Tuning the chiral environment of C2-symmetric diene ligands: Development of 3,7-disubstituted bicyclo[3.3.1]nona-2,6-dienes

Article abstract of DOI:10.1021/jo802437h

Through the structural analysis of bicyclo[3.3.1]nona-2,6-dienes, new C₂-symmetric chiral diene ligands 1 based on 3,7-disubstituted bicyclo[3.3.1]nona-2,6-diene framework have been designed and synthesized. These chiral ligands readily bind to

Full text of DOI:10.1021/jo802437h

Tuning the Chiral Environment of C2-Symmetric Diene Ligands:
Development of 3,7-Disubstituted Bicyclo[3.3.1]nona-2,6-dienes
Ryo Shintani,* Yoshitaka Ichikawa, Keishi Takatsu, Fu-Xue Chen, and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
shintani@kuchem.kyoto-u.ac.jp; thayashi@kuchem.kyoto-u.ac.jp
ReceiVed NoVember 1, 2008
Through the structural analysis of bicyclo[3.3.1]nona-2,6-dienes, new C2-symmetric chiral diene ligands
1 based on 3,7-disubstituted bicyclo[3.3.1]nona-2,6-diene framework have been designed and synthesized.
These chiral ligands readily bind to rhodium(I) and provide a different chiral environment from the existing
chiral dienes. The rhodium complexes thus obtained act as effective catalysts for 1,4-addition of alkenyl-
and arylboronic acids to various R,ꢀ-unsaturated ketones, including several combinations that were
previously difficult to provide high enantioselectivity.
Introduction
Chiral dienes have been recently recognized as effective
ligands for transition metal-catalyzed asymmetric reactions and
several research groups have witnessed the superiority of these
ligands to conventional phosphorus- and/or nitrogen-based
chiral ligands in some transformations.1 Among the chiral diene
ligands developed to date, the ones with C2-2,3a-m,4-6 or
pseudo-C2-symmetry3n-t have provided a particularly effective
chiral environment for asymmetric carbonscarbon bond-form-
ing reactions such as rhodium-catalyzed asymmetric 1,4-addition
reactions. Their effectiveness is considered to be based on the
rigid (pseudo-)C2-symmetry of the ligand framework, but
unfortunately, due to the high rigidity, currently available chiral
dienes cannot accommodate all the asymmetric catalysis one
wishes to accomplish with high stereoselectivity.
FIGURE 1. Chem3D representation of 2,3,6,7-tetramethylbicyclo-
[3.3.1]nona-2,6-diene (A) (left: front view; right: side view; M is a
transition metal, placed at the same distance from two olefins without
optimization).
For example, we previously reported the use of 2,6-
diarylbicyclo[3.3.1]nona-2,6-dienes, such as (R,R)-Ph-bnd*, as
effective ligands for the rhodium-catalyzed asymmetric arylation
of imines,4a but these ligands provided only moderate enanti-
oselectivity for 1,4-addition to electron-deficient olefins.4b By
analyzing the three-dimensional structure of 2,3,6,7-tetra-
methylbicyclo[3.3.1]nona-2,6-diene (A) as a model, two alkenes,
C2-C3 and C6-C7, are twisted by ca. 27.6° with each other
(Figure 1, right), and as a result, methyl groups on C3 and C7
(CR and CR′, respectively) are located closer to a metal (M)
(1) For reviews, see: (a) Johnson, J. B.; Rovis, T. Angew. Chem., Int. Ed.
2008, 47, 840. (b) Defieber, C.; Gru¨tzmacher, H.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2008, 47, 4482.
(2) Bicyclo[2.2.1]hepta-2,5-dienes:(a) Hayashi, T.; Ueyama, K.; Tokunaga,
N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508. (b) Shintani, R.; Ueyama,
K.; Yamada, I.; Hayashi, T. Org. Lett. 2004, 6, 3425. (c) Berthon-Gelloz, G.;
Hayashi, T. J. Org. Chem. 2006, 71, 8957.
10.1021/jo802437h CCC: $40.75
Published on Web 12/02/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 869–873 869

Shintani et al.
SCHEME 1a
a Conditions: (a) 2-PyNTf2 (2.4 equiv), KN(SiMe3)2 (2.3 equiv), THF,
-78 °C; 82%. (b) NiCl2(dppp) (2 mol %), RMgBr (6.0 equiv), THF, reflux;
70% for 1a, 85% for 1b. (c) HPLC resolution (chiralcel OD-H for 1a,
chiralcel OJ for 1b).
than those on C2 and C6 (Cꢀ and Cꢀ′, respectively) when this
diene forms a chelating metal complex. This simple analysis
using model compound A led us to design new C2-symmetric
chiral dienes, 3,7-disubstituted bicyclo[3.3.1]nona-2,6-dienes 1,
which are expected to provide a closer and more effective chiral
environment in their transition metal complexes.
