2-Substituted 2,3-dihydro-4H-1,3-benzoxazin-4-ones: Novel auxiliaries for stereoselective synthesis of 1-β-methylcarbapenems

Article abstract of DOI:10.1021/jo961866j

The dihydrobenzoxazone 9e, which is easily prepared from salicylamide 11 and cyclohexanone, serves as an efficient auxiliary in the synthesis of the 1-β-methylcarbapenem key intermediate 10. The stereocontrolled Reformatsky-type reactions of the acetoxyazetidinone 2 with the carboximides 6 gave the intermediates 7 with high diastereoselectivities in high chemical yields. The auxiliary 9e also acts as a good leaving guoup in the TMSCl-promoted Dieckmann-type cyclization leading to a 1-β-methylcarbapenem skeleton. By using this auxiliary, 10 was synthesized in 58% overall yield and four steps from 2.

Full text of DOI:10.1021/jo961866j

J . Org. Chem. 1997, 62, 2877-2884
2877
2-Su bstitu ted 2,3-Dih yd r o-4H-1,3-ben zoxa zin -4-on es: Novel
Au xilia r ies for Ster eoselective Syn th esis of
1-â-Meth ylca r ba p en em s1
Kazuhiko Kondo,* Masahiko Seki, Tooru Kuroda, Takeshi Yamanaka, and Tameo Iwasaki
Research Laboratory of Applied Biochemistry, Tanabe Seiyaku Co. Ltd., 3-16-89,
Kashima, Yodogawa-ku, Osaka 532, J apan
Received October 2, 1996X
The dihydrobenzoxazone 9e, which is easily prepared from salicylamide 11 and cyclohexanone,
serves as an efficient auxiliary in the synthesis of the 1-â-methylcarbapenem key intermediate 10.
The stereocontrolled Reformatsky-type reactions of the acetoxyazetidinone 2 with the carboximides
6 gave the intermediates 7 with high diastereoselectivities in high chemical yields. The auxiliary
9e also acts as a good leaving group in the TMSCl-promoted Dieckmann-type cyclization leading
to a 1-â-methylcarbapenem skeleton. By using this auxiliary, 10 was synthesized in 58% overall
yield and four steps from 2.
In tr od u ction
ing 2-oxazolidones 3 has been reported.5c,7 Although good
to excellent diastereoselectivities have been obtained,
The carbapenem class of â-lactam antibiotics, as
exemplified by thienamycin,2 has attracted considerable
attention because of their potent and broad-spectrum
antibacterial activities. Recently, carbapenems 1 bearing
a 1-â-methyl substituent at C-1 have been shown to
possess superior chemical and metabolic stability, while
maintaining the excellent antibacterial activities.3 This
discovery has prompted many synthetic organic chemists
to develop an efficient method for constructing the 1-â-
methylcarbapenem nucleus, and recent reviews4 describe
impressive progress in this area.
During the last decade, the diastereoselective aldol-
type condensations of the acetoxyazetidinone 2 with
enolates derived from carboximide auxiliaries have be-
come a major tool for stereocontrolled approach to 1-â-
methylcarbapenem key intermediates.4 These reactions
are thought to proceed via chelated transition states
which involve the attack of (Z)-enolates on the less
hindered face of an acylimine.5 Most of the aldol-type
condensations rely on auxiliaries derived from 2-oxazoli-
dones 35c and the closely related analogs, e. g., 1,3-
oxazolidine-2-thiones 46b and 1,3-thiazolidine-2-thiones
5.5a,d,6a Recently, the stereoselective synthesis of the key
intermediate via the Reformatsky-type reaction employ-
these auxiliaries possess at least one of the following
drawbacks: difficult accessibility, necessity of refunc-
tionalization before the subsequent ring construction,
difficulty in recycling the auxiliaries, and requirement
of expensive reagents. The use of these auxiliaries
having such drawbacks is particularly problematic in the
practical synthesis of the 1-â-methylcarbapenem antibi-
otics 1.
Our research has been focussed on the development
of an efficient auxiliary for the construction of the 1-â-
methylcarbapenem nucleus. As shown in Scheme 1, our
synthetic strategy involves two processes including the
stereoselective Reformatsky-type reaction7 and the Dieck-
mann-type cyclization.6b,9 We were interested in the use
of 2-substituted 1,3-dihydro-4H-1,3-benzoxazin-4-ones 9
as the auxiliaries, which can be prepared in a single step
from inexpensive salicylamide 11 (Scheme 2).8 The use
of the rigid oxazinone ring fused to the benzene ring
would result in an efficient asymmetric-induction in the
Reformatsky-type reaction of the acetoxyazetidinone 2
with the carboximides 6. In addition, we envisioned that
the auxiliaries would serve as a good leaving group in
the subsequent cyclization leading to the vinyl phosphate
10, a key intermediate in the synthesis of the 1-â-
methylcarbapenems 1. We report here a practical syn-
X Abstract published in Advance ACS Abstracts, April 1, 1997.
(1) Preliminary communication: Kondo, K.; Seki, M.; Kuroda, T.;
Yamanaka, T.; Iwasaki, T. J . Org. Chem. 1995, 60, 1096-1097.
(2) (a) Albers-Schonberg, G.; Arison, B. H.; Hensens, O. D.; Hirsh-
field, J .; Hoogsteen, K.; Kaczka, E. A.; Rhodes, R. E.; Kahan, J . S.;
Kahan, F. M.; Ractliffe, R. W.; Walton, E.; Ruswinkle, L. J .; Morin, R.
B.; Christensen, B. G. J . Am. Chem. Soc. 1978, 100, 6491-6499. (b)
Kahn, J . S.; Kahan, F. M.; Goegelman, R.; Currie, S. A.; J ackson, M.;
Stapley, E. O.; Miller, T. W.; Miller, A. K.; Hendlin, D.; Mochales, S.;
Hernandez, S.; Woodruff, H. B.; Birnbaum, J . J . Antibiot. 1979, 32,
1-12.
(3) Shih, D. H.; Baker, F.; Cama, L.; Christensen, B. G. Heterocycles
1984, 21, 29-40.
(4) (a) Ito, Y.; Terashima, S. Yuki Gouseikagaku Kyokai Shi 1989,
47, 606-618. (b) Berks, A. H. Tetrahedron 1996, 52, 331-375.
(5) (a) Nagao, Y.; Kumagai, T.; Tamai, S.; Abe, T.; Kuramoto, Y.;
Taga, T.; Aoyagi, S.; Nagase, Y.; Ochiai, M.; Inoue, Y.; Fujita, E. J .
Am. Chem. Soc. 1986, 108, 4673-4675. (b) Fuentes, L. M.; Shinkai,
I.; Saltsmann, T. N. J . Am. Chem. Soc. 1986, 108, 4675-4676. (c) Ito,
Y.; Sasaki, A.; Tamoto, K.; Sunagawa, M.; Terashima, S. Tetrahedron
1991, 47, 2801-2820. (d) Nagao, Y.; Nagase, Y.; Kumagai, T.;
Matsunaga, H.; Abe, T.; Shimada, O.; Hayashi, T.; Inoue, Y. J . Org.
Chem. 1992, 57, 4243-4249.
(7) Ito, Y.; Terashima, S. Tetrahedron Lett. 1987, 28, 6625-6628.
(8) See, for example: (a) Horrom, B. W.; Zaugg, H. E. J . Am. Chem.
Soc. 1950, 72, 721-724. For the base-catalized reactions, see: (b)
Gammill, R. B. J . Org. Chem. 1981, 46, 3340-3342.
(9) (a) Sibuya, M.; Kuretani, M.; Kubota, S. Tetrahedron 1982, 38,
2659-2665. (b) Hatanaka, M.; Yamamoto, Y.; Nitta, H.; Ishimaru, T.
Tetrahedron Lett. 1981, 22, 3883-3886. (c) Sowin, T. J .; Meyers, A. I.
J . Org. Chem. 1988, 53, 4154-4156. (d) Sunagawa, M.; Sasaki, A.;
Matsumura, H.; Goda, K.; Tamoto, K. Chem. Pharm. Bull. 1994, 42,
1381-1387.
(6) (a) Deziel, R.; Favreau, D. Tetrahedron Lett. 1986, 27, 5687-
5690. (b) Deziel, R.; Favreau, D. Tetrahedron Lett. 1989, 30, 1345-
1348.
S0022-3263(96)01866-X CCC: $14.00 © 1997 American Chemical Society

2878 J . Org. Chem., Vol. 62, No. 9, 1997
Kondo et al.
Ta ble 1. Zin c-In d u ced Refor m a tsk y-Typ e Rea ction of 2
Sch em e 1
w ith 6a -g
entry
7
R
yield, %a
â:Rb
mp, °C
1
2
3
4
5
6
7
a
b
c
d
e
f
Me
Bu
94
87
64
77
96
38
76
85:15
98:2
133-134d
oil
C
15H31
98:2c
85:15
92:8
oil
oil
-(CH2)4-
-(CH2)5-
-(CH2)6-
Bn
156-157d
146-147d
oil
89:11
99.6:0.4
g
a
b
Isolated yield. Determined by HPLC. c Determined by 1H-
d
NMR. Melting point of the pure â-isomer
Sch em e 2
F igu r e 1.
dust in refluxing THF. The results are summarized in
Table 1. The diastereoselectivity and the yield of the
azetizinones 7a -g depend largely on the structure of the
auxiliary. In general, the diastereoselectivity increases
with increasing the steric bulkiness of the C-2 substit-
uents on the axuiliary, while the yield decreases with the
increasing the steric bulkiness. The highest diastereo-
selectivity was found in the use of the benzyl derivative
6g (â:R ) 99.6:0.4), and the lowest selectivity was
observed in the use of the methyl derivative 6a and the
cyclopentyl derivative 6d (â:R ) 85:15). On the other
hand, the highest yield was obtained in the use of 6a and
the cyclohexyl derivative 6e. From practical point of
view, the diastereoselectivity as well as the chemical yield
in the Reformatsky-type reaction should be high. Fur-
thermore, the â-isomer should be separated easily by
direct crystallization. For the above reasons, we selected
the cyclohexyl derivative 7e as a key intermediate for
the target compound 10; direct crystallization of the crude
7e gave the pure â-isomer 7eâ in 75% yield based on 2.
