Asymmetric synthesis of 4-formyl-1-(ω-haloalkyl)-β-lactams and their transformation to functionalized piperazines and 1,4-diazepanes

Article abstract of DOI:10.1016/j.tet.2011.09.136

Chiral piperazine and 1,4-diazepane annulated β-lactams, prepared from the corresponding (3R,4S)-4-imidoyl-1-(ω-haloalkyl)azetidin-2-ones through reduction with sodium borohydride in ethanol, were transformed into novel methyl (R)-alkoxy-[(S)-piperazin-2-yl]acetates and methyl (R)-alkoxy-[(S)-1,4-diazepan-2-yl]acetates upon treatment with hydrogen chloride in methanol. On the other hand, bromination of (3R,4R)-1-allyl-4-formyl-β- lactams and (3R,4S)-1-allyl-4-imidoyl-β-lactams in dichloromethane, followed by sodium borohydride reduction of the resulting dibrominated azetidin-2-ones in ethanol, did not afford the envisaged bicyclic β-lactams but unexpectedly furnished (3R,4S)-1-(2-bromo-2-propenyl)azetidin-2-ones instead.

Full text of DOI:10.1016/j.tet.2011.09.136

Tetrahedron 68 (2012) 10827e10834
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric synthesis of 4-formyl-1-(u-haloalkyl)-b-lactams
and their transformation to functionalized piperazines
and 1,4-diazepanes
y
*
Stijn Dekeukeleire , Matthias D’hooghe , Matthieu Vanwalleghem, Willem Van Brabandt,
Norbert De Kimpe
*
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 May 2011
Received in revised form 21 September 2011
Accepted 29 September 2011
Available online 6 October 2011
Chiral piperazine and 1,4-diazepane annulated b-lactams, prepared from the corresponding (3R,4S)-4-
imidoyl-1-(u-haloalkyl)azetidin-2-ones through reduction with sodium borohydride in ethanol, were
transformed into novel methyl (R)-alkoxy-[(S)-piperazin-2-yl]acetates and methyl (R)-alkoxy-[(S)-1,4-
diazepan-2-yl]acetates upon treatment with hydrogen chloride in methanol. On the other hand, bro-
mination of (3R,4R)-1-allyl-4-formyl-b-lactams and (3R,4S)-1-allyl-4-imidoyl-b-lactams in dichloro-
methane, followed by sodium borohydride reduction of the resulting dibrominated azetidin-2-ones in
Keywords:
ethanol, did not afford the envisaged bicyclic
2-propenyl)azetidin-2-ones instead.
b
-lactams but unexpectedly furnished (3R,4S)-1-(2-bromo-
Ó 2011 Elsevier Ltd. All rights reserved.
b
-Lactams
Piperazines
Diazepanes
Vinyl bromides
Asymmetric synthesis
1. Introduction
In this paper, an efficient and straightforward approach toward
chiral methyl (piperazin-2-yl)acetates and methyl (1,4-diazepan-2-
yl)acetates is disclosed starting from 1,4-diazabicyclo[4.2.0]octan-
8-ones and 1,5-diazabicyclo[5.2.0]nonan-9-ones via ring opening
using a saturated solution of HCl in MeOH. Furthermore, an attempt
Piperazine and 1,4-diazepane chemistry is of significant phar-
maceutical importance because of the occurrence of these scaffolds
in a large number of biologically active compounds useful in dif-
ferent therapeutical areas.1 Hence, the search for new, functional-
ized piperazines and 1,4-diazepanes remains a relevant issue in
to extend this approach toward the use of 1-allyl-
b-lactams as
starting compounds is described, albeit resulting in the unexpected
medicinal chemistry. Furthermore, as
b
-amino acids and their de-
synthesis of 1-(2-bromo-2-propenyl)-
and subsequent NaBH4 reduction.
b
-lactams upon bromination
rivatives undergo little or no degradation by peptidases and thus
exhibit a potential biological activity,2 the preparation of optically
active piperazines and 1,4-diazepanes 1 and 2 comprises a valuable
entry toward new drug compounds. In that respect, the preparation
of a chiral (piperazin-2-yl)acetate as an intermediate in the syn-
thesis of a renin inhibitor via a diastereoselective Dieckmann cy-
clization has been described recently.3
2
R
O
R2
N
O
N
RO
N
RO
N
R1
R1
1
2
From a synthetic point of view, the use of chiral piperazine and
1,4-diazepane annulated
of the target compounds 1 and 2 as azetidin-2-ones are known to
be excellent building blocks (cfr. ‘
-lactam synthon method’).4
However, only one enantioselective approach to chiral (piperazin-
b-lactams could be useful in the synthesis
2. Results and discussion
The synthesis of chiral 4-formyl-1-(
5aed was performed by means of a slightly modified four-step
literature procedure.6,7 (R)-Glyceraldehyde acetonide 3 was con-
densed with 2-chloroethyl- or 3-bromopropylamine (in situ pre-
pared from the corresponding hydrohalide salts using 3 equiv of
Et3N) in dichloromethane in the presence of MgSO4, and the
b
u
-haloalkyl)-b-lactams
2-yl)acetates, starting from fused oxopiperazino-
b-lactams, is
available in the literature to date.5
* Corresponding authors. E-mail addresses: matthias.dhooghe@UGent.be (M.
D’hooghe), norbert.dekimpe@UGent.be (N. De Kimpe).
y
Aspirant of the Research Foundation-Flanders (FWO-Vlaanderen).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.136

10828
S. Dekeukeleire et al. / Tetrahedron 68 (2012) 10827e10834
resulting imines were used as substrates for a Staudinger reaction
using benzyloxy- or methoxyacetyl chloride in dichloromethane to
probably due to the lower ring strain compared with their six-
membered analogues.
synthesize
b
-lactams 4aed in a highly stereoselective way (Scheme
Because of the importance of chirality in medicinal chemistry, and
since asymmetric syntheses of optically active 2-substituted piper-
azines in general11 and chiral alkyl (piperazin-2-yl)acetates in par-
ticular5 are relatively scarce, this approach comprises a convenient
entry toward the latter class of compounds. Moreover, through var-
iation of the length of the 1-haloalkyl moiety in azetidin-2-ones
5aed, the preparation of chiral methyl [(S)-1,4-diazepan-2-yl]ace-
tates as the higher homologues has been made possible as well.
In order to extend the scope of this study, the use of (3R,4R)-1-
1, Table 1). The Staudinger reaction, in which an imine and a ketene
undergo a [2þ2]-cyclocondensation reaction, indeed comprises
a very reliable and robust method for the preparation of b-lactam
derivatives.8 The latter azetidin-2-ones 4aed could be easily con-
verted into the premised (3R,4R)-4-formyl- -lactams 5aed by
b
consecutive hydrolysis using 4-toluenesulfonic acid in THF and
oxidation of the resulting diol by sodium periodate in a two-phase
system of aqueous NaHCO3 and CH2Cl2 at room temperature for 2 h
(Scheme 1, Table 1).7 4-Formylazetidin-2-ones have proven to be
valuable synthons in organic chemistry, as they, for example, have
allyl-4-formyl-
b
-lactams 5eeg as starting compounds for the syn-
-lactams containing
thesis of oxa- and azaheterocyclic annulated
b
been used for the asymmetric synthesis of polycyclic
b-lactams,
an additional functionality (i.e., the presence of a bromine atom),
was then evaluated. Applying the same reaction protocol as de-
scribed above, the synthesis of chiral 1-allyl-4-formylazetidin-2-
indolizidine, and quinolizidine derivatives,9 and biologically active
compounds like biotin, cisapride, and sphingosines.10
1) 1 equiv XCH2(CH2)nNH2.HX
3 equiv Et3N
O
O
1) 1 equiv pTsOH
THF/H2O, Δ, 4 h
1.5 equiv MgSO4
CH2Cl2, rt, 1 h
O
H
R1O
R1O
O
O
H
S
O
R S
R R
H
R
N
N
2) 2 equiv NaIO4
NaHCO3
2) 1.3 equiv R1OCH2COCl
3 equiv Et3N
O
O
n
n
X
X
CH2Cl2, rt, 2 h
3
5a-d (83-95%)
CH2Cl2, 0 °C - rt, 15 h
4a-d (75-86%)
1) 1 equiv R2NH2
1.5 equiv MgSO4
CH2Cl2, rt, 1 h
2) 2 equiv NaBH4
EtOH, Δ, 1-3 h
1
H
R O
H
R1O
R2
N
H
O
R2
HCl-MeOH (conc)
0 °C, 1 h - rt, 15 h
R
R S
N
S
N
MeO HN
n
O
n
6a-i (41-87%)
7a-i (47-71%)
Scheme 1.
