Enantiomerically pure 1,3-dioxanes as highly selective NMDA and σ1 receptor ligands

Article abstract of DOI:10.1021/jm301166m

We synthesized and investigated the NMDA and σ₁ receptor affinity of enantiomerically pure 2-(2-phenyl-1,3-dioxan-4-yl)ethanamines 17-26. The primary amines (R,R)-18-20 with an axially oriented phenyl moiety in position 2 interacted with high e

Full text of DOI:10.1021/jm301166m

Brief Article
pubs.acs.org/jmc
Enantiomerically Pure 1,3-Dioxanes as Highly Selective NMDA and σ1
Receptor Ligands
Jens Kohler,† Klaus Bergander,‡ Jorg Fabian,† Dirk Schepmann,† and Bernhard Wunsch*,†
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†Institut fur Pharmazeutische und Medizinische Chemie, Westfalische Wilhelms-Universitat Munster, Hittorfstraße 58-62, D-48149
̈
̈
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̈
Munster, Germany
̈
‡Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster, Corrensstraße 40, D-48149 Munster, Germany
̈
̈
̈
̈
S
* Supporting Information
ABSTRACT: We synthesized and investigated the NMDA and σ1 receptor affinity of enantiomerically pure 2-(2-phenyl-1,3-
dioxan-4-yl)ethanamines 17−26. The primary amines (R,R)-18−20 with an axially oriented phenyl moiety in position 2
interacted with high enantioselectivity (eudismic ratios 70−130) and high affinity (Ki((R,R)-19) = 13 nM) with the PCP binding
site of the NMDA receptor. Introduction of an N-benzyl moiety led to potent σ1 ligands including compound (S,R)-22 (Ki = 6
nM) with an equatorially oriented phenyl moiety in position 2.
microstructure of the channel pore at the PCP binding site
(Figure 1).
INTRODUCTION
■
The NMDA (N-methyl-D-aspartate) receptor is an excitatory
ion channel receptor that is activated by (S)-glutamate.
Simultaneous binding of (S)-glutamate and glycine at the
NMDA receptor combined with depolarization of the cell
membrane leads to an opening of the channel and influx of
Ca2+ and Na+ ions.1 Because of this coagonistic mechanism, the
NMDA receptor allows a high synaptic plasticity that is
necessary for brain functions such as learning and memory.2,3
On the other hand, NMDA receptors are also involved in
pathophysiological processes caused by an increased concen-
tration of (S)-glutamate in the synaptic cleft. The high
concentration of (S)-glutamate leads to an increased influx of
Ca2+ ions, resulting in toxic effects (excitotoxicity). These toxic
effects can follow acute cerebral ischemia due to brain injury or
stroke. They are also involved in chronic processes such as the
neurodegenerative disorders Parkinson’s or Alzheimer’s disease.
Therefore, NMDA receptor antagonists blocking the increased
Ca2+ ion influx possess a potential for the treatment of these
disorders.3−6
Figure 1. Structures of compounds that bind at the PCP binding site
of the NMDA receptor (Ki values).
Known NMDA receptor antagonists include the hallucino-
genic compound phencyclidine (PCP, 1), which gave its name
to the binding site within the ion channel.7,8 and (S)-ketamine
(2), which is clinically used as a fast narcotic with analgesic
properties.9 The high affinity of phencyclidine (1) for the
receptor and the slow release from the binding site in the
channel pore lead to strong inhibition of the normal
neurotransmission and therefore clinically unacceptable side
effects such as hallucinations, drowsiness, and coma. In
contrast, memantine (3) has a rather low affinity but a short
dwell-time and is not known to affect normal brain
functions.5,10
To develop new drugs combining high affinity with fast off-
rate kinetics, the inner structure of the channel pore has to be
studied in more detail. Receptor binding studies of enantiomers
are of particular value for this purpose because their
physicochemical properties are identical whereas their three-
dimensional structure differs, thus giving insight into the
The piperidyl substituted 1,3-dioxolanes dexoxadrol (4) and
etoxadrol (5) belong to a series of enantiomerically pure
NMDA receptor antagonists.7,11−13 It has been shown that the
(2S,4S,2Spip)-configuration of etoxadrol (5) is crucial for
binding at the PCP binding site.14,15 Recently, we reported
on a series of racemic 1,3-dioxane derivatives with high NMDA
and σ1 receptor affinity.16,17 The aim of the present study was
to investigate the relationship between the structure of
enantiomerically pure 4-aminoethyl substituted 1,3-dioxanes 6
and their affinity to the NMDA receptor. We also analyzed the
structural differences responsible for high σ1 receptor affinity.18
Received: June 28, 2012
Published: September 27, 2012
© 2012 American Chemical Society
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Journal of Medicinal Chemistry
Brief Article
Stereoselective Acetalization. Azidodiols (S)-11 and
(R)-11 were used as chiral building blocks for the synthesis
of enantiomerically pure azido-1,3-dioxanes 12−16 with a
second chiral center at position 2. The acetalization of 11 with
benzaldehyde predominantly afforded 1,3-dioxanes 12 bearing
the phenyl moiety in equatorial position (Scheme 2, R1 = H),
RESULTS
■
The enantiomeric azidodiols (S)-11 and (R)-11, which
determine the configuration at position 4 of the desired
compounds, were synthesized using a lipase as chiral catalyst
(Scheme 1). Acetalization of (S)-11 and (R)-11 led to
azidodioxanes 12−16, establishing the second center of
chirality at position 2 (Scheme 2). Finally, azidodioxanes 12−
16 were converted into amines 17−21 and 22−26 (Scheme 3).
