A novel, mild, and facile method to prepare 6-methylidene pe nem derivatives

Article abstract of DOI:10.1021/jo049880g

A novel and mild method was established to synthesize 6-methylidene penem compounds. This method entails a MgBr₂/Et₃N-promoted aldol-type condensation on 6-bromopenem 12 with an appropriately substituted aldehyde to yield the interme

Full text of DOI:10.1021/jo049880g

A Novel, Mild , a n d F a cile Meth od To P r ep a r e 6-Meth ylid en e
P en em Der iva tives
Takao Abe,*,† Chisato Sato,† Hideki Ushirogochi,† Koichi Sato,† Tsuyoshi Takasaki,†
Takeshi Isoda,† Ado Mihira,† Itsuki Yamamura,† Kazuhiko Hayashi,† Toshio Kumagai,†
Satoshi Tamai,† Motoo Shiro,‡ Aranapakam M. Venkatesan,§ and Tarek S. Mansour§
Medical Research Laboratories, Wyeth Lederle J apan, Ltd., 1-6-34 Kashiwa-cho,
Shiki-shi, Saitama 353-8511, J apan, Rigaku Corporation, 3-9-12 Matsubara-cho,
Akishima-shi, Tokyo 196-8666, J apan, and Chemical & Screening Sciences, Wyeth Research,
401 North Middletown Road, Pearl River, New York 10965
takao_abe@meiji.co.jp
Received J anuary 21, 2004
A novel and mild method was established to synthesize 6-methylidene penem compounds. This
method entails a MgBr2/Et3N-promoted aldol-type condensation on 6-bromopenem 12 with an
appropriately substituted aldehyde to yield the intermediate acetylated bromohydrin, which was
smoothly converted to the final product with simultaneous deprotection of C3 carboxylic acid ester
using activated zinc dust and phosphate buffer at pH 6.5. This process provides a useful variation
of C-C bond formation method for penem derivatives and also serves as a practical synthetic method
to prepare 6-exomethylenepenem derivatives without racemization at the C5 position.
In tr od u ction
Penicillins and cephalosporins are among the most
widely used antibiotics. However, the development of
resistance to â-lactam antibiotics by different pathogens
severely limits these agents in treating bacterial infec-
tions.1 The most significant known mechanism related
to the development of bacterial resistance to the â-lactam
antibiotics is the production of class-A, class-B, and
class-C â-lactamases.2 In practice, only a few effective
â-lactamase inhibitors are clinically approved, which are
coadministered with a â-lactam antibiotics. Thus, clavu-
lanic acid 13a (given in combination with amoxicillin),
sulbactam 23b (given in combination with ampicillin), and
tazobactam 33c (given in combination with piperacillin)
are very effective inhibitors against class-A enzymes but
do not inhibit either class-C or class-B â-lactamases.
It has been recently shown that a number of 6-substi-
tuted methylidene penems such as BRL-42715 (4) and
SB-206999Z (5) are potent broad spectrum inhibitors
F IGURE 1. â-Lactamase inhibitors and 6-methylidene de-
rivatives.
of bacterial â-lactamases.4 In particular, BRL-42715
was advanced to a development stage. Unlike other
â-lactamase inhibitors, the 6-methylidene structural
feature imparts a unique mechanism of action to-
ward enzyme inhibition.5 In addition to these synthetic
penem derivatives, naturally occurring 6-methylidene
carbapenem derivatives such as asparenomycins (A, B,
and C, Figure 1) are known to be broad-spectrum
antibiotics with potent â-lactamase inhibitor activity.6 To
* To whom correspondence should be addressed. Present address:
Medicinal Chemistry Research Laboratories, Pharmaceutical Research
Department, Meiji Seika Kaisya, Ltd., 760 Morooka-cho, Kohoku-ku,
Yokohama 222-8567, J apan.
† Medical Research Laboratories, Wyeth Lederle J apan, Ltd.
‡ Rigaku Corp.
§ Chemical and Screening Sciences, Wyeth Research.
(1) (a) Sandanayaka, V. P.; Prashad, A. S. Curr. Med. Chem. 2002,
9, 1145. (b) Micetich, R. G.; Salama, S. M.; Maiti, S. N.; Reddy, A. V.
N.; Singh, R. Curr. Med. Chem. Anti-Infect. Agents 2002, 1, 193. (c)
Coleman, K. Exp. Opin. Invest. Drugs 1995, 4, 693. (d) Bush, K. Curr.
Pharm. Design 1999, 5, 839.
(4) (a) Bennett, I. S.; Broom, N. J . P.; Bruton, G.; Calvert, S. H.;
Clarke, B. P.; Coleman, K.; Edmondson, R.; Edwards, P.; J ones, D.;
Osborne, N. F.; Walker, G. J . Antibiot. 1991, 44, 331. (b) Bennett, I.
S.; Brooks, G.; Broom, N. J . P.; Calvert, S. H.; Coleman, K.; Francois,
I. J . Antibiot. 1991, 44, 969.
(5) (a) Yang, Y.; J anota, K.; Tabei, K.; Huang, N.; Siegal, M. M.;
Lin, Y. I.; Rasmussen, B. A.; Shlaes, D. M. J . Biol. Chem. 2000, 275,
26674. (b) Bulychev, A.; Massova, I.; Lerner, S. A.; Mobashery, S. J .
Am. Chem. Soc. 1995, 117, 4797.
(2) Bush, K.; J ocoby, G. A.; Medeiros, A. A. Antimicrob. Agents
Chemother. 1995, 39, 1211.
(3) (a) Reading, C.; Farmer, T. Biochem. J . 1981, 199, 779. (b)
English, A. R.; Retsema, J . A.; Girard, A. E.; Lynch, J . E.; Barth, W.
E. Antimicrob. Agents Chemother. 1978, 14, 414. (c) Micetich, R. G.;
Maiti, S. N.; Spevak, P.; Hall, T. W.; Yamabe, S.; Ishida, N.; Tanaka,
M.; Yamazaki, T.; Nakai, A.; Ogawa, K. J . Med. Chem. 1987, 30, 1469.
10.1021/jo049880g CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/12/2004
5850
J . Org. Chem. 2004, 69, 5850-5860

Preparation of 6-Methylidene Penem Derivatives
SCHEME 1 a
Resu lts a n d Discu ssion
PNB bromopenem 12 was synthesized from 6-amino-
penicillanic acid in an overall 23% yield by a modification
of the previously reported procedure.7 To our satisfaction,
the crystalline compound 12 demonstrated excellent
stability in the solid state at 40 °C.8 After solving this
stability problem, we examined the crucial aldol-type
condensation reaction using 12. Thus, bromopenem 12
was sequentially treated with Ph2NLi (Scheme 2) in THF
at -78 °C and aldehyde 67 at -78 °C for 1 h. The
resulting bromohydrin comprising a mixture of dia-
stereomers was proved to be relatively unstable and
difficult to isolate, so it was acetylated in situ with Ac2O
at 0 °C to afford the corresponding bromoacetates 14 in
43% yield, along with the formation of PNB ester of
thiazole-4-carboxylic acid 15 in 30% yield (Table 1, entry
1). Analyses of the crude products by a reverse phase
HPLC and LC-MS techniques10 showed that the product
14 consisted of a mixture of four diastereomeric isomers
(14a -d ) formed in the ratio of 40:22:25:13. These results
indicate that the PNB protecting group is compatible
with aldol-type condensation conditions, even though the
yield of the desired product is low.
This promising result prompted us to investigate
further Lewis acid mediated aldol-type condensation to
improve the yield and diastereoselectivity of this reaction.
It has been shown by Masamune, Seebach, and others11
that metal enolates, such as aluminum, magnesium,
boron, and other Lewis acids, can be utilized in aldol-
type condensation reactions to achieve improved dia-
stereoselectivity and yield. In addition to the selectivity
profile, it has been reported independently by Mansour,12
Rathke et al.,13 and Moreno-Manas et al.14 that the
acidity of the proton involved in the anion formation
process can be increased by the addition of Lewis acid.
Hence, we anticipated that adding Lewis acid such as
MgBr2 could facilitate the anion formation at the C6-
position of bromopenem 12. Toward this end, aldehyde
6 was reacted with 12 using Ph2NLi as a base (1.3 molar
equiv) and MgBr2‚Et2O (1.3 molar equiv) as the Lewis
acid at -78 °C for 1 h (Scheme 2). The aldol product was
isolated as bromoacetates 14 in excellent overall yield
(Table 1, entry 2). Analysis of the reaction mixture using
HPLC techniques revealed that only two diastereomers
14a and 14b were formed in the ratio of 1:6. It should
be noted here that aldehyde 6 was added immediately
after the formation of the lithium enolate. However, upon
the slow addition of 6 to the enolate (over 10 min), we
observed a decrease in the yield to 42%. On the basis of
these results, the aldol-type condensation between 12 and
6 was investigated in the presence of anhydrous MgBr2,
MgCl2, or MeMgBr/Ph2NH. As seen in Table 1, replacing
the MgBr2‚Et2O with MgBr2 resulted in a slight decrease
a
Key: (a) (1) Ph2NLi, THF-MeCN, -78 °C, (2) Ac2O; (b) Zn,
AcOH, TMEDA; (c) (1) Et2AlCl, anisole, CH2Cl2, -20 °C, (2)
Na2HPO4.
design broad-spectrum â-lactamase inhibitors as well as
to study their mechanism of action, we sought out an
efficient and practical method to synthesize 6-meth-
ylidene penem derivatives.
The general synthesis of 6-(substituted methylidene)
penems has been reported by the Beecham group (Scheme
1).7 However, when this procedure was repeated in our
laboratory, we encountered the following problems: First,
the precursor ester 9 underwent racemization at the C5
center in the solution state. This proved to be a fatal
aspect for scale-up synthesis and further evaluation of
the penem derivatives. Next, the initial aldol-type con-
densation reaction using LHMDS or lithium diphenyl-
amide (Ph2NLi) was very difficult to control resulting in
variable yields. Finally, the pivotal intermediate 7 was
relatively unstable on standing at room temperature over
a period of several days.8
Hence, to circumvent the above-mentioned problems,
a novel and facile method was devised to accomplish this
transformation. The instability issue relating to the
p-methoxybenzyl (PMB) protected intermediate 7 was
solved by replacing it with the more stable and crystalline
p-nitrobenzyl (PNB) derivative 12 (Scheme 2). It has been
shown that deprotection of PNB group on N-protected
amino acids or carbapenems can be achieved by hydro-
genolysis on Pd/C or zinc dust reduction in phosphate
buffer.9 Hence, we envisaged that this procedure could
be applied to the present situation, which would not only
deprotect the ester functionality, but also introduce the
6-methylidene linkage. Furthermore, introduction of the
PNB group was expected to not only avoid the unstable
precursor ester 9 but also improve the stability of the
pivotal intermediate 12.
