Stereoselective, solid phase-based synthesis of trans 3-alkyl-substituted β-lactams as analogues of cholesterol absorption inhibitors

Article abstract of DOI:10.1016/j.tet.2012.01.072

A straightforward solid phase-based strategy for the rapid generation of two small libraries of trans 3-alkyl-substituted β-lactams is described. For the glycine-derived library, a controlled excess of nonactivated acid chlorides was used to prevent oxazinone formation. The second library involved the attachment of Fmoc-protected p-aminophenol to Wang resin for the preparation of structurally-closed analogues of known cholesterol absorption inhibitors. This strategy allowed us to introduce diversity in the three variable positions of the β-lactam ring.

Full text of DOI:10.1016/j.tet.2012.01.072

Tetrahedron 68 (2012) 10780e10786
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective, solid phase-based synthesis of trans
3-alkyl-substituted
b-lactams as analogues of cholesterol
absorption inhibitors
ꢀ
ꢀ
Carina M.L. Delpiccolo, Sebastian A. Testero, Federico N. Leyes, Dora B. Boggian,
*
ꢀ
Cristian M. Camacho, Ernesto G. Mata
ꢀ
Instituto de Química Rosario (CONICETeUNR), Facultad de Ciencias Bioquímicas y Farmaceuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
A straightforward solid phase-based strategy for the rapid generation of two small libraries of trans 3-
Received 30 November 2011
Received in revised form 4 January 2012
Accepted 24 January 2012
Available online 28 January 2012
alkyl-substituted
b-lactams is described. For the glycine-derived library, a controlled excess of non-
activated acid chlorides was used to prevent oxazinone formation. The second library involved the at-
tachment of Fmoc-protected p-aminophenol to Wang resin for the preparation of structurally-closed
analogues of known cholesterol absorption inhibitors. This strategy allowed us to introduce diversity in
the three variable positions of the b-lactam ring.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Solid-phase synthesis
Beta-lactam derivatives
Cholesterol absorption inhibitors
1. Introduction
cephalosporins, carbapenems, carbacephems and monobactam.4
The usefulness of -lactam derivatives has been also demon-
b
Solid-phase organic synthesis (SPOS) has experienced a spec-
tacular growth since its beginning in the early nineties. With the
advent of the small-molecule combinatorial chemistry, the poten-
tial of SPOS for the generation of molecular diversity was immedi-
ately recognized and this methodology was successfully applied in
the field of drug discovery.1 The advantage of SPOS is the purifica-
tion step, a simple filtration avoids tiresome and time-consuming
separation techniques. Consequently, reagents can be added in ex-
cess in order to force the reactions to completion. Moreover, solid-
phase methodologies tolerate the use of high-boiling solvents, since
their elimination by evaporation is not necessary. More recently,
SPOS has gained interest in some particular areas of organic syn-
thesis in view of the effect of the spatial separation of substrates
achieved by immobilization on a polystyrene resin. This is re-
markably useful in cross coupling reactions to avoid undesired
homocoupling products,2 and in intramolecular macrocyclization
due to the ‘pseudo-dilution effect’.3 Therefore, there is a clear need
to expand the synthetic transformations and organic structures that
can be accomplished through solid-phase techniques.
strated in other important therapeutic areas like inhibition of
cholesterol absorption, prostate specific antigen, human tryptase,
thrombin and chymase, cysteine protease, human leukocyte elas-
tase and human cytomegalovirus protease.5 The therapeutic im-
portance of this structure is also clear from reports about b-lactams
related to the treatment of cancer,6 Parkinson7 and other neuro-
logical diseases.8 Furthermore,
b
-lactam compounds are very useful
-lactams in the
as synthetic building blocks.9
Excluding antibacterial activity, the use of
b
treatment of hypercholesterolaemia is their most significant ap-
plication. Dietary cholesterol consumption and intestinal choles-
terol absorption contribute to plasma cholesterol levels, and high
serum cholesterol level is the main risk factor for coronary heart
disease. In 1994, Burnett et al. reported the synthesis of several b-
lactams that were tested for their cholesterol absorption inhibitory
activity.10 They found that the compound (ꢀ)-SCH48461 (A, Fig. 1)
reduces cholesterol levels both in vivo and in vitro assays. The
design of these compounds was based on conformationally con-
strained variants of known ACAT (acyl-coenzime A cholesterol
acyltransferase) inhibitors.
b-Lactam skeleton has been widely recognized as one the most
significant heterocyclic structure in organic chemistry. It is present
in a variety of clinically relevant antibiotics, such as penicillins,
Based on the structure of active metabolites of A, Van Heek
et al.11 found (ꢀ)-SCH58235 (Ezetimibe, B, Fig. 1), which was ap-
proved as drug by FDA in 2002.12 The mechanism of action of these
b
-lactam derivatives does not appear to be similar to that of pre-
* Corresponding author. Tel./fax: þ54 341 4370477; e-mail addresses: mata@
vious hypolipidemic agents.13 In fact, it was recently established
iquir-conicet.gov.ar, emata@fbioyf.unr.edu.ar (E.G. Mata).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.072

C.M.L. Delpiccolo et al. / Tetrahedron 68 (2012) 10780e10786
10781
acylketenes are highly reactive and have a propensity to react with
dienophiles giving [4þ2] DielseAlder adducts. So, the acylketene
would react with an immobilized imine 3 to give the oxazinone 5
(Scheme 2).
A
B
Fig. 1. Cholesterol absorption inhibitors.
Scheme 2. Formation of oxazinone from acylketene and imine.
To prevent the formation of the oxazinone, we decided to de-
crease the amount of the alkanoyl chloride. For example, when the
reaction was performed using 2 equiv of 5-phenylvaleroyl chloride
(4a) and 4 equiv of triethylamine at reflux of toluene overnight, the
that Ezetimibe (B) blocks cholesterol absorption by interaction with
NiemannePick C1 Like 1 (NPC1L1) protein.14 While some recent
attempts to improve the activity of ezetimibe through the prepa-
ration of new analogues were unsuccessful, it is clear that this field
has not yet been thoroughly explored.15,16
expected b-lactam 8aa (Table 1, entry 1) was isolated but only in
26% overall yield. Due to the presence of the starting aldehyde in
the crude mixture, we assumed that the reaction was incomplete.
After several attempts, the best conditions were found when
a controlled excess of 4a (4 equiv) and triethylamine (8 equiv) were
added to the immobilized imine 3a and refluxed in toluene for 12 h.
