A practical synthesis of (S)- tert -butyl 3-methyl-1,4-diazepane-1- carboxylate, the key intermediate of rho-kinase inhibitor K-115

Article abstract of DOI:10.1055/s-0032-1316771

A practical synthesis of (S)-tert-butyl 3-methyl-1,4-diazepane-1- carboxylate has been established for supplying this key intermediate of Rho-kinase inhibitor K-115 in a multikilogram production. The chiral 1,4-diazepane was constructed by intramolecular Fukuyama-Mitsunobu cyclization of a N-nosyl diamino alcohol starting from the commercially available (S)- or (R)-2-aminopropan-1-ol. In the same manner, an enantiomeric pair of a structural isomer were prepared for demonstration of the synthetic utility.

Full text of DOI:10.1055/s-0032-1316771

PAPER
▌3171
paper
A Practical Synthesis of (S)-tert-Butyl 3-Methyl-1,4-diazepane-1-carboxylate,
the Key Intermediate of Rho–Kinase Inhibitor K-115
Synthesis of (S)-tert-Butyl 3-Methyl-1,4-diazepane-1-carboxylate
Noriaki Gomi, Akiyasu Kouketsu, Tadaaki Ohgiya, Kimiyuki Shibuya*
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022,
Japan
Fax +81(42)3950312; E-mail: k-sibuya@kowa.co.jp
Received: 20.06.2012; Accepted after revision: 10.08.2012
acceptable to us. Therefore, we had to develop an effi-
Abstract: A practical synthesis of (S)-tert-butyl 3-methyl-1,4-di-
cient, alternative synthesis. In order to solve the above-
azepane-1-carboxylate has been established for supplying this key
mentioned issues, we addressed the convergent synthesis
of K-115 and the requisite production of (S)-tert-butyl 3-
intermediate of Rho–kinase inhibitor K-115 in a multikilogram pro-
duction. The chiral 1,4-diazepane was constructed by intramolecu-
lar Fukuyama–Mitsunobu cyclization of a N-nosyl diamino alcohol methyl-1,4-diazepane-1-carboxylate [(S)-7] (Scheme 2).
starting from the commercially available (S)- or (R)-2-aminopro-
pan-1-ol. In the same manner, an enantiomeric pair of a structural
isomer were prepared for demonstration of the synthetic utility.
H
H
N
Cl
N
SO2
F
HO
SO2
F
MsO
SO2
F
Key words: 1,4-diazepane, Fukuyama–Mitsunobu cyclization,
cation-exchange resin, asymmetric molecule, Rho–kinase inhibitor
N•HCl
N
N
2
3
4
OH
H
N
(S)-4-Fluoro-5-[(2-methyl-1,4-diazepan-1-yl)sulfonyl]iso-
quinoline hydrochloride dihydrate (1), K-1151 (Figure 1),
a highly potent and selective Rho–kinase inhibitor having
the (S)-2-methyl-1,4-diazepane moiety, is a promising
candidate for the treatment of ocular hypertension with in-
traocular pressure-lowering activity and neuroprotection
of retinal ganglion cells injured in glaucoma.2 The S con-
figuration at the 2-position on the 1,4-diazepane ring of K-
115 plays the pivotal role for expressing the physiological
feature.
N
SO2
F
N
H
SO2
F
K-115
N
N
5
6
Scheme 1 Linear production method for K-115
Cl
Boc
SO2
F
N
K-115
+
NH
N•HCl
2
(S)-7
HN
N
SO2
F
Scheme 2 Convergent production method for K-115
N•HCl•2H2O
Several papers have described the preparation of chiral 2-
substituted 1,4-diazepane derivatives. Interestingly, a
Merck group reported the large-scale synthesis of MK-
4305, but the enantiopure substituted 5-methyl-1,4-diaze-
pane derivative was supplied by the diastereomeric salt
resolution of the racemate with dibenzoyl-D-tartaric acid
in a low yield.4 As well, others have reported small-scale
preparations by the reduction of dioxo-1,4-diazepanes5
and the creation of libraries of compounds (under micro-
wave irradiation conditions) in the solid phase.6 Franzyk
and co-workers reported the first study of the solution-
phase synthesis via the ring opening of activated aziridi-
nes;7 however, this methodology started with a substituted
aminoethanol with 3 equivalents of 2-nitrobenzenesulfo-
nyl chloride (2-nosyl chloride, 2-NsCl) in order to gener-
ate the hazardous N-nosylaziridine. This excess of 2-nosyl
chloride is unacceptable due to cost constraints. Further-
more, the procedure demanded a complicated handling in
the workup and HPLC purification. The application and
utility of these methodologies are limited and the outlined
K-115 (1)
Figure 1
Recently, we have reported the practical synthesis of K-
115 in a multikilogram production. This straightforward
synthesis was accomplished without protection and de-
protection steps and was well-acceptable from a synthetic
methodology viewpoint (Scheme 1).3 However, in consid-
eration of the convenience and robust large-scale produc-
tion of an Active Pharmaceutical Ingredient, many
improvements were needed, including a reduction in the
number of synthetic steps, control of the impurity profile
and improved cost-performance. In particular, the place-
ment of the expensive 4-fluoroisoquinoline-5-sulfonyl
chloride (2) in the early step of the linear synthesis was not
SYNTHESIS 2012, 44, 3171–3178
Advanced online publication: 31.08.2012
DOI: 10.1055/s-0032-1316771; Art ID: SS-2012-F0534-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

3172
N. Gomi et al.
PAPER
problems should be addressed prior to multikilogram- nopropan-1-ol.12 As previously discussed, there exists the
scale production. Next, we searched the patent literature8a potential for formation of the activated aziridine in situ
for the synthesis of (S)-7; however, the patent-disclosed (see 5, Scheme 1). In general, the 2-methyl group on the
intermediate prior to cyclization could easily be aziridine ring is expected to control the SN2 nucleophilic
decomposed8b due to the participation of the carbamate attack of 3-aminopropan-1-ol predominantly at the unsub-
group, with significant deterioration of the chemical yield. stituted aziridine carbon;13 however, a few percent of the
methyl isomer 11′ (and then 12′) could be formed from
Herewith, our attention was focused on the protection of
the diamine derivative and the cyclization step to form the
1,4-diazepane ring. Then, we revised our reported proce-
the N-nosylaziridine under the influence of the reaction
temperature (Scheme 4).3
dure to provide enantiopure (S)-7. For our synthetic plan,
the strategy for the construction of the 1,4-diazepane ring
was based in a similar way on a Fukuyama–Mitsunobu
N-alkyl cyclization reaction;9 however, in the place of
4-fluoroisoquinoline-5-sulfonyl chloride (2), we chose to
use 2-nosyl chloride.
H
HN
N
*
HO
N
H
Ns
N
*
Ns
11
H
12
N
*
MsO
Ns
10
According to the literature, we started the selective pro-
tection of the amino group of (S)-2-aminopropan-1-ol (8)
with the nosyl group which could be easily removed by
thiophenol under basic conditions;10 however, it was too
difficult to control the mononosylation under the conven-
tional basic conditions. Thus, bisnosylation of 8 simulta-
neously occurred to afford the N,O-bisnosylate,
accompanied by a small amount of the N-nosylaziri-
dine.7,11 After investigating the basic conditions for pro-
viding the mononosylate 9, we succeeded in obtaining
(S)-9 in 76% yield by the use of sodium hydrogen carbon-
ate as a base in tetrahydrofuran–water (Scheme 3).
