Novel approach to 5-substituted proline derivatives using a silver-catalyzed cyclization as the key step

Article abstract of DOI:10.1021/jo0484023

(Chemical Equation Presented) A novel synthetic approach to the synthesis of enantiomerically pure 2,5-disubstituted pyrrolines is described. The methodology involves a Ag-catalyzed 5-endo-dig cyclization of enantiopure aryl-substituted acetylene-containi

Full text of DOI:10.1021/jo0484023

Novel Approach to 5-Substituted Proline Derivatives Using a
Silver-Catalyzed Cyclization as the Key Step
Bart C. J. van Esseveldt, Paul W. H. Vervoort, Floris L. van Delft, and Floris P. J. T. Rutjes*
Radboud University Nijmegen, Institute for Molecules and Materials, Toernooiveld 1,
NL-6525 ED Nijmegen, The Netherlands
F.Rutjes@science.ru.nl
Received September 10, 2004
A novel synthetic approach to the synthesis of enantiomerically pure 2,5-disubstituted pyrrolines
is described. The methodology involves a Ag-catalyzed 5-endo-dig cyclization of enantiopure aryl-
substituted acetylene-containing amino acids. It has also been shown that the obtained pyrrolines
can be efficiently transformed into the corresponding saturated 5-aryl-substituted proline deriva-
tives.
CHART 1. Cis-5-phenylproline and (+)-RP 66803
Substituted prolines in general have gained consider-
able interest in recent years, which is reflected by the
number of stereoselective syntheses of proline derivatives
that have been reported in the literature.1 These non-
natural substituted proline analogues can be considered
as conformationally constrained amino acids and have
actually been applied in biologically active peptidomi-
metics as tools for establishing structure-activity rela-
tionships.2 Some of these proline analogues have also
been recognized as privileged elements in medicinal
chemistry among which the 5-aryl-substituted prolines
are the most prominent examples.3 Within this class of
proline analogues, cis-5-phenylproline (1) has attracted
special interest, being a key intermediate in the synthesis
of the nonpeptide cholecystokinin antagonist (+)-RP
66803 (Chart 1).4
ture.5 The most prominent synthetic pathway to cis-5-
aryl-substituted proline analogues 2 relies on the selective
ring opening of pyroglutamates such as 4 by organome-
tallic reagents and subsequent ring closure of the result-
ing ketone,6 leading to pyrrolines 3 (R ) Et) which can
then be selectively hydrogenated to the corresponding cis-
5-aryl-substituted prolines (Scheme 1).7
Building on methodology that has recently been de-
veloped in our group,8,9 we envisaged that the 2,5-
disubstituted pyrrolines of type 3 will be accessible
starting from optically active propargylglycine 6.10 In this
approach, the pyrrolines 3 (R ) Me) might be obtained
Consequently, a variety of synthetic approaches to cis-
5-phenylproline (1) have been reported in recent litera-
(1) For recent entries, see: (a) Del Valle, J. R.; Goodman, M. J. Org.
Chem. 2003, 68, 3923. (b) Pellegrini, N.; Schmitt, M.; Bourguignon,
J.-J. Tetrahedron Lett. 2003, 44, 6779. (c) Zhang, J.; Wang, W.; Xiong,
C.; Hruby, V. J. Tetrahedron Lett. 2003, 44, 1413. (d) Del Valle, J. R.;
Goodman, M. Angew. Chem., Int. Ed. 2002, 41, 1600. (e) Xia, Q.;
Ganem, B. Tetrahedron Lett. 2002, 43, 1597. (f) Flamant-Robin, C.;
Wian, Q.; Chiaroni, A.; Sasaki, N. A. Tetrahedron Lett. 2002, 43, 10475.
(g) Nevalainen, M.; Kauppinen, P. M.; Koskinen, A. M. P. J. Org. Chem.
2001, 66, 2061. (h) Kamenecka, T. M.; Park, Y.-J.; Lin, L. S.; Lanza,
T., Jr.; Hagmann, W. K. Tetrahedron Lett. 2001, 42, 8571.
