Synthesis of chiral spiropyrazoline-β-lactams and spirocyclopropyl- β-lactams from 6-alkylidenepenicillanates

Article abstract of DOI:10.1016/j.tet.2014.03.109

Chiral spiropyrazolinepenicillanates were obtained in a stereoselective fashion via 1,3-dipolar cycloaddition reactions of 6-alkylidenepenicillanates with diphenyldiazomethane, phenyldiazomethane, and diazomethane. Microwave-induced ring contraction of sp

Full text of DOI:10.1016/j.tet.2014.03.109

Tetrahedron 70 (2014) 3812e3821
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Synthesis of chiral spiropyrazoline-b-lactams and spirocyclopropyl-
b-lactams from 6-alkylidenepenicillanates
,
Bruna S. Santos a, Clara S.B. Gomes b, Teresa M.V.D. Pinho e Melo a
*
a Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
b
ꢀ
Centro de Química Estrutural, Departamento de Engenharia Química, Instituto Superior Tecnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral spiropyrazolinepenicillanates were obtained in a stereoselective fashion via 1,3-dipolar cycload-
dition reactions of 6-alkylidenepenicillanates with diphenyldiazomethane, phenyldiazomethane, and
Received 15 February 2014
Received in revised form 25 March 2014
Accepted 28 March 2014
diazomethane. Microwave-induced ring contraction of spiro-1-pyrazoline-
spirocyclopropylpenicillanates is also described.
b-lactams leading to chiral
Available online 12 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
6-Alkylidenepenicillanates
Spiropyrazolinepenicillanates
Spirocyclopropylpenicillanates
1,3-Dipolar cycloaddition
Ring contraction
Microwave-induced reactions
1. Introduction
microwave-induced nitrogen extrusion allowing the stereo-
selective synthesis of spirocyclopropyl-b
-lactams 5 (Scheme 1).3a
The
of a large class of antibiotics and also of several
hibitors.1 Spiro-
-lactams are also particularly interesting target
b
-lactam ring is the core structure of the biological activity
An alternative strategy to spiropyrazolinepenicillanates via 1,3-
b-lactamase in-
dipolar cycloaddition reactions of 6-alkylidenepenicillanates is
also known.4a,c Habich et al. described the reaction of 6-
€
b
molecules since some derivatives exhibit relevant biological prop-
erties, namely, cholesterol absorption inhibition, antibacterial ac-
alkylidenepenicillanates with diazomethane leading to spiro-2-
pyrazolinepenicillanates.4c On the other hand, diphenyldiazo-
methane reacted with 6-(1-benzyloxicarbonylmethylene)pen-
icillanates 6 to give spiro-1-pyrazolinepenicillanates 7, which
underwent thermally induced ring contraction to afford spi-
rocyclopropylpenicillanates 8 (Scheme 2).4a The synthesis of spi-
tivity, and antiviral activity.2 Therefore, the search for new spiro-
lactam derivatives is of great interest in medicinal chemistry.
b-
In the recent past, we have been interested in exploring the
reactivity of 6-diazopenicillanates and 6-alkylidenepenicillanates
as an approach to new spirocyclic penicillin analogues.3 In fact,
we reported the first examples of phosphane-catalyzed [3þ2] an-
nulation of allenoates to 6-alkylidenepenicillanates 1 leading to
rocyclopropylpenicillanates
via
rhodium-catalyzed
cyclopropanation of a 6-diazopenicillanate sulfone5b and via Cu(I)
catalyzed reaction of 6-bromopenicillanoyl magnesium bromide
chiral spirocyclopentenyl-b-lactams 2 having either two or three
with a,b
-unsaturated esters5a has also been reported.
consecutive stereogenic centers, including a quaternary chiral
center.3b The stereoselective 1,3-dipolar cycloaddition reactions of
6-diazopenicillanates was also explored.3a,4a,b Chiral spiro-2-
As part of our continuing investigations, this paper describes the
evaluation of the scope and selectivity of the 1,3-dipolar cycload-
dition of 6-alkylidenepenicillanates with diazo compounds as
a route to chiral spiropyrazolinepenicillanates, as well as the ster-
eoselective microwave-induced ring contraction of spiro-1-
pyrazolinepenicillanates to spirocyclopropylpenicillanates.
pyrazoline-
3H-pyrazole-
fashion, the major products resulting from the addition to the less
sterically hindered -side of the -lactam. Spiro-1-pyrazoline-
lactams obtained from the cycloaddition reaction of 6-
b
-lactams, spiro-1-pyrazoline-
b-lactams, and spiro-
b-lactams could be obtained in a stereoselective
a
b
b-
4
2. Results and discussion
diazopenicillanates 3 with N-substituted maleimides, undergo
6-(Z)-Alkylidenepenicillanates 1ae1d were obtained by the
Wittig reaction of the appropriate phosphorous ylide 9 with
* Corresponding author. E-mail address: tmelo@ci.uc.pt (T.M.V.D. Pinho e Melo).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.109

B.S. Santos et al. / Tetrahedron 70 (2014) 3812e3821
3813
Scheme 1. Synthesis of spiro-
b
-lactams from 6-alkylidenepenicillanates and 6-diazopenicillanates.3
Table 1
1,3-Dipolar cycloaddition reaction of diphenyldiazomethane with 6-
alkylidenepenicillanates 1a and 1b
Entry
b-Lactam 1
Reaction conditions
Isolated yield
1
2
3
1a
1a
1b
rt, 48 h
30 ꢀC, 24 h
30 ꢀC, 24 h
11a, 60%
11a, 75%
11b, 9%
Scheme 2. Synthesis of spirocyclopropylpenicillanates from 6-alkylidenepenicill
the same reaction at 30 ꢀC for 24 h, the yield was improved to 75%
(entry 2). The 2D NOESY spectrum (400 MHz) of chiral compound
anates.4a
11a showed cross peaks between H-40 and the
b-Me protons, but no
benzhydryl 6-oxopenicillanate (10), which was prepared by
correlation was observed between H-40 and H-5. The observed
stereoselectivity can be explained considering that the product
a known procedure (Scheme 3).3b,6,7
results from the addition to the less sterically hindered
a-side of the
R
O
b-lactam. On the other hand, the cycloaddition with less steric
hindrance allowed the selective synthesis of regioisomer 11a. This
result is in agreement with the previously reported cycloaddition of
O
O
O
DCM
- 55 ºC, 15 min
S
S
R
b
,
b
,
b
-trichloroethyl
icillanate with diphenyldiazomethane.4a
Diphenyldiazomethane also reacted
benzoylmethylene)penicillanate 1b to afford spiro-
6-(1-benzyloxycarbonylmethylene)pen-
N
N
42-66%
CO2CHPh2
PPh3
O
CO2CHPh2
with
6-(Z)-(1-
b-lactam 11b.
10
1a R = OMe
1b R = Ph
1c R = OtBu
1d R = Me
9a R = OMe
9b R = Ph
9c R = OtBu
9d R = Me
However, carrying out the reaction at 30 ꢀC for 24 h, the target
molecule could only be obtained in low yield (9%) (Table 1, entry 3).
Several attempts made to obtain compound 11b with higher yield
were unsuccessful.
Scheme 3. Synthesis of 6-(Z)-alkylidenepenicillanates 1.
The cycloaddition of 6-(Z)-(1-tert-butoxycarbonylmethylene)
penicillanate 1c with diphenyldiazomethane was stereoselective
but led to the formation of two products resulting from opposite
regiochemistries (Scheme 4). The reaction was carried out at 30 ꢀC
for 48 h producing chiral spiro-1-pyrazolinepenicillanate 11c (46%),
as the major product, together with spiro-b-lactam 12 (10%). Thus,
compound 12 was formed by isomerization of the initially formed
cycloadduct, regiosiomer of 11c, which could not be isolated under
Initially, we looked again into the cycloaddition of 6-(Z)-alkyli-
denepenicillanates with diphenyldiazomethane (Table 1). The 1,3-
dipolar cycloaddition of benzhydryl 6-(Z)-(1-methoxycarbonyl
methylene)penicillanate (1a) with diphenyldiazomethane at room
temperature for 48 h, gave the spiro-1-pyrazolinepenicillanate 11a
regio- and stereoselectively in 60% yield (entry 1). By carrying out

3814
B.S. Santos et al. / Tetrahedron 70 (2014) 3812e3821
mechanism involved in the cyclopropane formation is controversial
CO2t-Bu
H
N
N
since some reactions are stereospecific, some show high stereo-
selectivity and others are not selective. Thus, in some cases a con-
certed process has been suggested whereas in other cases a stepwise
cleavage of the 1-pyrazolines ring via biradical or zwitterionic in-
termediates followed by ring closure has been proposed.
Ph
Ph
S
N
CO2t-Bu
H
O
H
CO2CHPh2
11c 46%
S
Ph2CN2
+
We previously reported that spiro-1-pyrazoline-b-lactams ob-
tained from the cycloaddition reaction of 6-diazopenicillanates
DCM
30 ºC, 48 h
N
Ph
H
N
O
HN
N
S
CO2CHPh2
with N-substituted maleimides, undergo microwave-induced ring
1c
contraction to afford spirocyclopropyl-b
-lactams.3a In this case the
Ph
O
t-BuO2C
reaction was not stereospecific, which was rationalized considering
a stepwise mechanism via cleavage of the 1-pyrazoline ring leading
to an open-chain biradical followed by cyclopropane ring closure.
