Synthesis of the side chain of a novel carbapenem via iodine-mediated oxidative cyclization of (1R)-N-(1-aryl-3-butenyl)acetamide.

Article abstract of DOI:10.1248/cpb.50.423

A (2R,4S)-trans-disubstituted pyrrolidine ring system was constructed by employing iodine-mediated oxidative cyclization of (1R)-N-[1-(4-bromophenyl)-3-butenyl]acetamide 3 as a key step. The resulting diastereomeric mixture of (2R)-2-aryl-4-acetoxypyrroli

Full text of DOI:10.1248/cpb.50.423

March 2002
Notes
Chem. Pharm. Bull. 50(3) 423—425 (2002)
423
Synthesis of the Side Chain of a Novel Carbapenem via Iodine-Mediated
Oxidative Cyclization of (1R)-N-(1-Aryl-3-butenyl)acetamide
Takashi HASHIHAYATA,* Hiroki SAKOH, Yasuhiro GOTO, Koji YAMADA, and Hajime MORISHIMA
Banyu Tsukuba Research Institute, Okubo-3, Tsukuba, Ibaraki 300–2611, Japan.
Received October 3, 2001; accepted December 19, 2001
A (2R,4S)-trans-disubstituted pyrrolidine ring system was constructed by employing iodine-mediated oxida-
tive cyclization of (1R)-N-[1-(4-bromophenyl)-3-butenyl]acetamide 3 as a key step. The resulting diastereomeric
mixture of (2R)-2-aryl-4-acetoxypyrrolidine 4 was stereoselectively converted to the side-chain of a novel ultra-
broad-spectrum carbapenem 1, via (2R,4R)-2-aryl-4-hydroxypyrrolidine 7.
Key words 1b-methylcarbapenem; homoallylamine; I2-mediated oxidative cyclization
Results and Discussion
We synthesized a novel 1b-methyl carbapenem 1 and re-
ported that 1 had an unusual ultra-broad antimicrobial spec-
trum that covered clinically important strains including
MRSA and P. aeruginosa.1) In the initial approach to the
stereoselective preparation of 4-mercapto-2-arylpyrrolidine
9, a side-chain of 1, we used D-malic acid as a starting mater-
ial which was converted to the desired 2,4-disubstituted
pyrrolidine system with moderate overall yield via addition
reaction of aryl metal reagent with the relatively unstable bu-
tanal intermediate.2) We subsequently employed rather ex-
pensive (R)-4-hydroxy-2-pyrrolidone as a starting material.
Although satisfactory selectivity was not obtained to form
the 2-position, further improvements in the process for con-
structing 2,4-disubstituted pyrrolidine system was developed
with shortened steps and increased overall yield (Chart 1).3)
In this procedure, a phenyl group was introduced to a pro-
tected (R)-4-hydroxy-2-pyrrolidone 2 by using aryl-Grignard
reagent. Under the basic conditions of Grignard reaction, b-
alkoxy carbonyl system of pyrrolidone 2 and adduct were
likely to form a,b-unsaturated side products (over 10%). In
order to avoid such side reactions, we investigated the con-
struction of a 2-aryl-4-hydroxy pyrrolidine ring system from
a benzene derivative having an appropriate carbon chain cor-
responding to the pyrrolidine ring.
Homoallylamine is a useful building block of more com-
plex molecules including 3-hydroxypyrrolidine derivative.
Taddei and co-workers converted homoallylamine to 3-hy-
droxypyrrolidine via 3,4-epoxybutylamine and subsequent
cyclization under alkaline conditions with moderate yield.4)
We applied this procedure to 1-(4-bromophenyl)-3,4-epoxy-
butylamine; however, 2-aryl-4-hydroxypyrrolidine could not
be obtained in an acceptable yield. Takano et al. described an
efficient method for the stereoselective conversion of ho-
moallylamine to the chiral 2-substituted 4-hydroxypyrroli-
dine system by benzoylation and subsequent oxidation of the
resulting benzamide with iodide in an aqueous-organic sol-
vent.5) We have found that a 2-aryl-4-hydroxypyrrolidine sys-
tem could be obtained from the homoallylamine acetamide
derivative 3 by the application of this procedure.
