Preparation and properties of chiral 4-pyrrolidinopyridine (PPY) analogues with dual functional side chains

Article abstract of DOI:10.1016/S0040-4039(03)00021-2

Chiral 4-pyrrolidinopyridine analogues 8-13 with two distinct functional side chains at C(2) and C(4) of the pyrrolidine ring were prepared from 4-hydroxy-L-proline. We examined desymmetrization of meso-1,3-cyclohexanediol through enantioselective acylation using these catalysts and found that introduction of a C(4)-side chain was effective for improving both the chemo- and enantioselectivity of acylation.

Full text of DOI:10.1016/S0040-4039(03)00021-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1545–1548
Preparation and properties of chiral 4-pyrrolidinopyridine (PPY)
analogues with dual functional side chains
Takeo Kawabata,* Roland Stragies, Takayuki Fukaya, Yoshie Nagaoka, Hartmut Schedel and
Kaoru Fuji
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
Received 5 December 2002; revised 29 December 2002; accepted 7 January 2003
Abstract—Chiral 4-pyrrolidinopyridine analogues 8–13 with two distinct functional side chains at C(2) and C(4) of the pyrrolidine
ring were prepared from 4-hydroxy-L-proline. We examined desymmetrization of meso-1,3-cyclohexanediol through enantioselec-
tive acylation using these catalysts and found that introduction of a C(4)-side chain was effective for improving both the chemo-
and enantioselectivity of acylation. © 2003 Elsevier Science Ltd. All rights reserved.
Nonenzymatic kinetic resolution of racemic alcohols
via enantioselective acylation is a recent focus of syn-
Side-chain structures at C(4) of 8–13 were selected
based on the expected function of a 1,4-disubstituted
1
–3
8
thetic attention.
We developed chiral 4-pyrro-
imidazole subunit in 8 and 9 as a general base,
a
lidinopyridine (PPY) analogue 1 which could effectively
catalyze acylative kinetic resolution of racemic diol and3
amino alcohol derivatives with high enantioselectivity.
A unique feature of 1 is that chiral elements are not
present in the catalytically active pyridine ring.
Recently, we reported that chiral PPY analogue 2 could
also promote the acylative kinetic resolution of
tryptophan residue in 10 as a hydrogen-bond donor
and for p–p interaction, and a protected proline subunit
9
in 11–13 as a hydrogen-bond acceptor. Compound 4,
which is readily prepared from commercially available
trans-4-hydroxy-L-proline, was selected as a starting
material for the preparation of chiral nucleophilic cata-
lysts 8–13. Hydrogenolysis of 4 followed by condensa-
tion with 4-bromopyridine gave trans-2,4-disubstituted
pyrrolidinopyridine (5) in 50% yield. The key intermedi-
ate 6 for 8–13 was obtained in 87% yield by treatment
4,5
racemic-3 with a selectivity factor (s) of 8.1. The
structure of the peptide side chain at C(2) in 2 was
found to be closely related to the enantioselectivity of
4,6
10
the acylative catalysis. We report here the prepara-
tion and properties of a new class of chiral PPY
analogues 8–13 with dual functional side chains at C(2)
and C(4) on the pyrrolidine ring (Scheme 1). Our
hypothesis involves the expectation that a peptide side
chain at C(4) might participate in substrate-recognition
through hydrogen-bonding interaction with a sub-
of 5 with iodotrimethylsilane followed by 4 M HCl in
ethyl acetate. Condensation of 6 with
L-tryptophan
methyl ester was performed without protecting the 4-
hydroxyl group by treatment with 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride (EDCI) and
1-hydroxybenzotriazole (HOBT) in the presence of N-
methylmorpholine (NMM) to give 7 in 85% yield. A
second amino acid residue was easily introduced at C(4)
by the EDCI/HOBT method to give the desired cata-
lysts 8–13 in yields of 64–100%. In contrast to a recent
7
strate. Combinatorial introduction of functional side
chains at C(2) and C(4) is possible and may make it
possible to search for a catalyst that is most suitable for
the reaction of interest.
