Diastereoselective synthesis of β-Lactam-oxindole hybrids through a three-component reaction of azetidine-2,3-diones, α-diazo-oxindoles, and alcohols catalyzed by [Rh2(OAc)4]

Article abstract of DOI:10.1002/ejoc.201101625

β-Lactam-oxindole hybrids have been synthesized in good yields in a one-pot procedure through efficient and stereoselective capture of an oxonium ylide with azetidine-2,3-diones. The reaction allows high to moderate control of stereoselectivity, depending on the 3-diazo-oxindole precursor and the hydroxylic compound used. Two new quaternary stereogenic centers were formed; the stereochemistry at the C-3 quaternary center was controlled by a bulky substituent at C-4, whereas the stereoselectivity in the adjacent second quaternary stereogenic center was controlled by the α-diazo-oxindole. The stereochemistry of both quaternary centers has been unambiguously assigned by single-crystal X-ray diffraction. Densely functionalized β-lactam-oxindole hybrids have been prepared in a one-pot, multicomponent reaction between azetidine-2,3-diones, α-diazo-oxindoles, and alcohols. Two new stereogenic centers were formed; the stereochemistry at the new C-3 quaternary center was controlled by a bulky substituent at C-4, whereas the second new stereogenic center was controlled by the α-diazo-oxindole.

Full text of DOI:10.1002/ejoc.201101625

FULL PAPER
DOI: 10.1002/ejoc.201101625
Diastereoselective Synthesis of β-Lactam–Oxindole Hybrids Through a Three-
Component Reaction of Azetidine-2,3-diones, α-Diazo-oxindoles, and Alcohols
Catalyzed by [Rh2(OAc)4]
Benito Alcaide,*[a] Pedro Almendros,[b] Cristina Aragoncillo,[a] Ricardo Callejo,[a]
M. Pilar Ruiz,[a] and M. Rosario Torres[c]
Keywords: Multicomponent reactions / Nitrogen heterocycles / Lactams / Diazo compounds / Ylides / Rhodium
β-Lactam–oxindole hybrids have been synthesized in good
yields in a one-pot procedure through efficient and stereo-
selective capture of an oxonium ylide with azetidine-2,3-di-
ones. The reaction allows high to moderate control of stereo-
selectivity, depending on the 3-diazo-oxindole precursor and
the hydroxylic compound used. Two new quaternary stereo-
genic centers were formed; the stereochemistry at the C-3
quaternary center was controlled by a bulky substituent at
C-4, whereas the stereoselectivity in the adjacent second
quaternary stereogenic center was controlled by the α-diazo-
oxindole. The stereochemistry of both quaternary centers has
been unambiguously assigned by single-crystal X-ray dif-
fraction.
Introduction
The 3-substituted 3-hydroxy β-lactam constitutes an ef-
ficient carboxylate mimic,[1] showing auspicious activity in
acyl CoA-cholesterol acyltransferase inhibition assays.[2]
Furthermore, it is found in different monobactams with
interesting pharmacological activities such as sulfacezin (A;
Figure 1) and related compounds.[3] On the other hand, the
3-substituted 3-hydroxyoxindole skeleton occurs in many
biologically active molecules. Among them, oxindoles with
heteroatoms at the stereogenic center are a useful class of
compounds in the field of medicinal chemistry, including
the potent growth hormone secretagogue SM-130686 (B;
Figure 1).[4] Owing to the significance of this structural mo-
tif, several syntheses of these compounds have been re-
ported.[5] In particular, special attention has been focused
on asymmetric versions of these compounds.[6]
Figure 1. Representative compounds containing the 3-substituted
3-hydroxy β-lactam (A) and 3-substituted 3-hydroxyoxindole (B)
skeletons.
the RhII-catalyzed aldol-type three-component reaction of
methyl phenyldiazoacetate with an alcohol and an aldehyde,
affording highly substituted hydroxy acid derivatives with
several quaternary centers in a single step.[8] As shown in
Scheme 1, an oxonium ylide, generated in situ from a rho-
dium carbenoid, is captured by an aldehyde (imine) to af-
ford an aldol-type addition product.[8]
Generation of oxonium ylides by rhodium(II)-catalyzed
decomposition of α-diazocarbonyl compounds have been
extensively used in organic chemistry.[7] In this context, Hu
and co-workers have described a novel reaction involving
[a] Grupo de Lactamas y Heterociclos Bioactivos, Departamento
de Química Orgánica I, Unidad Asociada al CSIC, Facultad de
Química, Universidad Complutense de Madrid,
28040 Madrid, Spain
Scheme 1. Capture of oxonium ylides with aldehydes.
Fax: +34-91-39444103
Following our interest in the asymmetric synthesis of
nitrogenated compounds of biological significance,[9] in a
previous report we described the rhodium-catalyzed synthe-
sis of 3-hydroxy β-lactams through a three-component reac-
tion between azetidine-2,3-diones, ethyl diazoacetate, and
alcohols.[10] It was found that this multicomponent reaction
proceeds in good to moderate stereoselectivity depending
E-mail: alcaideb@quim.ucm.es
[b] Instituto de Química Orgánica General, Consejo Superior de
Investigaciones Científicas, CSIC,
Juan de la Cierva 3, 28006 Madrid, Spain
[c] Laboratorio de Difracción de Rayos X. Facultad de Química,
Universidad Complutense,
28040 Madrid, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101625.
Eur. J. Org. Chem. 2012, 2359–2366
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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B. Alcaide et al.
