Stereoselective multigram-scale synthesis of cis- and trans-β- phenylproline derivatives

Article abstract of DOI:10.1016/j.tet.2012.09.069

Efficient routes for the gram-scale preparation of the proline analogues that bear a phenyl substituent attached to the pyrrolidine β carbon (cis- and trans-β-phenylproline) have been developed. The cis derivative was synthesized from N-Boc-β-alanine in six steps and 78% overall yield. The generation of a vinyl triflate with full regiochemical control together with a high-yielding cross-coupling reaction and a completely stereoselective hydrogenation are at the basis of the high efficiency of the procedure. Epimerization of the cis β-phenylproline derivative with lithium bis(trimethylsilyl)amide provided access to the trans isomer.

Full text of DOI:10.1016/j.tet.2012.09.069

Tetrahedron 68 (2012) 9578e9582
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective multigram-scale synthesis of cis- and trans-b-phenylproline
derivatives
*
ꢀ
Isabel Rodríguez, M. Isabel Calaza, Ana I. Jimenez, Carlos Cativiela
ꢀ
ꢀ
ꢀ
Departamento de Química Organica, Instituto de Sintesis Química y Catalisis Homogenea (ISQCH), CSIC e Universidad de Zaragoza, 50009 Zaragoza, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient routes for the gram-scale preparation of the proline analogues that bear a phenyl substituent
Received 10 August 2012
Accepted 12 September 2012
Available online 19 September 2012
attached to the pyrrolidine
rivative was synthesized from N-Boc-
a vinyl triflate with full regiochemical control together with a high-yielding cross-coupling reaction and
a completely stereoselective hydrogenation are at the basis of the high efficiency of the procedure.
b
carbon (cis- and trans-
b-phenylproline) have been developed. The cis de-
b
-alanine in six steps and 78% overall yield. The generation of
Keywords:
Non-proteinogenic amino acid
Proline analogue
Epimerization of the cis
to the trans isomer.
b
-phenylproline derivative with lithium bis(trimethylsilyl)amide provided access
Ó 2012 Elsevier Ltd. All rights reserved.
b-Substituted proline
3-Phenylproline
Stereoselective synthesis
Vinyl triflate
1. Introduction
Among substituted prolines,
b-phenylproline (Fig. 1) features
a proline skeleton that bears an aromatic group at the
b
carbon of
The wide range of chemical, pharmacological and bio-
technological applications of proline1 has motivated the de-
velopment of synthetic methodologies for the preparation of a vast
range of proline analogues.2 In particular, very significant advances
have been made in the synthesis of proline analogues with modi-
fied conformational and functional properties for the development
of peptide-derived therapeutics.3 The reason for this is the key role
of proline in defining the secondary structure, and hence the bi-
ological behaviour, of peptides.4
the five-membered pyrrolidine ring. This proline analogue, which
can be regarded as a prolineephenylalanine hybrid, is especially
attractive because it combines the structural restrictions of proline4
with a specifically-oriented aromatic side chain. Moreover, the
stereochemical diversity of b-phenylproline, in which the phenyl
group may exhibit either a cis or a trans orientation with respect to
the carboxylic acid (Fig. 1), increases its potential as a tool for elu-
cidating the conformational requirements for optimal peptide-
receptor binding. Clearly, the utility of b-phenylproline to modu-
In this context, proline analogues that bear side chains be-
longing to other proteinogenic amino acids have elicited particular
interest.3d These proline-based residues, when incorporated into
peptides as surrogates of the coded amino acids, not only place
constraints on the peptide backbone but also serve as probes to
investigate the effect caused by the functional group and the con-
formation. Such combination of structural and functional proper-
ties makes substituted prolines very helpful tools for elucidating
receptor-bound bioactive conformations. Moreover, some prolines
functionalized with groups present in the side chains of other
proteinogenic amino acids are naturally occurring compounds or
constitute a part of bioactive natural products.5
late peptide conformation relies on its ability to retain the confor-
mational preferences of proline, which exhibits a high tendency to
* Corresponding author. Tel./fax: þ34 976 761210; e-mail address: cativiela@
Fig. 1. Structure of the different stereoisomers of
b-phenylproline. Note that positions
unizar.es (C. Cativiela).
