Enantioselective synthesis of axially chiral biaryls through rhodium-catalyzed complete intermolecular cross-cyclotrimerization of internal alkynes

Article abstract of DOI:10.1021/ol0511880

(Chemical Equation Presented) We have developed a cationic rhodium(I)/H8-BINAP complex-catalyzed complete intermolecular cross-cyclotrimerization of internal alkynes with dialkyl acetylenedicarboxylates. This reaction was successfully applied to enantiose

Full text of DOI:10.1021/ol0511880

ORGANIC
LETTERS
2005
Vol. 7, No. 14
3119-3121
Enantioselective Synthesis of Axially
Chiral Biaryls through
Rhodium-Catalyzed Complete
Intermolecular Cross-Cyclotrimerization
of Internal Alkynes
Ken Tanaka,*,† Goushi Nishida,† Masakazu Ogino,† Masao Hirano,† and
Keiichi Noguchi‡
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 May 20, 2005
ABSTRACT
We have developed a cationic rhodium(I)/H8-BINAP complex-catalyzed complete intermolecular cross-cyclotrimerization of internal alkynes
with dialkyl acetylenedicarboxylates. This reaction was successfully applied to enantioselective synthesis of axially chiral biaryls utilizing
internal alkynes bearing ortho-substituted phenyl and acetoxymethyl in each terminal position. The axial chirality is constructed at the formation
of benzene rings with high enantioselectivity (up to 96% ee).
Axially chiral biaryls are valuable structures for chiral ligands
and biologically active compounds,1,2 and various enantio-
selective methods for their synthesis have been reported to
date.3-5 These are mainly based on transition-metal-catalyzed
enantioselective cross-coupling approaches.3 Recently, a new
approach to their synthesis has been developed, which is
based on an enantioselective partial intramolecular [2 + 2
+ 2] cycloaddition between R,ω-diynes and nitriles6 or
alkynes.7,8 Although various transition metals catalyze alkyne
cyclotrimerization, it has been difficult to carry out complete
(3) Kumada coupling: (a) Hayashi, T.; Hayashizaki, K.; Ito, Y.
Tetrahedron Lett. 1989, 30, 215-218. (b) Hayashi, T.; Hayashizaki, K.;
Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 8153-8156. Suzuki
coupling: (c) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12051-
12052. (d) Cammidge, A. N.; Cre´py, K. V. L. Chem. Commun. 2000, 1723-
1724. Oxidative coupling: (e) Li, X.; Hewgley, J. B.; Mulrooney, C. A.;
Yang, J.; Kozlowski, M. C. J. Org. Chem. 2003, 68, 5500-5511. (f) Luo,
Z.; Liu, Q.; Gong, L.; Cui, X.; Mi, A.; Jiang, Y. Chem. Commun. 2002,
914-915. (g) Chu, C.-Y.; Hwang, D.-R.; Wang, S.-K.; Uang, B.-J. Chem.
Commun. 2001, 980-981. (h) Saito, S.; Kano, T.; Muto, H.; Nakadai, H.;
Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 8943-8944. (i) Nakajima,
M.; Kanayama, K.; Miyoshi, I.; Hashimoto, S.-I. Tetrahedron Lett. 1995,
36, 9519-9520. Cross-coupling of biaryl ditriflates: (j) Kamikawa, T.;
Hayashi, T. Tetrahedron 1999, 55, 3455-3466. (k) Hayashi, T.; Niizuma,
S.; Kamikawa, T.; Suzuki, N.; Uozumi, Y. J. Am. Chem. Soc. 1995, 117,
9101-9102. Cross-coupling of dinaphthothiophene: (l) Cho, Y.-H.; Kina,
A.; Shimada, T.; Hayashi, T. J. Org. Chem. 2004, 69, 3811-3823. (m)
Shimada, T.; Cho, Y.-H.; Hayashi, T. J. Am. Chem. Soc. 2002, 124, 13396-
13397.
† Department of Applied Chemistry.
‡ Instrumentation Analysis Center.
(1) (a) Bringmann, G.; Breuning, M.; Tasler, S. Synthesis 1999, 525-
558 and references therein. (b) Ojima, I. Catalytic Asymmetric Synthesis,
2nd ed.; John Wiley and Sons: New York, 2000.
(2) Synthesis of axially chiral biaryls using stoichiometric chiral
auxiliaries or chiral starting materials: (a) Bringmann, G.; Walter, R.;
Weirich, R. In Methods of Organic Chemistry (Houben Weyl), 4th ed.;
Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.;
Thieme: Stuttgart, 1995; Vol. E21a, p 567. (b) Bringmann, G.; Walter, R.;
Weirich, R. Angew. Chem., Int. Ed. Engl. 1990, 29, 977-991.
10.1021/ol0511880 CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/14/2005