5
b
report on the preparation of N-pyridinyl prolines, no
Keywords: pyrrolidinopyridine; nucleophilic catalyst; desymmetrization; chemoselectivity; combinatorial chemistry.
*
Corresponding author. Tel.: +81-774-38-3191; fax: +81-774-38-3197; e-mail: kawabata@scl.kyoto-u.ac.jp
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00021-2

1
546
T. Kawabata et al. / Tetrahedron Letters 44 (2003) 1545–1548
Scheme 1.
epimerization at C(2) was observed throughout the
transformation. All of these molecules displayed cata-
lytic activity for the acylation of alcohols.
at C(4) in the nucleophilic catalyst improved both the
chemo- and enantioselectivity of the acylation (entries
5, 6 versus 11, 12). To the best of our knowledge, this
is the first example of nonenzymatic enantioselective
1
1,12
13–15
We examined enantioselective desymmetrization of
acylation of 14.
meso-1,3-cyclohexanediol (14) (Table 1). Treatment of
14 with 1.3 mole equivalents of isobutyric anhydride in
The asymmetric desymmetrization of meso-1,2-diol 17
was also examined with catalysts 2 and 8–13 (Table 2).
Acylation of 17 with isobutyric anhydride in the pres-
ence of catalyst 2 in toluene gave mono-ester (1R,
the presence of 5 mol% of catalyst 1 and 1.4 mole
equivalents of 2,4,6-collidine in toluene at 20°C for 4 h
gave monoester 15 in 27% yield (32% ee), diester 16 in
48% yield, and 6% recovery of 14 (entry 3). The pre-
2
S)-18 in 60% ee and in 59% yield (entry 1). Only slight
dominant formation of 16 over 15 could be ascribed to
the fact that 14 is less soluble than 15 in toluene, and
the reaction mixture was suspended at an early stage of
the reaction. The corresponding reaction in a chloro-
form solution, however, gave a similar ratio of 15 to 16
differences were observed in the chemo- and enantiose-
lectivity of acylation with changes in the structure of
catalysts 8–13 (entries 2–9). The highest chemoselectiv-
ity (77%, entry 7) and enantioselectivity (65% ee, entry
9
) for mono-acylation were achieved with catalysts 11
(
entry 4). The observed chemoselectivity seems intrinsic
and 13, respectively. The difference in chirality at C(2%)
in the C(4)-side chains of 12 and 13 did not affect the
selectivity of acylation (entry 8 versus 9). The enan-
tiomeric purity of 18 is the result of enantioselective
acylation of 17 followed by kinetic resolution of 18.
The ee of 18 was increased with an increase in diester-
formation (entry 5 versus 6). This indicates that the
minor enantiomer 18 formed by enantioselective mono-
acylation of 17 is consumed faster than the major
enantiomer in the following kinetic resolution. In fact,
to the acylation of 14, since the ratio of 15 to 16
obtained by acylation with PPY was comparable to
that obtained with 1 (entries 1–4). Similar chemo- and
enantioselectivity was observed in acylation of 14 with
catalyst 2 (entries 3 versus 5). On the other hand,
monoester 15 was the major product of the acylation
with catalysts 8–11 (entries 7–12). Among them, cata-
lyst 10 gave the most improved chemoselectivity (60%,
entry 12) and enantioselectivity (52% ee, entry 11) for
acylation. Thus, the introduction of an ester side chain

T. Kawabata et al. / Tetrahedron Letters 44 (2003) 1545–1548
1547
Table 1. Enantioselective desymmetrization of meso-1,3-
diol 14
In conclusion, we have developed a new class of chiral
PPY analogues with two distinct functional side chains
at C(2) and C(4) of the pyrrolidine ring. Introduction of
the C(4)-side chain was effective for improving the chemo-
and enantioselectivity of acylation. Although these cata-
lysts are not yet practically useful, this approach provides
clues to the development of catalysts with the desired
substrate-specificity.
