A novel approach to a precursor of the carbapenem antibiotic PS-5 via aziridine stereospecific carbonylation

Article abstract of DOI:10.3987/COM-00-8974

Cobalt carbonyl-catalyzed carbonylative ring expansion of optically pure cis-1-benzyl-3-ethyl-2-hydroxymethylaziridine (5) to trans-β-lactam (8) afforded a key precursor of the carbapenem antibiotic (+)-PS-5. Aziridine (5) was obtained in both enantiomerically pure forms by Amano PS lipase - catalyzed esterification in n-hexane using vinyl acetate as acyl donor. The stereochemical pathway of the carbonylation reaction was proved by configurational assignments through chemical correlation.

Full text of DOI:10.3987/COM-00-8974

HETEROCYCLES, Vol. 53, No. 11, 2000, pp. 2379 - 2389, Received, 13th June, 2000
A NOVEL APPROACH TO A PRECURSOR
OF THE CARBAPENEM ANTIBIOTIC PS-5
VIA AZIRIDINE STEREOSPECIFIC CARBONYLATION
Paolo Davoli* and Fabio Prati
Dipartimento di Chimica, Università di Modena e Reggio Emilia
via Campi 183, 41100 Modena, Italy; email: davoli.chemistry@unimo.it
Abstract- Cobalt carbonyl-catalyzed carbonylative ring expansion ofoptically purecis-1-benzyl-
3-ethyl-2-hydroxymethylaziridine (5) to trans-β-lactam (8) afforded a key precursor of the
carbapenem antibiotic (+)-PS5.Aziridine(5) was obtained in both enantiomerically pure forms
by Amano PS lipase–catalyzed esterification in n-hexane using vinyl acetate as acyl donor. The
stereochemical pathway of the carbonylation reaction was proved by configurational assignments
through chemical correlation.
1. Introduction
Carbonylative ring expansion of aziridines in the presence of dicobalt octacarbonyl Co2(CO)8 as catalyst
has proved a useful reaction for the stereospecific synthesis of functionalized β-lactams in excellent
yields.1,2 The reaction proceeds through nucleophilic ring opening of the aziridine by the in situ generated
tetracarbonylcobaltate anion [Co(CO)4]–, followed by CO insertion and final ring closure to β-lactam. The
reaction is stereospecific and highly regioselective: from a cis-aziridine trans-β-lactams are obtained,
whereas cis-β-lactams are isolated from a trans-aziridine.1,2
We now wish to report that the versatility of this reaction can be applied to the synthesis of a β-lactam
precursor of carbapenem antibiotic from a suitable functionalized aziridine.
(+)-PS-5 is a natural carbapenem antibiotic isolated from cultures of Streptomyces cremeus and displays
activity against Gram-positive and Gram-negative bacteria as well as resistance towards β-lactamases.3 Its
structural features there include the carbapenem ring system, the trans substitution pattern of the β-lactam
NHAc
S
N
O
COOH
(+)-PS-5
ring and the ethyl side chain; it thus resembles the more widely known carbapenems, thienamycin and
imipenem.

A synthetic approach4 to (+)-PS-5 involves the construction of a β-lactam skeleton bearing an ethyl side
chain in position 3 and an acetoxy group or a precursor thereof in position 4, preferably in a trans
relationship. On the basis of our previous studies on cobalt-catalyzed carbonylation of cis-3-methyl-2-
hydroxymethylaziridine,1 the desired trans-4-acetoxy-β-lactam (12) was obtained by carbonylative ring
expansion of
a
suitable substituted cis-aziridine, optically pure cis-1-benzyl-3-ethyl-2-
hydroxymethylaziridine (5), which in turn was easily obtained from the parent aziridinecarboxylate (3),
following the retrosynthetic pathway here reported.
COOR
OAc
NH
OH
N
(+)-PS-5
N
O
Ph
Ph
3
5
12
2. Results and Discussion
Synthesis of cis-Aziridinecarboxylate (±)-3. – Addition of bromine to methyl trans-2-pentenoate (1),
previously synthesized by Fisher esterification5 of commercial trans-2-pentenoic acid gave methyl 2,3-
dibromopentenoate (2) (97% yield). Aminative cyclization of 2 with benzylamine in methanol afforded a
mixture of racemic cis- and trans-1-benzyl-3-ethyl-2-methoxycarbonylaziridines ((±)-3) and ((±)-4) in a
71:29 ratio and in 95% total yield. (Scheme 1)
Br
COOMe
COOMe
ii
i
N
N
+
COOMe
COOMe
Ph
cis-(±)-3
Ph
trans-(±)-4
Br
1
2
Scheme 1: i. Br2, CCl4 (97%); ii. PhCH2NH2, MeOH, rt (95%).
