Stereoselective synthesis of (2S,3R)- and (2R,3S)-iodoreboxetine; Potential SPECT imaging agents for the noradrenaline transporter

Article abstract of DOI:10.1039/b802819b

With the aim of developing a new SPECT imaging agent for the noradrenaline transporter, a twelve-step stereoselective synthesis of iodinated analogues of (2S,3R)- and (2R,3S)-reboxetine has been achieved from 4-bromobenzaldehyde. The key steps involve a S

Full text of DOI:10.1039/b802819b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereoselective synthesis of (2S,3R)- and (2R,3S)-iodoreboxetine; potential
SPECT imaging agents for the noradrenaline transporter†
Nicola K. Jobson,a Rosemary Spike,b Andrew R. Crawford,b Deborah Dewar,b Sally L. Pimlottc and
Andrew Sutherland*a
Received 19th February 2008, Accepted 25th March 2008
First published as an Advance Article on the web 30th April 2008
DOI: 10.1039/b802819b
With the aim of developing a new SPECT imaging agent for the noradrenaline transporter, a
twelve-step stereoselective synthesis of iodinated analogues of (2S,3R)- and (2R,3S)-reboxetine has
been achieved from 4-bromobenzaldehyde. The key steps involve a Sharpless asymmetric epoxidation
to establish the stereogenic centres and a copper catalysed aromatic halogen exchange reaction to
introduce the key iodine atom. In vitro testing of these compounds using a [3H]nisoxetine displacement
assay with homogenised rat brain shows both compounds to have significant affinity, with Ki values of
320.8 nM and 58.2 nM for (2S,3R)- and (2R,3S)-iodoreboxetine respectively.
and Tamagnan have recently designed and synthesised a range of
Introduction
iodinated analogues of 1 for the SPECT imaging of NAT.8,9 Testing
The noradrenaline transporter (NAT) is a transmembrane protein
located at the pre-synaptic terminal of noradrenergic neurons. The
of these compounds showed one compound in particular, iodo-
analogue 2 to have excellent affinity (Ki 2.47 nM), good selectivity
and significant potential as an imaging agent for NAT.9
principal physiological function of NAT is to regulate the amount
of noradrenaline in the synaptic cleft via a re-uptake mechanism.1,2
A change in the level of noradrenaline in the synapse results in a
down-regulation in the level of NAT within the brain.3 NAT has
been implicated in the patho-physiology of numerous neuropsy-
chiatric and neurodegenerative disorders including depression,
attention-deficit/hyperactivity disorder, anxiety and Alzheimer’s
disease.4–7
To further probe the link between NAT and these disorders
requires the development of a specific radioligand which could
be used in association with single photon emission computed
tomography (SPECT) or positron emission tomography (PET)
for the non-invasive imaging of the receptor. Such a radioligand
could be used to image changes in NAT density in vivo, resulting
in a better understanding of these neuropsychiatric and neurode-
generative disorders. To achieve this goal a number of studies
have investigated the radioiodination of compounds known to
have high affinity with NAT for in vivo SPECT imaging.8–10
A
typical compound used in such studies is reboxetine, the well-
known, selective noradrenaline re-uptake inhibitor.11 Reboxetine
is commercially available under the names Edronax, Prolift, Vestra
and Norebox for the treatment of depressive disorder and, while
the drug is marketed as a racemic mixture of (2R,3R)- and (2S,3S)-
enantiomers, it is (2S,3S)-reboxetine 1 that has the best affinity and
selectivity for NAT.12 Using this information, the groups of Saji
While much research has been done to develop SPECT imaging
agents based on (2S,3S)- and (2R,3R)-reboxetine, there have been
no reports of investigations using the (2S,3R)- and (2R,3S)-
stereoisomers. Moreover, little is known about the pharmacology
of these stereoisomers of reboxetine. In this paper, we report the
first stereoselective synthesis of iodinated analogues of (2S,3R)-
and (2R,3S)-reboxetine (3 and 4), compounds which could be
easily radioiodinated and used for SPECT imaging. We also report
preliminary biological data showing the high affinity of these
compounds for NAT.13
aWestChem, Department of Chemistry, The Joseph Black Building, Univer-
sity of Glasgow, Glasgow, UK G12 8QQ. E-mail: andrews@chem.gla.ac.uk;
Fax: +44 (0)141 330 4888; Tel: +44 (0)141 330 5936
bDivision of Clinical Neuroscience, Faculty of Medicine, University of
Glasgow, UK G12 8QQ
Results and discussion
cWest of Scotland Radionuclide Dispensary, University of Glasgow and North
Glasgow University Hospital NHS Trust, Glasgow, UK G11 6NT
A number of approaches have been developed for the preparation
of single stereoisomers of reboxetine analogues, including resolu-
tion of enantiomers, the use of the chiral pool and catalytic asym-
metric methods.14 Our approach to these compounds is shown
† Electronic Supplementary Information (ESI) available: 1H and 13C
NMR spectra for compounds 7, 6, 12, 13, 5, 14 and 3. See DOI:
10.1039/b802819b
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in Scheme 1. It was proposed that the key stereogenic centres
of analogue 3 could be created by the synthesis of an E-allylic
alcohol from 4-bromobenzaldehyde 9 which, following a Sharpless
asymmetric epoxidation, would give epoxide 8. Regioselective
ring-opening of 8 with 2-ethoxyphenol would give diol 7 and
subsequent selective functionalisation of the primary hydroxyl
would give amino alcohol 6. This would then be used to synthesise
the morpholine ring and a halogen exchange reaction would allow
incorporation of the key iodine atom to give the first target,
(2S,3R)-iodoreboxetine 3. We believed that such an approach
would also allow the preparation of the (2R,3S)-stereoisomer 4
by using the opposite enantiomer of diisopropyl tartrate during
the Sharpless asymmetric epoxidation step.
Scheme 2 Reagents and conditions: i. triethyl phosphonoacetate, DBU,
LiCl, MeCN, 100%; ii. DIBAL-H (2.2 eq.), Et2O, −78 ◦C to RT,
i
˚
100%; iii. (+)-DIPT, Ti(O Pr)4, t-BuOOH, 4A mol. sieves, CH2Cl2, 79%;
iv. 2-ethoxyphenol, NaOH (aq.), 70 ◦C, 67%; v. TsCl, Et3N, DMAP (cat.),
Et2O, 82%; vi. 25% NH3 (aq.), MeCN, 49%.
in 83% yield and this was then treated with sodium tert-butoxide
to give morpholinone 13 in 79% yield.14a Reduction of 13 under
mild conditions using borane·THF gave the corresponding amine
in 73% yield and this was subsequently Boc-protected, which
gave 5 in 75% yield. The last stage of the synthesis required the
introduction of the key iodine atom and this was achieved using a
copper catalysed aromatic halogen exchange reaction, previously
described by Klapars and Buchwald.17 Thus, reaction of bromide
5 with sodium iodide, 1,3-diaminopropane and catalytic amounts
of copper iodide gave iodide 14 in 49% yield. Finally, deprotection
of the amino group using TFA gave (2S,3R)-iodoreboxetine 3 in
57% yield.
