Chiral phosphine-olefin bidentate ligands in asymmetric catalysis: Rhodium-catalyzed asymmetric 1,4-addition of aryl boronic acids to maleimides

Article abstract of DOI:10.1002/anie.200501305

(Chemical Equation Presented) Two is better than one: Novel chiral phosphine - olefin ligands 1 a and 1 b act as bidentate ligands with some transition metals and have proved to be highly effective in the rhodium-catalyzed asymmetric 1,4-addition of aryl boronic acids to maleimides with high enantio-selectivity (see scheme).

Full text of DOI:10.1002/anie.200501305

Angewandte
Chemie
Addition Reactions
Chiral Phosphine–Olefin Bidentate Ligands in
Asymmetric Catalysis: Rhodium-Catalyzed
Asymmetric 1,4-Addition of Aryl Boronic Acids
to Maleimides**
Ryo Shintani, Wei-Liang Duan, Takashi Nagano,
Atsushi Okada, and Tamio Hayashi*
Transition-metal-catalyzed asymmetric transformations in the
presence of chiral ligands have proved to be one of the most
efficient methods for the construction of enantioenriched
chiral compounds from achiral precursors.[1] The design and
synthesis of novel chiral ligands have therefore been a topic of
great interest in organic and organometallic chemistry in the
past few decades. In late-transition-metal catalysis, the
development of phosphorus- and/or nitrogen-based chiral
ligands has been most extensively investigated. As concep-
tually novel chiral ligands, a series of chiral dienes were
recently introduced, which opened up a new dimension in the
field of asymmetric catalysis.[2,3] Herein we describe the
development of chiral phosphine–olefin ligands 1 and their
use in the rhodium-catalyzed asymmetric 1,4-addition of aryl
boronic acids to maleimides with the highest enantioselectiv-
ity reported to date in this class of substrates.
Chiral diene ligands that we developed have been shown
to be highly effective in various rhodium-catalyzed asym-
metric processes[2] and are superior to conventional chiral
bisphosphine ligands in some cases. There are, however, some
drawbacks in the use of these chiral dienes: for example,
diene ligands are generally weaker than phosphorus-based
ligands in their coordination ability to transition metals.[4] To
overcome this problem while still maintaining the advantages
of chiral dienes, we decided to develop chiral phosphine–
olefin ligands as a hybrid of bisphosphines and dienes which
would incorporate positive features of both frameworks,
namely, the high coordination ability of phosphines and the
good chiral environment created around the olefins
(Figure 1).
To realize the desired features of these phosphine–olefins,
we chose compound 1 as the target. During the course of our
study directed toward this goal, Grützmacher described the
preparation of chiral phosphine–olefin 2 and utilized it as a
[*] Dr. R. Shintani, W.-L. Duan, Dr. T. Nagano, A. Okada,
Prof. Dr. T. Hayashi
Department of Chemistry
Graduate School of Science, Kyoto University
Sakyo, Kyoto 606-8502 (Japan)
Fax: (+81)75-753-3988
E-mail: thayashi@kuchem.kyoto-u.ac.jp
[**] Support was 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 for this articleis availableon theWWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200501305
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Figure 1. Chiral phosphine–olefin ligands designed to incorporate posi-
tive features of bisphosphine and diene ligands.
ligand for the iridium-catalyzed asymmetric hydrogenation of
an imine with 86% ee.[5]
The synthesis of 1 began with known compound (Æ )-3[6]
(Scheme 1). Swern oxidation of alcohol (Æ )-3 followed by
ketalization with ethylene glycol provided (Æ )-4, which was
further converted into (Æ )-5 by lithiation, phosphination, and
then oxidation. Phosphine oxide (Æ )-5 was resolved by chiral
HPLC on a Chiralcel OD-H column to give each enantiomer
Figure 2. ORTEP illustration of [PdCl2((+)-1b)] with thermal ellipsoids
drawn at the 50% probability level (hydrogen atoms are omitted for
clarity).
palladium, in accordance with the initial design of this
novel hybrid ligand. The X-ray crystal structure also
establishes the absolute configuration of (+)-1b as
1R,4S,7R.[8] Furthermore, it shows that the local struc-
ture around the phosphorus center is achiral and that the
chirality mostly originates from the steric difference
between the two substituents (Ph and H) on the olefin.