After resin cleavage, esterification and purification by flash column
In continuation to our interest on new strategies for the prep-
aration of biologically promising compounds, we envisaged that
the development of a reliable solid phase-based synthesis of trans
3-alkyl-substituted b-lactams could be useful for the generation of
libraries for biological analysis, as well as mechanistic studies. Our
results are summarized in this paper.17
chromatography, b-lactam 8aa was obtained in 57% overall isolated
yield (based on initial loading level of Fmoc-Gly-Wang resin). The
resultant product was obtained with excellent selectivity, only the
3,4-trans stereoisomer was detected (based on analysis of 1H NMR
of the crude material). The stereochemistry of the b-lactam was
determined from the coupling constants of the protons attached at
C-3 and C-4 (y2 Hz).
2. Results and discussion
Among a large number of synthetic methods for the synthesis of
b
-lactam compounds, one of the most used is the [2þ2] cycload-
dition of imines with in situ-generated ketenes.18 This annulation of
activated carboxylic acids with imines in the presence of base is
called Staudinger reaction.19 Our first synthetic approach for the
After establishing the optimal conditions, we developed a li-
brary of different 3-alkyl-
b-lactams. As can be seen in Table 1, good
preparation of a model 3-alkyl-b-lactam was the application of the
solid-phase version of the Staudinger reaction.20 Starting from
commercial Fmoc-Gly-Wang resin (1), the amine group was
deprotected by standard conditions using 30% piperidine in DMF
(Scheme 1). This amine tethered to the solid support was con-
densed with p-anisaldehyde (2a), giving the imine 3a. For the
Staudinger reaction on solid phase, and in order to drive the re-
action to completion, a large excess of 5-phenylvaleroyl chloride
(4a) (15 equiv) and triethylamine (20 equiv) was added to
a dichloromethane suspension of the immobilized imine 3a at 0 ꢁC.
Surprisingly, after stirring for 12 h at room temperature, the oxa-
overall yields of the -lactams were obtained and only the trans
b
isomers were observed in all cases. While the 5-phenylvaleroyl
chloride (4a) was generated in situ from the corresponding acid,
propionyl and butyryl chlorides were prepared and used after
distillation (entries 6e10); in these cases, 3 equiv of the acid
chloride were the optimum conditions to achieve the best
performance.
The high stereoselectivity observed can be ascribedtothe effect of
the substituents at the b-lactam ring. According to the ketene-imine
mechanism,22,23 a zwiterionic intermediate III is initially formed
through the attack of the imine nitrogen at the carbonyl carbon of the
zinone 5aa was obtained, instead of the expected b-lactam. For-
ketene, followed by a direct ring closure (leading to the cis
or an isomerization-ring closure (leading to the trans
b
b
-lactam)
-lactam)
mation of the oxazinone was confirmed after releasing into
solution with 10% TFA/DCM followed by esterification with diazo-
methane, to give 6aa that was spectroscopically characterized.21
This compound was isolated in 40% overall yield, based on the
initial loading of the Fmoc-Gly-Wang resin.
(Scheme 3). Electron-donating groups in the ketene component (R)
accelerate the conrotatory ring closure due to the increase in nucle-
ophilicity of the enolate, yielding the thermodynamically less stable
Scheme 1. Synthesis of the unexpected oxazinone.
This result could be explained by the tendency of ketenes to
suffer dimerization to acylketenes, which is favoured by the excess
of alkanoyl chloride used in our strategy. It is known that
cis b-lactam (increase k1). In our case, a nonactivated aliphatic ketene
is formed, sothetendencytothedirect ringclosure is diminished and
the zwitterionic intermediate III could rotate to the sterically less

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C.M.L. Delpiccolo et al. / Tetrahedron 68 (2012) 10780e10786
Table 1
Solid-phase synthetic sequence for the preparation of 3-alkyl-b-lactams
Entry
b-Lactam
R1
R2
Yielda
%
1
2
3
4
5
6
7
8
9
8aa
8aa
8ba
8ca
8da
8ab
8cb
8ac
8ad
8dd
4-MeO
4-MeO
H
4-Me
4-Br
4-MeO
4-Me
4-MeO
4-MeO
4-Br
Ph(CH2)3
Ph(CH2)3
Ph(CH2)3
Ph(CH2)3
Ph(CH2)3
CH3
26b
57c
57c
56c
43c
52d
54d
51d
48d
50d
CH3
CH3CH2
CH3(CH2)3
CH3(CH2)3
10
a
Overall isolated yield after flash column chromatography (based on initial loading of Fmoc-Gly-Wang resin, five reaction steps).
Performed using 2 equiv of acid chloride and 4 equiv of Et3N.
Performed using 4 equiv of acid chloride and 8 equiv of Et3N.
b
c
d
Performed using 3 equiv of acid chloride and 6 equiv of Et3N.
formation of the product. After standard separation from the resin
and purification, the desired -lactam 15aa was obtained in 15%
b
isolated yield for the whole synthetic sequence (based on the initial
loading level of the Wang resin).
Interestingly, compound 15aa is a demethylated analogue of
cholesterol absorption inhibitor SCH48461 (see Fig. 1). A small li-
brary of 3-alkyl-1-aryl-b-lactams was then generated using the
activation by Mukaiyama’s reagent (Table 2). After five reaction
steps, different analogues of cholesterol absorption inhibitors were
obtained. The lower yields compared with the glycine-derived li-
brary might be explained because of the lower activity of the aro-
matic imine in the Staudinger reaction. In all cases, trans-selectivity
was excellent (the cis isomer was not identified by 1H NMR). Be-
sides, formation of the corresponding oxazinone was not detected
under the optimized conditions.
Scheme 3. Proposed mechanism for the Staudinger Reaction.22
congested iminiun ion IV, leading to the trans b-lactam (k2). It is clear
thatthesubstituentatposition3 rulesthestereochemicaloutcomein
our examples since no effect is observed when substituents in the
imine component are changed.
