Stereoselective synthesis of constrained norbornane-derived spiro-β-lactams

Article abstract of DOI:10.1016/j.tet.2012.11.048

New enantiopure polycyclic norbornane-derived spiro-β-lactams were synthesized by means of a Staudinger ketene-imine reaction between unsymmetrical bicyclic chiral ketenes, generated from differently substituted norbornane carboxylic acids, and (E)-N-benzyl-N-(phenylmethylene)amine, with high yields and moderate to good stereoselectivities. The diastereoisomeric results were rationalized taking into account the increasing steric encumbrance present on the norbornane skeleton and the stability of the products. The configurations of the newly formed stereocenters of spiro-β-lactams were assigned on the basis of 2D NMR experiments and X-ray analysis. Spiro-β-lactams were subjected to acid hydrolysis obtaining the corresponding norbornane-derived β-amino acids.

Full text of DOI:10.1016/j.tet.2012.11.048

Tetrahedron xxx (2012) 1e8
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of constrained norbornane-derived spiro-b-lactams
,
a
b
a
Giuseppe Cremonesi a , Piero Dalla Croce , Alessandra Forni , Concetta La Rosa
*
a
ꢀ
Universita degli Studi di Milano e DISFARM e Sezione di Chimica Generale e Organica ‘A. Marchesini’, V. Venezian 21, I-20133 Milano, Italy
b CNR-ISTM, V. Golgi 19, I-20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
New enantiopure polycyclic norbornane-derived spiro-b-lactams were synthesized by means of a Stau-
Received 3 September 2012
Received in revised form 26 October 2012
Accepted 13 November 2012
Available online xxx
dinger keteneeimine reaction between unsymmetrical bicyclic chiral ketenes, generated from differently
substituted norbornane carboxylic acids, and (E)-N-benzyl-N-(phenylmethylene)amine, with high yields
and moderate to good stereoselectivities. The diastereoisomeric results were rationalized taking into
account the increasing steric encumbrance present on the norbornane skeleton and the stability of the
products. The configurations of the newly formed stereocenters of spiro-
basis of 2D NMR experiments and X-ray analysis. Spiro- -lactams were subjected to acid hydrolysis
obtaining the corresponding norbornane-derived -amino acids.
Ó 2012 Elsevier Ltd. All rights reserved.
b-lactams were assigned on the
This paper is dedicated to the memory of
Dr. Alessandro Fedeli Bernardini
b
b
Keywords:
Spiro-b-lactams
Norbornane-derivatives
Staudinger reaction
b
-Amino acids
1. Introduction
the study of their synthesis and reactivity always receives an in-
creasing interest.14
2-Azetidinones, commonly known as
b
-lactams, are very in-
For many years our research group has been devoted to the
synthesis of new C3 spiro-fused 2-azetidinones by means of the
Staudinger reaction between heterocyclic asymmetric ketenes and
imines. In this way we obtained a library of compounds in which
teresting small heterocycles present as key structure in many bi-
ologically active compounds, in particular in most widely used
classes of antibiotics,1 and also in various products with a wide va-
riety of pharmacological activities.2e8 In addition to its fundamental
importance in medicinal chemistry, the 2-azetidinone scaffold is
a versatile intermediate in synthetic organic chemistry.9 For these
reasons their synthesis has received considerable attention over
recent years and, in particular, asymmetric synthesis by means of
a Staudinger keteneeimine reaction has been extensively studied.10
the
ring, such as 1,3-thiazolidine,15a,b pyrrolidine,15c pyperidine,15c and
1,3-oxazolidine.15c In particular
-lactams having a 3-spiro junction
b-lactam ring has a spiro junction with another heterocyclic
b
with 1,3-thiazolidine ring have proved to be useful intermediates to
obtain a variety of products depending on the type of junction and
experimental conditions used.16a,b We also realized stereoselective
Among all the structures containing
which this heterocycle is spiro-fused with another ring structure
b
-lactam scaffolds, those in
synthesis of spiro-
generated from natural amino acids, such as 4-hydroxy-
ne.17a Similarly, we obtained enantiomerically pure 1,3-
thiazolidine-spiro- -lactams starting from optically active 1,3-
thiazolidine-2-carboxylic acid synthesized from
-cysteine17b and
-valine.17b Then we transformed these lactams in enantiopure
b
-lactams using enantiopure chiral ketenes
L-proli-
are of particular interest. Indeed spiro-b-lactams are very attractive
compounds not only because of their antiviral11a and antibacterial
activity,11b but also because they inhibit cholesterol absorption,11c
b
L
so they are potential useful drugs. They can also act as
metics.12 Finally, spiro-
-lactams can be used as synthetic pre-
cursors for a number of useful synthetic units, such as cyclic
disubstituted
-amino acids and peptidomimetics.13 That is why
b
-turn mi-
L
b
monobactam derivatives by 1,3-thiazolidine moiety ring open-
a,a-
ing.18a Recently, we have also utilized enantiopure pyrroline-spiro-
b
b-lactams, obtained from protected 4-hydroxy-L-prolines, as sub-
strates toward
heterocyclic-spiro-
a
series of olefin reactions obtaining poly-
b
-lactam derivatives.18b
Our interest in the stereoselective synthesis of new enantiopure
spiro- -lactams by means of the Staudinger keteneeimine reaction
between chiral ketenes and imine led us to investigate the
b
* Corresponding author. Tel.: þ39 02 503 14473; fax: þ39 02 503 14476; e-mail
address: giuseppe.cremonesi@gmail.com (G. Cremonesi).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.048
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2
G. Cremonesi et al. / Tetrahedron xxx (2012) 1e8
reactivity of norbornene- or norbornane carboxylic acids as pre-
cursor of bicyclic ketenes intermediates (Fig. 1).
2. Results and discussion
2.1. Synthesis of carboxylic acids 1aed
H
R
O
C=N
All the carboxylic acids were prepared from commercial re-
agents using catalytic stereoselective synthesis or from chiral nat-
ural products. The synthesis of (1R,2R,4R)-bicyclo[2.2.1]hept-5-
ene-2-carboxylic acid 1a, in 98% ee, was accomplished by means
of a DielseAlder reaction between cyclopentadiene and ethyl ac-
rylate, using (S)-o-tolyl-CBS-oxazaborolidine as chiral catalyst,26a
followed by basic hydrolysis26b under phase-transfer conditions
(Scheme 1). Carboxylic acid 1a was catalytically reduced leading to
the corresponding saturated (1S,2R,4R)-bicyclo[2.2.1]heptane-2-
carboxylic acid27 1b (Scheme 1).
