Regio- and stereoselective ring-opening reaction of chiral aziridines: A facile synthesis of chiral β-amino alcohols

Article abstract of DOI:10.3987/COM-08-11537

The reaction of chiral 2-alkylsubstituted aziridines (1a-d) with acetic acid afforded β-amino alcohols with an (S)-chiral center at the β position (with respect to oxygen). In contrast, a reaction of the same chiral aziridines with acetyl chloride followe

Full text of DOI:10.3987/COM-08-11537

HETEROCYCLES, Vol. 78, No. 2, 2009
471
HETEROCYCLES, Vol. 78, No. 2, 2009, pp. 471 - 485. © The Japan Institute of Heterocyclic Chemistry
Received, 1st September, 2008, Accepted, 6th October, 2008, Published online, 9th October, 2008.
DOI: 10.3987/COM-08-11537
REGIO- AND STEREOSELECTIVE RING-OPENING REACTION OF
CHIRAL AZIRIDINES: A FACILE SYNTHESIS OF CHIRAL β-AMINO
ALCOHOLS
Kimio Higashiyama,* Masataka Matsumura, Hiroshi, Kojima, and Takayasu
Yamauchi
Institute of Medicinal Chemistry; Hoshi University, Ebara 2-4-41, Shinagawa-ku,
Tokyo 142-8501, Japan ; e-mail: kimio@hoshi.ac.jp
Abstract – The reaction of chiral 2-alkylsubstituted aziridines (1a-d) with acetic
acid afforded β-amino alcohols with an (S)-chiral center at the β position (with
respect to oxygen). In contrast, a reaction of the same chiral aziridines with acetyl
chloride followed by treatment with water gave β-amino alcohols that have an
(S)-chiral center at the α position. In addition, the reaction of the same chiral
aziridines with benzyl bromide followed by treatment with 2% sulfuric acid gave
the β-amino alcohols with an (R)-chiral center at the α position. Thus, we could
control the regioselectivity and stereoselectivity of the ring-opening reaction of
chiral aziridines (1a-d).
INTRODUCTION
Chiral aziridine derivatives are of interest not only for theoretical reasons but also because of the high
reactivity that arises from the release of strain energy inherent in a small ring. In fact, the regio- and
stereocontrolled ring-opening reaction of chiral aziridine using a reagents such as electrophiles,
nucleophiles, acids, and reducing agents, allows easy access to versatile synthetic intermediates for the
synthesis of biologically active N-containing compounds.1,2 In particular, there are many reports on the
ring-opening reaction of the chiral aziridine with oxygen nucleophiles,3 which gives the β-amino alcohol
unit included in many biologically active natural products and important pharmaceuticals.
The cleavage of the C(3)-N bond in aziridine-2-methanols by acetic acid treatment results in high
regioselectivity.4 The regioselective cleavage of the C(2)-N bond can also be achieved with
2-acylaziridines by using acid chloride and water,5 producing β-amino alcohols with substituents at
different positions. A second group reported that cleavage of 3-subsutituted N-ethoxycarbonyl

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HETEROCYCLES, Vol. 78, No. 2, 2009
aziridine-2-carboxylate could be controlled by using different metallic halides to synthesize different
α-amino and β-amino acids.6
We also recently reported a simple synthetic method for the synthesis of chiral 2-substituted aziridines.7
The reaction pathway consists of the diastereoselective addition of dimethylsulfonium methylide to the
chiral imines derived from (R)-O-methylphenylglycinol and various aldehydes, producing high
stereo-selectivity. This finding indicated the possibility for reacting chiral 2-substituted aziridines to
produce chiral β-amino alcohols. Herein, we report a regio- and stereoselective synthetic method for
chiral β-amino alcohols with multiple substituents.
RESULTS AND DISCUSSION
Initial reactions were performed on the chiral 2-alkylsubstituted aziridines, which were easily obtained
from our methodology, and acetic acid according to a modification of Lee’s procedure.4 The reaction
proceeds smoothly at the reflux temperature of toluene by treating substrates 1a-d with 2 equivalents of
acetic acid to yield the ring opening products (2a-d) in 82-93% yields, which have an (S)-chiral center at
the β position because of the C(3)-N bond cleavage of the aziridine ring. The reactions showed excellent
regioselectivity, except for reaction 1a, which has a sterically small substituent.
From these observations we believe that the reaction follows the same mechanism Lee proposed for the
ring-opening reaction of aziridine-2-methanol with acetic acid.4 This reaction proceeds through the
formation of an intermediate aziridinium salt with protonation by acetic acid, which undergoes a
regioselective ring-opening reaction by AcO- at the less hindered C(3) position (Scheme 1).
Scheme 1
Ph
Ph
Ph
1
HN
HN
AcOH
N
S
R
+
OMe
AcO
OMe
S
toluene
reflux
R
OMe
2
3
R
R
OAc
R
2a-d
1a-d
3a-d
Table 1. Reaction of Aziridines with Acetic Acid
ratio (2 : 3)b)
89 : 11
R
Me
Et
Yield of 2a)
82 %
a
b
c
97 : 3
93 %
95 : 5
Pr
83 %
99 : 1
i-Pr
90 %
d
a) Isolated yield. b) Estimated from the 1H-NMR (270MHz) spectrum.

HETEROCYCLES, Vol. 78, No. 2, 2009
473
Next, we tried a ring-opening reaction with acetyl chloride. The 2-substituted chiral aziridines (1a-d)
were reacted with acetyl chloride in THF at 0 °C, followed by treatment with excess water, to produce
β-amino alcohols having an (S)-chiral center at the α position due to C(2)-N bond cleavage of the
aziridine ring in 72-86% yields. The regioselectivity of this reaction was excellent, except for the reaction
for 1d, which possessed a sterically bulky substituent. The stereoselectivity of the ring-opening products
1
(4a-d) was extremely high, since no diastereomer signals for 4a-d were detected in the H-NMR
spectrum.
In this reaction, the S configuration of C(2) of the starting aziridine was completely retained in 4a-d, with
its position denoted by the α position of the β-amino alcohols (4a-d). The high regio- and stereocontrol of
this reaction probably proceeds through the formation an N-acylaziridinium salt resulting from the
reaction of acid chloride. Subsequently, this N-acylaziridinium salt undergoes a ring-opening reaction by
an anti-attack of chloride at the C(2) position. Next, the initial product of N-acyl-β-chloroamine is readily
reacted by the internal oxygen nucleophile by replacement of the chloride to make the oxazoline
derivative. Finally, by adding water, the oxazoline derivative was hydrolyzed to yield β-amino alcohols
(4a-d) as a final product in Scheme 2. N-Acylaziridine shows a ring expansion like other compounds in
this class, as discussed by Hori el al. and by Lee et al. 5,8
Scheme 2
Ph
Ph
Ph
HN
HN
1
1) AcCl
2 ) H2O
S
+
N
R
OMe
AcO
OMe
4a-d
S
R
OMe
Ph
S
2
3
R
OAc
R
1a-d
2a-d
H2O
Ph
CH3
CH3 Ph
CH3
+
N
+
N
O
O
N
O
OMe
Cl-
OMe
OMe
oxazoline deriv.
R
R
R
Cl
Table 2. Reaction of Aziridines with Acetyl Chloride
ratio (2 : 4)b)
2 : 98
R
Me
Et
Yield of 4a)
86 %
a
b
c
4 : 96
82 %
4 : 96
Pr
72 %
13 : 87
i-Pr
72 %
d
a) Isolated yield. b) Estimated from the 1H-NMR (270MHz) spectrum.

