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A new synthesis of 1β-methylcarbapenems using NBS-promoted cyclization as a key step
Tma,d,m
Lenen. Vol. 35. No. 34, pa. 63174320.1994 elscviisciaaM tillled in &.a Britain oo40-4034w4
s7.oLho.m
o040439(94p1244-x
A New Synthesis of l&Methylcarbapenems Using NBS-Promoted Cyclization as a Key Step iku, MasPhito Hayashi, Osamu Sakurai, Mosami Takahashi, Tsuyoshi Hiroshi Horikawa,* and TameoOI wasaki Dqutmsntof SynlhetiEChemistry, Rarasrch Lpborarocyof Applied Biocbdstry, Tanabe Seiydcu Co..Lkl., 3-1689. Krdima, Ym
Osaka 532. Japan
Abstract: A novel construction of lg-mcthylcarbapencm skeleton has been achieved by use of N~ii6a(NsStpmnoled cyclizalion ss a key s&p. The mcchmism Of the stempccrw cydipiion lading Y) l&med~ylcarbapmamisakodixussed.
1~Methylcarbapcnems have attracted much attention recently because of their potent and broad-specbum antibacterial activities in addition to their chemical and metabolic stability.11 ‘Ibe la-methylcarbapencm skeletons having a bicyclic ring system have been synthesized by the excelknt methodologies based on the Rh(II>catalyzed carbine insertion,t*2)the intramoleculer Wittig reaction?) the Dieckmann condensati&) and the E.schenmoscrsulfide contra&4.*) In amncction with our synthetic studle4 in search of a new carbapcnem having potent antibacterial activity, we now report a conceptually new synthetic method of lbmethylcarbapenem skeleton based on a novel ring construction utilizing NBS-promoted cyclization as a key step. It is welldocumented that the halcmium ion-induced cyclization leading to lactams is quite convenient in the synthesis of nitrogen-containing hctem~yclcs such as alkaloids@because of the mild reaction conditions and simplicity of the proccdun. Although Sc&trigonal mo& is unfavorable in the co~~~~ction of a 5-mcmbcrcd ring system.7) we anticipated that cycllzation of a-alkoxy enoatc A leading to the &slraI carbapenam B would proceed smoothly due to the effect of the electrondonating alkoxy group which could stabilize the developing positive charge on the carbon a to the ester group (Scheme 1). scl?eme 1
NBS co#
B R’, R2:lllkyl group
6317
TBS: &MutyldhnethyWlyf
6318
First of all. propionic acid derivative 18.9) was treated sequentially EtSH, followed
by hr-silylation
with TBSOTf
in the presence
with N. N%arbonyldiimidazole
of 2,6-lutidine
Compound 2 was then reduced according to the Fukuyama’s msthod(Et$iWlO%
and
to give 2 in 81% yield. Pd-C)l@ to aldehyde 3 in
quantitative
yield. Aldthyde 3 was treated with the sodium salt of phosphate 4 at 0 “C to give a mixture of the
(Z)-isomer
Sa and the (E)-isomer
Sb in 85% yield in a ratio of 2:l.
cleaved with n-BubNF in the presence of AcOH to give the Q-isomer
N-TBS group of Sa was selectively 6a.11) (&Isomer
6b was also obtained
from Sb under the same conditions.
!%R=TBS,X=OEt,Y=C Sb: R = TBS, X = C02Et, 6a:R=H,X=OEt,Y=CO,E1 6b:R=H,X=C02E1,Y=OEt
7a: X = OEt, Y = CO Et 7b: X = CO,E1, Y = aE1
Et Y =% Et
10
-
We next examined the NBS-promoted cyclization of 6 leading to 7. Treatment of 6p with 1 eq of NBS in CH,CN at room temperature gave the cyclized product 7a as a sole product in quantitative yield via S-endc+ ttigonal
mode cyclization.t2)
resulting in the formation
In a similar way. the (&)-isomer
of the C3-epimer
determined by both the NOE expctiment In order intermediate. phosphate
to gain an insight
6b was subjected to the cyclization analysis.14)
of this cyclization.