R
R
O
N
H
C
COOH
R
Fig. 1. Synthetic pathway for norbornane/ene-C3-spiro-b-lactams.
In the literature only one example of a norbornene-C3-spiro-
lactam has been reported but its synthesis was accomplished by
b-
means of a DielseAlder reaction between 3-methylidene-b-lactams
and cyclopentadiene.19 Similarly, norbornane-C3-spiro-azetidine-
2,4-diones were synthesized with a completely different way, i.e., the
photochemical isomerization of succinimides.20 Some reports regard
H
Ph
other synthesis of norbornene- or norbornane-C4-spiro-
Plumet et al. have reported the preparation of 7-oxanorbornene-C4-
spiro- -lactams by means of the Staudinger keteneeimine reaction
b-lactams:
N
Ph
TfO
O
B
H
o-tol
H
b
COOEt
+
R
R
between imines deriving from the 7-oxa-norbornen-2-one and acyl
chlorides.21 However, in this case, the norbornene-moiety was the
imine partner in the Staudinger reaction and consequently this led to
a spiro junction at the C-4 position of the 2-azetidinone ring. A C-4
spiro-fused 2-azetidinone was also obtained by means of the reaction
between 5-ethylidene-2-norbornene22a or camphene22b and chlor-
osulfonyl isocyanate, or between the 3-phenylimino-camphorqui-
none and diphenylketene.23 In no case, has the reaction of
a norbornane- or norbornene-derived ketene with an imine been
CH2Cl2
- 20°C
COOEt
R
NaOH
H2O
Et3BzN+Cl-
50°C
H
H
H2
Pd / C
R
R
R
S
COOH
R
COOH
R
1a
1b
Scheme 1.
reported in the synthesis of spiro-
cided to investigate this reaction.
b-lactams. For this reason we de-
The more encumbered carboxylic acids, the (1S,4R)-3,3-
dimethyl-bicyclo[2.2.1]heptane-2-carboxylic acid 1c and the
(1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2-carboxylic acid 1d,
were obtained as a mixture of endo/exo stereoisomers starting from
the natural bicyclic diterpenes (þ)-camphene and (þ)-camphor,
respectively, using, in this case, their chiral information as already
extensively done.28 (Scheme 2).
These spiro-
join the rigid structure of norbornane skeleton with the
ring versatility. For example, the hydrolysis of the lactam bond
could afford -amino acids. Moreover, in the case of norbornene
derived -lactams, the presence of the cyclic double bond could
lead to further transformations, such as 1,3-cycloaddition reactions
with 1,3-dipoles,18b potentially giving interesting polycyclic-
-lac-
b
-lactams are very attractive scaffolds because they
b
-lactam
b
b
As described for (ꢀ)-camphene,29 (þ)-camphene was subjected
to oxidative hydroboration giving a 85/15 endo/exo mixture of
camphanol, which following Jones oxidation provided carboxylic
acid 1c.
b
tam derivatives, or ring-opening-metathesis-cross metathesis re-
actions (ROM-CM) in presence of a suitable catalyst.21b
In order to produce different typologies of spiro-b-lactams and
(þ)-Camphor was first transformed into the corresponding
(ꢁ)-2-methylenebornane,30a by means of a Wittig reaction with
Ph3PCH3Br/nBuLi. The latter, similarly to (þ)-camphene, was sub-
jected to an oxidative hydroboration leading to the corresponding
2-(hydroxymethyl)bornane,30b which was directly oxidized with
Jones’ reagent to a 30/70 endo/exo mixture of carboxylic acid 1d30c
(Scheme 2).
to evaluate the steric effect on the diastereoselectivity of the
Staudinger reaction of the substituents present at different position
of the bicyclic framework, we planned the use of four different
ketenes deriving from carboxylic acids 1aed having differently
substituted norbornane skeletons (Fig. 2).
The formation of endo/exo mixtures of carboxylic acids 1c,d does
not constitute a problem since their C-2 configuration is lost when
the ketene is formed or when the intermediate N-acyl-iminium
salt, resulting from the condensation of the activated acid with the
imine, was deprotonated by the base.
COOH
H
H
COOH
COOH
COOH
1d
1a
1b
1c
H
CH2Ph
C=N
Ph
2.2. Generation of ketenes and spiro-b-lactams synthesis
2
Fig. 2. Selected substrates.
We first investigated the best conditions for generating the in-
termediate ketenes and carrying out the reaction with the imine 2.
Various activation methods were tried using the commercially
available racemic 80/20 endo/exo norbornane-2-carboxylic acid
(ꢀ)-1b. With N,N-dimethylchlorosulfitemethaniminium chloride
Though the Staudinger reaction was first described more than
100 years ago,24 its rationalization (and, consequently, its stereo-
chemical course) are still debated.25 In general, the stereochemistry
of the products depends on the nature of the substrates (stereo-
electronic aspects) and the experimental conditions. Also the ge-
ometry and electronic properties of imines play a key role in this
reaction: we decided to use the (E)-N-benzyl-N-(phenylmethylene)
amine 2 (Fig. 2) as a convenient imine partner, already widely used
by us,16b,17b due to its good nucleophilicity.14a
(SOCl2-DMF), a dehydrating reagent that is also used to prepare b-
lactams,31 the reaction of (ꢀ)-1b with 2, run in refluxing dichloro-
methane solution in presence of Et3N, led to unreacted (ꢀ)-1b and
poor yields of a mixture of diastereoisomeric spiro-b-lactams 3e6b
and the endo/exo bicycle[2.2.1]heptane-2-carboxylic acid benzyla-
mide 7b.32 This latter is obtained as a consequence of the hydrolysis
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G. Cremonesi et al. / Tetrahedron xxx (2012) 1e8
3
CrO3
H2SO4
COOH
CH2OH
1) BH3.Me2S
2) H2O2/OH-
S
S
S
R
R
R
0°- 10°C
1c
CrO3
H2SO4
0°- 10°C
Ph3PCH3Br
nBuLi
THF
65°C
1) BH3.Me2S
2) H2O2/OH-
R
R
R
R
R
S
S
S
O
CH2OH
CH2
COOH
1d
Scheme 2.
of the iminium salt resulting from the reaction of the activated acid
and imine (Scheme 3 and Table 1, entry 1). Only benzylamide and
unreacted(ꢀ)-1bwerealso obtainedrunning the reaction in toluene
solution and heating at T¼90 ꢂC (Table 1, entry 2).
ketene so preformed with imine 2 in toluene solution at 90 ꢂC
(Table 1, entry 8).
