C1-symmetric monosubstituted chiral diene ligands in asymmetric rhodium-catalyzed 1,4-addition reactions

Article abstract of DOI:10.1002/anie.200803230

One trumps two: Monosubstituted chiral bicyclo[2.2.2]octadiene ligands, derived from carvone, form complexes with rhodium to catalyze the asymmetric addition of boronic acid substrates to α,β-unsaturated ketones (see scheme). The 1,4-adducts are produced

Full text of DOI:10.1002/anie.200803230

Angewandte
Chemie
DOI: 10.1002/anie.200803230
Synthetic Methods
C1-Symmetric Monosubstituted Chiral Diene Ligands in Asymmetric
Rhodium-Catalyzed 1,4-Addition Reactions**
Thomas Gendrineau, Olivier Chuzel, Hendrik Eijsberg, Jean-Pierre Genet, and Sylvain Darses*
Asymmetric catalysis provides outstanding tools to introduce
chiral information to a substrate by using only catalytic
amounts of a chiral transition-metal complex.[1] The success of
these efficient asymmetric processes relies on the develop-
ment of chiral ligands that form a complex with the metal;
until very recently phosphorus-, nitrogen-, and oxygen-con-
taining chiral ligands were the only ones available. Recently,
the groups of Hayashi and Carreira independently reported
the use of chiral dienes in asymmetric catalysis:[2] high levels
of enantioselectivity were achieved in both the iridium-
catalyzed kinetic resolution of allyl carbonates[3] and the
rhodium-catalyzed 1,4-additions of organoboron reagents to
Michael acceptors.[4,5]
Major efforts in the development of these chiral diene
ligands have been focused on the latter reaction and on the
related rhodium-catalyzed addition of organoboron reagents
to imines.[6] In comparison to the use of phosphorus ligands,
diene ligands allowed reactions to be conducted at room
temperature with low catalytic amounts of the rhodium
catalyst. In the rhodium-catalyzed asymmetric 1,4-additions,
only C2-symmetric (or C2-like) disubstituted dienes allowed
high levels of enantioselectivity.[4,7–9] Although such dienes
are easily accessed, their syntheses are generally low yield-
ing,[6a,7e,n] requires either chiral chromatographic separa-
tion,[6b,c] asymmetric catalysis,[4] or the introduction of the
first substituent early in the synthesis,[8] therefore preventing
straightforward access to diene libraries. Moreover, it
appeared that ligands derived from a bicyclo[2.2.1]heptadiene
core showed moderate stability,[7a] and that the bicyclo-
[2.2.2]octadiene framework was the most suitable for the
rhodium-catalyzed addition of organometallic reagents to
Michael acceptors in terms of the enantioselectivity.[2,7,8]
The space around the rhodium center coordinated to
C2-symmetric chiral dienes is quite similar to that of the
rhodium coordinated to a conventional C2-symmetric chiral
phosphorous ligands such as 2,2’-bis(diphenylphosphanyl)-
1,1’-binaphthyl (binap). In the bis(phosphanyl), chirality is
frequently controlled by the face/edge orientation of the aryl
substituents at the phosphorus atom; whereas for dienes, the
chirality is controlled by the substituents attached to the
double bonds.[4,7,8] Because of their straightforward prepara-
tion, we wondered if C1-type diene ligands, bearing only one
substituent could be employed in rhodium-catalyzed
1,4-addition reactions with comparable efficiency.[10] Actually,
such C1-type diene ligands proved useful only in the iridium-
catalyzed kinetic resolution of allyl carbonates.[3]
In our continuing work on rhodium-catalyzed reactions
involving organoboron reagents,[11] we report herein that the
C2-symmetry of a chiral diene ligand is not necessary to
achieve high enantioselectivities in rhodium-catalyzed
1,4-additions, and that easily accessible (only four steps)
monosubstituted dienes with C1-symmetry compare favorably
to these disubstituted dienes.
