Synthesis and NMDA receptor affinity of ring and side chain homologues of dexoxadrol

Article abstract of DOI:10.1002/ejoc.200800727

Novel dexoxadrol derivatives with an expanded oxygen heterocycle (1,3-dioxane instead of 1,3-dioxolane), an enlarged distance between the two heterocycles, and an additional oxo group in the 4-position of the piperidine ring were synthesized and pharmacologically evaluated. The synthesis comprises a hetero-Diels-Alder reaction of imines with Danishefsky's diene (3), followed by a Lewis acid catalyzed conjugate reduction of the resulting dihydropyridones and hydrogenolytic debenzylation. The required aldehydes were synthesized by transacetalization of benzophenone dimethyl acetal (8) with pentane-1,3,5-triol (7), butane-1,2,4-triol (15), and 4-benzyloxybutane-1,3-diol (31), respectively, and subsequent Swern oxidation. Homodexoxadrols 39 were synthesized by the Cagliotti method with the use of p-toluenesulfonylhydrazide and NaBH₄ for the removal of the oxo group. The diastereomers were separated and the relative configuration was assigned by X-ray crystal structure analysis and comparison of spectroscopic and chromatographic data. Receptor binding studies with the radioligand [³H]-(+)-MK-801 demonstrated that an expanded O-heterocycle, an enlarged distance between the heterocycles, and an additional oxo group led to a considerable loss of affinity towards the phencyclidine binding site of the NMDA receptor. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800727

FULL PAPER
DOI: 10.1002/ejoc.200800727
Synthesis and NMDA Receptor Affinity of Ring and Side Chain Homologues
of Dexoxadrol
Michael Sax,[a] Roland Fröhlich,[b] Dirk Schepmann,[a] and Bernhard Wünsch*[a]
Dedicated to Prof. Dr. H. D. Stachel on the occasion of his 80th birthday
Keywords: Receptors / Hetero-Diels–Alder reaction / Danishefsky’s diene / Structure–affinity relationships / Oxygen hetero-
cycles
Novel dexoxadrol derivatives with an expanded oxygen
heterocycle (1,3-dioxane instead of 1,3-dioxolane), an en-
larged distance between the two heterocycles, and an ad-
ditional oxo group in the 4-position of the piperidine ring
were synthesized and pharmacologically evaluated. The syn-
thesis comprises a hetero-Diels–Alder reaction of imines with
Danishefsky’s diene (3), followed by a Lewis acid catalyzed
conjugate reduction of the resulting dihydropyridones and
hydrogenolytic debenzylation. The required aldehydes were
synthesized by transacetalization of benzophenone dimethyl
acetal (8) with pentane-1,3,5-triol (7), butane-1,2,4-triol (15),
and 4-benzyloxybutane-1,3-diol (31), respectively, and sub-
sequent Swern oxidation. Homodexoxadrols 39 were synthe-
sized by the Cagliotti method with the use of p-toluenesulfo-
nylhydrazide and NaBH4 for the removal of the oxo group.
The diastereomers were separated and the relative configu-
ration was assigned by X-ray crystal structure analysis and
comparison of spectroscopic and chromatographic data. Re-
ceptor binding studies with the radioligand [3H]-(+)-MK-801
demonstrated that an expanded O-heterocycle, an enlarged
distance between the heterocycles, and an additional oxo
group led to a considerable loss of affinity towards the phen-
cyclidine binding site of the NMDA receptor.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
However, the NMDA receptor is also involved in the devel-
opment of chronic neurodegenerative disorders including
Alzheimer’s disease, Parkinson’s disease, epilepsy, and
amyotrophic lateral sclerosis. Therefore, the NMDA recep-
tor represents an interesting target for the development of
novel drugs for the therapy of CNS disorders.[3,4]
There are several binding sites for the modulation of the
NMDA receptor activity. Our interest has been focused on
ligands interacting with the phencyclidine (PCP) binding
site, which is located within the ion channel pore. Because
interaction of ligands with the PCP binding site of the
NMDA receptor is only possible after opening of the cation
channel by NMDA agonists [e.g., (S)-glutamate] in the
presence of a coagonist (e.g., glycine), these ligands are
termed open-channel blockers (uncompetitive NMDA re-
ceptor antagonists).
Introduction
The excitatory amino acid neurotransmitters (S)-aspart-
ate and (S)-glutamate mediate their effects by activation of
glutamate receptors. The class of glutamate receptors is
subdivided into metabotropic (mGlu1-mGlu8) and iono-
tropic (iGlu) receptors. Within the class of ionotropic glut-
amate receptors (AMPA, kainate, NMDA), the NMDA re-
ceptor is the best-investigated subtype. It plays a crucial role
in several neurological processes including learning and
memory.[1,2] However, overstimulation of the NMDA recep-
tor with the endogenous ligand (S)-glutamate leads to an
increased opening of the associated cation channel and,
subsequently, to a massive influx of Ca2+ ions into the neu-
ron. The pathophysiological increase in the intracellular
Ca2+ concentration causes acute damage of neurons (excito-
toxicity), which is observed after stroke or brain injury.
In the mid 1960s piperidine derivatives with an acetalic
substituent in the 2-position were synthesized by Hardie
and coworkers.[5] These efforts led to the enantiomerically
pure compounds dexoxadrol and etoxadrol (Figure 1),
which were clinically evaluated as analgesic and anesthetic
drugs.[6,7] Unfortunately, in the clinical studies psychotomi-
metic side effects, unpleasant dreams and aberrations were
observed, which brought the clinical evaluation to an
end.[8,9] After detection of the NMDA receptor, it was
[a] Institut für Pharmazeutische und Medizinische Chemie der
Westfälischen Wilhelms-Universität Münster,
Hittorfstrasse 58-62, 48149 Münster, Germany
Fax: +49-251-832144
E-mail: wuensch@uni-muenster.de
[b] Organisch-chemisches Institut der Westfälischen Wilhelms-
Universität Münster,
Correnstraße 40, 48149 Münster, Germany
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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M. Sax, R. Fröhlich, D. Schepmann, B. Wünsch
FULL PAPER
shown that dexoxadrol and etoxadrol represent NMDA re-
Following this strategy we recently synthesized racemic
ceptor antagonists, which block the cation channel by inter- oxodexoxadrols 6 (general structure 1 with n = 0 and m
acting with the PCP binding site.[3,10,11] The corresponding = 1).[12] In receptor binding studies with radioligands syn-
Ki values are 39 nM for dexoxadrol[12] and 20 nM for etox- configured oxodexoxadrol syn-6 with the same relative con-
adrol.[13]
figuration as that of dexoxadrol showed moderate NMDA
receptor affinity (Ki = 470 nM). The anti-configured deriva-
tive, anti-6, as well as intermediate benzyl derivatives syn-5
and anti-5 do not interact significantly with the NMDA
receptor[12] (Figure 3).
Figure 1. Lead compounds dexoxadrol and etoxadrol.
Some structure–affinity relationship studies related to
these structurally and stereochemically interesting heterocy-
cles are given in the literature.[14,15] However, there are only
few studies concerning the size of the oxygen heterocycle
and the distance between the oxygen heterocycle and the
basic piperidine nitrogen atom.[13–16] Analogues with sub-
stituents in the piperidine ring were not included into struc-
ture–affinity relationship studies so far.
Our interest has been focused on dexoxadrol analogues
and homologues 1 differing from dexoxadrol in three fea-
tures: either the distance between the oxygen heterocycle
and the basic nitrogen atom is enlarged (1, n = 1) or the
oxygen heterocycle is expanded (1, m = 2) or both varia-
tions are performed (1, n = 1 and m = 2); furthermore, the
piperidine ring includes an additional functional group in
the 4-position (e.g., an oxo group; 1, X = O), which allows
further modifications of the piperidine heterocycle (Fig-
ure 2).
Figure 3. Dexoxadrol derivatives with an additional oxo group in
the 4-position of the piperidine moiety (oxodexoxadrol; com-
pounds are racemic, only one enantiomer is shown).
Herein, we wish to report on the synthesis, NMDA re-
ceptor affinity, and structure–affinity relationships of novel
dexoxadrol homologues 1 with an enlarged piperidine–oxy-
gen-heterocycle distance (n = 1), an expanded oxygen het-
erocycle (m = 2), an additional carbonyl moiety (X = O),
and combinations thereof. The key step of the synthesis will
be a hetero-Diels–Alder reaction[17] of imine intermediates
with Danishefsky’s diene (3).
The concept for the synthesis of dexoxadrol analogues
and homologues 1 is outlined in Figure 2. According to our
plan, benzophenone acetals 4 with an aldehyde side chain
will react after imine formation with Danishefsky’s diene
(3) in a hetero-Diels–Alder reaction to yield dihydropyr-
idones 2. Saturation of the double bond of vinylogous
Chemistry
At first, double homologues 14 of dexoxadrol with an
amide 2 and subsequent cleavage of the N-protecting group expanded oxygen heterocycle (1,3-dioxane instead of 1,3-
will end up with desired dexoxadrol homologues 1 bearing dioxolane) and an enlarged distance between the oxygen
an additional oxo group in the 4-position (X = O). A criti- and nitrogen heterocycles were synthesized. For this pur-
cal issue of this reaction sequence is the compatibility of pose, dioxanylacetaldehyde 10 was required as the starting
the benzophenone acetal substructure with the required re- material. Aldehyde 10 was prepared by transacetalization
action conditions, in particular for the Lewis acid catalyzed of benzophenone dimethyl ketal (8) with pentane-1,3,5-triol
hetero-Diels–Alder reaction, the hydrogenation of the (7)[18] and subsequent Swern oxidation[19] of resulting etha-
double bond and the cleavage of the N-protective group.
nol derivative 9 (Scheme 1).
Figure 2. Strategy for the synthesis of novel ring and side chain homologues of dexoxadrol.
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Ring and Side Chain Homologues of Dexoxadrol
Scheme 1. (a) THF, TosOH, reflux, 7 h, 91%; (b) CH2Cl2, (COCl)2, DMSO, NEt3, –78 °C, 87%; (c) HC(OCH3)3, BnNH2, room temp.,
5 h; (d) THF, Yb(OTf)3, 0 °C, 4 h, then room temp., 16 h, 74%; (e) THF, LiBEt3H, BF3·OEt2, –78 °C, 60 min, anti-13: 60%; syn-13:
23%; (f) MeOH, THF, Pd/C, H2 (balloon), room temp., 3.5 h, 89%; (g) MeOH, Pd/C, H2 (balloon), room temp., 5 h, 88%. All compounds
are racemic, only one enantiomer is shown.
In the key step, aldehyde 10 was condensed with benzyl- improvement in the yield was obtained by using BF3·OEt2
amine in trimethyl orthoformate[20] to afford imine 11. The (Table 1, entries 5 and 6). Increasing the reaction tempera-
progress of this transformation was controlled by IR spec- ture to –30 °C led to reduced yields (Table 1, entries 7 and
troscopy. Appearance of the band at 1668 cm–1 indicated 8). Thus, the best yield of the reduced piperidone (85%)
the formation of imine 11, whereas the C=O band at was achieved with 1.1 equiv. of LiBHEt3 in the presence of
1724 cm–1 disappeared. Without purification, imine 11 was 1.1 equiv. of BF3·OEt2 at –78 °C (Table 1, entry 6).
treated with Danishefsky’s diene (3)[21] in the presence of
the weak Lewis acid Yb(OTf)3.[22] After flash chromatog-
Table 1. Optimization of the reduction of the model compound 1-
benzyl-2-phenyl-2,3-dihydropyridin-4(1H)-one.
raphy, cycloaddition product 12 was isolated in 74% yield.
Integration of characteristic signals (signal of 5-H) in the
1H NMR spectrum revealed a 77:23 ratio of anti-12/syn-12.
The anti and syn stereodescriptors refer to the orientation
of the protons at the two centers of chirality in the heterocy-
clic rings. The basis of the assignment is the presentation of
the structures in the way shown in Schemes 1–6.
Entry Reducing agent (equiv.) Lewis acid (equiv.) Temp. Yield
According to the literature, the reduction of dihydropyr-
idones can be performed with a small excess of -Selectride
in THF at low temperature.[23,24] However, the reduction of
1-benzyl-2-phenyl-2,3-dihydropyridin-4(1H)-one,[25] which
served as a model compound, with -Selectride alone af-
forded only low yields of the corresponding piperidin-4-one.
