Highly enantioselective organocatalytic carbonyl-ene reaction with strongly acidic, chiral Bronsted acids as efficient catalysts

Article abstract of DOI:10.1002/anie.200802139

(Chemical Equation Presented) You can count on the counterion in ion-pair intermediates to induce high levels of asymmetry in the title reaction. The efficient transformation proceeds under mild reaction conditions in the presence of an air-stable N-triflylphosphoramide in a low catalyst loading of just 1 mol% to give substituted α-hydroxyesters in good yields and with excellent ee values (see scheme; R = aryl).

Full text of DOI:10.1002/anie.200802139

Communications
DOI: 10.1002/anie.200802139
Asymmetric Synthesis (2)
Highly Enantioselective Organocatalytic Carbonyl-Ene Reaction with
Strongly Acidic, Chiral Brønsted Acids as Efficient Catalysts**
Magnus Rueping,* Thomas Theissmann, Alexander Kuenkel, and RenØ M. Koenigs
Asymmetric Brønsted acid catalysis has emerged as a power-
ful tool in organic synthesis.[1] In particular, chiral phosphoric
acids have become established as useful organocatalysts for
highly enantioselective transformations. The central role
performed by the phosphoric acids in such reactions is the
activation of the electrophile by catalytic protonation to form
an intermediary ion pair composed of the activated (proton-
ated) electrophile and a chiral phosphate counterion. This
counterion induces the high enantioselectivities observed.
Various enantioselective transformations of aldimines and
ketimines have been carried out by applying this strategy.[2–3]
We demonstrated that not only imines,[4] but also carbonyl
compounds can be activated effectively by chiral phosphoric
acids.[5] Our studies also revealed superior catalysts to chiral
phosphates: Greatly improved reactivities and selectivities
were observed with the more acidic N-triflylphosphoramides,
which can also be used as catalysts for other transformations
of carbonyl groups. It is therefore astonishing that only four
enantioselective transformations with these effective acidic
catalysts have been developed to date: our Nazarov cycliza-
tions[5] and 1,2- and 1,4-additions,[6] as well as two cyclo-
addition reactions described by Yamamoto and co-workers.[7]
Herein we report a new application of these highly
reactive phosphoramides in the development of the first
highly enantioselective organocatalytic carbonyl-ene reac-
tion. The carbonyl-ene reaction is an important carbon–
carbon bond-forming reaction for the preparation of syntheti-
cally valuable homoallylic alcohols.[8] Substantial progress has
been made in the development of enantioselective inter- and
intramolecular variants with different metal catalysts, includ-
ing chiral aluminum, titanium, zinc, copper, palladium,
platinum, and chromium complexes.[9,10] However, a highly
enantioselective organocatalytic carbonyl-ene reaction has
not been described. Recently, Clarke et al. reported the
application of the Schreiner catalyst[11] (1,3-bis(3,5-bis(tri-
fluoromethyl)phenyl)thiourea) in the first organocatalytic
ene reaction.[12] However, the further extension of this
methodology to an asymmetric variant by using a chiral
thiourea derivative proved difficult; only low reactivities and
moderate selectivities were observed.[13] Given the impor-
tance of the carbonyl-ene reaction and the resulting products,
the development of an intermolecular, highly enantioselective
organocatalytic ene reaction appeared to us to be of great
significance. On the basis of our continuing studies on
Brønsted acid catalyzed carbonyl-group activations, we
believed that an asymmetric carbonyl-ene reaction should
be possible with the strongly acidic N-triflylphosphoramides
as catalysts [Eq. (1)].
