Stereoselective synthesis of a broad spectrum 1β-methylcarbapenem, J-114,870

Article abstract of DOI:10.1016/S0040-4020(00)00685-2

An ultra-broad spectrum carbapenem, J-114,870 (1), was synthesized from the corresponding C-2 side chain and 1β-methylcarbapenem enolphosphate. Synthesis of the C-2 side chain was accomplished by installation of the benzene part to (4R)-hydroxy-2-pyrrolidone 3, affording 2-phenylpyrrolidine 8a, and asymmetric Michael addition of chiral amine to α,β-unsaturated ester derived from 8a. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00685-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7705±7713
Stereoselective Synthesis of a Broad Spectrum
1b-Methylcarbapenem, J-114,870
*
Hideaki Imamura, Aya Shimizu, Hiroki Sato, Yuichi Sugimoto, Shunji Sakuraba,
Shigeru Nakajima, Shinnosuke Abe, Keiko Miura, Ikuko Nishimura, Koji Yamada
and Hajime Morishima
Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd., Okubo-3, Tsukuba 300-2611, Ibaraki, Japan
Received 27 June 2000; accepted 2 August 2000
AbstractÐAn ultra-broad spectrum carbapenem, J-114,870 (1), was synthesized from the corresponding C-2 side chain and 1b-methyl-
carbapenem enolphosphate. Synthesis of the C-2 side chain was accomplished by installation of the benzene part to (4R)-hydroxy-2-
pyrrolidone 3, affording 2-phenylpyrrolidine 8a, and asymmetric Michael addition of chiral amine to a,b-unsaturated ester derived from
8a. q 2000 Elsevier Science Ltd. All rights reserved.
Well-known 1b-methylcarbapenem antibiotics having a
(3S,5S)-cis-disubstituted pyrrolidine ring as the C-2 side
chain, such as meropenem,1 S-4661,2 and BO-2727,3 have
a broad antibacterial spectrum covering gram-positive and
gram-negative bacteria including Pseudomonas aeruginosa;
however, these traditional carbapenems lack activity against
methicillin-resistant Staphylococcus aureus (MRSA). In
contrast, J-114,870 (1), a novel carbapenem identi®ed by
us, shows ultra-broad antibacterial activity against MRSA
as well as P. aeruginosa, probably due to its unique (3S,5R)-
trans-disubstituted pyrrolidine ring C-2 side chain (see Fig.
1).4
As shown in Scheme 1, introduction of the aromatic portion
onto the 2-position of appropriately protected (R)-4-
hydroxy-2-pyrroridone 4 offered a more direct procedure
for constructing the 2-arylpyrrolidine ring system (a),
compared with the former method using b-alkoxy butanal
2 as a starting material.7 After formation of a,b-unsaturated
ester function (b), an optically active b-alanine amide
moiety was constructed by means of asymmetric Michael
addition of the chiral amine to afford the C-2 side chain thiol
with high diastereomeric purity.
Results and Discussion
In SAR studies,4 we constructed the (3S,5R)-trans-disub-
stituted pyrrolidine ring system of the C-2 side chain of
J-114,870 (1) and related compounds in many synthetic
steps with low overall yield, starting from the relatively
unstable b-alkoxy butanal 25 according to our previous
paper.6 In addition, we obtained the (S)-b-alanine amide
part of the C-2 side chain of 1 by chromatographic separa-
tion of the diastereomeric intermediates. Unfortunately it
was dif®cult to obtain a large amount of J-114,870 (1) by
this disadvantageous synthetic procedure. After identifying
1 as a promising candidate for further evaluation, we needed
effective procedures for the stereoselective construction of
the (3S,5R)-trans-disubstituted pyrrolidine ring and the
(S)-b-alanine amide systems of 1. Here we report a new
and practical way to synthesize J-114,870 (1).
Synthesis of 2-phenylpyrrolidine (6)
Selective silylation of a hydroxyl group of pyrrolidone 3 and
successive protection of amide nitrogen with a t-butoxy-
carbonyl (Boc) group provided a protected pyrrolidone 4
as a crystalline form in 92% yield. Grignard reagent 5
generated from 4-substituted bromobenzene was coupled
with pyrrolidone 4 at 08C, and formation of an adduct 6
was monitored by TLC. Product 6 could not be obtained
in reasonable yield after usual aqueous work up and the
following silica-gel chromatography, probably due to
Keywords: asymmetric Michael addition; 1b-methylcarbapenem;
J-114,870.
* Corresponding author. Tel.: 181-564-51-5627; fax: 181-564-51-7086;
e-mail: imamrahk@banyu.co.jp
Figure 1. Structure of J-114,870 (1).
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00685-2

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H. Imamura et al. / Tetrahedron 56 (2000) 7705±7713
Scheme 1. Synthesis of the C-2 side chain of J-114,870 (1).
decomposition via b-elimination of the silyloxy group of
6b, a linear form of the adduct 6. Therefore, the adduct
was isolated as a stable alcohol (7) by successive reduction
of 6 in the same vessel. When NaBH4 and MeOH was added
at 2108C after the completion of Grignard reaction, reduc-
tion of the ketone 6b proceeded smoothly to provide a stable
1,3-syn-alcohol 7a (51%, .99% de) possessing the desired
stereochemistry as the major isomer together with undesired
1,3-anti-alcohol 7b (17, 96% de) by separation on silica-gel
chromatography (Scheme 2). This reduction proceeded with
signi®cant diastereoselectivity (syn/antiˆca. 75/25), which
was reasonably explained by a 1,3-metal-chelated transition
state.
afforded 2,4-trans pyrrolidine 8b as an oil. Direct con-
version of 6a to the 2-aryl pyrrolidine ring system by
reductive elimination of the benzylic hydroxyl group
could not be achieved under various reaction conditions.8
Since the minor diastereomer 8b did not form crystals, a
more ef®cient and practical procedure was developed for the
isolation of 8a without column chromatographic separation.
A mixture of 7a and 7b was applied directly to pyrrolidine
formation reaction followed by acid cleavage of the acetal
protection to form crystals 8a from n-hexane solution.
Absolute con®guration of 8a was determined by X-ray
crystallographic analysis to be a (2R,4R) con®guration
(Fig. 2). Puri®cation of the ®ltrate by column chroma-
tography afforded (2S,4R)-trans isomer 8b (87% de) as an
oil. The key intermediate 8a thus obtained showed excellent
diastereomeric purity (.99% de).
Next, g-aminobutanol 7a thus obtained was cyclized to
2-aryl pyrrolidine 8a via the corresponding mesylate.
