[Insert Journal Citation information]
Highly Reactive Four-Membered Ring Nitrogen
Heterocycles. Synthesis and Properties
Benito Alcaide,1* Pedro Almendros2* & Cristina Aragoncillo1*
Addresses
1
Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Química Orgánica I, Unidad Asociada al CSIC,
Facultad de Química, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Email: alcaideb@quim.ucm.es, caragoncillo@quim.ucm.es
Fax: +34-91-39444103
2
Instituto de Química Orgánica General, Consejo Superior de Investigaciones Científicas, CSIC, Juan de la
Cierva 3, 28006 Madrid, Spain.
Email:palmendros@iqog.csic.es
Fax: +34-91-5644853
Four-membered nitrogen hetereocycles such as  -lactams (i.e. 2-azetidinones) and azetidines are useful
substrates in organic chemistry for the design and preparation of biologically active compounds by the
adequate functionalization in the different positions of the ring. In addition, they are also versatile
building blocks for the synthesis of other types of nitrogen-containing compounds with potential biological
properties.
Keywords: Azetidines, heterocycles,-lactams, rearrangements, stereoselectivity, strain
Introduction
has been employed as a synthetic tool for the
For many years, -lactams (i.e. 2-azetidinones) and
preparation of higher nitrogen heterocycles with
azetidines have catched the attention of organic
potential
chemists and medicinal researchers. The importance
summarizes recent reports on different aspects
of the stereoselective synthesis of -lactams is ever
related to the preparation and properties of these
increasing in light of structure-activity relationship
four-membered nitrogen heterocyclic rings and their
studies and the development of new derivatives of -
biological
activities.
In
particular,
lactam antibiotics, inhibitors of -lactamases and -
examples
collected
in
this
lactam derivatives with anticancer properties [1, 2].
published
in
past
In addition, it has been recognized the usefulness of
outstanding previous reports have been included as
-lactams
the
well. This review is divided in two sections, namely
preparation of all kind of nitrogen-containing target
-lactam and azetidine rings. First, for each section,
compounds [3]. On the other hand, the azetidine
we
ring is present in natural products of interest.
synthetic methodologies for constructing the four-
Besides, the strained nature of the azetidine skeleton
membered nitrogenated rings. Next, the syntheses
as
potential
building
blocks
for
biological
discuss
the
the
activity
[4].
This
most
review
two
review
have
years.
most representative
of
the
been
However
and
novel
1
fused,
involves the preparation of -amino acids or esters
azetidine
followed by cyclization (Scheme 1C). For example,
derivatives have been reviewed. Finally, we have
the research group of Melchiorre has described the
selected
enantioselective
and
properties
spirocyclic,
and
of
novel
bridged
a variety
of
monocyclic,
-lactam
and
examples concerning
the
synthesis
of
amino
esters
via
usefulness of -lactams and azetidines in synthesis,
Mannich reaction and subsequent cyclization under
for the preparation of different types of interesting
acidic conditions [11]. The corresponding -lactams
nitrogen-containing compounds.
have
been
obtained
in
excellent
yields
and
enantioselectivities. On the other hand, the Kinugasa
-Lactams
reaction [copper (I) catalyzed cycloaddition of a
Synthesis of the -lactam
terminal alkyne and a nitrone] represents an elegant
skeleton
approach toward -lactams because of its wide scope
There is a high number of synthesis of monocyclic -
[12].
lactams [5]. However, classical methods such as the
The
reaction
methyleneaziridine
Staudinger reaction (Scheme 1A) [6, 7], (which
involves
1
ring
promoted
by
opening
a
of
Grignard
reagent and a catalytic amount of CuI, followed by
usually affords predominantly the cis-diastereomer,
capture of the resultant metalloenamine with an
although altering the nature of the substrates and
electrophile (R3X). Subsequent addition of glacial
reaction conditions can often promote the formation
acetic acid followed by in situ generated ketene
of trans-isomer) [8, 9], and the Gilman-Speeter
afforded
reaction (Scheme 1B) [10] (reaction of enolates with
the
corresponding
-lactams
2,
via
Staudinger [2+2] cycloaddition, in moderate yields.
imines) are the most general synthetic methods
employed so far. In addition, a typical approach
Scheme 1. Synthesis of the -lactam ring via Staudinger [2+2] cycloaddition reaction (A), GilmanSpeeter reaction (B) and by cyclization of -amino acids or esters (C).
R1
R2
H
C
O
+
R2
R1
+
N
R3
MO
A
OR
N
R3
B
R1
R2
N
O
R3
C
R1
(R) HOOC
R2
NHR 3
2
On the other hand, there are only a few examples for
diastereoselectivities
the catalytic enantioselective Staudinger reaction.
enantioselectivities.
