Stereoselective entry to bicyclic β-lactams via free radical cyclization of 2-azetidinone-tethered bromohomoallylic alcohols

Article abstract of DOI:10.1055/s-2005-869985

Triphenyltin hydride-promoted reaction of β-lactamtethered bromodienes gave six-, seven-, or eight-membered bicyclic ring structures through intramolecular free radical cyclization. The cyclization precursors were synthesized by stereoselective tin-mediated carbonyl bromoallylation of 4-oxoazetidine-2-carbaldehydes in an aqueous environment. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869985

PAPER
2335
Stereoselective Entry to Bicyclic b-Lactams via Free Radical Cyclization of
2-Azetidinone-Tethered Bromohomoallylic Alcohols
Stereoselective
E
e
ntryto Bic
n
b
-
Lact a
i
m
s
to Alcaide,*a Pedro Almendros,*b Raquel Rodríguez-Acebesa
a
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, 28040-Madrid, Spain
Fax +34(91)3944103; E-mail: alcaideb@quim.ucm.es
b
Instituto de Química Orgánica General, CSIC, Juan de la Cierva 3, 28006-Madrid, Spain
Fax +34(91)564853; E-mail: iqoa392@iqog.csic.es
Received 16 February 2005; revised 7 April 2005
dehydes.7 It was found that the Barbier-type
bromoallylation reaction of b-lactam aldehydes promoted
by tin in the presence of catalytic amounts of different
Lewis or Brønsted acids in aqueous media was efficient.
Abstract: Triphenyltin hydride-promoted reaction of b-lactam-
tethered bromodienes gave six-, seven-, or eight-membered bicyclic
ring structures through intramolecular free radical cyclization. The
cyclization precursors were synthesized by stereoselective tin-me-
diated carbonyl bromoallylation of 4-oxoazetidine-2-carbaldehydes For the current work, bismuth(III) chloride was found to
in an aqueous environment.
be the additive of choice. Under the optimized conditions,
the carbonyl bromoallylation of aldehydes 1 gave the cor-
responding bromohomoallylic alcohols 2 in good yields
with high diastereoselectivities (Scheme 1). Additionally,
a,b-unsaturated esters were found to be completely unre-
active under these conditions, and the chemoselective bro-
moallylation of 4-oxoazetidine-2-carbaldehydes (+)-1c
and (+)-1d bearing an a,b-unsaturated ester moiety was
possible. None of the 1,4-addition product was obtained,
giving exclusively the alcohols (+)-2c and (+)-2d by ste-
reoselective addition to the aldehyde moiety. Sometimes,
bromohomoallylic alcohols anti-2 were obtained as a mi-
nor component from the metal-mediated bromoallylation
of aldehydes 1. Fortunately, in all cases the diastereomeric
alcohols 2 and anti-2 could be easily separated by gravity
flow chromatography.
Since their introduction in 1982,8 vinyl radical cycliza-
tions have proved to be extremely popular in organic syn-
thesis for the synthesis of five- or six-membered rings.9
The formation of rings with seven or more atoms results
in unfavorable reaction rates because the addition step is
often too slow to allow it to compete successfully with
other pathways open to the radical intermediate. Although
construction of medium-sized rings using free radical
methodology is difficult to achieve,10 we and others were
able to prepare medium-sized rings fused to 2-azetidin-
ones.11 In this context, it was planned to investigate this
closure strategy on some bromohomoallylic alcohols 2
bearing an extra alkene tether (Scheme 2). The tin-pro-
moted radical reaction of bromodienic alcohol (+)-2a
gave the eight-membered ring fused-b-lactam (+)-3 to-
gether with the homoallylic alcohol (+)-4. While the free
radical cyclization proceeded elegantly in bromodiene
(+)-2c to provide the desired non-conventional bicyclic b-
lactam (+)-5 as single isomer, bromodienes (+)-2b and
(+)-2d did not afford the desired bicycles. The 1-vinyl-3-
hydroxy-6-hexenyl radical (radical numbering) derived
from bromide ( )-2e afforded the seven-membered ring
fused bicycle ( )-6 which prevailed over the isomeric
product ( )-7 containing a six-membered ring. Triphenyl-
tin hydride-promoted cyclization of bromodiene ( )-2f af-
Key words: carbonyl additions, cyclizations, lactams, radical reac-
tions, tin
The stereodivergent synthesis of chiral b-lactams remains
a worthwhile goal for synthetic organic chemists. The de-
velopment of new derivatives of b-lactam antibiotics and
inhibitors of b-lactamases, as well as structure-activity re-
lationship studies, this has resulted in the synthesis of a
new structural type having the 2-azetidinone ring as a
common feature.1 In contrast to the diastereoselective ad-
dition of propenylmetal compounds to chiral aldehydes,
which is one of the most important reactions for the con-
struction of a carbon skeleton,2 the analogous reaction in-
volving bromoallylmetals has been scarcely investigated,3
despite the synthetic utility of the bromovinyl moiety in
bromohomoallylic alcohols.4 In view of our interest in the
synthesis of b-lactams and other nitrogenated compounds
of biological interest,5 efforts were directed towards ex-
ploring the metal-mediated bromoallylation of 4-oxoaze-
tidine-2-carbaldehydes/free radical reaction sequence, as
a novel stereocontrolled access to bicyclic b-lactams.