Therefore, a small series of this model reaction was per-
formed to investigate the reduction of the dihydropyridone
double bond with various reducing agents in the absence
and presence of the Lewis acids MAD [MAD = methyl
[°C]
[%]
1
2
3
4
5
6
7
8
-Selectride (1.2)
Superhydride (1.1)
-Selectride (2)
Superhydride (2)
-Selectride (1.1)
Superhydride (1.1)
-Selectride (1.1)
Superhydride (1.1)
–
–
–78
–78
–78
–78
–78
–78
–30
–30
36
42
41
41
69
85
53
66
MAD (2)
MAD (2)
BF3·OEt2 (1.1)
BF3·OEt2 (1.1)
BF3·OEt2 (1.1)
BF3·OEt2 (1.1)
aluminumbis(2,6-di-tert-butyl-4-methylphenoxide)[26]
]
and
The reaction conditions optimized for the model system
BF3·OEt2 (Table 1). It was shown that the reduction with (LiBHEt3, BF3·OEt2, –78 °C) were applied to acetal-substi-
-Selectride [LiBH(secBu)3] and Superhydride (LiBHEt3) tuted dihydropyridone 12 and desired piperidone 13 was
without a Lewis acid catalyst gave only yields of 36–42% isolated in 83% yield. The potentially acid-labile acetal sub-
(Table 1, entries 1 and 2). Whereas in the presence of MAD structure was not affected by these reaction conditions. At
the yield did not exceed 41% with -Selectride (Table 1, en- the reduced piperidone stage the diastereomers were sepa-
try 3) and Superhydride (Table 1, entry 4), a considerable rated by flash chromatography to provide anti-13 and syn-
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M. Sax, R. Fröhlich, D. Schepmann, B. Wünsch
FULL PAPER
13 in 60 and 23% yield, respectively. In the final step, the N- ent on the stereochemistry. The most potent stereoisomer is
benzyl protecting group of anti-13 and syn-13 was removed. the enantiomer with (S)-configuration at both centers of
Hydrogenolytic cleavage by using H2 (1 bar) in the presence chirality (i.e., dexoxadrol).[27,28] Therefore, the synthesis of
of Pd/C catalyst in methanol led to secondary amines anti- oxodexoxadrol homologues 22 was also performed by start-
14 and syn-14 in 89 and 88% yield, respectively.
ing with commercially available (S)-configured butane-
The second series of compounds comprises dexoxadrol 1,2,4-triol [(S)-15]. Enantiomerically pure (S)-butanetriol
homologues 22 with an additional methylene moiety be- (S)-15 provided enantiomerically pure piperidines (2S,4S)-
tween the piperidine and dioxolane heterocycles. It has been 21 (anti), (2R,4S)-21 (syn), (2S,4S)-22 (anti), and (2R,4S)-
shown that transacetalization of the benzophenone di- 22 (syn). Hereby, the stereochemistry of (2R,4S)-22 (syn)
methyl ketal (8) with the unsymmetrical butane-1,2,4-triol corresponds to the stereochemistry of dexoxadrol.
(15) under thermodynamic control predominantly led to
1,3-Dioxolanylmethylpiperidones anti-22 and syn-22 rep-
five-membered ketal 16.[16] Thus, heating of benzophenone resent dexoxadrol homologues with an enlarged distance
ketal 8 with racemic triol 15 provided an 89:11 mixture of between the piperidine and 1,3-dioxolane ring. In the next
regioisomeric ketals 16 and 17. The main regioisomer, 16, part, dexoxadrol homologues 37 with an enlarged O-hetero-
was separated by flash chromatography (yield 64%) and cycle (1,3-dioxane instead of 1,3-dioxolane) were envisaged.
subsequently oxidized with oxalyl chloride and DMSO At first it was tried to synthesize 1,3-dioxan-4-ylmethanol
(Swern oxidation) to yield aldehyde 18.
17 by transacetalization of 8 with butanetriol 15 under ki-
Next, imine 19, which was formed in situ by condensa- netic control (Scheme 2). However, the yields of 17 were
tion of aldehyde 18 with benzylamine, was treated with rather low and not reproducible, in particular, when the
Danishefsky’s diene (3) and Yb(OTf)3 to give dihydropyr- transformation was carried out on a large scale.
idone 20. The 76:24 ratio of anti-20/syn-20 is very similar
Therefore, alternatively pivalaldehyde (23) was treated
to the anti/syn ratio of dioxane analogue 12 (anti-12/syn-12, with butanetriol 15 in refluxing THF to afford regioisom-
77:23). After reduction of dihydropyridones 20 with eric acetals 24 and 25 (Scheme 3).[29] Desired cis-configured
LiBHEt3 and BF3·OEt2, the diastereomeric piperidines dioxane 24 was isolated in 41% yield after flash chromatog-
were separated to give anti-21 and syn-21 in 49 and 16% raphy. Swern oxidation of alcohol 24 led to aldehyde 26,
yield, respectively. Finally, hydrogenolytic cleavage of the N- which reacted with benzylamine and trimethyl orthofor-
benzyl group led to homologous oxodexoxadrol derivatives mate to form imine 27. Without isolation of 27, the hetero-
anti-22 and syn-22.
Diels–Alder reaction with Danishefsky’s diene (3) was per-
The NMDA receptor affinity and the pharmacological formed to obtain dihydropyridones 28. Surprisingly, in this
profile of dexoxadrol and its analogues are strongly depend- case the ratio anti-28/syn-28 was 7:93.
Scheme 2. (a) THF, TosOH, reflux, 4 h, 64%; (b) CH2Cl2, (COCl)2, DMSO, NEt3, –78 °C, 37%; (c) HC(OCH3)3, BnNH2, room temp.,
2.5 h; (d) THF, Yb(OTf)3, –10 °C - 0 °C, 4 h, then room temp. 16 h, 41%; (e) THF, LiBEt3H, BF3·OEt2, –78 °C, 90 min, anti-21: 49%;
syn-21: 16%; (f) MeOH, Pd/C, H2 (balloon), room temp., 3 h, 97%; (g) MeOH, Pd/C, H2 (balloon), room temp., 3.5 h, 89%. All
compounds are racemic, only one enantiomer is shown.
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Ring and Side Chain Homologues of Dexoxadrol
Scheme 3. (a) THF, TosOH, reflux, 23 h, 24: 41%; 25: 38%; (b) CH2Cl2, (COCl)2, DMSO, NEt3, –78 °C, 84%; (c) HC(OCH3)3, BnNH2,
room temp., 16 h; (d) THF, Yb(OTf)3, 0 °C, 4 h, then room temp., 16 h, 90%; (e) THF, LiBEt3H, BF3·OEt2, –78 °C, 60 min, 72%. All
compounds are racemic, only one enantiomer is shown.
According to our plan, pivalaldehyde acetal 28 should be tic solvent methanol for the aprotic solvent ethyl acetate,
hydrolyzed and the resulting 1,3-diol should be condensed which led to 1,3-dioxane 17 in 88% yield. Subsequent oxi-
with various ketones or ketals (e.g., 8) to give dexoxadrol dation of 17 with oxalyl chloride and DMSO afforded alde-
analogues and homologues. However, all attempts to cleave hyde 33 in 76% yield.
the pivalaldehyde acetal of 28 failed to produce the corre-
sponding 1,3-diol. In particular, trifluoroacetic acid in
methanol (51 h, room temp.) and p-toluenesulfonic acid in
THF (3 h, 66 °C) were not able to hydrolyze the acetal, and
HCl in aqueous dioxane at 50 °C led to complete decompo-
sition of 28 within 2 h.
Diastereomeric mixture 28 was reduced with LiBHEt3
and BF3·OEt2 to give piperidones 29 (anti-29/syn-29, 7:93).
Again, 10 equiv. of trifluoroacetic acid in aqueous dioxane
at 50 °C did not lead to acetal cleavage and a reaction tem-
perature of 70 °C led to decomposition of 29.
Scheme 4. (a) THF, BnBr, Bu4N+I–, NaH, room temp., 16 h, 86%;
(b) MeOH, Amberlyst® 15, reflux, 2 h (3x), 93%; (c) THF, 8,
TosOH, reflux, 19 h, 89%; (d) EtOAc, Pd/C, H2 (balloon), room
temp., 1.75 h, 88%; (e) CH2Cl2, (COCl)2, DMSO, NEt3, –78 °C,
76%. All compounds are racemic, only one enantiomer is shown.
Because the introduction of the benzophenone acetal at
the piperidone stage failed, in an alternative strategy the
benzophenone-derived 1,3-dioxane should be prepared at
the beginning of the synthesis. Thus, methanol derivative 24
was transformed into benzyl ether 30 upon treatment with
benzyl bromide and NaH (Scheme 4). The methanolysis of
After condensation of aldehyde 33 with benzylamine, re-
pivalaldehyde acetal 30 was catalyzed by a strong acidic ion sulting imine 34 was treated without further purification
exchange resin to obtain butane-1,3-diol 31, which repre- with Danishefsky’s diene (3) to yield diastereomeric dihy-
sents an interesting building block, as one of the three OH dropyridones anti-35 and syn-35 in
a 67:33 ratio
moieties of butane-1,2,4-triol is selectively protected. After (Scheme 5). LiBHEt3 reduction of the double bond of 35
filtration and evaporation of pivalaldehyde dimethyl acetal, provided piperidines anti-36 and syn-36. Because flash
diol 31 was used to form a new ketal with benzophenone chromatographic separation of diastereomers anti-36 and
dimethyl acetal (8). However, hydrogenolytic cleavage of the syn-36 failed, only a small sample of the diastereomeric
benzyl ether of 32 with H2 and Pd/C in methanol predomi- mixture of 36 was separated by preparative HPLC to get
nantly led to thermodynamically more stable 1,3-dioxolane the pure compounds for pharmacological evaluation. After
16. This isomerization was avoided by exchange of the pro- hydrogenolytic cleavage of the N-benzyl protective group,
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M. Sax, R. Fröhlich, D. Schepmann, B. Wünsch
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Scheme 5. (a) HC(OCH3)3, BnNH2, room temp., 3 h; (b) THF, Yb(OTf)3, –15 °C, 1 h, then room temp., 16 h, 92%; (c) THF, LiBEt3H,
BF3·OEt2, –78 °C, 60 min, 82%; the diastereomers anti-36 and syn-36 were separated by preparative HPLC; (d) MeOH, Pd/C, H2 (bal-
loon), room temp., 4.25 h, anti-37: 55%; syn-37: 34%. All compounds are racemic, only one enantiomer is shown.
diastereomers anti-37 and syn-37 were separated by flash 38 and syn-38 were separated by flash chromatography and
chromatography.
subsequently the benzyl protective group was removed by
Finally, the carbonyl moiety of 36 was removed to obtain hydrogenolysis to end up with secondary amines anti-39
dexoxadrol homologues 39 with a 1,3-dioxane moiety in- and syn-39. Considering the stereochemistry, syn-39 could
stead of the 1,3-dioxolane ring (homodexoxadrol 39) be assigned as racemic homodexoxadrol.
(Scheme 6). For this purpose, the Cagliotti method using p-
The relative stereochemistry of the respective syn and
toluenesulfonylhydrazide and NaBH4[30] was applied on the anti stereoisomers was determined by X-ray crystal struc-
diastereomeric mixture of 36. The resulting piperidines anti- ture analyses. Slow crystallization of anti-14 from a mixture
of CH2Cl2 and iPr2O provided monoclinic crystals, which
were suitable for X-ray crystal structure analysis (Figure 4).
This analysis proves the anti configuration of the two cen-
Scheme 6. (a) MeOH, p-toluenesulfonylhydrazide, reflux, 2 h, then
NaBH4, reflux, 6 h, anti-38: 13%; syn-38: 12%; (b) MeOH, Pd/C,
H2 (balloon), room temp., 1 h, 97%; (c) MeOH, THF, Pd/C, H2
(balloon), room temp., 1.5 h, 95%. All compounds are racemic,
only one enantiomer is shown.
Figure 4. X-ray crystal structure analysis of anti-14.
Table 2. Comparison of characteristic properties of diastereomeric anti/syn pairs: Comparison of the ratio of diastereomers formed during
1
the hetero-Diels–Alder reaction, the Rf values, and some characteristic signals in the H and 13C NMR spectra.
Compd.
Ratio of diastereomers
Rf value
Characteristic signals in the NMR spectra
1H NMR
13C NMR
5, 6[12]
12–14
20–22
28, 29
35–37
anti-5/syn-5
anti-12/syn-12
anti-20/syn-20
anti-28/syn-28
anti-35/syn-35
41:59
77:23
76:24
7:93
anti-5: 0.22
syn-5: 0.16
anti-6: 2.93 (“q”, 2-H), 3.40 (ddd, 6-H)[a]
syn-6: 3.10 (ddd, 2-H), 3.38 (ddd, 6-H)
anti-14: 3.34 (ddt, 2-H), 3.45 (ddd, 6-H)[a]
syn-14: 3.19 (m, 2-H), 3.40 (ddd, 6-H)
anti-22: 3.11 (m, 2-H), 3.29 (ddd, 6-H)
syn-22: 3.08 (m, 2-H), 3.37 (ddd, 6-H)
anti-29: 3.13 (m, 2-H), 3.44 (ddd, 6-H)
syn-29: 3.02 (m, 2-H), 3.13 (m, 6-H)
anti-37: 2.92 (ddd, 2-H), 3.42 (ddd, 6-H)
syn-37: 3.00 (dt, 2-H), 3.40 (ddd, 6-H)
60.0 (C-2)
59.1 (C-2)
54.0 (C-2)
55.8 (C-2)
53.2 (C-2)
56.4 (C-2)
62.3 (C-2)
62.9 (C-2)
61.2 (C-2)
61.1 (C-2)
anti-13: 0.30
syn-13: 0.19
anti-21 0.16
syn-21: 0.11
anti.29: 0.35
syn-29: 0.28
anti-36: 0.26
syn-36: 0.26
67:33
[a] The relative configuration of anti-6 and anti-14 was proven unambiguously by X-ray crystal structure analysis.
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Ring and Side Chain Homologues of Dexoxadrol
ters of chirality. Thus, the relative configuration of syn-12– Table 3. Affinity of the piperidine derivatives towards the phency-
clidine binding site of the NMDA, σ1, and σ2 receptors.
