Diastereoselective Synthesis of Cyclic Five-Membered trans,trans-Configured Nitrodiols by Double Henry Reaction of 1,4-Dialdehydes

Article abstract of DOI:10.1002/ardp.201500114

Conformationally constrained perhydroquinoxalines 4 show high κ receptor affinity, selectivity over related receptors and full agonistic activity. Since the κ affinity can be correlated with the dihedral angle of the ethylenediamine pharmacophore (4a: 55°/71°), the dihedral angles of the postulated cyclopentane derivative 5a (73°/84°) and indane derivative 6a (77°/81°) were calculated. The first step of the synthesis represents a double Henry reaction of 1,4-dialdehydes 8 and 10 with nitromethane, leading predominantly to the trans,trans-configured nitrodiols 9 and 11. X-ray crystal structure analyses of 9 and 11 led to dihedral angles O₂N-C-C-OH of 73.4 and 88.3°, respectively, which reflect the calculated dihedral angles of the hypothesized final products 5a and 6a. Since κ receptor affinity can be correlated with the dihedral angle of ethylenediamine pharmacophores, the dihedral angles of the postulated cyclopentane derivative 5a (73°/84°) and indane derivative 6a (77°/81°) were calculated. X-ray crystal structure analyses of the synthesized compounds 9 and 11 led to dihedral angles of 73.4 and 88.3°, respectively, reflecting the calculated dihedral angles of the hypothesized final products 5a and 6a.

Full text of DOI:10.1002/ardp.201500114

RCHH HARM
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Arch. Pharm. Chem. Life Sci. 2015, 348, 589–594
Archiv der Pharmazie
Full Paper
Diastereoselective Synthesis of Cyclic Five-Membered trans,trans-
Configured Nitrodiols by Double Henry Reaction of 1,4-
Dialdehydes
1
1
2
1,3
€
€
€
Janine Frohlich , Kirstin Lehmkuhl , Roland Frohlich , and Bernhard Wunsch
1
€
€
€
Institut fur Pharmazeutische und Medizinische Chemie der Westfalischen Wilhelms-Universitat
€
€
Munster, Munster, Germany
2
3
€
€
€
Organisch-Chemisches Institut der Universitat Munster, Munster, Germany
Cells-in-Motion Cluster of Excellence (EXC 1003–CiM), Westfalische Wilhelms-Universitat Munster,
€
€
€
€
Munster, Germany
Conformationally constrained perhydroquinoxalines 4 show high k receptor affinity, selectivity over
related receptors and full agonistic activity. Since the k affinity can be correlated with the dihedral angle
of the ethylenediamine pharmacophore (4a: 55°/71°), the dihedral angles of the postulated cyclopentane
derivative 5a (73°/84°) and indane derivative 6a (77°/81°) were calculated. The first step of the synthesis
represents a double Henry reaction of 1,4-dialdehydes 8 and 10 with nitromethane, leading
predominantly to the trans,trans-configured nitrodiols 9 and 11. X-ray crystal structure analyses of 9 and
11 led to dihedral angles O2N–C–C–OH of 73.4 and 88.3°, respectively, which reflect the calculated
dihedral angles of the hypothesized final products 5a and 6a.
Keywords: k Agonists / Dihedral angle / Double Henry reaction / Nitrocyclopentanediol / Nitroindanediol
/ trans,trans-Configuration
Received: March 26, 2015; Revised: April 17, 2015; Accepted: April 24, 2015
DOI 10.1002/ardp.201500114
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
side effects were observed during treatment of patients [4–6].