Having developed a synthetic route to (2S,3R)-iodoreboxetine
Scheme 1
3, the second target compound, (2R,3S)-iodoreboxetine
4
The first stage of the synthesis of 3 involved the preparation
of amino alcohol 6 (Scheme 2). 4-Bromobenzaldehyde 9 was
subjected to a Horner–Wadsworth–Emmons reaction with triethyl
phosphonoacetate under Masamune–Roush conditions, which
gave E-a,b-unsaturated ester 10 in quantitative yield.15 Reduction
of 10 using DIBAL-H gave E-allylic alcohol 11, again in quantita-
tive yield, and this underwent a Sharpless asymmetric epoxidation
with (+)-diisopropyl tartrate to give known epoxide 8 in 79% yield
and >98% ee.16 Introduction of the 2-ethoxyphenol group was
achieved by regioselective ring-opening of epoxide 8 with the
sodium salt of 2-ethoxyphenol, which gave diol 7 in 67% yield.
Selective activation of the primary alcohol with p-toluenesulfonyl
chloride and triethylamine gave the corresponding tosylate in 82%
yield, and this was reacted with an aqueous solution of ammonia
which gave amino alcohol 6 in a modest 49% yield.
was synthesised using the same approach. Thus, allylic al-
cohol 11 was subjected to a Sharpless asymmetric epoxi-
dation using (−)-diisopropyl tartrate to give (2R,3R)-[3-(4-
bromophenyl)oxiranyl]methanol 15 in 79% yield and this was
converted to (2R,3S)-iodoreboxetine 4 in the same nine-step
sequence as described for the (2S,3R)-stereoisomer 3 (Scheme 4).
During the preparation of the second stereoisomer 4, attempts
were made to optimise some of the steps. For example, during
the synthesis of 3, iodination using 1,3-diaminopropane as a
ligand for the copper iodide catalysed halogen exchange reaction
required a reaction time of 48 hours at 130 ◦C and only gave the
iodide 14 in 49% yield after substantial purification. However, on
screening a range of diamine ligands, we found the use of N,Nꢀ-
dimethylethylenediamine to be more useful, allowing the reaction
to be carried out in 24 hours at 120 ◦C, giving the corresponding
iodide more cleanly in 52% yield.17,18
Amino alcohol 6 was then converted to the desired (2S,3R)-
iodoreboxetine 3 in a six-step sequence (Scheme 3). Acetylation
of the amino group with chloroacetyl chloride gave compound 12
On successful preparation of both stereoisomers, these were
tested with homogenised rat brain using a [3H]nisoxetine
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Table 1 Binding affinity of reboxetine analogues with NAT
Entry
Compound
Ki/nMa
6.9 1.6
320.8 9.0
58.2 9.4
1
2
3
rac-1
3
4
a Ki values are the mean of 3 separate determinations.
NAT, with the (2R,3S)-stereoisomer 4 the most potent, with a
Ki value of 58.2 nM. While the iodinated (2S,3R)- and (2R,3S)-
compounds do not have the same level of affinity as the parent
compound, reboxetine, the (2R,3S)-iodo compound 4 in particu-
lar, still retains similar levels of affinity compared to the racemic
mixtures of iodinated (2S,3S)-and (2R,3R)-analogues previously
prepared.9 Thus, these results show that, the development of more
potent iodo-analogues around a (2R,3S)-morpholine backbone
may yield compounds that can act as effective SPECT imaging
agents for NAT.
Conclusions
In summary, we have developed a twelve-step synthesis of (2S,3R)-
and (2R,3S)-iodoreboxetine using a Sharpless asymmetric epoxi-
dation to establish the stereogenic centres, and a copper-mediated
aromatic halogen exchange reaction to incorporate the iodine
atom. Preliminary testing of these compounds shows the (2R,3S)-
compound 4 to be particularly potent, with similar levels of
affinity for the NAT in brain tissue to the more studied (2S,3S)-
and (2R,3R)-iodoreboxetine analogues. The work described here
represents the first generation of compounds from our study.
Work is currently underway on the synthesis of further analogues
of iodoreboxetine with the aim of discovering compounds with
greater affinity, for the eventual development of a SPECT imaging
agent for NAT.
Scheme 3 Reagents and conditions: i. chloroacetyl chloride, Et3N, MeCN,
83%; ii. sodium tert-butoxide, t-BuOH, 79%; iii. BH3·THF, THF, 73%;
iv. Boc2O, Et3N, DMAP (cat.), CH2Cl2, 75%; v. CuI (cat.), NaI, 1,3-di-
aminopropane (cat.), 1,4-dioxane, 49%; vi. TFA, CH2Cl2, 57%.
Experimental
All reactions were performed under a nitrogen atmosphere unless
otherwise noted. Reagents and starting materials were obtained
from commercial sources and used as received. THF and diethyl
ether were distilled from sodium and benzophenone. Lithium
chloride was oven dried (100 ◦C) for at least 12 h before use. Brine
refers to a saturated solution of sodium chloride. Flash column
chromatography was carried out using Fisher Matrex silica 60.
Macherey-Nagel aluminium backed plates pre-coated with silica
gel 60 (UV254) were used for thin layer chromatography and were
visualised by staining with KMnO4. 1H NMR and 13C NMR
spectra were recorded on a Bruker DPX 400 spectrometer with
chemical shift values in ppm relative to residual chloroform (dH
7.28 & dC 77.2) as standard. Infrared spectra were recorded using
sodium chloride plates on a JASCO FTIR 410 spectrometer and
mass spectra were obtained using a JEOL JMS-700 spectrometer.
Optical rotations were determined as solutions irradiating with
the sodium D line (k = 589 nm) using an AA series Automatic
polarimeter. [a]D Values are given in units 10−1 deg cm2 g−1.
Scheme 4 Reagents and conditions: i. (−)-DIPT, Ti(OiPr)4, t-BuOOH,
ꢀ
˚
4A mol. sieves, CH2Cl2, 79%; ii. CuI (cat.), NaI, N,N -dimethylethyl-
enediamine (cat.), 1,4-dioxane, 52%; iii. TFA, CH2Cl2, 57%.
displacement assay. Table 1 shows the Ki values for both com-
pounds along with racemic reboxetine, used as a standard. As can
be seen, both compounds 3 and 4 have substantial affinity with
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Ethyl (E)-4-bromocinnamate 1019
and the mixture stirred for 0.3 h. Dichloromethane (100 mL)
was added to the mixture and left to stir for a further 0.25 h.