intermolecular reaction of two or three different alkynes with
high selectivity.9 We anticipated that cross-cyclotrimerization
of two molecules of symmetrical internal alkynes and one
molecule of unsymmetrical internal alkynes, bearing ortho-
substituted phenyl at one terminal position, would construct
axial chirality during the formation of benzene rings (eq 1).
We recently reported a cationic rhodium(I)/H8-BINAP10
complex-catalyzed complete intermolecular cross cyclotri-
merization of terminal alkynes with dialkyl acetylenedicar-
boxylates.11,12 In this paper, we describe a cross-cyclo-
trimerization using internal alkynes and its application to the
enantioselective synthesis of axially chiral biaryls.
Table 1. Rhodium-Catalyzed Cross-Cyclotrimerization of
Internal Alkynes and Diethyl Acetylenedicarboxylate
entry
2
R1
n-Pr
(CH2)4CH3
Ph
Me
Ph
R2
n-Pr
Me
Me
CO2Et
CO2Et
CH2OMe
CH2OAc
3
yielda (%)
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
3aa
3ba
3ca
3da
3ea
3fa
76
69
68
82
72
82
0
CH2OMe
CH2OAc
2g
3ga
a Isolated yield.
We first investigated an intermolecular cross-cyclo-
trimerization of two different internal alkynes. Screening of
various alkynes and Rh(I) complexes revealed that Rh(I)+/
H8-BINAP catalyzed chemoselective intermolecular cross-
cyclotrimerization of two molecules of diethyl acetylenedi-
carboxylate (1a) and one molecule of internal alkynes (Table
1). Alkyl- (entries 1 and 2), aryl- (entry 3), and alkoxycar-
bonyl-substituted (entries 4 and 5) internal alkynes were
suitable substrates for this reaction. Interestingly, although
the reaction of 1,4-dimethoxy-2-butyne (2f) proceeded in
high yield (entry 6), no reaction was observed in the case of
1,4-diacetoxy-2-butyne (2g) (entry 7).
Next, the reaction of various 2-methylphenyl-substituted
internal alkynes 2h,i with dimethyl acetylenedicarboxylate
(1b) was investigated to construct axial chirality (Table 2).
Table 2. Optimization of Rhodium-Catalyzed Enantioselective
Cross-Cyclotrimerization
(4) Utilizing planar chiral arene chromium complex: (a) Watanabe, T.;
Tanaka, Y.; Shoda, R.; Sakamoto, R.; Kamikawa, K.; Uemura, M. J. Org.
Chem. 2004, 69, 4152-4158. (b) Kamikawa, K.; Sakamoto, T.; Tanaka,
Y.; Uemura, M. J. Org. Chem. 2003, 68, 9356-9363 and references therein.
(5) Chirality exchange from sp3 central chirality to axial chirality: Nishii,
Y.; Wakasugi, K.; Koga, K.; Tanabe, Y. J. Am. Chem. Soc. 2004, 126,
5358-5359.
(6) Gutnov, A.; Heller, B.; Fischer, C.; Drexler, H.-J.; Spannenberg, A.;
Sundermann, B.; Sundermann, C. Angew. Chem., Int. Ed. 2004, 43, 3795-
3797.
entry
2
R
ligand
3
yielda (%) ee (%)
(7) (a) Shibata, T.; Fujimoto, T.; Yokota, K.; Takagi, K. J. Am. Chem.
Soc. 2004, 126, 8382-8383. (b) Tanaka, K.; Nishida. G.; Wada, A.;
Noguchi, K. Angew. Chem., Int. Ed. 2004, 43, 6510-6512.
(8) Asymmetric cyclotrimerization of alkynes: (a) Sato, Y.; Nishimata,
T.; Mori, M. Heterocycles 1997, 44, 443-457. (b) Sato, Y.; Nishimata, T.;
Mori, M. J. Org. Chem. 1994, 59, 6133-6135. (c) Stara, I. G.; Stary, I.;
Kollarovic, A.; Teply, F.; Vyskocil, S.; Saman, D. Tetrahedron Lett. 1999,
40, 1993-1996.
1
2
3
4
5
2h
H
(S)-H8-BINAP (-)-3hb
23
<5
81
21
2i OMe (S)-H8-BINAP 3ib
2j OAc (S)-H8-BINAP (+)-3jb
2j OAc (R)-BINAP
2j OAc (S)-Segphos
89
77
(-)-3jb
3jb
16
<5
(9) For reviews, see: (a) Saito, S.; Yamamoto, Y. Chem. ReV. 2000,
100, 2901-2915. (b) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996,
96, 49-92. Catalytic complete intermolecular cross cyclotrimerization of
alkynes. For Ni, see: (c) Mori, N.; Ikeda, S.-I.; Odashima, K. Chem.
Commun. 2001, 181-182. (d) Sato, Y.; Ohashi, K.; Mori, M. Tetrahedron
Lett. 1999, 40, 5231-5234. For Pd, see: (e) Dieck, H. T.; Munz, C.; Mu¨ller,
C. J. Organomet. Chem. 1990, 384, 243-255. For Ir, see: (f) Takeuchi,
R.; Nakaya, Y. Org. Lett. 2003, 5, 3659-3662. For Rh, see: (g) Abdulla,
K.; Booth, B. L.; Stacey, C. J. Organomet. Chem. 1985, 293, 103-114.
For Ru, see: (h) Yamamoto, Y.; Ishii, J.; Nishiyama, H.; Itoh, K. J. Am.
Chem. Soc. 2004, 126, 3712-3713. For Co, see: (i) Chouraqui, G.; Petit,
M.; Aubert, C.; Malacria, M. Org. Lett. 2004, 6, 1519-1521.
(10) Zhang, X.; Mashimo, K.; Koyano, K.; Sayo, N.; Kumobayashi, H.;
Akutagawa, S.; Takaya, H. Tetrahedron Lett. 1991, 32, 7283-7286.
(11) (a) Tanaka, K.; Toyoda, K.; Wada, A.; Shirasaka, K.; Hirano, M.
Chem. Eur. J. 2005, 11, 1145-1156. (b) Tanaka, K.; Shirasaka, K. Org.
Lett. 2003, 5, 4697-4699.
a Isolated yield.
In the case of methyl- and methoxymethyl-substituted
alkynes 2h and 2i, cyclotrimerization of 1b proceeded rapidly
(entries 1 and 2). On the other hand, the use of an
acetoxymethyl-substituted alkyne 2j furnished an axially
chiral biaryl in high yield with high enantioselectivity (entry
3). The use of BINAP or Segphos13 led to poor results
(entries 4 and 5) (Figure 1).
The enantioselective intermolecular cross-cyclotrimeriza-
tion of various acyloxymethyl-substituted alkynes 2j-o and
(12) For pioneering work of the rhodium-catalyzed partial intramolecular
cross cyclotrimerization of alkynes, see: Grigg, R.; Scott, R.; Stevenson,
P. J. Chem. Soc., Perkin Trans. 1 1988, 1357-1364.
(13) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264-267.
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Org. Lett., Vol. 7, No. 14, 2005

