy, F.; Horton, D.; Masson, P.; Millet, J.;
Renaut, P.; Sepulchre, C.; Theveniaux, J. J. Actual. Chim. Ther. 1994, 21, 23–33.
5. Okayama, M.; Kimata, K.; Suzuki, S. J. Biochem. 1973, 74, 1069–1073.
6. Schwartz, N. B. J. Biol. Chem. 1977, 252, 6316–6321.
7. Dubb, J. W.; Henderson, L. S.; Okada, S. S.; Peyrou, V.; Samuels, R. E.; Sheth, S.;
Spera, P. A.; Toomey, J. R.; Wilson, D. Patent WO 2006060647, 2006; Chem.
Abstr. 2006, 145, 1040.
8. Barberousse, V.; Samreth, S.; Boubia, B.; Bellamy, F.; Peyrou, V. Patent FR
2860234, 2005; Chem. Abstr. 2005, 142, 336586.
3844
H
4-F Ph
H
H
H
H
4-F Ph
H
H
H
4-OMe Ph
H
H
H
H
H
Ac
H
H
H
4-F Ph
H
H
H
55
40
38
99
61
28
28
100
61
3945
4046
15b23
31b40
12b20
4147
4-F Ph
H
H
H
H
4-OMe Ph
H
H
H
4248
4-OMe Ph
H
4349
4-OMe Ph
a
Dosage = 6 mg/kg.
9. Compound 2 was obtained in 93% yield by deacetylation (MeONa, MeOH) of
performed under microwave heating. The best results were ob-
tained with Pd(dppf)Cl2ꢀCH2Cl2 as a catalyst and KOAc as a base
for the formation of the boron derivatives, and using
Pd(dppf)Cl2ꢀCH2Cl2 as a catalyst, and Na2CO3 as a base, for the cou-
pling step (Scheme 3).
As we had also planned to generate 5-thio-xylopyranosides of
acyl-substituted pyridinols (e.g., 35: Scheme 4)16 the possibility
of obtaining them by using Koenigs–Knorr glycosidations was ex-
plored. Unfortunately, this was not successful (very low yields) in
all but in a few cases (moderate yield). However, we found that
3616 could undergo a Stille cross coupling with 37 producing the
desired compound 35 and giving a 68% yield (Scheme 4).
In all cases the final step was a deacetylation reaction (using
MeONa/MeOH or NH3/MeOH) that generates the corresponding
non-protected 5-thio-xylopyranosides which were evaluated for
their biological properties.
the corresponding 2,3,4-tri-O-acetyl-b-
was obtained in 65% yield by glycosylation starting from 2,3,4-tri-O-acetyl b-
xylopyranosyl bromide and 3-pyridinol, using Ag2O as promoter and
D-xylopyranoside. The latter compound
D-
acetonitrile as solvent. Compound 2: Mp = 203–206 °C; ½ ꢁ ꢂ32 (c 0.5,
a 2D3
DMSO); 1H NMR (300 MHz, DMSO-d6) d ppm 3.15–3.45 (m, 4H), 3.75 (dd, 1H),
4.96 (d, J = 6.6 Hz, 1H), 5.09 (d, 1H), 5.15 (d, 1H), 5.42 (d, 1H), 7.33 (dd,
J = 4.6 Hz, 8.3 Hz, 1H), 7.44 (m, 1H), 8.23 (dd, J = 1.3 Hz, 4.6 Hz, 1H), 8.32 (d,
J = 2.8 Hz, 1H).
10. Compound 3 was obtained in 52% yield by deacetylation (MeONa, MeOH) of
the corresponding 2,3,4-tri-O-acetyl-b-
was obtained in 2% yield (after flash chromatography on silica gel) by
glycosylation starting from 2,3,4-tri-O-acetyl b- -xylopyranosyl bromide and
D-xylopyranoside. The latter compound
D
2-cyano-3-pyridinol using zinc chloride and silver imidazolate as promoters
and toluene and acetonitrile as solvents. Compound 3: Mp = 180–181 °C; ½a D20
ꢁ
310 (c 0.3, MeOH); 1H NMR (300 MHz, DMSO-d6) d ppm 2.46 (ddd, J = 13.3 Hz,
4.0 Hz, 1.4 Hz, 1H), 2.63 (dd, J = 13.3 Hz, 10.8 Hz, 1H), 3.45–3.67 (m, 2H), 3.72
(m, 1H), 5.11 (d, J = 4.3 Hz, 1H), 5.30 (d, J = 4.0 Hz, 1H), 5.49 (d, J = 5.0 Hz, 1H),
5.82 (dd, J = 1.3 Hz, 3.1 Hz, 1H), 7.73 (dd, J = 4.5 Hz, 8.8 Hz, 1H), 7.98 (dd,
J = 1.1 Hz, 8.8 Hz, 1H), 8.36 (dd, J = 1.1 Hz, 4.5 Hz, 1H).