FULL PAPER
on the alcohol used. Due the importance of the 3-hydroxy- was isolated as a single isomer in low yield (32%). Probably,
3-substituted β-lactam and 3-substituted 3-hydroxyoxindole the presence of the highly reactive NH bond, which forms
skeletons, and because of our interest in the preparation an ylide intermediate after attack of the metal carbene to
of synthetic hybrid products combining the properties of the lone pair of electrons on the heteroatom, is responsible
different natural products, we thought that it could be re- for the formation of the complex mixture. Thus, our next
warding to apply the previous methodology to the con- experiments examined the multicomponent reaction using
struction of β-lactam–oxindole hybrids in a single step N-methyl-protected 3-diazo-oxindole 2b. Reaction of 1a in
through an efficient and stereoselective trapping of an ox- the presence of 2b (1 equiv.), methanol (1.2 equiv.) and
onium ylide with azetidine-2,3-diones. Taking into account [Rh2(OAc)4] (1 mol-%), cleanly afforded β-lactam–oxindole
the current interest in using diazo-oxindoles for reaction hybrid 3b with moderate diastereoselectivity (syn/anti,
development,[11] we were particularly interested in probing 85:15) in good yield (89%). Fortunately, both isomers could
the process with these compounds.
be separated by flash chromatography. When azetidine-2,3-
diones (–)-1b and (Ϯ)-1c were used instead of α-keto β-
lactam 1a, the reactions proceeded in a similar manner, giv-
ing the corresponding β-lactam–oxindole hybrids 3c and 3d
(Table 1, entries 3A and 4A). Treatment of azetidine-2,3-di-
one (+)-1a and diazo-oxindole 2b with allylic alcohol, un-
der the same conditions, afforded compound 3e in good
yield but with low diastereoselectivity (65:35; Table 1, en-
try 5A).
Results and Discussion
Starting substrates, azetidine-2,3-diones 1a–c were pre-
pared both in racemic form and in optically pure form
using our methodology. Enantiopure azetidine-2,3-diones
(+)-1a and (–)-1b were obtained as single cis-enantiomers
from imines of (R)-2,3-O-isopropylideneglyceraldehyde,
through Staudinger reaction with acetoxyacetyl chloride in
the presence of Et3N, followed by sequential transesterifica-
tion and Swern oxidation, as previously reported.[12] Race-
mic azetidine-2,3-dione 1c was prepared from a tolyl-de-
rived imine following our previous procedure.[13] Diazo-isa-
tin 2c was synthesized by N-acylation of compound 2a with
p-nitrobenzoyl chloride,[14] and N-methyl diazocarbonyl
compounds 2b and 2d–f were prepared from the corre-
sponding NH-isatin through N-alkylation under standard
conditions (MeI, NaH, in DMF) followed by diazotization
using a modification of Carreira’s procedure (Figure 2).[14]
To obtain better diastereoselectivity in the three-compo-
nent reaction, the next stage was to treat azetidine-2,3-di-
ones with a more bulky diazo compound, PNB diazo-isatin
2c. When the reaction was performed with PNB diazo-isa-
tin and alcohol under the conditions described above, sim-
ilar diastereoselectivities and yields were obtained (Table 1,
entries 9A–15A). Unfortunately, in some cases, the mixture
of diastereoisomers could not be separated by flash
chromatography (Table 1, entries 11A, 12A, and 13A–15A).
To our delight, when titanium(IV) isopropoxide was used
instead of alcohols,[15] the corresponding β-lactam–oxin-
dole hybrids 3 were obtained in higher diastereoselectivities
and with moderate to good yields (Table 1, entries 6B–8B
and 13B–15B). In view of these results, we explored the role
of titanium(IV) isopropoxide in influencing the diastereo-
selectivity of the reaction by adding a catalytic amount
(20 mol-%) into the reaction of ketone 1a, diazo-oxindole
2c, and iPrOH. Thus, the expected compound 3m was ob-
tained as a mixture syn/anti (86:14) in 73% yield. On the
other hand, when the reaction was performed under the
same conditions using MeOH instead iPrOH, a 75:25 mix-
ture of 3i (syn/anti = 80:20; 52% yield) and 3m (syn/anti
Ͼ95:5; 4% yield) was obtained. The results obtained seem
to indicate that both reagents, alcohol, and titanium(IV)
isopropoxide react independently and that the use of a cata-
lytic amount of [Ti(iPrO)4] does not control the diastereo-
selectivity in the reaction of alcohols.
Figure 2. Starting materials used to study the multicomponent re-
action.
In all reactions tested, a small amount of the insertion
product, formed from reaction of 3-diazo-oxindole and the
corresponding alcohol, was detected in 20 to 50 mol-% by
1H NMR analysis of the crude product. However, when the
Our initial aim was to explore the reactivity of azetidine- reaction was carried out by slow addition of the 3-diazo-
2,3-dione 1a as a model system for the study of the three- oxindole, a dramatic reduction in the amount (5–8 mol-%)
component reaction with alcohols. Thus, reaction of 1a in of the insertion compound was observed.
the presence of 1.2 equivalents of 3-diazo-oxindole 2a and
Interestingly, the PNB group was easily removed by
1.2 equivalents of methanol under rhodium catalysis treatment of compound 3i with sodium methoxide in meth-
(1 mol-%) afforded a complex reaction mixture. However, anol at –45 °C, affording β-lactam–oxindole hybrid 3a in
after purification by flash chromatography, compound 3a 58% yield (Scheme 2). Thus, the characterization data and
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Diastereoselective Synthesis of β-Lactam–Oxindole Hybrids
Table 1. RhII-catalyzed aldol-type three-component reaction of azetidine-2,3-diones 1a–c.
