Practical synthesis of (R)-4-mercaptopyrrolidine-2-thione from L- aspartic acid. Preparation of a novel orally active 1-β-methylcarbapenem, TA-949

Article abstract of DOI:10.1021/jo991461+

A facile and economical synthesis of a novel orally active 1-β- methylcarbapenem, TA-949 (1), is described. The key process involves an efficient synthesis of the C-2 side chain (R)-4-mercaptopyrrolidine-2-thione 2 from L-aspartic acid and the construction of the 1-β-methylcarbapenem skeleton. The mercapto group of 2 with an R-configuration was formed via deaminative bromination of the amino group of L-aspartic acid β-methyl ester hydrochloride 12 followed by a complete S(N)2-type substitution with potassium benzenemethanethiolate. High-yield amination and cyclization of the chloride 15 to the pyrrolidin-2-one 16 was accomplished by a simple treatment with ammonia. Thiation of 16 and the Birch reduction of the resultant thiolactam 18 provided the C-2 side chain 2 in high yield with the asymmetric center retained as such. The side chain 2 was installed into the 1-β- methylcarbapenem skeleton either by coupling with the vinyl phosphate 5 or by the use of the counterattack strategy involving the Dieckmann-type cyclization of the thioester 8. Removal of the protective groups of the coupling product 6 followed by esterification provided TA-949 (1) in high yield.

Full text of DOI:10.1021/jo991461+

J . Org. Chem. 2000, 65, 517-522
517
P r a ctica l Syn th esis of (R)-4-Mer ca p top yr r olid in e-2-th ion e fr om
L-Asp a r tic Acid . P r ep a r a tion of a Novel Or a lly Active
1-â-Meth ylca r ba p en em , TA-949
Masahiko Seki,*,† Takeshi Yamanaka,‡ and Kazuhiko Kondo*,†
Product & Technology Development Laboratory and Discovery Research Laboratory,
Tanabe Seiyaku Co., Ltd., 3-16-89 Kashima, Yodogawa-ku, Osaka 532-8505, J apan
Received September 15, 1999
A facile and economical synthesis of a novel orally active 1-â-methylcarbapenem, TA-949 (1), is
described. The key process involves an efficient synthesis of the C-2 side chain (R)-4-mercapto-
pyrrolidine-2-thione 2 from L-aspartic acid and the construction of the 1-â-methylcarbapenem
skeleton. The mercapto group of 2 with an R-configuration was formed via deaminative bromination
of the amino group of L-aspartic acid â-methyl ester hydrochloride 12 followed by a complete SN2-
type substitution with potassium benzenemethanethiolate. High-yield amination and cyclization
of the chloride 15 to the pyrrolidin-2-one 16 was accomplished by a simple treatment with ammonia.
Thiation of 16 and the Birch reduction of the resultant thiolactam 18 provided the C-2 side chain
2 in high yield with the asymmetric center retained as such. The side chain 2 was installed into
the 1-â-methylcarbapenem skeleton either by coupling with the vinyl phosphate 5 or by the use of
the counterattack strategy involving the Dieckmann-type cyclization of the thioester 8. Removal
of the protective groups of the coupling product 6 followed by esterification provided TA-949 (1) in
high yield.
In tr od u ction
Resu lts a n d Discu ssion
The retrosynthetic analysis shown in Scheme 1 indi-
cates that TA-949 (1) is accessible by coupling the C-2
side chain 2 with a vinyl phosphate, 5, followed by
deprotection and esterification. The vinyl phosphate 5 is
derived from the acetoxyazetidinone 34 by the use of our
procedure utilizing the benzoxazinone derivative 4.5 The
counterattack method6 involving the Dieckmann-type
cyclization of the thioester 8 offers an attractive replace-
ment for the preparation of the carbapenem intermediate
6. The azetidinone propionic acid 7, readily available from
the acetoxyazetidinone 3 by coupling with the benzox-
azinone derivative 4,5 serves as the precursor for the
thioester 8.
Syn th esis of th e C-2 Sid e Ch a in 2. Known proce-
dures2b utilizing (S)-4-hydroxypyrrolidin-2-one 97 were
applied in our initial approach to the C-2 side chain 2
(Scheme 2). The yield of the Mitsunobu reaction of 9 with
thioacetic acid was, however, moderate because of pos-
sible side reactions initiated by the E2-type elimination
of the hydroxyl group at the 4-position. A more economi-
cal two-step procedure involving the SN2-type reaction
of potassium thioacetate with the mesylate 11 also gave
an unsatisfactory result.2b The synthesis of 2 from 9 is
The antibiotic 1-â-methylcarbapenems have been the
subject of much investigation because of their chemical
and metabolic stabilities as well as potent and broad
antibacterial activities.1 Although many candidates are
currently under clinical trials and some have already
been launched, orally active counterparts are of great
rarity2 and still in keen demand.
Our extensive efforts toward an orally active 1-â-
methylcarbapenem resulted in the discovery of a promis-
ing candidate, TA-949 (1), which carries an (R)-pyrrolidine-
2-thion-4-ylthio group at the C-2 position and an
isobutyryloxymethyl ester.3 For further investigation and
development, an efficient and economical synthetic method
of TA-949 (1) was required. In this paper, we detail a
novel and practical synthesis of the C-2 side chain 2 and
a preparation of TA-949 (1).
