An efficient synthesis of chiral terminal 1,2-diamines using an enantiomerically pure [1-(1′R)-methylbenzyl]aziridine-2-yl]methanol

Article abstract of DOI:10.1016/j.tet.2006.06.024

Enantiomerically pure terminal 1,2-diamines, which can serve as precursors for the synthesis of many biologically important compounds, were synthesized efficiently from a commercially available chiral [1-(1′R)-methylbenzyl]aziridine-2-yl]methanol. Various

Full text of DOI:10.1016/j.tet.2006.06.024

Tetrahedron 62 (2006) 8393–8397
An efficient synthesis of chiral terminal 1,2-diamines
using an enantiomerically pure [1-(10R)-
methylbenzyl]aziridine-2-yl]methanol
Baeck Kyoung Lee,a Min Sung Kim,a Heung Sik Hahm,a Dong Sub Kim,a
b,
Won Koo Leea, and Hyun-Joon Ha
*
*
aDepartment of Chemistry and Interdisciplinary Program of Integrated Biotechnology, Sogang University,
Seoul 121-742, Republic of Korea
bDepartment of Chemistry, Hankuk University of Foreign Studies, Yongin, Kyunggi-Do 449-719, Republic of Korea
Received 10 May 2006; revised 8 June 2006; accepted 8 June 2006
Available online 5 July 2006
The authors dedicate this article to Professor Peter Beak on the occasion of his 70th birthday
Abstract—Enantiomerically pure terminal 1,2-diamines, which can serve as precursors for the synthesis of many biologically important com-
pounds, were synthesized efficiently from a commercially available chiral [1-(10R)-methylbenzyl]aziridine-2-yl]methanol. Various enantio-
merically pure 2-vinylaziridines were prepared by Wittig reactions from aziridine-2-carboxaldehyde and the corresponding phosphonium
salts. The C(2)–N bond of the vinyl substituted aziridine ring was regioselectively cleaved by azidotrimethylsilane (TMSN3). The azido group
and the double bond were reduced successively to give the target compounds in high yields.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
pure starting materials. In addition, we need to consider dif-
ferent factors to establish generalized procedure for each
application.16 The requirement of more efficient preparative
pathways to enantiomerically pure terminal 1,2-diamines
prompted us to develop a simple and highly efficient new
synthetic route.
Compounds incorporating the terminal chiral 1,2-diamine
functionality attract attentions from a variety of scientific
areas. Previous research shows that some terminal 1,2-di-
amines and their derivatives have biological activities. For
example, 1,2-diaminoplatinum complexes are considered
as antitumor agents, biotins1 have been used as protein
immobilization agent in biosensor, and emeriamines2 are
used as inhibitors in fatty acid oxidation. These compounds
also play important roles in organic synthesis and they are
used as intermediates in the synthesis of heterocycles3 or
nitrogen containing macrocycles,4 chiral ligands, and
auxiliaries in catalytic asymmetric transformations.5
In this report we described an efficient preparative route to
enantiomerically pure terminal 1,2-diamines from commer-
cially available enantiomerically pure 2-hydroxymethyl-
aziridines.
2. Results and discussion
We previously reported the preparation and the application
of enantiomerically pure aziridine-2-carboxaldehydes from
commercially available aziridine-2-carboxylates.17 Starting
from the aldehydes (2R)-1a–g, a variety of 2-alkenyl aziri-
dines (2S)-2a–g were prepared efficiently as a cis/trans mix-
ture by Wittig reaction with the corresponding phosphonium
salts in high yields. We also prepared the diastereomeric
2-alkenyl aziridines (2R)-2h–l using the same reaction con-
ditions from (2S)-1h–l (Table 1; Scheme 1).
Although there has been a variety of applications, only a few
preparative methods are available for the chiral terminal 1,2-
diamines: from chiral alcohols,6 alkylimines,7 simple
heterocycles,8–10 2-(sufonyloxy)nitriles,11 nitrones,12 aziri-
dinium ion,13 and ephedrine or pseudoephedrine.14,15 How-
ever, each of the above methods has limited scope due to the
lack of stereoselectivity and availability of enantiomerically
Keywords: 1,2-Diamine; 2-Vinylaziridine; Wittig reaction; Ring opening;
Azidotrimethylsilane.