Leckta has been the pioneer to report the reaction of
and
Design,
ketenes with N-tosyl -iminoesters in presence of
excellent
synthesis
and
properties of monocyclic, fused,
quinine derivatives to afford -lactams with high
spirocyclic,
enantioselectivities [14]. Later on, Fu has reported
and
bridged
-
the reaction of ketenes with N-tosyl and N-triflyl
lactams
imines
trans--lactams,
The -lactam ring is the central motif of the main
respectively, using planar-chiral derivatives of 4-
drugs used for the treatment of diseases caused by
(dimethylamino)pyridine
More
bacterial infections. The increased resistance of
recently, the research group of Ye has demonstrated
bacteria to traditionally used -lactam antibiotics and
the efficiency of N-heterocyclic carbenes to catalyze
the ever growing new applications of these products
the Staudinger reaction of ketenes with imines
in enzyme inhibition, have triggered a renewed
(Scheme 2B) [16]. Under optimized conditions, the
interest in the design and synthesis of new systems
authors have reported that a wide variety of ketenes
having the -lactam ring in their structure.
to
afford
cis-
as
and
catalyst
[15].
3 and imines 4 smoothly react to afford the
corresponding -lactams 5 in good yields with high
Scheme 2. Synthesis of -lactams via Staudinger [2+2] cycloaddition reaction.
A
1. R2MgCl (3 eq) / CuI (20 mol %)
R2
R
2. R3X (2 eq) then AcOH (2 eq)
N
3. R4OCH2COCl (1.4 eq) / Et3N (4.4 eq) / CH2Cl2
1
R4O
R3
50 to 62%
N
O
R1
1
2
R2MgCl
OR4
O
R1
N
MgCl
•
NR 1
R3X
R2
2
R
R3
B
N
N
N
Ph
O
Boc
•
Ar1
+
R
3
N
BF4
Ph
R
Ph OTBS
(10 mol%)
Ar2
Ar1
N
Cs2CO3 (10 mol%) / THF / rt
Ar2
H
4
58 to 78%
(cis:trans = 91:9 to 99:1)
(ee = 91 to 99%)
O
Boc
5
Boc tert-butoxycarbonyl, ee enantiomeric excess, TBS tert-butyldimethylsilyl.
3
The
research
group
has
(“click chemistry” methodology). Thus, cycloaddition
prepared a library of 30 -lactams from an acetoxy-
reaction of propargyl--lactams 9 with O-protected
azetidinone, to test the inhibition of human fatty acid
2-azidosugars derived from
amide hydrolase (hFAAH) [17]. The 2-azetidinone
has led to a clean and completely anomer-specific
ring has been functionalized with lateral chains
reaction to form glycoconjugated -lactams 10 in
imitating the structure of the inhibitors, in order to
excellent yields (Scheme 3B). The demonstration
make hydrophobic contacts in the active site of the
that these molecules could act as glycomimetics of
target enzyme. To design this library, the authors
modulable shape has been achieved by a combined
have studied the chain length (nPr,
Bu) and the
NMR/docking approach employing a model fucose-
nature of the end group (aromatic or aliphatic) for
bending lectin, Ulex Europaeus Lectin I (UEL-I), as
both
receptor.
substituted
of
Marchand-Brynaert
positions
[N(1)
n
and
C(5)-O].
The
authors
have
observed
a
clear
interaction
acylated -lactams 7 in two steps (Scheme 3A).
mimetic and UEL-I. A recent related work has been
Esterification of compounds 7 with acyl chlorides and
reported by Iadonisi et al [19]. This research group
pyridine produced the corresponding azetidinones 8
has prepared a hybrid structure of the glycopeptide
in good yields. Compounds 8 have been identified as
antibiotic
inhibitors of hFAAH versus human monoacylglycerol
anchoring the -lactam ring in presence of a Lewis
lipase (hMGL), with IC50 values in the nanomolar
acid.
range (5-14 nM).
Usually, the search for new -lactam drugs has been
In recent years, there is a growing interest in the
focused on the design of strained bicyclic 1,4-fused
design
the
structures in order to increase the acylating power of
combination of two potential biological molecules.
the amide moiety in the -lactam ring. A high
For example, in 2008, Palomo and colleagues have
number of novel structures, including small, medium
reported the synthesis of saccharide/-lactam hybrid
and large rings fused to the -lactam skeleton have
peptide-mimetic as potential lectin antagonist [18].
been
The design has been carried out according to a
processes. Thus, the interest on the design and
“shape-modulating linker” using the Cu(I) catalyzed
preparation of fused, spirocyclic and bridged -
variant of the Huisgen 1,3-dipolar cycloaddition
lactams has growed up [20].
complex
structures
based
on
the
and L-fucose
Acetoxy-azetidinone 6 has been transformed into N-
of
between
D-mannose
mannopeptimycin
prepared
applying
L--fucose-substituted
disaccharide
different
by
cyclization
4
Scheme 3. Design and synthesis of monocyclic -lactams as potential selective inhibitors.