2 and 3 correspond, respectively, to the and carbons.
a
b
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.069

I. Rodríguez et al. / Tetrahedron 68 (2012) 9578e9582
9579
induce turns and, in particular, to occupy the iþ1 position of
turns.4 In this regard, we have recently studied the conformational
propensities of the cis and trans stereoisomers of
-phenylproline,6
and shown that they retain the ability of the natural amino acid to
induce -turns. Moreover, the additional aromatic substituent may
b
-
CO2Et
CO2Et 4 steps
Ph
CO2Me
AcHN
Ph
b
N
CHO
b
Boc
1
participate in aromatic interactions that increase the stability of the
-turn conformation.6
(cis/trans 7:3)
b
Several stereoisomers of
b-phenylproline have been in-
stereoselective saponification
Ph
CO2H
corporated into a number of bioactive peptides.3d,7 In particular, the
(2S,3R) stereoisomer was used in structure-based design of selec-
tive inhibitors of caspase-2, which is a leading target for Hunting-
ton’s disease.7a The same (2S,3R) stereoisomer afforded
peptidomimetics that are resistant to hydrolytic cleavage, exhibit
high binding affinity and are being studied as MHC-selective im-
munosuppressants for the treatment of rheumatoid arthritis and
multiple sclerosis.7bed In addition, several stereoisomers of
N
Boc
trans-2
Ph
Ph
CO2Me
CO2Me
N
Boc
cis-1
N
b
-phenylproline were employed to examine the role of a phenylal-
anine residue in the binding affinity of peptides for melanocortin,7e
Boc
trans-1
opioid7f or neurokinin7g,h receptors, or that of proline in the bind-
ing of
The demonstrated value of
development of synthetic routes to access its different stereoisomers.
Several methods that allow the preparation of one or more -phe-
nylproline stereoisomers in enantioenriched or optically pure form
have been reported.8 Some of them make use of
-proline or -pyro-
a
-conotoxins to nicotinic acetylcholine receptors.7i
1. chiral HPLC
2. hydrolysis
1. chiral HPLC
2. hydrolysis
b-phenylproline has stimulated the
Ph
Ph
CO2H
Ph
Ph
CO2H
b
CO2H
CO2H
N
N
N
N
Boc
(2R,3S)-2
L
L
Boc
(2R,3R)-2
Boc
Boc
glutamic acid (5-oxoproline) derivatives as chiral starting materi-
als.8aec Other routes are based on the cyclization of open-chain
precursors bearing a chiral auxiliary.8dej More recently, two pro-
cedures have been reported in which enantioselectivity is induced by
an organocatalytic process.8k,l In spite of the variety of strategies
available and their synthetic significance, a close analysis evidences
that the efficiency of these procedures for the preparation of multi-
(2S,3R)-2
(2S,3S)-2
Scheme 1. Access to all N-Boc-b-phenylproline stereoisomers in enantiomerically pure
form by HPLC resolution (polysaccharide-derived chiral columns) of racemic cis-1 and
trans-1, according to Ref. 9.
of the racemic b-phenylproline derivatives cis-1 and trans-1, which
gram quantities of (2S,3S)- and (2S,3R)-b-phenylproline (L-proline
have proven to be excellent precursors of the enantiopure N-Boc-
amino acids (Scheme 1).9
analogues) and the corresponding enantiomers is usually compro-
mised by the accessibilitytothehighlyelaborated startingprecursors,
the degree of stereocontrol achieved, the large number of synthetic
steps or low overall yields. Moreover, some of the procedures obviate
the analysis of the final compounds to determine the optical purity or
this is assumed to be that of the starting chiral synthon.
2. Results and discussion
We envisioned that the 2,3-dehydroprolinate 3 (Scheme 2) could
be a convenient precursor for the preparation of the desired cis-
phenylproline derivative, cis-1, because thepresence of a doublebond
connecting the and carbons would ensure a cis relative disposition
b-
On this basis, we searched for a more convenient methodology
to gain access to all four stereoisomers of
b-phenylproline in
a
b
enantiomerically pure form and gram-scale quantities. As a result,
of substituents upon hydrogenation. In turn, the synthesis of 3 could
be achieved by means of a palladium-mediated cross-coupling re-
actionwithphenylboronicacid. Vinyltriflate4(Scheme2)waschosen
as a convenient coupling partner11 since a similar oxygen-based
we have recently described9 a procedure based on the chromato-
graphic resolution of racemic N-Boc-protected b-phenylprolinates
of cis and trans stereochemistry (cis-1 and trans-1, Scheme 1). Sig-
nificant quantities (1.4e2.7 g) of each of the four stereoisomeric
electrophile has previously been employed for the b-functionaliza-
methyl N-Boc-b-phenylprolinates were thus obtained in optically
tion of proline by means of a Suzuki coupling.8a The projected vinyl
triflate 4 could be generated from ketoproline 5. The groups selected
for protection of the amino and carboxylic acid functions in com-
pounds 3e5 respond to our interest in developing a concise
pure form and subsequent deprotection of the ester function
allowed the isolation of the corresponding enantiopure amino acids
suitably protected for use in peptide synthesis9 (Scheme 1).