Isomerically pure aldehydes 1a–f were obtained follow-
ing our previously reported procedures.5,6 Enantiopure 2-
azetidinones 1a–d were obtained as single cis-enantio-
mers from imines [(R)-2,3-O-isopropylideneglyceralde-
hyde], through a Staudinger reaction with the appropriate
alkoxyacetyl chloride in the presence of triethylamine,
followed by sequential acidic acetonide hydrolysis,
and oxidative cleavage.5 Racemic compounds ( )-1d and
( )-1e were obtained as single cis-diastereoisomers, fol-
lowing our one-pot method from N,N-di(p-methoxyphe-
nyl)glyoxal diimine.6
Recently, we have developed protocols for coupling be-
tween 2,3-dibromopropene and 4-oxoazetidine-2-carbal-
SYNTHESIS 2005, No. 14, pp 2335–2340
x
x.
x
x
.
2
0
0
5
Advanced online publication: 27.06.2005
DOI: 10.1055/s-2005-869985; Art ID: T02005SS
© Georg Thieme Verlag Stuttgart · New York

2336
B. Alcaide et al.
PAPER
OH Br
OH Br
H
H
N
H
H
N
H
H
N
Br
MeO
MeO
MeO
O
a)
Br
+
+
R1
R1
Me
Me
O
O
O
R1
R1
(+)-1a R1 = H
(+)-1b R1 = Me
(+)-2a (70%)
(+)-2b (61%)
anti-(+)-2b (5%)
CO2Me
CO2Me
OH Br
H
H
N
H
O
H
N
Br
O
O
a)
Br
+
O
PMP
O
PMP
(+)-1c
(+)-2c (78%)
OH Br
OH Br
H
H
N
H
H
N
H
H
N
Br
MeO
MeO
MeO
O
a)
Br
+
+
O
O
O
CO2Me
(+)-1d
CO2Me
CO2Me
(+)-2d (64%)
anti-(+)-2d (6%)
OH Br
OH Br
H
H
N
H
H
N
H
H
N
Br
R2
R2
R2
a)
O
Br
+
+
O
PMP
O
PMP
O
PMP
(±)-1e R2 = H
(±)-1f R2 = Me
(±)-2e (88%)
(±)-2f (67%)
anti-(±)-2e (8%)
anti-(±)-2f (8%)
Scheme 1 Stereoselective preparation of bromohomoallylic alcohols 2 in aqueous media. Reagents and conditions: a) Sn, BiCl3, THF–H2O,
r.t.
OH
forded the expected fused 2-azetidinone ( )-8 as a single
isomer in fair yield.
OH Br
OH
H
H
N
H
H
N
H
H
N
MeO
MeO
MeO
a)
+
The bicyclic structures (by DEPT, HMQC, HMBC, and
COSY) and the stereochemistry (by vicinal proton cou-
plings and qualitative homonuclear NOE difference spec-
tra) of fused b-lactams 3 and 5–8 were established by one-
and two-dimensional NMR techniques. Taking into ac-
count that optically pure bromohomoallylic alcohols 2
could be obtained and cyclized, the stereochemistry for
adducts 2 was immediately deduced by comparison with
the NOE results of the bicyclic systems. The cis-stereo-
chemistry of the four-membered ring is set during the cy-
clization step to form the 2-azetidinone ring, and it is
transferred unaltered during further synthetic steps.
O
O
O
(+)-2a
(+)-3 (57%)
(+)-4 (17%)
CO2Me
MeO2C
OH Br
H
O
H
N
O
H
OH
a)
H
N
O
PMP
O
PMP
(+)-2c
(+)-5 (46%)
OH Br
H
H
N
Me
OH
H
OH
a)
H
H
H
+
In conclusion, we have shown that a combination of met-
al-mediated carbonyl-bromoallylation reaction and free
radical cyclization constitutes a novel stereocontrolled ac-
cess to fused bicyclic b-lactams of non-conventional
structure. These results open up the possibility of future
application to chiral building blocks other than 2-azetidi-
nones.
N
N
O
PMP
O
PMP
O
PMP
( )-2e
( )-6 (37%)
( )-7 (29%)
OH Br
H
H
N
Me
H
OH
a)
H
N
O
PMP
O
PMP
All commercially available compounds were used without further
( )-8 (40%)
( )-2f
1
purification. H NMR and 13C NMR spectra were recorded on a
Bruker AMX-500, Bruker Avance-300, Varian VRX-300S, or
Bruker AC-200. NMR spectra were recorded in CDCl3 solutions,
except where otherwise stated. Chemical shifts are given in ppm rel-
ative to TMS (1H, 0.0 ppm), or CDCl3 (13C, 76.9 ppm). Elemental
Scheme 2 Preparation of bicyclic b-lactams 3–7 via free radical cy-
clization of bromodienes 1. Reagents and conditions: a) Ph3SnH,
AIBN, C6H6, reflux (p-MeOPh = PMP).
Synthesis 2005, No. 14, 2335–2340 © Thieme Stuttgart · New York

PAPER
Stereoselective Entry to Bicyclic b-Lactams
IR (CHCl3): 3432, 1742 cm–1.
1H NMR (300 MHz): d = 1.69 (s, 3 H), 1.74 (s, 3 H), 2.61 (dd, 1 H,
J = 14.4, 5.6 Hz), 2.74 (dd, 1 H, J = 14.4, 8.1 Hz), 3.64 (s, 3 H), 3.65
(dd, 1 H, J = 8.7, 5.0 Hz), 3.71 (dd, 1 H, J = 16.6, 8.3 Hz), 4.04 (dd,
1 H, J = 14.9, 5.9 Hz), 4.19 (dt, 1 H, J = 7.6, 4.9 Hz), 4.55 (d, 1 H,
J = 4.9 Hz), 5.14 (m, 1 H), 5.54 (d, 1 H, J = 1.5 Hz), 5.72 (d, 1 H,
J = 1.5 Hz).