* Corresponding authors. Tel.: +82 2 7058449 (W.K.L.); tel.: +82 31
3304369; fax: +82 31 3304566 (H.-J.H.); e-mail addresses: wonkoo@
sogang.ac.kr; hjha@hufs.ac.kr
The aziridine ring C(2)–N bond is regioselectively cleaved
by treating the 2-alkenyl aziridines ((2S)-2a–g and
(2R)-2h–l) with 3 equiv of TMSN3 in CH2Cl2 to provide
1-amino-2-azido-3-alkenes. Based on our previous results,
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.024

8394
B. K. Lee et al. / Tetrahedron 62 (2006) 8393–8397
Table 1. Preparation of (2S)- and (2R)-2-alkenyl aziridines ((2S)-2a–g and
(2R)-2h–l) from enantiomerically pure (2R)- and (2S)-aziridine-2-carbox-
aldehydes ((2R)-1a–g and (2S)-1h–l)
transformations show that the absolute configuration at
C-2 of the final terminal 1,2-diamines is originated from
that of C-2 position of the chiral aziridines and results are
summarized in Table 2. The benzyl group on the nitrogen
was successfully removed by catalytic hydrogenation in
the presence of 20 wt % Pd(OH)2 at 140 psi of H2(g) to
give the terminal 1,2-diamine 4 in high yields (Scheme 3).
Entry
R
Yield (%)
2a
2b
2c
2d
2e
2f
2g
2h
2i
Phenyl
91
94
89
92
89
86
95
89
87
89
96
90
2-Cl-Phenyl
4-Biphenyl
Propyl
Nonyl
1-Naphthyl
Penta-F-phenyl
Phenyl
1-Naphthyl
4-Cl-Phenyl
Propyl
Table 2. Preparation of (2R)- and (2S)-1,2-diaminoalkanes ((2R)-3a–g
and (2S)-3h–l) from (2S)- and (2R)-2-alkenyl aziridines ((2S)-2a–g and
(2R)-2h–l)
Entry
R
Yield (%)a
2j
2k
2l
2a
2b
2c
2d
2e
2f
2g
2h
2i
Phenyl
80
85
83
86
80
79b
75b
77
81
80
78
81
Benzyl
2-Cl-Phenyl
4-Biphenyl
Propyl
Ph
Ph
R X-
Nonyl
Ph3P
O
H
1-Naphthyl
Penta-F-phenyl
Phenyl
1-Naphthyl
4-Cl-Phenyl
Propyl
Me
N
Me
N
R
LHMDS, THF
0 °C
H
H
(2R)-1a-g
(2S)-1h-l
(2S)-2a-g
(2R)-2h-l
2j
2k
2l
Benzyl
Scheme 1.
a
Isolated yields.
2HCl salts.
b
the regiochemistry of Lewis acid or protic acid catalyzed
nucleophilic ring opening reaction of N-a-methylbenzyl-2-
alkyl aziridine is determined by steric requirement of the
aziridine ring carbon and the ring opening reaction takes
place at the less sterically hindered C-3.18 However, in
case of acyl or vinyl substituted aziridine, the ring opening
reaction takes place at C-2 due to the assistance of the acti-
vating effect of the substituent (Fig. 1).
Ph
Pd(OH)2/MeOH
(R)
(R)
Ph
Ph
H2N
Me
N
H
H2(g), 140 psi
3 days
NH2
4
NH2
(2R)-3a
Scheme 3.
Ph
Ph
We have also applied the enantiomerically pure terminal
1,2-diamines for the preparation of orthogonally protected
2-substituted piperazine. The importance of substituted
piperazines can be found in a wide variety of pharmaco-
logically active compounds.19–23 The reaction of terminal
1,2-diamine (2S)-3h with RCHO and MgSO4 at room
temperature generated the corresponding imine, which was
then reduced with NaBH4 at 0 ꢀC to provide the 1-(10R)-
phenethyl-2-(S)-alkylamino-1,2-diamine 5 in high yields
(Scheme 4). Reductive cyclization of 5 with 40% aqueous
glyoxal solution in the presence of NaCNBH3 as the reduc-
ing agent in MeOH at 0 ꢀC proceeded smoothly and the
desired 2-substituted-1,4-piperazine 6 was isolated in high
yields (Scheme 5).
