Stereoselective synthesis of 2-azetidinones as cholesterol-absorption inhibitors

Article abstract of DOI:10.1016/S0957-4166(99)00566-2

The synthesis of two 2-azetidinones possessing powerful cholesterol- absorption inhibition properties has been accomplished by a short and highly stereoselective reaction sequence. The key step is the condensation of the titanium enolate of the easily prepared 2-pyridylthioester (R)-11 with imine 6 which affords the desired β-lactam intermediate in the correct relative and absolute configuration. Conversion to the pharmacologically active compounds is readily accomplished by simple functional group manipulation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00566-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4841–4849
Stereoselective synthesis of 2-azetidinones as cholesterol-
absorption inhibitors
Rita Annunziata, Maurizio Benaglia,∗ Mauro Cinquini and Franco Cozzi
Centro C.N.R. and Dipartimento di Chimica Organica e Industriale Universita’ di Milano via Golgi, 19-20133 Milano, Italy
Received 11 November 1999; accepted 8 December 1999
Abstract
The synthesis of two 2-azetidinones possessing powerful cholesterol-absorption inhibition properties has been
accomplished by a short and highly stereoselective reaction sequence. The key step is the condensation of the
titanium enolate of the easily prepared 2-pyridylthioester (R)-11 with imine 6 which affords the desired β-
lactam intermediate in the correct relative and absolute configuration. Conversion to the pharmacologically active
compounds is readily accomplished by simple functional group manipulation. © 2000 Elsevier Science Ltd. All
rights reserved.
1. Introduction
In addition to their well-recognized properties as antibiotics,1–3 β-lactams have been recently shown
to possess other relevant biological activities as inhibitors of prostate specific antigen,4 thrombin,5
human cytomegalovirus protein,6 human leukocyte elastase,7 and cholesterol absorption.8 In particular,
azetidinones 1–4 (Fig. 1) are potent orally active inhibitors of acyl-CoA, cholesterol acyltransferase, that
block absorption of intestinal cholesterol and limit cholesterol ester deposition in the vascular wall.9,10
Fig. 1. Structure of cholesterol absorption inhibiting 2-azetidinones
∗
Corresponding author. E-mail: franco.cozzi@unimi.it
0957-4166/99/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00566-2
tetasy 3200

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Synthesis of 1–4 and congeners both in racemic and enantiomerically enriched form have been
published,8–16 but a margin of improvement for the reported processes does exist. We here report new
syntheses of azetidinones (±)-1, (3R,4S)-1, and (30R,3S,4S)-2† based on the efficient one-pot preparation
of β-lactams by reaction of the titanium enolate17 of 2-pyridylthioesters with imines that we have
developed over the last few years.18–20
2. Results and discussion
Racemic 1 was very easily obtained in 91% yield by condensation of the titanium enolate of S-2-
pyridylthio-5-phenylvalerate 5 with imine 6 (Scheme 1, PMP=4-methoxyphenyl) in dichloromethane at
0°C. This reaction was completely stereoselective and afforded the product only as the 3,4-trans isomer,
as determined by 300 MHz 1H NMR analysis of the crude reaction mixture (in β-lactams Jtrans=1.5–3.0
Hz; Jcis=4.0–6.0 Hz).
Scheme 1. Stereoselective synthesis of racemic 2-azetidinone 1
Several approaches can be envisaged in order to obtain 1 in enantiomerically enriched form starting
from a pyridylthioester. These involve the use of boron enolates featuring enantiopure boron ligands,21
and of enantiomerically pure imines22,23 or thioesters.22,24 However, reaction of 5 with imine 6, carried
out in the presence of boron trichloride and (1R,2S)-N-methylephedrine,21 gave the product in extremely
low yield.
The use of lactaldehyde-derived imine (S)-7 was also unsuccessful (Scheme 2). Indeed, the titanium
enolate of thioester 5 reacted with 7 to give β-lactam 8 in 65% yield as a 85:15 mixture of 3,4-trans-4,40-
syn and 3,4-cis-4,40-syn isomers (see Scheme 2 for numbering). Oxygen deprotection and oxidation with
lead tetraacetate25 gave the 4-acetoxy derivative 9 in 40% unoptimized overall yield.
