Stereoselective cyclopropanation of chiral 5-substituted dihydro-2H-piperazines

Article abstract of DOI:10.1016/j.tetasy.2012.11.015

The Simmon-Smith cyclopropanation of enantiomerically enriched dehydropiperazines is reported. The reaction is highly stereoselective and allowed us to prepare new, enantiomerically enriched 3-substituted 2,5-diazabicyclo[4.1.0]heptane cores with high diastereomeric purity and a relative anti-configuration, which was assigned by NMR analysis.

Full text of DOI:10.1016/j.tetasy.2012.11.015

Tetrahedron: Asymmetry 24 (2013) 75–79
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective cyclopropanation of chiral 5-substituted
dihydro-2H-piperazines
Gianna Reginato a, , Maria Pia Catalani b, Alessandro Mordini a, Bernardo Pezzati a,b, Andrea Bernardelli b,
⇑
Silvia Davalli b, Nicola Pace b
a ICCOM–CNR, Via Madonna dela Piano, 10, 50019 Sesto Fiorentino, Italy
b Aptuit, Medicine Research Center, Via A. Fleming 4, 37135 Verona, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 October 2012
Accepted 20 November 2012
The Simmon–Smith cyclopropanation of enantiomerically enriched dehydropiperazines is reported. The
reaction is highly stereoselective and allowed us to prepare new, enantiomerically enriched 3-substituted
2,5-diazabicyclo[4.1.0]heptane cores with high diastereomeric purity and a relative anti-configuration,
which was assigned by NMR analysis.
Ó 2012 Elsevier Ltd. All rights reserved.
R1
N
R1
N
R1
N
R1
N
1. Introduction
The chemical diversity of biologically active compounds is ex-
tremely important in medicinal chemistry for the search for new
drug candidates with optimized pharmacological/pharmacokinetic
properties. The piperazine ring can be considered to be a ‘privi-
leged’ scaffold for drug discovery and optimization1–3 since many
pharmaceutical agents contain piperazines as part of their core
structures.4 Examples can be found in quinolone antibiotics,5
HIV-protease inhibitors,6 5HT-anxiolytics,7 antihypertensives,8
N
R2
N
R2
4
N
R2
N
R2
3
1
2
Scheme 1.
and d- and
j
-opioid receptor agonists.9–11 In addition to serving
reduce electron density at the ring nitrogen atoms through induc-
tive effects. It may also provide metabolic stability because of its
inherent bond angle. Since there is a lack of systematic studies
on cyclopropanations when chiral enamides are used,17 we
thought that to expand such a reaction to enantiomerically en-
riched substrates would be of interest in view of obtaining new
chiral and highly decorated piperazine scaffolds. Herein we report
our results on the Simmons–Smith cyclopropanation of functional-
ized and enantiomerically enriched dehydropiperazines, which
turned out to be highly stereoselective, and allowed the synthesis
of some new enantiomerically enriched 3-substituted 2,5-diazabi-
cyclo[4.1.0]heptane cores, which are fully characterized.
as base templates and substituents to give the desired properties
to a compound, piperazines can behave as bifunctional linking
agents to couple two components of an analogue through a rigid
three-dimensional diamine core structure.3
In order to find novel receptor ligands, various substituents
have been introduced onto the piperazine ring; derivatives bearing
substituents at the 3-position have been shown to interact strongly
with various receptors within the central nervous system.12 Other
structurally modified versions of piperazine found in pharmaceuti-
cals are ring-expanded homopiperazines such as 2, 2-methyl
piperazines such as 3 or compounds such as 2,5-diazabicy-
clo[4.1.0]heptane 4 (Scheme 1). This novel core has been used in
the synthesis of an analogue of the antibiotic Ciprofloxacin.13
The introduction of a fused cyclopropyl group is expected to
establish additional conformational constraints and has been
widely used in medicinal chemistry as well as in the synthesis of
peptidomimetics14,15 and polyamines.16 More specifically this moi-
ety can mimic cis-1,2-aminocyclopropane, a structural motif found
in a number of biologically active compounds, and is expected to
2. Results and discussion
Recently we reported on a general and highly stereoselective
approach to assess enantiomerically enriched 1,4,5-tri-substituted
oxopiperazines 5.18
This method is based on using naturally occurring amino acids
as chiral starting materials to control the substitution and stereo-
chemistry at the C-5 position. Orthogonal protection of the two
nitrogen atoms of the ring was also carried out to facilitate the
⇑
Corresponding author. Tel.: +39 055 5225255; fax: +39 055 5225203.
