Chiral amine-induced stereoselectivity in trans-β-lactam formation via Staudinger cycloaddition

Article abstract of DOI:10.1016/j.tet.2009.10.063

A series of chiral trans-β-lactams was obtained via Staudinger cycloaddition with low to moderate diastereoselectivity (up to 54% de) induced by a chiral amine component of the imine. It was shown that the direct connection of nitrogen to a chiral centre

Full text of DOI:10.1016/j.tet.2009.10.063

Tetrahedron 65 (2009) 10339–10347
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chiral amine-induced stereoselectivity in trans-b-lactam formation
via Staudinger cycloaddition
,
b,
Aleksandar R. Todorova, Vanya B. Kurteva a , Ranko P. Bontchev y, Nikolay G. Vassileva
*
a Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev str., bl. 9, 1113 Sofia, Bulgaria
b Cabot Corporation, 5401 Venice Ave. N.E., Albuquerque, NM 87113, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of chiral trans-b-lactams was obtained via Staudinger cycloaddition with low to moderate dia-
Received 18 May 2009
Received in revised form
26 September 2009
Accepted 15 October 2009
Available online 21 October 2009
stereoselectivity (up to 54% de) induced by a chiral amine component of the imine. It was shown that the
direct connection of nitrogen to a chiral centre is crucial to induce chirality; moderate asymmetric
induction was achieved by using isomeric 1-phenylethylamines, which are among the cheapest chiral
sources on the market, while low diastereoselectivity was obtained from 3-aminomethylpinane, where
the chiral centres are distant from nitrogen by a methylene group. It was shown, that an increase of the
reaction temperature from 110 ꢀC to 140 ꢀC led to commensurable results but speeded-up the trans-
formation significantly. The absolute configurations of phenylethylamine derivatives were determined by
X-ray analysis of selected samples.
Keywords:
Chiral b-lactams
Staudinger cycloaddition
Chiral amine auxiliaries
Trans-stereoselective
Diastereoselectivity
X-ray
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
transition state of the reaction offers diverse options to design
suitable partners of ketene and imine so that the product stereo-
Azetidine-2-ones, so-called
b
-lactams, are heterocyclic systems
selectivity can be efficiently controlled by the competition between
the direct ring-closure and the isomerization of the imine moiety in
the zwitterionic intermediates generated from imines and ketenes.
Ideally, there are three sites where a selectivity-directing group can
be located: the ketene, the aldehyde component of the imine, and
the amine component of the imine. In general, electron donating
ketene substituents and electron-withdrawing imine substituents
accelerate the direct ring-closure, leading to a preference for
of great importance as they exist as structural subunits in many
products of interest as pharmaceuticals and synthetic building
blocks.1–5 The subsequent development of a number of classes of
b
-lactam antibiotics has made this family of four-membered ring
amides one of the most successful classes of therapeutic agents to
date.6–10 The stereoisomerically pure azetidinones receive special
attention as the ring stereochemistry is closely related with their
biological activities. For instance, the penicillin and cephalosporin
cis-
stituents and electron donating imine substituents slow the direct
ring-closure, leading to a preference for trans- -lactam formation.
b-lactam formation; while electron-withdrawing ketene sub-
antibiotics possess cis-b-lactam units, whereas thienamycins and
trinems have trans- -lactam moieties.
b
b
Azetidinones are of widespread interest from the synthetic
point of view because of their reactivity.11 However, their skeleton
is one of the most difficult to synthesize due to the ring strain.12
Among the various methods reported for the construction of
The presence of a chiral centre at the adjacent sites of the reacting
groups can also dictate the preference for a particular diastereomer.
Various chiral acid derivatives, as ketene precursors, and chiral
imines have been reported to effect moderate to very high dia-
b
-lactam ring,13–17 the Staudinger [2þ2] ketene-imine cycloaddi-
stereoselectivity in b
-lactam ring construction.19–22 The asymmet-
tion reaction regarded as one of the most fundamental and versa-
tile routes for their stereoselective synthesis.18 The organized
ric Staudinger reaction has been successfully achieved with chiral
ketenes and with imines derived from chiral aldehydes and achiral
amines, while the number of reports on the asymmetric induction
caused by the amine auxiliary is quite limited, despite their broad
variability on the market. Chiral cis-azetidinones are obtained by
* Corresponding author. Tel.: þ359 2 9606156; fax: þ359 2 8700225.
E-mail address: vkurteva@orgchm.bas.bg (V.B. Kurteva).
using L
-alanine methyl ester,23 D-threonine derivatives,24 chiral
diols,25 1-phenylethylamine,26 1-naphthylethylamine,27 as chiral
auxiliaries; while, to the best of our knowledge, only Lassatella et al.
y
For crystallography aspects: Contact: Tel.: þ1 505 5634438; fax: þ1 505
3422168. ranko_bontchev@cabot-corp.com
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.063

10340
A.R. Todorov et al. / Tetrahedron 65 (2009) 10339–10347
report28 on the ‘unexpected formation of chiral trans-
b
-lactams’ via
CH-Me, and CH3 for 6–13 crude products. These diastereoisomers
were separated by high performance flash chromatography (HPFC)
on silica gel. As they posses very close or equal Rf-values, a mobile
phase with a gradient of polarity was used and pure isomers or
enriched fractions were isolated, respectively.
Staudinger-like cycloaddition of chiral N,N-dialkylhydrazones to a-
aminoketene, the selectivity being controlled by the temperature.29
In this paper, we report our study on the diastereoselectivity in
the formation of trans-b-lactams via Staudinger cycloaddition in-
duced by a chiral amine component of the imine.
The absolute configurations of the phenylethylamine azetidi-
nones 6–13 were determined by X-ray analysis of selected samples
of the isomers with lower Rf-values. The latter are solid products in
some cases, while the less polar ones are always viscous oils. The
crystals were grown by slow diffusion of hexane into chloroform
solutions of the enantiomeric products (3S,4R)-6 and (3R,4S)-7. The
thermal ellipsoid plots with labeling schemes obtained are given in
Figure 1.
As can be seen from Table 1, low to moderate asymmetric
induction in the ring construction was achieved by using phenyl-
ethylamine auxiliary (entries 3–10), while almost equimolar mix-
tures of trans-isomers were obtained from aminomethylpinane
derivatives (entries 1 and 2), where the chiral centres are distant
from the nitrogen. A comparison between 4-dimethylamino and
methoxy derivatives shows that all phenylethylamine products
were formed with similar efficacy, while the selectivity was mod-
erately influenced by the substituents on the aldehyde moiety.
Commensurable superiority of the less polar isomer was observed
in the formation of dimethylamino and 3,4-dimethoxy substituted
2. Results and discussion
The relatively cheap commercial chiral amines, (þ)-amino-
methylpinane and the isomeric 1-phenylethylamines, were chosen
as selectivity-directing sources in an attempt to investigate
the influence of the remoteness of the amine chiral centre from
nitrogen on the reaction selectivity. Additionally, molecules con-
taining a pinane unit have shown variable biological efficacies,
while the benzyl position of the amino group in phenylethylamines
was expected to assist the nucleophilic attack and to speed-up the
reaction.
A set of aromatic aldehydes with electron donating substituents
was used aiming to slow the direct closure and to accelerate the
isomerization of the zwitterionic intermediate; 4-dimethylamino-,
3,4-dimethoxy-, and 2,4,6-trimethoxybenzaldehyde and o-vanillin,
the latter leading to products possessing bulky substituents at the
o-position (12,13).
b-lactams (26/32 vs 26/26; entries 3,4 vs 5,6), while better selec-
The imine intermediates 3 were obtained quantitatively by
irradiating mixtures of an amine 1 and aldehyde 2 in a microwave
oven (Scheme 1), while the classical methods, such as azeotropic
distillation with Dean–Stark trap or in the presence of water-
trapping agents, led to low conversions and decomposition took
place during the purifications. The microwave transformation was
very fast and clean, no impurities or reagents were detected by
NMR spectroscopy, which allowed using these relatively unstable
products without chromatography purification.
tivity was achieved with bulky electron donating substituent in
o-position (26/32 vs 42/44; entries 3,4 vs 9,10) and the best with
three methoxy groups (26/32 vs 52/54; entries 3,4 vs 7,8).
The dependence of the selectivity on the reaction temperature
was studied on the example of the phenylethylamine derivatives
products 6–13 (entries 3–10). The lower temperature experiments
for the preparation of 7 led to decomposition at 60 ꢀC, where side-
product formation was only detected, and lower conversion with
the same selectivity at 80 ꢀC. When the temperature was increased
by performing the reaction in refluxing xylene, similar yields and
selectivities were obtained (Table 1, pathway B vs pathway A) but
much faster then in toluene (2 h vs 24 h). The only exception from
the common pattern of behaviour was the formation of vanillin
derivatives 12 and 13, where decomposition was detected in xylene
resulting in a serious decrease of the yields.
O
Ph
i
O
ii
*R
R
NH2
+
R
N
N
or iii
R
*R
R*
1
2
3a-3j
4-13
2-OH-3-OMe/
4-Me2N 3,4-(MeO)2 2,4,6-(MeO)3
R
In summary, ten pairs of b-lactams with trans-C3,C4-configura-
R*-NH2
2-(OCOR)-3-OMe
tion were obtained via Staudinger cycloaddition with low to
moderate diastereoselectivity induced by a chiral amine compo-
nent of the imine. It was found that 1-phenylethylamine is effective
as a chiral auxiliary, contrary to aminomethylpinane, where the
chiral centres are distant from the nitrogen. The absolute configu-
rations of all four possible trans-isomers of the four phenylethyl-
amine derivatives were determined by X-ray analysis of selected
samples. It was shown, that the transformation goes with com-
mensurable yields and selectivities in refluxing toluene and xylene,
but with much different rates, making the xylene protocol the
method of choice.
3a / 4
3c / 6
3d / 7
3b / 5
3e / 8
3f / 9
(+)-3-aminomethylpinane
(S)-1-phenylethylamine
3g / 10
3h / 11
3i / 12
3j / 13
(R)-1-phenylethylamine
Scheme 1. Preparation of azetidinones 4–13. i) MWI, 600–800 W, 2–4 min; ii)
PhCH2CH2COCl (1 equiv for 4–11, 2 equiv for 12,13), Et3N, toluene, reflux, 24 h; iii)
PhCH2CH2COCl (1 equiv for 4–11, 2 equiv for 12,13), Et3N, xylene, reflux, 2–3 h.