1
3
On the basis of H NMR spectral analysis (3Jcis > Jtrans)6 the cis stereochemistry was unambiguously
assigned to aziridine ((±)-3) (3J2,3 6.6 Hz) and trans stereochemistry to ((±)-4) (3J2,3 2.7 Hz).
In order to obtain PS-5 in optically pure form, enantiomerically pure aziridine (3) should be obtained: of
the several methods described in the literature7 for the asymmetric synthesis of aziridines, enzymatic
resolution is particularly suitable for aziridinecarboxylates.8 Optical resolution of 3 in antipodes was
therefore attempted by lipase-catalyzed enzymatic hydrolysis in phosphate buffer (pH 7.5) at 37 °C,
following a well established protocol for aziridinecarboxylates,8 but unfortunately all attempts failed.
Since the carboxy group is known to be detrimental for the carbonylation reaction,1 the ester function was
reduced to give the corresponding aziridino alcohol. Reduction of cis-aziridinecarboxylate ((±)-3) with
lithium aluminum hydride in tetrahydrofuran at room temperature thus provided cis-1-benzyl-3-ethyl-2-
hydroxymethylaziridine ((±)- 5) (86% yield).

Lipase-Catalyzed Resolution of Hydroxymethyl cis-Aziridine ((±)-5). – Amano PS lipase-catalyzed
esterification of ((±)-5) in n-hexane at 37 °C, using vinyl acetate as acyl donor,9 afforded optically pure
(+)-5, ee 92% (47% yield), as well as cis (+)-2-acetoxymethyl-1-benzyl-3-ethylaziridine (6), ee 96%
(50% yield) (Scheme 2). From this latter, optically pure (–)-5, ee 96% was obtained (98% yield) by
Amano PS lipase catalyzed hydrolysis in phospate buffer.
COOMe
OH
OH
OR
i
ii
N
N
N
+
N
Ph
cis-(±)-5
Ph
Ph
Ph
cis-(±)-3
cis-(+)-5
cis-(+)-6 R = Ac
ee 92%
ee 96%
iii
cis-(-)-5 R = H
ee 96%
Scheme 2: i. LiAlH4, THF, rt (86%); ii. Amano PS lipase, n-hexane, vinyl acetate, 37 °C; iii. Amano PS lipase, phosphate
buffer, 37 °C.
Synthesis of trans-β-Lactam ((–)-8) via Cobalt Carbonyl-Catalyzed Carbonylation and Derivatives. –
Since the absolute configuration of both (+) and (–)-5 was unknown, cis-hydroxymethylaziridine ((+)-5)
was arbitrarily chosen for the subsequent steps of the synthesis. (+)-5 was protected as TBDMS-ether
((+)-7), ee 92%, by treatment with tert-butyldimethylsilyl chloride and 4-dimethylaminopyridine in
dichloromethane at room temperature (91% yield). Aziridine ((+)-7) was subsequently treated with
carbon monoxide (500 psi) and Co2(CO)8 in 1,2-dimethoxyethane (DME) for 14 hours at 105 °C using a
12:1 ratio of aziridine/catalyst, to afford a 83:17 mixture of trans-β-lactams ((–)-8), ee 92%, and ((+)-9),
ee 92%, in a 93% total isolated yield. (Scheme 3)
OR
OR
Ph
RO
ii
N
+
N
N
Ph
O
O
Ph
cis-(+)-5 R = H
trans-(-)-8
trans-(+)-9
i
cis-(+)-7 R = TBDMS
Scheme 3: i. TBDMSCl, DMAP, CH2Cl2 (91%); ii. Co2(CO)8, CO (500 psi), 105 °C, DME (93%).
