Practical synthesis of a 1β-methylcarbapenem, J-111,225, using 4-mercapto-2-[4-(N-methylaminomethyl)phenyl]pyrrolidine as a precursor

Article abstract of DOI:10.1248/cpb.49.476

An effective and practical procedure for the synthesis of J-111,225 (1), a new 1β-methylcarbapenem, was developed using 4-mercapto-2-[4-(N-methylaminomethyl)phenyl]pyrrolidine (2a) as a precursor. The coupling reaction of 2a with p-nitrobenzyl (PNB)-prote

Full text of DOI:10.1248/cpb.49.476

476
Notes
Chem. Pharm. Bull. 49(4) 476—479 (2001)
Vol. 49, No. 4
b
Practical Synthesis of a 1 -Methylcarbapenem, J-111,225, Using
4-Mercapto-2-[4-(N-methylaminomethyl)phenyl]pyrrolidine as a
Precursor
Hideaki IMAMURA,* Aya SHIMIZU, Hiroki SATO, Yuichi SUGIMOTO, Shunji SAKURABA,
Koji YAMADA, and Hajime MORISHIMA
Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo-3, Tsukuba, Ibaraki 300–2611, Japan.
Received October 5, 2000; accepted December 17, 2000
An effective and practical procedure for the synthesis of J-111,225 (1), a new 1b-methylcarbapenem, was de-
veloped using 4-mercapto-2-[4-(N-methylaminomethyl)phenyl]pyrrolidine (2a) as a precursor. The coupling reac-
tion of 2a with p-nitrobenzyl (PNB)-protected 1b-methylcarbapenem enolphosphate 3a and successive removal of
PNB group afforded J-111,225 (1) in significantly increased yield compared to the ordinary procedure using a C-
2 side-chain thiol with amino-protective groups.
Key words 1b-methylcarbapenem; J-111,225; non-protected side-chain thiol; practical synthesis
We reported J-111,225 (1) as a new class of 1b-methylcar- such as those described above. In fact, large amounts of BO-
bapenem antibiotic which shows broad-spectrum antibacter- 2727, a carbapenem developed previously in our laboratory,
ial activity against gram-positive organisms including methi- was prepared in high yield using a non-protected thiol and
cillin-resistant Staphlococcus aureus (MRSA) and gram-neg- 3a.7) Based on this finding, we developed an effective and
ative organisms including Pseudomonas aeruginosa.1) As de- practical procedure for the synthesis of J-111,225 (1) using
scribed in our preceding paper,2) J-111,225 (1) was synthe- the non-protected C-2 side-chain thiol, 4-mercapto-2-[4-(N-
sized by the coupling reaction of a side-chain thiol 2c, the methylaminomethyl)phenyl]pyrrolidine 2a.
amino groups of which were protected with an allyloxycar-
The non-protected thiol 2a was prepared starting from an
bonyl (Alloc) group, with allyl-protected carbapenem aldehyde 5 as shown in Chart 2.8) Since reductive amination
enolphosphate 3b,3) followed by deprotection of the resulting of aldehyde 5 to introduce the N-methylamino function did
fully-protected J-111,225 (4c). Due to moderate yield not proceed in a reasonable yield, aldehyde 5 was first re-
(28%)4) of the final process yielding J-111,225 in addition to duced with sodium borohydride (NaBH4) in MeOH at 0 °C to
poor stability of enolphosphate 3b and potential toxicity of afford an alcohol 6 (91%), which was in turn treated with
tributyltin hydride used for deprotection,5) this allyl-protec- methanesulfonyl chloride (MsCl) and substituted with
tion procedure seemed unsuitable for preparation of a safety methylamine. Successive tert-butoxycarbonyl (Boc) protec-
assessment sample.
tion by di-tert-butyldicarbonate (Boc2O) formed 7 (77%),
Here, we describe the preparation of 4-mercapto-2-[4-(N- and desilylation of 7 provided an alcohol 8 (90%) as crystals.
