Solid-Phase Synthesis of 4-Arylazetidin-2-ones via Suzuki and Heck Cross-Coupling Reactions

Article abstract of DOI:10.1021/jo9711854

Application of the Suzuki and the Heck cross-coupling reactions for efficient synthesis of diverse biaryl- and styryl-substituted β-lactams on solid support using an optimized catalyst system is reported. The coupling of phenylboronic acid with the resin-bound 3-phenoxy-4-iodophenyl β-lactam 1a proceeded in 89% isolated yield by employing 20 mol % of the bidentate phosphine-palladium complex, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride {PdCl₂(dppf)} as catalyst in the presence of triethylamine (TEA, 10 equiv) in DMF at 65 °C for 12 h. Efficient cross-coupling of the iodophenyl β-lactam to heterocyclic boronates and aryl boronates substituted with various electron-donating and -withdrawing groups is also demonstrated. The reverse coupling reactions of immobilized arylboronic acid le with a variety of substituted aryl iodides were found to proceed in excellent yields using the same catalyst system in a 3/7 mixture (v/v) of H₂O:DMF at 40 °C. The use of this catalyst for the vinylation of aryl iodide la via the Heck reaction was also examined.

Full text of DOI:10.1021/jo9711854

7820
J . Org. Chem. 1997, 62, 7820-7826
Solid -P h a se Syn th esis of 4-Ar yla zetid in -2-on es via Su zu k i a n d
Heck Cr oss-Cou p lin g Rea ction s
Beatrice Ruhland,* Agnes Bombrun,# and Mark A. Gallop
Affymax Research Institute, 4001 Miranda Ave., Palo Alto, California 94304
Received J uly 1, 1997X
Application of the Suzuki and the Heck cross-coupling reactions for efficient synthesis of diverse
biaryl- and styryl-substituted â-lactams on solid support using an optimized catalyst system is
reported. The coupling of phenylboronic acid with the resin-bound 3-phenoxy-4-iodophenyl â-lactam
1a proceeded in 89% isolated yield by employing 20 mol % of the bidentate phosphine-palladium
complex, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride {PdCl2(dppf)} as catalyst
in the presence of triethylamine (TEA, 10 equiv) in DMF at 65 °C for 12 h. Efficient cross-coupling
of the iodophenyl â-lactam to heterocyclic boronates and aryl boronates substituted with various
electron-donating and -withdrawing groups is also demonstrated. The reverse coupling reactions
of immobilized arylboronic acid 1c with a variety of substituted aryl iodides were found to proceed
in excellent yields using the same catalyst system in a 3/7 mixture (v/v) of H2O:DMF at 40 °C.
The use of this catalyst for the vinylation of aryl iodide 1a via the Heck reaction was also examined.
In tr od u ction
structurally diverse â-lactams via a [2 + 2] cycloaddition
reaction of ketenes with resin-bound imines derived from
amino acids.6 To complement this strategy, we were
interested in producing combinatorial libraries of sub-
stituted 4-biaryl azetidin-2-ones that represent a novel
and pharmaceutically attractive class of â-lactams. Herein
we report an application of the Suzuki and the Heck
cross-coupling reactions for efficient synthesis of biaryl
and styryl â-lactams on solid support. In addition we
describe the first example of a resin-bound imine derived
from a boronic acid, prepared without prior protection,
and its application in [2 + 2] cycloaddition and subse-
quent Suzuki coupling reactions. Although there have
been several reports published on solid-phase palladium
catalyzed C-C bond formation, these methods require
different sets of conditions (catalysts, base, temperature)
depending upon the substrate (aryl iodides vs aryl
bromides; immobilized boronic acid vs immobilized aryl
halides). Our objective was to identify mild reaction
conditions requiring a single catalyst system that would
be suitable for the automated construction of libraries of
diverse biaryl- and styryl-substituted â-lactams and allow
complete conversion to product with a wide range of
substrates.
Combinatorial synthesis has emerged within the past
few years as an important new approach for the discovery
and optimization of pharmaceutical lead compounds.1
Generating diversely functionalized sets of many differ-
ent compound classes is currently a major preoccupation
within most drug companies. The types of structural
templates receiving particular attention include both
familiar heterocycles (e.g. benzodiazepines, â-lactams)
with proven pharmaceutical utility as well as novel or
less extensively investigated scaffolds with some intuitive
medicinal chemical appeal. Biaryl fragments represent
one class of structural motif that has been the focus of
considerable synthetic interest since the biaryl moiety
is an important pharmacophore present in many biologi-
cally active molecules.2 In particular, palladium-cata-
lyzed carbon-carbon bond formation provides a very
attractive method for the generation of libraries of diverse
biphenyl compounds. Recently, several groups have
described intermolecular palladium cross-coupling reac-
tions on solid support via Stille,3 Suzuki,4 and Heck5
reactions, yet applications of these synthetic strategies
to produce more complex biaryl heterocyclic molecules
have to date been rather limited in scope.3b,4f We recently
reported a solid-supported combinatorial synthesis of
Resu lts a n d Discu ssion
#
Glaxo Wellcome France, 25 Ave. Quebec, 91951 Les Ulis Cedex,
France.
X Abstract published in Advance ACS Abstracts, October 15, 1997.
(1) (a) For a survey of recent activities in the area of combinatorial
chemistry, see Chapman, K. T., J oyce, G. F., Still, W. C., Eds. Current
Opinion Chem. Biol. 1997, 1, 1-145. (b) Balkenhohl, F.; von dem
Bussche-Hunnefeld, C.; Lansky, A.; Zechel, C. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2288-2337. (c) Gordon, E. M.; Gallop, M. A.; Patel, D.
V. Acc. Chem. Res. 1996, 29, 144-154. (d) Terrett, N. K.; Gardner,
M.; Gordon, D. W.; Kobylecki, R. J .; Steele, J . Tetrahedron 1995, 51,
8135-8173. (e) Gallop, M. A.; Barrett, R. W.; Dower, W. J .; Fodor, S.
P. A.; Gordon, E. M. J . Med. Chem. 1994, 37, 1233-1251. (f) Gordon,
E. M.; Barrett, R. W.; Dower, W. J .; Fodor, S. P. A.; Gallop, M. A. J .
Med. Chem. 1994, 37, 1385-1401.
Our initial experiments began by studying the coupling
of phenylboronic acid with resin-bound 3-phenoxy-4-
iodophenyl â-lactam 1a , obtained as a mixture of two cis
diastereoisomers via [2 + 2] cycloaddition reaction of
phenoxy ketene with an alanine aldimine ester derivative
of Sasrin or Wang resin (Scheme 1). Since one recent
(4) (a) Frenette, R.; Friesen, R. W. Tetrahedron Lett. 1994, 35, 9177-
9180. (b) Backes, B. J .; Ellman, J . A. J . Am. Chem. Soc. 1994, 116,
11171-11172. (c) Guiles, J . W.; J ohnson, S. G.; Murray, W. V. J . Org.
Chem.. 1996, 61, 5169-5171. (d) Han, Y.; Walker, S. D.; Young, R. N.
Tetrahedron Lett. 1996, 37, 2703-2706. (e) Larhed, M.; Lindeberg, G.;
Halberg, A. Tetrahedron Lett. 1996, 37, 8219-8222. (f) Yoo S.; Seo J .;
Yi K.; Gong Y. Tetrahedron Lett. 1997, 38, 1203-1206.
(5) (a) Yu, K.-L.; Deshpande, M. S.; Vyas, D. M. Tetrahedron Lett.
1994, 35, 8919-8922. (b) Hiroshige, M.; Hauske, J . R.; Zhou, P.
Tetrahedron Lett. 1995, 36, 4567-4570. (c) Koh, J . S.; Ellman, J . A. J .
