Synthesis of strained tricyclic β-lactams by intramolecular [2+2] cycloaddition reactions of 2-azetidinone-tethered enallenols: Control of regioselectivity by selective alkene substitution

Article abstract of DOI:10.1002/chem.200500807

A convenient metal-free methodology for the preparation of structurally novel, strained tricyclic β-lactams containing a cyclobutane ring has been developed. The first examples accounting for the intramolecular [2+2] cycloaddition reactions in β-lactams h

Full text of DOI:10.1002/chem.200500807

FULL PAPER
DOI: 10.1002/chem.200500807
Synthesis of Strained Tricyclic b-Lactams by Intramolecular [2+2]
Cycloaddition Reactions of 2-Azetidinone-Tethered Enallenols: Control of
Regioselectivity by Selective Alkene Substitution
Benito Alcaide,*[a] Pedro Almendros,*[b] Cristina Aragoncillo,[a] María C. Redondo,[a] and
M. Rosario Torres[c]
Abstract:
A
convenient metal-free
molysis of 2-azetidinone-tethered enal-
lenols, which have been prepared in
aqueous media by regio- and diastereo-
selective indium-mediated carbonyl al-
lenylation of 4-oxoazetidine-2-carbal-
dehydes. Notably, the regioselectivity
of the cycloaddition can be tuned in
the allene component just by a subtle
variation in the substitution pattern of
the alkene component.
methodology for the preparation of
structurally novel, strained tricyclic b-
lactams containing a cyclobutane ring
has been developed. The first examples
accounting for the intramolecular
[2+2] cycloaddition reactions in b-lac-
tams have been achieved by the ther-
Keywords: allenes · cyclization · cy-
cloaddition · lactams · radicals
Introduction
cyclic b-lactam antibiotics, which are a new class of synthetic
antibacterial agents featuring good resistance to b-lactamas-
es and dehydropeptidases,[3] has triggered a renewed interest
in the building of new polycyclic b-lactam systems in an at-
tempt to move away from the classical b-lactam antibiotic
structures.[4] In addition, there are many important nonanti-
biotic uses of 2-azetidinones in fields ranging from enzyme
inhibition,[5] to the use of these products as starting materi-
als for the development of new synthetic methodologies.[6]
During the past decades the allene moiety has developed
from almost a rarity to an established member of the weap-
onry utilized in modern organic synthetic chemistry.[7] In
particular, the [2+2] cycloaddition reaction of allenes with
alkenes has been of special interest, because of the synthetic
importance of the methylenecyclobutane products pro-
duced.[8] However, this process has suffered from low
stereo- and positional selectivity. Intramolecularization of
the reactions, usually by placing the reacting group at a dis-
tance that produces five- or six-membered rings, should
solve the regioselectivity problems as larger rings are unfa-
vored.
The importance of the stereoselective synthesis of chiral b-
lactams is ever increasing in light of structure-activity rela-
tionship studies and the development of new derivatives of
the b-lactam antibiotics and inhibitors of b-lactamases.[1]
Due to increased bacterial resistance,[2] the discovery of tri-
[a] Prof. Dr. B. Alcaide, Dr. C. Aragoncillo, Dipl.-Chem. M. C. Redondo
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
[b] Dr. P. Almendros
Instituto de Química Orgµnica General
Consejo Superior de Investigaciones Científicas
Juan de la Cierva 3, 28006 Madrid (Spain)
Fax : (+34)91-564-4853
E-mail: iqoa392@iqog.csic.es
[c] Dr. M. R. Torres
Laboratorio de Difracción de Rayos X
Facultad de Química
Universidad Complutense de Madrid
E-28040 Madrid (Spain)
In our ongoing project, directed towards the preparation
of nitrogen-containing products of biological interest,[9] we
have initiated a study into the use of allenols in organic syn-
thesis. In this contribution, we present full details of the
formal [2+2] cycloaddition of the alkene partner with the
distal bond of the allene moiety in 2-azetidinone-tethered
enallenols,[10] together with a reversal of regioselectivity in
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author. It contains com-
pound characterization data and experimental procedures for com-
pounds 2a–m, (+)-3a, (+)-3b, (+)-4a, (+)-4b, (À)-4c, (Æ)-5a, (Æ)-
5b, (+)-6a, (+)-7b, (+)-7c, (Æ)-9c, (Æ)-10, and (Æ)-11.
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1539

the allene component just by a subtle variation of the substi-
tution pattern of the alkene to give cyclobutane fused b-lac-
tams.
was not achieved for the indium-mediated allenylation of al-
dehydes 1, the diastereomeric a-allenols 2 and anti-2 were
easily separated by gravity flow chromatography.