E-mail address: gianna.reginato@iccom.cnr.it (G. Reginato).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.11.015

76
G. Reginato et al. / Tetrahedron: Asymmetry 24 (2013) 75–79
Bn
N
Bn
1
NHBoc
OH
O
O
E
N
base
E
3
5
4
R
N
R
R
N
O
Boc
5
Boc
6
Bn
N
Bn
N
N
N
R
R
Boc
Boc
7
1
Scheme 2.
Bn
N
Bn
N
a R = CH3
b R = CH(CH3)2
ZnEt2
CH2I2
c R = CH2CH(CH3)2
d R =
Figure 2. 2D ROESY spectrum of compound 4a. Arrows indicate exchange peaks.
N
R
R
N
H2C
Boc
Boc
OBn
e R = CH2OBn
7a-e
4a-e
50-80%
easily transformed into more substituted 1,3,4,5-tetra-substituted
2-oxo-piperazines 6 via enolate formation and reaction with elec-
trophiles; anti substitution at C-3 was accomplished diastereose-
lectively (Scheme 2). Finally, we have shown that chiral
Scheme 3.
oxopiperazines 5 can be converted selectively into the correspond-
19
ing piperazines
1 or dihydro-2H-pyrazines 7 with LiAlH4
stepwise positioning of substituents with a view of using the oxo-
piperazine core as molecular scaffold. These compounds can be
(Scheme 2). These latter compounds 7a–d and the new dihydro-
2H-pyrazines 7e, obtained in good yield from naturally occurring
serine, were used as starting materials for the Simmons–Smith
cyclopropanation reaction reported herein (Scheme 3).
The reaction conditions used to introduce the cyclopropane
moiety into the scaffolds, involved the classical Simmons–Smith
procedure.20,21 Compounds 4a–e were thus obtained in excellent
yields (50–80%) after purification and as single diastereoisomers.
The diastereomeric purity and the relative anti-configuration
were assigned by 1H NMR analysis.
In the 1H NMR spectra of compounds 4a–e (see for instance
Fig. 1) splitting of all of the signals was observed at rt, because of
the presence of rotamers due to hindered rotation around the
amide bond. This is shown in Fig. 1 where the proton spectrum
of compound 4a in the region of interest (from 4.2 to 0 ppm) is re-
ported. The splitting for the more diagnostic signals allows for the
rotamer ratio estimation (60/40).
The presence of a fast equilibrium between the rotamers is con-
firmed by the presence of exchange peaks in the ROESY spectra
(see Fig. 2). Stereochemical analysis by means of 2D ROE and 1D
selective NOE spectroscopy was performed on compounds 4a–d,
and the relative anti stereochemistry was demonstrated.
An example of selective NOE experiments for compound 4a is
reported in Scheme 4. Irradiation of the methyl signal
(d = 1.23 ppm) resulted in the enhancement of Hd in accordance
with a syn relationship between this proton and the methyl group.
Boc
Hd
CH3
Hc
N
Hf
Hg
Ha
Hb
N
He
Bn
Figure 1. 1H NMR of compound 4a. Top: d = 10.0–0.0.
Scheme 4.

G. Reginato et al. / Tetrahedron: Asymmetry 24 (2013) 75–79
77
R
Bz
N
N
Boc
Boc
N
Hd
He
OBn
CH2
Hf
Hc
Ha
Hb
Zn
I
Hg
N
Scheme 6.
Bn
Scheme 5.
that similar to 6-alkyltetrahydropyridines,22 dihydro-2H-pyrazines
might prefer to adopt an axial orientation, which encourages re-
agent addition onto the olefin face opposite to the alkyl group.
Furthermore, irradiation at Hd produced an enhancement of Hf and
He. All of these observations proved an anti relationship between
CH3- and the cyclopropyl ring, which was also confirmed for com-
pounds 4b, c and e.
Due to overlapping of the diagnostic signals, particularly those
of Hd with the two protons of CH2 of the Tyr group and of He with
Ha, it was not possible to assign the relative stereochemistry of
compound 4d (Scheme 5) using the same experiment. Neverthe-
less we were able to address this point by using a double selective
1D TOCSY—NOESY experiment (Fig. 3).
