Synthesis of chiral spirocyclopentenyl-β-lactams through phosphane-catalyzed [3+2] annulation of allenoates with 6- alkylidenepenicillanates

Article abstract of DOI:10.1002/ejoc.201300153

The first examples of phosphane-catalyzed [3+2] annulation of allenoates to 6-alkylidenepenicillanates leading to chiral spirocyclopentenyl-β-lactams are reported. The synthesis of this new type of β-lactams involved the generation of either two or three

Full text of DOI:10.1002/ejoc.201300153

Job/Unit: O30153
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Pages: 10
FULL PAPER
Chiral β-Lactams
B. S. Santos,
T. M. V. D. Pinho e Melo* ............... 1–10
Synthesis of Chiral Spirocyclopentenyl-β-
lactams through Phosphane-Catalyzed
[3+2] Annulation of Allenoates with 6-
Alkylidenepenicillanates
The first examples of phosphane-catalyzed
[3+2] annulation of allenoates to 6-alkylid-
enepenicillanates leading to chiral spiro-
cyclopentenyl-β-lactams are reported. The
process involves the generation of either
two or three consecutive stereogenic cen-
ters, including a quaternary chiral center.
Keywords: Allenes / Annulation / Anti-
biotics / Drug discovery / Lactams / Spiro
compounds
0000, 0–0
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Job/Unit: O30153
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Date: 26-04-13 12:42:16
Pages: 10
B. S. Santos, T. M. V. D. Pinho e Melo
FULL PAPER
DOI: 10.1002/ejoc.201300153
Synthesis of Chiral Spirocyclopentenyl-β-lactams through Phosphane-Catalyzed
[3+2] Annulation of Allenoates with 6-Alkylidenepenicillanates
Bruna S. Santos[a] and Teresa M. V. D. Pinho e Melo*[a]
Keywords: Allenes / Annulation / Antibiotics / Drug discovery / Lactams / Spiro compounds
The first examples of phosphane-catalyzed [3+2] annulation
of allenoates to 6-alkylidenepenicillanates leading to chiral
spirocyclopentenyl-β-lactams are reported. The synthesis of
this new type of β-lactams involved the generation of either
two or three consecutive stereogenic centers, including a
quaternary chiral center. Although the reported methodology
is highly diastereoselective, the regioselectivity is dependent
on the nature of the methylenepenicillanate derivative and
on the nature of the allenoate γ-substituent.
pyrazoline-β-lactams, whereas with N-substituted male-
imides, spiro-1-pyrazoline-β-lactams are obtained. Micro-
wave-induced denitrogenation of these spiro-1-pyrazoline-
β-lactams allows the stereoselective synthesis of novel spiro-
cyclopropyl-β-lactams. 6-Diazopenicillanates also react
with electron-deficient alkynes to give the corresponding
spiro-3H-pyrazole-β-lactam as a single product.[5] The ob-
served stereoselectivity can be explained by considering that
the major product results from addition to the sterically less
hindered α-side of the β-lactam. Reaction of 6-diazopenicill-
anates with aromatic imines, aldehydes and ketones leading
to spiro-aziridine-penicillanates[6] and spiro-epoxide-penic-
illanates,[7] respectively, are also known. On the other hand,
6-alkylidenepenicillanates participate in 1,3-dipolar cyclo-
addition reactions with diphenyldiazomethane to give
spiro-1-pyrazolinepenicillanates, which undergo thermally
induced ring contraction to afford spirocyclopropylpenicill-
anates.[3a] Spirocyclopropylpenicillanates have also been
prepared through rhodium-catalyzed cyclopropanation of
a 6-diazopenicillanate sulfone[8a] and by the CuI-catalyzed
reaction of 6-bromopenicillanoylmagnesium bromide with
α,β-unsaturated esters.[8b]
Phosphane-catalyzed [3+2] annulations of allenoates
with electron-deficient alkenes is a powerful synthetic strat-
egy for the construction of cyclopentene derivatives.[9] Cris-
tau et al. found that in the presence of phosphanes the ad-
dition of nucleophiles to electron-deficient allenes takes
place at the β,γ-carbon–carbon double bond (umpolung ad-
dition).[10] They observed that the reaction of methyl 2,3-
butadienoate (1) with triphenylphosphane followed by the
addition of NaI affords 2, which undergoes nucleophilic at-
tack at the γ-carbon atom leading to 3. Lu et al. explored
the reactivity of 1,3-dipoles generated from allenoates and
phosphanes as the three-carbon synthon in formal [3+2]
cycloaddition reactions.[11] This pioneering work included
the synthesis of cyclopentene derivatives via allenoate-de-
rived 1,3-dipoles and electron-deficient alkenes. The reac-
Introduction
Since the discovery of penicillins and cephalosporins as
antibiotics, the chemistry of β-lactams has attracted con-
siderable attention. However, the extensive clinical use of
these antibacterial agents has resulted in an increasing
number of resistant strains of bacteria. Penicillin resistance
is often caused by the action of enzymes known as β-lact-
amases, which cleave the reactive β-lactam bond of the anti-
biotic making it ineffective. Thus, the β-lactam ring is the
core of the biological activity of a large class of antibiotics
and also of several β-lactamase inhibitors.[1] The demand
for more efficient β-lactam antibiotics and β-lactamase in-
hibitors has led to increasing interest in the design of new
functionalized 2-azetidinones.
β-Lactams are also interesting synthons in organic syn-
thesis, providing routes to α- and β-amino acids and pept-
ides.[2] Structures with a spiro-β-lactam core are also inter-
esting target molecules, because some derivatives exhibit
relevant biological properties, namely cholesterol absorp-
tion inhibition, antibacterial activity and antiviral activity.[3]
In peptidomimetic chemistry, spiro-β-lactams are used as β-
turn mimetics.[4] Thus, the search for new spiro-β-lactam
derivatives is of great interest in medicinal chemistry.
An approach to new penicillin analogues is to explore
the reactivity of 6-diazopenicillanates or 6-alkylidenepenic-
illanates for the functionalization at C-6, keeping the penic-
illanate nucleus. In fact, chiral spiro-2-pyrazolinepenicillan-
ates can be obtained from the 1,3-dipolar cycloaddition of
6-diazopenicillanates.[3a,3b,5] Our own contribution[5] estab-
lished that cycloaddition with dipolarophiles such as acry-
lonitrile, acrylates or methyl vinyl ketone affords spiro-2-
[a] Department of Chemistry, University of Coimbra,
3004-535 Coimbra, Portugal
E-mail: tmelo@ci.uc.pt
Homepage: http://www.uc.pt
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300153.