(6) Ona, H.; Uyeo, S. Tetrahedron Lett. 1984, 25, 2237.
(7) (a) Osborne, N. F.; Atkins, R. J .; Broom, N. J . P.; Coulton, S.;
Harbridge, J . B.; Harris, M. A.; Francois, I. S.; Walker, G. J . Chem.
Soc., Perkin. Trans. 1 1994, 179. (b) Osborne, N. F.; Broom, N. J . P.;
Coulton, S.; Harbridge, J . B.; Harris, M. A.; Francois, I. S.; Walker, G.
J . Chem. Soc., Perkin. Trans. 1 1989, 371. (c) Broom, N. J . P.;
Harrington, F. P. Int. Patent WO94/10178.
(8) The PMB bromopenem 7 intermediate decomposed to an extent
of 30% after standing at 40 °C for 7 days in the solid state while that
of the PNB bromopenem 12 did not decompose over 15 days after
standing under the same conditions.
(10) A mixture of the bromoacetates 14a and 14b showed same re-
tention time on the normal phase HPLC. The other minor diaster-
eomers 14c and 14d were unstable to isolate but detected by LC-MS.
(11) (a) Abiko, A.; Liu, J . F.; Masamune, S. J . Org. Chem. 1996, 61,
2590. (b) Ertas, M.; Seebach, D. Helv. Chim. Acta 1985, 68, 961. (c)
Takazawa, O.; Kogami, K.; Hayashi, K. Bull. Chem. Soc. J pn. 1985,
58, 2427. (d) Masamune, S.; Ellingboe, J . W.; Choy, W. J . Am. Chem.
Soc. 1982, 104, 5526.
(9) (a) Mansour, T. S.; Evans, C. A. Synth. Commun. 1989, 19, 667.
(b) Aoyagi, S.; Hayashi, T.; Kuramoto, Y. J P-2654076, U.S. Patent
4,977,256, 1990. (c) Kumagai, T.; Abe, T.; Fujimoto, Y.; Hayashi, T.;
Inoue, Y.; Nagao, Y. Heterocycles 1993, 36, 1729.
(12) Mansour, T. S. Tetrahedron Lett. 1988, 29, 3437.
(13) Rathke, M. W.; Cowan, P. J . J . Org. Chem. 1985, 50, 2622.
(14) Carvello, J .; Marquet, J .; Moreno-Manas, J . J . Chem. Soc.,
Chem. Commun. 1987, 644.
J . Org. Chem, Vol. 69, No. 18, 2004 5851

Abe et al.
SCHEME 2 a
a
Key: (a) Ph2NLi, -78 °C; (b) Ph2NLi, MgBr2‚Et2O, -78 °C; (c) Ac2O.
et al.16 that imines can undergo aldol-type condensation
reaction with an aldehyde in the presence of MgBr2 and
Et3N. These precedents seemed attractive to attempt the
use of a mild and safe base such as Et3N, because the
C6-proton is further activated by the presence of the
bromine substituent.
TABLE 1. Ald ol-Typ e Con d en sa tion of th e Br om op en em
12 a n d Ald eh yd e 6 Usin g Lith iu m Am id es/Lew is Acid s
aldol reaction
additive
acetylation
Ac2O
base
HPLCa
(molar
equiv)
(molar
equiv)
(molar time yield of
entry
equiv) (h)
14 (%)
Accordingly, compound 12 was reacted with aldehyde
6 in the presence of MgBr2 (1.2 molar equiv) and Et3N
(2.4 molar equiv) at -40 °C for 9 h (Table 2, entry 1). In
this reaction, both the enolization and the aldol-type
reaction proceeded smoothly, and the intermediate aldol
products were trapped as bromoacetate 14 by using Ac2O
at 0 °C. After the isolation of the products, it was
determined that the reaction proceeded in 75% yield with
the formation of two major diastereomers 14a and 14b
in a ratio of 1:10. We next investigated the effect of
temperature on this reaction, and as shown in Table 2
(entry 2), the yield increased to 89-93% with a rise in
the temperature from -40 to -20 °C. However, further
increase in the reaction temperature led to a decrease in
the yield (entries 4-6). When THF as the reaction solvent
was replaced with CH2Cl2, the composition of 14a -d was
changed to 20:63:8:9 (entry 3). As can be seen in entries
7 and 8, when the amount of MgBr2 was reduced from
2.4 to 0.6 molar equiv, the yield of 14 decreased dramati-
cally. The use of MgBr2‚Et2O did not alter the yield
significantly. However, when the Lewis acid was changed
to hydrated MgBr2 or MgCl2, the desired product was not
produced. The above-mentioned aldol-type condensation
reaction on 12 was further studied using different Lewis
acids such as AlCl3, TiCl4, and La(OTf)3 (entries 12-14).
The use of AlCl3 or TiCl4 did not result in any of the
desired product. However, La(OTf)3 afforded 14 (diaster-
1
2
3
4
5
6
7
Ph2NLi (1.3)
Ph2NLi (1.3)
Ph2NLi (1.3)
-
1.3
1.3
1.3
1.3
2.0
2.0
1.3
1
1
1
2
1
1
1
43
90
77
0
40
47
0
MgBr2‚Et2O (1.3)
MgBr2 (1.3)
MeMgBr (1.3) Ph2NH (1.3)
LDA (2.0)
LDA (2.0)
Ph2NLi (1.3)
-
MgBr2‚Et2O (1.3)
ZnCl2 (1.3)
a
Analytical HPLC conditions are shown in the Supporting
Information.
in the yield, and the other modifications resulted in
significant reduction in the yield of the desired aldol
products. Replacing the MgBr2 with ZnCl2 did not result
in any desired product. Even changing the base from
Ph2NLi to LDA decreased the yield drastically.
Whereas utilization of MgBr2 results in a satisfactory
yield, the use of Ph2NLi may pose some problems for
large-scale production, because immediate and successive
addition of Ph2NLi and aldehyde 6 is not practical, and
the resulting Ph2NH has to be removed by silica gel
column chromatography. An extensive literature15 survey
revealed that the C6-position of the penem nucleus is
always deprotonated using strong bases such as LHMDS,
LDA, or Ph2NLi, while others12,13 have shown that
enolization of certain ketones can be achieved by using
mild base such as i-Pr2NEt in the presence of Lewis acid
such as MgCl2. Interestingly, it has been shown by Nagao
(15) (a) Bouffard, C. F. A.; J ohnston, D. B. R.; Christensen, B. G. J .
Org. Chem. 1980, 45, 1130. (b) Pfaendlet, H. R.; Gosteli, J .; Woodward,
R. B. J . Chem. Soc. 1980, 100, 2039. (c) Bouffard, F. A.; Sallzmann, T.
N. Tetrahedron Lett. 1985, 26, 6285. (d) Aileen, F.; Bouffard, B. G.;
Christensen, B. G. J . Org. Chem. 1981, 46, 2208. (e) Dininno, F.;
Beatte, T. R. Christensen, B. G. J . Org. Chem. 1977, 42, 2960.
(16) (a) Sano, S.; Liu, X.-K.; Takebayashi, M.; Kobayashi, Y.; Tabata,
K.; Shiro, M.; Nagao, Y. Tetrahedron Lett. 1995, 36, 4101. (b) Hayashi,
K.; Kogiso, H.; Sano, S.; Nagao, Y. Synlett 1996, 1203. (c) Sugasawa,
T.; Toyoda, T.; Sasakura, K. Synth. Commun. 1979, 515. (d) Sugasawa,
T.; Toyoda, T. Tetrahedron Lett. 1979, 20, 1423. (e) Meyers, A. I.;
Yamamoto, Y. J . Am. Chem. Soc. 1979, 101, 2501.
5852 J . Org. Chem., Vol. 69, No. 18, 2004

Preparation of 6-Methylidene Penem Derivatives
TABLE 2. Ald ol-Typ e Con d en sa tion of th e Br om op en em 12 Usin g Et3N/Lew is Acid s
aldol reaction
Lewis acid
(molar equiv)
acetylation
time (h)
HPLCa yield
of 14 (%)
entry
T (°C)
time (h)
comments
1
2
3
MgBr2 (1.2)
MgBr2 (1.2)
MgBr2 (1.2)
-40
9
2-3
2-3
2
16
16
75
89-93
55
-20
-20
14a /14b/14c/14d ) 5:60:1:1b
THF was replaced with CH2Cl2,
14a /14b/14c/14d ) 20:63:8:9b
4
5
6
7
8
MgBr2 (1.2)
MgBr2 (1.2)
MgBr2 (1.2)
MgBr2 (2.4)
MgBr2 (0.6)
MgBr2‚Et2O (1.2)
MgBr2‚6H2O (1.2)
MgCl2 (0.6)
0
0
rt
0
0
0
0
0
1
1
0.83
1
1
1
1
1
2
17
2
2
2
2
2
2
18
18
73
79
56
70
18
68
0
1
dec
dec
9
10
11
12
13
AlCl3 (1.2)
TiCl2 (2.4)
-20
-78 to -10
rt
-45
-20
2
solvent: CH2Cl2 only
solvent: CH2Cl2 only
4 then
18
2 then
1.5
14
La(OTf)3 (1.2)
18
51
diastereomer ratio 14a /14b ) 1:7b
a,b
Analytical HPLC conditions are shown in the Supporting Information.
eomeric ratio ) 1:7) in a modest yield. It is clear that
the nature of the metal ion and the choice of the base
are crucial for an efficient aldol reaction to occur. Clearly,
the use of MgBr2 (1.2 molar equiv)/Et3N (2.4 molar equiv)
at -20 °C resulted in the best yield of 14 with the
diastereomeric ratio of 1:10 (entry 2), thus avoiding the
use of Ph2NLi as the base.
