Rhodium-catalyzed asymmetric construction of quaternary carbon stereocenters: Ligand-dependent regiocontrol in the 1,4-addition to substituted maleimides

Article abstract of DOI:10.1021/ja061430d

A rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to substituted maleimides has been described. The regioselectivity in this reaction is controlled by the choice of ligand (dienes or bisphosphines), and 1,4-adducts with a quaternary stereoc

Full text of DOI:10.1021/ja061430d

Published on Web 04/08/2006
Rhodium-Catalyzed Asymmetric Construction of Quaternary Carbon
Stereocenters: Ligand-Dependent Regiocontrol in the 1,4-Addition to
Substituted Maleimides
Ryo Shintani, Wei-Liang Duan, and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received March 1, 2006; E-mail: thayashi@kuchem.kyoto-u.ac.jp
Table 1. Rhodium-Catalyzed Asymmetric 1,4-Addition of
Phenylboronic Acid to Substituted Maleimides 1: Ligand Effect
Enantioselective construction of quaternary carbon stereocenters
is an important, but challenging, objective in organic chemistry.1
1,4-Addition of carbon nucleophiles to â,â-disubstituted R,â-
unsaturated compounds is potentially a useful strategy for efficient
assembly of this type of molecular skeleton. It is, therefore, of high
value to achieve such a transformation in a catalytic asymmetric
fashion.2 Some successful examples in this regard have begun to
appear in the copper-catalyzed asymmetric 1,4-addition of di-
alkylzinc reagents3 and trialkylaluminum reagents,4 and Carretero
recently reported a rhodium-catalyzed 1,4-addition of alkenylboronic
acids to R,â-unsaturated pyridyl sulfones for the construction of
quaternary carbon stereocenters.5 In this communication, we
describe the development of a rhodium-catalyzed asymmetric 1,4-
addition of arylboronic acids to 3-substituted maleimides (1),6
furnishing 3,3-disubstituted succinimides (2) in high regio- and
enantioselectivity (eq 1).
yield
(%)a
2/3b
(trans/cis)b
ee of 2
ee of 3 (%)
entry
1
ligand
(%)
(trans, cis)
1
2
3
4
5
6
7
8
1a (R,R)-Bn-bod*
1a (R,R)-Ph-bod*
1a (R)-binap
1a (R)-H8-binap
1b (R,R)-Bn-bod*
1b (R,R)-Ph-bod*
1b (R)-binap
93
94
99
98
94
94
98
98
22/78 (1.6/1)
15/85 (1/2.3)
85/15 (2.0/1)
87/13 (2.3/1)
20/80 (2.1/1)
11/89 (1/1.4)
75/25 (2.1/1)
81/19 (2.8/1)
73
97
96
97
84
93
95
96
82, 97
83, >99
68, 96
-19, 96
82, 93
79, 99
0, 96
1b (R)-H8-binap
-10, 94
a Combined yield of 2 and 3. b Determined by 1H NMR of the crude
material.
Table 2. Rhodium-Catalyzed Asymmetric 1,4-Addition of
Arylboronic Acids to Substituted Maleimides 1: Scope
We initially conducted a reaction of 1-benzyl-3-ethylmaleimide
(1a) with PhB(OH)2 in the presence of 2.5 mol % rhodium catalyst
bearing chiral diene7-9 (R,R)-Bn-bod*,7,8 obtaining 1-benzyl-3-ethyl-
4-phenylsuccinimide (3a) as the major product along with its
regioisomer 2a (2a/3a ) 22/78; Table 1, entry 1). Although the
trans/cis ratio of 3a was not very good (1.6/1), the enantioselectivity
was high in both diastereomers (trans, 82% ee; cis, 97% ee). The
employment of (R,R)-Ph-bod*7 as a ligand gave higher regio-
selectivity toward 3a (2a/3a ) 15/85; entry 2) with somewhat better
enantioselectivity (trans, 83% ee; cis, >99% ee). In contrast, the
use of bisphosphine ligands reversed the regioselectivity of 1,4-
addition, preferentially forming compound 2a.10 Thus, in the
presence of (R)-binap,11,12 the products were obtained in 99%
combined yield with 2a/3a ) 85/15, and the enantioselectivity of
2a was as high as 96% ee (entry 3). By changing the ligand to
(R)-H8-binap,13 the regioselectivity toward 2a was further enhanced
with maintaining the high enantiomeric excess (87/13, 97% ee; entry
