Solid phase β-lactams synthesis using the Staudinger reaction, monitored by 19F NMR spectroscopy

Article abstract of DOI:10.1016/S0040-4020(03)00553-2

We report the use of ¹⁹F NMR as a simple means to monitor reactions on a solid phase. Multi-step sequences including protection, coupling, deprotection, condensation, cycloaddition and cleavage steps are described in the case of multicomponent reactions involving fluorinated α-aminoesters, aldehydes and acid chlorides.

Full text of DOI:10.1016/S0040-4020(03)00553-2

Tetrahedron 59 (2003) 3719–3727
Solid phase b-lactams synthesis using the Staudinger reaction,
monitored by 19F NMR spectroscopy
Isabelle Le Roy,a Dominique Mouysset,a Serge Mignani,b Marc Vuilhorgneb and Lucien Stellaa
,
*
a
´
´
Universite d’Aix-Marseille III, Laboratoire de Chimie Moleculaire Organique, CNRS UMR 6517, 13397 Marseille Cedex 20, France
bAventis Pharma S.A., Centre de Recherche de Paris, 13 Quai Jules Guesde, BP 14, 94403 Vitry sur Seine Cedex, France
Received 9 January 2003; revised 19 March 2003; accepted 3 April 2003
Abstract—We report the use of 19F NMR as a simple means to monitor reactions on a solid phase. Multi-step sequences including
protection, coupling, deprotection, condensation, cycloaddition and cleavage steps are described in the case of multicomponent reactions
involving fluorinated a-aminoesters, aldehydes and acid chlorides. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
or Wang resin; the amine function is transformed into the
corresponding imine moiety by the condensation of an
aldehyde and finally, the fluorine atom is used as an
analytical probe for the recording of NMR spectra. Thus,
each of the chemical products linked to the resin is
characterized by a single 19F NMR-signal while the
respective chemical shift value is related to each chemical
step according to the close group modifications. The 19F
NMR spectroscopy shows the following advantages: great
sensitivity due to the natural abundance of 19F and broad
spreading out of the chemical shift values related to the
strong polarizability of the fluorine atom. Consequently, the
simplicity of the analytical follow-up—both qualitative and
quantitative—allows the rapid development of any new
synthetic step. In addition, such a simple technique is able to
produce a good quality spectrum in a usual NMR tube with
an ordinary NMR instrument. Indeed, the method is entirely
based on the fact that the resolution allows distinguishing
between the different species bond to the resin.
The fast development of Solid-Supported Combinatorial
Chemistry has increased in a spectacular way the com-
plexity and the diversity of reactions using solid support.1–9
This has resulted in a crucial need for non-destructive,
simple and effective analytical methods to control and
optimize such reactions.10,11 Indeed, the classical chroma-
tographic techniques, useful for the study of reactions in
solution, cannot be used as long as the starting materials,
substrates and reagents remain attached to the solid support.
In order to solve the lack of quantitative informations on the
advancement of reactions, and to control the possible
synthetic problems such as unexpected isomerization
reactions or formation of secondary products, it is necessary
to have useful methods, beside classical IR spec-
troscopy,12–16 to analyze the products still anchored to the
resins.
We previously showed that the imines of alkyl glyoxylates
act as good partners for Diels–Alder17–19 and Staudinger
cycloadditions.20 The imine of methyl glyoxylate obtained
from L-threonine, was used successfully in the stereo-
selective synthesis of optically pure b-lactamic-a-amino
esters.21 As part of our program directed towards the
development of the Staudinger reaction on solid-phase, we
considered the use of imines coming from commercially
available fluorinated a-amino-acids. Thus, the three chemi-
cal functions already present in these substrates can be used
for the realization of the following synthetic pathway: the
acid function is used to anchor the substrate on a Merrifield
Manatt and colleagues (1980) were the first to use 19F NMR
to control the advancement of peptide synthesis on
Merrifield resin.22 Starting from this observation, this
technique was used successfully in several studies,23–30
showing undeniable advantages such as save of time, money
and specific instrumentations compared to more sophisti-
cated techniques, such as magic angle spinning,31–36 as well
as presaturation of the signals of the support,37 generally
applied to the common nuclei such as 1H and 13C NMR and
others.38–40 However, the limitation of the simple method is
reached when the chemical shifts difference between the
substrate and the subsequent product (or by-product)
become lower than the resolution. Such limitations, due to
the solid state NMR interaction that broaden lines, could be
overcome if High Resolution Magic Angle Spinning
techniques were used.
Keywords: solid-phase synthesis; 19F NMR spectroscopy; a-amino-esters;
b-lactams; Staudinger cycloaddition.
*
Corresponding author. Tel.: þ33-491-288-231; fax: þ33-491-670-944;
e-mail: lucien.stella@univ.u-3mrs.fr
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00553-2

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I. Le Roy et al. / Tetrahedron 59 (2003) 3719–3727
In this paper we thus report the effectiveness, the simplicity
but the limitations of 19F NMR for the follow-up of a
complete chemical sequence using Merrifield and Wang
resins including the anchoring, deprotection, condensation,
cycloaddition and finally cleavage reactions.
containing 9, made possible the optimization of the amine
deprotection by completely avoiding the hydrazide for-
mation, using 3 equiv. of hydrazine in ethanol, at room
temperature during 48 h. The use of a large excess of
hydrazine led to the formation of 9 whereas a shorter
reaction time, or the use of DMF as solvent, gave only a
partial release of the amine group and consequently led to
the formation of a mixture of resins 5 and 7. The chemical
shift value observed for the hydrazide 9 (2118.8 ppm) is
very close to that of methyl DL-2-fluorophenylglycine ester
21 (2118.9 ppm), showing that the formation of 9 involved
the elimination of the phthaloyl group. On the other hand, in
identical experimental conditions, resin 6 was transformed
into 8 without the release of corresponding hydrazide 10.