Enantioselective Synthesis of Azidodiols (S)-11 and
(R)-11. The diester 7 was silylated with dimethylphenylsilyl
chloride and subsequently reduced with LiBH4 to obtain diol 8,
which was acetylated to afford diacetate 9. To obtain both
enantiomers (S)-10 and (R)-10 in high enantiomeric excess
(ee), two pathways were followed. At first, monoacetate (S)-10
was produced by acetylation of diol 8 using isopropenyl acetate
(IPA) as acylating agent and the lipase from Burkholderia
cepacia as catalyst in methyl tert-butyl ether (MTBE). The
enantiomer (R)-10 was synthesized by hydrolysis of diacetate 9
using the same lipase in aqueous NaHCO3 solution. Both
monoacetates (S)-10 and (R)-10 were transformed into
azidodiols (S)-11 and (R)-11 by a Mitsunobu reaction with
Zn(N3)2·(pyridine)2, diisopropyl azodicarboxylate (DIAD), and
PPh3 followed by removal of the protective groups (Scheme
1).18,19 The enantiomeric excess (ee) of (S)-11 and (R)-11 was
Scheme 2. Stereoselective Synthesis of Azido-1,3-dioxanes
a
12−16
Scheme 1. Synthesis of Enantiomerically Pure Azidodiols
a
(S)-11 (99.8% ee) and (R)-11 (98.0% ee)
a
After purification by preparative HPLC, all products were obtained
with >99.8% de. Reagents and conditions: (a) benzaldehyde (R1 = H)
or phenyl ketone (R1 = CH3, C2H5, C3H7, C(CH3)3), pTosOH,
toluene, Dean−Stark apparatus.
whereas phenyl ketones gave products 13−16 with an axially
oriented phenyl moiety (Scheme 2, R1 = CH3, C2H5, C3H7,
C(CH3)3). Generally, the axially oriented phenyl moiety of 2-
phenyl-1,3-dioxanes adopts a perpendicular conformation.21,22
The relative configuration of azidodioxanes 12−16 was
determined by NOE-NMR experiments. Irradiation of 12 at
5.6 ppm (2 Hax) led to an increased signal at 4.0 ppm (6 Hax
and 4 Hax) and vice versa, indicating an equatorial orientation
of the phenyl moiety. The axial orientation of the phenyl
moiety of 13−16 was proven by irradiation at 3.8 ppm (6 Hax
and 4 Hax), leading to an increased signal of the aromatic
protons in ortho position of the phenyl ring (7.4 ppm) and vice
versa.
a
Reagents and conditions: (a) Me2PhSiCl, imidazole, CH2Cl2; (b)
To quantify the diastereoselectivity of the acetalization
reaction, we analyzed the ratio of diastereomers in the crude
reaction mixtures resulting from acetalization of (S)-11 with
benzaldehyde and phenyl ketones. The respective diaster-
eomers were identified by identical mass spectra using APCI-
MS detection and quantified by integration of the UV
absorption at 210 nm. Major mass fragments detected with
high intensities were [MH-26]+ and [MH-28]+, which are
typical fragments of organic azides.23 It was found that the
acetalization of (S)-11 with benzaldehyde led to (R,S)-12 with
a diastereomeric excess (de) of 89.3%. In contrast to this result,
acetalization with propiophenone and butyrophenone gave the
(2S)-configured 1,3-dioxanes (S,S)-14 and (S,S)-15 with 95.1%
LiBH4, Et2O; (c) IPA, lipase Candida antarctica B, MTBE; (d) IPA,
lipase Burkholderia cepacia, MTBE; (e) lipase B. cepacia, NaHCO3-
solution; (f) Zn(N3)2·(pyridine)2, PPh3, DIAD, toluene; (g) 1. K2CO3,
CH3OH, 2. HCl 0.1 M.
determined by measuring the ee of the synthetic precursors
(S)-10 and (R)-10 and in addition after acylation with 4-
bromobenzoyl chloride. Both methods led to the same result.
