Enantioselective synthesis of fatty acid amide hydrolase inhibitors with 1, 3-disubstituted butan-2-one scaffold

Article abstract of DOI:10.1016/j.tetasy.2017.02.013

Fatty acid amide hydrolase is a key enzyme in the inactivation of the analgesic and anti-inflammatory endocannabinoid anandamide. Previously, the chiral compound 1-(1H-benzotriazol-1-yl)-3-(4-phenylphenoxy)butan-2-one was identified as a potent inhibitor of fatty acid amide hydrolase and is therefore of interest as a potential agent against pain and inflammation. Two different approaches for the enantioselective synthesis of fatty acid amide hydrolase inhibitors with a 1, 3-disubstituted butan-2-one scaffold were carried out. The first one uses the chiral epoxide 2-[1-(4-phenylphenoxy)ethyl]oxirane with an (R)- or (S)-configuration at the exocyclic stereocenter as central intermediates. These substances were obtained by separation of the non-stereoselectively synthesized epoxide into its racemic diastereomers by reversed phase chromatography followed by Jacobsen's hydrolytic kinetic resolution of each enantiomer with the (S)-configured oxirane ring. Furthermore, a chiral pool based enantioselective synthesis was developed. In that case, the starting compound for both target enantiomers was methyl 3, 4-O-isopropylidene-L-threonate. In comparison to the first approach, the chiral pool synthesis consisted of more steps, but generated the enantiomers with much better enantiomeric excess. Biological evaluation showed that the (R)-enantiomer inhibits isolated fatty acid amide hydrolase with a 200-fold higher activity than the (S)-enantiomer.

Full text of DOI:10.1016/j.tetasy.2017.02.013

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective synthesis of fatty acid amide hydrolase inhibitors
with 1,3-disubstituted butan-2-one scaffold
⇑
Tom R. Sundermann, Matthias Lehr
Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstrasse 48, D-48149 Münster, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Fatty acid amide hydrolase is a key enzyme in the inactivation of the analgesic and anti-inflammatory
endocannabinoid anandamide. Previously, the chiral compound 1-(1H-benzotriazol-1-yl)-3-(4-
phenylphenoxy)butan-2-one was identified as a potent inhibitor of fatty acid amide hydrolase and is
therefore of interest as a potential agent against pain and inflammation. Two different approaches for
the enantioselective synthesis of fatty acid amide hydrolase inhibitors with a 1,3-disubstituted butan-
Received 22 December 2016
Accepted 24 February 2017
Available online xxxx
2-one scaffold were carried out. The first one uses the chiral epoxide 2-[1-(4-phenylphenoxy)ethyl]oxi-
rane with an (R)- or (S)-configuration at the exocyclic stereocenter as central intermediates. These sub-
stances were obtained by separation of the non-stereoselectively synthesized epoxide into its racemic
diastereomers by reversed phase chromatography followed by Jacobsen’s hydrolytic kinetic resolution
of each enantiomer with the (S)-configured oxirane ring. Furthermore, a chiral pool based enantioselec-
tive synthesis was developed. In that case, the starting compound for both target enantiomers was
methyl 3,4-O-isopropylidene-L-threonate. In comparison to the first approach, the chiral pool synthesis
consisted of more steps, but generated the enantiomers with much better enantiomeric excess.
Biological evaluation showed that the (R)-enantiomer inhibits isolated fatty acid amide hydrolase with
a 200-fold higher activity than the (S)-enantiomer.
Ó 2017 Elsevier Ltd. All rights reserved.
1
. Introduction
2
of a methyl group at the CH -bridge connecting the carbonyl moi-
ety with the benzotriazole scaffold resulting in compound 2, led to
Anandamide is one principal endocannabinoid in the mam-
malian organism. It is formed ‘on demand’ during several patho-
logical disorders and mediates analgesic and anti-inflammatory
a drastic loss of activity. In contrast, a methyl substituent at the
other a-carbon atom of the carbonyl moiety increased inhibitory
1
,2
potency by approximately twofold. Since the additional methyl
group creates a stereogenic center, we were interested as to
whether the two enantiomers of the highly active fatty acid amide
hydrolase inhibitor 3 inhibit the enzyme to different extents. For
this reason, two stereoselective syntheses for the preparation of
(R)- and (S)-3 were established.
effects by activation of the cannabinoid receptors CB
1 2
and CB .
These two receptors are differentially distributed within the vari-
3
–5
ous cells.
While the CB
1
receptor is preferentially expressed in
receptor occurs mainly in the cells of
neuronal tissues, the CB
2
the immune system such as macrophages. An important enzyme
in the endocannabinoid metabolism is fatty acid amide hydrolase,
which rapidly cleaves the lipid mediator anandamide into arachi-
donic acid and ethanolamine (Fig. 1).6 Inhibitors of fatty acid
amide hydrolase were found to elevate anandamide levels and,
therefore, may represent new treatment options for pain and
inflammation.
2
. Results and discussion
–9
The original preparation of the racemic target compound 310
started from 4-phenylphenol 4, which was reacted with 3-chloro-
but-1-ene by Williamson ether synthesis to give 5 (Scheme 1). The
exocyclic double bond of this compound was converted into an
epoxide with m-chloroperoxybenzoic acid. The reaction of the
obtained intermediate 6 with benzotriazole led to a ring opening
of the epoxide with the formation of alcohol 7, which was finally
converted into ketone 3 by Dess-Martin oxidation.
Recently, we have found that the benzotriazolyl substituted
propan-2-one 1 (Fig. 2) is a potent inhibitor of rat brain fatty acid
1
0
amide hydrolase with an IC50 value in the low nanomolar range.
Structure–activity relationship studies revealed that introduction
⇑
Corresponding author. Tel.: +49 251 83 33331; fax: +49 251 83 32144.
E-mail address: lehrm@uni-muenster.de (M. Lehr).
Our first strategy for the synthesis of both enantiomers of 3 was
based on the discrete production of such isomers of 6, in which the
http://dx.doi.org/10.1016/j.tetasy.2017.02.013
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0
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2
T. R. Sundermann, M. Lehr / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
O
O
fatty acid
OH
N
H
amide hydrolase
OH
OH
+
2
H N
C
4
H
9
4 9
C H
anandamide
arachidonic acid
Figure 1. Cleavage of anandamide by fatty acid amide hydrolase.