The structure of 7eâ was confirmed by means of X-ray
crystallography.10
The preferential formation of the â-isomers 7a -gâ
would be explained by the chairlike transition state5
involving the imine 12 and the (Z)-enolate 13 (Figure 1).
The mechanism involving the intermediacy of the (Z)-
enolate 13 is supported by the following experiment.
Silylation of the crude reaction mixture obtained from
the reaction of 6e with zinc produced a 71:29 mixture of
the (Z)-silyl enol ether 14e and the reduced product 15e;
14e could be isolated in crystalline form. The structure
of 14e was determined by X-ray crystallography.10 It
may be deduced that the steric repulsion between â-ori-
ented bulky substituent R′ at C-2 of the auxiliary and
the imine 12 would not be critical factor in the diaste-
reofacial selection (Figure 1). However, the decrease in
chemical yields of the azetidinones 7 with increasing the
size of R′ suggests that the steric repulsion would induce
Sch em e 3
thesis of 10 by the use of the dihydrobenzoxazones 9 as
the auxiliaries.
Resu lts a n d Discu ssion
Zin c-In d u ced Refor m a tsk y-Typ e Rea ction . We
selected the achiral 2-substituted dihydrobenzoxazones
9 as the auxiliaries which were readily synthesized from
11. The requisite 9a -g were readily prepared in 69-
93% yields by the acid-catalyzed condensation of salicy-
lamide 11 with the corresponding ketones in toluene
(Scheme 2).8
Next, we attempted the bromopropionylation of 9a -
g. Recent work has shown that 2-oxazolidones 3 react
with 2-bromopropionyl bromide in the presence of butyl-
lithium or sodium hydride in THF to yield the N-acylated
products.5c However, bromopropionylation of 9 under the
same conditions as those used in the case of 3 gave the
carboximides 6 in low yields with concomitant formation
of several byproducts. The use of triethylamine as a base
also gave disappointing results. After screening a variety
of bases and solvents, we found that the bromopropio-
nylation is completed in a good yield by the use of
pyridine as a base and toluene or CH2Cl2 as a solvent.
Thus, the reaction of 9a -g with 1.2 equiv of the acyl
bromide in the presence of 1.2 equiv of pyridine at 5-25
°C gave 6a -g in high yields (64-87%).
Having established the method for the synthesis of 6a -
g, we focused our attention on the Reformatsky-type
reaction (Scheme 3). The best conditions involved the
treatment of 2 with 1.5 equiv of 6a -g and 3 equiv of zinc
(10) The author has deposited X-ray data with the Cambridge
Crystallographic Data Centre. The coordinates can be obtained, on
request, from the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, UK.

Stereoselective Synthesis of 1-â-Methylcarbapenems
J . Org. Chem., Vol. 62, No. 9, 1997 2879
Sch em e 4
Sch em e 5
the competing side-reactions by retarding the Refor-
matsky-type reaction leading to 7.
In order to obtain the carboxylic acid 16, which is an
intermediate for the synthesis of carbapenem antibiotics,4
we also examined the hydrolysis of the â-isomer 7eâ
(Scheme 4). Treatment of 7eâ with LiOH12 in aqueous
THF led to a complex mixture of products. When 7eâ
was treated with lithium hydroperoxide12 in aqueous
THF, the carboxylic acid 16 was obtained in 72% yield;
the auxiliary 9e was recovered in 92% yield.
suppresses the possible self-condensation16 of 13. We
have not attempted to refine the procedure to obtain
better yields.
TMSCl-P r om oted Dieck m a n n -Typ e Cycliza tion .
We next investigated the preparation of the vinyl phos-
phate 10 by the Dieckmann-type cyclization of the allyl
ester 8eâ (Scheme 5). The requisite 8eâ was prepared
in 96% yield by the reaction of the â-isomer 7eâ with allyl
bromoacetate in the presence of sodium bis(trimethylsi-
lyl)amide [NaN(TMS)2]. For the synthesis of the vinyl
phosphate 10 via the Dieckman-type cyclization, the
presence of good a leaving group, e. g., 2-pyridylthio9c and
phenylthio,9d on the C-4 side chain of the allyl ester 8eâ
is required. We have previously shown that TMSCl
promotes the Dieckmann-type cyclization of the thioesters,
presumably due to the effective trapping of the liberated
thiolate anions by TMSCl.17 We anticipated that the
dihydrobenzoxazone 9e would serve as a good leaving
group when the cyclization was carried out in the
presence of TMSCl. Silylation of the liberated dihy-
drobenzoxazone anion 17 to form the silyl ether 18 would
prevent the side reactions such as the phosphorylation
of 17, thereby leading to the recovery of the auxiliary 9e
by a simple workup.18 As expected, treatment of 8eâ with
2.5 equiv of NaN(TMS)2 and 1.3 equiv of TMSCl at -25
°C, followed by addition of 1.3 equiv of diphenyl phos-
phorochloridate at 0 °C in THF, gave the desired vinyl
phosphate 10 in 82% yield; the auxiliary 9e was recov-
Ma gn esiu m -In d u ced R efor m a t sk y-Typ e R ea c-
t ion . Efficient modifications of the Reformatsky
reaction13a have been reported by using magnesium as a
metal component13b and Cp2TiCl2-zinc system as a
catalyst.13c In order to improve the yield and diastereo-
selectivity of the â-isomer 7eâ, we investigated the
Reformatsky-type reaction using magnesium instead of
zinc (Scheme 3). The reaction of the acetoxyazetidinone
2 with the carboximide 6e and magnesium in the
presence of a catalytic amount of iodine in THF led to a
complex mixture of products. However, pretreatment of
4.5 equiv of magnesium with 3 equiv of 1,2-dibro-
momethane14 in THF followed by addition of 2 and 1.5
equiv of 6e (10 °C, 1 h) provided 7e in 54% yield with an
excellent diastereoselectivity (â:R ) 99:1). The use of a
catalytic amount of Cp2TiCl2 in this reaction resulted in
the improvement of the yield. Thus, treatment of 2 with
6e under the reaction conditions described above in the
presence of 10 mol % of Cp2TiCl2 at 0 °C for 30 min gave
7e in 73% yield (â:R ) 99:1). It is most likely that the
magnesium bromide formed from magnesium and 1,2-
dibromoethane could function as a Lewis acid and could
accelerate the generation of the reactive imine 12, which
would react with the enolate 13 to give the desired
product 7e. In addition, the activated magnesium gener-
ated by using 1,2-dibromoethane as an entrainer14 is
thought to facilitate the formation of the Reformatsky
reagent 13. Although the role of the Cp2TiCl2 is still
obscure, the increase in the yield of 7e may be due to
the formation of the titanium enolate,15 which probably
(11) Because the Reformatsky reagent is very susceptible to hy-
drolysis under the silylation conditions, it was not possible to obtain
the Z silyl enol ether 14e without concomitant formation of the reduced
product 15e. For the related silylation of the Reformatsky reagents,
see: (a) Slougui, N.; Rosseau, G. Synth. Commun. 1987, 17, 1-11. (b)
Kitagawa, O.; Taguchi, Y. Tetrahedron Lett. 1988, 29, 1803-1806.
(12) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett.
1987, 28, 6141-6144.
ered in 85% yield.19 No 1-R-methyl isomer was
detected.9d,20 When the reaction was performed in the
absence of TMSCl, 10 was obtained only in 18% yield
(13) (a) For review, see: Furstner, A. Synthesis 1989, 571-590. (b)
Moriwake, T. J . Org. Chem. 1966, 31, 983-985. (c) Ding, Y.; Zhao, G.
J . Chem. Soc., Chem. Commun. 1992, 941-942.
(16) Hussey, A. S.; Newman, M. S. J . Am. Chem. Soc. 1948, 70,
3024-3026.
(17) Seki, M.; Kondo, K.; Iwasaki, T. Synlett 1995, 315-316.
(18) For the Diekmann-type cyclization with alkyl halide as a
scavenger, see reference 9d.
(19) Attempts to isolate the silyl derivative 13b prior to aqueous
workup were unsuccessful.
(14) Lai, Y. H. Synthesis 1981, 585-604.
(15) (a) Adam, W.; Miller, M.; Prechtl, F. J . Org. Chem. 1994, 59,
2358-2364. (b) Van Draanen, N. A.; Arseniyadis, S.; Crimmins, M.
T.; Heathcock, C. H. J . Org. Chem. 1991, 56, 2499-2506.

2880 J . Org. Chem., Vol. 62, No. 9, 1997
Kondo et al.
Sch em e 6
tions as described above led to the formation of a complex
mixture of products; the desired vinyl phosphate 10 was
isolated only in 9% yield. The low yield of 10 may be
due to the poor leaving-group ability of the auxiliary 22e.
Con clu sion
We have demonstrated that the dihydrobenzoxazone
9e serves not only as an effective auxiliary in the
stereoselective Reformatsky-type reaction of the ac-
etoxyazetidinone 2 but also as a good leaving group in
the TMSCl-promoted Dieckmann-type cyclization leading
to the key intermediate 10. Thus, a practical and cost
effective method for the preparation of 1-â-methylcar-
bapenems 1 has been developed by using this auxiliary.
The ready availability, high reactivity, and unprec-
edented structural features of 9 should find wide ap-
plication in a variety of asymmetric syntheses.