Table 1
Synthesis of azetidin-2-ones 4aed and 4-formylazetidin-2-ones 5aed
Table 2
Synthesis of methyl (R)-[(S)-piperazin-2-yl]acetates 7aed and methyl (R)-[(S)-1,4-
diazepan-2-yl]acetates 7eei
Entry
X
n
R1
Compound
(% yield)
dr
Compound (% yield)
Entry
X
n
R1
R2
Compound (% yield)
1
2
3
4
Cl
Cl
Br
Br
1
1
2
2
Me
Bn
Me
Bn
4a (81%)
4b (86%)
4c (75%)
4d (77%)
91.5/8.5
93.5/6.5
95.5/4.5
94/6
5a (83%)
5b (94%)
5c (94%)
5d (95%)
1
2
3
4
5
6
7
8
9
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
1
1
1
1
2
2
2
2
2
Me
Me
Me
Bn
Me
Me
Me
Bn
Allyl
Bn
t-Bu
i-Pr
Bn
Allyl
i-Pr
t-Bu
Allyl
7a (66%)
7b (70%)
7c (63%)
7d (71%)
7e (68%)
7f (69%)
7g (47%)
7h (64%)
7i (63%)
Imination of 4-formyl-1-(2- and 3-haloalkyl)azetidin-2-ones
5aed upon treatment with 1 equiv of a primary amine in CH2Cl2
in the presence of MgSO4 and subsequent reduction with NaBH4 in
Bn
EtOH under reflux for 1e3 h afforded bicyclic b
-lactams 6,7 which
were then treated with a saturated solution of hydrogen chloride
gas in MeOH for 15 h at room temperature to afford novel methyl
(R)-[(S)-piperazin-2-yl]acetates 7aed and methyl (R)-[(S)-1,4-
diazepan-2-yl]acetates 7eei in good yields through acid-
ones 5eeg was achieved starting from allylamine, which, after
condensation with (R)-glyceraldehyde acetonide 3 in the presence
of MgSO4 and subsequent Staudinger reaction using three different
acetyl chlorides, afforded b-lactams 4eeg in high diastereomeric
promoted methanolysis of the b-lactam ring (Scheme 1, Table 2).
ratios (Scheme 2). Consecutive hydrolysis using 4-toluenesulfonic
acid and oxidation by sodium periodate then gave rise to 4-
formylazetidin-2-ones 5eeg, from which the spectral data were
in full correspondence with those reported in the literature
(Scheme 2).6
It should be noted that the yields (47e71%) are those obtained after
column chromatography on silica gel. When shorter reaction times
were applied, significant amounts of starting compound 6 were
recovered, especially for the 1,4-diazepane annulated
b-lactams,

S. Dekeukeleire et al. / Tetrahedron 68 (2012) 10827e10834
10829
1) 1 equiv allylamine
1.5 equiv MgSO4
CH2Cl2, rt, 1 h
O
O
1) 1 equiv pTsOH
THF/H2O, Δ, 4 h
O
H
R1O
O
R1O
O
O
H
S
O
R S
R R
H
R
2) 1.3 equiv R1OCH2COCl
3 equiv Et3N
CH2Cl2, 0 °C - rt, 15 h
2) 2 equiv NaIO4
NaHCO3
CH2Cl2, rt, 2 h
N
N
O
3
5e R1 = Ph (82%)
5f R1 = Me (83%)
5g R1 = Bn (89%)
4e R1 = Ph (77%, dr 94/6)
4f R1 = Me (75%, dr 96.5/3.5)
4g R1 = Bn (73%, dr 94.5/5.5)
OH
Br
1) 1 equiv Br2
R1O
O
R1O
O
CH2Cl2, -5 °C, 1 h
S
R
R
S
H
Br
N
N
2) 2 equiv NaBH4
EtOH, -5 °C to Δ, 1 h
O
Br
9a R1 = Ph (74%)
9b R1 = Me (65%)
9c R1 = Bn (59%)
8
Scheme 2.
In contrast to 4-formyl-1-(2- and 3-haloalkyl)-azetidin-2-ones
other hand, bromination at ꢀ78 ꢁC followed by reduction with
NaBH4 in EtOH afforded single reaction products, but spectral
analysis revealed that again 1-(2-bromo-2-propenyl)azetidin-2-
ones 11aeh were formed (Scheme 3, Table 3). A solvent switch
from EtOH to MeOH did not result in piperazine and morpholine
5aed, which selectively allowed the design of bicyclic b-lactams
via an intramolecular nucleophilic substitution reaction,6 the latter
azetidin-2-ones 5eeg could not be converted into morpholine and
piperazine annulated
b-lactams.
First, (3R,4R)-1-allyl-4-formyl-
b
-lactams 5eegweretreated with
annulated b-lactams either, but afforded a more complex reaction
mixture, still with 1-(2-bromo-2-propenyl)azetidin-2-ones as the
main reaction products.
1 equiv of bromine in dichloromethane for 1 h at ꢀ5 ꢁC (Scheme 2).
As the resulting 1-(2,3-dibromopropyl)azetidin-2-ones were ex-
pected to be fairly unstable at room temperature, the bromination
step was immediately followed byaddition of ethanol and 2 equiv of
Table 3
Synthesis of (3R,4S)-1-allyl-4-imidoyl-b-lactams 10 and (3R,4S)-4-(aminomethyl)-
NaBH4 at ꢀ5 ꢁC. Unfortunately, no bicyclic
b-lactams were observed,
1-(2-bromo-2-propenyl)azetidin-2-ones 11
but 1-(2-bromo-2-propenyl)azetidin-2-ones 9aec were formed
instead. This reaction probably proceeds through reduction of the
aldehyde function resulting in the formation of alkoxide anions 8,
which apparently do not give rise to a 6- or 7-exo-tet-cyclization as
they induce dehydrobromination through deprotonation of the C2
hydrogen atom of the 2,3-dibromopropyl moiety, affording vinyl
bromides 9aec in good yields (Scheme 2). Alternatively, sodium
ethoxide can also account for the latter deprotonation.
Entry
R1
R2
Compound (% yield)
Compound (% yield)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Me
Me
Bn
Bn
Bn
t-Bu
i-Pr
Bn
t-Bu
i-Pr
t-Bu
i-Pr
Bn
10a (90%)
10b (95%)
10c (97%)
10d (96%)
10e (98%)
10f (97%)
10g (95%)
10h (96%)
11a (71%)
11b (62%)
11c (48%)
11d (64%)
11e (60%)
11f (67%)
11g (82%)
11h (45%)
As the synthesis of oxaheterocyclic annulated b-lactams starting
from 1-allylazetidin-2-ones 5eeg was unsuccessful, the prepara-
tion of their nitrogen analogues was attempted. In that respect, 4-
In order to assess the chiral purity of vinyl bromides 11, com-
pound 11a was treated with 2 equiv of Pirkle alcohol prior to 1H
NMR analysis (CDCl3), pointing to an enantiomeric ratio of 94/6.
This observation confirms the preservation of the enantiomeric
purity throughout the reaction sequence, and corroborates the
importance of 4-imidoylazetidin-2-ones 10 as synthons for the
preparation of chiral target compounds.
In view of the surprising conversion of 1-allyl-b-lactams 5eeg
and 10aeh into vinyl bromides 9aec and 11aeh, as well as in order
to support the proposed reaction mechanism that indeed
formyl-
primary amines in dichloromethane in the presence of MgSO4,
furnishing 4-imidoyl- -lactams 10 in excellent yields after 1 h at
room temperature (Scheme 3, Table 3). When the aforementioned
reaction procedure was applied to 4-imidoyl-
b-lactams 5eeg were condensed with 1 equiv of different
b
b
-lactams 10, i.e.,
treatment with 1 equiv of bromine in dichloromethane at ꢀ5 ꢁC
and subsequent reduction with 2 equiv of NaBH4 in EtOH, a com-
plex reaction mixture was obtained, probably because of the in-
stability of the obtained dibromoimines at this temperature. On the
R2
R2
O
N
HN
1) 1 equiv Br2
R1O
O
R1O
O
R1O
O
1 equiv R2NH2
H
H
CH2Cl2, -78 °C, 2 h
Br
R
R
R S
R
S
N
N
N
1.5 equiv MgSO4
CH2Cl2, rt, 1 h
2) 2 equiv NaBH4
EtOH, -78 °C to Δ, 1 h
5e-g
11a-h (45-82%)
10a-h (90-98%)
Scheme 3.

10830
S. Dekeukeleire et al. / Tetrahedron 68 (2012) 10827e10834
dibrominated intermediates are formed, the preparation of (3R,4R)-
1-(2,3-dibromopropyl)-4-formylazetidin-2-one 13 was accom-
bromides in general are useful intermediates for carbonecarbon
and carboneheteroatom bond formation by transition metal-
plished analogous to the synthesis of
b
-lactams 5aed.6,7 Thus,
catalyzed coupling reactions,13 chiral
b-lactams 9aec and 11aeh
condensation of (R)-glyceraldehyde acetonide 3 with the hydro-
bromide salt of 2,3-dibromopropylamine in the presence of Et3N,
and Staudinger reaction of the resulting imine using phenoxyacetyl
chloride afforded a diastereomeric mixture of azetidin-2-one 12 (dr
w1/1, based on 1H NMR analysis), which was further converted into
(3R,4R)-1-(2,3-dibromopropyl)-4-formylazetidin-2-one 13 through
hydrolysis and subsequent oxidation. Reduction of aldehyde 13
with 2 equiv of NaBH4 in EtOH under reflux afforded (3R,4S)-1-(2-
bromo-2-propenyl)-4-hydroxymethyl-3-phenoxyazetidin-2-one
9a as the sole reaction product (Scheme 4).
could be of interest as building blocks toward novel biologically
active compounds. Furthermore, further elaboration of the double
bond in azetidin-2-one 9c was achieved using 1 equiv of bromine in
dichloromethane at room temperature for 18 h, affording 1-(2,2,3-
tribromopropyl)-
b
-lactam 16 in 82% yield (Scheme 6).
OH
OH
BnO
BnO
1 equiv Br2
Br
Br Br
R S
R S
N
N
Br
CH2Cl2, rt, 18 h
O
O
Br
9c
16 (82%)
Br
NH2.HBr
1) 1 equiv
1.5 equiv MgSO4
3 equiv Et3N
Scheme 6.
O
O
H
PhO
O
O
CH2Cl2, rt, 1 h
S
O
R S
H
Br
R
It should be noted that a totally different yet selective reactivity
is observed for anions 17, obtained as intermediates through re-
duction of the corresponding aldehydes or imines, depending on
the substitution pattern of the N-side chain. Apparently, a clean 7-
exo-tet-cyclization to bicycles 18 occurs when R¼H, whereas
dehydrobromination to vinyl bromides 19 prevails when R¼Br
(Scheme 7). Despite the increased steric hindrance due to the ad-
ditional bromine atom, the increased acidity of the proton at C2 of
the N-alkyl moiety and the decreased electrophilicity of the bro-
momethyl group in intermediates 17 control the reaction pathway
giving rise to deprotonation instead of cyclization when R¼Br.