In contrast with these observations, the synthesis of spi-
rocyclopropylpenicillanates 13 was stereospecific, which is an in-
dication that a concerted mechanism must be involved in the
CO2CHPh2
12 10%
Scheme 4. 1,3-Dipolar cycloaddition reaction of diphenyldiazomethane with 6-
alkylidenepenicillanate 1c.
the reaction conditions. The structural assignment of compound 12
was made on the basis of 2D HMQC and HMBC spectra (400 MHz).
In the HMQC spectrum, no connectivity was observed for a proton
with the chemical shift of 6.30 ppm confirming that this proton is
attached to a nitrogen atom. This result indicates that the presence
of the bulky 1-tert-butoxycarbonyl group makes the addition of the
diphenyldiazomethane with the phenyl groups pointing away from
the thiazolidine ring less favorable.
elimination of nitrogen from the spiro-1-pyrazoline-b-lactams 11.
The reactivity of 6-alkylidenepenicillanates towards diazo-
methane was then explored (Scheme 5). Diazomethane reacted
with 1a at 0 ꢀC for 2 h to afforded
b
-lactams 14a and 15a resulting
from both regiochemistries, isolated as single stereoisomers in each
case, in 84% overall yield. Note that spiro- -lactam 14a results from
b
the conversion of the initially formed cycloadduct that could not be
isolated under these reaction conditions. The same behavior was
observed in the reaction of 6-alkylidenepenicillanate 1c with
Unfortunately, attempts to carry out the 1,3-dipolar cycloaddi-
tion of benzhydryl 6-(Z)-(1-acetylmethylene)penicillanate (1d)
with diphenyldiazomethane were unsuccessful.
diazomethane at 0 ꢀC for 30 min, which produced
b-lactams 14c
and 15b in 88% overall yield.
The microwave-induced reactivity of spiro-1-pyrazoline
penicillanates 11ae11c was explored (Table 2). The attempt to carry
out the nitrogen extrusion from compound 11a in toluene under
microwave irradiation at 80 ꢀC for 2 min did not lead to the target
molecule (entry 1). However, when the reaction was performed at
100 ꢀC for 2 min, spirocyclopropylpenicillanate 13a was obtained in
37% yield (entry 2). Increasing the reaction time to 4 min afforded
cyclopropane derivative 13a in 64% yield (entry 3). The target com-
pound could be obtained in 99% yield by carrying out the ring con-
traction reaction of 11a under microwave irradiation at 120 ꢀC for
2 min (entry 4). Performing this reaction at higher temperature, using
1,2,4-trichlorobenzene (1,2,4-TCB) as solvent, resulted in lower yield
(entries 5 and 6). The optimized reaction conditions were applied to
the synthesis of cyclopropane 13b in high yield via microwave-
Interestingly, the reaction of 1b with diazomethane at 0 ꢀC for
only 30 min was regio- and stereoselective, leading to the cyclo-
adduct 16 and the isomeric derivative 14b, in 85% overall yield
(Scheme 5). By carrying out the same reaction for 3 h,
was obtained as the only product in 68% yield (Scheme 5).
The structure of spiro- -lactam 16 was determined by X-ray
b-lactam 14b
b
crystallography (Fig. 1). This compound crystallized as colorless
needles in the monoclinic system within C2 space group, showing
one molecule per asymmetric unit. In the molecule, there are four
chiral centers, C3, C5, C6, and C30, with relative configuration S, R, R
and S, respectively. The hydrogen atoms bonded to carbons C3 and
C5 of the penicillanate moiety are placed on opposite faces of the
fused rings. All distances and angles are within the expected values
for similar compounds.9
induced nitrogen extrusion of spiro-b-lactam 11c (entry 7). It
should be noted that compounds 13 were isolated by simple evapo-
ration of the solvent, without need of further purification.
The reaction of 6-(Z)-alkylidenepenicillanate 1d with diazo-
methane gave chiral spiro-b-lactam 14d as the only product, in 97%
yield (Scheme 5). Compound 14d was isolated by simple evapora-
tion of the solvent, without need of further purification. The
structural assignment of 14d was made on the basis of 2D COSY,
HMQC, HMBC, and DEPT spectra (400 MHz). In the HMQC spec-
trum, no connectivity was observed for a proton with the chemical
shift of 6.43 ppm confirming that this proton is attached to a ni-
trogen atom. The COSY spectrum showed cross peaks between the
NH and H-50 protons. Finally, the DEPT spectrum confirmed that the
protons with the 4.06 ppm chemical shift are geminal, belonging to
the methylene group.
It is worth noting that the 1,3-dipolar cycloaddition reactions of
diazomethane with 6-(Z)-alkylidenepenicillanates bearing carboxyl-
ate groups in the double bond were not regiospecific, whereas with
the acetyl and benzoyl 6-alkylidenepenicillanate derivatives regio-
specificity was observed. The expected regioselectivity for the 1,3-
dipolar cycloaddition of diazomethane with electron-deficient al-
kenes is the one observed for compounds 1b and 1d, with the carbon
Table 2
Synthesis of spirocyclopropyl-
b
-lactams 13 via ring contraction of the corresponding
spiro-1-pyrazoline-b-lactam 11
Ph
H
RO2C
Ph
H
N
RO2C
S
N
N
S
MW, Δ
Ph
Ph
H
N
H
O
O
CO2CHPh2
CO2CHPh2
13a R = Me
13b R = t-Bu
11a R = Me
11c R = t-Bu
Entry
b
-Lactam 11
Reaction conditions
Isolated yield
1
2
3
4
5
6
7
11a
11a
11a
11a
11a
11a
11b
80 ꢀC, 2 min, Toluene
100 ꢀC, 2 min, Toluene
100 ꢀC, 4 min, Toluene
120 ꢀC, 2 min, Toluene
200 ꢀC, 2 min, 1,2,4-TCB
250 ꢀC, 2 min, 1,2,4-TCB
120 ꢀC, 2 min, Toluene
13a, 0%
13a, 37%
13a, 64%
13a, 99%
13a, 89%
13a, 74%
13b, 91%
end of the dipole becoming bonded to the b-carbon of the substituted
alkene.10 Thus, a combination of electronic and steric factors must be
considered to explain the outcome of the reactions of diazomethane
with b-lactams 1a and 1c. It is noteworthy that the regioselectivity of
The preparation of cyclopropanes via ring contraction of 1-
pyrazolines is
well-known method.8 The nature of the
the reaction of diphenyldiazomethane with 6-(Z)-alkylidenepeni-
cillanates is determined by steric factors. Nevertheless, all the 6-
a

B.S. Santos et al. / Tetrahedron 70 (2014) 3812e3821
3815
R
O
H
H
RO2C
N
CH2N2, Et2O
H
H
N
H
N
H
N
CH2N2, Et2O
0 ºC, 30 min
R = Me
N
N
N
S
S
S
S
0 ºC, 30 min - 2 h
N
N
R = OMe
N
RO2C
H
MeOC
O
R = Ot-Bu
O
O
O
CO2CHPh2
CO2CHPh2
CO2CHPh2
CO2CHPh2
14a R = Me 53%
14c R = t-Bu 36%
1a R = OMe
1b R = Ph
15a R = Me 31%
15b R = t-Bu 52%
14d 97%
1c R = Ot-Bu
1d R = Me
COPh
H
H
H
H
N
H
N
CH2N2, Et2O
0 ºC, 3 h
CH2N2, Et2O
0 ºC, 30 min
N
N
N
N
S
S
S
N
N
N
R = Ph
R = Ph
PhOC
PhOC
H
O
O
O
CO2CHPh2
14b 68%
CO2CHPh2
14b 25%
CO2CHPh2
16 60%
Scheme 5. 1,3-Dipolar cycloaddition reaction of diazomethane with 6-alkylidenepenicillanates 1aed.
It is known that under thermal conditions the elimination of ni-
trogen from 1-pyrazolines can lead to the formation of alkenes.8
Corbett also described that the thermolysis of spirocyclic carbape-
nems in toluene, prepared by the addition of diazomethane to 6-
ethylidene olivanic acids, produce isopropylidene derivatives in-
stead of spirocyclopropanes.11 We also observed that by carrying out
the microwave irradiation of spiro-1-pyrazolinepenicillanate 15b at
200 ꢀC for 2 min 6-alkylidenepenicillanate 18b was obtained in 29%
yield (Scheme 7). Interestingly, the same behavior was observed
when a solution of spiro-b-lactam 15a in 1,2,4-trichlorobenzene was
irradiated at 250 ꢀC for 2 min giving
b-lactam 18a in 19% yield.
CO2R
H
RO2C
H
MW
Δ, 2 min
N
N
Me
S
S
N
1,2,4-TCB
N
H
O
O
CO2CHPh2
CO2CHPh2
15a R = Me
15b R = t-Bu
18a R = Me
18b R = t-Bu 29% (Δ = 200 ºC)
19% (Δ = 250 ºC)
Scheme 7. Synthesis of
spiro-1-pyrazoline-
b
-lactams 18 via microwave irradiation of the corresponding
b
-lactam 15.