Derivatization of the enantiopure 3-phenoxy a-allenol
(+)-2g with (R)- and (S)-acetylmandelic acids to give man-
delates 3 enabled the assignment of the configuration at the
carbinolic stereocenter (Scheme 3). The configuration at the
carbinolic chiral center of the product (+)-2g was establish-
ed by using Trostꢁs method, which involved a comparison of
Results and Discussion
The starting substrates, 4-oxoazetidine-2-carbaldehydes 1a–f
(Table 1), were prepared both in the racemic form and in
1
the H NMR chemical shifts of
the acetylmandelates (+)-3a
Table 1. Regio- and stereoselective allenylation of 4-oxoazetidine-2-carbaldehydes 1 in aqueous media.
and (+)-3b,[13] and was assumed
to be the same for the rest of
enantiopure b-lactams 2. The
configurational assignment for
the racemic series was con-
firmed by X-ray crystallography
of the C3-alkenyl adduct anti-
(Æ)-2j (Figure 1).[14] It should
be noted that the relative
1H NMR chemical shifts of the
b-lactamic and carbinolic pro-
Aldehyde
R1
R2
R3
Product
syn/anti ratio[a]
Yield [%][b]
(+)-1a
(+)-1a
(+)-1b
(+)-1b
(+)-1c
(+)-1d
(+)-1d
(Æ)-1e
(Æ)-1e
(Æ)-1 f
(Æ)-1 f
allyl
allyl
MeO
MeO
MeO
MeO
MeO
PhO
PhO
vinyl
Me
Ph
Me
Ph
Ph
Me
Ph
Me
Ph
Me
Ph
(+)-2a
(+)-2b
(+)-2c
(+)-2d
(+)-2e
(+)-2 f
95:5
75
64
68
61
51
79
58
60
89
72
63
100:0
85:15
100:0
100:0
90:10
100:0
10:90
70:30
10:90
65:35
3-methyl-but-2-enyl
3-methyl-but-2-enyl
methallyl
methallyl
methallyl
PMP
PMP
PMP
PMP
(+)-2g
anti-(Æ)-2h
vinyl
isopropenyl
isopropenyl
(Æ)-2i
anti-(Æ)-2j
(Æ)-2k
[a] The ratio was determined from the integration of well-resolved signals in the 1H NMR spectra (300 MHz) tons could be a diagnostic tool
of the crude reaction mixtures before purification. [b] Yield of pure, isolated product with correct analytical
and spectral data. PMP=4-MeOC6H4.
for the determination of the rel-
ative stereochemistries of 2-syn-
optically pure form by using standard methodology. Enan-
tiopure 2-azetidinones (+)-1a–d were obtained as single cis-
enantiomers from imines of (R)-2,3-O-isopropylideneglycer-
aldehyde, by means of a Staudinger reaction with methoxy-
or phenoxyacetyl chloride in the presence of Et3N, followed
by sequential acidic acetonide hydrolysis and oxidative
Scheme 1. Regioselective preparation of a-allenic alcohols 2 in aqueous
media. Reagents and conditions: a) In, THF, NHCl4 (aq sat.), RT, 3–16 h.
cleavage.[11] Racemic compounds (Æ)-1e and (Æ)-1 f were
obtained as single cis-diastereoisomers, following our one-
pot method from N,N-di-(p-methoxyphenyl)glyoxal di-
imine.[12] 2-Azetidinone-tethered allenols 2a–k (Table 1)
were obtained by a metal-mediated Barbier-type carbonyl-
allenylation reaction of b-lactam aldehydes 1a–f in aqueous
media by using our previously described methodologies
(Scheme 1, Table 1).[9d,e] a-Allenyl alcohol (+)-2l was pre-
pared by boron trifluoridediethyletherate-induced condensa-
Scheme 2. Regioselective preparation of a-allenic alcohol (+)-2l in anhy-
drous media. Reagents and conditions: a) BF3.Et2O, CH2Cl2, À788C, 1 h.
tion of 4-oxoazetidine-2-carbaldehydes (+)-1a with propar-
gyltrimethylsilane (Scheme 2). When total diastereocontrol
Abstract in Spanish: Se ha descubierto una metodología para
la preparación de b-lactamas tricíclicas tensionadas estructu-
ralmente novedosas sin la intervención de metales. La piróli-
sis de alenoles-b-lactµmicos, que se prepararon en medio
acuoso mediante la alenilación carbonílica de 4-oxoazetidin-
2-carbaldehidos, constituye el primer ejemplo de cicloadición
Scheme 3. Preparation of (R)- and (S)-acetylmandelates 3. Reagents and
conditions: a) DCC, DMAP (cat), CH2Cl2, RT, 16 h (DCC=N,N-dicyclo-
hexylcarbodiimide; DMAP=4-dimethylaminopyridine).
intramolecular [2+2] en b-lactamas. Mención especial
merece la regioselectividad observada, pudiØndose controlar
and 2-anti-allenols. For any pair of syn- and anti-diastereo-
mers, the b-lactamic (H3) and carbinolic hydrogens of the 2-
syn-isomers were approximately d=0.05–0.2 ppm upfield of
y modular con un simple cambio en la sustitución del alque-
no.