At the next stage in the solid-phase synthesis of analogues of
cholesterol absorption inhibitors, we decided to install the proper
3. Conclusions
substituent at position 1 of the
b
-lactam ring. Thus, we planned
A renewed interest in the synthesis of monocyclic b-lactams has
a new strategy using a p-aminophenol moiety as the solid-phase
linker. Fmoc-protected p-aminophenol (9, Scheme 4) was attached
to Wang resin using tetramethylamine azodicarboxylate (TMAD)
and tributylphosphine in THF/DCM (1/1). Optimal results were ob-
tained when the mixture was stirred overnight at room tempera-
ture.24 The Fmoc group in resin 10 was eliminated by treatment with
30% piperidine in DMF, and the resultant immobilized aniline was
condensed with p-anisaldehyde (2a) to perform the imine 11a. Two
been sparked due to the outstanding antihypercholesterolemic
activity of some of their derivatives. Herein, we report a solid-phase
synthetic sequence for the rapid generation of trans 3-alkyl-
substituted b-lactams. Key step was the Staudinger reaction be-
tween immobilized imines and in situ-generated ketenes. For the
glycine-derived library, acid chlorides were an efficient precursor of
the ketenes, while a controlled excess of them was used to avoid the
oxazinone by-product. On the other hand, activation of alkanoic
acid by Mukaiyama’s reagent was more effective for the prepara-
different conditions were tested for the b-lactam ring formation. In
the first approach, the immobilized imine 11a was refluxed in tol-
uene in the presence of 5-phenylvaleroyl chloride (4a) and trie-
thylamine, under the previously optimized conditions. After
releasing into solution with 10% TFA/DCM, the corresponding trans
tion 3-alkyl-1-aryl-
a small library where we have introduced diversity in the three
variable positions of the -lactam ring. In summary, we have
demonstrated the usefulness of the solid-phase synthesis for the
generation of structurally-closed analogues of known biologically
interesting compounds.
b-lactams. In this way, we have generated
b
b
-lactam 15aa was obtained in 9% isolated overall yield.25 Further
attempts to improve this yield were unsuccessful.
In the search for a more efficient procedure, the formation of the
ketene from an in situ activated carboxylic acid was tested.
Therefore, the resin-bound imine 11a was treated with triethyl-
amine (6 equiv), 5-phenylvaleric acid (12a) (2.5 equiv) and
Mukaiyama’s reagent (13) as acid-activating agent (3 equiv), fol-
lowed by refluxing in chloroform for 2 h.26 Then, the resin was
resubjected to the same reaction conditions to ensure the complete
4. Experimental section
4.1. General
Chemical reagents were purchased from commercial sources and
were used without further purification unless noted otherwise.

C.M.L. Delpiccolo et al. / Tetrahedron 68 (2012) 10780e10786
10783
Scheme 4. Sequence for the solid-phase synthesis of 3-alkyl-1-aryl-b-lactams.
Table 2
Library of 3-alkyl-1-aryl-b-lactams
Entry
b-Lactam
R1
R2
Method
Yielda
%
1
2
3
4
5
6
7
15aa
15aa
15ba
15da
15fa
15ac
15ac
4-MeOPh
4-MeOPh
Ph
4-BrPh
4-ClPh
Ph(CH2)3
Ph(CH2)3
Ph(CH2)3
Ph(CH2)3
Ph(CH2)3
CH3CH2
B
A
B
B
B
B
A
15
9
8
12
10
9
4-MeOPh
4-MeOPh
CH3CH2
d
a
Overall isolated yield after flash column chromatography (based on initial loading of Fmoc-Gly-Wang resin, five reaction steps).
Solvents were analytical grade or were purified by standard pro-
cedures prior to use. Infrared spectra (IR) were recorded on a Shi-
madzu Prestige 21 spectrophotometer and only partial spectral data
are listed. 1H NMR spectra were recorded on a Bruker avance at
300 MHz and on a Bruker AC200 at 200 MHz for 1H in CDCl3, in the
presence of TMS (0.00 ppm) as the internal standard. Conventional
and gel-phase 13C NMR spectra were recorded on the same apparatus
at 75 MHz and 50 MHz with CDCl3 as solvent and reference
(76.9 ppm), unlessotherwisestated.13C NMR assignments were made
on the basis of chemical shifts and proton multiplicities (from DEPT
spectra). Mass spectra were performed at the University of California
Riverside Mass Spectrometry Facility. Flash column chromatography
was performed using Merck silica gel 60 (230e400 mesh).27
CH2Cl2 (3ꢂ4 mL), MeOH (3ꢂ4 mL) and CH2Cl2 (1ꢂ4 mL), and dried
under high vacuum. Then, the resin was suspended in a 1% solution
of AcOH in DMF and p-anisaldehyde (2a) (45
mL, 0.375 mmol,
5 equiv) was added. The reaction was stirred 45 min at room tem-
perature, after that the resin was filtered, and reprocessed under the
same conditions. The resin was filtered and washed successively
with DMF (3ꢂ4 mL), CH2Cl2 (3ꢂ4 mL), MeOH (3ꢂ4 mL) and CH2Cl2
(1ꢂ4 mL), and dried to afford 3a. To a suspension of resin-bound
imine 3a (0.075 mmol) in dry toluene (2.2 mL) was added drop-
wise triethylamine (0.084 mL, 0.6 mmol, 8 equiv)and a solution of 4a
(4 equiv) in toluene (0.8 mL). The mixture was stirred at reflux
overnight. After that, the resin was filtered and washed with DMF
(3ꢂ4 mL), CH2Cl2 (3ꢂ4 mL), MeOH (3ꢂ4 mL) and CH2Cl2 (1ꢂ4 mL),
and finally dried in vacuo affording 7aa. Resin-bound b-lactam 7aa
4.2. Typical procedures
(0.097 g, 0.073 mmol, 0.75 mmol/g) was suspended in 10% TFA in
dichloromethane (3 mL) and was stirred at room temperature for
50 min. The reaction was filtered and the filtrate evaporated under
reduced pressure. The residue was dissolved in dichloromethane
(3 mL), stirred at 0 ꢁC, and a solution of diazomethane in ether were
added. Afterthe reactionwascompleted, the solventwasevaporated
and the crude product was purified by flash chromatography using
hexane/ethyl acetate (70:30) to afford 8aa (15.3 mg, 57%).
Preparation of 4a: A solution of 5-phenylvaleric acid (12a)
(0.053 g, 0.3 mmol, 4 equiv) and oxalyl chloride (0.040 mL,
0.45 mmol) were stirred in anhydrous dichloromethane (1.9 mL)
for 3 h, and then the mixture was evaporated in vacuo to afford the
crude 5-phenylvaleroyl chloride (4a), which was used without
further purification.