11. Western, E. C.; Daft, J. R.; Johnson, E. M.; Gannett, P. M.; Shaughnessy, K. H. J.
Org. Chem. 2003, 68, 6767–6774.
12. Aucagne, V.; Berteina-Raboin, S.; Guenot, P.; Agrofoglio, L. A. J. Comb. Chem.
2004, 6, 717–723.
13. Wan, J.; Zhu, R.; Xia, Y.; Qu, F.; Wu, Q.; Yang, G.; Neyts, J.; Peng, L. Tetrahedron
Lett. 2006, 47, 6727–6731.
14. Müller, H.; Tschierske, C. J. Chem. Soc., Chem. Commun. 1995, 645–646.
15. Félix, C.; Parrot-Lopez, H.; Kalchenko, V.; Coleman, A. W. Tetrahedron Lett. 1998,
39, 9171–9174.
The 5-thio-xylopyranosides novel chemical entities described
were screened using an antithrombotic model (see Wessler42,43
)
performed in the rat. Factor Xa is the thrombogenic agent. The
activity is expressed as the percentage of decrease of the thrombus
weight between control and treated animals. The compounds were
administered orally 2 h prior to the induction of thrombosis with
Factor Xa. Selected results are shown in Table 3.
16. Barberousse, V.; Bondoux, M.; Thomas, D.; Peyrou, V. Patent WO 2006100413;
Chem. Abstr. 2006, 145, 377529.
17. Barberousse, V.; Thomas, D.; Bondoux, M. Patent FR 2906248; Chem. Abstr.
2008, 148, 356077.
Due to the fact that these results (Table 3) are obtained after
oral administration, it is difficult to establish truly meaningful
structure–activity relationships. At this moment, we can, however,
conclude that (i) in the acetyl series, the 2-position seemed to be
favorable, (ii) in phenyl-substituted derivatives, the substituents
of the phenyl ring modulated the in vivo activity, (iii) in these latter
series, the position of the phenyl ring on the pyridine moiety is
important. Extensive biological experiments, in particular using
the galactosyltransferase50 (enzyme involved in the biosynthesis
of glycosaminoglycans: b4Gal-T7; EC 2.4.1.133), are ongoing.
These data demonstrate for the first time that palladium-cata-
lyzed reactions like Suzuki and Stille coupling reactions can be per-
formed on 5-thiosugars. This divergent strategy allows us to
generate large library of compounds in a short time. Many of the
new compounds prepared could not be obtained through glycosyl-
18. General procedure: To a solution of a halogeno derivative in DME were added
1.5 equiv of aqueous sodium carbonate, 0.1 equiv of Pd(dppf)Cl2ꢀCH2Cl2 and
2 equiv of boronic acid derivative. The mixture was heated for 20 min under
microwave heating at 120 °C, then cooled, diluted with water, and extracted by
ethyl acetate. The organic phase is washed with an aqueous solution of sodium
carbonate and water until neutral pH, dried over magnesium sulfate, and
concentrated under vacuum. The crude material is purified by
chromatography.
19. Mp = 147–151 °C; ½a D27
ꢁ
ꢂ91 (c 0.3, DMSO); 1H NMR (300 MHz, DMSO-d6) d
ppm 1.82 (s, 3H), 1.97 (s, 3H), 2.00 (s, 3H), 2.91 (dd, J = 4.8 Hz, 13.5 Hz, 1H),
3.03 (dd, J = 10.6 Hz, 13.5 Hz, 1H), 4.96 (ddd, J = 4.8 Hz, 9.5 Hz, 10.6 Hz, 1H),
5.21 (t, J = 9.5 Hz, 1H), 5.34 (dd, J = 8.8 Hz, 9.5 Hz, 1H), 5.91 (d, J = 8.8 Hz, 1H),
7.21 (t, J = 8.8 Hz, 2H), 7.46 (dd, J = 8.4 Hz, 4.4 Hz, 1H), 7.73–7.86 (m, 3H), 8.37
(dd, J = 1.2 Hz, 4.4 Hz, 1H).
