Stereoselective cyanation of 4-formyl and 4-imino-β-lactams: Application to the synthesis of polyfunctionalized γ-lactams

Article abstract of DOI:10.1016/j.tet.2012.02.062

The stereoselective reaction of 4-oxoazetidine-2-carbaldehydes and their corresponding imines with cyanide-based reagents give β-lactam α-aminonitriles, which are chameleonic building blocks for the controlled synthesis of a variety of new compounds including functionalized γ-lactams, succinimide derivatives, and diamino-lactams derivatives in optically pure form.

Full text of DOI:10.1016/j.tet.2012.02.062

Tetrahedron 68 (2012) 10761e10768
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective cyanation of 4-formyl and 4-imino-
application to the synthesis of polyfunctionalized
b-lactams:
g
-lactams
,
b
,
a
a
Benito Alcaide a , Pedro Almendros , Gema Cabrero , M. Pilar Ruiz
*
*
a
ꢀ
Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Química Organica I, Unidad Asociada al CSIC, Facultad de Química, Universidad Complutense de Madrid,
28040 Madrid, Spain
b
ꢀ
Instituto de Química Organica General, IQOG, Consejo Superior de Investigaciones Científicas, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective reaction of 4-oxoazetidine-2-carbaldehydes and their corresponding imines with
Received 25 November 2011
Received in revised form 17 February 2012
Accepted 24 February 2012
Available online 3 March 2012
cyanide-based reagents give b-lactam a-aminonitriles, which are chameleonic building blocks for the
controlled synthesis of a variety of new compounds including functionalized
derivatives, and diamino-lactams derivatives in optically pure form.
g-lactams, succinimide
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cyanides
Imines
b
g
-Lactams
-Lactams
Rearrangements
1. Introduction
versatile precursors to functionalized azacycles. In our continued
commitment to prepare b-lactams and heterocycles of biological
Functionalized
g
-lactams are emerging as a substructure pres-
interest,7 herein we report details of the controlled reactions be-
tween 2-azetidinone-derived imines and cyanide-based reagents
ent in natural and synthetic products possessing important bio-
activities.1 In particular, succinimide2 and pyroglutamic acid3 cores
have considerable chemical and medicinal importance as they are
involved in a wide range of relevant processes. On the other hand,
as a versatile synthetic tool for the preparation of functionalized
lactams and succinimide derivatives.
g-
the inherent strain and their convenient accessibility make
tams an attractive substrate class. In addition of the key role that
b-lac-
2. Results and discussion
b
-
lactams have played in medicinal chemistry, namely, the fight
against pathogenic bacteria, enzyme inhibition, in vitro antitumor
cytotoxicity, or gene activation,4 the use of 2-azetidinones as chiral
building blocks in organic synthesis is now well established.5 Be-
Taking into account our recent report on the cyanosilylation of
4-oxoazetidine-2-carbaldehydes,8 we decided to explore the
cyanation of imino-
ment of the appropriate enantiopure
amines in the presence of molecular sieves (4 A) in refluxing ben-
zene.9 Imino-
-lactams 1 were obtained in nearly quantitative
b
-lactams. Imines 1 were prepared by treat-
b
-lactam aldehyde with
ꢁ
sides, a-aminonitriles are versatile synthetic intermediates for the
synthesis of a variety of interesting compounds.6 Both the amino
and nitrile groups can be further transformed into a variety of
useful functional units. In light of the synthetic utility of both types
b
yields and were used without further purification. First, the re-
action of imines 1aed derived from alkyl amines with tert-butyl-
dimethylsilyl cyanide (TBDMSiCN) was selected (Table 1). The
of compounds, the stereoselective preparation of optically pure
b-
lactam -aminonitriles arises as an important endeavor. These
a
optimized conditions for the cyanosilylation of
b-lactam alde-
hydes8 (1.2 equiv of TBDMSiCN, 25 mol % Na2CO3, acetonitrile, rt)
were initially adopted. However, prolonged reaction times were
needed for a good conversion. Replacement of 25 mol % Na2CO3 by
10 mol % tetrabutylammonium cyanide (TBACN), both accelerated
polyfunctional hybrid molecules may undergo highly selective re-
duction and rearrangement reactions making them as potential
the reaction and allowed better isolated yields.
a-Aminonitriles
* Corresponding authors. Tel.: þ34 91 3944314; fax: þ34 91 3944103 (B.A.); tel.:
þ34 91 5618806; fax: þ34 91 5644853 (P.A.); e-mail addresses: alcaideb@qui-
m.ucm.es (B. Alcaide), Palmendros@iqog.csic.es (P. Almendros).
2aed were obtained as a mixture of two chromatographically
separable diastereomers (syn/anti, epimers at C40) in reasonable
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.062

10762
B. Alcaide et al. / Tetrahedron 68 (2012) 10761e10768
Table 1
The conversion of multi-step reactions into more environmen-
tally friendly one-pot processes is convenient in synthetic chem-
istry. Thus, the direct aminocyanation of -lactam aldehydes 5 was
Reaction of imino-b
-lactams 1 with TBDMSiCNa
b
attempted. The effect of different promoters (I2, BiCl3, H3NSO3, and
InCl3) on the aminocyanation of a model substrate, 4-oxoazetidine-
2-carbaldehyde 5a, in the presence of allylamine with trimethylsilyl
cyanide (TMSCN) was investigated. Every single Lewis acid was able
to catalyze the one-pot formation of a-aminonitrile 2a (Table 2).
These results show that under standard reaction conditions, I2
provided the best yield and diastereoselectivity. On the basis of the
above results, we chose to use I2 in our study. With the optimal
conditions in hand, the scope and limitation of the one-pot reaction
was tested with various combinations of aldehydes and amines
Imine R1
R2
R3
Catalyst t (h) Prod. syn/antib Yieldc (%)
(þ)-1a PMP MeO Allyl
(þ)-1a PMP MeO Allyl
(þ)-1b PMP MeO Bn
(þ)-1b PMP MeO Bn
Na2CO3 65
TBACN 4.5 2a
Na2CO3 68 2b
TBACN 4.5 2b
2a
78:22d
80:20d
74:26
74:26
68:32
78:22
55:45
dg
60
68
73
85
40e
50
85
68
64
65
(Table 2). a-Aminonitriles 2 were obtained as separable diastero-
(þ)-1c PMP MeO Propargyl Na2CO3 97
2c
2c
(þ)-1c PMP MeO Propargyl TBACN
24
meric mixtures, being the syn/anti ratio slightly superior to the
observed one using TBDMSiCN/TBACN in the sequential process.