A
H
A
H
Me
N
Me
N
R
R
Nu-
Nu-
Due to allylic activation,
Due to steric hindrance
Nu- attacks C(2)
Nu- attacks C(3)
A : proton or Lewis acid
Figure 1. Regiochemistry in aziridine ring opening reactions.
The treatment of 1-amino-2-azido-3-alkenes with LAH in
diethyl ether at 0 ꢀC provided the corresponding 1,2-di-
amino-3-alkenes in high yields. It was unnecessary to sepa-
rate the cis/trans mixture of the 1,2-diamino-3-alkenes since
the double bond was saturated by catalytic hydrogenation in
the presence of 20 wt % of Pd/C catalyst. The catalytic
hydrogenation in MeOH was completed in 1 h at room
temperature to provide the corresponding chiral terminal
1,2-diamines ((2R)-3a–g and (2S)-3h–l) and the results
are summarized in Scheme 2. Therefore, the present
Ph
Ph
1. R'CHO, MgSO4/MeOH
(S)
(S)
Ph
Ph
Me
N
H
Me
N
H
2. NaBH4, 0 °C
HN
R'
NH2
5a R' = Ph 94%
(2S)-3h
5b R' = Pentyl 83%
Scheme 4.
(R) or (S)
Ph
Ph
Ph
Ph
(S)
(CHO)2
Ph
(S)
Ph
1. TMSN3/CH2Cl2
R
Me
N
Me
N
Me
N
H
Me
N
H
R
NaCNBH3, MeOH
N
R'
2. LiAlH4/Ether, 0 °C
3. Pd/C, MeOH, H2(g)
HN
R'
NH2
0 °C
H
6a R' = Ph 85%
6b R' = Pentyl 87%
(2S)-2a-g
(2R)-2h-l
(2R)-3a-g
(2S)-3h-l
5a R' = Ph
5b R' = Pentyl
Scheme 2.
Scheme 5.

B. K. Lee et al. / Tetrahedron 62 (2006) 8393–8397
8395
In summary, an operationally simple and high yielding four-
step synthesis of 1-(N)-protected chiral terminal 1,2-diamine
compounds has been developed from commercially avail-
able enantiomerically pure aziridine-2-methanols. The
process includes regioselective ring opening of 2-vinyl
substituted aziridines by azidotrimethylsilane followed by
the sequential reduction of the azido group and the double
bond. We also developed an efficient new synthetic route
for the preparation of enantiomerically pure orthogonally
protected 2-substituted-1,4-piperazines using N0-alkylation
and intramolecular reductive cyclization.
38.1, 32.1, 24.6; Anal. Calcd for C18H23ClN2: C, 71.39; H,
7.66; N, 9.25. Found: C, 71.44; H, 7.75; N, 9.11.
Compound (2R)-3c: liquid, [a]2D4 +59.5 (c 2.7, CH2Cl2); 1H
NMR (500 MHz, CDCl3) d 7.39–7.19 (m, 14H), 3.62 (q,
J¼6.5 Hz, 1H), 2.71–2.50 (m, 3H), 2.31 (dd, J¼9.8,
5.9 Hz, 1H), 2.13 (m, 1H), 1.52 (m, 1H), 1.35 (m, 1H),
1.29 (d, J¼6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
146.0, 141.9, 139.7, 130.2, 129.4, 129.3, 128.5, 128.3,
127.6, 127.0, 126.9, 126.7, 125.9, 58.8, 54.4, 51.1, 38.0,
29.7, 24.5; Anal. Calcd for C24H28N2: C, 83.68; H, 8.19;
N, 8.13. Found: C, 83.61; H, 8.06; N, 8.22.
