1β-Methylcarbapenem intermediates via the thiolysis of a Meldrum's precursor

Article abstract of DOI:10.1016/S0040-4020(01)01082-1

5-{3-[1-(tert-Butyldimethylsilyloxy)ethyl]-4-oxo-azetidin-2-yl}-2,2,5- trimethyl-[1,3]dioxane-4,6-dione (3) has been submitted to nucleophilic attack with various nucleophiles. Meldrum's moiety transesterification, C4-substitution, β-lactam ring opening and Meldrum's moiety decarboxylation were observed. Reaction of 3 with ethanethiol and dimethylaminopyridine in ethanol quantitatively furnished ethyl 2-{3-[1-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-azetidin-2-yl}- thiopropionate as the 1:1 mixture of β (7a) and α (8a) diastereoisomers.

Full text of DOI:10.1016/S0040-4020(01)01082-1

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 10383±10389
1b-Methylcarbapenem intermediates via the thiolysis of a
Meldrum's precursor
a
Christophe Jacopin, Mathieu Laurent, Marc Belmans, Luc Kemps, Marcel Ceresiat
a
b
b
b
 Â
and Jacqueline Marchand-Brynaerta,p
a
   Ã
Unite de Chimie Organique et Medicinale, Universite Catholique de Louvain, Batiment Lavoisier, Place Louis Pasteur 1,
B-1348Louvain-la-Neuve, Belgium
Ã
Tessenderlo Chemie, rue du Trone 130, B-1050 Bruxelles, Belgium
b
Received 3 August 2001; revised 12 October 2001; accepted 1 November 2001
AbstractÐ5-{3-[1-(tert-Butyldimethylsilyloxy)ethyl]-4-oxo-azetidin-2-yl}-2,2,5-trimethyl-[1,3]dioxane-4,6-dione (3) has been submitted
to nucleophilic attack with various nucleophiles. Meldrum's moiety transesteri®cation, C4-substitution, b-lactam ringopeningand
Meldrum's moiety decarboxylation were observed. Reaction of 3 with ethanethiol and dimethylaminopyridine in ethanol quantitatively
furnished ethyl 2-{3-[1-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-azetidin-2-yl}-thiopropionate as the 1:1 mixture of b (7a) and a (8a)
diastereoisomers. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
requires expensive (chiral) reagents and/or (chiral) cata-
lysts, dif®cult to handle on the industrial scale.
Carbapenem antibiotics bearing1 b-methyl substituent
possess remarkable chemical and metabolic stability; they
are potent drugs against a variety of pathogens, including
multiple drugresistant bacteria. Therefore, the search for
ef®cient synthesis of these carbapenems has summoned up
considerable works.1 The main strategies make use of
acetoxy-azetidinone 12 as the chiral startingmaterial allow-
ingstereocontrolled substitution at C4 (Scheme 1). Intro-
duction of the methyl-substituted two-carbon chain of 2a
results from enolate addition,3 vinylation followed by
hydrogenation,4 or allylation followed by ozonolysis.5
Other methods are based on methylation of 2b, also
obtained from 1.6 In all cases the stereochemical control
of the C5 chiral center appears to be a dif®cult task, and
An alternative interestingapproach, disclosed independently
by the Takasago's7,8 and Merck's9±12 scientists, is based on the
diastereoselective decarboxylationof malonic precursors. The
2-methyl-malonate residue was introduced by reacting 1 with
2-methyl-malonate diesters in the presence of sodium hy-
dride,8 or with 2-methyl Meldrum's acid (2,2,5-trimethyl-
1,3-dioxan-4,6-dione) in the presence of triethylamine9
(Scheme 2). In both cases, the azetidinone N1 position was
further protected with a t-butyldimethylsilyl group before the
cleavage of the ester functions by using standard methods; the
resultingmalonic diacid was then decarboxylated in re¯uxing
ethyl acetate with formic acid as the catalyst. In a last step, the
N-protectinggroup was removed (®ve-step process from 1).
Scheme 1.
Keywords: azetidinones; carbapenems; decarboxylation.
Correspondingauthor. Tel.: 132-10-47-27-40; fax: 132-10-47-41-68; e-mail: marchand@chim.ucl.ac.be
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)01082-1

10384
C. Jacopin et al. / Tetrahedron 57 (2001) 10383±10389
Scheme 2. (i) Et3N (excess), EtOAc, re¯ux, 4 h.
We recently revisited the decarboxylation process of
Table 1.
Meldrum's derivative 3 with in mind the following
questions: is it possible, (i) to avoid the N-protection
and deprotection steps and, (ii) to perform the decarboxyl-
Entry
Conditions
Results
No reaction
No reaction
1
2
1 M HCl aq., CH2Cl2, 20±808C,
24 h
1 M HCl aq., CH2Cl2, Triton X-
100, 508C, 12 h
ative decomposition of the 2,2-dimethyl-1,3-dioxan-4,6-
(two-step process
13±15
dione ringin a one-step reaction
from 1)?