2
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Chiral Spirocyclopentenyl-β-lactams
Scheme 1. Phosphane-catalyzed reactions of allenoates.
tion with alkenes such as acrylates and methyl vinyl ketone pared from 6-aminopenicillanic acid (6-APA) according to
affords regioisomeric cyclopentenes 5 and 6. The selectivity a known procedure.[18] This method involves the conversion
towards the former regioisomer can be rationalized as re- of 6-APA into 6-hydroxypenicillanic acid, followed by ester-
sulting from the initial conjugate addition of the α-position ification and final oxidation to the 6-oxo derivative. How-
of the dipole to the alkene (Scheme 1).
ever, we decided to use an alternative method that proved
Since this disclosure, cycloaddition of allenoates to a to be a more efficient approach to 6-oxopenicillanate 11.[19]
wide range of electron-deficient alkenes has been This synthetic strategy involves the synthesis of 6-diazopen-
studied.[9,12–16] These included the use of chiral phosphanes icillanate from benzhydryl 6-β-aminopenicillanate,[20] fol-
for the enantioselective synthesis of cyclopentenes[14,15] as lowed by rhodium-catalyzed oxidation of the diazo deriva-
well as the use of chiral substrates to provide cyclopentenes tive in the presence of propylene oxide to give the target 6-
in a diastereoselective manner.[16] This annulation method- oxopenicillanate.
ology, when applied to exocyclic alkenes, provides an ap-
proach to spirocyclic compounds.[13,15,16a,16b]
In this context, we decided to study the phosphane-cata-
lyzed [3+2] cycloaddition of allenoates to 6-alkylidenepenic-
illanates 7 as a route to chiral spirocyclopentene-β-lactams
(Scheme 2). This chemistry would allow the generation of
two (8; R1 = H) or three (8; R1 ϶ H) consecutive stereo-
genic centers, including a quaternary stereocenter, leading
to a new class of penicillanate derivatives 9 and 10.
Scheme 3. Synthesis of 6-alkylidenepenicillanates 7.
The formal [3+2] cycloaddition of benzyl 2,3-butadieno-
ate (8a) with 6-alkylidenepenicillanates 7 was explored
(Table 1). Allenoate 8a reacted with 6-alkylidenepenicillan-
ate 7a in the presence of triphenylphosphane at room tem-
perature for 3 h, to produce regioisomeric spiro-β-lactams
13a and 14a, in 48% overall yield (Entry 1). By carrying out
the same reaction for 5 h, the overall yield was improved to
68% (Entry 2). The structural assignment of these chiral
compounds 13a and 14a was made on the basis of 2D
NOESY, HMQC and HMBC spectra (400 MHz). The
NOESY spectra of these compounds showed cross peaks
between 1Ј-H and the β-Me protons, but no correlation was
observed between 1Ј-H and 5-H.
Scheme 2. Synthetic strategy for the synthesis of chiral spirocy-
clopentenyl-β-lactams.
Results and Discussion
Quantum chemical calculations were carried out at the
6-Alkylidenepenicillanates 7 were obtained by Wittig re- Hartree–Fock level of theory by using the 6-31G(d) basis
action of the appropriate phosphorus ylide with 6-oxopen- set to determine the optimized geometries of spiro-β-lact-
icillanate 11 (Scheme 3).[17] Compound 11 was initially pre- ams 13a and 14a, followed by harmonic frequency calcula-
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B. S. Santos, T. M. V. D. Pinho e Melo
Table 1. Phosphane-catalyzed [3+2] annulation of allenoate 8a with 6-alkylidenepenicillanates 7a–d.
FULL PAPER
Entry
β-Lactam 7
Reaction conditions
Isolated yield [%]
α-Regioisomers 14
γ-Regioisomer 13
1
2
3
4
5
7a
7a
7b
7c
7d
r.t., 3 h
r.t., 5 h
r.t., 5 h
r.t., 5 h
r.t., 3 h
27
41
35
21
27
53
50 (31:69)[a]
41
–
1
[a] Regioisomeric ratio determined by H NMR spectroscopic analysis.
Figure 1. Optimized geometries of spiro-β-lactams 13a and 14a at the HF/6-31G(d) level.
tions, at the same level of theory, which allowed characteri- the 1-acetylmethylene derivative. However, with 1-benzoyl-
zation of the nature of the stationary points (Figure 1). The methylenepenicillanate the opposite regioselectivity was ob-
calculated structures corroborate the stereochemistry as- served. Thus, a combination of steric and electronic effects
signment of these β-lactams and are in agreement with the must be considered to explain the regioselectivity of these
NOE experiments.
The work was then extended to other 6-alkylidenepenic- γ-regioisomers were isolated as single stereoisomers.
illanates (Table 1). Benzyl 2,3-butadienoate (8a) reacted The reactivity of 6-alkylidenepenicillanates towards
[3+2] annulation reactions. It is noteworthy that the α- and
with 6-alkylidenepenicillanate 7b at room temperature for benzyl 2,3-pentadienoate (8b) in the presence of tri-
5 h to produce the spiro-β-lactams 13b and 14b in 88% phenylphosphane was also explored (Table 2). Spirocy-
overall yield (Entry 3). The reaction of 6-alkylidenepenicill- clopentenyl-β-lactam 15a was prepared as the only product
anate 7c with allenoate 8a at room temperature for 5 h also in 48% yield, by the [3+2] annulation reaction of allenoate
gave the regioisomeric spiro-β-lactams 13c and 14c, in 50% 8b with 7a (Entry 1). The stereochemistry assignment of
overall yield (Entry 4). Unfortunately, 13c and 14c could compound 15a was made on the basis of 2D NOESY ex-
not be separated by flash chromatography. Interestingly, the periments (400 MHz). In this spectrum, 1Ј-H showed corre-
reaction of 6-alkylidenepenicillanate 7d with the same allen- lation with the β-Me protons, but no cross peaks were ob-
oate at room temperature gave spiro-β-lactam 13d regio- served between 1Ј-H and 5-H nor between 1Ј-H and 2Ј-H.
selectively in 41% yield (Entry 5).
Benzyl 2,3-pentadienoate (8b) reacted with 7b at room
It has been previously observed that the formal phos- temperature for 5 h to give spiro-β-lactam 15b as a single
phane-catalyzed [3+2] cycloaddition of exocyclic alkenes to product, in 36% yield (Table 2, Entry 2). The chiral spiro-
allenoates can lead to a regioselection that differs from that β-lactam 15c was also obtained regio- and stereoselectively
observed in the cycloaddition with acrylates[15b] (see from the reaction of allenoate 8b with 6-alkylidenepenic-
Scheme 1). The results on the formal [3+2] cycloaddition of illanate 7d (Entry 3).
8a with 6-alkylidenepenicillanates 7 showed that the re-
The study of the reactivity of 6-alkylidenepenicillanates
gioselectivity depends on the nature of the methylenepenic- 7 towards γ-substituted allenoate 8b showed that the PPh3-
illanate derivative. In the case of 1-methoxycarbonylmethyl- catalyzed [3+2] cycloaddition also proceeds, with the re-
enepenicillanate the synthesis of the γ-regioisomer is fa- gioselective synthesis of the α-regioisomer being observed
vored, whereas the γ-regioisomer is formed exclusively from regardless of the nature of the methylenepenicillanate deriv-
4
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Chiral Spirocyclopentenyl-β-lactams
Table 2. Phosphane-catalyzed [3+2] annulation of allenoate 8b with was observed, but compound 17b was obtained in lower
6-alkylidenepenicillanates 7a, 7b and 7d.
yield (Entry 3). This result indicates that prolonged reaction
time leads to decomposition of the product. In fact, we be-
lieve that, in general, the isolated yields of the reported re-
actions of 6-alkylidenepenicillanates are affected by the ease
of the isolation or stability of products. It is worth noting
that the cycloaddition of 1-benzoylmethylenepenicillanate
(7b) with all the studied allenoates led to the synthesis of
the α-regioisomer as either the only or the major product.
