Diversity-oriented preparation of enantiopure spirocyclic 2-azetidinones from α-oxo-β-lactams through barbier-type reactions followed by metal-catalyzed cyclizations

Article abstract of DOI:10.1002/adsc.200600502

Novel, simple, and convenient strategies to diversely functionalized spirocyclic β-lactams have been developed by using different metal-mediated carbonyl addition/cyclization reaction sequences. Spirocyclization precursors, 2-azetidinone-tethered homoally

Full text of DOI:10.1002/adsc.200600502

FULL PAPERS
DOI: 10.1002/adsc.200600502
Diversity-Oriented Preparation of Enantiopure Spirocyclic
2-Azetidinones from a-Oxo-b-lactams through Barbier-Type
Reactions followed by Metal-Catalyzed Cyclizations
Benito Alcaide,a,* Pedro Almendros,b,* Teresa Martínez del Campo,a
and Raquel Rodríguez-Acebesa
a
Departamento de Química Orgµnica I. Facultad de Química. Universidad Complutense de Madrid, 28040 Madrid, Spain
Fax : (+34)-91-394-4103; e-mail: alcaideb@quim.ucm.es
Instituto de Química Orgµnica General, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
b
Fax : (+34)-91-5644853; e-mail: iqoa392@iqog.csic.es
Received: October 3, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Novel, simple, and convenient strategies to lective addition of stabilized organometallic reagents
diversely functionalized spirocyclic b-lactams have to azetidine-2,3-diones in an aqueous environment.
been developed by using different metal-mediated Ruthenium-, silver-, and palladium-catalyzed reac-
carbonyl addition/cyclization reaction sequences. Spi- tions of the above monocyclic unsaturated alcohol
rocyclization precursors, 2-azetidinone-tethered ho- derivatives provided oxaspiro-b-lactams.
moallylic alcohols, bromohomoallylic alcohols, ho-
À
mopropargylic alcohols, (buta-1,3-dien-2-yl)metha- Keywords: C C coupling; cyclization; lactams; palla-
nols, and a-allenols have been obtained by regiose- dium; spiro compounds
Introduction
ate spiro-bridge represents an attractive endeavour in
organic and medicinal chemistry. Our combined inter-
Systems containing one carbon atom common to two est in the area of b-lactams and the synthetic use of
rings, spirocyclic compounds, represent an important metals,[10] led us to explore novel, simple, and conven-
structural organization.[1] On the other hand, the im- ient metal-assisted methodologies for the preparation
portance of the stereoselective synthesis of b-lactams of diversely functionalized spiranic-2-azetidinones.[11]
is ever increasing in connection with structure-activity
relationship studies and the development of new de-
rivatives of the b-lactam antibiotics and inhibitors of Results and Discussion
b-lactamases.[2] In addition, there are many important
non-antibiotic uses of 2-azetidinones in fields ranging Starting substrates, enantiopure azetidine-2,3-diones
from enzyme inhibition,[3] to the use of these products (+)-1a and (À)-1b, were prepared from the corre-
as starting materials to develop new synthetic meth- sponding (R)-2,3-O-isopropylideneglyceraldehyde-de-
odologies.[4] Spirocyclic b-lactams behave as b-turn rived imine, via Staudinger reaction with acetoxyace-
mimetics,[5] as well as enzyme inhibitors,[6] they are tyl chloride in the presence of Et3N, followed by se-
precursors of a,a-disubstituted b-amino acids,[7] and quential transesterification and Swern oxidation.[12]
the spiranic b-lactam moiety is present in chartel- Homoallyl alcohol (+)-2, bromohomoallylic alcohols
lines,[8] a family of marine natural products. Due to (+)-3a and (À)-3b, homopropargylic alcohol (À)-4,
the importance of this structural framework, the de- (buta-1,3-dien-2-yl) alcohol (+)-5, and a-allenyl alco-
velopment of simple and convenient methodologies hols 6a–d were regiospecifically prepared using our
for the synthesis of the spiro-b-lactam assembly con- recently developed metal-mediated Barbier-type car-
tinues to be a challenging area in organic chemistry.[9] bonyl allylation, bromoallylation, 1,3-butadien-2-yla-
It occurred to us that the development of syntheses of tion, propargylation, or allenylation reactions of azeti-
aesthetically appealing molecular architectures con- dine-2,3-diones 1 in aqueous media (Scheme 1).[12]
taining both the b-lactam moiety and oxaheterocyclic
With the advent of well-defined, practically air-
frameworks linked with an interesting and appropri- stable, and functional-group tolerant metathesis cata-
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was smoothly prepared from (buta-1,3-dien-2-yl) alco-
hol (+)-5 (Scheme 2).
Our novel 2-azetidinone-tethered diene substrates
7–10 provided an opportunity to investigate the syn-
thetic potential of the spiro-forming RCM reaction.
The use of this approach in the synthesis of spirocyclic
2-azetidinones has not been hitherto applied. Our ob-
jective was the synthesis of oxaspiro-b-lactam struc-
tures containing five- and six-membered rings. Un-
fortunately, dienes 7–10 having a quaternary center
proved to be resistant to ring closure mediated by
Ru-based first generation Grubbsꢁ carbene under
smooth reaction conditions (5 mol%, CH2Cl2, 258C).
