Efficient asymmetric synthesis of (2R,3R)-3-{(1R)-1-[tert-Butyl(dimethyl)- siloxy]ethyl}-4-oxoazetidin-2-yl acetate

Article abstract of DOI:10.1055/s-0030-1258407

(2R,3R)-3-{(1R)-1-[tert-Butyl(dimethyl)siloxy]ethyl}-4-oxoazetidin-2-yl acetate was efficiently prepared from l-ascorbic acid. The key steps were the a highly diastereoselective [2 + 2] cycloaddition of diketene with an (S)-glyceraldehyde-derived ald?imine to give the ketone, stereoselective titanium tetrachloride mediated asymmetric reduction to give the corrsponding S-configured alcohol, and Mitsunobu inversion of the latter to give the desired R-configured alcohol. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1258407

PAPER
555
Efficient Asymmetric Synthesis of (2R,3R)-3-{(1R)-1-[tert-Butyl(dimethyl)-
siloxy]ethyl}-4-oxoazetidin-2-yl Acetate
(
2
R
,3
R
)-3-
i
{(
1
R
)-
a
1-[tert-But
n
s
-
iloxy]et
P
hyl}-4-oxoaze
i
tidin-2
n
-
yl Acetate g Huang,a Lei Zhao,a Shuang-Xi Gu,a Zhong-Hua Wang,a Hao Zhang,a Fen-Er Chen,*a,b Hui-Fang Dai*c
a
b
c
Department of Chemistry, Fudan University, 220 Handan Road, 200433 Shanghai, P. R. of China
Institute of Biomedical Science, Fudan University, 305 Fenglin Road, 200032 Shanghai, P. R. of China
School of Pharmacy, Fudan University, 826 Zhangheng Road, 201203 Shanghai, P. R. of China
Fax +86(21)65643811; E-mail: rfchen@fudan.edu.cn
Received 9 November 2010; revised 15 December 2010
Many literature reports describe asymmetric syntheses of
3 by various chiral techniques.1a One of the most conve-
nient approaches that has come to our attention is the
asymmetric [2+2] cycloaddition of diketene with various
Abstract: (2R,3R)-3-{(1R)-1-[tert-Butyl(dimethyl)siloxy]ethyl}-
4-oxoazetidin-2-yl acetate was efficiently prepared from L-ascorbic
acid. The key steps were the a highly diastereoselective [2 + 2] cy-
cloaddition of diketene with an (S)-glyceraldehyde-derived ald-
imine to give the ketone, stereoselective titanium tetrachloride chiral imines derived from various chiral pools, including
ethyl (S)-lactate,3 L-menthyl glyoxylate,4 and D-manni-
mediated asymmetric reduction to give the corrsponding S-config-
tol.5 However, the use of these processes for large-scale
ured alcohol, and Mitsunobu inversion of the latter to give the de-
sired R-configured alcohol.
preparation of the intermediate is limited by problems of
unsatisfactory chemical yields or low diastereoselectivi-
ties. An asymmetric synthesis of an N-substituted b-lac-
tam with 3-(1-hydroxyethyl) and a 4-acetoxy substituents
has been reported in which commercially available L-
Key words: carbapenems, penem, heterocycles, cycloadditions,
cyclizations
ascorbic acid (4) is used as a chiral pool.6a However, when
the procedure was repeated with a p-methoxyphenyl
group as the N-protecting group, a low stereoselectivity
was observed in the reduction by potassium borohydride
in methanol–tetrahydrofuran of the side-chain acetyl
group on the b-lactam ring. Here, we describe a high-
yielding and highly stereoselective synthesis of 3 in which
the pivotal steps are a [2 + 2] cycloaddition of diketene
with the chiral imine 8 derived from 4 and bulky (diphe-
nylmethyl)amine, a highly diastereoselective titanium
tetrachloride mediated reduction of the ketone 9a with
borane–pyridine complex as the reducing agent, and a
Mitsunobu inversion of alcohol 10b to give 10a.
Over the last three decades, carbapenems (1) and penems
(2) have been a focus of synthetic attention from academia
and industry because of their unique structures and their
potent broad-spectrum antibacterial activities and excel-
lent stabilities to b-lactamases.1 Considerable efforts have
been directed at the development of simple and elegant
approaches for the synthesis of such b-lactam antibiotics.
The most common strategy for synthesizing carbapenems
1 and penems 2 involves the initial construction of an ap-
propriately substituted monocyclic b-lactam 3 with the
correct stereochemistry at the C3 and C4 positions of the
b-lactam ring, and subsequent establishment of the five-
membered heterocyclic framework by chemical manipu-
lations at the N1 and C4 positions (Scheme 1).2 (2R,3R)-
3-{(1R)-1-[tert-Butyl(dimethyl)siloxy]ethyl}-4-oxoazeti-
din-2-yl acetate (3), which has three contiguous stereo-
genic centers corresponding the C5, C6, and C8 carbons
of 1 and 2 is recognized as a versatile chiral building block
for the asymmetric syntheses of 1 and 2, because its
acetoxy group can be easily replaced by a variety of nu-
cleophiles.1a
Our asymmetric synthesis began with the preparation of
the R-configured imine 8 (Scheme 2). The (S)-glyceralde-
hyde acetonide 7 was prepared from commercially avail-
able and inexpensive L-ascorbic acid (4) by a modified
literature procedure.6b Condensation of 7 with (diphenyl-
methyl)amine in the presence of magnesium sulfate in
dichloromethane at room temperature for 30 minutes gave
the imine 8 in almost quantitative yield.
Having prepared 8, we turned our attention to the synthe-
sis of the (3S,4S)-b-lactam 9a by a strategy involving an
asymmetric [2+2] cycloaddition.4,6a When the reaction
was carried out in the presence of one equivalent of imi-
dazole and five equivalents of diketene in anhydrous tet-
rahydrofuran at –15 °C for twenty-four hours, a mixture of
(3S,4S)-b-lactam 9a and (3R,4R)-b-lactam 9b was ob-
OH
OH
TBDMSO
H
H
H
H
N
H
H
X
8
OAc
6
5
4
(S)R1
3
4
2
N
NH
O
O
O
COOH
1 X = CH2, CH(Me)
2 X = S
3
1
Scheme 1 Retrosynthetic analysis of 1 and 2
tained in 78% yield. Analysis by H NMR spectroscopy
showed the presence of a 4.7:1 ratio of 9a and 9b. The sin-
gle diastereomer 9a was obtained in 54.3% yield by re-
crystallization from ethyl acetate–petroleum ether (1:1).
To improve the diastereoselectivity of this reaction, we
screened a variety of reaction conditions (solvent, cata-
SYNTHESIS 2011, No. 4, pp 0555–0562
Advanced online publication: 17.01.2011
DOI: 10.1055/s-0030-1258407; Art ID: F19710SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
1

556
J.-P. Huang et al.