The preparation of the racemic precursors to be resolved by
HPLC methods (cis-1 and trans-1)9 followed a reported procedure10
Ph
Ph
CO2Me
OTf
CO2Me
based on the formation of a cis/trans mixture of ethyl N-acetyl-b-
phenylprolinates and their separation by selective saponification of
the less hindered trans ester. However, we encountered difficulties
in efficiently separating this mixture of isomers. Even if re-
placement of the acetyl by a Boc moiety and modification of the
reaction conditions enhanced the selectivity of the saponification
process,9 a strict control of the experimental conditions is still
necessary to ensure a clean separation of cis-1 and trans-2 (Scheme
1). This made us consider the convenience to develop new methods
that would allow access to cis-1 and trans-1 in a selective manner,
thus obviating the need for the separation of cis/trans isomers by
saponification (note that these compounds are not separable by
standard column chromatography on silica gel). We report herein
a practical, highly stereoselective route for the efficient preparation
CO2Me
N
N
N
Boc
Boc
Boc
cis-1
3
4
O
CO2Me
N
Boc
5
Scheme 2. Retrosynthetic route for the preparation of cis-1.

9580
I. Rodríguez et al. / Tetrahedron 68 (2012) 9578e9582
preparation of the target compound (cis-1). At the same time, they
seem to be compatible with the type of synthetic transformations
outlined above. It is clear that the stereoelectronic nature of such
protecting groups will also be critical for the enolization process since
a regioselective generation of 4 will be essential to achieve stereo-
control during the subsequent hydrogenation step.
In this context, two N-Boc-protected vinyl triflates with the de-
sired double bond position have previously been reported in the
literature.12 Specifically, a vinyl triflate with a cyano group at C-2 of
the pyrrolidine ring has been employed as a precursor for the
decomposed by treatment with a catalytic amount of rhodium
diacetate in toluene at 85e90 ꢀC. The insertion occurs when the
electrophilic metal carbenoid associated with the
b-keto ester
causes the cleavage of the NeH bond concurrent with the forma-
tion of the CeN and CeH bonds. The process cleanly delivered pure
5 in nearly quantitative yield after column chromatography puri-
fication. Thus, the synthetic route outlined in Scheme 3 provided
multigram quantities of the desired ketoproline 5 in 96% overall
yield, and involving a single purification step.
Next, the regioselective generation of vinyl triflate 4 was un-
dertaken (Scheme 4). Treatment of ketoproline 5 with potassium
bis(trimethylsilyl)amide as a base combined with triflic anhydride
proved inefficient as the desired vinyl triflate (4) was isolated in
very low yield (8e18%) from a complex mixture of products. This
result is in contrast to that previously reported12b,16 for the analo-
gous ketoproline ethyl ester (KHMDS/THF, ꢁ78 ꢀC, 30 min; then
Tf2O, room temperature, 2 h, 52%), and prompted us to test alter-
native triflating agents. The use of N-phenyltriflimide under the
same reaction conditions afforded the desired vinyl triflate (4)
contaminated with a side product that was tentatively identified as
the regioisomeric vinyl triflate with a double bond between C-3 and
C-4. Fortunately, trapping the enolate with N-(5-chloro-2-pyridyl)
triflimide17 provided 4 as the only regioisomer and in a re-
producible 86% yield even when working on gram-scale quantities.