FIGURE 2. X-ray structure of [RhCl((S,S)-1a)]2 with thermal ellipsoids
drawn at the 50% probability level (shown as a monomer; hydrogen
atoms are omitted for clarity).
Results and Discussion
Preparation of 3,7-Disubstituted Bicyclo[3.3.1]nona-2,6-
dienes 1. The synthesis of 3,7-disubstituted bicyclo[3.3.1]nona-
2,6-dienes 1 begins with readily available bicyclo[3.3.1]nonane-
3,7-dione7 (2) in a straightforward manner (Scheme 1). Thus,
selective formation of ditriflate dl-3 followed by nickel-catalyzed
cross-coupling with an appropriate Grignard reagent gives dienes
1a (R ) phenyl) and 1b (R ) 4-methoxybenzyl) as racemates.
The racemic mixtures can be resolved by a preparative chiral
HPLC to give each enantiomer of 1a and 1b.
Structure of a Rhodium Complex Coordinated with 1. A
ligand exchange reaction of [RhCl(C2H4)2]2 with (S,S)-1a in
chloroform at 50 °C cleanly produced [RhCl((S,S)-1a)]2 and
recrystallization of this complex from THF/hexane afforded
single crystals suitable for X-ray analysis.8 The monomeric
(3) Bicyclo[2.2.2]octa-2,5-dienes:(a) Tokunaga, N.; Otomaru, Y.; Okamoto,
K.; Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.
(b) Otomaru, Y.; Okamoto, K.; Shintani, R.; Hayashi, T. J. Org. Chem. 2005,
70, 2503. (c) Shintani, R.; Kimura, T.; Hayashi, T. Chem. Commun. 2005, 3213.
(d) Shintani, R.; Tsurusaki, A.; Okamoto, K.; Hayashi, T. Angew. Chem., Int.
Ed. 2005, 44, 3909. (e) Shintani, R.; Okamoto, K.; Hayashi, T. Org. Lett. 2005,
7, 4757. (f) Hayashi, T.; Tokunaga, N.; Okamoto, K.; Shintani, R. Chem. Lett.
2005, 1480. (g) Chen, F.-X.; Kina, A.; Hayashi, T. Org. Lett. 2006, 8, 341. (h)
Nishimura, T.; Yasuhara, Y.; Hayashi, T. Org. Lett. 2006, 8, 979. (i) Tokunaga,
N.; Hayashi, T. AdV. Synth. Catal. 2007, 349, 513. (j) Duan, W.-L.; Imazaki,
Y.; Shintani, R.; Hayashi, T. Tetrahedron 2007, 63, 8529. (k) Shintani, R.;
Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem., Int. Ed. 2007, 46, 7277. (l)
Shintani, R.; Ichikawa, Y.; Hayashi, T.; Chen, J.; Nakao, Y.; Hiyama, T. Org.
Lett. 2007, 9, 4643. (m) So¨rgel, S.; Tokunaga, N.; Sasaki, K.; Okamoto, K.;
Hayashi, T. Org. Lett. 2008, 10, 589. (n) Defieber, C.; Paquin, J.-F.; Serna, S.;
Carreira, E. M. Org. Lett. 2004, 6, 3873. (o) Paquin, J.-F.; Defieber, C.;
Stephenson, C. R. J.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 10850. (p)
Paquin, J.-F.; Stephenson, C. R. J.; Defieber, C.; Carreira, E. M. Org. Lett. 2005,
7, 3821. (q) Fessard, T. C.; Andrews, S. P.; Motoyoshi, H.; Carreira, E. M.
Angew. Chem., Int. Ed. 2007, 46, 9331. (r) Miura, T.; Murakami, M. Org. Lett.
2005, 7, 3339. (s) Miura, T.; Murakami, M. Chem. Commun. 2005, 5676. (t)
Miura, T.; Takahashi, Y.; Murakami, M. Chem. Commun. 2007, 595.
(4) Bicyclo[3.3.1]nona-2,6-dienes: (a) Otomaru, Y.; Tokunaga, N.; Shintani,
R.; Hayashi, T. Org. Lett. 2005, 7, 307. (b) Otomaru, Y.; Kina, A.; Shintani, R.;
Hayashi, T. Tetrahedron: Asymmetry 2005, 16, 1673.