The reaction of benzyl 4-phenyl-2,3-butadienoate (8c)
and 6-alkylidenepenicillanate 7d at room temperature for
7 h led to the formation of spirocyclopentenyl-β-lactams
16c and 17c, in 43% overall yield (Table 3, Entry 4). By car-
rying out the same reaction for 24 h, the overall yield was
improved to 60% (Entry 5). The stereochemistry assign-
Entry β-Lactam 7 Reaction conditions Isolated yield of 15 [%]
ment of compounds 17b and 17c was also made on the
1
2
3
7a
7b
7d
r.t., 5 h
r.t., 5 h
r.t., 3 h
48
36
37
basis of 2D NOESY experiments (400 MHz). In these spec-
tra, 1Ј-H showed correlation with the β-Me protons and
with 2Ј-H. On the other hand, no correlation was observed
between 5-H and either 1Ј-H or 2Ј-H. It is noteworthy that
α-regioisomers 17 had a configuration at C-2Ј opposite to
that of compounds 15, resulting from the PPh3-catalyzed
reaction of 6-alkylidenepenicillanates when methyl-substi-
tuted allenoate 8b was used. Other examples are known in
which the stereochemical outcome of the cycloaddition of
exocyclic alkenes with allenoates bearing γ-substituents (Me
vs. Ph) depends on the nature of the substituent.[16a]
Finally, attempts to carry out the reaction of benzyl 4,4-
ethylphenyl-2,3-butadienoate with 6-alkylidenepenicillan-
ates 7a and 7b in the presence of triphenylphosphane were
unsuccessful.
ative, through a process in which three new chiral centers
are formed.
The study was then extended to the reaction of benzyl 4-
phenyl-2,3-butadienoate (8c) with 6-alkylidenepenicillan-
ates in the presence of triphenylphosphane (Table 3). Spiro-
β-lactam 16a was prepared in 56% yield as a single product
by the reaction of allene 8c with 6-alkylidenepenicillanate
7a at room temperature for 7 h (Entry 1). The assignment
of the stereochemistry of compound 16a was made on the
basis of 2D NOESY spectra (400 MHz), in which 1Ј-H
showed a correlation with the β-Me protons, but no cross
peaks were found between 1Ј-H and 5-H. On the other
The synthesis of the new spirocyclopentenyl-β-lactams
hand, cross peaks were observed between the 4Ј-H and 5- can be rationalized as shown in Scheme 4. Conjugate ad-
H, but no correlation was observed between 1Ј-H and 4Ј- dition of the dipole to the 6-alkylidenepenicillanates occurs
H.
to the sterically less hindered α-side of the β-lactam, fol-
Spirocyclopentenyl-β-lactam 17b was prepared regio- lowed by ring closure, proton transfer and elimination to
and stereoselectively in high yield (84%) by the reaction regenerate triphenylphosphane. The “butterfly” conforma-
of 6-alkylidenepenicillanate 7b with allenoate 8c at room tion of the penicillanate ring system ensures that reactions
temperature for 7 h (Table 3, Entry 2). When the reaction at the 6-position occur with high selectivity, involving the
was allowed to proceed for 24 h, the same regioselectivity approach of the reagents from this face.[1b,3f] The formation
Table 3. Phosphane-catalyzed [3+2] annulation of allenoate 8c with 6-alkylidenepenicillanates 7a, 7b and 7d.
Entry
β-Lactam 7
Reaction conditions
Isolated yield [%]
16
17
1
2
3
4
5
7a
7b
7b
7d
7d
r.t., 7 h
r.t., 7 h
r.t., 24 h
r.t., 7 h
r.t., 24 h
56
–
–
5
12
–
84
55
38
48
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B. S. Santos, T. M. V. D. Pinho e Melo
FULL PAPER
Scheme 4. Possible mechanism for the synthesis of spirocyclopentenyl-β-lactams.
were recorded with a Bruker Avance III instrument operating at
400 MHz and 100 MHz, respectively; chemical shifts are expressed
in ppm relatively to internal tetramethylsilane (TMS), and coupling
constants (J) are in Hertz. IR spectra were recorded with a Perkin-
Elmer 1720X FTIR spectrometer. Optical rotations were measured
with an Optical Activity AA-5 electrical polarimeter. Mass spectra
were recorded with a Hewlett-Packard 5989B spectrometer under
electrospray ionization (ESI). HR mass spectra were obtained with
an electrospray (ESI) TOF VG Autospec M spectrometer. Melting
points were recorded with a Reichert hot stage. Benzhydryl 6-β-
aminopenicillanate,[19] benzhydryl 6-oxopenicillinate,[20] phos-
phorus ylides 12a–d[21] and allenes 8a–d[22] were prepared as de-
scribed in the literature.
of α- and/or γ-regioisomers will depend on the initial attack
of the dipole at C-6 of the β-lactam, which can involve
either the α- or the γ-position. The different stereochemical
outcome observed in the synthesis of α-regioisomers 15 and
17, obtained from methyl- or phenyl-substituted allenoates,
respectively, can be explained by considering that the bulky
phenyl group trans to the triphenylphosphonium moiety of
the zwitterion will be favored, whereas the methyl substitu-
ent may accommodate a cis relationship.
Conclusions
General Procedure for the Synthesis of 6-Alkylidenepenicillanates:
Benzhydryl 6-oxopenicillinate 11[19] (2.73 mmol) was dissolved in
dichloromethane (13 mL), the solution was cooled to –55 °C under
nitrogen, and the appropriate phosphorus ylide (2.57 mmol) in
dichloromethane (30 mL) was added dropwise. Stirring was contin-
ued for 10 min, then the solution was warmed to room temperature
and washed with water (20 mL). The organic layer was separated,
dried, and concentrated under reduced pressure. The product was
purified by flash chromatography.
Herein, a synthetic methodology leading to a new type
of chiral spiro-β-lactam is described. For the first time,
phosphane-catalyzed [3+2] annulation of allenoates to 6-
alkylidenepenicillanates was explored, which gave access to
chiral spirocyclopentenyl-β-lactams in a process involving
the generation of either two or three consecutive stereogenic
centers, including a quaternary chiral center.
Benzhydryl 6-(Z)-(1-Methoxycarbonylmethylene)penicillanate (7a):
Prepared from 6-oxopenicillanate 11 (0.33 g, 0.87 mmol) and phos-
phorus ylide 12a (0.34 g, 0.83 mmol), as described in the general
procedure. After purification by flash chromatography (hexane/
ethyl acetate, 2:1), compound 7a was obtained as a brown oil
Experimental Section
General: Thin-layer chromatography (TLC) was performed on pre-
coated silica gel plates. Flash chromatography was performed on
silica gel 60 as the stationary phase. 1H and 13C NMR spectra
6
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Chiral Spirocyclopentenyl-β-lactams
(0.24 g, 0.55 mmol, 66%); [α]2D0 = +220 (c = 1, CH2Cl2). IR (film):
Upon completion, the solvent was removed under reduced pressure
and the crude product was purified by flash chromatography.
