Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor

Article abstract of DOI:10.1016/j.bmc.2015.05.017

Centrally acting noradrenaline reuptake inhibitor (NRI) is reportedly effective for patients with stress urinary incontinence (SUI) by increasing urethral closure in the clinical Phase IIa study with esreboxetine. Noradrenaline transporters are expressed in both central and peripheral nervous systems and the contribution of each site to efficacy has not been clarified. This report describes the development of a series of peripheral-selective 7-phenyl-1,4-oxazepane NRIs to investigate the contribution of the peripheral site to increasing urethral resistance in rats. (6S,7R)-1,4-Oxazepane derivative 7 exhibited noradrenaline transporter inhibition with high selectivity against inhibitions of serotonin and dopamine transporters. A replacement of hydroxyl with acetamide group contributed to enhancement of peripheral selectivity by increasing molecular polarity. Compound 12, N-{[(6S,7R)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methyl}acetamide 0.5 fumarate, which showed effectively no brain penetration in rats, increased urethral resistance in a dose-dependent manner and exhibited a maximal effect on par with esreboxetine. These results demonstrate that the urethral resistance-increasing effects of NRI in rats are mainly caused by the inhibition of noradrenaline transporters in the peripheral sites.

Full text of DOI:10.1016/j.bmc.2015.05.017

Accepted Manuscript
Design, Synthesis and Biological Evaluation of a Novel Series of Peripheral-
Selective Noradrenaline Reuptake Inhibitor
Ikuo Fujimori, Tomoya Yukawa, Taku Kamei, Yoshihisa Nakada, Nobuki
Sakauchi, Masami Yamada, Yusuke Ohba, Maiko Takiguchi, Masako Kuno,
Izumi Kamo, Hideyuki Nakagawa, Teruki Hamada, Tomoko Igari, Teruaki
Okuda, Satoshi Yamamoto, Tetsuya Tsukamoto, Yuji Ishichi, Hiroyuki Ueno
PII:
S0968-0896(15)00417-4
DOI:
http://dx.doi.org/10.1016/j.bmc.2015.05.017
BMC 12313
Reference:
To appear in:
Bioorganic & Medicinal Chemistry
Received Date:
Revised Date:
Accepted Date:
12 April 2015
6 May 2015
8 May 2015
Please cite this article as: Fujimori, I., Yukawa, T., Kamei, T., Nakada, Y., Sakauchi, N., Yamada, M., Ohba, Y.,
Takiguchi, M., Kuno, M., Kamo, I., Nakagawa, H., Hamada, T., Igari, T., Okuda, T., Yamamoto, S., Tsukamoto,
T., Ishichi, Y., Ueno, H., Design, Synthesis and Biological Evaluation of a Novel Series of Peripheral-Selective
Noradrenaline Reuptake Inhibitor, Bioorganic & Medicinal Chemistry (2015), doi: http://dx.doi.org/10.1016/j.bmc.
2
015.05.017
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Design, Synthesis and Biological Evaluation of a Novel Series of Peripheral-Selective
Noradrenaline Reuptake Inhibitor
Ikuo Fujimori, Tomoya Yukawa*, Taku Kamei, Yoshihisa Nakada, Nobuki Sakauchi, Masami Yamada,
Yusuke Ohba, Maiko Takiguchi, Masako Kuno, Izumi Kamo, Hideyuki Nakagawa, Teruki Hamada,
Tomoko Igari, Teruaki Okuda, Satoshi Yamamoto, Tetsuya Tsukamoto, Yuji Ishichi, Hiroyuki Ueno.
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraokahigashi 2-
chome, Fujisawa, Kanagawa 251-8555, Japan
Abstract
Centrally acting noradrenaline reuptake inhibitor (NRI) is reportedly effective for patients with
stress urinary incontinence (SUI) by increasing urethral closure in the clinical Phase IIa study with
esreboxetine. Noradrenaline transporters are expressed in both central and peripheral nervous systems
and the contribution of each site to efficacy has not been clarified. This report describes the
development of a series of peripheral-selective 7-phenyl-1,4-oxazepane NRIs to investigate the
contribution of the peripheral site to increasing urethral resistance in rats. (6S,7R)-1,4-Oxazepane
derivative 7 exhibited noradrenaline transporter inhibition with high selectivity against inhibitions of
serotonin and dopamine transporters. A replacement of hydroxyl with acetamide group contributed to
enhancement of peripheral selectivity by increasing molecular polarity. Compound 12, N-{[(6S,7R)-7-
(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methyl}acetamide 0.5 fumarate, which showed effectively no
brain penetration in rats, increased urethral resistance in a dose-dependent manner and exhibited a
maximal effect on par with esreboxetine. These results demonstrate that the urethral resistance-
increasing effects of NRI in rats are mainly caused by the inhibition of noradrenaline transporters in the
peripheral sites.
1

KEYWORDS: Peripheral-selective noradrenaline reuptake inhibitor, Stress urinary incontinence, 7-
Aryl-1,4-oxazepane derivatives.
ABBREVIATIONS: SUI, Stress urinary incontinence; DAT, dopamine transporter; SERT, serotonin
transporter; NET, norepinephrine transporter; hERG, human ether-a-go-go-related gene K+ channel;
CNS, central nervous system; Boc, tert-butoxycarbonyl.
*
Corresponding author. Tel: +81-466-32-1105. Fax: +81-466-29-4454;
e-mail: tomoya.yukawa@takeda.com
1
. Introduction
Stress urinary incontinence (SUI) is a disorder of lower urinary tract functions, and is defined as
involuntary urine leakage during events increasing abdominal pressure such as laughing, sneezing,
coughing and lifting. Prevalence of SUI in women increases over 20 years old, and it is reported that the
1
symptom is found in 33.9% of women aged 40 years and older. Current treatment options of SUI are
2
very limited; physical therapy and surgery are standard treatment. In 2004, duloxetine, an
antidepressant based on serotonin and noradrenaline reuptake inhibition, was approved for treatment of
3
SUI in only a few countries in EU. Esreboxetine, which is a centrally acting selective noradrenaline
reuptake inhibitor (NRI), also showed a significant reduction in frequency of incontinence episodes in
4
SUI patients compared with placebo in the US study. However, all the antidepressants, including
duloxetine are obliged to be labeled with a “black box warning” about increased risks of suicidality in
5
children, adolescent and young adults. Noradrenaline transporter (norepinephrine transporter, NET),
which is responsible for the reuptake of extracellular noradrenaline, is known to express in both central
and peripheral nervous systems. Central and peripheral enhancement of the noradrenaline system are
each recognized to have the potential to increase urethral resistance; the former acts at the presynaptic
2

cells of motor neurons innervating the external urethral sphincter in the sacral spinal cord, and the latter
6
acts at the terminus of the autonomic hypogastric nerve innervating the urethral smooth muscle.
However, contribution of each site to the efficacy was not clarified so far. It was considered that if
peripheral-selective NRIs, which inhibit the peripheral NET dominantly, showed anti-SUI effects, the
compounds would be useful drugs for the treatment of SUI without causing central adverse effects.
Therefore, we attempted to synthesize novel peripheral and monoamine selective NRIs, and assessed
their biological potential as a novel class of therapeutic agent for SUI.
The design of peripheral and monoamine selective NRIs is outlined in Figure 1. Most reported
7
monoamine reuptake inhibitors have a lipophilic aromatic ring and basic amino group as the core motif.
Among them, some structurally rigid inhibitors such as amitifadine or milnacipran possess two or three
carbon atoms between the aromatic ring and the amino group. We supposed these structures are
essential for the monoamine reuptake inhibitory activities, and generated a primary scaffold I, which
consists of an aromatic ring, a linker with three carbon atoms, and an amine moiety. Independent study
about two carbon atoms linker series will be disclosed in due course. On the other hand, 7-membered
1
,4-diazepan-2-one derivative II, a serotonin, noradrenaline and dopamine reuptake inhibitor (triple
reuptake inhibitor) was reported by our laboratory. This compound showed relatively noradrenaline
8
selective reuptake inhibition. As a design strategy for selective NRI, we applied the "7-membered ring"
of II as a noradrenaline selective core ring to "three carbon atoms" in a primary scaffold I, and designed
the core scaffold of 4-phenylazepine and 7-phenyl-1,4-oxazepane III. To achieve peripheral selectivity,
hydrophilic functional group (FG) was additionally located on the core ring to increase polarity of the
molecule. Indeed, similar approach was reported in peripherally restricted Cannabinoid 1 (CB1)
9
antagonist study, which is succeeded in reducing the psychiatric side effects. In a series of the studies,
the most common strategy is addition of polar groups to known brain penetrant CB1 antagonists to
1
0
provide peripherally-selective compounds. In addition, these classes of monoamine reuptake inhibitors
might have a drug-drug interaction liability through CYP2D6 inhibition and hERG inhibition due to the
3

1
1
cationic amphiphilic drug (CAD) structure. Aware of these risks, we evaluated and prioritized
compounds based on CYP2D6 inhibition.
We set out to explore novel peripheral-selective NRIs based on scaffold III, and found that 4-
phenylazepane derivative 1 and 7-phenyl-1,4-oxazepane derivative 2 demonstrated potent NET
inhibitory activity with moderate selectivity against serotonin transporter (SERT) and dopamine
transporter (DAT) inhibitions. Thus, we selected the compounds as leads, and studied the substituents R
on the benzene ring and the hydrophilic substituents FG to obtain the novel compounds with superior
NRI activity and peripheral selectivity.
[
Figure 1]
2
. Chemistry
The synthesis of the 4-phenylazepane derivative 1 is shown in Scheme 1. Addition of dichlorophenyl
magnesium bromide to commercially available cyclohexenyl ketone 18 and subsequent cyano group
addition afforded cyclohexyl ketone 20. After protection of the ketone 20 as the 1,3-dioxolane, the
nitrile of compound 21 was reduced to hydroxymethyl group in two steps. Deprotection of the 1,3-
dioxolane moiety of compound 22 and silylation of the hydroxyl group gave cyclohexanone 23. Ring
expansion by Beckmann rearrangement provided azepan-2-one derivative 24. The amide motif of
compound 24 was reduced to amine using borane-tetrahydrofuran complex. After treatment in acidic
condition, the amine group was protected by Boc group and deprotected by treating with hydrogen
chloride to afford the 4-phenylazepane derivative 1 as the HCl salt.
[
Scheme 1]
The synthesis of the 7-phenyl-1,4-oxazepane derivatives 2–4 is shown in Scheme 2. Commercially
available nitrile derivative 25 was transformed to phenylketone 26 using the corresponding Grignard
4