Entry[a]
Substrate
R1
R2
R3
R4
Reagent
t [h][c]
Product
syn/anti[e]
Yield [%]
[d]
1A
2A
3A
4A
5A
6A
6B
7A
7B
8A
8B
9A
10A
11A
12A
13A
13B
14A
14B
15A
15B
(+)-1a
(+)-1a
(–)-1b
(Ϯ)-1c
(+)-1a
(+)-1a
(+)-1a
(–)-1b
(–)-1b
(Ϯ)-1c
(Ϯ)-1c
(+)-1a
(–)-1b
(Ϯ)-1c
(+)-1a
(+)-1a
(+)-1a
(–)-1b
(–)-1b
(Ϯ)-1c
(Ϯ)-1c
PMP
PMP
Bn
PMP
PMP
PMP
PMP
Bn
Diox[b]
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
2-propenyl
iPr
iPr
iPr
iPr
iPr
iPr
Me
Me
Me
2-propenyl
iPr
iPr
iPr
MeOH
MeOH
MeOH
MeOH
allyl alcohol
iPrOH
[Ti(iPrO)4]
iPrOH
[Ti(iPrO)4]
iPrOH
[Ti(iPrO)4]
MeOH
MeOH
MeOH
allyl alcohol
iPrOH
[Ti(iPrO)4]
iPrOH
[Ti(iPrO)4]
iPrOH
[Ti(iPrO)4]
6
3a
3b
3c
3d
3e
3f
–
32[f]
Diox[b]
21
23
23
21
27
5
23
6
23
2
7
6
4
4
8
2
6
2
4
2
85:15
60:40
83:17
65:35
80:20
90:10
60:40
Ͼ95:5
65:35
Ͼ95:5
80:20
75:25
75:25
86:14
85:15
90:10
85:15
Ͼ 95:5
80:20
Ͼ95:5
76:13[g]
50:33[g]
73:14[g]
65:35[g]
68:16[g]
57[f]
Diox[b]
4-MeC6H4
Diox[b]
Diox[b]
Diox[b]
3f
Diox[b]
3g
3g
3h
3h
3i
3j
3k
3l
3m
3m
3n
3n
3o
3o
46:33[g]
60[f]
Bn
Diox[b]
Me
Me
Me
PMP
PMP
PMP
Bn
PMP
PMP
PMP
PMP
Bn
4-MeC6H4
4-MeC6H4
Diox[b]
56:30[g]
69[f]
PNB
PNB
PNB
PNB
PNB
PNB
PNB
PNB
PNB
PNB
77:19[g]
65:22[g]
92[h]
Diox[b]
4-MeC6H4
Diox[b]
96[h]
Diox[b]
95[h]
Diox[b]
54[f]
Diox[b]
89[h]
Bn
PMP
PMP
Diox[b]
iPr
iPr
iPr
42[f]
4-MeC6H4
4-MeC6H4
79[h]
71[f]
[a] “A” refers to the use of an alcohol (Method A described in the Exp. Section for the preparation of hybrids 3) and “B” refers to the
use of [Ti(iPrO)4] (Method B described in the Exp. Section for the preparation of hybrids 3). [b] Diox = 2,2-dimethyl-1,3-dioxolan-4-yl.
[c] Reaction progress was followed by TLC analysis. [d] A complex crude material was obtained; after purification, only the syn isomer
was isolated. [e] The ratio was determined by integration of well-resolved signals in the 1H NMR spectra (300 MHz) of the crude reaction
mixtures before purification. [f] Yield of pure syn isomer. [g] Yield of pure, isolated isomers with correct analytical and spectra data.
[h] Yield of pure, isolated mixture of isomers.
the stereochemistry of compound 3a, obtained by reaction yields (Table 2, entries 4–6). 5-Chloro-diazo-oxindole 2d
of azetidine-2,3-dione 1a, diazo-oxindole 2a and methanol, was the least reactive α-diazo compound tested, and ad-
was confirmed by comparison of both products.
dition of four equivalents was necessary to achieve conver-
sions of 73 and 80% (Table 2, entries 1 and 4, respectively).
Having established the optimal reaction conditions to
carry out the multicomponent reaction with alcohols and
titanium(IV) isopropoxide, our next aim was to evaluate the
feasibility of the applying the process using phenols. Thus,
the reaction was investigated with azetidine-2,3-dione 1a,
diazo-oxindole 2c, and phenol. In the event, β-lactam–oxin-
dole hybrid 3v was isolated as a mixture of diastereoisomers
(77:23) in moderate yield (50%; Scheme 3). Attempts to ex-
tend the scope of the process with other types of phenols
were unsuccessful. In fact, when the reaction was tested
with electron-withdrawing as well as electron-donating phe-
nols, only complex crude reaction mixtures were observed.
Unfortunately, formation of compound 3v through this
three-component methodology appears to be an isolated ex-
ample and we have not yet found a reasonable explanation
to account for this behavior.
Scheme 2. Deprotection of the PNB group in compound syn-(+)-
3i. Reagents and conditions: (i) MeONa, MeOH, –45 °C.
The scope of the three-component reaction was studied
by using azetidine-2,3-dione (+)-1a and either methanol or
[Ti(iPrO)4] with different substituted α-diazo-oxindoles
2d–f (Table 2). These experiments showed a similar behavior
to reactions using α-diazo-oxindoles 2a–c (see Table 1), and
compounds 3p–r were obtained in good yields with dia-
stereoselectivity values in the range 65:35–85:15 when meth-
anol was used (Table 2, entries 1–3). As expected, when the
The stereoselectivity of the multicomponent reaction
reaction was carried out with titanium(IV) isopropoxide, with azetidine-2,3-diones 1 is believed to be controlled by
the diastereoselectivity of the reaction increased to 95:5– the bulky chiral auxiliary at C-4 and the substituent in the
90:10, affording compounds 3s–u in reasonable to excellent diazo-compound, in which one face of the carbonyl group
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Table 2. RhII-catalyzed aldol-type three-component reaction of N-methyl-3-diazo-oxindoles 2d–f.
Entry Substrate R1
R2
R3
Reagent
t
Conversion
[%][b]
Product
syn/anti[c]
Yield
[%]
[h][a]
1
2
3
4
5
6
2d
2e
2f
2d
2e
2f
Cl
NO2
H
Cl
NO2
H
H
H
MeO
H
H
Me
Me
Me
iPr
iPr
iPr
MeOH
MeOH
MeOH
[Ti(iPrO)4]
[Ti(iPrO)4]
[Ti(iPrO)4]
48
23
21
5
2
2
73
3p
3q
3r
3s
3t
70:30
85:15
65:35
90:10
92:8
61:26[d]
100
100
80
100
100
83[e]
57:31[d]
63[f]
89[f]
MeO
3u
95:5
55[f]
1
[a] Reaction progress was followed by TLC. [b] The conversion was determined by integration of well-resolved signals in the H NMR
spectra (300 MHz) of the crude reaction mixtures before purification. [c] The ratio was determined by integration of well-resolved signals
in the 1H NMR spectra (300 MHz) of the crude reaction mixtures before purification. [d] Yield of pure, isolated isomers with correct
analytical and spectral data. [e] Yield of pure, isolated mixture of isomers. [f] Yield of pure syn isomer.
is blocked preferentially, thus the oxonium ylide species is
delivered to the less hindered face.[16] The stereochemical
outcome of the overall reaction of oxonium ylides to azetid-
ine-2,3-diones can be explained by the five-membered cyclic
transitions states TS1 and TS2 (Scheme 4).[17] Interaction
between the oxonium ylide, derived from diazo-isatin, with
H-4 of the β-lactam ring would cause the reaction to take
place mainly through TS1, in which the steric interactions
are minimized compared to TS2, affording the syn-isomer.
