Pd-Catalysed Synthesis of 5-Substituted Proline Derivatives from Acetylene-Containing Amino Acids

Article abstract of DOI:10.1055/s-2003-43337

2,5-Disubstituted pyrrolines have been synthesised via Pd-catalysed 5-endo-dig cyclisations of substituted acetylene-containing amino acids. It has also been shown that these pyrrolines can be efficiently transformed into the corresponding saturated proli

Full text of DOI:10.1055/s-2003-43337

2354
LETTER
Pd-Catalysed Synthesis of 5-Substituted Proline Derivatives from Acetylene-
Containing Amino Acids
P
d-Catalysed Syn
a
thesis of 5-
r
Substitu
t
ted Proline
DC
erivatives . J. van Esseveldt,a Floris L. van Delft,a Jan M. M. Smits,b René de Gelder,b Floris P. J. T. Rutjes*a
a
Department of Organic Chemistry, NSRIM, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Fax +31(24)3653393; E-mail: rutjes@sci.kun.nl
b
Department of Inorganic Chemistry, NSRIM, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Received 2 September 2003
Building on methodology that has recently been devel-
oped in our group,7,8 we anticipated that these pyrrolines
1 might be readily synthesised from the corresponding
protected precursors 2 via a Pd-catalysed 5-endo-dig cy-
clisation. Compounds 2, in turn, should be easily accessi-
ble from enantiopure 2-amino-4-pentynoic acid 39 whose
relatively inert side chain offers the possibility to intro-
duce a range of aromatic10 and aliphatic11 groups via Pd-
catalysis.12
Abstract: 2,5-Disubstituted pyrrolines have been synthesised via
Pd-catalysed 5-endo-dig cyclisations of substituted acetylene-con-
taining amino acids. It has also been shown that these pyrrolines can
be efficiently transformed into the corresponding saturated proline
derivatives.
Key words: Pd-catalysis, amino acids, acetylenes, cyclisations,
proline derivatives
Substituted prolines in general have gained considerable
interest in recent years, which is reflected by the number
of stereoselective syntheses of such prolines that have
been reported in the literature.1 These unnatural substitut-
ed proline derivatives can be considered as conformation-
ally constrained amino acids and, in fact, have already
been applied in biologically active peptides and peptido-
mimetics.2 Some of these proline derivatives have also
been recognized as a privileged element in medicinal
chemistry of which cis-5-phenylproline is the most prom-
inent example.3
In order to probe the feasibility of pyrroline formation via
a Pd-catalysed cyclisation, precursor 5 was synthesised
from the racemic 2-amino-4-pentynoic ester 4 via a Sono-
gashira-type coupling with iodobenzene affording 5 in
84% yield (Scheme 2).
a
b or c
HN
Ts
CO2Me
HN
Ts
CO2Me
MeO2C
NH2
The main existing synthetic approaches towards cis-5-
phenylproline and other 5-substituted proline derivatives
rely either on the convenient ring opening of pyroglu-
mates by organometallic reagents and subsequent ring
closure4 or on the stereoselective addition of organocu-
prate reagents to pyroglumate-derived N-acyliminium
ions.5 On the other hand, these molecules have recently
also been prepared in the group of Knight via iodine-me-
diated 5-endo-dig cyclisations of several homopropargyl-
ic sulfonamides.6
4
5 (84%)
6 (19%)
Scheme 2 Reagents and conditions: (a) Iodobenzene, PdCl2(PPh3)2,
CuI, Et2NH, Et2O, r.t., 2 h; (b) Pd(PPh3)4, K2CO3, DMF, 80 °C, 18 h;
(c) K2CO3, DMF, 80 °C.
Interestingly, subsequent subjection of 5 to previously re-
ported cyclisation conditions8 did not lead to the anticipat-
ed formation of the phenyl-substituted pyrroline. Instead,
a complex mixture of products was obtained, from which
elimination product 6, being the major product, could be
isolated as a single geometrical isomer in 19% yield.13
This is probably the result of base-mediated elimination of
p-toluenesulfinic acid,14 followed by isomerisation of the
imine double bond to the thermodynamically more stable
enamine position. The double bond of 6 was assigned the
sterically least hindered (Z)-geometry after conducting 1H
NMR NOE experiments. In line with this reasoning, the
same conversion could even be accomplished in a cleaner
fashion by heating 5 in DMF in the presence of K2CO3,
without the Pd-catalyst present (70% based on recovered
starting material).