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Synthesis of Tricyclic b-Lactams
FULL PAPER
formal [2+2] cycloaddition of the alkene with the distal
bond of the allene, most likely via a diradical intermediate.
The regioselectivity of the process is not affected by the sub-
stitution at the allene carbon. The cyclization of the allene
(+)-2l results in a somewhat slower rate of reaction, but
with similar regioselectivity.[16] Substitution patterns in enal-
lenes (+)-2a, (+)-2b, and (+)-2l were selected in order to
direct the regioselectivity of the cycloaddition to the six-
membered central-ring formation. However, it was found
that the thermal reaction produced tricycles 4, which bear a
central seven-membered ring. No traces of the exocyclic
methylene regioisomer were detected.
Figure 1. X-ray diffraction analysis of a-allenol anti-(Æ)-2j.
In a similar manner, 3-vinyl allenols anti-(Æ)-2h and
(Æ)-2i produced the C3–C4fused tricyclic 2-azetidinones
(Æ)-5a and (Æ)-5b. The present reaction was successfully
extended to the enallenes (+)-2c and (+)-2d, terminally dis-
ubstituted at the alkene moieties, producing the tricyles
(+)-6a and (+)-6b (Scheme 5). No other isomers or side
the analogous hydrogens of the 2-anti-isomers, whilst oppo-
site behavior was observed for the other b-lactamic proton
(H4). For the stereoselective addition of the organometallic
reagents to b-alkoxyaldehydes 1a–d, 1,5-metal chelation be-
tween the C3-alkoxy substituent and the oxygen aldehyde
should preferentially orient towards a 1,2-anti selectivity.
The lack of 1,5-chelation in 4-oxoazetidine-2-carbaldehydes
1a–f, can favor either 1,2-syn (Cram–Felkin–Ahn control, b-
alkoxyaldehydes 1a–d) or 1,2-anti addition (anti-Cram–
Felkin–Ahn control, b-alkenylaldehydes (Æ)-1e and
(Æ)-1 f), depending on the nature of the C3-group and the
nucleophile; these results demonstrate that controlling the
stereoselectivitity of these reactions is not a trivial matter.
Although, in theory, intramolecular cycloaddition reac-
tions of b-lactam-dienes could be used to prepare tricycles,
such reactions involving 2-azetidinone-tethered alkenes
have not been reported in the literature. Because of the in-
herent instability imparted by the cumulated double bond in
allenes, cycloaddition reactions take place easily relative to
an isolated double bond. Having obtained the enallenols 2,
the next stage was to react the allene group as a 2p-electron
donor in the [2+2] process.
A model thermal cyclization reaction for the enallenes 2
was carried out by heating a solution of N-allyl a-allenol
(+)-2a in toluene at 2208C in a sealed tube. The thermolysis
afforded, in reasonable yield and complete regio- and dia-
stereoselectivity, the tricyclic b-lactam (+)-4a, which bears a
cyclobutane ring (Scheme 4).[15] Enallenes (+)-2b and
Scheme 5. Regio- and diastereoselective preparation of tricyclic b-lactams
5
and 6. Reagents and conditions: a) toluene, 2208C, sealed tube,
(Æ)-5a: 4.5 h, (Æ)-5b: 3.5 h, (+)-6a: 14h, ( +)-6b: 8 h.
products were detected. Although complete conversion was
1
observed by TLC and H NMR spectrosopic analysis of the
crude reaction mixtures, some decomposition of the sensi-
tive tricycles 5 and 6 was detected during purification by
flash chromatography; this may be responsible for the mod-
erate isolated yields obtained in some cases.
Our observed regioselectivity for the thermal [2+2] cyclo-
addition is remarkable as it contrasts previously reported re-
lated examples in which the 2p-component was the internal
double bond of the allene moiety.[17] Only Padwa et al. have
reported a similar regioselectivity in their study of intramo-
lecular [2+2] cycloaddition reactions of (phenylsulfonyl)-
enallenes, which were used for the preparation of bicyclo-
[4.2.0]octene systems,[18] related to compounds 5. However,
Scheme 4. Regio- and diastereoselective preparation of tricyclic b-lactams
4. Reagents and conditions: a) toluene, 2208C, sealed tube, (+)-4a: 5 h,
(+)-4b: 3 h, (À)4c: 10 h.
(+)-2l also efficiently undergo [2+2] thermal cyclization to
afford the corresponding strained tricycles (+)-4b and
(À)-4c. The tricyclic ring structures 4a–c arise from the
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B. Alcaide, P. Almendros et al.
these authors were not able to prepare bicyclo-
[5.2.0]nonenes, related to compounds 4 and 6, obtaining in-
stead monocyclic-substituted cyclooctenes.[18]
(Scheme 7). There are several interesting features that are
noteworthy from this study. First, the regioselectivity. Upon
use of enallenol (Æ)-2k, both the [2+2] cycloaddition prod-
As substitution at every position of the alkene moiety in
2-azetidinone-tethered enallenols is possible, the effect of a
substituent at the internal position of the alkene double
bond was studied. Exposure of N-methallyl allenols (+)-2e–
g to the above thermal treatment afforded methylenecyclo-
butane 2-azetidinones (+)-7a–c as the only products
1
(Scheme 6). No other isomer was detected in the H NMR
Scheme 6. Regio- and diastereoselective preparation of tricyclic b-lactams
7. Reagents and conditions: a) toluene, 2208C, sealed tube, (+)-7a: 5 h,
(+)-7b: 8 h, (+)7c: 7 h.