This protocol was then applied to the reaction of enantiomeri-
cally pure 1aed with imine 2 leading to mixtures of the corre-
O
O
PhCH=NCH2Ph
2
O
C
1) activation
2) Base
COOH
N CH2Ph
Ph
( )
+
NH CH2Ph
endo/exo
( ) 7b
endo/exo
( )1b
3-6b
Scheme 3.
Table 1
Optimization of the reaction of (ꢀ) 1b with 2 under different activation conditions
Entry
1
Reaction conditions
Total yield of
14
b-lactams 3e6b (%)
Yield of amide 7b (%)
Unreacted (ꢀ) 1b (%)
1) SOCl2eDMF T¼0 ꢂC
2) Et3NeCH2Cl2ereflux
1) SOCl2eDMF T¼0 ꢂC
2) Et3NetolueneeT¼90 ꢂC
Mukaiyama’s reagent
Et3NeCH2Cl2ereflux
Mukaiyama’s reagent
DABCOeCH2Cl2ereflux
Mukaiyama’s reagent
DIPEAeCH2Cl2ereflux
37
45
67
62
50
80
64
80
d
2
3
4
5
6
7
8
d
8
13
16
24
10
21
d
15
d
d
d
70
Mukaiyama’s reagent
Et3NetolueneeT¼90 ꢂC
1) (COCl)2eDMF 0.1 mol %. T¼ꢁ5 ꢂC-rt
2) Et3NeCH2Cl2ert
1) (COCl)2eDMF 0.1 mol %. T¼ꢁ5 ꢂC-rt
d
2) Et3NetolueneeT¼90 ꢂC
We also applied our usual protocol to activate the carboxylic
group and generate in situ the intermediate ketene17b by heating
a mixture of carboxylic acid (ꢀ)-1b, imine 2 and 2-chloro-1-
methylpyridinium iodide, Mukaiyama’s reagent, in the presence of
different bases, such as Et3N, DABCO or DIPEA, but also in this case
sponding spiro-b-lactams. With 1a and 1b the reactions afforded all
the four possible diastereoisomers whose ratio was determined
from integration of the H-4 signals in the 1H NMR spectra of the
crude reaction mixtures (4.0e4.5 d) (Scheme 4 and Table 2). In the
case of 1c the reaction afforded only two diastereoisomers in nearly
equal amounts beside to a 23% yield of the endo/exo-N-benzyl-3,3-
dimethylbicyclo[2.2.1]heptane-2-carboxamide 7c, while in the case
of 1d a greater diastereoselectivity was observed only one di-
astereoisomer being obtained in 73% yield, together with a 12%
total yield of the other three diastereoisomers in 2.6:1:1 ratio.
the reactions afforded poor yields of b-lactams and benzylamide
(Table 1, entries 3e5). As already observed (Table 1, entry 2), re-
placement of dichloromethane with toluene as solvent and heating
at T¼90 ꢂC resulted only in amide formation (Table 1, entry 6).14a
So we switched to using the more reactive acyl chloride as ke-
tene precursor: the acyl chloride was obtained by reacting the acid
(ꢀ)-1b with oxalyl chloride in presence of a catalytic amount of
DMF.33 Subsequent treatment with Et3N and imine 2 in dichloro-
2.3. Assignment of the absolute configurations to spiro-b-
lactams
methane solution at room temperature did not afford
b-lactams
(Table 1, entry 7). On the contrary, the mixture of diastereoisomeric
The mixtures of spiro-b-lactams were partially separated by
b
-lactams 3e6b was obtained in good yield adding a toluene so-
means of column chromatography: only the more abundant
products 3aec, 4bec, and 5d were obtained pure enough to be
lution of TEA to the acyl chloride at T¼0 ꢂC, and then reacting the
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4
G. Cremonesi et al. / Tetrahedron xxx (2012) 1e8
Scheme 4.
2.4. Diastereoselectivity of Staudinger reaction on norbor-
nane ketenes
Table 2
Total yields and ratios of spiro-
b
-lactams 3e6(aec)
Carboxylic acid XeX
R
Total yield (%) Diastereoisomers ratio (%)
The mechanism of the Staudinger reaction has been the subject
of extensive studies.25 Although an asynchronous concerted re-
action pathway cannot be excluded, according to both experi-
mental and theoretical25c,d studies, using a nucleophilic imine, such
as (E)-2, the [2þ2] keteneeimine cycloaddition reaction occurs
with a stepwise mechanism. The attack of the imine on the least
hindered side of the ketene gives a zwitterionic intermediate,
which undergoes a subsequent conrotatory ring closure to generate
3
4
5
6
1a
1b
1c
CH]CH
CH2eCH2
CH2eCH2 CH3 68
H
H
98
94
46
53
47
27
29
53
20
9
7
9
d
d
fully characterized by means of analytical and spectroscopic data
(see Experimental section). The absolute configurations of the
newly formed C-3 and C-4 stereocenters were assigned by means
of suitable NOESY, COSY, HSQC, and HMBC experiments or by X-
ray analysis. In particular, in the NOESY spectra of the major di-
the spiro-b-lactam. In the reactions of unsymmetrical ketenes with
imines the stereoselectivity could be controlled by the torquoe-
lectronic effects that become more pronounced when the carbon-
ecarbon double bond of the ketene is substituted with
a heteroatom.14a,25b,25f,25m In addition, also the steric effects play an
important role in the stereoselectivity of the Staudinger reaction.25i
In the case of our norbornene/ane-derived substrates 1aed, the
stereochemical outcome of the reactions showed a moderate dia-
stereoselectivity as, except for 1c, all the four possible di-
astereoisomers were obtained. However, in the case of 1d the
reaction was more diastereoselective than in the other cases.