20. Mp = 137 °C; ½a D33
ꢁ
ꢂ79 (c 0.2, DMSO); 1H NMR (300 MHz, DMSO-d6) d ppm
2.52–2.70 (m, 2H), 3.14 (td, J = 8.8 Hz, 4.5 Hz 1H), 3.48 (m, 1H), 3.62 (td,
J = 8.5 Hz, 4.9 Hz, 1H), 3.81 (s, 3H), 5.13 (d, J = 4.5 Hz 1H), 5.19 (d, J = 4.1 Hz,
1H), 5.38 (d, J = 8.5 Hz, 1H), 5.55 (d, J = 4.9 Hz, 1H), 6.98 (d, J = 9.1 Hz, 2H), 7.31

3876
M. Bondoux et al. / Tetrahedron Letters 50 (2009) 3872–3876
(dd, J = 4.4 Hz, 8.5 Hz, 1H), 7.80 (dd, J = 1.1 Hz, 8.5 Hz, 1H), 7.99 (d, J = 9.1 Hz,
2H), 8.26 (dd, J = 1.1 Hz, 4.4 Hz, 1H).
35. Mp = 121 °C; ½a D27
ꢁ
ꢂ11 (c 0.2, DMSO); 1H NMR (300 MHz, DMSO-d6) d ppm 1.97
(s, 3H), 2.00 (s, 6H), 2.92 (dd, J = 4.4 Hz, 13.2 Hz, 1H), 3.03 (dd, J = 10.3 Hz,
13.2 Hz, 1H), 3.82 (s, 3H), 4.99 (ddd, J = 4.7 Hz, 9.5 Hz, 10.3 Hz, 1H), 5.23 (t,
J = 9.5 Hz, 1H), 5.35 (dd, J = 8.8 Hz, 9.5 Hz, 1H), 5.94 (d, J = 8.8 Hz, 1H), 6.91 (td,
J = 2.6 Hz, 8.4 Hz, 1H), 7.09 (dd, J = 2.6 Hz, 11.7 Hz, 1H), 7.42 (dd, J = 6.6 Hz,
8.4 Hz, 1H), 7.60 (dd, J = 1.8 Hz, 2.9 Hz, 1H), 8.30 (d, J = 2.9 Hz, 1H), 8.37 (d,
J = 1.8 Hz, 1H).
21. Mp = 110 °C; ½a D30
ꢁ
ꢂ49 (c 0.3, DMSO); 1H NMR (250 MHz, DMSO-d6) d ppm 1.83
(s, 3H), 1.96 (s, 3H), 1.99 (s, 3H), 2.89 (dd, J = 4.7 Hz, 13.4 Hz, 1H), 3.04 (dd,
J = 10.4 Hz, 13.4 Hz, 1H), 4.93 (ddd, J = 4.7 Hz, 9.5 Hz, 10.4 Hz, 1H), 5.18 (t,
J = 9.5 Hz, 1H), 5.26 (dd, J = 8.8 Hz, 9.5 Hz, 1H), 5.94 (d, J = 8.8 Hz, 1H), 7.26 (t,
J = 8.8 Hz, 2H), 7.41 (d, J = 4.9 Hz, 1H), 7.52 (dd, J = 4.9 Hz, 4.7 Hz, 2H), 8.36(d,
J = 4.7 Hz, 1H), 8.71 (s, 1H).
36. Mp = 65 °C; ½a 2D9
ꢁ
3 (c 0.2, DMSO); 1H NMR (250 MHz, DMSO-d6) d ppm 1.31 (s,
22. Mp = 193 °C; ½a D30
ꢁ
ꢂ92 (c 0.3, DMSO); 1H NMR (300 MHz, DMSO-d6) d ppm 1.84
3H), 1.33 (s, 3H), 1.97 (s, 3H), 2.01 (s, 6H), 2.96 (dd, J = 4.9 Hz, 13.4 Hz, 1H), 3.03
(dd, J = 10.2 Hz, 13.4 Hz, 1H), 4.72 (m, J = 6.0 Hz, 1H), 5.01 (ddd, J = 4.9 Hz,
9.3 Hz, 10.2 Hz, 1H), 5.23 (t, J = 9.3 Hz, 1H), 5.37 (dd, J = 8.8 Hz, 9.3 Hz, 1H), 6.05
(d, J = 8.8 Hz, 1H), 7.30 (t, J = 8.8 Hz, 1H), 7.54 (dt, J = 8.5 Hz, 1.1 Hz 1H), 7.68
(dd, J = 2.2 Hz, 12.6 Hz, 1H), 7.78 (t, J = 2.2 Hz, 1H), 8.31 (d, J = 2.5 Hz, 1H), 8.60
(d, J = 1.9 Hz, 1H).
(s, 3H), 1.97 (s, 3H), 1.99 (s, 3H), 2.88 (dd, 1H), 3.03 (dd, 1H), 3.81 (s, 3H), 4.93
(td, 1H), 5.19 (t, 1H), 5.29 (t, 1H), 5.94 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 9.1 Hz, 2H),
7.39 (d, J = 4.8 Hz, 1H), 7.45 (d, J = 9.1 Hz, 2H), 8.32 (d, J = 4.8 Hz, 1H), 8.68 (s,
1H) .