H
∗
HN
N
HO
N
H
Ns
∗
N
Ns
11'
12'
Scheme 4
After investigating various conditions for providing the
N-alkyl derivative 11, we determined the optimal condi-
tions (Scheme 3). In order to differentiate the two amino
groups in the 1,4-diazepane compound 12, the N-nosyl di-
amine 11 can be protected using the Boc group. Without
this protection, however, we conducted the intramolecular
Fukuyama–Mitsunobu N-alkyl cyclization, which
smoothly afforded 12 under mild conditions. Although
this reaction is very useful, the drawback was that the
product was accompanied by some impurities derived
from the spent reagents. In a large-scale production, the
problem was how to simplify the isolation of pure (S)-7.
Therefore, we made use of the basicity of 12 and isolated
the hydrochloride salt of 12 with the aim of separating it
from the soluble organic impurities. We were successful
in a multikilogram-scale production; (S)-12 was obtained
in 40% yield as a yellow solid. Thus obtained 1,4-diaze-
pane (S)-12 was protected with di-tert-butyl dicarbonate
(Boc2O) under basic conditions to afford the N-tert-bu-
toxycarbonyl-N′-nosyl-3-methyl-1,4-diazepane (S)-13 in
87% yield. Next, cleavage of the nosyl group with thio-
phenol and potassium carbonate gave the desired Boc-
protected secondary amine (S)-7 in 86% yield (>99.9%
ee). Herewith, we have accomplished a practical synthetic
method with easy scalability, isolation of crystals or sol-
ids, high chemical and enantiomeric purity, and efficient
cost, starting from commercially available reagents.
H
H
a
b
NH2
N
N
*
*
*
HO
HO
Ns
MsO
Ns
8
9
10
H
HN
c
d or e
N
*
HO
N
H
Ns
•HCl
Ns
N
*
11
12
Boc
Boc
N
N
f
g
N
NH
*
*
(S)-7 or (R)-7
Ns
13
Scheme 3 Reagents and conditions: (a) 2-NsCl, NaHCO3, THF,
H2O: (S)-9 (76%), (R)-9 (65%); (b) MsCl, NMM, CH2Cl2: (S)-10
(91%), (R)-10 (89%); (c) 3-aminopropan-1-ol, MeCN: (S)-11 (93%),
(R)-11 (100%); (d) DIAD, Ph3P, THF: (S)-12 (40%), (R)-12 as free
base (64%); (e) DIAD, Ph3P, THF, then Amberlyst® 15: (R)-12
(88%); (f) Boc2O, K2CO3, EtOH, H2O: (S)-13 (87%), (R)-13 (98%);
(g) PhSH, K2CO3, MeCN: (S)-7 (86%), (R)-7 (70%).
We next conducted the O-mesylation of 9 to afford the N-
nosyl-O-mesylate (S)-10 in 91% yield. Due to the high
cost of 2-nosyl chloride and atom economy, we opted for
the two-step process of nosylation–mesylation rather than
bisnosylation in our multikilogram-scale synthesis. Then,
the prepared N-nosyl-O-mesylate 10 was treated with 3
equivalents of 3-aminopropan-1-ol to afford the N-alkyl-
ated diamino alcohol 11 in a high yield. In this procedure,
we avoided handling the hazardous N-nosylaziridine and
also reduced the amounts of 2-nosyl chloride and 3-ami-
In the same manner, preparation of the enantiomer was
also accomplished to give (R)-12 as the free base in 64%
yield when using column chromatography.14 To over-
come the low cyclization yield, we adapted an efficient
isolation using a cation-exchange resin,15 Amberlyst® 15.
The advantage of the resin is that it simplifies the isolation
procedure. We performed this on the N-nosyl 1,4-diaze-
pane (R)-12 reaction mixture and easily washed the resin
Synthesis 2012, 44, 3171–3178
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of (S)-tert-Butyl 3-Methyl-1,4-diazepane-1-carboxylate
3173
with organic solvents in order to remove the impurities. need for column chromatography. Furthermore, these 1,4-
The desired product free base (R)-12 was extracted from diazepane derivatives are useful and important chiral
the resin and was afforded in a quantitative yield after am- building blocks and key intermediates for many agents.16
monia–methanol elution. Then, the N-nosyl 1,4-diaze- We are currently developing a concise synthesis of K-115.
pane was converted into its hydrochloride salt (R)-12
[88% yield from (R)-11]. The desired (R)-7 was also ob-
Commercially available reagents and solvents were used without
tained in high enantiomeric purity (99.8% ee). This resin
method provided not only high yield but also minimized
the risk of contamination with the potentially toxic
Mitsunobu reagents.
further purification. All reactions were carried out under argon or
N2 atmosphere unless otherwise noted. TLC analyses were carried
out on silica gel 60 F254 plates (Merck). Optical rotations were mea-
sured on a Jasco P-2200 polarimeter with a sodium (D line) lamp.
IR spectra were recorded on a Thermo Nicolet 370 FT-IR spectrom-
eter using a KBr or KCl pellet. 1H and 13C NMR spectra were ob-
tained on a Jeol JNM-AL 400 (400 MHz) spectrometer using CDCl3
or DMSO-d6 solvent with tetramethylsilane as internal standard un-
less otherwise noted. To avoid rotameric mixtures in the NMR spec-
tra, the carbamate samples were recorded at 100 °C (not calibrated)
in sealed NMR tubes. Mass spectra were obtained on a Jeol GCmate
MS-BU20, Jeol JMS-T100GCV, Waters Xevo G2 QTof or AB
SCIEX API 4000 QTRAP instrument. Elemental analyses (C, H, N)
were performed using a Yanaco MT-5 analyzer. Melting points
were determined in open glass capillaries on a Büchi B-545 melting
point apparatus (temperatures not corrected). The enantiopurities
were determined by HPLC analysis (Shimadzu LC-10Avp equip-
ment, CHIRALPAK® AD-H column, Daicel Chemical Industries,
Ltd.).
Next, we turned our attention to the determination of the
enantiopurity and to obtaining authentic samples to detect
the potential methyl isomers 17 derived from 11′ and 12′.
In order to obtain the 2-methyl regioisomers, we envi-
sioned the process outlined in Scheme 5. In a straightfor-
ward way, the N-nosyl group of 12 needs to be converted
into the N-Boc group. First, we protected 12 as the benzy-
loxycarbonyl derivative, followed by cleavage of the N-
nosyl group of 14 to obtain 15. Next, the free base of 15
was converted into N-Boc followed by hydrogenolysis of
the Cbz group of 16 to give the desired 2-methyl isomer,
(S)-17 (>99.9% ee) or (R)-17 (>99.9% ee).
(S)-N-(1-Hydroxypropan-2-yl)-2-nitrobenzenesulfonamide
[(S)-9]
Cbz
Cbz
N
N
a
b
12
To a soln of (S)-(+)-2-aminopropan-1-ol (8; 5.10 kg, 67.9 mol) and
NaHCO3 (8.80 kg, 105 mol) in H2O (24.5 L) was gradually added a
soln of 2-NsCl (14.7 kg, 65.5 mol) in THF (24.5 L) at 0 °C. The re-
action mixture was allowed to warm to r.t. and stirred for 15 h. The
mixture was poured into H2O (30 L), and extracted with EtOAc
(3 × 5 L). The combined organic layers were washed with brine
(2 × 700 mL), dried over anhyd MgSO4, filtered and concentrated
under reduced pressure. The residue was crystallized (EtOAc–
petroleum ether) to give (S)-9 as a pale yellow, crystalline solid;
yield: 13.1 kg (76%).
