A powerful chiral counteranion motif for asymmetric catalysis

Full text of DOI:10.1002/anie.200901768

Angewandte
Chemie
DOI: 10.1002/anie.200901768
Organocatalysis
A Powerful Chiral Counteranion Motif for Asymmetric Catalysis**
Pilar Garcꢀa-Garcꢀa, Frank Lay, Patricia Garcꢀa-Garcꢀa, Constantinos Rabalakos, and
Benjamin List*
Complementing metal salts and enzymes, organic molecules
have recently emerged as a third class of general enantiose-
lective catalysts.[1–3] As particularly successful strategies,
Lewis base organocatalysis and Brønsted acid organocatalysis
have inspired several dozens of highly useful reactions.
However, important challenges remain. Among them are
1) the evaluation of previously unexplored organic functional
groups, 2) the development of high turnover number catalysts,
and 3) the activation of simple aldehydes. Herein we report
progress towards meeting these challenges. We have identi-
fied the chiral disulfonimide functional group as a powerful
motif for asymmetric catalysis. In a first example, we show
that a highly active and selective disulfonimide catalyst
accelerates the asymmetric Mukaiyama aldol reaction.
This reaction is an archetypical transformation of simple
aldehydes used as electrophiles in combination with enol
silanes as nucleophiles. The reaction is typically catalyzed by
Lewis acids and asymmetric versions have traditionally
defined the state of the art in chiral Lewis acid catalysis.[4]
Important contributions have come from various research
groups[5–13] but high catalyst loadings are typically required. A
chiral titanium catalyst developed by Carreira et al. has
proven particularly general and is used at relatively low
catalysts loadings (0.5–5 mol%).[4] An elegant and comple-
mentary approach using chiral Lewis bases has been designed
by Denmark et al.[14] Very recently, even hydrogen-bonding
Brønsted acid catalysis has found utility for Mukaiyama aldol
reactions.[15–16] While Rawal and co-workers found chiral diols
to catalyze this reaction with good enantioselectivity, Jørgen-
sen and co-workers described moderately enantioselective
bis(sulfonamide) catalysts. However, high catalyst loadings
and highly activated substrates are generally required with
these systems.
ularly successful motif, Terada and Akiyama introduced
binol-derived phosphoric acids of type 1 (see Table 1) for
the activation of imines.[17,18] Nakashima and Yamamoto[19]
designed the corresponding N-triflyl phosphoramides of type
2, which are more acidic and have significantly expanded the
substrate scope by allowing the use of ketones as electrophilic
substrates.[20] However, neither phosphoric acids nor N-triflyl
phosphoramides have proven sufficiently active for the
utilization of unfunctionalized aldehydes,[21] a particularly
important substrate class for asymmetric catalysis.
Our research group is currently exploring alternative
chiral Brønsted acid motifs. Especially, very strong chiral
“super Brønsted acids”[22] have great potential for high-
performance asymmetric catalysis in general and are partic-
ularly promising for the activation of important but less basic
substrate classes such as aldehydes and olefins.[23,24] In
addition, their corresponding bases should be useful in
applications of asymmetric counteranion-directed catalysis
(ACDC).[25–27]
Recently, a highly acidic binaphthyl-derived chiral disul-
fonic acid catalyst has been designed and synthesized.[28–30]
The corresponding chiral cyclic disulfonimides have been
unknown but appeared to us as a particularly promising chiral
catalyst motif.[31] We were fascinated with the possibility that
chiral binaphthyl-derived sulfonic acids and disulfonimides
may resemble the relative reactivity of triflic acid (TfOH) and
of triflylimide (Tf2NH), which are both powerful Brønsted
acid catalysts. In addition, their corresponding silylated
species could be promising chiral Lewis acid catalysts:
Although TfOH (pKa = À5.9 in water) is much more
Brønsted acidic than Tf2NH (pKa = 1.7 in water), the relation-
ship is reversed if one regards the Lewis acidity of the
corresponding silylated species—TMSNTf2 is a much stronger
Lewis acid than TMSOTf.[32,33] Furthermore, of particular
interest to us is the C2-symmetric binaphthyl disulfonimide
topology, which differs significantly from that of the corre-
sponding pseudo-C2-symmetric phosphoric acids. Analysis of
the atom connectivity and three dimensional structures of
models revealed that the proton-carrying functional group is
buried deeper in the chiral pocket of the disulfonimide than in
that of the corresponding phosphate. Such a situation could
possibly lead to an enhanced stereochemical communication
between catalyst and substrate (Scheme 1).