(2) (a) Damour, D.; Herman, F.; Labaudinie`re, R.; Pantel, G.;
Vuilhorgne, M.; Mignani, S. Tetrahedron 1999, 55, 10135. (b) Schu-
macher, K. K.; Jiang, J.; Joullie´, M. M. Tetrahedron: Asymmetry 1998,
9, 47.
(4) Manfre´, F.; Pulicani, J. P. Tetrahedron: Asymmetry 1994, 5, 235.
(5) (a) Severino, E. A.; Costenaro, E. R.; Garcia, A. L. L.; Correia,
C. R. D. Org. Lett. 2003, 5, 305. (b) Davis, F. A.; Fang, T.; Goswami,
R. Org. Lett. 2002, 4, 1599. (c) Momotake, A.; Togo, H.; Yokoyama, M.
J. Chem. Soc., Perkin Trans. 1 1999, 1193. (d) Haddad, M.; Imoga¨ı,
H.; Larcheveˆque, M. J. Org. Chem. 1998, 63, 5680. (e) van Betsbrugge,
J.; van den Nest, W.; Verheyden, P.; Tourwe´, D. Tetrahedron 1998,
54, 1753.
(3) (a) Xu, Y.; Choi, J.; Calaza, M. I.; Turner, S.; Rapoport, H. J.
Org. Chem. 1999, 64, 4069. (b) Fournie-Zaluski, M.-C.; Coric, P.; Thery,
V.; Gonzalez, W.; Meudal, H.; Turcaud, S.; Michel, J.-B.; Roques, B.
P. J. Med. Chem. 1996, 39, 2594. (c) Kato, E.; Yamamoto, K.;
Kawashima, Y.; Watanabe, T.; Oya, M.; Iso, T.; Iwao, J. Chem. Pharm.
Bull. 1985, 33, 4836.
(6) (a) Molina, M. T.; Valle, C. D.; Escribano, A. M.; Ezquerra, J.;
Pedregal, C. Tetrahedron 1993, 49, 3801. (b) Ezquerra, J.; Mendoza,
J. D.; Pedregal, C.; Ramirez, C. Tetrahedron Lett. 1992, 33, 5589. (c)
Rudolph, A. C.; Machauer, R.; Martin, S. F. Tetrahedron Lett. 2004,
45, 4895.
(7) Lombart, H.-G.; Lubell, W. D. J. Org. Chem. 1994, 59, 6147.
10.1021/jo0484023 CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/26/2005
J. Org. Chem. 2005, 70, 1791-1795
1791

van Esseveldt et al.
SCHEME 1. Retrosynthetic Outline
SCHEME 3. Pd-Catalyzed Pyrroline Formationa
a Key: (a) iodobenzene, PdCl2(PPh3)2, CuI, Et2NH, Et2O, rt, 2
h. (b) i. HCl, EtOAc, rt, 3 h; ii. aq. NH3, dioxane/H2O (1:1 v/v), rt,
15 min. (c) PdCl2(MeCN)2, MeCN, reflux, 1 h.
TABLE 1. Evaluation of Several Metal-Catalysts
entry
catalysta
time (h)
yield of 11 (%)b
SCHEME 2. Pd-Catalyzed Formation of Cyclic
Imine 8
1
2
3
4
5
6
7
8
NaAuCl4
AgOTf
Cu(OTf)2
ZnCl2
AlCl3
Sn(OTf)2
Sc(OTf)3
Zn(OTf)2
0.5
1
1
6
58
67
48
65
24
36
>24
>24
>24
n.d.
n.d.
n.d.