3
4
5
6
7
HOAc±H2 (10:1), 708C, 5 h
EtOH, 608C, 72 h
2 M NaOH aq., MeOH, 508C, 1 h
1 M MeOLi aq., THF, 208C, 1 h
EtONa (2 equiv.), EtOH±THF
(1:1), 608C, 17 h
b-Lactam opening
No reaction
4a (87%)
b-Lactam opening
No reaction
2. Results and discussion
The precursor 3 was obtained in 87% yield by substitution
of acetoxy-azetidinone 1 with 2-methyl Meldrum's acid in
the presence of a large excess of triethylamine9 (Scheme 2).
Without protectingthe N1 position, we systematically
examined different classical conditions of ester hydrolysis
or transesteri®cation, as summarized in Table 1. No reaction
was observed in biphasic acidic media (entries 1 and 2), and
b-lactam openingoccurred in homogeneous acidic medium
(entry 3). Transesteri®cation in ethanol (entry 4) required a
basic catalyst (entry 5). Thus, dimethyl malonate derivative
4a (Scheme 3) was recovered when re¯uxing 3 in methanol
and aqueous sodium hydroxide; the same compound could
be obtained by reaction of acetoxy-azetidinone 1 with
sodium salt of dimethyl 2-methylmalonate.7
8
MeONa (1.5 equiv.), MeOH±
THF (1:1), 608C, 17 h
PhONa (2 equiv.), THF, 208C,
3 h
LiOH (2 equiv.), THF±H2 (5:1),
208C, 2 h
No reaction
5a (96%)
9
10
4b (50%)13
The authors mentioned that in the absence of a bulky N-
protectinggroup (Si tBuMe2), the major product resulted
from azetidinone ring opening. Moreover, the high dia-
stereoselectivity (b/a.90:10) of the enol intermediate
reprotonation was explained by particular conformational
effects due to the presence of this bulky substituent.10,11
Scheme 3. (i) MeOH, NaOH aq., 508C, 1 h; (ii) LiOH, THF±H2O, 508C, 1 h.
Scheme 4. (i) RXNa, THF, 208C or re¯ux, in the presence of 18-crown-6 or not (Table 2).

C. Jacopin et al. / Tetrahedron 57 (2001) 10383±10389
10385
Table 2.
Entry
Conditions
Results
1
2
3
4
5
HSNa (1.5 equiv.), THF±H2O (1:1), 658C, 17 h
PhSNa (2 equiv.), CH3CN, 808C, 24 h
PhSNa (2 equiv.), DMF, 208C, 24 h
PhSNa (2 equiv.), THF, 208C, 24 h
EtSNa (2 equiv.), CH3CN, 808C, 24 h
EtSNa (2 equiv.), THF, 208C, 24 h
b-Lactam opening
b-Lactam opening
b-Lactam opening
5b (95%)
b-Lactam opening
5c (92%)
6
7
8
9
10
EtSNa (2 equiv.), 18-crown-6, THF, 208C, 24 h
EtSNa (2 equiv.), 18-crown-6, THF±H2O, 608C, 12 h
MeSNa (1.5 equiv.), 18-crown-6, THF±H2O, 608C, 12 h
MeSNa (1.5 equiv.), 18-crown-6, THF±H2O, 208C, 24 h
5c16c (88%; 9:1)
6c (95%)
5d2216d (87%; 0.4:1)
6d (97%)
Treatment of 3 with alkoxides gave various results, from the
absence of transformation to the b-lactam destruction,
dependingon the experimental conditions (entries 6±8).
With sodium phenoxide, nucleophilic attack at C4 resulted
in quantitative formation of 4-phenoxy-azetidinone 5a16
(entry 9, Scheme 4). Lastly, basic hydrolysis with lithium
hydroxide in aqueous THF at room temperature, followed
by smooth acidi®cation, furnished the malonic diacid 4b9
(Scheme 3). Thus, in this ®rst set of experiments, the
Meldrum's moiety decomposition in a one-step reaction
accordingto route (c) of Scheme 5, was never observed;
only products resultingfrom routes (a) and (b) were
obtained. Therefore, we next decided to examine non-
classical conditions of transesteri®cation usingsulphur-
nucleophiles as reagents; such reactions are scarcely
described in the ®eld of Meldrum's acid chemistry.17,18
observed by treatment of 3 with sodium thiomethoxide
(entries 9 and 10). The spectroscopic features of 6d were
similar to those of 6c. Products resultingfrom the cleavage
of the b-lactam N1±C4 bond have been already mentioned
in the previous works devoted to the decarboxylation
strategy, but under acidic conditions.9,12 The quantitative
formation of 6, most probably from the carbanion inter-
mediate A (Scheme 5), demonstrated, at this stage, the
feasibility of a clean `one-step decomposition' of the
Meldrum's substituent of 3, initiated by a sulphur-nucleo-
phile. We speculated that in the presence of a proton source,
the enolate anion A could be quenched, without cleavage
of the azetidinone ring. Accordingly, a last series of
experiments was realized usingthiols as soft nucleophiles.
Treatment of 3 in re¯uxingethanethiol used as solvent and
reagent, slowly produced a mixture of the desired thioesters
7a23 and 8a, but in which the `wrong' a-isomer 8a was
largely the major compound (Scheme 6, Table 3, entry 1).