In
a parallel development, relatively strong chiral
Brønsted acid catalysts have recently emerged. As a partic-
[*] Dr. P. Garcꢀa-Garcꢀa,[+] F. Lay,[+] Dr. P. Garcꢀa-Garcꢀa, Dr. C. Rabalakos,
Prof. Dr. B. List
Max-Planck-Institut fꢁr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mꢁlheim an der Ruhr (Germany)
Fax: (+49)208-306-2999
E-mail: list@mpi-muelheim.mpg.de
[+] These authors contributed equally.
[**] Funding by the Max-Planck-Society, the DFG (Priority Program 1179,
Organocatalysis), the Fond der Chemischen Industrie, and the
Spanish Ministerio de Educaciꢂn y Ciencia (Fellowship to PiGG and
PaGG) is gratefully acknowledged. We thank Sebastian Hoffmann
for his early contributions to our studies and our HPLC department
for their support.
Indeed, a comparison of phosphoric acid 1 and phosphor-
amide 2, with the previously unknown disulfonic acid 3 and
disulfonimide 4, in the catalysis of the Mukaiyama aldol
reaction of naphthaldehyde 5a with ketene acetal 6a revealed
catalyst 4 to not only be far more active than the alternative
catalysts 1–3 but to also provide aldol product 7a with high
enantioselectivity of 90:10 e.r. (Table 1).[34]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901768.
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Table 2: Preliminary substrate scope of the Mukaiyama aldol reaction
catalyzed by disulfonimide 4.
Entry
1
Product 7
Catalyst loading Yield e.r.[b]
[mol%]
[%][a]
Scheme 1. Analysis of the structural topology differences of the phos-
phoric acid and disulfonimide catalyst motifs.
7a
7b
2
98
97:3
95:5
Table 1: Evaluation of different chiral acid catalyst motifs in the
Mukaiyama aldol reaction.
2
2
2
78
3
4
7c
98
82
96:4
97:3
7d
7e
2
2
5
92
70
96:4
90:10
6[c,d]
7e 0.1
7
7 f
7 f 0.1
7 f 0.05
2
93
80
70
92:8
90:10
90:10
8[c,e]
9[c,e]
10[f,g]
7g
7h
7h 0.1
7h 0.05
7h 0.01
2
2
86
86:14
Entry
Catalyst
Yield [%][a]
e.r.[b,c]
1
2
3
4
1
2
3
4
<2
<2
<2
–
–
–
11
95
90
90
88
93:7
93:7
93:7
88:12
12
13[h]
14[i,j]
>99
90:10
1
[a] Yield determined by H NMR spectroscopy using triphenylmethane
as the internal standard. [b] Determined by HPLC on a chiral stationary
phase. [c] See the Supporting Information for the determination of the
absolute configuration.
15[e,k]
7i
5
46
91:9
16[g,l]
7j
5
59
75:25
Disulfonimide 4 proved to be a highly active catalyst of
the Mukaiyama aldol reaction and gave full conversion to the
desired product 7a even at À788C. Moreover, at this temper-
ature, the enantioselectivity increased to 97:3 e.r. (Table 2,
entry 1). These reaction conditions could be applied to several
different substrate combinations with good results (Table 2).
The reaction is well suited for isobutyrate-derived ketene
acetals, which react with aromatic aldehydes to give the
corresponding aldol products 7a–c in high yields and enan-
tioselectivities (ꢀ 95:5 e.r.; Table 2, entries 1–3). An a,b-
unsaturated aldehyde could also be used with the same
nucleophile to give the desired product 7d in good yield and
with an e.r. of 97:3 (Table 2, entry 4). Even the more
challenging acetate-derived ketene acetal could be used and
upon reaction with different aldehydes provided the corre-
sponding products 7e–h in excellent yields and high enantio-
[a] Yield of isolated product. [b] Determined by GC or HPLC on a chiral
stationary phase. [c] -458C. [d] 96 h. [e] 112 h. [f] Reaction in pentane.