(3) (a) Iwasaki, T.; Kondo, K.; Horikawa, H.; Yamaguchi, T.;
Matsushita, T. U.S. Patent 5153187, Oct 6, 1992. (b) Seki, M.; Kondo,
K.; Iwasaki, T. 13th French-J apanese Symposium on Medicinal and
Fine Chemistry, Hayama, J apan, May 25-28, 1998; Abstract P-12.
(4) (a) Seki, M.; Miyake, T.; Yamanaka, T.; Ohmizu, H. Synlett 1996,
455. (b) Seki, M.; Yamanaka, T.; Miyake, T.; Ohmizu, H. Tetrahedron
Lett. 1996, 37, 5565. (c) Seki, M.; Furutani, T.; Miyake, T.; Yamanaka,
T.; Ohmizu, H. Tetrahedron: Asymmetry 1996, 7, 1241.
† Product & Technology Development Laboratory.
‡ Discovery Research Laboratory.
(1) For example see: (a) Shih, D. H.; Baker, F.; Cama, L.; Chris-
tensen, B. G. Heterocycles 1984, 21, 29. (b) Sunagawa, M.; Matsumura,
H.; Inoue, T.; Fukasawa, M.; Kato, M. J . Antibiot. 1990, 43, 519. (c)
Petersen,.P. J .; J acobus, N. V.; Weise, W. J ; Testa, R. T. Antimicrob.
Agents Chemother. 1991, 35, 203.
(5) (a) Kondo, K,; Seki, M.: Kuroda, T.; Yamanaka, T.; Iwasaki, T.
J . Org. Chem. 1995, 60, 1096. (b) Kondo, K,; Seki, M.: Kuroda, T.;
Yamanaka, T.; Iwasaki, T. J . Org. Chem. 1997, 62, 2877.
(2) (a) Rossi, T.; Biondi, S.; Contini, S.; Thomas, R. J .; Marchioro,
C. J . Am. Chem. Soc. 1995, 117, 9604. (b) Miyauchi, M.; Endo, R.;
Hisaoka, M.; Yasuda, H.; Kawamoto, I. J . Antibiot. 1997, 50, 429.
(6) (a) Seki, M.; Kondo, K.; Iwasaki, T. Synlett 1995, 315. (b) Seki,
M.; Kondo, K.; Iwasaki, T. J . Chem. Soc., Perkin Trans. 1 1996, 2851.
(7) Seki, M.; Kondo, K. Synthesis 1999, 745.
10.1021/jo991461+ CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/07/2000

518 J . Org. Chem., Vol. 65, No. 2, 2000
Seki et al.
Sch em e 1
Sch em e 3
with R-configuration was designed to form by deamina-
tive bromination of the amino group of L-aspartic acid
â-methyl ester hydrochloride 12 followed by the SN2-type
substitution with benzenemethanethiol. The pyrrolidin-
2-one ring would be constructed by amination of the
chloride 15 with ammonia followed by spontaneous
cyclization. Thiation of the pyrrolidin-2-one 16 and
cleavage of the benzyl protective group would afford 2.
The preparation of the chiral bromide 13 was ac-
complished in quantitative yield by diazotization of
L-aspartic acid â-methyl ester hydrochloride 12 in the
presence of potassium bromide (Scheme 4).10 The reaction
proceeds with complete retention of the configuration to
give the (S)-bromide 13 stereoselectively.10
Sch em e 4a
thus unsuitable for the practical large-scale preparation.
Chemoenzymatic synthesis of (R)-4-mercapto-2-pyrroli-
din-2-one has recently been reported.8 The key step
involves pig-liver esterase catalyzed asymmetric hydroly-
sis of achiral 3-mercaptoglutaric acid derivative. How-
ever, the method is not completely satisfactory because
the selectivity of the enzyme reaction is not complete and
the starting material is expensive.
Sch em e 2
a
Key: (a) NaNO2, NaBr, H2SO4; (b) BnSK, EtOH; (c) BH3‚SMe2;
(d) SOCl2, pyridine; (e) NH3, MeOH; (f) P2S5; (g) Na-NH3.
Introduction of a thiol group to the bromide 13 with
inversion of the configuration was our next subject for
investigation. Although the cesium salt of thiobenzoic
acid has successfully been employed for the SN2-type
thiolation of R-bromocarboxylic acids,11 potassium ben-
zenemethanethiolate was chosen in the present study
because of the intermediates’ stability for the subsequent
(9) For reviews on the utilization of aspartic acid in drug synthesis
see: (a) Matsumoto, K.; Seki, M. J . Synth. Org. Chem. J pn. 1991, 49,
26. (b) Seki, M.; Matsumoto, K. Bioindustry 1995, 12 (6), 5.
(10) Murakami, Y.; Koga, K.; Yamada, S. Chem. Pharm. Bull. 1978,
26, 307.
We envisioned a possible use of L-aspartic acid for the
synthesis of 2 (Scheme 3).9 The required mercapto group
(8) Kobayashi, S.; Kobayashi, K.; Hirai, K. Synlett 1999, 909.
(11) Strijtveen, B.; Kellog, R. M. Tetrahedron 1987, 43, 5039.

Preparation of 1-â-Methylcarbapenem TA-949
J . Org. Chem., Vol. 65, No. 2, 2000 519
Ta ble 1
Sch em e 5
entry solvent
temp (°C) period (h) ee (%)a
yield (%)b
gave the desired chiral thiol 2 in 85% yield. The optical
purity of the product 2 was confirmed to be >99.9% ee
by chiral HPLC.