Consequently, thereafter, we preferred to start from the
respective N-Boc-protected fluorinated amino acids 11 and
12 (Scheme 3). The anchoring to the Merrifield resin was
carried out in a dioxane/triethylamine mixture, while the
action of trifluoroacetic acid (2£10 min at room tempera-
ture) on resins 13 and 14, totally induced the release of the
amine group.
2. Results and discussion
2.1. Solid-phase synthesis
2.1.1. Protected amino-acid attachment to the solid
support followed by deprotection of the amine function.
ortho-Fluorophenylglycine 1 and para-fluorophenylalanine
2, protected as their respective phthalimide derivatives 3
and 4, were easily linked to Merrifield resin (Scheme 1) via
a classical synthetic method using triethylamine as a base to
give the corresponding supported-compounds 5 and 6.41 In
the following Schemes, we indicate in italic and between
brackets, the observed chemical shift value of the 19F signal
of the considered compound.
The 19F chemical shift values observed for resins 7 and 8,
are very close—or even identical—to those observed in
solution, for their corresponding methyl esters analogues
(methyl ortho fluorophenylglycine ester (21): 2118.9 ppm,
methyl para fluorophenylalanine ester (22): 2116.4 ppm)
respectively.
The chemical reaction follow-up using 19F NMR spec-
troscopy shows that the release of the amine function
leading to resin 7 is not as simple as previously predicted.41
Indeed, the hydrazine which has been used to cleave the
phthalimide group of 5, also leads to formation of
the hydrazide derivative 9 thus cleaving, partially or totally,
the linkage ester of 5 (Scheme 2).
In the case of the Wang resin, the fluorinated a-amino acids
were linked after protection using the Fmoc group. The
The 19F NMR analysis of both 7 and the washed residues
Scheme 1.
Scheme 2.
Scheme 3.

I. Le Roy et al. / Tetrahedron 59 (2003) 3719–3727
3721
Scheme 4.
release of the respective free amine of 17 and 18 resulted
from the action of a solution of 20% piperidine in DMF.
This procedure had to be repeated twice in order to be
quantitative (Scheme 4). Reproducibility of these results has
been confirmed by the systematic analysis of the different
resins.
centered at 2113.4 ppm) whereas in the case of the Wang
resin-bound amine 20, peaks centered at 2115.7 ppm were
observed. Thereafter, we demonstrated that these mixtures
did not allow the Staudinger reaction.
2.1.3. Staudinger reaction and cleavage step. Using the
Merrifield resin-bound imine 24 in dichloromethane, the
cycloaddition was carried out between 2788C and room
temperature by addition of benzyloxyacetyl chloride
(15 equiv.) in the presence of triethylamine (20 equiv.)
(Scheme 6). 19F NMR spectra of resin-bound cycloadduct
31 showed two peaks (2115.9 and 2116.1 ppm) corre-
sponding to the two cis diastereoisomers 30 already
obtained in liquid phase (respectively 2115.9 and
2116 ppm) as described later on. Cleavage of resin 31
using sodium methylate resulted in the two cis b-lactam
derivatives 34 with a 67:33 ratio as shown by 1H NMR and
GC analyses. After purification of the reaction mixture by
chromatography on silica gel, the two diastereoisomers 34a
and 34b were obtained in 68% yield (based on an initial
loading of the Merrifield resin of 1.2 mmol of Cl/g).
2.1.2. Imine formation. Merrifield resin-bound amines 7
and 8 reacted with 20 equiv. of benzaldehyde in a 1:1
mixture of methyl orthoformiate and dichloromethane as
solvent (Scheme 5).42 These chemical transformations have
been easily followed up using 19F fast NMR analysis due to
a significative chemical shift variation (þ0.3 ppm (from 7 to
23) and 20.2 ppm (from 8 to 24)).
Using the same experimental conditions, the Wang resin-
bound amines 19 and 20 were transformed into imines 25
and 26, respectively. Despite the small difference in
chemical shifts observed between the resin-amine signals
in 19 and 20, and the resin-imine signals in 25 and 26
(between 0.1 and 0.3 ppm), the reproducibility of these
values was significant enough to follow this transformation
until its term. At room temperature, the optimal experimen-
tal reaction time was 24 h.
In a similar way, the Merrifield resin-bound imine 23 was
treated with phenoxyacetyl or benzyloxyacetyl chlorides.
The advancement of the reaction was followed by 19F NMR
and comparison of the chemical shifts with those observed
in solution. GC analysis of the mixtures obtained from the
cleavage steps showed the presence of the respective
cycloadducts 32 and 33 in the same diastereoisomeric
ratio as the one measured using 19F NMR on resins 29 and
30, respectively. Thus, resins 29 and 30 were transformed
into the two corresponding cis diastereoisomeric mixtures
32a and 32b, and 33a and 33b, respectively, in 81 and 87%
yield with respective diastereoisomeric ratios of 73:27 and
77:23.
The similar formation of methyl glyoxylate imines was
unsuccessful. It has to be reported, however that using
standard liquid phase experimental reaction conditions
˚
(3 A-molecular sieves, CH2Cl2, rt), the protected threonine
efficiently condenses with methyl glyoxylate.21 The experi-
mental studies were carried out at room temperature using
both Merrifield and Wang resin, by modifying the quantity
of methyl glyoxylate (4–20 equiv.), the reaction time
(3–24 h), and the nature of the solvent used (TMOF,
TMOF–CH2Cl2 mixture). IR analysis of the resins provided
poor informations compared to 19F NMR analysis (showing
several signals). Thus, condensation of methyl glyoxylate
on the Wang resin-bound amine 19 gave a mixture of
compounds highlighted by 19F NMR technique (peaks
Using the Wang resin, we developed a b-lactam ring
formation from imine 26 prepared from DL-para-fluoro-
phenylalanine (Scheme 7).
Scheme 5.

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I. Le Roy et al. / Tetrahedron 59 (2003) 3719–3727
Scheme 6.
Scheme 7.
