Synthesis of NH-3-phenylsulfanyl- and NH-3-benzylsulfanyl-azetidinones from 1-phenylsulfanyl- or 1-benzylsulfanyl-3-aza-1,3-dienes

Article abstract of DOI:10.1016/j.tet.2003.10.004

The syntheses of NH-3-phenylsulfanyl- and NH-3-benzylsulfanyl-azetidinones, starting from 1-phenylsulfanyl- or 1-benzylsulfanyl-2-trimethylsilyloxy-3-aza- 1,3-dienes are reported.

Full text of DOI:10.1016/j.tet.2003.10.004

Tetrahedron 59 (2003) 9577–9582
Synthesis of NH-3-phenylsulfanyl- and
NH-3-benzylsulfanyl-azetidinones from 1-phenylsulfanyl-
or 1-benzylsulfanyl-3-aza-1,3-dienes
a,*
a
Mauro Panunzio, Alessandro Bongini, Emiliano Tamanini, Eileen Campana,
a
b
b
b
Giorgio Martelli, Paola Vicennati and Ilaria Zanardi
b
a
ISOF-CNR Dipartimento di Chimica ‘G. Ciamician’, Via Selmi, 2, I-40126 Bologna, Italy
ISOF-CNR Via Gobetti 101, I-40129 Bologna, Italy
b
Received 21 May 2003; revised 8 September 2003; accepted 2 October 2003
Abstract—The syntheses of NH-3-phenylsulfanyl- and NH-3-benzylsulfanyl-azetidinones, starting from 1-phenylsulfanyl- or 1-benzyl-
sulfanyl-2-trimethylsilyloxy-3-aza-1,3-dienes are reported.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
The development of synthetic routes to monocyclic
-azetidinones (b-lactams) was stimulated by the obser-
vation of antibacterial activity in monobactams and
2
1
norcardicins. While the interest in these materials as
antibiotics has waned, 2-azetidinones have served as
important intermediates in many other applications. They
are precursors to b-amino alcohols and b-amino acids,
which are useful building blocks for peptides containing
2
–4
non-protein amino acids.
2-Azetidinones have been used
to introduce the C-13 side-chain of the anticancer compound
Scheme 1. Reagents and conditions. (i) Hexane, LiHMD SA, 1 h, 258C;
(ii) TMSCl, 1 h, rt; (iii) TEA, 08C then rt; (iv) toluene at reflux, 10 h.
5
paclitaxel (taxol) and related analogues. 2-Azetidinones
have served as precursors to d-lactones in the total synthesis
of the macrolide antitumor antibiotic Lankacidin C. More
recently, certain C-3 heteroatom-substituted azetidinones have
displayed potent cholesterol absorption inhibitor activity
8
and human Cytomegalo virus protease inhibitor activity.
can be considered stable forms of the zwitterionic
intermediates invoked in the classical Staudinger reac-
6
1
2–16
tion.
strategy to the synthesis of 3-phenylsulfanyl- and 3-benzyl-
In this paper we report a further application of this
7
1
7–21
sulfanyl-azetidinones.
the preparation of an azadiene 4,
silylimine 2 and the corresponding phenylsulfanyl- or
benzylsulfanyl-ketene, formed in situ from the correspond-
ing phenylsulfanyl- or benzylsulfanyl-acetyl chloride 3 and
triethylamine (Scheme 1), followed by its ring closure to
and 6 by refluxing overnight in dry toluene. The
configuration of the azadiene has been assigned by Noe
In detail, the synthesis involves
2
2,23
from a N-trimethyl-
2
4
2
. Results and discussion
2
5
The synthetic approaches to 2-azetidinones are almost
countless, but the Staudinger approach from ketenes and
imines remains the most useful despite its venerable
5
9
–11
age.
Recently we have reported a new one-pot, two
step variant of this reaction via a 4p-conrotatory electro-
cyclization of neutral 2-trimethylsilyloxy-3-aza-1,3-dienes
variably substituted in positions 1 and 3. The intermediates
Keywords: azetidinones; cyclisation; dienes; silicon and compounds;
stereochemistry.
*
Corresponding author. Tel.: þ39-051-209-9508; fax: þ39-051-209-9456;
e-mail: panunzio@ciam.unibo.it
Figure 1.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.004

9578
M. Panunzio et al. / Tetrahedron 59 (2003) 9577–9582
experiments (in Figure 1 the Noe values and the structure of
compound 4d are reported as an example). By this protocol
a diastereomeric mixture of NH-b-lactams has been
obtained after usual work-up and silica gel flash chroma-
tography in varying yields and diastereomeric ratios
depending on the substituents of the azadiene. The results
are reported in Table 1. The yields of azetidinones are based
on the starting aldehydes (Scheme 1) and are calculated on
the pure isolated compounds. Table 1 warrants some
comments: although the yields are not high, they have not
been optimized and should be considered satisfactory since
it must be taken into account that reactions are performed in
a one-pot, three-step fashion (preparation of the imine,
reaction with acyl chloride and ring closure to the b-lactam
ring). The data reported show that the reaction, in term of
simple diastereoselectivity, is highly stereo-controlled since
only trans azetidinones, characterized by coupling constants
H –H of 2.0–2.5 Hz at H NMR spectra, are obtained.
