Synthesis of spirocyclopropyl γ-lactams by tandem intramolecular azetidine ring-opening/closing cascade reaction: Synthetic and mechanistic aspects

Article abstract of DOI:10.1016/j.tet.2012.03.111

The scope and limitations of a novel intramolecular azetidine ring-opening/closing cascade reaction affording spirocyclopropyl γ-lactams from azetidines in high regio- and stereoselectivity is reported. The key step of the process is a S_N2-type ring-opening of TMSOTf-activated azetidine rings by silyl ketene acetals generated by treatment with TMSOTf and TEA. This study is a very rare example of nucleophilic ring-opening of azetidines that does not require formation of quaternary azetidinium salts by N-alkylation or the use of N-electron-withdrawing groups. Application of this process to 2-azetidinone system led to a complete change in reactivity and provide 6-aza-bicyclo[3.2.0]heptane derivatives via an unprecedented Mukaiyama aldol-like reaction involving an ester acceptor and a silyl imidate.

Full text of DOI:10.1016/j.tet.2012.03.111

Tetrahedron 68 (2012) 4117e4128
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of spirocyclopropyl
g-lactams by tandem intramolecular azetidine
ring-opening/closing cascade reaction: synthetic and mechanistic aspects
,b,
Pierre-Antoine Nocquet a, Damien Hazelard a, Philippe Compain a
*
a
ꢀ
ꢁ
ꢁ
ꢁ
ꢀ
ꢁ
Laboratoire de Synthese Organique et Molecules Bioactives, Universite de Strasbourg/CNRS (UMR 7509), Ecole Europeenne de Chimie, Polymeres et Materiaux, 25 rue Becquerel,
67087 Strasbourg, France
b Institut Universitaire de France, 103 Bd Saint-Michel, 75005 Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The scope and limitations of a novel intramolecular azetidine ring-opening/closing cascade reaction
Received 27 February 2012
Received in revised form 21 March 2012
Accepted 28 March 2012
Available online 4 April 2012
affording spirocyclopropyl g-lactams from azetidines in high regio- and stereoselectivity is reported. The
key step of the process is a SN2-type ring-opening of TMSOTf-activated azetidine rings by silyl ketene
acetals generated by treatment with TMSOTf and TEA. This study is a very rare example of nucleophilic
ring-opening of azetidines that does not require formation of quaternary azetidinium salts by N-alkyl-
ation or the use of N-electron-withdrawing groups. Application of this process to 2-azetidinone system
led to a complete change in reactivity and provide 6-aza-bicyclo[3.2.0]heptane derivatives via an un-
precedented Mukaiyama aldol-like reaction involving an ester acceptor and a silyl imidate.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Domino reactions
Lactams
Azetidines
Nucleophilic ring-opening
Spirocyclic compounds
O
R
1. Introduction
H
N
HOHN
N
Spirocyclopropyl compounds have stimulated the imagination
of theoretical, synthetic, and medicinal chemists because of their
appealing structures and their pharmacological interests. The spi-
rocyclopropyl scaffold is indeed a useful tool for the design of
constrained bioactive molecules projecting pharmacophores into
the appropriate protein binding pockets. The 5-azaspiro[2.4]hep-
tane skeleton, combining a cyclopropane moiety and a pyrrolidine
moiety via a spiro carbon, is a structural motif present in various
biologically active molecules including anti-autoimmune and an-
tibacterial agents (Fig. 1).1,2 The addition of the 5-azaspiro[2.4]
heptane motif to various classes of well-known antibiotics, such as
carbapenem or fluoroquinolone derivatives, has been found to be
beneficial both in terms of antibacterial activity and pharmacoki-
O
F
O
N
O
O
AcHN
Ph
N
Oxazolidinone-based
antibacterial agents
TACE inhibitor
O
N
F
COOH
netic profiles.1aeh Spirocyclopropyl
g-lactams have also been used
N
as key intermediates in the synthesis of cyclopropyl amino acids.3
Despite recent progress in the area,4 the efficient stereoselective
synthesis of such constrained small ring systems remains a chal-
lenge. In connection with our work on novel class of iminosugars,5
Cl
H2N
O
F
Sitafloxacin
fluoroquinolone antibiotic
we have recently reported the synthesis of
a-spirocyclopropyl
NH2
2 steps
g
-lactams by novel tandem azetidine ring-opening/closing
a
HO2C
CO2H
t
CO2Bu
N
t
CO2Bu
* Corresponding author. Tel.: þ33 3 6885 2792; fax: þ33 3 6885 2742; e-mail
Fig. 1. Some examples of 5-azaspiro[2.4]heptane derivatives of biological interest.
address: philippe.compain@unistra.fr (P. Compain).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.111

4118
P.-A. Nocquet et al. / Tetrahedron 68 (2012) 4117e4128
cascade reaction (Scheme 1).6 In this intramolecular process, the
cyclopropane and the pyrrolidine rings are created in a single
synthetic operation in high stereoselectivity. Herein, we wish to
describe the full details of this study including mechanistic aspects
and reaction scope. We have especially investigated the effects of
varying the key structural elements of the reaction substrate, such
as chain length, ring size, and nitrogen atom basicity. The spiro-
cyclization reaction depicted on Scheme 1 represents a very rare
example of nucleophilic ring-opening of azetidines7 without for-
mation of quaternary azetidinium salts by N-alkylation or the use of
N-electron-withdrawing group.8e11 Ring-opening of azetidines in-
deed requires stronger activation than that of aziridines as a con-
sequence of reduced ring strain and electrophilicity. In a recent
relevant study, azetidinium derivatives were indeed shown to be
17,000 times less reactive than the corresponding aziridinium an-
alogs toward nucleophilic ring-opening.12
To extend the synthetic scope of the spiro-cyclization reaction,
we also synthesized -lactam 9, the 2-azetidinone analogue of 1
b
(Scheme 3). N-Benzyl glutamate diester 7 was readily obtained in
three steps from (S)-glutamate14 and converted to N-chloroacetyl
amino acid 8 as a prelude to ring-closure reaction. Cs2CO3-assisted
intramolecular alkylation15 afforded the expected
acceptable yields.
b
-lactam 9 in
3 steps
HO2C
CO2H
MeO2C
CO2Me
Ref. 14
NH2
NHBn
7
(S)-glutamate
CO2Me
MeO2C
CO2Me
b
a
CO2Me
N
Bn
N
O
Cl
Bn
8
9
Bn
TMSOTf (2 equiv)
TEA (2.5 equiv)
CO2Me
O
N
O
Scheme 3. Synthesis of
b-lactam 9. Reaction conditions: (a) chloroacetyl chloride
CO2Me
(1.5 equiv), propylene oxide (15 equiv), THF, 17 h, rt, 59%; (b) Cs2CO3 (3 equiv), CH3CN,
72e96 h, rt, 62%.
CH2Cl2
N
Bn
CO2Me
75%
1
Having test substrates 5 and 9 in hand, we investigated the
tandem reaction. Deactivation of the azetidine endocyclic nitrogen
atom was found to be detrimental to the process as no spiranic
2a > 98% de
-lactam 2a by tandem azetidine ring-
Scheme 1. Synthesis of spirocyclopropyl
opening/closing cascade reaction.
g
product could be obtained from N-Boc or N-Tos azetidines 5, or b-
lactam 9. Azetidine 5a remained almost unchanged after treatment
with TMSOTf and TEA whereas the secondary amine 6 was the only
product isolated in 20% yield from N-Boc azetidine 5b. Addition of
2. Results and discussion
2.1. Optimization and exploration of reaction scope
a carbonyl group to the azetidine ring to give a b-lactam led to
a complete change in reactivity. Under typical spiro-cyclization
conditions, 2-azetidinone 9 provided the 6-aza-bicyclo[3.2.0]hep-
tane derivatives 10 and 11 as mixture of diastereoisomers
(Scheme 4). This fused bicyclic system may reasonably be formed
by a reaction sequence involving in situ formation of O-silyl imidate
followed by intramolecular addition to the sterically less hindered
ester group. While there are several examples of Mukaiyama aldol
reaction of N,O-ketene acetals with aldehydes, the corresponding
reaction of ketones has been found to be more challenging due to
the lower reactivity of the ketone carbonyl group.16 Remarkably, to
our knowledge, the synthesis of 10 and 11 represents the first ex-
ample of a reaction of this type where the carbonyl reactant is an
ester. As shown by the results obtained with N-Boc and N-Tos
A systematic study on the influence of the experimental con-
ditions has shown that the best results were obtained when aze-
tidine 1 was treated with 2 equiv of TMSOTf in the presence of
2.5 equiv of TEA in dichloromethane.6 Decreasing the amount of
TMSOTf or TEA to 1 equiv was found to be detrimental as no re-
action took place, whereas the addition of more equivalents of
Lewis acid or base did not improve significantly the yield of the
reaction. The nature of the Lewis acid was also found to be crucial as
conversion of the azetidine starting material was observed only
with TMSOTf as indicated by a screening of various azaphilic or
oxophilic Lewis acids.6 To study the influence of diverse structural
parameters in the outcome of the spiro-cyclization reaction, vari-
ous test substrates were synthesized. We first explored azetidine
derivatives bearing an electron-withdrawing group at the nitrogen
center. The N-Boc or N-Tos azetidines 5 were obtained from the
corresponding N-benzyl analogue 1 synthesized in two steps from
TMSO
OMe
R
CO2Me
commercially available
a
,g
-dibromo ester 3 (Scheme 2).13
O
b
a
c
CO2Me
N
N
CO2Me
CO2Me
Br
O
Bn
O
Bn
CO2Me
10 R=TMS
11 R=H
9
b
a
CO2Me
N
N
MeO
Bn
Bn
O
Br
3
1
TMSO
4
O
OMe
O
CO2Me
5a R = Ts
R
N
c, d or e
N
5b R = Boc
6 R = H
CO2Me
Bn
Bn
N
R
OH
OH
14
Scheme 2. Synthesis of test substrates
5
and 6. Reaction conditions: (a) BnNH2
12 R=TMS
13 R=H
(1 equiv), NEt3 (3 equiv), CH3CN, 4 h, rt, 67%; (b) (i) LDA (1.1 equiv), THF, 1 h,
ꢀ78 ꢁC/ꢀ65 ꢁC; (ii) Methyl 3-bromopropionate (3 equiv), HMPA (6.3 equiv), THF,
16 h, ꢀ78 ꢁC/rt, 41%; (c) (i) Pd(OH)2/C 20%, HCO2H, H2, EtOH, 24 h, rt; (ii) TsCl
(1 equiv), NEt3 (3 equiv), CH2Cl2, 16 h, rt, 5a, 29%; (d) Pd(OH)2/C 20%, Boc2O (1.5 equiv),
H2, EtOH, 16 h, 5b, quant.; (e) Pd/C 10%, HCO2H, H2, MeOH, 24 h, rt, 6, 55%.
Scheme 4. Synthesis of bicyclic azetidinone 14. Reaction conditions: (a) TMSOTf
(3 equiv), NEt3 (4 equiv), CH2Cl2, 24 h, rt; (b) LiBH4, Et2O, 8 h, rt; (c) HCl 1 N, THF, 5 h, rt,
36% (for the three steps).

P.-A. Nocquet et al. / Tetrahedron 68 (2012) 4117e4128
4119
Table 1
azetidines 5, deactivation of the endocyclic nitrogen atom blocks
the key azetidine ring-opening step; when the reaction is per-
formed with -lactam 9, the Mukaiyama aldol-like reaction path-
Alkylation of azetidine 4a
Yieldb
b
RBr
Product
way becomes thus preponderant. In this process, in the presence of
an excess of TMSOTf and over time, a part of the silyl ketene acetal
CO2Me
derived from 9 is converted to its isomeric a
-silylated ester.17a It is
CO2Me
1 (n¼1)
45%
11%
14%
( )n
Br
( )n
CO2Me
CO2Me
noteworthy that 6-aza-bicyclo[3.2.0]heptane derivatives are
known to display antimalarials activity and have been used as
17 (n¼2)
18 (n¼4)
N
Bn
CO2Me
building blocks for the synthesis of bioactive b
-amino acids.18 To
confirm unambiguously the rather complex structures of 10 and 11,
our aim was to obtain a structurally simpler compound that may
crystallize and be characterized by X-ray crystallographic analysis
(Scheme 4).
Chemoselective reduction of the ester group by treatment with
4 equiv of LiBH4 provided the expected primary alcohol of 12 and 13
as a mixture. The one-pot acetal hydrolysis/desilylation reaction
under acidic conditions greatly simplified the bicycle structure by
removal of two asymmetric centers, providing ketone 14 as a single
diastereoisomer in 36% yield for the three steps. The structure of 14,
which was nicely crystallized from the ternary solvent system
CH2Cl2/hexane/diethyl ether, was unambiguously determined by
NMR spectroscopy and X-ray crystallographic analysis (Fig. 2).
Me
19c
12%
14%
CO2Me
Br
Me
Bn
N
CO2Me
CO2Me
Br
20
CO2Me
N
Me
Bn Me
a
Reaction conditions: (i) LDA (1.1 equiv), THF, 1 h, ꢀ78 ꢁC/ꢀ65 ꢁC; (ii) Bro-
moester (3 equiv), HMPA (6.3 equiv), THF, 20 h, ꢀ78 ꢁC/rt.
b
Isolated yield after purification by flash chromatography on silica gel.
c
Addition of the bromoester at ꢀ5 ꢁC in the absence of HMPA (see Experimental
section).
methylene units to favor azetidine ring-opening (formation of a six-
membered ring) over the Dieckmann reaction (formation of a dis-
favored seven-membered ring)17a led to a substrate (18) that was
not reactive under our typical cyclization conditions.
CO2Me
MeO
CO2Me
TMSO
( )n
a
( )n CO2Me
N
N
Bn
Bn
Fig. 2. Molecule structure (ORTEP)19 of compound 14. Thermal ellipsoid at 30%
probability.
17 n=2
18 n=4
21 n=1, 40% yield
n=3, not observed
Bn
tBu
CO2
tBu
CO2
The spiro-cyclization process was found to proceed even in the
absence of a nitrogen protecting group as shown by conversion of
N
O
c
b
CO2Me
N
N
secondary amine 6 to
prisingly, this reaction is in competition with the formation of
lactam 16, arising from the nucleophilic addition of the free amine
to the ester group in -position to the nitrogen atom. Lactams 15
b-lactam 15 (Scheme 5). However, not sur-
CO2Me
> 98% de
Bn
Bn
g-
22
23
2a
g
Scheme 6. Reaction of test substrates 17, 18, and 23. Reaction conditions: (a) TMSOTf
(2 equiv), NEt3 (2.5 equiv), CH2Cl2, 24 h, rt, 40%; (b) (i) LDA (1.1 equiv), THF, 1 h,
ꢀ78 ꢁC/ꢀ65 ꢁC; (ii) Methyl 3-bromopropionate (3 equiv), HMPA (6.3 equiv), THF,
20 h, ꢀ78 ꢁC/rt, 28%; (c) TMSOTf (2 equiv), NEt3 (2.5 equiv), CH2Cl2, 3 h, reflux, 8%.
and 16 were obtained in 21 and 20% yields, respectively, from
azetidine 6.
H
N
CO2Me
N
CO2Me
The reaction was found to be highly sensitive to the introduction
O
a
of substituents in
a- or b-position to the primary ester group;
+
CO2Me
azetidines 19 and 20, the methylated analogs of 1, did not partake in
the spiro-cyclization reaction. The influence of steric effects on the
cyclization process was explored with tert-butyl ester 23, which
afforded the expected spiranic lactam in a much lower yield than
the corresponding methyl ester analog 1 (Scheme 6). Reduction of
ring strain was found to be detrimental to the spiro-cyclization
process as demonstrated by the absence of reactivity of 25, the
pyrrolidine analog of 1, toward treatment with TMSOTf and TEA
(Scheme 7). Dithioester 26, prepared from diester 1 following the
procedure reported by Weinreb,20 was also not a substrate of the
spiro-cyclization reaction.
NH
CO2Me
O
6
15
16
> 98% de
Scheme 5. Synthesis of spiro- and fused-g-lactams. Reaction conditions: (a) TMSOTf
(2 equiv), NEt3 (2.5 equiv), CH2Cl2, 24 h, rt, 15 (21%), 16 (20%).
A set of alkylation reactions was performed from azetidine 4 to
obtain test substrates with various alkyl chain length and sub-
stituents (Table 1). The reaction proved difficult to effect in good
yields and the desired compounds were obtained in 11e45% yields.
Not surprisingly, treatment of 17 with TMSOTf and TEA provided
the expected spirocyclopentane 21, the increase of the alkyl chain
length by one methylene unit favoring the Dieckmann reaction
(Scheme 6).17 Further increase of the alkyl chain length by two
The limited substrate scope of the spiro-cyclization reaction
may be overcome by exploiting the reactivity of the tandem re-
action product 2a. A range of various 5-azaspiro[2.4]heptane