In Fig. 3 are reported the approaches of the imine to the ketene
leading to zwitterionic intermediates AeD whose ring closure af-
astereoisomer 3a, H-4 (
d
¼4.17) shows positive effect only with one
of the two H-30 (
d
¼1.45), while in the NOESY spectra of the minor
diastereoisomer 4a, H-4 (
d
¼4.48) shows positive effects with both
H-30 (
d
¼1.81 and 2.07) and also with H-10 (
d
¼2.61) and one H-70
(
d
¼0.94). With the aid of Dreiding’s molecular models, these ob-
servations allowed us to assign (3S,4R) and (3R,4S) configurations
to 3a and 4a, respectively. It is noteworthy that H-60 proton in 3a is
shielded by the C-4 phenyl and thereby its chemical shift drops
more than 1 ppm (
d
¼4.74) with respect to the corresponding
fords spiro-b-lactams 3e6. Taking into account the obtained re-
value of H-60 in 4a (
d
¼6.02). In the NOESY spectra of di-
sults, it is quite clear that the steric hindrance present on the
norbornane skeleton on the different approaches has little in-
fluence. In fact, from this point of view, the zwitterionic in-
termediates C and D should be favorite, especially with 1c (R¼Me).
Instead the two more abundant products 3aec and 4aec derive
from the zwitterionic intermediates A and B showing that the el-
ement governing the reaction is the stability of the products. In fact
the Dreiding models show that compounds 3aec and 4aec suffer of
minor steric hindrance respect to 5aec and 6aec and therefore
they should be more stable. With 1d, the prevalent compound 5d
derives from a zwitterionic intermediate analogous to C: in this
case the major diastereoselectivity observed could be ascribed to
the fact that the more stable compound derives also from the more
favorable approach. On the other hand, the experimental condi-
tions adopted, high temperatures and prolonged reaction times,
provide for a thermodynamic control of the reaction thus leading to
the more stable compounds even if they do not derive from the
more favorable approaches.
astereoisomer 5a, H-4 (
d
¼4.26) shows positive effects with H-70
(
d
¼1.18e1.22) and with H-10
(
d
¼3.08) but not with H-30: as
a consequence the (3R,4R) configurations were assigned to 5a and
(3S,4S) to the remaining compound 6a. The NOESY spectra of
compound 3b showed no useful positive effects in the de-
termination of the absolute configurations. On the contrary in the
NOESY spectra of compound 4b positive effects were observed
between H-4 (
d
¼4.03) and H-30 (
d
¼1.91) and H-70 (
¼0.82e0.90)
d
similarly to 4a. The configurations of 3e5b were confirmed by
means of catalytic hydrogenation (Pd/C, AcOEt, rt) of compound 3a
that afforded 3b and of the mixture 4a/5a¼2:1 that allowed
obtaining a mixture with the same ratio of 4b and 5b, respectively,
so determining the assignment of the same (3R,4R) configurations
to 5b and, consequently, (3S,4S) to 6b. The absolute configurations
(3R,4R) were assigned to compound 3c by means of the X-ray
analysis (see Supplementary data), while in the NOESY spectra of
4c positive effects were observed between H-4 (
d
¼4.51) and H-70
(
d
¼1.14e1.19) and one of the methyl groups ( ¼1.13) allowing to
d
assign the (3S,4S) configurations. Finally the same (3S,4S) config-
urations were assigned to 5d: in the NOESY spectra H-4 (
d
¼4.28)
2.5. Hydrolysis of spiro-b-lactams
shows positive effects with two methyl groups: one on C-70 and
the other on C-10. On the contrary, it was not possible to assign the
absolute configurations to compounds 3,4,6d because they were
inseparable.
Spiro-
conditions of hydrolysis, either basic or acidic, to obtain the cor-
responding norbornane-derived -amino acids (Scheme 5). In
b-lactams were subjected to numerous experimental
b
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G. Cremonesi et al. / Tetrahedron xxx (2012) 1e8
5
O
O
PhCH2
O
CH2Ph
Ph
H
conrotatory
ring closure
N
90° flip
90° flip
X
X
X
X
X
N
Ph
N
CH2Ph
CH2Ph
R
R
X
R
R
R
3
Ph
R
H
H
zwitterionic intermediate A
Ph
N
H
O
Ph
H
CH2Ph
conrotatory
ring closure
O
X
X
X
Ph
N
X
R
X
R
O
N
X
R
R
4
R
R
H
PhCH2
zwitterionic intermediate B
H
Ph
R
H
R
H
Ph
CH2Ph
conrotatory
ring closure
CH2Ph
CH2Ph
N
O
N
N
Ph
CH2Ph
90° flip
90° flip
X
X
X
X
X
X
O
R
O
R
R
R
5
zwitterionic intermediate C
CH2Ph
O
N
CH2Ph
H
conrotatory
ring closure
N
N
X
X
X
H
R
Ph
H
Ph
X
R
X
Ph
O
O
R
R
X
R
R
6
zwitterionic intermediate D
Fig. 3. Conrotatory ring closure of zwitterionic intermediates AeD.
Ph
H
O
CH2Ph
CH2Ph
N
COOH
N
NH
CH2Ph
X
X
Ph
X
X
O
H
Ph
H
8a-b
H
CH3
H3C
(+)
4c
( )
3a-b
( )
Ph
Ph
H
H
Ph
CH2Ph
N
CH Ph
NH
COOH
2
N
O
O
CH2Ph
(+)
( )4b
5d
( ) 9b
Scheme 5.
particular, racemic 3a was treated with different bases, such as
NaOH, LiOH, Cs2CO3 or CH3ONa or acids, such as HCl or HBr. The
lactam ring of (ꢀ)-3a was completely stable under basic hydrolysis
conditions (Table 3, entries 1e5) or acid catalyzed at room tem-
perature (Table 3, entry 6). By heating with HCl to 50 ꢂC, or higher
temperatures, or treating with HBr at room temperature, the nor-
bornene scaffold of (ꢀ)-3a underwent complete degradation (Table
3, entries 7e9) leading to a mixture of unidentified products pre-
sumably deriving from the reactive CeC double bond (as shown by
the disappearance of the olefinic system in 1H NMR). The norbor-
of hydrolytic conditions including an enzymatic one,34 but they
were stable in each case (Table 3, entries 16e21).