Unfortunately no significant facial-diastereoselectivity is
present in all the experiments performed and under the
experimental conditions used except for the example of
entry 5, Table 1. The absolute configuration of the products
5a, 6a, 5b, 6b, 5d, 6d, 5f, 6f and the relative configuration of
3
4
1
the racemic compounds 5c, 6c, 5e, 6e have been determined
0
1
4
4
from the H NMR coupling constants H –H on the basis of
the following observations and arguments. (1) In this paper
as well as in related papers on the syntheses of b-lactams,
1
2–16
carrying a silyloxy-alkyl side chain at position 4,
it
1
has been found, from H NMR data, that the two trans
diastereoisomers obtained can be assembled in two main
groups, irrespective of the exact nature of the substituents
Table 1. Synthesis of azetidinones 5 and 6
a
Products (ratio 5/6) Y %
Entry
R
Ar
in position 3: a group A presenting a coupling constant for
4
0
H –H within 1–3 Hz and a group B presenting a coupling
4
1
constant within 5–7 Hz. (2) The compound A , belonging
1
to group A and compound B , belonging to group B
1
PhS–
5a/6a (65/35)
5b/6b (66/34)
5c/6c (58/42)
50
40
31
(Scheme 2), have been elaborated to the same enantiomeric
pure compound (epc) C and, subsequently, to Aztreonam of
2
6,13
known configuration and optical activity.
and taking into account that the parent compound of A was
By this way,
1
2
3
PhCh
2
S–
1
the (S)-lactaldehyde, the parent compound of B was the
3
(
R)-lactaldehyde and that the trans relationship between H
4
PhS–
and H is not in discussion (J¼2.5 Hz), the absolute
1
1
configuration of A and B is so far established. Since the
0
4
4
coupling constants for H –H of the members of group A
1
4
5
PhS–
PhS–
5d/6d (57/43)
5e/6e (98/2)
35
40
are of the same magnitude of that of A , the coupling
4
0
constants for H –H of the members of group B are of
4
1
the same magnitude of that of B , and that the relationship
3
4
H –H is trans, according the values of their coupling
constants, we feel that we are allowed to attribute the
0
3
4
4
relative configuration of H –H –H for all compounds of
Table 1 above mentioned. (3) A further confirmation of the
correct stereochemical attributions comes out from a full
6
7
8
PhS–
PhS–
PhS–
5f/6f (55/45)
44
25
18
2
7
m
m
AM1 analysis on the two model compounds A and B
m
(
Chart 1): the analysis shows that A is best described by a
0
4
4
conformation in which the two hydrogens H –H are in a
m
5g
5h
gauche relationship, whilst B is best described by two
4
0
conformations in which the two hydrogens H –H are in
4
gauche and in anti relationship. Due to the larger presence
m
of anti conformers, to B a larger coupling constant then to
m
A
must be assigned. These theoretical calculations match
perfectly with the experimental results above reported.
Using as imine that derived from cinnamaldehyde (2j) a
mixture of the adducts 7a and 7b in 4/1 ratio and 20%
overall yield was obtained (Scheme 3). The formation of
compounds 7a and 7b from 4j, whose structure has been
confirmed by Noe experiments, presumably involves, under
the thermal conditions used, an electrocyclic disrotatory
ring closure with predominant formation of the cis-disubsti-
9
PhS–
5i
15
10
11
12
PhS–
PhS–
5j
0
5k
25
25
2
8,29
tuted adduct 7a. Phenylpropargilic- and 3-furan-2-yl-
propenyl imines, in contrast, gave rise only to the expected
PhCH S– 5l
2
b-lactams (entries 11,12,13 Table 1).
13
PhS–
5m
20
3
. Conclusion
a
1 13
All products gave analytical data ( H and C NMR, IR, Mass spectra)
consistent with the structures reported.
15
The results presented in this paper may be considered a new

M. Panunzio et al. / Tetrahedron 59 (2003) 9577–9582
9579
Scheme 2. (i) Ref. 13; (ii) Ref. 26.
Varian-Mercury 400 MHz. Chemical shifts are reported in d
scale and coupling constants (J) are reported in Hz. In
brackets are reported the values of diagnostic protons and
carbons. Infrared spectra were recorded as nujol mulls on a
Nicolet 205 FT-IR spectrophotometer. Optical rotation
measurements were carried out on a Perkin–Elmer 343
2
0
Polarimeter and specific rotation [a]D was reported in deg
per dm at the specified temperature and with the
concentration [c] given in g per 100 mL in CHCl . THF,
3
toluene, and heptane were distilled from benzophenone
ketyl. Mass spectra were recorded on Finningam-Mat.
Lithium bis(trimethylsilyl)amide (LiHMSDA) (1 M solu-
tion in hexane) was purchased from Lancaster.
4.2. Materials
Chart 1.
N-Trialkylsilylimines were prepared according to reported
2
5
procedures starting from the parent aldehydes. Triethyl-
amine was dried over KOH. Other solvents and reagents
were obtained commercially and were used as received. All
reactions were performed under nitrogen, and the yields are
referred to the whole process starting from the aldehyde
used in the preparation of imine.
Scheme 3.
4.3. Preparation of the (5S)-1-phenylsulfanyl-2-tri-
methylsilyloxy-3-aza-5-trisopropylsilyoxy-6-methyl-
hepta-1,3-diene (4d) as typical procedure
contribution to the synthesis of b-lactams via a two step
Staudinger reaction and demonstrate that this approach may
be used for the synthesis of variably 3-substituted
azetidinones. Work is in progress to extend these results
to the synthesis of more valuable compounds known to
present biological activity.
To a hexane solution of 1 mmol of [3-methyl-2-(S)-
triisopropyl-silanyloxy)-butylidene]-(trimethyl-silanyl)-
(
26
24
amine (2d), prepared according to a literature procedure,
were added, dropwise, at 08C, under efficient stirring, TEA
2 mmol, 280 mL)) followed by a hexane solution of
(
commercially available phenylsulfanylacetyl chloride (3)
(1 mmol, 148 mL). The solution was stirred at 08C for
4
. Experimental
40 min and then for 1 h at rt. During this time a copious
4
.1. General
precipitate occurred. The mixture was filtered under a
stream of nitrogen on Celite and from the filtrate the low-
boiling materials were removed under vacuum. An aliquot
Melting points were taken on a Mel-Temp apparatus and are
1
13
1
13
uncorrected. H and C NMR spectra were recorded in
CDCl on Varian Gemini-200, Varian INOVA 300 MHz or
of the yellow crude material was analyzed by IR, H and
NMR.
