Lewis acid-assisted ene cyclization of 2-azetidinone-tethered enals: Synthesis of enantiopure carbacepham derivatives

Article abstract of DOI:10.1002/asia.200900165

Diastereocontrolled Lewis acid-catalyzed preparation of enantiopure carbacepham derivatives have been developed starting from 2-azetidinone-tethered enals. The BF₃.Et₂O-promoted reaction of alkenylaldehydes 1 and 16 is effective as c

Full text of DOI:10.1002/asia.200900165

FULL PAPERS
DOI: 10.1002/asia.200900165
Lewis Acid-Assisted Ene Cyclization of 2-Azetidinone-Tethered Enals:
Synthesis of Enantiopure Carbacepham Derivatives
Benito Alcaide,*[a] Pedro Almendros,*[b] Carmen Pardo,[a]
Carolina Rodrꢀguez-Ranera,[a] and Alberto Rodrꢀguez-Vicente[a]
Abstract: Diastereocontrolled Lewis
acid-catalyzed preparation of enantio-
pure carbacepham derivatives have
been developed starting from 2-azetidi-
none-tethered enals. The BF3·Et2O-
promoted reaction of alkenylaldehydes
1 and 16 is effective as carbocyclization
protocol to afford 4-substituted 5-hy-
droxycarbacephams or 3-substituted
4,5-dihydroxycarbacephams, respective-
ly, by a type I carbonyl-ene reaction,
while the BF3·Et2O or SnCl4-mediated
type II carbonyl-ene cyclization of al-
kenylaldehydes 2 furnishes 3-methyl-
ene 5-hydroxycarbacephams along with
the corresponding 3-halo 5-hydroxycar-
bacepham. The stereochemical out-
come of these carbonyl-ene cyclizations
leading to carbacepham derivatives can
be explained in terms of six-membered,
cyclic chair-like transition-state models.
The formation of halocarbacepham de-
rivatives is proposed to proceed by a
stepwise mechanism.
Keywords: aldehydes
· alkenes ·
cyclization · ene reaction · lactams
Introduction
useful approach for the construction of cyclic ring systems,
which often results in high regio- and stereoselective obser-
vations.[5] The Lewis acid or thermally-induced cyclizations
of different unsaturated aldehydes have attracted a great
deal of interest in recent years, but there are no antecedents
in b-lactam chemistry.[6] The highly selective properties of
the ene reaction would seem to recommend its application
to the preparation of highly functionalized bicyclic b-lac-
tams. Our combined interest in the area of b-lactams and
the synthetic use of Lewis acids and metals,[7] led us to ex-
plore Lewis acid-mediated carbonyl-ene cyclization strat-
egies for the synthesis of bicyclic b-lactams of the carbape-
nam and carbacepham series, through both type I and type
II cyclization modes (Scheme 1).[8] A brief retrosynthetic
The b-lactam nucleus is the central core of the most impor-
tant pharmacophores for treatment of diseases caused by
bacterial infections.[1] Besides, there are many important
nonantibiotic uses of 2-azetidinones in fields ranging from
enzyme inhibition[2] to gene activation.[3] These biological
activities, combined with the fact that b-lactams are useful
intermediates for the preparation of a variety of high-
added-value products,[4] provide the motivation to explore
new methodologies toward the preparation of new b-lactam
derivatives. On the other hand, the carbonyl-ene reaction
has been a potentially powerful synthetic tool and also a
[a] Prof. Dr. B. Alcaide, Prof. C. Pardo, Dr. C. Rodrꢀguez-Ranera,
Dr. A. Rodrꢀguez-Vicente
Departamento de Quꢀmica Orgꢁnica I
Facultad de Quꢀmica
Universidad Complutense de Madrid
E-28040 Madrid (Spain)
Fax : (+34)91-3944103
E-mail: alcaideb@quim.ucm.es
[b] Dr. P. Almendros
Instituto de Quꢀmica Orgꢁnica General
Consejo Superior de Investigaciones Cientꢀficas, CSIC
Juan de la Cierva 3, 28006 Madrid (Spain)
Fax : (+34)91-5644853
E-mail: Palmendros@iqog.csic.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200900165.
Scheme 1. Retrosynthetic analysis for the carbapenam and carbacepham
skeletons through type I and type II carbonyl-ene reactions.
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analysis for the bicyclic b-lactam unit is illustrated in
Scheme 1.
5b, which was adopted from the literature methodology
(Scheme 2).[10]
Results and Discussion
The starting substrates, enantiopure cis-4-formyl-b-lactams
1a–f and 2a–c (Figure 1), were prepared using standard
Scheme 2. Preparation of enantiopure trans-4-formyl-b-lactams 3 and 4.
Reagents and conditions: i) Na2CO3, CH3CN-H2O, RT, 24 h; ii) NaN3,
DMF, reflux, 10 h; iii) (a)PTSA, THF-H2O, D, reflux, 2 h; (b)NaIO4,
NaHCO3, CH2Cl2, RT, 2 h. PTSA=p-Toluenesulfonic acid.
Figure 1. Structure of starting cis-4-formyl-b-lactams 1 and 2. PMP=4-
MeOC6H4, Pht=phtalimidoyl.
