Highly enantioselective construction of axial chirality by palladium-catalyzed cycloisomerization of N- alkenyl arylethynylamides

Article abstract of DOI:10.1021/ol900373z

A cationic palladium(ll)/(S)-xyl-Segphos complex catalyzes enantioselective cycloisomerizations of N-alkenyl arylethynylamldes leading to axlally chlral 4-aryl-2-pyridones In high yields with high ee values. The present catalysis represents the first enantioselective construction of axial chlrallty by the transition-metal-catalyzed cyclolsomerlzatlon.

Full text of DOI:10.1021/ol900373z

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1805-1808
Highly Enantioselective Construction of
Axial Chirality by Palladium-Catalyzed
Cycloisomerization of N-Alkenyl
Arylethynylamides
Hidetomo Imase,† Takeshi Suda,† Yu Shibata,† Keiichi Noguchi,‡ Masao Hirano,†
and Ken Tanaka*,†
Department of Applied Chemistry, Graduate School of Engineering, and
Instrumentation Analysis Center, Tokyo UniVersity of Agriculture and Technology,
Koganei, Tokyo 184-8588, Japan
tanaka-k@cc.tuat.ac.jp
Received February 22, 2009
ABSTRACT
A cationic palladium(II)/(S)-xyl-Segphos complex catalyzes enantioselective cycloisomerizations of N-alkenyl arylethynylamides leading to axially
chiral 4-aryl-2-pyridones in high yields with high ee values. The present catalysis represents the first enantioselective construction of axial
chirality by the transition-metal-catalyzed cycloisomerization.
Axially chiral biaryls are valuable structures for a large
number of chiral ligands and biologically active compounds.
Therefore, various atroposelective syntheses of these com-
pounds have been reported to date.1 As a conceptually new
approach, asymmetric aromatization through transition-metal-
catalyzed [2 + 2 + 2] cycloadditions has proven to be a
powerful method for this purpose.2 Following the pioneering
through enantioselective [2 + 2 + 2] cycloadditions cata-
lyzed by Co(I),2a Ir(I),2b and Rh(I) complexes.2c For the
synthesis of axially chiral 6-aryl-2-pyridones, we developed
the rhodium-catalyzed enantioselective [2 + 2 + 2] cycload-
dition of 1,6-diynes with isocyanates.2d
On the other hand, we have recently reported that a
cationic Au(I)/PPh3 complex catalyzes the cycloisomerization
of N-alkenyl alkynylamides, that can be readily prepared by
N-acylation of imines with alkynoyl chlorides, leading to
substituted 2-pyridones at room temperature.3 We anticipated
that N-alkenyl arylethynyl-amide 1 bearing a 2,6-disubstituted
phenyl group at an alkyne terminus would cyclize to give
axially chiral 4-aryl-2-pyridone 2 by using a chiral π-elec-
trophilic transition-metal complex as a catalyst (Scheme
1).4-6 In this reaction, π-complexation of the chiral transi-
work by Gutnov and Heller using chiral cobalt catalysts,2a
a
number of axially chiral biaryl syntheses have been achieved
† Department of Applied Chemistry.
‡ Instrumentation Analysis Center.
(1) For recent reviews, see: (a) Wallace, T. W. Org. Biomol. Chem.
2006, 4, 3197. (b) Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser,
M. J.; Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384.
(2) (a) Gutnov, A.; Heller, B.; Fischer, C.; Drexler, H.-J.; Spannenberg,
A.; Sundermann, B.; Sundermann, C. Angew. Chem., Int. Ed. 2004, 43,
3795. (b) Shibata, T.; Fujimoto, T.; Yokota, K.; Takagi, K. J. Am. Chem.
Soc. 2004, 126, 8382. (c) Tanaka, K.; Nishida, G.; Wada, A.; Noguchi, K.
Angew. Chem., Int. Ed. 2004, 43, 6510. (d) Tanaka, K.; Wada, A.; Noguchi,
K. Org. Lett. 2005, 7, 4737.
(3) Imase, H.; Noguchi, K.; Hirano, M.; Tanaka, K. Org. Lett. 2008,
10, 3563.
10.1021/ol900373z CCC: $40.75
Published on Web 03/12/2009
2009 American Chemical Society

