Efficient and highly stereoselective synthesis of a β-lactam inhibitor of the serine protease prostate-specific antigen

Article abstract of DOI:10.1016/S0968-0896(02)00017-2

An efficient synthesis of a β-lactam precursor of the serine protease, prostate-specific antigen inhibitor 1 has been accomplished. The synthesis relies on two completely stereoselective reactions that allow the introduction of the stereocenters at C-3 an

Full text of DOI:10.1016/S0968-0896(02)00017-2

Bioorganic & Medicinal Chemistry 10 (2002) 1813–1818
Efficient and Highly Stereoselective Synthesis of a ꢀ-Lactam
Inhibitor of the Serine Protease Prostate-Specific Antigen
Rita Annunziata, Maurizio Benaglia,* Mauro Cinquini,
Franco Cozzi and Alessandra Puglisi
Centro CNR and Dipartimento di Chimica Organica e Industriale, Universita’ degli Studi di Milano,
Via Golgi 19, I-20133 Milan, Italy
Received 4 October 2001;accepted 8 January 2002
Abstract—An efficient synthesis of a b-lactam precursor of the serine protease, prostate-specific antigen inhibitor 1 has been
accomplished. The synthesis relies on two completely stereoselective reactions that allow the introduction of the stereocenters at C-3
and C-4 of the azetidinone ring in a predictable manner. # 2002 Elsevier Science Ltd. All rights reserved.
Introduction
of b-lactams developed in our laboratories over the last
few years. This methodology5 involves the stereo-
selective condensation between the titanium enolate of a
2-pyridylthioester and an imine as the azetidinone ring
forming step.
The recognized ability of a variety of monocyclic b-lac-
tams to inhibit proteases1 led to the design of compound
1 (Fig. 1) as a powerful inhibitor of the serine protease,
prostate-specific antigen (PSA),2 a widely used marker
for prostate carcinoma.3 The recently discovered involve-
ment of PSA in some degenerative processes implicated
in the development of prostate and breast tumors4
makes b-lactam 1 and analogues important synthetic
targets.
Results and Discussion
In planning the synthesis of 2, a,b-dialkoxyimine (R)-3
was selected to introduce the b-lactam’s nitrogen and
C-4 atoms, and the carboxy function at C-4 in the target
molecule [via deprotection of the diol function in (R)-3
and its oxidative degradation]. Moreover, on the basis
of the known stereochemical preference of our b-lactam
synthesis,5 it was anticipated that the use of (R)-3 would
allow the generation of the C-4 stereocenter in the cor-
rect configuration and in a highly stereoselective fash-
ion.
Compound 1 has been synthesized in racemic (10 steps,
9.1% overall yield from 4-hydroxy hydrocinnamic acid)
and enantiopure form [14 steps, 0.9% overall yield from
(S)-aspartic acid].2 Here we report a new synthesis of
enantiopure 2 (Fig. 1), a known advanced precursor
of 1, that is based on a protocol for the preparation
Also the introduction of the benzylic substituent at C-3
in a cis position to the carboxy group at C-4 required
some synthetic planning. Since it was expected that the
use of a 2-pyridylthioester derived from 4-hydroxy
hydrocinnamic acid would mainly lead to a 3,4-trans
azetidinone,5,6 it was decided to stereoselectively intro-
duce the side chain at C-3 exploiting the previously
established stereocenter at C-4 (see above). Therefore,
2-pyridylthio acetoxyacetate 45 was selected as the eno-
late partner of the condensation. Deprotection of the
hydroxy group followed by oxidation to the ketone
Figure 1. Structure of PSA inhibitor 1 and precursor 2.
*Corresponding author. Tel.:+39-02-5031-4171;fax:+39-02-5031-
4159;e-mail: maurizio.benaglia@unimi.it
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00017-2

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R. Annunziata et al. / Bioorg. Med. Chem. 10 (2002) 1813–1818
figurated compound 9 in 98% yield. Hydroxy group
protection as the allyl ether (allyl bromide, K2CO3,
CH3CN, 50 ꢁC) gave crude compound 10, which was
then subjected to ketal hydrolysis (TFA, H2O, 0 ꢁC to
rt). Oxidative degradation of the crude diol 11 (NaIO4,
H2O, AcOEt, RT) gave the aldehyde 12 that was isolated
in 73% overall yield from 9.9 Oxidation to the crude acid
13 (Jones’ reagent, acetone, H2O, rt), followed by esteri-
fication (K2CO3, benzyl bromide, refluxing acetone)
gave compound 14 in 68% overall yield from 12.
At this stage, conversion of 14 into target 1 merely
required removal of the 4-methoxyphenyl group, intro-
duction of the side chain at nitrogen, and phenol
deprotection. To asses the feasibility of this approach,
nitrogen deprotection with CAN under Georg’s condi-
tions10 was attempted on a model compound featuring
an ethoxycarbonyl instead of the benzyloxycarbonyl
group at C-4 of 14. This reaction occurred in 70% yield
without affecting the allyl protection at the phenol oxy-
gen. For correlative purposes, however, compound 14
was first transformed (cat. Pd(OAc)2, PPh3, refluxing
EtOH;then wet SiO , rt) into crude phenol 15, which
2
was then protected as its TBDPS ether 16 under stan-
dard conditions (TBDPSCl, imidazole, DCM). Com-
pound 16, obtained in 51% overall yield from 14, was
finally converted into b-lactam 2 by CAN degradation
(CAN, CH3CN, H2O, ꢀ20 ꢁC, 70% yield), completing
the formal total synthesis of 1. Compound 2 was thus
obtained from 3 in 6.7% overall yield over 13 steps.