Reaction of this β-lactam with a variety of aryl nucleophiles, however, failed to produce the desired
adduct (3R,4S)-1, probably because the presence of the PMP group at nitrogen in 9 prevents the formation
of an endocyclic C–N double bond. The use of a large excess of 4-methoxyphenyllithium in combination
with BF3·OEt2 led to the formation of adduct 10 (40% yield, 75:25 mixture of diastereoisomers),
possibly by the mechanism shown in Scheme 2.
On the basis of these disappointing results and our previous experience,18–20,22,24 it was decided to
use the stereocenter of thioester (R)-11 as the stereodirecting element for the generation of the C-3 and
C-4 stereocenters of 1 and 2 (Scheme 3). Compound 11 was synthesized as follows. Ethyl 5-phenyl-
3-oxovalerate (obtained in 95% yield from 3-phenylpropanal following a described procedure)26 was
hydrolyzed with KOH. This carboxylate was enzymatically reduced for 7 to 15 days at 25°C27 with
baker’s yeast in water buffered with KH2PO4. The crude β-hydroxyacid was fully protected with t-
butyldimethylsilyl chloride,28 and the crude silyl ester (isolated by rapid filtration through a pad of silica
gel) was hydrolyzed28 and transformed into the desired (R)-S-2-pyridylthio-3-(t-butyldimethylsilyl)oxy-
†
C-3 of 1 and 2 share the same ligand disposition but have different configurational descriptors due to change in the ligand
priority.

R. Annunziata et al. / Tetrahedron: Asymmetry 10 (1999) 4841–4849
4843
Scheme 2. Attempted synthesis of (3R,4S)-1 from thioester 5 and imine 7
5-phenylvalerate 11, that was obtained in 51% overall yield from 3-phenylpropanal after just one chro-
1
matographic separation. Enantiomeric excess determination by H NMR spectroscopy in the presence
of Eu(hfc)3 showed that (R)-11 was ≥96% enantiomerically pure. The (R) absolute configuration was
tentatively assigned on the basis of the known tendency of baker’s yeast reduction of similar substrates
to afford the (R)-product,27 and the comparison of the sign of the specific rotation of 11 with that of the
known desilylated β-hydroxy 2-pyridylthioester.29 The subsequent conversion of 11 into azetidinone 2
confirmed the configurational assignment.
Scheme 3. Stereoselective synthesis of (30R,3S,4S)-2 and (3R,4S)-1 from thioester 11

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Condensation of the titanium enolate of (R)-11 with imine 6 gave adduct 12 in 37% yield‡ as a 94:6
mixture of 3,30-anti-3,4-trans and 3,30-syn-3,4-trans isomers, as determined by 1H NMR analysis of the
crude product (see Scheme 3 for numbering). Pure 3,30-anti 12, obtained by flash chromatography, was
then deprotected with tetrabutylammonium fluoride in THF to afford (30R,3S,4S)-2 in quantitative yield.
It should be noted that this represents the first stereoselective synthesis of 2. So far this product has been
prepared only by the poorly stereoselective aldol condensation between the 3-unsubstituted azetidinone
and 3-phenylpropanal, followed by HPLC resolution.13
The conversion of 2 into 1 requires deoxygenation of C-30. The conditions of this reaction were
established studying the transformation of the model compound 1322 to the known β-lactam 14.30
Conversion of 13 into its mesylate (MeSO2Cl, TEA, 94%) followed by NaBH4 reduction in DMSO at
50°C for 15 h31 gave a 60% yield of 14 (90% based on the recovered mesylate) that unfortunately was
isolated as a 60:40 mixture of trans and cis isomers. Shorter reduction times lowered the yield and led to
a similar extent of epimerization, thus showing that the stereomutation occurred before reduction.
A milder method was found in the conversion of 13 into its imidazolylthiocarboxylate (thiocarbonyl-
diimidazole, refluxing THF, 95%) followed by reaction with Bu3SnH in DMSO at 90°C for 5 h.32 By
this procedure 14 was obtained as a single trans isomer in 50% yield (68% based on the recovered ester).
Also in this case, NaBH4 reduction of the activated ester led to extensive epimerization.
Extension of this protocol to azetidinone 2 afforded β-lactam 1 in 51% overall yield (65% based on the
recovered activated ester), thus completing the stereoselective synthesis of the desired enantiomerically
pure compound from the easily available thioester (R)-11.
