Syntheses of 1beta-methylcarbapenems bearing 5-methyl-4-hydroxypyrrolidinone.

Article abstract of DOI:10.1248/cpb.50.415

A new series of 1beta-methylcarbapenems 1a-d bearing 5-methyl-4-mercaptopyrrolidinone rings has been prepared and evaluated for in vitro antibacterial activity and pharmacokinetic parameters. Most compounds showed excellent antibacterial activity and high

Full text of DOI:10.1248/cpb.50.415

March 2002
Notes
Chem. Pharm. Bull. 50(3) 415—418 (2002)
415
b
Syntheses of 1 -Methylcarbapenems Bearing 5-Methyl-4-
hydroxypyrrolidinone
Do Kyu PYUN,a,b Bong Jin KIM,a Hee Jung JUNG,a Jae Hak KIM,a Jin Soo LEE,c Won Koo LEE,b and
a
Cheol Hae LEE
Korea Research Institute of Chemical Technology,a P.O. Box 107, Yusung, Taejon 305–600, Korea, Department of
Chemistry, Sogang University,b Seoul 121–742, Korea, and Dong Wha Pharm. Ind. Co., Ltd.,c 189, Anyang, Kyunggido
430–017, Korea. Received September 19, 2001; accepted November 21, 2001
A new series of 1b-methylcarbapenems 1a—d bearing 5-methyl-4-mercaptopyrrolidinone rings has been
prepared and evaluated for in vitro antibacterial activity and pharmacokinetic parameters. Most compounds
showed excellent antibacterial activity and high stability to dehydropeptidase-1. We have synthesized optically
active 5-methyl-4-hydroxypyrrolidinones from enantiomerically pure aziridine esters.
Key words carbapenem; b-ketoester; hydrogenation; Mitsunobu reaction; a-hydroxy-b-amino acid
Carbapenems are the most potent b-lactam antibiotics, Chart 1. Treatment of the PNB-protected carbapenem enol-
which have a broad spectrum of antibacterial activity against phosphate 88) with freshly prepared thiols 7a—d in the pres-
both gram-positive and gram-negative organisms.1,2) The in- ence of DIPEA in CH3CN at 0—5 °C afforded the PNB-pro-
troduction of the 1b-methyl moiety to the carbapenem skele- tected 1b-methylcarbapenems 9a—d, respectively (Chart 1).
ton resulted in increased stability of carbapenems against de- Deprotection of the 4-nitrobenzyl group was accomplished
hydropeptidase-1 (DHP-1). For parenteral use, imipenem,3) by catalytic hydrogenation using 10% palladium on charcoal
panipenem,4) and meropenem5) have been launched on the in tetrahydrofuran (THF), EtOH, and morphorinopropanesul-
market, and several compounds are currently under clinical fonate (MOPS). The resulting carbapenem derivatives 1a—d
evaluation.
were purified by reverse-phase column chromatography and
Our attention was focused on the synthesis of 5-methyl-4- subsequent lyophilization. Optically active 5-methyl-4-mer-
hydroxypyrrolidinone which could be used as the synthon of captopyrrolidinones 7a—d were prepared from enantiomeri-
a-hydroxy-b-amino acid. Furthermore, we synthesized four cally pure aziridine ester 2, respectively, as shown in Chart 2.
enantio pure isomers of a 1b-methylcarbapenem derivative at
b-Keto esters 39) of aziridine were obtained from aziridine
the C-2 side chain, which were modified from R-83201,6) and ester 2 with the lithium enolate from ethyl acetate and LiH-
evaluated them for antibacterial activities and other biologi- MDS in THF. Reduction of the b-keto ester 3 with NaBH4 in
cal properties. We prepared the 5-methyl-4-mercaptopyrro- the presence of NH4Cl resulted in a diastereomeric mixture
lidinones from enantiomerically pure aziridine ester.7) In this of hydroxy aziridines 4 (approximately R/Sϭ1/1 to 2/1),
paper, we describe the synthesis of the 1b-methylcarbapen- which were readily separable by flash chromatography. We
ems (1a—d) and optically active 5-methyl-4-hydroxypyrro- did not optimize reduction conditions to obtain high stereo-
lidinones (5a—d).
selectivity. 5-Methyl-4-hydroxypyrrolidinones 5a—d were
The C-2 substituted derivatives of 1b-methylcarbapenem prepared from the aziridine propionates 4a—d through re-
were synthesized through the general procedure shown in gioselective reductive cleavage by catalytic hydrogenation in
Reagents and conditions: (a) 7a—d, DIPEA, CH3CN, 2 h, (b) Pd/C, H2, THF/EtOH/0.1 M MOPS buffer, 12 h.