The major part of the reaction mixture was composed
of unreacted dienes. While the reasons for this lack of
cyclization were not definitively established, we at-
tributed the low reactivity of the systems 7–10 to
either the ring strain inherent to the spirocyclic prod-
uct or kinetic problems associated with its formation.
It was found that dienic substrates 7–10 require more
vigorous conditions for ring closure. Spiro ring-closing
metathesis was achieved upon heating at reflux tem-
perature in a toluene solution. Under optimized con-
ditions (5 mol% Grubbsꢁ carbene, toluene 0.03M,
1108C), good yields of unusual b-lactams 11–13 con-
taining dihydrofuran, dihydropyran and dihydropyra-
none spiranic rings were obtained (Scheme 3). The
six-membered spiro compound (À)-14 which bears an
exocyclic methylene was achieved when the spirocy-
clization took place on triene (+)-10. No traces of the
five-membered regioisomer 15 could be detected, be-
cause only the least substituted double bond of the
1,3-diene system reacted (Scheme 3).
Enyne metathesis is the bond reorganization of an
alkene and an alkyne which has emerged as an impor-
tant new method for 1,3-diene synthesis.[14] We decide
to investigate the intramolecular version of this bond
reorganization in enyne-b-lactams. The allene moiety
represents a versatile and useful building block in or-
ganic synthesis, specially in the area of transition
Scheme 1. Regio- and estereoselective preparation of unsa-
turated alcohols 2–6.
lysts, e.g., the first, [Cl2
(PCy3)2Ru=CHPh], and metal-assisted reactions.[15] However, the information
second, [Cl2(Im)(Cy3P)Ru=CHPh], generations of available on the use of allenes in metathesis-type re-
ACHTREUNG
Grubbsꢁ ruthenium-based catalysts, ring-closing meta- actions is very scarce,[16] with only two available ex-
thesis (RCM) has become one of the most powerful amples on the exposure of the enallene moiety to
and reliable approaches to construct a ring system.[13] metathesis catalysts giving isomerization products.[17]
Our first task was to develop a method for the synthe- Enyne metathesis precursors (+)-16 and (+)-17 were
sis of appropriately substituted metathesis precursors. synthesized under phase-transfer conditions by treat-
The treatment of homoallyl alcohol (+)-2 either with ment of homoallyl alcohol (+)-2 or homopropargyl
allyl bromide or methyl propiolate, under different alcohol (À)-4 with propargyl bromide or allyl bro-
basic conditions, gave dienes (+)-7 and (+)-8, respec- mide, respectively. Enallene (+)-18 was achieved
tively (Scheme 2). Sodium hydride-promoted O-acyla- through sodium hydride-promoted O-acylation of a-
tion of alcohol (+)-2 with acryloyl chloride provides allenol (+)-6a with acryloyl chloride. Treatment of
dienic substrate (+)-9 (Scheme 2). To further expand enynes (+)-16 and (+)-17 with first generation
the scope of substrates to submit to RCM we thought Grubbsꢁ carbene under our diene ring-closing meta-
of the buta-1,3-dien-2-yl moiety, bearing an extra thesis conditions, did not furnish the desired spirocy-
alkene group. Following the same alkylation strategy cles. Our next attempts at cyclization were undertak-
used to obtain diene (+)-7, the required triene (+)-10 en by using the imidazolidinylidene analogue, the
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Preparation of Enantiopure Spirocyclic 2-Azetidinones
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Scheme 2. Preparation of metathesis precursors 7–10. Reagents and conditions: i) TBAI, CH2Cl2, NaOH (aq. 50%) (1:1),
room temperature, 16 h. ii) CH2Cl2, Et3N, 0 8C, 1 h. iii) NaH, THF, room temperature, 1 h.
more active second generation Grubbsꢁ carbene. In b-lactams (+)-16 and (+)-17 to afford the inner-outer-
this way, the spirocyclization was effective on enyne- ring dienes (cyclic dienes in which one of the double
bonds is endo-cyclic) (+)-19 and (+)-20 (Scheme 4).
Despite the lack of precedents for RCM on enallenes,
we submitted enallene (+)-18 to the second genera-
tion Grubbsꢁ catalyst. Interestingly, the spirocyclic
diene-2-azetidinone
(+)-21
was
generated
(Scheme 4). Despite the modest yield obtained in the
synthesis of compound (+)-21 (single isomer, 30%
for RCM step), it deserves special mention because,
to the best of our knowledge, successful exposure of
the enallene moiety to RCM reaction conditions has
not been previously reported. A plausible mechanism
for the formation of (+)-21 involves an initial allenyl-
propargyl rearrangement promoted by Grubbsꢁ car-
bene,[18] followed by RCM of the resulting enyne
(Scheme 5).