Preparation of
b
-lactam 7aa: Fmoc-Gly-Wang resin (1) (100 mg,
Preparation of b-lactam 15aa: Wang resin (500 mg, 0.55 mmol,
0.075 mmol, loading 0.75 mmol/g) was suspended in 30% piperidine
in DMF (3 mL). After stirring for 50 min at room temperature, the
mixture was filtered and washed sequentially with DMF (3ꢂ4 mL),
1.1 mmol/g) was swelled by gentle stirring in a 1:1 mixture of an-
hydrous THF/CH2Cl2 (8 mL) under a nitrogen atmosphere. Solid
TMAD (472 mg, 2.75 mmol, 5 equiv) was added with stirring until

10784
C.M.L. Delpiccolo et al. / Tetrahedron 68 (2012) 10780e10786
dissolution occurs. Phenol 9 (909 mg, 2.75 mmol, 5 equiv) was
added and the reaction mixture was stirred until complete disso-
lution occurs. Then, neat Bu3P (0.674 mL, 2.4 mmol, 5 equiv) was
added via syringe. The mixture was stirred overnight at room
temperature. After filtration, the resin 10 was sequentially washed
with THF (3ꢂ4 mL), CH2Cl2 (3ꢂ4 mL), MeOH (3ꢂ4 mL) and CH2Cl2
(4 mL), and finally dried under high vacuum. This Resin 10
(0.55 mmol) was suspended in 30% piperidine in DMF (5 mL) and
stirred for 50 min at room temperature. Then, the mixture was
filtered and washed successively with DMF (3ꢂ4 mL), CH2Cl2
(3ꢂ4 mL), MeOH (3ꢂ4 mL), CH2Cl2 (4 mL) and dried under high
vacuum. The resulting resin-bound aniline (0.55 mmol) was sus-
pended in a 1% solution of AcOH in anhydrous DMF (ca. 5 mL) and
p-anisaldehyde (2a) (0.33 mL, 2.75 mmol, 5 equiv) was added. The
reaction was stirred for 45 min at room temperature, after which
the resin was filtered, washed with anhydrous DMF (3ꢂ4 mL), and
resubjected to the same reaction conditions. After that, the resin
was filtered, washed successively with DMF (3ꢂ4 mL), CH2Cl2
(3ꢂ4 mL), MeOH (3ꢂ4 mL) and CH2Cl2 (1ꢂ4 mL), and dried under
high vacuum affording the support-bound aldimine 11a, which was
taken immediately to the next step.
5-phenylvaleric acid (12a) (245 mg, 1.37 mmol, 2.5 equiv) and
Et3N (0.46 mL, 3.3 mmol, 6 equiv) were dissolved in anhydrous
chloroform (6 mL) and added to a suspension of imine 11a
(0.55 mmol) in anhydrous chloroform (2 mL) under a nitrogen at-
mosphere. After a minute, 2-chloro-1-methylpyridinium iodide
(13) (Mukaiyama’s reagent, 421 mg, 1.65 mmol, 3 equiv) was added
and the suspension was refluxed for 2 h. Then, the reaction mixture
was filtered and the resin was washed successively with CH2Cl2
(3ꢂ5 mL), MeOH (3ꢂ5 mL) and CH2Cl2 (1ꢂ5 mL). After drying in
vacuo, the resin was resubjected to the same reaction conditions. A
(ester), 1660 cmꢀ1; 1H NMR (200 MHz, CDCl3):
d
1.09 (t, J¼7.4 Hz),
1.85 (s, 3H), 2.25e2.38 (m, J¼7.4 Hz, 2H), 3.25 (d, J¼18 Hz,1H), 3.64
(s, 3H), 3.83 (s, 3H), 4.46 (d, J¼18 Hz, 1H), 6.14 (s, 1H), 6.93 (d,
J¼8.8 Hz, 2H), 7.39 (d, J¼8.8 Hz, 2H). 13C NMR (50 MHz, CDCl3):
d
170.13, 166.38, 165.98, 160.83, 129.26, 126.58, 114.102, 104.06,
88.74, 55.24, 51.92, 44.13, 24.15, 10.91, 9.95. MS (EI) m/z (%): 319
(Mþ, 4.5), 262 (72), 192 (11), 148 (100), 134 (26), 121 (68).
4.2.3. (3SR,4RS)-3-(3-Phenylpropyl)-4-(4-methoxyphenyl)-1-me-
thoxycarbonylmethyl-azetidin-2-one (8aa). IR (film): 1768 (
b-lac-
tam), 1747 (ester) cmꢀ1; 1H NMR (200 MHz, CDCl3):
d
1.60e1.95 (m,
4H), 2.62 (t, J¼6.8 Hz, 2H), 3.05 (br t, J¼5.6 Hz, 1H), 3.40 (d, J¼18 Hz,
1H), 3.68 (s, 3H), 3.80 (s, 3H), 4.31 (d, J¼18 Hz, 1H), 4.45 (d, J¼2 Hz,
1H), 6.87e7.26 (m, 9H); 13C NMR (50 MHz, CDCl3):
d 170.77, 168.59,
159.77, 141.73, 129.18, 128.27, 128.22, 127.64, 125.71, 114.36, 61.32,
61.00, 55.23, 52.10, 40.90, 35.60, 28.80, 28.00. MS m/z (%): 367 (Mþ,
6), 259 (40), 250 (100), 224 (20), 208 (60),148 (72),121 (78), 91 (11);
HRMS calcd for C22H25NO4 (Mþ, m/z): 367.1784; found, 367.1796.
4.2.4. (3SR, 4RS)-3-(3-Phenylpropyl)-4-(4-methylphenyl)-1-methoxy-
carbonylmethyl-azetidin-2-one (8ca). IR (film): 1774 (
b-lactam),
1754 (ester) cmꢀ1; 1H NMR (200 MHz, CDCl3):
d
1.72e1.93 (m, 4H),
2.35 (s, 3H), 2.62 (t, J¼7.3 Hz, 2H), 3.01 (br t, J¼6, 2 Hz, 1H), 3.41 (d,
J¼18 Hz, 1H), 3.68 (s, 3H), 4.35 (d, J¼18 Hz, 1H), 4.48 (d, J¼2 Hz, 1H),
7.12e7.26 (m, 9H); 13C NMR (50 MHz, CDCl3):
d 170.73, 168.61,
141.70, 138.32, 134.31, 129.60, 128.26, 128.19, 126.24, 125.68, 61.44,
61.02, 52.11, 40.89, 35.58, 28.81, 28.00, 21.01. MS m/z (%): 351 (Mþ,
20), 292 (10), 259 (10), 234 (100), 208 (25), 192 (48), 145 (56), 131
(65), 105 (80), 91 (56), 43 (13); HRMS calcd for C22H25NO3 (Mþ, m/
z): 351.1834; found, 351.1837.
portion of the immobilized
b
-lactam 14aa (98 mg, 0.862 mmol/g,
4.2.5. (3SR,4RS)-4-(4-Bromophenyl)-3-(3-phenylpropyl)-1-methoxy-
0.084 mmol) was treated with 5 mL of 10% TFA in CH2Cl2 for 1 h. The
mixture was filtered and the filtrate was evaporated under reduced
carbonylmethyl-azetidin-2-one (8da). IR (film): 1778 (
b-lactam),
1760 (ester) cmꢀ1; 1H NMR (200 MHz, CDCl3):
d
1.78e1.90 (m, 4H),
pressure to give 24 mg of a crude
b
-lactam 14aa. This crude ma-
2.63 (t, J¼7.3 Hz, 2H), 3.03 (br t, J¼6.7, 2.2 Hz, 1H), 3.41 (d, J¼18 Hz,
1H), 3.69 (s, 3H), 4.33 (d, J¼18 Hz, 1H), 4.48 (d, J¼2.2 Hz, 1H),
terial was purified by column chromatography (hexane/AcOEt) to
provide 9.3 mg (0.034 mmol) of the compound 15aa (15% overall
yield, on the basis of the initial loading level of the Wang resin).