4120
P.-A. Nocquet et al. / Tetrahedron 68 (2012) 4117e4128
the reactive nucleophilic intermediate (the silyl ketene acetal) and
a
CO2Me
by activating the azetidine for the nucleophilic ring-opening and
the carbonyl of the tertiary ester group for the final amide bond
formation.
The proposed mechanism is supported by experimental evi-
dences and explains why azetidines 5 and 9 are not substrates of
the cyclization reaction; the best activation of the azetidine ring
with TMSOTf is indeed expected for an endocyclic amine. To avoid
CO2Me
N
N
CO2Me
Bn
24
Bn
25
COSEt
CO2Me
b
COSEt
CO2Me
the formation of the g-lactam and isolate the amino cyclopropane
N
N
intermediate of type A, the tertiary ester group was replaced by
a hydrogen atom and the reaction was performed from azetidine
2822a obtained from ester 4 in three steps (Scheme 9). Selective
reduction to the corresponding aldehyde22b followed by Wittig
Bn
Bn
1
26
Scheme 7. Synthesis of test substrates 25 and 26. Reaction conditions: (a) (i) LDA
(1.1 equiv), THF, 1 h, ꢀ78 ꢁC/ꢀ65 ꢁC; (ii) Methyl 3-bromopropionate (3 equiv), HMPA
(6.3 equiv), THF, 20 h, ꢀ78 ꢁC/rt, 45%; (b) AlMe3 (4 equiv), EtSH (4 equiv), CH2Cl2,
25 h, rt, 37%.
olefination afforded a,b unsaturated esters 27 (E/Z mixture: 7/3) in
72% yield. Chemoselective reduction of the double bond in the
presence of the ester group was performed by using a slight excess
of NaBH4 in the presence of CuCl at 0 ꢁC to give the desired product
28.22c Treatment of 28 with TMSOTf and TEA provided cyclopro-
pane 29a in 61% yield and 56% de (Scheme 9). It was established by
2D COSY and NOESY NMR experiments at the stage of the N-Ac
derivative 29b that the major epimer was in favor of the trans
product (See Supplementary data).
derivatives have thus been obtained in one-step by way of che-
moselective reduction of 2a. Reduction of the ester group by
treatment with SuperhydrideÒ afforded 2b in high yield whereas
access to the fully reduced pyrolidine analogue 2c was also easily
performed using LAH (Scheme 8). Primary alcohol 2b was effi-
ciently converted to bromide 2d in 79% yield by using PPh3/Br2 and
pyridine.
H
Bn
CO2Me
Bn
N
Bn
N
a,b
c
N
O
CO2Me
a
O
b
N
N
Bn
Bn
4
(E)-27
CO2Me
H
N
R
OH
CO2Me
2c
2a
2b R=OH
2d R=Br
c
d
CO2Me
NRBn
Scheme 8. Synthesis of 5-azaspiro[2.4]heptane derivatives 2 bearing different func-
tional groups. Reaction conditions: (a) LiBHEt3 (4 equiv), THF, 2.5 h, ꢀ78 ꢁC/ꢀ65 ꢁC,
89%; (b) LAH (3.5 equiv), THF, 3 h, reflux, quant.; (c) PPh3 (1.05 equiv), Br2 (1.05 equiv),
Pyridine (1 equiv), CH2Cl2, 72 h, rt, 79%.
Bn
29a R=H; 56% de
29b R=Ac; 56% de
28
e
Scheme 9. Synthesis of cyclopropanes 29. Reaction conditions: (a) DIBAL-H
(1.6 equiv), THF, 4 h, ꢀ78 ꢁC; (b) Ph3P]CHCO2Me (2.2 equiv), CH2Cl2, 16 h, 0 ꢁC/rt,
72% for the two steps (E/Z:7/3); (c) NaBH4 (2 equiv), CuCl (1.7 equiv), MeOH, 4 h, 0 ꢁC,
41%; (d) TMSOTf (2 equiv), NEt3 (2.5 equiv), CH2Cl2, 24 h, rt, 61%; (e) Ac2O (1.1 equiv),
CH2Cl2, 24 h, rt, 67%.
2.2. Mechanistic aspects
A tentative mechanism for the formation of the spirocyclopropyl
g
-lactam 2a is proposed in Fig. 3. We believe that the key step of the
process is a SN2-type ring-opening8,21 of the TMSOTf-activated
azetidine ring by the silyl ketene acetal generated by treatment
with TMSOTf and TEA.17a The amino ester A, thus obtained, finally
undergoes an intramolecular cyclization to afford the five-
membered lactam 2a by reaction of the amine function with the
Disappointing results obtained with 19, 20 and azetidine 23
bearing a bulky t-Bu ester group are compatible with the fact that
SN2 process is a mechanism known to be sensitive to steric hin-
drance. To confirm the ring-opening of the azetidine via a con-
certed SN2 mechanism, the reaction was first performed from
diastereoenriched azetidine 31a. Compound 31a was obtained from
ester group in g-position. This reaction proceeds in high regiose-
commercially available (R)-a-methylbenzylamine and dibromide 3
lectivity as no formation of six-membered lactam was detected.
Remarkably, in this process TMSOTf plays a triple role by generating
following the same strategy used for the synthesis of N-benzyla-
zetidine 1 (Schemes 2 and 10). Diastereoenriched azetidine 31a
(91% de) was isolated after separation by flash chromatography on
silica gel of the two diastereomers obtained after the alkylation
step. We were pleased to find that the spiro-cyclization reaction
performed from 31a proceeded without loss of the diastereomeric
excess (Scheme 10).
The tandem reaction was then performed with enantioenriched
azetidine (ꢀ)-1, which was obtained from 31a after a two step
deprotection/reprotection sequence. 1H NMR analysis of (ꢀ)-1 us-
ing the Pirkle chiral shift reagent TFAE23 showed that the enan-
tiomeric excess was 88% (See Supplementary data). Azetidine (ꢀ)-1
reacted under typical spiro-cyclization reaction conditions to give
CO2Me
CO2Me
TMSOTf
OTMS
CO2Me
N
Bn
N
TEA
OMe
O
+
Bn
TMS
1
Bn
N
+
O
TMS
CO2Me
MeO
TMSBnN
the expected
g
-lactam (þ)-2a with complete retention of the en-
CO2Me
> 98% de
antiomeric excess (Scheme 10).24,25 These results are in good
agreement with a mechanism involving a SN2-type ring-opening
reaction (Fig. 3). The high diastereoselectivity observed in favor of
the trans product may be rationalized as follows (Fig. 4).
A
2a
Fig. 3. Proposed mechanism for the spiro-cyclization reaction.

P.-A. Nocquet et al. / Tetrahedron 68 (2012) 4117e4128
4121
CO2Me
Br
R'O
H
OR
CO2Me
O
H
H
H
a
b
H
R'O
CO2Me
H
N
N
MeO
2'
2'
Me
Me
31
TMS
Bn
TMS
Br
OR
3
Ph
Ph
30
N
+
N
+
H
H
Bn
Me
Ph
CO2Me
T
T
2'
1'
c
N
O
*
CO2Me
N
CO2Me
CO2Me
Me
CO2Me
Ph
NHBn
NHBn
31a 91% de
d, e
32
> 96% de
minor
major
Fig. 5. Stereochemical pathway explaining the stereoselective formation of 29a.
Bn
CO2Me
N
O
f
3. Conclusion
1'
*
CO2Me
N
2'
CO2Me
(+)-2a 89% ee
Bn
In conclusion, a novel, highly stereoselective tandem intra-
molecular azetidine ring-opening/closing cascade reaction is
reported. In this one-step process, two cycles e a cyclopropane and
(-)-1 88% ee
Scheme 10. Stereochemical aspects of the spiro-cyclization reaction. Reaction condi-
-methylbenzylamine (1 equiv), CH3CN/
a
g-butyrolactam, and two asymmetric centers are created. The
tions: (a) K2CO3 (1 equiv), 3 (1 equiv), (R)-(þ)-
a
spiro-cyclization process was found to be particularly sensitive to
structural variations in the substrate because of the high density of
potential reactive centers present in its structure. Nevertheless,
chemoselective reduction of the tandem reaction product allows
access to various 5-azaspiro[2.4]heptane derivatives bearing dif-
ferent functionalities. In addition, the tandem reaction performed
with the 2-azetidinone analog of 1 led to the one-step formation of
a completely different fused bicyclic skeleton to give 6-aza-bicyclo
[3.2.0]heptane derivatives via an unprecedented Mukaiyama aldol-
like reaction of an ester acceptor with a silyl imidate.
H2O (1:5), 6.5 h, reflux, 64%; (b) (i) LDA (1.1 equiv), THF, 1 h, ꢀ78 ꢁC/ꢀ65 ꢁC, (ii)
Methyl 3-bromopropionate (3 equiv), HMPA (6.3 equiv), THF, 20 h, ꢀ78 ꢁC/rt, 31a
(18%), 31b (4%); (c) TMSOTf (2 equiv), NEt3 (2.5 equiv), CH2Cl2, 24 h, rt, 56%; (d) Pd/C
10%, HCO2H, H2, iPrOH, 24 h, rt; (e) BnBr (1.2 equiv), K2CO3 (1.2 equiv), CH3CN, 24 h, rt,
54% (two steps); (f) TMSOTf (2 equiv), NEt3 (2.5 equiv), CH2Cl2, 24 h, rt, 74%.
Bn
CO2Me
N
2'
O
1'
OTMS
OMe
TMSOTf
TEA
N
CO2Me
Bn
2a
1
4. Experimental section
4.1. General methods
R'O
H
OR
H
Tetrahydrofuran (THF) and diethyl ether (Et2O) were dried by
passage through an activated alumina column under Ar. Dichloro-
methane (CH2Cl2) was distilled over CaH2 under Ar. Triethylamine
(Et3N) was distilled over KOH under Ar and stored over KOH. All
reactions were performed in standard glassware under Ar. Flash
chromatographies were performed on silica gel 60 (230e400 mesh,
0.040e0.063 mm) purchased from E. Merck. Thin layer chroma-
tography (TLC) was performed on aluminum sheets coated with
silica gel 60 F254 purchased from E. Merck. IR spectra (cmꢀ1) were
recorded on a PerkineElmer Spectrum One Spectrophotometer.
NMR spectra were recorded on a Bruker AC 300 or AC 400 with
solvent peaks as reference. Carbon multiplicities were assigned by
distortionless enhancement by polarization transfer (DEPT) ex-
periments. The 1H signals were assigned by 2D experiments (COSY).
ESI-HRMS mass spectra were carried out on a Bruker MicroTOF
spectrometer. ESI-LRMS mass spectra were carried out on a MSQ
Thermo Fisher spectrometer. Specific rotations were determined at
room temperature (20 ꢁC) in a PerkineElmer 241 polarimeter for
CO2Me
H
CO2Me
R'O
H
2'
2'
TMS
TMS
Bn
OR
N
N
H
+
H
+
Bn
T
T
1
2
Fig. 4. Stereochemical pathway explaining the formation of 2a.
In the TMSOTf-induced azetidine SN2-type ring-opening, there
are two limiting reactive geometry generated by the rotation about
0
0
the C1 eC2 bond: antiperiplanar structures T1 and T2 leading to the
trans and the cis spiro-cyclization product, respectively. In these
structures, A1,3 steric strains are minimized and the CeN bond is
approximately perpendicular to the plan of the silyl ketene acetal.
T2 is expected to experience severe repulsion between the oxygen
lone-pairs of the ester and the silyl ketene acetal, whereas T1
minimizes such unfavorable dipoleedipole/electrostatic in-
teractions. Replacement of the ester group by a hydrogen atom to
suppress this effect indeed reduced the stereoselectivity of the
process and led to an inversion of the diastereoselectivity as shown
by the conversion of 28 to 29a (56% de, Scheme 9). This result may
sodium (
l¼589 nm).
4.1.1. Methyl N-benzyl-2-(3-methoxycarbonylethyl)azetidine-2-
carboxylate (1). A solution of LDA (2.68 mmol, 1.1 equiv) [pre-
pared from diisopropylamine (0.38 mL, 2.68 mmol) in THF (6.5 mL)
and n-BuLi (1.52 M in hexane, 1.8 mL, 2.68 mmol) stirred at ꢀ78 ꢁC
for 30 min] was added to a solution of methyl N-benzylazetidine-2-
carboxylate 4 (500 mg, 2.44 mmol, 1 equiv) in THF (3.2 mL), cooled
0
be explained by partial destabilization of structure T1 due to steric
interactions between the bulky silyl ketene acetal and the azetidine
methylene group at C-3 (Fig. 5).