The imines 3 were converted into the target azetidinones 4–13
via Staudinger [2þ2] ketene-imine cycloaddition by using 3-phe-
nylpropionyl chloride as a ketene precursor and triethylamine as
a base (Scheme 1). In the case of azetidinones 12 and 13 formation,
the cycloaddition reaction was performed in two-fold excess of ke-
tene precursor due to the presence of a free hydroxyl group. The
reactions were initially performed in refluxing toluene in an attempt
3. Experimental
3.1. General procedures
to achieve
b-lactam ring formation with trans-selectivity, in accor-
dance with the observed by Lassatella et al.28,29 dependence of the
ring stereochemistry on the reaction temperature. The trans-
formations proceeded in a relatively clean way and the azetidinones
4–13 were isolated in good to high yields, as shown in Table 1.
The products were obtained diastereoselectively as pairs of
isomers with the desired trans-C3,C4-configuration, i.e., (3R,4S) and
(3S,4R). The isomeric ratios were determined on the basis of the
relative integral intensities of the proton NMR resonances, which
are in areas free of other signals; CH-4 and CH2-N for 4-5 and CH-4,
All reagents were purchased from Aldrich, Merck and Fluka and
were used without any further purification. Toluene and xylene
were dried over sodium wire. The microwave irradiated reactions
(MWI) were performed in domestic household oven Panasonic
NN-S255W. Fluka silica gel/TLC-cards 60778 with fluorescent in-
dicator 254 nm were used for TLC chromatography and Rf-values
determination. The purifications were carried out on a Biotage
HorizonTM HPFC system on silica gel. The melting points were
determined in capillary tubes on MEL-TEMP 1102D-230 VAC

A.R. Todorov et al. / Tetrahedron 65 (2009) 10339–10347
10341
Table 1
Preparation of azetidin-2-ones 4–13
Entry
Starting imine
Conditionsa
Product
No.
Structureb
Yieldc
%
ded
%
O
O
N
N
1
3a
A
4
72
10
N
N
(3S,4R)
(3R,4S)
O
N
O
N
2
3b
A
5
70
6
O
O
(3R,4S)
(3S,4R)
O
O
O
N
O
N
A
B
87
92
26
28
3
3c
6
N
N
(3R,4S)
(3S,4R)
O
O
N
N
A
B
69
86
32
34
4
3d
7
N
N
(3R,4S)
(3S,4R)
O
O
N
N
A
B
73
67
26
24
5
3e
8
O
O
(3R,4S)
(3S,4R)
O
O
O
O
N
N
A
B
66
79
26
26
6
3f
9
O
O
(3S,4R)
(3R,4S)
O
O
O
O
N
N
O
A
B
76
83
52
48
7
3g
10
O
O
O
(3S,4R)
(3R,4S)
O
O
O
O
N
O
N
A
B
89
73
54
48
8
3h
11
O
O
O
(3R,4S)
(3S,4R)
O
(continued on next page)
O

10342
Table 1 (continued)
A.R. Todorov et al. / Tetrahedron 65 (2009) 10339–10347
Entry
Starting imine
Conditionsa
Product
No.
Structureb
Yieldc
%
ded
%
O
O
N
N
A
B
72
<10
42
43
O
O
O
O
9
3i
12
O
O
(3R,4S)
(3S,4R)
O
O
N
N
A
B
61
<10
44
44
10
3j
13
O
O
O
O
O
O
(3S,4R)
(3R,4S)
a
A: 110 ꢀC, 24 h; B: 140 ꢀC, 2–3 h.
b
c
The major diastereoisomer is drawn first.
After HPFC purification on silica gel.
d
Determined by 1H NMR spectra of the crude mixtures.
apparatus without corrections. The IR spectra were taken on
a Bruker Tensor 27 as chloroform solutions and were quoted in
cmꢁ1. The NMR spectra were recorded on a Bruker Avance DRX
250 and Bruker Avance IIþ 600 (indicated) spectrometers in
deuterochloroform; the chemical shifts were quoted in ppm in d-
values against tetramethylsilane (TMS) as an internal standard and
the coupling constants were calculated in Hertz. The assignments
of signals were confirmed by 2D techniques (COSY, NOESY, HSQC,
HMBC). The low resolution mass spectra were taken on a HP 5973
Mass Selective Detector, the high resolution mass spectra on a DFS
High Resolution Magnetic Sector MS, Thermo Scientific. The
optical rotations were recorded on a Perkin–Elmer Polarimeter 241
(Na-lamp, 589 nm, 1 dm cell, c 1 in CHCl3).
(a)
3.2. Preparation of imines 3
3.2.1. General procedure. A mixture of a chiral amine 1 (1 mmol)
and an aromatic aldehyde 2 (1 mmol) was irradiated in a domestic
household microwave oven in an open vessel with a power of
600–800 W for 2–4 min. The clean crude products (NMR) were
used in the next step without purification.
3.2.2. N-(4-Dimethylaminobenzylidene)-1-((1S,2S,3S,5R)-2,6,6-
trimethylbicyclo[3.1.1]heptan-3-yl)methanamine 3a. 295 mg, 99%
yield; IR 513, 592, 787, 821, 947, 1068, 1166, 1234, 1307, 1366, 1443,
1472, 1526, 1604, 1637, 1678, 2822, 2900, 2980; 1H NMR (250 MHz)
1
0.83 (d, 1H, J 9.4, ⁄2 CH2-7), 1.03 (s, 3H, CH3), 1.06 (d, 3H, J 7.1,
CH3-2), 1.19 (s, 3H, CH3), 1.54 (m, 1H, 1⁄2 CH2-4), 1.74–1.92 (m, 3H),
(b)
1
2.02–2.31 (m, 3H), 2.95 (s, 6H, 2ꢂCH3–N), 3.43 (m, 1H, ⁄2 CH2–
N]), 3.61 (m, 1H, 1⁄2 CH2–N]), 6.66 (d, 2H, J 8.9, CH-3 and CH-5
Ar), 7.60 (d, 2H, J 8.9, CH-2 and CH-6 Ar), 8.14 (s, 1H, CH]N);
(250 MHz) 13C NMR 21.7 (CH3), 22.9 (CH3), 28.0 (CH3), 32.4 (CH2),
33.5 (CH2), 37.4 (CH), 39.0 (Cquat-6), 40.1 (CH3–N), 40.9 (CH), 41.8
(CH), 48.1 (CH), 70.7 (CH2–N]), 111.6 (CH-3 and CH-5 Ar), 124.7
(Cquat-1 Ar), 129.4 (CH-2 and CH-6 Ar), 151.8 (Cquat-4 Ar), 160.4
(CH]N); MS m/z 298.
3.2.3. N-(3,4-Dimethoxybenzylidene)-1-((1S,2S,3S,5R)-2,6,6-trime-
thylbicyclo[3.1.1]heptan-3-yl)methanamine 3b. 309 mg, 98% yield;
IR 592, 613, 645, 731, 807, 871, 1026, 1136, 116þ1, 1238, 1267, 1327,
1340, 1383, 1420, 1453, 1464, 1512, 1586, 1598, 1644, 1683, 2836,
2903; 1H NMR (250 MHz) 0.84 (d, 1H, J 9.4, 1⁄2 CH2-7), 1.04 (s, 3H,
1
CH3), 1.08 (d, 3H, J 7.1, CH3-2), 1.20 (s, 3H, CH3), 1.55 (m, 1H, ⁄2
Figure 1. Thermal ellipsoid plot (50% probability level) and labeling scheme of the
structure of: a) (3S,4R)-6; b) (3R,4S)-7.
1
CH2-4), 1.76–1.94 (m, 3H), 2.04–2.33 (m, 3H), 3.48 (m, 1H,
⁄
2

A.R. Todorov et al. / Tetrahedron 65 (2009) 10339–10347
10343
1
CH2–N]), 3.64 (m, 1H, ⁄2 CH2–N]), 3.88 (s, 3H, OCH3), 3.92 (s,
1129, 1156, 1205, 1228, 1333, 1415, 1455, 1603, 1636, 2838, 2966; 1H
NMR (250 MHz) 1.60 (d, 3H, J 6.6, CH3–CH), 3.81 (s, 6H, 2ꢂOCH3),
3.82 (s, 3H, OCH3), 4.47 (q, 1H, J 6.6, 13.2, CH–CH3), 6.11 (s, 2H, CH-3
and CH-5 Ar), 7.20 (td, 1H, J 1.3, 7.4, CH-4 Ph), 7.32 (m, 2H, CH-3 and
CH-5 Ph), 7.48 (dd, 2H, J 1.3, 7.5, CH-2 and CH-6 Ph), 8.55 (s, 1H,
CH]N); 13C NMR (250 MHz) 25.2 (CH3–CH), 55.3 (OCH3), 56.0
(2ꢂOCH3), 71.0 (CH–CH3), 90.8 (CH-3 and CH-5 Ar), 107.9 (Cquat-1
Ar), 126.3 (CH-4 Ph), 126.6 (CH-2 and CH-6 Ph), 128.1 (CH-3 and CH-
5 Ph), 146.2 (Cquat-1 Ph), 154.6 (CH]N), 160.7 (Cquat-2 and Cquat-6
Ar), 162.3 (Cquat-4 Ar); MS m/z 299.
3H, OCH3), 6.86 (d, 1H, J 8.2, CH-5 Ar), 7.16 (dd, 1H, J 1.8, 8.2, CH-6
Ar), 7.43 (d, 1H, J 1.8, CH-2 Ar), 8.20 (s, 1H, CH]N); 13C NMR
(250 MHz) 21.7 (CH3), 23.0 (CH3), 28.0 (CH3), 32.5 (CH2), 33.6
(CH2), 37.3 (CH), 39.0 (Cquat-6), 40.9 (CH), 41.8 (CH), 48.14 (CH),
55.8 (OCH3), 70.5 (CH2–N]), 108.9 (CH-2 Ar), 110.5 (CH-5 Ar),
122.8 (CH-6 Ar), 129.7 (Cquat-1 Ar), 149.3 (Cquat-3 or Cquat-4 Ar),
151.2 (Cquat-3 or Cquat-4 Ar), 160.0 (CH]N); MS m/z 315.