methylaminomethyl)phenyl]pyrrolidine 2a, and its conver- Thioacetate 9 was obtained in high yield (91%) by substitu-
sion to J-111,225 (1) in significantly improved yield by a tion of a mesylate of 8 with potassium thioacetate (AcSK).
coupling reaction with 1b-methylcarbapenem p-nitrobenzyl All protective groups of 9, one Ac group and two Boc
(PNB) ester 3a and subsequent deprotection.
groups, were removed simultaneously in HCl/MeOH at re-
flux temperature to afford a naked side-chain thiol 2a as
crystals with two molar of HCl in 88% yield. Thus, multi-
Results and Discussion
In carbapenem chemistry, the amino function of the side- grams of the crystalline non-protected thiol 2a were obtained
chain thiol precursor is ordinarily protected by carbamate- in excellent overall yield from aldehyde 5 (50%).
type protective groups, such as p-nitrobenzyloxycarbonyl
The coupling reaction of 2a and PNB-protected enolphos-
(PNZ) or Alloc, to avoid cleavage of the unstable b-lactam phate 3a proceeded smoothly in the presence of triethyl-
moiety for the feasible synthesis of new carbapenems. In the amine (TEA) in N,N-dimethylformamide (DMF) at 4 °C. Un-
case of J-111,225 (1), deprotection of 4b, a coupling product desired cleavage of the b-lactam ring by the amino function
of the PNB-protected carbapenem enolphosphate 3a3) and of 2a was not observed in this coupling reaction. The reac-
the PNZ-protected side-chain thiol 2b, resulted in low yield tion mixture containing the resulting unstable adduct was im-
(22%).6) Simultaneous and complete removal of two PNZ mediately poured into morpholinopropanesulfonate (MOPS)
groups and one PNB group from 4b was practically impossi- buffer–tetrahydrofuran (THF) (pH 6.4) and subjected to cat-
ble under usual conditions. When deprotection of 4b was alytic hydrogenation to remove PNB protection. Purification
carried out under accelerated conditions, significant decom- using reversed-phase column chromatography and subse-
position of the product and of the partially deprotected inter- quent lyophilization afforded 1 in 58% yield. The yield of the
mediate were observed. The PNB- or PNZ-derived benzyl final stages including the coupling reaction and deprotection
residue formed by reductive deprotection of 4b obstructs pu- was greatly improved by employing naked thiol 2a as a pre-
rification of the resulting crude carbapenem to produce J- cursor. Especially, the deprotection process of 4a proceeded
111,225 (1) with unacceptable yield and purity.
smoothly compared to that of highly protected 4b and 4c.9)
The use of non-protected thiol side-chain without PNZ
Thus, the resulting amorphous solid was crystallized to af-
protective groups would probably eliminate disadvantages ford J-111,225 (1) in crystalline form in high yield (92%);
To whom correspondence should be addressed. e-mail: imamrahk@banyu.co.jp
© 2001 Pharmaceutical Society of Japan

April 2001
477
Chart 1
Chart 2
crystalline J-111,225 (1) possessed excellent purity and ex- spectrometer with tetramethylsilane (TMS) as an internal standard. 13C-
NMR spectra were recorded on a JEOL JNM-A500 and a JEOL JNM-
EX270. IR absorption spectra were recorded with a Horiba FT-200 spec-
trometer. Specific rotations were measured with a Jasco DIP-370 polarime-
hibited good solubility in water (Ͼ5%).
Conclusion
ter. Mass spectra (MS) were measured on a JEOL JMS-SX102A spectrome-
The non-protected side-chain thiol 2a was synthesized
from the aldehyde 5 in 8 steps, with 50% overall yield. The
coupling reaction of 2a and the PNB ester 3a, as well as sub-
sequent deprotection, proceeded smoothly to afford J-
111,225 (1) in 58% yield, while the PNZ-protected thiol 2b
and the Alloc-protected thiol 2c produced yields of 22% and
28%, respectively. The crystalline form of 1 was obtained in
high yield (92%) from the resulting amorphous powder. Fur-
ther optimization for the preparation of large amounts of J-
111,225 (1) is now under way, and the results will be re-
ported in the future.
ter. TLC was performed with Merck Kieselgel F254 precoated plates. The sil-
ica gel used for column chromatography was WAKO gel C-300. Reversed-
phase column chromatography was carried out using YMC-gel ODS-AQ
120-S50. All reactions involving air-sensitive reagents were performed
under nitrogen using syringe-septum cap techniques.