The success of this synthetic strategy relied on two
completely stereoselective transformations: the synthesis
of b-lactam 5 and the reduction of alkene 8. Both of
these reactions deserve some comments. The formation
of the 3,4-cis-4,40-syn azetidinone 5 was expected on the
basis of a model of stereoselection proposed in the
course of previous studies.11 This rationale involves
addition of the (E)-enolate of 4 (CIP rules)12 on the less
hindered diastereoface of the a-chelated (E)-imine 3 in a
cyclic transition structure (A, Fig. 2). The highly stereo-
selective reduction of the double bond in compound 8
can be explained simply on the basis of hydrogen addi-
tion from the side of the small substituent at C-4 (the H
atom) as in B (Fig. 2). This sort of rationalization has
ubiquitously been invoked to account for many stereo-
selective transformations involving a trigonal C atom at
position 3 of a b-lactam ring and occurring under the
influence of a stereocenter at C-4.13
Scheme 1. Stereoselective multistep synthesis of compound 2. Abbre-
viations: Py=2-pyridyl;PMP: 4-MeOPh;All: CH 2=CH-CH2-;TBPDS:
t-BuPh2Si. Reagents: (a) TiCl4, Et3N;(b) KOH;(c) P 2O5, DMSO;(d) 4-
BnOPhCH2PPh3Br, BuLi;(e), H 2, 10% Pd/C;(f) AllBr, K 2CO3;(g)
TFA, H2O;(h) NalO 4;(i) Jones reagent;(j) BnBr, K 2CO3;(k) PdOAc 2,
PPh3;then wet SiO 2;(l) TBDPSCl, imidazole;(m) Ce(NH 4)2(NO3)6.
would provide the required scenario for 3,4-cis stereo-
selective alkylation at C-3 via olefination and double
bond reduction.
Condensation5b of the titanium enolate derived from
2-pyridylthio acetoxyacetate 4 with the N-4-methoxy-
phenylimine of (S)-O,O-cyclohexylidene protected gly-
ceraldehyde 37 gave b-lactam (3S,4R,40R)-5 as a single
product in 65% isolated yield (Scheme 1). The stereo-
isomeric purity of this compound was determined by
1
300 MHz H NMR spectroscopy on the crude reaction
product. Ester hydrolysis (1 N aqueous KOH, THF/
MeOH 9:1) gave the 3-hydroxy substituted b-lactam 6
in 94% yield. Alternatively, this compound was con-
veniently prepared in a one-pot procedure carrying out
the hydrolysis on the crude b-lactam. This protocol
afforded compound 6 in 72% over the two steps. The
3-hydroxysubstituted azetidinone thus obtained was
oxidized following a modification of Palomo’s proce-
dure8 to ketone 7 (85% yield), which was then con-
verted into alkene 8 in 73% yield by standard Wittig
chemistry (4-benzyloxybenzyl triphenylphosphonium
bromide, BuLi, THF, ꢀ20 ꢁC). The 93:7 mixture of iso-
meric alkenes was then catalytically reduced (H2, cat
10% Pd/C, EtOH) to exclusively afford the 3,4-cis con-
Figure 2. Models of stereoselection A and B explaining the stereo-
selective formation of 5 and 9.

R. Annunziata et al. / Bioorg. Med. Chem. 10 (2002) 1813–1818
1815
Conclusion
61.9, 55.5, 36.3, 34.4, 25.0, 24.0, 23.8, 20.5. C20H25NO6
requires: C, 63.99;H, 6.71;N, 3.73. Found: C, 64.13;H,
6.56;N, 3. 64.
In conclusion, an efficient synthesis of a precursor of the
serine protease, prostate specific antigen inhibitor 1 has
been accomplished. The synthesis relies on two com-
pletely stereoselective reactions that allow the introduc-
tion of the stereocenters at C-3 and C-4 in a predictable
manner. It is also worth mentioning that the employed
reaction sequence can tolerate the introduction of points
of structural diversity at C-3, C-4 and N-1, thus opening
access to differently substituted compounds of poten-
tially stronger inhibiting capacity. From a more general
point of view, this work shows how even largely spec-
ulative rationalizations of the course of a stereoselective
reaction can prove to be a useful predictive tool in
designing an effective synthetic strategy.
(3S,4R,40R)-1-(4-Methoxyphenyl)-3-hydroxy-4-(1,4-diox-
aspiro[4.5]dec-2-yl)azetidin-2-one 6. To a stirred solution
of compound 5 (0.709 g, 1.89 mmol) in a 9:1 THF/
MeOH mixture as solvent (22 mL) cooled at 0 ꢁC,
NaOH (4.2 mL of a 1 N aqueous solution, 4.2 mmol)
was added dropwise. When the hydrolysis was com-
pleted (about 2 h, monitored by TLC), 1 N HCl was
cautiously added until pH 7 was reached. The organic
solvent was evaporated under vacuum, and the aqueous
phase was extracted with 3ꢂ20 mL of DCM. The
organic phase was dried over Na2SO4, the solvent was
evaporated under vacuum, and the residue was purified
by flash chromatography with a 60:40 hexanes/ethyl-
acetate mixture as eluant. The product (0.592 g) was
obtained in 94% yield as a white solid, mp 198–200 ꢁC.
