A rapid catalytic asymmetric synthesis of 1,3,4-trisubstituted pyrrolidines

Article abstract of DOI:10.1016/j.tetlet.2004.02.114

The asymmetric synthesis of 1,3,4-trisubstituted pyrrolidines was accomplished in two steps from readily available starting materials. A 1,3-dipolar cycloaddition of an azomethine ylide to a propiolate ester followed by a Rh-catalyzed asymmetric 1,4-arylation of the resulting pyrroline with an arylboronic acid provided the desired 1,3,4-trisubstituted pyrrolidine products in good to excellent enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2004.02.114

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3265–3268
A rapid catalytic asymmetric synthesis of 1,3,4-trisubstituted
pyrrolidinesq
Kevin M. Belyk,a,* Charlotte D. Beguin,a Michael Palucki,a Nelu Grinberg,b
Jimmy DaSilva,a David Askina and Nobuyoshi Yasudaa
aDepartment of Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
bDepartment of Analytical Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
Received 8 December 2003; revised 23 February 2004; accepted 24 February 2004
Abstract—The asymmetric synthesis of 1,3,4-trisubstituted pyrrolidines was accomplished in two steps from readily available
starting materials. A1,3-dipolar cycloaddition of an azomethine ylide to a propiolate ester followed by a Rh-catalyzed asymmetric
1,4-arylation of the resulting pyrroline with an arylboronic acid provided the desired 1,3,4-trisubstituted pyrrolidine products in
good to excellent enantioselectivities.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Substituted pyrrolidines are structural motifs found in
numerous natural products and biologically active
compounds.1 One such class of compounds recently
identified by Merck as CCR5 antagonists with potent
anti-HIV activity is a series of chiral 1,3,4-trisubstituted
pyrrolidines.2 This substitution pattern is also prevalent
in a series of recently reported pyrrolidine-based
monoamine transporter inhibitors,3 coagulation factor
Xa inhibitors,4 and endothelin receptor antagonists.5
Given their importance, we desired to develop a rapid
asymmetric synthesis of these chiral pyrrolidines from
readily available starting materials.
stabilized azomethine ylide 2 to an a,b-unsaturated
dipolarophile 1.6 An asymmetric variant of this reaction
utilizes oxazolidinone or camphorsultam-based chiral
auxiliaries Xc appended to the dipolarophile. This aux-
iliary-based approach was shown to give 1,3,4-trisub-
stituted pyrrolidine cycloadducts 3 and 4 with modest
diastereoselectivity (up to 48% de).7 Arecent report
utilizing both a chiral auxiliary and chiral azomethine
ylide (where R contains a stereogenic center) provided a
slight increase in selectivity.8 Indeed, our initial investi-
gations using these approaches verified that the cam-
phorsultam-based chiral auxiliary provided the best
results. However, several limitations of the chiral aux-
iliary-based approach (e.g. added steps to append and
remove the chiral auxiliary, modest selectivities, and
chromatography required to separate the undesired
One of the most direct and widely used methods for the
preparation of substituted pyrrolidines, as outlined in
Scheme 1, involves a 1,3-dipolar cycloaddition of non-
O
O
Ar
Ar
O
Xc
Xc
N
R
+
+
Ar
Xc
N
R
3
N
R
1
2
4
Scheme 1.
Keywords: Pyrrolidine; 1,3-Dipolar cycloaddition; Asymmetric 1,4-addition; Rhodium-catalyzed; Arylboronic acid.
q Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2004.02.114
* Corresponding author. Tel.: +1-7325941927; fax: +1-7325945170; e-mail: kevin_belyk@merck.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.114

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K. M. Belyk et al. / Tetrahedron Letters 45 (2004) 3265–3268
diastereomer) prompted us to develop a catalytic
method for the preparation of these chiral pyrrolidines.
because of its availability and the mild conditions under
which the ylide can be generated. The unsaturated esters
were found to be both air and thermally sensitive.11
While both 8a and 8b were found to be unstable oils,12
t-butyl ester 8c could be obtained as a stable solid with
excellent purity after a single crystallization. Formation
of a significant amount of double cycloaddition adduct 9
was observed in the case of 8c.