R2
A
OTBS
OH
OAc
O
O
R2COCl (2 eq) / py
2 steps
NH
R1
N
O
6
O
66 to 84%
O
R1
N
CH2Cl2 / rt
O
O
8
7
B
N3
NsHN
O
OR 1
N
CuSO4 (20 mol%)
N
CO 2Me
t
O
OR 1
N
CO 2Me
O
BuOH / H2O / THF
9
N
NsHN
sodium ascorbate (0.4 eq)
O
N
10
60 to 98%
Py pyridine, TBS tert-butyldimethylsilyl, Ns 2-nitrobenzenesulfonyl.
5-Oxacephams is a family of interesting -lactam
hydroxypipecolic acid analogues with a bicyclic -
antibiotics and -lactamase inhibitors [21]. In 2009,
lactam structure have been published [25]. One of
Chmielewski et al have reported the enantioselective
the synthesis is shown in Scheme 4B and involves
synthesis
via
hydrogenation reaction of azido -lactam 14 followed
intramolecular nucleophilic substitution at C(4) of the
by the addition of benzyl chloroformate to give the
starting 4-formyloxy-azetidinones in presence of a
4-hydroxypipecolic acid analogue 15 in 49% yield.
chiral Lewis acid [22]. Monocyclic -lactams 11 were
Recently, Marchand-Brynaert et al have investigated
treated with a stoichiometric amount of SnCl4 and
a new family of bicyclic 2-azetidinones, in which the
(S)-3,3'-bis--naphtyl-BINOL 12 as ligand to afford
-lactam skeleton is embedded in a 1,3-bridging
the corresponding 5-oxacephams 13 with excellent
large ring [26]. Thus, this research group has
enantiomeric excess in moderate yields (Scheme
designed and prepared four families of 1,3-bridged
4A). The authors have explained the low yields in
2-azetidinones, as potential inhibitors of penicillin-
terms of a kinetic resolution of the initially formed
binding proteins, via ring-closing metathesis [27].
racemic oxacephams. This mechanism has been
Ring closing metathesis of alkenyl 2-azetidinones 16
supported by the partial asymmetric destruction of
afforded 1,3-bridged azetidinones 17 in high yields
racemic product 13 in presence of the chiral catalyst.
(Scheme 5). Catalytic hydrogenation of compounds
4-Hydroxypipecolic
17
of
nonproteinogenic
3,4-benzo-5-oxacephams
acids
18
quantitatively.
against the -lactamase TEM-1 from E-coli has
synthetic products such as depsipeptide antibiotics
shown no activity at a concentration of 100 M.
[23], and HIV protease inhibitors such as palinavir
Interestingly, the authors found that 1,3-bridged -
[24].
lactams 17 and 18 were active to R39 inhibitor (an
syntheses
of
skeleton
-lactams
present in many biologically active natural and
two
This
furnished
Biochemical evaluation of compounds 17 and 18
2008,
acids.
natural
is
In
amino
are
novel
4-
5
enzyme usually used for a preliminary screening of
weight
D,D-peptidases
responsible
for
bacterial
penicillin-like compounds), whereas the monocyclic
resistance to -lactam antibiotics showed week to
precursors 16 were inactive. In addition, evaluation
modest activity.
of -lactams 1618 against a set of high-molecularScheme 4. Synthesis of fused -lactams.
(S)-3,3'-bis--naphthyl-BINOL
A
-naphthyl
H
O
O
SnCl4 (1 eq) / 12 (1 eq)
N
R
HO
OH
R
O
39 to 52%
11
OH
N
CH2Cl2 / 0 ºC
O
O
-naphthyl
(ee = 82 to 99%)
13
12
B
H H
N3
OH
O
H2N
H2 / Pd (C)
N
O
H H
OH
O
N
OH
H
H
N
AcOEt / rt
PMP
N
O
PMP
OH
BnOCOCl (1.1 eq)
Na2CO3
O
PMP
HN
H
H
14
OH
CBzN
H
N
H
H
CO 2H
CH2Cl2 / rt
N
O
PMP
49%
OH
N
O
PMP
15
trans-4-hydroxypipecolic acid
Cbz benzyloxycarbonyl, PMP p-methoxyphenyl, BINOL 1,1'-bi-2,2'-naphthol.
