Efficient stereoselective route to β-lactams and their application to the stereoselective synthesis of a key intermediate for carbapenem antibiotic (+)-PS-5

Article abstract of DOI:10.1039/a802419g

A combination of a stereoselective addition of benzenethiol to α,β-unsaturated carboxylic acid derivatives and a subsequent substitution reaction of the corresponding sulfonium group with O-alkyl-hydroxamate anion has provided a new practical and stereoselective method for the construction of 3,4-disubstituted cis- and trans-β-lactams. A successful application was demonstrated by the formal asymmetric synthesis of (+)-PS-5.

Full text of DOI:10.1039/a802419g

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Efficient stereoselective route to â-lactams and their application to
the stereoselective synthesis of a key intermediate for carbapenem
antibiotic (؉)-PS-51
Okiko Miyata, Yoko Fujiwara, Ichiya Ninomiya and Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
A combination of a stereoselective addition of benzenethiol to á,â-unsaturated carboxylic acid
derivatives and a subsequent substitution reaction of the corresponding sulfonium group with O-alkyl-
hydroxamate anion has provided a new practical and stereoselective method for the construction of
3,4-disubstituted cis- and trans-â-lactams. A successful application was demonstrated by the formal
asymmetric synthesis of (؉)-PS-5.
R1
Introduction
R1
The Michael-type addition of nucleophiles to α,β-unsaturated
carbonyl compounds is one of the most widely used reactions
known. Recently we found that nucleophilic addition of thiols
to electron-deficient olefins proceeds stereospecifically and with
high stereoselectivity in the presence of excess thiol as a proton
source, thus forming two contiguous stereogenic centers with a
phenylsulfanyl substituent which has high potential for further
conversion to various types of structures2 (Scheme 1). The
R2
R3OHNOC
Z -2
PhSH
R1
R3OHNOC
R2
E -1
PhSH
addition
R1
R2
R2
R3OHNOC
R3OHNOC
SPh
erythro- 3
SPh
threo - 4
R1
R1
R2
YOC
YOC
1) RX
1) RX
2) base
R2
(Z)-olefin
substitution
2) base
(E)-olefin
R3SM
R3SH
R
R3SM
R3SH
R1
R1
R
+
+
O
SPh
O
SPh
_
R1
R2
_
R1
R2
R3ON
R3ON
R2
R2
A
B
YOC
YOC
SR3
SR3
erythro-adduct
threo-adduct
H
H
H
H
R2
R1
O
R1
O
R2
3
N
N
OR3
OR3
PS-5
Whisky Lactone
cis-6
trans-5
Diltiazem
Sphingosine
Et
Et
OR
OR
YOC
YOC
Scheme 1
7
SPh
8
Y = chiral auxiliary
addition is thought to proceed via the course of rapid proton-
ation of the intermediary enolate formed by attack of the
nucleophile (RSM). Thus the erythro-adduct was obtained
stereoselectively from the (E)-olefin whilst the threo-adduct was
obtained predominantly from the (Z)-isomer under the con-
ditions employing an excessive amount of protic thiol. Fur-
thermore, we have shown asymmetric total synthesis of
(ϩ)-diltiazem,3 (ϩ)-whisky lactone,4 (ϩ)-PS-51 and -erythro-
C18-sphingosine5 on the basis of the successful expansion of
this addition reaction to an asymmetric addition reaction.2 In
this paper, we describe full details of the stereoselective syn-
thesis of substituted β-lactams and the asymmetric synthesis of
a key intermediate for the synthesis of carbapenem antibiotic
(ϩ)-PS-5.6 Our approach is shown in Scheme 2. The synthetic
strategy consists of two key steps: (i) stereospecific nucleophilic
H
H
H
H
N
Et
Et
OR
NHAc
S
N
O
O
R
CO2H
(+)-PS-5
(–)-9
R = TBDMS
Scheme 2
addition of the thiols (1 → 3 or 2 → 4) and (ii) stereo-
selective displacement of the corresponding sulfonium group
(3 → 5 or 4 → 6). S-Alkylation of the erythro-adduct 3,
generated from (E)-amide 1, and subsequent intramolecular
and stereoselective displacement of the resulting sulfonium
J. Chem. Soc., Perkin Trans. 1, 1998
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group with O-alkyl hydroxamate anion A would furnish the
trans-β-lactam 5. Since the pKa (pKa: 6–10) of the N᎐H in
the hydroxamate moiety is lower7 than that (pKa: ca. 25) of the
N᎐H in the amide group, the desired cyclization of the O-alkyl
hydroxamate anion is expected to proceed smoothly in the pres-
ence of a weak base without both competitive β-elimination
and epimerization to provide trans-β-lactam 5.8 In a similar
manner, the threo-adduct 4, prepared from (Z)-amide 2, would
be converted into cis-β-lactam 6. Furthermore, the usefulness
of this method can be demonstrated by the asymmetric
synthesis of a key intermediate, (Ϫ)-9, for the synthesis of the
carbapenem antibiotic (ϩ)-PS-5 by using oxazolidinone as a
chiral auxiliary.
molecular substitution to give the trans-lactam 13 with high
stereoselectivity (trans:cis = 90:10) in 60% yield. In a similar
manner, the (Z)-ester 14 was transformed into the cis-β-lactam
17 via the threo-adduct 152 and the threo-hydroxamate 16 with
high stereoselectivity (cis:trans = 92:8) (Scheme 3). The stereo-
structures of 13 and 17 were confirmed by their spectral data.
The trans-β-lactam 13 showed a molecular ion peak at m/z 205,
an IR absorption at 1752 cmϪ1 (β-lactam) and 1H NMR peaks
at δ 2.46 (1H, qd, J 7.5, 2, 3-H) and 3.21 (1H, qd, J 6, 2, 4-H).
Similarly, the cis-β-lactam 17 showed the following character-
istic spectra [m/z 205 (Mϩ), νmax 1754 cmϪ1 (β-lactam), δ 2.92
(1H, qd, J 7.5, 6, 3-H), 3.72 (1H, quint., J 6, 4-H)]. It has been
established11 that in the series of 3,4-disubstituted azetidinones,
the coupling constants (J values) between the 3- and 4-
hydrogens in the 3,4-trans series (2.2–2.8 Hz) are smaller than
those in the cis series (5.0–5.9 Hz). Their observation in the
present cases showed a J3,4 value of 2 Hz for 13 and a J3,4 value
of 6 Hz for 17. The result established that the β-lactam 13 is the
trans-isomer and the β-lactam 17 is the cis-isomer. Thus, we
have developed a new and simple synthetic method for making
3,4-disubstituted β-lactams.
Results and discussion
Stereoselective synthesis of cis- and trans-â-lactams
In the synthesis of carbapenem antibiotics, the difficulty in
achieving control of the relative and absolute stereochemistries
of the contiguous chiral centers and the construction of the
β-lactam ring has remained unresolved. Particularly, the stereo-
selective and practical method for the construction of the cis-
β-lactams has been unexploited compared with the many
known8 synthetic works on the trans-lactams. We now provide
a potential method for the stereoselective synthesis of both
cis- and trans-β-lactams.
Synthesis of a key intermediate for carbapenem antibiotic (؉)-
PS-5
Carbapenem antibiotics PS-5, PS-6 and thienamycin comprise
an interesting family of streptomycete metabolites character-
ized by the presence of the 7-oxo-1-azabicyclo[3.2.0]hept-2-ene-
2-carboxylic acid system.8 The main strategies towards their
We first investigated conversion of methyl tiglate [(E)-methyl
2-methylbut-2-enoate] into the trans-lactam as a model study
(Scheme 3). Methyl tiglate 10 was treated with 10 equiv. of
R1
Me
Me
H
H
4
5
i
ii
Me
Me
SPh
erythro-11
(e : t = 96 : 4)
3
MeO2C
6
R2
MeO2C
81%
N
99%
2
7
1
10
O
CO2H
R 2
Me
R1
H
H
N
Me
Me
Me
iii
H
HO
Me
S-CH2CH2NHAc
S-CH2CH2NH2
S-CH2CH2NHAc
PS-5
thienamycin
PS-6
BnOHNOC
60%
SPh
O
OBn
erythro-12
(e : t = 94 : 6)
trans-13
Carbapenem antibiotics
(trans : cis = 90 : 10)
synthesis usually take place first with the preparation of
an appropriately substituted monocyclic β-lactam 18 (a key
intermediate) with the correct stereochemistry at the C3- and
C4-positions of the β-lactam ring, followed by chemical
manipulations (18 → 19) at the N1- and C4-positions and
subsequent ring closure (19 → 20) to form the bicyclic
carbapenem system in the last steps of the synthesis (Scheme 4).