Efficient methods for preparing chiral homoallylamine
have been developed by several groups.6) According to the
report by Brown and co-workers,6a) chiral homoallylamine,
In this paper, we describe oxidative cyclization of the chi-
ral homoallyl acetamide 3, and subsequent stereoselective
conversion to the side-chain of 1.
Fig. 1. Structure of 1
Chart 1. Synthesis of 1 from Pyrrolidone 2
To whom correspondence should be addressed. e-mail: hshytatk@banyu.co.jp
© 2002 Pharmaceutical Society of Japan

424
Vol. 50, No. 3
Chart 2. Preparation of the Side-Chain
(1R)-1-(4-bromophenyl)-3-butenylamine, was prepared and as an internal standard. The 13C-NMR spectra were recorded on a JEOL
JNM-EX-270. IR absorption spectra were recorded on a Horiba FT-200
subsequently treated with acetic anhydride and triethylamine
spectrometer. Specific rotations were measured on a Jasco DIP-370 po-
to afford acetamide 3 with an acceptable yield (77%) and
larimeter. Mass spectra (MS) were measured on a JEOL JMS-SX102A spec-
enantiomeric excess (86% ee). Recrystallization of 3 in-
creased its optical purity (62%, Ͼ99% ee).
trometer. The silica-gel TLC was performed with Merck Kieselgel F254 pre-
coated plates. The silica gel used for column chromatography was WAKO
gel C-300. All reactions involving air-sensitive reagents were performed
under nitrogen atmosphere using syringe-septum cap techniques.
Oxidative cyclization of homoallylamine acetamide 3 took
place smoothly by the action of 3 equivalents of iodine in
THF–H2O (4 : 1) at room temperature. Under these condi-
tions, acetamide 3 was transformed to 4-acetoxy pyrrolidine
which was isolated after introduction of a tert-butoxycar-
bonyl (Boc) group, affording N-protected pyrrolidine 4 as a
diastereomeric mixture [(2R,4R)/(2R,4S)ϭ1/2]. Subsequent
alkaline hydrolysis of 4 gave 4-hydroxy pyrrolidine 5.
Swern oxidation of 4-hydroxy pyrrolidine 5 furnished a 4-
oxopyrrolidine 6 at a yield of 93%, and subsequent reduction
of 6 by NaBH4 provided the desired cis-(2R,4R)-2-aryl-4-hy-
droxypyrrolidine 7 in good yield (88%) with high diastereos-
electivity (97% de).7) Then, tert-butyl acrylate was intro-
duced to bromobenzene 7 by a conventional Heck reaction.8)
(1R)-N-[1-(4-bromophenyl)-3-butenyl]acetamide 3 A solution of 4-
bromobenzaldimine was obtained as follows: To a solution of 4-bromoben-
zaldehyde (1.00 g, 5.40 mmol) in THF (6 ml) was added lithium
bis(trimetylsilyl)amide (1 M in THF, 5.68 ml, 5.68 mmol) at 0 °C, and the
mixture was stirred for 15 h at the same temperature. To a solution of
Ipc2BCH2CHϭCH2 in THF, prepared from (ϩ)-DIP-ChlorideTM (1.91 g,
5.95 mmol), allylmagnesium chloride (2 M in THF, 2.97 ml, 5.95 mmol) and
THF (5.4 ml), were added 4-bromobenzaldimine solution and water (107 ml,
5.95 mmol) in THF (0.54 ml) at Ϫ78 °C. The reaction mixture was stirred
for 1 h at the same temperature, and then allowed to turn to room tempera-
ture. To a solution of aqueous NaOH (1 M, 6.48 ml, 6.48 mmol) and hydro-
gen peroxide (30% in H2O, 1.47 g, 13.0 mmol) was added the reaction mix-
ture at the same temperature, and the whole was poured into aqueous hy-
drochloride. After neutralization by K2CO3, the whole was extracted with
Et2O. The organic layer was washed with brine, dried over MgSO4, and
The resulting a,b-unsaturated ester 8 was converted to the evaporated under reduced pressure to afford (1R)-1-phenyl-3-butenylamine
which was used for the next reaction without further purification.