Fig. 1. ORTEP-3 diagram of spiropyrazolinepenicillanate 16, using 50% probability level
ellipsoids.
The reactivity of 6-alkylidenepenicillanates towards phenyl-
diazomethane was also studied (Table 3). Dipolar cycloaddition of
6-(methoxycarbonylmethylene)penicillanate 1a with phenyl-
diazomethane at 0 ꢀC for 30 min allowed the regio- and stereo-
alkylidenepenicillanates studied reacted with diazomethane in
a stereoselective fashion leading to products resulting from the ad-
dition to the less sterically hindered a-side of the b-lactam.
Several unsuccessful attempts were made in order to carry out
the microwave-induced nitrogen extrusion from compound 15a at
120, 140 or even at 160 ꢀC. However, spirocyclopropylpenicillanates
selective synthesis of chiral b-lactam 19a in 40% yield (entry 1).
When the reaction was performed with a longer reaction time the
same product was obtained in lower yield (entry 2). We observed
the same behavior for 6-(tert-butoxycarbonylmethylene)pen-
icillanate 1c in the reaction with phenyldiazomethane. Carrying out
17a and 17b could be obtained from spiro-b-lactams 15a and 16,
respectively, carrying out the microwave irradiation at 200 ꢀC for
2 min (Scheme 6).
the reaction at 0 ꢀC for 30 min gave
b
-lactam 19c in 52% yield (entry
6), whereas with a longer reaction time the yield was lower (entry
7). These results indicate that -lactams 19a and 19c are not very
stable under these reaction conditions.
The 1,3-dipolar cycloaddition
penicillanate 1b with phenyldiazomethane at 0 ꢀC for 30 min affor-
ded -lactam 19b (30%) together with the cycloadduct 20a isolated in
MeO2C
N
H
N
H
N
N
MeO2C
MW
b
S
S
2 min, 200 ºC
H
H
1,2,4-TCB
O
O
of
6-benzoylmethylene
CO2CHPh2
CO2CHPh2
17a 67%
15a
b
11% yield (entry 3). The structural assignment of compound 20a was
made on the basis of 2D NOESY, COSY, HMQC, and HMBC spectra
(400 MHz). The NOESY spectrum showed cross peaks between H-30
COPh
H
H
S
N
N
MW
PhOC
S
2 min, 200 ºC
1,2,4-TCB
H
N
N
and the b
-Me protons and between the H-50 and H-5 protons.
H
O
O
CO2CHPh2
CO2CHPh2
17b 30%
The molecular structure of compound 19b was unambiguously
established by X-ray crystallography (Fig. 2). This derivative crys-
tallized in the monoclinic system within P21 space group, as col-
orless plates. In the molecule present in the asymmetric unit, there
16
Scheme 6. Synthesis of spirocyclopropyl-
corresponding spiro-1-pyrazoline-
b
-lactams 17 via nitrogen extrusion of the
b
-lactam.

3816
B.S. Santos et al. / Tetrahedron 70 (2014) 3812e3821
Table 3
Phenyldiazomethane
penicillanate 1d at 0 ꢀC for 30 min, also giving two products,
lactam 19d and cycloadduct 20b in 77% overall yield (entry 8).
Spiro- -lactams 19b and 19d were obtained in higher yield when
reacted
with
6-acetylmethylene
1,3-Dipolar cycloaddition reaction of phenyldiazomethane with 6-alkylidene
penicillanates 1ae1d
b
-
R
O
b
H
the corresponding 6-alkylidenepenicillanate was allowed to react
with phenyldiazomethane for 4 h (entries 4 and 9). Furthermore, by
S
1a R = OMe
1b R = Ph
1c R = Ot-Bu
1d R = Me
N
increasing the reaction time to 6 h,
isolated as the only product (entries 5 and 10).
Finally, the quantitative synthesis
b-lactams 19b and 19d could be
O
CO2CHPh2
of
chiral
spi-
PhCHN2
Et2O
rocyclopropylpenicillanates 21a and 21b was also achieved under
microwave irradiation (120 ꢀC for 2 min) via the ring contraction
reaction of 20a and 20b, respectively (Scheme 8). These compounds
were isolated by removing the solvent, without need of further
purification. The structural assignment of compound 21b was made
on the basis of 2D NOESY, HMQC, and HMBC spectra (400 MHz).
From the HMBC spectrum, it was established that the carbon with
38.3 ppm chemical shift corresponds to C-10, since it shows corre-
lation with the COMe protons. On the other hand, the carbon with
37.8 ppm chemical shift corresponds to C-20 since it shows corre-
lation with the H-5 proton. Finally, the NOESY spectrum of the
compound showed cross peaks between H-20 and H-5.
ROC
N
N
Ph
Ph
H
H
N
H
N
N
S
S
N
H
H
O
ROC
H
O
CO2CHPh2
CO2CHPh2
20a R = Ph
20b R = Me
19a R = OMe
19b R = Ph
19c R = Ot-Bu
19d R = Me
Entry
b
-Lactam
Reaction conditions
Isolated yield (%)
19
20
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
1b
1c
1c
1d
1d
1d
0
0
0
0
0
0
0
0
0
0
ꢀC, 30 min
ꢀC, 1 h
40
34
30
35
45
52
33
65
71
67
d
d
11
0,9
d
d
d
12
7
ꢀC, 30 min
ꢀC, 4 h
Ph
ROC
N
N
Ph
H
N
H
N
ꢀC, 6 h
MW
120 ºC, 2 min
Toluene
ROC
S
S
ꢀC, 30 min
ꢀC, 1 h
H
O
H
H
H
O
ꢀC, 30 min
ꢀC, 4 h
CO2CHPh2
CO2CHPh2
20a R = Ph
20b R = Me
21a R = Ph 99%
21b R = Me 99%
10
ꢀC, 6 h
d
Scheme 8. Synthesis of spirocyclopropyl-b-lactams 21 via ring contraction of the
corresponding spiro-1-pyrazoline-b-lactams 20.
3. Conclusion
Spiro-1-pyrazolinepenicillanates were prepared regio- and ster-
eoselectively by the reaction of 6-(Z)-(1-methoxycarbonyl
methylene)- and 6-(Z)-(1-benzoylmethylene)penicillanates with
diphenyldiazomethane. However, starting from 6-(Z)-(1-tert-butox-
ycarbonylmethylene)penicillanate two products resulting from both
regiochemistries were obtained. The 1,3-dipolar cycloaddition re-
actions of diazomethane with 6-(1-tert-butoxycarbonylmethylene)-
and 6-(1-methoxycarbonylmethylene)penicillanates also led to two
regioisomers, whereas with the acetyl and benzoyl derivatives
regiospecificity was observed. Finally, phenyldiazomethane reacted
with
6-alkylidenepenicillanates
to
afford
spiropyr-
azolinepenicillanates regio- and stereoselectively.
All of these cycloaddition reactions of 6-alkylidene
penicillanates were stereoselective, which can be explained con-
sidering that addition to the less sterically hindered
lactam has occurred.
a-side of the b-
Finally, microwave-induced ring contraction of spiro-1-
pyrazolinepenicillanates to new spirocyclopropylpenicillanates
was also achieved. The process was stereospecific, which is an in-
dication that a concerted mechanism must be involved.
4. Experimental section
4.1. General
Fig. 2. ORTEP-3 diagram of compound 19b, using 50% probability level ellipsoids.
Microwave reactions were carried out in a microwave reactor
CEM Focused Synthesis System Discover S-Class using 10 mL mi-
crowave tubes. The reaction temperatures were measured by in-
frared surface detector during microwave heating. Thin-layer
chromatography (TLC) was performed on precoated silica gel
plates. Flash chromatography was performed on silica gel 60 as the
are four chiral centers, C3, C5, C6, and C50, with relative configu-
ration S, R, R and S, respectively. The hydrogen atoms bonded to the
C3 and C5 carbons of the penicillanate moiety are placed on op-
posite faces of the fused rings. All distances and angles are within
the expected values for similar compounds.

B.S. Santos et al. / Tetrahedron 70 (2014) 3812e3821
3817
stationary phase. 1H NMR spectra were recorded on an instrument
CO2t-Bu), 1.29 (s, 3H, 2
a-Me), 1.63 (s, 3H, 2
b
-Me), 4.15 (s, 1H, H-40),
operating at 400 MHz. 13C NMR spectra were recorded on an in-
strument operating at 100 MHz. Chemical shifts are expressed in
parts per million (ppm) relatively to internal tetramethylsilane
(TMS), and coupling constants (J) are in hertz (Hz). Infrared spectra
(IR) were recorded on a Fourier Transform spectrometer. Mass
spectra were recorded under electrospray ionization (ESI). High-
resolution mass spectra (HRMS) spectra were obtained on an
electron impact (EI) or electrospray (ESI) TOF mass spectrometer.