The ethylenediamine-based k agonist asimadoline contains a
Introduction
Agonists selectively activating k-opioid receptors in the
periphery are of great interest due to the absence of centrally
mediated side effects. The tetrapeptide FE 200665 containing
only (R)-configured amino acids represents an analgesically
active drug, which activates selectively k receptors in the
periphery [1–3] (Fig. 1). Although the morphinan derivative
nalfurafine, which is approved for the treatment of hemodi-
alysis-related uremic pruritus, has been described to activate
selectively k receptors in the periphery, centrally mediated
polar OH group at the pyrrolidine ring, which reduces the
passage of the blood–brain barrier. Asimadoline has success-
fully passed a phase II clinical trial for the treatment of
irritable bowel syndrome (IBS). Very recently, Tioga Pharma-
ceuticals, Inc. conducted a phase III clinical trial for the therapy
of diarrhea-predominant IBS (D-IBS) [7, 8].
Very recently, we have reported on the synthesis and
pharmacological activity of perhydroquinoxalines of type 4.
With appropriate decoration, that is, a dichlorophenylacetyl
moiety at N-1 and a pyrrolidinyl (X ¼ H) or hydroxypyrrolidinyl
(X ¼ OH) group at C-8, the quinoxalines 4 show very high
affinity toward the k-opioid receptor (Scheme 1). The residue
R at N-4, which is located outside the k-pharmacophoric
ethylenediamine system, allows the fine-tuning of the
pharmacodynamic and more importantly the pharmacokinet-
ic properties of quinoxalines 4. In terms of k-opioid receptor
affinity perhydroquinoxalines 4 with a proton, a small alkyl
€
€
Correspondence: Prof. Bernhard Wunsch, Institut fur Pharma-
€
zeutische und Medizinische Chemie der Westfalischen Wilhelms-
Universitat Munster, Corrensstraße 48, D-48149 Munster,
€
€
€
Germany.
E-mail: wuensch@uni-muenster.de
Fax: þ49-251-8332144
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Figure 1. k Receptor agonists predominantly
activating k receptors in the periphery.
group or a methxoxycarbonyl moiety at N-4 represent the
most promising compounds. All investigated perhydroqui-
noxalines 4 reveal excellent selectivity over related receptors
and are full agonists at the k-opioid receptor [9, 10].
membered nitrodiols. Following the same synthetic protocol
as described for the synthesis of quinoxalines 4 should result
in the five-membered analogs 5a and 6a starting with
succinaldehyde (8) and phthalaldehyde (10), respectively.
AM1 calculations provided dihedral angles of 73°/84° and
77°/81° for 5a and 6a, respectively (Fig. 2). Thus, the
exchange of the cyclohexane ring of 4a by the cyclopentane
ring of 5a or the benzannulated indane ring of 6a leads to a
slight increase of the crucial dihedral angle of the ethyl-
enediamine k-pharmacophore.
The high k affinity of the conformationally restricted
quinoxalines 4 was correlated with the dihedral angle
N(pyrrolidine)–C–C–N(acyl) of the k-pharmacophoric ethyl-
enediamine system [11, 12] (Fig. 2). Depending on the
substituent R, AM1 calculations provided two energetically
favored conformations of 4 with dihedral angles of 54ꢀ55
and 69ꢀ71°, respectively [10]. It is assumed that the calculated
dihedral angles of the conformationally restricted annulated
quinoxaline ring system are close to the optimal bioactive
conformation. Therefore, analogs of 4 with similar but not
identical dihedral angles were envisaged.
Results and discussion
In contrast to glutaraldehyde (1), the shorter homolog
succinaldehyde (8) is not commercially available due to its
high reactivity and thus polymerization tendency. Therefore,
succinaldehyde (8) was prepared by hydrolysis of the cyclic
acetal 7 with 1 M HCl [11] (Scheme 2).
The stereochemistry of 4 and thus the dihedral angle of the
k-pharmacophore were determined by the first reaction step
(Scheme 1). The double Henry reaction of glutaraldehyde (1)
with nitromethane (2) yielded the thermodynamically most
stable trans,trans-configured cyclohexane
3
[10, 13–15].
