Synthesis of 1β-methylcarbapenem antibiotic precursors by cyclization using π-allylpalladium complexes

Article abstract of DOI:10.1002/(SICI)1099-0690(199903)1999:3<621::AID-EJOC621>3.0.CO;2-A

An efficient diastereoselective multi-step synthesis of bicyclic 1β- methylcarbapenem antibiotic precursors has been developed, starting from the commercially available 4-acetoxyazetidin-2-one 4. Chiral ruthenium catalysts are used in the hydrogenation st

Full text of DOI:10.1002/(SICI)1099-0690(199903)1999:3<621::AID-EJOC621>3.0.CO;2-A

FULL PAPER
Synthesis of 1β-Methylcarbapenem Antibiotic Precursors by Cyclization
Using π-Allylpalladium Complexes
[a]
[a]
[a]
[a]
¨
Jean-Christophe Galland, Sylvain Roland, Joel Malpart, Monique Savignac,
and Jean-Pierre Genet*[a]
Keywords: 1β-Methylcarbapenems / Palladium / Ruthenium / Catalysis / Cyclizations / Stereoselective hydrogenation
An efficient diastereoselective multi-step synthesis of
bicyclic 1β-methylcarbapenem antibiotic precursors has
in the hydrogenation step to control the β-stereochemistry at
the 1-position, and a π-allylpalladium ring-closure strategy is
been developed, starting from the commercially available 4- used to form the functionalized carbapenem skeleton.
acetoxyazetidin-2-one 4. Chiral ruthenium catalysts are used
however, hydrogenation[6] of the exocyclic double bond
using non-chiral catalysts led to the expected 1-methyl com-
Introduction
Since the discovery by the Merck group in the early 1980s
of (ϩ)-thienamycin (1),[1] a natural fungal metabolite, the
carbapenems and, more recently, the 1β-methylcarbape-
nems 2,[2] have attracted considerable attention as some of
the more promising β-lactam antibiotics due to their chemi-
cal and metabolic stabilities as well as their potent antimi-
crobial activities. Owing to the lack of practical fermen-
tation methods, various synthetic efforts have been initiated
to construct the bicyclic skeleton of thienamycin and nu-
merous modifications have since been made aimed at in-
creasing its stability.[3] This has led to a wide family of car-
bapenem antibiotics with enhanced activities. The more
stable 1β-methylcarbapenems 2[4] have aroused particular
interest since the control of the the four stereogenic centers
represents an interesting synthetic challenge. Extensive
studies have shown the carboxylic acid 3, in which all the
stereogenic centers are installed, to be an effective inter-
mediate en route to such systems.
pound 7 as a 70:30 mixture of the β and α diastereomers.
Scheme 2
With the aim of increasing the diastereoselectivity and of
avoiding the final separation step, we developed a second
synthetic approach using π-allylpalladium methodology, in
which the configuration of the carbon atom at the 1-posi-
tion was easily controlled. Indeed, we envisaged that the
five-membered ring of the carbapenems could also be ob-
tained from a π-allylpalladium intermediate in which the
four stereogenic centers were already present prior to cycli-
zation (Scheme 3). This alternative approach appeared to
be particularly attractive as the 1-methyl configuration
could be introduced at an early stage of the synthesis by
hydrogenation of the allylic alcohol 8[7] under appropriate
conditions.[8] The 1β-methyl alcohol 9 could then be used
as a precursor of intermediates 15, suitable for the construc-
tion of the carbapenem skeleton.
Scheme 1
Recently, we succeeded in demonstrating the efficiency of
π-allylpalladium methodology in forming the five-mem-
bered ring of the carbapenems,[5] and we reported the syn-
thesis of bicyclic intermediates 6, which were obtained in
very good yields by cyclization of the appropriate benzoate
precursors 5 using catalytic Pd0 (Scheme 2). Unfortunately,
In this paper, we wish to report our multi-step prep-
aration of intermediates 15, as well as the results of studies
on the palladium-mediated cyclization reactions.
Results and Discussion
[a]
´
Ecole Nationale Superieure de Chimie de Paris, Laboratoire
The first key step of our procedure was to obtain the
1-methyl alcohol 9 with high diastereoselectivity. This was
efficiently achieved by catalytic hydrogenation of 8 using
chiral ruthenium complexes.[9] When the reaction was car-
`
´
de Synthese Selective Organique et Produits Naturels UMR
CNRS 7573,
11, rue Pierre et Marie Curie, F-75231 Paris, France
Fax: (internat.) ϩ 33-1/44071062
E-mail: genet@ext.jussieu.fr
Eur. J. Org. Chem. 1999, 621Ϫ626
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
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J.-C. Galland, S. Roland, J. Malpart, M. Savignac, J.-P. Genet
FULL PAPER
Scheme 3
ried out under 15 atm of hydrogen at 25°C in the presence
of the chiral ligand (R)-(ϩ)-BINAP, the β-methyl dia-
stereomer 9 was obtained in 90% yield with a de > 99%
(Scheme 4). The catalytically active species (R)-(ϩ)-Binap-
RuBr2 was easily obtained in situ by treatment of the com-
mercially available (cyclooctadiene)(2-methylallyl)2Ru com-
plex with the chiral ligand (R)-(ϩ)-BINAP and methanolic
hydrobromic acid solution. Similar diastereomeric excesses
could be achieved using the chiral ligand (R)-MeO-
BIPHEP.
Scheme 5. i) a) (ClCO)2, DMSO, CH2Cl2, Ϫ60°C, b) EtiPr2N; ii)
Ph3PϭCHCO2Et, THF, 60°C; iii) DIBALH, THF, Ϫ78°C; iv)
PhCOCl, Et3N, CH2Cl2, 0°C; v) LiHMDS, THF, BrCH2CO2Et,
Ϫ40°C; vi) LiHMDS, THF, Ϫ40°C, ClCO2Et or PhSSPh
Scheme 6
Scheme 4
Primary benzoates 15, suitable for use in the cyclization of two diastereomers. No reaction was observed at lower
study, were then obtained by Swern oxidation of the alcohol temperatures. Similar yields (45%) were obtained using pot-
9, which gave the expected aldehyde 10 in 84% yield, fol- assium hydride instead of sodium hydride (entry 2). These
lowed by Wittig reaction using (ethoxycarbonyl)methylene- reactions did not go to completion and we noticed that
triphenylphosphorane, which led quantitatively to the al- degradation and elimination reactions started to occur at
lylic ester 11 (Scheme 5). In this latter step, no epimeri- around 40°C. With E ϭ SPh (entry 3), no cyclized com-
zation of any of the stereogenic centers was detected. Re- pound was observed; only competitive degradation reac-
duction to the alcohol 12 using diisobutylaluminium tions occurred, in particular hydrogenolysis of the thi-
hydride followed by benzoylation gave the expected com- ophenyl group resulting in reversion to the monoester 14.