1
2
3
4
THF
DMF
H2O
25
25
25
25
96
17
17
3
12
48
72
98
42
53
53
77
Con str u ction of th e Ca r ba p en em Sk eleton . The
C-2 side chain 2 was installed into the carbapenem
skeleton in two ways. The vinyl phosphate 5 prepared
in 66% yield in three steps from acetoxyazetidinone 3 by
the use of the benzoxazinone derivative 45 was allowed
to react with 2 to provide the coupling product 6 in good
yield (78%) (Scheme 6). The compound 6 was readily
isolated by crystallization.
EtOH
a
b
Determined by HPLC. Isolated yield.
transformations. The reaction of potassium benzene-
methanethiolate with the bromide 13 was investigated
in various solvents (Table 1). Potassium benzenemethane-
thiolate was allowed to react with the bromide 13 in
tetrahydrofuran (THF) at 25 °C for 96 h to afford the
desired sulfide 14 in 42% yield with a poor selectivity
(12% ee) (Table 1, entry 1). The yield and the selectivity
were improved in a more polar N,N-dimethylformamide
(DMF) to give 14 in 44% ee and 53% yield (Table 1, entry
2). Protic polar solvents such as water and ethanol were
next examined for the reaction. It was found that in water
compound 14 was obtained with much improved selectiv-
ity (72% ee, 53% yield) (Table 1, entry 3). A prolonged
reaction period is undesirable due to racemization of the
starting chiral halide by counterattack of the halide anion
(in the present case, bromide anion) liberated by the
reaction.12 A shorter reaction period would thus improve
the selectivity. Such accelaration of the reaction and
improvement of the selectivity were realized in ethanol
to give the desired sulfide 14 in 3 h with excellent
selectivity (98% ee, 77% yield) (Table 1, entry 4).
The selective reduction of the carboxyl group of 14 in
the presence of an ester group was accomplished by
diborane-dimethyl sulfide complex to afford 17 in 98%
yield. The chlorination of 17 was carried out by the use
of thionyl chloride in the presence of pyridine to provide
the desired chloride 15 in 77% yield. Addition of DMF or
N,N-dimethylaniline instead of pyridine gave poorer
yields (58% and 67%, respectively) due to the precedent
lactonization of 17.
With the required chiral chloride 15 in hand, amina-
tion of 15 was investigated using ammonia. It was found
that treatment of the chloride 15 with ammonia in
methanol at ambient temperature for 17 h allowed the
concomitant amination and cyclization to provide 16 in
82% yield (Scheme 4). In this reaction, any byproducts
due to the E2-type elimination of the benzylthio group of
15 were not detected. We assumed that the formation of
a thiilanium salt, 19, suppressed the E2-type elimination
because the orientation of the C-3 carbon-sulfur bond
toward the methylene carbon-hydrogen bond is not
suitable for the antiperiplanar E2-type elimination
(Scheme 5).13
Sch em e 6
A conceptually attractive counterattack strategy was
applied to the coupling reaction. The side chain 2 was
first installed into the azetidinone derivative 206 using
dicyclohexylcarbodiimide (DCC) and N,N-(dimethyl-
amino)pyridine (DMAP) to give the thioester 8 in 83%
yield (Scheme 7). Treatment of 8 with 3.3 equiv of sodium
bis(trimethylsilylamide) [NaN(TMS)2] resulted in the
clean cyclization to afford an enolate anion, 21, and a
dianion, 22. Treatment of the reaction mixture with 2.3
equiv of chlorotrimethylsilane ensured the protection of
the side chain. Subsequent addition of diphenyl phos-
phorochloridate and elevation of the reaction temperature
provided the vinyl phosphate 5 which was detected by
thin-layer chromatography. The “counterattack” of the
thiolate anion to the in situ generated vinyl phosphate 5
was realized by addition of tetra-n-butylammonium
fluoride (TBAF) to give the desired coupling product 6
in 58% yield from 8 and in crystals.
P r ep a r a tion of TA-949. Removal of the hydroxyl and
carboxyl protective groups from the carbapenem deriva-
tive 6 was accomplished by our previously developed
procedures.14 The tert-butyldimethylsilyl group of 6 was
successfully cleaved by treatment with ammonium bi-
fluoride to give the alcohol 24 in 90% yield. The reaction
conditions were mild enough to keep the sensitive car-
The formation of the thiolactam 18 from the pyrrolidin-
2-one 16 was readily conducted by the use of phosphorus
pentasulfide to give 18 in 82% yield (Scheme 4). Cleavage
of the benzyl protective group of 18 by the Birch reduction
(12) Koh, K.; Ben, R. N.; Durst, T. Tetrahedron Lett. 1994, 35, 375.
(13) A similar type of suppression of the E2-type elimination was
observed in the zinc reagent derived from L-serine: J ackson, R. F. W.;
Moore, R. J .; Dexter, C. S. J . Org. Chem. 1998, 63, 7875.
(14) Seki, M.; Kondo, K.; Kuroda, T.; Yamanaka, T.; Iwasaki, T.
Synlett 1995, 609.

520 J . Org. Chem., Vol. 65, No. 2, 2000
Seki et al.