3.2.4. (S)-N-(4-Dimethylaminobenzylidene)-1-phenylethylamine
3c30. 249 mg, 99% yield; IR 522, 703, 761, 815, 970,1064,1183,1228,
1317, 1362, 1384, 1448, 1489, 1524, 1609, 1636, 2825, 2843, 2923,
2966, 3025; 1H NMR (250 MHz) 1.57 (d, 3H, J 6.7, CH3–CH), 2.96 (s,
6H, 2ꢂCH3–N), 4.46 (q,1H, J 6.7,13.3, CH–CH3), 6.66 (d, 2H, J 8.8, CH-
3 and CH-5 Ar), 7.19 (t,1H, J 7.1, CH-4 Ph), 7.30 (dd, 2H, J 7.1, 7.6, CH-3
and CH-5 Ph), 7.41 (d, 2H, J 7.6, CH-2 and CH-6 Ph), 7.64 (d, 2H, J 8.8,
CH-2 and CH-6 Ar), 8.22 (s, 1H, CH]N); 13C NMR (250 MHz) 24.8
(CH3–CH), 40.2 (CH3–N), 69.4 (CH–CH3), 111.6 (CH-3 and CH-5 Ar),
124.7 (Cquat-1 Ar), 126.58 (CH-4 Ph), 126.6 (CH-2 and CH-6 Ph),
128.2 (CH-3 and CH-5 Ph), 129.5 (CH-2 and CH-6 Ar), 145.8 (Cquat-1
Ph), 152.0 (Cquat-4 Ar), 159.3 (CH]N); MS m/z 252.
3.2.9. (R)-N-(2,4,6-Trimethoxybenzylidene)-1-phenylethylamine
3h. 295 mg, 99% yield; IR 542, 593, 701, 763, 813, 953, 1036, 1061,
1131, 1157, 1206, 1229, 1335, 1416, 1456, 1605, 1637, 2839, 2967; 1H
NMR (250 MHz) 1.60 (d, 3H, J 6.6, CH3–CH), 3.81 (s, 6H, 2ꢂOCH3),
3.82 (s, 3H, OCH3), 4.46 (q, 1H, J 6.6, 13.2, CH–CH3), 6.11 (s, 2H, CH-3
and CH-5 Ar), 7.20 (td, 1H, J 1.3, 7.2, CH-4 Ph), 7.31 (m, 2H, CH-3 and
CH-5 Ph), 7.48 (dd, 2H, J 1.3, 7.5, CH-2 and CH-6 Ph), 8.55 (s, 1H,
CH]N); 13C NMR (250 MHz) 25.2 (CH3–CH), 55.3 (OCH3), 56.0
(2ꢂOCH3), 71.0 (CH–CH3), 90.8 (CH-3 and CH-5 Ar), 107.9 (Cquat-1
Ar), 126.3 (CH-4 Ph), 126.6 (CH-2 and CH-6 Ph), 128.1 (CH-3 and CH-
5 Ph), 146.2 (Cquat-1 Ph), 154.6 (CH]N), 160.7 (Cquat-2 and Cquat-6
Ar), 162.3 (Cquat-4 Ar); MS m/z 299.
3.2.5. (R)-N-(4-Dimethylaminobenzylidene)-1-phenylethylamine
3d. 246 mg, 98% yield; IR 523, 704, 762, 816, 972, 1064, 1181, 1230,
1320, 1362, 1383, 1449, 1490, 1526, 1607, 1638, 2827, 2841, 2923,
2964, 3025; 1H NMR (250 MHz) 1.57 (d, 3H, J 6.7, CH3–CH), 2.98 (s,
6H, 2ꢂCH3–N), 4.47 (q,1H, J 6.7,13.3, CH–CH3), 6.68 (d, 2H, J 8.9, CH-
3 and CH-5 Ar), 7.20 (t, 1H, J 7.1, CH-4 Ph), 7.31 (dd, 2H, J 6.9, 7.6, CH-
3 and CH-5 Ph), 7.42 (d, 2H, J 6.9, CH-2 and CH-6 Ph), 7.65 (d, 2H, J
8.8, CH-2 and CH-6 Ar), 8.23 (s, 1H, CH]N); 13C NMR (250 MHz)
24.9 (CH3–CH), 40.2 (CH3–N), 69.4 (CH–CH3), 111.6 (CH-3 and CH-5
Ar), 124.7 (Cquat-1 Ar), 126.5 (CH-4 Ph), 126.6 (CH-2 and CH-6 Ph),
128.3 (CH-3 and CH-5 Ph), 129.6 (CH-2 and CH-6 Ar), 145.8 (Cquat-1
Ph), 152.0 (Cquat-4 Ar), 159.4 (CH]N); MS m/z 252.
3.2.10. (S)-N-(2-Hydroxy-3-methoxybenzylidene)-1-phenylethyl-
amine 3i. 252 mg, 99% yield; IR 535, 700, 738, 764, 840, 968, 1093,
1255, 1270, 1383, 1419, 1466, 1628, 2930, 2971, 3061; 1H NMR
(600 MHz) 1.62 (d, 3H, J 6.7, CH3–CH), 3.90 (s, 3H, OCH3), 4.56 (q,1H, J
6.7,13.3, CH–CH3), 6.80(t,1H, J 7.9, CH-5 Ar), 6.87(dd,1H, J 1.4, 7.9, CH-
4 Ar), 6.92 (dd,1H, J 1.4, 7.9, CH-6 Ar), 7.25 (td,1H, J 1.5, 7.3, CH-4 Ph),
7.34 (td, 2H, J 1.5, 7.4, CH-3 and CH-5 Ph), 7.37 (dd, 2H, J 1.5, 7.4, CH-2
and CH-6 Ph), 8.40 (s, 1H, CH]N) 14.18 (s, 1H, OH); 13C NMR
(600 MHz) 25.2 (CH3–CH), 56.1 (OCH3), 68.2 (CH–CH3), 113.9 (CH-4
Ar),117.9(CH-5 Ar),118.6 (Cquat-1Ar),122.9(CH-6Ar),126.3(CH-2 and
CH-6 Ph), 127.2 (CH-4 Ph), 128.7 (CH-3 and CH-5 Ph), 143.7 (Cquat-1
Ph), 148.4 (Cquat-3 Ar), 151.8 (Cquat-4 Ar), 163.4 (CH]N); MS m/z 255.
3.2.6. (S)-N-(3,4-Dimethoxybenzylidene)-1-phenylethylamine
3e. 263 mg, 98% yield; recrystallization from heptane; mp 71–
72 ꢀC; IR 541, 641, 704, 764, 813, 871, 927, 969, 1020, 1078, 1141,
1188, 1263, 1386, 1419, 1448, 1511, 1600, 1642, 2843, 2925, 2968,
3027, 3061; 1H NMR (250 MHz) 1.58 (d, 3H, J 6.7, CH3–CH), 3.88 (s,
3H, OCH3), 3.93 (s, 3H, OCH3), 4.51 (q, 1H, J 6.6, 13.2, CH–CH3), 6.86
(d, 1H, J 8.2, CH-5 Ar), 7.18 (dd, 1H, J 1.8, 8.3, CH-6 Ar), 7.25 (td, 1H, J
1.4, 7.3, CH-4 Ph), 7.33 (m, 2H, CH-3 and CH-5 Ph), 7.42 (dd, 2H, J 1.5,
7.6, CH-2 and CH-6 Ph), 7.48 (d, 1H, J 1.8, CH-2 Ar), 8.26 (s, 1H,
CH]N); 13C NMR (250 MHz) 24.7 (CH3–CH), 55.8 (OCH3), 55.9
(OCH3), 69.4 (CH–CH3), 109.1 (CH-2 Ar),110.4 (CH-5 Ar),122.9 (CH-6
Ar),126.6 (CH-2 and CH-6 Ph), 126.7 (CH-4 Ph), 128.3 (CH-3 and CH-
5 Ph), 129.7 (Cquat-1 Ar), 145.2 (Cquat-1 Ph), 149.2 (Cquat-3 or Cquat-4
Ar), 151.2 (Cquat-3 or Cquat-4 Ar), 158.8 (CH]N); MS m/z 269.
3.2.11. (R)-N-(2-Hydroxy-3-methoxybenzylidene)-1-phenylethyl-
amine 3j. 249 mg, 98% yield; IR 536, 700, 738, 764, 840, 968, 1093,
1255, 1270, 1383, 1419, 1466, 1628, 2932, 2971, 3061; 1H NMR
(600 MHz) 1.63 (d, 3H, J 6.7, CH3–CH), 3.91 (s, 3H, OCH3), 4.57 (q,1H, J
6.7,13.3, CH–CH3), 6.80(t,1H, J 7.9, CH-5 Ar), 6.87(dd,1H, J 1.5, 7.8, CH-
4 Ar), 6.92 (dd,1H, J 1.4, 7.9, CH-6 Ar), 7.26 (td,1H, J 1.5, 7.4, CH-4 Ph),
7.34 (td, 2H, J 1.5, 7.4, CH-3 and CH-5 Ph), 7.37 (dd, 2H, J 1.5, 7.4, CH-2
and CH-6 Ph), 8.40 (s, 1H, CH]N) 14.17 (s, 1H, OH); 13C NMR
(600 MHz) 25.2 (CH3–CH), 56.1 (OCH3), 68.2 (CH–CH3), 113.9 (CH-4
Ar),117.9(CH-5 Ar),118.6 (Cquat-1Ar),122.9(CH-6Ar),126.3(CH-2 and
CH-6 Ph), 127.3 (CH-4 Ph), 128.7 (CH-3 and CH-5 Ph), 143.7 (Cquat-1
Ph), 148.5 (Cquat-3 Ar), 151.8 (Cquat-4 Ar), 163.4 (CH]N); MS m/z 255.