C
3

9580
M. Panunzio et al. / Tetrahedron 59 (2003) 9577–9582
20
[a] ¼237 (c¼1, CHCl ); IR (CHCl ): 3420, 1768 cm21;
4
.3.1. (5S)-1-Phenylsulfanyl-2-trimethylsilyloxy-3-aza-5-
triisopropylsilyloxy-6-methyl-hepta-1,3-diene (4d). IR
D
3
3
d (200 MHz CDCl ) ppm: 7.59 (m, 2H, Ph), 7.30 (m,3H,
H
3
2
1
(
film): 1678 cm ; dH (400 MHz CDCl ) ppm: 7.66 (d,
3
Ph), 5.70 (bs, 1H, NH), 4.26 (dd, J ¼2.5 Hz, J ¼1.2 Hz,
1
2
J¼6.2 Hz, 1H, NvCH), 7.36–7.17 (m, 5H, Ph), 5.84 (s, 1H,
1H, CHSPh), 4.12 (dq, J ¼6.2 Hz, J ¼2.5 Hz, 1H,
1 2
PhSCH), 4.17 (dd, J ¼4.8 Hz, J ¼6.2 Hz, 1H, CHOTIPS),
CHOTIPS), 3.42 (pt, J¼2.5 Hz, 1H, CHNH), 1.25 (d, J¼
6.2 Hz, 3H, CH(OTIPS)Me), 1.01 (s, 21H, OSiiPr ); d
(50 MHz CDCl ) ppm: 166.9, 153.7, 133.2, 129.1, 128.1,
1
2
1
.96 (m, 1H, CH(OTIPS)CHMe ), 1.05 (s, 21H, OSiiPr ),
2 3
3
C
0
OSiMe ); d (100 MHz CDCl ) ppm: 161.6, 152.5, 136.5,
1
1
.97 (d, J¼6.4 Hz, 6H, CH(OTIPS)CHMe ), 0.31 (s, 9H,
2
3
67.3, 61.0, 53.4, 19.9, 18.1, 12.5; Ms (m/z): 380, 293, 227,
186, 149.
3
C
3
28.9, 127.9, 126.9, 102.5, 78.9, 34.4, 18.0, 17.9, 17.8, 17.7,
7.6, 12.3, 0.61).
4.4.4. (3R,4R)-3-Phenylsulfanyl-4-[(1S)-1-triisopropyl-
silanyloxy-ethyl]-azetidin-2-one (6a). Pale yellow oil,
4.4. Preparation of the (3S,4S)- and (3R,4R)-3-phenyl-
sulfanyl-4-[(1S)-1-triisopropylsilanyloxy-2-methyl-
propyl]-azetidin-2-one (5d) and 6d as typical procedure
Y¼17%, [Found: C 63.50, H 8.81. C H NO SSi requires
2
0
33
2
2
0
C 63.28, H 8.76]. R (CH Cl /acetone 97/3) 0.51; [a] ¼
f
2
2
D
2
3 3 H
1
þ54.8 (c¼0.7, CHCl ); IR (CHCl ): 3415, 1767 cm ; d
The crude azadiene 4d, prepared as reported above, was
dissolved in anhydrous toluene and refluxed overnight under
nitrogen. The mixture was poured in saturated ammonium
chloride solution and extracted with ethyl acetate
(200 MHz CDCl ) ppm: 7.58 (m, 2H, Ph), 7.30 (m, 3H, Ph),
3
5.88 (bs, 1H, NH), 3.92 (m, 2H, PhSCHþCHOTIPS), 3.35
(dd, J ¼2.6 Hz, J ¼6.8 Hz, 1H, NHCH), 1.15 (d, J¼6.2 Hz,
1
2
3H, CH(OTIPS)Me), 1.01 (m, 21H, OSiiPr ); d (50 MHz
3
C
(
the solvent removed. Flash chromatography (CH Cl /
3£10 mL). The organic layers were dried over Na SO ,
CDCl ) ppm: 167.4, 153.4, 133.0, 129.1, 127.9, 69.9, 61.6,
3
55.0, 20.1, 18.1, 12.6; Ms (m/z): 380, 293, 227, 186, 149.
2
4
2
2
acetone 97/3) of the residue yielded the title compounds
d and 6d as pale yellow oils in 50% yield (calculated on the
basis of the starting aldehyde) and 50/50 diastereomeric
ratio.