The mixture was transferred to a separating funnel and the water
layer removed. The organic layer was dried (MgSO4) and filtered
Lithium chloride (2.7 g, 65 mmol) was dissolved in acetonitrile
(40 mL). 1,8-Diazobicyclo[5.4.0]undec-7-ene (9.7 mL, 65 mmol)
and triethyl phosphonoacetate (12.9 mL, 65 mmol) were added
sequentially with stirring. A solution of 4-bromobenzaldehyde
(10.0 g, 54 mmol) in acetonitrile (60 mL) was added and the
mixture was allowed to stir at room temperature for 18 h. The
reaction mixture was concentrated in vacuo and the resulting
residue dissolved in ethyl acetate (150 mL). The solution was then
washed with water (4 × 100 mL) and the organic layer dried
(MgSO4). The filtrate was concentrated in vacuo to give ethyl (E)-
4-bromocinnamate 10 as a yellow oil (13.7 g, 100%). dH (400 MHz,
CDCl3) 1.33 (3H, t, J 7.2 Hz, OCH2CH3), 4.27 (2H, q, J 7.2 Hz,
OCH2CH3), 6.42 (1H, d, J 16.0 Hz, 2-H), 7.36–7.40 (2H, m, 2 ×
Ar H), 7.49–7.53 (2H, m, 2 × Ar H), 7.61 (1H, d, J 16.0 Hz, 3-H);
dC (100 MHz, CDCl3) 14.3 (CH3), 60.7 (CH2), 119.0 (CH), 124.5
(C), 129.5 (2 × CH), 132.2 (2 × CH), 133.4 (C), 143.2 (CH), 166.8
(C); m/z (EI) 253.9939 (M+. C11H11O279Br requires 253.9942), 209
(89%), 183 (23), 181 (21), 102 (100).
R
through a pad of Celiteꢀ which was then washed with diethyl
ether. The yellow solution was concentrated in vacuo. Purification
was carried out by flash column chromatography and elution with
60 : 40 ethyl acetate–petroleum ether (40–60 ◦C) gave (2S,3S)-[3-
(4-bromophenyl)◦oxiranyl]methanol 8 as a colourless solid (2.55 g,
79%). Mp 61–62 C (from petroleum ether–ethyl acetate) lit.16 67–
68 ◦C (from hexane–ethyl acetate); [a]D22 −38.6 (c 1.0, CHCl3), lit.16
[a]2D5 −35.2 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 1.74 (1H, dd, J
7.8, 5.0 Hz, OH), 3.17 (1H, dt, J 3.6, 2.2 Hz, 2-H), 3.81 (1H, ddd,
J 12.8, 7.8, 3.6 Hz, 1-HH), 3.91 (1H, d, J 2.2 Hz, 3-H), 4.05 (1H,
ddd, J 12.8, 5.0, 2.2 Hz, 1-HH), 7.14–7.18 (2H, m, 2 × Ar H),
7.46–7.50 (2H, m, 2 × Ar H); dC (100 MHz, CDCl3) 54.9 (CH),
61.0 (CH2), 62.4 (CH), 122.0 (C), 127.4 (2 × CH), 131.7 (2 × CH),
134.9 (C); m/z (EI) 227.9787 (M+. C9H9O279Br requires 227.9786),
212 (10%), 185 (34), 89 (75), 83 (100).
(2E)-3-(4-Bromophenyl)prop-2-en-1-ol 1120
(2R,3R)-[3-(4-Bromophenyl)oxiranyl]methanol 1516
Ethyl (E)-4-bromocinnamate 10 (7.0 g, 27.5 mmol) was dis-
solved in diethyl ether (120 mL) and the solution cooled to
−78 ◦C. DIBAL-H (60.4 mL, 60.4 mmol) was added to the
solution dropwise. After 1 h, the reaction mixture was allowed
to warm to room temperature and left to stir for 18 h. The yellow
solution was cooled to 0 ◦C, before the reaction was quenched
using a saturated solution of ammonium chloride (30 mL). The
The reaction was carried out as described above except using (−)-
diisopropyl tartrate. On a 20 mmol scale this gave (2R,3R)-[3-(4-
bromophenyl)oxiranyl]methanol 15 (3.56 g, 79%) as a colourless
◦
solid. Mp 61–62 C (from petroleum ether–ethyl acetate) lit.16
67–68 ◦C (from hexane–ethyl acetate); [a]D22 +31.7 (c 1.0, CHCl3);
spectroscopic data as described for 8.
R
white solution was filtered through a pad of Celiteꢀ using diethyl
ether and the filtrate concentrated in vacuo. The white solid
was recrystallised using ethyl acetate–petroleum ether (40–60 ◦C)
to give (2E)-3-(4-bromophenyl)◦prop-2-en-1-ol 11 as a colourless
solid (5.8 g, 100%). Mp 63–65 C (from ethyl acetate), lit.20 63–
65 ◦C; dH (400 MHz, CDCl3) 1.48 (1H, t, J 6.0 Hz, OH), 4.33 (2H,
dt, J 6.0, 1.6 Hz, 1-H2), 6.36 (1H, dt, J 16.0, 1.6 Hz, 2-H), 6.56
(1H, d, J 16.0 Hz, 3-H), 7.23–7.28 (2H, m, 2 × Ar H), 7.42–7.47
(2H, m, 2 × Ar H); dC (100 MHz, CDCl3) 63.6 (CH2), 121.5 (C),
128.0 (2 × CH), 129.3 (CH), 129.8 (CH), 131.7 (2 × CH), 136.0
(C); m/z (EI) 211.9840 (M+. C9H9O79Br requires 211.9837), 133
(100%), 115 (46), 83 (80).
(2S,3R)-3-(4-Bromophenyl)-3-(2-ethoxyphenoxy)propane-1,2-
diol 7
2-Ethoxyphenol (1.10 g, 7.9 mmol) was added to an aqueous
sodium hydroxide solution (0.30 g, 6.6 mmol in 70 mL water) and
the mixture was heated to 70 ◦C until the solid had dissolved. After
1 h of stirring, (2S,3S)-[3-(4-bromophenyl)oxiranyl]methanol 8
(1.50 g, 6.6 mmol) was added and the mixture left to stir for
4 h. The flask was then allowed to cool to room temperature
and acidified to pH 2–3 using 2 M hydrochloric acid. The bulk
solvent was decanted and the remaining solid suspended in
water, and then extracted using dichloromethane (2 × 100 mL)
followed by ethyl acetate (3 × 100 mL). The organic layers were
combined, dried (MgSO4) and the filtrate concentrated in vacuo.