We envisaged that the 2,5-disubstituted pyrrolines 1
might be valuable precursors to access novel 5-substituted
proline derivatives via stereoselective reduction of the
enamide moiety (Scheme 1).
R
CO2Me
N
HN
Ts
CO2Me
H2N
CO2H
Ts
R
1
2
3
Scheme 1
Having observed these results, we turned our attention to
earlier reported conditions7,15 and exposed cyclisation
precursor 5 to PdCl2(MeCN)2 in refluxing acetonitrile
(Scheme 3). These conditions led to the rapid formation of
SYNLETT 2003, No. 15, pp 2354–2358
0
1
.1
2
.2
0
0
3
Advanced online publication: 21.11.2003
DOI: 10.1055/s-2003-43337; Art ID: G22803ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Pd-Catalysed Synthesis of 5-Substituted Proline Derivatives
2355
pyrroline 7 as the sole product in 51% yield after column underwent cyclisation affording pyrrolines 22 and 23 in
chromatography. In addition, subjection of 5 to the same 44 and 51% yield, respectively (entries 4 and 5). Interest-
catalyst at room temperature also led to the formation of ingly, the sterically more hindered precursor 13 cyclised
cyclised product 7, albeit the reaction was significantly relatively cleanly, leading to the cyclic enamide 21 in an
slower.
acceptable yield of 68% (entry 3).
Crystallisation of this product afforded good quality crys-
tals that were subjected to an X-ray crystal structure anal-
ysis, unambiguously confirming its structure (Figure 1).16
We also wished to verify that no (partial) racemisation
had taken place in the cyclisation process, to ensure that
this sequence is suitable for the synthesis of enantiopure
proline derivatives. Thus, the enantiomerically pure cycli-
sation precursor 18 was subjected to the Pd-catalyst in re-
fluxing acetonitrile. This provided the pyrroline 24 as the
sole product in 48% yield without detectable loss of enan-
tiopurity according to chiral HPLC analysis.17
O
a or b
R
CO2Me +
HN
Ts
N
CO2Me
8 (15%)
HN
Ts
5: R = H
9: R = NH2 (91%)
CO2Me
Ts
R
7: R = H (51%)
10: R = NH2 (57%)
Scheme 3 Reagents and conditions: (a) PdCl2(MeCN)2, MeCN, re-
flux, 2 h; (b) PdCl2(MeCN)2, MeCN, r.t.
To explore the synthetic opportunities of the resulting pyr-
rolines, we set out to investigate the reduction of the enan-
tiopure pyrroline 24 to the corresponding saturated
proline derivative.
In the latter case, as the result of a competitive reaction,
ketone 8 was formed as a side product in 15% yield. This
result is markedly different from our earlier reported re-
sults, in which a similar Boc-protected compound did not
show any cyclisation.7 Furthermore, subjection of the sub-
stituted aniline 9, obtained in 91% yield starting from 2-
amino-4-pentynoic acid derivative 4, to the aforemen-
tioned catalyst in refluxing acetonitrile also led to the rap-
id formation of cyclic enamide 10 in 57% yield.
Surprisingly, exposure of 9 to the same conditions at room
temperature gave rise to the formation of 10 in 51% yield
after prolonged reaction times of over several days, but, in
that case, formation of the corresponding ketone was not
observed.
In order to gain insight in the scope and limitations of the
cyclisations, we prepared a variety of cyclisation precur-
sors via Sonogashira coupling between 2-amino-4-pen-
tynoic acid derivative 4 and several (substituted) aryl
iodides. The substituted acetylenes 11–18 were thus ob-
tained in good yields and subjected to the cyclisation con-
ditions at reflux (Table 1).
Figure 1 PLATON18 drawing of the X-ray crystal structures of pyr-
rolines 21 (left) and 26 (right).
First, compound 24 was subjected to straightforward hy-
drogenation conditions using Pd on carbon under a hydro-
gen atmosphere. These conditions, however, did not lead
to the reduction of the enamide moiety, but instead gave
partial decomposition probably as a result of hydrogenol-
ysis at the benzylic position. The reluctance of enamide 24
to undergo a catalytic hydrogenation might be explained
by the crystal structure of pyrroline 21 (Figure 1). This
structure clearly shows the shielding of the enamide dou-
ble bond by the p-toluenesulfonamide moiety from the
bottom side and the methyl ester from the top side, which
may severely hamper the approach of the double bond to
the catalyst surface. Next, we turned our attention to pre-
viously reported conditions,8 involving the reduction of
enamide 24 via the intermediate N-sulfonyliminium ion
25.19 This was achieved using a mixture of triethylsilane
(5 equiv), trifluoroacetic acid (5 equiv) and trifluoroacetic
anhydride (5 equiv) in CH2Cl2. The initially formed tertia-
ry iminium ion was trapped by the hydride donor to give
proline derivatives 26 and 27 as a 9:1 mixture of diastere-
oisomers in a combined yield of 74% (Scheme 4).
