Asymmetric synthesis of axially chiral biaryl diphosphine ligands by rhodium-catalyzed enantioselective intramolecular double [2 + 2 + 2] cycloaddition

Article abstract of DOI:10.1021/ol102927y

The concise synthesis of axially chiral biaryl diphosphine ligands by the rhodium-catalyzed intramolecular [2 + 2 + 2] cycloaddition of hexayne diphosphine oxides has been achieved. These new chiral diphosphine ligands could be employed as a ligand for the rhodiumcatalyzed asymmetric catalyses.

Full text of DOI:10.1021/ol102927y

ORGANIC
LETTERS
2011
Vol. 13, No. 3
362-365
Asymmetric Synthesis of Axially Chiral
Biaryl Diphosphine Ligands by
Rhodium-Catalyzed Enantioselective
Intramolecular Double [2 + 2 + 2]
Cycloaddition
Fumiya Mori,† Naohiro Fukawa,† Keiichi Noguchi,‡ 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 October 7, 2010
ABSTRACT
The concise synthesis of axially chiral biaryl diphosphine ligands by the rhodium-catalyzed intramolecular [2 + 2 + 2] cycloaddition of
hexayne diphosphine oxides has been achieved. These new chiral diphosphine ligands could be employed as a ligand for the rhodium-
catalyzed asymmetric catalyses.
C2-Symmetric axially chiral biaryl diphosphines have been
widely employed as ligands for various asymmetric cataly-
ses.1 Their conventional synthesis is based on the homo-
coupling reaction to construct C2-symmetric biaryl skeletons
followed by optical resolution and introduction of two
diarylphosphinoyl groups.1 Obviously, direct and enantiose-
lective introduction of two bulky diarylphosphinoyl groups
on biaryls is highly attractive.2-4 For the enantioselective
synthesis of biaryl phosphorus compounds, the enantiose-
lective Suzuki-Miyaura cross-coupling reactions of phos-
phorus-containing aryl halides and aryl boronic acids were
reported. However, this method is restricted to the synthesis
of sterically less demanding biaryl monophosphonates or
phosphine oxides.4 On the other hand, Doherty and co-
workers reported the cationic rhodium(I)/rac-BINAP complex-
catalyzed double [2 + 2 + 2] cycloaddition5-7 of a
diphenylphosphinoyl-substituted 1,3-butadiyne with terminal
1,6-diynes leading to achiral biaryl diphosphine oxides
(Scheme 1: R1 ) H, R2 ) Ph).8 Our research group reported
(1) For a review, see: Shimizu, H.; Nagasaki, I.; Saito, T. Tetrahedron
2005, 61, 5405.
(2) For recent reviews of the atroposelective biaryl synthesis, 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) Baudoin, O.
Eur. J. Org. Chem. 2005, 4223. (c) Wallace, T. W. Org. Biomol. Chem.
2006, 4, 3197. (d) Ogasawara, M.; Watanabe, S. Synthesis 2009, 1761. (e)
Kozlowski, M. C.; Morgan, B. J.; Linton, E. C. Chem. Soc. ReV. 2009, 38,
3193. For a recent review involving the atroposelective biaryl phosphane
synthesis, see: (f) Glueck, D. S. Chem.sEur. J. 2008, 14, 7108.
† Department of Applied Chemistry.
‡ Instrumentation Analysis Center.
10.1021/ol102927y  2011 American Chemical Society
Published on Web 12/27/2010

Scheme 1
Scheme 2
the cationic rhodium(I)/Segphos complex-catalyzed enanti-
oselective double [2 + 2 + 2] cycloaddition of a phospho-
nate-substituted 1,3-butadiyne with internal 1,6-diynes lead-
ing to C2-symmetric axially chiral biaryl diphosphonates with
excellent enantioselectivity (Scheme 1: R1 ) Me, R2 )
OEt).9 Unfortunately, C2-symmetric axially chiral biaryls
with two bulky diphenylphosphinoyl groups could not be
obtained by the cationic rhodium(I) complex-catalyzed
intermolecular double [2 + 2 + 2] cycloaddition (Scheme
1: R1 ) Me, R2 ) Ph).10
To overcome this limitation, an enantioselective intramo-
lecular [2 + 2 + 2] cycloaddition of hexayne 3a,11 bearing
two diphenylphosphinoyl groups at alkyne termini, leading
to C2-symmetric axially chiral biaryl diphosphine oxide 4a
was examined as shown in Scheme 2. Hexayne 3a was
readily prepared via the copper(I)-catalyzed monodiphe-
Figure 1
.