When aromatic amines were used, both sulphamic acid and mo-
lecular iodine catalyzed reactions gave the corresponding imines 1
(þ)-1d PMP MeO t-Bu
(þ)-1e PMP MeO PMP
TBACN
TBACN
Na2CO3 52
TBACN
3.7 2d
5
2ef
2ff
(þ)-1f Bn
(þ)-1f Bn
MeO PMP
MeO PMP
dg
dg
3.8 2ff
in quantitative yields instead of the expected a-aminonitriles 2e
a
All reactions were catalyzed by 25 mol % Na2CO3 or 10 mol % TBACN and were
carried out using an imine/TBDMSiCN ratio of 1:1.2 mmol.
and f, which were not observed in any case. On the contrary, BiCl3
was the catalyst of choice for the one-pot reaction with aromatic
amines achieving fair yields with a reasonable rate of reaction
(Table 2).
Demands for the efficient generation of functionalized and di-
verse drug like small molecules continue to stimulate the de-
velopment of versatile synthetic strategies. By inspecting the
b
The syn/anti ratio could not be determined by integration in the 1H NMR spectra
(300 MHz) of the crude reaction mixtures before purification, due to the absence of
well-resolved signals. The ratio was given in pure product after separation by
gravity flow chromatography on deactivated silica gel.
c
Yield of isolated products with correct analytical and spectral data.
The syn/anti ratio was determined by integration of well-resolved signals in the
d
1H NMR spectra (300 MHz) of the crude reaction mixtures before purification.
e
4-Oxoazetidine-2-carbaldehyde precursor (30%) was also recovered, arising
possible reactivity of
a-aminonitriles 2, we realized that their
from the hydrolysis of the starting imine.
rearrangement reactions should provide a stereoselective pathway
to polyfunctionalized masked pyroglutamic acids (Scheme 2).11
To successfully achieve our aim, we needed to find an expedient
f
a
-Aminonitriles 2e and 2f were obtained as unseparable syn/anti mixtures.
g
The syn/anti ratio could not be determined. PMP¼4-MeOC6H4.
transformation of the b-lactam aminonitrile hybrids into g-lactam
systems. First, sodium methoxide was tested as reagent for the
conversion of adducts 2 into the framework of pyroglutamic acids.
In the event, the g-lactam skeleton was obtained from adducts 2a,
yields (50e85%). The reaction of TBDMSiCN with imines 1e and 1f
derived from an aryl amine afforded the corresponding a-amino-
nitriles 2e and 2f,10 but as unseparable syn/anti mixture (Table 1).
It should be noted that the 1H NMR vicinal coupling constants of
2b, and 2h, affording 3,4-disubstituted pyroglutamides 6aec as
major products (Scheme 3). Amides 6 are formed as consequence of
the solvolysis of cyano group in the expected cyanides 7, probably
due to the water present in methanol. 3-Amino-4-alkoxy-5-
oxopyrrolidine-2-carbonitriles 7 could be also isolated from ami-
nonitriles 2a and 2h. While pyroglutamide 6b was obtained in
enantiopure form, partial epimerization at C5 was observed for
related 6a and 6c. Surprisingly, in addition of the rearranged ad-
ducts 6 and 7, 5-(arylimino)pyrrolidin-2-ones 8 were obtained as
side-products.
the H4 and H40 protons for the syn-2 and anti-2
a
-aminonitrile-
b-
lactams is a useful check of the relative stereochemistry (see
Supplementary data). For any pair of syn-2 and anti-2
a di-
astereomers, the vicinal coupling constant between H4 and H40 is
higher for syn-isomers (3JH4,H4 ¼9.7e4.6 Hz) than for anti-isomers
0
(3JH4,H4 ¼8.5e3.4 Hz). The observed syn-diastereoselectivity for
0
compounds 2 might be tentatively explained by invoking the Fel-
kineAnh model, analogous to related addition processes described
in our laboratories.8
When
materials, 5-(arylimino)pyrrolidin-2-ones 8 were formed as sole
products in moderate yields (Scheme 4).12 By contrast,
-(tert-
butylamino)nitrile 2d exclusively afforded the acyclic -cyano-
amino ester 9, which arises from the N1eC2 bond breakage of the
-lactam nucleus. Probably, the steric hindrance of the tert-butyl
a-(arylamino)nitriles 2e and 2f were used as starting
A likely catalytic cycle for the TBACN-catalyzed generation of
functionalized b-lactams 2 is outlined in Scheme 1. Initial activation
of TBDMSiCN by TBACN gave a pentacoordinate silicon species 3.
Salt 3, after coordination to the imine 1 affords complex 4, which
suffers an intramolecular cyanide transfer giving rise to a-amino-
a
g
b-
b
nitriles 2 with concurrent regeneration of the catalyst.
group may explain this different behavior. Chemical correlation
between imino derivative 8b and its corresponding succinimide 10
was achieved by hydrolysis of the former with 20% aqueous HCl in
acetonitrile (Scheme 5).9
Two competitive processes must be operating for the sodium
methoxide promoted transformation of b-lactam aminonitriles 2,
depending on the nature of the R3 substituent (Scheme 6). When R3
is aliphatic the rearrangement is the preferred pathway (path A) via
N1eC2
b-lactam cleavage, being favored the formation of pyro-
glutamic acid derivatives 6 and 7. By contrast, when R3 is aromatic
the above rearrangement is suppressed giving rise instead to the 5-
(arylimino)pyrrolidin-2-ones 8, which must be explained invoking
an N1eC4 b-lactam cleavage followed by cyclization (path B). In
this case, sodium methoxide should act as a base by deprotonating
the aminonitrile 2 to give carbanion 11, which must evolve to en-
Scheme 1. Plausible explanation for the reaction of imino-b-lactams 1 with
TBDMSiCN/Bu4NCN.
amine species 12 through N1eC4 bond breakage of the b-lactam

B. Alcaide et al. / Tetrahedron 68 (2012) 10761e10768
10763
Table 2
Direct aminocyanation of b
-lactam aldehydesa
NHR3
CN
NHR3
CN
H H
H H
H H
N
R2
O
R2
R2
O
O
catalyst (10 mol %)
CH3CN, RT
TMSCN
R3NH2
+
+
+
N
N
O
R1
R1
2
R1
5
syn-
anti-2
Aldehyde
R1
R2
R3
Catalyst
t (h)
Prod.
syn/antib
Yieldc (%)
(þ)-5a
(þ)-5a
(þ)-5a
(þ)-5a
(þ)-5a
(þ)-5a
(þ)-5a
(þ)-5b
(þ)-5c
(ꢀ)-5d
(þ)-5e
(þ)-5f
(þ)-5g
(þ)-5a
(þ)-5a
(þ)-5a
(þ)-5h
(þ)-5h
(þ)-5a
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
o-BrC6H4
Allyl
3-Butynyl
CH2]CBrCH2
PMP
PMP
PMP
Bn
Bn
PMP
MeO
MeO
MeO
MeO
MeO
MeO
MeO
PhO
Allyl
Allyl
Allyl
Allyl
Bn
I2
BiCl3
H3NSO3
InCl3
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
1
4
2
2a
2a
2a
2a
2b
2c
2d
2g
2h
2i
85:15
85:15
85:15
74:26
87:13d
79:21d
79:21
90:10d
84:16
58:42d
66:34
70:30
66:34
79
72
73
70
87
66
49
71
75
75
70
58
50
2.5
1.7
22
4.5
2.7
1
0.7
4.5
0.8
1.2
1
Propargyl
t-Bu
Allyl
Allyl
Bn
Propargyl
Allyl
Bn
PMP
PMP
PMP
PMP
PMP
BnO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
2je
2k
2le
f
f
H3NSO3
BiCl3
I2
BiCl3
I2
4
24
1
2ee
76:24
d
67
g
23
2fe
63:37
71:29
66
53
CH2]CBrCH2
5f
2mh
a
All reactions were carried out using an aldehyde/TMSCN ratio of 1:1.5 mmol and an aldehyde/amine ratio of 1:1 mmol.
b
c
The syn/anti ratio was determined by integration of well-resolved signals in the 1H NMR spectra (300 MHz) of the crude reaction mixtures before purification.