The solid was recrystallised from diethyl ether to give (2S,3R)-
3-(4-bromophenyl)-3-(2-ethoxyphenoxy)propane-1,2-diol 7 as a
colourless solid (1.50 g, 67%). Mp 77–78 ◦C (from diethyl ether);
(2S,3S)-[3-(4-Bromophenyl)oxiranyl]methanol 816
˚
Dichloromethane (150 mL) and activated 4 A molecular sieves
(3.0 g) were added to a round-bottomed flask and the solvent
cooled to −20 ◦C using an acetone–ice bath. (+)-Diisopropyl
tartrate (0.18 mL, 0.8 mmol) and titanium isopropoxide (0.2 mL,
0.7 mmol) were added sequentially with stirring. Anhydrous tert-
butyl hydroperoxide solution (3.2 mL, 35 mmol, 5.5 M in hexanes)
was added dropwise and the mixture was stirred at −20 ◦C for
0.5 h. A solution of (2E)-3-(4-bromophenyl)prop-2-en-1-ol 11
(3.0 g, 14 mmol) dissolved in dichloromethane (10 mL) was added
to the mixture dropwise over a period of 0.25 h. The mixture
was left to stir at −20 ◦C for 2.5 h. The flask was allowed to
warm to 0 ◦C and the reaction quenched using distilled water
(15 mL). The mixture was left to stir for 0.5 h while allowing
it to warm to room temperature. A solution of 30% sodium
hydroxide saturated with sodium chloride (75 mL) was added
mmax/cm−1 (NaCl) 3345 (OH), 2943 (CH), 1500 (C C), 1246, 732;
=
[a]2D2 −57.0 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 1.51 (3H, t, J
7.2 Hz, OCH2CH3), 3.13 (1H, dd, J 10.0, 3.4 Hz, 1-OH), 3.26 (1H,
d, J 8.0 Hz, 2-OH), 3.65 (1H, ddd, J 11.8, 10.0, 4.3, Hz, 1-HH),
3.84–3.89 (1H, m, 2-H), 3.95 (1H, dt, J 11.8, 3.4 Hz, 1-HH), 4.11
(2H, q, J 7.2 Hz, OCH2CH3), 5.22 (1H, d, J 4.3 Hz, 3-H), 6.59
(1H, dd, J 8.0, 1.6 Hz, 1 × Ar H), 6.71–6.75 (1H, m, 1 × Ar
H), 6.87–6.93 (2H, m, 2 × Ar H), 7.27–7.31 (2H, m, 2 × Ar H),
7.49–7.52 (2H, m, 2 × Ar H); dC (100 MHz, CDCl3) 14.8 (CH3),
62.1 (CH2), 64.2 (CH2), 74.2 (CH), 85.6 (CH), 112.5 (CH), 116.4
(CH), 120.8 (CH), 122.2 (C), 122.8 (CH), 128.2 (2 × CH), 131.9
(2 × CH), 137.1 (C), 146.8 (C), 149.2 (C); m/z (EI) 366.0465 (M+.
2372 | Org. Biomol. Chem., 2008, 6, 2369–2376
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C17H19O479Br requires 366.0467), 169 (11%), 138 (100), 110 (50),
83 (58), 47 (12).
(2-ethoxyphenoxy)-1-(toluenesulfonyloxy)propan-2-ol (2.42 g,
4.6 mmol). This gave (2R,3S)-1-amino-3-(4-bromophenyl)-3-(2-
ethoxyphenoxy)propan-2-ol as a colourless oil (0.97 g, 57%). [a]D22
+71.5 (c 1.1, CHCl3); spectroscopic data as described for 6.
(2R,3S)-3-(4-Bromophenyl)-3-(2-ethoxyphenoxy)propane-1,2-diol
The reaction was carried out as described above, using (2R,3R)-[3-
(4-bromophenyl)oxiranyl]methanol 15 (3.38 g, 14.8 mmol). This
gave (2R,3S)-3-(4-bromophenyl)-3-(2-ethoxyphenoxy)◦propane-
1,2-diol as a colourless solid (4.31 g, 79%). Mp 76–78 C (from
diethyl ether); [a]2D5 +64.6 (c 1.0, CHCl3); spectroscopic data as
described for 7.
(2S,3R)-1-Chloroacetylamino-3-(4-bromophenyl)-3-(2-
ethoxyphenoxy)propan-2-ol 12
(2S,3R)-1-Amino-3-(4-bromophenyl)-3-(2-ethoxyphenoxy)pro-
pan-2-ol 6 (0.15 g, 0.42 mmol) was dissolved in acetonitrile
(6.5 mL) and the mixture cooled to −10 ◦C using an acetone–
ice bath. Triethylamine (0.07 mL, 0.50 mmol) and chloroacetyl
chloride (0.04 mL, 0.46 mmol) were added sequentially and the
solution was allowed to stir at −10 ◦C for 1 h. The reaction
mixture was then warmed to room temperature and left to
stir for 18 h. The reaction mixture was concentrated in vacuo.
Purification was carried out by flash column chromatography
and elution with 50 : 50 ethyl acetate–petroleum ether (40–
60 ◦C) gave (2S,3R)-1-chloroacetylamino-3-(4-bromophenyl)-3-
(2-ethoxyphenoxy)propan-2-ol 12 as a colourless oil (0.15 g, 83%).
mmax/cm−1 (NaCl) 3423, 3020 (CH), 1660 (CO), 1215, 770; [a]2D2
−105.4 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 1.51 (3H, t, J 7.1 Hz,
OCH2CH3), 3.35 (1H, ddd, J 14.0, 7.4, 4.2 Hz, 1-HH), 3.73 (1H,
ddd, J 14.0, 7.2, 3.6 Hz, 1-HH), 3.98–4.00 (1H, m, 2-H), 4.03
(2H, s, CH2Cl), 4.12 (2H, q, J 7.1 Hz, OCH2CH3), 4.97 (1H, d, J
5.2 Hz, 3-H), 6.73–7.00 (4H, m, 4 × Ar H), 7.18 (1H, br s, NH),
7.33 (2H, d, J 8.4 Hz, 2 × Ar H), 7.52 (2H, d, J 8.4 Hz, 2 × Ar H);
dC (100 MHz, CDCl3) 14.9 (CH3), 41.9 (CH2), 42.6 (CH2), 64.5
(CH2), 73.1 (CH), 85.2 (CH), 113.4 (CH), 119.5 (CH), 121.2 (CH),
122.3 (C), 123.8 (CH), 128.8 (2 × CH), 131.8 (2 × CH) 137.0
(C), 147.2 (C), 149.9 (C), 166.9 (C); m/z (CI) 444.0399 (MH+.
C19H22O4N35Cl81Br requires 444.0400), 306 (100%), 304 (74), 226
(62), 192 (19), 139 (80).
(2S,3R)-1-Amino-3-(4-bromophenyl)-3-(2-ethoxyphenoxy)propan-
2-ol 6
(2S,3R)-3-(4-bromophenyl)-3-(2-ethoxyphenoxy)propane-1,2-diol
7 (0.55 g, 1.49 mmol) was dissolved in dichloromethane (50 mL)
and triethylamine (0.31 mL, 2.24 mmol), 4-dimethylamino-
pyridine (0.004 g, 0.04 mmol) and p-toluenesulfonyl chloride
(0.34 g, 1.79 mmol) were added sequentially with stirring.