Melting points were determined in open glass capillaries. Benz-
4.56 (s, 1H, H-3), 6.23 (s, 1H, H-5), 6.96 (s, 1H, CHPh2), 7.22e7.39 (m,
18H, AreH), 7.52 (d, 2H, 3J¼7.6 Hz, AreH); 13C NMR (100 MHz,
CDCl3) d 26.2, 27.4, 32.7, 51.2, 63.4, 69.9, 70.0, 78.5, 82.8,104.4,110.9,
126.6, 127.0, 127.2, 127.4, 127.6, 127.9, 128.0, 128.4, 128.5, 128.5,
128.7, 128.7, 139.1, 140.7, 143.9, 166.3, 166.5, 167.4; HRMS (ESI) m/z:
calcd for C40H40N3O5S [MþHþ] 674.26832, found 674.26934.
20
4.2.3.2. Compound 12. [
a
]
D
þ220 (c 0.25, CH2Cl2); IR (film)
3415,1782, 1741,1736 cmꢁ1; 1H NMR (400 MHz, CDCl3)
-Me), 1.60 (s, 9H, CO2t-Bu), 1.66 (s, 3H, 2 -Me), 4.61 (s, 1H, H-3),
4.78 (s, 1H, H-5), 6.30 (s, 1H, NH), 6.79 (s, 1H, CHPh2), 7.16e7.46 (m,
20H, AreH); 13C NMR (100 MHz, CDCl3)
27.7, 28.2, 29.8, 65.1, 68.4,
d 1.07 (s, 3H,
hydryl 6-
b
-aminopenicillanate,12 benzhydryl 6-oxopenicillinate,7
2a
b
6-alkylidenepenicillanates3b,6,7 1aec, phosphorus ylides,13 diphe-
nyldiazomethane,14 phenyldiazomethane,15 and diazomethane16
were prepared as described in the literature.
d
69.9, 73.8, 78.1, 82.7, 83.6, 127.2, 127.2, 127.3, 127.4, 127.5, 128.1,
128.2, 128.3, 128.3, 128.4, 128.5, 128.6, 130.1, 138.7, 139.2, 139.3,
142.3, 143.6, 160.9, 166.8, 167.2; HRMS (ESI) m/z: calcd for
4.2. General procedure for the 1,3-dipolar cycloaddition of 6-
alkylidenepenicillanates with diphenyldiazomethane
C
40H40N3O5S [MþHþ] 674.26832, found 674.26928.
To
a
mixture of the appropriate 6-alkylidenepenicillanate
4.3. General procedure for the 1,3-dipolar cycloaddition of 6-
alkylidenepenicillanates with diazomethane
(0.40 mmol) in dichloromethane (2 mL), a solution of the diphe-
nyldiazomethane (0.48 mmol) in dichloromethane (3 mL) was added
dropwise. The reaction mixturewas stirred under nitrogen for the time
and temperature indicated in each case. The reaction was monitored
by TLC. Upon completion, the solvent was removed under reduced
pressure and the crude product was purified by flash chromatography.
To a solution of the appropriate 6-alkylidenepenicillanate
(0.40 mmol) in diethyl ether (3 mL) at 0 ꢀC was added an excess
of ethereal diazomethane. The reaction mixture was manually
stirred for the time indicated in each case and monitored by TLC.
Excess of diazomethane was purged with nitrogen and the crude
product was purified by flash chromatography.
4.2.1. (40S,6S)-3-Benzhydryl 40-methoxycarbonyl-50,50-diphenyl-40,50-
dihydrospiro[penicillanate-6,30-(3H-pyrazole)]-3-carboxylate
(11a). Obtained from compound 1a (509 mg, 1.16 mmol) as de-
scribed in the general procedure (reaction time: 24 h, temperature
reaction: 30 ꢀC). After purification by flash chromatography (hex-
ane/ethyl acetate, 4:1), 11a was obtained as a yellow oil (552 mg,
4.3.1. (6R)-3-Benzhydryl
30-methoxycarbonyl-10,50-dihydrospiro
[penicillanate-6,40-(4H-pyrazole)]-3-carboxylate (14a) and (40S,6S)-
3-benzhydryl 40-methoxycarbonyl-40,50-dihydrospiro[penicillanate-
6,30-(3H-pyrazole)]-3-carboxylate (15a). Obtained from compound
1a (142 mg, 0.32 mmol) as described in the general procedure
(reaction time: 2 h). Purification of the crude product by flash
chromatography (hexane/ethyl acetate, 2:1), gave, in order of elu-
tion, 15a as a brown oil (80 mg, 0.17 mmol, 53%) and 14a as a col-
orless oil (47 mg, 0.10 mmol, 31%).
0.87 mmol, 75%); [
a
]
20 þ150 (c 1, CH2Cl2); IR (film) 1786, 1743, 1739,
D
1600 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.27 (s, 3H, 2
a
-Me), 1.62 (s,
3H, 2b
-Me), 3.06 (s, 3H, CO2Me), 4.22 (s, 1H, H-40), 4.60 (s, 1H, H-3),
6.19 (s, 1H, H-5), 6.97 (s, 1H, CHPh2), 7.187.36 (m, 18H, AreH), 7.55
(d, 2H, 3J¼7.6 Hz, AreH); 13C NMR (100 MHz, CDCl3)
d 25.9, 33.1,
50.5, 51.9, 63.2, 69.7, 70.0, 78.5,105.3,110.7, 127.2, 127.3, 127.4, 127.6,
127.9, 127.9, 128.3, 128.4, 128.6, 128.6, 128.7, 139.1, 139.1, 139.6,
140.5, 166.1, 166.3, 168.8; HRMS (ESI) m/z: calcd for C37H33N3NaO5S
[MþNaþ] 654.20331, found 654.20473.
20
4.3.1.1. Compound 14a. [
a
;
]
þ133 (c 0.75, CH2Cl2); IR (film)
D
3338, 1790, 1743, 1732 cmꢁ1
1H NMR (400 MHz, CDCl3)
d 1.24 (s,
3H, 2a-Me), 1.71 (s, 3H, 2b-Me), 3.83 (s, 3H, CO2Me), 4.05 (d, 1H,
2
2J¼11.6 Hz, H-50), 4.10 (d, 1H, J¼11.6 Hz, H-50), 4.67 (s, 1H, H-3),
4.2.2. (40S,6S)-3-Benzhydryl
40-benzoyl-50,50-diphenyl-40,50-dihy-
5.34 (s, 1H, H-5), 6.59 (br s, 1H, NH), 6.96 (s, 1H, CHPh2), 7.32e7.35
drospiro[penicillanate-6,30-(3H-pyrazole)]-3-carboxylate
(11b). Obtained from compound 1b (243 mg, 0.50 mmol) as de-
scribed in the general procedure (reaction time: 24 h, temperature
reaction: 30 ꢀC). After purification by flash chromatography (hex-
ane/ethyl acetate, 7:1), 11b was obtained as a yellow oil (31 mg,
(m, 10H, AreH); 13C NMR (100 MHz, CDCl3)
d 27.7, 29.6, 52.4, 57.5,
65.6, 67.3, 69.9, 72.7, 78.5, 126.9, 127.8, 128.2, 128.5, 128.6, 128.7,
138.9, 139.0, 139.2, 162.1, 167.2, 169.8; HRMS (ESI) m/z: calcd for
C
25H26 N3O5S [MþHþ] 480.15877, found 480.15859.
20
0.046 mmol, 9%); IR (film) 1782, 1743, 1673, 1597 cmꢁ1
(400 MHz, CDCl3)
;
1H NMR
1.01 (s, 3H), 1.13 (s, 3H), 4.50 (s, 1H), 4.63 (s, 1H),
4.3.1.2. Compound 15a. [
1782, 1743, 1736, 1545 cmꢁ1
3H, 2 -Me), 1.59 (s, 3H, 2
a
;
]
þ380 (c 0.75, CH2Cl2); IR (film)
D
d
1H NMR (400 MHz, CDCl3)
d 1.28 (s,
5.27 (s, 1H), 6.24 (s, 1H), 7.09e8.33 (m, 25H, AreH); HRMS (ESI) m/
a
b
-Me), 3.29 (dd, 1H, 3J¼8.8 and 1.6 Hz, H-
z: calcd for C42H36N3O4S [MþHþ] 678.24210, found 678.24237.
40), 3.67 (s, 3H, CO2Me), 4.63 (dd,1H, 2J¼18 Hz, 3J¼8.8 Hz, H-50), 4.64
(s,1H, H-3), 5.03 (dd,1H, 2J¼18 Hz, 3J¼1.6 Hz, H-50), 6.19 (s,1H, H-5),
6.99 (s, 1H, CHPh2), 7.31e7.38 (m, 10H, AreH); 13C NMR (100 MHz,
4.2.3. (40S,6S)-3-Benzhydryl 40-tert-butoxycarbonyl-50,50-diphenyl-
40,50-dihydrospiro[penicillanate-6,30-(3H-pyrazole)]-3-carboxylate
(11c) and (6R)-3-benzhydryl 30-tert-butoxycarbonyl-50,50-diphenyl-
10,50-dihydrospiro[penicillanate-6,40-(4H-pyrazole)]-3-carboxylate
(3). Obtained from compound 1c (231 mg, 0.48 mmol) as described
in the general procedure (reaction time: 48 h, temperature re-
action: 30 ꢀC). Purification of the crude product by flash chroma-
tography (hexane/ethyl acetate, 5:1), gave, in order of elution, 11c
as a yellow oil (148 mg, 0.22 mmol, 46%) and 12 as a yellow oil
(32 mg, 0.047 mmol, 10%).
