2,3-Dihydro-4H-1,3-oxazin-4-ones, novel auxiliaries for the stereoselective synthesis of 1β-methylcarbapenems

Article abstract of DOI:10.1055/s-2001-18778

Dihydrooxazinones 9, prepared from benzylcyanide in two steps serve as efficient auxiliaries for the stereoselective synthesis of β-methylcarbapenem intermediate 2. Reformatsky-type reactions of 4-acetoxyazetidinone with α-bromopropionyl dihydrooxazinone 10 provided β-methylazetidinones 4 in high diastereoselectivities. The auxiliaries 9 were also easily removed in the Dieckmann cyclization leading to β-methylcarbapenem skeletons. Practical synthesis of β-methylenolphosphates 2 from 4-acetoxyazetidinone 3 was achieved in three steps (61-77% overall yield).

Full text of DOI:10.1055/s-2001-18778

1950
LETTER
2,3-Dihydro-4H-1,3-oxazin-4-ones, Novel Auxiliaries for the Stereoselective
Synthesis of 1 -methylcarbapenems1
2
, 3-Dihydro-4
H
-1,
o
3-oxazin-4-ones:
A
K
uxiliaries for Ster
.
eoselective
SP
ynthesis yun,a Won J. Jeong,a Hee J. Jung,a Jae H. Kim,a Jin S. Lee,b Cheol H. Lee,a Bong J. Kim*a
a
Korea Research Institute of Chemical Technology, PO Box 107, Yusung, Taejon 305-600, Korea
Fax +82(42)8611291; E-mail: bjkim@pado.krict.re.kr
b
Dong Wha Pharm. Co., 189, Anyang, Kyunggido 430-017, Korea
Received 7 September 2001
Y
O
O
O
O
Abstract: Dihydrooxazinones 9, prepared from benzylcyanide in
two steps serve as efficient auxiliaries for the stereoselective syn-
thesis of -methylcarbapenem intermediate 2. Reformatsky-type re-
R4
HN
R
X
HN
R
HN
R2
R
R1
actions of 4-acetoxyazetidinone with
-bromopropionyl
CO2R3
R4
1R3 R3
dihydrooxazinone 10 provided -methylazetidinones 4 in high dias-
tereoselectivities. The auxiliaries 9 were also easily removed in the
Dieckmann cyclization leading to -methylcarbapenem skeletons.
Practical synthesis of -methylenolphosphates 2 from 4-ace-
toxyazetidinone 3 was achieved in three steps (61–77% overall
yield).
12; X, Y = O
13; X = O, Y = S
14; X, Y = S
11
9
Figure 2 Various auxiliaries
Key words: auxiliary, diastereoselective, -methylcarbapenem,
Reformatsky-type reaction, Dieckmann cyclization
were modified from 2,3-dihydro-4H-1,3-benzooxazin-4-
one 11.
As the oxazinone ring was fused to the benzene ring, it
would be expected to show an efficient asymmetric induc-
tion in the Reformatsky-type reaction. On the other hand,
our modified dihydrooxazinone auxiliaries would result
in very effective asymmetric induction in the reaction
with the 4-acetoxyazetidinone, even though it was not
fused with benzene ring. In addition, dihydrooxazinone
would serve as a good leaving group in the Dieckmann-
type cyclization9 for -methylenolphosphate 2.
The -methylcarbapenems 12 have received much atten-
tion because of their excellent therapeutic potential and
high stability to dehydropeptidase I(DHP-I) enzyme.
These results have prompted many organic chemists to
develop a useful and diastereoselective method for the
synthesis of 1 -methylcarbapenem moieties.3 The stereo-
selective introduction of the 1 -methyl substituent into
acetoxyazetidinone has been accomplished by using eno-
late derived from various auxiliaries such as 2-oxazolidi-
nones 12,4 1,3-oxazolidine-2-thiones 13,5 1,3-
thiazolidine-2-thiones 146 and 1,3-benzooxazine-4-ones
11.7
R4
CN
a
b
R4
CN
HO
CO2R3
7
8
OTBS
H
OTBS
H
OTBS
H
O
O
O
H
N
H
N
O
OAc
NH
R4
R4
c
SR
CO2R5
OP(OPh)2
HN
R2
N
Br
R1
O
O
O
R1
O
CO2R3
O
CO2R3
CO2R5
2
R2
3
1
10
9
Figure 1
Scheme 1 (a) Dialkyl oxalate, Na, MeOH (83%); (b) Ketone, Ac2O,
AcOH, H2SO4 (80%); (c) 2-Bromopropionyl bromide, pyridine, THF
(92%).