The double Henry reaction [16] of glutaraldehyde (1) with
nitromethane (2) has been performed with NaOH in aqueous
methanol at room temperature to give the nitrodiol 3 in 80%
yield [11, 13–15]. The same reaction conditions applied on
succinaldehyde (8) led to a fast conversion of 8, but the
nitrodiol 9 could not be isolated. We assume that the higher
Subsequent replacement of the hydroxy moieties by amino
groups did not alter the trans,trans-configuration during the
further synthesis.
Herein, we report on the double Henry reaction of 1,4-
dialdeyhdes with nitromethane (2) leading to five-
Scheme 1. Outline of the synthesis of the k agonists 4 showing the trans,trans-configuration determining double Henry reaction of
glutaraldehyde (1) and nitromethane (2). Reagents and reaction conditions: (a) NaOH, CH3OH, rt, 80% [10, 13–15].
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Figure 2. Comparison of the dihedral angles of the k-pharmacophore of quinoxaline 4a, cyclopentane analog 5a, and indane analog
6a. The conformational analysis was performed with force field MMFF94x of the molecular modelling program MOE (molecular
operating environment), version 2013.08 (Chemical Computing Group AG).
reactivity of succinaldehyde leading to undesired reactions
was the reason for this observation (Scheme 2).
the NO2 moiety relative to its neighbor protons (CH–OH). The
triplet for 2-H of the six-membered nitrodiol 3 (4.17 ppm,
J ¼ 9.9 Hz), which adopts a clean chair conformation with all
substituents in equatorial position, appears with a similar
chemical shift and similar coupling constants.
Several bases have been described for successful Henry
reactions (nitro–aldol reactions) including the phase transfer
catalyst cetyltrimethylammonium chloride/NaOH [17]; 1,1,3,3-
tetramethylguanidine [18], Cu(I)-salts in the presence of chiral
ligands [19], Bu4NF in THF [20], and DBU in THF [21]. Several of
these reaction conditions were investigated and finally it was
found that the base DBU in HF provided the trans,trans-
configured nitrodiol 9 in 17% yield. The yield of the five-
membered nitrodiol 9 was lower than the yield of the six-
membered nitrodiol 3, which was explained by the high
reactivity of succinaldehyde (8) giving rise to side products,
isolation problems of the very polar nitrodiol 9, which did not
crystallize from the reaction mixture, and the existence of
diastereomers.
After removal of the solvents CH2Cl2 and acetone, colorless
crystals of nitrodiol 9 were obtained, which were suitable for
X-ray crystal structure analysis. In Fig. 3, the structure of 9
proving unequivocally the trans,trans-configuration of the
five-membered nitrodiol is shown. The dihedral angle
between the protons in 1- and 2-position (H1–C1–C2–H2) is
172°, which is close to 180° and explains the large coupling
constant of 6.8 Hz. The calculated dihedral angle of 73°/84°
between the k-pharmacophoric elements pyrrolidinyl and
dichlorophenylacetamido in the final product 5a corresponds
nicely to the dihedral angle between the NO2 and OH
moieties in the nitrodiol 9 (73.4° for O2–C2–C1–N6). It can be
concluded that the dihedral angle between the NO2 moiety
and the OH group of the first synthetic product, the nitrodiol
9, can be used as model for the arrangement of the k-
pharmacophoric elements in the envisaged final product 5a.
According to the calculations, the dihedral angle of the k-
pharmacophoric elements of the potential indane analog 6a
(77°/81°) is similar but not identical to the corresponding
dihedral angle of 5a (73°/84°) (Fig. 2), which should at the end
influence the k affinity of 5a and 6a. For the synthesis of
benzannulated compounds, phthalaldehyde (10) was
employed as starting material in the double Henry reaction
with nitromethane (2). As described for succinaldehyde (8),
NaOH did not induce the reaction of phthalaldehyde with
nitromethane. Therefore, the weak base Bu4NF was used as
reported in the literature [17, 22], which provided the
nitrodiol 11 [23] in 55% yield. Reduction of the nitro moiety
The signals in the 1H NMR spectrum of 9 indicate the
existence of a symmetric, trans,trans-configured diastereo-
mer. The triplet at 4.56 ppm (1 H) with coupling constants of
6.8 Hz indicates trans-orientation of the proton adjacent to
Scheme 2. Synthesis of 2-nitrocyclopentane-1,3-diol (9).