In conclusion, a new and straightforward approach toward
chiral functionalized piperazines and 1,4-diazepanes via ring
N
2) 1.3 equiv PhOCH2COCl
3 equiv Et3N
CH2Cl2, 0 °C - rt, 15 h
O
Br
3
12 (72%)
(dr ∼ 1/1)
2) 2 equiv NaIO4
NaHCO3
1) 1 equiv pTsOH
THF/H2O, Δ, 4 h
CH2Cl2, rt, 2 h
O
OH
PhO
O
PhO
H
Br
2 equiv NaBH4
R S
R R
Br
N
N
EtOH, Δ, 2 h
O
Br
9a (54%)
13 (68%)
(dr ∼ 1/1)
opening of piperazine and 1,4-diazepane annulated
b-lactams,
derived from (3R,4R)-4-formyl-1-( -haloalkyl)azetidin-2-ones, has
u
Scheme 4.
been presented. However, an attempt to extend this methodology
toward the use of (3R,4R)-1-allyl-4-formylazetidin-2-ones as
starting compounds unexpectedly resulted in the selective forma-
tion of synthetically interesting (3R,4S)-1-(2-bromo-2-propenyl)-
Additional proof for the proposed intramolecular dehydro-
bromination protocol was provided through the bromination of
(3R,4R)-4-formyl-1-(2-methyl-2-propenyl)- -lactam 14, prepared
b
-lactams via a reductive dehydrobromination protocol.
b
according to a literature procedure starting from 2-methyl-2-
propenylamine,12 in CH2Cl2 at ꢀ5 ꢁC and subsequent reduction
with NaBH4 in EtOH (Scheme 5). As there is no proton available for
deprotonation at the C2-atom of the 2,3-dibromopropyl moiety, the
result of the reaction was expected to be a diastereomeric mixture
of (3R,4S)-1-(2,3-dibromo-2-methylpropyl)-4-hydroxymethyl-3-
phenoxyazetidin-2-ones 15. 1H NMR analysis (CDCl3) revealed
Z
ZH
H
R1O
R1O
O
R1O
O
Z
RS
R S
R S
R
Br
N
N
N
R = H
R = Br
O
Br
18
19
17
(Z = O, NR2)
that indeed the latter b-lactam 15 was formed in a diastereomeric
Scheme 7.
ratio of 84/16, from which only the major isomer could be isolated
in pure form through column chromatography on silica gel
(Scheme 5).
3. Experimental part
OH
3.1. Synthesis of methyl (R)-[(S)-piperazin-2-yl]acetates 7aed
and methyl (R)-2-[(S)-1,4-diazepan-2-yl]acetates 7eei
O
1) 1 equiv Br2
PhO
O
PhO
O
CH2Cl2, -5 °C, 1 h
H
R
S
R
R
Br
N
N
As a representative example, the synthesis of methyl (R)-benzy-
loxy-[(S)-4-(1-methylethyl)piperazin-2-yl]acetate 7d is described.
To an ice-cooled solution of (6S,7R)-7-benzyloxy-4-(1-methyl-
ethyl)-1,4-diazabicyclo[4.2.0]octan-8-one 6d7 (0.67 g, 2.4 mmol,
1 equiv)inMeOH(10 mL) wasadded dropwisea saturated solutionof
HCl in MeOH (40 mL). After stirring for 1 h at 0 ꢁC, the resulting re-
action mixture was warmed to room temperature and further stirred
for 15 h. Subsequently, a saturated NaHCO3 solutionwas added till pH
7.0. After vigorous stirring for 30 min, the reaction mixture was
extracted with CH2Cl2 (4ꢂ30 mL) and the combined organic phases
were dried over MgSO4. After filtration of the drying agent, evapo-
ration of the solvent in vacuo and purification via column
2) 2 equiv NaBH4
EtOH, -5 °C to Δ, 1 h
Br
14
15 (58%)
(dr 84/16)
Scheme 5.
Although no aza- and oxaheterocyclic annulated
could be prepared via bromination of 1-allyl-
b
-lactams
b
-lactams and sub-
sequent reduction, the synthesized azetidin-2-ones 9aec and
11aeh comprise an interesting class of compounds. As vinyl

S. Dekeukeleire et al. / Tetrahedron 68 (2012) 10827e10834
10831
chromatography on silica gel, pure methyl (R)-benzyloxy-[(S)-4-(1-
methylethyl)piperazin-2-yl]acetate 7d was obtained in 71% yield.
J¼13.8, 6.6, 4.7 Hz), 3.12 (1H, dꢂdꢂt, J¼13.6, 6.6, 1.2 Hz), 3.12e3.19
(1H, m), 3.20 (1H, dꢂdꢂd, J¼8.8, 5.4, 3.6 Hz), 3.41 (3H, s), 3.70 (1H, d,
J¼5.4 Hz), 3.77 (3H, s), 5.11e5.20 (2H, m), 5.86 (1H, dꢂdꢂt, J¼17.0,
3.1.1. Methyl
7a. Brown oil. Rf¼0.08 (CH2Cl2/MeOH 95/5). Yield 66%. [
0.95, CH2Cl2). 1H NMR (300 MHz, CDCl3):
1.93e2.07 (3H, m),
(R)-[(S)-4-allylpiperazin-2-yl]methoxyacetate
10.2, 6.6 Hz). 13C NMR (75 MHz, CDCl3):
d 30.90, 45.68, 51.91, 54.71,
a
]D þ24.2 (c
58.26, 58.78, 59.67, 61.67, 83.12, 117.53, 135.79, 171.78. IR (NaCl,
cmꢀ1): nNH¼3350; nC]O¼1751; nmax¼2933, 2830, 1642, 1459, 1437,
1346, 1272, 1197, 1122, 998. MS (70 eV): m/z (%) 243 (Mþþ1, 100).
d
2.68e2.78 (2H, m), 2.84 (1H, dꢂdꢂd, J¼12.1,10.6, 2.9 Hz), 2.93e3.02
(3H, m), 3.08 (1H, dꢂdꢂd, J¼9.5, 6.6, 2.9 Hz), 3.41 (3H, s), 3.72 (1H, d,
J¼6.6 Hz), 3.78 (3H, s), 5.13e5.22 (2H, m) 5.84 (1H, dꢂdꢂt, J¼17.2,
3.1.7. Methyl (R)-methoxy-[(S)-4-(1-methylethyl)-1,4-diazepan-2-yl]
10.3, 6.6 Hz). 13C NMR (75 MHz, CDCl3):
d
44.95, 51.82, 53.64, 55.24,
acetate 7g. Brown oil. Rf¼0.03 (CH2Cl2/MeOH 93/7). Yield 47%. [
a]
D
56.58, 58.55, 62.10, 82.26, 117.85, 134.92, 171.31. IR (NaCl, cmꢀ1):
nNH¼3347; nC]O¼1753; nmax¼3076, 2948, 2827, 1643, 1459, 1438,
1331, 1271, 1198, 1118, 1010. MS (70 eV): m/z (%) 229 (Mþþ1, 100).
þ15.2 (c 0.40, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d 1.05 and 1.08
(2ꢂ3H, 2ꢂd, J¼6.6 Hz), 1.58e1.90 (2H, m), 2.62e2.72 (2H, m),
2.76e2.89(3H, m), 2.97e3.06(2H,m),3.22e3.28(1H, m), 3.42(3H, s),
3.75 (1H, d, J¼5.2 Hz), 3.79 (3H, s).13C NMR (75 MHz, CDCl3):
d 17.48,
3.1.2. Methyl
7b. Brown oil. Rf¼0.11 (CH2Cl2/MeOH 95/5). Yield 70%. [
1.66, CH2Cl2). 1H NMR (300 MHz, CDCl3):
1.99e2.10 (2H, m), 2.17
(R)-[(S)-4-benzylpiperazin-2-yl]methoxyacetate
18.80, 31.09, 45.54, 50.35, 51.96, 54.46, 56.22, 58.83, 59.73, 83.04,
171.74. IR (NaCl, cmꢀ1): nNH¼3353; nC]O¼1753; nmax¼2927, 2854,
1460, 1361, 1270, 1196, 1122. MS (70 eV): m/z (%) 245 (Mþþ1, 100).
a
]
D þ19.9 (c
d
(1H, br s), 2.64e2.68 (2H, m), 2.80 (1H, dꢂdꢂd, J¼12.1, 10.5, 2.9 Hz),
2.94 (1H, dꢂdꢂd, J¼12.1, 3.3, 3.0 Hz), 3.08 (1H, dꢂdꢂd, J¼9.4, 6.2,
2.8 Hz), 3.38 (3H, s), 3.45 and 3.50 (2ꢂ1H, 2ꢂd, J¼13.1 Hz), 3.69 (3H,
s), 3.72 (1H, d, J¼6.2 Hz), 7.19e7.30 (5H, m). 13C NMR (75 MHz,
3.1.8. Methyl (R)-benzyloxy-[(S)-4-(1,1-dimethylethyl)-1,4-diazepan-
2-yl]acetate 7h. Brown oil. Rf¼0.07 (CH2Cl2/MeOH 95/5). Yield 64%.
[
a
]
D þ27.2 (c 0.66, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d 1.28 (9H, s),
CDCl3):
d
44.81, 51.82, 53.62, 55.30, 56.55, 58.61, 63.36, 82.05,
1.85e1.96 and 1.99e2.14 (2ꢂ1H, 2ꢂm), 2.81e2.88 (2H, m),
2.92e2.95 and 2.99e3.04 (2ꢂ1H, 2ꢂm), 3.05e3.25 (2H, m),
3.50e3.62 (1H, m), 3.78 (3H, s), 3.99 (1H, d, J¼4.6 Hz), 4.42 and 4.79
(2ꢂ1H, 2ꢂd, J¼11.7 Hz), 7.29e7.36 (5H, m). 13C NMR (75 MHz,
126.98, 128.13, 129.06, 137.93, 171.51. IR (NaCl, cmꢀ1): nNH¼3343;
nC]O¼1752; nmax¼2948, 2826, 1494, 1454, 1335, 1268, 1198, 1118,
1027, 1011. MS (70 eV): m/z (%) 279 (Mþþ1, 100).