14 and anti-12–14 is given as well. The anti configuration
of oxodexoxadrol derivative anti-6 was also proven by X-
ray crystal structure analysis.[13] The relative configuration
of the residual dexoxadrol analogues and homologues 20–
22, 28, 29, and 35–39 was unequivocally deduced from these
R
NMDA affin-
ity
Inhibition at Inhibition at Inhibition at
Compd.
σ1 affinity
σ2 affinity
c = 10 µ [%] c = 10 µ [%] c = 10 µ [%]
anti-513
syn-513
Bn
Bn
H
5
4
16
6
0
0
0
46
Ͼ80
27
10
32
0
Ͼ95
Ͼ95
0
36
1
two X-ray crystal structure analyses by comparison of H
and 13C NMR spectra, chromatographic behavior, and the
ratio of diastereomers that were formed during the hetero-
Diels–Alder reaction. Details of this comparison are given
in Table 2.
anti-613
syn-613
1.4Ϯ0.09 µ[a]
0
H
470Ϯ173 nM[a]
anti-13
syn-13
anti-14
syn-14
anti-21 (rac)
syn-21 (rac)
Bn
Bn
H
14
6
0
7–40
12
32
26
25
0
0
26
8
0
2
0
0
15
51%
14 µ[a]
29
H
30
Bn
Bn
Bn
Bn
H
H
H
1.1Ϯ0.32 µ[a]
1.6Ϯ0.35 µ[a]
0.81 µ[a]
0.77 µ[a]
5.53 µ[a]
1.7 µ[a]
0
Receptor Affinity
The affinity of the novel dexoxadrol analogues and (2S,4S)-21
(2R,4S)-21
homologues for the PCP binding site of the NMDA recep-
anti-22 (rac)
tor was determined in competition experiments by using the
syn-22 (rac)
5
0
1
0
radioligand [3H]-(+)-MK-801. Fresh pig brain cortex mem-
(2S,4S)-22
(2R,4S)-22
anti-36
syn-36
brane preparations were employed as receptor material.[31]
H
14
Bn
Bn
H
4.5 µ[a]
3.6 µ[a]
4.0 µ[a]
0
3.6 µ[a]
In addition to the NMDA receptor binding, the affinity
43
0
9
towards σ receptors was also included in this study, because
anti-37
some potent NMDA antagonists also interact with σ recep-
syn-37
H
tors and vice versa.[32,33] In the σ assays the radioligands
anti-38
Bn
Bn
H
3.4 µ[a]
3.5 µ[a]
1.9 µ[a]
7.2 µ[a]
–
6.9 µ[a]
34
[3H]-(+)-pentazocine (σ1) and [3H]-ditolylguanidine (σ2) syn-38
0
anti-39
syn-39
Dexoxadrol
9200 nM[a]
6400 nM[a]
39Ϯ10 nM[a]
2.4 µ[a]
4.7 µ[a]
–
and membrane preparations from guinea pig brains (σ1)
H
and rat livers (σ2) were used.[34,35]
At first, the displacement of the radioligands in the pres-
ence of relatively high concentrations (10 µ) of the test
compounds is measured. Only when in this screening ex-
periment a considerable reduction of radioligand binding
was observed the complete competition curve was recorded.
Otherwise in Table 3 only the inhibition (in%) of the ra-
dioligand binding at 10 µ of the test compound is given.
In Table 3 the receptor affinities of the synthesized com-
pounds are summarized. In comparison to the NMDA re-
ceptor affinity of oxodexoxadrol syn-6 (Ki = 470 nM),[13]
oxygen ring-expanded analogues anti-37 and syn-37, the
compounds with an additional methylene moiety between
the two heterocycles, anti-22 and syn-22, and the com-
pounds with additional methylene moieties in the oxygen
heterocycle and in the spacer, anti-14 and syn-14, reveal
very-low NMDA receptor affinity. Moreover, homodexox-
adrols anti-39 and syn-39 without the carbonyl moiety in
the piperidine ring only interact in the low micromolar
range (Ki = 9.2 and 6.4 µ) with the phencyclidine binding
site of the NMDA receptor.
According to structure–affinity relationships, the nitro-
gen atom of dexoxadrol or etoxadrol should not be substi-
tuted.[15] Therefore, the negligible NMDA receptor affinity
of the synthetic intermediates bearing a benzyl moiety at
the N-atom (13, 21, 36, 38) is not surprising.
In the σ1 and σ2 assays, very-low affinity of the test com-
pounds was observed. Only the enantiomerically pure
spacer homologous N-benzyl derivatives (2S,4S)-21 (anti)
and (2R,4S)-21 (syn) interacted in the submicromolar range
with the σ1 receptor. However, the Ki values of 810 nM and
770 nM are still rather high. Nevertheless, the σ1 receptor
[a] Ki value: For potent compounds the Ki value was measured
(n = 3). For compounds showing high Ki values (low potency) the
Ki value was recorded only once.
the 4-position of the 1,3-dioxolane ring, as corresponding
racemates anti-21 and syn-21 are less potent.
Diastereomeric homodexoxadrols anti-39 and syn-39,
which only differ from dexoxadrol by expansion of the 1,3-
dioxolane ring to a 1,3-dioxane ring, show σ1 and σ2 affin-
ity in the low micromolar range. Thus, the σ1 and σ2 affinity
of these compounds is comparable or even higher than that
of their NMDA receptor affinity.
Conclusion
The potent NMDA receptor antagonist dexoxadrol has
been modified in three directions: expansion of the 1,3-di-
oxolane ring to a 1,3-dioxane ring, enlargement of the dis-
tance between the two heterocycles, and introduction of an
additional oxo group in the 4-position of the piperidine
ring. The dexoxadrol modifications became accessible by
following a novel synthetic strategy by using a hetero-Diels–
Alder reaction. Receptor binding studies showed that all
three variations of the parent molecule led to a considerable
decrease in the affinity towards the phencyclidine binding
site of the NMDA receptor.
Experimental
General: Unless otherwise noted, moisture-sensitive reactions were
conducted under an atmosphere of dry nitrogen. THF was dried
seems to prefer the stereoisomers with (S)-configuration at with sodium/benzophenone and was freshly distilled before use.
Eur. J. Org. Chem. 2008, 6015–6028
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6021

M. Sax, R. Fröhlich, D. Schepmann, B. Wünsch
FULL PAPER
Methanol was dried with magnesium and iodine, distilled, and
stored over 4 Å molecular sieves. DMF was dried with CaH2, fil-
tered, distilled, and stored over 3 Å molecular sieves. Yb(OTf)3 (Al-
drich) was stored in a desiccator over P4O10 in vacuo at room tem-
perature. Danishefsky’s diene (3) was prepared according to ref.[21]
and stored under an atmosphere of nitrogen at –25 °C.[12] Thin-
layer chromatography (tlc): Silica gel 60 F254 plates (Merck). Flash
chromatography (fc): Silica gel 60, 40–64 µm (Merck); parentheses
include: diameter of the column, eluent, fraction size, Rf. Melting
point: Melting point apparatus SMP 3 (Stuart Scientific), uncor-
rected. MS: MAT GCQ (Thermo-Finnigan). EI = electron impact,
ESI = electrospray ionization. IR: IR spectrophotometer 480Plus
FT-ATR-IR (Jasco). Optical rotation: Polarimeter 341 (Perkin–El-
mer); 1.0-dm tube, concentration c [g/100 mL], temperature 20 °C.
1H NMR (400 MHz), 13C NMR (100 MHz): Mercury-400BB spec-
trometer (Varian); δ in ppm relative to tetramethylsilane; coupling
constants are given with 0.5 Hz resolution; the assignments of 13C
and 1H NMR signals were supported by 2D NMR techniques. Ele-
mental analysis: CHN-Rapid Analysator (Fons-Heraeus). Prepara-
tive HPLC: Pump L-7150, autosampler L-7200, UV-detector L-
7400, interface D-7000, data transfer D-line cable and PCI-GPIB
card, HSM software (Merck-Hitachi).
3026 (w, Aryl-H), 2956 (m, –C–H), 2729 [w, CH(=O)], 1724 (s,
C=O), 1196 (s)/1096 (s, C–O–C) cm–1. 1H NMR (CDCl3): δ = 1.41
(dq, J = 12.8, 2.2 Hz, 1 H, 5-Heq), 1.87 (dddd, J = 12.9, 11.6, 10.1,
7.6 Hz, 1 H, 5-Hax), 2.51 (ddd, J = 16.8, 4.3, 1.4 Hz, 1 H,
CH2CHO), 2.79 (ddd, J = 16.7, 7.9, 2.3 Hz, 1 H, CH2CHO), 3.99–
4.02 (m, 2 H, 6-H), 4.43 (dddd, J = 11.8, 7.9, 4.1, 2.7 Hz, 1 H, 4-
H), 7.09–7.24 (m, 4 H, -Ph), 7.33 (t, J = 7.8 Hz, 2 H, -Ph), 7.40
(dd, J = 8.4, 1.4 Hz, 2 H, -Ph), 7.49 (dd, J = 8.6, 1.2 Hz, 2 H, -Ph),
9.88 (dd, J = 2.2, 1.5 Hz, 1 H, -CHO) ppm. 13C NMR (CDCl3): δ
= 31.1 (C-5), 50.1 (CH2CHO), 61.5 (C-6), 66.4 (C-4), 101.8 (C-2),
125.3 (2 Ph-C), 127.6 (2 Ph-C), 128.0 (Ph-C), 128.15 (Ph-C), 128.25
(2 Ph-C), 129.2 (2 Ph-C), 140.0/144.9 (2 quart. Ph-C), 200.6
(-CHO) ppm. C18H18O3 (282.3). MS (70 eV): m/z (%) = 282 (2)
[M]+, 205 (59) [M – Ph], 105 (77) [PhCO], 77 (100) [Ph].
(RS)-1-Benzyl-2-{[(RS) and (SR)-2,2-Diphenyl-1,3-dioxan-4-yl]-
methyl}-2,3-dihydropyridin-4(1H)-one (anti-12 and syn-12): A solu-
tion of aldehyde 10 (2.43 g, 8.60 mmol) and benzylamine (940 µL,
8.60 mmol) in trimethyl orthoformate (30 mL) was stirred at room
temperature for 5 h. The solvent was removed in vacuo, and the
residual pale yellow oil (imine 11, ν = 1668 cm–1) was dissolved in
THF (55 mL). A solution of Yb(OTf)3 (1.066 g, 1.72 mmol) in
THF (10 mL) was added, and the mixture was cooled down to
2-(2,2-Diphenyl-1,3-dioxan-4-yl)ethanol (9): Pentane-1,3,5-triol[18] 0 °C and stirred for 15 min. Then, Danishefsky’s diene (3, 3.27 mL,
(7, 899 mg, 7.48 mmol) and benzophenone dimethyl acetal (8,
1.878 g, 8.23 mmol) were dissolved in THF (18 mL) and a spoon
of Na2SO4 was added. Then, a dried (Na2SO4) solution of p-tolu-
enesulfonic acid monohydrate in THF (0.033 , 11.3 mL,
0.37 mmol) was added. The reaction mixture was heated to reflux
for 7 h. After cooling, Et2O and saturated NaHCO3 were added.
The organic layer was separated, and the aqueous layer was ex-
tracted with Et2O (2ϫ). The combined organic layer was dried
(K2CO3), filtered, and concentrated in vacuo, and the residue was
purified by fc (5 cm; n-hexane/EtOAc, 60:40; 40 mL, Rf = 0.21).
Colorless oil, which crystallized at 4 °C, colorless solid, m.p.
17.19 mmol) was added, and the mixture was stirred for 4 h at 0 °C
and for 16 h at room temperature. Water (15 mL) and after 15 min
Et2O were added, and the mixture was washed with a mixture of
saturated solutions of NaHCO3/NaCl/water (1:1:1). The aqueous
layer was extracted with Et2O (2ϫ), and the combined organic layer
was dried (K2CO3), filtered, and concentrated in vacuo, and the
residue was purified by fc (8 cm; petroleum ether/EtOAc, 25:75;
40 mL, Rf = 0.19). Pale yellow oil. Yield: 2.81 g (74%). IR (neat):
ν = 3060 (w)/3028 (w, –C=C–H), 1636 (m, C=O), 1579 (s, C=C),
˜
1
1197 (m) cm–1. H NMR (CDCl3): δ = 1.32 (dq, J = 12.8, 2.3 Hz,
0.77 H, CH2CH2O°), 1.37 (dq, J = 13.0, 2.1 Hz, 0.23 H,
59.0 °C. Yield: 1.936 g (91%). IR (neat): ν = 3427 (br. m, O–H), CH2CH2Ox), 1.74–1.90 (m, 1.23 H, CHCH2CHx and CH2CH2Ox
˜
3026 (w, C=C–H), 2925 (m, C–H), 1196 (s)/1096 (s, C–O–C) cm–1.
