A new synthesis of a key intermediate of β-lactam antibiotics via diastereoselective alkylation of β-hydroxy ester

Full text of DOI:10.1021/jo000467s

8372
J . Org. Chem. 2000, 65, 8372-8374
Sch em e 1
A New Syn th esis of a Key In ter m ed ia te of
â-La cta m An tibiotics via Dia ster eoselective
Alk yla tion of â-Hyd r oxy Ester
Won-Hun Ham,*,† Chang-Young Oh,† Yiu-Suk Lee,† and
J in-Hyun J eong‡
College of Pharmacy, SungKyunKwan University,
Suwon 440-746, Korea, and College of Pharmacy,
Kyung Hee University, Seoul 130-701, Korea
whham@speed.skku.ac.kr
Received March 28, 2000
The carbapenems, penems, monobactams, and tri-
bactams have attracted considerable attention because
of their potent activity and broad antimicrobial spectra.
Since acetoxyazetidinone 1 is a common intermediate for
the synthesis of many antibiotics, it has been the subject
of considerable synthetic activities.1 This important
intermediate can be obtained through C-4 oxidation by
means of a Ru-catalyzed reaction2 such that the azeti-
dinone 2 can be considered the true target. In a previous
communication, we have reported an entirely new ap-
proach to the synthesis of a chiral 1â-methylcarbapenem
key intermediate via diastereoselective alkylation of
methyl (R)-3-hydroxybutyrate 4 and regioselective cu-
prate ring opening of a chiral epoxide.3 On the basis of
this study, it occurred to us that diastereoselective
alkylation with benzyl chloromethyl ether (BOMCl) of the
dianion of 4, which is a common starting material in
â-lactam chemistry1,4 and subsequent simple transforma-
tion of the resulting discriminative alcohol functionality
might enable us to stereoselectively produce an azetidi-
none 2. In this paper, we present full details about
diastereoselective alkylation of 4 and describe convenient
synthesis of an azetidinone 2.
Generally, alkylation of the dianion of â-hydroxy esters
has been shown to yield products of high diastereomeric
excess with predictable stereochemistry, but in the case
of the alkylation of the dianion with BOMCl the benzyl
ether was afforded with moderate diastereoselectivity (ca.
10:1) and low conversion yield (ca. 50%).5 Previously,
Sakai and co-workers reported the alkylation of cyclic
â-hydroxy ester with BOMCl; the use of 1.7 equiv of LDA
as a base and HMPA as an additive produced the benzyl
ether in 84% isolated yield, but the diastereoselectivity
Ta ble 1. Dia ster eoselective Alk yla tion of Meth yl
3-(R)-Hyd r oxy bu ta n oa te
entry
equiv of LDA
additivea
yield (%)
dr (5a :5b)b
1
2
3
4
5
6
7
8
9
2.0
1.7
1.7
2.0
2.0
2.2
2.2
2.4
2.4
no
40
61
33
70
35
75
42
78
39
12:1
>25:1
23:1
25:1
20:1
12:1
10:1
4:1
HMPA
DMPU
HMPA
DMPU
HMPA
DMPU
HMPA
DMPU
4:1
Amount of additives: HMPA (5%), DMPU (10%). b Determined
by GC.
a
was not reported.6 This result was sharply contrasted
with Ireland’s study. In this case, alkylation of the 4 with
BOMCl using 2.5 equiv of LDA afforded the benzyl ether
and the alternate diastereomer in a ratio of 14:1 and
42.2% isolated yield (76.2% based on unrecovered starting
material). Therefore, we tried to improve the yield and
the diastereoselectivity of this reaction by using HMPA
or DMPU as an additive and varying amount of a base.
The results are summarized in Table 1. The reaction of
dianion of 4 generated from LDA with freshly distilled
BOMCl (1.4 equiv) in THF at -78 °C was monitored by
analytical TLC for 2.5 h. Following usual workup,
purification with silica gel column chromatography using
n-hexanes/EtOAc (2:1) as eluent gave a 12:1 mixture of
5a and 5b in 40% isolated yield (entry 1). The ratio of
5a and 5b was monitored by GC on a capillary column.