Reagents and reaction conditions: (a) HCl 1 M, 90°C, 1 h, 77%.
(b) 2, DBU, THF, rt 2 h, 17%.
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7.3 Hz. The dihedral angle between the NO2 and OH moieties
is 88.3°. This angle is larger than the calculated dihedral
angle for the envisaged final product 6a (77°/81°) as well as
the recorded dihedral angle of the analogous cyclopentane
derivative 9 (73.4°).
Conclusions
High k affinity was achieved for conformationally constrained
perhydroquinoxalines 4 with a dihedral angle of 55°/71° of
the ethylenediamine k-pharmacophore. AM1 calculations of
the cyclopentane and indane analogs 5a and 6a revealed
larger dihedral angles of 73°/84° and 77°/81°, respectively. The
dihedral angles between the NO2 and OH moieties deter-
mined in X-ray crystal structure analysis of nitrodiols 9 and 11
are 73.4 and 88.3°, respectively, reflecting the orientation of
the pharmacophoric elements in the potential final products
5a and 6a. The double Henry reaction of dialdehydes 1,8, and
10 with nitromethane required careful optimization, respec-
tively, and led predominantly to the trans,trans-configured
products 3, 9, and 11.
Figure 3. X-ray crystal structure of 9. Thermal ellipsoids are
shown at 30% probability. Some important distances, bond
̊
angles and dihedral angles: distances; C1–C2 1.512(5) A; C1–C5
̊
̊
1.523(5) A; C1–N6 1.482(5) A; bond angles: C1–C2–O2 112.8(3)°;
C1–C5–O5 113.6(4)°; C1–C2–C3 102.8(3)°; C2–C1–C5 103.0(3);
dihedral angles: O2–C2–C1–N6 73.4(4)°: H1–C1–C2–H2 171.5°;
O5–C5–C1–N6 72.2(4)°; N6–C1–C2–C3 164.8(3)°.
Experimental
Chemistry general
with H2 and Raney-Ni afforded the aminodiol 12 [24], which
was acylated to give the amide 13 (Scheme 3).
Unless otherwise noted, moisture sensitive reactions were
conducted under dry nitrogen. THF was dried with sodium/
benzophenone and was freshly distilled before use. Thin layer
chromatography (tlc): Silica gel 60 F254 plates (Merck). Flash
chromatography (fc): Silica gel 60, 40–64 mm (Merck); paren-
theses include: diameter of the column, length of column,
fraction size, eluent, Rf value. Melting point: melting point
The 1H NMR spectra of the 1,2,3-trisubstituted indanes 11–
13 indicate a symmetric trans,trans-configured structure.
The coupling constants of the triplet for the proton in 2-
position of the three compounds 11–13 are very similar (7.3–
7.7 Hz) indicating large dihedral angles. According to the X-
ray crystal structure analysis of the nitrodiol 11 [25], the
dihedral angle between the protons in 1- and 2-position is
154°, which fits nicely to the observed coupling constant of
apparatus SMP
3 (Stuart Scientific), uncorrected. IR: IR
spectrophotometer 480Plus FT-ATR-IR (Jasco). 1H NMR
(400 MHz): Mercury plus 400 spectrometer (Varian); d in
Scheme 3. Synthesis of 1,2,3-trisubstituted
indane derivatives. Reagents and reaction con-
ditions: (a) 2, Bu4NF, THF, rt, 1 h, 55%. (b) H2 (1
bar), Raney-Ni, CH3OH, rt, 3 h, 90%. (c)
ClCH2COCl, NEt3, DMF, rt, 30 min, 64%.