It should be noted here that the stereochemistry of the
major isomer formed via the magnesium enolate is
different from that via the lithium enolate based on
isolating each single component by silica gel column
chromatography.16a Thus, the absolute stereochemistry
of the major isomer obtained via the magnesium enolate
was determined to be 14b by X-ray crystallographic
analysis of the p-nitrobenzoyl ester 16 (Figure 2), whereas
that formed via the lithium enolate was not clearly
assigned, but it could likely be 14a based on the NOE
experiments.7 This stereochemical outcome clearly shows
a preference for attack by the aldehyde 6 from the more
hindered face, the concave side of the bromopenem,
suggesting a degree of pyramidalization at the C6-
position in the bromine-substituted enolate.
This stereochemical proposal was further supported by
the ab initio calculations of the bromine substituted and
unsubstituted enolates of penems (Figure 3). The di-
hedral angle of Br-C6-C7-C5 for the lithium enolate
of bromopenem and unsubstituted penem was 166.23°
and 173.74°, respectively. The HOMO potential map
showed the reaction region was positioned on the concave
site in the enolate of bromopenem, while it was spread
over both the concave and convex site of the enolate of
unsubstituted penem.
F IGURE 2. Stereochemistry of the bromoacetate, 14a , 14b,
and the p-nitrobenzoyl ester 16.
â-lactam ring facilitating deprotonation and resulting in
the magnesium enolate approaching the magnesium
coordinated aldehyde 6 subsequently, the transition state
for the reaction between the enolate and the aldehyde
adopts an open-chain conformation resulting in high
diastereomeric selectivity for 14b.
To investigate the versatility of the above-mentioned
procedure, various aldehydes were reacted with bromo-
penem 12, and the results are shown in Table 3. These
examples demonstrated the generality of this process,
which is applicable to aliphatic, aromatic, and hetero-
cyclic aldehydes.17 The overall yields range from 42 to
84%. The absolute stereochemistry of the major bromo-
hydrins 17a and 17c was determined by X-ray crystal-
lographic analysis. In these cases, the stereochemistry
at C8 was opposite to that of 13b, the main product from
aldehyde 6 and bromopenem 12 (Figure 5).
These results clearly demonstrate that the chelating
ability of the aldehyde plays an important role in direct-
ing the stereoselectivity of the reaction as shown in
Figure 4.
The difference in the stereochemical outcome that we
observed in each metal enolate can be explained mecha-
nistically as depicted in Figure 4. A possible explanation
for the formation of 14b can be due to the excess amount
of MgBr2 that interacts with the carbonyl group of the
(17) The MgBr2/Et3N-promoted aldol-type condensation of 12 did not
proceed with nitrile, ester, activated amide such as imidazolide, 1,3-
thiazolidine-2-thione amide, and Weinreb’s amide.
J . Org. Chem, Vol. 69, No. 18, 2004 5853

Abe et al.
F IGURE 3. HOMO potential map of bromine-substituted and unsubstituted enolates of penems, calculated by Spartan ‘O2 using
the 3-21g* basis set.
F IGURE 4. Plausible reaction mechanisms.
After standardizing this novel aldol-type condensation
procedure, we next turned our attention to the reductive
elimination procedure to introduce a Z-double bond
between the C6 and C8 carbon atoms. Since the resulting
6-methylidene penem compounds are prone to decompo-
sition at a pH >9 and <5, a neutral procedure9c was
devised using freshly prepared activated zinc dust18 and
0.5 M (pH 6.5) phosphate buffer. The amount of zinc dust
required for this transformation was found to be about
four times the weight of the bromoacetate. After exploring
different solvent systems to carry out this transformation
at room temperature, MeCN/THF (1:2) emerged as the
most suitable combination. At this juncture, it is very
important to mention that the use of activated zinc dust/
phosphate buffer not only introduces exclusively the
Z-double bond between the C6 and C8 carbon atoms, but
also results in concomitant deprotection of the carboxyl
(18) Commercially available zinc dust was activated with 1 N HCl
for 15 min and filtered. It was washed well with deionized water and
used as such.
5854 J . Org. Chem., Vol. 69, No. 18, 2004

Preparation of 6-Methylidene Penem Derivatives
TABLE 3. MgBr 2/Et3N-P r om oted Ald ol-Typ e Con d en sa tion of 12 w ith Va r iou s Ald eh yd es
Con clu sion
In conclusion, the formation of an anion at the C6-
position of penem is extremely useful for the preparation
of various penem-based antibiotics and â-lactamase
inhibitors. Previously, this was achieved by using a
strong base such as LHMDS, LDA, MeMgBr, or Ph2NLi.
In the present paper, it has been shown that the MgBr2/
Et3N-mediated procedure can be applied to labile 6-bromo
penem derivatives. This C6-C8 bond formation reaction
was shown to be a rather mild, efficient, and useful
variation of the aldol reaction. In this paper, we have also
described a mild and efficient reductive elimination
procedure that can be applied to other pH-sensitive
molecules such as penems.
F IGURE 5. Stereochemistry of 17a and 17c.
TABLE 4. Com p a r ison of th e Op tica l P u r ity of
Com p ou n d 5
eea
entry
1
(%)
comments
0.1 enantiomeric mixture; prepared from the
racemized precursor 9
2
3
4
96.3 a crystalline solid; procedure outlined in ref 7
Exp er im en ta l Section
>99
a re-crystallized solid; procedure outlined in ref 7
a crude amorphous solid; prepared by
MgBr2‚Et2O/Ph2NLi method
2,3-Dih yd r oim id a zo[2,1-b]t h ia zole-6-ca r b oxa ld eh yd e
(6) a n d p-Meth oxyben zyl (5R,6S)-6-Br om o-7-oxo-4-th ia -
1-a za b icyclo[3.2.0]h ep t -2-en e-2-ca r b oxyla t e (7). Com-
pounds 6 and 7 were prepared by the procedure as described
in the literature.7
>99
>99
>99
>99
5
6
7
a crystalline solid; prepared by
MgBr2‚Et2O/Ph2NLi method
a crude amorphous solid; prepared by
MgBr2/Et3N method
a crystalline solid; prepared by
MgBr2/Et3N method
6: 1H NMR (CDCl3) δ 3.88 (t, J ) 7.3 Hz, 2H), 4.27 (t, J )
7.3 Hz, 2H), 7.65 (s, 1H), 9.72 (s, 1H).
7: 1H NMR (CDCl3) δ 3.80 (s, 3H), 5.14 (d, J ) 1.5 Hz, 1H),
5.18 and 5.22 (AB, J ) 12.0 Hz, 2H), 5.75 (d, J ) 1.5 Hz, 1H),
6.89 (d, J ) 8.7 Hz, 2H), 7.25 (s, 1H), 7.34 (d, J ) 8.7 Hz, 2H).
4-Meth oxyben zyl (5R)-(Z)-6-(2,3-Dih yd r oim id a zo[2,1-
b]th ia zol-6-ylm eth ylen e)-7-oxo-4-th ia -1-a za bicyclo[3.2.0]-
h ep t-2-en e-2-ca r boxylic Acid (9). The ester 9 was synthe-
sized by the procedure as outlined by Osborne et al.7
Enantiomeric excess (%) of 9 was determined to be 93% ee by
chiral HPLC (system B): mp 144 °C dec; HPLC area ratio
a
Chiral HPLC conditions are shown in the Supporting Informa-
tion.
functionality, thus avoiding an extra deprotection step.
Additionally, this mild and direct transformation avoids
racemization at the C5 position unlike the earlier litera-
ture reports and results in a product with high optical
purity (Table 4) due to the avoidance of a stepwise
procedure.7
Finally, the applicability of this process for scale-up
synthesis was confirmed by preparing a 112-g batch of 5
in 50% isolated yield starting from 250 g of bromopenem
12.
100%, contents 100% (system A); [R]20 +577.40 (c 0.001,
D
MeCN) [lit.7 a yellow form [R]20 +522 (c 0.001, MeCN)]; IR
D
(KBr) 1768, 1699, 1235 cm-1; 1H NMR (CDCl3) δ 3.80 (s, 3H),
3.82 (t, J ) 7.4 Hz, 2H), 4.18 (t, J ) 7.4 Hz, 2H), 5.14 and
5.25 (AB, J ) 12.1 Hz, 2H), 6.58 (d, J ) 0.8 Hz, 1H), 6.84 (d,
J ) 0.8 Hz, 1H), 6.89 (d, J ) 8.6 Hz, 2H), 7.20 (s, 1H), 7.23 (s,
1H), 7.36 (d, J ) 8.6 Hz, 2H).
J . Org. Chem, Vol. 69, No. 18, 2004 5855

Abe et al.
Ra cem iza tion of 9. The ester 9 (604 mg, 1.4 mmol, 93%
ee) was dissolved in a mixture of toluene-EtOAc-CH2Cl2
mixed solvent (7:2:1, 200 mL) and allowed to stand in a light-
resistant bottle for 8 days at 35 °C. The solvent of the mixture
was evaporated under reduced pressure, and the resulting
residue was dried in vacuo to obtain a yellow solid (594 mg,
of 6-bromopenicillanic acid was taken to next step without any
purification.
Anhydrous K2CO3 (288 g, 2.08 mol), DMF (2.8 L), and
p-nitrobenzyl bromide (500 g, 2.31 mol) were successively
added to the 6-bromopenicillanic acid, and the mixture was
stirred at 35-40 °C for 1 h. The reaction solution was poured
into a mixture of water (2.8 L) and extracted with CH2Cl2 (3.4
L). The organic layer was washed with water (2.8 L) and brine
(3 L) and cooled to -2 °C. The resulting p-nitrobenzyl 6-bromo-
penicillanate was taken to the next step without purification.
98% yield by HPLC assay (system A), 3% ee, [R]20 +8.72 (c
D
0.002, MeCN)). The solid (519 mg) was triturated with EtOAc
(13 mL) for 1.5 h at rt to obtain a racemate of 9 as a yellow
crystalline solid [484 mg, HPLC area ratio 100%, contents
100% (system A), 93% yield, 1.3% ee (system B)]: mp 180 °C
In order for analytical characterization, a small portion (1/
100 w/w) of the organic layer was applied to silica gel column
chromatography and eluted with EtOAc-hexane (4:1) to obtain
p-nitrobenzyl 6-bromopenicillanate as a colorless solid (7.2 g,
dec; [R]20 +3.33 (c 0.001, MeCN); IR (KBr) 1778, 1701, 1235
D
cm-1; 1H NMR (CDCl3) δ 3.80 (s, 3H), 3.82 (t, J ) 7.3 Hz, 2H),
4.18 (t, J ) 7.3 Hz, 2H), 5.17 and 5.23 (AB, J ) 12.1 Hz, 2H),
6.58 (d, J ) 0.8 Hz, 1H), 6.84 (d, J ) 0.8 Hz, 1H), 6.89 (d, J )
8.6 Hz, 2H), 7.20 (s, 1H), 7.23 (s, 1H), 7.36 (d, J ) 8.6 Hz,
2H). Anal. Calcd for C20H17N3O4S2: C, 56.19; H, 4.01; N, 9.83.
