Diastereoselective synthesis of (2R,4R)-2-aryl-4-hydroxypyrrolidine: Preparation of the side chain of novel carbapenem

Article abstract of DOI:10.1248/cpb.49.1500

Improved synthesis of the trans-3,5-disubstituted pyrrolidin-3-ylthio side-chain of the novel carbapenem 1 was achieved via stereoselective reduction of the 1-aryl-1-butanone derivative 5 and successive intramolecular cyclization of the resulting chiral alcohol 6. The 1-aryl-1-butanone derivative 5 was obtained by a coupling reaction of protected 4-hydroxy-2-pyrrolidone with aryl-Grignard reagent.

Full text of DOI:10.1248/cpb.49.1500

1500
Notes
Chem. Pharm. Bull. 49(11) 1500—1502 (2001)
Vol. 49, No. 11
Diastereoselective Synthesis of (2R,4R)-2-Aryl-4-hydroxypyrrolidine:
Preparation of the Side Chain of Novel Carbapenem
Takashi HASHIHAYATA,* Hiroki SAKOH, Yasuhiro GOTO, Masaaki HIROSE, Shunji SAKURABA,
Hideaki IMAMURA, Yuichi SUGIMOTO, Koji YAMADA, and Hajime MORISHIMA
Banyu Tsukuba Research Institute, Okubo-3, Tsukuba, Ibaraki 300–2611, Japan.
Received July 24, 2001; accepted August 29, 2001
Improved synthesis of the trans-3,5-disubstituted pyrrolidin-3-ylthio side-chain of the novel carbapenem 1
was achieved via stereoselective reduction of the 1-aryl-1-butanone derivative 5 and successive intramolecular cy-
clization of the resulting chiral alcohol 6. The 1-aryl-1-butanone derivative 5 was obtained by a coupling reaction
of protected 4-hydroxy-2-pyrrolidone with aryl-Grignard reagent.
Key words diastereoselective reduction; 1-aryl-1-butanone; 1b-methylcarbapenem
Our recent report demonstrated that 1 is a novel 1b- Results and Discussion
methylcarbapenem with good safety profiles and an unusual
According to our reported procedure, the addition reaction
ultra-broad antimicrobial spectrum covering clinically impor- of protected (R)-4-hydroxy-2-pyrrolidone 3 and aryl-Grig-
tant strains such as methicillin-resistant Staphylococcus au- nard reagent 4 was carried out to form 1-aryl-1-butanone 5
reus (MRSA) and Pseudomonas aeruginosa.1) We also re- and its cyclic aminal form 5Ј, which was converted to (1S)-
ported the synthesis of 1 by employing two procedures for butanol 6 with moderate selectivity by an in situ reduction
the construction of the trans-3,5-disubstituted pyrrolidin-3- with NaBH4. The selectivity of such an in situ reduction
ylthio side-chain.2) One of these procedures employed (R)-4- could not be improved despite using several reducing agents.
hydroxy-2-pyrrolidone as the starting material and provided In order to investigate diastereoselective reduction, the ke-
hundreds of grams of 12a); however, the step that introduced a tone 5 was isolated by treating aminal 5Ј with sodium hy-
chiral center at C-2 of the trans-2,4-disubstituted pyrrolidine droxide for complete conversion to the ketone 5 and by sub-
ring proceeded with moderate selectivity, producing poor sequent silica gel chromatography.
overall yield (Chart 1). In this report, we describe the im-
The reduction of isolated 5 with NaBH4 proceeded with
proved method of constructing the trans-2,4-disubstituted similar diastereoselectivity (46% de) compared with the ‘in
pyrrolidine system via stereoselective reduction of 1-aryl-1- situ’ reduction described in our previous paper. Improved se-
butanone 5 formed by a coupling reaction of the protected 4- lectivities were observed when trialkylborohydrides were
hydroxy-2-pyrrolidone 3 with aryl-Grinard reagent 4.