Ta ble 2. Zin c-In d u ced Refor m a tsk y-In d u ced Rea ction of
23a ,e,h w ith 2
yield, %a
â:Rb
Exp er im en ta l Section
entry
24
R
Gen er a l. Melting points are uncorrected. 1H NMR were
recorded on a 200 MHz spectrometer and are reported in δ
values. Mass spectra were taken at an ionizing potential of
70 eV. Analytical HPLC was conducted on a 4.6 mm i.d. ×
150 mm Capcell Pac C18, SG-120 (Shiseido) column at a column
temperature of 40 °C and UV detection at 254 nm. Flash
column chromatography (FCC) was carried out on 230-400
mesh silica gel, eluting with the solvents indicated. All
solvents were distilled and dried according to standard pro-
cedures prior to use. (3R,4R)-4-Acetoxy-3-[(R)-1-(tert-butyldim-
ethylsilyloxy)ethyl]-2-azetidinone (1) was obtained from Kane-
gafutikagakukogyo Co., Ltd. Zinc dust was purchased from
E. Merck (zinc powder GR, particle size <60 µm) and used
without purification.
1
2
3
a
e
h
Me
-(CH2)5-
H
75
84
28
94:6
95:5
63:37
a
b
Isolated yield. Determined by HPLC.
along with the phosphate 1921 (15%) and intractable
byproducts. These results suggest that the silylation of
17 would be much faster than that of the cyclized enolate
20, leading to the silyl enol ether 21 which is probably
unreactive toward the phosphorylation. The vinyl phos-
phate 10 thus obtained was transformed into the thio-
vinyl derivatives 1 by the known method.22 Very re-
cently, we found a novel procedure for the deprotection
of the TBDMS ether of carbapenems by using inexpensive
ammonium bifluoride.23 We have also found a new
method for the deprotection of allyl ester of carbapenems
employing palladium acetate-P(OEt)3.23 By utilizing
these two deprotection-methods, we succeeded in the
large-scale preparation of a 1-â-methylcarbapenem an-
tibiotic 1.
Rea ction of P yr r olid on es. On the basis of the above
results, we further explored an alternate synthetic
method of the vinyl phosphonate 10 using the structur-
ally related pyrrolidones 22a ,e,h 24 as the auxiliaries
(Scheme 6). The zinc-mediated Reformatsky-type reac-
tion of the acetoxyazetidinone 2 with the carboximide 23e
gave the cyclohexyl derivative 24e in a highly diastereo-
selective manner (â:R ) 95:5) and in 84% isolated yield
(Table 2).25 In contrast to the case of dihydrobenzoxazone
series, the yield of the azetizinones 24 increases with
increasing the steric bulkiness of the C-5 substituents
on the auxiliary.
Gen er a l P r oced u r e for Dih yd r oben zoxa zon e. Sp ir o-
[2H-1,3-ben zoxa zin e-2,1′-cycloh exa n ]-4(3H)-on e (9e). A
mixture of salicylamide 11 (100 g, 0.73 mol), cyclohexanone
(107 g, 1.09 mol), and p-toluenesulfonic acid monohydrate (13.9
g, 0.073 mol) in toluene (500 mL) was refluxed under condi-
tions removal of water using a Dean-Stark apparatus for 8 h
or until 90% of the theoretical amount of water was removed.
After gradual cooling down to 10 °C, the mixture was stirred
for 1 h at the same temperature. The resulting crystals were
collected, washed successively with toluene (100 mL) and
2-propanol (100 mL), and dried at 50 °C to afford 145.5 g (92%)
of 9e as colorless crystals: mp 189-192 °C (lit.8a mp 188-190
1
°C); H NMR (DMSO-d6) δ 1.20-1.30 (m, 1H), 1.50-1.70 (m,
6H), 1.90-2.10 (m, 3H), 6.90-7.10 (m, 2H), 7.40-7.50 (m, 1H),
7.70-7.80 (m, 1H), 8.64 (brs, 1H); IR (KBr) 2939, 1670, 1608
cm-1; MS m/ z 217 (M+). Anal. Calcd for C13H15NO2: C, 71.87;
H, 6.96; N, 6.45. Found: C, 71.88; H, 7.02; N, 6.42.
2,3-Dih yd r o-2,2-d im eth yl-4H-1,3-ben zoxa zin -4-on e (9a )
was isolated in 72% yield as colorless crystals: mp 136-138
°C (from hexane-AcOEt) (lit.8a mp 135-137 °C); 1H NMR
(CDCl3) δ 1.69 (s, 6H), 6.80-7.00 (m, 2H), 7.30-7.50 (m, 1H),
7.80-7.90 (m, 2H); IR (KBr) 3186, 1677, 1614 cm-1; MS m/ z
177 (M+). Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N,
7.90. Found: C, 67.56; H, 6.02; N, 7.80.
Unfortunately, the TMSCl-promoted Dieckmann-type
cyclization of the allyl ester 25e under the same condi-
2,2-Dibu tyl-2,3-d ih yd r o-4H-1,3-ben zoxa zin -4-on e (9b)
was isolated in 93% yield after FCC (hexane/AcOEt 95:5) of
the crude product as a colorless oil: 1H NMR (CDCl3) δ 0.80-
1.00 (m, 6H), 1.20-1.50 (m, 8H), 1.80-2.00 (m, 4H), 6.87-
6.91 (m, 1H), 6.99-7.07 (m, 1H), 7.15 (s, 1H), 7.39-7.48 (m,
1H), 7.88-7.93 (m, 1H); IR (KBr) 2957, 1678, 1610 cm-1; MS
m/ z 261 (M+). Anal. Calcd for C16H23NO2: C, 73.53; H, 8.87;
N, 5.36. Found: C, 73.50; H, 8.90; N, 5.42.
2,3-Dih yd r o-2,2-d ip en ta d eca n yl-4H-1,3-ben zoxa zin -4-
on e (9c) was isolated in 85% yield after FCC (hexane/AcOEt
95:5) of the crude product as a yellow oil: 1H NMR (CDCl3) δ
0.88 (t, J ) 6.4 Hz, 6H), 1.00-1.90 (m, 56H), 6.48 (s, 1H), 6.87-
6.92 (m, 1H), 7.00-7.08 (m, 1H), 7.38-7.48 (m, 1H), 7.88-
7.93 (m, 1H); IR (KBr) 2955, 1676, 1612 cm-1; MS m/ z 569
(20) Fuentes, L. M.; Shinkai, I.; King, A.; Purick, R.; Reamer, R. A.;
Schmitt, S. M.; Cama, L.; Christensen, B. G. J . Org. Chem. 1987, 52,
2563-2567.
(21) The structure of the phosphate 19 was confirmed through X-ray
analysis.10
(22) For example, see: reference 3.
(23) Seki, M.; Kondo, K.; Kuroda, T.; Yamanaka, T.; Iwasaki, T.
Synlett 1995, 609-611.
(24) (a) Moffett, R. B. Org. Synth. 1963, 4, 652-653. (b) Moffett,
R. B. Org. Synth. 1963, 4, 357-359.
(25) After completion of our work, a similar transformation using
pyrrolidones was reported in a patent literature: Asai, H.; Suzuki, K.;
Nakada, J .; Ishikawa, M.; Nakagawa, S. J apanese Patent 06,065,195
Mar 8, 1994. Chem. Abstr. 1994, 121, 35188m. For a related method,
see: Sunakawa, J .; Tamoto, K. J apanese Patent 02,178,262 J ul 11,
1990. Chem. Abstr. 1991, 114, 23689t.

Stereoselective Synthesis of 1-â-Methylcarbapenems
J . Org. Chem., Vol. 62, No. 9, 1997 2881
(M+). Anal. Calcd for C38H67NO2: C, 80.08; H, 11.85; N, 2.46.
Found: C, 80.15; H, 11.89; N, 2.61.
1H), 6.90-7.00 (m, 1H), 7.00-7.15 (m, 1H), 7.46-7.60 (m, 1H),
7.90-7.97 (m, 1H); IR (KBr) 1725, 1686, 1612 cm-1; MS m/ z
397 (M+ + 1). Anal. Calcd for C19H26BrNO3: C, 57.58; H, 6.61;
N, 3.53. Found: C, 57.37; H, 6.71; N, 3.81.
3-(2-Br om op r op ion yl)-2,3-d ih yd r o-2,2-d ip en ta d eca n yl-
4H-1,3-ben zoxa zin -4-on e (6c) was isolated in 64% yield after
FCC (hexane/AcOEt 95:5) of the crude product as a pale yellow
oil: 1H NMR (CDCl3) δ 0.88 (t, J ) 6.4 Hz, 6H), 1.00-2.50 (m,
56H), 1.96 (d, J ) 6.7 Hz, 3H), 5.26 (q, J ) 6.6 Hz, 1H), 6.91-
6.96 (m, 1H), 7.04-7.12 (m, 1H), 7.48-7.57 (m, 1H), 7.92-
7.97 (m, 1H); IR (KBr) 1722, 1685, 1614 cm-1; MS m/ z 705
(M+ + 1). Anal. Calcd for C41H70BrNO3: C, 69.86; H, 10.01;
N, 1.99. Found: C, 69.68; H, 9.95; N, 2.03.
3-(2-Br om op r op ion yl)sp ir o[2H -1,3-b en zoxa zin e-2,1′-
cyclop en ta n ]-4(3H)-on e (6d ) was isolated in 67% yield as
colorless crystals: mp 76-78 °C (from CHCl3-MeOH); 1H
NMR (CDCl3) δ 1.70-2.60 (m, 8H), 1.97 (d, J ) 8.7 Hz, 3H),
5.25 (q, J ) 8.7 Hz, 1H), 6.90-7.20 (m, 2H), 7.50-7.60 (m,
1H), 7.91-7.95 (m, 1H); IR (KBr) 1722, 1685, 1611 cm-1; MS
m/ z 339 (M+ + 1). Anal. Calcd for C15H16BrNO3: C, 53.27;
H, 4.77; N, 4.14. Found: C, 53.12; H, 4.67; N, 3.98.