The structures of the two β-lactam regioisomers ((–)-8) and ((+)-9) were determined by NMR and MS
spectroscopies: the relative trans stereochemistry was unequivocally assigned on the basis of the 3J3,4 (2.1
Hz).
trans-β-Lactam ((–)-8) represents a suitable precursor for the carbapenem antibiotic PS-5 through the
intermediate (12a).4 Debenzylation of (–)-8 by treatment with sodium in liquid ammonia10 at –42 °C gave
trans-β-lactam ((–)-10) (63% yield) (Scheme 4). Removal of the TBDMS group by tetra n-
butylammonium fluoride in tetrahydrofuran at room temperature11 easily provided the 4-hydroxymethyl
derivative (trans-(–)-11) in quantitative yield. Subsequent oxidation with lead tetraacetate in refluxing

benzene in the presence of CaCO3 4,12 gave a mixture of 4-acetoxy-β-lactams (trans-(–)-12a) and (cis-(+)-
12b) in a 1:1 ratio, albeit in low yields.13
OAc
OAc
NH
OR
Ph
OR
i
iii
+
N
NH
NH
O
O
O
O
trans-(-)-8
trans-(-)-10 R = TBDMS
trans-(-)-11 R = H
trans-(-)-12a
cis-(+)-12b
ii
Scheme 4: i. Na, liquid NH3, –42 °C (63%); ii. TBAF, THF, rt (100%); iii. Pb(OAc)4, CaCO3, benzene, reflux (15%).
This lack of selectivity does not actually affect the overall result of the synthesis, for the subsequent
displacement of the acetoxy group to PS-5 is reported with equilibration to the more stable trans
configuration.4
Configurational Assignment: Chemical Correlation. – In order to assign the configurations of the
stereocenters of (–)-8, the carbonylation product (trans-(–)-8) was correlated with the configurationally
known trans-4-acetoxy-β-lactam ((–)-12a).4 (Scheme 5)
OAc
NH
OR
OR
Ph
OR
N
N
NH
O
O
O
Ph
(2R,3R)
(3S,4R)
(3S,4S)
(3S,4R)
trans-(-)-8
trans-(-)-12a
cis-(+)-5 R = H
trans-(-)-10, R = TBDMS
trans-(-)-11, R = H
cis-(+)-7 R = TBDMS
Scheme 5
trans-β-Lactam ((–)-12a) was known to have (3S,4S) absolute configuration:4 since oxidation does not
involve the C3 stereocenter of trans-(–)-11, we can deduce the same S configuration for this stereocenter.
The trans relationship between the substituents at the C3 and C4 stereocenters in (–)-11 consequently
assigns the R configuration to the C4 stereocenter. We can therefore infer the same (3S,4R) configuration
for the stereocenters of (–)-8. This correlation can be extended also to the cis-aziridine ((+)-5), for which
absolute configuration (2R,3R) can be deduced. In fact the carbonylation of cis-aziridine ((+)-7) to trans-
β-lactam ((–)-8) does not affect the C2 stereocenter of the aziridine which must have the same R
configuration as the β-lactam C4 stereocenter. The cis stereochemistry of aziridine ((+)-5) forces the C3
stereocenter to have R absolute configuration. This assignment highlights the inversion of configuration at
C3 during the carbonylative ring expansion of cis-aziridine ((+)-7) to trans-β-lactam ((–)-8), which
confirms the SN2 global mechanism for the cobalt carbonyl-catalyzed carbonylation reported in the
literature.1,2 Furthermore, from the (2R,3R) absolute configuration of (+)-5 we can infer the (3S,4R)
configuration to the trans-β-lactam ((+)-9).
The configurational assignment showed that (–)-12a was obtained from (+)-5. Since the precursor of (+)-
PS-5 is known4 to be the dextrorotatory enantiomer ((+)-12a), the synthesis of this latter must start from

(–)-5, obtained as described in Scheme 5, following the same procedure.
3. Conclusions
Despite the low yield observed in the last step, the reported synthetic pathway represents a novel
stereospecific approach to carbapenem antibiotic PS-5 via cobalt carbonyl-catalyzed carbonylative ring
expansion of a suitable functionalized optically pure cis-aziridine. The carbonylation reaction, i.e. the key
step of the whole synthesis, proved stereospecific, highly regioselective and afforded excellent yield.
Moreover, correlation of trans-β-lactam ((–)-8) with the configurationally known trans-4-acetoxy β-
lactam ((–)-12a) allowed us the configurational assignments to the stereocenters of the synthesized trans-
β-lactams ((–)-8, (+)-9, (–)-10 and (–)-11) and of cis-aziridines ((+)-5, (+)-6 and (+)-7).