reagent. After addition of acetonitrile anion to 26, the cyano group was reduced to give the
corresponding amine 28. Reductive alkylation of the amine with benzaldehyde and subsequent acylation
with chloroacetyl chloride furnished amide 29. Intramolecular cyclization of 29 under basic condition
afforded 7-phenyl-1,4-oxazepan-3-one 30. After reduction of amide 30 to amine derivative 31,
replacement of the N-benzyl with Boc protection gave compound 32, followed by removal of the p-
methoxy benzyl group of 32 using ceric ammonium nitrate afford hydroxymethyl derivative 33. Finally,
optical resolution of 33 was carried out using preparative chiral HPLC and typical deprotection gave 7-
phenyl-1,4-oxazepane derivatives 2–4 as the HCl salt.
[
Scheme 2]
The preparation of 6-hydroxymethyl 7-phenyl-1,4-oxazepane derivatives 5–8 is illustrated in Scheme
. Morita-Baylis-Hillman reaction of dichlorobenzaldehyde 34 with methyl acrylate afforded ester 35.
3
Michael addition of benzyl amine gave a mixture of two diastereomers (rac-36, rac-37), which were
separated by silica gel column chromatography. After transformation of the methyl ester rac-36 to the
silyl ether rac-38 via a hydroxymethyl intermediate, N-selective acylation with chloroacetyl chloride
gave amide rac-39. Cyclization of rac-39 under basic conditions gave 6-substituted 1,4-oxazepan-3-one
rac-40. After reduction of the amide group, N-benzyl group was replaced with Boc along with de-
protection of hydroxyl group afforded hydroxymethyl derivative rac-42. Optical resolution of rac-42
using preparative chiral HPLC, followed by typical deprotection of Boc group afforded (6S,7R)-7 and
(6R,7S)-8. Erythro isomer rac-37 was converted to hydroxymethyl derivative (6S,7S)-5 and (6R,7R)-6
in the similar manner as threo isomer. The absolute stereochemistry of 5 and 7 were confirmed by
single-crystal X-ray analysis (Figure 2).
[
Scheme 3]
5

[
Figure 2]
The preparation of (6S,7R)-7-phenyl-1,4-oxazepane derivatives 9–17 is shown in Scheme 4.
Carboxylic acid 45 was prepared by Pinnick oxidation via aldehyde intermediate 44 and subsequent
condensation with the desired amines and typical deprotection of Boc gave corresponding carboxamides
9
4
–11. The hydroxyl group of compound 43a–e was converted into an amine 48a–e via the mesylate
6a–e and azide 47a–e, and was then treated with acetyl chloride and hydrogen chloride furnish
acetamide 12 and 14–17 as the HCl or fumaric acid salt. Extended acetamide 13 was synthesized via a
cyano intermediate followed by reduction of the cyano group, acetylation of the amine with acetyl
chloride and treatment in hydrochloric acid.
[
Scheme 4]
3
. Results and discussion
The synthesized compounds were evaluated for their in vitro reuptake inhibitory activity against
human NET, SERT and DAT, expressed as IC50 values. Brain penetration was evaluated by
investigating NET occupancy in rat brain after intravenous injection at 3 mg/kg.
First, we evaluated configuration of the substituents on the 7-membered ring and position of the
hydrophilic substituents FG in III (Table 1). In an initial SAR study, the 3,4-dichlorophenyl group was
1
1
adopted as a NET selective Ar moiety on this oxazepane/azepane system. The 4-Phenylazepane
derivative 1 and 7-phenyl-1,4-oxazepane derivative 2 showed potent NET inhibitory activity with
moderate selectivity against SERT and DAT. The oxazepane derivative 2 demonstrated weaker
CYP2D6 inhibition than the corresponding azepane 1 (19% vs 44%) suggesting that a lower ClogP
1
2
value is favorable to avoid this liability (ClogP; 2: 1.9, 1: 2.9). The (7S)-isomer 4 showed
approximately 100-fold potent NET inhibition compared to the (7R)-isomer 3. In contrast, neither SERT
nor DAT inhibitory activity was affected by the absolute configuration. These results indicated that the
6

absolute configuration of 7-position on 1,4-oxazepane ring was critical for the NET inhibitory activity
in the 7-hydroxymethyl series. Interestingly, potent NET inhibition was conserved among four
stereoisomers [5 (6S,7S), 6 (6R,7R), 7 (6S,7R) and 8 (6R,7S)] in the 6-hydroxymethyl series. DAT
inhibitory activities were weak in all the stereo isomers. On the other hand, SERT inhibitory activity
was dependent on the configuration of phenyl groups. The (7S)-isomers 5 and 8 showed stronger SERT
inhibition than the (7R)-isomers 6 and 7. Between the (7R)-isomers, the trans isomer 7 exhibited higher
selectivity against SERT and DAT than the cis isomer 6. Regarding CYP2D6 inhibition, the trans
isomers showed lower potential than cis isomers (5 and 6 vs 7 and 8). Among the evaluated compounds,
the (6S,7R)-compound 7 showed the most potent NET inhibitory activity, the highest selectivity against
SERT and DAT inhibitions, and relatively low CYP2D6 liability. Thus we selected this stereoisomer as
the core template.
[
Table 1]
Compound 7 showed highly selective NRI profiles. However, peripheral selectivity, which was
estimated by rat brain NET occupancy, was insufficient, as rat brain NET occupancy was 68%,
indicating that the compound penetrated into the brain as shown in Table 2. To achieve superior
peripheral selectivity, introduction of amide motif at the 6-position was conducted (Table 2).
Replacement of hydroxymethyl group with carbamoyl group (9) gave a reduction in NET inhibitory
activity. Methyl capping of the carbamoyl nitrogen atom (10 and 11) increased NET inhibitory activity
along with lipophilicity (CLogP; 9: 1.8, 10: 2.1, 11: 2.6), resulting in poor peripheral selectivity (rat
brain NET occupancy = 68%). Enhancement of DAT inhibition was observed in compound 11.
Inversion of the amide linker (12) enhanced NET inhibition. In addition, compound 12 showed excellent
peripheral selectivity. The profiles appear to be correlated with the ClogP values. Linker extension (13)
decreased the inhibitory activity, suggesting that the length of the linker is critical, especially for the
NET inhibition. Next, substituents on benzene ring were evaluated to investigate the effects on
7

1
3
selectivity against SERT and DAT. Replacement of the chlorine atom at the 3-position on benzene
ring with fluorine (14) retained high selectivity. Meanwhile, similar exchange at the 4-position (15)
decreased the selectivity. These replacements maintained the peripheral selective profiles. Replacement
of the 3 or 4-chlorine with a methyl group (16 and 17) also did not improve selectivity against SERT
and DAT. Among the evaluated compounds, compound 12 demonstrated the most potent and selective
NET inhibition as well as the greatest peripheral selectivity and a reduced potential for the liabilities
1
4
often seen with CAD structures (CYP2D6 at 10 μM: 26%, hERG inhibition at 10 μM: 15%). Thus,
compound 12 was selected for further in vivo evaluation.
[
Table 2]
The in vivo activities of compound 12 were evaluated by measuring effects on leak point pressure,
which indicates urethral resistance, in rats. The leak point pressure was measured at 0.5 h after i.v.
administration of compound 12 and 0.5 h after s.c. administration of esreboxetine. As shown in Figure 3,
compound 12 significantly increased urethral resistance in a dose-dependent manner and the maximum
leak point pressure elevation was comparable to that by esreboxetine. Considering the negative CNS-
penetrating property of compound 12 (NET occupancy = -14%), the urethral resistance-increasing
effects of compound 12 in rats were suggested to be mainly mediated by the inhibition of peripheral
NET. Esreboxetine treatment increases urethral closure in the rat model, as well as in a human clinical
trial, and this increased urethral closure appears to decrease the frequency of incontinence episodes in
1
6
SUI patients. Taken together, these findings suggest that peripheral-selective NRI have the potential to
show anti-SUI efficacy in humans.
[
Figure 3]
4
. Conclusion
8

Novel peripheral-selective NRIs were designed, and a compound with low CNS-penetration property
was evaluated in a model of SUI. Optimization of (6S,7R)-1,4-oxazepane derivatives led to the potent
and highly NET selective compound 12 which exhibited excellent peripheral selective effects.
Compound 12 showed significant increase in urethral resistance in rats with the comparable maximum
effects to the central acting, and clinically effective esreboxetine. These results suggest that urethral
resistance-increasing effects of NRI are mainly caused by inhibition of NETs in the peripheral sites and
this series of peripheral-selective NRIs would be a novel class of therapeutic agent for SUI.
5
5
. Experimental Section
.1. Chemistry
Melting points were determined with a Yanagimoto melting point apparatus or a Büchi melting point
1
apparatus B-545 and are uncorrected. H NMR spectra were obtained at 300 MHz on a Varian Ultra-300,
or a Bruker DPX-300 spectrometer. Chemical shifts are given in δ values (ppm) using tetramethylsilane
as the internal standard. Peak multiplicities are expressed as follows: s, singlet; d, doublet; t, triplet; q,
quartet; dd, doublet of doublet; ddd, doublet of doublet of doublets; dt, double triplet; td, triple doublet;
quin., quintet; brs, broad singlet; m, multiplet. Elemental analyses were carried out by Takeda
Analytical Laboratories Ltd. Reactions were followed by TLC on Silica gel 60 F 254 precoated TLC
9

plates (E. Merck) or NH TLC plates (Fuji Silysia Chemical Ltd.). Chromatographic separations were
carried out on silica gel 60 (0.063–0.200 or 0.040–0.063 mm, E. Merck) or basic silica gel
(Chromatorex® NH, 100–200 mesh, Fuji Silysia Chemical Ltd.) using the indicated eluents. Yields are
unoptimized. The HPLC analyses were performed using a Shimadzu UFLC instrument. Elution was
done with a gradient of 5–90% solvent B in solvent A (solvent A was 0.1% TFA in water, and solvent B
-1
was 0.1% TFA in MeCN) through a L-column 2 ODS (3.0 × 50 mm, 2 μm) column at 1.2 mL min .
Area % purity was measured at 254 nm. Abbreviations for solvents are the following: Et O, diethyl
2
ether; MeOH, methanol; EtOH, ethanol; BuOH, butanol; EtOAc, ethyl acetate; THF, tetrahydrofuran;
DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; MeCN, acetonitrile; CDCl , chroloform-d;
3
Et N, triethylamine; Boc O, di-tert-butyl dicarbonate; TBDMSCl, tert-butyldimethylsilyl chloride;
3
2
WSC•HCl, water soluble carbodiimide hydrochloride (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
hydrochloride); HOBt•NH , 1-hydroxybenzotriazole ammonium salt; DIBAL-H, diisobutylaluminium
3
hydride; DMAP, N,N-dimethyl-4-aminopyridine.
5
.1.1. Typical procedure of obtaining compounds 1–17 by deprotection of Boc.
Typical procedure A: To a solution of Boc intermediate in EtOH (0.2 M) was added 14.7 M HCl in
EtOH (10–100 eq.) at room temperature. The mixture was stirred at room temperature for 1–24 h and
then concentrated in vacuo. The residue was crystallized or triturated with EtOAc-hexane to give target
compound.
Typical procedure B: To a solution of Boc intermediate was added 4 M HCl in EtOAc (10–100 eq.)
at room temperature. The mixture was stirred at room temperature for 1–24 h and then concentrated in
vacuo. The residue was crystallized or triturated with EtOAc-hexane to give target compound.
5
.1.2. 3-(3,4-Dichlorophenyl)cyclohex-2-enone (19). A suspension of Mg (1.04 g, 42.8 mmol) in
THF (10 mL) was added 4-bromo-1,2-dichlorobenzene (9.67 g, 42.8 mmol) in THF (20 mL) and I (1
2
spatura) at room temperature. The mixture was stirred at 45°C under N for 1 h and then 3-
2
ethoxycyclohex-2-en-1-one 18 (4.76 mL, 35.7 mmol) in THF (10 mL) was added at 0°C. The mixture
was stirred at room temperature under N for 1 h. The mixture was added with 1 M HCl aq. at 0°C,
2
1
0