Analogously, when the reaction is performed in the pres-
ence of titanium(IV) isopropoxide, transition state TS3 is
found to be more favorable than TS4, because the coordi-
nation of the titanium atom to both functionalities of azeti-
dine-2,3-dione and the oxonium ylide results in less pro-
nounced steric interactions in TS3 that in transition state
TS4.
Scheme 3. Multicomponent reaction of azetidine-2,3-dione 1a, di-
azo-oxindole 2c, and phenol in the presence of [Rh2(OAc)4]. Rea-
gents and conditions: (i) [Rh2(OAc)4] (1 mol-%), CH2Cl2, Δ.
Scheme 4. Proposed transitions states used to explain the stereochemical outcome of the reaction of oxonium ylides with azetidine-2,3-
diones.
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Diastereoselective Synthesis of β-Lactam–Oxindole Hybrids
(2.2 mmol), and [Rh2(OAc)4] (0.01 mmol) in anhydrous dichloro-
methane (8 mL). The reaction mixture was stirred at reflux tem-
perature until disappearance of the starting material was observed
(TLC). The reaction mixture was allowed to cool to room tempera-
ture and filtered through a short path of Celite. The solvent was
removed under reduced pressure and the residue was purified by
flash chromatography.
The structural and configurational assignment of com-
pounds 3 was unequivocally assigned by single-crystal X-
ray analysis of compound syn-(+)-3f (Figure 3).[18]
Method B: 3-Diazo-oxindole 2 (1.2 mmol) in anhydrous dichloro-
methane (2 mL) was added to a refluxing solution of azetidine-2,3-
dione
1 (1 mmol), [Ti(iPrO)4] (1.2 mmol) and [Rh2(OAc)4]
(0.01 mmol) in anhydrous dichloromethane (8 mL). The reaction
mixture was stirred at reflux temperature until disappearance of
the starting material was observed (TLC). The reaction mixture
was allowed to cool to room temperature, diluted with EtOAc
(27 mL), washed with NH4Cl (satd.) (18 mL), then extracted with
EtOAc (2ϫ18 mL). The organic extract was dried (MgSO4), con-
centrated under reduced pressure, and the residue was purified by
flash chromatography.
β-Lactam–oxindole Hybrid 3b: Method A; from azetidine-2,3-dione
(+)-1a (39 mg, 0.13 mmol), the less polar compound syn-(+)-3b
(42 mg, 76%) and the more polar compound anti-(+)-3b (14 mg,
13%) were obtained after flash chromatography (n-hexane/ethyl
acetate, 2:1).
Figure 3. X-ray diffraction analysis of compound syn-(+)-3f.
syn-(+)-3b: White solid; m.p. 117–120 °C (n-hexane/ethyl acetate);
[α]D = +14.3 (c = 0.3, CHCl3). 1H NMR (300 MHz, CDCl3, 25 °C):
δ = 7.78 (dd, J = 7.4, 0.7 Hz, 1 H, Ar-H), 7.45 (AAЈXXЈ, 2 H, Ar-
H), 7.38 (td, J = 7.7, 1.3 Hz, 1 H, Ar-H), 7.12 (td, J = 7.7, 0.8 Hz,
1 H, Ar-H), 6.88 (AAЈXXЈ, 2 H, Ar-H), 6.87–6.89 (m, 1 H, Ar-H),
5.16 (d, J = 4.1 Hz, 1 H, CH), 4.42 (td, J = 6.8, 4.1 Hz, 1 H, OCH),
4.15 (dd, J = 8.9, 6.6 Hz, 1 H, OCHH), 3.97 (dd, J = 8.9, 7.2 Hz,
1 H, OCHH), 3.80 (s, 3 H, Me), 3.26 (s, 3 H, Me), 3.04 (s, 3 H,
Me), 1.32 (s, 3 H, Me), 1.37 (s, 3 H, Me) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 173.9 (NC=O), 165.5 (NC=O), 156.8 (C), 145.0
(C), 130.6 (CH), 130.4 (C), 126.6 (CH), 123.3 (CH), 123.2 (C),
120.6 (CH), 114.1 (CH), 109.7 (C), 108.4 (CH), 87.2 (C), 82.3 (C),
76.0 (OCH), 66.4 (OCH2), 60.8 (CH), 55.4 (OMe), 53.2 (OMe),
Conclusions
The present study provides a rapid, stereoselective syn-
thesis of β-lactam–oxindole hybrids through a multicompo-
nent reaction between azetidine-2,3-diones, 3-diazo-oxin-
doles, and alcohols in the presence of catalytic amounts of
[Rh2(OAc)4]. Interestingly, two new quaternary stereogenic
centers are formed with moderate to high diastereoselectivi-
ties.