The palladium-catalyzed coupling of olefins with
aryl or vinyl halides, known as the Heck reaction, is a
standard method for carbon-carbon bond formation
in organic synthesis.[19] We set out to evaluate a novel
strategy for the construction of the oxacyclic core of
spiranic b-lactams, which is based on a Heck spirocy-
clization. The cyclization precursors (+)-22a and (+)-
22b were easily prepared through a Michael-type pro-
cess by treatment of bromohomoallylic alcohols (+)-
3a and (À)-3b with methyl propiolate in the presence
of Et3N. The palladium-catalyzed reaction of bromo
dienes 22 was complete after a few hours, and afford-
ed spirocycles (+)-23a and (+)-23b as single regio-
Scheme 3. Preparation of spirocyclic b-lactams 11–14
through RCM. Reagents and conditions: i) [Cl2(PCy3)2Ru=
AHCTREUNG
CHPh], toluene, reflux; 11: 7 h; 12: 16 h; 13: 33 h; 14: 12 h. and stereoisomers (Scheme 6). The Heck spirocycliza-
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Benito Alcaide et al.
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Scheme 4. Preparation of spirocyclic b-lactams 19–21 through enyne metathesis. Reagents and conditions: i) Propargyl bro-
mide, TBAI, CH2Cl2, NaOH (aq. 50%) (1:1), room temperature, 16 h. ii) [Cl2(Im)(Cy3P)Ru=CHPh], toluene, reflux; 19: 6 h;
AHCTREUNG
20: 4 h; 21: 16 h. iii) Allyl bromide, TBAI, CH2Cl2, NaOH (aq. 50%) (1:1), room temperature, 16 h. (iv) Acryloyl chloride,
NaH, THF, room temperature, 1 h.
Scheme 6. Preparation of spirocyclic b-lactams 23 through
Heck reaction. Reagents and conditions: i) Methyl propio-
late, CH2Cl2, Et3N, 0 8C, 1 h. ii) Pd
DMF, 1058C; 23a: 6 h; 23b: 4 h.
A
Taking into account that allenes bearing a nucleo-
philic center can be cyclized on treatment with a wide
variety of transition metal catalysts,[20] we turned our
attention to metal-based cyclization reactions in our
b-lactam-tethered a-allenic alcohols 6. Our initial
work began with the AgNO3-induced reaction of a-al-
Scheme 5. Mechanistic explanation for the formation of spi-
rocycle 21.
tion reaction is regioselective, giving five-membered lenols 6a–d, to give, with concomitant acetonide
heterocycles. In addition, it is stereoselective because cleavage, the spirocyclic dihydrofurans 24a–d in quan-
the Heck adducts were obtained as single geometric titative yields (Scheme 7).[21] The use of the Pd-
isomers.
A
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Preparation of Enantiopure Spirocyclic 2-Azetidinones
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tion of epoxide (À)-26 involves concomitant ring
opening of the b-lactam nucleus, probably because of
the ring strain of the intermediate spirocyclic epoxy-
2-azetidinone which cannot survive under the reaction
conditions. The transformation of allenols 6 into spi-
rocyclic disubstituted dihydrofuran b-lactams 28 was
readily achieved in high yields, by treatment with allyl
bromide or 2,3-dibromopropene in the presence of
palladium(II) chloride (5 mol%) (Scheme 8).
Scheme 9 outlines a mechanistic hypothesis for the
achievement of compounds (À)-26 and (À)-27. The
Pd(0)-catalyzed insertion of iodobenzene generated
the corresponding (p-allyl)palladium intermediate 29.
Then, an intramolecular oxycyclization reaction on
the (p-allyl)palladium complex must account for the
formation of the spiranic oxirane intermediate 30 or
its regioisomer (À)-27. Subsequent b-lactam ring
opening of the spirocyclic epoxy-2-azetidinone 30
under the reaction conditions, afforded the oxirane b-
amino acid (À)-26. The formation of spirocyclic azeti-
dinones 28 could be explained following a Pd(II)-cat-
alyzed mechanism.[23] Initial Pd(II)-coordination gave
an allenepalladium complex 31. Species 31 suffers an
intramolecular cycloetherification reaction to give the
palladadihydrofurans 32. Intermediate 32 reacted
with the appropriate allyl bromide to form intermedi-
ates 33 which, after dehalopalladation, generated
spiro-b-lactams 28 with concomitant regeneration of
the Pd(II) species (Scheme 10).
Scheme 7. Silver-promoted preparation of spirocyclic b-lac-
tams 24 and 25. Reagents and conditions: i) AgNO3
(1 equiv.), acetone-H2O(1:1), reflux; 24a: 3 h; 24b: 6 h; 24c:
6h; 24d: 6 h. ii) 5 mol% Pd(PPh3)4, Ag2CO3 (2 equivs.), tol-
G
uene, sealed tube, 1808C; 24a: 0.5 h; 25b: 4 h.
To expand the scope of these interesting intramo-
lecular allene cyclizations, we decided to test the reac-
tivity of the carbamate moiety as internal nucleophile
in the intramolecular metal-catalyzed addition to al-
lenes by using a Pd–Cu bimetallic system. a-Allenols
(+)-6a and (+)-6b were derivatizated through reac-
tion with tosyl isocyanate to give the a-allene carba-
mates (+)-34a and (À)-34b. Interestingly, the 1,2-bro-
moamidation of the allenes 34 took place smoothly,
obtaining the spiranic oxazolidinone-b-lactams (+)-
35a and (+)-35b as single isomers (Scheme 11). Next,
we decided to test if this transformation could be ac-
cessible through the palladium(II)-catalyzed reaction
of the allenol moiety itself. The bromodihydrofurans
(À)-36a and (+)-36b were prepared as single isomers
via the palladium-induced intramolecular 2,3-oxybro-
mination of a-allenols (À)-6c and (À)-6d
(Scheme 11). Of special interest is the reversal on the
regioselectivity in the nucleophilic insertion of alle-
Scheme 8. Palladium-promoted preparation of spirocyclic b-
lactams 27 and 28. Reagents and conditions: i) PhI
(1.1 equivs.), 5 mol% Pd(PPh3)4, K2CO3 (4 equivs.), DMF,
A
858C, 45 h. ii) 5 mol% PdCl2, DMF, room temperature, 28a:
3 h, 28b: 2 h; 28c: 4 h; 28d: 1.5 h; 28e: 23 h.