23. Mp = 208–209 °C; ½a D25
ꢁ
ꢂ84 (c 0.1, DMSO); 1H NMR (300 MHz, DMSO-d6) d
ppm 2.59 (dd, J = 13.4 Hz, 4.8 Hz, 1H), 2.69 (dd,, J = 13.4 Hz, 10.4 Hz, 1H), 3.14
(td, J = 8.8 Hz, 4.5 Hz, 1H), 3.49 (m, 1H), 3.61 (td, J = 8.8 Hz, 4.8 Hz, 1H), 5.05 (d,
J = 4.5 Hz, 1H), 5.16 (d,, J = 4.5 Hz, 1H), 5.46 (d, J = 8.8 Hz, 1H), 5.56 (d, J = 4.8 Hz,
1H), 7.35 (t, J = 9.2 Hz, 2H), 7.76–7.87 (m, 3H), 8.36 (d, J = 2.9 Hz, 1H), 8.52 (d,
J = 2.2 Hz, 1H).
37. Mp = 62 °C; ½a 3D0
ꢁ
ꢂ4 (c 0.2, DMSO); 1H NMR (300 MHz, DMSO-d6) d ppm 1.96 (s,
3H), 2.00 (s, 6H), 2.94 (dd, J = 5.1 Hz, 13.4 Hz, 1H), 3.02 (dd, J = 10.6 Hz, 13.4 Hz,
1H), 3.85 (s, 3H), 4.99 (ddd, J = 5.1 Hz, 9.5 Hz, 10.6 Hz, 1H), 5.22 (t, J = 9.5 Hz, 1H),
5.35 (dd, J = 8.8 Hz, 9.5 Hz, 1H), 5.98 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 10.2 Hz, 2H),
7.60–7.63 (m, 1H), 8.33 (d, J = 1.5 Hz, 1H), 8.39 (d, J = 2.6 Hz, 1H).
24. Mp = 156 °C; ½a D25
ꢁ
ꢂ11 (c 0.4, DMSO); 1H NMR (300 MHz, DMSO-d6) d ppm 1.97
38. Mp = 161 °C; ½a D33
ꢁ
ꢂ16 (c 0.3, DMSO); 1H NMR (250 MHz, DMSO-d6) d ppm 1.97
(s, 3H), 2.01 (s, 6H), 2.95 (dd, J = 13.3 Hz, 4.8 Hz, 1H), 3.05 (dd, J = 13.3 Hz,
10.4 Hz, 1H), 3.82 (s, 3H), 5.00 (td, J = 8.9 Hz, 4.8 Hz, 1H), 5.24 (t, J = 8.9 Hz, 1H),
5.37 (t, J = 8.9 Hz, 1H), 6.05 (d, J = 8.9 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.71 (d,
J = 8.8 Hz, 2H), 7.74 (m, 1H), 8.29 (s, 1H), 8.58 (s, 1H).
(s, 3H), 2.01 (s, 6H), 2.33 (d, J = 1.9 Hz, 3H), 2.95 (dd, J = 4.9 Hz, 13.4 Hz, 1H),
3.04 (dd, J = 10.1 Hz, 13.4 Hz, 1H), 5.01 (ddd, J = 4.9 Hz, 9.6 Hz, 10.1 Hz, 1H),
5.23 (t, J = 9.6 Hz, 1H), 5.37 (dd, J = 8.8 Hz, 9.6 Hz, 1H), 6.05 (d, J = 8.8 Hz, 1H),
7.28 (dd, J = 8.6 Hz, 9.5 Hz, 1H), 7.57–7.66 (m, 1H), 7.70 (dd, J = 1.6 Hz, 7.4 Hz,
1H), 7.76 (dd, J = 1.9 Hz, 2.7 Hz, 1H), 8.34 (d, J = 2.7 Hz, 1H), 8.58 (d, J = 1.9 Hz,
1H).
25. Mp = 121 °C; ½a D27
ꢁ
ꢂ9 (c 0.3, DMSO); 1H NMR (300 MHz, DMSO-d6) d ppm 1.97
(s, 3H), 2.01 (s, 6H), 2.94 (dd, J = 5.1 Hz, 13.5 Hz, 1H), 3.03 (dd, J = 10.2 Hz,
13.5 Hz, 1H), 4.99 (ddd, J = 5.1 Hz, 9.5 Hz, 10.2 Hz, 1H), 5.22 (t, J = 9.5 Hz, 1H),
5.36 (dd, J = 8.8 Hz, 9.5 Hz, 1H), 6.01 (d, J = 8.8 Hz, 1H), 7.27 (tdd, J = 0.8 Hz,
2.6 Hz, 8.4 Hz, 1H), 7.46 (ddd, J = 2.6 Hz, 9.2 Hz, 11.0 Hz, 1H), 7.66–7.74 (m,
2H), 8.40 (d, J = 2.9 Hz, 1H), 8.45 (t, J = 1.8 Hz, 1H).