Experimental Section
26.3 (Me), 26.2 (Me), 25.5 (Me) ppm. IR (KBr): ν = 3345,
˜
General Methods: Melting points were measured with a Gallen-
kamp apparatus. IR spectra were recorded with a Perkin–Elmer
781 spectrophotometer. 1H and 13C NMR spectra were recorded
with a Bruker Avance-300 spectrometer. NMR spectra were re-
corded in CDCl3 solutions, except where otherwise stated; chemical
shifts are given in ppm relative to TMS (1H, δ = 0.0 ppm), or
CDCl3 (13C, δ = 77.0 ppm). IR spectra were recorded with a Bruker
Tensor 27 spectrometer. Low- and high-resolution mass spectra
were recorded with an AGILENT 6520 Accurate-Mass QTOF LC/
MS spectrometer using electronic impact (EI) or electrospray
modes (ES) unless otherwise stated. Specific rotation [α]D is given
in 10–1 deg cm2 g–1 at 20 °C, and the concentration (c) is expressed
in g per 100 mL. All commercially available compounds were used
without further purification. Flame-dried glassware and standard
Schlenk techniques were used for moisture-sensitive reactions.
Flash chromatography was performed with Merck silica gel 60
(230–400 mesh). Reactions were monitored by TLC (Kiesegel 60F-
254); UV light (λ = 254 nm) and a solution of phosphomolybdic
acid in EtOH (1 g of phosphomolybdic acid hydrate, 100 mL) were
used to develop the plates.
1725 cm–1; HRMS (ESI): calcd. for C25H29N2O7 [M + H]+
469.1975; found 469.1973.
anti-(+)-3b: Colorless oil; [α]D = +29.2 (c = 0.4, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.42 (d, J = 7.5 Hz, 1 H, Ar-H),
7.35 (AAЈXXЈ, 2 H, Ar-H), 7.33–7.39 (m, 1 H, Ar-H), 7.00 (t, J =
7.5 Hz, 1 H, Ar-H), 6.90 (d, J = 7.9 Hz, 1 H, Ar-H), 6.76 (AAЈXXЈ,
2 H, Ar-H), 4.41 (q, J = 7.1 Hz, 1 H, CH), 4.38 (s, 1 H, OH), 4.20
(dd, J = 9.1, 6.7 Hz, 1 H, OCHH), 3.92 (d, J = 7.4 Hz, 1 H, CH),
3.76 (s, 3 H, Me), 3.70 (dd, J = 9.1, 6.4 Hz, 1 H, OCHH), 3.21 (s, 3
H, Me), 3.13 (s, 3 H, Me), 1.37 (s, 3 H, Me), 1.29 (s, 3 H, Me) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 172.8 (NC=O), 163.7
(NC=O), 156.6 (C), 144.3 (C), 131.0 (CH), 130.0 (C), 126.2 (CH),
123.4 (CH), 122.0 (C), 120.2 (CH), 113.8 (CH), 109.6 (C), 108.7
(CH), 86.4 (C), 82.6 (C), 76.6 (OCH), 66.6 (OCH2), 62.7 (CH),
55.3 (OMe), 53.8 (OMe), 26.5 (Me), 26.3 (Me), 25.0 (Me) ppm.
IR (CHCl ): ν = 3352, 1748, 1723 cm–1; HRMS (ESI): calcd. for
˜
3
C25H28N2O7 [M + Na]+ 491.1794; found 491.1797.
β-Lactam–Oxindole Hybrid 3c: Method A; from azetidine-2,3-di-
one (–)-1b (62 mg, 0.23 mmol), the less polar compound syn-(–)-3c
(51 mg, 50%) and the more polar compound anti-(+)-3c (34 mg,
33%) were isolated after purification by flash chromatography (n-
hexane/ethyl acetate, 3:1).
General Procedure for the Synthesis of β-Lactam–Oxindole Hybrids
3 Through Multicomponent Reaction
Method A: 3-Diazo-oxindole 2 (2.2 mmol) in anhydrous dichloro-
methane (11 mL) was added slowly over 5 h to a refluxing solution
of the azetidine-2,3-dione 1 (1 mmol), the corresponding alcohol
1
syn-(–)-3c: Colorless oil; [α]D = –46.4 (c = 0.2, CHCl3). H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.83 (d, J = 7.0 Hz, 1 H, Ar-H),
Eur. J. Org. Chem. 2012, 2359–2366
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2363

B. Alcaide et al.
FULL PAPER
7.37 (td, J = 7.8, 1.2 Hz, 1 H, Ar-H), 7.28–7.35 (m, 5 H, Ar-H),
7.12 (td, J = 7.6, 0.7 Hz, 1 H, Ar-H), 6.84 (d, J = 7.7 Hz, 1 H, Ar-
H), 5.03 (d, J = 15.0 Hz, 1 H, NCHH), 4.43 (d, J = 3.8 Hz, 1 H,
CH), 4.33–4.38 (m, 1 H, OCH), 4.21 (s, 1 H, OH), 4.12 (d, J =
15.1 Hz, 1 H, NCHH), 4.04 (dd, J = 9.0, 7.2 Hz, 1 H, OCHH),
3.80 (dd, J = 9.1, 4.8 Hz, 1 H, OCHH), 3.19 (s, 3 H, Me), 3.04 (s,
H, OCHH), 4.18 (s, 1 H, OH), 3.86 (d, J = 7.6 Hz, 1 H, CH), 3.76
(s, 3 H, OMe), 3.74 (dd, J = 9.0, 6.4 Hz, 1 H, OCHH), 3.45 (sept,
J = 6.1 Hz, 1 H, CHMe2), 3.22 (s, 3 H, Me), 1.29 (s, 3 H, Me),
1.16 (d, J = 6.1 Hz, 3 H, CHMe2), 1.05 (d, J = 6.0 Hz, 3 H,
CHMe2) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 173.7
(NC=O), 163.7 (NC=O), 156.5 (C), 144.0 (C), 130.8 (CH), 130.2
3 H, Me), 1.43 (s, 3 H, Me), 1.31 (s, 3 H, Me) ppm. 13C NMR (C), 126.5 (CH), 123.2 (C, CH), 120.0 (CH), 113.8 (CH), 109.5
(75 MHz, CDCl3, 25 °C): δ = 173.8 (NC=O), 168.0 (NC=O), 144.9 (CMe2), 108.6 (CH), 86.5 (C), 81.9 (C), 76.8 (OCH), 70.8 (CHMe2),
(C), 134.5 (C), 130.4 (CH), 128.7 (CH), 128.4 (CH), 127.5 (CH), 66.7 (OCH2), 62.8 (CH), 55.4 (OMe), 26.6 (Me), 26.3 (Me), 25.1
126.9 (CH), 123.42 (C), 123.38 (CH), 110.0 (CMe2), 108.1 (CH),
88.1 (C), 82.2 (C3), 74.5 (OCH), 66.4 (OCH2), 59.9 (CH), 52.8
(Me), 23.9 (Me), 23.2 (Me) ppm. IR (CHCl ): ν = 3362, 1734 cm–1;
˜
3
HRMS (ESI): calcd. for C27H33N2NaO7 [M + Na]+ 519.2107;
(OMe), 44.7 (NCH2), 26.21 (Me), 26.17 (Me), 24.8 (Me) ppm. IR found 519.2112.