1
ν = 1779, 1743, 1732 cm–1. H NMR (400 MHz, CDCl ): δ = 1.27
˜
3
(s, 3 H, 2α-Me), 1.56 (s, 3 H, 2β-Me), 3.81 (s, 3 H, CO2Me), 4.66
(s, 1 H, 3-H), 6.03 (s, 1 H, 5-H), 6.31 (s, 1 H, CHCO2Me), 6.96 (s, 1
H, CHPh2), 7.32–7.38 (m, 10 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 25.4, 33.6, 52.5, 63.9, 69.0, 70.7, 78.5, 115.4, 127.1,
127.6, 128.2, 128.4, 128.6, 128.7, 139.1, 139.2, 156.8, 164.2, 166.3,
166.7 ppm. MS (ESI): m/z (%) = 460 (45) [M + Na+], 279 (7), 167
(100). HRMS (ESI): calcd. for C24H23NNaO5S [M + Na+]
460.11891; found 460.11841.
(1ЈR,6R)-3-Benzhydryl 2Ј-Benzyl 1Ј-Methyl Spiro(cyclopent-3-enyl)-
5Ј,6-penicillanate-1Ј,2Ј,3-tricarboxylate (13a) and (1ЈR,6S)-3-Benz-
hydryl 4Ј-Benzyl 1Ј-Methyl Spiro(cyclopent-4-enyl)-5Ј,6-penicillan-
ate-1Ј,4Ј,3-tricarboxylate (14a): Obtained from allene 8a (71 mg,
0.41 mmol) and 6-alkylidenepenicillanate 7a (180 mg, 0.41 mmol)
as described in the general procedure (reaction time: 5 h). Purifica-
tion of the crude product by flash chromatography (hexane/ethyl
acetate, 3:1, then hexane/ethyl acetate, 2:1), gave, in order of elu-
tion, 13a as a yellow oil (101 mg, 0.17 mmol, 41%) and 14a as a
yellow oil (66 mg, 0.11 mmol, 27%).
Benzhydryl 6-(Z)-(1-Benzoylmethylene)penicillanate (7b): Prepared
from 6-oxopenicillanate 11 (1.00 g, 2.62 mmol) and phosphorus
ylide 12b (0.94 g, 2.47 mmol), as described in the general procedure.
After purification by flash chromatography (hexane/ethyl acetate,
2:1), compound 7b was obtained as a yellow oil (0.57 g, 1.18 mmol,
Compound 13a: [α]2D0 = +210 (c = 1, CH Cl ). IR (film): ν = 1777,
˜
2
2
1745, 1727, 1686 cm–1. H NMR (400 MHz, CDCl3): δ = 1.23 (s,
1
3 H, 2α-Me), 1.59 (s, 3 H, 2β-Me), 3.05 (dd, 2J = 18.4, 3J = 2.8 Hz,
1 H, 4Ј-H), 3.32 (pseudo-d, J = 18.4 Hz, 1 H, 4Ј-H), 3.66 (s, 3 H,
48%); [α]2D0 = +110 (c = 1, CH Cl ). IR (film): ν = 1774, 1745,
2
˜
2
2
1638 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.28 (s, 3 H, 2α-Me),
1.59 (s, 3 H, 2β-Me), 4.68 (s, 1 H, 3-H), 6.16 (s, 1 H, 5-H), 6.98 (s,
1 H, CHPh2), 7.31–7.41 (m, 10 H, Ar-H), 7.50–7.54 (m, 2 H, Ar-
H), 7.62–7.66 (m, 1 H, Ar-H), 7.99 (d, 3J = 7.6 Hz, 2 H, Ar-H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 25.5, 33.4, 63.8, 69.7, 71.1,
78.4, 116.2, 127.1, 127.5, 128.2, 128.4, 128.6, 128.7, 129.0, 134.1,
135.0, 137.0, 139.0, 139.2, 156.3, 166.8, 167.4, 188.3 ppm. MS
(ESI): m/z (%) = 506 (17) [M + Na+], 279 (7), 167 (100). HRMS
(ESI): calcd. for C29H25NNaO4S [M + Na+] 506.13965; found
506.13752.
CO2Me), 4.06 (s, 1 H, 1Ј-H), 4.53 (s, 1 H, 3-H), 5.12 (d, 2J =
12.4 Hz, 1 H, CH2Ph), 5.23 (d, 2J = 12.4 Hz, 1 H, CH2Ph), 5.40
(s, 1 H, 5-H), 6.93 (s, 1 H, CHPh2), 7.00 (br. s, 1 H, 3Ј-H), 7.32–
7.36 (m, 15 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 26.0,
32.8, 40.0, 52.2, 52.5, 63.5, 66.6, 67.9, 68.7, 70.8, 78.4, 127.0, 127.6,
128.2, 128.3, 128.4, 128.5, 128.6, 134.3, 135.6, 139.2, 145.2, 162.5,
166.9, 171.7, 175.3 ppm. MS (ESI): m/z (%) = 634 (87) [M + Na+],
492 (24), 167 (100). HRMS (ESI): calcd. for C35H33NNaO7S [M +
Na+] 634.18699; found 634.18726.
Compound 14a: [α]2D0 = +220 (c = 0.75, CH Cl ). IR (film): ν =
˜
2
2
1772, 1735, 1732, 1716 cm–1. 1H NMR (400 MHz, CDCl3): δ =
Benzhydryl
6-(Z)-(1-tert-Butoxycarbonylmethylene)penicillanate
2
3
1.10 (s, 3 H, 2α-Me), 1.50 (s, 3 H, 2β-Me), 2.54 (dd, J = 18.8, J
(7c): Prepared from 6-oxopenicillanate 11 (1.08 g, 2.83 mmol) and
phosphorus ylide 12c (1.00 g, 2.66 mmol), as described in the gene-
ral procedure. After purification by flash chromatography (hexane/
ethyl acetate, 2:1), compound 7c was obtained as a brown oil
2
3
= 2.4 Hz, 1 H, 2Ј-H), 3.01 (ddd, J = 18.8, J = 8.4 and 2.0 Hz, 1
H, 2Ј-H), 3.48 (pseudo-d, 3J = 8.4 Hz, 1 H, 1Ј-H), 3.61 (s, 3 H,
CO2Me), 4.48 (s, 1 H, 3-H), 5.11 (s, 2 H, CH2Ph), 6.08 (s, 1 H, 5-
H), 6.86 (s, 1 H, CHPh2), 6.93 (br. s, 1 H, 3Ј-H), 7.18–7.39 (m, 15
H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.6, 32.3, 35.3,
46.8, 51.4, 61.4, 65.4, 67.6, 69.7, 72.0, 77.2, 126.3, 126.4, 127.1,
127.2, 127.3, 127.5, 132.6, 134.6, 138.4, 145.0, 161.4, 165.5, 172.1,
172.4 ppm. MS (ESI): m/z (%) = 634 (100) [M + Na+], 167 (82).