4). A similar trend was observed with substrate 1b (R ) Me; entries
5-8), and the absolute configurations of trans-3b and cis-3b in
entry 5 were determined to be (4R) by converting them to trans-4
and cis-4, respectively (eq 2).14
yield
ee of 2
entry
1
Ar
(%)a
2/3 ratiob
(%)
1
2
3
4
5
6
1a
1a
1a
1a
1b
1b
1b
1c
1c
Ph
98
95
90
82
98
95
95
90
85
87/13
92/8
97
97
96
90
96
90
96
98
98
3-ClC6H4
2-naphthyl
2-MeC6H4
Ph
4-MeOC6H4
4-FC6H4
Ph
86/14
>98/2
81/19
84/16
86/14
97/3
7
8c
9c
4-MeC6H4
97/3
a Combined yield of 2 and 3. b Determined by 1H NMR of the crude
material. c The reaction was conducted for 5 h with 5 mol % of catalyst
and 5.0 equiv of ArB(OH)2.
We have determined that the scope of this asymmetric construc-
tion of quaternary carbon stereocenters catalyzed by Rh/(R)-H8-
binap is fairly broad (Table 2). Both substrates 1a and 1b can react
with various arylboronic acids with high regioselectivity (81/19-
92/8; entries 1-3 and 5-7), furnishing desired 1,4-adducts 2 with
excellent enantioselectivity (90-97% ee). It is worth noting that
an o-tolyl group can be installed in 1a with almost perfect
regioselectivity (>98/2, 90% ee; entry 4). Furthermore, substrate
1c (R ) i-Pr) undergoes the 1,4-addition with very high regio- and
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J. AM. CHEM. SOC. 2006, 128, 5628-5629
10.1021/ja061430d CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
the phenyl group on the ligand, Rh/(R)-H8-binap provides (R)-
isomers and Rh/(R,R)-Ph-bod* provides (4R)-isomers, respec-
tively.15
In summary, we have developed a rhodium-catalyzed asymmetric
1,4-addition of arylboronic acids to 3-substituted maleimides. The
regioselectivity has been controlled by the choice of ligand (dienes
or bisphosphines), and 1,4-adducts with a quaternary stereocenter
can be obtained with high regio- and enantioselectivity by the use
of (R)-H8-binap.
Figure 1. Proposed stereochemical pathway for the asymmetric 1,4-addition
to a 3-substituted maleimide catalyzed by Rh/(R)-H8-binap.
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 (21 COE on Kyoto
University Alliance for Chemistry).
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
Figure 2. Proposed stereochemical pathway for the asymmetric 1,4-addition
to a 3-substituted maleimide catalyzed by Rh/(R,R)-Ph-bod*.
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The observed regioselectivity in these 1,4-additions to 3-substi-
tuted maleimides can be explained as follows. In the presence of a
rhodium catalyst bearing (R)-H8-binap (Figure 1), due to the severe
steric repulsion between the substituent R on maleimide and the
phenyl group sticking out from the phosphorus atom of the ligand,
maleimide preferentially coordinates to rhodium, keeping its R
group away from the ligand phenyl group, leading to the selective
formation of 2.
In contrast, in the presence of (R,R)-Ph-bod* (Figure 2), the
upward orientation of the phenyl substituent on the diene ligand
significantly reduces the steric repulsion with the R group on
maleimide. As a result, the steric hindrance between an aryl group
on the rhodium and the R group on maleimide becomes the
dominant factor, leading to selective insertion of maleimide toward
the formation of 3.
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Tetrahedron: Asymmetry 1999, 10, 3877.
(15) Currently, we do not fully understand the exact factors that determine the
ratio of trans and cis in the formation of 1,4-adducts 3.
With regard to the absolute configurations, to avoid the unfavor-
able steric interaction between the imide moiety of maleimide and
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