pound 13 in 80% yield. The azetidinone nitrogen atom was
To increase the yield of the desired reaction and to avoid
then alkylated using lithium hexamethyldisilazanide and competitive elimination reactions, especially in the case of
ethyl α-bromoacetate to give the ester 14 in 93% yield. The the thiophenyl group, we carried out the cyclization under
ethoxycarbonylmethyl chain on the nitrogen atom was sub- milder conditions. Specifically, we wanted to avoid the use
sequently treated with 2.4 equivalents of lithium hexa- of hydrides, which seemed to induce the degradation side-
methyldisilazanide and either ethyl chloroformate or di- reactions. We felt that the carbonate method described by
phenyl disulfide. In this way, the benzoates 15a and 15b Tsuji,[10] which involves the use of a carbonate rather than
were obtained in yields of 92% and 84%, respectively.
an acetate or a benzoate as the leaving group, might be
The palladium-catalyzed cyclization (Scheme 6) was first suitable as the reaction occurs under neutral conditions. In-
studied under the conditions that gave the best results in deed, during the formation of the π-allylpalladium inter-
our first synthetic approach.
mediate, the base (ethoxide) is gradually generated in situ
The anions of the two benzoates 15a and 15b were gener- in the reaction mixture with simultaneous evolution of car-
ated using sodium or potassium hydride as the base and the bon dioxide.
reactions were performed in THF in the presence of 0.2
In order to study this new approach, the appropriate al-
equivalent of Pd/dppe, preformed from Pd(OAc)2 and di- lylic carbonates 19 were synthesized from the allylic alcohol
phenylphosphanylethane at 25°C. The results of these cycli- 12 (Scheme 7). Derivatization of the latter with ethyl
zations are presented in Table 1.
chloroformate gave 17 in 96% yield. Subsequent steps of the
With E ϭ COOEt (entry 1), the cyclization occurred synthesis were the same as those in the case of the benzo-
within 2 h upon heating the solution at 60°C using sodium ates. Because of its instability, the crude thiophenyl inter-
hydride as the base, giving 16a in 48% yield as a mixture mediate was not isolated in this sequence, but was directly
622
Eur. J. Org. Chem. 1999, 621Ϫ626

1β-Methylcarbapenem Antibiotic Precursors by Cyclization Using π-Allylpalladium Complexes
FULL PAPER
oxidized to sulfone 19b using Oxone and wet alumina in Table 1. Results of the palladium-mediated cyclizations
refluxing chloroform.[11]
Entry Substrate Pd complex
Conditions
Yields[a]
1
2
3
4
5
6
7
15a
15a
15b
19a
19a
19a
19b
20% Pd/dppe[c] NaH, 60°C, 2 h 48%
20% Pd/dppe
20% Pd/dppe
20% Pd/dppe
100% Pd/dppe
KH, 60°C, 2 h 45%
NaH, 60°C, 2 h Ϫ[b]
60°C, 3 h
60°C, 2 h
30%
100%
67%
59%
10% Pd/dppb[d] 30°C, 0.5 h
10% Pd/dppb
30°C, 1 h
[a]
[b]
Yields of isolated compounds. Ϫ Degradation of the starting
material. Ϫ [c] Preformed from 20 mol-% Pd(OAc)2 and 30% dppe.
Ϫ
[d]
Preformed from 10 mol-% Pd(OAc)2 and 20% dppb.
Scheme 7. i) ClCO2Et, pyr, CH2Cl2, 0°C; ii) LiHMDS,
BrCH2CO2Et, Ϫ78°C, ClCO2Et; iii) LiHMDS, BrCH2CO2Et,
Ϫ78°C, ClCO2Et or a) LiHMDS, Ϫ78°C, PhSSPh, b) Oxone,
Al2O3, CHCl3, ∆T
carbonate as the leaving group and Pd/dppb as the catalyst.
This strategy has allowed us direct access to bicyclic com-
pounds 16 functionalized at the 2-position.
The results of the cyclizations are presented in Table 1
(entries 4Ϫ7). Our first attempt was run with diester 19a,
using 10% of the Pd/dppe complex in THF (entry 4). No
reaction was observed at temperatures below 60°C. At this
temperature, the cyclization appeared to be very slow and
stopped after 0.5 h. Increasing the temperature to reflux did
not improve the formation of the desired bicyclic com-
pound. Nevertheless, compared to the benzoate method,
the reaction was very clean and the cyclized compound 16a
was isolated in 30% yield with no degradation of the reco-
vered starting carbonate. In order to determine whether the
difficulties encountered in forming bicyclic compounds
were due to intramolecular steric factors or were directly
related to the catalyst, the same reaction was run using 1
equivalent of Pd/dppe (entry 5). To our surprise, the cy-
clized compound 16a was then obtained quantitatively,
showing that the phosphane used (dppe) was unsuitable and
probably led to the generation of an unstable palladium
catalyst at the temperature used for the reaction. A signifi-
cant improvement was achieved using the more Љopen“
phosphane diphenylphosphanylbutane (dppb) instead of
dppe (entry 6). Indeed, under these conditions, the cycliza-
tion occurred at a lower temperature of 30°C, reflecting the
increased reactivity of the catalyst. This reaction gave the
expected compound 16a in 67% yield within 0.5 h. Finally,
when the same reaction was performed with the sulfonyl
substrate 19b, the bicyclic intermediate 16b was obtained in
59% yield (entry 7). Reaction conditions (catalyst, ligand/
catalyst ratio, solvent, temperature, etc.) were not opti-
mized.
Experimental Section
General: All reactions were carried out under argon with exclusion
of moisture. Solvents were dried and distilled prior to use or were
HPLC grade. All reagents were of commercial origin and were
taken from freshly opened containers or distilled before use. Lith-
ium hexamethyldisilazanide (LiHMDS) was prepared in situ from
2.5  nBuLi in hexane and HMDS, which were allowed to react
for 30 min at Ϫ40°C in THF. Sodium and potassium hydrides,
stored as suspensions in oil, were washed with pentane prior to
use. Satd. NH4Cl denotes saturated aqueous ammonium chloride
solution. Ϫ 1H- and 13C-NMR spectra were recorded with a Bruker
AC 200 spectrometer. Ϫ Infrared spectra were recorded with a Per-
kin-Elmer 983G spectrophotometer. Ϫ Elemental analyses were
´
performed at the Regional Microanalysis Service (Universite
Pierre-et-Marie-Curie, Paris).