Org. Chem. 1996, 61, 4494-4495.
(6) Ruhland, B.; Bhandari, A.; Gordon, E. M.; Gallop, M. A. J . Am.
Chem. Soc. 1996, 118, 253-254.
(2) (a) McCarthy, P. A. Med. Res. Rev. 1993, 13, 139-159. (b) Duncia,
J . V.; Carini, D. J .; Chin, A. T.; J ohnson, A. L.; Price, W. A.; Wong, P.
C.; Wexler, R. R.; Timmermans, P. B. M. W. M. Med. Res. Rev. 1992,
12, 149-191. (c) Pavia, M. R.; Cohen, M. P.; Dilley, G. J .; Dubuc, G.
R.; Durgin, T. L.; Forman, F. W.; Hediger, M. E.; Milot, G.; Powers, T.
S.; Sucholeiki, I.; Zhou, S.; Hangauer, D. G. Bioorg. Med. Chem. Lett.
1996, 4, 659-666.
(3) (a) Deshpande, M. S. Tetrahedron Lett. 1994, 35, 5613-5614.
(b) Plunkett, M. J .; Ellman, J . A. J . Am. Chem. Soc. 1995, 117, 3306-
3307. (c) Forman, F. W.; Sucholeiki, I. J . Org. Chem. 1995, 60, 523-
528.
S0022-3263(97)01185-7 CCC: $14.00 © 1997 American Chemical Society

Solid-Phase Synthesis of 4-Arylazetidin-2-ones
J . Org. Chem., Vol. 62, No. 22, 1997 7821
Sch em e 1a
Ta ble 1. Cou p lin g of Resin -Bou n d Ar yl Iod id e 1a w ith
P h en ylbor on ic Acid
entry
catalyst systema
conversionb(yield,%)c
1
2
3
4
5
6
{Pd(PPh3)4}-TEAd
100 (55)
60
32
32
{Pd(OAc)2}-P(o-tol)3 -TEAf
e
{Pd(OAc)2}-TEAf
g
{Pd2dba3}-K2CO3
{Pd2dba3}-TEAd
32
{PdCl2(dppf)}-TEAf
100 (89)h
a
Reaction run with 1a , boronic acid (4 equiv), and catalyst (20
mol %) in DMF at 65 °C under argon atmosphere for 12-24 h.
b
Conversion estimated from 1H NMR and HPLC. c Isolated yields
a
Sasrin, Wang, or ArgoGel-MB-OH resins can be used for the
of 2a after purification by HPLC, over the four-step sequence,
synthesis of 1a and 1b, and for the coupling reactions of 1a and
1b with boronates. ArgoGel-MB-OH is the resin of choice for
synthesis of 1c and for the coupling reactions of 1c with aryl
d
based on the initial resin loading. 20 equiv. e 40 mol %. f 10 equiv.
h
g2 equiv. 100% (81) from 1b.
b
iodides. RB(OH)2 used with 1a and 1b, RI used with 1c.
catalyst systems containing more hindered phosphines
such as tri-o-tolyl phosphine (P(o-tol)3) or catalysts
without phosphine ligands such as palladium(II) acetate
{Pd(OAc)2} and tris(dibenzylideneacetone)dipalladium
{Pd2(dba)3} were explored but found to be only moder-
ately reactive. We found, however, that the desired
biphenyl â-lactam could be obtained in 89% isolated yield
by employing modest quantities (20 mol %) of the
bidentate phosphine-palladium complex, [1,1′-bis(diphe-
nylphosphino)ferrocene]palladium(II) dichloride {PdCl2-
(dppf)} in the presence of TEA (10 equiv) in DMF at 65
°C for 12 h. Interestingly, the bromophenyl analogue,
1b, which is expected to be significantly less reactive than
the iodo derivative, also exhibited excellent conversion
with this catalyst system.
The high efficiency of this catalyst has been ascribed
to its large P-Pd-P angle therefore allowing facile
reductive elimination during the catalytic cycle.9 Inter-
estingly, and in contrast to our finding that {PdCl2(dppf)}
works best for biaryl coupling in this â-lactam system,
Guiles and co-workers reported that while {PdCl2(dppf)}
is the catalyst of choice for a coupling reaction involving
an alkenyl borane, it is completely unreactive in a
biphenyl coupling (at room temperature).4c To establish
the broad applicability of our reaction conditions, we were
next interested in determining the extent of the biaryl
â-lactam coupling with heterocyclic boronates and aryl
boronates substituted with various electron-donating and
-withdrawing groups. As shown in Table 2, a wide array
of functionalized boronic acids can be used. HPLC and
1H NMR analysis of the crude products indicated that
the reactions were typically driven to completion, and
upon purification by preparative HPLC, pure biaryl
products were obtained in high yields (within 65-83%
based upon the initial loading of the amino acid) even
when electron-deficient boronic acids (3-acetamidophe-
nylboronic acid) or ortho-substituted boronic acids (2-
methoxyphenylboronic acid) were used. In accord with
Sch em e 2
report has suggested that the solid-phase Suzuki reaction
can be conducted at room temperature using tetrakis-
(triphenylphosphine)palladium {Pd(PPh3)4 } as catalyst,4c
we were interested in applying these conditions to the
â-lactam scaffold. In our hands, exposure of 1a to a
variety of catalyst systems in homogeneous or heteroge-
neous media gave no Suzuki cross-coupling product with
phenylboronic acid at ambient temperature.7 The reac-
tion mixture had to be heated in DMF for coupling to
occur. The resulting products were cleaved from the
support with TFA-CH2Cl2 and analyzed using reversed-
phase HPLC, 1H NMR spectroscopy, and electrospray
mass spectrometry. These results show that the typical
Suzuki reaction conditions in which {Pd(PPh3)4} was
used as catalyst afforded complete conversion of 1a (see
Table 1). However, the desired biaryl â-lactam 2a was
isolated in only 55% yield along with a tetraarylphos-
phonium â-lactam byproduct resulting from quaterniza-
tion of triphenylphosphine by the iodophenyl â-lactam.8
Treatment of 1a with {Pd(PPh3)4} in DMF at 40 °C in
the presence of triethylamine (TEA) and in the absence
of the boronic acid quantitatively converted the iodide
to this byproduct. To circumvent this side reaction,
(7) In our hands, attempts to reproduce the room-temperature
conditions described by Guiles et al. for coupling Sasrin (or Wang)-
bound 4-iodobenzoic acid with phenylboronic acid by employing 10 mol
% of Pd2(dba)3 as catalyst in the presence of 2 equiv of K2CO3 in DMF
for 24 h under a nitrogen atmosphere proved largely unsuccessful.
Analysis of the crude by HPLC (λ ) 254 nm and λ ) 280 nm) showed
13% of 4-phenylbenzoic acid and 87% of unreacted 4-iodobenzoic acid.
(8) Analysis of the byproduct, obtained as a mixture of two cis
diastereoisomers: MS (ESI): m/z 572; 1H NMR (300 MHz, acetone-
d6) δ: 8.0-6.8 (m, 24H), 5.8 (d, 1H), 5.7 (d, 1H), 5.65 (d, 1 H), 5.55 (d,
1 H), 4.6 (q, 1 H), 4.2 (q, 1 H), 1.6 (d, 3 H), 1.2 (d, 3 H).
(9) Hayashi, T.; Konoshi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J . Am. Chem. Soc. 1984, 106, 158-163.