Preparation of oxazinone 6aa: To the resin 3a (0.092 mmol)
suspended in anhydrous dichlorometane (2.7 mL) at 0 ꢁC was
added dropwise triethylamine (0.26 mL, 1.8 mmol, 20 equiv) and
the solution of crude 5-phenylvaleroyl chloride (4a) (15 equiv) in
dichloromethane (1.8 mL). The reaction was stirred at room tem-
perature overnight. Then, the resin was filtered and washed with
DMF (3ꢂ4 mL), CH2Cl2 (3ꢂ4 mL), MeOH (3ꢂ4 mL) and CH2Cl2
(1ꢂ4 mL), and dried in vacuo affording 5aa. Resin-bound oxazinone
5aa (0.133 g, 0.089 mmol, 0.67 mmol/g) was suspended in 10% TFA
in dichloromethane (3.5 mL) and stirred at room temperature for
50 min. After that, the reaction was filtered and the filtrate evap-
orated in vacuo. The residue was dissolved in dichloromethane
(3.5 mL) at 0 ꢁC, and a solution of diazomethane in ether was added.
After the reaction was completed, the solvent was evaporated and
the crude product was purified by flash chromatography using
hexane/ethyl acetate (80:20) to give 6aa (18.6 mg, 40%).
7.11e7.26 (m, 9H); 13C NMR (50 MHz, CDCl3):
d 170.37, 168.44,
141.57, 136.64, 132.14, 128.25, 127.98, 126.24, 125.77, 122.37, 61.33,
61.10, 52.17, 41.06, 35.56, 28.76, 27.97. MS (DEI) m/z (%): 415 (Mþ, 4),
256 (15), 182 (10), 169 (15), 144 (43), 116 (53), 104 (60), 91 (100), 79
(16), 65 (18), 55 (29); HRMS calcd for C21H22BrNO3 (Mþ, m/z):
415.0783; found, 415.0788.
4.2.6. (3SR,4RS)-3-Methyl-4-(4-methoxyphenyl)-1-methoxy-
carbonylmethyl-azetidin-2-one (8ab). IR (film): 1765 (
b
-lactam),
1747 (ester) cmꢀ1 1H NMR (200 MHz, CDCl3):
;
d
1.43 (d, J¼7.4 Hz,
3H), 3.01e3.14 (qd, J¼2, 7.4 Hz, 1H), 3.42 (d, J¼18 Hz, 1H), 3.71 (s,
3H), 3.81 (s, 3H), 4.32 (d, J¼18 Hz, 1H), 4.39 (d, J¼2 Hz, 1H), 6.91 (d,
J¼8.7 Hz, 2H), 7.23 (d, J¼8.7 Hz, 2H); 13C NMR (50 MHz, CDCl3):
d
171.44, 168.61, 159.78, 129.08, 127.67, 114.28, 62.87, 55.76, 52.23,
52.12, 40.94,12.66. MS m/z (%): 263 (Mþ, 20), 248 (36), 232 (55),148
(100), 121 (50), 91 (14), 77 (12); HRMS calcd for C14H17NO4 (Mþ, m/
z): 263.1158; found, 263.1158.
4.2.7. (3SR,4RS)-3-Methyl-4-(4-methylphenyl)-1-methoxy-
4.2.1. 6-(4-Phenylbutyl)-5-(3-phenylpropyl)-2,3-dihydro-3-methox-
carbonylmethyl-azetidin-2-one (8cb). IR (film): 1775 (
b
-lactam),
ycarbonylmethyl-2-(4-methoxyphenyl)-[1,3]oxazin-4-one (6aa). 1H
1754 (ester) cmꢀ1; 1H NMR (200 MHz, CDCl3):
d
1.43 (d, J¼7.3 Hz, 3H),
NMR (200 MHz, CDCl3):
3.26 (d, J¼17.6 Hz, 1H), 3.64 (s, 3H), 4.47 (d, J¼17.6 Hz, 1H), 6.10 (s,
1H), 6.90e7.38 (m, 14H); 13C NMR (50 MHz, CDCl3):
169.97,
d
1.52e1.80 (m, 6H), 1.82e2.69 (m, 8H),
2.36 (s, 3H), 3.02e3.14 (dq, J¼2, 7.3 Hz,1H), 3.43 (d, J¼18 Hz,1H), 3.71
(s, 3H), 4.35 (d, J¼18 Hz,1H), 4.41 (d, J¼2 Hz,1H), 7.19 (s, 4H); 13C NMR
d
(50 MHz, CDCl3): d 171.39, 168.58, 138.36, 134.27, 129.56, 126.29,
165.70, 164.82, 160.83, 141.97, 142.27, 129.22, 128.33, 128.18, 126.66,
125.62, 125.51, 109.89, 88.57, 55.22, 51.87, 44.21, 35.62, 35.39, 31.54,
30.75, 30.28, 26.33, 24.73.
63.10, 55.84, 52.10, 41.01, 21.00, 12.67. MS m/z (%): 247 (Mþ, 2), 232
(17), 219 (24), 192 (13), 132 (100), 117 (80), 105 (28), 91 (15); HRMS
calcd for C14H17NO3 (Mþ, m/z): 247.1208; found, 247.1207.
4.2.2. 6-Ethyl-2,3-dihydro-3-methoxycarbonylmethyl-2-(4-me-
4.2.8. (3SR,4RS)-3-(3-Phenylpropyl)-4-(phenyl)-1-methoxy-
thoxyphenyl)-5-methyl-[1,3]oxazin-4-one (6ab). IR (film): 1750
carbonylmethyl-azetidin-2-one (8ba). IR (film): 1775 (b-lactam),

C.M.L. Delpiccolo et al. / Tetrahedron 68 (2012) 10780e10786
10785
1754 (ester) cmꢀ1; 1H NMR (200 MHz, CDCl3):
d
1.80e1.91 (m, 4H),
(m, 4H); 13C NMR (75 MHz, CDCl3):
d
167.0, 152.3, 141.5, 137.1, 132.4,
2.62 (t, J¼7.3 Hz, 2H), 3.07 (br t, J¼6, 2 Hz, 1H), 3.42 (d, J¼18 Hz, 1H),
130.9, 128.4, 127.6, 126.0, 122.3, 118.4, 115.9, 60.6, 60.5, 35.7, 28.9,
28.4; HRMS calcd for C24H23BrNO2 (MHþ, m/z): 436.0912; found,
436.0915.