CDCl3) d 24.7, 32.4, 39.3, 51.7, 62.6, 68.2, 68.4, 77.6, 80.4,107.5, 126.2,
126.4, 127.3, 127.4, 127.6, 127.7, 138.0, 138.0, 165.1, 166.2, 169.7;
HRMS (ESI) m/z: calcd for C25H26N3O5S [MþHþ] 480.15877, found
480.15944.
4.3.2. (6R)-3-Benzhydryl 30-benzoyl-10,50-dihydrospiro[penicillanate-
6,40-(4H-pyrazole)]-3-carboxylate (14b) and (30S,6R)-3-benzhydryl
30-benzoyl-30,40-dihydrospiro[penicillanate-6,40-(5H-pyrazole)]-3-
carboxylate (16). Obtained from compound 1b (68 mg, 0.14 mmol)
as described in the general procedure (reaction time: 30 min).
Purification of the crude product by flash chromatography (hexane/
ethyl acetate, 3:1), gave, in order of elution, 16 as a white solid
4.2.3.1. Compound 11c. [
1743, 1721, 1601 cmꢁ1
a
]
D
20 þ155 (c 1.4, CH2Cl2); IR (film) 1786,
;
1H NMR (400 MHz, CDCl3)
d
0.95 (s, 9H,

3818
B.S. Santos et al. / Tetrahedron 70 (2014) 3812e3821
(44 mg, 0.084 mmol, 60%) and 14b as a yellow pale solid (18 mg,
1.73 (s, 3H, 2b
-Me), 2.40 (s, 3H, COMe), 4.03e4.10 (m, 2H, H-50),
0.034 mmol, 25%)
4.76 (s, 1H, H-3), 5.30 (s, 1H, H-5), 6.43 (br s, 1H, NH), 6.96 (s, 1H,
CHPh2), 7.31e7.35 (m, 10H, AreH); 13C NMR (100 MHz, CDCl3)
4.3.2.1. Compound 14b. Mp 170.9e172.5 ꢀC (decomposes
d 26.0, 27.8, 29.4, 57.6, 65.5, 66.6, 70.1, 72.5, 78.3, 126.9, 127.8,
>150 ꢀC) (from hexane/ethyl acetate); [
a]
20 þ130 (c 0.5, CH2Cl2); IR
128.1, 128.4, 128.6, 128.6, 139.1, 139.3, 147.3, 167.4, 169.9, 192.3;
HRMS (ESI) m/z: calcd for C25H26N3O4S [MþHþ] 464.16385, found
464.16386.
D
(film) 3419, 1786, 1745, 1637 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.22
(s, 3H, 2a-Me), 1.68 (s, 3H, 2b
-Me), 4.07e4.15 (m, 2H, H-50), 4.82 (s,
1H, H-3), 5.40 (s, 1H, H-5), 6.56 (br s, 1H, NH), 6.97 (s, 1H, CHPh2),
7.30e7.55 (m, 13H, AreH), 7.99 (d, 2H, 3J¼7.6 Hz, AreH); 13C NMR
4.4. General procedure for the 1,3-dipolar cycloaddition of 6-
alkylidenepenicillanates with phenyldiazomethane
(100 MHz, CDCl3) d 27.8, 29.7, 56.9, 65.9, 68.1, 70.1, 72.9, 78.4, 126.9,
127.8,128.1,128.1,128.4,128.6,128.6,129.9,132.5,137.0,139.1,139.2,
146.6, 167.4, 169.8, 187.1; HRMS (ESI) m/z: calcd for C30H28N3O4S
[MþHþ] 526.17921, found 526.17950.
To a solution of the appropriate 6-alkylidenepenicillanate
(0.40 mmol) in diethyl ether (3 mL) at 0 ꢀC was added an ex-
cess of ethereal phenyldiazomethane. The reaction mixture was
stirred under nitrogen for the time indicated in each case. The
reaction was monitored by TLC. Upon completion, excess of
phenyldiazomethane was destroyed with acetic acid. The sol-
vent was removed under reduced pressure and the crude
product was purified by flash chromatography, except otherwise
indicated.
4.3.2.2. Compound 16. Mp 183.6e185.0 ꢀC (decomposes>
169 ꢀC) (from hexane/ethyl acetate); [
a
]
20 þ333 (c 0.3, CH2Cl2); IR
D
(KBr) 1770, 1738, 1664, 1597 cmꢁ1
1.15 (s, 3H, 2 -Me), 1.49 (s, 3H, 2
;
1H NMR (400 MHz, CDCl3)
d
a
b
-Me), 4.50 (s, 1H, H-3), 5.51 (dd,
1H, 2J¼18 Hz, J¼2 Hz, H-50), 5.36 (d, 1H, J¼18 Hz, H-50), 5.56 (s,
1H, H-5), 6.79 (d, 1H, 4J¼2 Hz, H-30), 6.94 (s, 1H, CHPh2), 7.31e7.38
(m, 10H, AreH), 7.56e7.60 (m, 2H, AreH), 7.67e7.71 (m, 1H,
4
2
AreH), 8.28 (d, 2H, 4J¼7.6 Hz); 13C NMR (100 MHz, CDCl3)
d
26.3,
4.4.1. (50S,6R)-3-Benzhydryl 30-methoxycarbonyl-50-phenyl-10,50-di-
hydrospiro[penicillanate-6,40-(4H-pyrazole)]-3-carboxylate
(19a). Obtained from compound 1a (250 mg, 0.57 mmol) as de-
scribed in the general procedure (reaction time: 30 min). After
purification by flash chromatography (hexane/ethyl acetate, 6:1 to
hexane/ethyl acetate, 2:1), 19a was obtained as a colorless oil
31.4, 63.3, 63.5, 69.3, 69.4, 78.5, 82.9, 94.5, 127.0, 127.7, 128.3,
128.5, 128.6, 128.7, 129.1, 129.4, 134.6, 136.1, 138.9, 139.1, 166.8,
174.7, 191.4; HRMS (ESI) m/z: calcd for C30H28N3O4S [MþHþ]
526.17950, found 526.18050.
4.3.3. (6R)-3-Benzhydryl 30-tert-butoxycarbonyl-10,50-dihydrospiro
(130 mg, 0.23 mmol, 40%); [
1786, 1736 cmꢁ1
1.64 (s, 3H, 2
a
]
20 þ115 (c 1.3, CH2Cl2); IR (film) 3344,
D
[penicillanate-6,40-(4H-pyrazole)]-3-carboxylate (14c) and (40S,6S)-
;
1H NMR (400 MHz, CDCl3)
d
1.06 (s, 3H, 2
a
-Me),
3-benzhydryl
40-tert-butoxycarbonyl-40,50-dihydrospiro[pen-
b
-Me), 3.85 (s, 3H, CO2Me), 4.55 (s,1H, H-3), 4.76 (s, 1H,
icillanate-6,30-(3H-pyrazole)]-3-carboxylate (15b). Obtained from
compound 1c (108 mg, 0.23 mmol) as described in the general
procedure (reaction time: 30 min). Purification of the crude prod-
uct by flash chromatography (hexane/ethyl acetate, 3:1), gave, in
order of elution,14c as a yellow oil (60 mg, 0.12 mmol, 52%) and 15b
as a yellow solid (43 mg, 0.082 mmol, 36%).
H-5), 5.48 (d, 1H, 3J¼2.4 Hz, H-50), 6.75 (d, 1H, 3J¼2.4 Hz, NH), 6.79
(s, 1H, CHPh2), 7.187.42 (m, 15H, AreH); 13C NMR (100 MHz, CDCl3)
d
27.7, 29.5, 59.4, 65.7, 66.7, 69.8, 70.9, 71.7, 78.2, 127.0, 127.3, 127.3,
120.1,128.3,128.5,128.6,129.1,132.7,139.2,139.3,140.1,162.0,166.7,
169.7; HRMS (ESI) m/z: calcd for C31H30N3O5S [MþHþ] 556.19007,
found 556.18920.
20
4.3.3.1. Compound 14c. Mp 82.8e84.7 ꢀC; [
CH2Cl2); IR (KBr) 3350, 1793, 1751, 1701 cmꢁ1
a
]
þ130 (c 1,
4.4.2. (50S,6R)-3-Benzhydryl 30-benzoyl-50-phenyl-10,50-dihydrospiro
D
;
1H NMR (400 MHz,
[penicillanate-6,40-(4H-pyrazole)]-3-carboxylate
(19b)
30-benzoyl-50-phenyl-30,40-dihydrospiro
[penicillanate-6,40-(5H-pyrazole)]-3-carboxylate
(20a). Obtained
and
CDCl3)
d
1.24 (s, 3H, 2
a
-Me), 1.56 (s, 9H, CO2t-Bu), 1.70 (s, 3H, 2
b
-
(30S,50S,6R)-3-benzhydryl
2
2
Me), 4.02 (d, 1H, J¼11.2 Hz, H-50), 4.08 (d, 1H, J¼11.2 Hz, H-50),
4.69 (s, 1H, H-3), 5.34 (s, 1H, H-5), 6.18 (br s, 1H, NH), 6.96 (s, 1H,
from compound 1b (194 mg, 0.40 mmol) as described in the general
procedure (reaction time: 30 min). Compound 20a precipitates
during reaction and was recovered by filtration at the end as
a white solid (26 mg, 0.043 mmol, 11%). Purification of the crude
product by flash chromatography (hexane/ethyl acetate, 6:1 to
hexane/ethyl acetate, 2:1), gave 19b as a white solid (72 mg,
0.12 mmol, 30%).