Scheme 5. Synthesis of bridged -lactams.
O
O
O
H
Pr
N
Grubbs cat.
(2nd generation) (5 mol%)
CH2Cl 2 / rt
O
O
16
O
O
83 to 92%
O
H
Pr
AcOEt / rt
N
O
H
Pr
H2 (1 atm) / Pd (C) (5 mol%)
100%
N
O
O
O
17
18
6
Chartellines are a family of marine alkaloids, isolated
Taking into account that the -lactam ring system in
from
exquisitely
combination with 1,2,3-triazole moiety is present in a
complicated architecture formed by three biologically
number of drugs such as the anti -lactamase
important heterocycles: indolenine, imidazole and -
tazobactam and the cephalosporin cefatrizine, Hazra
lactam [28]. The asymmetric synthesis of the spiro-
and co-workers have reported the synthesis, as well
-lactam core of chartellines has been published by
as the antimicrobial and cytotoxic activities of bis--
the research group of Iwabuchi [29]. The synthetic
lactams linked through 1,2,3-triazole ring [32].
strategy starting from indole 19 using 5 mol% of
Synthesis of -lactamic hybrids has been achieved
rhodium catalyst 20 to give spirocycle 21, involves
using the “click chemistry” methodology between -
the
lactamic azides 25 and alkynes 26 in a mixture of
Chartella
papyracea,
formation
of
with
the
an
nitrogen-substituted
spirocenter, via aziridine intermediate 22 (Scheme
t
6). The following five steps include ozonolysis of the
ascorbate at 70ºC (Scheme 7). Dimeric compounds
exo-methylene
and
27 have been obtained in excellent yields. The
reduction of the carbamate followed by oxidation to
dimers prepared were tested in vitro for antifungal
give -amino alcohol 23. Finally, lactamization of
and antibacterial activity using a variety of fungal
compound 23 in the presence of tris(2-oxo-3-
strains against Escherichia coli and Staphylococcus
benzoxazolinyl)phosphine
aureus. Most of the dimers have shown moderate to
moiety,
N-Boc
protection
oxide
yielded
BuOHH2O
(7:3) with
CuSO4·5H2O
and
sodium
enantioenriched spiro--lactam 24.
good antifungal and antibacterial activity. However,
In recent years, much effort has been expended in
only one of the compounds 27 showed comparable
the preparation of bis--lactams, as potential starting
activity to that of tetracycline and ampicillin against
materials
S. aureus with a MIC value of 16g mL-1. In addition,
for
macrocycles,
the
synthesis
with
potential
of
functionalized
in
the authors have reported that compounds 27 did
supramolecular chemistry [30]. For example, the
not show any significant cytotoxicity to the tested
synthesis of bis--lactams via a tandem Cu-promoted
cell lines.
alkyne-homocoupling
followed
applications
by
double
[2+2]
allenyne cycloaddition has been reported [31].
7
Scheme 6. Synthesis of the spiro--lactam core of chartellines.
O
Bn
N
O
O O
Rh
O
Rh
NH 2
O
O
O
NH
N RhLn*
20 (5 mol%) / PhI(OAc)2 (1.4 eq)
Me
MgO (2.5 eq) / CH2Cl2 / 
N
Boc
O
O
20
N
Boc
Me
N
Boc
22
19
21
5 steps
53%
O
O
P
O
R
N
O
O
O
Cl
1
OH
N
N
R2
Br
NH
NH 2
3
NH
O
N
Br
(1.5 eq)
chartellines
O
Et3N / CH3CN / 
N
Me
N
Me
47%
23
24
Boc tert-butoxycarbonyl.
Scheme 7. Design, synthesis and biological evaluation of dimers linked with bis--lactam and 1,2,3triazole.
O
O
OH
X
+
HO
R
H
N
H
O
H
Ph
OH
Sodium ascorbate (0.5 eq)
CuSO4·5H2O (5 mol%)
N
N
H
Ph
R
OH
OH
DMF / H2O / MWI
Ph
H
H
N3
26
N N
X
N3
H
92 to 95%
Ph
H
R
O
H
N
OH
25
27
O
N
N
O
N N
X
O
Synthesis and properties of
employed
nitrogen-containing compounds
synthesis [3]. Taking into account the ring strain of
from -lactams
Besides the key role of -lactams as potential
antibiotics, additional impetus on -lactam chemistry
has been provided by the introduction of the lactam synthon method, a term coined by Ojima
[33], according to which 2-azetidinones can be
the
as
-lactam
useful
moiety
building
along
blocks
with
the
in
organic
adequate
functionalization in the different positions of the ring,
a variety of nitrogen-containing target compounds
can be obtained. In addition, it is important to
consider that most of the contributions described are
unexpected transformations.