3.2.7. (R)-N-(3,4-Dimethoxybenzylidene)-1-phenylethylamine
3f31. 265 mg, 98% yield; IR 541, 641, 704, 764, 813, 871, 927, 969,
1020, 1077, 1141, 1188, 1264, 1386, 1419, 1448, 1511, 1600, 16414,
2843, 2925, 2968, 3026, 3060; 1H NMR (250 MHz) 1.58 (d, 3H, J 6.7,
CH3–CH), 3.90 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 4.52 (q, 1H, J 6.6,
13.3, CH–CH3), 6.86 (d, 1H, J 8.2, CH-5 Ar), 7.17 (dd, 1H, J 1.8, 8.2, CH-
6 Ar), 7.23 (td, 1H, J 1.4, 7.3, CH-4 Ph), 7.33 (m, 2H, CH-3 and CH-5
Ph), 7.42 (dd, 2H, J 1.5, 7.7, CH-2 and CH-6 Ph), 7.48 (d, 1H, J 1.8, CH-2
Ar), 8.27 (s, 1H, CH]N); 13C NMR (250 MHz) 24.8 (CH3–CH), 55.9
(OCH3), 56.0 (OCH3), 69.4 (CH–CH3), 109.2 (CH-2 Ar), 110.4 (CH-5
Ar), 123.0 (CH-6 Ar), 126.6 (CH-2 and CH-6 Ph), 126.8 (CH-4 Ph),
128.4 (CH-3 and CH-5 Ph), 129.8 (Cquat-1 Ar), 145.3 (Cquat-1 Ph),
149.3 (Cquat-3 or Cquat-4 Ar), 151.3 (Cquat-3 or Cquat-4 Ar), 158.9
(CH]N); MS m/z 269.
3.3. Preparation of azetidin-2-ones 4–13
3.3.1. General procedure. To
a refluxing solution of imine 3
(1 mmol) and Et3N (1.5 mmol) in toluene or xylene (15 mL) 3-
phenylpropionyl chloride (1 mmol for 4-11; 2 mmol for 12 and 13)
was added and the mixture was refluxed for 24 h (in toluene) or for
2–3 h (in xylene). The products were partitioned between water
and toluene/xylene. The organic phase was washed with brine,
dried over Na2SO4, evaporated to dryness, and purified by PHFC on
silica gel. Mobile phase with a gradient of polarity from ether:
hexane 10:90 to ether:hexane 80:20 was used. The enriched frac-
tions of stereoisomers of the products 4, 5, and 9 were isolated,
instead of pure isomers, due to much closed Rf-values.
The yields and selectivities are summarized in Table 1.
The trans-3,4-isomers of aminomethylpinane derivatives 4 and
5 are indicated as a and b for simplicity; the less polar isomer is a,
3.2.8. (S)-N-(2,4,6-Trimethoxybenzylidene)-1-phenylethylamine
3g. 296 mg, 99% yield; IR 541, 591, 700, 762, 811, 952, 1034, 1060,

10344
A.R. Todorov et al. / Tetrahedron 65 (2009) 10339–10347
the more polar is b. The couple components have equal Rf-values
and only partial separations were achieved.
(CH3), 27.8 (CH3), 33.0 (CH2-4 Pin), 33.6 (CH2-7 Pin), 34.1 (CH2), 36.0
(CH-1 Pin), 38.6 (Cquat-6 Pin), 40.9 (CH-3 Pin), 41.3 (CH-5 Pin), 47.7
(CH-2 Pin), 49.2 (CH2-N), 55.8 (CH3–O), 60.8 (CH-3), 61.4 (CH-4),108.8
(CH-2 Ar), 111.1 (CH-5 Ar),118.7 (CH-6 Ar),126.5 (CH-4 Ph),128.5 (CH-
3 and CH-5 Ph), 129.0 (CH-2 and CH-6 Ph), 130.2 (Cquat), 138.1 (Cquat),
148.9 (Cquat-OCH3), 149.3 (Cquat-OCH3), 169.8 (C]O).
3.3.2. 3-Benzyl-4-(4-(dimethylamino)phenyl)-1-(((1S,2S,3S,5R)-
2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)methyl)azetidin-2-one 4. IR
700, 823, 947, 1074, 1122, 1274, 1289, 1354, 1454, 1525, 1615, 1748,
2809, 2857, 2870, 2923, 3027, 3062, 3086, 3370; MS m/z 430; HRMS
(EI): calcd for C29H38N2O (Mþ): 430.2984, found: 430.2965.
3.3.3.2. Isomer 5b. Rf 0.12 (ether:hexane 1:1); colourless oil; 1H
NMR (600 MHz) 0.63 (d, 1H, J 9.8, 1⁄2 CH2-7 Pin), 0.78 (d, 3H, J 7.2,
CH3-2 Pin), 0.85 (s, 3H, CH3),1.10 (s, 3H, CH3),1.38 (ddd,1H, J 2.5, 5.8,
12.7, 1⁄2 CH2-4 Pin), 1.45 (tdd, 1H, J 1.8, 7.0, 13.9, CH-3 Pin), 1.69 (m,
3H, CH-1, CH-2, and 1⁄2 CH-4 Pin),1.71 (m,1H, CH-5 Pin), 2.20 (m,1H,
1⁄2 CH2-7 Pin), 2.63 (dd,1H, J 3.9,13.4,1⁄2 CH2–N), 2.96 (dd,1H, J 9.0,
14.5, 1⁄2 CH2), 3.14 (dd, 1H, J 4.9, 14.6, 1⁄2 CH2), 3.18 (m, 1H, CH-3),
3.30 (dd, 1H, J 10.0, 13.5, 1⁄2 CH2–N), 3.71 (s, 3H, OCH3), 3.80 (s, 3H,
OCH3), 4.16 (d,1H, J 1.9, CH-4), 6.74 (d,1H, J 8.2, CH-5 Ar), 6.66 (dd,1H,
J 2.0, 8.2, CH-6 Ar), 6.45 (d,1H, J 2.0, CH-2 Ar), 7.19 (tt,1H, J 1.4, 7.1, CH-
4 Ph), 7.23 (dt, 2H, J 1.7, 6.7, CH-2 and CH-6 Ph), 7.26 (td, 2H, J 1.4, 7.1,
CH-3 and CH-5 Ph); 13C NMR (600 MHz) 21.4 (CH3-2 Pin), 22.9 (CH3),
27.8 (CH3), 32.1(CH2-4 Pin), 33.7 (CH2-7 Pin), 34.3 (CH2), 34.5 (CH-1
Pin), 38.7 (Cquat-6 Pin), 40.5 (CH-3 Pin), 41.3 (CH-5 Pin), 47.5 (CH-2
Pin), 48.3 (CH2-N), 55.8 (CH3–O), 59.7 (CH-4), 60.58 (CH-3), 108.6
(CH-2 Ar), 111.1 (CH-5 Ar), 118.6 (CH-6 Ar), 126.5 (CH-4 Ph), 128.5
(CH-3 and CH-5 Ph), 129.1 (CH-2 and CH-6 Ph), 130.1 (Cquat), 138.0
(Cquat), 148.9 (Cquat-OCH3), 149.3 (Cquat-OCH3), 170.0 (C]O).
3.3.2.1. Isomer 4a. Rf 0.26 (ether:hexane 1:1), 0.40 (ether:
hexane 2:3, three times developed plates); colourless oil; 1H NMR
(600 MHz) 0.60 (d,1H, J 9.7, 1⁄2 CH2-7 Pin), 0.89 (s, 3H, CH3), 0.98 (d,
3H, J 7.2, CH3-2 Pin),1.14 (s, 3H, CH3),1.28 (ddd,1H, J 2.4, 6.3,13.2, 1⁄2
CH2-4Pin),1.61(dtd,1H, J 1.9, 7.1,14.2, CH-3Pin),1.69(td,1H, J 2.0, 6.7,
CH-2 Pin),1.72 (t,1H, CH-1 Pin),1.80 (m,1H, CH-5 Pin),1.83 (m,1H,1⁄2
CH2-4 Pin), 2.20 (ddt,1H, J 2.2, 6.3,12.2,1⁄2 CH2-7 Pin), 2.49 (dd,1H, J
8.2,13.9,1⁄2 CH2-N), 2.94 (s, 6H, 2ꢂCH3–N), 3.08 (dd,1H, J 7.1, 14.7, 1⁄2
CH2), 3.16 (dd,1H, J 5.3,14.7,1⁄2 CH2), 3.27 (ddd,1H, J 1.9, 5.3, 7.8, CH-
3), 3.46 (dd,1H, J 5.9,13.9,1⁄2 CH2–N), 4.24 (d,1H, J 1.9, CH-4), 6.67 (d,
2H, J 8.7, CH-3 and CH-5 Ar), 7.08 (d, 2H, J 8.7, CH-2 and CH-6 Ar), 7.19
(tt, 1H, J 1.4, 7.1, CH-4 Ph), 7.23 (dt, 2H, J 1.6, 6.7, CH-2 and CH-6 Ph),
7.27 (td, 2H, J 1.4, 7.2, CH-3 and CH-5 Ph); 13C NMR (600 MHz) 21.7
(CH3-2 Pin), 23.0 (CH3), 27.9 (CH3), 32.9 (CH2-4 Pin), 33.7 (CH2-7 Pin),
34.2 (CH2), 36.0 (CH-1 Pin), 38.6 (Cquat-6 Pin), 40.4 (CH3-N), 41.0 (CH-
3 Pin), 41.4 (CH-5 Pin), 47.8 (CH-2Pin), 48.8 (CH2-N), 60.4 (CH-3), 61.3
(CH-4),112.5 (CH-3 and CH-5 Ar),124.8 (Cquat),126.4 (CH-4 Ph),127.5
(CH-2 and CH-6 Ar),128.4 (CH-3 and CH-5 Ph),129.0 (CH-2 and CH-6
Ph), 138.2 (Cquat), 150.5 (Cquat), 170.1 (C]O).
3.3.4. 3-Benzyl-4-(4-(dimethylamino)phenyl)-1-((S)-1-phenyl-
ethyl)azetidin-2-one 6. MS m/z 384; HRMS (EI): calcd for C26H28N2O
(Mþ): 384.2202, found: 384.2199.