4122
P.-A. Nocquet et al. / Tetrahedron 68 (2012) 4117e4128
to ꢀ78 ꢁC. The reaction mixture was allowed to warm to ꢀ65 ꢁC
(l h), cooled again to ꢀ78 ꢁC and a mixture of methyl 3-
crude product was purified by flash chromatography (AcOEt/pen-
tane,1:5 to 1:1) to afford (þ)-2a (62 mg, 74%, ee 89%) as a yellow oil.
bromopropionate (0.8 mL, 7.31 mmol,
3
equiv) and HMPA
½
a 2D0
ꢃ
þ157 (c 0.8, CHCl3).
(2.7 mL, 15.35 mmol, 6.3 equiv) in THF (2.5 mL) was added. The
solution was allowed to warm to rt and then stirred for 16 h. Then
the reaction was quenched with saturated aqueous NH4Cl and was
extracted with Et2O (3ꢂ5 mL). The combined organic layer was
dried over Na2SO4, filtered and concentrated under reduced pres-
sure. The crude product was purified by flash chromatography
(AcOEt/petroleum ether, 1:7 to 1:1) to afford the diester 1 (291 mg,
41%) as a yellow oil. TLC Rf 0.63 (silica gel, AcOEt/petroleum ether,
4.1.5. (1R*,3R*)-N-Benzyl-1-hydroxymethyl-5-azaspiro[2.4]heptan-
4-one (2b). To a solution of 2a (84 mg, 0.32 mmol, 1 equiv) in THF
(0.5 mL) cooled to ꢀ78 ꢁC, was added LiBHEt3 (1 M in THF, 1.3 mL,
1.30 mmol, 4 equiv). The solution was stirred 1 h at ꢀ78 ꢁC and 1.5 h
at ꢀ65 ꢁC. Saturated aqueous NaHCO3 (0.4 mL) was added and the
solution was allowed to warm to 0 ꢁC. H2O2 35% (90
mL) was added
and the solution was stirred at 0 ꢁC for 20 min. The solution was
concentrated under reduced pressure. Water was added and the
reaction was extracted with CH2Cl2 (3ꢂ2 mL). The combined or-
ganic layer was dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified by flash chro-
matography (MeOH/CH2Cl2, 5:95) to afford 2b (67 mg, 89%) as
a white powder. TLC Rf 0.30 (silica gel, MeOH/CH2Cl2, 5:95); IR
1:2); IR (film) 1726 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 7.32e7.16 (m,
5H, Ph), 3.77 (s, 3H, CO2Me), 3.69 (d, 1H, J¼13.2 Hz, CH2Ph), 3.65 (s,
3H, CO2Me), 3.58 (d, 1H, J¼13.0 Hz, CH2Ph), 3.17 (m, 2H, H-4),
2.52e1.96 (m, 6H, H-3, H-10, H-20); 13C NMR (75 MHz, CDCl3)
d 173.8
(CO), 173.5 (CO), 138.3 (CqeAr), 128.6 (2CHeAr), 128.3 (2CHeAr),
127.0 (1CHeAr), 71.5 (C-2), 56.0 (CH2Ph), 51.7 (OCH3), 51.6 (OCH3),
49.7 (C-4), 29.6 (C-10 or C-20), 29.0 (C-10 or C-20), 25.6 (C-3); HRMS
(ESI) [MþNa]þ calcd for C16H21NO4Na: 314.136, found 314.135.
(film) 3389, 1665 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.43e7.25 (m,
5H, Ph), 4.60 (d, 1H, J¼14.6 Hz, CH2Ph), 4.45 (d, 1H, J¼14.6 Hz,
CH2Ph), 3.89 (dd, 1H, J¼11.5, 5.7 Hz, CH2OH), 3.46 (m, 1H, CH2OH),
3.39 (m, 2H, H-6), 2.31 (m, 1H, H-1), 2.01 (m, 1H, H-7a), 1.77 (m, 1H,
H-7b), 1.38 (dd, 1H, J¼9.1, 4.2 Hz, H-2a), 0.64 (dd, 1H, J¼6.3, 4.4 Hz,
4.1.2. Methyl N-benzyl-2-(3-methoxycarbonylethyl)azetidine-2-
carboxylate ((ꢀ)-1). Pd/C 10% (50 mg) and two drops of HCO2H
were added to a solution of 31a (126 mg, 0.41 mmol, 1 equiv) in
iPrOH (3 mL). The solution was placed under H2 atmosphere and
stirred until disappearance of the starting material (24 h). Saturated
aqueous NaHCO3 (1 mL) was added and the solution was filtered
through Celite and concentrated under reduced pressure. The so-
lution was dissolved in CH3CN (2 mL). K2CO3 (68 mg, 0.49 mmol,
H-2b); 13C NMR (100 MHz, CDCl3)
d 176.1 (NCO), 136.7 (CqeAr),
128.8 (2CHeAr), 128.3 (2CHeAr), 127.7 (1CHeAr), 63.1 (CH2OH),
47.4 (CH2Ph), 44.5 (C-6), 27.2 (C-3), 25.1 (C-1), 22.4 (C-7), 17.6 (C-2);
HRMS (ESI) [MþNa]þ calcd for C14H17NO2Na: 254.115, found
254.117.
1.2 equiv) and BnBr (59
m
L, 0.49 mmol, 1.2 equiv) were added and
4.1.6. (1S,3S)-N-Benzyl-1-hydroxymethyl-5-azaspiro[2.4]heptan-4-
one ((þ)-2b). To a solution of (þ)-2a (34 mg, 0.13 mmol, 1 equiv, ee
89%) in THF (1 mL) cooled to ꢀ78 ꢁC, was added LiBHEt3 (1 M in
THF, 0.52 mL, 0.52 mmol, 4 equiv). The solution was stirred 1 h at
ꢀ78 ꢁC and 1.5 h at ꢀ65 ꢁC. Saturated aqueous NaHCO3 (0.2 mL) was
added and the solution was allowed to warm to 0 ꢁC. H2O2 35%
the solution was stirred at rt until disappearance of the starting
material (24 h). Then the reaction was quenched with water and
was extracted with AcOEt (3ꢂ2 mL). The combined organic layer
was dried over Na2SO4, filtered and concentrated under reduced
pressure. The crude product was purified by flash chromatography
(AcOEt/petroleum ether, 1:7 to 1:1) to afford the diester (ꢀ)-1
(20 m
L) was added and the solution was stirred at 0 ꢁC for 20 min.
(65 mg, 54%, ee 88%) as a yellow oil. ½a D20
ꢃ
ꢀ14 (c 0.7, CHCl3).
The solution was concentrated under reduced pressure. Water was
added and the reaction was extracted with CH2Cl2 (3ꢂ2 mL). The
combined organic layer was dried over Na2SO4, filtered and con-
centrated under reduced pressure. The crude product was purified
by flash chromatography (MeOH/CH2Cl2, 5:95) to afford (þ)-2b
4.1.3. (1R*,3R*)-N-Benzyl-1-methoxycarbonyl-5-azaspiro[2.4]hep-
tan-4-one (2a). To a solution of azetidine 1 (80 mg, 0.28 mmol,
1 equiv) in CH2Cl2 (1 mL) cooled to 0 ꢁC was added NEt3 (96
mL,
0.69 mmol, 2.5 equiv) and TMSOTf (0.1 mL, 0.55 mmol, 2 equiv). The
solution was stirred at rt for 24 h. Then the reaction was quenched
with saturated aqueous NaHCO3 and was extracted with CH2Cl2
(3ꢂ2 mL). The combined organic layer was dried over Na2SO4, fil-
tered and concentrated under reduced pressure. The crude product
was purified by flash chromatography (AcOEt/pentane, 1:5 to 1:1)
to afford 2a (54 mg, 75%) as a yellow oil. TLC Rf 0.30 (silica gel,
(26 mg, 85%) as a white powder. ½a D20
þ29 (c 1.0, CHCl3).
ꢃ
4.1.7. (1R*,3R*)-N-Benzyl-1-hydroxymethyl-5-azaspiro[2.4]heptane
(2c). LAH (34 mg, 0.89 mmol, 3.5 equiv) was added to a solution of
2a (66.2 mg, 0.26 mmol) in THF (1.4 mL) cooled at 0 ꢁC. The solution
was stirred at reflux for 3 h. After cooling at 0 ꢁC, H2O (1 mL) was
carefully added. Then 10% NaOH (2 mL) and H2O (3 mL) were
added. The solution was filtered through Celite and concentrated
under reduced pressure to afford 2c (55 mg, quant.) as a yellow oil.
AcOEt/petroleum ether, 1:2); IR (film) 1728, 1688 cmꢀ1
(300 MHz, CDCl3)
;
1H NMR
d
7.38e7.21 (m, 5H, Ph), 4.51 (d, 1H, J¼14.7 Hz,
CH2Ph), 4.45 (d, 1H, J¼14.7 Hz, CH2Ph), 3.71 (s, 3H, CO2Me), 3.32 (m,
2H, H-6), 2.28 (dd,1H, J¼8.8, 6.1 Hz, H-1), 2.19 (dd, 2H, J¼8.3, 6.3 Hz,
H-7), 1.58 (dd, 1H, J¼8.8, 4.0 Hz, H-2a), 1.35 (dd, 1H, J¼5.9, 4.1 Hz, H-
IR (film) 3342 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 7.31e7.16 (m, 5H,
Ph), 4.12e3.88 (br s, 1H, OH), 3.64e3.51 (m, 3H, CH2OH, CH2Ph),
3.25 (dd, 1H, J¼11.1, 8.6 Hz, CH2OH), 2.80 (m, 1H, H-6), 2.61 (m, 1H,
H-6), 2.49 (d, 1H, J¼9.1 Hz, H-4a), 2.37 (d, 1H, J¼9.1 Hz, H-4b), 1.97
(m, 1H, H-7a), 1.62 (m, 1H, H-7b), 1.04 (m, 1H, H-1), 0.68 (dd, 1H,
J¼8.8, 4.9 Hz, H-2a), 0.27 (t, 1H, J¼5.2 Hz, 1H, H-2b); 13C NMR
2b); 13C NMR (100 MHz, CDCl3)
d 173.6 (CO), 172.1 (NCO), 136.3
(CqeAr), 128.9 (2CHeAr), 128.4 (2CHeAr), 127.8 (1CHeAr), 52.0
(OCH3), 47.6 (CH2Ph), 44.2 (C-6), 31.6 (C-3), 25.3 (C-1), 22.9 (C-7),
19.3 (C-2); HRMS (ESI) [MþNa]þ calcd for C15H17NO3Na: 282.110,
found 282.110.
(75 MHz, CDCl3)
d 138.5 (CqeAr), 129.1 (2CHeAr), 128.4 (2CHeAr),
127.2 (1CHeAr), 63.9 (C-4 or CH2OH), 63.7 (C-4 or CH2OH), 60.9
(CH2Ph), 55.0 (C-6), 28.8 (C-7), 25.25 (C-1), 25.2 (C-3), 17.0 (C-2);
HRMS (ESI) [MþH]þ calcd for C14H20NO: 218.154, found 218.153.
4.1.4. (1S,3S)-N-Benzyl-1-methoxycarbonyl-5-azaspiro[2.4]heptan-
4-one ((þ)-2a). To a solution of azetidine (ꢀ)-1 (94 mg, 0.32 mmol,
1 equiv, ee 88%) in CH2Cl2 (1 mL) cooled to 0 ꢁC was added NEt3
(0.11 mL, 0.80 mmol, 2.5 equiv) and TMSOTf (0.12 mL, 0.64 mmol,
2 equiv). The solution was stirred at rt for 24 h. Then the reaction
was quenched with saturated aqueous NaHCO3 and was extracted
with CH2Cl2 (3ꢂ2 mL). The combined organic layer was dried over
Na2SO4, filtered and concentrated under reduced pressure. The
4.1.8. (1R*,3R*)-N-Benzyl-1-bromomethyl-5-azaspiro[2.4]heptan-4-
one (2d). To a solution of PPh3 (407 mg, 1.55 mmol, 1.05 equiv) in
CH2Cl2 (7 mL) cooled at ꢀ30 ꢁC, was added Br2 (80
mL, 1.55 mmol,
1.05 equiv). The solution was stirred for 15 min between ꢀ30 ꢁC and
ꢀ15 ꢁC. A mixture of 2b (342 mg, 1.48 mmol, 1 equiv) and pyridine
(120
mL, 1.48 mmol, 1 equiv) in CH2Cl2 (2 mL) was added. The