8
The pyrrolidine skeleton is present in many natural
lactam at N(1)-C(2) positions [38]. More recently,
products and pharmacologically active compounds
this
[34]. In particular, polyhydroxylated pyrrolidines,
Paterson to the design and preparation of hybrids
dihydroxylated pyrrolidin-2-ones and their synthetic
with potential anticancer activity [39].
analogues have attracted a great deal of attention
Oseltamivir
due to their biological activities, such as glycosidase
commercialized with the name of TamifluTM. The
inhibitors [35]. It has been recently published the
Mandai research group chose this molecule as a
unexpected reaction of -lactams, in presence of a
target
catalytic amount of iodine, to give hydroxylated
sequence is shown in Scheme 9 where the key step
pyrrolidin-2-ones [36]. Reaction of C(3) alkoxy-
is the one-pot ring opening of the -lactam nucleus.
substituted formyl--lactams 28 in presence of tert-
Starting
butyldimethylsilyl cyanide using iodine as catalyst
functionalized -lactam 32 is achieved in six steps,
afforded
pyrrolidinone
which includes preparation of imine followed by
derivatives 29, in reasonable yields and good to
[2+2] cycloaddition with the corresponding acid
excellent diastereoselectivities, instead the expected
chloride, to obtain the -lactam in 28% yield.
addition products (cyanohydrins) to the carbonyl
Acetylation of compound 32 and subsequent reaction
group of the aldehyde (Scheme 8A).
with an excess of EtSH and Et3N afforded the ring-
De Kimpe has reported the preparation of bicyclic -
opening product, thiol ester 33, in 94% yield. The
lactams
total synthesis of oseltamivir was completed in five
the
30
expansion
from
products,
monocyclic
-lactams
31
in
protocol
has
is
from
been
a
successfully
potent
L-methionine
from
anti-influenza
[40].
L-methionine,
drug
synthetic
synthesis
intermediates
intramolecular aldol condensation of the formed
[37].
Treatment
of
hydroformylation
of
additional
8B)
including
The
by
presence of AgBF4 and pyridine via N-acyliminium
(Scheme
steps
applied
and
monocyclic -lactams 31 with AgBF4 and pyridine has
dialdehyde.
afforded cis- and trans-bicyclic -lactams 30 in
Kainods is a family of natural products with a potent
moderate yields.
anthelminthic
As we introduced this section, Ojima has been one of
activities in the mammalian central nervous system
the pioneers to employ the -lactam ring for the
[41]. In particular, kainic acid has been used in
construction of other type of nitrogen-compounds
neuropharmacology for stimulation of nerve cells
[33]. Taking into account that the -lactam moiety is
such as Alzheimer's disease [42]. As a matter of its
a masked -amino acid, this author has developed a
importance and the costly due to the limited stock
protocol to introduce the side chain at C(13) position
from
of baccatin III, involving the ring opening of the -
compounds is desirable.
natural
properties
resources,
and
neurotransmitting
synthesis
of
these
Scheme 8. Synthesis of pyrrolidines via ring expansion of -lactams.
9
A
R1O
R1O
H H
CHO
N
CN
O
CH 3CN / rt
R2
O
OTBS
TBSCN / I2 (10 mol%)
R2
57 to 80%
(syn:anti = 86:14 to 100:0)
28
H
N
29
B
Cl
R1O
Toluene / 
N
( )n
17 to 57%
XR 2
R1O
+
O
cis-30
(trans:cis = 63:37 to 72:28)
31
X
( )n
N
R2
H
X
AgBF4 (1 eq) / py (1 eq)
O
R2
H
R1O
( )n
N
O
trans-30
TBS tert-butyldimethylsilyl, py pyridine.
Scheme 9. Synthesis of oseltamivir via ring opening of the -lactam nucleus.
a) LiHMDS (2 eq)
NHBoc
O
6 steps
MeO 2C
SMe
H H
NPhth
THF / 78 ºC
O
COSEt
O
b) AcCl (2 eq) / 78 ºC
NH
28%
AcHN
c) EtSH (5eq) / Et3N (5 eq)
O
94% yield
32
77%
NPhth
78 ºC to 20 ºC
L-methionine
CO 2Et
5 steps
AcHN
NH 2
oseltamivir
33
Boc tert-butoxycarbonyl, Phth phthaloyl.