Experimental
IR: 3295, 1750 cmꢀ1. [a]2D3 ꢀ60.8 (c 0.72). H NMR: d
1
Melting points are uncorrected. 1H and 13C NMR
spectra were recorded on CDCl3 solutions at 300 and
75 MHz, respectively. Resonances are in ppm downfield
from TMS;coupling constants are in Hz. FTIR spectra
were recorded on pure liquids or Nujol film. Optical
rotations were measured on DCM solutions. Thioester
45b and 4-benzyloxybenzyl triphenylphosphonium bro-
mide14 were known compounds, that were prepared
according to the literature procedures. Imine 3 was pre-
pared from the corresponding aldehyde7 as described
for its enantiomer.5b
7.71 (B part of an AB system, J=8.0 Hz, 2H), 6.88 (A
part of an AB system, J=8.0 Hz, 2H), 4.97 (d, J=5.0
Hz, 1H), 4.43 (q, J=7.0 Hz, 1H), 4.27 (dd, J=7.0, 8.5
Hz, 1H), 4.24 (dd, J=5.0, 7.0 Hz, 1H), 3.82 (dd, J=7.0,
8.5 Hz, 1H), 3.79 (s, 3H), 1.70–1.33 (m, 10H). 13C
NMR: d 166.0, 156.9, 130.4, 120.2, 114.2, 111.0, 76.6,
75.9, 65.7, 65.2, 55.4, 36.5, 34.8, 25.2, 24.1, 23.9.
C18H23NO5 requires: C, 64.85;H, 6.95;N, 4.20. Found:
C, 64.63;H, 6.78;N, 4.40.
(4R,40R)-1-(4-Methoxyphenyl)-4-(1,4-dioxaspiro[4.5]dec-
2-yl)azetidin-2,3-dione 7. P2O5 (0.070 g, 0.49 mmol) was
added in one portion to anhydrous DMSO (2 mL) kept
under nitrogen. After 5 min, a solution of compound 6
(0.117 g, 0.35 mmol) in anhydrous DMSO (1 mL) was
added to the resulting mixture, and this was stirred at rt
for 20 h. The reaction was monitored by TLC and small
portions of P2O5 were added (if necessary) to drive the
reaction to completion. The reaction mixture was then
poured into a saturated aqueous solution of NaHCO3
(30 mL), and the resulting solution was extracted with
3ꢂ10 mL of DCM. The combined organic extracts were
dried over Na2SO4, the solvent was evaporated under
vacuum, and the residue was purified by flash chroma-
tography with a 60:40 hexanes/ethylacetate mixture as
eluant. The product (0.098 g) was obtained in 85% yield
(3S,4R,40R)-1-(4-Methoxyphenyl)-3-acetoxy-4-(1,4-diox-
aspiro[4.5]dec-2-yl)azetidin-2-one 5. To a stirred solution
of thioester 4 (2.11 g, 10 mmol) in anhydrous DCM (30
mL) cooled at ꢀ78 ꢁC and kept under nitrogen, TiCl4
(11 mL of a 1 M solution in DCM, 11 mmol) was added
dropwise. Triethylamine (1.7 mL, 12 mmol) was then
added dropwise, and the resulting dark purple solution
was stirred at ꢀ78 ꢁC for 20 min. Imine 3 (1.38 g, 5
mmol) dissolved in DCM (20 mL) was then added
dropwise, and the resulting mixture was stirred at
ꢀ78 ꢁC for 6 h and then allowed to slowly warm-up to
rt. After stirring overnight, the reaction was quenched
by the addition of a saturated aqueous solution of
NaHCO3 and the mixture was filtered through a Celite
cake. The organic layer was separated, and the aqueous
layer was extracted with 3ꢂ25 mL of DCM. The com-
bined organic layers were dried over Na2SO4, the sol-
vent was evaporated under vacuum, and the crude
residue was purified by flash chromatography with a
60:40 hexanes/ethylacetate mixture as eluant. The pro-
duct (1.22 g) was obtained in 65% yield as a pale yellow
solid, mp 101–103 ꢁC. IR: 1765, 1760 cmꢀ1. [a]2D3 ꢀ50.3
as a yellow solid, mp 111–113 ꢁC. IR: 1810, 1760 cmꢀ1
.
[a]2D3 ꢀ39.8 (c 0.62). H NMR: d 7.85 (B part of an AB
system, J=9.1 Hz, 2H), 6.98 (A part of an AB system,
J=9.1 Hz, 2H), 4.66 (d, J=7.2 Hz, 1H), 4.33 (q, J=7.2
Hz, 1H), 4.14 (AB system, J=7.2, 8.0 Hz, 2H), 3.87 (s,
3H), 1.73–1.40 (m, 10H). 13C NMR: d 191.4, 60.0,
158.4, 130.6, 120.2, 114.6, 111.3, 75.1, 65.4, 55.7, 36.4,
34.8, 25.1, 24.2, 23.9. C18H21NO5 requires: C, 65.24;H,
6.39;N, 4.23. Found: C, 65.48;H, 6.55;N, 4.18.
1
(c 0.32). H NMR: d 7.70 (B part of an AB system,
(4S,40R)-1-(4-Methoxyphenyl)-3-(4-phenylmethoxyphenyl-
methylidene)-4-(1,4-dioxaspiro[4.5] dec-2-yl)azetidin-2-
one 8 (mixture of E and Z isomers). To a stirred suspen-
sion of 4-benzyloxybenzyl triphenylphosphonium bro-
mide (0.240 g, 0.444 mmol) in anhydrous THF (5 mL),
cooled at ꢀ20 ꢁC and kept under nitrogen, BuLi (0.325
mL of a 1.5 M solution in hexanes) was added. The
1
J=8.3 Hz, 2H), 6.89 (A part of an AB system, J=8.3
Hz, 2H), 6.03 (d, J=5.1 Hz, 1H), 4.37 (dt, J=6.4, 8.7
Hz, 1H), 4.31 (dd, J=5.1, 8.7 Hz, 1H), 4.08 (dd, J=6.4,
8.8 Hz, 1H), 3.81 (s, 3H), 3.64 (dd, J=6.4, 8.8 Hz, 1H),
2.18 (s, 3H), 1.73–1.33 (m, 10H). 13C NMR: d 169.0,
167.0, 156.0, 131.1, 119.0, 113.9, 110.9, 76.2, 73.0, 66.0,

1816
R. Annunziata et al. / Bioorg. Med. Chem. 10 (2002) 1813–1818
mixture was stirred at ꢀ20 ꢁC for 40 min, whereupon its
color became bright red. Compound 7 (0.098 g, 0.296
mmol) in THF (5 mL) was then added dropwise at
ꢀ20 ꢁC, and the mixture was stirred for 2 h at that
temperature. The reaction was then quenched by the
addition of a saturated aqueous solution of NH4Cl, and
the aqueous layer was extracted with 2ꢂ20 mL of
DCM. The combined organic extracts were dried over
Na2SO4, the solvent was evaporated under vacuum, and
the residue was purified by flash chromatography with a
80:20 hexanes/ethylacetate mixture as eluant. The pro-
duct (0.111 g) was obtained in 73% yield as a 93:7 mix-
ture of two isomers. C32H33NO5 requires: C, 75.12;H,
6.50;N, 2.74. Found: C, 75.36;H, 6.78;N, 2.58. During
the chromatographic separation pure fractions of each
isomer were obtained. The major isomer had mp 113–
best carried out with a fresh, active sample of catalyst.
