Evidence of the electronic factor for the highly enantioselective catalytic efficiency of Cinchona-derived phase-transfer catalysts

Article abstract of DOI:10.1021/ol050123u

(Chemical Equation Presented) The Cinchona alkaloid-derived quaternary ammonium salts containing 2′-N-oxypyridine and 2′-cyanobenzene moieties were prepared and evaluated as phase-transfer catalysts in the enantioselective alkylation of glycine imine este

Full text of DOI:10.1021/ol050123u

ORGANIC
LETTERS
2
005
Vol. 7, No. 6
129-1131
Evidence of the Electronic Factor for
the Highly Enantioselective Catalytic
Efficiency of Cinchona-Derived
Phase-Transfer Catalysts
1
Mi-Sook Yoo, Byeong-Seon Jeong, Jeong-Hee Lee, Hyeung-geun Park,* and
Sang-sup Jew*
Research Institute of Pharmaceutical Sciences and College of Pharmacy,
Seoul National UniVersity, Seoul 151-742, Korea
hgpk@plaza.snu.ac.kr
Received January 20, 2005
ABSTRACT
The Cinchona alkaloid-derived quaternary ammonium salts containing 2
evaluated as phase-transfer catalysts in the enantioselective alkylation of glycine imine ester 1. The N-oxypyridine and cyanobenzene moieties
might play an important role to form a rigid conformation by coordinating with H O via hydrogen bonding leading to high enantioselectivity
97 >99% ee), which provides evidence of an electronic factor for the high enantioselective catalytic efficiency in phase-transfer alkylation.
′-N-oxypyridine and 2′-cyanobenzene moieties were prepared and
2
(
∼
Recently, quaternary ammonium salts derived from Cinchona
alkaloids have been successfully applied to the asymmetric
1
phase-transfer catalytic alkylation. The asymmetric alkyla-
tion of the glycine imine ester 1, a precursor of the
enantioselective synthesis of natural and unnatural R-amino
acids, has been studied extensively (eq 1).2
It has been proposed that the high enantioselectivity was
due to steric bulkiness of the N -arylmethyl group in
(
1) (a) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc.
984, 106, 446. (b) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem.
Soc. 1989, 111, 2353. (c) Lygo, B.; Wainwright, P. G. Tetrahedron Lett.
1
1
+
1
Cinchona-derived catalyst. Formation of the geometrically
most stable ion pair between E-enolate anion of 1 and the
bridgehead ammonium cation and the following addition of
electrophile accessed exclusively to one face of the ion-paired
enolate to yield optically enriched R-amino acid derivatives.
Recent findings from our laboratory demonstrated, how-
997, 38, 8595. (d) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc.
997, 119, 12414. (e) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem.
Soc. 1999, 121, 6519. (f) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka,
K. J. Am. Chem. Soc. 2000, 122, 5228. (g) Jew, S.-s.; Jeong, B.-S.; Yoo,
M.-S.; Huh, H.; Park, H.-g. Chem. Commun. 2001, 1244. (h) Park, H.-g.;
Jeong, B.-S.; Yoo, M.-S.; Park, M.-k.; Huh, H.; Jew, S.-s. Tetrahedron Lett.
001, 42, 4645. (i) Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park,
M.-k.; Lee, Y.-J.; Kim, M.-J.; Jew, S.-s. Angew. Chem., Int. Ed. 2002, 41,
036. (j) Jew, S.-s.; Lee, Y.-J.; Lee, J.; Kang, M. J.; Jeong, B.-S.; Lee,
J.-H.; Yoo, M.-S.; Kim, M.-J.; Choi, S.-h.; Ku, J.-M.; Park, H.-g. Angew.
Chem., Int. Ed. 2004, 43, 2382.
2
+
ever, that the electronic effect of the N -arylmethyl unit in
3
the catalyst is also responsible for high enantioselectivity.3
Catalysts 3 and 4 containing 2′-F showed enhanced enantio-
selectivity compared to those of nonsubstituted analogues,
(
2) (a) Maruoka, K.; Ooi, T. Chem. ReV. 2003, 103, 3013. (b) O’Donnell,
M. J. Acc. Chem. Res. 2004, 37, 506.
1
0.1021/ol050123u CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/24/2005