Yield of isolated products with correct analytical and spectral data.
d
The syn/anti ratio could not be determined by integration in the 1H NMR spectra (300 MHz) of the crude reaction mixtures before purification, due to the absence of well-
resolved signals. The ratio was given in pure product after separation by gravity flow chromatography on deactivated silica gel.
e
a
-Aminonitriles 2e, 2f, 2j, and 2l were obtained as unseparable syn/anti mixtures.
f
Imine 1e was obtained in quantitative yield.
Imine 1f was obtained in quantitative yield.
Imine 1g must be isolated first, and then treated with TMSCN and I2. PMP¼4-MeOC6H4.
a
-Aminonitrile was not formed at longer reaction times.
-Aminonitrile was not formed at longer reaction times.
g
h
a
nucleus. Species 12 isomerizes to the more stable imidoyl cyanide
through a desmotropic equilibrium13 and suffers a final cyclization
to the 1-(p-anisyl)substituted 5-(imino)pyrrolidin-2-one 8, which
PMP
MeO
HN
H
H
NaOMe (1.1 equiv.)
MeO
Scheme 2. Possible selective N1eC2
azetidinone aminonitrile hybrids.
b-lactam ring cleavage/cyclization of 2-
CN
PMP
O
NPMP
MeOH, RT, 4.8 h
N
N
PMP
O
2e
(+)-8d (41%)
(sy n:anti 76:24)
PMP
HN
MeO
O
H
H
NaOMe (1.1 equiv.)
MeOH, RT, 5.5 h
MeO
CN
NPMP
N
N
Bn
O
Bn
(+)-8b (38%)
2f
(syn:anti 63:37)
But
HN
OMe NHBut
CN
H
H
NaOMe (1 equiv.)
MeOH, RT, 4.5 h
MeO
O
MeO
CN
PMP
N
O
NHPMP
(+)-9 (60%)
anti-(+)-2d
Scheme 3. Sodium methoxide promoted transformation of b-lactam aminonitriles into
functionalized pyroglutamides. aThe syn/anti ratio for compound 6a could not be de-
terminedby 1HNMR. bA 74:26syn/antiratioforcompound6cwasdeterminedby1H NMR.
Scheme 4. Sodium methoxide promoted transformation of
into imino- -lactam and -amino ester adducts.
b-lactam aminonitriles
g
b

10764
B. Alcaide et al. / Tetrahedron 68 (2012) 10761e10768
the reactions of aminonitriles 2a, 2b, and 2h, were conducted in
MeO
O
MeO
O
a saturated solution of HCl(g) in methanol at room temperature, it
gave rise to optically pure pyroglutamides 6aec in moderate yields.
Attempts were made to improve the above method by using
different acidic conditions such as H2SO4/DCM in different condi-
tions (Table 3). Interestingly, treatment of aminonitrile 2a with
a H2SO4/MeOH (1:2) mixture at room temperature, gave enantio-
HCl (20% aq.)
CH3CN, RT
O
NPMP
N
Bn
N
Bn
(+)-10
8b
(+)-
pure 5-cyano-g-lactam 7a in a 77% yield without byproducts. To our
Scheme 5. Hydrolysis of 5-(arylimino)pyrrolidin-2-one 8b into succinimide 10.
delight, absence of hydrolysis of the cyanide group was observed.
The results with aminonitriles 2 bearing different substituents
were similar to the case of 2a (Table 4). It should be mentioned that
starting from the mixture (syn/anti) of the two chromatographically
unseparable diastereomers 2f, the corresponding 3-amino-4-
alkoxy-5-oxopyrrolidine-2-carbonitriles syn-7f and anti-7f could
be isolated as pure compounds. Besides, a similar behavior was
observed for
der these reaction conditions. The cyclic structures and the ste-
reochemistry of 5-oxopyrrolidine-2-carbonitriles were
a-(alkylamino)nitriles and a-(arylamino) nitriles un-
7
established by one- and two-dimensional NMR techniques and
NOESY-1D experiments (see Fig. S1 and Table S2 in Supplementary
data). The values for vicinal coupling constants show unequivocally
a transecis orientation for protons H3eH4/H4eH5 in compounds
syn-7 and transetrans in compounds anti-7, in agreement with that
we previously reported for related products.7d
Table 4
Acid promoted transformation of
b
-lactam aminonitriles 2 into functionalized 5-
oxopyrrolidine-2-carbonitriles 7
R2
NHR1
R4 R5
H
H
R2
Scheme 6. Mechanistic explanation for the sodium methoxide promoted trans-
formation of -lactam aminonitriles 2.
R5
NHR3
H2SO4 / MeOH (1:2)
RT
b
R4
O
N
N
R1
R3
O
experiments a further isomerization to 1-(alkyl)substituted 5-
(imino)pyrrolidin-2-one 8 when R1 is aromatic. This isomerization
should occur due to the attack of the lactam carbonyl group by
a nucleophile (methoxide or cyanide), followed by ring-opening
and ring-closing of the amidine species 14 through the more ba-
sic nitrogen atom.
In order to improve the formation of pyroglutamic acid de-
rivatives 6 and 7 from b-lactam aminonitriles 2, acidic conditions
were explored (Table 3). We performed an initial experiment in
which aminonitrile 2h was treated with 35 mol % aqueous HCl, and
we observed the formation of a complex mixture. Happily, when
4 = CN, R5 = H
syn-7 R4 = CN, R5 = H
2
syn-
R
4
5
anti-2 R4 = H, R5 = CN
7
anti- R = H, R = CN
Aminonitrile R1
R2
R3
t (h) Product
Yielda (%)
syn-(þ)-2a PMP MeO Allyl
64 syn-(þ)-7a
63 anti-(þ)-7a
63 syn-(þ)-7b
54 syn-(þ)-7c
77
56
66
60
80
35
anti-(þ)-2a PMP MeO Allyl
syn-(þ)-2b
syn-(ꢁ)-2h
syn-(þ)-2c
syn-(þ)-2g
2fb
PMP MeO Bn
PMP BnO Allyl
PMP MeO Propargyl 63 syn-(þ)-7d
PMP PhO Allyl
Bn MeO PMP
143 syn-(þ)-7e
48 syn-(þ)-7f/anti-(þ)e7f 43:25
a
Yield of isolated products with correct analytical and spectral data.