To investigate the potential of these ligands 1 in
asymmetric catalysis, we chose to explore the rhodium-
catalyzed 1,4-addition of aryl boronic acids to malei-
mides. As shown in Equation (1), the reaction of N-
Scheme 1. a) oxalyl chloride, DMSO, Et3N, CH2Cl2, 96%; b) cat. TsOH, ethylene glycol,
C6H6, 94%; c) 1) tBuLi, THF; then ClPPh2; 2) aqueous H2O2, acetone, 63% (over two
steps); d) chiral HPLC resolution (OD-H column); e) aqueous HCl (1n), THF, 99%;
f) LDA, THF; then PyNTf2, 89%; g) cat. [NiCl2(dppp)], BnMgBr, Et2O, 86% (for
R=Bn); or cat. [PdCl2(dppf)], PhMgBr, Et2O, 86% (for R=Ph); h) HSiCl3, Et3N, C6H6,
90% for (+)-1a and 84% for (+)-1b. DMSO=dimethylsulfoxide; Ts=p-toluenesul-
fonyl; LDA=lithium diisopropylamide; Tf =trifluoromethanesulfonyl; dppp=pro-
pane-l,3-diylbis(diphenylphosphane); dppf=1,1’-bis(diphenylphosphino)ferrocene.
of 5, and then the ketal was cleaved to afford enantiopure
ketone (+)-6. Conversion of (+)-6 into its enol triflate,
followed by Grignard cross-coupling and reduction with
silane, completed the synthesis of (+)-1a (R = Bn, 39%
overall yield) and (+)-1b (R = Ph, 36% overall yield).
We then carried out some complexation experiments with
several transition metals to observe their mode of coordina-
tion. Thus, treatment of ligand (+)-1b (31P NMR: d =
1
À17.1 ppm; H NMR: d = 6.31 ppm for the olefinic H atom)
with 1 equivalent of [Rh(acac)(C2H4)2] (acac = acetylaceto-
nate) in dichloromethane at room temperature generated a
new species, which showed a doublet at d = 65.0 ppm (J =
185 Hz) in the 31P NMR spectrum and the signal for the
olefinic H atom of (+)-1b was shifted upfield to d = 3.82 ppm
in the 1H NMR spectrum, thus indicating that both the
phosphorus atom and the olefin were directly bound to
rhodium. Similarly, a 1:1 mixture of (+)-1b and [PdCl2-
(MeCN)2] in benzene led to the clean formation of
[PdCl2((+)-1b)]. Recrystallization of this complexfrom
dichloromethane/benzene afforded single crystals suitable
for X-ray crystallographic analysis.[7] As shown in Figure 2,
(+)-1b does act as a phosphine–olefin bidentate ligand with
benzylmaleimide with PhB(OH)2 in the presence of (R)-
binap, a typical chiral bisphosphine ligand for rhodium-
catalyzed asymmetric 1,4-additions,[9] gave the 1,4-adduct
with only 58% ee. The use of chiral norbornadiene (R,R)-7,
which was reported by us as the benchmark ligand in the 1,4-
addition to maleimides,[2b] led to the desired product with
69% ee. The use of benzyl-substituted phosphine–olefin (+)-
1a significantly improved the enantioselectivity to 91% ee.
By changing the substituent on the olefin from benzyl to
phenyl ((+)-1b), the selectivity was improved further
(93% ee).