3.68 (s, 3H), 4.36 (d, J¼18 Hz, 1H), 4.51 (d, J¼2 Hz,1H), 7.12e7.38 (m,
10H); 13C NMR (50 MHz, CDCl3):
d 170.64, 168.659, 141.71, 137.52,
128.96, 128.45, 128.24, 126.30, 125.73, 77.54, 76.90, 76.27, 61.68,
61.21, 52.12, 41.05, 35.62, 28.82, 28.06. HRMS calcd for C21H23NO3
(Mþ, m/z): 337.1678; found, 337.1686.
4.2.15. (3SR, 4RS)-1-(4-Hydroxyphenyl)-4-(4-chlorophenyl)-3-(3-
phenylpropyl)-azetidin-2-one (15fa). IR (film): 2926, 1714 (
b-lac-
tam) cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
7.35e7.11 (m,11H), 6.70 (d,
4.2.9. (3SR,4RS)-3-Ethyl-1-methoxycarbonylmethyl-4-(4-methoxy-
J¼8.8 Hz, 2H), 4.56 (d, J¼2.5 Hz, 1H), 3.07e3.02 (m, 1H), 2.63 (t,
phenyl)-azetidin-2-one (8ac). IR (film): 1773 (
b
-lactam), 1754 (es-
J¼7.1 Hz, 2H), 1.89e1.78 (m, 4H); 13C NMR (75 MHz, CDCl3):
d 167.0,
ter) cmꢀ1 1H NMR (200 MHz, CDCl3):
;
d
1.06 (t, J¼7.4 Hz, 3H),
152.2, 141.5, 136.6, 134.3, 131.0, 129.4, 128.4, 127.3, 126.0, 118.4,
115.8, 60.6, 60.5, 35.7, 28.9, 28.4; HRMS calcd for C24H23ClNO2
(MHþ, m/z): 392.1417; found, 392.1424.
1.79e2.00 (m, 2H), 3.01 (ddd, J¼2, 6.2 and 8.2 Hz, 1H), 3.41 (d,
J¼18 Hz, 1H), 3.71(s, 3H), 3.81 (s, 3H), 4.34 (d, J¼18 Hz, 1H), 4.49 (d,
J¼2 Hz, 1H), 6.91 (d, J¼8.6 Hz, 2H), 7.23 (d, J¼8.6 Hz, 2H); 13C NMR
(50 MHz, CDCl3):
d
170.79, 168.66, 159.69, 129.40, 127.60, 114.31,
4.2.16. (3SR, 4RS)-1-(4-Hydroxyphenyl)-4-(4-methoxyphenyl)-3-
62.52, 60.77, 55.23, 52.11, 40.81, 21.44, 11.27. MS m/z (%): 277 (Mþ,
20), 248 (100), 208 (32), 192 (16), 162 (31), 148 (90), 134 (22), 121
(70), 91 (30), 77 (12); HRMS calcd for C15H19NO4 (Mþ, m/z):
277.1314; found, 277.1307.
ethyl-azetidin-2-one (15ac). IR (film): 2924, 1721 (
b ;
-lactam) cmꢀ1
1H NMR (300 MHz, CDCl3):
d
7.25 (d, J¼8.8 Hz, 2H), 7.16 (d, J¼8.8 Hz,
2H), 6.89 (d, J¼8.8 Hz, 2H), 6.71 (d, J¼8.8 Hz, 2H), 4.57 (d, J¼2.3 Hz,
1H), 3.80 (s, 3H), 3.04e2.98 (m, 1H), 2.00e1.79 (m, 2H), 1.08 (t,
J¼7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 167.6, 159.6, 152.0, 131.3,
4.2.10. (3SR,4RS)-3-Butyl-4-(4-methoxyphenyl)-1-methoxy-
130.1, 127.2, 118.5, 115.7, 114.5, 61.9, 60.6, 55.3, 21.9, 11.5; HRMS
carbonylmethyl-azetidin-2-one (8ad). IR (film): 1770 (
b
-lactam),
calcd for C18H20NO3 (MHþ, m/z): 298.1443; found, 298.1447.
1752 (ester) cmꢀ1; 1H NMR (200 MHz, CDCl3):
d
0.89 (t, J¼7 Hz, 3H),
1.44e1.26 (m, 4H), 1.90e1.75 (m, 2H), 3.03 (dt, J¼2, 6.2 Hz, 1H), 3.40
(d, J¼18 Hz, 1H), 3.70 (s, 3H), 3.81 (s, 3H), 4.33 (d, J¼18 Hz, 1H), 4.46
(d, J¼2 Hz, 1H), 6.90 (d, J¼8.7 Hz, 2H), 7.22 (d, J¼8.7 Hz, 2H); 13C
Acknowledgements
Financial support from Consejo Nacional de Investigaciones
NMR (50 MHz, CDCl3):
d 170.96, 168.65, 159.72, 129.41, 127.62,
ꢀ
ꢀ
Científicas y Tecnicas (CONICET), Agencia Nacional de Promocion
114.32, 61.39, 61.22, 55.22, 52.08, 40.85, 29.22, 28.08, 22.43, 13.71.
MS m/z (%): 305 (Mþ, 12), 274 (24), 248 (82), 208 (54), 192 (36), 148
(100); 134 (26), 121 (74), 91 (32), 77 (14), 55 (24); HRMS calcd for
C17H23NO4 (Mþ, m/z): 305.1627; found, 305.1639.
ꢀ
Científica y Tecnologica and Universidad Nacional de Rosario from
Argentina is gratefully acknowledged.