The cycloaddition step has been performed under the same
experimental reaction conditions as those already used for
the Merrifield resin. The 19F NMR spectra of 35 showed two
peaks at 2115.8 and 2116.0 ppm, corresponding to the
cycloadducts obtained in solution (2115.9 and 2116.0) or
on the Merrifield resin (2115.9 and 2116.1). The treatment
of 35 with a 95% trifluoroacetic acid aqueous solution,
followed by a standard esterification reaction of the
reaction mixture using thionyl chloride in methanol, gave
b-lactams 34a and 34b in 38% yield with a 65:35 ratio
(with an initial loading of the Wang resin of 1.0 mmol/g). In
addition, the use of sodium methylate in methanol was
also applied to 35 and led to a cis cycloadduct mixture of
34a and 34b, with a diastereoisomeric ratio of 69:31 in 87%
yield.
bound compound without breaking any chemical bond. The
19F NMR linewidth for the compounds linked to the resin
was generally about 40 Hz.
2.2. Solution-phase synthesis
We have carried out the same series of reactions in solution,
in order to compare the results with those previously
obtained on solid phase. We focused our attention on the
imines of DL-ortho-fluorophenylglycine 1, DL-para-fluor-
ophenylalanine 2 and their corresponding non-fluorinated
analogs. We applied the Staudinger’s experimental reaction
conditions described by Ojima to imines of the benzal-
dehyde 27, 28, 35 and 36: Addition to the imine of
2.1 equiv. of triethylamine in a dichloromethane solution at
2788C, followed by the dropwise addition of 2 equiv. of
benzyloxyacetyl and phenoxyacetyl chlorides. After the
usual workup, the GC analysis of the crude product showed
beside the desired cis b-lactams, the presence of unreacted
imines or amides corresponding to the hydrolysis of the
iminium salt itself resulting from the condensation of acid
chloride with the corresponding imine. Then a preparative
chromatography on silica gel gave the expected cyclo-
adducts as a diastereoisomeric mixture, as reported in
Table 1.
19F NMR was finally used to monitor all the synthetic
sequences leading to compounds 1 to 34. Good quality
spectra, equal or better than 10 Hz resolution were obtained
using a classical liquid NMR probe at low field (Bruker
AC100 operating at 94.2 MHz for 19F observation).
Approximately 80 mg of resin were swelled in 0.4–
0.5 mL of CDCl3 for 15 min and then sonicated for 1 min
to enhance the homogeneity of the considered mixture. We
assume that sonication improve the swelling of the resin-

I. Le Roy et al. / Tetrahedron 59 (2003) 3719–3727
3723
Table 1. Staudinger reactions in solution
Entry
R1
Imine
R3
Acyl chloride
Product ratio (%)a
b-Lactams 5
Imine
b-lactam
Amide
Yieldb
d.r.c
1
2
3
4
5
6
C6H5
3a
3b
3b
3c
3c
3d
PhCH2O
PhCH2O
PhO
PhCH2O
PhO
PhCH2O
4a
4a
4b
4a
4b
4a
3a (0)
5a (92)
5b (63)
5c (93)
5d (57)
5e(95)
6a (8)
6b (0)
6c (0)
6d (10)
6e (3)
6f (1)
43
34
51
35
57
20
67/33
58/42
55/45
74/26
74/26
63/37
C6H4CH2
C6H4CH2
oF-C6H4
oF-C6H4
pF-C6H4CH2
3b (37)
3b (7)
3c (33)
3c (2)
3d (68)
5f (31)
a
Determined by GC analysis of the crude product.
(%) Determined after chromatographic purification.
b
c
1
The diastereoisomeric ratio was determined by GC analysis and by H and 19F NMR spectroscopy.
The value of the coupling constants of the C3 and C4 vicinal
protons (,4.7 Hz) is in agreement with the cis b-lactam
cycles. The diastereoisomeric ratios were determined by 1H,
19F NMR and GC analyses. Interestingly, the diastereio-
meric excesses obtained with the fluorinated amino acids
were slightly higher than those obtained with the corre-
sponding unfluorinated analogues. This result was even
more pronounced with the use of DL-ortho fluorophenyl-
glycine, for which the fluorine atom is located closer to the
reaction center. The diastereoisomeric ratios obtained for
the cycloadducts using solid phase synthesis (Merrifield and
Wang resins) were close to those obtained in liquid phase
while yields were higher in the solid phase case. The
syntheses described herein complete the results already
obtained by Gallop et al. using Sasrin resin.43
performed using Macherey–Nagel silica gel 60 (63–
200 mm). GC was carried out on a Shimadzu GC-14A
chromatograph with a J&W capillary column SE 30 (5%),
30 m length, 0.32 mm i.d., with 1 bar N2 carrier gas
pressure. The chromatograph was interfaced with a
Shimadzu C-R6A chromatopac integrator. Retention times
(tR) are given for the following oven programmed heating
(injector at 2508C): from 1108C (5 min) to 2808C (5 min) at
38C/min rate. Distillations with Kugelrohr apparatus were
performed on a Bu¨chi GRK-51 instrument. 1H and 13C
NMR spectra were obtained on a Brucker AC 200
spectrometer, for solutions in CDCl3. Chemical shifts are
reported as d values in parts per million (ppm) relative to
residual CHCl3 (dH 7.27 ppm) and CDCl3 (dC 77.23 ppm) as
internal standards respectively. H-decoupled 19F NMR
spectra were recorded with a Bruker AC 100 spectrometer
operating at 94.2 MHz for resin suspensions in CDCl3.
(CFCl3 d 0.00 ppm as internal standard). A standard pulse
sequence was used (pulse 8 ms; relax. delay 2 s; 64 scans).