In 2008, Fukuyama has published the total synthesis
starting -lactam 34 followed by activation of the -
of
lactam ring with a Cbz group, compound 35 was
()-kainic
acid
starting
from
commercially
available 2-azetidinone 34 (Scheme 10) [43]. After
introduction
of
a
carbobutoxymethyl
group
obtained in good yield.
on
Scheme 10. Synthesis of ()-kainic acid via ring opening of the -lactam nucleus.
TBSO
CO 2tBu
H H
OAc
Me
(6 eq)
a) ZnBr
NH
TBSO
CO 2tBu
Me
NCbz
THF / O ºC to rt
O
H H
O
b) CbzCl (1.1 eq) / LiHMDS (1.1 eq)
34
35
THF / 78 ºC to rt
85%
NaBH 4 (eq) / EtOH
0 ºC / 6h
80%
Me
CO 2H
H
H
N
H
CO 2H
H
()-kainic acid
Me
3 steps
61%
H
O
CO 2Me
Me
O
3 steps
Boc
N
76%
H
OTBS
CO 2tBu
HO
NHCbz
37
NHCbz
36
Boc tert-butoxycarbonyl, Cbz benzyloxycarbonyl, TBS tert-butyldimethylsilyl.
10
Reduction of -lactam 35 with NaBH4 afforded amino
activity
alcohol 36, formed by ring opening of the -lactam
bearing the azetidine-2-carboxamide skeleton [48].
at N(1)C(2) bond, in good yield. The following three
In 2009, Cavelier and coworkers have described the
step synthesis involves the introduction of the
synthesis of L-azetidine-2-carboxylic acid [49]. The
glycine ester and subsequent cyclization under acidic
authors have envisioned two strategies, Mitsunobu
conditions to form the lactone ring. The total
reaction
synthesis of ()-kainic acid was completed in three
Starting from aminoalcohol 38, the protection of
additional steps from 37.
amino group has resulted in the formation of
with
an
important
different
class
properties
of
and
applications widely used in drug design. Besides, the
azetidine skeleton is present in a variety of natural
products and pharmacologically active compounds
[44]. There are a variety of methods for the
preparation of azetidines. Among them, the most
powerful method is the reduction of 2-azetidinones
hydrides
[45].
However,
this
procedure is not very general, because in some
cases instead the expected azetidine, the -amino
alcohol
is
obtained
as
a
sole
product.
Other
methodologies are based on the preparation of an
alicyclic
precursor
followed
by
intramolecular
cyclization [46].
applications
11A).
protection of both amino and hydroxyl groups by
using
SES
chloride,
afforded
compound
41.
Cyclization of compound 41 under smooth basic
conditions afforded azetidine 40 in 63% overall yield.
On the other hand, Malik has described the synthesis
of
azetidines
42
via
arenesulfonylaziridines
dimethylsulfoxonium
ring
43
in
methylide
expansion
the
of
1-
presence
of
under
microwave
conditions [50]. Interestingly, cis-aziridines have
yielded trans-azetidines and trans-aziridines have led
to cis-azetidines (Scheme 11B).
In 2009, the research group of Ragan described the
synthesis of CE-178,253 [51]. This compound is a
CB1 receptor antagonist for the management of
metabolic disorders, such as obesity. The synthetic
The azetidine-2-carboxylic acid skeleton is present in
important
(Scheme
hydroxyl group by a good leaving group. Thus,
constitute
nucleophilic
N-alkylation
compounds
yield. Direct alkylation was achieved by changing the
azetidines
by
direct
lincosamides,
conditions to afford azetidine 40 in 50% overall
Synthesis and properties of
azaheterocycles
or
azetidine
compound 39, which was submitted to Mitsunobu
Azetidines
Azetidines
of
entities
showing
numerous
in pharmaceutical and
potential
agrochemical
fields. As an example, this structure is found in
nicotianamine which plays a significant role in plants
route involves the preparation of pyrazolotriazininone
intermediate 44 from commercially available 2chlorobenzoyl acetonitrile. Clorotriazine 44 has been
coupled with azetidine bis (HCl) salt 45 using iPr2NEt
(Scheme 12).
as an iron transporter [47]. Recently, O'Dowd et al
have
prepared
and
evaluated
the
antibacterial
11
Recently, Carreira and co-workers have designed
have been analyzed with respect to their lipophilicity,
novel azetidine-based azaspirocyclic frameworks as
aqueous solubility, metabolic stability, and amine
surrogates for piperazines, piperidines, morpholines
basicity.