The use of the latter triflimide with lithium bis(trimethylsilyl)am-
ide as a base provided the inseparable mixture of triflates pre-
viously observed. Accordingly, the combination of potassium
bis(trimethylsilyl)amide and N-(5-chloro-2-pyridyl)triflimide is
essential to ensure complete regioselectivity in the formation of the
desired vinyl triflate (4) and to allow its isolation in high yield.
preparation of cis-configured
b-substituted proline carbox-
amides.12a More recently, Chen et al. described the use of an analo-
gous vinyl triflate, namely the ethyl ester derivative, for the
preparation of a variety of
b-arylpyrrolidine-2-carboxamide de-
rivatives to study their effect as melanocortin-4-receptor ligands.12b
In the latter case, although the authors described that the vinyl tri-
flateundergoes a cross-coupling reactionwith phenylboronic acid in
good yield, the cis-configured N-Boc-protected b-phenylproline was
obtained in only 16% overall yield. This low yield was mainly due to
an ineffective preparation of therequiredketoproline bymeans of an
intramolecular Dieckmann condensation followed by a triflation
reaction. Indeed, the generation of 3-oxoproline derivatives by
means of an intramolecular condensation of Dieckmann type, with
potassium tert-butoxide in toluene at 0 ꢀC, has been reported to
occur in moderate yield due to the difficulty in achieving regio-
chemical control during the cyclization.12b,13
In view of this, we undertook a more efficient preparation of 5
starting from inexpensive, commercially available N-Boc-protected
b
-alanine. The desired ketoproline was prepared by means of an
intramolecular NeH insertion reaction mediated by a metal car-
benoid as the cyclization step (Scheme 3).14 Firstly, the
-keto ester
6 was prepared through the modified Claisen reaction14a initially
reported by Masamune.15 Thus, the carbonyl group in
-alanine
b
O
OTf
CO2Me
b
a
b
was activated with N,N0-carbonyldiimidazole and the resulting
imidazolide was treated with a magnesium enolate generated un-
der mild reaction conditions from the potassium salt of mono-
methyl malonate. The nucleophilic addition provided access to the
CO2Me
N
Boc
N
Boc
86%
96%
5
4
b
-keto ester 6 after a spontaneous decarboxylation occurring dur-
Ph
Ph
CO2Me
ing the acidic workup.
c
82%
yield from 5
O
CO2Me
N
N
Boc
CO2Me
CO2K
99%
a
CO2Me
CO2H
Boc
+
BocHN
BocHN
3
cis-1
6
Scheme 4. Synthesis of cis-1 from ketoproline 5. Reagents and conditions: (a) KHMDS,
THF, ꢁ78 ꢀC, 40 min; then N-(5-chloro-2-pyridyl)triflimide, THF, ꢁ78 ꢀC to rt. (b)
PhB(OH)2, PdCl2(dppf), K2CO3, toluene/MeOH, 80e85 ꢀC. (c) H2, Pd/C, MeOH, rt.
O
O
c
b
CO2Me
BocHN
CO2Me
N
Thevinyltriflate4 was then submitted to a cross-coupling reaction
N2
Boc
5
to incorporate the phenyl substituent at the
b position. Treatmentof 4
7
with phenylboronic acid and potassium carbonate in the presence of
96% overall yield
b-alanine. Reagents and conditions:
(a) N,N0-carbonyldiimidazole, MgCl2, THF, rt; (b) 3-carboxybenzenesulfonyl azide, Et3N,
CH3CN, rt; (c) Rh2(OAc)4, toluene, 85e90 ꢀC.
a
catalytic amount of [1,1-bis(diphenylphosphino)ferrocene]
dichloropalladium (II) provided 3 in high yield (Scheme 4).12b This
reaction was carried out immediately after the chromatographic pu-
rification of 4 to avoid thermal decomposition.18 Finally, the catalytic
hydrogenation of 3 under standard conditions rendered cis-1 as the
only stereoisomer in nearly quantitative yield (Scheme 4).
Scheme 3. Synthesis of ketoproline 5 from N-Boc-
The crude b-keto ester was subjected to a diazo transfer reaction
Therefore, we have developed a methodology that provides
employing 3-carboxybenzenesulfonyl azide, prepared as described
by Sorensen et al.14a (Scheme 3). Similar results were obtained
when using commercially available 4-acetamidobenzenesulfonyl
access to the desired derivative of cis-b-phenylproline, cis-1, in high
overall yield (78%), and through transformations that proceed with
full stereochemical control. The route has been applied to the
preparation of multigram quantities of cis-1 and is amenable to
larger-scale production, with only a few chromatographic purifi-
cations being necessary.