Chart 1
To whom correspondence should be addressed. e-mail: bjkim@pado.krict.re.kr
© 2002 Pharmaceutical Society of Japan

416
Vol. 50, No. 3
Reagents and conditions: (a) EtOAc, LiHMDS, THF, Ϫ78 °C, 1.5 h, (b) NH4Cl, NaBH4, H2O/EtOH, 1 h, (c) Pd(OH)2, H2 (60 psi), EtOH, 12 h, (d) PPh3, DEAD, AcSH,
DMF/THF, 3 h, (e) 2 N-NaOH, MeOH, 0.5 h.
Chart 2
Fig. 1. NOE Enhancement of 5a—d
Table 1. In Vitro Antibacterial Activity of Carbapenem-Substituted 5-Methyl-4-mercaptopyrrolidinone (MIC, mg/ml)
Strains
1a
1b
1c
1d
Meropenem
R-83201
Streptococcus pyogenes 308A
Streptococcus pyogenes 77A
Streptococcus faecium MD8b
Staphylococcus aureus 285
Staphylococcus aureus 503
Escherichia coli 078
0.025
0.025
6.250
0.195
0.195
0.025
0.025
0.013
0.025
0.049
6.250
0.781
0.192
0.049
0.098
0.098
0.013
0.025
6.250
0.391
0.195
0.098
0.781
0.098
0.049
0.025
6.250
0.391
0.195
0.025
0.049
0.025
0.013
0.007
6.250
0.195
0.049
0.025
0.025
0.025
0.195
0.098
0.049
0.049
0.049
0.098
0.025
100
0.013
0.013
6.250
0.098
0.049
0.025
0.025
0.013
6.250
0.781
0.049
0.195
0.025
0.195
0.013
—
Escherichia coli DC0
Escherichia coli TEM
Pseudomonas aeruginosa 9027
Pseudomonas aeruginosa 1771M
Salmonella typhimurium
Klebsiella oxytoca 1082E
Klebsiella aerogenes 1522E
Enterobacter cloacae P99
Enterobacter cloacae 1321E
DHP-1 stability
25.0
25.0
50.0
25.0
1.563
0.049
0.195
0.025
0.391
0.025
1.563
0.195
3.125
0.195
3.125
0.098
1.563
0.195
1.563
0.195
1.563
0.098
6.250
0.049
0.391
0.049
1.563
0.025
141
63
102
60
confirmed by 1H-NMR and nuclear Overhauser effect (NOE)
experiments (Fig. 1). 5-Methyl-4-hydroxypyrrolidinones 5a—
d were converted to the thioacetates 6a—d by the Mitsunobu
reaction using PPh3, diethylazodicarboxylate (DEAD), and
thiolacetic acid in N,N-dimethylformamide (DMF) and THF.
Thiols 7a—d, applicable for coupling with carbapenem
enolphosphate 8, were prepared by deacetylation under basic
conditions.
the presence of Pd(OH)2.
We found that aziridine ring reduction proceeded much
faster than debenzylation during the catalytic hydrogenation
of the aziridine propionates. Subsequent ring opening,
debenzylation, and intramolecular cyclization proceeded in a
one-pot process. The best result of the reductive clevage of
the C(3)–N bond was obtained when using 20 wt% of Pearl-
man’s catalyst and the concentration of the substrate was
0.2 M in MeOH. The absolute stereochemistry of 5a—d was

March 2002
417
Conclusion
Hz, 1H), 2.25 (s, 1H), 2.15 (d, Jϭ7.7 Hz, 1H), 2.06 (d, Jϭ5.7 Hz, 1H), 1.96
(d, Jϭ3.5 Hz, 1H), 1.65 (m, 1H), 1.49 (d, Jϭ6.5 Hz, 3H), 1.44 (d, Jϭ6.5 Hz,
3H), 1.19 (t, Jϭ7.1 Hz, 3H); 13C-NMR (CDCl3, 50 MHz) d: 171.1, 144.0,
128.3, 127.2, 126.7, 69.3, 66.7, 60.0, 41.3, 40.0, 30.9, 22.2, 13.9; HR-MS
(EI) Calcd for C15H21NO3, 263.1521; Found 263.1509. 4d: 1H-NMR
(CDCl3, 200 MHz) d 7.34—7.25 (m, 5H), 4.06 (q, Jϭ7.1 Hz, 2H), 3.75 (dd,
Jϭ5.1, 12.0 Hz, 1H), 2.97 (s, 1H), 2.53 (q, Jϭ6.5 Hz, 1H), 2.21 (dd, Jϭ2.0,
5.0 Hz, 2H), 1.96 (d, Jϭ3.5 Hz, 1H), 1.69—1.62 (m, 1H), 1.48 (d, Jϭ6.5 Hz,
1H), 1.43 (d, Jϭ6.5 Hz, 3H), 1.20 (t, Jϭ7.1 Hz, 3H); 13C-NMR (CDCl3,
50 MHz) d: 171.7, 143.9, 128.3, 127.1, 126.6, 69.3, 66.9, 60.3, 41.1, 39.1,
30.8, 22.5, 13.9; HR-MS (EI) Calcd for C15H21NO3, 263.1521; Found
263.1502.