Under these conditions with (+)-1b as the ligand, various
N-substituted maleimides can be employed in the reaction
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with PhB(OH)2 to furnish the 1,4-adducts in uniformly high
yield and enantioselectivity (Table 1, entries 1–5). With
respect to the nucleophilic component, a variety of aryl
boronic acids can be coupled with N-benzylmaleimide with
high stereoselectivity as well (Table 1, entries 6–10).
with LiAlH4 furnished pyrrolidine 12 in 98% yield, which is
an enantiomer of the potent a-2-adrenoceptor antagonist
developed by Novartis.[10]
The stereochemical outcome of these Rh–(+)-1b-cata-
lyzed 1,4-additions can be rationalized as depicted in Figure 3,
Table 1: Rh–(+)-1b-catalyzed asymmetric 1,4-addition of aryl boronic
acids to maleimides.
Entry
R
Ar
Yield [%]
ee [%]
Figure 3. Proposed stereochemical pathway for the asymmetric 1,4-
addition to a maleimide catalyzed by Rh–(+)-1b.
1
2
3
4
5
6
7
8
9
MePh
Cy
CHPh2
CPh3
Ph
Bn
Bn
Bn
Bn
91
88
96
95
95
88
98
98
90
90
Ph
Ph
Ph
Ph
Ph
94
94
94
90
93
93
89
92
95
assuming that the maleimide approaches the aryl rhodium
species bearing ligand (+)-1b cis to the olefin portion of the
ligand. To avoid the steric repulsion between the imide moiety
of maleimide and the phenyl group on the olefin, the product
thus obtained should be an S isomer, which is consistent with
the observed stereochemistry.
4-MeOC6H4
4-FC6H4
3,5-MeO2C6H3
2-MeC6H4
10
Bn
98
The Rh–(+)-1b catalyst is highly effective for asymmetric
1,4-addition to other a,b-unsaturated carbonyl compounds as
well. For example, both cyclic enones and enoates[11] furnish
the corresponding 1,4-adducts in high yield and enantiose-
lectivity [Eq. (4) and Eq. (5)].
To show the utility of this highly enantioselective 1,4-
addition to maleimides catalyzed by Rh–(+)-1b, we con-
ducted a deprotection reaction of N-trityl 1,4-adduct 8 with
94% ee [Eq. (2)]. Thus, treatment of 8 with trifluoroacetic
acid in dichloromethane at room temperature furnished the
desired product 9 in 90% yield with minimal erosion of the ee
value.
The present asymmetric catalysis can also be applied to an
enantioselective synthesis of biologically active compounds.
Thus, addition of 2-MeOC6H4B(OH)2 to maleimide 10 under
Rh–(+)-1b catalysis led to 1,4-adduct 11 in 83% yield with
92% ee [Eq. (3)]. Reduction of the two carbonyl groups of 11
In summary, we have designed and synthesized novel
chiral phosphine–olefin ligands. These ligands act as bidentate
with some transition metals and have proved to be highly
effective in the rhodium-catalyzed asymmetric 1,4-addition of
aryl boronic acids to maleimides. Future studies will involve
the exploration of further applications of these ligands to
various transition-metal-catalyzed asymmetric processes.
Experimental Section
Procedure for Table 1: KOH (0.10 mL, 0.10 mmol; 1.0m aqueous) was
added to a solution of [{RhCl((+)-1b)}2] (4.9 mg, 10 mmol Rh) in 1,4-
dioxane (0.50 mL), and the resulting solution was stirred for 5 min at
room temperature. After addition of ArB(OH)2 (0.60 mmol) and
stirring for 5 min, this mixture was transferred to a vessel containing
maleimide (0.20 mmol) with additional 1,4-dioxane (0.50 mL). The
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resulting mixture was stirred for 3 h at 508C and was then passed
through a pad of silica gel with EtOAc. The solvent was removed
under vacuum, and the residue was purified by chromatography on
silica gel with EtOAc/hexane to afford the 1,4-adduct.
Received: April 14, 2005
Revised: May 12, 2005
Published online: June 23, 2005
Keywords: alkenes · asymmetric catalysis · boron · P ligands ·
.
rhodium
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