Enantioselective synthesis of tetra-ortho-substituted axially chiral biaryls through rhodium-catalyzed double [2 + 2 + 2] cycloaddition

Article abstract of DOI:10.1021/ol0611550

We have established an enantioselective synthesis of both C₂ symmetric and unsymmetric tetra-ortho-substituted axially chiral biaryls through rhodium-catalyzed double [2 + 2 + 2] cycloaddition (up to >99% ee). This method serves as an attractiv

Full text of DOI:10.1021/ol0611550

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3489-3492
Enantioselective Synthesis of
Tetra-ortho-Substituted Axially Chiral
Biaryls through Rhodium-Catalyzed
Double [2
Goushi Nishida,† Nanami Suzuki,† Keiichi Noguchi,‡ and Ken Tanaka*,†
+ 2 + 2] Cycloaddition
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 11, 2006
ABSTRACT
We have established an enantioselective synthesis of both C2 symmetric and unsymmetric tetra-ortho-substituted axially chiral biaryls through
rhodium-catalyzed double [2 2] cycloaddition (up to >99% ee). This method serves as an attractive new route to enantioenriched
+
2 +
tetra-ortho-substituted axially chiral biaryls in view of the one-step access to substrate diynes and tetraynes starting from readily available
alkynes.
Tetra-ortho-substituted biaryls, having highly stable axial
chirality, are valuable structures for chiral ligands used in a
variety of asymmetric reactions,1 and various enantioselective
methods for their synthesis have been reported to date.2 In
general, these are based on transition-metal-catalyzed cross-
or homo-coupling of two aryl units where the axial chirality
is constructed at the formation of the aryl-aryl bond.3-9 The
enantioselective coupling of sterically encumbered 2,6-
disubstituted arenes, which furnishes tetra-ortho-substituted
(4) For Suzuki coupling, see: (a) Nicolaou, K. C.; Li, H.; Boddy, C. N.
C.; Ramanjulu, J. M.; Yue, T.-Y.; Natarajan, S.; Chu, X.-J.; Bra¨se, S.;
Ru¨bsam, F. Chem. Eur. J. 1999, 5, 2584. (b) Cammidge, A. N.; Cre´py, K.
V. L. Chem. Commun. 2000, 1723. (c) Yin, J.; Buchwald, S. L. J. Am.
Chem. Soc. 2000, 122, 12051. (d) Castanet, A.-S.; Colobert, F.; Broutin,
P.-E.; Obringer, M. Tetrahedron: Asymmetry 2002, 13, 659. For a review
of the asymmetric Suzuki coupling route to axially chiral biaryls, see:
Baudoin, O. Eur. J. Org. Chem. 2005, 4223-4229.
(5) For oxidative coupling, see: (a) Brussee, J.; Jansen, A. C. A.
Tetrahedron Lett. 1983, 24, 3261. (b) Smrcina, M.; Lorenc, M.; Hanus,
V.; Kocovsky, P. Synlett 1991, 231. (c) Smrcina, M.; Vyskocil, S.; Maca,
B.; Pola´sek, M.; Claxtone, T. A.; Abbott, A. P.; Kocovsky, P. J. Org. Chem.
1994, 59, 2156. (d) Nakajima, M.; Kanayama, K.; Miyoshi, I.; Hashimoto,
S.-I. Tetrahedron Lett. 1995, 36, 9519. (e) Nakajima, M.; Miyoshi, I.;
Kanayama, K.; Hashimoto, S.; Noji, M.; Koga, K. J. Org. Chem. 1999, 64,
2264. (f) Saito, S.; Kano, T.; Muto, H.; Nakadai, H.; Yamamoto, H. J. Am.
Chem. Soc. 1999, 121, 8943. (g) Chu, C.-Y,; Hwang, D.-R.; Wang, S.-K.;
Uang, B.-J. Chem. Commun. 2001, 980. (h) Li, X.; Yang, J.; Kozlowski,
M. C. Org. Lett. 2001, 3, 1137. (i) Luo, Z.; Liu, Q.; Gong, L.; Cui, X.; Mi,
A.; Jiang, Y. Chem. Commun. 2002, 914. (j) Barhate, N. B.; Chen, C.-T.
Org. Lett. 2002, 4, 2529. (k) Luo, Z.; Liu, Q.; Gong, L.; Cui, X.; Mi, A.;
† Department of Applied Chemistry.
‡ Instrumentation Analysis Center.
(1) For a review of chiral biaryl-type bisphosphine ligands, see: Shimizu,
H.; Nagasaki, I.; Saito, T. Tetrahedron 2005, 61, 5405.
(2) For reviews, see: (a) Bringmann, G.; Mortimer, A. J. P.; Keller, P.
A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005,
44, 5384. (b) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. ReV. 2002, 102, 1359. (c) Lloyd-Williams, P.; Giralt, E. Chem. Soc.
ReV. 2001, 30, 145. (d) Bolm, C.; Hildebrand, J. P.; Muz, K.; Hermanns,
N. Angew. Chem., Int. Ed. 2001, 40, 3284. (e) Bringmann, G.; Walter, R.;
Weirich, R. Angew. Chem., Int. Ed. Engl. 1990, 29, 977.
(3) For Kumada coupling, see: (a) Hayashi, T.; Hayashizaki, K.; Kiyoi,
T.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 8153. (b) Hayashi, T.; Hayashizaki,
K.; Ito, Y. Tetrahedron Lett. 1989, 30, 215.
10.1021/ol0611550 CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/07/2006