Structures of axially chiral biaryl diphosphine ligands.
(3) For enantioselective synthesis of axially chiral biaryl monophos-
phonates and monophosphine oxides by the rhodium-catalyzed [2 + 2 +
2] cycloaddition, see: (a) Nishida, G.; Noguchi, K.; Hirano, M.; Tanaka,
K. Angew. Chem., Int. Ed. 2007, 46, 3951. For an example of enantiose-
lective synthesis of a biaryl monophosphine sulfide, see: (b) Kondoh, A.;
Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2007, 129, 6996. By using
chiral cobalt(I) catalysts, see: (c) Heller, B.; Gutnov, A.; Fischer, C.; Drexler,
H.-J.; Spannenberg, A.; Redkin, D.; Sundermann, C.; Sundermann, B.
Chem.sEur. J. 2007, 13, 1117. For enantioselective synthesis of P-
stereogenic phosphine oxides, see: (d) Nishida, G.; Noguchi, K.; Hirano,
M.; Tanaka, K. Angew. Chem., Int. Ed. 2008, 47, 3410.
nylphosphination12,13 of known triyne 114 followed by
oxidation of phosphine to generate phosphine oxide 2a and
oxidative homocoupling of 2a. The [2 + 2 + 2] cycloaddition
of hexayne 3a in the presence of cationic rhodium(I)/axially
chiral biaryl diphosphine (Figure 1) complexes was then
examined (Table 1). We were pleased to find that the reaction
of 3a leading to biaryl 4a proceeded at room temperature
by using H8-BINAP as a ligand (entry 1). Interestingly, the
yield of 4a is dependent on the dihedral angle of the biaryl
diphosphine ligands [dihedral angle:15 H8-BINAP (entry 1)
> BINAP (entry 2) > Segphos (entry 3); yield of 4a: entry
1 > entry 2 > entry 3]. As the highest enantioselectivity was
obtained by using BINAP, the effect of the steric bulk of
the aryl group on the phosphorus of BINAP was examined
(entries 4 and 5). The study revealed that the use of tol-
BINAP increased both yield and enantioselectivity (entry 4),
while that of xyl-BINAP failed to furnish 4a (entry 5).
(4) (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12051.
(b) Uozumi, Y.; Matsuura, Y.; Arakawa, T.; Yamada, Y. M. A. Angew.
Chem., Int. Ed. 2009, 48, 2708. (c) Shen, X.; Jones, G. O.; Watson, D. A.;
Bhayana, B.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 11278.
(5) For a review of atroposelective biaryl synthesis by the transition
metal-catalyzed [2 + 2 + 2] cycloaddition, see: Tanaka, K. Chem. Asian
J. 2009, 4, 508.
(6) For our first discovery of the cationic rhodium(I)/biaryl diphosphine
complex-catalyzed [2 + 2 + 2] cycloaddition, see: (a) Tanaka, K.; Shirasaka,
K. Org. Lett. 2003, 5, 4697. For our account, see: (b) Tanaka, K. Synlett
2007, 1977.
(7) For enantioselective synthesis of axially chiral biarylcarboxylates
by the rhodium-catalyzed double [2 + 2 + 2] cycloaddition, see: Nishida,
G.; Suzuki, N.; Noguchi, K.; Tanaka, K. Org. Lett. 2006, 8, 3489.