Initial investigations focused on validating the ring closure
of 2-azetidinone-tethered enals 1–4 bearing variable lengths
of the linking chain, different connectivity patterns of the re-
active sites, different substituted terminal or internal alkene
moieties, and different cis/trans stereochemistry. This study
was aimed at comparing the efficiency of different Lewis
acid catalysts. For substrates 1a and 1b featuring the N-(3-
methyl-2-butenyl) motif, the ene cyclization did not proceed
to afford the 1,4-fused [4,5]-systems 7a or 7b using neither
BF3·Et2O nor SnCl4 (Figure 2). The poor reactivity of these
methodology from the [2+2]-cycloaddition reactions of (R)-
2,3-O-isopropylideneglyceraldehyde imines with the appro-
priate substituted acetyl chloride in the presence of Et3N,
followed by sequential acidic acetonide hydrolysis, and oxi-
dative glycol cleavage.[9] The susceptibility of the reaction to
stereochemically different b-lactam aldehydes was also ex-
amined, by exploring the possibility of employing trans-4-
formyl-b-lactams 3 and 4. Optically pure trans-2-azetidi-
nones 3 and 4 were prepared from cis-2-azetidinones 5a and
Abstract in Spanish: Se ha desarrollado una nueva metodo-
logꢀa sintꢃtica a sistemas b-lactꢁmicos bicꢀclicos basada en
ciclaciones oxoꢃnicas de los tipos I y II catalizadas por
ꢁcidos de Lewis de diferentes alquenil-4-oxoazetidin-2-car-
baldehꢀdos. De esta forma, se ha podido acceder, de manera
sencilla y diastereoselectiva, a sistemas de carbacefam fun-
cionalizados en forma ꢄpticamente pura. De interꢃs particu-
lar resultan los 2-metoxicarbonil-5-hidroxicarbacefams, ya
que la presencia de un grupo carbonilo contiguo al nitrꢄge-
no b-lactꢁmico en los sistemas bicꢀclicos es un requisito fun-
damental para la actividad biolꢄgica de los antibiꢄticos b-
lactꢁmicos. En las ciclaciones oxoꢃnicas de tipo I se ha ob-
servado una fuerte influencia de la estereoquꢀmica del al-
dehido b-lactꢁmico de partida sobre la estereoselectividad
de la reacciꢄn, siendo total para los aldehidos cis y baja o
moderada para los isꢄmeros trans. En las ciclaciones oxoꢃni-
cas de tipo II de diferentes aldehidos b-lactꢁmicos, utilizan-
do tanto SnCl4 como BF3.Et2O como catalizador, junto con
los hidroxi-metilencarbacefams esperados, se han obtenido,
en casi todos los casos, los correspondientes 3-cloro- o 3-
fluorocarbacefams, en proporciꢄn variable dependiendo del
catalizador utilizado. Este comportamiento, descrito para
ꢁcidos de Lewis tales como Me2AlCl o TiCl4, es desconocido
para los ꢁcidos de Lewis utilizados por nosotros.
Figure 2. Structure of carbacephams 7 obtained through type I carbonyl-
ene cyclization of 2-azetidinone-tethered enals 1.
substrates is likely the result of geometric constraints in the
reactive conformations arising from the rigid angular dispo-
sition imparted by the planar lactam group.[11] Fortunately,
the desired 6-exo ring closure took place efficiently using
homologous substrate 1c, stereoselectively providing carba-
cepham 7c in good yield as pure product both with
BF3·Et2O or SnCl4. Among the Lewis acids used in this
study, BF3·Et2O showed the highest activity. Other tested
metal salts such as ZnI2, InCl3, and InACTHNUTRGNE(UNG OTf)3 were less effec-
tive for the carbonyl-ene cyclization. Similar results were
obtained starting from enals 1d and 1e affording com-
pounds 7d and 7e, respectively, in good yields in their corre-
sponding reactions with BF3·Et2O (see both Ref. [6] and
Table S1 in the Supporting Information for data).
To further probe the scope of this transformation, we
tested the tolerance of the Lewis acid-catalyzed cyclizative
ene-reaction to structural alterations at different sites of 2-
azetidinone-tethered-enal precursors. When an alkene sub-
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stituent was moved from position N1 to C3, as in 3,4-teth-
ered enal 1 f, it also furnished the corresponding 3,4-fused
[4,6]-system 8 in good yield and as only one isomer in its re-
action with SnCl4. However, the use of BF3·Et2O yielded a
complex mixture of products with complete disappearance
of the starting material. Interestingly, we found that ene cyc-
lization of trans-b-lactam substrates 3 and 4 proceeds under
the established conditions to give a mixture of epimeric cy-
cloadducts 9 and 11 at the carbinolic stereocenters. The
product ratio suggests a decreased diastereoselectivity on re-
placing the cis- for the trans-4-formyl-b-lactam nucleus. In
addition to the formation of the anticipated ene cycload-
ducts as major products, chlorocarbacepham derivative 10
was also observed in the SnCl4-promoted reaction of 2-azeti-
dinone-tethered enal 3 (Scheme 3). Despite this behavior
having a precedent when Lewis acid catalysts, such as
Me2AlCl or TiCl4, are used as promoters of the intramolecu-
lar olefinic aldehyde ene reaction, it is unknown for
SnCl4.[12]
Scheme 4. Preparation of methoxycarbonyl-functionalized 2-azetidinone-
tethered enals 12a and 12b. Reagents and conditions: i) LDA, 1-bromo-
3-methylbut-2-ene, THF, from ꢀ78 to 08C, 12 h. ii) (a)PTSA, THF-H2O,
D, 2 h; (b)NaIO4, NaHCO3, CH2Cl2, RT, 2 h. PTSA=p-Toluenesulfonic
acid.
meric carbacephams 15aM and 15am, which were isolated
in 33% and 17% yields, respectively, as pure products after
chromatography (Scheme 5). A similar result was observed
for the case of enal 12b, giving cycloadducts 15bM and
15bm (Scheme 5).
Scheme 5. Type I carbonyl-ene cyclization of methoxycarbonyl-function-
alized 2-azetidinone-tethered enals 12a and 12b. Reagents and condi-
tions: i) BF3·Et2O (1.2 equiv), CH2Cl2, 08C, 2 h.