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CaCO3, H2O
30% H2O2
30–50 °C, 4 h
HO
HO
O
AcCl
acetone, r.t., 6 h
O
O
O
O
O
73%
92%
HO
OH
HO
OH
4
5
65% Ca(ClO)2
AcONa/AcOH, H2O
50 °C, 35 min
Ph
Ph
O
O
O
O
(Ph)2CHNH2, MgSO4
CH2Cl2, r.t., 0.5 h
N
COO–1/2Ca2+
OH
O
CHO
O
50%
99.7%
7
8
6
Scheme 2 Scheme for the synthesis of R-configured imine 8
lyst, and temperature); the results are summarized in
Table 1. It was evident that, of the solvents tested, tetrahy-
drofuran was best for this reaction (entries 1–4). A signif-
icant increase in diastereoselectivity occurred when 4-
methyl-1H-imidazole was used as a catalyst instead of im-
idazole (entries 4 and 6). It is noteworthy that none of the
desired product was obtained when 2-methyl-1H-imida-
zole was used as catalyst (entry 5). A decrease in the reac-
tion temperature improved the diastereoselectivity of the
cycloaddition reaction (entries 6–9), and a remarkable im-
provement in diastereoselectivity was observed when the
reaction was performed at –78 °C (entry 9). The stable
configuration of 9a was assigned on the basis of two-di-
mensional (2D) NOESY NMR spectroscopy techniques,
which showed a strong NOE interaction between the C4-
H atom (d = 4.16 ppm, dd, J = 2.4, 7.0 Hz) and the C7-H
atom (d = 4.01 ppm, m), confirming their cis orientation,
and a weak NOE correlation between the C3-H atom (d =
3.88 ppm, d, J = 2.4 Hz) and the C4-H atom, implying a
trans orientation (Figure 1).
Table 1 Optimization of Conditions for the [2+2] Cycloaddition of
Imine 8 with Diketene
O
H
O
H
H
5
7
O
Ph
3 4
N
O
Ph
9a
Ph
Ph
diketene
catalyst
O
N
+
O
O
O
H
O
H
H
8
O
Ph
N
Ph
9b
Entry Conditionsa
Yield Ratio
(%)b 9a/9bc
1
2
3
4
5
6
7
8
9
imidazole, toluene, –15 °C, 24 h
imidazole, CH2Cl2, –15 °C, 24 h
imidazole, MeCN, –15 °C, 24 h
imidazole, THF, –15 °C, 24 h
71
82
84
78
–
2.5:1
3.3:1
4.1:1
4.7:1
–
weak NOE
strong NOE
weak NOE
H
H
O
H
O
H
H
O
HO
H
H
2-methyl-1H-imidazole, THF, –15 °C, 24 h
4-methyl-1H-imidazole, THF, –15 °C, 24 h
4-methyl-1H-imidazole, THF, –35 °C, 72 h
5
7
5
7
O
3
4
O
3
4
N
strong NOE
N
78
82
8.0:1
12.8:1
18.1:1
23:1
Ph
Ph
O
O
Ph
Ph
H
H
O
H
HO
H
9a
10a
4-methyl-1H-imidazole,, THF, –55 °C, 120 h 87
4-methyl-1H-imidazole,, THF, –78 °C, 168 h 85
5
7
O
3 4
N
Ph
O
a General reaction conditions: the reaction was carried out in the pres-
ence of catalyst (1 equiv) and diketene (5 equiv) in anhyd solvent.
b Yield of crude products.
Ph
10b
c Determined by 1H NMR spectroscopy by integration of the signals
for the acetyl protons, which appeared as two singlets in the isomeric
mixture.
Figure 1 NOE correlations for 9a, 10a, and 10b
In attempts to prepare azetidinone 10a, three sets of reduc-
ing systems (potassium borohydride in methanol–tetrahy- highly diastereoselective titanium tetrachloride mediated
drofuran, potassium tris(sec-butyl)borohydride and reductions of a-chiral ketones using borane–pyridine as a
potassium iodide in tetrahydrofuran, and potassium tri- reducing reagent have been reported,8 and, interestingly,
ethyborohydride in tetrahydrofuran)6a,7 were examined the reduction of 9a also proceeded well upon treatment
for the stereoselective reduction of 9a. A diastereoisomer- with titanium tetrachloride in tetrahydrofuran at –78 °C
ic mixture of 10a and its epimer 10b was obtained with for 10 minutes followed by diastereoselective reduction
low diastereoselectivity (Table 2, entries 1–3). Several with borane–pyridine at –78 °C for 15 minutes; 10b and
Synthesis 2011, No. 4, 555–562 © Thieme Stuttgart · New York

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(2R,3R)-3-{(1R)-1-[tert-Butyl(dimethyl)siloxy]ethyl}-4-oxoazetidin-2-yl Acetate
557
Table 2 Optimization of Diastereoselective Reduction of b-Lactam 9a
OH
H
OH
H
O
H
O
O
O
H
H
H H
H
H
N
5
5
O
O
O
3
4
3
4
+
N
N
Ph
Ph
Ph
O
O
O
Ph
Ph
Ph
9a
10a
10b
Entry
Reaction system
Temp (°C)
–20
Time (min)
Yield (%)
Ratio 10a/10ba
1.5:1
1
2
3
4
5
6
7
KBH4, THF–MeOH
K(s-Bu)3BH, KI, THF
KEt3BH, THF
40
15
25
25
25
25
25
99
99
99
98
99
98
99
0
2.5:1
–78
5.9:1
TiCl4, Py⋅BH3, THF
–78
1:21
TiCl4,(i-Pr)2NH⋅BH3, THF
TiCl4, BH3⋅THF
–78
1:13.6
1:6.3
–78
TiCl4, KBHEt3, THF
–78
1:4.8
a Determined by 1H NMR of the mixture of 10a and 10b.
its epimer 10a were obtained in 98% yield with excellent The diastereoselectivity of this reduction can be explained
diastereoselectivity (dr 21:1; Table 2, entry 4). A 75% in terms of the formation of a chelate of 9a with titanium
yield of pure 10b was obtained by recrystallization from tetrachloride to give intermediate 9c, and attack by pyri-
ethyl acetate. Note that a low diastereoselectivity was ob- dine–borane at the less hindered re-face of the carbonyl
served when borane–pyridine was replaced with other re- group of 9c to give diastereomer 10b predominantly
ducing agents under the same conditions (Table 2, entries (Scheme 3).8
5–7).
