Preparation of functionalised monobactams from pyridones

Article abstract of DOI:10.1016/j.tetlet.2009.03.045

A novel synthesis of functionalised monobactams in high isolated yields is described. The procedure involves photochemical cyclisation of commercially available 2-pyridones followed by ring-opening cross-metathesis.

Full text of DOI:10.1016/j.tetlet.2009.03.045

Tetrahedron Letters 50 (2009) 3580–3584
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation of functionalised monobactams from pyridones
*
Mauro F. A. Adamo , Paolo Disetti, Linda Piras
Centre for Synthesis and Chemical Biology (CSCB), Department of Pharmaceutical and Medicinal Chemistry, The Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2,
Dublin, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel synthesis of functionalised monobactams in high isolated yields is described. The procedure
involves photochemical cyclisation of commercially available 2-pyridones followed by ring-opening
cross-metathesis.
Received 14 January 2009
Revised 4 March 2009
Accepted 9 March 2009
Available online 13 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
2-Pyridone
Monobactam
Photochemistry
Ring-opening cross-metathesis
The b-lactam skeleton is the common structural element in the
penicillin family and is responsible for the observed biological activ-
ity. An alarming increase in bacterial resistance to b-lactam antibiot-
ics has emerged which has stimulated research towards new
antibiotic compounds.1 As a result, several synthetic and semi-syn-
thetic compounds containing the b-lactam ring have been prepared
and subsequently tested.2 The discovery of nocardicins 1 (Fig. 1) has
demonstrated for the first time that b-lactams do not require a con-
formationally constrained bicyclic structure to have anti-bacterial
properties, suggesting that a suitably functionalised 2-azetidinone
ring as in 2 constitutes an adequate pharmacophore.3
It has been reported that monocyclic b-lactams are remarkably
active, not only as antibacterials, but also as inhibitors of cytomeg-
alovirus protease,4 cholesterol absorption5 and human tryptase.6
These discoveries have encouraged the synthetic community to-
wards finding alternative methods for their preparation allowing
rapid construction of novel classes of monobactams.
As a part of our ongoing studies on the generation of chemical
diversity using aromatic heterocycles,7–12 we envisaged a novel
synthesis of monobactams starting from commercially available
2-pyridones (Scheme 1). 2-Pyridones possess a low degree of aro-
maticity, and for this reason, they often have been employed as
dienes in Diels-Alder reactions.13 They have also been reported to
undergo photochemical electrocyclisation to furnish bicyclic struc-
tures 4.14 The cyclisation is stereoselective and only cis-fused bicy-
pounds 3 contain two alkene moieties that in turn could be em-
ployed to prepare libraries of monobactams for biological
evaluation. As ring strain is the major driving force promoting
ring-opening metathesis (ROM)/cross-metathesis (CM) se-
quences,15 we were sufficiently confident on the viability of the
reaction leading from 4 to 3 (Scheme 1). Importantly, in this syn-
thesis, variation of the alkene component in the ROM/CM step or
introduction of a substituent in the pyridone substrate would fur-
nish an efficient means to generate libraries of compounds.
Herein, we report our preliminary results on the development
of the synthetic strategy highlighted in Scheme 1. We started our
investigation by submitting several commercially available 2-pyri-
dones to photochemical-induced electrocyclisation (Table 1). A lit-
erature survey revealed the following facts:14 (a) the cyclisation
was faster when a methoxy substituent was present at position 4
of the 2-pyridone: typically, 4-methoxy-2-pyridone cyclised upon
irradiation in 2–4 h, while the unsubstituted 2-pyridone required
over 70 h; (b) while a large variety of solvents could be employed
in this reaction, it appeared that each 2-pyridone required a spe-
cific solvent to ensure high conversion; (c) the yields of cycload-
ducts 4 were generally low, although quantitative conversions of
5 were often reported.14a With the aim of obtaining compounds
4a–e in sufficient amounts for preparative studies, we studied
the reaction of 2-pyridones 5a–e in several solvents including tol-
uene, CH3CN, EtOH, EtOAc and MeOH (Table 1).
clic compounds
compounds 4 were metathesis active, their reaction with alkenes
would furnish a novel means to produce monobactams 3. Com-
4
were obtained. It was reasoned that if
Irradiation of compounds 5a–d always proceeded to quantita-
tive conversion. However, the isolated yields of compounds 4a–d
after silica gel chromatography were never greater than 30–35%.