extracted with EtOAc, washed with water and brine, dried over MgSO and concentrated in vacuo. The
4
residue was purified by column chromatography (silica gel, hexane/EtOAc) to give 19 (5.51 g, 64%) as
1
a colorless crystal. H NMR (300 MHz, CDCl ) δ 2.16 (2H, quin, J = 6.3 Hz), 2.43−2.54 (2H, m), 2.72
3
(2H, td, J = 6.0, 1.5 Hz), 6.37 (1H, t, J = 1.5 Hz), 7.33−7.41 (1H, m), 7.45−7.51 (1H, m), 7.61 (1H, d, J
=
2.3 Hz).
5
.1.3. 1-(3,4-Dichlorophenyl)-3-oxocyclohexanecarbonitrile (20). To a solution of 19 (5.0 g, 20.7
mmol) in DMF (60 mL) and water (15 mL) was added Et N hydrochloride (4.28 g, 31.1 mmol) and
3
potassium cyanide (2.70 g, 41.5 mmol) at room temperature. The mixture was stirred at 90°C for 3 h.
The mixture was poured into sat. NaHCO aq. at room temperature, extracted with EtOAc, washed with
3
sat. NH Cl aq. and brine, dried over MgSO and concentrated in vacuo. The residue was purified by
4
4
1
column chromatography (silica gel, hexane/EtOAc) to give 20 (1.50 g, 27%) as a colorless oil. H NMR
300 MHz, CDCl ) δ 2.10−2.27 (3H, m), 2.33−2.48 (2H, m), 2.55−2.65 (1H, m), 2.75−2.83 (1H, m),
(
3
2
.86−2.94 (1H, m), 7.33 (1H, dd, J = 8.5, 2.5 Hz), 7.52 (1H, d, J = 8.3 Hz), 7.57 (1H, d, J = 2.3 Hz).
5
.1.4. 7-(3,4-Dichlorophenyl)-1,4-dioxaspiro[4.5]decane-7-carbonitrile (21). To a solution of 20
(1.5 g, 5.59 mmol) in toluene (15 mL) was added ethylene glycol (620 μL, 11.2 mmol) and pyridinium
p-toluenesulfonate (70.0 mg, 0.28 mmol) at room temperature. The mixture was stirred 125°C for 3 h.
The mixture was poured into water, extracted with EtOAc, washed with brine, dried over MgSO and
4
concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane/EtOAc)
1
to give 21 (1.30 g, 74%) as a colorless oil. H NMR (300 MHz, CDCl ) δ 1.48–1.64 (1H, m), 1.65–1.78
3
(1H, m), 1.82–1.98 (3H, m), 2.08–2.39 (3H, m), 3.88–4.01 (2H, m), 4.05–4.17 (2H, m), 7.32–7.39 (1H,
m), 7.42–7.51 (1H, m), 7.60 (1H, d, J = 2.3 Hz).
5
.1.5. (7-(3,4-Dichlorophenyl)-1,4-dioxaspiro[4.5]decan-7-yl)methanol (22). To a solution of 21
1.3 g, 4.16 mmol) in toluene (15 mL) was added 1.6 M DIBAL-H in toluene (3.61 mL, 5.41 mmol)
under N at -78°C. The mixture was stirred at -78°C to room temperature under N for 1 h and then 1 M
(
2
2
HCl aq. (1.6 mL) was added. After stirring for 1 h, the mixture was poured into water, extracted with
1
1

EtOAc, washed with and brine, dried over MgSO and concentrated in vacuo. The residue was purified
4
by column chromatography (silica gel, hexane/EtOAc) to give 7-(3,4-dichlorophenyl)-1,4-
1
dioxaspiro[4.5]decane-7-carbaldehyde (920 mg, 70%) as a colorless oil. H NMR (300 MHz, CDCl ) δ
3
1
.50 (2H, d, J = 5.3 Hz), 1.70–1.88 (3H, m), 2.00 (1H, s), 2.50–2.65 (2H, m), 3.90–4.08 (4H, m), 7.11
(1H, dd, J = 8.7, 2.3 Hz), 7.33–7.46 (2H, m), 9.35 (1H, d, J = 1.9 Hz). To a solution of 7-(3,4-
dichlorophenyl)-1,4-dioxaspiro[4.5]decane-7-carbaldehyde (920 mg, 2.92 mmol) in MeOH (10 mL)
was added NaBH (120 mg, 3.17 mmol) at 0°C. The mixture was stirred at 0°C to room temperature
4
overnight. The mixture was neutralized with 0.1 M HCl aq. at 0°C, extracted with EtOAc, washed with
water and brine, dried over MgSO and concentrated in vacuo. The residue was purified by column
4
1
chromatography (silica gel, hexane/EtOAc) to give 22 (910 mg, 98%) as a colorless oil. H NMR (300
MHz, CDCl ) δ 1.45–1.56 (1H, m), 1.59–1.99 (7H, m), 2.16 (1H, d, J = 14.0 Hz), 3.60–3.71 (1H, m),
3
3
.75–3.85 (1H, m), 3.86–4.07 (4H, m), 7.22 (1H, dd, J = 8.3, 2.3 Hz), 7.39 (1H, d, J = 8.7 Hz), 7.46
(1H, d, J = 2.3 Hz).
5
.1.6. 3-((tert-Butyldimethylsilyloxy)methyl)-3-(3,4-dichlorophenyl)cyclohexanone (23). To a
solution of 22 (910 mg, 2.87 mmol) in acetone (5 mL) was added 1 M HCl aq. (5 mL, 5.00 mmol) at
room temperature. The mixture was stirred 65°C for 3 h. The mixture was poured into water at room
temperature, extracted with EtOAc, washed with brine, dried over MgSO and concentrated in vacuo.
4
The residue was purified by column chromatography (silica gel, hexane/EtOAc) to give a colorless oil.
To a solution of the oil in THF (5 mL) was added TBDMSCl (452 mg, 3.00 mmol), Et N (569 μL, 4.09
3
mmol) and DMAP (10 mg, 0.08 mmol) at room temperature. The mixture was stirred 65°C overnight.
The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer
was separated, washed with brine, dried over MgSO and concentrated in vacuo. The residue was
4
purified by column chromatography (silica gel, hexane/EtOAc) to give 23 (880 mg, 79%) as a colorless
1
oil. H NMR (300 MHz, CDCl ) δ -0.01–0.04 (6H, m), 0.80–0.95 (9H, m), 1.52–1.64 (1H, m), 1.87–
3
1
2

2
.04 (1H, m), 2.13–2.45 (4H, m), 2.71–2.90 (2H, m), 3.37–3.50 (1H, m), 3.54–3.67 (1H, m), 7.21 (1H,
dd, J = 8.7, 2.3 Hz), 7.44 (1H, d, J = 8.3 Hz), 7.47 (1H, d, J = 2.3 Hz).
5
.1.7. 5-((tert-Butyldimethylsilyloxy)methyl)-5-(3,4-dichlorophenyl)azepan-2-one (24). To a
solution of 23 (880 mg, 2.27 mmol) in MeOH (2 mL) and pyridine (2 mL) was added hydroxylamine
hydrochloride (316 mg, 4.54 mmol). The mixture was stirred at 65°C for 1 h. The mixture was poured
into water at room temperature, extracted with EtOAc, washed with brine, dried over MgSO and
4
concentrated in vacuo. The residue in pyridine (4 mL) was added p-toluenesulfonyl chloride (866 mg,
4
.54 mmol) and DMAP (10 mg, 0.08 mmol). The mixture was stirred 80°C overnight. The mixture was
poured into water at room temperature, extracted with EtOAc, washed with brine, dried over MgSO4
and concentrated in vacuo. The residue was purified by column chromatography (silica gel,
1
hexane/EtOAc) to give 24 (66 mg, 7%) as a colorless oil. H NMR (300 MHz, CDCl ) δ -0.05–0.05 (6H,
3
m), 0.89–0.98 (9H, m), 1.65–1.80 (1H, m), 1.87–2.09 (2H, m), 2.48–2.62 (1H, m), 2.88–2.98 (1H, m),
3
.03–3.12 (1H, m), 3.17–3.43 (2H, m), 3.48 (2H, s), 6.01 (1H, brs), 7.41–7.46 (1H, m), 7.48–7.53 (1H,
+
m), 7.61 (1H, d, J = 2.3 Hz). MS m/z: 402 [M+H] .
5
.1.8. tert-Butyl 4-(3,4-dichlorophenyl)-4-(hydroxymethyl)azepane-1-carboxylate. To a solution of
4 (66 mg, 0.16 mmol) in THF (2 mL) was added 1.2 M borane-tetrahydrofuran complex THF solution
2 mL, 2.40 mmol) at room temperature. The mixture was stirred 65°C for 2 h and then 1 M HCl aq. (1
2
(
mL, 1.00 mmol) was added. The mixture was stirred at 60°C for 1 h. After cooling to room temperature,
Et N (500 μL, 3.60 mmol) and Boc O (57 μL, 0.25 mmol) were added. The mixture was stirred at room
3
2
temperature for 3 h. The mixture was poured into water, extracted with EtOAc, washed with brine, dried
over MgSO and concentrated in vacuo. The residue was purified by column chromatography (silica gel,
4
hexane/EtOAc) to give tert-butyl 4-(3,4-dichlorophenyl)-4-(hydroxymethyl)azepane-1-carboxylate
1
(
53.0 mg, 86%) as a colorless oil. H NMR (300 MHz, CDCl ) δ 1.27 (1H, brs), 1.33–1.44 (9H, m),
3
1
.57–1.69 (2H, m), 1.73–1.93 (2H, m), 2.18–2.42 (2H, m), 3.02–3.39 (3H, m), 3.46 (2H, s), 3.51–3.79
(1H, m), 7.15 (1H, dd, J = 8.5, 1.7 Hz), 7.38 (1H, d, J = 1.9 Hz), 7.44 (1H, d, J = 8.7 Hz).
1
3

