Stereoselective synthesis and receptor binding of conformationally restricted and flexible 2,4-disubstituted 1,3-dioxanes derived from benzomorphans

Article abstract of DOI:10.1002/(SICI)1521-4184(199912)332:12<413::AID-ARDP413>3.0.CO;2-0

The key steps in the stereoselective synthesis of the tricyclic aminomethyl derivatives 19 and 20 and the aminoethyl substituted 1,3-dioxanes 24 and 25 are nucleophilic addition of aryllithium intermediates to the nitroalkene 13, intramolecular transaceta

Full text of DOI:10.1002/(SICI)1521-4184(199912)332:12<413::AID-ARDP413>3.0.CO;2-0

Full Papers
Stereoselective Synthesis and Receptor Binding of Conformationally
Restricted and Flexible 2,4-Disubstituted 1,3-Dioxanes Derived from
Benzomorphans
a)
b)
c)
b)
Bernhard Wünsch* , Gerd Bauschke , Heike Diekmann , and Georg Höfner
a) Pharmazeutisches Institut der Universität Freiburg, Hermann-Herder-Straße 9, D-79104 Freiburg, Germany
b) Institut für Pharmazie – Zentrum für Pharmaforschung der Universität München, Butenandtstr. 7, D-81377 München, Germany
c) Fujisawa GmbH, Levelingstr. 12, D-81673 München, Germany
Key Words: Benzomorphan analogues; 1,3-dioxanes, 2,4-disubstituted; nitroalkenes, stereoselective addition of aryl-
lithium to; transacetalization; receptor binding studies; affinity to NMDA receptors; µ-receptors, κ-receptors, σ-receptors
Summary
The key steps in the stereoselective synthesis of the tricyclic
aminomethyl derivatives 19 and 20 and the aminoethyl substituted
1,3-dioxanes 24 and 25 are nucleophilic addition of aryllithium
intermediates to the nitroalkene 13, intramolecular transacetaliza-
tion of the addition products 15 and 16 (only for the tricyclic
derivatives 19 and 20) and subsequent reduction of the nitro group.
The affinities of the secondary and tertiary amines 19c,d, 20c,d,
24c,d, and 25c,d for the ion channel binding site of the NMDA
receptor, for µ-, κ-, and σ-receptors have been investigated. In the
group of tricyclic compounds only 19d shows remarkable σ-recep-
tor affinity (Ki = 21.6/1.10 µM). In the 1,3-dioxane series the
moderate µ- (Ki = 27.8 µM) and κ-receptor affinity (Ki = 36 µM)
as well as the high σ-receptor affinity (Ki = 3.3 µM) of the
(S,S,S)-configurated methylamine 24c should be emphasized. The
pentan-1-ol 26, the side product isolated during the synthesis of
24c, is of particular interest because of its considerable affinity to
µ- (Ki = 16.0 µM), κ- (Ki = 2.8 µM), and σ-receptors (Ki =
14.5/1.26 µM). The biphasic competition curves obtained during
σ-receptor binding studies of 19d and 26 (two Ki values) may be
explained by different interaction with σ-receptor subtypes.
Scheme 1
The µ- and κ-receptor affinity is retained in levorotatory
benzomorphans bearing a proton [(–)-1a] or a small methyl
group [(–)-1b] instead of the 3-methylbut-2-en-1-yl residue
at the nitrogen atom (see Scheme 1). However, the dextroro-
tatory enantiomers (+)-1a and (+)-1b show little σ-receptor
affinity but high affinity and selectivity for the ion channel
binding site of the NMDA receptor complex. Therefore, the
dextrorotatory benzomorphan derivatives, in particular (+)-
1a and (+)-1b, are of interest as neuroprotective and anticon-
[2,4]
vulsant agents
.
A crucial structural feature for high receptor binding is the
distance between the aromatic ring system and the basic
nitrogen atom. Counting the carbon atoms the benzomor-
phans can be regarded as 2-phenylethylamine and 3-phenyl-
propylamine derivatives. In the course of our studies on novel
CNS active compounds we have prepared several tricyclic
benzomorphan analogues with heteroatoms in different ring
Introduction
Depending on the substitution pattern and the stereochem-
istry, benzomorphans (1) can display high affinity for various
receptors in the central nervous system (CNS) . The best
known benzomorphan derivative is the opioid analgesic pent-
azocine [(±)-1c, Fortral ] with a 3-methylbut-2-en-1-yl resi-
due at the nitrogen atom (see Scheme 1) . The mixed partial
agonistic/partial antagonistic activity of pentazocine results
from binding of the levorotatory enantiomer (–)-1c to κ-
opioid receptors (agonistic) and µ-opioid-receptors (antago-
nistic). After application of pentazocine racemate (±)-1c
psychotomimetic side effects are often observed, which are
[1]
[5]
positions. Especially strong CNS effects and consider-
®
able receptor affinities have been found in those tricycles
with a 2-phenylethylamine or a 3-phenylpropylamine sub-
[2]
[6]
structure . In particular, the high σ-receptor binding of
5,6,7,8,9,10-hexahydro-5,9-epoxybenzocycloocten-7-am-
[7]
ines should be emphasized
.
This concept of retaining the tricyclic benzomorphan struc-
ture but changing the electronic features of the tricyclic ring
system by incorporation of heteroatoms in different ring
positions led us to the design of 6-aminomethyl-1,5-epoxy-
mainly caused by interaction of the dextrorotatory enan-
tiomer (+)-1c with σ-receptors
[3]
.
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0365-6233/99/1212/0413 $17.50 +.50/0

414
Wünsch, Bauschke, Diekmann, and Höfner
tween 0 and 39%. Additionally, all attempts to hydrolyze the
enol ether 6 to give the corresponding aldehyde failed. There-
fore, we looked for another strategy to obtain the tricyclic
amines 2.
In the second approach we intended to use the nitro group
as precursor of the amino functionality of 2 (see Scheme 4).
The nitromethyl substituted tricycle 7 should be built up by
an intramolecular transacetalization of 8, which already con-
tains the aldehyde and 1,3-diol moieties both protected as
acetals. The β-phenyl nitroalkane 8 should be prepared by a
Michael addition of an aryl metal intermediate to the ni-
troalkene 9, which in turn should be available by nitro aldol
condensation of the aldehyde 10.
Scheme 2
2-benzoxocines 2, which also include the 2-phenylethyl-
amine substructure (see Scheme 2). In this communication
we report on the stereoselective synthesis of the aminomethyl
substituted tricycles 2 as well as their affinities to µ-, κ-, σ-,
and NMDA-receptors. The 1,3-dioxanes 3, which are derived
from 2 by opening the tricyclic ring system (and doubling the
phenyl moiety), are also included in this study. It should be
mentioned that the compounds 3 differ distinctly from the
5
tricycles 2, since they prefer to adopt the C -conformation
2
of the 1,3-dioxane ring with both substituents in the equatorial
position.
Chemistry
[8]
In our first approach an intramolecular Heck reaction was
planned as key step for the construction of the tricyclic
framework (see Scheme 3). The educt for this synthesis was
the 1,3-dioxane-4-carbaldehyde 4, which was prepared by
regio- and diastereoselective transacetalization of 2-bromo-
benzaldehyde dimethyl acetal with the (S)-butane-1,2,4-triol
[5d,9]
and subsequent Swern oxidation
. Wittig reaction of the
aldehyde 4 with (methoxymethyl)triphenylphosphonium
chloride and potassium tert-butanolate furnished the enol
ether 5 as mixture of (Z) and (E) isomers [(Z)-5:(E)-5 =
56:44]. The intramolecular Heck reaction of the (methoxy-
vinyl) and (2-bromophenyl) substituted 1,3-dioxane 5 suc-
Scheme 4
ceeded with the catalyst [Pd(PPh ) ] and triethylamine in a
3 4
(S)-2,4-Dihydroxybutanal with its 1,3-diol moiety pro-
sealed tube at 140 °C to afford the tricyclic enol ether 6. The
chemical shift of the signal of the vinylic proton (δ = 6.82
ppm) points to (Z)-configuration of the double bond. In spite
of several modifications of the Heck reaction conditions
(catalyst, base, solvent, temperature, time) the yield of the
cyclization product 6 was not reproducible and varied be-
[10]
tected as benzylidene acetal 11
bon building block (see Scheme 5). Henry reaction
was selected as four car-
[11]
of the
aldehyde 11 with nitromethane in the presence of sodium
methanolate furnished the nitroaldol adduct 12 (75:25 mix-
ture of diastereomers), which was dehydrated by methanesul-
fonyl chloride and triethylamine to give the (E)-configurated
nitroalkene 13 in 95% yield. The aryl lithium intermediate,
generated by bromine/lithium exchange at the bromobenzal-
[12]
dehyde acetal 14 with n-butyllithium, was added
to the
nitro activated alkene 13 to provide the diastereomeric addi-
tion products 15 and 16 (ratio 67:33). Heating of the 15/16
mixture with dilute HCl led to hydrolysis of the acetals
liberating an aldehyde and a 1,3-diol, which combined spon-
taneously to give the tricyclic acetals 17 and 18. After flash
chromatographic separation the diastereomeric nitromethyl
substituted tricycles 17 and 18 were isolated in 49% and 25%
yield, respectively. The configuration of the newly formed
stereogenic center in position 6 of the tricycles 17 and 18 was
deduced from the chemical shifts of the 6-H signals (17: δ =
3.55 ppm; 18: δ = 4.35 ppm) and the 5-H/6-H coupling
Scheme 3
constants (17: J
≈ 0 Hz, 18: J
= 5.9 Hz).