7822 J . Org. Chem., Vol. 62, No. 22, 1997
Ta ble 2. Cou p lin g of Resin -Bou n d Ar yl Iod id e 1a w ith a Va r iety of Bor on ic Acid sa
Ruhland et al.
a
Reactions conditions reported in Table 1, entry 6. b Products were isolated as a 1:1 mixture of two cis isomers. c Isolated yields calculated
d
as described in Table 1. Yields obtained using aryl bromide 1b.
our previous results, compounds 2a -g were isolated as
∼1:1 mixtures of cis diastereomers, and comparable
product yields were obtained from both Sasrin and Wang
resins.
boronic acid 1c was synthesized on Wang and Sasrin
resins by standard [2 + 2] cycloaddition reaction of an
immobilized phenylboronic acid imine.10 Analyzing a
1
cleaved sample of 1c by H NMR and MS revealed that
From the perspective of structural diversification in a
library synthesis, it would be preferable to conduct
Suzuki cross-coupling reactions using resin-bound bo-
ronic acids or boronic esters since the variety of com-
mercially available substituted aryl iodides is much
greater than for substituted boronates. Therefore, we
were interested in modifying our Suzuki coupling sub-
strate from the resin-bound phenyl iodide 1a to the
immobilized â-lactam phenylboronic acid 1c. Although
the Suzuki cross-coupling reaction of polymer-supported
aryl iodides has been well documented, the reverse
coupling reaction of resin bound arylboronic acids or
boronic esters has received less attention. Guiles et al.
have observed that Suzuki coupling reactions with resin-
bound boronates proceed at lower rates and in poorer
yields than for the alternate orientation.4c The phenyl-
the â-lactam boronic acid was obtained in only 80% purity
due to incomplete cycloaddition reaction.11 By switching
from a polystyrene resin to a poly(ethylene glycol)-grafted
resin (ArgoGel-MB-OH), the desired boronic acid 1c was
obtained with >95% purity.
The results of coupling the ArgoGel-bound boronic acid
1c with iodobenzene using our above-mentioned Suzuki
coupling conditions resulted in only 30% conversion to
the desired biaryl â-lactam 2a (see Table 3).
It was found that addition of water to the reaction
medium was critical for driving the reaction to comple-
tion. When {PdCl2(dppf)} plus TEA (10 equiv) was
(10) For the formation of the phenyl boronic acid imine the use of 4
Å molecular sieves as a dehydrating agent was preferred to use of
trimethyl orthoformate, which resulted in incomplete imine formation.

Solid-Phase Synthesis of 4-Arylazetidin-2-ones
J . Org. Chem., Vol. 62, No. 22, 1997 7823
Ta ble 3. Su zu k i Cr oss-Cou p lin g Rea ction of 1c w ith a
Va r iety of Ar yl Iod id es
including {Pd(OAc)2}/PPh3/K2CO3 or {Pd(OAc)2}/P(o-tol)3/
TEA, were found to be ineffective here. The use of
{PdCl2(dppf)} in Heck reactions has previously only been
reported once in the context of an intramolecular cycliza-
tion.14
In conclusion, this report illustrates the use of a single
catalyst system, {PdCl2(dppf)}-TEA, to promote C-C
bond formation around a â-lactam template via Suzuki
and Heck cross-coupling reactions. The remarkable
versatility and stability of this catalyst obviates the
requirement for an inert reaction atmosphere, and the
mild coupling conditions simplify and expand the scope
of Pd-catalyzed C-C bond formation and should facilitate
automation of this chemistry. In addition, these reac-
tions should be well suited for the generation of combi-
natorial libraries of diversely substituted 4-aryl â-lactams
as well as other aryl templates.
X-C6H4I
X
conversion
entry
catalyst systema
product (%yield)b
1
2
3
4
5
6
H
H
H
H
PdCl2(dppf)-TEA-DMF
2a
2a
2a
2a
2b
2e
30
60
100 (86)
100 (86)
100 (60)
100 (72)
PdCl2(dppf)-TEA-DMF, 10% H2O
PdCl2(dppf)-TEA-DMF, 30% H2O
Pd(PPh3)4-K2CO3-DMF, 10% H2O
4-OMe PdCl2(dppf)-TEA-DMF, 30% H2O
3-NO2 PdCl2(dppf)-TEA-DMF, 30% H2O
a
Reactions were carried out at 40 °C in DMF or DMF/H2O for
12-24 h using a mixture of 1c, phenyl iodide (10 equiv), catalyst
b
(20 mol %), and TEA (10 equiv). Isolated yields calculated as
described in Table 1.
employed as catalyst in a 3/7 mixture (v/v) of H2O:DMF
at 40 °C without exclusion of air, the biaryl â-lactam 2a
was obtained in excellent yield. In contrast to biaryl
couplings with the immobilized aryl iodide, it was found
that in these reverse couplings, the nature of the solid
support had a dramatic effect on the coupling yields. By
using a polystyrene resin like Wang or Sasrin, the
coupling of boronic acid 1c proceeded with only 60%
conversion. It is possible that the presence of water
deactivates these polystyrene resins by decreasing their
swelling properties. The scope of the Suzuki coupling of
1c using the above conditions was examined by using
phenyl iodides substituted with electron-donating and
electron-withdrawing groups. These results (Table 3)
show that biaryl couplings with an immobilized boronic
acid proceed in good yields and with similar efficiency to
the couplings with immobilized aryl iodides. The utility
of this “boronic down” strategy should be further en-
hanced by the direct conversion of resin-bound aryl
halides into boronate esters using Miyaura’s reagent as
described in two recent reports.12a,b
Exp er im en ta l Section
Gen er a l. Reagents were purchased from Aldrich, P&B,
Lancaster, Bachem Bioscience, and Argonaut and were used
as received, unless otherwise noted. All reactions carried out
at room temperature were conducted in standard peptide
vessels placed on a shaker. Reactions performed at elevated
temperature were conducted in glass vials using a heat block
placed on a shaker. 1H and 13C NMR spectra were measured
in the indicated solvent with tetramethylsilane as internal
reference. Mass spectra were obtained with either ESI or FAB
as the ionization method. Analytical HPLC was performed
on a Beckman Gold Analytic 126 apparatus with a diode array
detector model 168 equipped with a Econosphere C-18 reversed-
phase column. Detection was performed by UV monitoring
at λ ) 220 nm and λ ) 280 nm. Semipreparative chromatog-
raphy was performed on a Beckman 110B apparatus equipped
with a Waters RCM (25 × 10 cm) C-18 reversed-phase column
monitoring at λ ) 220 nm.
Encouraged by finding that one catalyst system, {PdCl2-
(dppf)}-TEA, can be used for Suzuki biaryl coupling with
either resin-bound halides or boronic acids, we were
interested in extending the use of this catalyst to the
vinylation of aryl iodide 1a .
cis-1-((S)-1-Ca r b oxyet h yl)-3-p h en oxy-4-(4′-iod op h en -
yl)a zetid in -2-on e (1a ). Sasrin resin preloaded with N-Fmoc-
alanine (0.24 mmol, i.e., 0.4 g of resin, loading 0.6 mmol/g)
was treated with a solution of 30% piperidine in DMF for 45
min to remove the Fmoc protecting group. The resin was
rinsed with DMF, CH2Cl2, MeOH, and Et2O and dried under
reduced pressure. The resin was suspended in 8 mL of a 1:1
mixture of CH2Cl2 and trimethyl orthoformate, and 4-iodo-
benzaldehyde (0.55 g, 10 equiv) was added. After shaking for
4 h, the resin was rinsed with DMF, CH2Cl2, MeOH, and Et2O
and dried under reduced pressure. The resin was transferred
to a glass vial, suspended in CH2Cl2 (4 mL), and cooled at 0
°C. To the suspension was added triethylamine (0.68 mL, 20
equiv), followed by a slow addition of phenoxyacetyl chloride
(0.5 mL, 15 equiv). The resulting slurry was left at 0 °C for 5
min and stirred overnight at room temperature. The resin
was filtered, rinsed with DMF, CH2Cl2, MeOH, and Et2O, and
dried under reduced pressure. The product was cleaved from
the support by treating 50 mg of the resin with a solution of
3% (v/v) of TFA/CH2Cl2 for 45 min. After filtration and
removal of the solvent, the residue was purified by preparative
HPLC to give the title compound (12 mg, 95%) as a gum (1.2:1
mixture of cis diastereoisomers): MS (ESI) m/z 438 (M + H+);
HRMS (FAB) m/z calcd for C18H17INO4 (M + H+) 438.0202,
found 438.0203.