spectrum of the crude reaction mixtures. The regioselective
1
Scheme 7. Preparation of strained tricyclic b-lactams 8–11. Reagents and
conditions: a) toluene, 2208C, sealed tube, (Æ)-8, (Æ)-9a: 2 h; (Æ)-10,
(Æ)-11: 1.5 h; (Æ)-9b: 2 h.
assignment is based on the H NMR pattern of the vinylic
protons. Of the possible regioisomers, only compounds 7
were formed, as is apparent from the H NMR spectra in
1
which the vinylic groups appear as two sharp singlets at d=
4.95–4.99 and 4.97–5.01 ppm. Additional signals for com-
pounds 7 appeared as a multiplet or doublets at d=2.54–
2.82 ppm, suggesting the presence of only a methylene
group on the cyclobutane ring. Vinylic proton signals were
uct at the internal double bond (Æ)-10 and the unexpected
distal cycloadduct (Æ)-11 were obtained in 40% and 13%
yields, respectively. Full regiocontrol was achieved for enal-
lenes anti-(Æ)-2j and anti-(Æ)-2k. Second, the diastereose-
lectivity. The C3-isopropenyl a-allenols employed in
Scheme 7 are structurally equivalent to the N-methallyl a-al-
lenols of Scheme 6. However, the thermal treatment of enal-
lene anti-(Æ)-2j resulted in a mixture of two separable dia-
stereomers. The intramolecular cycloaddition of anti-(Æ)-2k
provided the tricycle (Æ)-9b in 40% yield as a single regio-
and diastereomer. The stereochemical relationship of tricy-
cle (Æ)-8 was established by X-ray diffraction analysis
(Figure 2).[21] To see if the [2+2] cycloaddition reaction is re-
versible, the separated cycloadducts (Æ)-8, (Æ)-9a, (Æ)-9b,
(Æ)-10, and (Æ)-11 were subjected to the reaction condi-
tions again. However, after heating a solution of the separat-
ed cycloadducts 8–11 in toluene at 2208C in a sealed tube
for 8 h, they remained unaltered.
1
not detected by H NMR spectroscopy for tricycles 4–6. In
fact, adducts 4 and 5 produced several multiplets (d=1.61–
3.58 ppm) in the 1H NMR spectra corresponding to two
methylene groups on the cyclobutane ring. However, the
13C NMR spectra for compounds 7 produced one signal at
d=113.6–113.7 ppm, characteristic of the C=CH2 vinylic
carbon atom of compounds 7.
Notably, the presence of an internal substituent on the
alkene moiety switched the regioselectivity. The successful
reversal of regioselectivity in the allene component, just by
a subtle variation in the substitution of the alkene moiety, is
an important development. In our case, it allowed for the
preparation of a diverse array of structurally novel strained
tricyclic b-lactams. For example, enantiopure compounds
7a–c are remarkable as they bear two quaternary stereogen-
ic centers.[19] As a result of steric congestion, the stereocon-
trolled construction of carbon atoms containing four carbon
ligands, all-carbon quaternary centers, is a formidable chal-
lenge for chemical synthesis. This challenge is magnified
when the central carbon is stereogenic.[20]
Thermal [2+2] cycloaddition reactions,[22] normally helped
by Lewis acids, are much less common than photochemical
ones,[23] and usually they are assumed to occur through the
participation of dipolar or diradical intermediates. In our
case, when a catalytic amount of hydroquinone was added,
the reaction rate was considerably reduced and the product
yield fell dramatically. This fact is consistent with the in-
volvement of a radical mechanism. The formation of fused,
strained tricycles 4–6 can be rationalized by a mechanism
that includes an exocyclic diradical intermediate 12 through
To further explore the regio- and diastereoselectivity of
the present formal [2+2] cycloaddition, the reactions of 2-
azetidinones anti-(Æ)-2j, (Æ)-2k, and anti-(Æ)-2k, bearing
an isopropenyl group on one side (C3) and the allenol
moiety on the other side (C4), were investigated
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Synthesis of Tricyclic b-Lactams
FULL PAPER
Scheme 9. Rationalization for the thermal preparation of strained tricy-
clic b-lactams 7–10.
Figure 2. X-ray diffraction analysis of tricyclic b-lactam (Æ)-8.
initial carbon–carbon bond formation involving the central
allene and proximal alkene carbon atoms (path A,
Scheme 8). An alternative mechanism for the thermal reac-
group exclusively produced addition at the b,g-double bond,
while the enallenes 2e–g,j,k, which bear a methyl group at
the internal olefinic carbon underwent a formal [2+2] cyclo-
addition reaction at the a,b-double bond. Path A
(Scheme 8) looks valid for the formation of products 4–6.