When alcohol 7a was treated with methanesulfonyl chloride
(MsCl) in the presence of triethylamine (Et3N), intramo-
lecular cyclization took place spontaneously under basic
conditions without the formation of any mesylated inter-
mediate, which could be monitored by TLC. The cyclized
product was treated with p-toluenesulfonic acid mono-
hydrate ( p-TsOH´H2O) at atmospheric temperature to afford
2,4-cis pyrrolidine 8a as a crystalline form. Similarly, 7b
Construction of the b-alanine amide structure
Of the many approaches for synthesizing chiral b-amino-
carboxylic acid derivatives, we employed asymmetric
Michael addition reported by Davies and Ichihara as a direct
and practical method to obtain the C-2 side chain of
Scheme 2. Synthesis of the key intermediate 8a.

H. Imamura et al. / Tetrahedron 56 (2000) 7705±7713
7707
Figure 2. ORTEP drawing (50% ellipsoid) of 8a.
J-114,870 (1).9 Indeed, Michael addition of a chiral amine
10a to an a,b-unsaturated ester 9 having appropriate protec-
tive groups provided the chiral center of the b-alanine amide
structure with good diastereoselectivity (Scheme 3).
ester 9a yielded an adduct 11a in moderate yield together
with a signi®cant amount of amide 12 as a by-product (total
66% conversion). Since the moderate yield might be due to
a steric hindrance of the bulky TBS group of 9a, silyl protec-
tion was removed by the action of tetrabutylammonium
¯uoride prior to the Michael reaction. A signi®cant increase
in yield was observed to afford the desired product 11b
when desilylated ester 9b was used; however, amide 12
was also formed (total 94% conversion).
Aldehyde 8a described above was converted to an a,b-
unsaturated ester 9a by conventional Horner±Emmons reac-
tion in high yield (96%). Reaction of a lithium salt of (R)-N-
(a-methylbenzyl)benzylamine 10a with the conjugated
Scheme 3. Asymmetric Michael addition.

7708
H. Imamura et al. / Tetrahedron 56 (2000) 7705±7713
Figure 3. MTPA amides for the advanced Mosher method.
To avoid the undesired formation of amide 12, more bulky
esters, iso-propyl ester 9c and tert-butyl ester 9d, were
prepared from aldehyde 8a by the same method as the
ethyl ester 9b. As expected, formation of the amide 12
was completely suppressed and the adduct 11d was
produced in an almost quantitative yield (99%) when the
most bulky ester 9d was used. This diastereoselective
Michael addition reaction has proceeded according to the
reaction mechanism which was suggested by Davies et al.,9c
in case of (S)-N-(a-methylbenzyl)benzylamine provided
C70-(R)-isomer with 96% de in high yield. Catalytic hydro-
genolysis using Pd(OH)2 on carbon (Degussa type) removed
benzyl and phenethyl residues on the nitrogen of 11d to
yield 13d in excellent yield (98%) without affecting the
other benzylic carbon±nitrogen bonds of 11d. The dia-
stereoselectivity of the present conjugated addition reaction
was measured by HPLC analysis of 13 using a CHIRAL-
CEL OD-RH (150£4.6 mm) column.
Stereochemistry of b-aminoester
Absolute con®guration of the newly formed chiral center of
11a was determined by the advanced Mosher method.10
Amides 14a and the corresponding diastereomer 14b (Fig.
3)10 were prepared from 11a and its diastereomer, respec-
tively, by the following reactions: (1) removal of the benzyl
and phenethyl groups by hydrogenolysis, (2) acylation with
(S)-(1)-a-methoxy-a-(tri¯uoromethyl)phenylacetyl (MTPA)
Table 1. 1H NMR of MTPA amides, 14a and 14b
Proton
14a
2
3
4
5
20
30
70
80
100
110
4.077
4.087
1.720
2.400
±
4.452
4.454
2.918
3.034
2.921
3.039
7.356
7.411
7.142
7.259
5.442
5.440
2.850
2.921
2.807
2.900
4.084
4.023
1.187
1.137
14b
2.403
a
Dd£1023 ppm
210
±
23
22
23
25
255
2117
22
143
121
161
150
a Overlapped with water signal.
Scheme 4. Synthesis of J-114,870 (1).

H. Imamura et al. / Tetrahedron 56 (2000) 7705±7713
7709
1
chloride, and (3) removal of Boc protection using TFA. H
NMR (Table 1)11 of the thus prepared MTPA amides indi-
cated that 11a had (S) con®guration at the C-70 position.
pyrrolidone 4. To a solution of (R)-4-hydroxy-2-pyrro-
lidone 3 (500 g, 4.95 mol) in DMF (2500 ml) were added
tert-butyldimethylchlorosilane (784 g, 5.21 mol) and imida-
zole (506 g, 7.43 mol) under a nitrogen atmosphere at 08C
and the mixture was stirred for 30 min at room temperature.
The mixture was poured into H2O and the resulting pre-
cipitate was collected by ®ltration and dried to give (R)-4-
tert-butyldimethylsiloxy-2-prrolidone (1054 g, 99%) as
white crystals. Mp 73±748C; [a]2D0ˆ9.8 (c 1.0, CHCl3); IR
(Nujol) nmax 1704, 1660 cm21; 1H NMR (300 MHz, CDCl3)
d 0.08 (6H, s), 0.89 (9H, s), 2.25 (1H, dd, Jˆ17.0, 6.8 Hz),
2.27 (1H, dd, Jˆ17.0, 4.3 Hz), 3.23 (1H, dd, Jˆ9.9,
3.5 Hz), 3.58 (1H, dd, Jˆ9.9, 6.1 Hz); 4.56 (1H, dddd,
Jˆ6.8, 6.1, 4.3, 3.5 Hz), 5.66 (1H, br s); 13C NMR
(67.5 MHz, CDCl3), d 24.9, 24.8, 17.9, 25.6, 40.4, 51.6,
67.8, 176.6; FAB-HRMS Calcd for C10H22NO2Si (M1H)1:
216.1420, Found 216.1416; Anal. Calcd for C10H21NO2Si:
C, 55.77; H, 9.83; N, 6.50, Found: C, 55.57; H, 9.87; N,
6.54.
Synthesis of J-114,870 (1)
The primary amino group of 13d was protected with a Boc
group to afford 15 as crystals (98% de), which was
converted to amide 16 through three steps: (1) alkaline
hydrolysis of the ester, (2) simultaneous mesylation of the
resulting carboxylic acid and sec-hydroxyl group by MsCl-
triethylamine and (3) chemo-selective ammonolysis of the
mixed anhydride generated in situ. The mesyloxy group of
16 was displaced with AcSK in DMF to afford a thioaceate
17 (62% yield from 15, .99% de). Removal of the Boc
protecting group of 17 by HCl/EtOAc and the subsequent
treatment with allyloxycarbonyl (Alloc) chloride afforded
18 in a good yield (92%).