5
4.4.5. (3S,4S)-3-Benzylsulfanyl-4-[(1S)-1-triisopropyl-
silanyloxy-ethyl]-azetidin-2-one (5b). Pale yellow oil,
Y¼26%, [Found: C 64.30, H 9.01. C H NO SSi requires
2
1
35
2
C 64.07, H 8.96]. R (cyclohexane/ethyl acetate 75/25) 0.45;
f
2
0
21
4.4.1. (3S,4S)-3-Phenylsulfanyl-4-[(1S)-1-triisopropyl-
silanyloxy-2-methyl-propyl]-azetidin-2-one (5d). Pale
[a] ¼277 (c¼1, CHCl ); IR (CHCl ): 3415, 1764 cm
d (200 MHz CDCl ) ppm: 7.35–7.25 (m, 5H, Ph), 5.67
H 3
;
D
3
3
yellow oil, Y¼20%, [Found: C 65.01, H 9.09. C H NO
(bs, 1H, NH), 4.02 (d, J¼13.2 Hz, 1H, CH SPh), 4.00 (dd,
2
2
37
2
2
SSi requires C 64.81, H 9.15]. R (CH Cl /acetone 97/3)
2
J ¼2.9 Hz, J ¼6.2 Hz 1H, CHOTIPS), 3.90 (dd, J ¼
f
2
1
2
1
2
0
21
0
d (400 MHz CDCl ) ppm: 7.60 (m, 2H, Ph), 7.35 (m, 3H,
.38; [a] ¼224 (c¼1, CHCl ); IR (CHCl ): 1760 cm
;
2.3 Hz, J ¼1.5 Hz, 1H, CHSPh), 3.85 (d, J¼13.2 Hz, 1H,
D
3
3
2
CH SPh), 3.36 (dd, J ¼2.3 Hz, J ¼2.9 Hz, 1H, NHCH),
H
3
2
1
2
Ph), 5.58 (bs, 1H, NH), 4.35 (dd, J ¼2.1 Hz, J ¼1.2 Hz,
1.08 (d, J¼6.2 Hz, 3H, CH(OTIPS)Me), 1.00 (m, 21H,
1
2
1
H, PhSCH), 3.90 (dd, J ¼1.5 Hz, J ¼4.0 Hz, 1H,
1 2
OSiiPr ; d (75 MHz CDCl ) ppm: 167.5, 137.5, 129.1,
3
1
2
C
3
CHOTIPS), 3.45 (dd, J ¼1.5 Hz, J ¼2.1 Hz, 1H, CHNH),
128.5, 127.2, 67.5, 61.5, 49.9, 35.1, 19.7, 18.1, 12.5; Ms
(m/z): 394, 307, 259, 227, 186, 143, 91.
1
.92 (m, 1H, CH(OTIPS)CHMe ), 1.05 (s, 21H, OSiiPr ),
2
3
1
.00 (d, J¼7.2 Hz, 3H, CH(OTIPS)CHMe ), 0.93 (d,
2
J¼7.2 Hz, 3H, CH(OTIPS)CHMe ); d (100 MHz CDCl )
4.4.6. (3R,4R)-3-Benzylsulfanyl-4-[(1S)-1-triisopropyl-
silanyloxy-ethyl]-azetidin-2-one (6b). Pale yellow oil,
Y¼14%, [Found: C 64.32, H 9.00. C H NO SSi requires
2
C
3
ppm: 167.7, 133.5, 131.7, 129.1, 128.2, 75.5, 56.0, 53.2,
3.4, 19.0, 18.2, 16.6, 12.9; Ms (m/z): 407, 364, 321, 214.
3
2
1
35
2
C 64.07, H 8.96]. R (cyclohexane/ethyl acetate 75/25)
f
2
0
4
.4.2. (3R,4R)-3-Phenylsulfanyl-4-[(1S)-1-triisopropyl-
0.38; [a] ¼þ110 (c¼0.9, CHCl ); IR (CHCl ): 3241,
1759 cm2 ; d (200 MHz CDCl ) ppm: 7.36–7.25 (m, 5H,
H 3
D
3
3
1
silanyloxy-2-methyl-propyl]-azetidin-2-one (6d). Pale
yellow oil, Y¼15%, [Found: C; 64.95, H 9.08. C H NO
Ph), 6.29 (bs, 1H, NH), 4.03 (d, J¼13.1 Hz, 1H, CH SPh),
2
2
37
2
2
SSi requires C 64.81, H 9.15]. R (CH Cl /acetone 97/3)
f
3.91 (m, 1H, CHOTIPS), 3.83 (d, J¼13.1 Hz, 1H, CH SPh),
2
2
2
2
0
0
1
7
.45; [a] ¼58 (c¼0.2, CHCl ); IR (CHCl ): 3424,
3.67 (dd, J ¼2.3 Hz, J ¼1.5 Hz, 1H, BzSCH), 3.32 (dd,
D
3
3
1
2
765 cm2 ; d (400 MHz CDCl ) ppm: 7.60 (m, 2H, Ph),
1
J ¼2.3 Hz, J ¼6.0 Hz, 1H, CHNH), 1.11 (d, J¼6.3 Hz, 3H,
CH(OTIPS)Me), 1.01 (m, 21H, OSiiPr ); d (75 MHz
3 C
H
3
1
2
.30 (m, 3H, Ph), 5.73 (bs, 1H, NH), 3.93 (dd, J ¼2.6 Hz,
1
J ¼1.0 Hz, 1H, PhSCH), 3.75 (dd, J ¼3.0 Hz, J ¼7.2 Hz,
CDCl ) ppm: 167.1, 137.2, 129.1, 128.5, 127.3, 69.8, 61.8,
3
50.8, 34.8, 20.1, 18.1, 12.5; Ms (m/z): 394, 307, 259, 227,
186, 143, 91.
2
1
2
1
CHNH), 1.92 (m, 1H, CH(OTIPS)CHMe ), 1.05 (s, 27H,
H, CHOTIPS), 3.45 (dd, J ¼2.6 Hz, J ¼7.2 Hz, 1H,
1
2
2
CH(OTIPS)CHMe þOSiiPr ); d (100 MHz CDCl ) ppm:
2
3
C
3
p
p
p
1
1
67.8, 133.4, 131.5, 129.2, 128.3, 78.6, 56.6, 55.8, 33.1,
8.2, 18.1, 17.2, 13.0; Ms (m/z): 407, 364, 321, 214.