Addition of HMPA was effective in both yield and
diastereoselectivity. The yield and the diasteroselectivity
was improved to 61% and >25:1 when 1.7 equiv of LDA
was used (entry 2). When excess amounts of base (2.2
and 2.4 equiv) were employed, there were dramatic
improvements in yield (75% and 78%) while diastereo-
meric ratios were decreased (entries 6 and 8). Use of
cyclic urea DMPU, which was recommended as a sub-
stitute for HMPA for safety reasons, gave no significant
improvement in diasteroselectivity compared to HMPA
with decreased yield (entries 3, 5, 7, and 9). As a result
† SungKyunKwan University.
‡ Kyung Hee University.
(1) (a) Ohtake, H.; Imada, Y.; Murahashi, S.-I. J . Org. Chem. 1999,
64, 3790. (b) Cainelli, G.; Galletti, P.; Giacomini, D. Tetrahedron Lett.
1998, 39, 7779. (c) For a review, see: Berks, A. H. Tetrahedron 1996,
52, 331 and references therein.
(2) (a) Murahashi, S.-I.; Naota, T.; Kuwabara, T.; Saito, T.; Kumo-
bayashi, H.; Akutagawa, S. J . Am. Chem. Soc. 1990, 112, 7820. (b)
Murahashi, S.-I.; Saito, T.; Naota, T.; Kumobayashi, H.; Akutagawa,
S. Tetrahedron Lett. 1991, 32, 5991.
(3) Oh, C.-Y.; Ham W.-H. Chem. Commun. 1999, 2365.
(4) (a) Nakatsuka, T.; Iwata, H.; Tanaka, R.; Imajo, S.; Ishiguro,
M. J . Chem. Soc., Chem. Commun. 1991, 662. (b) Noyori, R.; Ikeda,
T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa,
S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J . Am. Chem.
Soc. 1989, 111, 9134.
(5) (a) Hatakeyama, S.; Ochi, N.; Numata, H.; Takano, S. J . Chem.
Soc., Chem. Commun. 1988, 1202. (b) Ireland, R. E.; Wardle, R. B. J .
Org. Chem. 1987, 52, 1780. (c) Muraoka, O.; Toyooka, N.; Oshima, Y.;
Narita, N.; Momose, T. Heterocycles 1989, 29, 269.
(6) Fang, C.; Suganuma, K.; Suemune, H.; Sakai, K. J . Chem. Soc.,
Perkin Trans. 1 1991, 1549.
10.1021/jo000467s CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/02/2000

Notes
J . Org. Chem., Vol. 65, No. 24, 2000 8373
Sch em e 2a
In summary, we report on the convenient synthesis of
an important carbapenem intermediate 2 via diastereo-
selective benzyloxymethylation of methyl (R)-3-hydroxy-
butyrate 4 followed by one-pot reduction and protection
as the key steps.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points (mp) were determined on
a micro melting point apparatus and are uncorrected. Infrared-
(IR) spectra are reported in wavenumbers (cm-1). Unless
1
otherwise noted, H NMR (500 MHz) and 13C NMR (125 MHz)
spectra were measured in CDCl3 using SiMe4 (δ ) 0 ppm) and
the center line of the CDCl3 triplet (δ ) 77.1 ppm) as internal
standards, respectively. Methyl (R)-3-hydroxybutyrate and
benzyl chloromethyl ether were purchased from Tokyo Kasei
Kogyo Co., Ltd. All other chemicals were of commercial grade
and used without further purification or, if necessary, purified
by distillation or crystallization prior to use.