FIGURE 3. Selected bond distances and angles for [RhCl((S,S)-1a)]2
(top) and [RhCl((R,R)-Tol-Bnd*)]2 (bottom).
structure is shown in Figure 2 and its selected bond distances
and angles are summarized in Figure 3 along with those of
[RhCl((R,R)-Tol-bnd*)]2 for comparison.4b The core bicyclo-
[3.3.1]nona-2,6-diene structures are similar between these two
complexes: two double bonds C2-C3 and C6-C7 are not
parallel but twisted by 21-23°, and as a result, the C3-Rh-C7
angle (103-104°) becomes much larger than that of C2-Rh-C6
(84-87°). Because (S,S)-1a has substituents at C3 and C7, rather
than at C2 and C6, the most significant structural difference
between [RhCl((S,S)-1a)]2 and [RhCl((R,R)-Tol-bnd*)]2 is the
(5) Bicyclo[3.3.0]octa-2,5-dienes: (a) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-
H.; Lin, G.-Q. J. Am. Chem. Soc. 2007, 129, 5336. (b) Helbig, S.; Sauer, S.;
Cramer, N.; Laschat, S.; Baro, A.; Frey, W. AdV. Synth. Catal. 2007, 349, 2331.
(6) Cycloocta-1,5-dienes: (a) Kina, A.; Ueyama, K.; Hayashi, T. Org. Lett.
2005, 7, 5889 See also. (b) La¨ng, F.; Breher, F.; Stein, D.; Gru¨tzmacher, H.
Organometallics 2005, 24, 2997.
(8) The crystal structure has been deposited at the Cambridge Crystallographic
Data Centre (deposition number: CCDC 683881). The data can be obtained free
of charge via the Internet at www.ccdc.cam.ac.uk/conts/retrieving.html.
(7) Zalikowski, J. A.; Gilbert, K. E.; Borden, W. T. J. Org. Chem. 1980, 45,
346. This diketone is also commercially available (e.g, Aldrich).
870 J. Org. Chem. Vol. 74, No. 2, 2009

DeVelopment of Substituted Bicyclo[3.3.1]nona-2,6-dienes
TABLE 1. Rhodium-Catalyzed Asymmetric 1,4-Addition of
(E)-1-Heptenylboronic Acid (5a) to
(E)-3-Dimethylphenylsilyl-1-phenyl-2-propen-1-one (4a)
TABLE 2. Rh/(S,S)-1b-Catalyzed Asymmetric 1,4-Addition of
Organoboronic Acids 5 to r,ꢀ-Unsaturated Ketones 4
entry
diene
ee (%)a
1
2
3
4
5
6
7
8
(R,R)-Ph-bod*
(R,R)-Bn-bod*
(R,R)-Mb-bod*
(S,S)-Ph-bnd*
(S,S)-Bn-bnd*
(S,S)-Mb-bnd*
(S,S)-1a
52
43
44
30
6
7
75
97
entry
4
5
product
yield (%)a
ee (%)b
1
2
3
4
5
4a
4a
4a
4a
4b
4b
4c
4c
4c
4d
4e
4e
4f
5a
5b
5c
5d
5d
5d
5a
5a
5d
5d
5d
5d
5d
5d
5e
5e
5f
6aa
6ab
6ac
6ad
6bd
6bd
6ca
6ca
6cd
6dd
6ed
6ed
6fd
6gd
6be
6ce
6cf
91
72
82
86
94
97
91
73
95
89
81
78
63
52
87
91
83
86
97 (S)
92 (S)
87 (S)
96 (S)
99 (R)
90 (R)
99 (R)
88 (R)
99 (R)
99 (R)
95 (S)
89 (R)
93 (S)
96 (R)
96 (R)
98 (R)
98 (R)
97 (R)
(S,S)-1b
a Ee was determined by HPLC on a Chiralpak AD-H column with
hexane/2-propanol ) 100/1.
6c (ref 3n)
7
8d (ref 2a)
9
10
11e
12f (ref 3n)
13e
14e g
4g
4b
4c
4c
4c
,
15
16
17
18
positions of C10 and C16. Thus, the C10-Rh-C16 angle and
the Rh-C10 distance for [RhCl((S,S)-1a)]2 are 158° and 2.99
Å, respectively, whereas the corresponding angle and distance
for [RhCl((R,R)-Tol-bnd*)]2 are 137° and 3.13 Å, respectively.
These data clearly show that the substituents on the olefins of
(S,S)-1a are indeed located closer to the rhodium metal, thereby
creating a more effective C2-symmetric chiral environment
around it compared to previously developed (R,R)-Tol-bnd*.
In addition, the deviation of C10 from the Cl(1)-Rh(1)-Cl(2)
plane in [RhCl((S,S)-1a)]2 (1.89 Å) and that in [RhCl((R,R)-
Tol-bnd*)]2 (1.17 Å) are also very different from each other.
These structural differences observed here might indicate the
possibility of achieving higher stereoselectivity with ligand 1
in the reactions where existing chiral dienes such as bnd* and
bod* 3a-m can induce only moderate enantioselectivity.