It was also noticed that upon deposition of crude 4a–d on silica
gel several additional side products were formed. Further
studies concluded that neutral alumina was the best medium for
* Corresponding author. Tel.: +353 1 4022208; fax: +353 1 4022168.
E-mail address: madamo@rcsi.ie (M.F.A. Adamo).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.045

M. F. A. Adamo et al. / Tetrahedron Letters 50 (2009) 3580–3584
3581
NOH
H
H
N
HOOC
OH
O
O
NH
N
NH
2
O
O
COOH
1
2
Figure 1.
can be attributed to deactivation of the metathesis catalyst: (a)
the 2-azetidinone ring impedes delocalisation of the nitrogen lone
pair, hence this could act as a ligand. (b) During the purification of
compounds 6–13, a discrete compound was repeatedly obtained
containing monobactam and ruthenium; as yet we have not estab-
lished the structure of this compound. (c) Free cyclohexylphos-
phine was obtained in the crude reaction mixture, indicating
displacement of the ligand from the metal.
R
hv
ROM/CM
HN
N
H
O
HN
O
O
3
4
5
Scheme 1.
In order to obviate these problems, we decided to protect the
nitrogen in compounds 4a and 4c prior to metathesis. Compounds
4a and 4c were protected as their N-Boc derivatives by reaction
with (Boc)2O and triethylamine.16 N-Boc protected 4a and 4c were
subsequently reacted with ethylene and Grubbs’ catalyst I. Unfor-
tunately, this reaction did not produce the desired ROM/CM com-
pounds and starting materials were recovered unreacted. The
nitrogen of compounds 4a and 4c was instead protected using sil-
icon-based protecting groups. This was achieved in DMF using an
excess of TMSCl, TBDPSCl or TBDMSCl (1–2 equiv) and NEt3 as
the base (Table 3). While N-TMS and N-TBDPS monobactams 14–
15 and 17–18 were obtained only in moderate yields (Table 3, en-
tries 1, 2 and 4, 5), N-TBDMS monobactams 16 and 19 were ob-
tained in excellent isolated yields.14c
We submitted compounds 14–19 to ROM/CM metathesis using
Grubbs’ catalyst I (0.1 equiv) and excess ethylene (Table 4).
Delightfully, reaction of N-TBDPS protected bicyclic compounds
15 and 18 proceeded to completion and gave the expected alkenes
21 and 24 in good isolated yields (Table 4, entries 2 and 5). N-
TBDMS-protected compounds 16 and 19 gave the corresponding
ring-opened compounds 22 and 25 in excellent isolated yields (Ta-
ble 4, entries 3 and 6). Reaction of N-TMS-protected 14 and 17 gave
a complex reaction mixture (Table 4, entries 1 and 4).
We have also demonstrated that the TBDMS group in com-
pounds 22 and 25 can be removed by reaction with KF (1.1 equiv)
in MeOH at À20 °C to give monobactams 6 and 11 in yields of over
80%. The cleavage of the silicon-protecting group was accompanied
by partial isomerisation, resulting in formation of 5–8% of the more
stable trans-6 and trans-11 isomers which were isolated and fully
characterised (Scheme 2).
In conclusion, we have developed a novel route to alkene-func-
tionalised monobactams. The synthesis made use of commercially
available 2-pyridones and alkenes and furnished stereodefined
monobactams in high yields. The methodology presented is modu-
lar in nature and allows introduction of diversity by variation of
one component at a time. Studies on the use of compounds 6
and 11 in diversity-oriented synthesis and for the preparation of
unnatural b-amino acids are in progress.