(3S,4R)-3-{(1R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-[(1S)-(2-
hydroxy-1-methyl)ethyl]azetidin-2-one (9): To a solution of 5 mg of
(ϩ)-(R)-Binap (1 mol-%) and 2.6 mg (1 mol-%) of (cod)(2-methyl-
allyl)2Ru in acetone (1 mL), was added 113 µL (0.018 mmol, 2.2
mol-%) of a 0.16  solution of hydrobromic acid in methanol. The
mixture was stirred for 30 min at 25°C and then the solvents were
removed under inert atmosphere. The residue was dried in vacuo
and a solution of the alcohol 8 (235 mg, 0.824 mmol) in methanol
(3 mL) was added. The resulting solution was stirred for 60 h at
25°C under hydrogen at 17 bar. The mixture was then concentrated
and the crude product was purified by flash chromatography on
silica gel (AcOEt/cyclohexane, 8:2) to give the expected compound
25
(213 mg, 90%) as a white solid; m.p. 86Ϫ88°C. Ϫ [α]D ϭ Ϫ17
(c ϭ 1.5, CHCl3). Ϫ IR: ν˜ ϭ 3370, 3060, 2915, 2840, 1755 cmϪ1
.
Ϫ 1H NMR (CDCl3): δ ϭ 6.46 (s, 1 H), 4.13 (dq, 1 H, J ϭ 6.2 and
8.9 Hz), 3.57 (dd, 1 H, J ϭ 4.6 and 11.8 Hz), 3.47 (dd, 1 H, J ϭ
8.4 and 11.8 Hz), 3.28 (dd, 1 H, J ϭ 1.7 and 8.9 Hz), 3.15 (dd, 1
H, J ϭ 2.1 and 8.9 Hz), 1.85 (m, 1 H), 1.35 (d, 3 H, J ϭ 6.2 Hz),
0.91 (s, 9 H), 0.90 (d, 3 H, J ϭ 7.6 Hz), 0.13 (s, 6 H). Ϫ 13C NMR
(CDCl3): δ ϭ 168.7, 68.2, 66.0, 62.3, 57.0, 40.1, 25.7, 22.8, 17.9,
13.3, Ϫ4.5, Ϫ4.6.
In summary, we have established a route to optically pure
1β-methylcarbapenem precursors using a π-allylpalladium
ring-closure strategy. In our procedure, the β-methyl stereo-
chemistry is efficiently controlled by hydrogenation in the
presence of chiral ruthenium catalysts. A practical six-step
synthesis of the precursors 15 and 19, suitable for use in
cyclization studies, has been developed starting from the β-
methyl alcohol 9, with overall yields ranging from 32% to
56%. The efficiency of the cyclization reaction has been
found to be closely related to the nature of the base and the
(3S,4R)-3-{(1R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-[(1S)-1-
(formyl)ethyl]azetidin-2-one (10): To a solution of 88 µL (1.01
mmol) of oxalyl chloride in CH2Cl2 (2 mL), a solution of DMSO
(167 µL, 2.354 mmol) in CH2Cl2 (2 mL) was added dropwise at
Ϫ60°C. The mixture was stirred for 30 min at Ϫ60°C and then a
phosphane used. The best results have been obtained using solution of the alcohol 9 (193 mg, 0.672 mmol) in CH2Cl2 (4 mL)
Eur. J. Org. Chem. 1999, 621Ϫ626 623

J.-C. Galland, S. Roland, J. Malpart, M. Savignac, J.-P. Genet
FULL PAPER
was added. After 1 h at the same temperature, 761 µL (4.371 mmol)
of diisopropylethylamine was added. The mixture was allowed to
ethylamine were added at 0°C. The mixture was stirred for 16 h at
0°C, then neutralized with 2 mL of satd. NH4Cl, and the aqueous
warm to 25°C, diluted with 8 mL of water, and extracted with layer was extracted with CH2Cl2. The combined organic layers were
AcOEt (3 ϫ 10 mL). The combined organic layers were washed
with water, dried with Na2SO4, filtered, and concentrated. The
crude residue was purified by flash chromatography on silica gel
dried with Na2SO4, filtered, and concentrated. The crude residue
was purified by flash chromatography on silica gel (AcOEt/cyclo-
hexane, 4:6) to give the expected compound (103 mg, 88%) as a
25
(AcOEt/cyclohexane, 8:2) to give the expected compound (161 mg, white solid; m.p. 84°C. Ϫ [α]D ϭ Ϫ24 (c ϭ 1.32, CHCl3). Ϫ IR:
25
1
84%) as a white solid; m.p. 70Ϫ75°C. Ϫ [α]D ϭ Ϫ17 (c ϭ 1.36, ν˜ ϭ 3410, 1755, 1710 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 8.2Ϫ7.85
1
CHCl3). Ϫ IR: ν˜ ϭ 1760, 1725 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ
(m, 5 H), 6.25 (s, 1 H), 5.85Ϫ5.68 (m, 2 H), 4.78 (d, 2 H), 4.2 (m,
1 H), 3.53 (dd, 1 H, J ϭ 7.8 and 2.1 Hz), 2.88 (m, 1 H), 2.81 (m,
9.76 (s, 1 H), 5.92 (s, 1 H), 4.2 (m, 1 H), 3.94 (dd, 1 H, J ϭ 2.3
and 5.4 Hz), 3.0 (dd, 1 H, J ϭ 2.3 and 5.2 Hz), 2.67 (m, 1 H), 1.23 1 H), 1.08 (d, 3 H, J ϭ 6.3 Hz), 1.05 (d, 3 H, J ϭ 6.7 Hz), 0.88 (s,
(d, 3 H, J ϭ 6.2 Hz), 1.21 (d, 3 H, J ϭ 7.2 Hz), 0.88 (s, 9 H), 0.08 9 H), 0.07 (s, 6 H). Ϫ 13C NMR (CDCl3): δ ϭ 168.9, 166.2, 136.1,
(s, 6 H). Ϫ 13C NMR (CDCl3): δ ϭ 202.3, 168.4, 65.6, 61.8, 50.4,
132.9, 129.5, 128.3, 125.3, 65.05, 64.98, 62.1, 54.7, 40.6, 25.7, 22.9,
49.3, 25.6, 22.5, 17.8, 9.2, Ϫ4.4, Ϫ5.0. Ϫ C14H27NO3Si (285.46): 17.8, 16.3, Ϫ4.4, Ϫ5.0. Ϫ C23H35NO4Si (417.62): calcd. C 66.15,
calcd. C 58.91, H 9.53, N 4.91; found C 58.92, H 9.45, N 4.79.