The Heck reaction is a very useful process for preparing
disubstituted olefins,13 and by applying it to our â-lactam
system we further increase the potential for preparing
diversely functionalized 4-aryl â-lactams. By coupling
the resin-bound iodide 1a with ethyl acrylate at 40 °C,
in the presence of 20 mol % {PdCl2(dppf)} in a 9/1 mixture
(v/v) of DMF:H2O containing TEA (10 equiv) and tet-
rabutylammonium iodide (TBAI, 2 equiv), the styryl
â-lactam derivative 3a was obtained in 90% yield after
purification by preparative HPLC (Scheme 2). This
method was found to work well with a variety of vinyl
derivatives including acrylonitrile and acrylamides to
afford highly functionalized 4-styryl â-lactams. Other
catalyst systems commonly used in Heck reactions,
(11) With Sasrin and Wang resins the desired â-lactam was
contaminated with a byproduct that was characterized as 4. Running
the reaction under more stringent conditions (rigorously dried reagents
and vessels, plus elevated temperature for the imine formation) did
not prevent its formation. Compound 4 was isolated by semipreparative
HPLC and analyzed by 1H NMR (300 MHz, acetone-d6) δ: 7.28-7.22
(m, 3H), 6.98-6.88 (m, 2H), 4.5 (q, J ) 7.3 Hz, 1H), 4.4 (s, 2H), 1.4 (d,
J ) 7.3 Hz, 3H).
Major isomer: 1H NMR (300 MHz, CDCl3) δ: 7.70-7.60 (m,
2H), 7.20-7.10 (m, 4H), 6.94 (t, J ) 7.5 Hz, 1H), 6.75 (d, J )
8.0 Hz, 2H), 5.52 (d, J ) 4.7 Hz, 1H), 5.20 (d, J ) 4.7 Hz, 1H),
4.72 (q, J ) 7.5 Hz, 1H), 1.22 (d, J ) 7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ: 176.4, 168.5, 158.2, 139.1, 139.0 (2C),
135.6, 132.2, 130.9 (2C), 123.9, 117.1 (2C), 96.4, 82.9, 63.5, 51.5,
17.4.
Minor isomer: 1H NMR (300 MHz, CDCl3) δ: 7.70-7.60 (m,
2H), 7.20-7.10 (m, 4H), 6.94 (t, J ) 7.5 Hz, 1H), 6.75 (d, J )
8.0 Hz, 2H), 5.48 (d, J ) 4.7 Hz, 1H), 5.02 (d, J ) 4.7 Hz, 1H),
(12) (a) Piettre, S.; Baltzer, S. Tetrahedron Lett. 1997, 38, 1197-
1200. (b) Brown S. D.; Armstrong R. W. J . Am. Chem. Soc. 1996, 118,
6331-6332.
(14) Brown, J . M.; Perez-Torrente, J .; Alcock, N. A.; Clase, H. J .
Organometallics 1995, 14, 207-213.
(13) Heck, R. F. Org. React. 1982, 27, 345-390.

7824 J . Org. Chem., Vol. 62, No. 22, 1997
Ruhland et al.
4.05 (q, J ) 7.5 Hz, 1H), 1.73 (d, J ) 7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ: 176.1, 168.5, 158.2, 139.1, 139.0 (2C),
135.6, 132.1, 130.9 (2C), 123.9, 117.1 (2C), 96.4, 83.0, 64.1, 53.3,
16.9.
Cl2, respectively. After removal of residual traces of catalyst
by quick filtration through a 200 mg silica bed with ethyl
acetate, the residue was purified by preparative HPLC to give
the title compound (10.5 mg, 89%) as a white solid (1.2:1
mixture of cis diastereoisomers): MS (ESI) m/z 410 (M + Na+);
HRMS (FAB) calcd for C24H22NO4 (M + H+) 388.1549, found
388.1543.
cis-1-((S)-1-Ca r boxyeth yl)-3-p h en oxy-4-(4′-br om op h e-
n yl)a zetid in -2-on e (1b). After following the above procedure
using 4-bromobenzaldehyde, the title compound was obtained
(10.8 mg, 92%) as a white powder (1.2:1 mixture of cis
diastereoisomers): MS (ESI) m/z 390 (M + H+); HRMS (FAB)
calcd for C18H17NBrO4 (M + H+) 390.0341, found 390.0338.
Major isomer: 1H NMR (300 MHz, CDCl3) δ: 7.49-7.41 (m,
2H), 7.36-7.25 (m, 2H), 7.15 (t, J ) 7.7 Hz, 2H), 6.92 (t, J )
7.4 Hz, 1H), 6.74 (d, J ) 7.7 Hz, 2H), 5.52 (d, J ) 4.7 Hz, 1H),
5.22 (d, J ) 4.7 Hz, 1H), 4.70 (q, J ) 7.5 Hz, 1H), 1.20 (d, J )
7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ: 176.5, 168.6, 158.2,
134.9, 133.1 (2C), 132.04 (2C), 130.9 (2C), 124.6, 123.9, 117.1
(2C), 82.8, 63.4, 51.5, 17.4.
Minor isomer: 1H NMR (300 MHz, CDCl3) δ: 7.49-7.41 (m,
2H), 7.36-7.25 (m, 2H), 7.15 (t, J ) 7.7 Hz, 2H), 6.92 (t, J )
7.4 Hz, 1H), 6.74 (d, J ) 7.7 Hz, 2H), 5.22 (d, 1H, J ) 4.7 Hz),
5.02 (d, J ) 4.7 Hz, 1H), 4.02 (q, J ) 7.5 Hz, 1H), 1.71 (d, J )
7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ: 176.2, 167.8, 158.2,
133.5, 133.1 (2C), 131.9 (2C), 130.9 (2C), 124.7, 123.9, 117.1
(2C), 82.9, 63.9, 53.3, 16.9.
Major isomer: 1H NMR (300 MHz, CDCl3) δ: 7.65-7.32 (m,
9H), 7.15 (t, J ) 7.7 Hz, 2H), 6.91 (t, J ) 7.3 Hz, 1H), 6.78 (d,
J ) 7.4 Hz, 2H), 5.57 (d, J ) 4.5 Hz, 1H), 5.30 (d, J ) 4.5 Hz,
1H), 4.77 (q, J ) 7.5 Hz, 1H), 1.28 (d, J ) 7.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ: 176.3, 168.7, 158.4, 143.1, 141.9,
134.6, 130.8 (2C), 130.7 (2C), 130.4 (2C), 129.1, 128.6 (2C),
128.4 (2C), 123.7, 117.2 (2C), 83.2, 63.8, 51.4, 17.5.