P.-A. Nocquet et al. / Tetrahedron 68 (2012) 4117e4128
4123
solution was stirred at rt for 3 days. The solution was then con-
centrated under reduced pressure. The crude product was purified
by flash chromatography (MeOH/CH2Cl2, 0:100 to 5:95) to afford 2d
(343 mg, 79%) as a pale yellow oil. TLC Rf 0.59 (silica gel, MeOH/
H-4a), 3.76 (s, 3H, CO2Me), 3.74 (m, 1H, H-4b), 3.68 (s, 3H, CO2Me),
2.70e2.10 (m, 6H, H-3, H-10, H-20), 1.41 (s, 9H, C(CH3)3); 13C NMR
(100 MHz, CDCl3)
d 173.8 (CO), 172.7 (CO), 155.5 (NCO), 80.4
(C(CH3)3), 70.4 (C-2), 52.4 (OCH3), 51.8 (OCH3), 45.1 (C-4), 30.5 (C-10
or C-20), 29.1 (C-10 or C-20), 28.4 (C(CH3)3), 25.3 (C-3); HRMS (ESI)
[MþNa]þ calcd for C14H23NO6Na: 324.142, found 324.142.
CH2Cl2, 5:95); IR (film) 1682 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d
7.39e7.20 (m, 5H, Ph), 4.56 (d, 1H, J¼14.7 Hz, CH2Ph), 4.44 (d, 1H,
J¼14.9 Hz, CH2Ph), 3.72 (dd, 1H, J¼13.5, 5.9 Hz, CH2Br), 3.38 (m, 2H,
H-6), 3.07 (t, 1H, J¼10.3 Hz, CH2Br), 2.25 (m, 1H, H-7a), 2.08e1.87
(m, 2H, H-1, H-7b), 1.54 (dd, 1H, J¼9.0, 4.7 Hz, H-2a), 0.66 (t, 1H,
4.1.12. Methyl 2-(3-methoxycarbonylethyl)azetidine-2-carboxylate
(6). To a solution of azetidine 1 (250 mg, 0.85 mmol, 1 equiv) in
MeOH (4 mL) was added Pd/C 10% (250 mg) and few drops of
HCO2H. The solution was placed under H2 atmosphere and stirred
until disappearance of the starting material (24 h). Saturated
aqueous NaHCO3 (1 mL) was added and the solution was filtered
through Celite and concentrated under reduced pressure. The crude
product was purified by flash chromatography (MeOH/CH2Cl2þ1%
NEt3, 0:100 to 5:95) to afford 6 (96 mg, 55%) as a colorless oil. TLC Rf
J¼5.4 Hz, H-2b); 13C NMR (100 MHz, CDCl3)
d 175.0 (NCO), 136.5
(CqeAr), 128.8 (2CHeAr), 128.1 (2CHeAr), 127.6 (1CHeAr), 47.3
(CH2Ph), 44.4 (C-6), 33.8 (CH2Br), 29.7 (C-3), 25.6 (C-1), 21.3 (C-7),
20.9 (C-2); HRMS (ESI) [MþNa]þ calcd for C14H16BrNONa: 316.031,
found 316.030.
4.1.9. Methyl N-benzylazetidine-2-carboxylate (4). To a solution of
methyl 1,3-dibromopropionate (7.8 mL, 55.2 mmol, 1 equiv) in
CH3CN (120 mL), were added NEt3 (23 mL, 166 mmol, 3 equiv) and
benzylamine (6 mL, 55.2 mmol,1 equiv). The solution was heated to
reflux and stirred for 4 h. After cooling, water (70 mL) was added
and the product was extracted with Et2O (3ꢂ40 mL). The combined
organic layer was dried over MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified by flash
chromatography (AcOEt/petroleum ether, 1:7 to 2:1) to afford
azetidine 4 (7.58 g, 67%) as an orange oil. TLC Rf 0.21 (silica gel,
0.26 (silica gel, MeOH/CH2Cl2, 5:95); IR (film) 1729 cmꢀ1 1H NMR
;
(300 MHz, CDCl3)
d 3.77 (s, 3H, CO2Me), 3.66 (s, 3H, CO2Me), 3.53
(m, 1H, H-4a), 3.30 (m, 1H, H-4b), 2.50e2.31 (m, 4H, H-3, H-10 or H-
20), 2.23 (m, 1H, H-10a or H-20a), 2.18e2.07 (m, 2H, NH, H-10b or H-
20b); 13C NMR (75 MHz, CDCl3)
d 176.9 (CO), 173.6 (CO), 67.0 (C-2),
52.6 (OCH3), 51.8 (OCH3), 41.6 (C-4), 34.5 (C-10 or C-20), 30.6 (C-10 or
C-20), 28.7 (C-3); HRMS (ESI) [MþNa]þ calcd for C9H15NO4Na:
224.089, found 224.089.
AcOEt/petroleum ether, 1:3); 1H NMR (300 MHz, CDCl3)
d
7.33e7.17
4.1.13. Dimethyl-(S)-2-[N-benzyl-N-(2-chloroacetyl)amino]pentane-
dioate (8). To a solution of 7 (1.00 g, 3.77 mmol, 1 equiv) in THF
(19 mL), was added chloroacetyl chloride (0.45 mL, 5.65 mmol,
1.5 equiv) and propylene oxide (4.0 mL, 56.5 mmol, 15 equiv). The
solution was stirred for 17 h and concentrated under reduced
pressure. The crude product was purified by flash chromatography
(AcOEt/petroleum ether, 1:3 to 1:1) to afford 8 (773 mg, 59%) as
a colorless oil. TLC Rf 0.44 (silica gel, AcOEt/petroleum ether, 2:3);
(m, 5H, Ph), 3.78 (d, 1H, J¼12.6 Hz, CH2Ph), 3.71 (t, 1H, J¼8.4 Hz, H-
1), 3.60 (s, 3H, CO2Me), 3.56 (d, 1H, J¼12.6 Hz, CH2Ph), 3.29 (m, 1H,
H-4a), 2.91 (m, 1H, H-4b), 2.34 (m, 1H, H-3a), 2.18 (m, 1H, H-3b).
Spectroscopic data are in accordance with literature data.26
4.1.10. Methyl N-tosyl-2-(3-methoxycarbonylethyl)azetidine-2-
carboxylate (5a). To a solution of azetidine 1 (200 mg, 0.69 mmol,
1 equiv) in EtOH (1 mL) was added Pd(OH)2/C 20% (20 mg) and few
drops of HCO2H. The solution was placed under H2 atmosphere and
stirred until disappearance of the starting material (24 h). The so-
lution was filtered through Celite and concentrated under reduced
pressure. The crude product was dissolved in CH2Cl2 (7 mL) and
cooled to 0 ꢁC. NEt3 (0.3 mL, 2.06 mmol, 3 equiv) and TsCl (131 mg,
0.69 mmol, 1 equiv) were added and the solution was stirred
overnight at rt. The reaction was quenched with water and was
extracted with CH2Cl2 (3ꢂ4 mL). The combined organic layer was
dried over MgSO4, filtered and concentrated under reduced pres-
sure. The crude product was purified by flash chromatography
(AcOEt/petroleum ether, 1:9 to 1:1) to afford 5a (71 mg, 29%) as
a white powder. TLC Rf 0.21 (silica gel, AcOEt/petroleum ether, 1:2);
1H NMR (300 MHz, CDCl3)
d 7.45e7.20 (m, 5H, Ph), 4.77e4.56 (m,
2H, CH2Cl), 4.41 (m, 1H, CHCO2Me), 4.10 (d, 1H, J¼12.9 Hz, CH2Ph),
4.03 (d, 1H, J¼12.6 Hz, CH2Ph), 3.63 (s, 6H, CO2Me), 2.48e2.00 (m,
4H, CH2CH2CO2Me). Spectroscopic data are in accordance with lit-
erature data.14
4.1.14. Methyl N-benzyl-2-(3-methoxycarbonylethyl)-4-
oxoazetidine-2-carboxylate (9). To
a solution of 8 (372 mg,
1.07 mmol, 1 equiv) in CH3CN (13 mL) was added Cs2CO3 (1.05 g,
3.21 mmol, 3 equiv). The solution was stirred at rt until disap-
pearance of the starting material (72e96 h). The solution was
concentrated under reduced pressure. Water and AcOEt were
added. The reaction was extracted with AcOEt (3ꢂ5 mL). The
combined organic layer was dried over Na2SO4, filtered and con-
centrated under reduced pressure. The crude product was purified
by flash chromatography (AcOEt/petroleum ether, 1:3 to 1:1) to
afford 9 (202 mg, 62%) as a yellow oil. TLC Rf 0.23 (silica gel, AcOEt/
IR (film) 1733 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 7.68 (d, 2H,
J¼6.4 Hz, CHeAr), 7.29 (d, 2H, J¼8.3 Hz, CHeAr), 4.03 (m, 1H, H-4a),
3.82 (m, 1H, H-4b), 3.67 (s, 3H, CO2Me), 3.60 (s, 3H, CO2Me),
2.57e2.32 (m, 5H, H-3a, H-10, H-20), 2.41 (s, 3H, C(CH3)-Ar), 2.20 (m,
1H, H-3b); 13C NMR (75 MHz, CDCl3)
d
173.3 (CO), 171.2 (CO), 143.5
petroleum ether, 2:3); IR (film) 1754, 1732 cmꢀ1
;
1H NMR
(C(CH3)-Ar), 137.2 (CqeAr), 129.6 (2CHeAr), 127.3 (2CHeAr), 74.4
(C-2), 52.6 (OCH3), 51.9 (OCH3), 47.5 (C-4), 31.0 (C-10 or C-20), 28.8
(C-10 or C-20), 24.9 (C-3), 21.6 (C(CH3)-Ar); HRMS (ESI): m/z 378.096
([MþNa]þ, calcd for C16H21NO6SNa: 378.095).
(300 MHz, CDCl3)
d
7.33e7.19 (m, 5H, Ph), 4.44 (d, 1H, J¼15.4 Hz,
CH2Ph), 4.35 (d, 1H, J¼15.4 Hz, CH2Ph), 3.59 (s, 3H, CO2Me), 3.51 (s,
3H, CO2Me), 3.24 (d, 1H, J¼14.7 Hz, H-3a), 2.84 (d, 1H, J¼14.7 Hz, H-
3b), 2.31e1.86 (m, 4H, H-10, H-20); 13C NMR (75 MHz, CDCl3)
d 172.6
(CO), 171.4 (CO), 166.0 (C-2), 135.9 (CqeAr), 128.83 (2CHeAr),
128.75 (2CHeAr), 127.9 (1CHeAr), 61.8 (C-4), 52.6 (OCH3), 52.0
(OCH3), 45.9 (CH2Ph), 45.1 (C-3), 28.8 (C-10 or C-20), 28.5 (C-10 or C-
20); HRMS (ESI) [MþNa]þ calcd for C16H19NO5Na: 328.116, found
328.113.
4.1.11. Methyl N-tert-butyloxycarbonyl-2-(3-methoxycarbonylethyl)
azetidine-2-carboxylate (5b). To a solution of azetidine 1 (150 mg,
0.51 mmol, 1 equiv) in EtOH (2 mL) was added Pd(OH)2/C 20%
(22 mg) and Boc2O (169 mg, 0.77 mmol,1.5 equiv). The solution was
placed under H2 atmosphere and stirred overnight. The solution
was filtered through Celite and concentrated under reduced pres-
sure. The crude product was purified by flash chromatography
(AcOEt/petroleum ether, 1:4 to 1:2) to afford 5b (157 mg, quant.) as
a pale yellow oil. TLC Rf 0.21 (silica gel, AcOEt/petroleum ether, 1:2);
4.1.15. (1S*,5S*)-N-Benzyl-5-(hydroxymethyl)-6-azabicyclo[3.2.0]
heptan-2,7-dione (14). To a solution of 9 (150 mg, 0.49 mmol,
1 equiv) in CH2Cl2 (1.5 mL) cooled to 0 ꢁC, was added NEt3 (274
m
L,
L, 1.47 mmol, 3 equiv). The
solution was stirred at rt for 24 h. Saturated aqueous NaHCO3 (1 mL)
1.97 mmol, 4 equiv) and TMSOTf (267
m
IR (film) 1737, 1702 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 3.97 (m, 1H,