1H NMR (CDCl3): δ = 1.38–1.43 (m, 1 H, 5-Heq), 1.82 (dddd, J =
14.5, 7.0, 4.9, 3.7 Hz, 1 H, CH2CH2OH), 1.91–2.03 (m, 2 H, 5-
Hax and CH2CH2OH), 2.20 (br. s, 1 H, -OH), 3.90–3.99 (m, 2 H,
CH2CH2OH), 4.01–4.11 (m, 2 H, 6-H), 4.15–4.22 (m, 1 H, 4-H),
7.17–7.31 (m, 4 H, -Ph), 7.41 (t, J = 7.6 Hz, 2 H, -Ph), 7.47 (dd, J
and CH2CH2°), 1.93 (“dt”, J = 14.5, 4.8 Hz, 0.77 H, CHCH2CH°),
2.14 (ddd, J = 13.6, 11.5, 2.1 Hz, 0.23 H, CHCH2CHx), 2.24 (ddd,
J = 14.4, 7.8, 6.6 Hz, 0.77 H, CHCH2CH°), 2.36 (dt, J = 16.5,
1.5 Hz, 0.23 H, 3-Hx), 2.37 (ddd, J = 16.3, 3.3, 0.9 Hz, 0.77 H, 3-
H°), 2.75 (dd, J = 16.4, 6.7 Hz, 0.77 H, 3-H°), 2.82 (ddd, J = 16.5,
6.9, 1.1 Hz, 0.23 H, 3-Hx), 3.68 (tt, J = 7.1, 3.6 Hz, 0.77 H, 2-H°),
= 8.4, 1.4 Hz, 2 H, -Ph), 7.54 (dd, J = 8.4, 1.3 Hz, 2 H, -Ph) ppm. 3.87 (tt, J = 11.0, 2.0 Hz, 0.23 H, OCHx), 3.94–4.08 (m, 3 H, OCH°
13C NMR (CDCl3): δ = 29.2 (C-5), 36.6 (CH2CH2OH), 58.3
(CH2CH2OH), 59.7 (C-6), 68.0 (C-4), 99.6 (C-2), 123.3 (2 Ph-C),
125.6 (2 Ph-C), 125.9 (Ph-C), 126.0 (Ph-C), 126.2 (2 Ph-C), 127.1
and 2ϫOCH2° and 2-Hx and 2ϫOCH2 ), 4.35 (d, J = 15.3 Hz,
x
x
0.77 H, PhCH2°), 4.39 (d, J = 14.3 Hz, 0.23 H, PhCH2 ), 4.41 (d,
J = 15.3 Hz, 0.77 H, PhCH2°), 4.43 (d, J = 14.8 Hz, 0.23 H,
(2 Ph-C), 138.1/143.0 (2 quart. Ph-C) ppm. C18H20O3 (284.4). MS PhCH2 ), 4.95 (dd, J = 7.4, 1.0 Hz, 0.23 H, 5-Hx), 5.00 (dd, J =
x
(70 eV): m/z (%) = 284 (4) [M]+, 207 (54) [M – Ph], 105 (65) 7.4, 0.9 Hz, 0.77 H, 5-H°), 7.06 (dd, J = 7.4, 0.9 Hz, 0.77 H, 6-H°),
[PhCO], 77 (100) [Ph].
7.11 (dd, J = 7.4, 1.1 Hz, 0.23 H, 6-Hx), 7.16–7.41 (m, 12 H, -Ph),
7.48 (m, 3 H, -Ph); ° = index for anti-12 (77%, integration of 5-H°
signal), x = index for syn-12 (23%, integration of 5-Hx signal) ppm.
13C NMR (CDCl3): δ = 31.0 (CH2CH2O°), 31.8 (CH2CH2Ox), 34.1
(CHCH2CHx), 36.5 (CHCH2CH°), 38.7 (C-3x), 41.3 (C-3°), 51.6
2-(2,2-Diphenyl-1,3-dioxan-4-yl)acetaldehyde (10): Under an atmo-
sphere of N2, CH2Cl2 (55 mL) and oxalyl chloride (1.02 mL,
11.95 mmol) were cooled down to –78 °C. Then, a solution of dry
DMSO (1.70 mL, 23.90 mmol) in CH2Cl2 (14 mL) was added drop-
wise, and the mixture was stirred for 10 min at –78 °C. Afterwards,
a solution of alcohol 9 (2.831 g, 9.96 mmol) in CH2Cl2 (14 mL)
was added slowly, and the mixture was stirred for 30 min at –78 °C
before NEt3 (6.90 mL, 49.79 mmol) was added. After warming to
room temperature, n-hexane was added (100 mL), the mixture was
filtered, and the precipitate was washed with Et2O. The organic
layer was concentrated (600 mbar, 40 °C) and the filtration pro-
cedure was repeated. Then, the solvent was completely removed,
and the residue was purified by fc (6 cm; petroleum ether/EtOAc,
80:20; 40 mL, Rf = 0.26). Colorless oil, which crystallized at 4 °C,
(C-2x), 53.1 (C-2°), 57.8 (PhCH2 ), 58.2 (PhCH2°), 61.4 (OCH2°),
x
61.6 (OCH2 ), 66.6 (OCHx), 68.5 (OCH°), 97.1 (C-5x), 97.9 (C-5°),
x
101.3 (OCOx), 101.6 (OCO°), 125.2/125.5/127.1/127.5/127.6/127.9/
128.0/128.16/128.21/128.24/128.3/128.5/128.7/129.2/129.27/129.31
(15 Ph-Cx + 15 Ph-C°), 136.7/140.3/144.9 (quart. Ph-C°), 136.5/
140.2/145.2 (quart. Ph-Cx), 152.9 (C-6°), 153.0 (C-6x), 190.2 (C-4x),
190.7 (C-4°) ppm. C29H29NO3 (439.6). MS (70 eV): m/z (%) = 439
(5) [M]+, 257 (72) [M – Ph2CO], 186 (98) [M – diphenyldioxanyl-
methyl], 91 (100) [PhCH2].
(2RS)-1-Benzyl-2-{[(4RS)-2,2-diphenyl-1,3-dioxan-4-yl]methyl}-
piperidin-4-one (anti-13) and (2RS)-1-Benzyl-2-{[(4SR)-2,2-di-
colorless solid, m.p. 79.4 °C. Yield: 2.453 g (87%). IR (neat): ν =
˜
6022
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6015–6028

Ring and Side Chain Homologues of Dexoxadrol
phenyl-1,3-dioxan-4-yl]methyl}piperidin-4-one (syn-13): Under an
atmosphere of N2, dihydropyridone 12 (mixture of anti-12 and syn-
12, 413.3 mg, 0.94 mmol) was dissolved in THF (9.4 mL), and the
solution was cooled down to –78 °C. Then, BF3·OEt2 (131 µL,
1.03 mmol) was added and after stirring for 30 min at –78 °C a
solution of Superhydride® (LiBEt3H 1  in THF, 1.03 mL,
1.03 mmol) was added slowly. Stirring of the reaction mixture was
which crystallized upon standing at room temperature. Yield:
156.2 mg (89%). Recrystallization from CH2Cl2/iPr2O gave color-
less crystals, which were suitable for X-ray crystal structure analy-
sis, m.p. 151.9 °C (decomp.). IR (neat): ν = = 3279 (w, N–H), 3060
˜
(w, C=C–H), 2956 (s)/2882 (m, C–H), 1699 (s, C=O), 1191 (s)/1104
(s)/1023 (s, C–O–C) cm–1. 1H NMR (CDCl3): δ = 1.37 (dq, J =
12.9, 2.3 Hz, 1 H, CH2CH2O), 1.70 (ddd, J = 14.4, 9.2, 3.4 Hz, 1
continued for 60 min at –78 °C. Then, a saturated solution of H, CHCH2CH), 1.80 (ddd, J = 14.3, 8.2, 3.4 Hz, 1 H, CHCH2CH),
NaHCO3 (200 µL) and EtOAc (20 mL) were added. The mixture
was warmed to room temperature, and it was then washed with
saturated solutions of NaHCO3 (1ϫ) and NaCl (1ϫ). The organic
layer was dried (K2CO3), filtered, and concentrated in vacuo, and
the residue was purified by fc (4 cm; petroleum ether/EtOAc, 70:30;
20 mL). At first anti-13 then syn-13 was eluted.
1.87 (br. s, 1 H, NH), 1.94 (dtd, J = 13.0, 11.7, 6.0 Hz, 1 H,
CH2CH2O), 2.20 (dd, J = 13.7, 11.3 Hz, 1 H, 3-H), 2.37–2.48 (m,
3 H, 3-H and 2ϫ5-H), 2.98 (ddd, J = 12.4, 10.2, 5.3 Hz, 1 H, 6-
H), 3.34 (ddt, J = 11.7, 8.9, 3.1 Hz, 1 H, 2-H), 3.45 (ddd, J = 12.4,
5.8, 3.2 Hz, 1 H, 6-H), 4.01–4.15 (m, 3 H, OCH und 2ϫOCH2),
7.19–7.21 (m, 1 H, Ph), 7.25–7.29 (m, 3 H, Ph), 7.38 (dd, J = 8.4,
6.9 Hz, 2 H, Ph), 7.49–7.53 (m, 4 H, Ph) ppm. 13C NMR (CDCl3):
δ = 31.2 (CH2CH2O), 43.0 (CHCH2CH), 43.1 (C-5), 45.8 (C-6),
50.3 (C-3), 54.0 (C-2), 61.9 (OCH2), 67.9 (OCH), 101.5 (OCO),
125.2 (2 Ph-C), 127.5 (2 Ph-C), 128.0 (1 Ph-C), 128.1 (1 Ph-C),
128.3 (2 Ph-C), 129.1 (2 Ph-C), 140.6/145.1 (2 quart. Ph-C), 209.4
(C-4) ppm. C22H25NO3 (351.4): calcd. C 75.19, H 7.17, N 3.99;
found C 74.81, H 7.09, N 4.26. MS (70 eV): m/z (%) = 351 (4)
[M]+, 274 (5) [M – Ph], 169 (56) [M – Ph2CO], 111 (80) [2-methylen-
piperidin-4-one], 105 (62) [PhCO], 98 (44) [piperidin-4-one], 77
(100) [Ph].
anti-13: (Rf = 0.30): Colorless solid, m.p. 119.9 °C. Yield: 249 mg
(60%). IR (neat): ν = 3026 (w, C=C–H), 2952 (m, C–H), 1707 (s,
˜
C=O), 1197 (s)/1098 (s, C–O–C) cm–1. 1H NMR (CDCl3): δ = 1.32
(dq, J = 12.9, 2.1 Hz, 1 H, CH2CH2O), 1.77 (ddd, J = 14.5, 8.7,
5.6 Hz, 1 H, CHCH2CH), 1.82–1.92 (m, 2 H, CHCH2CH and
CH2CH2O), 2.31–2.38 (m, 1 H, 5-H), 2.39–2.49 (m, 2 H, 3-H and
5-H), 2.69 (ddd, J = 14.1, 4.7, 1.2 Hz, 1 H, 3-H), 2.96 (dt, J = 13.1,
6.4 Hz, 1 H, 6-H), 3.09 (ddd, J = 13.3, 7.7, 5.3 Hz, 1 H, 6-H), 3.66–
3.72 (m, 1 H, 2-H), 3.89 (s, 2 H, PhCH2), 3.97–4.10 (m, 2 H,
OCH2), 4.13–4.22 (m, 1 H, OCH), 7.19–7.37 (m, 11 H, Ph), 7.49–
7.56 (m, 4 H, Ph) ppm. 13C NMR (CDCl3): δ = 31.7 (CH2CH2O),
38.2 (C-5), 39.0 (CHCH2CH), 44.9 (C-3), 47.3 (C-6), 54.4 (PhCH2),
58.0 (C-2), 61.7 (OCH2), 67.9 (OCH), 101.5 (OCO), 125.4/127.5/
127.76/127.85/127.89/128.3/128.7/128.9/129.2 (15 Ph-C), 139.0/
140.6/145.3 (3 quart. Ph-C), 209.6 (C-4) ppm. C29H31NO3 (441.6):
calcd. C 78.88, H 7.08, N 3.1; found C 78.47, H 7.12, N 3.01. MS
(70 eV): m/z (%) = 442 (1) [M + H]+, 364 (1) [M – Ph], 259 (10)
[M – Ph2CO], 188 (55) [1 – benzylpiperidin-4-one], 105 (17)
[PhCO], 91 (100) [PhCH2].
(2RS)-2-{[(4SR)-2,2-Diphenyl-1,3-dioxan-4-yl]methyl}piperidin-4-
one (syn-14): To a solution of benzylpiperidinone syn-13 (52.2 mg,
0.12 mmol) dissolved in MeOH (4 mL) was added Pd/C 10 %
(21.4 mg), and the suspension was vigorously stirred under an H2
atmosphere (balloon) for 5 h at room temperature. The mixture was
filtered through Celite, which was rinsed with MeOH several times,
the filtrate was concentrated to dryness, and the residue was puri-
fied by fc (2 cm; EtOAc/MeOH/NH3conc, 94:5:1; 10 mL; Rf = 0.24).