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The reaction of the same chiral aziridines (1a-d) with benzyl bromide afforded the β-bromoamines (5a-d)
by C(2)-N bond cleavage of the aziridine ring. Next, hydroxylation of the β-bromoamines (5a-d) with 2%
sulfuric acid at 90 °C for 4 h gave the β-amino alcohols (6a-d) with (R)-chiral centers at the α position in
good yields. However, an equivalent of benzyl bromide and reaction solvent concentration influenced
chemical yield and stereoselectivity. The optimum condition for ring opening with benzyl bromide is
using it at a 10-fold excess, with a 40-fold excess of acetone versus the aziridine. When reacting the chiral
aziridines (1a-d) under these conditions, 5a-d was obtained as a single diastereomer with a yield of 90%
or more (Scheme 3). The stereochemistry of β-bromoamines (5a-d) was estimated by X-ray analysis of
5d’, which was produced by the ring-opening reaction of 1d with 4-bromobenzyl bromide (Figure 1).9
The first step seems to have proceeded through the formation of an aziridinium intermediate by
N-benzylation, which underwent a regiospecific ring opening reaction through anti-attack of bromide at
the C(2) position.10 Further, the addition of water at the C(2) position could be explained by neighboring
group participation of the nitrogen atom, resulting in a highly activated aziridinium salt that underwent
water attack to give the C(2) addition products.
Scheme 3
Ph
Ph
Ph
R
Ph
Ph
PhCH2Br
2% H2SO4
N
1
N
N
R
HO
OMe
S
Br
OMe
5a-d
R
OMe
2
3
R
R
R
6a-d
1a-d
+
Ph
Ph
Ph Ph
Ph Ph
N
+
+
S
N
N
OMe
R
OMe
Br-
OMe
R
R
OH
7a-d
H2O
Table 3. Reaction of Aziridines with Benzyl bromide
ratio (6 : 7)b)
> 99 : 0
95 : 5
R
Me
Et
Yield of 6a)
65 %
Yield of 5a)
90 %
a
b
c
59 %
93 %
96 : 4
Pr
57 %
92 %
99 : 1
i-Pr
73 %
d
92 %
a) Isolated yield. b) Estimated from the 1H-NMR (270MHz) spectrum.

HETEROCYCLES, Vol. 78, No. 2, 2009
475
(Br)
R
Br
Ph
OMe
(O)
(N)
N
R
H
R
(Br)
Br
Figure 1. ORTEP view of compound (5d').
Confirmation of the absolute stereochemistry of ring opening products (2a-d, 4a-d and 6a-d) was
estimated (Scheme 4 and 5). In the case of ring opening products (2a-d), hydrogenolysis of 2d with
Pd(OH)2/H2 and subsequent hydrolysis with 10% HCl afforded valinol, and its spectrum and optical
rotation date were consistent with commercially available (S)-valinol. Therefore, the absolute
configuration of 2a-d that had been obtained from the reaction of the chiral aziridine and the acetic acid
was the (S,R) form (Scheme 4).
Scheme 4
Ph
NH2
1) Pd(OH)2
2) 10% HCl
HN
S
OMe
OAc
OH
(S)-valinol
2d
On the other hand, the absolute configuration of the chiral center formed by a new ring opening product
(4a-d and 6a-d) was estimated by comparing 8a or 9a obtained from another synthetic route (Scheme 5).
Namely, condensation of 2-methoxyacetophenone with (R)-1-amino-2-propanol in toluene gave a
sensitive oxazolidine, which was reduced by LAH to give the separable chiral β-amino alcohol [(+)-8a
and (-)-9a]. Meanwhile, reduction by LAH of the ring-opening product (4a) afforded a β-amino alcohol
[(-)-8a] with the same NMR data of (+)-8a of another synthetic route, but with opposite specific rotation.
Moreover, the removal of the benzyl group of the ring-opening product (6a) by catalytic hydrogenation
gave the β-amino alcohol [(-)-9a] with the same NMR data and specific rotation of (-)-9a of another
synthetic route. These experimental results show that the compound (-)-8a has (2S,1’R) stereochemistry,
and compound (-)-9a has (2R,1’R) stereochemistry. Therefore, the absolute configuration of 4a-d

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HETEROCYCLES, Vol. 78, No. 2, 2009
obtained from the reaction of the acetyl chloride was the (2S,1’R) form, and 6a-d that had been obtained
from the reaction of the benzyl bromide was estimated to be the (2R,1’R) form.
Ph
Scheme 5
HN
S
HO
OMe
R
Me
Ph
Ph
OMe
NH2
(+)-8a: [α]D +55.5
OMe
NH
LiAlH4
THF
O
toluene
reflux
O
R
+
Ph
HO
Me
HN
R
R
Me
HO
OMe
R
Me
(-)-9a: [α]D -122.9
Ph
Ph
HN
HN
R
R
AcO
OMe
HO
OMe
LiAlH
4
Ph
S
1
Me
Ph
Me
4a
N
R
(-)-8a: [α]D
-56.0
S
OMe
2
3
R
Ph
Ph
1a-d
Pd(OH)2
N
HN
R
R
HO
OMe
HO
OMe
R
Me
Me
6a
(-)-9a: [α]D -123.2
In conclusion, we developed an efficient and practical method for preparing chiral β-amino alcohols from
regio- and stereocontrolled ring-opening reactions of chiral aziridine. Moreover, this synthesis method
can synthesize various chiral β-amino alcohols by selecting ring-opening reagents while using a single
chiral aziridine as a raw material. We believe that the present reaction will be useful for constructing
biologically important compounds. Further study in this area is under investigation in our laboratory.
EXPERIMENTAL
General: Melting points were measured with a Yanagimoto Micro melting point apparatus without
1
collection. IR spectra were recorded on a JASCO FT/IR-200, and major absorption is listed in cm-1. H

