A versatile strategy for the solid-phase synthesis of penicillin derivatives: Efficient preparation of 2β-methyl substituted penams as β-lactamase inhibitor analogues

Article abstract of DOI:10.1055/s-2006-950214

A convenient solid-phase method for the synthesis of 2β-methyl substituted penicillins using commercially available resins is described. Functionalization of Merrifield and Wang resin bound penam derivatives was performed by penicillin sulfoxide rearrangement and the products were released from the supports under mild conditions. The utility of this methodology has been demonstrated by synthesizing a small library of penicillin derivatives in moderate to very good overall isolated yields for the multistep synthetic sequence. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950214

PAPER
3397
A Versatile Strategy for the Solid-Phase Synthesis of Penicillin Derivatives:
Efficient Preparation of 2b-Methyl Substituted Penams as b-Lactamase
Inhibitor Analogues
Solid-Phase
Synth
o
esis of
2
b
-M
r
ethyl Sub
a
stituted Penams B. Boggián, Ernesto G. Mata*
Instituto de Química Orgánica de Síntesis (CONICET - UNR), Facultad de Ciencias Bioquímicas y Farmacéuticas,
Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina
Fax +54(341)4370477; E-mail: mata@iquios.gov.ar
Received 12 May 2006; revised 19 June 2006
inhibitors active, not only against class A b-lactamases,
Abstract: A convenient solid-phase method for the synthesis of 2b-
methyl substituted penicillins using commercially available resins
is described. Functionalization of Merrifield and Wang resin bound
penam derivatives was performed by penicillin sulfoxide rearrange-
ment and the products were released from the supports under mild
conditions. The utility of this methodology has been demonstrated
by synthesizing a small library of penicillin derivatives in moderate
to very good overall isolated yields for the multistep synthetic se-
quence.
but also against class C enzymes.7
During the course of our efforts to develop new therapeu-
tic agents for bacterial diseases,7b,c,8 we became interested
in developing a solid-phase synthetic strategy suitable for
the generation of 2b-methyl substituted penicillin libraries
that could be used for screening new b-lactamase inhibitor
analogues. Though solid-phase organic synthesis (SPOS)
has been widely used for the preparation of a large number
of structurally diverse small organic molecules for combi-
natorial libraries,9 its application to properly functional-
ized bicyclic b-lactams is still to be fully developed.10 In
this paper, we present the results from an extensive study
on the attachment of penicillins to two different polysty-
rene resins and their subsequent functionalization on these
solid supports.11 This work has led to the development of
a convenient method for the synthesis of biologically rel-
evant penicillin derivatives.12
Key words: solid-phase synthesis, combinatorial chemistry, peni-
cillins, rearrangement, sulfoxides
Many decades after their discovery, penicillins and related
b-lactam compounds remain the most commonly pre-
scribed antimicrobials.1 However, the rapid evolution of
bacterial resistance is a cause of major concern in the in-
fectious disease area.2 The most common form of bacteri-
al resistance to b-lactam antibiotics is the production of b-
lactamase enzymes,3 which efficiently hydrolyze the
amide bond of the b-lactam ring to give products that are
devoid of antibacterial activity. b-Lactamases can be
grouped into four classes, based on primary sequence ho-
mology: classes A, C and D are serine enzymes, while
class B are zinc metalloenzymes. Successful treatment of
resistant bacteria can often be effected by the co-adminis-
tration of an antibiotic and a b-lactamase inhibitor.4 The
problem of increasing bacterial resistance against the
standard therapy has stimulated further research into b-
lactam chemistry, which has focused on two major areas:
a) the synthesis of compounds stable to b-lactamase, that
possess both high potency and a broad spectrum of activ-
ity both in vitro and in vivo; b) synthesis of new and more
efficient inhibitors of both metallo- and serine-b-lacta-
mases.
O
O
N
S
N
N
N
O
CO2H
1
Figure 1
Merrifield (3) and Wang (4) resins were selected as poly-
mer supports for the immobilization of penicillins
(Scheme 1) and it was found that both could be used to
tether the 6,6-dibromopenicillanic acid (2) starting mate-
rial. The former could be coupled using potassium fluo-
ride in DMF, to give the Merrifield resin bound penicillin
5(M), whilst the latter reacted in the presence of DCC and
catalytic DMAP to give the corresponding Wang resin
bound compound [5(W)]. The progress of the reactions
were monitored by the change in absorption of the b-lac-
tam and ester carbonyl absorption moieties at 1780 and
1740 cm–1, respectively, by solid-phase FT-IR.13
Current commercial serine-b-lactamase inhibitors are
only useful against bacterial strains producing class A b-
lactamases. Among these inhibitors, tazobactam 15
(Figure 1), is the most active,6 and interest in 2b-substitut-
ed penam derivatives has been increasing considerably
since its discovery. In recent years, some of these deriva-
tives have emerged as a second generation of b-lactamase
In homogeneous phase reactions, penicillin sulfoxide re-
arrangement is the usual route to 2b-methyl substituted
penicillins. In order to develop a convenient methodology
for the synthesis of 2b-methyl substituted penicillins on
solid supports, we therefore investigated the solid-phase
oxidation of resin-bound penicillins 5(M) and 5(W). Us-
SYNTHESIS 2006, No. 20, pp 3397–3404
x
x.
x
x
.
2
0
0
6
Advanced online publication: 21.08.2006
DOI: 10.1055/s-2006-950214; Art ID: M03206SS
© Georg Thieme Verlag Stuttgart · New York

3398
D. B. Boggián, E. G. Mata
PAPER
ing a controlled excess of m-chloroperbenzoic acid MBT) to give the unsymmetrical disulfide 12 (Scheme 2),
(MCPBA) (1.4 equivalents, 20 hours, 0 °C), we found that which can be isolated and purified. Recyclization of 12 in
the corresponding sulfoxides 6(M) and 6(W) could, in- the presence of a halide source proceeds via the episulfo-
deed, be selectively obtained as the sole product. In con- nium halide B. This intermediate must be b-oriented, and
trast, when 5(M) was treated with a large excess of is formed by the addition of the sulfenyl halide (A) to the
MCPBA (5 equivalents, 96 hours, room temperature), sul- double bond. Finally, the episulfonium is opened by a nu-
fone 7(M) was obtained exclusively. No reaction was ob- cleophilic attack by the halide.16 In solution chemistry, a
served with other oxidizing systems such as Oxone/ major drawback of this rearrangement is the isolation of
acetone or KMnO4/AcOH. The oxidation reactions were the disulfide 12 which usually requires a series of at least
monitored by FT-IR and final characterization was two chromatographic purification steps in order to elimi-
achieved after detachment from the support.
nate by-products.