Colorless oil, which crystallized upon standing at room tempera-
ture, colorless solid, m.p. 140.1 °C. Yield: 36.3 mg (88%). IR (neat):
syn-13: (R = 0.19): Colorless oil. Yield: 94 mg (23%). IR (neat): ν
˜
f
ν = 3355 (w)/3318 (w, N–H), 3060 (w, C=C–H), 2954 (m)/2874 (m,
˜
C–H), 1710 (s, C=O), 1197 (m)/1100 (s, C–O–C) cm–1. 1H NMR
(CDCl3): δ = 1.40 (dq, J = 13.0, 2.2 Hz, 1 H, CH2CH2O), 1.58
(ddd, J = 14.2, 4.9, 3.6 Hz, 1 H, CHCH2CH), 1.84–2.04 (m, 2 H,
CHCH2CH and CH2CH2O), 2.20 (ddd, J = 13.9, 11.3, 0.9 Hz, 1
H, 3-H), 2.38 (ddt, J = 14.3, 3.6, 2.1 Hz, 1 H, 5-H), 2.42–2.51 (m,
2 H, 3-H and 5-H), 2.83 (br. s, 1 H, NH), 2.97 (td, J = 11.9, 3.7 Hz,
1 H, 6-H), 3.16–3.22 (m, 1 H, 2-H), 3.40 (ddd, J = 12.0, 6.7, 2.4 Hz,
1 H, 6-H), 4.00–4.08 (m, 3 H, OCH and 2ϫOCH2), 7.19–7.32 (m,
4 H, Ph), 7.40–7.49 (m, 6 H, Ph) ppm. 13C NMR (CDCl3): δ =
31.6 (CH2CH2O), 42.8 (C-5), 43.4 (CHCH2CH), 45.8 (C-6), 49.7
(C-3), 55.8 (C-2), 61.8 (OCH2), 69.7 (OCH), 101.6 (OCO), 125.5
(2 Ph-C), 127.6 (2 Ph-C), 128.1 (1 Ph-C), 128.2 (1 Ph-C), 128.3 (2
Ph-C), 129.2 (2 Ph-C), 140.1/144.9 (2 quart. Ph-C), 209.1 (C-4)
ppm. C22H25NO3 (351.4). MS (70 eV): m/z (%) = 351 (1.3) [M]+,
182 (40) [Ph2CO], 169 (12) [M – Ph2CO], 111 (75) [2-methylenepip-
eridin-4-one], 105 (73) [PhCO], 98 (33) [piperidin-4-one], 77 (100)
[Ph]. Purity by HPLC, Method 1: stat. phase: RP18 Supersphere
(Merck), mob. phase: methanol/phosphate buffer (pH 7.5) = 7/3,
flow 0.8 mL/min, volume of injection 5 µL (c = 2 mg/mL), T =
20 °C, λ = 220 nm: tR = 9.5 min, purity 95.2%. Method 2: stat.
phase: RP8e LiChrosphere (Merck), mob. phase: methanol/phos-
phate buffer (pH 7.5) = 6/4, flow 1.0 mL/min, volume of injection
10 µL (c = 10 mg/mL), T = 20 °C, λ = 249 nm: tR = 12.5 min,
purity = 97.0%.
= 3026 (w, C=C–H), 2957 (s, C–H), 1711 (s, C=O), 1197 (s)/1099
1
(s, C–O–C) cm–1. H NMR (CDCl3): δ = 1.34 (br. d, J = 13.3 Hz,
1 H, CH2 CH2 O), 1.51 (ddd, J = 13.5, 9.9, 3.3 Hz, 1 H,
CHCH2CH), 1.80–1.94 (m, 1 H, CH2CH2O), 2.09 (ddd, J = 13.6,
9.2, 4.2 Hz, 1 H, CHCH2CH), 2.28–2.44 (m, 2 H, 3-H und 5-H),
2.56 (m, 1 H, 5-H), 2.77 (dd, J = 14.1, 5.1 Hz, 1 H, 3-H), 2.92 (dt,
J = 12.0, 5.8 Hz, 1 H, 6-H), 3.05 (ddd, J = 12.6, 9.3, 3.7 Hz, 1 H,
6-H), 3.59–3.67 (m, 1 H, 2-H), 3.84 (d, J = 13.5 Hz, 1 H, PhCH2),
3.89 (d, J = 13.7 Hz, 1 H, PhCH2), 3.92–4.00 (m, 1 H, OCH), 4.02–
4.09 (m, 2 H, OCH2), 7.17–7.43 (m, 15 H, -Ph) ppm. 13C NMR
(CDCl3): δ = 31.8 (CH2CH2O), 36.5 (CHCH2CH), 40.2 (C-5), 44.7
(C-3), 47.8 (C-6), 55.7 (C-2), 56.9 (PhCH2), 61.8 (OCH2), 67.7
(OCH), 101.4 (OCO), 125.3 (2 Ph-C), 127.4 (2 Ph-C), 127.5 (Ph-
C), 127.8 (Ph-C), 128.0 (Ph-C), 128.2 (2 Ph-C), 128.7 (2 Ph-C),
128.9 (2 Ph-C), 129.1 (2 Ph-C), 139.0/140.6 (2 quart. Ph-C), 145.2
(quart. Bn-C), 210.0 (C-4) ppm. C29H31NO3 (441.6): calcd. C
78.88, H 7.08, N 3.17; found C 78.68, H 7.14, N 2.92. MS (70 eV):
m/z (%) = 441 (1) [M]+, 258 (19) [M – Ph2CO], 187 (47) [1-benzyl-
piperidin-4-one], 104 (16) [PhCO], 90 (100) [PhCH2].
(2RS)-2-{[(4RS)-2,2-Diphenyl-1,3-dioxan-4-yl]methyl}piperidin-4-
one (anti-14): To a solution of benzylpiperidinone anti-13
(221.8 mg, 0.50 mmol) dissolved in MeOH (8.4 mL) and THF
(2.0 mL) was added Pd/C 10% (88.7 mg), and the suspension was
vigorously stirred under an H2 atmosphere (balloon) for 3.5 h at
room temperature. The reaction mixture was filtered through Ce-
lite, which was rinsed with MeOH several times, the filtrate was
concentrated to dryness, and the residue was purified by fc (3 cm;
EtOAc/MeOH/NH3conc = 94:5:1; 10 mL; Rf = 0.37). Colorless oil,
(2RS)-1-Benzyl-2-{[(4RS)-2,2-diphenyl-1,3-dioxolan-4-
yl]methyl}piperidin-4-one (anti-21) and (2RS)-1-Benzyl-2-{[(4SR)-
2,2-diphenyl-1,3-dioxolan-4-yl]methyl}piperidin-4-one (syn-21): Un-
der an atmosphere of N2 the mixture of diastereomers anti-20 and
Eur. J. Org. Chem. 2008, 6015–6028
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6023

M. Sax, R. Fröhlich, D. Schepmann, B. Wünsch
FULL PAPER
syn-20 (780 mg, 1.83 mmol) was dissolved in THF (18 mL), where-
upon the solution was cooled down to –78 °C. BF3·OEt2 (256 µL,
2.0 mmol) was added, and the mixture was stirred for 15 min at
–78 °C. Then, a Superhydride® solution (1  in THF, 2.0 mL,
2.0 mmol) was added dropwise, and the mixture was stirred for
MeOH several times, the filtrate was concentrated, and the residue
was purified by fc (3 cm; EtOAc/MeOH/NH3conc, 94:5:1; 20 mL; Rf
= 0.19). Pale yellow oil. Yield: 199 mg (97%). IR (neat): ν = 3330
˜
(w, N–H), 3060 (w, C=C–H), 2950 (m, C–H), 1709 (s, C=O), 1206
1
(s)/1068 (s, C–O–C–) cm–1. H NMR (CDCl3): δ = 1.73–1.84 (m,
90 min at –78 °C. Then, a saturated solution of NaHCO3 (360 µL) 3 H, 2ϫCHCH2CH and NH), 2.16 (dd, J = 13.5, 11.5 Hz, 1 H, 3-
and EtOAc (36 mL) were added, whereupon the mixture was
warmed to room temperature. The organic layer was separated,
washed with brine (1ϫ), dried (K2CO3), and filtered. After evapo-
ration of the solvent the diastereomers were separated by fc
(5.5 cm; petroleum ether/EtOAc, 80:20; 30 mL).
H), 2.30–2.42 (m, 2 H, 2ϫ5-H), 2.46 (ddd, J = 14.0, 3.0, 1.5 Hz,
1 H, 3-H), 2.82 (ddd, J = 12.5, 10.6, 5.1 Hz, 1 H, 6-H), 3.08–3.14
(m, 1 H, 2-H), 3.29 (ddd, J = 12.6, 5.9, 3.1 Hz, 1 H, 6-H), 3.71
(dd, J = 7.9, 7.1 Hz, 1 H, OCH2), 4.15 (dd, J = 7.6, 6.7 Hz, 1 H,
OCH2), 4.34 (qd, J = 6.8, 5.1 Hz, 1 H, OCH), 7.24–7.35 (m, 6 H,
Ph), 7.45–7.52 (m, 4 H, Ph) ppm. 13C NMR (CDCl3): δ = 38.3
(CHCH2CH), 40.9 (C-5), 43.6 (C-6), 47.9 (C-3), 53.2 (C-2), 68.0
(OCH2), 72.2 (OCH), 107.9 (OCO), 124.1 (2 Ph-C), 124.2 (2 Ph-
C), 126.19 (1 Ph-C), 126.23 (2 Ph-C), 126.25 (1 Ph-C), 126.32 (2
Ph-C), 140.4/140.6 (2 quart. benzophenone-C), 207.1 (C-4) ppm.
ppm. C21H23NO3 (337.4): calcd. C 74.75, H 6.87, N 4.15; found C
74.82, H 7.05, N 4.24. MS (70 eV): m/z (%) = 338 (5) [M + H]+,
260 (11) [M – Ph], 165 (30) [C13H9 fluorenyl cation], 138 (36) [M –
Ph2CO2 – H = 2-allyl-4-oxopiperidiniume], 111 (39) [2-methylene-
piperidinone], 98 (100) [piperidinone].
anti-21: (Rf = 0.16): Colorless solid, m.p. 106.7 °C. Yield: 381 mg
(49%). IR (neat): ν = 3060 (w, C=C–H), 2942 (m, C–H), 1710 (s,
˜
1
C=O), 1205 (m)/1069 (m, C–O–C–) cm–1. H NMR (CDCl3): δ =
1.76 (ddd, J = 14.3, 8.1, 6.1 Hz, 1 H, CHCH2CH), 1.86 (ddd, J =
14.3, 8.3, 4.6 Hz, 1 H, CHCH2CH), 2.23 (dtd, J = 14.3, 4.4, 1.8 Hz,
1 H, 5-H), 2.31 (ddd, J = 14.0, 4.3, 1.9 Hz, 1 H, 3-H), 2.52 (dddd,
J = 14.8, 9.1, 5.6, 1.2 Hz, 1 H, 5-H), 2.76 (ddd, J = 14.0, 5.6,
1.2 Hz, 1 H, 3-H), 2.89 (ddd, J = 13.6, 5.9, 4.8, 1.0 Hz, 1 H, 6-H),
3.01 (ddd, J = 13.6, 9.5, 4.2 Hz, 1 H, 6-H), 3.42–3.49 (m, 1 H, 2-
H), 3.64 (t, J = 7.6 Hz, 1 H, OCH2), 3.84 (d, J = 13.3 Hz, 1 H,
PhCH2), 3.91 (d, J = 13.7 Hz, 1 H, PhCH2), 4.12 (dd, J = 7.6,
6.5 Hz, 1 H, OCH2), 4.31 (qd, J = 7.3, 4.6 Hz, 1 H, OCH), 7.23–
7.36 (m, 11 H, Ph), 7.44–7.47 (m, 2 H, Ph), 7.49–7.52 (m, 2 H, Ph)
ppm. 13C NMR (CDCl3): δ = 35.9 (CHCH2CH), 38.6 (C-5), 44.6
(C-3), 46.9 (C-6), 56.7 (PhCH2), 58.9 (C-2), 70.3 (OCH2), 74.5
(OCH), 109.7 (OCO), 126.3 (2 Ph-C), 126.4 (2 Ph-C), 127.6 (1 Ph-
C), 128.17 (1 Ph-C), 128.26 (1 Ph-C), 128.28 (2 Ph-C), 128.4 (2 Ph-
C), 128.7 (2 Ph-C), 128.8 (2 Ph-C), 139.1 (quart. benzyl-C), 142.85/
142.86 (2 quart. benzophenone-C), 209.5 (C-4) ppm. C28H29NO3
(427.6): calcd. C 78.66, H 6.84, N 3.28; found C 78.58, H 6.88, N
3.25. MS (70 eV): m/z (%) = 350 (1.8) [M – Ph]+, 245 (4) [M –
Ph2CO], 188 (61) [M – diphenyldioxolanylmethyl = 1-benzylpiper-
idin-4-one], 105 (16) [PhCO], 91 (100) [PhCH2].
