Chiral norbornadienes as efficient ligands for the rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to fumaric and maleic compounds

Article abstract of DOI:10.1021/ol048421z

(Chemical Equation Presented) A rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to fumaric and maleic compounds has been developed. While phosphorus-based chiral ligands fail to induce high stereoselectivity, chiral norbornadiene ligands have proved to be uniquely effective to achieve high enantioselectivity in these 1,4-addition reactions.

Full text of DOI:10.1021/ol048421z

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3425-3427
Chiral Norbornadienes as Efficient
Ligands for the Rhodium-Catalyzed
Asymmetric 1,4-Addition of Arylboronic
Acids to Fumaric and Maleic
Compounds
Ryo Shintani, Kazuhito Ueyama, Ichiro Yamada, and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo,
Kyoto 606-8502, Japan
thayashi@kuchem.kyoto-u.ac.jp
Received August 10, 2004
ABSTRACT
A rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to fumaric and maleic compounds has been developed. While phosphorus-
based chiral ligands fail to induce high stereoselectivity, chiral norbornadiene ligands have proved to be uniquely effective to achieve high
enantioselectivity in these 1,4-addition reactions.
1,4-Addition to electron-deficient alkenes is a useful strategy
for the construction of carbon-carbon bonds.1 The develop-
ment of its enantioselective variant by chiral catalysts has
therefore been investigated extensively,2 with R,â-unsaturated
ketones (e.g., 2-cyclohexen-1-one) being the most commonly
studied substrates. In contrast to these substrates, asymmetric
1,4-additions to fumaric or maleic compounds have met
much less success, despite the fact that 1,4-addition products
of these compounds are synthetically useful 2-substituted 1,4-
dicarbonyl compounds. In fact, to the best of our knowledge,
there have been no successful reports on catalytic asymmetric
1,4-addition of organometallic reagents to fumaric or maleic
substrates.3,4 In this paper, we demonstrate our significant
progress toward this goal: specifically, a rhodium/chiral
norbornadiene catalyst is highly effective for asymmetric 1,4-
(1) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Tetrahedron Organic Chemistry Series Vol. 9; Pergamon: Tarrytown, NY,
1992.
(2) For an overview, see: (a) Tomioka, K.; Nagaoka, Y. In Compre-
hensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer-Verlag: Berlin, 1999; Chapter 31.1. (b) Yamaguchi, M. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yama-
moto, H., Eds.; Springer-Verlag: Berlin, 1999; Chapter 31.2. (c) Krause,
N.; Hoffmann-Roder, A. Synthesis 2001, 171.
(3) There are some reports on nonasymmetric rhodium-catalyzed 1,4-
addition to these compounds. (a) 1,4-Addition of triphenylbismuth to diethyl
maleate: Venkatraman, S.; Li, C.-J. Tetrahedron Lett. 2001, 42, 781. (b)
1,4-Addition of trimethylphenyllead to dimethyl fumarate and maleate:
Ding, R.; Chen, Y.-J.; Wang, D.; Li, C.-J. Synlett 2001, 1470.
(4) For an example of diastereoselective 1,4-addition to fumarates with
a chiral auxiliary, see: Sibi, M. P.; Liu, P.; Ji, J.; Hajra, S.; Chen, J.-x. J.
Org. Chem. 2002, 67, 1738.
10.1021/ol048421z CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/24/2004