3. Conclusion
In conclusion, a short and highly stereoselective synthesis of the target cholesterol inhibitors 1 and
2 has been accomplished using the easily generated stereocenter of (R)-11 as the only element of
stereocontrol. From the preparative point of view, this procedure favorably compares with the existing
ones, especially in the case of the synthesis of compound 2. These results served also to confirm the
reliability of the model of stereoselection that was proposed to explain the stereochemical outcome of
the condensation of β-silyloxy 2-pyridylthioesters with imines.22 Extension of a similar protocol to the
synthesis of other pharmacologically active 2-azetidinones is currently underway in our laboratories.
4. Experimental
4.1. Synthesis of S-2-pyridylthio 5-phenylvalerate 5
To a stirred 1 M solution of commercially available 5-phenylvaleric acid (0.178 g, 1 mmol) in CH2Cl2,
triphenylphosphine (0.315 g, 1.2 mmol) and dipyridyl disulfide (0.242 g, 1.1 mmol) were added in this
order. The solution was stirred at room temperature for 24 h, and the reaction quenched by the addition of
water. The organic phase was separated, the aqueous phase was repeatedly extracted with CH2Cl2 and the
‡
The low yield of this reaction, for which we do not have any explanation at present, is surprising. For instance, the analog of
11 derived from (R)-3-hydroxybutanoic acid (Me instead of Ph-CH2-CH2 in 11) reacted with imines related to 6 in 60 to 95%
yield with similar stereoselectivity (see Refs. 22 and 24). Various attempts to improve the yield of 12 (by changing the reagent
stoichiometry or the reaction temperature, or by replacing titanium tetrachloride with tin tetrachloride) were unsuccessful. It
is also worth mentioning that the Staudinger cycloaddition between the ketene corresponding to 11 and imine 6 carried out in
refluxing toluene gave 12 in 40% yield as a 60:40 mixture of 3,30-anti-3,4-trans and 3,30-syn-3,4-trans isomers.

R. Annunziata et al. / Tetrahedron: Asymmetry 10 (1999) 4841–4849
4845
combined organic phases were dried and concentrated under vacuum. The resulting residue was purified
by flash chromatography with a 60:40 hexanes:diethyl ether mixture as eluant to give the product as a
1
pale yellow oil in 98% yield. IR: 1695 cm−1. H NMR (300 MHz, CDCl3): δ 8.60 (1H, d, J=4.2 Hz),
7.73 (1H, t, J=5.6 Hz), 7.61 (1H, d, J=5.6 Hz), 7.15–7.27 (6H, m), 2.74 (2H, t, J=7.0 Hz), 2.63 (2H, t,
J=7.0 Hz), 1.70–1.75 (4H, m). 13C NMR (75 MHz, CDCl3): δ 196.1, 151.3, 150.2, 141.7, 137.2, 130.1,
128.3, 125.7, 123.4, 43.9, 35.4, 30.5, 24.8. Elem. anal.: C16H17NOS requires: C, 70.81; H, 6.31; N, 5.16.
Found: C, 70.73; H, 6.23; N, 5.21.
4.2. Synthesis of (3R)-S-2-pyridylthio 3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-phenylvalerate 11
Enzymatic reduction: A solution of potassium 5-phenyl-3-oxovalerate (1.0 g) in water (40 mL) was
added to a suspension of baker’s yeast (25 g), glucose (28 g), MgSO4 (0.03 g), and KH2PO4 (0.06 g) in
water (40 mL) which was previously stirred at 25°C for 30 min. The resulting suspension was stirred for
1 week, whereupon small portions of glucose were added from time to time. CH2Cl2 and 1N HCl were
then added so that the aqueous phase had pH 1. The resulting mixture was filtered through Celite, and
the filtrate was washed thoroughly with CH2Cl2. The organic phase was separated and the aqueous phase
was extracted three times with CH2Cl2. The combined organic phases were dried and concentrated under
vacuum to give the crude product in 99% yield. This was used without further purification.
Silylation: To a stirred 1 M solution of the hydroxyacid (1–2 mmol) in dry CH2Cl2, imidazole (5 mol
equiv.) and t-butyldimethylsilyl chloride (2.5 mol equiv.) were added in this order. After stirring overnight
at room temperature the reaction was quenched by the addition of water. The organic phase was separated
and the aqueous phase was extracted twice with CH2Cl2. The combined organic phases were dried and
concentrated under vacuum to give the crude product that was filtered through a pad of silica gel with a
95:5 hexane:diethyl ether mixture as eluant. The product was not further purified.