H 8.45, N 3.35; found C 66.02, H 8.35, N 3.25.
(3S,4R)-3-{(1R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-[(1S,2E)-(3-
ethoxycarbonyl-1-methyl)-1-propenyl]azetidin-2-one (11): A solution
of aldehyde 10 (70 mg, 0.246 mmol) and (ethoxycarbonyl)methy-
(3S,4R)-3-{(1R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-[(1S,2E)-(4-
benzoyloxy-1-methyl)-2-butenyl]-1-[(ethoxycarbonyl)methyl]azetidin-
2-one (14): To a solution of LiHMDS (0.1 mmol) in THF (1 mL),
lenetriphenylphosphorane (99 mg, 0.27 mmol) in THF (1 mL) was a solution of benzoate 13 (40 mg, 0.096 mmol) in THF (2 mL) was
stirred at 60°C for 2 h. The solvent was then removed, the residue
was redissolved in diethyl ether, and the resulting solution was
washed with water. The aqueous layer was extracted with ether.
The combined organic layers were washed with brine, dried with
MgSO4, and concentrated. The crude residue was purified by flash
chromatography on silica gel (AcOEt/cyclohexane, 1:1) to give the
added dropwise at Ϫ40°C. The mixture was stirred for 15 min at
Ϫ40°C and then cooled to Ϫ78°C, whereupon 19.5 µL (0.115
mmol) of ethyl 2-bromoacetate was added dropwise. The solution
was subsequently stirred for 2 h at Ϫ40°C and then neutralized by
the addition of 2 mL of satd. NH4Cl. The aqueous layer was ex-
tracted with AcOEt. The combined organic layers were dried with
expected compound (86 mg, 99%) as a white solid; m.p. 62°C. Ϫ Na2SO4, filtered, and concentrated. The crude residue was purified
[α]D25 ϭ Ϫ25 (c ϭ 1.2, CHCl3). Ϫ IR: ν˜ ϭ 1753, 1707, 1649 cmϪ1
1H NMR (CDCl3): δ ϭ 6.87 (dd, 1 H, J ϭ 15.7 and 7.8 Hz),
.
by flash chromatography on silica gel (AcOEt/cyclohexane, 2:8) to
give the expected compound (45 mg, 93%) as a colourless oil. Ϫ
Ϫ
6.2 (s, 1 H), 5.87 (dd, 1 H, J ϭ 15.7 and 1.2 Hz), 4.25Ϫ4.1 (m, 3 [α]D25 ϭ Ϫ34 (c ϭ 1.4, CHCl3). Ϫ IR: ν˜ ϭ 1765, 1740, 1710 cmϪ1
.
H), 3.6 (dd, 1 H, J ϭ 7.3 and 2.1 Hz), 2.82 (m, 1 H), 2.5 (m, 1 H),
1.28 (t, 3 H, J ϭ 7 Hz), 1.15 (d, 3 H, J ϭ 6.3 Hz), 1.14 (d, 3 H,
Ϫ
1H NMR (CDCl3): δ ϭ 8.1Ϫ8.0 (m, 2 H), 7.6Ϫ7.4 (m, 3 H),
6.0Ϫ5.7 (m, 2 H), 4.8 (s, 1 H), 4.77 (s, 1 H), 4.25Ϫ4.05 (m, 4 H),
J ϭ 10 Hz), 0.87 (s, 9 H), 0.07 (s, 6 H). Ϫ 13C NMR (CDCl3): δ ϭ 3.9Ϫ3.7 (m, 2 H), 2.88 (dd, 1 H, J ϭ 6.1 and 2 Hz), 2.64 (m, 1 H),
168.5, 166.0, 148.4, 122.2, 65.0, 62.1, 60.3, 54.0, 40.4, 25.6, 22.8,
17.8, 15.5, 14.1, Ϫ4.5, Ϫ5.0. Ϫ C18H33NO4Si (355.55): calcd. C
60.81, H 9.35, N 3.94; found C 60.90, H 9.20, N 3.80.
1.27 (t, 3 H, J ϭ 7.1 Hz), 1.23 (d, 3 H, J ϭ 6.1 Hz), 1.12 (d, 3 H,
J ϭ 6.8 Hz), 0.9 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H). Ϫ 13C NMR
(CDCl3): δ ϭ 168.1, 166.3, 135.9, 132.9, 129.5, 128.2, 125.4, 66.0,
65.1, 61.3, 60.3, 59.9, 42.3, 37.0, 25.7, 22.9, 17.7, 15.8, 14.0, Ϫ4.5,
Ϫ5.0. Ϫ C27H41NO6Si (503.71): calcd. C 64.38, H 8.20, N 2.78;
found C 64.33, H 8.08, N 2.81.
(3S,4R)-3-{(1R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-[(1S,2E)-(4-
hydroxy-1-methyl)-2-butenyl]azetidin-2-one (12): To a solution of es-
ter 11 (100 mg, 0.282 mmol) in THF (1.5 mL), 1.13 mL of a 1
 solution of diisobutylaluminium hydride in CH2Cl2 was added (3S,4R)-3-{(1R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-[(1S,2E)-(4-
dropwise at Ϫ78°C. The mixture was stirred for 2 h at Ϫ78°C and benzoyloxy-1-methyl)-2-butenyl]-1-[bis(ethoxycarbonyl)methyl]-
then for 0.5 h at 25°C. The solution was subsequently hydrolysed
at Ϫ78°C by the dropwise addition of 0.5 mL of water. After
warming to room temp., 0.5 mL of brine was added and the mix-
azetidin-2-one (15a): To a solution of LiHMDS (0.295 mmol) in
THF (1 mL), a solution of benzoate 14 (62 mg, 0.123 mmol) in
THF (1 mL) followed by 28 µL (0.295 mmol) of ethyl chloro-
ture was filtered through Celite by washing the solid residues with formate were added dropwise at Ϫ78°C. The resulting mixture was
AcOEt. The filtrate was dried with MgSO4, filtered, and concen-
trated. The residue was taken up in AcOEt, the resulting solution
was quickly filtered through silica gel, and concentrated to give 81
stirred for 2 h at Ϫ78°C, then neutralized with 1 mL of satd.