The reaction mixture was stirred for 3 h before being diluted
with diethyl ether (20 mL) and washed with 2 M hydrochloric
acid (30 mL). The organic layer was dried (MgSO4) and the
filtrate concentrated in vacuo to give (2S,3R)-3-(4-bromophenyl)-
3-(2-ethoxyphenoxy)-1-(toluenesulfonyloxy)propan-2-ol as
a
colourless oil (0.64 g, 82%). (2S,3R)-3-(4-Bromophenyl)-3-
(2-ethoxyphenoxy)-1-(toluenesulfonyloxy)propan-2-ol (0.64 g,
1.23 mmol) was dissolved in acetonitrile (40 mL) and 25%
aqueous ammonia solution (50 mL) was added. The reaction
mixture was left to stir for 96 h in a sealed round-bottomed flask.
The acetonitrile was removed in vacuo and the aqueous solution
diluted with distilled water (100 mL). The aqueous solution was
then extracted with ethyl acetate (3 × 100 mL), dried (MgSO4)
and the filtrate concentrated in vacuo. Purification was carried
out by flash chromatography and elution with 90 : 10 ethyl
acetate–methanol gave (2S,3R)-1-amino-3-(4-bromophenyl)-3-
(2-ethoxyphenoxy)propan-2-ol 6 as a colourless solid (0.22 g,
(2R,3S)-1-Chloroacetylamino-3-(4-bromophenyl)-3-(2-
ethoxyphenoxy)propan-2-ol
◦
49%). Mp 60–62 C (from diethyl ether); mmax/cm−1 (neat) 3338,
The reaction was carried out as described above, using (2R,3S)-
1-amino-3-(4-bromophenyl)-3-(2-ethoxyphenoxy)propan-2-ol
(1.50 g, 4.10 mmol). This gave (2R,3S)-1-chloroacetylamino-3-(4-
bromophenyl)-3-(2-ethoxyphenoxy)propan-2-ol as a colourless oil
(1.11 g, 62%). [a]2D2 +114.6 (c 1.1, CHCl3); spectroscopic data as
described for 12.
22
=
3303, 2901 (CH), 2115, 1593 (C C); [a]D −68.8 (c 1.0, CHCl3); dH
(400 MHz, CDCl3) 1.47 (3H, t, J 7.0 Hz, OCH2CH3), 2.92 (1H,
dd, J 12.8, 4.6 Hz, 1-HH), 3.03 (1H, dd, J 12.8, 5.6 Hz, 1-HH),
3.99 (1H, m, 2-H), 4.06 (2H, q, J 7.0 Hz, OCH2CH3), 5.11 (1H,
d, J 4.6 Hz, 3-H), 6.63 (1H, dd, J 8.0, 1.4 Hz, 1 × Ar H), 6.72
(1H, dt, J 8.0, 1.4 Hz, 1 × Ar H), 6.85–6.93 (2H, m, 2 × Ar H),
7.27 (2H, d, J 8.2 Hz, 2 × Ar H), 7.47 (2H, d, J 8.2 Hz, 2 × Ar
H); dC (100 MHz, CDCl3) 14.7 (CH3), 42.3 (CH2), 64.3 (CH2),
74.4 (CH), 84.5 (CH), 113.2 (CH), 117.7 (CH), 120.9 (CH), 121.9
(C), 122.8 (CH), 128.7 (2 × CH), 131.5 (2 × CH), 137.8 (C), 147.2
(C), 149.7 (C); m/z (CI) 366.0699 (MH+ C17H21O3N79Br requires
366.0705), 365 (3%), 138 (100), 171 (12), 110 (77), 60 (14).
(2S,3R)-2-[(4-Bromobenzyl)-(2-ethoxyphenoxy)methyl]morpholin-
5-one 13
A solution of (2S,3R)-1-chloroacetylamino-3-(4-bromophenyl)-
3-(2-ethoxyphenoxy)propan-2-ol 12 (0.35 g, 0.79 mmol) in tert-
butanol (4 mL) was added dropwise to a solution of potassium tert-
butoxide (0.19 g, 2.0 mmol) in tert-butanol (1.0 mL) at 40 ◦C. The
reaction mixture was allowed to stir for 3 h at this temperature. The
solution was acidified to pH 2–3 by the addition of 2 M hydrochlo-
ric and then concentrated in vacuo. The residue was suspended
in water (50 mL) and the aqueous solution extracted with ethyl
acetate (3 × 50 mL), dried (MgSO4), and the filtrate concentrated
in vacuo. Purification was carried out by dry flash chromatog-
raphy and elution with 100% ethyl acetate gave (2S,3R)-2-[(4-
bromobenzyl)-(2-ethoxyphenoxy)methyl]morpholin-5-one 13 as a
(2R,3S)-1-Amino-3-(4-bromophenyl)-3-(2-ethoxyphenoxy)propan-
2-ol
The tosylation reaction was carried out as described above, using
(2R,3S)-3-(4-bromophenyl)-3-(2-ethoxyphenoxy)propane-1,2-
diol (3.26 g, 8.88 mmol). This gave (2R,3S)-3-(4-bromophenyl)-
3-(2-ethoxyphenoxy)-1-(toluenesulfonyloxy)propan-2-ol as
a
colourless oil (2.42 g, 44%). The aminolysis reaction was carried
out as described above using (2R,3S)-3-(4-bromophenyl)-3-
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colourless oil (0.25 g, 79%). mmax/cm−1 (NaCl) 3410 (NH), 3019
(CH), 2400, 1679 (CO), 1500, 1216; [a]2D5 −79.5 (c 0.6, CHCl3); dH
(400 MHz, CDCl3) 1.46 (3H, t, J 7.0 Hz, OCH2CH3), 3.66–3.80
(2H, m, 3-H2), 3.99–4.02 (1H, m, 2-H), 4.04–4.29 (4H, m, 6-H2,
OCH2CH3), 5.04 (1H, d, J 7.6 Hz, 2-CH), 6.27 (1H, br s, NH),
6.64–6.94 (4H, m, 4 × Ar H), 7.29–7.32 (2H, m, 2 × Ar H), 7.46–
7.51 (2H, m, 2 × Ar H); dC (100 MHz, CDCl3) 15.1 (CH3), 43.9
(CH2), 64.3 (CH2), 67.8 (CH2), 76.0 (CH), 81.5 (CH), 113.6 (CH),
118.4 (CH), 120.7 (CH), 122.4 (C), 123.2 (CH), 129.0 (2 × CH),
131.6 (2 × CH), 137.3 (C), 146.5 (C), 149.9 (C), 168.5 (C); m/z
(EI) 407.0562 (M+. C19H20O4N81Br requires 407.0558), 269 (73%),
267 (73), 171 (86), 169 (87), 138 (100).
(0.85 g, 2.1 mmol). This gave (2R,3S)-2-[(4-bromophenyl)-(2-
ethoxyphenoxy)methyl]morpholine as a colourless oil (0.09 g,
11%). [a]2D2 +46.8 (c 1.0, CHCl3); spectroscopic data as described
for 17.