(O)n
S
Br
Br
M
O
S
Cl
S
N
X
X
S
S
Br
Br
H
S
3
SH
N
S
Y
Y
(e)
N
N
(a)
N
N
O
O
∆
C
CO2H
O
O
2
M
Z
– H2O
O
O
C
C
OR
OR
O
12
O
5(M) n = 0
6(M) n = 1
7(M) n = 2
(c)
11
W
OH
(d)
4
Z
(b)
X
Z
S
S
S
Y
Z
(O)n
S
(O)n
S
N
N
N
Br
Br
Br
O
(e) or (f)
Br
C
C
C
OR
O
OR
OR
O
O
N
N
B
A
13
O
O
C
C
W
OH
O
O
O
Scheme 2
n = 0
n = 1
n = 2
8
9
5(W) n = 0
6(W) n = 1
(c)
10
Treatment of the Wang resin bound sulfoxide 6(W) with
2-MBT in refluxing toluene, followed by addition of sul-
furyl chloride (Cl2SO2), cleavage from the resin with 10%
Scheme 1 Reagents and conditions: (a) 3, KF, DMF, 60 °C, 24 h;
(b) 4, DCC, DMAP (cat.), CH2Cl2–DMF, r.t., 4 h; (c) MCPBA (1.4
equiv), CH2Cl2, 0 °C, 20 h; (d) MCPBA (5 equiv), CH2Cl2, r.t., 96 h; TFA in dichloromethane, and esterification with diazo-
(e) AlCl3, CH2Cl2/MeNO2, 0 °C, 30 min; (f) 10% TFA in CH2Cl2, r.t.,
30 min.
methane (Scheme 3) gave a 1:1 mixture of the desired
O
Br
S
In the case of Wang resin bound penicillins, we found that
Br
10% trifluoroacetic acid (TFA) was sufficient to com-
N
pletely release the penicillin from the support; however,
O
C
W
hydrolysis of the product from the more acid-stable Mer-
rifield resin proved more problematic. Since the preferred
method for cleaving this linkage with anhydrous HF14
would be incompatible with the sensitive functional
groups such as the b-lactam ring, alternative, milder meth-
ods were investigated. It was found that the use of the
Lewis acid, aluminium chloride, resulted in the smooth re-
lease of the desired products from the solid support. Thus,
Merrifield resin bound penicillins 5(M), 6(M) and 7(M)
(Scheme 1) were treated with aluminum chloride in a
dichloromethane–nitromethane mixture15 to afford the
corresponding penicillanic acids 8, 9 and 10 in 98%, 96%
and 80% yields, respectively. Similar results were ob-
tained with the Wang resin bound penicillins 5(W) and
6(W), with penicillanic acids 8 and 9 obtained in 91% and
96% yields, respectively.
O
O
6(W)
(a)
S
N
S
C
Br
Br
S
N
S
S
Br
Br
S
+
N
N
O
O
C
W
Cl
W
O
O
O
O
15(W)
(b)
14(W)
Br
Br
S
N
S
S
Br
Br
S
+
N
N
O
O
C
C
OR
16(W) R =
17 R = Me
OR
O
O
W
W
R =
15(W)
(c)
(c)
In the proposed mechanism for the penicillin sulfoxide re-
arrangement to the 2b-halomethyl penam derivatives, the
sulfenic acid, formed by a thermal rearrangement of sul-
foxide 11, is trapped by 2-mercaptobenzothiazole (2-
18 R = Me
Scheme 3 Reagents and conditions: (a) 2-MBT (4 equiv), toluene,
reflux, 4 h; (b) Cl2SO2, CH2Cl2, –40 °C; (c) (i) 10% TFA in CH2Cl2,
r.t., 30 min; (ii) CH2N2, Et2O.
Synthesis 2006, No. 20, 3397–3404 © Thieme Stuttgart · New York

PAPER
Solid-Phase Synthesis of 2b-Methyl Substituted Penams
3399
O
O
Br
Br
S
S
Br
Br
Cl
Cl
(f)
S
N
N
O
O
O
Br
S
N
Br
(b)
S
C
C
S
Br
Br
(a)
OR
OR
O
O
W
M
M
21(M)R=
N
16(W) R=
N
(e)
O
O
(d)
C
C
22 R= Me
16(M) R=
OR
OR
O
O
(e)
Br
(c)
17 R= Me
W
W
M
6(W)
R=
14(W) R=
14(M) R=
O
O
S
Br
M
6(M) R=
S
Br
Br
Br
Br
(f)
N
N
O
O
C
C
OR
R=
OR
O
O
M
M
19(M) R=
23(M)
(e)
(e)
20 R= Me
24 R= Me
Scheme 4 Reagents and conditions: (a) 2-MBT (1.5 equiv.), benzene, reflux, 12 h; (b) Cl2SO2, CH2Cl2, –40 °C; (c) Br2, acetamide, CH2Cl2,
r.t.; (d) (i) 10% TFA in CH2Cl2, r.t., 30 min; (ii) CH2N2, Et2O; (e) (i) AlCl3, CH2Cl2/NO2Me, 0 °C, 30 min; (ii) CH2N2, Et2O; (f) MCPBA (12
equiv), CH2Cl2, r.t., 72 h.
product 17, and the 2b-(benzothiazo-2-yl)thiomethyl pen- (based on the loading of the Merrifield resin). In this way,
icillin 18 in a 25% overall yield. The 13C gel-phase NMR the 2b-methyl substituted penicillin was obtained, in high
spectrum17 of the resin before the addition of sulfuryl yield, avoiding the series of column chromatography pu-
chloride, showed the presence of the disulfide 14(W) to- rification steps that were required in the solution-phase
gether with the 2b-(heterocyclyl)thiomethyl derivative equivalent.
15(W).
The efficient synthesis of the disulfide 14(M) encouraged
This finding was totally unexpected considering previous us to synthesize the 2b-bromomethyl derivative (20).
reports of the reaction in the homogeneous phase.18 It can, Treatment of the disulfide 14(M) with bromine, in the
however, be rationalized by a premature release of 2- presence of acetamide, afforded the derivative 19(M)
MBT from the disulfide 14(W), leading to the formation which, after cleavage and esterification, led to 2b-bro-
of an episulfomiun ion similar to B (Scheme 2) which, in momethyl penicillin 20 in 50% overall isolated yield
turn, undergoes nucleophilic attack by the 2-MBT anion (based on loading of the Merrifield resin). Alternatively,
to give the 2b-methyl derivative 15(W).
oxidation of resin-bound sulfides 16(M) and 19(M) with
an excess of MCPBA, led exclusively to the sulfones
21(M) and 23(M), respectively.
We therefore carefully re-examined the reaction condi-
tions and found that the key points were temperature and
the number of 2-MBT equivalents used. The thermolysis
that produced compound 15(W) was avoided by heating
the reaction mixture in benzene at reflux with 1.5 equiva-
lents of 2-MBT. Under these conditions, disulfide 14(W)
was formed exclusively (Scheme 4). Thus, further treat-
ment with sulfuryl chloride in dichloromethane at –40 °C,
cleavage from the Wang resin and esterification with di-
azomethane, led to the 2b-chloromethyl penicillin 17, al-
beit in low yield, probably due to a premature detachment
from Wang resin.