CDCl3): d 25.65, 29.36, 45.33, 48.51, 52.16, 57.79, 60.58, 72.84, 79.81,
3.1.3. Methyl (R)-methoxy-[(S)-4-(1,1-dimethylethyl)piperazin-2-yl]
128.16, 128.40, 128.50, 137.02, 171.28. IR (NaCl, cmꢀ1): nNH¼3296;
nC]O¼1749; nmax¼2953, 2721, 2608, 1455, 1436, 1269, 1206, 1120,
1028. MS (70 eV): m/z (%) 335 (Mþþ1, 100).
acetate 7c. Brown oil. Rf¼0.05 (CH2Cl2/MeOH 95/5). Yield 63%. [
a]
D
þ39.1 (c 0.13, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d 1.09 (9H, s),
2.15e2.29 (2H, m), 2.83e2.90 (3H, m), 3.02 (1H, dꢂdꢂd, J¼12.1, 3.4,
3.4 Hz), 3.10e3.14 (1H, m), 3.42 (3H, s), 3.77 (1H, d, J¼5.2 Hz), 3.78
3.1.9. Methyl
7i. Brown oil. Rf¼0.04 (CH2Cl2/MeOH 95/5). Yield 63%. [
1.40, CH2Cl2). 1H NMR (300 MHz, CDCl3):
1.59e1.83 (2H, m), 2.33
(R)-((S)-4-allyl-1,4-diazepan-2-yl)benzyloxyacetate
(3H, s). 13C NMR (75 MHz, CDCl3):
d
25.71, 45.38, 46.28, 48.11, 51.99,
a]D þ44.9 (c
54.74, 56.92, 58.77, 82.26, 171.64. IR (NaCl, cmꢀ1): nNH¼3340; nC]
d
¼1746; nmax¼2973, 2831, 1458, 1437, 1361, 1279, 1204, 1115, 1018.
(1H, br s), 2.50e2.61 (2H, m), 2.71e2.83 (3H, m), 2.99 (1H, dꢂdꢂd,
J¼13.8, 6.9, 4.4 Hz), 3.04e3.19 (2H, m), 3.24 (1H, dꢂdꢂd, J¼8.7, 5.0,
3.5 Hz), 3.74 (3H, s), 3.89 (1H, d, J¼5.0 Hz), 4.39 and 4.73 (2ꢂ1H,
2ꢂd, J¼11.6 Hz), 5.08e5.19 (2H, m), 5.83 (1H, dꢂdꢂt, J¼17.0, 10.2,
O
MS (70 eV): m/z (%) 245 (Mþþ1, 100).
3.1.4. Methyl (R)-benzyloxy-[(S)-4-(1-methylethyl)piperazin-2-yl]ac-
etate 7d. Brown oil. Rf¼0.05 (CH2Cl2/MeOH 95/5). Yield 71%. [
a
]
6.5 Hz), 7.25e7.42 (5H, m). 13C NMR (75 MHz, CDCl3):
d 30.93, 45.67,
D
þ32.2 (c 0.53, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d
1.00 and 1.02
51.82, 54.61, 58.54, 59.65, 61.55, 72.75, 80.49, 117.34, 127.92, 128.16,
(2ꢂ3H, 2ꢂd, J¼6.2 Hz), 2.13e2.24 (2H, m), 2.33 (1H, br s), 2.60e2.71
(3H, m), 2.80 (1H, dꢂdꢂd, J¼12.0, 10.5, 3.0 Hz), 2.97 (1H, dꢂdꢂd,
J¼12.0, 3.0, 3.0 Hz), 3.11 (1H, dꢂdꢂd, J¼9.4, 6.4, 2.9 Hz), 3.75 (3H, s),
3.95 (1H, d, J¼6.4 Hz), 4.43 and 4.69 (2ꢂ1H, 2ꢂd, J¼11.6 Hz),
128.34, 135.92, 137.25, 171.86. IR (NaCl, cmꢀ1): nNH¼3348; nC]
¼1751; nmax¼2930, 1699, 1642, 1497, 1455, 1344, 1271, 1205, 1165,
O
1113, 1027. MS (70 eV): m/z (%) 319 (Mþþ1, 100).
7.26e7.35 (5H, m). 13C NMR (75 MHz, CDCl3):
d
17.76, 18.54, 45.27,
3.2. Synthesis of (3R,4S)-1-allyl-4-imidoyl-b-lactams 10
48.92, 51.01, 51.91, 54.80, 56.87, 73.00, 80.05, 128.07, 128.33, 128.42,
137.08, 171.64. IR (NaCl, cmꢀ1): nNH¼3344; nC]O¼1751; nmax¼2964,
2818, 1455, 1437, 1332, 1268, 1203, 1181, 1140, 1114, 1060, 1019. MS
(70 eV): m/z (%) 307 (Mþþ1, 100).
As a representative example, the synthesis of (3R,4S)-1-allyl-3-
benzyloxy-4-{(E)-[((1,1-dimethylethyl)imino)methyl]}azetidin-2-
one 10f is described. In a 100 mL flask, (3R,4R)-1-allyl-3-benzyloxy-
4-formylazetidin-2-one 5c (0.91 g, 3.7 mmol, 1 equiv) was dis-
solved in CH2Cl2 (50 mL) and MgSO4 (0.71 g, 5.6 mmol, 1.5 equiv)
was added. Subsequently, tert-butylamine (0.25 g, 3.7 mmol,
1 equiv) was added and the resulting reaction mixture was stirred
at room temperature for 1 h. After filtration of MgSO4, the solvent
was evaporated in vacuo, yielding 4-imidoylazetidin-2-one 10f
(1.08 g, 97%).
3.1.5. Methyl
7e. Brown oil. Rf¼0.10 (CH2Cl2/MeOH 95/5). Yield 68%. [
0.64, CH2Cl2). 1H NMR (300 MHz, CDCl3):
1.59e1.83 (2H, m), 1.98
(R)-[(S)-4-benzyl-1,4-diazepan-2-yl]methoxyacetate
a]
D þ17.2 (c
d
(1H, br s, NH), 2.53e2.63 (2H, m), 2.70e2.80 (2H, m), 2.84 (1H,
dꢂdꢂd, J¼13.8, 8.0, 4.1 Hz), 3.03 (1H, dꢂdꢂd, J¼13.8, 6.7, 4.6 Hz),
3.19 (1H, dꢂdꢂd, J¼8.8, 5.5, 3.3 Hz), 3.36 (3H, s), 3.61 (1H, d,
J¼13.5 Hz), 3.65 (1H, d, J¼5.5 Hz), 3.66 (3H, s), 3.70 (1H, d,
All the imines 10 were obtained in high purity (>95% based on
NMR) and used as such in the next reaction step due to their hy-
drolytic instability.
J¼13.5 Hz), 7.19e7.35 (5H, m). 13C NMR (75 MHz, CDCl3):
d 31.10,
45.79, 51.77, 54.58, 58.69, 60.06, 62.65, 83.23,126.83,128.16,128.68,
139.57, 171.80. IR (NaCl, cmꢀ1): nNH¼3350; nC]O¼1751; nmax¼2933,
2829, 1494, 1454, 1436, 1352; 1269, 1196, 1121, 1072, 1029. MS
(70 eV): m/z (%) 293 (Mþþ1, 100).
3.2.1. (3R,4S)-1-Allyl-4-{(E)-[((1,1-dimethylethyl)imino)methyl]}-3-
phenoxyazetidin-2-one 10a. Colorless oil. Yield 90%. 1H NMR
(300 MHz, CDCl3):
d
0.99 (9H, s), 3.94 (2H, dꢂt, J¼6.6, 1.2 Hz), 4.45
3.1.6. Methyl
7f. Brown oil. Rf¼0.06 (CH2Cl2/MeOH 95/5). Yield 69%. [
0.48, CH2Cl2). 1H NMR (300 MHz, CDCl3):
1.62e1.85 (2H, m), 2.26
(1H, br s), 2.53e2.62 (2H, m), 2.73e2.87 (3H, m), 3.03 (1H, dꢂdꢂd,
(R)-[(S)-4-allyl-1,4-diazepan-2-yl]methoxyacetate
(1H, dꢂd, J¼6.9, 4.5 Hz), 5.20e5.30 (2H, m), 5.40 (1H, d, J¼4.5 Hz),
5.70e5.90 (1H, m), 6.89e7.01 and 7.22e7.32 (3H and 2H, 2ꢂm),
a
]D þ16.6 (c
d
7.53 (1H, d, J¼6.9 Hz). 13C NMR (75 MHz, ref¼CDCl3):
d 29.17, 44.21,
58.12, 62.04, 81.42, 115.30, 119.97, 122.38, 129.60, 131.16, 154.80,

10832
S. Dekeukeleire et al. / Tetrahedron 68 (2012) 10827e10834
156.71, 164.89. IR (NaCl, cmꢀ1): nC]O¼1761; nC]N¼1667; nC]
(1H, m), 7.28e7.38 (5H, m), 7.66 (1H, d, J¼6.9 Hz). 13C NMR (75 MHz,
¼1644; nmax¼2967, 2930, 1598, 1495, 1397, 1233, 752, 690. MS
CDCl3):d23.82, 43.77, 60.97, 61.30, 72.81, 83.20,119.49,127.82,128.10,
C
(70 eV): m/z (%) 287 (Mþþ1, 100).
128.47, 131.24, 136.56, 158.42, 166.56. IR (NaCl, cmꢀ1): nC]O¼1767;
nC]N¼1668; nC]C¼1645; nmax¼2968, 1529, 1498, 1455, 1396, 1157,
739, 699. MS (70 eV) m/z (%): 287 (Mþþ1, 100).