(8) Doherty, S.; Knight, J. G.; Smyth, C. H.; Harrington, R. W.; Clegg,
W. Org. Lett. 2007, 9, 4925.
(9) Nishida, G.; Ogaki, S.; Yusa, Y.; Yokozawa, T.; Noguchi, K.;
Tanaka, K. Org. Lett. 2008, 10, 2849.
(10) Enantioselective synthesis of tri-ortho-substituted axially chiral
biaryl diphosphine oxides via the stepwise double [2 + 2 + 2] cycloaddition
was reported. See: Doherty, S.; Smyth, C. H.; Harrington, R. W.; Clegg,
W. Organometallics 2008, 27, 4837.
(12) Afanasiev, V. V.; Beletskaya, I. P.; Kazankova, M. A.; Efimova,
I. V.; Antipin, M. U. Synthesis 2003, 2835
(13) Bis-diphenylphosphination of triyne 1 proceeded as a side
reaction.
.
(11) For atroposelective biaryl synthesis by the iridium-catalyzed
intramolecular double [2 + 2 + 2] cycloaddition of hexaynes, see: (a)
Shibata, T.; Yoshida, S.; Arai, Y.; Otsuka, M.; Endo, K. Tetrahedron 2008,
64, 821. For racemic biaryl synthesis by the iron-catalyzed intramolecular
double [2 + 2 + 2] cycloaddition of a hexayne, see: (b) Saino, N.; Kogure,
D.; Okamoto, S. Org. Lett. 2005, 7, 3065. (c) Saino, N.; Kogure, D.; Kase,
K.; Okamoto, S. J. Organomet. Chem. 2006, 691, 3129.
(14) Grigg, R.; Scott, R.; Stevenson, P. J. Chem. Soc., Perkin Trans. 1
1988, 1357.
(15) (a) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264. (b) Jeulin, S.;
Duprat de Paule, S.; Ratovelomanana-Vidal, V.; Geneˆt, J.-P.; Champion,
N.; Dellis, P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5799.
Org. Lett., Vol. 13, No. 3, 2011
363

Scheme 3
Table 1. Rh-Catalyzed Enantioselective Intramolecular Double
[2 + 2 + 2] Cycloaddition of Hexayne 3a Leading to Biaryl
4aa
entry
ligand
yield (%)b
ee (%)
1
2
3
4
5
(S)-H8-BINAP
(S)-BINAP
(S)-Segphos
(S)-tol-BINAP
(S)-xyl-BINAP
44
30
8
46
0
58 (R)
82 (R)
78 (R)
92 (R)
a [Rh(cod)2]BF4 (0.0050 mmol), ligand (0.0050 mmol), 3a (0.050 mmol),
and CH2Cl2 (2.0 mL) were used. b Isolated yield.
Scheme 4
Enantiopure diphosphine oxide (-)-4a could be readily
obtained by a single recrystallization from EtOAc in high
yield. Subsequent reduction with HSiCl3/Me2NC6H5 fur-
nished enantiopure (+)-5a in high yield without racemization.
The scale-up of the present enantioselective intramolecular
double [2 + 2 + 2] cycloaddition was successfully ac-
complished. The reaction of hexayne 3a (7.25 g) in the
presence of the cationic rhodium(I)/(R)-tol-BINAP complex
(10 mol %) at room temperature furnished diphosphine oxide
(+)-4a (4.01 g) with higher yield and ee value than those of
the small scale reaction. A subsequent recrystallization from
EtOAc furnished enantiopure (+)-4a (3.65 g) in high yield.
The absolute configurations of axially chiral biaryl diphos-
phine oxide (-)-4a and diphosphine (+)-5a were unambigu-
ously determined to be R by the anomalous dispersion
method (Figure 2).
reaction conditions shown in Scheme 2, the yields and
ee values were lower than those of biaryl 4a.16
Scheme 4 depicts a possible mechanism for the selective
formation of diphosphine oxide (R)-4a by using (S)-tol-
BINAP as a ligand. The first intramolecular [2 + 2 + 2]
cycloaddition of hexayne 3a proceeds to give triyne A. The
second [2 + 2 + 2] cycloaddition through intermediate B,
as a result of the coordination of triarylphosphine oxide
moiety of A to rhodium and the avoidance of steric repulsion
between the alkynylphosphine oxide moiety of A and the
axial phenyl group of (S)-tol-BINAP, would furnish (R)-4a.