2337
analyses were obtained at the UCM Microanalysis Service (Facul-
tad de Farmacia, UCM, Madrid). Low and high resolution mass
spectra were taken on a HP5989A spectrometer using CI modes un-
less otherwise stated. Electrospray ionization (ESI) was performed
on a Bruker ESQUIRE LC at 400 eV. Specific rotation [a]D is given
in deg cm2 g–1 at 20 °C, and the concentration (c) is expressed in g
per 100 mL.
13C NMR (75 MHz): d = 166.4, 137.8, 129.6, 119.2, 116.9, 83.8,
67.7, 59.2, 58.3, 45.7, 38.1, 25.5, 17.7.
MS (EI): m/z = 320 [M(81Br)+, 98], 318 [M(79Br)+, 100].
Bromohomoallylic Alcohols; General Procedure
2,3-Dibromopropene (600 mg, 3 mmol) was added to a well stirred
suspension of the appropriate aldehyde 1 (1.0 mmol), Sn powder
(178 mg, 1.5 mmol), and BiCl3 (63 mg, 0.2 mmol) in THF–H2O
(1:1, 10 mL) at r.t. After disappearance of the starting material
(TLC), sat aq NaHCO3 (10 mL) was added at 0 °C, and the mixture
was allowed to warm to r.t., before being extracted with EtOAc
(3 × 10 mL). The organic extract was washed with brine, dried
(MgSO4), and concentrated under reduced pressure. Chromatogra-
phy of the residue (hexanes–EtOAc) gave analytically pure com-
pounds 2.
Anal. Calcd for C13H20NO3Br: C, 49.07; H, 6.34; N, 4.40. Found: C,
48.95; H, 6.30; N, 4.38.
3-[2-(3-Bromo-(R)-1-hydroxybut-3-enyl)-1-(4-methoxyphe-
nyl)-(2S,3R)-4-oxoazetidin-3-yloxy]acrylic Acid Methyl Ester
[(+)-2c]
From (+)-1c (168 mg, 0.55 mmol); 183 mg (78%) of compound
(+)-2d was obtained as a colorless oil after purification by flash
chromatography (hexanes–EtOAc, 2:1).
(3R,4S)-1-Allyl-4-[(R)-3-bromo-1-hydroxybut-3-enyl]-3-meth-
oxyazetidin-2-one [(+)-2a]
[a]D +145.7 (c 1.0, CHCl3).
Prepared from (+)-1a (106 mg, 0.63 mmol); 128 mg (70%) of com-
pound (+)-2a was obtained as a colorless oil after purification by
flash chromatography (hexanes–ethyl acetate, 1:1).
IR (CHCl3): 3430, 1742, 1715 cm–1.
1H NMR (300 MHz): d = 2.36 (br s, 1 H), 2.64 (m, 2 H), 3.71 (s, 3
H), 3.78 (s, 3 H), 4.39 (m, 2 H), 5.18 (d, 1 H, J = 4.6 Hz), 5.56 (d, 1
H, J = 1.9 Hz), 5.59 (d, 1 H, J = 13.2 Hz), 5.69 (d, 1 H, J = 1.2 Hz),
6.86 (d, 2 H, J = 9.0 Hz),7.45 (d, 2 H, J = 9.0 Hz), 7.59 (d, 1 H,
J = 12.2 Hz).
13C NMR (75 MHz): d = 167.1, 161.5, 159.7, 157.0, 130.1, 128.7,
120.5, 120.3, 114.1, 100.5, 80.7, 68.9, 60.1, 55.4, 51.3, 45.5.
[a]D +44.9 (c 1.0, CHCl3).
IR (CHCl3): 3430, 1741 cm–1.
1H NMR (300 MHz): d = 2.60 (br s, 1 H), 2.64 (s, 1 H), 2.67 (d, 1
H, J = 1.0 Hz), 3.63 (s, 3 H), 3.76 (t, 1 H, J = 4.5 Hz), 3.83 (dt, 1 H,
J = 6.8, 1.1 Hz), 4.10 (dt, 1 H, J = 5.4, 1.6 Hz), 4.21 (m, 1 H), 4.52
(d, 1 H, J = 5.1 Hz), 5.22 (d, 1 H, J = 1.0 Hz), 5.29 (dq, 1 H, J = 7.6,
1.2 Hz), 5.56 (d, 1 H, J = 1.7 Hz), 5.72 (d, 1 H, J = 1.2 Hz), 5.79 (m,
1 H).
MS (EI): m/z = 427 [M(81Br)+, 18], 425 [M(79Br)+, 18], 149 [100].
Anal. Calcd for C18H20NO6Br: C, 50.72; H, 4.73; N, 3.29. Found: C,
50.80; H, 4.80; N, 3.26.
13C NMR (75 MHz): d = 167.4, 132.0, 129.5, 120.0, 118.7, 83.3,
68.4, 59.9, 59.5, 45.7, 44.2.
MS (EI): m/z = 291 [M(81Br)+, 98], 289 [M(79Br)+, 100].
Bromohomoallyl Alcohol (+)-2d
Prepared from (+)-1d (155 mg, 0.73 mmol); 156 mg (64%) of the
less polar compound (+)-2d and 14 mg (6%) of the more polar com-
pound, its anti-epimer were obtained after purification by column
chromatography (hexanes–EtOAc, 2:1).