(CHCl ): ν = 3327, 1751, 1725 cm–1; HRMS (ESI): calcd. for
˜
3
β-Lactam–oxindole Hybrid 3i: Method A; from azetidine-2,3-dione
(+)-1a (54 mg, 0.19 mmol), the less polar compound syn-(+)-3i
(82 mg, 77%) and the more polar compound anti-(–)-3i (21 mg,
19%) were isolated after purification by flash chromatography (n-
hexane/ ethyl acetate, 4:1).
C25H29N2O6 [M + H]+ 453.2026; found: 453.2017.
1
anti-(+)-3c: Colorless oil; [α]D = +47.8 (c = 0.2, CHCl3). H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.45 (dd, J = 7.4, 0.7 Hz, 1 H, Ar-
H), 7.36 (td, J = 7.7, 1.2 Hz, 1 H, Ar-H), 7.10–7.18 (m, 3 H, Ar-
H), 7.04 (td, J = 7.7, 0.7 Hz, 1 H, Ar-H), 6.84–6.86 (d, J = 7.2 Hz,
2 H, Ar-H), 6.84 (d, J = 7.6 Hz, 1 H), 4.69 (d, J = 14.9 Hz, 1 H,
NCHH), 4.35–4.31 (m, 1 H, CH), 4.14 (br. s, 1 H, OH), 4.10 (d, J
= 14.8 Hz, 1 H, NCHH), 4.06 (dd, J = 9.2, 6.6 Hz, 1 H, OCHH),
3.51 (dd, J = 9.2, 5.4 Hz, 1 H, OCHH), 3.19 (s, 3 H, Me), 3.12 (s,
3 H, Me), 3.03 (d, J = 8.3 Hz, 1 H, CH), 1.10 (s, 3 H, Me), 1.26
(s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 173.0
(NC=O), 165.9 (NC=O), 144.5 (C), 134.9 (C), 131.0 (CH), 128.4
(CH), 128.1 (CH), 127.2 (CH), 126.3 (CH), 123.7 (CH), 121.8 (C),
109.3 (CMe2), 108.6 (CH), 87.0 (C), 82.2 (C), 76.2 (OCH), 66.5
(OCH2), 60.8 (CH), 53.7 (OMe), 44.7 (NCH2), 26.3 (Me), 26.1
syn-(+)-3i: White solid; m.p. 142–144 °C (n-hexane/ethyl acetate);
[α]D = +182.0 (c = 0.3, CHCl3). 1H NMR (300 MHz, CDCl3,
25 °C): δ = 8.33 (AAЈXXЈ, 2 H, Ar-H), 7.97 (d, J = 7.4 Hz, 1 H,
Ar-H), 7.95 (AAЈXXЈ, 2 H, Ar-H), 7.89 (dd, J = 7.6, 0.9 Hz, 1 H,
Ar-H), 7.50 (td, J = 7.9, 1.3 Hz, 1 H, Ar-H), 7.40 (AAЈXXЈ, 2 H,
Ar-H), 7.35 (td, J = 7.6 Hz, 1 H, Ar-H), 6.90 (AAЈXXЈ, 2 H, Ar-
H), 5.05 (d, J = 3.4 Hz, 1 H, CH), 4.57 (s, 1 H, OH), 4.31 (td, J =
6.7, 3.4 Hz, 1 H, OCH), 4.11 (dd, J = 8.8, 6.6 Hz, 1 H, OCHH),
3.87 (dd, J = 8.8, 6.9 Hz, 1 H, OCHH), 3.81 (s, 3 H, Me), 3.11 (s,
3 H, Me), 1.37 (s, 3 H, Me), 1.34 (s, 3 H, Me) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 175.4 (NC=O), 166.7 (NC=O), 164.8
(NC=O), 157.2 (C), 150.1 (C), 141.2 (C), 139.7 (C), 131.1 (CH),
130.0 (C, CH), 126.9 (CH), 125.9 (CH), 123.5 (CH), 122.7 (C),
120.8 (CH), 115.1 (CH), 114.3 (CH), 110.2 (CMe2), 87.9 (C), 82.9
(C), 75.5 (OCH), 66.2 (OCH2), 60.4 (CH), 55.4 (OMe), 57.8 (OMe),
(Me), 25.0 (Me) ppm. IR (CHCl ): ν = 3348, 1756, 1725 cm–1;
˜
3
HRMS (ESI): calcd. for C25H29N2O6 [M + H]+ 453.2026; found
453.2022.
β-Lactam–oxindole Hybrid 3f: Method A; from azetidine-2,3-dione
(+)-1a (44 mg, 0.15 mmol), the less polar compound syn-(+)-3f
(50 mg, 68%) and the more polar compound anti-(+)-3f (12 mg,
16%) were obtained after flash chromatography (n-hexane/ethyl
acetate, 3:1).
26.1 (Me), 25.6 (Me) ppm. IR (KBr): ν = 3268, 1757, 1711 cm–1;
˜
HRMS (ESI): calcd. for C31H30N3O10 [M + H]+ 604.1931; found
604.1926.
1
anti-(–)-3i: Colorless oil; [α]D = –152.3 (c = 0.4, CHCl3). H NMR
Method B: From azetidine-2,3-dione (+)-1a (43 mg, 0.15 mmol),
the less polar compound syn-(+)-3f (43 mg, 57%) was obtained af-
ter flash chromatography (n-hexane/ethyl acetate, 3:1).