used (Table 1). The reduction of 5 with lithium triethylboro-
hydride (Super-Hydride®) and lithium 9-borobicyclo[3.3.1]-
Chart 1
* To whom correspondence should be addressed. e-mail: hshytatk@banyu.co.jp
© 2001 Pharmaceutical Society of Japan

November 2001
1501
Table. 1. Diastereoselective Reduction of Ketone 5
presence of 20 mol% of 10 at 20 °C resulted in excellent se-
lectivity (97% de) and good yield (95%) (entry 2).4)
Intramolecular cyclization of the carbinol 6 produced the
2,4-disubstituted pyrrolidine 7 via the corresponding mesy-
late, which was formed by methanesulfonyl chloride (MsCl)
in the presence of Et3N. After removing dimethylacetal with
p-toluenesulfonic acid (TsOH) in aqueous tetrahydrofuran
(THF), the product was crystallized, resulting in the 2,4-di-
substituted pyrrolidine 7 with increased purity (Ͼ99% de),
which was converted to the side-chain thiol 8 as in our previ-
ous report.2a)
Reductant
5
6
Solvent
6
Temperature
(°C)
Entry
Reductant
Solvent
% de
(yield: %)
1
2
3
4
NaBH4
LS-Selectride
Super-Hydride
MeOH
THF
THF
Ϫ40
Ϫ70
Ϫ70
Ϫ70
46 (90)
60 (49)a)
78 (95)
80 (99)
Lithium 9-BBN hydride THF
a) 46% of 5 was recovered.
Conclusion
Diastereoselective reduction of the ketone 5 with Super-
Hydride® or lithium 9-BBN hydride provided increased se-
lectivity (78—80% de) compared with the NaBH4 reduction
(46% de). Further improvement of the selectivity was
achieved by diastereoselective reduction of 5 using chiral b-
diketonato cobalt(II) complex 9 or chiral oxazaborolidine 10
(up to 97% de). Intramolecular cyclization of the resulting
chiral alcohol 6 yielded the 2,4-disubstituted pyrrolidine 7,
the purity of which was increased to Ͼ99% de by crystalliza-
tion.
Table. 2. Diastereoselective Reduction of Ketone 5 Using Chiral b-Keto-
nato Cobalt(II) Complex 9
Temperature
(°C)
6
Entry
Catalyst (mol%) Coreductanta)
% de (yield: %)
Experimental
1
2
3
4
1
2
2
2
A
A
A
B
Ϫ60
Ϫ60
Ϫ20
Ϫ20
84 (95)
82 (91)
86 (95)
82 (96)
General Methods Melting points were measured on a METTLER FP62
melting point apparatus and were not corrected. The H-NMR spectra were
1
recorded on a Varian VXR-300 spectrometer with tetramethylsilane (TMS)
as an internal standard. The 13C-NMR spectra were recorded on a JOEL
JNM-A500. IR absorption spectra were recorded on a Horiba FT-200 spec-
trometer. Specific rotations were measured on a Jasco DIP-370 polarimeter.
Mass spectra (MS) were measured on a JEOL JMS-SX102A spectrometer.
Silica gel TLC was performed with Merck Kieselgel F254 precoated plates,
and the silica gel used for column chromatography was WAKO gel C-300.
a) Preparation of coreductant A: NaBH4/EtOH/THFAϭ1/3/14, rt, 20 min. B: NaBH4/
EtOH/THFAϭ1/1/14, 0 °C, 3 h.
Table. 3. Diastereoselective Reduction of Ketone 5 Using Chiral Oxaz- All reactions involving air-sensitive reagents were performed under a nitro-
aborolidine 10
gen atmosphere using syringe-septum cap techniques.
(3R)-4-tert-Butoxycarbonylamino-3-tert-butyldimethylsiloxy-1-(4-
dimethoxymethylphenyl)butanone 5 The solution of 4-bromobenzalde-
hyde dimethylacetal (5.50 g, 26.2 mmol) in THF (10 ml) was added dropwise
to a mixture of Mg turning (636 mg, 26.2 mmol) in THF (20 ml) under a ni-
trogen atmosphere maintained over 70 °C. After the addition was complete,
the reaction mixture was allowed to cool at room temperature. Formed Grig-
nard reagent was added to a solution of (R)-4-tert-butyldimethylsiloxy-1-
tert-butoxycarbonyl-2-pyrrolidone 3 (2.63 g, 8.34 mmol) in THF (30 ml)
under a nitrogen atmosphere at Ϫ30 °C. After being stirred for 30 min at the
same temperature, the mixture was poured into saturated aqueous NH4Cl,
and the whole was extracted with EtOAc. To the organic layer (200 ml) was
added 1 N aqueous NaOH (45 ml) at room temperature, and the mixture was
stirred for 1.5 h at the same temperature. The organic layer was separated
and washed with brine, dried over MgSO4, and evaporated under reduced
pressure. The residue was purified by silica gel column chromatography (n-
hexane/EtOAc/Et3Nϭ90/10/0.1—80/20/0.1) to yield 5 (2.80 g, 72%) as a
colorless oil. [a]D20 ϩ31.2 (cϭ1.0, CHCl3); IR (KBr) nmax 3701, 2956, 1699,
Temperature
(°C)
6
Entry
Catalyst (mol%)
Time (h)
% de (yield: %)
1
2
3
10
20
20
20
20
0
2
0.3
19
76 (96)
97 (95)
95 (95)
nonane (9-BBN) hydride resulted in acceptable selectivities
with 78% de and 80% de, respectively, while the use of
lithium trisiamylborohydride (LS-Selectride®) resulted in
moderate selectivity (60% de).