and
concept of replacing a six-membered monocyclic unit
thiomorpholines
biochemical
with
properties
physicochemical
of
potential
and
druglike
in
a
The
drug
authors
have
candidate
discussed
by
a
that
the
corresponding
structures [52]. In particular, this research group
spiro[3.3]heptane analogue is worth implementing,
has developed the synthesis of various heteroatom-
as it may significantly improve relevant aspects of
substituted spiro[3.3]heptanes with C2 symmetry
the
[53]. Azetidine-spirocycles 46 and 47 were prepared
aqueous solubility and reducing both lipophilicity and
from dibromide 48. After removal of the N-tosyl
metabolic degradation. In the same report, the
group of bicycle 46, functionalization of the amine
authors have demonstrated the usefulness of this
furnished the desired diazaspiro[3.3]heptanes 47 in
family of compounds for the synthesis of analogues
good yields (Scheme 13). Spirocycles 46 and 47
of the antibacterial compound ciprofloxacin [53].
pharmacokinetic
profile
by
increasing
the
Scheme 11. Synthesis of azetidines.
A
CO 2tBu
HO
CO 2tBu
SESCl (1 eq) / Et3N (1.3 eq)
NH 2
HO
DMF / 0 ºC
NHSES
67%
38
CO 2tBu
PPh3 / DEAD
THF / 0 ºC then rt
86%
39
NSES
40
CO 2H
N
H
N
CO 2H
NH 2
CO 2H
nicotianamine
CO 2tBu
SESCl (2 eq) / Et3N (4 eq)
CsCO 3 (4 eq) / CH 3CN
SESO
DMF / 0 ºC
NHSES
rt
41
66%
97%
B
X
O
+
SO2
N
R2
CH 2
SMe2
R2
R1
MW (160 W) / 90 ºC
Al2O3
N
SO2
68 to 79%
R1
43
42
X
DEAD diethyl azodicarboxylate, SES 2-(trimethylsilyl)ethanesulfonyl.
12
Scheme 12. Synthesis of CE-178,253, an azetidine-based CB1 antagonist.
Me
Me
NH 2
O
CN
N
NH
N
Cl
Me
45
O
6 steps
35%
Cl
·2HCl
NH
Cl
N
NH (1.05 eq)
i
N
N
N
Cl
Pr2NEt / CH2Cl2
O
N
N
HN
78%
Cl
Cl
NH 2
Me
CE-178,253
44
Scheme 13. Synthesis of spiro-azetidines.
Br
Ts
Piperonylamine (2 eq)
N
i
Br
a) Mg, MeOH, ultrasound
Ts
N R1
N
Pr2NEt (5 eq)
90%
48
R2
b) different reaction conditions
62 to 71%
46 R1 = piperonyl
N R1
N
47
Ts p-toluenesulfonyl.
Synthesis and properties of
reaction of 2-aryl-N-tosylazetidines 51 with nitriles,
nitrogen-containing compounds
in presence of Cu(OTf)2, to afford a variety of
substituted tetrahydropyrimidines 52 (Scheme 14B)
from azetidines
Albeit the associated ring strain of the azetidine
moiety presents some difficulties in its preparation, it
is profitable for the synthesis of other nitrogenated
such
as
pyrrolidines
[54]
and
pyrimidines [55] are important building blocks in the
design and synthesis of many natural products and
pharmaceuticals.
rearrangement
Couty
of
has
Medium-sized nitrogen-heterocycles are found in
natural products with biological activity, however
their
compounds via ring opening [4].
Azaheterocycles
[57].
described
2-hydroxyalkylazetidines
the
using
diethylaminosulfur trifluoride (DAST) [56]. Primary
and secondary azetidinol substrates 49 rearranged
into 3-fluoropyrrolidines 50, as single diastereomers
in fair to good yields, on reacting with 1.5 equiv. of
DAST (Scheme 14A).
In 2009, the research group of Ghorai has described
the ring-opening followed by [4+2] cycloaddition
preparation
present
some
difficulties.
The
research group of Couty has described the first
example of ring expansion of azetidines 53 into
azocanes (eight-membered nitrogen heterocycles)
54 (Scheme 14C) [58]. The scope of this reaction is
restricted to activated monosubstituted alkynes. The
relative configuration of the stereocenters in the
reacting azetidine is also an important parameter.
While 2,3-trans-vinyl azetidine 53 gave the expected
ring expansion product 54, the corresponding 2,3cis-isomer
gave
the
competitive
ring
opening
product. This ring expansion takes place via a [3,3]sigmatropic rearrangement of the starting 2-alkenyl
azetidines reacting with activated alkynes.
13
3-Substituted indoles are important building blocks
effectively with N-tosylazetidines. The corresponding
for
ring-opened
the
synthesis
molecules.