Recently, the stereoselective synthesis of the key interme-
diate via the Reformatsky-type reaction has been report-
ed.8 With an aim to avoid expensive or toxic reagents, we
investigated the Reformatsky-type reaction. Our research
has been focused on the development of an efficient aux-
iliary for the introduction of the -methylcarbapenem nu-
cleus. We were interested in the use of 2-substituted 2,3-
dihydro-4H-1,3-oxazin-4-ones 9 as the auxiliaries, which
We describe here a practical synthesis of -methylenol-
phosphate 2 by selecting dihydrooxazinones as the achiral
auxiliaries. 2-Substituted dihydrooxazinone 9 was synthe-
sized from benzyl cyanide 7 in two steps.10 Preparation of
the substituted pyruvic esters 8 was achieved by treating
dialkyloxalate with benzyl cyanide in the presence of a
base such as sodium methoxide in 83% yield. 2-Substitut-
ed dihydrooxazinones 9 were readily prepared by an acid-
catalyzed condensation of the substituted pyruvic esters 8
with the corresponding ketones in 80% yield. Acylation of
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1950,1952,ftx,en;Y18601ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
2,3-Dihydro-4H-1,3-oxazin-4-ones: Auxiliaries for Stereoselective Synthesis
Table Reformatsky-type Reaction of 3 with 10
1951
OTBS
H
b
OAc
NH
R1
R2
R3
R4
Yield,%a
54
:
A
B
C
D
E
F
Me
Me
nBu
Bn
Me
Me
Me
Me
Me
Me
Me
Et
Ph
89:11
98:2
96:4
95:5
92:8
97:3
95:5
98:2
89:11
O
3
nBu
Ph
50
a
Bn
Ph
35
R4
(CH2)5
(CH2)5
(CH2)5
(CH2)5
(CH2)5
4-furan
Ph
97
O
O
CO2R3
OTBS
H
OTBS
H
Ph-4-OMe
Ph-4-Cl
Ph-4-NO2
Ph
86
H
H
N
O
b
CO2H
88
R1 R2
NH
NH
O
O
G
H
I
20
4
6
O
85
R4
HN
Me
Ph
82
c
a Isolation Yield.
b Determined by HPLC.
R1
O
CO2R3
R2
9
R4
O
CO2R3
OTBS
H
OTBS
H
N
H
H
-Methylenolphosphate 2 was prepared in 80–84%
(Scheme 2) yields from the esters 5 using a known proce-
dure[NaHMDS, TMSCl, ClPO(OPh)2].7,9 The auxiliary 9
could be recovered from the reaction mixture by direct
crystallization in 82% yield. The various -methylcarbap-
enems 1 can be synthesized from -methylenolphosphate
2 with various thioalkyl derivatives.15
N
O
O
OP(OPh)2
R1 R2
O
N
d
O
O
CO2R5
CO2R5
5
2
Scheme 2 (a) Zn dust, 10, THF, reflux (97%); (b) LiOH, H2O2,
H2O/THF (82%); (c) Alkyl bromoacetate, NaHMDS, THF (85–95%);
(d) NaHMDS, TMSCl, ClPO(OPh)2, THF (80–84%).
We demonstrated that 2-substituted dihydrooxazinones 9
served not only as efficient auxiliaries in the stereoselec-
tive Reformatsky-type reactions of 4-acetoxyazetidinone
3 but also as good leaving groups in the Dieckmann-type
cyclization leading to -methylenolphosphate 2. Using
these novel achiral auxiliaries we have developed a prac-
tical and cost effective method for the preparation of -
methylcarbapenem antibiotics. The ready availability and
high reactivity of the dihydrooxazinone 9 will lead us to
study its further applications in a variety of asymmetric
syntheses.
the dihydrooxazinones 9 with 2-bromopropionyl bromide
in the presence of pyridine gave the -bromopropionydi-
hydrooxazinones 1011 in 92% yield (Scheme 1).
As shown in Scheme 2, the zinc enolates were produced
in situ from -bromopropionydihydrooxazinones 10 and
the zinc enolates were effectively reacted with 4-ace-
toxyazetidinone 3 in refluxing THF to give the -methyl-
azetidinones 4. The highest diastereoselectivity( :
=
98:2) was achieved when n-butyl and cyclohexyl deriva-
tives were used and the lowest diasteroselectivity( : =
89:11) was observed in case of methyl derivatives (Ta-
ble).
Acknowledgement
The authors are grateful to the Dong-Wha Pharm. Co. for financial
support. We also thank to Prof. Won. K. Lee at Sogang University
for helpful discussions.