5-H/6-H
5-H/6-H
Arch. Pharm. Pharm. Med. Chem. 332, 413–421 (1999)

2,4-Disubstituted 1,3-Dioxanes
415
23 was deduced by comparison of the chromatographic be-
1
haviour and the H NMR spectroscopic data of the phenyl
addition products 22 and 23 with the 2-(dimethoxymethyl)-
phenyl addition products 15 and 16.
Scheme 5
Reduction of the nitromethyl derivatives 17 and 18 with H
2
and Pd/C provided the primary amines 19a and 20a, respec-
tively (see Scheme 6). The methylamines 19c and 20c were
obtained by acylation of the primary amines 19a and 20a with
Scheme 7
methyl chloroformate ( 19b,
20b) and subsequent
LiAlH reduction. Reductive methylation with formaldehyde
4
[13]
and NaBH CN
transformed the primary amines 19a and
20a into the dimethylamines 19d and 20d, respectively.
In analogy to the tricyclic nitro derivatives 17 and 18 the
reduction of the 2-nitroethyl substituted 1,3-dioxanes 22 and
23 succeeded by catalytic hydrogenation (see Scheme 7).
3
However, reduction with LiAlH followed by acylation of the
4
resulting primary amines 24a and 25a with methyl chlorofor-
mate gave better yields of the carbamates 24b and 25b.
Therefore, the LiAlH reduction was chosen as standard
4
procedure for the reduction of 22 and 23. Since the quantita-
tive separation of the nitro derivatives 22 and 23 turned out
to be very troublesome, the diastereomeric separation was
usually performed at the stage of the carbamates24b and 25b.
The separated carbamates 24b and 25b were reduced with
LiAlH to provide the methylamines 24c and 25c, which
4
Scheme 6
were reductively methylated with formaldehyde and
[13]
NaBH CN
to yield the dimethylamines 24d and 25d,
3
respectively.
In order to obtain the ring B opened analogues 3 phenyl-
[12]
In an initial attempt a very large excess of LiAlH was
employed for the reduction of the (S,S,S)-configurated car-
bamate 24b. Surprisingly, the large excess of LiAlH com-
bined with the prolonged reaction time did not only lead to
reduction of the carbamate moiety but also to reductive
lithium without further substituents was added
to the
4
nitroalkene 13 (see Scheme 7). The diastereomeric addition
products 22 and 23 were formed in the same ratio (67:33) as
the lithiobenzaldehyde acetal addition products 15 and 16.
The main diastereomer 22 could be separated by flash chro-
4
matography and purified by recrystallization. The configura- opening of the 1,3-dioxane ring to furnish the 3-benzyl-
tion of the new stereogenic center in the side chain of 22 and oxypentan-1-ol 26 as main product (50% yield). Because of
Arch. Pharm. Pharm. Med. Chem. 332, 413–421 (1999)

416
Wünsch, Bauschke, Diekmann, and Höfner
the structural similarity to the 1,3-dioxanes 24 and 25 the Surprisingly, the best µ-receptor affinity was found for the
alcohol 26 was included into the receptor binding studies.
pentan-1-ol 26, whose K value of 16.0 µM is only one order
i
higher than the K value of tramadol (K = 1.7 µM).
i
i
The results of the κ-receptor screening made it reasonable
Receptor Binding Studies
only to determine the K values for the (S,S,S)-configurated
i
[4a,14]
[15]
[15]
[16]
1,3-dioxane 24c and the pentan-1-ol 26 (see Table 1). In
The NMDA-
, µ- , κ- , and σ-receptor
affini-
comparison with tramadol (κ: K = 43 µM) the 1,3-dioxane
i
ties of the tricyclic and ring B opened methyl- and dimethyl-
amines 19c,d, 20c,d, 24c,d, and 25c,d as well as the
1,3-dioxane ring opened derivative 26 were investigated in
competition experiments with radioligands.
24c displayed a similar κ-receptor affinity (K = 36 µM),
i
whereas the pentan-1-ol 26 bound in the low micromolar
range (K = 2.8 µM) to the κ-receptor.
i
3
In the group of the tricyclic compounds 19c,d, 20c,d, which
are devoid of NMDA-, µ-, and κ-receptor affinity, the (S,S,S)-
configurated dimethylamine 19d showed considerable affin-
The following radioligands were employed: [ H]-(+)-MK
801 for binding at the ion channel binding site of the NMDA-
3
3
receptor, [ H]-DAMGO for µ-receptor binding, [ H]-U
3
ity for the σ-receptor (K = 4.8 µM). The mathematical
69,593 for κ-receptor binding, and [ H]-di-(o-tolyl)guanidine
i
description of the competition curve as a biphasic curve fits,
however, much better to the experimental data, leading to two
for σ-receptor binding. At first, the receptor affinity of each
test compound was screened with two concentrations, 1 µM
and 100 µM. The complete competition curves were only
recorded for those compounds, which revealed considerable
radioligand competition at these concentrations.
At the concentrations 1 µM and 100 µM only the 1,3-diox-
ane derivatives 24d (tertiary amine) and 25c (secondary
amine) showed promising NMDA receptor affinity. How-
ever, recording of the whole competition curves with six
K values of 21.6 µM and 1.10 µM (see Table 1). Presumably,
i
the biphasic competition curve results from different interac-
tionsof 19dwithσ - andσ -receptor subtypes, which are both
1
2
[16]
labelled by the radioligand di-(o-tolyl)guanidine
.
With the exception of 24d σ-receptor affinity was observed
in the screening of the 1,3-dioxanes 24 and 25 (see Table 1).
Whereas high K values were found for the (S,S,R)-configu-
i
rated 1,3-dioxanes 25c (K = 35 µM) and 25d (K = 17.1 µM),
concentrations of 24d and 25c led to K values of 58 µM for
i
i
i
the (S,S,S)-configurated 1,3-dioxane 24c revealed noticeable
σ-receptor affinity (K = 3.3 µM ± 0.11 µM).
24d and 151 µM for 25c (see Table 1). Thus, in this series of
compounds the affinity for the ion channel binding site of the
NMDA receptor complex was not further investigated.
i
A comparable σ-receptor affinity (K = 3.7 µM) was deter-
i
mined for the pentan-1-ol 26, which differs from 24c only in
the reductive cleavage of the 1,3-dioxane ring (see Table 1).
In contrast to the 1,3-dioxane 24c the competition curve of
Table 1. Affinities for the phencyclidine binding site of the NMDA receptor
as well as for µ-, κ-, and σ-receptors
——————————————————————————————
the pentan-1-ol 26 was biphasic giving rise to two K values,
i
Cmpd
NMDA
µ
κ
σ
14.5 µM (± 0.4 µM) and 1.26 µM (± 0.24 µM). This phenome-
non may be explained by different interactions of 26 with
σ-receptor subtypes (compare 19d).
(Ki in µM)
(Ki in µM)
(Ki in µM)
(Ki in µM)
——————————————————————————————
19c
19d
20c
20d
–
–
–
–
–
–
–
–
–
–
–
–
180
21.6/1.10
Acknowledgements
–
–
We thank the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie for financial support and Degussa AG for donating
chemicals.
24c
24d
25c
25d
–
27.8
–
36
–
3.3 (± 0.11)
Experimental
58
–
151
–
46
97
–
35
Chemistry
–
17.1
General: Unless otherwise stated, moisture sensitive reactions were con-
ducted under dry nitrogen.– THF was distilled from sodium benzophenone
ketyl prior to use.– Flash chromatography (fc)[17]: Silica gel 60, 0.040–
0.063 mm (Merck).– Melting points: Melting point apparatus Dr. Tottoli
(Büchi), uncorrected.– Optical rotation: Polarimeter 241 (Perkin Elmer);
1.0 dm tube; concentration c [g/100 mL]; temperature 20 °C.– Elemental
analyses: CHN elemental analyser Rapid (Heraeus).– MS: Mass spectrome-
ter 5989A (Hewlett Packard); CI = chemical ionisation.– IR: IR spectro-
photometer 1600 FT-IR and 2000 FT-IR (Perkin-Elmer).– 1H NMR
(400 MHz), 13C NMR (100 MHz): GSX FT NMR spectrometer (Jeol),
tetramethylsilane as internal standard, δ in ppm.
26
–
16.0
1.7
2.8
14.5 (± 0.4) /
1.26 (± 0.24)
Phencyclidine
Tramadol
0.109
43
Haloperidol
0.0085
——————————————————————————————
–: At concentrations of 1µM and 100 µM the test compounds did not compete
significantly with the radioligands.
(2S,4S)-2-(2-Bromophenyl)-4-[(E) and (Z)-2-methoxyvinyl]-1,3-dioxane (5)
In the screening for µ-receptor affinity the 1,3-dioxanes
24c, 25c, and 25d as well as the pentan-1-ol 26 competed well
with the radioligand [ H]-DAMGO. The exact determination
Potassium tert-butanolate (0.70 g, 6.0 mmol) was slowly added to a cooled
(–20 °C) suspension of methoxymethyl-triphenylphosphonium chloride
(1.50 g, 4.4 mmol) in THF (8 mL). The orange mixture was stirred for 15
min at –10 °C, then a solution of 4[9] (1.0 g, 3.7 mmol) in THF (10 mL) was
added and the mixture was stirred for 20 min at –10 °C and for additional
3
of the µ-receptor affinity provided high K values: 27.8 µM
i
for 24c, 46 µM for 25c, and 97 µM for 25d (see Table 1).