5
.1.9. (4-(3,4-Dichlorophenyl)azepan-4-yl)methanol monohydrochloride (1). Typical procedure A,
1
5
7%, Colorless solid. H NMR (300 MHz, DMSO-d ) δ 1.45–1.66 (1H, m), 1.86 (2H, dd, J = 14.6, 10.0
6
Hz), 2.01–2.22 (2H, m), 2.33 (1H, dd, J = 15.9, 8.0 Hz), 2.88 (1H, dd, J = 13.6, 9.5 Hz), 3.01 (2H, t, J
=
5.1 Hz), 3.16–3.28 (1H, m), 3.35 (2H, d, J = 5.3 Hz), 4.89 (1H, t, J = 5.3 Hz), 7.32–7.41 (1H, m),
+
7
9
.54–7.66 (2H, m), 8.95 (2H, brs). MS m/z: 274.1 [M+H] .
5
.1.10. 1-(3,4-Dichlorophenyl)-2-(4-methoxyphenoxy)ethanone (26). To a suspension of Mg (2.23 g,
1.7 mmol) and I (5 mg) in Et O (20 mL) was added a solution of 1-bromo-3,4-dichlorobenzene (20.7
2
2
g, 91.7 mmol) in Et O (20 mL), and the mixture was stirred at 35°C for 1 h. The mixture was cooled to -
2
1
0°C, and Et O (100 mL) was added. A solution of [(4-methoxybenzyl)oxy]acetonitrile 25 (10 g, 61.2
2
mmol) in Et O (20 mL) was added dropwise at -10°C, and the mixture was stirred for 1 h to room
2
temperature. To the mixture was added 1 M HCl aq. (200 mL), and the mixture was stirred for 1 h,
extracted with EtOAc, washed with water and brine, dried over MgSO and concentrated in vacuo. The
4
residue was purified by column chromatography (NH silica gel, hexane/EtOAc) to give 26 (15.6 g,
1
8
1%) as a pale yellow solid. H NMR (300 MHz, CDCl ) δ 3.72–3.86 (3H, m), 5.12 (2H, s), 6.76–6.98
3
(4H, m), 7.57 (1H, d, J = 8.3 Hz), 7.84 (1H, dd, J = 8.5, 2.1 Hz), 8.09 (1H, d, J = 1.9 Hz).
5
.1.11. 3-(3,4-Dichlorophenyl)-3-hydroxy-4-(4-methoxyphenoxy)butanenitrile (27). To a mixed
solution of MeCN (241 μL, 4.5 mmol) and THF (2 mL) was added dropwise a solution of n-
butyllithium in hexane (1.6 M, 3 mL, 4.81 mmol), and the mixture was stirred at -78°C for 30 min. To
the mixture was added dropwise a solution of 26 (1.0 g, 3.21 mmol) in THF (3 mL), and the mixture
was stirred at -78°C for 10 min, and then stirred for 1 h to room temperature. To the mixture was added
water, and the mixture was extracted with EtOAc, washed with brine, dried over MgSO and
4
concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane/EtOAc)
1
to give 27 (932 mg, 82%). H NMR (300 MHz, CDCl ) δ 2.86–3.14 (2H, m), 3.29 (1H, s), 3.77 (3H, s),
3
4
.06–4.24 (2H, m), 6.84 (4H, s), 7.33–7.42 (1H, m), 7.50 (1H, d, J = 8.7 Hz), 7.70 (1H, d, J = 2.3 Hz).
1
4

5
.1.12. 4-Amino-2-(3,4-dichlorophenyl)-1-(4-methoxyphenoxy)butan-2-ol (28). To a suspension of
LiAlH (2.53 g, 66.6 mmol) in Et O (50 mL) was added AlCl (2.96 g, 22.2 mmol), and the mixture was
4
2
3
stirred at 0°C for 30 min. To the mixture was added dropwise a solution of 27 (11.7 g, 33.3 mmol) in
THF (50 mL), and the mixture was stirred at 0°C for 15 min, and then stirred to room temperature for 2
h. Ice was added and the precipitate was filtered off through Celite. The filtrate was diluted with water,
extracted with EtOAc, washed with brine, dried over MgSO and concentrated in vacuo to give 28 (10.8
4
1
g, 91%). H NMR (300 MHz, CDCl ) δ 1.94–2.10 (1H, m), 2.25 (1H, ddd, J = 14.4, 10.2, 3.8 Hz),
3
2
3
.63–2.83 (1H, m), 2.99–3.14 (1H, m), 3.17–3.47 (3H, m), 3.68–3.78 (3H, m), 3.85 (1H, d, J = 9.1 Hz),
.94–4.05 (1H, m), 6.67–6.89 (4H, m), 7.41 (2H, s), 7.75 (1H, s).
5
.1.13.
N-Benzyl-2-chloro-N-[3-(3,4-dichlorophenyl)-3-hydroxy-4-(4-
methoxyphenoxy)butyl]acetamide (29). To a solution of 28 (500 mg, 1.40 mmol) in MeOH (2 mL)
was added MgSO (253 mg, 2.1 mmol), Et N (78 μL, 0.56 mmol) and benzaldehyde (148 μL, 1.47
4
3
mmol), and the mixture was stirred at room temperature for 1.5 h. To the mixture was added NaBH4
264 mg, 7.0 mmol), and the mixture was stirred at 0°C for 10 min, and then stirred to room temperature
(
for 1.5 h. The mixture was filtered through Celite and the filtrate was concentrated. The residue was
diluted with water, extracted with EtOAc, washed with brine, dried over MgSO and concentrated in
4
vacuo to give an oil (440 mg). To a solution of the oil in THF (3 mL) was added Et N (149 μL, 1.08
3
mmol) and chloroacetyl chloride (86 μL, 1.08 mmol), and the mixture was stirred at 0°C for 10 min, and
then stirred to room temperature for 2 h. The mixture was diluted with water, extracted with EtOAc,
washed with brine, dried over MgSO and concentrated in vacuo. The residue was purified by column
4
1
chromatography (silica gel, hexane/EtOAc) to give 29 (395 mg, 69%) as a colorless solid. H NMR
(
300 MHz, CDCl ) δ 2.13–2.43 (2H, m), 2.99 (1H, ddd, J = 15.4, 11.0, 4.9 Hz), 3.26–3.60 (2H, m),
3
3
.68–4.22 (7H, m), 4.40–4.66 (2H, m), 6.67–6.97 (4H, m), 7.07–7.72 (8H, m).
5
.1.14. 4-Benzyl-7-(3,4-dichlorophenyl)-7-[(4-methoxyphenoxy)methyl]-1,4-oxazepan-3-one (30).
To a solution of 29 (390 mg, 0.75 mmol) in THF (40 mL) was added NaOtBu (72 mg, 0.75 mmol), and
1
5

the mixture was stirred at 0°C for 2 h and then stirred to room temperature for 14 h. After adding water,
the mixture was concentrated. The residue was diluted with water, extracted with EtOAc, washed with
brine, dried over MgSO and concentrated in vacuo. The residue was purified by column
4
1
chromatography (silica gel, hexane/EtOAc) to give 30 (256 mg, 70%) as a colorless oil. H NMR (300
MHz, CDCl ) δ 2.36 (1H, dd, J = 15.3, 10.0 Hz), 2.80 (1H, dd, J = 15.6, 8.1 Hz), 3.22 (1H, dd, J = 13.8,
3
7
4
.7 Hz), 3.56–3.88 (5H, m), 4.00 (1H, d, J = 9.4 Hz), 4.20 (1H, d, J = 17.0 Hz), 4.41–4.62 (2H, m),
.63–4.76 (1H, m), 6.60–6.85 (4H, m), 7.15–7.40 (6H, m), 7.45 (1H, d, J = 8.7 Hz), 7.53 (1H, d, J = 1.9
+
Hz). MS m/z: 486.1 [M+H] .
5
.1.15. 4-Benzyl-7-(3,4-dichlorophenyl)-7-[(4-methoxyphenoxy)methyl]-1,4-oxazepane (31). To a
solution of LiAlH (351 mg, 9.24 mmol) in Et O (10 mL) was added AlCl (412 mg, 3.08 mmol), and
4
2
3
the mixture was stirred at 0°C for 10 min. To the mixture was added dropwise a solution of 30 (2.25 g,
4
2
.62 mmol) in THF (10 mL) and the mixture was stirred at 0°C for 15 min and to room temperature for
h. After adding ice, the precipitate was filtered off through Celite. The filtrate was diluted with water,
extracted with EtOAc, washed with brine, dried over MgSO and concentrated in vacuo to give 31 (1.18
4
1
g, 49%) as a oil. H NMR (300 MHz, CDCl ) δ 2.18–2.45 (1H, m), 2.52–2.88 (5H, m), 3.46–3.63 (2H,
3
m), 3.63–3.84 (5H, m), 3.85–4.00 (2H, m), 6.57–6.83 (4H, m), 7.16–7.44 (7H, m), 7.60 (1H, d, J = 2.3
+
Hz). MS m/z: 472.4 [M+H]
5
.1.16.
tert-Butyl
7-(3,4-dichlorophenyl)-7-[(4-methoxyphenoxy)methyl]-1,4-oxazepane-4-
carboxylate (32). To a solution of 31 (1.18 g, 2.5 mmol) in MeCN (5 mL) was added Et N (415 μL,
3
3
.00 mmol) and 1-chloroethyl chloroformate (327 μL, 3.00 mmol), and the mixture was stirred at 90°C
for 1.5 h. The solvent was evaporated under reduced pressure and MeOH (20 mL) was added to the
residue. The mixture was stirred at 80°C for 1 h and then solvent was evaporated under reduced
pressure. To a solution of the residue in THF (5 mL) was added Et N (415 μL, 3.00 mmol) and Boc O
3
2
(689 μL, 3.00 mmol), and the mixture was stirred at room temperature for 1.5 h. The reaction mixture
was added water, extracted with EtOAc, washed with brine, dried over MgSO and concentrated in
4
1
6