Subjection of precursor 11, substituted with an electron-
donating methoxy group, led to the formation of the cor-
responding cyclic enamide in 49% yield (entry 1). Like-
wise, the p-methyl substituted precursor 12 underwent
cyclisation to give pyrroline 20 in 50% yield (entry 2). In
contrast to these results, not shown in Table 1, the cycli-
sation of the precursor derived from 2-amino-4-pentynoic
ester 4 and p-nitrophenyl iodide did not lead to the corre-
sponding cyclised product, indicating that the cyclisation
is sensitive to electronic effects. In addition, the enan-
tiopure 2-pyridyl substituted acetylene 16 did not undergo
a cyclisation but lead to substantial recovery of the start-
ing material. Likewise, the 3-pyridyl substituted acetylene
17 did not undergo cyclisation (entry 6). Presumably, in
both cases, this behaviour could be attributed to the elec-
tron deficient nature of the pyridyl moiety. The naphthyl
substituted acetylene 14 as well as 15 – containing a phar-
maceutically relevant fluorophenyl substituent – both
Synlett 2003, No. 15, 2354–2358 © Thieme Stuttgart · New York

2356
B. C. J. van Esseveldt et al.
LETTER
Table 1 Pd-Catalysed Cyclisations of Functionalised Cyclisation Precursors
Entry
1
Precursor
Product
Yield (%)a
49
OMe
CO2Me
N
MeO
Ts
19
HN
Ts
CO2Me
11 (79%)
2
50
Me
CO2Me
N
Me
Ts
20
HN
Ts
CO2Me
12 (82%)
3
4
5
68
44
51
CO2Me
N
Ts
Me
Me
21
HN
Ts
CO2Me
13 (81%)
CO2Me
N
Ts
HN
Ts
CO2Me
22
14 (81%)
F
CO2Me
N
F
Ts
23
HN
Ts
CO2Me
15 (78%)
6
No cyclisation
Y
X
HN
Ts
CO2Me
16 (75%; X = N, Y = CH)
17 (86%; X = CH, Y = N)
7
48
CO2Me
N
Ts
24
HN
Ts
CO2Me
[a]D +82.9
18 (79%)
a Isolated yield after column chromatography.
Synlett 2003, No. 15, 2354–2358 © Thieme Stuttgart · New York

LETTER
Pd-Catalysed Synthesis of 5-Substituted Proline Derivatives
2357
(4) (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.
b
a
no
reduction
CO2Me
CO2Me
N
N
Ts
Ts
(5) (a) Wallén, E. A. A.; Christiaans, J. A. M.; Gynther, J.;
Vepsäläinen, J. Tetrahedron Lett. 2003, 44, 2081.
(b) Halab, L.; Bélec, L.; Lubell, W. D. Tetrahedron 2001,
57, 6439. (c) Collado, I.; Ezquerra, J.; Pedregal, C. J. Org.
Chem. 1995, 60, 5011.
25
24
CO2Me
+
CO2Me
N
N
Ts
Ts
(6) (a) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc.,
Perkin Trans. 1 2002, 622. (b) Knight, D. W.; Redfern, A.
L.; Gilmore, J. Chem. Commun. 1998, 2207.
26
27
26 / 27 = 9 : 1 (74%)
(7) van Esseveldt, B. C. J.; van Delft, F. L.; de Gelder, R.;
Rutjes, F. P. J. T. Org. Lett. 2003, 5, 1717.
Scheme 4 Reagents and conditions: (a) H2, Pd/C, EtOAc, r.t.; (b)
Et3SiH, TFA, TFAA, CH2Cl2, 0 °C to r.t., 1.5 h.
(8) (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.
Luckily, proline derivative 26 could be obtained in a pure
form by repeated column chromatography and crystallisa-
tion, after which its structure was unambiguously identi-
fied by means of X-ray crystal structure analysis
(Figure 1).16 This result clearly established the cis-proline
derivative 26 to be the major isomer.20 The use of triphe-
nylsilane as a more bulky hydride source under the same
conditions did not lead to an improvement of the diastere-
oisomeric ratio, in fact the proline derivatives 26 and 27
were then obtained as a 7.5:1 mixture of isomers in a
somewhat lower combined yield of 67%.
