Synthesis of polycyclic β-lactams. Evolution of tertiary radicals generated by Cp2TiCl from 1,5- and 1,6-epoxynitriles

Article abstract of DOI:10.1016/j.tet.2011.11.015

Radical cyclisation induced by Cp₂TiCl of several 1,5- and 1,6-epoxynitriles derived from β-lactams gave 3-oxo-4-methyl-4- hydroxymethylcarbapenams or 4-oxo-5-methylbenzocarbacephems. Apart from these polycyclic β-lactams, the generated alkyl tertiary radicals also evolved to enamides through β-fragmentation and reduction and the tertiary homobenzyl radicals gave a 3,4-trans-6-hydroxymonolactam by hydrogen transfer.

Full text of DOI:10.1016/j.tet.2011.11.015

Tetrahedron 68 (2012) 10794e10805
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of polycyclic b-lactams. Evolution of tertiary radicals
generated by Cp2TiCl from 1,5- and 1,6-epoxynitriles
*
ꢀ
Laura M. Monleon, Manuel Grande, Josefa Anaya
ꢀ
Departamento de Química Organica, Facultad de Ciencias Químicas, Universidad de Salamanca, E-37008 Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2011
Received in revised form 26 October 2011
Accepted 7 November 2011
Available online 15 November 2011
Radical cyclisation induced by Cp2TiCl of several 1,5- and 1,6-epoxynitriles derived from b-lactams
gave 3-oxo-4-methyl-4-hydroxymethylcarbapenams or 4-oxo-5-methylbenzocarbacephems. Apart
from these polycyclic -lactams, the generated alkyl tertiary radicals also evolved to enamides through
-fragmentation and reduction and the tertiary homobenzyl radicals gave 3,4-trans-6-
hydroxymonolactam by hydrogen transfer.
b
b
a
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Radical cyclisation
Titanocene monochloride
Tertiary homobenzyl radicals
Methylbenzocarbacephems
Epoxymonolactams
1. Introduction
However, the increasing resistance of bacteria to classical
lactam antibiotics5 is well documented and is the origin of
a growing interest in the synthesis of new -lactams, which could
supersede the destructive action of
-lactamases.6
An approach to deactivate these enzymes consists of modifying
the structure of classical -lactam antibiotics, trying to make them
insensitive to the -lactamase attack. An alternative to avoid the
enzymatic destruction of the antibiotics uses a compound that
disables the -lactamase in synergy with a -lactam antibiotic.
In this context, benzocarbapenems and benzocarbacephems
have been designed as inactivators of -lactamases. These potent
b-
The discovery of natural and synthetic
b
-lactam antibiotics of
b
the carbapenem,1 I, carbacephem,2 II, and trilactam,3 III, types4
(Fig. 1) with improved biological activity and resistance to en-
zymes has provoked a continuing development of high level
methodologies to prepare these compounds.
b
b
b
b
b
6
7
5
4
8
5
7
6
10
11
9
6
5
b
4
antibacterial properties of trilactam type compounds have, there-
3
4
8
7
3
fore, recently made these substances a major synthetic objective7 in
N
N
N
3
1
1
1
2
2
O
O
O
2
the
b-lactam field.
On the other hand, free radical reactions applied to synthetic
5
I
II
III
4
7
6
6
5
problems have successfully been used for preparing a number of
synthetic targets, including the synthesis of five- and six-
membered carbocyclic and heterocyclic compounds,8 and the in-
terest in these reactions continues to increase.
4
3
3
8
7
N
N
1
1
2
2
O
O
Among these free radical reactions, the reductive opening of an
epoxide via single-electron transfer (SET) to a radical intermediate
promoted by titanocene monochloride (Cp2TiCl), and the sub-
sequent radical trapping reaction, represent a valuable synthetic
tool that has been used in deoxygenations, reductions and intra-
and intermolecular carbonecarbon bond forming reactions.9 Thus,
titanium(III) chloride has been extensively used as a mild and
useful reagent for chemical transformations such as the reduction
of aromatic aldehydes,10 glycosyl halides,11 vicinal dihalides,12
Benzocarbapenem
Benzocarbacephem
Fig. 1. Bi- and tricyclic
b
-lactam skeletons.
* Corresponding author. Tel.: þ34 923 294 482; fax: þ34 923 294 574; e-mail
address: janay@usal.es (J. Anaya).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.015

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L.M. Monleon et al. / Tetrahedron 68 (2012) 10794e10805
10795
sulfoxides,13 etc. In particular, bis(cyclopentadienyl)-titanium(III)
chloride is a well known titanium (III) reagent that is effective in
promoting radical carbonecarbon bond formation. Many of the
reported reactions involve either carbonyl compounds,14 epox-
ides15 or alkyl halides16 as radical precursors. Alkenes or alkynes,15
carbonyl compounds9c,17 or the cyano group9h,18 have been re-
ported as radical acceptors.
Staudinger reaction using
D
-glucosamine as chiral auxiliary.20
The racemic epoxynitriles 2e523 were prepared from mono-
lactams 7e10, which were also obtained by ketene-imine cyclo-
addition24 between methoxyacetyl chloride in the presence of TEA
and the imines obtained from methacrylaldehyde or trans-a-
methylcinnamaldehyde and the O-silyl derivative of 2-amino-
2,2-dimethylethanol or o-cyanoaniline. The Staudinger cycloaddi-
tion reactions carried out with derivatives of 2-amino-2,2-
dimethylethanol afforded the racemic cis-2-azetidinones 7 and 8
in 46% and 82% yields, respectively. In contrast, the use of o-cya-
noaniline as starting amine gave, in 79% yield, a 2:3 mixture of 3,4-
cis- and 3,4-trans-2-azetidinones 9 and 10, from which any of the
pure isomers could be isolated by chromatography on silica gel.
In connection with our current research interest in the prepa-
ration8i,19 and biological activities20 of
b-lactams, we have recently
reported the cyclisations of benzyl radicals generated from epox-
yolefin-, epoxyaldehyde- and epoxynitrile-2-azetidinones21 with
Cp2TiCl for the preparation of bi- and tricyclic b-lactam compounds.
In order to extend this methodology, we have studied the re-
activity of the epoxynitriles 1e5 with titanocene monochloride
with the prospect of being able to prepare a great variety of poly-
D-Glucosamine
H2N
H2N
CN
OH
a, b, c
cyclic
b-lactams (Fig. 2). Some preliminary results have already
Rf.20
been published.22
H H
MeO
Ph
5
H
H
O
H
H
O
6
H
H
N
O
3 4
H H
N
MeO
Ph
MeO
Ph
CN
5
MeO
R'
CN
MeO
R'
2' CH(SEt)2
H
O
a, c
3
4
N
3
4
6
2
O
N
N
CN
O
1'
1
O
O
OTBDS
MeO
O
O
H
O
H
H
O
O
Ph
CN
O
7: R'= H
O
2:
R' = H
R' = Ph
= Sg
4:
3,4-cis
3,4-trans
O
4
8:
R'= Ph
3:
5:
= Sg
N
1'
6
O
1
f, g
d
Ti
Cp2 Cl
9: 3,4-cis
10:
H
H
N
3,4-trans
H H
N
MeO
R'
Ph
MeO
Ti
O
(IV)
5
h
H
H
H
H
R'
Ph
CHO
R1
6
MeO
O
MeO
O
O
Ti
O
(IV)
N
H
11:
Sg
N
N
15: R'= H
H
H
N
O
e
1
O
R
R
N
R = CHO
MeO
Ph
CN
16: R'= Ph
12: R1=
CO2Me
RI
RII
j
h
O
OH
R'
H
H
N
H
H
H
H
N
O
MeO
Ph
O
H
H
N
MeO
CO2Me
R'
CN
MeO
Ph
4a,b:
OH
3,4-cis
5
MeO
5a,b: 3,4-trans
O
N
O
O
na:
α
O
5
-epoxy
R2
MeO
O
R1
OH
Ph
III
R2
MeO
H
Sg
13a,b
nb: 5β-epoxy
R1
Ph
I
H
H
N
17: R'= H
18:
OH
H
H
O
R'= Ph
H
H
O
O
MeO
R'
CN
5
i
N
h
O
N
O
IV
H
H
N
O
O
II
MeO
Ph
R1
R'
R2
5
j
R1; R2
H; Sg
Fig. 2. Anticipated reactivity of epoxynitriles 1e5 with Cp2TiCl.
CHO
Sg
14a,b
O
1a,b Ph
2a,b
H
H
The homolytic cleavage of the oxirane ring by action of Cp2TiCl
could afford two radical types from the epoxynitriles 1, 3, 4 and 5:
the tertiary homobenzyl radical RI and the benzyl radical RII, which
is probably more stabilized. On the other side, only the tertiary alkyl
radical RI should be generated from the epoxide 2. Both the tertiary
radical RI and the benzyl radical RII, could yield the bi- and tricyclic
compounds I, III and II, IV, respectively, after intramolecular ad-
dition to the C^N triple bond followed by the habitual acid
hydrolysis.
Me; Me
Ph
3a,b
Scheme 1. Reagents and conditions: (a) methacrylaldehyde or trans-a-methyl-
cinnamaldehyde, CH2Cl2, rt, for 7 and reflux, for 8; toluene, reflux, for 9 and 10; (b)
tBu(Me)2SiCl, py/DMAP, rt; (c) MeOCH2COCl, TEA, CH2Cl2, rt; (d) PhI(CF3CO2)2/NaHCO3,
9:1 CH3CN/H2O, rt; (e) Ph3P]CHeCO2Me, THF, rt; (f) HCl (0.1 M), MeOH, rt; (g) (COCl)2,
DMSO, TEA, CH2Cl2, ꢀ78 ꢁC; (h) m-CPBA, NaHCO3, CH2Cl2, rt; (i) O3, CH2Cl2, ꢀ78 ꢁC,
then Me2S, 0 ꢁC; (j) Me2NeNH2, MeOH, rt, then MMPP, 0 ꢁC.
Deprotection of dithioacetal group in the optically pure mono-
lactam 6 with [bis(trifluoroacetoxy)iodo]benzene yielded alde-
hyde 11, which was used without further purification in the Wittig
reaction with (methoxycarbonylmethylene)triphenylphosphorane
to form the conjugated alkene 12 in 88% yield. The regioselective
epoxidation with m-CPBA of the styryl group in 12 afforded a 1:1
mixture of the pure epoxyesters 13a and 13b in 71% yield after
2. Results and discussion
2.1. Preparation of the cyanoepoxy-2-azetidinones 1e5
The optically pure cyanoepoxy-2-azetidinone 1 was synthesized
from the 2-azetidinone 6 (Scheme 1), which was prepared by

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L.M. Monleon et al. / Tetrahedron 68 (2012) 10794e10805
10796
the chromatographic purification. The ozonolysis of each one of
these epoxides 13 yielded the pure epoxyaldehydes 14a and 14b in
94% and 85% yields, respectively. Treatment of 14a and 14b with
N,N-dimethylhydrazine, followed by oxidation with magnesium
monoperoxyphathalate (MMPP),25 gave the corresponding cya-
noepoxides 1a and 1b in 36% and 28% yields, respectively. A similar
transformation of the aldehyde 11 into the epoxynitriles 1 was not
possible because of the lability of the acetonides to the acid
medium.
The formation of the cyanoepoxides 2 and 3 from the racemic
2-azetidinones 7 and 8 was carried out in four steps. Desilylation
and Swern oxidation of both monolactams 7 and 8 afforded
the aldehydes 15 and 16 in 49% and 73% yields, respectively.