Inspired by the efficiency of the ene strategy on 4-formyl-
b-lactams, the feasibility of projected transformations was
examined by employing their a-alkoxy b-lactam homologues
bearing an N-3-methyl-2-butenyl moiety. Aldehyde 16a was
prepared from dihydroxy-2-azetidinone 18 by our recently
reported procedure for related 1,2-diol-b-lactam systems.[13]
Protection of the hydroxy groups with an excess of trime-
thylsilyl chloride/triethylamine/DMAP (cat.), followed by
Swern oxidation of the resulting disilyl derivative 19, gave
the required aldehyde 16a (Scheme 6). The starting 4-oxo-
azetidine-2-(a-t-butyldimethylsilyloxy) acetaldehyde 16b
was prepared with the service of thiazole as latent formyl
group, by means of the thiazole-based one-carbon homolo-
gation.[14] The conversion of 4-oxoazetidine-2-carbaldehyde
1b into a-silyloxy b-lactam acetaldehyde 16b was carried
out through a three-step reaction sequence involving 2-(tri-
methylsilyl)thiazole (TMST) addition to afford alcohol 20,
hydroxyl protection to give ether 21, and aldehyde unmask-
ing. Carbaldehyde 16b was obtained as a single isomer in
reasonable yield (Scheme 7).[15] The addition of TMST to 4-
oxoazetidine-2-carbaldehydes is not a trivial process, be-
cause we have recently reported that the addition reaction
of TMST to N-aryl-4-formyl-b-lactams gave enantiopure a-
Scheme 3. Type I carbonyl-ene cyclization of 3,4-tethered enal 1 f and
trans-4-formyl-b-lactams
3 and 4. Reagents and conditions: i) SnCl4
(1.2 equiv), CH2Cl2, 08C, 2 h; ii) BF3·Et2O (1.2 equiv), CH2Cl2, 08C, 2 h.
While the above results clearly established that 2-azetidi-
none-tethered enals were excellent substrates for type I car-
bonyl-ene cyclizations, the reactions were not appropriate
for the synthesis of bioactive b-lactam carboxylic acids. For
this ene approach to find utility in the generation of novel
drug candidates, it is essential to show its capability of in-
stalling a carboxylic-acid motif adjacent to the lactam nitro-
gen. Thus, we next explored ene reactions of more function-
alized 2-azetidinone-tethered alkenylaldehydes 12, which
bears an extra methoxycarbonyl group contiguous to the ni-
trogen. The routine synthetic sequence for the preparation
of starting enals 12a and 12b as isomeric mixtures is shown
in Scheme 4. Arising from both the difficulty of separation
as well as the instability, a mixture of crude isomeric me-
thoxycarbonyl-functionalized 2-azetidinone-tethered enals
were used for the ene reaction. BF3·Et2O-promoted cycliza-
tion of enal 12a afforded an easily separable mixture of iso-
ꢀ
alkoxy-g-keto acid derivatives via a novel N1 C4-bond
breakage of the b-lactam nucleus.[16] After obtaining the 2-
azetidinone-tethered enals 16, the next stage was to carry
out the intramolecular carbonyl-ene reaction. Because of
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Lewis Acid-Assisted Ene Cyclization
bered cycle fused to the b-lactam ring, bearing two contigu-
ous oxygenated moieties in a trans disposition. Stereochemi-
cal correlation between adducts 22a and 22b was obtained
by deprotection of TBS-adduct 22bM with TBAF to afford
diol 22a (Scheme 8).
Scheme 8. Stereochemical correlation between adducts 22a and 22bM.
Reagents and conditions: i) TBAF, THF, 08C, 0.5 h. TBS=t-Butyldime-
thylsilyl.
Scheme 6. Type I carbonyl-ene cyclization of TMS-protected 2-azetidi-
none-tethered enal 16a. Reagents and conditions: i) PTSA, THF-H2O, D,
3 h; ii) Me3SiCl, Et3N, DMAP, CH2Cl2, RT, 17 h; iii) DMSO, (ClCO)2,
CH2Cl2, ꢀ788C, then Et3N, iv) BF3·Et2O (1.2 equiv), CH2Cl2, 08C, 2 h.
DMAP=4-dimethylaminopyridine, PTSA=p-toluenesulfonic acid, and
TMS=trimethylsilyl.
To study the synthesis of the aminocarbacepham nucleus
from a 2-azetidinone-tethered imine through a type I ene re-
action, a new substrate was obtained according to Scheme 9.
the considerable loss of material during chromatographic
purification, the crude mixture of TMS–enal 16a was used
without further purification for the ene cyclization. TMS
cleavage was observed and dihydroxycarbacepham 22a was
obtained in modest yield during the cyclization of TMS-enal
16a in the presence of BF3·Et2O (Scheme 6). In the case of
TBS-enal 16b, lower diastereoselectivity was observed (mix-
ture of two epimers at the new carbinolic stereocenter in an
85:15 ratio), but the yield was considerably improved
(Scheme 7). Fortunately, the diastereomeric cycloadducts
22bM and 22bm were separated by column chromatogra-
phy.
Scheme 9. Type I imino-ene cyclization of 2-azetidinone-tethered imine
23. Reagents and conditions: i) allylamine, MgSO4, CH2Cl2, RT, 15 h.
ii) BF3·Et2O (1.2 equiv), CH2Cl2, 08C, 12 h.
Treatment of 2-azetidinone-tethered enal 1c with allylamine
in the presence of anhydrous MgSO4 afforded the corre-
sponding N-allylimine 23, which was directly taken into an
imino-ene cyclization in the presence of a BF3·Et2O promot-
er to give bicyclic b-lactam 24 as a single diastereomer
(Scheme 9). b-Lactam imines result from the above experi-
ment as suitable precursors for the imino-ene cyclization.
With the basic methodology for the synthesis of carbacep-
ham derivatives through a type I carbonyl-ene reaction, our
attention was turned to the study of type II carbonyl-ene
cyclization on 2-azetidinone-tethered enals 2. The scope and
limitations of the type II carbonyl-ene cyclization of enals 2
promoted by SnCl4 and BF3·Et2O was investigated. The re-
sults are given in Scheme 10. The reaction of enals 2a–c
with SnCl4 under the same conditions as described above for
type I carbonyl-ene reaction was investigated first. Enals
2a–c were converted into their respective ene adducts 25a–c
as single isomers (R=PhO, Pht) or as a diastereomeric mix-
ture (R=N3), in which the b-diastereomer predominated.
Interestingly, along with compound 25, chlorocarbacepham
derivatives 26 were also obtained as by-products in the
SnCl4-promoted reaction. During the course of this study,
we also noted that substrates 2 furnished two structurally
different products under the BF3·Et2O-promoted conditions.