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ppm related to tetramethylsilane; coupling constants are
given with 0.5 Hz resolution. MS: EI ¼ electron impact, ESI ¼
electro spray ionization: MicroTof (Bruker Daltonics, Bremen),
calibration with sodium formate clusters before measure-
ment. HPLC method for determination of the product purity:
Merck Hitachi equipment; UV detector: L-7400; autosampler:
L-7200; pump: L-7100; degasser: L-7614; Method 1: column:
LiChrospher1 60 RP-select B (5 mm), 250–4 mm cartridge; flow
rate: 1.00 mL/min; injection volume: 5.0 mL; detection at
l ¼ 210 nm; solvents: A: water with 0.05% v/v trifluoroacetic
acid; B: acetonitrile with 0.05% v/v trifluoroacetic acid:
gradient elution: (A %): 0–4 min: 90%, 4–29 min: gradient
from 90 to 0%, 29–31 min: 0%, 31–31.5 min: gradient from 0
to 90%, 31.5–40 min: 90%.
7-CH). FT-IR: n (cmꢀ1) ¼ 3350 (s, n(OH)), 1549 (s, nasym(NO2)),
1374 (m, nsym(NO2)). Purity (HPLC): 92.2%, tR ¼ 7.78. MS (ESI):
m/z ¼ 194 [MþꢀH].
(2r)-2-Aminoindane-1,3-diol (12) [24,26]
Raney-Ni (1.0 mL, approximately 0.60 g Ni) was added to a
solution of 11 (0.99 g, 5.1 mmol) in CH3OH (12 mL). The
suspension was stirred under H2 (1 bar) at rt for 3 h. Then it
was filtered and the solvent was removed in vacuo. Colorless
solid, mp 188–190°C (Ref. [24] 168°C), yield 0.75 g (90%).
C9H11NO2 (165.2). Rf ¼ 0.20 (CH3OH/CH2Cl2 2:8). 1H NMR
(CD3OD): d (ppm) ¼ 3.10 (t, 3J ¼ 7.6 Hz, 1H, 2-CH), 4.60 (d,
3J ¼ 7.6 Hz, 2H, 1-CH, 3-CH), 7.29–7.31 (m, 2H, 5-CH, 6-CH),
7.34–7.36 (m, 2H, 4-CH, 7-CH). FT-IR: n (cmꢀ1) ¼ 3360 (s, n(OH)),
–
3286 (s, n(NH)), 744 (s, n(C C), 1,2-disubstituted aryl). HR-MS
–
(2r)-2-Nitrocyclopentane-1,3-diol (9)
(APCI): m/z ¼ 166.0910, calcd. 166.0863 for C9H11NO2Hþ
A
mixture of 2,5-dimethoxytetrahydrofuran (7, 2.0 g,
[MþH]þ.
12.5 mmol) and 0.1 M HCl (10 mL) was heated to 90°C for
1 h. NaHCO3 and a saturated solution of NaCl were added and
the mixture was extracted with ethyl acetate (3ꢁ). The
combined organic layers were dried (Na2SO4) and concentrat-
ed in vacuo to obtain succinaldehyde (8) as colorless oil, yield
1.02 g (77%). 1H NMR (CDCl3): d (ppm) ¼ 2.81 (s, 4H, 2-CH2, 3-
2-Chloro-N-[(2r)-1,3-dihydroxyindan-2-yl]acetamide (13)
Under N2 at 0°C chloroacetyl chloride (0.04 mL, 0.6 mmol) was
added slowly (1.5 h) to a solution of 2-aminoindane-1,3-diol
12 (0.10 g, 0.60 mmol) and NEt3 (0.08 mL) in DMF (4 mL). The
mixture was stirred at rt for 30 min, concentrated in vacuo and
the residue was purified by fc (3 cm, 15 cm, 30 mL, CH2Cl2/