N
NH
*
*
Ns
14
15
Cbz
N
HN
c
d
N
N
*
*
Boc
Boc
16
(S)-17 or (R)-17
Scheme 5 Reagents and conditions: (a) CbzCl, NaHCO3, THF, H2O:
(S)-14 (97%), (R)-14 (100%); (b) PhSH, K2CO3, MeCN: (S)-15
(60%), (R)-15 (88%); (c) Boc2O, K2CO3, EtOH, H2O: (S)-16 (99%),
(R)-16 (99%); (d) H2, Pd/C, MeOH: (S)-17 (96%), (R)-17 (74%).
20
Mp 82–83 °C; [α]D +100.8 (c 1.06, CHCl3); Rf = 0.19 (hexane–
EtOAc, 1:1).
IR (KBr): 3558, 3323, 1540, 1527, 1366, 1349, 1174, 1055 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.14 (d, J = 6.8 Hz, 3 H, CH3),
1.85 (br s, 1 H, OH), 3.47–3.66 (m, 3 H, CHCH2), 5.48 (d, J = 6.8
Hz, 1 H, NH), 7.72–7.79 (m, 2 H, ArH), 7.86–7.92 (m, 1 H, ArH),
8.15–8.20 (m, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 17.7, 52.4, 66.1, 125.4, 130.8,
132.9, 133.6, 134.4, 147.8.
In conclusion, we have established a practical and reliable
synthetic method for (S)-tert-butyl 3-methyl-1,4-diaze-
pane-1-carboxylate [(S)-7] with a high enantiomeric puri-
ty in a multikilogram-scale production. In addition, we
have provided viable syntheses of the enantiopure isomer,
FAB-MS: m/z = 261 [M + H]+.
(R)-tert-butyl
3-methyl-1,4-diazepane-1-carboxylate
[(R)-7], and an enantiomeric pair of structural isomers,
(S)-tert-butyl 2-methyl-1,4-diazepane-1-carboxylate [(S)-
17] and (R)-tert-butyl 2-methyl-1,4-diazepane-1-carbox-
ylate [(R)-17], for the determination of enantiopurity and
demonstration of the synthetic utility (Figure 2).
Anal. Calcd for C9H12N2O5S: C, 41.53; H, 4.65; N, 10.76. Found:
C, 41.59; H, 4.60; N, 10.79.
(R)-N-(1-Hydroxypropan-2-yl)-2-nitrobenzenesulfonamide
[(R)-9]
Yield: 163 g (65%); pale yellow, crystalline solid.
20
Mp 82–83 °C; [α]D –100.7 (c 1.09, CHCl3); Rf = 0.19 (hexane–
EtOAc, 1:1).
Boc
Boc
N
N
HN
HN
NH
NH
N
N
IR (KBr): 3558, 3323, 1541, 1527, 1366, 1349, 1174, 1055 cm–1.
Boc
Boc
1H NMR (400 MHz, CDCl3): δ = 1.13 (d, J = 6.8 Hz, 3 H, CH3),
2.05 (br s, 1 H, OH), 3.47–3.66 (m, 3 H, CHCH2), 5.57 (d, J = 6.8
Hz, 1 H, NH), 7.72–7.79 (m, 2 H, ArH), 7.85–7.90 (m, 1 H, ArH),
8.14–8.20 (m, 1 H, ArH).
(S)-7
(R)-7
(S)-17
(R)-17
Figure 2
13C NMR (100 MHz, CDCl3): δ = 17.7, 52.4, 66.1, 125.4, 130.8,
132.9, 133.6, 134.4, 147.8.
FAB-MS: m/z = 261 [M + H]+.
This approach has enabled us to make process-scalable
products with simple purification techniques without the
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3171–3178

3174
N. Gomi et al.
PAPER
Anal. Calcd for C9H12N2O5S: C, 41.53; H, 4.65; N, 10.76. Found:
C, 41.65; H, 4.59; N, 10.79.
13C NMR (100 MHz, CDCl3): δ = 19.4, 31.1, 48.7, 50.2, 54.8, 63.2,
125.3, 130.8, 132.8, 133.5, 134.4, 147.8.
HRMS: m/z [M + H]+ calcd for C12H20N3O5S: 318.1124; found:
318.1133.
(S)-2-(2-Nitrophenylsulfonamido)propyl Methanesulfonate
[(S)-10]
To a soln of (S)-9 (6.20 kg, 23.8 mol) and NMM (3.13 kg, 30.9
mmol) in CH2Cl2 (32 L) was gradually added a soln of MsCl (3.27
kg, 28.5 mol) in CH2Cl2 (2 L) at 0 °C. The reaction mixture was al-
lowed to warm to r.t. and stirred for 20 h. To the mixture was added
H2O (10 L), and the precipitated product was collected by filtration
and dried under reduced pressure to give (S)-10 as a pale yellow,
crystalline solid; yield: 7.30 kg (91%).
(R)-N-{1-[(3-Hydroxypropyl)amino]propan-2-yl}-2-nitroben-
zenesulfonamide [(R)-11]
Yield: 174 g (100%); yellow oil.
[α]D20 –77.9 (c 1.00, CHCl3); Rf = 0.14 (CHCl3–MeOH, 5:1).
IR (KBr): 3315, 2937, 1541, 1365, 1169 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.11 (d, J = 6.8 Hz, 3 H, CH3),
1.61–1.72 (m, 2 H, CH2), 2.65 (dd, J = 12.6, 7.5 Hz, 1 H, CHH),
2.70 (dd, J = 12.6, 4.8 Hz, 1 H, CHH), 2.78 (dd, J = 6.0, 6.0 Hz, 2
H, CH2), 3.56–3.65 (m, 1 H, CH), 3.61 (br s, 3 H, 2 × NH, OH),
3.71–3.77 (m, 2 H, CH2), 7.71–7.78 (m, 2 H, ArH), 7.83–7.88 (m,
1 H, ArH), 8.15–8.20 (m, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 19.4, 30.9, 48.7, 50.1, 54.7, 63.1,
125.3, 130.8, 132.9, 133.5, 134.4, 147.9.
HRMS: m/z [M + H]+ calcd for C12H20N3O5S: 318.1124; found:
318.1140.
20
Mp 125–126 °C; [α]D +34.5 (c 0.52, CHCl3); Rf = 0.25 (hexane–
EtOAc, 1:1).
IR (KBr): 3340, 1538, 1531, 1368, 1359, 1351, 1187, 1178, 1156
cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.25 (d, J = 6.8 Hz, 3 H, CH3),
3.00 (s, 3 H, CH3), 3.84–3.94 (m, 1 H, CH), 4.11–4.19 (m, 2 H,
CH2), 5.54 (d, J = 7.6 Hz, 1 H, NH), 7.74–7.80 (m, 2 H, ArH), 7.88–
7.94 (m, 1 H, ArH), 8.14–8.20 (m, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 18.0, 37.4, 49.6, 71.4, 125.6,
130.7, 133.1, 133.8, 134.3, 147.8.
FAB-MS: m/z = 339 [M + H]+.
(S)-2-Methyl-1-[(2-nitrophenyl)sulfonyl]-1,4-diazepane Hydro-
chloride [(S)-12]
To a soln of (S)-11 (6.10 kg, 19.2 mol) and Ph3P (6.50 kg, 24.8 mol)
in THF (35 L) was gradually added a soln of DIAD (5.20 kg, 25.7
mol) in THF (5 L) at 0 °C. The reaction mixture was allowed to
warm to r.t. and stirred for 18 h. The mixture was concentrated un-
der reduced pressure and the residue was dissolved in EtOAc (15 L).