vacuo. The residue was purified by column chromatography (silica gel, hexane/EtOAc) to give 32 (793
1
mg, 66%). H NMR (300 MHz, CDCl ) δ 1.44 (9H, s), 2.12–2.36 (1H, m), 2.71 (1H, dd, J = 15.3, 7.3
3
Hz), 3.25–3.63 (3H, m), 3.67–4.00 (8H, m), 6.64–6.89 (4H, m), 7.18–7.33 (1H, m), 7.43 (1H, d, J = 8.3
+
Hz), 7.57 (1H, d, J = 2.3 Hz). MS m/z: 382.1 [M+H-Boc]
5
.1.17. tert-Butyl 7-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (33). To
a solution of 32 (639 mg, 1.32 mmol) in MeCN (8 mL) and water (2 mL) was added ceric ammonium
nitrate (2.18 g, 4.00 mmol) at 0°C, and the mixture was stirred at 0°C for 30 min. The mixture was
added water, extracted with EtOAc, washed with brine, dried over MgSO and concentrated in vacuo.
4
The residue was purified by column chromatography (silica gel, hexane/EtOAc) to give 33 (440 mg,
1
8
8%). H NMR (300 MHz, CDCl ) δ 1.42 (9H, s), 1.87–2.08 (1H, m), 2.17 (1H, d, J = 9.1 Hz), 2.45
3
(1H, dd, J = 14.9, 7.4 Hz), 3.20–3.97 (8H, m), 7.19 (1H, dd, J = 8.5, 2.1 Hz), 7.39–7.52 (2H, m). MS
+
m/z: 320.3 [M+H-tBu] .
5
.1.18. tert-Butyl (7S)-7-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate,
tert-Butyl (7R)-7-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate.
A
racemate (50.4 g) of 33 was separated by SFC (column: CHIRALPAK AD-H, 30 mmID×250 mmL,
manufactured by DAICEL CHEMICAL INDUSTRIES, LTD., mobile phase: carbon dioxide/2-propanol
=
65/35) to give (7S)-compound having a longer retention time and (7R)-compound having a shorter
retention time.
5
.1.19. [7-(3,4-Dichlorophenyl)-1,4-oxazepan-7-yl]methanol monohydrochloride (2). Typical
1
procedure B, 99%, Colorless solid. H NMR (300 MHz, DMSO-d ) δ 2.36 (1H, dd, J = 16.3, 9.8 Hz),
6
2
3
.76 (1H, dd, J = 16.3, 8.0 Hz), 3.13 (3H, brs), 3.24–3.52 (3H, m), 3.62 (1H, dd, J = 13.8, 7.8 Hz),
.93–4.08 (1H, m), 4.97–5.21 (1H, m), 7.35 (1H, dd, J = 8.3, 1.9 Hz), 7.57 (1H, d, J = 1.9 Hz), 7.63
+
(
1H, d, J = 8.7 Hz), 9.18 (2H, brs). MS m/z: 276.2 [M+H] .
1
7

5
.1.20. [(7R)-7-(3,4-Dichlorophenyl)-1,4-oxazepan-7-yl]methanol monohydrochloride (3). Typical
1
procedure B, 82%, Colorless crystal. H NMR (300 MHz, DMSO–d ) δ 2.36 (1H, dd, J = 16.4, 9.6 Hz),
6
2
.76 (1H, dd, J = 16.4, 7.7 Hz), 3.00–3.20 (3H, m), 3.24–3.37 (2H, m), 3.40–3.49 (1H, m), 3.56–3.69
(1H, m), 3.94–4.07 (1H, m), 5.09 (1H, t, J = 5.9 Hz), 7.35 (1H, dd, J = 8.5, 2.1 Hz), 7.57 (1H, d, J = 2.3
+
o
Hz), 7.60–7.67 (1H, m), 9.00–9.27 (2H, m). MS m/z: 276.1 [M+H] . Mp: 235–238 C. Anal. Calcd for
C H NO Cl : C,46.10; H,5.16; N,4.48. Found: C,46.17; H,5.12; N,4.53.
12
16
2
3
5
.1.21. [(7S)-7-(3,4-Dichlorophenyl)-1,4-oxazepan-7-yl]methanol monohydrochloride (4). Typical
1
procedure B, 79%, Colorless crystal. H NMR (300 MHz, DMSO-d ) δ 2.34 (1H, dd, J = 16.2, 9.8 Hz),
6
2
.76 (1H, dd, J = 16.6, 7.6 Hz), 3.01–3.21 (3H, m), 3.24–3.37 (2H, m), 3.40–3.50 (1H, m), 3.55–3.67
(1H, m), 3.95–4.07 (1H, m), 5.08 (1H, t, J = 5.9 Hz), 7.35 (1H, dd, J = 8.7, 2.3 Hz), 7.57 (1H, d, J = 1.9
+
o
Hz), 7.61–7.67 (1H, m), 8.83–9.24 (2H, m). MS m/z: 276.1 [M+H] . Mp: 235–238 C. Anal. Calcd for
25
C H NO Cl : C,46.10; H,5.16; N,4.48. Found: C,46.01; H,5.17; N,4.59. [α] +46.5 (c 0.25, MeOH).
12
16
2
3
D
5
.1.22. Methyl 2-[(3,4-dichlorophenyl)(hydroxy)methyl]prop-2-enoate (35). Methyl acrylate (96
mL, 1.1 mol) was added to a mixture of 34 (125 g, 714 mmol) and 1,4-Diazabicyclo[2.2.2]octane (24.0
g, 214 mmol) in MeCN (100 mL) at room temperature. The mixture was stirred at room temperature for
3
days. The mixture was concentrated in vacuo. The residue was purified by column chromatography
1
(
silica gel, hexane/EtOAc) to give 35 (155 g, 83%) as a colorless oil. H NMR (300 MHz, CDCl ) δ
3
3
.17 (1H, d, J = 6.0 Hz), 3.75 (3H, s), 5.50 (1H, d, J = 5.7 Hz), 5.85 (1H, s), 6.37 (1H, s), 7.22 (1H, dd,
J = 8.3, 1.9 Hz), 7.41 (1H, d, J = 8.3 Hz), 7.48 (1H, d, J = 1.9 Hz).
5
.1.23. Methyl (2RS,3RS)-2-[(benzylamino)methyl]-3-(3,4-dichlorophenyl)-3-hydroxypropanoate
(rac-36), Methyl (2SR,3RS)-2-[(benzylamino)methyl]-3-(3,4-dichlorophenyl)-3-hydroxypropanoate
(
rac-37). To a mixture of 35 (13.6 g, 52.1 mmol) and Et N (8.74 mL, 62.6 mmol) in MeOH (100 mL)
3
was added benzylamine (6.84 mL, 62.6 mmol), and the mixture was stirred at room temperature for 3
days. The mixture was concentrated under reduced pressure, and the residue was purified by column
chromatography (silica gel, hexane/EtOAc) to give the less polar rac-36 (12.7 g, 63%) and more polar
1
8

1
rac-37 (4.17 g, 21%). rac-36: H NMR (300 MHz, CDCl ) δ 2.66–2.76 (2H, m), 3.11–3.23 (1H, m),
3
3
.66–3.79 (5H, m), 5.27 (1H, d, J = 4.9 Hz), 7.10 (1H, dd, J = 8.3, 1.5 Hz), 7.26–7.40 (6H, m), 7.45
1
(
1H, d, J = 1.9 Hz). rac-37: H NMR (300 MHz, CDCl ) δ 2.85–2.98 (2H, m), 3.01–3.12 (1H, m), 3.58
3
(3H, s), 3.71–3.86 (2H, m), 5.12 (1H, d, J = 3.8 Hz), 7.09 (1H, dd, J = 8.3, 1.9 Hz), 7.26–7.45 (7H, m).
5
.1.24.
(1RS,2SR)-3-(Benzylamino)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-(3,4-
dichlorophenyl)propan-1-ol (rac-38). To a suspension of CaCl (67.8 g, 611 mmol) in THF (450 mL)
2
and EtOH (200 mL) was added NaBH (30.8 g, 815 mmol) at room temperature. To the mixture was
4
added dropwise rac-36 (150 g, 407 mmol) in THF (200 mL) and EtOH (200 mL) at 0°C. The mixture
was stirred at room temperature overnight. The mixture was neutralized with 6M HCl aq. (160 mL) at
0
°C and stirred at room temperature overnight. The mixture was neutralized with 8M NaOH aq. (40
mL), and then filtered through Celite. The filtrate was concentrated in vacuo, extracted with EtOAc,
washed with brine, dried over MgSO and concentrated in vacuo to give an colorless oil. To a solution
4
of the oil in THF (1 L) was added Et N (62.6 mL, 449 mmol) at 0°C and then TBDMSCl (61.6 g, 409
3
mmol) in THF (350 mL) was added at room temperature. The mixture was stirred overnight, and then
imidazole (33.4 g, 490 mmol) was added. The mixture was stirred at room temperature for 5h, and then
DMAP (21 g, 172 mmol) was added. After stirring overnight, the mixture was poured into water and
extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO and
4
concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane/EtOAc)
1
to give rac-38 (113 g, 61%) as a colorless oil. H NMR (300 MHz, CDCl ) δ 0.00 (6H, s), 0.88 (9H, s),
3
1
.68–1.81 (1H, m), 2.84–3.06 (2H, m), 3.40–3.49 (1H, m), 3.49–3.59 (1H, m), 3.77 (2H, s), 4.82–4.90
+
(
1H, m), 7.12–7.17 (1H, m), 7.25–7.39 (6H, m), 7.46 (1H, d, J = 1.9 Hz). MS m/z: 454.1 [M+H] .
5
.1.25. N-Benzyl-N-[(2RS,3SR)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(3,4-dichlorophenyl)-
3
-hydroxypropyl]-2-chloroacetamide (rac-39). A solution of 2-chloroacetyl chloride (28.1 mL, 351
mmol) in THF (200 mL) was added to a mixture of rac-38 (145 g, 319 mmol) and Et N (53.4 mL, 383
3
mmol) in THF (1 L) at 0°C dropwise. The mixture was stirred at ambient temperature over weekend and
1
9