from the protected precursors 5 via cleavage of the Boc-
group, followed by a metal-catalyzed intramolecular
5-endo-dig cyclization as the key step. Compounds 5, in
turn, should be easily accessible from propargylglycine
6 by using a Pd-catalyzed Sonogashira coupling to
introduce a range of aromatic groups.11 Metal-catalyzed
intramolecular additions of amines onto substituted
acetylenes have already been reported in the literature
using relatively simple (substituted) alkynylamines as
the cyclization precursors.12 A representative example is
the intramolecular aminopalladation of alkyne 7, which
upon treatment with PdCl2(MeCN)2 led to the five-
membered cyclic imine 8 in a reasonable yield (Scheme
2).12b
This literature precedent, in combination with the
facile access to enantiopure propargylglycine 6, inspired
us to use it in the synthesis of the 2,5-disubstituted
pyrrolines 3 (R ) Me). This sequence might then eventu-
ally serve as a novel approach to cis-5-phenylproline (1)
and related 5-aryl-substituted proline analogues.
To investigate the feasibility of pyrroline formation via
a similar Pd-catalyzed cyclization, amino acid 10 was
a All reactions were conducted in refluxing MeCN using 10 mol
% of the indicated catalyst. b Isolated yield calculated from precur-
sor 10.
synthesized from the enantiomerically pure propargyl-
glycine derivative 98a via a Sonogashira-type coupling13
with iodobenzene affording cyclization precursor 10 in
91% yield (Scheme 3).
Subsequent cleavage of the Boc-group of precursor 10
generated the corresponding free amino ester, which was
immediately exposed to PdCl2(MeCN)2 in refluxing ac-
etonitrile. We were pleased to find that these conditions
led to the rapid formation of pyrroline 11 in 47% yield
after column chromatography. Furthermore, we proved
using chiral HPLC (Chiralcel OD) that no (partial)
racemization had taken place during the whole synthetic
sequence. Interestingly, the formation of pyrroline 11
could also be accomplished by refluxing the intermediate
free amino ester in acetonitrile, without the presence of
the Pd-catalyst, albeit that the reaction did not go to
completion even after prolonged reaction times of over
24 h.
This observation prompted us to investigate the forma-
tion of pyrroline 11 more carefully to optimize the
cyclization reaction. Therefore, several other Lewis acidic
metal catalysts were used in this reaction and compared
in terms of yield of 11 and reaction times. As can be
inferred from Table 1, some of the investigated Lewis
acids were very reactive catalysts, leading to the rapid
formation of pyrroline 11 (entries 1-3). From this group
of metal salts, NaAuCl4 had previously been shown to
be an excellent catalyst in similar cycloisomerizations.12c
In our case, however, this catalyst gave a fast reaction,
but turned out to be less effective affording 11 in a yield
of 58% (entry 1). The use of AgOTf also led to a rapid
formation of pyrroline 11, which was isolated in an even
higher yield of 67% (entry 2).
(8) (a) van Esseveldt, B. C. J.; van Delft, F. L.; de Gelder, R.; Rutjes,
F. P. J. T. Org. Lett. 2003, 5, 1717. (b) van Esseveldt, B. C. J.; van
Delft, F. L.; Smits, J. M. M.; de Gelder, R.; Rutjes, F. P. J. T. Synlett
2003, 2354. (c) van Esseveldt, B. C. J.; van Delft, F. L.; Smits, J. M.
M.; de Gelder, R.; Schoemaker, H. E.; Rutjes, F. P. J. T. Adv. Synth.
Catal. 2004, 346, 823.
(9) (a) Wolf, L. B.; Tjen, K. C. M. F.; ten Brink, H. T.; Blaauw, R.
H.; Hiemstra, H.; Schoemaker, H. E.; Rutjes, F. P. J. T. Adv. Synth.
Catal. 2002, 344, 70. (b) Wolf, L. B.; Tjen, K. C. M. F.; Rutjes, F. P. J.
T.; Hiemstra, H.; Schoemaker, H. E. Tetrahedron Lett. 1998, 39, 5081.