N
N
a small amount of water (0.5–0.75 equiv) in the presence of the
chiral Jacobsen catalyst (S,S)-Co(III)(salen)(OAc)-complex until
about 50% of the epoxide had disappeared on TLC. The remaining
epoxides, which possessed an (R)- and (S)-configuration, respec-
tively, at the exocyclic stereogenic center, were purified by silica
gel chromatography and reacted with benzotriazole separately to
give the butan-2-ols (R,R)-7 and (R,S)-7 (Scheme 2). Finally, the chi-
ral alcohol moiety of these compounds was oxidized with Dess-
Martin periodinane to yield the desired enantiomers of 3 (note:
the enantiomers of 3 obtained in this first synthetic approach are
O
O
N
R1
: R and R2 = H
R2
inhibition of fatty acid
amide hydrolase
1
1
2
3
IC50 = 0.012 µM
50
1
2
: R = H; R = CH
3
IC = 0.63 µM
1
2
50
IC = 0.013 µM
: R = CH ; R = H
3
Figure 2. Fatty acid amide hydrolase inhibitors with central ketone moiety.
⁄
marked with an in the following). The enantiomeric excess of
exocyclic stereogenic center had either an (R)- or (S)-configuration,
respectively. These compounds should then each be separately
reacted in the same way as 6 to yield (R)-3 and (S)-3. Hence, for
the preparation of the desired (R)- and (S)-configured intermedi-
ates, oxirane 6 should be separated into its two racemic diastere-
omers by preparative HPLC followed by Jacobsen’s hydrolytic
kinetic resolution1 of the terminal racemic oxirane rings with a
Co(salen) catalyst (Scheme 2).
Chromatographic separation of the isomers of 6 could be
achieved on a 100 mg scale using a reversed phase C18 column
using acetonitrile/water (60:40, v/v) as eluent. The obtained race-
mic diastereomers (S,S)-/(R,R)-6 and (R,S)-/(S,R)-6 (Scheme 2)
showed some subtle differences in their 1H NMR spectra. In the
spectrum of the racemic product eluted first, the signals of the pro-
each compound was measured by chiral HPLC. The ee values deter-
⁄
⁄
mined were 81% for (R)-3 and 42% for (S)-3 . In particular, the
⁄
value for (S)-3 was not satisfactory. The time used for the hydrol-
ysis of the oxiranes was obviously not been long enough. Monitor-
ing the disappearance of the (S)-configured chiral epoxides during
the hydrolytic kinetic resolution by chiral HPLC could have been a
possibility to optimize the enantioselectivity of this reaction
sequence. However, we preferred to establish a chiral pool synthe-
sis to afford (R)-3 and (S)-3 with a higher enantiomeric excess
instead.
1
The synthesis of (R)-3 started from methyl 3,4-O-isopropyli-
dene-L-threonate 9, which was converted in four steps into the
(
S,S)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl 4-methylbenzene-
13–17
sulfonate (S,S)-14 using published procedures (Scheme 3).
2
tons of the cyclic CH -group appear at 2.72 ppm and 2.88 ppm,
The tosylate group of this central intermediate was substituted
by reaction with sodium 4-phenylphenolate. The acetonide pro-
tecting group of the resulting phenyl ether (S,R)-15 was removed
with HCl in THF and the primary alcohol moiety of resulting diol
while the corresponding signals of the product with longer reten-
tion time show chemical shifts of 2.78 ppm and 2.84 ppm. Thus
in the first case, the two signals are further apart (0.16 ppm) than
in the second one (0.06 ppm). Similar differences had been found
in the spectra of the structurally related diastereomers (R)-2-[(S)-
(S,R)-16 was transformed into a tosyl ester with p-toluenesulfonyl
chloride. Treatment of this compound (S,R)-17 with K CO in
2
3
1
-(benzyloxy)ethyl]oxirane and (S)-2-[(S)-1-(benzyloxy)ethyl]oxi-
methanol/THF led to the formation of an oxirane ring (S,R)-6,
which was subsequently opened by reaction with benzotriazole
to afford the secondary alcohol (S,R)-7. Dess-Martin oxidation of
the alcohol group finally gave the desired ketone (R)-3. Chiral HPLC
analysis revealed an enantiomeric excess of 92% for this compound
1
2
rane. The signals of the protons of the cyclic methylene group
of the (S,S)-configured derivative were further separated from each
other than those of the (R,S)-configured compound. Therefore, our
working hypothesis was that the racemic diastereomer, which
elutes first, consists of the (R,R)- and (S,S)-enantiomers, while the
diastereomer with the longer retention time is the racemate of
the (R,S)- and (S,R)-enantiomers.
(
for chromatogram: see Supplementary Information). Furthermore,
with this enantiomer in hand it could be shown retrospectively
that the assignment of the stereochemistry made above for the
The enantiomers, which had an (S)-configuration at the stere-
ogenic center of the epoxide, should be selectively hydrolyzed to
diastereomeric epoxides (R,R)-6 and (R,S)-6 with the aid of 1
H
NMR spectra was correct.
1
,2-diols (Scheme 2). Thus, the two racemates were treated with
O
OH
O
O
c
a
b
CH
3
CH
N
3
6
5
4
N
N
O
3
N
OH
3
O
N
O
N
d
CH
3
CH
7
Scheme 1. Non-stereoselective synthesis of 3:10 (a) 3-chlorobut-1-ene, NaOH, water, DMF, 45 °C, 24 h; (b) m-chloroperoxybenzoic acid, CH
benzotriazole, Cs CO , toluene, reflux, 40 h; (d) Dess-Martin periodinane, CH Cl , room temperature, 3 h.
2
Cl
2
, room temperature, 6 d; (c)
2
3
2
2
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T. R. Sundermann, M. Lehr / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
O
O
CH
3
6
a
O
O
O
O
O
(S)
O
(R)
O
(S)
O
(R)
(
S)
(R)
(R)
(S)
CH
3
CH
3
CH
3
CH
3
(
S,S)-6
(R,R)-6
(R,S)-6
(S,R)-6
OH
b
b
OH
O
(S)
OH
O
(R)
OH
(S)
O
O
(S)
O
(R)
O
(S)
CH
3
(R)
(R)
CH
3
(
S,S)-8
CH
3
CH
3
(S,R)-8
(
R,R)-6
(R,S)-6
c
c
N
N
N
OH
N
N
OH
O (S) (R)
O
(R)
N
(
R)
CH
3
CH3
(R,R)-7
(R,S)-7
d
d
N
N
O
3
N
N
O
N
N
O
(R)
O (S)
CH
CH3
(
R)-3*
(S)-3*
⁄
⁄
Scheme 2. Enantioselective synthesis of (R)-3 and (S)-3 via chromatographic separation of diastereomeric oxirane precursors followed by Jacobsen’s hydrolytic kinetic
0
resolution of the obtained oxirane enantiomers: (a) chromatographic separation by reversed phase C18 HPLC; (b) (S,S)-(+)-N,N -bis(3,5-di-tert-butylsalicylidene)-1,2-
2 3 2 2
cyclohexanediamino-cobalt(II), acetic acid, toluene, THF, 12–16 h; (c) benzotriazole, Cs CO , toluene, reflux, 3 d; (b) Dess-Martin periodinane, CH Cl , room temperature, 4 h.