The samples were prepared in a 5-mm i.d. standard NMR
tube, with the appropriate resin (ca. 80 mg), swelled in
CDCl3 (0.5 mL) and sonicated for 1 min. Splitting patterns
are described as singlet (s), doublet (d), triplet (t), quartet
(q), multiplet (m), broad (br). Coupling constants J are given
in Hertz. All structures were assigned after extensive 2D
NMR studies (COSY and HSQC). Infrared (IR) spectra
were obtained using an IR-FT Nicolet 20 SXB spectro-
photometer (KBr pellets) and are reported in cm21. Solid-
phase syntheses were performed on a Merrifield resin
(France Biochem or Sigma; 200–400 mesh, approx.
1.2 mmol/g) or a Wang resin (Advanced ChemTech
PS/1%DVB, 100–200 mesh, 1.0 mmol/g).
3. Conclusion
We have developed some very versatile multi-steps solid
phase syntheses for the preparation of b-lactams from
imines of benzaldehyde derived from fluorinated a-amino
acids. The easy control of the reactions was performed using
19F NMR on the intermediates, using classical liquid NMR
parameters. This alternative to more sophisticated tech-
niques such as HR MAS—not always available—works
well provided the chemical shifts difference between the
substrate and the subsequent product is higher than 0.1 ppm.
4. Experimental
4.1. General methods and materials
4.2. N-Phthaloyl-protected fluoro-amino acids 3 and 4
Unless otherwise noted, materials were obtained from
commercial suppliers and used without further purification.
CH2Cl2 was dried over potassium carbonate distilled and
Finely powdered phthalic anhydride (876 mg, 5.9 mmol)
and Et3N (80 mL) were added to a suspension of the
fluoroamino acid (DL-2-fluorophenylglycine 1 or DL-4-
fluorophenylalanine 2, 5.9 mmol) in toluene (20 mL). The
mixture were refluxed for 3 h. After solvent evaporation, the
crude solid residue was diluted with cold water (12 mL) and
0.12 mL HCl were added. After stirring for 3 h at room
temperature, the filtration then washing with cold H2O
˚
stored over 4 A molecular sieves. Et3N was dried over KOH
(pellets). Reactions were carried out under an atmosphere of
argon. TLC was carried out on Merck silica gel 60 F254
analytical Plate (0.2 mm thickness) visualised by using UV
light, iodine vapor, or by means of a 5% ethanolic solution
of molybdophosphoric acid. Column chromatography was

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I. Le Roy et al. / Tetrahedron 59 (2003) 3719–3727
(10 mL) and drying (IR lamp) afforded a white solid:
N-phthaloyl-DL-2-fluorophenylglycine 3, yield 84%, 19F
NMR (CDCl3, 94.2 MHz) d: 2116.0, GC tR 20 min, or
N-Phthaloyl-DL-4-fluorophenylalanine 4, yield 97%, 19F
NMR (CDCl3, 94.2 MHz) d: 2115.9; GC tR 28 min.
94.2 MHz) d: 2119.5; GC tR 19 min; N-tBoc-DL-4-
fluorophenylalanine 12 19F NMR (CDCl3, 94.2 MHz) d:
2115.9; GC tR 21 min.
4.7. Merrifield resin-bound N-t-Boc-protected fluoro-
amino acids 13 and 14
4.3. Merrifield resin-bound N-phthaloyl-protected
fluoro-amino acids 5 and 6
To the Merrifield resin (482 mg, 0.58 mmol), swelled in
dioxane (30 mL) were added the appropriate N-t-Boc-
fluoro-amino-acid (11 or 12, 2.9 mmol) followed by Et3N
(1.22 mL) and the reaction mixture was refluxed for 96 h.
The reaction was filtered and the resin whashed with a 1:1:1
solution of dioxane–H2O–HCl (v:v:v; 60 mL), 1:1 solution
of dioxane–H2O (v:v; 60 mL), dioxane (60 mL), EtOH
(60 mL), CH2Cl2 (60 mL). The resins were dried in vacuo
and analyzed by 19F NMR (CDCl3, 94.2 MHz) d: 13
2117.5; 14 2116.0.
To the Merrifield resin (1 g, 1.2 mmol), swelled in dioxane
(15 mL), was added the appropriate N-phthaloyl-protected
fluoro-amino acid (3 or 4, 6 mmol) and the reaction was
mixed at 1018C for 96 h. The resin was filtered, washed
with a 1:1:1 solution of dioxane–H2O–HCl (v:v:v, 60 mL),
1:1 solution of dioxane–H2O (v:v, 60 mL), ethanol
(60 mL) and CH2Cl2, dried in vacuo overnight and
analyzed by 19F NMR (CDCl3, 94.2 MHz) d: 5 2116.0; 6
2115.9.
4.8. Fmoc-fluoro-amino acids 15 and 16
4.4. General procedure for the deprotection of
Merrifield resin-bound N-phthaloyl fluoro-amino acids 5
and 6
The fluoro-amino acid (1 or 2, 5 mmol) was dissolved in a
10% Na2CO3 solution (10 mL) at 08C, and then the
9-fluorenylmethyl-N-hydroxysuccinimide (Fmoc-Osu,
4.2 mmol) in dioxane (10 mL) was added. The resulting
solution was mixed at room temperature until no Fmoc-Osu
remains by TLC analysis (typically 5 h). The mixture is
diluted in H2O (120 mL) and the aqueous layer is extracted
with Et2O (30 mL) and EtOAc (2£10 mL). The aqueous
layer was then cooled to 08C, acidified to pH 2 by addition
of HCl 6N, and the resulting suspension was extracted by
EtOAc (6£10 mL). The combined organic extracts were
washed with a saturated NaCl solution, dried over Na2SO4,
and concentrated by evaporation. The product was obtained
by precipitation upon addition of petroleum ether. Fmoc-
DL-2-fluorophenylglycine 15: yield 83%; 19F NMR
(CD3OD, 94.2 MHz) d: 2115.4; Fmoc-DL-4-fluoropheny-
lalanine 16: yield 75%; 19F NMR (CD3OD, 94.2 MHz): d:
2114.95.