The synthesis of chiral monosubstituted diene ligands was
inspired by the work of Carreira and co-workers.[3] Enantio-
pure ketone A (Scheme 1) was prepared in two steps on large
Scheme 1. Preparation of monosubstituted chiral diene ligands. a) See
reference [12]; b) LDA, Comins reagent, THF, À788C (81%); c)see the
Supporting Information.
scale by bromination of commercial (À)-carvone and sub-
sequent cyclization and separation of the resulting diastereo-
isomers.[12] Triflation of the lithium enolate by using Comins
reagent[13] afforded bicyclic triflate (+)-B in 81% yield. In
contrast to a previous report involving organozinc reagents,[3]
the diene substituent was introduced by a palladium-cata-
lyzed cross-coupling reaction with either Grignard reagents,
arylboronic acids, or potassium aryltrifluoroborates.[14] For
the introduction of an aromatic substituent, the best con-
ditions employed arylboronic acids as coupling partners
(PdCl2(dppf), K2CO3, DMF, 1008C; dppf = 1,1’-bis(diphenyl-
phosphanyl)ferrocene).[15] However, under these unoptimized
conditions slightly lower yields were obtained by using ortho-
substituted arylboronic acids. The monosubstituted chiral
dienes ((SRR)-Ln)[16] were easily prepared in moderate to
good yields from (À)-carvone by using this methodology.
[*] T. Gendrineau, Dr. O. Chuzel, H. Eijsberg, Prof. J.-P. Genet,
Dr. S. Darses
Laboratoire de Synth›se SØlective Organique (UMR 7573), Ecole
Nationale SupØrieure de Chimie de Paris
11 rue P&M Curie, 75231 Paris cedex 05 (France)
Fax: (+33)1-4407-1062
E-mail: sylvain-darses@enscp.fr
[**] This work was support by the Centre National de la Recherche
Scientifique (CNRS). T. Gendrineau thanks the Minist›re de
l’Education et de la Recherche for a grant.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803230.
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Communications
Table 1: Ligand screening in the rhodium-catalyzed addition of
PhB(OH)2 (2a) to a,b-unsaturated substrates 1b and 1d.[a]
Elements of diversity were introduced in the last step of the
synthesis, allowing fast generation of a library of ligands. The
enantiomers ((RSS)-Ln) were obtained in identical yields
from (+)-carvone.
Entry[a]
Chiral diene
Yield [%] (ee [%])[b]
3ba
3da
We evaluated the ability of these monosubstituted chiral
diene ligands to control the enantioselectivity in the rhodium-
catalyzed 1,4-addition of boronic acids to Michael acceptors.
Gratifyingly, the reaction of cyclohexenone (1b) with phenyl-
boronic acid (2a) was efficiently catalyzed by a rhodium
complex generated from ligand L3 and commercially avail-
able [{Rh(CH2CH2)2Cl}2], and enantio-enriched product 3ba
was obtained with 92% enantiomeric excess by using
previously reported conditions (Scheme 2).[4] An improved
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
91 (39)
90 (90)
81 (95)
87 (91)
88 (96)
>99 (91)
86 (98)
82 (92)
93 (91)
91 (85)
99 (89)
90 (93)
>99 (95)
93 (91)
56 (90)
58 (83)
57 (80)
56 (90)
9
L9
69 (87)
10
11
12
13
14
L10
L11
L12
L13
L14
[a] Reactions conditions: 1 (0.5 mmol), 2 (2 equiv), [{Rh(CH2CH2)2Cl}2]
(2 mol% Rh), (SRR)-Ln (2.2 mol%; from (À)-carvone), and KOH
(2.2 mol%) in MeOH/CH2Cl2 (10:1; 1 mL) at room temperature.