39. Mp = 120 °C; ½a D34
ꢁ
ꢂ20 (c 0.3, DMSO); 1H NMR (300 MHz, DMSO-d6) d ppm 1.96
(s, 3H), 2.00 (s, 6H), 2.26 (s, 3H), 2.93 (dd, J = 5.1 Hz, 13.4 Hz, 1H), 3.02 (dd,
J = 10.3 Hz, 13.4 Hz, 1H), 4.99 (ddd, J = 5.1 Hz, 9.5 Hz, 10.3 Hz, 1H), 5.21 (t,
J = 9.5 Hz, 1H), 5.36 (dd, J = 9.2 Hz, 9.5 Hz, 1H), 5.97 (d, J = 9.2 Hz, 1H), 7.15 (td,
J = 3.3 Hz, 8.4 Hz, 1H), 7.23 (dd, J = 2.6 Hz, 10.2 Hz, 1H), 7.32 (dd, J = 5.9 Hz,
8.4 Hz, 1H), 7.54 (dd, J = 1.8 Hz, 2.9 Hz, 1H), 8.25 (d, J = 1.5 Hz, 1H), 8.34 (d,
J = 2.9 Hz, 1H).
26. Mp = 115 °C; ½a D27
ꢁ
ꢂ11 (c 0.4, DMSO); 1H NMR (300 MHz, DMSO-d6) d ppm 1.97
(s, 3H), 2.00 (s, 6H), 2.93 (dd, J = 4.8 Hz, 13.5 Hz, 1H), 3.02 (dd, J = 10.6 Hz,
13.5 Hz, 1H), 4.99 (ddd, J = 4.8 Hz, 9.5 Hz, 10.6 Hz, 1H), 5.22 (t, J = 9.5 Hz, 1H),
5.36 (dd, J = 8.8 Hz, 9.5 Hz, 1H), 5.98 (d, J = 8.8 Hz, 1H), 7.39 (td, J = 2.6 Hz,
8.4 Hz, 1H), 7.58 (dd, J = 6.2 Hz, 8.8 Hz, 1H), 7.61–7.66 (m, 2H), 8.33(d,
J = 2.6 Hz, 1H), 8.40 (t, J = 2.9 Hz, 1H).
40. Mp = 180–183 °C; ½a D30
ꢁ
ꢂ50 (c 0.1, DMSO); 1H NMR (300 MHz, DMSO-d6) d
ppm 2.54–2.74 (m, 2H), 3.14 (t, J = 8.5 Hz, 1H), 3.50 (td, J = 8.5 Hz, 5.2 Hz, 1H),
3.60 (t, J = 8.5 Hz, 1H), 4.8–5.8 (broad, 3H), 5.32 (d, J = 8.5 Hz, 1H), 7.29 (t,
J = 9.1 Hz, 2H), 7.66 (dd, J = 3.0 Hz, 8.9 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 8.07 (dd,
J = 5.8 Hz, 9.1 Hz, 2H) 8.45 (d, J = 3.0 Hz, 1H).
27. Mp = 176–180 °C; ½a D32
ꢁ
ꢂ13 (c 0.1, DMSO); 1H NMR (250 MHz, DMSO-d6) d
ppm 1.97 (s, 3H), 2.01 (s, 6H), 3.00 (m, 2H), 5.01 (ddd, J = 4.4 Hz, 9.3 Hz,
10.4 Hz, 1H), 5.22 (t, J = 9.3 Hz, 1H), 5.36 (dd, J = 9.1 Hz, 9.3 Hz, 1H), 6.05 (d,
J = 9.1 Hz, 1H), 7.69 (t, J = 9.0 Hz, 1H), 7.87 (dd, J = 1.9 Hz, 2.7 Hz, 1H), 8.20 (ddd,
J = 2.5 Hz, 5.2 Hz, 9.1 Hz, 1H), 8.38 (dd, J = 2.4 Hz, 6.3 Hz, 1H), 8.45 (d, J = 2.7 Hz,
1H), 8.67 (d, J = 1.9 Hz, 1H).