For the synthesis of (S)-3, (S)-1-((S)-2,2-dimethyl-1,3-dioxolan-
-yl)ethan-1-ol (S,S)-13 was used as a starting material (Scheme 3).
cursors by reversed phase chromatography, followed by Jacobsen’s
hydrolytic kinetic resolution of one of the oxirane enantiomers but
this led to products with moderate enantiomeric excess. However,
with a chiral pool synthesis starting from methyl 3,4-O-isopropyli-
4
The configuration of the exocyclic stereogenic center of this com-
pound was inverted using a Mitsunobu reaction. Next, (S,R)-13
was treated with 4-phenylphenol in a Mitsunobu etherification
to give the (S,S)-configured phenyl alkyl ether (S,S)-15. The final
steps of the synthesis were accomplished analogously to the
preparation of (R)-3 from (S,R)-15. The target compound (S)-3
was obtained with 99% ee.
dene-L-threonate, both enantiomers of 3 could be obtained with
high enantiomeric purity [96% ee in case of (R)-3 and 99% ee in case
of (S)-3]. The application of the first approach to the enantioselec-
tive synthesis of related 1,3-disubstituted butan-2-one derivatives
could result in problems, e.g. due to an insufficient chromato-
graphic separation of the diastereomers or their incompatibility
with the Jacobsen catalyst. In contrast, the outlined chiral pool syn-
thesis represents a straightforward method for the synthesis of
related enantiopure 1,3-disubstituted butan-2-ones and butan-2-
ols, respectively, which could be of interest in medicinal chemistry
research.
Both target compounds were evaluated for fatty acid amide
hydrolase inhibition in an assay using the enzyme isolated from
rat brain and the fluorogenic substrate N-(2-hydroxyethyl)-4-
pyren-1-ylbutanamide.18 For the racemic butan-2-one 3, an IC50
value of 0.013 mM had been measured.10 The enantiomers (R)-3
and (S)-3 showed striking differences in their inhibitory potency.
With an IC50 value of 0.0063 mM, the (R)-configured derivative
was approximately 200-fold more active than that with the (S)-
configuration, whose IC50 value was 1.2 mM. A similar influence
of the position of a simple methyl group located at a stereocenter
on activity has been observed for the marketed drug ibuprofen.
Thus, (S)-ibuprofen is approximately 160-fold more potent in
4
4
. Experimental
.1. General
Column chromatography was performed on silica gel 60, par-
1
9,20
inhibiting prostaglandin synthesis than its (R)-enantiomer.
ticle size 0.040–0.063 mm, from Macherey & Nagel. Melting
points were determined on a Büchi B-540 apparatus and are
1
3
. Conclusion
uncorrected. H NMR spectra were recorded on a Varian Mercury
Plus 400 spectrometer (400 MHz) or an Agilent DD2 spectrometer
1
3
The enantiomers of the fatty acid amide hydrolase inhibitor 1-
1H-benzotriazol-1-yl)-3-(4-phenylphenoxy)butan-2-one 3 could
be synthesized by two different routes. The first approach was
via the chromatographic separation of diastereomeric oxirane pre-
(600 MHz). C NMR spectra were measured on a Varian Mercury
Plus 400 spectrometer (101 MHz) or an Agilent DD2 spectrometer
(151 MHz). Electron ionization (EI) mass spectra were obtained
on a Finnigan GCQ apparatus. The high-resolution mass spectra
(
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T. R. Sundermann, M. Lehr / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
O
O
O
O
O
O
a
O
b
O
c
(
S)
(S)
(S)
O
Ts
(
S)
H
3
CO
HO
(S)
O
(S)
(
S)
(S)
9
10
11
OH
OH
OH
O
12
d
O
O
HO (S)
(S)
(
S,S)-13
CH
3
e
l
O
O
O
O
O
(
)
O
O
m
O
O
(R)
f
O
S
HO
(R)
O
(S)
(S)
Ts
(S)
(S)
(S)
(
S,R)-15
(S,S)-14
(S,R)-13
(S,S)-15
CH
CH
3
CH
CH3
g
3
3
g
OH
OH
OH
OH
h
h
O
(R)
OH
O (R)
O
O
O
(S)
O
O (S)
OH
(S)
(S)
Ts
(S)
Ts
(S,S)-17
(S)
CH
3
(S,R)-
16
CH
3
CH3
CH
3
(S,R)-17
(S,S)-16
i
i
N
N
N
OH
N
N
OH
O
O
O
(R)
O
(R)
(S)
O
(S)
N
j
(S)
j
(S)
(S)
(S)
CH
3
CH
CH3
CH3
3
(S,R)-7
(S,R)-6
(S,S)-6
(S,S)-7
k
O
N
N
N
O
N
N
N
k
O
(R)
O
(S)
CH
3
CH
3
(
R)-3
(S)-3
Scheme 3. Chiral pool synthesis of (R)-3 and (S)-3: (a) LiAlH
methanol, room temperature, 3 h; (d) LiAlH , THF, 0 °C, 2 h; (e) tosyl chloride, 4-dimethylaminopyridine, triethylamine, CH
NaH, DMF, 80 °C, 3 h; (g) 1 M HCl, THF, room temperature, 24 h - 48 h; (h) dibutyltin oxide, triethylamine, CH Cl , tosyl chloride, room temperature, 12 h; (i) K
THF, room temperature, 2 h; (j) benzotriazole, Cs CO , toluene, DMF, reflux, 1 d; (k) Dess-Martin periodinane, CH Cl , room temperature, 4 h; (l) triphenylphosphine, benzoic
acid, benzene, DIAD, room temperature, 20 h; (m) 4-phenylphenol, triphenylphosphine, THF, DIAD, room temperature, 20 h.