a
b
Entry
Catalyst
Solvent
15:16:14 (%)
Ee of 15 (%)
1
2
3
4
5
6
7
8
9
PPYc
Toluene
CHCl3
Toluene
CHCl3
Toluene
CHCl3
Toluene
CHCl3
19:48:5
35:39:4
27:48:6
32:46:2
30:43:12
44:29:8
37:35:9
49:31:7
43:28:12
53:22:9
48:32:9
60:28:5
45:36:19
44:9:37
–
–
References
PPYc
1
32
34
28
23
33
20
44
32
52
41
39
24
1
. For a leading reference of asymmetric acylation of alco-
hols: Ichikawa, J.; Asami, M.; Mukaiyama, T. Chem.
Lett. 1984, 949.
1
2
2
8
8
9
9
10
10
11
11
2
. (a) Vedejs, E.; Daugulis, O.; Diver, S. T. J. Org. Chem.
1996, 61, 430; (b) Vedejs, E.; Chen, X. J. Am. Chem. Soc.
1996, 118, 1809; (c) Ruble, J. C.; Latham, H. A.; Fu, G.
C. J. Am. Chem. Soc. 1997, 119, 1492; (d) Miller, S. J.;
Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.;
Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629; (e)
Oriyama, T.; Imai, K.; Sano, T.; Hosoya, T. Tetrahedron
Lett. 1998, 39, 3529; (f) Vedejs, E.; Daugulis, O. J. Am.
Chem. Soc. 1999, 121, 5813; (g) Tao, B.; Ruble, J. C.;
Hoic, D. A.; Fu, G. C. J. Am. Chem. Soc. 1999, 121,
5091; (h) Sano, T.; Imai, K.; Ohashi, K.; Oriyama, T.
Chem. Lett. 1999, 265; (i) Iwasaki, F.; Maki, T.;
Nakashima, W.; Onomura, O.; Matsumura, Y. Org. Lett.
Toluene
CHCl3
Toluene
10
11
12
13
14
CHCl3
Toluene
CHCl3
a
b
c
Yields determined by 1H NMR with dibenzyl ether as an internal
standard.
Determined by GC analysis with a chiral stationary phase, beta-
DEX™ 225.
4
-Pyrrolidinopyridine.
1999, 1, 969; (j) Spivey, A. C.; Fekner, T.; Spey, E. S. J.
Org. Chem. 2000, 65, 3154; (k) Naraku, G.; Shimomoto,
N.; Hanamoto, T.; Inanaga, J. Enantiomer 2000, 5, 135;
Table 2. Enantioselective desymmetrization of meso-1,2-
diol 17
(
l) Spivey, A. C.; Maddaford, A.; Fekner, T.; Redgrave,
A. J.; Frampton, C. S. J. Chem. Soc., Perkin Trans. 1
000, 3460.
2
3
. (a) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J.
Am. Chem. Soc. 1997, 119, 3169; (b) Kawabata, T.;
Yamamoto, K.; Momose, Y.; Yoshida, H.; Nagaoka, Y.;
Fuji, K. Chem. Commun. 2001, 2700.
a
b,c
Entry
Catalyst
18:19:17 (%)
Ee of 18 (%)
4. Kawabata, T.; Stragies, R.; Fukaya, T.; Fuji, K. Chirality
1
2
3
4
5
6
7
8
9
2
8
9
10
11
11
11
12
13
59:26:11
52:26:6
65:22:7
72:19:3
61:27:7
59:13:21
77:18:5
64:28:6
61:27:6
60
43
58
54
59
50
51
63
65
2003, 15, 71.
5. Preparation of PPY analogues from proline has been
reported, see: (a) Delaney, E. J.; Wood, L. E.; Klotz, I.