While the expected ene cycloadducts 25a–c were mainly
produced, a small amount of fluorocarbacephams 27a–c
were also isolated as single diastereomers (Scheme 10).
Even though low yielding, the formation of bicycles 27 is re-
NMR experiments of derivatives 22 satisfactorily estab-
lished information about the presence of a new six-mem-
Scheme 7. Type I carbonyl-ene cyclization of TMS-protected 2-azetidi-
none-tethered enal 16b. Reagents and conditions: i) TMST, DCM, RT,
16 h; ii) TBAF, THF, 08C, 0.5 h, quantitative yield. iii) TBSOTf, Et3N,
DMAP, DMF, RT, 1 h. iv) (a)Me2SO4, TBAI (cat), NaOH (aq 50%)-
DCM (1:1), RT, 24 h; (b)MeOTf, MeCN, RT, 15 min; (c)NaBH4, MeOH,
RT, 10 min; (d)MeCN, AgNO3, H2O, RT, 10 min. v) BF3·Et2O
(1.2 equiv), CH2Cl2, 08C, 2 h. TBAF=tetrabutylammonium fluoride,
TBS=t-butyldimethylsilyl, and TMST=2-(trimethylsilyl)thiazole.
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Scheme 10. Type II carbonyl-ene cyclization of 2-azetidinone-tethered
enals 2. Reagents and conditions: i) SnCl4 (1.2 equiv), CH2Cl2, 08C, 2a:
5 h; 2b: 24 h; 2c: 6 h. ii) BF3·Et2O (1.2 equiv), CH2Cl2, 08C, 2a: 5 h; 2b:
24 h; 2c: 6 h.
markable because fluorinated analogues of biologically rele-
vant compounds are increasingly important as modern phar-
maceutical and plant protection agents.[17] Furthermore, de-
spite BF3·Et2O being one of the most widely used Lewis
acids, it is scarcely used as fluorine source.[18]
Scheme 11. Proposed models for type I ene-cyclization of 1,4-tethered b-
lactam enals leading to hydroxycarbacephams.
The stereospecificity of the fluorination reaction, namely,
the formation of fluorocarbacephams 27 with a cis disposi-
tion between fluoro and hydroxyl groups suggests a stepwise
mechanism, and can be rationalized through initial partici-
pation of an aldehyde-BF3·Et2O complex and further evolu-
tion to zwitterions 28 followed by an intramolecular [1,5]
fluoride shift to fluoro-alkoxide 29, which finally gives fluo-
rocarbacephams 27 after hydrolysis (see Scheme S1 in the
Supporting Information).
adduct 9m as the minor isomer, being the less constrained
transition state IV leading to the preferred bicycle 9M.
The explanation proposed in Scheme 12 for the SnCl4-in-
duced ene-cyclization of 3,4-tethered b-lactam enal 1 f is
closely related to the above proposal (Scheme 11) for 1,4-
tethered enals, and should account for the formation of
product 8 through a cyclic transition state V involving a che-
The cyclic structures and the stereochemistries of carba-
cephams 7–11, 15, 22, and 24–27 were established by NMR
one- and two- dimensional techniques and NOE experi-
ments. The cis or trans stereochemistry of the four-mem-
bered 2-azetidinone ring is set previously to the ene reac-
tion, and it is transferred unaltered during the cyclization
step.[19] Both the values for vicinal homonuclear coupling
1
1
1
ꢀ
ꢀ
constants ( H H and H F) as well as NOESY experiments
(see Tables S2–S5 and Figures S1–S2 in the Supporting In-
formation for data) show unequivocally the relative configu-
rations of all the protons in carbacepham derivatives.
Scheme 12. Proposed model for type I ene-cyclization of 3,4-tethered b-
lactam enal 1 f leading to hydroxycarbacepham 8.
A rational accounting for the formation of carbacephams
7, 15 (obtained from cis-b-lactam enals), and 9–11 (obtained
from trans-b-lactam enals) as well as the stereochemical out-
come of the carbonyl-ene cyclization are depicted in
Scheme 11.[20] Thus, a six-membered cyclic chair-like transi-
tion-state model I with minimization of interactions would
account for the exclusive formation of the (S)-configured C5
carbinolic stereocenter in carbacephams 7 and 15, while the
state model II may also be operative for trans- b-lactam
enals 4, thus explaining a diminished diastereoselectivity in
carbacephams 11. Analogously, unfavorable steric interac-
tions in transition state III could explain the formation of
lation of the SnCl4 by the oxygen of the aldehyde with par-
ticipation of the oxygen of the alkoxy group.
The stereoselectivity of the Lewis acid-promoted ene re-
actions of silyloxy-protected 2-azetidinone-tethered enals 16
parallels the selectivity observed for the cyclization of 2-aze-
tidinone-tethered enals 1. On the basis of this analogy, we
propose the cyclic chair-like transition-state models VI and
VII for the achievement of compounds 22 (Scheme 13).
As it was mentioned before (Scheme 10), type II carbon-
yl-ene cyclization on 2-azetidinone-tethered enals 2 fur-
nished along with the expected ene adducts 25, halocarba-
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Lewis Acid-Assisted Ene Cyclization
Experimental Section
General Methods
1H NMR and 13C NMR spectra were recorded on a Bruker Avance-300,
Varian VRX-300S, or Bruker AC-200. NMR spectra were recorded in
CDCl3 solutions, unless otherwise stated. Chemical shifts are given in
ppm relative to TMS (1H, 0.0 ppm), or CDCl3 (13C, 76.9 ppm). Low and
high resolution mass spectra were taken on an HP5989 A spectrometer
using the electronic impact (EI) or electrospray modes (ES) unless other-
wise stated. Specific rotation [a]D is given in 10ꢀ1 degcm2 gꢀ1 at 208C, and
the concentration (c) is expressed in g per 100 mL. All commercially
available compounds were used without further purification.
General Procedure for the Ene-Cyclization Reaction of 2-Azetidinone-
Tethered Enals: Synthesis of Carbacephams
Scheme 13. Proposed models for type I ene-cyclization of silyloxy-pro-
tected 2-azetidinone-tethered enals leading to dihydroxycarbacephams.