3.2.2. (3R,4S)-1-Allyl-4-{(E)-[((1-methylethyl)imino)methyl]}-3-
phenoxyazetidin-2-one 10b. Colorless oil. Yield 95%. 1H NMR
(300 MHz, CDCl3):
d
0.84 and 1.10 (2ꢂ3H, 2ꢂd, J¼6.3 Hz, (CH3)2),
3.2.8. (3R,4S)-1-Allyl-3-benzyloxy-4-{(E)-[(benzylimino)methyl]}
3.29 (1H, sept, J¼6.3 Hz), 3.87e4.03 (2H, m), 4.44 (1H, dꢂd, J¼7.0,
4.6 Hz), 5.22e5.28 (2H, m), 5.38 (1H, d, J¼4.6 Hz), 5.70e5.88 (1H,
m), 6.92e7.16 and 7.23e7.34 (3H and 2H, 2ꢂm), 7.61 (1H, d,
azetidin-2-one 10h. Colorless oil. Yield 96%. 1H NMR (300 MHz,
CDCl3):
d
3.79 (1H, dꢂd, J¼15.4, 6.2 Hz), 3.91 (1H, dꢂd, J¼15.4,
5.6 Hz), 4.27 (1H, dꢂd, J¼6.4, 4.7 Hz), 4.54e4.61 (3H, m), 4.70 (1H,
d, J¼11.8 Hz), 4.82 (1H, d, J¼4.7 Hz), 5.10e5.17 (2H, m), 5.61e5.75
(1H, m), 7.20e7.33 (10H, m), 7.72 (1H, d, J¼6.4 Hz). 13C NMR
J¼7.0 Hz). 13C NMR (75 MHz, ref¼CDCl3):
d 23.52, 23.69, 44.18,
61.34, 61.51, 81.57, 115.41, 120.00, 122.47, 129.64, 131.04, 156.83,
157.26, 164.90. IR (NaCl, cmꢀ1): nC]O¼1760; nC]N¼1666; nC]
(75 MHz, CDCl3): d 43.76, 60.80, 65.03, 72.94, 83.27, 119.38, 127.90,
¼1644; nmax¼2967, 2928, 1598, 1494, 1396, 1232, 753, 690. MS
128.07,128.54,131.12,136.53,138.12,161.95,166.47. IR (NaCl, cmꢀ1):
nC]O¼1767; nC]N¼1669; nC]C¼1645; nmax¼3030, 2909, 2870, 1604,
1524, 1496, 1454, 1397, 1027, 738, 699. MS (70 eV) m/z (%): 335
(Mþþ1, 100).
C
(70 eV): m/z (%) 273 (Mþþ1, 100).
3.2.3. (3R,4S)-1-Allyl-4-{(E)-[(benzylimino)methyl]}-3-
phenoxyazetidin-2-one 10c. Colorless oil. Yield 97%. 1H NMR
(300 MHz, CDCl3):
d
3.84e3.92 and 3.97e4.06 (2ꢂ1H, 2ꢂm), 4.50
3.3. Synthesis of (3R,4S)-1-(2-bromo-2-propenyl)azetidin-2-
ones 9 and 11
(1H, dꢂd, J¼13.5, 1.2 Hz), 4.53 (1H, dꢂd, J¼6.6, 4.6 Hz), 4.61 (1H,
dꢂd, J¼13.5, 1.2 Hz), 5.18e5.30 (2H, m), 5.40 (1H, d, J¼4.6 Hz),
5.68e5.82 (1H, m), 6.93e7.12 and 7.21e7.35 (4H and 6H, 2ꢂm), 7.73
As a representative example, the synthesis of (3R,4S)-1-(2-bromo-
2-propenyl)-4-[(1,1-dimethylethylamino)methyl]-3-phenoxyazeti-
din-2-one 11a is described. In a two-necked flask of 100 mL, 4-
(1H, dꢂt, J¼6.6, 1.2 Hz). 13C NMR (75 MHz, ref¼CDCl3):
d 44.16,
61.16, 65.07, 81.72, 115.47, 119.91, 122.60, 127.31, 128.14, 128.64,
129.77, 130.98, 137.79, 156.98, 160.89, 164.97. IR (NaCl, cmꢀ1): nC]
imidoyl-b-lactam 10a (4.1 mmol, 1 equiv) was dissolved in dry
¼1758; nC]N¼1667; nC]C¼1645; nmax¼2919, 1598, 1494, 1397,
CH2Cl2 (10 mL), and the mixture was placed under N2 atmosphere at
ꢀ78 ꢁC. A solution of bromine (0.65 g, 4.1 mmol,1 equiv) in dry CH2Cl2
(5 mL) was added dropwise, and the resulting mixture was stirred for
2 h at ꢀ78 ꢁC. Subsequently, NaBH4 (0.32 g, 8.2 mmol, 2 equiv) and
EtOH (50 mL) were added, and the reaction mixture was allowed to
warm to room temperature. After 15 min, the reaction mixture was
heated under reflux for 1 h. The reaction mixture was poured into
water (50 mL) and extracted with CH2Cl2 (3ꢂ50 mL). The combined
organic fractions were dried (MgSO4) and the solvent was evaporated
in vacuo. Further purification was performed by column chromatog-
raphy on silica gel, yielding pure (3R,4S)-1-(2-bromo-2-propenyl)-4-
[(1,1-dimethylethylamino)methyl]-3-phenoxyazetidin-2-one 11a in
74% yield. An analogous procedure was applied for the synthesis of
compounds 9.
O
1232, 752, 736, 691. MS (70 eV): m/z (%) 321 (Mþþ1, 100).
3.2.4. (3R,4S)-1-Allyl-3-methoxy-4-{(E)-[((1,1-dimethylethyl)imino)
methyl]}azetidin-2-one 10d. Colorless oil. Yield 96%. 1H NMR
(300 MHz, CDCl3):
d 1.21 (9H, s), 3.43 (3H, s), 3.85e3.89 (2H, m),
4.22 (1H, dꢂd, J¼6.9, 4.7 Hz), 4.66 (1H, d, J¼4.7 Hz), 5.16e5.18 and
5.21e5.23 (2ꢂ1H, 2ꢂm), 5.66e5.79 (1H, m), 7.59 (1H, d, J¼6.9 Hz).
13C NMR (75 MHz, ref¼CDCl3):
d 29.51, 43.91, 58.12, 58.87, 61.88,
85.63, 119.63, 131.44, 156.05, 166.49. IR (NaCl, cmꢀ1): nC]O¼1757;
nC]N¼1668; nC]C¼1645; nmax¼2967, 2932, 1394, 1212, 1035. MS
(70 eV): m/z (%) 225 (Mþþ1, 49).
3.2.5. (3R,4S)-1-Allyl-3-methoxy-4-{(E)-[((1-methylethyl)imino)
methyl]}azetidin-2-one 10e. Colorless oil. Yield 98%. 1H NMR
(300 MHz, CDCl3):
d
1.18 (6H, d, J¼6.3 Hz), 3.41e3.54 (1H, m), 3.45
3.3.1. (3R,4S)-1-(2-Bromo-2-propenyl)-4-hydroxymethyl-3-
(3H, s), 3.84 (1H, dꢂd, J¼15.8, 6.4 Hz), 3.91 (1H, dꢂd, J¼15.8,
5.6 Hz), 4.22 (1H, dꢂd, J¼6.9, 4.7 Hz), 4.65 (1H, d, J¼4.7 Hz),
5.18e5.19 and 5.22e5.23 (2ꢂ1H, 2ꢂm), 5.66e5.79 (1H, m), 7.64
phenoxyazetidin-2-one 9a. Light-yellow oil. Rf¼0.24 (hexane/EtOAc
3/2). Yield 74%. [
a
]
D þ45 (c 1.30, CHCl3). 1H NMR (300 MHz, CDCl3):
d
2.00 (1H, brs), 3.98e4.03 (2H, m), 4.00 (1H, d, J¼15.7 Hz), 4.08e4.12
(1H, d, J¼6.9 Hz). 13C NMR (75 MHz, ref¼CDCl3):
d
23.89, 23.96,
(1H, m), 4.47 (1H, d, J¼15.7 Hz), 5.37 (1H, d, J¼5.0 Hz), 5.67 (1H, d,
J¼1.8 Hz), 5.92 (1H, dꢂd, J¼1.8, 0.8 Hz), 7.03e7.11 and 7.29e7.35 (3H
43.87, 58.94, 61.07, 61.48, 85.56, 119.68, 131.28, 158.45, 166.49. IR
(NaCl, cmꢀ1): nC]O¼1756; nC]N¼1666; nC]C¼1644; nmax¼2967,
2931, 1383, 1211, 1149, 1033, 930. MS (70 eV): m/z (%) 211 (Mþþ1,
100).
and 2H, 2ꢂm). 13C NMR (75 MHz, ref¼CDCl3):
d 49.13, 58.27, 60.01,
81.13, 115.77, 120.81, 122.98, 126.80, 129.88, 157.21, 165.85. IR (NaCl,
cmꢀ1): nOH¼3436; nC]O¼1744; nC]C¼1630; nmax¼2924, 1590, 1400,
1232, 1045, 753, 690. MS (70 eV): m/z (%) 312/4 (Mþþ1, 100).
3.2.6. (3R,4S)-1-Allyl-3-benzyloxy-4-{(E)-[((1,1-dimethylethyl)im-
ino)methyl]}azetidin-2-one 10f. Colorless oil. Yield 97%. 1H NMR
3.3.2. (3R,4S)-1-(2-Bromo-2-propenyl)-4-hydroxymethyl-3-
(300 MHz, CDCl3):
d
1.18 (9H, s), 3.86 (2H, d, J¼6.3 Hz), 4.23 (1H,
methoxyazetidin-2-one 9b. Light-yellow oil. Rf¼0.13 (hexane/EtOAc
dꢂd, J¼6.9, 4.5 Hz), 4.59 and 4.67 (2ꢂ1H, 2ꢂd, J¼11.8 Hz), 4.83 (1H,
d, J¼4.5 Hz), 5.15e5.22 (2H, m), 5.65e5.79 (1H, m), 7.27e7.39 (5H,
1/1). Yield 65%. [
a
]
D
þ38.2 (c 0.75, CHCl3). 1H NMR (300 MHz,
CDCl3): d 2.37 (1H, br s), 3.63 (3H, s), 3.87e3.99 (4H, m), 4.39 (1H, d,
m), 7.62 (1H, d, J¼6.9 Hz). 13C NMR (75 MHz, CDCl3):
d
29.38, 43.79,
J¼16.0 Hz), 4.64 (1H, d, J¼4.4 Hz), 5.63 (1H, d, J¼1.7 Hz), 5.87e5.89
61.71, 72.69, 83.27, 119.44, 127.64, 127.99, 128.42, 131.37, 136.59,
(1H, m). 13C NMR (75 MHz, ref¼CDCl3):
d 48.59, 57.77, 59.60, 59.68,
155.92, 166.56. IR (NaCl, cmꢀ1): nC]O¼1766; nC]N¼1668; nC]
84.32, 120.41, 126.93, 167.39. IR (NaCl, cmꢀ1): nOH¼3420; nC]
¼1645; nmax¼2969, 1531, 1498, 1455, 1394, 1213, 739, 699. MS
¼1750; nC]C¼1631; nmax¼2923, 1459, 1265, 1046, 736, 704. MS
O
C
(70 eV) m/z (%): 301 (Mþþ1, 100).