we tried to isolate
When the reaction was carried out at 0 “C for 5 min and subsequently
buffer @H 7.0). a mixture of the N-brominated
when the reaction was further continued
from the less him&ted
quenched
a reaction with 0.2 M
8’5) and 7a in a ratio of 1:l was obtained;
under the same reaction conditions, is initiated by bromination
would then migrate to the olefin n-bond 9. Subsequently,
compound
reaction,
of 7a and 7b was
yield. 13) The stereochemistry
and the X-ray crystallographic
into the mechanism
These results indicate that the reaction intermediate
7b in quantitative
8 was gradually converted to 7a.
of the nitrogen a-face
atom.
The bromonium
to form the bridged
bromonium
ion ion
the resulting anion on the amide nitrogen would attack on the carbon a to ethoxy
group, giving the anti adduct 7e (Scheme 2). With the desired carbapenam 7a. b in hand, we next examined several trials, 10, which is an important
precursor
yield by treatment of 7a with CHQCI-Nal
same reaction conditions.
for the synthesis
in CH$N.
conversion
to the carbapenem.
of carbapenems,t@
was obtained
17) Epimer 7b was also converted
After in 75%
to 10 under the
6319
Schomo 2
Ptau8lbto mochanlsm of the N8Gpmnotod
NBS
cycliation
t
&Et
1
?a In summary, we found a convenient
method for the construction of 1p-mcthylcarbapcnam
the novel NBS-promoted cyclization reaction. Further transformation of the functionalized other useful lj3-methylcarbapenems is now under investigation. Acknowledgment:
skckton
using
catbapenams 7 into
We are grateful to Dr. A. Kinumaki in our company for the NMR experiments
and to Dr.
T. Da-m in our company for the X-my study. References
1. 2.
and
Notes
a) D. H. Shih, F. Baker, L. Cama, and B. G. Christensen, Heterocycles. 21, 29 (1984) b) M. Sunagawa. H. Matsumuta. T. moue. M. Fukasawa, and M. Kato. J. Anribiorics. 43.519 (1990). T. N. Salzmann. R. W. Ratcliffe. B. G. Christensen. and F. A. Bouffard, 1. Am. Chem. Sot.. 102. 6161 (1980).
J. Am. Chem. Sot., 100, 8006 (1978) b) C. Battisitini,
3.
a) L. D. Cama and B. G. Christensen,
4.
Scarafile, M. Foglio, and G. Franceschi, Tetrahedron Lett., 25, 2395 (1984) c) A. Yoshida. Y. Tajima, N. Take&, and S. Oida, ibid., 25. 2793 (1984). a) M. Hatanaka. Y. Yamamoto. H. Nitta, and T. Ishimatu, Terruhedron Lett.. 22. 3883 (1981) b) T. J. Sowin. and A. I. Meyers, J. Org. Chem., 53.4154
C.
(1988) c) R. Dcziel and D. Favreau, Tetrahedron
Len.. 30, 1345 (1989).
5. 6.
0. Sakurai, T. Ogiku, M. Takahashi, H. Horikawa, and T. Iwasaki, Terrahedron L-err., in press. a) S. Knapp and D. V. Patel, J. Am. Chem. Sot., 105.6985 (1983) b) Y. Tamant, S. Kawamura, K. Tetrahedron L&t., 25, 1063 (1984) c) S. Knapp, K. E. Rodtiques. A. T. Levorse. and R. M. Ornaf, ibid., 26, 1803 (1985) d) E. J. Corey, C.-P. Chen. and G. A. Reichard,
Tanaka, and Z. Yoshida.
ibid., 30, 5547 (1989) e) Y. G. Kim and J. K. Cha, ibid., 30, 5721 (1989) f) R. M. Williams
F. Miknis,
ibid.,
Heterocycles,
7.
J. E. Baldwin,
31.
4297
(1990)
g) S. Kane,
T. Yokomatsu,
26, 359 (1987). J. Chem. Sot.,
Chem. Commun..
1976, 734.
H. Iwasawa,
and G.
and S. Shibuya,
6320
8.