Table 1
R2
R3
R2
R1
R3
R4
R1
O
300 nm
solvent
R4
HN
N
H
O
5
4
Entry Substrate R1
R2
R3
R4
Solventa Product Yieldb (%)
1
2
3
4
5
5a
5b
5c
5d
5e
H
OCH3
H
H
H
H
H
CH3
H
H
H
H
H
CH3
H
H
H
H
H
CH3CN
CH3CN
EtOAc
EtOH
4a
4b
4c
4d
4e
65
70
75
70
—
CH3 EtOAc
a
Reactions carried out by irradiating with a monochromatic 300 nm lamp at a
concentration of 10À3 M in a Hanovia chamber.
b
Isolated yields after column chromatography on neutral alumina.
purification allowing compounds 4a–d to be obtained in 65–75%
isolated yields. Although previously reported,14b the conversion
of 5e into 4e did not proceed in our hands. We next studied the
ROM/CM of compounds 4a and 4c which were selected as exam-
ples of unsubstituted and substituted cyclobutenes. Reactions of
4a and 4c with ethylene were carried out using 0.1 equiv of Grub-
bs’ catalyst I, Grubbs’ catalyst II and Hoveyda catalyst II. The best
results were obtained using Grubbs’ catalyst I and dichlorometh-
ane as solvent. Initially, Grubbs’ catalyst I was added in one portion
at the onset of the reaction. Later it was found that cleaner and
higher yielding reactions were obtained by dropwise addition of
a freshly prepared solution of the ruthenium catalyst in dichloro-
methane. Reaction of 4a and 4c with ethylene in the presence of
0.1 equiv of Grubbs’ I did not go to completion giving only 50%
and 28% yields, respectively, of compounds 6 and 11 (Table 2, en-
tries 1 and 4) together with recovered starting material. Addition
of further amounts of ethylene did not improve the yields.
The reaction of 4a and ethylene proceeded to full conversion
after addition of a further 0.15 equiv of ruthenium catalyst to the
reaction mixture, giving compound 6 in nearly 80% yield. Increas-
ing the temperature did not lead to an improved yield. Reaction of
4a with styrene or 1-hexene furnished the expected two regioi-
somers 7, 8 and 9, 10 in low yields (Table 2, entries 2 and 3). Reac-
tion of 4c and styrene or 1-hexene furnished only regioisomers 12
and 13 in low yields (Table 2, entries 5 and 6).
1. Preparation of 2-aza-bicyclo[2.2.0]hex-5-en-3-one 4a
1H-Pyridin-2-one 5a (0.02 mol) in CH3CN (500 mL) was irradi-
ated with UV light (300 nm) at room temperature for 65 h using
a Hanovia reactor. The crude product was purified by neutral
Al2O3 column chromatography (eluent: petroleum ether/ethyl ace-
tate, 1:1) to give compound 4a as a pale yellow solid (65% yield).
Mp = 65–66 °C, Rf = 0.10 (eluent: petroleum ether/ethyl acetate,
1:1); 1H NMR (400 MHz, CDCl3) dH 6.59 (1H, m), 7.98 (1H, m),
The following observations suggested that incomplete conver-
sion in the experiments employing 0.1 equiv of catalyst (Table 2)

3582
M. F. A. Adamo et al. / Tetrahedron Letters 50 (2009) 3580–3584
Table 2
ROM/CM of compounds 4a and 4c
Entry
Reactant
Alkenea
Product
Yieldb (%)
1
4a
Ethylene
50
HN
O
6
Ph
Ph
2
3
4a
4a
Styrene
7 (7%)/8 (5%)
HN
HN
O
O
8
7
C H
4
C H
4
9
9
1-Hexene
9 (9%)/10 (3%)
HN
10
HN
O
O
9
4
4c
Ethylene
28
HN
11
O
Ph
5
4c
4c
Styrene
15
10
HN
12
O
C4H9
6
1-Hexene
HN
13
O
a
Ethylene was used in large excess; 5 equiv of styrene and 1-hexene were used.