(2S,3R)-2-[(4-Bromophenyl)-(2-ethoxyphenoxy)methyl]-N-tert-
butoxycarbonylmorpholine 5
(2S,3R)-2-[(4-Bromophenyl)-(2-ethoxyphenoxy)methyl]morpho-
line (0.14 g, 0.4 mmol) was dissolved in dichloromethane (3 mL).
Triethylamine (0.055 mL, 0.4 mmol), dimethylaminopyridine
(0.01 g, 0.07 mmol) and di-tert-butyl dicarbonate (0.09 g,
0.4 mmol) were added sequentially with stirring and the reaction
mixture allowed to stir at room temperature for 18 h. The reaction
mixture was concentrated in vacuo. Purification was carried out
using flash column chromatography and elution with 20 : 80
ethyl acetate–petroleum ether (40–60 ◦C) gave (2S,3R)-2-[(4-
bromophenyl)-(2-ethoxyphenoxy)methyl]-N-tert-butoxycarbo-
(2R,3S)-2-[(4-Bromobenzyl)-(2-ethoxyphenoxy)methyl]morpholin-
5-one
The reaction was carried out as described above, using
(2R,3S)-1-chloroacetylamino-3-(4-bromophenyl)-3-(2-ethoxyphe-
noxy)propan-2-ol (1.07 g, 2.42 mmol). This gave (2R,3S)-2-[(4-
bromobenzyl)-(2-ethoxyphenoxy)methyl]morpholin-5-one as a
colourless oil (0.89 g, 90%). [a]2D2 +80.0 (c 0.9, CHCl3);
spectroscopic data as described for 13.
nylmorpholine 5 as a colourless oil (0.13 g, 75%). mmax/cm−1
24
=
(NaCl) 2925 (CH), 1695 (CO), 1500 (C C), 1259, 1106; [a]D
−34.8 (c 0.5, CHCl3); dH (400 MHz, CDCl3) 1.44–1.47 (12H,
m, OCH2CH3, C(CH3)3), 2.94–3.00 (2H, m, 3-HH, 5-HH), 3.46
(1H, td, J 11.6, 2.8 Hz, 5-HH), 3.71–3.74 (1H, m, 2-H), 3.86
(2H, dd, J 11.6, 2.8 Hz, 6-H2), 3.97–4.06 (2H, m, OCH2CH3),
4.34 (1H, d, J 13.2 Hz, 3-HH), 5.02 (1H, br m, 2-CH), 6.70–6.91
(4H, m, 4 × Ar H), 7.30 (2H, d, J 8.4 Hz, 2 × Ar H), 7.45 (2H,
d, J 8.4 Hz, 2 × Ar H); dC (100 MHz, CDCl3) 14.0 (CH3), 27.4
(3 × CH3), 42.2 (CH2), 46.1 (CH2), 63.4 (CH2), 65.7 (CH2), 78.1
(CH), 79.0 (C), 81.7 (CH), 113.9 (CH), 117.2 (CH), 120.7 (CH),
121.0 (C), 121.6 (CH), 129.2 (2 × CH), 130.3 (2 × CH), 136.6
(C), 146.1 (C), 148.9 (C), 153.8 (C); m/z (EI) 491.1302 (M+.
C24H30O5N79Br requires 491.1307), 298 (90%), 254 (99), 138.0 (89),
57 (100).
(2S,3R)-2-[(4-Bromophenyl)-(2-ethoxyphenoxy)-
methyl]morpholine 17
(2S,3R)-2-[(4-Bromobenzyl)-(2-ethoxyphenoxy)methyl]morpho-
lin-5-one 13 (0.20 g, 0.5 mmol) was dissolved in THF (0.5 mL)
and the solution cooled to 0 ◦C. Borane·THF complex (1.10 mL,
1.1 mmol) was added to the solution dropwise with stirring. After
0.5 h, the solution was heated under reflux for 4 h. After cooling
in an ice bath, the excess borane was destroyed by the addition
of distilled water (1 mL) and the solution was concentrated
in vacuo. The residue was dissolved in 6 M hydrochloric acid
(5 mL) and allowed to stir for 0.25 h. The solution was then
concentrated in vacuo and the residue dissolved in 2 M sodium
hydroxide (5 mL). The aqueous solution was extracted using
chloroform (3 × 5 mL) and the organic layers combined, dried
(MgSO4), and the filtrate concentrated in vacuo to give (2S,3R)-2-
[(4-bromophenyl)-(2-ethoxyphenoxy)methyl]morpholine 17 as a
colourless oil (0.12 g, 73%). mmax/cm−1 (NaCl) 3413 (NH), 2925
(CH), 2345, 1638, 1593; [a]2D5 −67.5 (c 0.2, CHCl3); dH (400 MHz,
CDCl3) 1.45 (3H, t, J 7.0 Hz, OCH2CH3), 2.81–2.94 (3H, m, 5-H2,
3-HH), 3.37 (1H, br d, J 12.4 Hz, 3-HH), 3.53 (1H, td, J 11.2,
2.8 Hz, 6-HH) 3.75–3.80 (1H, m, 2-H), 3.86 (1H, br d, J 11.2 Hz,
6-HH), 4.05 (2H, q, J 7.0 Hz, OCH2CH3), 4.98 (1H, d, J 6.8 Hz,
2-CH), 6.64–6.89 (4H, m, 4 × Ar H), 7.29 (2H, d, J 8.4 Hz, 2 × Ar
H), 7.45 (2H, d, J 8.4 Hz, 2 × Ar H); dC (100 MHz, CDCl3) 15.1
(CH3), 44.6 (CH2), 46.4 (CH2), 64.4 (CH2), 66.5 (CH2), 78.1 (CH),
82.2 (CH), 113.7 (CH), 118.1 (CH), 120.7 (CH), 122.1 (C), 122.8
(CH), 129.1 (2 × CH), 131.5 (2 × CH), 137.5 (C), 146.9 (C), 149.9
(C); m/z (EI) 393.0756 (M+. C19H22O3N81Br requires 393.0765),
255 (86%), 253 (86), 169 (27), 86 (99), 84 (100).
(2R,3S)-2-[(4-Bromophenyl)-(2-ethoxyphenoxy)methyl]-N-tert-
butoxycarbonylmorpholine 16
The reaction was carried out as described above, using (2R,3S)-2-
[(4-bromophenyl)-(2-ethoxyphenoxy)methyl]morpholine (0.06 g,
0.18 mmol). This gave (2R,3S)-2-[(4-bromophenyl)-(2-ethoxy-
phenoxy)methyl]-N-tert-butoxycarbonylmorpholine 16 as
a
colourless oil (0.04 g, 53%). [a]2D6 +38.8 (c 1.1, CHCl3); spectro-
scopic data as described for 5.