4.4.7. (3S ,4S )-3-Phenylsulfanyl-4-[(1S )-1-tert-butyl-
dimethyl-silanyloxy-propyl]-azetidin-2-one (5c). Pale
yellow solid mp: 1008C. Y¼18%, [Found: C 61.37, H
8.28. C H NO SSi requires C 61.49, H 8.31]. R (cyclo-
Following the general procedure reported above for
azadiene 4d and azetidinones 5d and 6d, the compounds
1
8
29
2
f
hexane/ethyl acetate 75/25) 0.60; IR (CHCl ): 3415,
3
1769 cm2 ; dH (200 MHz CDCl ) ppm: 7.65–7.27 (m,
1
5
a–5m and 6a–6f were obtained.
3
5
H, Ph), 5.79 (bs, 1H, NH), 4.28 (dd, J ¼2.4 Hz, J ¼
1
2
4
.4.3. (3S,4S)-3-Phenylsulfanyl-4-[(1S)-1-triisopropyl-
1.0 Hz, 1H, PhSCH), 3.74 (dt, J ¼2.4 Hz, J ¼6.0 Hz, 1H,
1 2
silanyloxy-ethyl]-azetidin-2-one (5a). Pale yellow oil,
Y¼33%, [Found: C 63.42, H 8.80. C H NO SSi requires
CHOTBDMS), 3.40 (t, J¼2.4 Hz, 1H, CHNH), 1.50 (m, 2H,
CH CH ), 0.91 (t, J¼7.32 Hz, 3H, CH CH ), 0.85 (s,
9H, OSiMe tBu) 0.04 (s, 3H, OSiMe tBu), 0.02 (s, 3H,
2 2
2
0
33
2
2
3
2
3
C 63.28, H 8.76]. R (CH Cl /acetone 97/3) 0.47;
2
f
2

M. Panunzio et al. / Tetrahedron 59 (2003) 9577–9582
9581
2
0
OSiMe tBu); d (75 MHz CDCl ) ppm: 167.1, 133.3, 132.2,
2
C 67.98, H 7.99]. R (CH Cl ) 0.31; [a] ¼þ45 (c¼1.65,
CHCl ); IR (CHCl ): 3419, 1767 cm ; d (200 MHz
3 3 H
C
3
f
2
2
D
2
1
1
2
29.3, 128.0, 72.1, 58.8, 53.2, 27.6, 25.8, 18.1, 9.6, 24.5,
4.6; Ms (m/z): 352, 317,279, 251, 199, 144.
CDCl ) ppm: 7.50 (m, 10H, PhþPh), 5.90 (bs, 1H, NH),
3
4
.81 (d, J¼6.0 Hz, 1H, CHOTIPS), 4.07 (dd, J ¼2.5 Hz,
1
p
p
p
4.4.8. (3R ,4R )-3-Phenylsulfanyl-4-[(1S )-1-t-butyl-
dimethyllsilylanoxy-propyl]-azetidin-2-one (6c). Pale
J ¼1.0 Hz, 1H, PhSCH), 3.60 (dd, J ¼2.5 Hz, J ¼6.0 Hz,
2
1
2
1H, CHNH), 0.9–1.1 (m, 21H, OSiiPr); d (50 MHz
C
yellow oil, Y¼13%, [Found: C 61.61, H 8.34. C H NO
CDCl ) ppm: 166.4, 140.7, 133.2, 133.2, 131.8, 129.0,
3
128.6, 128.1, 126.4, 76.1, 62.0, 54.8, 17.8, 12.3; Ms (m/z):
442, 398, 355, 289, 248, 115.
1
8
29
2
SSi requires C 61.49, H 8.31]. R (cyclohexane/ethyl acetate
f
2
1
7
CDCl ) ppm: 7.65–7.27(m, 5H, Ph), 5.73 (bs, 1H, NH),
5/25) 0.42; IR (CHCl ): 3424, 1768 cm ; d (200 MHz
3
H
3
p
p
3
1
.93 (dd, J ¼2.5 Hz, J ¼1.2 Hz, 1H, PhSCH), 3.60 (m,
4.4.13. (3S ,4S )-3-Phenylsulfanyl-4-thiophen-azetidin-
2-one (5g). Pale yellow solid mp: 86–888C. Y¼25%,
[Found: C 59.60, H 4.26. C H NOS requires C 59.74, H
1
2
H, CHOTBDMS), 3.40 (dd, J ¼2.5 Hz, J ¼7.0 Hz, 1H,
1
2
NHCH), 1.50 (m, 2H, CH CH ), 0.90 (t, J¼6.8 Hz,
2
3
13 11
2
3H, CH CH ), 0.85 (s, 9H, OSitBuMe ), 0.05 (s, 3H,
OSitBuMe ), 0.02 (s, 3H, OSitBuMe ); d (75 MHz CDCl )
4.24]. R (CH Cl /ethyl acetate 90/10) 0.57; IR (CHCl ):
f 2 2 3
2
3
2
3408, 1773 cm2 ; d (200 MHz CDCl ) ppm: 7.50 (m, 2H,
1
2
2
C
3
H 3
ppm: 166.4, 153.7, 133.3, 129.3, 128.3, 74.9, 59.1, 55.4,
thiophen-2-yl), 7.30 (m, 4H, Ph), 7.0 (m, 2H, Phþthiophen-
2-yl), 6.35 (bs, 1H, NH), 4.75(d, J¼2.2 Hz, 1H, CHNH),
4.29 (dd, J ¼2.2 Hz, J ¼0.94 Hz, 1H, PhSCH); d
27.3, 25.8, 15.0, 9.0, 4.2, 4.4; Ms (m/z): 352, 306,279, 251,
199, 145.