NH4Cl, and extracted with AcOEt. The combined organic layers
were dried with Na2SO4, filtered, and concentrated to give the ex-
mg (90%) of the expected compound as a white solid; m.p. 90°C. pected compound (65 mg, 92%) as a colourless oil. Ϫ 1H NMR
25
Ϫ [α]D ϭ Ϫ33 (c ϭ 0.76, CHCl3). Ϫ IR: ν˜ ϭ 3410, 1750, 1685
(CDCl3): δ ϭ 8.1Ϫ7.35 (m, 5 H), 6.0 (dd, 1 H, J ϭ 15.6 and 6 Hz),
1
cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 6.0 (s, 1 H), 5.8Ϫ5.55 (m, 2 H), 5.75 (dt, 1 H, J ϭ 15.6 and 6.1 Hz), 5.15 (s, 1 H), 4.8 (d, 2 H, J ϭ
4.25Ϫ4.1 (m, 3 H), 3.53 (dd, 1 H, J ϭ 7 and 2 Hz), 2.81 (m, 1 H), 6.1 Hz), 4.35Ϫ4.1 (m, 5 H), 4.08 (dd, 1 H, J ϭ 2.5 and 4.9 Hz),
2.37 (m, 1 H), 1.8 (m, 1 H), 1.17 (d, 3 H, J ϭ 6.3 Hz), 1.08 (d, 3 2.88 (dd, 1 H, J ϭ 2.5 and 6.3 Hz), 2.77 (m, 1 H), 1.4Ϫ1.15 (m, 9
H, J ϭ 6.7 Hz), 0.9 (s, 9 H), 0.07 (s, 6 H). Ϫ 13C NMR (CDCl3):
H), 1.11 (d, 3 H, J ϭ 6.8 Hz), 0.9 (s, 9 H), 0.08 (s, 3 H), 0.06 (s, 3
δ ϭ 169.4, 132.5, 130.4, 65.2, 63.1, 61.3, 54.8, 39.8, 25.7, 22.9, 17.8, H). Ϫ 13C NMR (CDCl3): δ ϭ 168.4, 166.2, 165.6, 164.8, 135.3,
16, Ϫ4.4, Ϫ5.0. Ϫ C16H31NO3Si (313.51): calcd. C 61.30, H 9.97,
N 4.47; found C 61.39, H 9.85, N 4.34.
132.8, 130.1, 129.5, 128.2, 125.5, 65.9, 65.3, 62.3, 62.2, 61.0, 60.3,
59.9, 56.9, 36.4, 25.7, 22.9, 17.8, 16.1, 13.8, Ϫ4.6, Ϫ4.7. Ϫ
C30H45NO8Si (575.77): calcd. C 62.58, H 7.88, N 2.43; found C
62.61, H 7.89, N 2.40.
(3S,4R)-3-{(1R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-[(1S,2E)-(4-
benzoyloxy-1-methyl)-2-butenyl]azetidin-2-one (13): To a solution of
alcohol 12 (88 mg, 0.28 mmol) in CH2Cl2 (3.5 mL), 36 µL (0.31 (3S,4R)-3-{(1R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-[(1S,2E)-(4-
mmol) of benzoyl chloride followed by 82 µL (0.59 mmol) of tri-
benzoyloxy-1-methyl)-2-butenyl]-1-{[(phenylthio)ethoxycarbonyl]-
624
Eur. J. Org. Chem. 1999, 621Ϫ626

1β-Methylcarbapenem Antibiotic Precursors by Cyclization Using π-Allylpalladium Complexes
FULL PAPER
methyl}azetidin-2-one (15b): To a solution of LiHMDS (0.48 mmol)
136.2, 124.9, 67.8, 65.9, 63.9, 61.3, 60.3, 59.8, 42.2, 37.1, 25.7, 22.9,
in THF (1 mL), a solution of benzoate 14 (100 mg, 0.2 mmol) in 17.8, 15.7, 14.2, Ϫ4.4, Ϫ4.8. Ϫ MS (EI); m/z: 456, 414. Ϫ
THF (1 mL) followed by a solution of diphenyl disulfide (104 mg,
0.48 mmol) in THF (0.5 mL) were added dropwise at Ϫ78°C. The
solution was stirred for 3.5 h at Ϫ78°C, then neutralized with 1
mL of satd. NH4Cl, and extracted with AcOEt. The combined or-
ganic layers were dried with Na2SO4, filtered, and concentrated.
The crude residue was purified by flash chromatography on silica
gel (AcOEt/cyclohexane, 2:8) to give the expected compound (102
mg, 84%) as a pale-yellow oil. The product was obtained as a mix-
C23H41NO7Si (471.66): calcd. C 58.57, H 8.76, N 2.97; found C
58.74, H 8.76, N 2.98.
(3S,4R)-3-{(1R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-[(1S,2E)-(4-
ethoxycarbonyloxy-1-methyl)-2-butenyl]-1-[bis(ethoxycarbonyl)-
methyl]azetidin-2-one (19a): To a solution of LiHMDS (0.88 mmol)
in THF (3 mL), a solution of carbonate 18 (173 mg, 0.367 mmol)
in THF (3 mL) followed by 84 µL (0.88 mmol) of ethyl chloro-
formate were added dropwise at Ϫ78°C. The resulting mixture was
stirred for 2 h at Ϫ78°C, then neutralized with satd. NH4Cl, and
extracted with AcOEt. The combined organic layers were dried
with Na2SO4, filtered, and concentrated. The crude residue was
purified by flash chromatography on silica gel (AcOEt/cyclohexane,
2:8) to give the expected compound (148 mg, 74%) as a colourless
1
ture of two diastereomers, which were not separated. Ϫ H NMR
(CDCl3): δ ϭ 8.15Ϫ7.2 (m, 10 H), [6.1, 5.85 (2 s, 1 H)], 6.1Ϫ5.65
(m, 2 H), [4.9, 4.68 (2 d, 2 H, J ϭ 5.3, 6.0 Hz)], 4.3Ϫ4.05 (m, 3
H), 3.7Ϫ2.7 (m, 3 H), [1.26, 1.23 (2 t, 3 H, J ϭ 7.15 Hz)], [1.19,
1.17 (2 d, 3 H, J ϭ 6.2, 6.9 Hz)], [1.11, 1.08 (2 d, 3 H, J ϭ 6.0, 6.9
Hz)], 0.85 (s, 9 H), [0.21, 0.07, 0.04, Ϫ0.02 (4 s, 6 H)]. Ϫ 13C NMR
(CDCl3): δ ϭ 168.6, 167.6, 166.7, 166.2, 137Ϫ121, 67.5, 65.4, 65.3,
62.5, 62.0, 60.9, 60.8, 59.3, 59.1, 58.5, 58.4, 36.0, 25.5, 22.9, 22.6,
17.8, 16.3, 15.8, 13.9, Ϫ4.3, Ϫ4.5, Ϫ4.8, Ϫ5.1. Ϫ C33H45NO6SiS
(611.87): calcd. C 64.78, H 7.41, N 2.29; found C 64.64, H 7.28,
N 2.24.
oil. Ϫ [α]D25 ϭ Ϫ57 (c ϭ 1.2, CHCl3). Ϫ IR: ν˜ ϭ 1750, 1258 cmϪ1
Ϫ
.