4
, THF, 0 °C, 3 h; (b) dibutyltin oxide, triethylamine, CH
2
Cl
2
, tosyl chloride, room temperature, 8 h; (c) K
Cl , room temperature, 12 h; (f) 4-phenylphenol,
CO , methanol,
2 3
CO ,
4
2
2
2
2
2
3
2
3
2
2
(
HRMS) were recorded on a Bruker micrOTOF-Q II spectrometer
perature for 2 d. After the addition of ethyl acetate, the organic
phase was washed successively with saturated aqueous sodium
thiosulfate solution, saturated aqueous sodium bicarbonate solu-
applying electrospray chemical ionization (ESI) or atmospheric
pressure chemical ionization (APCI). For preparative reversed
phase HPLC a Knauer pump P2.1L and a Shimazu SPD-6A UV
detector were used. Chromatograms were recorded with Mac-
DAcq32 Control Software from Bischoff. As stationary phase, a
Knauer RP18 Eurospher II 5 mm column (20 mm (I.D.) ꢀ
2 4
tion and brine. The organic layer was dried over Na SO , concen-
trated, and chromatographed on silica gel (hexane/ethyl acetate,
19:1) to yield 6 as a solid (0.670 g, 67%). The two obtained diastere-
omers were separated with preparative RP HPLC (acetonitrile/
water, 60:40) to yield the racemates (R,R)-6/(S,S)-6 (0.341 g, 34%)
2
50 mm) with a RP18 Eurospher II 5 mm guard column (20 mm
(
I.D.) ꢀ 30 mm) was applied. The flow rate was 25 mL/min. The
and (R,S)-6/(S,R)-6 (0.209 g, 21%) as solids. (R,R)-6/(S,S)-6:
1
compounds were dissolved in DMSO and the injected sample vol-
ume was 0.5–1 mL. The detection wavelength was set at 254 nm.
The substances were obtained as solids after distilling off the
organic solvent and freeze-drying the remaining aqueous phase
using a Christ alpha 1–2 LD plus apparatus. Optical rotations were
measured on a Perkin Elmer polarimeter 341. Chiral HPLC-analy-
sis was performed on a Daicel ChiralpakÒ IA 5 mm column
C H
16 16
O
2
(240.3); mp 67–68 °C; H NMR (400 MHz, CDCl
3
): d
1.44 (dd, J = 6.4 Hz and 0.5 Hz, 3H), 2.72 (dd, J = 4.9 Hz and
2.7 Hz, 1H), 2.88 (t, J = 4.5 Hz, 1H), 3.19–3.24 (m, 1H), 4.25 (quint,
J = 6.3 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 7.41
(t, J = 7.6 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.53–7.58 (m, 2H); 13
C
3
NMR (101 MHz, CDCl ): d 17.2, 44.6, 54.9, 75.1, 116.5, 126.8,
126.9, 128.3, 128.9, 134.5, 140.9, 157.6; HRMS (APCI, direct probe)
+
(
4.6 mm (I.D.) ꢀ 250 mm) using isohexane/isopropanol (90:10, v/
m/z [M+H] calculated: 241.1223, found: 241.1230.
16 16 2
C H O
(240.3); mp 64–65 °C; 1H NMR
v) as mobile phase at a flow rate of 1 mL/min. The detection
wavelength was 254 nm.
(R,S)-6/(S,R)-6:
(400 MHz, CDCl ): d 1.44 (d, J = 6.2 Hz, 3H), 2.78 (dd, J = 5.1 Hz
3
and 2.6 Hz, 1H), 2.84 (dd, J = 4.5 Hz and 3.9 Hz, 1H), 3.15 (td,
J = 4.2 Hz and 2.7 Hz, 1H), 4.37 (qd, J = 6.3 Hz and 4.5 Hz, 1H),
4
4
4
.2. Synthetic procedures
6
.99 (d, J = 8.6 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.6 Hz,
13
.2.1. 2-[1-(4-Phenylphenoxy)ethyl]oxirane 6
2H), 7.51 (d, J = 8.7 Hz, 2H), 7.53–7.57 (m, 2H);
C NMR
A solution of 1-(but-3-en-2-yloxy)-4-phenylbenzene10 (0.94 g,
3
(101 MHz, CDCl ): d 17.0, 45.6, 54.2, 73.7, 116.6, 126.9, 128.3,
+
.19 mmol) in dry CH
2
Cl
2
(3 mL) was treated with m-chloroperox-
128.9, 134.6, 140.8, 157.4; HRMS (APCI, direct probe) m/z [M+H]
ybenzoic acid (ꢁ70%) (2.07 g, 8.40 mmol) and stirred at room tem-
calculated: 241.1223, found: 241.1222.
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T. R. Sundermann, M. Lehr / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
4
.2.2. (R)-2-[(R)-1-(4-Phenylphenoxy)ethyl]oxirane (R,R)-6
A solution of (S,S)-(+)-N,N -bis(3,5-di-tert-butylsalicylidene)-
4.2.6. (R)-1-(1H-Benzotriazol-1-yl)-3-(4-phenylphenoxy)butan-
0
⁄
2-one (R)-3
Under a nitrogen atmosphere, a solution of (R,R)-7 (0.105 g,
0.29 mmol) in dry CH Cl (5 mL) was treated with Dess-Martin
1
,2-cyclohexanediamino-cobalt(II) (0.100 g, 0.17 mmol) in dry
toluene (2 mL) was treated with acetic acid (19.0 mL, 0.33 mmol)
2
2
and stirred under air for 1 h. The solvent was then removed under
periodinane reagent (0.186 g, 0.44 mmol) and stirred at room tem-
perature for 4 h. A mixture of 5% aqueous sodium thiosulfate and
saturated aqueous sodium bicarbonate solution (1:1, v/v) was then
added. After stirring for 10 min, the reaction mixture was repeat-
reduced pressure and
.83 mmol) in dry THF (3 mL) was added. The mixture was treated
with water (8.2 mL, 0.46 mmol) and stirred at room temperature for
6 h. After addition of cyclohexane (10 mL), the reaction mixture
was dried over Na SO , concentrated, and chromatographed on sil-
ica gel (hexane/ethyl acetate, 19:1) to yield (R,R)-6 as an oil
a solution of (R,R)-6/(S,S)-6 (0.200 g,
0
1
2 2
edly extracted with CH Cl . The combined organic layers were
2
4
dried over Na SO , filtered and concentrated. The crude product
2
4
was purified by silica gel chromatography (hexane/ethyl acetate,
8:2) followed by preparative RP HPLC (acetonitrile/water, 60:40)
1
(
0.113 g, 57%). The H NMR of this compound matched that of
⁄
the racemate (R,R)-6/(S,S)-6.