Anal. Calcd for C11H16NO3Br: C, 45.53; H, 5.56; N, 4.83. Found: C,
45.62; H, 5.54; N, 4.80.
Bromohomoallyl Alcohol (+)-2b
2-[2-(3-Bromo-(R)-1-hydroxybut-3-enyl)-3-methoxy-(2S,3R)-4-
oxoazetidin-1-yl]acrylic Acid Methyl Ester [(+)-2d]
Colorless oil; [a]D +75.1 (c 0.9, CHCl3).
IR (CHCl3): 3429, 1741, 1648 cm–1.
Prepared from (+)-1b (145 mg, 0.73 mmol); 143 mg (61%) of the
less polar compound (+)-2b and 12 mg (5%) of the more polar com-
pound, its anti-epimer were obtained after purification by column
chromatography (hexanes–EtOAc, 2:1).
1H NMR (300 MHz): d = 2.53 (m, 3 H), 3.65 (s, 3 H), 3.80 (s, 3 H),
4.22 (m, 1 H), 4.51 (t, 1 H, J = 5.0 Hz), 4.64 (d, 1 H, J = 5.4 Hz),
5.53 (d, 1 H, J = 1.7 Hz), 5.67 (d, 1 H, J = 1.2 Hz), 6.05 (s, 1 H),
6.15 (s, 1 H).
(3R,4S)-4-[(R)-3-Bromo-1-hydroxybut-3-enyl]-3-methoxy-1-(3-
methylbut-2-enyl)azetidin-2-one [(+)-2b]
Colorless oil; [a]D +41.8 (c 1.0, CHCl3).
IR (CHCl3): 3434, 1740 cm–1.
13C NMR (75 MHz): d = 166.7, 163.5, 131.6, 129.5, 120.0, 117.8,
1H NMR (300 MHz): d = 1.67 (s, 3 H), 1.74 (s, 3 H), 2.64 (d, 2 H,
J = 6.3 Hz), 3.61 (s, 3 H), 3.72 (t, 1 H, J = 4.5 Hz), 3.76 (dd, 1 H,
J = 15.4, 7.6 Hz), 4.09 (dd, 1 H, J = 15.4, 6.1 Hz), 4.18 (td, 1 H,
J = 6.5, 4.0 Hz), 4.47 (d, 1 H, J = 4.9 Hz), 5.15 (m, 1 H), 5.56 (d, 1
H, J = 1.5 Hz), 5.70 (d, 1 H, J = 1.5 Hz).
83.6, 68.5, 61.9, 59.9, 52.7, 45.6.
MS (EI): m/z = 358 [M(81Br)+, 98], 356 [M(79Br)+, 100].
Anal. Calcd for C12H16NO5Br: C, 43.13; H, 4.83; N, 4.19. Found: C,
43.20; H, 4.80; N, 4.17.
13C NMR (75 MHz): d = 167.0, 137.3, 129.6, 119.7, 117.8, 83.2,
68.2, 59.4, 59.3, 45.5, 38.3, 25.5, 17.9.
MS (EI): m/z = 320 [M(81Br)+, 98], 318 [M(79Br)+, 100].
2-[2-(3-Bromo-(S)-1-hydroxybut-3-enyl)-3-methoxy-(2S,3R)-4-
oxoazetidin-1-yl]acrylic Acid Methyl Ester [anti-(+)-2d]
Colorless oil; [a]D +80.6 (c 1.1, CHCl3).
IR (CHCl3): 3430, 1741, 1647 cm–1.
Anal. Calcd for C13H20NO3Br: C, 49.07; H, 6.34; N, 4.40. Found: C,
49.17; H, 6.38; N, 4.37.
1H NMR (300 MHz): d = 2.68 (m, 3 H), 3.69 (s, 3 H), 3.82 (s, 3 H),
4.24 (m, 1 H), 4.53 (dd, 1 H, J = 5.1, 3.7 Hz), 4.71 (d, 1 H, J = 5.4
Hz), 5.55 (d, 1 H, J = 1.7 Hz), 5.72 (d, 1 H, J = 1.2 Hz), 6.11 (s, 1
H), 6.26 (s, 1 H).
(3R,4S)-4-[(S)-3-Bromo-1-hydroxybut-3-enyl]-3-methoxy-1-(3-
methylbut-2-enyl)azetidin-2-one [anti-(+)-2b]
Colorless oil; [a]D +61.5 (c 1.3, CHCl3).
Synthesis 2005, No. 14, 2335–2340 © Thieme Stuttgart · New York

2338
B. Alcaide et al.
PAPER
13C NMR (75 MHz): d = 166.3, 163.1, 130.7, 129.6, 119.7, 117.6,
MS (EI): m/z = 368 [M(81Br)+, 35], 366 [M(79Br)+, 35], 149 [100].
84.4, 68.8, 61.7, 59.9, 52.8, 45.7.
MS (ES): m/z = 358 [M(81Br)+, 98], 356 [M(79Br)+, 100].
Anal. Calcd for C17H20NO3Br: C, 55.75; H, 5.50; N, 3.82. Found: C,
55.89; H, 5.47; N, 3.80.
Anal. Calcd for C12H16NO5Br: C, 43.13; H, 4.83; N, 4.19. Found: C,
43.22; H, 4.81; N, 4.21.
(3RS, 4SR)-4-[(SR)-3-Bromo-1-hydroxybut-3-enyl]-3-isopro-
penyl-1-(4-methoxyphenyl)azetidin-2-one [anti-( )-2f]
Colorless oil.