respectively while they exert virtually the same steric effect
Figure 1). We have proposed that the high enantioselec-
crystal structure by internal hydrogen bonding, similar to
fluorobenzenes. These reports prompted us to prepare new
6
(
Cinchona alkaloid-derived ammonium salts bearing N-oxy-
pyridine and cyanobenzene moieties at 2′ position which
were expected to show similar electronic effects as those
with 2′-F-phenyl ring (3, 4).
+
+
N -(1-Oxypyridin-2-ylmethyl)-cinchona catalyst 7 and N -
1-cyanobenzyl)-cinchona catalyst 9 were prepared from (-)-
(
cinchonidine along with 2-chloromethylpyridine-1-oxide and
-cyanobenzyl chloride, respectively by previously reported
2
3
methods. To confirm the electronic effect of the N-oxide
and cyano group functionality, 2′-pyridine analogue 6 and
2
′-acetylene analogue 8 were prepared, respectively.
Figure 2. Stereoview of plausible hydrogen bonding between
catalyst 10 and H O.
2
Figure 1. Electronically modified Cinchona alkaloid quaternary
ammonium salts.
The capability of the catalysts 6-9 along with 5 on the
introduction of enantioselectivity was evaluated by the
benzylation of 1 with 5 mol % of each catalyst, benzyl
bromide, and 50% aqueous KOH in toluene-chloroform
tivities might be due to more rigid conformations of catalysts
caused by the electronic interactions involving water between
C(9)-O and 2′-F in catalyst, for instance, hydrogen bonding
or induced dipole-dipole interaction.
(volume ratio ) 7:3) at 0 °C for 5 h (Table 1). As shown in
Table 1, the replacement of phenyl ring (5, 70% ee) with
Hydrogen bonds are important because of the effects that
they have on the properties of compounds. Hydrogen bond-
ing, especially the intramolecular variety, changes many
chemical properties. For example, it often plays a significant
role in determining reaction rates by influencing the con-
Table 1. Evaluation of Catalytic Efficiency Using Catalytic
Phase-Transfer Benzylationa
4
formation of molecules, and it is also important in maintain-
ing the three-dimensional structures of protein and nucleic
b
c
d
5
entry
catalyst
T (°C)
yield (%)
% ee (config )
acid molecules. In addition to CO
2
H, OH, and NH that are
1
2
3
4
5
6
7
8
9
5
6
0
0
92
95
92
90
95
94
95
94
96
70 (S)
61 (S)
90 (S)
75 (S)
92 (S)
96 (S)
98 (S)
96 (S)
98 (S)
typical functional groups to form hydrogen bonds, N-oxy-
pyridine and cyanobenzene were reported to form a stable
7
0
8
0
9
0
(3) (a) Jew, S.-s.; Yoo, M.-S.; Jeong, B.-S.; Park, I. Y.; Park, H.-g. Org.
10
10
11
11
0
Lett. 2002, 4, 4245. (b) Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.;
Park, B.-s.; Kim, M. G.; Jew, S.-s. Tetrahedron Lett. 2003, 44, 3497.
-20
0
(
4) For reviews of the effect of hydrogen bonding on reactivity, see:
a) Sadekov, I. D.; Minkin, V. I.; Lutskii, A. E. Russ. Chem. ReV. 1970,
9, 179. (b) Hibbert, F.; Emsley, J. AdV. Phys. Org. Chem. 1990, 26, 255.
5) (a) Wipf, P.; Heimgartner, H. HelV. Chim. Acta 1988, 71, 258. (b)
Hodgkin, E. E.; Clark, J. D.; Miller, K. R.; Marshall, G. R. Biopolymers
990, 30, 533. (c) Di Blasio, B.; Pavone, V.; Lombardi, A.; Pedone, C.;
-20
(
a
The reaction was carried out with 5.0 equiv of benzyl bromide and
0.0 equiv of 50% aqueous KOH in the presence of 5.0 mol % of catalyst
3
1
(
in toluene/chloroform (7:3) under the given temperature conditions.
b
Isolated yields. c The enantiopurity was determined by HPLC analysis of
1
the benzylated imine 2e using a chiral column (Chiralcel OD) with hexanes/
Benedetti, E. Biopolymers 1993, 33, 1037. (d) Toniolo, C.; Crisma, M.;
Formaggio, F.; Valle, G.; Cavicchioni, G.; Pr e´ cigoux, G.; Aubry, A.;
Kamphius, J. Biopolymers 1993, 33, 1061. (e) Toniolo, C. Jassen Chim.
Acta 1993, 11, 10. (f) Karle, I. L.; Rao, R. B.; Prasad, S.; Kaul, R.; Balaram,
P. J. Am. Chem. Soc. 1994, 116, 10355. (g) Formaggio, F.; Pantano, M.;
Crisma, M.; Bonora, G. M.; Toniolo, C.; Kamphius, J. J. Chem. Soc., Perkin
Trans. 2 1995, 1097. (h) Benedetti, E. Biopolymers 1996, 40, 3. (i) Karle,
I. L.; Kaul, R.; Rao, R. B.; Raghothama, S.; Balaram, P. J. Am. Chem. Soc.
2
-propanol (500:2.5) as the eluent. d The absolute configuration was
confirmed by comparison of the HPLC retention time of an authentic sample,
which was synthesized independently by reported procedures.
1
-3
pyridine (6, 61% ee) resulted in a decrease in the enantio-
selectivity. In contrast, the N-oxypyridine derivative (7, 90%
1
997, 119, 12048.
1130
Org. Lett., Vol. 7, No. 6, 2005