CH3OH 9:1, Rf ¼ 0.50). Colorless solid, mp 190–192°C, yield
0.09 g (64%). C11H12ClNO3 (241.7). 1H NMR (CD3OD): d
(ppm) ¼ 4.12 (t, 3J ¼ 7.7 Hz, 1H, 2-CH), 4.16 (s, 2H, CH2-Cl), 4.95
(d, 3J ¼ 7.7 Hz, 2H, 1-CH, 3-CH), 7.32–7.34 (m, 2H, 5-CH. 6-CH),
7.35–7.37 (m, 2H, 4-CH, 7-CH). 13C NMR (CD3OD): d (ppm)
¼ 43.4 (CH2Cl), 70.9 (C-2), 75.9 (C-1, C-3), 124.3 (C-4, C-7), 129.5
–
CH ), 9.82 (s, 2H, 2 ꢁ CH O). Succinaldehyde (8, 0.30 g,
–
2
3.5 mmol) was dissolved in THF (4 mL) and the solution was
cooled to 0°C. Within a period of 30 min, DBU (0.26 mL,
1.25 mmol) was added to this solution and afterwards
nitromethane (2, 0.19 mL, 3.5 mmol) was added. The mixture
was stirred at rt for 2 h, then it was neutralized by addition of
HOAc. After addition of H2O (10 mL), the aqueous layer was
extracted with ethyl acetate (5 ꢁ 20 mL), the combined
organic layers were dried (Na2SO4), concentrated in vacuo
and the residue was purified by fc (3 cm, 15 cm, 20 mL, CH2Cl2/
acetone 95:5, Rf ¼ 0.45 [CH2Cl2/acetone 90:10]). Evaporation
of the solvent led to a colorless solid, mp 68°C, yield 90 mg
(17%). C5H9NO4 (147.1). 1H NMR (CD3OD): d (ppm) ¼ 1.76–
1.80 (m, 2H, 4-CH2, 5-CH2), 2.08–2.12 (m, 2H, 4-CH2, 5-CH2),
4.43–4.46 (m, 2H, 1-CH, 3-CH), 4.56 (t, 3J ¼ 6.8 Hz, 1H, 2-CH).
13C NMR (CD3OD): d (ppm) ¼ 31.1 (C-4, C-5), 76.1 (C-1, C-3),
101.2 (C-2). FT-IR: n (cmꢀ1) ¼ 3305 (s, n(OH)), 1543 (s, n(NO2)),
1342 (s, nasym(NO2)), 1040 (s, n(C–O)). HR-MS (APCI): m/z ¼
ꢀ1
–
(C-5, C-6), 142.4 (C-3a, C-7a), 170.2 (C O). FT-IR: n (cm
)
–
¼ 3360 (s, n(OH)), 3251 (s, n(NH)), 2900 (s, n(CH)). HR-MS (ESI):
m/z ¼ 264.0405, calcd. 264.0398 for C11H12ClNO3Naþ (M-
(
35Cl)þNa]þ. Purity (HPLC): 90.6%, tR ¼ 5.42 min. Analysis:
calcd. C 54.67 H 5.00 N 5.80; found C 55.23 H 5.32 N 5.35.
X-ray crystal structure analysis of 9
Removal of the solvents CH2Cl2 and acetone after fc led to
colorless crystals, which were suitable for X-ray crystal
structure analysis.
þ
147.0817, calcd. 147.0764 for C5H9NO4 [M]þ.
X-ray diffraction
Data sets were collected with a Nonius KappaCCD diffrac-
tometer. Programs used: data collection, COLLECT (R. W. W.
Hooft, Bruker AXS, 2008, Delft, The Netherlands); data
reduction Denzo-SMN [27]; absorption correction, Denzo [28];
structure solution SHELXS-97 [29]; structure refinement
SHELXL-97 [30] and graphics, XP (BrukerAXS, 2000). Thermals
ellipsoids are shown with 30% probability, R values are given
for observed reflections, and wR2 values are given for all
reflections.