3. Experimental
Compound (2R)-3d: liquid, [a]2D4 +127.1 (c 3.1, CH2Cl2); 1H
NMR (300 MHz, CDCl3) d 7.39–7.23 (m, 5H), 3.74 (q,
J¼6.5 Hz, 1H), 2.74 (m, 1H), 2.51 (qd, J¼11.6, 3.4 Hz,
1H), 2.21 (qd, J¼11.4, 2.9 Hz, 1H), 1.35 (d, J¼6.5 Hz,
3H), 1.31–1.24 (m, 8H), 0.86 (t, J¼6.3 Hz, 3H); 13C NMR
(755 MHz, CDCl3) 146.2, 128.6, 127.1, 126.8, 126.9, 58.9,
54.8, 51.7, 36.5, 32.2, 26.0, 24.7, 22.8, 14.2; Anal. Calcd
for C15H26N2: C, 76.87; H, 11.18; N, 11.95. Found: C,
76.80; H, 11.10; N, 12.05.
3.1. General methods
All reactions were carried out using standard Schlenk tech-
nique in an N2 atmosphere. Solvents were dried by standard
methods and distilled under N2. Flash chromatography was
performed with 230–400 mesh silica gel. Melting points
were determined on a capillary melting point apparatus
1
and are uncorrected. H NMR and 13C NMR spectra were
obtained on a Varian Gemini 300 and 500 MHz spectro-
meters. NMR spectra were recorded in parts per million
(d) relative to the peak for tetramethylsilane (d¼0.00) as
an internal standard unless stated otherwise and are reported
as follows: chemical shift, multiplicity (br¼broad, s¼
singlet, t¼triplet, q¼quartet, m¼multiplet), coupling con-
stant, and integration. Elemental analyses were performed
by an elemental analyzer. Optical rotations were obtained
on a digital polarimeter. Data are reported as follows: [a]D24
(concentration (g/1000 mL), solvent). Solvents and liquid
reagents were transferred using hypodermic syringes. All
other reagents and solvents used were reagent grade.
All glassware was dried in an oven at 150 ꢀC prior to use.
Small- and medium-scale purifications were performed
using flash chromatography.
Compound (2R)-3e: liquid, [a]2D4 ꢁ69.2 (c 1.0, CH2Cl2); 1H
NMR (500 MHz, CDCl3) d 7.35–7.19 (m, 5H), 3.72 (q,
J¼6.5 Hz, 1H), 2.72 (m, 1H), 2.50 (qd, J¼11.6, 3.5 Hz,
1H), 2.20 (qd, J¼11.6, 2.5 Hz, 1H), 1.35 (d, J¼6.5 Hz,
3H), 1.29–1.23 (m, 20H), 0.88 (t, J¼6.3 Hz, 3H); 13C
NMR (125 MHz, CDCl3) 146.2, 128.6, 127.0, 126.7, 58.9,
58.4, 55.0, 51.6, 36.7, 32.1, 29.9, 29.8, 29.7, 29.6, 29.5,
26.3, 24.6, 22.9, 14.4; Anal. Calcd for C21H38N2: C,
79.18; H, 12.02; N, 8.79. Found: C, 79.22; H, 12.32; N, 8.65.