This sequence provides a selective TOCSY edited preparation
(STEP) followed by a selective 1D NOESY. A 1H NMR spectrum of
compound 4d (Fig. 3A) was acquired, followed by a 1D-TOCSY, in
which selection of the Hf resonance resulted in a magnetization
transfer to all of the protons of the cyclopropyl ring, while elimi-
nating all of the other resonances (Fig. 3B). The second half of
the sequence was a selective NOE module, whereby one of the res-
onances present in the TOCSY subspectrum could be saturated. For
compound 4d, He (d = 2.7–2.5 ppm) was irradiated in the NOESY
step, thus solving the problem of signal overlapping. Enhancement
of the CH2 signals of the Tyr group (evidenced with arrows in
Fig. 3D) was observed, thus confirming the anti-relationship be-
tween the substituent and the cyclopropyl groups.
3. Conclusion
In conclusion the cyclopropanation of chiral dehydro pipera-
zines was studied using classical Simmons–Smith reaction condi-
tions. The process was highly stereoselective and allowed us to
obtain some new enantiomerically enriched 3-substituted 2,5-
diazabicyclo[4.1.0]heptane cores. Selected NMR experiment al-
lowed us to unequivocally identify the relative configurations of
the new stereocentres formed.
4. Experimental
4.1. General methods
Reactions were monitored by TLC on SiO2, detection was made
using a basic KMnO4 solution. Flash column chromatography was
performed using glass columns (10–50 mm wide) and SiO2 (230–
400 mesh). NMR spectra were acquired at 25 °C on a Agilent
VNMRS500 spectrometer equipped with a 5 mm Triple Resonance
1H{13C/15N} cryoprobe operating at 499.774 MHz and on a Bruker
400 MHz AVANCE III™ instruments spectrometer. Samples were
A rationale for the high level of diastereoselectivity we observed
in this reaction is put forward in Scheme 6 and is based on the fact
H +CH
d
2
H +H
e
a
H +H
H
f
g
b
H
c
A
B
C
D
3.1 3.0 2.9 2.8 2.7 2.6 2.5 2.4 2.3 2.2
4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0
Figure 3. 1H NMR (A), 1D TOCSY (B) and 1D NOESY (C and D) spectra of compound 4d. Arrows indicate signals of the CH2 of the Tyr group for both rotamers.

78
G. Reginato et al. / Tetrahedron: Asymmetry 24 (2013) 75–79
prepared by dissolving each compound in 0.75 mL of chloroform-d.
Chemical shifts are referenced to the residual solvent peak (chloro-
form-d, 7.27 ppm). 2D gCOSY experiments were acquired with the
following conditions: spectral width of 7000 Hz in both f1 and f2,
1 K data points in time domain with zero filling to 2 K, 256 incre-
ments for each data set with linear prediction to 1 K and zero filling
to 4 K, number of scans 2, processing with sine bell squared in both
dimensions. 2D 1H–13C gHSQCAD experiments were acquired
using a spectral width of 25,000 Hz in f1 and 7000 Hz in f2. Were
collected a total of 128 increments processed to 1 K with linear
prediction and to 2 K with zero filling, 4 scans each, with relaxation
delay 1 s. Data were processed with gaussian in both dimensions
with zero filling in f2. 2D 1H–13C gHMBCAD experiments were ac-
quired using a spectral width of 30,000 Hz in f1 and 7000 Hz in f2.
We collected a total of 256 increments processed to 1 K with linear
separated and the aqueous layer was extracted with more ether.
The combined organic phases were dried over Na2SO4, filtered
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography.