Sch em e 7a
acetoxyazetidinone 3 through the route described in
Schemes 6 and 8. The C-2 side chain 2 was efficiently
synthesized from L-aspartic acid â-methyl ester hydro-
chloride 12 in 33% overall yield in seven steps. The 1-â-
methylcarbapenem skeleton was constructed in a highly
efficient manner by the use of the benzoxazinone deriva-
tive and/or the counterattack method. The simple pro-
cedure and economical operation would provide a prac-
tical appraoch to the synthesis of the orally active 1-â-
methylcarbapenem TA-949 (1).
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points are uncorrected.
1
Infrared spectra are reported as λmax (cm-1). H and 13C NMR
are reported in δ values. Mass spectra were taken at an
ionizing potential of 70 eV. Thin-layer chromatography was
performed on E. Merck 0.25 mm precoated glass-backed plates
(60 F254). Development was accomplished using either 20%
phosphomolybdic acid in ethanol-heat or visualized by UV
light where feasible. Flash chromatography was accomplished
using Kieselgel 60 (230-400 mesh, E. Merck). Tetrahydro-
furan was distilled from calcium hydride and stored over 4 Å
molecular sieves.
(S)-2-Br om o-3-m eth oxyca r bon ylp r op ion ic Acid (13).
To a solution of L-aspartic acid â-methyl ester hydrochloride
12 (155 g, 0.843 mol) in water (1900 mL) were added sulfuric
acid (433 g, 4.31 mol) and potassium bromide (402 g, 3.38 mol)
at 20 °C. Sodium nitrite (69.8 g, 1.01 mol) in water (150 mL)
was then added at 10-12 °C over 45 min. After the addition,
the mixture was stirred at 10-15 °C for 2 h and extracted
with ethyl acetate. The organic layer was washed with water,
dried over anhydrous magnesium sulfate, and evaporated in
vacuo to give 13 (181.5 g, quantitative) as a colorless oil: IR
(Nujol) 1746 cm-1; 1H NMR (CDCl3) δ 9.84 (br s, 1H), 4.63 (dd,
J ) 6.6, 4.6 Hz, 1H), 3.74 (s, 3H), 3.31 (dd, J ) 6.6, 18 Hz,
1H), 3.01 (dd, J ) 6, 18 Hz, 1H); 13C NMR (CDCl3) δ 203.3 (s),
a
Key: (a) (i) TBS-Cl, NaH, (ii) BrCH2CO2Allyl, NaH, (iii) citric
acid; (b) 2, DCC, DMAP; (c) (i) NaN(TMS)2, (ii) TMS-Cl, (iii)
ClP(O)(OPh)2, (iv) TBAF.
Sch em e 8a
34.6 (d), 53.7 (2t); SIMS m/z 212 (M+ + 1); [R]25 -52.60° (c,
D
1.02, MeOH).
P ota ssiu m Ben zen em eth a n eth iola te. CAUTION: This
compound has an extremely bad smell and should be prepared
and handled in a well-ventilated hood. Benzenemethanethiol
(100 g, 0.805 mol) was added to a solution of potassium
hydroxide (85%, 38.4 g, 0.684 mol) in methanol (1 L) at 5-10
°C, and the mixture was stirred at 5-10 °C for 10 min and at
20 °C for 15 min. The mixture was evaporated in vacuo and
coevaporated with toluene (2 × 300 mL). The residue was
triturated in ether (300 mL), and the crystals formed were
collected and dried under reduced pressure to afford potassium
benzenemethanethiolate (100.1 g, 90%) in colorless crystals.
(R)-2-Ben zylt h io-3-m et h oxyca r b on ylp r op ion ic Acid
(14). Potassium benzenemethanethiolate (122 g, 0.752 mol)
was added to a mixture of 13 (79.4 g, 0.376 mol) in ethanol
(500 mL) at 5 °C, and the mixture was stirred at 25 °C for 3
h. After the mixture was acidified to pH 3-4 by 2 N
hydrochloric acid, ethanol was removed by evaporation. The
mixture was extracted with chloroform, dried over anhydrous
magnesium sulfate, and evaporated in vacuo. The crystals
formed were collected by adding n-hexane to afford 14 (73.9
g, 77%) as colorless crystals: mp 91-92 °C; IR (Nujol) 1730,
1708 cm-1; 1H NMR (CDCl3) δ 11.09 (br s, 1H), 7.21-7.41 (m,
5H), 4.00 (d, J ) 13 Hz, 1H), 3.86 (d, J ) 13 Hz, 1H), 3.66 (s,
3H), 3.58 (dd, J ) 5, 10 Hz, 1H), 2.94 (dd, J ) 10, 14 Hz, 1H),
2.58 (dd, J ) 5, 14 Hz, 1H); 13C NMR (CDCl3) δ 177.8, 170.4,
137.0 (3s), 129.2, 126.6, 127.5 (3d), 52.1 (q), 40.7 (d), 36.4, 35.7
(2t); MS m/z 254 (M+); [R]25D +200.78° (c, 1.03, MeOH); optical
purity 98.0% ee (HPLC: CHIRAL PAC AD (Daicel), n-hexane:
ethanol:trifluoroacetic acid ) 90:10:0.1, 1 mL/min, 30 °C, 254
nm). Anal. Calcd for C12H14O4S: C, 56.67; H, 5.55. Found: C,
56.87; H, 5.63.
a
Key: (a) NH4F‚HF; (b) Pd(OAc)2, P(OEt)3, NaHCO3, H2O, (c)
ICH2OCO-i-Pr, i-Pr2EtN.