(+)-25a and (+)-25b albeit in modest yields nols 6, by comparison with the cyclization of the car-
(Scheme 7). bamate derivatives 34 under the same reaction condi-
The palladium-catalyzed cyclizative coupling reac- tions. The palladium-catalyzed intramolecular cycliza-
tion of a-allenols 6 with aryl and alkenyl halides was tion of simple g-allenic alcohols has been recently re-
explored next. It was observed that the Pd
(PPh3)4-cat- ported by Bäckvall and co-workers.[24] However, the
G
alyzed reaction of a-allenol (+)-6a and iodobenzene dramatic change on the regioselectivity by the effect
afforded as main product the oxirane b-amino acid of the tether length should be noted . These authors
(À)-26, together with the regioisomeric spiranic dihy- obtained the 1,2-addition products, while we obtained
drofuran-b-lactam (À)-27 (Scheme 8).[22] The forma- the 2,3-addition products.
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Scheme 9. Mechanistic explanation for the formation of spirocycles 26 and 27.
Scheme 11. Palladium/copper-promoted preparation of spi-
rocyclic b-lactams 35 and 36. Reagents and conditions: i)
TsNCO, NaH, THF, room temperature, 3 h. ii) Pd
LiBr, Cu(OAc)2, K2CO3, MeCN, O2, room temperature;
35a: 24 h; 35b: 4 d; 36a: 23 h; 36b: 6 d.
A
Scheme 10. Mechanistic explanation for the formation of
spirocyclic b-lactams 28.
AHCTREUNG
A likely mechanism for the generation of spirocy- framework, which is an important structural motif in
cles 35 and 36 should involve the initial formation of some biologically relevant compounds. We have
a (p-allyl)palladium species. The allenepalladium shown that the use of Barbier-type carbonyl addition
complex 37 and 31 are formed initially and suffer a reactions on azetidine-2,3-diones followed by metal-
nucleophilic attack by the bromide to produce s-allyl- promoted cyclizations on the resulting unsaturated al-
palladium species, which rapidly equilibrate to the cohols is a useful methodology for the preparation of
corresponding (p-allyl)palladium intermediates 38 a variety of diversely functionalized oxaspirocyclic 2-
and 39. Then, an intramolecular cycloetherification azetidinones.
reaction on the (p-allyl)palladium complex must ac-
count for the formation of spiranic oxazolidinones
and bromodihydrofuran intermediates 35 and 36
(Scheme 12 and Scheme 13).
Experimental Section
General Methods
Conclusions
Melting points were taken using a Gallenkamp apparatus
and are uncorrected. IR spectra were recorded on a Perkin–
1
Elmer 781 spectrophotometer. H NMR and 13C NMR spec-
In conclusion, the present study provides the first di-
versity-oriented preparation of the spiro-b-lactam tra were recorded on a Bruker Avance-300, Varian VRX-
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General Procedure for the Ring-Closing Metathesis
(RCM) Reaction of Precursors 7–10 and 16–18;
Preparation of Spirocyclic b-Lactams 11–14 and 19–
21
To a solution of the appropriate precursor (0.20 mmol) in
anhydrous toluene (6 mL), protected from the sunlight, was
added in portions [Cl2
A
AHCTREUNG
mixture was heated at reflux until complete disappearance
of the starting material (TLC), and was concentrated under
reduced pressure. Chromatography of the residue eluting
with ethyl acetate/hexanes or ethyl acetate/dichloromethane
mixtures gave analytically pure compounds 11–14 or 19–
21.[25]
Scheme 12. Mechanistic explanation for the formation of
spirocyclic b-lactams 35.
General Procedure for the Heck Reaction of
Bromodienes 22; Preparation of Spirocyclic b-
Lactams 23
Palladium(II) acetate (0.03 mmol), triphenylphosphine
(0.07 mmol), and potassium carbonate (7.0 mmol) were se-
quentially added to a solution of the corresponding bromo-
diene 22 (1.0 mmol) in dimethylformamide (15 mL), and the
mixture was heated at 1058C in a sealed tube. After disap-
pearance of the starting material (TLC), the reaction mix-
ture was cooled at room temperature and diluted with ethyl
acetate (10 mL). The organic phase was washed with water
(4”5 mL) and brine (3”5 mL), dried (MgSO4), and concen-
trated under reduced pressure. Chromatography of the resi-
due eluting with hexanes/ethyl acetate or dichloromethane/
ethyl acetate mixtures gave analytically pure spiranic b-lac-
tams 23.[25]
General Procedure for the Silver-Induced Reaction of
a-Allenols 6; Preparation of Spirocyclic b-Lactams 24
Scheme 13. Mechanistic explanation for the formation of
spirocyclic b-lactams 36.