Addition of an organic base, such as triethylamine (entry 2),
1,4-diazabicyclo[2.2.2]octane (entry 3), diisopropylamine
(entry 4), or N-dimethylaminopyridine (DMAP) (entry 5),
accelerated the reaction, and slightly increased the ratio
of the b-isomer 7a, the required precursor of 1b-methyl-
carbapenems. Addition of ethanol as co-solvent (entry 6)
improved the b/a isomers ratio. Finally, the best conditions
involved the use of a mixture of ethanethiol and ethanol as
protic nucleophilic medium, and the addition of DMAP as
soft base (entry 8); a 50:50 mixture of stereoisomers was
obtained. This result could not be improved by using iso-
propanol or tertio-butanol as co-solvents (entries 7, 9 and
10). Thiophenol appeared to be less reactive than ethane-
thiol (entries 11 and 12), with a less favorable b/a isomers
Sodium hydrosul®de and sodiumthiophenoxide in polar
solvents destroyed the b-lactam ring(Table 2, entries
1±3); in THF, at room temperature, sodium thiophenoxide
substituted quantitatively the Meldrum's moiety of
compound 3 to furnish thiophenoxy-azetidinone 5b19±21
(Scheme 4, Table 2, entry 4). Similarly, sodium thio-
ethoxide reacted with 3 to give 5c5 (entry 6); in the presence
of crown-ether, some open-product 6c was formed together
with 5c (entry 7, Scheme 4). But, in re¯uxingmoist THF,
with crown-ether, open-product 6c was quantitatively
1
obtained (entry 8). This compound is characterized in H
NMR by a singlet at 1.90 d (Me±CvC) and a doublet at
6.93 d (H±CvC); in the 13C NMR spectrum, two ole®nic
carbons (133.7 and 139.6 d) and two carbonyl carbons
(172.6 and 193.7 d) are visible. Such a competition between
routes (a) and (c)1(d), as illustrated in Scheme 5, was also
Scheme 5. (a) Nucleophilic attack on C4 and elimination of the Meldrum's substitutent; (b) transesteri®cation or saponi®cation of the Meldrum's substituent;
(c) nucleophilic attack on Meldrum's carbonyl, elimination of acetone and decarboxylation; (d) cleavage of the N1±C4 bond; (e) protonation of the enolate A.

10386
C. Jacopin et al. / Tetrahedron 57 (2001) 10383±10389
Scheme 6. (i) RSH, base, solvent, heating(Table 3); (ii) NaOH±H O, then HCl.
2
ratio (entry 13); a 40:60 mixture of compounds 7b24±27 and
8b was obtained (Scheme 6). tertio-Butanethiol was also
less reactive (entries 14 and 16), but gave a stereoselectivity
similar to that of ethanethiol (entry 15); stereoisomers 7c28
and 8c25 were formed in equimolar ratio (Scheme 6). Thus,
the `one-step' nucleophilic decomposition of the Meldrum's
moiety was not particularly in¯uenced by steric effects,
consideringthe thiol reagent (EtSH, PhSH, tBuSH) and
the alcohol co-solvent (EtOH, iPrOH, tBuOH). The role
of the organic base was further investigated, but without
success: stronger bases, such as DBU (1,8-diazabicyclo-
[5.4.0]undec-7-ene) and DBN (1,5-diazabicyclo[4.3.0]non-
5-ene), led to the b-lactam ringopenin;g chiral bases
derived from alkaloids29,30 did not improve the b/a stereo-
selectivity.
spondingacids 2a and 9 (Scheme 6), already described in
the previous literature.6,31
3. Conclusion
This work pointed out the various possibilities of nucleo-
philic attack on b-lactam 3 (Scheme 5) substituted with a
Meldrum's acid moiety. The competition between the pos-
sible mechanisms appeared hardly manageable. However,
signi®cant differences were observed between O- and
S-nucleophiles. Charged oxygen-species in aprotic solvent
mainly attacked the C2 (MeOLi; b-lactam ringdestruction),
or the C4 positions (PhONa; substitution of the Meldrum's
group), while, in protic medium, the malonic carbonyls
reacted to give hydrolysis (LiOH±H2O) or transesteri®-
cation products (NaOH±MeOH) without concomitant
extrusion of CO2. Charged sulphur-species attacked either
the C4 position, or the Meldrum's part. In this last case,
decarboxylation occurred, followed by the cleavage of the
b-lactam C4±N1 bond. Finally, neutral sulphur-species in
protic medium furnished exclusively the thioesters derived
from attack on one malonic carbonyl, followed by extrusion
The thioesters 7a±c and 8a±c, obtained in one-step from
the Meldrum's precursor (3), were characterized by NMR
spectroscopy: H5 proton gave a signal at 2.8±2.7 and 2.7±
2.6 d in the b and a series, respectively; the b-lactamic
protons, H3 and H4, were visible around 3 and 3.9 d in
the b series, and around 2.8 and 3.7 d in the a series.
Saponi®cation of 7a and 8a as usual furnished the corre-
Table 3.