[b] Yield of isolated product. The ee values shown in parentheses were
determined by chiral HPLC methods.
ee values are observed with dienes bearing electron-with-
drawing substituents (Table 1, entry 10). Some of these
ligands were also evaluated in the 1,4-addition of 2a to
lactone 1d (Table 1), and the highest enantioselectivity was
achieved by using di-ortho-substituted chiral diene L7 in the
formation of 1,4-addition adduct 3da. Compared to cyclo-
hexenone, the enantioselectivity levels were lower (ꢀ 90%),
but comparable to those obtained by using C2-type disub-
stituted chiral diene ligands.[8a]
Scheme 2. Monosubstituted chiral dienes in rhodium-catalyzed
1,4-addtion of boronic acids to a,b-unsaturated substrates.
enantioselectivity (95% ee by using ligand L3) was achieved
by conducting the reaction in methanol/dichloromethane
(10:1; instead of the classical dioxane/water (10:1) solvent
system).[17] The rhodium catalyst precursor was prepared
by coordination of the chiral diene to commercial
[{Rh(CH2CH2)2Cl}2] in dichloromethane with subsequent
treatment by a methanolic solution of KOH to generate the
hydroxy–rhodium complex.
The scope of the reaction was evaluated by using diene
(À)-L7, which was prepared from (À)-carvone (Table 2).
Cyclic enones underwent clean reaction with different
arylboronic acids at room temperature (Table 2, entries 1–
11). Enantioselectivities ranging from 93 to 98% were
achieved by using this chiral diene ligand and the ee values
were within the range and even above those observed with
C2-type symmetry chiral dienes previously reported.[4,7–9] The
enantiomer of 3ba was obtained by using the enantiomer
(+)-L7 as the ligand (Table 2, entries 3 and 4). A slightly
lower enantiomeric excess was observed in the reaction of
cyclohexenone (1b) with ortho-substituted boronic acid 2g
(Table 2, entry 10). Good enantioselectivities were also
achieved for the reaction of boronic acids with lactones
(Table 2, entries 12–15). Higher ee values were observed for
six-membered rings compared to five-membered rings; sim-
ilar to observations made by others.[4,7,8] Indeed, enantiose-
lectivities obtained for cyclic a,b-unsaturated substrates by
using monosubstituted chiral diene L7 compared favorably
and even surpassed those obtained with previously reported
dienes. A preliminary result concerning the addition of
phenylboronic acid (2a) to linear a,b-unsaturated amide 1 f,
was encouraging; the expected 1,4-addition adduct was
formed in good yield and with an enantioselectivity of 90%
(Table 2, entry 16).
Under these optimized conditions, we evaluated the
library of chiral diene ligands in the rhodium-catalyzed
1,4-addition of 2a to cyclohexenone (1b; Table 1,
Scheme 2). Overall, high enantioselectivities were obtained
for the formation of 3ba by using aryl-substituted dienes
(from 85% to 98% ee). However, the presence of a methyl-
ene bridge in the ligand, such as in L1, resulted in moderate
chiral induction. In contrast to C2-like symmetric ligands
where benzyl or alkyl substituents were perfectly suitable, a
rigid and bulky substituent in the monosubstituted dienes is
essential to achieve high enantioselectivity.[4,7,8] Among the
aryl-substituted ligands evaluated, it appeared that the
presence of ortho substituents was essential to access enan-
tioselectivities above 95%. To our delight, an enantiomeric
excess of 98% was obtained by using ligand L7, which had
two ortho-methyl substituents on the aromatic ring. This
result constitutes the highest enantiomeric excess reported for
the phenylation of substrate 1b by using chiral dienes. The
electronic nature of the substituents on the aromatic ring does
have some influence on the enantioselectivities: lower
A monosubstitution of the chiral diene ligand is sufficient
to achieve high enantioselectivity in the rhodium-catalyzed