Sp ir o[2H -1,3-b e n zoxa zin e -2,1′-cyclop e n t a n ]-4(3H )-
on e (9d ) was isolated in 69% yield after FCC (hexane/AcOEt
95:5) of the crude product as a colorless oil (lit.8b mp 135-137
°C): 1H NMR (DMSO-d6) δ 1.62-2.20 (m, 8H), 6.95-7.15 (m,
2H), 7.45-7.55 (m, 1H), 7.74-7.79 (m, 1H), 8.78 (brs, 1H); IR
(KBr) 3185, 1671, 1611 cm-1; MS m/ z 203 (M+). Anal. Calcd
for C12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found: C, 70.67;
H, 6.62; N, 6.89.
Sp ir o[2H -1,3-b e n zoxa zin e -2,1′-cycloh e p t a n ]-4(3H )-
on e (9f) was isolated in 86% yield as colorless crystals: mp
154-156 °C (from hexane) (lit.8b mp 155.1-156.8 °C); 1H NMR
(CDCl3) δ 1.40-1.85 (m, 8H), 1.96 (dd, J ) 9.0, 14.5 Hz, 2H),
2.26 (dd, J ) 7.9, 14.4 Hz, 2H), 6.90-6.95 (m, 1H), 7.04-7.09
(m, 1H), 7.39-7.49 (m, 1H), 7.87-7.93 (m, 1H); IR (KBr) 1667,
1612, 1418, 1385 cm-1; MS m/ z 231 (M+). Anal. Calcd for
C14H17NO2: C, 72.70; H, 7.41; N, 6.06. Found: C, 72.84; H,
7.51; N, 6.43.
2,2-Diben zyl-2,3-d ih yd r o-4H-1,3-ben zoxa zin -4-on e (9g)
was isolated in 74% yield as colorless crystals: mp 159-161
°C (from Et2O); 1H NMR (CDCl3) δ 3.16 (s, 4H), 6.99-7.06 (m,
2H), 7.06-7.30 (m, 10H), 7.40-7.51 (m, 2H), 7.82-7.87 (m,
1H); IR (KBr) 3066, 1676, 1612 cm-1; MS m/ z 330 (M+ + 1).
Anal. Calcd for C22H19NO2: C, 80.22; H, 5.81; N, 4.25.
Found: C, 80.26; H, 6.04; N, 4.08.
3-(2-Br om op r op ion yl)sp ir o[2H -1,3-b en zoxa zin e-2,1′-
cycloh ep ta n ]-4(3H)-on e (6f) was isolated in 92% yield after
FCC (hexane/AcOEt 10:1) of the crude product as a pale yellow
1
solid: mp 94-96 °C; H NMR (CDCl3) δ 1.30-2.00 (m, 8H),
1.92 (d, J ) 6.6 Hz, 3H), 2.10-2.65 (m, 4H), 5.19 (q, J ) 6.6
Hz, 1H), 6.97-7.03 (m, 1H), 7.06-7.15 (m, 1H), 7.50-7.60 (m,
P r ep a r a tion of P yr r olid on es. 5,5-Dim eth yl-2-p yr r o-
lid in on e (22a ) was prepared according to the literature24 in
86% yield after distillation as a colorless solid: bp 125 °C/13
mmHg (lit.24 bp 126.5-128.5 °C/12 mmHg); mp 39-40 °C (lit.24
mp 42-43 °C); 1H NMR (CDCl3) δ 1.29 (s, 6H), 1.92 (t, J ) 7.9
Hz, 2H), 2.42 (t, J ) 8.0 Hz, 2H), 6.93 (brs, 1H); IR (KBr) 3222,
1H), 7.89-7.95 (m, 1H); IR (KBr) 1717, 1684, 1610, 1469 cm-1
;
MS m/ z 367 (M+ + 1). Anal. Calcd for C17H20BrNO3: C,
55.75; H, 5.50; N, 3.82. Found: C, 55.55; H, 5.54; N, 4.14.
3-(2-Br om op r op ion yl)-2,2-d ib en zyl-4-2,3-d ih yd r o-4H -
1,3-ben zoxa zin -4-on e (6g) was isolated in 77% yield as
colorless crystals: mp 114-115 °C (from i-Pr2O); 1H NMR
(CDCl3) δ 1.45 (d, J ) 6 Hz, 3H), 3.23 (d, J ) 16 Hz, 1H), 3.40
(d, J ) 16 Hz, 1H), 3.72 (d, J ) 16 Hz, 2H), 5.25 (q, J ) 6 Hz,
1H), 7.00-7.12 (m, 2H), 7.10-7.35 (m, 10H), 7.55-7.64 (m,
1H), 7.80-7.85 (m, 1H); IR (KBr) 1694, 1611 cm-1; MS m/ z
464 (M+). Anal. Calcd for C25H22BrNO3: C, 64.66; H, 4.78;
N, 3.02. Found: C, 64.88; H, 4.99; N, 2.99.
1699, 1388 cm-1; MS m/ z 113 (M+). Anal. Calcd for C6H11
-
NO: C, 63.69; H, 9.80; N, 12.38. Found: C, 63.85; H, 9.90; N,
12.55.
Sp ir o(p yr r olid in e-5,1′-cycloh exa n )-2-on e (22e) was pre-
pared according to the literature24 in 65% yield from nitro-
cyclohexane after FCC(CHCl3/Et2O 20:1) of the crude product
as a colorless solid: mp 130-131 °C; 1H NMR (CDCl3) δ 1.30-
1.70 (m, 10H), 1.90 (t, J ) 8.1 Hz, 2H), 2.38 (t, J ) 8.1 Hz,
2H), 7.08 (brs, 1H); IR (KBr) 3210, 1693, 1278 cm-1; MS m/ z
153 (M+). Anal. Calcd for C9H15NO: C, 70.55; H, 9.87; N,
9.14. Found: C, 70.43; H, 9.86; N, 9.28.
1-(2-Br om op r op ion yl)-2-p yr r olid on e (23h ) was isolated
in 92% yield after FCC (hexane/AcOEt 2:1) of the crude product
as a colorless oil: 1H NMR (CDCl3) δ 1.82 (d, J ) 6.8 Hz, 3H),
2.01-2.17 (m, 2H), 2.61-2.71 (m, 2H), 3.82-3.90 (m, 2H), 5.69
(q, J ) 6.8 Hz, 1H); IR (KBr) 1740, 1694, 1367, 1255 cm-1
;
Gen er a l P r oced u r e for th e Acyla tion of Au xilia r ies.
3-(2-Br om op r op ion yl)sp ir o[2H -1,3-b en zoxa zin e-2,1′-cy-
cloh exa n ]-4(3H)-on e (6e). To a mixture of 9e (140 g, 0.644
mol), pyridine (61.1 g, 0.773 mol) and toluene (700 mL) was
added 2-bromopropionyl bromide (168 g, 0.773 mol) at 5 to 15
°C. This mixture was stirred at the same temperature for 30
min and then at 25 °C for 17 h. The reaction mixture was
poured into water (700 mL). The organic layer was washed
successively with saturated aqueous NaHCO3 (100 mL) and
brine (60 mL), dried over anhydrous MgSO4, and evaporated
in vacuo. The residue was dissolved in 2-propanol (60 mL) at
50 to 55 °C, gradually cooled to 10 °C, and stirred at the same
temperature for 1 h. The resulting crystals were collected,
washed with 2-propanol (140 mL), and dried at 40 °C for 17 h
to afford 197.3 g (87%) of 6e as colorless crystals: mp 74-76
MS m/ z 221 (M+ + 1). Anal. Calcd for C7H10BrNO2: C, 38.21;
H, 4.58; N, 6.36. Found: C, 38.12; H, 4.80; N, 6.19.
1-(2-Br om opr opion yl)-5,5-dim eth yl-2-pyr r olidon e (23a)
was isolated in 79% yield after FCC (hexane/AcOEt 4:1) of the
crude product as a colorless oil: 1H NMR (CDCl3) δ 1.52 (s,
6H), 1.80 (d, J ) 6.7 Hz, 3H), 1.87-1.99 (m, 2H), 2.52-2.61
(m, 2H), 5.76 (q, J ) 6.7 Hz, 1H); IR (KBr) 1740, 1699, 1356,
1293 cm-1; MS m/ z 250 (M+ + 1). Anal. Calcd for C9H14
-
BrNO2: C, 43.57; H, 5.69; N, 5.65. Found: C, 43.71; H, 5.56;
N, 5.49.
1-(2-Br om op r op ion yl)sp ir o(p yr r olid in e-5,1′-cycloh ex-
a n )-2-on e (23e) was isolated in 34% yield after FCC (CHCl3/
Et2O 20:1) of the crude product as a colorless solid: mp 46-
48 °C; 1H NMR (CDCl3) δ 1.10-2.00 (m, 10H), 1.79 (d, J ) 6.7
Hz, 3H), 2.40-2.60 (m, 4H), 5.80 (q, J ) 6.7 Hz, 1H); IR (KBr)
1740, 1698, 1451 cm-1; MS m/ z 289 (M+ + 1). Anal. Calcd
for C12H18BrNO2: C, 54.56; H, 5.15; N, 3.98. Found: C, 54.47;
H, 5.26; N, 4.03.
Gen er a l P r oced u r e for Zin c-In d u ced Refor m a tsk y-
Typ e Rea ction . 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-(ter t-Bu tyld i-
m eth ylsilyloxy)eth yl]-2-oxoazetidin -4-yl]pr opion yl}spir o-
[2H-1,3-ben zoxazin e-2,1′-cycloh exan ]-4(3H)-on e (7eâ) an d
its 3-{(2S)-2-[(3S,4R)-3-[(1R)-1-(ter t-bu tyldim eth ylsilyloxy)-
eth yl]-2-oxoa zetid in -4-yl]p r op ion yl} isom er (7er). A mix-
ture of 2 (5.0 g, 17.4 mmol) and zinc dust (3.4 g, 52 mg-atom)
in THF (50 mL) was heated under reflux for 5 min. To the
refluxing mixture was added dropwise a solution of the
bromide 6e (9.2 g, 26.1 mmol) in THF (20 mL) over 15 min.