Arch. Pharm. Pharm. Med. Chem. 332, 413–421 (1999)

2,4-Disubstituted 1,3-Dioxanes
417
16 h at room temperature. After addition of water (15 mL) and CH2Cl2
(15 mL) the layers were separated, the aqueous layer was extracted with
CH2Cl2 (3×), the organic layers were dried (MgSO4) and concentrated in
[α]578
= –50.9, [α]589 = –47.9 (c = 1.15 in CHCl3).– C12H13NO4 (235.2)
calcd. C 61.3 H 5.57 N 5.95 found C 61.6 H 5.96 N 5.79.– MS (CI): m/z =
236 (M + H+).– IR (film): ν = 1526 cm–1 (NO2), 1353 (NO2), 1140 (C-O),
1025 (C-O).– 1H NMR (CDCl3): δ (ppm) = 1.77 (dt, J = 12.5/2.2 Hz, 1 H,
5-H equatorial), 1.97 (qd, J = 12.5/5.1 Hz, 1 H, 5-H axial), 4.04 (td, J =
12.5/2.2 Hz, 1 H, 6-H axial), 4.36 (dd, J = 12.5/5.1 Hz, 1 H, 6-H equatorial),
4.71 (dt, J = 12.5/2.2 Hz, 1 H, 4-H axial), 5.61 (s, 1 H, 2-H), 7.21–7.26 (m,
2 H, arom.), 7.36–7.42 (m, 3 H, arom. and CH=CHNO2), 7.47–7.51 (m, 2 H,
arom. and CH=CHNO2).
1
vacuo. According to the H NMR spectrum of the unpurified product the
ratio of (Z)-5:(E)-5 is 56:44. The residue was purified by fc (diameter of the
column 3 cm, petroleum ether/acetone 9:1, Rf = 0.31). Colourless oil, yield
0.59 g (53%).– C13H15BrO3 (299.2) calcd. C 52.2 H 5.05 found C 52.0 H
5.35.– MS (EI): m/z = 300, 298 (M+).– IR (film): = 2927, 2854 cm–1 (C-H),
1654 (C=C), 1095 (C-O).– 1H NMR (CDCl3): δ (ppm) = 1.57–1.60 (m, 0.44
H, 5-H equatorial), 1.59 (dd, J = 13.2/1.5 Hz, 0.56 H, 5-H equatorial), 1.93
(qd, J = 13.2/4.4 Hz, 0.56 H, 5-H axial), 2.02 (qd, J = 13.2/4.4 Hz, 0.44 H,
5-H axial), 3.56 (s, 3 × 0.44 H, OCH3), 3.63 (s, 3 × 0.56 H, OCH3), 4.05 (td,
J = 12.5/2.2 Hz, 1 H, 6-H axial), 4.25 (dd, J = 12.5/4.4 Hz, 1 H, 6-H
equatorial), 4.28–4.36 (m, 0.44 H, 4-H), 4.56 (dd, J = 8.1/6.6 Hz, 0.56 H,
CH=CHOCH3), 4.85–4.93 (m, 0.56 H, 4-H), 4.88 (dd, J = 12.5/8.1 Hz, 0.44
H, CH=CHOCH3), 5.82 (s, 0.44 H, 2-H), 5.86 (s, 0.56 H, 2-H), 5.98 (d, J =
6.6 Hz, 0.56 H, CH=CHOCH3), 6.67(d, J = 12.5 Hz, 0.44 H, CH=CHOCH3),
7.15–7.19 (m, 1 H, arom.), 7.29–7.34 (m, 1 H, arom.), 7.50 (d, J = 8.1 Hz, 1
H, arom.), 7.70 (dd, J = 8.1/1.5 Hz, 1 H, arom.).– 13C NMR (CDCl3): (ppm)
= 31.6 (t, C-5 (Z)), 32.5 (t, C-5 (E)), 55.8 (q, OCH3, (E)), 60.0 (q, OCH3 (Z)),
67.1 (t, C-6), 67.2 (t, C-6), 71.8 (d, C-4 (E)), 76.0 (d, C-4 (Z)), 100.3 (d, C-2),
100.6 (d, C-2), 103.0 (d, CH=CHOCH3, (E)), 106.6 (d, CH=CHOCH3 (Z)),
122.4 (s, arom.), 127.5 (d, arom.), 127.9 (d, arom.), 128.2 (d, arom.), 128.3
(d, arom), 130.1 (d; arom.), 130.2 (d, arom.), 132.49 (d, arom.), 132.54 (d,
arom.), 137.4 (s, arom.), 137.5 (s, arom.), 148.0 (d, CH=CHOCH3), 150.8
(d, CH=CHOCH3).
2-{(1S)- and (1R)-2-Nitro-1-[(2S,4S)-2-phenyl-1,3-dioxan-4-yl]ethyl}benz-
aldehyde Dimethyl Acetal (15 and 16)
n-Butyllithium (1.6 molar in n-hexane, 9.0 mL, 14.4 mmol) was added at
–78 °C to a solution of 2-bromobenzaldehyde dimethyl acetal 14[14] (3.3 g,
14.3 mmol) in THF (30 mL) and the reaction mixture was stirred for 15 min
at –78 °C. Additionally, a solution of 13 (2.88 g, 12.3 mmol) in THF (30 mL)
was added. After stirring the reaction mixture for 3.5 h at –78 °C a half
concentrated solution of NH4Cl (30 mL) and CH2Cl2 (30 mL) were added,
the organic layer was separated, dried (Na2SO4), and concentrated in vacuo.
The residue was filtered over silica gel (petroleum ether/ethyl acetate 80:20,
Rf = 0.40). Colourless oil, yield 4.27 g (90.0%).– C21H25NO6 (387.4) calcd.
C 65.1 H 6.50 N 3.62 found C 65.3 H 6.59 N 3.37 .– MS: m/z = 324 [M–63
(OCH3, CH3OH)], 163 (2-phenyl-1,3-dioxan-4-yl).– IR (film): ν = 2960
cm–1 (CH), 1553 (NO2), 1382 (NO2), 1101 (C-O).– H NMR (CDCl3): δ
1
(ppm) = 1.25 (dd, J = 12.5/1.5 Hz, 0.67 H, 5-H equatorial), 1.41 (dd, J =
12.5/1.5 Hz, 0.33 H, 5-H equatorial), 1.62 (qd, J = 12.5/5.1 Hz, 0.33 H, 5-H
axial), 1.86 (qd, J = 12.5/5.1 Hz, 0.67 H, 5-H axial), 3.33 (s, 3 × 0.33 H,
OCH3), 3.35 (s, 3 × 0.33 H, OCH3), 3.36 (s, 3 × 0.67 H, OCH3), 3.38 (s, 3 ×
0.67 H, OCH3), 3.87 (td, J = 12.5/2.2 Hz, 0.67 H, 6-H axial), 3.92 (td, J =
12.5/1.5 Hz, 0.33 H, 6-H axial), 4.15–4.31 [m, 3 × 0.67 H and 2 × 0.33 H,
4-H axial (1 H), 6-H equatorial (1 H), CHCH2NO2 (0.67 H)], 4.44 (td, J =
7.3/3.7 Hz, 0.33 H, CHCH2NO2), 4.65 (dd, J = 12.5/7.3 Hz, 0.33 H,
CHCH2NO2), 4.78 (dd, J = 12.5/8.1 Hz, 0.67 H, CHCH2NO2), 4.98 (dd, J =
12.5/5.1 Hz, 1 H, CHCH2NO2), 5.41 [s, 0.33 H, aryl-CH(OR)2], 5.50 [s, 0.33
H, aryl-CH(OR)2], 5.52 [s, 0.67 H, aryl-CH(OR)2], 5.54 [s, 0.67 H, aryl-
CH(OR)2], 7.29–7.44 (m, 6 H, arom.), 7.48–7.51 (m, 2 H, arom.), 7.57 (d, J
= 8.1 Hz, 0.67 H, arom.), 7.65 (dd, J = 7.3/1.5 Hz, 0.33 H, arom.). Ratio 15:16
= 67:33.
(1S,5S)-(Z)-(–)-6-(Methoxymethylene)-3,4,5,6-tetrahydro-1,5-epoxy-
1H-2-benzoxocine (6)
A mixture of 5 (0.46 g, 2.1 mmol, mixture of (E)- and (Z)-isomers),
tetrakistriphenylphosphane palladium (0) [Pd(PPh3)4] (0.71 g, 0.64 mmol),
triethylamine (0.4 mL, 2.1 mmol) and acetonitrile (20 mL) was heated in a
sealed tube at 140 °C for 48 h. Then, the suspension was filtered, the filtrate
was concentrated in vacuo and the residue was purified by fc (diameter of
the column 3 cm, petroleum ether/acetone 9:1, Rf = 0.30). Colourless oil,
yield 0.18 g (39%), [α]589 = –28.2 (c = 0.90 in CHCl3).– C13H14O3 (218.3)
calcd. C 71.5 H 6.47 found C 71.4 H 6.64.– MS: m/z = 218 (M+).– IR (film):
ν = 1692 cm–1 (C=CHOCH3), 1104 (C-O).– 1H NMR (CDCl3): δ (ppm) =
1.47 (dq, J = 13.2/1.5 Hz, 1 H, 4-H equatorial), 2.54 (tt, J = 13.2/5.5 Hz, 1
H, 4-H axial), 3.68–3.76 (m, 2 H, 3-H), 3.77 (s, 3 H, OCH3), 5.20 (d, J =
5.5 Hz, 1 H, 5-H), 5.84 (s, 1 H, 1-H), 6.82 (s, 1 H, CHOCH3), 7.14–7.18 (m,
2 H, arom.), 7.22–7.28 (m, 1 H, arom.), 7.47 (d, J = 8.1 Hz, 1 H, arom.).
(1S,5S,6S)-(+)-6-(Nitromethyl)-3,4,5,6-tetrahydro-1,5-epoxy-1H-2-benz-
oxocine (17) and (1S,5S,6R)-(+)-6-(Nitromethyl)-3,4,5,6-tetrahydro-
1,5-epoxy-1H-2-benzoxocine (18)
A solution of 15/16 (ratio 67:33, 120 mg, 0.31 mmol) in 0.1 N HCl (2 mL)
and dioxane (10 mL) was heated to reflux for 1 h and stirred at room
temperature for 16 h. Then, water (10 mL) and CH2Cl2 were added, the
organic layer was separated, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by fc (diameter of the column 1 cm, petroleum
ether/ethyl acetate 90:10, fractions 5 mL).