EXPERIMENTAL
The instrumentation has already been described.8 1H and 13C NMR spectra were recorded in CDCl3
solution on 200 MHz and 400 MHz spectrometers. Chemical shifts are reported in δ values from TMS as
internal standard. Coupling constants (J) are given in Hz. All organic solvents were dried and distilled by
standard methods prior to use and all reactions were carried out using oven-dried glassware.
Chromatographic purification of compounds was performed on silica gel (φ 0.05-0.20 mm). The metal
catalyst Co2(CO)8 was purchased from Merck; trans-2-pentenoic acid was purchased from Aldrich. The
enzyme Amano PS lipase was generously gifted by Amano Pharmaceutical Company, Ltd. (Nagoya,
Japan) and used without further purification.
The assignments of the observed NMR (1H, 13C) resonances of (–)-8 and (+)-9 were carried out using 2D-
heteronuclear correlated spectroscopy (H,C-COSY).14 Enantiomeric excesses (ee’s) were determined by
1
the analysis of the H NMR spectra recorded in CDCl3 in the presence of a 1.5- to 3-fold excess of the
chiral solvating agent (R)-(–)-2,2,2-trifluoro-1-(9-anthryl)ethanol (Ega Chemie). The ee of aziridino
alcohol ((+)-5) was evaluated after its conversion into the corresponding (–)-6 acetoxy derivative by
treatment with acetyl chloride in dichloromethane at 0 °C in the presence of triethylamine. The
determination of ee’s is accurate to ±5%.15
Methyl trans-2-Pentenoate (1)5 – Esterification of commercial trans-2-pentenoic acid was carried out
according to the literature procedure. 1H NMR (200 MHz): δ 1.70 (3H, t, J 7.4), 2.23 (2H, ddq, J 1.7, 6.4,
7.4), 3.72 (3H, s), 5.82 (1H, dt, J 15.7, 1.7), 7.02 (1H, dt, J 15.7, 6.4). MS m/z: 114 (M+), 99, 83 (base
peak), 82, 72, 71, 59, 55.
Methyl 2,3-Dibromopentanoate (2)16 – Bromine (1.28 mL, 24.92 mmol) was added dropwise at rt to a

stirred solution of 1 (2.81 g, 24.68 mmol) in carbon tetrachloride (120 mL). The reaction mixture was
gently refluxed for 2 h until decoloration: the solution was then cooled and evaporated in vacuo to afford
methyl 2,3-dibromopentenoate (2) (6.54 g, 97 %) as an orange liquid which was used without further
1
purification. H NMR (200 MHz): δ 1.10 (3H, t, J 7.2), 1.91 (1H, m), 2.32 (1H, m), 3.83 (3H, s), 4.32-
4.73 (2H, m). MS m/z: 277-275-273 [(M+1)+], 276-274-272 (M+), 245-243-241, 217-215-213, 195-193,
163-161, 135-133, 113 (base peak), 81, 59, 55.
cis-(±)-1-Benzyl-3-ethyl-2-methoxycarbonylaziridine
(3)
and
trans-(±)-1-benzyl-3-ethyl-2-
methoxycarbonylaziridine (4) – A solution of methyl 2,3-dibromopentanoate (2) (7.65 g, 27.94 mmol) in
methanol (70 mL) was slowly added at 0 °C to a stirred solution of benzylamine (12.6 mL, 115.35 mmol)
in methanol (200 mL). The reaction mixture was stirred overnight and allowed to warm to rt. After rotary
evaporation of the solvent, the residue was dissolved in ether (180 mL), washed with water (360 mL) and
the aqueous phase extracted with ether (3×90 mL). The combined organic phases were dried (MgSO4) and
concentrated to give a crude brown-yellowish oil which was chromatographed (light petroleum/ether
80:20 and then 60:40) to afford the cis-aziridine (3) (4.02 g) and the trans-aziridine (4) (1.81 g) as
yellowish oils in a 69:31 ratio and in 95% total yield. cis-Aziridine (3) was further purified by in vacuo
1
distillation on a Vigreux column: colourless oil, bp 102 °C (0.6 mmHg). H NMR spectroscopy showed
compound trans-4 as a 72:28 mixture of two invertomers at nitrogen, due to slow nitrogen inversion on
the NMR scale.
cis-(±)-(3): 1H NMR (200 MHz): δ 0.88 (3H, t, J 7.4), 1.39-1.77 (2H, m), 1.87 (1H, q, J 6.6), 2.26 (1H, d,
J 6.6), 3.53 (1H, d, J 13.5), 3.62 (1H, d, J 13.5), 3.72 (3H, s), 7.22-7.36 (5H, m). MS m/z: 219 (M+), 204,
190, 160, 146, 131, 128, 91 (base peak), 68, 65. Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39.