The use of less active catalysts required longer reaction
times and in some cases led to the formation of minor
1
amounts (about 10%) of a trans b-lactam. This had H
NMR: d 7.58 (B part of an AB system, J=9.0 Hz, 2H),
7.11 (B part of an AB system, J=8.4 Hz, 2H), 6.87 (A
part of an AB system, J=9.0 Hz, 2H), 6.77 (A part of
an AB system, J=8.4 Hz, 2H), 4.23 (q, J=7.1 Hz, 1H),
3.83 (dd, J=7.5, 2.1 Hz, 1H), 3.81 (s, 3H), 3.74 (dd,
J=8.6, 7.1 Hz, 1H), 3.15 (B part of an AB system,
J=13.5, 8.9 Hz, 1H), 3.08 (dt, J=8.9, 2.1 Hz, 1H), 3.04
(dd, J=8.6, 7.1 Hz, 1H), 2.83 (A part of an AB system,
J=13.5, 8.9 Hz, 1H), 1.67–130 (m, 10H).
(3S,4S,40R)-1-(4-Methoxyphenyl)-3-[4-(2-propenyloxy)-
phenylmethyl]-4-(1,4-dioxaspiro[4.5]dec-2-yl) azetidin-2-
one 10. A mixture of compound 9 (0.060 g, 0.142
mmol), allylbromide (0.041 mL, 0.469 mmol), K2CO3
(0.065 g, 0.469 mmol) in acetonitrile (4 mL) was stirred
at 50 ꢁC for 60 h. The solvent was then evaporated
under vacuum and the residue was taken up in DCM
(10 mL). The solid was filtered off and the filtrate was
concentrated under vacuum. The crude product was
purified by flash chromatography with a 70:30 hexanes/
ethylacetate mixture as eluant. The product (0.066 g)
was obtained in quantitative yield as a waxy, pale yel-
115 ꢁC. IR: 1740, 1511 cmꢀ1. [a]2D3 ꢀ181.0 (c 1.48). H
1
NMR: d 7.54 (B part of an AB system, J=9.2 Hz, 2H),
7.51 (B part of an AB system, J=9.8 Hz, 2H), 7.43 (m,
5H),7.14 (d, J=1.0 Hz, 1H), 6.99 (A part of an AB
system, J=9.2 Hz, 2H), 6.92 (A part of an AB system,
J=9.8 Hz, 2H), 5.29 (dd, J=1.0, 4.3 Hz, 1H), 5.12 (s,
2H), 4.58 (dt, J=6.4, 4.3 Hz, 1H), 3.83 (s, 3H), 3.77 (AB
system, J=8.0, 6.4 Hz, 2H), 1.60–1.30 (m, 10H). 13C
NMR: d 160.5, 157.0, 136.5, 132.0, 131.9, 130.7, 128.6,
128.05, 127.4, 127.2, 118.7, 115.0, 114.2, 110.5, 76.6,
70.0, 65.4, 60.5, 55.5, 36.3, 34.8, 25.1, 24.0, 23.9. The
low solid. IR: 1746, 1513 cmꢀ1. [a]D23 ꢀ66.7 (c 1.32). H
1
minor isomer had mp 87–90 ꢁC. IR: 1730, 1511 cmꢀ1
.
NMR: d 7.56 (B part of an AB system, J=9.0 Hz, 2H),
7.20 (B part of an AB system, J=8.4 Hz, 2H), 6.85 (A
part of an AB system, J=9.0 Hz, 4H), 6.08 (m, 1H),
5.43 (ddt, J=16.0, 3.0, 1.6 Hz, 1H), 5.29 (dd, J=12.0,
3.0 Hz, 1H), 4.58–4.51 (m, 2H), 4.33 (q, J=7.5 Hz, 1H),
4.21 (dd, J=7.5, 6.0 Hz, 1H), 3.89 (dd, J=8.5, 7.5 Hz,
1H), 3.73 (dt, J=8.0, 6.0 Hz, 1H), 3.66 (s, 3H), 3.50 (dd,
J=8.5, 7.5 Hz, 1H), 3.23 (B part of an AB system, J=8.0,
16.0 Hz, 1H), 2.90 (A part of an AB system, J=8.0, 16.0
Hz, 1H), 1.67–1.30 (m, 10H). 13C NMR: d 167.4, 157.6,
156.5, 133.0, 131.5, 130.4, 129.4, 120.7, 117.8, 115.1,
113.9, 110.7, 75.9, 69.0, 66.7, 58.6, 55.6, 51.7, 36.4, 34.6,
30.3, 25.2, 24.1, 23.9. C28H33NO5 requires: C, 72.55;H,
7.17;N, 3.02. Found: C, 72.27;H, 7.33;N, 2.87.