For this case, the Me group at R3 stabilizes the exocyclic di-
radical, and the presence of the double bond promotes the
allylic radical 12 over the alternate endocyclic vinylic radical
13 in path B. However, it could be presumed that for the
formation of compounds 7–10, path D (Scheme 9) is more
reasonable. The simultaneous stabilization of the endocyclic
diradical 15 by the presence of a methyl substituent and al-
lylic stabilization makes this radical favored over the exocy-
clic diradical 14. Substitution on the allene moiety affects
the rate of the reaction, presumably by influencing the sta-
bility of the allylic portion of the resulting exocyclic diradi-
cal intermediate 12. Thus, for example, cyclization of the
enallenol (+)-2l requires 10 h for completion, whereas the
reaction of substituted analogues (+)-2a and (+)-2b is com-
plete in 5 h and 3 h, respectively.
Scheme 8. Rationalization for the thermal preparation of strained tricy-
clic b-lactams 4–6.
tion, which leads to tricyclic 2-azetidinones 4–6 is proposed
in path B (Scheme 8). This pathway involves an endocyclic
diradical intermediate 13, arising from the initial attack of
the terminal olefinic carbon onto the distal allene carbon.
For both pathways, the final step must involve a rapid ring-
closure of the diradical intermediates, before bond rotation
can occur.
Analogously, the thermal formation of fused, strained tri-
cycles 7–10 can be rationalized by a mechanism which in-
cludes an exocyclic diradical intermediate 14 through initial
carbon–carbon bond formation involving the proximal
allene and internal alkene carbon atoms (path C, Scheme 9).
An alternative pathway leading to tricyclic 2-azetidinones 7–
10 is proposed in path D (Scheme 9). This proposal involves
an endocyclic diradical intermediate 15, arising from the ini-
tial attack of the terminal olefinic carbon onto the central
allene carbon. The final ring-closing step of the diradical in-
termediates accounts for the cyclobutane formation.
The structures and stereochemistries of compounds 4–11
were assigned by NMR spectroscopic studies. The cis-stereo-
chemistry of the four-membered b-lactam ring was set
during the cyclization step to form the 2-azetidinone nu-
cleus, and it was transferred unaltered during the following
synthetic steps. The tricyclic structures (by DEPT, HMQC,
HMBC, and COSY) and the stereochemical relationships
(by vicinal proton couplings and qualitative homonuclear
NOE difference spectra) of fused cyclobutane b-lactams 4–
11 were established by NMR spectroscopic one- and two-di-
mensional techniques. This structural and configurational as-
signment was confirmed by an X-ray diffraction analysis of
the cycloadduct (Æ)-8, which is the major product from the
cyclization of enallenol (Æ)-2j.[24]
Selected NOE enhancements which are in agreement
with the proposed stereochemistries are shown in Figure 3.
As an example, NOE irradiation of the less shielded proton
of the C2 methylene group (trinem numbering) in com-
pound (+)-6b gave an increment both on the H3 proton
(7%) and the H8 proton (4%). Irradiation of the more
shielded proton of the C2 methylene group in compound
(+)-6b resulted in a 4% increment on the signal corre-
It seems that the regioselectivity in this type of [2+2] cy-
cloaddition reaction is determined by the presence or ab-
sence of an alkyl substituent at the internal alkene carbon
atom, as the enallenes 2a–d,h,i,l that are lacking a methyl
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B. Alcaide, P. Almendros et al.
the a,b-double bond. Taking both of these observations to-
gether, this cyclization reaction has the potential to signifi-
cantly extend the utility of the allenol moiety in synthesis.