Ph
Ph
O
O
Br
Br
S
S
Br
Br
S
(a)
N
N
N
O
O
C
C
OR
OR
O
O
M
M
25(M) R=
25(W) R=
6(M) R=
6(W) R=
(b)
W
W
(c)
26 R= Me
As the Merrifield resin is a more acid-stable support than
the Wang resin, we decided to apply the protocol de-
scribed above to this support (Scheme 4). Starting from
the 6,6-dibromopenicillanate sulfoxide tethered to Merri-
field resin [6(M)], treatment with 2-MBT under the opti-
mized conditions (1.5 equiv, benzene reflux), gave
exclusively the unsymmetrical disulfide 14(M), which
then underwent recyclization to 16(M) upon the addition
of sulfuryl chloride in dichloromethane at –40 °C.19 After
cleavage with AlCl3 and esterification with diazomethane,
the methyl 6,6-dibromo-2b-chloromethylpenicillanate
(17) was obtained in an overall isolated yield of 70%
Scheme 5 Reagents and conditions: (a) 4,5-diphenyl-2-oxazole-thi-
ol (4 equiv), p-TsOH (cat.), toluene, 90 °C, 4 h; (b) (i) AlCl3, CH2Cl2/
NO2Me, 0 °C, 30 min; (ii) CH2N2, Et2O; (c) (i) 10% TFA in CH2Cl2,
r.t., 30 min; (ii) CH2N2, Et2O.
The unexpected formation of 2b-(benzothiazo-2-yl)thi-
omethyl penicillin 18 (Scheme 3) during initial attempts
to obtain the 2b-halomethyl penam derivatives, led us to
investigate the solid-phase synthesis of 2b-(heterocy-
clyl)thiomethyl penicillins. Heterocyclic thio- structural
moieties have been found in a series of pharmaceutical
antibacterial compounds, particularly in b-lactams, with
Synthesis 2006, No. 20, 3397–3404 © Thieme Stuttgart · New York

3400
D. B. Boggián, E. G. Mata
PAPER
excellent activity against methicillin-resistant Staphylo- was conducted with excess of 4,5-diphenyl-2-oxazole-thi-
coccus aureus (MRSA),20 which is a bacteria resistant to ol (4 equiv) and catalytic amounts of p-toluenesulfonic
most of the antibiotics commercially available. We antic- acid in toluene (Scheme 5). The Merrifield resin bound
ipated that the use of a large excess of a heterocyclic thiol, penicillin derivative 25(M) was then cleaved and esteri-
combined with longer reaction times and the absence of a fied with diazomethane, to give the 2b-[(4,5-diphenyl-ox-
nucleophile, would yield such hetercyclic thio-penicillins. azol-2-yl)thio]methyl penam derivative (26) in 48%
However, it became apparent that the reaction did not go isolated yields after column chromatography (based on
to completion unless catalytic p-toluenesulfonic acid was initial loading of the Merrifield resin). The same reaction
also present. Therefore, the thermolysis of sulfoxide 6(M) sequence was carried out using Wang resin as the solid
Table 1 Solid-Phase Synthesis of Penicillin Derivatives
(O)n
S
(O)n
S
O
X
X
X
S
Y
Y
Y
Z
Z
N
N
N
O
O
O
C
C
C
O
O
OMe
O
O
O
Entry
Product
17
X
Y
n
0
0
2
2
0
Z
Yield (%)a
1
2
3
4
5
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Br
Cl
Br
70
20
50
22
37
24
34
26
48 (65)
O
Ph
Ph
S
N
O
6
7
8
9
27
18
28
29
Br
Br
Br
Br
Br
Br
Br
Br
0
0
0
0
49 (30)
52 (60)
44 (48)
55
S
S
N
S
N
S
OEt
S
N
Me
N
N
N
S
S
N
S
10
30
Br
Br
0
48
N
11
12
31
32
Cl
Cl
H
H
0
0
Cl
24
33 (46)
O
Ph
Ph
S
N
O
13
14
15
33
34
35
Cl
Cl
Cl
H
H
H
0
0
0
35
S
S
N
S
36 (39)
42 (44)
N
S
OEt
S
N
16
36
Br
H
0
Cl
25
a Overall isolated yields using Merrifield resin as support, after flash column chromatography of the corresponding methyl ester (based on the
initial loading level of the resin). Data in parentheses are isolated yields using Wang resin as support.
Synthesis 2006, No. 20, 3397–3404 © Thieme Stuttgart · New York

PAPER
Solid-Phase Synthesis of 2b-Methyl Substituted Penams
3401
vents: CH2Cl2, EtOAc, MeOH, and finally with CH2Cl2. The resin
6(M) was then dried in vacuo overnight. A portion of this resin (241
mg, 0.153 mmol) was swollen in benzene (5.9 mL) for 30 min, treat-
ed with 2-mercaptobenzothiazole (38 mg, 0.23 mmol, 1.5 equiv)
and the suspension was gently stirred at reflux for 12 h. Filtration,
washing (3 × 2.5 mL) each with CH2Cl2, EtOAc, DMF, MeOH, and
drying in vacuo overnight, afforded the resin intermediate 14(M). A
portion of resin-bound disulfide 14(M) (99 mg, 0.06 mmol) was
then swollen in CH2Cl2 (1.3 mL) for 30 min, cooled to –40 °C and
treated with sulfuryl chloride (9 mg, 0.067 mmol). The reaction
mixture was stirred for 1 h at the same temperature and then
quenched by adding NaHCO3 (5%, 2.5 mL). The resulting resin
16(M) was collected by filtration, washed with H2O (2.5 mL) and
then with MeOH, EtOAc, CH2Cl2 (3 × 2.5 mL each), and dried in
vacuo overnight. Merrifield resin bound penicillin 16(M) (75 mg,
0.475 mmol/g, theoretical load) was swollen in CH2Cl2 (1 mL) for
30 min at r.t.. After cooling to 0 °C, AlCl3 (25 mg, 0.187 mmol, 4
equiv) in NO2Me (0.45 mL) was added and the mixture stirred for
30 min at the same temperature. The resin was filtered and washed
with EtOAc (3 × 2 mL). The filtrate was transferred to a separating
funnel, washed with 0.5 N HCl (2 × 2.5 mL) and the aqueous layer
was extracted with EtOAc (3 mL). After drying and evaporation,
the combined extracts were treated with CH2N2 in Et2O to afford the
crude product that was then purified by flash column chromatogra-
phy (silica gel, EtOAc–hexane, 2:98) to give pure 17 as white crys-
tals (16 mg, 70% overall yield based on initial loading of the
Merrifield resin).
support. In this case, the 2b-[(4,5-diphenyl-oxazol-2-
yl)thio]methyl penicillin 26 was obtained in 65% isolated
yield, after release from the support with 10% TFA. No
detachment of the resin was detected by TLC during ther-
molysis.
By applying the optimized conditions, we developed an
efficient Merrifield and Wang resin based synthetic strat-
egy for the generation of a library, based on the penicillin
sulfoxide rearrangement. The results are summarized in
Table 1. A series of 2b-methyl substituted penam deriva-
tives were obtained with various substituents at positions
1, 6 and 2b-methyl, which are sulbactam21and tazobactam
analogues. Isolated yields, after flash column chromatog-
raphy, ranged from moderate to very good for the multi-
step synthetic sequence.22
In summary, we have demonstrated the feasibility of ap-
plying solid-phase synthesis to penicillin derivatives. The
attachment of penicillins onto commercially available res-
ins, such as Merrifield and Wang resins, was optimized.
We have also demonstrated the applicability of mild
cleavage conditions, such as AlCl3 and 10% trifluoroace-
tic acid, which are compatible with these sensitive mole-
cules. Finally, we have carried out the functionalization of
penam derivatives on solid-supports, leading to the devel-
opment of a convenient method for the synthesis of 2b-
methyl substituted penicillins using the commercially
available and cost-effective Merrifield and Wang resins.