Asymmetric 1,4-Addition Reactions Catalyzed by Rh/
(S,S)-1. To evaluate the potential of newly synthesized ligand
1, we initially examined a rhodium-catalyzed asymmetric 1,4-
addition9 of linear 1-alkenylboronic acids to ꢀ-silyl R,ꢀ-
unsaturated ketones for the synthesis of chiral allylsilanes,10
which we previously attempted by using linear 1-alkenylsilicon
reagents as the nucleophile, achieving only up to 56% ee with
5g
6cg
a Isolated yield. b Ee was determined by chiral HPLC with
hexane/2-propanol. c Data from ref 3n, using (R,R)-7 as a ligand at 25
°C. d Data from ref 2a, using (R,R)-Bn-nbd* as a ligand at 50 °C. e The
reaction was conducted with 3 equiv of 5d in the presence of 10 mol %
catalyst. f Data from ref 3n, using (S,S)-7 as a ligand at 25 °C. g The
reaction was conducted at 20 °C.
(S,S)-Ph-bod* as the ligand.3l The reaction of (E)-3-dimeth-
ylphenylsilyl-1-phenyl-2-propen-1-one (4a) with (E)-1-hepte-
nylboronic acid (5a) was conducted in the presence of a Rh/
chiral diene catalyst (5 mol % Rh) at 30 °C and the results are
summarized in Table 1. As was the case with linear 1-alkenyl-
silicon reagents as the nucleophile, the use of (R,R)-Ph-bod*
as the ligand gave 1,4-adduct 6aa with moderate enantioselec-
tivity (52% ee; entry 1), and somewhat lower ee was observed
by using structurally similar (R,R)-Bn-bod* or (R,R)-Mb-bod*
(43% ee and 44% ee, respectively; entries 2 and 3). The use of
(S,S)-Ph-bnd* resulted in even lower enantioselectivity (30%
ee; entry 4), and (S,S)-Bn-bnd* or (S,S)-Mb-bnd* also gave 6aa
with low ee (6% ee and 7% ee, respectively; entries 5 and 6).
In contrast, significantly higher enantioselectivity was realized
by employing (S,S)-1a as the ligand (75% ee; entry 7). The
best ee was achieved by changing the substituent of ligand 1
from phenyl to 4-methoxybenzyl ((S,S)-1b) (97% ee; entry 8).11
Under the conditions with (S,S)-1b as a ligand, not only
1-heptenyl but some other alkenyl groups can be installed to
(9) For reviews on rhodium-catalyzed asymmetric 1,4-additions, see: (a)
Christoffers, J.; Koripelly, G.; Rosiak, A.; Ro¨ssle, M. Synthesis 2007, 1279. (b)
Hayashi, T. Bull. Chem. Soc. Jpn. 2004, 77, 13. (c) Hayashi, T.; Yamasaki, K.
Chem. ReV. 2003, 103, 2829. (d) Fagnou, K.; Lautens, M. Chem. ReV. 2003,
103, 169. (e) Bolm, C.; Hildebrand, J. P.; Mun˜iz, K.; Hermanns, N. Angew.
Chem., Int. Ed. 2001, 40, 3284.
(10) For examples of transition metal-catalyzed asymmetric synthesis of chiral
allylsilanes, see: (a) Hayashi, T.; Konishi, M.; Okamoto, Y.; Kabeta, K.; Kumada,
M. J. Org. Chem. 1986, 51, 3772. (b) Hayashi, T.; Han, J. W.; Takeda, A.;
Tang, J.; Nohmi, K.; Mukaide, K.; Tsuji, H.; Uozumi, Y. AdV. Synth. Catal.
2001, 343, 279. (c) Hayashi, T.; Ohno, A.; Lu, S.; Matsumoto, Y.; Fukuyo, E.;
Yanagi, K. J. Am. Chem. Soc. 1994, 116, 4221. (d) Hayashi, T.; Iwamura, H.;
Uozumi, Y. Tetrahedron Lett. 1994, 35, 4813. (e) Ohmura, T.; Taniguchi, H.;
Suginome, M. J. Am. Chem. Soc. 2006, 128, 13682. (f) Kacprzynski, M. A.;
May, T. L.; Kazane, S. A.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46,
4638. See also: (g) Kacprzynski, M. A.; Kazane, S. A.; May, T. L.; Hoveyda,
A. H. Org. Lett. 2007, 9, 3187.
(11) The methoxy groups were introduced for the purpose of chiral HPLC
resolution of 1.
J. Org. Chem. Vol. 74, No. 2, 2009 871

Shintani et al.