(70 eV): m/z (%) 250/2 (Mþþ1, 20).
3.2.7. (3R,4S)-1-Allyl-3-benzyloxy-4-{(E)-[((1-methylethyl)imino)
3.3.3. (3R,4S)-3-Benzyloxy-1-(2-bromo-2-propenyl)-4-
methyl]}azetidin-2-one 10g. Colorless oil. Yield 95%. 1H NMR
hydroxymethylazetidin-2-one 9c. Colorless oil. Yield 59%. Rf¼0.25
(300 MHz, CDCl3):
d
1.16 (6H, d, J¼6.3 Hz), 3.42 (1H, sept, J¼6.3 Hz),
(hexane/EtOAc 3/2). [
a
]
þ38 (c 1.00, CH2Cl2). 1H NMR (300 MHz,
D
3.79e3.94(2H, m), 4.21(1H, dꢂd, J¼6.9, 4.7 Hz), 4.62and4.70(2ꢂ1H,
2ꢂd, J¼11.8 Hz), 4.83 (1H, d, J¼4.7 Hz), 5.12e5.17 (2H, m), 5.65e5.79
CDCl3):
d
3.83e3.86 (3H, m), 3.89 and 4.40 (2ꢂ1H, 2ꢂd, J¼16.0 Hz),
4.70 (1H, d, J¼11.7 Hz), 4.81 (1H, d, J¼4.7 Hz), 4.95 (1H, d,

S. Dekeukeleire et al. / Tetrahedron 68 (2012) 10827e10834
10833
J¼11.7 Hz), 5.62 (1H, d, J¼1.9 Hz), 5.86 (1H, dꢂt, J¼1.9, 1.1 Hz),
7.30e7.41 (5H, m). 13C NMR (75 MHz, CDCl3):
48.58, 57.97, 59.65,
73.56, 81.85, 120.28, 126.83, 128.16, 128.39, 128.65, 136.47, 167.43. IR
(NaCl, cmꢀ1): nOH¼3419; nC]O¼1756; nC]C¼1631; nmax¼2928,
2875, 1671, 1497, 1455. MS (70 eV) m/z (%): 326/8 (Mþþ1, 100).
(NaCl, cmꢀ1): nNH¼3331; nC]O¼1753; nC]C¼1630; nmax¼2960,
2932, 1393, 1213, 1109, 1043. MS (70 eV): m/z (%) 291/3 (Mþþ1,
100). HRMS (ESI) calcd for C11H20BrN2O2 291.0708 [MþH]þ, found
291.0713.
d
3.3.9. (3R,4S)-3-Benzyloxy-1-(2-bromo-2-propenyl)-4-[(1,1-
3.3.4. (3R,4S)-1-(2-Bromo-2-propenyl)-4-[(1,1-dimethylethylamino)
dimethylethylamino)methyl]-azetidin-2-one 11f. Colorless oil. Yield
methyl]-3-phenoxyazetidin-2-one 11a. White crystals. Mp 70 ꢁC.
67%. Rf¼0.15 (CH2Cl2/MeOH 95/5). [
a
]
þ23 (c 1.00, CH2Cl2). 1H
D
Rf¼0.18 (CH2Cl2/MeOH 95/5). Yield 71%. [
a
]
D þ54.5 (c 1.79, CHCl3).
NMR (300 MHz, CDCl3):
d
1.04 (9H, s), 2.81 (1H, dꢂd, J¼11.8,
1H NMR (300 MHz, CDCl3):
d
1.05 (9H, s), 2.90 (1H, dꢂd, J¼11.9,
5.8 Hz), 2.87 (1H, dꢂd, J¼11.8, 6.6 Hz), 3.77e3.83 (1H, m), 4.00 and
4.28 (2ꢂ1H, 2ꢂd, J¼15.7 Hz), 4.68 (1H, d, J¼11.8 Hz), 4.95 (1H, d,
J¼5.0 Hz), 4.91 (1H, d, J¼11.8 Hz), 5.59 (1H, d, J¼2.1 Hz), 5.82 (1H,
dꢂd, J¼2.1, 1.0 Hz), 7.28e7.36 (5H, m). 13C NMR (75 MHz, CDCl3):
5.9 Hz), 3.00 (1H, dꢂd, J¼11.9, 6.3 Hz), 4.01e4.07 (1H, m), 4.09 and
4.38 (2ꢂ1H, 2ꢂd, J¼15.6 Hz), 5.33 (1H, d, J¼5.0 Hz), 5.66 and 5.88
(2ꢂ1H, 2ꢂd, J¼1.5 Hz), 7.00e7.09 and 7.28e7.33 (3H and 2H, 2ꢂm).
13C NMR (75 MHz, ref¼CDCl3):
d
28.97, 41.55, 49.22, 50.55, 58.55,
d 28.84, 41.53, 48.74, 50.26, 58.13, 73.10, 81.73, 119.92, 127.38,
80.55, 115.56, 120.52, 122.44, 127.25, 129.74, 157.55, 166.14. IR (KBr,
cmꢀ1): nNH¼3324; nC]O¼1758; nC]C¼1630; nmax¼2963, 1591, 1494,
1234, 753, 734, 690. MS (70 eV): m/z (%) 367/9 (Mþþ1, 100). HRMS
(ESI) calcd for C17H24BrN2O2 367.1021 [MþH]þ, found 367.1003.
127.81, 127.98, 128.42, 137.08, 167.67. IR (NaCl, cmꢀ1): nNH¼3311;
nC]O¼1757; nC]C¼1630; nmax¼2964, 2867, 1455, 1392, 1232, 1027,
737, 699. MS (70 eV) m/z (%): 381/3 (Mþþ1, 100).
3.3.10. (3R,4S)-3-Benzyloxy-1-(2-bromo-2-propenyl)-4-[(1-
3.3.5. (3R,4S)-1-(2-Bromo-2-propenyl)-4-[(1-methylethylamino)
methylethylamino)methyl]azetidin-2-one 11g. Colorless oil. Yield
methyl]-3-phenoxyazetidin-2-one 11b. Yellow oil. Rf¼0.04 (CH2Cl2/
82%. Rf¼0.12 (CH2Cl2/MeOH 95/5). [
a
]
þ20 (c 1.00, CH2Cl2). 1H
D
MeOH 97/3). Yield 62%. [
a
]
þ113.9 (c 0.65, CHCl3). 1H NMR
NMR (300 MHz, CDCl3):
d
1.01 and 1.02 (2ꢂ3H, 2ꢂd, J¼6.3 Hz), 2.75
D
(300 MHz, CDCl3):
d
1.45 and 1.46 (2ꢂ3H, 2ꢂd, J¼6.1 Hz), 3.34e3.41
(1H, sept, J¼6.3 Hz), 2.87 (1H, dꢂd, J¼12.1, 5.8 Hz), 2.94 (1H, dꢂd,
J¼12.1, 6.9 Hz), 3.83e3.89 (1H, m), 3.99 and 4.30 (2ꢂ1H, 2ꢂd,
J¼15.7 Hz), 4.70 (1H, d, J¼11.8 Hz), 4.76 (1H, d, J¼5.0 Hz), 4.94 (1H,
d, J¼11.8 Hz), 5.61 (1H, d, J¼2.0 Hz), 5.83 (1H, dꢂd, J¼2.0, 1.0 Hz),
(3H, m), 4.21 and 4.34 (2ꢂ1H, 2ꢂd, J¼15.4 Hz), 4.62e4.68 (1H, m),
5.47 (1H, d, J¼5.0 Hz), 5.66 (1H, d, J¼2.1 Hz), 6.09 (1H, dꢂd, J¼2.1,
1.1 Hz), 7.02e7.07, 7.19e7.22 and 7.27e7.35 (1H, 2H and 2H, 3ꢂm).
13C NMR (75 MHz, ref¼CDCl3):
d
19.49, 19.66, 42.24, 49.45, 51.72,
7.30e7.36 (5H, m). 13C NMR (75 MHz, CDCl3):
d 22.78, 22.89, 45.87,
54.59, 81.50,116.43,122.40,123.13,126.70,129.88,156.86,165.70. IR
(NaCl, cmꢀ1): nNH¼3406; nC]O¼1762; nC]C¼1630; nmax¼2941,1592,
1494, 1934, 1234, 909, 754, 727, 690. MS (70 eV): m/z (%) 353/5
(Mþþ1, 100).
48.80, 49.10, 57.61, 73.16, 81.78, 120.02, 127.34, 127.87, 128.05,
128.49, 137.08, 167.74. IR (NaCl, cmꢀ1): nNH¼3336; nC]O¼1756; nC]
¼1631; nmax¼2963, 2928, 1674, 1455, 1398, 1110, 738, 699. MS
C
(70 eV) m/z (%): 367/9 (Mþþ1, 100).
3.3.6. (3R,4S)-4-[(Benzylamino)methyl]-1-(2-bromo-2-propenyl)-3-
3.3.11. (3R,4S)-4-[(Benzylamino)methyl]-3-benzyloxy-1-(2-bromo-
phenoxyazetidin-2-one 11c. Yellow oil. Rf¼0.48 (CH2Cl2/MeOH 95/
2-propenyl)azetidin-2-one 11h. Colorless oil. Yield 45%. Rf¼0.5
5). Yield 48%. [
a
]
D þ38.7 (c 1.03, CHCl3). 1H NMR (300 MHz, CDCl3):
(CH2Cl2/MeOH 95/5).