Found: C, 71.20; H, 7.83; N, 6.39.
1
trans-(±)-(4): H NMR (400 MHz): major invertomer: δ 0.87 (3H, t, J 7.4), 1.38-1.59 (2H, m), 2.27 (1H,
dt, J 2.7, 5.9), 2.51 (1H, d, J 2.7), 3.69 (3H, s), 3.91 (1H, d, J 13.5), 3.99 (1H, d, J 13.5), 7.29-7.41 (5H,
m); minor invertomer: δ 1.09 (3H, t, J 7.3), 1.59-1.83 (2H, m), 2.05 (1H, m), 2.49 (1H, m), 3.72 (3H, s),
3.65 (1H, d, J 13.8), 3.92 (1H, d, J 13.8), 7.22-7.29 (5H, m). MS m/z: 219 (M+), 204, 190, 160, 146, 131,
128, 91 (base peak), 68, 65. Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C, 71.24; H,
7.84; N, 6.36.
cis-(±)-1-Benzyl-3-ethyl-2-hydroxymethylaziridine (5) – 1.0 M LiAlH4 solution in THF (13.7 mL) was
slowly added dropwise through a dropping funnel to a stirred solution of cis-aziridine ((±)-3) (1.5 g, 6.85
mmol) in freshly distilled anhydrous THF (14 mL) at rt. After 40 min TLC (ether/light petroleum 80:20)
showed total disappearance of the starting material: the reaction mixture was then cooled to 0 °C and

carefully quenched by dropwise addition of 0.67 mL of water, followed by 0.67 mL of a 0.15 N NaOH
solution. The white inorganic precipitate was filtered off and washed with abundant ether (150 mL): the
filtrate was dried (MgSO4) and the solvent evaporated under reduced pressure. Chromatography on silica
gel (ether/light petroleum 80:20 and finally pure ether) gave cis-(±)-5 as a light pink sticky oil (1.12 g,
1
86%). H NMR (200 MHz): δ 0.88 (3H, t, J 7.3), 1.42 (2H, m), 1.62 (1H, q, J 6.6), 1.84 (1H, dt, J 5.0,
6.6), 2.38 (1H, br), 3.45 (1H, d, J 13.1), 3.48 (1H, dd, J 11.4, 6.8), 3.55 (1H, d, J 13.1), 3.71 (1H, dd, J
11.4, 5.0), 7.22-7.36 (5H, m). MS m/z: 190 ([M–1]+), 160, 146, 117, 100, 91, 72 (base peak), 65. Anal.
Calcd for C12H17NO: C, 75.35; H, 8.96; N, 7.32. Found: C, 75.33; H, 8.98; N, 7.33.
Lipase-Catalyzed Resolution of cis-(±)-1-Benzyl-3-ethyl-2-hydroxymethylaziridine (5) – Amano PS
Lipase (657 mg) was added to a mechanically stirred solution of cis-aziridine ((±)-5) (1.31 g, 6.88 mmol)
in n-hexane (65 mL) in a double-necked round bottom flask placed in a thermostatic bath at 37 °C. Vinyl
acetate (3.2 mL, 34.72 mmol) was then added: after 35 min the reaction mixture was filtered to remove
the enzyme and concentrated in vacuo. Chromatography (ether/light petroleum 70:30) afforded unreacted
cis-(2R,3R)-(+)-1-benzyl-3-ethyl-2-hydroxymethylaziridine (5) (620 mg, 47%), which was further
purified by in vacuo distillation (colorless viscous oil, bp 150 °C/4×10–5 mbar), [α]D +29.4° (c 1.4,
MeOH), ee 92%, and cis-(2S,3S)-(+)-2-acetoxymethyl-1-benzyl-3-ethylaziridine (6) (797 mg, 50%), [α]D
+15.1° (c 2.7, CHCl3), ee 96%. 1H NMR (200 MHz): δ 0.96 (3H, t, J 7.3), 1.39-1.64 (3H, m), 1.64 (1H, q,
J 6.6), 1.89 (1H, dt, J 7.3, 6.1), 2.01 (3H, s), 3.46 (1H, d, J 13.2), 3.60 (1H, d, J 13.2), 4.06 (1H, dd, J 7.3,
11.7), 4.19 (1H, dd, J 5.7, 11.7), 7.23-7.40 (5H, m). MS m/z: 174 ([M–59]+), 160, 142, 100, 91, 72, 65, 43
(base peak). Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C, 72.10; H, 8.18; N, 5.97.