Silver nitrate (0.20 mmol) was added to a stirred solution of
the corresponding a-allenol 6 (0.20 mmol) in acetone/water
(1:1) (0.4 mL). The reaction was refluxed until disappear-
ance of the starting material (TLC). The mixture was al-
lowed to reach room temperature before brine (2 mL) was
added, and then it was extracted with ethyl acetate (4”
5 mL). The organic extract was washed with brine and dried
(MgSO4). Removal of solvent under reduced pressure yield-
ed the corresponding spiranic dihydrofuran adducts 24 in
analytically pure form.[25]
300S or Bruker AC-200. NMR spectra were recorded in
CDCl3 solutions, except where 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 spec-
tra were taken on an HP5989A spectrometer using the elec-
tronic impact (EI) or electrospray modes (ES) unless other-
wise stated. Optical rotations were measured using
a
Pd(0)-Catalyzed Cyclization of a-Allenols 6;
Preparation of Spirocyclic b-Lactams 25
Perkin–Elmer 241 polarimeter. Specific rotation [a]D is
given in deg cm2 gÀ1 at 258C, and the concentration (c) is ex-
pressed in g per 100 mL. All commercially available com-
pounds were used without further purification. THF was dis-
tilled from Na-benzophenone. Benzene, dichloromethane
and triethylamine were distilled from CaH2. Flame-dried
glassware and standard Schlenk techniques were used for
moisture sensitive reactions. Flash chromatography was per-
formed using Merck silica gel 60 (230–400 mesh).
[Pd(PPh3)4] (15 mg, 0.013 mmol) was added to a mixture of
A
the corresponding a-allenol 6 (0.25 mmol), and silver car-
bonate (138 mg, 0.5 mmol) in DMF (2 mL) under Ar, and
the resulting mixture was heated at 1808C until disappear-
ance of the starting material (TLC). The reaction was then
quenched with brine (2.5 mL), the mixture was extracted
with ethyl acetate (4”5 mL), and the combined extracts
were washed twice with brine and dried (MgSO4). Removal
of solvent under reduced pressure yielded the corresponding
spiranic dihydrofuran adducts 25 in analytically pure
form.[25]
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Benito Alcaide et al.
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The organic phase was diluted with brine (2 mL), extracted
with ethyl acetate (3”5 mL), washed with brine (2 mL),
dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue eluting with hexanes/ethyl
acetate mixtures gave analytically pure spiranic 2-azetidi-
nones 36.[25]
Pd(0)-Catalyzed Coupling Cyclization of a-Allenol
(+)-6a with PhI; Preparation of Oxirane g-Amino
Acid (À)-26 and Spirocyclic b-Lactam (À)-27
[Pd(PPh3)4] (7.2 mg, 0.006 mmol) was added to a mixture of
A
a-allenol (+)-6a (40 mg, 0.12 mmol), phenyl iodide (26 mg,
0.13 mmol), and potassium carbonate (66 mg, 0.48 mmol) in
DMF (1 mL) under Ar, and the resulting mixture was
heated at 858C for 45 h. The reaction was then quenched
with brine (1.2 mL), the mixture was extracted with ethyl
acetate (4”2 mL), and the combined extracts were washed
twice with brine and dried (MgSO4). Removal of solvent
under reduced pressure yielded 17 mg (33%) of the more
polar compound (À)-26 and 6 mg (12%) of the less polar
compound (À)-27 after chromatography eluting with hex-
anes/ethyl acetate (1:1).[25]
Supporting Information
Compound characterization data for all compounds as well
as experimental procedures not included in the Experimen-
tal Section.
Acknowledgements
We would like to thank the DGI-MEC (Projects BQU2003–
07793-C02–01 and CTQ2006-10292) and CAM-UCM (Grant
GR45/05) for financial support. R. R.-A. and T. M. C. thank
the MEC for predoctoral grants.
General Procedure for the Pd(II)-Catalyzed Coupling
Reaction of a-Allenols 6 with Allyl Bromide;
Preparation of Spirocyclic b-Lactams 28
Palladium(II) chloride (0.005 mmol) was added to a stirred
solution of the corresponding a-allenol 6 (0.10 mmol) in
N,N-dimethylformamide (0.6 mL). The reaction mixture was
stirred under an argon atmosphere until disappearance of
the starting material (TLC). Water (0.5 mL) was added
before being extracted with ethyl acetate (3”4 mL). The or-
ganic phase was washed with water (2”2 mL), dried
(MgSO4) and concentrated under reduced pressure. Chro-
matography of the residue eluting with hexanes/ethyl ace-
tate mixtures gave analytically pure spiranic 2-azetidinones
28.[25]
References
[1] For reviews, see: a) R. Pradhan, M. Patra, A. K.
Behera; B. K. Mishra; R. K. Behera, Tetrahedron 2006,
62, 779; b) M. Sannigrahi, Tetrahedron 1999, 55, 9007;
c) C. L. Heathcock, S. L. Graham, M. C. Pirrung, F.
Plavac, C. T. White, Spirocyclic Systems, in: The Total
Synthesis of Natural Products, (Ed.: J. ApSimon), John
Wiley and Sons, New York, 1983; Vol. 5, pp 264–313.