(10) This trifunctional amino acid (2-amino-4-pentynoic acid) is
commercially available but in our group also readily prepared via a
chemoenzymatic procedure that has been developed in collaboration
with DSM Research (Geleen, The Netherlands): (a) Wolf, L. B.; Sonke,
T.; Tjen, K. C. M. F.; Kaptein, B.; Broxterman, Q. B.; Schoemaker, H.
E.; Rutjes, F. P. J. T. Adv. Synth. Catal. 2001, 343, 662. (b) Sonke, T.;
Kaptein, B.; Boesten, W. H. J.; Broxterman, Q. B.; Kamphuis, J.;
Formaggio, F.; Toniolo, C.; Rutjes, F. P. J. T.; Schoemaker, H. E. In
Stereoselective Biocatalysis; Patel, R. N., Ed.; Marcel Dekker: New
York, 2000; p 23.
Using ZnCl2 as the catalyst, 11 was obtained in a
similar yield of 65%, but the reaction required more time
(11) Rutjes, F. P. J. T.; Wolf, L. B.; Schoemaker, H. E. J. Chem.
Soc., Perkin Trans. 1 2000, 4197.
(12) (a) Campi, E. M.; Jackson, W. R. J. Organomet. Chem. 1996,
523, 205. (b) Fukuda, Y.; Matsubara, S.; Utimoto, K. J. Org. Chem.
1991, 56, 5812. (c) Fukuda, Y.; Utimoto, K. Synthesis 1991, 975. (d)
Jacobi, P. A.; Liu, H. J. Org. Chem. 2000, 65, 7676 and references
therein.
(13) The Pd-catalyzed functionalization of propargylglycine deriva-
tives with aromatic groups under Sonogashira-type conditions has
already been described: Crisp, G. T.; Robinson, T. A. Tetrahedron 1992,
48, 3239.
1792 J. Org. Chem., Vol. 70, No. 5, 2005

Novel Approach to 5-Substituted Proline Derivatives
TABLE 2. Scope of Ag-Catalyzed Pyrroline Formation
to go to completion (entry 4). In addition, Cu(OTf)2
appeared to be an equally effective catalyst compared to
the initially used Pd(II)-catalyst (entry 3). In AlCl3, a slow
cycloisomerization was observed affording pyrroline 11
in a somewhat lower yield of 36% (entry 5). In all other
cases, the reaction did not go to completion, even after
prolonged reaction times of over 24 h (entries 6-8) so
that the yield eventually was not determined.
By analyzing these results, we concluded that AgOTf
would be the catalyst of choice in the synthesis of other
pyrrolines. Considering the high reactivity of the Ag-
catalyst, we reasoned that lowering the reaction temper-
ature might benefit the formation and thereby the yield
of pyrroline 11. To verify this reasoning, we converted
the Boc-protected precursor 10 in the corresponding free
amino ester which was then subjected to 10 mol % of
AgOTf in MeCN at room temperature. Indeed, these mild
conditions resulted in the formation of 11 in an improved
yield of 72%, although the reaction needed more time to
go to completion. More importantly, a similar increase
in yield upon lowering the temperature to room temper-
ature was not observed using NaAuCl4 as the catalyst.
These optimized conditions clearly have advantages
over the initially proposed Pd-catalyzed reactions. First
of all, the reaction proceeds readily at room temperature,
thus providing mild reaction conditions. Furthermore, in
comparison with our previous cyclization examples, there
is no protection of the nitrogen atom necessary.8,9 Pleased
with this result, we set out to gain insight in the scope
and limitations of the observed cycloisomerization. There-
fore, we prepared a variety of cyclization precursors via
Sonogashira couplings of propargylglycine derivative 9
with several substituted aryl iodides. The substituted
acetylenes 12-16 were thus obtained in good yields and,
after generation of the corresponding amino esters,
subjected to the Ag-catalyst in MeCN at room tempera-
ture (Table 2). Subjection of the amino ester derived from
precursor 12 to the Ag-catalyst led to the formation of
the corresponding pyrroline 17 in 65% yield (entry 1).