The ee of the (S)-configured compounds was 99.8%, and the ee
of the (R)-configured compounds 98.0%. The absolute
configuration of the compounds was determined by means of
exciton coupled circular dichroism (ECCD) of the correspond-
ing bis-4-bromobenzoates.18−20
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Journal of Medicinal Chemistry
Brief Article
a
Scheme 3. Conversion of Azido-1,3-dioxanes 12−16 into Primary Amines 17−21 and Benzylamines 22−26
a
Reagents and conditions: (a) H2, Pd/C, EtOAc; (b) benzaldehyde, NaBH(OAc)3, CH2Cl2.
a
Table 1. NMDA Receptor (PCP Binding Site) and σ1 Receptor Affinities of 17−26
compd
(R,S)-17
R1
R2
NMDA Ki SEM [nM]
eudismic ratio
σ1 Ki SEM [nM]
H
H
NH2
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
50 19
(S,R)-17
NH2
(S,S)-18
CH3
NH2
6120 630
46 17
130
115
70
(R,R)-18
(S,S)-19
CH3
NH2
C2H5
C2H5
C3H7
C3H7
C(CH3)3
C(CH3)3
H
NH2
1490 250
(R,R)-19
(S,S)-20
NH2
13
1530 670
21
1
NH2
(R,R)-20
(S,S)-21
NH2
3
NH2
400 47
304 35
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
59 12
383 41
429 140
1.3
(R,R)-21
(R,S)-22
NH2
NHBn
NHBn
NHBn
NHBn
NHBn
NHBn
NHBn
NHBn
NHBn
NHBn
(S,R)-22
H
6.0
11
17
28
20
1
3
2
6
3
(S,S)-23
CH3
(R,R)-23
(S,S)-24
CH3
C2H5
C2H5
C3H7
C3H7
C(CH3)3
C(CH3)3
(R,R)-24
(S,S)-25
136 23
72
253 11
128
(R,R)-25
(S,S)-26
9
(R,R)-26
phencyclidine (1)
(S)-ketamine (2)
memantine (3)
2
b
dexoxadrol (4)
32
7
c
racemic 17
>10000
>10000
>10000
c
racemic 19
23
3
8
(+)-MK-801
(+)-pentazocine
haloperidol
2
6
6
2
2
a
b
R1 and R2 refer to the structures shown in Scheme 3. Several studies report that the NMDA receptor affinities of dexoxadrol (4) and etoxadrol (5)
are very similar.14−17 Resynthesized according to literature.16
c
de and 97.9% de, respectively. The minor diastereomers of
(R,S)-12, (S,S)-14, and (S,S)-15 turned out to be rather
unstable, and those of (S,S)-13 and (S,S)-16 could not be
detected. For the following preparation of amines, the 1,3-
dioxanes 12−16 were purified by preparative HPLC, which led
to the isolation of the major diastereomers with purities >99.8%
de, respectively.
primary amines 17−21 (Scheme 3). Subsequently, reductive
monobenzylation of 17−21 was performed with one equivalent
of benzaldehyde and NaBH(OAc)3 affording benzylamines
22−26.
DISCUSSION
■
Affinity toward the PCP Binding Site of the NMDA
Receptor. The primary amines (R,R)-18−21 showed high
affinity to the PCP binding site, whereas the introduction of a
Preparation of Amines 17−26. Azidodioxanes 12−16
were reduced with H2 in the presence of Pd/C to obtain
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Journal of Medicinal Chemistry
Brief Article
Elmer), 1.0 dm tube, concentration c (g/100 mL), 20 °C, the unit
[deg·mL·dm−1·g−1] is omitted.
benzyl residue at the amino moiety (22−26) resulted in a
complete loss of NMDA receptor affinity (Table 1). Probably
due to the equatorial orientation of the phenyl ring, the
benzaldehyde derivatives 17 did not interact with the NMDA
receptor, indicating that the affinity of the primary amines 17−
21 strongly depends on the axial perpendicular orientation of
the phenyl moiety.