addition of arylboronic acids to fumaric acid diesters and
maleimides.
asymmetric 1,4-addition to R,â-enones,10 did not provide a
satisfactory result either (32% ee; entry 4).
In 1998, we described a rhodium-catalyzed asymmetric
1,4-addition of organoboronic acids to R,â-unsaturated
ketones in the presence of (S)-binap.5 Since then various
chiral ligands have been used in this reaction, and bisphos-
phine ligands have proved to be particularly effective.6 Based
on these precedents, we initially employed chiral bisphos-
phine ligands in the reaction of di-tert-butyl fumarate with
PhB(OH)2 in the presence of 5 mol % rhodium (Table 1).
Last year, we initiated a program directed toward the
development of chiral dienes as conceptually novel ligands
for asymmetric catalysis, and we described the synthesis of
chiral norbornadiene (R,R)-5a and its application to the
rhodium-catalyzed asymmetric 1,4-addition reactions.11 In
contrast to the phosphorus-based chiral ligands, the use of
ligand 5a in the 1,4-addition to di-tert-butyl fumarate
significantly improved the enantioselectivity to 90% ee, with
a slight decrease in reactivity (78% yield; entry 5). A
modification of substitutents in 5a to bulkier mesitylmethyl
groups (5b)12 kept the same level of stereoselection with an
increased reactivity (90% yield, 90% ee (S); entry 6).13 The
absolute configuration of the 1,4-adduct 6a was determined
by comparison of the optical rotation of its reduction
derivative 7 with the literature value as shown in eq 1.14
Under these conditions with (R,R)-5b, not only electron-rich
or electron-deficient aromatic (entries 7 and 8) but also
sterically hindered aromatic (entries 9 and 10) groups can
be installed in high enantioselectivity (6b-e, 86-91% ee).
Table 1. Rhodium-Catalyzed Asymmetric 1,4-Addition of
Arylboronic Acids to Di-tert-butyl Fumarate
entry
Ar
ligand
product yielda (%) eeb (%)
1
2
3
4c
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
(R)-1
(R)-2
(S)-3
(S)-4
(R,R)-5a
(R,R)-5b
6a
6a
6a
6a
6a
6a
6b
6c
6d
6e
96
99
94
50
78
90
78
85
91
80
21 (R)
3 (R)
13 (S)
32 (S)
90 (S)
90 (S)
86 (S)d
90 (S)d
87 (S)d
91 (S)d,e
4-MeOC6H4 (R,R)-5b
4-FC6H4
2-naphthyl
2-MeC6H4
High enantioselectivity with the chiral norbornadiene
ligand was also observed in the asymmetric 1,4-additions to
maleimides, which are substrates of particular interest
because the 1,4-adducts are synthetically and biologically
important R-substituted succinimides.15 The reaction of
N-methylmaleimide with PhB(OH)2 in the presence of
bisphosphine ligands produced the 1,4-adduct 8a in moderate
ee of 28-51% (Table 2, entries 1-3), and the use of
phosphoramidite ligand (S)-4 did not improve the enantio-
selectivity (45% ee; entry 4). Conversely, the use of chiral
norbornadiene ligand (R,R)-5a gave 8a in much higher ee
of 70% (entry 5), and the newly developed analogue (R,R)-
5b further enhanced the enantioselectivity up to 85% ee
(entry 6). Other N-substituents on maleimide, such as
(R,R)-5b
(R,R)-5b
(R,R)-5b
10
a Isolated yield. b Determined by HPLC on a Chiralpak AD-H column
with hexane/2-propanol ) 95/5 unless otherwise noted. c 11 mol % of ligand
was used. d The absolute configuration was assigned by analogy with entries
1-6. e ee was determined by HPLC on a Chiralcel OD-H column with
hexane/2-propanol ) 500/1.
(10) Boiteau, J.-G.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2003,
68, 9481.
(11) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem.
Soc. 2003, 125, 11508. Chiral bicyclo[2.2.2]octadienes have recently been
reported: Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem.
Soc. 2004, 126, 1628.
The use of (R)-binap 1,7 however, produced the 1,4-adduct
6a only in 21% ee (entry 1), and other ligands, such as (R)-
segphos 28 and (S)-P-phos 3,9 turned out to be ineffective
as well (3-13% ee; entries 2 and 3). In addition, phosphor-
amidite ligand (S)-4, which is also known to be effective in
(12) (R,R)-5b was synthesized following the procedure for (R,R)-5a (ref
11) using mesitylmethylmagnesium chloride in place of benzylmagnesium
bromide: [R]20 -77.3 (c 1.00, CHCl3).
D
(13) Notes: (a) Smaller ester groups (e.g., dimethyl or diisopropyl
fumarate) lead to the decrease in enantioselectivity. A similar trend has
been observed in the asymmetric 1,4-additions to (E)-2-hexenoates: Takaya,
Y.; Senda, T.; Kurushima, H.; Ogasawara, M.; Hayashi, T. Tetrahedron:
Asymmetry 1999, 10, 4047. See also: Sakuma, S.; Sakai, M.; Itooka, R.;
Miyaura, N. J. Org. Chem. 2000, 65, 5951. (b) Fumaric acid diesters provide
better stereoselection than the corresponding maleic acid diesters.
(14) Agami, C.; Couty, F.; Evano, G. Eur. J. Org. Chem. 2002, 29.
(15) For some biological studies of R-substituted succinimides, see: (a)
Jacyno, J. M.; Lin, N.-H.; Holladay, M. W.; Sullivan, J. P. Curr. Top Plant
Physiol. 1995, 15, 294. (b) Ahmed, S. Drug Des DiscoVery 1996, 14, 77.
(c) Curtin, M. L.; Garland, R. B.; Heyman, H. R.; Frey, R. R.; Michaelides,
M. R.; Li, J.; Pease, L. J.; Glaser, K. B.; Marcotte, P. A., Davidsen, S. K.
Bioorg. Med. Chem. Lett. 2002, 12, 2919.
(5) (a) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N.
J. Am. Chem. Soc. 1998, 120, 5579. (b) Hayashi, T.; Takahashi, M.; Takaya,
Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052.
(6) For reviews, see: (a) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003,
103, 2829. (b) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169.
(7) Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi, H.;
Taketomi, T.; Akutagawa, S.; Noyori, R. J. Org. Chem. 1986, 51, 629.
(8) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264.
(9) Shi, Q.; Xu, L.; Li, X.; Jia, X.; Wang, R.; Au-Yeung, T. T.-L.; Chan,
A. S. C.; Hayashi, T.; Cao, R.; Hong, M. Tetrahedron Lett. 2003, 44, 6505.
3426
Org. Lett., Vol. 6, No. 19, 2004