(2R,3R)-Meth yl 2-[(Ben zyloxy)m eth yl]-3-h ydr oxybu tyr ate
(5a ). To a solution of diisopropylamine (28 mL, 0.20 mmol) and
n-BuLi (1.6 M in hexane, 131.3 mL) in THF (455 mL) at -78 °C
was added a solution of methyl (R)-3-hydroxybutyrate (11.812
g, 0.1mol) in THF (228 mL) over 15 min. After 60 min, a solution
of benzyl chloromethyl ether (18.6 mL, 0.14mol) in HMPA
(32 mL) was added over 5 min, and the reaction mixture was
stirred for 3 h. The mixture was quenched by saturated aqueous
NH4Cl solution (200 mL) and extracted with Et2O. The combined
organic layer was washed with brine, dried (MgSO4), filtered,
and concentrated under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 2:1, hex-
anes/EtOAc) to afford the benzyl ether 5a (16.7 g, 70%) as a
colorless liquid. 1H NMR (CDCl3, 500 MHz) δ 1.22 (d, 3H, J )
6.5 Hz), 2.75 (q, 1H, J ) 6 Hz), 2.81 (br d, 1H), 3.73 (s, 3H), 3.76
(abx, 1H, J ) 9.4, 6.0 Hz), 3.77 (abx, 1H, J ) 9.4, 6.0 Hz), 4.13
(dq, 1H, J ) 6.0, 6.5 Hz), 4.52 (q, 2H), 7.25-7.4 (m, 5H); 13C
NMR (CDCl3, 125 MHz) δ 21.76, 52.55, 53.19, 67.18, 69.29, 74.07,
128.34, 128.46, 129.10, 138.46, 174.29, IR (CHCl3) 3530, 3010,
a
Reagents and conditions: (a) TBDMSCl, imidazole, DMF, rt,
(90%); (b) DIBALH, Et2O, -78 °C (86%); (c) (C6H5O)2P(O)N3,
DEAD, Ph3P, THF, rt (95%); (d) Pd(OH)2, (BOC)2O, H2 (50 psi),
EtOAc, rt (81%); (e) RuCl3, NalO4, CHCl3-CCl4-H2O (2:2:3), rt
(85%) (f) 30% TFA in CH2Cl2, 0 °C then Et3N, (2-PyS)2, Ph3P,
CH3CN, 65 °C (71% for two steps).
of extensive examination of various conditions, we found
that reaction of 4 with BOMCl (1.4 equiv) using 2.0 equiv
of LDA as a base and HMPA as an additive gave the
desired diastereomer 5a as the major compound with
high diastereoselectivity and good yield (entry 4).
The synthetic approach to azetidinone 2 is outlined in
Scheme 2. R-Benzyloxymethylated â-hydroxy butanoate
5a , which was obtained under the optimal condition was
silylated with TBDMSCl in 90% yield and followed by a
DIBALH reduction in diethyl ether at -78 °C to afford
alcohol 3 in 86% yield. To convert this alcohol to â-amino
acid, which is the precursor of azetidinone 2, azide was
introduced by modified Bose conditions7 using Ph3P,
DEAD, and diphenylphosphoryl azide (DPPA) in 94%
yield. Fortunately, the resulting azide 7 could be directly
converted to N-BOC protected alcohol 8 by means of a
multireaction one-pot procedure. Thus, the simultaneous
reduction of the azide and benzyl ether moieties and
subsequent protection of the resulting amino group as
tert-butoxycarbamoyl occurred by simple treatment of
Pd(OH)2 in the presence of (Boc)2O in EtOAc under H2
atmosphere (50 psi) for 24 h in 82% yield. The alcohol 8
was oxidized to its corresponding acid by RuCl3/NaIO4
system in 85% yield, deprotection of the Boc group
with diluted TFA in CH2Cl2 generated the â-amino acid
9, and the treatment of 9 with 2,2′-dipyridyl disulfide
and Ph3P according to Ohno’s procedure8 afforded aze-
tidinone 2 in 71% yield for the two steps. The physico-
chemical properties of 2 obtained by the present synthesis
were in complete agreement with those reported in the
literature.9
2950, 2920, 2870, 1730, 1455 cm-1; [R]25 -7.935° (c 1.01,
D
CHCl3); MS (CI) m/z 239 (M + H); HRMS (CI) calcd for C13H19O4
(M + H) 239. 1285, found 239.1278 (-2.3 ppm error).