Minor isomer: 1H NMR (300 MHz, CDCl3) δ: 7.65-7.32 (m,
9H), 7.15 (t, J ) 7.7 Hz, 2H), 6.91 (t, J ) 7.3 Hz, 1H), 6.78 (d,
J ) 7.4 Hz, 2H), 5.52 (d, J ) 4.5 Hz, 1H), 5.12 (d, J ) 4.5 Hz,
1H), 4.05 (q, J ) 7.5 Hz, 1H), 1.79 (d, J ) 7.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ: 175.9, 168.0, 158.4, 143.3, 141.9,
133.3, 130.8 (2C), 130.7 (2C), 130.4 (2C), 129.1, 128.6 (2C),
128.4 (2C), 123.7, 117.2 (2C), 83.3, 64.4, 53.3, 17.0.
cis-1-((S)-1-Ca r boxyeth yl)-3-p h en oxy-4-(4′′-m eth oxy-4′-
bip h en yl)a zetid in -2-on e (2b). After following the above
procedure using 4-methoxyphenylboronic acid, the title com-
pound was obtained (10.0 mg, 80%) as a white powder (1.2:1
mixture of cis diastereoisomers): MS (ESI) m/z 418 (M + H+);
HRMS (FAB) calcd for C25H24NO5 (M + H+) 418.1654, found:
418.1648.
cis-1-((S)-1-Ca r boxyeth yl)-3-p h en oxy-4-(4′-bor on op h e-
n yl)a zetid in -2-on e (1c). ArgoGel-MB-OH resin loaded with
N-Fmoc-alanine (0.11 mmol, i.e., 0.3 g of resin, loading 0.37
mmol/g) was treated with a solution of 30% piperidine in DMF
for 45 min to remove the Fmoc protecting group. The resin
was rinsed with DMF, CH2Cl2, MeOH and Et2O and dried
under reduced pressure. The resin was suspended in DMF (4
mL), and 4-formylbenzeneboronic acid (0.17 g, 10 equiv) was
added. After stirring for 16 h at 40 °C in the presence of 4 Å
molecular sieves, the reaction was transferred to an Alltech
filter to remove the molecular sieves which remain at the
bottom of the reaction vessel. The resin was rinsed with DMF
and CH2Cl2, transferred to a glass vial, suspended in CH2Cl2
(5 mL), and cooled to 0 °C. To the suspension was added TEA
(0.17 mL, 12 equiv) followed by a slow addition of phenoxy-
acetyl chloride (0.14 mL, 10 equiv). The resulting slurry was
left at 0 °C for 5 min and stirred overnight at room temper-
ature. The resin was filtered, rinsed with DMF and CH2Cl2,
and dried under reduced pressure. The product was cleaved
from the support by treating 50 mg of the resin with a solution
of 5% (v/v) of TFA/CH2Cl2 for 45 min. After filtration and
removal of the solvent, the residue was purified by preparative
HPLC to give the title compound (6 mg, 92%) as a white solid
(1.2:1 mixture of cis diastereoisomers): MS (ESI) m/z 356 (M
+ H+).
Major isomer: 1H NMR (300 MHz, CDCl3) δ: 7.55-7.42 (m,
6H), 7.15 (t, J ) 8.7 Hz, 2H), 6.98 (d, J ) 8.7 Hz, 2H), 6.89 (t,
J ) 7.2 Hz, 1H), 6.78 (d, J ) 7.7 Hz, 2H), 5.55 (d, J ) 4.5 Hz,
1H), 5.28 (d, J ) 4.5 Hz, 1H), 4.72 (q, J ) 7.5 Hz, 1H), 3.82 (s,
3H), 1.27 (d, J ) 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δSPCLN 176.2, 168.6, 160.9, 158.5, 142.7, 134.4, 132.6, 130.8
(3C), 130.7 (2C), 129.6 (2C), 127.9, 123.7, 117.2 (2C), 115.8 (2C),
83.2, 63.8, 56.9, 51.5, 17.5.
Minor isomer: 1H NMR (300 MHz, CDCl3) δ: 7.55-7.42 (m,
6H), 7.15 (t, J ) 8.7 Hz, 2H), 6.98 (d, J ) 8.7 Hz, 2H), 6.89 (t,
J ) 7.2 Hz, 1H), 6.78 (d, J ) 7.7 Hz, 2H), 5.51 (d, J ) 4.5 Hz,
1H), 5.09 (d, J ) 4.5 Hz, 1H), 4.07 (q, J ) 7.5 Hz, 1H), 3.82 (s,
3H), 1.78 (d, J ) 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ:
175.8, 167.9, 160.9, 158.5, 142.9, 134.0, 132.6, 130.8 (3C), 130.7
(2C), 129.6 (2C), 128.1, 123.7, 117.2 (2C), 115.8 (2C), 83.2, 64.4,
56.9, 53.3, 17.0.
cis-1-((S)-1-Ca r boxyeth yl)-3-p h en oxy-4-(3′′-m eth oxy-4′-
bip h en yl)a zetid in -2-on e (2c). After following the above
procedure using 3-methoxyphenylboronic acid the title com-
pound was obtained (9.0 mg, 72%) as a beige powder (1.2:1
mixture of cis diastereoisomers): MS (ESI) m/z 418 (M + H+);
HRMS (FAB) calcd for C25H24NO5 (M + H+) 418.1654, found
418.1656.
Major isomer: 1H NMR (300 MHz, acetone-d6) δ: 7.78 (d, J
) 8.1 Hz, 2H), 7.48 (t, J ) 8.1 Hz, 2H), 7.08-7.21 (m, 2H),
6.78-6.88 (m, 3H), 5.60 (d, J ) 4.7 Hz, 1H), 5.39 (d, J ) 4.7
Major isomer: 1H NMR (300 MHz, CDCl3) δ: 7.59-7.42 (m,
4H), 7.35 (t, J ) 8.0 Hz, 1H), 7.21-7.05 (m, 4H), 6.92 (d, J )
7.6 Hz, 2H), 6.75 (d, J ) 7.6 Hz, 2H), 5.56 (d, J ) 4.0 Hz, 1H),
5.30 (d, J ) 4.0 Hz, 1H), 4.75 (q, J ) 7.4 Hz, 1H), 3.86 (s, 3H),
1.26 (d, J ) 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ: 176.6,
168.9, 161.5, 158.4, 143.4, 143.0, 134.7, 131.4, 130.9 (3C), 130.7
(2C), 128.5 (2C), 123.8, 121.1, 117.2, 114.5, 114.4, 83.0, 63.9,
56.9, 51.6, 17.4.
Hz, 1H), 4.58 (q, J ) 7.3 Hz, 1H), 1.18 (d, J ) 7.3 Hz, 3H); 13
C
NMR (75 MHz, acetone-d6) δ: 173.6, 167.9, 159.5, 139.8, 136.1,
136.09 (2C), 131.5 (2C), 130.3 (2C), 123.9, 117.6 (2C), 83.9,
64.2, 52.2, 17.7.
Minor isomer: 1H NMR (300 MHz, acetone-d6) δ: 7.78 (d,
J ) 8.1 Hz, 2H), 7.48 (t, J ) 8.1 Hz, 2H), 7.08-7.21 (m, 2H),
6.78-6.88 (m, 3H), 5.58 (d, J ) 4.7 Hz, 1H), 5.27 (d, J ) 4.7
Minor isomer: 1H NMR (300 MHz, CDCl3) δ: 7.59-7.42 (m,
4H), 7.35 (t, J ) 8.0 Hz, 1H), 7.21-7.05 (m, 4H), 6.92 (d, J )
7.6 Hz, 2H), 6.75 (d, J ) 7.6 Hz, 2H), 5.53 (d, J ) 4.0 Hz, 1H),
5.12 (d, J ) 4.0 Hz, 1H), 4.05 (q, J ) 7.4 Hz, 1H), 3.86 (s, 3H),
1.78 (d, J ) 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ: 176.3,
168.2, 161.5, 158.4, 143.4, 143.2, 133.4, 131.4, 130.9 (3C), 130.7
(2C), 128.6, 128.5, 123.8, 121.1, 117.2, 114.5, 114.4, 83.1, 64.5,
56.9, 51.6, 17.0.