5-Methyl-4-hydroxypyrrolidinones (5a—d) were synthe-
sized from the enantiomerically pure aziridine ester (2) in 3
steps, with subsequent 50% overall yield. The nonprotected
side-chain thiols (7a—d) were prepared from 5a—d by the
Mitsunobu reaction and deacetylation. 1b-Methylcarbapen-
ems bearing 5-methyl-4-mercaptopyrrolidinones were syn-
thesized from PNB-protected carbapenem enolphosphate (8)
and thiols (7a—d). Some effects of the chiral center in the C-
2 side chain were observed on in vitro activities and pharma-
cokinetic parameters. Comparison of stereoisomers indicated
that 1a shows greater antibacterial activity than the others. In
addition, the degradation rate of 1a with DHP-1 was slower
than the others.
5(S)-Methyl-4(R)-hydroxypyrrolidinone (5a) To
a solution of 4a
(1.13 g, 4.32 mmol) in 21 ml of EtOH was added Pd(OH)2 (350 mg). The
mixture was stirred under 60 psi of hydrogen for 12 h at room temperature.
The reaction mixture was filtered and washed with 10 ml of MeOH and then
concentrated under reduced pressure. Purification by silica gel flash chro-
matography (EtOAc/n-hexaneϭ1 : 4) gave 390 mg (80%) of 5a as a white
1
Experimental
solid. H-NMR (CD3OD, 200 MHz) d: 4.01 (ddd, Jϭ3.0, 4.0, 6.8 Hz, 1H),
General NMR spectra were recorded on Varian Gemini 200 spectrome- 3.51 (dq, Jϭ3.0, 6.5 Hz, 1H), 2.68 (dd, Jϭ6.8, 17.1 Hz, 1H), 2.18 (dd, Jϭ
ters operating at 200 MHz (1H) and 50 MHz (13C) in deuteriochloroform 4.0, 17.1 Hz, 1H), 1.20 (d, Jϭ6.5 Hz, 3H); 13C-NMR (CD3OD, 50 MHz) d:
(CDCl3), deuteriomethanol (CD3OD), or deuterium oxide (D2O). THF and 177.9, 74.5, 60.4, 40.3, 19.7; HR-MS (EI) Calcd for C5H9NO2, 115.0633;
ether were distilled from sodium-benzophenone ketyl at atmospheric pres- Found 115.0632.
sure immediately prior to use. Methylene chloride and dimethyl sulfoxide
(DMSO) were distilled from calcium hydride. All other reagents and sol-
vents used were of reagent grade.
5(S)-Methyl-4(S)-hydroxypyrrolidinone (5b) 1H-NMR (CD3OD,
200 MHz) d: 4.31 (dd, Jϭ2.6, 4.4 Hz, 1H), 3.77 (dd, Jϭ5.0, 6.5 Hz, 1H),
2.62 (dd, Jϭ6.2, 17.1 Hz, 1H), 2.21 (dd, Jϭ2.6, 17.1 Hz, 1H), 1.19 (d,
Ethyl 3-Oxo-3-[1-(1؅(S)-a-methylbenzyl)-aziridin-2(S)-yl]-propionate Jϭ6.5 Hz, 3H); 13C-NMR (CD3OD, 50 MHz) d: 178.8, 70.0, 56.6, 41.6,
(3) To a solution of LiHMDS (9.95 ml, 9.95 mmol) in 15 ml of THF under 14.6; HR-MS (EI) Calcd for C5H9NO2, 115.0633; Found 115.0634.
a nitrogen atmosphere at Ϫ78 °C was added EtOAc (1.0 ml, 9.94 mmol). The
5(R)-Methyl-4(R)-hydroxypyrrolidinone (5c) 1H-NMR (CD3OD, 200
reaction mixture was stirred for 30 min at Ϫ78 °C and then treated with 2 MHz) d: 4.31 (ddd, Jϭ2.5, 5.0, 6.0 Hz, 1H), 3.77 (dq, Jϭ5.0, 6.5 Hz, 1H),
(1.09 g, 4.97 mmol) in 10 ml of THF at Ϫ78 °C. The mixture was stirred for 2.64 (dd, Jϭ6.1, 17.0 Hz, 1H), 2.21 (dd, Jϭ2.6, 17.0 Hz, 1H), 1.20 (d,
1 h, quenched with 3 ml of water at Ϫ78 °C, and then warmed to room tem-
perature. The combined organic layer was separated and washed with 5 ml of 14.6; HR-MS (EI) Calcd for C5H9NO2, 115.0633; Found 115.0632.
brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced
5(R)-Methyl-4(S)-hydroxypyrrolidinone (5d) 1H-NMR (CD3OD, 200
Jϭ6.5 Hz, 3H); 13C-NMR (CD3OD, 50 MHz) d: 178.7, 70.0, 56.5, 41.6,
pressure. Purification by silica gel flash chromatography (EtOAc/n-hexaneϭ MHz) d: 4.01 (dt, Jϭ3.1, 4.1 Hz, 1H), 3.52 (dq, Jϭ3.1, 6.5 Hz, 1H), 2.68
1 : 4) gave 0.97 g (75%) of 3 as a yellow oil. 1H-NMR (CDCl3, 200 MHz) d: (dd, Jϭ6.7, 17.2 Hz, 1H), 2.18 (dd, Jϭ4.1, 17.2 Hz, 1H), 1.20 (d, Jϭ6.5 Hz,
7.31—7.26 (m, 5H), 4.10 (q, Jϭ7.2 Hz, 2H), 3.36 (d, Jϭ5.4 Hz, 2H), 2.58 3H); 13C-NMR (CD3OD, 50 MHz) d: 178.1, 75.3, 61.2, 41.2, 20.5; HR-MS
(q, Jϭ6.5 Hz, 1H), 2.34 (d, Jϭ3.0 Hz, 1H), 2.21 (dd, Jϭ3.0, 7.0 Hz, 1H), (EI) Calcd for C5H9NO2, 115.0633; Found 115.0633.
1.86 (d, Jϭ7.0 Hz, 1H), 1.44 (d, Jϭ6.5 Hz, 3H), 1.21 (t, Jϭ7.2 Hz, 3H); 13C-
5(S)-Methyl-4(S)-acetylthiopyrrolidinone (6a) To a solution of 5a
NMR (CDCl3, 50 MHz) d: 200.8, 167.0, 143.4, 128.3, 127.2, 126.3, 69.4, (310 mg, 2.76 mmol) in 13.5 ml of THF/DMF (11.5/2 ml) under nitrogen at
61.0, 44.3, 44.0, 34.9, 23.3, 13.8; high resolution (HR)-MS (electron impact 0 °C was added PPh3 (870 mg, 3.31 mmol) and DEAD (0.52 ml, 3.31 mmol).
(EI)) Calcd for C15H19NO3, 261.1364; Found 261.1373.
The mixture was stirred for 30 min at 0 °C and then AcSH (0.39 ml,
Ethyl 3-Oxo-3-[1-(1؅(S)-a-methylbenzyl)-aziridin-2(R)-yl]-propionate 3.59 mmol) added. The mixture was stirred for 2 h at room temperature and
(3؅) 1H-NMR (CDCl3, 200 MHz) d: 7.37—7.26 (m, 5H), 4.19 (q, Jϭ7.2
Hz, 2H), 3.42 (d, Jϭ11.2 Hz, 2H), 2.59 (q, Jϭ6.5 Hz, 1H), 2.34 (dd, Jϭ3.0,
6.8 Hz, 1H), 2.11 (d, Jϭ3.0 Hz, 1H), 1.72 (d, Jϭ6.8 Hz, 1H), 1.42 (d, Jϭ6.5
then concentrated under reduced pressure. Purification by silica gel flash
chromatography (EtOAc/n-hexaneϭ1 : 4) gave 285 mg (60%) of 6a as a
1
white foam. H-NMR (CDCl3, 200 MHz) d: 6.86 (s, 1H), 4.28 (dd, Jϭ2.6,
Hz, 3H), 1.28 (t, Jϭ7.2 Hz, 3H); 13C-NMR (CDCl3, 50 MHz) d: 201.4, 4.4 Hz, 1H), 4.06 (dd, Jϭ5.0, 6.5 Hz, 1H), 2.88 (dd, Jϭ8.3, 18.0 Hz, 1H),
167.0, 143.4, 128.2, 127.1, 126.4, 68.9, 61.0, 44.9, 43.6, 34.0, 23.0, 13.8; 2.36 (s, 3H), 2.33 (dd, Jϭ7.1, 16.7 Hz, 1H), 1.18 (d, Jϭ6.6 Hz, 3H); 13C-
HR-MS (EI) Calcd for C15H19NO3, 261.1364; Found 261.1366.
Ethyl 3(R)-Hydroxy-3-[1-(1؅(S)-a-methylbenzyl)-aziridin-2(S)-yl]-pro-
pionate (4a) and Ethyl 3(S)-hydroxy-3-[1-(1؅(S)-a-methylbenzyl)-aziridin-
NMR (CDCl3, 50 MHz) d: 194.4, 175.1, 53.4, 43.1, 36.6, 29.8, 18.5; HR-
MS (EI) Calcd for C7H11NO2S, 173.0510; Found 173.0507.