D. R. Bender,
A. M. DeMarco,
2411 (1992) and mfemnces
D. G. Melillo.
S. M. Riseman.
and I. Shinkai,
J. Org. Chem., 57.
cited therein.
9.
For a review see: Y. Ito and S. Tetashima,
10.
T. Fukuyama.
11.
The xqiochemistry
of 60 and 6b was determined on the basis of IH NMR specaa; the vinyl protons of
6a and 6b appeared
at 8 5.93 and 8 4.81, respectively.
vinyl proton and EtO-mcthylene 12.
J. Syn. Org. Gem.,
47. 606 (1989).
/pt..
S.-C. Lin. and L. Lin. J. Am. Chem. Sot., 112. 7050 (1990).
A typical procedure
For 6b, NOE (14.9%) was observed
protons.
is as follows:
to a solution
of 6s (50 mg. 0.125 mmol)
added NBS (25 mg. 0.138 mmol) all at once at 20 “C and the mixture mixture was poumd into saturated aqueous NasS&
and extracted
Column chromatography
tH NMR spectrum J=6.2Hz.
3H), 1.20 (t, J=7.OHz,
lH), 3.20 (t,J=3.7Hz, 13.
3H), 1.21 (d. J=6.OHz,
The stereochemistry
at C2 of 7s and lb
spectra;
NOE between
15.
11 which was easily obtainable
Cambridge
Crystallogndphic
12H). 2.66-2.85 J=lO.2Hz,
3H), 2.62-2.83
lH), 4.15-4.38
3H), 1.36 (t, /=7.1Hz, 1H). 3.85-4.37
(m.
(m. 3H).
3H), 2.68-2.81
(m,
(m. 6H).
determined
on the basis of 1H NMR
(5.4% for 7a and 4.1% for 7b). The stexr.cchcmistry analysis of 6(1-benzoybxy)ethyl
by the X-ray crystallographic
derivative
1H NMR spectrum
3H), 1.32 (t, J=7.lHz,
was unambiguously
Hz and H6 was observed
The residue was purified
6 0.06 (s. 3H), 0.07 (s, 3H), 0.88 (s, YH), 1.20 (d,
IH), 3.75 (d. J=l0.8Hz,
was confirmed
The
The organic layer was
= 10: 1) to give la (58 mg, 97%) as a syrup.
3H), 1.30 (t, J=6.9Hz.
3.1Hz.
at C3 of these epimers
in vacua.
(m, 3H). 4.18 (d.J=ll.3Hz,
MHz. CDCls):
lH), 3.13 (dd, J=5.4,
(2 ml) was
6 0.06 (s. 3H). 0.07 (s. 3H). 0.88 (s. 9H), 1.16 (d.
3H). 1.23 (d, J=7.0Hz,
IH), 3.78-4.05
tH NMR spectrum of 7b (200 J=7.4Hz,
14.
(n-hexane:AcOEt
of 7a (200 MHz. CDCls):
in CHsCN
was stirred for 30 min.
with AcOEt.
washed with HsO. with brine, dried over MgS04. and concentrated by SQ
between
from 7a. Full crystal data for 11 has been deposited
at the
Data Centre.
of 8 (200 MHz. CDCls): (m. IH). 3.16 (t. /=2.5Hz,
1H). The related acylhypoiodide
6 0.06 (s, 3H), 0.07 (s. 3H). 0.88 (s. 9H), 1.10-1.36 (m, lH), 3.77-4.05 intermediate
(m, 3H), 4.19-4.42
was suggested
(m, 3H). 6.03 (d,
in the iodolactonization:
P. A.
Bartlett and J. Myerson. 1. Am. Chem. Sot., 100. 3950 (1978). 16.
Transformation Bateson,
of descysteaminylthienamycin
P. M. Roberts,
T. C. Smale,
to 2-substituted
and R. Southgate.
carbapenems
J. Chem. Sot.,
185. 17.
A. Oku, T. Harada.
and K. Kita. Terrahedron Lett.. 23. 681 (1982).
(Received in Japan 7 April 1994; accepted 27 May 1994)
has been known: Chem. Commun..