3
3
1H NMR (CDCl3) δ 7.38 (d, JHH ) 7.9 Hz, 4H), 7.29 (t, JHH
enone 4a with high efficiency (72-91% yield, 87-97% ee;
Table 2, entries 1-4). Addition of alkenylboronic acids under
the present conditions is applicable to various simple R,ꢀ-
unsaturated ketones as well, and particularly high enantiose-
lectivities are observed for cyclic enones regardless of their ring
sizes (99% ee; entries 5, 7, 9, and 10). The use of acyclic enones
also gives the 1,4-adducts with high enantioselectivity (93-96%
ee; entries 11, 13, and 14), but the chemical yields are somewhat
diminished even with a higher catalyst loading. It is worth noting
that the enantioselectivities achieved with (S,S)-1b are signifi-
cantly higher than those reported with ligands (R,R)- or (S,S)-7
(89-90% ee; entries 6 and 12)3n and (R,R)-Bn-nbd* (88% ee;
entry 8).2a In addition to alkenyl nucleophlies, arylboronic acids
can also be employed to give the corresponding ꢀ-aryl ketones
in high yield and ee (83-91% yield, 96-98% ee; entries
15-18).
3
4
) 7.6 Hz, 4H), 7.21 (tt, JHH ) 7.3 Hz and JHH ) 1.2 Hz, 2H),
3
4
6.22 (dd, JHH ) 6.0 Hz and JHH ) 1.7 Hz, 2H), 2.90-2.84 (m,
2
2H), 2.74-2.67 (m, 2H), 2.42 (d, JHH ) 17.1 Hz, 2H), 1.85 (t,
3JHH ) 2.9 Hz, 2H). 13C NMR (CDCl3) δ 142.2, 135.0, 128.7, 128.3,
126.8, 125.3, 33.3, 29.3, 28.4. Anal. Calcd for C21H20: C, 92.60;
H, 7.40. Found: C, 92.38; H, 7.57.
(1S,5S)-3,7-Bis(4-methoxylbenzyl)bicyclo[3.3.1]nona-2,6-diene
((S,S)-1b). 4-Methoxybenzylmagnesium bromide (2.20 mL, 1.45
mmol; 0.66 M solution in THF) was added to a solution of
compound 3 (101 mg, 0.243 mmol) and NiCl2(dppp) (2.6 mg, 4.8
µmol) in THF (1.0 mL) at room temperature. The mixture was
refluxed for 17 h and the reaction was quenched with saturated aq
NH4Cl at room temperature. After extraction with Et2O, the organic
layer was dried over MgSO4, filtered, and concentrated under
vacuum. The residue was chromatographed on silica gel with
EtOAc/hexane ) 1/50 and further purified by GPC with chloroform
to afford (()-1b as a white solid (74.7 mg, 0.207 mmol; 85% yield).
(()-1b was resolved into each enantiomer by preparative HPLC,
using a Daicel Chiralcel OJ column with hexane/2-propanol ) 98/
2, flow ) 15 mL/min. Retention times: 27 min [(1R,5R)-enanti-
omer], 43 min [(1S,5S)-enantiomer]. [R]25D +158 (c 0.99, CHCl3).
Conclusions
We have designed and synthesized 3,7-disubstituted bicyclo-
[3.3.1]nona-2,6-dienes 1 as new C2-symmetric chiral diene
ligands to provide a different chiral environment from the
previously described chiral dienes. These chiral ligands 1 readily
bind to rhodium(I) and the rhodium complexes thus obtained
act as effective catalysts for 1,4-addition of alkenyl- and
arylboronic acids to various R,ꢀ-unsaturated ketones, including
several combinations that were previously difficult to provide
high enantioselectivity.
3
3
1H NMR (CDCl3) δ 7.05 (d, JHH ) 8.7 Hz, 4H), 6.83 (d, JHH
) 8.7 Hz, 4H), 5.44 (d, 3JHH ) 5.2 Hz, 2H), 3.81 (s, 6H), 3.22 (d,
2JHH ) 14.8 Hz, 2H), 3.18 (d, 2JHH ) 14.8 Hz, 2H), 2.49-2.40 (m,
2
3
2H), 2.10 (dd, JHH ) 16.9 Hz and JHH ) 5.2 Hz, 2H), 1.72 (d,
2JHH ) 17.1 Hz, 2H), 1.62 (t, 3JHH ) 2.9 Hz, 2H). 13C NMR (CDCl3)
δ 157.9, 135.6, 132.6, 129.9, 127.5, 113.7, 55.4, 43.3, 34.1, 29.1,
28.8. Anal. Calcd for C25H28O2: C, 83.29; H, 7.83. Found: C, 83.03;
H, 7.96.