Compound (2R)-3h: liquid, [a]2D4 +109.8 (c 1.3, CH2Cl2); 1H
NMR (300 MHz, CDCl3) d 7.35–7.19 (m, 10H), 3.72 (q,
J¼6.5 Hz, 1H), 2.78–2.47 (m, 4H), 2.30 (qd, J¼11.6,
8.4 Hz, 1H), 1.74–1.46 (m, 1H), 1.34 (d, J¼6.5 Hz, 3H);
13C NMR (75 MHz, CDCl3) 146.3, 142.4, 128.7, 128.6,
128.5, 127.1, 126.8, 126.0, 59.0, 55.0, 51.3, 38.2, 32.8,
24.6; Anal. Calcd for C18H24N2: C, 80.55; H, 9.01; N,
10.44. Found: C, 80.60; H, 9.13; N, 10.41.
3.1.1. Preparation of the 4-phenyl-N-[(R)-(D)-a-methyl-
benzyl]butane-1,2(R)-diamine ((2R)-3a). To a solution of
1,2-diamino-3-alkene (120 mg, 0.43 mmol)18a in 1.42 mL
of MeOH was added Pd/C (24 mg, 20 wt %). The reaction
mixture was stirred at room temperature with 1 atm of
H2(g) for 1 h and then the catalyst was filtered and concen-
trated in vacuo. Purification by silica gel flash chromato-
graphy (CH2Cl2/MeOH 50:50) provided 109 mg (90%) of
the product (2R)-3a as a yellow oil. [a]2D4 +123.5 (c 3.5,
CH2Cl2); 1H NMR (500 MHz, CDCl3) d 7.32–7.16 (m,
10H), 3.73 (q, J¼6.6 Hz, 1H), 2.81 (m, 1H), 2.68 (m, 1H),
2.55 (m, 2H), 2.19 (dd, J¼11.5, 8.6 Hz, 1H), 1.66 (m, 1H),
1.53 (m, 1H), 1.34 (d, J¼6.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) 146.2, 142.4, 128.7, 128.6, 128.5,
127.1, 126.8, 126.0, 59.0, 54.9, 51.3, 38.2, 32.8, 24.6;
Anal. Calcd for C18H24N2: C, 80.55; H, 9.01; N, 10.44.
Found: C, 80.47; H, 9.12; N, 10.45.
Compound (2R)-3i: liquid, [a]2D4 +64.6 (c 0.5, CH2Cl2); 1H
NMR (500 MHz, CDCl3) d 7.34–7.13 (m, 12H), 3.70 (q,
J¼6.5 Hz, 1H), 2.90–2.69 (m, 3H), 2.56 (qd, J¼11.6,
3.5 Hz, 1H), 2.31 (qd, J¼11.6, 8.4 Hz, 1H), 1.84–1.56 (m,
2H), 1.34 (d, J¼6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
145.8, 139.8, 133.8, 132.1, 128.6, 128.1, 127.7, 127.5,
127.4, 127.0, 126.7, 126.4, 126.0, 125.3, 58.3, 54.2, 51.0,
37.9, 32.8, 24.7; HRMS (EI) calcd for C22H26N2:
318.2096, found: 318.2099.
Compound (2R)-3j: liquid, [a]2D4 +53.0 (c 1.9, CH2Cl2); 1H
NMR (300 MHz, CDCl3) d 7.34–7.05 (m, 9H), 3.73 (q,
J¼6.5 Hz, 1H), 2.80 (m, 1H), 2.76–2.49 (m, 3H), 2.20 (qd,
J¼8.7, 3.7 Hz, 1H), 1.76–1.43 (m, 2H), 1.34 (d, J¼6.5 Hz,
3H); 13C NMR (75 MHz, CDCl3) 145.9, 140.8, 129.9,
128.7, 128.6, 127.2, 126.8, 126.0, 58.4, 54.3, 51.0, 38.0,
32.1, 24.8; Anal. Calcd for C18H23ClN2: C, 71.39; H, 7.66;
N, 9.25. Found: C, 71.46; H, 7.65; N, 9.14.
Compound (2R)-3b: liquid, [a]2D4 +27.3 (c 1.1, CH2Cl2); 1H
NMR (300 MHz, CDCl3) d 7.35–7.05 (m, 9H), 3.71 (q,
J¼6.5 Hz, 1H), 2.76–2.45 (m, 4H), 2.31 (td, J¼8.4,
3.0 Hz, 1H), 1.69 (m, 1H), 1.55 (m, 1H), 1.34 (d,
J¼6.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) 146.2, 140.8,
129.9, 128.7, 128.6, 127.1, 126.8, 126.0, 59.0, 55.0, 51.2,
Compound (2R)-3k: liquid, [a]2D4 +387.0 (c 5.0, CH2Cl2);
1H NMR (500 MHz, CDCl3) d 7.35–7.22 (m, 5H), 3.74

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B. K. Lee et al. / Tetrahedron 62 (2006) 8393–8397
(q, J¼6.5 Hz, 1H), 2.74 (m, 1H), 2.54 (dd, J¼11.6, 3.4 Hz,
1H), 2.14 (dd, J¼11.4, 8.8 Hz, 1H), 1.35 (d, J¼6.5 Hz,
3H), 1.25–1.06 (m, 8H), 0.87 (t, J¼5.9 Hz, 3H); 13C NMR
(125 MHz, CDCl3) 145.8, 128.6, 127.0, 126.8, 58.5, 54.7,
51.6, 36.7, 32.2, 26.1, 24.9, 22.8, 14.3; Anal. Calcd for
C15H26N2: C, 76.87; H, 11.18; N, 11.95. Found: C, 76.90;
H, 11.16; N, 12.01.