to yield (R)-3 as a solid (0.041 g, 40%). C22
H
19
N
3
O
2
(357.41); mp
2
0
1
49–150 °C; specific rotation ½
enantiomeric excess (chiral HPLC): 81.2%; H NMR (400 MHz,
CDCl ): d 1.69 (s, 3H), 5.00 (q, J = 6.8 Hz, 1H), 5.61 (d, J = 18.8 Hz,
H), 5.93 (d, J = 18.9 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 7.16 (dd,
J = 8.3 Hz and 0.9 Hz, 1H), 7.32–7.41 (m, 2H), 7.41–7.49 (m, 3H),
.55–7.63 (m, 4H), 8.08 (dd, J = 8.3 Hz and 1.0 Hz, 1H); 13C NMR
151 MHz, CDCl ): d 17.8, 53.0, 78.7, 109.1, 115.6, 120.4, 124.2,
aꢂ
= +14.5 (c 1, ethyl acetate);
D
1
4
.2.3. (R)-2-[(S)-1-(4-Phenylphenoxy)ethyl]oxirane (R,S)-6
A solution of (S,S)-(+)-N,N -bis(3,5-di-tert-butylsalicylidene)-
0
3
1
1
,2-cyclohexanediamino-cobalt(II) (0.075 g, 0.12 mmol) in dry
toluene (2 mL) was treated with acetic acid (14.3 mL, 0.25 mmol)
and stirred under air at room temperature for 1 h. The solvent
was removed under reduced pressure and a solution of (R,S)-6/(S,
R)-6 (0.150 g, 0.62 mmol) in dry THF (3 mL) was added. The reac-
tion mixture was treated with water (8.4 mL, 0.47 mmol) and stir-
red for further 12 h. After the addition of cyclohexane (10 mL),
7
(
3
127.0, 127.3, 127.9, 129.0, 129.0, 133.7, 135.9, 140.4, 146.2,
1
56.4, 202.8; HRMS (APCI, direct probe) m/z [M+H]+ calculated:
358.1550, found: 358.1589.
the reaction mixture was dried over Na
chromatographed on silica gel (hexane/ethyl acetate, 19:1) to yield
R,S)-6 as an oil (0.090 g, 60%). The 1H NMR of this compound
matched that of the racemate (R,S)-6/(S,R)-6.
2 4
SO , concentrated, and
4
.2.7. (S)-1-(1H-Benzotriazol-1-yl)-3-(4-phenylphenoxy)butan-
⁄
2-one (S)-3
(
Compound (R,S)-7 (0.105 g, 0.29 mmol) in dry CH
2 2
Cl (5 mL)
was oxidized with Dess-Martin periodinane reagent (0.186 g,
0
.44 mmol) according to the procedure described for the prepara-
4
.2.4. (2R,3R)-1-(1H-Benzotriazol-1-yl)-3-(4-phenylphenoxy)
butan-2-ol (R,R)-7
At first, Cs CO (0.325 g, 1.00 mmol) and benzotriazole (0.238 g,
.00 mmol) were added to solution of (R,R)-6 (0.120 g,
.50 mmol) in dry toluene (10 mL). The mixture was heated at
⁄
tion of (R)-3 . The crude product was purified by silica gel chro-
matography (hexane/ethyl acetate, 8:2) to yield (S)-3 as a solid
⁄
2
3
(
19 3 2
0.060 g, 58%). C22H N O (357.4); mp 142–143 °C; specific rota-
2
0
a
20
D
tion ½
aꢂ
= ꢃ6.7 (c 1, ethyl acetate); enantiomeric excess (chiral
1 13
⁄
HPLC): 42.1%; the H NMR and C NMR matched that of (R)-3 ;
reflux for 3 d. After addition of water, the mixture was exhaustively
extracted with ethyl acetate. The combined organic layers were
+
HRMS (APCI, direct probe) m/z [M+H] calculated: 358.1550, found:
3
58.1561.
dried over Na
gel (hexane/ethyl acetate, 8:2) to yield (R,R)-7 as an oil (0.112 g,
2%). C22 ): d 1.49 (d,
(359.4); 1H NMR (600 MHz, CDCl
J = 6.3 Hz, 3H), 4.36 (dt, J = 6.8 Hz and 4.4 Hz, 1H), 4.37–4.45 (m,
H), 4.84 (dd, J = 14.4 Hz and 6.7 Hz, 1H), 4.89 (dd, J = 14.4 Hz
and 4.2 Hz, 1H), 6.96 (d, J = 8.6 Hz, 2H), 7.29–7.36 (m, 2H), 7.39–
.47 (m, 3H), 7.50 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 7.7 Hz, 2H), 7.61
d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H); 13C NMR (151 MHz,
CDCl ): d 15.5, 50.5, 73.6, 74.4, 110.3, 116.5, 119.8, 124.2, 126.9,
27.0, 127.6, 128.5, 128.9, 134.0, 134.9, 140.7, 145.7, 156.6; HRMS
2 4
SO , concentrated, and chromatographed on silica
4
.2.8. (S)-2,2-Dimethyl-4-[(R)-1-(4-phenylphenoxy)ethyl]-1,3-
6
H
21
N
3
O
2
3
dioxolane (S,R)-15
Sodium hydride (60% dispersion in mineral oil) (0.073 g,
.83 mmol) was added at room temperature to a solution of 4-
1
1
phenylphenol (0.312 g, 1.83 mmol) in dry DMF (8 mL). The mixture
was stirred for 30 min until no further formation of hydrogen could
be observed. A solution of (S,S)-14 (0.50 g, 1.66 mmol) in dry
DMF (8 mL) was then added dropwise and the mixture was heated
at 80 °C for 3 h. After the addition of water (50 mL), the solution
was extracted with ethyl acetate. The combined organic layers
7
(
13
3
1
+
(
APCI, direct probe) m/z [M+H] calculated: 360.1707, found:
3
60.1702.
were dried over Na
2 4
SO , concentrated, and chromatographed on
silica gel (cyclohexane/ethyl acetate, 9:1) to yield (S,R)-15 as a solid
2
0
4
.2.5. (2R,3S)-3-1-(1H-Benzotriazol-1-yl)-(4-phenylphenoxy)
(
0.16 g, 32%). C19
H
22
O
3
(298.4); specific rotation ½
ethyl acetate); H NMR (400 MHz, DMSO-d ): d 1.23 (d, J = 6.1 Hz,
H), 1.27 (s, 3H), 1.32 (s, 3H), 3.79 (dd, J = 8.4 Hz and 5.8 Hz, 1H),
.06 (dd, J = 8.4 Hz and 6.7 Hz, 1H), 4.16 (q, J = 5.8 Hz, 1H), 4.46
a
ꢂ
= ꢃ24.0 (c 1,
D
1
butan-2-ol (R,S)-7
6
2
Compound (R,S)-6 (0.080 g, 0.33 mmol) was treated with Cs -
3
4
3
CO (0.217 g, 0.67 mmol) and benzotriazole (0.157 g, 1.32 mmol)
analogously to the synthesis of (R,R)-7. The crude product was
chromatographed on silica gel (hexane/ethyl acetate, 8:2) to yield
(
7
quint, J = 6.0 Hz, 1H), 7.02 (d, J = 8.7 Hz, 2H), 7.23–7.33 (m, 1H),
1
3
.35–7.45 (m, 2H), 7.52–7.61 (m, 4H);
C NMR (101 MHz,
1
(
(
4
R,S)-7 as an oil (0.084 g, 70%). C22
600 MHz, CDCl
.78 (ddd, J = 14.3 Hz, 7.0 Hz and 1.6 Hz, 1H), 4.98 (dd, J = 14.3 Hz
and 2.7 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 7.32 (tt, J = 7.3 Hz and
H
21
N
3
O
2
(359.4); H NMR
DMSO-d
26.7, 127.8, 128.9, 132.8, 139.8, 157.1; HRMS (ESI+) m/z [M+H]
calculated: 299.1642, found: 299.1654.