The solution was acidified with 6 M HCl until pH 4. The precipitat-
ed product was collected by filtration and dried under reduced pres-
sure to give (S)-12 as a yellow solid; yield: 2.76 kg (40%).
Anal. Calcd for C10H14N2O7S2: C, 35.50; H, 4.17; N, 8.28. Found:
C, 35.40; H, 4.07; N, 8.20.
(R)-2-(2-Nitrophenylsulfonamido)propyl Methanesulfonate
[(R)-10]
Yield: 187 g (89%); pale yellow, crystalline solid.
20
Mp 123–125 °C; [α]D –34.4 (c 0.55, CHCl3); Rf = 0.25 (hexane–
EtOAc, 1:1).
Mp 146–147 °C; [α]D20 +136.1 (c 0.52, MeOH).
IR (KCl): 3333, 2938, 2811, 1532, 1374, 1348, 1160 cm–1.
IR (KBr): 3341, 1539, 1531, 1368, 1359, 1352, 1186, 1178, 1156
cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.25 (d, J = 6.8 Hz, 3 H, CH3),
3.00 (s, 3 H, CH3), 3.84–3.94 (m, 1 H, CH), 4.11–4.19 (m, 2 H,
CH2), 5.55 (d, J = 7.8 Hz, 1 H, NH), 7.74–7.81 (m, 2 H, ArH), 7.88–
7.94 (m, 1 H, ArH), 8.15–8.19 (m, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 18.0, 37.5, 49.6, 71.5, 125.7,
130.7, 133.1, 133.8, 134.3, 147.9.
1H NMR (400 MHz, DMSO-d6): δ = 1.09 (d, J = 6.8 Hz, 3 H, CH3),
1.82–2.03 (m, 2 H, CH2), 3.04 (ddd, J = 14.5, 9.5, 4.4 Hz, 1 H,
CHH), 3.13–3.21 (m, 2 H, 2 × CHH), 3.39 (dd, J = 14.5, 4.4 Hz, 1
H, CHH), 3.48 (ddd, J = 15.4, 9.5, 4.4 Hz, 1 H, CHH), 3.74 (ddd,
J = 15.4, 4.4, 4.4 Hz, 1 H, CHH), 4.32–4.42 (m, 1 H, CH), 7.85–
7.94 (m, 2 H, ArH), 8.01 (dd, J = 7.2, 1.8 Hz, 1 H, ArH), 8.09 (dd,
J = 7.2, 1.8 Hz, 1 H, ArH), 9.52 (br s, 2 H, NH2).
13C NMR (100 MHz, DMSO-d6): δ = 16.2, 26.5, 41.7, 45.6, 50.0,
50.5, 124.3, 129.6, 132.4, 132.6, 134.6, 147.4.
FD-MS: m/z = 300 [M + H – HCl]+.
FAB-MS: m/z = 339 [M + H]+.
Anal. Calcd for C10H14N2O7S2: C, 35.50; H, 4.17; N, 8.28. Found:
C, 35.35; H, 4.07; N, 8.28.
(S)-N-{1-[(3-Hydroxypropyl)amino]propan-2-yl}-2-nitroben-
zenesulfonamide [(S)-11]
Anal. Calcd for C12H18ClN3O4S·H2O: C, 40.73; H, 5.70; Cl, 10.02;
N, 11.88. Found: C, 40.64; H, 5.63; Cl, 10.03; N, 11.66.
To a soln of 3-aminopropan-1-ol (5.00 kg, 66.6 mol) in MeCN (35
L) was gradually added a soln of (S)-10 (7.00 kg, 20.7 mol) in
MeCN (35 L) at r.t. The reaction mixture was stirred for 16 h then
concentrated under reduced pressure. To the residue was added H2O
(10 L). The solution was acidified with 6 M HCl until pH 4. The pre-
cipitate was filtered off. The filtrate was made alkaline by adding
K2CO3 until pH 9, and then extracted with EtOAc (8 × 3 L). The
combined organic layers were dried over anhyd Na2SO4, filtered
and concentrated under reduced pressure to give (S)-11 as a yellow
oil; yield: 6.10 kg (93%).
(R)-2-Methyl-1-[(2-nitrophenyl)sulfonyl]-1,4-diazepane [(R)-12
Free Base]
To a soln of (R)-11 (172 g, 542 mmol) and Ph3P (182 g, 692 mmol)
in THF (980 mL) was gradually added a soln of DIAD (140 g, 692
mmol) in THF (140 mL) at 0 °C. The reaction mixture was allowed
to warm to r.t. and stirred for 18 h. The mixture was concentrated
under reduced pressure. The residue was purified by column chro-
matography (silica gel, 0 to 9% MeOH–CHCl3) to give the free base
(R)-12 as a yellow solid; yield: 104 g (64%).
20
[α]D20 +77.9 (c 1.00, CHCl3); Rf = 0.14 (CHCl3–MeOH, 5:1).
Mp 86–89 °C; [α]D –191.4 (c 0.51, CHCl3); Rf = 0.52 (CHCl3–
MeOH–aq NH3, 100:9:1).
IR (KBr): 2954, 1540, 1376, 1330, 1155 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.99 (d, J = 6.8 Hz, 3 H, CH3),
1.64–1.79 (m, 2 H, CH2), 1.86 (s, 1 H, NH), 2.52 (dd, J = 15.1, 9.3
Hz, 1 H, CHH), 2.69 (ddd, J = 15.1, 9.3, 4.4 Hz, 1 H, CHH), 3.08
(ddd, J = 15.1, 4.4, 4.4 Hz, 1 H, CHH), 3.20 (ddd, J = 15.1, 9.3, 4.4
Hz, 1 H, CHH), 3.26 (dd, J = 14.6, 4.4 Hz, 1 H, CHH), 3.85 (ddd,
IR (KBr): 3330, 2937, 1542, 1365, 1170 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.11 (d, J = 6.8 Hz, 3 H, CH3),
1.59–1.70 (m, 2 H, CH2), 2.61 (dd, J = 12.6, 7.5 Hz, 1 H, CHH),
2.68 (dd, J = 12.6, 4.8 Hz, 1 H, CHH), 2.75 (dd, J = 6.0, 6.0 Hz, 2
H, CH2), 3.32 (br s, 3 H, 2 × NH, OH), 3.54–3.62 (m, 1 H, CH),
3.68–3.76 (m, 2 H, CH2), 7.72–7.78 (m, 2 H, ArH), 7.83–7.89 (m,
1 H, ArH), 8.14–8.18 (m, 1 H, ArH).
Synthesis 2012, 44, 3171–3178
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of (S)-tert-Butyl 3-Methyl-1,4-diazepane-1-carboxylate
3175
J = 15.5, 4.4, 4.4 Hz, 1 H, CHH), 4.08–4.18 (m, 1 H, CH), 7.61–
7.71 (m, 3 H, ArH), 8.13–8.19 (m, 1 H, ArH).
Anal. Calcd for C17H25N3O6S: C, 51.11; H, 6.31; N, 10.52. Found:
C, 51.05; H, 6.30; N, 10.39.
13C NMR (100 MHz, CDCl3): δ = 16.9, 32.2, 42.3, 50.1, 54.7, 56.2,
124.1, 130.9, 131.6, 133.2, 134.7, 147.9.
FAB-MS: m/z = 300 [M + H]+.