The treatment of these compounds with N,N-dimethylhydrazine
followed by oxidation with magnesium monoperoxyphthalate
(MMPP),25 afforded the corresponding nitriles 17 and 18 in 71%
and 73% yields, respectively. The epoxidation of 17 and 18 with m-
CPBA gave 1:2 and 2:3 diastereomeric mixtures of the cyanoe-
poxy-2-azetidinones 2a/2b and 3a/3b in 59% and 75% yields, re-
spectively, from which any of the isomers could be isolated as
a pure substance by chromatography on silica gel.
as pure substances (we could isolate only very small amounts of
the isomers 4a and 5b).
The cis and trans configurations for the b-lactam ring shown in
Scheme 1 for compounds 1e18 were deduced from the coupling
constants observed between the H3 and H4 protons in their 1H
NMR spectra. From these data, a relative cis configuration was
clearly established for compounds 1e4, 6e9 and 11e18 (Jꢂ4.4 Hz)
and a trans configuration for 5 and 10 (Jꢂ1.8 Hz).26 The (3S,4R)
absolute configuration for compounds 1, 6 and 11e14 was proposed
from the [
a
]
D
data of 6 by comparison with those of the 10,10-
dithyanyl derivative, whose absolute configuration has been
established by X-ray crystal structure analysis.27
The C5 and C6 configurations depicted in Scheme 1 for the
cyanoepoxy-2-azetidinones 1e5 could only be deduced from
the 1H NMR data for the trans-epoxides 5. Thus, the ROESY
correlation between H4 and H6 observed for the isomer 5a and
the absence of this correlation in 5b are in agreement with
a (5a,6a)-epoxy configuration for 5a and (5b,6b)-epoxy for 5b.
On the contrary, the configurations of the oxirane ring in the
cis-isomers 4 were proposed from the configurational assign-
ments of the cyclisation product 22ab (Table 1) obtained by
reaction of the epoxide 4b with Cp2TiCl, as will be discussed
below.
Finally, a 1:2 mixture of isomers 9 and 10, by epoxidation
with m-CPBA, yielded a 2:3:6:4 diastereomeric mixture of epox-
ylactams 4a/4b/5a/5b in 97% yield, from which all the benzoe-
poxynitriles 4 and 5 were isolated by column chromatography
The C5 and C6 configurations for the epoxides 1e3 were ten-
tatively assigned as follows.
Table 1
Reaction of the epoxides 1e5 with Cp2TiCl
Entry
Epoxynitriles
Methoda
Time, h
Products, yieldb
S.m.c
Ph
OH
6
H
H
N
O
5
MeO
Ph
MeO
4
3
A
B
A
B
1.5
2.5
1
19a, 9%
59%
39%
54%
36%
2
CN
O
1
2
1a
N
2'
1
CN
O
19a, 14%
19b, 22%
19b, 34%
1'
O
H
O
1b
O
6'
3'
5'
4'
O
1.5
O
7' O
= Sg
OH
R1
1a,b
19a,b (6α/β-OH)
H
H
MeO
OH
O
4
2
5
6
3
A
B
3
3
20a/b (1:5), 6%
20a/b (1:5), 32%
2a/b (3:8), 21%
2a/b (3:8), 16%
7
3
4
2a/b (1:2)
3a/b (2:3)
N
1
O
H
H
N
O
MeO
R'
CN
20a,b (4β/α-Me)
O
H
H
N
MeO
2a,b: R'= H
3a,b: R'= Ph
Ad
Bd
1
5
21b, 4%
21b, 32%
3a/b (1:1), 59%
d
O
O
21b
H
H
MeO
O
5
2
4
Ad
Bd
Ad
Bd
3
3
3
3
22ab, 14%
22ab, 36%
23ba, 8%
73%
49%
56%
36%
6
7
8
3
5
6
4b
5a
N
4'
3'
1
O
H
H
O
MeO
Ph
CN
1'
3
4
2'
23ba, 13%
N
22ab (5α-Me,6β)
23ba (5β-Me,6α)
O
4
(3,4-cis)
(3,4-trans)
H
H
H
5
6
Ph
MeO
5
3
4
A
B
5
2
24b, 16%
24b, 9%
4a/5b (1:3), 82%
4a/5b (1:3), 79%
2
7
4a/5b (1:4)
OH
H
N
6'
1'
1
O
5'
2'
NC
24b
4'
3'
a
Method A: the Ti(III) reagent was dropped onto the epoxynitrile. Method B: the epoxynitrile was dropped onto the Ti(III) reagent.
Isolated yield after column chromatography.
Recovered starting material.
b
c
d
Benzaldehyde, which was not quantified, was also formed in this reaction.

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L.M. Monleon et al. / Tetrahedron 68 (2012) 10794e10805
10797
For the epoxides 1 and 2, this assignment was made from the 1H
NMR data and the geometrical parameters obtained from the
C4eC5 rotational isomers of minimum energy.28 From this con-
formational analysis it emerges that the minimum energy rotam-
the enamides 19a and 19b (Table 1, entries 1 and 2), whereas the
epoxybenzonitrile 4a was recovered and the trans-isomer 5b
afforded the monolactam 24b (Table 1, entry 7).
The treatment of a 1:2 mixture of epoxides 2a/2b with Cp2TiCl
gave a 1:5 mixture of carbapenams 20a/20b in 6% and 32% yields
by direct and inverse addition, respectively, and a 3:8 mixture
of the starting materials was recovered in 21% and 16% yields
(Table 1, entry 3). As it has been reported,22 the reactions of the
epoxynitriles 3a,b, 4b and 5a with Cp2TiCl, by both A and B
methods, afforded benzaldehyde and the corresponding cyclisa-
tion compounds 21b, 22ab and 23ba, respectively (Table 1, en-
tries 4e6).
ers for the b- and a-epoxides are those shown in Fig. 3. There are
several relative minima for each diastereomer but the gaps be-
tween the lowest and the next energy minima for 2b and 2a are 6.6
and 4.6 kcal/mol, respectively, which implies a population above
99% at room temperature for the most stable rotamers.29 Accord-
ingly, the shielding effect of the oxirane ring on the hydrogen atom
H4 should be stronger for the b-isomers than for the a-isomers, in
which H4 is less exposed to the shielding of the epoxide ring. Thus,
for the isomers with a more shielded signal for H4, we propose the
The reaction products 19e24 were characterized by HRMS (Q-
TOF), IR and NMR (including two-dimensional experiments) data.
The spectroscopic data for the enamides 19 were quite different
(5b,6b)-epoxy configuration, epoxides 1b and 2b, and, conse-
quently, the (5
a
,6
a
)-epoxy configuration for 1a and 2a.
from those expected for
lactam IR absorption bands (
b-lactam compounds. The absence of the b-
n
ꢂ1740 cmꢀ1) and the presence of
amide (1690 cmꢀ1 for 19a and 1685 cmꢀ1 for 19b), hydroxyl
(3427 cmꢀ1 for 19a and 3455 cmꢀ1 for 19b) and nitrile (2252 cmꢀ1
for 19a and 2251 cmꢀ1 for 19b) IR absorption bands imply the ab-
H
H
R'
R'
H
O
H
O
H
H
MeO
MeO
sence of the
NMR spectra do not show the characteristic signals for the proton
geminal to the methoxy group in cis-2-azetidinones
b
-lactam ring in their structures. In addition, the 1H
Me
Me
N
CN
R1 R2
1b, 2b
N
CN
R1 R2
1a, 2a
(d:
O
O
4.50e4.60 ppm, d, J>2 Hz). On the other hand, the presence in their
13C NMR spectra of only one signal for gem-dimethyl group
(C70eMe2) in addition to the presence in the 1H NMR spectra of
a doublet assigned to an olefinic hydrogen (H30), indicate the
elimination of an acetone molecule. The trans stereochemistry for
the C4]C5 double bond shown in Table 1 for the enamides 19a,b
was assigned by comparison of the observed ROESY correlations in
these compounds between the hydrogen atoms H4/H40 and those
predicted for the corresponding minimized structures.28
R' R1 R2
H4
1a 4.17
1b 3.63
Sg
Ph H
3.83
2a
H Me Me
3.42
2b
Fig. 3. Minimum energy conformers for epoxides 1 and 2.
The C5 and C6 configurations for the epoxides 3 were proposed
from their respective polarities (Rf) and 1H NMR data (Fig. 4) by
comparison with the cyanoepoxy-2-azetidinones 1. From these
data, it can be deduced that the less polar isomer 1a shows the
hydrogen atoms H4 and H6 unshielded in comparison with those of
the more polar isomer 1b. Similar values were observed for the
racemic epoxides 3 and consequently, we propose for the less polar
The presence of a ketone function in the structures of com-
pounds 20a,b was evident by the signal in the 13C NMR spectra at
d
¼221.4 ppm. This functional group, as well as the signals for an
alpha methylene geminal to hydroxyl group (
d¼4.29 s for 20a and
dA¼3.61, d, J¼11.1 Hz; dB¼3.85, d, J¼11.1 Hz for 20b) in their 1H NMR
spectra are in agreement with the structures shown in Table 1 for
these bicyclic compounds. The C4 stereochemistry proposed for
compounds 20 was deduced from the C5 configuration of the
starting material 2a and 2b that reacts to form 20a and 20b, re-
spectively. Furthermore, as described above, in these carbapenams,
the hydrogens H8 appear in 1H NMR approximately at the same
field for isomer 20a but show different values for 20b. This fact
suggests that the methoxy and hydroxymethyl groups should be
spatially close in isomer 20b, making the hydroxymethyl sub-
stituent to have a restricted torsion, contrary to what occurs in 20a.
In a similar manner, the structure proposed in Table 1 for car-
bapenam 21b was deduced from the signal in the 13C NMR spec-
isomer 3a the (5
a
,6a
)-epoxy configuration and for the more polar
isomer 3b, the (5
b
,6b)-epoxy configuration.
R1 R2
Rf
H4
H6
H H
MeO
O
a
0.65 4.17 4.31
1a
a
1b 0.57 3.63 3.65
Ph
H Sg
b
3a 0.52 4.06 4.10
N
O
CN
Me Me
b
3b 0.51 3.68 3.94
a
R2
R1
4:6 hexanes/EtOAc as eluent
b
7:3 benzene/EtOAc as eluent
trum at
d
¼218.4 ppm and the C4 configuration was proposed from
the coupling constant observed in the 1H NMR spectrum for the
Fig. 4. Selected physical data for the cyanoepoxy-2-azetidinones 1 and 3.
vicinal H4 and H5 protons (J4,5¼8.7 Hz).
The spectroscopic data of the benzofused tricyclic
b-lactams
2.2. Reactions of cyanoepoxy-2-azetidinones with Cp2TiCl
22ab and 23ba were very similar to those previously described for
the carbapenam 21b, except for the presence in their spectra of
signals for a 1,2-disubstituted benzene and the absence of a gem-
dimethyl group. The C5 configuration shown in Table 1 for the 5-
methylbenzocarbacephems 22ab and 23ba was proposed from
the coupling constants of H5 with the vicinal proton H6
(J5,6¼12.8 Hz, in 22ab; J5,6¼12.9 Hz, in 23ba), which are character-
istic of the trans arrangement between these hydrogen atoms in
both compounds. The proposed C5 stereochemistry for compounds
22ab and 23ba allowed us to assign the oxirane ring stereochem-
The reactions of the epoxynitriles 1e5 with titanocene mono-
chloride15a (Table 1) were first examined by slow addition of
a green solution of Cp2TiCl in THF to a THF solution of the epoxide
(method A), but in these conditions large amounts of un-
transformed starting materials were recovered. Therefore, we
carried out these reactions by inverse addition, i.e., the solution of
the epoxynitrile was dropped onto the green solution of the Ti(III)
reagent (method B).