1
2
C
(
50 MHz CDCl ) ppm: 166.2, 142.3, 132.6, 132.0, 129.2,
3
p
.4.9. (3S ,4S )-3-Phenylsulfanyl-4-[(1S )-1-tert-butyl-
p
p
4
128.1, 127.3, 125.7, 125.4, 63.6, 55.6; Ms (m/z): 261, 218,
185, 112.
dimethylsilanyloxy-2,2-dimethyl-propyl]-azetidin-2-one
5e). Pale yellow solid mp: 139–1408C. Y¼39%, [Found: C
3.46, H 8.72. C H NO SSi requires C 63.28, H 8.76]. R
f
(
p
p
6
4.4.14. (3S ,4S )-4-Phenyl-3-phenylsulfanyl-azetidin-2-
one (5h). Pale yellow solid mp: 98–998C. Y¼18%, [Found:
C 70.76, H 5.15. C H NOS requires C 70.56, H 5.13]. R
f
2
0
33
2
2
1
(CH Cl ) 0.55; IR (CHCl ): 1766 cm ; dH (200 MHz
2 2 3
CDCl ) ppm: 7.60 (m, 2H, Ph), 7.30 (m, 3H, Ph), 5.68 (bs,
3
15 13
2
1
1
H, NH), 4.28 (d, J¼2.2 Hz, 1H, PhSCH), 3.58 (dd,
(CH Cl /acetone 98/2) 0.38; IR (CHCl ): 1769 cm ; dH
2 2 3
J ¼2.2 Hz, J ¼0.8 Hz, 1H, CHNH), 3.46 (bs, 1H,
(200 MHz CDCl ) ppm: 7.52 (m, 2H, Ph), 7.4 (m, 8H, Ph),
3
1
2
CHtBu), 0.96 (s, 9H, CH(OTBDMS)tBu), 0.92 (s, 9H,
OSiMe tBu), 0.05 (s, 6H, OSiMe tBu); d (75 MHz CDCl )
ppm: 168.0, 133.3, 132.0, 129.1, 128.1, 78.8, 56.0, 53.0,
6.18 (bs, 1H, NH), 4.53 (d, J¼2.4 Hz, 1H, CHNH), 4.18 (dd,
J ¼2.4 Hz, J ¼0.84 Hz, 1H, PhSCH); d (75 MHz CDCl )
2
2
C
3
1
2
C
3
ppm: 166.6, 138.3, 132.8, 132.1, 129.2, 129.0, 128.7, 128.1,
125.7, 62.9, 59.2; Ms (m/z): 255, 212, 178, 106, 77.
35.3, 26.8, 26.2, 18.5, 3.3, 4.2; Ms (m/z): 380, 340, 279, 201,
172.
p
.4.15. (3S ,4S )-3-Phenylsulfanyl-4-(4-methoxy-phenyl)-
p
4
p
p
p
4.4.10. (3R ,4R )-3-Phenylsulfanyl-4-[(1S )-1-tert-
butyl-dimethyl-silanyloxy-2,2-dimethyl-propyl]-azeti-
azetidin-2-one (5i). Pale yellow oil, Y¼15%, [Found: C
67.14, H 5.28. C H NO S requires C 67.34, H 5.30]. R
f
1
6
15
2
din-2-one (6e). Pale yellow oil, Y¼1%, [Found: C 63.50, H
(cyclohexane/ethyl acetate 60/40) 0.27; IR (CHCl ):
3
1756 cm2 ; dH (200 MHz CDCl ) ppm: 7.48 (m, 2H,
1
8
.70. C H NO SSi requires C 63.28, H 8.76]. R (CH Cl )
2
2
0
33
2
f
2
3
2
1
0
.76; IR (CHCl ): 3412, 1766 cm ; d (200 MHz CDCl )
3
p-MeO-Ph), 7.25 (m, 5H, Ph), 6.87 (d, 2H, p-MeO-Ph), 6.05
(bs, 1H, NH), 4.45 (d, J¼2.3 Hz, 1H, CHNH), 4.13 (dd,
J ¼2.3 Hz, J ¼0.94 Hz, 1H, PhSCH), 3.80 (s, 3H); d
H
3
ppm: 7.60 (m, 2H, Ph), 7.30 (m, 3H, Ph), 5.62 (bs, 1H, NH),
.87 (dd, J ¼1.3 Hz, J ¼2.2 Hz, 1H, PhSCH), 3.43 (dd,
3
1
2
1
2
C
J ¼2.2 Hz, J ¼7.6 Hz, 1H, CHNH), 3.35 (d, J¼7.6 Hz, 1H,
(75 MHz CDCl ) ppm: 166.6, 160.0, 153.6, 132.5, 130.3,
1
2
3
CHOTBDMS), 1.1 (s, 9H, CH(OTBDMS)tBu), 0.98 (s, 9H,
OSiMe tBu), 0.16 (s, 6H, OSiMe tBu); d (75 MHz CDCl )
ppm: 169.4, 133.1, 132.3, 129.1, 127.2, 81.8, 81.4, 73.0,
129.2, 128.0, 127.0, 114.4, 62.8, 59.1, 55.4; Ms (m/z): 285,
242, 227, 211, 197, 178, 165, 149, 136, 121, 77.
2
2
C
3
35.3, 26.8, 26.2, 18.5, 3.3, 4.2; Ms (m/z): 380, 340, 279, 201,
172.