Me
Me
i
ii
Me
SPh
MeO2C
MeO2C
82%
85%
Me
14
threo-15
(t : e = 86 : 14)
Me
H
H
Me
Me
β-lactam
formation
β-lactam
elaboration
Me
iii
H
H
R1
O
R2
BnOHNOC
58%
N
Starting
material
4
SPh
threo-16
(t : e = 85 : 15)
3
O
OBn
NR3
cis-17
(cis : trans = 92 : 8)
18
Scheme 3 Reagents: i, 0.1 equiv. PhSLi, 10 equiv. PhSH; ii, BnO-
NH2ؒHCl, Me3Al; iii, 1) MeI, AgClO4, 2) K2CO3
carbapenem
formation
H
H
H
H
R1
R1
COOH
benzenethiol in the presence of 0.1 equiv. of lithium benzene-
thiolate to give an inseparable mixture of the erythro- and
threo-adducts 112 and 152 in 99% yield with a ratio of 96:4
which was determined by 1H NMR spectroscopy. Treatment of
erythro-11 (erythro:threo = 96:4) with benzyloxylamine hydro-
chloride and trimethylaluminium9 afforded the O-benzyl
hydroxamate 12 (erythro:threo = 94:6) in 81% yield. S-
Alkylation of the sulfide 12 (erythro:threo = 94:6) with methyl
iodide in the presence of silver perchlorate4,10 followed by
treatment of the resulting sulfonium salt with potassium
carbonate caused it to undergo smooth lactamization by intra-
R4
NR4
19
N
O
O
CO2H
20
Scheme 4
Since in the asymmetric synthesis of PS-5, the first step of
stereoselective β-lactam formation is a crucial step, we focused
our attention on exploring a synthetic route to PS-5 applying
our newly found strategy established above.
Before approaching its asymmetric synthesis, we examined
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J. Chem. Soc., Perkin Trans. 1, 1998

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the synthesis of the key racemic intermediate 9 for ( )-PS-5.
The requisite (E)-olefin 24 was prepared by the conventional
method involving the Wittig–Horner reaction and subsequent
olefin isomerization (Scheme 5). The Swern oxidation of 3-
Et
H
H
N
Et
OBn
ii
OBn
i
MeOHNOC
SPh
96%
O
83%
OMe
(±)-trans-29 (trans : cis = 95 : 5)
(e : t = 91: 9)
(±)-erythro-28
(2S,3S)-28
i
OBn
22
(trans : cis = 97 : 3)
(3R,4R)-29
HO
OBn
OHC
51%
21
Et
O
ii
H
H
N
H
H
N
P(OEt)2
EtO2C
91%
Et
OH
Et
OTBDMS
iii
23
1
:
1
95%
O
Et
H
O
TBDMS
(+)-PS-5
[a]D26 : –34.2 (c 1.0, CHCl3)
Et
(±)-9
iii
OBn
(±)-30
(3R,4R)-30
EtO2C
EtO2C
(–)-(3R,4R)-9
95%
25
24
OBn
lit. –37.73 (c 2.25, CHCl3)19
–30.1 (c 2.90, CHCl3)13
iv
v
90%
Et
63%
Scheme 6 Reagents: i, 1) MeI, AgClO4, 2) K2CO3; ii, Ca, liq. NH3; iii,
Et
TBDMSOTf, 2,6-lutidine
OBn
OBn
EtO2C
peak at m/z 263, an IR absorption at 1760 cmϪ1 (β-lactam) and
1H NMR peaks at δ 2.57 (1H, ddd, J 8, 6, 2, 3-H) and 3.71 (1H,
ddd, J 7.5, 6, 2, 4-H).
MeOHNOC
27
83%
SPh
v
iv
(±)-erythro-26
(e : t =85 : 15)
Next, ( )-29 was converted into ( )-9, a known13 key inter-
mediate for the synthesis of ( )-PS-5. Reductive cleavage of
both the N᎐O and O᎐CH2Ph bonds of ( )-29 by use of cal-
cium17,18 in liquid ammonia proceeded smoothly to give the
desired product ( )-30 in 96% yield whilst the conventional
method,13,16 using sodium metal (Na/liq. NH3, Ϫ78 ЊC), was
unsuccessful. Finally, treatment of ( )-30 with TBDMSOTf in
the presence of 2,6-lutidine afforded the disilylated ( )-β-
lactam 9, which was identical with an authentic specimen on
comparison of their spectral data (Scheme 6).13,19
10%
OBn
Et
MeOHNOC
SPh
(±)-erythro-28
(e : t = 86 : 14) from 26
(e : t = 91: 9) from 27
Scheme 5 Reagents: i, (COCl)2, DMSO; ii, NaH; iii, (PhS)2; iv, 0.1
equiv. PhSLi, 10 equiv. PhSH; v, MeONH2ؒHCl, Me3Al
The above result established that a new synthetic route to PS-
5 based on the racemic compound ( )-9 was successful and was
then applied to the asymmetric synthesis of (Ϫ)-β-lactam 9. We
first examined the addition of benzenethiol to the olefins having
oxazolidinone20 as a chiral auxiliary (Scheme 7, Table 1).
benzyloxypropanol 21 followed by the Wittig–Horner reaction
of the resulting aldehyde 2212,13 with the phosphonate 2314 gave
a 1:1 mixture of (E)-24 and (Z)-25 in 91% combined yield. The
unstable (Z)-25 was isomerized to the stable (E)-24 upon
heating at 100 ЊC in the presence of diphenyl disulfide.15 (E)-
Ester 24 and the corresponding hydroxamate 27, which was
readily prepared in 63% yield from the former by treatment
with methoxylamine hydrochloride in the presence of trimethyl-
aluminium, were subjected to the Michael-type addition of
benzenethiol. (E)-24 was treated with benzenethiol in the pres-
ence of lithium benzenethiolate at room temperature to give a
mixture of two adducts, ( )-erythro-26 and its ( )-threo-isomer,
as an inseparable mixture in 90% yield with a ratio of 85:15.
The addition reaction of benzenethiol to the hydroxamate 27
proceeded smoothly at 60 ЊC to give a mixture of two adducts,
( )-erythro-28 and its ( )-threo-isomer, as an inseparable
mixture in 83% yield with high stereoselectivity (erythro:
threo = 91:9) (Scheme 5). Unfortunately, treatment of the
( )-erythro-ester 26 (erythro:threo = 85:15) with methoxyl-
amine hydrochloride in the presence of trimethylaluminium
gave the corresponding O-methyl ( )-hydroxamate 28 (erythro:
threo = 86:14) in only 10% yield as an isolated product in
addition to a complex mixture. The structure of the ( )-erythro-
adduct 28 was determined by the facts that it showed a molec-
ular ion peak at m/z 373 and 1H NMR peaks at δ 2.18 (1H, m,
2-H) and 3.54 (1H, td, J 7.5, 4, 3-H). The relative configuration
of the ( )-erythro-28 was established by its chemical conversion
into the ( )-trans-β-lactam 29 (trans:cis = 95:5) which was
accomplished in 83% yield through S-alkylation of ( )-28
(erythro:threo = 91:9) and subsequent treatment of the result-
ing sulfonium salt with potassium carbonate (Scheme 6). The
( )-trans-azetidinone 29 thus prepared showed a molecular ion
O
NH
Et
Et
O
OBn
OBn
O
N
YOC
BunLi
86%
O
O
24: Y = OEt
LiOH
68%
33
31a; Y = OH
31b; Y = Cl
PhSH
PhSLi
SOCl2
–78 °C
Et
Et
2'R
2'S
OBn
+
OBn
O
N
O
N
3'S
3'R
SPh
SPh
O
O
O
O
(2'R,3'R)-35
(2'S,3'S)-34
Scheme 7
Unsaturated chiral imide 33 was readily prepared by condens-
ation of the acid chloride 31b with the lithiated oxazolidinone.
The imide (E)-33 was treated with 10 equiv. of benzenethiol in
the presence of 1 equiv. of lithium benzenethiolate in THF at
Ϫ78 ЊC to give a mixture of two products (2ЈS,3ЈS)-34 and
J. Chem. Soc., Perkin Trans. 1, 1998
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Table 1 Addition reaction of benzenethiol to the chiral imide 33
PhS-Li
1H
H
H
SPh
R2
PhSLi/PhSH
(equiv.)