J. H. 1980.
Lenen. Vol. 35. No. 34, pa. 63174320.1994 elscviisciaaM tillled in &.a Britain oo40-4034w4
s7.oLho.m
o040439(94p1244-x
A New Synthesis of l&Methylcarbapenems Using NBS-Promoted Cyclization as a Key Step iku, MasPhito Hayashi, Osamu Sakurai, Mosami Takahashi, Tsuyoshi Hiroshi Horikawa,* and TameoOI wasaki Dqutmsntof SynlhetiEChemistry, Rarasrch Lpborarocyof Applied Biocbdstry, Tanabe Seiydcu Co..Lkl., 3-1689. Krdima, Ym
Osaka 532. Japan
Abstract: A novel construction of lg-mcthylcarbapencm skeleton has been achieved by use of N~ii6a(NsStpmnoled cyclizalion ss a key s&p. The mcchmism Of the stempccrw cydipiion lading Y) l&med~ylcarbapmamisakodixussed.
1~Methylcarbapcnems have attracted much attention recently because of their potent and broad-specbum antibacterial activities in addition to their chemical and metabolic stability.11 ‘Ibe la-methylcarbapencm skeletons having a bicyclic ring system have been synthesized by the excelknt methodologies based on the Rh(II>catalyzed carbine insertion,t*2)the intramoleculer Wittig reaction?) the Dieckmann condensati&) and the E.schenmoscrsulfide contra&4.*) In amncction with our synthetic studle4 in search of a new carbapcnem having potent antibacterial activity, we now report a conceptually new synthetic method of lbmethylcarbapenem skeleton based on a novel ring construction utilizing NBS-promoted cyclization as a key step. It is welldocumented that the halcmium ion-induced cyclization leading to lactams is quite convenient in the synthesis of nitrogen-containing hctem~yclcs such as alkaloids@because of the mild reaction conditions and simplicity of the proccdun. Although Sc&trigonal mo& is unfavorable in the co~~~~ction of a 5-mcmbcrcd ring system.7) we anticipated that cycllzation of a-alkoxy enoatc A leading to the &slraI carbapenam B would proceed smoothly due to the effect of the electrondonating alkoxy group which could stabilize the developing positive charge on the carbon a to the ester group (Scheme 1). scl?eme 1
NBS co#
B R’, R2:lllkyl group
6317
TBS: &MutyldhnethyWlyf
6318
First of all. propionic acid derivative 18.9) was treated sequentially EtSH, followed
by hr-silylation
with TBSOTf
in the presence
with N. N%arbonyldiimidazole
of 2,6-lutidine
Compound 2 was then reduced according to the Fukuyama’s msthod(Et$iWlO%
and
to give 2 in 81% yield. Pd-C)l@ to aldehyde 3 in
quantitative
yield. Aldthyde 3 was treated with the sodium salt of phosphate 4 at 0 “C to give a mixture of the
(Z)-isomer
Sa and the (E)-isomer
Sb in 85% yield in a ratio of 2:l.
cleaved with n-BubNF in the presence of AcOH to give the Q-isomer
N-TBS group of Sa was selectively 6a.11) (&Isomer
6b was also obtained
from Sb under the same conditions.
!%R=TBS,X=OEt,Y=C Sb: R = TBS, X = C02Et, 6a:R=H,X=OEt,Y=CO,E1 6b:R=H,X=C02E1,Y=OEt
7a: X = OEt, Y = CO Et 7b: X = CO,E1, Y = aE1
Et Y =% Et
10
-
We next examined the NBS-promoted cyclization of 6 leading to 7. Treatment of 6p with 1 eq of NBS in CH,CN at room temperature gave the cyclized product 7a as a sole product in quantitative yield via S-endc+ ttigonal
mode cyclization.t2)
resulting in the formation
In a similar way. the (&)-isomer
of the C3-epimer
determined by both the NOE expctiment In order intermediate. phosphate
to gain an insight
6b was subjected to the cyclization analysis.14)
of this cyclization.
we tried to isolate
When the reaction was carried out at 0 “C for 5 min and subsequently
buffer @H 7.0). a mixture of the N-brominated
when the reaction was further continued
from the less him&ted
quenched
a reaction with 0.2 M
8’5) and 7a in a ratio of 1:l was obtained;
under the same reaction conditions, is initiated by bromination
would then migrate to the olefin n-bond 9. Subsequently,
compound
reaction,
of 7a and 7b was
yield. 13) The stereochemistry
and the X-ray crystallographic
into the mechanism
These results indicate that the reaction intermediate
7b in quantitative
8 was gradually converted to 7a.
of the nitrogen a-face
atom.