After refluxing for 5 min, the mixture was cooled, poured into
phosphate buffer (pH 7.0, 200 mL), and extracted with CH2-
Cl2 (1 × 200 mL, 2 × 50 mL). The combined extracts were
washed with brine, dried over anhydrous MgSO4, and evapo-
1
°C; H NMR (CDCl3) δ 1.20-2.50 (m, 10H), 1.92 (d, J ) 6.6
Hz, 3H), 5.14 (q, J ) 6.6 Hz, 1H), 7.00-7.15 (m, 2H), 7.50-
7.60 (m, 1H), 7.90-7.95 (m, 1H); IR (KBr) 1723, 1682, 1613
cm-1; MS m/ z 353 (M+ + 1). Anal. Calcd for C16H18BrNO3:
C, 54.56; H, 5.15; N, 3.98. Found: C, 54.47; H, 5.26; N, 4.03.
3-(2-Br om opr opion yl)-2,3-dih yd r o-2,2-dim eth yl-4H-1,3-
ben zoxa zin -4-on e (6a ) was isolated in 72% yield as colorless
crystals: mp 63-66 °C (from hexane); 1H NMR (CDCl3) δ 1.75
(s, 3H), 1.90 (s, 3H), 1.92 (d, J ) 6 Hz, 3H), 5.22 (q, J ) 6Hz,
1H), 6.94-6.98 (m, 1H), 7.07-7.16 (m, 1H), 7.50-7.59 (m, 1H),
7.92-7.96 (m, 1H); IR (KBr) 1730, 1683, 1613 cm-1; MS m/ z
313 (M+ + 1). Anal. Calcd for C13H14BrNO3: C, 50.02; H, 4.52;
N, 4.49. Found: C, 50.07; H, 4.48; N, 4.63.
3-(2-Br om op r op ion yl)-2,2-d ibu tyl-2,3-d ih yd r o-4H-1,3-
ben zoxa zin -4-on e (6b) was isolated in 75% yield after FCC
(hexane/AcOEt 95:5) of the crude product as a colorless oil:
1H NMR (CDCl3) δ 0.70-0.90 (m, 6H), 1.10-1.70 (m, 8H), 1.96
(d, J ) 6.6 Hz, 3H), 2.00-2.50 (m, 4H), 5.25 (q, J ) 6.6 Hz,

2882 J . Org. Chem., Vol. 62, No. 9, 1997
Kondo et al.
rated in vacuo. The residue was purified by FCC (hexane/
AcOEt 4:1) to afford 8.3 g (95%) of 7eâ and 7eR (92/8,
estimated by HPLC), CH3CN/H2O 70:30, 1 mL/min, retention
time, 7eâ: 12.3 min, 7eR: 14.1 min). 1H NMR (CDCl3) δ 0.07
(s, 6H), 0.87 (s, 9H), 1.22 (d, J ) 6.3 Hz, 3H), 1.26 (d, J ) 7.1
Hz, 3H), 1.50-2.50 (m, 10H), 2.75-2.85 (m, 1H, R), 3.18-3.22
(m, 1H, â), 3.48-3.62 (m, 1H), 3.80-3.95 (m, 1H, R), 4.01-
4.05 (m, 1H, â), 4.18-4.24 (m, 1H), 5.93 (s, 1H, â), 6.10 (s, 1H,
R), 6.97-7.03 (m, 1H), 7.07-7.16 (m, 1H), 7.49-7.59 (m, 1H),
7.90-7.96 (m, 1H). A pure sample of 7eâ was obtained as
follows: the crude residue obtained by the evaporation of the
extracts was dissolved in a mixed solvent of EtOH and water
(65:35, 175 mL) at 90 to 95 °C. The mixture was gradually
cooled to 25 °C and stirred at 5 to 10 °C for 1 h. The resulting
crystals were collected, washed with a cooled mixture of EtOH
and water (65:35, 20 mL), and dried at 40 °C for 17 h to afford
6.5 g (75% based on 2) of pure 7eâ as colorless crystals: mp
156-157 °C; 1H NMR (CDCl3) δ 0.07 (s, 6H), 0.87 (s, 9H), 1.22
(d, J ) 6.3 Hz, 3H), 1.26 (d, J ) 7.1 Hz, 3H), 1.50-2.50 (m,
10H), 3.18-3.22 (m, 1H), 3.48-3.62 (m, 1H), 4.01-4.05 (m,
1H), 4.18-4.24 (m, 1H), 5.93 (s, 1H), 6.97-7.03 (m, 1H), 7.07-
7.16 (m, 1H), 7.49-7.59 (m, 1H), 7.90-7.96 (m, 1H); 13C NMR
(CDCl3) δ 183.2, 168.5, 163.4, 155.3 (4s), 136.0, 128.3, 122.4,
117.3 (4d), 117.3, 95.2 (2s), 65.4, 61.3, 51.6, 45.9 (4d), 33.1 (2t),
25.8 (q), 24.3 (t), 22.6 (q), 22.4, 22.3 (2t), 18.0 (s), 13.1 (q), -4.2
(q); IR (KBr) 2931, 1760, 1717, 1687, 1613 cm-1; MS m/ z 501
2-oxoa zetid in -4-yl]p r op ion yl} isom er (7cR) were isolated
in 64% yield after FCC (hexane/AcOEt 95:5) of the crude
product (7câ:7cR ) 98:2 estimated by 1H-NMR) as a pale
yellow oil: 1H NMR (CDCl3) δ 0.07 (s, 6H), 0.85 (s, 9H), 1.00-
2.40 (m, 68H), 2.78-2.82 (m, 1H, R), 3.14-3.18 (m, 1H, â),
3.65-3.85 (m, 1H), 3.90-4.00 (m, 1H, R), 4.06-4.10 (m, 1H,
â), 4.15-4.27 (m, 1H), 5.97 (s, 1H, â), 6.74-6.90 (m, 1H), 7.04-
7.13 (m, 1H), 7.48-7.57 (m, 1H), 7.89-7.95 (m, 1H); IR (Nujol)
;
2956, 1762, 1702, 1694 cm- MS m/ z 853 (M+ + 1). Anal.
Calcd for C52H92N2O5Si: C, 73.19; H, 10.87; N, 3.28. Found:
C, 73.05; H, 11.01; N, 3.19.
3-{(2R)-2-[(3S,4R)-3-[(1R)-1-(ter t-Bu tyldim eth ylsilyloxy)-
et h yl]-2-oxoa zet id in -4-yl]p r op ion yl}sp ir o[2,3-d ih yd r o-
4H-1,3-ben zoxa zin e-2,1′-cyclop en ta n ]-4-on e (7d â) a n d its
3-{(2S)-2-[(2S,4R)-3-[(1R)-1-(ter t-bu tyld im eth ylsilyloxy)-
eth yl]-2-oxoa zetid in -4-yl]p r op ion yl} isom er (7d R) were
isolated in 77% yield after FCC (hexane/AcOEt 4:1) of the
crude product (7d â:7d R ) 85:15 estimated by HPLC (CH3CN/
H2O 70:30, 0.5 mL/min, retention time: 7d â: 24.4 min, 7d R:
27.3 min) as a viscous oil: 1H NMR (CDCl3) δ 0.07 (s, 6H),
0.87 (s, 9H), 1.22 (d, J ) 6.2 Hz, 3H), 1.28 (d, J ) 7.0 Hz, 3H),
1.70-2.30 (m, 8H), 2.74-2.78 (m, 1H, R), 3.19-3.23 (m, 1H,
â), 3.60-3.71 (m, 1H), 3.72-3.79 (m, 1H, R), 3.99-4.03 (m,
1H, â), 4.10-4.20 (m, 1H), 5.96 (s, 1H, â), 6.03 (s, 1H, R), 6.92-
6.96 (m, 1H), 7.07-7.15 (m, 1H), 7.48-7.57 (m, 1H), 7.91-
7.96 (m, 1H); IR (Nujol) 2934, 1760, 1715, 1686, 1613, 1588
(M+ + 1); [R]25 + 39.2° (c, 1.01, MeOH). Anal. Calcd for
cm-1; MS m/ z 487 (M+ + 1); [R]25 +20.35° (c, 1.02, MeOH).
D
D
C27H40N2O5Si: C, 64.77; H, 8.05; N, 5.59. Found: C, 64.55;
H, 7.88; N, 6.02.
Anal. Calcd for C26H38N2O5Si: C, 64.17; H, 7.87; N, 5.76.
Found: C, 64.29; H, 8.01; N, 6.00.