(1R)- and (1S)-2-Nitro-1-[(2S,4S)-2-phenyl-1,3-dioxan-4-yl]ethan-1-ol (12)
A solution of NaOCH3, prepared by addition of sodium metal (2.2 g,
96 mmol) to methanol (30 mL), was added to a solution of 11[10] (4.97 g,
25.9 mmol) and nitromethane (4.42 g, 72.4 mmol) in methanol (70 mL). The
reaction mixture was stirred for 24 h at room temperature, then a half
saturated solution of NH4Cl (60 mL) was added and the mixture was ex-
tracted with CH2Cl2. The organic layer was dried (Na2SO4), concentrated in
vacuo, and the residue was recrystallized from iPr2O. Colourless solid
(iPr2O), m.p. 108–115 °C, yield 6.36 g (97%).– C12H15NO5 (253.3) calcd.
C 56.9 H 5.97 N 5.53 found C 56.7 H 6.04 N 5.52.– MS: m/z = 253 (M+).–
IR (KBr): ν = 3430 cm–1 (OH), 1559 (NO2), 1387 (NO2), 1094 (C-O).– 1H
NMR (CDCl3): δ (ppm) = 1.81–1.85 (m, 2 H, 5-H), 2.66 (d, J = 7.3 Hz, 0.25
H, OH), 2.80 (d, J = 5.9 Hz, 0.75 H, OH), 3.91–4.06 (m, 2 H, 6-H axial and
4-H axial), 4.33–4.38 (m, 2 H, 6-H equatorial and CHOH), 4.54 (dd, J =
13.9/8.8 Hz, 0.75 H, CH2NO2), 4.56–4.64 (m, 2 × 0.25 H, CH2NO2), 4,73
(dd, J = 13.9/2.2 Hz, 0.75 H, CH2NO2), 5.52 (s, 0,75 H, 2-H), 5.56 (s, 0.25
H, 2-H), 7.37–7.46 (m, 5 H, arom.). Ratio of diastereomers 75:25.
17 [fractions 9–22, Rf = 0.39 (petroleum ether/ethyl acetate 80:20)]: Pale
yellow oil, yield 36 mg (49.4%), [α]546 = +57.2, [α]578 = +51.3, [α]589
=
+49.4 (c = 0.635 in CHCl3).– C12H13NO4 (235.2) calcd. C 61.3 H 5.57 N
5.95 found C 61.8 H 5.68 N 5.69.– MS (CI): m/z = 236 (M + H+).– IR (film):
1
ν = 2925 cm–1 (C-H), 1548 (NO2), 1375 (NO2), 1113 (C-O).– H NMR
(CDCl3): δ (ppm) = 1.23 (dd, J = 13.2/2.9 Hz, 1 H, 4-H equatorial), 2.67 (tt,
J = 13.2/6.6 Hz, 1 H, 4-H axial), 3.50 (td, J = 13.2/2.9 Hz, 1 H, 3-H axial),
3.55 (dd, J = 9.9/3.7 Hz, 1 H, 6-H), 3.65 (dd, J = 13.2/6.6 Hz, 1 H, 3-H
equatorial), 4.33 (d, J = 6.6 Hz, 1 H, 5-H), 4.47 (dd, J = 13.9/3.7 Hz, 1 H,
CH2NO2), 4.74 (dd, J = 13.9/9.9 Hz, 1 H, CH2NO2), 5.87 (s, 1 H, 1-H),
7.22–7.25 (m, 2 H, arom.), 7.36–7.39 (m, 2 H, arom.).
18 [fractions 23–32, Rf = 0.33 (petroleum ether/ethyl acetate 80:20)]: Pale
yellow oil, yield 18 mg (24.7%), [α]546 = +6.3, [α]578 = +4.7, [α]589 = +4.1
(c = 0.68 in CHCl3).– C12H13NO4 (235.2) calcd. C 61.3 H 5.57 N 5.95 found
C 61.6 H 5.70 N 5.50.– MS (CI): m/z = 236 (M + H+).– IR (film): ν =
2961 cm–1 (C-H), 1559 (NO2), 1376 (NO2), 1099 (C-O).– 1H NMR (CDCl3):
δ (ppm) = 1.65 (dd, J = 13.2/2.2 Hz, 1 H, 4-H equatorial), 2.55 (tt, J =
13.2/6.6 Hz, 1 H, 4-H axial), 3.51 (td, J = 13.2/2.2 Hz, 1 H, 3-H axial), 3.69
(dd, J = 13.2/6.6 Hz, 1 H, 3-H equatorial), 4.35 (dt, J = 10.3/5.9 Hz, 1 H,
6-H), 4.44 ("t", J = 6.6 Hz, 1 H, 5-H), 4.52 (dd, J = 13.2/10.3 Hz, 1 H,
CH2NO2), 5.07 (dd, J = 13.2/5.1 Hz, 1 H, CH2NO2), 5.90 (s, 1 H, 1-H), 7.18
(2S,4S)-(–)-4-[(E)-2-Nitrovinyl]-2-phenyl-1,3-dioxane (13)
To a cooled (0 °C) solution of 12 (1.36 g, 5.37 mmol) in CH2Cl2 (20 mL)
solutions of NEt3 (1.74 g, 17.2 mmol) in CH2Cl2 (2.5 mL) and CH3SO2Cl
(0.81 g, 7.04 mmol) in CH2Cl2 (2.5 mL) were added successively. After
stirring for 2.5 h at room temperature the reaction mixture was poured into
1 N HCl (50 mL), the organic layer was separated, dried (Na2SO4), and
evaporated in vacuo. Pale yellow oil, yield 1.20 g (95%), [α]546 = –60.3,
Arch. Pharm. Pharm. Med. Chem. 332, 413–421 (1999)

418
Wünsch, Bauschke, Diekmann, and Höfner
(d, J = 6.6 Hz, 1 H, arom.), 7.23–7.25 (m, 1 H, arom.), 7.34–7.37 (m, 2 H,
arom.).
(233.3) calcd. C 72.1 H 8.21 N 6.00 found C 71.8 H 8.50 N 5.78.– MS: m/z
= 233 (M+).– IR (film): ν = 2947 cm–1 (C-H), 1109 (C-O).– 1H NMR
(CDCl3): δ (ppm) = 1.42 (dd, J = 13.7/3.0 Hz, 1 H, 4-H equatorial), 2.15 [dd,
J = 12.0/3.0 Hz, 1 H, CH2N(CH3)2], 2.31 [s, 6 H, CH2N(CH3)2], 2.60–2.70
(m, 2 H, 4-H axial and 6-H), 2.76 ["t", J = 12.0 Hz, 1 H, CH2N(CH3)2], 3.56
(td, J = 11.8/3.0 Hz, 1 H, 3-H axial), 3.63 (dd, J = 11.8/7.1 Hz, 1 H, 3-H
equatorial), 4.60 (d, J = 6.0 Hz, 1 H, 5-H), 5.83 (s, 1 H, 1-H), 7.15–7.19 (m,
2 H, arom.), 7.26 (dd, J = 7.3/1.3 Hz, 1 H, arom.), 7.32 (td, J = 7.3/1.3 Hz, 1
H, arom.).
1-[(1S,5S,6S)-3,4,5,6-Tetrahydro-1,5-epoxy-1H-2-benzoxocin-6-yl]meth-
anamine (19a)
To a solution of 17 (70 mg, 0.30 mmol) in CH3OH (3 mL) the catalyst
Pd/C (10%, 20 mg) was added and the reaction mixture was stirred under a
hydrogen atmosphere (1.3 bar) for 2 h. The reaction mixture was filtered and
concentrated in vacuo. Colourless oil, yield 54 mg (88.4%). 1H NMR
(CDCl3): δ (ppm) = 1.38 (dd, J = 13.5/3.0 Hz, 1 H, 4-H equatorial), 1.91 (s
broad, 2 H, CH2NH2), 2.53–2.63 (m, 2 H, 4-H axial, 6-H), 2.95 (d, J = 6.0 Hz,
2 H, CH2NH2), 3.48 (td, J = 12.0/3.0 Hz, 1 H, 3-H axial), 3.55 (dd, J =
12.0/6.6 Hz, 1 H, 3-H equatorial), 4.43 (d, J = 6.0 Hz, 1 H, 5-H), 5.77 (s, 1
H, 1-H), 7.08–7.23 (m, 3 H, arom.), 7.27 (td, J = 7.3/1.3 Hz, 1 H arom.). The
primary amine 19a was used for the preparation of 19b–19d without further
purification.
1-[(1S,5S,6R)-3,4,5,6-Tetrahydro-1,5-epoxy-1H-2-benzoxocin-6-yl]meth-
anamine (20a)
Pd/C (10%, 35 mg) was added to a solution of 18 (75 mg, 0.32 mmol) in
methanol (10 mL) and the reaction mixture was stirred under a hydrogen
atmosphere (1.3 bar) for 23 h at room temperature. Then, it was filtered and
the solvent was evaporated in vacuo. Colourless oil, yield 53 mg (81.0%).