Inversion of the azetidinone 10b to the desired diastereo-
The stable configuration of 10b was characterized by isomer 10a was performed by Mitsunobu reaction with di-
means of a 2D NOESY experiment, which showed a ethyl azodicarboxylate, triphenylphosphine, and benzoic
strong NOE correlation between the C3-H proton (d = acid at room temperature for 2.5 hours, and subsequent al-
2.83 ppm, dd, J = 2.4, 6.4 Hz) and the C5-H proton (d = kaline hydrolysis of the resulting R-configured formate
4.03 ppm, m), suggesting that the hydroxy group at the C5 10c to provide the desired azetidinone 10a in 88% overall
position in 10b adopts an S-configuration (Figure 1). This yield (Scheme 4).10 2D NOESY experiments showed that
absolute configuration was confirmed by means of X-ray the hydroxy group at the C5 position in 10a adopts an R-
diffraction (Figure 2).9 Furthermore, the single-crystal configuration, resulting in a weak NOE correlation be-
configuration of 10b established that the framework of 9a tween the C3-H proton (d = 2.79 ppm, dd, J = 2.4, 6.8 Hz)
had been correctly assigned.
and the C5-H proton (d = 3.72 ppm, m) (Figure 1).
Another attempt at inversion of 10b into 10a was made by
mesylation of 10b with mesyl chloride and triethylamine,
followed by SN2 neucleophilic replacement with 1,8-di-
azabicyclo[5.4.0]undec-7-ene and acetic acid in dichlo-
romethane. This gave a separable mixture of 10e and two
byproducts 10f and 10g in a ratio of 60:35:5.11 10e, isolat-
ed by chromatography, was smoothly hydrolyzed to 10a
by treatment with potassium carbonate in methanol.
Acetonide 10a was deprotected in the presence of 1 M
aqueous sulfuric acid at room temperature for 24 hours to
give the vicinal diol 11 in 80% yield (Scheme 5). Oxida-
tion of the diol 11 by treatment with silica gel supported
sodium metaperiodate (Shing’s protocol)12 gave aldehyde
12 in 92% yield. Potassium permanganate mediated selec-
tive oxidation of 12 under alkaline condition in aqueous
tetrahydrofuran at room temperature gave the acid 13 in
86% yield.13 Acid 13 was converted into the correspond-
ing acetate 14 in 72% yield by treatment with lead tetra-
N,N-dimethylformamide.13
Figure 2 X-ray crystal structure of 10b
acetate in anhydrous
Synthesis 2011, No. 4, 555–562 © Thieme Stuttgart · New York

558
J.-P. Huang et al.
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9a
TiCl4
OH
O
O
O
H
H
N
Ph
Si
N
H2B
Re
O
O
Si
Ph
unfavored 10a
H
H
N
BH3⋅py
H
O
O
O
O
H
H
N
Cl4Ti
O
Ph
Re
OH
O
O
Cl4Ti
Ph
O
Ph
H
H
N
9c
Ph
O
Ph
Ph
favored 10b
Scheme 3 Proposed mechanism for the titanium-mediated reduction of azetidinone 9a
O
PhCOO
O
H
H
N
Ph3P, BzOH
DEAD, THF, 0–25 °C
2.5 h
K2CO3, MeOH
r.t., 2 h
10a
Ph
89%
99 %
O
Ph
K2CO3, MeOH
r.t., 2 h
10c
10b
OMs
O
OAc
O
O
MsCl, Et3N
DBU, AcOH
toluene
80 °C, 4 h
O
O
O
H
H
N
H
H
N
H
CH2Cl2
0–25 °C, 2 h
3
4
+
N
80%
Ph
Ph
Ph
O
O
O
Ph
10d
Ph
10e
Ph
(E)-10f / (Z)-10g
Scheme 4 Synthetic scheme for the preparation of 10a
Subsequently, alcohol 14 was protected by treatment with
chloro(tert-butyl)(dimethyl)silane in the presence of imi-
dazole in anhydrous N,N-dimethylformamide at room
temperature for 12 h to give ester 15 in 82% yield. The N-
benzhydryl group of ester 15 was cleaved by treatment
with a stoichiometric amount of N-bromosuccinimide and
a catalytic amount of bromine under UV irradiation in
dichloromethane/water. Hydrolysis with 4-toluenesulfon-
ic acid in aqueous acetone provided the b-lactam 3 in 68%
overall yield.14
OH
O
OH
OH
H
H
N
NaIO4/SiO2/H2O
H2SO4, MeOH
r.t., 24 h
CH2Cl2, r.t., 20 min
10a
80%
92%
Ph
Ph
11
KMnO4, K2CO3
THF, H2O, r.t.
24 h
OH
O
OH
H
H
H
H
N
Pb(OAc)4, AcOH
DMF, 65 °C, 2 h
CHO
COOH
Ph
86%
72%
N
Ph
O
In conclusion, we have developed a convenient asymmet-
ric synthesis of the azetidinone 3 starting from L-ascorbic
acid. Further efforts toward the asymmetric syntheses of
carbapenems (1) and penems (2) by utilizing this pivotal
intermediate are underway, and will be reported in due
course.
Ph
12
Ph
13
NBS, Br2 (cat.)
CH2Cl2/H2O
hν, r.t., 3 h;
then p-TsOH
MeCN–H2O
OAc
dark, r.t., 12 h
OH
O
OTBDMS
TBDMSCl
imidazole
H
H
N
H
H
OAc
DMF, r.t., 12 h
3
68 %
82%
N
Ph
Ph
O
Ph
14
Ph
15
Anhydrous (anhyd) THF was distilled from sodium/benzophenone
before use. Anhyd CH2Cl2 and toluene were distilled from CaH2.
Anhyd DMF was distilled from CaH2 under reduced pressure. Other
reagents were obtained from commercial sources and were used as
received. All melting points were measured on a WRS-1B digital
Scheme 5 Scheme for the synthesis of azetidinone 3
melting-point apparatus and are uncorrected. 1H (400 MHz) and 13
C
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(2R,3R)-3-{(1R)-1-[tert-Butyl(dimethyl)siloxy]ethyl}-4-oxoazetidin-2-yl Acetate
559
(100 MHz) NMR spectra were recorded on a Bruker Avance 400
spectrometer in CDCl3, CD3OD, or D2O using TMS and CDCl3
(13C, d = 77.0) or CD3OD (13C, d = 49.0) as internal standards. Cou-
pling constants (J values) are given in hertz. Mass spectra were re-
13C NMR (100 MHz, CDCl3): d = 201.54, 111.07, 79.73, 65.36,
26.09, 24.99.
MS (EI): m/z = 130 [M]+.
corded on
a Waters Quattro Micromass instrument using
[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methylene}-1,1-diphenyl-
methanamine (8)
electrospray ionization techniques. IR spectra were recorded on a
Jasco FT/IR-4200 spectrometer. Optical rotations were measured
on a Jasco P1020 digital polarimeter.
A mixture of aldehyde 7 (26.2 g, 0.2 mol), Ph2CHNH2 (36.6 g, 0.2
mol), CH2Cl2 (130 mL), and anhyd MgSO4 (26 g) was stirred at r.t.
for 30 min. The suspension was filtered and the filtrate was concen-
trated under reduced pressure to give a colorless oil; yield: 59 g
(99.7%). This was used directly in the next step without any further
purification.