41. Mp = 208 °C; ½a D29
ꢁ
12 (c 0.3, DMSO); 1H NMR (300 MHz, DMSO-d6) d ppm 1.98
(s, 3H), 2.01 (s, 6H), 2.94 (dd, J = 4.8 Hz, 13.5 Hz, 1H), 3.04 (dd, J = 10.6 Hz,
13.5 Hz, 1H), 3.81 (s, 3H), 5.00 (ddd, J = 4.8 Hz, 9.5 Hz, 10.6 Hz, 1H), 5.25 (t,
J = 9.5 Hz, 1H), 5.35 (dd, J = 8.8 Hz, 9.5 Hz, 1H), 5.92 (d, J = 8.8 Hz, 1H), 7.02 (d,
J = 9.1 Hz, 2H), 7.57 (dd, J = 2.9 Hz, 8.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1 H), 7.97 (d,
J = 9.1 Hz, 2 H), 8.38 (d, J = 2.9 Hz, 1H).
28. Mp = 223 °C; ½a D26
ꢁ
ꢂ2 (c 0.2, DMSO); 1H NMR (250 MHz, DMSO-d6) d ppm 1.97
(s, 3H), 2.02 (s, 6H), 3.01 (m, 2H), 5.02 (ddd, J = 5.1 Hz, 9.3 Hz, 10.4 Hz, 1H), 5.22
(t, J = 9.3 Hz, 1H), 5.39 (dd, J = 8.8 Hz, 9.3 Hz, 1H), 6.08 (d, J = 8.8 Hz, 1H), 7.87
(dd, J = 1.7 Hz, 8.2 Hz, 1H), 7.93 (t, J = 2.3 Hz, 1H), 8.01–8.12 (m, 2H), 8.46 (d,
J = 2.7 Hz, 1H), 8.74 (d, J = 1.9 Hz, 1H).
42. Wessler, S.; Reimer, M.; Sheps, M. J. Appl. Physiol. 1959, 14, 943–946.
43. Fareed, J.; Walenga, J. M.; Kumar, A.; Rock, A. Semin. Thromb. Hemost. 1985, 11,
155–175.
29. Mp = 129–132 °C; ½a D30
ꢁ
ꢂ21 (c 0.1, DMSO); 1H NMR (300 MHz, DMSO-d6) d
44. Mp = 178–179 °C; ½a D24
ꢁ
ꢂ76 (c 0.1, DMSO); 1H NMR (300 MHz, DMSO-d6) d
ppm 1.98 (s, 3H), 2.01 (s, 6H), 3.00 (m, 2H), 5.01 (ddd, J = 5.1 Hz, 9.5 Hz,
10.3 Hz, 1H), 5.22 (t, J = 9.5 Hz, 1H), 5.39 (dd, J = 8.8 Hz, 9.5 Hz, 1H), 6.07 (d,
J = 8.8 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.89 (dd, J = 0.8 Hz, 2.6 Hz, 1H), 7.92 (dt,
J = 1.5 Hz, 7.7 Hz, 1H), 8.12 (ddd, J = 0.8 Hz, 1.8 Hz, 7.8 Hz, 1H) 8.28 (t,
J = 1.8 Hz, 1H), 8.42 (d, J = 2.9 Hz, 1H), 8.69 (d, J = 1.8 Hz, 1H).
ppm 2.55–2.75 (m, 2H), 2.59 (s, 3H), 3.14 (t, J = 8.8 Hz, 1H), 3.49 (m, 1H), 3.61
(t, J = 8.8 Hz, 1H), 5.09 (s, 1H), 5.18 (s, 1H), 5.42 (d, J = 8.8 Hz, 1H), 5.60 (s, 1H),
7.73 (dd, J = 2.7 Hz, 8.8 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 8.47 (d, 2.7 Hz, 1H).
45. Mp = 107–113 °C; ½a D28
ꢁ
ꢂ56 (c 0.1, DMSO); 1H NMR (300 MHz, DMSO-d6) d
ppm 2.52–2.70 (m, 2H), 3.15 (td, 1H), 3.48 (m, 1H), 3.61 (td, 1H), 5.11 (d, 1H),
5.17 (d, 1H), 5.39 (d, J = 8.4 Hz, 1H), 5.56 (d, 1H), 7.24 (t, J = 9.2 Hz, 2H), 7.38
(dd, J = 4.4 Hz, 8.8 Hz, 1H), 7.85 (dd, J = 1.5 Hz, 8.8 Hz, 1H), 8.06 (dd, J = 5.9 Hz,