To a solution of the starting 2-azetidinone-tethered enal 1–4, 12, and 16
(1 mmol) in dry CH2Cl2 (10 mL) under argon at 08C, the appropriate
Lewis acid (BF3·OEt2 or SnCl4) (1.2 mmol) was added dropwise. The re-
action mixture was stirred at this temperature and periodically monitored
by TLC. Upon completion of the reaction, the mixture was allowed to
reach room temperature and was quenched with NaHCO3 (sat.). After
extraction of the mixture with CH2Cl2 (3ꢅ10 mL), the organic layer was
dried over MgSO4, and the solvent was removed under reduced pressure.
Chromatography of the residue using EtOAc/hexanes mixtures as eluent
gave analytically pure carbacephams 7–11, 15, 22, and 24–27. Spectro-
scopic and analytical data for carbacepham derivatives follow.[22]
cepham derivatives 26, and 27. Applying similar models to
the type I carbonyl-ene cyclization of 2-azetidinone-tethered
enals 1 for type II carbonyl-ene cyclization of 2-azetidinone-
tethered enals 2, a likely explanation for the formation of
carbacephams 25 is based on the transition state VIII
through a concerted mechanism (Scheme 14). The formation
of syn-hydroxyhaloderivatives 26 and 27 may be related to
the assumption that a stepwise annulation proceeding via an
Preparation of Carbacephams (+)-15aM and (+)-15am: From the epi-
meric mixture of aldehydes 12a (31 mg, 0.09 mmol), and after chroma-
tography of the residue using hexanes/ethyl acetate (2:1) as eluent, the
less polar compound (+)-15aM (10 mg, 33%) and the more polar com-
pound (+)-15am (5 mg, 17%) were obtained.
Carbacepham (+)-15aM: Colorless oil; ½aꢁ2D0 =+8.0 (c=1.0 in CHCl3);
IR (CHCl3): n˜ =3440, 1748, 1740 cmꢀ1 1H NMR (300 MHz, CDCl3,
;
258C): d=1.73 (s, 3H, Me), 1.91 (brs, 1H, OH), 1.96 (ddd, J=6.7, 12.9,
13.7 Hz, 1H, H3a), 2.14 (ddd, J=1.3, 3.2, 13.7 Hz, 1H, H3e), 2.29 (m, 1H,
H4), 3.79 (dd, J=8.8, 9.5 Hz, 1H, H5), 3.81 (s, 3H, OMe), 3.95 (dd, J=
3.9, 8.5 Hz, 1H, H6), 4.68 (dd, J=1.0, 6.6 Hz, 1H, H2), 4.92 (brs, 1H, C=
CHH), 5.00 (t, J=1.5 Hz, 1H, C=CHH), 5.42 (d, J=3.9 Hz, 1H, H7),
7.07–7.12 (m, 3H, Ar), 7.32 ppm (m, 2H, Ar); 13C NMR (75 MHz,
CDCl3, 258C): d=170.0 (CO2Me), 164.8 (C8), 157.3, 143.0 (C=CH2),
129.5 (m), 122.5 (p), 115.7 (o), 114.9 (C=CH2), 82.0 (C7), 66.4 (C5), 58.2
(C6), 52.7 (CO2CH3), 49.2 (C2), 46.4 (C4), 31.8 (C3), 19.3 ppm (Me);
HRMS (ES): m/z (%) calcd for C18H21NO5: 332.1498 [M+H]+; found:
332.1493.
Scheme 14. Proposed models for type II ene-cyclization of b-lactam enals
leading to carbacephams and halocarbacephams.
Carbacepham (+)-15am: Colorless oil; ½aꢁ2D0 =+22.0 (c=1.0 in CHCl3);
IR (CHCl3): n˜ =3434, 1750, 1742 cmꢀ1 1H NMR (300 MHz, CDCl3,
;
aldehyde-MXn complex IX, which leads to the formation of
a zwitterion type X is a competitive process (Scheme 14).[21]
258C): d=1.65 (brs, 1H, OH), 1.77 (brs, 3H, Me), 1.90 (dt, J=3.7, 13.4,
Hz, 1H, H3e), 2.07 (dt, J=11.4, 13.4 Hz, 1H, H3a), 2.31 (m, J=3.1, 10.0,
12.4 Hz, 1H, H4), 3.70 (dd, J=4.2, 8.3 Hz, 1H, H6), 3.75–3.85 (m, 2H,
H2, H5), 3.86 (s, 3H, CO2Me), 4.95 (brs, 1H, C=CHH), 5.00 (t, J=
1.6 Hz, 1H, C=CHH), 5.35 (dd, J=1.0, 4.2 Hz, 1H, H7), 7.00–7.20 (m,
3H, Ar), 7.30 ppm (m, 2H, Ar) ; 13C NMR (75 MHz, CDCl3, 258C): d=
167.8 (CO2Me), 167.6 (C8), 157.3, 143.3 (C=CH2), 129.5, 122.6, 115.8,
114.9 (C=CH2), 81.7 (C7), 66.2 (C5), 59.6 (C6), 54.3 (CO2CH3), 52.9 (C2),
48.9 (C4), 31.6 (C3), 19.2 ppm (Me); HRMS (ES): m/z (%) calcd for
C18H21NO5: 332.1498 [M+H]+; found: 332.1492.
Conclusions
In summary, it was found that a variety of 2-azetidinone-
tethered enals can be transformed into functionalized bicy-
clic b-lactams of the carbacephem antibiotic class by Lewis
acid-promoted intramolecular ene reactions. The stereo-
chemical outcome of these carbonyl-ene cyclizations leading
to carbacepham derivatives can be explained in terms of six-
membered, cyclic chair-like transition-state models. The for-
mation of halocarbacepham derivatives is proposed to pro-
ceed by a stepwise mechanism.
Preparation of Carbacephams (+)-22bM and (+)-22bm: From aldehyde
(ꢀ)-17b (54 mg, 0.16 mmol), and after chromatography of the residue
using hexanes/ethyl acetate/triethylamine (1:1:0.01) as eluent, the less
polar compound (+)-22bM (35 mg, 65%) and the more polar compound
(+)-22bm (8 mg, 15%) were obtained.