Found: C, 56.07; H, 4.00; N, 9.69.
75% yield): mp 74-76 °C; [R]20 +130.54 (c 0.002, CHCl3); IR
D
(KBr) 1786, 1742, 1523, 1347 cm-1; H NMR (CDCl3) δ 1.41
1
(s, 3H), 1.62 (s, 3H), 4.61 (s, 1H), 4.83 (d, J ) 1.5 Hz, 1H),
5.25 and 5.34 (AB, J ) 13.0 Hz, 2H), 5.41 (d, J ) 1.5 Hz, 1H),
7.56 (d, J ) 8.7 Hz, 2H), 8.26 (d, J ) 8.7 Hz, 2H); HRMS (EI)
calcd for C15H15N2O5SBr (MW) 413.9885, found m/z 413.9868
(M+). Anal. Calcd for C15H15N2O5SBr: C, 43.39; H, 3.64; N,
6.75. Found: C, 43.49; H, 3.62; N, 6.86.
Sod iu m (5RS)-(Z)-6-(2,3-Dih yd r oim id a zo[2,1-b]th ia zol-
6-ylm et h ylen e)-7-oxo-4-t h ia -1-a za b icyclo[3.2.0]h ep t -2-
en e-2-ca r boxyla te (Ra cem ized 5, P r ep a r ed fr om th e
Ra cem a te of 9). The PMB protective group of the above
racemate 9 (214 mg, 0.5 mmol) was deprotected by a modified
Beecham’s procedure.7 The reaction vessel was covered with
foil to exclude light. Et2AlCl (1 M) in hexane solution (1.56
mL) was added to a dry CH2Cl2 (2.6 mL) solution of anisole
(0.07 mL) at -20 °C. A dry CH2Cl2 (12 mL) solution of the
racemate 9 (214 mg) was added gradually to the mixture for
15 min at -20 °C. The reaction mixture was stirred for 1 h 40
min at -10 °C. A solution of Na2HPO4‚12H2O (3.6 g) in H2O
(13 mL) was added to the reaction mixture below -5 °C and
stirred for 30 min at ice-bath temperature. Celite (428 mg)
was added to the reaction solution and stirred for 30 min. The
mixture was filtered through a pad of Celite. The pad was
washed with water and CH2Cl2, and then the aqueous layer
was separated. The aqueous layer was concentrated to 25 mL
under high vacuum at 30 °C. The concentrate was applied to
Diaion HP-21 (30 mL, Mitsubishi Kasei Co. Ltd.) resin column
chromatography. After adsorbtion, the column was eluted with
water and then with 2.5-5% MeCN-water. The combined
active fractions were concentrated to 770 mg under high
vacuum at 30 °C. Acetone (1.5 mL) was added to the concen-
trate at rt, and it was stirred for 30 min in an ice bath. More
acetone was added to the mixture in 0.75 mL portions every
30 min over a 1.5 h period at ice-bath temperature (total 3
mL of acetone was added). After being stirred for 30 min in
an ice bath, the resulting precipitate was filtered, washed with
acetone, and dried in vacuo for 15.5 h at rt. The racemized 5
was obtained as a yellow crystalline solid (81 mg, HPLC area
ratio 100% (system C). HPLC contents 94.8% as a mono-
hydrate form, yield 46%, 0.1% ee by chiral HPLC (system D):
m-CPBA (355 g, 2.06 mol) was added to the stirred solution
of p-nitrobenzyl 6-bromopenicillanate over a period of 15 min,
and the mixture was stirred for an additional 10 min. The
reaction mixture was diluted with EtOAc (4.8 L) and washed
with a saturated solution of NaHCO3 (7.6 L). The organic layer
was separated, and the aqueous layer was reextracted with
EtOAc (3.9 L). The combined organic layers were washed with
water (3.9 L) and brine (3.9 L), dried (MgSO4), and evaporated
under reduced pressure at 30 °C. The residual solid was
triturated with EtOAc (1.8 L) for 30 min, and hexane (5.4 L)
was added dropwise to this mixture over 1 h. The solid was
filtered off, and the filter cake was washed with EtOAc-
hexane (1:4, 0.8 L). The solid was air-dried for 1 h and dried
in vacuo overnight at rt. Sulfoxide 18 was obtained as a pale-
yellow crystalline solid (768 g, 77% yield). The obtained
material was used as is for the next reaction.
A small portion of the solid was applied to silica gel
column chromatography, eluted with EtOAc-hexane (1:1)
and recrystallized from EtOAc. Sulfoxide 18 was obtained
as a colorless solid: mp 118-120 °C dec; [R]20 +161.58 (c
D
0.004, CHCl3); IR (KBr) 1794, 1739, 1521, 1347, 1051 cm-1
;
1H NMR (CDCl3) δ 1.17 (s, 3H), 1.69 (s, 3H), 4.60 (s, 1H), 5.04
(d, J ) 1.5 Hz, 1H), 5.10 (d, J ) 1.5 Hz, 1H), 5.30 and 5.37
(AB, J ) 12.9 Hz, 2H), 7.56 (d, J ) 8.7 Hz, 2H), 8.27 (d, J )
8.7 Hz, 2H); HRMS (EI) calcd for C15H15N2O6SBr (MW)
429.98342, found m/z 429.9797 (M+). Anal. Calcd for C15H15N2O6-
SBr: C, 41.78; H, 3.51; N, 6.50. Found: C, 41.76; H, 3.47; N,
6.41.
p-Nitr oben zyl 2-[(3S,4R)-3-Br om o-4-for m ylth io-2-oxo-
a zetid in -1-yl]-3-m eth ylbu t-2-en oa te (19). Sulfoxide 18 (766
g, 1.78 mol) and mercaptobenzothiazole (294 g, 1.76 mol) were
heated in refluxing toluene (2.4 L) with a provision for the
azeotropic removal of water (Dean-Stark apparatus) for 1 h.
The reaction mixture was cooled to 0 °C and used as is for the
next reaction.
mp 190 °C dec; [R]20 +1.87 (c 0.0011, MeCN); IR (KBr) 1755,
D
1684 cm-1; H NMR (D2O) δ 3.70 (t, J ) 7.4 Hz, 2H), 4.06 (t,
1
J ) 7.4 Hz, 2H), 6.32 (s, 1H), 6.75 (s, 1H), 6.82 (s, 1H), 7.32 (s,
1H); HRMS (FAB) calcd for C12H8N3O3S2Na2 (MW + Na)
351.9802, found m/z 351.9788 (M+ + Na). Anal. Calcd for
C
12H8N3O3S2Na‚2.1H2O: C, 39.25; H, 3.35; N, 11.44. Found:
C, 39.02; H, 2.97; N, 11.31.
A small portion (0.56% w/w) of the mixture was evaporated
under reduced pressure. The residue was purified by silica
gel column chromatography by eluting with EtOAc-hexane
(2:5) to obtain p-nitrobenzyl (2R)-2-[(3S,4R)-4-(benzothiazol-
2-yldithio)-3-bromo-2-oxoazetidin-1-yl]-3-methylbut-3-enoate
as a pale-yellow solid (5.67 g, 98% yield): mp 120-122 °C
Syn th esis of p-Nitr oben zyl (5R,6S)-6-Br om o-7-oxo-4-
th ia -1-a za bicyclo[3.2.0]h ep t-2-en e-2-ca r boxyla te 12. p-
Nitr oben zyl 6-Br om op en icilla n a te 1-Oxid e (18). 6-Amino-
penicillanic acid (500 g. 2.31 mol) was added to a cooled
solution of MeOH (3.5 L), water (1.36 L), and 48% w/w
hydrobromic acid (1.36 L, 12.02 mol) at -10 °C. After the
addition was complete, the mixture was cooled to -15 °C.
NaNO2 solution (235 g dissolved in 660 mL of water) was
added over 30 min, and the resulting solution was stirred
without cooling for a further 30 min. To the resulting reaction
mixture was added NaCl (240 g), and the mixture was
extracted with CH2Cl2 (2 × 3 L). The combined organic layers
were washed with brine (3 L), dried (MgSO4), and concentrated
to 1.6 L under reduced pressure at 25 °C. The residual solution
(toluene); [R]20 -154.19 (c 0.005, CHCl3); IR (KBr) 1792,
D
1737, 1520, 1347 cm-1
;
1H NMR (CDCl3) δ 1.92 (s, 3H),
4.87 (s, 1H), 5.05 (brs, 1H), 5.10 (d, J ) 1.7 Hz, 1H),
5.17-5.25 (m, 4H), 7.37-7.41 (m, 1H), 7.41-7.50 (m, 3H),
7.81 (d, J ) 8.0 Hz, 1H), 7.90 (d, J ) 8.0 Hz, 1H), 8.20 (d,
J
) 8.8 Hz, 2H); HRMS (EI) calcd for
(MW) 578.9592, found m/z 578.9606 (M+). Anal. Calcd for
22H18N3O5S3Br: C, 45.52; H, 3.13; N, 7.24. Found: C, 45.79;
H, 3.15; N, 7.10.
C22H18N3O5S3Br
C
5856 J . Org. Chem., Vol. 69, No. 18, 2004

Preparation of 6-Methylidene Penem Derivatives
The cooled reaction mixture was treated with Et3N (25 mL,
0.18 mol) and stirred at 0 °C for 2 h, and the resulting
suspension was used as is for next step.
was air-dried for 1 h and dried in vacuo overnight at rt.