Hydrolysis of thioaceate 18 by sodium hydroxide in metha-
nol formed a thiol compound that was coupled with
1b-methylcarbapenem diphenylphosphate 1911 in the
presence of diisopropylethylamine to provide the adduct
20 in 82% yield. Deprotection of 20 by the method of
Guibe et al.12 and puri®cation of the resulting residue on
reversed phase column chromatography yielded J-114,870
(1) in 75% yield (.99% de) (see Scheme 4).
To a solution of (R)-4-tert-butyldimethylsiloxy-2-pyrro-
lidone (1054 g, 4.90 mol) in CH3CN (1000 ml) were
added consecutively 4-dimethylaminopyridine (340 g,
2.78 mol), triethylamine (298 g, 2.94 mol) and Boc2O
(1123 g, 5.14 mol) under a nitrogen atmosphere at 08C.
The reaction mixture was stirred for overnight at room
temperature and then poured into H2O. The whole was
extracted with EtOAc and the organic layer was washed
successively with 1 M aqueous HCl, 1 M aqueous NaOH
and brine, dried over MgSO4, and concentrated under
reduced pressure. The resulting precipitate was washed
with hexane and dried to give 4 (1423 g, 92.1%) as white
crystals. Mp 108±1098C; [a]2D0ˆ26.8 (c 1.0, CHCl3); IR
In summary, J-114,870 (1) was synthesized in 18 steps with
9% overall yield using (4R)-hydroxy-2-pyrrolidone 3 as a
starting material. The aromatic portion of the C-2 side chain
was installed directly on the pyrrolidone 4 by simple opera-
tions including the addition of the Grignard reagent and
cyclization to afford optically active 2-phenylpyrrolidine
8a. Stereoselective construction of the b-alanine amide
structure was successfully achieved by means of asym-
metric Michael reaction of the chiral amine with conjugated
ester 9d derived from 8a.
1
(Nujol) nmax 1766 cm21; H NMR (300 MHz, CDCl3) d
0.08 (6H, s), 0.88 (9H, s), 1.53 (9H, s), 2.45 (1H, dd,
Jˆ17.3, 3.4 Hz), 2.72 (1H, dd, Jˆ17.3, 6.3 Hz), 3.62 (1H,
dd, Jˆ11.2, 3.0 Hz), 3.86 (1H, dd, Jˆ11.2, 5.3 Hz), 4.56
(1H, dddd, Jˆ6.3, 5.3, 3.4, 3.0 Hz); 13C NMR (67.5 MHz,
CDCl3), d 24.6, 24.5, 18.2, 25.9, 28.3, 43.4, 55.7, 64.1,
83.1, 150.2, 172.4; FAB-HRMS Calcd for C15H30NO4Si
(M1H)1: 316.1944, Found 316.1927; Anal. Calcd for
C15H29NO4Si: C, 57.11; H, 9.27; N, 4.44, Found: C,
56.99; H, 9.36; N, 4.54.
Experimental
General methods
(1S,3R)-4-tert-Butoxycarbonylamino-3-tert-butyldimethyl-
siloxy-1-(4-dimethoxymethylphenyl)butanol 7a and (1R,
3R)-4-tert-butoxycarbonylamino-3-tert-butyldimethyl-
siloxy-1-(4-dimethoxymethylphenyl)butanol 7b. To a
suspension of Mg (1.7 g, 69.8 mmol) in THF (30 ml) was
added 4-bromobenzaldehyde dimethylacetal (8.1 g, 34.9
mmol) dropwise under a nitrogen atmosphere at room
temperature, and the mixture was stirred for 1 h at re¯ux
temperature. The reaction mixture was allowed to cool at
room temperature. To this mixture was added a solution of 4
(5.5 g, 17.4 mmol) in THF (40 ml) over 1.5 h under a nitro-
gen atmosphere at 08C. Then MeOH (35 ml) and NaBH4
(991 mg, 26.1 mmol) were immediately added to the reac-
tion mixture at 2108C. The mixture was poured into 10%
aqueous NH4Cl and the whole was extracted with EtOAc.
The organic layer was washed with brine, dried over
MgSO4, and evaporated under reduced pressure. Puri®-
cation of the residue by silica gel column chromatography
(n-hexane/EtOAcˆ5:1±4:1) gave 7a (4.21 g, 51.5%) and
Melting points were measured on a METTLER FP62
melting point apparatus and were not corrected. The H
1
NMR spectra were recorded on a Varian VXR-300 spectro-
meter, Varian Gemini-300 and JEOL JNM-A500 spectro-
meter with tetramethylsilane (TMS) as an internal standard.
13C NMR spectra were recorded on a JEOL JNM-A500 and
JEOL JNM-EX270. IR absorption spectra were recorded
with a Horiba FT-200 spectrometer. Speci®c rotations
were measured with a Jasco DIP-370 polarimeter. Mass
spectra (MS) were measured on a JEOL JMS-SX102A spec-
trometer. TLC was performed with Merck Kieselgel F254
precoated plates. The silica gel used for column chroma-
tography was WAKO gel C-300. Reversed phase column
chromatography was carried out on YMC-gel ODS-AQ
120-S50. All reactions involving air-sensitive reagents
were performed under nitrogen using syringe-septum cap
techniques.
(R)-1-tert-Butoxycarbonyl-4-tert-butyldimethylsiloxy-2-

7710
H. Imamura et al. / Tetrahedron 56 (2000) 7705±7713
7b (1.37 g, 16.8%). [HPLC analysis: column, YMC-pack
Pro C18 AS-303 (250£4.6 mm); detection 220 nm; eluent,
10 mM (NH4)2HPO4/CH3CNˆ30:70; ¯ow rate, 1.2 ml/min;
tR of 7a, 17.3 min; tR of 7b, 16.0 min]. 7a: .99% de; [a]D20
211.6 (c 1.0, CHCl3); IR (Nujol) nmax 1712, 1693 cm21; 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,
Jˆ8.4 Hz), 7.42 (2H, d, Jˆ8.4 Hz); FAB-HRMS Calcd for
C24H43NO6SiNa (M1Na)1: 492.2757, Found 492.2745. 7b:
96% de; [a]2D0ˆ114.8 (c 1.0, CHCl3); IR (Nujol) nmax 1714,
X-ray crystallographic data of 8a. A colorless plate crystal
having approximate dimensions of 0.25£0.18£0.35 mm3
was mounted on a glass ®ber. All data were collected on a
Rigaku AFC7R single crystal diffractometer, using Cu Ka
Ê
radiation (lˆ1.5418 A), v ±2u scans, to a maximum 2u
value of 120.18. C22H35NO4Si, Mˆ405.61, orthorhombic,
Ê
Ê
Ê
aˆ14.745(2) A, bˆ25.978(1) A, cˆ6.272(1) A, Vˆ
Ê 3
2402.6(5) A , space group P212121 (#19), Zˆ4, Dcalcˆ
1.12 g/cm3, mˆ10.6 cm21. A total of 2109 re¯ections
were collected. All data were corrected for Lorentz and
polar factors. All calculations were performed using the
teXsan [Crystal Structure Analysis Package, Molecular
Structure Corporation (1985 and 1992)]. The structure was
solved by a direct method. All non-hydrogen atoms were
re®ned anisotropically. Hydrogen atoms were included but
not re®ned. The ®nal cycle of full-matrix least-squares
re®nement was based on 2082 observed re¯ections
[I.0.00s(I)] and 248 variable parameters and converged
(largest parameter shift was 0.00 times its esd) with
unweighted and weighted agreement factors of: Rˆ0.056
RW ˆ0.052. The maximum and minimum peaks on the
®nal difference Fourier map corresponded to 0.49 and
1
1695 cm21; H NMR (300 MHz, CDCl3) d 0.12 (6H, s),
0.92 (9H, s), 1.44 (9H, s), 1.85 (2H, m), 3.17 (1H, m),
3.32 (6H, s), 4.06 (1H, m), 4.76 (1H, m), 4.90 (1H, m),
5.34 (1H, s), 7.35 (2H, d, Jˆ8.3 Hz), 7.42 (2H, d, Jˆ
8.3 Hz); FAB-HRMS Calcd for C24H43NO6SiNa (M1
Na)1: 492.2757, Found 492.2740.