Preparation of [RhCl((S,S)-1)]2. A solution of [RhCl(C2H4)2]2
(138 mg, 0.710 mmol Rh) and (S,S)-1 (0.620 mmol) in chloroform
(30 mL) was stirred for 4 h at 50 °C. The reaction mixture was
directly passed through a pad of silica gel with chloroform and the
solvent was removed under vacuum to afford crude [RhCl((S,S)-
1)]2, which was further purified as described below.
Experimental Section
Preparation of Chiral Dienes 1. dl-3,7-Bis(trifluoromethane-
sulfonyloxy)bicyclo[3.3.1]nona-2,6-diene (dl-3). KN(SiMe3)2 (46.0
mL, 23.0 mmol; 0.50 M solution in toluene) was slowly added to
a solution of bicyclo[3.3.1]nona-3,7-dione (1.52 g, 9.99 mmol) and
N-(2-pyridyl)triflimide (8.63 g, 24.1 mmol) in THF (30 mL) at -78
°C, and the resulting mixture was stirred for 1 h at -78 °C. The
reaction was quenched with saturated aq NaHCO3 and the mixture
was warmed to room temperature. After extraction with Et2O, the
organic layer was washed with 10% aq NaOH, dried over Na2SO4,
filtered, and concentrated under vacuum. The residue was chro-
matographed on silica gel with EtOAc/hexane ) 1/20 to afford
compound 3 as a white solid (3.39 g, 8.14 mmol; 82% yield (dl/
achiral ) 94/6)).
[RhCl((S,S)-1a)]2. The product was recrystallized from THF/
hexane under nitrogen to afford pure [RhCl((S,S)-1a)]2 as red
crystals (72% yield). [R]25 -682 (c 0.24, CHCl3).
D
1H NMR (CDCl3) δ 7.70-7.40 (m, 4H), 7.29 (t, 3JHH ) 7.3 Hz,
2H), 7.21 (t, 3JHH ) 7.6 Hz, 4H), 4.22 (d, 3JHH ) 4.6 Hz, 2H), 3.67
(dd, 2JHH ) 15.2 Hz and 3JHH ) 3.8 Hz, 2H), 2.26-2.17 (m, 2H),
2
2.07 (d, JHH ) 15.3 Hz, 2H), 1.15 (br s, 2H). 13C NMR (CDCl3)
1
δ 144.4, 127.7, 127.6, 127.4, 93.1 (d, JCRh ) 11.9 Hz), 66.8 (d,
1JCRh ) 13.4 Hz), 45.9, 31.6, 27.8. Anal. Calcd for C42H40Cl2Rh2:
C, 61.41; H, 4.91. Found: C, 61.45; H, 4.88.
1H NMR (CDCl3) δ 5.84 (dd, 3JHH ) 6.3 Hz and 4JHH ) 1.6 Hz,
2H), 2.92-2.86 (m, 2H), 2.68 (dd, 2JHH ) 17.2 Hz and 3JHH ) 5.5
[RhCl((S,S)-1b)]2. The product was chromatographed on silica
gel with EtOAc/hexane ) 1/20 to afford pure [RhCl((S,S)-1b)]2 as
2
3
Hz, 2H), 2.23 (d, JHH ) 17.4 Hz, 2H), 1.77 (t, JHH ) 2.9 Hz,
2H). 13C NMR (CDCl3) δ 149.3, 120.9, 118.6 (q, 1JCF ) 320 Hz),
32.7, 28.2, 26.7. Anal. Calcd for C11H10O2F6S2: C, 31.74; H, 2.42.
Found: C, 31.74; H, 2.34.
an orange solid (81% yield). [R]25 -182 (c 0.20, CHCl3).
D
1H NMR (CDCl3) δ 7.20 (d, JHH ) 8.5 Hz, 4H), 6.84 (d, JHH
3
3
3
2
) 8.6 Hz, 4H), 4.09 (d, JHH ) 5.7 Hz, 2H), 3.87 (d, JHH ) 13.9
Hz, 2H), 3.80 (s, 6H), 3.18 (d, 2JHH ) 13.8 Hz, 2H), 3.06 (dd, 2JHH
(1S,5S)-3,7-Diphenylbicyclo[3.3.1]nona-2,6-diene ((S,S)-1a). Phe-
nylmagnesium bromide (2.20 mL, 2.18 mmol; 0.99 M solution in
THF) was added to a solution of compound 3 (151 mg, 0.363 mmol)
and NiCl2(dppp) (3.9 mg, 7.2 µmol) in THF (1.5 mL) at room
temperature. The mixture was refluxed for 17 h and the reaction
was quenched with saturated aq NH4Cl at room temperature. After
extraction with Et2O, the organic layer was dried over MgSO4,
filtered, and concentrated under vacuum. The residue was chro-
matographed on silica gel with EtOAc/hexane ) 1/50 and further
purified by GPC with chloroform to afford (()-1a as a white solid
(68.8 mg, 0.253 mmol; 70% yield). (()-1a was resolved into each
enantiomer by preparative HPLC, using a Daicel Chiralcel OD-H
column with hexane/2-propanol ) 500/1, flow ) 8.0 mL/min.