HRMS (ESI): calcd. for C35H33NNaO7S [M + Na+] 634.18699;
found 634.18757.
(0.64 g, 1.33 mmol, 50%); [α]2D0 = +150 (c = 0.4, CH2Cl2). IR (film):
1
ν = 1780, 1745, 1723 cm–1. H NMR (400 MHz, CDCl ): δ = 1.28
˜
3
(s, 3 H, 2α-Me), 1.52 (s, 9 H, CO2tBu), 1.57 (s, 3 H, 2β-Me), 4.65
(s, 1 H, 3-H), 5.99 (s, 1 H, 5-H), 6.19 (s, 1 H, CHCO2tBu), 6.95 (s, 1
H, CHPh2), 7.30–7.37 (m, 10 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 25.5, 28.1, 33.8, 63.9, 69.2, 70.7, 78.4, 82.8, 118.1,
127.1, 127.5, 128.2, 128.6, 128.7, 139.1, 139.2, 155.1, 62.9,
166.8 ppm. MS (ESI): m/z (%) = 502 (68) [M + Na+], 167 (100).
HRMS (ESI): calcd. for C27H29NNaO5S [M + Na+] 502.16586;
found 502.16531.
(1ЈR,6R)-3-Benzhydryl 2Ј-Benzyl 1Ј-Benzoylspiro(cyclopent-3-enyl)-
5Ј,6-penicillanate-3,2Ј-dicarboxylate (13b) and (1ЈR,6S)-3-Benzhy-
dryl 4Ј-Benzyl 1Ј-Benzoylspiro(cyclopent-4-enyl)-5Ј,6-penicillanate-
3,4Ј-dicarboxylate (14b): Obtained from allene 8a (70 mg,
0.40 mmol) and 6-alkylidenepenicillanate 7b (193 mg, 0.40 mmol)
as described in the general procedure (reaction time: 5 h). Purifica-
tion of the crude product by flash chromatography (hexane/ethyl
acetate, 5:1), gave, in order of elution, 13b as a yellow oil (94 mg,
0.14 mmol, 35%) and 14b as a fluffy yellow solid (138 mg,
0.21 mmol, 53%).
Benzhydryl 6-(Z)-(1-Acetylmethylene)penicillanate (7d): Prepared
from 6-oxopenicillanate 11 (2.86 g, 7.50 mmol) and phosphorus
ylide 12d (2.24 g, 7.04 mmol), as described in the general procedure.
After purification by flash chromatography (hexane/ethyl acetate,
2:1), compound 7d was obtained as a brown oil (1.25 g, 2.97 mmol,
42%); [α]2D0 = +230 (c = 1, CH Cl ). IR (film): ν = 1776, 1744,
˜
2
2
1655 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.27 (s, 3 H, 2α-Me),
1.56 (s, 3 H, 2β-Me), 2.35 (s, 3 H, COMe), 4.66 (s, 1 H, 3-H), 6.03
(s, 1 H, 5-H), 6.54 (s, 1 H, CHCOMe), 6.96 (s, 1 H, CHPh2), 7.31–
7.38 (m, 10 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.4,
31.3, 33.6, 64.0, 69.4, 70.9, 78.5, 120.0, 127.1, 127.6, 128.2, 128.4,
128.6, 128.7, 139.1, 139.2, 154.2, 166.7, 167.7, 196.2 ppm. MS
(ESI): m/z (%) = 422 (100) [M + H+], 268 (43). HRMS (ESI): calcd.
for C24H24NO4S [M + H+] 422.14206; found 422.14104.
Compound 13b: [α]2D0 = +280 (c = 1, CH Cl ). IR (film): ν = 1775,
˜
2
2
1746, 1716, 1671 cm–1. H NMR (400 MHz, CDCl3): δ = 1.11 (s,
1
3 H, 2α-Me), 1.51 (s, 3 H, 2β-Me), 3.10 (dd, 2J = 18.4, 3J = 2.8 Hz,
1 H, 4Ј-H), 3.55 (pseudo-d, J = 18.4 Hz, 1 H, 4Ј-H), 4.53 (s, 1 H,
2
3-H), 4.96 (s, 2 H, CH2Ph), 5.17 (br. s, 1 H, 1Ј-H), 5.43 (s, 1 H, 5-
H), 6.91 (s, 1 H, CHPh2), 7.06 (br. s, 1 H, 3Ј-H), 7.13 (m, 2 H, Ar-
H), 7.25–7.41 (m, 15 H, Ar-H), 7.52–7.56 (m, 1 H, Ar-H), 8.06 (d,
3J = 7.6 Hz, 2 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
26.0, 32.4, 40.7, 52.7, 64.1, 66.6, 69.0, 70.6, 71.1, 78.3, 127.0, 127.6,
128.2, 128.3, 128.3, 128.4, 128.5, 128.6, 128.6, 129.3, 133.5, 135.3,
135.8, 137.3, 139.1, 139.2, 145.8, 162.7, 166.9, 176.3, 201.0 ppm.
MS (ESI): m/z (%) = 680 (16) [M + Na+], 492 (8), 167 (100).
HRMS (ESI): calcd. for C40H35NNaO6S [M + Na+] 680.20773;
found 680.20745.
General Procedure for the Synthesis of Spirocyclopentenyl-β-lact-
ams: To a mixture of the appropriate 6-alkylidenepenicillanate
(0.40 mmol) and PPh3 (20 mol-%) in toluene (3 mL), a solution of
the allene 7 (0.40 mmol) in toluene (2 mL) was added. The reaction
mixture was stirred at room temperature under nitrogen for the
time indicated in each case. The reaction was monitored by TLC.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O30153
/KAP1
Date: 26-04-13 12:42:16
Pages: 10
B. S. Santos, T. M. V. D. Pinho e Melo
FULL PAPER
Compound 14b: M.p. 110–112 °C; [α]2D0 = +385 (c = 1, CH2Cl2). IR
(1ЈR,2ЈR,6S)-3-Benzhydryl 4Ј-Benzyl 1Ј-Methyl 2Ј-Methylspiro(cy-
(KBr): ν = 1781, 1750, 1721, 1677 cm–1. 1H NMR (400 MHz, clopent-4-enyl)-5Ј,6-penicillanate-1Ј,4Ј,3-tricarboxylate (15a): Ob-
˜
CDCl3): δ = 1.11 (s, 3 H, 2α-Me), 1.52 (s, 3 H, 2β-Me), 2.51 (dd, tained from allene 8b (79 mg, 0.42 mmol) and 6-alkylidenepenicil-
3
2
3
2J = 18.8, J = 2.4 Hz, 1 H, 2Ј-H), 3.20 (ddd, J = 18.8, J = 8.4
and 2.0 Hz, 1 H, 2Ј-H), 4.55 (s, 1 H, 3-H), 4.56 (pseudo-d, 3J =
8.4 Hz, 1 H, 1Ј-H), 5.21 (s, 2 H, CH2Ph), 6.29 (s, 1 H, 5-H), 6.91
(br. s, 1 H, 3Ј-H), 6.94 (s, 1 H, CHPh2), 7.29–7.51 (m, 17 H, Ar-
lanate 7a (184 mg, 0.42 mmol) as described in the general pro-
cedure (reaction time: 5 h). After purification by flash chromatog-
raphy (hexane/ethyl acetate, 7:1) to 4:1), 15a was obtained as a
yellow oil (109 mg, 0.17 mmol, 40%). [α]2D0 = +200 (c = 1, CH2Cl2).