4.4.16. (3,4-cis)-3-Phenylsulfanyl-4-phenyl-3,4-dihydro-
1H-pyridin-2-one (7a). Pale yellow oil, Y¼16%, [Found:
C 72.87, H: 5.39. C H NOS requires C 72.57, H 5.37]. R
f
1
7
15
4.4.11. (3S,4S)-3-Phenylsulfanyl-4-[(1S)-tri-isopropyl-
silanyloxy-phenyl]-azetidin-2-one (5f). Pale yellow oil,
(CH Cl /ethyl acetate 90/10) 0.55; IR (CHCl ): 3620, 3017,
2 2 3
1688, 1659 cm2 ; d (200 MHz CDCl ) ppm: 8.06 (bs, 1H,
1
H 3
Y¼24%, [Found: C 68.25, H 8.02. C H NO SSi requires
NH), 7.60–7.56 (m, 2H, Ph), 7.42–7.12 (m, 8H, Ph), 6.24
(dd, J ¼4.66 Hz, J ¼7.74 Hz, 1H, NHCH), 5.24 (m, 1H,
2
5
35
2
2
0
C 67.98, H 7.99]. R (CH Cl ) 0.38; [a] ¼215.45 (c¼1.65,
f
2
2
D
1
2
2
1
CHCl ); IR (CHCl ): 3413, 2946, 1767 cm ; d (200 MHz
3
NHCHvCH), 3.86 (m, 1H, PhSCH), 3.85 (m, 1H, PhCH);
d (75 MHz CDCl ) ppm: 168.4, 140.0, 133.1, 132.9, 129.0,
128.9, 128.1, 127.5, 127.0, 125.0, 105.7, 53.7, 44.7; Ms
3
H
CDCl ) ppm: 7.47 (m, 2H, Ph), 7.28 (m, 8H, Ph), 5.62 (bs,
3
C
3
1
H, NH), 4.85 (d, J¼4.5 Hz, 1H, CHOTIPS), 4.07 (dd,
J ¼2.4 Hz, J ¼1.1 Hz, 1H, PhSCH), 3.60 (dd, J ¼2.4 Hz,
(m/z): 281, 172, 132, 115, 105, 77.
1
2
1
J ¼4.5 Hz, 1H, CHNH), 0.98–0.92 (m, 21H, OSiiPr); d
2
C
(
50 MHz CDCl ) ppm: 166.5, 140.1, 133.6, 131.9, 129.0,
3
4.4.17. (3,4-trans)-3-Phenylsulfanyl-4-phenyl-3,4-dihydro-
1H-pyridin-2-one (7b). Pale yellow oil, Y¼4%, [Found: C
72.80, H 5.39. C H NOS requires C 72.57, H 5.37]. R
1
(
28.4, 128.3, 128.2, 126.5, 75.1, 61.0, 54.6, 17.8, 12.3; Ms
m/z): 442, 398, 355, 289, 248, 115.
1
7
15
f
(CH Cl /ethyl acetate 90/10) 0.44; IR (CHCl ): 3620, 3018,
1656, 1521 cm ; dH (200 MHz CDCl ) ppm: 7.52–7.05
2 2 3
2
1
4
.4.12. (3R,4R)-3-Phenylsulfanyl-4-[(1S)-triisopropyl-
3
silanyloxy-phenyl]-azetidin-2-one (6f). Pale yellow oil,
Y¼20%, [Found: C 68.22, H 8.01. C H NO SSi requires
(m, 11H, 2PhþNH), 6.28 (m, 1H, PhCH), 5.39 (m, 1H,
NHCHvCH), 4.24 (m, 1H, NHCH), 3.98 (d, J¼5.7 Hz, 1H,
2
5
35
2

9582
M. Panunzio et al. / Tetrahedron 59 (2003) 9577–9582
PhSCH). dC (75 MHz CDCl ) ppm: 169.7, 138.8, 138.1,
3
In Enantioselective Synthesis of b-Amino Acids. Juaristi, E.,
Ed.; Wiley-VCH: New York, 1997; pp 279–350.
134.8, 132.4, 129.7, 129.6, 129.0, 128.9, 128.6, 128.5,
127.5, 127.4, 125.7, 108.0, 59.7, 42.9; Ms (m/z): 281, 172,
132, 115, 105, 77.
4. Palomo, C.; Oiarbide, M.; Ganboa, I.; Miranda, J. I.
Tetrahedron Lett. 2001, 42, 8955–8958.
5
. Ojima, I.; Ming Sun, C.; Zucco, M.; Park, Y. H.; Duclos, O.;
Kuduk, S. Tetrahedron Lett. 1993, 34, 4149–4152.
p
.4.18. (3S ,4S )-3-Phenylsulfanyl-4-phenylethynyl-
p
4
azetidin-2-one (5k). Pale yellow oil, Y¼25%, [Found: C
2.87, H 4.68. C H NOS requires C 73.09, H 4.69]. R
f
6. Kende, A. S.; Liu, K.; Kaidor, I.; Dorey, G.; Koch, K. J. Am.
Chem. Soc. 1995, 117, 8558–8570.
7
1
7
13
(
cyclohexane/ethyl acetate 80/20) 0.35; IR (CHCl ): 3413,
3
7. McKittrick, B. A.; Ma, K.; McPhail, A. T. J. Med. Chem.
1998, 41, 752–759.
775 cm2 ; dH (200 MHz CDCl ) ppm: 7.58–7.31 (m,
1
1
1
1
3
0H, 2Ph), 6.21 (bs, 1H, NH), 4.53(dd, J ¼2.4, J ¼1.4 Hz,
8. Ogilvic, W. W.; Yoakim, C.; Do, F.; Hache, B.; Lagace, L.;
Naud, J.; O’Meara, J. A.; Reziel, R. Bioorg. Med. Chem. 1999,
7, 1521–1531.
1
2
H, PhSCH), 4.29 (d, J¼2.4 Hz, 1H, CHNH); d (50 MHz
C
CDCl ) ppm: 165.4, 132.7, 131.2, 131.8, 129.3, 129.1,
3
1
2
28.5, 128.3, 121.8, 86.9, 84.9, 62.2, 46.7; Ms (m/z): 279,
35, 202, 130, 121, 105, 77.
9. Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Eur.