(2R,4R)-1-tert-Butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[4-(hy-
droxymethyl)phenyl]pyrrolidine (6) To a solution of 5 (214.5 g, 530
mmol) in MeOH (4500 ml) was added NaBH4 (22.2 g, 587 mmol) dropwise
under a nitrogen atmosphere at 0 °C. After stirring for 30 min at 0 °C, the re-
action mixture was quenched by adding 10% aqueous NH4Cl (500 ml) and
poured into H2O (4500 ml). The whole was extracted with EtOAc, and the
organic layer was washed with brine, dried over MgSO4, and evaporated
under reduced pressure. The residue was purified by silica gel column chro-
matography (n-hexane/EtOAcϭ5 : 1—4 : 1) to give 6 (196.5 g, 91.1%) as a
1
Experimental
colorless oil. [a]D20 ϩ34.6° (cϭ1.0, CHCl3); IR (KBr) nmax 1700 cmϪ1; H-
Melting points were measured on a Yanaco mp micromelting point appa- NMR (300 MHz, CDCl3) d: 0.08 (6H, s), 0.80 (9H, s), 1.16 (6H, s), 1.44
ratus and were not corrected. The 1H-NMR spectra were recorded on a Var- (3H, s), 1.87 (1H, m), 2.50 (1H, m), 3.40 (1H, m), 3.86 (1H, m), 4.37 (1H,
ian VXR-300 spectrometer, a Varian Gemini-300 and a JEOL JNM-A500 m), 4.66 (2H, s), [4.72 (0.7H, m), 4.87 (0.3H, m), each rotamer], 7.26 (4H,

478
Vol. 49, No. 4
s); 13C-NMR (67.5 MHz, CDCl3, major signals) d: Ϫ5.0, Ϫ4.9, 17.8, 25.6,
28.0, 44.6, 54.6, 60.0, 64.6, 69.8, 79.4, 125.9, 126.5, 139.3, 143.8, 154.4;
FAB-HR-MS Calcd for C22H38NO4Si (MϩH)ϩ: 408.2570, Found 408.2572.
(2R,4R)-2-[4-(N-tert-Butoxycarbonyl-N-methylaminomethyl)phenyl]-
ture was allowed to cool to room temperature to form the precipitate and was
subsequently stirred further for another hour at 0 °C. The resulting precipi-
tates were collected by filtration and dried to give 2a (55.7 g, 87.6%) as col-
orless crystals. [a]D20 Ϫ30.6° (cϭ1.0, H2O); IR (KBr) nmax 2945, 1598 cmϪ1
;
1H-NMR (500 MHz, D2O) d: 2.54 (1H, m), 2.79 (3H, s), 2.83 (1H, m), 3.48
(1H, dd, Jϭ12.4, 4.1 Hz), 2.98 (1H, dd, Jϭ12.4, 6.5 Hz), 4.10 (1H, m), 4.31
(2H, s), 5.22 (1H, dd, Jϭ10.5, 7.0 Hz), 7.62 (4H, s); 13C-NMR (125 MHz,
D2O) d: 31.8, 34.7, 39.7, 51.4, 53.7, 60.8, 128.1, 130.2, 131.8, 134.9; FAB-
HR-MS Calcd for C12H19N2S (MϩH)ϩ: 223.1269, Found 223.1255. Anal.
Calcd for C12H18N2S (2HCl: C, 48.81; H, 6.83; N, 9.49, Found: C, 48.88; H,
6.99; N, 9.35.