(2RS)-2-[(4SR)-2,2-Diphenyl-1,3-dioxolan-4-ylmethyl]piperidin-4-
one (syn-22): 10% Pd/C (42.1 mg) was added to a solution of N-
benzylpiperidinone syn-21 (103.5 mg, 0.24 mmol) in dry MeOH/
THF (2:1, 6 mL), and the mixture was vigorously stirred under an
H2 atmosphere (balloon) at room temperature for 3.5 h. The reac-
tion mixture was filtered through Celite, which was rinsed with
MeOH several times, the filtrate was concentrated, and the residue
was purified by fc (2 cm; EtOAc/MeOH/NH3conc, 94:5:1; 10 mL; Rf
= 0.19). Colorless oil. Yield: 72.4 mg (89%). IR (neat): ν = 3352
˜
(w, N–H), 3060 (w, C=C–H), 2923 (m, C–H), 1711 (s, C=O), 1207
1
(s)/1067 (s, C–O–C–) cm–1. H NMR (CDCl3): δ = 1.68 (ddd, J =
14.1, 4.7, 3.7 Hz, 1 H, CHCH2CH), 1.93 (ddd, J = 14.1, 9.1, 7.6 Hz,
1 H, CHCH2CH), 2.22 (ddd, J = 14.0, 11.3, 0.9 Hz, 1 H, 3-H),
2.35 (ddt, J = 14.4, 3.6, 2.1 Hz, 1 H, 5-H), 2.40–2.51 (m, 2 H, 3-H
and 5-H), 2.90 (td, J = 12.0, 3.6 Hz, 1 H, 6-H), 2.91 (br. s, 1 H,
NH), 3.05–3.12 (m, 1 H, 2-H), 3.37 (ddd, J = 12.0, 6.7, 2.4 Hz, 1
H, 6-H), 3.68 (t, J = 7.5 Hz, 1 H, OCH2), 4.14 (dd, J = 7.9, 6.6 Hz,
1 H, OCH2), 4.28 (dtd, J = 9.2, 6.9, 3.6 Hz, 1 H, OCH), 7.25–7.36
(m, 6 H, Ph), 7.45–7.50 (m, 4 H, Ph) ppm. 13C NMR (CDCl3): δ
= 40.3 (CHCH2CH), 42.6 (C-5), 45.6 (C-6), 49.3 (C-3), 56.4 (C-2),
70.4 (OCH2), 75.2 (OCH), 110.3 (OCO), 126.40 (2 Ph-C), 126.43
(2 Ph-C), 128.32 (2 Ph-C), 128.37 (1 Ph-C), 128.43 (1 Ph-C), 128.44
(2 Ph-C), 142.4/142.5 (2 quart. benzophenone-C), 208.9 (C-4) ppm.
C21H23NO3 (337.4): calcd. C 74.75, H 6.87, N 4.15; found C 74.76,
H 6.91, N 4.30. MS (70 eV): m/z (%) = 338 (5) [M + H]+, 260 (13)
[M – Ph], 239 (5) [M – piperidinone = diphenyldioxolanylmethyl],
138 (36) [M – Ph2CO2 = 2-allyl-4-oxopiperidiniume], 98 (100) [pip-
eridinone].
syn-21: (Rf = 0.11): Colorless oil. Yield: 127.7 mg (16%). IR (neat):
ν = 3062 (w, C=C–H), 2924 (s, C–H), 1714 (s, C=O), 1206 (m)/
˜
1069 (m, C–O–C–) cm–1. 1H NMR (CDCl3): δ = 1.52 (ddd, J =
13.3, 8.8, 4.8 Hz, 1 H, CHCH2CH), 1.96 (ddd, J = 13.9, 8.5, 5.3 Hz,
1 H, CHCH2CH), 2.22 (dtd, J = 14.4, 4.8, 1.7 Hz, 1 H, 5-H), 2.30
(ddd, J = 14.1, 4.8, 1.9 Hz, 1 H, 3-H), 2.42 (dddd, J = 14.5, 8.9,
5.8, 1.2 Hz, 1 H, 5-H), 2.66 (ddd, J = 14.0, 5.4, 0.9 Hz, 1 H, 3-H),
2.76 (dt, J = 12.3, 6.0 Hz, 1 H, 6-H), 2.94 (ddd, J = 13.1, 9.0,
4.3 Hz, 1 H, 6-H), 3.31 (m, 1 H, 2-H), 3.55 (dd, J = 7.8, 6.9 Hz, 1
H, OCH2), 3.63 (d, J = 13.7 Hz, 1 H, PhCH2), 3.71 (d, J = 13.3 Hz,
1 H, PhCH2), 3.99 (dd, J = 7.8, 6.5 Hz, 1 H, OCH2), 4.21 (dtd, J
= 8.4, 6.6, 4.7 Hz, 1 H, OCH), 7.19–7.28 (m, 11 H, Ph), 7.37–7.42
(m, 4 H, Ph) ppm. 13C NMR (CDCl3): δ = 34.5 (CHCH2CH), 39.9
(C-5), 44.5 (C-3), 47.7 (C-6), 56.9 (PhCH2), 57.7 (C-2), 70.2
(OCH2), 73.9 (OCH), 109.9 (OCO), 126.29 (2 Ph-C), 126.31 (2 Ph-
C), 127.5 (1 Ph-C), 128.2 (1 Ph-C), 128.28 (3 Ph-C), 128.4 (2 Ph-
C), 128.7 (2 Ph-C), 128.8 (2 Ph-C), 139.1 (quart. benzyl-C), 142.7/
142.9 (2 quart. benzophenone-C), 209.8 (C-4) ppm. C28H29NO3
(427.6): calcd. C 78.66, H 6.84, N 3.28; found C 78.11, H 6.82, N
3.57. MS (70 eV): m/z (%) = 350 (2) [M – Ph]+, 245 (3) [M –
Ph2CO], 188 (70) [M – diphenyldioxolanylmethyl = 1-benzylpiper-
idin-4-one], 105 (14) [PhCO], 91 (100) [PhCH2].
cis-4-(Benzyloxymethyl)-2-tert-butyl-1,3-dioxane (30): Under an at-
mosphere of N2 benzyl bromide (6.46 mL, 54.4 mmol) was added
to a solution of Bu4N+I– (1.01 g, 2.72 mmol) and 24 (2.37 g,
13.6 mmol) in THF (200 mL). Then, a dispersion of NaH (60%,
0.598 g, 15 mmol) was slowly added, and the mixture was stirred
for 16 h at room temperature. The mixture was filtered and after
addition of a small amount of silica gel the filtrate was concen-
trated in vacuo. The residue was purified by fc (8 cm; n-hexane/
(2RS)-2-[(4RS)-2,2-Diphenyl-1,3-dioxolan-4-ylmethyl]piperidin-4- EtOAc, 9:1; 40 mL; Rf = 0.34). Colorless oil. Yield: 3.08 g (86%).
one (anti-22): 10% Pd/C (105 mg) was added to a solution of N-
benzylpiperidinone anti-21 (261 mg, 0.61 mmol) in dry MeOH/
THF (2:1, 12 mL), and the suspension was vigorously stirred under
an H2 atmosphere (balloon) at room temperature for 3 h. The reac-
tion mixture was filtered through Celite, which was rinsed with
IR (neat): ν = 3064 (w, C=C–H), 2956 (s, C–H), 1044 (s, C–O–C),
˜
734 (m, Aryl–C–H), 696 (m, out-of-plane) cm–1 1H NMR
.
(CDCl3): δ = 0.93 [s, 9 H, C(CH3)3], 1.43 (dtd, J = 13.1, 2.6, 1.4 Hz,
1 H, 5-Heq), 1.68 (dddd, J = 13.0, 12.5, 11.5, 5.1 Hz, 1 H, 5-Hax),
3.47 (dd, J = 10.5, 4.6 Hz, 1 H, BnOCH2), 3.58 (dd, J = 10.5,
6024
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6015–6028

Ring and Side Chain Homologues of Dexoxadrol
5.9 Hz, 1 H, BnOCH2), 3.72 (ddd, J = 12.4, 11.4, 2.6 Hz, 1 H, 6-
H), 3.83–3.89 (m, 1 H, 4-H), 4.13 (s, 1 H, 2-H), 4.14 (ddd, J =
2 H, CH2CH2O and 5-H), 2.47–2.60 (m, 2 H, 3-H and 5-H), 2.79
(dd, J = 14.8, 6.9 Hz, 1 H, 3-H), 2.92–3.01 (m, 1 H, 6-H), 3.18–
11.3, 5.2, 1.4 Hz, 1 H, 6-H), 4.59 (d, J = 12.1 Hz, 1 H, PhCH2), 3.24 (m, 1 H, 2-H), 3.60 (ddd, J = 13.4, 9.7, 3.9 Hz, 1 H, 6-H),
4.66 (d, J = 12.1 Hz, 1 H, PhCH2), 7.27–7.37 (m, 5 H, Ph-H) ppm. 3.95–4.08 (m, 4 H, OCH and OCH2 and 2ϫPhCH2), 4.09–4.16 (m,
13C NMR (CDCl3): δ = 25.0 [3 C, C(CH3)3], 28.5 (C-5), 35.1
[-C(CH3)3], 66.7 (C-6), 73.4 (BnOCH2), 73.7 (PhCH2), 76.9 (C-4),
107.6 (C-2), 127.77 (para Ph-C), 127.84 (2 C, ortho Ph-C), 128.6 (2
C, meta Ph-C), 138.7 (quart. Ph-C) ppm. C16H24O3 (264.4). MS
1 H, OCH2), 7.14–7.19 (m, 1 H, Ph-H), 7.21–7.41 (m, 10 H, Ph-
H), 7.44–7.49 (m, 2 H, Ph-H), 7.51–7.56 (m, 2 H, Ph-H) ppm. 13C
NMR (CDCl3): δ = 27.6 (CH2CH2O), 38.2 (C-5), 40.4 (C-3), 48.6
(C-6), 58.8 (PhCH2), 61.7 (OCH2), 62.9 (C-2), 73.9 (OCH), 102.1
(70 eV): m/z (%) = 265 (9) [M + H]+, 178 (15) [M – tert-butylCHO], (OCO), 125.1 (2 Ph-C), 127.4 (2 Ph-C), 127.5 (Ph-C), 127.7 (Ph-
105 (33) [PhCO], 91 (100) [PhCH2].
C), 128.0 (Ph-C), 128.2 (2 Ph-C), 128.6 (2 Ph-C), 128.7 (2 Ph-C),
129.2 (2 Ph-C), 139.5/140.4 (quart. benzophenone-C), 145.2 (quart.
PhCH2-C), 209.50 (C-4) ppm. C28H29NO3 (427.6): calcd. C 78.66,
H 6.84, N 3.28; found C 78.04, H 6.93, N 3.25. MS (70 eV): m/z
(%) = 427 (0.4) [M]+, 350 (3) [M – Ph], 188 (42) [M – diphenyldiox-
anyl = 1-benzylpiperidin-4-on-2-yl], 91 (100) [PhCH2].
4-(Benzyloxy)butane-1,3-diol (31): 1,3-Dioxane 30 (1.00 g,
3.78 mmol) was dissolved in methanol (38 mL) and Amberlyst® 15
(378 mg) was added. The mixture was heated to reflux for 2 h, and
it was then concentrated in vacuo. Methanol (38 mL) was added,
and the mixture was heated to reflux for another 2 h. The pro-
cedure was repeated once more for 1 h. After complete transforma-
tion (tlc control), the mixture was filtered, the filtrate was concen-
trated in vacuo, and the residue was purified by fc (5 cm, EtOAc,
30 mL, Rf = 0.22). Colorless solid, m.p. 74.9–75.5 °C. Yield:
syn-36: Colorless oil, “yield” 67 mg (33%). IR (neat): ν = 3060 (w,
˜
C=C–H), 2931 (m, C–H), 1706 (s, C=O), 1093 (s, C–O–C), 744 (s,
1
aryl–C–H), 707 (s)/696 (s, out-of-plane) cm–1. H NMR (CDCl3):
δ = 1.67–1.84 (m, 2 H, 2ϫCH2CH2O), 2.23 (br. d, J = 14.7 Hz, 1
H, 5-H), 2.60 (ddd, J = 15.1, 8.9, 6.5 Hz, 1 H, 5-H), 2.76 (dd, J =
14.5, 6.2 Hz, 1 H, 3-H), 2.92–3.07 (m, 3 H, 3-H and 2ϫ6-H), 3.15–
3.24 (m, 1 H, 2-H), 3.88 (d, J = 13.5 Hz, 1 H, PhCH2), 3.91–4.05
(m, 3 H, OCH and OCH2 and PhCH2), 4.06–4.14 (m, 1 H, OCH2),
7.13–7.20 (m, 1 H, Ph-H), 7.20–7.44 (m, 10 H, Ph-H), 7.44–7.50
(m, 2 H, Ph-H), 7.50–7.56 (m, 2 H, Ph-H) ppm. 13C NMR
(CDCl3): δ = 28.9 (CH2CH2O), 38.2 (C-5), 39.0 (C-3), 48.1 (C-6),
57.8 (PhCH2), 61.7 (OCH2), 64.8 (C-2), 70.9 (OCH), 101.8 (OCO),
125.3 (2 Ph-C), 127.7 (2 Ph-C), 127.9 (Ph-C), 128.0 (Ph-C), 128.2
(2 Ph-C), 128.7 (2 Ph-C), 128.8 (2 Ph-C), 129.2 (2 Ph-C), 139.0/
140.0 (quart. benzophenone-C), 145.0 (quart. PhCH2-C), 209.4 (C-
4) ppm. C28H29NO3 (427.6): calcd. C 78.66, H 6.84, N 3.28; found
C 78.07, H 6.95, N 3.17. MS (70 eV): m/z (%) = 427 (0.2) [M]+,
350 (2.3) [M – Ph], 188 (48) [M – diphenyldioxanyl = 1-benzylpip-
eridin-4-on-2-yl], 91 (100) [PhCH2].