(2S,3R)-2-[(4-Iodophenyl)-(2-ethoxyphenoxy)methyl]-N-tert-
butoxycarbonylmorpholine 14
A Schlenk tube was charged with copper iodide (0.001 g,
0.005 mmol) and sodium iodide (0.01 g, 0.14 mmol), and the
tube evacuated and back filled with argon. 1,3-Diaminopropane
(0.0005 g, 0.007 mmol) and (2S,3R)-2-[(4-bromophenyl)-
(2-ethoxyphenoxy)methyl]-N-tert-butoxycarbonylmorpholine
5
(0.03 g, 0.07 mmol) dissolved in 1,4-dioxane (1 mL) were added
under argon. The Schlenk tube was sealed using a Teflon valve
and the reaction mixture stirred at 130 ◦C for 48 h. The resulting
suspension was cooled to room temperature and diluted with
25% aqueous ammonia solution (2 mL) and poured onto water
(20 mL). The aqueous solution was washed with dichloromethane
(3 × 15 mL) and the organic layers combined, dried (MgSO4) and
(2R,3S)-2-[(4-Bromophenyl)-(2-ethoxyphenoxy)-
methyl]morpholine
The reaction was carried out as described above, using (2R,3S)-
2-[(4-bromobenzyl)-(2-ethoxyphenoxy)methyl]morpholin-5-one
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the filtrate concentrated in vacuo. Purification was carried out us-
ing column chromatography and elution with 20 : 80 ethyl acetate–
petroleum ether (40–60 ◦C) gave (2S,3R)-2-[(4-iodophenyl)-(2-
ethoxyphenoxy)methyl]-N-tert-butoxycarbonylmorpholine 14 as
2 × Ar H), 7.65 (2H, d, J 8.4 Hz, 2 × Ar H); dC (100 MHz, CDCl3)
14.0 (CH3), 45.0 (CH2), 47.9 (CH2), 64.5 (CH2), 67.8 (CH2), 77.3
(CH), 82.3 (CH), 113.7 (CH), 117.6 (CH), 120.8 (CH), 122.4 (CH),
129.3 (2 × CH), 130.3 (C), 136.3 (2 × CH), 137.8 (C), 146.3 (C),
148.7 (C); m/z (EI) 439.0642 (M+. C19H22O3NI requires 439.0644),
301 (99%), 220 (96), 138 (61), 85 (77), 56 (100).
a colourless oil (0.02 g, 49%). mmax/cm−1 (NaCl) 2976 (CH), 2357,
25
=
1695 (CO), 1502 (C C), 1254; [a]D −37.1 (c 2.5, CHCl3); dH
(400 MHz, CDCl3) 1.44–1.47 (12H, m, OCH2CH3, (CH3)3), 2.90–
3.01 (2H, m, 3-HH, 5-HH), 3.46 (1H, td, J 11.6, 2.4 Hz, 5-HH),
3.70–3.74 (1H, m, 2-H), 3.86 (2H, dd, J 11.6, 2.4 Hz, 6-H2), 4.05–
4.11 (2H, m, OCH2CH3), 4.42 (1H, br d, J 13.2 Hz, 3-HH), 5.00
(1H, br m, 2-CH), 6.70–6.88 (4H, m, 4 × Ar H), 7.16 (2H, d, J
8.2 Hz, 2 × Ar H), 7.65 (2H, d, J 8.2 Hz, 2 × Ar H); dC (100 MHz,
CDCl3) 14.0 (CH3), 27.4 (3 × CH3), 42.3 (CH2), 44.1 (CH2), 63.4
(CH2), 65.8 (CH2), 77.2 (C), 78.1 (CH), 80.7 (CH), 112.9 (CH),
117.1 (CH), 119.7 (CH), 121.6 (CH), 128.4 (2 × CH), 130.4 (C),
136.3 (2 × Ar C), 137.3 (C), 146.1 (C), 148.9 (C), 153.8 (C); m/z
(EI) 539.1166 (M+. C24H30O5NI requires 539.1169), 346 (93%), 302
(94), 217 (44), 138 (73), 57 (100).
(2R,3S)-2-[(4-Iodophenyl)-(2-ethoxyphenoxy)methyl]morpholine 4
The reaction was carried out as described above, using
(2R,3S)-2-[(4-iodophenyl)-(2-ethoxyphenoxy)methyl]-N -tert-
butoxycarbonylmorpholine (0.02 g, 0.04 mmol). This gave
(2R,3S)-2-[(4-iodophenyl)-(2-ethoxyphenoxy)methyl]morpholine
4 as a colourless oil (0.01 g, 57%). [a]2D2 +38.3 (c 0.9, CHCl3);
spectroscopic data as described for 3.
[3H]Nisoxetine competition binding assays
Whole brains, excluding the cerebellum, were obtained from male
adult Sprague-Dawley rats and homogenised using a Polytron in
ice-cold 50 mM Tris-HCl, pH 7.4, containing 300 mM NaCl and
5 mM KCl (1 : 10 volumes). Homogenates were centrifuged at
25 400 g for 0.25 h at 4 ◦C and the resulting pellet was washed
(3×) by resuspension and centrifugation then stored at −50 ◦C
until use. For determination of Ki values, aliquots of membrane
suspensions (750–850 lg of protein) were incubated for 4 h at
(2R,3S)-2-[(4-Iodophenyl)-(2-ethoxyphenoxy)methyl]-N-tert-
butoxycarbonylmorpholine
A Schlenk tube was charged with copper iodide (0.01 g,
0.05 mmol) and sodium iodide (0.027 g, 0.18 mmol), and the
tube evacuated and back filled with argon. N,Nꢀ-Dimethyl-
ethylenediamine (0.01 mL, 0.10 mmol) and a solution of
(2R,3S)-2-[(4-bromophenyl)-(2-ethoxyphenoxy)methyl]-N-tert-
butoxycarbonylmorpholine 16 in butan-1-ol (0.04 g, 0.09 mmol
in 3 mL) were added under argon. The Schlenk tube was sealed
using a Teflon valve and the reaction mixture stirred at 120 ◦C
for 24 h. The resulting suspension was concentrated in vacuo
and the crude material dissolved in diethyl ether (20 mL), and
washed with ammonia solution (1 mL of 30% NH3 (aq) in 20 mL
water) followed by water (2 × 20 mL). The organic fractions were
combined, dried (MgSO4) and the filtrate concentrated in vacuo
to give (2R,3S)-2-[(4-iodophenyl)-(2-ethoxyphenoxy)methyl]-N-
tert-butoxycarbonylmorpholine as a colourless oil (0.03 g, 52%).
[a]2D2 +43.2 (c 2.2, CHCl3); spectroscopic data as described for 14.
4
◦C in 50 mM Tris-HCl, pH 7.4, containing 300 mM NaCl
and 5 mM KCl with 1.2 nM [3H]nisoxetine (71 Ci/mmol, GE
Healthcare) in the presence or absence of 14–16 concentrations
of the competitor (range 1 pM–200 lM). The total incubation
volume was 0.5 mL and non-specific binding was determined in
the presence of 10 lM reboxetine. The reaction was terminated
by rapid filtration through Whatman GF/B glass fibre filters pre-
soaked in 0.5% polyethylenimine using a Brandel cell harvester.