1-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidine (7) To
a
solution of 6 (239 g, 587 mmol) in CH2Cl2 (4700 ml) were added TEA
(119 g, 1.17 mol) and MsCl (50 ml, 746 mmol) under a nitrogen atmosphere
at Ϫ30 °C. After stirring for 15 min at Ϫ30 °C, the reaction mixture was
poured into H2O, and the whole was extracted with EtOAc. The organic
layer was washed with brine and dried over MgSO4. Forty percent methy-
lamine/MeOH (1920 ml, 25 mol) was immediately added to the filtrate at
Ϫ10 °C after removal of MgSO4 by filtration, and the mixture was stirred for
30 min at the same temperature. The mixture was evaporated under reduced
pressure, and the residue was dissolved in 1,4-dioxane (1000 ml) and H2O
(250 ml). To this solution were added TEA (119 g, 1.17 mol) and Boc2O
(128 g, 588 mmol) at 10—15 °C, and the mixture was stirred for 30 min at
10—15 °C. The reaction mixture was poured into H2O, and the whole was
extracted with EtOAc. The organic layer was washed with brine, dried over
MgSO4, and evaporated under reduced pressure. The residue was purified by
silica gel column chromatography (n-hexane/EtOAcϭ5 : 1) to give 7 (237 g,
77.4%) as a colorless oil. [a]D20 ϩ31.6° (cϭ1.0, CHCl3); IR (Nujol) nmax
(1R,5S,6S)-6-[(R)-1-Hydroxyethyl]-2-[(3S,5R)-5-(4-(N-methylamino-
methyl)phenyl)pyrrolidin-3-ylthio]-1-carbapen-2-em-3-carboxylic Acid
Dihydrochloride (1) To a mixture of 2a (1.46 g, 3.7 mmol) and p-ni-
trobenzyl (1R,5S,6S)-2-diphenylphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-
methyl-1-carbapen-2-em-3-carboxylate (2.2 g, 3.7 mmol) in DMF (27 ml)
was added TEA (1.24 g, 12.2 mmol) dropwise at Ϫ40 °C, and the mixture
was stirred for 10 h at 4 °C. The reaction mixture was poured into THF
(66 ml) and 0.25 M sodium MOPS buffer (66 ml, pH 6.4), and to this mixture
was added 10% Pd/C (420 mg). The mixture was stirred for 3 h under a hy-
drogen atmosphere (3.0 kg/cm2) at room temperature. The catalyst was fil-
tered off and washed with H2O (ca. 200 ml). The combined filtrate and
washings were washed with CH2Cl2 and concentrated under reduced pres-
sure to ca. 30 ml. The aqueous layer was adjusted to pH 6.4 with 1 M aque-
ous HCl and subjected to reversed-phase column chromatography. The elu-
ent was monitored by HPLC, and the fractions eluted with 10—15%
CH3CN/H2O containing the desired compound were combined, and adjusted
to pH 5.8 with 1 M aqueous HCl. The resulting solution was concentrated
under reduced pressure to ca. 10 ml and lyophilized to give (1R,5S,6S)-6-
[(R)-1-hydroxyethyl]-2-[(3S,5R)-5-[4-(N-methylaminomethyl)phenyl]pyrro-
lidin-3-ylthio]-1-carbapen-2-em-3-carboxylic acid monohydrochloride as a
white amorphous powder (963 mg, 58.1%).
1
1704 cmϪ1; H-NMR (300 MHz, CDCl3) d: 0.08 (6H, s), 0.78 (9H, s), 1.14
(6H, s), 1.44 (12H, s), 1.88 (1H, m), 2.48 (1H, m), 2.73 (3H, br s), 3.42 (1H,
m), 3.83 (1H, m), 4.32 (1H, m), 4.43 (2H, s), 4.69 [(0.7H, m), 4.88 (0.3H,
m), each rotamer], 7.12 (2H, d, Jϭ7.3 Hz), 7.20 (2H, d, Jϭ7.3 Hz); 13C-
NMR (67.5 MHz, CDCl3, major signals) d: Ϫ4.7, Ϫ4.6, 18.1, 25.9, 28.4,
28.7, 34.0, 44.9, 53.7, 55.1, 60.3, 70.3, 79.6, 126.5, 127.2, 136.3, 144.2,
154.7, 156.7; FAB-HR-MS Calcd for C28H49N2O5Si (MϩH)ϩ: 521.3411,
Found 521.3426.