To the appropriate phthaloyl Merrifield resin (5 or 6,
200 mg, 0.2 mmol), swelled in ethanol (3 mL) was added
hydrazine monohydrate (3 equiv. 0.6 mmol) and the
suspension was mixed at room temperature for 48 h. The
resin was filtered, washed with EtOH (2£20 mL), CH2Cl2
(2£20 mL), and dried in vacuo overnight. Resin-bound
amino acid 7 and 8 were then analyzed 19F NMR (CDCl3,
94.2 MHz) d: 7 2118.5; 8 2116.4. The combined organic
washes were evaporated and the residues were also analyzed
by NMR 19F (CDCl3, 94.2 MHz) hydrazide 9 d: 2118.8.
4.5. General procedure for the deprotection of
Merrifield resin-bound N-tBoc-fluoro-amino acids 13
and 14
The appropriate tBoc-protected Merrifield resin (13 or 14,
600 mg) was treated at room temperature with a 1:1 solution
of TFA/CH2Cl2 (v:v, 10 mL) for 10 min, washed with
CH2Cl2 (20 mL), and treated again with a 1:1 solution of
TFA/CH2Cl2 (v:v, 10 mL) for 10 min. The resin was shaken
twice in 15 mL of a 5% solution of iPr2NEt in CH2Cl2 (v:v).
The collected resin (7 or 8) was washed with CH2Cl2
(2£40 mL), dried in vacuo, and analyzed by NMR 19F as
previously.
4.9. Wang resin-bound Fmoc-protected fluoro-amino
acids 17 and 18
Wang resin (1 g, 1 mmol/g), DMAP (0.049 g, 0.4 mmol),
and Fmoc-protected fluoro amino acid 15 or 16 (4 mmol)
were suspended in a 4:3 solution of CH2Cl2/DMF (v:v,
17.5 mL). To this suspension DIC (4 mmol, 0.625 mL) was
added and the resulting mixture was shaken for 2 h at room
temperature. The resin was collected by filtration, washed
with DMF (4£10 mL) and CH2Cl2 (4£10 mL), dried in
vacuo, and analyzed by 19F NMR (CDCl3, 94.2 MHz) d: 17
2117.5; 18 2115.7.
4.6. General procedure for the preparation of N-tBoc-
protected fluoro-amino acids 11 and 12
To the amino-acid 1 or 2 (3 mmol) in a 2:1:1 mixture of
dioxane/H2O/NaOH 1N (v:v:v, 12 mL) cooled to 08C, di-
tert-butyl-pyrocarbonate (720 mg, 3.3 mmol) was added,
under stirring. The resulting mixture was shaken at room
temperature for 30 min then cooled to 08C. EtOAc was
added (9 mL) and the resulting solution was acidified to pH
2–3 by addition of a 10% solution of citric acid in H2O. The
aqueous layer was further extracted with EtOAc (3£20 mL)
and the combined organic layers were washed with
H2O (2£10 mL), dried (Na2SO4) and concentrated to
afford the N-t-Boc-amino-acid 11 or 12 quantitatively.
N-tBoc-DL-2-fluorophenylglycine 11 NMR 19F (CDCl3,
4.10. Deprotection of the Wang resin-bound Fmoc-
fluoro-amino acids 17 and 18
To the Fmoc-Wang resins (17 or 18, 0.5 g) was added
20% piperidine/DMF solution (5 mL), and the
suspension was mixed at room temperature for 20 min.
The resin was filtered, and the same treatment repeated
again. The resin was filtered, washed with DMF (2£10 mL),
CH2Cl2 (2£10 mL), dried in vacuo overnight, and
analyzed by 19F NMR (CDCl3, 94.2 MHz) d: 19 2118.6;
20 2116.3.

I. Le Roy et al. / Tetrahedron 59 (2003) 3719–3727
3725
4.11. General procedure for the preparation of methyl
esters of fluoro-amino acids 21 and 22
chloride or phenoxy-acetyl chloride, 2.1 mmol)., was
added dropwise, via syringe, at 2788C. The resulting
mixture was stirred at room temperature for 18 h. Then, the
mixture was diluted with CH2Cl2 (10 mL), washed with
H2O (10 mL), HCl 0.1 M (10 mL), saturated solution of
NaHCO3 (10 mL), then with a saturated solution of NaCl.
The organic phase was dried over MgSO4, then filtered. The
solvent was evaporated under reduced pressure to give the
crude b-lactam. A sample of the crude product was used to
To the fluoro-amino acid (1 or 2, 2.95 mmol) suspended in
MeOH (10 mL), SOCl2 (280 mL 3.84 mmol) was slowly
added, and the mixture was refluxed for 18 h. After
evaporation of MeOH and excess of SOCl2, the amino
ester hydrochloride, was suspended in CH2Cl2 (10 mL) and
Et3N was added (826 mL 5.8 mmol). The mixture was
stirred at room temperature for 10 min and concentrated in
vacuo. The crude residue is suspended in Et2O, and after
filtration of Et3N, HCl and evaporation of the solvent,
amino-ester was obtained quantitatively. Methyl 2-fluoro-
phenyl glycinate 21: GC tR 6.5 min; 1H NMR (CDCl3,
200 MHz) d: 7.37–7.00 (m, 4H, C6H4F); 4.83 (s, 1H, CH);
3.69 (s, 3H, COOCH3); 2.03 (s, 2H, NH2); 19F NMR
(CDCl3, 94.2 MHz) d: 2118.9.; methyl 4-fluorophenyl
alaninate 22: GC tR 8.4 min; 1H NMR (CDCl3, 200 MHz) d:
7.27–6.94 (m, 5H, C6H5); 3.74 (t, 1H, CH); 3.70 (s, 3H,
COOCH3); 2.94 (m, 2H, CH2); 19F NMR (CDCl3,
94.2 MHz) d: 2116.4.
1
measure the isomers ratio either by GC and H NMR. The
product was further purified by silica gel column chroma-
tography, then conveniently characterized.
