Highly enantioselective organocatalytic formation of a quaternary carbon center via chiral Bronsted acid catalyzed self-coupling of enamides

Article abstract of DOI:10.1039/b804477e

The enantioselective BINOL-phosphate catalyzed formation of a quaternary carbon center, bearing a N-atom has been achieved through the self-coupling reaction of enamides; the corresponding products have been isolated in up to >99% ee and their application

Full text of DOI:10.1039/b804477e

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Highly enantioselective organocatalytic formation of a quaternary carbon
center via chiral Brønsted acid catalyzed self-coupling of enamidesw
Christine Baudequin, Alexandru Zamfir and Svetlana B. Tsogoeva*
Received (in Cambridge, UK) 17th March 2008, Accepted 27th June 2008
First published as an Advance Article on the web 5th August 2008
DOI: 10.1039/b804477e
The enantioselective BINOL-phosphate catalyzed formation of
a quaternary carbon center, bearing a N-atom has been achieved
through the self-coupling reaction of enamides; the correspond-
ing products have been isolated in up to 499% ee and their
application for the synthesis of versatile synthetic building
blocks—b-aminoketones—has been demonstrated.
Scheme 1 Self-condensation of enecarbamates.
The central task in the synthesis of organic compounds, simple
or complex, is the construction of C–C bonds. Stereoselective
as Brønsted acid organocatalysts for several enantioselective
C–C bond forming reactions are of particular interest for the
C–C bond-forming reactions, including the aza-ene-type reac-
preparation of enantiopure complex natural products and
tion of N-benzoylimines with enecarbamates giving products
with tertiary carbon centers.7d Later, several research
pharmaceutically important compounds. While tremendous
groups,8–10 notably the groups of Rueping8 and List,9 reported
progress has been made in developing methods for enantio-
selective generation of tertiary carbon centers, the enantioselec-
the application of BINOL-phosphates in the development of
tive construction of quaternary carbon centers, and in
different highly enantioselective transformations. In most
particular, those bearing a nitrogen or other heteroatom, is
cases the key aspect of catalysis is the bifunctional character
still one of the most challenging tasks in organic chemistry.1
Recently, Kobayashi and co-workers have reported that
enamides and enecarbamates can be used as nucleophiles, react-
ing with several electrophiles in the presence of metallic Lewis
acids.2 Furthermore, it was found that enamides and enecarba-
mates could undergo a self-coupling reaction on treatment with
a strong Brønsted or Lewis acid such as TfOH, Sc(OTf)3, or
Cu(OTf)2, which indicated, that an equilibrium between enamide
A and ketimine B existed under acidic conditions (Scheme 1).2a,e
This reaction has apparently not been further investigated.
However, this transformation is very suitable for the generation
of quaternary stereocenters with nitrogen-containing substi-
tuents. These compounds could potentially be used as precur-
sors for the synthesis of unnatural a-substituted a-amino acids
through oxidative cleavage of the double bond, as synthetic
intermediates for the preparation of chiral diamines through
hydrogenation, or for b-aminoketones via acidic hydrolysis of
their imine intermediates. In particular, b-aminoketones, and
their derivatives have many attractive applications, for example
in the area of pharmaceutical products,3 as well as in polymer
chemistry4 with respect to paints and surface active agents.
This motivated us to develop an enantioselective version of
the self-coupling reaction of enamides using chiral Brønsted
acid organocatalysts.5 Recently, the research groups of Akiyama6
and Terada7 independently developed BINOL-phosphates
(Lewis acid/Lewis base) of the phosphoric acid moiety.6b,e,7c,d
Terada and Sorimachi,7f and Zhou10d and co-workers have
recently demonstrated that enamides (or enecarbamates) read-
ily isomerize to imines under the influence of bifunctional
BINOL-derived phosphoric acids and can be utilized as
electrophilic components in Friedel–Crafts reactions.
We therefore expected that chiral BINOL-phosphates will
facilitate the above mentioned equilibrium between enamide A
and ketimine B (Scheme 1) and catalyze the subsequent
enantioselective C–C bond forming reaction.
Herein we successfully realize this anticipation, and report a
highly enantioselective (85–99% ee) formation of quaternary
carbon centers through self-coupling of different enamides,
catalyzed by chiral BINOL-phosphate.
Our studies commenced with the screening of chiral phos-
phoric acid catalysts ((R)-1a–e), easily prepared according to
known procedures,6–9 and bearing various types of substi-
tuents at the 3,30-position on the binaphthyl backbone, for the
self-coupling reaction of 2 in toluene at room temperature
(Table 1, entries 1–5).
While an almost racemic mixture was obtained in 68% yield
with catalyst (R)-1a, 56% ee and similarly good yield (70%) was
observed for product 3 when 3,30-phenyl-substituted BINOL-
phosphate (R)-1b was used (Table 1, entries 1 and 2). Intri-
guingly, much higher enantioselectivity (96% ee, entry 3) was
obtained applying catalyst (R)-1c, which contains a nitro group
in the para-position of the 3,30-phenyl-substituent of BINOL-
phosphate. This indicates that both the steric and electronic
properties of 3,30-substituents are crucial for achieving high
enantioselectivity. Notably, the phosphoric acid catalysts (R)-1d
and (R)-1e with too sterically demanding 3,30-substituents gave
Department of Chemistry and Pharmacy, Chair of Organic Chemistry I,
University of Erlangen-Nuremberg, Henkestrasse 42, 91054 Erlangen,
Germany. E-mail: tsogoeva@chemie.uni-erlangen.de;
Fax: +49-09131-85-26865
w Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b804477e
ꢀc
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Chem. Commun., 2008, 4637–4639 | 4637