(2R,4R)-2-[4-(N-tert-Butoxycarbonyl-N-methylaminomethyl)phenyl]-
1-tert-butoxycarbonyl-4-hydroxypyrrolidine (8) To
a solution of 7
(182 g, 350 mmol) in THF (2000 ml) was added tetra-n-butylammonium flu-
oride (1 M in THF, 368 ml, 368 mmol) under a nitrogen atmosphere at 0 °C.
After stirring for 1 h at 0 °C, the mixture was poured into H2O (2000 ml),
and the whole was extracted with EtOAc. The organic layer was washed
with brine, dried over MgSO4, and evaporated under reduced pressure. The
residue was purified by silica gel column chromatography (n-
hexane/EtOAcϭ1 : 2) to give 8 (128 g, 90.1%) as colorless crystals. mp
123—124 °C; [a]D20 ϩ53.6° (cϭ1.0, CHCl3); IR (Nujol) nmax 3401, 1702,
1666 cmϪ1; 1H-NMR (300 MHz, CDCl3) d: 1.18 (6H, s), 1.41 (12H, s), 1.96
(1H, m), 2.54 (1H, m), 2.77 (3H, br s), 3.53(1H, dd, Jϭ11.7, 4.3 Hz), 3.83
(1H, m), 4.39 (2H, s), 4.43 (1H, m), [4.69 (0.6H, m), 4.94 (0.4H, m), each
rotamer], 7.15 (2H, d, Jϭ7.9 Hz), 7.24 (2H, d, Jϭ7.9 Hz); 13C-NMR
(67.5 MHz, CDCl3, major signals) d: 28.3, 28.6, 34.0, 44.3, 52.4, 55.4, 60.3,
69.2, 79.7, 126.3, 127.6, 136.3, 144.1, 154.6, 156.1; FAB-HR-MS Calcd for
C22H35N2O5 (MϩH)ϩ: 407.2546, Found 407.2547. Anal. Calcd for
C22H34N2O5: C, 65.00; H, 8.43; N, 6.89, Found: C, 64.92; H, 8.55; N, 6.84.
(2R,4S)-4-Acetylthio-2-[4-(N-tert-butoxycarbonyl-N-methylamino-
methyl)phenyl]-1-tert-butoxycarbonylpyrrolidine (9) To a solution of 8
(128 g, 315 mmol) in CH2Cl2 (2600 ml) were added TEA (64 g, 631 mmol)
and MsCl (25.6 ml, 331 mmol) under a nitrogen atmosphere at Ϫ30 °C.
After stirring for 30 min at Ϫ30 °C, the reaction mixture was poured into
H2O (1300 ml), and the whole was extracted with EtOAc. The organic layer
was washed with brine, dried over MgSO4, and evaporated under reduced
pressure. To a solution of the residue in DMF (3000 ml) was added AcSK
(108 g, 945 mmol) under a nitrogen atmosphere at room temperature, and the
mixture was stirred for 10 h at 55 °C. The resulting mixture was poured into
H2O, and the whole was extracted with EtOAc. The organic layer was
washed with brine, dried over MgSO4, and evaporated under reduced pres-
sure. The residue was purified by silica gel column chromatography (n-
hexane/EtOAcϭ3 : 1) to give 9 (133 g, 90.9%) as a brown oil. [a]D20 ϩ40.4°
(cϭ1.0, CHCl3); IR (Nujol) nmax 1700 cmϪ1; 1H-NMR (300 MHz, CDCl3) d:
1.16 (6H, s), 1.43 (12H, s), 2.22 (2H, m), 2.78 (3H, br s), 3.46 (0.5H, br s),
3.61 (0.5H, br s), 4.02 (2H, m), 4.39 (2H, s), [4.81 (0.5H, m), 4.97 (0.5H,
m), each rotamer], 7.14 (4H, br s); 13C-NMR (67.5 MHz, CDCl3, major sig-
nals) d: 28.1, 28.5, 30.6, 34.0, 39.6, 41.9, 52.8, 60.4, 79.6, 125.8, 127.5,
136.8, 142.9, 154.1, 155.8, 194.9; FAB-HR-MS Calcd for C24H37N2O5S
(MϩH)ϩ: 465.2423, Found 465.2402.