In general, the diastereoselectivity was increased accord-
ing to the steric bulkiness of the C-2 substituted auxiliary,
however the chemical yield was decreased with the steric
bulkiness. 2-Cyclohexyl substituted dihydrooxazinone
was selected as the most efficient auxiliary for the con-
struction of -methylcarbapenem nucleus 412 which was
provided in 97% yield( : = 95:5). When the crude prod-
uct 4 was directly recrystallized from hexane, the pure -
isomer was obtained in 80% yield from the 4-acetoxyaze-
tidinone. The stereoscopic and optical data of -methy-
lazetidinone 6 were identical with those of commercially
available -methylazetidinone 6.13 The cyclohexyl deriv-
ative 4 was converted into the various esters 5 by treat-
ment with alkyl or aryl bromoacetates14 in the presence of
NaHMDS in 90% yield.
References
(1) Pyun, D. K.; Jeong, W. J.; Jung, H. J.; Kim, J. H.; Lee, C. H.;
Kim, B. J. Abstracts of Papers, 221st National Meeting of
the American Chemical Society, San Diego; American
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(2) For example: (a) Sunagawa, M.; Matsumura, H.; Inoue, T.;
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Tetrahedron 1996, 52(2), 331.
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Synlett 2001, No. 12, 1950–1952 ISSN 0936-5214 © Thieme Stuttgart · New York

1952
D. K. Pyun et al.
LETTER
(4) (a) Fuentes, L. M.; Shinkai, I.; Salzmann, T. N. J. Am. Chem.
Soc. 1986, 108, 4675. (b) Deziel, R.; Favreau, D.; Ito, Y.;
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Tetrahedron 1991, 47, 2801.
(5) Deziel, R.; Favreau, D. Tetrahedron Lett. 1989, 30, 1345.
(6) (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. (b) Nagao,
Y.; Nagase, Y.; Kumagai, T.; Matsunaga, H.; Abe, T.;
Shimada, O.; Hayashi, T.; Inoue, Y. J. Org. Chem. 1992, 57,
4243. (c) Deziel, R.; Favreau, D. Tetrahedron Lett. 1986, 27,
5687.
(7) (a) Kondo, K.; Seki, M.; Kuroda, T.; Yamanaka, T.; Iwasaki,
T. J. Org. Chem. 1995, 60, 1096. (b) Seki, M.; Kondo, K.;
Iwasaki, T. J. Chem. Soc., Perkin Trans. 1 1996, 2851.
(c) Kondo, K.; Seki, M.; Kuroda, T.; Yamanaka, T.; Iwasaki,
T. J. Org. Chem. 1997, 62, 2877.
(8) (a) Ito, Y.; Terashima, S. Tetrahedron Lett. 1987, 28, 6625.
(b) Ito, Y.; Sasaki, A.; Tamoto, K.; Sunagawa, M.;
Terashima, S. Tetrahedron 1991, 47, 2801.
MHz) –4.3, –5.1, 13.4, 17.7, 22.4, 24.6, 25.2, 25.6, 45.2,
51.6, 52.5, 60.8, 65.1, 95.4, 115.8, 127.8, 128.2, 129.7,
130.1, 150.8, 161.7, 163.4, 168.4, 181.3; MS (70 eV) m/z
544, 487, 318.,
Compound 4d: 1H NMR (CDCl3, 200 MHz) 0.07 (s, 6 H),
0.87 (s, 9 H), 1.20 (d, J = 6.1 Hz, 3 H), 1.25 (d, J = 7.1 Hz,
3 H), 1.74 (m, 6 H), 2.11–2.38 (m, 4 H), 3.20 (dd, J = 2.5,
3.4 Hz, 1 H), 3.41–3.54 (dt, J = 6.9, 11.1 Hz, 1 H), 3.69 (m,
3 H), 3.97 (m, 1 H), 4.23 (m, 1 H), 5.98 (s, 1 H), 3.93 (dd,
J = 2.2, 4.2 Hz, 1 H), 4.17 (q, J = 5.9 Hz, 1 H), 6.02 (s, 1 H),
7.21–7.36 (m, 5 H); 13C NMR (CDCl3, 50 MHz) –5.0, –4.3,
13.4, 17.8, 21.9, 22.0, 22.5, 24.1, 25.6, 32.0, 32.2, 45.6, 51.5,
52.7, 60.9, 65.2, 76.8, 116.8, 128.4, 129.8, 130.3, 150.3,