Bromopenem 12 (109.6 g, 42% yield) was obtained as a pale-
brown crystalline solid. The obtained material was quantified
and used for next reaction as it is. A small portion of the
material was further triturated with EtOAc for structure
assignment to obtain a colorless crystalline solid [cont 100%
by HPLC (system F)]: mp 148-151 °C; [R]20D +41.69 (c 0.004,
A small portion (0.49% w/w) of the above-mentioned reaction
mixture was washed with 1 N HCl, water, saturated NaHCO3,
and brine, dried (MgSO4), and evaporated under reduced pres-
sure. The residue was purified by silica gel column chroma-
tography for structure assignment and eluted with EtOAc-
hexane (1:3) to obtain p-nitrobenzyl 2-[(3S,4R)-4-(benzothiazol-
2-yldithio)-3-bromo-2-oxoazetidin-1-yl]-3-methylbut-2-enoate
as a colorless crystalline solid (4.16 g, 80% yield from 18): mp
121-122 °C (EtOAc); [R]20D -71.50 (c 0.005, CHCl3); IR (KBr)
1767, 1723, 1518, 1349 cm-1; 1H NMR (CDCl3) δ 2.01 (s, 3H),
2.24 (s, 3H), 5.01 (d, J ) 1.7 Hz, 1H), 5.24 and 5.30 (AB, J )
13.1 Hz, 2H), 5.35 (d, J ) 1.7 Hz, 1H), 7.34-7.42 (m, 1H),
7.48-7.57 (m, 3H), 7.80 (d, J ) 8.0 Hz, 1H), 7.90 (d, J ) 8.0
Hz, 1H), 8.14 (d, J ) 8.7 Hz, 2H); HRMS (EI) calcd for
CHCl3); IR (KBr) 1791, 1723, 1516, 1328 cm-1 1H NMR
;
(CDCl3) δ 5.20 (d, J ) 1.5 Hz, 1H), 5.29 and 5.43 (AB, J )
13.5 Hz, 2H), 5.81 (d, J ) 1.5 Hz, 1H), 7.37 (s, 1H), 7.60 (d, J
) 8.7 Hz, 2H), 8.25 (d, J ) 8.7 Hz, 2H); HRMS (EI) calcd for
C
13H9N2O5SBr (MW) 383.9416, found m/z 383.9417 (M+). Anal.
Calcd for C13H9N2O5SBr: C, 40.54; H, 2.36; N, 7.27. Found:
C, 40.57; H, 2.44; N, 7.15.
Sta bility of p-Meth oxyben zyl Br om op en em 7 a n d
p-Nitr oben zyl Br om op en em 12 in a Solid Sta te. Each of
the bromopenems 7 and 12 were weighed accurately (∼10 mg)
into light-resistant vials (1 mL × 14) and allowed to stand at
40 °C for 14 days. Samples were quantified by HPLC (condition
F) on 1, 2, 4, 7, and 14 days. Each remaining ratio (%) was
shown as follows.
7: 100% (initial), 99.7% (1 d), 95.3% (2 d), 72.9% (4 d), 69.8%
(7 d).
12: 100% (initial), 100% (1 d), 99.6% (2 d), 100% (4 d), 98.7%
(7 d), 98.4% (14 d).
C
22H18N3O5S3Br (MW) 578.9592, found m/z 578.9548 (M+).
Anal. Calcd for C22H18N3O5S3Br: C, 45.52; H, 3.13; N, 7.24.
Found: C, 45.46; H, 3.14; N, 7.15. The polar fraction contained
the symmetric disulfide as a colorless solid (0.68 g, 19% yield).
p-Nitrobenzyl 2-[(3R,4R)-3-bromo-4-[(3R′,4R′)-3′-bromo-1′-[2′-
methyl-1′-(p-nitrobenzyloxycarbonyl)prop-1-enyl]-2′-oxoazeti-
din-4′-yldithio]-2-oxo-azetidin-1-yl]-3-methylbut-2-enoate: 1H
NMR (CDCl3) δ 2.01 (s, 6H), 2.29 (s, 6H), 4.73 (d, J ) 1.7 Hz,
2H), 5.06 (d, J ) 1.7 Hz, 2H), 5.32 (s, 4H), 7.54 (d, J ) 8.6 Hz,
4H), 8.24 (d, J ) 8.6 Hz, 4H).
p-Nitr oben zyl (5R,6S)-6-Br om o-6-[(R)-h yd r oxy-(2,3-d i-
h yd r oim id a zo[2,1-b]th ia zol-6-yl)m eth yl]-7-oxo-4-th ia -1-
a za bicyclo[3.2.0]h ep t-2-en e-2-ca r boxyla te (13a ), by Us-
in g P h 2NLi. n-BuLi (7.5 mL, 12 mmol, 1.57 M in hexane) was
added to a dry THF solution (24 mL) of Ph2NH (2030 mg, 12
mmol) at -40 °C. The mixture was cooled to -78 °C, and a
dry THF (76 mL) solution of bromopenem 12 (3080 mg, 8
mmol) was added to the Ph2NLi solution over a period of 5
min. After being stirred for 5 min, the vigorously stirred
mixture was treated, in one portion, with a dry MeCN solution
(51 mL) of aldehyde 6 (1360 mg, 8.8 mmol). The reaction
mixture was stirred for 1.5 h at -78 °C, quenched with
aqueous solution of NH4Cl, and extracted with EtOAc. The
organic layer was separated and washed with water and brine.
The organic layer was dried (MgSO4) and concentrated under
reduced pressure. The HPLC analysis (system H) of the crude
product showed the product was a mixture of four diastereo-
mers in the ratio of 13a /13b/13c/13d ) 57:21:16:6. The residue
was applied to silica gel column chromatography and eluted
with EtOAc-hexane (1:2 to 1:1) to obtain 13a as a pale-yellow
amorphous solid (357 mg, 8% yield): [R]20D +146.03 (c 0.0039,
The resulting suspension was cooled to -20 °C. HCO2H (360
g, 7.82 mol), Ac2O (798 g, 7.82 mol), and pyridine (145 g, 1.83
mol) were added sequentially maintaining the temperature
below -10 °C. The mixture was cooled to -20 °C. Ph3P (473
g, 1.80 mol) was added in portions over a period of 10 min
maintaining the temperature between -15 and -10 °C. After
being stirred at -15 to -10 °C for further 1 h, the resulting
suspension was cooled to -30 °C and then filtered. The
residual solid was rinsed with cold (-30 °C) toluene (500 mL).
The combined filtrate was washed successively with a mixture
of ice-water (2 L), ice-cold brine (0.26 L), and NaHCO3 solution
(2 × 2.6 L). The organic layer was dried (MgSO4) and
evaporated. The residue was applied to silica gel (6 kg) column
chromatography and eluted with EtOAc-hexane (1:2), and the
title compound was crystallized from a cold 2-propanol (800
mL). The solid was filtered off, washed with a cold 2-propanol
(400 mL), air-dried for 1 h, and dried over P2O5 in vacuo at rt
overnight. The title compound 19 was obtained as a reddish-
yellow crystalline solid (567 g, 72% yield). The obtained
material was used for next reaction as is: mp 107-108 °C
MeCN); IR (KBr) 1790, 1713 cm-1 1H NMR (CDCl3) δ 2.61
;
(EtOAc-hexane); [R]20 +63.22 (c 0.007, CHCl3); IR (KBr)
D
(brd, J ) 6.0 Hz, 1H), 3.80-3.84 (m, 2H), 4.13-4.17 (m, 2H),
5.26 and 5.48 (AB, J ) 13.5 Hz, 2H), 5.51 (brd, J ) 6.0 Hz,
1H), 6.13 (s, 1H), 7.07 (s, 1H), 7.44 (s, 1H), 7.62 (d, J ) 8.8
Hz, 2H), 8.24 (d, J ) 8.8 Hz, 2H); HRMS (FAB) calcd for
1780, 1723, 1682, 1519, 1344 cm-1; H NMR (CDCl3) δ 2.00
1
(s, 3H), 2.30 (s, 3H), 4.82 (d, J ) 1.9 Hz, 1H), 5.32 and 5.38
(AB, J ) 13.3 Hz, 2H), 5.81 (d, J ) 1.9 Hz, 1H), 7.61 (d, J )
8.6 Hz, 2H), 8.25 (d, J ) 8.6 Hz, 2H), 10.09 (s, 1H); HRMS
C
+ H).
19H16N4O6S2Br (MW + H) 538.9695, found m/z 538.9695 (M+
(EI) calcd for
C16H15N2O6SBr (MW) 441.9834, found m/z
441.9831 (M+). Anal. Calcd for C16H15N2O6SBr: C, 43.35; H,
3.41; N, 6.32. Found: C, 43.21; H, 3.43; N, 6.22.
p-Nitr oben zyl (5R,6S)-6-Br om o-6-[(R)-a cetoxy(2,3-d i-
h yd r oim id a zo[2,1-b]th ia zol-6-yl)m eth yl]-7-oxo-4-th ia -1-
azabicyclo[3.2.0]h ept-2-en e-2-car boxylate (14a). To a stirred
CH2Cl2 (2 mL) solution of bromohydrin 13a (148 mg, 0.275
mmol) were added pyridine (22 mg, 0.275 mmol), Ac2O (28 mg,
0.275 mmol), and DMAP (3 mg, 0.025 mmol) at rt successively.
The reaction mixture was stirred for 3 h at rt. The mixture
was diluted with CHCl3 and washed with dilute NaHCO3
solution, saturated NH4Cl solution, and brine. The organic
layer was dried (MgSO4) and concentrated under reduced
pressure. The residue was applied to silica gel column chro-
matography and eluted with EtOAc-hexane (1:2 to 1:1) to
p-Nitrobenzyl(5R,6S)-6-Bromo-7-oxo-4-thia-1-azabicyclo-
[3.2.0]h ep t-2-en e-2-ca r boxyla te (12). Compound 19 (300 g,
0.68 mol) was dissolved in EtOAc (7.5 L) and cooled to
-70 °C. Ozonized oxygen was passed through the reaction
mixture for ca. 1.5 h until a blue color persisted. The solution
was purged with nitrogen for 2.5 h and treated with P(OMe)3
(383 mL, 3.25 mol) at -70 °C. The mixture was warmed
slowly and stirred at ambient temperature for 17 h. The
solution was then heated to gentle reflux for 45 min. After
cooling to rt, the mixture was diluted with EtOAc (1.25 L)
and washed with water (2 × 2.5 L) and then brine (2.5 L).