1H NMR (CDCl3): δ (ppm) = 1.79 (d, J = 13.2 Hz, 1 H, 4-H equatorial), 2.07
(s broad, 2 H, CH2NH2), 2.44–2.54 (m, 2 H, 4-H axial, CH2NH2), 2.94 (dd,
J = 11.7/9.1 Hz, 1 H, CH2NH2), 3.51–3.68 (m, 3 H, 3-H axial, 3-H equatorial,
6-H), 4.53 ("t", J = 5.8 Hz, 1 H, 5-H), 5.88 (s, 1 H, 1-H), 7.19 (d, J = 7.3 Hz,
1 H, 7-H or 10-H), 7.26 (t, J = 7.3 Hz, 1 H, 8-H or 9-H), 7.32 (t, J = 7.3 Hz,
1 H, 9-H or 8-H), 7.40 (d, J = 7.3 Hz, 1 H, 10-H or 7-H). The primary amine
20a was used for the preparation of 20b–20d without further purification.
(+)-Methyl N-{1-[(1S,5S,6S)-3,4,5,6-tetrahydro-1,5-epoxy-1H-2-benz-
oxocin-6-yl]methyl}carbamate (19b)
To an ice-cold solution of 19a (80 mg, 0.39 mmol) in THF (2 mL) solu-
tions of triethylamine (55 mg, 0.54 mmol) in THF (0.5 mL) and methyl
chloroformate (50 mg, 0.53 mmol) in THF (0.5 mL) were added succes-
sively. After stirring for 4 h at room temperature an aqueous solution of
Na2CO3 (10%, 10 mL) and CH2Cl2 (15 mL) were added, the organic layer
was separated, dried (Na2SO4), concentrated in vacuo, and the residue was
recrystallized. Colourless solid (iPr2O), m.p. 182–183 °C, yield 84 mg
(81.8%), [α]546 = +8.6, [α]578 = +8.8, [α]589 = +8.2 (c = 0.575 in CHCl3).–
C14H17NO4 (263.3) calcd. C 63.9 H 6.51 N 5.32 found C 64.2 H 6.67 N 5.09.–
MS: m/z = 263 (M+), 176 (M–CHNHCO2CH3).– IR (KBr): ν = 3353 cm–1
Methyl N-{1-[(1S,5S,6R)-3,4,5,6-tetrahydro-1,5-epoxy-1H-2-benzoxocin-
6-yl]methyl}carbamate (20b)
As described for 19b the primary amine 20a (245 mg, 1.20 mmol) was
acylated with methyl chloroformate (370 mg, 3.92 mmol) and triethylamine
(395 mg, 3.91 mmol) in THF (10 mL). The residual colourless oil (20b,
270 mg, 85.9%) was reduced without purification.
1
(NH), 1696 (C=O), 1529 (amide II), 1272 (C-O), 1094 (C-O).– H NMR
(CDCl3): δ (ppm) = 1.38 (dd, J = 13.3/3.4 Hz, 1 H, 4-H equatorial), 2.57 (tt,
J = 13.3/6.4 Hz, 1 H, 4-H axial), 2.84 (dd, J = 6.8/5.6 Hz, 1 H, 6-H), 3.28–3.41
(m, 2 H, CH2NH), 3.46 (ddd, J = 13.3/11.5/3.4 Hz, 1 H, 3-H axial), 3.55 (dd,
J = 11.5/6.4 Hz, 1 H, 3-H equatorial), 3.60 (s, 3 H, OCH3), 4.27 (d, J = 6.4 Hz,
1 H, 5-H), 5.01 (s broad, 1 H, NH), 5.78 (s, 1 H, 1-H), 7.11 (d, J = 7.3 Hz, 1
H, arom.), 7.20–7.30 (m, 3 H, arom.).
(+)-N-Methyl-1-[(1S,5S,6R)-3,4,5,6-tetrahydro-1,5-epoxy-1H-2-benz-
oxocin-6-yl]methanamine (20c)
At 0 °C a solution of unpurified 20b (196 mg, 0.75 mmol) in THF (10 mL)
was added to a suspension of LiAlH4 (400 mg, 10.5 mmol) in THF (30 mL).
The reaction mixture was stirred for 48 h at room temperature, then water
(2 mL) was cautiously added, the mixture was filtered, the filtrate was dried
(Na2SO4), concentrated in vacuo, and the residuewaspurifiedbyfc (diameter
of the column 1 cm, CH2Cl2/CH3OH 80:20, fractions of 5 mL). The fractions
2–10 (Rf = 0.33) were concentrated in vacuo. Colourless oil, yield 64.2 mg
(39.3%), [α]546 = +19.6, [α]578 = +16.3, [α]589 = +15.5 (c = 1.3 in CHCl3).–
C13H17NO2 (219.3) calcd. C 71.2 H 7.81 N 6.39 found C 71.5 H 7.96 N 6.55.–
MS: m/z = 219 (M+), 176 (M–CHNHCH3).– IR (film): ν = 3322 cm–1 (NH),
2936 (C-H), 1095 (C-O).– 1H NMR (CDCl3): δ (ppm) = 1.76 (dd, J =
12.6/1.5 Hz, 1 H, 4-H equatorial), 2.41–2.50 (m, 1 H, 4-H axial), 2.51 (s, 3
H, NHCH3), 2.76 (dd, J = 12.0/9.8 Hz, 1 H, CH2NHCH3), 3.27 (dd, J =
12.0/5.6 Hz, 1 H, CH2NHCH3), 3.50–3.57 and 3.63–3.72 (m, together 4 H,
3-H axial, 3-H equatorial, 6-H, NHCH3), 4.44 ("t", J = 6.4 Hz, 1 H, 5-H),
5.88 (s, 1 H, 1-H), 7.18 (dd, J = 7.7/1.5 Hz, 1 H, 7-H or 10-H), 7.25 (t, J =
7.7 Hz, 1 H, 8-H or 9-H), 7.32 (td, J = 7.7/1.5 Hz, 1 H, 9-H or 8-H), 7.46 (d,
J = 7.7 Hz, 1 H, 10-H or 7-H).
(+)-N-Methyl-1-[(1S,5S,6S)-3,4,5,6-tetrahydro-1,5-epoxy-1H-2-benz-
oxocin-6-yl]methanamine (19c)
At 0 °C a solution of 19b (68 mg, 0.26 mmol) in Et2O (3 mL) and THF
(3 mL) was slowly added to a suspension of LiAlH4 (120 mg, 3.2 mmol) in
Et2O (3 mL). The reaction mixture was stirred for 30 h at room temperature,
then water (0.5 mL) was cautiously added, and the mixture was filtered. The
filtrate was extracted with 1 N HCl (3 × 5 mL), after addition of 2 N NaOH
(pH 10) the aqueous layer was extracted with CH2Cl2 (5 × 15 mL), the
CH2Cl2 layer was dried (MgSO4), and concentrated in vacuo. Colourless oil,
yield 47.1 mg (83.2%), [α]546 = +85.0, [α]578 = +74.1, [α]589 = +71.3 (c =
0.32 in CHCl3).– C13H17NO2 (219.3) calcd. C 71.2 H 7.81 N 6.39 found C
71.5 H 7.93 N 5.91.– MS (CI): m/z = 220 (M + H+).– IR (film): ν = 3322 cm–1
(NH), 2951 (C-H), 1107 (C-O).– 1H NMR (CDCl3): δ (ppm) = 1.38 (dd, J =
12.7/2.7 Hz, 1 H, 4-H equatorial), 2.24 (s broad, 1 H, NH), 2.41 (s, 3 H,
NHCH3), 2.58 (tt, J = 12.7/6.6 Hz, 1 H, 4-H axial), 2.68 (dd, J = 9.2/4.3 Hz,
1 H, 6-H), 2.72 (dd, J = 12.0/4.3 Hz, 1 H, CH2NHCH3), 2.88 (dd, J =
12.0/9.2 Hz, 1 H, CH2NHCH3), 3.48 (td, J = 12.7/2.7 Hz, 1 H, 3-H axial),
3.55 (dd, J = 12.7/6.6 Hz, 1 H, 3-H equatorial), 4.44 (d, J = 6.6 Hz, 1 H, 5-H),
5.77 (s, 1 H, 1-H), 7.10 (d, J = 7.3 Hz, 1 H, arom.), 7.17–7.22 (m, 2 H, arom.),
7.27 (td, J = 7.3/1.3 Hz, 1 H, arom.).
(–)-N,N-Dimethyl-1-[(1S,5S,6R)-3,4,5,6-tetrahydro-1,5-epoxy-1H-2-benz-
oxocin-6-yl]methanamine (20d)
As described for 19d the primary amine 20a (37 mg, 0.18 mmol) was
reductively methylated with formaldehyde (35% in water, 1.2 mL) and
NaBH3CN (110 mg, 1.75 mmol) in methanol (5 mL). FC purification (di-
ameter of the column 1 cm, CH2Cl2/ethyl acetate 70:30, Rf = 0.18) gave a
(+)-N,N-Dimethyl-1-[(1S,5S,6S)-3,4,5,6-tetrahydro-1,5-epoxy-1H-2-benz-
oxocin-6-yl]methanamine (19d)
colourless oil, yield 31.1 mg (74.0%), [α]546 = –6.2, [α]578 = –6.1, [α]589
=
–6.4 (c = 0.99 in CHCl3).– C14H19NO2 (233.3) calcd. C 72.1 H 8.21 N 6.00
found C 72.1 H 8.31 N 5.71.– MS (CI): m/z = 234 (M + H+).– IR (film): ν =
2955 cm–1 (C-H), 1099 (C-O).– 1H NMR (CDCl3): δ (ppm) = 1.70 (dd, J =
14.1/2.4 Hz, 1 H, 4-H equatorial), 2.29 [s, 6 H, N(CH3)2], 2.42–2.52 [m, 2
H, 4-H axial, CH2N(CH3)2], 2.81 [dd, J = 12.4/6.0 Hz, 1 H, CH2N(CH3)2],
3.52 (td, J = 12.5/2.4 Hz, 1 H, 3-H axial), 3.57–3.67 (m, 2 H, 3-H equatorial,
6-H), 4.39 ("t", J = 6.4 Hz, 1 H, 5-H), 5.88 (s, 1 H, 1-H), 7.18 (dd, J =
7.3/1.7 Hz, 1 H, 7-H or 10-H), 7.24 (t, J = 7.3 Hz, 1 H, 8-H or 9-H), 7.31 (td,
J = 7.3/1.7 Hz, 1 H, 9-H or 8-H), 7.48 (d, J = 7.3 Hz, 1 H, 10-H or 7-H).