Compounds 7−11. Dimethyl 3-hydroxyglutarate (7) was
purchased from Sigma-Aldrich, and compounds 8, 9, (S)-10, (R)-10,
(S)-11, and (R)-11 were synthesized and characterized as described in
the literature.18,19 A batch of azidodiol (S)-11 with 99.8% ee and
azidodiol (R)-11 with 98.0% ee was used for production of all further
compounds.
The eudismic ratios of the primary amines 18−21 decreased
with increasing size of the second substituent in position 2 (see
Table 1): very high eudismic ratios were found for the
acetophenone derivatives 18 (R1 = CH3, 130: 1) and the
propiophenone derivatives 19 (R1 = C2H5, 115: 1). (R,R)-19 is
the most potent NMDA receptor ligand of this series with a Ki
value of 13 nM.
Etoxadrol (5) and its homologue (R,R)-19 share the axially
oriented phenyl moiety and the ethyl moiety at position 2 as
common features. Both compounds are highly flexible because
the piperidine moiety of etoxadrol (5) as well as the 2-
aminoethyl moiety of (R,R)-19 can rotate freely. However, it is
interesting that the (2R,4R)-configured dioxane (R,R)-19 binds
to the NMDA receptor with a 115-fold higher affinity than its
(2S,4S)-configured enantiomer (S,S)-19 although the absolute
configuration of etoxadrol is (2S,4S,2Spip).
Affinity toward the σ1 Receptor. The primary amines
17−21 did not interact with the σ1 receptor. In contrast, the
corresponding benzylamines 22−26 displayed high σ1 receptor
affinity but lacked any NMDA receptor affinity. This
observation is in good accordance with different σ1
pharmacophore models, which defined at least two hydro-
phobic residues attached to a basic amino moiety as structural
requirements.24 However, the eudismic ratios of the benzyl-
amines 22−25 to the σ1 receptor are considerably lower than
the eudismic ratios of the primary amines 18−22 to the NMDA
receptor. The highest eudismic ratio of 8:1 was found for the
enantiomeric benzaldehyde derivatives 22. (S,R)-22 is the
compound with the highest σ1 receptor affinity (Ki = 6.0 nM)
of this series.
General Procedure A for Acetalization of Azidodiols 11 to
Obtain 1,3-Dioxanes 12−16. Azidodiol (S)-11 or (R)-11 (4.2
mmol/0.9 mmol), the respective ketone or aldehyde (2 equiv), and 4-
toluenesulfonic acid monohydrate (10 mg/2.5 mg) were heated to
reflux in toluene (15 mL/3 mL). The water formed was removed with
a Dean−Stark apparatus. After 1 h. the water was removed from the
separator, the water separator was filled with molecular sieve (3 Å),
and fresh toluene was added. The reaction mixture was heated to
reflux for further 3 h and then concentrated (5 mL/1 mL) by
removing toluene. The residue was cooled to rt, CHCl3 (80 mL) was
added, and the mixture was washed with a saturated solution of
NaHCO3 (50 mL). The organic layer was dried (Na2SO4) znc
concentrated in vacuo, and the remaining crude material was purified
by preparative HPLC.
General Procedure B for Reduction of Azides 12−16 to
Primary Amines 17−21. In a Schlenk flask, the respective
azidodioxane 12−16 (3 mmol of (4S)-configured compounds/0.6
mmol of (4R)-configured compounds) was dissolved in ethyl acetate
(40 mL/10 mL), which had been dried over molecular sieve (3 Å).
Pd/C (10%, 80 mg/15 mg) was added, and the mixture was stirred
under a H2 atmosphere (balloon, 5 L) for 5 h at rt. Every hour, a part
of the gas phase was released (250−500 mL) and replaced by H2 if
necessary. Then the reaction mixture was filtered, concentrated in
vacuo, and purified by fc (eluent: homogeneous mixture of CH2Cl2/
methanol/NH3 solution (25%) 470/25/4). Compounds 17 and 18
were additionally purified by preparative HPLC.
General Procedure C for Conversion of Primary Amines 17−
21 into Benzylamines 22−26. The respective primary amine 17−
21 (1 mmol of (S)-configured compounds/0.25 mmol of (R)-
configured compounds) was dissolved in CH2Cl2 (20 mL/5 mL).