We started our investigations of the Brønsted acid
catalyzed ene reaction by testing various combinations of
alkene donors and carbonyl acceptors. Preliminary studies
revealed that N-triflylphosphoramides catalyze intermolecu-
lar carbonyl-ene reactions of various glyoxalate and pyruvate
derivatives. The corresponding a-hydroxy esters, valuable
pharmaceutical intermediates and chiral building blocks for
natural products synthesis, were isolated in good yields. Next,
we explored an asymmetric variant of the ene reaction by
employing the chiral N-triflylphosphoramide catalysts 1a–j
and the a,a,a-trifluoropyruvate 3a as the carbonyl acceptor
(Table 1).a-Trifluoromethyl esters, such as the products4, are
of great significance for the synthesis of pharmaceuticals and
agrochemicals owing to their unique electronic structure,
which affects both their pharmacodynamic and pharmaco-
kinetic properties.[14,15]
Thus, the reaction of a-methylstyrene 2a with the
trifluoropyruvate 3a in the presence of a catalytic amount
of the chiral N-triflylphosphoramides 1a–1j provided the
desired a-hydroxyester 4a. The best result with regard to
reactivity, yield, and selectivity was observed with catalyst 1j,
which provided the desired product 4a with 94% ee.
Further optimization of the reaction focused on the
temperature and the solvent employed, as both played a
crucial role in our earlier studies on Brønsted acid catalyzed
reactions. The N-triflylphosphoramide-catalyzed ene reaction
can be carried out in various apolar, nonprotic solvents at
different temperatures. However, the use of aromatic solvents
gave the best results: The a-hydroxy ester 4a was formed in
o-xylene at 108C with 96% ee (see the Supporting Informa-
tion).[16]
[*] Prof. Dr. M. Rueping, T. Theissmann, A. Kuenkel, R. M. Koenigs
Degussa Endowed Professorship
Institute for Organic Chemistry and Chemical Biology
Johann Wolfgang Goethe University
Max-von-Laue Strasse 7, 60438 Frankfurt am Main (Germany)
Fax: (+49)69-798-29248
E-mail: M.rueping@chemie.uni-frankfurt.de
[**] We thank Evonik Degussa and the DFG (Priority Programme
Organocatalysis) for financial support, as well as the Fonds der
Chemischen Industrie for a scholarship awarded to A.K.
Interestingly, in chlorinated solvents, the dimerization of
methylstyrene occurred, and 5a and 5b were isolated as the
Supporting information for thisarticle isavailable on the WWW
under http://dx.doi.org/10.1002/anie.200802139.
6798
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Chemie
Table 1: Survey of N-triflylphosphoramide catalysts for the enantioselec-
Table 2: Evaluation of the catalyst loading and ester moiety.[a]
tive Brønsted acid catalyzed carbonyl-ene reaction.[a]
Entry
1 (mol%)
R
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
1g (10)
1g (5)
1g (2)
1g (1)
1g (0.1)
1g (1)
1j (1)
Me (3b)
Me (3b)
Me (3b)
Me (3b)
Me (3b)
Et (3a)
74
83
66
82
46
86
76
84
84
84
88
81
93
96
Entry
1
R
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1h
1i
phenyl
25
23
26
23
38
25
13
26
38
34
41
63
32
52
24
61
70
34
15
86
53
81
36
28
26
77
86
56
7
2-naphthyl
3,5-(CF3)2C6H3
phenanthryl
anthracenyl
biphenyl
p-NO2C6H4
SiPh2Me [H8]
SiPh3 [H8]
Et (3a)
[a] Reaction conditions: 2 (0.20 mmol), 3 (2.0 equiv), 1, o-xylene (2 mL).
[b] Yield of the isolated product after column chromatography. [c] The
ee value wasdetermined by HPLC on a chiral phase.
Table 3: Scope of the Brønsted acid catalyzed carbonyl-ene reaction.[a]
10
1j
p-MeOC6H4 [H8]
94
[a] Reaction conditions: 2a, 3a (2.0 equiv), 1 (5 mol%), benzene (2 mL).
[b] The yield wasdetermined after column chromatography. [c] The
ee value wasdetermined by HPLC on a chiral phase.
Entry
R
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Ph (2a)
76
69
92
91
96
88
95
87
83
92
87
96
93
55
85
89
71
96
92
96
96
95
92
95
97
94
92
96
95
95
93
92
97
93
p-MeOC6H4 (2b)
p-MeC6H4 (2c)
m-MeC6H4 (2d)
p-EtC6H4 (2e)
p-FC6H4 (2 f)
2-naphthyl (2g)
biphenyl (2h)
p-tBuC6H4 (2i)
m,p-Me2C6H3 (2j)
major products. This result not only demonstrates the high
acidity of the N-triflylphosphoramide catalysts; more impor-
tantly, it opens up many further possibilities for new Brønsted
À
À
acid catalyzed C H activation and C C bond-forming
reactions.