5(S)-Methyl-4(R)-acetylthiopyrrolidinone (6b) 1H-NMR (CDCl3, 200
2(S)-yl]-propionate (4b) To a solution of 3 (1.56 g, 5.96 mmol) and NH4Cl MHz) d: 6.21 (s, 1H), 3.79—3.60 (m, 2H), 2.88 (dd, Jϭ6.8, 17.1 Hz, 1H),
(6.38 g, 0.11 mol) in 95 ml of 80% aqueous EtOH was added NaBH4 (1.13 g, 2.35 (s, 3H), 2.33 (dd, Jϭ4.0, 17.1 Hz, 1H), 1.30 (d, Jϭ6.1 Hz, 3H); 13C-
29.84 mol) in three portions. The mixture was stirred for 1 h at room temper- NMR (CDCl3, 50 MHz) d: 194.2, 174.8, 56.0, 43.0, 36.8, 30.0, 19.9; HR-
ature and then quenched with water. The mixture was concentrated under re- MS (EI) Calcd for C7H11NO2S, 173.0510; Found 173.0513.
duced pressure and then extracted with EtOAc (30 ml). The combined or-
5(R)-Methyl-4(S)-acetylthiopyrrolidinone (6c) 1H-NMR (CDCl3, 200
ganic layer separated was washed with 10 ml of brine, dried over anhydrous MHz) d: 6.05 (s, 1H), 3.79—3.63 (m, 2H), 2.87 (dd, Jϭ6.7, 17.2 Hz, 1H),
MgSO4, filtered, and concentrated under reduced pressure. Purification by 2.34 (s, 3H), 2.31 (dd, Jϭ4.1, 17.2 Hz, 1H), 1.30 (d, Jϭ6.1 Hz, 3H); 13C-
silica gel flash chromatography (EtOAc/n-hexaneϭ1 : 4) gave 0.65 g (41%)
of 4a and 0.68 g (44%) of 4b as yellow oil. 4a: 1H-NMR (CDCl3, 200 MHz) MS (EI) Calcd for C7H11NO2S, 173.0510; Found 173.0503.
d: 7.38—7.21 (m, 5H), 4.27 (q, Jϭ7.1 Hz, 2H), 4.05 (q, Jϭ6.5 Hz, 1H),
5(R)-Methyl-4(R)-acetylthiopyrrolidinone (6d) 1H-NMR (CDCl3, 200
NMR (CDCl3, 50 MHz) d: 194.1, 174.2, 55.9, 43.0, 36.8, 29.9, 19.9; HR-
3.17 (s, 1H), 2.65 (dd, Jϭ2.7, 4.3 Hz, 2H), 2.57 (q, Jϭ6.5 Hz, 1H), 1.75 (dd, MHz) d: 6.33 (s, 1H), 4.31 (ddd, Jϭ2.5, 5.0, 6.0 Hz, 1H), 4.10 (dq, Jϭ5.0,
Jϭ1.7, 3.0 Hz, 2H), 1.45 (d, Jϭ6.5 Hz, 3H), 1.28 (t, Jϭ7.1 Hz, 3H); HR-MS 6.0 Hz, 1H), 2.77 (dd, Jϭ8.4, 17.2 Hz, 1H), 2.36 (s, 3H), 2.33 (dd, Jϭ8.4,
(EI) Calcd for C15H21NO3, 263.1521; Found 263.1520. 4b: 1H-NMR 16.6 Hz, 1H), 1.18 (d, Jϭ6.5 Hz, 3H); 13C-NMR (CDCl3, 50 MHz) d: 194.6,
(CDCl3, 200 MHz) d: 7.38—7.25 (m, 5H), 4.19 (q, Jϭ7.1 Hz, 2H), 3.91—
3.80 (m, 1H), 2.82 (d, Jϭ6.3 Hz, 1H), 2.62 (dd, Jϭ2.8, 4.3 Hz, 2H), 2.55 (q,
Jϭ6.5 Hz, 1H), 1.75 (dd, Jϭ1.7, 3.1 Hz, 2H), 1.43 (d, Jϭ6.5 Hz, 3H), 1.28
(t, Jϭ7.1 Hz, 3H); 13C-NMR (CDCl3, 50 MHz) d: 171.0, 143.8, 127.9,
175.5, 52.3, 42.1, 36.7, 30.4, 17.6; HR-MS (EI) Calcd for C7H11NO2S,
173.0510; Found 173.0503.
5(S)-Methyl-4(S)-thiopyrrolidinone (7a) To a solution of 6a (135 mg,
0.77 mmol) in 8 ml of MeOH at 0 °C was added 2 N-NaOH (0.38 ml). The
126.7, 126.4, 68.7, 67.8, 60.2, 43.4, 40.2, 30.5, 23.1, 13.8; HR-MS (EI) mixture was stirred for 30 min and then treated AcOH (0.04 ml, 0.85 mmol).
Calcd for C15H21NO3, 263.1521; Found 263.1518.