A syn/anti mixture (63:37) of aminonitrile 2f was used. PMP¼4-MeOC6H4.
Table 3
b
Acid promoted transformation of b-lactam aminonitriles 2 into functionalized py-
roglutamides 6
R2
NHR1
CONH2
NHR3
Chemical correlation between cyano derivative 7b and its cor-
H H
R2
responding pyroglutamide 6b was achieved through hydrolysis of
the former by treatment at room temperature with a H2SO4/CH2Cl2
(1:100) mixture (Scheme 7).
acid
CN
O
N
N
solvent, RT
R1
R3
O
MeO
O
NHPMP
CN
MeO
O
NHPMP
CONH2
NHBn
CN
2
syn-
H
H
N
6
syn-
H2SO4/MeOH (1:2)
RT, 63 h
H2SO4/CH2Cl2 (1:100)
RT, 19 h
MeO
N
Bn
N
Bn
Aminonitrile R1 R2
R3 Acid/solvent
t (h) Product
8b dc
Yielda (%)
O
PMP
syn-(+)-2b
7b
syn-(+)- (66%)
6b
sy n-(+)- (53%)
syn-(ꢁ)-2h PMP BnO Allyl HCl concd/MeOH (1:40)
syn-(þ)-2a PMP MeO Allyl HCl (g)/MeOH
syn-(þ)-2b PMP MeO Bn HCl (g)/MeOH
syn-(ꢁ)-2h PMP BnO Allyl HCl (g)/MeOH
d
6
syn-(þ)-6a 36
6.3 syn-(þ)-6b 40
syn-(þ)-6c 32
Scheme 7. Hydrolysis of 5-oxopyrrolidine-2-carbonitrile 7b into pyroglutamide 6b.
6
syn-(þ)-2b PMP MeO Bn H2SO4 concd/DCM (1:100) 4.3 syn-(þ)-6b
0
Next, we decided to attempt the selective reduction of
nonitrile- -lactams 2. Among different reducing agents we selected
the use of NiCl2$6H2O with excess of NaBH4 in methanol, namely,
a-ami-
syn-(þ)-2b PMP MeO Bn H2SO4 concd/DCM (1:50) 44 syn-(þ)-6b 50
b
syn-(þ)-2b PMP MeO Bn H2SO4 concd/DCM (1:30) 20 syn-(þ)-6b 19
syn-(þ)-2b PMP MeO Bn H2SO4 concd/DCM (1:10)
4.5 syn-(þ)-6b 10
our optimized conditions for the reduction of b-lactam cyanohy-
a
Yield of isolated products with correct analytical and spectral data.
The experiment was carried out at reflux temperature.
A complex reaction mixture was obtained. PMP¼4-MeOC6H4.
drins.8 In the event, the reduction of the cyano group was achieved
in a total chemoselective fashion using the NaBH4/NiCl2/methanol
b
c

B. Alcaide et al. / Tetrahedron 68 (2012) 10761e10768
10765
system in the presence of di-tert-butyl dicarbonate as trapping
agent, to afford diamino- -lactams 15 in reasonable yields (Table 5).
Importantly, the -lactam ring stereochemistry was unaffected by
this manner, compounds 18a,b and 19 were prepared in fair yields
(Scheme 8). Unfortunately, starting from the unseparable mixture
of acetamides 16, the mixture of isomers (syn/anti) of compounds
19 could not be separated by bench chromatography. Finally, di-
amines 16 were transformed into imidazolidinone-b-lactam hy-
brids 20 by sequential exposure to trifluoroacetic acid and
b
b
this process. Interestingly, starting from the syn/anti mixture of
diastereomers 2e and 2f, the corresponding diamines syn-15b,c and
anti-15b,c could be isolated as pure compounds after chromato-
graphic separation. The vicinal coupling constants (3J4,4 ) of the two
triphosgene in presence of Hunig’s base (Scheme 8).
0
€
protons (H4 in the b-lactam ring, hydrogen a to the nitrogen) lo-
cated at the single bond connecting the ring and the diamino
moiety were diagnostic of the relative stereochemistry of these
stereocenters. The vicinal coupling constants values for major iso-
mers syn-15 (6.0e8.4 Hz) are larger than that for the minor isomers
anti-15 (2.2e3.0 Hz).
3. Conclusions
In conclusion, the stereoselective reaction between 2-
azetidinone-derived imines and cyanide-based reagents give the
corresponding
a-aminonitriles 2. These enantiopure b-lactam
aminonitrile hybrids are versatile building blocks for the controlled
synthesis of a variety of new compounds including functionalized
Table 5
Chemoselective reduction of
b
-lactam aminonitriles 2 into diamino-
b
-lactams 15
g-lactams 6 and 7, succinimide derivatives 8, and diamino-b-lac-
NHR3
NHR3
tams derivatives 15e20 in optically pure form.
H
H
N
H
H
N
NaBH4 (7 equiv.)
NiCl2.6H2O (1 equiv.)
(R4)2O (2 equiv.)
MeOH, RT
NHR4
R2
O
R2
O
CN
4. Experimental section
4.1. General information
R1
R1
2
15 (R4 = Boc)
16 (R4 = Ac)
1H NMR and 13C NMR spectra were recorded on a Bruker Avance
AVIII-700 with cryoprobe, Bruker AMX-500, Bruker Avance-300,
Varian VRX-300S or Bruker AC-200. NMR spectra were recorded
in CDCl3 solutions, except otherwise stated. Chemical shifts are
given in parts per million relative to TMS (1H, 0.0 ppm), or CDCl3
Aminonitrile R1 R2
R3 R4 t (min) Product
syn/anti Ratio Yielda (%)
syn-(þ)-2b PMP MeO Bn Boc 20
syn-(þ)-15a 100:0
36
71
81
55
2eb
2fc
2fc
PMP MeO PMP Boc 25
Bn MeO PMP Boc 30
Bn MeO PMP Ac 25
15b
15c
16d
76:24
63:37
63:37
(
13C, 77.0 ppm). Low and high resolution mass spectra were taken
on an AGILENT 6520 Accurate-Mass QTOF LC/MS spectrometer
using the electronic impact (EI) or electrospray modes (ES) unless
otherwise stated. IR spectra were recorded on a Bruker Tensor 27
a
Yield of isolated products with correct analytical and spectral data.
A syn/anti mixture (76:24) of aminonitrile 2e was used.
A syn/anti mixture (63:37) of aminonitrile 2f was used.