1H NMR (CDCl3): δ ϭ 5.94 (dd, 1 H, J ϭ 15.6 and 6.0 Hz),
5.8Ϫ5.5 (m, 1 H), 5.14 (s, 1 H), 4.59 (d, 2 H, J ϭ 6.2 Hz), 4.4Ϫ4.1
(m, 7 H), 4.1Ϫ4.0 (m, 1 H), 2.85 (dd, 1 H, J ϭ 6.4 and 2.3 Hz),
2.75 (m, 1 H), 1.31 (t, 9 H, J ϭ 7.1 Hz), 1.22 (d, 3 H, J ϭ 6.2 Hz),
1.08 (d, 3 H, J ϭ 6.9 Hz), 0.87 (s, 9 H), 0.08 (s, 3 H), 0.06 (s, 3 H).
Ϫ
13C NMR (CDCl3): δ ϭ 168.3, 165.6, 164.7, 154.8, 135.7, 124.9,
(3S,4R)-3-{(1R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-[(1S,2E)-(4-
68.0, 65.8, 63.8, 62.3, 62.1, 60.9, 59.8, 56.8, 36.1, 25.6, 22.8, 17.7,
16.0, 14.1, 13.9, Ϫ4.6. Ϫ MS (EI); m/z: 561, 544. Ϫ C26H45NO9Si
(543.73): calcd. C 57.43, H 8.34, N 2.58; found C 57.46, H 8.39,
N 2.56.
ethoxycarbonyloxy-1-methyl)-2-butenyl]azetidin-2-one (17): To
a
solution of alcohol 12 (573 mg, 1.83 mmol) in CH2Cl2 (19.5 mL),
296 µL (3.66 mmol) of pyridine followed by 210 µL (2.2 mmol) of
ethyl chloroformate were added at 0°C. The mixture was slowly
allowed to warm to 25°C, then stirred at this temperature for 2 h,
and neutralized by the addition of 10 mL of satd. NH4Cl. The
aqueous layer was extracted with CH2Cl2. The combined organic
layers were washed with water, dried with Na2SO4, filtered, and
concentrated. The crude residue was purified by flash chromatogra-
(3S,4R)-3-{(1R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-[(1S,2E)-(4-
ethoxycarbonyloxy-1-methyl)-2-butenyl]-1-{[(phenylsulfonyl)-
ethoxycarbonyl]methyl}azetidin-2-one (19b): To
a solution of
LiHMDS (0.91 mmol) in THF (1.8 mL), a solution of carbonate
18 (179 mg, 0.38 mmol) in THF (2 mL) followed by a solution of
diphenyl disulfide (0.46 mmol) in THF (1 mL) were added drop-
wise at Ϫ78°C. The resulting mixture was stirred for 3 h at Ϫ78°C,
then neutralized with satd. NH4Cl (2 mL), and extracted with
AcOEt. The combined organic layers were dried with Na2SO4, fil-
tered, and concentrated. The crude product was dissolved in CHCl3
(3 mL) and added to a mixture of Oxone (2.27 mmol) and wet
alumina (758 mg of a homogeneous powder obtained by mixing 1
mL of H2O with 5 g of alumina). The resulting slurry was refluxed
for 4 h, then cooled to 25°C, filtered, and the solid was washed
with CH2Cl2. The combined organic phases were dried with
Na2SO4, filtered, and concentrated. The crude residue was purified
by flash chromatography on silica gel (AcOEt/cyclohexane, 2:8) to
give the expected compound (125 mg, 54%) as a pale-yellow oil;
phy on silica gel (AcOEt/cyclohexane, 4:6) to give the expected
25
compound (677 mg, 96%) as a white solid; m.p. 61°C. Ϫ [α]D
ϭ
1
Ϫ24 (c ϭ 0.75, CHCl3). Ϫ IR: ν˜ ϭ 3235, 1744, 1264 cmϪ1. Ϫ H
NMR (CDCl3): δ ϭ 5.97 (s, 1 H), 5.85Ϫ5.55 (m, 2 H), 4.58 (d, 2
H, J ϭ 5.0 Hz), 4.3Ϫ4.1 (m, 3 H), 3.51 (dd, 1 H, J ϭ 7.6 and 1.9
Hz), 2.79 (m, 1 H), 2.36 (m, 1 H), 1.31 (t, 3 H, J ϭ 7.1 Hz), 1.15
(d, 3 H, J ϭ 6.3 Hz), 1.08 (d, 3 H, J ϭ 6.7 Hz), 0.87 (s, 9 H), 0.06
(s, 6 H). Ϫ 13C NMR (CDCl3): δ ϭ 168.6, 154.8, 136.5, 124.7, 67.7,
64.9, 64.0, 61.9, 54.5, 40.4, 25.7, 22.9, 17.9, 16.1, 14.2, Ϫ4.4, Ϫ5.0.
Ϫ MS (EI); m/z: 370, 328. Ϫ C19H35NO5Si (385.57): calcd. C 59.19,
H 9.15, N 3.63; found C 59.32, H 9.10, N 3.59.
(3S,4R)-3-{(1R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-[(1S,2E)-(4-
ethoxycarbonyloxy-1-methyl)-2-butenyl]-1-[(ethoxycarbonyl)-
methyl]azetidin-2-one (18): To a solution of carbonate 17 (171 mg,
0.443 mmol) in THF (9 mL), a solution of LiHMDS (0.487 mmol)
in THF (4.6 mL) was added dropwise at Ϫ40°C. The resulting
solution was stirred for 25 min at Ϫ40°C, and then 59 µL (0.531
mmol) of ethyl bromoacetate was added dropwise at Ϫ78°C. The
mixture was stirred for 2 h at Ϫ40°C, and then neutralized by the
addition of satd. NH4Cl (8 mL). The aqueous layer was extracted
with AcOEt and the combined organic layers were dried with
Na2SO4, filtered, and concentrated. The crude residue was purified
by flash chromatography on silica gel (AcOEt/cyclohexane, 2:8) to
mixture of two diastereomers. Ϫ IR: ν˜ ϭ 1748, 1584, 1150 cmϪ1
Ϫ
.