Hz, 1H), 4.08 (q, J ) 7.3 Hz, 1H), 1.67 (d, J ) 7.3 Hz, 3H); 13
C
NMR (75 MHz, acetone-d6)) δ: 173.4, 167.6, 159.5, 138.6,
136.1, 136.0 (2C), 131.5 (2C), 130.3 (2C), 124.0, 117.6 (2C),
84.0, 64.7, 53.8, 17.3.
Gen er a l Meth od for Su zu k i Cr oss-Cou p lin g Rea ction
of Resin -Bou n d Ha lid e. cis-1-((S)-1-Ca r boxyeth yl)-3-
p h en oxy-4-(4′-bip h en yl)a zetid in -2-on e (2a ). Resin-bound
cis-1-((S)-1-carboxyethyl)-3-phenoxy-4-(4′-iodophenyl)azetidin-
2-one (1a ) (200 mg, loading 0.6 mmol/g) was swollen in DMF
(3 mL), and the suspension was flushed with argon for 5 min.
To this slurry were added phenylboronic acid (0.06 g, 4 equiv),
{PdCl2(dppf)} (0.02 g, 20 mol %), and triethylamine (1.7 mL,
10 equiv). The resulting mixture was heated at 65 °C
overnight. After cooling to 23 °C, the resin was filtered, rinsed
with DMF, CH2Cl2, and Et2O, and dried under reduced
pressure. The product was cleaved from the support by
treating 50 mg of the resin (Sasrin or Wang) for 45 min with
a solution of 5% (v/v) of TFA/CH2Cl2 or 50% (v/v) TFA/CH2-
cis-1-((S)-1-Ca r boxyeth yl)-3-p h en oxy-4-(2′′-m eth oxy-4′-
bip h en yl)a zetid in -2-on e (2d ). After following the above
procedure using 2-methoxyphenylboronic acid, the title com-
pound was obtained (8.2 mg, 65%) as a beige powder (1.2:1
mixture of cis diastereoisomers): MS (ESI) m/z 418 (M + H+);
HRMS (FAB) calcd for C25H24NO5 (M + H+) 418.1654, found
418.1653.
Major isomer: 1H NMR (300 MHz, CDCl3) δ: 7.52-7.38 (m,
4H), 7.38-7.22 (m, 2H), 7.13 (t, J ) 7.4 Hz, 2H), 7.08-6.92
(m, 2H), 6.90 (t, J ) 7.4 Hz, 1H), 6.76 (d, J ) 4.0 Hz, 2H),

Solid-Phase Synthesis of 4-Arylazetidin-2-ones
J . Org. Chem., Vol. 62, No. 22, 1997 7825
5.55 (d, J ) 4.6 Hz, 1H), 5.27 (d, J ) 4.6 Hz, 1H), 4.73 (q, J )
7.5 Hz, 1H), 3.76 (s, 3H), 1.28 (d, J ) 7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ: 176.6, 169.0, 158.5, 158.0, 140.6, 134.0,
132.4 (2C), 131.5, 131.0, 130.8 (3C), 130.4, 129.9 (2C), 123.7,
122.5, 117.4, 113.1, 83.1, 64.0, 57.2, 51.7, 17.4.
134.9, 133.4, 131.0, 130.9 (2C), 129.7, 127.1 (2C), 126.7, 125.1,
123.8, 117.1 (2C), 83.3, 64.4, 53.3, 17.0.
Gen er a l Meth od for Su zu k i Cr oss-Cou p lin g Rea ction
of Resin -Bou n d Bor on ic Acid 1c. cis-1-((S)-1-Ca r boxy-
eth yl)-3-p h en oxy-4-(3′′-n itr o-4′-bip h en yl)a zetid in -2-on e
(2e). ArgoGel-MB-OH-bound cis-1-((S)-1-Carboxyethyl)-3-phe-
noxy-4-(4′-bororophenyl)azetidin-2-one (1c) (0.16 g, loading
0.37 mmol/g) was swollen in a mixture of DMF (2 mL) and
water (0.6 mL). To this slurry was added 3-nitrophenyl iodide
(0.06 g, 4 equiv), {PdCl2(dppf)} (0.01 g, 20 mol %), and TEA
(84 µL, 10 equiv). The resulting mixture was heated at 40 °C
overnight. After cooling to room temperature, the solvent was
drained off, and the beads were washed with DMF, CH2Cl2,
MeOH, and Et2O and dried under reduced pressure. The
product was cleaved by treating the resin with 5% (v/v) TFA/
CH2Cl2 for 45 min. After removal of residual traces of catalyst
by quick filtration through a 200 mg silica bed with ethyl
acetate, the residue was concentrated under reduced pressure
and purified by preparative HPLC to give the title compound
(22.7 mg, 89%) as a white powder (1.2:1 mixture of cis
diastereoisomers).
Gen er a l Meth od for Heck Cou p lin g Rea ction of Resin -
bou n d Iod id e 1a . cis-1-((S)-1-Ca r boxyeth yl)-3-p h en oxy-
4-(4′-(tr a n s-2′′-(eth oxyca r bon yl)vin yl)p h en yl)a zetid in -2-
on e (3a ). Sasrin-bound cis-1-((S)-2-propionic acid)-3-phenoxy-
4-(4′-iodophenyl)azetidin-2-one (1a ) (45 mg, initial loading 0.6
mmol/g) was swollen in a mixture of DMF/H2O/TEA (360/40/
40 µL). To this slurry were added ethyl acrylate (30 µL, 10
equiv), {PdCl2(dppf)} (0.02 g, 20 mol %), and tetrabutylam-
monium iodide (0.02 g, 2 equiv). The resulting mixture was
heated at 40 °C overnight. After cooling to room temperature,
the solvent was drained off, and the beads were washed with
DMF, CH2Cl2, MeOH, and Et2O and dried under reduced
pressure. The product was cleaved from resin by treatment
with 3% (v/v) (for Sasrin) or 10% (v/v) (for ArgoGel-MB-OH)
TFA/CH2Cl2 for 45 min. After removal of residual traces of
catalyst by quick filtration through a 200 mg silica bed with
ethyl acetate, the filtrate was concentrated under reduced
pressure, and the residue purified by preparative HPLC to give
the title compound (10.0 mg, 90%) as an orange gum (1.2:1
mixture of cis diastereoisomers): MS (ESI) m/z 410 (M + H+);
HRMS calcd for C23H24NO6: 410.1600 (M + H+), found:
410.1609.
Major isomer: 1H NMR (300 MHz, CDCl3) δ: 7.6 (d, J )
16.0 Hz, 1H), 7.4 (s, 4H), 7.1 (t, 2H, J ) 7.6 Hz), 6.9 (t, 1H, J
) 7.4 Hz), 6.7 (d, 2H, J ) 7.7 Hz), 6.4 (d, 1H, J ) 16.0 Hz),
5.54 (br s, 1H), 5.3 (br s, 1H), 4.7 (q, 1H, J ) 7.4 Hz), 4.25 (q,
2H, J ) 7.1 Hz), 1.75 (d, 3H, J ) 7.4 Hz), 1.2 (t, 3H, J ) 7.1
Hz); 13C NMR (75 MHz, CDCl3) δ: 175.6, 168.5, 168.4, 158.2,
145.4, 138.2, 136.5, 130.9 (4C), 129.4 (2C), 123.8, 120.5, 117.1,
83.1, 63.6, 62.2, 41.8, 17.5, 15.9.
