A highly diastereoselective synthesis of a 1-β-methylcarbapenem intermediate using titanium enolate of 2′-hydroxypropiophenone

Article abstract of DOI:10.1016/j.tet.2003.11.048

A key 1-β-methylcarbapenem intermediate is synthesized from a highly diastereoselective condensation between the titanium enolate of 2′-hydroxypropiophenone with 4-acetoxy-β-lactam followed by ozonolysis of the resulting ketone to the carboxylic acid.

Full text of DOI:10.1016/j.tet.2003.11.048

Tetrahedron 60 (2004) 867–870
A highly diastereoselective synthesis of a 1-b-methylcarbapenem
intermediate using titanium enolate of 20-hydroxypropiophenone
You-Sang Lee,a Won-Keun Choung,a Kyoung Hoon Kim,a Tae Won Kangb and Deok-Chan Haa
,
*
aDepartment of Chemistry, Korea University, Seoul 136-701, South Korea
bCKD Research Institute, Chonan 330-330, South Korea
Received 7 October 2003; revised 19 November 2003; accepted 19 November 2003
Abstract—A key 1-b-methylcarbapenem intermediate is synthesized from a highly diastereoselective condensation between the titanium
enolate of 20-hydroxypropiophenone with 4-acetoxy-b-lactam followed by ozonolysis of the resulting ketone to the carboxylic acid.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
In our earlier study, we used lithium enolates of the readily
available propiophenone derivatives for an aldol-type
condensation with 2 followed by Baeyer–Villiger oxidation
of the resulting ketone 3 with hydrogen peroxide under
basic condition to generate 1.6 The b-selectivity in this
condensation was low (,4:1), and, the transenolization
between the enolate of the propiophenone and the acetate
group of 2 caused about 30% of recovered 2. Also, the
oxidation of 3 with H2O2/NaOH provided unpredictable
yield of 1 due to the b-lactam ring cleavage with a
prolonged exposure of the reaction mixture to the basic
media. Thus, an alternative approach has been pursued for
more selective condensation between 2 and enolates of the
propiophenone derivatives, together with a more reliable
method for the oxidative conversion of the resulting ketone
to 1.7
In the synthesis of 1-b-methylcarbapenems with increased
chemical and metabolic stability retaining the potent
antibacterial activity of thienamycin, b-lactam 1 is serving
as a key intermediate.1 Most of the efforts for the synthesis
of 1 have been devoted to the stereoselective introduction of
2-propionic acid moiety to the C(4) position of the
commercially available 4-acetoxy-b-lactam 2.2 Diverse
metal enolates of propionic acid derivatives having chiral
and achiral auxiliaries were devised, including 2-oxazo-
lidinones,3a 2-picolyl thiols,4 and 2,3-dihydro-4H-1,3-
benzoxazin-4-ones,5 for the improved b-selectivity of 1.
But, still more easily accessible auxiliary and convenient
reaction conditions have to be devised for more stereo-
selective and economic introduction of 2-propionic acid unit
to 1.
2. Results and discussion
We used hydroxy- and methoxy-substituted propiophenones
4a–c, which are commercially available in low cost, as a
synthon for 2-propionic acid in expectation that the
electron-rich aroyl group of 3 could be oxidized to the
corresponding carboxylic acid in 1. The titanium enolate of
20-hydroxypropiophenone (4a), generated from 4a, titanium
tetrachloride and tri-n-butylamine, was condensed with 2 in
high b-selectivity (Table 1). The yield of this reaction
depends heavily on the amount of the enolate used. With the
use of less than 2 equiv. of the enolate, the yields were
sharply decreasing (entries 1 and 2). The reaction was best
optimized with the use of 2.3 equiv. of the Ti(IV)-enolate to
give 82% of 3a after SiO2 chromatography with 98:2 b/a
diastereselectivity (entry 3). Conveniently, the crude
mixture after the aqueous workup was directly recrystal-
lized in ethyl acetate-hexanes to provide 78% of 3a with
Keywords: Azetidinones; Carbapenems; Stereoselective; Condensation;
Enolates; Ozonolysis.