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Table 1 Optimization of reaction conditions
were obtained for enamides bearing electron-withdrawing or
electron-donating groups in the para-position of the aromatic
ring (entries 4 and 5). These results clearly demonstrate that
steric, rather than electronic properties, influence the reactivity
of substrates in this BINOL-phosphate catalyzed reaction.
Further exploration concentrated on the enamide protecting
group, as it was expected also to influence the reaction
reactivity. We indeed found that the bulkiness of R1 in the
N-protecting group effected the reactivities: the larger the R1,
the lower the yield (Table 2, entry 1 vs. 6 and 7; entry 4 vs. 8).
These results can be rationalized by the fact that the bulky
substituents impair the approach of the substrate to the 3,
30-substituted (R)-BINOL-phosphate 1c, resulting in lower
conversion rates. Notably, in all cases, the products were
obtained with high enantiomeric excess of 85–99% (Table 2).
Based on the experimental results and reported mechanistic
assumptions for different transformations catalyzed by BINOL-
phosphates,6–10 we postulate the mechanism of the self-coupling
reaction (Fig. 1). In this sequence, the first step (Fig. 1a)
concerns the equilibrium between enamide and ketimine forms
in the presence of a chiral Brønsted acid. The next steps
(Fig. 1b) cause a coupling reaction, due to the dual function
of the phosphoric acid group. While the formed N-acyl-
ketimine can easily be protonated through the Lewis acidic
part of the phosphoric acid moiety to form an iminium cation
intermediate as a good electrophile (as it has already been
reported by Terada and co-workers for aza-ene-type reaction7d),
the NH group of the enamide (nucleophile), can form an
NHꢁ ꢁ ꢁO hydrogen bond with the Lewis basic phosphoryl
oxygen atom. Following this tight ion pair formation, a
subsequent bond recombination and release of chiral
BINOL-phosphate results in the desired product.
Entry
Catalyst
Solvent
t/h
Yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1c
1c
1c
1c
1c
1c
Toluene
Toluene
Toluene
Toluene
Toluene
CHCl3
Toluene
CH3CN
THF
72
72
72
72
72
72
24
24
24
24
24
68
70
79
Trace
12
66
56
—
4
56
96
9
25
96
97
—
96
96
95
9
49
414
64
10
11
a
Diethyl ether
CH2Cl2
Yield of isolated product after column chromatography on SiO2.
Enantioselectivities were determined by chiral HPLC analysis
(Daicel Chiralcel OD) in comparison with authentic racemic material.
b
only very low yields (up to 12%) and enantioselectivities (up to
25% ee) (Table 1, entries 4 and 5).
Further solvent-screening studies with the selected catalyst
(R)-1c (Table 1, entries 6–11) demonstrated, that toluene,
initially chosen, also proved to be the optimal solvent under
the reaction conditions used.
Self-coupling of various enamides was then investigated using
(R)-1c as the catalyst in toluene (Table 2). The effect of
substituents in the aromatic ring of the enamide on the reactiv-
ity and enantioselectivity was first examined. Whereas either no
conversion or only low yield (up to 15%, entries 2 and 3 vs.
entry 1) was observed for enamides, which contain electron-
withdrawing groups in the ortho- or meta-position in the
aromatic ring, similarly good yields, 82 and 83%, respectively,
Table 2 Asymmetric self-coupling of enamides by using BINOL-
phosphate (R)-1c
Entry
R1
Ar
Yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
a
Me
Me
Me
Me
Me
Et
C6H5
79
—
15
82
83
70
35
63
96
—
88
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-MeOC6H4