[g] Room temperature. [h] 0.1M concentration. [i] 08C. [j] 72 h. [k] 2M
concentration. [l] 49 h.
selectivities (Table 2, entries 5, 7, 10, and 11). In these cases,
we also investigated the effect of lowering the catalyst loading
on the outcome of the reactions. An amount of only 0.1 mol%
turned out to be sufficient to give the desired products 7e,f,h
in good to excellent yields while maintaining high enantiose-
lectivity (Table 2, entries 6, 8, and 12). Even lower catalyst
amounts can be used with good results (Table 2, entries 9, 13,
and 14) and product 7h was obtained in high yield and an e.r.
of 88:12 with a remarkably low catalyst loading of 0.01 mol%.
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Finally, aliphatic aldehydes were also tested and provided
pivaldehyde- and hydrocinnamaldehyde-derived products 7i
and 7j with good yields and reasonably good enantioselec-
tivities (Table 2, entries 15 and 16).
There are two plausible mechanistic pathways that explain
the observed reactivity. Accordingly, the acid may directly
protonate the aldehyde to form an ion pair in analogy to the
mechanism proposed for the analogous phosphoric-acid-
catalyzed Mukaiyama–Mannich reaction.[35]
of the two large silyl and disulfonimide fragments of structure
8 should weaken the covalent bond between them, thus
resulting in a more ionic-like situation that resembles the
“frustrated Lewis pair” motif of Stephan and co-workers.[37]
In summary, with the presented chiral disulfonimide
structure, we have designed a powerful new motif for
asymmetric catalysis. As a first illustration, a highly efficient
and enantioselective Mukaiyama aldol reaction has been
developed. Turnover numbers of up to 8800 could be
achieved. Such numbers are rare in organocatalysis and to
the best of our knowledge are unprecedented in enantiose-
lective Mukaiyama aldol reactions, thus illustrating the
potential of this catalyst type for high-performance asym-
metric catalysis. The proposed mechanism immediately
suggests a general solution to problems of asymmetric
Lewis acid catalysis that are associated with non-enantiose-
lective “background” reactions promoted by the achiral R3Si-
cation.[38] Therefore, species 8 represents a powerful catalyst
for asymmetric silicon catalysis and a number of reactions
catalyzed by TMSNTf2, and similar catalysts should be now
accessible in an enantioselective fashion. The designed chiral
disulfonimide motif is also expected to find applications in
other areas. Thus, various reactions that can be catalyzed by
Tf2NH and related structures[22] may now be conducted in an
asymmetric manner. More significantly, its corresponding
base, the disulfonimide anion, should be of use as a new
powerful chiral anion for ACDC in combination within
various catalyst motifs including transition metal ions and
organic cations. Ultimately, the prospect arises that even
more active catalysts will be developed leading to high-
performance organocatalysis and Lewis acid catalysis with
turnover numbers possibly rivaling those seen with the very
best transition metal catalysts and biocatalysts.
Alternatively, the catalyst may be first silylated by the
ketene acetal, thus providing an N-silyl disulfonimide that
could activate the aldehyde through O-silylation. As catalyst
activity does not seem to correlate to Brønsted acidity, the
latter Lewis acid mechanism seems to be more likely. In
addition, preliminary NMR studies suggest this mechanism to
be operative.[34] Thus, we could show by NMR spectroscopy
that the ketene acetal rapidly silylates catalyst 4. The resulting
species indeed promotes the aldol process and does so even in
the presence of 2,6-di-terbutyl-4-methyl pyridine. This base
inhibits any potential Brønsted acid catalysis and has
previously been used to differentiate between Lewis acid
and Brønsted acid catalyzed pathways.[36] According to the
mechanistic scheme, the actual catalyst is N-silyl imide 8,
which is generated upon initial reaction of catalyst 4 with the
ketene acetal (Scheme 2). Aldehyde activation is then
realized through silyl transfer from imide 8 to generate an
oxonium ion. Asymmetric induction occurs by stereochemical
communication within ion pair 9, consisting of the disulfoni-
mide anion and the O-silylated oxonium cation. Its reaction
with the ketene acetal then provides product 7a through ion
pair intermediate 10. This mechanistic proposal is in line with
our recently introduced concept of asymmetric counteranion-
directed catalysis.[25–27]
The powerful Lewis acidity of catalyst 8 may result from
the steric requirements of its constituents. The space demand
Received: April 1, 2009
Published online: May 13, 2009
Keywords: disulfonimides · homogeneous catalysis ·
.
Mukaiyama aldol reaction · organocatalysis
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