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, except when otherwise stated. Chemical shifts
are given in ppm relative to TMS (1H, d=0.0 ppm), or CDCl3 (13C, d=
76.9 ppm). Low and high resolution mass spectra were taken on a
HP5989A spectrometer by using the electronic impact (EI) or electro-
spray (ES) modes, unless otherwise stated. Specific rotation [a]D is given
in 10À1 degcm2 gÀ1 at 208C, and the concentration (c) is expressed in
g per 100 mL. All commercially available compounds were used without
further purification. Aldehydes (+)-1a,[11a] (+)-1d,[11b] (Æ)-1e,[12b] and
(Æ)-1 f.[12b] were prepared according to our previously reported proce-
dures. Data for a-allenols (+)-2a, (+)-2b, (Æ)-2h, (Æ)-2i, and (+)-2l
can be found in reference [9e], whilst data for tricycles (+)-4a, (+)-4b,
and (Æ)-5a can be found in the Supporting Information of the prelimina-
ry communication for this paper.[10]
General procedure for the preparation of strained tricyclic b-lactams 4–
11: A solution of the corresponding enallenol 2 (0.20 mmol) in toluene
(10 mL) was heated in a sealed tube at 2208C until the starting material
had been consumed (determined by TLC analysis). The reaction mixture
was allowed to cool to room temperature, and then the solvent was re-
moved under reduced pressure. After purification by flash chromatogra-
phy tricycles 4–11 were obtained. Spectroscopic and analytical data for
some representative forms of compounds 4–11 follow.[25]
Tricycle (+)-6b: By starting from enallenol (70 mg, 0.22 mmol) (+)-2d,
followed by chromatography of the product residue (hexanes/EtOAc
3:1), compound (+)-6b (40 mg, 57%) was produced as a colorless oil;
Rf =0.30 (hexanes/EtOAc 3:1); 1H NMR (300 MHz, CDCl3, 258C): d=
7.31 (m, 5H; ArH), 4.66 (d, J=0.8 Hz, 1H; H8), 4.53 (dd, J=4.6, 1.2 Hz,
1H; H10), 4.01 (dd, J=12.7, 5.6 Hz, 1H; NCHH), 3.86 (dd, J=4.6,
1.0 Hz, 1H; H9), 3.64(s, 3H, OMe), 3.40 (m, 1H, NCH H), 2.98 (m, 1H;
H3), 2.63 (m, 2H, H5+H5’), 1.70 (d, J=1.7 Hz, 1H; OH), 1.19 and
1.09 ppm (s, each 3H; Me (”2)); 13C NMR (75 MHz, CDCl3, 258C): d=
165.9 (C11), 142.7, 139.8, 135.1, 128.2 (Ar), 127.9, 126.5 (Ar), 84.5 (C10),
72.6 (C8), 59.6 (C9), 59.5 (OMe), 49.9 (C3), 43.3 (C5), 39.8, 32.9, 29.7
(Me), 23.9 ppm (Me); IR (CHCl3): n˜ =3215, 1742 cmÀ1; MS (ES): m/z
(%): 314(100) [ M+H]+, 313 (12) [M]+; elemental analysis (%) calcd for
C19H23NO3 (313.4): C 72.82, H 7.40, N 4.47; found C 72.95, H 7.36, N
4.44.
Figure 3. Selected NOE spectroscopic data for tricyclic b-lactams 4–11.
sponding to one of the C4methyl groups. Irradiation of the
H3 proton in compound (+)-6b gave a NOE enhancement
on the other C4methyl hydrogens (5%), together with a
4% increment on the signal of the H8 proton. As another
example, irradiation of the H3 hydrogen (trinem number-
ing) in compound (Æ)-9b resulted in a 6% increment on
the H2 proton and an absence of NOE enhancement on the
phenyl signals. NOE irradiation of the protons on the
methyl group in compound (Æ)-9b gave a 4% increment on
the phenyl hydrogens, but no enhancement was observed on
the H8 proton. Similar figures were observed on performing
NOE experiments for the rest of tricycles 4–11.
Tricycle (+)-7a: By starting from enallenol (58 mg, 0.19 mmol) (+)-2e,
followed by chromatography of the product residue (hexanes/EtOAc
3:1), compound (+)-7a (32 mg, 56%) was produced as a colorless oil;
1
Rf =0.32 (hexanes/EtOAc 3:1); [a]D =+21.5 (c=0.8 in CHCl3); H NMR
(300 MHz, CDCl3, 258C): d=7.31 (m, 5H; ArH), 4.97 and 4.95 (s, each
1H; =CH2), 4.57 (d, J=5.1 Hz, 1H; H9), 4.03 (m, 3H; NCHH, H7+H8),
3.82 (d, J=15.5 Hz, 1H; NCHH), 3.64(s, 3H; OMe), 2.76 (s, 1H; H4),
2.74(s, 1H; H4 ’), 1.75 ppm (s, 3H; Me); 13C NMR (75 MHz, CDCl3,
258C): d=167.8 (C10), 139.9 (C=CH2), 131.6 (Ar), 128.3 (Ar), 128.1,
123.1, 113.7 (C=CH2), 84.9, 83.1 (C9), 75.7, 69.2 (C7), 59.7, 59.5, 47.8
(NCH2), 25.0 (C4); 20.3 (Me); IR (CHCl3): n˜ =3223, 1750 cmÀ1; MS
(ES): m/z (%): 300 (100) [M+H]+, 299 (9) [M]+; elemental analysis (%)
calcd for C18H21NO3 (299.4): C 72.22, H 7.07, N 4.68; found C 72.19, H
7.04, N 4.71.
Conclusion
In conclusion, we have presented a convenient metal-free
methodology for the synthesis of racemic and enantiopure
strained tricyclic b-lactams containing a cyclobutane ring by
means of intramolecular formal [2+2] cycloaddition reac-
tions in 2-azetidinone-tethered enallenols. Interestingly, the
regioselectivity of this thermal cyclization is determined by
the presence or absence of an alkyl substituent at the inter-
nal alkene carbon atom. Enallenols lacking a methyl group
exclusively produced addition at the b,g-double bond, while
enallenols bearing a methyl group at the internal olefinic
carbon underwent a formal [2+2] cycloaddition reaction at
Preparation of tricycles (Æ)-8 and (Æ)-9a: By starting from a-allenic al-
cohol (75 mg, 0.25 mmol) (Æ)-2j, followed by chromatography of the
product residue (hexanes/EtOAc 5:1), the less polar compound (Æ)-8
(30 mg, 40%) and the more polar compound (Æ)-9a (15 mg, 20%) were
obtained.