Hydrolysis of the ester: To a solution of the silylester (0.422 g, 1 mmol) in MeOH (13 mL), water (2
mL), and THF (2 mL), K2CO3 (0.414 g, 3 mmol) was added. After 2 h the hydrolysis was completed (by
TLC) and the solvents were evaporated under vacuum. The residue was dissolved in CH2Cl2 (20 mL)
and 1N HCl was slowly added with stirring until the aqueous phase had pH 5. The organic phase was
separated, washed with water, dried, and concentrated under vacuum. The crude residue was used as such
for the following step.
Synthesis of the thioester: To a stirred 1 M solution of the acid in CH2Cl2, triphenylphosphine (0.315
g, 1.2 mmol) and dipyridyl disulfide (0.242 g, 1.1 mmol) were added in this order. The solution was
stirred at room temperature for 24 h, and the reaction quenched by the addition of water. The organic
phase was separated, the aqueous phase was repeatedly extracted with CH2Cl2 and the combined organic
phases were dried and concentrated under vacuum. The residue was purified by flash chromatography
23
with a 50:50 hexanes:diethyl ether mixture as eluant. The product was a pale yellow oil that had [α]D
−33.1 (c 0.9 in CH2Cl2). IR: 1708 cm−1. 1H NMR (300 MHz, CDCl3): δ 8.63 (1H, d, J=4.2 Hz), 7.77
(1H, t, J=5.6 Hz), 7.63 (1H, d, 5.6 Hz), 7.30 (1H, dd, J=5.6, 4.2 Hz), 7.21–7.28 (5H, m), 4.25–4.30 (1H,
m), 2.90 (2H, AB system, J=11.0, 6.5, 5.6 Hz), 2.65–2.70 (2H, m), 190–1.95 (2H, m), 0.93 (9H, s), 0.10
(3H, s), 0.08 (3H, s). 13C NMR (75 MHz, CDCl3): δ 194.0, 151.6, 150.3, 141.8, 137.0, 129.8, 128.4,
128.3, 125.6, 125.4, 69.0, 521.7, 39.0, 31.0, 25.8, 18.0, −4.6, −4.7. Elem. anal: C22H31NO2SSi requires:
C, 65.79; H, 7.78; N, 3.49. Found: C, 65.91; H, 7.83; N, 3.39.
1
¯
Compound 11 was shown to be > 96% enantiomerically pure by H NMR analysis carried out in
CDCl3 in the presence of the chiral shift reagent Eu(hfc)3 in conditions pre-established on racemic 11.
To this end the signals of the pyridine nucleus were exploited.

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4.3. General procedure for the synthesis of β-lactams 1, 8, and 12
To a 0.05 M solution of thioester (1–10 mmol) and TiCl4 (1 M solution in CH2Cl2, 1 mol equiv.)
in dry CH2Cl2 cooled at −78°C and kept under nitrogen, triethylamine (1.1 mol equiv.) was added
dropwise. The dark purple solution was stirred at −78°C for 15 min, and a 1 M solution of imine (0.5
mol equiv.) in CH2Cl2 was added dropwise. After 5 h stirring at −78°C, the reaction was warmed to
room temperature, and the mixture stirred overnight. The reaction was quenched by the addition of a
satd solution of NaHCO3 and the resulting slurry was filtered through a Celite cake. The organic phase
was separated and the aqueous phase was extracted twice with CH2Cl2. The combined organic phases
were dried and concentrated under vacuum. The residue was dissolved in THF and treated with a 1 M
aqueous solution of KOH (2 mol equiv.) to hydrolyze the excess of thioester. This procedure does not
alter the diastereoisomeric composition and greatly simplifies the NMR analysis of the crude product.
Diethyl ether was added to the mixture and the organic phase was separated, washed with brine, dried,
1
and concentrated under vacuum to give the crude product that was analyzed by H NMR to determine
the diastereoisomeric ratio. Flash chromatography with a 80:20 or a 70:30 hexanes:diethyl ether mixture
as eluant gave the pure product in the yields reported in the text.
4.4. (±)-1,4-Di(4-methoxyphenyl)-3-(3-phenylpropyl)azetidin-2-one 1
The title compound had spectral data in agreement with those reported.8 Mp 96–98°C (lit.8
96–97.5°C).