3. Conclusions
We have synthesized new, enantiomerically pure, highly con-
strained norbornane-derived spiro-b-lactams by reacting optically
active, non-symmetrical, bicyclic ketenes in a Staudinger ketene-
eimine reaction. This is the first example of the generation of
norbornane-C3-spiro-b-lactams through the reaction between
nane spiro-
b
-lactam (ꢀ)-3b showed to be more stable under acid
norbornane-derived ketenes and imines. The stereochemical out-
come of the reaction is influenced by the presence of encumbering
groups in the cyclic ketenes. In fact a better selectivity was obtained
when some methyl groups are present near to the carbon bearing
hydrolysis conditions and among the different acids tested, (Table
3, entries 10e14), the better results were obtained with HBr in
acetic acid at room temperature: in these conditions the amino acid
(ꢀ)-8b was obtained in 73% yield. The same protocol applied to
the carboxylic functionality. These spiro-
b-lactams showed to be
spiro-
b
-lactam (ꢀ)-4b afforded the diastereoisomeric amino acid
very resistant to -lactam ring hydrolysis; only with HBr in AcOH
b
(ꢀ)-9b in 71% yield (Table 3, entry 15). Finally, the enantiomerically
the amidic bond was broken affording the corresponding
norbornane-derived amino acids. The particular skeletons of these
pure spiro-
b
-lactams (þ)-4c and (þ)-5d were subjected to a variety
Please cite this article in press as: Cremonesi, G.; et al., Tetrahedron (2012), http://dx.doi.org/10.1016/j.tet.2012.11.048

6
G. Cremonesi et al. / Tetrahedron xxx (2012) 1e8
Table 3
Hydrolysis of spiro-
b
-lactams
Spiro-
Entry
b
-lactam
Base/acid
Experimental conditions
Products (%)
3/4
8/9
1
2
3
4
5
6
7
8
(ꢀ)-3a
(ꢀ)-3a
(ꢀ)-3a
(ꢀ)-3a
(ꢀ)-3a
(ꢀ)-3a
(ꢀ)-3a
(ꢀ)-3a
(ꢀ)-3a
(ꢀ)-3b
(ꢀ)-3b
(ꢀ)-3b
(ꢀ)-3b
(ꢀ)-3b
(ꢀ)-4b
(þ)-4c
(þ)-4c
(þ)-4c
(þ)-5d
(þ)-5d
(þ)-5d
NaOH 5%
NaOH 32%
LiOH
Cs2CO3
CH3ONa
HClaq 10 N
HClaq 10 N
HClaq 10 N
HBr 32%
Dowex 50X8
HClaq 10 N
HIaq 57%
H2SO4 aq 50%
HBr 32%
HBr 32%
THF/65 ꢂC/6 h
100
100
100
100
100
100
15
0
0
0
0
0
0
0
0
0
0
trace
0
0
73
71
0
0
0
Dioxane/100 ꢂC/10 h
H2O/THF/65 ꢂC/6 h
H2O/Dioxane/50 ꢂC/24 h
CH3OH/50 ꢂC/24 h
Dioxane/rt/72 h
Dioxane/50 ꢂC/4 h
Dioxane/100 ꢂC/10 h
AcOH/rt/16 h
0
0
9
10
11
12
13
14
15
16
17
18
19
20
21
THF/60 ꢂC/7 h
Dioxane/100 ꢂC/24 h
AcOH/rt/24 h
AcOH/rt/72 h
AcOH/rt/16 h
100
0
100
100
0
AcOH/rt/16 h
0
HClaq 10%
HBr 32%
Lipase from Candida antarctica
HBr 32%
HClaq 10%
HClaq 10%
Dioxane/100 ꢂC/24 h
AcOH/rt/48 h
100
100
100
100
100
100
Toluene/60 ꢂC/48 h
AcOH/rt/48 h
0
0
0
AcOH/100 ꢂC/48 h
Dioxane/150 ꢂC/mw/3 h
spiro-
b
-lactams and of the corresponding amino acids are of in-
4.2.1. (1’R,3S,4R,4’R)-1-Benzyl-4-phenyl-2H-spiro[azetidine-3,20-bi-
cyclo[2.2.1]hept[5]en]-2-one (3a). Colorless solid (45%); mp
terest for the synthesis of peptides conformational restricted. In
fact their incorporation in the amino acid chains may alter the
secondary structure of the peptide as their rigid structure results in
a constrained conformation, with consequent variation of the
peptide properties itself.
103e104 ꢂC (hexane).
½
a 2D0
ꢃ
þ47.7 (c 3.0, EtOH). 1H NMR:
d
1.22e1.33 (m, 1H, H-70); 1.45 (dd, J 11.9, 2.6, 1H, H-30); 1.82 (d, J
8.5, 1H, H-70); 2.29 (dd, J 11.9, 3.6, 1H, H-30); 2.81e2.85 (m, 1H, H-
40); 2.89e2.93 (m, 1H, H-10); 3.86 (d, J 15.0, 1H, CH2Ph); 4.17 (s, 1H,
H-4); 4.74 (dd, J 5.6, 2.7, 1H, H-60); 4.87 (d, J 15.0, 1H, CH2Ph); 6.03
(dd, J 5.6, 3.0, 1H, H-50); 7.15e7.40 (m, 10H, Ph). 13C NMR:
d 36.9/
4. Experimental section
44.0 (C-30/C-70); 42.1/46.3 (C-10/C-40); 47.3 (CH2Ph); 65.3 (C-4);
66.7 (C-3); 127.3e128.6 (Ph); 133.3/138.6 (C-60/C-50); 135.8/136.5
(Ph); 174.4 (C-2). IR (Nujol): 1746 (vCO, NeCO). Anal. Calcd for
4.1. General
C
22H21NO: C, 83.78; H, 6.71; N, 4.44. Found: C, 83.67; H 6.45; N,
1H and 13C NMR spectra were recorded using a 300 MHz spec-
trometer. Chemical shifts (d) are given in parts per million in re-
4.31. MS-EI (m/z): 315 [M]þ.
lation to TMS; the solvent was CDCl3 unless otherwise specified. All
of the coupling constants (J) are in Hertz. IR spectra (in cmꢁ1) were
determined using a FT-IR spectrometer. The optical rotation values
were measured at 25 ꢂC. Carboxylic acids 1aed were prepared as
previously reported. (þ)-Camphene, (þ)-camphor, and imine 2
were obtained from commercial sources.