bapenem skeleton and the C-2 side chain intact during
the reaction. Removal of the allyl protective group of 24
was best conducted using inexpensive palladium acetate
in aqueous THF.14 The product rapidly crystallized out
during the reaction to give the sodium salt 25 in 87%
yield. Finally, esterification of 25 with isobutyryloxy-
methyl iodide gave TA-949 (1) in 83% yield. The absolute
structure of TA-949 (1) prepared by the present method
was unequivocally confirmed by X-ray crystallographic
analysis.15
Con clu sion
An orally active 1-â-methylcarbapenem, TA-949 (1),
was synthesized in 33% overall yield in eight steps from
Meth yl (R)-3-Ben zylth io-4-h yd r oxybu ta n oa te (17). To
a solution of the compound 14 (4.78 g, 0.0188 mol) was added
BH3‚SMe2 (10 M, 2.04 mL, 0.0204 mol) at -20 °C, and the
(15) The X-ray data of TA-949 (1) have been deposited at the
Cambridge Crystallographic Data Centre.

Preparation of 1-â-Methylcarbapenem TA-949
J . Org. Chem., Vol. 65, No. 2, 2000 521
mixture was gradually warmed to 25 °C for 1 h. After the
mixture was refluxed for 1 h, the mixture was carefully treated
with methanol at 20 °C and evaporated in vacuo. The residue
was purified by silica gel column chromatography (n-hexane:
AcOEt ) 4:1) to afford 17 (4.44 g, 98%) as a colorless oil: IR
(Nujol) 3458, 1738 cm-1; 1H NMR (CDCl3) δ 7.20-7.40 (m, 5H),
3.79 (s, 2H), 3.68 (s, 3H), 3.59 (dd, J ) 1.2, 5.7 Hz, 1H), 3.17
(dd, J ) 5.6, 7.1 Hz, 1H), 2.61 (dd, J ) 6.9, 10.5 Hz, 2H); MS
crystals: mp 47-48 °C; IR (Nujol) 1540 cm-1; 1H NMR (CDCl3)
δ 8.71 (brs, 1H), 4.00-4.15 (s, 1H), 3.65-3.85 (m, 1H), 3.52-
3.65 (m, 1H), 2.93 (dd, J ) 8. 18 Hz, 1H), 2.87 (dd, J ) 6. 18
Hz, 1H), 2.00 (d, J ) 8 Hz, 1H); 13C NMR (CDCl3) δ 203.3 (s),
59.1, 53.7 (2t), 34.6 (d); SIMS m/z 134 (M+ + 1); [R]25D -109.56°
(c, 1.07, MeOH). Anal. Calcd for C4H7NS2: C, 36.06; H, 5.30;
N, 10.51. Found: C, 36.26; H, 5.23; N, 10.72. The product thiol
2 was converted back to the corresponding benzyl thioether
by treatment with benzyl bromide and i-Pr2EtN and was
shown to be optically pure (>99.9% ee) by HPLC (CHIRAL
PAC OJ (Daicel), n-hexane:2-propanol ) 3:7, 0.5 mL/min, 30
°C, 215 nm).
m/z 240 (M+); [R]25 +8.30° (c, 0.976, MeOH); optical purity
D
99.0% ee (HPLC: CHIRAL PAC AD (Daicel), n-hexane:
ethanol:trifluoroacetic acid ) 90:10:0.1, 1 mL/min, 30 °C, 254
nm).
Meth yl (R)-3-Ben zylth io-4-ch lor obu ta n oa te (15). To a
mixture of 17 (6 g, 0.025 mol) in chloroform (50 mL) were
added pyridine (2.02 mL, 0.025 mol) and thionyl chloride (1.91
mL, 0.026 mol) at 5-10 °C, and the mixture was stirred at
5-10 °C for 1 h. The mixture was evaporated in vacuo and
dissolved in ethyl acetate (100 mL). The mixture was washed
successively with 2 N hydrochloric acid and water, dried over
anhydrous magnesium sulfate, and evaporated in vacuo. The
residue was purified by silica gel column chromatography (n-
hexane:AcOEt ) 10:1) to afford 15 (4.94 g, 77%) as a colorless
Allyl (4R,5R,6S)-6-[(R)-1-(ter t-Bu tyld im eth ylsilyloxy)-
et h yl]-3-[(R)-p yr r olid in e-2-t h ion -4-ylt h io)]-4-m et h yl-7-
oxo-1-a za bicyclo[3.2.0]h ep t-2-en e-2-ca r boxyla te (6). To a
solution of 55 (6.01 g, 9.8 mmol) in DMF (12 mL) were added
2 (1.43 g, 10.8 mmol) and N,N-diisopropylethylamine (2.22 mL,
12.7 mmol) at -30 °C, and the mixture was stirred at 0-5 °C
for 2 h. Phosphate buffer (0.1 M, K2HPO4, pH 7.0, 50 mL) was
added to the reaction mixture, and it was extracted with