It was already reported that axially chiral 3,3′-disubstituted
biaryl diphosphines are superior ligands than BINAP in the
rhodium-catalyzed asymmetric hydrogenation of disubstituted
alkenes, such as 2-acetamidoacrylic acid derivatives 6a and
6b.17,18 Therefore application of ligand (R)-(+)-5a in the
Figure 2. ORTEP diagrams of diphosphine oxide (R)-(-)-4a (left)
and diphosphine (R)-(+)-5a (right) with ellipsoids at 30% prob-
abilities. All hydrogen atoms were omitted for simplicity.
(16) In the reaction of 3b, a pure mono-annulation product was isolated
in 23% yield as a byproduct. In the reaction of 3c, an unidentified mixture
of byproducts was generated.
(17) (a) Tang, W.; Chi, Y.; Zhang, X. Org. Lett. 2002, 4, 1695. (b)
Shibata, T.; Tsuruta, H.; Danjo, H.; Imamoto, T. J. Mol. Catal. A: Chem.
2003, 196, 117. (c) Wu, S.; He, M.; Zhang, X. Tetrahedron: Asymmetry
2004, 15, 2177. (d) Hopkins, J. M.; Dalrymple, S. A.; Parvez, M.; Keay,
B. A. Org. Lett. 2005, 7, 3765. (e) Rankic, D. A.; Hopkins, J. M.; Parvez,
M.; Keay, B. A. Synlett 2009, 2513. For applications in palladium-catalyzed
asymmetric reactions, see: (f) Gorobets, E.; Sun, G.-R.; Wheatley, B. M. M.;
Parvez, M.; Keay, B. A. Tetrahedron Lett. 2004, 45, 3597. (g) Gorobets,
E.; Sun, G.-R.; Wheatley, B. M. M.; Parvez, M.; Keay, B. A. Tetrahedron
Lett. 2004, 45, 3597. (h) Hopkins, J. M.; Gorobets, E.; Wheatley, B. M. M.;
Parvez, M.; Keay, B. A. Synlett 2006, 3120. (i) Rankic, D. A.; Lucciola,
Enantioselective synthesis of sterically more demanding
C2-symmetric axially chiral biaryl diphosphine oxides 4b and
4c was also examined as shown in Scheme 3. Although the
enantioselective intramolecular [2 + 2 + 2] cycloadditions
of hexayne di(p-tolyl)phosphine oxide 3b and hexayne
di(3,5-xylyl)phosphinoyl oxide 3c proceeded to give the
corresponding biaryls 4b and 4c, respectively, under the same
D.; Keay, B. A. Tetrahedron Lett. 2010, 51, 5724
.
364
Org. Lett., Vol. 13, No. 3, 2011

Scheme 5
Table 2. Comparison of Enantioselectivity between (R)-(+)-5a,
(+)-5b, (+)-5c, and (S)-BINAP in Rh-Catalyzed Asymmetric
Hydrogenation of Disubstituted Alkenes 6a-da
entry
6
R1
R2
ligand
7
ee (%)
1
2
3
4
5
6
7
8
6a OMe NHAc
6a OMe NHAc
(R)-(+)-5a
(R)-7a
98
25
96
23
78
76
48
18
(S)-BINAP (R)-7a
(R)-(+)-5a (R)-7b
(S)-BINAP (R)-7b
(S)-7c
6c OMe CH2CO2Me (S)-BINAP (S)-7c
6b OH
6b OH
NHAc
NHAc
6c OMe CH2CO2Me (R)-(+)-5a
briefly. Interestingly, the rhodium-catalyzed asymmetric [2
+ 2 + 2] cycloaddition of 1,6-enyne 8 with ethyl phenyl-
propiolate (9) using (R)-(+)-5a as a ligand furnished a pair
of two regioisomeric products 10 and 11 with 72:28
regioselectivity and good ee values; this regioselectivity is
contrary to that using (S)-BINAP (10/11 ) 29:71) (Scheme
5).19 With regard to enantioselectivity, the opposite facial
enantioselections were observed between (R)-(+)-5a and (S)-
BINAP.