(300 MHz, CDCl3, 25 °C): δ = 7.98 (d, J = 8.0 Hz, 1 H, Ar-H),
7.71 (dd, J = 7.6, 0.9 Hz, 1 H, Ar-H), 7.60 (AAЈXXЈ, 2 H, Ar-H),
7.53–7.58 (m, 1 H, Ar-H), 7.51 (AAЈXXЈ, 2 H, Ar-H), 7.40
(AAЈXXЈ, 2 H, Ar-H), 7.37 (td, J = 7.6, 0.9 Hz, 1 H, Ar-H), 6.95
(AAЈXXЈ, 2 H, Ar-H), 4.93 (d, J = 5.0 Hz, 1 H, CH), 4.50 (q, J =
6.1 Hz, 1 H, OCH), 4.27 (s, 1 H, OH), 4.19 (dd, J = 8.8, 6.8 Hz, 1
H, OCHH), 3.96 (dd, J = 9.0, 6.6 Hz, 1 H, OCHH), 3.92 (s, 3 H,
Me), 3.13 (s, 3 H, Me), 1.38 (s, 3 H, Me), 1.35 (s, 3 H, Me) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 173.7 (NC=O), 166.9
(NC=O), 163.3 (NC=O), 157.6 (C), 149.7 (C), 140.2 (C), 139.2 (C),
131.4 (CH), 129.6 (C), 129.5 (CH), 127.2 (CH), 125.8 (CH), 123.3
(CH), 122.4 (C), 120.7 (CH), 115.6 (CH), 114.5 (CH), 110.3
(CMe2), 86.8 (C), 83.3 (C), 75.8 (OCH), 66.4 (OCH2), 60.9 (CH),
55.5 (OMe), 53.8 (OMe), 26.3 (Me), 25.2 (CH3) ppm. IR (CHCl3):
syn-(+)-3f: White solid; m.p. 156–157 °C (n-hexane/ethyl acetate);
[α]D = +40.7 (c = 0.7, CHCl3). 1H NMR (300 MHz, CDCl3, 25 °C):
δ = 7.80 (d, J = 7.4 Hz, 1 H, Ar-H), 7.41 (AAЈXXЈ, 2 H, Ar-H),
7.37 (t, J = 7.7 Hz, 1 H, Ar-H), 7.10 (t, J = 7.2 Hz, 1 H, Ar-H),
6.88 (AAЈXXЈ, 2 H, Ar-H), 6.86 (d, J = 7.6 Hz, 1 H, Ar-H), 5.19
(d, J = 3.8 Hz, 1 H, CH), 4.45 (td, J = 7.1, 3.8 Hz, 1 H, CH), 4.37
(br. s, 1 H, OH), 4.16 (dd, J = 8.8, 6.7 Hz, 1 H, OCHH), 3.95 (dd,
J = 8.7, 7.2 Hz, 1 H, OCHH), 3.81 (s, 3 H, OMe), 3.48 (sept, J =
6.1 Hz, 1 H, CHMe2), 3.25 (s, 3 H, Me), 1.37 (s, 3 H, Me), 1.32 (s,
3 H, Me), 1.04 (d, J = 6.1 Hz, 3 H, CHMe2), 0.86 (d, J = 6.1 Hz,
3 H, CHMe2) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 175.0
(NC=O), 166.1 (NC=O), 156.7 (C), 144.5 (C), 130.5 (C), 130.3
(CH), 126.8 (CH), 124.6 (C), 123.0 (CH), 120.6 (CH), 114.1 (CH),
ν
=
3361, 1759, 1706 cm–1; HRMS (ESI): calcd. for
C31H29N3NaO10 [M + Na]+ 626.1751; found 626.1748.
˜
109.7 (CMe2), 108.3 (CH), 87.8 (C), 81.0 (C), 75.8 (OCH), 69.6 β-Lactam–Oxindole Hybrid 3v: Method A; from azetidine-2,3-di-
(CHMe2), 66.4 (OCH2), 60.8 (CH), 55.4 (OMe), 26.3 (Me), 26.2 one (+)-1a (52 mg, 0.18 mmol), an inseparable mixture of syn/anti
(Me), 25.5 (Me), 23.8 (Me), 23.1 (Me) ppm. IR (KBr): ν = 3347, isomers (ratio 77:23, 60 mg, 50%) was obtained after flash
˜
1723 cm–1; HRMS (ESI): calcd. for C27H33N2O7 [M + H]+
497.2288; found 497.2285.
chromatography (n-hexane/ethyl acetate, 3:1).
syn-3v: Colorless oil. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 8.25
(AAЈXXЈ, 2 H, Ar-H), 8.07 (d, J = 6.9 Hz, 1 H, Ar-H), 7.90 (d, J
= 8.2 Hz, 1 H, Ar-H), 7.64 (AAЈXXЈ, 2 H, Ar-H), 7.48–7.52 (m, 1
H, Ar-H), 7.45 (AAЈXXЈ, 2 H, Ar-H), 7.35 (td, J = 7.5 Hz, 1 H,
1
anti-(+)-3f: Colorless oil; [α]D = +8.5 (c = 0.2, CHCl3). H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.43 (d, J = 7.3 Hz, 1 H, Ar-H),
7.36 (AAЈXXЈ, 2 H, Ar-H), 7.32–7.37 (m, 1 H, Ar-H), 6.97 (t, J =
7.2 Hz, 1 H, Ar-H), 6.89 (d, J = 8.2 Hz, 1 H, Ar-H), 6.76 (AAЈXXЈ, Ar-H), 7.13–7.18 (m, 2 H, Ar-H), 7.04–7.09 (m, 1 H, Ar-H), 6.93
2 H, Ar-H), 4.37–4.44 (m, 1 H, OCH), 4.22 (dd, J = 9.1, 6.6 Hz, 1 (AAЈXXЈ, 2 H, Ar-H), 6.62–6.67 (m, 2 H, Ar-H), 5.32 (d, J =
2364
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2359–2366

Diastereoselective Synthesis of β-Lactam–Oxindole Hybrids
[4]
[5]
[6]
2.6 Hz, 1 H, CH), 4.70 (s, 1 H, OH), 4.37 (td, J = 6.7, 2.7 Hz, 1
H, OCH), 4.12 (dd, J = 9.0, 6.0 Hz, 3 H, OCHH), 3.92 (dd, J =
9.4, 6.4 Hz, 1 H, OCHH), 3.82 (s, 3 H, Me), 1.36 (s, 3 H, Me), 1.35
(s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 173.8
(NC=O), 166.6 (NC=O), 164.9 (NC=O), 157.3 (C), 154.3 (C),
150.0 (C), 140.5 (C), 139.4 (C), 131.3 (CH), 130.0 (CH), 129.9 (C),
129.6 (CH), 127.4 (CH), 126.1 (CH), 124.5 (CH), 123.8 (C), 123.4
(CH), 120.8 (CH), 120.2 (CH), 114.9 (CH), 114.6 (CH), 110.3
(CMe2), 88.3 (C), 83.2 (C), 75.3 (C), 66.1 (OCH2), 60.4 (C), 55.4
(OMe), 26.0 (Me), 25.6 (Me) ppm. HRMS (ESI): calcd. for
C36H31N3O10 [M + H]+ 665.2082; found 665.2100.