[a]2D3 221.1 (c 0.34). H NMR: d 8.03 (B part of an AB
system, J=8.8 Hz, 2H), 7.67 (B part of an AB system,
J=9.2 Hz, 2H), 7.41 (m, 5H), 7.02 (A part of an AB
system, J=8.8 Hz, 2H), 6.92 (A part of an AB system,
J=9.2 Hz, 2H), 6.45 (s, 1H), 5.12 (s, 2H), 4.54 (d,
J=6.3 Hz, 1H), 4.52 (q, J=6.4 Hz, 1H), ), 4.11 (dd,
J=8.2, 6.4 Hz, 1H), 3.97 (dd, J=8.2, 6.4 Hz, 1H), 3.83
(s, 3H), 1.70–1.35 (m, 10H). 13C NMR: d 162.0, 160.0,
156.2, 136.5, 132.6, 131.5, 131.1, 128.6, 127.4, 127.0,
126.2,118.9, 115.0, 114.4, 110.45, 75.3, 70.1, 65.4, 61.8,
55.5, 35.6, 34.6, 25.0, 23.8, 23.7.
1
(3S,4S,40R)-1-(4-Methoxyphenyl)-3-(4-hydroxyphenyl-
methyl)-4-(1,4-dioxaspiro[4.5]dec-2-yl) azetidin-2-one 9.
A suspension of compound 8 (0.090 g, 0.176 mmol)
and 10% Pd/C (0.035 g) in absolute EtOH was shaken
at RT under H2 for 3 h. The mixture was then filtered
through a Celite cake, that was thoroughly washed with
DCM. The organic solvent was evaporated under
vacuum The crude product (0.074 g) was obtained in
quantitative yield as a white solid, mp 86–89 ꢁC. IR:
3390, 1753 cmꢀ1. [a]D23 ꢀ44.5 (c 0.4). 1H NMR: d 7.57 (B
part of an AB system, J=9.0 Hz, 2H), 7.14 (B part of
an AB system, J=8.4 Hz, 2H), 6.87 (A part of an AB
system, J=9.0 Hz, 2H), 6.77 (A part of an AB system,
J=8.4 Hz, 2H), 4.36 (q, J=6.5 Hz, 1H), 4.22 (dd,
J=6.5, 5.0 Hz, 1H), 3.94 (dd, J=8.5, 6.5 Hz, 1H), 3.81
(s, 3H), 3.74 (dt, J=8.0, 5.0 Hz, 1H), 3.55 (dd, J=8.5,
6.5 Hz, 1H), 3.19 (B part of an AB system, J=8.0, 16.0
Hz, 1H), 2.88 (A part of an AB system, J=8.0, 16.0 Hz,
1H), 1.67–1.30 (m, 10H). 13C NMR: d 167.55, 156.0,
154.7, 130.0, 129.5, 120.7, 119.8, 115.6, 113.7, 110.7,
75.8, 66.5, 58.6, 51.5, 55.5, 36.3, 34.6, 30.3, 25.0, 23.9,
23.8. C25H29NO5 requires: C, 70.90;H, 6.90;N, 3.31.
Found: C, 71.08;H, 6.88;N, 3.49. This reaction was
(3S,4S)-1-(4-Methoxyphenyl)-3-[4-(2-propenyloxy)phenyl-
methyl]-4-formylazetidin-2-one 12. Ketal hydrolysis. A
solution of compound 10 (0.060 g, 0.129 mmol) in a 1:1
TFA/water mixture (4 mL) was stirred overnight while
allowing the reaction temperature to rise from 0 ꢁC to
rt. Solid K2CO3 was then added until gas evolution had
subsided. The mixture was then extracted with 3ꢂ5 mL
of EtOAc. The combined organic extracts were washed
with a saturated aqueous solution of Na2CO3 and dried
over Na2SO4. The solvent was evaporated under
vacuum to give the crude product that was used without
further purification.
Diol oxidation. To a stirred solution of diol in a 1:1
EtOAc/water mixture (4 mL) cooled at 0 ꢁC, solid
NaIO4 (0.110 g, 0.516 mmol) was added in one portion.
The mixture was monitored by TLC. After about 2 h
stirring at 0 ꢁC, the mixture was extracted with 3ꢂ5 mL
of EtOAc. The combined organic extracts were dried
over Na2SO4, the solvent was evaporated under

R. Annunziata et al. / Bioorg. Med. Chem. 10 (2002) 1813–1818
1817
vacuum, and the crude product was purified by flash
chromatography with a 70:30 hexanes/EtOAc mixture
as eluant. Aldehyde 12 (0.033 g), a thick oil, was thus
obtained in 73% yield from compound 10. IR: 1746,
g, 0.0044 mmol), and triphenylphosphine (0.005 g, 0.019
mmol) in EtOH (1 mL) was refluxed for 60 min. To the
cooled mixture wet SiO2 (ca. 0.2 g) was added and the
resulting slurry was stirred at rt for 5 min. The mixture
was then diluted with EtOH (10 mL), filtered through a
Celite cake, and concentrated under vacuum. The resi-
due was filtered through a short column of silica gel
with a 75:25 hexanes/EtOAc mixture as eluant to give
the crude phenol 15 (1H NMR: d 7.38–7.29 (m, 5H),
7.25–7.18 (m, 6H), 6.85 (d, J=9.0 Hz, 2H), 5.20 (B part
of an AB system, J=12.0 Hz, 1H), 4.98 (A part of an
AB system, J=12.0 Hz, 1H), 4.65 (d, J=6.0 Hz, 1H),
3.97 (ddd, J=10.0, 6.8, 6.0 Hz, 1H), 3.80 (s, 3H), 3.23
(B part of an AB system, J=15.0, 6.8 Hz, 1H), 2.95 (A
part of an AB system, J=15.0, 10.0 Hz, 1H) that was
used as such in the following step.