Carbacepham (+)-22bM: Colorless solid; m.p.: 170–1728C; ½aꢁ2D0 =+12.3
(c=1.0 in CHCl3); IR (KBr): n˜ =3442, 1747 cmꢀ1 1H NMR (300 MHz,
;
CDCl3, 258C): d=0.08 (s, 3H, Si-Me), 0.10 (s, 3H, Si-Me), 0.91 (s, 9H,
tBu), 1.79 (s, 3H, Me), 2.83 (dd, J=5.5, 12.5 Hz, 1H, H3), 2.99 (t, J=
12.6 Hz, 1H, H2a), 3.49 (s, 3H, OMe), 3.65 (dd, J=5.5, 13.1 Hz, 1H,
H2e), 3.80 (dd, J=2.2, 4.8 Hz, 1H, H6), 3.88 (dd, J=1.5, 4.6 Hz, 1H, H4),
Chem. Asian J. 2009, 4, 1604 – 1611
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B. Alcaide, P. Almendros et al.
FULL PAPERS
4.20 (dd, J=2.1, 4.2 Hz, 1H, H5), 4.47 (dd, J=1.3, 4.8 Hz, 1H, H7), 4.79
(brs, 1H, C=CHH), 5.06 ppm (brs, 1H, C=CHH); 13C NMR (75 MHz,
CDCl3, 258C): d=168.8 (C8), 143.5 (C=CH2), 112.6 (C=CH2), 83.8 (C7),
69.1 (C4), 66.5 (C5), 59.1 (OMe), 52.0 (C6), 39.5 (C3), 35.5 (C2), 25.8
(tBu) 23.0 (Me), ꢀ4.41 (Si-Me), ꢀ5.10 (Si-Me). 3431 (OH), 1742 (C=O).
342 (M++1, 1), 284 (M+ꢀ57, 29), 201 ppm (100); elemental analysis:
calcd (%) for C17H31NO4Si (341.5): C 59.79, H 9.15, N 4.10; found:
C 59.92, H 9.09, N 4.15.
Acknowledgements
Support for this work by the DGI-MEC (CTQ2006-10292) and UCM-
BSCH (Grant GR58/08) are gratefully acknowledged. C.R.R. and A.R.V.
thank the DGI (CEC-Comunidad de Madrid) for a predoctoral and post-
doctoral fellowship, respectively.
Carbacepham (+)-22bm: Colorless solid; m.p.: 152–1548C; ½aꢁ2D0 =+53.3
[1] See for example: a) D. Niccolai, L. Tarsi, R. J. Thomas, Chem.
Commun. 1997, 2333; b) R. Southgate, Contemp. Org. Synth. 1994,
1, 417; c) R. Southgate, C. Branch, S. Coulton, E. Hunt in Recent
Progress in the Chemical Synthesis of Antibiotics and Related Micro-
bial Products, Vol. 2 (Ed.: G. Lukacs), Springer, Berlin, 1993,
pp. 621; d) The Chemistry of b-Lactams (Ed.: M. I. Page), Chapman
and Hall, London, 1992A; e) Chemistry and Biology of b-Lactam
Antibiotics, Vols. 1–3 (Ed.: R. B. Morin, M. Gorman), Academic,
New York, 1982.
[2] Some of the more notable advances concern the development of
mechanism-based serine protease inhibitors of elastase, cytomegalo-
virus protease, thrombin, prostate specific antigen, and cell metasta-
sis and as inhibitors of acyl-CoA cholesterol acyl transferase. For a
review, see: a) G. Veinberg, M. Vorona, I. Shestakova, I. Kanepe, E.
Lukevics, Curr. Med. Chem. 2003, 10, 1741. For recent selected ex-
amples, see: b) P. C. Hogan, E. J. Corey, J. Am. Chem. Soc. 2005,
127, 15386; c) J. W. Clader, J. Med. Chem. 2004, 47, 1; d) L. Kværnø,
T. Ritter, M. Werder, H. Hauser, E. M. Carreira, Angew. Chem.
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nett, Curr. Med. Chem. 2004, 11, 1873.
[3] It has been reported that b-lactams act to modulate the expression
of glutamate neurotransmitter transporters by gene activation. See:
J. D. Rothstein, S. Patel, M. R. Regan, C. Haenggeli, Y. H. Huang,
D. E. Bergles, L. Jin, M. D. Hoberg, S. Vidensky, D. S. Chung, S. V.
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73.
[4] a- and b-amino acids, alkaloids, heterocycles, taxoids, and other
types of compounds of biological and medicinal interest have been
prepared through the b-lactam synthon method. For selected re-
views, see: a) B. Alcaide, P. Almendros, C. Aragoncillo, Chem. Rev.
2007, 107, 4437; b) B. Alcaide, P. Almendros, Curr. Med. Chem.
2004, 11, 1921; c) A. R. A. S. Deshmukh, B. M. Bhawal, D. Krish-
naswamy, V. V. Govande, B. A. Shinkre, A. Jayanthi, Curr. Med.
Chem. 2004, 11, 1889; d) B. Alcaide, P. Almendros, Synlett 2002,
0381; e) C. Palomo, J. M. Aizpurua, I. Ganboa, M. Oiarbide, Synlett
2001, 1813; f) B. Alcaide, P. Almendros, Chem. Soc. Rev. 2001, 30,
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1755.