As shown in Table 1, all the studied cyanoepoxy-2-azetidinones,
except for 1a,b, 4a and 5b, led to the corresponding cyclisation
products, 20e23. Epoxynitriles 1a and 1b yielded, by both methods,
istry for the starting epoxides as (5
epoxy for 5a, respectively. Hence, the epoxide 4a, which did not
react with Cp2TiCl, should have the (5 ,6 )-epoxy configuration.
b,6b)-epoxy for 4b and (5a,6a)-
a
a

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L.M. Monleon et al. / Tetrahedron 68 (2012) 10794e10805
10798
The spectroscopic data of monolactam 24b were very similar to
generated from the epoxides 1a,b evolve by b-fragmentation to
those of the alkene 10 but with the following differences: pres-
ence of a hydroxyl IR absorption band (3354 cmꢀ1), absence of the
signals for the C5]C6 double bond in IR and NMR spectra, and the
shielding of the signals for hydrogen H6 and carbons C5 and C6 in
the NMR spectra. All these facts prompted us to assign the
structure depicted in Table 1 to compound 24b. The C5 and C6
the stabilized radicals R3 [pathway a)],8m,30 which are reduced
by the Ti(III) reagent to form the anions A. These anions, by
the acidic work, evolve to the intermediates B, which can
give the enamides 19a,b by elimination of
a molecule of
dimethylketone.19d,21c
Both alkyl and homobenzyl radicals R2 generated from
epoxides 2e5, except that formed from 5b, cyclise to the or-
stereochemistry proposed for this compound as C5e
aMe and
C6e OH was initially proposed from that of its precursor epoxide
b
ganometallic species C [pathway b)] and then give the b-
5b, on the basis that the reductive opening of the oxirane ring
with titanocene monochloride does not modify the configura-
tion.21,22 This was further confirmed by the coupling constants
observed in the 1H NMR spectrum between hydrogen atoms H4/
H5 (J4,5¼9.0 Hz) and H5/H6 (J5,6¼1.2 Hz), which are in agreement
with cis and trans dispositions between these protons,
respectively.
hydroxyketones 20a,b and D by hydrolysis. These latest com-
pounds, by a retroaldol reaction with loss of benzaldehyde, could
form the bi- and tricyclic products 21b and 22ab or 23ba,
respectively.
The formation of compound 24b from epoxide 5b is more
controversial since the alkyl tertiary radicals with Cp2TiCl evolve
preferably by elimination of titanium oxide18b,31 instead of by
reduction. In addition, there are not literature precedents for
tertiary homobenzyl radicals as R2. On this basis, the mono-
The reactivity of the cianoepoxy-2-azetidinones 1e5 with
Cp2TiCl could be explained as summarized in Scheme 2.
Ph
OH
Ph
OTi(IV)
Ph
OTi(IV)
TiCp2Cl
MeO
O
MeO
MeO
H H
N
O
3
3
MeO
R'
5
Cp2TiCl
H3O
N
N
N
6
CN
CN
CN
O
O
O
CN
H
R1
H
R1
H
R1
O
R
O
O
(1-5)--Ti(III)
O
H
O
O
R3
A
R'
B
O
OTi(IV)
H H
N
H H
N
H Ha
c N
a)
c)
5
MeO
Ti(IV)
MeO
R'
6
H3O
MeO
Ph
b)
O
20a,b
N
b
OTi(IV)
CN
R
O
N
19a,b
O
O
R
R1
R
Ph
b
C
H
R2
O
H H
N
H H
Ph
Ti
MeO
MeO
[H2O]
H
21b
22ab
23ba
a
H3O
Cp2TiCl
Cp2Ti(OH2)Cl
O
24b
O
(IV)
N
O
R
O
PhCHO
Cp2Ti(OH)Cl
D
NC
E
Scheme 2. Proposed pathways explaining the formation of the compounds 19e24.
Both C6eO and C5eO bonds in the structure (1e5)/Ti(III),
formed by coordination of the corresponding epoxynitriles 1e5
with the Ti(III) reagent, may cleave to give the secondary and
tertiary radical intermediates R1 and R2, respectively [except in
2/Ti(III), from which only the tertiary alkyl radical R2 should be
generated because R0¼H]. The reductive opening of the oxirane
ring with Cp2TiCl should take place with the formation of the
best stabilized benzyl radical intermediate R1, however, as it has
been reported,22 the evolution to the reaction products 19e24
reflects the reversibility of the oxirane ring opening, as all these
products should come from the less stable tertiary homobenzyl
radical R2. This radical should be more reactive and have better
accessibility to the cyano group than the benzyl radical R1,
driving the equilibrium towards the observed products. However,
as we have also observed,21d this behaviour did not occur when
the homobenzyl radical was secondary. This is probably because
it is not stabilized enough to be in an appreciable amount in
equilibrium with the benzyl radical. In that case, the cyclisation
products came only from the addition of the benzyl radical to the
cyano group.
lactam 24b could form itself by an hydrogen transfer process32
[pathway c)] from the Cp2TiIII(OH2)Cl complex, formed between
the Cp2TiCl reagent and traces of water present in the reaction
medium, to the radicals R2 (E, Scheme 2) followed by acid hy-
drolysis. However, in all our studies under the same reaction
conditions,21,22 only in this case we have observed the above
reported hydrogen transfer process. Perhaps, the presence of the
aromatic ring on the amidic nitrogen in those tertiary homo-
benzyl radicals R2, which are not able to cyclise could destabilize
the radicals R3 generated through a C3eC4 bond cleavage
[pathway a)]. This prevents the evolution to the corresponding
enamides and could also explain the reaction of the radical R2
generated from the epoxybenzonitrile 5b with the Cp2TiIII(OH2)Cl
complex.
The benzaldehyde elimination process could also be
explained through a radical mechanism (Scheme 3). The alkyl-
and aryl-radicals R2 could form, after cyclisation, the new rad-
icals R4, in equilibrium with the alkoxy radicals R5, which
could lose benzaldehyde through a typical
b-cleavage, gener-
ating the new radical R6. These radicals evolve by reduction
Therefore, the tertiary radicals R2 seem to progress through
very different pathways. The tertiary homobenzyl radicals
followed by hydrolysis to the bi- and tricyclic b-lactams 21 and
22 or 23.

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L.M. Monleon et al. / Tetrahedron 68 (2012) 10794e10805
10799
similar to those previously reported21,22 and all this could indicate
that this type of radicals prefer the polar multiple bonds as radical
acceptors. The coordination between the Ti(III) and the heteroatom
(O or specially N) of multiple bonds may be favourable for the n-exo
radical process.18,33 Moreover, as we have recently reported,34 an
effective cyclic coordination between the Ti(III) reagent with the
nitrile and carbonyl or oxirane functions may generate N-titanai-
midoyl radicals (acyl radical precursors) by homolytic cleavage of
the C^N triple bond. With respect to the tertiary homobenzyl
radicals, the above reported reactivity should indicate that the
evolution of this type of radicals is very dependent on the sub-
stituent at N1 as well as on the relative configuration of the oxirane
ring. Therefore, the tertiary homobenzyl radicals generated from
R'
Ti(IV)
H
H
H
H
N
O
N
MeO
R'
MeO
b)
b
OTi(IV)
N
R
N
O
O
R
R2
R4
C
H
H
MeO
H3O
MeO
R'
D
OH
PhCHO
H
H
H
N
N
O
N
R
O
G
20a,b
Ti(IV)
R
O
the optically pure cis-2-azetidinones 1a,b, with the
D-glucosamine
R5
rest at N1, evolve by -fragmentation of the C3eC4 bond of the b-
b
21b
22ab
23ba
lactam ring; the 3,4-cis tertiary homobenzyl radicals generated
from both the epoxynitriles 2a,b, 3b and the epoxybenzonitrile 4b
evolve by addition to the C^N triple bond; the 3,4-trans tertiary
homobenzyl radical generated from the epoxybenzonitrile 5a
cyclises as well, whereas its isomer, generated from 5b, is reduced
by the Cp2TiIII(OH2)Cl species.
Further studies are required to clarify the reactivity of the ter-
tiary homobenzyl radicals here reported and it may as well be
necessary to evaluate the influence of other groups at the C5 po-
sition of these radicals.
PhCHO
H3O
Ti(IV)
H
H
N
H
N
MeO
MeO
O
Cp2TiCl
N
N
Ti(IV)
Ti(IV)
R
R
O
F
R6
Scheme 3. Proposed radical mechanism explaining the formation of the compounds
21b, 22ab and 23ba.
However, we suppose that the benzaldehyde elimination pro-
cess should preferably take place by rearrangement of D in acid
medium (Scheme 2), because the 4-(hydroxyphenylmethyl)-car-
bapenams 20a,b cannot be formed from F. The presence of the
Cp2TiCl in the reaction medium should give rise to the reduction or
to the intramolecular coupling of benzaldehyde,10 instead of lead-
4. Experimental section
4.1. General methods
Flash chromatographies were run on silica gel (Merck 60,
230e400 mesh) and thin layer chromatographies (TLC), on com-
mercial silica gel plates (Merck F-254). Mass spectra (MS) were
recorded on a VG TS-250 spectrometer: EI at 70 eV; Q-TOF; HRMS
with m-nitrobenzyl alcohol matrix and 10 KeV acceleration po-
tential. IR spectra were recorded as neat film on Bomem MB-100
and Nicolet IR-100 instruments. 1H and 13C NMR spectra were ob-
tained on Bruker WP200SY and Varian Mercury 400DRX in-
struments (200 and 400 MHz, respectively) in CDCl3 solutions with
tetramethylsilane as internal standard. Solvents and reagents were
purified according to standard techniques.
ing to the carbapenams 20. On the other hand, the
b-hydroxy-
methylketenes 20 have not evolved by formaldehyde elimination.
We propose as a reason to explain this behaviour the higher energy
of the CaeCb bond in these compounds 20 with respect to those of
the intermediates D (Scheme 2), which undergo the benzaldehyde
elimination process. Finally, the diastereoselectivity observed in the
formation of the isolated reaction products 21b, 22ab and 23ba,
tautomers of G (Scheme 3), may be explained by the thermody-
namic stability. A molecular modelling study to determine the
difference of energy minima between each pair of diastereomers28
reveals energy differences of 0.6 (for 21b), 2.5 (for 22ab) and
1.2 kcal/mol (for 23ba), being the products with trans arrangement
of the H4 and H5 or H5 and H6 pairs of atoms more stable in all
cases.
4.2. Preparation of imines
The imines used as substrates in this work were obtained
according to one of the following two methods. Method A: a mix-
ture of the corresponding aldehyde (10.0 mmol) and 2-amino-2,2-
The product distribution in all these reactions seems to be di-
rected by stereoelectronic effects. The specific formation of the bi-
and tricyclic b-lactams 20, 21 and 22, 23 suggests that the opening
ꢁ
dimethylethanol (10.0 mmol) in CH2Cl2 (100.0 mL) with 4 A mo-
lecular sieve was heated at 50 ꢁC until the starting material dis-
appeared in TLC. Then, the mixture was filtered through CeliteÒ and
the solvent was removed under reduced pressure. To a cooled (0 ꢁC)
solution of the obtained imine and catalytic amounts of DMAP in
anhydrous pyridine (40.0 mL), tert-butyldimethylsilyl chloride
(3.0 g, 20.0 mmol) was added under argon atmosphere. The
resulting mixture was allowed to warm to room temperature and
was stirred overnight. The crude mixture was poured onto a cold
solution of NH4Cl and extracted with CH2Cl2 (3ꢄ20 mL). The or-
ganic layer was washed with brine, dried (anhydrous Na2SO4) and
concentrated under reduced pressure. The crude silylated imine
obtained was used without further purification in the Staudinger
reaction. Method B: a mixture of trans-cinnamaldehyde (1.40 mL,
10.00 mmol) and o-cyanoaniline (1.25 g, 10.00 mmol) in toluene
of the oxirane ring and the radical addition to the C^N triple bond
proceed with configuration inversion at C6, as we have previously
observed in related studies.21,22 Therefore, the ability of the gen-
erated R2 radicals to cyclise depends on the accessibility of the
triple bond by the tertiary radicals and on the correct alignment of
the C5 sꢃ and the radical acceptors
p orbitals. An analysis of the
*
molecular models28 let us verify that the R2 radicals can get close to
ꢁ
the different radical acceptors (<4 A), but the orientation of the sꢃ
and
p orbitals seems to be best arranged for cyclisation in the
*
epoxynitriles 2a,b, 3b, 4b and 5a, in agreement with the experi-
mental results.