HETEROCYCLES, Vol. 78, No. 2, 2009
477
13
and C NMR spectra were obtained on a JEOL GSX 270 instrument, and chemical sifts are reported in
ppm on the δ-scale from internal Me4Si. MS spectra were measured with a JEOL JMS 600 spectrometer
by using the chemical ionization(CI) with isobutene and the electron impact(EI) methods. Elemental
analyses were performed on a Perkin-Elmer 240-B instrument. Optical rotation were taken with a
JASCO-DIP-1000 polarimeter at rt. Column chromatography was performed on silica gel (45−75µm,
Wakogel C-300). The reaction solvents were prepared as the following. THF was distilled over potassium
metal. Dichloromethane was distilled over phosphorus pentoxide.
General procedure for the ring-opening reaction of aziridine with acetic acid.
A mixture of aziridine (3.0 mmol) and acetic acid (6.0 mmol) in toluene (15 mL) was stirred at reflux
temperature for 4 h. After cooling, the reaction mixture was quenched with saturated aqueous Na2CO3 (10
mL). The organic layer was separated, and aqueous layer was extracted with Et2O (10 mL x 2). The
combined organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was
evaporated to give the crude product, which was purified by silica gel flash chromatography with
hexane/EtOAc (1 : 1) to afford pure product (2a-d) as a viscous oil.
(1S, 1'R)-N-(2'-Methoxy-1'-phenylethyl)-1-acetoxymethylethylamine (2a).
[α]D -70.43 (c 1.10, CHCl3). 1H NMR (270 MHz, CDCl3): δ = 1.00 (d, J = 6.6Hz, 3H), 1.91 (brs, 1H),
2.07 (s, 3H), 2.76-2.86 (m, 1H), 3.33-3.44 (m, 2H), 3.35 (s, 3H), 3.94 (dd, J = 4.8, 11.0Hz, 1H), 4.04 (dd,
J = 4.6, 8.2Hz, 1H), 4.09 (dd, J = 4.8, 11.0Hz, 1H), 7.22-7.40 (m, 5H). 13C NMR (67.8 MHz, CDCl3): δ =
170.79, 141.01, 128.21, 127.38, 127.25, 77.63, 66.62, 59.64, 58.43, 48.96, 20.61, 19.13. IR (film): 3339,
2980, 2930, 2895, 2822, 1740, 1460, 1375, 1230, 1118 cm-1. MS m/z: CI, 252 (M++1). Anal. Calcd for
C14H21NO3: C, 66.91; H, 8.42; N, 5.57. Found: C, 66.82; H, 8.40; N, 5.54.
Minor component: (2R, 1'R)-N-(2'-Methoxy-1'-phenylethyl)-2-acetoxypropylamine (3a).
1H NMR (270 MHz, CDCl3): δ = 1.18 (d, J = 6.4Hz, 3H), 2.03 (brs, 1H), 2.06 (s, 3H), 2.55 (dd, J = 6.9,
12.9Hz, 1H), 2.63 (dd, J = 4.0, 12.9Hz, 1H), 3.32-3.44 (m, 2H), 3.36 (s, 3H), 3.90 (dd, J = 4.2, 8.8Hz,
1H), 4.97-5.08 (m, 1H), 7.24-7.39 (m, 5H).
(1S, 1'R)-N-(2'-Methoxy-1'-phenylethyl)-1-acetoxymethylpropylamine (2b).
[α]D -92.86 (c 1.07, CHCl3). 1H NMR (270 MHz, CDCl3): δ = 0.88 (t, J = 7.3Hz, 3H), 1.35-1.47 (m, 2H),
1.91 (brs, 1H), 2.07 (s, 3H), 2.46-2.54 (m, 1H), 3.34-3.41 (m, 2H), 3.35 (s, 3H), 3.96 (dd, J = 4.0, 11.2Hz,
1H), 4.04 (dd, J = 5.5, 7.3Hz, 1H), 4.09 (dd, J = 4.6, 11.2Hz, 1H), 7.23-7.40 (m, 5H). 13C NMR (67.8
MHz, CDCl3): δ = 170.94, 140.86, 128.18, 127.58, 127.30, 77.77, 64.49, 59.16, 58.42, 54.24, 25.96,
20.74, 10.44. IR (film): 3340, 2960, 2930, 2880, 2821, 1740, 1465, 1380, 1230, 1118 cm-1. MS m/z: CI,
266 (M++1). Anal. Calcd for C15H23NO3: C, 67.90; H, 8.74; N, 5.28. Found: C, 67.83; H, 8.72; N, 5.31.
Minor component: (2R, 1'R)-N-(2'-Methoxy-1'-phenylethyl)-2-acetoxybutylamine (3b).