Likewise, precursor 13, substituted with an electron-
donating o-methoxy group, could be conveniently con-
verted into pyrroline 18 in 69% yield (entry 2). Acetylene
14 bearing an electron-withdrawing p-nitro substituent
underwent, after generation of the amino ester, a smooth
cyclization affording 19 in 80% yield (entry 3), indicating
that the cyclization reaction is not very sensitive to
electronic effects. The sterically more hindered precursor
15 underwent cyclization to pyrroline 20 in a somewhat
lower yield of 54% (entry 4). Finally, acetylene 16
containing the pharmaceutically relevant p-fluorophenyl
substituent could also be converted into pyrroline 21 in
a reasonable yield of 64% (entry 5).
a Isolated yield after column chromatography.
SCHEME 4. Ag-Catalyzed Formation of
Pyridyl-Substituted Pyrrolinesa
a Key: (a) i. HCl, EtOAc, rt, 3 h; ii. Et3N, CHCl3, rt, 30 min. (b)
AgOTf, MeCN, reflux, 1 h. (c) AgOTf, MeCN, rt, 6 h.
With the successful cyclization conditions in hand, we
decided to extend this methodology to the synthesis of
similar pyrrolines substituted with biologically interest-
ing pyridyl moieties. Therefore, propargylglycine deriva-
tive 9 was first coupled under the Sonogashira conditions
with 2- and 3-iodopyridine to afford the pyridyl-substi-
tuted precursors 22 and 23 in 85 and 91% yield, respec-
tively (Scheme 4). First, precursor 22 was deprotected
in a quantitative fashion, after which the initial liberation
of the free amine using aqueous NH3 turned out to be
troublesome. Fortunately, this problem could be overcome
by switching to other conditions, that is, Et3N in chloro-
form, leading to a smooth formation of the free amino
ester of 22. Subjection of this amino ester to the Ag-
catalyst at room temperature did not give any reaction;
however, heating at reflux temperature led to a rapid
formation of pyrroline 24 in a somewhat lower yield of
38%. Interestingly, pyrroline 24 is an ester derivative of
the natural product pyrimine (25), an Fe(II)-binding
agent which has been isolated from the species Pseudomo-
nas GH.14
Likewise, precursor 23 was deprotected and the result-
ing amino ester already underwent, in contrast to the
J. Org. Chem, Vol. 70, No. 5, 2005 1793

van Esseveldt et al.
SCHEME 5. Ag-Catalyzed Cyclizations of
Homologous Cyclization Precursorsa
SCHEME 6. Hydrogenation to Give 5-Substituted
Proline Analoguesa
SCHEME 7. Formation of Pipecolic Acid
Analogue 34
a Key: (a) iodobenzene, PdCl2(PPh3)2, CuI, Et2NH, Et2O, rt, 2
h. (b) i. HCl, EtOAc, rt, 3 h; ii. aq. NH3, dioxane/H2O (1:1 v/v), rt,
15 min. (c) AgOTf, MeCN, reflux, 1 h.
character of the nonconjugated imine, which can cause
deprotonation at the R-position.
Having explored the cycloisomerization of differently
substituted cyclization precursors, we turned our atten-
tion to the hydrogenation of some of the pyrrolines to
complete the approach to 5-substituted proline analogues.
First, the 3-pyridyl-substituted pyrroline 26 was sub-
jected to straightforward hydrogenation conditions using
Pd on carbon under an atmospheric hydrogen pressure
(Scheme 6). These conditions3a led to a smooth and
quantitative conversion of 26, providing the cis-substi-
tuted proline analogue 33 as the sole product (indicated
by 1H NMR upon analysis of the crude reaction mixture).