IR (CHCl3): 3430, 1745 cm–1.
1H NMR (300 MHz): d = 1.93 (s, 3 H), 2.15 (br s, 1 H), 2.47 (dd, 1
H, J = 14.4, 9.8 Hz), 2.71 (d, 1 H, J = 14.1 Hz), 3.80 (s, 3 H), 4.10
(d, 1 H, J = 5.9 Hz), 4.29 (m, 1 H), 4.40 (dd, 1 H, J = 6.2, 3.8 Hz),
5.25 (t, 1 H, J = 1.3 Hz), 5.28 (d, 1 H, J = 1.0 Hz), 5.53 (dd, 1 H,
J = 1.7, 0.5 Hz), 5.64 (m, 1 H), 6.89 (d, 2 H, J = 9.0 Hz), 7.50 (d, 2
H, J = 9.0 Hz).
Bromohomoallyl Alcohol [( )-2e]
Prepared from ( )-1e (230 mg, 0.996 mmol); 309 mg (88%) of the
less polar compound ( )-2e and 27 mg (8%) of the more polar com-
pound, its anti-epimer were obtained after purification by column
chromatography (CH2Cl2–EtOAc, 20:1),
(3RS,4SR)-4-[(RS)-3-Bromo-1-hydroxybut-3-enyl]-1-(4-meth-
oxyphenyl)-3-vinylazetidin-2-one [( )-2e]
Colorless solid; mp 119–120 °C (hexanes–EtOAc).
IR (KBr): 3431, 1741 cm–1.
13C NMR (75 MHz): d = 165.6, 156.6, 136.9, 131.3, 129.7, 120.7,
119.9, 117.7, 114.2, 68.3, 59.6, 57.7, 55.6, 46.0, 23.3.
1H NMR (300 MHz): d = 2.26 (d, 1 H, J = 3.9 Hz), 2.53 (dd, 1 H,
J = 14.5, 8.9 Hz), 2.69 (d, 1 H, J = 14.4 Hz), 3.78 (s, 3 H), 4.00 (dd,
1 H, J = 8.8, 5.6 Hz), 4.21 (m, 2 H), 5.43 (ddd, 1 H, J = 10.0, 1.5,
0.5 Hz), 5.47 (dt, 1 H, J = 17.1, 1.5 Hz), 5.55 (d, 1 H, J = 1.5 Hz),
5.69 (s, 1 H), 5.99 (ddd, 1 H, J = 17.1, 10.0, 8.8 Hz), 6.85 (d, 2 H,
J = 9.0 Hz), 7.47 (d, 2 H, J = 9.0 Hz).
13C NMR (75 MHz): d = 165.8, 156.7, 131.2, 129.0, 128.8, 122.8,
120.7, 120.6, 114.1, 70.3, 59.2, 55.6, 55.1, 45.9.
MS (EI): m/z = 353 [M(81Br)+, 22], 351 [M(79Br)+, 22], 149 [100].
MS (EI): m/z = 368 [M(81Br)+, 27], 366 [M(79Br)+, 27], 149 [100].
Anal. Calcd for C17H20NO3Br: C, 55.75; H, 5.50; N, 3.82. Found: C,
55.62; H, 5.47; N, 3.84.
Free Radical Cyclization of Bromohomoallylic Alcohols 2; Gen-
eral Procedure
A solution of the appropriate vinyl bromide 2 (0.40 mmol), triphe-
nyltin hydride (0.60 mmol) and AIBN (cat.) in benzene (35 mL)
was heated at reflux until the starting material had completely dis-
appeared (TLC). The reaction mixture was allowed to cool to r.t.,
the solvent was removed under reduced pressure, and bicycles 3 and
5–8 were obtained after purification by flash chromatography on
silica gel (hexanes–EtOAc–Et3N).
Anal. Calcd for C16H18NO3Br: C, 54.56; H, 5.15; N, 3.98. Found: C,
54.65; H, 5.11; N, 4.00.
(3RS,4SR)-4-[(SR)-3-Bromo-1-hydroxybut-3-enyl]-1-(4-meth-
oxyphenyl)-3-vinylazetidin-2-one, [anti-( )-2e]
Colorless oil.
IR (CHCl3): 427, 1739 cm–1.
1H NMR (300 MHz): d = 2.17 (d, 1 H, J = 5.7 Hz), 2.68 (m, 2 H),
3.80 (s, 3 H), 4.09 (dd, 1 H, J = 8.5, 5.9 Hz), 4.28 (dd, 1 H, J = 5.9,
2.9 Hz), 4.53 (m, 2 H), 5.38 (dd, 1 H, J = 11.0, 1.0 Hz), 5.45 (dt, 1
H, J = 18.3, 1.3 Hz), 5.56 (d, 1 H, J = 1.7 Hz), 5.70 (d, 1 H, J = 1.7
Hz), 6.25 (ddd, 1 H, J = 17.1, 10.2, 8.9 Hz), 6.90 (d, 2 H, J = 9.0
Hz), 7.41 (d, 2 H, J = 9.0 Hz).
Bicycle (+)-3
Prepared from (+)-2a (51 mg, 0.18 mmol); 8 mg (17%) of the less
polar compound (+)-4 and 16 mg (57%) of the more polar com-
pound (+)-3 were obtained after purification by column chromatog-
raphy (hexanes–EtOAc, 1:1; 1% Et3N).
(7R,8S,9R)-7-Hydroxy-9-methoxy-5-methylene-1-azabicy-
clo[6.2.0]decan-10-one [(+)-3]
Colorless oil; [a]D +113.4 (c 0.5, CHCl3).