3. Conclusions
ꢁ
In this work, we report the reactivity of the tertiary alkyl and
tertiary homobenzyl radicals generated with Cp2TiCl from cya-
noepoxy-2-azetidinones. The reactivity observed for the tertiary
alkyl radicals generated from epoxynitriles 2a,b has been very
(50.00 mL) was heated under reflux in the presence of 4 A molec-
ular sieve and catalytic amounts of Mg(ClO4)2 in a DeaneStark
apparatus until the starting material disappeared in TLC and then
the solvent was removed under reduced pressure. The obtained

ꢀ
L.M. Monleon et al. / Tetrahedron 68 (2012) 10794e10805
10800
crude imine was used without further purification in the Stau-
dinger reaction.
(1H, d, J 7.8 Hz), 7.10e7.70 (6H, m), 7.98 (1H, d, J 9.0 Hz), 8.19 (1H,
dd, J 7.8, 8.2 Hz) ppm; 13C NMR (100 MHz, CDCl3)
13.8, 58.2, 67.6,
d
88.8, 101.4, 119.2, 122.3, 125.3, 127.1, 128.8 (2C), 129.1 (2C), 129.7,
131.7, 134.2, 136.6, 137.5, 143.9, 167.7 ppm; HMRS (Q-TOF) calcd for
C20H18N2O2Na (Mþþ23) 341.1260, found 341.1261.
4.3. Preparation of monolactams by [2D2] ketene-imine
cycloaddition reaction (Staudinger reaction)
To a solution of the crude imine (1.0 mmol) and TEA (0.34 mL,
2.4 mmol) in dry CH2Cl2 (10.0 mL), a solution of methoxyacetyl
chloride (0.11 mL, 1.2 mmol) in CH2Cl2 (0.60 mL) was added drop-
wise under argon atmosphere. The mixture was stirred at room
temperature until the starting material disappeared. The reaction
product was then poured onto a saturated NH4Cl solution at 0 ꢁC,
extracted with CH2Cl2 (3ꢄ10 mL) and washed successively with
water and brine solution. The organic layer was dried and the
residue was purified by column chromatography using hexanes/
ethyl acetate mixtures as the eluent.
4.4. Preparation of monolactam 12
To a solution of monolactam 6b (1.1 g, 2.0 mmol) and NaHCO3
(503 mg, 6.0 mmol) in 9:1 CH3CN/H2O (20.0 mL), [bis(tri-
fluoroacetoxy)iodo]benzene (1.3 g, 3.0 mmol) was added and the
mixture was stirred at room temperature. After 30 min, the
resulting mixture was concentrated to dryness, solved in ethyl ac-
etate, washed with brine (3ꢄ10 mL), dried (Na2SO4) and concen-
trated under reduced pressure. The resulting crude product,
aldehyde 11 (880 mg, 1.9 mmol), without further purification, was
solved in THF (20.0 mL) and a solution of (methoxycarbonyl-
methylene)triphenylphosphorane (707 mg, 2.1 mmol) in THF
(20.0 mL) was added drop-wise under argon atmosphere. The
mixture was stirred at room temperature until the starting material
disappeared and then it was poured onto a cold NH4Cl solution,
extracted with EtOAc (3ꢄ10 mL) and concentrated to dryness. The
purification by column chromatography (70% hexanes/EtOAc) of
the reaction crude product gave 868 mg of alkene 12 (88%).
4.3.1. 3-Methoxy-1-(1,1-dimethyl-2-tert-butyldimethylsilyloxyethyl)-
4-(1-methylethenyl)-2-azetidinone (7). Prepared in 46% yield (3.0 g,
9.2 mmol) by Staudinger reaction during 22 h with the imine ob-
tained from methacrylaldehyde (1.65 mL, 20.0 mmol) according to
the method A at room temperature in 24 h using CH2Cl2 as solvent
and TEA as base. Rf (4:1 hexanes/EtOAc) 0.44; IR (film)
1475, 1363, 1262, 1212, 1105, 1033, 837, 786 cmꢀ1
(200 MHz, CDCl3) 0.00 (6H, s), 0.87 (9H, s), 1.13 (3H, s), 1.30 (3H, s),
n
3080, 1755,
;
1H NMR
d
1.81 (3H, s), 3.39 (3H, s), 3.40 (1H, d, J 9.7 Hz), 3.74 (1H, d, J 9.7 Hz),
4.31 (1H, d, J 5.1 Hz), 4.36 (1H, d, J 5.1 Hz), 5.02 (1H, s), 5.04 (1H, s)
4.4.1. (ꢀ)1-[(10,20-Dideoxy-30,40;50,60-di-O-isopropylene-10-methox-
ycarbonylmethylene)-D b-methoxy-4b-[(E)-1-
-20-glucosyl]-3
ppm; 13C NMR (50 MHz, CDCl3)
d
18.1, 19.3, 22.3, 23.1, 25.8 (5C),
methylstyryl]-2-azetidinone [(ꢀ)12]. Rf (3:2 hexanes/EtOAc) 0.44;
25
57.9, 58.7, 63.8, 68.2, 83.4, 115.5, 142.8, 167.2 ppm; HMRS (Q-TOF)
[a
]
ꢀ56 (c 1.0, CHCl3); IR (film)
n
1761, 1750, 1600, 1500, 740,
D
calcd for C17H34NO3Si (Mþþ1) 328.2302, found 328.2308.
700 cmꢀ1; 1H NMR (200 MHz, CDCl3)
d 1.31 (3H, s), 1.33 (3H, s), 1.36
(3H, s), 1.40 (3H, s), 1.95 (3H, s), 3.45 (3H, s), 3.70 (1H, dd, J 6.8,
7.1 Hz), 3.73 (3H, s), 3.87 (1H, dd, J 5.6, 8.6 Hz), 3.92e4.00 (2H, m),
4.11 (1H, dd, J 6.5, 8.6 Hz), 4.40 (1H, dd, J 4.8, 6.8 Hz), 4.45 (1H, d, J
4.8 Hz), 4.65 (1H, d, J 4.8 Hz), 6.08 (1H, d, J 15.6 Hz), 6.60 (1H, s), 7.20
(1H, dd, J 8.3, 15.6 Hz), 7.25e7.35 (5H, m) ppm; 13C NMR (100 MHz,
4.3.2. 3-Methoxy-1-(1,1-dimethyl-2-tert-butyldimethylsilylox-
yethyl)-4-[(E)-1-methylstyryl]-2-azetidinone (8). Prepared in 82%
yield (5.0 g, 12.3 mmol) by Staudinger reaction during 10 h with the
imine obtained from trans-
15.0 mmol) according to the method A in 5 h. Rf (4:1 hexanes/EtOAc)
0.40; IR (film)
1753, 1474, 1346, 1115, 837, 700 cmꢀ1 1H NMR
(200 MHz, CDCl3) 0.06 (6H, s), 0.91 (9H, s), 1.20 (3H, s),1.39 (3H, s),
a-methylcinnamaldehyde (2.1 mL,
CDCl3)
d 20.9, 25.1, 26.4, 27.6, 27.7, 51.7, 58.8, 58.9, 67.3, 67.5, 77.3,
n
;
79.7, 80.5, 85.2, 109.9, 110.6, 125.2, 127.0, 128.2 (2C), 129.0 (2C),
130.9, 133.0, 136.8, 140.5, 165.8, 166.9 ppm; HRMS (Q-TOF) calcd for
C28H37NO8Na (Mþþ23) 538.2411, found 538.2430.
d
1.99 (3H, s), 3.42 (3H, s), 3.48 (1H, d, J 4.8 Hz), 3.79 (1H, d, J 4.8 Hz),
4.47 (2H, s), 6.56 (1H, s), 7.30e7.40 (5H, m) ppm; 13C NMR (50 MHz,
CDCl3)
d
15.4, 18.2, 22.6, 23.2, 25.9 (5C), 58.1, 58.7, 66.3, 68.4, 84.0,
4.5. Preparation of epoxyesters 13a,b
126.9, 128.3 (2C), 129.0 (2C), 129.8, 135.6, 137.3, 167.2 ppm; HMRS
(Q-TOF) calcd for C23H37NO3NaSi (Mþþ23) 426.2435, found
426.2419.
A solution of the alkene 12 (1.02 g,1.98 mmol), m-CPBA (733 mg,
2.97 mmol) and NaHCO3 (250 mg, 2.97 mmol) in dry CH2Cl2
(20.0 mL) was stirred under argon atmosphere at room tempera-
ture until the disappearance of the starting material was observed
by 1H NMR (4 h). The reaction was then quenched with 10% v/v
aqueous Na2S2O3 and the aqueous layer was separated and
extracted with ethyl acetate (3ꢄ15 mL). The combined organic
extracts were washed with a saturated solution of NaHCO3 and
with brine and dried (anhydrous Na2SO4). Then the solvent was
evaporated under reduced pressure and the crude product was
purified by column chromatography using hexanes/EtOAc mixtures
as the eluent. A 1:1 mixture of 13a and 13b in 71% yield (748 mg,
1.4 mmol) was obtained, from which both isomers could be isolated
as pure substances.
4.3.3. cis-1-(o-Cyanophenyl)-3-methoxy-4-[(E)-1-methylstyryl]-2-
azetidinone (9) and trans-1-(o-cyanophenyl)-3-methoxy-4-[(E)-1-
methylstyryl]-2-azetidinone (10). Prepared in 79% yield (5.0 g,
15.7 mmol) as a 2:3 mixture by Staudinger reaction during 20 h
with the imine obtained from trans-a-methylcinnamaldehyde
(2.8 mL, 20.0 mmol) according to the method B in 8 h.