4.5. (3S,4S,40S)-1-(4-Methoxyphenyl)-3-(3-phenylpropyl)-4-[1-[[(1,1-dimethylethyl)dimethylsilyl]-
oxy]ethyl]azetidin-2-one 8
23
The title compound was a thick oil. It had [α]D −31.3 (c 0.5 in CH2Cl2). IR: 1742 cm−1. 1H NMR
(300 MHz, CDCl3): δ 7.40 (2H, A part of AB system, J=8.7 Hz), 7.10–7.30 (5H, m), 6.87 (2H, B part of
AB system, J=8.7 Hz), 4.19 (1H, q, J=6.2 Hz), 3.73 (1H, dd, J=6.0 Hz), 3.02 (1H, dt, J=6.2, 2.1 Hz), 2.68
(2H, t, J=7.1 Hz), 1.80–1.90 (4H, m), 1.14 (3H, d, J=6.0 Hz), 0.85 (9H, s), −0.05 (3H, s), −0.11 (3H, s).
13C NMR (75 MHz, CDCl3): δ 167.5, 155.0, 141.5, 132.0, 128.4, 125.0, 119.5, 114.2, 69.6, 62.9, 55.5,
51.3, 35.7, 28.9, 28.3, 19.2, 17.9, −4.2, −4.7. Elem. anal.: C27H39NO3Si requires: C, 71.48; H, 8.66; N,
3.09. Found: C, 71.67; H, 8.83; N, 3.02.
4.6. (30R,3S,4S)-1,4-Di(4-methoxyphenyl)-3-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-phenylpropyl]-
azetidin-2-one 12
23
The title compound was a thick oil. It had [α]D −39.4 (c 0.07 in CHCl3). IR: 1740 cm−1. 1H NMR
(300 MHz, CDCl3): δ 7.36 (2H, A part of AB system, J=8.7 Hz), 7.30 (2H, B part of AB system, J=8.7
Hz), 7.15–7.28 (5H, m), 7.08 (2H, A part of AB system, J=8.7 Hz), 6.94 (2H, B part of AB system, J=8.7
Hz), 5.15 (1H, d, J=2.4 Hz), 4.15 (1H, dt, J=7.4, 2.4 Hz), 3.82 (6H, s), 3.28 (1H, t, J=2.4 Hz), 2.54 (2H,
t, J=8.1 Hz), 1.90–2.00 (2H, m), 0.82 (9H, s), 0.13 (3H, s), 0.07 (3H, s). 13C NMR (75 MHz, CDCl3): δ
165.7, 159.5, 155.7, 141.0, 130.2, 128.4, 128.3, 128.0, 125.9, 118.5, 114.5, 114.1 68.4, 65.2, 55.4, 55.3,
38.7, 31.6, 28.9, 25.7, 17.9, −4.2, −4.7. Elem. anal.: C32H41NO4Si requires: C, 72.27; H, 7.78; N, 2.63.
Found: C, 72.49; H, 7.83; N, 2.58.

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4847
4.7. Attempted conversion of 8 to 1. Synthesis of (3R,4R)-1-(4-methoxyphenyl)-3-(3-phenyl)propyl-4-
acetoxy azetidin-2-one 9
Compound 8 was desilylated in standard conditions with tetrabutylammonium fluoride in THF (see
below for the synthesis of 2) to give the alcohol in quantitative yield. The crude material was converted
into the product following the procedure for the lead tetraacetate promoted oxidation described by
Cainelli et al.25 Compound 9 was obtained as a low melting solid. A 76:24 mixture of trans and cis
23
1
isomers had [α]D −13.4 (c 2.0 in CH2Cl2). IR: 1756, 1731 cm−1. H NMR (300 MHz, CDCl3) of
major (trans) isomer: δ 7.35 (2H, A part of AB system, J=8.8 Hz), 7.25–7.35 (3H, m), 7.15–7.25 (2H,
m), 6.90 (2H, B part of AB system, J=8.8 Hz), 6.19 (1H, d, J=1.1 Hz); 3.80 (3H, s), 3.23 (1H, dt, J=6.2,
1.1 Hz), 2.67 (2H, t, J=6.2 Hz); 2.13 (3H, s), 1.83–1.96 (4H, m). 1H NMR (300 MHz, CDCl3) of minor
(cis) isomer: δ 7.35 (2H, A part of AB system, J=8.8 Hz), 7.25–7.35 (3H, m), 7.15–7.25 (2H, m), 6.90
(2H, B part of AB system, J=8.8 Hz), 6.61 (1H, d, J=4.3 Hz); 3.80 (3H, s), 3.50 (1H, dt, J=6.0, 4.3 Hz),
2.67 (2H, t, J=6.0 Hz); 2.08 (3H, s), 1.83–1.96 (4H, m). 13C NMR (75 MHz, CDCl3) of major (trans)
isomer: δ 170.3, 165.2, 156.7, 141.6, 130.0, 128.4, 125.9, 118.5, 114.5, 80.1, 58.5, 55.5, 35.7, 28.5, 26.5,
23.8. 13C NMR (75 MHz, CDCl3) of minor (cis) isomer: δ 170.4, 165.3, 156.7, 141.6, 130.0, 128.4,
125.9, 118.5, 114.5, 76.9, 58.5, 55.5, 35.7, 29.0, 26.5, 23.9. Elem. anal.: C21H23NO4 requires: C, 71.37;
H, 6.56; N, 3.96. Found: C, 71.47; H, 6.39; N, 3.88.