Met h yl (2R,3R)-2-[(Ben zyloxy)m et h yl]-3-(ter t-b u t yld i-
m eth ylsiloxy)bu tyr a te (6). To a stirred solution of the alcohol
5a (15 g, 62.95 mmol) in DMF (100 mL) were added imidazole
(5.14 g, 75.5 mmol) and TBDMSCl (11.4 g, 75.54 mmol). The
reaction mixture was stirred for 5 h, diluted with Et2O (400 mL),
and washed with H2O and brine. The combined organic layer
was dried (MgSO4), filtered, concentrated, and purified by flash
column chromatography (silica gel, 15:1, hexanes/EtOAc) to
afford the desired silyl ether 6 (19.9 g, 90%) as a colorless liquid.
1H NMR (CDCl3, 500 MHz) δ 0.04 (d, 6H), 0.85 (s, 9H), 1.16 (d,
3H), 2.78 (m, 1H), 3.58 (q, 1H, J ) 6.5, 9 Hz), 3.70 (q, 1H, J )
6.5, 9.5 Hz), 3.70 (s, 3H), 4.09 (dq, 1H, J ) 6.5 Hz, 3.5 Hz), 4.51
(q, 2H), 7.27∼7.36 (m, 5H); 13C NMR (CDCl3, 125 MHz) δ -4.48,
-3.61, 18.56, 22.61, 26.36, 52.22, 55.14, 68.14, 68.73, 73.87,
128.30, 129.05, 138.79, 173.73; IR (CHCl3) 2950, 2930, 2850,
1730, 1455, 1440 cm-1; [R]22 -8.941° (c 1.01, CHCl3); MS (CI)
D
m/z 353 (M + H); HRMS (CI) calcd for C19H33O4Si (M + H)
353.2149, found 353.2148 (-0.2 ppm error).
(2R,3R)-2-[(Ben zyloxy)m et h yl]-3-(ter t-b u t yld im et h yl-
siloxy)bu ta n -1-ol (3). To a stirred solution of the silyl ether 6
(12.68 g, 36 mmol) in Et2O (120 mL) at -78 °C was added
DIBALH (1.5M in toluene, 52.5 mL) followed by stirring for 1
h. After addition of EtOAc (5 mL) and a saturated sodium
potassium tartrate solution (150 mL) at -78 °C, the reaction
mixture was stirred at 25 °C for 1 h. The layers were separated,
and the aqueous layer was extracted with Et2O. The combined
organic extracts were dried (MgSO4), filtered, and concentrated.
The oily residue was purified by flash column chromatography
(silica gel, 6:1, hexanes/EtOAc) to afford 3 (10 g, 86%) as a
(7) (a) Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre,
D. J .; Grabows, E. J . J . J . Org. Chem. 1993, 58, 5886. (b) Lal, B.;
Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahedron Lett. 1977,
1977.
(8) (a) Kobayashi, S.; Iimori, T.; Izawa, T.; Ohno, M. J . Am. Chem.
Soc. 1981, 103, 2406.
1
colorless liquid. H NMR (CDCl3, 500 MHz) δ 0.08 (d, 6H), 0.88
(s, 9H), 1.23 (d, 3H, J ) 6.5 Hz), 1.71∼1.74 (m, 1H), 3.63 (q, 1H,
J ) 6.5, 9 Hz), 3.69 (q, 1H, J ) 6.5, 9.5 Hz), 3.74 (q, 1H, J ) 4,
11.5 Hz), 4.0 (q, 1H, J ) 4, 11 Hz), 4.15∼4.20 (dq, 1H, J ) 6.5
Hz, 3.5 Hz), 4.49∼4.55 (q, 2H), 7.27∼7.37 (m, 5H); 13C NMR
(CDCl3, 125 MHz) δ -4.45, -3.66, 18.55, 22.68, 26.47, 47.50,
(9) Nagao, Y.; Nagase, Y.; Kumagai, T.; Matsunaga, H.; Abe, T.;
Shimada, O.; Hayashi, T.; Inoue, Y. J . Org. Chem. 1992, 57, 4243.