IR (CHCl3): 3434, 1744 cm–1.
13C NMR (75 MHz): d = 165.4, 156.6, 130.7, 130.0, 129.4, 121.8,
1H NMR (300 MHz): d = 2.03 (m, 1 H), 2.22 (m, 1 H), 2.35 (m, 1
H), 2.45 (ddd, 1 H, J = 14.3, 5.1, 0.8 Hz), 2.60 (dd, 1 H, J = 14.3,
6.2 Hz), 3.02 (br s, 1 H), 3.13 (ddd, 1 H, J = 14.8, 9.1, 1.7 Hz), 3.63
(s, 3 H), 3.64 (m, 2 H), 3.89 (dd, 1 H, J = 4.8, 1.3 Hz), 4.18 (t, 1 H,
J = 5.4 Hz), 4.50 (dd, 1 H, J = 4.8, 0.6 Hz), 4.93 (s, 1 H), 4.95 (s, 1
H).
13C NMR (75 MHz): d = 167.4, 144.8, 117.8, 84.2, 68.1, 60.4, 60.0,
42.1, 40.1, 36.0, 25.3.
MS (EI): m/z = 211 [M+, 100].
120.5, 119.3, 114.6, 66.9, 58.7, 55.8, 55.6, 44.9.
MS (EI): m/z = 353 [M(81Br)+, 26], 351 [M(79Br)+, 26], 149 [100].
Anal. Calcd for C16H18NO3Br: C, 54.56; H, 5.15; N, 3.98. Found: C,
54.46; H, 5.12; N, 3.95.
Bromohomoallyl Alcohol ( )-2f
Prepared from ( )-1f (150 mg, 0.612 mmol); 153 mg (67%) of the
more polar compound ( )-2f and 18 mg (8%) of the less polar com-
pound, its anti-epimer, were obtained after purification by column
chromatography (hexanes–EtOAc,5:1).
Anal. Calcd for C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C,
62.65; H, 8.14; N, 6.60.
(3RS,4SR)-4-[(RS)-3-Bromo-1-hydroxybut-3-enyl]-3-isoprope-
nyl-1-(4-methoxyphenyl)azetidin-2-one [( )-2f]
Colorless oil.
IR (CHCl3): 3434, 1744 cm–1.
(3R,4S)-1-Allyl-4-[(R)-1-hydroxybut-3-enyl]-3-methoxyazeti-
din-2-one, [(+)-4]
Colorless oil; [a]D +52.1 (c 0.8, CHCl3).
1H NMR (300 MHz): d = 1.94 (s, 3 H), 2.19 (br s, 1 H), 2.59 (m, 2
H), 3.78 (s, 3 H), 4.00 (d, 1 H, J = 5.1 Hz), 4.28 (m, 2 H), 5.21 (d, 1
H, J = 0.7 Hz), 5.25 (t, 1 H, J = 1.5 Hz), 5.54 (dd, 1 H, J = 1.7, 0.5
Hz), 5.67 (m, 1 H), 6.86 (d, 2 H, J = 9.0 Hz), 7.46 (d, 2 H, J = 9.0
Hz).
13C NMR (75 MHz): d = 165.9, 156.9, 137.4, 131.2, 129.3, 121.1,
120.6, 118.9, 114.2, 69.7, 59.7, 57.7, 55.6, 46.1, 22.9.
IR (CHCl3): 3428, 1740 cm–1.
1H NMR (300 MHz): d = 2.29 (m, 2 H), 2.46 (br s, 1 H), 3.62 (s, 3
H), 3.72 (t, 1 H, J = 4.8 Hz), 3.87 (m, 2 H), 4.16 (ddt, 1 H, J = 15.7,
5.0, 1.6 Hz), 4.49 (d, 1 H, J = 4.9 Hz), 5.20 (m, 4 H), 5.83 (m, 2 H).
13C NMR (75 MHz): d = 167.9, 134.5, 132.4, 118.9, 118.7, 83.7,
70.3, 60.5, 59.9, 44.6, 39.0.
MS (EI): m/z = 211 [M+, 100].
Synthesis 2005, No. 14, 2335–2340 © Thieme Stuttgart · New York

PAPER
Stereoselective Entry to Bicyclic b-Lactams
2339
Anal. Calcd for C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C,
62.66; H, 8.08; N, 6.61.
(1RS,2RS,6RS,7SR)-6-Hydroxy-8-(4-methoxyphenyl)-2-meth-
yl-4-methylene-8-azabicyclo[5.2.0]nonan-9-one [( )-8]
Prepared from ( )-2f (57 mg, 0.134 mmol); 15 mg (40%) of com-
pound ( )-8 was obtained as a colorless oil after purification by
flash chromatography (CH2Cl2–EtOAc, 20:1, 1% Et3N).
(2R,6R,7S)-[6-Hydroxy-8-(4-methoxyphenyl)-4-methylene-9-
oxo-2-oxa-8-azabicyclo[5.2.0]non-3-yl]acetic Acid Methyl Ester
[(+)-5]
Prepared from (+)-2c (57 mg, 0.134 mmol); 21 mg (46%) of com-
pound (+)-5 was obtained as a colorless oil after purification by
flash chromatography (hexanes–EtOAc, 3:2; 1% Et3N).
IR (CHCl3): 3436, 1741 cm–1.