This strategy is potentially very useful for the generation
of libraries of interesting compounds for biological
screening.
Mp 135 °C.
IR (KBr): 1780 (b-lactam), 1752 (ester) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.54 (s, 3 H, Me-a), 3.58 (AB sys-
tem, J = 12 Hz, 1 H, CH2Cl), 3.67 (AB system, J = 12 Hz, 1 H,
CH2Cl), 3.82 (s, 3 H, Me ester), 5.09 (s, 1 H, 3-H), 5.85 (s, 1 H, 5-
H).
13C NMR (50 MHz, CDCl3): d = 21.08, 51.9, 52.61, 58.26, 64.12,
68.32, 80.03, 163.56, 166.57.
MS (DEI): m/z (%) = 409 (26), 407 (35), 405 (17) [M+], 295 (63),
293 (73), 291 (27), 218 (18), 172 (52), 59 (100).
HRMS (DEI): m/z [M+] calcd for C9H10Br2ClNO3S: 404.8437;
found: 404.8428.
Chemical reagents were purchased from commercial sources and
were used without further purification unless noted otherwise. Melt-
ing points were taken on a Ernst Leitz melting point apparatus and
are uncorrected. Infrared spectra (IR) were recorded on a Bruker
IFS25 or Shimadzu FT-IR 8101 spectrophotometers and only par-
1
Anal. Calcd for C9H10Br2ClNO3S: C, 26.53; H, 2.47; N, 3.44; Br,
39.22. Found: C, 26.63; H, 2.40; N, 3.35; Br, 39.36.
tial spectral data are listed. H NMR spectra were recorded on a
Bruker AC200 at 200 MHz in CDCl3 unless otherwise stated, in the
presence of TMS as the internal standard. 13C NMR spectra were re-
corded on the same apparatus at 50 MHz with CDCl3 as solvent and
reference (76.9 ppm), unless otherwise stated. Elemental analyses
were performed by Atlantic Microlab, Inc., Norcross, GA, U.S.A.
Mass spectra were performed at the University of California River-
side Mass Spectrometry Facility, using a Micromass VG7070EHF
Spectrometer and GC-MS analyses were carried out on a Hewlett
Packard 5898A apparatus.
Methyl 6,6-Dibromo-2b-(bromomethyl)-2a-methylpenam-3a-
carboxylate (20)
IR (film): 1790 (b-lactam), 1760 (ester) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.57 (s, 3 H, Me-a), 3.54 (AB sys-
tem, J = 11 Hz, 1 H, CH2Br), 3.62 (AB system, J = 11 Hz, 1 H,
CH2Br), 3.83 (s, 3 H, Me ester), 5.15 (s, 1 H, 3-H), 5.88 (s, 1 H, 5-
H).
13C NMR (50 MHz, CDCl3): d = 22.24, 41.4, 52.61, 58.30, 64.92,
Methyl 6,6-Dibromo-2b-(chloromethyl)-2a-methylpenam-3a-
carboxylate (17); Typical Procedure
67.87, 80.23, 163.59, 166.60.
MS (DEI): m/z (%) = 455 (15), 453 (45), 451 (41), 449 116) [M+],
341 (21), 339 (50), 337 (49), 335 (18), 192 (24), 172 (97), 112 (56),
59 (100).
HRMS (DEI): m/z [M+] calcd for C9H10Br3NO3S: 448.7931; found:
448.7925.
Merrifield resin (3) (1g, ~0.8 mmol/g) was first swollen in DMF (7
mL) for approximately 30 min. In sequential order, 6,6-dibro-
mopenicillanic acid (2) (0.431 g, 1.2 mmol) in DMF (1 mL) and KF
(0.14 g, 1.4 mmol) were added to the reaction vessel at r.t. under an
argon atmosphere. The reaction was stirred at 60 °C for 24 h and
then filtered, washed with EtOH (3 × 4 mL), H2O (3 × 4 mL),
MeOH (3 × 4 mL) and CH2Cl2 (3 × 4 mL), and finally dried in vacuo
to give the Merrifield resin bound 6,6-dibromopenicillin 5(M). An
aliquot of 5(M) (478 mg, 0.62 mmol/g) was swollen by gentle stir-
ring in CH2Cl2 (5 mL) for 30 min. m-Chloroperbenzoic acid (66 mg,
0.379 mmol) in CH2Cl2 (1.5 mL) was added at 0 °C and the reaction
mixture was stirred overnight at the same temperature. After filtra-
tion, the resin was washed (3 × 3 mL) with each of the following sol-
Methyl 6a-Chloro-2b-(chloromethyl)-2a-methylpenam-3a-car-
boxylate (31)
Mp 112 °C.
IR (KBr): 1790 (b-lactam), 1748 (ester) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.55 (s, 3 H, Me-a), 3.48 (AB sys-
tem, J = 12 Hz, 1 H, CH2Cl), 3.62 (AB system, J = 12 Hz, 1 H,
Synthesis 2006, No. 20, 3397–3404 © Thieme Stuttgart · New York

3402
D. B. Boggián, E. G. Mata
PAPER
CH2Cl), 3.81 (s, 3 H, Me ester), 4.75 (d, J = 1.1 Hz, 1 H, 6-H), 5.07
(s, 1 H, 3-H), 5.41 (d, J = 1.1 Hz, 1 H, 5-H).
13C NMR (50 MHz, CDCl3): d = 21.02, 52.51, 63.78, 64.18, 68.57,
70.77, 165.47, 166.86.
1H NMR (200 MHz, CDCl3): d = 1.58 (s, 3 H, Me-a), 3.85 (s, 3 H,
Me ester), 3.86 (AB system, J = 12 Hz, 1 H, CH2Cl), 4.05 (AB sys-
tem, J = 12 Hz, 1 H, CH2Cl), 4.77 (s, 1 H, 3-H), 5.06 (s, 1 H, 5-H).
13C NMR (50 MHz, CDCl3): d = 15.75, 44.36, 44.91, 53.50, 60.54,
67.59, 74.99, 163.18, 165.39.
MS (DEI): m/z (%) = 285 (21), 283 (30) [M+], 210 (36), 208 (100),
169 (70), 59 (46).
HRMS (DEI): m/z [M+] calcd for C9H11Cl2NO3S: 282.9837; found:
282.9836.
MS (DCI/NH3): m/z (%) = 461 (18), 459 (77), 457 (100), 455 (42)
[M + NH4 ], 379 (14.8), 262 (11.7), 260 (13.4), 113 (26).
+
+
HRMS (DCI/NH3): m/z [M + NH4 ] calcd for C9H14Br2ClN2O5S:
454.8679; found: 454.8689.
Anal. Calcd for C9H11Cl2NO3S: C, 38.04; H, 3.90; N, 4.93; Cl,
24.95. Found: C, 37.80; H, 3.89; N, 4.84; Cl, 25.15.
Merrifield Resin Supported Synthesis of Methyl 6,6-Dibromo-
2b-{[(4,5-diphenyl-oxazol-2-yl)thio]methyl}-2a-methylpenam-
3a-carboxylate (26); Typical Procedure
Methyl 6a-Bromo-2b-(chloromethyl)-2a-methylpenam-3a-car-
boxylate (36)
Merrifield resin bound 6,6-dibromo penicillin sulfoxide 6(M) (210
mg, 0.132 mmol) was swollen in toluene (3 mL) at r.t. for 30 min.