Diamines 16 were obtained as unseparable syn/anti mixtures. PMP¼4-
b
c
spectrometer. Specific rotation [a]
is given in 10ꢁ1 deg cm2 gꢁ1 at
d
D
20 ꢂC, and the concentration (c) is expressed in grams per 100 mL.
All commercially available compounds were used without further
purification.
MeOC6H4.
We examined the ability of diamines 15 to react with different
reagents. Ring expansion of diamino- -lactams 15 in presence of
b
sodium methoxide in methanol reliably give 4-amino-5-(amino-
methyl)-3-alkoxypyrrolidin-2-ones 17 (Scheme 8). Pyrrolidinone
formation through N1eC2 bond cleavage of the b-lactam nucleus
4.2. General procedures for the synthesis of
aminonitriles 2
b-lactam a-
must be driven by relief of the strain associated with the four-
membered ring on forming a more stable five-membered ring.
Next, the exocyclic p-anisylamino group in compounds 15 was
converted into a tert-butyl carbamate by oxidation with (diac-
etoxyiodo)benzene (DIB) in MeOH/AcOH followed by reaction with
di-tert-butyl dicarbonate of the resulting primary amino group. In
4.2.1. Reaction of imino-b-lactams 1 with TBDMSiCN. Method A. A
solution of TBDMSiCN (0.80 mmol) in anhydrous acetonitrile
(1.1 mL) and TBACN (0.07 mmol) in anhydrous acetonitrile (1.1 mL)
was sequentially added dropwise via syringe to a stirred solution of
the appropriate imine 1 (0.67 mmol) in the same solvent (2.2 mL) at
rt and under argon atmosphere. The mixture was stirred at rt until
disappearance of starting material (TLC). Then, a saturated aqueous
NaCl solution (7 mL) was added and the resulting mixture was
extracted with DCM (4ꢃ30 mL). The organic layer was dried
(MgSO4), filtered, and concentrated under reduced pressure. After
flash chromatography of the residue on deactivated silica gel,
eluting with hexanes/ethyl acetate mixtures, the two separated
syn/anti isomers of 2-azetidinone aminonitriles 2 were obtained.13
4.2.2. Direct aminocyanation of
b-lactam aldehydes 5. Method
B. The appropriate amine (1 mmol) and TMSCN (1.5 mmol) were
sequentially added dropwise via syringe to a stirred solution of the
corresponding 4-oxoazetidine-2-carbaldehyde
5 (1 mmol) and
catalyst (0.1 mmol of iodine, BiCl3, InCl3 or H3NSO3) in anhydrous
acetonitrile (5 mL) at rt and under argon atmosphere. The mixture
was stirred at rt until disappearance of starting material (TLC).
Then, ethyl acetate (30 mL) was added and the resulting mixture
was successively washed with water (15 mL) and saturated aque-
ous NaCl solution (15 mL). The organic layer was dried (MgSO4),
filtered, and concentrated under reduced pressure. After flash
chromatography of the residue on deactivated silica gel, eluting
Scheme 8. Transformation of
dicarbamates 18, amide carbamate 19, and imidazolidinones 20.
b-lactam diamines 15 into functionalized g-lactams 17,

10766
B. Alcaide et al. / Tetrahedron 68 (2012) 10761e10768
with hexanes/ethyl acetate mixtures, the two separated syn/anti
isomers of 2-azetidinone aminonitriles 2 were obtained.14
3344, 1683 cmꢁ1
;
dH (300 MHz, CDCl3) 3.51 (1H, dd, Jab¼14.9 Hz,
JHa,]CH¼7.6 Hz, NCHaHb), 3.65 (3H, s, CH3OeC3), 3.76 (3H, s,
CH3OeC6H4), 4.13e4.38 (4H, m, H5, H4, H3 and NCHaHb), 5.23 (1H,
d, Jtrans¼16.1 Hz, CH]CHcisHtrans), 5.25 (1H, d, Jcis¼9.8 Hz, CH]
CHcisHtrans), 5.74 (3H, m, CH]CHcisHtrans and CONH2), 6.81 (4H, m,
Ar); dC (75 MHz, CDCl3) 44.9 (NCH2), 55.7 (CH3OeC6H4), 57.7 (C4),
59.08 (CH3OeC3), 60.10 (C5), 80.87 (C3), 114.9, 115.0 (2CHAr m-
OCH3 and 2CHAr o-OCH3), 119.4 (CH]CH2), 131.3 (CH]CH2), 140.0
(CAr ipso-NH), 152.9 (CAr ipso-OCH3), 171.0, 171.7 (NeC]O and
CONH2).
4.2.3.
a-Aminonitrile 2a. 4.2.3.1. Method A. By starting from imine
(þ)-1a (62 mg, 0.44 mmol), followed by chromatography of the
product residue (hexanes/EtOAc 4:1), the more polar compound
syn-(þ)-2a (60 mg, 54%) and the less polar compound anti-(þ)-2a
(15 mg, 14%) were obtained.
4.2.3.2. Method B. By starting from imine (þ)-1a (150 mg,
0.64 mmol) and molecular iodine as catalyst, followed by chro-
matography of the product residue (hexanes/EtOAc 4:1), the more
polar compound syn-(þ)-2a (129 mg, 67%) and the less polar
compound anti-(þ)-2a (23 mg, 12%) were obtained.
4.4. General procedure for the acid promoted transformation
of b-lactam aminonitriles 2 into functionalized 5-
oxopyrrolidine-2-carbonitriles 7
4.2.3.3.
a
-Aminonitrile
syn-(þ)-2a. Colorless
solid;
mp
dH
Concentrated sulfuric acid (3.5 mL) was slowly added to a solu-
tion of the appropriate a-aminonitrile 2 (0.30 mmol) in methanol
85e86 ꢂC; [
a
]
D
þ112.5 (c 0.5, CHCl3); nmax (CHCl3) 1755 cmꢁ1
;
(300 MHz, CDCl3) 3.27 (1H, m, NCHaHb), 3.56 (1H, m, NCHaHb), 3.73
(3H, s, CH3OeC3), 3.80 (3H, s, CH3OeC6H4), 4.15 (1H, dd,
(7 mL), and then stirred at rt, under argon, until disappearance of
starting material (TLC). The reaction mixture was neutralized with
saturated aqueous solution of sodium hydrogen carbonate (15 mL)
and solid sodium hydrogen carbonate. The reaction mixture was
concentrated under reduced pressure and extracted with ethyl
acetate (5ꢃ30 mL). The organic layer was dried (MgSO4), filtered,
and concentrated under reduced pressure. After flash chromatog-
raphy of the residue on silica gel, eluting with hexanes/ethyl acetate
mixtures, compounds 7 were obtained.