[2] Hot topic: b-Lactams: Synthesis Stereochemistry, Syn-
thons and Biological Evaluation, (Ed.: B. K. Banik),
Curr. Med. Chem. 2004, 11, issue 14.
[3] For selected reviews, see: a) J. W. Clader, J. Med.
Chem. 2004, 47, 1; b) G. Veinberg, M. Vorona, I. Shes-
takova, I. Kanepe, E. Lukevics, Curr. Med. Chem. 2003,
10, 1741; for selected examples, see: c) 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. Toan, L. I. Bruijn, Z.-z. Su, P. Gupta, P. B.
Fisher, Nature 2005, 433, 73; d) P. C. Hogan, E. J.
Corey, J. Am. Chem. Soc. 2005, 127, 15386; e) L. Kvaer-
no, T. Ritter, M. Werder, H. Hauser, E. M. Carreira,
Angew. Chem. 2004, 116, 4753; Angew. Chem. Int. Ed.
2004, 43, 4653; ; f) D. A. Burnett, Curr. Med. Chem.
2004, 11, 1873; g) G. Veinberg, M. Vorona, I. Shestako-
va, I. Kanepe, E. Lukevics, Curr. Med. Chem. 2003, 10,
1741; h) M. I. Page, A. P. Laws, Tetrahedron 2000, 56,
5631; i) T. M. Haley, S. J. Angier, A. D. Borthwick, R.
Singh, R. G. Micetich, Drugs 2000, 3, 512.
General Procedure for the Palladium(II)-Catalyzed
Cyclization of a-Allenic Carbamates 34; Preparation
of Spirocyclic b-Lactams 35
Palladium(II) acetate (0.012 mmol), lithium bromide
(0.656 mmol), potassium carbonate (0.16 mmol) and cop-
per(II) acetate (0.28 mmol) were sequentially added to a
stirred solution of the corresponding a-allenic carbamate 34
(0.134 mmol) in acetonitrile (7 mL). The resulting suspen-
sion was stirred at room temperature under an oxygen at-
mosphere until disappearance of the starting material
(TLC). The organic phase was diluted with brine (2 mL), ex-
tracted with ethyl acetate (3”5 mL), washed with brine
(2 mL), dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue eluting with hex-
anes/ethyl acetate mixtures gave analytically pure spiranic 2-
azetidinones 35.[25]
General Procedure for the Palladium(II)-Catalyzed
Oxybromination of a-Allenic Alcohols 6; Preparation
of Spirocyclic b-Lactams 36
[4] For reviews, see: a) B. Alcaide, P. Almendros, Curr.
Med. Chem. 2004, 11, 1921; b) A. R. A. S. Deshmukh,
B. M. Bhawal, D. Krishnaswamy, V. V. Govande, B. A.
Shinkre, A. Jayanthi, Curr. Med. Chem. 2004, 11, 1889;
c) B. Alcaide, P. Almendros, Synlett 2002, 381; d) C.
Palomo, J. M. Aizpurua, I. Ganboa, M. Oiarbide, Syn-
lett 2001, 1813; e) B. Alcaide, P. Almendros, Chem. Soc.
Rev. 2001, 30, 226; f) C. Palomo, J. M. Aizpurua, I.
Ganboa, M. Oiarbide, Amino acids 1999, 16, 321; g) I.;
Ojima, F. Delaloge, Chem. Soc. Rev. 1997, 26, 377;
Palladium(II) acetate (0.01 mmol), lithium bromide
(0.74 mmol), potassium carbonate (0.18 mmol) and copper-
(II) acetate (0.32 mmol) were sequentially added to a stirred
solution of the corresponding a-allenic alcohol
6
(0.15 mmol) in acetonitrile (5 mL). The resulting suspension
was stirred at room temperature under an oxygen atmos-
phere until disappearance of the starting material (TLC).
756
www.asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 749 – 758

Preparation of Enantiopure Spirocyclic 2-Azetidinones
FULL PAPERS
h) M. S. Manhas, D. R. Wagle, J. Chiang, A. K. Bose,
Heterocycles 1988, 27, 1755.
[11] For a preliminary communication of a part of this
work, see: B. Alcaide, P. Almendros, T. Martínez del
Campo, R. Rodríguez-Acebes, Tetrahedron Lett. 2004,
45, 6429.
[12] a) B. Alcaide, P. Almendros, C. Aragoncillo, R. Rodrí-
guez-Acebes, J. Org. Chem. 2004, 69, 826; b) B. Al-
caide, P. Almendros, R. Rodríguez-Acebes, J. Org.
Chem. 2002, 67, 1925; c) B. Alcaide, P. Almendros, C.
Aragoncillo, R. Rodríguez-Acebes, J. Org. Chem. 2001,
66, 5208; d) B. Alcaide, P. Almendros, C. Aragoncillo,
Org. Lett. 2000, 2, 1411.
[13] For some reviews on olefin metathesis, see: a) A. Dei-
ters, S. F. Martin, Chem. Rev. 2004, 104, 2199; b) Hand-
book of Metathesis, Vols. 1–3, (Ed.: R. H. Grubbs),
Wiley-VCH: Weinheim, 2003; c) R. R. Schrock, A. H.