Our retrosynthetic analysis of 1,3,4-trisubstituted pyrr-
olidines is shown in Scheme 2. Pyrroline 5 can be
obtained via 1,3-dipolar cycloaddition of azomethine
ylide 2 with propiolate ester 6.9 Asymmetric 1,4-aryla-
tion of 5 could subsequently be accomplished with an
arylboronic acid10 to afford the nonracemic 1,3,4-tri-
substituted pyrrolidines. This novel two step catalytic
route is attractive due not only to the readily available
starting materials, but to the ability to prepare either
chiral antipode simply by selecting the appropriate
enantiomer of the chiral ligand.
The Rh-catalyzed 1,4-conjugate addition of phenyl-
boronic acid to 8c was subsequently investigated in the
presence of a variety of Rh(I) catalysts and different
solvents. The results of these studies are shown in Table
1.
Avariety of substituted pyrroline esters were prepared,
as shown in Scheme 3, under acid-catalyzed 1,3-dipolar
cycloaddition conditions utilizing commercially avail-
able N-benzyl-N-(methoxymethyl)-trimethylsilylmethyl-
amine (7) as the azomethine ylide source and
commercially available propiolate esters as dipolaro-
philes.9 Protected azomethine precursor 7 was chosen
The 1,4-addition reaction provided the desired 1,3,4-
trisubstituted pyrrolidine 11c in only 13% yield when
using conditions similar to those reported by Miyuara
and co-workers (entry 1).13 The reaction was sluggish
and 8c was found to be unstable at high reaction tem-
peratures. The use of [Rh(Cl)(C2H2)]2/BINAP and
KOH in place of Rh(acac)(C2H2)2/BINAP, gave slightly
O
O
O
OR
Ar
OR
OR
Ar-B(OH)2
N
R
*
*
+
N
R
N
R
5
2
6
Scheme 2.
Ph
O
O
O
OR
Ph
O
N
N
PhB(OH)2, Rh( I),
BINAP
OR
OR
+
MeO
N
SiMe3
cat. CF3CO2H
CH2Cl2,
OR
+
N
N
Ph
6a = Me
b = Et
Ph
11
Ph
8a-c
7
% Yield 8 (9)
a = 75 (5)
Ph
9a-c
c = tBu
b = 86 (3)
c = 65 (18)
Scheme 3.
Table 1. Catalyst screening experiments for the Rh(I)/BINAP-catalyzed 1,4-addition of PhB(OH)2 to 8c.
Entry
Rh catalysta
Temperature (ꢁC)b
Solventc
Time (h)
Assay yield 11cd (%)e
1
2
3
4
5
6
7
Rh(acac)(C2H2)2
f
[Rh(Cl)(C2H2)]2
100
50
75
50
50
50
50
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
THF/H2O
16
16
16
16
16
16
16
13
36
[Rh(Cl)(C2H2)]2
[Rh(Cl)(C2H2)]2
[Rh(OH)(cod)]2
[Rh(OH)(cod)]2
[Rh(OH)(cod)]2
34
21
Dioxane/H2O
THF/H2O
(EtOCH2)2/H2O
92
95 (70)g
51
a All experiments were run in the presence of 0.06 equiv Rh, 0.09 equiv BINAP, and 2.5 equiv PhB(OH)2.
b Oil bath temperature in which reaction flask was immersed in.
c All experiments were run in the presence of 7 equiv H2O and at a concentration of 0.2 M.
d Assay yield was determined by HPLC versus an external standard solution of the purified substrate.
e Isolated yield in parenthesis.
f KOH (0.06 equiv) was used as an additive.
g Isolated yield reported is the average of three runs.

K. M. Belyk et al. / Tetrahedron Letters 45 (2004) 3265–3268
3267
O
O
O
2.5 equiv. Ar-B(OH)2,
Ar
Ar
0.03 equiv. [Rh(OH)(cod)]2,
OR
OR
OH
0.09 equiv. (S)-BINAP,
8 equiv. TFA,
N
N
N
1,2-dichloroethane,
reflux
7 equiv. H2O,
THF
Ph
11-19
Ph
Ph
8a-c
20-22
Scheme 4.