Interestingly, proline derivative 33 can also be regarded
as a nicotine analogue which generally may have biologi-
cal relevance as a ligand for the nicotinic acetylcholine
receptor.15
The catalytic hydrogenation of pyrroline 11 under
identical conditions led to the formation of the desired
proline analogue 1. However, in this case the reduction
of the imine was severely hampered by partial hydro-
genolysis at the benzylic position. This competitive reac-
tion could be efficiently suppressed by using previously
reported conditions,16,3b leading solely to the cis-sub-
stituted proline analogue 1 in a quantitative yield. In
addition, the six-membered cyclic imine 32 was subjected
to hydrogenation conditions but gave no clean formation
of the corresponding pipecolic acid analogue 34. Instead,
imine 32 appeared to be moderately labile under these
conditions giving also several unidentifiable side prod-
ucts. Luckily, pipecolic acid 34 could be isolated in pure
form from this mixture by column chromatography in
40% yield as a single diastereoisomer according to 1H and
13C NMR (Scheme 7). By analogy to the stereochemistry
in the reduction of the pyrrolines 11 and 26, the relative
configuration of the substituents of 34 was tentatively
assigned to be cis.
2-pyridyl-substituted amino ester, cycloisomerization at
room temperature affording pyrroline 26 in a yield of
69%.
Encouraged by the cyclization results, we started to
investigate the feasibility of synthesizing homologous
cyclic imines starting from the homo- and bishomopro-
pargylglycine derivatives 27 and 28, using the same
synthetic pathway. Thus, the Pd-catalyzed Sonogashira
coupling of the optically active homo- and bishomopro-
pargylglycine derivatives 27 and 28 with iodobenzene
afforded the cyclization precursors 29 and 30 in 85 and
82% yield, respectively (Scheme 5). First, the amino ester
derived from precursor 29 was subjected to AgOTf at
reflux temperature since we anticipated that the possible
formation of a six-membered ring might require higher
reaction temperatures. These conditions gave a rapid
cyclization of the amino ester to pyrroline 31 as the sole
product in 52% yield after purification by column chro-
matography. In contrast to the previously obtained
pyrrolines, this benzyl-substituted pyrroline turned out
to be a rather labile compound that slowly decomposed.
The formation of 31 can be explained by a Ag-mediated
cyclization in an exclusive 5-exo-dig fashion giving the
corresponding intermediate conjugated enamine, followed
by isomerization of the exocyclic enamine double bond
to the apparently thermodynamically more stable imine
position (Scheme 5). Under the same conditions, the
amino ester derived from the homologous precursor 30
cyclized in a similar manner exclusively in a 6-exo-dig
manner affording the six-membered cyclic imine 32 as
the sole product in an acceptable yield of 48%. In this
case, the obtained imine proved to be a more stable
compound, allowing a thorough analysis. During the
analysis, it became clear that imine 32 showed no optical
activity, which indicates a significant extent of racem-
ization. The fact that racemization does not take place
in the pyrroline systems might be due to the more basic
(15) (a) Glennon, R. A.; Dukat, M. Med. Chem. Res. 1996, 465. (b)
McDonald, I. A.; Cosford, N.; Vemier, J.-M. Annu. Rep. Med. Chem.
1995, 30, 41.
(16) Petersen, J. S.; Fels, G.; Rapoport, H. J. Am. Chem. Soc. 1984,
106, 4539.
(14) Shiman, R.; Neilands, J. B. Biochemistry 1965, 4, 2233.