*
Corresponding author. Tel.: þ82-2-3290-3131; fax: þ82-2-3290-3121;
e-mail address: dechha@korea.ac.kr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.048

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Y.-S. Lee et al. / Tetrahedron 60 (2004) 867–870
Table 1. Condensation of titanium enolate of propiophenones 4a–c with 2
Entry Ketone
TiCl4
n-Bu3N
Product Yieldb
(%)
Dec
(%)
(equiv.)a (equiv.)a (equiv.)a
1
2
3
4
5
6
4a (1.0) 1.0
4a (1.8) 1.8
4a (2.3) 2.3
4a (3.0) 3.0
4b (2.3) 2.3
4c (2.3) 2.3
3.0
4.6
5.6
7.0
3.3
3.3
3a
3a
3a
3a
3b
3c
28
63
91
93
82 (78)d 96 (98)d,e
32
44
57
96
75
85
Scheme 2.
3. Conclusions
a
b
c
Equivalence relative to the amount of 2 used.
Yields after SiO2 chromatography.
In conclusion, we developed a new practical method for the
synthesis of a key 1-b-methylcarbapenem intermediate
using a highly diastereoselective condensat0ion of 4-acetoxy-
b-lactam with a titanium enolate of 2 -hydroxypropio-
phenone and oxidative conversion of the resulting ketone
to the carboxylic acid with a dry ozonation method.
Eventually, 2-hydroxyphenyl group of the cheaply available
20-hydroxypropiophenone served as an excellent achiral
auxiliary for the highly diastereoselective introduction of
2-propionic acid needed for a 1-b-methylcarbapenem
synthesis.
The diastereomeric excess was determined by 1H NMR of the crude
product.
d
e
Yield and diastereomeric excess in the parenthesis refer to those after
recrystallization of the crude product.
Determined by HPLC analysis.
99:1 b-selectivity. The reaction did not proceed with the use
of Ti(OiPr)4 or TiCl2(OiPr)2, and, also, with the use of
triethylamine instead of tri-n-butylamine.8 Methoxypropio-
phenones, 4b and 4c, provided the corresponding 3b and 3c
with much lower yields and diastereoselectivities than the
use of 4a under the same condition (entries 5 and 6).
Unexpectedly, 20-methoxy derivative 4b showed a lower
diastereoselectivity than 40-methoxy derivative 4c. Lack of
an intramolecular chelation of the poorly basic phenyl ether
oxygen 0in 4b with the titanium enolate and the resulting tilt
of the 2 -methoxyphenyl ring from the plane of the enolate
may be the reason for the decreased selectivity in the
condensation (Scheme 1).
4. Experimental
4.1. General
IR spectra were recorded on a Bomem MB-104 spectro-
photometer. Optical rotations were measured with a
Rudolph Research Autopol III polarimeter. 1H NMR spectra
were recorded on a Varian Germini 300 (300 MHz) with
TMS as an internal reference. 13C NMR spectra were
recorded on a Bruker AMX 400 (100 MHz) with TMS or
CDCl3 as an internal reference. Elemental analyses were
obtained from Sogang Organic Chemistry Research Center,
Seoul. Chiral HPLC analysis was performed on a Jasco LC-
1500 Series HPLC system with a UV detector. TLC was
performed on Merck silica gel 60 F254 precoated glass
backed plates. Dichloromethane and tri-n-butylamine were
dried by distillation over CaH2 before use. All reactions
were carried out in oven-dried glassware under an argon
atmosphere.
The enhanced stereoselectivity in the formation of 3a can be
explained with the selective Z-enolate formation from 4a
through the bidentated Ti(IV)-enolate, and a tight coordi-
nation in the six-membered transition state of the resulting
enolate with the acylimine generated from 2, as shown in
5a. The need for more than 2 equiv. of Ti(IV)-enolate of 4a
for an improved result may be due to the presence of less
reactive acetoxy-substituted enolate 5b.