(2r)-2-Nitroindane-1,3-diol (11) [22,25,26]
TBAF (Bu4NF, 0.60 g, 1.5 mmol) was added to a solution of o-
phthalaldehyde (10, 1.50 g, 11.2 mmol) and nitromethane (2,
0.60 mL, 11.2 mmol) in THF (10 mL) and the mixture was
stirred at rt for 1 h. The mixture was concentrated in vacuo
and the residue was purified by fc (3 cm, 10 cm, 30 mL,
cyclohexane/ethyl acetate 8:2, Rf ¼ 0.20). The solvent was
removed in vacuo and the resulting solid was recrystallized
with ethyl acetate. Colorless solid, mp 168°C (Ref. [23] 166–
168°C), yield 1.20 g (55%, Ref. [22] 66%). C9H9NO4 (195.2).
1H NMR (DMSO-d6): d (ppm) ¼ 4.85 (t, 3J ¼ 7.3 Hz, 1H, 2-CH),
5.37 (t, 3J ¼ 7.3 Hz, 2H, 1-CH, 3-CH), 6.50 (d, 3J ¼ 7.3 Hz, 2H,
2 ꢁ OH), 7.31–7.36 (m, 2H, 5-CH, 6-CH), 7.37–7.41 (m, 2H, 4-CH,
X-ray crystal structure analysis of 9
Formula C5H9NO4, M ¼ 147.13, colorless crystal, 0.33 ꢁ 0.13
̊
ꢁ 0.06 mm, a ¼ 6.5281(3), b ¼ 6.5281(3), c ¼ 13.5558(6) A, a
¼ 90, b ¼ 90, g ¼ 120°, V ¼ 500.3(1) A , rcalc ¼ 1.465 g cmꢀ3
,
3
̊
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J. Frohlich et al.
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m ¼ 0.128 mmꢀ1, empirical absorption correction (0.959 ꢂ T
ꢂ 0.992), Z ¼ 3, trigonal, space group P3(1) (No. 144),
R. D. Murray, M. A. Simon, Br. J. Pharmacol. 1994, 113,
1317–1327.
̊
€
l ¼ 0.71073 A, T ¼ 223(2) K, v and f scans, 3145 reflections
[9] C. Bourgeois, E. Werfel, D. Schepmann, B. Wunsch,
collected (ꢃh, ꢃk, ꢃl), 1139 independent (Rint ¼ 0.042) and
1011 observed reflections [I > 2s(I)], 99 refined parameters,
R ¼ 0.053, wR2 ¼ 0.112, max. (min.) residual electron density
Bioorg. Med. Chem. 2014, 22, 3316–3324.
[10] C. Bourgeois, E. Werfel, F. Galla, K. Lehmkuhl, H. Torres-
ꢁ
€
Gomez, D. Schepmann, B. Kogel, T. Christoph,
0.19 (ꢀ0.17) e.Aꢀ3, the hydrogens at O2 and O5 atoms were
W. Straßburger, W. Englberger, M. Soeberdt, S. Huwel,
̊
€
€
refined freely; others were calculated and refined as riding
H.-J. Galla, B. Wunsch, J. Med. Chem. 2014, 57, 6845–
atoms. CCDC: 1055750.
6860.
€
€
[11] D. Kracht, E. Rack, D. Schepmann, R. Frohlich, B. Wunsch,
Org. Biomol. Chem. 2010, 8, 212–225.
This work was performed within the framework of the
International Research Training Group ‘Complex Functional
Systems in Chemistry: Design, Synthesis and Applications’ in
collaboration with the University of Nagoya. Financial support
[12] G. Subramanian, G. Paterlini, D. L. Larson,
P. S. Portoghese, D. M. Ferguson, J. Med. Chem. 1998,
41, 4777–4789.
€
[13] F. W. Lichtenthaler, T. Nakagawa, A. El-Scherbiney,
Angew. Chem. 1967, 79, 530–531.
[14] F. W. Lichtenthaler, T. Nakagawa, A. El-Scherbiney,
Chem. Ber. 1968, 101, 1837–1845.
of this project by the IRTG Munster—Nagoya and the
Deutsche Forschungsgemeinschaft is gratefully
acknowledged.