The organic layer was dried (MgSO4) and evaporated under
reduced pressure at 25 °C. The residual solid was triturated
with EtOAc (0.6 L). Hexane (0.45 L) was added dropwise to
this mixture over 50 min. The separated solid was filtered off,
and the filter cake was washed with EtOAc-hexane (1:1, 2 ×
200 mL) and then EtOAc-hexane (1:2, 300 mL). The solid
obtain 14a as yellow viscous oil (145 mg, 91% yield): [R]20
D
+127.44 (c 0.0045, CHCl3); IR (KBr) 1798, 1753, 1720 cm-1
;
1H NMR (CDCl3) δ 2.24 (s, 3H), 3.76-3.86 (m, 2H), 4.10-4.21
(m, 2H), 5.27 and 5.45 (AB, J ) 13.6 Hz, 2H), 6.08 (s, 1H),
6.79 (s, 1H), 6.91 (s, 1H), 7.44 (s, 1H), 7.59-7.65 (m, 2H), 8.24
(d, J ) 8.6 Hz, 2H); HRMS (FAB) calcd for C21H18N4O7S2Br
(MW + H) 580.9800, found m/z 580.9775 (M+ + H).
J . Org. Chem, Vol. 69, No. 18, 2004 5857

Abe et al.
p-Nitr oben zyl (5R,6S)-6-Br om o-6-[(S)-h yd r oxy(2,3-d i-
h yd r oim id a zo[2,1-b]th ia zol-6-yl)m eth yl]-7-oxo-4-th ia -1-
a za bicyclo[3.2.0]h ep t-2-en e-2-ca r boxyla te (13b), by Us-
in g An h yd r ou s MgBr 2 a n d Et3N. To a stirred solution of
anhydrous MgBr2 (1100 mg, 6 mmol) in dry MeCN (40 mL)
was added the aldehyde 6 (826 mg, 5.5 mmol) under an argon
atmosphere at rt. A white solid deposited over 30 min. A dry
THF solution (40 mL) of bromopenem 12 (1950 mg, 5 mmol)
was added, and the mixture was cooled to -20 °C. Et3N (1.68
mL, 12 mmol) was added to the mixture in one portion. The
reaction vessel was covered with foil to exclude light. The
reaction mixture was stirred for 2.5 h at -20 °C. The reaction
mixture was diluted with EtOAc and washed with 5% citric
acid aqueous solution, saturated NaHCO3, and brine. The
organic layer was dried (MgSO4) and filtered through a pad
of Celite. The pad was washed with EtOAc. The filtrate was
concentrated under reduced pressure. The HPLC and LC-
MS analyses (system H and G) of the crude product showed
the product was a mixture of four diastereomers in the ratio
of 13a /13b/13c/13d ) 11:85:2:1. The residue was applied to
silica gel column chromatography and eluted with EtOAc-
hexane (1:2 to 1:1) to give 13b as a pale-yellow amorphous
to obtain 14 as two diastereomeric mixture (14a /14b ) 4:1, a
yellow amorphous solid, 58 mg, 25% yield) along with the PNB
ester of thiazole-4-carboxylic acid 15 (a yellow solid, 32 mg,
30% yield).
14: 1H NMR (CDCl3) δ 2.00 (s, 3H × 1/5), 2.24 (s, 3H × 4/5),
3.76-3.86 (m, 2H), 4.10-4.21 (m, 2H), 5.27 and 5.45 (AB, J )
13.6 Hz, 2H), 6.08 (s, 1H × 4/5), 6.23 (s, 1H × 1/5), 6.30 (s, 1H
× 1/5), 6.79 (s, 1H × 4/5), 6.91 (s, 1H × 4/5), 7.15 (s, 1H ×
1/5), 7.44 (s, 1H × 4/5), 7.48 (s, 1H × 1/5), 7.59-7.65 (m, 2H),
8.24 (d, J ) 8.6 Hz, 2H).
15: mp 173-174 °C; IR (KBr) 1728, 1511, 1343 cm-1 1H
;
NMR (CDCl3) δ 5.51 (s, 2H), 7.64 (d, J ) 8.7 Hz, 2H), 8.25 (d,
J ) 8.7 Hz, 2H), 8.32 (d, J ) 2.0 Hz, 1H), 8.89 (d, J ) 2.0 Hz,
1H); HRMS (FAB) calcd for C11H9N2O4S (MW + H) 265.0283,
found m/z 265.0294 (M+ + H). Anal. Calcd for C11H8N2O4S:
C, 50.00; H, 3.05; N, 10.60. Found: C, 50.02; H, 3.19; N, 10.45.
Sequ en tia l Syn th esis of p-Nitr oben zyl (5R)-6-Br om o-
6-[a c e t o x y (2,3-d i h y d r o i m i d a z o [2,1-b ]t h i a z o l-6-y l)-
m eth yl]-7-oxo-4-th ia -1-a za bicyclo[3.2.0]h ep t-2-en e-2-ca r -
boxyla te 14 by Usin g P h 2NLi a n d MgBr 2‚Et2O (Ta ble 1,
En tr y 2). MgBr2‚Et2O (335 mg, 1.3 mmol) was added to a dry
THF (12 mL) solution of bromopenem 12 (385 mg, 1.0 mmol)
under an argon atmosphere at rt. The suspension was cooled
to -78 °C. The reaction vessel was covered with foil to exclude
light. Ph2NLi, prepared by adding n-BuLi (0.87 mL, 1.57 M
in hexane) to a dry THF solution (4 mL) of Ph2NH (220 mg,
1.3 mmol) at -20 °C, was added to the vigorously stirred
suspension in one portion. After 15-20 s, the vigorously stirred
mixture was treated, in one portion, with a dry MeCN solution
(5 mL) of aldehyde 6 (170 mg, 1.1 mmol). The reaction mixture
was stirred for 1 h at -78 °C and treated with Ac2O (133 mg,
1.3 mmol) in one portion. The reaction mixture was warmed
to 0 °C and stirred for 1 h at 0 °C. The mixture was diluted
with EtOAc and washed with water and brine. The organic
layer was dried (MgSO4) and concentrated under reduced
pressure. LC-MS and HPLC analyses (system G and H) of
the crude product showed 14 was formed in 90% yield as a
mixture of four diastereomers in the ratio of 14a /14b/14c/14d
) 14:82:2:1. The residue was applied to silica gel column
chromatography and eluted with EtOAc-hexane (1:2 to 1:1)
to obtain 14 as two diastereomeric mixture (14a /14b ) 1:6 by
1H NMR, a colorless amorphous solid, 447 mg, 77% yield): 1H
NMR (CDCl3) δ 2.00 (s, 3H × 6/7), 2.24 (s, 3H × 1/7), 3.76-
3.86 (m, 2H), 4.10-4.21 (m, 2H), 5.27 and 5.45 (AB, J ) 13.6
Hz, 2H), 6.08 (s, 1H × 1/7), 6.23 (s, 1H × 6/7), 6.30 (s, 1H ×
6/7), 6.79 (s, 1H × 1/7), 6.91 (s, 1H × 1/7), 7.15 (s, 1H × 6/7),
7.44 (s, 1H × 1/7), 7.48 (s, 1H × 6/7), 7.59-7.65 (m, 2H), 8.24
(d, J ) 8.6 Hz, 2H).
solid (452 mg, 17% yield): [R]20 +105.1 (c 0.0039, CHCl3); IR
D
(KBr) 1794, 1717 cm-1; 1H NMR (CDCl3) δ 3.72-3.88 (m, 3H),
4.13-4.25 (m, 2H), 5.22 (brd, J ) 4.4 Hz, 1H), 5.28 and 5.46
(AB, J ) 13.5 Hz, 2H), 6.12 (s, 1H), 7.11 (s, 1H), 7.41 (s, 1H),
7.62 (d, J ) 8.6 Hz, 2H), 8.25 (d, J ) 8.6 Hz, 2H); HRMS (FAB)
calcd for C19H16N4O6S2Br (MW + H) 538.9695, found m/z
538.9645 (M+ + H). The mixed fraction contained the diaster-
eomeric mixtures of 13a and 13b (1044 mg, 39% yield).
p-Nitr oben zyl (5R,6S)-6-Br om o-6-[(S)-a cetoxy(2,3-d i-
h yd r oim id a zo[2,1-b]th ia zol-6-yl)m eth yl]-7-oxo-4-th ia -1-
a za b icyclo[3.2.0]h ep t -2-en e-2-ca r b oxyla t e (14b ). To a
stirred solution of bromohydrin 13b (120 mg, 0.2 mmol) in
CH2Cl2 (2 mL) were added Ac2O (35 mg, 0.3 mmol), pyridine
(27 mg, 0.3 mmol), and DMAP (2.5 mg, 0.02 mmol) at 0 °C
successively. The reaction mixture was warmed to rt and
stirred for 16 h. The mixture was diluted with EtOAc and
washed with 1 N HCl, saturated NaHCO3, and brine. The
organic layer was dried (MgSO4) and concentrated under
reduced pressure. The residue was applied to silica gel column
chromatography and eluted with EtOAc-hexane (1:1) to obtain
14b as a yellow amorphous solid (89 mg, 69% yield): [R]20
D
+266.3 (c 0.0036, CHCl3); IR (KBr) 1798, 1717 cm-1; 1H NMR
(CDCl3) δ 2.00 (s, 3H), 3.76-3.86 (m, 2H), 4.10-4.21 (m, 2H),
5.27 and 5.45 (AB, J ) 13.6 Hz, 2H), 6.23 (s, 1H), 6.30 (s, 1H),
7.15 (s, 1H), 7.48 (s, 1H), 7.62 (d, J ) 8.6 Hz, 2H), 8.24 (d, J
) 8.6 Hz, 2H); HRMS (FAB) calcd for C21H18N4O7S2Br (MW
+ H) 580.9800, found m/z 580.9764 (M+ + H).