To a solution of the above in CHCl3 (10 ml) were added triethylamine
(934 ml, 6.71 mmol) and acetic anhydride (506 ml, 5.36 mmol) at 0 °C. The
mixture was stirred for 30 min at the same temperature and poured into
side-chain 9 according to the procedure reported by our labo-
latory.3)
Conclusion
4% aqueous NaHCO3 and extracted with CHCl3. The organic layer was
washed with brine, dried over MgSO4, and evaporated under reduced pres-
sure. The residue was purified on silica gel column chromatography (n-
hexane/EtOAcϭ4/6) to give 3 (1.12 g, 77%, 86% ee) as a colorless solid.
Subsequent recrystallization from CHCl3–n-hexane afforded 3 (894 mg,
62%, Ͼ99% ee) as a colorless solid. The enantiomeric purity of 3 was deter-
mined by HPLC analysis [column, Daicel Chiralcel OJ (4.6fϫ250 mm);
eluent, n-hexane : iso-PrOHϭ95 : 5; flow rate, 1.0 ml/min; detection, UV
250 nm; tR, (1R)-isomer (3); 21.0 min, (1S)-isomer; 26.8 min]. mp 161—
162 °C; [a]D20 ϩ116.8 (cϭ1.0, CHCl3); IR (KBr) nmax 3292, 1653, 1541,
A convenient method for the synthesis of a side-chain of 1
was developed via oxidative cyclization of (1R)-N-[1-(4-bro-
mophenyl)-3-butenyl]acetamide 3. The resulting 2,4-disub-
stituted pyrrolidine 5 was successfully converted to the side-
chain of 1 via stereoselective reduction of 4-oxopyrrolidine 6
to introduce a (4R)-carbinol center and using the Heck reac-
tion to install an acrylate unit.
1
Experimental
1371, 1009, 820 cmϪ1; H-NMR (300 MHz, CDCl3) d 2.65 (2H, dd, Jϭ7.0,
General Methods Melting points were measured on a BUCHI B-545 7.0 Hz), 5.18 (2H, m), 5.74 (1H, m), 6.42 (1H, d, Jϭ7.3 Hz), 7.21 (3H, m),
1
melting point apparatus and were not corrected. The H-NMR spectra were 7.45 (4H, m), 7.75 (2H, d, Jϭ6.9 Hz) FAB-HR-MS Calcd for C12H15BrNO
recorded on a Varian VXR-300 spectrometer with tetramethylsilane (TMS) (MϩH)ϩ: 268.0337, Found 268.0344.

March 2002
425
tert-Butyl (2R)-2-(4-bromophenyl)-4-hydroxypyrrolidinecarboxylate 5
To a solution of 3 (Ͼ99% ee, 1.00 g, 3.73 mmol) in THF–H2O (4 : 1, 10 ml)
was added iodine (2.84 g, 11.2 mmol) at room temperature. The mixture was
stirred for 7.5 h at the same temperature and poured into the mixture of satu-
rated aqueous NaHCO3 and saturated aqueous Na2S2O3. The organic layer
was washed with brine, dried over Na2SO4, and evaporated under reduced
pressure to give (2R)-2-(4-bromophenyl)pyrrolidin-4-yl acetate (1.87 g),
which was used for the next reaction without further purification.
To a solution of (2R)-2-(4-bromophenyl)pyrrolidin-4-yl acetate obtained
above (1.81 g) in 1,4-dioxane–H2O (1 : 1, 30 ml) was added Boc2O (867 mg,
3.97 mmol) at pHϭ9, which was maintained using 1 M aqueous NaOH at
room temperature. The reaction mixture was poured into the mixture of
EtOAc and water. The organic layer was washed with brine, dried over
Na2SO4, and evaporated under reduced pressure to give tert-butyl (2R)-2-(4-
bromophenyl)-4-acetoxypyrrolidinecarboxylate 4 (1.66 g), which was used
for the next reaction without further purification.