Preparation of the Crystalline Form of J-111,225 (1) A solution of
the amorphous powder (1.05 g, 2.23 mmol) in 85% EtOH/H2O (21 ml) con-
taining 5 M aqueous HCl (538 ml) was seeded at room temperature, and the
mixture was stirred for 1 h at 0 °C. The resulting crystalline solid was col-
lected by filtration, washed successively with 85% EtOH/H2O and acetone,
and dried to give 1 as dihydrochloride (1.04 g, 91.9%). [a]D20 ϩ9.0° (cϭ1.0,
H2O); IR (KBr) nmax 3373, 1751, 1587, 1392, 1086 cmϪ1 1H-NMR
;
(500 MHz, D2O, as monohydrochloride) d: 1.02 (3H, d, Jϭ7.3 Hz), 1.08
(3H, d, Jϭ6.4 Hz), 2.33 (1H, dd, Jϭ14.0, 6.7 Hz), 2.52 (3H, s), 2.57 (1H,
m), 3.17 (1H, dq, Jϭ9.1, 7.3 Hz), 3.27 (2H, m), 3.70 (1H, dd, Jϭ12.8,
5.8 Hz), 4.04 (5H, m), 4.88 (1H, dd, Jϭ11.0, 6.7 Hz), 7.35 (4H, m); 13C-
NMR (125 MHz, D2O, as monohydrochloride) d: 15.4, 19.7, 31.9, 35.9,
40.7, 42.1, 51.4, 51.9, 55.6, 58.5, 61.2, 64.7, 128.1, 130.2, 131.8, 134.2,
135.2, 136.7, 167.3, 176.3; FAB-HR-MS m/z Calcd for C22H30N3O4S
(MϩH)ϩ: 432.1957, Found 432.1950; Anal. Calcd for C22H29N3O4S (2HCl
H2O: C, 50.57; H, 6.37; N, 8.04; S, 6.14; Found: C, 50.87; H, 6.45; N, 7.83;
S, 6.02.
Acknowledgements We are grateful to Mr. Dan Johnson, Merck & Co.,
Inc. for his critical reading of this manuscript.
References and Notes
1) a) Nagano R., Adachi Y., Imamura H., Yamada K., Hashizume T.,
Morishima H., Antimicrob. Agents Chemother., 43, 2497—2503
(1999); b) Nagano R., Shibata K., Adachi Y., Imamura H., Hashizume
T., Morishima H., ibid., 44, 489—495 (2000); c) Nagano R., Adachi
Y., Hashizume T., Morishima H., J. Antimicrob. Chemother., 45,
271—276 (2000); d) Shibata K., Nagano R., Hashizume T., Mor-
ishima H., ibid., 45, 379—382 (2000); e) Imamura H., Ohtake N.,
Shimizu A., Sato H., Sugimoto Y., Sakuraba S., Nagano R., Nakano
M., Abe S., Suzuki-Sato C., Nishimura I., Kojima H., Tsuchiya Y., Ya-
mada K., Hashizume T., Morishima H., Bioorg. Med. Chem., 8,
1969—1982 (2000).
2) Imamura H., Shimizu A., Sato H., Sugimoto Y., Sakuraba S., Nagano
R., Yamada K., Hashizume T., Morishima H., J. Antibiotics, 53, 314—
316 (2000).
(2R,4S)-2-[4-(N-Methylaminomethyl)phenyl]-4-mercaptopyrrolidine
3) a) Berks A. H., Tetrahedron, 52, 331—375 (1996); b) Deziel R., Endo
M., Tetrahedron Lett., 29, 61—64 (1988); c) Shih D. H., Baker F.,
Cama L., Christensen B. G., Heterocycles, 21, 29—40 (1984).