NaBH3CN (110 mg, 1.75 mmol) was added to a solution of 19a (53.5 mg,
0.26 mmol) and formaldehyde (35% in water, 1.2 mL) in methanol (5 mL)
and the reaction mixture was stirred for 2 h at room temperature. CH2Cl2
(10 mL) and a solution of Na2CO3 (10%, 5 mL) were added, the organic layer
was separated, dried (MgSO4), concentrated in vacuo, and the residue was
filtered over silica gel (10 g of silica gel, CH2Cl2/CH3OH 90:10, Rf = 0.57).
Colourless oil, which solidified on standing, yield 54.5 mg (89.6%), [α]546
= +78.6, [α]578 = +68.8, [α]589 = +66.1 (c = 2.53 in CHCl3).– C14H19NO2
Arch. Pharm. Pharm. Med. Chem. 332, 413–421 (1999)

2,4-Disubstituted 1,3-Dioxanes
419
(2S,4S)-4-[(S)-2-Nitro-1-phenylethyl]-2-phenyl-1,3-dioxane (22) and
(2S,4S)-4-[(R)-2-Nitro-1-phenylethyl]-2-phenyl-1,3-dioxane (23)
C
20H23NO4 (341.4) calcd. C 70.4 H 6.79 N 4.10 found C 69.9 H 7.03 N 4.30.–
MS (CI): m/z = 342 (M + H+).– IR (KBr): ν = 3346 cm–1 (NH), 1722 (C=O),
1
1526 (amide II), 1258 (C-O), 1114 (C-O).– H NMR (CDCl3): δ (ppm) =
At –78 °C a solution of n-butyllithium (1.6 molar in n-hexane, 15.9 mL,
25.4 mmol) was added to a solution of bromobenzene (21, 3.99 g,
25.4 mmol) in THF (50 mL). The reaction mixture was stirred for 15 min at
–78 °C, then a solution of 13 (5.3 g, 22.6 mmol) in THF (50 mL) was slowly
added. After stirring for 5.5 h at –78 °C a half concentrated solution of NH4Cl
(300 mL) was added and the mixture was extracted with CH2Cl2. The organic
layer was dried (Na2SO4), concentrated in vacuo, and the residue was
purified by fc [diameter of the column 2 cm, petroleum ether/ethyl acetate
95:5, Rf = 0.49–0.51 (petroleum ether/ethyl acetate 80:20)]. Colourless oil,
yield 6.3 g (89%).– C18H19NO4 (313.4) calcd. C 69.0 H 6.11 N 4.47 found
C 69.4 H 6.19 N 3.97.– MS: m/z = 313 (M+).– IR (film): ν = 1552 cm–1 (NO2),
1.37 (d broad, J = 12.0 Hz, 1 H, 5-H equatorial), 1.74 (qd, J = 12.0/4.9 Hz,
1 H, 5-H axial), 3.05–3.08(m, 1 H, C6H5CHCH2), 3.58–3.78 (m, 2 H, CH2N),
3.65 (s, 3 H, CO2CH3), 3.93 (td, J = 12.0/2.1 Hz, 1 H, 6-H axial), 4.15–4.20
(m, 2 H, 4-H axial, 6-H equatorial), 4.77 (s broad, 1 H, NH), 5.50 (s, 1 H,
2-H axial), 7.27–7.40 (m, 8 H, arom.), 7.45 (dd, J = 7.7/1.7 Hz, 2 H, arom.).
(2S)-(+)-N-Methyl-2-phenyl-2-[(2S,4S)-2-phenyl-1,3-dioxan-4-yl]ethan-
1-amine (24c)
At 0 °C a solution of 24b (66.8 mg, 0.20 mmol) in Et2O (10 mL) was
slowly added to a solution of LiAlH4 (1.0 molar in THF, 0.4 mL, 0.4 mmol).
The reaction mixture was stirred for 23 h at room temperature. Water
(0.5 mL) was cautiously added, the mixture was dried (Na2SO4), filtered, the
filtrate was concentrated in vacuo, and the residue was purified by fc
(diameter of the column 1 cm, CH2Cl2/CH3OH 9:1, Rf = 0.25). Colourless
oil, yield 49.5 mg (85%), [α]546 = +39.0, [α]578 = +34.1, [α]589 = +32.5 (c =
0.88 in CHCl3).– C19H23NO2 (297.4) calcd. C 76.7 H 7.80 N 4.71 found C
76.6 H 8.15 N 4.50.– MS (CI):m/z = 298 (M + H+).– IR (film): ν = 3450–3400
cm–1 (broad, NH), 2959 (C-H), 1107 (C-O).– 1H NMR (CDCl3): δ (ppm) =
1.11 (dt, J = 12.0/2.1 Hz, 1 H, 5-H equatorial), 1.68 (qd, J = 12.0/4.4 Hz, 1
H, 5-H axial), 1.98 (s, broad, 1 H, NH), 2.33 (s, 3 H, NHCH3), 2.91 (dd, J =
11.8/8.3 Hz, 1 H, CHCH2N), 3.03 (td, J = 8.3/5.6 Hz, 1 H, CHCH2N), 3.27
(dd, J = 11.8/5.6 Hz, 1 H, CHCH2N), 3.78 (td, J = 12.0/2.1 Hz, 1 H, 6-H
axial), 4.00 (ddd, J = 11.6/8.3/2.1 Hz, 1 H, 4-H axial), 4.11 (dd, J =
11.5/4.4 Hz, 1 H, 6-H equatorial), 5.48 (s, 1 H, 2-H axial), 7.17–7.22 (m, 3
H, arom.), 7.26–7.34 (m, 5 H, arom.), 7.44 (dd, J = 7.3/1.3 Hz, 2 H, arom.).
1
1380 (NO2), 1139 (C-O), 1100 (C-O), 1022 (C-O).– H NMR (CDCl3): δ
(ppm) = 1.25 (dt, J = 12.2/2.1 Hz, 0.67 H, 5-H equatorial), 1.36 (dt, J =
12.2/2.1 Hz, 0.33 H, 5-H equatorial), 1.66 (qd, J = 12.0/4.5 Hz, 0.33 H, 5-H
axial), 1.79 (qd, J = 12.0/4.5 Hz, 0.67 H, 5-H axial), 3.65–3.75 (m, 1 H,
CHCH2NO2), 3.86 (td, J = 12.0/2.1 Hz, 0.67 H, 6-H axial), 3.93 (td, J =
12.0/2.1 Hz, 0.33 H, 6-H axial), 4.06 (ddd, J = 12.0/9.4/2.1 Hz, 0.67 H, 4-H
axial), 4.16–4.22 [m, 1.33 H, 4-H axial (0.33 H) and 6-H equatorial (1 H)],
4.72 (dd, J = 13.0/9.4 Hz, 0.67 H, CHCH2NO2), 4.76 (dd, J = 13.3/7.9 Hz,
0.33 H, CHCH2NO2), 4.99 (dd, J = 13.3/7.3 Hz, 0.33 H, CHCH2NO2), 5.07
(dd, J = 13.0/4.9 Hz, 0.67 H, CHCH2NO2), 5.51 (s, 0.33 H, 2-H axial), 5.53
(s, 0.67 H, 2-H axial), 7.25–7.49 (m, 10 H, arom.). Ratio of diastereomers 22
and 23 = 67:33.
The main diastereomer 22 could be separated and purified by fc [conditions
see above, Rf = 0.49 (petroleum ether/ethyl acetate 80:20)] and recrystalli-
zation. Colourless solid (iPr2O), m.p. 86–87 °C, [α]546 = +85.4, [α]578
=
+74.0, [α]589 = +71.3 (c = 0.24 in CHCl3).– C18H19NO4 (313.4) calcd. C
69.0 H 6.11 N 4.47 found C 68.8 H 6.20 N 4.53.– MS: m/z = 313 (M+).– IR
(KBr): ν = 1553 cm–1 (NO2), 1385 (NO2), 1138 (C-O), 1101 (C-O), 1026
(2S)-(+)-N,N-Dimethyl-2-phenyl-2-[(2S,4S)-2-phenyl-1,3-dioxan-4-yl]-
ethan-1-amine (24d)
1
(C-O).– H NMR (CDCl3): δ (ppm) = 1.25 (dt, J = 12.2/2.1 Hz, 1 H, 5-H
equatorial), 1.79(qd, J = 12.0/4.5 Hz, 1 H, 5-H axial), 3.68 (td, J = 9.4/4.9 Hz,
1 H, CHCH2NO2), 3.86 (td, J = 12.0/2.1 Hz, 1 H, 6-H axial), 4.06 (ddd, J =
12.0/9.4/2.1 Hz, 1 H, 4-H axial), 4.21 (dd, J = 12.0/4.5 Hz, 1 H, 6-H
equatorial), 4.72 (dd, J = 13.0/9.4 Hz, 1 H, CHCH2NO2), 5.07 (dd, J =
13.0/4.9 Hz, 1 H, CHCH2NO2), 5.53 (s, 1 H, 2-H axial), 7.27–7.49 (m, 10
H, arom.).