1H NMR (CDCl3): δ ϭ 8.1Ϫ7.5 (m, 5 H), 6.4Ϫ5.3 (m, 2 H),
[5.77, 5.58 (2 s, 1 H)], [4.65, 4.58 (2 d, 2 H, J ϭ 6.2 Hz)], 4.4Ϫ4.0
(m, 6 H), 3.3Ϫ2.7 (m, 2 H), 1.4Ϫ1.0 (m, 12 H), 0.9Ϫ0.7 (m, 9 H),
0.2Ϫ0.0 (m, 6 H). Ϫ 13C NMR (CDCl3): δ ϭ 169.6, 168.8, 162.2,
161.4, 154.9, 138.1, 137.5, 135.8, 135.2, 134.5, 129.3, 129.2, 129.0,
125.5, 125.0, 73.4, 68.2, 67.1, 64.8, 63.9, 62.7, 61.4, 60.6, 59.6, 36.2,
35.2, 25.8, 25.7, 22.8, 17.8, 17.6, 16.3, 15.7, 14.2, 13.7, Ϫ4.1, Ϫ4.6,
Ϫ5.0. Ϫ MS (EI); m/z: 629, 612. Ϫ C29H45NO9SSi (611.82): calcd.
C 56.93, H 7.41, N 2.29; found C 54.76, H 7.08, N 1.87.
give the expected compound (173 mg, 83%) as a yellow oil. Ϫ
(4S,5R,6S)-6-{(1R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-2,2-
25
[α]D ϭ Ϫ41 (c ϭ 0.85, CHCl3). Ϫ IR: ν˜ ϭ 1747, 1258 cmϪ1. Ϫ bis(ethoxycarbonyl)-3-(1-ethenyl)-4-methyl-1-azabicyclo[3.2.0]-
1H NMR (CDCl3): δ ϭ 6.0Ϫ5.5 (m, 2 H), 4.58 (d, 2 H, J ϭ 5.9
heptan-7-one (16a). ؊ Method A (Benzoates): To a suspension of
Hz), 4.3Ϫ4.0 (m, 6 H), 3.8 (dd, 1 H, J ϭ 5 and 2.2 Hz), 3.76 (d, 1 sodium hydride (3.5 mg, 0.14 mmol) in THF (0.5 mL), a solution
H, J ϭ 17.8 Hz), 2.85 (dd, 1 H, J ϭ 6.1 and 2.2 Hz), 2.62 (m, 1 of benzoate 15a (61 mg, 0.106 mmol) in THF (0.5 mL) was added
H), 1.35Ϫ1.2 (m, 9 H), 1.1 (d, 3 H, J ϭ 6.8 Hz), 0.87 (s, 9 H), 0.08 at 0°C. The mixture was stirred for 15 min at 25°C and then the
(s, 3 H), 0.06 (s, 3 H). Ϫ 13C NMR (CDCl3): δ ϭ 168.1, 154.8, catalyst, preformed for 1 h at 25°C from 4.8 mg (20 mol-%) of
Eur. J. Org. Chem. 1999, 621Ϫ626
625

J.-C. Galland, S. Roland, J. Malpart, M. Savignac, J.-P. Genet
FULL PAPER
Pd(OAc)2 and 12.7 mg (30 mol-%) of dppe in THF (0.5 mL), was
added. The resulting mixture was heated at 60°C for 2 h, then
neutralized by the addition of 2 mL of satd. NH4Cl, and extracted
with diethyl ether. The organic layer was dried with Na2SO4, fil-
tered, and concentrated. The crude product was purified by flash
chromatography on silica gel (AcOEt/cyclohexane, 2:8) to give the
expected compound (24 mg, 48%) as a colourless oil; mixture of
two diastereomers. Ϫ Method B (Carbonates): To the catalyst, pre-
formed for 0.5 h at 30°C from 2.1 mg (10 mol-%) of Pd(OAc)2 and
7.8 mg (20 mol-%) of dppb (diphenylphosphanylbutane) in THF
(0.5 mL), a solution of carbonate 19a (50 mg, 0.09 mmol) in THF
(1 mL) was added dropwise. The resulting mixture was stirred for
1 h at 30°C, then diluted with AcOEt, neutralized by the addition
of satd. NH4Cl (2 mL), and extracted with AcOEt. The combined
organic layers were dried with Na2SO4, filtered, and concentrated.
The crude product was purified by flash chromatography on silica
gel (AcOEt/cyclohexane, 1:9, ϩ 0.75% Et3N) to give the expected
compound (27 mg, 67%) as a colourless oil; mixture of two dia-
stereomers. Ϫ IR: ν˜ ϭ 3235, 1770, 1740 cmϪ1. Ϫ Diastereomer 1:
1H NMR (CDCl3): δ ϭ 5.68 (ddd, 1 H, J ϭ 16.8 and 9.8 Hz), 5.33
(dd, 1 H, J ϭ 16.8 and 2.0 Hz), 5.20 (dd, 1 H, J ϭ 9.8 and 2.0
Hz), 4.4Ϫ4.0 (m, 6 H), 4.0Ϫ3.8 (m, 1 H), 3.13 (dd, 1 H, J ϭ 2.3
and 4.9 Hz), 2.45 (m, 1 H), 1.4Ϫ1.15 (m, 9 H), 1.1 (d, 3 H, J ϭ
7.6 Hz), 0.9 (s, 9 H), 0.07 (s, 6 H). Ϫ 13C NMR (CDCl3): δ ϭ
168.9, 168.3, 165.2, 131.9, 120.4, 73.4, 65.1, 62.2, 62.0, 59.0, 58.7,
58.5, 38.8, 25.6, 22.4, 17.8, 13.8, 10.8, Ϫ4.4, Ϫ5.2. Ϫ Diastereomer
Acknowledgments
We thank Dr. P. Siret and Dr. F. Jung (Zeneca-Pharma) for a gen-
erous gift of 4-acetoxyazetidin-2-one, and the MESR for the re-
spective grants allocated to S. R. and J.-C. G.
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J. S. Kahan, F. Kahan, R. Goegelman, S. A. Currie, M.
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[1b]
Antibiot. 1979, 32, 1Ϫ12. Ϫ
G. Albers-Schönberg, B. H.
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D. H. Shih, F. Baker, L. Cama, B. G. Christensen, Hetero-
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F. M. Kahan, H. Kropp, J. G. Sundelof, J. Birnbaum, J.