5,6-O-Isopropylidene-L-ascorbic Acid (5)
AcCl (88 mL, 1.24 mol) was added dropwise to a stirred soln of L-
ascorbic acid (4, 200 g, 1.136 mol) in acetone (500 mL) and the
mixture was stirred at 40 °C for 2 h. The mixture was then cooled to
0 °C and filtered. The residue was washed with cold acetone (200
mL) and dried to give a white solid; yield: 179 g (73%); mp 208.3–
208.4 °C (Lit.15 218–219 °C).
IR (CHCl3): 3061, 3026, 2986, 2935, 2870, 1671, 1493, 1453, 1371
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.30 (s, 3 H, CH3), 1.33 (s, 3 H,
CH3), 3.91 (dd, J = 6.0, 8.4 Hz, 1 H, OCH2), 4.12 (dd, J = 6.8, 8.4
Hz, 1 H, OCH2), 4.62 (td, J = 4.8, 6.0, 6.8 Hz, 1 H, CHCH2O), 5.34
(s, 1 H, CHPh), 7.10–7.23 (m, 10 H, ArH), 7.72 (d, J = 4.8 Hz, 1 H,
CH=N).
13C NMR (100 MHz, CDCl3): d = 163.56, 142.99, 142.89, 128.49,
127.58, 127.46, 127.14, 127.11, 110.19, 67.38, 26.49, 25.41.
IR (KBr): 3241, 3080, 1754, 1663 cm–1.
1H NMR (400 MHz, CD3OD): d = 1.34 (s, 3 H, CH3), 1.35 (s, 3 H,
CH3), 4.05 (dd, J = 6.6, 8.8 Hz, 1 H, OCH2), 4.19 (dd, J = 6.6, 8.0
Hz, 1 H, OCH2), 4.34 (m, 1 H, OCHCH2), 4.68 (d, J = 4.4, 1 H,
CHCOH), 4.90 (br, 2 H, OH).
13C NMR (100 MHz, CD3OD): d = 153.32, 118.61, 109.73, 75.49,
69.23, 65.06, 62.16, 24.85, 24.30.
MS (EI): m/z = 295.4 [M]+.
Anal. Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74. Found: C,
77.18; H, 7.15; N, 4.75.
Calcium Bis[(2R)-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl](hy-
droxy)acetate] (6)
30% aq H2O2 (315 mL) was added to a vigorously stirred suspen-
sion of lactone 5 (170 g, 0.787 mol), CaCO3 (157.4 g, 1.574 mol),
and antifoaming agent (2 drops) in H2O (1 L) while the temperature
of the mixture was kept at 30–35 °C. The mixture was stirred at r.t.
for 3 h and then at 50 °C for 1 h. Excess H2O2 was destroyed by ad-
dition of activated MnO2 (1.7 g, 19.5 mmol), and stirring was con-
tinued at 50 °C for 30 min. The mixture was filtered and the filtrate
was concentrated to ~240 mL in vacuo. Acetone (800 mL) was add-
ed, and the mixture was cooled to below 10 °C and kept overnight.
The suspension was filtered and the residue was dried to give a
white solid; yield: 141 g (92%); mp 258.3–260.1 °C (dec.) (Lit.16
257–261 °C); [a]D25 +23.8 (c 0.9, H2O) [Lit.16 +23.6 (c 0.974,
H2O)].
(3S,4S)-3-Acetyl-4-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-
(diphenylmethyl)azetidin-2-one (9a)
Diketene (30 mL) was added dropwise to a soln of amine 8 (22 g,
74.5 mmol) and 4-methyl-1H-imidazole (6.35 g, 77.4 mmol) in anhyd
THF (150 mL) at –78 °C, and the mixture was stirred at –78 °C for
7 d. The solvent was evaporated and CH2Cl2 (300 mL) was added
to the residue. The resulting mixture was washed successively with
1 M H2SO4 (2 × 40 mL), 2 M NaOH (20 mL), and H2O. The organic
layer was dried (MgSO4) and concentrated in vacuo to give a 23:1
mixture of 9a and 9b; yield: 24 g (85%). The residue was crystal-
lized from EtOAc–PE (1:1) to give the single isomer 9a as a white
solid; yield: 19.2 g (68%); mp 101.1–101.9 °C; [a]D23 +50.8 (c 1,
CHCl3).
IR (KBr): 3391, 1611 cm–1.
IR (KBr): 3025, 2979, 2967, 2935, 2885, 1761, 1709 cm–1.
1H NMR (400 MHz, D2O): d = 1.29 (s, 3 H, CH3), 1.37 (s, 3 H,
CH3), 3.88 (dd, J = 6.8, 8.4 Hz, 1 H, OCH2), 3.96 (d, J = 4.9 Hz, 1
H, CHOH), 4.07 (dd, J = 6.8, 8.4 Hz 1 H, OCH2), 4.33–4.38 (m, 1
H, OCH).
13C NMR (100 MHz, D2O): d = 109.85, 77.06, 72.22, 65.52, 25.20,
24.12.
1H NMR (400 MHz, CDCl3): d = 1.23 (s, 3 H, CH3), 1.33 (s, 3 H,
CH3), 2.29 (s, 3 H, CH3), 3.61 (dd, J = 6.0, 9.0 Hz, 1 H, OCH2), 3.81
(dd, J = 6.8, 9.0 Hz, 1 H, OCH2), 3.88 (d, J = 2.4 Hz 1 H, C3H), 4.01
(m, 1 H, OCH), 4.16 (dd, J = 2.4, 7.0 Hz, 1 H, C4H), 5.90 (s, 1 H,
CHPh), 7.24–7.36 (m, 10 H, ArH).
13C NMR (100 MHz, CDCl3): d = 199.35, 162.13, 138.80, 138.74,
128.60, 128.52, 128.43, 127.99, 127.77, 127.74, 110.33, 76.47,
65.47, 63.57, 62.67, 55.24, 29.78, 26.55, 24.78.
MS (ESI): m/z = 175.2 [M + Ca]+.
MS (EI): m/z = 379 [M]+.
(4S)-2,2-Dimethyl-1,3-dioxolane-4-carbaldehyde (7)
NaOAc (171 g, 2.09 mol) and AcOH (165 mL, 2.90 mol) were add-
ed to a stirred suspension of calcium salt 6 (97.2 g, 0.50 mol) in H2O
(1.25 L) at r.t., and the mixture was heated to 50 °C. 65% solid
Ca(OCl)2 (65.7 g) was added portionwise over 35 minute. The heat-
er was then removed and the pH of the mixture was adjusted to 8
with Na2CO3. The suspension was filtered and the residue was
washed with CH2Cl2 (3 × 200 mL). The organic phase was separat-
ed and the aqueous layer was extracted with CH2Cl2 (6 × 50 mL).