3-{(2R)-2-[(3S,4R)-3-[(1R)-1-(ter t-Bu tyldim eth ylsilyloxy)-
eth yl]-2-oxoa zetid in -4-yl]p r op ion yl}-2,3-d ih yd r o-2,2-d i-
m eth yl-4H-1,3-ben zoxa zin -4-on e (7a â) a n d its 3-{(2S)-2-
[(3S,4R)-3-[(1R)-1-(ter t-b u t yld im et h ylsilyloxy)et h yl]-2-
oxoa zetid in -4-yl]p r op ion yl} isom er (7a R) were isolated in
94% yield after FCC (hexane/AcOEt 9:1) of the crude product
(7a â:7a R ) 85:15 estimated by HPLC, CH3CN/H2O 65:35, 1
mL/min, retention time, 7a â: 9.34 min, 7a R: 10.33 min): 1H
NMR (CDCl3) δ 0.08 (s, 6H), 0.85 (s, 9H), 1.23 (d, J ) 6.3 Hz,
3H), 1.27 (d, J ) 7.0 Hz, 3H), 1.76 (s, 3H), 1.78 (s, 3H), 2.80-
2.85 (m, 1H, R), 3.15-3.25 (m, 1H, â), 3.55-3.70 (m, 1H). 3.80-
3.87 (m, 1H, R), 4.00-4.05 (m, 1H, â), 4.14-4.28 (m, 1H), 6.01
(s, 1H, â), 6.08 (s, 1H, R), 6.92-6.97 (m, 1H), 7.07-7.15 (m,
1H), 7.49-7.59 (m, 1H), 7.90-7.95 (m, 1H). A pure sample of
7a â was obtained according to the procedure described above
3-{(2R)-2-[(3S,4R)-3-[(1R)-1-(ter t-Bu tyldim eth ylsilyloxy)-
et h yl]-2-oxoa zet id in -4-yl]p r op ion yl}sp ir o[2,3-d ih yd r o-
4H-1,3-ben zoxa zid in e-2,1′-cycloh ep ta n ]-4-on e (7fâ) a n d
its 3-{(2S)-2-[(3S,4R)-3-[(1R)-1-(ter t-bu tyldim eth ylsilyloxy)-
eth yl]-2-oxoa zetid in -4-yl]p r op ion yl} isom er (7fR) were
isolated in 38% yield after FCC (hexane/AcOEt 4:1) of the
crude product (7fâ:7fR ) 89:11 estimated by HPLC (CH3CN/
H2O 70:30, 0.5 mL/min, retention time, 7fâ: 21.5 min, 7fR:
25.0 min). 1H NMR (CDCl3) δ 0.07 (s, 6H), 0.85 (s, 9H), 1.22
(d, J ) 6.3 Hz, 3H), 1.26 (d, J ) 7.0 Hz, 3H), 1.40-1.90 (m,
8H), 1.90-2.45 (m, 4H), 2.75-2.90 (m, 1H, R), 3.15-3.25 (m,
1H, â), 3.48-3.66 (m, 1H), 3.80-3.87 (m, 1H, R), 4.01-4.06
(m, 1H, â), 4.10-4.30 (m, 1H), 5.95 (s, 1H, â), 6.06 (s, 1H, R),
6.96-7.01 (m, 1H), 7.06-7.15 (m, 1H), 7.49-7.59 (m, 1H),
7.89-7.94 (m, 1H). A pure sample of 7fâ was obtained
according to the procedure described above in 23% yield based
on 2: mp 146-147 °C (from hexane); 1H NMR (CDCl3) δ 0.07
(s, 6H), 0.85 (s, 9H), 1.22 (d, J ) 6.3 Hz, 3H), 1.26 (d, J ) 7.0
Hz, 3H), 1.40-1.90 (m, 8H), 1.90-2.45 (m, 4H), 3.15-3.25 (m,
1H), 3.48-3.66 (m, 1H), 4.01-4.06 (m, 1H), 4.10-4.30 (m, 1H),
5.95 (s, 1H), 6.96-7.01 (m, 1H), 7.06-7.15 (m, 1H), 7.49-7.59
(m, 1H), 7.89-7.94 (m, 1H); IR (KBr) 1761, 1721, 1685, 1611,
1
in 60% yield based on 2: mp 133-134 °C (from hexane); H
NMR (CDCl3) δ 0.08 (s, 6H), 0.85 (s, 9H), 1.23 (d, J ) 6.3 Hz,
3H), 1.27 (d, J ) 7.0 Hz, 3H), 1.76 (s, 3H), 1.78 (s, 3H), 3.15-
3.25 (m, 1H), 3.55-3.70 (m, 1H), 4.00-4.05 (m, 1H), 4.14-
4.28 (m, 1H), 6.08 (s, 1H), 6.92-6.97 (m, 1H), 7.07-7.15 (m,
1H), 7.49-7.59 (m, 1H), 7.90-7.95 (m, 1H); IR (KBr) 2930,
;
2760, 1761, 1720, 1691, 1613, 1585 cm- MS m/ z 461 (M+
+
1); [R]25D + 39.0° (c, 1.01, MeOH). Anal. Calcd for C24H36N2O5-
Si: C, 62.58; H, 7.88; N, 6.08. Found: C, 62.34; H, 7.67; N,
6.01.
1469 cm-1; MS m/ z 515 (M+ + 1); [R]25 +38.8° (c, 0.55,
D
MeOH). Anal. Calcd for C28H42N2O5Si: C, 65.34; H, 8.22; N,
4.67. Found: C, 65.45; H, 8.36; N, 4.58.
3-{(2R)-2-[(3S,4R)-3-[(1R)-1-(ter t-Bu tyldim eth ylsilyloxy)-
eth yl]-2-oxoa zetid in -4-yl]p r op ion yl}-2,2-d ibu tyl-2,3-d ih y-
d r o-4H -1,3-b en zoxa zin -4-on e (7b â) a n d it s 3-{(2S)-2-
[(3S,4R)-3-[(1R)-1-(ter t-b u t yld im et h ylsilyloxy)et h yl]-2-
oxoa zetid in -4-yl]p r op ion yl} isom er (7bR) were isolated in
87% yield after FCC (hexane/AcOEt 95:5) of the crude product
(7bâ:7bR ) 98:2 estimated by HPLC, CH3CN/H2O 70:30, 1 mL/
min, retention time, 7bâ: 29.3 min, 7bR: 33.5 min) as a
viscous oil: 1H NMR (CDCl3) δ 0.08 (s, 6H), 0.86 (s, 9H), 1.23
(d, J ) 6.3 Hz, 3H), 1.29 (d, J ) 7.0 Hz, 3H), 1.40-1.65 (m,
12H), 1.95-2.50 (m, 6H), 2.75-2.85 (m, 1H, R), 3.10-3.20 (m,
1H, â), 3.70-3.83 (m, 1H), 3.90-4.05 (m, 1H, R), 4.07-4.10
(m, 1H, â), 4.15-4.28 (m, 1H), 6.00 (s, 1H, â), 6.09 (s, 1H, R),
6.88-6.95 (m, 1H), 7.05-7.13 (m, 1H), 7.49-7.58 (m, 1H),
7.90-7.95 (m, 1H); IR (Nujol) 2958, 1763, 1705, 1695, 1612
3-{(2R)-2-[(3S,4R)-3-[(1R)-1-(ter t-Bu tyldim eth ylsilyloxy)-
eth yl]-2-oxoa zetid in -4-yl]p r op ion yl}-2,2-d iben zyl-2,3-d i-
h yd r o-4H-1,3-ben zoxa zin -4-on e (7gâ) a n d its 3-{(2S)-2-
[(3S,4R)-3-[(1R)-1-(ter t-b u t yld im et h ylsilyloxy)et h yl]-2-
oxa zetid in -4-yl]p r op ion yl} isom er (7gR) were isolated in
76% yield after FCC (hexane/AcOEt 95:5) of the crude product
(7gâ:7gR ) 99.6:0.4 estimated by HPLC (CH3CN/H2O 70:30,
1 mL/min, retention time, 7gâ: 30.26 min, 7gR: 34.65 min)
as a colorless solid: mp 75-78 °C; 1H NMR (CDCl3) δ 0.05 (s,
6H), 0.52 (d, J ) 7.0 Hz, 3H), 0.82 (s, 9H), 0.80-0.94 (m, 1H),
1.20 (d, J ) 6.3 Hz, 3H), 1.20-1.35 (m, 3H), 2.93-2.96 (m,
1H), 3.15-3.35 (m, 2H), 3.40-3.80 (m, 3H), 4.05-4.17 (m, 1H),
5.50 (s, 1H), 7.09-7.25 (m, 12H), 7.60-7.69 (m, 1H), 7.88-
7.93 (m, 1H); IR (Nujol) 2930, 1760, 1695, 1612, 1592 cm-1
;
MS m/ z 613 (M+ + 1); [R]25 +43.8° (c, 1.03, MeOH). Anal.
D
cm-1; MS m/ z 545 (M+ + 1); [R]25 +35.3° (c, 1.06, MeOH).
Calcd for C36H44N2O5Si: C, 70.56; H, 7.24; N, 4.57. Found:
C, 70.33; H, 7.49; N, 4.88.
D
Anal. Calcd for C30H48N2O5Si: C, 66.14; H, 8.88; N, 5.14.
Found: C, 66.35; H, 8.99; N, 4.93.
3-{(2R)-2-[(3S,4R)-3-[(1R)-1-(ter t-Bu tyldim eth ylsilyloxy)-
eth yl]-2-oxoa zetid in -4-yl]p r op ion yl}-2,3-d ih yd r o-2,2-d i-
p en ta d eca n yl-4H-1,3-ben zoxa zin -4-on e (7câ) a n d its 3-{-
(2S)-2-[(3S,4R)-3-[(1R)-1-(ter t-bu tyldim eth ylsilyloxy)eth yl]-
3-{(2R)-2-[(3S,4R)-3-[(1R)-1-(ter t-Bu tyldim eth ylsilyloxy)-
eth yl]-2-oxoazetidin -4-yl]pr opion yl}-2-pyr r olidon e (24h â)
a n d its 3-[(2S)-2-[(3S,4R)-3-[(1R)-1-(ter t-bu tyld im eth yl-
silyloxy)et h yl]-2-oxop yr r olid in -4-yl]p r op ion yl} isom er
(24h R) were isolated in 28% yield after FCC (hexane/AcOEt

Stereoselective Synthesis of 1-â-Methylcarbapenems
J . Org. Chem., Vol. 62, No. 9, 1997 2883
1:2) of the crude product (24h â:24h R ) 63:37 estimated by
HPLC (CH3CN/H2O 45:55, 1 mL/min, retention time, 24h â:
13.3 min, 24h R: 15.4 min) as a colorless solid: mp 68-140
°C; 1H NMR (CDCl3) δ -0.07 (s, 6H), 0.85, 0.86 (3s, 9H), 1.18
(d, J ) 6.4 Hz, 3H), 1.24 (d, J ) 6.2 Hz, 3H, R), 1.25 (d, J )
6.2 Hz, 3H, â), 1.95-2.12 (m, 2H), 2.58-2.67 (m, 2H), 2.77-
2.80 (m, 1H, R), 2.95-2.98 (m, 1H, â), 3.60-3.85 (m, 1H, R),
3.89-3.93 (m, 1H, â), 3.80 (t, J ) 7.5 Hz, 2H), 4.03-4.30 (m,
2H), 5.91 (s, 1H, R), 5.98 (s, 1H, â); IR (KBr) 1765, 1743, 1685,
1461 cm-1; MS m/ z 325 (M+ - 43). Anal. Calcd for
C18H32N2O4Si: C, 58.66; H, 8.75; N, 7.60. Found: C, 58.81;
H, 8.91; N, 7.54.