Supplementary data
4.2.11. (3SR, 4RS)-4-(4-Bromophenyl)-3-butyl-1-methoxycarbonyl-
1H and 13C NMR spectra for all new synthetic compounds are
available in the Supplementary data. Supplementary data related to
this article can be found online at doi:10.1016/j.tet.2012.01.072.
methyl-azetidin-2-one (8dd). IR (film): 1777 (
b
-lactam), 1754 (es-
ter) cmꢀ1 1H NMR (200 MHz, CDCl3):
;
d
0.89 (t, J¼7 Hz, 3H),
1.26e1.44 (m, 4H), 1.71e1.97 (m, 2H), 3.02 (dt, J¼2, 6.5 Hz, 1H), 3.41
(d, J¼18 Hz, 1H), 3.71 (s, 3H), 4.35 (d, J¼18 Hz, 1H), 4.49 (d, J¼2 Hz,
1H), 7.18 (d, J¼8.4 Hz, 2H), 7.51 (d, J¼8.4 Hz, 2H); 13C NMR (50 MHz,
References and notes
CDCl3): d 170.65, 168.49, 136.81, 132.13, 127.99, 122.30, 61.56, 61.22,
1. (a) Dolle, R. E.; Le Bourdonnec, B.; Worm, K.; Morales, G. A.; Thomas, C. J.;
Zhang, W. J. Comb. Chem. 2010, 12, 765; (b) Dolle, R. E.; Le Bourdonnec, B.;
Goodman, A. J.; Morales, G. A.; Thomas, C. J.; Zhang, W. J. Comb. Chem. 2009, 11,
739; (c) Dolle, R. E.; Le Bourdonnec, B.; Goodman, A. J.; Morales, G. A.; Thomas,
C. J.; Zhang, W. J. Comb. Chem. 2008, 10, 753; (d) Dolle, R. E.; Le Bourdonnec, B.;
Goodman, A. J.; Morales, G. A.; Salvino, J. M.; Zhang, W. J. Comb. Chem. 2007, 9,
855; (e) Dolle, R. E.; Le Bourdonnec, B.; Morales, G. A.; Moriarty, K. J.; Salvino, J.
M. J. Comb. Chem. 2006, 8, 597; (f) Dolle, R. E. J. Comb. Chem. 2005, 7, 739.
2. (a) Poeylaut-Palena, A. A.; Mata, E. G. Org. Biomol. Chem. 2010, 8, 3947; (b)
Young, D. D.; Deiters, A. Angew. Chem., Int. Ed. 2007, 46, 5187.
52.18, 41.02, 29.22, 28.07, 22.41,13.70. MS (DEI) m/z (%): 353 (Mþ, 5),
324 (6), 255 (19), 237 (81), 181 (52), 116 (100), 55 (15); HRMS calcd
for C16H20BrNO3 (Mþ, m/z): 353.0627; found, 353.0637.
4.2.12. (3SR, 4RS)-1-(4-Hydroxyphenyl)-4-(4-methoxyphenyl)-3-(3-
phenylpropyl)-azetidin-2-one (15aa). IR (film): 2926, 1720 (
b-lac-
tam) cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
7.28e7.12 (m, 9H), 6.87 (d,
3. Mazur, S.; Jayalekshmy, P. J. Am. Chem. Soc. 1979, 101, 677.
4. (a) Llarrull, L. I.; Testero, S. A.; Fisher, J. F.; Mobashery, S. Curr. Opin. Microbiol.
2010, 13, 551; (b) Testero, S. A.; Fisher, J. F.; Mobashery, S. b-Lactam Antibiotics
In Burger’s Medicinal Chemistry, Drug Discovery and Development, 7th ed.;
Abraham, D. J., Rotella, D. P., Eds.; John Wiley & Sons: New York, NY, 2010;
pp 257e402; (c) Singh, G. S. Mini-Rev. Med. Chem. 2004, 4, 69; (d) Singh, G. S.
Mini-Rev. Med. Chem. 2004, 4, 93.
J¼8.8 Hz, 2H), 6.69 (d, J¼8.8 Hz, 2H), 4.54 (d, J¼2.3 Hz, 1H), 3.79 (s,
3H), 3.08e3.03 (m, 1H), 2.62 (t, J¼7.3 Hz, 2H),1.96e1.78 (m, 4H); 13C
NMR (75 MHz, CDCl3): d 167.5, 159.5, 152.1, 141.6, 131.0, 129.7, 128.3,
127.1, 125.8, 118.4, 115.6, 114.5, 60.9, 60.2, 55.2, 35.6, 28.8, 28.2;
HRMS calcd for C25H26NO3 (MHþ, m/z): 388.1913; found, 388.1911.
5. For different biological applications of b-lactams, see: Mehta, P. D.; Sengar, N. P.
S.; Pathak, A. K. Eur. J. Med. Chem. 2010, 45, 5541.
4.2.13. (3SR, 4RS)-1-(4-Hydroxyphenyl)-4-phenyl-3-(3-
6. (a) O’Boyle, N. M.; Carr, M.; Keely, N. O.; Knox, A. J. S.; McCabe, T.; Lloyd, D. G.;
Zisterer, D. M.; Meegan, M. J. Eur. J. Org. Chem. 2011, 46, 4595; (b) Banik, B. K.;
Banik, I.; Becker, F. F. Eur. J. Med. Chem. 2010, 45, 845; (c) Banik, B. K.; Banik, I.;
Becker, F. F. Bioorg. Med. Chem. 2005, 13, 3611; (d) Banik, B. K.; Becker, F. F.;
Banik, I. Bioorg. Med. Chem. 2004, 12, 2523; (e) Sun, L.; Vasilevich, N. I.; Fuselier,
J. A.; Hocart, S. J.; Coy, D. H. Bioorg. Med. Chem. Lett. 2004, 14, 2041; (f) Banik, I.;
Becker, F. F.; Banik, B. K. J. Med. Chem. 2003, 46, 12.
7. Srivastava, V. K.; Palit, G.; Singh, S.; Dhawan, R.; Shanker, K. J. Indian Chem. Soc.
1990, 67, 335.
8. Miller, T. M.; Cleveland, D. W. Science 2005, 307, 361.
phenylpropyl)-azetidin-2-one (15ba). IR (film): 2925, 1714 (
b-lac-
tam) cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d
7.36e7.14 (m, 12H), 6.71
(d, J¼8.8 Hz, 2H), 4.58 (d, J¼2.3 Hz, 1H), 3.09e3.06 (m, 1H), 2.64 (t,
J¼7.3 Hz, 2H), 1.98e1.79 (m, 4H); 13C NMR (75 MHz, CDCl3):
d 167.3,
152.0, 141.7, 138.1, 131.4, 129.2, 128.4, 125.9, 118.4, 115.7, 61.3, 60.4,
35.7, 28.9, 28.4; HRMS calcd for C24H24NO2 (MHþ, m/z): 358.1807;
found, 358.1805.
9. (a) Alcaide, B.; Almendros, P. Chem. Rec. 2011, 11, 311; (b) Alcaide, B.; Al-
mendros, P.; Aragoncillo, C. Chem. Rev. 2007, 107, 4437; (c) Alcaide, B.; Al-
mendros, P. Curr. Med. Chem. 2004, 11, 1921; (d) Deshmukh, A. R. A. S.;
Bhawal, B. M.; Krishnaswamy, D.; Govande, V. V.; Shinkre, B. A.; Jayanthi, A.