The combined organic phases were collected, dried (MgSO4), fil-
tered, and concentrated in vacuo to give a colorless oil; yield: 32.4
g (50%); [a]D25 –63.7 (c 1.0, CHCl3) (Lit.15 –63.5).
Anal. Calcd for C23H25NO4: C, 72.80; H, 6.64; N, 3.69. Found: C,
72.71; H, 6.66; N, 3.70.
(3S,4S)-4-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-(diphenyl-
methyl)-3-[(1R)-1-hydroxyethyl]azetidin-2-one (10a) and
-3-[(1S)-1-hydroxyethyl]azetidin-2-one (10b)
TiCl4 (0.88 mL) was added to a soln of ketone 9a (2.68 g, 7.05
mmol) in anhyd CH2Cl2 at –78 °C, and the mixture was stirred for
10 min. BH3⋅py (0.66 g, 7.1 mmol) was slowly added and the mix-
ture was stirred at –78 °C for 15 min. 1 N HCl (5 mL) was added,
and the temperature of the mixture rose to 25 °C. The organic phase
was washed successively with 1 M H2SO4 (2 × 5 mL) and H2O (2 ×
5 mL), dried (MgSO4), filtered, and concentrated in vacuo to give
1:21 epimeric mixture of 10a and 10b; yield: 2.64 g (98%). This
IR (CHCl3): 2988, 1735 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.32 (s, 3 H, CH3), 1.39 (s, 3 H,
CH3), 4.00–4.10 (m, 2 H, OCH2), 4.29–4.32 (m, 1 H, OCHCH2),
9.61 (d, J = 2.0 Hz, 1 H, CHO).
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J.-P. Huang et al.
PAPER
was recrystallized (EtOAc) to give pure 10b as a white solid; yield:
2.02 g (75%); mp 142.5–142.7 °C.
IR (KBr): 3463, 1717 cm–1.
13C NMR (100 MHz, CDCl3): d = 21.39, 24.29, 26.06, 56.53, 57.84,
61.69, 64.94, 65.20, 109.63, 127.14, 127.74, 127.92, 128.02,
128.22, 138.32, 138.98, 166.54.
MS (ESI): m/z = 382 [M + H]+.
1H NMR (400 MHz, CDCl3): d = 1.22 (s, 3 H, CH3), 1.26 (d, J = 6.4
Hz, 3 H, CH3CH), 1.32 (s, 3 H, CH3), 2.83 (dd, J = 2.4, 6.4 Hz, 1 H,
C3H), 3.57 (dd, J = 2.4, 7.6 Hz, 1 H, C4H), 3.62 (dd, J = 6.0, 8.8 Hz,
1 H, OCH2), 3.82 (dd, J = 6.8, 8.8 Hz, 1 H, OCH2), 4.03 (m, 2 H,
CHOH, OCH), 5.93 (s, 1 H, CHPh), 7.27–7.35 (m, 10 H, ArH).
13C NMR (100 MHz, CDCl3): d = 21.33, 24.82, 26.61, 56.42, 57.34,
62.21, 65.55, 66.14, 77.13, 110.18, 127.67, 127.71, 128.20, 128.45,
128.55, 128.72, 138.66, 139.34, 167.82.
Anal. Calcd for C23H27NO4: C, 72.47; H, 7.13; N, 3.67. Found: C,
72.54; H, 7.14; N, 3.66.
(1R)-1-[(2S,3S)-2-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-
(diphenylmethyl)-4-oxoazetidin-3-yl]ethyl Methanesulfonate
(10d)
MsCl (0.30 g, 2.62 mmol) was added dropwise to a soln of 10b (0.5
g, 1.31 mmol) and Et3N (0.40 g, 3.93 mmol) in CH2Cl2 (10 mL)
cooled to 0 °C in an ice bath. When the addition was complete, the
mixture was stirred at r.t. for 2 h. The reaction was then quenched
with 1 M aq HCl (6 mL). The organic phase was separated, washed
with 5% aq NaHCO3 (10 mL), dried (MgSO4), and concentrated un-
der reduced pressure to give a crude product that was purified by
chromatography [silica gel, EtOAc–PE (1:5)] to give a colorless oil;
yield: 0.48 g (80%).
MS (EI): m/z = 381 [M]+.
Anal. Calcd for C23H27NO4: C, 72.47; H, 7.13; N, 3.67. Found: C,
72.57; H, 7.14; N, 3.66.
Crystallographic data for compound 10b have been deposited with
the Cambridge Crystallographic Data Centre as supplementary pub-
lication CCDC 654872; copies can be obtained free of charge on ap-
plication to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44(1223)336033 or email: deposit@ccdc.cam.ac.uk].
IR (CHCl3): 1644 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.24 (s, 3 H, CH3), 1.37 (s, 3 H,
CH3), 1.52 (d, J = 6.4 Hz, 3 H, CH3CH), 2.89 (s, 3 H, CH3SO), 3.10
(dd, J = 2.4, 3.6 Hz, 1 H, C3H), 3.65 (dd, J = 6.0, 8.4 Hz, 1 H,
OCH2), 3.73 (dd, J = 2.4, 7.2 Hz, 1 H, C4H), 3.86 (dd, J = 6.4, 8.4
Hz, 1 H, OCH2), 4.09 (m, 1 H, CHCH2), 4.99–5.05 (m, 1 H, CHOS,
5.94 (s, 1 H, CHPh), 7.28–7.38 (m, 10 H, ArH).
13C NMR (100 MHz, CDCl3): d = 162.69, 137.73, 137.40, 126.87,
126.57, 126.35, 126.10, 125.53, 107.62, 75.62, 73.38, 63.70, 60.51,
54.08, 52.97, 36.13, 24.69, 23.37, 16.76.
(1R)-1-[(2S,3S)-2-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-
(diphenylmethyl)-4-oxoazetidin-3-yl]ethyl Benzoate (10c)
A soln of DEAD (1.43 mL) in anhyd THF (5 mL) was added drop-
wise to a soln of 10b (2.0 g, 5.24 mmol), Ph3P (5.34 g, 20.4 mmol),
and BzOH (0.64 g, 5.24 mmol) in anhyd THF (55 mL) at r.t., and
the mixture was stirred at the r.t. for 2.5 h. The mixture was then
poured into phosphate buffer (pH 5; 100 mL) and extracted with
EtOAc (3 × 20 mL). The solvent was evaporated and the residue
was washed with hot H2O to give a white solid; yield: 2.27 g (89%);
mp 91.6–93.2 °C.
Anal. Calcd for C24H29NO6S: C, 62.73; H, 6.36; N, 3.05. Found: C,
62.80; H, 6.34; N, 3.04.