Entry
Conditions
Baseb
Yield
Thiola
Solvent (ratio)
T (8C)
Time (h)
%
Compound
b/ac
1
2
3
4
5
6
7
8
EtSH
EtSH
EtSH
EtSH
EtSH
EtSH
EtSH
EtSH
EtSH
EtSH
PhSH
PhSH
PhSH
tBuSH
tBuSH
tBuSH
±
±
±
±
±
Et3N
DABCO
DIPEA
DMAP
±
40
40
40
40
40
65
65
65
65
65
80
80
80
65
65
65
17
6
6
6
5
24
17
6
17
17
24
24
17
17
17
17
40d
99
7a/8a
7a/8a
7a/8a
7a/8a
7a/8a
7a/8a
±
7a/8a
7a/8a
7a/8a
±
7:93
19:81
22:78
24:76
33:67
48:52
±
50:50
38:62
42:58
±
96
95
±
86d
97
EtOH (1:4)
iPrOH (1:1)
EtOH (1:2)
iPrOH (1:2)
tBuOH (1:2)
±
EtOH (1:1)
EtOH (1:1)
EtOH (1:2)
iPrOH (1:2)
tBuOH (1:2)
±
0d
DMAP
DMAP
DMAP
±
98d
97
9
10
11
12
13
14
15
16
38d
0d
±
0d
±
±
DMAP
DMAP
DMAP
DMAP
97
7b/8b
7c/8c
7c/8c
±
40:60
36:64
50:50
±
70d,e
50d
0d
a
Large excess.
One equivalent.
b
c
d
e
1H NMR analysis of the crude mixtures.
Startingmaterial recovered.
20% of 6 (b-lactam openingproduct).

C. Jacopin et al. / Tetrahedron 57 (2001) 10383±10389
10387
of acetone and CO2, without cleavage of the b-lactam ring.
Thus, these simple experimental conditions allowed the
preparation of carbapenem precursors in two steps from
acetoxy-azetidinone 1. The control of the C5 chiral center
remains to be optimized: actually our best results give a 1:1
ratio of b and a diastereoisomers which could be separated
after hydrolysis, by selective crystallization.6,31 We are
now examiningthe possibility of enantioselective proto-
nation32,33 of enolate intermediates (A, Scheme 5) derived
from 7, 8.
4.1.2. 2-{3-[1-(tert-Butyldimethylsilyloxy)ethyl]-4-oxo-
azetidin-2-yl}-2-methyl-malonic acid, dimethyl ester
(4a). To a solution of 3 (100 mg, 0.259 mmol) in methanol
(2 mL) and water (0.5 mL) was added 2 M NaOH (0.26 mL,
0.52 mmol, 2 equiv.). The mixture was stirred at 508C for
1 h, then diluted with CH2Cl2 and washed with brine. The
organic phase was dried (MgSO4) and concentrated to
furnish 4a (85 mg, 87% yield) which could be puri®ed by
¯ash column-chromatography on silica gel (elution with
30% EtOAc/hexane): mp 122.4±122.68C (white solid);
[Found: C, 54.82; H, 8.48; N, 3.73. C17H31NO6Si requires
C, 54.67; H, 8.37; N, 3.75%]; Rf (30% EtOAc/hexane) 0.33;
dH (200 MHz, CDCl3) 6.11 (br s, 1H, NH), 4.18 (m, 1H,
Me±CH(OTBDMS)±), 4.13 (d, 1H, Jˆ2.1 Hz, H-2), 3.72
(s, 6H, ±OMe), 2.97 (m, 1H, H-3), 1.44 (s, 3H, Me), 1.08 (d,
3H, Jˆ6.3 Hz, Me±CH(OTBDMS)±), 0.84 (s, 9H, Si±Bu),
0.03 (s, 6H, Si±Me); dC (50 MHz, CDCl3) 170.9, 167.7,
64.6, 60.3, 59.9, 55.7, 52.8, 52.5, 25.7, 22.3, 20.9, 16.5,
14.1, 24.4, 25.0; m/z (CI) 374 (MH1, 44), 358 (23), 316
(16), 231 (12), 199 (17), 89 (100%).
4. Experimental
4.1. General
The meltingpoints were determined with an electrothermal
microscope and are uncorrected. The speci®c rotations
(^0.2) were determined on a Perkin±Elmer 241 MC polari-
meter (concentration in g/100 mL). The IR spectra were
taken with a Bio-Rad FTS 135 instrument, and calibrated
with polystyrene (1601 cm21). The 1H and 13C NMR spectra
were recorded on Varian Gemini 200±300 (at 200±
300 MHz for proton and 50±75 MHz for carbon), or Bruker
AM-500 spectrometers (at 500 MHz for proton and
125 MHz for carbon); the chemical shifts are reported in
ppm down®eld from tetramethylsilane (internal standard).
The mass spectra were obtained on a Finnigan-MAT
TSQ-70 instrument at 70 eV (chemical ionization mode).
The microanalyses were performed at the Christopher
Ingold Laboratories of the University College London.
4.1.3. 2-{3-[1-(tert-Butyldimethylsilyloxy)ethyl]-4-oxo-
azetidin-2-yl}-2-methyl-malonic acid (4b). To a solution
of 3 (100 mg, 0.259 mmol) in THF (5 mL) and water (1 mL)
was added LiOH (22 mg, 0.54 mmol, 2 equiv.). The mixture
was stirred at 208C for 2 h, then concentrated under vacuum.
The residue was dissolved in water and extracted with ether.