4.4. (1S,3S,6R)-tert-Butyl 5-benzyl-3-methyl-2,5-
diazabicyclo[4.1.0]heptane-2-carboxylate 4a
Dihydro-2H-pyrazine 7a (118 mg, 0.41 mmol) in Et2O (10 mL)
was reacted with ZnEt2 (1.67 mL, 1.67 mmol) in diethyl ether
(6 mL) and CH2I2 (0.12 mL, 1.43 mmol). Work-up and purification
[cyclohexene/ethyl acetate = 4/1] gave 4a as a colourless amor-
phous solid (54 mg, 45%). (4a, major conformer): 1H NMR
(500 MHz, CDCl3) d: 7.38 [d, 2H, J = 7.3 Hz], 7.33 [t, 2H,
J = 7.5 Hz]: 7.29–7.24 [m, 1H]; 4.05–3.97 [m, 1H]; 3.72 [d, 1H,
J = 12.7 Hz]; 3.61 [d, 1H, J = 12.7 Hz]; 2.74–2.68 [m, 1H]; 2.52–
2.42 [m, 2H]; 2.38–2.29 [m, 1H]; 1.67–1.58 [m, 1H]; 1.49 [s, 9H];
1.23 [d, 3 H, J = 6.6 Hz]; 0.52–0.45 [m, 2H]. 13C NMR (101 MHz,
CDCl3) d: 156.2; 138.4; 128.9(2C); 128.3(2C); 127.1; 79.3; 60.9;
52.7; 45.8; 36.2; 28.6(x3); 26.2; 17.4; 7.2) UPLC/MS: Rt = 0.72 min,
prediction and to 2 K with zero filling, 16 scans each. The experi-
2,3
ments were optimized for an average
J
CH
value of 8 Hz (delay
60 ms). Data were processed with gaussian in f1 and sine bell
squared in f2 with zero filling in f2. 2D ROESY experiments were
acquired with a mixing time of 300 ms using a spectral width of
7000 Hz in both f1 and f2. Were collected a total of 256 increments
processed to 1 K with linear prediction and to 4 K with zero filling,
16 scans each. Data were processed with gaussian in both dimen-
sions with zero filling in f2. For 1D–stepNOESY a 1D TOCSY was
preliminarily acquired using a spectral width of 8000 Hz, 16 K
complex data points, 150 ms during the spin lock, and a number
of scans 16–64. For one of the TOCSY correlations, a 1D NOESY
was collected applying a mixing time of 500–800 ms and 64–
1024 scans. Polarimetric measurements were performed at
k = 589 nm, and the temperature is specified case by case. All com-
mercial reagents were used without further purification. Oxopiper-
azines 1a–d were prepared according to the literature.23 THF was
dried by distillation over sodium benzophenone ketyl. CH2Cl2
was dried over CaCl2, and stored over 4 Å molecular sieves. DMF
was distilled over CaCl2, and stored over 4 Å molecular sieves.
Petroleum ether, unless specified, is the 40–70 °C boiling fraction.
[M+H] = 303.2;
18H26N2O2: C, 71.49; H, 8.67; N, 9.26. Found: C, 71.43; H, 8.64;
N, 9.27.
½
a 2D8
ꢂ
¼ þ3:2 (c 1.0, CHCl3). Anal. Calcd for
C
4.5. (1S,3S,6R)-tert-Butyl 5-benzyl-3-isopropyl-2,5-diaza
bicyclo[4.1.0]heptane-2-carboxylate 4b
Dihydro-2H-pyrazine 7b (100 mg, 0.32 mmol) in Et2O (8 mL)
was reacted with ZnEt2 (1.29 mL, 1.29 mmol) in diethyl ether
(6 mL) and CH2I2 (0.09 mL, 1.13 mmol). Work-up and purification
[cyclohexene/ethyl acetate = 9/1] gave 4b as a colourless viscous
oil (73 mg, 70%). (4b, two conformers 1/1): 1H NMR (500 MHz,
CDCl3) d: 7.37 [d, 5H, J = 7.6 Hz]; 7.32 [t, 2H, J = 7.5 Hz]; 7.28–
7.24 [m, 1H], 3.71 [d, 1H, J = 13.0 Hz], 3.50 [d, 1H, J = 13.0 Hz],
3.50–3.27 [m, 1H]; 2.82–2.67 [m, 2H]; 2.55–2.43 [m, 2H]; 2.26–
2.16 [m, 1H]; 2.13 [dd, 1H, J = 11.7, 2.9 Hz]; 1.50–1.45 [m, 9H];
0.94–0.84 [m, 6H]; 0.63–0.44 [m, 2H]. 13C NMR (101 MHz, CDCl3)
d: 156.2; 138.4; 128.9 (ꢁ2); 128.2 (ꢁ2); 127.1; 79.3; 61.1; 56.5;
48.9; 36.1; 28.5 (ꢁ3); 26.9; 26.8; 19.8 (ꢁ2); 6.5. UPLC/MS:
4.2. (R)-tert-Butyl 4-benzyl-2-(benzyloxymethyl)-3,4-
dihydropyrazine-1(2H)-carboxylate 7e
Rt = 0.95 min [M+H] = 331.0; ½a D28
¼ ꢀ24:3 (c 1.0, CHCl3). Anal.