3-{(2R)-2-[(3S,4R)-3-[(1R)-1-(ter t-Bu tyldim eth ylsilyloxy)-
eth yl]-2-oxoa zetid in -4-yl]p r op ion yl}-5,5-d im eth yl-2-p yr -
r olid in on e (24aâ) a n d its 3-{(2S)-2-[(3S,4R)-3-[(1R)-1-(ter t-
b u t y l d i m e t h y l s i l y l o x y )e t h y l ]-2 -o x o p y r r o l i d i n -4 -
yl]p r op ion yl} isom er (24a R) were isolated in 73% yield after
FCC (hexane/AcOEt 2:1) of the crude product (24a â:24a R )
94:6 estimated by HPLC (CH3CN/H2O 60:40, 1 mL/min,
retention time, 24a â: 10.9 min, 24a R; 12.7 min) as colorless
crytals: mp 132-134 °C (from i-Pr2O); 1H NMR (CDCl3) δ 0.05
(s, 6H), 0.85 (s, 9H), 1.14 (d, J ) 6.9 Hz, 3H), 1.19 (d, J ) 7.5
Hz, 3H), 1.43 (s, 6H), 1.81 (t, J ) 8.1 Hz, 2H), 2.47 (t, J ) 8.1
Hz, 2H), 2.70-2.80 (m, 1H, R), 2.95-3.00 (m, 1H, â), 3.60-
3.85 (m, 1H, R), 3.88-3.91 (m, 1H, â), 4.01-4.24 (m, 2H), 5.85
(s, 1H, â); IR (KBr) 1763, 1737, 1693 cm-1; MS m/ z 353 (M+
- 43); [R]25D +0.74° (c, 1.09, MeOH, 24a â:24a R ) 94:6). Anal.
Calcd for C20H36N2O4Si: C, 60.57; H, 9.15; N, 7.06. Found:
C, 60.37; H, 9.10; N, 6.91.
The resulting precipitate was collected by filteration, washed
with H2O, and dried to afford 200 mg (92%) of 9e as a colorless
solid. The filtrate was washed with CHCl3, and the aqueous
layer was acidified to pH 1 with 10% aqueous HCl. The
mixture was extracted with AcOEt. The organic layer was
dried over anhydrous MgSO4 and evaporated in vacuo. The
residual solid was recrystallized from hexane/AcOEt to afford
216 mg of 16 (72%) as colorless crystals: mp 146-147 °C; [R]25
D
+33.5° (c, 1.0, MeOH) [lit.7 mp 147 °C; [R]25 +32.4° (c, 0.17,
D
MeOH)].
Ma gn esiu m -In d u ced Refor m a tsk y-Typ e Rea ction . (a )
With ou t Ad d ed Cp 2TiCl2. To a suspension of magnesium
(0.44 g, 18 mg-atom) in THF (10 mL) was added dropwise a
solution of 1,2-dibromoethane (2.26 g, 12.0 mmol) in THF (5
mL). The mixture was heated under reflux for 30 min and
cooled to -5 °C. To the mixture was added dropwise a solution
of 2 (1.15 g, 4.0 mmol) and 6e (2.11 g, 6.0 mmol) in THF (5
mL) at the same temperature. The mixture was stirred at 10
°C for 1 h. The reaction mixture was quenched with phosphate
buffer (pH 7.0, 30 mL) and extracted with AcOEt (2 × 30 mL).
The combined extracts were washed with brine (30 mL), dried
over anhydrous MgSO4, and evaporated in vacuo. The residue
was purified by FCC (hexane/AcOEt 3:1) to afford a mixture
of 7eâ and 7eR (99:1, HPLC) as a colorless solid. Recrystal-
lization from 65% aqueous EtOH gave pure 7eâ (0.54 g, 54%)
as colorless crystals, identical with the authentic sample
prepared as above.
(b) With Cp 2TiCl2. To a suspension of magnesium (0.22
g, 9 mg-atom) in THF (5 mL) was added dropwise a solution
of 1,2-dibromoethane (1.13 g, 6.0 mmol) in THF (3 mL). The
resulting mixture was heated under reflux for 30 min. After
cooling to 0 °C, Cp2TiCl2 (0.075 g, 0.3 mmol) was added, and
the mixture was stirred for 5 min. To this mixture, a solution
of 2 (0.57 g, 2.0 mmol) and 6e (1.06 g, 3.0 mmol) in THF (3
mL) was added dropwise, and the mixture was stirred for 30
min at 0 °C. The reaction mixture was quenched with
saturated aqueous NH4Cl (30 mL) and extracted with AcOEt
(2 × 30 mL). The combined extracts were washed with brine
(30 mL), dried over anhydrous MgSO4, and evaporated in
vacuo to afford a mixture of 7eâ and 7eR (99:1, HPLC) as a
colorless solid. This material was recrystallized as described
in a to give 0.73 g (73%) of pure 7eâ, identical with that
prepared as above.
3-{(2R)-2-[(3S,4R)-3-[(1R)-1-(ter t-Bu tyldim eth ylsilyloxy)-
et h yl]-2-oxoa zet id in -4-yl]p r op ion yl}sp ir o[p yr r olid on e-
5,1′-cycloh exa n ]-2-on e (24eâ) a n d its 3-{(2S)-2-[(3S,4R)-
3 -[ ( 1 R ) -1 -( t e r t -b u t y l d i m e t h y l s i l y l o x y ) e t h y l ] -2 -
oxop yr r olid in -4-yl]p r op ion yl} isom er (24eR) were isolated
in 84% yield (24eâ:24eR ) 95:5 estimated by HPLC (CH3CN/
H2O 60:40, 1 mL/min, retention time, 24eâ: 15.8 min, 24eR:
19.1 min) as colorless crystals: mp 110-111 °C (from hexane);
1H NMR (CDCl3) δ -0.01 (s, 3H), 0.06 (s, 3H), 0.86 (s, 9H),
1.14 (d, J ) 6.5 Hz, 3H), 1.20 (d, J ) 6.3 Hz, 3H), 1.20-1.80
(m, 8H), 1.80-2.10 (m, 2H), 2.44-2.58 (m, 2H), 2.50-2.60 (m,
2H), 2.75-2.85 (m, 1H, R), 2.95-3.05 (m, 1H, â), 3.65-3.80
(m, 1H, R), 3.90-3.92 (m, 1H, â), 4.05-4.25 (m, 2H), 5.88 (s,
1H, â); IR (KBr) 1765, 1732, 1699, 1461 cm-1; MS m/ z 436
(M+); [R]25 -7.68° (c, 0.99, MeOH, 24eâ:24eR ) 95:5). Anal.
3-{(2R)-2-[(3S,4R)-1-[(Allyloxycar bon yl)m eth yl]-3-[(1R)-
1-(ter t-bu tyld im eth ylsilyloxy)eth yl]-2-oxoa zetid in -4-yl]-
p r op ion yl}sp ir o[2H-1,3-ben zoxa zin e-2,1′-cycloh exa n ]-4-
(3H)-on e (8eâ). To a solution of the azetidinone 7eâ (7.1 g,
0.0142 mol) and allyl bromoacetate (2.94 g, 0.0164 mol) in THF
(36 mL) was added NaN(TMS)2 (1 M in THF) (17 mL, 0.017
mol) at -50 to -45 °C over 15 min. After stirring at -45 °C
for 1 h, the mixture was poured into 10% aqueous citric acid
(100 mL) and extracted with AcOEt (1 × 100 mL, 1 × 50 mL).
The combined extracts were washed successively with water
(100 mL), saturated aqueous NaHCO3 (100 mL), and water
(100 mL), dried over anhydrous MgSO4, and evaporated in
vacuo. The residue was purified by FCC (hexane/AcOEt 8:1)
to afford 8.07 g (95%) of 8eâ as a colorless viscous oil: 1H NMR
(CDCl3) δ 0.05 (s, 3H), 0.06 (s, 3H), 0.77 (s, 9H), 1.28 (d, J )
7.2 Hz, 3H), 1.29 (d, J ) 7.1 Hz, 3H), 1.60-1.80 (m, 6H), 1.90-
2.40 (m, 4H), 3.06 (dd, J ) 2.2, 7.3 Hz, 1H), 3.64 (dq, J ) 2.2,
7.0 Hz, 1H), 4.05-4.20 (m, 2H), 3.99 (d, J ) 17.9 Hz, 1H), 4.35
(d, J ) 17.9 Hz, 1H), 4.55-4.70 (m, 2H), 5.20-5.45 (m, 2H),
5.80-6.05 (m, 1H), 6.95-7.15 (m, 2H), 7.50-7.60 (m, 1H),
7.90-8.00 (m, 1H); IR (KBr) 2936, 1768, 1740, 1710, 1680,
D
Calcd for C23H40N2O4Si: C, 63.26; H, 9.23; N, 6.42. Found:
C, 63.31; H, 9.42; N, 6.15.