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HETEROCYCLES, Vol. 78, No. 2, 2009
1H NMR (270 MHz, CDCl3): δ = 0.81 (t, J = 7.4Hz, 3H), 1.57 (quintet, J = 7.4Hz, 2H), 1.99 (brs, 1H),
2.08 (s, 3H), 2.55 (dd, J = 9.9, 13.0Hz, 1H), 2.65 (dd, J = 3.6, 13.0Hz, 1H), 3.32-3.43 (m, 2H), 3.35 (s,
3H), 3.49 (dd, J = 4.2, 8.8Hz, 1H), 4.86-4.95 (m, 1H), 7.22-7.39 (m, 5H).
(1S, 1'R)-N-(2'-Methoxy-1'-phenylethyl)-1-acetoxymethylbutylamine (2c).
[α]D -83.29 (c 1.15, CHCl3). 1H NMR (270 MHz, CDCl3): δ = 0.81 (t, J = 7.0Hz, 3H), 1.20-1.49 (m, 4H),
1.95 (brs, 1H), 2.07 (s, 3H), 2.54-2.62 (m, 1H), 3.37 (s, 3H), 3.37-3.41 (m, 2H), 3.94 (dd, J = 3.9, 11.3Hz,
1H), 4.08 (t, J = 6.4Hz, 1H), 4.09 (dd, J = 4.5, 11.3Hz, 1H), 7.22-7.40 (m, 5H). 13C NMR (67.8 MHz,
CDCl3): δ = 170.41, 140.71, 127.95, 127.40, 127.07, 77.63, 64.64, 58.89, 58.10, 52.18, 35.32, 20.40,
18.80, 13.71. IR (film): 3339, 2960, 2931, 2875, 2821, 1740, 1454, 1380, 1235, 1120 cm-1. MS m/z: CI,
280 (M++1). Anal. Calcd for C16H25NO3: C, 68.79; H, 9.02; N, 5.01. Found: C, 68.70; H, 9.04; N, 5.03.
Minor component: (2R, 1'R)-N-(2'-Methoxy-1'-phenylethyl)-2-acetoxypentylamine (3c).
1H NMR (270 MHz, CDCl3): δ = 0.87 (t, J = 7.4Hz, 3H), 1.18-1.29 (m, 2H), 1.43-1.57 (m, 2H), 2.07 (s,
3H), 2.09 (brs, 1H), 2.56 (dd, J = 6.8, 13.0Hz, 1H), 2.64 (dd, J = 3.8, 13.0Hz, 1H), 3.32-3.43 (m, 2H),
3.35 (s, 3H), 3.90 (dd, J = 4.3, 8.7Hz, 1H), 4.95-5.03 (m, 1H), 7.23-7.39 (m, 5H).
(1S, 1'R)-N-(2'-Methoxy-1'-phenylethyl)-1-acetoxymethyl-2-methylpropylamine (2d).
[α]D -95.47 (c 1.09, CHCl3). 1H NMR (270 MHz, CDCl3): δ = 0.89 (d, J = 6.8Hz, 3H), 0.92 (d, J = 6.8Hz,
3H), 1.60-1.82 (m, 1H), 1.86 (brs, 1H), 2.06 (s, 3H), 2.29-3.34 (m, 1H), 3.35 (s, 3H), 3.37-3.43 (m, 2H),
4.04 (dd, J = 4.1, 11.5Hz, 1H), 4.07 (t, J = 7.6Hz, 1H), 4.23 (dd, J = 4.7, 11.5Hz, 1H), 7.22-7.40 (m, 5H).
13C NMR (67.8 MHz, CDCl3): δ = 170.90, 140.87, 128.09, 127.79, 127.27, 77.84, 63.07, 59.38, 58.37,
57.81, 30.12, 20.77, 19.28, 18.51. IR (film): 3340, 2960, 2930, 2890, 2821, 1740, 1458, 1380, 1228, 1107
cm-1. MS m/z: CI, 280 (M++1). Anal. Calcd for C16H25NO3: C, 68.79; H, 9.02; N, 5.01. Found: C, 68.74;
H, 8.91; N, 5.04.
Minor component: (2R, 1'R)-N-(2'-Methoxy-1'-phenylethyl)-2-acetoxy-3-methylbutylamine (3d).
1H NMR (270 MHz, CDCl3): δ = 0.79 (d, J = 6.8Hz, 3H), 0.84 (d, J = 6.8Hz, 3H), 1.86-1.97 (m, 1H),
1.95 (brs, 1H), 2.10 (s, 3H), 2.58 (dd, J = 7.0, 13.2Hz, 1H), 2.63 (dd, J = 3.6, 13.2Hz, 1H), 3.31-3.41 (m,
2H), 3.33 (s, 3H), 3.88 (dd, J = 4.3, 8.7Hz, 1H), 4.70-4.84 (m, 1H), 7.22-7.38 (m, 5H).
General procedure for the ring-opening reaction of aziridine with acetyl chloride/H2O.
To the stirred solution of aziridine (3.0 mmol) in anhydrous THF (20 mL) at 0°C under nitrogen
atmosphere, acetyl chloride (4.5 mmol) was added dropwise. After the reaction mixture was stirred for 1
h at 0°C, H2O (5 mL) was then added and stirred for 20 min at room temperature. The reaction mixture
was made basic with saturated aqueous Na2CO3 (25 mL). The aqueous layer was extracted with Et2O (15
mL x 3). The combined extracts were washed with brine, dried over anhydrous Na2SO4, and the solvent
was evaporated to give the crude product, which was purified by silica gel flash chromatography with