ꢂ
At first, (S)-1-(benzyl)-4-tert-butoxycarbonyl-5-(phenylmeth-
oxy)-methyl-2-oxopiperazine 5e (500 mg, 1.22 mmol) was dis-
solved in THF (10 mL) and the solution was cooled down to
ꢀ30 °C. Next, LiAlH4 solution in THF (2 M, 0.914 ml 1.5 equiv) was
added and the mixture was kept at this temperature for 2 h. The
reaction was warmed up to 0 °C and quenched by the slow addition
of water. After extraction with EtOAc, the organic phases were col-
lected and dried over Na2SO4. Evaporation of the solvent gave
448 mg of 7e (93%) which was used without further purification.
White amorphous solid. (7e, major conformer): 1H NMR
(500 MHz, CDCl3) d: 7.33–7.25 [m, 10H], 5.81 [d, 1H, J = 6.4 Hz],
5.34 [d, 1H, J = 6.4 Hz]; 4.52 [br s, 2H]; 3.98 [s, 2H]; 3.64–3.50 [m,
2H]; 3.55–3.43 [m, 1H]; 2.78 [m, 2H]; 1.49 [s, 9H]. 13C NMR
(101 MHz, CDCl3) d: 156.3; 137.9(2C); 128.4(2C); 128.2(2C);
127.6(2C); 127.4; 127.3(2C); 126.9; 118.9; 101.5; 80.3; 73.0; 67.7;
58.9; 49.3; 45.9; 28.3(ꢁ3). UPLC/MS: Rt = 1.46 min, [M+H] = 395.3
Calcd for C20H30N2O2: C, 72.69; H, 9.15; N, 8.48. Found: C, 72.74;
H, 9.12; N, 8.51.
4.6. (1S,3S,6R)-tert-Butyl 5-benzyl-3-isobutyl-2,5-diaza
bicyclo[4.1.0]heptane-2-carboxylate 4c
Dihydro-2H-pyrazine 7c (57 mg, 0.17 mmol) in Et2O (2 mL) was
reacted with ZnEt2 (0.73 mL, 0.73 mmol) in diethyl ether (1 mL)
and CH2I2 (0.05 mL, 0.62 mmol). Work-up and purification [petro-
leum ether/ethyl acetate = 20/1] gave 4c as a colourless oil (32 mg,
54%). Rf: 0.62. (4c, major conformer): 1H NMR (400 MHz, CDCl3) d:
7.38–7.20 (m, 5H); 3.98–3.91 [m, 1H]; 3.73 [d, 1H, JAB = 12.8 Hz];
3.53 [d, 1H, JAB = 12.8 Hz]; 2.81–2.76 [m, 1H]; 2.58–2.46 [m, 2H];
2.25–2.20 [m, 1H]; 1.67–1.58 [m, 1H]; 1.48 [s, 9H]; 0.90 [d, 3H,
J = 2.0 Hz]; 0.89 [d, 3H, J = 2.0 Hz]; 0.58–0.54 (m, 2H). 13C NMR
(100 MHz, CDCl3) d: 155.9; 138.3; 128.9; 128.2; 127.1; 79.7;
60.9; 51.1; 49.2; 40.3; 35.7; 28.5(ꢁ3); 26.3; 24.7; 22.9; 22.8; 6.0.
4.3. Synthesis of 2,5-diazabicyclo[4.1.0]heptanes 4a–d: general
procedure
UPLC/MS: Rt = 1.03, [Ms+H] = 345.28. ½a D28
¼ þ2:6(c 1.0 CHCl3).
ꢂ
Anal. Calcd for C21H32N2O2: C, 73.22; H, 9.36; N, 8.13. Found: C,
73.35; H, 9.42; N, 8.16.