3-[(Z)-1-(Tr im et h ylsilyloxy)-1-p r op en yl]sp ir o[2H -1,3-
ben zoxa zin e-2,1′-cycloh exa n ]-4-(3H)-on e (14e). To a mix-
ture of 6e (494 mg, 1.4 mmol) and zinc dust (189 mg, 2.9 mg-
atom) in THF-d8 (6 mL) was added TMSCl (1.78 mL, 14 mmol)
at room temperature under nitrogen atmosphere. The mixture
was heated under reflux for 3 min. After cooling, analysis of
1
this mixture by H NMR spectroscopy indicated to be a 71:29
mixture of 14e and 3-propionylspiro[2H-1,3-benzoxazine-2,1′-
cyclohexan]-4(3H)-one (15e): 1H NMR (CDCl3) δ 0.23 (s, 9H,
14e), 1.50-2.40 (m, 10H), 1.21 (t, J ) 7.4 Hz, 3H, 15e), 1.65
(d, J ) 6.8 Hz, 3H, 14e), 2.84 (q, J ) 7.4 Hz, 2H, 15e), 4.76 (q,
J ) 6.8 Hz, 1H, 14e), 6.93-7.14 (m, 2H), 7.39-7.57 (m, 1H),
7.91-7.98 (m, 1H). THe reaction mixture was quenched with
water (5 mL) and extracted with ACOEt (10 mL). The organic
layer was washed with water, dried over anhydrous MgSO4,
and evaporated in vacuo. THe residue was crystallized from
hexane at -20 °C to afford 164 mg of 14e (27%) as colorless
crystals: mp 116-117 °C; 1H NMR (CDCl3) δ 0.23 (s, 9H),
1.50-2.40 (m, 10H), 1.65 (d, J ) 6.8 Hz, 3H), 4.76 (q, J ) 6.8
Hz, 1H), 6.93-7.14 (m, 2H), 7.39-7.57 (m, 1H), 7.91-7.98 (m,
1H); IR (KBr) 1673, 1613, 1468 cm-1; MS m/ z 345 (M+). Anal.
Calcd for C19H27NO3Si: C, 66.05; H, 7.88; N, 4.05. Found: C,
66.16; H, 7.89; N, 4.01
(3S,4S)-3-[(R)-1-(ter t-Bu t yld im et h ylsilyloxy)et h yl]-4-
[(R)-1-ca r boxyeth yl]-2-a zetizin on e (16). To a solution of
7eâ (500 mg, 1.0 mmol) in THF 15 mL) and water (5 mL) were
added 30% aqueous H2O2 (0.9 mL, 8.0 mmol) and LiOH (84
mg, 2.0 mmol) at 0 °C. The mixture was stirred at the same
temperature for 1 h. To this mixture was added 1.5 N aqueous
Na2SO4 (5 mL) at 0 °C, and the THF was evaporated in vacuo.
1612, 1588 cm-1; MS m/ z 599 (M+ + 1); [R]25 -3.77° (c, 0.88,
D
MeOH). Anal. Calcd for C32H46N2O7Si: C, 64.19; H, 7.74; N,
4.68. Found: C, 64.45; H, 8.02; N, 4.89.
3-{(2R)-2-[(3S,4R)-1-[(Allyloxycar bon yl)m eth yl]-3-[(1R)-
1-(ter t-bu tyld im eth ylsilyloxy)eth yl]-2-oxoa zetid in -4-yl]-
pr opion yl}spir o[pyr r olidon e-5,1′-cycloh exan ]-2-on e (25e)
was isolated in 89% yield after FCC(hexane/AcOEt 4:1) of the
crude product as a colorless oil: 1H NMR (CDCl3) δ 0.05 (s,
3H), 0.07 (s, 3H), 0.85 (s, 9H), 1.17 (d, J ) 7.0 Hz, 3H), 1.27
(d, J ) 6.1 Hz, 3H), 1.30-1.80 (m, 8H), 1.80-2.10 (m, 2H),
2.37-2.60 (m, 2H), 2.43-2.51 (m, 2H), 2.95-3.01 (m, 1H),
3.70-3.80 (m, 2H), 4.00-4.25 (m, 3H), 4.63 (d, J ) 5.6 Hz,

2884 J . Org. Chem., Vol. 62, No. 9, 1997
Kondo et al.
2H), 5.20-5.39 (m, 2H), 5.82-6.20 (m, 1H); IR (KBr) 2934,
1764, 1745, 1693 cm-1; MS m/ z 534 (M+); [R]25D +7.20° (c, 1.00,
MeOH). Anal. Calcd for C28H46N2O6Si: C, 62.89; H, 8.67; N,
5.24. Found: C, 62.99; H, 8.75; N, 5.11.
mmol) in THF (6 mL) at -35 to -25 °C over 1 min, and the
mixture was stirred at the same temperature for 10 min.
Diphenyl phosphorochloride (0.67 g, 2.5 mmol) was added at
-30 °C, and the mixture was stirred at 0 °C for 2 h. The
reaction mixture was processed as described above. The crude
product obtained from the evaporation was suspended in
i-Pr2O (10 mL) and stirred at 5 °C for 1 h. The resulting
crystals were collected by filteration to recover 0.38 g (87% of
9e. The filtrate was evaporated in vacuo, and the residue was
purified by FCC (hexane:AcOEt ) 4:1) to afford 0.22 g (18%)
of 10, identical with the authentic sample prepared as above.
The second fraction contained 19, which was recrystallized
from AcOEt to afford 135 mg (15%) of 19 as colorless crystals:
mp 100-102 °C; 1H NMR (CDCl3) δ 1.20-2.20 (m, 10H), 6.60-
7.60 (m, 14H); IR (KBr) 1673, 1589, 1485 cm-1; MS m/ z 449
(M+). Anal. Calcd for C25H24NO5P: C, 66.81; H, 5.38; N, 3.12.
Found: C, 66.96; H, 5.51; N, 3.05.
Dieck m a n n -Typ e Cycliza tion . (a ) With TMSCl. Allyl
(4R,5R,6S)-6-[(R)-1-(ter t-bu tyld im eth ylsilyloxy)eth yl]-3-
(d ip h en oxyp h osp h or yloxy)-4-m eth yl-7-oxo-1-a za bicyclo-
[3.2.0]h ep t-2-en e-2-ca r boxyla te (10). Into a solution of
NaN(TMS)2 (1 M in THF, 34 mL, 34.0 mmol) was added
dropwise 8eâ (8.07 g, 13.5 mmol) in THF (42 mL) at -35 to
-25 °C over 10 min. TMSCl (1.91 g, 17.6 mmol) was added
at -30 °C and the mixture was stirred at the same temper-
ature for 2 min. Diphenyl phosphorochloridate (4.54 g, 16.9
mmol) was then added at -30 °C, and the mixture was stirred
at 0 °C for 2 h. The reaction mixture was poured into
phosphate buffer (pH 7.0, 100 mL) and extracted with AcOEt
(1 × 100 mL, 1 × 50 mL). The combined extracts were washed
successively with the phosphate buffer (2 × 100 mL) and brine
(100 mL), dried over anhydrous MgSO4, and evaporated in
vacuo. The residue was suspended in hexane (70 mL) and
stirred at 5 °C for 1 h. The resulting crystals were collected
by filteration and washed with hexane to recover 2.6 g (85%)
of 9e. The filtrate was evaporated in vacuo, and the residue
was purified by FCC (hexane/AcOEt 4:1) to afford 6.76 g (82%)
of 10 as a viscous colorless oil: 1H NMR (CDCl3) δ 0.07 (s,
6H), 0.88 (s, 9H), 1.18 (d, J ) 7.5 Hz, 3H), 1.22 (d, J ) 6.3 Hz,
3H), 3.20-3.30 (m, 1H), 3.30-3.50 (m, 1H), 4.00-4.30 (m, 2H),
4.64 (d, J ) 5.4 Hz, 2H), 5.10-5.40 (m, 2H), 5.75-5.95 (m,
1H), 7.10-7.40 (m, 10H); 13C NMR (CDCl3) δ 175.4, 159.0,
154.9, 150.1 (4s), 131.4, 130.0, 129.9, 126.0, 125.9, 120.0 (6d),
119.8, 119.0 (2s), 118.4 (1), 66.0 (d), 65.6 (t), 61.3, 54.2, 39.4
(3d), 25.7, 22.4 (2q), 17.9 (s), 14.6, -4.2, -5.0 (3q); IR (Nujol)
(c) Cycliza tion of 25e. To a solution of NaN(TMS)2 (1 M
in THF, 1.20 mL, 1.2 mmol) in THF (1.5 mL) was added
dropwise a solution of 25e (301 mg, 0.56 mmol) in THF (1 mL)
at 0 °C. The mixture was stirred at the same temperature
for 30 min. TMSCl (64 mg, 0.59 mmol) was added at -50 °C,
and the mixture was stirred at the same temperature for 10
min. Diphenyl phosphorochloridate (166 mg, 0.62 mmol) was
then added at the same temperature, and the mixture was
stirred at 0 °C for 16 h. The reaction mixture was processed
as above. The crude product was purified by FCC (hexane/
AcOEt 4:1) to give 31 mg (9%) of 10, identical with that
prepared as above.
Ack n ow led gm en t. We express our thanks to Drs.
T. Tosa and K. Matsumoto of this company for their
encouragement and interest. The authors are indebted
to Mrs. K. Aoe and H. Hiramatsu of this company for
the X-ray analysis.
2931, 1786, 1718, 1638, 1591, 1490 cm-1; MS m/ z 614 (M+
+
1); [R]25D +48.1° (c, 0.99, MeOH). Anal. Calcd for C31H40NO8-
PSi: C, 60.67; H, 6.57; N, 2.28. Found: C, 60.78; H, 6.79; N,
2.55.
(b) With ou t TMSCl. To a solution of NaN(TMS)2 (1 M in
THF, 5.0 mL, 5.0 mmol) was added dropwise 8eâ (1.2 g, 2.0
J O961866J