4.3.3.1. Compound 9. Rf (9:1 benzene/EtOAc) 0.61; IR (film)
n
2225, 1765, 1640, 1497, 1458, 1373, 1145 cmꢀ1 1H NMR (400 MHz,
;
CDCl3) d 1.91 (3H, s), 3.58 (3H, s), 4.90 (1H, d, J 5.3 Hz), 5.51 (1H, d, J
5.3 Hz), 6.66 (1H, s), 7.20 (1H, dd, J 7.7, 8.5 Hz), 7.26e7.35 (6H, m),
7.58 (1H, dt, J 0.6, 7.7 Hz), 8.19 (1H, dd, J 0.6, 8.5 Hz) ppm; 13C NMR
(100 MHz, CDCl3)
d
14.9, 59.4, 66.7, 85.5, 101.4, 117.3, 122.4, 125.0,
4.5.1. (ꢀ)1-[(10,20-Dideoxy-30,40;50,60-di-O-isopropylene-10-methox-
127.0 (3C), 128.1 (2C), 129.0, 131.0, 131.8, 134.0, 136.6, 139.1,
166.1 ppm; HMRS (Q-TOF) calcd for C20H18N2O2Na (Mþþ23)
341.1260, found 341.1245.
ycarbonylmethylene)-D b-[(1a,2a)-epoxy-1-methyl-2-
-20-glucosyl]-4
phenylethyl]-3
EtOAc) 0.40; [
1080, 700 cmꢀ1; 1H NMR (400 MHz, CDCl3)
b
-methoxy-2-azetidinone [(ꢀ)13a]. Rf (3:2 hexanes/
25
a
]
ꢀ41 (c 1.0, CHCl3); IR (film)
n
1761, 1738, 1215,
D
d
1.06 (3H, s), 1.25 (3H,
4.3.3.2. Compound 10 (data from a 2:3 mixture of 9 and 10). Rf
s), 1.31 (3H, s), 1.33 (3H, s), 1.46 (3H, s), 3.61 (3H, s), 3.62 (1H, d, J
5.0 Hz), 3.67 (1H, dd, J 5.0, 8.5 Hz), 3.70 (3H, s), 3.89 (1H, dd, J 4.2,
8.6 Hz), 3.95e4.05 (1H, m), 4.14 (1H, dd, J 6.4, 8.6 Hz), 4.15 (1H, s),
4.17 (1H, t, J 8.5 Hz), 4.47 (1H, dd, J 5.0, 8.5 Hz), 4.60 (1H, d, J 5.0 Hz),
(9:1 benzene/EtOAc) 0.57; IR (film)
1361, 1144, 761 cmꢀ1; 1H NMR (400 MHz, CDCl3)
(3H, s), 4.55 (1H, d, J 1.8 Hz), 5.12 (1H, d, J 1.8 Hz), 6.56 (1H, s), 6.74
n
2224, 1761, 1607, 1493, 1453,
d
1.93 (3H, s), 3.64

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L.M. Monleon et al. / Tetrahedron 68 (2012) 10794e10805
10801
6.10 (1H, d, J 16.1 Hz), 7.13 (1H, dd, J 8.5, 16.1 Hz), 7.25e7.40 (5H, m)
ppm; 13C NMR (100 MHz, CDCl3)
14.9, 25.1 (2C), 26.2, 27.9, 51.7,
(Q-TOF) calcd for
498.2092.
C
25H33NO8Na (Mþþ23) 498.2098, found
d
59.3 (2C), 59.7, 62.2, 67.5, 76.7, 79.4, 80.4 (2C), 83.2, 109.9, 110.6,
125.5, 126.3 (3C), 127.4, 128.0, 128.7, 140.3, 165.8, 167.2 ppm; HRMS
(Q-TOF) calcd for C28H38NO9 (Mþþ1) 532.2541, found 532.2559.
4.7. Preparation of Aldehydes 15 and 16
To a solution of the corresponding silylated compounds 7 or 8
(1.0 mmol) in methanol (15.0 mL), 0.1 M HCl (9.0 mL) was added.
The resulting mixtures were stirred at room temperature for 2 h
and then, it was neutralized with solid NaHCO3. The methanol was
evaporated under reduced pressure and the resulting aqueous
layers were extracted with ethyl acetate (3ꢄ15 mL). The combined
organic extracts were washed with brine, dried (anhydrous
Na2SO4) and the solvent was removed in vacuo. The crude products
were purified by flash chromatography (80% hexanes/EtOAc) and
subsequently used in the Swern oxidation.
4.5.2. (ꢀ)1-[(10,20-Dideoxy-30,40;50,60-di-O-isopropylene-10-methox-
ycarbonylmethylene)-D b-[(1b,2b)-epoxy-1-methyl-2-
-20-glucosyl]-4
phenylethyl]-3
EtOAc) 0.32; [
1080, 700 cmꢀ1; 1H NMR (400 MHz, CDCl3)
b
-methoxy-2-azetidinone [(ꢀ)13b]. Rf (3:2 hexanes/
25
a
]
ꢀ43 (c 1.0, CHCl3); IR (film)
n
1761, 1738, 1220,
D
d
1.16 (3H, s), 1.34 (3H,
s), 1.36 (3H, s), 1.38 (3H, s), 1.46 (3H, s), 3.56 (3H, s), 3.59 (1H, d, J
5.2 Hz), 3.73 (3H, s), 3.70e3.80 (1H, m), 3.86 (1H, s), 3.90 (1H, dd, J
3.5, 8.5 Hz), 4.00e4.10 (1H, m), 4.15 (1H, dd, J 4.4, 8.5 Hz), 4.20 (1H,
dd, J 5.2, 8.5 Hz), 4.50 (1H, dd, J 5.2, 8.5 Hz), 4.60 (1H, d, J 5.2 Hz),
6.15 (1H, d, J 15.7 Hz), 7.15 (1H, dd, J 8.5, 15.7 Hz), 7.25e7.35 (5H,
Swern oxidation. To a cooled (ꢀ78 ꢁC) solution of oxalyl chlor-
ide (6.7 mL, 77.2 mmol) in anhydrous CH2Cl2 (213.0 mL), a solution
of freshly distilled DMSO (15.1 mL, 212.0 mmol) in anhydrous
CH2Cl2 (10.0 mL) was added drop-wise under argon. The resulting
mixture was stirred for 5 min keeping the temperature at ꢀ78 ꢁC
and then, a solution of the corresponding above prepared alcohol
(38.6 mmol) in anhydrous CH2Cl2 (50.0 mL) was added drop-wise
for a 1 h period. The reaction mixture was stirred for 30 min
at ꢀ78 ꢁC and then, TEA (19.1 mL, 115.0 mmol) was added. The re-
action mixture was vigorously stirred for 40 min at ꢀ78 ꢁC and then
it was allowed to warm to 0 ꢁC and stirred for 2 h. The crude
mixture was poured onto water and extracted with ethyl acetate
(3ꢄ30 mL). The organic extracts were washed with a saturated
NaHCO3 solution and with brine. Then they were dried (anhydrous
Na2SO4) and concentrated under reduced pressure and the crude
product obtained was used for reaction without further
purification.
m) ppm; 13C NMR (100 MHz, CDCl3)
d 13.2, 25.2, 26.2 (2C), 27.8,
51.7, 59.2, 59.5, 60.9, 61.9, 66.6, 67.5, 76.6, 79.9 (2C), 83.3, 110.0,
110.7, 125.5, 126.4 (3C), 128.2 (2C), 134.8, 140.1, 165.8, 169.9 ppm;
HRMS (Q-TOF) calcd for C28H38NO9 (Mþþ1) 532.2541, found
532.2534.
4.6. Preparation of epoxyaldehydes 14a,b
A solution of monolactam 13a or 13b (1.0 mmol) in CH2Cl2
(25.0 mL) at ꢀ78 ꢁC was treated first with an O3 current until
saturation (blue colour) and then with an O2 current for 20 min.
Subsequently, excess Me2S was added and the reaction mixture
was stirred for 1 h at 0 ꢁC. The solvent was then evaporated under
reduced pressure and the resulting dry residues were solved in
EtOAc, washed with brine (2ꢄ15 mL), dried over anhydrous
Na2SO4, filtered and concentrated. The obtained crude products
were purified by column chromatography (hexanes/EtOAc
mixtures).
4.7.1. 3-Methoxy-1-(1,1-dimethyl-1-formylmethyl)-4-(1-
methylethenyl)-2-azetidinone (15). Prepared in 49% yield (1.7 g,
8.3 mmol) from 7 (3.2 g, 9.8 mmol). Rf (7:3 hexanes/EtOAc) 0.19; IR
4.6.1. (ꢀ)1-[(10,20-Dideoxy-30,40;50,60-di-O-isopropylene-20-for-
(film)
843 cmꢀ1; 1H NMR (200 MHz, CDCl3)
(3H, s), 3.46 (3H, s), 4.34 (1H, d, J 5.1 Hz), 4.60 (1H, d, J 5.1 Hz), 5.10
(2H, s), 9.55 (1H, s) ppm; 13C NMR (50 MHz, CDCl3)
19.3, 20.2,
n
3080, 2690, 1748, 1725, 1455, 1368, 1218, 1091, 1027,
mylmethyl)-
phenylethyl]-3
D
-20-glucosyl]-4
-methoxy-2-azetidinone [(ꢀ)14a]. Prepared in 94%
b
-[(1
a
,2
a
)-epoxy-1-methyl-2-
d
1.32 (3H, s), 1.48 (3H, s), 1.85
b
yield (800 mg, 1.68 mmol) from epoxide 13a (950 mg, 1.79 mmol).
d
25
Rf (1:1 hexanes/EtOAc) 0.40; [
1770, 1729, 1465, 1383, 1225, 1072, 761, 715 cmꢀ1
(400 MHz, CDCl3) 1.06 (3H, s), 1.34 (3H, s), 1.37 (3H, s), 1.40 (3H, s),
a
]
ꢀ40 (c 1.0, CHCl3); IR (film)
n
20.7, 58.9, 63.3, 63.4, 83.9, 116.4, 141.5, 167.8, 198.4 ppm; HMRS (Q-
D
;
1H NMR
TOF) calcd for C11H17NO3Na (Mþþ23) 234.1101, found 234.1109.
d
1.47 (3H, s), 3.64 (3H, s), 3.80 (1H, d, J 6.0 Hz), 3.82 (1H, d, J 6.9 Hz),
3.95 (1H, dd, J 5.2, 8.7 Hz), 4.05e4.15 (1H, m), 4.10 (1H, dd, J 5.3,
8.4 Hz), 4.19 (1H, dd, J 5.8, 8.7 Hz), 4.34 (1H, s), 4.61 (1H, dd, J 5.3,
6.9 Hz), 4.70 (1H, d, J 6.0 Hz), 7.26e7.36 (5H, m), 9.81 (1H, s) ppm;
4.7.2. 3-Methoxy-1-(1,1-dimethyl-1-formylmethyl)-4-[(E)-1-
methylstyryl]-2-azetidinone (16). Prepared in 73% yield (2.00 g,
6.84 mmol) from 8 (5.00 g, 12.30 mmol). Rf (1:1 hexanes/EtOAc)
0.39; IR (film)
NMR (200 MHz, CDCl3) d 1.35 (3H, s), 1.50 (3H, s), 1.99 (3H, s), 3.44
n ;
2720, 1759, 1720, 1358, 1222, 1040, 705 cmꢀ1 1H
13C NMR (100 MHz, CDCl3)
d
15.3, 24.9, 26.5, 27.0, 27.2, 59.1, 59.4,
61.6, 62.3, 65.1, 67.7, 77.0, 78.0, 78.8, 83.5, 110.1, 110.4, 126.3 (2C),
127.5, 128.0 (2C), 135.5, 168.1, 194.7 ppm; HRMS (Q-TOF) calcd for
C25H33NO8Na (Mþþ23) 498.2098, found 498.2102.
(3H, s), 4.47 (1H, d, J 4.9 Hz), 4.66 (1H, d, J 4.9 Hz), 6.58 (1H, s),
7.20e7.40 (5H, m), 9.58 (1H, s) ppm; 13C NMR (50 MHz, CDCl3)
d
15.3, 20.2, 20.7, 58.8, 63.4, 65.6, 84.3, 127.0, 128.2 (2C), 128.9 (2C),
130.6, 134.1, 136.8, 167.6, 198.3 ppm; HMRS (Q-TOF) calcd for
4.6.2. (ꢀ)1-[(10,20-Dideoxy-30,40;50,60-di-O-isopropylene-20-for-
C17H21NO3Na (Mþþ23) 310.1414, found 310.1424.
mylmethyl)-
phenylethyl]-3
D
-20-glucosyl]-4
b-[(1b,2b)-epoxy-1-methyl-2-
-methoxy-2-azetidinone [(ꢀ)14b]. Prepared in 85%
b
4.8. Preparation of nitriles 1a, 1b, 17 and 18
yield (580 mg, 1.52 mmol) from epoxide 13b (760 mg, 1.43 mmol).