J4 ,NH¼11.2 Hz, J4 ,4¼5.1 Hz, H40), 4.43 (1H, t, J4,3¼J4,4 ¼5.1 Hz, H4), 4.75
(1H, d, J3,4¼5.1 Hz, H3), 5.19 (1H, dd, Jcis¼10.2 Hz, Jgem¼1.4 Hz, CH]
CHcisHtrans), 5.27 (1H, dd, Jtrans¼17.2 Hz, Jgem¼1.5 Hz, CH]CHcisHtrans),
5.79 (1H, dddd, Jtrans¼16.9 Hz, Jcis¼10.2 Hz, JCH],Ha¼6.4 Hz,
JCH],Hb¼5.2 Hz, CH]CHcisHtrans), 6.89 (2H, AA0XX0, 2CHAr o-OCH3),
7.34 (2H, AA0XX0, 2CHAr m-OCH3); dC (75 MHz, CDCl3) 49.3 (C40), 50.6
(NCH2), 55.5 (CH3OeC6H4), 56.7 (C4), 59.3 (CH3OeC3), 82.5 (C3),114.6
(2CHAr m-NeC]O),117.0 (CN),118.1 (CH]CH2),119.2 (2CHAr o-NeC]
O), 129.5 (CAr ipso-NeC]O), 134.5 (CH]CH2), 157.0 (CAr ipso-OCH3),
163.4 (NeC]O); m/z (EI) 301 (Mþ$, 49), 274 (8), 243 (84), 215 (22),178
(65),149 (100),134 (71). Anal. Calcd for C16H19N3O3: C, 63.77; H, 6.36;
N, 13.94. Found: C, 63.92; H, 6.28; N, 13.83.
0
0
0
4.4.1. 5-Oxopyrrolidine-2-carbonitrile syn-(þ)-7a. From 96 mg
(0.32 mmol) of
a
-aminonitrile syn-(þ)-2a, compound syn-(þ)-7a
(74 mg, 77%) was obtained as a pale brown oil; [
a]
D
þ140.8 (c 1.0,
CHCl3); nmax (CHCl3) 3362, 1717 cmꢁ1
;
dH (300 MHz, CDCl3) 3.69 (1H,
dd, Jab¼15.4 Hz, JHa,]CH¼7.6 Hz, NCHaHb), 3.74 (3H, s, CH3OeC3), 3.77
(3H, s, CH3OeC6H4), 4.02 (1H, d, J5,4¼9.0 Hz, H5), 4.19 (1H, dd,
J4,5¼9.4 Hz, J4,3¼7.2 Hz, H4), 4.38 (1H, dd, Jab¼15.0 Hz, JHb,]CH¼5.2 Hz,
NCHaHb), 4.57 (1H, d, J3,4¼7.1 Hz, H3), 5.35 (1H, d, Jtrans¼16.8 Hz, CH]
CHcisHtrans), 5.36 (1H, d, Jcis¼9.8 Hz, CH]CHcisHtrans), 5.74 (1H, dddd,
Jtrans¼16.1 Hz, Jcis¼10.7 Hz, J]CH,Ha¼7.7 Hz, J]CH,Hb¼5.3 Hz, CH]
CHcisHtrans), 6.72 (2H, AA0BB0, 2CHAr o-OCH3), 6.83 (2H, AA0BB0, 2CHAr
m-OCH3); dC (75 MHz, CDCl3) 44.9 (NCH2), 49.9 (C5), 55.6
(CH3OeC6H4), 57.8 (C4), 59.6 (CH3OeC3), 80.5 (C3), 114.8 (CN), 115.1,
116.2 (2CHAr m-OCH3 and 2CHAr o-OCH3), 121.2 (CH]CH2), 130.0
(CH]CH2),138.6 (CAr ipso-NH),153.9 (CAr ipso-OCH3),169.8(NeC]O);
m/z (EI) 301 (Mþ., 100), 286 (3), 256 (21), 179 (37), 164 (57), 149 (33),
134 (35).
4.2.3.4.
a
-Aminonitrile anti-(þ)-2a. Colorless oil; [
a
]
D þ355.1 (c
0.4, CHCl3); nmax (CHCl3) 3338, 1752 cmꢁ1
;
dH (300 MHz, CDCl3) 3.19
(1H, dd, Jab¼14.0 Hz, JHa,CH]¼7.0 Hz, NCHaHb), 3.48 (1H, dd,
Jab¼14.0 Hz, JHb,CH]¼5.0 Hz, NCHaHb), 3.73 (3H, s, CH3OeC3), 3.80
(3H, s, CH3OeC6H4), 4.14 (1H, d, J4 ,4¼3.4 Hz, H40), 4.48 (1H, dd,
0
0
J4,3¼4.9 Hz, J4,4 ¼3.9 Hz, H4), 4.77 (1H, d, J3,4¼4.9 Hz, H3), 5.03 (1H,
dd, Jcis¼10.0 Hz, Jgem¼1.2 Hz, CH]CHcisHtrans), 5.12 (1H, dd,
Jtrans¼17.2 Hz, Jgem¼1.3 Hz, CH]CHcisHtrans), 5.51 (1H, dddd,
Jtrans¼17.0 Hz, Jcis¼10.0 Hz, JCH
]
,Ha
¼6.8 Hz, JCH
]
¼5.0 Hz, CH]
,Hb
CHcisHtrans), 6.89 (2H, AA0XX0, 2CHAr o-OCH3), 7.31 (2H, AA0XX0,
2CHAr m-OCH3); dC (75 MHz, CDCl3) 47.2 (C40), 50.1 (NCH2), 55.5
(CH3OeC6H4), 57.9 (C4), 60.5 (CH3OeC3), 83.4 (C3), 114.6 (2CHAr m-
NeC]O), 117.9 (CN), 118.1 (CH]CH2), 119.4 (2CHAr o-NeC]O),
129.5 (CAr ipso-NeC]O), 134.4 (CH]CH2), 157.0 (CAr ipso-OCH3),
163.8 (NeC]O); m/z (EI) 301 (Mþ$, 70), 274 (8), 243 (66), 215 (18),
178 (100), 149 (69), 134 (55).
4.5. General procedure for the chemoselective reduction of
lactam aminonitriles 2 into diamino- -lactams 15
b-
b
Sodium borohydride (3.85 mmol) was slowly added over a so-
lution of the appropriate -aminonitrile 2 (0.55 mmol), nickel(II)
4.3. General procedure for the acid promoted transformation
a
of
b
-lactam aminonitriles 2 into functionalized
chloride hexahydrate (0.55 mmol), and di-tert-butyl dicarbonate
(1.1 mmol) in methanol (4.6 mL), at 0 ꢂC under argon. The reaction
mixture was allowed to warm to room temperature and was stirred
until disappearance of starting material (TLC). Methanol was
evaporated under vacuum and, the resulting crude was diluted
with ethyl acetate (110 mL). Then, a saturated aqueous solution of
NaHCO3 was added (55 mL). The resulting mixture was filtered
through a pad of Celite and the filtrate was extracted with ethyl
acetate (4ꢃ55 mL). The organic layer was dried (MgSO4) and con-
centrated under reduced pressure. Flash chromatography on silica
gel of the residue, eluting with hexanes/ethyl acetate mixtures gave
pyroglutamides 6
HCl(g) was bubbled during 1 h through a solution of the appro-
priate a-aminonitrile 2 (0.17 mmol) in methanol (4.2 mL), and then
stirredatrtuntildisappearanceofstartingmaterial(TLC). Thereaction
mixture was concentrated under reduced pressure, diluted with
dichloromethane (20 mL), washed with saturated aqueous sodium
hydrogen carbonate (2ꢃ10 mL), and brine (10 mL). The organic layer
was dried (MgSO4), filtered, and concentrated under reduced pres-
sure. After flash chromatography of the residue on silica gel, eluting
with hexanes/ethyl acetate (1:1), compounds 6 were obtained.
b-lactam carbamates 15.