3.3.2.2. Isomer 4b. Rf 0.26 (ether:hexane 1:1), 0.37 (ether:
hexane 2:3, three times developed plates); colourless oil; 1H NMR
(600 MHz) 0.67 (d, 1H, J 9.8, 1⁄2 CH2-7 Pin), 0.83 (d, 3H, J 7.2, CH3-2
Pin), 0.91 (s, 3H, CH3),1.16 (s, 3H, CH3),1.40 (dd,1H, J 2.6, 7.8,1⁄2 CH2-
4 Ar), 1.61 (tdd, 1H, J 1.7, 7.0, 13.9, CH-3 Ar), 1.69 (m, 3H, CH-1, CH-2,
and 1⁄2 CH-4 Ar), 1.82 (m, 1H, CH-5 Ar), 2.24 (m, 1H, 1⁄2 CH2-7 Ar),
2.62 (dd, 1H, J 3.4, 13.6, 1⁄2 CH2–N), 2.94 (s, 6H, 2ꢂCH3–N), 3.06 (dd,
1H, J 8.4, 14.7, 1⁄2 CH2), 3.14 (dd, 1H, J 5.1, 14.7, 1⁄2 CH2), 3.27 (m, 1H,
CH-3), 3.32 (dd, 1H, J 9.6, 13.6, 1⁄2 CH2–N), 4.20 (d, 1H, J 1.9, CH-4),
6.67 (d, 2H, J 8.8, CH-3 and CH-5 Ar), 7.05 (d, 2H, J 8.8, CH-2 and CH-6
Ar), 7.19 (tt,1H, J 1.4, 7.1, CH-4 Ph), 7.23 (dt, 2H, J 1.7, 6.7, CH-2 and CH-
6 Ph), 7.26 (td, 2H, J 1.4, 7.4, CH-3 and CH-5 Ph); 13C NMR (600 MHz)
21.4 (CH3-2 Pin), 22.9 (CH3), 27.9 (CH3), 32.1 (CH2-4 Pin), 33.7 (CH2-7
Pin), 34.2(CH2), 34.6(CH-1 Pin), 38.7 (Cquat-6Pin), 40.4(CH3–N), 40.6
(CH-3 Pin), 41.4 (CH-5 Pin), 47.6 (CH-2 Pin), 48.0 (CH2–N), 59.6 (CH-
4), 60.1 (CH-3), 112.5 (CH-3 and CH-5 Ar), 124.6 (Cquat), 126.4 (CH-4
Ph),127.4 (CH-2 and CH-6 Ar),128.4 (CH-3 and CH-5 Ph),129.6 (CH-2
and CH-6 Ph), 138.1 (Cquat), 150.5 (Cquat), 170.2 (C]O).
3.3.4.1. (3R,4S)-6. Rf 0.27 (ether:hexane 1:1), 0.40 (ether:hexane
1:1, two times developed plates); colourless oil; IR 701, 757, 825,
1166, 1350, 1371, 1525, 1599, 1613, 1743, 2736, 2805, 2931, 2979,
3028, 3061, 3085, 3446; 1H NMR (600 MHz) 1.71 (d, 3H, J 7.2, CH3–
CH), 2.93 (s, 6H, 2ꢂCH3–N), 3.05 (m, 2H, CH2), 3.27 (ddd,1H, J 2.1, 5.3,
7.4, CH-3), 3.93 (d, 1H, J 2.1, CH-4), 4.09 (q, 1H, J 7.2, 14.3, CH–CH3),
6.62 (d, 2H, J 8.7, CH-3 and CH-5 Ar), 6.94 (m, 2H, CH Ph), 6.95 (d, 2H, J
8.7, CH-2 and CH-6 Ar), 7.19 (m, 6H, CH Ph), 7.26 (m, 2H, CH Ph); 13C
NMR (600 MHz) 20.4 (CH3–CH), 33.6 (CH2), 40.2 (CH3–N), 54.2 (CH–
CH3), 58.6 (CH-4), 59.4 (CH-3), 112.2 (CH-3 and CH-5 Ar), 124.6
(Cquat),126.2 (CH Ar),126.3 (CH Ar),126.9 (CH Ar),127.4 (CH Ar),127.8
(CH Ar),128.2 (CH Ar),128.2 (CH Ar),129.0 (CH Ar),137.8 (Cquat),141.5
(Cquat), 150.2 (Cquat), 169.6 (C]O); [
a
]
D ꢁ21.3ꢀ (c 1, CHCl3).
3.3.4.2. (3S,4R)-6. Rf 0.21 (ether:hexane 1:1), 0.32 (ether:
hexane 1:1, two times developed plates); white crystals (hexane);
mp 105–106 ꢀC; IR 697, 757, 797, 827, 1227, 1367, 1386, 1456, 1497,
1525, 1616, 1731, 2809, 2906, 2935, 2984, 3028, 3058, 3086, 3448;
1H NMR (600 MHz) 1.23 (d, 3H, J 7.2, CH3-CH), 2.94 (s, 6H, 2ꢂCH3–
N), 3.02 (m, 2H, CH2), 3.29 (ddd,1H, J 2.1, 5.3, 7.4, CH-3), 3.90 (d,1H, J
2.1, CH-4), 4.94 (q, 1H, J 7.2, 14.3, CH–CH3), 6.62 (d, 2H, J 8.7, CH-3
and CH-5 Ar), 6.94 (m, 2H, CH Ph), 6.95 (d, 2H, J 8.7, CH-2 and CH-6
Ar), 7.19 (m, 6H, CH Ph), 7.26 (m, 2H, CH Ph); 13C NMR (600 MHz)
18.5 (CH3–CH), 33.4 (CH2), 40.1 (CH3–N), 51.2 (CH–CH3), 58.9 (CH-
4), 59.2 (CH-3), 112.0 (CH-3 and CH-5 Ar), 125.8 (Cquat), 126.1 (CH
Ar), 126.3 (CH Ar), 126.9 (CH Ar), 127.5 (CH Ar), 127.8 (CH Ar), 128.2
(CH Ar),128.2 (CH Ar),129.0 (CH Ar), 137.8 (Cquat), 141.5 (Cquat), 150.2
3.3.3. 3-Benzyl-4-(3,4-dimethoxyphenyl)-1-(((1S,2S,3S,5R)-2,6,6-tri-
methylbicyclo[3.1.1]heptan-3-yl)methyl)azetidin-2-one 5. IR 755,
1028, 1139, 1162, 1239, 1263, 1454, 1465, 1517, 1594, 1605, 1748,
2837, 2871, 2907, 2935, 3026, 3062, 3484; MS m/z 447; HRMS (EI):
calcd for C29H37NO3 (Mþ): 447.2773, found: 447.2748.
3.3.3.1. Isomer 5a. Rf 0.12 (ether:hexane 1:1); colourless oil; 1H
NMR (600 MHz)0.55(d,1H, J 9.8,1⁄2 CH2-7 Pin), 0.84(s, 3H, CH3), 0.94
(d, 3H,J7.2, CH3-2Pin),1.09(s, 3H, CH3),1.24(ddd,1H, J2.6,5.9,13.4,1⁄2
CH2-4 Pin), 1.57 (dtd, 1H, J 1.9, 7.1, 14.2, CH-3 Pin), 1.64 (m, 1H, CH-2
Pin),1.70 (m,1H, CH-1Pin),1.68(m,1H, CH-5 Pin),1.57(m,1H,1⁄2 CH2-
4 Pin), 2.16 (m,1H, 1⁄2 CH2-7 Pin), 2.49 (dd, 1H, J 8.3,13.8, 1⁄2 CH2-N),
2.98 (dd,1H, J 9.0,14.4, 1⁄2 CH2), 3.14 (dd,1H, J 4.9,14.6, 1⁄2 CH2), 3.19
(m, 1H, CH-3), 3.86 (dd, 1H, J 6.0, 13.9, 1⁄2 CH2-N), 3.72 (s, 3H, OCH3),
3.80 (s, 3H, OCH3), 4.21 (d, 1H, J 1.9, CH-4), 6.74 (d, 1H, J 8.2, CH-5 Ar),
6.65 (d,1H, J 2.0, 8.2, CH-6 Ar), 6.46 (d,1H, J 2.0, CH-2 Ar), 7.19 (tt,1H, J
1.4, 7.1, CH-4 Ph), 7.23 (dt, 2H, J 1.6, 6.7, CH-2and CH-6Ph), 7.28 (td, 2H,
J 1.4, 7.1, CH-3and CH-5Ph);13C NMR (600 MHz)21.7(CH3-2 Pin), 22.9
(Cquat), 170.0 (C]O); [
a
]
D þ18.6ꢀ (c 1, CHCl3).
3.3.5. 3-Benzyl-4-(4-(dimethylamino)phenyl)-1-((R)-1-phenyl-
ethyl)azetidin-2-one 7. MS m/z 384; HRMS (EI): calcd for C26H28N2O
(Mþ): 384.2202, found: 384.2184.
3.3.5.1. (3S,4R)-7. Rf 0.27 (ether:hexane 1:1), 0.40 (ether:hexane
1:1, two times developed plates); colourless oil; IR 701, 755, 1349,
1454, 1496, 1519, 1612, 1677, 1742, 2933, 3007, 3028, 3062, 3334; 1H

A.R. Todorov et al. / Tetrahedron 65 (2009) 10339–10347
10345
NMR (600 MHz) 1.71 (d, 3H, J 7.2, CH3–CH), 2.93 (s, 6H, 2ꢂCH3–N),
3.05 (m, 2H, CH2), 3.27 (ddd, 1H, J 2.1, 5.3, 7.4, CH-3), 3.93 (d, 1H, J 2.1,
CH-4), 4.09(q,1H, J 7.2,14.3, CH–CH3), 6.62(d, 2H, J 8.7, CH-3and CH-5
Ar), 6.94 (m, 2H, CH Ph), 6.95 (d, 2H, J 8.7, CH-2 and CH-6 Ar), 7.19 (m,
6H, CH Ph), 7.26 (m, 2H, CH Ph); 13C NMR (600 MHz) 20.4 (CH3–CH),
33.6 (CH2), 40.2 (CH3–N), 54.2 (CH–CH3), 58.6 (CH-4), 59.4 (CH-3),
112.2 (CH-3 and CH-5 Ar), 124.6 (Cquat), 126.2 (CH Ar), 126.3 (CH Ar),
126.9 (CH Ar),127.4(CH Ar),127.8(CH Ar),128.2(CH Ar),128.2 (CH Ar),
1028,1138,1163,1238,1264,1311,1422,1454,1464,1496,1517,1594,
1605, 1745, 2836, 2934, 3001, 3028, 3062, 3085, 3471; 1H NMR
(600 MHz) 1.68 (d, 3H, J 7.2, CH3–CH), 3.01 (dd, 1H, J 8.4, 14.6, 1⁄2
CH2), 3.13 (dd,1H, J 5.1,14.6, 1⁄2 CH2), 3.25 (ddd,1H, J 2.1, 5.1, 7.8, CH-
3), 3.66 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.02 (d,1H, J 2.1, CH-4), 4.30
(q, 1H, J 7.2, 14.3, CH-CH3), 6.37 (d, 1H, J 2.0, CH-2 Ar), 6.62 (dd, 1H, J
2.0, 8.2, CH-6 Ar), 6.74 (d,1H, J 8.2, CH-5 Ar), 6.99 (dd, 2H, J 2.0, 7.8, CH
Ph), 7.21 (m, 6H, CH Ph), 7.28 (m, 2H, CH Ph); 13C NMR (600 MHz)
19.8 (CH3–CH), 33.8 (CH2), 53.9 (CH–CH3), 55.5 (OCH3), 55.7 (OCH3),
58.8 (CH-4), 59.8 (CH-3),108.8 (CH-2 Ar),110.8 (CH-5 Ar),118.7 (CH-6
Ar), 126.4 (CH Ph), 126.6 (CH Ph), 127.2 (CH Ph), 128.3 (CH Ph), 128.4
(CH Ph), 129.1 (CH Ph), 130.2 (Cquat), 137.7 (Cquat), 141.2 (Cquat), 148.6
(Cquat-OCH3), 149.0 (Cquat-OCH3), 169.6 (C]O).