Ratio
Yield (%) 34:35
R1
H
O
O
R
O
O
N
O
R2
Entry
Time (h)
Solv.
N
O
2'
Et
1'
1
2
1/10
1/10
5
5
THF
THF
33
74
74:26
75:25
THF
Li
SPh
Et
Li
SPh
H-SPh
C
[ϩLiI (1.3 equiv.)]
E
s-trans
3
4
5/10
1/10
5
0.6
THF
Et2O
97
100
80:20
50:50
R1 = Pri
R2 =
OBn
O
(2ЈR,3ЈR)-35 in 33% yield with a ratio of 74:26 (entry 1). These
diastereomers were separated by medium pressure column
chromatography. In the presence of lithium iodide as an addi-
tive, a mixture of two adducts 34 and 35 was obtained in 74%
yield with almost the same diastereoselectivity (entry 2).
Employment of 5 equiv. of lithium benzenethiolate improved
the yield and the ratio of a mixture of 34 and 35 to 97% yield
and 80:20, respectively (entry 3). The addition reaction in
diethyl ether proceeded very smoothly but the stereoselectivity
was markedly diminished giving a 1:1 mixture of 34 and 35
(entry 4). The structures of the adducts 34 and 35 were deter-
mined based on the facts that these adducts showed a molecular
H
Et
R1
O
Et
N
OBn
N
O
R2
O
Li
SPh
SPh
O
O
H
D
(2'S,3'S)-34
s-cis
Scheme 9
Et
1
ion peak at m/z 455 and H NMR peaks due to the 2- and 3-
i
OBn
O
HN
hydrogens as shown in the Experimental section. The absolute
configuration of (2ЈS,3ЈS)-34 was established by its chemical
conversion into the known13,19 intermediate (Ϫ)-9 for the syn-
thesis of (ϩ)-PS-5. The absolute configuration of the minor
adduct (2ЈR,3ЈR)-35 was determined as follows (Scheme 8). As
(2'S,3'S)-34
O
O
SPh
NHOMe
84%
38
Et
OBn
Et
5%
MeOHNOC
ii 97%
2R
OBn
(2'S,3'S)-34
BnSOC
27
SPh
(2S,3S)-28
3S
SPh
(2R,3S)-36
[α]D –71.1 (c 2.90, CHCl3)
iv
86%
Et
Et
2S
Et
OBn
(2'R,3'R)-35
BnSOC
3R
OBn
OBn
iii
BnSOC
HO2C
SPh
(2S,3R)-37
SPh
SPh
(2R,3S)-36
27
96%
[α]D +70.3 (c 2.56, CHCl3)
(2S,3S)-39
Scheme 8
Scheme 10 Reagents: i, MeONH2ؒHCl, Me3Al; ii, BunLi, BnSH,
Me3Al; iii, CF3CO2Ag, H2O; iv, MeONH2ؒHCl, WSC
described later, (2ЈS,3ЈS)-34 and (2ЈR,3ЈR)-35 were converted
into the enantiomeric thioesters (2R,3S)-36 and (2S,3R)-37,
respectively which showed identical IR and H NMR spectra.
Comparison of the optical rotation of (2S,3R)-37 with that
of (2R,3S)-36 established unambiguously their absolute
configurations.
and trimethylaluminium.9,22 However, the desired hydroxamate
(2S,3S)-28 was obtained in only 5% yield, although the
undesired amide 38 was obtained in 84% yield as a result of
the attack of methoxylamine onto the oxazolidinone carbonyl
group. Recently, we have found4 that the aluminium thiobenz-
yloxy ‘ate’ complex is an excellent reagent for the cleavage of
N-acyloxazolidinones and camphor sultams. Therefore, this
method was applied to (2ЈS,3ЈS)-34. As expected, removal of
the chiral auxiliary by treatment with the aluminium thiobenz-
yloxy ‘ate’ complex was smoothly achieved to give the thioester
(2R,3S)-36 in 97% yield, which was also obtained in 63% yield
by a known23 approach employing lithium phenylmethanethi-
olate as a nucleophile. Hydrolysis of the thioester (2R,3S)-36 in
the presence of silver trifluoroacetate proceeded smoothly to
give the corresponding acid (2S,3S)-39 in 96% yield which was
also obtained, but in only 45% yield, in the presence of silver
perchlorate.4 (2S,3S)-39 was then treated with methoxylamine
hydrochloride in the presence of 1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide hydrochloride (WSC) to give the desired
hydroxamate (2S,3S)-28 in 86% yield. According to the pro-
cedure established with the racemic ( )-9, formation of the aze-
tidinone (3R,4R)-29, cleavage of both the N᎐O and O᎐CH2Ph
bonds of (3R,4R)-29 and subsequent disilylation afforded the
disilylated β-lactam (3R,4R)-9, [α]D26 Ϫ34.2 (c 0.79, CHCl3) {lit.,19
[α]D Ϫ37.73 (c 2.25, CHCl3); lit.,13 [α]D Ϫ30.1 (c 2.9, CHCl3)} in
1
We propose the possible reaction pathway for the addition of
benzenethiol to 33 in THF as shown in Scheme 9.2b,3b,21 It is
presumed that both carbonyl groups of the α,β-unsaturated
carboxylic acid moiety and the chiral auxiliary would be fixed
by chelation with lithium benzenethiolate. The conformation
of the chiral imide with respect to the rotamers arising from
rotation about the C-1Ј–C-2Ј axis would be in the s-trans form
C due to steric hindrance between the ethyl and the isopropyl
groups on the chiral auxiliary found in the corresponding s-cis
conformation D. Addition of lithium benzenethiolate to the
metal coordinated imide C would occur from the β-face,
according to the 1,5-asymmetric induction by the isopropyl
group on the oxazolidinone ring, to form the enolate E. The
following protonation of E would occur from the α-face, due
to the stereoelectronic effect2b of the newly introduced sulfur
group in overcoming the steric hindrance of the isopropyl
group, to give (2ЈS,3ЈS)-34.
We then investigated conversion of (2ЈS,3ЈS)-34 into (2S,3S)-
28 via cleavage of the chiral auxiliary (Scheme 10). We first
attempted transamination of 34 into hydroxamate (2S,3S)-28
in one step by treatment with methoxylamine hydrochloride
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J. Chem. Soc., Perkin Trans. 1, 1998

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42% overall yield from the carboxylic acid 31a in a nine-step
sequence (Scheme 6). Since (3R,4R)-9 had previously been
transformed into (ϩ)-PS-5,24–27 the present method provides a
new highly efficient asymmetric synthesis of (ϩ)-PS-5.
In conclusion, we have now developed a new strategy for the
stereoselective construction of the β-lactam ring via stereo-
specific nucleophilic addition of thiols and the stereoselective
displacement of the corresponding sulfonium group with O-
alkyl hydroxamate anions. This method has been successfully
applied to the asymmetric synthesis of a key intermediate for
the synthesis of carbapenem antibiotic (ϩ)-PS-5.
onium salt in acetone (7 cm3) and the mixture was refluxed for
2 h. After addition of water, the mixture was extracted with
CH2Cl2. The extract was dried and concentrated to give the
residue which was purified by MPCC (CH2Cl2–AcOEt 10:1) to
give the trans-azetidinone 13 (trans:cis = 90:10) as a colorless
oil (37 mg, 60%). The ratio of trans- to cis-products was deter-
1
mined by 200 MHz H NMR spectroscopy. νmax/cmϪ1 1752
(NCO) (Found: Mϩ, 205.1105. C12H15NO2 requires M,
205.1102). trans-13; δH(200 MHz) 7.46 (5H, m, Ph), 5.02 and
4.98 (2H, ABq, J 12, OCH2Ph), 3.21 (1H, qd, J 6, 2, 4-H), 2.46
(1H, qd, J 7.5, 2, 3-H), 1.24 (3H, d, J 7.5, 3-Me) and 1.19 (3H,
d, J 6, 4-Me).