4.3.1. Pyroglutamide-syn-(þ)-6a. From 50 mg (0.17 mmol) of
aminonitrile syn-(þ)-2a, compound syn-(þ)-6a (19 mg, 36%) was
obtained as a pale brown oil; [
D þ60.2 (c 0.6, CHCl3); nmax (CHCl3)
a
-
4.5.1. Diamino-
-aminonitrile syn-(þ)-2b, compound syn-(þ)-15a (70 mg, 36%)
was obtained as a colorless oil; [
þ45.9 (c 0.8, CHCl3); nmax
b
-lactam sin-(þ)-15a. From 150 mg (0.43 mmol) of
a
a]
a]
D

B. Alcaide et al. / Tetrahedron 68 (2012) 10761e10768
10767
(CHCl3) 3362, 1717 cmꢁ1
;
dH (300 MHz, CDCl3) 1.42 (9H, s,
residue eluting with hexanes/ethyl acetate mixtures afforded ana-
lytically pure carbamates 18 or amide 19.
(CH3)3CeO), 3.29e3.38 (3H, m, CH2NCO and H40), 3.66 (3H, s,
CH3OeC3), 3.74 (1H, d, Jab¼12.9 Hz, NCHaHbPh), 3.79 (3H, s,
CH3OeC6H4), 3.86 (1H, d, Jab¼13.2 Hz, NCHaHbPh), 4.32 (1H, t,
4.7.1.1. Functionalized dicarbamate syn-(þ)-18a. From 103 mg
0
J4,3¼J4,4 ¼5.8 Hz, H4), 4.62 (1H, d, J3,4¼5.3 Hz, H3), 4.93 (1H, br s,
(0.22 mmol) of diamino-
b
-lactam syn-(þ)-15a, compound syn-
NHC]O), 6.86 (2H, AA0XX0, 2CHAr o-OCH3), 7.17e7.32 (5H, m, Ar),
7.35 (2H, AA0XX0, 2CHAr m-OCH3); dC (75 MHz, CDCl3) 28.3
[(CH3)3CeO], 40.4 (CH2NHCO), 52.0 (NCH2Ph), 55.4 (CH3OeC6H4),
56.8, 58.8 (C40 and C4), 59.5 (CH3OeC3), 79.2 ((CH3)3CeO), 83.1
(C3), 114.4 (2CHAr m-NeC]O), 119.5 (2CHAr o-NeC]O), 127.0 (CHAr
p-CH2),127.9,128.3 (2CHAr m-CH2 and 2CHAr o-CH2),130.7 (CAr ipso-
NeC]O), 140.1 (CAr ipso-CH2), 156.2 (OC]ONH), 156.7 (CAr ipso-
OCH3), 165.2 (NeC]O); m/z (EI) 455 (Mþ$, 19), 399 (27), 382 (8),
325 (34), 249 (19), 193 (88), 176 (34), 149 (23), 91 (100).
(þ)-18a (31 mg, 31%) was obtained as a colorless solid; mp
170e173 ꢂC; [
þ36.7 (c 0.3, CHCl3); nmax (CHCl3) 3356, 1737,
1681 cmꢁ1
dH (300 MHz, CDCl3) 1.40 (9H, s, (CH3)3CeO), 3.16 (1H, m,
a]
D
;
CHaHb), 3.63 (1H, m, CHaHb), 3.70 (3H, s, CH3OeC3), 3.79 (3H, s,
CH3OeC6H4), 4.40 (2H, m, H40 and H4), 4.66 (1H, d, J3,4¼05.1 Hz, H3),
0
4.66 (1H, m, CH2NHC]O), 5.16 (1H, d, JNH,4 ¼7.3 Hz, C4 eNHC]O),
6.88(2H, AA0XX0, 2CHAr m-NeC]O), 7.38 (2H, AA0XX0, 2CHAr o-NeC]
O); dC (75 MHz, CDCl3) 28.2, 28.3 (2ꢃ(CH3)3C-O), 40.5 (CH2), 55.5
(2ꢃCH3OeC6H4), 56.4, 56.9 (C40 and C4), 59.4 (CH3O-C3), 79.4, 79.8
(2ꢃ(CH3)3CeO), 83.0 (C3), 114.6 (2CHAr m-NeC]O), 118.9 (2CHAr o-
NeC]O),130.2 (CAr ipsoeN-C]O),152.2,155.9 (2ꢃOC]ONH),156.7
(CAr ipso-OCH3),164.3 (NeC]O); m/z (EI) 465 (Mþ$,19), 365 (26), 309
(48),149 (52),130 (80), 57 (100). Anal. Calcd for C23H35N3O7: C, 59.34;
H, 7.58; N, 9.03. Found: C, 59.41; H, 7.62; N, 8.98.
4.6. General procedure for the transformation of
diamines 15 into functionalized -lactams 17
b-lactam
g
A solution of the appropriate diamino-b-lactam 15 (0.11 mmol)
in methanol (2.6 mL) was added at rt under argon to sodium
methoxide (0.13 mmol). The reaction mixture was stirred at room
temperature until complete disappearance of the starting material
(TLC) and then brine (5 mL) was added. Methanol was removed
under reduced pressure, and the aqueous residue was extracted
with ethyl acetate (5ꢃ10 mL). The organic extract was dried over
MgSO4, and the solvent was removed under reduced pressure.
Chromatography of the residue eluting with ethyl acetate/hexanes
(1:3) gave analytically pure compounds 17.
4.7.2. Preparation of imidazolidinone syn-(þ)-20. To a solution of the
carbamate syn-(þ)-15c (78 mg, 0.17 mmol) in anhydrous dichloro-
methane (1.2 mL), trifluoroacetic acid (0.38 mL, 5.12 mmol) was
slowly added under argon atmosphere at rt. Upon complete addition,
the reaction mixture was stirred at rt for 1 h, and a 30%aq NH3 solution
was added until mixture was made basic. Then, solid NaCl was added,
and the aqueous residue was extracted with ethyl acetate (5ꢃ15 mL).