At 0 °C a solution of the pure diastereomer 22 (130 mg, 0.42 mmol) in
THF (10 mL) was slowly added to a suspension of LiAlH4 (160 mg,
4.2 mmol) in Et2O (8 mL). After stirring for 23 h at room temperature water
(3 mL) was cautiously added, then it was dried (Na2SO4), filtered, and
concentrated in vacuo. The residue (the primary amine 24a, yield 108 mg,
0.38 mmol, 91.9%) was dissolved in methanol (10 mL). Subsequently, for-
maldehyde (35% in water, 2.0 mL) and NaBH3CN (170 mg, 2.7 mmol) were
added and the reaction mixture was stirred for 3.5 h at room temperature.
Then, a solution of Na2CO3 (10%, 20 mL) and CH2Cl2 (20 mL) were added,
the organic layer was separated, dried (MgSO4), evaporated in vacuo, and
the residue was purified by fc (diameter of the column 2 cm, CH2Cl2/CH3OH
95:5, Rf = 0.36). Colourless oil, yield 71 mg (55.0% calculated from 22),
[α]546 = +16.8, [α]578 = +14.9, [α]589 = +14.3 (c = 0.325 in CHCl3).–
(+)-Methyl N-{(2S)-2-phenyl-2-[(2S,4S)-2-phenyl-1,3-dioxan-4-yl]ethyl}-
carbamate (24b) and (–)-Methyl N-{(2R)-2-Phenyl-2-[(2S,4S)-2-phenyl-
1,3-dioxan-4-yl]ethyl}carbamate (25b)
At 0 °C a solution of 22 and 23 (ratio 67:33, 500 mg, 1.6 mmol) in Et2O
(40 mL) was added to a suspension of LiAlH4 (600 mg, 15.8 mmol) in Et2O
(15 mL). The reaction mixture was stirred for 22 h at room temperature.
Water (5 mL) was cautiously added at 0 °C, then the mixture was dried
(Na2SO4), the Et2O layer was separated and concentrated in vacuo. The
residue (the primary amines 24a, 25a, colourless oil, 400 mg, 88%) was
dissolved in CH2Cl2 (30 mL), cooled in an ice bath, and treated successively
with solutions of NEt3 (300 mg, 2.98 mmol) in CH2Cl2 (2.5 mL) and methyl
chloroformate (275 mg, 2.91 mmol) in CH2Cl2 (2.5 mL). After stirring for
20 h at room temperature a saturated solution of Na2CO3 (15 mL) was added,
the organic layer was separated, dried (Na2SO4), and concentrated in vacuo.
The residue (450 mg) was separated by fc (diameter of the column 3 cm,
petroleum ether/ethyl acetate 80:20, fractions 15 mL).
C
20H25NO2 (311.4) calcd. C 77.1 H 8.09 N 4.50 found C 77.0 H 8.21 N 4.50.–
MS: m/z = 311 (M+).– IR (film): ν = 2856 cm–1 (C-H), 1127 (C-O).– H
NMR (CDCl3): δ (ppm) = 1.03 (dt, J = 13.2/1.9 Hz, 1 H, 5-H equatorial),
1.63 (qd, J = 13.2/4.5 Hz, 1 H, 5-H axial), 2.11 [s, 6 H, N(CH3)2], 2.73 (dd,
J = 13.4/9.8 Hz, 1 H, CHCH2NMe2), 2.84–2.97 (m, 2 H, CHCH2NMe2), 3.76
(td, J = 11.5/1.9 Hz, 1 H, 6-H axial), 3.85 (ddd, J = 13.2/5.6/1.9 Hz, 1 H, 4-H
axial); 4.03 (dd, J = 11.5/4.5 Hz, 1 H, 6-H equatorial), 5.44 (s, 1 H, 2-H axial),
7.14–7.20 (m, 3 H, arom.), 7.23–7.31 (m, 6 H, arom.), 7.43 (d, J = 6.6 Hz, 1
H, arom.).
1
24b (fractions 11–19, Rf = 0.18): Colourless solid (iPr2O), m.p. 106–
107 °C, yield 175 mg (32%, calculated from 22/23), [α]546 = +51.9, [α]578
= +45.2, [α]589 = +43.4 (c = 0.58 in CHCl3).– C20H23NO4 (341.4) calcd. C
70.4 H 6.79 N 4.10 found C 70.4 H 6.77 N 4.09.– MS (CI): m/z = 342 (M +
H+).– IR (KBr): ν = 3440 cm–1 (NH), 1724 (C=O), 1511 (amide II), 1248
(C-O), 1097 (C-O).– 1H NMR (CDCl3): δ (ppm) = 1.20 (dd, J = 12.4/2.6 Hz,
1 H, 5-H equatorial), 1.71–1.80 (m, 1 H, 5-H axial), 2.92–2.96 (m, 1 H,
C6H5CHCH2), 3.51–3.56 (m, 1 H, CH2N), 3.59 (s, 3 H, CO2CH3), 3.86 (td,
J = 12.0/2.6 Hz, 1 H, 6-H axial), 3.88–3.98 (m, 1 H, CH2N), 4.05 (”t”, J =
9.4 Hz, 1 H, 4-H axial), 4.19 (dd, J = 12.0/4.3 Hz, 1 H, 6-H equatorial), 4.86
(s broad, 1 H, NH), 5.55 (s, 1 H, 2-H axial), 7.21 (d, J = 7.3 Hz, 2 H, arom.),
7.28–7.40 (m, 6 H, arom.), 7.53 (d, J = 7.3 Hz, 2 H, arom.).
(2R)-(–)-N-Methyl-2-phenyl-2-[(2S,4S)-2-phenyl-1,3-dioxan-4-yl]ethan-
1-amine (25c)
As described for 24c the carbamate 25b (233.7 mg, 0.68 mmol) was
reduced with LiAlH4 (500 mg, 12.5 mmol) in Et2O (40 mL) during 18 h at
room temperature. The crude reaction product was purified by fc (diameter
of the column 1 cm, CH2Cl2/CH3OH 9:1, Rf = 0.23). Colourless oil, yield
188 mg (92.4%), [α]546 = –47.7, [α]578 = –41.0, [α]589 = –38.7 (c = 0.15 in
CHCl3).– C19H23NO2 (297.4) calcd. C 76.7 H 7.80 N 4.71 found C 76.3 H
8.13 N 4.81.– MS (CI): m/z = 298 (M + H+).– IR (film): ν = 3325 cm–1 (broad,
NH), 2848 (C-H), 1111 (C-O).– 1H NMR (CDCl3): δ (ppm) = 1.33 (dd, J =
12.4/2.6 Hz, 1 H, 5-H equatorial), 1.66 (qd, J = 12.4/4.9 Hz, 1 H, 5-H axial),
2.11 (s broad, 1 H, NHCH3), 2.31 (s, 3 H, NHCH3), 2.95–3.02 (m, 3 H,
CHCH2N), 3.85 (td, J = 12.4/2.6 Hz, 1 H, 6-H axial), 4.07–4.13 (m, 2 H, 4-H
25b (fractions 20–32, Rf = 0.12): yield 88 mg (16%, calculated from
22/23), [α]546 = –44.1, [α]578 = –38.5, [α]589 = –36.7 (c = 1.10 in CHCl3).–
Arch. Pharm. Pharm. Med. Chem. 332, 413–421 (1999)

420
Wünsch, Bauschke, Diekmann, and Höfner
axial and 6-H equatorial), 5.42 (s, 1 H, 2-H axial), 7.17–730 (m, 8 H, arom.),
7.36 (dd, J = 7.3/1.3 Hz, 2 H, arom.).
tions of test compounds for 80 min at 25 °C. The samples were rapidly
filtered under reduced pressure through GF/C filters and the filters were
washed with ice-cold buffer (10 mL). Bound radioactivity trapped on the
filters was determined by liquid scintillation spectrometry. Nonspecific
binding was determined with 1 µM (+)-MK 801.
(2R)-(–)-N,N-Dimethyl-2-phenyl-2-[(2S,4S)-2-phenyl-1,3-dioxan-4-yl]-
ethan-1-amine (25d)
NaBH3CN (120 mg, 1.9 mmol) was added to a solution of 25c (85 mg,
0.29 mmol) and formaldehyde (35% in water, 1.4 mL) in methanol (10 mL)
and the reaction mixture was stirred for 20 h at room temperature. Then, a
solution of Na2CO3 (10%, 20 mL) and CH2Cl2 (20 mL) were added, the
organic layer was separated, dried (MgSO4), and the residue was purified by
fc (diameter of the column 1 cm, CH2Cl2/CH3OH 90:10, Rf = 0.34). Colour-
less oil, yield 31 mg (34.8%), [α]546 = –61.1, [α]578 = –52.6, [α]589 = –51.1
(c = 0.23 in CHCl3).– C20H25NO2 (311.4) calcd. C 77.1 H 8.09 N 4.50 found
C 76.8 H 8.30 N 4.65.– MS: m/z = 311 (M+).– IR (film): ν = 2856 cm–1 (C-H),
1113 (C-O).– 1H NMR (CDCl3): δ (ppm) = 1.29 (dt, J = 12.4/2.1 Hz, 1 H,
5-H equatorial), 1.61 (qd, J = 12.4/5.1 Hz, 1 H, 5-H axial), 2.18 [s, 6 H,
N(CH3)2], 2.56 (dd, J = 15.2/9.8 Hz, 1 H, CHCH2NMe2), 2.84–2.90 (m, 2
H, CHCH2NMe2), 3.86 (td, J = 12.4/2.1 Hz, 1 H, 6-H axial), 4.08 (dd, J =
12.4/5.1 Hz, 1 H, 6-H equatorial), 4.15 (dt, J = 12.4/2.1 Hz, 1 H, 4-H axial),
5.45 (s, 1 H, 2-H axial), 7.14–7.20 (m, 2 H, arom.), 7.21–7.24 (m, 3 H, arom.),
7.29–7.30 (m, 3 H, arom.), 7.38–7.40 (m, 2 H, arom.).
