Dual catalysis: A combined enantioselective bronsted acid and metal-catalyzed reaction - Metal catalysis with chiral counterions

Article abstract of DOI:10.1002/anie.200702439

(Chemical Equation Presented) Double take: The combination of enantioselective Bronsted acid catalyzed activation and metal-catalyzed alkynylation of α-imino esters under mild reaction conditions leads to amino acids in high yields and with excellent e.r.

Full text of DOI:10.1002/anie.200702439

Angewandte
Chemie
DOI: 10.1002/anie.200702439
Enantioselective Catalysis
Dual Catalysis: A Combined Enantioselective Brønsted Acid and
Metal-Catalyzed Reaction—Metal Catalysis with Chiral Counterions**
Magnus Rueping,* Andrey P. Antonchick, and Claus Brinkmann
The application of chiral Brønsted acids in asymmetric
organocatalysis is continuously increasing.[1–3] Various highly
enantioselective, metal-free reactions have been developed,
most of which are based on the activation of the electrophile
through protonation to form a chiral ion pair. Different
nucleophiles have been added to aldemines and ketoimines in
an enantioselective fashion by using this approach.[2,3] We
were able to demonstrate that the electrophile and nucleo-
phile could be simultaneously activated in a combined process
catalyzed by two Brønsted acids. This led to the development
of the first enantioselective Mannich and Mannich–Michael
reactions catalyzed directly by Brønsted acids.[2g–i] More
recently, we developed the first activation of “pure” carbonyl
compounds catalyzed by a chiral Brønsted acid which resulted
in the first organocatalytic, enantioselective Nazarov cycliza-
tion.[2k] We now present a new dual catalysis procedure, which
comprises a combined and cooperative enantioselective
Brønsted acid and a metal-catalyzed alkynylation.
simultaneously (Scheme 1). This approach should lead to the
formation of an intermediary chiral ion pair A and an achiral
metal complex B, which after subsequent reaction give the
desired amino acid 5 and the regenerated catalysts.
The enantioselective addition of organometallic com-
pounds to imines is one of the most important reactions for
the preparation of chiral amines.[4] This is also valid for the
alkynylations of nitrones, enamines, and aldemines, which
afford the corresponding propagylamines.[5,6] Although vari-
ous metal-catalyzed, enantioselective alkyne additions to
imines have been reported, the enantioselective alkynylation
of a-imino esters has been neglected, even though the
resulting amino acids are of great biological interest.[5l] This
may be due to the basic reaction conditions employed, which
often lead to racemization and loss of enantioselectivity.
In this context we decided to examine the alkynylation of
a-imino esters catalyzed by a Brønsted acid. Based on our
earlier work[2] on asymmetric ion pair catalysis we wondered
whether the combination of a chiral Brønsted acid catalyst
and a metal catalyst would lead to the valuable a-alkynylated
amino acids. Our new concept is based on two parallel
catalytic cycles I and II, in which the activation of the
electrophile 2 by a chiral Brønsted acid (1) catalyst and the
activation of the nucleophile 4 by a metal salt (3) proceed
Scheme 1. Combined enantioselective Brønsted acid and metal-cata-
lyzed alkynylation of a-imino esters. PG=protecting group.
In previous work we demonstrated that chiral binol
hydrogen phosphates 1 (binol = 1,1’-bi-2-naphthyl) are excel-
lent Brønsted acid catalysts for chiral ion-pair catalysis.
Therefore, we decided to initially use these as chiral catalysts
for the activation of the a-imino esters 2 (catalysis cycle I). As
a metal salt (3) for the activation of the alkyne 4 (catalysis
cycle II) we used silver salts, as earlier studies demonstrated
that alkynyl–silver derivatives are stable in protic media and
hydrolysis can only be achieved in the presence of strong
acids, such as hydrochloric acid or trifluoromethane sulfonic
acid.[7]
Hence, we carried out the first enantioselective alkynyla-
tions of a-imino ester 2a with phenylacetylene (4a) in the
presence of 5 mol% silver acetate[8] and different binol
phosphates 1a–i or triflylphosphoramides 1j/k (5–10 mol%,
Table 1). From this survey, the best enantiomeric ratios for
amino acid 5a were obtained when binol phosphates 1g and
1i were used (e.r. 91:9; Table 1, entries 8 and 10). The use of
the corresponding triflylphosphoramides 1j and 1k resulted
in considerably lower selectivity (Table 1, entries 11 and 12).