4.8. Synthesis of N-4-methoxyphenyl 2-(3-phenylpropyl)-3-hydroxy-3-(4-methoxyphenyl)propane amide
10
A solution of 9 (0.172 g, 0.5 mmol) and BF3·OEt2 (0.064 mL, 0.5 mmol) in dry THF (10 mL) was
added at −78°C to a stirred solution of 4-methoxyphenyllithium (2.5 mol equiv.) in THF (20 mL) kept
under nitrogen. The mixture was warmed up to −40°C and stirred at that temperature for 5 h. The reaction
temperature was allowed to rise to room temperature, and the stirring was continued for additional 5 h.
The reaction was quenched by the addition of a satd aqueous solution of ammonium chloride. The organic
phase was separated, dried, and concentrated under vacuum. The crude product was purified by flash
chromatography with a 40:60 hexanes:diethyl ether as eluant to afford the product as a 75:25 mixture of
diastereoisomers. The product was a waxeous solid. IR: 3400, 1610 cm−1. 1H NMR (300 MHz, CDCl3)
of major isomer: δ 7.43 (1H, brs), 7.10–7.30 (9H, m), 6.78–6.90 (4H, m), 5.00 (1H, d, J=4.0 Hz), 3.81
(3H, s), 3.79 (3H, s), 3.33 (1H, brs), 2.55–2.65 (2H, m), 2.40–2.50 (2H, m), 1.50–1.90 (4H, m).1H NMR
(300 MHz, CDCl3) of minor isomer: δ 7.33 (1H, brs), 7.10–7.30 (9H, m), 6.78–6.90 (4H, m), 4.91 (1H,
d, J=6.0 Hz), 3.81 (3H, s), 3.79 (3H, s), 3.46 (1H, brs), 2.55–2.65 (2H, m), 2.40–2.50 (2H, m), 1.50–1.90
(4H, m). 13C NMR (75 MHz, CDCl3) of major isomer: δ 172.8, 159.1, 157.0, 142.1, 133.8, 130.4, 128.4,
127.5, 125.7, 122.2, 114.0, 74.1, 55.5, 55.4, 54.9, 35.9, 29.5, 26.3. 13C NMR (75 MHz, CDCl3) of minor
isomer: δ 172.8, 159.1, 157.0, 141.2, 134.7, 130.4, 128.3, 127.3, 125.8, 122.3, 113.9, 75.1, 55.5, 55.4,
55.3, 35.9, 30.0, 29.3. Elem. anal.: C26H29NO4 requires: C, 74.44; H, 6.97; N, 3.34. Found: C, 74.57; H,
6.90; N, 3.39.