CHPh2), 7.35 (br s, 10H, AreH); 13C NMR (100 MHz, CDCl3)
d 27.8,
28.1, 29.5, 57.3, 65.6, 67.7, 69.9, 72.4, 78.4, 82.3, 126.9, 127.7, 128.2,
128.4, 128.6, 128.6, 139.0, 139.2, 141.5, 161.0, 167.3, 169.6; HRMS
(ESI) m/z: calcd for C28H31N3NaO5S [MþNaþ] 544.18766, found
544.18678.
20
4.3.3.2. Compound 15b. [
a
]
þ347 (c 0.75, CH2Cl2); IR (film)
D
1776, 1743, 1597 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.31 (s, 3H, 2
a
-
4.4.2.1. Compound 19b. Mp 172.3e173.5 ꢀC (decomposes
Me), 1.41 (s, 9H, CO2t-Bu), 1.61 (s, 3H, 2
b
-Me), 3.19 (d, 1H,
>130 ꢀC) (from hexane/ethyl acetate); [
a]
20 þ120 (c 0.5, CH2Cl2); IR
D
3J¼8.4 Hz, H-40), 4.56 (dd, 1H, 2J¼17.6 Hz, 3J¼8.4 Hz, H-50), 4.64 (s,
(KBr) 3330, 1766, 1741, 1628 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.06
2
1H, H-3), 4.98 (d, 1H, J¼17.6 Hz, H-50), 6.23 (s, 1H, H-5), 6.99 (s,
(s, 3H, 2a-Me), 1.61 (s, 3H, 2b-Me), 4.70 (s, 1H, H-3), 4.85 (s, 1H, H-
1H, CHPh2), 7.31e7.81 (m, 10H, AreH); 13C NMR (100 MHz, CDCl3)
5), 5.52 (d, 1H, 3J¼2.4 Hz, H-50), 6.78 (d, 1H, 3J¼2.4 Hz, NH), 6.79 (s,
d
24.9, 26.8, 32.2, 40.9, 62.6, 68.3, 68.6, 77.6, 80.2, 82.0, 107.1, 126.1,
1H, CHPh2), 7.187.59 (m, 18H, AreH), 8.06 (d, 2H, 3J¼7.2 Hz, AreH);
126.4, 127.2, 127.4, 127.6, 127.7, 138.1, 165.3, 166.4, 168.0; HRMS
(ESI) m/z: calcd for C28H32N3O5S [MþHþ] 522.20572, found
522.20581.
13C NMR (100 MHz, CDCl3)
d 27.9, 29.8, 66.1, 66.9, 70.0, 71.2, 71.7,
78.2,126.9,127.3,128.0,128.1,128.2,128.5,128.5,129.2,130.0,132.6,
132.9, 136.8, 139.2, 139.4, 147.8, 166.8, 169.9, 187.1; HRMS (ESI) m/z:
calcd for C36H32N3O4S [MþHþ] 602.21080, found 602.21162.
4.3.4. (6R)-3-Benzhydryl 30-acetyl-10,50-dihydrospiro[penicillanate-
6,40-(4H-pyrazole)]-3-carboxylate (14d). Obtained from com-
pound 1d (143 mg, 0.34 mmol) as described in the general pro-
cedure (reaction time: 30 min). The solvent was removed under
4.4.2.2. Compound 20a. Mp 140.8e141.7 ꢀC (from hexane/
diethyl ether); [
a
]
20 þ514 (c 0.35, CH2Cl2); IR (KBr) 1770, 1739, 1670,
D
1597 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.12 (s, 3H, 2
a
-Me), 1.43 (s,
reduced pressure and 14d was obtained as a yellow oil (153 mg,
3H, 2b
-Me), 4.31 (s, 1H, H-3), 5.71 (s, 1H, H-5), 6.14 (br s, 1H, H-50),
20
0.33 mmol, 97%); [
a
]
þ120 (c 1, CH2Cl2); IR (film) 3348, 1784,
6.82 (s, 1H, CHPh2), 7.30 (br s, 1H, H-30), 7.31e7.36 (m, 10H, AreH),
7.58-7.62 (m, 2H, AreH), 7.68e7.72 (m, 1H, AreH), 8.34 (d, 2H,
D
1747, 1666 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.22 (s, 3H, 2a-Me),

B.S. Santos et al. / Tetrahedron 70 (2014) 3812e3821
3819
3J¼7.6 Hz, AreH); 13C NMR (100 MHz, CDCl3)
d
26.0, 32.5, 63.5, 68.5,
general procedure (reaction time: 2 min, temperature reaction:
120 ꢀC, solvent: toluene). The solvent was removed under reduced
pressure and 13a was obtained as a white solid (100 mg, 0.17 mmol,
69.2, 71.2, 78.2, 95.9, 96.1, 127.0, 127.3, 128.0, 128.2, 128.3, 128.6,
128.6, 128.8, 129.0, 129.1, 129.5, 133.3, 134.7, 136.1, 139.1, 139.2,
166.3, 171.8, 191.4; HRMS (ESI) m/z: calcd for C36H32N3O4S [MþHþ]
602.21080, found 602.21202.
99%). Mp 83.9e85.9 ꢀC (from hexane/ethyl acetate); [
a
]
20 þ175 (c 1,
D
CH2Cl2); IR (KBr) 1788, 1736, 1685 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.21 (s, 3H, 2
1H, CO2Me), 4.57 (s, 1H, H-3), 5.87 (s, 1H, H-5), 6.98 (s, 1H, CHPh2),
7.16e7.42 (m, 20H, AreH); 13C NMR (100 MHz, CDCl3)
26.4, 31.4,
a-Me), 1.58 (s, 3H, 2b
-Me), 3.23 (s, 1H, H-20), 3.60 (s,
4.4.3. (50S,6R)-3-Benzhydryl 30-tert-butoxycarbonyl-50-phenyl-10,50-
dihydrospiro[penicillanate-6,40-(4H-pyrazole)]-3-carboxylate
(19c). Obtained from compound 1c (121 mg, 0.25 mmol) as de-
scribed in the general procedure (reaction time: 30 min). After
d
34.2, 48.2, 52.1, 54.3, 62.6, 68.3, 69.6, 78.3, 127.0, 127.6, 127.7, 127.7,
128.1, 128.2, 128.4, 128.6, 128.6, 128.7, 128.8, 128.9, 137.9, 139.2,
139.5, 140.3, 167.4, 167.9, 174.3; HRMS (ESI) m/z: calcd for
purification by flash chromatography (hexane/ethyl acetate, 2:1),
20
19c was obtained as a yellow oil (75 mg, 0.13 mmol, 52%); [
a
]
C
37H34NO5S [MþHþ] 604.21522, found 604.21668.
D
þ115 (c 1, CH2Cl2); IR (film) 3342, 1786, 1735, 1709 cmꢁ1
;
1H NMR
(400 MHz, CDCl3)
d
1.06 (s, 3H, 2
a
-Me), 1.57 (s, 9H, CO2t-Bu), 1.64 (s,
4.5.2. (20S,6S)-3-Benzhydryl 20-tert-butoxycarbonyl-10,10-diphenyl-
spiro[cyclopropane-30, 6-penicillanate]-3-carboxylate
(13b). Obtained from compound 11c (75 mg, 0.11 mmol) as de-
scribed in the general procedure (reaction time: 2 min, temperature
reaction: 120 ꢀC, solvent: toluene). The solvent was removed under
3H, 2b-Me), 4.57 (s, 1H, H-3), 4.75 (s, 1H, H-5), 5.46 (d, 1H,
3J¼2.8 Hz, H-50), 6.51 (d, 1H, 3J¼2.8 Hz, NH), 6.79 (s, 1H, CHPh2),
7.16e7.43 (m, 15H, AreH); 13C NMR (100 MHz, CDCl3)
d 27.8, 28.2,
29.3, 65.6, 66.7, 69.8, 71.1, 71.4, 78.2, 82.5, 127.0, 127.2, 127.4, 128.1,
128.2, 128.5, 128.6, 129.0, 129.1, 133.1, 139.2, 139.4, 142.1, 161.0,
166.8, 169.9; HRMS (ESI) m/z: calcd for C34H36N3O5S [MþXþ]
598.23702, found 598.23766.
reduced pressure and 13b was obtained as a yellow oil (63 mg,
20
0.10 mmol, 91%); [
a]
þ150 (c 0.5, CH2Cl2); IR (film) 1786, 1743,
D
1720 cmꢁ1; 1H NMR (400 MHz, CDCl3)
3H, CO2t-Bu), 1.58 (s, 3H, 2
-Me), 3.13 (s, 1H, H-20), 4.56 (s, 1H, H-3),
5.91 (s, 1H, H-5), 6.97 (s, 1H, CHPh2), 7.25e7.40 (m, 20H, AreH); 13
NMR (100 MHz, CDCl3) 25.7, 26.9, 30.4, 34.2, 47.1, 53.4, 61.6, 67.6,
d 1.23 (s, 3H, 2a-Me), 1.33 (s,
b
4.4.4. (50S,6R)-3-Benzhydryl 30-acetyl-50-phenyl-10,50-dihydrospiro
[penicillanate-6,40-(4H-pyrazole)]-3-carboxylate
C
(19d)
and
d
(30S,50S,6R)-3-benzhydryl 30-acetyl-50-phenyl-30,40-dihydrospiro[pen-
icillanate-6,40-(5H-pyrazole)]-3-carboxylate (20b). Obtained from
compound 1d (169 mg, 0.40 mmol) as described in the general
procedure (reaction time: 30 min). Compound 20b precipitates
during reaction and is recovered by filtration at the end as a white
solid (26 mg, 0.048 mmol,12%). Purification of the crude product by
flash chromatography (hexane/ethyl acetate, 5:1 to hexane/ethyl
acetate, 1:1) gave 19d as a white solid (141 mg, 0.26 mmol, 65%).