azide for the diazo-transfer step. Although the resulting
a-diazo-
b-keto ester 7 is stable for purification by silica gel chromatography,
there is no need for purification at this stage of the synthesis and
the crude material was submitted to intramolecular cyclization. The
The epimerization of cis-1 would represent a very concise way
to access the trans stereoisomer. Actually, treatment of a cis/trans
NeH insertion reaction took place when compound
7 was

I. Rodríguez et al. / Tetrahedron 68 (2012) 9578e9582
9581
mixture of ethyl N-acetyl-
b
-phenylprolinates with sodium eth-
points were determined on a Gallenkamp apparatus. IR spectra
were registered on a Nicolet Avatar 360 FTIR spectrophotometer;
nmax is given for the main absorption bands. 1H and 13C NMR spectra
were recorded on a Bruker AV-400 instrument at room tempera-
ture using the residual solvent signal as the internal standard;
oxide in ethanol has been reported to increase the percentage of
the initially minor trans isomer to about 70%.10 However, as com-
mented above, a selective saponification process is required to
separate the mixture of isomers, since the ca. 30% of cis ester
remaining in the epimerized mixture makes unfeasible their sep-
aration by standard chromatographic procedures.
chemical shifts (d) are expressed in parts per million and coupling
constants (J) in hertz. High-resolution mass spectra were obtained
This situation prompted us to study the epimerization of cis-1.
The use of sodium alkoxides for this purpose did not improve sig-
nificantly the results previously reported10 for the epimerization of
on a Bruker Microtof-Q spectrometer.
4.2. Synthesis of methyl N-(tert-butoxycarbonyl)-3-
oxopyrrolidine-2-carboxylate, 5
cis/trans mixtures of ethyl N-acetyl-b-phenylprolinates. In contrast,
treatment of cis-1 with excess lithium bis(trimethylsilyl)amide at
room temperature for 2 h cleanly afforded a 5:95 ratio of cis-1/
trans-1, from which the trans isomer was isolated pure in 63% yield
after column chromatography (Scheme 5). Increase of this yield by
extensive chromatographic purification was not attempted. For
large-scale production, the most practical approach to increase the
final yield of pure trans-1 would certainly be epimerization of the
remaining trans-enriched mixture to regain a 5:95 cis/trans ratio
prior to further chromatographic separation. In fact, isolation of
pure trans isomer by routine chromatographic procedures is only
possible when small percentages of the cis isomer remain in the
mixture.
A
solution of N-(tert-butoxycarbonyl)-b-alanine (6.00 g,
31.71 mmol) in anhydrous tetrahydrofuran (100 mL) under an ar-
gon atmosphere was treated with N,N0-carbonyldiimidazole (7.24 g,
38.05 mmol). After stirring at room temperature for 1 h, previously
mixed magnesium chloride (3.00 g, 31.51 mmol) and monomethyl
monopotassium malonate (9.84 g, 63.02 mmol) were added. The
resulting mixture was kept under an argon atmosphere and was
stirred at room temperature for an additional 18 h. The solvent was
evaporated and the residue was dissolved in ethyl acetate (100 mL)
and washed with 5% aqueous KHSO4 (2ꢂ50 mL), 5% aqueous
NaHCO3 (2ꢂ50 mL) and brine (2ꢂ50 mL). The organic layer was
dried over MgSO4, filtered and evaporated under reduced pressure
to afford 6 as a pale yellow oil (7.70 g, 31.39 mmol). The crude
compound was dissolved in anhydrous acetonitrile (100 mL), under
an argon atmosphere, and 3-carboxybenzenesulfonyl azide (7.84 g,
34.53 mmol) was added in one portion, followed by triethylamine
(13.13 mL, 94.17 mmol). The resulting mixture was stirred at room
temperature for 1 h. The solvent was concentrated in vacuo and the
residue was dissolved in diethyl ether (100 mL) and washed with
saturated aqueous NaHCO3 (2ꢂ50 mL), and saturated aqueous
NH4Cl (2ꢂ50 mL). The organic layer was dried over MgSO4, filtered
and evaporated under reduced pressure to afford 7 as an orange oil
(8.35 g, 30.78 mmol) that was taken on without further purifica-
tion. It was dissolved in anhydrous toluene (300 mL), under an
argon atmosphere, and Rh2(OAc)4 (0.068 g, 0.15 mmol) was added.
The reaction mixture was heated at 85e90 ꢀC for approximately
30 min in a preheated oil bath. The solvent was evaporated to
dryness and the residue was purified by column chromatography
(eluent: hexanes/ethyl acetate 3:1) to afford pure 5 as a white solid
Ph
Ph
Ph
CO2Me
a
CO2Me
CO2Me
N
N
N
Boc
cis-1
Boc
cis-1
Boc
5 : 95 trans-1
63%
after column
chromatography
Scheme 5. Epimerization of cis-1 to give trans-1. Reagents and conditions: (a) 1.