4.2.2. (1’R,3R,4S,4’R)-1-Benzyl-4-phenyl-2H-spiro[azetidine-3,20-bi-
cyclo[2.2.1]hept[5]en]-2-one (4a). (26.5%). 1H NMR (in mixture with
5a):
d
0.94 (broad d, J 8.6, 1H, H-70); 1.13 (broad d, J 8.6, 1H, H-70);
1.81 (dd, J 12.0, 2.7, 1H, H-30); 2.07 (dd, J 12.0, 3.6, 1H, H-30); 2.61
(broad s, 1H, H-10); 2.90 (broad s, 1H, H-40); 3.94 (d, J 15.0, 1H,
CH2Ph); 4.48 (s, 1H, H-4); 4.95 (d, J 15.0, 1H, CH2Ph); 6.02 (dd, J 5.6,
2.8, 1H, H-60); 6.21 (dd, J 5.6, 3.1, 1H, H-50); 7.15e7.40 (m, 10H, Ph).
13C NMR:
d
37.5/44.6 (C-30/C-70); 42.1/46.0 (C-10/C-40); 47.7
4.2. General procedure for the synthesis of spiro-b-lactams
3e6
(CH2Ph); 65.7 (C-3); 66.9 (C-4); 127.6e129.2 (Ph); 133.1/139.3 (C-60/
C-50); 135.7/136.1 (Ph); 173.6 (C-2). HRMS (FT-ICR)-(ESIþ) calcd for
C22H21NNaOþ338.1515; found 338.1511.
To a solution of the carboxylic acid 1aed (7 mmol) in dry CH2Cl2
(20 mL), cooled at T¼ꢁ5 ꢂC, was added a solution of oxalyl chloride
(35 mmol) and N,N-dimethylformamide (0.7 mmol) in dry CH2Cl2
(20 mL) dropwise over 1 h, under a nitrogen atmosphere. The
mixture was stirred at room temperature for 3 h. The solvent and
the oxalyl chloride excess was removed by evaporation at reduced
pressure and the residue was dissolved in dry toluene (10 mL),
cooled at T¼0 ꢂC and added with a solution of TEA (7 mmol) in dry
toluene (10 mL). After 30 min the mixture was added, over
30e40 min, to a solution of imine 2 (3.5 mmol) in dry toluene
(10 mL) heated at T¼90 ꢂC. The reaction was heated at reflux
temperature for 20 h. After cooling, the solution was washed with
5% aq HCl, and then with H2O. The organic layer was dried (Na2SO4)
and the solvent was removed under reduced pressure. The crude
products were purified by flash chromatography (SiO2, n-hexane/
AcOEt¼97:3 for 3e6a, n-hexane/AcOEt¼95:5 for 3e6b, CH2Cl2/
AcOEt¼99:1 for 3e4c and for 4d).
4.2.3. (1’R,3R,4R,4’R)-1-Benzyl-4-phenyl-2H-spiro[azetidine-3,20-bi-
cyclo[2.2.1]hept[5]en]-2-one (5a). (19.5%); 1H NMR (in mixture with
4a):
d
1.18e1.22 (m, 1H, H-70); 1.23e1.25 (m, 1H, H-30); 1.31e1.33
(m, 1H, H-30); 1.47e1.49 (m, 1H, H-70); 2.77 (broad s, 1H, H-40); 3.08
(broad s, 1H, H-10); 3.85 (d, J 14.9, 1H, CH2Ph); 4.26 (s, 1H, H-4); 4.97
(d, J 14.9, 1H, CH2Ph); 6.15e6.19 (m, 1H, H-60); 6.31e6.36 (m, 1H, H-
50); 7.15e7.40 (m, 10H, Ph). 13C NMR:
d
32.6/44.3 (C-30/C-70); 43.4/
52.3 (C-10/C-40); 48.7 (CH2Ph); 66.8 (C-4); 67.1 (C-3); 127.6e129.2
(Ph); 133.5/139.6 (C-60/C-50); 136.1/137.4 (Ph); 173.3 (C-2). HRMS
(FT-ICR)-(ESIþ) calcd for C22H21NNaOþ338.1515; found 338.1511.
4.2.4. (1’S,3S,4R,4’R)-1-Benzyl-4-phenyl-2H-spiro[azetidine-3,20-bi-
cyclo[2.2.1]heptan]-2-one (3b). Colorless solid (50%); mp 94e96 ꢂ
C
(pentane). ½a 2D0
ꢃ
ꢁ33.5 (c 0.52, CH2Cl2). 1H NMR:
d 0.58e0.64 (m, 1H,
H-60); 0.79e0.91 (m, 1H, H-50); 1.00e1.11 (m, 1H, H-60); 1.19 (d, J 9.8,
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G. Cremonesi et al. / Tetrahedron xxx (2012) 1e8
7
1H, H-70); 1.21e1.42 (m, 1H, H-50); 1.47 (dd, J 12.7, 2.8, 1H, H-30);
1.96 (d, J 9.8, 1H, H-70); 2.20 (dt, J 12.7, 3.1, 1H, H-30); 2.23e2.32 (m,
1H, H-40); 2.43 (d, J 4.6, 1H, H-10); 3.74 (d, J 15.0, 1H, CH2Ph); 4.31 (s,
1H, H-4); 4.80 (d, J 15.0, 1H, CH2Ph); 7.07e7.36 (m, 10H, Ph). 13C
(vCO, NeCO). Anal. Calcd for C25H29NO: C, 83.52; H, 8.13; N, 3.90.
Found: C, 83.29; H 8.26; N, 3.87. MS-FABþ (m/z): 360[MH]þ.