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Table 2: Monosubstituted chiral diene (À)-(SRR)-L7 in rhodium-cata-
lyzed 1,4-addition of boronic acids to a,b-unsaturated substrates.[a]
Experimental Section
Typical procedure for the rhodium-catalyzed 1,4-addition of boronic
acids to a,b-unsaturated substrates: A septum-capped vial, equipped
with a magnetic stirring bar, was charged with [{Rh(CH2CH2)2Cl}2]
(2.0 mg, 2 mol% Rh) and chiral diene L7 (3.0 mg, 2.2 mol%). The
vial was closed, evacuated under vacuum and placed under an argon
atmosphere. Degassed dichloromethane (100 mL) was added and the
mixture was stirred for 15 min at room temperature. A methanolic
KOH solution (0.22m, 50 mL, 2.2 mol%) was added to the mixture
which was then stirred for 15 min at room temperature. Another
septum-capped vial, equipped with a magnetic stirring bar, was
charged with the a,b-unsaturated substrate (0.5 mmol) and arylbor-
onic acid (1 mmol). The vial was closed, evacuated under vacuum and
placed under an argon atmosphere. Degassed methanol (850 mL) and
the previously prepared catalyst solution were added and the mixture
was stirred at room temperature for 1 h. After evaporation of the
solvent, the crude residue was purified by using column chromatog-
raphy with silica gel to afford pure 1,4-addition adduct.
Entry
1
RB(OH)2
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1c
1d
1e
1e
1e
1 f
2a
2c
2a
2a
2b
2c
2d
2e
2 f
2g
2a
2a
2g
2b
2a
2a
95 (3aa)
85 (3ac)
>99 (3ba)
89 (3ba)
83 (3bb)
93 (3bc)
84 (3bd)
77 (3be)
66 (3bf)
45 (3bg)
53[e] (3ca)
56 (3da)
95 (3eg)
95 (3eb)
95 (3ea)
40 (3 fa)
96 (S)
96
98 (S)
97 (R)[d]
98
95
98
93
98
75 (S)
93
90
86
97
9
10
11
12
13
14
15
16
97
90
Received: July 3, 2008
Published online: September 4, 2008
[a] Reactions conditions: 1 (0.5 mmol), 2 (2 equiv), [{Rh(CH2CH2)2Cl}2]
(2 mol% Rh), (À)-(SRR)-L7 (2.2 mol%), KOH (2.2 mol%) in MeOH/
CH2Cl2 (10:1; 1 mL) at room temperature. [b] Yield of isolated product.
[c] The ee values were determined by chiral HPLC methods. [d] (+)-
(RSS)-L7 used as ligand. [e] Used 3 equivalents of arylboronic acid.
Keywords: asymmetric synthesis · boron · diene ligands ·
.
Michael addition · rhodium
addition of boronic acids to a,b-unsaturated substrates, which
is similar to the observation by Carreira and co-workers in the
iridium-catalyzed kinetic resolution of allyl carbonates.[3]
These observations can be readily explained by considering
that coordination of the unsaturated substrate to rhodium
occurs after the transmetalation of the organoborane so that
an aryl substituent is present on the rhodium center.[18] This
aryl group blocks one of the substituents of the disubstituted
chiral diene, suggesting that the substituent has little effect on
selectivity (Scheme 3a). Only one substituent on the diene is
sufficient for chiral recognition (steric interaction) of one face
of the incoming a,b-unsaturated substrate (Scheme 3b).
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monosubstituted (b) chiral diene ligands.
We have demonstrated, for the first time, that monosub-
stituted chiral dienes are well-suited ligands in the rhodium-
catalyzed asymmetric 1,4-addition of boronic acids to
a,b-unsaturated substrates. These ligands can be easily
accessed (four steps from commercially available carvones),
and allow high enantioselectivities to be obtained for the
À
formation of a new C C bond in the b position of Michael
acceptors. The preparation of this monosubstituted ligand is
straightforward and high yielding, permitting access to a large
library of chiral ligands derived from either enantiomer of
cheap, commercially available carvones, which will be of great
interest in asymmetric catalysis.
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Communications
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