4.14.1. cis-Methyl(3-benzyloxy-2-oxo-4-phenyl-azetidin-
1-yl)-(2-fluoro-phenyl)acetate 32a-b. Major isomer:
1
(74%); H NMR (CDCl3, 200 MHz) d: 6.96 (m, 14H, 2
C6H5 and C6H4F); 5.75 (s, 1H, CHC6H4F); 5.13 (d, 1H,
J¼4.64 Hz, CHcycle); 5.00 (d, 1H, J¼4.64 Hz, CHcycle); 4.16
(m, 2H, CH2Ph); 3.75 (s, 3H, COOCH3); 13C NMR (CDCl3,
50 MHz) d: 169 (CvO); 167 (CvO); 136.3 (Cipso arom);
133.6 (Cipso arom); 130, 129, 128 (CH arom); 124 (C–F);
115 (CHarom); 83.7(CHPh); 72.4 (CH2Ph); 62.9 (CHcycle);
53.0 (CHcycle); 52.3 (CH3); GC tR 38.6 min.; minor isomer
4.12. Solution phase procedure for the preparation of
imines 27 and 28
1
(26%): H NMR (CDCl3, 200 MHz) d: 6.96 (m, 14H, 2
C6H5 and C6H4F); 5.51 (s, 1H, CHC6H4F); 4.88 (d, 1H,
J¼4.62 Hz, CHcycle); 4.70 (d, 1H, J¼4.62 Hz, CHcycle); 4.16
(m, 2H, CH2Ph); 3.62 (s, 3H, COOCH3). 19F NMR (CDCl3,
94.2 MHz) d: 2115.7; 2115.8; GC tR 39.1 min; calcd for
C25H22NFO4 C, 71.59; H, 5.29; N, 3.34; found C, 71.49; H,
5.30; N, 3.27.
To a stirred solution of benzaldehyde (165 mL, 1.63 mmol)
in CH2Cl2 (20 mL) at room temperature, under argon, were
added the a-amino-ester (21 or 22, 1.63 mmol) and 300 mg
˚
of 4 A molecular sieves. The mixture was stirred until no
aminoester remains by GC analysis (typically 24 h), and
then filtered. The solvent was evaporated in vacuo to give
the corresponding crude imine. Methyl (benzylidene-
amino)-(2-fluorophenyl)-acetate 27 1H NMR (CDCl3,
200 MHz): d 8.35 (s, 1H, CHvN); 7.81–6.99 (m, 9H,
C6H5 and C6H4F); 5.5 (s, 1H, CH); 3.69 (s, 3H, COOCH3);
NMR 19F (CDCl3, 94.2 MHz) d: 2118.5; GC tR 21.9 min.
Methyl 2-(benzylidene-amino)-3-(4-fluorophenyl)-propio-
nate 28 1H NMR (CDCl3, 200 MHz) d: 7.68 (s, 1H,
CHvN); 7.66–7.37 (m, 5H, C6H5); 7.25–6.86 (m, 4H,
C6H4F); 4.12 (m, 1H, CH); 3.73 (s, 3H, COOCH3); 3.22 (m,
2H, CH2); 19F NMR (CDCl3, 94.2 MHz) d 2116.6; GC tR
22.7 min.
4.14.2. cis-Methyl(3-phenoxy-2-oxo-4-phenyl-azetidin-1-
yl)-(2-fluoro-phenyl)acetate 33a-b. Major isomer: (74%);
1H NMR (CDCl3, 200 MHz) d: 6.95 (m, 14H, 2C6H5 and
C6H4F); 5.81 (s, 1H, CHC6H4F); 5.56 (d, 1H, J¼4.64 Hz,
CHcycle); 5.32 (d, 1H, J¼4.64 Hz, CHcycle); 3.78 (s, 3H,
COOCH3); 13C NMR (CDCl3, 50 MHz) d: 169.1 (CvO);
166.2 (CvO); 156.8 (Carom–O); 132.7 (Cipso arom); 131,
130, 129, 128, 127 (CH arom); 124 (C–F); 122 (CH arom);
115 (CH arom); 82.0 (CHC6H4F); 63.1 (CHcycle); 53.1
(CHcycle); 52.5 (CH3); GC tR 37.3 min; minor isomer (26%):
1H NMR (CDCl3, 200 MHz) d: 6.95 (m, 14H, 2 C6H5 and
C6H4F); 5.57 (s, 1H, CHC6H4F); 5.46 (d, 1H, J¼4.62 Hz,
CHcycle); 4.93 (d, 1H, J¼4.62 Hz, CHcycle); 3.64 (s, 3H,
COOCH3); 13C NMR (CDCl3, 50 MHz): d: 168.4 (CvO);
166.0 (CvO); 157.9 (Carom–O); 132.8 (Cipso arom); 131,
130, 129, 128, 127 (CH arom); 124 (C–F); 122 (CH arom);
115 (CH arom); 81.6 (CHC6H4F); 63.5 (CHcycle); 53.4
(CHcycle); 52.9 (CH3). 19F NMR (CDCl3, 94.2 MHz) d:
2115.7; 2115.9; GC tR 37.6 min. Calcd for C24H20NFO4
C, 71.10; H, 4.97; N, 3.45; found C, 71.06; H, 5.06; N, 3.41.
4.13. Solid phase procedure for the preparation of imines
23 and 24
To the appropriate Merrifield resin-amine 7 or 8, or Wang
resin-amine 19 or 20 (0.2 mmol, 1 equiv.), swelled in a 1:1
solution of TMOF/CH2Cl2 (v:v, 8 mL), was added benzal-
dehyde (4 mmol, 20 equiv.) and the reaction mixed at room
temperature for 24 h. The resin was washed with CH2Cl2
(2£20 mL), MeOH (2£20 mL), CH2Cl2 (20 mL), dried in
vacuo and analyzed by 19F NMR (CDCl3, 94.2 MHz) d:
Merrifield resin-bound imine 23 2118.3; Merrifield resin-
bound imine 24 2116.6; Wang resin-bound imine 25
2118.5; Wang resin-bound imine 26 2116.6.