The aqueous phase was acidi®ed with 1N HCl (to reach pH
2) and extracted with ethyl acetate (3£). Dryingover
MgSO4 and concentration gave the known malonic
derivative 4b9 (45 mg, 50% yield); Rf (AcOEt) 0.22; dH
(200 MHz, CD3OD) 4.15 (m, 2H, H-2 and Me±
CH(OTBDMS)±), 2.97 (m, 1H, H-3), 1.35 (s, 3H, Me),
1.10 (d, 3H, Jˆ6.4 Hz, Me±CH(OTBDMS)±), 0.83 (s,
9H, Si±Bu), 0.02 (s, 3H, one of the Si±Me), 0.01 (s, 3H,
one of the Si±Me); dC (50 MHz, CD3OD) 174.2, 173.8,
171.6, 65.9, 60.4, 56.7, 53.6, 30.7, 26.3, 22.6, 18.8, 16.8,
24.1, 24.8.
Thin-layer chromatography was carried out on silica gel 60
plates F254 (Merck, 0.2 mm thick); visualization was
effected with UV light, or phosphomolybdic acid.
Column-chromatography (under medium pressure) was
carried out with Merck silica gel 60 of 230±240 mesh
ASTM.
4.1.4. (3R,4R)-4-Phenyloxy-3-[(5R)-10-(tert-butyldimethyl-
silyloxy)ethyl]-azetidin-2-one (5a). To a solution of 3
(100 mg, 0.259 mmol) in THF (10 mL) was added sodium
phenoxide (60 mg, 2 equiv.). The mixture was stirred at
208C for 2 h, then concentrated under vacuum. Addition
of ethyl acetate, washingwith brine, dryingand concen-
tration gave known 5a16 (80 mg, 96% yield); dH (300
MHz, CDCl3) 7.34 (t, 2H, Jˆ8 Hz, Ph), 7.07 (t, 1H, Jˆ
8 Hz, Ph), 6.93 (d, 2H, Jˆ8 Hz, Ph), 6.46 (br s, 1H, NH),
5.72 (s, 1H, H-2), 4.25 (dq, 1H, Jˆ3 and 7 Hz, Me±
CH(OTBDMS)±), 3.33 (d, 1H, Jˆ3 Hz, H-3), 1.29 (d, 3H,
Jˆ7 Hz, Me±CH(OTBDMS)±), 0.89 (s, 9H, Si±Bu), 0.07
(s, 3H, one of the Si±Me), 0.06 (s, 3H, one of the Si±Me).
4.1.1. 5-{3-[1-(tert-Butyldimethylsilyloxy)ethyl]-4-oxo-
azetidin-2-yl}-2,2,5-trimethyl-[1,3]dioxane-4,6-dione (3).
To a solution of (3R,4R)-4-acetoxy-3-[(5R)-10-tert-butyl-
dimethylsilyloxy)ethyl]-azetidin-2-one 1 (1 g, 3.48 mmol)
in ethyl acetate (100 mL) were added 2,2,5-trimethyl-1,3-
dioxane-4,6-dione (826 mg, 5.22 mmol) and triethylamine
(12 mL). The mixture was re¯uxed for 4 h, then diluted with
ethyl acetate and washed with brine. After dryingover
MgSO4 and concentration, the solid residue was puri®ed
by ¯ash column-chromatography on silica gel (elution
with 30% EtOAc/hexane) to give 3 (1.17 g, 87% yield) as
white crystals. Mp 87±888C; [Found: C, 55.82; H, 8.20; N,
3.54. C18H31NO6Si requires C, 56.08; H, 8.10; N, 3.63%];
20
4.1.5.
methylsilyloxy)ethyl]-azetidin-2-one (5b). A mixture of
(100 mg, 0.259 mmol) and sodium thiophenoxide
(3R,4R)-4-Phenylthioxy-3-[(5R)-10-tert-butyldi-
Rf (30% EtOAc/hexane) 0.26; [a]D ˆ10.042 (c 0.53,
CH2Cl2); nmax (KBr) 3200, 1768, 1742 cm21; dH (200
MHz, CDCl3) 6.20 (1H, br s, NH), 4.15 (1H, m, Me±
CH(OTBDMS)±), 4.09 (d, 1H, Jˆ2 Hz, H-2), 3.48 (m,
1H, H-3), 1.72 (s, 3H, one of the CMe2), 1.68 (s, 3H, one
of the CMe2), 1.56 (s, 3H, Me), 1.12 (d, 3H, Jˆ6.3 Hz, Me±
CH(OTBDMS)±), 0.79 (s, 9H, Si±Bu), 0.01 (s, 6H, Si±Me);
dC (50 MHz, CDCl3) 168.8, 168.4, 167.7, 105.4, 64.7, 61.2,
55.6, 50.9, 29.9, 28.2, 25.7, 22.7, 18.6, 17.8, 24.4, 25.0; m/z
(CI) 386.5 (MH1, 22), 370.5 (40), 328.5 (100), 285.3 (64%).