The authors have declared no conflict of interest.
[15] M. Eberle, M. Missbach, D. Seebach, Org. Synth. Coll.
2003, 8, 332–340.
[16] L. Henry, Compt. Rend. 1895, 120, 1265–1268.
[17] R. Ballini, G. Bosica, J. Org. Chem. 1997, 62, 425–427.
[18] D. Simoni, F. P. Invidiata, S. Manfredini, R. Ferroni,
I. Lampronti, M. Roberti, G. P. Pollini, Tetrahedron Lett.
1997, 38, 2749–2752.
[19] D. White, S. Shaw, Org. Lett., 2012, 14, 6270–6273.
[20] S. Hanessian, P. V. Devasthale, Tetrahedron Lett. 1996,
37, 987–990.
References
[1] L. Arendt-Nielsen, A. E. Olesen, C. Staahl, F. Menzaghi,
S. Kell, G. Y. Wong, Anesthesiology 2009, 111, 616–624.
[2] T. W. Vanderah, C. D. Schteingart, J. Trojnar, J.-L. Junien,
J. Lai, P. J.-M. Riviere, J. Pharmacol. Exp. Ther. 2004, 310,
326–333.
[3] T. W. Vanderah, T. Largent-Milnes, J. Lai, F. Porreca,
R. A. Houghten, F. Menzaghi, K. Wisniewski, J. Stalewski,
J. Sueiras-Diaz, R. Galyean, C. Schteingart, J.-L. Junien,
[21] S. Ogawa, K. Washida, Eur. J. Org. Chem. 1998, 1929–
1934.
[22] L. G. Ruano, V. Marcos, J. An. Suanzes, L. Marzo,
ꢀ
ꢁ
J. Trojnar, P. J.-M. Riviere, Eur. J. Pharmacol. 2008, 583,
J. Aleman, Chem. Eur. J. 2009, 15, 6576–6580.
62–72.
[23] H. H. Baer, B. Achmatowicz, J. Org. Chem. 1964, 29,
3180–3185.
[24] S. Carboni, Gazz. Chim. Ital. 1951, 81, 9–74.
[25] S. Nordensen, J. Skramstad, E. Flotra, Acta Chem. Scand.
1984, 38, 461–467.
[26] Although compounds 11 and 12 have been already
described in the literature, spectroscopic data of the
compounds are missing and are therefore included in
this manuscript.
[27] Z. Otwinowski, W. Minor, Methods Enzymol. 1997, 276,
307–326.
[4] N. P. R. Nieland, H. A. Moynihan, S. Carrington,
J. Broadbear, J. H. Woods, J. R. Traynor, S. M. Husbands,
J. W. Lewis, J. Med. Chem. 2006, 49, 5333–5338.
[5] H. Kumagai, T. Ebata, K. Takamori, H. Kumagai, T. Ebata,
K. Takamori, T. Muramatsu, H. Nakamoto, H. Suzuki,
Nephrol. Dial. Transplant. 2010, 25, 1251–1257.
[6] http://www.ema.europa.eu/ema/index.jsp?curl=pages/
medicines/human/medicines/002683/smops/Negative/
human_smop_000631.jsp&mid=WC0b01ac058001d127.
2013, EMA/790619/2013, EMEA/H/C/002683.
[7] M. D. Camilleri, Neurogastroenterol. Motil. 2008, 20,
971–979.
[28] Z. Otwinowski, D. Borek, W. Majewski, W. Minor, Acta
Crystallogr. 2003, A59, 228–234.
[8] A. Barber, G. D. Bartoszyk, H. M. Bender, R. Gottschlich,
H. E. Greiner, J. Harting, F. Mauler, K.-O. Minck,
[29] G. M. Sheldrick, Acta Crystallogr. 1990, A46, 467–473.
[30] G. M. Sheldrick, Acta Crystallogr. 2008, A64, 112–122.
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