IR (KBr): 1733, 1716 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.21 (s, 3 H, CH3), 1.31 (s, 3 H,
CH3), 1.47 (d, J = 6 Hz 3 H, CH3CH), 3.06 (dd, J = 2.4, 7.6 Hz, 1
H, C3H), 3.57 (dd, J = 6.8, 8.4 Hz, 1 H, OCH2), 3.80 (dd, J = 2.4,
7.6 Hz, 1 H,C4H), 3.85 (dd, J = 6.4, 8.4 Hz, 1 H, OCH2), 4.09 (m, 1
H, CHCH2O), 5.43–5.50 (m, 1 H, OCHCH3), 5.94 (s, 1 H, CHPh),
7.29–7.58 (m, 15 H, ArH).
13C NMR (100 MHz, CDCl3): d = 165.59, 165.24, 139.36, 138.79,
133.16, 129.61, 128.78, 128.58, 128.50, 128.48, 128.08, 127.74,
127.66, 110.27, 68.86, 65.90, 62.35, 57.84, 56.29, 26.56, 24.89,
18.88.
(1R)-1-[(2R,3R)-2-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-
(diphenylmethyl)-4-oxoazetidin-3-yl]ethyl Acetate (10e) and
(3E,4S)- and (3Z,4S)-4-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-
(diphenylmethyl)-3-ethylideneazetidin-2-one (10f and 10g)
AcOH (0.11 g, 1.76 mmol) was added to a soln of DBU (0.13 g,
0.88 mmol) in toluene (5 mL) and the mixture was stirred at r.t. for
30 min. Mesylate 10d (0.20 g, 0.44 mmol) was then added and the
mixture was heated at 80 °C with stirring for 4 h. The mixture was
then cooled to r.t., diluted with toluene (20 mL), and washed suc-
cessively with 1 M HCl (5 mL), 5% aq NaHCO3 (10 mL), and brine
(10 mL). The organic phase was dried (MgSO4) and concentrated
under reduced pressure to give a crude mixture that was separated
by flash chromatography [EtOAc–PE (1:8)] to give 10e as a color-
less oil; yield 0.09 g (52%). The elimination byproducts 10f and 10g
were also obtained as colorless oils; yield: 10f: 0.053 g (29%); 10g:
0.007 g (4%).
MS (ESI): m/z = 486.5 [M + H]+.
Anal. Calcd for C30H31NO5: C, 74.21; H, 6.43; N, 2.88. Found: C,
74.31; H, 6.42; N, 2.87.
(3S,4S)-4-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-(diphenyl-
methyl)-3-[(1R)-1-hydroxyethyl]azetidin-2-one (10a)
Benzoate 10c (2.27 g, 4.67 mmol) was dissolved in MeOH (30 mL).
K2CO3 (2 g, 14.4 mmol) was added and the mixture was stirred at
r.t. for 30 min, then concentrated in vacuo. The residue was mixed
with CH2Cl2 (30 mL) and H2O (30 mL), and the organic phase was
dried (MgSO4) and concentrated under reduced pressure to give a
white solid; yield: 1.76 g (99%); mp 102.5–103.5 °C; [a]D22 +38.8
(c 1, MeOH).
10e
1H NMR (400 MHz, CDCl3): d = 1.24 (s, 3 H, CH3), 1.34 (d, J = 6.4
Hz, 3 H, CH3CH), 1.36 (s, 3 H, CH3), 1.99 (s, 3 H, CH3CO), 2.92
(dd, J = 2.4, 7.2 Hz, 1 H, C3H), 3.63 (dd, J = 6.4, 8.8 Hz, 1 H,
OCH2), 3.68 (dd, J = 2.4, 7.2 Hz, 1 H, C4H), 3.84 (dd, J = 6.4, 8.4
Hz, 1 H, OCH2), 4.05 (m, 1 H, CHCH2O), 5.17 (m, 1 H, CH3CH),
5.93 (s, 1 H, CHPh), 7.28–7.38 (m, 10 H, ArH).
IR (KBr): 3427, 1720 cm–1.
13C NMR (100 MHz, CDCl3): d = 18.75, 21.15, 24.86, 26.61, 56.07,
57.48, 62.30, 65.70, 68.22, 77.23, 110.28, 127.71, 128.18, 128.45,
128.58, 128.70, 138.79, 139.35, 165.46, 169.94.
1H NMR (400 MHz, CDCl3): d = 1.23 (s, 3 H, CH3), 1.27 (d, J = 2.4
Hz, 3 H, CH3), 1.35 (s, 3 H, CH3), 2.79 (dd, J = 2.4, 6.8 Hz, 1 H,
C3H), 3.69–3.75 (m, 2 H, HOCH, OCH2), 3.78 (dd, J = 6.4, 8.8 Hz,
1 H, OCH2), 4.03 (dd, J = 6.8, 12.6 Hz, 1 H, C4H), 4.08–4.12 (m, 1
H, CHOH), 5.95 (s, 1 H, CHPh), 7.27–7.36 (m, 10 H, ArH).
Anal. Calcd for C25H29NO5: C, 70.90; H, 6.90; N, 3.31. Found: C,
70.84; H, 7.00; N, 3.32.
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(2R,3R)-3-{(1R)-1-[tert-Butyl(dimethyl)siloxy]ethyl}-4-oxoazetidin-2-yl Acetate
561
10f
C4H), 4.27–4.29 (m, 1 H), 6.12 (s, 1 H, CHPh), 7.22–7.34 (m, 10 H,
ArH), 8.98 (d, J = 4.4 Hz, 1 H, CHO).
13C NMR (100 MHz, CDCl3): d = 21.07, 59.10, 59.46, 60.48, 60.94,
127.75, 128.72, 128.88, 129.08, 128.62, 138.12, 138.37, 167.16,
198.27.
1H NMR (400 MHz, CDCl3): d = 1.24 (s, 3 H, CH3), 1.35 (s, 3 H,
CH3), 2.04 (d, J = 7.2 Hz, 3 H, CH3CH), 3.66–3.71 (m, 1 H, OCH2),
3.86–3.91 (m, 1 H, OCH2), 4.05 (d, J = 3.6 Hz, 1 H, C4H), 4.03–
4.09 (m, 1 H, CHCH2O), 5.63 (q, J = 7.2 Hz, 1 H, CH3CH), 6.04 (s,
1 H, CHPh), 7.27–7.37 (m, 10 H, ArH).
MS (ESI): m/z = 310 [M + H]+.
13C NMR (100 MHz, CDCl3): d = 14.74, 24.95, 26.58, 61.15, 62.13,
65.81, 109.72, 126.68, 127.55, 127.66, 128.19, 128.43, 128.48,
128.87, 136.86, 138.92, 139.73, 163.86.
Anal. Calcd for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C,
73.75; H, 6.20; N, 4.54.
Anal. Calcd for C23H25NO3: C, 76.01; H, 6.93; N, 3.85. Found: C,
76.04; H, 6.92; N, 3.86.