ee) gave considerable enhancement in enantiomeric excess,
which implied N-oxypyridine moiety plays a crucial role in
enantioselectivity.
Table 2. Catalytic Enantioselective Phase-Transfer Alkylation
Using Catalysts 10 and 11a
The 2′-CN-catalyst 9 also showed dramatic enhancement
(92% ee) compared to the reference catalyst 5. However,
despite the steric similarity to the 2′-CN catalyst 9, the 2′-
acetylene analogue 8 showed only marginal increase in
enantioselectivity (75% ee), suggesting that the nitrogen atom
in the 2′-CN moiety is important in the increase of enanti-
oselectivity.
We speculate that the difference in enantioselectivity
between pyridine (6) and N-oxypyridine (7) derivatives, and
acetylenylbenzene (8) and cyanobenzene (9) derivatives
might be caused by the electronegativity requirement for
hydrogen bonding. The results are in agreement with those
3
of the 2′-F-containing catalysts. Therefore, the results herein
along with our previous findings support the hypothesis that
hydrogen bonding between water and Cinchona catalyst
could provide the more rigid conformation leading to high
enantioselectivity (Figure 2).
We then further prepared 10 and 11 to enhance the
catalytic efficiency in two steps from (-)-hydrocinchonidine.
It has been reported that O-allyl derivatives are more efficient
catalysts than their free OH analogues.1 The same tendency
was observed in 3-ethyl derivatives versus 3-vinyl ana-
,3
1
,3
logues. In line with general tendencies described above,
the enantioselectivity was enhanced to 96% ee at 0 °C in
the both case of 10 and 11 (entries 6 and 8), and improved
to even higher enantiomeric excess (98% ee) at lower
reaction temperature (-20 °C, entries 7 and 9). Moreover,
when 10 and 11 were employed for the alkylation with
various alkyl halides, excellent enantioselectivities (97∼>99%
ee) were obtained in both nonactive aliphatic and active alkyl
halides as shown in Table 2.
In conclusion, N(1)-2′-N-oxypyridinylmethyl and N(1)-
2′-cyanobenzyl derivatives of Cinchona alkaloid were de-
veloped as electronically modified version of chiral phase-
transfer catalysts. Considerable enhancement of catalytic
efficiency in the enantioselective phase-transfer alkylation
of the glycine anion equivalent 1 was observed. The new
evidences might indicate that the electronic factor could be
an important factor in enantioselectivity along with conven-
tional steric bulkiness. N(1)-O(9)-cyclized Cinchona am-
monium salts and non-Cinchona quaternary ammonium salts
containing F, N-oxypyridine, and cyanobenzene groups are
now under investigation.
a
The reaction conditions were same as Table 1 except in the case of the
alkyl halides. b Isolated yields. c The enantiopurity was determined by HPLC
analysis of the alkylated imine 2 using a chiral column (Chiralcel OD) with
hexanes/2-propanol as eluents. d The absolute configuration was assigned
by the relative retention times of both enantiomers determined previ-
ously.1
-3
Acknowledgment. This work was supported by a grant
R01-2002-000-0005-0) from the Basic Research Program
of the KOSEF (2004).
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterizations of the new
catalysts. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
(6) (a) Ulku, D.; Huddle, B. P.; Morrow, J. C. Acta Crystallogr. 1971,
B27, 432. (b) Thalladi, V. R.; Weiss, H.-C.; Blaeser, D.; Boese, R.; Nangia,
A.; Desiraju, G. R. J. Am. Chem. Soc. 1998, 120, 8702.
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