The mixture was dried over Na2SO4, filtered, and concentrated under re-
Ethyl 3(R)-Hydroxy-3-[1-(1؅(S)-a-methylbenzyl)-aziridin-2(R)-yl]- duced pressure. Purification by silica gel flash chromatography (EtOAc/n-
1
propionate (4c) and Ethyl 3(S)-Hydroxy-3-[1-(1؅(S)-a-methylbenzyl)- hexaneϭ1 : 4) gave 92 mg (91%) of 6a as a white foam. H-NMR (CD3OD,
aziridin-2(R)-yl]-propionate (4d) 4c: 1H-NMR (CDCl3, 200 MHz) d: 200 MHz) d: 3.89 (quin, Jϭ6.4 Hz, 1H), 3.73 (dd, Jϭ5.7, 13.5 Hz, 1H), 2.79
7.34—7.26 (m, 5H), 4.06 (q, Jϭ7.1 Hz, 2H), 3.77 (m, 1H), 2.49 (q, Jϭ6.5
(dd, Jϭ7.6, 17.0 Hz, 1H), 2.27 (dd, Jϭ5.8, 17.0 Hz, 1H), 1.24 (d, Jϭ6.4 Hz,

418
Vol. 50, No. 3
3H).
lution of 9a (134 mg, 0.28 mmol) in THF/EtOH/0.1 M-Mops buffer (4.5/
7/11.5 ml) was added Pd/C (50 mg). The mixture was stirred under balloon
5(S)-Methyl-4(R)-thiopyrrolidinone (7b) 1H-NMR (CD3OD, 200 MHz)
d: 3.52 (quin, Jϭ6.5 Hz, 1H), 3.05 (dd, Jϭ8.4, 15.2 Hz, 1H), 2.77 (dd, Jϭ pressure of hydrogen for 15 h at room temperature. The reaction mixture was
7.1, 16.8 Hz, 1H), 2.31 (dd, Jϭ8.6, 16.8 Hz, 1H), 1.27 (d, Jϭ6.5 Hz, 3H).
filtered and washed with MeOH and then concentrated under reduced pres-
sure. To a solution of residue was added SEH (47 mg, 0.28 mmol) and then
5(R)-Methyl-4(S)-thiopyrrolidinone (7c) 1H-NMR (CD3OD, 200 MHz)
d: 3.54 (quin, Jϭ6.2 Hz, 1H), 3.07 (dd, Jϭ8.4, 15.1 Hz, 1H), 2.79 (dd, Jϭ stirred for 10 min. The aqueous layer washed with EtOAc. The combined
8.2, 16.8 Hz, 1H), 2.32 (dd, Jϭ8.6, 16.8 Hz, 1H), 1.28 (d, Jϭ6.2 Hz, 3H).
aqueous layers were purified by reverse-phase column chromatography and
then lyophilized to give 1a (390 mg, 80%) as a white amorphous solid. H-
1
5(R)-Methyl-4(R)-thiopyrrolidinone (7d) 1H-NMR (CD3OD, 200 MHz)
d: 3.89 (quin, Jϭ6.5 Hz, 1H), 3.71 (dd, Jϭ7.1, 13.5 Hz, 1H), 2.77 (dd, Jϭ NMR (D2O, 200 MHz) d: 4.06—3.82 (m, 4H), 3.27—3.16 (m, 1H), 3.23
7.7, 16.8 Hz, 1H), 2.26 (dd, Jϭ5.9, 16.8 Hz, 1H), 1.24 (d, Jϭ6.4 Hz, 3H).
4-Nitrobenzyl (1R,5S,6S)-6-[(R)-1-Hydroxyethyl]-1-methyl-2-[(S)-2(S)-
methyl-5-oxopyrrolidin-3-ylthio]-1-carbapen-2-em-3-carboxylate (9a) To
a solution of 7a (140 mg, 0.91 mmol) in 7 ml of CH3CN under nitrogen at 41.9, 36.2, 20.7, 17.1, 16.2; HR-MS (FAB) Calcd for C15H20N2O5NaS,
0 °C was added p-nitrobenzyl (1R,5S,6S)-2-diphenylphosporyloxy-6-[(R)-1- 363.0990; Found 363.0993.