(R)-tert-Butyl 3-Methyl-4-[(2-nitrophenyl)sulfonyl]-1,4-diaze-
pane-1-carboxylate [(R)-13]
Yield: 21.1 g (98%); yellow crystalline solid.
Mp 113–114 °C; [α]D20 –104.8 (c 1.00, CHCl3); Rf = 0.36 (hexane–
EtOAc, 1:1).
IR (KBr): 2975, 1685, 1674, 1543, 1366, 1334, 1171 cm–1.
Anal. Calcd for C12H17N3O4S: C, 48.15; H, 5.72; N, 14.04. Found:
C, 48.10; H, 5.64; N, 13.92.
(R)-2-Methyl-1-[(2-nitrophenyl)sulfonyl]-1,4-diazepane Hydro-
chloride [(R)-12]
1H NMR (400 MHz, DMSO-d6, 100 °C): δ = 0.90 (d, J = 6.8 Hz, 3
H, CH3), 1.40 (s, 9 H, t-Bu), 1.66–1.74 (m, 2 H, CH2), 3.01–3.13 (m,
1 H, CHH), 3.14 (dd, J = 15.2, 8.3 Hz, 1 H, CHH), 3.20–3.29 (m, 1
H, CHH), 3.62 (dd, J = 15.2, 4.1 Hz, 2 H, 2 × CHH), 3.74 (ddd,
J = 15.2, 4.1, 4.1 Hz, 1 H, CHH), 4.21–4.31 (m, 1 H, CH), 7.78–
7.87 (m, 3 H, ArH), 7.96–8.00 (m, 1 H, ArH).
13C NMR (100 MHz, DMSO-d6, 100 °C): δ = 15.1, 27.6, 27.6, 27.6,
28.7, 41.5, 46.4, 51.6, 51.8, 78.4, 123.6, 129.3, 131.7, 132.7, 133.7,
147.2, 153.5.
To a soln of (R)-11 (7.13 g, 22.5 mmol) and Ph3P (7.08 g, 27.0
mmol) in THF (80 mL) was gradually added DIAD (5.46 g, 27.0
mmol) at 0 °C. The reaction mixture was allowed to warm to r.t. and
stirred for 12 h. To the mixture was added Amberlyst® 15 (29 g) and
the suspension was gently shaken for 9 h at r.t. The resin was fil-
tered and washed with THF (300 mL), followed by MeOH (300
mL), and finally eluted with 7 M NH3 in MeOH (700 mL) to obtain
the product. The filtrate was concentrated under reduced pressure to
give the crude free base (7.12 g) as an oil. To a soln of 4 M HCl in
EtOAc (50 mL) was added a soln of the above product in EtOAc (50
mL) at 0 °C. The precipitated product was collected by filtration
and dried under reduced pressure to give (R)-12 as a white solid;
yield: 6.66 g (88%).
MS (ESI): m/z = 400 [M + H]+.
HRMS: m/z [M + Na]+ calcd for C17H25N3O6SNa: 422.1362; found:
422.1370.
Anal. Calcd for C17H25N3O6S: C, 51.11; H, 6.31; N, 10.52. Found:
C, 50.95; H, 6.20; N, 10.45.
Mp 146–148 °C; [α]D20 –136.1 (c 0.51, MeOH).
IR (KCl): 3334, 2938, 2811, 1532, 1374, 1348, 1160 cm–1.
(S)-tert-Butyl 3-Methyl-1,4-diazepane-1-carboxylate [(S)-7]
To a soln of (S)-13 (2.60 kg, 6.51 mol) and K2CO3 (1.79 kg, 13.0
mol) in MeCN (20 L) was added PhSH (2.15 kg, 19.5 mol) at r.t.
The reaction mixture was stirred at r.t. for 18 h. After the comple-
tion of denosylation was monitored by HPLC, the insoluble materi-
al was filtered off. The filtrate was concentrated under reduced
pressure. To the residue was added ice–water (5 L). The resulting
solution was acidified with 2 M HCl until pH 3. The aqueous layer
was washed with EtOAc (3 × 500 mL), and was made alkaline with
K2CO3 until pH 9, and then extracted with EtOAc (4 × 1 L). The
combined organic layers were dried over anhyd Na2SO4 and con-
centrated under reduced pressure to give (S)-7 as a pale yellow oil;
yield: 1.20 kg (86%); >99.9% ee (by HPLC).
1H NMR (400 MHz, DMSO-d6): δ = 1.08 (d, J = 6.8 Hz, 3 H, CH3),
1.82–2.02 (m, 2 H, CH2), 3.04 (ddd, J = 14.5, 9.5, 4.4 Hz, 1 H,
CHH), 3.12–3.21 (m, 2 H, 2 × CHH), 3.39 (dd, J = 14.5, 4.4 Hz, 1
H, CHH), 3.48 (ddd, J = 15.4, 9.5, 4.4 Hz, 1 H, CHH), 3.74 (ddd,
J = 15.4, 4.4, 4.4 Hz, 1 H, CHH), 4.31–4.42 (m, 1 H, CH), 7.85–
7.94 (m, 2 H, ArH), 8.01 (dd, J = 7.2, 1.8 Hz, 1 H, ArH), 8.09 (dd,
J = 7.2, 1.8 Hz, 1 H, ArH), 9.18 (br s, 1 H, NH), 9.84 (br s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 16.3, 26.6, 41.8, 45.7, 50.1,
50.5, 124.4, 129.7, 132.5, 132.7, 134.7, 147.5.
FD-MS: m/z = 300 [M + H – HCl]+.
Anal. Calcd for C12H18ClN3O4S·H2O: C, 40.73; H, 5.70; Cl, 10.02;
N, 11.88. Found: C, 40.65; H, 5.60; Cl, 10.06; N, 11.73.
[α]D20 +8.7 (c 1.07, CHCl3); Rf = 0.30 (CHCl3–8 M NH3 in MeOH,
10:1).
(S)-tert-Butyl 3-Methyl-4-[(2-nitrophenyl)sulfonyl]-1,4-diaze-
pane-1-carboxylate [(S)-13]
IR (KBr): 3317, 2973, 1695, 1418, 1165 cm–1.
To a soln of (S)-12 (2.70 kg, 8.04 mol) and K2CO3 (1.50 kg, 10.9
mol) in EtOH (12 L) and H2O (12 L) was gradually added Boc2O
(2.00 kg, 9.16 mol) at 0 °C. The reaction mixture was allowed to
warm to r.t. and stirred for 2 h. The mixture was concentrated under
reduced pressure. To the residue was added H2O (30 L). The precip-
itated product was collected by filtration, washed with H2O and
dried under reduced pressure to give (S)-13 as a yellow crystalline
solid; yield: 2.80 kg (87%).
Mp 113–114 °C; [α]D20 +105.0 (c 1.01, CHCl3); Rf = 0.36 (hexane–
EtOAc, 1:1).
IR (KBr): 2976, 1685, 1674, 1542, 1366, 1334, 1170 cm–1.
1H NMR (400 MHz, DMSO-d6, 100 °C): δ = 0.90 (d, J = 6.8 Hz, 3
H, CH3), 1.40 (s, 9 H, t-Bu), 1.66–1.74 (m, 2 H, CH2), 3.02–3.13 (m,
1 H, CHH), 3.14 (dd, J = 15.2, 8.3 Hz, 1 H, CHH), 3.20–3.29 (m, 1
H, CHH), 3.62 (dd, J = 15.2, 4.1 Hz, 2 H, 2 × CHH), 3.74 (ddd,
J = 15.2, 4.1, 4.1 Hz, 1 H, CHH), 4.22–4.31 (m, 1 H, CH), 7.78–
7.87 (m, 3 H, ArH), 7.97–8.00 (m, 1 H, ArH).