1690 cmꢀ1. [a]2D3 ꢀ39.3 (c 0.28). H NMR: d 9.64 (d,
1
J=2.8 Hz, 1H), 7.24 (B part of an AB system, J=9.0
Hz, 2H), 7.17 (B part of an AB system, J=8.6 Hz, 2H),
6.89 (A part of an AB system, J=9.0 Hz, 2H), 6.88 (A
part of an AB system, J=8.6 Hz, 2H), 6.10–6.00 (m,
1H), 5.43 (dq, J=17.0, 1.6 Hz, 1H), 5.29 (dq, J=10.3,
1.4 Hz, 1H), 4.57 (dd, J=6.1, 2.8 Hz, 1H), 4.59–4.51 (m,
2H), 4.03 (dt, J=9.3, 6.7 Hz, 1H), 3.88 (s, 3H), 3.20 (B
part of an AB system, J=15.0, 6.7 Hz, 1H), 2.93 (A part
of an AB system, J=15.0, 6.7 Hz, 1H). 13C NMR: d
199.1, 165.0, 157.5,157.4, 133.2, 131.5, 130.0, 129.7,
117.8, 117.7, 115.1, 114.4, 68.8, 60.0, 55.5, 55.0, 30.3.
C21H21NO4 requires: C, 71.78;H, 6.02;N, 3.99. Found:
C, 71.70;H, 6.22;N, 3.83.
Silylation. To a stirred solution of crude phenol 15 in
DCM (1 mL), t-butyldiphenylchlorosilane (0.010 mL,
0.0394 mmol) and imidazole (0.005 g, 0.073 mmol) were
added in this order. After 3 h stirring at rt, the same
amounts of silylating agent and imidazole, dissolved in
DCM (1 mL), were added, and stirring was continued
overnight. Water (1 mL) and DCM (5 mL) were then
added, the organic phase was separated, washed with
water (2 mL), and dried over over Na2SO4. The solvent
was evaporated under vacuum to give the crude product
that was purified by flash chromatography with 90:10,
then 70:30, then 30:70 mixtures of hexanes and EtOAc
as eluants. The product 16 (0.013 g, 51%) was obtained
as an oil. IR: 1750 cmꢀ1. [a]2D3 16.3 (c 0.05). 1H NMR: d
7.65–7.76 (m, 5H), 7.43–7.28 (m, 10H), 7.19 (B part of
an AB system, J=8.8 Hz, 2H), 6.93 (B part of an AB
system, J=8.8 Hz, 2H), 6.83 (A part of an AB system,
J=8.8 Hz, 2H), 6.70 (A part of an AB system, J=8.8
Hz, 2H), 5.15 (B part of an AB system, J=12.1 Hz,
1H), 4.88 (A part of an AB system, J=12.1 Hz, 1H),
4.58 (d, J=6.0 Hz, 1H), 3.87 (dt, J=9.3, 6.0 Hz, 1H),
3.79 (s, 3H), 3.08 (B part of an AB system, J=15.0, 6.0
Hz, 1H), 2.81 (A part of an AB system, J=15.0, 9.3 Hz,
1H), 1.11 (s, 9H). 13C NMR: d 169.0, 165.0, 156.7,
154.0, 136.5, 134.5, 132.0, 130.0, 129.8, 129.3, 129.0,
128.5, 120.0, 118.0, 115.5, 67.5, 55.5, 55.0, 53.0, 30.0,
26.5, 18.0. C41H41NO5Si requires: C, 75.08;H, 6.30;N,
2.14. Found: C, 75.36;H, 6.43;N, 2.02.
(3S,4S)-1-(4-Methoxyphenyl)-3-[4-(2-propenyloxy)phenyl-
methyl]-4-benzyloxycarbonyl azetidin-2-one 14. Aldehyde
oxidation. A mixture of aldehyde 12 (0.0351 g, 0.1
mmol), CrO3 (0.100 g, 1 mmol), concentrated sulfuric
acid (0.026 mL), water (56 mL), and acetone (5 mL) was
stirred at rt for 15 min. The mixture was then extracted
with EtOAc (2ꢂ15 mL), and the combined organic
phases were washed with water and dried over Na2SO4.
The solvent was evaporated under vacuum to give the
crude acid 13 that was used without further purification.
Ester formation. To a solution of 13 in acetone (10
mL), benzylbromide (0.0142 mL, 0.12 mmol) and
K2CO3 (0.030 g, 0.22 mmol) were added in this order.
The mixture was stirred at rt for 2.5 h. The solvent was
then evaporated under vacuum, and EtOAc (20 mL)
was added to the residue. Water was then added, and
the organic phase was separated and washed with a
saturated aqueous solution of NaCl. The separated
organic phase was dried over Na2SO4. The solvent was
evaporated under vacuum to give the crude ester that
was purified by flash chromatography with a 90:10 and
then 70:30 hexanes/EtOAc mixture as eluant. Ester 14
(0.031 g), a thick oil, was thus obtained in 68% yield
from compound 12. IR: 1752 cmꢀ1. [a]D23 ꢀ20.4 (c 0.1).