Optically pure cis-(2S,3S)-(–)-5 was obtained as follows: Amano PS lipase (50 mg) was added to a
suspension of cis-(2S,3S)-(+)- 6, ee 96% (500 mg) in phosphate buffer (pH 7.5, 0.1 M, 25 mL) and stirred
at 37 °C for 20 h. The reaction mixture was extracted with ethyl acetate (4×20 mL); the combined organic
phases were washed with water (20 mL) and brine (20 mL), dried over MgSO4 and evaporated.
Chromatography on silica gel (light petroleum/ether 70:30) gave cis-(2S,3S)-(–)-5 (396 mg, 98% yield),
[α]D –30.5° (c 1.6, MeOH), ee 96%.
cis-(2R,3R)-(+)-1-Benzyl-2-(tert-butyldimethylsilyloxy)methyl-3-ethylaziridine (7) – cis-Aziridine ((+)-
5), ee 92% (322 mg, 1.69 mmol) was dissolved in anhydrous CH2Cl2 (10 mL): DMAP (515 mg, 4.22
mmol) and TBDMSCl (305 mg, 2.02 mmol) were added at rt under magnetic stirring and nitrogen
atmosphere. After 40 min the reaction mixture was diluted with CH2Cl2 (10 mL), washed with water
(2×20 mL) and brine (20 mL), dried over MgSO4 and rotary evaporated. Chromatography on silica gel
(light petroleum/ether 90:10) gave cis-(+)-7 as a light yellow oil (468 mg, 91%), [α]D +14.0° (c 2.3,

1
CHCl3), ee 92%. H NMR (200 MHz): δ 0.094 (6H, s), 0.94 (9H, s), 0.96 (3H, t, J 7.1), 1.29-1.63 (3H,
m), 1.81 (1H, q, J 6.2), 3.48 (1H, d, J 13.4), 3.59 (1H, d, J 13.4), 3.62 (1H, dd, J 6.5, 10.9), 3.81 (1H, dd,
J 5.8, 10.9), 7.24-7.42 (5H, m). MS m/z: 305 (M+), 290, 276, 248, 214, 206, 174, 160, 158, 91 (base
peak), 75, 73. Anal. Calcd for C18H31NOSi: C, 70.76; H, 10.23; N, 4.58. Found: C, 70.86; H, 10.25; N,
4.57.
trans-(3S,4R)-(–)-1-Benzyl-4-(tert-butyldimethylsilyloxy)methyl-3-ethylazetidin-2-one (8) and trans-
(3S,4R)-(–)-1-benzyl-3-(tert-butyldimethylsilyloxy)methyl-4-ethylazetidin-2-one (9) – In a 45-mL
stainless steel autoclave equipped with a glass liner and a stirring bar, cis-aziridine ((+)-7) (395 mg, 1.29
mmol) was dissolved in freshly distilled anhydrous and O2 free DME (10 mL) and Co2(CO)8 (38 mg, 0.11
mmol) was added. After purging four times with 300 psi CO, the autoclave was charged with 500 psi CO
and kept in an oil bath for 14 h at 105 °C. The autoclave was then opened and ether was added to the
brown clear solution to decompose the catalyst. After 1 h, the reaction mixture was filtered through a
small silica gel column, washed with abundant ether and concentrated in vacuo. Chromatography on
silica gel (light petroleum/ether 70:30) afforded, as light yellow oils, the two β-lactams regioisomers
trans-(3S,4R)-(–)-8 (323 mg), [α]D –44.4° (c 1.6, CHCl3), ee 92% and trans-(3S,4R)-(+)-9 (77 mg), [α]D
+22.3° (c 1.1, CHCl3), ee 92% in a 83:17 ratio and in 93% total isolated yield (carbonylation of racemic
(±)-7 proceeded instead with 99% yield).