9.2 Hz, 2H), 8.30 (dd, J = 1.5 Hz, 4.4 Hz, 1H).
30. Mp = 112–115 °C; ½a D32
ꢁ
1 (c 0.1, DMSO); 1H NMR (250 MHz, DMSO-d6) d ppm
1.97 (s, 3H), 2.01 (s, 6H), 2.95 (dd, J = 4.9 Hz, 13.4 Hz, 1H), 3.04 (dd, J = 10.4 Hz,
13.4 Hz, 1H), 3.84 (s, 3H), 5.00 (ddd, J = 4.9 Hz, 9.6 Hz, 10.4 Hz, 1H), 5.24 (t,
J = 9.6 Hz, 1H), 5.37 (dd, J = 8.8 Hz, 9.6 Hz, 1H), 6.06 (d, J = 8.8 Hz, 1H), 7.03
(ddd, J = 1.1 Hz, 2.5 Hz, 8.2 Hz, 1H), 7.27–7.36 (m, 2H), 7.44 (t, J = 8.0 Hz, 1H),
7.79 (dd, J = 1.9 Hz, 2.7 Hz, 1H), 8.34 (d, J = 2.7 Hz, 1H), 8.61 (d, J = 1.7 Hz, 1H).
46. Mp = 219 °C; ½a D30
ꢁ
ꢂ70 (c 0.3, DMSO); 1H NMR (300 MHz, DMSO-d6) d ppm 2.55
(dd, J = 13.5 Hz, 4.6 Hz, 1H), 2.65 (dd, J = 13.5 Hz, 10.2 Hz, 1H), 3.13 (td,
J = 8.6 Hz, 4.6 Hz, 1H), 3.45 (m, 1H), 3.54 (td, J = 8.6 Hz, 5.3 Hz, 1H), 5.08 (d,
J = 4.6 Hz, 1H), 5.14 (d, J = 4.5 Hz, 1H), 5.46 (d, J = 8.6 Hz, 1H), 5.53 (d, J = 5.3 Hz,
1H), 7.28 (t, J = 8.8 Hz, 2H), 7.39 (d, J = 4.9 Hz, 1H), 7.76 (dd, J = 5.5 Hz, 8.8 Hz,
2H), 8.30 (d, J = 4.9 Hz, 1H), 8.72 (s, 1H).
31. Mp = 135 °C; ½a D31
ꢁ
ꢂ3 (c 0.3, DMSO); 1H NMR (250 MHz, DMSO-d6) d ppm 1.28
(s, 3H), 1.31 (s, 3H), 1.97 (s, 3H), 2.01 (s, 6H), 2.94 (dd, J = 4.7 Hz, 13.2 Hz, 1H),
3.04 (dd, J = 10.4 Hz, 13.2 Hz, 1H), 4.70 (m, J = 6.0 Hz, 1H), 5.00 (ddd, J = 4.7 Hz,
9.4 Hz, 10.4 Hz, 1H), 5.24 (t, J = 9.4 Hz, 1H), 5.37 (dd, J = 9.1 Hz, 9.4 Hz, 1H), 6.05
(d, J = 9.1 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.74 (dd,
J = 1.9 Hz, 2.7 Hz, 1H), 8.27 (d, J = 2.7 Hz, 1H), 8.56 (d, J = 1.9 Hz, 1H).
47. Mp = 228 °C; ½a D30
ꢁ
ꢂ80 (c 0.5, DMSO); 1H NMR (300 MHz, DMSO-d6) d ppm 2.55
(dd, J = 4.9 Hz, 13.5 Hz, 1H) 2.64 (dd, J = 10.2 Hz, 13.5 Hz, 1H), 3.13 (td,
J = 8.8 Hz, 4.7 Hz, 1H), 3.45 (m, 1H), 3.55 (td, J = 8.5 Hz, 4.9 Hz, 1H), 3.81 (s,
3H) 5.06 (d, J = 4.7 Hz 1H), 5.13 (d, J = 4.4 Hz, 1H), 5.44 (d, J = 8.8 Hz, 1H), 5.48
(d, J = 4.9 Hz, 1H), 7.01(d, J = 9.1 Hz, 2H), 7.36 (d, J = 4.9 Hz, 1H), 7.68 (d,
J = 9.1 Hz, 2H), 8.25 (d, J = 4.9 Hz, 1H), 8.67 (s, 1H).