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Deprotection of the PNB Group in syn-(+)-3i. Synthesis of the β-
Lactam–Oxindole syn-(+)-3a: Sodium methoxide (3.5 mg,
0.06 mmol) was added to a well-stirred solution of syn-(+)-3i
(32 mg, 0.05 mmol) in MeOH (1.3 mL) at –45 °C. After 15 min,
brine (2.5 mL) was added and the methanol was removed under
reduced pressure. The mixture was extracted with EtOAc
(5ϫ5 mL), dried (MgSO4), and the solvent was removed under
reduced pressure. The residue was purified by flash chromatog-
raphy (n-hexane/ethyl acetate, 1:1) to give pure syn-(+)-3a (14 mg,
58%). White solid; m.p. 126–128 °C (n-hexane/ethyl acetate); [α]D
1
= +50.9 (c = 0.6, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ
= 7.87 (br. s, 1 H, NH), 7.78 (d, J = 7.4 Hz, 1 H, Ar-H), 7.47
(AAЈXXЈ, 2 H, Ar-H), 7.31 (td, J = 7.7, 1.2 Hz, 1 H, Ar-H), 7.11
(td, J = 7.6, 0.9 Hz, 1 H, Ar-H), 6.89 (AAЈXXЈ, 2 H, Ar-H), 6.88
(d, J = 7.7 Hz, 1 H, Ar-H), 5.11 (d, J = 4.2 Hz, 1 H, CH), 4.40–
4.46 (m, 1 H, CH), 4.40 (br. s, 1 H, OH), 4.15 (dd, J = 8.8, 6.6 Hz,
1 H, OCHH), 3.92 (dd, J = 8.8, 7.2 Hz, 1 H, OCHH), 3.81 (s, 3
H, Me), 3.11 (s, 3 H, Me), 1.37 (s, 3 H, Me), 1.33 (s, 3 H, Me) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 175.6 (NC=O), 165.5
(NC=O), 156.9 (C), 142.0 (C), 130.7 (CH), 130.4 (C), 127.1 (CH),
123.5 (C), 123.4 (CH), 120.7 (CH), 114.2 (CH), 110.3 (CH), 109.8
(CMe2), 87.1 (C), 82.6 (C), 76.0 (OCH), 66.4 (OCH2), 60.8 (CH),
[7]
55.4 (OMe), 33.4 (OMe), 26.2 (Me), 25.5 (Me) ppm. IR (KBr): ν
˜
= 3362, 1731 cm–1; HRMS (ESI): calcd. for C24H27N2O7 [M +
H]+ 455.1818; found 455.1818.
Supporting Information (see footnote on the first page of this arti-
cle): Full spectroscopic and analytical data for compounds not in-
cluded in the Exp. Section above are described. Characterization
data and experimental procedures for compounds 2, 3d, 3e, 3g, 3h
and 3j–u, as well as X-ray data for compound syn-(+)-3f, and cop-
ies of NMR spectra for all new compounds are provided.
[8]
Acknowledgments
We would like to thank Ministerio de Ciencia e Innovación (MIC-
INN) (project number CTQ2009-09318), Comunidad Autónoma
de Madrid (CAM) (project number S2009/PPQ-1752) and UCM-
Santander (grant number GR35/10-A) for financial support. R. C.
thanks the Ministerio de Educación y Ciencia (MEC) for a predoc-
toral grant.
[9]
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2365

B. Alcaide et al.
FULL PAPER
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[18] X-ray data of syn-(+)-3f: crystallized from n-hexane/CH2Cl2 at
20 °C. C24H29NO6 (495.54); tetragonal; space group = P4(3); a
= 11.172(2), b = 11.172(2), c = 20.816(5) Å; α = 90, β = 90, γ
= 90°; V = 2598.2 (10) Å3; Z = 4; ρcalcd. = 1.267 mgm–3; μ =
0.092 mm–1; F(000)= 1052. A transparent crystal of dimensions
0.48ϫ0.09ϫ0.09 mm3 was used; 4551 [R(int) = 0.01830] inde-
pendent reflections were collected. Data were collected [Mo-Kα
radiation (λ = 0.71073 Å)] over a hemisphere of the reciprocal
space by combination of three exposure sets. Each exposure of
20 s and 30 s covered 0.3 in γ. The structure was solved by
direct methods and Fourier synthesis. It was refined by full-
matrix least-squares procedures on F2 (SHELXL-97). The non-
hydrogen atoms were refined anisotropically. The hydrogen
atoms were refined only in terms of their coordinates. CCDC-
831957 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.cam.ac.uk/
data_request/cif.
Received: November 10, 2011
Published Online: March 8, 2012
2366
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2359–2366