Experimental
threo-2-Methyl-N-benzyloxy-3-(phenylsulfanyl)butanamide 16
According to the method previously described,2 the threo-ester
152 (threo:erythro = 86:14) was prepared by the addition of
benzenethiol to (Z)-methyl 2-methylbut-2-enoate. According
to the procedure described for the preparation of erythro-
hydroxamate 12, a solution of threo-15 (threo:erythro = 86:14)
(134 mg, 0.6 mmol), O-benzylhydroxylamine hydrochloride and
trimethylaluminium in toluene was stirred at 60 ЊC for 3 h. The
crude product was purified by MPCC (CH2Cl2) to give a
mixture of the threo-hydroxamate 16 and the erythro-isomer
(threo:erythro = 85:15) (155 mg, 82%) as a colorless oil. The
ratio of erythro- to threo-adducts was determined by 200 MHz
1H NMR spectroscopy. νmax/cmϪ1 3398 (NH) and 1692 (NCO)
(Found: Mϩ, 315.1277. C18H21NO2S requires M, 315.1291).
threo-16; δH(200 MHz) 8.84 (1H, s, NH), 7.50–7.20 (10H, m,
Ph × 2), 4.91 (2H, s, OCH2Ph), 3.46 (1H, m, 3-H), 2.16 (1H, m,
2-H), 1.24 and 1.12 (each 3H, d, J 7, Me × 2).
1H and 13C NMR spectra were measured using Varian Gemini-
200 (1H, 200 MHz), Varian Gemini-300 (1H, 300 MHz) and
VXR-500 (1H, 500 MHz; 13C, 125 MHz) instruments for solu-
tions in deuteriochloroform, unless otherwise stated (tetra-
methylsilane was used as the internal reference); J values are
given in Hz. IR spectra were measured with a Perkin-Elmer
1600 FTIR machine for solutions in chloroform, unless other-
wise stated and mass spectra were taken with an Hitachi
M-4100 spectrometer. Mps were determined with a Kofler-type
hot-stage apparatus and are uncorrected. All reactions were
performed under nitrogen and extracts from the reaction
mixtures were washed with water, dried (MgSO4) and con-
centrated under reduced pressure. TLC was performed
on precoated silica gel 60F254 (0.25 mm thick, Merck) with
UV detection at 254 and 300 nm. Medium-pressure column
chromatography (MPCC) was undertaken on a 530-4-10V
apparatus (Yamazen) with Lobar größe B (310-25, Lichroprep
Si60, Merck) as column absorbent. For flash column chrom-
atography (FCC), Merck Kieselgel 60 (230–400 mesh) was
used. Short column chromatography (SCC) was undertaken on
a short glass filter using Merck Kieselgel 60 (230–400 mesh)
under reduced pressure. For inseparable mixtures, the 1H NMR
spectra of the major isomer is assigned.
cis-3,4-Dimethyl-1-(benzyloxy)azetidin-2-one 17
According to the procedure described for the preparation of
trans-13, the threo-16 (threo:erythro = 85:15) (190 mg, 0.6
mmol) was alkylated with methyl iodide in the presence of
silver perchlorate and the resulting sulfonium salt was treated
with K2CO3. The crude product was purified by MPCC
(CH2Cl2) to give the cis-azetidinone 17 (cis:trans = 92:8) as a
colorless oil (71 mg, 58%). The ratio of trans- to cis-products
was determined by 200 MHz 1H NMR spectroscopy. νmax/cmϪ1
1754 (NCO) (Found: Mϩ, 205.1092. C12H15NO2 requires M,
205.1102). cis-17; δH(200 MHz) 7.44 (5H, m, Ph), 4.98 (2H,
s, OCH2Ph), 3.72 (1H, quint., J 6, 4-H), 2.92 (1H, qd, J 7.5, 6,
3-H), 1.10 (3H, d, J 7.5, 3-Me) and 1.03 (3H, d, J 6, 4-Me).
erythro-2-Methyl-N-benzyloxy-3-(phenylsulfanyl)butanamide 12
According to the method previously described,2 the erythro-
ester 112 (erythro:threo = 96:4) was prepared by the addition
of benzenethiol to (E)-methyl 2-methylbut-2-enoate. Trimethyl-
aluminium (2  solution in hexane; 1.2 cm3, 2.4 mmol) was
added with stirring at 0 ЊC to a suspension of O-benzyl-
hydroxylamine hydrochloride (382 mg, 2.4 mmol) in toluene
(2.4 cm3). This resulting solution was added with stirring at
room temperature to a solution of the erythro-ester 11 (269 mg,
1.2 mmol) in toluene (4 cm3). After being stirred at 60 ЊC for
1 h, the mixture was acidified with 10% hydrochloric acid and
extracted with CH2Cl2. The organic layer was washed, dried
and concentrated to give a residue which was purified by
MPCC (CH2Cl2) to give a mixture of the erythro-hydroxamate
12 and its threo-isomer (erythro:threo = 94:6) (306 mg, 81%) as
a colorless oil. The ratio of erythro- to threo-adducts was
determined by 200 MHz 1H NMR spectroscopy. νmax/cmϪ1 3398
(NH) and 1690 (NCO) (Found: Mϩ, 315.1290. C18H21NO2S
requires M, 315.1291). erythro-12; δH(200 MHz) 8.44 (1H, s,
NH), 7.50–7.22 (10H, m, Ph × 2), 4.95 (2H, s, OCH2Ph), 3.38
(1H, quint., J 7, 3-H), 2.19 (1H, m, 2-H) and 1.28 (6H, d, J 7,
Me × 2).
(E)-Ethyl 2-ethyl-5-(benzyloxy)pent-2-enoate 24
According to the literature procedure,12,13 aldehyde 2212,13
was prepared from alcohol 21. A solution of triethyl α-
phosphonopropionate 2314 in THF (50 cm3) was added at 0 ЊC
to a stirred suspension of NaH (60% dispersion in mineral oil;
0.8 g, 20 mmol) in THF (10 cm3). After being stirred at room
temperature for 0.5 h, a solution of the aldehyde 22 (3.28 g, 20
mmol) in THF (50 cm3) was added dropwise at 0 ЊC and the
whole was stirred at the same temperature for 1 h. The resulting
solution was poured into ice-cooled water (20 cm3) and then
extracted with Et2O. The extract was washed with saturated
aqueous NaCl, dried and concentrated to give a mixture of (E)-
ester 24 and (Z)-ester 25 (24:25 = 1:1) as a colorless oil (4.8 g,
91%). The ratio of (E)- to (Z)-esters was determined by 200
1
MHz H NMR spectroscopy. δH(200 MHz) 7.40 (5H, m, Ph),
6.79 [0.5H, t, J 7, (E)-3-H], 6.00 [0.5H, t, J 7, (Z)-3-H], 4.59 and
4.58 (each 1H, s, OCH2Ph), 4.24 (2H, m, OCH2Me), 3.60 [1H, t,
J 7, (E)-5-H2], 3.58 [1H, t, J 7, (Z)-5-H2], 2.80 (1H), 2.56 (1H)
and 2.36 (2H) (each q, J 7, 4-H2 and 2-CH2) and 1.40–0.96 (6H,
m, Me × 2). A solution of a mixture of (E)- and (Z)-esters 24
and 25 (3.6 g, 14 mmol) and diphenyl disulfide15 (914 mg, 4.2
mmol) in THF (170 cm3) was refluxed for 3 h. The mixture was
then cooled and the solvent was removed under reduced pres-
sure. The residue was purified by MPCC (n-hexane–AcOEt
15:1) to give the (E)-ester 24 as a colorless oil (3.5 g, 95%).
trans-3,4-Dimethyl-1-(benzyloxy)azetidin-2-one 13
Methyl iodide (2 cm3, 31 mmol) was added with stirring at room
temperature to a solution of the erythro-12 (95 mg, 0.3 mmol)
(erythro:threo = 94:6) and silver perchlorate (280 mg, 1.4
mmol) in MeCN (4 cm3). After being stirred at room temper-
ature for 15 h, the mixture was filtered to remove the resulting
silver iodide. The filtrate was concentrated to give the sulfonium
salt. To a stirred suspension of K2CO3 (360 mg, 2.6 mmol) in
refluxing acetone (12 cm3) was added a solution of the sulf-
J. Chem. Soc., Perkin Trans. 1, 1998
2171

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νmax/cmϪ1 1702 (COOEt); m/z (CI) 263 (MHϩ); δH(200 MHz)
7.40 (5H, s, Ph), 6.79 (1H, t, J 7, 3-H), 4.58 (2H, s, OCH2Ph),
4.24 (2H, q, J 7, OCH2Me), 3.60 (2H, t, J 7, 5-H2), 2.56 and
2.36 (each 2H, q, J 7, 4-H2 and 2-CH2), 1.32 (3H, t, J 7,
OCH2Me) and 1.02 (3H, t, J 7, CH2Me).
identical with the authentic sample, prepared from ( )-erythro-
26 based on a comparison of their spectral data.