1H NMR: d 7.30–7.39 (m, 5H), 7.19–7.27 (m, 6H), 7.13
(d, J=8.6 Hz, 2H), 6.05–6.10 (m, 1H), 5.42 (dq,
J=17.0, 1.6 Hz, 1H), 5.28 (dq, J=10.3, 1.4 Hz, 1H),
5.16 (B part of an AB system, J=10.3 Hz, 1H), 5.02 (A
part of an AB system, J=10.3 Hz, 1H), 4.63 (d, J=5.0
Hz, 1H), 4.51 (bd, J=5.4 Hz, 2H), 4.03 (ddd, J=9.0,
6.7, 5.0 Hz, 1H), 3.80 (s, 3H), 3.12 (B part of an AB
system, J=15.0, 6.7 Hz, 1H), 2.90 (A part of an AB
system, J=15.0, 9.0 Hz, 1H). 13C NMR: d 169.3, 165.1,
154.4, 154.3, 133.0, 129.5, 129.4, 128.6, 128.2, 127.1,
126.4, 118.5, 117.9, 114.8, 114.4, 113.1, 67.5, 60.1, 55.5,
55.0, 50.8, 30.9. C28H27NO5 requires: C, 73.50;H, 5.95;
N, 3.06. Found: C, 73.78;H, 6.13;N, 2.94.
(3S,4S)-3-[4-[(1,1-Dimethyethyl)diphenylsilyl]oxy]phenyl-
methyl]-4-benzyloxycarbonyl azetidin-2-one 2. To a stir-
red solution of compound 16 (0.012 g, 0.0183 mmol) in
acetonitrile (2 mL) cooled at ꢀ20 ꢁC, CAN (0.040 g,
0.073 mmol) in water (1.0 mL) was added in one por-
tion. After 0.5 h stirring at a reaction temperature rang-
ing from ꢀ20 to ꢀ10 ꢁC, the reaction was quenched by
the addition of saturated aqueous solutions of NaHSO3
and NaHCO3. The mixture was extracted with diethy-
lether (2ꢂ10 mL), and the combined organic extracts
were dried over Na2SO4. The solvent was evaporated
under vacuum to give the crude product that was puri-
fied by flash chromatography with a 70:30 mixture of
hexanes and EtOAc as eluants. The product 2 (0.007 g,
70%) was obtained as very thick oil that solidified while
stored in the freezer. IR: 3295, 1755 cmꢀ1. [a]D23 12.0
(3S,4S)-1-(4-Methoxyphenyl)-3-[4-[(1,1-dimethyethyl)di-
phenylsilyl]oxy]phenylmethyl]-4-benzyloxycarbonyl azeti-
din-2-one 16. Allyl group removal. A mixture of
compound 14 (0.018 g, 0.0394 mmol), Pd(OAc)2 (0.001

1818
R. Annunziata et al. / Bioorg. Med. Chem. 10 (2002) 1813–1818
1
(c 0.05). H NMR: d 7.55–7.45 (m, 4H), 7.40–7.25 (m,
11H), 6.91 (B part of an AB system, J=8.5 Hz, 2H),
6.69 (A part of an AB system, J=8.5 Hz, 2H), 5.95 (bs,
1H), 5.13 (B part of an AB system, J=12.1 Hz, 1H),
4.87 (A part of an AB system, J=12.1 Hz, 1H), 4.30 (d,
J=6.0 Hz, 1H), 3.85 (q, J=6.0 Hz, 1H), 2.97 (B part of
an AB system, J=15.0, 6.0 Hz, 1H), 2.73 (A part of an
AB system, J=15.0, 6.0 Hz, 1H), 1.11 (s, 9H). 13C
NMR: d 170.5, 169.5, 155.0, 136.0, 135.0, 134.0, 132.0,
130.0, 129.0, 128.5, 119.5, 67.5, 56.0, 52.5, 31.0, 26.5,
19.0. C34H35NO4Si requires: C, 74.28;H, 6.42;N, 2.55.
Found: C, 74.44;H, 6.51;N, 2.38.
Schirmeister, T.;Otto, H. H. Pharmazie 2000, 55, 798. (p)
Demarcus, M.;Ganadu, M. L.;Mura, G. M.;Porcheddu, A.;
Quaranta, L.;Reginato, G.;Taddei, M. J. Org. Chem. 2001,
66, 697. (q) Beardsell, M.;Hinchliffe, P. S.;Wood, J. M.;
Wilmouth, R. C.;Schofield, C. J.;Page, M. I. J. Chem. Soc.
Chem. Commun. 2001.
2. Adlington, R. M.;Baldwin, J. E.;Chen, B.;Cooper, S. L.;
McCoull, W.;Pritchard, G. J.;Howe, T. J.;Becker, G. W.;
Hermann, R. B.;McNulty, A. M.;Neubauer, B. L. Bioorg.
Med. Chem. Lett. 1997, 7, 1689.
3. Oestering, J. E. J. Urol 1991, 145, 907, and references
therein.
4. (a) Peehl, D. M. Cancer 1995, 75, 2021. (b) Diamandis,
E. P.;Yu, H. J. Clin. Endocrinol. Metab. 1995, 80, 1515.
5. (a) Review: Benaglia, M.;Cinquini, M.;Cozzi, F. Eur. J.
Org. Chem 2000, 563. (b) For a reference particularly relevant
to this work, see: Annunziata, R.;Cinquini, M.;Cozzi, F.;
Cozzi, P. G. J. Org. Chem. 1992, 57, 4155. (c) For recent
applications not included in ref 5a, see: Annunziata, R.;
Benaglia, M.;Cinquini, M.;Cozzi, F.;Poletti, L.;Raimondi,
L.;Perboni, A. Eur. J. Org. Chem 1999, 3067. (d) Annunziata,
R.;Benaglia, M.;Cinquini, M.;Cozzi, F. Tetrahedron: Asym-
metry 1999, 10, 4841.
Acknowledgement
We thank MURST (Progetto Nazionale Stereoselezione
in Sintesi Organica. Metodologie ed Applicazioni) and
CNR for financial support.
6. Indeed, condensation of the titanium enolate of the 2-pyri-
dylthioester derived from 4-allyloxy hydrocinnamic acid with
the N-4-methoxyphenylimine derived from ethylglyoxylate
gave a 50:50 mixture of trans and cis b-lactams in 70% yield.