H), 7.58–7.62 (m, 1 H, Ar-H), 7.94 (d, 3J = 7.2 Hz, 1 H, Ar-H) IR (film): ν = 1778, 1743, 1731, 1728 cm–1. 1H NMR (400 MHz,
˜
ppm. 13C NMR (100 MHz, CDCl3): δ = 24.7, 31.6, 34.8, 48.3, 61.5,
65.4, 68.0, 69.9, 72.8, 77.2, 126.3, 126.3, 127.0, 127.1, 127.2, 127.3,
127.4, 127.5, 127.5, 127.9, 132.5, 133.2, 134.0, 134.7, 138.5, 143.7,
161.4, 165.6, 173.2, 197.2 ppm. MS (ESI): m/z (%) = 680 (64) [M
CDCl3): δ = 1.22 (s, 3 H, 2α-Me), 1.37 (d, 3J = 7.2 Hz, 3 H, 2Ј-
Me), 1.59 (s, 3 H, 2β-Me), 3.28–3.32 (m, 1 H, 2Ј-H), 3.64 (s, 3 H,
2
CO2Me), 4.10 (br. s, 1 H, 1Ј-H), 4.53 (s, 1 H, 3-H), 5.09 (d, J =
12.4 Hz, 1 H, CH2Ph), 5.26 (d, 2J = 12.4 Hz, 1 H, CH2Ph), 5.49
(s, 1 H, 5-H), 6.92 (br. s, 2 H, CHPh2 and 3Ј-H), 7.33–7.36 (m, 15
H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.4, 26.0, 32.7,
45.2, 52.5, 52.6, 63.3, 66.7, 68.0, 68.9, 69.5, 78.4, 127.0, 127.6,
128.2, 128.3, 128.4, 128.6, 128.6, 132.3, 135.6, 139.1, 139.3, 150.0,
162.8, 166.9, 172.0, 176.2 ppm. MS (ESI): m/z (%) = 648 (100) [M
+ Na+], 626 (20), 492 (15), 196 (92). HRMS (ESI): calcd. for
C36H35NNaO7S [M + Na+] 648.20264; found 648.20469.
+
Na+], 658 (20), 167 (100). HRMS (ESI): calcd. for
C40H35NNaO6S [M + Na+] 680.20773; found 680.20760.
(1ЈR,6R)-3-Benzhydryl 2Ј-Benzyl 1Ј-tert-Butyl Spiro(cyclopent-3-
enyl)-5Ј,6-penicillanate-1Ј,2Ј,3-tricarboxylate (13c) and (1ЈR,6S)-3-
Benzhydryl 4Ј-Benzyl 1Ј-tert-Butyl Spiro(cyclopent-4-enyl)-5Ј,6-pen-
icillanate-1Ј,4Ј,3-tricarboxylate (14c): Obtained from allene 8a
(72 mg, 0.41 mmol) and 6-alkylidenepenicillanate 7c (198 mg,
0.41 mmol) as described in the general procedure (reaction time:
5 h). Purification by flash chromatography (hexane/ethyl acetate,
3:1) gave a mixture of compounds 13c and 14c as a colorless oil
(135 mg, 0.21 mmol, 50%).
(1ЈR,2ЈR,6S)-3-Benzhydryl 4Ј-Benzyl 1Ј-Benzoyl-2Ј-methylspiro(cy-
clopent-4-enyl)-5Ј,6-penicillanate-3,4Ј-dicarboxylate (15b): Obtained
from allene 8b (62 mg, 0.33 mmol) and 6-alkylidenepenicillanate 7b
(158 mg, 0.33 mmol) as described in the general procedure (reac-
tion time: 5 h). After purification by flash chromatography (hexane/
ethyl acetate, 4:1 to 2:1), 15b was obtained as a fluffy yellow solid
(83 mg, 0.12 mmol, 36%); m.p. 64–66 °C; [α]2D0 = +240 (c = 1,
Compound 13c: IR (film): ν = 1774, 1746, 1720, 1631 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 1.16 (s, 3 H, 2α-Me), 1.30 (s, 9 H,
˜
2
3
CH Cl ). IR (KBr): ν = 1769, 1743, 1717, 1678 cm–1. 1H NMR
CO2tBu), 1.54 (s, 3 H, 2β-Me), 2.92 (dd, J = 18.4, J = 2.8 Hz, 1
˜
2
2
H, 4Ј-H), 3.21 (pseudo-d, 2J = 18.4 Hz, 1 H, 4Ј-H), 3.88 (s, 1 H,
3
(400 MHz, CDCl3): δ = 1.10 (s, 3 H, 2α-Me), 1.48 (d, J = 10 Hz,
3 H, 2Ј-Me), 1.56 (s, 3 H, 2β-Me), 2.81–2.84 (m, 1 H, 2Ј-H), 4.11
(br. s, 1 H, 1Ј-H), 4.55 (s, 1 H, 3-H), 5.20 (m, 2 H, CH2Ph), 6.23
(s, 1 H, 5-H), 6.86 (d, 3J = 2.8 Hz, 1 H, 3Ј-H), 6.93 (s, 1 H, CHPh2),
2
1Ј-H), 4.46 (s, 1 H, 3-H), 5.13 (d, J = 2.0 Hz, 1 H, CH2Ph), 5.36
(s, 1 H, 5-H), 6.86 (s, 1 H, CHPh2), 6.93 (br. s, 1 H, 3Ј-H), 7.18–
7.39 (m, 15 H, Ar-H) ppm. MS (ESI): m/z (%) = 654 (17) [M +
H+], 598 (14), 167 (100). HRMS (ESI): calcd. for C38H40NO7S [M
+ H+] 654.25200; found 654.25266.
3
7.26–7.52 (m, 17 H, Ar-H), 7.60–7.63 (m, 1 H, Ar-H), 7.93 (d, J
= 7.2 Hz, 2 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.3,
25.7, 32.7, 43.6, 56.3, 62.4, 66.4, 69.2, 71.1, 73.7, 78.2, 127.4, 128.1,
128.1, 128.2, 128.4, 128.5, 128.6, 129.0, 132.9, 133.5, 135.5, 135.7,
139.6, 149.9, 162.6, 166.7, 174.0, 198.0 ppm. MS (ESI): m/z (%) =
672 (100) [M + H+], 313 (39), 221 (32), 196 (80). HRMS (ESI):
calcd. for C41H38NO6S [M + H+] 672.24144; found 672.24251.