(2R,4R)-1-tert-Butoxycarbonyl-4-tert-butyldimethylsiloxy-
2-(4-formylphenyl)pyrrolidine 8a and (2S,4R)-1-tert-
butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(4-formyl-
phenyl)pyrrolidine 8b. To a mixture of 7a and 7b (13.1 g,
28.0 mmol; 7a/7bˆ75/25) in CH2Cl2 (260 ml) were added
triethylamine (8.5 g, 84.0 mmol) and methanesulfonyl
chloride (3.53 g, 30.8 mmol) under a nitrogen atmosphere
at 2608C. 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 pressure.
The residue was dissolved in THF (50 ml) and H2O (8 ml),
and was treated with p-TsOH´H2O (500 mg, 2.82 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 crystallized from n-hexane, collected by
®ltration and dried to give 8a (6.4 g, 56.3%) as colorless
plate crystals. The ®ltrate was concentrated under reduced
pressure, and the residue was puri®ed by silica gel column
chromatography (n-hexane/EtOAcˆ10:1±6:1) to give 8b
(1.9 g, 16.7%) as a colorless oil. [HPLC analysis: column,
YMC ODS-AQ AQ-303 (250£4.6 mm); detection 254 nm;
eluent, CH3CN/10 mM aqueous (NH4)2PO4ˆ80: 20; ¯ow
rate, 1.0 ml/min; tR of 8a, 14.2 min; tR of 8b, 14.8 min].
8a: .99% de; mp 102±1038C; [a]2D0ˆ149.0 (c 1.0,
Ê 3
2
20.25 e /A , respectively.
Details of the crystal structure determination at 123 K for
both form I and form II can be obtained from the Director,
Cambridge Cryatallographic Data Centre (CCDC), 12 Union
Road, Cambridge, Cambridgeshire CB2 1EZ, England. Any
request for this supplementary data should quote the full
literature citation and the reference number 135/319.
(2R,4R)-1-tert-Butoxycarbonyl-2-[4-[(E)-2-(tert-butoxy-
carbonyl)vinyl]phenyl]-4-hydroxypyrrolidine 9d. To a
solution of tert-butyl diethyl phosphonoacetate (37.3 g,
148 mmol) in THF (300 ml) was added 60% NaH (5.92 g,
148 mmol) dropwise at 08C, and the mixture was stirred for
30 min at the same temperature. A solution of 8a (50 g,
123 mmol) in THF (100 ml) was added dropwise at 08C,
and the mixture was stirred for 1 h at the same temperature.
The 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. To a solution of the residue in THF (200 ml)
was added tetra-n-butylammonium ¯uoride (1 M in THF,
123 ml, 123 mmol) at room temperature. The mixture was
poured into H2O and the whole was extracted with EtOAc.
The organic layer was washed with phosphate buffer (pH
6.0) and brine, dried over MgSO4, and evaporated under
reduced pressure. The mixture was poured into n-hexane
and the resulting precipitate was collected by ®ltration and
dried to give 9d (44.3 g, 92.2%) as white crystals. Mp 196±
1978C; [a]2D0ˆ171.8 (c 1.0, CHCl3); IR (Nujol) nmax 3401,
1
CHCl3); IR (KBr) nmax 1708, 1673, 1606 cm21; 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, Jˆ7.0 Hz), 7.78 (2H, d, Jˆ7.0 Hz), 9.96 (1H,
s); 13C NMR (125 MHz, CDCl3, major signals) d 25.2,
25.1, 17.7, 25.4, 28.0, 44.1, 55.1, 60.2, 70.1, 79.7, 126.6,
129.5, 134.9, 152.1, 154.2, 191.9; FAB-HRMS Calcd for
C22H36NO4Si (M1H)1: 406.2414, Found 406.2390; Anal.
Calcd for C22H36NO4Si: C, 65.15; H, 8.70; N, 3.45, Found:
C, 65.11; H, 8.84; N, 3.52. 8b: 87% de; [a]2D0ˆ245.0 (c 1.0,
1
1693, 1645, 1434, 1324, 987 cm21; H NMR (300 MHz,
CDCl3) d 1.23 (6H, br s), 1.44 (12H, s), 1.96 (1H, m),
2.61 (1H, m), 3.58 (1H, d, Jˆ10.3, 2.5 Hz), 3.87 (1H, m),
4.48 (1H, m), 4.89 (1H, m), 6.33 (1H, d, Jˆ16.3 Hz), 7.29
(2H, d, Jˆ8.2 Hz), 7.45 (2H, d, Jˆ8.2 Hz), 7.57 (1H, d,
Jˆ16.3 Hz); 13C NMR (67.5 MHz, CDCl3, major signals)
d 28.6, 44.3, 55.2, 60.5, 70.1, 80.3, 80.8, 120.0, 126.6,
128.4, 133.5, 143.7, 154.8, 166.9; FAB-HRMS Calcd for
C22H32NO5 (M1H)1: 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.
1
CHCl3); IR (KBr) nmax 1714, 1685, 1603 cm21; H NMR
(300 MHz, CDCl3) d 0.08 (6H, s), 0.86(9H, s), 1.12 (6H, s),
1.41 (3H, s), 1.84 (1H, m), 2.28 (1H, m), 3.60 (2H, m), 4.38
(1H, m), 4.89 (0.7H, m), 5.01 (0.3H, m), 7.34 (2H, d,
Jˆ8.3 Hz), 7.81 (2H, d, Jˆ8.3 Hz), 9.96 (1H, s); FAB-
HRMS Calcd for C22H36NO4SiNa (M1Na)1: 428.2233,
Found 428.2242.