The bromonium
to form the bridged
bromonium
ion ion
the resulting anion on the amide nitrogen would attack on the carbon a to ethoxy
group, giving the anti adduct 7e (Scheme 2). With the desired carbapenam 7a. b in hand, we next examined several trials, 10, which is an important
precursor
yield by treatment of 7a with CHQCI-Nal
same reaction conditions.
for the synthesis
in CH$N.
conversion
to the carbapenem.
of carbapenems,t@
was obtained
17) Epimer 7b was also converted
After in 75%
to 10 under the
6319
Schomo 2
Ptau8lbto mochanlsm of the N8Gpmnotod
NBS
cycliation
t
&Et
1
?a In summary, we found a convenient
method for the construction of 1p-mcthylcarbapcnam
the novel NBS-promoted cyclization reaction. Further transformation of the functionalized other useful lj3-methylcarbapenems is now under investigation. Acknowledgment:
skckton
using
catbapenams 7 into
We are grateful to Dr. A. Kinumaki in our company for the NMR experiments
and to Dr.
T. Da-m in our company for the X-my study. References
1. 2.
and
Notes
a) D. H. Shih, F. Baker, L. Cama, and B. G. Christensen, Heterocycles. 21, 29 (1984) b) M. Sunagawa. H. Matsumuta. T. moue. M. Fukasawa, and M. Kato. J. Anribiorics. 43.519 (1990). T. N. Salzmann. R. W. Ratcliffe. B. G. Christensen. and F. A. Bouffard, 1. Am. Chem. Sot.. 102. 6161 (1980).
J. Am. Chem. Sot., 100, 8006 (1978) b) C. Battisitini,
3.
a) L. D. Cama and B. G. Christensen,
4.
Scarafile, M. Foglio, and G. Franceschi, Tetrahedron Lett., 25, 2395 (1984) c) A. Yoshida. Y. Tajima, N. Take&, and S. Oida, ibid., 25. 2793 (1984). a) M. Hatanaka. Y. Yamamoto. H. Nitta, and T. Ishimatu, Terruhedron Lett.. 22. 3883 (1981) b) T. J. Sowin. and A. I. Meyers, J. Org. Chem., 53.4154
C.
(1988) c) R. Dcziel and D. Favreau, Tetrahedron
Len.. 30, 1345 (1989).
5. 6.
0. Sakurai, T. Ogiku, M. Takahashi, H. Horikawa, and T. Iwasaki, Terrahedron L-err., in press. a) S. Knapp and D. V. Patel, J. Am. Chem. Sot., 105.6985 (1983) b) Y. Tamant, S. Kawamura, K. Tetrahedron L&t., 25, 1063 (1984) c) S. Knapp, K. E. Rodtiques. A. T. Levorse. and R. M. Ornaf, ibid., 26, 1803 (1985) d) E. J. Corey, C.-P. Chen. and G. A. Reichard,
Tanaka, and Z. Yoshida.
ibid., 30, 5547 (1989) e) Y. G. Kim and J. K. Cha, ibid., 30, 5721 (1989) f) R. M. Williams
F. Miknis,
ibid.,
Heterocycles,
7.
J. E. Baldwin,
31.
4297
(1990)
g) S. Kane,
T. Yokomatsu,
26, 359 (1987). J. Chem. Sot.,
Chem. Commun..
1976, 734.
H. Iwasawa,
and G.
and S. Shibuya,
6320
8.