(2R,3R)-1-(Diphenylmethyl)-3-[(1R)-1-hydroxyethyl]-4-oxoaze-
tidine-2-carboxylic Acid (13)
A mixture of KMnO4 (3.8 g, 24.3 mmol) and K2CO3 (5.0 g, 36.5
mmol) in H2O (80 mL) was added to a soln of 12 (5 g, 16.2 mmol)
in THF (120 mL), and the mixture was stirred at r.t. for 12 h. The
precipitated inorganic materials were filtered off, and the THF was
evaporated in vacuo. The aqueous layer was washed with EtOAc (2
× 10) to remove neutral compounds and then acidified to pH 4 with
6 M HCl and extracted again with EtOAc (3 × 20). The organic lay-
er was dried (MgSO4) and concentrated in vacuo to give white crys-
tals; yield: 4.52 g (86%); mp 172.3–172.8 °C; [a]D21.6 +0.144 (c
1.46, MeOH).
10g
1H NMR (400 MHz, CDCl3): d = 1.21 (s, 3 H, CH3), 1.36 (s, 3 H,
CH3), 1.79 (d, J = 7.6 Hz, 3 H, CH3CH), 3.69 (m, 1 H, OCH2), 3.77
(m, 1 H, OCH2), 4.01–4.06 (m, 1 H, CHCH2O), 4.34 (d, J = 5.6 Hz,
1 H, C4H), 6.04 (s, 1 H, CHPh), 6.29 (dq, J = 1.2, 7.6 Hz, 1 H,
CH3CH), 7.27–7.37 (m, 10 H, ArH).
Anal. Calcd for C23H25NO3: C, 76.01; H, 6.93; N, 3.85. Found: C,
76.03; H, 6.94; N, 3.86.
(3R,4R)-4-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-(diphenyl-
methyl)-3-[(1S)-1-hydroxyethyl]azetidin-2-one (10a) (Alterna-
tive Route)
K2CO3 (0.06 g, 0.46 mmol) was added to a soln of 10e (0.09 g, 0.23
mmol) in MeOH (5 mL) at r.t., and the mixture was stirred for 30
min then concentrated in vacuo. The residue was mixed with
CH2Cl2 (5 mL) and H2O (5 mL). The organic phase was dried
(MgSO4) and concentrated under reduced pressure to give a white
solid; yield: 0.086 g (98%).
IR (KBr): 3528, 3480, 1707, 1735 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.27 (d, J = 6.4 Hz, 3 H, CH3),
3.24 (dd, J = 2.4, 3.2 Hz, 1 H, C3H), 4.19 (d, J = 2.4 Hz, 1 H, C4H),
4.24–4.30 (m, 1 H), 5.92 (s, 1 H, CHPh), 7.14–7.25 (m, 10 H, ArH).
13C NMR (100 MHz,CDCl3): d = 21.24, 52.75, 61.87, 62.52, 63.83,
127.92, 128.40, 128.48, 128.56, 128.62, 137.98, 138.13, 167.61,
174.86.
MS (ESI): m/z = 347.4 [M + Na]+.
Anal. Calcd for C19H19NO4: C, 70.14; H, 5.89; N, 4.31. Found: C,
70.18; H, 5.88; N, 4.32.
(3R,4R)-4-[(1R)-1,2-Dihydroxyethyl]-1-(diphenylmethyl)-3-
[(1S)-1-hydroxyethyl]azetidin-2-one (11)
1 M H2SO4 (78 mL) was added to a soln of 10a (10 g, 26.2 mmol)
in MeOH (100 mL), and the mixture was stirred at r.t. for 24 h. The
pH of the mixture was the adjusted to 7 with sat. aq NaHCO3. The
MeOH was evaporated off, and the aq layer was extracted with
EtOAc. The combined organic phase was dried (MgSO4) and con-
centrated in vacuo to give a white solid; yield 7.1 g (80%). This was
used directly in the next step without further purification.
(2R,3R)-1-(Diphenylmethyl)-3-[(1R)-1-hydroxyethyl]-4-oxoaze-
tidin-2-yl Acetate (14)
AcOH (6 mL) and Pb(OAc)4 (6.5 g, 14.8 mmol) were added succes-
sively to a soln of acid 13 (4 g, 12.3 mmol) in anhyd DMF (40 mL),
and the suspension was heated at 65 °C for 2 h under N2. The mix-
ture was then added to H2O (40 mL) and extracted with EtOAc (2 ×
50 mL). The combined organic phases were washed with sat. aq
NaHCO3, dried (MgSO4), and concentrated in vacuo to give a white
solid; yield: 3.0 g (72%); [a]D30 +24.9 (c 1.1, MeOH).
IR (KBr): 3394, 1731 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.21 (d, J = 6.4 Hz, 3 H, CH3),
2.80 (dd, J = 2.4, 8.0 Hz 1 H, C3H), 3.45–3.55 (m, 2 H, OCH2),
3.61–3.65 (m, 2 H, CH3CHOH, C4H), 3.85–3.92 (m, 1 H,
CHOHCH2), 5.94 (s, 1 H, CHPh), 7.23–7.34 (m, 10 H, ArH).
13C NMR (100 MHz, CDCl3): d = 21.7, 58.16, 59.08, 62.83, 64.25,
66.28, 74.48, 127.73, 127.76, 128.05, 128.54, 128.66, 128.75,
138.89, 139.45, 167.41.
IR (KBr): 3460, 1767, 1748 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.22 (d, J = 6.4 Hz, 3 H, CH3CH),
1.82 (s, 3 H, COCH3), 2.58 (d, J = 3.6 Hz, 1 H, OH), 3.04 (dd,
J = 0.8, 6.8 Hz, 1 H, C3H), 4.01–4.05 (m, 1 H, CH3CH), 5.74 (d,
J = 0.8 Hz, 1 H, C4H), 5.93 (s, 1 H, CHPh), 7.14–7.27 (m, 10 H,
ArH).
13C NMR (100 MHz CDCl3): d = 20.80, 20.92, 60.89, 64.38, 65.11,
79.29, 127.73, 128.09, 128.13, 128.51, 128.56, 128.78, 137.75,
138.46, 165.59, 170.54.
MS (ESI): m/z = 363.4 [M + Na]+.
Anal. Calcd for C20H23NO4: C, 70.36; H, 6.79; N, 4.10. Found: C,
70.33; H, 6.80; N, 4.09.
MS (ESI): m/z = 362 [M + Na]+.
(2R,3R)-1-(Diphenylmethyl)-3-[(1R)-1-hydroxyethyl]-4-oxoaze-
tidine-2-carbaldehyde (12)
NaIO4 supported on silica gel (21.5 g, mNaIO4/mSiO2/mH2O 1:4:2) was
added to a soln of 11 (5 g, 14.7 mmol) in CH2Cl2 (50 mL), and the
mixture was stirred at r.t. for 3 h then filtered. The filtrate was con-
centrated in vacuo to give a white solid; yield: 4.18 g (92%). This
was used directly in the next step without further purification.