3.1.4. Preparation of the 2-N-benzyl-4-phenyl-N-(1(R)-
(D)-a-methylbenzyl)butane-1,2(S)-diamine (5a). To a
solution of 4-phenyl-N-[1(R)-a-methylbenzyl]butane-1,2(S)-
diamine 3h (100 mg, 0.37 mmol) in 1.86 mL of MeOH
under nitrogen atmosphere was added benzaldehyde
(0.08 mL, 0.75 mmol) at room temperature. To the mixture
was added MgSO4 (90 mg, 0.75 mmol) and stirred for 6 h.
To the mixture was slowly added NaBH4 (21 mg,
0.56 mmol) at 0 ꢀC. The mixture was stirred for 30 min at
0 ꢀC. The reaction was quenched with water at room temper-
ature. The aqueous layer was extracted with CH2Cl2. The
combined extract was dried over MgSO4, and the solvent
was evaporated to give the crude product, which was purified
by silica gel flash chromatography with 30% EtOAc/hexane
to give 125 mg (94%) of the product 5a as a colorless oil;
Compound (2R)-3l: liquid, [a]2D4 +54.5 (c 0.5, CH2Cl2); 1H
NMR (300 MHz, CDCl3) d 7.33–7.22 (m, 10H), 3.72 (q,
J¼6.6 Hz, 1H), 2.78 (m, 1H), 2.59–2.42 (m, 3H), 2.14 (dd,
J¼11.6, 8.7 Hz, 1H), 1.72–1.40 (m, 2H), 1.33 (d, J¼
6.6 Hz, 3H), 1.29–1.17 (m, 2H); 13C NMR (75 MHz,
CDCl3) 146.0, 142.6, 128.7, 128.6, 128.5, 127.1, 126.8,
126.0, 58.5, 54.4, 51.5, 36.2, 29.4, 28.3, 24.9; Anal. Calcd
for C15H26N2: C, 80.80; H, 9.28; N, 9.92. Found: C, 80.92;
H, 9.51; N, 10.11.
1
[a]2D4 +14.5 (c 0.1, CH2Cl2); H NMR (500 MHz, CDCl3)
d 7.30–7.10 (m, 15H), 3.70 (q, J¼13.1 Hz, 2H), 3.61 (q,
J¼6.5 Hz, 1H), 2.69–2.45 (m, 4H), 2.34 (dd, J¼11.4,
7.4 Hz, 1H), 1.84–1.60 (m, 2H), 1.32 (d, J¼6.5 Hz, 3H);
13C NMR (125 MHz, CDCl3) 146.0, 142.6, 141.1, 128.7,
128.6, 128.5, 128.4, 128.3, 127.0, 126.9, 126.8, 125.9,
58.2, 56.2, 51.0, 50.4, 34.6, 32.4, 24.9; HRMS (EI) calcd
for C25H30N2: 358.2409, found: 358.2414.
3.1.2. Preparation of the 2HCl salt of 4-naphthyl-N-[(R)-
(D)-a-methylbenzyl]butane-1,2(R)-diamine ((2R)-3f*).
To a solution of 4-naphthyl-N-[(R)-(+)-a-methylbenzyl]-
butane-1,2(R)-diamine (2R)-3f (90 mg, 0.28 mmol) in
1.40 mL of THF under nitrogen atmosphere was added
concd HCl at room temperature. The mixture was stirred
for 2 h at room temperature. After evaporation, Et2O was
added and the product was filtered and recrystallized from
Et2O to give 102 mg (92%) of (2R)-3f* as a white solid;
mp 294–295 ꢀC; [a]D24 +14.8 (c 1.5, DMSO); 1H NMR
(500 MHz, CDCl3) d 7.88–7.82 (m, 3H), 7.71 (s, 1H), 7.64
(d, J¼6.6 Hz, 1H), 7.51–7.38 (m, 6H), 4.41 (q, J¼6.3 Hz,
1H), 3.59 (m, 1H), 3.37 (m, 1H), 3.02 (d, J¼12.1 Hz, 1H),
2.80 (t, J¼7.8 Hz, 1H), 2.01 (m, 1H), 1.64 (d, J¼6.6 Hz,
3H); 13C NMR (125 MHz, CDCl3) 138.1, 137.2, 133.1,
131.7, 129.0, 128.9, 127.9, 127.8, 127.5, 127.3, 127.2,
126.2, 126.1, 125.4, 58.3, 48.1, 47.0, 32.2, 30.6, 19.2;
Anal. Calcd for C22H23Cl2N2: C, 67.51; H, 7.21; N, 7.16.