(9) This trifunctional amino acid(propargylglycine) is
commercially available, but in our group also readily
prepared via a chemo-enzymatic 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, 23.
(10) Tykwinski, R. R. Angew. Chem. Int. Ed. 2003, 42, 1566.
(11) IJsselstijn, M.; Kaiser, J.; van Delft, F. L.; Schoemaker, H.
E.; Rutjes, F. P. J. T. Amino Acids 2003, 24, 263.
In conclusion, we have shown that the synthesis of 2,5-
disubstituted pyrrolines can be achieved via 5-endo-dig
Pd-catalysed cyclisation of acetylene-containing amino
acids in reasonable yields. It has also been demonstrated
that this pathway in case of enantiopure starting materials
proceeds without detectable racemisation and thus can be
applied to the synthesis of enantiomerically pure proline
derivatives. In addition, we have demonstrated the feasi-
bility of converting the obtained pyrrolines in an efficient
manner into the corresponding saturated 5-aryl substitut-
ed proline derivatives.
(12) Rutjes, F. P. J. T.; Wolf, L. B.; Schoemaker, H. E. J. Chem.
Soc., Perkin Trans. 1 2000, 4197.
(13) All new compounds were obtained in analytically pure form
and were appropriately characterised by IR, mp, 1H and 13
NMR, high resolution mass data and rotational values.
(14) Similar elimination of p-toluenesulfinic acid from
sulfonamide moieties has previously been observed:
(a) Ferreira, P. M. T.; Maia, H. L. S.; Monteiro, L. S.
Tetrahedron Lett. 2002, 43, 4491. (b) Ferreira, P. M. T.;
Maia, H. L. S.; Monteiro, L. S.; Sacramento, J. J. Chem.
Soc., Perkin Trans. 1 2001, 3167.
C
Acknowledgement
(15) Rudisill, D. E.; Stille, J. K. J. Org. Chem. 1989, 54, 5856.
(16) Crystallographic data of structures 21 and 26 have both been
deposited at the Cambridge Crystallographic Data Centre
and have been allocated the deposition numbers CCDC
212273 and CCDC 212274, respectively.
1
A. E. M. Swolfs is kindly acknowledged for assisting with the H
NMR NOE measurements of compound 6.
(17) To determine the enantiopurity of compound 24, racemic 24
was synthesised and separated on a Chiralcel OD column
(eluant: i-PrOH/hexane = 1:9). Using this assay, the ee of
pyrroline 24 was determined to be >99%.
(18) Spek, A. L. PLATON, A Multipurpose Crystallographic
Tool, 2002, Utrecht University, Utrecht, The Netherlands.
(19) For a review on N-acyliminium ions and related structures,
see: Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000,
56, 3817.
(20) Typical experimental procedures and data were as follows.
Formation of Enyne 6: To a solution of 5 (418 mg, 1.17
mmol) in DMF (20 mL), K2CO3 (808 mg, 5.85 mmol) and
Pd(PPh3)4 (71 mg, 0.06 mmol) were added and the reaction
mixture was stirred at 80 °C. Upon completion (TLC), the
reaction mixture was poured into sat. aq. NaHCO3 (40 mL)
and the aqueous layer was extracted with Et2O (30 ml, 3×).
The combined organic layers were washed with brine (30
mL), dried (MgSO4) and concentrated in vacuo. The crude
References
(1) (a) Zhang, J.; Wang, W.; Xiong, C.; Hruby, V. J.
Tetrahedron Lett. 2003, 44, 1413. (b) Del Valle, J. R.;
Goodman, M. Angew. Chem. Int. Ed. 2002, 41, 1600.
(c) Flamant-Robin, C.; Wian, Q.; Chiaroni, A.; Sasaki, N. A.
Tetrahedron Lett. 2002, 58, 10475. (d) Davis, F. A.; Fang,
T.; Goswami, R. Org. Lett. 2002, 4, 1599. (e) Van
Betsbrugge, J.; Van Den Nest, W.; Verheyden, P.; Tourwé,
D. Tetrahedron 1998, 54, 1753.
(2) (a) Damour, D.; Herman, F.; Labaudinière, R.; Pantel, G.;
Vuilhorgne, M.; Mignani, S. Tetrahedron 1999, 55, 10135.
(b) Schumacher, K. K.; Jiang, J.; Joullié, M. M.
Tetrahedron: Asymmetry 1998, 9, 47.