1794 J. Org. Chem., Vol. 70, No. 5, 2005

Novel Approach to 5-Substituted Proline Derivatives
stirred at room temperature and monitored with TLC. After
complete conversion of the starting material, the mixture was
concentrated in vacuo to afford the corresponding HCl-salt. A
solution of the HCl-salt in dioxane/water (15 mL, 1:1 v/v) was
treated dropwise at room temperature with 25% aqueous
NH4OH until the mixture had reached pH 10. The aqueous
solution was extracted with CH2Cl2 (3 × 25 mL) and the
combined organic layers were dried over MgSO4 and concen-
trated in vacuo. The remaining crude amino ester was
subsequently dissolved in MeCN (10 mL), and AgOTf (32 mg,
0.13 mmol) was added. The mixture was stirred at reflux
temperature and monitored by TLC. Upon completion, the
reaction mixture was concentrated in vacuo and the crude
product was purified by chromatography (EtOAc/heptane )
1:3) to afford 11 (185 mg, 0.91 mmol, 72%) as a light-yellow
oil. The enantiopurity was confirmed by chiral HPLC analysis
(Chiralcel OD, hexane/2-propanol 9:1). Rf 0.42 (EtOAc/heptane
) 1:1); [R]D +104.1 (c 1.0, CH2Cl2); IR (neat) 2951, 1734, 1612,
Conclusions
A novel approach to 5-substituted proline analogues
is described. We have shown that the synthesis of 2,5-
disubstituted pyrrolines can be achieved via a mild Ag-
catalyzed 5-endo-dig cyclization of propargylglycine de-
rivatives as the key step. We have also demonstrated that
the developed methodology could also be applied to
homologous acetylenic amino acids, leading to other
proline and pipecolic acid derivatives. Finally, we have
shown for two examples that the obtained pyrrolines can
be easily converted into the corresponding 5-substituted
proline analogues.
Experimental Section
General. All reactions were carried out under an atmo-
sphere of dry nitrogen, unless stated otherwise. Infrared (IR)
spectra were obtained using an FTIR spectrometer, and
wavelengths (ν) are reported in cm-1. Optical rotations were
measured, using concentrations (c) in g/100 mL in the indi-
cated solvents. 1H and 13C nuclear magnetic reasonance (NMR)
spectra were determined in CDCl3, unless indicated otherwise.
Chemical shifts (δ) are given in ppm downfield from tetra-
methylsilane. Flash chromatography was performed with
Acros Organics silica gel (0.035-0.070 nm) using the indicated
solvent (mixture). Rf values were obtained by using thin-layer
chromatography (TLC) on silica gel-coated glass plates (Merck
silica gel 60 F254) with the aforementioned solvent (mixture),
unless noted otherwise. THF and Et2O were distilled from
sodium and benzophenone as indicator. Heptane, EtOAc, and
CH2Cl2 were distilled from CaH2. Et2NH was distilled from
and stored over KOH. If necessary, other solvents were
distilled from the appropriate drying agents prior to use.
Unless stated otherwise, all commercially available reagents
were used as received.
Methyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-phenyl-
4-pentynoate (10). To a solution of 9 (364 mg, 1.60 mmol),
iodobenzene (398 mg, 1.95 mmol) and Et2NH (0.83 mL, 8.04
mmol) in Et2O (18 mL), CuI (31 mg, 0.16 mmol), and PdCl2-
(PPh3)2 (58 mg, 0.08 mmol) were added and the resulting
mixture was stirred for 2 h at room temperature. The reaction
mixture was poured into a saturated aqueous solution of
NH4Cl (40 mL) and after separation of the organic layer the
aqueous layer was extracted with Et2O (2 × 25 mL). The
combined organic layers were washed with brine (25 mL),
dried over MgSO4, and concentrated in vacuo. The crude
product was purified by chromatography (EtOAc/heptane )
1:6) to afford 10 (444 mg, 1.46 mmol, 91%) as a yellow oil. Rf
0.28 (EtOAc/heptane ) 1:4); [R]D +71.3 (c 1.0, CH2Cl2); IR
(neat) 3375, 2977, 1747, 1716, 1598; 1H NMR (300 MHz,
CDCl3) δ 7.38 (m, 2H), 7.28 (m, 3H), 5.42 (d, J ) 8.3 Hz, 1H),
4.56 (m, 1H), 3.79 (s, 3H), 2.95 (m, 2H), 1.46 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 171.1, 154.9, 131.5, 128.0, 127.6, 122.8,
83.7, 83.4, 79.8, 52.3, 52.1, 28.1, 23.6; HRMS (EI) calcd for
C17H21NO4 303.1471, found 303.1471.