(c=0.5 in CHCl3); IR (KBr): n˜ =3430, 1740 cmꢀ1 1H NMR (300 MHz,
;
CDCl3, 258C): d=0.10 (s, 3H, Si-Me), 0.12 (s, 3H, Si-Me), 0.93 (s, 9H,
tBu), 1.74 (s, 3H, Me), 2.68 (ddd, J=1.6, 11.3, 13.3 Hz, 1H, H2a), 2.86
(dt, J=6.0, 11.0 Hz, 1H, H3), 3.51 (s, 3H, OMe), 3.53 (dd, J=2.1, 5.1 Hz,
1H, H6), 3.62 (ddd, J=1.5, 4.9, 10.6 Hz, 1H, H4), 3.88 (dd, J=6.0,
13.3 Hz, 1H, H2e), 4.28 (t, J=1.6 Hz, 1H, H5), 4.49 (dd, J=1.7, 4.8 Hz,
1H, H7), 4.93 (brs, 1H, C=CHH), 5.04 ppm (t, J=1.5 Hz, 1H, C=CHH);
13C NMR (75 MHz, CDCl3, 258C): d=168.8 (C8), 143.5 (C=CH2), 112.6
(C=CH2), 83.8 (C7), 69.1 (C4), 66.5 (C5), 59.1 (OMe), 52.0 (C6), 39.5
(C3), 35.5 (C2), 25.8 (tBu) 23.0 (Me), ꢀ4.41 (Si-Me), ꢀ5.10 ppm (Si-Me);
elemental analysis: calcd (%) for C17H31NO4Si (341.5): C 59.79, H 9.15,
N 4.10; found: C 59.65, H 9.14, N 4.04.
Carbacepham (+)-24: From imine 23 (297 mg, 0.95 mmol), and after
chromatography of the residue using hexanes/ethyl acetate (2:1) as
20
eluent gave compound (+)-24 (208 mg, 70%) as a colorless oil. ½aꢁD
=
+291.8 (c=1.0 in CHCl3); IR (CHCl3): n˜ =3447, 1750 cmꢀ1 1H NMR
;
(300 MHz, CDCl3, 258C): d=1.70 (m, 2H, H3a, H3e), 1.74 (s, 3H, Me),
2.21 (dt, J=4.1, 10.9 Hz, 1H, H4), 2.78 (dddd, J=1.4, 4.5, 11.9, 13.3 Hz,
1H, H2a), 3.01 (dd, J=8.5, 10.5 Hz, 1H, H5), 3.28 (m, 2H, NCH2), 3.58
(dd, J=4.4, 8.5 Hz, 1H, H6), 3.90 (ddd, J=1.5, 5.1, 13.7 Hz, 1H, H2e),
4.90–5.10 (m, 4H, 2=CH2), 5.35 (dd, J=1.5, 4.4 Hz, 1H, H7), 5.87 (tdd,
J=5.9, 10.1, 17.1 Hz, 1H, CH=CH2), 7.02 (m, 1H, Ar), 7.16 (m, 2H, Ar),
7.31 ppm (m, 2H, Ar); 13C NMR (75 MHz, CDCl3, 258C): d=165.0 (C8),
157.7 (Ar), 144.8 (C=CH2), 136.9 (CH=CH2), 129.5 (Ar), 122.2 (Ar),
115.9 (Ar), 115.5 (=CH2), 114.3 (=CH2), 82.4 (C7), 60.0 (C6), 53.2 (C5),
50.3 (NCH2), 48.9 (C4), 37.8 (C2), 29.7 (C3), 18.5 ppm (Me); HRMS
(ES): m/z (%) calcd for C19H25N2O2: 313.1916 [M+H]+; found: 313.1920.
Preparation of Carbacephams (ꢀ)-25b and (ꢀ)-27b: From aldehyde (ꢀ)-
2b (197 mg, 0.66 mmol), and after chromatography of the residue using
hexanes/ethyl acetate (1:1) as eluent, the less polar compound (ꢀ)-25b
(94 mg, 46%) and the more polar compound (ꢀ)-27b (21 mg, 10%) were
obtained.
Carbacepham (ꢀ)-25b: Colorless solid; m. p. 220–2228C; ½aꢁ2D0 =ꢀ53.5
(c=1.4 in CHCl3); IR (KBr): n˜ =3393, 1742 cmꢀ1 1H NMR (300 MHz,
;
CDCl3, 258C): d=2.19 (t, J=11.8 Hz, 1H, H4a), 2.68 (dd, J=4.5,
13.0 Hz, 1H, H4e), 3.43 (d, J=14.9 Hz, 1H, H2a), 3.62 (dd, J=4.5, 8.7 Hz,
1H, H6), 3.95 (ddd, J=4.4, 8.6, 10.7 Hz, 1H, H5), 4.32 (d, J=14.7 Hz,
1H, H2e), 5.00 (s, 1H, C=CHH), 5.04 (s, 1H, C=CHH), 5.44 (dd, J=1.6,
4.5 Hz, 1H, H7), 7.75 (m, 2H, Ar), 7.83 ppm (m, 2H, Ar); 13C NMR
(75 MHz, CDCl3, 258C): d=167.4 (NC=O, 2), 162.6 (C8), 138.1 (C3),
134.5, 131.6, 123.7, 113.4 (=CH2), 67.3 (C5), 59.2 (C6), 56.9 (C7), 44.2
(C2), 41.2 ppm (C4); MS (EI): m/z (%): 298 (2) [M]+, 202 (100); elemen-
tal analysis: calcd (%) for C16H14N2O4 (298.3): C 64.42, H 4.73, N 9.39;
found: C 64.32, H 4.78, N 9.34.
[5] For a recent review on the carbonyl-ene reaction, see: M. L. Clarke,
M. B. France, Tetrahedron 2008, 64, 9003.
[6] For a preliminary communication of a part of this work, see: B. Al-
caide, C. Pardo, C. Rodrꢀguez-Ranera, A. Rodrꢀguez-Vicente, Org.
Lett. 2001, 3, 4205.
[7] a) B. Alcaide, P. Almendros, T. Martꢀnez del Campo, M. T. Quirꢄs,
Chem. Eur. J. 2009, 15, 3344; b) B. Alcaide, P. Almendros, R. Carra-
scosa, T. Martꢀnez del Campo, Chem. Eur. J. 2009, 15, 2496; c) B. Al-
caide, P. Almendros, T. Martꢀnez del Campo, E. Soriano, J. L.
Marco-Contelles, Chem. Eur. J. 2009, 15, 1901; d) B. Alcaide, P. Al-
mendros, T. Martꢀnez del Campo, Chem. Eur. J. 2008, 14, 7756; e) B.
Alcaide, P. Almendros, G. Cabrero, M. P. Ruiz, Chem. Commun.