Compound 14c: IR (film): ν = 1774, 1746, 1720, 1631 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 1.13 (s, 3 H, 2α-Me), 1.35 (s, 9 H,
CO2tBu), 1.52 (s, 3 H, 2β-Me), 2.50 (dd, J = 18.8, J = 2.8 Hz, 1
H, 1 H, 2ЈH), 3.01 (ddd, J = 18.8, J = 8.4 and 1.6 Hz, 1 H, 1 H,
˜
2
3
2
3
3
2Ј-H), 3.37 (pseudo-d, J = 8.4 Hz, 1 H, 1Ј-H), 4.48 (s, 1 H, 3-H),
5.10 (s, 2 H, CH2Ph), 6.11 (s, 1 H, 5-H), 6.86 (s, 1 H, CHPh2), 6.93
(br. s, 1 H, 3Ј-H), 7.26–7.36 (m, 15 H, Ar-H) ppm. MS (ESI): m/z
(%) = 654 (17) [M + H+], 598 (14), 167 (100). HRMS (ESI): calcd.
for C38H40NO7S [M + H+] 654.25200; found 654.25266.
(1ЈR,2ЈR,6S)-3-Benzhydryl 4Ј-Benzyl 1Ј-Acetyl-2Ј-methylspiro(cy-
clopent-4-enyl)-5Ј,6-penicillanate-3,4Ј-dicarboxylate (15c): Obtained
from allene 8b (77 mg, 0.41 mmol) and 6-alkylidenepenicillanate 7d
(172 mg, 0.41 mmol) as described in the general procedure (reac-
tion time: 3 h). After purification by flash chromatography (hexane/
ethyl acetate, 4:1 to 2:1), 15c was obtained as a yellow oil (93 mg,
(1ЈR,6R)-3-Benzhydryl 2Ј-Benzyl 1Ј-Acetylspiro(cyclopent-3-enyl)-
5Ј,6-penicillanate-3,2Ј-dicarboxylate (13d): Obtained from allene 8a
(71 mg, 0.41 mmol) and 6-alkylidenepenicillanate 7d (172 mg,
0.41 mmol) as described in the general procedure (reaction time:
3 h). After purification by flash chromatography (hexane/ethyl
acetate, 4:1 to 2:1), 13d was obtained as a yellow oil (99 mg,
0.15 mmol, 37%); [α]2D0 = +220 (c = 0.75, CH Cl ). IR (film): ν =
˜
2
2
1769, 1741, 1711, 1638 cm–1. 1H NMR (400 MHz, CDCl3): δ =
3
1.16 (s, 3 H, 2α-Me), 1.42 (d, J = 7.2 Hz, 3 H, 2Ј-Me), 1.56 (s, 3
H, 2β-Me), 2.27 (s, 3 H, COMe), 2.78–2.79 (m, 1 H, 2Ј-H), 3.27
2
(br. s, 1 H, 1Ј-H), 4.54 (s, 1 H, 3-H), 5.15 (d, J = 12.4 Hz, 1 H,
0.17 mmol, 41%); [α]2D0 = +220 (c = 0.5, CH Cl ). IR (KBr): ν =
˜
CH2Ph), 5.19 (d, 2J = 12.4 Hz, 1 H, CH2Ph), 6.12 (s, 1 H, 5-H),
2
2
1775, 1744, 1709, 1630 cm–1. 1H NMR (400 MHz, CDCl3): δ =
3
6.83 (d, J = 2.4 Hz, 1 H, 3Ј-H), 6.93 (s, 1 H, CHPh2), 7.26–7.46
1.22 (s, 3 H, 2α-Me), 1.62 (s, 3 H, 2β-Me), 2.42 (s, 3 H, COMe),
(m, 15 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.1,
25.7, 29.4, 35.2, 42.6, 61.1, 62.5, 66.4, 69.0, 71.0, 73.5, 78.2, 127.3,
128.1, 128.1, 128.2, 128.4, 128.5, 132.5, 135.7, 139.5, 149.8, 162.5,
166.7, 173.6, 206.1 ppm. MS (ESI): m/z (%) = 610 (100) [M + H+],
558 (7). HRMS (ESI): calcd. for C36H36NO6S [M + H+] 610.22579;
found 610.22352.
2
3
2.99 (dd, J = 18.4, J = 2.8 Hz, 1 H, 1 H, 4Ј-H), 3.33 (pseudo-d,
2J = 18.4 Hz, 1 H, 1 H, 4Ј-H), 4.28 (s, 1 H, 1Ј-H), 4.54 (s, 1 H, 3-
2
2
H), 5.15 (d, J = 12.4 Hz, 1 H, CH2Ph), 5.20 (d, J = 12.4 Hz, 1
H, CH2Ph), 5.42 (s, 1 H, 5-H), 6.93 (s, 1 H, CHPh2), 6.98 (br. s, 1
H, 3Ј-H), 7.26–7.36 (m, 15 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 26.1, 32.6, 32.8, 40.1, 58.4, 63.8, 66.8, 69.0, 69.7, 70.9,
78.3, 127.0, 127.8, 128.2, 128.4, 128.5, 128.6, 128.6, 134.8, 135.4,
139.1, 139.2, 145.6, 163.1, 166.9, 176.0, 209.3 ppm. MS (ESI): m/z
(1ЈR,4ЈR,6R)-3-Benzhydryl 2Ј-Benzyl 1Ј-Methyl 4Ј-Phenylspiro(cy-
clopent-3-enyl)-5Ј,6-penicillanate-1Ј,2Ј,3-tricarboxylate (16a): Ob-
(%) = 596 (60) [M + H+], 568 (100), 540 (36), 351 (30). HRMS tained from allene 8c (98 mg, 0.39 mmol) and 6-alkylidenepenicil-
(ESI): calcd. for C35H34NO6S [M
596.20818.
+
H+] 596.21013; found
lanate 7a (169 mg, 0.39 mmol) as described in the general pro-
cedure (reaction time: 7 h). After purification by flash chromatog-
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30153
/KAP1
Date: 26-04-13 12:42:16
Pages: 10
Chiral Spirocyclopentenyl-β-lactams
raphy (hexane/ethyl acetate, 5:1), 16a was obtained as a colorless
oil (153 mg, 0.22 mmol, 56%); [α]2D0 = +105 (c = 1, CH2Cl2). IR
(s, 1 H, 5-H), 6.85 (d, 3J = 2.8 Hz, 1 H, 3Ј-H), 6.94 (s, 1 H, CHPh2),
7.25–7.48 (m, 20 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ
(film): ν = 1775, 1720, 1682, 1645 cm–1. 1H NMR (400 MHz, = 25.6, 30.6, 33.0, 54.2, 61.3, 62.4, 66.6, 69.0, 71.6, 74.6, 78.3,
˜
CDCl3): δ = 1.11 (s, 3 H, 2α-Me), 1.56 (s, 3 H, 2β-Me), 3.60 (s, 3
127.3, 127.4, 128.0, 128.1, 128.3, 128.4, 128.6, 129.0, 133.9, 135.6,
139.5, 139.9, 146.7, 162.3, 166.7, 173.3, 206.4 ppm. MS (ESI): m/z
(%) = 672 (100) [M + H+], 588 (21), 422 (12), 326 (18). HRMS
(ESI): calcd. for C41H38NO6S [M
672.23885.