Freshly distilled benzaldehyde (1 equiv) was added, and the mixture
was stirred at rt. After stirring for 1 h, NaBH(OAc)3 (1.4 equiv) was
added, and the mixture was stirred at rt for further 16 h. Then the
mixture was diluted with CH2Cl2 (40 mL) and carefully washed with a
saturated solution of NaHCO3 (50 mL). The aqueous layer was
extracted with CH2Cl2 (2 × 50 mL), the combined CH2Cl2 layers
were dried (Na2SO4), concentrated in vacuo, and the residue was
purified by fc using the same eluent as for purification of the primary
amines 17−21.
(2R,4R)-2-(2-Ethyl-2-phenyl-1,3-dioxan-4-yl)ethan-1-amine
((R,R)-19). According to general procedure B, (R,R)-14 (172 mg, 0.66
mmol) was treated with H2. Purification by fc (3 cm, 20 cm, 10 mL, Rf
= 0.11). Pale-yellow oil, yield 124 mg (80%). [α]20D = −16.0 (c = 1.00,
CH2Cl2). 1H NMR (CDCl3): δ (ppm) = 0.79 (t, J = 7.5 Hz, 3H, CH2-
CH3), 1.25 (dtd, J = 12.8/2.3/1.6 Hz, 1H, 5-Heq), 1.38 (s, 2H, CH2-
CH2-NH2), 1.50−1.81 (m, 5H, CH2-CH2-NH2 and 5-Hax and CH2-
CH3), 2.82−2.99 (m, 2H, CH2-CH2-NH2), 3.71−3.87 (m, 2H, 6-Hax
and 4-Hax), 3.88 (ddd, J = 11.4/5.3/1.3 Hz, 1H, 6-Heq), 7.26−7.41 (m,
5H, Harom).
The σ2 receptor affinities of compounds 17−26 were also
investigated. It was found that the primary amines 17−21 did
not interact with the σ2 receptor. For benzylamines 22−26, the
σ2 receptor affinities were rather low (>0.2 μM).
CONCLUSION
■
Ring and side chain homologation of the NMDA receptor
antagonist etoxadrol (5) provided 2-(2-phenyl-1,3-dioxan-4-
yl)ethanamines 17−26. The primary amines (R,R)-18, (R,R)-
19, and (R,R)-20 interact with high affinity and enantiose-
lectivity with the PCP binding site of the NMDA receptor. It is
concluded that the axial orientation of the phenyl moiety in
position 2 of these compounds is responsible for the high
NMDA receptor affinity. Transformation of the primary amines
into benzylamines led to potent σ1 receptor ligands without any
NMDA receptor affinity. In summary, introduction of an N-
benzyl moiety and changing the configuration at the acetalic
position changes the NMDA ligand (R,R)-19 (Ki(NMDA) = 13
nM) into the potent σ1 receptor ligand (S,R)-22 (Ki(σ1) = 6
nM).
(2S,4R)-N-Benzyl-2-(2-phenyl-1,3-dioxan-4-yl)ethan-1-amine
((S,R)-22). According to general procedure C, (S,R)-17 (63 mg, 0.30
mmol) was reacted with benzaldehyde (33 mg, 0.31 mmol) and
NaBH(OAc)3 (92 mg, 0.43 mmol). Purification by fc (2 cm, 22 cm, 5
mL, Rf = 0.27). Pale-yellow oil, yield 58 mg (63%). [α]20D = +42.4 (c =
0.98, CH2Cl2). 1H NMR (CDCl3): δ (ppm) = 1.51 (dtd, J = 13.3/2.4/
1.4 Hz, 1H, 5-Heq), 1.73−1.94 (m, 4H, CH2-CH2-NHBn and 5-Hax
and CH2-CH2-NHBn), 2.83 (t, J = 6.8 Hz, 2H, CH2-CH2-NHBn),
3.80 (s, 2H, NH-CH2-Ph), 3.93−4.02 (m, 2H, 6-Hax and 4-Hax), 4.26
(ddd, J = 11.4/5.0/1.3 Hz, 1H, 6-Heq), 5.51 (s, 1H, 2-Hax), 7.22−7.38
(m, 8H, Harom), 7.45−7.48 (m, 2H, Harom).