8374 J . Org. Chem., Vol. 65, No. 24, 2000
Notes
62.93, 69.76, 71.29, 74.15, 128.38, 128.45, 129.12, 138.86; IR
filtered through a Celite pad, and concentrated. The crude
product was purified by flash column chromatography (1:1
hexnanes/EtOAc) to afford acid 9 (0.85 g, 85%) as a white solid.
mp 120-121 °C; 1H NMR (CDCl3, 500 MHz) rotamer δ 0.06,
0.12 (2br, 6H), 0.90 (s, 9H), 1.22 (d, 3H, J ) 6.5 Hz), 1.43, 1.47
(2br, 9H), 2.59, 2.69 (2br, 1H), 3.18, 3.25 (2br, 1H), 3.48, 3.56
(2br, 1H), 4.07, 4.26 (2br, 1H), 5.22, 6.46 (2br, 1H); 13C NMR
(CDCl3, 125 MHz) rotamer δ -4.51, -3.87, 18.54, 21.12, 22.71,
26.34, 29.07, 38.81, 40.62, 52.81, 54.76, 68.89, 69.28, 80.16,
156.68, 175.80, 176.78; IR (KBr) 3319, 3273, 2979, 2956, 2932,
2859, 1725, 1699, 1653, 1475, 1409, 1366 cm-1; MS (CI) m/z 348
(M + H); HRMS(CI) calcd for C18H34NO5Si (M + H) 348.2207,
found 348.2207 (+0.2 ppm error).
(neat) 3453, 2955, 2930, 2891, 2857, 1468, 1366, 1254 cm-1; [R]28
D
-8.271° (c 0.71, CHCl3); MS (CI) m/z 325 (M + H); HRMS (CI)
calcd for C18H33O3Si (M + H) 325.2200, found 239.2194 (-1.5
ppm error).
(1R,2R)-3-Azid o-2-[(b en zyloxy)m et h yl]-(1-m et h ylp r o-
p oxy)-ter t-bu tyld im eth ylsila n e (7). To a stirred solution of
alcohol 3 (4.8 g, 14.8 mmol), Ph3P (7.75 g, 29.6 mmol), and DEAD
(4.7 mL, 29.6 mmol) in THF (50 mL) was added a solution of
DPPA (6.4 mL, 29.6 mmol) in THF (2 mL) at room temperature.
The reaction mixture was stirred for 2 h, and the reaction
mixture was evaporated and purified by flash chromatography
(10:1 hexnanes/EtOAc) to afford azide 7 (4.9 g, 95%) as a
1
colorless oil. H NMR (CDCl3, 500 MHz) δ 0.04 (d, 6H), 0.88 (s,
(3S)-3-[(1R)-1-[(ter t-Bu tyldim eth ylsilyl)oxy]eth yl]azetidin -
2-on e (2). To a stirred solution of acid 9 (300 mg, 0.863 mmol)
in CH2Cl2 (2 mL) at 0 °C was added 0.5 mL of 30% TFA in
CH2Cl2. When no starting material could be detected by TLC,
the reaction mixture was concentrated in vacuo and dissolved
in CH3CN (17.3 mL). To this solution was added Et3N (0.12 mL).
After 5 min, Ph3P (272 mg, 1.036 mmol) and 2-Aldrithiol (22.82
mg, 1.036 mmol) were added and stirred for 12 h at 60 °C. The
reaction mixture was diluted with H2O and extracted with
EtOAc. The combined organic layer was washed with saturated
brine, dried (MgSO4), filtered, and concentrated. The crude
product was purified by flash column chromatography to afford
azetidinone (140 mg, 71%) as a white solid. mp 67-68 °C (lit.8
9H), 1.23 (d, 3H, J ) 6.5 Hz), 1.18 (m, 1H), 3.38 (q, 1H, J ) 7.1,
12.2 Hz), 3.45 (q, 1H, J ) 6.0, 9.1 Hz), 3.51 (q, 1H, J ) 7.1, 4.8
Hz), 3.53 (q, 1H, J ) 5.1, 9.1 Hz), 3.98 (m, 1H), 4.46∼4.53 (q,
2H), 7.26∼7.37 (m, 5H); 13C NMR (CDCl3, 125 MHz) δ -4.32,
-3.53, 18.69, 22.23, 26.52, 47.27, 50.27, 67.25, 69.07, 73.97,
128.35, 128.40, 129.09, 138.91; IR (neat) 2956, 2931, 2893, 2858,
2099, 1458 cm-1; MS (CI) m/z 350 (M + H); HRMS (CI) calcd
for C18H32N3O2Si (M + H) 350.2265, found 350.2264 (+0.2 ppm
error).