LiHMDS, THF, rt; 2. H2O.
3. Conclusion
A very efficient methodology for the preparation of methyl cis-
N-Boc-b-phenylprolinate employing b-alanine as the starting ma-
terial has been developed. Completely regio- and stereoselective
high-yielding transformations have allowed the isolation of this cis-
b
-phenylproline derivative in 78% overall yield. In turn, this com-
(7.41 g, 30.47 mmol, 96% overall yield). Mp 56 ꢀC. IR (neat)
1772, 1745, 1707 cmꢁ1. 1H NMR (CDCl3, 400 MHz)
1.39, 1.46 (two s,
9H), 2.59e2.76 (dd, 2H, J¼8.4, 6.8 Hz), 3.66e3.94 (m, 5H), 4.46, 4.54
(two s, 1H). 13C NMR (CDCl3, 100 MHz)
(duplicate signals are
observed for most carbons) 28.09, 28.19; 36.37, 37.06; 41.52, 42.17;
52.86, 53.00; 65.20, 65.60; 81.15; 153.75; 166.69; 204.52. HRMS
(ESI) C11H17NNaO5 [MþNa]þ: calcd 266.0999, found 266.1004.
n 2979,
pound furnished the corresponding trans stereoisomer through an
epimerization process. The high stereoselectivity achieved during
the epimerization allowed the isolation of the trans-b-phenylpro-
line derivative by standard chromatographic procedures. The pro-
cedure has been applied to the synthesis of gram quantities of the
d
d
target
duction. The
b
-phenylprolinates and is amenable to larger-scale pro-
-phenylproline derivatives prepared have been
b
shown to be excellent precursors of the enantiopure N-Boc amino
acids.9 The new synthetic route developed circumvented the need
for the separation of cis/trans isomers by selective saponification, as
4.3. Synthesis of methyl N-(tert-butoxycarbonyl)-3-
trifluoromethanesulfonyl-D
2-pyrroline-2-carboxylate, 4
required in the procedure previously reported for these
b-phenyl-
proline derivatives.9
A 0.5 M solution of KHMDS in toluene (77.70 mL, 38.85 mmol)
was added by syringe to a stirred solution of 5 (6.30 g, 25.90 mmol)
in anhydrous tetrahydrofuran (190 mL) cooled at ꢁ78 ꢀC. After
40 min stirring, N-(5-chloro-2-pyridyl)triflimide (12.20 g,
31.08 mmol) was added. The cooling bath was removed and the
solution was allowed to stir for an additional 4 h while warming up
to room temperature. The solvent was evaporated to dryness and
the residue was purified by column chromatography (eluent:
hexanes/ethyl acetate 6:1) to afford pure 4 as a light yellow oil
4. Experimental
4.1. General
All reagents were used as received from commercial suppliers
without further purification. Thin-layer chromatography (TLC) was
performed on MachereyeNagel PolygramÒ SIL G/UV254 precoated
silica gel polyester plates. The products were visualized by expo-
sure to UV light, iodine vapour or an ethanolic solution of phos-
phomolybdic acid. Column chromatography was performed using
60 M (0.04e0.063 mm) silica gel from MachereyeNagel. Melting
(8.36 g, 22.27 mmol, 86% yield). IR (neat)
1407, 1370, 1324, 1216, 1139, 1030, 989 cmꢁ1
400 MHz)
1.43 (s, 9H), 2.94 (m, 2H), 3.86 (s, 3H), 3.96 (m, 2H). 13
NMR (CDCl3, 100 MHz) 28.13, 28.93, 46.22, 52.72, 82.60, 113.62,
n
2981, 1750, 1716, 1429,
.
1H NMR (CDCl3,
d
C
d

9582
I. Rodríguez et al. / Tetrahedron 68 (2012) 9578e9582
116.81, 120.00, 123.18, 128.30, 137.87, 152.41, 159.66. HRMS (ESI)
References and notes
C12H16F3NNaO7S [MþNa]þ: calcd 398.0492, found 398.0494.
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2. Panday, S. K. Tetrahedron: Asymmetry 2011, 22, 1817e1847.
