2190-2192 Cooperative catalysis in multicomponent reactions: Highly enantioselective synthesis of γ-hydroxyketones with a quaternary carbon stereocenter

Article abstract of DOI:10.1002/anie.200904905

Chemical Equation Presented Together they make a difference: An aryl diazoacetate, H₂O, and an α, β-unsaturated 2-acyl imidazole give γ-hydroxyketones with a quaternary carbon stereocenter with excellent selectivity only if all three catalyst components shown in the scheme are present. The Michael addition step did not occur when a similar reagent mixture was treated with the [Rh₂(OAc)₄] catalyst alone. OTf=triflate, Ts = p-tosyl.

Full text of DOI:10.1002/anie.200904905

Communications
DOI: 10.1002/anie.200904905
Multicomponent Reactions
Cooperative Catalysis in Multicomponent Reactions: Highly
Enantioselective Synthesis of g-Hydroxyketones with a Quaternary
Carbon Stereocenter**
Xiao-Yu Guan, Li-Ping Yang, and Wenhao Hu*
Multicomponent reactions (MCRs) offer substantial advan-
tages over traditional approaches for the rapid generation of
complex molecular architectures in a convergent and atom-
economical manner.[1] Progress has recently been made with
enantioselective multicomponent reactions, which enable the
efficient preparation of chiral molecules from simple starting
materials.[2] In recent years, cooperative catalysis, including
dual-metal catalysis and metal–organo catalysis, has gained
much attention in traditional two-component organic trans-
formations owing to its ability to enhance selectivity and
reactivity in the reactions.[3] In multicomponent reactions
involving the formation of two or more chemical bonds,
cooperative catalysis provides an opportunity to control the
Scheme 1. Reaction-pathway change through cocatalysis. Bn=benzyl,
L=ligand.
order of bond formation to produce different types of
molecules, as the appropriate combination of compatible
cocatalysts can affect the intrinsic reaction kinetics in a
designed way to activate the desired component selectively.
As reactive intermediates, oxonium ylides are known to
undergo synthetically useful transformations.[4] For example,
transition-metal-catalyzed diastereo- and enantioselective
yield (Table 1, entry 1). We envisioned that an appropriate
Lewis acid cocatalyst would activate 3a[7] through the
formation of a five-membered-ring chelated intermediate.
À
Subsequently, the oxonium ylide intermediate in the O H
À
O H insertions of diazo compounds into alcohols or water
insertion could be trapped by activated 3a through a Michael-
type addition to give the product of three-component
coupling. To validate this hypothesis, we screened a number
of Lewis acids as cocatalysts. Although Mg(OTf)2, Mg(ClO4)2,
and Cu(OTf)2 were ineffective in the reaction, we did isolate a
three-component-coupling product when we used Zn(OTf)2,
Sc(OTf)3, or Yb(OTf)3 as a cocatalyst (Table 1, entries 2–4).
We were surprised to find that the obtained three-component-
coupling product 4a was derived from 1a, 3a, and water
rather than the alcohol starting material 2. This result
indicated that incidental water in the reaction system
participated in the reaction. The formation of 4a can be
accounted for by the higher nucleophilicity of the oxonium
ylide formed with H2O than that of the corresponding ylide
generated with the alcohol. Among the effective cocatalysts,
Zn(OTf)2 gave the best result, with the formation of 4a in
85% yield with d.r. 80:20 in favor of the syn isomer (Table 1,
entry 4).
have been studied in some detail.[5] We communicate herein
that in a reaction mixture of four components—methyl
phenyldiazoacetate (1), benzyl alcohol (2), water, and the
À
conjugated enone 3a—the traditional O H insertion product
5 was obtained by using [Rh2(OAc)4] alone as the catalyst,
whereas the use of a cooperative catalytic system containing
[Rh2(OAc)4] as well as a Lewis acid (LA) and/or a Brønsted
acid changed the reaction pathway to give the g-hydroxyke-
tone 4a in good yield (Scheme 1). The trapping with a
Michael acceptor of an oxonium ylide generated in situ from
an aryl diazoacetate and water has not been reported
previously.[6]
Our initial study began with the reaction of methyl
phenyldiazoacetate (1a), benzyl alcohol (2), and the a,b-
unsaturated 2-acyl imidazole 3a. The use of [Rh2(OAc)4]
À
alone as the catalyst gave the O H insertion product 5 in 65%
The above observations led us to use water (1.5 equiv)
instead of benzyl alcohol in subsequent reactions. With the
aim of developing an enantioselective process, we screened
the chiral ligands L1–L3 in the novel three-component
reaction in combination with the Lewis acid Zn(OTf)2
(Table 1, entries 5–7). The complex (S)-tBu-box–Zn(OTf)2
(L1–Zn(OTf)2) was the most efficient cocatalyst, with the
formation of 4a in 75% yield with d.r. 90:10 and an ee value of
91% for the major syn isomer (Table 1, entry 5). The effects
of solvent and temperature on the reaction were also
[*] Dr. X.-Y. Guan, Prof. L.-P. Yang, Prof. W. Hu
Department of Chemistry, East China Normal University
Shanghai 20062 (China)
Fax: (+86)21-6223-3176
E-mail: whu@chem.ecnu.edu.cn
[**] We are grateful for financial support from the National Science