Table 2. Results for the Rh-catalyzed 1,4-addition of ArB(OH)2 to 8a–c and saponification
Entry
Ar–B(OH)2
Ar ¼
3-F–C6H4
Temperature (ꢁC)a
Time (h)
Isolated yield (% ee)b 11–19
Isolated yieldc (% ee)d 20–22
1e
2e
3e
4
100
100
100
50
16
16
16
4
51 (65) 12a
55 (81) 12b
28 (91) 12c
74 (96) 12c
70 (95) 11c
76 (89) 13c
23 (95) 14c
52 (78) 15c
87 (84) 16c
79 (85) 17c
No rxn 18c
10 (-) 19c
3-F–C6H4
3-F–C6H4
3-F–C6H4
Ph
5
50
50
4
85 (96) 20
78 (89) 21
6
4-CH3–C6H4
3-CF3–C6H4
4-OMe–C6H4
4-Cl–C6H4
2-Napthelene
1-Napthelene
2-CH3–C6H4
4
7
50
50
24
19f
19
19
19
19
8
92 (78) 22
9
50
50
10
11
12
50
50
a Oil bath temperature in which reaction flask was immersed in.
b ee Determined by HPLC analysis of the isolated substrate on a chiral column.
c Overall isolated yield from 8c.
d ee Determined by SFC analysis of the isolated substrate on a chiral column.
e Rh(acac)(C2H2)2 (0.06 equiv) was used as catalyst and dioxane/H2O as solvent.
f Another 0.03 equiv of [Rh(OH)(cod)]2 was added to the reaction after 4 h.
improved results (entry 2).14 Increasing the reaction
temperature did not improve the yield (entry 3).
Replacing dioxane with THF as solvent also did not
improve the yield (entry 4). It was ultimately found that
use of [Rh(OH)(cod)]2/BINAP gave the best results for
the 1,4-addition (entries 5–7).15 Use of THF/H2O as
solvent with this catalyst provided the highest assay
yields (typically 89–98%). Isolation of 11c, however,
proved difficult. Pyrrolidine 11c was found to be
unstable to silica gel and alumina chromatography. For
example, a 20–30% loss of 11c was observed over silica
gel chromatography. However, direct saponification of
the crude ester to the carboxylic acid provided a stable
pyrrolidine intermediate that could be purified by crys-
tallization. The addition of a saponification step also
provides a substrate that can be readily esterified, cou-
pled or reduced.
with electron-deficient arylboronic acids under the
optimized conditions.16 The 1,4-addition reaction,
however, did not work with sterically hindered boronic
acids (entries 11 and 12). Direct saponification of the
crude 1,4-addition adduct to the corresponding car-
boxylic acid provided a higher overall yield of the 1,4-
addition adduct from 8c in certain cases (entries 20–22).
The trans geometry of 20 was confirmed by NOE. The
absolute configuration was not determined.
In summary, we have demonstrated the rapid asym-
metric synthesis of 1,3,4-trisubstituted pyrrolidines in
two steps utilizing readily available starting materials. A
series of pyrroline derivatives were prepared via 1,3-
dipolar cycloaddition and subsequently found to
undergo Rh-catalyzed asymmetric 1,4-addition with a
variety of arylboronic acids in moderate to good
isolated yields and in excellent enantioselectivities. The
results reported herein represent a completely new
application of the Rh-catalyzed asymmetric 1,4-addition
reaction as well as an improved method for the asym-
metric synthesis of 1,3,4-disubstituted pyrrolidines.
We next investigated the scope of the asymmetric 1,4-
addition reaction, as outlined in Scheme 4. Avariety of
arylboronic acids were examined in the 1,4-addition and
some of the resulting crude pyrrolidine esters were
converted directly to their corresponding free carboxylic
acids. The results of these studies are summarized in
Table 2.
Acknowledgements
The enantioselectivity for the 1,4-addition was observed
to increase with the steric bulkiness of the propiolate
ester (entries 1–3). It was found that the Rh-catalyzed
1,4-addition worked well with either electron neutral
arylboronic acids, electron-rich arylboronic acids, and
The authors would like to thank S. Pollard and M. Biba
for their assistance in developing the SFC assays initially
used to characterize the chiral pyrrolidines. The authors

3268
K. M. Belyk et al. / Tetrahedron Letters 45 (2004) 3265–3268
J. S.; Park, T. H.; Kim, M. H.; Kim, W. J. Synthesis 1990,
753–754.