Table 1. Screening of Chiral Catalystsa
entry
catalyst
convn (%)
yield (%)b
ee (%)
1c
2c
3c
4
AuSMe/(R)-BINAP/AgBF4
[Ag(CH3CN)4]BF4/(R)-BINAP
[Rh((R)-BINAP)]BF4
[Pd(CH3CN)4](BF4)2/1.2(R)-BINAP
[Pd(CH3CN)4](BF4)2/1.2(R)-H8-BINAP
[Pd(CH3CN)4](BF4)2/1.2(R)-Segphos
[Pd(CH3CN)4](BF4)2/1.2(R)-Segphos
[Pd(CH3CN)4](BF4)2/1.2(R)-tol-Segphos
[Pd(CH3CN)4](BF4)2/1.2(S)-xyl-Segphos
100
8
100
100
87
100
100
100
100
50
<2
59
62
64
79
93
86
96
<5
-
64 (+)
81 (+)
89 (+)
90 (+)
88 (+)
87 (+)
94 (-)
5
6
7d
8d
9d
a Catalyst (0.0050 mmol), 1a (0.10 mmol), and (CH2Cl)2 (1.0 mL) were used. b Isolated yield. c Catalyst: 10 mol %. d Catalyst (0.010 mmol), 1a (0.20
mmol), and (CH2Cl)2 (1.0 mL) were used.
tion-metal complex with the triple bond would facilitate the
cyclization and induce enantioselective construction of axial
chirality through close interaction between the chiral catalyst
and the aryl group adjacent to the triple bond.
and 4a8 (Figure 1), showed potent pharmaceutical activities.
The method shown in Scheme 1 can provide new analogues
of this important class of compounds in enantiomerically
enriched forms.
Importantly, a number of 4-aryl-2-pyridone derivatives,
especially 4-arylquinolin-2(1H)-one derivatives such as 37
(4) Recently, a Au(I)-catalyzed cycloisomerization of (arene)chromium
complexes with 1,5-enynes directed towards axially chiral biaryls was
reported; see: Michon, C.; Liu, S.; Hiragushi, S.; Uenishi, J.; Uemura, M.
Synlett 2008, 1321.
(5) For recent reviews of cycloisomerizations of 1,n-enynes, see: (a)
Michelet, V.; Toullec, P. Y.; Geneˆt, J.-P. Angew. Chem., Int. Ed. 2008, 47,
4268. (b) Zhang, L.; Sun, J.; Kozmin, S. A. AdV. Synth. Catal. 2006, 348,
2271. (c) Bruneau, C. Angew. Chem., Int. Ed. 2005, 44, 2328. (d) An˜orbe,
L.; Domı´nguez, G.; Pe´rez-Castells, J. Chem.-Eur. J. 2004, 10, 4938.
(6) For selected recent examples of π-electrophilic transition-metal
complex-catalyzed cycloisomerizations of 1,5-enynes leading to six-
membered heterocycles and carbocycles, see: (a) Minnihan, E. C.; Colletti,
S. L.; Toste, F. D.; Shen, H. C. J. Org. Chem. 2007, 72, 6287. (b) Sherry,
B. D.; Maus, L.; Laforteza, B. N.; Toste, F. D. J. Am. Chem. Soc. 2006,
128, 8132. (c) Sun, J.; Conley, M. P.; Zhang, L.; Kozmin, S. A. J. Am.
Chem. Soc. 2006, 128, 9705. (d) Shibata, T.; Ueno, Y.; Kanda, K. Synlett
2006, 411. (e) Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128,
4592. (f) Nieto-Oberhuber, C.; MuNunez, M. P.; Nevado, C.; Herrero-
Gomez, E.; Raducan, M.; Echavarren, A. M. Chem.-Eur. J. 2006, 12, 1677.
(g) Grise, C. M.; Barriault, L. Org. Lett. 2006, 8, 5905. (h) Fehr, C.; Galindo,
J. Angew. Chem., Int. Ed. 2006, 45, 2901. (i) Imagawa, H.; Iyenaga, T.;
Nishizawa, M. Org. Lett. 2005, 7, 451. (j) Zhang, L.; Kozmin, S. A. J. Am.
Chem. Soc. 2005, 127, 6962. (k) Mamane, V.; Hannen, P.; Fu¨rstner, A.
Chem.-Eur. J. 2004, 10, 4556. (l) Zhang, L.; Kozmin, S. A. J. Am. Chem.
Soc. 2004, 126, 11806. (m) Shen, H.-C.; Pal, S.; Lian, J.-J.; Liu, R.-S. J. Am.
Chem. Soc. 2003, 125, 15762, and references therein.
Figure 1. Biologically active 4-aryl-2-pyridone derivatives.
We first investigated the reaction of N-cyclohexenyl
alkynylamide 1a bearing a 2-methoxynaphthyl group at an
alkyne terminus as a model substrate (Table 1). In our
(8) Compound 4a and its derivatives have been identified by Bristol-
Myers Squibb as potent maxi-K channel openers useful for the treatment
of male erectile dysfunction; see: (a) Hewawasam, P.; Fan, W.; Ding, M.;
Flint, K.; Cook, D.; Goggings, G. D.; Myers, R. A.; Gribkoff, V. K.;
Boissard, C. G.; Dworetzky, S. I.; Starret, J. E.; Lodge, N. J. J. Med. Chem.
2003, 46, 2819. (b) Glasnov, T. N.; Stadlbauer, W.; Kappe, C. O. J. Org.
Chem. 2005, 70, 3864, and references therein.
(7) Compounds 3 are patented by Teikoku Hormone Mfg. Co., Ltd. as
oxytocin antagonists; see: Shiraiwa, M.; Ota, S.; Takefuchi, K.; Uchida,
H.; Saegusa, M.; Mitsubori, T.; Yoshizawa, M. JP 2003146972, 2003.
1806
Org. Lett., Vol. 11, No. 8, 2009