3
(68 mg, 2 equiv.) in THF (10 mL) was stirred overnight at
208C, then worked-up as above, to furnish known 5b19
(83 mg, 95% yield); dH (200 MHz, CDCl3) 7.48 (m, 2H,
Ph), 7.34 (m, 3H, Ph), 6.29 (br s, 1H, NH), 5.06 (d, 1H,
Jˆ2.4 Hz, H-2), 4.15 (m, 1H, Me±CH(OTBDMS)±), 3.02
(m, 1H, H-3), 1.23 (d, 3H, Jˆ6.6 Hz, Me±CH(OTBDMS)±
), 0.86 (s, 9H, Si±Bu), 0.06 (s, 3H, one of the Si±Me), 0.05

10388
C. Jacopin et al. / Tetrahedron 57 (2001) 10383±10389
(s, 3H, one of the Si±Me); dC (50 MHz, CDCl3) 167.7,
134.4, 132.5, 130.0, 129.3, 66.2, 65.2, 56.9, 26.4, 22.9,
18.6, 23.6, 24.4.
4.1.9. 2-{3-[1-(tert-Butyldimethylsilyloxy)ethyl]-4-oxo-
azetidin-2-yl}-thiopropionic acid, ethyl esters (7a) and
(8a). A solution of 3 (100 mg, 0.259 mmol) and ethanethiol
(1 mL) in ethanol (4 mL) was heated at 608C for 24 h, then
diluted with ethyl acetate (7 mL) and washed successively
4.1.6.
(3R,4R)-4-Ethylthioxy-3-[(5R)-10-(tert-butyldi-
methylsilyloxy)ethyl]-azetidin-2-one (5c). A mixture of 3
(100 mg, 0.259 mmol) and sodium ethanethiolate (42 mg,
2 equiv.) in THF (10 mL) was stirred for 24 h at 208C,
then worked-up as above, to furnish known 5c5 (69 mg,
92% yield); dH (200 MHz, CDCl3) 6.0 (br s, 1H, NH),
4.85 (d, 1H, Jˆ2.5 Hz, H-2), 4.27 (m, 1H, Me±
CH(OTBDMS)±), 3.15 (m, 1H, H-3), 2.66 (q, 2H, Jˆ
7.5 Hz, ±SCH2CH3), 1.30 (t, 3H, Jˆ7.5 Hz, ±SCH2CH3),
1.25 (d, 3H, Jˆ6.9 Hz, Me±CH(OTBDMS)±), 0.88 (s,
9H, Si±Bu), 0.07 (s, 6H, Si±Me).
with 0.5 M HCl and brine (2£). Dryingover MSgO
,
4
concentration and ¯ash chromatography on silica gel
(elution with 30% EtOAc/hexane) gave a 1:1 mixture of
7a (b-isomer) and 8a (a-isomer) as a white solid (87 mg,
97% yield): mp 113.7±114.98C; [Found: C, 55.68; H, 9.33;
N, 3.82. C16H31NO3SSi requires C, 55.61; H, 9.04; N,
4.05%]; Rf (30% EtOAc/hexane) 0.74; nmax (KBr) 3116,
3093, 1763, 1717, 1680 cm21; dH (500 MHz, CDCl3)
(a-isomer 8a) 5.95 (br s, 1H, NH), 4.17 (dq, 1H, Jˆ5.3
and 6.0 Hz, Me±CH(OTBDMS)±), 3.73 (dd, 1H, Jˆ2.1
and 9.8 Hz, H-2), 2.90 (m, 2H, ±SCH2CH3), 2.78 (dd, 1H,
Jˆ2.1 and 5.3 Hz, H-3), 2.72 (qd, 1H, Jˆ7.0 and 9.8 Hz,
±CH(Me)±COSEt), 1.26 (t, 3H, Jˆ7.2 Hz, ±SCH2CH3),
1.26 (d, 3H, Jˆ7.6 Hz, Me), 1.23 (d, 3H, Jˆ6.0 Hz, Me±
CH(OTBDMS)±), 0.87 (s, 9H, Si±Bu), 0.08 (s, 3H, one of
the Si±Me), 0.07 (s, 3H, one of the Si±Me)Ð(b-isomer 7a)
5.86 (br s, 1H, NH), 4.17 (dq, 1H, Jˆ4.3 and 6.0 Hz, Me±
CH(OTBDMS)±), 3.87 (dd, 1H, Jˆ2.1 and 5.9 Hz, H-2),
2.99 (dd, 1H, Jˆ2.1 and 4.3 Hz, H-3), 2.90 (m, 2H,
±SCH2CH3), 2.84 (qd, 1H, Jˆ7.0 and 5.9 Hz, ±CH(Me)±
COSEt), 1.26 (t, 3H, Jˆ7.2 Hz, ±SCH2CH3), 1.26
(d, 3H, Jˆ7.0 Hz, Me), 1.14 (d, 3H, Jˆ6.0 Hz, Me±
CH(OTBDMS)±), 0.87 (s, 9H, Si±Bu), 0.08 (s, 3H, Si±
Me), 0.07 (s, 3H, Si±Me); dC (125 MHz, CDCl3) (a-isomer
8a) 201.7, 167.5, 65.3, 63.6, 53.1, 52.7, 23.2, 22.7, 17.8,
15.1, 14.5, 24.4, 24.9Ð(b-isomer 7a) 202.3, 169.1,
64.9, 61.9, 51.8, 51.1, 25.7, 22.8, 22.2, 17.8, 15.1, 13.1,
24.4, 24.9; m/z (CI) 346.5 (MH1, 100), 330.0 (52), 288.0
(40), 170.9 (40), 145.9 (69%).