[
a
]
þ35 (c 1.00, CH2Cl2). 1H NMR
D
d
2.98 (1H, dꢂd, J¼12.9, 6.2 Hz), 3.05 (1H, dꢂd, J¼12.9, 5.9 Hz), 3.78
(300 MHz, CDCl3):
d
1.98 (1H, br s), 2.87 (1H, dꢂd, J¼12.4, 5.5 Hz),
(2H, s), 4.02 (1H, d, J¼15.7 Hz), 4.06e4.12 (1H, m), 4.40 (1H, d,
J¼15.7 Hz), 5.32 (1H, d, J¼4.6 Hz), 5.61 (1H, d, J¼1.8 Hz), 5.78 (1H,
dꢂd, J¼1.8, 0.8 Hz), 7.00e7.06 and 7.24e7.33 (3H and 7H, 2ꢂm). 13C
2.94 (1H, dꢂd, J¼12.4, 6.3 Hz), 3.75 (2H, s), 3.84e3.89 (1H, m),
3.91 and 4.30 (2ꢂ1H, 2ꢂd, J¼16.0 Hz), 4.67 (1H, d, J¼11.6 Hz), 4.74
(1H, d, J¼5.0 Hz), 4.90 (1H, d, J¼11.6 Hz), 5.56 (1H, d, J¼2.0 Hz),
5.74 (1H, dꢂd, J¼2.0 Hz, J¼1.0 Hz), 7.22e7.38 (10H, m). 13C NMR
NMR (75 MHz, ref¼CDCl3):
d 47.62, 49.17, 54.18, 57.48, 80.64, 115.60,
120.55, 122.52, 127.36, 128.20, 128.61, 129.77, 139.61, 157.45, 165.99.
IR (NaCl, cmꢀ1): nNH¼3319; nC]O¼1756; nC]C¼1630; nmax¼2926,
1590, 1494, 1235, 908, 752, 730, 691. MS (70 eV): m/z (%) 401/3
(Mþþ1, 100).
(75 MHz, CDCl3): d 47.61, 48.69, 54.17, 57.18, 73.18, 81.75, 119.98,
127.06, 127.98, 128.04, 128.08, 128.42, 128.49, 136.99, 139.93,
167.66. IR (NaCl, cmꢀ1): nNH¼3329; nC]O¼1758; nC]C¼1630;
nmax¼2922, 1454, 1397, 1027, 738, 698. MS (70 eV) m/z (%): 415/7
(Mþþ1, 100).
3.3.7. (3R,4S)-1-(2-Bromo-2-propenyl)-3-methoxy-4-[(1,1-
dimethylethylamino)methyl]-azetidin-2-one 11d. Light-yellow oil.
3.4. Synthesis of (3R,4R)-1-(2,3-dibromopropyl)-4-formyl-3-
Rf¼0.21 (CH2Cl2/MeOH 95/5). Yield 64%. [
a
]
D þ63.4 (c 0.97, CHCl3).
phenoxyazetidin-2-one 13
1H NMR (300 MHz, CDCl3):
d
1.13 (9H, s), 2.62 (1H, br s), 2.86 (1H,
dꢂd, J¼11.8, 5.8 Hz), 2.93 (1H, dꢂd, J¼11.8, 6.9 Hz), 3.59 (3H, s),
3.83e3.91 (1H, m), 4.03 and 4.28 (2ꢂ1H, 2ꢂd, J¼16.0 Hz), 4.59 (1H,
d, J¼5.0 Hz), 5.63 (1H, d, J¼2.2 Hz), 5.86 (1H, s). 13C NMR (75 MHz,
The synthesis of (3R,4R)-1-(2,3-dibromopropyl)-4-formyl-3-
phenoxyazetidin-2-one 13 was performed by means of a slightly
modified four-step literature procedure using the hydrobromide
salt of 2,3-dibromopropylamine as the starting material.7 Com-
pound 13 was obtained as a mixture of diastereomers (dr w 1/1).
ref¼CDCl3):
d 28.64, 41.26, 48.88, 51.29, 57.78, 59.42, 83.94, 120.29,
127.42, 167.81. IR (NaCl, cmꢀ1): nNH¼3310; nC]O¼1750; nC]C¼1630;
nmax¼2960, 2930, 1389, 1213, 1117, 1049. MS (70 eV): m/z (%) 305/7
(Mþþ1, 100). HRMS (ESI) calcd for C12H22BrN2O2 305.0865 [MþH]þ,
found 305.0852.
3.4.1. (3R,4R)-1-(2,3-Dibromopropyl)-4-formyl-3-phenoxyazetidin-
2-one 13. Spectral data of one isomer isolated by column chroma-
tography (SiO2). Light-yellow oil. Yield 68%. Rf¼0.28 (hexane/EtOAc
3.3.8. (3R,4S)-1-(2-Bromo-2-propenyl)-3-methoxy-4-[(1-
methylethylamino)methyl]azetidin-2-one 11e. Light-yellow oil.
1/1).1H NMR (300 MHz, CDCl3):
d
3.70 (1H, dꢂd, J¼11.0, 8.3 Hz), 3.81
(1H, dꢂd, J¼11.0, 4.4 Hz), 3.93 (1H, dꢂd, J¼15.2, 4.7 Hz), 4.01 (1H,
dꢂd, J¼15.2, 6.4 Hz), 4.29e4.37 (1H, m), 4.77 (1H, dꢂd, J¼5.2,1.1 Hz),
5.58 (1H, d, J¼5.2 Hz), 7.00e7.07 and 7.25e7.32 (3H and 2H, 2ꢂm),
Rf¼0.13 (CH2Cl2/MeOH 95/5). Yield 60%. [
a
]
D þ67.1 (c 1.26, CHCl3).
1H NMR (300 MHz, CDCl3):
d
1.31 (6H, d, J¼6.1 Hz), 3.08e3.22 (3H,
m), 3.65 (3H, s), 4.08 (1H, d, J¼15.7 Hz), 4.19e4.23 (1H, m), 4.26
(1H, d, J¼15.7 Hz), 4.72 (1H, d, J¼4.4 Hz), 5.66 and 5.96 (2ꢂ1H,
9.70 (1H, d, J¼1.1 Hz). 13C NMR (75 MHz, ref¼CDCl3):
d 33.52, 46.62,
48.15, 64.82, 82.37, 115.51, 123.22, 129.94, 156.80, 165.52, 196.95. IR
(ATR, cmꢀ1): nNC]O¼1760; nHC]O¼1730; nmax¼1596, 1496, 1400,
1226, 690. MS (70 eV) m/z (%): 390/2/4 (Mþþ1, 100).
2ꢂd, J¼2.2 Hz). 13C NMR (75 MHz, ref¼CDCl3):
d 20.61, 20.73,
43.40, 49.04, 50.71, 55.43, 59.62, 84.01, 121.27, 127.07, 167.58. IR

10834
S. Dekeukeleire et al. / Tetrahedron 68 (2012) 10827e10834
€
€
€
S.; Wunsch, B. Eur. J. Med. Chem. 2006, 41, 387; (c) Bedurftig, S.; Wunsch, B.
Bioorg. Med. Chem. 2004, 12, 3299; (d) Cole, A. G.; Stroke, I. L.; Brescia, M.-R.;
Simhadri, S.; Zhang, J. J.; Hussain, Z.; Snider, M.; Haskell, C.; Ribeiro, S.;
Appell, K. C.; Henderson, I.; Webb, M. L. Bioorg. Med. Chem. Lett. 2006, 16,
200; (e) Levin, J. I.; DiJoseph, J. F.; Killar, L. M.; Sung, A.; Walter, T.; Sharr, M.
A.; Roth, C. E.; Skotnicki, J. S.; Albright, J. D. Bioorg. Med. Chem. Lett. 1998, 8,
2657.
3.5. Synthesis of (3R,4S)-1-(2,3-dibromo-2-methylpropyl)-4-
hydroxymethyl-3-phenoxyazetidin-2-one 15
The synthesis of (3R,4S)-1-(2,3-dibromo-2-methylpropyl)-4-
hydroxymethyl-3-phenoxyazetidin-2-one 15 was analogous to the
synthesis of (3R,4S)-1-(2-bromo-2-propenyl)-4-hydroxymethyl-3-
phenoxyazetidin-2-one 9a, using (3R,4R)-4-formyl-1-(2-methyl-2-
propenyl)-3-phenoxyazetidin-2-one 14 as the starting material.
Compound 15 was obtained as a mixture of diastereomers (dr 84/
16). The major isomer was isolated through column chromatogra-
phy on silica gel.
€ €
2. (a) Fulop, F. Chem. Rev. 2001, 101, 2181; (b) Hamuro, Y.; Schneider, J. P.; DeGrado,
W. F. J. Am. Chem. Soc. 1999, 121, 12200; (c) Gademann, K.; Hintermann, T.;
Schreiber, J. V. Curr. Med. Chem. 1999, 6, 905; (d) Steer, D. L.; Lew, R. A.; Perl-
mutter, P.; Smith, A. I.; Aquilar, M. I. Curr. Med. Chem. 2002, 9, 811; (e) Fulop, F.;
€ €
ꢀ
Martinek, T. A.; Toth, G. K. Chem. Soc. Rev. 2006, 35, 323; (f) Gauzy, C.; Saby, B.;
Pereira, E.; Faure, S.; Aitken, D. J. Synlett 2006, 1394; (g) Hjelmgaard, T.; Faure,
S.; Lemoine, P.; Viossat, B.; Aitken, D. J. Org. Lett. 2008, 10, 841; (h) Seebach, D.;
Gardiner, J. Acc. Chem. Res. 2008, 41, 1366; (i) Seebach, D.; Beck, A. K.; Capone,
S.; Deniau, G.; Groselj, U.; Zass, E. Synthesis 2009, 1.
3.5.1. (3R,4S)-1-(2,3-Dibromo-2-methylpropyl)-4-hydroxymethyl-3-
phenoxyazetidin-2-one 15. Spectral data of the major isomer. White
crystals. Mp 87e88 ꢁC. Rf¼0.13 (hexane/EtOAc 4/1). Yield 58%. 1H
3. Gauvreau, D.; Hughes, G. J.; Lau, S. Y. W.; McKay, D. J.; O’Shea, P. D.; Sidler, R. R.;
Yu, B.; Davies, I. W. Org. Lett. 2010, 12, 5146.
4. (a) Ojima, I. Acc. Chem. Res. 1995, 28, 383; (b) Ojima, I.; Delaloge, F. Chem.