Subsequently, diastereoselective reductions of ketone 5
by chiral reducing agents were carried out. The combination
of the commercially available b-diketonato cobalt(II) com-
plex derived from (1S,2S)-(Ϫ)-1,2-diphenylethylenediamine,
NaBH4, EtOH, and tetrahydrofurfuryl alcohol (THFA) re-
duced 5 smoothly to produce 6 (Table 2).3) Acceptable selec-
tivity (86% de) and good yield (95%) were obtained by using
2 mol% of Co(II) complex 9 at Ϫ20 °C (entry 3).
1511, 1101, 1054, 835, 777 cmϪ1 1H-NMR (300 MHz, CDCl3) d Ϫ0.05
;
(3H, s), 0.08 (3H, s), 0.81 (9H, s), 1.42 (9H, s), 3.14 (2H, m), 3.32 (6H, s),
4.46 (1H, m), 4.80 (1H, br s), 5.44 (1H, s), 7.54 (2H, d, Jϭ8.3 Hz), 7.95 (2H,
d, Jϭ8.3 Hz); FAB-high resolution (HR)-MS m/z Calcd for C24H41NO6SiNa
(MϩNa)ϩ: 490.2601, Found 490.2604.
(1S,3R)-4-tert-Butoxycarbonylamino-3-tert-butyldimethylsiloxy-1-(4-
dimethoxymethylphenyl)butanol 6. I) Reduction of 5 Using Lithium
9-BBN Hydride Lithium 9-BBN hydride (1 M in THF, 321 ml, 0.321
mmol) was added to a solution of 5 (100 mg, 0.214 mmol) in THF (2.0 ml)
under a nitrogen atmosphere at Ϫ70 °C. After being stirred for 1 h at the
same temperature, the reaction mixture was poured into saturated aqueous
NH4Cl, and the whole was extracted with EtOAc. The organic layer was
washed with brine, dried over MgSO4, and evaporated under reduced pres-
sure. NaBO3–4H2O (98.8 mg, 0.642 mmol) was added to the suspension of
the residue in THF–H2O (2.4 ml, 1 : 2) at room temperature, and the mixture
Chiral oxazaborolidine was also effective, and (R)-oxaza-
borolidine 10 formed the desired (S) configuration to yield 6
(Table 3). The reduction of 5 with BH3–Me2S complex in the was stirred for 18 h at the same temperature. The mixture was poured into

1502
Vol. 49, No. 11
water, 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/EtOAc/Et3Nϭ90/10/0.1—70/30/0.1) to yield 6 (100 mg, 99%, 80%
de) as a colorless oil. The enantiomeric purity of 6 was determined by HPLC
analysis [column, YMC ProC18 AS-303 (4.6fϫ250 mm); eluent, 10 mM
(NH4)2HPO4/CH3CNϭ30/70; flow rate, 1.0 ml/min; detection, UV 230 nm;
tR, (1R)-isomer; 28.6 min, (1S)-isomer (6); 30.9 min].
formylphenyl)pyrrolidine 7 Triethylamine (71.1 ml, 0.510 mmol) and
MsCl (14.5 ml, 0.187 mmol) were added to a solution of 6 (80.0 mg,
0.17 mmol, 97% de) in CH2Cl2 (1.6 ml) under a nitrogen atmosphere at
Ϫ60 °C. After being stirred for 30 min, the reaction mixture was poured into
H2O, and the whole was extracted with CH2Cl2. The organic layer was
washed with brine, dried over MgSO4, and evaporated under reduced pres-
sure. The residue was dissolved in THF (1 ml) and H2O (0.2 ml), and was
treated with p-TsOH–H2O (3.2 mg, 17 mmol) for 1 h at room temperature.
The mixture was poured into H2O, and the whole was extracted with EtOAc.
The organic layer was washed with 5% aqueous NaHCO3 and brine, dried
over MgSO4, and evaporated under reduced pressure. The residue was crys-
tallized from n-hexane, collected by filtration, and dried to yield 7 (51.0 mg,
74%, Ͼ99% de) as colorless plate crystals. The enantiomeric purity of 7 was
determined by HPLC analysis [column, YMC ODS-AQ AQ-303 (4.6fϫ
250 mm); eluent, 10 mM (NH4)2HPO4/CH3CNϭ20/80; flow rate, 1.0 ml/min;
detection, UV 254 nm; tR, (2R)-isomer (7); 14.2 min, (2S)-isomer; 14.8 min].