689 mg (93%). IR (neat): ν = 3368 (br. s, O–H), 3062 (w, C=C–H),
˜
2921 (s, C–H), 1072 (s, C–O), 736 (m, aryl–C–H), 697 (m, out-of-
1
plane) cm–1. H NMR (CDCl3): δ = 1.67–1.72 (m, 2 H, 2-H), 2.70
(s, 2 H, -OH), 3.40 (dd, J = 9.5, 7.4 Hz, 1 H, 4-H), 3.49 (dd, J =
9.5, 3.6 Hz, 1 H, 4-H), 3.79–3.84 (m, 2 H, 1-H), 4.02–4.09 (m, 1
H, 3-H), 4.56 (s, 2 H, PhCH2), 7.27–7.39 (m, 5 H, Ph-H) ppm. 13
C
NMR (CDCl3): δ = 35.1 (C-2), 61.2 (C-1), 70.4 (C-3), 73.6
(PhCH2), 74.6 (C-4), 128.0 (2 C, ortho Ph-C), 128.1 (para Ph-C),
128.7 (2 C, meta Ph-C), 138.0 (quart. Ph-C) ppm. C11H16O3
(196.3): calcd. C 67.32, H 8.2; found C 67.27, H 8.16. MS (70 eV):
m/z (%) = 107 (51) [PhCH2O], 91 (100) [PhCH2].
(2RS)-1-Benzyl-2-[(4RS) and (4SR)-2,2-Diphenyl-1,3-dioxan-4-yl]-
piperidin-4-one (anti-36 and syn-36): Under an atmosphere of N2
dihydropyridone 35 (1.90 g, 4.47 mmol) was dissolved in THF
(44.7 mL), and the solution was cooled down to –78 °C. BF3·OEt2
(622 µL, 4.91 mmol) was added, and the mixture was stirred for
55 min at –78 °C. Then, Superhydride® (1  in THF, 4.91 mL,
4.91 mmol) was added dropwise, and the mixture was stirred for
60 min at –78 °C. A saturated NaHCO3 solution (1.2 mL) and
EtOAc (100 mL) were added at –78 °C, and the mixture was
warmed to room temperature and subsequently washed with a sat-
urated solution of NaHCO3, water, and a saturated solution of
NaCl. The organic layer was dried (K2CO3), filtered, and concen-
trated in vacuo, and the residue was purified by fc (8 cm; n-hexane/
EtOAc, 7:3; 100 mL; Rf = 0.26). Colorless resin. Yield: 1.58 g
(82 %). According to the 1H NMR spectrum the ratio of dia-
stereomers anti-36/syn-36 was 68:32. C28H29NO3 (427.6): calcd. C
78.66, H 6.84, N 3.28; found C 78.25, H 6.88, N 3.25.
(2RS)-2-[(4RS)-2,2-Diphenyl-1,3-dioxan-4-yl]piperidin-4-one (anti-
37) and (2RS)-2-[(4SR)-2,2-Diphenyl-1,3-dioxan-4-yl)]piperidin-4-
one (syn-37): To a solution of benzylpiperidinone 36 (mixture of
anti-36 and syn-36, 712 mg, 1.67 mmol) dissolved in dry MeOH
(35 mL) was added 10% Pd/C (285 mg), and the suspension was
vigorously stirred under an H2 atmosphere (balloon) at room tem-
perature for 4.25 h. The reaction mixture was filtered through Ce-
lite, which was rinsed with MeOH several times, the filtrate was
concentrated in vacuo, and the residue was purified by fc (5.5 cm;
cyclohexane/EtOAc, 1:1 + 1% N,N-dimethylethylamine; 40 mL).
anti-37: (Rf = 0.13): Colorless solid, m.p. 153.2 °C (decomp.). Yield:
343 mg (55%). IR (neat): ν = 3341 (w, N–H), 3059 (w, C=C–H),
˜
2925 (w, C–H), 1711 (s, C=O), 1097 (s, C–O), 748 (m, aryl–C–H),
706 (m)/696 (m, out-of-plane) cm–1. 1H NMR (CDCl3): δ = 1.31
(dq, J = 12.9, 2.0 Hz, 1 H, OCH2CH2,eq), 1.95 (qd, J = 12.4,
5.3 Hz, 1 H, OCH2CH2,ax), 1.98 (s wide, 1 H, NH), 2.24 (dd, J =
13.8, 11.4 Hz, 1 H, 3-H), 2.28–2.37 (m, 2 H, 3-H and 5-H), 2.45
(ddd, J = 14.1, 12.4, 6.8 Hz, 1 H, 5-H), 2.85 (td, J = 12.1, 3.5 Hz,
1 H, 6-H), 2.92 (ddd, J = 10.8, 6.8, 3.9 Hz, 1 H, 2-H), 3.42 (ddd,
J = 12.2, 6.7, 2.1 Hz, 1 H, 6-H), 3.86 (ddd, J = 11.6, 6.6, 2.5 Hz,
1 H, OCH), 3.94 (td, J = 12.0, 2.5 Hz, 1 H, OCH2), 4.03 (ddd, J
= 11.5, 5.2, 1.4 Hz, 1 H, OCH2), 7.13–7.26 (m, 4 H, Ph-H), 7.33–
7.40 (m, 4 H, Ph-H), 7.43–7.47 (m, 2 H, Ph-H) ppm. 13C NMR
(CDCl3): δ = 27.5 (OCH2CH2), 42.8 (C-5), 44.7 (C-3), 45.5 (C-6),
61.3 (OCH2), 61.8 (C-2), 73.5 (OCH), 101.8 (OCO), 125.6 (2 Ph-
C), 127.8 (2 Ph-C), 128.21 (Ph-C), 128.24 (Ph-C), 128.28 (2 Ph-
C), 129.3 (2 Ph-C), 139.6/144.9 (2 quart. Ph-C), 209.0 (C-4) ppm.
C21H23NO3 (337.4): calcd. C 74.75, H 6.87, N 4.15; found C 74.37,
Diastereomeric mixture anti-36 and syn-36 (200 mg) was separated
by preparative HPLC: column RP18 Gemini 5 µm (Phenomenex),
250 mmϫ21.2 mm, room temperature., flow 20 mL/min, mobile
phase acetonitrile/water = 6:4 + 0.1% N,N-dimethylethylamine, de-
tection at λ = 220 nm, injection volume 400 µL (c = 50 mg/mL), 10
runs. The fractions containing anti-36 and syn-36 were combined,
respectively, a saturated solution of NaHCO3 and solid NaCl were
added, and the mixture was extracted with EtOAc (3ϫ). The com-
bined organic layer was dried (K2CO3), filtered, and concentrated
in vacuo, and the residues were purified by fc, respectively (2 cm;
n-hexane/EtOAc, 7:3; 10 mL; Rf = 0.26).
anti-36: Colorless oil, “yield” 117 mg (59%). IR (neat): ν = 3060
˜
(w, C=C–H), 2929 (w, C–H), 1711 (s, C=O), 1090 (s, C–O–C), 747
(m)/732 (m, Aryl–C–H), 708 (s)/696 (s, out-of-plane) cm–1 1H
.
NMR (CDCl3): δ = 1.22–1.31 (m, 1 H, CH2CH2O-), 2.25–2.38 (m,
Eur. J. Org. Chem. 2008, 6015–6028
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6025

M. Sax, R. Fröhlich, D. Schepmann, B. Wünsch
FULL PAPER
H 6.94, N 3.97. MS (70 eV): m/z (%) = 260 (6) [M – Ph]+, 239 (2-
H, 6-H), 3.44 (d, J = 14.0 Hz, 1 H, PhCH2), 3.88 (d, J = 13.8 Hz,
diphenyl-1,3-dioxan-4-yl, 10) [2], 167 (28) [Ph2CH], 98 (100) [M – 1 H, PhCH2), 3.92 (td, J = 11.8, 3.9 Hz, 1 H, OCH2), 4.06 (ddd, J
diphenyldioxanyl = piperidin-4-on-2-yl].
= 11.3, 4.9, 1.3 Hz, 1 H, OCH2), 4.41 (ddd, J = 11.5, 5.1, 1.9 Hz,
1 H, OCH), 7.17–7.34 (m, 9 H, Ph), 7.42 (t, J = 7.6 Hz, 2 H, para-
benzophenone-H), 7.48–7.53 (m, 2 H, ortho-benzophenone-H),
7.56–7.61 (m, 2 H, ortho-benzophenone-H) ppm. 13C NMR
(CDCl3): δ = 21.5 (C-4), 23.2 (C-3 + C-5), 23.8 (OCH2CH2), 50.5
(C-6), 56.8 (PhCH2), 60.0 (OCH2), 62.1 (C-2), 68.3 (OCH), 99.7
(OCO), 123.5 (2 Ph-C), 124.7 (1 Ph-C), 125.6 (2 Ph-C), 125.7 (1
Ph-C), 125.9 (1 Ph-C), 126.0 (2 Ph-C), 126.2 (2 Ph-C), 126.6 (2 Ph-
C), 126.9 (2 Ph-C), 138.0/138.5 (2 quart. benzophenone-C), 143.2
(quart. PhCH2-C) ppm. C28H31NO2 (413.6): calcd. C 81.32, H 7.56,
N 3.39; found C 80.77, H 7.57, N 3.71. MS (70 eV): m/z (%) = 336
(3) [M – Ph]+, 174 (100) [M – diphenyldioxane = N-benzylpiper-
idin-2-yl], 91 (84) [PhCH2].
syn-37: (Rf = 0.08): Colorless solid, m.p. 144 °C (decomp.). Yield:
190 mg (34%). IR (neat): ν = 3339 (w, N–H), 3060 (w, C=C–H),
˜
1711 (s, C=O), 1101 (s, C–O–C), 748 (m, aryl–C–H), 707 (m)/696
cm–1. (m, out-of-plane). 1H NMR (CDCl3): δ = 1.33 (dq, J = 12.8,
1.7 Hz, 1 H, OCH2CH2,eq), 2.01 (qd, J = 12.3, 5.2 Hz, 1 H, OCH2-
CH2,ax), 2.10 (br. s, 1 H, NH), 2.29–2.42 (m, 3 H, 1ϫ3-H and
2ϫ5-H), 2.50 (ddd, J = 13.9, 3.0, 1.6 Hz, 1 H, 3-H), 2.86 (td, J =
12.0, 4.3 Hz, 1 H, 6-H), 3.00 (dt, J = 11.4, 3.6 Hz, 1 H, 2-H), 3.40
(ddd, J = 12.6, 6.2, 2.4 Hz, 1 H, 6-H), 3.91–3.99 (m, 2 H, OCH
and OCH2), 4.01–4.08 (m, 1 H, OCH2), 7.12–7.25 (m, 4 H, Ph-H),
7.32–7.39 (m, 4 H, Ph-H), 7.43–7.46 (m, 2 H, Ph-H) ppm. 13C
NMR (CDCl3): δ = 26.6 (OCH2CH2), 43.4 (C-5), 44.5 (C-3), 45.9
(C-6), 61.1 (C-2), 61.6 (OCH2), 73.0 (OCH), 101.8 (OCO), 125.6
(2 Ph-C), 127.8 (2 Ph-C), 128.18 (Ph-C), 128.23 (Ph-C), 128.27 (2
Ph-C), 129.2 (2 Ph-C), 139.7/144.9 (2 quart. Ph-C), 209.5 (C-4)
ppm. C21H23NO3 (337.4): calcd. C 74.75, H 6.87, N 4.15; found C
74.52, H 6.92, N 4.16. MS (70 eV): m/z (%) = 260 (6) [M –
Ph]+, 239 (2-diphenyl-1,3-dioxan-4-yl, 13) [2], 238 (2-diphenyl-4H-
1,3-dioxin, 15) [2], 183 (25) [Ph2CHO], 105 (59) [PhCO], 98 (100)
[M – diphenyldioxanyl = piperidin-4-on-2-yl].
(2RS)-2-[(4RS)-2,2-Diphenyl-1,3-dioxan-4-yl]piperidine
(anti-39):
To a solution of anti-38 (118.1 mg, 0.29 mmol) dissolved in dry
MeOH (6 mL) was added 10% Pd/C (43.3 mg), and the suspension
was vigorously stirred under an H2 atmosphere (balloon) at room
temperature for 1 h. The reaction mixture was filtered through Ce-
lite, which was rinsed with MeOH several times, the filtrate was
concentrated in vacuo, and the residue was purified by fc (2 cm;
EtOAc/MeOH/NH3conc, 94:5:1; 10 mL; Rf = 0.27). Colorless oil,
which crystallized upon standing at 4 °C, m.p. 107.3 °C. Yield:
(2RS)-1-Benzyl-2-[(4RS)-2,2-diphenyl-1,3-dioxan-4-yl]piperidine
(anti-38) and (2RS)-1-Benzyl-2-[(4SR)-2,2-diphenyl-1,3-dioxan-4-yl]-
piperidine (syn-38): To a solution of benzylpiperidinone 36 (mixture
of anti-36 and syn-36, 1.09 g, 2.54 mmol) dissolved in dry MeOH
(50 mL) was added p-toluenesulfonylhydrazide (947 mg,
5.08 mmol), and the mixture was heated to reflux for 2 h. After
cooling down, NaBH4 (961.6 mg, 25.4 mmol) was added, and the
mixture was heated at reflux for 6 h. After cooling down, MeOH,
Et2O, and a saturated solution of NaHCO3 were added. The
formed precipitate was dissolved by addition of water and Et2O.
The organic layer was separated, and the aqueous layer was ex-
tracted with Et2O (2ϫ). The organic layer was dried (K2CO3), fil-
tered, and concentrated in vacuo, and the residue was purified by
fc (7.5 cm; n-hexane/EtOAc, 8:2; 40 mL).