H. Imamura et al. / Tetrahedron 56 (2000) 7705±7713
7711
(2R,4R)-1-tert-Butoxycarbonyl-4-hydroxy-2-[4-[(S)-1-
[(R)-N-benzyl-N-(a-methylbenzyl)amino]-2-tert-butoxy-
carbonylethyl]phenyl]pyrrolidine 11d. To a solution of
(41.6 g, 82.0%) as white crystals. [HPLC analysis: column,
DAICEL CHIRALPACK OD-H (250£4.6 mm); detection
230 nm; eluent, n-hexane/iso-PrOHˆ95: 5; ¯ow rate,
1.0 ml/min; tR of 15, 19.6 min; tR of corresponding 70-(R)-
isomer, 22.9 min], 98% de; mp 171±1728C; [a]2D0ˆ118.2
(c 1.0, CHCl3); IR (Nujol) nmax 3428, 3369, 1716, 1677,
(R)-N-(a-methylbenzyl)-N-benzylamine
10a
(13.6 g,
64.3 mmol) in THF (150 ml) was added n-BuLi (1.58 M
in n-hexane, 40.7 ml, 64.3 mmol) dropwise under a nitrogen
atmosphere at 08C, and the mixture was stirred for 30 min at
the same temperature. A solution of 9d (5 g, 12.9 mmol) in
THF (70 ml) was added dropwise at 2778C, and the mixture
was stirred for 1 h at the same temperature. The mixture was
poured into saturated aqueous NH4Cl and the whole was
extracted with EtOAc. The organic layer was washed with
1 M aqueous HCl, 1 M aqueous NaOH, and brine, dried
over MgSO4, and evaporated under reduced pressure. The
residue was puri®ed by silica gel column chromatography
(n-hexane/EtOAcˆ1:1±1:2) to give 11d (7.65 g, 99.2%) as
a colorless oil. [a]D20ˆ133.6 (c 1.0, CHCl3); IR (Nujol) nmax
1
1670 cm21; H NMR (300 MHz, CDCl3) d 1.18 (6H, br
s), 1.34 (9H, s), 1.41 (12H, s), 1.95 (1H, m), 2.57 (1H, m),
2.72 (2H, m), 3.54 (1H, dd, Jˆ11.9, 4.0 Hz), 3.86 (1H, br s),
4.43 (1H, m), 4.82 (1H, br s), 5.03 (1H, br s), 5.43 (1H, br s),
7.22 (4H, s); 13C NMR (67.5 MHz, CDCl3, major signals) d
27.8, 28.1, 28.2, 42.0, 43.9, 51.0, 54.6, 59.8, 69.6, 79.5,
81.0, 125.7, 126.1, 139.7, 143.7, 154.4, 154.9, 170.1;
FAB-HRMS Calcd for C27H42N2O7Na (M1Na)1:
529.2890, Found 529.2898; Anal. Calcd for C27H42N2O7:
C, 64.01; H, 8.36; N, 5.53, Found: C, 64.06; H, 8.58; N,
5.51.
3398, 1693, 1652, 1417, 1257, 723 cm21
;
1H NMR
(300 MHz, CDCl3) d 1.12 (6H, br s), 1.22 (15H, s), 1.94
(1H, m), 2.53 (3H, m), 3.54 (1H, d, Jˆ12.0, 3.8 Hz), 3.65
(2H, s), 3.88 (1H, m), 3.94 (1H, q, Jˆ6.9 Hz), 4.37 (1H, dd,
Jˆ9.2, 5.5 Hz), 4.42 (1H, m), 4.79 (1H, br s), 7.22 (14H, m);
FAB-HRMS Calcd for C37H49N2O5 (M1H)1: 601.3641,
Found 601.3618.
(2R,4R)-1-tert-Butoxycarbonyl-2-[4-[(S)-1-tert-butoxy-
carbonylamino-2-carbamoylethyl]phenyl]-4-mesyloxy-
pyrrolidine 16. To a solution of 15 (34.2 g, 67.6 mmol) in
EtOH (210 ml) and H2O (80 ml) was added 5 M aqueous
NaOH (68 ml, 338 mmol) at 08C, and the mixture was
stirred for 1 h at 1008C. After neutralization and evapora-
tion, 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 used for the next
reaction without further puri®cation. The spectrum data of
the puri®ed (2R,4R)-1-tert-butoxycarbonyl-2-[4-[(S)-1-tert-
butoxycarbonylamino-2-carboxyethyl]phenyl]-4-hydroxy-
pyrrolidine is shown below. [HPLC analysis: column,
DAICEL CHIRALPACK OD-RH (150£4.6 mm); detection
230 nm; eluent, CH3CN/0.5 M aqueous NaClO4 10.5 M
aqueous HClO4 (pH 2.0)ˆ275:725; ¯ow rate, 0.2 ml/min;
tR of title compound, 40.3 min; tR of corresponding 70-(R)-
isomer, 44.8 min], 98% de; [a]2D0ˆ112.6 (c 1.0, MeOH); IR
(2R,4R)-2-[4-[(S)-1-Amino-2-tert-butoxycarbonylethyl]-
phenyl]-1-tert-butoxycarbonyl-4-hydroxypyrrolidine
acetic acid 13d. To a solution of 11d (6.75 g, 11.2 mmol) in
MeOH (160 ml) were added acetic acid (771 ml,
13.4 mmol) and palladium hydroxide on carbon (Degussa
type, 1.6 g) and the resultant suspension was stirred with
3.5 atm of hydrogen at room temperature for 20 h. After
®ltration and evaporation, the resulting precipitate was
washed with n-hexane and dried to afford 13d (5.14 g,
98.0%) as white crystals. [HPLC analysis: column,
DAICEL CHIRALPACK OD-RH (150£4.6 mm); detection
230 nm; eluent, CH3CN/0.5 M aqueous NaClO4 10.5 M
aqueous HClO4 (pH 2.0)ˆ30:70; ¯ow rate, 0.2 ml/min; tR
of corresponding 70-(R)-isomer, 30.3 min; tR of 13d,
33.6 min], 94% de; mp 131±1338C; [a]2D0ˆ157.8 (c 1.0,
MeOH); IR (Nujol) nmax 3392, 1720, 1627, 1556, 1178,
(Nujol) nmax 1727, 1695, 1687, 1662 cm21 1H NMR
;
(300 MHz, CDCl3) d 1.13 (6H, br s), 1.42 (12H, br s),
1.96 (1H, m), 2.53 (1H, m), 2.84 (2H, m), 3.54 (1H,m),
3.80 (1H, m), 4.40 (1H, m), 4.74 (1H, br s), 5.03 (1H, m),
5.53 (1H, br s), 7.22 (4H, s); FAB-HRMS Calcd for
C23H34N2O7Na (M1Na)1: 473.2264, Found 473.2273.