HETEROCYCLES, Vol. 78, No. 2, 2009
479
hexane/EtOAc (1 : 1) to afford pure product (4a-d) as a viscous oil.
(2S, 1'R)-N-(2'-Methoxy-1'-phenylethyl)-2-acetoxypropylamine (4a).
[α]D -56.67 (c 1.09, CHCl3). 1H NMR (270 MHz, CDCl3): δ = 1.19 (d, J = 6.3Hz, 3H), 2.04 (s, 3H), 2.10
(brs, 1H), 2.46 (dd, J = 4.6, 12.2Hz, 1H), 2.65 (dd, J = 7.7, 12.2Hz, 1H), 3.33-3.45 (m, 2H), 3.37 (s, 3H),
3.87 (dd, J = 4.1, 9.1Hz, 1H), 4.89-4.96 (m, 1H), 7.24-7.39 (m, 5H). 13C NMR (67.8 MHz, CDCl3): δ =
170.15, 140.28, 128.03, 127.26, 127.20, 77.49, 70.82, 62.48, 58.37, 51.70, 20.92, 17.74. IR (film): 3340,
2980, 2931, 2890, 2821, 1740, 1478, 1371, 1240, 1109 cm-1. MS m/z: CI, 252 (M++1). Anal. Calcd for
C14H21NO3HCl: C, 58.43; H, 7.70; N, 4.86. Found: C, 58.21; H, 7.74; N, 4.99. HCl salt: colorless crystal,
mp 100°C (Et2O).
(2S, 1'R)-N-(2'-Methoxy-1'-phenylethyl)-2-acetoxybutylamine (4b).
[α]D -71.02 (c 0.98, CHCl3). 1H NMR (270 MHz, CDCl3): δ = 0.83 (t, J = 7.5Hz, 3H), 1.49-1.67 (m, 2H),
2.02 (brs, 1H), 2.05 (s, 3H), 2.52 (dd, J = 4.9, 12.3Hz, 1H), 2.63 (dd, J = 7.0, 12.3Hz, 1H), 3.32-3.44 (m,
13
2H), 3.36 (s, 3H), 3.86 (dd, J = 4.2, 9.0Hz, 1H), 4.83-4.88 (m, 1H), 7.25-7.39 (m, 5H). C NMR (67.8
MHz, CDCl3): δ = 170.71, 140.50, 128.27, 127.46. 127.38, 77.68, 75.43, 62.77, 58.64, 49.88, 25.04,
21.16, 9.34. IR (film): 3340, 2970, 2935, 2880, 2821, 1740, 1458, 1371, 1240, 1110 cm-1. MS m/z: CI,
266 (M++1). Anal. Calcd for C15H23NO3HCl: C, 59.69; H, 8.01; N, 4.64 Found: C, 59.47; H, 8.01; N, 4.59.
HCl salt: colorless crystal, mp 105°C (Et2O).
(2S, 1'R)-N-(2'-Methoxy-1'-phenylethyl)-2-acetoxypentylamine (4c).
[α]D -62.99 (c 1.17, CHCl3). 1H NMR (270 MHz, CDCl3): δ = 0.87 (t, J = 7.3Hz, 3H), 1.22-1.35 (m, 2H),
1.48-1.57 (m, 2H), 2.00 (brs, 1H), 2.05 (s, 3H), 2.52 (dd, J = 4.8, 12.4Hz, 1H), 2.63 (dd, J = 7.0, 12.4Hz,
1H), 3.34-3.45 (m, 2H), 3.37 (s, 3H), 3.86 (dd, J = 4.3, 8.9Hz, 1H), 4.88-4.97 (m, 1H), 7.23-7.39 (m, 5H).
13C NMR (67.8 MHz, CDCl3): δ = 170.02, 140.27, 127.93, 127.14, 127.03, 77.37, 73.68, 62.46, 58.19,
50.10, 33.99, 20.61, 18.02, 13.48. IR (film): 3340, 2960, 2931, 2871, 2821, 1740, 1459, 1378, 1240, 1110
cm-1. MS m/z: CI, 280 (M++1). Anal. Calcd for C16H25NO3: C, 68.79; H, 9.02; N, 5.01. Found: C, 68.60;
H, 9.08; N, 5.04.
(2S, 1'R)-N-(2'-Methoxy-1'-phenylethyl)-2-acetoxy-3-methylbutylamine (4d).
[α]D -62.02 (c 1.22, CHCl3). 1H NMR (270 MHz, CDCl3): δ = 0.82 (d, J = 6.8Hz, 3H), 0.86 (d, J = 6.8Hz,
3H), 1.75 (brs, 1H), 1.83-1.99 (m, 1H), 2.07 (s, 3H), 2.56 (dd, J = 4.8, 12.4Hz, 1H), 2.61 (dd, J = 6.9,
12.4Hz, 1H), 3.32-3.44 (m, 2H), 3.36 (s, 3H), 3.84 (dd, J = 4.2, 9.0Hz, 1H), 4.77-4.83 (m, 1H), 7.22-7.39
(m, 5H). 13C NMR (67.8 MHz, CDCl3): δ = 170.42, 140.36, 128.03, 127.24, 127.14, 78.13, 77.47, 62.68,
58.35, 47.84, 29.45, 20.67, 18.29, 17.04. IR (film): 3340, 2961, 2930, 2880, 2822, 1738, 1453, 1372,
1240, 1110 cm-1. MS m/z: CI, 280 (M++1). Anal. Calcd for C16H25NO3: C, 68.79; H, 9.02; N, 5.01.
Found: C, 68.64; H, 8.95; N, 5.08.
General procedure for the ring-opening reaction of aziridine with benzyl bromide.