1H NMR (300 MHz): d = 1.22 (d, 3 H, J = 6.4 Hz), 1.94 (d, 1 H,
J = 5.9 Hz), 2.37 (m, 5 H), 3.10 (dd, 1 H, J = 7.3, 4.6 Hz), 3.78 (s,
3 H), 4.08 (m, 1 H), 4.25 (dd, 1 H, J = 13.7, 5.9 Hz), 4.84 (s, 1 H),
5.58 (s, 1H), 6.86 (d, 2 H, J = 9.0 Hz), 7.52 (d, 2 H, J = 9.0 Hz).
[a]D +58.2 (c 0.8, CHCl3).
IR (CHCl3): 3432, 1744, 1730 cm–1.
13C NMR (75 MHz): d = 168.1, 154.4, 133.4, 131.2, 125.5, 120.1,
1H NMR (300 MHz): d = 2.07 (br s, 1 H), 2.42 (dd, 1 H, J = 14.3,
8.8 Hz), 2.60 (dd, 1 H, J = 15.2, 6.3 Hz), 2.84 (dd, 1 H, J = 15.2, 7.2
Hz), 2.98 (dd, 1 H, J = 14.5, 6.4 Hz), 3.70 (s, 3 H), 3.79 (s, 3 H),
4.16 (dd, 1 H, J = 8.6, 3.5 Hz), 4.49 (q, 1 H, J = 8.0 Hz), 4.55 (t, 1
H, J = 3.9 Hz), 4.78 (d, 1 H, J = 3.9 Hz), 5.17 (s, 1 H), 5.20 (s, 1 H),
6.85 (d, 2 H, J = 9.0 Hz), 7.58 (d, 2 H, J = 9.0 Hz).
114.1, 63.9, 60.8, 57.8, 55.5, 53.0, 45.2, 40.1, 8.1.
MS (ES): m/z = 288 [M+ + 1, 100], 287 [M+, 22].
Anal. Calcd for C17H21NO3: C, 71.06; H, 7.37; N, 4.87. Found: C,
71.17; H, 7.33; N, 4.90.
13C NMR (75 MHz): d = 170.4, 162.5, 156.6, 143.0, 131.2, 119.5,
118.5, 114.2, 80.2, 79.8, 72.0, 62.6, 55.5, 52.0, 40.2, 38.9.
Acknowledgment
We would like to thank the DGI-MCYT (Project BQU2003-07793-
C02-01) for financial support. R. R.-A. thanks the MCYT for a pre-
doctoral grant.
MS (ES): m/z = 360 [M+ + 1, 11], 347 [100].
Anal. Calcd for C18H21NO6: C, 62.24; H, 6.09; N, 4.03. Found: C,
62.36; H, 6.12; N, 4.02.
References
Bicycles ( )-6 and ( )-7
Prepared from ( )-2e (45 mg, 0.13 mmol); 13 mg (37%) of the more
polar compound ( )-6 and 10 mg (29%) of the less polar compound
( )-7 were obtained after purification by column chromatography
(hexanes–EtOAc, 2:1; 1% Et3N).
(1) (a) Hot Topic: b-Lactams: Synthesis, Stereochemistry,
Synthons, and Biological Evaluation: Banik, B. K. Curr.
Med. Chem. 2004, 11, issue 14. (b) Walsh, C. Antibiotics:
Actions Origins Resistance; ASM Press: Washington DC,
2003. (c) Mascaretti, O. A. Bacteria versus Antibacterial
Agents; ASM Press: Washington DC, 2003. (d) Niccolai,
D.; Tarsi, L.; Thomas, R. J. Chem. Commun. 1997, 2333.
(e) The Chemistry of b-Lactams; Page, M. I., Ed.; Chapman
and Hall: London, 1992.
(1R,6R,7S)-6-Hydroxy-8-(4-methoxyphenyl)-4-methylene-8-
azabicyclo[5.2.0]nonan-9-one [( )-6]
Colorless oil.
IR (CHCl3): 3433, 1745 cm–1.
1H NMR (300 MHz): d = 1.87 (m, 2 H), 2.06 (m, 1 H), 2.32 (m, 2
H), 2.48 (m, 2 H), 3.57 (m, 1 H), 3.80 (s, 3 H), 4.35 (m, 2 H), 4.86
(d, 1 H, J = 2.2 Hz), 4.96 (d, 1 H, J = 2.2 Hz), 6.88 (d, 2 H, J = 9.0
Hz), 7.44 (d, 2 H, J = 9.0 Hz).
13C NMR (75 MHz): d = 167.2, 156.3, 144.9, 131.0, 119.3, 116.2,
114.4, 69.6, 59.6, 55.5, 51.6, 41.8, 35.4, 25.5.
(2) For reviews on allylmetal additions see: (a) Kennedy, J. W.
J.; Hall, D. G. Angew. Chem. Int. Ed. 2003, 42, 4732.
(b) Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763.
(c) Roush, W. R.; Chemler, C. R. In Modern Carbonyl
Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000,
Chap. 11. (d) Denmark, S. E.; Almstead, N. G. In Modern
Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim,
2000, Chap. 10. (e) Thomas, E. J. Chem. Commun. 1997,
411. (f) Marshall, J. A. Chem. Rev. 1996, 96, 31.
(g) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207.
(3) (a) Trost, B. M.; Coppola, B. P. J. Am. Chem. Soc. 1982,
104, 6879. (b) Mandai, T.; Nokami, J.; Yano, T.; Yoshinaga,
Y.; Otera, J. J. Org. Chem. 1984, 49, 172. (c) Kurosu, M.;
Lin, M.-H.; Kishi, Y. J. Am. Chem. Soc. 2004, 126, 12248.