6
) d 15.8, 25.2, 26.4, 65.7, 73.9, 77.6, 108.8, 116.2, 126.2,
+
3
): d 1.48 (d, J = 5.8 Hz, 3H), 4.34–4.42 (m, 2H),
1
1
.1 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.40–7.46 (m, 3H), 7.50 (d,
4
.2.9. (2S,3R)-3-(4-Phenylphenoxy)butane-1,2-diol (S,R)-16
A solution of (S,R)-15 (0.160 g, 0.54 mmol) in THF (10 mL) was
1
3
J = 8.7 Hz, 2H), 7.52–7.58 (m, 3H), 8.02 (d, J = 8.8 Hz, 1H);
NMR (151 MHz, CDCl ): d 15.8, 50.5, 73.8, 74.7, 110.0, 116.4,
3
C
treated with aqueous 1 M hydrochloric acid (2 mL) and stirred at
room temperature for 48 h. After evaporation of the solvent under
reduced pressure, the residue was dissolved in toluene (2 mL) and
chromatographed on silica gel (cyclohexane/ethyl acetate, 1:1) to
1
1
20.0, 124.3, 126.9, 127.0, 127.7, 128.5, 128.9, 133.9, 134.8,
40.7, 145.7, 156.6; HRMS (APCI, direct probe) m/z [M+H] calcu-
+
lated: 360.1707, found: 360.1732.
Please cite this article in press as: Sundermann, T. R. ; Lehr, M. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.
tetasy.2017.02.013

6
T. R. Sundermann, M. Lehr / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
⁄
yield (S,R)-16 as a solid (0.108 g, 78%). C16
400 MHz, CDCl ): d 1.38 (d, J = 6.1 Hz, 3H), 3.79–3.93 (m, 3H),
.53 (quint, J = 6.0 Hz, 1H), 6.99 (d, J = 8.7 Hz, 2H), 7.28–7.35 (m,
H
18
O
3
(258.3); 1H NMR
tion of (R)-3 . The crude product was purified by silica gel chro-
matography (hexane/ethyl acetate, 8:2) to yield (R)-3 as a white
(
4
1
3
solid (0.041 g, 63%). C22
H
19
N
3
O
2
(357.4); mp 150–151 °C; specific
13
20
H), 7.42 (t, J = 7.7 Hz, 2H), 7.49–7.59 (m, 4H);
) d 15.6, 63.2, 74.1, 75.5, 116.5, 126.9, 126.9,
28.5, 128.9, 134.7, 140.8, 157.0; HRMS (APCI, direct probe) m/z
C
NMR
rotation ½
aꢂ
= +16.3 (c 1, ethyl acetate); enantiomeric excess (chi-
D
1
(
1
151 MHz, CDCl
3
ral HPLC): 92.3%; H NMR (400 MHz, CDCl ): d 1.69 (s, 3H), 5.00 (q,
J = 6.8 Hz, 1H), 5.61 (d, J = 18.8 Hz, 1H), 5.93 (d, J = 18.9 Hz, 1H),
7.05 (d, J = 8.8 Hz, 2H), 7.16 (dd, J = 8.3 Hz and 0.9 Hz, 1H), 7.32–
3
+
[M+H] calculated: 259.1329, found: 259.1331.
7
.41 (m, 2H), 7.41–7.49 (m, 3H), 7.55–7.63 (m, 4H), 8.08 (dd,
+
4
.2.10. (2S,3R)-2-Hydroxybutyl-3-(4-phenylphenoxy) 4-
J = 8.3 Hz and 1.0 Hz, 1H); HRMS (APCI, direct probe) m/z [M+H]
methylbenzenesulfonate (S,R)-17
calculated: 358.1550, found: 358.1589.
Tosyl chloride (0.074 g, 0.39 mmol) was added in small portions
to a solution of (S,R)-16 (0.100 g, 0.39 mmol), dibutyltin oxide
4.2.14. (S)-4-[(S)-2,2-Dimethyl-1-(4-phenylphenoxy)ethyl]-1,3-
dioxolane (S,S)-15
(
0.048 g, 0.19 mmol) and triethylamine (0.161 mL, 1.16 mmol) in
dry CH Cl (5 mL). The mixture was stirred at room temperature
for 12 h. After washing three times with 1 M KHSO and brine,
the organic layer was dried over Na SO , concentrated, and chro-
matographed on silica gel (cyclohexane/ethyl acetate, 8:2) to yield
2
2
A solution of (R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethan-
1
4
4
1-ol (S,R)-13. (0.160 g, 1.09 mmol), triphenylphosphine (0.314 g,
1.20 mmol) and 4-phenylphenol (0.371 g, 2.18 mmol) in dry THF
(22 mL) was treated dropwise with a solution of diisopropyl azodi-
carboxylate (DIAD) (0.255 g, 1.26 mmol) in dry THF (8 ml) over a
period of 2 h and then stirred at room temperature for 20 h. After
evaporation of the solvent under reduced pressure, the residue
was dissolved in toluene (2 mL) and chromatographed on silica
gel (cyclohexane/ethyl acetate, 19:1) to yield (S,S)-15 as a white
2
4
1
(
S,R)-17 as a white solid (0.130 g, 81%). C23
24 5
H O S (412.5); H NMR
(
400 MHz, CDCl ): d 1.35 (d, J = 6.2 Hz, 3H), 2.41 (s, 3H), 3.99 (td,
3
J = 6.2 Hz and 3.6 Hz, 1H), 4.16 (dd, J = 10.4 Hz and 6.2 Hz, 1H),
4.31 (dd, J = 10.4 Hz and 3.6 Hz, 1H), 4.41 (quint, J = 6.2 Hz, 1H),
6.86–6.92 (m, 2H), 7.27–7.35 (m, 3H), 7.39–7.46 (m, 2H), 7.47–
7
.52 (m, 2H), 7.52–7.57 (m, 2H), 7.75–7.80 (m, 2H); 13C NMR
solid (0.142 g, 43%).