Retention times: 24 min [(1S,5S)-enantiomer], 30 min [(1R,5R)-
3
) 15.4 Hz and JHH ) 3.7 Hz, 2H), 2.06-1.97 (m, 2H), 1.89 (d,
2JHH ) 15.3 Hz, 2H), 0.81 (br s, 2H). 13C NMR (CDCl3) δ 158.2,
1
1
132.9, 129.7, 113.9, 100.4 (d, JCRh ) 13.4 Hz), 72.1 (d, JCRh
)
13.4 Hz), 55.4, 47.9, 45.6, 31.3, 27.3. HRMS (ESI-TOF) calcd for
C50H56O4Cl3Rh2 (M + Cl-) 1031.1360, found 1031.1382.
Preparation of (1R,4R)-2,5-Bis(4-methoxybenzyl)bicyclo[2.2.2]-
octa-2,5-diene ((R,R)-Mb-bod*). 4-Methoxybenzylmagnesium chlo-
ride (12.0 mL, 3.61 mmol; 0.301 M solution in THF) was added
toasolutionofdl-2,5-bis(trifluoromethanesulfonyloxy)bicyclo[2.2.2]octa-
2,5-diene (241 mg, 0.600 mmol) and PdCl2(dppf) (8.8 mg, 12 µmol)
in Et2O (3.0 mL) at room temperature. The mixture was stirred for
9 h at 45 °C and the reaction was quenched with saturated aq NH4Cl
at room temperature. After extraction with Et2O, the organic layer
was dried over MgSO4, filtered, and concentrated under vacuum.
The residue was purified by silica gel preparative TLC with EtOAc/
hexane ) 1/10 and further purified by GPC with chloroform to
afford (()-Mb-bod* as a white solid (143 mg, 0.412 mmol; 69%
enantiomer]. [R]25 +27.4 (c 0.99, CHCl3). The absolute config-
D
uration was determined by X-ray crystallographic analysis of its
rhodium complex [RhCl((S,S)-1a)]2 (see Supporting Information
for details).
872 J. Org. Chem. Vol. 74, No. 2, 2009

DeVelopment of Substituted Bicyclo[3.3.1]nona-2,6-dienes
yield). (()-Mb-bod* was resolved into each enantiomer by a
preparative HPLC, using a Daicel Chiralpak AD-H column with
hexane/2-propanol ) 150/1, flow ) 15 mL/min. Retention times:
11 min [(S,S)-enantiomer], 17 min [(R,R)-enantiomer]. [R]20D +86.0
(c 0.64, CHCl3).
mixture was refluxed for 20 h and the reaction was quenched
with saturated aq NH4Cl at room temperature. After extraction
with Et2O, the organic layer was dried over MgSO4, filtered,
and concentrated under vacuum. The residue was purified by
silica gel preparative TLC with CH2Cl2/hexane ) 1/1 and further
purified by GPC with chloroform to afford (()-Mb-bnd* as a
white solid (252 mg, 0.698 mmol; 70% yield). (()-Mb-bnd*
was resolved into each enantiomer by a preparative HPLC, using
a Daicel Chiralcel OD-H column with hexane/2-propanol ) 100/
1, flow ) 12 mL/min. Retention times: 43 min [(S,S)-enanti-
omer], 47 min [(R,R)-enantiomer]. [R]20D -97.3 (c 1.05, CHCl3).
1H NMR (CDCl3) δ 7.04 (d, JHH ) 8.5 Hz, 4H), 6.81 (d, JHH
) 8.5 Hz, 4H), 5.80 (d, 3JHH ) 6.1 Hz, 2H), 3.79 (s, 6H), 3.39 (d,
2JHH ) 15.5 Hz, 2H), 3.35 (d, 2JHH ) 15.4 Hz, 2H), 3.24-3.22 (m,
2H), 1.26-1.18 (m, 2H), 1.13-1.08 (m, 2H). 13C NMR (CDCl3) δ
158.0, 147.7, 131.9, 130.0, 128.1, 113.7, 55.4, 41.2, 39.4, 26.2.
Anal. Calcd for C24H26O2: C, 83.20; H, 7.56. Found: C, 83.22; H,
7.69.