1
659 cm21; H NMR (300 MHz, CD3OD) d 1.14 (6H, br
s), 1.39 (12H, s), 1.82 (1H, m), 1.91 (3H, s), 2.59 (1H, m),
2.78 (1H, dd, Jˆ15.7, 7.4 Hz), 2.86 (1H, dd, Jˆ15.7,
7.2 Hz), 3.42 (1H, m), 3.83 (1H, dd, Jˆ12.5, 6.5 Hz), 4.38
(1H, m), 4.49 (1H, m), 7.36 (4H, br s); 13C NMR (67.5 MHz,
CD3OD, major signals) d 24.3, 29.0, 29.3, 42.2, 45.7, 53.7,
56.4, 62.4, 70.7, 81.8, 83.6, 128.5, 128.9, 138.0, 148.1,
157.0, 171.5, 180.1; FAB-HRMS Calcd for C22H35N2O5
(M1H)1: 407.2586, Found 407.2569; Anal. Calcd for
C22H34N2O5´CH3COOH: C, 61.78; H, 8.21; N, 6.00,
Found: C, 61.90; H, 8.40; N, 5.91.
To a solution of the above in THF (600 ml) were added
triethylamine (47 ml, 338 mmol) and methanesulfonyl
chloride (15.7 ml, 203 mmol) under a nitrogen atomsphere
at 2208C. The mixture was stirred for 20 min at the same
temperature and 28% aqueous NH3 was added dropwise.
After evaporation, the reaction mixture was poured into
H2O and the whole was extracted with EtOAc. The organic
layer was washed with 3 M aqueous NaOH and brine, dried
over MgSO4, and evaporated under reduced pressure. The
residue was dissolved in EtOH/H2O and the resulting pre-
cipitate was collected by ®ltration to afford 16 (26.7 g,
75.0%) as a crystalline solid. [HPLC analysis: column,
DAICEL CHIRALPACK OD-RH (150£4.6 mm); detection
230 nm; eluent, CH3CN/0.5 M aqueous NaClO4 10.5 M
aqueous HClO4 (pH 2.0)ˆ65:35; ¯ow rate, 0.2 ml/min; tR
of 16, 26.0 min; tR of corresponding 70-(R)-isomer, 29.0
min], .99% de; mp 97±998C; [a]2D0ˆ112.8 (c 1.0,
CHCl3); IR (Nujol) nmax 3218, 1708, 1699, 1687, 1652,
(2R,4R)-1-tert-Butoxycarbonyl-2-[4-[(S)-1-tert-butoxy-
carbonylamino-2-tert-butoxycarbonylethyl]phenyl]-4-
hydroxypyrrolidine 15. To a solution of 13d (46.8 g,
100 mmol) in 1,4-dioxane (350 ml) and H2O (150 ml) was
added (Boc)2O (24 g, 110 mmol) maintained at pH 10 using
5 M aqueous NaOH at room temperature. 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 crystallized from n-hexane/EtOAc to give 15
1
912 cm21; H NMR (300 MHz, CDCl3) d 1.12 (6H, br s),

7712
H. Imamura et al. / Tetrahedron 56 (2000) 7705±7713
1.38 (12H, s), 2.34 (1H, m), 2.67 (3H, m), 2.69 (3H, br s),
3.83 (1H,m), 3.92 (1H, br s), 4.96 (1H, m), 5.23 (1H, br s),
5.29 (1H, br s), 5.98 (1H, br s), 7.19 (2H, d, Jˆ8.4 Hz), 7.24
(2H, d, Jˆ8.4 Hz); 13C NMR (67.5 MHz, CDCl3, major
signals) d 28.7, 38.8, 40.9, 42.1, 51.8, 53.3, 59.6, 69.3,
80.0, 80.7, 126.1, 126.5, 138.6, 140.8, 154.5, 155.8, 167.0,
173.4; FAB-HRMS Calcd for C24H37N3O8SNa (M1Na)1:
550.2199, Found 550.2195; Anal. Calcd for C24H37N3O8S´1/
2H2O: C, 53.72; H, 7.14; N, 7.83; S, 5.98, Found: C, 53.53;
H, 7.12; N, 7.53; S, 6.27.
1-allyloxycarbonylamino-2-carbamoylethyl]phenyl]-
pyrrolidin-3-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-
carbapen-2-em-3-carboxylate 20. To an ice-cooled
solution of 18 (3.6 g, 7.58 mmol) in MeOH (50 ml) was
added 1 M aqueous NaOH (8.4 ml, 8.4 mmol) under a nitro-
gen atmosphere. After being stirred for 30 min at the same
temperature, the reaction mixture was adjusted to pH 7.0
with 1 M aqueous HCl and concentrated under reduced
pressure. The 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. To a stirred solution of the residue in
CH3CN (20 ml), allyl (1R,5S,6S)-2-diphenylphosphoryl-
oxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-
carboxylate 19 (3.79 g, 7.58 mmol) and diisopropylethyl-
amine (1.58 ml, 9.1 mmol) in CH3CN (80 ml) were added
dropwise at 08C. After being stirred overnight at 48C under a
nitrogen atmosphere, the 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 puri®ed by silica gel
column chromatography (acetone) to give 20 as a foam
(4.23 g, 82.0%). [HPLC analysis: column, DAICEL CHIR-
ALPACK AD (250£4.6 mm2); detection 290 nm; eluent,
n-hexane/EtOHˆ60:40; ¯ow rate, 1.0 ml/min; tR of 20,
14.2 min; tR of corresponding 120-(R)-isomer, 11.0 min],
.99% de; [a]2D0ˆ169.4 (c 1.0, CHCl3); IR (Nujol) nmax
(2R,4S)-4-Acetylthio-1-tert-butoxycarbonyl-2-[4-[(S)-1-
tert-butoxycarbonylamino-2-carbamoylethyl]phenyl]
pyrrolidine 17. To a solution of 16 (26.7 g, 50.6 mmol) in
DMF (900 ml) was added potassium thioacetate (17.3 g,
152 mmol) under a nitrogen atmosphere at room tempera-
ture, and the mixture was stirred for 10 h at 558C. 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
pressure. The residue was dissolved in acetone/H2O and
the resulting precipitate was collected by ®ltration to afford
17 (21.2 g, 82.6%) as a crystalline solid. [HPLC analysis:
column, DAICEL CHIRALPACK OD (250£4.6 mm2);