4.9. Synthesis of (30R,3S,4S)-1,4-di(4-methoxyphenyl)-3-[(1-hydroxy-3-phenyl)propyl]azetidin-2-one 2
To a stirred solution of 12 (0.133 g, 0.25 mmol) dissolved in dry THF (5 mL), tetrabutylammonium
fluoride trihydrate (0.158 g, 0.5 mmol) was added, and the resulting mixture was stirred overnight. The
reaction was quenched with water. After addition of diethyl ether the organic phase was separated and
the aqueous phase was extracted twice with CH2Cl2. The combined organic phases were dried and
concentrated under vacuum to give a residue that was purified by flash chromatography with a 50:50

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23
hexanes:diethyl ether mixture as eluant. The product (0.103 g, 99%) was a solid, mp 153–155°C; [α]D
−39.6 (c 0.5 in CHCl3). IR: 3400, 1741 cm−1. H NMR (300 MHz, CDCl3): δ 7.31 (4H, two A parts
of AB systems, J=8.7 Hz), 7.20–7.30 (5H, m), 6.92 (2H, B part of one of the two AB systems, J=8.7
Hz), 6.78 (2H, B part of other of the two AB systems, J=8.7 Hz), 5.05 (1H, d, J=2.4 Hz), 4.50 (1H,
brs), 4.18–4.26 (1H, m), 3.81 (3H, s), 3.75 (3H, s), 3.18 (1H, dd, J=5.2, 2.4 Hz), 2.82 (1H, A part of AB
system, J=15.0, 8.6 Hz), 2.67 (1H, A part of AB system, J=15.0, 8.6 Hz), 1.92–2.02 (2H, m). 13C NMR
(75 MHz, CDCl3): δ 165.0, 159.5, 156.0, 141.5, 131.5, 130.0, 128.6, 128.3, 126.0, 118.6, 114.6, 114.3,
68.1, 66.0, 56.2, 55.4, 55.2, 36.8, 31.9. Elem. anal.: C26H27NO4 requires: C, 74.80; H, 6.52; N, 3.35.
Found: C, 74.67; H, 6.69; N, 3.38.
1
4.10. Synthesis of (3R,4S)-1
Synthesis of the activated ester: A mixture of 2 (0.100 g, 0.24 mmol) and thiocarbonyl diimidazole
(0.190 g, 1.2 mmol) in dry THF (5 mL) was refluxed overnight. To the cooled mixture a satd aqueous
solution of ammonium chloride was added, and the organic phase was separated. The aqueous phase was
extracted twice with diethyl ether and the combined organic phases were dried and concentrated under
vacuum to give the crude product that was purified by flash chromatography with a 70:30 hexanes:diethyl
23
ether mixture as eluant. The product (0.094 g, 94%) was a solid, mp 150–152°C; [α]D +20.5 (c 0.33
in CHCl3). IR: 1746, 1098, 1028 cm−1. 1H NMR (300 MHz, CDCl3): δ 7.55 ( 1H, brs), 7.50 (1H, brs),
7.23 (2H, A part of AB system, J=8.0 Hz), 7.17 (2H, A part of AB system, J=8.7 Hz), 7.10–7.20 (5H,
m), 7.00 (1H, brs), 6.87 (2H, B part of AB system, J=8.7 Hz), 6.80 (2H, B part of AB system, J=8.0
Hz), 6.27 (1H, dt, J=7.6, 4.6 Hz), 5.02 (1H, d, J=2.4 Hz), 3.81 (3H, s), 3.76 (3H, s), 3.53 (1H, dd, J=7.6,
2.4 Hz), 2.73–2.83 (2H, m), 2.34 (2H, AB system, J=15.6, 8.0, 7.0 Hz). 13C NMR (75 MHz, CDCl3): δ
183.5, 161.9, 160.0, 153.0, 140.1, 136.3, 131.0, 128.5, 128.2, 126.9, 126.3, 118.4, 117.9, 114.6, 114.4,
81.5, 63.3, 58.1, 55.4, 55.3, 33.9, 31.1. Elem. anal.: C30H29N3O4S requires: C, 68.29; H, 5.54; N, 7.96.
Found: C, 68.47; H, 5.69; N, 7.78.
Deoxygenation: To a stirred solution of the activated ester (0.052 g, 0.1 mmol) in dry DMSO (2 mL)
kept at 90°C under nitrogen, freshly opened Bu3SnH (0.087 g, 0.3 mmol) and AIBN (0.002 g) were
added. The mixture was stirred for 4 h, while equal portions of AIBN were added every hour. The cooled
reaction mixture was poured into water and extracted several times with diethyl ether. The combined
organic phases were washed with brine, dried, and concentrated under vacuum to give the crude product
that was purified by flash chromatography with a 50:50 hexanes:diethyl ether mixture as eluant. This
purification allowed recovery of some of the unreacted activated ester. The product, a white solid, had
analytical and spectral data identical to those reported in the literature: mp 46–48°C (lit.8 46.5–48°C);
[α]D23=−19.1 (c 0.1 in MeOH) (lit.8 [α]D23=−19.3 (c 6.23 in MeOH)).
Acknowledgements
Partial financial support by MURST-Progetto Nazionale Stereoselezione in Sintesi Organica. Meto-
dologie ed Applicazioni is gratefully acknowledged.
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