4.1.1. (3S,4R)-3-[(R)-1-(t-Butyldimethylsiloxy)ethyl]-4-
[(R)-1-(2-hydroxybenzoyl)ethyl]-2-azetidinone (3a). To
a solution of 20-hydroxypropiophenone 4a (1.29 mL,
9.37 mmol) in 20 mL of dichloromethane at 278 8C was
added slowly titanium tetrachloride (1.00 mL, 9.37 mmol)
followed by tri-n-butylamine (5.50 mL, 23.0 mmol). The
mixture was stirred for 30 min at the temperature and
another 30 min at 240 8C. A solution of 2 (1.17 g,
4.07 mmol) in 14 mL of dichloromethane was added to
the mixture dropwise, and the resulting solution was stirred
at 220 8C for 10 h. The mixture was quenched with 80 mL
of sat. NH4Cl and extracted three times with 100 mL
portions of ethyl acetate. The combined organic layers were
dried over MgSO4, filtered and concentrated under reduced
pressure. The residual solid was recrystallized in ethyl
acetate and hexanes to give 1.20 g (78%, b/a¼99:1) of 3a
as a white solid: 98% de by HPLC analysis (Chiralpak
CAPCELL PAK C18, 4:6 H2O/CH3CN, 1 mL/min, 254 nm
UV detector), tR¼11.6 min for 3a b-form, and tR¼13.8 min
Scheme 1.
Since the oxidation of 3a with m-CPBA was too slow to be a
practical method, and the use of H2O2/NaOH provided
unpredictable yield of 1, decomposition of 2-hydroxy-
benzoyl group of 3a using ozone into a carboxyl group of 1
had been studied. Among the ozonolysis conditions studied,
dry ozonation method was found to be most successful.9
Passing a stream of ozone at 278 8C through the silica gel
pre-adsorbed with 3a, warming the mixture to ambient
temperature followed by washing the silica gel with ethyl
acetate provided conveniently the acid 1 in 60% yield in a
reproducible manner (Scheme 2).

Y.-S. Lee et al. / Tetrahedron 60 (2004) 867–870
869
for a-form; Rf¼0.35 (1:1 ethyl acetate/hexanes);
[a]2D5¼279.8 (c 1.4, EtOH); mp¼170–171 8C; IR (KBr)
inseparable diastereomeric mixture. The ratio of a and b
diastereomers was determined by integration of the 1H
NMR signals of Ar/H doublets at 8.07 ppm (a-isomer) and
7.94 ppm (b-isomer). Spectral data for major b-Isomer:
1
1760, 1634 cm21; H NMR (300 MHz, CDCl3) d 0.05 (s,
3H), 0.08 (s, 3H), 0.86 (s, 9H), 1.15 (d, J¼6 Hz, 3H), 1.34
(d, J¼5 Hz, 3H), 2.92 (dd, J¼5, 2 Hz, 1H), 3.75 (dq, J¼6,
5 Hz, 1H), 4.00 (dd, J¼5, 2 Hz, 1H), 4.12 (m, 1H), 6.00 (br
s, 1H), 6.93–7.74 (m, 4H), 12.27 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 24.77, 24.00, 13.67, 18.17, 22.65,
25.98, 42.82, 52.01, 62.17, 65.56, 118.34, 119.27, 119.41,
130.00, 137.32, 163.60, 168.45, 209.00; Anal. Calcd for
C20H31NO4Si: C, 63.62; H, 8.28; N, 3.71. Found: C, 63.63;
H, 8.42; N, 3.67.
Rf¼0.17 (1:2, EtOAc/hexanes); IR (KBr) 1757, 1669 cm21
;
1H NMR (300 MHz, CDCl3) d 0.04 (s, 3H), 0.06 (s, 3H),
0.86 (s, 9H), 1.15 (d, J¼6 Hz, 3H), 1.27 (d, J¼5 Hz, 3H),
2.88 (dd, J¼5, 2 Hz, 1H), 3.66 (dq, J¼6, 5 Hz, 1H), 3.88 (s,
3H), 3.97 (dd, J¼5, 2 Hz, 1H), 4.16 (quint, J¼5 Hz, 1H),
6.06 (br s, 1H), 6.95 (d, J¼9 Hz, 2H), 7.94 (d, J¼9 Hz, 2H);
13C NMR (100 MHz, CDCl3) d 25.10, 24.33, 13.07, 17.84,
22.34, 25.66, 42.50, 51.97, 55.44, 61.65, 65.37, 113.93,
128.63, 130.62, 163.79, 168.41, 201.09; Anal. Calcd for
C21H33NO4Si: C, 64.41; H, 8.49; N, 3.58. Found: C, 64.46;
H, 8.44; N, 3.32.