( )-trans-3-Ethyl-1-methoxy-4-[2-(benzyloxy)ethyl]azetidin-2-
one 29
According to the procedure described for the preparation of the
trans-13, ( )-erythro-28 (erythro:threo = 91:9) (116 mg, 0.3
mmol) was alkylated with methyl iodide in the presence of
silver perchlorate and then the resulting sulfonium salt was
treated with K2CO3. The crude product was purified by MPCC
(AcOEt–CH2Cl2 1:10) to give the ( )-trans-azetidinone 29
(trans:cis 95:5) as a colorless oil (66 mg, 83%). The ratio of
( )-Ethyl erythro-2-ethyl-5-benzyloxy-3-(phenylsulfanyl)pent-
anoate 26
Benzenethiol (0.38 cm3, 3.7 mmol) was added with stirring at
0 ЊC to a solution of n-butyllithium (1.63  solution in hexane;
0.02 cm3, 0.037 mmol) in THF (2.5 cm3) to give a solution of a
10:0.1 mixture of benzenethiol and lithium benzenethiolate. To
the resulting solution was added a solution of 24 (97 mg, 0.37
mmol) in THF (2.5 cm3) at room temperature. After being
stirred at room temperature for 2 h, the mixture was made
alkaline by adding 5% aqueous NaOH and extracted with
CH2Cl2. The extract was washed, dried and concentrated to
give the residue which was purified by MPCC (n-hexane–
CH2Cl2 1:1) to give a mixture of ( )-erythro-26 and the threo-
isomer (erythro:threo = 85:15) (124 mg, 90%) as a colorless
oil. The ratio of erythro- to threo-adducts was determined by
200 MHz 1H NMR spectroscopy. νmax/cmϪ1 1724 (CO2Et)
(Found: Mϩ, 372.1758. C22H28O3S requires M, 372.1758).
erythro-26; δH(200 MHz) 7.50–7.20 (10H, m, Ph × 2), 4.48 (2H,
s, OCH2Ph), 4.10 (2H, m, OCH2Me), 3.82–3.60 (2H, m, 5-H2),
3.51 (1H, ddd, J 11.5, 8, 4.5, 3-H), 2.50 (1H, ddd, J 10, 8, 4.5,
2-H), 2.16–1.66 (4H, m, 2-H2 and 4-H2), 1.22 (3H, t, J 7,
OCH2Me) and 0.88 (3H, t, J 7, CH2Me).
1
trans- to cis-products was determined by 200 MHz H NMR
spectroscopy. νmax/cmϪ1 1760 (NCO) (Found: Mϩ, 263.1549.
C15H21NO3 requires M, 263.1521) (Found: C, 66.8; H, 7.9; N,
1
–
5.1. C15H21NO3ؒ3H2O requires C, 66.9; H, 8.1; N, 5.2%). ( )-
trans-29; δH(200 MHz) 7.40–7.26 (5H, m, Ph), 4.50 (2H, s,
OCH2Ph), 3.75 (3H, s, OMe), 3.71 (1H, ddd, J 7.5, 6, 2, 4-H),
3.60 (2H, m, OCH2), 2.57 (1H, ddd, J 8, 6, 2, 3-H), 2.14 (1H,
dq, J 14, 6, 4-CH), 1.91 (1H, dtd, J 14, 7.5, 6, 4-CH), 1.80–1.50
(2H, m, 3-CH2) and 1.00 (3H, t, J 7.5, Me); δC 166.2 (s), 138.0
(s), 128.4 (d), 127.8 (d), 127.7 (d), 73.3 (t), 66.9 (t), 63.6 (q), 60.7
(d), 52.6 (d), 32.9 (t), 21.3 (t), 11.4 (q).
( )-trans-3-Ethyl-1-[(1,1-dimethylethyl)dimethylsilyl]-4-{2-
[(1,1-dimethylethyl)dimethylsilyloxy]ethyl}azetidin-2-one 9
Metallic calcium (58 mg, 1.45 mmol) was added to liquid
ammmonia (10 cm3) at Ϫ78 ЊC with stirring. A solution of ( )-
29 (trans:cis = 95:5) (50 mg, 0.19 mmol) in THF (0.3 cm3) was
added to the above solution and the resulting blue-colored
solution was stirred for 2 h. Ammonium chloride was added
until the blue color disappeared, then the liquid ammonia was
evaporated to give a residue, to which water was added. The
resulting mixture was extracted with CH2Cl2. The extract was
( )-erythro-2-Ethyl-N-methoxy-5-benzyloxy-3-(phenylsulfanyl)-
pentanamide 28
According to the procedure described for the preparation of the
erythro-hydroxamate 12, a solution of ( )-erythro-26 (erythro:
threo = 85:15) (74 mg, 0.2 mmol), methoxylamine hydro-
chloride and trimethylaluminium in toluene (1.5 cm3) was
stirred under reflux for 3 h. The crude product was purified by
MPCC (CH2Cl2–n-hexane 1:1) to give a mixture of the ( )-
erythro-hydroxamate 28 and the threo-isomer (erythro:threo =
86:14) (7 mg, 10%) as a colorless oil. The ratio of erythro- to
washed, dried and concentrated to give the ( )-alcohol 30. νmax
/
cmϪ1 3500–3400 (NH, OH) and 1760 (NCO); δH(200 MHz)
3.90–3.64 (2H, m, OCH2), 3.48 (1H, ddd, J 8, 5.5, 2, 4-H), 2.78
(1H, br t, J 8, 3-H), 2.00–1.50 (4H, m, 4-CH2 and 3-CH2) and
1.02 (3H, t, J 8, Me).
1
threo-adducts was determined by 200 MHz H NMR spec-
According to the literature,13,19 a solution of the ( )-alcohol
30 (15 mg, 0.1 mmol), 2,6-lutidine (0.12 cm3, 1.1 mmol) and
TBDMSOTf (0.09 cm3, 0.4 mmol) in CH2Cl2 (5 cm3) was
stirred at 0 ЊC for 1 h. After addition of MeOH (0.25 cm3), the
mixture was concentrated to give the residue which was purified
by FCC (n-hexane–AcOEt 92:8) to give the disilylated ( )-
lactam 9 as a colorless oil (35 mg, 95%). νmax/cmϪ1 1720 (NCO)
[Found (CI): Mϩ ϩ 1, 372.2752. C19H41NO2Si2 ϩ H requires
M ϩ 1, 263.1521]; δH(500 MHz) 3.64 (2H, m, OCH2), 3.37 (1H,
dt, J 10.5, 2.5, 4-H), 2.79 (1H, ddd, J 7.5, 5.5, 2.5, 3-H), 2.15–
1.54 (4H, m, 4-CH2 and 3-CH2), 1.01 (3H, t, J 7, Me), 0.96 and
0.86 (each 9H, s, But × 2), 0.24 (3H, s, SiMe), 0.21 (3H, s, SiMe)
troscopy. νmax/cmϪ1 3400 (NH), 1694 (NCO) (Found: Mϩ,
373.1703. C21H27NO3S requires M, 373.1701). 28; δH(200 MHz)
8.70 (1H, br s, NH), 7.44–7.30 (10H, m, Ph × 2), 4.52 and 4.46
(2H, ABq, J 11, OCH2Ph), 3.90 (1H, m, 5-H), 3.66 (1H, m,
5-H), 3.64 (3H, s, OMe), 3.54 (1H, td, J 7.5, 4, 3-H), 2.18 (1H,
m, 2-H), 1.99 (1H, m, 4-H), 1.91–1.76 (3H, m, 2-CH2 and 4-H)
and 0.86 (3H, t, J 7, CH2Me).
(E)-2-Ethyl-N-methoxy-5-(benzyloxy)pent-2-enamide 27
According to the procedure described for the preparation of the
hydroxamate 12, a solution of the ester 24 (286 mg, 1.1 mmol),
methoxylamine hydrochloride and trimethylaluminium in
toluene was stirred at 60 ЊC for 5 h. The crude product was
purified by MPCC (CH2Cl2–AcOEt 5:1) to give the (E)-
hydroxamate 27 (182 mg, 63%) as a colorless oil; νmax/cmϪ1
3404 (NH), 1680 (NCO) (Found: Mϩ, 263.1507. C15H21NO3
requires M, 263.2519); δH(200 MHz) 8.59 (1H, br s, NH), 7.44–
7.30 (5H, m, Ph), 6.12 (1H, t, J 7, 3-H), 4.54 (2H, s, OCH2Ph),
3.79 (3H, s, OMe), 3.56 (2H, t, J 7, 5-H2), 2.46 and 2.32 (each
2H, q, J 7, 4-H2 and 2-CH2) and 1.00 (3H, t, J 7, CH2Me).