Investigation of the µ-Receptor Affinity[15]
The test was performed with the radioligand [3H]-DAMGO
(2053.5 GBq/mmol; Du Pont de Nemours) and bovine striatal membrane
preparations as receptor material. Buffer: Tris HCl 50 mM, pH = 7.5.
Nonspecific binding was determined with 1 µM Naloxon.
Performance: According to ref.[15a]
.
Investigation of the κ-Receptor Affinity[15]
The test was performed with the radioligand [3H]-U 69,593
(1753 GBq/mmol; Du Pont de Nemours) and bovine striatal membrane
preparations as receptor material. Buffer: Tris HCl 50 mM, pH = 7.5.
Nonspecific binding was determined with 1 µM U 50,488.
Performance: According to ref.[15a]
.
Investigation of the σ-Receptor Affinity[16]
The test was performed with the radioligand [3H]-Ditolylguanidine
(1302.4 GBq/mmol; Du Pont de Nemours) andhomogenisedguineapigbrain
(Dunkin Hartley, Harlan) preparations as receptor material. Buffer: Tris HCl
50 mM, pH = 7.4.
Performance: 250 µg of protein were incubated with various concentra-
tions of test compounds (usually solutions in buffer), 3 nM [3H]-Ditolyl-
guanidine, 50 mM Tris HCl pH 7.4 in 250 µL medium (total volume) for
90 min at 25 °C. The samples were rapidly filtered under reduced pressure
through GF/C filters and the filters were washed with ice-cold buffer (5 ×
1 mL). Bound radioactivity trapped on the filters was determined by liquid
scintillation spectrometry after addition of the scintillation cocktail. Nonspe-
cific binding was determined with 10 µM Haloperidol.
(3S,4S)-(–)-3-Benzyloxy-5-(methylamino)-4-phenylpentan-1-ol (26)
A solution of 24b (54.5 mg, 0.16 mmol) in Et2O (6 mL) was slowly added
to an ice cold suspension of LiAlH4 (150 mg, 3.75 mmol) in Et2O (4 mL).
The ice bath was removed and the reaction mixture was stirred for 17 h at
room temperature. Then, LiAlH4 (95 mg, 2.4 mmol) was added, the reaction
mixture was stirred for 3 h, and an additional portion of LiAlH4 (270 mg,
6.75 mmol) was added. After stirring for additional 24 h at room temperature
water (2 mL) was cautiously added, the suspension was dried (Na2SO4),
filtered, and the organic layer was concentrated in vacuo. The residue
(48.1 mg) was dissolved in 1 N HCl (10 mL), the aqueous layer was washed
with Et2O, then 1 N NaOH (13 mL) was added, the aqueous layer was
extracted with Et2O (5 ×), the Et2O layer was dried (MgSO4) and concen-
trated in vacuo. Colourless oil, yield 23.7 mg (49.6%), [α]546 = –30.0, [α]578
= –26.8, [α]589 = –24.1 (c = 0.11 in CHCl3).– C19H25NO2 (299.4) calcd. C
76.2 H 8.41 N 4.68 found C 76.1 H 8.52 N 4.72.– MS (CI): m/z = 300 (M +
References and Notes
H+).– IR (film): ν = 3314 cm–1 (OH, NH), 2855 (C-H), 1101 (C-O).– H
1
[1] [1a] G. R. Lenz, S. M. Evans, D. E. Walters, A. I. Hopfinger, Opiates,
Academic Press, New York, London, 1986, pp. 250ff.– [1b] A. F. Casy,
R. T. Parfitt, Opioid Analgesics, Pergamon Press, new York, London,
1986, pp. 153ff.
NMR (CDCl3): δ (ppm) = 1.53–1.58 (m, 2 H, 2-H), 2.45 (s, 3 H, NHCH3),
2.75 (td, J = 9.8/3.8 Hz, 1 H, 4-H), 2.97 (dd, J = 12.0/3.8 Hz, 1 H, 5-H), 3.14
(dd, J = 12.0/9.8 Hz, 1 H, 5-H), 3.58 (td, J = 6.4/2.1 Hz, 2 H, 1-H), 4.13 (td,
J = 9.8/4.0 Hz, 1 H, 3-H), 4.43 (d, J = 12.0 Hz, 1 H, C6H5CH2O), 4.46 (d, J
= 12.0 Hz, 1 H, C6H5CH2O), 7.14 (d, J = 7.3 Hz, 2 H, arom.), 7.22 (d, J =
7.3 Hz, 1 H, arom.), 7.26–7.32 (m, 7 H, arom.). Signals for the OH and NH
protons could not be detected.
[2] [2a] E. Freye, Schmerz – pain – doleur 1986, 44–54.– [2b] Arzneistoff-
profile 1981, 1–4.
[3] [3a] F. I. Carroll, P. Abraham, K. Parham, X. Bai, X. Zhang, G. A.
Brine, S. W. Mascarella, B. R. Martin, E. L. May, C. Sauss, L. Di Paolo,
P. Wallace, J. M. Walker, W. D. Bowen, J. Med. Chem. 1992, 35,
2812–2818.– [3b] F. I. Carroll, X. Bai, X. Zhang, G. A. Brine, S. W.
Mascarella, L. Di Paolo, P. Wallace, J. M. Walker, W. D. Bowen, Med.
Chem. Res. 1992, 2, 3–9.– [3c] E. L. May, M. D. Aceto, E. R. Bowman,
C. Bentley, B. R. Martin, L. S. Harris, F. Medzihradsky, M. V. Mattson,
A. E. Jacobson, J. Med. Chem. 1994, 37, 3408–3418. [3d] S. W.
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Receptor Binding Studies
General: Filter: Whatman GF/C, presoaked in buffer for 1–1.5 h before
use.– Filtration was performed with a Brandel 24-well cell harvester.–
Scintillation cocktail: Rotiszint eco plus (Carl Roth GmbH).– Liquid scintil-
lation analyzer: TriCarb 1600 (Canberra Packard), counting efficiency
55%.– All experiments were carried out in triplicate.– IC50 values were
determined with the program Inplot 4.0 (GraphPad Software TM) by non-
linear regression analysis.– Ki values were calculated according to Cheng
and Prussoff[18].– For compounds with high affinity (low Ki values) mean
values ± SEM from three independent experiments are given.
[4] [4a] E. H. F. Wong, J. A. Kemp, Annu. Rev. Pharmacol. Toxicol. 1991,
31, 401–425.– [4b] P. L. Ornstein, V. J. Klimkowski, In Excitatory
Amino Acid Receptors–Design of Agonists and Antagonists; P.
Krogsgaard-Larsen, J. J. Hensen, Ed.; Ellis Horwood Ltd., Chichester,
1992; pp 183 ff.
Investigation of the Affinity for the Phencyclidine Binding Site of the NMDA
Receptor[14]
The test was performed with the radioligand [3H]-(+)-MK 801
(825 GBq/mmol; Du Pont de Nemours) and receptor preparations from rat
brain (cerebral cortex, Du Pont de Nemours, suspension in HEPES buffer,
storage at –20 °C) [14c]. Buffer: HEPES 20 mM (HEPES = 2-[4-(2-hydroxy-
ethyl)piperazin-1-yl]ethanesulfonic acid), pH = 7.4.
Performance: 200 µL of receptor preparation was incubated in 250 µL
medium (total volume) containing 100 µM glutamic acid, 30 µM glycine, 20
µM HEPES (pH 7.4), about 2 nM [3H]-(+)-MK 801 and various concentra-
[5] [5a] B. Wünsch, M. Zott, G. Höfner, Liebigs Ann. Chem. 1992, 1225–
1230.– [5b] B. Wünsch, G. Höfner, G. Bauschke, Arch. Pharm. (Wein-
heim, Ger.) 1993, 326, 101–113.– [5c] Wünsch, M. Zott, G. Höfner,
Arch. Pharm. (Weinheim, Ger.) 1993, 326, 823–830.– [5d] B. Wünsch,
H. Diekmann, G. Höfner, Tetrahedron: Asymmetry 1995, 6, 1527–
1530.
[6] The receptor affinities of the tricyclic amines described in ref.[5] will
be published in due course.
Arch. Pharm. Pharm. Med. Chem. 332, 413–421 (1999)

2,4-Disubstituted 1,3-Dioxanes
421
[13] R. F. Borch, M. D. Bernstein, H. D. Durst, J. Am. Chem. Soc. 1971, 93,
[7] The Ki values (σ-receptor affinity) of the diastereomeric N,N-dimethyl-
5,6,7,8,9,10-hexahydro-5,9-epoxybenzocycloocten-7-amines are
3.0 µM and 0.70 µM, respectively.[6]
2897–2904.
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[11] G. Rosini, R. Ballini, Synthesis 1988, 833–847.
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Received: July 26, 1999 [FP412]
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Chu, Y. Wang, W.-C. Chen, Y.-M. Lin, W.-W. Lin, M.-C. Yan, J.-Y.
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Arch. Pharm. Pharm. Med. Chem. 332, 413–421 (1999)