biaryls, has been realized in several examples, e.g., nickel-
or palladium-catalyzed cross-coupling of unfunctionalized
2,6-disubstituted arenes,3,4b oxidative homo-coupling of
2-naphthol derivatives,5 and Grignard cross-coupling of
dibenzothiophenes.7 However, the efficient catalytic method,
which can be applicable to the enantioselective synthesis of
functionalized axially chiral tetra-ortho-substituted biaryls,
is an important challenge.
Recently, a new approach to the synthesis of axially chiral
tri-ortho-substituted biaryls has been developed, which is
based on an enantioselective [2 + 2 + 2] cycloaddition10,11
between internal alkynes bearing an ortho-substituted phenyl
group and nitriles,12 isocyanates,13 or alkynes.14-18 We
anticipated that an enantioselective two-step synthesis of C2
symmetric tetra-ortho-substituted axially chiral biaryls could
be realized through double [2 + 2 + 2] cycloaddition of
electron-deficient 1,6-diynes, prepared in one step from
readily available terminal 1,6-diynes, with 1,3-diynes (Scheme
1, Type-1) or ether-linked tetraynes, prepared in one step
munication, we describe an enantioselective synthesis of
functionalized tetra-ortho-substituted axially chiral biaryls
through rhodium-catalyzed double [2 + 2 + 2] cycloaddition.
We first investigated the reaction of electron-deficient
malonate-derived 1,6-diyne 1a and 1,3-diyne 2a in the
presence of various Rh(I)+/modified-BINAP complexes
(Type-1).20 We were pleased to find that the use of 5% Rh-
(I)+/(S)-Segphos [(4,4′-bi-1,3-benzodioxole)-5,5′-diylbis-
(diphenylphosphine)]21 complex furnished the corresponding
C2 symmetric tetra-ortho-substituted biaryl (-)-3aa in 59%
yield with >99% ee (Table 1, entry 1). Not only diacetoxy-
Table 1. Enantioselective Synthesis of C2 Symmetric
Tetra-ortho-Substituted Axially Chiral Biaryls 3
Scheme 1. Enantioselective Two-Step Synthesis of C2
Symmetric Tetra-ortho-Substituted Axially Chiral Biaryls
a Isolated yield. b Isolated yield of mono-annulation product 4 (Scheme
2).
substituted 2,4-hexadiyne 2a but also dimethoxy-substituted
(10) For recent reviews, see: (a) Kotha, S.; Brahmachary, E.; Lahiri, K.
Eur. J. Org. Chem. 2005, 4741. (b) Yamamoto, Y. Curr. Org. Chem. 2005,
9, 503. (c) Varela, J.; Saa´, C. Chem. ReV. 2003, 103, 3787. (d) Saito, S.;
Yamamoto, Y. Chem. ReV. 2000, 100, 2901. (e) Malacria, M.; Aubert, C.;
Renaud J. L. In Science of Synthesis: Houben-Weyl Methods for Molecular
Transformations; Lautens, M., Trost, B. M., Eds.; Georg Thieme Verlag:
New York, 2001; Vol. 1, pp 439-530. (f) Fujiwara, M.; Ojima, I. In Modern
Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley: New
York, 2005; Chapter 7, pp 129-150.
(11) For chirality transfer benzannulation, see: (a) Vorogushin, A. V.;
Wulff, W. D.; Hansen, H.-J. J. Am. Chem. Soc. 2002, 124, 6512. (b) Nishii,
Y.; Wakasugi, K.; Koga, K.; Tanabe, Y. J. Am. Chem. Soc. 2004, 126,
5358.
from readily available 2,4-hexadiyne-1,6-diol, with electron-
deficient monoynes (Scheme 1, Type-2).19 In this Com-
Jiang, Y. Angew. Chem., Int. Ed. 2002, 41, 4532. (l) Chu, C.-Y.; Uang,
B.-J. Tetrahedron: Asymmetry 2003, 14, 53. (m) Li, X.; Hewgley, J. B.;
Mulrooney, C. A.; Yang, J.; Kozlowski, M. C. J. Org. Chem. 2003, 68,
5500 and references therein.
(12) Gutnov, A.; Heller, B.; Fischer, C.; Drexler, H.-J.; Spannenberg,
A.; Sundermann, B.; Sundermann, C. Angew. Chem., Int. Ed. 2004, 43,
3795.
(6) For cross-coupling of biaryl ditriflates, see: (a) Hayashi, T.; Niizuma,
S.; Kamikawa, T.; Suzuki, N.; Uozumi, Y. J. Am. Chem. Soc. 1995, 117,
9101. (b) Kamikawa, T.; Uozumi, Y.; Hayashi, T. Tetrahedron Lett. 1996,
37, 3161. (c) Kamikawa, T.; Hayashi, T. Tetrahedron 1999, 55, 3455.
(7) For asymmetric ring-opening of dinaphthothiophene by Grignard
cross-coupling, see: (a) Shimada, T.; Cho, Y.-H.; Hayashi, T. J. Am. Chem.
Soc. 2002, 124, 13396. (b) Cho, Y.-H.; Kina, A.; Shimada, T.; Hayashi, T.
J. Org. Chem. 2004, 69, 3811.
(8) For asymmetric ring-opening of biaryl lactones, see: (a) Bringmann,
G.; Breuning, M.; Tasler, S. Synthesis 1999, 525. (b) Bringmann, G.;
Breuning, M.; Pfeifer, R.-M.; Schenk, W. A.; Kamikawa, K.; Uemura, M.
J. Organomet. Chem. 2002, 661, 31. (c) Bringmann, G.; Tasler, S.; Pfeifer,
R.-M.; Breuning, M. J. Organomet. Chem. 2002, 661, 49.
(13) Tanaka, K.; Wada, A.; Noguchi, K. Org. Lett. 2005, 7, 4737.
(14) For Ir, see: (a) Shibata, T.; Fujimoto, T.; Yokota, K.; Takagi, K. J.
Am. Chem. Soc. 2004, 126, 8382. (b) Shibata, T.; Tsuchikama, K. Chem.
Commun. 2005, 6017.
(15) For Rh, see: (a) Tanaka, K.; Nishida. G.; Wada, A.; Noguchi, K.
Angew. Chem., Int. Ed. 2004, 43, 6510. (b) Tanaka, K.; Nishida, G.; Ogino,
M.; Hirano, M.; Noguchi, K. Org. Lett. 2005, 7, 3119.
(16) For enantioselective synthesis of axially chiral anilides through Rh-
catalyzed [2 + 2 + 2] cycloaddition, see: Tanaka, K.; Takeishi, K.;
Noguchi, K. J. Am. Chem. Soc. 2006, 128, 4586.
(17) For Rh(I)+/modified-BINAP-catalyzed chemo- and regioselective
intermolecular alkyne cyclotrimerization, see: (a) Tanaka, K.; Shirasaka,
K. Org. Lett. 2003, 5, 4697. (b) Tanaka, K.; Toyoda, K.; Wada, A.;
Shirasaka, K.; Hirano, M. Chem. Eur. J. 2005, 11, 1145.
(9) For utilization of planar chiral arene chromium complex, see: (a)
Watanabe, T.; Tanaka, Y.; Shoda, R.; Sakamoto, R.; Kamikawa, K.; Uemura,
M. J. Org. Chem. 2004, 69, 4152. (b) Kamikawa, K.; Sakamoto, T.; Tanaka,
Y.; Uemura, M. J. Org. Chem. 2003, 68, 9356 and references therein.
(18) For pioneering work for rhodium-catalyzed cross-alkyne cyclotri-
merization, see: (a) Mu¨ller, E. Synthesis 1974, 761. (b) Grigg, R.; Scott,
R.; Stevenson, P. J. Chem. Soc., Perkin Trans. 1 1988, 1357.
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Org. Lett., Vol. 8, No. 16, 2006