J. Org. Chem. 1999, 3223–3235.
1
0. Georg, G. I.; Ravikumar, V. T. Stereocontrolled Ketene-imine
Cycloaddition Reaction. In The Organic Chemistry of
b-Lactams. Georg, G., Ed.; VCH: New York, 1993; pp
318–323.
p
.4.19. (3S ,4S )-3-Benzylsulfanyl-4-phenylethynyl-
p
4
azetidin-2-one (5l). Pale yellow solid mp: 109–1128C.
Y¼25%, [Found: C 73.80, H: 5.17. C H NOS requires C
1
8 15
73.69, H 5.15]. R (cyclohexane/ethyl acetate 80/20) 0.29;
IR (CHCl ): 3413, 1774 cm ; d (200 MHz CDCl ) ppm:
11. Hegedus, L. S.; Montgomery, J.; Narukawa, Y.; Snustad, D. C.
J. Am. Chem. Soc. 1991, 113, 5784–5791.
12. Bandini, E.; Martelli, G.; Spunta, G.; Bongini, A.; Panunzio,
M. Tetrahedron Lett. 1996, 37, 4409–4412.
13. Bandini, E.; Martelli, G.; Spunta, G.; Panunzio, M. Synlett
1996, 1017–1018.
f
2
1
3
H
3
7
.73–7.26 (m, 10H, 2Ph), 6.42 (bs, 1H, NH), 4.23 (m, 1H,
BzSCH), 4.16 (d, J¼1.9 Hz, 1H, CHNH), 3.96 (d, J¼
3.2 Hz, 1H, PhCH S), 3.87 (d, J¼13.2 Hz, 1H, PhCH S);
1
2
2
d (50 MHz CDCl ) ppm: 165.8, 137.0, 131.6, 129.1, 128.9,
C
3
1
(
28.7, 128.4, 127.5, 121.7, 86.5, 85.0, 59.5, 47.4, 35.4; Ms
m/z): 293, 260, 247, 217, 202, 171, 158, 144, 130, 115,
14. Bandini, E.; Favi, G.; Martelli, G.; Panunzio, M.; Piersanti, G.
Org. Lett. 2000, 2, 1077–1079.
9
2, 77.
15. Bongini, A.; Panunzio, M.; Piersanti, G.; Bandini, E.; Martelli,
G.; Spunta, G.; Venturini, A. Eur. J. Org. Chem. 2000,
2379–2390.
p
p
4
2
4
.4.20. (3S ,4S )-3-Phenylsulfanyl-4-furan-2yl-azetidin-
-one (5m). Pale yellow oil, Y¼20%, [Found: C 66.67, H
.85. C H NO S requires C 66.40, H 4.83]. R (cyclo-
16. Bongini, A.; Panunzio, M.; Tamanini, E.; Martelli, G.;
Vicennati, P.; Monari, M. Tetrahedon: Asymmetry 2003, 14,
993–998.
1
5
13
2
f
hexane/ethyl acetate 70/30) 0.28; IR (CHCl ): 3422,
3
1
766 cm2 ; dH (400 MHz CDCl ) ppm: 7.75 (bs, 1H,
1
17. Bari, S. S.; Sharma, A. K.; Sethi, M. K. Indian J. Chem., Sec. B
1998, 37, 1114–1119.
3
NH), 7.57 (m, 2H, PhþCHvCHO), 7.32 (m, 4H, Ph), 6.25
(
(
(
dd, J ¼2.0 Hz, J ¼3.2 Hz, 1H, CHvCH–O), 6.20
18. van der Veen, J. M.; Bari, S. S.; Krishnan, L.; Manhas, M. S.;
Bose, A. J. Org. Chem. 1989, 54, 5758–5762.
19. Lawlor, M. D.; Lee, T. W.; Danheiser, R. L. J. Org. Chem.
2000, 65, 4375–4384.
1
2
dd, J ¼4.8 Hz, J ¼7.6 Hz, 1H, NHCH–CHvCH–), 6.09
1
1
d, J¼3.2 Hz, 1H, CHvC–O), 5.21 (m, 1H, NHCH–
CHvCH), 4.01 (m, 1H, PhSCH), 3.94 (dd, J ¼1.6 Hz,
1
J ¼6 Hz, 1H, CHNH); d (75 MHz CDCl ) ppm: 169.1,
20. Zhou, F.; Rosen, J.; Lachicotte, R. J. J. Org. Chem. 1998, 63,
5403–5412.
1
C
3
1
1
1
52.4, 143.5, 132.9, 132.8, 129.1, 128.1, 125.8, 110.3,
06.2, 103.0, 50.8, 38.4; Ms (m/z): 271, 239, 205, 162, 149,
22, 105.
21. Teng, M.; Miller, M. J. J. Am. Chem. Soc. 1993, 115,
548–554.
2
2. Ghosez, L.; Bayard, P.; Nshimyumukiza, P.; Gouverneur, V.;
Sainte, F.; Beaudegnies, R.; Rivera, M.; Frisque-Hesbain,
A. M.; Wynants, C. Tetrahedron 1995, 51, 11021–11042.
3. Ghosez, L. Pure Appl. Chem. 1996, 68, 15–22.
Acknowledgements
2
2
4. Panunzio, M.; Zarantonello, P. Org. Process Res. Dev. 1998,
P. V. thanks Vicuron-Pharmaceuticals (Gerenzano, Italy),
E. C. thanks Farchemia (Treviglio) and E. T. thanks
GlaxoSmithKline (Verona-Italy) for financial support.
2
, 49–59.
2
5. (a) Tidwell, T. T. Ketenes. Wiley: New York, 1995. (b) Lynch,
J. E.; Riserman, S. M.; Laswell, W. L.; Tschaen, D. M.;
Volante, R. P.; Smith, G. B.; Shinkai, I. J. Org. Chem. 1989,
5
4, 3792–3796.
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