AcOEt (2 × 50 mL). The combined extracts were washed with
brine (80 mL), dried over anhydrous magnesium sulfate, and
evaporated in vacuo. The residue was crystallized from a mixed
solvent of n-hexane and AcOEt (10:1) to afford 6 (4.18 g, 78%)
as colorless crystals: mp 130-133 °C; IR (Nujol) 1766, 1708
cm-1; 1H NMR (CDCl3) δ 8.58 (s, 1H), 5.77-5.93 (m, 1H), 5.14-
5.40 (m, 2H), 4.55-4.75 (m, 2H), 3.56-4.19 (m, 4H), 3.45-
3.60 (m, 1H), 2.85-3.35 (m, 4H), 1.16 (d, J ) 6.3 Hz, 6H), 0.80
(s, 9H), 0.00 (s, 6H); 13C NMR (CDCl3) δ 210.6, 180.4, 168.2,
153.2 (4s), 139.2 (d), 135.4 (s), 126.3 (t), 73.7 (d), 73.7 (t), 68.3,
63.7 (2d), 62.2, 59.6 (2t), 51.7, 47.7 (2d), 33.5, 30.2 (2q), 25.7
1
oil: IR (Nujol) 1738 cm-1; H NMR (CDCl3) δ 7.20-7.40 (m,
5H), 3.90 (s, 2H), 3.67 (s, 3H), 3.44-3.70 (m, 2H), 3.15-3.31
(m, 1H), 2.90 (dd, J ) 7, 16 Hz, 1H), 2.50 (dd, J ) 8.5, 16 Hz,
1H); 13C NMR (CDCl3) δ 171.2, 137.7 (2s), 130.0, 129.7, 127.4
(3d), 51.8 (q), 47.2 (t), 42.8 (d), 37.2, 36.6 (2t); MS m/z 258 (M+);
[R]25 -19.7° (c, 0.965, MeOH); optical purity 100% ee
D
(HPLC: CHIRAL PAC AD (Daicel), n-hexane:ethanol:tri-
fluoroacetic acid ) 90:10:0.1, 1 mL/min, 30 °C, 254 nm).
(R)-4-Ben zylth iop yr r olid in -2-on e (16). Compound 15 (2
g, 7.8 mmol) was dissolved in ammonia in methanol (21.5%
w/w, 12 mL), and the mixture was stirred at 25 °C for 72 h.
The mixture was evaporated in vacuo, and water (50 mL) was
added. The mixture was extracted with chloroform, dried over
anhydrous magnesium sulfate, and evaporated in vacuo. The
residue was purified by silica gel column chromatography
(CHCl3:EtOH ) 30:1) to afford 16 (1.32 g, 82%) as colorless
(s), 24.7, 3.6, 2.8 (3q); SIMS m/z 497 (M+ + 1); [R]25 +1.4° (c,
D
1.2, MeOH). Anal. Calcd for C23H36N2O4S2Si: C, 55.61; H, 7.30;
N, 5.64. Found: C, 55.43; H, 7.22; N, 5.81.
S-[(R)-P yr r olid in e-2-t h ion -4-yl]-(R)-2-{(3S,4S)-1-a llyl-
oxycar bon ylm eth yl-3-[(1R)-1-(ter t-bu tyldim eth ylsilyloxy)-
eth yl]-2-oxoa zetid in -4-yl}th iop r op ion a te (8). To a solution
of compound 206 (1 g, 2.5 mmol) in CH3CN were added N,N-
dimethylaminopyridine (30 mg, 0.25 mmol), compound 2 (336
mg, 2.53 mmol), and dicyclohexylcarbodiimide (632 mg, 3.06
mmol) at 10 °C, and the mixture was stirred at 10 °C for 20 h.
The mixture was filtered to remove insoluble materials, and
the filtrate was evaporated in vacuo. The residue was chro-
matographed on silica gel (n-hexane:CHCl3:AcOEt ) 5:5:4) to
afford 8 (1.07 g, 83%) as a colorless oil: IR (Nujol) 1747, 1676
cm-1; 1H NMR (CDCl3) δ 8.47 (s, 1H), 5.75-5.92 (m, 1H), 5.17-
5.34 (m, 2H), 4.55-4.59 (m, 2H), 4.20 (d, J ) 17.9 Hz, 1H),
4.01-4.24 (m, 4H), 3.79 (d, J ) 17.9 Hz, 1H), 3.22-3.50 (m,
2H), 2.74-3.02 (m, 3H), 1.16-1.20 (m, 6H), 0.80 (s, 9H), 0.02
(s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3) δ 202.2, 200.0, 167.2
(3s), 130.7 (d), 110.3 (t), 85.6 (d), 85.2 (t), 60.4, 56.3 (2d), 55.1
(t), 48.5 (d), 47.7, 41.9 (2t), 38.1 (d), 25.0, 21.9 (2q), 17.1 (s),
1
crystals: mp 75-76 °C; IR (Nujol) 3224, 1690 cm-1; H NMR
(CDCl3) δ 7.15-7.40 (m, 5H), 6.73 (br s, 1H), 3.76 (s, 2H), 3.50-
3.62 (m, 1H), 3.28-3.46 (m, 1H), 3.15-3.25 (m, 1H), 2.59 (dd,
J ) 8, 17 Hz, 1H), 2.25 (dd, J ) 6, 17 Hz, 1H); 13C NMR
(CDCl3) δ 176.5, 137.8 (2s), 128.7, 127.6 (2d), 48.1, 37.8 (2t),
37.5 (d), 36.1 (t); MS m/z 207 (M+); [R]25D -9.2° (c, 1.0, MeOH);
optical purity 97% ee (HPLC: CHIRAL PAC OJ (Daicel),
n-hexane:2-propanol ) 65:35, 0.5 mL/min, 30 °C, 254 nm).