M. J. Am. Chem. Soc. 1982, 104, 799; (b) Priem, G.;
Anson, M. S.; Macdonald, S. J. F.; Pelotier, B.; Camp-
bell, I. B. Tetrahedron Lett. 2002, 43, 6001.
d
e
6
. For examples, acylative kinetic resolution of racemic-3
catalyzed by 20 and 21 proceeds with selectivity factors of
11 and 1.6, respectively, see Ref. 4.
a
Yield determined by 1H NMR with dibenzyl ether as an internal
standard.
b
Determined by GC analysis with a chiral stationary phase, gamma-
DEX™ 225.
c
d
e
(
1R,2S)-Isomer was obtained in each entry.
.9 Equiv. of isobutyric anhydride was used.
Run in CHCl3.
0
7
. It has been reported that N-methylimidazole analogues
with peptide side chains effectively promote asymmetric
acylation and phosphorylation of alcohols, see: (a) Jarvo,
E. R.; Copeland, G. T.; Papaioannou, N.; Bonitatebus,
P. J., Jr.; Miller, S. J. J. Am. Chem. Soc. 1999, 121,
11638; (b) Sculimbrene, B. R.; Morgan, A. J.; Miller, S. J.
J. Am. Soc. Chem. 2002, 124, 11653.
kinetic resolution of racemic-18 by acylation with isobu-
tyric anhydride in the presence of 12 gave (1R, 2S)-18
in 54% ee at 68% conversion (s=2.7). Thus, the enan-
tiomeric purity of 18 was enhanced by the cooperative
1
6
effects of consecutive acylation processes, which is often
17
observed in the enzymatic hydrolysis of diesters.

1
548
T. Kawabata et al. / Tetrahedron Letters 44 (2003) 1545–1548
−
1
8
. While 1,5-disubsituted imidazoles are known to be active
nucleophilic catalysts (Ref. 7), 1,4-disubsituted surrogates
are not.
1543, 1518, 1440, 1227, 1007 cm ; MS (FAB) m/z (rel
+
intensity) 619 (MH , 3), 335 (4), 181 (6), 169 (100);
HRMS calcd for C H N O , M , 619.2880 (MH ),
+
+
32
39
6
7
9. Trzeciak, A.; Bannwarth, W. Synthesis 1996, 1433.
found m/z 619.2875.
1
0. Jung, M. E.; Lyster, M. A. J. Am. Chem. Soc. 1977, 99,
68.
1. For examples, acylative kinetic resolution of racemic-3
with isobutyric anhydride was promoted by 5 mol% of 8,
13. For an example of enzymatic desymmetrization of meso-
1,3-cyclohexanediol, see: Mattson, A.; Orrenius, C.;
Oehrner, N.; Unelius, C. R.; Hult, K.; Norin, T. Acta
Chem. Scand. 1996, 50, 918.
9
1
9
(
9
, and 10 to give (1S, 2R)-3 in 88% ee at 68% conversion
s=6.3), in 83% ee at 67% conversion (s=5.6), and in
9% ee at 78% conversion (s=7.6), respectively.
2. Selected data: 7: Colorless prisms (MeOH/Et O), mp
14. For examples of nonenzymatic acylative desymmetriza-
tion of meso-diols, see: (a) Terashima, S.; Yamada, S.
Tetrahedron Lett. 1977, 18, 1001; (b) Duhamel, L.; Her-
man, T. Tetrahedron Lett. 1985, 26, 3099; (c) Ishihara,
K.; Kubota, M.; Yamamoto, H. Synlett 1994, 611; (d)
Yamada, S.; Katsumata, H. Chem. Lett. 1998, 995; (e)
Oriyama, T.; Imai, K.; Sano, T.; Hosoya, T. Tetrahedron
Lett. 1998, 39, 3529. Also see Ref. 2a.