129.0 (CHAr),137.8(Cquat),141.5(Cquat),150.2(Cquat),169.6(C]O);[
a]
D
þ21.8ꢀ (c 1, CHCl3).
3.3.5.2. (3R,4S)-7. Rf 0.21 (ether:hexane 1:1), 0.32 (ether:hexane
1:1, two times developed plates); white crystals (hexane); mp 105–
106 ꢀC; IR 700, 755, 1351, 1454, 1496, 1520, 1610, 1675, 1737, 2807,
2933, 2979, 3005, 3028, 3062, 3086, 3325; 1H NMR (600 MHz) 1.23
(d, 3H, J 7.2, CH3–CH), 2.94 (s, 6H, 2ꢂCH3–N), 3.02 (m, 2H, CH2), 3.29
(ddd,1H, J 2.1, 5.3, 7.4, and CH-5 Ar), 6.94 (m, 2H, CH Ph), 6.95 (d, 2H, J
8.7, CH-2 and CH-6 Ar), 7.19 (m, 6H, CH Ph), 7.26 (m, 2H, CH Ph); 13C
NMR (600 MHz) 18.5 (CH3–CH), 33.4 (CH2), 40.1 (CH3–N), 51.2 (CH–
CH3), 58.9 (CH-4), 59.2 (CH-3), 112.0 (CH-3 and CH-5 Ar), 125.8
(Cquat),126.1 (CH Ar),126.3 (CH Ar),126.9 (CH Ar),127.5 (CH Ar),127.8
(CH Ar),128.2 (CH Ar),128.2 (CH Ar),129.0 (CH Ar),137.8 (Cquat),141.5
3.3.7.2. (3R,4S)-9. Rf 0.10 (ether:hexane 1:1), 0.18 (ether:hexane
1:1, two times developed plates); colourless oil; IR 700, 735, 759,
1028, 1139, 1162, 1238, 1264, 1314, 1377, 1422, 1454, 1464, 1496,
1518, 1594, 1605, 1745, 2836, 2852, 2934, 2956, 3029, 3062, 3086,
3469; 1H NMR (600 MHz) 1.33 (d, 3H, J 7.2, CH3–CH), 2.93 (dd, 1H, J
8.3, 14.7, 1⁄2 CH2), 3.07 (dd, 1H, J 5.3, 14.7, 1⁄2 CH2), 3.27 (ddd, 1H, J
2.1, 5.3, 7.8, CH-3), 3.69 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.96 (d, 1H,
J 2.1, CH-4), 4.84 (q, 1H, J 7.2, 14.3, CH-CH3), 6.54 (d, 1H, J 2.0, CH-2
Ar), 6.64 (dd, 1H, J 2.0, 8.2, CH-6 Ar), 6.74 (d, 1H, J 8.2, CH-5 Ar), 7.07
(dd, 2H, J 2.0, 7.8, CH Ph), 7.14 (d, 2H, J 7.1, CH Ph), 7.21 (m, 6H, CH
Ph); 13C NMR (600 MHz) 19.0 (CH3–CH), 33.9 (CH2), 52.4 (CH–CH3),
55.7 (OCH3), 55.8 (OCH3), 59.6 (CH-4), 59.9 (CH-3), 109.1 (CH-2 Ar),
111.0 (CH-5 Ar), 119.2 (CH-6 Ar), 126.4 (CH Ph), 126.6 (CH Ph), 127.1
(CH Ph), 128.3 (CH Ph), 128.4 (CH Ph), 129.0 (CH Ph), 130.2 (Cquat),
137.7 (Cquat), 141.2 (Cquat), 148.6 (Cquat-OCH3), 149.0 (Cquat-OCH3),
169.8 (C]O).
(Cquat), 150.2 (Cquat), 170.0 (C]O); [
a]
D ꢁ20.9ꢀ (c 1, CHCl3).
3.3.6. 3-Benzyl-4-(3,4-dimethoxyphenyl)-1-((S)-1-phenyl-
ethyl)azetidin-2-one 8. MS m/z 401; HRMS (EI): calcd for C26H27NO3
(Mþ): 401.1991, found: 401.1986.
3.3.6.1. (3R,4S)-8. Rf 0.11 (ether:hexane 1:1), 0.23 (ether:hexane
1:1, two times developed plates); colourless oil; IR 701, 760, 1028,
1138, 1163, 1238, 1264, 1311,1374, 1422, 1454,1464,1496, 1517,1593,
1605,1745, 2836, 2934, 3028, 3062, 3469, 3593; 1H NMR (600 MHz)
1.68 (d, 3H, J 7.2, CH3–CH), 3.01 (dd, 1H, J 8.4, 14.6, 1⁄2 CH2), 3.13 (dd,
1H, J 5.1,14.6, 1⁄2 CH2), 3.25 (ddd,1H, J 2.0, 5.1, 7.8, CH-3), 3.66 (s, 3H,
OCH3), 3.84 (s, 3H, OCH3), 4.02 (d, 1H, J 2.1, CH-4), 4.30 (q, 1H, J 7.2,
14.3, CH–CH3), 6.37 (d,1H, J 2.0, CH-2 Ar), 6.62 (dd,1H, J 2.0, 8.2, CH-6
Ar), 6.74 (d,1H, J 8.2, CH-5 Ar), 6.99 (dd, 2H, J 2.0, 7.8, CH Ph), 7.21 (m,
6H, CH Ph), 7.28 (m, 2H, CH Ph); 13C NMR (600 MHz) 19.8 (CH3–CH),
33.8 (CH2), 53.9 (CH–CH3), 55.5 (OCH3), 55.7 (OCH3), 58.8 (CH-4),
59.8 (CH-3), 108.8 (CH-2 Ar), 110.8 (CH-5 Ar), 118.7 (CH-6 Ar), 126.4
(CH Ph), 126.6 (CH Ph), 127.2 (CH Ph), 128.3 (CH Ph), 128.4 (CH Ph),
3.3.8. 3-Benzyl-4-(2,4,6-trimethoxyphenyl)-1-((S)-1-phenyl-
ethyl)azetidin-2-one 10. MS m/z 431; HRMS (EI): calcd for
C27H29NO4 (Mþ): 431.2097, found: 431.2081.
3.3.8.1. (3R,4S)-10. Rf 0.36 (ether:hexane 4:1); mp 64–65 ꢀC; IR
700, 815, 918, 953, 1036, 1120, 1153, 1204, 1227, 1325, 1453, 1495,
1590, 1606, 1731, 2841, 2938, 2970, 3001, 3026, 3060, 3085, 3447;
1H NMR (600 MHz) 1.53 (d, 3H, J 7.1, CH3–CH), 3.01 (A part of ABX,
dd, 1H, J 8.2, 14.5, 1⁄2 CH2), 3.07 (B part of ABX, dd, 1H, J 5.1, 14.5, 1⁄2
CH2), 3.58 (s, 6H, OCH3-2 and OCH3-6 Ar), 3.66 (ddd, 1H, J 2.2, 5.1,
8.2, CH-3), 3.77 (s, 3H, OCH3-4 Ar), 4.32 (q, 1H, J 7.1, 14.2, CH-CH3),
4.82 (d, 1H, J 2.2, CH-4), 5.94 (s, 2H, CH-3 and CH-5 Ar), 6.90 (m, 2H,
CH Ph), 7.10 (m, 3H, CH Ph), 7.18 (m, 1H, CH Ph), 7.23 (m, 4H, CH Ph);
13C NMR (600 MHz) 19.0 (CH3–CH), 34.6 (CH2), 50.4 (CH-4), 52.8
(CH-CH3), 54.8 (CH-3), 55.3 (OCH3-4), 55.4 (OCH3-2 and OCH3-6),
90.4 (CH-3 and CH-5 Ar), 104.5 (Cquat-1 Ar), 126.1 (CH Ph), 126.7 (CH
Ph), 126.8 (2 CH Ph), 127.9 (2 CH Ph), 128.2 (2 CH Ph), 129.2 (2 CH
Ph), 138.9 (Cquat Ph), 141.3 (Cquat Ph), 160.2 (Cquat-2 and Cquat-6 Ar),
129.1 (CH Ph), 130.2 (Cquat), 137.7 (Cquat), 141.2 (Cquat), 148.6 (Cquat
-
OCH3), 149.0 (Cquat-OCH3), 169.6 (C]O); [
a]
D ꢁ34.6ꢀ (c 1, CHCl3).