4.4. Synthesis of methyl N-(tert-butoxycarbonyl)-3-phenyl-
D
ꢀ
3. (a) Sayago, F. J.; Laborda, P.; Calaza, M. I.; Jimenez, A. I.; Cativiela, C. Eur. J. Org.
2-pyrroline-2-carboxylate, 3
ꢀ~
Chem. 2011, 2011e2028; (b) Cativiela, C.; Ordonez, M. Tetrahedron: Asymmetry
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Royal Society of Chemistry: Cambridge, 2005; Vol. 8, pp 216e273; (e) Cativiela,
C.; Díaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645e732.
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G. D.; Gierasch, L. M.; Smith, J. A. Adv. Protein Chem. 1985, 37, 1e109; (c)
Chakrabarti, P.; Pal, D. Prog. Biophys. Mol. Biol. 2001, 76, 1e102.
To a solution of 4 (7.20 g, 19.18 mmol) and phenylboronic acid
(4.68 g, 38.36 mmol) in a 10:1 mixture of toluene/methanol
(154 mL), potassium carbonate (4.00 g, 28.94 mmol) and [1,1-
bis(diphenylphosphino)ferrocene] dichloropalladium (II) (700 mg,
0.96 mmol) were added. The reaction mixture was stirred at
80e85 ꢀC for 18 h. The solvent was concentrated in vacuo and the
resulting residue was purified by silica gel column chromatography
(eluent: hexanes/ethyl acetate 4:1) to afford pure 3 as a white solid
5. Mauger, A. B. J. Nat. Prod. 1996, 59, 1205e1211.
ꢀ
ꢀ
6. Fatas, P.; Jimenez, A. I.; Calaza, M. I.; Cativiela, C. Org. Biomol. Chem. 2012, 10,
640e651.
(5.60 g, 18.46 mmol, 96% yield). Mp 66 ꢀC. IR (neat)
1701, 1627 cmꢁ1. 1H NMR (CDCl3, 400 MHz)
1.49 (s, 9H), 3.04 (m,
2H), 3.83 (s, 3H), 3.97 (m, 2H), 7.22e7.38 (m, 5H). 13C NMR (CDCl3,
n 2978, 1739,
7. (a) Maillard, M. C.; Brookfield, F. A.; Courtney, S. M.; Eustache, F. M.; Gemkow,
M. J.; Handel, R. K.; Johnson, L. C.; Johnson, P. D.; Kerry, M. A.; Krieger, F.;
d
~
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Meniconi, M.; Munoz-Sanjuan, I.; Palfrey, J. J.; Park, H.; Schaertl, S.; Taylor, M.
G.; Weddell, D.; Dominguez, C. Bioorg. Med. Chem. 2011, 19, 5833e5851; (b)
Falcioni, F.; Ito, K.; Vidovic, D.; Belunis, C.; Campbell, R.; Berthel, S. J.; Bolin, D.
R.; Gillespie, P. B.; Huby, N.; Olson, G. L.; Sarabu, R.; Guenot, J.; Madison, V.;
Hammer, J.; Sinigaglia, F.; Steinmetz, M.; Nagy, Z. A. Nat. Biotechnol. 1999, 17,
562e567; (c) Bolin, D. R.; Swain, A. L.; Sarabu, R.; Berthel, S. J.; Gillespie, P.;
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Jiang, N.; Falcioni, F.; Campbell, R.; Cox, D.; Gaizband, D.; Belunis, C. J.; Vidovic,
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Guenot, J.; Nagy, Z.; Olson, G. L. J. Med. Chem. 2000, 43, 2135e2148; (d) Ro-
sloniec, E. F.; Brandstetter, T.; Leyer, S.; Schwaiger, F.-W.; Nagy, Z. A. J. Auto-
immun. 2006, 27, 182e195; (e) Cai, M.; Cai, C.; Mayorov, A. V.; Xiong, C.; Cabello,
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J. R.; Mosberg, H. I.; Traynor, J. R. J. Pharmacol. Exp. Ther. 2000, 295, 960e966; (g)
Tong, Y.; Fobian, Y. M.; Wu, M.; Boyd, N. D.; Moeller, K. D. J. Org. Chem. 2000, 65,
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100 MHz)
d 28.38, 32.25, 46.68, 52.53, 81.55, 126.47, 127.66, 128.51,
129.74, 133.88, 151.93, 164.49. HRMS (ESI) C17H21NNaO4 [MþNa]þ:
calcd 326.1363, found 326.1358.