D. R. Bender,
A. M. DeMarco,
2411 (1992) and mfemnces
D. G. Melillo.
S. M. Riseman.
and I. Shinkai,
J. Org. Chem., 57.
cited therein.
9.
For a review see: Y. Ito and S. Tetashima,
10.
T. Fukuyama.
11.
The xqiochemistry
of 60 and 6b was determined on the basis of IH NMR specaa; the vinyl protons of
6a and 6b appeared
at 8 5.93 and 8 4.81, respectively.
vinyl proton and EtO-mcthylene 12.
J. Syn. Org. Gem.,
47. 606 (1989).
/pt..
S.-C. Lin. and L. Lin. J. Am. Chem. Sot., 112. 7050 (1990).
A typical procedure
For 6b, NOE (14.9%) was observed
protons.
is as follows:
to a solution
of 6s (50 mg. 0.125 mmol)
added NBS (25 mg. 0.138 mmol) all at once at 20 “C and the mixture mixture was poumd into saturated aqueous NasS&
and extracted
Column chromatography
tH NMR spectrum J=6.2Hz.
3H), 1.20 (t, J=7.OHz,
lH), 3.20 (t,J=3.7Hz, 13.
3H), 1.21 (d. J=6.OHz,
The stereochemistry
at C2 of 7s and lb
spectra;
NOE between
15.
11 which was easily obtainable
Cambridge
Crystallogndphic
12H). 2.66-2.85 J=lO.2Hz,
3H), 2.62-2.83
lH), 4.15-4.38
3H), 1.36 (t, /=7.1Hz, 1H). 3.85-4.37
(m.
(m. 3H).
3H), 2.68-2.81
(m,
(m. 6H).
determined
on the basis of 1H NMR
(5.4% for 7a and 4.1% for 7b). The stexr.cchcmistry analysis of 6(1-benzoybxy)ethyl
by the X-ray crystallographic
derivative
1H NMR spectrum
3H), 1.32 (t, J=7.lHz,
was unambiguously
Hz and H6 was observed
The residue was purified
6 0.06 (s. 3H), 0.07 (s, 3H), 0.88 (s, YH), 1.20 (d,
IH), 3.75 (d. J=l0.8Hz,
was confirmed
The
The organic layer was
= 10: 1) to give la (58 mg, 97%) as a syrup.
3H), 1.30 (t, J=6.9Hz.
3.1Hz.
at C3 of these epimers
in vacua.
(m, 3H). 4.18 (d.J=ll.3Hz,
MHz. CDCls):
lH), 3.13 (dd, J=5.4,
(2 ml) was
6 0.06 (s. 3H). 0.07 (s. 3H). 0.88 (s. 9H), 1.16 (d.
3H). 1.23 (d, J=7.0Hz,
IH), 3.78-4.05
tH NMR spectrum of 7b (200 J=7.4Hz,
14.
(n-hexane:AcOEt
of 7a (200 MHz. CDCls):
in CHsCN
was stirred for 30 min.
with AcOEt.
washed with HsO. with brine, dried over MgS04. and concentrated by SQ
between
from 7a. Full crystal data for 11 has been deposited
at the
Data Centre.
of 8 (200 MHz. CDCls): (m. IH). 3.16 (t. /=2.5Hz,
1H). The related acylhypoiodide
6 0.06 (s, 3H), 0.07 (s. 3H). 0.88 (s. 9H), 1.10-1.36 (m, lH), 3.77-4.05 intermediate
(m, 3H), 4.19-4.42
was suggested
(m, 3H). 6.03 (d,
in the iodolactonization:
P. A.
Bartlett and J. Myerson. 1. Am. Chem. Sot., 100. 3950 (1978). 16.
Transformation Bateson,
of descysteaminylthienamycin
P. M. Roberts,
T. C. Smale,
to 2-substituted
and R. Southgate.
carbapenems
J. Chem. Sot.,
185. 17.
A. Oku, T. Harada.
and K. Kita. Terrahedron Lett.. 23. 681 (1982).
(Received in Japan 7 April 1994; accepted 27 May 1994)
has been known: Chem. Commun..
J. H. 1980.