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A mixture of aziridine (1.5 mmol) and benzyl bromide (15.0 mmol) in acetone (4.5 mL) was heated for
12 h at 60°C under nitrogen atmosphere. After cooling, the reaction mixture was evaporated to give the
crude product, which was purified by silica gel flash chromatography with hexane/EtOAc (16 : 1) to
afford pure product (5a-d) as a viscous oil.
(2R, 1’R)-N-Benzyl-N-(2’-methoxy-1’-phenylethyl)-2-bromopropylamine (5a).
[α]D -45.9 (c 1.05, CHCl3). 1H NMR (270 MHz, CDCl3): δ = 1.48 (d, J = 6.6Hz, 3H), 2.70 (dd, J = 7.5,
13.9Hz, 1H), 3.11 (dd, J = 6.4, 13.9Hz, 1H), 3.36 (s, 3H), 3.63 (d, J = 14.0Hz, 1H), 3.78 (d, J = 14.0Hz,
1H), 3.83-3.93 (m, 3H), 4.02 (t, J = 6.5Hz, 1H), 7.26-7.37 (m, 10H). 13C NMR (67.8 MHz, CDCl3): δ =
139.54, 138.76, 128.67, 128.38, 128.12, 128.01, 127.17, 126.97, 72.21, 62.86, 60.13, 58.71, 56.11, 49.17,
23.46. IR(film): 3028, 2980, 2920, 2878, 1600, 1497, 1453, 1375, 1200, 1120 cm-1. MS m/z: EI, 361(M+).
HRMS: m/z calcd for C19H24BrNO 361.1041, Found 361.1025.
(2R, 1’R)-N-Benzyl-N-(2’-methoxy-1’-phenylethyl)-2-bromobutylamine (5b).
[α]D -47.2 (c 1.14, CHCl3). 1H NMR (270 MHz, CDCl3): δ = 0.83 (t, J = 7.3Hz, 3H), 1.38-1.52 (m, 1H),
1.82-1.94 (m, 1H), 2.80 (dd, J = 7.5, 14.0Hz, 1H), 3.10 (dd, J = 6.6, 14.0Hz, 1H), 3.35 (s, 3H), 3.62 (d, J
13
= 14.0Hz, 1H), 3.73-3.94 (m, 4H), 4.02 (t, J = 6.3Hz, 1H), 7.24-7.37(m, 10H). C NMR (67.8 MHz,
CDCl3): δ = 139.30, 138.41, 128.57, 128.29, 128.00, 127.90, 127.09, 126.87, 71.97, 62.89, 58.56, 58.35,
57.93, 55.95, 28.64, 11.47. IR(film): 3027, 2970, 2925, 2878, 1600, 1497, 1452, 1378, 1198, 1120 cm-1.
MS m/z: EI, 375(M+). HRMS: m/z calcd for C20H26BrNO 375.1197, Found 375.1191.
(2R, 1’R)-N-Benzyl-N-(2’-methoxy-1’-phenylethyl)-2-bromopentylamine (5c).
[α]D -34.0 (c 1.12, CHCl3). 1H NMR (270 MHz, CDCl3): δ = 0.78 (t, J = 7.3Hz, 3H), 1.20-1.51 (m, 2H),
1.68-1.81 (m, 2H), 2.79 (dd, J = 7.1, 14.1Hz, 1H), 3.10 (dd, J = 6.8, 14.1Hz, 1H), 3.35 (s, 3H), 3.62 (d, J
13
= 14.0Hz, 1H), 3.73-3.94 (m, 4H), 4.02 (dd, J = 5.9, 7.1Hz, 1H), 7.26-7.35 (m, 10H). C NMR (67.8
MHz, CDCl3): δ = 139.50, 138.62, 128.59, 128.29, 128.00, 127.89, 127.05, 126.85, 72.08, 62.98, 58.94,
58.58, 56.06, 55.94, 37.65, 20.07, 13.09. IR(film): 3026, 2960, 2930, 2873, 1600, 1497, 1453, 1372, 1195,
1118 cm-1. MS m/z: EI, 389(M+). HRMS: m/z calcd for C21H28BrNO 389.1354, Found 389.1349.
(2R, 1’R)-N-Benzyl-N-(2’-methoxy-1’-phenylethyl)-2-bromo-3-methylbutylamine (5d).
[α]D -53.9 (c 1.01, CHCl3). 1H NMR (270 MHz, CDCl3): δ = 0.54 (d, J = 6.7Hz, 3H), 0.86 (d, J = 6.7Hz,
3H), 1.84-1.90 (m, 1H), 2.84 (dd, J = 7.6, 14.1Hz, 1H), 3.08 (dd, J = 6.6, 14.1Hz, 1H), 3.36 (s, 3H), 3.64
(d, J = 13.8Hz, 1H), 3.76 (d, J = 13.8Hz, 1H), 3.82-4.00 (m, 3H), 4.02 (dd, J = 5.7, 7.3Hz, 1H), 7.24-7.37
13
(m, 10H). C NMR (67.8 MHz, CDCl3): δ = 139.83, 139.11, 128.85, 128.53, 128.24, 128.13, 127.24,
127.06, 71.97, 64.78, 62.78, 58.87, 56.69, 56.12, 30.29, 21.53, 16.45. IR (film): 3028, 2962, 2927, 2875,
1600, 1497, 1457, 1363, 1195, 1120 cm-1. MS m/z: EI, 389(M+). HRMS: m/z calcd for C21H28BrNO
389.1354, Found 389.1335.
(2R, 1’R)-N-(4-Bromobenzyl)-N-(2’-methoxy-1’-phenylethyl)-2-bromo-3-methylbutylamine (5d’).

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Compound (5d’) was obtained from 1d using the 4-bromobenzyl bromide instead of benzyl bromide by
the same procedure used for 5d. Yield: 70%, colorless crystal, mp 47°C (hexane). [α]D -55.6 (c 1.00,
CHCl3). 1H NMR (270 MHz, CDCl3): δ = 0.59 (d, J = 6.6Hz, 3H), 0.89 (d, J = 6.6Hz, 3H), 1.94 (quintet,
J = 6.6Hz, 1H), 2.81 (dd, J = 7.1, 14.1Hz, 1H), 3.07 (dd, J = 7.0, 14.1Hz, 1H), 3.35 (s, 3H), 3.59 (d, J =
14.2Hz, 1H), 3.72 (d, J = 14.2Hz, 1H), 3.77-4.01 (m, 4H), 7.23-7.46 (m, 9H). MS m/z: EI, 469(M+).
HRMS(CI): m/z calcd for C21H28Br2NO 470.0518, Found 470.0529.
General procedure for the reaction of β-bromoamines (5a-d) with 2% H2SO4.
The stirred solution of 5a-d (1.0 mmol) in 2% aqueous H2SO4 (20 mL) was heated for 4 h at 90°C. After
cooling the reaction mixture was made basic with saturated aqueous Na2CO3, and extracted with CH2Cl2
(20 mL x 3). The combined extracts were washed with brine, dried over anhydrous Na2SO4, and the
solvent was evaporated to give the crude product, which was purified by silica gel flash chromatography
with hexane/EtOAc (5 : 1) to afford pure product (6a-d) as a viscous oil.
(2R, 1'R)-1-[N-Benzyl-N-(2'-methoxy-1'-phenylethyl)amino]propan-2-ol (6a).
[α]D -114.0 (c 0.90, CHCl3). 1H NMR (270 MHz, CDCl3): δ = 1.10 (d, J = 6.3Hz, 3H), 2.31 (dd, J = 2.5,
13.2Hz, 1H), 2.67 (dd, J = 10.4, 13.2Hz, 1H), 3.34 (s, 3H), 3.42 (d, J = 14.1Hz, 1H), 3.48 (dd, J = 4.9,
9.9Hz, 1H), 3.75-3.83 (m, 1H), 3.80 (d, J = 14.1Hz, 1H), 3.90 (t, J = 9.9Hz, 1H), 4.03 (dd, J = 4.9, 9.9Hz,
1H), 4.20 (brs, 1H), 7.16-7.37 (m, 10H). 13C NMR (67.8 MHz, CDCl3): δ = 139.36, 136.72, 128.71,
128.56, 128.42, 128.33, 127.67, 127.10, 72.39, 63.63, 61.15, 58.59, 57.15, 55.64, 19.70. IR(film): 3448,
3027, 2962, 2928, 2880, 1600, 1497, 1452, 1372, 1198, 1119, 1092 cm-1. MS m/z: CI, 300(M++1). Anal.
Cacld for C19H25NO2: C, 76.22; H, 8.42; N, 4.68. Found: C, 76.03; H, 8.52; N, 4.76.
(2R, 1'R)-1-[N-Benzyl-N-(2'-methoxy-1'-phenylethyl)amino]butan-2-ol (6b).
[α]D -111.0 (c 1.00, CHCl3). 1H NMR (270 MHz, CDCl3): δ = 0.96 (t, J = 7.4Hz, 3H), 1.30-1.52 (m, 2H),
2.34 (dd, J = 2.4, 13.1Hz, 1H), 2.69 (dd, J = 10.3, 13.1Hz, 1H), 3.33 (s, 3H), 3.40 (d, J = 14.2Hz, 1H),
3.47 (dd, J = 4.9, 10.0Hz, 1H), 3.52-3.63 (m, 1H), 3.90 (t, J = 10.0Hz, 1H), 4.03 (dd, J = 4.9, 10.0Hz, 1H),
13
4.22 (brs, 1H), 7.23-7.40 (m. 10H). C NMR (67.8 MHz, CDCl3): δ = 139.33, 136.63, 128.74, 128.58,
128.40, 128.33, 127.67, 127.08, 72.33, 68.92, 60.98, 58.58, 55.46, 55.23, 27.41, 10.11. IR(film): 3440,
3028, 2960, 2928, 2880, 1600, 1497, 1452, 1372, 1198, 1120, 1093 cm-1. MS m/z: CI, 314(M++1). Anal.
Cacld for C20H27NO2: C, 76.64; H, 8.68; N, 4.47. Found: C, 76.52; H, 8.81; N, 4.44.
Minor component: (2S, 1'R)-2-[N-Benzyl-N-(2’-methoxy-1’-phenylethyl)amino]butan-1-ol (7b).
1H NMR (270 MHz, CDCl3): δ = 0.90 (t, J = 7.4Hz, 3H), 1.25-1.37 (m, 1H), 1.57-1.66 (m, 1H), 2.80-2.93
(m, 1H), 3.13 (t, J = 10.3Hz, 1H), 3.36 (s, 3H), 3.64-3.90 (m, 5H), 4.22 (dd, J = 5.7, 8.0Hz, 1H),
7.10-7.46 (m, 10H).
(2R, 1'R)-1-[N-Benzyl-N-(2'-methoxy-1'-phenylethyl)amino]pentan-2-ol (6c).