4.5. Synthesis of methyl cis-N-(tert-butoxycarbonyl)-3-
phenylpyrrolidine-2-carboxylate, cis-1
A mixture of 3 (5.60 g, 18.46 mmol) and 10% Pd/C (600 mg) in
methanol (56 mL) was stirred overnight at room temperature un-
der an atmospheric pressure of hydrogen gas. The catalyst was
filtered off and washed with methanol. The solvent was concen-
trated in vacuo to afford pure cis-1 as a white solid (5.60 g,
18.34 mmol, 99% yield). Spectroscopic data were coincident with
those reported.9
8. (a) Kamenecka, T. M.; Park, Y.-J.; Lin, L. S.; Lanza, T., Jr.; Hagmann, W. K. Tet-
rahedron Lett. 2001, 42, 8571e8573; (b) Herdeis, C.; Hubmann, H. P.; Lotter, H.
Tetrahedron: Asymmetry 1994, 5, 351e354; (c) Oba, M.; Saegusa, T.; Nishiyama,
N.; Nishiyama, K. Tetrahedron 2009, 65, 128e133; (d) Flamant-Robin, C.; Wang,
Q.; Chiaroni, A.; Sasaki, N. A. Tetrahedron 2002, 58, 10475e10484; (e) Solo-
shonok, V. A.; Ueki, H.; Tiwari, R.; Cai, C.; Hruby, V. J. J. Org. Chem. 2004, 69,
4984e4990; (f) Micheli, F.; Di Fabio, R.; Marchioro, C. Il Farmaco 1999, 54,
4.6. Synthesis of methyl trans-N-(tert-butoxycarbonyl)-3-
phenylpyrrolidine-2-carboxylate, trans-1
€
A 1 M solution of LiHMDS in tetrahydrofuran (14.73 mL,
14.73 mmol) was added dropwise to a solution of cis-1 (3.00 g,
9.82 mmol) in tetrahydrofuran (80 mL) and the resulting mixture
was stirred for 2 h at room temperature. After quenching with
water, the mixture was extracted with diethyl ether (3ꢂ50 mL) and
washed with brine (50 mL). The organic layer was dried over
MgSO4, filtered and evaporated under reduced pressure. The crude
5:95 mixture of cis/trans isomers was submitted to column chro-
matography (eluent: hexanes/ethyl acetate 3:1) to afford pure
trans-1 (1.90 g, 6.22 mmol, 63% yield); further chromatographic
purification of the remaining diastereomeric mixture to increase
the isolated yield of trans-1 was not carried out. Spectroscopic data
were coincident with those reported.9
461e464; (g) Schollkopf, U.; Pettig, D.; Busse, U.; Egert, E.; Dyrbusch, M. Syn-
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€
9801e9808; (j) Laabs, S.; Munch, W.; Bats, J. W.; Nubbemeyer, U. Tetrahedron
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Lett. 2009, 11, 4056e4059; (l) Rios, R.; Ibrahem, I.; Vesely, J.; Sunden, H.;
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Cordova, A. Tetrahedron Lett. 2007, 48, 8695e8699.
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9. Fatas, P.; Gil, A. M.; Calaza, M. I.; Jimenez, A. I.; Cativiela, C. Chirality, http://dx.
doi.org/10.1002/chir.22101.
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M. W. J. Org. Chem. 1990, 55, 270e275.
11. For a recent review on the access and applications of vinyl triflates derived from
1,3-dicarbonyl compounds, see: Chassaing, S.; Specklin, S.; Weibel, J.-M.; Pale, P.
Tetrahedron 2012, 68, 7245e7273.
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Marinkovic, D.; Fleck, B. A.; Wen, J.; Foster, A. C.; Chen, C. Bioorg. Med. Chem.
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M. P.; Feldman, P. L.; Rapoport, H. J. Org. Chem. 1985, 50, 5223e5230.
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Acknowledgements
The authors thank the Ministerio de Ciencia
cioneFEDER (grant CTQ2010-17436; FPI fellowship to I.R.) and
e Innova-
16. A detailed experimental procedure is not given.
ꢀ
17. (a) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299e6302; (b)
Comins, D. L.; Dehghani, A.; Foti, C. J.; Joseph, S. P. Org. Synth. 1997, 74, 77e83.
18. Vinyl triflate 4 also proved stable when stored overnight at ꢁ20 ꢀC.
ꢀ
Gobierno de AragoneFSE (research group E40) for financial
support.