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2149Ϫ2152. Ϫ
R. Noyori, M. Kitamura, K. Nagai, Y.
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Droghini, Can. J. Chem. 1988, 66, 1400Ϫ1404. Ϫ [4d] C. U. Kim,
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Ϫ
Ϫ
F. Shirai, T. Nakai, J. Org. Chem. 1987, 52, 5491Ϫ5492.
A. Martel, J. P. Davris, C. Bachand, J. Corbeil, M. Me-
[4g]
1
2: H NMR (CDCl3): δ ϭ 5.57 (ddd, 1 H, J ϭ 17.3, 9.9 and 7.7
[4h]
nard, Can. J. Chem. 1988, 66, 1537Ϫ1539. Ϫ
R. Deziel, D.
Hz), 5.29 (dd, 1 H, J ϭ 17.3 and 1.7 Hz), 5.20 (dd, 1 H, J ϭ 10.6
and 1.7 Hz), 4.4Ϫ4.0 (m, 6 H), 3.1 (dd, 1 H, J ϭ 7.1 and 3.3 Hz),
3.0 (dd, 1 H, J ϭ 11.6 and 7.7 Hz), 2.45 (m, 1 H), 1.4Ϫ1.15 (m, 9
H), 1.1 (d, 3 H, J ϭ 7.6 Hz), 0.9 (s, 9 H), 0.1 (s, 6 H). Ϫ IR: ν˜ ϭ
3235, 1770, 1740 cmϪ1. Ϫ MS (EI); m/z: 438, 398. Ϫ C23H39NO6Si
(453.65): calcd. C 60.90, H 8.66, N 3.09; found C 60.91, H 8.56,
N 2.99.
Favreau, Tetrahedron Lett. 1986, 27, 5687Ϫ5690. Ϫ [4i] H. Fliri,
C.-P. Mak, J. Org. Chem. 1985, 50, 3438Ϫ3442. Ϫ [4j] Y. Nagao,
T. Kumagai, S. Tamai, T. Abe, Y. Kuramoto, T. Taga, S. Aoyagi,
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[4k]
1986, 108, 4673Ϫ4675. Ϫ
Y. Nagao, T. Kumagai, S. Tamai,
Y. Nagase, Y. Inoue, M. Shiro, J. Org. Chem. 1992, 57,
[4l]
4232Ϫ4237. Ϫ
L. M. Fuentes, I. Shinkai, T. N. Salzmann,
J. Am. Chem. Soc. 1986, 108, 4675Ϫ4676. Ϫ [4m] T. Shibata, K.
Lino, T. Takana, T. Hashimoto, Y. Kameyama, Y. Sugimura,
Tetrahedron Lett. 1985, 26, 4739Ϫ4742. Ϫ [4n] J. T. Sowin, A. I.
[4o]
(4S,5R,6S)-6-{(1R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-2-ethoxy-
carbonyl-2-phenylsulfonyl-3-(1-ethenyl)-4-methyl-1-azabicyclo-
[3.2.0]heptan-7-one (16b): To the catalyst, preformed for 0.5 h at
30°C from 4.1 mg (10 mol-%) of Pd(OAc)2 and 15.6 mg (20 mol-
%) of dppb in THF (1 mL), a solution of sulfone 19b (112 mg, 0.18
mmol) in THF (2 mL) was added dropwise. The resulting mixture
was stirred for 1 h at 30°C, then diluted with AcOEt, neutralized
by the addition of satd. NH4Cl (3 mL), and extracted with AcOEt.
The combined organic layers were dried with Na2SO4, filtered, and
concentrated. The crude product was purified by flash chromatog-
raphy on silica gel (AcOEt/cyclohexane, 15:85) to give the expected
compound (56 mg, 59%) as a white solid; mixture of four dia-
stereomers. Ϫ IR: ν˜ ϭ 1770, 1740, 1150 cmϪ1. Ϫ 1H NMR
(CDCl3): δ ϭ 8.04 (s, 1 H), 7.7Ϫ7.4 (m, 3 H), 5.8Ϫ5.55 (m, 1 H),
5.47 (dd, 1 H, J ϭ 16.8 and 1.9 Hz), 5.32 (dd, 1 H, J ϭ 9.6 and
1.8 Hz), 4.4Ϫ4.0 (m, 5 H), 3.20 (dd, 1 H, J ϭ 2.5 and 5.5 Hz), 2.68
(m, 1 H), 1.25 (d, 3 H, J ϭ 6.1 Hz), 1.15 (t, 3 H, J ϭ 7.1 Hz), 1.09
(d, 3 H, J ϭ 7.6 Hz), 0.92 (s, 9 H), 0.12 (s, 6 H). Ϫ 13C NMR
(CDCl3): δ ϭ 167.5, 162.7, 137.1, 134.0, 130.7, 130.6, 128.5, 122.2,
88.0, 65.6, 62.9, 60.7, 59.7, 58.1, 39.4, 25.7, 22.5, 17.9, 13.7, 11.4,
Ϫ4.3, Ϫ4.7. Ϫ MS (EI); m/z: 438, 398. Ϫ C26H39NO6SSi (521.75):
calcd. C 59.85, H 7.53, N 2.68; found C 59.86, H 7.55, N 2.65.
Meyers, J. Org. Chem. 1988, 53, 4154Ϫ4156. Ϫ
O. Sakurai,
M. Takahashi, T. Ogiku, M. Hayashi, H. Horikawa, T. Iwasaki,
[4p]
Tetrahedron Lett. 1994, 35, 6317Ϫ6320. Ϫ
S. H. Kang, H.
[4q]
S. Lee, Tetrahedron Lett. 1995, 36, 6713Ϫ6716. Ϫ
O. S. Sa-
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[4r]
X. E. Hu, T. P. Demuth, Jr., J. Org. Chem. 1998, 63,
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[7]
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For the preparation of 4-[1-(hydroxymethyl)ethenyl]azetidinone
8 from commercially available 4-acetoxyazetidinone 4, see
ref.[4d]
[8]
M. Kitamura, K. Nagai, Y. Hsiao, R. Noyori, Tetrahedron Lett.
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[9] [9a]
ˆ
J.-P. Genet, C. Pinel, V. Ratovelomanana-Vidal, S. Mallart,
X. Pfister, M.-C. Can˜o de Andrade, J.-A. Laffitte, Tetrahedron:
Asymmetry 1994, 5, 665Ϫ674. Ϫ
[9b]
ˆ
J.-P. Genet, C. Pinel, V.
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