4.2.9. endo/exo-(1S,4R)-N-Benzyl-3,3-dimethylbicyclo[2.2.1]
hep-
NMR:
d
22.6/29.1/37.7 (C-30/C-50/C-60/C-70); 36.4/39.3 (C-10/C-40);
tane-2-carboxamide (7c). Amorphous solid (23%). 1H NMR:
d
0.95
43.2 (CH2Ph); 64.9 (C-4); 66.5 (C-3); 127.1e128.5 (Ph); 135.8/136.7
(Ph); 174.1 (C-2). IR (Nujol): 1746 (vCO, NeCO). Anal. Calcd for
(s, 3H, Me); 1.10 (s, 3H, Me); 0.87e1.45 (m, 6H); 1.60e1.70 (m, 1H);
2.15 (d, J 9.9,1H); 2.34 (broad s,1H); 4.32e4.44 (m, 2H, CH2Ph); 5.78
C
22H23NO: C, 83.24; H, 7.30; N, 4.41. Found: C, 83.05; H 7.18; N, 4.28.
(broad s, 1H); 7.24e7.33 (m, 5H, Ph). 13C NMR:
d 23.9/29.0/37.6 (C-5/
MS-EI (m/z): 317[M]þ.
C-6/C-7); 25.4/28.0 (2Me); 41.3/47.8 (C-1/C-4); 42.2 (C-3); 43.3
(CH2Ph); 60.8 (C-2); 127.3e128.5 (Ph); 138.6 (Ph); 173.5 (C]O). IR
(Nujol): 1651 (vCO, NeCO). Anal. Calcd for C17H23NO: C, 79.33; H,
9.01; N, 5.44. Found: C, 79.25; H 8.87; N, 5.28.
4.2.5. (1’S,3R,4S,4’R)-1-Benzyl-4-phenyl-2H-spiro[azetidine-3,20-bi-
cyclo[2.2.1]heptan]-2-one (4b). Colorless solid (27%); mp
112e113 ꢂC (hexane). ½a 2D0
ꢃ
þ65.8 (c 1.43, CH2Cl2). 1H NMR:
d
0.82e0.90 (m, 2H, H-70); 1.23e1.34 (m, 1H, H-60); 1.36e1.52 (m,
4.3. General procedure for the hydrolysis of spiro-
b-lactams
2H, H-50); 1.91 (broad s, 2H, H-30); 2.05 (d, J 4.3,1H, H-10); 2.06e2.18
(m, 1H, H-60); 2.29 (broad s, 1H, H-40); 3.89 (d, J 15.0, 1H, CH2Ph);
4.03 (s, 1H, H-4); 4.93 (d, J 15.0, 1H, CH2Ph); 7.15e7.42 (m, 10H, Ph).
A solution of spiro- -lactam 3b or 4b (2.5 mmol) in HBr 32% in
b
AcOH (5 mL) was stirred at room temperature for 16 h. The mixture
was added with water (5 mL) and extracted with CH2Cl2. The or-
ganic layer was washed with NH3 7% until basic pH, dried (Na2SO4)
and the solvent was removed under reduced pressure. The crude
product was purified by flash chromatography (SiO2, AcOEt).
13C NMR:
d
23.6/29.1/38.1/39.4 (C-30/C-50/C-60/C-70); 36.5/40.1 (C-
10/C-40); 44.1 (CH2Ph); 66.5 (C-3); 69.9 (C-4); 127.5e128.8 (Ph);
135.7/135.9 (Ph); 173.7 (C-2). IR (Nujol): 1746 (vCO, NeCO). Anal.
Calcd for C22H23NO: C, 83.24; H, 7.30; N, 4.41. Found: C, 83.12; H
7.21; N, 4.29. MS-EI (m/z): 317[M]þ.
4.3.1. (1S*,2S*,4R*)-2-[(R*)-(Benzylamino)(phenyl)methyl]
[2.2.1]heptane-2-carboxylic acid (8b). Colorless solid (73%); mp
103e105 ꢂC. 1H NMR (CD3OD):
1.22e2.23 (m, 10H); 3.79 (AB syst.,
2H, NeCH2); 4.32 (s, 1H, NeCH); 7.33e7.53 (m, 10H, Ph). 13C NMR
(CD3OD): 24.4/29.8/40.4/44.0 (C-3/C-5/C-6/C-7); 37.5/44.2 (C-1/
C-4); 50.2 (CH2Ph); 56.5 (C-2); 67.6 (NeCH); 129.7e130.7 (Ph);
134.0/135.3 (Ph); 183.3 (C]O). IR (Nujol): 1636 (vCO, NeCO). Anal.
Calcd for C22H25NO2: C, 78.77; H, 7.51; N, 4.18. Found: C, 78.65; H
7.37; N, 4.06. MS-FABþ (m/z): 336[MH]þ.
bicyclo
4.2.6. (1’S,3R,4R,4’R)-1-Benzyl-30,30-dimethyl-4-phenyl-2H-spiro
[azetidine-3,20-bicyclo[2.2.1]heptan]-2-one (3c). Colorless solid
d
(32%); mp 107e109 ꢂC (hexane). ½a D20
ꢃ
ꢁ3.8 (c 1, CH2Cl2). 1H NMR:
d
0.46e0.51 (m, 1H); 0.71e0.88 (m, 1H); 1.05 (s, 3H, Me); 1.04e1.18
d
(m, 2H); 1.17 (s, 3H, Me); 1.39e1.45 (m, 1H); 1.78 (broad s, 1H, H-
10/H-40); 2.25 (d, J 10.0, 1H); 2.45 (d, J 4.9, 1H, H-40/H-10); 3.66 (d, J
15.1, 1H, CH2Ph); 4.41 (s, 1H, H-4); 4.86 (d, J 15.1, 1H, CH2Ph);
7.08e7.36 (m, 10H, Ph). 13C NMR:
d
21.4/24.7/35.7 (C-50/C-60/C-70);
26.7/27.8 (2Me); 39.9 (C-30); 43.2 (CH2Ph); 42.8/49.0 (C-10/C-40);
60.4 (C-4); 74.2 (C-3); 127.5e128.9 (Ph); 136.2/136.9 (Ph); 172.5
(C-2). IR (Nujol): 1747 (vCO, NeCO). Anal. Calcd for C24H27NO: C,
83.44; H, 7.88; N, 4.05. Found: C, 83.37; H 7.76; N, 3.97. MS-FABþ
(m/z): 346[MH]þ. Single crystals suitable for X-ray structure de-
termination were obtained by precipitation from hexane. Crys-
tallographic data (excluding structure factors) for 3c have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 891441. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK, (fax: þ44-(0)1223-336033 or e-
mail: deposit@ccdc.cam.ac.uk).