3
3
1H NMR (CDCl3) δ7.08 (d, 3JHH ) 8.5 Hz, 4H), 6.82 (d, 3JHH
)
3
Preparation of (1S,5S)-2,6-Dibenzylbicyclo[3.3.1]nona-2,6-di-
ene ((S,S)-Bn-bnd*). Benzylmagnesium bromide (22.0 mL, 24.2
mmol; 1.1 M solution in Et2O) was added to a solution of dl-2,6-
bis(trifluoromethanesulfonyloxy)bicyclo[3.3.1]nona-2,6-diene (1.70
g, 4.08 mmol) and NiCl2(dppp) (44 mg, 81 µmol) in THF (15 mL)
at room temperature. The mixture was refluxed for 6 h and the
reaction was quenched with saturated aq NH4Cl at room temper-
ature. After extraction with Et2O, the organic layer was dried over
MgSO4, filtered, and concentrated under vacuum. The residue was
chromatographed on silica gel with EtOAc/hexane ) 1/50 and
further purified by GPC with chloroform to afford (()-Bn-bnd* as
a white solid (790 mg, 2.63 mmol; 64% yield). (()-Bn-bnd* was
resolved into each enantiomer by a preparative HPLC, using a
Daicel Chiralcel OJ column with hexane/2-propanol ) 100/1, flow
) 14 mL/min. Retention times: 15 min [(R,R)-enantiomer], 22 min
8.7 Hz, 4H), 5.33 (d, JHH ) 3.8 Hz, 2H), 3.78 (s, 6H), 3.28 (d,
2JHH ) 15.0 Hz, 2H), 3.21 (d, 2JHH ) 15.0 Hz, 2H), 2.23-2.19 (m,
2
3
4H), 2.00 (dd, JHH ) 16.4 Hz and JHH ) 4.2 Hz, 2H), 1.54 (t,
3JHH ) 2.8 Hz, 2H). 13C NMR (CDCl3) δ 158.0, 140.8, 132.8, 130.0,
121.2, 113.8, 55.4, 41.7, 30.8, 30.0. Anal. Calcd for C25H28O2: C,
83.29; H, 7.83. Found: C, 83.26; H, 7.94.
General Procedure for Rh/(S,S)-1b-Catalyzed Asymmetric
1,4-Addition (Table 2). KOH (0.10 mL, 0.10 mmol; 1.0 M
aqueous) was added to a solution of [RhCl((S,S)-1b)]2 (4.7 mg, 10
µmol Rh) in 1,4-dioxane (1.0 mL), and the resulting solution was
stirred for 5 min at room temperature. RB(OH)2 5 (0.40 mmol)
and R,ꢀ-unsaturated ketone 4 (0.20 mmol) were then added to it,
and the resulting mixture was stirred for 3-12 h at 30 °C. After
passing through a pad of silica gel with EtOAc, the solvent was
removed under vacuum. The residue was purified by silica gel
preparative TLC with EtOAc/hexane to afford 1,4-adduct 6.
[(S,S)-enantiomer]. [R]20 -110 (c 1.02, CHCl3).
D
1H NMR (CDCl3) δ 7.31-7.27 (m, 4H), 7.22-7.17 (m, 6H),
3
2
5.37 (d, JHH ) 4.9 Hz, 2H), 3.37 (d, JHH ) 15.0 Hz, 2H), 3.28
(dd, 2JHH ) 15.0 Hz and 4JHH ) 1.6 Hz, 2H), 2.28-2.21 (m, 4H),
Acknowledgment. Support has been provided in part by a
Grant-in-Aid for Scientific Research, the Ministry of Education,
Culture, Sports, Science and Technology, Japan (the Global
COE Program “Integrated Materials Science” on Kyoto Uni-
versity).
2.02 (dd, 2JHH ) 16.2 Hz and 3JHH ) 4.0 Hz, 2H), 1.57 (t, 3JHH
)
2.4 Hz, 2H). 13C NMR (CDCl3) δ 140.7, 140.4, 129.1, 128.3, 126.0,
121.5, 42.6, 30.8, 30.04, 29.96. Anal. Calcd for C23H24: C, 91.95;
H, 8.05. Found: C, 92.11; H, 8.18.
Preparation of (1S,5S)-2,6-Bis(4-methoxylbenzyl)bicyclo[3.3.1]-
nona-2,6-diene ((S,S)-Mb-bnd*). 4-Methoxybenzylmagnesium chlo-
ride (7.31 mL, 6.00 mmol; 0.821 M solution in THF) was added
to a solution of dl-2,6-bis(trifluoromethanesulfonyloxy)bicyclo-
[3.3.1]nona-2,6-diene (415 mg, 0.997 mmol) and NiCl2(dppp)
(11 mg, 20 µmol) in THF (2.0 mL) at room temperature. The
Supporting Information Available: Analytical data for 1,4-
adducts 6 and X-ray data for [RhCl((S,S)-1a)]2. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO802437H
J. Org. Chem. Vol. 74, No. 2, 2009 873