4.14.3. cis-Methyl(3-benzyloxy-2-oxo-4-phenyl-azetidin-
1-yl)-3-(4-fluoro-phenyl) propionate 34a-b. Major isomer:
(63%); 1H NMR (CDCl3, 200 MHz) d: 7.31–6.85 (m, 14H,
2C6H5 and C6H4F); 4.81 (d, 1H, J¼4.64 Hz, CHcycle); 4.67
(d, 1H, J¼4.64 Hz, CHcycle); 4.15 (m, 2H, CH2Ph); 3.95 (m,
1H, CHCH2); 3.64 (s, 3H, COOCH3); 3.27 (d, 2H, CHCH2);
13C NMR (CDCl3, 50 MHz) d: 133 (Cipso arom); 132 (Cipso
arom); 131–128 (CH arom); 116–115 (CH in C6H4F); 83.3
(CHCH2); 72.4 (CH2Ph); 62.9 (CHcycle); 58 (CHcycle); 52.7
(CH3); 34.7 (CH2); GC tR 39.8 min; minor isomer (37%):
1H NMR (CDCl3, 200 MHz) d: 7.31–6.85 (m, 14H, 2 C6H5
4.14. Solution phase procedure for the synthesis of
b-lactams
To a stirred solution of crude imine (158, 159, 139 or 160,
1 mmol) and Et3N (2.3 mmol), in dry CH2Cl2 (5 mL), under
argon, the substituted acid chloride (benzyloxy-acetyl

3726
I. Le Roy et al. / Tetrahedron 59 (2003) 3719–3727
and C6H4F); 4.80 (d, 1H, J¼4.64 Hz, CHcycle); 4.61 (d, 1H,
J¼4.64 Hz, CHcycle); 4.16 (m, 2H, CH2Ph); 3.95 (m, 1H,
CHcycle); 4.68 (d, 1H, J¼4.62 Hz, CHcycle); 4.07 (m, 1H,
CHCH2Ph); 3.67 (s, 3H, COOCH3); 3.27 (d, 1H,
J¼4.88 Hz, Ha in CH2); 3.03 (d, 1H, Hb in CH2); 13C
NMR (CDCl3, 50 MHz) d: 169.7 (CvO); 165.9 (CvO);
136.2 (Cipso arom); 132.4 (Cipso arom); 129, 128, 127 (CH
arom); 121 (CH arom); 115 (CH arom); 81.4 (CHCH2); 63.5
(CHcycle); 56.6 (CHcycle); 52.5 (CH3); 35.9 (CH2); GC tR
39.1 min; calcd for C25H23NO4 C, 74.79; H, 5.77; N, 3.48;
found C, 74.44; H, 5.88; N, 3.21.
CHCH2); 3.68 (s, 3H, COOCH3); 3.20 (d, 2H, CHCH2); 13
C
NMR (CDCl3, 50 MHz) d: 133 (Cipso arom); 132 (Cipso
arom); 131, 130, 129, 128 (CH arom); 116, 115 (CH in
C6H4F); 83.3 (CHCH2); 72.4 (CH2Ph); 63.4 (CHcycle); 58
(CHcycle); 52.6 (CH3); 35.3 (CH2). NMR 19F(CDCl3,
94.2 MHz) d: 2115.9; 2116.0; GC tR 40.6 min; MS: 91
(100), 109 (13), 210 (19), 286 (11), 433 (0.8); calcd for
C26H24NFO4 C, 72.04; H, 5.58; N, 3.23; found C, 71.99; H,
5.60; N, 3.15.
4.15. Solid phase (Merrifield or Wang resins) procedure
for the synthesis of b-lactams
4.14.4. cis-Methyl (3-benzyloxy-2-oxo-4-phenyl-azetidin-
1-yl)-phenyl acetate 37a-b. Major isomer: (67%); 1H NMR
(CDCl3, 200 MHz) d: 7.35–6.89 (m, 10H, 2 C6H5); 5.5 (s,
1H, CHPh); 5.09 (d, 1H, J¼4.57 Hz, CHcycle); 4.95 (d, 1H,
J¼4.55 Hz, CHcycle); 4.15 (m, 2H, CH2Ph); 3.71 (s, 3H,
COOCH3); 13C NMR (CDCl3, 50 MHz) d: 169 (CvO); 167
(CvO); 136 (Cipso arom); 132 (Cipso arom); 129, 128, 127
(CH arom); 83.2 (CHPh); 72 (CH2Ph); 62.8 (CHcycle); 58.2
(CHcycle); 52.7 (CH3); GC tR 38.3 min; minor isomer:
(33%); 1H NMR (CDCl3, 200 MHz): d: 7.35–6.89 (m, 10H,
2 C6H5); 5.32 (s, 1H, CHPh); 4.82 (d, 1H, J¼4.66 Hz,
CHcycle); 4.63 (d, 1H, J¼4.64 Hz, CHcycle); 4.08 (m, 2H,
CH2Ph); 3.54 (s, 3H, COOCH3); NMR 13C (CDCl3,
50 MHz) d: 168.8 (CvO); 166.9 (CvO); 136 (Cipso
arom); 134 (Cipso arom); 129, 128, 127 (CH arom); 83.0
(CHPh); 72.3 (CH2Ph); 63.1 (CHcycle); 59.6 (CHcycle); 52.5
(CH3); GC tR 38.6 min.
To the Merrifield-imine resin (23 or 24, 0.2 mmol) or Wang-
imine resin (35, 0.2 mmol) swelled in CH2Cl2 (5 mL) was
added slowly, at 2788C, Et3N (560 mL, 4 mmol), and
dropwise, the substituted acid chloride R3CH2COCl
(benzyloxyacetyl chloride or phenoxyacetyl chloride,
3 mmol). The reaction was mixed at room temperature for
18 or 24 h, then filtered. The resin was washed with DMF
(2£15 mL), CH2Cl2 (2£15 mL), MeOH (2£15 mL), Et2O
(2£15 mL), CH2Cl2 (20 mL), and dried in vacuo, to provide
resins Merrifield-b-lactam-resin 29, 30 and 31, or Wang-b-
lactam-resin 35 analyzed by NMR 19F (CDCl3, 94.2 MHz)
d: 29 2115.58 and 2115.6; 30 2115.3 and 2115.6; 31
2115.8 and 2116.1; 35 2115.8 and 2116.0.