Scheme 1
.
Our Concept for Enantioselective Cycloisomerization
Table 2. Enantioselective Cycloisomerization of 1a-ja
previous report, cationic Au(I) and Ag(I) complexes showed
higher catalytic activity than that of cationic Rh(I) and Pd(II)
complexes for the cycloisomerization of N-alkenyl alkyny-
lamide leading to 2-pyridones.3 On the contrary, screening
of cationic transition-metal complexes with (R)-BINAP
ligand (entries 1-4) revealed that the Rh(I) and Pd(II)
complexes (entries 3 and 4)9 showed significantly higher
catalytic activity and/or enantioselectivity than that of the
Au(I) and Ag(I) complexes (entries 1 and 2),10,11 and the
use of the cationic Pd(II)/(R)-BINAP complex furnished the
desired axially chiral 4-aryl-2-pyridone 2a with the highest
yield and ee (entry 4). Among axially chiral biaryl bispho-
sphine ligands examined (entries 4-6), the use of (R)-
Segphos furnished 2a with both high yield and ee (entry 6).
Further improved yield and ee were achieved by using (S)-
xyl-Segphos as a ligand at high concentration (entry 9).
Thus, we next explore the scope of this enantioselective
cycloisomerization (Table 2). The reaction of N-neopenty-
lamide 1b (entry 2) slightly lowered both yield and ee of
the corresponding 2-pyridone than those of N-benzylamide
1a (entry 1). Not only N-cyclohexenyl (1a) but also N-
cyclopentenyl (1c, entry 3) and acyclic N-alkenyl (1d and
1e, entries 4 and 5) alkynylamides furnished the desired
pyridones in high yields with high ee’s. The present
cycloisomerization is not restricted to the naphthalene
derivatives. Both 2-methoxytetrahydronaphthalene (1g, entry
7) and 2-methoxy-6-methylbenzene (1h, entry 8) derivatives
furnished the corresponding pyridones in high yields with
high ee’s. Furthermore, methyl- (1i, entry 9) and chloro-
substituted benzodioxole derivatives (1j, entry 10) could also
participate in this reaction. The presence of the 2-alkoxy-
substituted aryl group at the alkyne terminus is important to
(9) For examples of cationic Pd(II)/chiral biaryl bisphosphine complex-
catalyzed enantioselective cycloisomerizations of 1,6- and 1,7-enynes, see:
(a) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2764. (b)
Mikami, K.; Hatano, M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5767. (c)
Hatano, M.; Mikami, K. J. Am. Chem. Soc. 2003, 125, 4704. (d) Hatano,
M.; Terada, M.; Mikami, K. Angew. Chem., Int. Ed. 2001, 40, 249.
(10) For an example of a cationic Au(I)/chiral biaryl bisphosphine
complex-catalyzed enantioselective cycloisomerization of 1,6-enynes, see:
Munoz, M. P.; Adrio, J.; Carretero, J. C.; Echavarren, A. M. Organometallics
a Reactions were conducted using [Pd(CH3CN)4](BF4)2 (0.010 mmol),
(S)-xyl-Segphos (0.012 mmol), 1a-j (0.20 mmol), and (CH2Cl)2 (1.0 mL)
at rt. b Isolated yield. c Nine percent recovery of 1f.
realize both high reactivity and enantioselectivity. Although
2-methylnaphthalene derivative 1f could participate in this
reaction, the reaction was sluggish and the ee was moderate
(entry 6).
2005, 24, 1293
.
(11) For an example of a cationic Ag(I)/chiral biaryl bisphosphine
complex-catalyzed enantioselective cycloisomerization of 1,6-enynes, see:
Bardaj, M.; Crespo, O.; Laguna, A.; Fischer, A. K. Inorg. Chim. Acta 2000,
304, 7
.
Org. Lett., Vol. 11, No. 8, 2009
1807