detection 230 nm; eluent, n-hexane/iso-PrOHˆ80:20; ¯ow
rate, 0.5 ml/min; tR of corresponding 70-(R)-isomer,
18.8 min; tR of 17, 20.9 min], .99% de; mp 187±1898C;
[a]2D0ˆ113.6 (c 1.0, CHCl3); IR (Nujol) nmax 3222, 1702,
1699, 1687, 1650 cm21; 1H NMR (300 MHz, CDCl3) d 1.18
(6H, br s), 1.43 (12H, s), 2.22 (1H, m), 2.33 (3H, s), 2.36
(1H, m), 2.74 (2H, br s), 3.51 (1H,m), 4.01 (2H, m), 4.99
(1H, m), 5.28 (1H, br s), 5.69 (1H, br s), 5.87 (1H, br s), 7.14
(2H, d, Jˆ8.2 Hz), 7.26 (2H, d, Jˆ8.2 Hz); 13C NMR
(67.5 MHz, CDCl3, major signals) d 28.7, 30.9, 36.8,
39.8, 42.1, 51.8, 53.1, 60.6, 79.9, 80.1, 125.9, 126.0,
126.5, 126.8, 143.1, 154.5, 155.8, 162.9, 173.5, 195.5;
FAB-HRMS Calcd for C25H37N3O6SNa (M1Na)1:
1
3340, 1780, 1668, 1645, 1147, 971, 721 cm21; H NMR
(300 MHz, CDCl3) d 1.18 (3H, d, Jˆ7.0 Hz), 1.33 (3H, d,
Jˆ6.3 Hz), 1 79 (1H, m), 2.24 (1H, m), 2.46 (1H, m), 2.68
(2H, m), 3.22 (1H, dd, Jˆ7.2, 2.4 Hz), 3.30 (1H, m), 3.72
(2H, m), 4.03 (1H, m), 4.22 (2H, m), 4.42 (1H, m), 4.53 (2H,
m), 4.67 (1H, dd, Jˆ12.1, 4.2 Hz), 4.83 (1H, dd, Jˆ13.5,
5.4 Hz), 5.18 (5H, m), 5.43 (2H, m), 5.90 (3H, m), 6.43 (1H,
m), 7.21 (1H, d, Jˆ7.6 Hz), 7.25 (1H, d, Jˆ7.6 Hz); FAB-
HRMS Calcd for C34H42N4O9SNa (M1Na)1: 705.2570,
Found 705.2569.
530.2301,
Found
530.2293;
Anal.
Calcd
for
C25H37N3O6S´1/2H2O: C, 58.12; H, 7.41; N, 8.13; S, 6.21,
Found: C, 58.35; H, 7.55; N, 8.33; S, 6.02.
(1R,5S,6S)-2-[(3S,5R)-5-[4-[(S)-1-Amino-2-carbamoyl-
ethyl]phenyl]pyrrolidin-3-ylthio]-6-[(R)-1-hydroxy-
ethyl]-1-methyl-1-carbapen-2-em-3-carboxylic
acid
(2R,4S)-4-Acetylthio-1-allyloxycarbonyl-2-[4-[(S)-1-allyl-
oxycarbonylamino-2-carbamoylethyl]phenyl] pyrroli-
dine 18. To a solution of 17 (1.0 g, 1.97 mmol) in EtOAc
(10 ml) was added 4 M HCl/EtOAc (20 ml), and the mixture
was stirred for 6 h at room temperature. After evaporation,
to the suspension of the residue in CH2Cl2 (40 ml) were
added triethylamine (2.75 ml, 19.7 mmol) and allyl chloro-
formate (627 ml, 5.91 mmol) at 2108C. 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 puri®ed by silica gel column chromatography
(EtOAc/acetoneˆ8:1) to give 18 (863 mg, 92.1%) as a
foam. [a]2D5ˆ19.6 (c 1.0, CHCl3); IR (Nujol) nmax 1687,
1648, 1263 cm21; 1H NMR (300 MHz, CDCl3) d 2.26 (1H,
m), 2.33 (3H, s), 2.72 (2H, br s), 3.59 (1H,m), 4.03 (2H, m),
4.46 (1H, m), 4.54 (2H, s), 5.03 (3H, m), 5.26 (4H, m), 5.68
(1H, br s), 5.90 (1H, m), 6.28 (1H, br s), 7.16 (2H, d,
Jˆ8.3 Hz), 7.29 (2H, d, Jˆ8.3 Hz); FAB-HRMS Calcd
for C23H30N3O6S (M1H)1: 476.1855, Found 476.1876.
hydrochloride 1 (J-114,870). To an ice-cooled solution
of 20 (35 g, 51.1 mmol) in CH2Cl2 (1400 ml) were succes-
sively added H2O (11.2 ml), bis(triphenylphosphine)palla-
dium(II) dichloride (2.17 g, 3.08 mmol) and tributyltin
hydride (67.0 g, 230 mmol) under a nitrogen atmosphere.
After being stirred for 15 min at the same temperature, the
reaction mixture was poured into H2O. The separated
aqueous layer was washed with CH2Cl2 and concentrated
under reduced pressure to ca. 1700 ml. After removal of the
insoluble matter by ®ltration, the concentrated aqueous
layer was subjected to reversed phase column chroma-
tography. The eluent was monitored by HPLC and the
fraction eluted with 5±10% CH3CN/H2O were combined
and adjusted to pH 5.8 with 1 M aqueous HCl. The
combined fractions were concentrated under reduced
pressure and lyophilized to give 1 (19.6 g, 74.5%). [HPLC
analysis: column, YMC ProC18 AS-303 (250£4.6 mm2);
detection 220 nm; eluent, 20 mM NaH2PO4/MeOHˆ99:1±
90:10 (5 min, gradient mode)±90:10 (10 min, isocratic
mode)±50:50 (30 min, gradient mode); ¯ow rate, 1.0 ml/
min; tR of 1, 15.5 min; tR of corresponding 120-(R)-isomer,
16.8 min]; .99% de; [a]2D0ˆ11.2 (c 1.0, H2O); IR (KBr)
Allyl (1R,5S,6S)-2-[(3S,5R)-1-allyloxycarbonyl-5-[4-[(S)-

H. Imamura et al. / Tetrahedron 56 (2000) 7705±7713
7713
nmax 1751, 1672, 1585, 1388, 1259, 1147, 773, 665 cm21
;
1H NMR (500 MHz, D2O) d 1.04 (3H, d, Jˆ7.0 Hz), 1.08
(3H, d, Jˆ6.4 Hz), 2.36 (1H, dd, Jˆ14.0, 7.0 Hz), 2.61 (1H,
m), 2.81 (1H, dd, Jˆ15.6, 7.3 Hz), 2.88 (1H, dd, Jˆ15.6,
7.3), 3.18 (1H, dq, Jˆ8.8, 7.0 Hz), 3.28 (1H, dd, Jˆ5.8,
2.8 Hz), 3.31 (1H, br d, Jˆ12.8 Hz), 3.72 (1H, dd, Jˆ
12.8, 5.8 Hz), 4.05 (3H, m), 4.59 (1H, t, Jˆ7.3 Hz), 4.92
(1H, dd, Jˆ11.0, 7.0 Hz), 7.36 (4H, m); 13C NMR
(125 MHz, D2O) d 15.3, 19.7, 35.7, 37.8, 40.7, 42.0, 51.2,
51.8, 55.6, 58.5, 61.2, 64.7, 127.6, 128.2, 134.3, 134.7,
136.3, 136.5, 167.3, 173.3, 176.3; FAB-HRMS Calcd for
C23H31N4O5S (M1H)1: 475.2015, Found 475.2011; Anal.