Table 2. Rhodium-Catalyzed 1,4-Addition of Arylboronic
Acids to Maleimides
entry ligand
R
Ar
product yielda (%) eeb (%)
1
2
3
(R)-1
(R)-2
(S)-3
Me Ph
Me Ph
Me Ph
Me Ph
8a
8a
8a
8a
8a
8a
8b
8c
8d
8e
8f
(100)
(100)
(98)
(100)
(89)
(88)
85
88
77
88
92
51
47
28
45
70
85
87
69 (R)
84
85
82
84
92
4c (S)-4
5
6
7
(R,R)-5a Me Ph
(R,R)-5b Me Ph
(R,R)-5b Cy Ph
8d (R,R)-5b Bn Ph
Figure 1. ORTEP illustration of [RhCl((R,R)-5a)]2 with thermal
ellipsoids drawn at the 50% probability level (shown as a monomer
for clarity).
9
10
11
12
13
(R,R)-5b Cy 4-MeOC6H4
(R,R)-5b Cy 4-FC6H4
(R,R)-5b Cy 3-ClC6H4
(R,R)-5b Cy 2-naphthyl
(R,R)-5b Cy 2-MeC6H4
8g
8h
93
95
fumaric and maleic compounds can be proposed as depicted
in Figure 2, leading to the observed stereochemical outcome
in both cases.
a Isolated yield. Numbers in parentheses are conversions (%) determined
1
by H NMR of the crude mixture. b Determined by HPLC on a Chiralpak
AD-H column (entries 1-6, 10-13) or a Chiralcel OD-H column (entries
7-9) with hexane/2-propanol ) 90/10. c 11 mol % of ligand was used.
d The absolute configuration was determined by comparison of the optical
rotation with the literature value (see ref 16).
cyclohexyl group, are also suitable, leading to the 1,4-adduct
8b with high enantiomeric excess in the presence of a Rh/
(R,R)-5b catalyst (87% ee; entry 7). To determine the
absolute configuration, N-benzylmaleimide was employed,
whose 1,4-adduct 8c was assigned to be (R)-enriched based
on the sign of the optical rotation ([R]20 -33.7 (c 1.20,
D
CHCl3); entry 8).16 With this catalyst system, the reaction
tolerates a wide range of arylboronic acids, providing
uniformly high yield and ee (8d-h, 77-95% yield, 82-
92% ee; entries 9-13).
Figure 2. Proposed stereochemical pathways for the asymmetric
1,4-addition to a fumaric acid diester (left) and a maleimide (right)
catalyzed by rhodium/chiral norbornadiene.
In summary, we have developed a rhodium-catalyzed
asymmetric 1,4-addition of arylboronic acids to fumaric acid
diesters and maleimides. By employing a chiral norborna-
diene as ligand, we have efficiently coupled a range of
arylboronic acids with these substrates in very good enan-
tiomeric excess. The origin of stereocontrol in these reactions
can be rationalized by the crystal structure of a rhodium/
chiral norbornadiene complex.
An X-ray crystal structure of [RhCl((R,R)-5a)]2 shows that
the steric difference between a bulky arylmethyl group and
a small hydrogen on the ligand is effectively dissecting the
space in a C2-fashion, thereby creating a very good chiral
environment around the rhodium (Figure 1). This steric
differentiation is much more effective in the present asym-
metric reactions than other systems such as Rh/(R)-binap,
whose origin of stereocontrol comes from the face-and-edge
difference of the phenyl groups on phosphorus atoms of (R)-
binap.17,18 Based on the crystal structure of Rh/(R,R)-5a, a
stereochemical course of the asymmetric 1,4-addition to
Acknowledgment. Support has been provided in part by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan
(21 COE on Kyoto University Alliance for Chemistry).
(16) [R]20D +38 (CHCl3) for (S): Bettoni, G.; Franchini, C.; Morlacchi,
F.; Tangari, N.; Tortorella, V. J. Org. Chem. 1976, 41, 2780.
(17) For an example of the X-ray crystal structure of a Rh/(R)-binap
complex, see: Miyashita, A.; Takaya, H.; Souchi, T.; Noyori, R. Tetrahe-
dron 1984, 40, 1245.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(18) For discussion on the origin of stereocontrol in the 1,4-addition
reactions catalyzed by Rh/binap, see refs 5 and 6.
OL048421Z
Org. Lett., Vol. 6, No. 19, 2004
3427