Hoveyda, Angew. Chem. 2003, 115, 4740; Angew.
Chem. Int. Ed. 2003, 42, 4592; ; d) R. H. Grubbs, T. M.
Trnka, Acc. Chem. Res. 2001, 34, 18; e) A. Fꢃrstner,
Angew. Chem. 2000, 112, 3140; Angew. Chem. Int. Ed.
2000, 39, 3012; ; f) R. R. Schrock, A. H. Hoveyda,
Chem. Eur. J. 2001, 7, 945; g) A. Fꢃrstner, Synlett 1999,
1523; h) D. L. Wright, Curr. Org. Chem. 1999, 3, 211;
i) R. H. Grubbs, S. Chang, Tetrahedron 1998, 54, 4413;
j) S. K. Armstrong, J. Chem. Soc., Perkin Trans. 1 1998,
371.
[14] For recent enyne metathesis reviews, see: a) S. T.
Diver, A. J. Giessert, Chem. Rev. 2004, 104, 1317; b) M.
Mori, Enyne Metathesis, in: Handbook of Metathesis,
(Ed.: R. H. Grubbs), Wiley-VCH, Weinheim, 2003,
Vol. 2, pp 176–204; c) C. S. Poulsen, R. Madsen, Syn-
thesis 2003, 1.
[15] For reviews, see: a) S. Ma, Chem. Rev. 2005, 105, 2829;
b) Modern Allene Chemistry, (Eds.: N. Krause, A. S. K.
Hashmi), Wiley-VCH, Weinheim, 2004; c) B. Alcaide,
P. Almendros, Eur. J. Org. Chem. 2004, 3377; d) S. Ma,
Acc. Chem. Res. 2003, 36, 701; e) A. S. K. Hashmi,
Angew. Chem. 2000, 112, 3737; Angew. Chem. Int. Ed.
2000, 39, 3590; f) R. Zimmer, C. U. Dinesh, E. Nandan-
an, F. A. Khan, Chem. Rev. 2000, 100, 3067.
[16] To the best of our knowledge, there have been only
two successful examples of metathesis that involve al-
lenes. For the ring-closing metathesis of allenynes, see:
a) M. Murakami, S. Kadowaki, T. Matsuda, Org. Lett.
2005, 7, 3953; for the cross-metathesis of monosubsti-
tuted allenes, see: b) M. Ahmed, T. Arnauld, A. G. M.
Barrett, D. C. Braddock, K. Flack, P. A. Procopiou,
Org. Lett. 2000, 2, 551.
[17] For isomerization of the allene to the 1,3-diene moiety,
see: a) S. S. Kinderman, J. H. van Maarseveen, H. E.
Schoemaker, H. Hiemstra, F. P. J. T. Rutjes, Org. Lett.
2001, 3, 2045; for the cycloisomerization reaction, see:
b) C. Mukai, R. Itoh, Tetrahedron Lett. 2006, 47, 3971.
[18] For overviews on non metathetic behavior patterns of
Grubbsꢁ carbene, see: a) B. Alcaide, P. Almendros,
Chem. Eur. J. 2003, 9, 1258; b) B. Schmidt, Eur. J. Org.
Chem. 2004, 1865.
[19] For reviews, see: a) P. J. Guiry, D. Kiely, Curr. Org.
Chem. 2004, 8, 781; b) M. T. Reetz, J. G. de Vries,
Chem. Commun. 2004, 1559; c) I. P. Beletskaya, A. V.
Cheprakov, Chem. Rev. 2000, 100, 3009; d) C. Amatore,
A. Jutand, Acc. Chem. Res. 2000, 33, 314; e) J. T. Link,
L. E. Overman, in: Metal-Catalyzed Cross-Coupling
[5] a) H. Bittermann, P. Gmeiner, J. Org. Chem. 2006, 71,
97; b) H. Bittermann, F. Bçckler, J. Einsiedel, P.
Gmeiner, Chem. Eur. J. 2006, 12, 6315; c) A. Macías,
A. Morµn Ramallal, E. Alonso, C. del Pozo, J. Gon-
zµlez, J. Org. Chem. 2006, 71, 7721; d) E. Alonso, F.
Lꢂpez-Ortiz, C. del Pozo, E. Peralta, A. Macías, J. Gon-
zµlez, J. Org. Chem. 2001, 66, 6333.
[6] For their evaluation as cholesterol absorption inhibi-
tors, see: a) T. Kambara, K. Tomioka, J. Org. Chem.
1999, 64, 9282; for their evaluation as inhibitors of po-
liovirus and rhinovirus 3C-proteinases, see: b) J. W.
Skiles, D. McNeil, Tetrahedron Lett. 1990, 31, 7277.
[7] a) A. Macías, E. Alonso, C. del Pozo, A. Venturini, J.
Gonzµlez, J. Org. Chem. 2004, 69, 7004; b) A. Macías,
E. Alonso, C. del Pozo, J. Gonzµlez, Tetrahedron Lett.
2004, 45, 4657; c) E. Alonso, C. del Pozo, J. Gonzµlez,
Synlett 2002, 69; d) R. E. Dolle, C. S. Li, R. Novelli,
L. I. Kruse, D. Eggleston, J. Org. Chem. 1992, 57, 128.
[8] a) C. Sun, X. Lin, S. M. Weinreb, J. Org. Chem. 2006,
71, 3159; b) P. S. Baran, R. A. Shenvi, C. A. Mitsos,
Angew. Chem. 2005, 117, 3780; Angew. Chem. Int. Ed.