4.3.2. (1S*,2R*,4R*)-2-[(S*)-(Benzylamino)(phenyl)methyl] bicyclo
[2.2.1]heptane-2-carboxylic acid (9b). Amorphous solid (71%). 1H
NMR (CD3OD):
3.96 (s, 1H, NeCH); 7.26e7.43 (m, 10H, Ph). 13C NMR (CD3OD):
28.6/28.8/38.9/39.3 (C-3/C-5/C-6/C-7); 38.7/42.5 (C-1/C-4); 51.6
d 1.00e2.44 (m, 10H); 3.81 (AB syst., 2H, NeCH2);
d
(CH2Ph); 58.9 (C-2); 68.7 (NeCH); 128.9e131.2 (Ph); 135.2/136.5
(Ph); 180.3 (C]O). IR (Nujol): 1641 (vCO, NeCO). Anal. Calcd for
C
22H25NO2: C, 78.77; H, 7.51; N, 4.18. Found: C, 78.54; H 7.31; N,
4.03. MS-FABþ (m/z): 336[MH]þ.
Acknowledgements
4.2.7. (1’S,3S,4S,4’R)-1-Benzyl-30,30-dimethyl-4-phenyl-2H-spiro
[azetidine-3,20-bicyclo[2.2.1]heptan]-2-one (4c). Colorless solid
The authors thank MIURePRIN 2008 for financial support.
(36%); mp 131e133 ꢂC (hexane). ½a D20
ꢃ
þ1.78 (c 0.2, CH2Cl2). 1H NMR:
Supplementary data
d
0.77 (d, J 10.1, 1H); 1.13 (s, 3H, Me); 1.14e1.19 (m, 1H, H-70); 1.24 (s,
3H, Me); 1.21e1.27 (m, 2H); 1.70 (broad s, 1H); 1.75e1.84 (m, 1H);
2.02 (broad s, 1H); 2.15e2.25 (m, 1H); 3.74 (d, J 15.0, 1H, CH2Ph);
4.51 (s, 1H, H-4); 4.97 (d, J 15.0, 1H, CH2Ph); 7.12e7.40 (m, 10H, Ph).
Copies of 1H and 13C NMR of all compounds, NOESYexperiments
and X-ray figure. Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2012.11.048.
13C NMR:
d
22.3/24.5/35.9 (C-50/C-60/C-70); 24.1/29.6 (2Me); 42.1
(C-30); 43.7 (CH2Ph); 42.4/49.2 (C-10/C-40); 61.1 (C-4); 73.4 (C-3);
127.5e128.5 (Ph); 135.9/136.0 (Ph); 172.3 (C-2). IR (Nujol): 1745
(vCO, NeCO). Anal. Calcd for C24H27NO: C, 83.44; H, 7.88; N, 4.05.
Found: C, 83.39; H 7.80; N, 3.95. MS-FABþ (m/z): 346[MH]þ.
References and notes
1. For reviews on antibiotic activity of
Chemistry and Biology of -Lactam Antibiotics; Academic: New York, NY, 1982;
Vols. 2e3; (b) Page, M. I. The Chemistry of -Lactams; Chapman and Hall: Lon-
b-lactams, see: (a) Morin, R. B.; Gorman, M.
b
b
don, 1992; (c) Coulton, S.; Hunt, E. In Recent Progress in the Chemical Synthesis of
Antibiotics and Related Microbial Products; Lukacs, G., Ed.; Springer: Berlin, 1993;
Vol. 2, p 621; (d) Singh, G. S. Mini-Rev. Med. Chem. 2004, 4, 93.
2. (a) Mehta, P. D.; Sengar, N. P. S.; Pathak, A. K. Eur. J. Med. Chem. 2010, 45, 5541;
(b) Galletti, P.; Giacomini, D. Curr. Med. Chem. 2011, 18, 4265.
3. For biological activity as thrombin inhibitors see: Han, W. T.; Trehan, A. K.;
Wright, J. J. K.; Federici, M. E.; Seiler, S. M.; Meanwell, N. A. Bioorg. Med. Chem.
1995, 3, 1123.
4. For biological activity as cholesterol absorption inhibitors see: (a) Burnett, D. A.;
Caplen, M. A.; Davis, H. R., Jr.; Burrier, R. E.; Clader, J. W. J. Med. Chem. 1994, 37,
1733; (b) Vaccaro, W. D.; Sher, R.; Davis, H. R., Jr. Bioorg. Med. Chem. Lett. 1998, 8,
35; (c) Vaccaro, W. D.; Davis, H. R., Jr. Bioorg. Med. Chem. Lett. 1998, 8, 313.
4.2.8. (1’R,3S,4S,4’R)-1-Benzyl-10,70,70-trimethyl-4-phenyl-2H-spiro
[azetidine-3,20-bicyclo[2.2.1]heptan]-2-one (5d). Colorless solid
(58%); mp 161e162 ꢂC (hexane). ½a D20
ꢃ
þ23.5 (c 1.1, CH2Cl2). 1H NMR:
d
0.47 (s, 3H, Me); 0.80 (s, 3H, Me); 0.94 (s, 3H, Me); 1.19e1.69 (m,
6H); 2.48e2.62 (m, 1H); 3.57 (d, J 14.78, 1H, CH2Ph); 4.28 (s, 1H, H-
4); 4.84 (d, J 14.8, 1H, CH2Ph); 7.07e7.37 (m, 10H, Ph). 13C NMR:
d
11.8/18.9/20.0 (3Me); 27.7/33.8 (C-50/C-60); 31.3 (C-30); 43.6
(CH2Ph); 45.9 (C-40); 48.6 (C-70); 51.7 (C-10); 63.9 (C-4); 70.1 (C-3);
127.5e128.6 (Ph); 135.5/136.0 (Ph); 173.3 (C-2). IR (Nujol): 1733
Please cite this article in press as: Cremonesi, G.; et al., Tetrahedron (2012), http://dx.doi.org/10.1016/j.tet.2012.11.048

8
G. Cremonesi et al. / Tetrahedron xxx (2012) 1e8
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