trans-(3S,4R)-(–)-8: 1H NMR (400 MHz): δ 0.035 (6H, s, tBuMe2Si–), 0.89 (9H, s, tBuMe2Si–), 0.97 (3H,
t, J 7.4, CH3CH2–), 1.60 (1H, ddq, J 8.8, 13.9, 7.4, CH3CH2–), 1.79 (1H, ddq, J 5.7, 13.9, 7.4, CH3CH2–),
2.84 (1H, dddd, J 0.7, 2.1, 5.7, 8.8, CH3CH2CH–), 3.24 (1H, ddd, J 2.1, 4.3, 5.4, –CHCH2O–), 3.65 (1H,
dd, J 5.4, 10.8, –CH2O–), 3.69 (1H, dd, J 4.3, 10.8, –CH2O–), 4.09 (1H, d, J 15.0, –CH2Ph), 4.70 (1H, d,
13
J 15.0, –CH2Ph), 7.25-7.36 (5H, m, aromatic). C NMR: δ –4.86 (tBuMe2Si–), –4.84 (tBuMe2Si–), 12.3
(CH3CH2–), 18.9 (Me3CMe2Si–), 21.9 (CH3CH2–), 26.5 (Me3CMe2Si–), 45.5 (–CH2Ph), 54.5
(CH3CH2CH–), 58.8 (–CHCH2O–), 64.4 (–CH2O–), 128.2, 128.9, 129.3, 137.2, 170.8 (carbonyl). MS
m/z: 333 (M+), 332, 318, 305, 288, 276, 248, 207, 206 (base peak), 188, 143, 91, 75, 73. Anal. Calcd for
C19H31NO2Si: C, 68.42; H, 9.37; N, 4.20. Found: C, 68.50; H, 9.35; N, 4.18.
trans-(3S,4R)-(+)-9: 1H NMR (400 MHz): δ 0.058 (6H, s, tBuMe2Si–), 0.87 (3H, t, J 7.5, –CH2CH3), 0.88
t
(9H, s, BuMe2Si–), 1.34-1.46 (1H, m, –CH2CH3), 1.66-1.84 (1H, m, –CH2CH3), 2.92 (1H, dddd, J 0.6,
2.1, 3.7, 5.8, –OCH2CH–), 3.42 (1H, ddd, J 2.1, 4.1, 8.9, –CHCH2CH3), 3.87 (1H, dd, J 3.7, 10.8, –
OCH2–), 3.91 (1H, dd, J 5.8, 10.8, –OCH2–), 4.10 (1H, d, J 15.4, –CH2Ph), 4.65 (1H, d, J 15.4, –CH2Ph),
7.25-7.35 (5H, m, aromatic). 13C NMR: δ –4.8 (tBuMe2Si–), –4.7 (tBuMe2Si–), 10.3 (–CH2CH3), 19.0
(Me3CMe2Si–), 25.7 (–CH2CH3), 26.5 (Me3CMe2Si–), 44.4 (–CH2Ph), 57.2 (–CH CH2CH3), 58.5 (–
OCH2CH–), 60.6 (–OCH2–), 128.2, 128.8, 129.3, 136.8, 168.4 (carbonyl). MS m/z: 334 [(M+1)+], 333,

332, 318, 304, 277, 276 (base peak), 246, 219, 184, 143, 129, 91, 75, 73. Anal. Calcd for C19H31NO2Si:
C, 68.42; H, 9.37; N, 4.20. Found: C, 68.53; H, 9.39; N, 4.17.
trans-(3S,4R)-(–)-4-(tert-Butyldimethylsilyloxy)methyl-3-ethylazetidin-2-one (10) – Sodium (131 mg,
5.70 mmol) was dissolved in liquid ammonia (12 mL) in a 50 mL schlenk tube cooled at – 42 °C and a
solution of trans-(–)-8 ee 92% (602 mg, 1.81 mmol) in anhydrous THF (4 mL) was added dropwise via
syringe under vigorous stirring. After 5 min the reaction mixture was quenched by adding solid
ammonium chloride until disappearance of the dark blue color. Liquid ammonia was left to evaporate,
thus obtaining a lemon-yellow solution which was filtered to remove solid NaCl and washed with
abundant ether. After rotary evaporation, the crude sticky light yellow oil was chromatographed
(ether/light petroleum 50:50) to afford trans-(–)-10 (275 mg, 63%) as a colorless viscous liquid, [α]D –
1
25.6° (c 1.2, CHCl3). H NMR (200 MHz): δ 0.070 (6H, s), 0.90 (9H, s), 1.02 (3H, t, J 7.4), 1.59-1.90
(2H, m), 2.79 (1H, dddd, J 1.4, 2.2, 6.1, 8.5), 3.41 (1H, ddd, J 2.2, 4.7, 6.5), 3.64 (1H, dd, J 6.5, 10.5),
3.76 (1H, dd, J 4.7, 10.5), 5.93 (1H, br). MS m/z: 243 (M+), 228, 200, 186, 158, 143, 116 (base peak), 98.