2,4-hexadiyne 2b are suitable substrates in this process, and
biaryl (-)-3ab was obtained in 48% yield with 98% ee (entry
2). In these reactions, mono-annulation products were
generated as byproducts. The use of 1,6-diyne 1b, having
no quaternary center in the tether, furnished mono-annulation
product 4 in 56% yield as a major product, although biaryl
(+)-3ba was obtained in 30% yield with >99% ee (entry
3). The X-ray crystallographic analysis revealed the R
configuration for the biaryl (+)-3ba (Figure 1).
screening various Rh(I)+/modified-BINAP complexes, we
found that the use of 5% Rh(I)+/(S)-Segphos complex
furnished the corresponding C2 symmetric axially chiral
biaryl (+)-8ab with excellent ee (98% ee), although the yield
was low (Table 2, entry 1). The use of methyl-substituted
Table 2. Enantioselective Synthesis of C2 Symmetric
Tetra-ortho-Substituted Axially Chiral Biaryls 8
[5% [Rh(cod)2]BF4/(S)-Segphos, CH2Cl2, rt, 16 h]
Figure 1. ORTEP diagram of (R)-(+)-3ba.
The isolated mono-annulation product 4 could be used for
the enantioselective complete intermolecular [2 + 2 + 2]
cycloaddition with diethyl acetylenedicarboxylate (5a) using
10% Rh(I)+/(R)-BINAP complex as catalyst, and unsym-
metrical tetra-ortho-substituted biaryl (-)-6 was obtained in
94% yield with 93% ee (Scheme 2).15b
Scheme 2. Enantioselective Synthesis of Unsymmetrical
Tetra-ortho-Substituted Axially Chiral Biaryl 6
a Isolated yield. b Isolated as a mixture of 8ac and another regioisomer.
1
Yield of 8ac was determined by H NMR. The corresponding diol of 8ac
was isolated in pure form in 77% isolated yield from 8ac by treatment
with LiAlH4.
internal tetrayne 7b or terminal monoyne 5c instead of 7a
or 5c increased the yield of the corresponding biaryls to 52%
or 44%, respectively, but decreased the ee to 69% or 70%
(entries 2 and 3). The X-ray crystallographic analysis
revealed S configuration for the biaryl (+)-8bb (Figure 2).
Importantly, this double [2 + 2 + 2] cycloaddition could be
applied to the axially chiral bipyridine synthesis using ethyl
cyanoformate 5d, which furnished bipyridine (+)-8bd in
Next, the reaction of terminal tetrayne 7a with electron-
deficient monoyne 5b was investigated (Type-2). After
(19) Some achiral double [2 + 2 + 2] cycloadditions were reported.
For biaryls, see: (a) Yamamoto, Y.; Arakawa, T.; Ogawa, R.; Itoh, K. J.
Am. Chem. Soc. 2003, 125, 12143. (b) Saino, N.; Kogure, D.; Okamoto, S.
Org. Lett. 2005, 7, 3065. For bipyridines, see: (c) Varela, J. A.; Castedo,
L.; Maestro, M.; Mahia, J.; Saa`, C. Chem. Eur. J. 2001, 7, 5203. (d)
Yamamoto, Y.; Ogawa, R.; Itoh, K. J. Am. Chem. Soc. 2001, 123, 6189.
(20) The use of 1,6-diynes having no alkoxycarbonyl group did not
furnish the desired biaryls.
(21) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264.
Org. Lett., Vol. 8, No. 16, 2006
3491