4,5-Diphenyl-2-oxazole-thiol (134 mg, 0.53 mmol, 4 equiv) and
catalytic p-TsOH, were successively added to the suspension and
the mixture was heated at 95 °C for 4 h. The resin was thoroughly
washed with CH2Cl2, AcOEt, DMF, MeOH, and dried in vacuo
overnight. Merrifield resin bound 2b-[(4,5-diphenyl-oxazol-2-
yl)thio]methyl penicillin [25(M)] (198.8 mg, 0.53 mmol/g theoreti-
cal load) was then cleaved with AlCl3 as described for 16(M), fol-
lowed by esterification with CH2N2 to give the crude product that
was purified by column chromatography (silica gel, EtOAc–hex-
ane, 15:85) to give pure 26 as an oil (43 mg, 48% overall yield based
on initial loading of the Merrifield resin).
IR (film): 1790 (b-lactam), 1752 (ester) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.55 (s, 3 H, Me-a), 3.51 (AB sys-
tem, J = 11 Hz, 1 H, CH2Cl), 3.62 (AB system, J = 11 Hz, 1 H,
CH2Cl), 3.81 (s, 3 H, Me ester), 4.80 (d, J = 1.3 Hz, 1 H, 6-H), 5.08
(s, 1 H, 3-H), 5.48 (d, J = 1.3 Hz, 1 H, 5-H).
13C NMR (50 MHz, CDCl3): d = 21.06, 49.63, 52.47, 52.56, 64.43,
68.76, 70.05, 166.06, 166.85.
MS (DEI): m/z (%) = 329 (24), 327 (23) [M+], 217 (20), 215 (84),
213 (58), 210 (40), 208 (100), 112 (43), 59 (76).
HRMS (DEI): m/z [M+] calcd for C9H11BrClNO3S: 326.9332;
found: 326.9344.
IR (film): 1798 (b-lactam), 1747 (ester) cm–1.
Methyl 6,6-Dibromo-2b-(bromomethyl)-2a-methylpenam-3a-
carboxylate 1,1-Dioxide (24); Typical Procedure
1H NMR (200 MHz, CDCl3): d = 1.58 (s, 3 H, Me-a), 3.68 (AB sys-
tem, J = 14 Hz, 1 H, CH2S-Het), 3.78 (AB system, J = 14 Hz, 1 H,
CH2S-Het), 3.81 (s, 3 H, Me ester), 4.95 (s, 1 H, 3-H), 5.85 (s, 1 H,
5-H), 7.33–7.66 (m, 10 H, Ar).
13C NMR (50 MHz, CDCl3): d = 22.32, 45.59, 52.59, 58.45, 66.55,
69.23, 80.29, 126.28, 127.71, 128.22, 128.43, 128.55, 131.64,
136.28, 147.63, 157.41, 163.71, 166.51.
MS (FAB): m/z (%) = 627 (20.8), 625 (48.5), 623 (22.8) [MH+], 307
(20), 289 (15), 254 (52.4), 154 (100) [matrix].
HRMS–FAB: m/z [M + H+] calcd for C24H21Br2N2O4S2: 622.9309;
found: 622.9300.
Merrifield resin bound 6,6-dibromo-2b-bromomethyl penicillin
19(M) (0.224 g, 0.606 mmol/g, theoretical load) was swollen in
CH2Cl2 (5 mL) for 30 min. To this slurry, MCPBA (0.281 g, 1.63
mmol, 12 equiv) was added and the mixture was stirred at r.t. for 72
h. The resin was then filtered, washed with MeOH (3 mL) and
CH2Cl2 (3 mL) (this sequence of washing is repeated three times),
and dried in vacuo. Merrifield resin bound penicillin sulfone 23(M)
(150 mg, 0.593 mmol/g, theoretical load) was swollen in CH2Cl2 (3
mL) for at r.t. 30 min. After cooling to 0 °C, AlCl3 (48 mg, 0.359
mmol, 4 equiv) in NO2Me (1.4 mL) was added and the mixture
stirred for 30 min at the same temperature. The resin was filtered
and washed with EtOAc (3 × 4 mL). The filtrate was transferred to
a separating funnel, washed with 0.5N HCl (2 × 5 mL) and the aque-
ous layers extracted with EtOAc (5 mL). After drying and evapora-
tion, the combined extracts were treated with CH2N2 in Et2O to
afford the crude product that was then purified by flash column
chromatography (silica gel, EtOAc–hexane, 10:90) to give pure 24
(14.5 mg, 34% overall yield based on initial loading of the Merri-
field resin).
Wang Resin Supported Synthesis of Methyl 6,6-Dibromo-2b-
{[(4,5-diphenyl-oxazol-2-yl)thio]methyl}-2a-methylpenam-3a-
carboxylate (26); Typical Procedure
Wang resin (6) (1.643 g, 0.96 mmol/g) was suspended in a mixture
of CH2Cl2–DMF (1:1, 24 mL) and stirred with 6,6-dibromopenicil-
lanic acid (2a) (1.5 g, 4.178 mmol), DCC (1.55g, 7.5 mmol) and cat-
alytic DMAP for 4 h. The reaction mixture was then filtered,
washed with CH2Cl2 (3 × 6 mL), DMF (3 × 6 mL) and MeOH (3 ×
6 mL), and dried in vacuo to give the Wang resin bound 6,6-dibro-
mopenicillin 5(W). An aliquot of 5(W) (478 mg, 0.62 mmol/g) was
swollen by gentle stirring in CH2Cl2 (5 mL) for 30 min and MCPBA
(66 mg, 0.379 mmol) in CH2Cl2 (1.5 mL) was added at 0 °C. The
reaction mixture was stirred overnight at the same temperature. Af-
ter filtration, the resin was washed with CH2Cl2 (3 × 3 mL), DMF
(3 × 3 mL) and MeOH (3 × 3 mL), and finally with CH2Cl2 (3 × 3
mL). The resin-bound sulfoxide 6(W) was then dried in vacuo over-
night. A portion of this resin (241 mg, 0.153 mmol) was swollen in
toluene (3 mL) at r.t. for 30 min. 4,5-Diphenyl-2-oxazole-thiol
(75.2 mg, 0.50 mmol, 4 equiv) and catalytic p-TsOH, were succes-
sively added to the suspension and the mixture was heated at 95 °C
for 4 h. The resin was thoroughly washed with CH2Cl2, AcOEt,
DMF, MeOH, and dried in vacuo overnight. Wang resin bound 2b-
[(4,5-diphenyl-oxazol-2-yl)thio]methyl penicillin [25(W)] (198.8
mg, 0.53 mmol/g theoretical load) was then treated with 10% TFA
in CH2Cl2 (6 mL) for 50 min. The mixture was filtered, washed with
CH2Cl2 (2 × 4 mL) and the filtrate evaporated under reduced pres-
IR (film): 1815 (b-lactam), 1757 (ester) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.59 (s, 3 H, Me-a), 3.70 (AB sys-
tem, J = 11.5 Hz, 1 H, CH2Br), 3.87 (AB system, J = 11.5 Hz, 1 H,
CH2Br), 3.87 (s, 3 H, Me ester), 4.85 (s, 1 H, 3-H), 5.08 (s, 1 H, 5-
H).