2005, 44, 3714; ; c) T. Nishikawa, S. Kajii, M. Isobe,
Synlett 2004, 2025; d) J. L. Pinder, S. M. Weinreb, Tetra-
hedron Lett. 2003, 44, 4141.
[9] a) Y. Cheng, B. Wang, L.-Q. Cheng, J. Org. Chem.
2006, 71, 4418; b) D. J. Wardrop, M. S. Burge, J. Org.
Chem. 2005, 70, 10271; c) J. Robertson, S. J. Bell, A.
Krivokapic, Org. Biomol. Chem. 2005, 3, 4246; d) G.
Cremonesi, P. DallaCroce, F. Fontana, A. Forni, C. La
Rosa, Tetrahedron: Asymmetry 2005, 16, 3371; e) R.
Medel, M. C. Murcia, J. Plumet, Helv. Chim. Acta 2005,
88, 1387; f) A. B. Khasanov, M. M. Ramirez-Wein-
house, T. R. Webb, M. Thiruvazhi, J. Org. Chem. 2004,
69, 5766; g) N. S. Chowdari, J. T. Suri, C. F. Barbas III,
Org. Lett. 2004, 6, 2507; h) C. del Pozo, A. Macías, F.
Lꢂpez-Ortiz, M. A. Maestro, E. Alonso, J. Gonzµlez,
Eur. J. Org. Chem. 2004, 535; i) O. Arjona, M. C.
Murcia, J. Plumet, Tetrahedron Lett. 2002, 34, 6405;
j) E. Alonso, C. del Pozo, J. Gonzµlez, J. Chem. Soc.,
Perkin Trans. 1 2002, 571; k) X. Lin, S. M. Weinreb, Tet-
rahedron Lett. 2001, 42, 2631; l) P. DallaCroce, R. Fer-
raccioli, C. La Rosa, Tetrahedron 1999, 55, 201; m) S.
Anklam, J. Liebscher, Tetrahedron 1998, 54, 6369.
[10] See, for instance: a) B. Alcaide, P. Almendros, T. Martí-
nez del Campo, Angew. Chem. 2006, 118, 4613; Angew.
Chem. Int. Ed. 2006, 45, 4501; ; b) B. Alcaide, P. Al-
mendros, J. M. Alonso, Chem. Eur. J. 2006, 12, 2874;
c) B. Alcaide, P. Almendros, A. Luna, M. R. Torres, J.
Org. Chem. 2006, 71, 4818; d) B. Alcaide, P. Almen-
dros, M. C. Redondo, Chem. Commun. 2006, 2616;
e) B. Alcaide, P. Almendros, R. Rodríguez-Acebes, J.
Org. Chem. 2006, 71, 2346; f) B. Alcaide, P. Almendros,
C. Aragoncillo, M. C. Redondo, M. R. Torres, Chem.
Eur. J. 2006, 12, 1539; g) B. Alcaide, P. Almendros, R.
Rodríguez-Acebes, Chem. Eur. J. 2005, 11, 5708; h) B.
Alcaide, P. Almendros, G. Cabrero, M. P. Ruiz, Org.
Lett. 2005, 7, 3981; i) B. Alcaide, P. Almendros, R. Ro-
dríguez-Acebes, J. Org. Chem. 2005, 70, 3198; j) B. Al-
caide, P. Almendros, R. Rodríguez-Acebes, J. Org.
Chem. 2005, 70, 2713.
Adv. Synth. Catal. 2007, 349, 749 – 758
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
757

Benito Alcaide et al.
FULL PAPERS
Reactions, (Eds.: F. Diederich, P. J. Stang), Wiley-VCH:
Weinheim, 1998, Chapter 6; f) J. T. Link, L. E. Over-
man, in: Metal-Catalyzed Cross-Coupling Reactions,
(Eds.: A. de Meijere, F. E. Meyer), Wiley-VCH, Wein-
heim, 1998, Chapter 3; g) G. T. Crisp, Chem. Soc., Rev.
1998, 27, 427.
Org. Chem. 1995, 60, 5550; b) J. A. Marshall, K. G.
Pinney, J. Org. Chem. 1993, 58, 7180.
[22] For the Pd(0)-catalyzed insertion-cyclization reaction
of a-allenols with aryl halides, see: S. Ma, S. Zhao, J.
Am. Chem. Soc. 1999, 121, 7943.
[23] S. Ma, W. Gao, J. Org. Chem. 2002, 67, 6104.
[24] C. Jonasson, A. Horvµth, J.-E. Bäckvall, J. Am. Chem.
Soc. 2000, 122, 9600.
[20] For a review, see: a) R. W. Bates, V. Satcharoen, Chem.
Soc. Rev. 2002, 31, 12.
[21] For pioneering Ag(I)-catalyzed cyclization of 2,3-alle-
nols, see: a) J. A. Marshall, R. H. Yu, J. F. Perkins, J.
[25] Full spectroscopic and analytical data for all com-
pounds are given in the Supporting Information.
758
www.asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 749 – 758