1
and 0.04 (6H, s, SiMe2). The H NMR and IR spectra were
identical with those of an authentic sample.13,19
(E,S)-4-(1-Methylethyl)-3-[2-ethyl-1-oxo-5-(benzyloxy)pent-2-
enyl]oxazolidin-2-one 33
A solution of the ester 24 (553 mg, 2.1 mmol) and LiOH (170
mg, 7 mmol) in THF–H2O–MeOH (1:1:2) (4 cm3) was stirred
at room temperature for 3.5 h. The mixture was acidified with
10% hydrochloric acid at 0 ЊC and extracted with CH2Cl2. The
organic layer was washed, dried and concentrated to give the
residue which was purified by SCC (AcOEt–CH2Cl2 1:1)
and recrystallized from n-hexane to give the corresponding
carboxylic acid 31a (335 mg, 68%) as colorless crystals mp 47–
48 ЊC. νmax/cmϪ1 3100–2500 and 1686 (COOH) (Found: C,
71.77; H, 7.74. C4H18O3 requires C, 71.49; H, 7.76%); δH(200
MHz) 10.71 (1H, br s, OH), 7.24 (5H, m, Ph), 6.50 (1H, t, J 7,
3-H), 4.48 (2H, s, OCH2Ph), 3.53 (2H, t, J 7, 5-H2), 2.50 (2H, q,
J 7, 4-H2), 2.26 (2H, q, J 7, 2-CH2) and 1.01 (3H, t, J 7, Me).
A solution of SOCl2 (0.5 cm3, 6.8 mmol) and 31a (110 mg,
Addition of benzenethiol to hydroxamate 27
According to the procedure described for the preparation of
( )-erythro-26, a solution of 27 (145 mg, 0.55 mmol), PhSH
(5.5 mmol) and PhSLi (0.055 mmol) in THF (3 cm3) was stirred
under reflux for 2 h. The crude product was purified by MPCC
(n-hexane–CH2Cl2 1:1) to give a mixture of ( )-erythro-28 and
its threo-isomer (erythro:threo = 91:9) (170 mg, 82%) as a color-
less oil. The ratio of erythro- to threo-adducts was determined
1
by 200 MHz H NMR spectroscopy. The ( )-erythro-28 was
2172
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
0.47 mmol) in benzene (16 cm3) was stirred under reflux for 1 h.
The solvent was removed under reduced pressure to give the
acid chloride 31b (110 mg) as a pale yellow oil. According to the
literature,20 (S)-4-(1-methylethyl)oxazolidin-2-one (58 mg, 0.45
mmol) was lithiated with n-butyllithium in THF at Ϫ78 ЊC and
successively acylated with the acid chloride 31b (110 mg, 0.47
mmol). The crude product was purified by MPCC (CH2Cl2) to
give the imide 33 (140 mg, 86%) as a pale yellow oil; [α]D28 ϩ33.7
(c 3.09, CHCl3); νmax/cmϪ1 1778 and 1682 (CONHCOO)
(Found: Mϩ, 345.1942. C20H27NO4 requires M, 345.1939);
δH(200 MHz) 7.25 (5H, m, Ph), 6.00 (1H, t, J 6, 3Ј-H), 4.55 (2H,
s, OCH2Ph), 4.54 (1H, m, 4-H), 4.32 (1H, t, J 8, 5-H), 4.19 (1H,
dd, J 8, 6, 5-H), 3.56 (2H, t, J 7, 5Ј-H2), 2.60–2.24 (5H, m,
4Ј-H2 , 2Ј-CH2 and 4-CH), 1.03 (3H, t, J 8, CH2Me) and 0.90
(6H, d, J 8, CHMe2).
2-ethyl-N-methoxy-5-(benzyloxy)-3-(phenylsulfanyl)pentan-
amide 28 (1 mg, 5%) as a colorless oil and (1ЈS,2S,3S)-2-ethyl-
N-[2Ј-(methoxyaminocarbonyloxy)-1Ј-(1-methylethyl)ethyl]-5-
benzyloxy-3-(phenylsulfanyl)pentanamide 38 (21 mg, 84%) as a
1
colorless oil. The H NMR and IR spectra of (2S,3S)-28 were
identical with those of ( )-28. 28: [α]D26 ϩ3.4 (c 2.54, CHCl3).
38: νmax/cmϪ1 3436 (NH), 1742, 1670 (NCO) (Found: Mϩ,
502.2491. C27H38N2O5S requires M, 502.2499); δH(500 MHz)
8.30 (1H, br s, CONHOMe), 7.38–7.20 (10H, m, Ph × 2), 5.64
(1H, br d, J 9, CONH), 4.50 and 4.47 (2H, ABq, J 12,
OCH2Ph), 4.29 (1H, dd, J 11, 3.5, 2Ј-H), 4.12 (1H, m, 1Ј-H),
3.92 (1H, dd, J 11, 9, 2Ј-H), 3.83 (1H, ddd, J 9, 7, 6, 5-H), 3.64
(1H, dt, J 9, 7, 5-H), 3.35 (1H, td, J 9, 3.5, 3-H), 2.13–1.96 (3H,
m, 2-CH2 and 4-H), 1.76–1.65 (3H, m, 2-H, 4-H and 1Ј-CH),
0.92 and 0.85 (each 3H, d, J 7, CHMe2) and 0.88 (3H, t, J 7.5,
CH2Me); [α]D24 Ϫ5.3 (c 0.94, CHCl3).
Addition of benzenethiol to chiral imide 33 (Table 1, entry 3)
Benzenethiol (1 cm3, 10.8 mmol) was added with stirring at 0 ЊC
to a solution of n-butyllithium (1.63  solution in hexane; 2.3
cm3, 3.6 mmol) in THF (5 cm3) to give a solution of a 2:1
mixture of benzenethiol and lithium benzenethiolate. To the
resulting solution was added a solution of 33 (250 mg, 0.72
mmol) in THF (5 cm3) at Ϫ78 ЊC. After being stirred at Ϫ78 ЊC
for 5 h, the mixture was made alkaline by adding 5% aqueous
NaOH and extracted with CH2Cl2. The extract was dried and
concentrated to give the residue which was purified by MPCC
(n-hexane–AcOEt 3:1) to give (2ЈS,3ЈS,4S)-4-(1-methylethyl)-
3-[2Ј-ethyl-1Ј-oxo-5Ј-benzyloxy-3Ј-(phenylsulfanyl)pentyl]oxa-
zolidin-2-one 34 as a colorless oil (257 mg, 78%) and
(2ЈR,3ЈR,4S)-4-(1-methylethyl)-3-[2Ј-ethyl-1Ј-oxo-5Ј-benzyl-
oxy-3Ј-(phenylsulfanyl)pentyl]oxazolidin-2-one 35 as a color-
less oil (64 mg, 19%). 34: [α]D26 Ϫ2.5 (c 2.77, CHCl3); νmax/cmϪ1
1778 and 1692 (CONCOO) (Found: Mϩ, 455.2110. C26H33-
(2R,3S)-S-Benzyl 2-ethyl-5-benzyloxy-3-(phenylsulfanyl)-
pentanethioate 36
(A) Using aluminium thiobenzyloxy ‘ate’ complex. Phenyl-
methanethiol (0.08 cm3, 0.7 mmol) and trimethylaluminium
(2  solution in hexane; 0.45 cm3, 0.9 mmol) were added drop-
wise with stirring at 0 ЊC to a solution of n-butyllithium (1.63 
solution in hexane; 0.45 cm3, 0.7 mmol) in THF (6 cm3). After
being stirred at 0 ЊC for 0.5 h, the resulting solution was added
at 0 ЊC to a solution of (2ЈS,3ЈS)-34 (159 mg, 0.35 mmol) in
THF (10 cm3). After being stirred at 0 ЊC for 1.5 h, the mixture
was acidified with 10% hydrochloric acid and extracted with
CH2Cl2. The organic layer was washed with 5% aqueous
NaOH, dried and concentrated to give the residue which was
purified by MPCC (n-hexane–CH2Cl2 4:1) to give (2R,3S)-36
(153 mg, 97%) as a colorless oil; νmax/cmϪ1 1676 (COS)
(Found: Mϩ, 450.1701. C27H30O2S2 requires M, 450.1686);
δH(500 MHz) 7.27 (15H, m, Ph × 3), 4.44 and 4.41 (2H, ABq,
J 12, OCH2Ph), 4.15 and 4.11 (2H, ABq, J 14, SCH2Ph), 3.75
(1H, td, J 9, 5, 5-H), 3.65 (1H, ddd, J 9, 6, 4, 5-H), 3.50 (1H,
ddd, J 10, 6.5, 5, 3-H), 2.70 (1H, ddd, J 10, 7, 5, 2-H), 2.06–2.13
(1H, m, 4-H), 1.79–1.90 (2H, m, 2-CH2), 1.72 (1H, m, 4-H) and
0.86 (3H, t, J 7.5, Me); [α]D27 Ϫ71.1 (c 2.90, CHCl3).