Found: C, 67.54; H, 7.24; N, 7.08.
Compound 5b: liquid, [a]2D4 +6.9 (c 0.3, CH2Cl2); 1H NMR
(500 MHz, CDCl3) d 7.31–7.12 (m, 10H), 3.72 (q, J¼
6.5 Hz, 1H), 2.63–2.45 (m, 6H), 2.31 (dd, J¼12.4, 8.5 Hz,
1H), 1.79–1.10 (m, 13H), 0.89 (t, J¼6.7 Hz, 3H); 13C
NMR (125 MHz, CDCl3) 146.3, 142.8, 128.7, 128.6,
128.5, 127.0, 126.9, 125.9, 58.6, 57.5, 50.8, 47.1, 34.8,
32.7, 32.1, 30.8, 27.4, 24.9, 22.9, 14.3; Anal. Calcd for
C24H36N2: C, 81.76; H, 10.29; N, 7.95. Found: C, 81.90;
H, 10.21; N, 8.05.
3.1.5. Preparation of the 1-N-benzyl-2(R)-phenethyl-
N-(4(R)-(D)-a-methylbenzyl)piperazine (6a). To a solu-
tion of 2-N-benzyl-4-phenyl-N-(1(R)-(+)-a-methylbenzyl)-
butane-1,2(S)-diamine 5a (120 mg, 0.33 mmol) in MeOH
(0.01 M, 33.5 mL) under nitrogen atmosphere was added
glyoxal (0.05 mL, 0.47 mmol) and NaCNBH3 (43.0 mg,
0.67 mmol) at 0 ꢀC. The mixture was stirred for 14 h. The
reaction was quenched with water at room temperature.
The solvent was evaporated and washed with NaHCO3.
The aqueous layer was extracted with CH2Cl2. The com-
bined extract was dried over MgSO4, and the solvent was
evaporated to give the crude product, which was purified
by silica gel flash chromatography with 30% EtOAc/hexane
to give 110 mg (85%) of the product 6a as a yellow oil;
Compound (2R)-3g*: mp 264–265 ꢀC; [a]D24 +28.8 (c 1.8,
DMSO); 1H NMR (300 MHz, CDCl3) d 7.72–7.43 (m,
5H), 4.59 (q, J¼6.6 Hz, 1H), 3.74 (m, 1H), 3.52–3.41 (m,
2H), 3.21 (d, J¼4.3 Hz, 1H), 2.94 (t, J¼8.1 Hz, 1H), 2.16–
2.04 (m, 2H), 1.89 (d, J¼6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) 137.3, 131.1, 131.0, 130.7, 130.6, 129.2, 129.1,
127.8, 61.5, 50.3, 48.1, 32.7, 31.5, 19.2; Anal. Calcd for
C18H21F5Cl2N2: C, 50.13; H, 4.91; N, 6.50. Found: C,
50.20; H, 5.02; N, 6.37.