(3) (a) 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. (b) Manfré, F.; Pulicani, J. P.
Tetrahedron: Asymmetry 1994, 5, 235.
Synlett 2003, No. 15, 2354–2358 © Thieme Stuttgart · New York

2358
B. C. J. van Esseveldt et al.
LETTER
128.0, 128.0, 127.9, 115.3, 63.5, 53.0, 32.7, 21.7. HRMS
product was purified by chromatography (EtOAc/
heptane = 1:9) to afford 6 (45 mg, 0.22 mmol, 19%) as a
yellow solid. Rf = 0.23 (EtOAc/heptane = 1:9). IR(neat):
3448, 3354, 1705, 1614, 1591, 1487, 1441 cm–1. Mp 49.4 °C.
1H NMR (300 MHz, CDCl3): d = 7.44 (m, 2 H), 7.31 (m, 3
H), 5.59 (s, 1 H), 4.57 (br s, 2 H), 3.82 (s, 3 H). 13C NMR (75
MHz, CDCl3): d = 164.0, 141.2, 131.1, 128.3, 128.1, 123.4,
100.3, 86.6, 85.7, 52.8. HRMS (EI) calcd for C12H11NO2:
201.0790. Found: 201.0792.
Formation of Pyrroline 24: To a solution of 18 (396 mg,
1.11 mmol) in MeCN (12 mL), PdCl2(MeCN)2 (29 mg, 0.11
mmol) was added and the reaction mixture was refluxed.
Upon completion (TLC), the reaction mixture was
concentrated in vacuo and the crude product was purified by
chromatography (EtOAc/heptane = 1:3) to afford 24 (192
mg, 0.54 mmol, 48%) as a white solid. Rf = 0.36 (EtOAc/
heptane = 1:2); [a]D +82.9 (c 1.0, CH2Cl2). Mp 88.3 °C.
IR(neat): 2947, 1736, 1595, 1493, 1444 cm–1. 1H NMR (300
MHz, CDCl3): d = 7.54 (m, 4 H), 7.29 (m, 5 H), 5.35 (dd,
J = 2.1, 3.6 Hz, 1 H), 4.91 (dd, J = 2.1, 9.3 Hz, 1 H), 3.81 (s,
3 H), 2.56 (ddd, J = 2.4, 3.6, 17.1 Hz, 1 H), 2.42 (s, 3 H),
2.31 (ddd, J = 2.1, 9.6, 17.1 Hz, 1 H). 13C NMR (75 MHz,
CDCl3): d = 171.9, 144.9, 144.2, 134.2, 132.6, 129.6, 129.0,
(EI) calcd for C19H19NO4S: 357.1035. Found: 357.1032.
Formation of Proline Derivative 26: To a solution of 24
(120 mg, 0.34 mmol) in CH2Cl2 (6 mL), Et3SiH (0.27 mL,
1.70 mmol), TFAA (0.24 mL, 1.70 mmol) and TFA (0.13
mL, 1.70 mmol) were added at 0 °C. The reaction mixture
was allowed to reach r.t. and stirred until the reaction had
reached completion (TLC). The reaction mixture was
concentrated in vacuo and purified by chromatography
(EtOAc/heptane = 1:4) to afford a diastereomeric mixture of
26 and the trans-isomer 27 (26/27 = 9:1, 90 mg, 0.25 mmol,
74%). Purification of this mixture by chromatography
(EtOAc/heptane = 1:5) followed by crystallisation from
Et2O gave diastereomerically pure 26 as a white solid. Rf =
0.60 (EtOAc/heptane = 1:1); [a]D –68.9 (c 0.5, CH2Cl2). Mp
130.3 °C. IR(neat): 1745, 1597, 1495, 1344 cm–1. 1H NMR
(300 MHz, CDCl3): d = 7.52 (d, J = 8.4 Hz, 2 H), 7.40 (m, 2
H), 7.18 (m, 5 H), 4.77 (t, J = 6.6 Hz, 1 H), 4.57 (t, J = 6.3
Hz, 1 H), 3.79 (s, 3 H), 2.36 (s, 3 H), 2.04 (m, 4 H). 13C NMR
(75 MHz, CDCl3): d = 172.5, 143.3, 141.1, 135.4, 129.2,
128.1, 127.7, 127.2, 127.0, 65.1, 62.2, 52.7, 36.1, 29.7, 21.8.
HRMS (EI) calcd for C19H21NO4S: 359.1191. Found:
359.1183.
Synlett 2003, No. 15, 2354–2358 © Thieme Stuttgart · New York