Scheme 3. Enantioselective Synthesis of Unsymmetrical
Tetra-ortho-Substituted Axially Chiral Biaryls 10 and 11
Figure 2. ORTEP diagram of (S)-(+)-8bb.
38% yield with 98% ee, although achiral regioisomers were
generated in >50% yield (entry 4). Furthermore, the reaction
of phenyl-substituted tetrayne 7c with isocyanate 5e furnished
bipyridone (-)-8ce in 89% yield with 52% ee (entry 5).
Interestingly, the reaction of phenyl-substituted tetrayne
7c with 5b in the presence of 5% Rh(I)+/(S)-Segphos
complex furnished mono-annulation product 9 in 35% yield,
and no corresponding biaryl was generated. The use of Rh-
(I)+/BINAP complex improved the yield of 9 to 52%. The
isolated mono-annulation product 9 could be used for the
enantioselective [2 + 2 + 2] cycloaddition with nitrile 5d
and isocyanate 5e using Rh(I)+/(S)-Segphos complex as
catalyst, which furnished axially chiral aryl pyridine (+)-10
in 76% yield with 98% ee and axially chiral aryl pyridone
(+)-11 in 63% yield with 67% ee, respectively (Scheme 3).
alkynes. Expanding the scope and exploration of the mech-
anism of enantioselection are currently under investigation.
Acknowledgment. This work was supported by Asahi
Glass Fundation and Uehara Memorial Fundation. We thank
Takasago International Corporation for the gift of Segphos.
In conclusion, we have established an enantioselective
synthesis of both C2 symmetric and unsymmetric tetra-ortho-
substituted axially chiral biaryls through rhodium-catalyzed
double [2 + 2 + 2] cycloaddition. This method serves as an
attractive new route to enantioenriched tetra-ortho-substituted
axially chiral biaryls in view of the one-step access to
substrate diynes and tetraynes starting from readily available
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and X-ray crystal-
lographic files in CIF format. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0611550
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Org. Lett., Vol. 8, No. 16, 2006