32. Mp = 145 °C; ½a D32
ꢁ
ꢂ8 (c 0.3, DMSO); 1H NMR (250 MHz, DMSO-d6) d ppm 1.97
(s, 3H), 2.01 (s, 6H), 2.94 (dd, J = 4.9 Hz, 13.4 Hz, 1H), 3.03 (dd, J = 10.4 Hz,
13.4 Hz, 1H), 3.81 (s, 3H), 3.86 (s, 3H), 5.00 (ddd, J = 4.9 Hz, 9.4 Hz, 10.4 Hz, 1H),
5.22 (t, J = 9.4 Hz, 1H), 5.37 (dd, J = 8.8 Hz, 9.4 Hz, 1H), 6.05 (d, J = 8.8 Hz, 1H),
7.08 (d, J = 8.8 Hz, 1H), 7.29 (dd, J = 2.2 Hz, 8.0 Hz, 1H), 7.30 (s, 1H), 7.73 (dd,
J = 1.9 Hz, 2.7 Hz, 1H), 8.31 (d, J = 2.5 Hz, 1H), 8.61 (d, J = 1.6 Hz, 1H).
48. Mp = 216 °C; ½a D20
ꢁ
ꢂ91 (c 0.1, DMSO); 1H NMR (300 MHz, DMSO-d6) d ppm 2.58
(dd, J = 13.4 Hz, 4.5 Hz, 1H), 2.70 (dd, J = 13.4 Hz, 10.0 Hz, 1H), 3.14 (td,
J = 8.5 Hz, 4.5 Hz, 1H), 3.50 (m, 1H), 3.60 (td, J = 8.5 Hz, 4.5 Hz, 1H), 3.82 (s, 3H),
5.04 (d, J = 4.5 Hz, 1H), 5.15 (d, J = 4.5 Hz, 1H), 5.44 (d, J = 8.5 Hz, 1H), 5.55 (d,
J = 4.5 Hz, 1H), 7.07 (d, J = 9.1 Hz, 2H), 7.70 (d, J = 9.1 Hz, 2H), 7.77 (dd,
J = 1.9 Hz, 2.5 Hz, 1H), 8.31 (d, J = 2.5 Hz, 1H), 8.50 (d, J = 1.9 Hz, 1H).
33. Mp = 146 °C; ½a D29
ꢁ
0 (c 0.2, DMSO); 1H NMR (250 MHz, DMSO-d6) d ppm 1.97 (s,
3H), 2.01 (s, 6H), 2.30 (s, 6H), 2.94 (dd, J = 4.7 Hz, 13.4 Hz, 1H), 3.04 (dd,
J = 10.2 Hz, 13.4 Hz, 1H), 3.70 (s, 3H), 5.00 (ddd, J = 4.7 Hz, 9.6 Hz, 10.2 Hz, 1H),
5.25 (t, J = 9.6 Hz, 1H), 5.37 (dd, J = 8.8 Hz, 9.6 Hz, 1H), 6.05 (d, J = 8.8 Hz, 1H),
7.42 (s, 2H), 7.71 (dd, J = 1.9 Hz, 2.7 Hz, 1H), 8.30 (d, J = 2.7 Hz, 1H), 8.55 (d,
J = 1.9 Hz, 1H).
49. Mp = 164 °C; ½a D29
ꢁ
ꢂ37 (c 0.2, DMSO); 1H NMR (300 MHz, DMSO-d6) d ppm
2.55–2.72 (m, 2H), 3.13 (t, J = 8.7 Hz, 1H), 3.49 (m, 1H), 3.60 (t, J = 8.7 Hz, 1H),
3.81 (s, 3H), 4.6–5.9 (broad, 3 H), 5.29 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H),
7.61 (dd, J = 2.9 Hz, 8.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.8 Hz, 2H),
8.41 (d, J = 2.9 Hz, 1H).
34. Mp = 155 °C; ½a D32
ꢁ
ꢂ7 (c 0.3, DMSO); 1H NMR (300 MHz, DMSO-d6) d ppm 1.97
(s, 3H), 2.01 (s, 6H), 2.96 (dd, J = 4.7 Hz, 13.5 Hz, 1H), 3.03 (dd, J = 10.2 Hz,
13.5 Hz, 1H), 3.92 (s, 3H), 5.01 (ddd, J = 4.7 Hz, 9.5 Hz, 10.2 Hz, 1H), 5.23 (t,
J = 9.5 Hz, 1H), 5.37 (dd, J = 8.8 Hz, 9.5 Hz, 1H), 6.07 (d, J = 8.8 Hz, 1H), 7.29 (d,
J = 8.8 Hz, 1H), 7.74 (dd, J = 2.2 Hz, 8.4 Hz, 1H), 7.78 (dd, J = 2.2 Hz, 2.6 Hz, 1H),
7.87 (d, J = 2.6 Hz, 1H), 8.31 (d, J = 2.6 Hz, 1H), 8.60 (d, J = 1.8 Hz, 1H).
50. Almeida, R.; Levery, S. B.; Mandel, U.; Kresse, H.; Schwientek, T.; Bennett, E. P.;
Clausen, H. J. Biol. Chem. 1999, 274, 26165–26171.