In further experiments, the solvent as well as the protect-
ing group were varied (Table 2). The combined Brønsted acid
and silver-catalyzed alkyne addition can be performed in
different aromatic and halogenated solvents (Table 2,
entries 1–6), with the best selectivities being obtained when
toluene was used (Table 2, entry 2). Varying the protecting
group and the use of sterically more demanding residues in
[*] Prof. Dr. M. Rueping, Dr. A. P. Antonchick, Dipl.-Chem. C. Brinkmann
Degussa Endowed Professorship
Institute of Organic Chemistryand Chemical Biology
Johann Wolfgang Goethe-Universität Frankfurt am Main
Max-von-Laue Strasse 7, 60438 Frankfurt am Main (Germany)
Fax: (+49)69-798-29248
E-mail: M.rueping@chemie.uni-frankfurt.de
[**] We gratefullyacknowledge Degussa AG and DFG (Schwerpunkt-
programm Organokatalyse) for financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Chiral Brønsted acids in the enantioselective silver-catalyzed
Table 3: Variation of the metal salts, catalyst loading, and N-PMP-imino
alkyne addition.
ester.
Entry[a]
MX
MX [mol%]
1g [mol%]
R
e.r.[b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
–
–
10
5
5
5
5
5
5
2.5
2.5
5
5
5
5
5
5
10
–
2
Et
Et
Et
Et
Et
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
n.d.[c]
n.d.
76:24
86:14
91:9
AcOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOBz
Ag2O
Ag2CO3
AgCO2CF3
AgSO3CF3
AgNO3
AgBF4
1
Entry[a]
Ar
X
1 [mol%]
e.r.[b]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1g
1h
1i
phenyl[c]
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
10
5
10
10
5
57:14
55:45
55:45
54:46
62:38
49:51
86:14
91:9
69:31
91:9
41:59
31:69
5
10
10
20
5
5
5
10
10
10
10
10
10
4-biphenyl
1-naphthyl[c]
2-naphthyl
94:6
87:13
65:35
55:45
73:27
85:15
72:28
81:19
79:21
92:8
3,5-(CF3)2-C6H3
3,5-tBu2-PMP
9-phenanthryl
9-phenanthryl
[H]8Ph3Si
9-anthracenyl
9-phenanthryl[d]
9-anthracenyl[d]
5
5
10
5
10
10
10
10
11
12
1j
1k
NHTf
NHTf
CuOAc
Cu(OAc)2
93:7
[a] Reaction conditions: 2a, 4a, 5–10 mol% 1, 5 mol% AgOAc at room
temperature in toluene. [b] Enantioselectivities were determined by
HPLC analysis. [c] Reaction performed at 458C. [d] In CHCl3. PMP=p-
methoxyphenyl, Tf=triflate, [H]8Ph3Si=(R)-3,3’-bis(triphenylsilyl)octa-
hydrobinol phosphate.
[a] Reaction conditions: 2a, 4a, 1g, AgOAc in toluene at room temper-
ature. [b] Enantioselectivities were determined byHPLC analysis. [c] Not
determined. Bz=benzyl.
nation of 5 mol% silver acetate and 10 mol% 1g gave 5a with
an enantiomeric ratio of 91:9 (Table 3, entry 5)[9] The use of
larger or smaller amounts of Brønsted acid 1g resulted in a
loss of enantioselectivity (Table 3, entries 3, 4, and 7). No
product formation was observed if only Brønsted acid 1g or
the silver acetate were used (Table 3, entries 1 and 2). Copper
acetates could also be employed, however the reactivities
were considerably reduced compared with the silver salts
(Table 3, entries 15 and 16). The best enantiomeric ratios
(e.r. 94:6) were obtained by changing to the a-imino methyl
ester 2b in the presence of 1g and silver acetate (Table 3,
entry 6). We examined a variety of aryl-substituted alkynes in
the combined catalysis procedure under these optimized
conditions. In general the amino acid products 6a–h were
obtained in good yields and enantiomeric ratios (Table 4).[10]
With regard to the reaction mechanism, we can not
exclude an exchange of the metal counterion, which leads to
the formation of a chiral silver complex [Eq. (1)]. This would
Table 2: Evaluation
of
solvents
and
protecting
groups.