(2R,3R)-[3-(ter t-Bu tyld im eth ylsiloxy)-2-(h yd r oxym eth -
yl)bu tyl]ca r ba m ic Acid ter t-Bu tyl Ester (8). A suspension
of azide 7 (1.7 g, 4.9 mmol), Pd(OH)2 (100 mg), and Boc2O in
EtOAc (15 mL) was hydrogenated under H2 (50 psi) for 1day.
The reaction mixture was filtered through Celite and evaporated.
The oily residue was purified by flash chromatography (3:1
hexnanes/EtOAc) to afford alcohol 8 (1.32 g, 81.4%) as a white
1
mp 67-68 °C); H NMR (CDCl3, 500 MHz) δ 0.08 (d, 6H), 0.88
(s, 9H), 1.19 (d, 3H, J ) 6.24 Hz), 3.23 (qt, 1H), 3.29 (t, 1H, J )
5.1 Hz), 3.35 (q, 1H, J ) 5.1, 2.55 Hz), 4.21 (m, 1H, J ) 6.24,
4.54 Hz), 5.76 (br s, 1H); 13C NMR (CDCl3, 125 MHz) δ -4.31,
-3.56, 18.66, 22.25, 26.42, 38.34, 60.03, 65.96, 170.20; IR (neat)
1
solid. mp 43-45 °C; H NMR (CDCl3, 500 MHz) δ 0.07 (d, 6H),
0.88 (s, 9H), 1.2 (d, 3H, J ) 6 Hz), 1.44 (s, 9H), 1.63 (m, 1H),
3.22 (dt, 1H), 3.47 (m, 1H), 3.62 (m, 2H), 3.96 (m, 1H), 5.01 (br,
1H); 13C NMR (CDCl3, 125 MHz) δ -4.38, -3.54, 18.59, 22.40,
26.53, 29.05, 37.95, 48.45, 62.26, 69.86, 80.21, 158.10; IR (neat)
3189, 2959, 2929, 2894, 2857, 1746, 1469, 1370 cm-1; [R]27
D
-74.2° (c 0.7, CHCl3) (lit.8 [R]22 -74.1° (c 1.73, CHCl3));
D
MS (CI) m/z 230 (M + H); HRMS (CI) calcd for C11H24NO2Si
(M + H) 230.1578, found 230.1573 (-1.5 ppm error).
3410, 2956, 2931, 2891, 2859, 1695, 1511, 1470, 1391, 1367 cm-1
;
MS (CI) m/z 334 (M + H); HRMS (CI) calcd for C16H36NO4Si
Ack n ow led gm en t. The generous financial support
from GITP is gratefully acknowledged.
(M + H) 334.2415, found 334.2420 (+1.8 ppm error).
(2R,3R)-2-(ter t-Bu t oxyca r b on yla m in om et h yl)-3-(ter t-
bu tyld im eth ylsiloxy)bu tyr ic Acid (9). To a vigorously stirred
solution of alcohol 8 (0.96 g, 2.9 mmol) in CH3CN/CCl4/H2O
(1/1/1.5, 24.6 mL) were added NaIO4 (2.5 g, 11.72 mmol) and
RuCl3 (2.2.mol %, 13.1 mg). After 4 h, the reaction mixture was
diluted with CH2Cl2 (30 mL), and the layers were separated.
The upper aqueous layer was extracted with CH2Cl2 (10 mL ×
3). The combined organic extracts were dried (MgSO4), filtered,
and concentrated. The resulting residue was diluted with ether,
Su p p or tin g In for m a tion Ava ila ble: Copies of 1 H NMR
and 13C NMR spectra of compounds 2, 3, and 5-9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O000467S