Tricycle (Æ)-8: Colorless solid; m.p. 113–1158C; Rf =0.23 (hexanes/
1
EtOAc 5:1); H NMR (300 MHz, CDCl3, 258C): d=7.45 and 6.85 (d, J=
1544
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Chem. Eur. J. 2006, 12, 1539 – 1546

Synthesis of Tricyclic b-Lactams
FULL PAPER
9.0 Hz, each 2H; ArH), 4.85 (t, J=2.2 Hz, 2H; =CH2), 4.57 (dd, J=5.8,
4.6 Hz, 1H; H2), 4.07 (brs, 1H; H3), 3.78 (s, 3H; OMe), 3.38 (d, J=
4.6 Hz, 1H; H8), 3.19 (dt, J=16.0, 1.9 Hz, 1H; H6), 2.51 (dt, J=16.0,
2.9 Hz, 1H; H6’), 1.75 (brs, 1H; OH), 1.26 (s, 3H; Me), 1.15 ppm (s, 3H;
Me); 13C NMR (75 MHz, CDCl3, 258C): d=165.8 (C9), 156.1, 151.2 (C=
CH2), 131.6, 118.6 (Ar), 114.2 (Ar), 106.9 (C=CH2), 82.5 (C2), 62.8, 61.2,
61.1, 55.4(OMe), 14.3, 37.8 (C6), 21.9 (Me), 20.5 ppm (Me); IR
(CHCl3): n˜ =3310, 1734cm À1; MS (EI): m/z (%): 300 (20) [M+H]+, 299
(100) [M]+; elemental analysis (%) calcd for C18H21NO3 (299.4): C 72.22,
H 7.07, N 4.68; found C 72.09, H 7.03, N 4.70.
Pecunioso, F. Busi, S. A. Contini, D. Donati, M. Maffeis, D. A. Pizzi,
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[5] 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 selected examples,
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Tricycle (Æ)-9a: Colorless solid; m.p. 120–1228C; Rf =0.12 (hexanes/
1
ETOAc 5:1); H NMR (300 MHz, CDCl3, 258C): d=7.48 and 6.85 (d, J=
9.0 Hz, each 2H; ArH), 4.85 (t, J=2.7 Hz, 1H; =CHH), 4.79 (t, J=
1.7 Hz, 1H; =CHH), 4.72 (t, J=4.4 Hz, 1H; H2), 4.51 (d, J=5.1 Hz, 1H;
H3), 3.71 (s, 3H; MeO), 3.43 (d, J=4.1 Hz, 1H; H8), 2.54 (dt, J=15.0,
2.7 Hz, 1H; H6), 2.35 (dt, J=15.0, 1.7 Hz, 1H, H6’), 1.59 (brs, 1H; OH),
1.36 (s, 3H; Me), 1.06 ppm (s, 3H, Me); 13C NMR (75 MHz, CDCl3,
258C): d=166.1 (C9), 156.0, 151.9 (C=CH2), 120.3, 118.5 (Ar), 114.1
(Ar), 103.9 (C=CH2), 80.2 (C2), 62.2, 61.1, 59.5, 55.3 (OMe), 44.3, 42.9
(C6), 18.0 (Me), 13.1 ppm (Me); IR (CHCl3): n=3312, 1738 cmÀ1; MS
(EI): m/z (%): 300 (21) [M+H]+, 299 (100) [M]+; elemental analysis (%)
calcd for C18H21NO3 (299.4): C 72.22, H 7.07, N 4.68; found C 72.33, H
7.10, N 4.66.
Tricycle (Æ)-9b: By starting from enallenol anti-(Æ)-2k (40 mg,
0.11 mmol), followed by chromatography of the product residue (hex-
anes/EtOAc 2:1), compound (Æ)-9b (16 mg, 40%) was produced as a
1
colorless oil; Rf =0.30 (hexanes/EtOAc 2:1); H NMR (300 MHz, CDCl3,
258C): d=7.25 (m, 7H; ArH), 6.82 (d, J=9.0 Hz, 2H; ArH), 5.20 (t, J=
2.5 Hz, 1H; =CHH), 5.13 (brs, 1H; =CHH), 4.81 (t, J=5.3 Hz, 1H; H2),
4.61 (d, J=5.5 Hz, 1H; H3), 3.71 (s, 3H; OMe), 3.56 (d, J=4.5 Hz, 1H;
H8), 2.48 and 2.61 (dt, J=10.2, 1.5 Hz, each H; H6+H6’), 1.68 (brs, 1H;
OH), 1.91 ppm (s, 3H; Me); 13C NMR (75 MHz, CDCl3, 258C): d=165.1
(C9), 155.9, 149.2, 134.9 (C=CH2), 132.1, 129.1 (Ar), 128.3 (Ar), 127.0
(Ar), 118.3 (Ar), 114.0 (Ar), 109.1 (C=CH2), 80.3 (C2), 70.8, 63.2, 62.3,
55.3 (OMe), 47.1 (C7), 43.5 (C6), 20.7 ppm (Me); IR (CHCl3): n˜ =3240,
1733 cmÀ1; MS (EI): m/z (%): 362 (25) [M+H]+, 361 (100) [M]+; elemen-
tal analysis (%) calcd for C23H23NO3 (361.4): C 76.43, H 6.41, N 3.88;
found C 76.30, H 6.37, N 3.91.