Figure 1. Structures of modified BINAP ligands.
1 was investigated using Rh(I)+/(S)-H8-BINAP, and high
enantioselectivities were achieved in each reaction (Table
3). The reaction of both acetoxymethyl- and propioxymethyl-
Figure 2. ORTEP diagram of (R)-(-)-3nb.
Table 3. Rhodium-Catalyzed Enantioselective
Cross-Cyclotrimerization of Internal Alkynes and Dialkyl
Acetylenedicarboxylates
followed by the coordination of 2n to form complex B, due
to avoidance of the steric interaction between Br atom of
2n and PPh2 group of (S)-H8-BINAP. Reductive elimination
of rhodium gives (R)-(-)-3nb and regenerates the rhodium
catalyst.14
Scheme 1
yielda ee
entry
1
2
Ar
R
3
(%) (%)
1
2
3
4
5
6
7
1a 2j
2-MeC6H4 OAc
(+)-3jab
80
73
70
67
61
89
75c
93
91
92
84
91
95
96
1b 2k 2-MeC6H4 OCOEt (+)-3kb
1b 2l
1b 2m 2-ClC6H4
1b 2n 2-BrC6H4
1b 2o 1-naphthyl OAc
2-EtC6H4
OAc
OAc
OAc
(+)-3lb
(+)-3mb
(R)-(-)-3nb
(+)-3ob
1a 2p 1-naphthyl CH2OH (+)-3pa
a Isolated yield. b (R)-H8-BINAP was used. c Isolated as the correspond-
ing acetate by treatment with Ac2O/Et3N.
substituted alkynes 2j and 2k with 1a and 1b proceeded in
high yield and ee, respectively (entries 1 and 2). Not only
2-methylphenyl-, but also 2-ethylphenyl- (entry 3), 2-chlo-
rophenyl- (entry 4), 2-bromophenyl- (entry 5), and 1-naph-
thyl-substituted (entry 6) alkynes were suitable substrates in
this process. Interestingly, although the reaction of an
acetoxyethyl-/1-naphthyl-substituted alkyne with 1a pro-
ceeded in low yield and ee (20%, 28% ee), the reaction of
a hydroxyethyl-/1-naphthyl-substituted alkyne 2p with 1a
proceeded in high yield and ee (entry 7). The absolute
configuration of (-)-3nb was determined to be R by
anomalous dispersion method (Figure 2).
In conclusion, we have developed a rhodium-catalyzed
enantioselective complete intermolecular cross cyclotrimer-
ization of internal alkynes for the synthesis of axially chiral
biaryls. Detailed mechanistic study and expansion of the
scope are underway in our laboratory.
Acknowledgment. This work was supported by Asahi
Glass Fundation. We thank Takasago International Corp. for
the gift of H8-BINAP and Segphos.
Scheme 1 depicts a plausible mechanism of the selective
formation of (R)-(-)-3nb. Chemo- and enantioselectivity are
determined by preferential formation of metallacycle A
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and X-ray crystal-
lographic files (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) Indeed, in the cross cyclotrimerization shown in Table 3, starting
materials 2 and homo-cyclotrimerization products of 1 were isolated other
than the desired cross-cyclotrimerization products.
OL0511880
Org. Lett., Vol. 7, No. 14, 2005
3121