The organic extract was dried (MgSO4) and the solvent was removed
under reduced pressure. To a solution of the crude diamine in anhy-
drous dichloromethane (1.3 mL), N,N-diisopropylethylamine
(0.88 mL, 0.51 mmol) was slowly added under argon atmosphere at
0 ꢂC. Upon complete addition, the reaction mixture was stirred at 0 ꢂC
for 15 min, and a solution of triphosgene (61 mg, 0.21 mmol) in an-
hydrous dichloromethane (0.6 mL) was added dropwise. The reaction
mixture was stirred at rt for an additional 1 h. The reaction mixture
wasdilutedwithdichloromethane(15 mL), washed withwater(4 mL)
and brine (4 mL). The organic layer was dried (MgSO4), filtered, and
concentrated under reduced pressure. After flash chromatography of
the residue on silica gel, eluting with hexanes/ethyl acetate (2:1),
compound syn-(þ)-20 (20 mg, 30%) was obtained as a pale brown oil.
4.6.1. Functionalized
diamino-
-lactam syn-(þ)-15a, compound syn-(þ)-17a (31 mg,
62%) was obtained as a pale brown oil; [
þ31.1 (c 0.6, CHCl3);
nmax (CHCl3) 3327, 1701 cmꢁ1
dH (300 MHz, CDCl3) 1.45 (9H, s,
g
-lactam (þ)-17a. From 50 mg (0.11 mmol) of
b
a]
D
;
(CH3)3C-O), 3.03 (1H, m, CHaHbNH), 3.40 (1H, dd, Jab¼14.5 Hz,
JHb,5¼8.9 Hz, CHaHbNH), 3.64 (1H, m, H5), 3.69 (3H, s, CH3OeC3),
3.73 (3H, s, CH3OeC6H4), 3.91 (1H, d, J3,4¼9.3 Hz, H3), 4.04 (1H, m,
H4), 4.29 (1H, d, Jab¼15.0 Hz, NCHaHbPh), 4.40 (1H, br s, NHC]O),
4.81 (1H, d, Jab¼14.4 Hz, NCHaHbPh), 6.67 (2H, AA0BB0, 2CHAr o-
OCH3), 6.76 (2H, AA0BB0, 2CHAr m-OCH3), 7.33e7.35 (5H, m, Ar); dC
(75 MHz, CDCl3) 28.3 [(CH3)3CeO], 37.0 (CH2NH), 45.2 (NCH2Ph),
55.7 (CH3OeC6H4), 57.2, 58.1 (C40 and C4), 59.2 (CH3OeC3), 80.5
[(CH3)3CeO], 81.4 (C3), 115.0 (2CHAr m-NH and 2CHAr o-NH), 128.1
(CHAr p-CH2), 128.3, 129.0 (2CHAr m-CH2 and 2CHAr o-CH2), 136.0
(CAr ipso-CH2), 140.8 (CAr ipso-NH), 152.8 (CAr ipso-OCH3), 156.1
(OC]ONH), 171.3 (NeC]O); m/z (EI) 455 (Mþ$, 68), 399 (100), 382
(17), 354 (15), 293 (49), 123 (46), 91 (80), 57 (20).
[
a
]
D þ4.6 (c 0.6, CHCl3); nmax (CHCl3) 1778, 1748 cmꢁ1
; dH (300 MHz,
CDCl3)3.48(1H,d,Jab¼15.0 Hz, NCHaHbPh), 3.61 (3H, s, CH3OeC3),3.70
0
0
(1H, dd, J4,4 ¼6.3 Hz, J4,3¼5.2 Hz, H4), 3.72 (1H, t, Jab¼JHa,4 ¼10.8 Hz,
CHaHbNHCO), 3.83 (3H, s, CH3OeC6H4), 3.86 (1H, dd, Jab¼11.5 Hz,
0
JHb,4 ¼3.8 Hz, CHaHbNHCO), 4.26 (1H, d, Jab¼15.0 Hz, NCHaHbPh), 4.36
(1H, ddd, J4 ,Ha¼9.9 Hz, J4 ,4¼6.3 Hz, J4 ,Hb¼3.8 Hz, H40), 4.48 (1H, d,
J3,4¼5.2 Hz, H3), 6.96 (2H, AA0XX0, 2CHAr o-OCH3), 7.08e7.11 (2H, m, Ar)
7.30 (2H, AA0XX0, 2CHAr m-OCH3), 7.35e7.37 (3H, m, Ar); dC (75 MHz,
CDCl3) 45.0, 45.2 (CH2NHCO and NCH2Ph), 52.7 (C40), 55.5
(CH3OeC6H4), 57.9 (C4), 59.8 (CH3OeC3), 83.9 (C3), 114.8 (2CHAr m-
NeC]O), 124.8 (2CHAr o-NeC]O), 128.3, 129.2 (2CHAr m-CH2 and
2CHAr o-CH2), 128.5 (CHAr p-CH2), 128.9 (CAr ipso-NeC]O), 134.8 (CAr
ipso-CH2), 158.2 (CAr ipso-OCH3 and NC]ONH), 167.6 (NeC]O); m/z
(EI) 236 (100), 191 (15), 91 (32).
0
0
0
4.7. General procedures for transformations of
diamines 15
b-lactam
4.7.1. Preparation of dicarbamates 18 or amide carbamate 19. To
a solution of diacetoxy iodobenzene (DIB) (0.88 mmol) in a mixture
of methanol (2.6 mL) and acetic acid (0.05 mL), a solution of the
corresponding diamino-b-lactam 15 (0.22 mmol) in methanol
(0.6 mL) was slowly added (over 30 min). Upon complete addition,
the reaction mixture was stirred at rt for 30 min. Then, a 10% aq HCl
solution (2.6 mL, wt %) was added. The mixture was stirred for
30 min, at which time a 10% aq Na2S2O3 solution (2.6 mL, wt %) was
added, and stirring was allowed to continue for an additional 30 min.
Afterthat sodium carbonatewasadded untilsolutionwasmade basic
and, a solution of di-tert-butyl dicarbonate or acetic anhydride
(0.88 mmol) in DCM (1 mL) was added as required. The mixture was
stirred overnight at rt. Afterward, methanol was removed under re-
duced pressure and the resulting mixture was extracted with DCM
(4ꢃ20 mL). The organic layer was dried (MgSO4) and concentrated
under reduced pressure. Flash chromatography on silica gel of the
Acknowledgements
Support for this work by the DGI-MICINN (Project CTQ2009-
09318), Comunidad Autonoma de Madrid (Project S2009/PPQ-
1752), and Santander-UCM (Project GR35/10) is gratefully ac-
knowledged. G.C. thanks MEC for a predoctoral grant.
ꢀ
Supplementary data
Supplementary data related to this article can be found in the
online version, at doi:10.1016/j.tet.2012.02.062.

10768
B. Alcaide et al. / Tetrahedron 68 (2012) 10761e10768
Chem. 2004, 11, 1889; (d) Alcaide, B.; Almendros, P. Synlett 2002, 381; (e) Pal-
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14. Full spectroscopic and analytical data for compounds not included in this ex-
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