13C NMR (50 MHz, CDCl3): d = 16.87, 31.71, 45.25, 53.48, 61.29,
67.12, 75.31, 163.13, 165.40.
MS (DCI/NH3): m/z (%) = 505 (37), 503 (100), 501 (99.6), 499 (35)
+
[M + NH4 ], 425 (11), 423 (22), 421 (12), 340 (35), 262 (42), 260
(40), 113 (73).
+
HRMS (DCI/NH3): m/z [M + NH4 ] calcd for C9H14Br3N2O5S:
498.8174; found: 498,8156.
Methyl 6,6-Dibromo-2b-(chloromethyl)-2a-methylpenam-3a-
carboxylate 1,1-Dioxide (22)
IR (film): 1805 (b-lactam), 1750 (ester) cm–1.
Synthesis 2006, No. 20, 3397–3404 © Thieme Stuttgart · New York

PAPER
Solid-Phase Synthesis of 2b-Methyl Substituted Penams
3403
sure. Esterification of the residue with CH2N2 afforded pure 26 as
an oil (26.3 mg, 65% overall yield based on initial loading of Wang
resin).
459 (22), 410 (27), 408 (25), 294 (35.5), 292 (38.6), 214 (70), 117
(100).
HRMS (DCI/NH3): m/z calcd for C11H14Br2N5O3S2: 485.8905;
found: 485.8904.
Methyl 6,6-Dibromo-2b-{[(benzoxazol-2-yl)thio]}methyl-2a-
methylpenam-3a-carboxylate (27)
Anal. Calcd for C11H14Br2N5O3S2: C, 27.12; H, 2.69; N, 14.37; Br,
32.80. Found: C, 27.62; H, 2.71; N, 14.08; Br, 32.84.
IR (film): 1785 (b-lactam), 1748 (ester) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.56 (s, 3 H, Me-a), 3.71 (AB sys-
tem, J = 14 Hz, 1 H, CH2S-Het), 3.82 (s, 3 H, Me ester), 3.91 (AB
system, J = 14 Hz, 1 H, CH2S-Het), 4.91 (s, 1 H, 3-H), 5.86 (s, 1 H,
5-H), 7.25–7.62 (m, 4 H, Ar).
13C NMR (50 MHz, CDCl3): d = 22.26, 45.18, 52.63, 58.50, 66.79,
69.20, 80.44, 109.97, 118.52, 124.19, 124.42, 141.42, 152.01,
163.35, 163.63, 166.46, 166.57.
MS (DCI/NH3): m/z (%) = 525 (49), 523 (100), 521 (46) [M + H]+,
445 (11), 433 (10.3), 399 (13), 152 (60).
HRMS (DCI/NH3): m/z [M + H]+ calcd. for C16H15Br2N2O4S2:
520.8840; found: 520.8840.
Methyl 6,6-Dibromo-2b-{[(4,5-dihydrothiazol-2-yl)thio]meth-
yl}-2a-methylpenam-3a-carboxylate (30)
IR (film): 1785 (b-lactam), 1740 (ester) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.49 (s, 3 H, Me-a), 3.42 (t, 1 H,
CH2), 3.47 (AB system, J = 14 Hz, 1 H, CH2S-Het), 3.78 (AB sys-
tem, J = 14 Hz, 1 H, CH2S-Het), 3.80 (s, 3 H, Me ester), 4.18 (t,
1 H, CH2), 4.84 (s, 1 H, 3-H), 5.81 (s, 1 H, 5-H).
13C NMR (50 MHz, CDCl3): d = 22.31, 35.93, 44.75, 52.55, 58.61,
63.57, 66.56, 69.19, 80.26, 163.41, 164.19, 166.67.
MS (DCI/NH3): m/z (%) = 493 (58), 491 (100), 489 (43.6) [M + H]+,
413 (4.2), 411 (5), 120 (7.2).
HRMS (DCI/NH3): m/z [M + H]+ calcd for C12H15Br2N2O3S3:
488.8612; found: 488.8627.
Methyl 6,6-Dibromo-2b-{[(benzothiazol-2-yl)thio]methyl}-2a-
methylpenam-3a-carboxylate (18)
IR (film): 1789 (b-lactam), 1748 (ester) cm–1.
Methyl 6a-Chloro-2b-{[(4,5-diphenyloxazol-2-yl)thio]methyl}-
2a-methylpenam-3a-carboxylate (32)
1H NMR (200 MHz, CDCl3): d = 1.54 (s, 3 H, Me-a), 3.77 (AB sys-
tem, J = 14 Hz, 1 H, CH2S-Het), 3.80 (s, 3 H, Me ester), 4.04 (AB
system, J = 14 Hz, 1 H, CH2S-Het), 4.97 (s, 1 H, 3-H), 5.85 (s, 1 H,
5-H), 7.26–7.43 (m, 2 H, Ar), 7.75 (d, J = 9 Hz, 1 H, Ar), 7.89 (d,
J = 9 Hz, 1 H, Ar).
13C NMR (50 MHz, CDCl3): d = 22.49, 45.45, 52.6, 58.63, 66.71,
69.44, 80.37, 120.93, 121.67, 124.51, 126.08, 135.50, 152.51,
163.44, 164.78, 166.61.
MS (DCI/NH3): m/z (%) = 541 (57), 539 (100), 537 (45) [M + H]+,
461 (11), 459 (10.5), 168 (30.2).
HRMS (DCI/NH3): m/z [M + H]+ calcd for C16H15Br2N2O3S3:
536.8612; found: 536.8591.
IR (film): 1790 (b-lactam), 1747 (ester) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.56 (s, 3 H, Me-a), 3.54 (AB sys-
tem, J = 14 Hz, 1 H, CH2S-Het), 3.80 (s, 3 H, Me ester), 3.85 (AB
system, J = 14 Hz, 1 H, CH2S-Het), 4.88 (s, 1 H, 3-H), 4.98 (d,
J = 1.3 Hz, 1 H, 6-H), 5.34 (d, J = 1.3 Hz, 1 H, 5-H), 7.33–7.66 (m,
10 H, Ar).
13C NMR (50 MHz, CDCl3): d = 23.46, 46.62, 52.90, 63.55, 67.13,
69.86, 71.29, 126.73, 128.04, 128.66, 128.95, 128.99, 131.89,
136.52, 148.04, 158.22, 166.51, 167.32.
MS (DCI/NH3): m/z (%) = 503 (45), 501 (100) [M + H]+, 467 (5),
254 (69.3).
HRMS (DCI/NH3): m/z [M + H]+ calcd for C24H22ClN2O4S2:
501.0710; found: 501.0716.
Methyl 6,6-Dibromo-2b-{[(6-ethoxy-benzothiazol-2-
yl)thio]methyl}-2a-methylpenam-3a-carboxylate (28)
IR (film): 1798 (b-lactam), 1748 (ester) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.44 (t, J = 7 Hz, 3 H, Me), 1.54
(s, 3 H, Me-a), 3.74 (AB system, J = 14 Hz, 1 H, CH2S-Het), 3.80
(s, 3 H, Me ester), 3.96 (AB system, J = 14 Hz, 1 H, CH2S-Het),
4.06 (q, J = 7 Hz, 2 H, CH2), 4.97 (s, 1 H, 3-H), 5.83 (s, 1 H, 5-H),
6.95–7.21 (m, 2 H, Ar), 7.77 (d, J = 9 Hz, 1 H, Ar).