(4) See for example: (a) Trost, B. M.; Corte, J. R.; Gudiksen, M.
S. Angew. Chem. Int. Ed. 1999, 38, 3662. (b) Crimmins, M.
T.; She, J. J. Am. Chem. Soc. 2004, 126, 12790.
MS (EI): m/z = 273 [M+, 100].
Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12. Found: C,
70.22; H, 7.04; N, 5.15.
(1RS,2RS,5RS,6SR)-5-Hydroxy-7-(4-methoxyphenyl)-2-meth-
yl-3-methylene-7-azabicyclo[4.2.0]octan-8-one [( )-7]
Colorless oil.
IR (CHCl3): 3432, 1743 cm–1.
1H NMR (300 MHz): d = 1.31 (d, 3 H, J = 6.6 Hz), 2.03 (d, 1 H,
J = 5.4 Hz), 2.38 (ddd, 1 H, J = 16.1, 9.0, 1.2 Hz), 2.55 (m, 2 H),
3.10 (dd, 1 H, J = 7.4, 6.0 Hz), 3.79 (s, 3 H), 4.07 (t, 1 H, J = 5.4
Hz), 4.27 (m, 1 H), 4.94 (s, 1H), 4.97 (s, 1 H), 6.88 (d, 2 H, J = 9.0
Hz),7.53 (d, 2 H, J = 9.0 Hz).
(5) See for instance: (a) Alcaide, B.; Almendros, P.; Alonso, J.
M. J. Org. Chem. 2004, 69, 993. (b) Alcaide, B.;
Almendros, P.; Redondo, M. C. Org. Lett. 2004, 6, 1765.
(c) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Rodríguez-
Acebes, R. J. Org. Chem. 2004, 69, 826. (d) Alcaide, B.;
Almendros, P.; Alonso, J. M. Chem.–Eur. J. 2003, 9, 5793.
(e) Alcaide, B.; Almendros, P.; Aragoncillo, C. Org. Lett.
2003, 5, 3795. (f) Alcaide, B.; Almendros, P.; Alonso, J. M.;
Aly, M. F. Chem.–Eur. J. 2003, 9, 3415.
13C NMR (75 MHz): d = 167.1, 156.1, 145.4, 131.3, 118.6, 114.4,
111.3, 68.6, 56.8, 55.5, 54.2, 37.1, 32.9, 19.1.
MS (ES): m/z = 296 [M+ + 23, 100], 273 [M+, 12].
Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12. Found: C,
70.42; H, 7.05; N, 5.10.
(6) (a) Alcaide, B.; Martín-Cantalejo, Y.; Plumet, J.; Rodríguez-
López, J.; Sierra, M. A. Tetrahedron Lett. 1991, 32, 803.
(b) Alcaide, B.; Martín-Cantalejo, Y.; Pérez-Castells, J.;
Rodríguez-López, J.; Sierra, M. A.; Monge, A.; Pérez-
García, V. J. Org. Chem. 1992, 57, 5921.
Synthesis 2005, No. 14, 2335–2340 © Thieme Stuttgart · New York

2340
B. Alcaide et al.
PAPER
interactions between the methylene groups. For reviews
see: (a) Galli, L.; Mandolini, L. Eur. J. Org. Chem. 2000,
3117. (b) Illuminati, G.; Mandolini, L. Acc. Chem. Res.
1981, 14, 95.
(7) Alcaide, B.; Almendros, P.; Rodríguez-Acebes, R. J. Org.
Chem. 2005, 71, 2713.
(8) Stork, G.; Baine, N. H. J. Am. Chem. Soc. 1982, 104, 2321.
(9) (a) Zard, S. Z. Radicals Reactions in Organic Synthesis;
Oxford University Press Inc.: New York, 2003. (b) Giese,
B.; Kopping, B.; Göbel, T.; Dickhaut, J.; Thoma, G.;
Kulicke, K. J.; Trach, F. Org. React. 1996, 48, 301.
(c) Motherwell, W. B.; Crich, D. Free Radical Chain
Reactions in Organic Synthesis; Academic Press: London,
1992. (d) Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem.
Rev. 1991, 91, 1237. (e) Curran, D. P. Synthesis 1988, 417.
(f) Curran, D. P. Synthesis 1988, 489.
(11) The only available examples are: (a) Deshmukh, A. R. A.
S.; Jayanthi, A.; Thiagarajan, K.; Puranik, V. G.; Bhawal, B.
M. Synthesis 2004, 2965. (b) Jayanthi, A.; Puranik, V. G.;
Deshmukh, A. R. A. S. Synlett 2004, 1249. (c) Alcaide, B.;
Almendros, P.; Pardo, C.; Rodríguez-Ranera, C.; Rodríguez-
Vicente, V. J. Org. Chem. 2003, 68, 3106. (d) Alcaide, B.;
Almendros, P.; Aragoncillo, C. J. Org. Chem. 2001, 66,
1612. (e) Penfold, D. J.; Pike, K.; Genge, A.; Anson, M.;
Kitteringham, J.; Kilburn, J. D. Tetrahedron Lett. 2000, 41,
10347. (f) Knight, J.; Parsons, P. J. J. Chem. Soc., Perkin
Trans. 1 1987, 1237. (g) Knight, J.; Parsons, P. J.;
Southgate, R. J. Chem. Soc., Chem. Commun. 1986, 78.
(10) The synthesis of medium-sized rings has usually been
hampered by entropic/enthalpic factors and transannular
Synthesis 2005, No. 14, 2335–2340 © Thieme Stuttgart · New York