eluent, n-hexane : iso-PrOHϭ95 : 5; flow rate, 1.0 ml/min; detection, UV
250 nm; tR, (2R,4S)-isomer; 8.1 min, (2S,4R)-isomer; 10.3 min, (2S,4S)-iso-
mer; 12.1 min, and (2R,4R)-isomer (7); 17.1 min]. mp 164—165 °C; [a]D20
ϩ62.2 (cϭ1.0, CHCl3); IR (KBr) nmax 3365, 2978, 1662, 1419, 1126, 1084,
771 cmϪ1 1H-NMR (300 MHz, CDCl3) d: 1.22, 1.43 (each 9H, br s), 1.94
;
(1H, ddd, Jϭ4.3, 4.3, 13.3 Hz), 2.57 (1H, ddd, Jϭ5.4, 8.5, 13.3 Hz), 3.55
(1H, dd, Jϭ3.7, 11.7 Hz), 3.83 (1H, br s), 4.47 (1H, m), 4.80 (1H, m), 7.16
(2H, d, Jϭ8.4 Hz), 7.43 (2H, d, Jϭ8.4 Hz); FAB-HR-MS Calcd for
C15H20BrNO3Na (MϩNa)ϩ: 364.0524, Found 364.0521.
(2R,4R)-1-tert-Butoxycarbonyl-2-[4-[(E)-2-(tert-butoxycarbonyl)-
vinyl]phenyl]-4-hydroxypyrrolidine
8 To a solution of 7 (150 mg,
0.44 mmol) in CH3CN (5 ml) were added Pd(OAc)2 (5.00 mg, 0.0022 mmol),
tris(2-methylphenyl)phosphine (27.0 mg, 0.089 mmol), triethylamine (0.18
ml, 0.13 mmol), and tert-butyl acrylate (160 mg, 0.89 mmol) at room tem-
perature. The mixture was stirred at refluxed temperature for 6 h and poured
into the mixture of aqueous NH4Cl and EtOAc. The organic layer was dried
over MgSO4 and evaporated under reduced pressure. The residue was puri-
fied on silica gel column chromatography (n-hexane/EtOAcϭ1 : 1) to give 8
(155 mg, 91%) as a colorless solid. mp 196—197 °C; [a]D20 ϩ71.8 (cϭ1.0,
CHCl3); IR (Nujol) nmax 3401, 1693, 1645, 1434, 1324, 987 cmϪ1; 1H-NMR
(300 MHz, CDCl3) d: 1.23 (6H, br s), 1.44 (12H, s), 1.94 (1H, m), 2.61 (1H,
m), 3.58 (1H, dd, Jϭ2.5, 10.3 Hz), 3.87 (1H, m), 4.48 (1H, m), 4.89 (1H,
m), 6.33 (1H, d, Jϭ16.3 Hz), 7.29 (2H, d, Jϭ8.2 Hz), 7.45 (2H, d,
Jϭ8.2 Hz), 7.57 (1H, d, Jϭ16.3 Hz); 13C-NMR (67.5 MHz, CDCl3, major
signals) d: 28.6, 44.3, 55.2, 60.5, 70.1, 80.3, 120.0, 126.6, 128.4, 133.5,
143.7, 154.8, 166.9; FAB-HR-MS Calcd for C22H32NO5 (MϩH)ϩ: 390.2280,
Found 390.2277; Anal. Calcd for C22H31NO5: C, 67.84; H, 8.02; N, 3.60,
Found: C, 67.83; H, 8.21; N, 3.53.
To a solution of 4 (1.60 g) obtained above in MeOH (10 ml) was added
aqueous NaOH (1 M, 2.66 ml, 2.66 mmol) at 0 °C. The mixture was stirred
for 1 h at the same temperature. The reaction mixture was neutralized
by aqueous HCl and poured into EtOAc. The organic layer was washed
with brine, dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified on silica gel column chromatography (n-
hexane/EtOAcϭ1/1) to give 5 (978 mg, 82%) as a colorless solid. mp 132—
133 °C; IR (KBr) nmax 3425, 2976, 1682, 1423, 1162, 1084, 1009, 770 cmϪ1
;
1H-NMR (300 MHz, CDCl3) d: 2.00 (3H, s), 2.65 (2H, dd, Jϭ6.9, 6.9 Hz),
5.07 (3H, m), 5.66 (2H, m), 7.15 (2H, d, Jϭ6.5 Hz), 7.45 (2H, d, Jϭ6.5 Hz);
FAB-HR-MS Calcd for C15H20BrNO3Na (MϩNa)ϩ: 364.0524, Found
364.0531.