Anal. Calcd for C11H13NOS: C, 63.72; H, 6.32; N, 6.76.
Found: C, 63.87; H, 6.54; N, 6.56.
(R)-4-Ben zylth iop yr r olid in e-2-th ion e (18). A mixture of
16 (20 g, 0.0964 mol) and phosphorus pentasulfide (4.88 g,
0.0212 mol) in chloroform (64 mL) was stirred at 25 °C for 5
h. The mixture was poured into saturated aqueous sodium
bicarbonate (20 mL), extracted with chloroform, washed with
water, dried over anhydrous magnesium sulfate, and evapo-
rated in vacuo. The residue was crystallized from toluene to
afford 18 (17.65 g, 82%) as colorless crystals: mp 86-88 °C;
IR (Nujol) 1603 cm-1; 1H NMR (CDCl3) δ 8.41 (br s, 1H), 7.20-
7.40 (m, 5H), 3.76 (s, 2H), 3.70-3.90 (m, 1H), 3.40-3.60 (m,
2H), 3.10 (ABqd, J ) 6.5, 8.4, 18.1, 49.2 Hz, 2H); 13C NMR
(CDCl3) δ 203.7, 137.5 (2s), 128.8, 128,7, 127.5 (3d), 55.9, 50.2
(2t), 39.4 (d), 36.2 (t); SIMS m/z 224 (M+ + 1); [R]25D -13.7° (c,
1.0, MeOH); optical purity >99.9% ee (HPLC: CHIRAL PAC
OJ (Daicel), n-hexane:2-propanol ) 3:7, 0.5 mL/min, 30 °C,
215 nm). Anal. Calcd for C11H13NS2: C, 59.15; H, 5.87; N, 6.27.
Found: C, 59.16; H, 5.88; N, 6.22.
(R)-4-Mer ca p top yr r olid in e-2-th ion e (2). Compound 18
(1 g, 4.48 mmol) was dissolved in liquid ammonia (20 mL). To
the solution was added sodium (225 mg, 14.5 mmol) over 20
min, and the mixture was stirred for 20 min. Ammonium
chloride (5 g) was added to the reaction mixture, and ammonia
was removed. The residue was acidified (pH 1) with 1 N
aqueous HCl and extracted with chloroform. The combined
extracts were dried over anhydrous magnesium sulfate and
evaporated in vacuo. The crystals formed were collected by
adding n-hexane to afford 2 (507 mg, 85%) as colorless
11.6 (q); SIMS m/z 515 (M+ + 1); [R]25 -3.9° (c, 1.5, MeOH).
D
Allyl (4R,5R,6S)-6-[(R)-1-(ter t-Bu tyld im eth ylsilyloxy)-
eth yl]-3-[(R)-pyr r olidin e-2-th ion -4-ylth io]-4-m eth yl-7-oxo-
1-a za bicyclo[3.2.0]h ep t-2-en e-2-ca r boxyla te (6) (Cou n ter -
a tta ck Meth od ). To a solution of NaN(TMS)2 (1 M in THF,
6.6 mL, 6.6 mmol) was added the compound 8 (1.03 g, 2 mmol)
in THF (6 mL) at -60 to -50 °C over 5 min, and the mixture
was stirred at -50 °C for 10 min. Chlorotrimethylsilane (0.58
mL, 4.6 mmol) was added at -60 °C, and the mixture was
stirred at -60 °C for 15 min. Diphenyl phosphorochloridate
(0.44 mL, 2.1 mmol) was added at -60 °C, and the mixture
was stirred at 0 °C for 1.5 h. To the mixture was added DMF
(10 mL) at 0 °C followed by n-Bu4NF (1 M in THF, 1.6 mL) at
-60 °C. The mixture was stirred at -50 °C for 30 min and
gradually warmed to -20 °C for 1 h. The mixture was poured
into phosphate buffer (0.2 M, K2HPO4, pH 7.0, 10 mL),
extracted with AcOEt, washed with water, dried over anhy-
drous magnesium sulfate, and evaporated in vacuo. The
residue was chromatographed on silica gel (CHCl3:n-hexane:
AcOEt ) 5:5:4) to afford 6 (575 mg, 58%) as colorless crystals.
Allyl (4R,5R,6S)-6-[(R)-1-(Hyd r oxy)eth yl]-3-[(R)-p yr r ol-
idin e-2-th ion -4-ylth io]-4-m eth yl-7-oxo-1-azabicyclo[3.2.0]-
h ep t-2-en e-2-ca r boxyla te (24). To a solution of 6 (69 g, 0.134

522 J . Org. Chem., Vol. 65, No. 2, 2000
Seki et al.
mol) in a mixture of DMF (518 mL) and N-methylpyrrolidone
(173 mL) was added ammonium bifluoride (30.6 g, 0.536 mol)
at 20 °C, and the mixture was stirred at 20 °C for 108 h.
Phosphate buffer (0.2 M, K2HPO4, pH 7.0, 2 L) was added to
the reaction mixture and extracted with AcOEt. The combined
organic phases were washed with water (1 L), dried over
anhydrous magnesium sulfate, and evaporated in vacuo. The
crystals formed were collected by adding n-hexane to afford
24 (47.8 g, 90%) as colorless crystals: mp 144-145 °C; IR
60.2 (3d), 57.8, 54.4 (2t), 45.5, 42.0 (2d), 22.9, 18.8 (2q); SIMS
25
m/z 365 (M+
+ 1); [R]D +1.7° (c, 1.0, H2O).