3.3.6.2. (3S,4R)-8. Rf 0.10 (ether:hexane 1:1), 0.18 (ether:hexane
1:1, two times developed plates); colourless oil; IR 700, 731, 759,
913, 1028, 1139, 1162, 1238, 1264, 1314, 1376, 1422, 1454, 1464, 1496,
1518, 1594, 1605, 1744, 2836, 2934, 2975, 3002, 3028, 3062, 3086,
3360, 3469; 1H NMR (600 MHz) 1.33 (d, 3H, J 7.2, CH3–CH), 2.93 (dd,
1H, J 8.3, 14.7, 1⁄2 CH2), 3.07 (dd, 1H, J 5.3, 14.7, 1⁄2 CH2), 3.27 (ddd,
1H, J 2.1, 5.3, 7.8, CH-3), 3.69 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.96
(d, 1H, J 2.1, CH-4), 4.84 (q, 1H, J 7.2, 14.3, CH–CH3), 6.54 (d, 1H, J 2.0,
CH-2 Ar), 6.64 (dd, 1H, J 2.0, 8.2, CH-6 Ar), 6.74 (d,1H, J 8.2, CH-5 Ar),
7.07 (dd, 2H, J 2.0, 7.8, CH Ph), 7.14 (d, 2H, J 7.1, CH Ph), 7.21 (m, 6H,
CH Ph); 13C NMR (600 MHz) 19.0 (CH3–CH), 33.9 (CH2), 52.4 (CH–
CH3), 55.7 (OCH3), 55.8 (OCH3), 59.6 (CH-4), 59.9 (CH-3), 109.1 (CH-
2 Ar), 111.0 (CH-5 Ar), 119.2 (CH-6 Ar), 126.4 (CH Ph), 126.6 (CH Ph),
127.1 (CH Ph), 128.3 (CH Ph), 128.4 (CH Ph), 129.0 (CH Ph), 130.2
161.1 (Cquat-4 Ar), 170.3 (C]O); [
a]
þ2.7ꢀ (c 1, CHCl3).
D
3.3.8.2. (3S,4R)-10. Rf 0.28 (ether:hexane 4:1); colourless oil; IR
700, 732, 818, 912, 953, 1040, 1061, 1124, 1155, 1206, 1229, 1328,
1393, 1421, 1438, 1454, 1467, 1496, 1590, 1607, 1734, 2841, 2936,
3028, 3062, 3086, 3458; 1H NMR (600 MHz) 1.21 (d, 3H, J 7.1,
CH3–CH), 2.93 (A part of ABX, dd, 1H, J 8.3, 14.6, 1⁄2 CH2), 3.01 (B
part of ABX, dd, 1H, J 5.0, 14.6, 1⁄2 CH2), 3.64 (s, 6H, OCH3-2 and
OCH3-6 Ar), 3.72 (ddd, 1H, J 2.2, 5.0, 8.3, CH-3), 3.79 (s, 3H, OCH3-4
Ar), 4.76 (d, 1H, J 2.2, CH-4), 4.80 (q, 1H, J 7.1, 14.2, CH–CH3), 6.02 (s,
2H, CH-3 and CH-5 Ar), 6.98 (m, 2H, CH Ph), 7.15 (m, 3H, CH Ph), 7.20
(m, 5H, CH Ph); 13C NMR (600 MHz) 17.6 (CH3–CH), 34.4 (CH2), 50.7
(CH-4), 51.3 (CH–CH3), 54.7 (CH-3), 55.2 (OCH3-4), 55.4 (OCH3-2
and OCH3-6), 90.4 (CH-3 and CH-5 Ar), 105.6 (Cquat-1 Ar), 126.1 (CH
Ph), 127.0 (CH Ph), 127.2 (2 CH Ph), 128.1 (2 CH Ph), 128.2 (2 CH Ph),
129.1 (2 CH Ph), 138.8 (Cquat Ph), 140.4 (Cquat Ph), 160.2 (Cquat-2 and
(Cquat), 137.7 (Cquat), 141.2 (Cquat), 148.6 (Cquat-OCH3), 149.0 (Cquat
-
OCH3), 169.8 (C]O); [
a]
þ27.4ꢀ (c 1, CHCl3).
D
3.3.7. 3-Benzyl-4-(3,4-dimethoxyphenyl)-1-((R)-1-phenyl-
ethyl)azetidin-2-one 9. MS m/z 401; HRMS (EI): calcd for C26H27NO3
(Mþ): 401.1991, found: 401.1985.
3.3.7.1. (3S,4R)-9. Rf 0.11 (ether:hexane 1:1), 0.23 (ether:hexane
1:1, two times developed plates); colourless oil; IR 701, 734, 759,
Cquat-6 Ar), 161.2 (Cquat-4 Ar), 170.2 (C]O); [
a
]
D
ꢁ4.1ꢀ (c 1, CHCl3).

10346
A.R. Todorov et al. / Tetrahedron 65 (2009) 10339–10347
3.3.9. 3-Benzyl-4-(2,4,6-trimethoxyphenyl)-1-((R)-1-phenyl-
ethyl)azetidin-2-one 11. MS m/z 431; HRMS (EI): calcd for C27H29NO4
(M+): 431.2097, found: 431.2091.
(CH3–CH), 30.6 (CH2-Ph ester), 33.1 (CH2-Ph), 35.1 (CH2–CO), 51.7
(CH–CH3), 51.8 (CH-4), 55.9 (OCH3), 59.5 (CH-3), 111.5 (CH-Ar), 118.9
(CH-Ar), 126.4 (CH-Ar), 126.6 (CH-Ar), 126.7 (CH-Ar), 127.1 (2ꢂCH-
Ar), 127.3 (CH-Ar), 128.3 (2ꢂCH-Ar), 128.4 (2ꢂCH-Ar), 128.45
(2ꢂCH-Ar), 128.6 (2ꢂCH-Ar), 129.3 (2ꢂCH-Ar), 132.4 (Cquat), 137.3
(Cquat), 138.0 (Cquat), 139.8 (Cquat), 140.1 (Cquat), 151.1 (Cquat), 169.8
3.3.9.1. (3S,4R)-11. Rf 0.36 (ether:hexane 4:1); mp 64–65 ꢀC; IR
700, 817, 952, 1039, 1061, 1122, 1155, 1206, 1229, 1327, 1421, 1454,
1467, 1496, 1591, 1607, 1735, 2840, 2938, 2972, 3028, 3062, 3086,
3468; 1H NMR (600 MHz) 1.53 (d, 3H, J 7.1, CH3–CH), 3.01 (A part of
ABX, dd, 1H, J 8.2, 14.5, 1⁄2 CH2), 3.07 (B part of ABX, dd, 1H, J 5.1,
14.5, 1⁄2 CH2), 3.58 (s, 6H, OCH3-2 and OCH3-6 Ar), 3.66 (ddd, 1H, J
2.2, 5.1, 8.2, CH-3), 3.77 (s, 3H, OCH3-4 Ar), 4.32 (q,1H, J 7.1,14.2, CH–
CH3), 4.82 (d, 1H, J 2.2, CH-4), 5.94 (s, 2H, CH-3 and CH-5 Ar), 6.90
(m, 2H, CH Ph), 7.10 (m, 3H, CH Ph), 7.18 (m, 1H, CH Ph), 7.23 (m, 4H,
CH Ph); 13C NMR (600 MHz) 19.0 (CH3–CH), 34.6 (CH2), 50.4 (CH-4),
52.8 (CH–CH3), 54.8 (CH-3), 55.3 (OCH3-4), 55.4 (OCH3-2 and OCH3-
6), 90.4 (CH-3 and CH-5 Ar), 104.5 (Cquat-1 Ar), 126.1 (CH Ph), 126.7
(CH Ph), 126.8 (2 CH Ph), 127.9 (2 CH Ph), 128.2 (2 CH Ph), 129.2 (2
CH Ph), 138.9 (Cquat Ph), 141.3 (Cquat Ph), 160.2 (Cquat-2 and Cquat-6
(C]O), 170.3 (C]O); [
a]
ꢁ11.1ꢀ (c 1, CHCl3).
D
3.3.11. 3-Benzyl-4-(2-(2-phenylethylcarbonyloxy)-3-methoxy-
phenyl)-1-((R)-1-phenylethyl)azetidin-2-one 13. MS m/z 519; HRMS
(EI): calcd for C34H33NO4 (Mþ): 519.2410, found: 519.2408.
3.3.11.1. (3S,4R)-13. Rf 0.22 (ether:hexane 1:1), 0.35 (ether:-
hexane 1:1, two times developed plates); colourless oil; IR 700, 765,
1126, 1276, 1310, 1441, 1454, 1481, 12,937, 2979, 3005, 3028, 3062,
3086, 3504; 1H NMR (600 MHz) 1.61 (d, 3H, J 7.1, CH3–CH), 2.80 (t,
2H, J 7.7, CH2–CO), 2.90 (dd, 1H, J 5.4, 14.6, 1⁄2 CH2), 2.95 (t, 2H, J 7.6,
CH2-Ph ester), 3.04 (dd,1H, J 6.1,14.6, 1⁄2 CH2), 3.36 (td,1H, J 2.1, 6.0,
CH-3), 3.72 (s, 3H, OCH3), 4.05 (d, 1H, J 2.2, CH-4), 4.08 (q, 1H, J 7.1,
14.2, CH–CH3), 6.74 (dd, 1H, J 1.2, 7.8, CH Ar), 6.86 (m, 3H, Ar), 7.07–
7.33 (m, 14H, Ph); 13C NMR (600 MHz) 20.3 (CH3–CH), 30.6 (CH2-Ph
ester), 33.3 (CH2-Ph), 35.1 (CH2–CO), 52.5 (CH-4), 54.9 (CH–CH3),
55.9 (OCH3), 58.8 (CH-3), 111.7 (CH-Ar), 118.9 (CH-Ar), 126.3 (CH-
Ar), 126.55 (CH-Ar), 126.6 (2ꢂCH-Ar), 126.7 (CH-Ar), 127.2 (CH-Ar),
128.3 (2ꢂCH-Ar), 128.4 (2ꢂCH-Ar), 128.45 (2ꢂCH-Ar), 128.5
(2ꢂCH-Ar),129.5 (2ꢂCH-Ar),130.9 (Cquat),137.4 (Cquat),138.4 (Cquat),
140.2 (Cquat), 141.1 (Cquat), 151.2 (Cquat), 169.5 (C]O), 170.5 (C]O);
Ar), 161.1 (Cquat-4 Ar), 170.3 (C]O); [
a
]
D
ꢁ0.1ꢀ (c 1, CHCl3).