13C NMR (50 MHz, CDCl3): d = 14.68, 22.55, 45.88, 52.53, 58.62,
64.07, 66.68, 69.51, 80.38, 104.79, 115.44, 122.20, 136.91, 147.12,
156.60, 161.32, 163.44, 166.67.
MS (FAB): m/z (%) = 585 (30.6), 583 (68.4), 581 (26) [M + H]+,
543 (13), 518 (11), 212 (97.5), 211 (100), 147 (99.6).
Methyl 6a-Chloro-2b-{[(benzoxazol-2-yl)thio]}-2a-methyl-
penam-3a-carboxylate (33)
IR (film): 1790 (b-lactam), 1748 (ester) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.58 (s, 3 H, Me-a), 3.63 (AB sys-
tem, J = 14 Hz, 1 H, CH2S-Het), 3.81 (s, 3 H, Me ester), 3.89 (AB
system, J = 14 Hz, 1 H, CH2S-Het), 4.90 (s, 1 H, 3-H), 5.06 (d,
J = 1.3 Hz, 1 H, 6-H), 5.38 (d, J = 1.3 Hz, 1 H, 5-H), 7.25–7.62 (m,
4 H, Ar).
13C NMR (50 MHz, CDCl3): d = 23.08, 45.82, 52.49, 63.23, 66.75,
69.33, 71.02, 109.97, 118.47, 124.22, 124.48, 141.30, 152.09,
163.50, 165.78, 166.85.
HRMS (FAB): m/z [M + H]+ calcd for C18H19Br2N2O4S3: 580.8874;
found: 580.8894.
MS (DCI/NH3): m/z (%): 401 (40.7), 399 (100) [M + H]+, 250
(17.6), 248 (46.2), 214 (15), 172 (22), 152 (92.5).
HRMS (DCI/NH3): m/z [M + H]+ calcd for C16H16ClN2O4S2:
399.0240; found: 399.0235.
Methyl 6,6-Dibromo-2b-{[(1-methyl-1H-tetrazol-5-
yl)thio]methyl}-2a-methylpenam-3a-carboxylate (29)
Mp 168 °C.
IR (KBr): 1780 (b-lactam), 1740 (ester) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.55 (s, 3 H, Me-a), 3.77 (AB sys-
tem, J = 14 Hz, 1H, CH2S-Het), 3.83 (s, 3 H, Me ester), 3.91 (AB
system, J = 14 Hz, 1 H, CH2S-Het), 3.95 (s, 3 H, Me), 4.85 (s, 1 H,
3-H), 5.85 (s, 1 H, 5-H).
Methyl 6a-Chloro-2b-{[(benzothiazol-2-yl)thio]methyl}-2a-
methylpenam-3a-carboxylate (34)
IR (film): 1790 (b-lactam), 1748 (ester) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.56 (s, 3 H, Me-a), 3.66 (d, AB
system, J = 14 Hz, 1 H, CH2S-Het), 3.80 (s, 3 H, Me ester), 4.05 (d,
AB system, J = 14 Hz, 1 H, CH2S-Het), 4.91 (s, 1 H, 3-H), 5.05 (d,
J = 1.4 Hz, 1 H, 6-H), 5.36 (d, J = 1.4 Hz, 1 H, 5-H), 7.26–7.47 (m,
2 H, Ar), 7.73–7.91 (m, 2 H, Ar).
13C NMR (50 MHz, CDCl3): d = 22.58, 33.45, 46.15, 52.71, 58.05,
66.71, 69.36, 80.32, 153.38, 163.67, 166.27.
MS (DCI/NH3): m/z (%) = 490 (20), 488 (34), 486 (14) [M + H]+,
13C NMR (50 MHz, CDCl3): d = 23.25, 45.94, 52.46, 63.37, 66.98,
Synthesis 2006, No. 20, 3397–3404 © Thieme Stuttgart · New York

3404
D. B. Boggián, E. G. Mata
PAPER
Nidamarthy, D. Bioorg. Med. Chem. Lett. 1999, 9, 1997.
(g) Phillips, O. A.; Reddy, A. V. N.; Setti, E. L.; Spevak, P.;
Czajkowski, D. P.; Atwal, H.; Salama, S.; Micetich, R. G.;
Maiti, S. N. Bioorg. Med. Chem. 2005, 13, 2847.
(8) (a) Boschetti, C. E.; Mata, E. G.; Mascaretti, O. A.; Cricco,
J. A.; Coux, G.; Roveri, O. A. Bioorg. Med. Chem. Lett.
1995, 5, 2033. (b) Boschetti, C. E.; Mata, E. G.; Mascaretti,
O. A.; Cricco, J. A.; Coux, G.; Lodeyro, A.; Roveri, O. A. J.
Braz. Chem. Soc. 1996, 7, 285.
(9) (a) Seneci, P. Solid-Phase Synthesis and Combinatorial
Technologies; Wiley: New York, 2000. (b) Obrecht, D.;
Villalgordo, J. M. Solid-Supported Combinatorial and
Parallel Synthesis of Small-Molecular-Weight Compound
Libraries; Elsevier Science Ltd.: New York, 1998.
(c) Solid-Phase Organic Synthesis; Burgess, K., Ed.; Wiley:
New York, 2000. (d) Solid-Phase Organic Synthesis;
Czarnik, A. W., Ed.; Wiley: New York, 2001. (e) Dörwald,
F. Z. Organic Synthesis on Solid Phase: Supports, Linkers,
Reactions; Wiley-VCH: Weinheim, 2002, 2nd Ed.
(10) For reviews on solid-phase synthesis of b-lactams, see:
(a) Mata, E. G. Curr. Pharm. Design 1999, 5, 955.
(b) Laborde, M. A.; Mata, E. G. Mini-Rev. Med. Chem.
2006, 6, 107.
69.69, 70.96, 121.05, 121.51, 124.58, 126.22, 135.56, 152.33,
165.09, 165.88, 166.99.
MS (DCI/NH3): m/z (%): 417 (32), 415 (88) [M + H]+, 250 (12), 248
(16.7), 214 (16.4), 168 (100).
HRMS (DCI/NH3): m/z calcd for C16H16ClN2O3S3: 415.0012;
found: 415.0020.
Methyl 6a-Chloro-2b-{[(6-ethoxy-benzothiazol-2-yl)thio]meth-
yl}-2a-methylpenam-3a-carboxylate (35)
IR (film): 1790 (b-lactam), 1748 (ester) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.43 (t, J = 7 Hz, 3 H, Me), 1.54
(s, 3 H, Me-a), 3.60 (AB system, J = 14 Hz, 1 H, CH2S-Het), 3.79
(s, 3 H, Me ester), 4.00 (AB system, J = 14 Hz, 1 H, CH2S-Het),
4.06 (q, J = 7 Hz, 2 H, CH2), 4.90 (s, 1 H, 3-H), 5.02 (d, J = 1.4 Hz,
1 H, 6-H), 5.34 (d, J = 1.4 Hz, 1 H, 5-H), 6.98–7.22 (m, 2 H, Ar),
7.74 (d, J = 9 Hz, 1 H, Ar).