68.4, 77.2, 81.5, 125.5, 126.0, 126.4, 126.5, 126.5, 126.6, 127.0, 127.1,
127.4, 127.5, 127.6, 127.6, 127.7, 127.8, 127.9, 137.2, 138.2, 138.4, 139.6,
142.8, 165.5, 166.5, 173.7; HRMS (ESI) m/z: calcd for C40H40NO5S
[MþHþ] 646.26217, found 646.26119.
4.5.3. (10S,6R)-3-Benzhydryl 10-methoxycarbonylspiro[cyclopropane-
30,6-penicillanate]-3-carboxylate (17a). Obtained from compound
15a (30 mg, 0.063 mmol) as described in the general procedure
(reaction time: 2 min, temperature reaction: 200 ꢀC, solvent: 1,2,4-
trichlorobenzene). After purification by flash chromatography
4.4.4.1. Compound 19d. Mp 142.8e144.2 ꢀC (from hexane/
diethyl ether); [
a
]
20 þ171 (c 0.35, CH2Cl2); IR (KBr) 3344, 1768,1753,
(hexane to hexane/ethyl acetate, 1:1), 17a was obtained as a yellow
D
20
1662 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.03 (s, 3H, 2
a
-Me), 1.66 (s,
oil (19 mg, 0.042 mmol, 67%); [
a
]
D
þ146 (c 1.3, CH2Cl2); IR (film)
3H, 2
b
-Me), 2.43 (s, 3H, COMe), 4.65 (s, 1H, H-3), 4.72 (s, 1H, H-5),
1784, 1732, 1639 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.23 (s, 3H, 2a-
5.44 (d, 1H, 3J¼2.0 Hz, H-50), 6.64 (d, 1H, 3J¼2.0 Hz, NH), 6.80 (s, 1H,
Me), 1.56 (s, 3H, 2
b
-Me), 1.78 (dd, 1H, 2J¼8.4 Hz, J¼6.0 Hz, H-20),
3
CHPh2), 7.187.41 (m, 15H, AreH); 13C NMR (100 MHz, CDCl3)
d
25.9,
1.87 (pseudo-t, 1H, J¼6.0 Hz, H-10), 2.40 (dd, 1H, 2J¼8.4 Hz,
3J¼6.0 Hz, H-20), 3.74 (s, 3H, CO2Me), 4.55 (s,1H, H-3), 5.49 (s,1H, H-
5), 6.19 (s, 1H, H-5), 6.95 (s, 1H, CHPh2), 7.30e7.36 (m, 10H, AreH);
3
27.9, 29.3, 65.7, 66.3, 70.0, 70.2, 71.9, 78.1, 126.9, 127.3, 127.4, 128.0,
128.2, 128.5, 128.5, 129.1, 129.2, 133.0, 139.2, 139.4, 148.3, 166.9,
170.0, 192.5; HRMS (ESI) m/z: calcd for C31H30N3O4S [MþHþ]
540.19515, found 540.19425.
13C NMR (100 MHz, CDCl3)
d 15.9, 22.9, 24.9, 31.6, 46.5, 51.4, 62.0,
68.2, 68.4, 77.3, 126.0, 126.6, 127.1, 127.3, 127.3, 127.5, 127.6, 129.0,
131.4, 138.2, 138.2, 166.0, 169.2, 174.6; HRMS (ESI) m/z: calcd for
C
4.4.4.2. Compound 20b. Mp 142.4e143.8 ꢀC (from hexane/
25H25NNaO5S [MþNaþ] 474.13456, found 474.13395.
20
diethyl ether); [
a
]
þ590 (c 1, CH2Cl2); IR (KBr) 1770, 1738, 1710,
D
1595 cmꢁ1; 1H NMR (400 MHz, CDCl3)
3H, 2 -Me), 2.66 (s, 3H, COMe), 4.32 (s, 1H, H-3), 5.60 (s, 1H, H-5),
5.93 (s, 1H, H-50), 6.27 (s, 1H, H-30), 6.82 (s, 1H, CHPh2), 7.187.33 (m,
15H, AreH); 13C NMR (100 MHz, CDCl3)
26.0, 32.4, 33.0, 63.6, 68.3,
d
1.18 (s, 3H, 2
a
-Me), 1.54 (s,
4.5.4. (10S,6R)-3-Benzhydryl 10-benzoylspiro[cyclopropane-30,6-
penicillanate]-3-carboxylate (17b). Obtained from compound 16
(39 mg, 0.074 mmol) as described in the general procedure (re-
action time: 2 min, temperature reaction: 200 ꢀC, solvent: 1,2,4-
trichlorobenzene). After purification by flash chromatography
b
d
69.1, 70.6, 78.3, 95.7, 99.7, 127.0, 127.3, 127.9, 128.2, 128.4, 128.6,
128.8, 129.0, 133.1, 139.0, 139.2, 166.2, 171.4, 199.8; HRMS (ESI) m/z:
calcd for C31H30N3O4S [MþHþ] 540.19515, found 540.19424.
(hexane to hexane/ethyl acetate, 1:1), 17b was obtained as a brown
20
oil (11 mg, 0.022 mmol, 30%); [
a]
þ200 (c 0.2, CH2Cl2); IR (film)
D
1778, 1745, 1668 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.16 (s, 3H, 2a-
3
4.5. General procedure for the synthesis of spirocyclopropyl-
-lactams
Me), 1.47 (s, 3H, 2
b
-Me), 1.92 (dd, 1H, 2J¼8.4 Hz, J¼5.2 HZ, H-20),
3
b
2.09 (pseudo-t, 1H, J¼5.2 HZ, H-10), 3.44 (dd, 1H, 2J¼8.4 Hz,
3J¼5.2 HZ, H-20), 4.49 (s, 1H, H-3), 5.56 (s, 1H, H-5), 6.95 (s, 1H,
CHPh2), 7.28e7.39 (m, 10H, AreH), 7.48e7.52 (m, 2H, AreH),
7.59e7.63 (m, 1H, AreH), 7.99 (d, 1H, 3J¼8.0 Hz, AreH); 13C NMR
A suspension of the appropriate spiro-b-lactam (0.10 mmol) in
the appropriate solvent (1 mL) was irradiated in the microwave
reactor with the time and temperature indicated in each case. The
solvent was removed under reduced pressure, except otherwise
indicated.
(100 MHz, CDCl3) d 19.1, 26.0, 26.5, 31.8, 50.9, 63.1, 69.2, 78.3, 126.5,
127.0, 127.6, 128.1, 128.3, 128.3, 128.6, 128.6, 128.7, 133.6, 137.7,
139.2, 139.3, 167.2, 176.2, 196.2; HRMS (ESI) m/z: calcd for
C
30H27NNaO4S [MþNaþ] 520.15530, found 520.15493.
4.5.1. (20S,6S)-3-Benzhydryl 20-methoxycarbonyl-10,10-diphenylspiro
[cyclopropane-30,6-penicillanate]-3-carboxylate
(13a). Obtained
from compound 11a (107 mg, 0.17 mmol) as described in the
4.5.5. 3-Benzhydryl
6-(Z)-(1-methoxycarbonylethylene)pen-
icillanate-3-carboxylate (18a). Obtained from compound 15a

3820
B.S. Santos et al. / Tetrahedron 70 (2014) 3812e3821
(69 mg, 0.14 mmol) as described in the general procedure (reaction
time:
min, temperature reaction: 250 ꢀC, solvent: 1,2,4-
trichlorobenzene). After purification by flash chromatography
Cryosystem open-flow nitrogen cryostat, at 150 K. Cell parameters
were retrieved using Bruker SMART software and refined using
Bruker SAINT on all observed reflections. Absorption corrections
were applied using SADABS.17 Structure solution and refinement
were performed using direct methods with the programs SIR9718
and SIR200419 included in the package of programs WINGX-
Version 1.80.0520 and SHELXL.21 Both crystal structures were re-
fined to convergence, even though the crystal of compound 16 was
of poor quality, presenting relatively high Rint (0.1269) and low ratio
of observed/unique reflections. Non-hydrogen atoms were refined
with anisotropic thermal parameters. Except for the NH groups, all
hydrogen atoms were inserted in idealized positions and allowed to
refine riding on the parent carbon atom with CeH distances of 0.95,
2
(hexane to hexane/ethyl acetate, 4:1), 18a was obtained as a brown
20
oil (12 mg, 0.027 mmol, 19%); [
a
]
D
þ100 (c 0.2, CH2Cl2); IR (film)
1768, 1751, 1726 cmꢁ1; 1H NMR (400 MHz, CDCl3)
Me), 1.56 (s, 3H, 2
-Me), 2.20 (s, 3H, C10-Me), 3.81 (s, 3H, CO2Me),
4.63 (s, 1H, H-3), 5.95 (s, 1H, H-5), 6.96 (s, 1H, CHPh2), 7.34e7.38 (m,
10H, AreH); 13C NMR (100 MHz, CDCl3)
14.5, 25.6, 33.4, 52.5, 63.5,
d 1.25 (s, 3H, 2a-
b
d
69.8, 70.4, 78.3, 126.5, 127.1, 127.6, 128.2, 128.4, 128.5, 128.6, 128.6,
139.2, 139.3, 149.3, 165.6, 167.1, 167.7; HRMS (ESI) m/z: calcd for
C
25H25NNaO5S [MþNaþ] 474.13456, found 474.13425.