C
19
H
22
O
3
(298.4); specific rotation
): d
2
0
1
(
151 MHz, CDCl
3
) d 15.6, 21.8, 70.9, 72.3) 73.7, 116.3, 126.9,
½
a
ꢂ
= ꢃ25.0 (c 1, ethyl acetate); H NMR (400 MHz, DMSO-d
6
D
1
1
4
27.0, 128.1, 128.4, 128.9, 130.1, 132.5, 134.7, 140.7, 145.3,
56.6; HRMS (ESI+) m/z [M+H] calculated: 413.1417, found:
13.1410.
1.19 (d, J = 6.2 Hz, 3H), 1.30 (s, 3H), 1.36 (s, 3H), 3.75 (dd,
J = 8.3 Hz and 7.0 Hz, 1H), 4.04 (dd, J = 8.3 Hz and 6.7 Hz, 1H),
4.22 (q, J = 6.7 Hz, 1H), 4.54 (quint, J = 6.2 Hz, 1H), 7.03 (d,
J = 8.8 Hz, 2H), 7.27–7.34 (m, 1H), 7.39–7.46 (m, 2H), 7.54–7.64
+
1
3
4
.2.11. (S)-2-[(R)-1-(4-Phenylphenoxy)ethyl]oxirane (S,R)-6
A solution of (S,R)-17 (0.125 g, 0.30 mmol) in dry MeOH (5 mL)
6
(m, 4H); C NMR (101 MHz, DMSO-d ): d 15.2, 25.4, 26.3, 65.0,
73.9, 77.6, 108.8, 116.0, 126.1, 126.7, 127.8, 128.8, 132.6, 139.8,
+
and dry THF (1 mL) was treated with K
2
CO
3
(0.125 g, 0.90 mmol)
157.1; HRMS (APCI, direct probe) m/z [M+H] calculated:
and stirred at room temperature for 2 h. After the addition of
water, the mixture was extracted exhaustively with ethyl acetate.
299.1642, found: 299.1640.
The combined organic layers were dried over Na
trated, and chromatographed on silica gel (cyclohexane/ethyl acet-
2
SO
4
, concen-
4.2.15. (2S,3S)-3-(4-Phenylphenoxy)butane-1,2-diol (S,S)-16
A solution of (S,S)-15 (0.135 g, 0.45 mmol) in dry THF (10 mL)
was treated with 1 M hydrochloric acid (2 mL) and stirred at room
temperature for 24 h. After evaporation of the solvent under
reduced pressure, the residue was dissolved in toluene (2 mL)
and chromatographed on silica gel (cyclohexane/ethyl acetate,
ate, 19:1 to 9:1) to yield (S,R)-6 as a white solid (0.061 g, 84%).
1
C
3
3
1
16
H
16
O
2
(240.3); H NMR (400 MHz, CDCl
3
): d 1.44 (d, J = 6.2 Hz,
H), 2.78 (dd, J = 5.1 Hz and 2.6 Hz, 1H), 2.84 (t, J = 4.5 Hz, 1H),
.15 (td, J = 4.2 Hz and 2.7 Hz, 1H), 4.37 (qd, J = 6.3 Hz and 4.5 Hz,
H), 6.99 (d, J = 8.6 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.42 (t,
1:1) to yield (S,S)-16 as an oil (0.113 g, 97%). C16
H
18
O
3
(258.3);
1
J = 7.6 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.53–7.57 (m, 2H); HRMS
H NMR (400 MHz, DMSO-d ): d 1.21 (d, J = 6.4 Hz, 3H,), 3.41 (dd,
6
+
(
APCI, direct probe) m/z [M+H] calculated: 241.1223, found:
J = 10.6 Hz and 6.0 Hz, 1H), 3.45–3.55 (m, 2H), 4.47 (qd, J = 6.3 Hz
2
41.1188.
and 4.0 Hz, 1H), 6.96–7.03 (m, 2H), 7.24–7.31 (m, 1H), 7.37–7.43
(
m, 2H), 7.51–7.60 (m, 4H); HRMS (APCI, direct probe) m/z [M
+
4
.2.12. (2S,3R)-1-(1H-Benzotriazol-1-yl)-3-(4-phenylphenoxy)
+H] calculated: 259.1329, found: 259.1359.
butan-2-ol (S,R)-7
To a solution of (S,R)-17 (0.065 g, 0.27 mmol) in dry toluene
4.2.16. (2S,3S)-2-Hydroxy 3-(4-phenylphenoxy)butyl 4-
methylbenzenesulfonate (S,S)-17
(
5 mL) and dry DMF (1 mL) were added Cs
2
CO
3
(0.176 g,
0
.54 mmol) and benzotriazole (0.129 g, 1.08 mmol) and the mix-
Compound (S,S)-17 was synthesized from (S,S)-16 (0.115 g,
0.45 mmol) in the same manner as described for compound (S,R)-
ture was heated at reflux for 1 d. After the addition of water, the
mixture was extracted with ethyl acetate. The combined organic
layers were dried over Na
24 5
17. The product was obtained as a solid (0.119 g, 65%). C23H O S
1
2
SO
4
,
concentrated, and chro-
3
(412.5); H NMR (400 MHz, CDCl ): d 1.34 (dd, J = 6.3 Hz and
matographed on silica gel (hexane/ethyl acetate, 8:2) to yield (S,
0.6 Hz, 3H), 2.41 (s, 3H), 3.94 (q, J = 5.0 Hz, 1H), 4.17 (ddd,
J = 5.1 Hz, 2.4 Hz and 0.6 Hz, 2H), 4.51 (qd, J = 6.3 Hz and 4.2 Hz,
1H), 6.89–6.95 (m, 2H), 7.27–7.35 (m, 3H), 7.40–7.46 (m, 2H),
1
R)-7 as a colourless oil (0.065 g, 67%). C22
NMR (400 MHz, CDCl ): d 1.48 (d, J = 5.7 Hz, 3H), 4.33–4.46 (m,
H), 4.80 (dd, J = 14.3 Hz and 7.0 Hz, 1H), 5.00 (dd, J = 14.3 Hz
and 2.6 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 7.29–7.47 (m, 5H), 7.48–
21 3 2
H N O (359.4); H
3
2
7.47–7.53 (m, 2H), 7.53–7.58 (m, 2H), 7.75–7.80 (m, 2H); 13
C
3
NMR (101 MHz, CDCl ) d 15.5, 21.8, 70.1, 72.3, 73.4, 116.5, 126.9,
7
1
.50 (m, 2H), 7.52–7.61 (m, 3H), 8.05 (dt, J = 8.4 Hz and 1.0 Hz,
H); HRMS (APCI, direct probe) m/z [M+H] calculated: 360.1707,
127.0, 128.1, 128.4, 128.9, 130.1, 132.6, 134.9, 140.7,145.2, 156.6;
HRMS (APCI, direct probe) m/z [M+H] calculated: 413.1417, found:
+
+
found: 360.1712.