IR (KBr): 3420, 1733, 1715 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.20 (d, J = 6.4 Hz, 3 H, CH3),
3.08 (dd, J = 2.4, 3.6 Hz, 1 H, C3H), 4.22 (dd, J = 2.4, 4.4 Hz, 1 H,
Anal. Calcd for C20H21NO4: C, 70.78; H, 6.24; N, 4.13. Found: C,
70.83; H, 6.23; N, 4.14.
(2R,3R)-3-{(1R)-1-[tert-Butyl(dimethyl)siloxy]ethyl}-1-(diphe-
nylmethyl)-4-oxoazetidin-2-yl Acetate (15)
TBDMSCl (2.5 g, 16.5 mmol) and imidazole (2.8 g, 41.3 mmol)
were added successively to a soln of acetate 14 (2 g, 5.9 mmol) in
DMF (20 mL), and the mixture was stirred at r.t. for 24 h. The mix-
ture was then diluted with EtOAc (40 mL), and washed with dilute
HCl and H2O. The organic phase was dried (MgSO4) and concen-
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J.-P. Huang et al.
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Zarini, F.; Franceschi, G. Heterocycles 1990, 30, 799.
trated in vacuo to give an oil; yield: 2.19 g (82%); [a]D26 +45.26 (c
0.38, MeOH).
IR (CHCl3): 1775, 1745 cm–1.
1H NMR (400 MHz, CDCl3): d = –0.09 (s, 3 H, CH3), –0.03 (s, 3 H,
CH3), 0.79 (s, 9 H, CH3), 1.14 (d, J = 6.4 Hz, 3 H, CH3CH), 1.72 (s,
3 H, COCH3), 3.06 (dd, J = 1.2, 3.6 Hz, 1 H, C3H), 4.08–4.14 (m, 1
H, CH3CH), 5.91 (s, 1 H, CHPh), 6.13 (d, J = 1.2 Hz, 1 H, C4-H),
7.16–7.27 (m, 10 H, ArH).
13C NMR (100 MHz, CDCl3): d = –4.84, 17.86, 20.61, 22.18, 25.69,
60.48, 64.06, 64.86, 77.52, 127.38, 127.84, 128.06, 128.25, 128.55,
128.58, 137.84, 138.75, 165.93, 169.47.
(e) Corraz, A. J.; Dax, S. L.; Dunlap, N. K.;
Georgopapadakou, N. H.; Keith, D. D.; Pruess, D. L.;
Rossman, P. L.; Then, R.; Unowsky, J.; Wei, C. C. J. Med.
Chem. 1992, 35, 1828. (f) Kondo, K.; Seki, M.; Kuroda, T.;
Yamanaka, T.; Iwasaki, T. J. Org. Chem. 1995, 60, 1096.
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MS (ESI): m/z = 476 [M + Na]+.
Anal. Calcd for C26H35NO4Si: C, 68.84; H, 7.78; N, 3.09. Found: C,
68.89; H, 7.77; N, 3.08.
(2S,3R)-3-((1S)-1-[tert-Butyl(dimethyl)siloxy]ethyl)-4-oxoazeti-
din-2-yl Acetate (3)
NBS (1 g, 5.6 mmol) was added to a soln of acetate 15 (2.24 g, 5.1
mmol) and Br2 [1.3 mL of a soln of Br2 (0.1 mL) in CH2Cl2 (10 mL),
0.25 mmol] in CH2Cl2 (70 mL) and H2O (45 mL). The mixture was
stirred and irradiated by UV lamps at r.t. for 24 h, then washed with
5% aq NaHSO3 until it became colorless. The organic phase was
then concentrated in vacuo. The residue was dissolved in 1:1 ace-
tone–H2O (70 mL) containing TsOH (0.94 g, 4.9 mmol), and the
mixture was stirred in the dark at r.t. for 24 h. The acetone was evap-
orated off and the aqueous layer was extracted with EtOAc (3 × 30
mL). The resulting organic phase was dried (MgSO4) and concen-
trated in vacuo to give a residue that was purified by column chro-
matography [EtOAc–PE (1:5) to give a white solid; yield: 1.0 g
(68%); mp 106.7–107.0 °C (Lit.17 106–107 °C; [a]D20 +49.5 (c 0.5,
CHCl3) [Lit.17 [a]D25 +51.0 (c 0.9, CHCl3)].
(9) Zhang, H.; Chen, F.-E.; Chen, M.-Q. Acta Crystallogr., Sect
E.: Struct. Rep. Online 2007, 63, o3099.
(10) Ahn, C.; Correia, R.; DeShong, P. J. Org. Chem. 2002, 67,
1751.
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Tetrahedron: Asymmetry 2010, 21, 277.
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2622. (b) Chen, F. E.; Zhao, J. F.; Xiong, F. J.; Xie, B.;
Zhang, P. Carbohydr. Res. 2007, 342, 2461.
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T.; Ikeda, M. J. Org. Chem. 1995, 60, 1276.
(14) (a) Laurent, M.; Belmans, M.; Kemps, L.; Cérésiat, M.;
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2004, 69, 3194. (c) Laurent, M.; Cérésiat, M.; Marchand-
Brynaert, J. Eur. J. Org. Chem. 2006, 3755.
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Weigele, M. J. Org. Chem. 1985, 50, 3462.
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1273.
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H. Tetrahedron: Asymmetry 1996, 7, 1241.
IR (KBr): 1777 cm–1.
1H NMR (400 MHz, CDCl3): d = –0.06 (s, 3 H, CH3), –0.01 (s, 3 H,
CH3), 0.793 (s, 9 H, CH3), 1.19 (d, J = 6.4 Hz, 3 H, CH3CH), 2.04
(s, 3 H, CH3CO), 3.11 (dd, J = 1.2, 3.2 Hz 1 H, C3H), 4.15 (m, 1 H,
CH3CH), 5.76 (d, J = 1.2 Hz, 1 H, C4H), 6.33 (s, 1 H, NH).
13C NMR (100 MHz, CDCl3) d = –5.19, –4.32, 17.92, 20.89, 22.32,
25.68, 63.86, 65.04, 75.12, 166.53, 171.26.
MS (ESI): m/z = 310 [M + Na]+.
Anal. Calcd for C13H25NO4Si: C, 54.32; H, 8.77; N, 4.87. Found: C,
54.28; H, 8.78; N, 4.86.
References
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Ganguly, A. K. Med. Res. Rev. 1988, 8, 393. (d) Alpegiani,
M.; Bedeschi, A.; Giudici, F.; Perrone, E.; Visentin, G.;
Synthesis 2011, No. 4, 555–562 © Thieme Stuttgart · New York