Isob u t yr yloxym et h yl (4R,5R,6S)-6-[(R)-1-(H yd r oxy)-
et h yl]-3-[(R)-p yr r olid in e-2-t h ion -4-ylt h io)]-4-m et h yl-7-
oxo-1-a za bicyclo[3.2.0]h ep t-2-en e-2-ca r boxyla te, TA-949
(1). To a solution of 25 (2 g, content: 88.1%, 4.84 mmol) in
DMF (13.2 mL) and N-methylpyrrolidone (4.4 mL) was added
4 Å molecular sieves (3.2 g), and the mixture was stirred for
30 min. N,N-Diisopropylethylamine (189 mg, 1.46 mmol) and
isobutyryloxymethyl iodide (1.27 g, 5.57 mmol) were added at
-15 °C, and the mixture was stirred at -10 °C for 1.5 h. The
reaction mixture was poured into a mixture of phosphate
buffer (0.2 M, K2HPO4, pH 7.0, 50 mL) and ice (50 g) and
extracted with AcOEt (2 × 30 mL). The combined organic
phases were washed with water (2 × 50 mL), dried over
anhydrous magnesium sulfate, and evaporated in vacuo. The
residue was crystallized from AcOEt (2 mL) and diisopropyl
ether (50 mL) to afford 1 (1.77 g, 83%) as colorless crystals:
1
(Nujol) 1749, 1688 cm-1; H NMR (DMSO-d3) δ 10.37, 5.82-
6.01 (m, 1H), 5.07-5.46 (m, 2H), 4.55-4.79 (m, 2H), 3.97-
4.27 (m, 4H), 3.23-3.46 (m, 5H), 2.67-2.78 (m, 1H), 1.15 (d,
J ) 6.1 Hz, 6H); 13C NMR (DMSO-d3) δ 214.1, 186.9, 173.0,
162.1 (4s), 145.2 (d), 138.1 (s), 130.8, 77.8 (2t), 77.2, 72.6, 68.5
(3d), 67.1, 65.3 (2t), 56.1, 52.6 (2d), 34.8, 29.9 (2q); SIMS m/z
383 (M+ + 1); [R]D +4.3° (c, 0.88, MeOH). Anal. Calcd for
25
C
17H22N2O4S2: C, 53.38; H, 5.80; N, 7.32. Found: C, 53.42; H,
5.63; N, 7.44.
Sod iu m (4R,5R,6S)-6-[(R)-1-(Hyd r oxy)eth yl]-3-[(R)-p yr -
r olid in e-2-th ion -4-ylth io)]-4-m eth yl-7-oxo-1-a za bicyclo-
[3.2.0]h ep t-2-en e-2-ca r boxyla te (25). A mixture of sodium
bicarbonate (10.2 g, 0.121 mol) and dimedone (10.2 g, 0.0725
mol) in water (121 mL) was sonicated for 10 min. Compound
24 (46.3 g, 0.121 mol), triethyl phosphite (7.02 g, 0.0402 mol),
palladium acetate (1.33 g, 5.9 mmol), and THF (968 mL) were
added, and the mixture was stirred at 35-37 °C for 45 min.
To the mixture was added THF (968 mL), and the resulting
mixture was stirred at 0 °C for 1 h. The crystals formed were
collected, washed with THF, and dried at 25 °C for 4 h under
reduced pressure to afford 25 (45.48 g, 87% (net yield); the
crystals contained water (12.86%) and THF (2.8%)) as colorless
crystals: mp 140-150 °C dec; IR (Nujol) 1746, 1594 cm-1; 1H
NMR (CDCl3) δ 4.09-4.32, 3.28-3.71 (m, 4H), 2.91-3.01 (m,
1H), 1.30 (d, J ) 6.4 Hz, 3H), 1.22 (d, J ) 7.2 Hz, 3H); 13C
NMR (CDCl3) δ 205.0, 179.1, 170.4, 141.9, 136.0 (5s), 67.9, 61.2,
1
mp 153.9 °C; IR (Nujol) 1750, 1705 cm-1; H NMR (CDCl3) δ
10.36 (s, 1H), 5.87 (d, J ) 5.9 Hz, 1H), 5.74 (d, J ) 5.9 Hz,
1H), 5.09 (d, J ) 5 Hz, 1H), 3.94-4.35 (m, 4H), 3.24-3.50 (m,
4H), 2.47-2.80 (m, 2H), 1.14 (d, J ) 11.1 Hz, 3H), 1.10 (d, J
) 12.2 Hz, 3H); 13C NMR (CDCl3) δ 200.7, 174.5, 173.6, 158.7,
151.3, 123.8 (6s), 78.8 (t), 63.8, 59.5, 55.1 (3d), 53.7, 52.0 (2t),
43.0, 39.3, 32.7 (3d), 21.4, 18.1, 16.5 (3q); SIMS m/z 444 (M+
25
+ 1); [R]D +14.2° (c, 1.0, MeOH). Anal. Calcd for C19H26
-
N2O6S2: C, 51.57; H, 5.92; N, 6.33. Found: C, 51.66; H, 5.88;
N, 6.32.
Ack n ow led gm en t. We are indebted to Mr. Hajime
Hiramatsu of Tanabe Seiyaku Co., Ltd., for the X-ray
analysis.
J O991461+