Calcd for C22H30N4O5S´HCl´2H2O: C, 50.50; H, 6.45; N,
10.24; S, 5.86, Found: C, 50.61; H, 6.55; N, 10.32; S, 5.60.
Acknowledgements
We are grateful to Ms Anne Dobbins, Merck & Co. Inc. for
her critical reading of this manuscript.
References
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(2R,4R)-4-tert-Butyldimethylsiloxy-2-[4-[(S)-1-[(R)-
(a-methoxy-a-tri¯uoromethyl)benzyl-carbonylamino]-
2-ethoxycarbonylethyl]phenyl]pyrrolidine 14a and
(2R,4R)-4-tert-butyldimethyl-siloxy-2-[4-[(S)-1-[(S)-(a-
methoxy-a-tri¯uoromethyl)benzylcarbonylamino]-2-
4. (a) Imamura, H.; Ohtake, N.; Shimizu, A.; Jona, H.; Sato, H.;
Nagano, R.; Ushijima, R.; Yamada, K.; Hashizume, T.;
Morishima, H. Bioorg. Med. Chem. Lett. 2000, 10, 109±113.
(b) Imamura, H.; Ohtake, N.; Shimizu, A.; Sato, H.; Sugimoto,
Y.; Sakuraba, S.; Kiyonaga, H.; Suzuki-Sato, C.; Nakano, M.;
Nagano, R.; Yamada, K.; Hashizume, T.; Morishima, H. Bioorg.
Med. Chem. Lett. 2000, 10, 115±118. (c) Nagano, R.; Shibata, K.;
Adachi, Y.; Imamura, H.; Hashizume, T.; Morishima, H. Anti-
microb. Agents Chemother. 2000, 44, 489±495. (d) Shibata, K.;
Nagano, R.; Hashizume, T.; Morishima, H. J. Antimicrob.
Chemother. 2000, 45, 379±382.
ethoxycarbonylethyl]phenyl]pyrrolidine 14b. To
a
solution of 11a (431 mg, 0.63 mmol) in EtOH (10 ml) was
added Pd(OH)2 (Degussa type, 200 mg), and the mixture
was stirred for 36 h under a hydrogen atmosphere. The
catalyst was ®ltered off and washed with EtOH. The ®ltrate
and washings were combined and concentrated under
reduced pressure. To a solution of the residue in THF
(15 ml) were added triethylamine (127 mg, 1.26 mmol)
and
(S)-(1)-a-methoxy-a-(tri¯uoromethyl)phenylacetyl
chloride (192 mg, 0.76 mmol) at 08C, and the mixture was
stirred for overnight at room temperature. The 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. To a
solution of the residue in CH2Cl2 (6 ml) was added TFA
(0.5 ml) at 08C, and the mixture was further stirred for 1 h
at the same temperature. The 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 puri®ed by silica
gel column chromatography (CHCl3/MeOHˆ20:1±10:1) to
give 14a (176 mg, 46.0%) as a colorless oil. Similarly, the
corresponding 70-(R) isomer (178 mg, 0.26 mmol) obtained
by using (S)-N-(a-methylbenzyl)-N-benzylamine afforded
5. Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.;
Nomizu, S.; Moriwake, T. Chem. Lett. 1984, 1389, 1392.
6. Imamura, H.; Ohtake, N.; Sakuraba, S.; Shimizu, A.; Yamada,
K.; Morishima, H. Chem. Pharm. Bull. 2000, 48, 310±311.
7. Imamura, H.; Shimizu, A.; Sato, H.; Sugimoto, Y.; Sakuraba,
S.; Nagano, R.; Yamada, K.; Hashizume, T.; Morishima, H.
J. Antibiotics 2000, 53, 314±316.
8. (a) Yoda, H.; Nakajima, T.; Takabe, K. Tetrahedron Lett. 1996,
37, 5531±5534. (b) Yoda, H.; Yamazaki, H.; Kawauchi, M.;
Takabe, K. Tetrahedron: Asymmetry 1995, 6, 2669±2672.
(c) Yoda, H.; Yamazaki, H.; Takabe, K. Tetrahedron: Asymmetry
1996, 7, 373±374.
9. (a) Davis, S. G.; Ichihara, O.; Walters, A. S. Synlett 1993, 461±
462. (b) Davis, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991,
2, 183±186. (c) Costello, J. F.; Davis, S. G.; Ichihara, O.
Tetrahedron: Asymmetry 1994, 5, 1999±2008.
14b (74.4 mg, 47.0%) as
a
colorless oil. 14a:
[a]2D0ˆ219.2 (c 1.0, CHCl3); IR (Neat) nmax 3413, 3340,
1731, 1693, 1506, 1095, 1020, 837, 756 cm21; H NMR
1
10. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092±4096.
(500 MHz, CDCl3) data are shown in Table 1; FAB-
HRMS Calcd for C31H44N2O5F3Si (M1H)1: 609.2972,
Found 609.2943; 14b: [a]2D0ˆ128.0 (c 1.0, CHCl3); IR
(Neat) nmax 3412, 3333, 1736, 1695, 1498, 1096, 1020,
11. (a) Berks, A. H. Tetrahedron 1996, 52, 331±375. (b) Deziel,
R.; Endo, M. Tetrahedron Lett. 1988, 29, 61±64. (c) Shih, D. H.;
Baker, F.; Cama, L.; Christensen, B. G. Heterocycles 1984, 21,
29±40.
837, 756 cm21 1H NMR (500 MHz, CDCl3) data was
;
12. Dangles, O.; Guibe, F.; Balavoine, G.; Lavielle, S.;
Marquet, A. J. Org. Chem. 1987, 52, 4984±4993.
showed in Table 1; FAB-HRMS Calcd for C31H44N2O5F3Si
(M1H)1: 609.2972, Found 609.2980.