4124
P.-A. Nocquet et al. / Tetrahedron 68 (2012) 4117e4128
was added and the product was extracted with CH2Cl2 (3ꢂ3 mL).
The combined organic layer was dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude product was pu-
rified by flash chromatography (AcOEt/petroleum etherþ1% NEt3,
1:7) to afford 10 and 11 (131 mg, mixture of diastereomers) as
a colorless oil. HRMS (ESI) [MþNa]þ calcd for C22H35NO5Si2Na:
472.195, found 472.193; HRMS (ESI) [MþNa]þ calcd for
C19H27NO5SiNa: 400.155, found 400.154.
2.5 equiv) and TMSOTf (162 mL, 0.89 mmol, 2 equiv). The solution
was stirred at rt for 24 h. Then the reaction was quenched with
saturated aqueous NaHCO3 and was extracted with CH2Cl2
(3ꢂ2 mL). The combined organic layer was dried over Na2SO4, fil-
tered and concentrated under reduced pressure. The crude product
was purified by flash chromatography (MeOH/CH2Cl2þ1% NEt3,
0:100 to 5:95) to afford 15 (16 mg, 21%) as a colorless oil and 16
(15 mg, 20%) as a yellow oil.
Analytical samples of two diastereomers of 10 were obtained
after a careful purification.
Compound 15: TLC Rf 0.27 (silica gel, MeOH/CH2Cl2, 5:95); IR
(film) 1728, 1698 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 5.84 (br s, 1H,
Compound 10a: colorless oil. TLC Rf 0.70 (silica gel, AcOEt/pe-
NH), 3.72 (s, 3H, CO2Me), 3.47 (m, 2H, H-6), 2.33 (m, 2H, H-7), 2.21
troleum ether, 1:3); IR (film) 1761, 1742 cmꢀ1
;
1H NMR (300 MHz,
(dd, 1H, J¼8.9, 6.1 Hz, H-1), 1.52 (dd, 1H, J¼8.9, 4.1 Hz, H-2a), 1.36
CDCl3)
d
7.35e7.27 (m, 5H, Ph), 4.63 (d, 1H, J¼14.9 Hz, CH2Ph), 4.27
(dd, 1H, J¼6.0, 4.0 Hz, H-2b); 13C NMR (100 MHz, CDCl3)
d 177.0
(d, 1H, J¼14.9 Hz, CH2Ph), 3.79 (s, 1H, H-1), 3.65 (s, 3H, CO2Me), 3.17
(s, 3H, OCH3), 1.79 (t, 1H, J¼13.5 Hz, H-3), 1.48e1.30 (m, 2H, H-4),
0.25 (s, 9H, OTMS), ꢀ0.10 (s, 9H, C-TMS); 13C NMR (100 MHz, CDCl3)
(CO), 172.0 (NCO), 52.1 (C-1), 39.7 (C-6), 30.4 (C-3), 25.2 (C-7), 19.0
(C-2); HRMS (ESI) [MþNa]þ calcd for C8H11NO3Na: 192.063, found
192.065.
d
171.6 (CO), 165.1 (C-7), 136.3 (CqeAr), 129.0 (2CHeAr), 128.0
Compound 16: TLC Rf 0.43 (silica gel, MeOH/CH2Cl2, 5:95); IR
(2CHeAr), 127.8 (1CHeAr), 107.6 (C-2), 68.9 (C-5), 63.8 (C-1), 52.4
(OCH3), 49.4 (OCH3), 44.8 (CH2Ph), 37.4 (C-3), 29.5 (C-4), 2.0
(Si(CH3)3), ꢀ1.1 (Si(CH3)3); HRMS (ESI) [MþNa]þ calcd for
C22H35NO5Si2Na: 472.195, found 472.193.
(film) 1735, 1706 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 4.05 (m, 1H, H-
7a), 3.90 (td, 1H, J¼9.6, 4.5 Hz, H-7b), 3.83 (s, 3H, CO2Me), 2.88 (m,
1H, H-6a), 2.81e2.56 (m, 3H, H-4þH-6b), 2.44e2.20 (m, 2H, H-3);
13C NMR (75 MHz, CDCl3)
d 184.7 (CO), 173.4 (NCO), 71.1 (C-5), 52.9
Compound 10b: white powder. TLC Rf 0.59 (silica gel, AcOEt/
(OCH3), 48.6 (C-7), 34.8 (C-3 or C-4), 34.4 (C-3 or C-4), 31.8 (C-6);
HRMS (ESI) [MþNa]þ calcd for C8H11NO3Na: 192.063, found
192.061.
petroleum ether,1:3); IR (film) 1762,1743 cmꢀ1; 1H NMR (300 MHz,
CDCl3)
d
7.35e7.27 (m, 5H, Ph), 4.71 (d, 1H, J¼14.9 Hz, CH2Ph), 4.20
(d, 1H, J¼14.9 Hz, CH2Ph), 3.76 (s, 1H, H-1), 3.69 (s, 3H, CO2Me), 3.45
(s, 3H, OCH3), 1.80 (t, 1H, J¼15.2 Hz, H-3), 1.48e1.36 (m, 2H, H-4),
0.15 (s, 9H, OTMS), ꢀ0.12 (s, 9H, C-TMS); 13C NMR (75 MHz, CDCl3)
4.1.17. Methyl N-benzyl-2-(4-methoxycarbonylpropyl)azetidine-2-
carboxylate (17). A solution of LDA (1.07 mmol, 1.1 equiv) [pre-
pared from diisopropylamine (0.15 mL, 1.07 mmol) in THF (2.5 mL)
and n-BuLi (1.5 M in hexane, 0.7 mL, 1.07 mmol) stirred at ꢀ78 ꢁC
for 30 min] was added to a solution of 4 (200 mg, 0.97 mmol,
1 equiv) in THF (1.4 mL), cooled to ꢀ78 ꢁC. The reaction mixture
was allowed to warm up to ꢀ65 ꢁC (l h), cooled again to ꢀ78 ꢁC and
a mixture of methyl 4-bromobutyrate (0.37 mL, 2.92 mmol,
3 equiv) and HMPA (1.1 mL, 6.14 mmol, 6.3 equiv) in THF (2.3 mL)
was added. The solution was allowed to warm to rt and then
stirred for 16 h. Then the reaction was quenched with saturated
aqueous NH4Cl and was extracted with Et2O (3ꢂ3 mL). The com-
bined organic layer was dried over Na2SO4, filtered and concen-
trated under reduced pressure. The crude product was purified by
flash chromatography (AcOEt/petroleum ether, 1:9 to 1:1) to af-
ford 17 (32 mg, 11%) as a yellow oil. TLC Rf 0.66 (silica gel, AcOEt/
d
171.4 (CO), 164.5 (C-7), 135.9 (CqeAr), 129.0 (2CHeAr), 128.9
(2CHeAr), 128.1 (1CHeAr), 109.3 (C-2), 68.6 (C-5), 68.0 (C-1), 52.9
(OCH3), 52.4 (OCH3), 44.9 (CH2Ph), 35.8 (C-3), 29.9 (C-4), 2.2
(Si(CH3)3), ꢀ1.3 (Si(CH3)3); HRMS (ESI) [MþNa]þ calcd for
C22H35NO5Si2Na: 472.195, found 472.193.
To a solution of LiBH4 (25 mg) in Et2O (5.5 mL), was added
a solution of 10 and 11 (131 mg) in Et2O (2.3 mL). The solution was
stirred at rt for 8 h. The solution was filtered and washed with Et2O
then with MeOH. The solution was concentrated under reduced
pressure and dissolved with CH2Cl2. The organic layer was washed
with brine, dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified by flash chro-
matography (AcOEt/petroleum ether gradientþ1% NEt3, 1:5 to 1:0)
to afford 12 and 13 (91 mg, mixture of diastereomers) as a colorless
oil. IR (film) 3410, 1728 cmꢀ1; HRMS (ESI) [MþNa]þ calcd for
C21H35NO4Si2Na: 444.200, found 444.198; HRMS (ESI) [MþNa]þ
calcd for C18H27NO4SiNa: 372.160, found 372.159.
petroleum ether, 1:2); IR (film) 1733 cmꢀ1
;
1H NMR (300 MHz,
CDCl3) 7.34e7.16 (m, 5H, Ph), 3.76 (s, 3H, CO2Me), 3.68 (d, 1H,
d
J¼12.9 Hz, CH2Ph), 3.67 (s, 3H, CO2Me), 3.59 (d, 1H, J¼12.9 Hz,
CH2Ph), 3.20e3.08 (m, 2H, H-4), 2.52 (m, 1H, H-3a), 2.34 (t, 2H,
J¼7.4 Hz, H-30), 2.02 (m, 1H, H-3b), 1.92 (dd, 1H, J¼11.6, 5.2 Hz, H-
10a), 1.82 (m, 1H, H-10b), 1.67 (m, 1H, H-20a), 1.53 (m, 1H, H-20b); 13C
To a solution of 12 and 13 (91 mg) in THF (4 mL), was added HCl
1 N (0.5 mL). The mixture was stirred at rt for 5 h. Saturated
aqueous NaHCO3 (2 mL) was added and the product was extracted
with CH2Cl2 (3ꢂ3 mL). The combined organic layer was dried over
Na2SO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash chromatography (MeOH/
CH2Cl2, 5:95) to afford 14 (43 mg, 36% in three steps) as a white
solid. TLC Rf 0.18 (silica gel, MeOH/CH2Cl2, 5:95); IR (film) 1743,
NMR (75 MHz, CDCl3)
d 173.8 (2 CO), 138.5 (CqeAr), 128.6
(2CHeAr), 128.3 (2CHeAr), 127.0 (1CHeAr), 72.1 (C-2), 56.1
(CH2Ph), 51.7 (OCH3), 51.6 (OCH3), 49.8 (C-4), 34.2 (C-10 or C-30),
34.0 (C-10 or C-30), 26.0 (C-3), 19.6 (C-20); HRMS (ESI) [MþNa]þ
calcd for C17H23NO4Na: 328.152, found 328.151.
1705 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 7.34e7.19 (m, 5H, Ph), 4.43
(d, 1H, J¼15.2 Hz, CH2Ph), 4.31 (d, 1H, J¼15.2 Hz, CH2Ph), 3.71e3.55
(m, 2H, CH2OH), 3.50 (s,1H, H-1), 2.53 (m, 1H, H-3a), 2.27 (m,1H, H-
3b), 1.90 (ddd, 1H, J¼14.2, 9.1, 1.1 Hz, H-4a), 1.69 (m, 1H, H-4b), 1.36
4.1.18. Methyl N-benzyl-2-(6-methoxycarbonylpentyl)azetidine-2-
carboxylate (18). A solution of LDA (1.07 mmol, 1.1 equiv) [pre-
pared from diisopropylamine (0.15 mL, 1.07 mmol) in THF (2.5 mL)
and n-BuLi (1.5 M in hexane, 0.7 mL, 1.07 mmol) stirred at ꢀ78 ꢁC
for 30 min] was added to a solution of 4 (200 mg, 0.97 mmol,
1 equiv) in THF (1.4 ml), cooled to ꢀ78 ꢁC. The reaction mixture was
allowed to warm up to ꢀ65 ꢁC (l h), cooled again to ꢀ78 ꢁC and
a mixture of methyl 6-bromohexanoate (0.46 mL, 2.92 mmol,
3 equiv) and HMPA (1.1 mL, 6.14 mmol, 6.3 equiv) in THF (2.3 mL)
was added. The solution was allowed to warm to rt and then stirred
for 16 h. Then the reaction was quenched with saturated aqueous
NH4Cl and was extracted with Et2O (3ꢂ3 mL). The combined or-
ganic layer was dried over Na2SO4, filtered and concentrated under
(br s, 1H, OH); 13C NMR (75 MHz, CDCl3)
d 207.3 (CO), 160.5 (C-7),
136.1 (CqeAr), 129.3 (2CHeAr), 128.52 (2CHeAr), 128.49 (1CHeAr),
68.4 (C-5), 66.2 (C-1), 63.5 (CH2OH), 44.7 (CH2Ph), 36.2 (C-3), 24.5
(C-4); HRMS (ESI) [MþNa]þ calcd for C14H15NO3Na: 268.094, found
268.091.
4.1.16. (1R*,3R*)-1-Methoxycarbonyl-5-azaspiro[2.4]heptan-4-one
(15) and methyl 2-oxo-1-azabicyclo[3.2.0]heptane-5-carboxylate
(16). To a solution of azetidine 6 (90 mg, 0.45 mmol, 1 equiv) in
CH2Cl2 (1 mL) cooled to 0 ꢁC was added NEt3 (156
mL, 1.12 mmol,