25
Rf (1:1 hexanes/EtOAc) 0.33; [
1768, 1739, 1458, 1388, 1230, 1066, 744, 697 cmꢀ1
(400 MHz, CDCl3) 1.19 (3H, s), 1.34 (3H, s), 1.41 (3H, s), 1.44 (3H, s),
a]
ꢀ54 (c 1.0, CHCl3); IR (film)
n
To a stirred solution of the corresponding aldehyde 14a, 14b, 15
or 16 (1.0 mmol) in dry methanol (5.7 mL) under argon atmo-
sphere, N,N-dimethylhydrazine (0.11 mL, 1.43 mmol) was slowly
added. After the completion of the addition, the reaction mixture
was stirred at room temperature until the starting material dis-
appeared in TLC (overnight). The reaction mixture was then cooled
to 0 ꢁC and a solution of magnesium monoperoxyphthalate (1.9 g,
3.0 mmol) in dry methanol (4.3 mL) was added and the resulting
mixture was stirred for 10 min at 0 ꢁC. Methanol was removed
under reduced pressure and the crude residue was diluted with
D
;
1H NMR
d
1.45 (3H, s), 3.60 (3H, s), 3.65 (1H, s), 3.75 (1H, d, J 5.4 Hz), 3.89 (1H,
dd, J 7.0, 8.4 Hz), 3.95 (1H, dd, J 5.6, 8.6 Hz), 4.07e4.15 (1H, m), 4.20
(1H, dd, J 6.4, 8.6 Hz), 4.31 (1H, dd, J 0.5, 5.9 Hz), 4.65 (1H, dd, J 5.9,
7.0 Hz), 4.75 (1H, d, J 5.4 Hz), 7.26e7.38 (5H, m), 9.88 (1H, d, J
0.5 Hz) ppm; 13C NMR (100 MHz, CDCl3)
d 13.0, 25.0, 26.2, 26.9,
27.0, 59.3, 60.6, 61.7, 64.8, 67.1, 67.9, 76.6, 77.7, 78.9, 83.5, 110.2,
110.5, 126.4 (2C), 127.8, 128.2 (2C), 134.8, 167.2, 194.9 ppm; HRMS

ꢀ
L.M. Monleon et al. / Tetrahedron 68 (2012) 10794e10805
10802
CH2Cl2. The organic solution was washed twice with brine, dried
(anhydrous Na2SO4) and concentrated under reduced pressure.
The crude product obtained was purified by column chromatog-
raphy, with hexanes/ethyl acetate mixtures as the eluent.
methylethyl]-3-methoxy-1-(1,1-dimethyl-1-cyanomethyl)-2-
azetidinone (2b). Prepared in 59% yield (740 mg, 3.30 mmol) as
a 1:2 mixture from 17 (1.17 g, 5.60 mmol) in 48 h. Data for the 1:2
mixture of 2a and 2b (in parentheses, the 2a isomer): Rf (3:2
benzene/EtOAc) 0.33 (0.34); IR (film)
n
2246, 1766, 1642, 1458, 913,
1.45 (1.43) (3H, s), 1.76
4.8.1. (ꢀ)1-[(20-Cyanomethyl-10,20-dideoxy-30,40;50,60-di-O-iso-
860, 736 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
propylene)-
D
-20-glucosyl]-4
b
-[(1
a
,2
a
)-epoxy-1-methyl-2-
(1.72) (3H, s), 1.84 (1.78) (3H, s), 2.70 (2.71) (1H, d, J 4.3 Hz), 2.84
(2H, d, J 4.3 Hz), 3.42 (3.83) (1H, d, J 5.6 (5.3) Hz), 3.52 (3.57) (3H, s),
4.49 (4.53) (1H, d, J 5.6 (5.3) Hz) ppm; 13C NMR (100 MHz, CDCl3)
phenylethyl]-3
b
-methoxy-2-azetidinone [(ꢀ)1a]. Prepared in 36%
yield (270 mg, 0.57 mmol) from 14a (750 mg, 1.58 mmol). Rf (2:3
hexanes/EtOAc) 0.65; [
a
]
25 ꢀ37 (c 1.0, CHCl3); IR (film)
n
2251, 1779,
1.11
d 17.9 (18.6), 26.1 (26.0), 26.5 (26.1), 49.6 (49.8), 51.8 (51.5), 54.8
D
1389, 1235, 1069, 744, 697 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
(55.3), 59.4 (59.5), 65.0 (61.2), 82.7 (82.9), 119.6 (119.5), 166.5 ppm;
HMRS (Q-TOF) calcd for C11H16N2O3Na (Mþþ23) 247.1053, found
247.1052.
(3H, s), 1.36 (3H, s), 1.38 (3H, s), 1.42 (3H, s), 1.49 (3H, s), 3.65 (3H, s),
3.92 (1H, dd, J 3.9, 7.8 Hz), 3.96 (1H, dd, J 3.4, 8.5 Hz), 3.97 (1H, dd, J
4.8, 8.5 Hz), 4.12e4.18 (1H, m), 4.17 (1H, d, J 5.4 Hz), 4.31 (1H, s),
4.52 (1H, dd, J 3.9, 8.3 Hz), 4.68 (1H, d, J 5.4 Hz), 4.71 (1H, d, J
4.9.2. 4-[(1
a
,2
a
)-Epoxy-1-methyl-2-phenylethyl]-3-methoxy-1-(1,1-
,2 )-epoxy-
8.3 Hz), 7.30e7.39 (5H, m) ppm; 13C NMR (100 MHz, CDCl3)
d
14.5,
dimethyl-1-cyanomethyl)-2-azetidinone (3a) and 4-[(1b b
25.2, 26.6, 28.0, 28.1, 46.9, 59.5, 59.7, 61.8, 62.5, 67.1, 78.5, 78.7, 79.8,
84.1, 110.3, 112.0, 113.2, 126.4 (2C), 127.6, 128.1 (2C), 135.1,
166.9 ppm; HRMS (Q-TOF) calcd for C25H32N2O7Na (Mþþ23)
495.2102, found 495.2114.
1-methyl-2-phenylethyl]-3-methoxy-1-(1,1-dimethyl-1-
cyanomethyl)-2-azetidinone (3b). Prepared in 75% yield (475 mg,
1.6 mmol) as a 2:3 mixture from 18 (600 mg, 2.1 mmol) in 31 h.
Data for the 2:3 mixture of 3a and 3b (in parentheses, the 3a iso-
mer): Rf (7:3 benzene/EtOAc) 0.51 (0.52); IR (film)
n
2242, 1777,
1.18
4.8.2. (ꢀ)1-[(20-Cyanomethyl-10,20-dideoxy-30,40;50,60-di-O-iso-
1460, 1221, 1036, 762, 708 cmꢀ1 1H NMR (200 MHz, CDCl3)
;
d
propylene)-
D
-20-glucosyl]-4
b
-[(1
b
,2
b
)-epoxy-1-methyl-2-
(1.13) (3H, s), 1.81 (1.13) (3H, s), 1.88 (1.18) (3H, s), 3.60 (3.63) (3H, s),
phenylethyl]-3
b
-methoxy-2-azetidinone [(ꢀ)1b]. Isolated in 28%
3.68 (4.06) (1H, d, J 8.6 (5.1) Hz), 3.94 (4.10) (1H, s), 4.60 (2H, d, J 8.6
yield (154 mg, 0.33 mmol) from 14b (560 mg, 1.18 mmol). Rf (2:3
(5.1) Hz), 7.26e7.40 (10H, m) ppm; 13C NMR (50 MHz, CDCl3)
d 13.6
hexanes/EtOAc) 0.57; [
a
]
D
25 ꢀ62 (c 1.0, CHCl3); IR (film)
n
2255, 1779,
1.23
(14.4), 26.2 (13.6), 26.7 (14.4), 49.8, 50.1, 59.6 (61.8), 61.4 (60.5), 66.0
(62.4), 82.9 (83.2), 119.6, 126.5 (127.8) (2C), 128.3 (128.0) (3C), 134.7
(135.0), 166.7 ppm; HMRS (Q-TOF) calcd for C17H20N2O3Na
(Mþþ23) 323.1366, found 323.1355.
1381, 1222, 1083, 742, 708 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
(3H, s), 1.38 (3H, s), 1.42 (3H, s), 1.49 (3H, s), 1.50 (3H, s), 3.59 (3H, s),
3.63 (1H, d, J 5.8 Hz), 3.65 (1H, s), 3.95e4.05 (2H, m), 4.14e4.20 (2H,
m), 4.56 (1H, dd, J 4.4, 7.9 Hz), 4.70 (1H, d, J 5.8 Hz), 4.72 (1H, d, J
7.9 Hz), 7.26e7.40 (5H, m) ppm; 13C NMR (100 MHz, CDCl3)
d
12.8,
4.9.3. cis-1-(o-Cyanophenyl)-4-[(1
phenylethyl]-3-methoxy-2-azetidinone (4a), cis-1-(o-cyanophenyl)-
4-[(1 ,2 )-epoxy-1-methyl-2-phenylethyl]-3-methoxy-2-azetidinone
(4b), trans-1-(o-cyanophenyl)-4-[(1 ,2 )-epoxy-1-methyl-2-
phenylethyl]-3-methoxy-2-azetidinone (5a) and trans-1-(o-cyano-
phenyl)-4-[(1 ,2 )-epoxy-1-methyl-2-phenylethyl]-3-methoxy-2-
a,2a)-epoxy-1-methyl-2-
25.2, 26.4, 27.9, 28.1, 46.7, 59.4, 61.4, 62.5, 66.9, 67.0, 76.0, 77.9, 79.9,
84.1, 110.4, 112.1, 113.2, 126.5 (2C), 127.7, 128.2 (2C), 134.5,
166.9 ppm; HRMS (Q-TOF) calcd for C25H32N2O7Na (Mþþ23)
495.2102, found 495.2108.
b
b
a
a
b
b
4.8.3. 3-Methoxy-1-(1,1-dimethyl-1-cyanomethyl)-4-(1-
methylethenyl)-2-azetidinone (17). Prepared in 71% yield (1.21 g,
5.82 mmol) from 15 (1.73 g, 8.20 mmol). Rf (3:2 hexanes/EtOAc)
azetidinone (5b). Prepared in 97% yield (1.0 g, 3.0 mmol) as
a 2:3:6:4 mixture from a 1:2 mixture of 9 and 10 (1.0 g, 3.1 mmol) in
33 h. Different amounts of the pure epoxides 4a (7 mg), 4b
(250 mg), 5a (240 mg) and 5b (9 mg) were isolated by successive
column chromatographies of enriched mixtures.
0.48; IR (film)
1H NMR (200 MHz, CDCl3)
3.43 (3H, s), 4.37 (1H, d, J 5.1 Hz), 4.53 (1H, d, J 5.1 Hz), 5.16 (1H, s)
ppm; 13C NMR (50 MHz, CDCl3)
19.0, 25.7, 26.1, 50.0, 58.9, 63.7,
n ;
3080, 2235, 1771, 1458, 1347, 1214, 1028, 842 cmꢀ1
d
1.69 (3H, s), 1.74 (3H, s), 1.86 (3H, s),
d
4.9.3.1. Compound 4a. Rf (95:5 benzene/EtOAc) 0.37; IR (film)
2225, 1763, 1505, 1453, 1362, 1148 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 1.17 (3H, s), 3.72 (3H, s), 4.13 (1H, s), 4.84 (1H, d, J 5.3 Hz), 5.27 (1H,
n
84.2, 117.5, 119.4, 140.3, 166.3 ppm; HMRS (Q-TOF) calcd for
C11H16N2O2Na (Mþþ23) 231.1104, found 231.1101.
d, J 5.3 Hz), 7.21 (1H, dt, J 1.2, 8.1 Hz), 7.25e7.31 (5H, m), 7.56 (1H, dt,
J 1.2, 8.1 Hz), 7.63 (1H, dd, J 1.2, 8.1 Hz), 8.04 (1H, dd, J 1.2, 8.1 Hz)
4.8.4. 3-Methoxy-1-(1,1-dimethyl-1-cyanomethyl)-4-[(E)-1-
methylstyryl]-2-azetidinone (18). Prepared in 73% yield (736 mg,
2.63 mmol) from 16 (1.02 g, 3.60 mmol). Rf (1:1 hexanes/EtOAc)
ppm; 13C NMR (100 MHz, CDCl3)
d 14.3, 59.4, 59.8, 61.8, 62.0, 84.1,
102.1, 117.7, 122.1, 125.0, 126.3 (2C), 127.6, 128.1 (2C), 129.0, 133.8,
135.1, 139.2, 166.2 ppm; HRMS (Q-TOF) calcd for C20H18N2O3Na
(Mþþ23) 357.1210, found 357.1205.