Minor isomer: 1H NMR (300 MHz, CDCl3) δ: 7.6 (d, 1H, J
) 16.0 Hz), 7.4 (s, 4H), 7.1 (t, 2H, J ) 7.6 Hz), 6.9 (t, 1H, J )
7.4 Hz), 6.7 (d, 2H, J ) 7.7 Hz), 6.4 (d, 1H, J ) 16.0 Hz), 5.5
(br s, 1H), 5.01 (br s, 1H), 4.25 (q, 2H, J ) 7.1 Hz), 4.05 (q,
1H, J ) 7.4 Hz), 1.75 (d, 3H, J ) 7.4 Hz), 1.3 (t, 2H, J ) 7.1
Hz); 13C NMR (75 MHz, CDCl3) δ: 175.2, 168.5, 167.7, 158.2,
145.4, 136.7, 136.6, 130.8 (4C), 129.5 (2C), 123.8, 120.4, 117.1,
83.2, 64.2, 62.2, 41.8, 17.1, 15.9.
cis-1-((S)-1-Ca r boxyeth yl)-3-p h en oxy-4-(4′-(tr a n s-2′′-cy-
a n ovin yl)p h en yl)a zetid in -2-on e (3b). After following the
above procedure using ArgoGel-MB-OH-bound 1a (0.68 mmol/
g) and acrylonitrile, the title compound was obtained (17 mg,
71%) as a white powder (1.2:1 mixture of cis diastereoiso-
mers): MS (ESI) m/z 363 (M + H+); HRMS calcd for
C21H18N2O4: 363.1345 (M + H+), found: 363.1339.
Minor isomer: 1H NMR (300 MHz, CDCl3) δ: 7.52-7.38 (m,
4H), 7.38-7.22 (m, 2H), 7.13 (t, J ) 7.4 Hz, 2H), 7.08-6.92
(m, 2H), 6.90 (t, J ) 7.4 Hz, 1H), 6.76 (d, J ) 4.0 Hz, 2H),
5.51 (d, J ) 4.6 Hz, 1H), 5.08 (d, J ) 4.6 Hz, 1H), 4.03 (q, J )
7.5 Hz, 1H), 3.77 (s, 3H), 1.80 (d, J ) 7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ: 176.4, 168.3, 158.45, 158.0, 140.7, 132.7,
132.4 (2C), 131.5, 131.0, 130.80 (3C), 130.5, 129.8 (2C), 123.7,
122.5, 117.4, 113.1, 83.3, 64.6, 57.2, 53.6, 17.4.
cis-1-((S)-1-Ca r boxyeth yl)-3-p h en oxy-4-(3′′-n itr o-4′-bi-
p h en yl)a zetid in -2-on e (2e). After following the above pro-
cedure using 3-nitrophenylboronic acid, the title compound was
obtained (10.0 mg, 77%) as a white powder (1.2:1 mixture of
cis diastereoisomers): MS (ESI) m/z 433 (M + H+); HRMS
(FAB) calcd for C24H21N2O6 (M + H+) 433.1400, found 433.1397.
Major isomer: 1H NMR (300 MHz, CDCl3) δ: 8.41 (s, 1H),
8.21 (d, J ) 7.8 Hz, 1H), 7.90 (d, J ) 7.5 Hz, 1H), 7.63-7.52
(m, 5H), 7.15 (t, J ) 8.0 Hz, 2H), 6.90 (t, J ) 7.0 Hz, 1H), 6.77
(d, J ) 7.6 Hz, 2H), 5.58 (d, J ) 4.8 Hz, 1H), 5.33 (d, J ) 4.8
Hz, 1H), 4.75 (q, J ) 7.3 Hz, 1H), 1.27 (d, J ) 7.3 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) δ: 176.2, 168.7, 158.3, 150.3, 143.6,
140.6, 136.2, 134.5, 131.4, 131.2, 131.1, 130.9 (2C), 128.5, 123.8
(2C), 123.5 (2C), 171.1 (2C), 83.1, 63.7, 51.6, 17.5.
Minor isomer: 1H NMR (300 MHz, CDCl3) δ: 8.41 (s, 1H),
8.21 (d, J ) 7.8 Hz, 1H), 7.90 (d, J ) 7.5 Hz, 1H), 7.63-7.52
(m, 5H), 7.15 (t, J ) 8.0 Hz, 2H), 6.90 (t, J ) 7.0 Hz, 1H), 6.77
(d, J ) 7.6 Hz, 2H), 5.54 (d, J ) 4.8 Hz, 1H), 5.14 (d, J ) 4.8
Hz, 1H), 4.11 (q, J ) 7.3 Hz, 1H), 1.78 (d, J ) 7.3 Hz, 3H); 13
C
NMR (75 Mhz, CDCl3) δ: 175.9, 167.9, 158.3, 150.3, 143.6,
140.8, 136.2, 134.9, 131.4, 131.2, 131.1, 130.9 (2C), 128.7, 123.8
(2C), 123.5 (2C), 171.1 (2C), 83.1, 64.3, 53.4, 16.9.
cis-1-((S)-1-Ca r boxyeth yl)-3-p h en oxy-4-(3′′-a ceta m id o-
4′-bip h en yl)a zetid in -2-on e (2f). After following the above
procedure using 3-acetamidophenylboronic acid, the title
compound was obtained (9.4 mg, 70%) as a white powder (1.2:1
mixture of cis diastereoisomers): MS (ESI) m/z 445 (M + H+);
HRMS (FAB) calcd for C26H25N2O5 (M + H+) 445.1763, found
445.1756.
Major isomer: 1H NMR (300 MHz, CDCl3) δ: 7.73 (s, 1H),
7.58-7.28 (m, 8H), 7.13 (t, J ) 8 Hz, 2H), 6.89 (t, J ) 7 Hz,
1H), 6.75 (d, J ) 7.5 Hz, 2H), 5.55 (d, J ) 4.5 Hz, 1H), 5.28 (d,
J ) 4.5 Hz, 1H), 4.69 (q, J ) 7.4 Hz, 1H), 2.23 (s, 3H), 1.25 (d,
J ) 7.4 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ: 173.2, 169.8,
166.7, 166.4, 157.8, 141.3, 141.2, 135.7, 134.7,130.6 (7C), 127.3,
122.6, 118.5, 116.5 (2C), 82.3, 62.3, 51.3, 25.5, 17.0.
Minor isomer: 1H NMR (300 MHz, CDCl3) δ: 7.65 (s, 1H),
7.58-7.28 (m, 8H), 7.13 (t, J ) 8 Hz, 2H), 6.89 (t, J ) 7 Hz,
1H), 6.75 (d, J ) 7.5 Hz, 2H), 5.51 (d, J ) 4.5 Hz, 1H), 5.11 (d,
J ) 4.5 Hz, 1H), 4.23 (q, J ) 7.4 Hz, 1H), 2.22 (s, 3H), 1.68 (d,
J ) 7.4 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ: 173.05,
169.8, 166.7, 166.4, 157.8, 141.4, 141.2, 141.1, 135.7, 134.6,
130.6 (7C), 127.3, 123.0, 119.5, 118.5, 116.5 (2C), 82.3, 62.7,
52.5, 25.4, 16.6.
cis-1-((S)-1-Ca r boxyeth yl)-3-p h en oxy-4-(2′′-th iop h en e-
yl-4′-bip h en yl)a zet id in -2-on e (2g). After following the
above procedure using 2-thienylboronic acid the title compound
was obtained (9.8 mg, 83%) as a white powder (1.2:1 mixture
of cis diastereoisomers): MS (ESI) m/z 394 (M + H+); HRMS
calcd for C22H20NO4S (M + H+) 394.1113, found: 394.1117.
Major isomer: 1H NMR (300 MHz, CDCl3) δ: 7.62-7.51 (m,
2H), 7.38-7.50 (m, 2H), 7.37-7.22 (m, 2H), 7.15 (t, J ) 7.7
Hz, 2H), 7.08-7.02 (m, 1H), 6.91 (t, J ) 7.3 Hz, 1H), 6.78 (d,
J ) 8.2 Hz, 2H), 5.55 (d, J ) 4.0 Hz, 1H), 5.26 (d, J ) 4.0 Hz,
1H), 4.74 (q, J ) 7.5 Hz, 1H), 1.25 (d, J ) 7.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ: 176.6, 168.7, 158.4, 145.1, 136.4,
134.9, 133.4, 130.9, 131.0 (2C), 129.7, 127.3 (2C), 126.8, 125.0,
123.8, 117.1 (2C), 83.1, 63.8, 51.5, 17.4.