P.-A. Nocquet et al. / Tetrahedron 68 (2012) 4117e4128
4125
reduced pressure. The crude product was purified by flash chro-
matography (AcOEt/petroleum ether, 1:9 to 1:1) to afford 18
(45 mg, 14%) as a pale yellow oil. TLC Rf 0.67 (silica gel, AcOEt/pe-
troleum ether, 1:2); IR (film) 1724 cmꢀ1; 1H NMR (300 MHz, CDCl3)
4), 38.6 (CH2CH), 35.7 (CH(CH3)), 26.7 (C-3), 18.8 (CH3); HRMS (ESI)
[MþH]þ calcd for C17H24NO4: 306.170, found 306.169.
4.1.21. N-Benzyl-5-methoxy-5-(trimethylsilyl)oxy-6-methoxycarbonyl-
1-aza-spiro[3.4]octane (21). To a solution of azetidine 17 (32 mg,
0.10 mmol, 1 equiv) in CH2Cl2 (1 mL) cooled to 0 ꢁC was added TEA
d
7.35e7.15 (m, 5H, Ph), 3.75 (s, 3H, CO2Me), 3.66 (s, 3H, CO2Me),
3.67e3.62 (m, 2H, CH2Ph), 3.19e3.05 (m, 2H, H-4), 2.52 (m, 1H, H-
3a), 2.30 (t, 2H, J¼7.43 Hz, H-50), 2.04e1.86 (m, 2H, H-3bþH-10a),
1.79 (m, 1H, H-10b), 1.70e1.56 (m, 2H, H-40), 1.43e1.02 (m, 4H, H-20,
(37 mL, 0.26 mmol, 2.5 equiv) and TMSOTf (38 mL, 0.21 mmol, 2 equiv).
The solution was stirred at rt for 24 h. Then the reaction was
quenched with saturated aqueous NaHCO3 and was extracted with
CH2Cl2 (3ꢂ2 mL). The combined organic layer was dried over Na2SO4,
filtered and concentrated under reduced pressure. The crude product
was purified by flash chromatography (AcOEt/pentane, 1:7 to 1:5) to
afford 21 (16 mg, 40%) as a yellow oil: TLC Rf 0.72 (silica gel, AcOEt/
petroleum ether, 1:2); IR (film) 1741 cmꢀ1; 1H NMR (300 MHz, CDCl3)
H-30); 13C NMR (75 MHz, CDCl3)
d 174.3 (CO), 174.2 (CO), 138.7
(CqeAr), 128.7 (2CHeAr), 128.4 (2CHeAr), 127.0 (1CHeAr), 72.3 (C-
2), 56.1 (CH2Ph), 51.61 (OCH3), 51.56 (OCH3), 49.8 (C-4), 34.1 (C-50),
29.6 (C-10), 26.3 (C-20, C-40), 25.0 (C-3), 23.7 (C-30); HRMS (ESI)
[MþH]þ calcd for C19H28NO4: 334.201, found 334.201.
4.1.19. Methyl N-benzyl-2-(3-methoxycarbonyl-1-methylethyl)azeti-
dine-2-carboxylate (19). A solution of 4 (200 mg, 0.97 mmol,
1 equiv) in THF (2.4 mL) was added to a solution of LDA
(1.07 mmol, 1.1 equiv) cooled to ꢀ40 ꢁC [prepared from diiso-
propylamine (0.15 mL, 1.07 mmol) in THF (2.5 mL) and n-BuLi
(1.5 M in hexane, 0.7 mL, 1.07 mmol) stirred at ꢀ78 ꢁC for 30 min].
The reaction mixture was stirred for 50 min and then warmed up
to ꢀ5 ꢁC. A solution of methyl 3-bromo-3-methylpropionate
(185 mg, 1.02 mmol, 1.05 equiv) in THF (1 mL) was added. The
solution was allowed to warm to rt and then stirred for 16 h. Then
the reaction was quenched with brine and was extracted with
Et2O (3ꢂ3 mL). The combined organic layer was dried over
Na2SO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash chromatography (AcOEt/pe-
troleum ether, 1:7 to 1:3) to afford 19 (37 mg, 12%) as a yellow oil.
TLC Rf 0.73 (silica gel, AcOEt/petroleum ether, 1:2); IR (film)
d
7.35e7.11 (m, 5H, Ph), 4.01 (d, 1H, J¼13.2 Hz, CH2Ph), 3.62 (s, 3H,
CO2Me), 3.37 (d, 1H, J¼13.0 Hz, CH2Ph), 3.24 (s, 3H, OCH3), 3.10e2.95
(m, 2H, H-2a, H-6), 2.74 (m, 1H, H-2b), 2.27e1.88 (m, 4H, H-3a, H-7a,
H-8), 1.75 (m, 1H, H-7b), 1.57 (m, 1H, H-3b), 0.23 (s, 9H, SiMe3); 13C
NMR (75 MHz, C6D6)
d 172.7 (CO), 139.4 (CqeAr), 128.9e126.9
(5CHeAr), 109.8 (C-5), 76.6 (C-4), 57.7 (CH2Ph), 51.1 (OCH3), 49.6
(OCH3), 49.3 (C-2), 46.5 (C-6), 27.2 (C-8), 25.2 (C-3), 20.9 (C-7), 2.3
(Si(CH3)3); HRMS (ESI) [MþH]þ calcd for C20H32NO4Si: 378.210,
found 378.212.
4.1.22. tert-Butyl N-benzylazetidine-2-carboxylate (22). To a solu-
tion of tert-butyl 1,3-dibromopropionate (0.2 mL, 1.03 mmol,
1 equiv) in CH3CN (1.1 mL), was added benzylamine (0.34 mL,
3.10 mmol, 3 equiv). The solution was stirred at rt for 1 h then
heated at 55 ꢁC and stirred for 24 h. After cooling, 5% aqueous
NaHCO3 (5 mL) was added and the product was extracted with Et2O
(3ꢂ3 mL). The combined organic layer was dried over MgSO4, fil-
tered and concentrated under reduced pressure. The crude product
was purified by flash chromatography (AcOEt/petroleum ether, 1:7
to 1:5) to afford azetidine 22 (163 mg, 64%) as a yellow oil. TLC Rf
0.42 (silica gel, AcOEt/petroleum ether, 1:3); IR (film) 1738,
1734 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 7.35e7.15 (m, 5H, Ph),
3.85 (d, 1H, J¼13.2 Hz, CH2Ph), 3.81 (s, 3H, CO2Me), 3.66 (s, 3H,
CO2Me), 3.28 (d, 1H, J¼13.2 Hz, CH2Ph), 3.18 (m, 1H, H-4a), 2.98
(m, 1H, H-4b), 2.57 (m, 1H, CH(CH3)), 2.48e2.36 (m, 2H, H-3a,
CH2CO2Me), 2.25e2.13 (m, 1H, CH2CO2Me), 2.06 (m, 1H, H-3b),
1.04 (d, 3H, J¼6.9 Hz, CH3); 13C NMR (75 MHz, CDCl3)
d
173.6 (CO),
1717 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 7.31e7.16 (m, 5H, Ph), 3.80
(d, 1H, J¼12.6 Hz, CH2Ph), 3.58 (t, 1H, J¼8.4 Hz, H-2), 3.51 (d, 1H,
J¼12.6 Hz, CH2Ph), 3.24 (m, 1H, H-4a), 2.85 (m, 1H, H-4b), 2.29 (m,
1H, H-3a), 2.11 (m, 1H, H-3b), 1.37 (s, 9H, t-Bu); 13C NMR (75 MHz,
172.8 (CO), 138.5 (CqeAr), 128.45 (2CHeAr), 128.40 (2CHeAr),
127.0 (1CHeAr), 75.8 (C-2), 57.6 (CH2Ph), 51.7 (OCH3), 51.5 (OCH3),
49.8 (C-4), 36.7 (CH(CH3)), 36.3 (CH2CO2Me), 23.9 (C-3), 14.4
(CH3); HRMS (ESI) [MþH]þ calcd for C17H24NO4: 306.170, found
306.170.
CDCl3) d 172.0 (CO),137.6 (CqeAr),129.3 (2CHeAr),128.4 (2CHeAr),
127.3 (1CHeAr), 80.8 (C(CH3)3), 65.3 (C-2), 62.6 (CH2Ph), 50.8 (C-4),
28.1 (C(CH3)3), 21.6 (C-3); HRMS (ESI) [MþH]þ calcd for C15H22NO2:
248.165, found 248.165.
4.1.20. Methyl N-benzyl-2-(3-methoxycarbonyl-(S)-2-methylethyl)
azetidine-2-carboxylate (20). A solutionofLDA (1.07 mmol,1.1 equiv)
[prepared from diisopropylamine (0.15 mL, 1.07 mmol) in THF
(2.5 mL) and n-BuLi (1.38 M in hexane, 0.77 mL,1.07 mmol) stirred at
ꢀ78 ꢁC for 30 min] was added to a solution of 4 (200 mg, 0.97 mmol,
1 equiv) in THF (1.3 mL), cooled to ꢀ78 ꢁC. The reaction mixture was
allowed to warm up to ꢀ65 ꢁC (l h), cooled again to ꢀ78 ꢁC and
a mixture of methyl (R)-(þ)-3-bromo-2-methylpropionate (0.37 mL,
2.92 mmol, 3 equiv) and HMPA (1.1 mL, 6.14 mmol, 6.3 equiv) in THF
(2.3 mL) was added. The solution was allowed to warm to rt and then
stirred for 16 h. Then the reaction was quenched with saturated
aqueous NH4Cl and was extracted with Et2O (3ꢂ3 mL). The combined
organic layer was dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified by flash chroma-
tography (AcOEt/petroleum ether,1:9 to 1:3) to afford 20 (41 mg,14%)
as a yellow oil. TLC Rf 0.58 (silica gel, AcOEt/petroleum ether, 1:3); IR
4.1.23. tert-Butyl N-benzyl-2-(3-methoxycarbonylethyl)azetidine-2-
carboxylate (23). A solution of LDA (1.11 mmol, 1.1 equiv) [pre-
pared from diisopropylamine (0.16 mL, 1.11 mmol) in THF (3 mL)
and n-BuLi (1.43 M in hexane, 0.77 mL, 1.11 mmol) stirred at ꢀ78 ꢁC
for 30 min] was added to a solution of 22 (250 mg, 1.01 mmol,
1 equiv) in THF (1.3 mL), cooled to ꢀ78 ꢁC. The reaction mixture was
allowed to warm up to ꢀ65 ꢁC (l h), cooled again to ꢀ78 ꢁC and
a mixture of methyl 3-bromopropionate (0.3 mL, 3.03 mmol,
3 equiv) and HMPA (1.1 mL, 6.37 mmol, 6.3 equiv) in THF (2.5 mL)
was added. The solution was allowed to warm to rt and then stirred
for 16 h. Then the reaction was quenched with saturated aqueous
NH4Cl and was extracted with Et2O (3ꢂ4 mL). The combined or-
ganic layer was dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified by flash chro-
matography (AcOEt/petroleum ether, 1:9 to 1:7) to afford 23
(96 mg, 28%) as a yellow oil. TLC Rf 0.57 (silica gel, AcOEt/petroleum
(film) 1729 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.32e7.19 (m, 5H, Ph),
3.77 (s, 3H, CO2Me), 3.72 (d, 1H, J¼12.9 Hz, CH2Ph), 3.65 (s, 3H,
CO2Me), 3.50 (d, 1H, J¼12.9 Hz, CH2Ph), 3.21e3.10 (m, 2H, H-4), 2.65
(m, 1H, CH(CH3)), 2.52 (m, 1H, H-3a), 2.41 (dd, 1H, J¼13.9, 7.6 Hz,
CH2CH), 2.07 (m, 1H, H-3b), 1.88 (dd, 1H, J¼13.9, 5.7 Hz, CH2CH), 1.19
ether, 1:3); IR (film) 1738, 1717 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d
7.32e7.16 (m, 5H, Ph), 3.71 (d, 1H, J¼12.9 Hz, CH2Ph), 3.66 (s, 3H,
CO2Me), 3.65 (d,1H, J¼12.9 Hz, CH2Ph), 3.13 (m, 2H, H-4), 2.50e2.05
(d, 3H, J¼7.0 Hz, CH3); 13C NMR (100 MHz, CDCl3)
d 177.0 (CO), 173.4
(CO), 138.4 (CqeAr), 128.7 (2CHeAr), 128.4 (2CHeAr), 127.1
(1CHeAr), 71.9 (C-2), 56.0 (CH2Ph), 51.8 (OCH3), 51.6 (OCH3), 50.1 (C-
(m, 5H, H-3a, H-10, H-20), 1.94 (m, 1H, H-3b), 1.51 (s, 9H, t-Bu); 13C
NMR (75 MHz, CDCl3)
(2CHeAr), 128.4 (2CHeAr), 127.0 (1CHeAr), 81.5 (C(CH3)3), 71.9 (C-
d 174.0 (CO), 172.3 (CO), 138.7 (CqeAr), 128.6