Filters were washed three times rapidly in ice-cold Tris buffer
and the radioactivity determined by liquid scintillation counting.
For each compound, 3 independent competition curves were
performed with triplicate samples. Ki Values were derived from
nonlinear regression analysis using GraphPad Prism Version 4
(GraphPad Software Inc.) and a Kd value for [3H]nisoxetine
(1.7 nM) determined under the same assay conditions.
(2S,3R)-2-[(4-Iodophenyl)-(2-ethoxyphenoxy)methyl]morpholine 3
Trifluoroacetic acid (1 mL, 0.06 mmol) was added to a so-
lution of (2S,3R)-2-[(4-iodophenyl)-(2-ethoxyphenoxy)methyl]-
N-tert-butoxycarbonylmorpholine 14 (0.02 g, 0.04 mmol) in
dichloromethane (5 mL). The reaction mixture was allowed to
stir at room temperature for 4 h. The reaction mixture was
concentrated in vacuo and the crude material redissolved in
dichloromethane (10 mL) and washed with a saturated sodium
hydrogen carbonate solution (10 mL). The organic layer was
separated, dried (MgSO4) and the filtrate concentrated in vacuo
to give (2S,3R)-2-[(4-iodophenyl)-(2-ethoxyphenoxy)methyl]mor-
Acknowledgements
Financial support from the EPSRC (DTA award to NKJ), BBSRC
(Industrial Studentship with GSK to ARC) and Medical Research
Scotland is gratefully acknowledged.
Notes and references
1 S. G. Amara and M. J. Kuhar, Annu. Rev. Neurosci., 1993, 16, 73.
2 R. D. Blakely and A. L. Bauman, Curr. Opin. Neurobiol., 2000, 10,
328.
pholine 3 as a colourless oil (0.01 g, 57%). mmax/cm−1 (NaCl) 3421
23
3 M.-Y. Zhu and G. A. Ordway, J. Neurochem., 1997, 68, 134.
4 M. K. Spillmann, A. J. W. Van der Does, M. A. Rankin, R. D. Vuolo,
J. E. Alpert, A. A. Nierenberg, J. F. Rosenbaum, D. Hayden, D.
Schoenfeld and M. Fava, Psychopharmacology, 2001, 155, 123.
5 J. Biederman and T. Spencer, Biol. Psychiatry, 1999, 46, 1234.
6 S. Hisamichi, A. Y. Moon, A. Aoyagi, T. Hara, K. Abe, R. Yamazaki, Y.
Kumagae, S. Naruto, K. Koyama, S. Marumoto, K. Tago, N. Toda, K.
Takami, N. Yamada, M. Ori, H. Kogen and T. Kaneko, J. Pharmacol.
Sci. (Tokyo, Jpn), 2003, 93, 95.
=
(NH), 2084 (CH), 1639 (C C), 1500, 1255; [a]D −38.0 (c 0.9,
CHCl3); dH (400 MHz, CDCl3) 1.45 (3H, t, J 7.0 Hz, OCH2CH3),
1.93 (1H, br s, NH), 2.78–2.94 (3H, m, 3-HH, 5-H2,), 3.37 (1H, br
d, J 11.6 Hz, 3-HH), 3.53 (1H, br t, J 12.4 Hz, 6-HH), 3.77 (1H,
m, 2-H), 3.87 (1H, br d, J 12.4 Hz, 6-HH), 4.06 (2H, qd, J 7.0,
2.0 Hz, OCH2CH3), 4.97 (1H, d, J 7.0 Hz, 2-CH), 6.64–6.73 (2H,
m, 2 × Ar H), 6.84–6.89 (2H, m, 2 × Ar H), 7.16 (2H, d, J 8.4 Hz,
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The Royal Society of Chemistry 2008
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7 S. M. Tejani-Butt, J. X. Yang and H. Zaffar, Brain Res., 1993, 631, 147.
8 N. Kanegawa, Y. Kiyono, H. Kimura, T. Sugita, S. Kajiyama, H.
Kawashima, M. Ueda, Y. Kuge and H. Saji, Eur. J. Nucl. Med. Mol.
Imaging, 2006, 33, 639.
9 G. D. Tamagnan, E. Brenner, D. Alagille, J. K. Staley, C. Haile, A.
Koren, M. Early, R. M. Baldwin, F. I. Tarazi, R. J. Baldessarini, N.
Jarkas, M. M. Goodman and J. P. Seibyl, Bioorg. Med. Chem. Lett.,
2007, 17, 533.
14 (a) P. Melloni, A. Della Torre, E. Lazzari, G. Mazzini and M. Meroni,
Tetrahedron, 1985, 41, 1393; (b) E. Brenner, R. M. Baldwin and G.
Tamagnan, Org. Lett., 2005, 7, 937; (c) W. W. Harding, M. Hodge,
Z. Wang, W. L. Woolverton, D. Parrish, J. R. Deschamps and T. E.
Prisinzano, Tetrahedron: Asymmetry, 2005, 16, 2249; (d) S. A. Siddiqui,
U. C. Narkhede, R. J. Lahoti and K. V. Srinivasan, Synlett, 2006, 1771;
(e) T.-X. Me´tro, D. Gomez Pardo and J. Cossy, J. Org. Chem., 2008,
73, 707.
10 B. Lakshmi, M.-P. Kung, B. Lieberman, J. Zhao, R. Waterhouse and
H. F. Kung, Nucl. Med. Biol., 2008, 35, 43.
11 M. Hajos, J. C. Fleishaker, J. K. Filipiak-Reisner, M. T. Brown and
E. H. F. Wong, CNS Drug Rev., 2004, 10, 23.
12 E. H. F. Wong, S. Ahmed, R. C. Marshall, R. McArthur, D. P. Taylor,
L. Birgerson and P. Cetera, Patent WO 2001 001 973, 2001.
13 Part of this work has been previously reported as conference pro-
ceedings of the Ninth International Symposium on the Synthesis and
Applications of Isotopically Labelled Compounds, Edinburgh, 2006: R.
Bischoff, D. J. Hamilton, N. K. Jobson and A. Sutherland, J. Labelled
Compd. Radiopharm., 2007, 50, 323.
15 M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S.
Masumune, W. R. Roush and T. Sakai, Tetrahedron Lett., 1984, 25,
2183.
16 Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H. Masamune and
B. K. Sharpless, J. Am. Chem. Soc., 1987, 109, 5765.
17 A. Klapars and S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 14844.
18 L. Stevenson, S. L. Pimlott and A. Sutherland, Tetrahedron Lett., 2007,
48, 7137.
19 A. Costa, C. Najera and J. M. Sansano, J. Org. Chem., 2002, 67, 5216.
20 E. A. Couladouros, I. C. Soufli, V. I. Moutsos and R. K. Chadha,
Chem.–Eur. J., 1998, 4, 33.
2376 | Org. Biomol. Chem., 2008, 6, 2369–2376
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