Soc. Rev. 1997, 26, 377; (c) Alcaide, B.; Almendros, P. Synlett 2002, 381; (d)
Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Curr. Med. Chem. 2004,
11, 1837; (e) Deshmukh, A. R. A. S.; Bhawal, B. M.; Krishnaswamy, D.; Go-
vande, V. V.; Shinkre, B. A.; Jayanthi, A. Curr. Med. Chem. 2004, 11, 1889; (f)
Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Rev. 2007, 107, 4437; (g)
D’hooghe, M.; Dekeukeleire, S.; Leemans, E.; De Kimpe, N. Pure Appl. Chem.
2010, 82, 1749; (h) Singh, G. S.; D’hooghe, M.; De Kimpe, N. Tetrahedron 2011,
67, 1989.
5. Viso, A.; de la Pradilla, R. F.; Flores, A. Tetrahedron Lett. 2006, 47, 8911.
6. (a) Bose, A. K.; Manhas, M. S.; van der Veen, J. M.; Bari, S. S.; Wagle, D. R.; Hegde,
V. R.; Krishnan, L. Tetrahedron Lett. 1985, 26, 33; (b) Bose, A. K.; Hegde, V. R.;
Wagle, D. R.; Bari, S. S.; Manhas, M. S. J. Chem. Soc., Chem. Commun. 1986, 161;
(c) Wagle, D. R.; Garai, C.; Chiang, J.; Monteleone, M. G.; Kurys, B. E.; Stroh-
meyer, T. W.; Hegde, V. R.; Manhas, M. S.; Bose, A. K. J. Org. Chem. 1988, 53,
4227; (d) Wagle, D. R.; Garai, C.; Monteleone, M. G.; Bose, A. K. Tetrahedron Lett.
1988, 29, 1649; (e) Manhas, M. S.; Wagle, D. R.; Chiang, J.; Bose, A. K. Hetero-
cycles 1988, 27, 1755; (f) Banik, B. K.; Manhas, M. S.; Kaluza, Z.; Barakat, K. J.;
Bose, A. K. Tetrahedron Lett. 1992, 33, 3603; (g) Banik, B. K.; Manhas, M. S.; Bose,
A. K. J. Org. Chem. 1993, 58, 307; (h) Grigg, R.; Thornton-Pett, M.; Xu, J.; Xu, L.-H.
Tetrahedron 1999, 55, 13841.
NMR (300 MHz, CDCl3):
d
1.91 (3H, s), 2.16 (1H, dꢂd, J¼8.9, 4.7 Hz),
3.55 (1H, d, J¼15.1 Hz), 3.81 and 3.91 (2ꢂ1H, 2ꢂd, J¼10.5 Hz),
4.07e4.17 (2H, m), 4.18 (1H, d, J¼15.1 Hz), 4.35e4.39 (1H, m), 5.38
(1H, d, J¼5.0 Hz), 7.01e7.12 and 7.29e7.35 (3H and 2H, 2ꢂm). 13C
NMR (75 MHz, ref¼CDCl3):
d 28.99, 40.19, 50.36, 58.68, 59.95, 64.61,
80.99, 115.92, 123.09, 129.88, 157.15, 167.33. IR (ATR, cmꢀ1):
nOH¼3402; nC]O¼1728; nmax¼2926, 1494, 1365, 1224, 1050, 752,
692. MS (70 eV): m/z (%) 406/8/10 (Mþþ1, 100).
3.6. Synthesis of (3R,4S)-3-benzyloxy-1-(2,2,3-
tribromopropyl)-4-hydroxymethylazetidin-2-one 16
To a solution of (3R,4S)-3-benzyloxy-1-(2-bromo-2-propenyl)-
4-hydroxymethylazetidin-2-one 9c (0.30 g, 0.92 mmol, 1 equiv) in
dry CH2Cl2 (20 mL) was added
a solution of Br2 (0.15 g,
7. Van Brabandt, W.; Vanwalleghem, M.; D’hooghe, M.; De Kimpe, N. J. Org. Chem.
2006, 71, 7083.
0.92 mmol, 1 equiv) in dry CH2Cl2 (10 mL). After stirring at room
temperature for 18 h, the solvent was evaporated and crude
(3R,4S)-3-benzyloxy-1-(2,2,3-tribromopropyl)-4-
hydroxymethylazetidin-2-one 16 was obtained, which was puri-
fied by column chromatography on silica gel to give the pure
compound 16 in 82% yield.
8. (a) Cossio, F. P.; Ugalde, J. M.; Lopez, X.; Lecea, B.; Palomo, C. J. Am. Chem. Soc.
1993, 115, 995; (b) Singh, G. S.; D’hooghe, M.; De Kimpe, N. In Comprehensive
Heterocyclic Chemistry III; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Padwa, A.,
Eds.; Chapter “Azetidines, Azetines, and Azetes: Monocyclic”; Elsevier: Oxford,
2008; vol. 2, pp 1e110; (c) Palomo, C.; Aizpurua, J. M.; Inaki, G.; Oiarbide, M.
Eur. J. Org. Chem. 1999, 3223; (d) Singh, G. S Tetrahedron 2003, 59, 7631; (e) Fu,
N.; Tidwell, T. T. Tetrahedron 2008, 64, 10465; (f) Cossio, F. P.; Arrieta, A.; Sierra,
M. A. Acc. Chem. Res. 2008, 41, 925.
9. (a) Alcaide, B.; Pardo, C.; Saez, E. Synlett 2002, 85; (b) Alcaide, B.; Almendros,
P.; Pardo, C.; Rodriguez-Ranera, C.; Rodriguez-Vicente, A. J. Org. Chem. 2003,
68, 3106; (c) Alcaide, B.; Almendros, P.; Rodríguez-Acebes, R. J. Org. Chem.
2005, 70, 2713; (d) Alcaide, B.; Saez, E. Eur. J. Org. Chem. 2005, 1680; (e)
Alcaide, B.; Almendros, P.; Aragoncillo, C.; Redondo, M. C.; Torres, M. R.
Chem.dEur. J. 2006, 12, 1539; (f) Alcaide, B.; Almendros, P.; Aragoncillo, C.;
Redondo, M. C. J. Org. Chem. 2007, 72, 1604; (g) Alcaide, B.; Almendros, P.;
Pardo, C.; Rodriguez-Ranera, C.; Rodriguez-Vicente, A. Chem. Asian J. 2009, 4,
1604.
3.6.1. (3R,4S)-3-Benzyloxy-1-(2,2,3-tribromopropyl)-4-
hydroxymethylazetidin-2-one 16. Yellow oil. Yield 82%. Rf¼0.35
(hexane/EtOAc 3/2). [
a
]
þ57 (c 1.00, CH2Cl2). 1H NMR (300 MHz,
D
CDCl3):
d
3.87 (1H, d, J¼15.4 Hz), 3.93 (1H, dꢂd, J¼13.2, 1.9 Hz), 4.04
(1H, dꢂd, J¼13.2, 3.3 Hz), 4.15 (1H, d, J¼11.8 Hz), 4.17 (1H, m), 4.21
(1H, d, J¼11.8 Hz), 4.51 (1H, d, J¼15.4 Hz), 4.71 (1H, d, J¼11.6 Hz),
4.85 (1H, d, J¼5.0 Hz), 4.96 (1H, d, J¼11.6 Hz), 7.31e7.42 (5H, m). 13C
NMR (75 MHz, CDCl3):
d 42.38, 53.41, 58.35, 59.62, 64.65, 73.68,
10. (a) Kale, A. S.; Puranik, V. G.; Rakkeb, A.; Deshmukh, A. R. A. S. Synthesis 2007,
1159; (b) Kale, A. S.; Sakle, P. S.; Gumaste, V. K.; Deshmukh, A. R. A. S. Synthesis
2007, 2631; (c) Shirode, N. M.; Likhite, A. P.; Gumaste, V. K.; Deshmukh, A. R. A.
S. Tetrahedron 2008, 64, 7191.
81.64, 128.24, 128.53, 128.73, 136.16, 168.54. IR (NaCl, cmꢀ1):
nOH¼3418; nC]O¼1759; nmax¼2925, 1394, 1158, 1047. MS (70 eV) m/
z (%): 484/86/88/90 (Mþþ1, 100).
11. (a) Orena, M.; Porzi, G.; Sandri, S. J. Org. Chem. 1992, 57, 6532; (b) Williams, A. J.;
Chaktong, S.; Gray, D.; Lawrence, R. M.; Gallagher, T. Org. Lett. 2003, 5, 811; (c)
Schanen, V.; Riche, C.; Chiaroni, A.; Quirion, J.-C.; Husson, H.-P. Tetrahedron Lett.
1994, 35, 2533; (d) Palomo, C.; Ganboa, I.; Cuevas, C.; Boschetti, C.; Linden, A.
Tetrahedron Lett. 1997, 38, 1591.
Acknowledgements
ꢁ
12. Alcaide, B.; Pardo, C.; Rodríguez-Ranera, C.; Rodrõguez-Vicente, A. Org. Lett.
The authors are indebted to the ‘Research Foundation-Flanders’
(FWO-Vlaanderen) and to Ghent University (GOA) for financial
support.
2001, 3, 4205.
13. For recent examples, see: (a) D’hooghe, M.; Van Brabandt, W.; De Kimpe, N.
J. Org. Chem. 2004, 69, 2703; (b) Sun, C.; Fang, Y.; Li, S.; Zhang, Y.; Zhao, Q.;
Zhu, S.; Li, C. Org. Lett. 2009, 11, 4084; (c) Zhao, Q.; Li, C. Org. Lett. 2008, 10,
4037; (d) Lemhadri, M.; Battace, A.; Berthiol, F.; Zair, T.; Doucet, H.; Santelli,
M. Synthesis 2008, 1142; (e) Liao, Q.; Wang, Y.; Zhang, L.; Xi, C. J. Org. Chem.
2009, 74, 6371; (f) Mao, J.; Xie, G.; Zhan, J.; Hua, Q.; Shi, D. Adv. Synth. Catal.
2009, 351, 1268.
References and notes
1. (a) Chaudhary, P.; Kumar, R.; Verma, A. K.; Singh, D.; Yadav, V.; Chhilar, A. K.;
€
Sharma, G. L.; Chandra, R. Bioorg. Med. Chem. 2006, 14, 1819; (b) Bedurftig,