3
H, CO2Me), 4.22 (s, 1 H, 1Ј-H), 4.46 (d, J = 2.4 Hz, 1 H, 4Ј-H),
2
4.51 (s, 1 H, 3-H), 4.81 (s, 1 H, 5-H), 5.13 (d, J = 12.4 Hz, 1 H,
CH2Ph), 5.31 (d, 2J = 12.4 Hz, 1 H, CH2Ph), 6.89 (s, 1 H, CHPh2),
6.98 (br. s, 1 H, 3Ј-H), 7.22–7.38 (m, 20 H, Ar-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 25.9, 32.6, 52.3, 52.8, 57.3, 63.2, 66.9, 68.8,
68.9, 69.0, 78.2, 127.0, 127.4, 128.1, 128.2, 128.3, 128.4, 128.4,
128.6, 128.6, 128.6, 128.8, 129.5, 134.6, 135.6, 139.0, 139.3, 146.2,
162.7, 166.7, 171.7, 176.5 ppm. MS (ESI): m/z (%) = 710 (3) [M +
Na+], 460 (7), 167 (100). HRMS (ESI): calcd. for C41H37NNaO7S
[M + Na+] 710.21829; found 710.21877.
+
H+] 672.24144; found
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra for compounds 7 and 13–17.
NOESY, HMQC and HMBC spectra of selected compounds.
Acknowledgments
(1ЈR,2ЈS,6S)-3-Benzhydryl 4Ј-Benzyl 1Ј-Benzoyl-2Ј-phenylspiro(cy-
clopent-4-enyl)-5Ј,6-penicillanate-3,4Ј-dicarboxylate (17b): Obtained
from allene 8c (79 mg, 0.32 mmol) and 6-alkylidenepenicillanate 7b
(155 mg, 0.32 mmol) as described in the general procedure (reac-
tion time: 7 h). After purification by flash chromatography (hexane/
ethyl acetate, 7:1) to 5:1), 17b was obtained as a fluffy yellow solid
(197 mg, 0.27 mmol, 84%); m.p. 72–74 °C; [α]2D0 = +190 (c = 1,
Thanks are due to Fundação para a Ciência e a Tecnologia (SFRH/
BD/63622/2009 and PEst-C/QUI/UI0313/2011) for financial sup-
port. We acknowledge the Nuclear Magnetic Resonance Labora-
tory of the Coimbra Chemitry Centre (http://www.nmrccc.uc.pt),
University of Coimbra for obtaining the NMR spectroscopic data
and AtralCipan for providing the 6-aminopenicillanic acid. We also
thank Cláudio M. Nunes for carrying out the computational calcu-
lations.
CH Cl ). IR (film): ν = 1770, 1743, 1720, 1676 cm–1. 1H NMR
˜
2
2
(400 MHz, CDCl3): δ = 1.08 (s, 3 H, 2α-Me), 1.40 (s, 3 H, 2β-Me),
3.87 (br. s, 1 H, 2Ј-H), 4.49 (br. s, 1 H, 1Ј-H), 4.52 (s, 1 H, 3-H),
5.20 (d, 2J = 12.4 Hz, 1 H, CH2Ph), 5.27 (d, 2J = 12.4 Hz, 1 H,
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3
CH2Ph), 6.22 (s, 1 H, 5-H), 6.88 (d, J = 2.8 Hz, 1 H, 3Ј-H), 6.94
(s, 1 H, CHPh2), 7.26–7.48 (m, 22 H, Ar-H), 7.60–7.62 (m, 1 H,
Ar-H), 7.88 (d, 3J = 7.6 Hz, 2 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 24.6, 31.4, 54.1, 55.2, 61.2, 65.6, 68.1, 70.8, 74.0, 77.2,
126.3, 126.3, 126.9, 127.0, 127.1, 127.2, 127.3, 127.5, 127.5, 127.6,
127.7, 127.9, 127.9, 132.6, 133.0, 134.4, 134.6, 138.3, 138.5, 145.9,
161.4, 165.7, 172.7, 197.2 ppm. MS (ESI): m/z (%) = 734 (61) [M
+ H+], 167 (100). HRMS (ESI): calcd. for C46H40NO6S [M + H+]
734.25709, found 734.25773.
(1ЈR,4ЈR,6R)-3-Benzhydryl 2Ј-Benzyl 1Ј-Acetyl-4Ј-phenylspiro(cy-
clopent-3-enyl)-5Ј,6-penicillanate-3,2Ј-dicarboxylate
(16c)
and
(1ЈR,2ЈS,6S)-3-Benzhydryl 4Ј-Benzyl 1Ј-Acetyl-2Ј-phenylspiro(cy-
clopent-4-enyl)-5Ј,6-penicillanate-3,4Ј-dicarboxylate (17c): Obtained
from allene 8c (100 mg, 0.40 mmol) and 6-alkylidenepenicillanate
7d (169 mg, 0.40 mmol) as described in the general procedure (reac-
tion time: 24 h). Purification of the crude product by flash
chromatography (hexane/ethyl acetate, 5:1), gave, in order of elu-
tion, 16c as a colorless oil (32 mg, 0.048 mmol, 12%) and 17c as a
colorless oil (130 mg, 0.19 mmol, 48%).
Compound 16a: [α]2D0 = +67 (c = 0.9, CH Cl ). IR (film): ν = 1775,
˜
2
2
1
1741, 1712, 1638 cm–1. H NMR (400 MHz, CDCl3): δ = 1.01 (s,
3 H, 2α-Me), 1.52 (s, 3 H, 2β-Me), 2.42 (s, 3 H, COMe), 4.36 (d,
3J = 1.6 Hz, 1 H, 4Ј-H), 4.42 (s, 1 H, 1Ј-H), 4.45 (s, 1 H, 3-H), 4.70
(s, 1 H, 5-H), 5.09 (d, 2J = 12.4 Hz, 1 H, CH2Ph), 5.18 (d, 2J =
12.4 Hz, 1 H, CH2Ph), 6.82 (s, 1 H, CHPh2), 6.87 (br. s, 1 H, 3Ј-
H), 7.15–7.29 (m, 20 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 26.2, 32.3, 33.8, 57.0, 58.8, 63.6, 67.0, 69.0, 69.1, 70.7, 78.2,
127.0, 127.4, 128.1, 128.2, 128.4, 128.5, 128.6, 128.6, 128.7, 129.8,
135.2, 135.2, 136.6, 139.0, 139.3, 146.2, 163.1, 166.7, 177.4,
208.5 ppm. MS (ESI): m/z (%) = 672 (100) [M + H+], 644 (40), 557
(51), 501 (65), 422 (22). HRMS (ESI): calcd. for C41H38NO6S [M
+ H+] 672.24144; found 672.23893.
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O30153
/KAP1
Date: 26-04-13 12:42:16
Pages: 10
B. S. Santos, T. M. V. D. Pinho e Melo
FULL PAPER
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Received: January 29, 2013
Published Online: ᭿
10
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