Isolated yields after column chromatography.
b
4.38 (1H, m), 4.11 (1H, m); 13C NMR (106.6 MHz) dC 172.1, 142.5,
140.5, 59.6, 50.8; HRMS found: M+ 95.0375, C5H5NO requires
95.0371, m/z: 95 (100%, M+).14b
diethyl ether (3 Â 10 mL). The combined organic layer was washed
with saturated NaCl (10 mL), then dried over Na2SO4 and evapo-
rated in vacuo. The crude residue was purified by silica gel column
chromatography (previously deactivated with NEt3) (eluent:
diethyl ether/petroleum ether, 1:5) to give compounds 16 and 19.
2. Preparationof5-methyl-2-aza-bicyclo[2.2.0]hex-5-en-3-one4c
4-Methylpyridone 5c (0.5 mmol) in ethyl acetate (500 mL) was
irradiated with UV light (300 nm) for 2 h at room temperature.
The crude product was purified by neutral Al2O3 column chroma-
tography (eluent: petroleum ether/ethyl acetate, 1:1) to give
compound 4c as a colourless solid (75% yield), MP = 55–56 °C,
Rf = 0.15 (eluent: petroleum ether/ethyl acetate, 1:1); 1H NMR
(400 MHz, CDCl3) dH 6.12 (1H, m), 4.21 (1H, m), 3.99 (1H, m),
1.85 (3H, m); 13C NMR (106.6 MHz, CDCl3) dC 172.8, 151.7,
134.4, 61.0, 47.2, 16.5.14b
3.1. 2-(tert-Butyl-dimethylsilanyl)-2-aza-bicyclo[2.2.0]hex-5-
en-3-one 16
Yellow oil, yield: 90%, Rf = 0.68 (eluent: diethyl ether/petroleum
ether, 1:5); 1H NMR (400 MHz, CDCl3) dH 6.60 (1H, m), 6.49 (1H,
m), 4.31 (1H, m), 4.14 (1H, m), 0.92 (9H, s), 0.20 (3H, s), 0.17
(3H, s); 13C NMR (100.6 MHz) dC 175.3, 143.0, 141.2, 60.1, 52.0,
25.9, 18.2, À6.3, À6.7; HRMS found: M+ 209.1237, C11H19NOSi re-
quires 209.1236, m/z: 209 (100%, M+).14c
3. Procedure for the preparation of compounds 16 and 1914c
3.2. 2-(tert-Butyl-dimethylsilanyl)-5-methyl-2-aza-
bicyclo[2.2.0]hex-5-en-3-one 19
To a solution of compound 4a or 4c (1 mmol) in DMF (2 mL) at
0 °C were sequentially added triethylamine (1.3 mmol) and tert-
butyldimethylsilyl chloride (1.3 equiv). The reaction was allowed
to reach room temperature and stirred for 2 h, then extracted with
Yellow oil, yield: 90%, Rf = 0.63 (eluent: diethyl ether/petroleum
ether, 1:5); 1H NMR (400 MHz, CDCl3) dH 6.15 (1H, m), 4.15 (1H,
m), 4.03 (1H, m), 1.89 (3H, m), 0.92 (9H, s), 0.20 (3H, s), 0.16

M. F. A. Adamo et al. / Tetrahedron Letters 50 (2009) 3580–3584
3583
Table 3
Table 4
Protection of photoisomers 4a and 4c
ROM/CM of compounds 14–19 with ethylene
Entry
Substrate
Reactant
Product
Yielda (%)
25
Entry
Substrate
Product
Yielda (%)
TMS
TMS
N
N
1
4a
TMSCl
14
1
14
—
20
O
O
TBDPS
N
2
3
4
4a
4a
4c
TBDPSCl
TBDMSCl
TMSCl
60
90
51
15
TBDPS
O
N
O
2
3
4
5
15
16
17
18
19
60
89
—
21
TBDMS
N
16
O
TBDMS
O
N
TMS
O
22
N
17
TMS
N
TBDPS
N
23
5
4c
4c
TBDPCl
28
90
18
O
O
TBDMS
N
TBDPS
O
6
TBDMSCl
19
N
53
90
24
25
O
a
Isolated yields after column chromatography.