13C NMR (50 MHz, CDCl3): d = 14.77, 23.30, 46.30, 52.52, 63.44,
64.18, 67.02, 69.80, 71.01, 105.05, 115.56, 122.05, 136.97, 156.71,
165.95, 167.10.
MS (DCI/NH3): m/z (%) = 461 (32.7), 459 (52.6) [M + H]+, 250
(13), 214 (19), 212 (100).
(11) For solid-phase synthesis of 3,4-disubstituted b-lactams,
see: (a) Delpiccolo, C. M. L.; Mata, E. G. Tetrahedron:
Asymmetry 2002, 13, 905. (b) Delpiccolo, C. M. L.; Fraga,
M. A.; Mata, E. G. J. Comb. Chem. 2003, 5, 208.
(c) Delpiccolo, C. M. L.; Mata, E. G. Tetrahedron Lett.
2004, 45, 4085. (d) Delpiccolo, C. M. L.; Méndez, L.; Fraga,
M. A.; Mata, E. G. J. Comb. Chem. 2005, 7, 331.
(12) For a short publication of part of this work, see: Delpiccolo,
C. M. L.; Mata, E. G. Tetrahedron: Asymmetry 1999, 10,
3893.
HRMS (DCI/NH3): m/z calcd for C18H20ClN2O4S3: 459.0274;
found: 459.0270.
Acknowledgment
Financial support from Consejo Nacional de Investigaciones
Científicas y Técnicas (CONICET), Argentina; Agencia Nacional
de Promoción Científica y Tecnológica (Argentina); Fundación
Antorchas (Argentina), Universidad Nacional de Rosario (Argenti-
na) and Royal Society of Chemistry (U.K.) is gratefully acknowled-
ged.
(13) Beebe, X.; Schore, N. E.; Kurth, M. J. J. Org. Chem. 1995,
60, 4196.
(14) Stewart, J. M.; Young, J. D. Solid Phase Peptide Synthesis;
Pierce Chemical Company: Rockford, 1984, 38.
References
(15) (a) Mata, E. G. Tetrahedron Lett. 1997, 38, 6335. (b) Ma,
S.; Duan, D.; Shi, Z. Org. Lett. 2000, 2, 1419. (c) Cironi,
P.; Manzanares, I.; Albericio, F.; Alvarez, M. Org. Lett.
2003, 5, 2959. (d) Marfil, M.; Albericio, F.; Alvarez, M.
Tetrahedron 2004, 60, 8659. (e) Cironi, P.; Cuevas, C.;
Albericio, F.; Alvarez, M. Tetrahedron 2004, 60, 8669.
(f) Olsen, C. A.; Parera, N.; Albericio, F.; Alvarez, M.
Tetrahedron Lett. 2005, 46, 2041.
(16) Kamiya, T.; Tevaji, T.; Hashimoto, M.; Nakaguchi, O.; Oku,
T. Tetrahedron Lett. 1973, 3001.
(17) Giralt, E.; Rizo, J.; Pedroso, E. Tetrahedron 1984, 40, 4141.
(18) Formation of these 2b-(heterocyclyl)thiomethyl derivatives
had not been previously reported in solution chemistry under
similar conditions, see: Gottstein, W. J.; Haynes, U. J.;
McGregor, D. N. J. Med. Chem. 1985, 28, 518.
(1) Kidwai, M.; Sapra, P.; Bhushan, K. R. Curr. Med. Chem.
1999, 6, 195.
(2) (a) Neu, H. C. Science 1992, 257, 1064. (b) Davies, J.
Science 1994, 264, 375.
(3) Bush, K. Curr. Pharm. Des. 1999, 5, 839.
(4) (a) Mascaretti, O. A.; Boschetti, C. E.; Danelon, G. O.; Mata,
E. G.; Roveri, O. A. Curr. Med. Chem. 1995, 1, 441.
(b) Mascaretti, O. A.; Danelon, G. O.; Setti, E. L.; Laborde,
M.; Mata, E. G. Curr. Pharm. Des. 1999, 5, 939. (c) Maiti,
S. N.; Phillips, O. A.; Micetich, R. G.; Livermore, D. M.
Curr. Med. Chem. 1998, 5, 441.
(5) Micetich, R. G.; Maiti, S. N.; Spevak, P.; Hall, T. W.;
Yamabe, S.; Ishida, N.; Tanaka, M.; Yamazaki, T.; Nakai,
A.; Ogawa, K. J. Med. Chem. 1987, 30, 1469.
(6) Iman, Z.; Nyda, K.; Avi, Y. Int. J. Pharm. 1997, 153, 115.
(7) For reports on biologically active 2b-substituted penam
derivatives, see: (a) Richter, H. G. F.; Angehrn, P.;
Hubschwerlen, C.; Kania, M.; Page, M. G. P.; Specklin, J.-
L.; Winkler, F. K. J. Med. Chem. 1996, 39, 3712.
(b) Danelon, G. O.; Mata, E. G.; Mascaretti, O. A.; Girardini,
J.; Marro, M.; Roveri, O. A. Bioorg. Med. Chem. Lett. 1995,
5, 2037. (c) Danelon, G. O.; Mascaretti, O. A.; Radice, M.;
Power, P.; Calcagno, M. L.; Mata, E. G.; Gutkind, G. J.
Antimicrob. Chemother. 1998, 41, 313. (d) Reddy, N. A. V.;
Setti, E. L.; Phillips, O. A.; Czajkowski, D. P.; Atwal, H.;
Atchison, K.; Micetich, R. G.; Maiti, S. N. J. Antibiot. 1997,
50, 276. (e) Czajkowski, D. P.; Reddy, A. V. N.; Setti, E. L.;
Phillips, O. A.; Micetich, R. G.; Kunugita, C.; Maiti, S. N.
Bioorg. Med. Chem. Lett. 1997, 7, 11. (f) Buynak, J. D.;
Rao, A. S.; Doppalapudi, V. R.; Adam, G.; Petersen, P. J.;
(19) Alpegiani, M.; Giudici, F.; Perrone, E.; Borghi, D.
Tetrahedron Lett. 1990, 31, 3509.
(20) (a) Hecker, S. C.; Cho, I.-S.; Glinka, T. W.; Zhang, Z. J.;
Prince, M. E.; Lee, V. J.; Christensen, B. G.; Boggs, A.;
Chamberland, S.; Malouin, F.; Parr, T. R.; Annamalai, T.;
Blais, J.; Bond, E. L.; Case, L.; Chan, C.; Crase, J.; Frith, R.;
Griffith, D.; Harford, L.; Liu, N.; Ludwikow, M.; Mathias,
K.; Rea, D.; Williams, R. J. Antibiot. 1998, 51, 722.
(b) Yamazaki, H.; Tsuchida, Y.; Satoh, H.; Kawashima, S.;
Hanaki, H.; Hiramatsu, K. J. Antibiot. 2000, 53, 546.
(21) Aswapokee, N.; Neu, H. C. J. Antibiot. 1978, 31, 123.
(22) Oxidation of resin-bound 2b-(heterocyclyl)thiomethyl
penicillins to the corresponding sulfones was not carried out;
however, this reaction is expected to be difficult to achieve
due to the presence of two or more sulfur atoms in the
molecule.
Synthesis 2006, No. 20, 3397–3404 © Thieme Stuttgart · New York