only one example of successful asymmetric addition in water
is reported by using an amphiphilic resin-supported BINAP
ligand at 100 °C.5 In this paper, we disclose our development
of a highly practical and efficient catalytic asymmetric 1,4-
addition in water using an easily accessible new chiral diene
ligand.6,7
Scheme 2. Preparation of New Bicyclo[3.3.0] Dienes
In an earlier work, we reported our discovery of a new
family of C2-symmetric chiral diene ligands (represented by
1) bearing a simple bicyclo[3.3.0] backbone and their
successful application in the Rh-catalyzed enantioselective
arylation of N-tosylarylimines with arylboronic acids.8a More
recently, we described the use of these dienes in Rh-catalyzed
asymmetric 1,4-addition of arylboronic acids to R,ꢀ-unsatur-
ated carbonyl compounds under mild conditions.8b Encour-
aged by this success, we envisioned exploring this bicyclo-
[3.3.0] system for further design of new chiral dienes with
different catalytic properties. We hypothesized that incor-
poration of a hydrophilic group such as hydroxyl into the
tetrahydropentalene framework may generate a hydrophilic
or water-soluble chiral diene ligand, which should facili-
tate the related asymmetric catalysis in aqueous media
(Scheme 1).
To determine whether these dienes are hydrophilic or water
soluble, we checked their solubilities in water. As expected,
we found that diol diene 2 was highly soluble in water (>800
mg/mL). Interestingly, for dienes 5 and 6 that contain ketal
and carbonyl groups, we also observed their solubilities in
water of about 5 and 50 mg/mL, respectively. In comparison,
the previously utilized diphenyl diene 1 is insoluble in
water.12
To test our hypothesis of performing asymmetric catalysis
in water, we examined these new C2-symmetric bicyclo-
[3.3.0] dienes in the rhodium-catalyzed asymmetric 1,4-
addition of arylboronic acids to R,ꢀ-unsaturated carbonyl
compounds. The reaction of 2-cyclohexenone (7a) with
phenylboronic acid in water was first investigated, and the
reslts are shown in Table 1. To our delight, aqueous catalysis
Scheme 1. New Hydrophilic Bicyclo[3.3.0] Diene Hypothesis
Table 1. Ligand Screening and Catalyst Loadinga
Synthesis of the designed 1,4-dihydroxy-substituted bicy-
clo[3.3.0] diene 2 was performed as depicted in Scheme 2.
Following a literature procedure,9 enantiomerically pure
diketone (3aR,6aR)-310 was subjected to ketalization with
ethylene glycol in refluxing toluene, followed by bromination
with pyridinium tribromide in THF at -78 °C to give the
dibromo diketal 4 in two simple steps. Treatment of 4 with
NaOMe in DMSO afforded the elimination product 5. Ketal
removal and DIBAL-H reduction of the resulting carbonyls11
provided the desired enantiopure diene (1S,3aR,4S,6aR)-2 in
good yield. Notably, intermediates (3aR,6aR)-5 and 6 with
a tetrahydropentalene framework may also be useful diene
ligands for asymmetric catalysis.
entry ligand catalyst (mol %) time (h) yieldb (%) eec (%)
1
2
3
4
5
6
2
5
5
5
1
3
3
3
1
0.5
3
3
0.5
0.5
0.5
6
12
0.2
18
96
62
94
94
81
92
19
93
86
89
93
93
94
66
5
6d
7
(5) Otomaru, Y.; Senda, T.; Hayashi, T. Org. Lett. 2004, 6, 3357.
(6) For two leading reviews on chiral diene ligands in asymmetric
catalysis, see: (a) Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 3364. (b)
Defieber, C.; Gru¨tzmacher, H.; Carreira, E. M. Angew. Chem., Int. Ed. 2008,
a The reaction was carried out with 2-cyclohexenone (0.50 mmol),
phenylboronic acid (1.00 mmol), diene (1.1 equiv to Rh), and 1.5 M aq
K3PO4 (0.17 mL) in H2O (1.7 mL) at room temperature, unless otherwise
noted. b Isolated yield. c Determined by chiral HPLC analysis. d Performed
in dioxane/H2O (10:1).
47, 4482
.
(7) For examples of Rh-diene catalysis in asymmetric 1,4-addition, see:
(a) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, H. J. Am. Chem.
Soc. 2003, 125, 11508. (b) Shintani, R.; Ueyama, K.; Yamada, I.; Hayashi,
T. Org. Lett. 2004, 6, 3425. (c) Defieber, C.; Paquin, J.-F.; Serna, S.;
Carreira, E. M. Org. Lett. 2004, 6, 3873. (d) Paquin, J.-F.; Stephenson,
C. R. J.; Defieber, C.; Carreira, E. M. Org. Lett. 2005, 7, 3821. (e) Shintani,
R.; Okamoto, K.; Hayashi, T. Org. Lett. 2005, 7, 4757. (f) Paquin, J.-F.;
Defieber, C.; Stephenson, C. R. J.; Carreira, E. M. J. Am. Chem. Soc. 2005,
127, 10850. (g) Chen, F.-X.; Kina, A.; Hayashi, T. Org. Lett. 2006, 8, 341.
(h) Helbig, S.; Sauer, S.; Cramer, N.; Laschat, S.; Baro, A.; Frey, W. AdV.
Synth. Catal. 2007, 349, 2331. (i) Tokunaga, N.; Hayashi, T. AdV. Synth.
by 3 mol % of hydrophilic dienes 5, 6, and 2 were all
successful, and the reactions went to completion within 0.5 h
at room temperature without using any organic cosolvent,
indicating that these dienes could act as efficient ligand and
form highly active catalytic species in water. Most gratify-
ingly, the use of diketal diene 5 was found to be optimal,
Catal. 2007, 349, 513
.
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Org. Lett., Vol. 10, No. 18, 2008