À
p-BrC6H4 C6H4 (2k)
tetralinyl (2l)
indanyl (2m)
p-ClC6H4 (2n)
[d]
p-iPrC6H4 (2o)
[d]
p-IC6H4 (2p)
Therefore, we examined the catalytic enantioselective
carbonyl-ene reaction in the presence of different amounts of
the N-triflylphosphoramides 1 (Table 2). With the chiral
Brønsted acid catalyst 1g, we were able to decrease the
catalyst loading from 10 to 0.1 mol% without a considerable
loss in selectivity (Table 2, entries 1–5). However, the best
result with regard to both reactivity and selectivity was
observed with 1 mol% of the chiral Brønsted acid 1j in the
[d]
p-BrC6H4 (2q)
[a] Reaction conditions: 2, 3a (2.0 equiv), 1j (1 mol%), 0.25m solution
in o-xylene. [b] Yield of the isolated product after column chromatog-
raphy. [c] The ee value wasdetermined by HPLC or GC on a chiral phase.
[d] The reaction wascarried out with catalyst 1g at À208.
reaction of the ethyl ester 3a with a-methylstyrene (Table 2, counterion. These less reactive Ca-complexes exhibit a
entry 7).
We investigated the scope of the Brønsted acid catalyzed
phosphoramide/calcium ratio of 2:1.[18] However, total reflec-
tion X-ray fluorescence (TXRF) measurements and the X-ray
crystal structure of 1j (Figure 1) show unambiguously that the
acidification of the calcium complex results in the calcium-
free, completely protonated, highly reactive N-triflylphos-
phoramide. These results dispel the theory that the corre-
sponding calcium complex may act as the catalyst in such
reactions.
In the crystalline state, the Brønsted acid 1j exists as a
dimer in which the nitrogen atom is protonated and forms a
hydrogen bond to the Lewis basic oxygen atom of the second
phosphoramide group. In contrast, no dimeric structures were
observed by diffusion-ordered spectroscopy (DOSY) for 1j
dissolved in toluene. Therefore, we conclude that the actual
enantioselective carbonyl-ene reaction with respect to the
styrene substrate under the optimized reaction conditions
(Table 3). A broad range of styrene derivatives, 2a–q, with
electron-withdrawing and electron-donating substituents
underwent the desired reaction with 3a to provide the
a-hydroxyesters 4a–q in good yields with excellent enantio-
selectivities (92–97% ee).[17]
With regard to the reaction mechanism and catalyst
structure, we were able to obtain suitable crystals of the actual
N-triflylphosphoramide catalyst 1j. Previously, only X-ray
crystal structures of salts of these strongly acidic Brønsted
acids were known, typically with a calcium atom as a chelating
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Communications
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organocatalytic carbonyl-ene reaction, which led to a range of
substituted a-hydroxyesters in good yields with excellent
enantioselectivities (92–97% ee). This efficient reaction pro-
ceeds under mild conditions with just 1 mol% of an air-stable,
highly reactive Brønsted acid catalyst and provides direct
access to optically active compounds with quaternary stereo-
centers from simple and readily available starting materials.
Furthermore, we have described the structure of the chiral
Brønsted acids for the first time and demonstrated that the
actual catalyst in this very efficient organocatalytic non-
covalent carbonyl-group activation is the protonated
N-triflylphosphoramide. This information is important for
future catalyst design and the development of further
Brønsted acid catalyzed reactions.
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Received: May 7, 2008
Published online: July 24, 2008
Keywords: asymmetric catalysis · Brønsted acids ·
.
carbonyl-ene reaction · ion pairs· organocatalysis
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[17] See the Supporting Information for detailed procedures and the
characterization of all products.
[18] A detailed description of the procedure for the synthesis of the
catalysts, the structural investigations by TXRF and DOSY, and
the crystal structures of the phosphoramide/calcium complexes
and N-triflylphosphoramides will be reported in due course.
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