Scheme 2. Possible Mechanism for Enantioselection
Figure 2
5.
.
Synthesis (left) and ORTEP drawing (right) of (S)-(-)-
To introduce various substituents at the 3-position of the
pyridone ring by coupling reactions, the synthesis of a
3-bromo derivative was then examined by the same method
for the preparation of pharmaceutical intermediate 4b.8b
Pleasingly, bromination of pyridone (-)-2b proceeded by
treatment with NBS to give 4-aryl-3-bromo-2-pyridone (-)-5
in 60% isolated yield without racemization. The absolute
configuration of (-)-5 was determined to be S by X-ray
crystallographic analysis (Figure 2).
transition-metal complex-catalyzed cycloisomerization. Fu-
ture studies will focus on the application of this strategy to
the enantioselective synthesis of various chiral aromatic
compounds.
Possible mechanism for the selective formation of axially
chiral 4-aryl-2-pyridone (R)-2b through the cationic Pd(II)/
(S)-xyl-Segphos complex-catalyzed enantioselective cycloi-
somerization of N-cyclohexenyl alkynylamide 1b is shown
in Scheme 2. Avoidance of the steric interaction between
the alkene moiety of 1b and equatorial aryl group on the
phosphorus atom of (S)-xyl-Segphos in chelating intermediate
A might control the axial chirality of 4-aryl-2-pyridone (R)-
2b.
Acknowledgment. This work was supported partly by a
Grant-in-Aid for Scientific Research (Nos. 20675002 and
19350046) from MEXT, Japan. We thank Takasago Int. Co.
for the gift of H8-BINAP and Segphos derivatives.
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and X-ray crystal-
lographic information files. This material is available free
of charge via the Internet at http://pubs.acs.org.
In conclusion, we have achieved the first enantioselective
construction of axial chirality by the chiral π-electrophilic
OL900373Z
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Org. Lett., Vol. 11, No. 8, 2009