1
2
20
1
2
17–220°C. [h]D −62 (c 1.0, MeOH). H NMR (400
MHz, CD OD) l 7.81 (d, J=6.3 Hz, 2H), 7.56 (J=8.1
Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.12 (td, J=8.1, 1.2
Hz, 1H), 7.10 (s, 1H), 7.04 (td, J=8.1, 1.0 Hz, 1H), 6.12
3
(
(
d, J=6.3 Hz, 2H), 4.78 (dd, J=7.3, 5.3 Hz, 1H), 4.40
quintet, J=5.1 Hz, 1H), 4.20 (t, J=6.1 Hz, 1H), 3.70 (s,
15. Typical procedure for enantioselective desymmetrization
of 14 (Table 1, entry 11): Isobutyric anhydride (22 mL,
0.13 mmol) was added to a solution of 14 (12 mg, 0.10
mmol), 10 (3.6 mg, 5 mmol), and 2,4,6-collidine (19 mL,
0.14 mmol) in 0.5 mL of toluene at 20°C. The mixture
was stirred at 20°C for 4 h. The reaction mixture was
diluted with ethyl acetate and washed with 1 M HCl, satd
3
H), 3.60 (dd, J=10.0, 5.1 Hz, 1H), 3.38 (dd, J=15.4, 5.3
Hz, 1H), 3.25 (J=10.0, 4.4 Hz, 1H), 3.17 (dd, J=15.4,
0.0 Hz, 1H), 2.30–2.23 (m, 1H), 2.05–1.98 (m, 1H); IR
1
−
1
(KBr) 3294, 1741, 1667, 1601, 1520, 1227, 1005 cm ; MS
+
m/z (rel intensity) 408 (M , 20), 279 (30), 163 (100);
HRMS calcd for C H N O , M , 408.1798, found m/z
+
aq. NaHCO , and brine, dried with Na SO , filtered and
22
24
4
4
3 2 4
4
1
08.1770. 11: Colorless prisms (MeOH/Et O), mp 128–
evaporated in vacuo. Yields of 15, 16, and 14 were
2
20
1
32°C. [h] −61 (c 1.0, CHCl3). H NMR (400 MHz,
determined to be 48, 32, and 9%, respectively by 300
D
1
CDCl ) l 9.14, 9.11 (two s, ratio=1:5, 1H), 8.13 (d,
MHz H NMR with dibenzyl ether an internal standard.
3
J=6.6 Hz, 2H), 7.46, 7.45 (two d, J=8.1 and 8.1 Hz,
ratio=5:1, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.17 (td, J=8.1,
Enantiomeric purity of 15 was determined to be 52% ee
by GLC analysis with beta-DEX™ 225 at 115°C, t
=65,
R
1
.0 Hz, 1H), 7.10 (td, J=8.1, 0.7 Hz, 1H), 6.90 (d, J=2.2
67 min.
Hz, 1H), 6.79, 6.71 (two q, J=4.9 and 4.9 Hz, ratio=5:1,
16. Similar cooperative effect, albeit less significant, was
observed in the acylation of 14 with 10 in toluene: Kinetic
resolution of racemic-15 with 10 in toluene gave recov-
ered 15 in 18% ee at 47% conversion (s=1.8) whose
absolute configuration was same as that obtained by
mono-acylation of 14 with 10.
1
4
H), 6.60 (d, J=8.1 Hz, 1H), 6.22 (d, J=6.6 Hz, 2H),
.93 (quint, J=5.1 Hz, 1H), 4.87–4.80 (m, 1H), 4.50, 4.34
(
(
two dd, J=8.3, 2.2 and 8.8, 2.2 Hz, ratio=5:1, 1H), 4.11
dd, J=9.0, 6.1, 1H), 3.69 (s, 3H), 3.64–3.35 (m, 4H),
3
.24–3.18 (m, 2H), 2.84, 2.70 (two d, J=4.9 and 4.9 Hz,
ratio=1:5, 3H), 2.67–2.46 (m, 4H), 2.36–2.29 (m, 2H),
.16–1.88 (m, 4H); IR (KBr) 3286, 1737, 1660, 1601,
17. Wang, Y.-F.; Chen, C.-S.; Girdaukas, G.; Sih, C. J. J.
2
Am. Chem. Soc. 1984, 106, 3695.