89.7 mg (97%). IR (neat): ν = 3337 (w, NH), 3059 (w, C=C–H),
˜
2930 (s, C–H), 1195 (s)/1098 (s, C–O), 745 (m, aryl–C–H), 705 (s)/
1
694 (s, out-of-plane) cm–1. H NMR (CDCl3): δ = 1.17–1.45 (m, 4
H, 3-H and 4-H and 5-H and OCH2CH2,eq), 1.50–1.60 (m, 1 H, 5-
H), 1.75–1.84 (m, 2 H, 3-H and 4-H), 2.01 (qd, J = 12.4, 5.2 Hz, 1
H, OCH2CH2,ax), 2.09 (br. s, 1 H, NH), 2.60 (td, J = 11.8, 2.7 Hz,
1 H, 6-H), 2.68 (ddd, J = 10.7, 4.9, 2.1 Hz, 1 H, 2-H), 3.03–3.10
(m, 1 H, 6-H), 3.77 (ddd, J = 11.7, 5.0, 2.4 Hz, 1 H, OCH), 3.91
(td, J = 11.9, 2.5 Hz, 1 H, OCH2), 4.02 (ddd, J = 11.4, 5.1, 1.5 Hz,
1 H, OCH2), 7.10–7.24 (m, 4 H, Ph-H), 7.32 (t, J = 7.6 Hz, 2 H,
para-Ph-H), 7.38–7.48 (m, 4 H, Ph-H) ppm. 13C NMR (CDCl3): δ
= 24.7 (C-4), 26.7 (OCH2CH2 and C-5), 28.1 (C-3), 47.2 (C-6), 60.6
(C-2), 61.8 (OCH2), 74.0 (OCH), 101.5 (OCO), 125.6 (2 Ph-C),
127.8 (2 Ph-C), 127.95 (Ph-C), 127.97 (Ph-C), 128.2 (2 Ph-C), 129.1
(2 Ph-C), 140.2/145.3 (2 quart. Ph-C) ppm. C21H25NO2 (323.4):
calcd. C 77.99, H 7.79, N 4.33; found C 77.50, H 7.73, N 4.71. MS
(70 eV): m/z (%) = 323 (0.6) [M]+, 124 (14) [2-allylpiperidinyl], 84
(100) [M – diphenyldioxanyl = piperidin-2-yl].
anti-38: (Rf = 0.36): Colorless oil. Yield: 141 mg (13%). IR (neat):
ν = 3060 (w, C=C–H), 2929 (s, C–H), 1095 (s, C–O), 743 (m, Aryl–
˜
1
C–H), 705 (m)/694 (s, out-of-plane) cm–1. H NMR (CDCl3): δ =
1.22–1.35 (m, 1 H, 5-H), 1.44–1.63 (m, 3 H, 4-H and 5-H and
OCH2CH2), 1.65–1.79 (m, 3 H, 2ϫ3-H and 4-H), 1.87 (qd, J =
12.4, 5.1 Hz, 1 H, OCH2CH2), 2.19–2.27 (m, 1 H, 6-H), 2.53–2.60
(m, 1 H, 2-H), 2.64–2.72 (m, 1 H, 6-H), 3.43 (d, J = 13.9 Hz, 1 H,
PhCH2), 3.97 (td, J = 11.8, 2.3 Hz, 1 H, OCH2), 4.02–4.16 (m, 3
H, PhCH2 and OCH and OCH2), 7.06–7.31 (m, 11 H, Ph), 7.40–
7.49 (m, 4 H, ortho-benzophenone-H) ppm. 13C NMR (CDCl3): δ
= 19.8 (C-5), 20.8 (C-4), 21.0 (C-3), 26.2 (OCH2CH2), 47.9 (C-6),
55.3 (PhCH2), 60.2 (OCH2), 61.3 (C-2), 69.0 (OCH), 99.4 (OCO),
123.2 (2 Ph-C), 124.7 (1 Ph-C), 125.5 (2 Ph-C), 125.6 (1 Ph-C),
125.7 (1 Ph-C), 126.1 (2 Ph-C), 126.2 (2 Ph-C), 126.6 (2 Ph-C),
126.9 (2 Ph-C), 138.4/138.7 (2 quart. benzophenone-C), 143.3
(quart. PhCH2-C) ppm. C28H31NO2 (413.6): calcd. C 81.32, H 7.56,
N 3.39; found C 80.87, H 7.56, N 3.38. MS (70 eV): m/z (%) = 336
(4) [M – Ph]+, 174 (100) [M – diphenyldioxane = N-benzylpiper-
idin-2-yl], 91 (99.6) [PhCH2].
(2RS)-2-[(4SR)-2,2-Diphenyl-1,3-dioxan-4-yl]piperidine (syn-39): To
a solution of syn-39 (90.2 mg, 0.22 mmol) dissolved in dry MeOH/
THF (5:1, 6 mL) was added 10% Pd/C (37 mg), and the suspension
was vigorously stirred under an H2 atmosphere (balloon) at room
temperature for 1.5 h. The reaction mixture was filtered through
Celite, which was rinsed with MeOH several times, the filtrate was
concentrated in vacuo, and the residue was purified by fc (2 cm;
EtOAc/MeOH/NH3conc, 94:5:1; 10 mL; Rf = 0.37). Colorless oil,
which crystallized upon standing at 4 °C, colorless solid, m.p.
143.7 °C. Yield: 67.4 mg (95%). IR (neat): ν = 3335 (m, N–H),
˜
3054 (w, C=C–H), 2933 (s)/2909 (s, C–H), 1197 (s)/1092 (s)/1006
(s, C–O), 759 (s, aryl–C–H), 705 (m)/695 (s, out-of-plane) cm–1. 1H
NMR (CDCl3): δ = 1.08 (qd, J = 12.1, 3.7 Hz, 1 H, 3-H), 1.27
(qt, J = 12.7, 4.0 Hz, 1 H, 4-H), 1.37 (dq, J = 12.9, 2.2 Hz, 1 H,
OCH2CH2,eq), 1.40–1.60 (m, 3 H, 3-H und 2ϫ5-H), 1.71–1.80 (m,
1 H, 4-H), 1.81 (qd, J = 12.3, 5.3 Hz, 1 H, OCH2CH2,ax), 2.53–
syn-38: (Rf = 0.27): Colorless oil. Yield: 123.6 mg (12%). IR (neat):
ν = 3060 (w, C=C–H), 2931 (s, C–H), 1196 (s)/1101 (s)/1025 (s, C– 2.62 (m, 3 H, 2-H and 6-H and NH), 3.06–3.13 (m, 1 H, 6-H), 3.76
˜
O), 745 (m)/731 (m, aryl–C–H), 705 (s)/695 (s, out-of-plane) cm–1.
1H NMR (CDCl3): δ = 1.26–1.74 (m, 6 H, 3-H and 2ϫ4-H and
2ϫ5-H and OCH2CH2), 1.99–2.11 (m, 2 H, 3-H and OCH2CH2),
(ddd, J = 11.4, 7.9, 2.7 Hz, 1 H, OCH), 3.91 (td, J = 12.0, 2.6 Hz,
1 H, OCH2), 4.00 (ddd, J = 11.5, 5.3, 1.4 Hz, 1 H, OCH2), 7.10–
7.23 (m, 4 H, Ph-H), 7.33 (t, J = 7.7 Hz, 2 H, para-Ph-H), 7.39–
2.15–2.25 (m, 1 H, 6-H), 2.64–2.71 (m, 1 H, 2-H), 2.85–2.92 (m, 1 7.43 (m, 2 H, Ph-H), 7.47–7.49 (m, 2 H, Ph-H) ppm. 13C NMR
6026
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6015–6028

Ring and Side Chain Homologues of Dexoxadrol
(CDCl3): δ = 24.6 (C-4), 26.2 (C-5), 27.4 (C-3), 27.8 (OCH2CH2),
47.0 (C-6), 61.4 (OCH2), 62.0 (C-2), 74.2 (OCH), 101.4 (OCO),
125.6 (2 Ph-C), 127.9 (2 Ph-C), 127.94 (Ph-C), 127.97 (Ph-C), 128.2
(2 Ph-C), 129.2 (2 Ph-C), 140.0/145.3 (2 quart. Ph-C) ppm.
C21H25NO2 (323.4). MS (70 eV): m/z (%) = 246 (7) [M – Ph]+, 105
(10) [PhCO], 84 (100) [M – diphenyldioxanyl = piperidin-2-yl]. Pu-
rity by HPLC. Method 1: stationary phase: RP18 Supersphere
(Merck), mobile phase: methanol/water = 7:3, flow 0.8 mL/min,
volume of injection 10 µL (c = 2 mg/mL), T = 20 °C, λ = 220 nm:
tR = 19.7 min, purity 94.6%. Method 2: stationary phase: RP18
Gemini 5 µm, (Phenomenex), mobile phase: acetonitrile/water =
6:4 + 0.1% of N,N-dimethylethylamine, flow 1.0 mL/min, volume
pended in buffer, the protein concentration was determined accord-
ing to the method of Bradford[43] by using bovine serum albumin
as standard, and subsequently the preparation was frozen (–83 °C)
in 1.5 mL portions containing about 0.8 mg of protein/mL.
Performing of the NMDA Assay:[31] The test was performed with
the radioligand [3H]-(+)-MK–801 (22.0 Ci/mmol; Perkin–Elmer).
The thawed membrane preparation (about 100 µg of the protein)
was incubated with various concentrations of test compounds,
2 nM [3H]–(+)–MK–801, and TRIS/EDTA-buffer (5 m/1 m, pH
7.5) in a total volume of 200 µL for 180 min at room temperature.
The incubation was terminated by rapid filtration through the pre-
soaked filtermats by using the cell harvester. After washing each
well with water (5ϫ1300 µL), the filtermats were dried at 95 °C.
Subsequently, the solid scintillator was placed on the filtermat and
melted at 95 °C. After 5 min, the solid scintillator was allowed to
solidify at room temperature. The bound radioactivity trapped on
the filters was counted in the scintillation analyzer. The nonspecific
binding was determined with 10 µ (+)–MK–801. The Kd value of
the radioligand [3H]-(+)-MK-801 is 2.26 nM.
of injection 15 µL (c = 10 mg/mL), T = 20 °C, λ = 248 nm: tR
=
13.0 min, purity = 94.6%.
X-ray Crystal Structure Determination: Data set was collected with
a Nonius KappaCCD diffractometer, equipped with a rotating an-
ode generator. Programs used: data collection COLLECT,[36] data
reduction Denzo-SMN,[37] absorption correction SORTAV,[38,39]
structure solution SHELXS-97,[39] structure refinement SHELXL-
97,[40] graphics SCHAKAL.[41] Data for anti-14: Formula
C22H25NO3, M = 351.43, colorless crystal 0.40ϫ0.30ϫ0.25 mm,
a = 15.784(1) Å, b = 8.310(1) Å, c = 14.109(1) Å, β = 93.33(1)°, V
= 1847.5(3) Å3, ρcalcd. = 1.263 gcm–3, µ = 0.084 mm–1, empirical
absorption correction (0.967ՅTՅ0.979), Z = 4, monoclinic, space
group P21/c (No. 14), λ = 0.71073 Å, T = 198(2) K, ω and φ scans,
10905 reflections collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] = 0.66 Å–1, 4389
Determination of the σ1 and σ2 Receptor Affinity: The receptor
preparations for the σ1 (guinea pig brains) and σ2 (rat liver) assays
were obtained as described in the literature. The assays were per-
formed according to ref.[31,34]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and analytical and spectroscopic data of
compounds 16–18, 20, 24–26, 28, 29, 32, 33, and 35 and those of
enantiomerically pure compounds (S)-16, (S)-18, (S,S)-20, (R,S)-
20, (S,S)-21, (S,R)-21, (S,S)-22, and (R,S)-22.
independent (Rint
= 0.044) and 3050 observed reflections
[IՆ2σ(I)], 240 refined parameters, R = 0.046, wR2 = 0.121, max.
(min.) residual electron density 0.21 (–0.19) eÅ–3, hydrogen atoms
calculated and refined as riding atoms. CCDC-693633 contains the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
We are grateful to Degussa AG, Janssen-Cilag GmbH, and Bristol-
Myers Squibb for donation of chemicals and reference compounds.
Receptor Binding Studies
Materials and General Procedures: Homogenizer: Elvehjem Potter
(B. Braun Biotech International). Centrifuge: High-speed cooling
centrifuge model Sorvall RC-5C plus (Thermo Finnigan). Filter:
Printed Filtermat Typ B (Perkin–Elmer), presoaked in 0.5%
aqueous polyethylenimine for 2 h at room temperature before use.
The filtration was carried out with a MicroBeta FilterMate-96 Har-
vester (Perkin–Elmer). The scintillation analysis was performed by
using Meltilex (Typ A) solid scintillator (Perkin–Elmer). The solid
scintillator was melted on the filtermat at a temperature of 95 °C
for 5 min. After solidification of the scintillator at room tempera-
ture, the scintillation was measured by using a MicroBeta Trilux
scintillation analyzer (Perkin–Elmer). The counting efficiency was
40%. All experiments were carried out in triplicates by using stan-
dard 96-well-multiplates (Diagonal). The IC50 values were deter-
mined in competition experiments with six concentrations of the
test compounds and were calculated with the program GraphPad
Prism® 3.0 (GraphPad Software) by nonlinear regression analysis.
The Ki values were calculated according to Cheng and Prusoff[42]
and are given as mean value + SEM from three independent experi-
ments.
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Received: July 22, 2008
Published Online: October 31, 2008
6028
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6015–6028