A solution of dihydro-2H-pyrazine 7 (1 equiv) in Et2O was
added to a solution of ZnEt2 (1 M in hexane, 4 equiv) in diethyl
ether. The reaction mixture was stirred at rt for 10 min after which
CH2I2 (4 equiv) was added and left to stir overnight at rt. After cool-
ing to 0 °C, an NH4Cl saturated solution was added and the result-
ing mixture was filtered through a Celite pad. The phases were
4.7. (1S,3S,6R)-tert-Butyl 5-benzyl-3-(4-benzylbenzyl)-2,5-
diazabicyclo[4.1.0]heptane-2-carboxylate 4d
Dihydro-2H-pyrazine 7d (100 mg, 0.2 mmol) in Et2O (10 mL)
was reacted with ZnEt2 (0.85 mL, 0.85 mmol) in diethyl ether

G. Reginato et al. / Tetrahedron: Asymmetry 24 (2013) 75–79
79
(3 mL) and CH2I2 (0.06 mL, 0.76 mmol). Work-up and purification
References
[cyclohexane/ethyl acetate gradient 9/1 to 0/1] gave 4d as a pale
brown viscous oil (75 mg, 73%). (4d, major conformer): 1H NMR
(500 MHz, CDCl3) d: 7.45–7.42 [m, 2H]; 7.39 [t, 4H, J = 7.3 Hz];
7.36–7.31 [m, 3H]; 7.30–7.25 [m, 1H]; 7.16 [d, 1H J = 8.6 Hz];
7.07 [d, 1H J = 8.6 Hz]; 6.85 [dd, 2H, J = 8.3, 6.6 Hz]; 5.04 [s,
2H]; 3.84–3.78 [m, 1H]; 3.70 [d, 1H, J = 12.7 Hz]; 3.54 [d, 1H,
J = 12.7 Hz]; 2.93–2.856 [m, 3H]; 2.65–2.59 [m, 1H]; 2.53 [dd,
1H, J = 11.6, 3.1 Hz]; 2.18 (dd, 1H, J = 11.6, 3.1 Hz]; 1.36 [s,
9H]; 0.65–0.60 [m, 1H]; 0.60–0.55 [m, 1H]. 13C NMR (101 MHz,
CDCl3) d: 157.3; 155.63; 138.18; 137.22; 131.67; 130.33 (ꢁ2);
129.16 (ꢁ2); 128.59 (ꢁ2); 128.26 (ꢁ2); 127.92; 127.42 (ꢁ2);
127.18; 114.72 (ꢁ2); 79.42; 70.05; 61.10; 53.10; 49.40; 36.83;
35.65; 28.53 (ꢁ3); 26.71; 5.50. UPLC/MS: Rt = 1.35 min
1. Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter,
W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.;
Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J.
Med. Chem. 1988, 31, 2235.
2. Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.; Barluenga, S.;
Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939.
3. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
4. Vieth, M.; Siegel, M. G.; Higgs, R. E.; Watson, I. A.; Robertson, D. H.; Savin, K. A.;
Durst, G. L.; Hipskind, P. A. J. Med. Chem. 2004, 47, 224.
5. Miyamota, T.; Matsumoto, J.; Chiba, K.; Egawa, H.; Shibamori, K.; Minamida, A.;
Nishimura, Y.; Okada, H.; Kataoka, M.; Fujita, M.; Hirose, T.; Nakano, J. J. Med.
Chem. 1990, 33, 1645.
6. Serradji, N.; Bensaid, O.; Martin, M.; Kan, E.; Bosquet, N. D.; Redeuilh, C.; Huet,
J.; Heymans, F.; Lamouri, A.; Clayette, P.; Dong, C. Z.; Dormont, D.; Godfroid, J. J.
J. Med. Chem. 2000, 43, 2149.
7. Parihar, H. S.; Suryanarayanan, A.; Ma, C.; Joshi, P.; Venkataraman, P.; Schulte,
K. M.; Kirschbaum, K. S. Bioorg. Med. Chem. Lett. 2001, 11, 2133.
8. Giardinh, D.; Gulini, U.; Massi, M.; Piloni, M. G.; Pompei, P.; Rafaiani, G.;
Melchiorre, C. J. Med. Chem. 1993, 36, 690.
[M+H] = 485.4.
31H36N2O3: C, 76.83; H, 7.49; N, 5.78. Found: C, 76.78; H,
7.47; N, 5.75.