13C NMR (100 MHz, DMSO-d6, 100 °C): δ = 15.1, 27.6, 27.6, 27.6,
28.7, 41.5, 46.4, 51.6, 51.8, 78.4, 123.6, 129.3, 131.7, 132.7, 133.7,
147.2, 153.5.
1H NMR (400 MHz, DMSO-d6, 100 °C): δ = 0.94 (d, J = 6.8 Hz, 3
H, CH3), 1.40 (s, 9 H, t-Bu), 1.52–1.63 (m, 1 H, CHH), 1.69–1.79
(m, 1 H, CHH), 2.42–2.50 (m, 1 H, CHH), 2.60–2.68 (m, 1 H,
CHH), 2.70–2.79 (m, 1 H, CH), 2.97 (ddd, J = 13.8, 4.5, 4.5 Hz, 1
H, CHH), 3.17 (ddd, J = 13.8, 7.7, 6.1 Hz, 1 H, CHH), 3.54 (ddd,
J = 13.8, 6.1, 6.1 Hz, 1 H, CHH), 3.60 (dd, J = 13.8, 2.7 Hz, 1 H,
CHH).
13C NMR (100 MHz, DMSO-d6, 100 °C): δ = 18.9, 27.7, 27.7, 27.7,
29.4, 45.0, 45.1, 53.9, 55.4, 77.6, 154.1.
MS (EI): m/z = 214 [M+].
HRMS: m/z [M+] calcd for C11H22N2O2: 214.1681; found:
214.1680.
(R)-tert-Butyl 3-Methyl-1,4-diazepane-1-carboxylate [(R)-7]
Yield: 7.95 g (70%); 99.8% ee (by HPLC); pale yellow oil.
[α]D20 –8.6 (c 1.13, CHCl3); Rf = 0.30 (CHCl3–8 M NH3 in MeOH,
10:1).
IR (KBr): 3314, 2973, 1691, 1414, 1165 cm–1.
1H NMR (400 MHz, DMSO-d6, 100 °C): δ = 0.95 (d, J = 6.8 Hz, 3
H, CH3), 1.40 (s, 9 H, t-Bu), 1.52–1.64 (m, 1 H, CHH), 1.69–1.79
(m, 1 H, CHH), 2.42–2.50 (m, 1 H, CHH), 2.60–2.69 (m, 1 H,
CHH), 2.71–2.80 (m, 1 H, CH), 2.97 (ddd, J = 13.8, 4.5, 4.5 Hz, 1
H, CHH), 3.17 (ddd, J = 13.8, 7.7, 6.1 Hz, 1 H, CHH), 3.54 (ddd,
MS (ESI): m/z = 400 [M + H]+.
HRMS: m/z [M + Na]+ calcd for C17H25N3O6SNa: 422.1362; found:
422.1386.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3171–3178

3176
N. Gomi et al.
PAPER
J = 13.8, 6.1, 6.1 Hz, 1 H, CHH), 3.60 (dd, J = 13.8, 2.7 Hz, 1 H,
CHH).
13C NMR (100 MHz, DMSO-d6, 100 °C): δ = 18.9, 27.7, 27.7, 27.7,
29.4, 45.0, 45.1, 53.9, 55.3, 77.6, 154.1.
MS (EI): m/z = 214 [M+].
IR (KBr): 3318, 2938, 1693, 1422, 1225 cm–1.
1H NMR (400 MHz, DMSO-d6, 100 °C): δ = 0.99 (d, J = 5.9 Hz, 3
H, CH3), 1.61–1.83 (m, 2 H, CH2), 2.54 (ddd, J = 13.8, 10.2, 4.1 Hz,
1 H, CHH), 2.81–2.90 (m, 2 H, CH + CHH), 3.01 (ddd, J = 13.8,
4.1, 4.1 Hz, 1 H, CHH), 3.30 (ddd, J = 14.0, 7.5, 5.9 Hz, 1 H, CHH),
3.39 (br s, 1 H, NH), 3.58–3.73 (m, 2 H, 2 × CHH), 5.08 (s, 2 H,
CH2), 7.26–7.37 (m, 5 H, ArH).
HRMS: m/z [M+] calcd for C11H22N2O2: 214.1681; found:
214.1683.
13C NMR (100 MHz, DMSO-d6, 100 °C): δ = 18.4, 28.6, 44.8, 45.1,
53.8, 54.4, 65.6, 126.8, 126.8, 127.1, 127.8, 127.8, 136.8, 154.7.
MS (EI): m/z = 248 [M+].
(S)-Benzyl 3-Methyl-4-[(2-nitrophenyl)sulfonyl]-1,4-diazepane-
1-carboxylate [(S)-14]
To a soln of (S)-12 as the free base (5.92 g, 19.8 mmol) and
NaHCO3 (2.50 g, 29.8 mmol) in THF (20 mL) and H2O (20 mL)
was gradually added a soln of CbzCl (4.72 g, 27.7 mmol) in THF
(20 mL) at 0 °C. The reaction mixture was allowed to warm to r.t.
and stirred for 15 h. The mixture was extracted with EtOAc (3 × 40
mL). The combined organic layers were dried over anhyd Na2SO4
and concentrated under reduced pressure. The residue was purified
by column chromatography (silica gel, 0 to 9% MeOH–CHCl3) to
give (S)-14 as a yellow oil; yield: 8.36 g (97%).
[α]D20 +91.4 (c 0.78, CHCl3); Rf = 0.34 (hexane–EtOAc, 1:1).
IR (KBr): 2958, 1700, 1543, 1423, 1373, 1159 cm–1.
1H NMR (400 MHz, DMSO-d6, 100 °C): δ = 0.93 (d, J = 6.8 Hz, 3
H, CH3), 1.66–1.74 (m, 2 H, CH2), 3.08–3.34 (m, 3 H, 3 × CHH),
3.67–3.81 (m, 3 H, 3 × CHH), 4.23–4.33 (m, 1 H, CH), 5.02 (d,
J = 12.7 Hz, 1 H, CHH), 5.07 (d, J = 12.7 Hz, 1 H, CHH), 7.26–7.38
(m, 5 H, ArH), 7.76–7.86 (m, 3 H, ArH), 7.95 (d, J = 7.8 Hz, 1 H,
ArH).
HRMS: m/z [M+] calcd for C14H20N2O2: 248.1525; found:
248.1516.
(R)-Benzyl 3-Methyl-1,4-diazepane-1-carboxylate [(R)-15]
Yield: 32.7 g (88%); yellow oil.
20
[α]D –7.9 (c 0.62, CHCl3); Rf = 0.36 (CHCl3–MeOH–aq NH3,
100:9:1).
IR (KBr): 3315, 2934, 1695, 1422, 1224 cm–1.
1H NMR (400 MHz, DMSO-d6, 100 °C): δ = 0.95 (d, J = 5.9 Hz, 3
H, CH3), 1.55–1.79 (m, 2 H, CH2), 1.83 (br s, 1 H, NH), 2.47 (ddd,
J = 13.8, 10.2, 4.1 Hz, 1 H, CHH), 2.71–2.81 (m, 2 H, CH + CHH),
2.97 (ddd, J = 13.8, 4.1, 4.1 Hz, 1 H, CHH), 3.28 (ddd, J = 13.8, 7.5,
5.7 Hz, 1 H, CHH), 3.57–3.71 (m, 2 H, 2 × CHH), 5.08 (s, 2 H,
CH2), 7.25–7.37 (m, 5 H, ArH).