Major isomer: 1H NMR (300 MHz, CDCl3) δ: 7.77-7.31 (m,
4H), 7.43 (d, J ) 16.6 Hz, 1H), 7.16-7.10 (m, 2H), 6.89 (t, J )
7.4 Hz, 1H), 6.74-6.70 (m, 2H), 5.86 (d, J ) 16.5 Hz, 1H), 5.55
(d, J ) 4.7 Hz, 1H), 5.27 (d, J ) 4.7 Hz, 1H), 4.72 (q, J ) 7.4
Hz, 1H), 1.72 (d, J ) 7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ: 172.3, 167.0, 166.3, 156.7, 150.2, 138.2, 136.8, 129.5 (2C),
129.4 (2C), 127.3, 122.3, 118.2, 115.4 (2C), 96.8, 81.6, 61.9, 50.2,
16.0.
Minor isomer: 1H NMR (300 MHz, CDCl3) δ: 7.77-7.31 (m,
4H), 7.41 (d, J ) 15.6 Hz, 1H), 7.16-7.10 (m, 2H), 6.89 (t, J )
7.41 Hz, 1H), 6.74-6.70 (m, 2H), 5.85 (d, J ) 16.8 Hz, 1H),
Minor isomer: 1H NMR (300 MHz, CDCl3) δ: 7.62-7.51 (m,
2H), 7.38-7.50 (m, 2H), 7.37-7.22 (m, 2H), 7.15 (t, J ) 7.7
Hz, 2H), 7.08-7.02 (m, 1H), 6.91 (t, J ) 7.3 Hz, 1H), 6.78 (d,
J ) 8.2 Hz, 2H), 5.50 (d, J ) 4.0 Hz, 1H), 5.05 (d, J ) 4.0 Hz,
1H), 4.05 (q, J ) 7.5 Hz, 1H), 1.75 (d, J ) 7.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ: 176.4, 167.9, 158.4, 145.1, 136.5,

7826 J . Org. Chem., Vol. 62, No. 22, 1997
Ruhland et al.
5.52 (d, J ) 4.6 Hz, 1H), 5.09 (d, J ) 4.7 Hz, 1H), 4.06 (q, J )
7.4 Hz, 1H), 1.21 (d, J ) 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ: 172.6, 167.1, 167.0, 156.7, 150.2, 137.9, 136.4, 129.5
(2C), 129.4 (2C), 127.4, 122.3, 118.2, 115.2(2C), 96.8, 81.5, 62.6,
52.3, 15.7.
bound 1a (0.103 mmol) and N,N-dimethylacrylamide, the title
compound was obtained (25 mg, 60%) as a white powder (1.2:1
mixture of cis diastereoisomers): MS (ESI) m/z 409 (M + H+);
HRMS calcd for C23H24N2O5: 409.1763 (M + H+), found:
409.1756.
cis-1-((S)-1-Ca r b oxyet h yl)-3-p h en oxy-4-(4′-(tr a n s-2′′-
ca r ba m oylvin yl)p h en yl)a zetid in -2-on e (3c). After follow-
ing the above procedure using ArgoGel-MB-OH-bound 1a
(0.103 mmol) and acrylamide, the title compound was obtained
(25 mg, 64%) as a white powder (1.2:1 mixture of cis diaste-
reoisomers): MS (ESI) m/z 381 (M + H+); HRMS calcd for
C21H20N2O5: 381.1450 (M + H+), found: 381.1455.
Major isomer: 1H NMR (300 MHz, CDCl3) δ: 7.77-7.31 (m,
4H), 7.43 (d, J ) 16.6 Hz, 1H), 7.16-7.10 (m, 2H), 6.89 (t, J )
7.4 Hz, 1H), 6.74-6.70 (m, 2H), 5.86 (d, J ) 16.5 Hz, 1H), 5.55
(d, J ) 4.7 Hz, 1H), 5.27 (d, J ) 4.7 Hz, 1H), 4.72 (q, J ) 7.4
Hz, 1H), 1.72 (d, J ) 7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ: 172.3, 167.0, 166.3, 156.7, 150.2, 138.2, 136.8, 129.5 (2C),
129.4 (2C), 127.3, 122.3, 118.2, 115.4 (2C), 96.8, 81.6, 61.9, 50.2,
16.0.
Major isomer: 1H NMR (300 MHz, CDCl3) δ: 7.58 (d, J )
15.5 Hz, 1H), 7.45-7.37 (m, 4H), 7.12 (t, J ) 7.9 Hz, 2H), 6.87
(t, J ) 7.4 Hz, 1H), 6.82 (d, J ) 15.5 Hz, 1H), 6.72 (d, J ) 7.6
Hz, 1H), 5.51 (d, J ) 4.7 Hz, 1H), 5.28 (d, J ) 4.7 Hz, 1H),
4.02 (q, J ) 7.4 Hz, 1H), 3.17 (s, 3H), 3.07 (s, 3H), 1.69 (d, J
) 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ: 175.0, 170.5,
169.7, 159.7, 144.6, 139.5, 138.4, 132.1 (2C), 131.8 (2C), 130.2
(2C), 124.5, 120.6, 117.8 (2C), (2C), 83.9, 65.0, 53.3, 39.5, 37.8,
17.8.
Minor isomer: 1H NMR (300 MHz, CDCl3) δ: 7.57 (d, J )
15.5 Hz, 1H), 7.45-7.37 (m, 4H), 7.12 (t, J ) 7.9, 2H), 6.87 (t,
J ) 7.4 Hz, 1H), 6.82 (d, J ) 15.5 Hz, 1H), 6.71 (d, J ) 7.6 Hz,
1H), 5.47 (d, J ) 4.6 Hz, 1H), 5.08 (d, J ) 4.6 Hz, 1H), 4.68 (q,
J ) 7.4 Hz, 1H), 3.17 (s, 3H), 3.07 (s, 3H), 1.11 (d, J ) 7.7 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ: 174.8, 170.5, 170.2, 159.6,
144.6, 139.4, 132.2, 132.09 (2C), 131.8 (2C), 130.2 (2C), 124.5,
120.6, 117.8 (2C), 83.8, 65.4, 54.6, 37.8, 39.4, 17.3.
Minor isomer: 1H NMR (300 MHz, CDCl3) δ: 7.77-7.31 (m,
4H), 7.41 (d, J ) 15.6 Hz, 1H), 7.16-7.10 (m, 2H), 6.89 (t, J )
7.4 Hz, 1H), 6.74-6.70 (m, 2H), 5.85 (d, J ) 16.8 Hz, 1H), 5.52
(d, J ) 4.64 Hz, 1H), 5.09 (d, J ) 4.7 Hz, 1H), 4.06 (q, J ) 7.4
Hz, 1H), 1.21 (d, J ) 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ: 172.6, 167.1, 167.0, 156.7, 150.2, 137.9, 136.4, 129.5 (2C),
129.4 (2C), 127.4, 122.3, 118.2, 115.2 (2C), 96.8, 81.5, 62.6, 52.3,
15.7.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR data of
1a -c, 2a -g, 3a -d (14 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
cis-1-((S)-1-Ca r b oxyet h yl)-3-p h en oxy-4-(4′-(tr a n s-2′′-
(d im eth ylca r ba m oyl)vin yl)p h en yl)a zetid in -2-on e (3d ).
After following the above procedure using ArgoGel-MB-OH-
J O9711854