3.3.9.2. (3R,4S)-11. Rf 0.28 (ether:hexane 4:1); colourless oil; IR
700, 818, 953, 1124, 1155, 1206, 1230, 1422, 1454, 1467, 1496, 1591,
1607, 1735, 2841, 2937, 2974, 3028, 3062, 3460; 1H NMR
(600 MHz) 1.21 (d, 3H, J 7.1, CH3–CH), 2.93 (A part of ABX, dd, 1H, J
8.3, 14.6, 1⁄2 CH2), 3.01 (B part of ABX, dd, 1H, J 5.0, 14.6, 1⁄2 CH2),
3.64 (s, 6H, OCH3-2 and OCH3-6 Ar), 3.72 (ddd, 1H, J 2.2, 5.0, 8.3,
CH-3), 3.79 (s, 3H, OCH3-4 Ar), 4.76 (d, 1H, J 2.2, CH-4), 4.80 (q, 1H,
J 7.1, 14.2, CH–CH3), 6.02 (s, 2H, CH-3 and CH-5 Ar), 6.98 (m, 2H, CH
Ph), 7.15 (m, 3H, CH Ph), 7.20 (m, 5H, CH Ph); 13C NMR (600 MHz)
17.6 (CH3–CH), 34.4 (CH2), 50.7 (CH-4), 51.3 (CH-CH3), 54.7 (CH-3),
55.2 (OCH3-4), 55.4 (OCH3-2 and OCH3-6), 90.4 (CH-3 and CH-5
Ar), 105.6 (Cquat-1 Ar), 126.1 (CH Ph), 127.0 (CH Ph), 127.2 (2 CH Ph),
128.1 (2 CH Ph), 128.2 (2 CH Ph), 129.1 (2 CH Ph), 138.8 (Cquat Ph),
140.4 (Cquat Ph), 160.2 (Cquat-2 and Cquat-6 Ar), 161.2 (Cquat-4 Ar),
[a
]
D ꢁ31.1ꢀ (c 1, CHCl3).
3.3.11.2. (3R,4S)-13. Rf 0.18 (ether:hexane 1:1), 0.27 (ether:
hexane 1:1, two times developed plates); colourless oil; IR 700, 753,
1078,1126, 1170,1275,1310,1379,1441,1454,1481,1496,1587,1605,
1748, 2841, 2934, 2977, 3029, 3062, 3087, 3486; 1H NMR (600 MHz)
1.19 (d, 3H, J 7.1, CH3–CH), 2.76 (t, 2H, J 7.8, CH2–CO), 2.85 (dd, 1H, J
5.5, 14.6, 1⁄2 CH2), 2.96 (m, 3H, 1⁄2 CH2 and CH2-Ph ester), 3.32 (td,
1H, J 2.2, 5.8, CH-3), 3.74 (s, 3H, OCH3), 4.11 (d, 1H, J 2.2, CH-4), 4.86
(q, 1H, J 7.2, 14.3, CH–CH3), 6.86 (dd, 1H, J 1.3, 8.1, CH Ar), 6.97 (m,
3H, Ar), 7.08–7.36 (m, 14H, Ph); 13C NMR (600 MHz) 18.2 (CH3–CH),
30.6 (CH2-Ph ester), 33.1 (CH2-Ph), 35.1 (CH2–CO), 51.7 (CH–CH3),
51.8 (CH-4), 55.9 (OCH3), 59.5 (CH-3), 111.5 (CH-Ar), 118.9 (CH-Ar),
126.4 (CH-Ar), 126.6 (CH-Ar), 126.7 (CH-Ar), 127.1 (2ꢂCH-Ar), 127.3
(CH-Ar), 128.3 (2ꢂCH-Ar), 128.4 (2ꢂCH-Ar), 128.45 (2ꢂCH-Ar),
128.6 (2ꢂCH-Ar), 129.3 (2ꢂCH-Ar), 132.4 (Cquat), 137.3 (Cquat), 138.0
(Cquat), 139.8 (Cquat), 140.1 (Cquat), 151.1 (Cquat), 169.8 (C]O), 170.3
170.2 (C]O); [
a
]
þ0.3ꢀ (c 1, CHCl3).
D
3.3.10. 3-Benzyl-4-(2-(2-phenylethylcarbonyloxy)-3-methoxy-
phenyl)-1-((S)-1-phenylethyl)azetidin-2-one 12. MS m/z 519; HRMS
(EI): calcd for C34H33NO4 (Mþ): 519.2410, found: 519.2404.
3.3.10.1. (3R,4S)-12. Rf 0.22 (ether:hexane 1:1), 0.35 (ether:-
hexane 1:1, two times developed plates); colourless oil; IR 700, 754,
1125, 1171, 1276, 1310, 1441, 1454,1481, 1496, 1587, 1606, 1746, 2840,
2937, 3028, 3062, 3086, 3481; 1H NMR (600 MHz) 1.61 (d, 3H, J 7.1,
CH3–CH), 2.80 (t, 2H, J 7.7, CH2–CO), 2.90 (dd,1H, J 5.4,14.6, 1⁄2 CH2),
2.95 (t, 2H, J 7.6, CH2-Ph ester), 3.04 (dd, 1H, J 6.1, 14.6, 1⁄2 CH2), 3.36
(td, 1H, J 2.1, 6.0, CH-3), 3.72 (s, 3H, OCH3), 4.05 (d, 1H, J 2.2, CH-4),
4.08 (q, 1H, J 7.1, 14.2, CH-CH3), 6.74 (dd, 1H, J 1.2, 7.8, CH Ar), 6.86
(m, 3H, Ar), 7.07–7.33 (m, 14H, Ph); 13C NMR (600 MHz) 20.3 (CH3–
CH), 30.6 (CH2-Ph ester), 33.3 (CH2-Ph), 35.1 (CH2–CO), 52.5 (CH-4),
54.9 (CH-CH3), 55.9 (OCH3), 58.8 (CH-3), 111.7 (CH-Ar), 118.9 (CH-
Ar), 126.3 (CH-Ar), 126.55 (CH-Ar), 126.6 (2ꢂCH-Ar), 126.7 (CH-Ar),
127.2 (CH-Ar), 128.3 (2ꢂCH-Ar), 128.4 (2ꢂCH-Ar), 128.45 (2ꢂCH-
Ar), 128.5 (2ꢂCH-Ar), 129.5 (2ꢂCH-Ar), 130.9 (Cquat), 137.4 (Cquat),
138.4 (Cquat), 140.2 (Cquat), 141.1 (Cquat), 151.2 (Cquat), 169.5 (C]O),
(C]O); [
a]
þ10.0ꢀ (c 1, CHCl3).
D
3.4. X-ray crystallographic investigations
Colourless prism-shaped crystals
of
dimensions
0.32ꢂ0.12ꢂ0.03 mm or 0.56ꢂ0.34ꢂ0.12 mm were selected for
structural analysis of (3S,4R)-6 and (3R,4S)-7, respectively. Intensity
data for this compound were collected using a diffractometer with
a Bruker APEX ccd area detector32 and graphite-monochromated Mo
K
a
radiation (
parameters were determined from a non-linear least squares fit of
3859 or 4702 peaks in the range 2.64<
<27.77ꢀ or 2.21< <27.89ꢀ. A
total of 9167 or 9859datawere measured in the range 1.89<
<26.00ꢀ
using oscillation frames. The data were corrected for absorption by
l
¼0.71073 Å). The samples were cooled to 100(2) K. Cell
170.5 (C]O); [
a]
þ27.6ꢀ (c 1, CHCl3).
q
q
D
q
3.3.10.2. (3S,4R)-12. Rf 0.18 (ether:hexane 1:1), 0.27 (ether:
hexane 1:1, two times developed plates); colourless oil; IR 699, 748,
770, 1078, 1125, 1170, 1275, 1310, 1378, 1441, 1454, 1481, 1496, 1587,
1605, 1747, 2850, 2931, 3004, 3029, 3062, 3087, 3487; 1H NMR
(600 MHz) 1.19 (d, 3H, J 7.1, CH3–CH), 2.76 (t, 2H, J 7.8, CH2–CO), 2.85
(dd, 1H, J 5.5, 14.6, 1⁄2 CH2), 2.96 (m, 3H, 1⁄2 CH2 and CH2-Ph ester),
3.32 (td, 1H, J 2.2, 5.8, CH-3), 3.74 (s, 3H, OCH3), 4.11 (d, 1H, J 2.2, CH-
4), 4.86 (q, 1H, J 7.2, 14.3, CH–CH3), 6.86 (dd, 1H, J 1.3, 8.1, CH Ar),
6.97 (m, 3H, Ar), 7.08–7.36 (m, 14H, Ph); 13C NMR (600 MHz) 18.2
u
the semi-empirical method33 giving minimum and maximum
transmission factors of 0.973 and 0.996 or 0.956 and 0.992. The data
were merged to form a set of 4058 or 4120 independent data with
R(int)¼0.0329 or 0.0350 and a coverage of 99.8% or 99.9%.
The orthorhombic space group P212121 was determined for both
compounds by systematic absences and statistical tests and verified
by subsequent refinement. The structures were solved by direct
methods and refined by full-matrix least squares methods on F2.34

A.R. Todorov et al. / Tetrahedron 65 (2009) 10339–10347
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10347
Hydrogen atom positions were initially determined by geometry
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with anisotropic displacement parameters. Hydrogen atom dis-
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displacement parameters of the bonded atoms. A total of 262 pa-
rameters were refined for both samples against 4058 or 4120 data
to give wR(F2)¼0.0989 or 0.1045 and S¼1.007 or 1.004 for weights
of w¼1/[s2 (F2)þ(0.0460 P)2þ0.3000 P] or w¼1/[s2 (F2)þ(0.0500
P)2þ0.4000 P], where P¼[Fo2þ2F2c]/3. The final R(F) was 0.0434 for
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was 0.000 in the final refinement cycles. The final difference map
had maxima and minima of 0.177 or 0.210 and ꢁ0.209 e/Å3 or
ꢁ0.169 e/Å3, respectively.
Full crystallographic data for this paper in cif-format can be
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The financial support by the National Research Fund of Bulgaria
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framework of the Program ‘Promotion of the Research Potential
through Unique Scientific Equipment’, Project UNA-17/2005, is
gratefully acknowledged.
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