(dd, Jϭ2.6, 6.2 Hz, 1H), 2.60 (dd, Jϭ8.2, 17.1 Hz, 1H), 2.20 (dd, Jϭ7.5,
17.1 Hz, 1H), 1.06 (d, Jϭ6.1 Hz, 3H), 0.98 (d, Jϭ6.5 Hz, 6H); 13C-NMR
(D2O, 50 MHz) d: 178.8, 178.1, 164.1, 131.5, 119.8, 65.4, 56.2, 54.8, 50.5,
hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate
mmol) and DIPEA (0.12 ml, 1.00 mmol). The mixture was stirred for 2 h at
8
(430 mg, 0.72
Sodium (1R,5S,6S)-6-[(R)-1-Hydroxyethyl]-1-methyl-2-[(R)-2(S)-methyl-
5-oxopyrrolidin-3-ylthio]-1-carbapen-2-em-3-carboxylate (1b) 1H-NMR
0—5 °C and then quenched with phosphate buffer solution (pH 7.0). The (D2O, 200 MHz) d: 3.77 (q, Jϭ6.4 Hz, 1H), 3.94 (dd, Jϭ2.5, 9.4 Hz, 1H),
mixture was extracted with Et2O and washed with brine. The combined or- 3.42 (dq, Jϭ6.0, 11.2 Hz, 1H), 3.39—3.33 (m, 1H), 3.17 (dd, Jϭ2.5, 6.0 Hz,
ganic extracts were dried over anhydrous MgSO4, filtered, and concentrated 1H), 3.06 (dt, Jϭ7.5, 16.4 Hz, 1H), 2.75 (dd, Jϭ7.9, 18.5 Hz, 1H), 2.18 (dd,
under reduced pressure. Purification by silica gel flash chromatography Jϭ5.3, 18.5 Hz, 1H), 1.06 (d, Jϭ6.4 Hz, 3H), 1.02 (d, Jϭ6.1 Hz, 3H), 0.94
(EtOAc/n-hexaneϭ1 : 4) gave 175 mg (40%) of 9a as a yellow foam. 1H- (d, Jϭ7.1 Hz, 3H); 13C-NMR (D2O, 50 MHz) d: 168.4, 166.9, 164.4, 135.1,
NMR (CDCl3, 200 MHz) d: 8.23 (d, Jϭ8.7 Hz, 2H), 7.68 (d, Jϭ8.6 Hz, 2H), 114.8, 74.2, 68.1, 58.5, 48.6, 46.9, 35.8, 34.2, 26.5, 25.0, 10.0; HR-MS
5.40 (dd, Jϭ13.8, 49.2 Hz, 2H), 4.24 (dd, Jϭ2.5, 9.0 Hz, 1H), 4.2—3.97 (m,
3H), 3.46—3.35 (m, 1H), 3.28 (dd, Jϭ2.5, 7.1 Hz, 1H), 2.76 (dd, Jϭ7.9,
17.1 Hz, 1H), 2.38 (dd, Jϭ8.3, 17.1 Hz, 1H), 1.34 (d, Jϭ6.3 Hz, 3H), 1.28
(FAB) Calcd for C15H20N2O5NaS, 363.0990; Found 363.0975.
Sodium (1R,5S,6S)-6-[(R)-1-Hydroxyethyl]-1-methyl-2-[(S)-2(R)-methyl-
5-oxopyrrolidin-3-ylthio]-1-carbapen-2-em-3-carboxylate (1c) 1H-NMR
(d, Jϭ7.3 Hz, 3H), 1.24 (d, Jϭ6.3 Hz, 3H); 13C-NMR (CDCl3, 50 MHz) d: (D2O, 200 MHz) d: 4.27—4.20 (m, 2H), 3.74 (dd, Jϭ3.9, 6.5 Hz, 1H), 3.62
174.7, 173.0, 159.9, 150.0, 147.2, 142.6, 127.9, 124.3, 123.3, 65.1, 59.5,
56.1, 53.6, 43.8, 42.0, 35.5, 21.1, 17.1, 16.4; HR-MS (FAB) Calcd for
C22H26N3O7S, 476.1491; Found 476.1494.
4-Nitrobenzyl (1R,5S,6S)-6-[(R)-1-Hydroxyethyl]-1-methyl-2-[(R)-2(S)-
methyl-5-oxopyrrolidin-3-ylthio]-1-carbapen-2-em-3-carboxylate (9b)
1H-NMR (CDCl3, 200 MHz) d: 8.23 (d, Jϭ8.7 Hz, 2H), 7.66 (d, Jϭ9.0 Hz,
2H), 5.37 (dd, Jϭ13.8, 46.6 Hz, 2H), 4.25 (dd, Jϭ2.6, 9.3 Hz, 1H), 4.19 (q,
(q, Jϭ5.0 Hz, 1H), 3.46 (dd, Jϭ2.8, 5.9 Hz, 1H), 3.41—3.31 (m, 1H), 2.98
(dd, Jϭ8.6, 17.9 Hz, 1H), 2.34 (dd, Jϭ7.9, 18.5 Hz, 1H), 1.28 (d, Jϭ6.5 Hz,
6H), 1.20 (d, Jϭ7.1 Hz, 3H); 13C-NMR (D2O, 50 MHz) d: 178.1, 176.8,
175.5, 139.3, 98.1, 65.3, 61.5, 59.1, 56.1, 44.5, 42.9, 36.3, 20.3, 19.7, 16.1;
HR-MS (FAB) Calcd for C15H20N2O5NaS, 363.0990; Found 363.0990.