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[α]D -101.5 (c 1.02, CHCl3). 1H NMR (270 MHz, CDCl3): δ = 0.91 (t, J = 7.3Hz, 3H), 1.21-1.53 (m, 4H),
2.32 (dd, J = 2.4, 13.1Hz, 1H), 2.68 (dd, J = 10.4, 13.1Hz, 1H), 3.33 (s, 3H), 3.41 (d, J = 14.1Hz, 1H),
3.47 (dd, J = 4.9, 9.9Hz, 1H), 3.63 (m, 1H), 3.80 (d, J = 14.1Hz, 1H), 3.90 (t, J = 9.9Hz, 1H), 4.03 (dd, J
= 4.9, 9.9Hz, 1H), 4.21 (brs, 1H), 7.23-7.39 (m, 10H). 13C NMR (67.8 MHz, CDCl3): δ = 139.33, 136.66,
128.76, 128.61, 128.43, 128.35, 127.69, 127.11, 72.37, 67.29, 61.06, 58.61, 55.68, 55.53, 36.78, 19.00,
14.22. IR(film): 3452, 3028, 2960, 2928, 2874, 1600, 1497, 1452, 1373, 1198, 1120, 1095 cm-1. MS m/z:
CI, 328 (M++1). Anal. Cacld for C21H29NO2: C, 77.02; H, 8.93; N, 4.28. Found: C, 76.95; H, 9.04; N,
4.30.
Minor component: (2S, 1'R)-2-[N-Benzyl-N-(2’-methoxy-1’-phenylethyl)amino]pentan-1-ol (7c).
1H NMR (270 MHz, CDCl3): δ = 0.93 (t, J = 7.3Hz, 3H), 1.24-1.34 (m, 4H), 2.84-3.02 (m, 1H), 3.13 (t, J
= 10.1Hz, 1H), 3.36 (s, 3H), 3.69 (dd, J = 5.8, 9.7Hz, 1H), 3.73 (d, J = 14.0Hz, 1H), 3.84 (d, J = 14.0Hz,
1H), 3.81-3.89 (m, 2H), 4.11 (dd, J = 5.8, 8.1Hz, 1H), 7.21-7.46 (m, 10H).
(2R, 1'R)-1-[N-Benzyl-N-(2'-methoxy-1'-phenylethyl)amino]-3-methylbutan-2-ol (6d).
[α]D -124.8 (c 0.90, CHCl3). 1H NMR (270 MHz, CDCl3): δ = 0.88 (d, J = 6.8Hz, 3H), 0.97 (d, J = 6.8Hz,
3H), 1.57-1.67 (m, 1H), 2.37 (dd, J = 2.5, 13.0Hz, 1H), 2.61 (dd, J = 10.4, 13.0Hz, 1H), 3.33 (s, 3H),
3.33-3.43 (m, 1H), 3.38 (d, J = 14.1Hz, 1H), 3.47 (dd, J = 5.0, 10.0Hz, 1H,), 3.82 (d, J = 14.1Hz, 1H),
13
3.90 (t, J = 10.0Hz, 1H), 4.03 (dd, J = 5.0, 10.0Hz, 1H), 4.27 (brs, 1H), 7.26-7.41 (m, 10H). C NMR
(67.8 MHz, CDCl3): δ = 139.20, 136.50, 128.76, 128.58, 128.36, 128.30, 127.65, 127.05, 72.26, 72.03,
60.89, 58.54, 55.24, 52.82, 32.01, 18.47, 18.36. IR (film): 3448, 3028, 2960, 2927, 2878, 1600, 1497,
1452, 1371, 1198, 1120, 1095 cm-1. MS m/z: CI, 328 (M++1). Anal. Calcd for C21H29NO2: C, 77.02; H,
8.93; N, 4.28. Found: C, 76.82; H, 9.03; N, 4.31.
Minor component: (2S, 1'R)-2-[N-Benzyl-N-(2’-methoxy-1’-phenylethyl)amino]-3-methylbutan-1-ol
(7d).
1H NMR (270 MHz, CDCl3): δ = 0.84 (d, J = 6.8Hz, 3H), 0.86 (d, J = 6.8Hz, 3H), 1.74-1.87 (m, 1H),
2.68-2.73 (m, 1H), 3.21 (t, J = 9.9Hz, 1H), 3.31 (s, 3H), 3.45 (m, 1H), 3.54 (dd, J = 5.4, 8.7Hz, 1H), 3.77
(t, J = 8.7Hz, 1H) 3.84 (d, J = 14.7Hz, 1H), 3.96 (d, J = 14.7Hz, 1H), 4.14 (dd, J = 5.4, 8.7Hz, 1H),
7.22-7.42 (m, 10H).
The another synthetic route of (+)-8a and (-)-9a.
A mixture of 2-methoxyacetophenone (1.0 g, 6.65 mmol) and (R)-1-amino-2-propanol (0.5 g, 6.65 mmol)
in toluene (50 mL) was refluxed for 1.5 h using a Dean-Stark trap. After cooling, the reaction mixture was
concentrated to give the residue, which was dissolved in THF (10 mL). The above THF solution was
added dropwise to a suspension of lithium aluminum hydride (0.26 g, 6.85 mmol) in dry THF (40 mL) at
rt over a 10 min period. After stirred for 1 h, the excess hydride was decomposed by the slow addition of