1
1574, 1433; H NMR (300 MHz, CDCl3) δ 7.84 (dd, J ) 1.5,
7.8 Hz, 2H), 7.31-7.41 (m, 3H), 4.89 (ddt, J ) 8.8, 6.7, 1.7 Hz,
1H), 3.76 (s, 3H), 3.14 (dddd, J ) 16.6, 10.1, 5.5, 2.1 Hz, 1H),
2.95 (dddd, J ) 16.6, 8.7, 6.8, 2.0 Hz, 1H), 2.29 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 175.7, 173.0, 133.6, 130.8, 128.3,
127.9, 74.6, 52.4, 35.6, 26.6; HRMS (EI) calcd for C12H13NO2
203.0946, found 203.0948.
Methyl (2S,5R)-5-phenyltetrahydro-1H-2-pyrrolecar-
boxylate (1). To a solution of 11 (308 mg, 1.52 mmol) in MeOH
(3 mL), PtO2 (10 mg, 0.04 mmol) was added. The solution was
subjected to hydrogen (30 bar) and stirred for 3 h at room
temperature. The reaction mixture was filtered over Hyflo and
concentrated in vacuo to afford 1 (308 mg, 1.50 mmol, 99%)
as a light-yellow oil. An analytically pure sample was obtained
after chromatography (EtOAc/heptane ) 1:2). Rf 0.15; [R]D
+
20.1 (c 1.0, CH2Cl2); IR (neat) 3356, 2950, 1731, 1610, 1502,
1
1459; H NMR (300 MHz, CDCl3) δ 7.40 (dd, J ) 0.6, 7.5 Hz,
2H), 7.26 (m, 3H), 4.18 (dd, J ) 5.7, 9.0 Hz, 1H), 3.92 (dd, J )
5.1, 8.1 Hz, 1H), 3.76 (s, 3H), 2.17 (m, 4H), 1.72 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 175.3, 143.2, 128.4, 127.1, 126.7, 63.7,
60.2, 52.3, 34.5, 30.8; HRMS (CI) calcd for C12H16NO2 (MH+)
206.1181, found 206.1179.
Methyl 6-benzyl-2-piperidinecarboxylate (34). To a
solution of 32 (108 mg, 0.47 mmol) in MeOH (10 mL), 10%
Pd/C (15 mg, 0.01 mmol) was added. The black suspension was
subjected to hydrogen (1 atm) and stirred for 2 h at room
temperature. The reaction mixture was filtered over Hyflo and
concentrated in vacuo. Purification by chromatography (EtOAc/
heptane ) 1:1) afforded 34 (44 mg, 0.19 mmol, 40%) as a
colorless oil. Rf 0.17; IR (neat) 3332, 2931, 2852, 2791, 1739,
1603, 1495, 1435; 1H NMR (300 MHz, CDCl3) δ 7.25 (m, 2H),
7.18 (m, 3H), 3.66 (s, 3H), 3.26 (dd, J ) 2.7, 10.8 Hz, 1H), 2.70
(m, 3H), 2.03-1.84 (m, 3H), 1.64 (m, 1H), 1.48-1.14 (m, 3H);
13C NMR (75 MHz, CDCl3) δ 173.3, 138.7, 129.1, 128.4, 126.3,
59.5, 58.0, 52.1, 43.8, 32.1, 29.3, 24.7; HRMS (EI) calcd for
C14H19NO2 233.1371, found 233.1374.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 12-24, 26,
29, and 30-34. 1H and 13C NMR spectra for compounds 1, 11,
24, 26, and 31-34. This material is available free of charge
via the Internet at http://pubs.acs.org.
Methyl (2S)-5-phenyl-3,4-dihydro-2H-2-pyrrolecarbox-
ylate (11). To a solution of precursor 10 (383 mg, 1.26 mmol)
in EtOAc (5 mL), a ∼3 M solution of HCl in EtOAc (2 mL)
was added dropwise at room temperature. The mixture was
JO0484023
J. Org. Chem, Vol. 70, No. 5, 2005 1795