Mp 102—103 °C; [a]D20 ϩ49.0 (cϭ1.0, CHCl3); IR (KBr) lmax 1708, 1673,
II) Reduction of 5 Using b-Diketonato Cobalt(II) Complex 9 as a
Catalyst EtOH (97.6 ml, 1.67 mmol) and tetrahydrofurfuryl alcohol (757
ml, 7.81 mmol) were added to a mixture of NaBH4 (21.1 mg, 0.558 mmol) in
CHCl3 (10 ml) under a nitrogen atmosphere at room temperature, and the
mixture was stirred for 20 min at the same temperature. The resulting mix-
ture and (1S,2S)-N,NЈ-bis[3-oxo-2-(2,4,6-trimethylbenzoyl)butylidene]-1,2-
diphenylethylenediaminato cobalt(II) (2.9 mg, 4.16 mmol) were added to the
solution of 5 (120 mg, 0.257 mmol) in CHCl3 (4.0 ml) under a nitrogen at-
mosphere at Ϫ20 °C. After being stirred for 1.5 h at the same temperature,
the reaction mixture was poured into saturated aqueous NH4Cl, 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/EtOAc/Et3Nϭ
90/10/0.1—70/30/0.1) to yield 6 (115 mg, 95%, 86% de) as a colorless oil.
III) Reduction of 5 Using Oxazaborolidine 10 BH3–Me2S (2 M in
THF, 214 ml, 0.428 mmol) was added to a solution of (R)-5,5-diphenyl-2-
methyl-3,4-propano-1,3,2-oxazaborolidine (11.9 mg, 42.8 mmol) in THF
(1.0 ml) under a nitrogen atmosphere at 20 °C, and the mixture was stirred
for 15 min at the same temperature. A solution of 5 (100 mg, 0.214 mmol) in
THF (1.0 ml) was added to the mixture under a nitrogen atmosphere at
20 °C. After being stirred for 20 min at the same temperature, the reaction
mixture was poured into the solution MeOH–brine, and the whole was ex-
tracted with EtOAc. The organic layer was washed with brine, dried over
MgSO4, and evaporated under reduced pressure. NaBO3–4H2O (98.8 mg,
0.642 mmol) was added to the suspension of the residue in THF–H2O
(2.4 ml, 1 : 2) at room temperature, and the mixture was stirred for 18 h at
the same temperature. The mixture was poured into water, 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 puri-
fied by silica gel column chromatography (n-hexane/EtOAc/Et3Nϭ90/10/
0.1—70/30/0.1) to yield 6 (95.7 mg, 95%, 97% de) as a colorless oil. [a]D20
1
1606 cmϪ1; H-NMR (300 MHz, CDCl3) d 0.03 (6H, s), 0.72 (9H, s), 1.18
(6H, s), 1.43 (3H, s), 1.88 (1H, m), 2.48 (1H, m), 3.43 (1H, m), 3.80 (1H,
m), 4.40 (1H, m), 4.79 (0.34H, m), 4.81 (0.66H, m), 7.40 (2H, d, Jϭ7.0 Hz),
7.78 (2H, d, Jϭ7.0 Hz); 13C-NMR (125 MHz, CDCl3, major signals) d Ϫ5.2,
Ϫ5.1, 17.7, 25.4, 28.0, 44.1, 55.1, 60.2, 70.1, 79.7, 126.6, 129.5, 134.9,
152.1, 191.9; FAB-HR-MS m/z Calcd for C22H36NO4Si (MϩH)ϩ: 406.2414,
Found 406.2390; Anal. Calcd for C22H35NO4Si: C, 65.15; H, 8.70; N, 3.45,
Found: C, 65.11; H, 8.84; N, 3.52.
Acknowledgments We are grateful to Ms Jocelyn Winward, Merck &
Co., Inc. for her critical reading of this manuscript.
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Ϫ15.2 (cϭ1.0, CHCl3); IR (Nujol) nmax 1712, 1693 cmϪ1 1H-NMR (300
;
MHz, CDCl3) d 0.11 (6H, s), 0.91 (9H, s), 1.44 (9H, s), 1.84 (2H, m), 3.21
(1H, m), 3.31 (6H, s), 4.08 (1H, m), 4.80 (1H, m), 4.91 (1H, m), 5.37 (1H,
s), 7.35 (2H, d, Jϭ8.4 Hz), 7.42 (2H, d, Jϭ8.4 Hz); FAB-HR-MS m/z Calcd
for C24H43NO6SiNa (MϩNa)ϩ: 492.2757, Found 492.2745.
(2R,4R)-1-tert-Butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(4-