4) The yields of the coupling reaction of 2c with 3b and subsequent de-
protection were 64.3% and 43.4%, respectively.
Dihydrochloride (2a)
A solution of 9 (100 g, 215 mmol) in 10%
HCl/MeOH (1000 ml) was stirred for 1 h at reflux temperature under a nitro-
gen atmosphere. After the removal of the solvent under reduced pressure,
the residue was dissolved in EtOH (1000 ml), and the solution was stirred
for 1 h at reflux temperature under a nitrogen atmosphere. The reaction mix-
5) Dangles O., Guibe F., Balavoine G., Lavielle S., Marquet A., J. Org.

April 2001
Chem., 52, 4984—4993 (1987).
6) The yields of the coupling reaction of 2b with 3a and subsequent de-
protection were 63.6% and 34.6%, respectively.
7) Ohtake N., Okamoto O., Mitomo R., Kato Y., Yamamoto K., Haga Y.,
Fukatsu H., Nakagawa S., J. Antibiotics, 50, 598—613 (1997).
8) Imamura H., Shimizu A., Sato H., Sugimoto Y., Sakuraba S., Naka-
jima S., Abe S., Miura K., Nishimura I., Yamada K., Morishima H.,
Tetrahedron, 56, 7705—7713 (2000).
479
3.32 (2H, m), 3.80 (2H, m), 4.05 (1H, m), 4.35 (5H, m), 5.15 (6H, m),
5.52 (2H, m), 7.37 (6H m), 7.66 (2H, d, Jϭ8.8 Hz), 8.00 (2H, m), 8.22
(4H, d, Jϭ8.8 Hz); FAB-HR-MS m/z Calcd for C45H45N6O14S
(MϩH)ϩ: 925.2714, Found 925.2725. Allyl (1R,5S,6S)-2-[(3S,5R)-1-
allyloxycarbonyl-5-[4-(N-methyl-N-allyloxycarbonylaminomethyl)-
phenyl]pyrrolidin-3-ylthio]-6-[(R)-1-hydroxyethyl]-1-methy-1-car-
bapen-2-em-3-carboxylate (4c) IR (KBr) nmax 3367, 1754 cmϪ1 1H-
;
NMR (300 MHz, CDCl3) d 1.22 (3H, d, Jϭ7.2 Hz), 1.36 (3H, d,
Jϭ6.3 Hz), 2.26 (1H, m), 2.40 (1H, m), 2.87 (3H, s), 3.23 (1H, dd,
Jϭ7.1, 2.6 Hz), 3.30 (1H, m), 3.73 (2H, m), 4.03 (1H, m), 4.24 (2H,
m), 4.46 (2H s), 4.58 (1H, m), 4.64 (2H, m) 4.69 (1H m), 4.83 (1H,
dd, Jϭ13.5, 5.5 Hz), 4.93 (1H, m), 5.12 (1H, m), 5.34 (6H, m), 5.93
(3H, m), 7.17 (4H, m); FAB-HR-MS m/z Calcd for C33H42N3O8S
(MϩH)ϩ: 640.2693, Found 640.2691.
9) Spectral data were collected for 4b and 4c. p-Nitrobenzyl (1R,5S,6S)-
2-[(3S,5R)-5-[4-(N-methyl-N-p-nitrobenzyloxycarbonylaminomethyl)-
phenyl]pyrrolidin-1-p-nitrobenzyloxycarbonyl-3-ylthio]-6-[(R)-1-hy-
droxyethyl]-1-methy-1-carbapen-2-em-3-carboxylate (4b) IR (KBr)
n
max 3377, 1764, 1587 cmϪ1; 1H-NMR (300 MHz, CDCl3) d 1.16 (3H,
d, Jϭ6.7 Hz), 1.25 (3H, m), 2.28 (1H, m), 2.32 (3H, s), 2.45 (1H, m),