2008, 615; f) B. Alcaide, P. Almendros, R. Carrascosa, M. C. Redon-
do, Chem. Eur. J. 2008, 14, 637; g) B. Alcaide, P. Almendros, T. Mar-
tꢀnez del Campo, Angew. Chem. 2007, 119, 6804; Angew. Chem. Int.
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Campo, Angew. Chem. 2006, 118, 4613; Angew. Chem. Int. Ed. 2006,
45, 4501.
Carbacepham (ꢀ)-27b: Colorless solid; m. p. 191–1938C; ½aꢁ2D0 =ꢀ2.7
(c=1.2 in CHCl3); IR (KBr): n˜ =3369, 1736, 1720 cmꢀ1
;
1H NMR
(300 MHz, CDCl3, 258C): d=1.70 (d, J=23.4 Hz, 3H, Me), 1.87 (dt, J=
10.1, 12.1 Hz, 1H, H4a), 2.26 (ddd, J=4.6, 9.4, 12.8 Hz, 1H, H4e), 2.98 (t,
J=11.8 Hz, 1H, H2a), 3.58 (dd, J=4.6, 8.1 Hz, 1H, H6), 3.86 (dd, J=1.5,
13.1 Hz, 1H, H2e), 4.01 (m, 1H, H5), 5.46 (dd, J=1.4, 4.6 Hz, 1H, H7),
7.77 (m, 2H, Ar), 7.86 ppm (m, 2H, Ar); 13C NMR (75 MHz, CDCl3,
258C): d=167.5 (NC=O, 2), 162.9 (C8), 134.7, 131.5, 123.9, 92.6 (d, J=
176.4 Hz, C3), 64.7 (d, J=11.0 Hz, C5), 59.2 (d, J=1.1 Hz, C6), 56.5 (d,
J=3.2 Hz, C7), 47.9 (d, J=34.3 Hz, C2), 44.0 (d, J=20.6 Hz, C4),
24.1 ppm (d, J=23.8 Hz, Me); elemental analysis: calcd (%) for
C16H15FN2O4 (318.3): C 60.37, H 4.75, N 8.80; found: C 60.50, H 4.70,
N 8.87.
[8] Carbapenems and carbacephems are promising new families of b-
lactam antibiotics closely related to the widely used penicillins and
cephalosporins, with similar antibacterial profiles but with greater
chemical stability and enhanced pharmacokinetic properties. For
1610
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Chem. Asian J. 2009, 4, 1604 – 1611

Lewis Acid-Assisted Ene Cyclization
recent reviews on these biologically relevant systems, see: a) J.
Marchand-Brynaert, C. Brulꢃ in Comprehensive Heterocyclic
Chemistry III, vol. 2 (Eds.: A. R. Katritzky, C. A. Ramsden, E. F. V.
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Chemistry III, Vol. 2 (Eds.: A. R. Katritzky, C. A. Ramsden, E. F. V.
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Chemistry, Blackwell Publishing, Oxford, UK, 2004; c) P. Kirsch,
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[19] The assignment of cis stereochemistry to b-lactam derivatives is
based on the observed coupling constants of about 5.0 Hz for me-
thine protons H3 and H4, whereas trans-stereochemistry is consis-
tent with methine coupling constants of approximately 2.0 Hz in
their 1H NMR spectra. The assignment of relative stereochemistry
based on the observed coupling constant for methine protons H3
and H4 is a very well-established criterium in b-lactam chemistry.
See, for example: B. Alcaide, P. Almendros, N. R. Salgado, A. Ro-
drꢀguez-Vicente, J. Org. Chem. 2000, 65, 4453.
[9] B. Alcaide, P. Almendros, Chem. Soc. Rev. 2001, 30, 226.
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V. R. Hedge, M. S. Manhas, A. K. Bose, J. Org. Chem. 1988, 53,
4227.
[11] Besides, it is known that in type I ene cyclizations, formation of cy-
clohexanols is faster than formation of cyclopentanols arising from
the greater ring strain of cyclopentanols (n=6>5@7).
[12] N. H. Andersen, S. W. Hadley, J. D. Kelly, E. R. Bacon, J. Org.
Chem. 1985, 50, 4144.
[13] B. Alcaide, E. Sꢁez, Eur. J. Org. Chem. 2005, 1680.
[14] A. Dondoni, A. Marra, Chem. Rev. 2004, 104, 2557.
[20] For mechanistic aspects on the carbonyl-ene cyclization reaction,
see: a) N. Mondal, C. S. Mandal, G. K. Das, J. Mol. Struct. 2004, 680,
73; b) D. Ch. Braddock, K. K. Hii, J. M. Brown, Angew. Chem. 1998,
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Sawa, M. Terada, Tetrahedron: Asymmetry 1991, 2, 1403; d) K.
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1987, 52, 5419.
[21] The stepwise mechanism is often termed as a Prins cyclization.
[22] Experimental procedures as well as full spectroscopic and analytical
data for compounds not included in this Experimental Section are
described in the Supporting Information.
[15] The observed syn diastereoselectivity for the addition of the TMST
step might be tentatively explained by invoking the Felkin–Anh
model, analogous to the related addition processes described in our
laboratories. See: a) B. Alcaide, P. Almendros, R. Rodrꢀguez-
Acebes, J. Org. Chem. 2005, 70, 2713; b) B. Alcaide, P. Almendros,
J. M. Alonso, J. Org. Chem. 2004, 69, 993; c) B. Alcaide, P. Almen-
dros, C. Aragoncillo, Chem. Eur. J. 2002, 8, 1719.
[16] B. Alcaide, P. Almendros, M. C. Redondo, Org. Lett. 2004, 6, 1765.
[17] Fluorinated compounds play a very important role in life sciences
arising from the introduction of a fluorine atom into an organic mol-
ecule, which shows profound changes in its chemical and biological
nature: a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem.
Soc. Rev. 2008, 37, 320; b) R. D. Chambers, Fluorine in Organic
Received: May 6, 2009
Published online: August 17, 2009
Chem. Asian J. 2009, 4, 1604 – 1611
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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