1
3.1.3. Preparation of the 4-phenyl-butane-1,2(R)-di-
amine (4). To a solution of 4-phenyl-N-[1(R)-(+)-a-methyl-
benzyl]butane-1,2(R)-diamine (2R)-3a (80 mg, 0.30 mmol)
in 1.49 mL of MeOH under H2(g) was added Pd(OH)2 at
room temperature. The mixture was stirred for 70 h under
120 psi of H2(g) at room temperature, then the catalyst was
filtered and washed with MeOH. The solvent was evaporated
to give the product as yellow oil which was purified by silica
gel flash chromatography with 50% CH2Cl2/MeOH to give
[a]2D4 +14.5 (c 0.1, CH2Cl2); H NMR (500 MHz, CDCl3)
d 7.30–7.05 (m, 15H), 3.94 (d, J¼13.3 Hz, 1H), 3.32 (q,
J¼6.6 Hz, 1H), 3.26 (d, J¼13.2 Hz, 1H), 2.74–2.59
(m, 3H), 2.52–2.43 (m, 3H), 2.39–2.23 (m, 3H), 2.03–1.87
(m, 2H), 1.35 (q, J¼6.6 Hz, 3H); 13C NMR (125 MHz,
CDCl3) 144.4, 142.8, 139.2, 129.1, 128.6, 128.5, 128.4,
128.3, 127.8, 127.0, 126.9, 125.9, 65.2, 59.4, 58.0, 54.8,
51.1, 50.4, 34.7, 32.3, 20.2; Anal. Calcd for C27H32N2: C,
84.33; H, 8.39; N, 7.28. Found: C, 84.29; H, 8.24; N, 7.32.
1
46 mg (93%) of 4; [a]2D4 ꢁ4.2 (c 0.2, CH2Cl2); H NMR
(300 MHz, CDCl3) d 7.30–7.16 (m, 5H), 2.81–2.61 (m,
4H), 2.49 (dd, J¼12.2, 7.4 Hz, 1H), 1.74 (m, 1H), 1.59 (m,
1H); 13C NMR (75 MHz, CDCl3) 142.4, 128.7, 128.6,
126.1, 53.5, 49.0, 37.7, 32.8; Anal. Calcd for C10H16N2: C,
73.13; H, 9.82; N, 17.06. Found: C, 73.22; H, 9.96; N, 16.98.
Compound 6b: liquid, [a]2D4 +39.6 (c 0.6, CH2Cl2); 1H NMR
(300 MHz, CDCl3) d 7.32–7.14 (m, 10H), 3.32 (q,
J¼6.5 Hz, 1H), 2.80–2.20 (m, 12H), 1.84 (d, J¼6.8 Hz,
1H), 1.36 (d, J¼6.6 Hz, 3H), 1.31–1.19 (m, 8H), 0.87 (q,
J¼6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) 144.6, 142.9,

B. K. Lee et al. / Tetrahedron 62 (2006) 8393–8397
8397
10. Coldham, I.; Copley, R. C. B.; Haxwell, T. F. N.; Howard, S.
Org. Lett. 2001, 3, 3799.
11. Effenberger, F.; Kremser, A.; Stelzer, U. Tetrahedron:
Asymmetry 1996, 7, 607.
128.6, 128.5, 128.4, 127.9, 127.1, 126.0, 65.2, 64.9, 59.0,
54.9, 53.8, 50.7, 32.7, 32.1, 27.6, 26.4, 22.9, 20.3, 15.3,
14.3; Anal. Calcd for C26H38N2: C, 82.48; H, 10.12; N,
7.40. Found: C, 82.29; H, 9.97; N, 7.34.
12. Zhong, Y.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2004, 6, 3953.
13. O’Brien, P.; Towers, T. D. J. Org. Chem. 2002, 67, 304.
14. Dieter, K. R.; Deo, N.; Lagu, B.; Dieter, J. J. Org. Chem. 1992,
57, 1663.
Acknowledgements
15. Kokotos, G.; Constantinou-Kokotou, V. J. Chem. Res., Synop.
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17. Hwang, G. I.; Chung, J. H.; Lee, W. K. J. Org. Chem. 1996, 61,
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18. (a) Shin, S. H.; Han, E. Y.; Park, C. S.; Lee, W. K.; Ha, H.-J.
Tetrahedron: Asymmetry 2000, 11, 3293; (b) Legters, J.;
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We gratefully acknowledge the financial support of the fol-
lowing institutions: The Korea Science and Engineering
Foundation (R01-2005-000-10032-0 and the Center for
Bioactive Molecular Hybrides to H.-J.H.), Korea Research
Foundation (KRF-2002-070-C00060 to W.K.L.), and
Imagene for providing enantiomerically pure chiral aziri-
dines. W.K.L. acknowledges the research grant from Sogang
University in 2001 and 2005.
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