413.1467.
4
2
.2.13. (R)-1-(1H-Benzotriazol-1-yl)-3-(4-phenylphenoxy)butan-
-one (R)-3
4.2.17. (S)-2-[(S)-1-(4-Phenylphenoxy)ethyl]oxirane (S,S)-6
Compound (S,S)-6 was synthesized from (S,S)-17 (0.115 g,
0.28 mmol) in the same manner as described for compound (S,R)-
Compound (S,R)-7 (0.065 g, 0.18 mmol) in dry CH
was oxidized with Dess-Martin periodinane reagent (0.114 g,
.27 mmol) according to the procedure described for the prepara-
2 2
Cl (5 mL)
16 2
6. The product was obtained as a solid (0.066 g, 99%). C16H O
1
0
3
(240.3); H NMR (400 MHz, CDCl ): d 1.44 (dd, J = 6.5 Hz and
Please cite this article in press as: Sundermann, T. R. ; Lehr, M. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.
tetasy.2017.02.013

T. R. Sundermann, M. Lehr / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
0
.6 Hz, 3H), 2.72 (ddd, J = 4.8 Hz, 2.7 Hz and 0.6 Hz, 1H), 2.88 (ddt,
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J = 4.6 Hz, 4.1 Hz and 0.5 Hz, 1H), 3.17–3.25 (m, 1H), 4.18–4.30 (m,
1.
2.
3.
Fowler, C. J. Fundam. Clin. Pharmacol. 2006, 20, 549–562.
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7
H), 7.01–7.06 (m, 2H), 7.27–7.33 (m, 1H), 7.38–7.44 (m, 2H),
.49–7.53 (m, 2H), 7.53–7.57 (m, 2H); HRMS (APCI, direct probe)
+
m/z [M+H] calculated: 241.1223, found: 241.1242.
4
.
McAllister, S. D.; Glass, M. Prostaglandins Leukot. Essent. Fatty Acids 2002, 66,
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.2.18. (2S,3S)-1-(1H-Benzotriazol-1-yl)-3-(4-phenylphenoxy)
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8
Compound (S,S)-7 was synthesized from (S,S)-6 (0.065 g,
.
.
Labar, G.; Michaux, C. Chem. Biodivers. 2007, 4, 1882–1902.
Fezza, F.; De Simone, C.; Amadio, D.; Maccarrone, M. Subcell. Biochem. 2008, 49,
1
0
.27 mmol) in the same manner as described above for (S,R)-7.
The product was obtained as a solid (0.061 g, 63%). C22
21 3 2
H N O
01–132.
9. Ahn, K.; McKinney, M. K.; Cravatt, B. F. Chem. Rev. 2008, 108, 1687–1707.
0. Zahov, S.; Garzinsky, D.; Hanekamp, W.; Lehr, M. Bioorg. Med. Chem. 2017, 25,
25–837.
1
(
4
7
359.4); H NMR (400 MHz, CDCl
3
): d 1.49 (d, J = 6.1 Hz, 3H),
.30–4.43 (m, 2H), 4.83–4.97 (m, 2H), 6.92–6.98 (m, 2H), 7.28–
.47 (m, 5H), 7.48–7.56 (m, 4H), 7.59–7.67 (m, 1H), 8.06 (dq,
1
8
1
1
1
1. Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936–
+
J = 8.4 Hz and 0.8 Hz, 1H); HRMS (APCI, direct probe) m/z [M+H]
calculated: 360.1707, found: 360.1728.
938.
2. Ojika, M.; Kigoshi, H.; Yoshida, Y.; Ishigaki, T.; Nisiwaki, M.; Tsukada, I.;
Arakawa, M.; Ekimoto, H.; Yamada, K. Tetrahedron 2007, 63, 3138–3167.
3. Holy, A. Collect. Czech. Chem. Commun. 1984, 49, 2148–2166.
4
2
.2.19. (S)-1-(1H-Benzotriazol-1-yl)-3-(4-phenylphenoxy)butan-
-one (S)-3
14. Abushanab, E.; Vemishetti, P.; Leiby, R. W.; Singh, H. K.; Mikkilineni, A. B.; Wu,
D. C. J.; Saibaba, R.; Panzica, R. P. J. Org. Chem. 1988, 53, 2598–2602.
1
5. Yang, H.; Kuroda, H.; Miyashita, M.; Irie, H. Chem. Pharm. Bull. 1992, 40, 1616–
618.
16. Ravi Kumar, A.; Santhosh Reddy, J.; Venkateswara Rao, B. Tetrahedron Lett.
003, 44, 5687–5689.
17. Sharma, G. V. M.; Cherukupalli, G. R Tetrahedron Asymmetry 2006, 17, 1081–
088.
Compound (S)-3 was synthesized from (S)-7 (0.061 g,
.17 mmol) in the same manner as described above for (R)-3. The
1
0
2
19 3 2
product was obtained as a solid (0.041 g, 68%). C22H N O
2
D
0
(
357.4); mp 142–143 °C; specific rotation ½
acetate); enantiomeric excess (chiral HPLC): 99.0%; H NMR
400 MHz, CDCl ): d 1.69 (s, 3H), 5.00 (q, J = 6.8 Hz, 1H), 5.61 (d,
J = 18.8 Hz, 1H), 5.93 (d, J = 18.9 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H),
.16 (dd, J = 8.3 Hz and 0.9 Hz, 1H), 7.32–7.41 (m, 2H), 7.41–7.49
m, 3H), 7.55–7.63 (m, 4H), 8.08 (dd, J = 8.3 Hz and 1.0 Hz, 1H);
a
ꢂ
= ꢃ17.5 (c 1, ethyl
1
1
18. Holtfrerich, A.; Hanekamp, W.; Lehr, M. Eur. J. Med. Chem. 2013, 63, 64–75.
19. Caldwell, J.; Hutt, A. J.; Fournel Gigleux, S. Biochem. Pharmacol. 1988, 37, 105–
(
3
114.
20. Adams, S. S.; Bresloff, P.; Mason, C. G. J. Pharm. Pharmacol. 1976, 28, 256–257.
7
(
+
HRMS (APCI, direct probe) m/z [M+H] calculated: 358.1550, found:
58.1576.
3
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2017.02.
0
13.
Please cite this article in press as: Sundermann, T. R. ; Lehr, M. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.
tetasy.2017.02.013