4126
P.-A. Nocquet et al. / Tetrahedron 68 (2012) 4117e4128
2), 55.9 (CH2Ph), 51.8 (OCH3), 49.8 (C-4), 29.6 (C-10 or C-20), 29.1 (C-
10 or C-20), 28.4 (C(CH3)3), 25.7 (C-3); HRMS (ESI) [MþH]þ calcd for
C19H28NO4: 334.201, found 334.200.
was allowed to warm to rt and stirred for 16 h. Saturated aqueous
NH4Cl was added at 0 ꢁC and the reaction mixture was extracted
with CH2Cl2 (3ꢂ2 mL). The combined organic layer was dried over
Na2SO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash chromatography (AcOEt/pe-
troleum ether, 1:4 to 1:3) to afford (E)-27 (160 mg, 50%) and (Z)-27
(72 mg, 22%) as yellow oils.
4.1.24. Methyl N-benzyl-2-(3-methoxycarbonylethyl)pyrrolidine-2-
carboxylate (25). A solution of LDA (1.00 mmol, 1.1 equiv) [pre-
pared from diisopropylamine (0.14 mL, 1.00 mmol) in THF (2.8 mL)
and n-BuLi (1.4 M in hexane, 0.7 mL, 1.00 mmol) stirred at ꢀ78 ꢁC
for 30 min] was added to a solution of 24 (200 mg, 0.91 mmol,
1 equiv) in THF (1.1 mL), cooled to ꢀ78 ꢁC. The reaction mixture was
allowed to warm up to ꢀ65 ꢁC (l h), cooled again to ꢀ78 ꢁC and
a mixture of methyl 3-bromopropionate (0.3 mL, 2.74 mmol,
3 equiv) and HMPA (1.0 mL, 5.75 mmol, 6.3 equiv) in THF (2.3 mL)
was added. The solution was allowed to warm to rt and then stirred
for 16 h. Then the reaction was quenched with saturated aqueous
NH4Cl and was extracted with Et2O (3ꢂ4 mL). The combined or-
ganic layer was dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified by flash chro-
matography (AcOEt/petroleum ether, 0:100 to 20:80) to afford 25
(125 mg, 45%) as a yellow oil. TLC Rf 0.57 (silica gel, AcOEt/petro-
(E)-27: TLC Rf 0.40 (silica gel, AcOEt/petroleum ether, 1:1); 1H
NMR (300 MHz, CDCl3)
d
7.39e7.19 (m, 5H, Ph), 6.93 (dd, 1H, J¼15.7,
5.6 Hz, CH]CHCO2Et), 5.97 (dd, 1H, J¼15.7, 1.3 Hz, CH]CHCO2Et),
3.81e3.67 (m, 2H, H-2, CH2Ph), 3.72 (s, 3H, CO2Me), 3.44 (d, 1H,
J¼12.8 Hz, CH2Ph), 3.33e3.24 (m, 1H, H-4a), 2.94e2.83 (m, 1H, H-
4b), 2.25e2.13 (m, 1H, H-3a), 2.11e1.96 (m, 1H, H-3b); 13C NMR
(100 MHz, CDCl3) d 167.2 (CO),149.2 (CH]CHCO2Et), 137.8 (CqeAr),
128.9 (2CHeAr), 128.4 (2CHeAr), 127.3 (1CHeAr), 120.4 (CH]
CHCO2Et), 65.5 (C-2), 62.1 (CH2Ph), 51.5 (OCH3), 51.3 (C-4), 24.9 (C-
3); LRMS (ESI): m/z 232.0 [MþH]þ. Spectroscopic data are in ac-
cordance with literature data.22
(Z)-27: TLC Rf 0.30 (silica gel, AcOEt/petroleum ether, 1:1); 1H
NMR (300 MHz, CDCl3)
d
7.34e7.17 (m, 5H, Ph), 6.26 (dd, 1H, J¼11.7,
leum ether, 1:3); IR (film) 1723 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
7.2 Hz, CH]CHCO2Et), 5.57 (dd, 1H, J¼11.5, 1.5 Hz, CH]CHCO2Et),
4.74e4.62 (m, 1H, H-2), 3.70 (s, 3H, CO2Me), 3.64 (d, 1H, J¼12.4 Hz,
CH2Ph), 3.57 (d, 1H, J¼12.5 Hz, CH2Ph) 3.39e3.29 (m, 1H, H-4a),
2.99e2.82 (m, 1H, H-4b), 2.41e2.29 (m, 1H, H-3a), 2.09e1.93 (m,
1H, H-3b).
d
7.36e7.18 (m, 5H, Ph), 3.94 (d, 1H, J¼13.5 Hz, CH2Ph), 3.74 (s, 3H,
CO2Me), 3.68 (s, 3H, CO2Me), 3.30 (d, 1H, J¼13.5 Hz, CH2Ph), 2.92
(m, 1H, H-5a), 2.61e2.33 (m, 3H, H-5b, H-10 or H-20), 2.33e2.14 (m,
2H, H-3a, H-10a or H-20a), 2.07 (m, 1H, H-10b or H-20b), 1.89e1.63
(m, 3H, H-3b, H-4); 13C NMR (75 MHz, CDCl3)
d 174.8 (CO), 174.4
(CO), 140.1 (CqeAr), 128.37 (2CHeAr), 128.36 (2CHeAr), 126.9
(1CHeAr), 70.0 (C-2), 53.4 (CH2Ph), 51.8 (CH3), 51.5 (C-5), 51.4
(CH3), 33.9 (C-3), 29.6 (C-10 or C-20), 29.4 (C-10 or C-20), 22.0 (C-4);
HRMS (ESI) [MþH]þ calcd for C17H24NO4: 306.170, found 306.170.
4.1.27. N-Benzyl-2-methoxycarbonylethylazetidine (28). To a solu-
tion of (E)-27 (74 mg, 0.32 mmol 1 equiv) in MeOH (2 mL) cooled to
0 ꢁC, was added CuCl (54 mg, 0.54 mmol,1.7 equiv). After 1 or 2 min,
NaBH4 (24 mg, 0.63 mmol, 2 equiv) was added. The solution was
stirred 4 h at 0 ꢁC. The reaction mixture was diluted with ether and
saturated aqueous NH4Cl was added. The mixture was extracted
with AcOEt (3ꢂ2 mL). The combined organic layer was dried over
MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash chromatography (AcOEt/pe-
troleum ether, 1:5 to 1:0) to afford desired product 28 (30 mg, 41%).
TLC Rf 0.15 (silica gel, AcOEt/petroleum ether, 1:1); 1H NMR
4.1.25. Ethyl N-benzyl-2-(3-ethylthiocarbonylethyl)azetidine-2-
carboxylthioate (26). To a solution of AlMe3 (2 M in toluene,
0.69 mL, 1.37 mmol, 4 equiv) in CH2Cl2 (1.4 mL) cooled to 0 ꢁC, was
added EtSH (0.1 mL, 1.37 mmol, 4 equiv). The solution was stirred at
rt for 15 min. A solution of 1 (100 mg, 0.34 mmol, 1 equiv) in CH2Cl2
(0.2 mL) was added. The solution was stirred for 25 h. After cooling
to 0 ꢁC, Et2O (3 mL) followed by saturated aqueous NH4Cl (1 mL)
were added. The solution was stirred and then filtered. The organic
layer was washed with brine, dried over Na2SO4, filtered and con-
centrated under reduced pressure. The crude product was purified
by flash chromatography (AcOEt/petroleum ether, 1:0 to 1:9) to
afford 26 (45 mg, 37%) as a yellow oil. TLC Rf 0.56 (silica gel, AcOEt/
(300 MHz, CDCl3)
d
7.34e7.19 (m, 5H, Ph), 3.71 (d, 1H, J¼12.7 Hz,
CH2Ph), 3.65 (s, 3H, CO2Me), 3.44 (d, 1H, J¼12.7 Hz, CH2Ph),
3.33e3.12 (m, 2H, CHN), 2.84e2.73 (m,1H, CHN), 2.38e2.17 (m, 2H),
2.07e1.95 (m, 1H), 1.90e1.71 (m, 3H). Spectroscopic data are in
accordance with literature data.22
petroleum ether, 1:2); IR (film) 1674 cmꢀ1
CDCl3)
;
1H NMR (300 MHz,
4.1.28. 1-Methoxycarbonyl-2-(2-benzylamino)ethylcyclopropane
(29a). To a solution of 28 (85 mg, 0.36 mmol, 1 equiv) in CH2Cl2
(1 mL) cooled to 0 ꢁC was added NEt3 (0.13 mL, 0.91 mmol,
2.5 equiv) and TMSOTf (0.13 mL, 0.73 mmol, 2 equiv). The solution
was stirred at rt for 24 h. Then the reaction was quenched with
saturated aqueous NaHCO3 and was extracted with CH2Cl2
(3ꢂ2 mL). The combined organic layer was dried over Na2SO4, fil-
tered and concentrated under reduced pressure. The crude product
was purified by flash chromatography (MeOH/CH2Cl2, 1:99 to
10:90) to afford 29a (52 mg, 61%, 56% de) as a yellow oil. TLC Rf 0.33
d
7.45e7.20 (m, 5H, Ph), 3.98 (d, 1H, J¼12.6 Hz, CH2Ph), 3.59
(d, 1H, J¼12.6 Hz, CH2Ph), 3.22 (m, 1H, H-4a), 3.06 (m, 1H, H-4b),
2.90 (q, 2H, J¼7.4 Hz, CH2CH3), 2.88e2.78 (m, 3H, H-20a, CH2CH3),
2.69 (m, 1H, H-20b), 2.43e2.24 (m, 3H, H-3, H-10a), 2.03 (m, 1H, H-
10b), 1.32e1.22 (m, 6H, 2CH2CH3); 13C NMR (75 MHz, CDCl3)
d 206.0
(CO), 199.1 (CO), 137.9 (CqeAr), 128.8 (2CHeAr), 128.5 (2CHeAr),
127.2 (1CHeAr), 74.8 (C-2), 55.1 (CH2Ph), 48.6 (C-4), 39.5 (C-20), 27.7
(C-10), 26.5 (C-3), 23.5 (CH2CH3), 23.1 (CH2CH3), 14.9 (CH2CH3), 14.7
(CH2CH3); HRMS (ESI) [MþH]þ calcd for C18H26NO2S2: 352.140,
found 352.135.
(silica gel, MeOH/CH2Cl2, 1:9); IR (film) 1726 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) 7.41e7.18 (m, 5H, Ph), 3.85 (s, 2H, CH2Ph), 3.66
d
4.1.26. Methyl 3-(1-benzylazetidin-2-yl)acrylate (27). To a solution
of azetidine 4 (285 mg, 1.40 mmol, 1 equiv) in THF (3 mL) cooled to
ꢀ78 ꢁC was added DIBAL-H (1 M in hexane, 2.2 mL, 2.2 mmol,
1.6 equiv). The solution was stirred at this temperature for 4 h. Then
the reaction was quenched with MeOH (0.3 mL) and the solution
was allowed to warm to 0 ꢁC. Saturated aqueous NH4Cl (0.7 mL)
was added and the solution was stirred 15 min then filtered and
concentrated to afford the corresponding aldehyde, which was
used without purification for the Wittig reaction. To a solution of
the aldehyde in CH2Cl2 (13 mL) cooled to 0 ꢁC was added por-
tionwise Ph3P]CHCO2Me (1 g, 2.99 mmol, 2.1 equiv). The solution
(s, 3H, CO2Me), 2.76 (t, 2H, J¼7.4 Hz, H-5), 1.67e1.51 (m, 2H, H-4),
1.45e1.32 (m, 2H, H-1, H-2), 1.17 (m, 1H, H-3a), 0.73 (m, 1H, H-3b);
13C NMR (75 MHz, CDCl3)
d 174.8 (CO), 140.1 (CqeAr), 128.5
(2CHeAr), 128.2 (2CHeAr), 127.1 (1CHeAr), 54.0 (CH2Ph), 51.8
(OCH3), 48.8 (C-5), 33.4 (C-4), 20.9 (C-1 or C-2), 19.9 (C-1 or C-2),
15.4 (C-3); HRMS (ESI) [MþH]þ calcd for C14H20NO2: 234.159, found
234.151.
4.1.29. Methyl 2-(2-(N-benzylacetamido)ethyl)cyclopropanecarboxy-
late (29b). To a solution of 29a (52 mg, 0.22 mmol, 1 equiv) in CH2Cl2
(1.4 mL), was added Ac2O (23 mL, 0.24 mmol, 1.1 equiv). The solution

P.-A. Nocquet et al. / Tetrahedron 68 (2012) 4117e4128
4127
was stirred at rt for 24 h and then concentrated. Et2O (3 mL) was
added and the organic phase was washed with saturated aqueous
NaHCO3 (2ꢂ2 mL) and with water (2 mL). The crude product was
purified by flash chromatography (AcOEt/petroleum ether, 1:5 to 1:0)
to afford 29b (41 mg, 67%, 56% de) as a yellow oil. TLC Rf 0.19 (silica gel,
d 7.37e7.16 (m, 5H, Ph), 3.74 (s, 3H, CO2Me), 3.70 (s, 3H, CO2Me),
3.63 (q,1H, J¼6.3 Hz, CHCH3), 3.12 (m, 1H, H-4a), 2.96 (m, 1H, H-4b),
2.59e2.37 (m, 2H, H-20), 2.34e2.17 (m, 3H, H-3a, H-10), 1.97 (m, 1H,
H-3b), 1.16 (d, 1H, J¼6.4 Hz, CH3); 13C NMR (75 MHz, CDCl3)
d 174.2
(CO), 173.5 (CO), 144.0 (CqeAr), 128.4 (2CHeAr), 127.5 (2CHeAr),
127.2 (1CHeAr), 71.2 (C-2), 61.8 (CHCH3), 51.8 (OCH3), 51.6 (OCH3),
48.6 (C-4), 31.5 (C-10 or C-20), 29.3 (C-10 or C-20), 24.6 (C-3), 22.3
(CH3); HRMS (ESI) [MþH]þ calcd for C17H24NO4: 306.170, found
306.169.
AcOEt/petroleum ether, 1:1); IR (film) 1723, 1641 cmꢀ1
;
1H NMR
7.37e7.20 (m, 5H, Ph), 4.59e4.45 (m,
(400 MHz, DMSO-d6, 373 K)
d
2H, CH2Ph), 3.60 (s, 3H, CO2Me), 3.42e3.21 (m, 2H, CH2NBnAc), 2.05
(s, 3H, COCH3), 1.59e1.48 (m, 2H, CHCH2CH2N), 1.42 (m, 1H,
CHCO2Me), 1.31e1.20 (m, 1H, CH), 1.03 (m, 1H, CHCH2CH), 0.82e0.70
(m, 1H, CHCH2CH); HRMS (ESI) [MþNa]þ calcd for C16H21NO3Na:
298.141, found 298.142.
4.1.32. (1S*,3S*)-N-(R)-(a)-Methylbenzyl-1-methoxycarbonyl-5-aza-
spiro[2.4]heptan-4-one (32). To a solution of azetidine 31a (90 mg,
0.29 mmol, 1 equiv) in CH2Cl2 (1 mL) cooled to 0 ꢁC was added NEt3
4.1.30. Methyl (2R,5R)-
a
-methylbenzylazetidine-2-carboxylate (30a)
(102 mL, 0.74 mmol, 2.5 equiv) and TMSOTf (106 mL, 0.59 mmol,
and methyl (2S,5R)- -methylbenzylazetidine-2-carboxylate (30b). To
a solution of K2CO3 (1.5 g, 10.6 mmol, 1 equiv) in CH3CN/H2O (1:5,
30 mL), were added methyl 1,3-dibromopropionate (1.5 mL,
a
2 equiv). The solution was stirred at rt for 24 h. Then the reaction
was quenched with saturated aqueous NaHCO3 and was extracted
with CH2Cl2 (3ꢂ2 mL). The combined organic layer was dried over
Na2SO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash chromatography (AcOEt/pen-
tane, 1:9 to 1:7) to afford 32 (48 mg, 56%) as a yellow oil. TLC Rf 0.23
10.6 mmol, 1 equiv) and (R)-(þ)-a-methylbenzylamine (1.4 mL,
10.6 mmol,1 equiv). The solution was heated to reflux and stirred for
6.5 h. After cooling, water (10 mL) was added and the product was
extracted with Et2O (3ꢂ8 mL). The combined organic layer was dried
over Na2SO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash chromatography (AcOEt/petro-
leum ether, 1:7 to 1:2) to afford azetidines 30a (735 mg, 32%) and
30b (734 mg, 32%) as yellow oils.
(silica gel, AcOEt/petroleum ether, 1:3); ½a D20
ꢃ
þ296 (c 1.0, CHCl3); IR
(film) 1728, 1682 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
7.34e7.17 (m,
5H, Ph), 5.45 (q, 1H, J¼7.1 Hz, CHCH3), 3.66 (s, 3H, CO2Me), 3.32 (m,
1H, H-6a), 3.00 (td, 1H, J¼8.9, 6.0 Hz, H-6b), 2.25e1.97 (m, 3H, H-
1þH-7), 1.51 (m, 1H, H-2a), 1.50 (d, 3H, J¼6.6 Hz, CH3), 1.25 (m, 1H,
Compound 30a: TLC Rf 0.54 (silica gel, AcOEt/petroleum ether,
H-2b); 13C NMR (75 MHz, CDCl3)
d 173.0 (CO), 172.1 (NCO), 140.0
1:2); ½a 2D0
ꢃ
þ122 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3)
(CqeAr), 128.7 (2CHeAr), 127.6 (2CHeAr), 127.2 (1CHeAr), 52.0
(OCH3), 50.0 (CHCH3), 39.9 (C-6), 31.9 (C-3), 25.2 (C-1), 22.8 (C-7),
19.1 (C-2), 16.2 (CH3); HRMS (ESI) [MþNa]þ calcd for C16H19NO3Na:
296.126, found 296.126.
d
7.30e7.16 (m, 5H, Ph), 3.73e3.65 (m, 1H, H-2), 3.69 (s, 3H, CO2Me),
3.39 (q, 1H, J¼6.6 Hz, H-5), 3.05 (m, 1H, H-4a), 2.74 (m, 1H, H-4b),
2.29e2.05 (m, 2H, H-3), 1.16 (d, 3H, J¼6.6 Hz, CH3). Spectroscopic
data are in accordance with literature data.27
Compound 30b: TLC Rf 0.30 (silica gel, AcOEt/petroleum ether,
Acknowledgements
1:2) ½a 2D0
ꢃ
ꢀ31 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.33e7.16
(m, 5H, Ph), 3.63e3.52 (m, 2H, H-2, H-4a), 3.41e3.29 (m, 1H, H-5),
3.33 (s, 3H, CO2Me), 3.01 (m, 1H, H-4b), 2.30 (m, 1H, H-3a), 2.13 (m,
1H, H-3b), 1.28 (d, 3H, J¼6.4 Hz, CH3). Spectroscopic data are in
accordance with literature data.27
This work was supported by the ‘Institut Universitaire de France’
(IUF), the CNRS, the University of Strasbourg and a doctoral fel-
lowship from the French Department of Research to P.-A.N. We
further thank Michel Schmitt for NMR measurements.
4.1.31. Methyl
N-(R)-a-methylbenzyl-2-(3-methoxycarbonylethyl)
azetidine-2-carboxylate (31). A solution of LDA (3.01 mmol,
1.1 equiv) [prepared from diisopropylamine (0.42 mL, 3.01 mmol)
in THF (7 mL) and n-BuLi (1.56 M in hexane, 1.9 mL, 3.01 mmol)
stirred at ꢀ78 ꢁC for 30 min] was added to a solution of 30 (600 mg,
2.74 mmol, 1 equiv) in THF (3.6 mL), cooled to ꢀ78 ꢁC. The reaction
mixture was allowed to warm up to ꢀ65 ꢁC (l h), cooled again to
ꢀ78 ꢁC and a mixture of methyl 3-bromopropionate (0.9 mL,
8.21 mmol, 3 equiv) and HMPA (3.0 mL,17.2 mmol, 6.3 equiv) in THF
(6.5 mL) was added. The solution was allowed to warm to rt and
then stirred for 16 h. Then the reaction was quenched with satu-
rated aqueous NH4Cl and was extracted with Et2O (3ꢂ6 mL). The
combined organic layer was dried over Na2SO4, filtered and con-
centrated under reduced pressure. The crude product was purified
by flash chromatography (CH2Cl2) to afford 31a (147 mg, 18%) and
31b (36 mg, 4%) as yellow oils.
Supplementary data
The copies of the 1H NMR spectra for all products (except for 27
and 28) and copies of 13C NMR spectra for all new products (except
for 29b). Crystal data for compounds (þ)-2b and 14. The copies of
1H NMR spectra related to the ee. determination of (ꢀ)-1 and (þ)-2
using Pirkle’s reagent. Supplementary data related to this article
can be found online at doi:10.1016/j.tet.2012.03.111.
References and notes
1. See for examples: (a) Kimura, Y.; Atarashi, S.; Kawakami, K.; Sato, K.; Hayakawa,
I. J. Med. Chem. 1994, 37, 3344e3352; (b) Satoh, K.; Imura, A.; Miyadera, A.;
Kanai, K.; Yukimoto, Y. Chem. Pharm. Bull. 1998, 46, 587e590; (c) Kim, S.-Y.;
Park, H.-B.; Cho, J.-H.; Yoo, K.-H.; Oh, C.-H. Bioorg. Med. Chem. Lett. 2009, 19,
2558e2561; (d) Park, H.-B.; Jo, N.-H.; Hong, J.-H.; Chei, J.-H.; Cho, J.-H.; Yoo, K.-
H.; OH, C.-H. Arch. Pharm. Chem. Life Sci. 2007, 340, 530e537; (e) Cianchetta, G.;
Mannhold, R.; Cruciani, G.; Baroni, M.; Cecchetti, V. J. Med. Chem. 2004, 47,
3193e3201; (f) Jiraskova, N. Curr. Opin. Invest. Drugs 2000, 1, 31e34; (g) Yoshida,
T.; Yamamoto, Y.; Orita, H.; Kakiuchi, M.; Takahashi, Y.; Itakura, M.; Kado, N.;
Yasuda, S.; Kato, H.; Itoh, Y. Chem. Pharm. Bull. 1996, 44, 1376e1386; (h) Taka-
hashi, Y.; Masuda, N.; Otsuki, M.; Miki, M.; Nishino, T. Antimicrob. Agents Che-
mother. 1997, 41, 1326e1330; (i) Guo, Z.; Orth, P.; Wong, S.-C.; Lavey, B. J.; Shih,
N.-Y.; Niu, X.; Lundell, D. J.; Madison, V.; Kozlowski, J. A. Bioorg. Med. Chem. Lett.
2009, 19, 54e57.
Compound 31a: TLC Rf 0.67 (silica gel, Et2O/CH2Cl2, 1:5); ½a D20
ꢃ
þ64 (c 1.0, CHCl3); IR (film) 1726 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
7.31e7.16 (m, 5H, Ph), 3.70 (s, 3H, CO2Me), 3.64 (s, 3H, CO2Me),
3.62 (m, 1H, CHCH3), 3.37e3.27 (m, 2H, H-4), 2.37e2.15 (m, 3H, H-
3a, H-20), 2.00 (m, 1H, H-3b), 1.85e1.61 (m, 2H, H-10), 1.18 (d, 1H,
J¼3.4 Hz, CH3); 13C NMR (75 MHz, CDCl3)
d 173.9 (CO), 173.2 (CO),
144.0 (CqeAr), 128.0 (2CHeAr), 127.6 (2CHeAr), 127.3 (1CHeAr),
71.6 (C-2), 61.0 (CHCH3), 51.5 (OCH3), 51.2 (OCH3), 48.7 (C-4), 30.4
(C-10 or C-20), 28.9 (C-10 or C-20), 24.8 (C-3), 21.6 (CH3); HRMS (ESI)
[MþNa]þ calcd for C17H23NO4Na: 328.152, found 328.152.
2. Spirocyclopropyl
b-lactams were also found to display interesting biological
activity, see for examples: (a) Sandanayaka, V. P.; Prashad, A. S.; Yang, Y.;
Williamson, R. T.; Lin, Y. I.; Mansour, T. S. J. Med. Chem. 2003, 46, 2569e2571;
(b) Singh, G. S.; D’hooghe, M.; De Kimpe, N. Tetrahedron 2011, 67, 1989e2012.
3. (a) Moody, C. M.; Young, D. W. J. Chem. Soc., Perkin Trans. 1 1997, 3519e3530; (b)
Petter, R. C.; Banerjee, S.; Englard, S. J. Org. Chem. 1990, 55, 3088e3097.
Compound 31b: TLC Rf 0.76 (silica gel, Et2O/CH2Cl2, 1:5); ½a D20
ꢃ
þ76 (c 0.5, CHCl3); IR (film) 1725 cmꢀ1; 1H NMR (300 MHz, CDCl3)