0.53; IR (film)
NMR (200 MHz, CDCl3)
(3H, s), 4.51 (1H, d, J 5.2 Hz), 4.63 (1H, d, J 5.2 Hz), 6.66 (1H, s),
7.26e7.34 (5H, m) ppm; 13C NMR (50 MHz, CDCl3)
19.3, 26.0, 26.3,
n ;
2260, 1760, 1343, 1219, 1039, 740, 709 cmꢀ1 1H
d
1.74 (3H, s), 1.82 (3H, s), 2.02 (3H, s), 3.46
d
4.9.3.2. Compound 4b. Rf (95:5 benzene/EtOAc) 0.27; IR (film)
2230, 1773, 1603, 1547, 1449, 1022, 765 cmꢀ1 1H NMR (400 MHz,
CDCl3) 1.12 (3H, s), 3.73 (3H, s), 3.93 (1H, s), 4.85 (1H, d, J 5.6 Hz),
n
50.3, 59.0, 66.3, 84.9, 119.8, 127.0, 127.3, 128.3 (2C), 129.0, 131.8,
136.7, 139.7, 166.5 ppm; HMRS (Q-TOF) calcd for C17H20N2O2Na
(Mþþ23) 307.1417, found 307.1425.
;
d
4.89 (1H, d, J 5.6 Hz), 7.25e7.34 (6H, m), 7.63 (1H, dt, J 1.3, 7.9 Hz),
7.67 (1H, dd, J 1.2, 6.5 Hz), 7.95 (1H, dd, J 1.3, 7.9 Hz) ppm; 13C NMR
4.9. Preparation of epoxymonolactams 2, 3, 4 and 5
(100 MHz, CDCl3) d 13.5, 59.9, 60.2, 61.4, 64.9, 83.9, 102.8, 117.1,
122.7, 125.6, 126.4 (2C), 127.8, 128.2 (2C), 134.1, 134.2, 134.6, 139.0,
166.0 ppm; HRMS (Q-TOF) calcd for C20H18N2O3Na (Mþþ23)
357.1210, found 357.1218.
A solution of the corresponding alkene (1.0 mmol) in dry CH2Cl2
(10.0 mL) was treated with m-CPBA (370 mg, 1.5 mmol) and
NaHCO3 (126 mg, 1.5 mmol) according to the same experimental
procedure described for the preparation of the epoxides 13a,b.
4.9.3.3. Compound 5a. Rf (95:5 benzene/EtOAc) 0.40; IR (film)
2224, 1774, 1602, 1456, 1375, 1284, 1016, 768 cmꢀ1 1H NMR
(400 MHz, CDCl3) 1.22 (3H, s), 3.66 (3H, s), 3.89 (1H, s), 4.76 (1H, d,
J 1.9 Hz), 4.81 (1H, d, J 1.9 Hz), 7.22e7.34 (6H, m), 7.62 (1H, dt, J 1.0,
n
;
4.9.1. 4-[(1
a
,2)-Epoxy-1-methylethyl]-3-methoxy-1-(1,1-dimethyl-1-
,2)-epoxy-1-
d
cyanomethyl)-2-azetidinone (2a) and 4-[(1
b

ꢀ
L.M. Monleon et al. / Tetrahedron 68 (2012) 10794e10805
10803
7.4 Hz), 7.69 (1H, dd, J 1.2, 7.4 Hz), 7.98 (1H, dd, J 1.0, 8.4 Hz) ppm;
13C NMR (100 MHz, CDCl3)
13.7, 58.5, 61.8 (2C), 64.2, 86.0, 101.4,
117.2, 122.4, 125.3, 126.3 (2C), 128.0, 128.2 (2C), 134.1, 134.3, 138.8
(2C), 164.5 ppm; HRMS (Q-TOF) calcd for C20H18N2O3Na (Mþþ23)
357.1210, found 357.1220.
according to the method A (1 h) and the method B (1.5 h), re-
25
d
spectively. Rf (2:3 hexanes/EtOAc) 0.42; [
(film)
3455, 2251, 1685, 1077, 857, 738, 708 cmꢀ1
(400 MHz, CDCl3) 1.41 (3H, s), 1.48 (3H, s), 1.59 (3H, s), 3.35 (3H, s),
a
]
D
þ7 (c 1.0, CHCl3); IR
n
;
1H NMR
d
3.82 (1H, d, J 15.4 Hz), 3.96 (1H, d, J 15.4 Hz), 4.00 (1H, dd, J 4.6,
8.2 Hz), 4.07e4.12 (1H, m), 4.15 (1H, dd, J 6.2, 8.2 Hz), 4.41 (1H, dd, J
4.2, 8.1 Hz), 5.26 (1H, s), 5.83 (1H, d, J 8.1 Hz), 6.51 (1H, s), 7.32e7.38
4.9.3.4. Compound 5b. Rf (95:5 benzene/EtOAc) 0.31; IR (film)
2229, 1779, 1600, 1498, 1459, 1372, 1139, 767 cmꢀ1 1H NMR
(400 MHz, CDCl3) 1.11 (3H, s), 3.63 (3H, s), 4.20 (1H, s), 4.65 (1H, d,
n
;
(5H, m) ppm; 13C NMR (100 MHz, CDCl3)
d 13.2, 26.5, 27.7, 48.7,
d
59.2, 67.0, 70.8, 76.4, 77.1, 79.8, 110.3, 112.1, 115.0, 118.9, 126.3 (2C),
128.3, 128.8 (2C), 140.8, 147.2, 169.5 ppm; HRMS (Q-TOF) calcd for
C22H28N2O6Na (Mþþ23) 439.2262, found 439.2293.
J 1.8 Hz), 4.77 (1H, d, J 1.8 Hz), 7.24e7.34 (6H, m), 7.59 (1H, dt, J 1.3,
7.9 Hz), 7.66 (1H, dd, J 1.4, 7.9 Hz), 7.82 (1H, dd, J 1.3, 8.1 Hz) ppm;
13C NMR (100 MHz, CDCl3)
d 12.6, 58.4, 61.6, 62.3, 64.6, 86.2, 103.4,
117.2, 122.8, 125.7, 126.3 (2C), 128.0, 128.2 (2C), 133.8, 134.0, 134.3,
138.4, 164.1 ppm; HRMS (Q-TOF) calcd for C20H18N2O3Na (Mþþ23)
357.1210, found 357.1220.
4.10.3. 4
oxo-5 H-carbapenam (20a) and
2,2-dimethyl-4 -methyl-3-oxo-5 H-carbapenam (20b). Prepared as
a
-Hydroxymethyl-6
b
-methoxy-2,2-dimethyl-4
b
-methyl-3-
a
4
b-hydroxymethyl-6
b-methoxy-
a
a
a 1:5 mixture in 6% (21 mg) and 32% (114 mg) yields from a 1:2
mixture of 2a and 2b (350 mg, 1.6 mmol) according to the method A
(3 h) and the method B (3 h), respectively. Data for the 1:5 mixture
of 20a and 20b (in parentheses, the 20a isomer): Rf (1:1 benzene/
4.10. Radical reactions induced by Cp2TiCl
In situ generation of titanocene monochloride (Cp2TiCl). To
548 mg (2.2 mmol) of titanocene dichloride in anhydrous and
strictly deoxygenated THF (12.5 mL, c 0.176 M), 262 mg (4.0 mmol)
of activated zinc granules was added. The resulting red mixture
was then vigorously stirred under argon atmosphere with rigorous
exclusion of oxygen until a green colour was observed (about
20 min).
EtOAc) 0.34; IR (film)
n
3473, 1746, 1464, 1341, 1229, 1153, 1029,
1.12 (0.97) (3H, s), 1.17 (1.10)
841 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
(3H, s), 1.62 (1.64) (3H, s), 2.12 (2H, br s), 3.51 (6H, s), 3.61 (1H, d, J
11.1 Hz), 3.85 (1H, d, J 11.1 Hz), 4.12 (4.07) (1H, d, J 4.5 Hz), (4.29)
(2H, s), 4.77 (4.75) (1H, d, J 4.5 Hz) ppm; 13C NMR (100 MHz, CDCl3)
d
16.3 (16.5), 21.7 (21.8), 23.1 (23.3), 54.6, 55.7, 59.2, 64.0 (65.0), 65.2
Radical reactions with Cp2TiCl. Method A (direct addition): A THF
green suspension of Cp2TiCl, generated in situ from Cp2TiCl2 and
Zn0 as described above, was added drop-wise through cannula to
a solution of the corresponding epoxide (1.0 mmol) in THF
(17.0 mL, c 0.058 M). The resulting reaction mixture was stirred
until a colour change from green to orange occurred or until the
disappearance of the starting material was observed by TLC. Then
the reaction was quenched with 10% v/v aqueous KH2PO4 (30.0 mL)
and the resulting aqueous phase was extracted with ethyl acetate.
The organic combined extracts were filtered through CeliteÒ, dried
(anhydrous Na2SO4) and concentrated in vacuo. The crude product
obtained was purified by column chromatography using hexanes/
EtOAc mixtures as the eluent. Method B (inverse addition): a solu-
tion of the corresponding epoxide (1.0 mmol) in THF (17.0 mL) was
added drop-wise through cannula to a THF green suspension of
Cp2TiCl, generated as reported above. The reaction mixture was
stirred at room temperature until a colour change from green to
orange occurred or until the disappearance of the starting material
was observed by TLC, and then it was worked up as reported for
method A.
(66.9), 84.7, 171.0, 221.4 ppm; HRMS (Q-TOF) calcd for C11H17NO4Na
(Mþþ23) 250.1055, found 250.1050.
4.10.4. 6b-Methoxy-2,2-dimethyl-4a-methyl-3-oxo-5aH-carbape-
nam (21b). Prepared in 4% (10 mg) and 45% (80 mg) yields from
a 2:3 mixture of 3a and 3b (375 mg, 1.25 mmol) according to the
method A (1 h) and the method B (5 h), respectively. Unquantified
benzaldehyde was also obtained in these reactions. Rf (7:3 ben-
zene/EtOAc) 0.50; IR (film)
n
3500, 1774, 1755, 1658, 1028,
1.12 (3H, s), 1.53 (3H, s), 1.21
710 cmꢀ1; 1H NMR (200 MHz, CDCl3)
d
(3H, d, J 7.1 Hz), 2.73 (1H, dq, J 7.1, 8.7 Hz), 3.52 (3H, s), 3.62 (1H, dd,
J 4.0, 8.7 Hz), 4.68 (1H, d, J 4.0 Hz) ppm; 13C NMR (50 MHz, CDCl3)
d
12.5, 21.0, 23.4, 41.0, 58.9, 59.1, 64.4, 83.4,170.9, 218.4 ppm; HRMS
(Q-TOF) calcd for C10H15NO3Na (Mþþ23) 220.0944, found
220.0949.