then concentrated in vacuo. The residue was diluted with water, extracted with EtOAc, washed with
water and brine, dried over Na SO and concentrated in vacuo to give rac-39 (169 g, quant.). MS m/z:
2
4
+
5
14.1 [M+H-OH] .
5
.1.26. (6RS,7SR)-4-Benzyl-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-(3,4-dichlorophenyl)-1,4-
oxazepan-3-one (rac-40). 1 M NaOH aq. (479 mL, 479 mmol) was added to a solution of rac-39 (169 g,
19 mmol) in THF (1.2 L). The mixture was stirred at room temperature overnight and then
3
concentrated in vacuo. The residue was diluted with water, extracted with EtOAc, washed with water
and brine, dried over Na SO and concentrated in vacuo. The residue was purified by column
2
4
1
chromatography (silica gel, hexane/EtOAc) to give rac-40 (100 g, 64%) as colorless oil. H NMR (300
MHz, CDCl ) δ -0.06 (6H, d, J = 1.5 Hz), 0.85 (9H, s), 1.90–2.03 (1H, m), 3.20 (1H, dd, J = 10.4, 6.6
3
Hz), 3.32 (1H, dd, J = 10.4, 4.3 Hz), 3.53–3.63 (1H, m), 3.63–3.71 (1H, m), 4.31 (1H, d, J = 1.5 Hz),
4
.33–4.38 (1H, m), 4.47 (1H, d, J = 14.4 Hz), 4.51–4.58 (1H, m), 4.85 (1H, d, J = 14.4 Hz), 7.13 (1H,
+
dd, J = 8.3, 2.3 Hz), 7.27–7.45 (7H, m). MS m/z: 494.0 [M+H] .
5
.1.27. (6RS,7SR)-4-Benzyl-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-(3,4-dichlorophenyl)-1,4-
oxazepane (rac-41). To a suspension of AlCl (16.2 g, 122 mmol) in THF (800 mL) was added LiAlH
3
4
(13.9 g, 365 mmol) at 0°C and the mixture was stirred at 0°C for 20 min. A solution of rac-40 (100 g,
2
03 mmol) in THF (500 mL) was added to the mixture at 0°C for 2 h. After being stirred at 0°C for 3.5
h, a solution of potassium sodium (+)-tartrate tetrahydrate (286 g, 1.01 mol) in water (500 mL) was
added to the reaction mixture at 0°C. The mixture was stirred overnight. The precipitate was removed
by filtration, and the filtrate was concentrated in vacuo. The residue was diluted with water, extracted
with EtOAc, washed with brine, dried over Na SO and concentrated in vacuo to give rac-41 (94 g,
2
4
1
9
2
4
6%) as colorless oil. H NMR (300 MHz, CDCl ) δ -0.05 (6H, s), 0.83 (9H, s), 2.07–2.23 (1H, m),
3
.57–2.77 (2H, m), 2.88 (2H, d, J = 3.8 Hz), 3.39–3.49 (1H, m), 3.51–3.64 (2H, m), 3.65 (2H, s), 3.93–
.04 (1H, m), 4.42 (1H, d, J = 8.3 Hz), 7.22 (1H, dd, J = 8.3, 2.3 Hz), 7.24–7.42 (6H, m), 7.49 (1H, d, J
=
2.3 Hz).
2
0

5
.1.28.
tert-Butyl
(6RS,7SR)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-
carboxylate (rac-42). Chloroformic acid 1-chloroethyl ester (25.5 mL, 234 mmol) was added to a
solution of rac-41 (93.7 g, 195 mmol) in MeCN (1 L). The mixture was stirred at room temperature for
3
0 min and then concentrated in vacuo. 1 M HCl aq. (10 mL) was added to the residue in MeOH (1 L).
The mixture was stirred at 80°C for 2 h. After cooling, the mixture was added Boc O (47.0 mL, 205
2
mmol) and Et N (32.6 mL, 234 mmol) at 0°C. The mixture was stirred at room temperature overnight
3
and then concentrated in vacuo. The residue was diluted with water, extracted with EtOAc, washed with
brine, dried over Na SO and concentrated in vacuo. The residue was purified by column
2
4
1
chromatography (silica gel, hexane/EtOAc) to give rac-42 (67.3 g, 92%) as colorless oil. H NMR (300
MHz, CDCl ) δ 1.51 (9H, s), 2.06–2.19 (1H, m), 3.05–3.30 (2H, m), 3.43 (1H, dd, J = 14.7, 6.4 Hz),
3
3
.49–3.67 (2H, m), 4.04–4.12 (3H, m), 4.21 (1H, dd, J = 10.0, 4.7 Hz), 4.33 (1H, d, J = 9.8 Hz), 7.19
+
(
1H, dd, J = 8.3, 1.9 Hz), 7.40 (1H, d, J = 8.3 Hz), 7.48 (1H, d, J = 1.9 Hz). MS m/z: 275.9 [M+H] .
5
.1.29. tert-Butyl (6S,7R)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate,
tert-Butyl (6R,7S)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate. Rac-42
67.3 g) was separated by HPLC (CHIRALPAK AD, 50 mmID×500 mmL, manufactured by DAICEL
CHEMICAL INDUSTRIES, LTD., mobile phase: hexane/ethanol = 900/100) to give (6S,7R)-42 (31.3 g,
99.9% ee., recovery rate 100%) having a shorter retention time and (6R,7S)-42 (29.9 g, >99.6% ee.,
recovery rate 98%) having a longer retention time.
(
>
5
.1.30. ((6S,7R)-7-(3,4-Dichlorophenyl)-1,4-oxazepan-6-yl)methanol monohydrochloride (7).
1
Typical procedure A, 95%, Colorless crystal. H NMR (300 MHz, DMSO-d ) δ 2.36–2.46 (1H, m),
6
3
4
2
.05–3.31 (5H, m), 3.42–3.52 (1H, m), 3.74–3.86 (1H, m), 3.99–4.11 (1H, m), 4.44 (1H, d, J = 10.2 Hz),
.93–5.03 (1H, m), 7.38 (1H, dd, J = 8.3, 1.9 Hz), 7.64–7.70 (2H, m), 9.07–9.51 (2H, m). MS m/z:
+
76.1 [M+H] . Anal. Calcd for C H NO Cl •0.5 H O: C,44.81;H,5.33;N,4.35. Found:
1
2
16
2
3
2
25
C,44.81;H,5.17;N,4.28. [α] +13.5 (c 0.25, MeOH).
D
2
1

5
.1.31. ((6R,7S)-7-(3,4-Dichlorophenyl)-1,4-oxazepan-6-yl)methanol monohydrochloride (8).
1
Typical procedure A, 90%, Colorless solid. H NMR (300 MHz, DMSO-d ) δ 2.43–2.48 (1H, m), 3.07–
6
3
4
.17 (2H, m), 3.20–3.30 (3H, m), 3.41–3.53 (1H, m), 3.75–3.90 (1H, m), 4.06 (1H, dt, J = 13.9, 4.4 Hz),
.45 (1H, d, J = 10.2 Hz), 4.97 (1H, brs), 7.39 (1H, dd, J = 8.3, 2.3 Hz), 7.63–7.71 (2H, m), 9.49 (2H,
+
25
brs). MS m/z: 276.1 [M+H] . [α] –16.8 (c 0.25, MeOH).
D
Cis derivatives 5 and 6 were prepared in a similar manner as trans isomer.
5
.1.32.
(1RS,2RS)-3-(Benzylamino)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-(3,4-
1
dichlorophenyl)propan-1-ol.
64%. H NMR (300 MHz, CDCl ) δ -0.02–0.02 (6H, m), 0.82–
3
0
3
.91 (9H, m), 2.01–2.13 (1H, m), 2.65–2.74 (1H, m), 2.80–2.91 (1H, m), 3.36 (1H, dd, J = 10.5, 6.4 Hz),
.55 (1H, dd, J = 10.5, 6.0 Hz), 3.71–3.84 (2H, m), 5.01 (1H, d, J = 3.8 Hz), 7.09 (1H, dt, J = 8.3, 1.1
+
Hz), 7.26–7.38 (6H, m), 7.43 (1H, d, J = 1.9 Hz). MS m/z: 454.1 [M+H] .
5
.1.33. N-Benzyl-N-[(2RS,3RS)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(3,4-dichlorophenyl)-
+
3
-hydroxypropyl]-2-chloroacetamide. Quant. MS m/z: 514.1 [M+H-OH] .
5
.1.34. (6RS,7RS)-4-Benzyl-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-(3,4-dichlorophenyl)-1,4-
1
oxazepan-3-one. 78%. H NMR (300 MHz, CDCl ) δ -0.10 (3H, s), -0.07 (3H, s), 0.83 (9H, s), 2.16–
3
2
.30 (1H, m), 3.18 (1H, dd, J = 10.4, 4.7 Hz), 3.42–3.55 (2H, m), 3.72 (1H, dd, J = 14.7, 6.8 Hz), 4.12
(1H, d, J = 14.4 Hz), 4.34 (1H, d, J = 15.1 Hz), 4.58–4.72 (2H, m), 5.28 (1H, d, J = 14.7 Hz), 7.09 (1H,
+
dd, J = 8.5, 2.5 Hz), 7.27–7.45 (7H, m). MS m/z: 494.2 [M+H] .
5
.1.35. (6RS,7RS)-4-Benzyl-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-(3,4-dichlorophenyl)-1,4-
1
oxazepane. Quant. H NMR (300 MHz, CDCl ) δ -0.11 (3H, s), -0.09 (3H, s), 0.74–0.83 (9H, m), 2.35–
3
2
.49 (1H, m), 2.56–2.86 (4H, m), 3.18–3.27 (1H, m), 3.31–3.41 (1H, m), 3.62–3.79 (3H, m), 3.85–3.95
1H, m), 4.98 (1H, d, J = 4.5 Hz), 7.18 (1H, dd, J = 8.3, 1.9 Hz), 7.24–7.41 (6H, m), 7.48 (1H, d, J =
.9 Hz).
(
1
2
2

5
.1.36.
tert-Butyl
(6RS,7RS)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-
1
carboxylate. 88%. H NMR (300 MHz, CDCl ) δ 1.43–1.55 (9H, m), 2.24–2.39 (1H, m), 3.08–3.96
3
(7H, m), 4.14–4.33 (2H, m), 4.64 (1H, d, J = 2.3 Hz), 7.10 (1H, dd, J = 8.3, 1.5 Hz), 7.30–7.45 (2H, m).
5
.1.37. tert-Butyl (6S,7S)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate,
tert-Butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate. tert-
Butyl (6RS,7RS)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (15.8 g) was
separated by HPLC (CHIRALPAK AD, 50 mmID×500 mmL, manufactured by DAICEL CHEMICAL
INDUSTRIES, LTD., mobile phase: hexane/2-propanol = 800/200) to give (6S,7S)-compound (7.9 g,
>99.9% ee., recovery rate 100%) having a shorter retention time and (6R,7R)-compound (7.4 g, >99.9%
ee., recovery rate 93%) having a longer retention time.
5
.1.38. [(6S,7S)-7-(3,4-Dichlorophenyl)-1,4-oxazepan-6-yl]methanol monohydrochloride
(5).
1
Typical procedure A, 35%, Colorless solid. H NMR (300 MHz, DMSO-d ) δ 2.65 (1H, brs), 2.96–3.16
6
(2H, m), 3.19–3.41 (4H, m), 3.85–3.98 (1H, m), 3.99–4.10 (1H, m), 4.82 (1H, brs), 5.02 (1H, d, J = 4.1
+
25
Hz), 7.35 (1H, dd, J = 8.7, 1.5 Hz), 7.58–7.65 (2H, m), 9.35 (2H, brs). MS m/z: 276.1 [M+H] . [α]
-
D
6
2.7 (c 0.25, MeOH).
5
.1.39. [(6R,7R)-7-(3,4-Dichlorophenyl)-1,4-oxazepan-6-yl]methanol monohydrochloride (6).
1
Typical procedure A, 81%, Colorless solid. H NMR (300 MHz, DMSO-d ) δ 2.59–2.72 (1H, m), 2.97–
6
3
.17 (2H, m), 3.17–3.34 (4H, m), 3.85–3.99 (1H, m), 3.99–4.11 (1H, m), 4.82 (1H, brs), 5.02 (1H, d, J
4.5 Hz), 7.35 (1H, dd, J = 8.3, 1.9 Hz), 7.57–7.66 (2H, m), 9.24 (1H, brs), 9.61 (1H, brs). MS m/z:
=
+
25
2
76.1 [M+H] . [α] +64.6 (c 0.25, MeOH).
D
5
.1.40. tert-Butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-formyl-1,4-oxazepane-4-carboxylate (44). To a
solution of 43a (8.3 g, 22.1 mmol) in MeCN (110 mL) was added Dess-Martin periodinane (11.2 g, 26.5
mmol) at 0°C. The mixture was stirred at 0°C for 4 h, and then NaHCO aq. and Na S O aq. were
3
2
2
3
added. After 30 min, the mixture was extracted with EtOAc, washed with water and brine, dried over
2
3