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483
water and mixture was filtered through a Celite. Evaporation of the filtrate gave a colorless oil, which was
purified by silica gel flash chromatography with hexane/EtOAc (1 : 3) to afford pure product [(+)-8a and
(-)-9a].
(2R,1’S)-(2’-Methoxy-1’-phenylethyl)amino-2-propanol[(+)-8a].
1
Yield: 33 %, colorless oil. [α]D +55.5 (c 1.08, CHCl3). H NMR (270 MHz, CDCl3): δ = 1.80 (d, J =
6.3Hz, 3H), 2.41 (brs, 2H), 2.42 (dd, J = 8.5, 12.2Hz, 1H,), 2.54 (dd, J = 3.5, 12.2Hz, 1H), 3.37 (s, 3H),
13
3.43-3.48 (m, 2H), 3.55-3.67 (m, 1H), 3.86 (dd, J = 5.4, 7.4Hz, 1H), 7.23-7.37 (m, 5H). C NMR (67.8
MHz, CDCl3): δ = 140.89, 128.43, 127.52, 127.42, 77.46, 66.49, 63.29, 58.79, 55.26, 20.77. IR (film):
3317, 3060, 2970, 2923, 2882, 1600, 1448, 1380, 1232, 1198, 1109 cm-1. MS m/z: CI, 210 (M++1). Anal.
Cacld for C12H19NO2: C, 68.87; H, 9.15; N, 6.69. Found: C, 68.92; H, 9.20; N, 6.59.
(2R,1’R)-(2’-Methoxy-1’-phenylethyl)amino-2-propanol[(-)-9a].
Yield: 38 %, colorless crystal, mp 68°C (hexane-Et2O). [α]D -122.9 (c 1.12, CHCl3). 1H NMR (270 MHz,
CDCl3): δ = 1.07 (d, J = 6.3Hz, 3H), 2.22 (dd, J = 9.8, 11.8Hz, 1H), 2.45 (brs, 2H), 2.62 (dd, J = 2.7,
11.8Hz, 1H), 3.38 (s, 3H), 3.43-3.49 (m, 2H), 3.73-3.84 (m, 1H), 3.92 (dd, J = 4.0, 9.1Hz, 1H), 7.26-7.34
13
(m, 5H). C NMR (67.8 MHz, CDCl3): δ = 140.23, 128.44, 127.51, 127.45, 77.64, 66.06, 62.11, 58.77,
54.35, 20.08. IR(KBr): 3430, 3062, 2970, 2930, 2892, 1600, 1453, 1379, 1218, 1197, 1108 cm-1. MS m/z:
CI, 210 (M++1). Anal. Cacld for C12H19NO2: C, 68.87; H, 9.15; N, 6.69. Found: C, 68.92; H, 9.28; N,
6.62.
Reduction of ring-opening product (4a) by LAH.
To a stirred suspension of LiAlH4 (76.0 mg, 2.0 mmol) in THF (5 mL) was added ring-opening product
(4a) (0.5 g, 2.0 mmol) in THF (5 mL) at rt. The reaction mixture was stirred for 6 h after which the excess
of hydride was decomposed by the slow addition of water and the mixture was filtered through a little
Celite. Evaporation of the filtrate gave a colorless oil, which was purified by silica gel flash
chromatography with hexane/EtOAc (1 : 1) to afford pure product [(-)-8a].
Yield: 70 %, colorless oil. [α]D -56.0 (c 1.14, CHCl3). The spectral data are identical with above-
mentioned authentic sample [(+)-8a].
Hydrogenation of ring-opening product (6a) by Pd(OH)2/H2.
A solution of ring-opening product (6a) (0.45 g, 1.5 mmol) in methanol (20 mL) and 20% palladium
hydroxide on carbon (10 mg) under H2 for 6 h at rt. The reaction mixture was then filtered through a little
Celite and the filtrate was evaporated under reduced pressure to give a residue, which was purified by
silica gel flash chromatography with hexane/EtOAc (1 : 1) to afford pure product [(-)-9a].
Yield: 65 %, colorless oil. [α]D -123.2 (c 1.00, CHCl3). The spectral data are identical with above-

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HETEROCYCLES, Vol. 78, No. 2, 2009
mentioned authentic sample [(-)-9a].
ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology of Japan and by The Open Research Center Project.
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9. X-Ray Crystal structure determinations: A colorless prismatic crystal of C21H27NOBr2 having an

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approximate dimension of 0.4 x 0.4 x 0.4 mm grown from hexane was used for the data collection of
a Rigaku AFC7R diffractometer with graphic monochromated Cu-Kα radiation ( r = 1.54178 Å) and
rotating anode generator. Crystal data of 5d’: M = 469.26; orthorhombic, space group P212121 (#19),
Z = 4 with a = 10.979(2) Å, b = 19.261(4) Å, c = 10.289(1) Å, V = 2175.8(6) Å3, and Dcale
=
1.432g/cm3. All calculations were performed using the teXsan program. The structure was solved by
direct methods and expanded using Fourier techniques. The final R- and RW-factors after full-matrix
least-squares refinement were 0.043 and 0.040, respectively, based on 1475 observed reflections
(I>3.00σ(I)).
10. M. D’hooghe and N. De Kimpe, Synlett, 2006, 2089; M. D’hooghe, M. Rottiers, R. Jolie, and N. De
Kimpe, Synlett, 2005, 931; M. D’hooghe, A. Waterinckx, and N. De Kimpe, J. Org. Chem., 2005, 70,
227; N. De Kimpe, D. De Smaele, and Z. Sakonyi, J. Org. Chem., 1997, 62, 2448; N. De Kimpe, R.
Jolie, and D. De Smaele, J. Chem. Soc., Chem. Commun., 1994, 1221.