7. (a) The synthesis of (S)-O,O-cyclohexylideneglyceraldehyde
References and Notes
1. (a) Firestone, R. A.;Barker, P. L.;Pisano, J. M.;Ashe,
B. M.;Dahlgren, M. E. Tetrahedron 1990, 46, 2255. (b) Shah,
S. K.;Dorn, C. P., Jr.;Finke, P. E.;Hale, J. J.;Hagmann,
W. K.;Brause, K. A.;Chandler, G. O.;Kissinger, B. M.;
Weston, H.;Knight, W. B.;Maycock, A. L.;Dellea, P. S.;
Fletcher, D. S.;Hand, K. M.;Mumford, R. A.;Underwood,
D. J.;Doherty, J. B. J. Med. Chem. 1992, 35, 3745. (c) Han,
W. T.;Trehan, A. K.;Wright, J. K. K.;Federici, M. E.;Seiler,
S. M.;Meanwell, N. A. Bioorg. Med. Chem. 1995, 3, 1123. (d)
has been described: Grauert, M.;Scho llkopf, U. Liebigs Ann.
¨
Chem. 1985, 1817. (b) Yoshida, J.;Nagakawa, M.;Seki, H.;
Hino, T. J. Chem. Soc., Perkin Trans. 1 1992, 343. (c) How-
ever, in our hands, only the application of the method descri-
bed in ref 7a afforded the product in good and reproducible
yields. Modification of a procedure employed to obtained
(S)-glyceraldehyde acetonide [ Jung, M. E.;Shaw, T. J. J. Am.
Chem. Soc. 1980, 102, 6304] was also ineffective.
8. Palomo, C.;Aizpurua, J. M.;Ganboa, I.;Carreaux, F.;
Cuevas, C.;Maneiro, E.;Ontoria, J. M. J. Org. Chem. 1994,
59, 3123.
Wu, Z.;Georg, G. I.;Cathers, B. E.;Schloss, J. V.
Bioorg.
Med. Chem. Lett. 1996, 6, 983. (e) Pitlik, J.;Townsend, C. A.
Bioorg. Med. Chem. Lett. 1997, 7, 3129. (f) Borthwick, A. D.;
Weingarten, G.;Haley, T. M.;Tomaszewski, M.;Wang, W.;
Hu, Z.;Bedard, J.;Jin, H.;Yuen, L.;Mansour, T. S.
Bioorg.
9. The direct conversion of diol 11 into acid 13, attempted
following the procedure described by Palomo et al. for related
compounds (Palomo, C.;Aizpurua, J. M.;Mielgo, A.;Lin-
den, A. J. Org. Chem. 1996, 61, 9186) led to extensive product
decomposition..
Med. Chem. Lett. 1998, 8, 365. (g) Deziel, R.;Malenfant, E.
Bioorg. Med. Chem. Lett. 1996, 6, 1437. (h) Yoakim, C.;
Ogilvie, W. W.;Cameron, D. R.;Chabot, C.;Guse, I.;Hache
B.;Naud, J.;O’Meara, J. A.;Plante, R.;Deziel, R. J. Med.
,
Chem. 1998, 41, 2882. (i) Wilmouth, R. C.;Westwood, N. J.;
Anderson, K.;Brownlee, W.;Claridge, T. D. W.;Clifton, I. J.;
Pritchard, G. J.;Aplin, R. T.;Schofield, C. J. Biochemistry
1998, 37, 17506. (j) Bonneau, P. R.;Hasani, F.;Plouffe, C.;
Malenfant, E.;LaPlante, S. R.;Guse, I.;Ogilvie, W. W.;
Plante, R.;Davidson, W. C.;Hopkins, J. L.;Morelock, M. M.;
Cordingley, M. G.;Deziel, R. J. Am. Chem. Soc. 1999, 121,
2965. (k) La Plante, S. R.;Bonneau, P. R.;Aubry, N.;
Cameron, D. R.;Deziel, R.;Grand-Maitre, C.;Plouffe, C.;
Tong, L.;Kawai, S. H. J. Am. Chem. Soc. 1999, 121, 2974. (l)
Ogilvie, W. W.;Yoakim, C.;Do, F.;Hache, B.;Lagace, L.;
Naud, J.;O’Meara, J. A.;Deziel, R. Bioorg. Med. Chem. 1999,
7, 1521. (m) Taylor, P.;Anderson, V.;Dowden, J.;Flitsch,
10. Georg, G. I.;Kant, J.;Gill, H. S. J. Am. Chem. Soc. 1987,
109, 1129.
11. Annunziata, R.;Benaglia, M.;Cinquini, M.;Cozzi, F.;
Ponzini, F.;Raimondi, L. Tetrahedron 1994, 50, 2939.
12. The assignment of configuration to this and other tita-
nium enolates was based on NMR experiment as described in
ref 5b. Very recently, this assignment has independently been
confirmed: Cooke, J. W. B.;Berry, M. B.;Caine, D. M.;
Cardwell, K. S.;Cook, J. S.;Hodgson, A. J. Org. Chem. 2001,
66, 334.
13. (a) For recent reviews, see: Ojima, I.;Delaloge, F. Chem.
Soc. Rev. 1997, 26, 377. (b) Palomo, C.;Aizpurua, J. M.;
Ganboa, I.;Oiarbide, M. Eur. J. Org. Chem 1999, 3223.
14. Barton, D. H. R.;Chow, Y. L.;Cox, A.;Kirby, G. W. J.
Chem. Soc. 1965, 3571.
S. L.;Turner, N. J.;Loughran, K.;Walkinnshaw, M. D.
J.
Biol. Chem. 1999, 274, 24901. (n) Imming, P.;Klar, P.;Dix, D.
J. Med. Chem. 2000, 43, 4328. (o) Achilles, K.;Schneider, M.;