Foundation of China (Grant No. 20932003, 20872036) and for
sponsorship from Shanghai (09JC1404901, 51K03117).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904905.
2190
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Chemie
Table 1: Catalyst screening and optimization of the reaction conditions
Table 2: Enantioselective three-component reaction of various diazo
compounds 1 and a,b-unsaturated 2-acyl imidazoles 3 with H2O.[a]
for the three-component reaction.[a]
Entry Ar
Ar’
Yield [%][b] d.r.[c]
ee [%][d]
1
2
3
4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-BrC6H4 (3b)
p-ClC6H4 (3c)
p-FC6H4 (3d)
p-NO2C6H4 (3e)
78 (4b)
75 (4c)
70 (4d)
86 (4e)
97:3
99:1
99:1
95:5
92:8
95:5
96
94
96
90
99
97
Entry
LA
L
3
T
Yield of 4[b]
d.r.[c]
ee[d]
5[e]
6[e]
7
p-MeOC6H4 (3 f) 60 (4 f)
(mol%)
[8]
[%]
[%]
p-MeC6H4 (3g)
1-naphthyl (3i)
o-ClC6H4 (3k)
o-BrC6H4 (3l)
o-NO2C6H4 (3m) 70 (4m)
o-OMeC6H4 (3n) 61 (4n)
63 (4g)
75 (4i)
61 (4k)
73 (4l)
1[e]
2[e]
3[e]
4[e]
5
6
7
8
–
–
–
–
–
L1
L2
L3
L1
L1
L1
L1
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
25
25
25
25
25
0[f]
45
80
85
75
40
70
81
86
75
78
n.a.
n.a
n.a.
n.a.
n.a.
91
29
85
96
50
86:14 95
8
9
10
11
12
13
14
15
99:1
99:1
98:2
96:4
99:1
94:6
99:1
99:1
97
97
95
96
96
93
93
85
LA1 (20)
LA2 (20)
LA3 (20)
LA3 (20)
LA3 (20)
LA3 (20)
LA3 (20)
LA3 (20)
LA3 (30)
LA3 (30)
79:21
80:20
80:20
90:10
83:17
86:14
94:6
80:20
90:10
97:3
m-BrC6H4 (3o)
m-NO2C6H4 (3p) 61 (4p)
81 (4o)
25
25
p-OMeC6H4 Ph (3a)
m-ClC6H4 Ph (3a)
80 (4j)
72 (4q)
À8
9[g]
10
11[h]
20
À8
À8
56
96
[a] For reaction conditions, see the Supporting Information. [b] Yield of
the isolated product. [c] The diastereomeric ratio was determined by
1H NMR spectroscopy of the crude reaction mixture. [d] The ee value was
determined by HPLC. [e] (S)-tBu-box–Zn(OTf)2: 50 mol%.
[a] Reaction conditions: 1/H2O/3=2.5:1.5:1, [3]=0.025 mmolmLÀ1 in
CH2Cl2, inert atmosphere, 6–12 h. [b] Yield of isolated 4. [c] The
diastereomeric ratio was determined by 1H NMR spectroscopy of the
crude reaction mixture. [d] The ee value was determined by HPLC.
according to a procedure similar to a reported procedure[7b]
(Scheme 2). Optically active g-hydroxy carboxylic acid deriv-
atives are key intermediates and building blocks in the
À
[e] Benzyl alcohol (2; 0.15 mmol) was added. [f] The O H insertion
product 5 was obtained in 65% yield. [g] Excess H2O (4 equiv) was used.
[h] TsOH (40 mol%) was added. Tf=trifluoromethanesulfonyl, Ts=p-
toluenesulfonyl.
investigated (see the Supporting Information). The best
results were obtained when the reaction was carried out in
the solvent dichloromethane at a reaction temperature of
À88C (Table 1, entry 8). The amount of water had a
significant effect on the reaction. For example, when an
excess amount of water (4 equiv) was used, the enantioselec-
tivity decreased significantly to 50% ee (Table 1, entry 9). We
next attempted to extend the optimized reaction to the
bromo-substituted acyl imidazole substrate 3b. However, the
enantioselectivity of the product 4b decreased significantly to
56% ee (Table 1, entry 10). We discovered that the addition
of an additional Brønsted acid significantly increased the rate
and selectivity of the reaction. With the addition of TsOH
(40 mol%), product 4b was obtained in 78% yield with d.r.
97:3 and 96% ee (Table 1, entry 11). The role of the acid
additive is not yet clear, but it is likely that the Brønsted acid
activates the a,b-unsaturated 2-acyl imidazole 3b through
H bonding to this substrate.
The catalyst combination [Rh2(OAc)4], (S)-tBu-box–Zn-
(OTf)2, and TsOH was applied to other acyl imidazoles 3 and
aryl diazoacetates under the optimized reaction conditions
(Table 2). Excellent diastereo- and enantioselectivity were
consistently observed in the reaction. The configuration of the
major isomer of the brominated analogue 4b was determined
to be 2S,3S by single-crystal X-ray analysis, and that of other
compounds was tentatively assigned by analogy.
Scheme 2. Synthesis of the carboxylic acid derivative 6. DBU=1,8-
diazabicyclo[5.4.0]undec-7-ene.
synthesis of natural products and pharmaceuticals.[8] Signifi-
cant efforts have already been made in the preparation of
chiral g-hydroxy carboxylic acid derivatives;[9] we now add an
efficient method for the construction of such a framework
with contiguous quaternary and trisubstituted stereogenic
carbon centers.[10]
In summary, we have developed an enantioselective
three-component reaction of diazo compounds with H2O
and a,b-unsaturated 2-acyl imidazoles in the presence of
[Rh2(OAc)4], (S)-tBu-box–Zn(OTf)2, and TsOH. The reac-
tion provides an efficient route to g-hydroxyketone deriva-
tives containing a stereogenic quaternary carbon center in
good yield with excellent enantioselectivity. We anticipate
that the concept of cooperative catalysis will be applicable to
the discovery of more novel multicomponent reactions.
Experimental Section
Typical procedure: CH2Cl2 was distilled over calcium hydride until a
water content of 0.05% (w/w) in the solvent was reached. The water
The 2-acyl imidazole products 4 can be transformed
readily into the corresponding carboxylic acid derivatives
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2191

