catalytic activity and enantioselectivity, particularly in the
asymmetric 1,4-addition of arylboronic acids to R,β-un-
saturated carbonyl compounds.6 Compared with Michael
acceptors such as R,β-unsaturated amides, aldehydes, and
ketones, which all perform successfully in catalytic asym-
metric Rh-catalyzed arylation reactions, fumaric or maleic
acid derivatives are less reactive and have thus received far
less attention. To the best of our knowledge, only one
example of the enantioselective arylation of fumarate esters
has been described, and it came from Hayashi’s laboratory.5a
A significant problem usually encountered in these systems is
that conventional chiral phosphorus-based ligands are often
ineffective in promoting the Rh-catalyzed asymmetric addi-
tion reaction of phenylboronic acid to fumarates. This is not
the case with bulky, substituted diene ligand 1, which is able
to induce high enantioselectivityinthisprocess(upto90%ee)
(Figure. 1).5a As part of our continuing efforts in the
development of chiral 2,5-diaryl-substituted bicyclo[2.2.1]
diene ligands that are stable, easy to prepare, and behave
with high fidelity in enantioselective metal-catalyzed asym-
metric transformations, diene ligands 2d and 2h were recently
synthesized and found to be extremely effective chiral modi-
fiers for the Rh-catalyzed conjugate addition of various
arylboronic acids to acyclic and cyclic R,β-unsaturated car-
bonyl compounds, respectively.7 It was entirely natural,
therefore, that we should wish to extend our studies to the
asymmetric 1,4-addition of arylboronic acids to fumarate
and maleate esters to establish possible efficacy of diene
ligands 2 in these notoriously difficult Michael acceptor
systems.
fumarate esters 3a was studied in the cosolvent mixture of
MeOH and CH2Cl2 (10:1). The catalytic reaction was
complete within 1 h and afforded the desired product
(5aa) in 89% yield but with poor enantioselectivity (34%
ee) (entry 1). The enantioinduction could be enhanced to
77% ee and 99% ee in the case of diethyl (3b) and di-tert-
butyl fumarates (3c), respectively (entries 2 and 3). High ee
(98%) was also observed using di-tert-butyl maleate as a
substrate (entry 4). Next, the effect of catalyst loading on
the reaction with substrate 3c was screened. In the presence
of 1 mol % of the rhodium/2a complex, the reaction was
found to produce 92% of adduct 5ca with 97% ee, which
was not that much different from when 3 mol % of the
catalyst was used (entries 5 and 6). Subsequently, the effect
of having different aryl substituents in the ligands was
investigatedwithregardtoreaction outcome. Ligandswith
p-methyl phenyl or p-biphenyl substituents were initially
studied (ligands 2b and 2c, entries 7 and 8), followed by
dienes with 1- and 2-naphthyl groups (ligands 2d and 2e,
entries 9 and 10) or electron-withdrawing substituents at
4-position of benzenoid systems (ligands 2fÀh, entries
11À13). All of these gave rise to levels of enantioselectivity
similar to those with ligand 2a in the aforementioned
process.
Table 1. Asymmetric Conjugate Addition of Phenylboronic
Acid to Fumaric Estersa
entry
ligand
R
Rh (x mol %)
yieldb (%)
eec (%)
Figure 1. Chiral bicyclo[2.2.1] diene ligands.
1
2
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
Me
Et
5.0
5.0
5.0
5.0
3.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
89
99
99
83
87
92
81
99
95
99
62
96
97
34
77
99
98
98
97
96
95
96
97
97
97
97
Our studies commenced with identifying the ideal com-
bination of fumarate ester functionality and chiral catalyst
that could offer high selectivity in the conjugate addition
reaction (Table 1). Initially, addition of phenylboronic
acid (4a), in the presence of 5 mol % of Rh/2a, to dimethyl
3
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
4d
5
6
7
8
9
(6) For pioneering work using chiral diene ligands in the enantio-
selective transformation, see: (a) Hayashi, T.; Ueyama, K.; Tokunaga,
N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508. (b) Fischer, C.;
Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem. Soc. 2004, 126,
1628. The effects of the substitution of the chiral dienes for efficient
chiral control were reported: (c) Gendrineau, T.; Chuzel, O.; Eijsberg,
H.; Genet, J.-P.; Darses, S. Angew. Chem., Int. Ed. 2008, 47, 7669. (d)
Gendrineau, T.; Genet, J.-P.; Darses, S. Org. Lett. 2009, 11, 3486. For
reviews, see: (e) Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 3364. (f)
10
11
12
13
2g
2h
a The reaction was conducted with 1 mmol of substrate 3. b Cali-
brated GC yield using nÀdecane as an internal standard. c Determined
by chiral HPLC; see the Supporting Information. d Di-tert-butyl maleate
was used, and (S)-5ca was obtained.
€
Defieber, C.; Grutzmacher, H.; Carreira, E. M. Angew. Chem., Int. Ed.
2008, 47, 4482. (g) Shintani, R.; Hayashi, T. Aldrichimica Acta 2009, 42,
31. (h) Tian, P.; Dong, H.-Q.; Lin, G.-Q. ACS Catal. 2012, 2, 95.
(7) (a) Wei, W.-T.; Yeh, J.-Y.; Kuo, T.-S.; Wu, H.-L. Chem.;Eur. J.
2011, 17, 11405. (b) Liu, C.-C.; Janmanchi, D.; Chen, C.-C.; Wu, H.-L.
Eur. J. Org. Chem. 2012, 2503.
Because the structural effect of various ligands on the
enantioselectivity was subtle, ligand 2a was used for
B
Org. Lett., Vol. XX, No. XX, XXXX