4.1.2. (3S,4R)-3-[(R)-1-(t-Butyldimethylsiloxy)ethyl]-4-
[(R)-1-(2-methoxybenzoyl)ethyl]-2-azetidinone (3b). To
a solution of 20-methoxypropiophenone 4b (340 mg,
2.07 mmol) in 5 mL of dichloromethane at 278 8C was
added slowly titanium tetrachloride (0.22 mL, 2.07 mmol)
followed by tri-n-butylamine (0.71 mL, 3.0 mmol). The
mixture was stirred for 30 min at the temperature and
another 30 min at 240 8C. A solution of 2 (260 mg,
0.90 mmol) in 2.5 mL of dichloromethane was added to
the mixture dropwise, and the resulting solution was stirred
at 220 8C for 10 h. The mixture was quenched with 20 mL
of sat. NH4Cl and extracted three times with 30-mL portions
of ethyl acetate. The combined organic layers were dried
over MgSO4, filtered and concentrated under reduced
pressure. The residual white solid was purified by silica
gel flash chromatogaphy (1:2 ethyl acetate/hexanes) to give
154 mg (44%, b/a¼7:1) of 3b as a chromatographically
inseparable diastereomeric mixture. The ratio of a and b
diastereomers was determined by integration of the 1H
NMR signals of C(3)/H at 2.81 ppm (a-isomer) and
2.93 ppm (b-isomer). Spectral data for major b-isomer:
4.1.4. (3S,4R)-3-[(R)-1-(t-Butyldimethylsiloxy)ethyl]-4-
[(R)-1-carboxyethyl]-2-azetidinone (1). A solution of 3a
(206 mg, 0.546 mmol) in 50 mL of dichloromethane was
added 5.4 g of silica gel (70–130 mesh) followed by the
removal of the solvent under reduced pressure. The silica
gel pre-adsorbed with 3a in 500 mL Erlenmeyer flask was
passed with ozone at 278 8C for 10 min followed by
warming the flask to room temperature. The silica gel was
washed with ethyl acetate, filtered and concentrated under
reduced pressure. The residue was purified by flash
chromatography (3:2 hexanes/ethyl acetate) to give 1 as a
white solid (98 mg, 60%): mp 140–143 8C. Spectral data
(1H NMR, IR) of 1 are identical with those reported.1
Acknowledgements
This work was financially supported by the Center for
Molecular Design and Synthesis (CMDS) at KAIST and
ChongKunDang Pharm.
Rf¼0.25 (1:2, EtOAc/hexanes); IR (KBr) 1759, 1672 cm21
;
1H NMR (300 MHz, CDCl3) d 0.04 (s, 3H), 0.07 (s, 3H),
0.86 (s, 9H), 1.20 (d, J¼6 Hz, 3H), 1.21 (d, J¼5 Hz, 3H),
2.93 (dd, J¼5, 2 Hz, 1H), 3.78 (dq, J¼6, 5 Hz, 1H), 3.90 (s,
3H), 4.04 (dd, J¼5, 2 Hz, 1H), 4.12 (quint, J¼5 Hz, 1H),
5.89 (br s, 1H), 6.96–7.60 (m, 4H); 13C NMR (100 MHz,
CDCl3) d 25.15, 24.31, 12.07, 17.83, 22.42, 25.65, 47.52,
51.71, 55.41, 61.30, 65.50, 111.38, 120.81, 127.80, 130.33,
133.60, 158.01, 168.54, 205.55; Anal. Calcd for
C21H33NO4Si: C, 64.41; H, 8.49; N, 3.58. Found: C,
64.33; H, 8.67; N, 3.36.
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