Communications
serves as a reactant in the multicomponent reaction, and the amount
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of water is critical for the success of the reaction. Zinc(II) triflate
(10.8 mg, 0.03 mmol) and (S)-tBu-box (10.5 mg, 0.036 mmol) were
placed in a flame-dried vial, which was then capped with a septum.
CH2Cl2 (1 mL) was added, and the mixture was stirred for 1 h at 258C.
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A
solution of 3-(4-bromophenyl)-1-(1-methyl-1H-imidazol-2-
yl)prop-2-en-1-one (3b; 0.1 mmol), [Rh2(OAc)4] (1 mg,
0.0022 mmol), and 4-toluenesulfonic acid (8 mg, 0.042 mmol) in
CH2Cl2 (2 mL) was then added, and the resulting mixture was stirred
for 5 min at room temperature, then cooled to À88C and stirred for
10 min at this temperature. Methyl phenyldiazoacetate (1a; 44 mg,
0.25 mmol) in CH2Cl2 (1 mL) was then added, and the reaction
mixture was stirred for 6–12 h at À88C until completion of the
reaction was indicated by TLC. The reaction mixture was concen-
trated under reduced pressure, and the diastereomeric ratio of the
crude product was determined by 1H NMR spectroscopic analysis.
The crude product was purified by flash chromatography on silica gel
(eluent: EtOAc/light petroleum 1:3) to give 4b (35.6 mg, 78%). The
optical purity of the product was determined by HPLC analysis on a
chiral phase (Daicel Chiralpak AD-H column).
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Received: September 2, 2009
Published online: November 5, 2009
Keywords: asymmetric synthesis · cooperative catalysis ·
.
Michael addition · multicomponent reactions · oxonium ylides
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