In conclusion, we have achieved the concise asymmetric
synthesis of axially chiral biaryl diphosphine ligands by the
rhodium-catalyzed intramolecular [2 + 2 + 2] cycloaddition
of hexayne diphosphine oxides. These new chiral diphos-
phine ligands could be employed as a ligand for the rhodium-
catalyzed asymmetric catalyses. Future work will focus on
further optimization of the large-scale synthesis of these new
chiral biaryl diphosphine ligands and their application in
various asymmetric catalyses.
6d NPh2 Ph
6d NPh2 Ph
(R)-(+)-5a
(S)-BINAP (-)-7d
(+)-7d
a All reactions were completed under the conditions.
rhodium-catalyzed asymmetric hydrogenation of disubstituted
alkenes including 6a and 6b was briefly examined, and the
observed enantioselectivities were compared to those with
(S)-BINAP under the same reaction conditions (Table 2).
Significantly higher enantioselectivities were observed with
(R)-(+)-5a than those with (S)-BINAP in the hydrogenation
of 6a and 6b (entries 1 and 3 vs entries 2 and 4). In the
hydrogenation of itaconic acid dimethyl ester (6c), good
enantioselectivities were observed by using both (R)-(+)-
5a and (S)-BINAP (entries 5 and 6). Interestingly, the same
facial enantioselections were observed between (R)-(+)-5a
and (S)-BINAP in the hydrogenation of 6a-c (entries 1-6).
The hydrogenation of acrylamide derivative 6d with (R)-
(+)-5a showed higher enantioselectivity than that with (S)-
BINAP (entry 7 vs entry 8), although the ee value was
moderate.
Acknowledgment. This work was supported partly by a
Grant-in-Aid for Scientific Research (No. 20675002) from
MEXT, Japan. We thank Mr. Tomohiko Hakamada and Mr.
Tohru Yokozawa (Takasago International Corporation) for
their experiments, Takasago International Corporation for the
gift of H8-BINAP, Segphos, tol-BINAP, and xyl-BINAP, and
Umicore for generous support in supplying a rhodium
complex.
Application of ligand (R)-(+)-5a in the rhodium-catalyzed
asymmetric C-C bond forming reaction was also examined
(18) For a review of new chiral phosphorus ligands for enantioselective
hydrogenation, see: (a) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
(b) Zhang, W.; Chi, Y.; Zhang, X. Acc. Chem. Res. 2007, 40, 1278
.
(19) For the cationic rhodium(I)/axially chiral biaryl diphosphine
complex-catalyzed regio- and enantioselective [2 + 2 + 2] cycloaddition
of 1,6-enynes with alkynes, see: (a) Evans, P. A.; Lai, K. W.; Sawyer, J. R.
J. Am. Chem. Soc. 2005, 127, 12466. (b) Shibata, T.; Arai, Y.; Tahara, Y.
Org. Lett. 2005, 7, 4955. During the preparation of this manuscript, the
regiodivergent ligand (xyl-BINAP vs PPh3)-controlled rhodium-catalyzed
[2 + 2 + 2] cycloaddition of 1,6-enynes with alkyl-substituted methyl
propiolates was reported. See: (c) Evans, P. A.; Sawyer, J. R.; Inglesby,
P. A. Angew. Chem., Int. Ed. 2010, 49, 5746.
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and X-ray crystal-
lographic files. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL102927Y
Org. Lett., Vol. 13, No. 3, 2011
365