In
of
2009,
various
biologically
Yadav
has
active
reported
the
products
55
were
obtained
by
preferential attack of indole at the benzylic position.
preparation of 3-substituted indoles 55 via C(3)
The regioselectivity of the ring-opening have
been
alkylation of indoles 56 with azetidines 57 using
explained in terms of the stability of the benzylic
InBr3 as catalyst under mild conditions (Scheme 15)
carbocation intermediate formed.
[59]. The authors have observed that both electronrich as well as electron deficient indoles react
Scheme 14. Synthesis of pyrrolidines (A), tetrahydropyrimidines (B) and azocanes (C) via ring
expansion of azetidines.
A
OH
Ph
Ph
F
DAST (1.5 eq)
R
CH2Cl2 / 0ºC to rt
N
R
N
62 to 80%
49
50
B
R
RCN / Cu(OTf)
N
Ar
2
(1 eq)
N
Ts
N
80 ºC
Ts
55 to 70%
Ar
51
52
C
R
R
Ph
CO 2Et (5 eq)
Ph
CH 2Cl 2 / rt
N
Bn
CO 2Et
N
45 to 82%
Bn
53
54
DAST diethylaminosulfur trifluoride, Tf trifluoromethanesulfonyl, Ts p-toluenesulfonyl.
Scheme 15. Ring opening of azetidines to give 3-substituted indoles.
Ph
R2
Ph
R1
N
H
56
+
N
Ts
InBr3 (10 mol%)
R2
R1
DCE / 
N
H
74 to 80%
57
NHTs
55
Ts p-toluenesulfonyl.
14
•
Conclusion
The chemistry of -lactams and azetidines is in a
1.
of special interest
Banik
BK
:
-Lactams:
Synthesis,
privilege position in chemistry, medicine and natural
stereochemistry, synthons and biological
products disciplines due to their interesting biological
evaluation. Curr. Med. Chem. (2004) 11(14):
activities.
Thus,
importance
since
of
this
the
discovery
of
four-membered
the
nitrogen
1813-1964.
•• A special issue dedicated to the synthesis,
reactivity and biological properties of -lactams.
heterocycles, intensive efforts have been devoted in
both the design and synthesis of novel azetidines
2.
Banik BK, Banik I, Becker FF: Novel anticancer
-lactams.
In:
Hetereocyclic
Scaffolds
I.
and -lactams with potential biological activity. In
(Series: Topics in Heterocyclic Chemistry, Vol.
fact, many researches from around the world have
22)
3.
new
-lactam
and
azetidine
derivatives and the preparation of novel nitrogencontaining
structures,
synthetic
organic
will
be
chemists
a
challenge
and
an
exciting
Ciencia
Santander
Central
GR58/08)
for
Hispano
financial
C:
-
• Describes the key role of  -lactams as building
blocks for the preparation of a vast variety of
nitrogen containing compounds.
4.
Couty F, Gwilherm E: Azetidines: new tools
Synlett (2009) (19): 3053-3064.
e
Innovación
synthetic
Complutense-Banco
(UCM-BSCH)
support.
C.
A.
(Grant
thanks
tool
for
the
preparation
of
different
nitrogen derivatives.
5.
Aranda MT, Pérez-Faginas P, González-Muñiz R:
An update on the synthesis of -lactams.
Autónoma de Madrid (CAM) (Project S2009/PPQUniversidad
Aragoncillo
• Describes the importance of the azetidine ring as
(DGI-MICINN) (Project CTQ2009-09318), Comunidad
and
P,
for the synthesis of nitrogen heterocycles.
We would like to thank the Dirección General de
1752)
Almendros
for
Acknowledgments
de
B,
4492.
opportunity for biological evaluations.
Investigación-Ministerio
Alcaide
products. Chem. Rev. (2007) 107(11): 4437-
blocks in synthesis. It is likely that in the near future,
of
SpringerVerlag,
stereoselective synthesis of non--lactam
lactams and azetidines makes them valuable building
synthesis
(Ed),
Lactams: Versatile building blocks for the
containig structures that can be prepared from -
the
BK
BerlinHeidelberg, (2010): 349-374.
contributed to show the synthetic value of -lactams
and azetidines. In addition, the diversity of nitrogen-
Banik
Curr. Org. Synth. (2009) 6(3): 325-341.
• Describes the most recent synthetic aspects of
stereoselective synthesis of  -lactams.
6.
Fu N, Tidwell TT: Preparation of -lactams by
[2+2] cycloaddition of ketenes and imines.
Ministerio de Ciencia e Innovación (MICINN) for a
Tetrahedron (2008) 64(46): 10465-10496.
Ramón y Cajal contract co-financed by the European
Social Fund.
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