4.1.7.
5-(tert-Butyldimethylsilyloxy)-4-carbamoyl-2-
methyl-hex-2-enethioic acid, ethyl ester (6c). To a solu-
tion of 3 (100 mg, 0.259 mmol) in THF (5 mL) and water
(60 mL), were added sodium ethanethiolate (32 mg,
1.5 equiv.) and 18-crown-6 (38 mg, 0.55 equiv.). The
mixture was re¯uxed overnight, then diluted with ethyl
acetate and washed with brine. The organic layer was
dried (MgSO4), concentrated under vacuum, and puri®ed
by ¯ash column-chromatography on silica gel (elution
with 30% AcOEt/hexane) to give 6c (85 mg, 93%) as a
white solid; mp 86.2±878C; [Found: C, 55.82; H, 9.28; N,
3.79. C16H31NO3SSi requires C, 55.61; H, 9.04; N, 3.79%];
20
Rf (30% AcOEt/hexane) 0.64; [a]D ˆ10.68 (cˆ2.19,
CH2Cl2); nmax (KBr) 3429, 1691, 1646 cm21; dH (300
MHz, CDCl3) 6.93 (d, 1H, Jˆ7.6 Hz, H±Cv), 6.12 (br s,
1H, one of the NH), 5.30 (br s, 1H, one of the NH), 4.22 (m,
1H, Me±CH(OTBDMS)±), 3.30 (dd, 1H, Jˆ5 and 7.6 Hz,
H-3), 2.91 (q, 2H, Jˆ7.3 Hz, ±SCH2CH3), 1.90 (s, 3H,
Me±Cv), 1.26 (t, 3H, Jˆ7.3 Hz, ±SCH2CH3), 1.16 (d,
3H, Jˆ6.0 Hz, Me±CH(OTBDMS)±), 0.88 (s, 9H, Si±
Bu), 0.09 (s, 3H, one of the Si±Me), 0.08 (s, 3H, one of
the Si±Me); dC (CDCl3, 75 MHz) 193.7, 172.6, 139.6,
133.7, 69.3, 53.4, 25.7, 23.4, 21.2, 17.9, 14.6, 13.0, 24.5,
24.9; m/z (CI) 346.3 (MH1, 6), 302.2 (8), 240.2 (100),
159.1 (17), 126.1 (13), 103.1 (13%).
4.1.10. 2-{3-[1-(tert-Butyldimethylsilyloxy)ethyl]-4-oxo-
azetidin-2-yl}-thiopropionic acid, phenyl esters (7b)
and (8b). A solution of 3 (100 mg, 0.259 mmol), thiophenol
(2 mL) and dimethylaminopyridine (30 mg) in ethanol
(2 mL) was heated at 808C for 17 h, then diluted with
ethyl acetate and worked-up as above to give a 1:1.5 mixture
of 7b (b-isomer) and 8b (a-isomer) as a white solid
(100 mg, 98% yield) mp 89±89.58C; [Found: C, 60.30; H,
8.23; N, 3.13. C20H31NO3SSi´0.3H2O requires C, 60.15; H
7.94; N 3.50]; Rf (30% EtOAc/hexane) 0.71; dH (300 MHz,
CDCl3) (a-isomer 8b) 7.35±7.44 (m, 5H, Ph), 6.07 (br s,
1H, NH), 4.20 (m, 1H, Me±CH(OTBDMS)±), 3.78 (dd, 1H,
Jˆ2.1 Hz and 9.6 Hz, H-2), 2.80±2.93 (m, 2H, ±CH(Me)±
COSPh and H-3), 1.36 (d, 3H, Jˆ7.8 Hz, Me), 1.24 (d, 3H,
Jˆ6.3 Hz, Me±CH(OTBDMS)±), 0.86 (s, 9H, Si±Bu), 0.08
(s, 3H, one of the Si±Me), 0.07 (s, 3H, one of the Si±Me)Ð
(a-isomer 7b) 7.35±7.44 (m, 5H, Ph), 5.98 (br s, 1H, NH),
4.20 (m, 1H, Me±CH(OTBDMS)±), 3.94 (dd, 1H, Jˆ
2.1 Hz and 5.4 Hz, H-2), 2.90±3.05 (m, 2H, ±CH(Me)±
COSPh and H-3), 1.32 (d, 3H, Jˆ6.9 Hz, Me), 1.18 (d,
3H, Jˆ6.3 Hz, Me±CH(OTBDMS)±), 0.87 (s, 9H, Si±
Bu), 0.08 (s, 3H, one of the Si±Me), 0.07 (s, 3H, one of
the Si±Me); dC (75 MHz, CDCl3) (a and b isomers) 200.1,
167.7, 134.5, 134.3, 129.7, 129.3, 65.0 and 65.4, 62.0 and
63.7, 52.8 and 53.1, 50.8 and 51.7, 25.7, 22.5 and 22.9, 17.9,
13.2 and 15.3, 25.1 and 24.8; m/z (CI) 394.3 (MH1, 100),
378.3 (54), 346.3 (67), 336.2 (45), 330.2 (34), 288.2 (26),
219.1 (38), 111.1 (31%).