13C NMR (100 MHz, DMSO-d6, 100 °C): δ = 19.0, 29.4, 45.2, 45.2,
53.8, 55.4, 65.5, 126.8, 126.8, 127.1, 127.7, 127.7, 136.8, 154.7.
MS (EI): m/z = 248 [M+].
HRMS: m/z [M+] calcd for C14H20N2O2: 248.1525; found:
13C NMR (100 MHz, DMSO-d6, 100 °C): δ = 15.3, 28.4, 41.3, 46.8,
51.6, 51.8, 65.9, 123.6, 126.9, 126.9, 127.2, 127.8, 127.8, 129.3,
131.7, 132.5, 133.8, 136.5, 147.1, 154.3.
HRMS: m/z [M + H]+ calcd for C20H24N3O6S: 434.1386; found:
434.1411.
248.1512.
(S)-4-Benzyl 1-tert-Butyl 2-Methyl-1,4-diazepane-1,4-dicarbox-
ylate [(S)-16]
To a soln of (S)-15 (2.73 g, 11.0 mmol) and K2CO3 (2.28 g, 16.5
mmol) in EtOH (15 mL) and H2O (8 mL) was gradually added
Boc2O (3.60 g, 16.5 mmol) at 0 °C. The reaction mixture was al-
lowed to warm to r.t. and stirred for 1.5 h. The mixture was diluted
with H2O (50 mL) and extracted with EtOAc (2 × 50 mL). The com-
bined organic layers were dried over anhyd Na2SO4 and concentrat-
ed under reduced pressure. The residue was purified by column
chromatography (silica gel, 33 to 66% EtOAc–hexane) to give (S)-
16 as a white solid; yield: 3.80 g (99%).
Mp 77 °C; [α]D20 +44.6 (c 0.63, CHCl3); Rf = 0.38 (hexane–EtOAc,
2:1).
IR (KBr): 2971, 1697, 1685, 1428, 1259, 1168 cm–1.
1H NMR (400 MHz, DMSO-d6, 100 °C): δ = 0.98 (d, J = 6.8 Hz, 3
H, CH3), 1.36 (s, 9 H, t-Bu), 1.51–1.71 (m, 2 H, CH2), 2.92–2.99 (m,
1 H, CHH), 2.93 (dd, J = 14.8, 10.8 Hz, 1 H, CHH), 2.99 (ddd,
J = 14.8, 10.8, 2.0 Hz, 1 H, CHH), 3.63–3.71 (m, 1 H, CHH), 3.78
(dd, J = 14.8, 6.0 Hz, 1 H, CHH), 3.83–3.90 (m, 1 H, CHH), 4.29–
4.40 (m, 1 H, CH), 5.03 (d, J = 12.7 Hz, 1 H, CHH), 5.07 (d,
J = 12.7 Hz, 1 H, CHH), 7.26–7.36 (m, 5 H, ArH).
13C NMR (100 MHz, DMSO-d6, 100 °C): δ = 15.6, 27.6, 27.6, 27.6,
27.6, 39.6, 47.5, 47.5, 51.8, 65.7, 78.0, 126.7, 126.7, 127.1, 127.8,
127.8, 136.6, 154.0, 154.2.
(R)-Benzyl 3-Methyl-4-[(2-nitrophenyl)sulfonyl]-1,4-diaze-
pane-1-carboxylate [(R)-14]
Yield: 65.0 g (100%); yellow oil.
[α]D20 –91.2 (c 0.90, CHCl3); Rf = 0.34 (hexane–EtOAc, 1:1).
IR (KBr): 2959, 1699, 1544, 1424, 1373, 1159 cm–1.
1H NMR (400 MHz, DMSO-d6, 100 °C): δ = 0.93 (d, J = 6.8 Hz, 3
H, CH3), 1.66–1.74 (m, 2 H, CH2), 3.10–3.34 (m, 3 H, 3 × CHH),
3.67–3.81 (m, 3 H, 3 × CHH), 4.23–4.33 (m, 1 H, CH), 5.02 (d,
J = 12.7 Hz, 1 H, CHH), 5.07 (d, J = 12.7 Hz, 1 H, CHH), 7.27–7.37
(m, 5 H, ArH), 7.76–7.85 (m, 3 H, ArH), 7.95 (d, J = 7.8 Hz, 1 H,
ArH).
13C NMR (100 MHz, DMSO-d6, 100 °C): δ = 15.3, 28.3, 41.3, 46.8,
51.6, 51.8, 65.9, 123.5, 126.8, 126.8, 127.1, 127.7, 127.7, 129.3,
131.6, 132.5, 133.7, 136.4, 147.1, 154.3.
HRMS: m/z [M + H]+ calcd for C20H24N3O6S: 434.1386; found:
434.1407.
(S)-Benzyl 3-Methyl-1,4-diazepane-1-carboxylate [(S)-15]
To a soln of (S)-14 (8.26 g, 19.1 mmol) and K2CO3 (5.27 g, 38.1
mmol) in MeCN (83 mL) was added PhSH (3.9 mL, 38.1 mol) at r.t.
The reaction mixture was stirred at 50 °C for 6.5 h. The mixture was
diluted with H2O (240 mL) and extracted with EtOAc (3 × 80 mL).
The combined organic layers were extracted with 2 M HCl (3 × 80
mL). The combined aqueous layers were made alkaline by adding
K2CO3 until pH 12, and then extracted with EtOAc (3 × 80 mL).
The combined organic layers were dried over anhyd Na2SO4 and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, 0 to 18% MeOH–CHCl3) to
give (S)-15 as a yellow oil; yield: 2.83 g (60%).
MS (EI): m/z = 348 [M+].
HRMS: m/z [M+] calcd for C19H28N2O4: 348.2049; found:
348.2050.
(R)-4-Benzyl 1-tert-Butyl 2-Methyl-1,4-diazepane-1,4-dicarbox-
ylate [(R)-16]
Yield: 45.3 g (99%); pale yellow solid.
Mp 77 °C; [α]D20 –44.0 (c 0.93, CHCl3); Rf = 0.38 (hexane–EtOAc,
2:1).
20
[α]D +7.6 (c 0.50, CHCl3); Rf = 0.36 (CHCl3–MeOH–aq NH3,
100:9:1).
Synthesis 2012, 44, 3171–3178
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of (S)-tert-Butyl 3-Methyl-1,4-diazepane-1-carboxylate
3177
IR (KBr): 2974, 1690, 1425, 1256, 1166 cm–1.
References
1H NMR (400 MHz, DMSO-d6, 100 °C): δ = 0.98 (d, J = 6.8 Hz, 3
H, CH3), 1.36 (s, 9 H, t-Bu), 1.52–1.70 (m, 2 H, CH2), 2.92–2.99 (m,
1 H, CHH), 2.92 (dd, J = 14.1, 10.3 Hz, 1 H, CHH), 2.99 (ddd,
J = 14.1, 10.3, 2.5 Hz, 1 H, CHH), 3.62–3.71 (m, 1 H, CHH), 3.78
(dd, J = 14.1, 6.1 Hz, 1 H, CHH), 3.82–3.90 (m, 1 H, CHH), 4.29–
4.40 (m, 1 H, CH), 5.03 (d, J = 12.7 Hz, 1 H, CHH), 5.07 (d,
J = 12.7 Hz, 1 H, CHH), 7.25–7.36 (m, 5 H, ArH).