4.10.5. 7b-Methoxy-5a-methyl-4-oxo-6aH-2,3-benzocarbacephem
(22ab). Prepared in 14% (12 mg) and 36% (30 mg) yields from 4b
(120 mg, 0.36 mmol) according to the method A (3 h) and the
method B (3 h), respectively. Unquantified benzaldehyde was also
obtained in these reactions. Rf (95:5 benzene/EtOAc) 0.28; IR (film)
4.10.1. (þ)N-[(10-Cyano-20,30-didehydro-20,30-dideoxy-50,60-O-iso-
n
1759, 1685, 1611, 1485, 1376, 1135, 1027, 758 cmꢀ1
;
1H NMR
propylene)-
D
-20-glucosyl]-N-[300
a
-hydroxy-200-methyl-300-phenyl-
(400 MHz, CDCl3) d 1.26 (3H, d, J 6.5 Hz), 3.01 (1H, dq, J 6.5, 12.8 Hz),
100(E)-propenyl]-3-methoxyazetamide [(þ)19a]. Prepared in 9%
3.68 (3H, s), 3.98 (1H, dd, J 4.5, 12.8 Hz), 4.79 (1H, d, J 4.5 Hz), 7.21
(1H, dt, J 1.2, 7.9 Hz), 7.52 (1H, dt, J 1.4, 7.9 Hz), 7.55 (1H, dd, J 1.2,
7.9 Hz), 7.95 (1H, dd, J 1.4, 7.9 Hz) ppm; 13C NMR (100 MHz, CDCl3)
(10 mg) and 14% (15 mg) yields from 1a (125 mg, 0.26 mmol)
according to the method A (1.5 h) and the method B (2.5 h), re-
25
spectively. Rf (2:3 hexanes/EtOAc) 0.49; [
a
]
þ3 (c 1.0, CHCl3); IR
d 10.5, 40.5, 57.7, 59.5, 84.9, 119.4, 123.2, 124.7, 127.7, 134.9, 138.0,
(film)
n
3427, 2252, 1690, 1077, 849 cmꢀ1D
;
1H NMR (400 MHz,
163.7, 194.8 ppm; HRMS (Q-TOF) calcd for C13H13NO3Na (Mþþ23)
CDCl3)
d
1.37 (6H, s), 1.49 (3H, s), 3.36 (3H, s), 3.86 (1H, d, J 7.9 Hz),
254.0788, found 254.0795.
3.93 (1H, d, J 7.9 Hz), 3.98 (1H, dd, J 4.4, 14.3 Hz), 4.09e4.12 (1H, m),
4.16 (1H, dd, J 6.0, 14.3 Hz), 4.42 (1H, dd, J 4.3, 7.8 Hz), 5.26 (1H, s),
5.84 (1H, d, J 7.8 Hz), 6.14 (1H, d, J 2.8 Hz), 7.22e7.41 (5H, m) ppm;
4.10.6. 7b-Methoxy-5b-methyl-4-oxo-6bH-2,3-benzocarbacephem
(23ba). Prepared in 8% (6 mg) and 13% (10 mg) yields from 5a
(110 mg, 0.33 mmol) according to the method A (3 h) and the
method B (3 h), respectively. Unquantified benzaldehyde was also
obtained in these reactions. Rf (95:5 benzene/EtOAc) 0.25; IR (film)
13C NMR (100 MHz, CDCl3)
d 12.7, 24.8, 26.5, 48.6, 59.2, 67.1, 70.8,
76.2, 77.5, 79.7, 110.3, 111.1, 116.7, 119.6, 126.3 (2C), 128.2, 128.8 (2C),
142.1, 155.1, 173.2 ppm; HRMS (Q-TOF) calcd for C22H28N2O6Na
(Mþþ23) 439.2262, found 439.2230.
n
1761, 1684, 1597, 1479, 1379, 1138, 1019, 765 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d 1.36 (3H, d, J 6.6 Hz), 2.76 (1H, dq, J 6.6, 12.9 Hz),
4.10.2. (þ)N-[(10-Cyano-20,30-didehydro-20,30-dideoxy-50,60-O-iso-
3.60 (3H, s), 3.88 (1H, dd, J 2.0, 12.9 Hz), 4.66 (1H, d, J 2.0 Hz), 7.19
(1H, dt, J 1.0, 7.9 Hz), 7.57 (1H, dt, J 1.5, 7.9 Hz), 7.65 (1H, dd, J 1.0,
7.9 Hz), 7.91 (1H, dd, J 1.5, 7.9 Hz) ppm; 13C NMR (100 MHz, CDCl3)
propylene)-D b
-20-glucosyl]-N-[300 -hydroxy-200-methyl-300-phenyl-
100(E)-propenyl]-3-methoxyazetamide [(þ)19b]. Prepared in 22%
(14 mg) and 34% (21 mg) yields from 1b (70 mg, 0.15 mmol)
d
10.1, 43.9, 58.1, 61.4, 90.3, 118.7, 121.9, 124.5, 127.9, 135.2, 138.3,

ꢀ
L.M. Monleon et al. / Tetrahedron 68 (2012) 10794e10805
10804
161.3, 193.3 ppm; HRMS (Q-TOF) calcd for C13H13NO3Na (Mþþ23)
Chapter 3.3; (d) Zard, S. Z. Radical Reactions in Organic Synthesis; Oxford Uni-
~
versity Press: New York, NY, 2003; (e) Justicia, J.; Rosales, A.; Bunuel, E.; Oller-
254.0788, found 254.0800.
ꢀ
ꢀ
Lopez, J. L.; Valdivia, M.; Haïdur, A.; Oltra, J. E.; Barrero, A. F.; Cardenas, D. J.;
Cuerva, J. M. Chem.dEur. J. 2004, 10, 1778e1788; (f) Justicia, J.; Oltra, J. E.;
~
ꢀ
Barrero, A. F.; Guadano, A.; Gonzalez-Coloma, A.; Cuerva, J. M. Eur. J. Org. Chem.
4.10.7. trans-1-(o-Cyanophenyl)-4
a-(2b-hydroxy-1a-methyl-2-
ꢀ
2005, 712e718; (g) Barrero, A. F.; Quílez del Moral, J. F.; Sanchez, E. M.; Arteaga,
J. F. Eur. J. Org. Chem. 2006, 1627e1641; (h) Cuerva, J. M.; Justicia, J.; Oller-Lopez,
J. L.; Bazdi, B.; Oltra, J. E. Mini-Rev. Org. Chem. 2006, 3, 23e35; For selected
references on the use of radicals in
D. H. R.; Gero, S. D.; Grande, M.; Martín, N. M.; Tachdjian, C. Angew. Chem., Int.
Ed. Engl. 1993, 32, 867e869; (j) Anaya, J.; Barton, D. H. R.; Caballero, M. C.; Gero,
S. D.; Grande, M.; Laso, N. M. Tetrahedron: Asymmetry 1994, 5, 2137e2140; (k)
Penfold, D. J.; Pike, K.; Genge, A.; Anson, M.; Kitteringham, J.; Kilburn, J. D.
Tetrahedron Lett. 2000, 41, 10347e10351; (l) Alcaide, B.; Almendros, P.; Ara-
goncillo, C. J. Org. Chem. 2001, 66, 1612e1620; (m) Alcaide, B.; Almendros, P.;
Aragoncillo, C. Org. Lett. 2003, 5, 3795e3798; (n) Alcaide, B.; Almendros, P.;
Rodríguez-Vicente, A.; Ruiz, M. P. Tetrahedron 2005, 61, 2767e2778; (o) Lee-
mans, E.; D’hooghe, M.; Dejaegher, Y.; Tornroos, K. W.; De Kimpe, N. J. Org.
Chem. 2008, 73, 1422e1428.
9. (a) Gansauer, A.; Pierobon, M.; Bluhm, H. Angew. Chem., Int. Ed. 1998, 37,
101e103; (b) Gansauer, A. Synlett 1998, 801e809; (c) Fernandez-Mateos, A.;
phenylethyl)-3 -methoxy-2-azetidinone (24b). Prepared in 16%
b
ꢀ
(21 mg) and 9% (3 mg) yields from a 1:4 mixture of 4a and 5b
(167 mg, 0.50 mmol) according to the method A (5 h) and the
method B (2 h), respectively. Rf (95:5 benzene/EtOAc) 0.13; IR (film)
b-lactam synthesis, see: (i) Anaya, J.; Barton,
ꢀ
ꢀ
n
3354, 2222, 1767, 1584, 1451, 1301, 1101, 746 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d 1.73 (3H, d, J 1.2 Hz), 3.48 (3H, s), 4.64 (1H, dd, J
1.8, 9.0 Hz), 5.21 (1H, d, J 1.8 Hz), 5.29 (1H, d, J 1.2 Hz), 5.71 (1H, ddq,
J 1.2, 9.0 Hz), 7.17e7.61 (7H, m), 7.60 (1H, dt, J 1.3, 8.5 Hz), 8.42 (1H,
dd, J 1.3, 8.5 Hz), 9.12 (1H, br s) ppm; 13C NMR (100 MHz, CDCl3)
€
d
13.3, 56.9, 78.3, 78.4 (2C), 116.3, 120.1, 121.0, 124.3, 126.4, 126.9,
127.7, 128.1, 128.5 (2C), 132.3, 140.0, 141.5, 146.4, 169.5 ppm; HRMS
(Q-TOF) calcd for C20H20N2O3Na (Mþþ23) 359.1340, found
359.1335.
€
€
ꢀ
ꢀ
Martín de la Nava, E.; Pascual Coca, G.; Ramos Silvo, A.; Rubio Gonzalez, R. Org.
Lett. 1999, 1, 607e609; (d) Gansauer, A.; Bluhm, H. Chem. Rev. 2000, 100,
2771e2788; (e) Gansauer, A.; Pierobon, M.; Bluhm, H. Synthesis 2001, 16,
2500e2520; (f) Li, J. J. Tetrahedron 2001, 57, 1e24; (g) Gansauer, A.; Pierobon,
€
€
Acknowledgements
€
ꢀ
M.; Bluhm, H. Angew. Chem., Int. Ed. 2002, 41, 3206e3208; (h) Fernandez-Ma-
ꢀ
teos, A.; Mateos Buron, L.; Rabanedo Clemente, R.; Ramos Silvo, A. I.; Rubio
ꢀ
Financial support for this work from the Junta de Castilla y Leon
(SA046A08) is gratefully acknowledged. We would also like to ac-
ꢀ
€
Gonzalez, R. Synlett 2004, 1011e1014; (i) Gansauer, A.; Justicia, J.; Fan, C.-A.;
Worgull, D.; Piestert, F. Top. Curr. Chem. 2007, 279, 25e52.
€
€
10. (a) Gansauer, A. Chem. Commun. 1997, 457e458; (b) Gansauer, A. Synlett 1997,
ꢀ
knowledge Dr. Luís Simon Rubio for his useful suggestions.
€
363e364; (c) Gansauer, A.; Bauer, D. J. Org. Chem. 1998, 63, 2070e2071; (d)
Dunlap, M. S.; Nicholas, K. M. J. Organomet. Chem. 2001, 630, 125e131; (e) Oller-
Lopez, J. L.; Campana, A. G.; Cuerva, J. M.; Oltra, J. E. Synthesis 2005, 2619e2622;
ꢀ
~
Supplementary data
ꢀ
ꢀ
€
(f) Estevez, R. E.; Oller-Lopez, J. L.; Robles, R.; Melgarejo, C. R.; Gansauer, A.;
Cuerva, J. M.; Oltra, J. E. Org. Lett. 2006, 8, 5433e5436; (g) Hirao, T. Top. Curr.
Chem. 2007, 279, 53e75.
1H and 13C NMR spectra of 21b and 1H NMR, 13C NMR and two-
dimensional (COSY, ROESY, HMQC and HMBC) spectra of 19a,b,
20a,b, 22ab, 23ba and 24b are included. Supplementary data as-
sociated with this article can be found in online version, at
doi:10.1016/j.tet.2011.11.015. These data include MOL files and
InChiKeys of the most important compounds described in this
article.
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