(B) Using lithium benzylthiolate. Phenylmethanethiol (0.028
cm3, 0.24 mmol) was added dropwise with stirring at 0 ЊC to
a solution of n-butyllithium (1.63  solution in hexane; 0.1 cm3,
0.18 mmol) in THF (3 cm3). After being stirred at 0 ЊC for
0.5 h, the resulting solution was added at 0 ЊC to a solution of
(2ЈS,3ЈS)-34 (56 mg, 0.12 mmol) in THF (3 cm3). After being
stirred at 0 ЊC for 1.5 h, the mixture was made alkaline by
addition of 5% aqueous NaOH and extracted with CH2Cl2.
The organic layer was washed, dried and concentrated to give
the residue which was purified by MPCC (n-hexane–CH2Cl2
4:1) to give (2R,3S)-36 (34 mg, 63%) as a colorless oil. The 1H
NMR spectra and IR spectra of (2R,3S)-36 were identical with
those of the sample prepared in (A).
NO4S requires M, 455.2128) (Found: C, 67.7; H, 7.3; N, 3.0.
1
–
C26H33NO4Sؒ H2O requires C, 67.9; H, 7.3; N, 3.0%); δH(500
MHz) 7.39–74.21 (10H, m, Ph × 2), 4.49 (1H, m, 4-H), 4.48 and
4.45 (2H, ABq, J 12, OCH2Ph), 4.24 (1H, t, J 9, 5-H), 4.18 (2H,
m, 3Ј- and 5-H), 3.79 (1H, dt, J 10, 5.5, 5Ј-H), 3.70 (1H, ddd,
J 10, 7, 5, 5Ј-H), 3.61 (1H, ddd, J 10, 6, 4, 2-H), 2.27 (1H, m,
CHMe2), 2.13 (1H, m, 4Ј-H), 1.95–1.78 (3H, m, 4Ј-H and
CH2Me), 0.89 (3H, d, J 7, CHMe), 0.87 (3H, t, J 7, CH2Me)
and 0.80 (3H, d, J 7, CHMe); δC 174.3 (s), 153.7 (s), 138.6 (s),
135.6 (s), 131.6 (d), 128.9 (d), 128.3 (d), 127.6 (d), 127.4 (d),
126.8 (d), 72.8 (t), 67.6 (t), 63.0 (t), 58.6 (d), 48.9 (d), 48.6 (d),
33.2 (t), 28.4 (d), 22.6 (t), 18.1 (q), 14.6 (q), 11.6 (q). 35: [α]D26
ϩ77.2 (c 2.63, CHCl3); νmax/cmϪ1 1777 and 1695 (CONCOO)
(Found: Mϩ, 455.2110. C26H33NO4S requires M, 455.2128)
2
–
(Found: C, 66.8; H, 7.4; N, 3.0. C26H33NO4Sؒ3H2O requires
C, 66.8; H, 7.2; N, 3.0%); δH(500 MHz) 7.40–7.18 (10H, m,
Ph × 2), 4.50 and 4.44 (2H, ABq, J 12, OCH2Ph), 4.24 (1H,
ddd, J 9, 4, 3, 4-H), 4.15 (1H, ddd, J 9, 7.5, 5, 3Ј-H), 4.08 (1H,
dd, J 9, 3, 5-H), 3.96 (1H, t, J 9, 5-H), 3.78–3.69 (2H, m, 5Ј-H2),
3.59 (1H, br ddd, J 10, 7, 3.5, 2Ј-H), 2.33 (1H, m, 4-CH), 2.08–
1.96 (2H, m, 2Ј-CH2), 1.92–1.82 (2H, m, 4Ј-H2), 0.91 and 0.84
(each 3H, d, J 7, CHMe2) and 0.89 (3H, t, J 7, CH2Me); δC
174.3 (s), 153.6 (s), 138.5 (s), 135.7 (s), 131.9 (d), 128.9 (d), 128.3
(d), 127.6 (d), 127.5 (d), 126.9 (d), 72.9 (t), 67.6 (t), 63.0 (t), 58.7
(d), 48.6 (d), 48.2 (d), 32.7 (t), 28.5 (d), 23.1 (t), 18.0 (q), 14.6
(q), 10.9 (q).
(2S,3R)-S-Benzyl 2-ethyl-5-benzyloxy-3-(phenylsulfanyl)-
pentanethioate 37
According to the procedure described for preparation of
(2R,3S)-36, a solution of (2ЈR,3ЈR)-35 (75 mg, 0.16 mmol) and
aluminium thiobenzyloxy ‘ate’ complex in THF was stirred at
0 ЊC for 1.5 h. The crude product was purified by MPCC
(n-hexane–CH2Cl2 4:1) to give (2S,3R)-37 (68 mg, 95%). The
1H NMR and IR spectra of 37 were identical with those of 36.
[α]D27 ϩ70.3 (c 2.56, CHCl3).
Conversion of (2ЈS,3ЈS)-34 into (2S,3S)-28
Trimethylaluminium (2  solution in hexane; 0.23 cm3, 0.45
mmol) was added with stirring at 0 ЊC to a suspension of
methoxylamine hydrochloride (38 mg, 0.45 mmol) in THF (0.3
cm3). The resulting solution was added at 0 ЊC to a solution of
(2ЈS,3ЈS)-34 (25 mg, 0.05 mmol) in THF (5 cm3). After being
stirred at 0 ЊC for 7 h, the mixture was acidified with 10%
hydrochloric acid and extracted with CH2Cl2. The organic layer
was washed, dried and concentrated to give the residue which
was purified by MPCC (AcOEt–CH2Cl2 5:1) to give (2S,3S)-
(2S,3S)-2-Ethyl-5-benzyloxy-3-(phenylsulfanyl)pentanoic acid
39
(A) Using silver trifluoroacetate. Silver trifluoroacetate (260
mg, 1.2 mmol) was added with stirring to a solution of the
thioester 36 (41 mg, 0.09 mmol) in THF–H2O (3:1) (2 cm3).
After being stirred under reflux for 5 h, the mixture was acid-
ified with 10% hydrochloric acid and extracted with CH2Cl2.
J. Chem. Soc., Perkin Trans. 1, 1998
2173

View Article Online
2 (a) O. Miyata, T. Shinada, T. Naito and I. Ninomiya, Chem. Pharm.
The organic layer was washed, dried and concentrated to give
the residue which was purified by SCC (CH2Cl2–MeOH 10:1)
to give the carboxylic acid 39 (30 mg, 96%) as a colorless
amorphous solid; νmax/cmϪ1 3000–2600, 1692 (COOH) (Found:
Mϩ, 344.1449. C20H24O3S requires M, 344.1445); δH(500 MHz)
7.50–7.22 (10H, m, Ph × 2), 4.50 (2H, s, OCH2Ph), 3.92–3.60
(2H, m, 5-CH2), 3.60–3.46 (1H, m, 3-H), 2.60–2.48 (1H, m, 2-H),
2.20–1.64 (4H, m, 4-H2 and 2-CH2) and 0.94 (3H, t, J 8, Me).
(B) Using silver perchlorate. According to method A, a solu-
tion of the thioester 36 (20 mg, 0.04 mmol) and silver perchlor-
ate (130 mg, 0.63 mmol) in THF–H2O (3:1) (0.8 cm3) was
stirred under reflux for 5 h. The crude product was purified by
SCC (CH2Cl2–MeOH 10:1) to give the carboxylic acid 39 (6
Bull., 1989, 37, 3158; (b) O. Miyata, T. Shinada, I. Ninomiya,
T. Naito, T. Date, K. Okamura and S. Inagaki, J. Org. Chem., 1991,
56, 6556.
3 (a) O. Miyata, T. Shinada, I. Ninomiya and T. Naito, Tetrahedron
Lett., 1991, 32, 3519; (b) O. Miyata, T. Shinada, I. Ninomiya and
T. Naito, Tetrahedron, 1997, 53, 2421.
4 (a) O. Miyata, T. Shinada, N. Kawakami, K. Taji, I. Ninomiya,
T. Naito, T. Date and K. Okamura, Chem. Pharm. Bull., 1992, 40,
2579; (b) O. Miyata, Y. Fujiwara, A. Nishiguchi, H. Honda,
T. Shinada, I. Ninomiya and T. Naito, Synlett, 1994, 637.
5 O. Miyata, S. Yamaguchi, I. Ninomiya, T. Naito and K. Okamura,
Chem. Pharm. Bull., 1996, 44, 636.