EXPERIMENTAL SECTION
■
General. Flash chromatography (fc): silica gel 60, 40−63 μm
(diameter, length of the column, fraction size, Rf value). 1H NMR and
13C NMR: Unity Mercury Plus 400 spectrometer (Varian), INOVA
500 spectrometer (Varian). Optical rotation: Polarimeter 341 (Perkin-
Purity of Compounds 17−26 (HPLC). Column: LiChrospher 60
RP select B (250 mm, 4 mm) with precolumn (4 mm, 4 mm). Eluent:
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Journal of Medicinal Chemistry
Brief Article
A = water plus 0.05% TFA (v/v), B = acetonitrile plus 0.05% TFA (v/
v). Gradient: 0.0−4.0 min 90% A, 4.0−29.0 min from 90% A to 0% A,
29.0−31.0 min 0% A, 31.0−31.5 min from 0% A to 90% A, 31.5−40.0
min 90% A. Flow rate: 1 mL/min. UV detection: 210 nm. The purity
of all compounds was ≥98%.
Receptor Binding Studies. The affinities of 17−26 toward the
PCP binding site of the NMDA receptor were determined in
competition experiments using [3H]-(+)-MK-801 as radioligand and
membrane preparations from pig brain cortex as receptor material.
The σ1 receptor binding assay was carried out with homogenates of
guinea pig brains as receptor material and [3H]-(+)-pentazocine as
radioligand. These experiments had been optimized with respect to
previously reported binding studies.16
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F.; Rice, K. C.; Woods, J. H.; Winger, G.; Solomon, R. E.; Lessor, R.
A.; Silverton, J. V. Enantiomeric and diastereomeric dioxadrols:
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ASSOCIATED CONTENT
* Supporting Information
■
S
Purity data of the primary amines 17−21 and the benzyl
amines 22−26; synthesis of compounds 12−26 and data
thereof; materials and procedures for the NMDA, σ1, and σ2
receptor binding assays and σ2 receptor affinities; HPLC
methods; ee of (S)-10 and (R)-10; ee of the bis-4-
bromobenzoates of (S)-11 and (R)-11; CD-/UV-spectra of
the bis-4-bromobenzoates of (S)-11 and (R)-11; de of (R,S)-
12, (S,S)-14 and (S,S)-15; 1H NMR and NOE spectra of (R,S)-
12, (S,S)-13, (S,S)-14, (S,S)-15, and (S,S)-16. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) Thurkauf, A.; Mattson, M. V.; Richardson, S.; Mirsadeghi, S.;
Ornstein, P. L.; Harrison, E. A., Jr.; Rice, K. C.; Jacobson, A. E.; Monn,
J. A. Analogues of the dioxolanes dexoxadrol and etoxadrol as potential
phencyclidine-like agents. Synthesis and structure−activity relation-
ships. J. Med. Chem. 1992, 35, 1323−1329.
AUTHOR INFORMATION
Corresponding Author
*Phone: +49 251 83 33311, Fax: +49 251 83 32144, E mail:
wuensch@uni-muenster.de.
(16) Utech, T.; Kohler, J.; Wunsch, B. Synthesis of 4-(aminoalkyl)
̈
̈
■
substituted 1,3-dioxanes as potent NMDA and σ receptor antagonists.
Eur. J. Med. Chem. 2011, 46, 2157−2169.
(17) Aepkers, M.; Wunsch, B. Structure−affinity relationship studies
̈
of non-competitive NMDA receptor antagonists derived from
Notes
dexoxadrol and etoxadrol. Bioorg. Med. Chem. 2005, 13, 6836−6849.
The authors declare no competing financial interest.
(18) Kohler, J.; Wunsch, B. Lipase catalyzed enantioselective
̈
̈
desymmetrization of a prochiral pentane-1,3,5-triol derivative.
Tetrahedron: Asymmetry 2006, 17, 3091−3099.
ABBREVIATIONS USED
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(19) Kohler, J.; Wunsch, B. Conversion of a pentane-1,3,5-triol
̈
̈
NMDA, N-methyl-D-aspartate; PCP, phencyclidine (= 1-(1-
phenylcyclohexyl)piperidine); DIAD, diisopropyl azodicarbox-
ylate; PPh3, triphenylphosphane; SEM, standard error of the
mean; APCI, atmospheric-pressure chemical ionization; ATR,
attenuated total reflectance; fc, flash chromatography
derivative using lipases as chiral catalysts and possible function of the
lid for the regulation of substrate selectivity and enantioselectivity.
Biocatal. Biotransform. 2012, 30, 217−225.
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(21) Bailey, W. F.; Connon, H.; Eliel, E. L.; Wiberg, K. B.
Calorimetric determination of the conformational enthalpy and
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(22) Nader, F. W.; Eliel, E. L. Conformational analysis. XXII.
Conformational equilibria in 2-substituted 1,3-dioxanes. J. Am. Chem.
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