162.1, 163.9, 168.3, 182.2, 187.9; MS (70 eV) m/z 584, 527,
365, 323, 176., HRMS (EI) Calcd. for C31H44N2O7Si
584.2917, Found 584.2905.,
Compound 4e: 1H NMR (CDCl3, 200 MHz) 0.06 (s, 6 H),
0.86 (s, 9 H), 0.96 (t, J = 7.1 Hz, 3 H), 1.18 (d, J = 6.3 Hz, 3
H), 1.24 (d, J = 7.1 Hz, 3 H), 1.71–2.37 (m, 10 H), 3.20 (m,
1 H), 3.43–3.49 (m, 1 H), 3.93 (dd, J = 2.0, 4.8 Hz, 1 H), 4.05
(q, J = 7.1 Hz, 2 H), 4.16 (dd, J = 5.1, 6.0 Hz, 1 H), 6.22 (s,
1 H), 7.20–7.37 (m, 5 H); 13C NMR (CDCl3, 50 MHz) –5.1,
–4.3, 13.3, 13.4, 17.7, 21.8, 21.9, 22.5, 24.1, 25.6, 32.0, 32.2,
45.6, 51.5, 60.9, 61.9, 65.2, 96.7, 116.4, 127.8, 128.2, 129.8,
130.4, 150.7, 161.5, 163.9, 168.3, 182.1; MS (70 eV) m/z
598, 541, 513, 365, 190.,
(9) (a) Sibuya, M.; Kuretani, M.; Kubota, S. Tetrahedron 1982,
38, 2659. (b) Hatanaka, M.; Yamamoto, Y.; Nitta, H.;
Ishimaru, T. Tetrahedron Lett. 1981, 22, 3883. (c) Sowin,
T. J.; Meyers, A. I. J. Org. Chem. 1988, 53, 4154.
(d) Sunagawa, M.; Sasaki, A.; Matsumura, H.; Goda, K.;
Tamoto, K. Chem. Pharm. Bull. 1994, 42, 1381.
(10) (a) Skinner, G. S. J. Am. Chem. Soc. 1966, 55, 2036.
(b) Stambach, J. F.; Jung, L.; Hug, R. Heterocycles 1994, 38,
297.
Compound 4h: 1H NMR (CDCl3, 200 MHz) 0.00 (s, 6 H),
0.80 (s, 9 H), 1.11 (d, J = 6.4 Hz, 3 H), 1.16 (d, J = 6.8 Hz,
3 H), 1.64 (m, 6 H), 2.00–2.41 (m, 4 H), 3.16 (m, 1 H), 3.35–
3.48 (m, 1 H), 3.60 (s, 3 H), 3.75 (s, 3 H), 3.86 (m, 1 H),
4.03–4.17 (m, 1 H), 5.88 (s, 1 H), 6.82 (d, J = 8.8 Hz, 2 H),
7.07 (d, J = 8.8 Hz, 2 H); 13C NMR (CDCl3, 50 MHz) –5.0,
–4.2, 13.5, 17.9, 22.1, 22.6, 24.2, 25.7, 32.1, 32.4, 45.6, 51.6,
52.8, 55.2, 61.0, 65.3, 96.8, 113.6, 116.4, 122.4, 131.1,
151.0, 159.7, 164.2, 165.4, 168.3, 182.3; MS (70 eV) m/z
614, 557, 380, 323, 266, 160.,
(11) Compound 10a: 1H NMR (CDCl3, 200 MHz) 1.84 (d, J =
6.8 Hz, 3 H), 1.93 (d, J = 4.2 Hz, 6 H), 3.63 (s, 3 H), 5.12 (q,
J = 6.6 Hz, 1 H), 7.21–7.27(m, 2 H), 7.36–7.40(m, 3 H); 13
C
NMR (CDCl3, 50 MHz) 20.3, 23.7, 25.8, 44.8, 52.8, 95.4,
115.7, 128.1, 128.5, 129.8, 130.1, 151.2, 161.8, 163.8,
171.9, 175.5; MS (70 eV) m/z 396, 338, 316, 302, 275.,
Compound 10b: 1H NMR (CDCl3, 200 MHz) 0.93 (t, J =
7.1 Hz, 6 H), 1.26–1.63 (m, 8 H), 1.87 (d, J = 6.7 Hz, 3 H),
2.09–2.17 (m, 2 H), 2.35–2.43 (m, 2 H), 3.61 (s, 3 H), 5.15
(q, J = 6.7 Hz, 1 H), 7.19–7.41 (m, 5 H); 13C NMR (CDCl3,
50 MHz) 13.7, 22.5, 24.7, 25.5, 34.4, 35.5, 45.0, 52.7,
100.7, 115.0, 128.1, 128.4, 129.8, 130.2, 150.9, 151.4,
161.8, 164.6, 175.5.,
Compound 4i: 1H NMR (CDCl3, 200 MHz) 0.00 (s, 6 H),
0.80 (s, 9 H), 1.12 (d, J = 6.4 Hz, 3 H), 1.19 (d, J = 7.0 Hz,
3 H), 1.88–2.06 (m, 1 H), 2.12–2.29 (m, 1 H), 2.45–2.78 (m,
2 H), 3.09–3.20 (m, 1 H), 3.32–3.53 (m, 1 H), 3.59 (s, 3 H),
3.67–3.98 (m, 5 H), 4.01–4.20 (m, 1 H), 5.84 (s, 1 H), 7.08–
7.22 (m, 2 H), 7.23–7.41 (m, 3 H); 13C NMR (CDCl3, 50
MHz) –5.4, –4.3, 13.4, 17.8, 22.5, 25.7, 32.8, 45.7, 51.6,
52.9, 61.0, 63.5, 65.2, 94.0, 117.2, 128.1, 128.6, 129.8,
150.1, 161.8, 163.4, 168.4, 181.9., MS (70 eV) m/z 586, 558,
529, 501, 325.