Entry[a]
Solvent
R
OMe
OMe
OMe
OMe
OMe
OMe
OEt
e.r.[b]
1
2
3
4
5
6
7
8
9
benzene
toluene
p-xylene
CH2Cl2
CHCl3
(nBu)2O
toluene
toluene
toluene
toluene
86:14
91:9
84:16
76:24
53:47
73:27
82:18
88:12
58:42
76:24
Opentyl
OCF3
OPh
10
[a] Reaction conditions: 2a, 4a 10 mol% 1g, 5 mol% AgOAc at room
temperature. [b] Enantioselectivities were determined byHPLC analysis.
the 4-position resulted in lower enantiomeric ratios (Table 2,
entries 7–10).
Having established the best conditions with respect to the
solvents, temperature, protecting group, and chiral Brønsted
acids, we decided to further optimize the reaction by
examining different metal salts and catalyst loadings
(Table 3). While the alkynylation could be successfully
performed with various silver salts (Table 3, entries 7–14) as
well as copper salts (Table 3, entries 15 and 16), the combi-
lead to the first example of a reaction catalyzed by a chiral
metal complex[11] in combination with a chiral Brønsted acid
catalyst.[12]
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Table 4: Products (with e.r. values and yields) of the catalytic enantio-
selective alkynylation with aryl-substituted alkynes.[a,b]
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[a] Reaction conditions: 2b, 4a–h (2 equiv), 10 mol% 1g, 5 mol%
AgOAc at 308C in toluene. [b] Yield after chromatography. Enantiose-
lectivities were determined byHPLC analysis using a chiral stationary
phase.[13]
In summary, we have reported a new dual catalysis
procedure, in which an enantioselective activation catalyzed
by a Brønsted acid is combined with a metal-catalyzed
alkynylation. The special features are the mild reaction
conditions and the operational simplicity and practicability,
which even negate the need to preform the catalyst. The new
amino acids obtained have been isolated in good yields and
with excellent enantiomeric ratios (up to e.r. 96:4). Further-
more, this unprecedented dual catalysis procedure represents
not only the first addition of an organometallic compound to a
aldimine activated with a binol phosphate, but more impor-
tantly, in this process both the metal salt and the Brønsted
acid can be employed in catalytic amounts. We assume the
reaction mechanism involves the formation of a chiral silver–
binol phosphate complex, which results in a new metal-
catalyzed reaction, in which the chiral counterion induces the
enantioselectivity.
Further work will be directed toward a more detailed
examination and application of the dual catalysis procedure
as well as asymmetric metal catalysis with chiral counterions.
Received: June 5, 2007
Published online: August 10, 2007
Keywords: alkynes · asymmetric catalysis · binol phosphate ·
.
silver
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[9] The reduced enantioselectivities can be explained by the ability
of AgNO3 or AgOTf to catalyze the reaction without the
addition of Brønsted acids (see Refs. [6–8]).
[10] This represents the first example of an enantioselective alkyny-
lation with phenylacetylene and its derivatives. The use of alkyl-
substituted alkynes have been reported in Ref. [5l].
[12] Experiments with chiral silver–binol complexes in combination
with the achiral Brønsted acid diphenyl hydrogen phosphates
resulted in racemic product.
[13] Experiments for the determination of the absolute configuration
are given in the Supporting Information.
[14] Note added in proof (July 31, 2007): After the acceptance of our
manuscript a further article on metal catalysis with chiral
counterions appeared: G. L. Hamilton, E. J. Kang, M. Mba,
F. D. Toste, Science 2007, 317, 496.
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