Anal. Calcd for C12H25NO2Si: C, 59.21; H, 10.35; N, 5.75. Found: C, 59.25; H, 10.34; N, 5.77.
trans-(3S,4R)-(–)-3-Ethyl-4-hydroxymethylazetidin-2-one (11) – Tetrabutylammonium fluoride (345
mg, 1.322 mmol) was dissolved in dry THF (1 mL) and added dropwise at rt under nitrogen flow to a
stirred solution of trans-(–)-10 (268 mg, 1.103 mmol) in THF (5 mL). After 30 min the reaction mixture
was rotary evaporated and the crude residue purified by chromatography on silica gel (ether/light
petroleum/MeOH 82:9:9) to give trans-(–)-11 as a colorless sticky oil (142 mg, 100%), [α]D –44.7° (c
1.2, CHCl3). 1H NMR (200 MHz): δ 1.01 (3H, t, J 7.4), 1.56-1.91 (2H, m), 2.86 (1H, dddd, J 1.3, 2.0, 6.2,
8.4), 3.47 (1H, m), 3.62 (2H, m), 3.82 (1H, m), 6.82 (1H, br). MS m/z: 130 [(M+1)+], 98, 86, 70, 68, 57
(base peak), 55. Anal. Calcd for C6H11NO2: C, 55.8; H, 8.58; N, 10.84. Found: C, 55.75; H, 8.60; N,
10.87.
trans-(3S,4S)-(–)-4-Acetoxy-3-ethyl-azetidin-2-one (12a) and cis-(+)-4-acetoxy-3-ethylazetidin-2-one
(12b)4,12 – Lead tetraacetate (749 mg, 1.69 mmol) and calcium carbonate (169 mg, 1.69 mmol) were
added to 5 mL of anhydrous benzene and the mixture was refluxed for 15 min. A solution of trans (–)-11
(109 mg, 0.84 mmol) in benzene (5 mL) was added dropwise. After refluxing for 4 h, the mixture was
filtered, washed with abundant ether and rotary evaporated to give a brown residue which was dissolved
in water (20 mL) and extracted with ether (3×15 mL). The combined organic phases were dried (MgSO4)
and concentrated in vacuo. Column chromatography (ether/light petroleum 50:50) gave trans-4-acetoxy
derivative ((3S,4S)-(–)-12a) (10 mg), [α]D –96.9° (c 0.95, CHCl3) [lit.,4 (3R,4R) [α]D +100° (CHCl3)] and

cis-4-acetoxy derivative ((–)-12b) (10 mg), [α]D +18.5° (c 0.95, CDCl3), both as a colorless liquid, in a
total 15% isolated yield.
1
trans-(3S,4S)-(–)-12a: H NMR (200 MHz): δ 1.06 (3H, t, J 7.4), 1.63-1.92 (2H, m), 2.12 (3H, s), 3.17
(1H, ddd, J 1.1, 6.7, 7.8), 5.54 (1H, d, J 1.1), 6.46 (1H, br). MS m/z: 158 [(M+1)+], 114, 98, 72, 70, 57
(base peak), 55.
1
cis-(+)-12b: H NMR (200 MHz): δ 1.07 (3H, t, J 7.4), 1.68-1.85 (2H, m), 2.13 (3H, s), 3.28 (1H, m),
5.87 (1H, d, J 4.3), 6.43 (1H, br). MS m/z: 158 [(M+1)+], 114, 98, 72, 70, 57 (base peak), 55.
ACKNOWLEDGEMENTS
We are grateful to the Ministero dell’Università e della Ricerca Scientifica (MURST) for financial
support. We thank the Centro Interdipartimentale Grandi Strumenti, Università di Modena, for
spectroscopical measurements. Amano Pharmaceutical Company, Ltd. (Nagoya, Japan) is gratefully
acknowledged for a generous gift of Lipase PS.
REFERENCES AND NOTES
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