Sodium (1R,5S,6S)-6-[(R)-1-Hydroxyethyl]-1-methyl-2-[(R)-2(R)-methyl-
5-oxopyrrolidin-3-ylthio]-1-carbapen-2-em-3-carboxylate (1d) 1H-NMR
Jϭ6.5 Hz, 1H), 3.63 (q, Jϭ6.1 Hz, 1H), 3.52—3.30 (m, 2H), 3.26 (dd, Jϭ (D2O, 200 MHz) d: 4.28—4.10 (m, 4H), 3.45 (dd, Jϭ2.5, 5.1 Hz, 1H), 3.38
2.6, 7.3 Hz, 1H), 2.87 (dd, Jϭ8.0, 17.1 Hz, 1H), 2.46 (dd, Jϭ6.7, 17.1 Hz, (m, 1H), 2.94 (dd, Jϭ6.8, 17.1 Hz, 1H), 2.46 (dd, Jϭ4.3, 17.1 Hz, 1H), 1.33
1H), 1.38 (d, Jϭ6.1 Hz, 3H), 1.31 (d, Jϭ7.4 Hz, 3H), 1.28 (d, Jϭ7.1 Hz, (d, Jϭ4.3 Hz, 3H), 1.31 (d, Jϭ7.8 Hz, 3H), 1.20 (d, Jϭ6.8 Hz, 3H); 13C-
3H); 13C-NMR (CDCl3, 50 MHz) d: 174.1, 172.5, 159.2, 147.5, 142.2,
NMR (D2O, 50 MHz) d: 177.2, 176.3, 170.2, 139.6, 109.8, 65.9, 59.2, 56.8,
135.6, 127.4, 126.5, 122.0, 121.5, 118.9, 71.8, 63.4, 58.3, 55.7, 50.5, 43.8, 53.8, 43.9, 43.1, 40.5, 27.2, 20.8, 16.5; HR-MS (FAB) Calcd for
41.7, 36.8, 24.7, 19.9, 14.1; HR-MS (FAB) Calcd for C22H26N3O7S, C15H20N2O5NaS, 363.0990; Found 363.0989.
476.1491; Found 476.1504.
4-Nitrobenzyl (1R,5S,6S)-6-[(R)-1-Hydroxyethyl]-1-methyl-2-[(S)-2(R)-
methyl-5-oxopyrrolidin-3-ylthio]-1-carbapen-2-em-3-carboxylate (9c)
1H-NMR (CDCl3, 200 MHz) d: 8.22 (d, Jϭ8.7 Hz, 2H), 7.65 (d, Jϭ8.9 Hz,
2H), 6.23 (s, 1H), 5.36 (dd, Jϭ13.8, 56.0 Hz, 2H), 4.28 (dd, Jϭ2.4, 9.3 Hz,
2H), 3.68 (q, Jϭ6.0 Hz, 1H), 3.50—3.39 (m, 1H), 3.34 (m, 1H), 3.30 (dd,
Jϭ2.5, 6.7 Hz, 1H), 2.87 (dd, Jϭ8.5, 17.4 Hz, 1H), 2.37 (dd, Jϭ7.0, 17.4 Hz,
1H), 1.36 (d, Jϭ6.3 Hz, 3H), 1.31 (d, Jϭ6.3 Hz, 3H), 1.27 (d, Jϭ7.2 Hz,
3H); 13C-NMR (CDCl3, 50 MHz) d: 174.5, 172.9, 159.9, 148.7, 147.2,
142.7, 127.9, 125.4, 123.4, 65.2, 59.8, 58.0, 55.7, 45.3, 43.8, 36.8, 21.5,
20.5, 16.6, 13.9; HR-MS (FAB) Calcd for C22H26N3O7S, 476.1491; Fund
476.1484.
4-Nitrobenzyl (1R,5S,6S)-6-[(R)-1-Hydroxyethyl]-1-methyl-2-[(R)-2(R)-
methyl-5-oxopyrrolidin-3-ylthio]-1-carbapen-2-em-3-carboxylate (9d)
1H-NMR (CDCl3, 200 MHz) d: 8.06 (d, Jϭ8.7 Hz, 2H), 7.50 (d, Jϭ9.0 Hz,
2H), 5.21 (dd, Jϭ13.8, 47.6 Hz, 2H), 4.06 (dd, Jϭ2.4, 9.2 Hz, 1H), 4.03—
3.79 (m, 3H), 3.25—3.16 (m, 1H), 3.09 (dd, Jϭ2.5, 7.6 Hz, 1H), 2.65 (dd,
Jϭ7.4, 16.9 Hz, 1H), 2.27 (dd, Jϭ5.7, 16.9 Hz, 1H), 1.17 (d, Jϭ6.1 Hz, 3H),
1.15 (d, Jϭ6.2 Hz, 3H), 1.09 (d, Jϭ6.5 Hz, 3H); 13C-NMR (CDCl3, 50 MHz)
d: 173.4, 172.4, 158.6, 147.7, 142.2, 137.7, 127.5, 126.6, 121.9, 121.4,
118.6, 72.9, 63.4, 58.5, 54.3, 50.5, 42.3, 41.7, 36.2, 24.7, 19.7, 14.9; HR-MS
(FAB) Calcd for C22H26N3O7S, 476.1491; Found 476.1486.
Acknowledgment We are grateful to the Ministry of Science and Tech-
nology (MOST) of Korea for financial support.
References and Notes
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Sodium (1R,5S,6S)-6-[(R)-1-Hydroxyethyl]-1-methyl-2-[(S)-2(S)-methyl-
5-oxopyrrolidin-3-ylthio]-1-carbapen-2-em-3-carboxylate (1a) To a so-
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