4.16. General procedure for recovery and analysis of
b-lactams from Merrifield resins
4.14.5. cis-Methyl 2-(3-benzyloxy-2-oxo-4-phenyl-azeti-
din-1-yl)-3-phenyl propionate 38a-b. Major isomer:
(58%); 1H NMR (CDCl3, 200 MHz) d: 7.30–6.85 (m,
15H, 3 C6H5); 4.79 (d, 1H, J¼4.64 Hz, CHcycle); 4.69 (d,
1H, J¼4.64 Hz, CHcycle); 4.09 (m, 3H, CHCH2 and
CH2Ph); 3.62 (s, 3H, COOCH3); 3.30 (d, 2H, J¼5.12 Hz,
CHCH2); 13C NMR (CDCl3, 50 MHz) d: 169.9 (CvO);
167.6 (CvO); 137, 136, 133 (Cipso arom); 129, 128, 127
(CH arom); 83 (CHCH2); 72.1 (CH2Ph); 62.7 (CHcycle);
58.3 (CHcycle); 52 (CH3); 35 (CH2); GC tR 39.7 min; minor
To the Merrifield-b-lactam-resin (29, 30 or 31, 150 mg,
0.180 mmol) swelled in a 1:4 MeOH/THF solution (v:v,
6 mL) was added a 1 M solution of NaOMe in MeOH
(40 mL) and the suspension was mixed at room temperature
18 h. The resin was filtered, washed with 1:1 solution of
MeOH/THF (v:v, 40 mL), THF (40 mL), MeOH (40 mL),
and CH2Cl2 (40 mL). The combined organic washes were
evaporated, after drying, to provide the crude b-lactams
analyzed by GC and NMR. For 1H and 19F NMR, see above.
GC 32a-b: (61 mg, 81%) 73:27 tR 38.6 and 39.1 min; 33a-b:
(63 mg, 87%) 77:23 tR 37.3 and 37.6 min; 34a-b: (53 mg,
68%) 67:33 tR 39.8 and 40.6 min.
1
isomer: (42%); H NMR (CDCl3, 200 MHz) d: 7.30–6.85
(m, 15H, 3 C6H5); 4.78 (d, 1H, J¼4.62 Hz, CHcycle); 4.50 (d,
1H, J¼4.62 Hz, CHcycle); 4.09 (m, 3H, CHCH2 and
CH2Ph); 3.67 (s, 3H, COOCH3); 3.23 (d, 2H, J¼5.12 Hz,
CHCH2); 13C NMR (CDCl3, 50 MHz) d: 169.8 (CvO);
167.1 (CvO); 137, 136, 134 (Cipso arom); 129, 128, 127
(CH arom); 83 (CHCH2); 72.3 (CH2Ph); 63.4 (CHcycle);
56.5 (CHcycle); 52 (CH3); 36 (CH2); GC tR 40.0 min; calcd
for C26H25NO4: C, 75.16; H, 6.06; N, 3.37; found C, 74.92;
H, 6.26; N, 3.17.
4.17. Cleavage of cycloadducts from Wang resin
4.17.1. By TFA treatment and esterification. The resin
35 (150 mg, 0.15 mmol) was treated with a 5% solution of
TFA in H2O (7.5 mL) and the suspension shaken for 1.5 h
at room temperature. The resin was filtered and washed
with CH2Cl2 (2£20 mL). Filtration and evaporation in
vacuo produced an oily residue (50 mg) to which SOCl2
(16 mL) was added in MeOH (5 mL), and the mixture
was then refluxed for 18 h. Concentration in vacuo
afforded 25 mg (38%) of 34a-b GC 65:35 tR 39.8 and
40.6 min.
4.14.6. cis-Methyl 2-(3-phenoxy-2-oxo-4-phenyl-azeti-
din-1-yl)-3-phenyl propionate 39a-b. Major isomer:
1
(55%); H NMR (CDCl3, 200 MHz) d: 6.95 (m, 15H, 3
C6H5); 5.34 (d, 1H, CHcycle); 4.88 (d, 1H, J¼4.88 Hz,
CHcycle); 4.07 (m, 1H, CHCH2Ph); 3.62 (s, 3H, COOCH3);
3.34 (d, 1H, J¼5.14 Hz, Ha in CH2); 3.02 (d, 1H, Hb in
CH2); 13C NMR (CDCl3, 50 MHz) d: 169.6 (CvO); 166.4
(CvO); 136.8 (Cipso arom); 133.2 (Cipso arom); 129, 128,
127 (CH arom); 121 (CH arom); 115 (CH arom); 81.6
(CHCH2); 62.7 (CHcycle); 58.5 (CHcycle); 52.6 (CH3); 35.3
4.17.2. By MeONa/MeOH treatment. To a suspension of
resin 35 (150 mg, 0.15 mmol) in a 1:4 solution of MeOH/
THF (5 mL) was added a 1 M solution of NaOMe in MeOH
(22 mL) and the mixture was shaken for 18 h at room
temperature. The resin was separated by filtration, washed
with THF (20 mL), MeOH (20 mL), and CH2Cl2 (20 mL).
The combined organic washes were dried, evaporated, and
1
(CH2); GC tR 38.8 min; minor isomer: (45%); H NMR
(CDCl3, 200 MHz) d: 6.95 (m, 15H, 3 C6H5); 5.31 (d, 1H,

I. Le Roy et al. / Tetrahedron 59 (2003) 3719–3727
3727
´
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21. Mignani, S.; Mouysset, D.; Le Roy, I.; Stella, L. Synth.
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