Na SO and concentrated in vacuo. The residue was purified by column chromatography (silica gel,
2
4
1
hexane/EtOAc) to give 44 (5.41 g, 66%) as a colorless oil. H NMR (300 MHz, CDCl ) δ 1.43–1.56 (9H,
3
m), 2.87–3.37 (2H, m), 3.48–3.77 (2H, m), 3.80–4.20 (2H, m), 4.34 (1H, d, J = 15.1 Hz), 4.69–5.13 (1H,
m), 7.18 (1H, d, J = 8.3 Hz), 7.33–7.40 (1H, m), 7.40–7.56 (1H, m), 9.46–9.85 (1H, m). MS m/z: 274.0
+
[
M+H-Boc] .
5
.1.41. (6R,7R)-4-(tert-Butoxycarbonyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-6-carboxylic acid
(45). To a mixture of 44 (5.4 g, 14.4 mmol), 2-methyl-2-butene (34 mL, 32 mmol) and t-BuOH (75 mL)
in THF (75 mL) was added sodium chlorite (7.83 g, 86.6 mmol) and sodium dihydrogenphosphate (12.1
g, 101 mmol) in H O (120 mL) at 0°C. The mixture was stirred at 0°C for 2 h. The mixture was poured
2
into water, extracted with EtOAc, washed with water and brine, dried over MgSO and concentrated in
4
vacuo. The residue was purified by column chromatography (silica gel, hexane/EtOAc) to give 45 (4.49
1
g, 80%) as a yellow amorphous solid. H NMR (300 MHz, CDCl ) δ 1.34–1.56 (9H, m), 2.73–3.08 (1H,
3
m), 3.14–3.91 (3H, m), 3.94–4.25 (3H, m), 4.73 (1H, d, J = 10.2 Hz), 7.16 (1H, dd, J = 8.3, 1.9 Hz),
7
.37 (1H, d, J = 8.3 Hz), 7.45 (1H, d, J = 1.9 Hz).
5
.1.42. (6R,7R)-tert-Butyl 6-carbamoyl-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate. To a
solution of 45 (150 mg, 0.38 mmol) in DMF (1.92 mL) was added WSC•HCl (88 mg, 0.46 mmol) and
HOBt•NH (70.2 mg, 0.46 mmol). The mixture was stirred at room temperature overnight. The mixture
3
was poured into water and extracted with EtOAc. The organic layer was separated, washed with water
and brine, dried over Na SO and concentrated in vacuo. The residue was purified by column
2
4
chromatography (NH silica gel, hexane/EtOAc) to give (6R,7R)-tert-butyl 6-carbamoyl-7-(3,4-
1
dichlorophenyl)-1,4-oxazepane-4-carboxylate. (183 mg, quant.) as a colorless oil. H NMR (300 MHz,
CDCl ) δ 1.50 (9H, s), 2.49–2.86 (1H, m), 3.46–4.05 (6H, m), 4.75 (1H, d, J = 9.1 Hz), 5.05–6.38 (2H,
3
m), 7.17 (1H, dd, J = 8.3, 1.9 Hz), 7.38 (1H, d, J = 8.0 Hz), 7.46 (1H, d, J = 1.9 Hz). MS m/z: 289.0
+
[
M+H-Boc] .
2
4

5
.1.43. (6R,7R)-7-(3,4-Dichlorophenyl)-1,4-oxazepane-6-carboxamide monohydrochloride (9).
1
Typical procedure A, 91%, Colorless crystal. H NMR (300 MHz, DMSO-d ) δ 3.06–3.18 (1H, m),
6
3
.21–3.48 (4H, m), 3.86–3.99 (1H, m), 4.03–4.14 (1H, m), 4.77 (1H, d, J = 9.8 Hz), 7.09 (1H, s), 7.29
(1H, dd, J = 8.3, 1.9 Hz), 7.53–7.60 (2H, m), 7.63 (1H, d, J = 8.3 Hz), 9.27–9.69 (2H, m). MS m/z:
+
2
89.0 [M+H] . Anal. Calcd for C H N O Cl •0.2 H O: C,43.78;H,4.71;N,8.51. Found:
1
2
15
2
2
3
2
25
C,43.81;H,4.68;N,8.59. [α] +8.7 (c 0.25, MeOH).
D
Compounds 10 and 11 were prepared in same manner using corresponding amine, followed by typical
deprotection.
5
.1.44.
(6R,7R)-7-(3,4-Dichlorophenyl)-N-methyl-1,4-oxazepane-6-carboxamide
1
monohydrochloride (10). Typical procedure B, 29% in two steps, Colorless solid. H NMR (300 MHz,
DMSO-d ) δ 2.40 (3H, d, J = 4.5 Hz), 3.05–3.15 (1H, m), 3.22–3.46 (4H, m), 3.88–4.02 (1H, m), 4.05–
6
4
.16 (1H, m), 4.78 (1H, d, J = 9.8 Hz), 7.20–7.27 (1H, m), 7.55 (1H, d, J = 1.5 Hz), 7.61 (1H, d, J = 8.3
+
25
D
Hz), 7.99–8.09 (1H, m), 9.44–9.71 (2H, m). MS m/z: 303.0 [M+H] . [α] -19.2 (c 0.25, MeOH).
5
.1.45.
(6R,7R)-tert-Butyl
7-(3,4-dichlorophenyl)-6-(dimethylcarbamoyl)-1,4-oxazepane-4-
1
carboxylate. 69%, Colorless solid. H NMR (300 MHz, CDCl ) δ 1.45–1.53 (9H, m), 2.67–2.84 (6H,
3
m), 2.99–3.57 (2H, m), 3.75–4.24 (3H, m), 4.72–4.87 (1H, m), 7.14 (1H, dd, J =8.3, 1.9 Hz), 7.36 (1H,
+
d, J =8.3 Hz), 7.44 (1H, d, J =1.9 Hz). MS m/z: 417.1 [M+H] .
5
.1.46.
(6R,7R)-7-(3,4-Dichlorophenyl)-N,N-dimethyl-1,4-oxazepane-6-carboxamide
1
monohydrochloride (11). Typical procedure B, 60%, Colorless solid. H NMR (300 MHz, DMSO-d )
6
δ 2.65 (6H, d, J =1.5 Hz), 3.15–3.28 (1H, m), 3.36–3.52 (3H, m), 3.83–4.10 (2H, m), 4.11–4.24 (1H, m),
4
9
.75 (1H, d, J =9.8 Hz), 7.25 (1H, dd, J =8.5, 2.1 Hz), 7.55 (1H, d, J =2.3 Hz), 7.64 (1H, d, J =8.3 Hz),
+
25
.58 (2H, brs). MS m/z: 317.3 [M+H] . [α] -12.0 (c 0.25, MeOH).
D
5
.1.47. tert-Butyl (6S,7R)-7-(3,4-Dichlorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-
4
-carboxylate (46a). To a solution of 43a (4.66 g, 12.4 mmol) in THF (50 mL) was added Et N (3.45
3
2
5

mL, 24.8 mmol) and methanesulfonyl chloride (1.44 mL, 18.6 mmol) at 0°C. The mixture was stirred at
°C for 2 h and at room temperature for 3 h. The mixture was neutralized with sat. NaHCO aq.,
0
3
extracted with EtOAc, washed with water and brine, dried over Na SO and concentrated in vacuo to
2
4
1
give 46a (5.73 g, quant.) as colorless oil. H NMR (300 MHz, CDCl ) δ 1.50 (9H, s), 2.33–2.46 (1H, m),
3
2
.89 (1H, brs), 3.02 (2H, brs), 3.41–3.55 (1H, m), 3.57–3.90 (4H, m), 3.97–4.16 (3H, m), 4.20 (1H, d, J
9.4 Hz), 7.16 (1H, dd, J = 8.3, 1.9 Hz), 7.41–7.47 (2H, m).
=
5
.1.48. tert-Butyl (6S,7R)-6-(azidomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate
(47a). To a solution of 46a (10 g, 22.0 mmol) in DMF (100 mL) was added sodium azide (2.15 g, 33.0
mmol) at room temperature. The mixture was stirred at 80°C for 3 h. The mixture was poured into water
at room temperature, extracted with EtOAc, washed with sat. NH Cl aq. and water, dried over MgSO
4
4
and concentrated in vacuo. The residue was purified by column chromatography (silica gel,
+
hexane/EtOAc) to give 47a (8.89 g, quant.) as a colorless amorphous solid. MS m/z: 301.0 [M+H-Boc] .
5
.1.49. tert-Butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate
(48a). To a solution of 47a (8.89 g, 22.2 mmol) in THF (85 mL) and water (17 mL) was added
triphenylphosphine (6.97 g, 26.6 mmol). The mixture was stirred at room temperature overnight. The
mixture was poured into water, extracted with EtOAc, washed with water and brine, dried over MgSO4
and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc–
1
MeOH) to give 48a (7.62 g, 92%) as a colorless oil. H NMR (300 MHz, CDCl ) δ 1.38–1.60 (9H, m),
3
1
.84–2.04 (1H, m), 2.36–2.75 (2H, m), 3.23–3.39 (1H, m), 3.45–3.70 (2H, m), 3.76–4.25 (4H, m), 7.16
+
(
1H, d, J =7.9 Hz), 7.34–7.47 (2H, m). MS m/z: 375.4 [M+H] .
5
.1.50.
tert-Butyl
(6R,7R)-6-[(acetylamino)methyl]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-
carboxylate. Acetyl chloride (86 μL, 1.20 mmol) was added to a solution of 48a (300 mg, 0.80 mmol)
and Et N (167 μL, 1.20 mmol) in THF (4 mL) at room temperature. The mixture was poured into water,
3
extracted with EtOAc, washed with brine, dried over MgSO and concentrated in vacuo. The residue
4
was purified by column chromatography (silica gel, hexane/EtOAc) to give tert-butyl (6R,7R)-6-
2
6