Sequ en tia l Syn th esis of p-Nitr oben zyl (5R)-6-Br om o-
6-[a c e t o x y (2,3-d i h y d r o i m i d a z o [2,1-b ]t h i a z o l-6-y l)-
m eth yl]-7-oxo-4-th ia -1-a za bicyclo[3.2.0]h ep t-2-en e-2-ca r -
boxyla te 14 by Usin g An h yd r ou s MgBr 2 a n d Et3N (Ta ble
2, En tr y 2). Aldehyde 6 (88 mg, 0.57 mmol) was added to a
dry MeCN (4 mL) solution of anhydrous MgBr2 (115 mg, 0.62
mmol) under an argon atmosphere at rt, and a colorless powder
deposited over 30 min. A dry THF solution (4 mL) of bromo-
penem 12 (200 mg, 0.52 mmol) was added, and the mixture
was cooled to -20 °C. Et3N (0.17 mL, 1.25 mmol) was added
to the mixture in one portion. The reaction vessel was covered
with foil to exclude light. The reaction mixture was stirred
for 3 h at -20 °C and treated with Ac2O (106 mg, 1.04 mmol)
in one portion. The reaction mixture was warmed to 0 °C and
stirred for 16 h at 0 °C. The mixture was diluted with EtOAc
and washed with 5% citric acid aqueous solution, saturated
NaHCO3, and brine. The organic layer was dried (MgSO4) and
filtered through a pad of Celite. The pad was washed with
EtOAc. HPLC and LC-MS analysis (system H and G) of the
organic layer showed 14 was produced in 90% yield as a
mixture of four diastereomers in the ratio of 14a /14b/14c/14d
) 5:60:1:1. The filtrate was concentrated under reduced
pressure. The residue was applied to silica gel column chro-
matography and eluted with EtOAc-hexane (1:2 to 1:1) to
Sequ en tia l Syn th esis of p-Nitr oben zyl (5R)-6-Br om o-
6-[a c e t o x y (2,3-d i h y d r o i m i d a z o [2,1-b ]t h i a z o l-6-y l)-
m eth yl]-7-oxo-4-th ia -1-a za bicyclo[3.2.0]h ep t-2-en e-2-ca r -
boxyla te 14 by Usin g P h 2NLi (Ta ble 1, En tr y 1). A dry
THF (4 mL) solution of bromopenem 12 (154 mg, 0.4 mmol)
was cooled to -78 °C under an argon atmosphere. The reaction
vessel was covered with foil to exclude light. Ph2NLi, prepared
by adding n-BuLi (0.33 mL, 1.57 M in hexane) to a dry THF
solution (1 mL) of Ph2NH (88 mg, 0.52 mmol) at -40 °C, was
added to the vigorously stirred suspension in one portion. After
being stirred for 5 min, the vigorously stirred mixture was
treated, in one portion, with a dry MeCN solution (3 mL) of
aldehyde 6 (75 mg, 0.49 mmol). The reaction mixture was
stirred for 1 h at -78 °C and treated with Ac2O (53 mg, 0.52
mmol) in one portion. The reaction mixture was warmed to 0
°C and stirred for 1 h at 0 °C. The mixture was diluted with
EtOAc and washed with water and brine. LC-MS and HPLC
analyses (system G and H) of the organic layer showed 14 was
formed in 43% yield as a mixture of four diastereomers in the
ratio of 14a /14b/14c/14d ) 40:22:25:13 (2:1:1:0.2 by 1H NMR).
The organic layer was dried (MgSO4) and concentrated under
reduced pressure. The residue was applied to silica gel column
chromatography and eluted with EtOAc-hexane (1:2 to 1:1)
5858 J . Org. Chem., Vol. 69, No. 18, 2004

Preparation of 6-Methylidene Penem Derivatives
obtain 14 as two diastereomeric mixture (14a /14b ) 1:10 by
1H NMR, a pale-yellow amorphous solid, 257 mg, 85% yield):
1H NMR (CDCl3) δ 2.00 (s, 3H × 10/11), 2.24 (s, 3H × 1/11),
3.76-3.86 (m, 2H), 4.10-4.21 (m, 2H), 5.27 and 5.45 (AB, J )
13.6 Hz, 2H), 6.08 (s, 1H × 1/11), 6.23 (s, 1H × 10/11), 6.30 (s,
1H × 10/11), 6.79 (s, 1H × 1/11), 6.91 (s, 1H × 1/11), 7.15 (s,
1H × 10/11), 7.44 (s, 1H × 1/11), 7.48 (s, 1H × 10/11), 7.59-
7.65 (m, 2H), 8.24 (d, J ) 8.6 Hz, 2H).
1H NMR (CDCl3) δ 0.97 (d, J ) 6.6 Hz, 3H), 1.00 (d, J ) 6.6
Hz, 3H), 0.99-1.06 (m, 1H), 1.78 (ddd, J ) 3.9, 10.2, 14.2 Hz,
1H), 1.92-1.98 (m, 1H), 2.26 (d, J ) 5.2 Hz, 1H), 4.27 (dd, J
) 5.2, 10.2 Hz, 1H), 5.29 and 5.46 (AB, J ) 13.4 Hz, 2H), 5.97
(s, 1H), 7.38 (s, 1H), 7.60 (d, J ) 8.8 Hz, 2H), 8.24 (d, J ) 8.8
Hz, 2H); HRMS (FAB) calcd for C18H20N2O6SBr (MW + H)
471.0225, found m/z 471.0186 (M+ + H).
p-Nitr oben zyl (5R,6S)-6-Br om o-6-[(R)-h yd r oxyp h en yl-
m eth yl]-7-oxo-4-th ia -1-a za bicyclo[3.2.0]h ep t-2-en e-2-ca r -
boxyla te (17c). The stereochemistry was supported by an
X-ray crystallographic structure determination. Single iso-
mer: pale-yellow crystals; mp 160-163 °C dec (CHCl3-EtOAc);
p-Nitr oben zyl (5R,6S)-6-Br om o-6-[(S)-p-n itr oben zoyl-
oxy(2,3-d ih yd r oim id a zo[2,1-b]th ia zol-6-yl)m eth yl]-7-oxo-
4-th ia -1-a za bicyclo[3.2.0]h ep t-2-en e-2-ca r boxyla te (16).
Aldehyde 6 (1.24 g, 8.0 mmol) was added to a dry MeCN (50
mL) solution of anhydrous MgBr2 (1.61 g, 8.8 mmol) under an
argon atmosphere at rt. Colorless powder deposited over 30
min. A dry THF solution (45 mL) of bromopenem 12 (2.80 g,
7.3 mmol) was added, and the mixture was cooled to -20 °C.
Et3N (2.43 mL, 17.5 mmol) was added in one portion, and the
reaction vessel was covered with foil to exclude light. The
reaction mixture was stirred for 2.5 h at -20 °C and treated
with a dry THF solution (5 mL) of the p-nitrobenzoyl chloride
(2.03 g, 10.9 mmol) in one portion. The reaction mixture was
warmed to 0 °C and stirred for 1 h at this temperature and
subsequently diluted with EtOAc. The organic layer was
washed with 5% citric acid aqueous solution, saturated
NaHCO3, and brine. It was dried (MgSO4) and filtered through
a pad of Celite. The pad was washed with EtOAc. The filtrate
was concentrated under reduced pressure. The residue was
applied to silica gel column chromatography and eluted with
CHCl3 to obtain 16 as a colorless crystalline solid (663 mg,
13% yield). The material was recrystallized several times from
EtOA-DMF, and a single crystal was obtained. The stereo-
chemistry was supported by an X-ray crystallographic struc-
[R]20 +64.78 (c 0.00372, CHCl3); IR (KBr) 1782, 1717 cm-1
;
D
1H NMR (CDCl3) δ 2.96 (brs, 1H), 5.30 and 5.47 (AB, J ) 13.5
Hz, 2H), 5.44 (s, 1H), 6.04 (s, 1H), 7.37-7.44 (m, 4H), 7.49-
7.53 (m, 2H), 7.62 (d, J ) 8.7 Hz, 2H), 8.25 (d, J ) 8.7 Hz,
2H); HRMS (FAB) calcd for
C20H16N2O6SBr (MW + H)
490.9912, found m/z 490.9907 (M+ + H).
p -Nit r ob en zyl (5R)-6-Br om o-6-(1-h yd r oxy-3-p h en yl-
a llyl)-7-oxo-4-t h ia -1-a za b icyclo[3.2.0]h ep t -2-en e-2-ca r -
boxyla te (17d ). Single isomer: pale-yellow amorphous solid;
[R]20 +123.74 (c 0.00396, CHCl3); IR (KBr) 1794, 1717 cm-1
;
D
1H NMR (CDCl3) δ 2.63 (d, J ) 5.1 Hz, 1H), 4.95 (dd, J ) 5.1,
7.0 Hz, 1H), 5.29 and 5.46 (AB, J ) 13.4 Hz, 2H), 5.96 (s, 1H),
6.22 (dd, J ) 6.0, 7.0 Hz, 1H), 6.84 (d, J ) 6.0 Hz, 1H), 7.29-
7.38 (m, 3H), 7.38-7.44 (m, 3H), 7.60 (d, J ) 8.6 Hz, 2H), 8.24
(d, J ) 8.6 Hz, 2H); HRMS (FAB) calcd for C22H17N2O6SBrNa
(MW + Na) 538.9888, found m/z 538.9913 (M+ + Na).
4-For m yl-2-ph en ylim idazole-1-car boxylic Acid 4-Nitr o-
ben zyl Ester . The title aldehyde was synthesized from
4-formyl-2-phenylimidazole by a conventional procedure using
p-nitrobenzyl chloroformate: colorless solid; mp 122-125 °C;
ture determination: mp 153-156 °C dec; [R]20 +327.1 (c
IR (KBr) 3153, 1760, 1689, 1515, 1398, 1347, 985 cm-1 1H
;
D
0.0037, DMF); IR (KBr) 1779, 1730, 1713 cm-1
;
1H NMR
NMR (CDCl3) δ 5.40 (s. 2H), 7.32 (d, J ) 8.6 Hz, 2H), 7.41-
7.52 (m, 3H), 7.56-7.58 (m, 2H), 8.18-8.21 (m, 2H), 8.22 (s,
1H), 9.97 (s, 1H); HRMS (EI) calcd for C18H13N3O5 (MW)
351.0855, found m/z 351.0855 (M+).
(CDCl3) δ 3.77-3.86 (m, 2H), 4.11-4.24 (m, 2H), 5.26 and 5.43
(AB, 2H, J ) 13.5 Hz), 6.41 (s, 1H), 6.51 (s, 1H), 7.26 (s, 1H),
7.58-7.60 (m, 3H), 8.09-8.12 (m, 2H), 8.20-8.22 (m, 4H);
HRMS (FAB) calcd for C26H19N5O9S2Br (MW + H) 687.9808,
found m/z 678.9781 (M+ + H). Anal. Calcd for C26H18N5-
O9S2Br: C, 45.36; H, 2.64; N, 10.17. Found: C, 45.15; H, 2.66;
N, 10.07.