Curr. Med. Chem. 2004, 11, 1889; (e) Alcaide, B.; Almendros, P. Synlett 2002,
381; (f) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Synlett 2001,
1813; (g) Alcaide, B.; Almendros, P. Chem. Soc. Rev. 2001, 30, 226.
4.2.14. (3SR, 4RS)-1-(4-Hydroxyphenyl)-4-(4-bromophenyl)-3-(3-
phenylpropyl)-azetidin-2-one (15da). IR (film): 2925, 1714 (
b
-lac-
tam) cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d
7.47 (d, J¼8.3 Hz, 2H),
7.26e7.12 (m, 9H), 6.70 (d, J¼8.6 Hz, 2H), 5.30 (br s, 1H), 4.54 (d,
J¼2.1 Hz, 1H), 3.04e3.01 (m, 1H), 2.63 (t, J¼7.2 Hz, 2H), 1.92e1.77

10786
C.M.L. Delpiccolo et al. / Tetrahedron 68 (2012) 10780e10786
10. Burnett, D. A.; Caplen, M. A.; Davis, H. R.; Burrier, R. E.; Clader, J. W. J. Med. Chem.
1994, 37, 1733.
11. Van Heek, M.; France, C. F.; Compton, D. S.; McLeod, R. L.; Yumibe, N. P.; Alton,
Lett. 2000, 41, 6551; (f) Rosenblum, S. B.; Huynh, T.; Afonso, A.; Davis, H. R., Jr.
Tetrahedron 2000, 56, 5735; (g) Wu, G.; Wong, Y.; Chen, X.; Ding, Z. J. Org. Chem.
1999, 64, 3714; (h) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F. Tetra-
hedron: Asymmetry 1999, 10, 4841; (i) Browne, M.; Burnett, D. A.; Caplen, M. A.;
Chen, L.-Y.; Clader, J. W.; Domalski, M.; Dugar, S.; Pushpavanam, P.; Sher, R.;
Vaccaro, W.; Viziano, M.; Zhao, H. Tetrahedron Lett. 1995, 36, 2555.
K. B.; Sibertz, E. J.; Davis, H. R. J. Pharmacol. Exp. Ther. 1997, 283, 157.
€
12. Muller, G. Drug Discovery Today 2003, 8, 681.
13. Salisbury, B. G.; Davis, H. R.; Burrier, R. E.; Burnett, D. A.; Boykow, G.; Caplen, M.
A.; Clemmons, A. L.; Compton, D. S.; Hoos, L. M.; McGregor, D. G.; Schnitzer-
Polokoff, R.; Smith, A. A.; Weig, B. C.; Zilli, D. L.; Clader, J. W.; Sybertz, E. J.
Atherosclerosis 1995, 115, 45.
14. Garcia-Calvo, M.; Lisnock, J.; Bull, H. G.; Hawes, B. E.; Burnett, D. A.; Braun, M. P.;
Crona, J. H.; Davis, H. R.; Dean, D. C.; Detmers, P. A.; Graziano, M. P.; Hughes, M.;
MacIntyre, D. E.; Ogawa, A.; O’Neil, K. A.; Iyer, S. P. N.; Shevell, D. E.; Smith, M.
M.; Tang, Y. S.; Makarewicz, A. M.; Ujjainwalla, F.; Altmann, S. W.; Chapman, K.
T.; Thornberry, N. A. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 8132.
15. Xu, X.; Fu, R.; Chen, J.; Chenc, S.; Baia, X. Bioorg. Med. Chem. Lett. 2007, 17, 101.
16. Wang, Y.; Zhang, H.; Wenlong Huang, W.; Kong, J.; Zhou, J.; Zhang, B. Eur. J. Med.
Chem. 2009, 44, 1638.
ꢀ
20. (a) Delpiccolo, C. M. L.; Mendez, L.; Fraga, M. A.; Mata, E. G. J. Comb. Chem. 2005,
7, 331; (b) Delpiccolo, C. M. L.; Mata, E. G. Tetrahedron: Asymmetry 2002, 13, 905.
21. Formation of a related oxazinone has been previously described in homoge-
€
neous phase, see: Gunda, T. E.; Vieth, S.; Kover, K. E.; Sztaricskai, F. Tetrahedron
Lett. 1990, 31, 6707.
22. For a more detailed explanation, see: (a) Xu, J. ARKIVOC 2009, ix, 21; (b) Jiao, L.;
Liang, Y.; Xu, J. J. Am. Chem. Soc. 2006, 128, 6060; (c) Wang, Y.; Liang, Y.; Jiao, L.;
Du, D.-M.; Xu, J. J. Org. Chem. 2006, 71, 6983.
23. Previous evidence for the formation of trans-
b-lactams in thermodynamics
conditions have been described, see: Alcaide, B.; Almendros, P.; Salgado, N. R.;
Rodríguez-Vicente, A. J. Org. Chem. 2000, 65, 4453.
17. A short communication of part of this work has already been published, see:
Delpiccolo, C. M. L.; Mata, E. G. Tetrahedron Lett. 2004, 45, 4085.
18. Fu, N.; Tidwell, T. T. Tetrahedron 2008, 64, 10465.
24. Testero, S. A.; Mata, E. G. Org. Lett. 2006, 8, 4783.
25. No more product was obtained after new treatments of the resin with higher
concentrations of TFA (30 and 50%) and longer reaction times, showing that
complete separation from the solid support was achieved with 10% TFA. Ad-
ditionally, oxidative cleavage was tested (using CAN as reagent), but a not
identifiable mixture of products was obtained, see: Kobayashi, S.; Akiyama, R.
Tetrahedron Lett. 1998, 39, 9211.
19. For previous solution-phase synthesis of 3-alkyl-
b-lactams, see: (a) Michalac,
M.; Stodulski, M.; Stecko, S.; Mames, A.; Panfil, I.; Soluch, M.; Furman, B.;
Chmielewski, M. J. Org. Chem. 2011, 76, 6931; (b) Limanto, J.; Krska, S. W.;
Dorner, B. T.; Vazquez, E.; Yoshikawa, N.; Tan, L. Org. Lett. 2010, 12, 512; (c)
Banik, B. M.; Banik, I.; Becker, F. F. Eur. J. Med. Chem. 2010, 45, 846; (d) Linder, M.
R.; Podlech, J. Org. Lett. 2001, 3, 1849; (e) Banik, B. M.; Becker, F. F. Tetrahedron
26. Delpiccolo, C. M. L.; Fraga, M. A.; Mata, E. G. J. Comb. Chem. 2003, 5, 208.
27. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.