[
(acetylamino)methyl]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (272 mg, 82%) as a
1
colorless amorphous solid. H NMR (300 MHz, CDCl ) δ 1.51 (9H, s), 1.98 (3H, s), 2.26 (1H, brs),
3
2
.93–3.62 (5H, m), 3.89–4.20 (4H, m), 7.17–7.25 (2H, m), 7.42 (1H, d, J =8.3 Hz), 7.52 (1H, s). MS
+
m/z: 317.0 [M+H-Boc] .
5
.1.51. N-(((6S,7R)-7-(3,4-Dichlorophenyl)-1,4-oxazepan-6-yl)methyl)acetamide 0.5 fumarate (12).
To a solution of tert-butyl (6R,7R)-6-[(acetylamino)methyl]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-
carboxylate (310 mg, 0.74 mmol) in EtOH (1 mL) was added 14.7 M HCl in EtOH (2 mL). The mixture
was stirred at room temperature for 3 h and concentrated in vacuo. The residue was neutralized with 1
M NaOH aq., diluted with water, extracted with EtOAc, washed with water and brine, dried over
MgSO , filtered and concentrated in vacuo. The residue was purified by column chromatography (NH
4
silica gel, hexane/EtOAc). The residue in EtOAc (3 mL) was added a solution of fumaric acid (83.9 mg,
0
.72 mmol) in EtOH (2 mL) and concentrated in vacuo. The residue was crystallized from EtOAc–
1
EtOH to give 12 (187 mg, 67%) as a colorless crystal. H NMR (300 MHz, DMSO-d ) δ 1.73 (3H, s),
6
2
.21 (1H, td, J = 8.8, 4.3 Hz), 2.78–3.10 (6H, m), 3.60 (1H, ddd, J = 12.8, 7.9, 4.9 Hz), 3.92 (1H, dt, J
12.8, 3.6 Hz), 4.28 (1H, d, J = 9.4 Hz), 6.49 (1H, s), 7.39 (1H, dd, J = 8.3, 1.9 Hz), 7.53–7.65 (1H,
=
+
o
m), 7.67 (1H, d, J = 1.9 Hz), 7.90 (1H, t, J = 5.5 Hz). MS m/z: 317.3 [M+H] . Mp: 167–170 C. Anal.
Calcd for C H Cl N O •0.5C H O •0.2H O: C,50.72; H,5.43; N,7.39. Found: C,50.62; H,5.24; N,7.43.
1
4
18
2
2
2
4
4
4
2
2
5
[
α] –7.4 (c 0.25, MeOH).
D
Compounds 14–17 were prepared in same manner using 43b–43e.
5
.1.52.
(6S,7R)-tert-Butyl
7-(4-chloro-3-fluorophenyl)-6-((methylsulfonyloxy)methyl)-1,4-
1
oxazepane-4-carboxylate (46b). Quant., Pale yellow oil. H NMR (300 MHz, CDCl ) δ 1.50 (9H, s),
3
2
7
.30–2.46 (1H, m), 3.41–4.38 (12H, m), 7.05 (1H, d, J = 7.9 Hz), 7.15 (1H, dd, J = 9.6, 1.7 Hz), 7.34–
.46 (1H, m).
2
7

5
.1.53.
(6S,7R)-tert-Butyl
6-(azidomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-
1
carboxylate (47b). 64%, Colorless oil. H NMR (300 MHz, CDCl ) δ 1.51 (9H, s), 2.09–2.36 (1H, m),
3
+
3
.13–4.43 (9H, m), 7.00–7.23 (2H, m), 7.34–7.50 (1H, m). MS m/z: 285.2 [M+H-Boc] .
5
.1.54.
(6R,7R)-tert-Butyl
6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-
1
carboxylate (48b). 82%, Colorless oil. H NMR (300 MHz, CDCl ) δ 1.51 (9H, s), 1.83–2.12 (1H, m),
3
2
.44–2.68 (2H, m), 3.24–3.46 (1H, m), 3.47–4.24 (6H, m), 7.04 (1H, d, J = 7.5 Hz), 7.15 (1H, d, J = 9.8
+
Hz), 7.31–7.43 (1H, m). MS m/z: 359.2 [M+H] .
5
.1.55. (6R,7R)-tert-Butyl 6-(acetamidomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-
1
carboxylate. 49%, Colorless oil. H NMR (300 MHz, CDCl ) δ 1.51 (9H, s), 1.98 (3H, s), 2.17–2.34
3
(
1H, m), 2.96–3.43 (4H, m), 3.47–3.65 (1H, m), 3.93–4.19 (4H, m), 7.13 (1H, d, J = 8.3 Hz), 7.19–7.25
1H, m), 7.36 (1H, t, J = 7.9 Hz).
(
5
.1.56.
N-(((6S,7R)-7-(4-Chloro-3-fluorophenyl)-1,4-oxazepan-6-yl)methyl)acetamide
1
monohydrochloride (14). Typical procedure A, 98%, Colorless solid. H NMR (300 MHz, DMSO-d )
6
δ 1.79 (3H, s), 2.56–2.72 (1H, m), 2.74–3.01 (2H, m), 3.01–3.40 (4H, m), 3.74–3.90 (1H, m), 3.92–4.09
(1H, m), 4.43 (1H, d, J = 9.8 Hz), 7.35 (1H, d, J = 7.9 Hz), 7.53–7.68 (2H, m), 8.12–8.28 (1H, m), 9.44
+
(
1H, brs), 9.93 (1H, brs). MS m/z: 301.3 [M+H] .
5
.1.57.
(6S,7R)-tert-Butyl
7-(3-chloro-4-fluorophenyl)-6-((methylsulfonyloxy)methyl)-1,4-
1
oxazepane-4-carboxylate (46c). 98%, Colorless oil. H NMR (300 MHz, CDCl ) δ 1.50 (9H, brs), 2.40
3
(1H, brs), 2.79–3.12 (3H, m), 3.39–3.56 (1H, m), 3.57–3.92 (4H, m), 3.95–4.17 (3H, m), 4.20 (1H, d, J
=
9.8 Hz), 7.09–7.24 (2H, m), 7.40 (1H, dd, J = 7.0, 2.1 Hz).
5
.1.58.
(6S,7R)-tert-Butyl
6-(azidomethyl)-7-(3-chloro-4-fluorophenyl)-1,4-oxazepane-4-
1
carboxylate (47c). Quant., Colorless solid. H NMR (300 MHz, CDCl ) δ 1.51 (9H, brs), 2.14 (1H, brs),
3
3
7
.18 (2H, d, J = 8.3 Hz), 3.46–3.91 (5H, m), 4.02–4.24 (2H, m), 7.08–7.23 (2H, m), 7.38 (1H, dd, J =
+
.2, 1.9 Hz). MS m/z: 285.4 [M+H-Boc] .
2
8

5
.1.59.
(6R,7R)-tert-Butyl
6-(aminomethyl)-7-(3-chloro-4-fluorophenyl)-1,4-oxazepane-4-
1
carboxylate (48c). 92%, Colorless oil. H NMR (300 MHz, CDCl ) δ 1.49 (9H, s), 1.83–2.04 (1H, m),
3
2
7
.39–2.66 (2H, m), 3.32 (1H, d, J = 4.2 Hz), 3.48–3.70 (2H, m), 3.76–4.14 (4H, m), 7.04–7.14 (1H, m),
+
.17 (1H, d, J = 7.2 Hz), 7.39 (1H, d, J = 6.8 Hz). MS m/z: 359.2 [M+H] .
5
.1.60. (6R,7R)-tert-Butyl 6-(acetamidomethyl)-7-(3-chloro-4-fluorophenyl)-1,4-oxazepane-4-
1
carboxylate. Quant., Colorless oil. H NMR (300 MHz, CDCl ) δ 1.51 (9H, s), 1.98 (3H, s), 2.27 (1H,
3
brs), 2.92–3.31 (3H, m), 3.37 (1H, dd, J = 14.9, 5.1 Hz), 3.48–3.62 (1H, m), 3.94–4.08 (3H, m), 4.08–
4
3
.17 (1H, m), 7.06–7.15 (1H, m), 7.19 (1H, brs), 7.24–7.30 (1H, m), 7.47 (1H, d, J = 7.2 Hz). MS m/z:
+
01.3 [M+H-Boc] .
5
.1.61.
N-(((6S,7R)-7-(3-Chloro-4-fluorophenyl)-1,4-oxazepan-6-yl)methyl)acetamide
0.5
fumarate (15). The compound was prepared in the similar manner with compound 12. 43%, Colorless
1
crystal. H NMR (300 MHz, DMSO-d ) δ 1.74 (3H, s), 2.20 (1H, td, J = 9.0, 4.0 Hz), 2.78–3.06 (6H,
6
m), 3.60 (1H, ddd, J = 12.9, 8.0, 4.9 Hz), 3.91 (1H, dt, J = 12.8, 3.5 Hz), 4.27 (1H, d, J = 9.6 Hz), 6.52
+
25
D
(
1H, s), 7.38–7.44 (2H, m), 7.62 (1H, d, J = 7.7 Hz), 7.81–7.96 (1H, m). MS m/z: 301.1 [M+H] . [α]
-9.9 (c 0.25, MeOH).
5
.1.62.
(6S,7R)-tert-Butyl
6-(azidomethyl)-7-(4-chloro-3-methylphenyl)-1,4-oxazepane-4-
1
carboxylate (47d). 25% in two steps from 43d, H NMR (300 MHz, CDCl ) δ 1.45–1.56 (9H, m),
3
2
.12–2.27 (1H, m), 2.38 (3H, s), 3.09–3.26 (2H, m), 3.41–3.91 (5H, m), 4.01–4.19 (2H, m), 7.06 (1H, d,
+
J = 7.9 Hz), 7.17 (1H, s), 7.32 (1H, d, J = 8.3 Hz). MS m/z: 281.0 [M+H-Boc] .
5
.1.63.
(6R,7R)-tert-Butyl
6-(aminomethyl)-7-(4-chloro-3-methylphenyl)-1,4-oxazepane-4-
+
carboxylate (48d). 94%, Colorless oil. MS m/z: 355.3 [M+H] .
5
.1.64. (6R,7R)-tert-Butyl 6-(acetamidomethyl)-7-(4-chloro-3-methylphenyl)-1,4-oxazepane-4-
+
carboxylate. 79%, Colorless oil. MS m/z: 397.3 [M+H] .
2
9