Gen er a l P r oced u r e for MgBr 2/Et3N-P r om oted Ald ol-
Typ e Con d en sa tion (Ta ble 3). To a dry MeCN mixture of
aldehyde (1.1-3 molar equiv) and anhydrous MgBr2 (1.2-4
molar equiv) was added a dry THF solution of bromopenem
12 under a nitrogen atmosphere at rt. The reaction mixture
was cooled to -20 °C, and Et3N (2.4-4 molar equiv) was added
in one portion. The reaction vessel was covered with foil to
exclude light. The mixture was stirred for 3 to 4 h at -20 °C.
The mixture was diluted with EtOAc and washed with water,
saturated NaHCO3, and brine. The organic layer was dried
(MgSO4) and filtered through a pad of Celite. The filtrate was
concentrated under reduced pressure. The crude product was
purified by silica gel column chromatography to obtain an
isolated aldol adduct.
p-Nitr oben zyl (5R)-6-Br om o-6-[h yd r oxy[1-(p-n itr oben -
zyloxyca r b on yl)-2-p h en yl-1H -im id a zol-4-yl]m et h yl]-7-
oxo-4-t h ia -1-a za b icyclo[3.2.0]h ep t -2-en e-2-ca r b oxyla t e
(17e). Diastereomeric mixture: pale-yellow amorphous solid;
IR (KBr) 1794, 1720 cm-1; 1H NMR (CDCl3) δ 2.84 (d, J ) 6.6
Hz, 1H × 0.54), 3.49 (d, J ) 6.1 Hz, 1H × 0.07), 3.75 (d, J )
6.1 Hz, 1H × 0.13), 3.86 (d, J ) 8.5 Hz, 1H × 0.26), 5.21-5.64
(m, 5H), 6.13 (s, 1H × 0.26), 6.15 (s, 1H × 0.54), 6.40 (s, 1H ×
0.07), 6.50 (s, 1H × 0.13), 7.32-7.73 (m, 11H), 8.18-8.25 (m,
4H); HRMS (FAB) calcd for
C31H23N5O10SBr (MW + H)
736.0349, found m/z 736.0317 (M+ + H).
p -Nit r ob en zyl (5R)-6-Br om o-6-(h yd r oxyt h ia zol-2-yl-
m eth yl)-7-oxo-4-th ia -1-a za bicyclo[3.2.0]-h ep t-2-en e-2-ca r -
boxyla te (17f). Single isomer: colorless amorphous solid; mp
83-85.5 °C dec; [R]20 +233.91 (c 0.00369, CHCl3); IR (KBr)
D
1783, 1717 cm-1; 1H NMR (CDCl3) δ 3.26 (d, J ) 6.5 Hz, 1H),
5.29 and 5.47 (AB, J ) 13.4 Hz, 2H), 5.83 (d, J ) 6.5 Hz, 1H),
6.19 (s, 1H), 7.40 (d, J ) 3.2 Hz, 1H), 7.46 (s, 1H), 7.61 (d, J
) 8.8 Hz, 2H), 7.77 (d, J ) 3.2 Hz, 1H), 8.24 (d, J ) 8.8 Hz,
p-Nitr oben zyl (5R,6S)-6-Br om o-6-[(R)-1-h yd r oxyeth yl]-
7-oxo-4-t h ia -1-a za b icyclo[3.2.0]h ep t -2-en e-2-ca r b oxyl-
a te (17a ). The stereochemistry was supported by an X-ray
crystallographic structure determination. Single isomer: pale-
2H); HRMS (FAB) calcd for
C17H13N3O6S2Br (MW + H)
497.9429, found m/z 497.9453 (M+ + H).
Sod iu m (5R)-(Z)-6-(2,3-Dih yd r oim id a zo[2,1-b]th ia zol-
6-ylm et h ylen e)-7-oxo-4-t h ia -1-a za b icyclo[3.2.0]h ep t -2-
en e-2-ca r boxyla te (5), P r ep a r ed fr om Br om op en em 12.
Aldehyde 6 (110.1 g, 0.714 mol) was added to a dry MeCN (5
L) solution of anhydrous MgBr2 (143.4 g, 0.779 mol) under an
argon atmosphere at rt. Colorless powder deposited over a
period of 30 min. A dry THF solution (5 L) of bromopenem 12
(250 g, 0.649 mol) was transferred to the suspension via a
PTFE tube under positive argon pressure over 12 min. After
the reaction mixture was cooled to -20 °C, Et3N (217 mL,
1.557 mol) was added in one portion. The reaction vessel was
covered with foil to exclude light. The reaction mixture was
stirred for 3 h at -20 °C and treated with Ac2O (133 g, 1.303
mol) in one portion. The reaction mixture was warmed to 0
yellow crystals; mp 148-151 °C dec (CHCl3-hexane); [R]20
D
+9.26 (c 0.00396, CHCl3); IR (KBr) 1784, 1705 cm-1; 1H NMR
(CDCl3) δ 1.33 (d, J ) 6.1 Hz, 3H), 2.40 (d, J ) 5.1 Hz, 1H),
4.36-4.41 (m, 1H), 5.29 and 5.45 (AB, J ) 13.4 Hz, 2H), 5.98
(s, 1H), 7.37 (s, 1H), 7.61 (d, J ) 8.8 Hz, 2H), 8.24 (d, J ) 8.8
Hz, 2H); HRMS (FAB) calcd for C15H13N2NaO6SBr (MW + Na)
450.9575, found m/z 450.9540 (M+ + Na). Anal. Calcd for
C
15H13N2O6SBr: C, 41.97; H, 3.05; N, 6.53. Found: C, 41.60;
H, 3.03; N, 6.41.
p-Nitr oben zyl (5R)-6-Br om o-6-[1-h yd r oxy-2-m eth yl-
p r op yl]-7-oxo-4-th ia -1-a za bicyclo[3.2.0]h ep t-2-en e-2-ca r -
boxyla te (17b). Single isomer: pale-yellow amorphous solid;
[R]20 +52.78 (c 0.00396, CHCl3); IR (KBr) 1782, 1717 cm-1
;
D
J . Org. Chem, Vol. 69, No. 18, 2004 5859

Abe et al.
°C and stirred for 16 h at 0 °C. The mixture was diluted with
EtOAc (20 L) and washed with 5% citric acid (10 L) aqueous
solution, saturated NaHCO3 (10 L), and brine (10 L). The
organic layer was dried (MgSO4) and filtered through a pad
of Celite. The pad was washed with EtOAc (1.4 L). The filtrate
was concentrated under reduced pressure at 30 °C. The
residual brown oil contains 327 g (87% yield) of 14 from HPLC
assay (system G). The resulting oil was used for the next
reaction as is.
The residual brown oil of 14 was dissolved in THF (5.4 L)
and MeCN (2.5 L). Freshly activated zinc dust (1.5 kg) was
added rapidly with 0.5 M phosphate buffer (pH 6.5, 7.9 L).
The reaction vessel was covered with foil to exclude light. The
reaction mixture was vigorously stirred for 2.5 h maintaining
the temperature about 35 °C. The mixture was cooled to 3 °C,
and an ice-cold 1 M NaOH (ca. 1750 mL) was added to adjust
pH to 8 at below 3 °C. The mixture was diluted with EtOAc (4
L) and filtered through a pad of Celite. The pad was washed
with water (2.5 L), and the aqueous layer was separated. The
aqueous layer, containing 150 g of 5 (81% yield from 14, 70%
yield from 12) from the HPLC assay (system C), was concen-
trated to 8.85 kg (ca. 8 L) under high vacuum at 35 °C.
The concentrate was applied to Sepabeads SP-207 (7 L,
Mitsubishi Kasei Co. Ltd.) resin column chromatography. After
absorbing, the column was eluted with water (14 L) and then
with 20% MeCN-water to give the purified active fractions
of the title compound.
at 3 °C (total 5 L of acetone). After the mixture was stirred
for 1 h at 3 °C, the solid was filtered off, and the filter cake
was washed with acetone (800 mL). The solid was air-dried
under excluding light for 1 h and dried in vacuo overnight at
rt to give 5 (112 g, HPLC area ratio 100%, contents 96.5%
(system C), 100% ee by chiral HPLC (system D), 57% yield
from 14, 50% yield from 12) as a yellow crystalline solid. A
small portion of the solid was further purified by recrystalli-
zation to obtain a pure material (HPLC contents, 100%): mp
208 °C dec; [R]20D +521.4 (c 0.0053, H2O); IR (KBr) 1752, 1679
cm-1; 1H NMR (D2O) δ 3.80 (t, J ) 7.4 Hz, 2H), 4.14-4.20 (m,
2H), 6.42 (s, 1H), 6.82 (s, 1H), 6.96 (s, 1H), 7.42 (s, 1H); HRMS
(FAB) calcd for C12H8N3O3S2Na2 (MW + Na) 351.9802, found
m/z 351.9815 (M+ + Na). Anal. Calcd for C12H8N3O3S2Na‚
1.2H2O: C, 41.07; H, 2.99; N, 11.96. Found: C, 41.06; H, 2.91;
N, 11.96.
Ackn owledgm en t. The X-ray crystallographic analy-
sis of 16 was performed at the Faculty of Pharma-
ceutical Sciences, The University of Kumamoto. The
elemetal analysis and mass spectra were recorded at
the Faculty of Pharmaceutical Sciences, The University
of Tokushima. The authors thank Drs. M. Kolb, M.
Fawzi, and D. Shlaes for useful discussions.
Su p p or tin g In for m a tion Ava ila ble: HPLC analytic con-
ditions, 1H NMR spectra of all compounds, chiral HPLC charts
of compounds 5 and 9, and ORTEP drawings of compounds
16, 17a , and 17c. This material is available free of charge via
the Internet at http://pubs.acs.org.
The combined fractions were concentrated to 1.25 kg (ca. 1
L) under high vacuum at 35 °C. Acetone (2.5 L) was added to
the concentrate with stirring at rt. The mixture was cooled to
3 °C and then stirred for 30 min. Acetone was added to the
mixture in 625 mL portions every 30 min over a period of 4 h
J O049880G
5860 J . Org. Chem., Vol. 69, No. 18, 2004