tert-Butyl (2R)-2-(4-bromophenyl)-4-oxopyrrolidinecarboxylate 6 To
a solution of (COCl)2 (861 mg, 6.78 mmol) in CH2Cl2 (14 ml) was added
DMSO (1.13 ml, 13.6 mmol) at Ϫ78 °C, and the solution was stirred for
10 min at the same temperature. The solution of 5 (909 mg, 2.26 mmol) in
CH2Cl2 (8 ml) was added to the reaction mixture over 5 min, and the reaction
mixture was stirred at the same temperature for 15 min and then at Ϫ50 °C
for 30 min. The solution was treated with triethylamine (3.33 ml, 20.3 mmol)
at the same temperature, and was allowed to warm to room temperature over
30 min. The reaction mixture was poured into the mixture of CHCl3 and sat-
urated aqueous NH4Cl. The organic layer was washed with brine, dried over
MgSO4, and evaporated under reduced pressure. The residue was purified on
silica gel column chromatography (n-hexane/EtOAcϭ3/1) to give 6 (843 mg,
93%) as a pale yellow solid. mp 93—94 °C; [a]D20 ϩ5.2 (cϭ1.0, CHCl3); IR
Acknowledgment We are grateful to Ms. Kimberley Marcopul and Mr.
Dan Johnson, Merck & Co., Inc., for their critical readings of this manu-
script.
References and Notes
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S., Nagano R., Nakano M., Abe S., Suzuki-Sato C., Nishimura I., Ko-
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shima H., Chem. Pharm. Bull., 48, 310—311 (2000).
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jima S., Abe S., Miura K., Nishimura I., Yamada K., Morishima H.,
Tetrahedron, 56, 7705—7713 (2000).
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1355—1358 (1993).
5) a) Takano S., Iwabuchi Y., Ogasawara K., J. Chem. Soc., Chem. Com-
mun., 1988, 1527—1528; b) Idem, Heterocycles, 29, 1861—1864
(1989).
6) a) Chen G. M., Ramachandran P. V., Brown H. C., Angew. Chem. Int.
Ed., 38, 825—826 (1999); b) Wu M. J., Pridgen L. N., Synlett, 1990,
636—637; c) Basile T., Bocoum A., Savoia D., Umani-Ronchi A., J.
Org. Chem., 59, 7766—7773 (1994).
7) Hanna P. E., J. Heterocycl. Chem., 1973, 747—753.
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(1981).
1
(KBr) nmax 2978, 1753, 1687, 1406, 1161, 1012, 824, 509 cmϪ1; H-NMR
(300 MHz, CDCl3) d: 1.38 (9H, br s), 2.53 (1H, dd, Jϭ2.8, 18.4 Hz), 3.13
(1H, dd, Jϭ10.1, 18.4 Hz), 3.87 (1H, d, Jϭ19.4 Hz), 4.08 (1H, d,
Jϭ19.4 Hz), 5.32 (1H, br s), 7.07 (2H, d, Jϭ8.4 Hz), 7.47 (2H, d, Jϭ8.4 Hz);
FAB-HR-MS Calcd for C15H18BrNO3Na (MϩNa)ϩ: 362.0368, Found
362.0369.
tert-Butyl (2R,4R)-2-(4-bromophenyl)-4-hydroxypyrrolidinecarboxyl-
ate 7 To a solution of 6 (165 mg, 4.85 mmol) in EtOH (3 ml) was added
NaBH4 (87.0 mg, 2.43 mmol) over 3 min at 0 °C. The mixture was stirred for
10 min at the same temperature and poured into the mixture of aqueous
NH4Cl and CHCl3. The organic layer was washed with brine, dried over
MgSO4, and evaporated under reduced pressure. The residue was purified on
silica gel column chromatography (n-hexane/EtOAcϭ6/4) to give 7 (146 mg,
88%) as a colorless solid. The enantiomeric purity of 7 (97% de) was deter-
mined by HPLC analysis [column, Daicel Chiralcel OJ (4.6fϫ250 mm);