6 Recent syntheses of (ϩ)-PS-5: (a) P. A. Jacobi, S. Murphree,
R. Shaun, Z. Frederic and W. Zheng, J. Org. Chem., 1996, 61, 2413;
(b) H. Ishibashi, C. Kameoka, K. Kodama and M. Ikeda,
Tetrahedron, 1996, 52, 489; (c) D. Tanner and P. Somfai, Bioorg.
Med. Chem. Lett., 1993, 2415; (d) E. Bandini, G. Cainelli,
G. Martelli, M. Panunzio and G. Spunta, Gazz. Chim. Ital., 1993,
123, 509; (e) Y. Kita, N. Shibata, T. Miki, Y. Takemura and O.
Tamura, Chem. Pharm. Bull., 1992, 40, 12; ( f ) H. Hiromichi,
T. Yamanaka, N. Matsunaga, M. Fuji and Y. Kita, Synlett, 1992, 35;
(g) P. Andreoli, G. Cainelli, M. Panunzio, B. Mauro, M. Elisa,
G. Martelli and G. Spunta, J. Org. Chem., 1991, 56, 5984; (h)
C. Palomo, F. Cossio, J. M. Ontoria and J. M. Odriozola,
Tetrahedron Lett., 1991, 32, 3105.
7 B. C. Challis and J. A. Challis, Comprehensive Organic Chemistry,
eds. D. H. R. Barton and W. D. Ollis, Pergamon Press, Oxford, 1971,
vol. 2, p. 1040.
8 C. Palomo, Recent Progress in the Chemical Synthesis of Antibiotics,
eds. G. Lukacs and M. Ohno, Springer-Verlag, Berlin, 1990,
p. 565.
9 J. I. Levin, E. Turos and S. M. Weinreb, Synth. Commun., 1982, 12,
989.
10 H. Matsuyama, T. Nakamura and N. Kamigata, J. Org. Chem.,
1989, 54, 5218.
11 D. E. Davis and R. C. Storr, Comprehensive Heterocyclic Chemistry,
eds. A. R. Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984,
vol. 7, p. 237.
1
mg, 45%) as a colorless amorphous solid. The H NMR and
IR spectra of 39 were identical with those of the sample
prepared in (A).
(2S,3S)-2-Ethyl-N-methoxy-5-benzyloxy-3-(phenylsulfanyl)-
pentanamide 28
A solution of methoxylamine hydrochloride (44 mg, 0.5 mmol)
in H2O (0.25 cm3) was added under stirring at room temper-
ature to a solution of the carboxylic acid 39 (90 mg, 0.26 mmol)
in THF–H2O (6:1) (0.5 cm3). Then a solution of 1-ethyl-3-
(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC)
(96 mg, 0.5 mmol) in H2O (0.25 cm3) was added under stirring
at room temperature to the resulting mixture. After being
stirred for 5 h, the mixture was acidified with 10% hydrochloric
acid and extracted with CH2Cl2. The organic layer was
washed, dried and concentrated to give the residue which was
purified by SCC (CH2Cl2–MeOH 10:1) to give the (2S,3S)-
hydroxamate 28 (83 mg, 86%). 28 was identical with the product
28 formed from 34 based on comparison of their spectra and
optical rotation.
12 K. Omura and O. Swern, Tetrahedron, 1978, 34, 1651.
13 C. Gennari and P. G. Cozzi, J. Org. Chem., 1988, 53, 4015.
14 G. Gallagher, Jr. and R. L. Webb, Synthesis, 1973, 122.
15 O. Miyata, T. Shinada, I. Ninomiya and T. Naito, Synthesis, 1990,
1123.
16 D. M. Floyd, A. W. Fritz, J. Pluscec, E. R. Weaver and C. M.
Cimarusti, J. Org. Chem., 1982, 47, 5160.
17 L. N. Mander, Comprehensive Organic Synthesis, eds. B. M. Trost
and I. Fleming, Pergamon Press, New York, 1991, vol. 8, p. 492.
18 T. Naito, N. Kojima, O. Miyata and I. Ninomiya, J. Chem. Soc.,
Perkin Trans. 1, 1990, 1271.
19 M. Shibasaki, Y. Ishida, G. Iwasaki and T. Iimori, J. Org. Chem.,
1987, 52, 3489.
20 (a) D. A. Evans, J. M. Takacs, L. R. McGee, M. D. Ennis, D. J.
Mathre and J. Bartroli, Pure Appl. Chem., 1981, 53, 1109; (b) D. A.
Evans, K. T. Chapman and J. Bisaha, J. Am. Chem. Soc., 1988, 110,
1238.
21 Conformational studies of α,β-unsaturated carbonyl compounds
with chiral auxiliaries in the asymmetric conjugate addition are
shown in recent publications; (a) K. Tomioka, T. Suenaga and
K. Koga, Tetrahedron Lett., 1986, 27, 369; (b) M.-J. Wu, C.-C. Wu
and T.-C. Tseng, J. Org. Chem., 1994, 59, 7188; (c) M. Kanai,
A. Muraoka, T. Tanaka, M. Sawada, N. Ikota and K. Tomioka,
Tetrahedron Lett., 1995, 36, 9349; (d) K. Tomioka, A. Muraoka and
M. Kanai, J. Org. Chem., 1995, 60, 6188.
(3R, trans)-3-Ethyl-1-methoxy-4-[2-(benzyloxy)ethyl]azetidin-2-
one 29
According to the procedure described for the preparation of the
trans-13, the (2S,3S)-28 (112 mg, 0.3 mmol) was alkylated with
methyl iodide in the presence of silver perchlorate and then the
resulting sulfonium salt was treated with K2CO3. The crude
product was purified by MPCC (AcOEt–CH2Cl2 1:10) to give
(3R,4R)-29 (trans:cis = 97:3) as a colorless oil (65 mg, 83%).
The ratio of trans- to cis-products was determined by 200 MHz
1H NMR spectroscopy. The 1H NMR and IR spectra of
(3R,4R)-29 were identical with those of ( )-29; [α]D26 ϩ1.32
(c 2.27, CHCl3).
(3R, trans)-3-Ethyl-1-[(1,1-dimethylethyl)dimethylsilyl]-4-{2-
[(1,1-dimethylethyl)dimethylsilyloxy]ethyl}azetidin-2-one 9
According to the procedure described for the preparation
of ( )-9, (3R,4R)-29 (trans:cis = 97:3) (59 mg, 0.2 mmol) was
converted into the disilylated (3R, trans)-β-lactam 9 (70 mg,
91%) as a colorless oil. The 1H NMR and IR spectra of
(3R, trans)-β-lactam 9 were identical with those of ( )-9; [α]D26
Ϫ34.2 (c 0.79, CHCl3) {lit. [α]D Ϫ37.73 (c 2.25, CHCl3),19 Ϫ30.1
(c 2.9, CHCl3)13}.
22 D. A. Evans and E. B. Sjogren, Tetrahedron Lett., 1986, 27,
3119.
23 R. E. Damon and G. M. Coppola, Tetrahedron Lett., 1990, 31,
2849.
Acknowledgements
24 T. Kametani, T. Honda, A. Nakayama, Y. Sasaki, T. Mochizuki and
K. Fukumoto, J. Chem. Soc., Perkin Trans. 1, 1981, 2228.
25 D. Favara, A. Omodei-Sale, P. Consonni and A. Depaoli,
Tetrahedron Lett., 1982, 23, 3105.
26 R. W. Ratcliffe, T. N. Salzmann and B. G. Christensen, Tetrahedron
Lett., 1980, 21, 31.
27 T. Nagahara and T. Kametani, Heterocycles, 1987, 25, 729.
This work was partly supported by a Grant-in-Aid for scientific
research (No. 09672293) from the Ministry of Education,
Science, Sports and Culture, Japan and the Science Research
Promotion Fund of the Japan Private School Promotion
Foundation for research grants.
References
Paper 8/02419G
Received 30th March 1998
Accepted 21st May 1998
1 O. Miyata, Y. Fujiwara, I. Ninomiya and T. Naito, J. Chem. Soc.,
Perkin Trans. 1, 1993, 2861.
2174
J. Chem. Soc., Perkin Trans. 1, 1998