ꢁ
4.5.6. 3-Benzhydryl
6-(Z)-(1-tert-butoxycarbonylethylene)pen-
0.98, 0.99, and 1.0 A for aromatic, methyl, methylene, and methine
icillanate-3-carboxylate (18b). Obtained from compound 15b
(36 mg, 0.069 mmol) as described in the general procedure (re-
action time: 2 min, temperature reaction: 200 ꢀC, solvent: 1,2,4-
trichlorobenzene). After purification by flash chromatography
H atoms, respectively, and with Uiso(H)¼1.2Ueq(C). Graphic pre-
sentations were prepared with ORTEP-III.22 CCDC 993025 (for 16)
and 993026 (for 19b) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
(hexane to hexane/ethyl acetate, 5:1), 18a was obtained as a brown
20
oil (10 mg, 0.020 mmol, 29%); [
a
]
D
þ75 (c 0.15, CH2Cl2); IR (film)
1770, 1720, 1697 cmꢁ1; 1H NMR (400 MHz, CDCl3)
Me), 1.52 (s, 9H, CO2t-Bu), 1.56 (s, 3H, 2
-Me), 2.16 (s, 3H, C10-Me),
4.63 (s, 1H, H-3), 5.92 (s, 1H, H-5), 6.94 (s, 1H, CHPh2), 7.30e7.39 (m,
10H, AreH); 13C NMR (100 MHz, CDCl3)
14.5, 25.6, 33.9, 63.6, 70.1,
d 1.28 (s, 3H, 2a-
b
4.6.1. Crystallographic data for (30S,6R)-3-benzhydryl 30-benzoyl-
30,40-dihydrospiro[penicillanate-6,40-(5H-pyrazole)]-3-carboxylate
(16). C30H27N3O4S, M¼525.62, monoclinic, C 2 with unit cell,
d
¼90ꢀ,
b
¼121.91(2)ꢀ,
ꢁ
ꢁ
ꢁ
70.5, 78.3, 82.8, 127.0, 127.5, 128.2, 128.3, 128.6, 130.1, 130.8, 139.3,
148.1, 164.2, 167.0, 168.2; HRMS (ESI) m/z: calcd for C28H32NO5S
[MþHþ] 494.19957, found 494.20000.
a¼29.915(6) A, b¼5.897(2) A, c¼17.503(6) A,
a
3
ꢁ
ꢀ
g
¼90 , V¼2621.0(15) A . rcalcd¼1.332 g cmꢁ3, Z¼4,
m
¼0.165 mmꢁ1
.
R[I>2
s
(I)]¼0.1030 and Rw¼0.2485 for 2247 independent
reflections.
4.5.7. (10S,20R,6R)-3-Benzhydryl 10-benzoyl-20-phenylspiro[cyclopro-
pane-30,6-penicillanate]-3-carboxylate (21a). Obtained from com-
pound 20a (31 mg, 0.052 mmol) as described in the general
procedure (reaction time: 2 min, temperature reaction: 120 ꢀC,
solvent: toluene). The solvent was removed under reduced pres-
sure and 21a was obtained as a yellow oil (27 mg, 0.050 mmol,
4.6.2. Crystallographic data for (50S,6R)-3-benzhydryl 30-benzoyl-50-
phenyl-10,50-dihydrospiro[penicillanate-6,40-(4H-pyrazole)]-3-
carboxylate (19b). C36H31N3O4S, M¼601.70, monoclinic, P21 with
¼90ꢀ,
ꢁ
ꢁ
ꢁ
unit cell, a¼10.9401(4) A, b¼10.2024(4) A, c¼13.9470(6) A,
a
3
ꢀ
ꢁ
b
¼94.678(2)ꢀ,
g
¼90 , V¼1551.51(11) A . rcalcd¼1.288 g cmꢁ3, Z¼2,
99%); [
a
]
D
20 þ100 (c 0.2, CH2Cl2); IR (film) 1778, 1747, 1666 cmꢁ1; 1H
m
¼0.149 mmꢁ1. R[I>2
(I)]¼0.0369 and Rw¼0.0781 for 4409 in-
s
NMR (400 MHz, CDCl3)
d
1.19 (s, 3H, 2
a
-Me), 1.50 (s, 3H, 2
b
-Me),
dependent reflections.
3.50 (d, 1H, 3J¼6.4 Hz), 3.82 (d, 1H, 3J¼6.4 Hz), 4.50 (s, 1H, H-3), 5.65
(s, 1H, H-5), 6.94 (s, 1H, CHPh2), 7.24e7.50 (m, 18H, AreH), 8.02 (d,
Acknowledgements
2H, 3J¼7.6 Hz, AreH); 13C NMR (100 MHz, CDCl3)
d 26.4, 31.3, 34.9,
38.6, 56.6, 63.1, 69.2, 69.3, 78.3,127.0,127.6,127.7,127.8,128.1,128.4,
128.6, 128.8, 133.7, 135.3, 137.6, 139.2, 139.3, 167.3, 174.2, 195.4;
HRMS (ESI) m/z: calcd for C36H32NO4S [MþHþ] 574.20466, found
574.20676.
~
^
Thanks are due to Fundac¸ ao para a Ciencia e a Tecnologia (SFRH/
BD/63622/2009, SFRH/BPD/64423/2009, RECI/QEQ-QIN70189/
2012, PEst-OE/QUI/UI0313/2014 and PEst-OE/QUI/UI0100/2013) for
financial support. We acknowledge the Nuclear Magnetic Reso-
nance Laboratory of the Coimbra Chemistry Center
(www.nmrccc.uc.pt), University of Coimbra for obtaining the NMR
data. C.S.B.G. thanks Prof. M. Teresa Duarte for valuable discussions
on X-ray crystallography.
4.5.8. (10S,20R,6R)-3-Benzhydryl 10-acetyl-20-phenylspiro[cyclopro-
pane-30,6-penicillanate]-3-carboxylate (21b). Obtained from com-
pound 20b (30 mg, 0.056 mmol) as described in the general
procedure (reaction time: 2 min, temperature reaction: 120 ꢀC,
solvent: toluene). The solvent was removed under reduced pres-
sure and 21b was obtained as a yellow oil (29 mg, 0.056 mmol,
Supplementary data
20 þ222 (c 0.45, CH2Cl2); IR (film) 1778,1747,1701 cmꢁ1; 1H
1H NMR, 13C NMR, NOESY, COSY, HMQC, HMBC and DEPT spectra
for selected compounds. ORTEP, bond lengths and angles of com-
pounds 16 and 19b determined by X-ray crystallography. Supple-
mentary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.03.109.
99%); [
NMR (400 MHz, CDCl3)
a
]
D
d 1.23 (s, 3H, 2a-Me), 1.60 (s, 3H, 2b-Me),
2.41 (s, 3H, COMe), 3.12 (d, 1H, 3J¼6.4 Hz), 3.28 (d, 1H, 3J¼6.4 Hz),
4.51 (s, 1H, H-3), 5.53 (s, 1H, H-5), 6.93 (s, 1H, CHPh2), 7.25e7.34 (m,
15H, AreH); 13C NMR (100 MHz, CDCl3)
d 26.4, 31.7, 32.6, 37.8, 38.3,
56.2, 63.2, 69.1, 78.3, 127.0, 127.5, 127.7, 128.2, 128.4, 128.5, 128.6,
128.6, 135.1, 139.1, 139.2, 167.2, 173.9, 203.5; HRMS (ESI) m/z: calcd
for C31H30NO4S [MþHþ] 512.18901, found 512.18908.
References and notes
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Chapter 1.20, pp 623e658; (c) Fisher, J. F.; Meroueh, S. O.; Mobashery, S. Chem.
4.6. X-ray diffraction
Crystals of compounds 16 and 19b were selected, covered with
polyfluoroether oil, and mounted on a nylon loop. Crystallographic
ꢀ
Rev. 2005, 105, 395e424; (d) Perez-Llarena, F. J.; Bou, G. Curr. Med. Chem. 2009,
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ꢁ
monochromated Mo K
a
radiation (
l
¼0.71073 A) on a Bruker AXS-
KAPPA APEX II diffractometer equipped with an Oxford

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3821
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