4128
P.-A. Nocquet et al. / Tetrahedron 68 (2012) 4117e4128
4. For recent examples see: (a) Liu, T.-L.; He, Z.-L.; Tao, H.-Y.; Cai, Y.-P.; Wang, C.-J.
Chem. Commun. 2011, 2616e2618; (b) Yao, Y.; Fan, W.; Li, W.; Ma, X.; Zhu, L.;
Xie, X.; Zhang, Z. J. Org. Chem. 2011, 76, 2807e2813.
Battistini, L.; Burreddu, P.; Pinna, L.; Pelosi, G.; Casiraghi, G. Eur. J. Org. Chem.
2008, 2273e2287; (c) Ellis, J. M.; Overman, L. E.; Tanner, H. R.; Wang, J. J. Org.
Chem. 2008, 73, 9151e9154; (d) Battistini, L.; Curti, C.; Zanardi, F.; Rassu, G.;
Auzzas, L.; Casiraghi, G. J. Org. Chem. 2004, 69, 2611e2613.
5. For recent examples see: (a) Compain, P.; Decroocq, C.; Iehl, J.; Holler, M.; Ha-
ꢁ
zelard, D.; Mena Barragan, T.; Ortiz Mellet, C.; Nierengarten, J.-F. Angew. Chem.,
17. (a) Hoye, T. R.; Dvornikovs, V.; Sizova, E. Org. Lett. 2006, 8, 5191e5194; (b)
Rietsch, V.; Miesch, L.; Yamashita, D.; Miesch, M. Eur. J. Org. Chem. 2010,
6944e6948.
Int. Ed. 2010, 49, 5753e5756; (b) Decroocq, C.; Rodríguez-Lucena, D.; Russo, V.;
ꢁ
Mena Barragan, T.; Ortiz Mellet, C.; Compain, P. Chem.dEur. J. 2011, 17,
13825e13831; (c) Chagnault, V.; Compain, P.; Lewinski, K.; Ikeda, K.; Asano, N.;
Martin, O. R. J. Org. Chem. 2009, 74, 3179e3182; (d) Godin, G.; Garnier, E.; Com-
pain, P.; Martin, O. R.; Ikeda, K.; Asano, N. Tetrahedron Lett. 2004, 45, 579e581.
6. Nocquet, P.-A.; Hazelard, D.; Compain, P. Eur. J. Org. Chem. 2011, 6619e6623.
7. For a review on novel syntheses of azetidines see: (a) Brandi, A.; Cicchi, S.;
Cordero, F. M. Chem. Rev. 2008, 108, 3988e4035; (b) Bott, T. M.; West, F. G.
Heterocycles 2012, 84, 223e264.
8. (a) Couty, F.; Evano, G. Synlett 2009, 3053e3064; (b) Couty, F.; Durrat, F.; Evano,
G. In Targets in Heterocyclic SystemsdChemistry and Properties; Attanasi, O. A.,
Spinelli, D., Eds.; Italian Society of Chemistry: Rome, 2005; Vol. 9, pp 186e210.
9. For examples of intramolecular ring-opening reactions of N-alkylated azeti-
dines with amines see: Vargas-Sanchez, M.; Couty, F.; Evano, G.; Prim, D.;
Marrot, J. Org. Lett. 2005, 7, 5861e5864.
18. See for examples: (a) Nivsarkar, M.; Thavaselvam, D.; Prasanna, S.; Sharma, M.;
Kaushik, M. P. Bioorg. Med. Chem. Lett. 2005, 15, 1371e1373; (b) Besada, P.;
ꢁ
ꢁ
Gonzalez-Moa, M. J.; Teran, C.; Teijeira, M.; Santana, L. Nucleosides Nucleotides
Nucleic Acids 2003, 22, 759e761; (c) Evans, C. D.; Mahon, M. F.; Andrews, P. C.;
Muir, J.; Bull, S. D. Org. Lett. 2011, 13, 6276e6279.
19. (a) CCDC-867757 contains the Supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif; (b) ORTEP-3
for Windows Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565e566.
20. Hatch, R. P.; Weinreb, S. M. J. Org. Chem. 1977, 42, 3960e3961.
21. (a) Van Brabandt, W.; Van Landeghem, R.; De Kimpe, N. Org. Lett. 2006, 8,
1105e1108; (b) Blakemore, D. C.; Chiva, J.-Y.; Thistlethwaite, I. Synlett 2011,
1101e1104; (c) Mollet, K.; Catak, S.; Waroquier, M.; Van Speybroeck, V.;
D’hooghe, M.; De Kimpe, N. J. Org. Chem. 2011, 76, 8364e8375; (d) Mollet,
K.; Broeckx, L.; D’hooghe, M.; De Kimpe, N. Heterocycles 2012, 84,
431e447.
10. For examples of opening of azetidinium ions or N-sulfonyl azetidines with C-
nucleophiles see: (a) Couty, F.; David, O.; Drouillat, B. Tetrahedron Lett. 2007, 48,
ꢁ
9180e9184; (b) Bakalarz-Jeziorna, A.; Helinski, J.; Krawiecka, B. J. Chem. Soc.,
Perkin Trans. 1 2001, 1086e1090; (c) Ungureanu, I.; Klotz, P.; Shoenfelder, A.;
Mann, A. Chem. Commun. 2001, 958e959; (d) Yadav, J. S.; Reddy, B. V. S.; Nar-
asimhulu, G.; Satheesh, G. Synlett 2009, 727e730.
22. (a) Barrett, A. G. M.; Dozzo, P.; White, A. J. P.; Williams, D. J. Tetrahedron 2002,
58, 7303e7313; (b) Koya, S.; Yamanoi, K.; Yamasaki, R.; Azumaya, I.; Masu, H.;
Saito, S. Org. Lett. 2009, 11, 5438e5441; (c) In our hands, application of the
procedure reported by Barrett, et al. for the chemoselective reduction of the
double bond using large excess of NaBH4 at room temperature (Ref. 22a) led to
the undesired fully reduced product.
23. Pirkle, W. H.; Hoover, D. J. Top. Stereochem. 1982, 13, 263e331.
24. The enantiomeric excess of (þ)-2a was determined by 1H NMR analysis using
the Pirkle chiral shift reagent TFAE (See Supplementary data).
25. The absolute configurations of (þ)-2a were determined by an X-ray crystal-
lographic analysis of the corresponding primary alcohol (þ)-2b (See
Supplementary data).
26. Baktharaman, S.; Selvakumar, S.; Singh, V. K. Org. Lett. 2006, 8, 4335e4338.
27. Starmans, W. A. J.; Walgers, R. W. A.; Thijs, L.; De Gelder, R.; Smits, J. M. M.;
Zwanenburg, B. Tetrahedron 1998, 54, 4991e5004.
11. For the synthesis of three-membered rings by way of azetidine ring-opening
reactions see: (a) Alex, A.; Larmanjat, B.; Marrot, J.; Couty, F.; David, O. Chem.
Commun. 2007, 2500e2502; (b) Couty, F.; David, O.; Larmanjat, B.; Marrot, J. J.
Org. Chem. 2007, 72, 1058e1061.
12. De Rycke, N.; David, O.; Couty, F. Org. Lett. 2011, 13, 1836e1839.
13. Evans, G. B.; Furneaux, R. H.; Greatrex, B.; Murkin, A. S.; Schramm, V. L.; Tyler, P.
C. J. Med. Chem. 2008, 51, 948e956.
€
14. Weigl, M.; Wunsch, B. Tetrahedron 2002, 58, 1173e1183.
ꢁ
ꢁ
15. Gerona-Navarro, G.; Bonache, M. A.; Herranz, R.; García-Lopez, M. T.; Gonzalez-
~
Muniz, R. J. Org. Chem. 2001, 66, 3538e3547.
16. See for examples: (a) Gondi, V. B.; Hagihara, K.; Rawal, V. H. Angew. Chem., Int.
Ed. 2009, 48, 776e779; (b) Zanardi, F.; Curti, C.; Sartori, A.; Rassu, G.; Roggio, A.;