½
a 2D8
ꢂ
¼ ꢀ13:2 (c 1.5, CHCl3). Anal. Calcd for
C
9. Lopez, J. A.; Okayama, T.; Hosohata, K.; Davis, P.; Porreca, F.; Yamamura, H. I.;
Hruby, V. J. J. Med. Chem. 1999, 42, 5359.
10. Naylor, A.; Judd, D. E.; Lloyd, J. E.; Scopes, D. I.; Hayes, A. G.; Birch, P. J. J. Med.
Chem. 1993, 36, 2075.
11. Soukara, S.; Maier, C. A.; Predoiu, U.; Ehret, A.; Jackisch, R.; Wünsch, B. J. Med.
Chem. 2001, 44, 2814.
4.8. (1S,3S,6R)-tert-Butyl 5-benzyl-3-[(benzyloxy)methyl]-2,5-
diazabicyclo[4.1.0]heptane-2-carboxylate 4e
12. Bedürftig, S.; Wünsch, B. Eur. J. Med. Chem. 2006, 41, 387.
13. Taylor, R. R. R.; Twin, H. C.; Wen, W. W.; Mallot, R. J.; Lough, A. J.; Gray-Owen, S.
D.; Batey, R. A. Tetrahedron 2010, 66, 3370.
14. See for instance: Reichelt, A.; Gaul, C.; Frey, R. R.; Kennedy, A.; Martin, S. F. J.
Org. Chem., 2002, 67, 4062.
15. See for instance: Pol, S. D.; Zorn, C.; Klein, C. D.; Zerbe, O.; Reiser, O. Angew.
Chem., Int. Ed. 2004, 43, 511.
16. See for instance: Casero, R. A. J.; Woster, P. M. J. Med. Chem. 2009, 52, 4551.
17. Song, Z.; Lu, T.; Hsung, R. P.; Al-Rashid, Z. F.; Ko, C.; Tang, Y. Angew. Chem., Int.
Ed. 2007, 46, 4069. and ref. cited.
Dihydro-2H-pyrazine 7e (205 mg, 0.52 mmol) in Et2O (10 ml)
was reacted with ZnEt2 (2.1 mL, 2.1 mmol) in Et2O (5 mL) and
CH2I2 (0.147 mL, 1.80 mmol). Work-up and purification [cyclo-
hexane/ethyl acetate = 8/2] gave 4e as a colourless viscous oil
(142 mg, 67%). (4e, major conformer): 1H NMR (500 MHz, CHCl3)
d ppm: 7.39–7.23 [m, 10H]; 4.59 [d, 1H, J = 12.2 Hz]; 4.53 (d, 1H,
J = 12.2 Hz); 4.19–4.13 [m, 1H]; 3.75–3.66 [m, 2H]; 3.64–3.54 [m,
2H]; 2.89–2.83 [m, 1H]; 2.70 [m, 1H]; 2.42 [m, 1H]; 2.30 [m, 1H];
1.50 [s, 9H]; 0.59–0.51 [m, 1H]; 0.48 [q, 1H, J = 6.5 Hz]. 13C NMR
(101 MHz, CHCl3) d ppm: 156.40; 138.69; 138.19; 128.58–128.25
(ꢁ9); 79.56; 72.87; 68.90; 48.81; 48.20; 36.28; 28.55 (ꢁ3);
18. Reginato, G.; Di Credico, B.; Andreotti, D.; Paio, A.; Donati, D. Tetrahedron:
Asymmetry 2007, 18, 2680.
19. Reginato, G.; Credico, B. D.; Andreotti, D.; Mingardi, A.; Paio, A.; Donati, D.;
Pezzati, B.; Mordini, A. Tetrahedron Asymmetry 2010, 21, 191.
20. Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323.
21. Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977.
22. Pattenden, L. C.; Adams, H.; Smith, S. A.; Harrity, J. P. A. Tetrahedron 2008, 64,
2951.
26.69; 7.31. UPLC/MS: Rt = 1.1 min [M+H] = 409.3 ½a D28
¼ þ19:1
ꢂ
(c 1, CHCl3). Anal. Calcd for C25H32N2O3: C, 73.50; H, 7.90; N,
6.86. Found: C, 73.46; H, 7.88; N, 6.83.
23. Reginato, G.; DiCredico, B.; Andreotti, D.; Mingardi, A.; Paio, A.; Donati, D.
Tetrahedron: Asymmetry 2007, 18, 2680.