C6H5
499c
88
85
97
499
Pr
Pr
C6H5
4-ClC6H4
Yield of isolated product after column chromatography on SiO2.
Enantioselectivities were determined by chiral HPLC analysis in
b
comparison with authentic racemic material. [a]2D5 = ꢂ365 (c = 0.1,
c
Fig. 1 A plausible mechanism for the self-coupling reaction of
CH2Cl2).
enamides leading to a quaternary carbon center.
ꢀc
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Scheme 2 Conversion to b-aminoketone with the quaternary carbon
center bonded to nitrogen.
4 For a review on application of b-aminoketones (Mannich bases) in
polymer chemistry, see M. Tramontini, L. Angiolini and N.
Ghedini, Polymer, 1988, 29, 771.
According to the proposed mechanism, 3,30-substituents of
the BINOL-phosphate catalyst might have unfavourable steric
interactions (Fig. 1b) with the bulky R1 group (e.g. Et, Pr),
and with the substituents at the ortho- or meta-position in the
aromatic ring of the enamide, and therefore could account for
the outcome of the reaction described above (Table 2).
Considering the ubiquity of chiral amines, where the nitrogen is
adjacent to quaternary carbon atoms, application of the asym-
metric self-coupling reaction of enamides to the synthesis of
useful chiral target molecules, e.g. b-aminoketones, is envisioned.
Notably, while various synthetic routes to different enantio-
merically pure b-aminoketones with tertiary carbon centers
have been developed in recent years (the most widespread of
which is based on the Mannich reactions),11 the reports on
asymmetric synthesis of b-aminocarbonyl compounds with
quaternary carbon bearing a nitrogen atom are scarce and
restricted to the synthesis of derivatives containing the geminal
amino and fluoroalkyl groups.12
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11 For general reviews on Mannich reactions, see: (a) M. Arend, B.
Westermann and N. Risch, Angew. Chem., Int. Ed., 1998, 37, 1044;
(b) S. F. Martin, Acc. Chem. Res., 2002, 35, 895; (c) A. Cordova,
Acc. Chem. Res., 2004, 37, 102. For recent reviews on the organo-
catalytic asymmetric Mannich reactions, see: (d) J. M. M. Verkade,
L. J. C. van Hemert, P. J. L. M. Quaedflieg and F. P. J. T. Rutjes,
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Matsui, Chem. Commun., 2004, 1928; (b) S. Fustero, D. Jiminez,
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Here we demonstrate, for the first time, that the present self-
coupling reaction of enamides could successfully be applied to
the synthesis of potentially useful synthetic building blocks—
b-alkyl-b-aminoketones. (Scheme 2). Treatment of the selected
adduct (with 99% ee) of the self-coupling reaction with
2N HCl in H2O–THF provided the corresponding
b-methyl-b-aminoketone ([a]2D5 = ꢂ22; c = 0.1, CH2Cl2) in
95% isolated yield and 98% ee (Scheme 2).
In summary, we have successfully developed a highly enan-
tioselective Brønsted acid catalyzed self-coupling reaction of
enamides providing quaternary carbon bearing a nitrogen atom
and demonstrated its application for asymmetric synthesis of
useful synthetic intermediates—b-methyl-b-aminoketones.
The authors gratefully acknowledge the Deutsche For-
schungsgemeinschaft (Schwerpunktprogramm 1179 ‘‘Organo-
katalyse’’) for generous financial support.
Notes and references
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3 For examples of pharmaceutically important b-aminoketones, see:
(a) J. R. Dimmock, K. K. Sidhu, M. Chen, R. S. Reid, T. M. Allen,
ꢀc
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Chem. Commun., 2008, 4637–4639 | 4639