TBDMS
O
(3H, s); 13C NMR (106.6 MHz, CDCl3) dC 175.8, 152.3, 134.9, 61.5,
48.3, 25.9, 18.2, 16.7, À6.3, À6.7; HRMS found: M+ 223.1402,
C12H21NOSi requires 223.1392, m/z: 223 (100%, M+).14c
N
6
a
Isolated yields after column chromatography.
4. Procedure for the preparation of compounds 22 and 25
To a solution of compound 16 or 19 (1 mmol) in dry CH2Cl2
(7 mL), were added Grubbs’ I catalyst (10% mol) dissolved in dry
CH2Cl2 (7 mL) and ethylene under pressure (300 psi). This reaction
was carried out using a Parr 5500 series bench-top compact reac-
tor. After 4 h the reaction was filtered, the organic layer was evap-
orated in vacuo and the crude residue was purified by silica gel
column chromatography (eluent: diethyl ether/petroleum ether,
1:5) to give compound 22 or 25. It was important to deactivate
the silica gel using NEt3 prior to chromatography.
(400 MHz, CDCl3) dH 5.69 (1H, dt, J = 17.2, 10.0 Hz), 5.20 (1H, dd,
J = 17.2, 1.4 Hz), 5.12 (1H, dd, J = 10, 1.4 Hz), 4.99 (1H, s), 4.89
(1H, s), 4.01 (1H, dd, J = 10, 6 Hz), 3.93 (1H, d, J = 6 Hz), 1.51 (3H,
s), 0.85 (9H, s), 0.10 (3H, s), 0.09 (3H, s); 13C NMR (106.6 MHz,
CDCl3) dC 173.0; 137.39; 136.82; 119.3; 114.5; 61.6; 56.6; 26.3;
22.2; 18.3; À5.2; À5.59; HRMS found: M+ 251.1704, C14H25NOSi
requires 251.1705, m/z: 251 (100%, M+).
5. Procedure for the preparation of compounds 6 and 11
4.1. 1-(tert-Butyl-dimethylsilanyl)-3,4-divinyl-azetidin-2-one
22
To a solution of N-TBDMS-protected azetidinone 22 or 25
(1 mmol) in methanol (10 mL) at À20 °C was slowly added so-
lid potassium fluoride (1.1 mmol). The reaction mixture was
stirred for 50 min, and the solvent was evaporated in vacuo.
The crude residue was purified by flash column chromatogra-
phy (eluent: petroleum ether/ethyl acetate, 1:1) to afford com-
pound 6 or 11.
Yellow oil, yield 89%, Rf = 0.85 (eluent: diethyl ether/petroleum
ether, 1:1), IR: mmax (neat)/cmÀ1: 3241, 2932, 1765; 1H NMR
(400 MHz, CDCl3) dH 5.81–5.66 (2H, m), 5.33–5.19 (4H, m), 4.15–
4.04 (2H, m), 0.93 (9H, s), 0.20 (3H, s), 0.16 (3H, s); 13C NMR
(100.6 MHz) dC 173.1, 137.3, 129.6, 119.7, 119.1, 59.0, 56.8, 26.4,
18.4, À5.3, À5.5; HRMS found: M+ 237.1555, C13H23NOSi requires
237.1549, m/z: 237 (100%, M+).