13C NMR (100 MHz, DMSO-d6, 100 °C): δ = 15.6, 27.6, 27.6, 27.6,
27.6, 39.6, 47.5, 47.5, 51.8, 65.6, 77.9, 126.7, 126.7, 127.1, 127.7,
127.7, 136.6, 154.0, 154.1.
(1) Ohshima, T.; Hidaka, H.; Shiratsuchi, M.; Onogi, K.; Oda,
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2007, 48, E-Abstract 4805. (b) Mizuno, K.; Ohta, M.; Mori,
J.; Ozawa, T.; Nishio, M.; Hidaka, H.; Sawanobori, K.
Invest. Ophthalmol. Vis. Sci. 2008, 49, E-Abstract 1640.
(c) Mizuno, K.; Isobe, T.; Koide, T.; Watanabe, M.; Kaneko,
Y.; Inokuchi, Y.; Matsumoto, J.; Tanabe, S. Invest.
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(d) Tanihara, H.; Abe, H.; Kuwayama, Y.; Yamamoto, T.;
Araie, M. Invest. Ophthalmol. Vis. Sci. 2011, 52, E-Abstract
220. (e) Yamamoto, T.; Abe, H.; Kuwayama, Y.; Tanihara,
H.; Araie, M. Invest. Ophthalmol. Vis. Sci. 2011, 52, E-
Abstract 216.
(3) Gomi, N.; Ohgiya, T.; Shibuya, K.; Katsuyama, J.;
Masumoto, M.; Sakai, H. Heterocycles 2011, 83, 1771.
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Reamer, R. A.; Sheen, F. J.; Stewart, G. W.; Strotman, N. A.;
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(5) Revesz, L.; Bollbuck, B.; Buhl, T.; Eder, J.; Esser, R.; Feifel,
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MS (EI): m/z = 348 [M+].
HRMS: m/z [M+] calcd for C19H28N2O4: 348.2049; found:
348.2048.
(S)-tert-Butyl 2-Methyl-1,4-diazepane-1-carboxylate [(S)-17]
To a soln of (S)-16 (3.70 g, 10.6 mmol) in MeOH (30 mL) was add-
ed 10% Pd/C (370 mg). The reaction mixture was stirred at r.t. for
15 h under a hydrogen atmosphere. The catalyst was removed by fil-
tration through a pad of Celite®. The filtrate was concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (silica gel, 1 to 18% MeOH–CHCl3) to give (S)-17 as a pale
yellow oil; yield: 2.18 g (96%); >99.9% ee (by HPLC).
[α]D20 +56.8 (c 1.13, CHCl3); Rf = 0.33 (CHCl3–MeOH, 5:1).
IR (KBr): 3349, 2974, 1684, 1413, 1173 cm–1.
1H NMR (400 MHz, DMSO-d6, 100 °C): δ = 0.95 (d, J = 6.8 Hz, 3
H, CH3), 1.40 (s, 9 H, t-Bu), 1.47–1.57 (m, 2 H, CH2), 2.34 (dd,
J = 14.3, 10.0 Hz, 1 H, CHH), 2.46–2.54 (m, 1 H, CHH), 2.64 (br s,
1 H, NH), 2.83–2.93 (m, 2 H, 2 × CHH), 3.03 (dd, J = 14.3, 5.7 Hz,
1 H, CHH), 3.64 (ddd, J = 14.3, 3.4, 3.4 Hz, 1 H, CHH), 3.92–4.03
(m, 1 H, CH).
13C NMR (100 MHz, DMSO-d6, 100 °C): δ = 16.2, 27.7, 27.7, 27.7,
30.7, 39.5, 49.3, 51.9, 54.5, 77.4, 154.2.
MS (EI): m/z = 214 [M+].
HRMS: m/z [M+] calcd for C11H22N2O2: 214.1681; found:
(6) (a) Olsen, C. A.; Christensen, C.; Nielsen, B.; Farah, M. M.;
Witt, M.; Clausen, R. P.; Kristensen, J. L.; Franzyk, H.;
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Chem. 2009, 74, 5652.
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1999020620, 1999; Chem. Abstr. 1999, 130, 306596.
(b) The resulting mesylate was stored in the refrigerator
overnight and showed significant decomposition from in situ
generation of methanesulfonic acid which subsequently
cleaved the N-Boc group.
(9) (a) Kan, T.; Kobayashi, H.; Fukuyama, T. Synlett 2002, 697.
(b) Kan, T.; Fujiwara, A.; Kobayashi, H.; Fukuyama, T.
Tetrahedron 2002, 58, 6267. (c) Suzuki, M.; Kambe, M.;
Tokuyama, H.; Fukuyama, T. J. Org. Chem. 2004, 69, 2831.
(d) Zapf, C. W.; Del, Valle. J. R.; Goodman, M. Bioorg.
Med. Chem. Lett. 2005, 15, 4033. (e) Hovinen, J.; Sillanpää,
R. Tetrahedron Lett. 2005, 46, 4387. (f) Miyazaki, T.;
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214.1682.
(R)-tert-Butyl 2-Methyl-1,4-diazepane-1-carboxylate [(R)-17]
Yield: 20.6 g (74%); >99.9% ee (by HPLC); yellow oil.
[α]D20 –56.5 (c 1.21, CHCl3); Rf = 0.33 (CHCl3–MeOH, 5:1).
IR (KBr): 3348, 2973, 1685, 1413, 1174 cm–1.
1H NMR (400 MHz, DMSO-d6, 100 °C): δ = 0.96 (d, J = 6.8 Hz, 3
H, CH3), 1.41 (s, 9 H, t-Bu), 1.52–1.60 (m, 2 H, CH2), 2.43 (dd,
J = 14.3, 10.4 Hz, 1 H, CHH), 2.51–2.60 (m, 1 H, CHH), 2.86–2.99
(m, 2 H, 2 × CHH), 3.10 (dd, J = 14.3, 5.7 Hz, 1 H, CHH), 3.54 (br
s, 1 H, NH), 3.66 (ddd, J = 14.3, 3.4, 3.4 Hz, 1 H, CHH), 3.96–4.07
(m, 1 H, CH).
(10) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373. (b) Maligres, P. E.; See, M. M.; Askin, D.;
Reider, P. J. Tetrahedron Lett. 1997, 38, 5253.
13C NMR (100 MHz, DMSO-d6, 100 °C): δ = 16.2, 27.8, 27.8, 27.8,
29.9, 39.5, 48.8, 51.2, 53.7, 77.6, 154.1.
MS (EI): m/z = 214 [M+].
HRMS: m/z [M+] calcd for C11H22N2O2: 214.1681; found:
214.1684.
(c) Golantsov, N. E.; Karchava, A. V.; Yurovskaya, M. A.
Chem. Heterocycl. Compd. 2008, 44, 263.
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(12) Franzyk and co-workers’ conditions called for 15
equivalents of 3-aminopropan-1-ol; see ref. 7.
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D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599. (b) McCoull,
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(14) Purification of the product was tedious due to the large
amounts of triphenylphosphane oxide and diisopropyl
hydrazine-1,2-dicarboxylate.
Acknowledgment
We thank Dr. S. Tanabe, Director, Executive Officer at Tokyo New
Drug Research Laboratories, Kowa Co., Ltd. for his encouragement
and support, and also Dr. K. Swiss, Kowa Research Institute for his
help in preparing the manuscript.
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