12. Both 8a and 8c were found to significantly degrade within
one week, even with storage at )20 ꢁC under argon.
13. Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J. Org.
Chem. 2000, 65, 5951–5955.
would also like to thank R. Reamer assistance in NMR
characterization of the pyrrolidines and P. Dormer for
carrying out all NOE experiments.
14. Hayashi, T.; Takahashi, M.; Takaya, T.; Ogasawara, M.
J. Am. Chem. Soc. 2002, 124, 5052–5058.
References and notes
15. For preparation of [Rh(OH)(cod)]2, see: Uson, R.; Oro,
L. A.; Cabeza, J. A. Inorg. Synth. 1985, 23, 129.
1. For example, see: The Alkaloids: Chemistry and Biol-
ogy; Cordell, G. A., Ed.; Academic: San Diego, 2000; Vol.
54.
16. Pyrrolidine 11c was prepared as follows: Phenylboronic
acid (1.18 g, 9.6 mmol), (S)-Binap (220 mg, 0.35 mmol),
[Rh(OH)(cod)]2 (52 mg, 0.1 mmol), and 8c (1.0 g,
3.8 mmol) were charged to a Schlenk tube, purged with
Argon, and then diluted with THF (23 mL) and water
(490 lL, 27 mmol). The resulting deep-red solution was
warmed to 50 ꢁC for 16 h and then quenched with sat.
NaHCO3 (70 mL). The layers were separated and the
aqueous layer extracted with CH2Cl2 (100 mL). The
organic layer was concentrated and the oil purified by
flash chromatography (SiO2, 10% EtOAc:hexanes) to
provide 11c in 71% yield as a colorless oil (1.06 g).
1H NMR: (400 MHz, CDCl3): d 7.2–7.5 (10H, m), 3.6–3.9
(4H, m); 3.00–3.15 (2H, m), 2.9 (1H, m), 3.7 (1H, m). 13C
NMR (CDCl3): d 28.16, 47.20, 52.86, 57.46, 60.07, 61.92,
80.61, 126.46, 127.06, 127.59, 128.35, 128.52, 128.72,
139.06, 144.61, 173.45. Alternatively, the crude reaction
mixture could be directly saponified as follows: TFA
(2.3 mL, 30 mmol) was added to a solution of crude 11c
(1.2 g, 3.6 mmol) in 1,2-dichloroethane (15 mL) and heated
at reflux for 6 h. Aqueous NaOH (1 N) was added at 20 ꢁC
until the pH of the aqueous phase measured 6.8. The
layers were separated and the organic layer concentrated
to ꢀ2 mL, at which point acetone (10 mL) was added to
complete precipitation of 20. The suspension was filtered
and the solids washed with 2 · 5 mL of water. The white
solid was dried under vacuum to provide 910 mg of trans-
1-benzyl-4-phenylpyrrolidine-3-carboxylic acid (20) in
85% overall yield from 8c. 1H NMR (500 MHz, CD3OD):
d 7.52 (m, 2H), 7.44–7.41 (om, 3H), 7.36 (m, 2H), 7.31 (m,
2H), 7.24 (m, 1H), 4.34 (AB doublet, Dm ¼ 6:2, 2H), 3.85
(dt, J ¼ 10:7, 8.3 Hz, 1H), 3.70 (dd, J ¼ 10:7, 8.3 Hz, 1H),
3.57 (d, J ¼ 8:3 Hz, 2H), 3.27 (t, J ¼ 10:7 Hz, 1H), 3.20 (q,
J ¼ 8:3 Hz, 1H) ppm. 13C NMR (125 MHz, CD3OD):
d 177.91, 140.96, 133.30, 131.50, 130.74, 130.37, 130.00,
128.75, 128.54, 61.10, 59.89, 58.55, 53.49, 48.55 ppm.
Results for all NOE experiments can be found in the
Supplementary data section.
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