5.1. cis-3,4-Divinyl-azetidin-2-one 6
4.2. 1-(tert-Butyl-dimethylsilanyl)-3-isopropenyl-4-vinyl-
azetidin-2-one 25
Brown oil, yield 81%, Rf = 0.54 (eluent: petroleum ether/ethyl
acetate, 1:1), IR: mmax (neat)/cmÀ1: 3241, 2932, 1765; 1H NMR
(400 MHz, CDCl3) dH 5.80–5.70 (1H, m), 5.68–5.61 (1H, m), 5.30–
5.18 (4H, m), 4.24 (1H, t, J = 5.6 Hz), 3.95 (1H, t, J = 6.4 Hz); 13C
NMR (100.6 MHz) dC 168.6, 134.9, 129.1, 120.4, 118.5, 58.75,
Dark oil, yield 90%, Rf = 0.83 (eluent diethyl ether/petroleum
ether, 1:1), IR: mmax (neat)/cmÀ1: 3080, 1758, 1415, 891; 1H NMR

3584
M. F. A. Adamo et al. / Tetrahedron Letters 50 (2009) 3580–3584
TBDMS
O
KF (1.1 equiv)
MeOH
N
HN
HN
R1
R1
R1
O
O
10
1
:
R1 = H trans-6
R1 = CH3 trans-11
R1 = H 22
R1 = CH3 25
R1 = H cis-6
R1 = CH3 cis-11
Scheme 2.
54.3; HRMS found: M+ 123.0689, C7H9NO requires 123.0684, m/z:
Acknowledgements
123 (100%, M+).
We acknowledge the PTRLI cycle III for a grant to MFAA, IRCSET
and SFI RFP2006 for support to P.D. and L.P.
5.2. trans-3,4-Divinyl-azetidin-2-one 6
Brown oil, yield 9%, Rf = 0.44 (eluent: petroleum ether/ethyl
acetate, 1:1), IR: mmax (neat)/cmÀ1: 3239, 2930, 1765; 1H NMR
(400 MHz, CDCl3) dH 5.93–5.81 (2H, m), 5.25–5.14 (4H, m), 3.90–
3.88 (1H, m) 3.47 (1H, d, J = 6.4 Hz); 13C NMR (100.6 MHz) dC
168.3, 136.5, 130.7, 119.4, 117.4, 62.1, 56.8. HRMS found: M+
123.0679, C7H9NO requires 123.0684, m/z: 123 (100%, M+).
References and notes
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5.3. cis-3-Isopropenyl-4-vinyl-azetidin-2-one 11
Brown oil, yield 75%, Rf = 0.53 (eluent: petroleum ether/ethyl
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(400 MHz, CDCl3) dH 5.75 (1H, ddd, J = 17.2, 10.0, 7.6 Hz), 5.26
(1H, d, J = 17.2 Hz) 5.20 (1H, d, J = 10.0 Hz), 5.01 (1H, s), 4.96 (1H,
s), 4.21–4.18 (1H, m), 3.91 (1H, d, J = 5.6 Hz), 1.59 (3H, s); 13C
NMR (100.6 MHz) dC 168.4, 138.1, 136.9, 119.2; 115.1, 61.5, 54.5,
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15. Grela, K. Angew. Chem., Int. Ed. 2008, 47, 5504.
Brown oil, yield 8%, Rf = 0.47, (petroleum ether:,ethyl acetate
1:1), IR: mmax (neat)/cmÀ1: 3232, 2928, 1754; 1H NMR (400 MHz,
CDCl3) dH 5.97 (1H, ddd, J = 17.2, 10.4, 7.2 Hz), 5.34 (1H, d,
J = 17.2 Hz), 5.22 (1H, d, J = 10.4 Hz), 5.00 (1H, s) 4.96 (1H, s),
4.00 (1H, dd, J = 7.2, 2 Hz), 3.52 (1H, m, J = 2 Hz), 1.82 (3H, s); 13C
NMR (100.6 MHz) dC 168.2, 138.1, 137.0, 117.4; 114.1, 65.2, 55.7,
29.7. HRMS found: M+ 137.0846, C8H11NO requires 137.0841, m/
z: 137 (100%, M+).
16. Youcef, R. A.; Boucheron, C.; Guillarme, S.; Legoupy, S.; Dubreuil, D.; Huet, F.
Synthesis 2006, 633.