4.1.8. 5-(tert-Butyldimethylsilyloxy)-4-carbamoyl-2-methyl-
hex-2-enethioic acid, methyl ester (6d). 6d was prepared
as 6c, from 3 (100 mg, 0.259 mmol), sodium methanethio-
late (27 mg, 1.5 equiv.), 18-crown-6 (27 mg, 0.4 equiv.),
acetonitrile (5 mL) and water (60 mL), stirred at 208C for
24 h. Work-up as usual and chromatography (elution with
30% EtOAc/hexane) furnished a white solid (84 mg, 97%
yield); mp 95.4±96.58C; [Found: C, 54.90; H, 9.01; N, 4.17.
C15H29NO3SSi requires C, 54.34; H 8.82; N, 4.22%] Rf
20
(30% EtOAc/hexane) 0.62; [a]D ˆ10.96 (cˆ2.61,
CH2Cl2); nmax (KBr) 3421, 1691, 1652 cm21; dH (CDCl3,
300 MHz) 6.91 (dd, 1H, Jˆ1.8 and 9.6 Hz, H±Cv), 6.12
(br s, 1H, one of the NH), 5.87 (br s, 1H, one of the NH),
4.23 (m, 1H, Me±CH(OTBDMS)±), 3.27 (dd, 1H, Jˆ
3.6 Hz and 9.6 Hz, H-3), 2.33 (s, 3H, ±SMe), 1.91 (d, 3H,
Jˆ1.8 Hz, Me±Cv), 1.17 (d, 3H, Jˆ6.3 Hz, Me±CH±
(OTBDMS)±), 0.87 (s, 9H, Si±Bu), 0.08 (s, 3H, one of the
Si±Me), 0.07 (s, 3H, one of the Si±Me); dC (CDCl3,
75 MHz) 194.4, 173.0, 139.7, 134.0, 69.4, 53.5, 25.9,
21.4, 18.0, 13.3, 11.9, 24.3, 24.8; m/z (CI) 332 (MH1,
100), 316.1 (31), 274.0 (23), 240.0 (16), 88.9 (60%).

C. Jacopin et al. / Tetrahedron 57 (2001) 10383±10389
10389
6. Shih, D. H.; Baker, F.; Cama, L.; Christensen, B. G. Hetero-
cycles 1984, 21, 29±40.
4.1.11. 2-{3-[1-(tert-Butyldimethylsilyloxy)ethyl]-4-oxo-
azetidin-2-yl}-thiopropionic acid, tertio-butyl esters (7c)
and (8c). A solution of 3 (100 mg, 0.259 mmol), tertio-
butanethiol (1 mL) and dimethylaminopyridine (30 mg) in
iso-propanol (2 mL) was heated at 658C for 17 h, then
diluted with ethyl acetate and worked-up as above to give
a 1:1:2 mixture of 7c (b-isomer), 8c (a-isomer), and 3
(startingmaterial) as a white gummy solid (quantitative
7. Miura, T.; Murayama, T.; Yoshida, A.; Kobayashi, T. Eur.
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1
yield). The H NMR data of 7c and 8c were identical to
those previously reported by endo.28
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4.1.12. (3S,4S)-3-[(10R)-10-tert-Butyldimethylsilyloxy)-
ethyl]-4-[10-carboxyethyl]-azetidin-2-ones (2a) and (9).
A 1:7 mixture of 7a and 8a (56 mg, 0.16 mmol) in methanol
(1.7 mL) and water (0.5 mL) was treated with 2.5 M NaOH
(0.2 mL) and stirred at 208C for 2 days. The mixture was
diluted with water (10 mL) and extracted with ether. The
aqueous phase was acidi®ed with cc HCl and extracted with
ethyl acetate (2£). The organic phase was washed with
brine, dried (MgSO4) and concentrated to afford a 1:3
mixture of the known acids 2a6,31 and 96,28 as a white
solid (45 mg, 94% yield): dH (300 MHz, CDCl3) 2a: 6.18
(br s, 1H, NH), 4.20 (m, 1H, Me±CH(OTBDMS)±), 3.95
(dd, 1H, Jˆ2 and 5 Hz, H-2), 3.03 (dd, 1H, Jˆ2 and 4.5 Hz,
H-3), 2.76 (m, 1H, ±CH(Me)± COOH), 1.28 (d, 3H, Jˆ
7.5 Hz, Me), 1.19 (d, 3H, Jˆ7 Hz, Me±CH(OTBDMS)±),
0.89 (s, 9H, Si±Bu), 0.10 (s, 3H, one of the Si±Me), 0.09 (s,
3H, one of the Si±Me); 9: 6.47 (br s, 1H, NH), 4.20 (m, 1H,
Me±CH(OTBDMS)±), 3.70 (dd, 1H, Jˆ2 and 9.9 Hz, H-2),
2.79 (dd, 1H, Jˆ2 and 6 Hz, H-3), 2.57 (m, 1H, ±CH(Me)±
COOH), 1.27 (d, 3H, Jˆ7 Hz, Me), 1.24 (d, 3H, Jˆ6 Hz,
Me±CH(OTBDMS)±), 0.87 (s, 9H, Si±Bu), 0.08 (s, 3H, one
of the Si±Me), 0.07 (s, 3H, one of the Si±Me).
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