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Acknowledgements
Support for this work by the DGI-MCYT (Project BQU2003–07793-
C02–01) is gratefully acknowledged. C.A. and M.C.R. thank the CAM
and MEC, respectively, for predoctoral grants.
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1545

B. Alcaide, P. Almendros et al.
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[21] X-ray data for (Æ)-8: crystallized from EtOAc/n-hexane at 208C;
C18H21NO3 (Mr =299.36); triclinic; space group=PÀ1; a=6.8434(8),
b=7.4150(8), c=16.0555(18) Š; a=82.663(2), b=87.921(2), g=
76.361(2)8; V=785.24(15) Š3; Z=2; 1calcd =1.266 mgmÀ3
;
m=
0.086 mmÀ1; F(000)=320. A transparent crystal of dimensions 0.08”
0.28”0.32 mm3 was used. 2727 [R(int)=0.0531] independent reflec-
tions were collected on a Bruker Smart CCD difractomer using
graphite-monochromated MoKa radiation (l=0.71073 Š). Data were
collected over a hemisphere of the reciprocal space by combination
of three exposure sets. Each exposure of 20 s and 30 s covered 0.3 in
w. The structure was solved by direct methods and Fourier synthesis.
It was refined by full-matrix least-squares procedures on F2
(SHELXL-97). The nonhydrogen atoms were refined anisotropical-
ly. The hydrogen atoms were refined only in terms of their coordi-
nates. CCDC-254723 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
[14] X-ray data of anti-(Æ)-2j: crystallized from EtOAc/n-hexane at
208C; C18H21NO3 (Mr =299.36); monoclinic; space group=P2(1)/n;
a=11.8192(16), b=8.0200(11), c=17.379(2) Š; a=90, b=91.320(3),
g=908;
V=1646.9(4) Š3;
Z=4;
1calcd =1.207 mgmÀ3
;
m=
0.082 mmÀ1; F(000)=640. A transparent crystal of dimensions 0.11”
0.17”0.20 mm3 was used; 2883 [R(int)=0.1020] independent reflec-
tions were collected on a Bruker Smart CCD difractomer with
graphite-monochromated MoKa radiation (l=0.71073 Š). Data were
collected over a hemisphere of the reciprocal space by combination
of three exposure sets. Each exposure of 20 s and 30 s covered 0.3 in
w. The structure was solved by direct methods and Fourier synthesis.
It was refined by full-matrix least-squares procedures on F2
(SHELXL-97). The nonhydrogen atoms were refined anisotropical-
ly. The hydrogen atoms were refined only in terms of their coordi-
nates. CCDC-254722 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
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[15] The methodology of the asymmetric formation of cyclobutane deriv-
atives is limited in preparative organic chemistry. For an example
see: Methods of Organic Chemistry, Vol. E17e (Ed.: A. de Meijere),
Houben-Weyl, Thieme, Stuttgart, 1997.
[16] It has been reported that different substitution patterns at the allene
moiety (double bonds tethered either to the a-position or the g-posi-
tion of the allene) switched the regioselectivity of the [2+2] cycload-
dition of phenylsulfonyl enallenes. See: A. Padwa, H. Lipka, S. H.
Watterson, S. S. Murphree, J. Org. Chem. 2003, 68, 6238.
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[24] Taking into account that allenic alcohols 2 could be obtained and cy-
clized to tricyclic b-lactams, the stereochemistry at the carbinolic
stereogenic center for compounds 2 was immediately deduced by
comparison with the NOE and X-Ray spectroscopic results for the
tricyclic b-lactams 4–11.
[25] Full spectroscopic and analytical data for compounds not included
in this Experimental Section are described in the Supporting Infor-
mation.
[20] For reviews see: a) I. Denissova, L. Barriault, Tetrahedron 2003, 59,
10105; b) A. Mann, J. Christoffers, Angew. Chem. 2001, 113, 4725;
Angew. Chem. Int. Ed. 2001, 40, 4591; ; c) E. J. Corey, A. Guzmµn-
Received: July 13, 2005
Published online: November 18, 2005
1546
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Chem. Eur. J. 2006, 12, 1539 – 1546