Compound 10d: 1H NMR (CDCl3, 200 MHz) 1.84 (d, J =
6.5 Hz, 3 H), 1.11–2.66 (m, 10 H), 3.64 (s, 3 H), 5.06 (q, J =
6.5 Hz, 1 H), 7.21–7.41 (m, 5 H); 13C NMR (CDCl3, 50
MHz) 21.5, 24.0, 32.1, 45.2, 52.6, 53.3, 94.6, 116.2, 127.8,
128.2, 129.7, 130.1, 150.8, 161.8, 163.9, 175.7; MS (70 eV)
m/z 437, 356, 204, 176; HRMS (EI) Calcd. for C20H22NO5Br
435.0681, Found 435.0699.,
(13) White crystal (82%), mp 147 °C; [ ]25D = –33.6 (c, 1.0,
MeOH); 1H NMR (CD3OD, 200 MHz) 4.22 (dq, J = 6.1,
2.0 Hz, 1 H), 3.80 (dd, J = 7.0, 2.0 Hz, 1 H), 3.00 (t, J = 2.0
Hz, 1 H), 2.58 (quint, J = 7.2 Hz, 1 H), 1.21 (d, J = 7.2 Hz,
3 H), 1.18 (d, J = 6.1 Hz, 3 H), 0.88 (s, 9 H), 0.08 (s, 6 H).
(14) Alkyl or aryl bromoacetate; allyl bromoacetate, 4-t-butyl-
benzyl bromoacetate, 4-nitrobenzyl bromoacetate were
prepared from bromoacetyl bromide with alkyl or aryl
alcohol in the presence of pyridine in CH2Cl2 at 0 °C.
(15) (a) Kawamoto, I. Drugs Future 1998, 23, 181.
(b) Sunagawa, M.; Sasaki, A. Heterocycles 2001, 54, 497.
(c) Hanessian, S.; Desilets, D.; Bennani, Y. L. J. Org. Chem.
1990, 55, 3098. (d) Dezel, R. Tetrahedron Lett. 1987, 28,
4371.
Compound 10e: 1H NMR (CDCl3, 200 MHz) 1.20–1.80
(m, 6 H), 1.83 (d, J = 6.8 Hz, 3 H), 1.89–2.78 (m, 4 H), 3.68
(s, 3 H), 3.82 (s, 3 H), 5.02 (q, J = 6.2 Hz, 1 H), 6.88 (d, J =
8.4 Hz, 2 H), 7.16 (d, J = 8.2 Hz, 2 H); 13C NMR (CDCl3, 50
MHz) 20.3, 21.7, 22.2, 24.2, 31.4, 32.3, 45.3, 52.8, 55.2,
96.5, 113.6, 116.0, 122.2, 131.1, 150.9, 159.7, 162.2, 164.4,
176.0; MS (70 eV) m/z 467, 408, 386, 298, 206.
(12) Compound 4a: 1H NMR (CDCl3, 200 MHz) 0.06 (s, 6 H),
0.86 (s, 9 H), 1.18 (d, J = 6.2 Hz, 3 H), 1.24 (d, J = 7.2 Hz,
3 H), 3.17–4.04 (m, 1 H), 3.45–3.60 (m, 1 H), 3.62 (s, 3 H),
3.90–3.98 (m, 1 H), 4.09–4.18 (m, 1 H), 5.91 (s, 1 H), 7.18–
7.29 (m, 3 H), 7.31–7.41 (m, 2 H); 13C NMR (CDCl3, 50
Synlett 2001, No. 12, 1950–1952 ISSN 0936-5214 © Thieme Stuttgart · New York