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.